DESIGN OF NEW C(sp3)-H FUNCTIONALIZATION THROUGH HALOGEN CATALYSIS
Thomas Duhamel
Departamento de Química Orgánica e Inorgánica
Programa de Doctorado “Síntesis y Reactividad Química”
Tesis Doctoral 2020
DESIGN OF NEW C(sp3)-H FUNCTIONALIZATION THROUGH HALOGEN CATALYSIS
Thomas Duhamel
Departamento de Química Orgánica e Inorgánica
Programa de Doctorado “Síntesis y Reactividad Química”
Memoria presentada para optar al grado de Doctor en Química
Dissertation submitted to apply for the Degree of Doctor of Philosophy in Chemistry
RESUMEN DEL CONTENIDO DE TESIS DOCTORAL
1.- Título de la Tesis Español/Otro Idioma: Desarrollo de nuevos Inglés: Design of new C(sp3)-H funcionalizaciones C(sp3)-H a través de functionalization through halogen catalysis catálisis de halógenos
2.- Autor Nombre: Duhamel Thomas Lionel Gerard DNI/Pasaporte/NIE: Y5131539T
Programa de Doctorado: SÍNTESIS Y REACTIVIDAD QUÍMICA Órgano responsable: Universidad de Oviedo
RESUMEN (en español)
Durante mi tesis, he desarrollado nuevas metodologías para funcionalización C(sp3)-H mediante catálisis con halógenos. He diseñado nuevas estrategias empleando yodo molecular o sales de bromo para generar nuevas reacciones de aminación y/o oxigenación. En particular, mediante el empleo de la reacción de Hofmann-Löffer para la formación de pirrolidinas.
-010 (Reg.2018) -010 (Reg.2018) Al principio de mi doctorado, no había antecedentes del uso de catálisis de bromo para la C(sp3)-H aminación. Averiguamos que, la combinación de la sal de bromuro amónico junto a
VOA CPBA podría generar análogos de pirrolidina. Para ello, el uso de sulfonamidas nos permitió
- m generar in situ el enlace N-Br, seguido de rotura homolítica del enlace mediante irradiación de luz generaría el radical amidilo. Este radical genera la transferencia del átomo de hidrógeno en MAT
- la posición 5 selectivamente posicionando el átomo de bromo en dicha posición. Este intermedio cicla directamente a través del ataque nucleofílico de la sulfonamida generando el
FOR anillo de pirrolidina. Complementariamente, aislamos y caracterizamos por primera vez la especia N-Br. Además, cuando el proceso de abstracción y transferencia de hidrógeno no puede tener lugar, la formación de oxaziridina se observa como producto.
Además, también llevé a cabo catálisis de yodo cooperativa junto a un catalizador fotoredox. El mecanismo es similar al descrito anteriormente. La especie hipoyodito, formada a partir de la desproporción del yodo en presencia de agua, es la especie activa que generaba el enlace N-I in situ. Cálculos experimentales se llevaron a cabo para la especie N-I para estudiar el momento exacto de la rotura homolítica empleando sulfonamidas, donde el uso de LEDs azules resultó ser la más efectiva. Se determinó que las LEDs azules tendrían un doble uso en la reacción generando el radical amidilo y, por otro lado, excitando al reactivo TPT. Tras la formación de la pirrolidina, el TPT vuelve a oxidar el HI generado en la reacción y el oxígeno reoxida el TPT a su forma activa. Usando este mismo protocolo se pueden generar análogos de lactonas.
Una de las limitaciones que presentan estos dos protocolos descritos anteriormente es la necesidad de una posición alifática activada, como bencílica o a a un heteroátomo para la ciclación nucleofílica. Para ello, empleamos un oxidante que aceleraría la formación de pirrolidinas, el cual, es capaz de oxidar el yoduro de alquilo, intermedio de la reacción. Como resultado, generamos una especie de I(III) que es un excelente grupo saliente para acelerar la ciclación. Tras varios intentos de optimización, decidimos emplear una mezcla de yodo molecular, mCPBA como oxidante y t-BuOH como co-disolvente. En este caso, t-BuOH en combinación con yodo molecular generaría la especie t-BuOI que formaría el enlace N-I en nuestro sistema. El mecanismo es similar al descrito anteriormente con la ayuda de una segunda oxidación que nos da acceso a posiciones no activadas para la formación de pirrolidinas.
Finalmente, para mi último proyecto decidimos emplear otro grupo protector, en este caso sulfamidas que selectivamente funcionalizan en posición 1,6, para generar selectivamente aminaciones alifáticas. Este grupo protector nos dio acceso a 1,3-diaminas mediante el uso de
acetonitrilo como fuente de nitrógeno sobre posiciones terciarias. El mecanismo es similar a la reacción Riiter, donde la iodinación sobre la posición terciaria tiene lugar, seguido de oxidación y ataque del acetonitrilo en presencia de agua generaría la acetamida. Además, oxigenaciones pueden tener lugar usando este protocolo.
RESUMEN (en Inglés)
During my doctoral thesis, I designed new C(sp3)-H functionalization using halogen catalysis. I developed various procedures using either molecular iodine or a bromide salt to perform new amination and oxygenation reactions. In particular, I focused on the so-called Hofmann-Löffler reaction to access valuable pyrrolidine formation.
When I started, no bromide catalysis was developed for the latter. We found out that a combination of an ammonium bromide salt with mCPBA could provide the corresponding pyrrolidines. Using sulfonamides as starting materials, we could generate in-situ the N-Br bond. A homolytic cleavage by daylight irradiation affords the nitrogen-centered radical. Subsequent 1,5-HAT occurs followed by a bromination to selectively provide an alkylbromide intermediate. Further cyclization process yields the final pyrrolidines. For the first time, the N-brominated intermediate could be isolated and fully characterized. As an extension of this work, when the 1,5-HAT could not proceed, oxaziridines were synthesized instead.
Then, a cooperative catalysis between molecular iodine and an organic dye was designed. The mechanism is similar to the one described above. It was found that hypoiodite, formed from the disproportionation of iodine in the presence of water, was the active species generating the N-I bond in-situ. Calculations have been carried out on the N-I bond on sulfonamides to know their exact cleavage condition. It was found out that blue LEDs could undergo the homolytic cleavage of such N-I bond. Therefore, the light has a dual role in this procedure since it is also exciting the organic dye TPT which has its maximum absorption wavelength in the blue region of the visible spectrum. After the final pyrrolidine formation, TPT oxidizes the HI extruded during the cyclization step. Remarkably, oxygen is the terminal oxidant of this transformation since it is re- oxidizing TPT. Using the same cooperative catalysis, lactonization could be achieved as well.
The major limitation of this two precedent procedures is the requirement of an activated carbon position to have a rapid cyclization step. The idea, to accelerate the formation of the pyrrolidines is to implement an oxidant in the reaction system which is able to oxidize the alkyliodine intermediate. As a result, we would have a alkyliodine(III) intermediate, well known to be an excellent nucleofuge. After an extensive optimization, we found out that the combination of molecular iodine and mCPBA using tert-butanol as co-solvent was efficient. As previously, molecular iodine in the presence of water disproportionates in hypoiodite HOI. This inorganic species with tert-butanol generates tert-butyl hypoiodite thus leading to the in-situ formation of the N-I bond. Following the same mechanism than above-mentioned, the alkyliodine intermediate is generated. An extra oxidation step by mCPBA forms the alkyliodine(III) intermediate crucial for the access of non-activated carbon position for the formation of pyrrolidines.
Finally, as my last project, we wondered whether another protecting group than sulfonamides could undergo selective amination reaction. We focused on sulfamides that are well-known to perform 1,6-HAT. While trying to cyclize on activated benzylic position, we could access 1,3- diamines easily. But, at non-activated secondary position, the reaction did not proceed. The alkyliodine intermediate was isolated instead. As a result, we tried at the slightly more activated tertiary non-activated position. A new aminated product coming from a Ritter-type amination was isolated. Therefore, after the selective 1,6-HAT followed by the iodination at the targeted tertiary position, a molecule of acetonitrile, used as solvent, displaces the iodine to generate in the presence of water an acetamide. Using this protocol, oxygenation have been performed as well.
SR. PRESIDENTE DE LA COMISIÓN ACADÉMICA DEL PROGRAMA DE DOCTORADO EN ______
A mes parents,
To my parents
« Un être qui pense c’est un être qui doute »
René Descartes (Les Méditations métaphysiques, 1641)
“To raise new questions, new possibilities, to regard old problems from a new angle, requires creative imagination and marks real advance in science”
Albert Einstein
Acknowledgements
Acknowledgements
To begin with, I would like to thank my PhD supervisor, Prof. Dr. Kilian Muñiz who gave me the opportunity to carry out my PhD in his group. Dramatically and unexpectedly, Kilian passed away early this year and I would like to honor his memory as much as I can. I will always be grateful to him. The truth is that the university of Tarragona did not recognize my diplomas and my credits, so they rejected my application. But Kilian believed in me in the first place and fought for me to find another Spanish university that would recognize my credits. He finally managed to do so, and I was enrolled with his beloved University of Oviedo. From the really beginning, he was mentoring me and pushed me a lot to always provide the best results that I could. I thank him for all what he taught to me during the seminars, in the lab or inside his office, for all the discussion and debates we had regarding chemistry. I will always remember the discussions in his office about old German chemists, or about old chemistry thesis that he had in collection. I would like to thank him for all the professional travels I did to go to conferences. It gave me the opportunity to meet interesting people and to learn more about chemistry. But Kilian was not only an expert in chemistry, but he was also interested in a lot of different fields such as art, music, food, wines… He had an amazing culture and he was always a pleasure to talk with him about Life. I want to remember all the good moments we had together around a table in a restaurant for the Christmas dinner, during a calçotada in february… Thanks to him, I discovered the province and the culture of Asturias, his favorite place in the world and I fell in love. I had the opportunity to stay two weeks there and I understood what he was looking for in Asturias, a place to be in peace, a place where while opening a window, a mountain half hidden in the clouds makes you dreaming, a place where you eat and drink well… We were having funny moments as well talking about French strikes, about politics, about Lufthansa, his favorite airline company. I want to remember his voice, his intonation while saying “who is the PhD advisor of?” or its famous “tremendous”. I hope wherever he is now, he is in peace and proud of what I will become. I would like to warmly thank Prof. Dr. Rubén Martín who was willing to supervise the writing of the thesis after Kilian’s loss. I particularly thank Prof. Dr Miquel Pericàs as well for all his help and support. I want to thank Prof. Dr José Manuel González and Prof. Dr. Alfredo Ballesteros, my tutor for all their support and tame taken answering my tons of e-mails. I am also grateful to the University of Oviedo for having given me the opportunity to do my PhD.
19 Acknowledgements
I want to thank our secretary, Sorania Jiménez, who was not only a support for the administration but an extremely important moral support during these terrible days. Next, I want to thank all the group members that I met. Claudio Martínez, Nicola Lucchetti, Terry Tomakinian, Peter Becker, Laura Fra, Hongwei Zhang, Martín Romero, Belén García, Laura Barreiro, Francesca Ghiringhelli, Sebastian Herold, Alexandra Bosnidou, Julien Bergès, Anna Sib, Anastasia Tkacheva, Andrea Flores, Mario Martínez, Ionna Sideri, Ana Mateos, Jorge Saavedra, Christian Suárez, Eric Cots, Matthew Wheatley, Eleni Georgiou, Estefanía Del Castillo, Daniel Bafaluy, Aliénor Jeandin. I would like to thank Peter Becker for having taking care of me at the beginning of the PhD. He taught me the “basic” of the lab and a lot of bench techniques. We shared two publications together and it was pleasant to work with you. I want to particularly thank Laura Barreiro for all the good moments we shared. You have an important place in my life. You were a crucial support for me when I arrived. Thanks to you, I found the strength to overcome the issues during my PhD and when I arrived in Spain. Francesca, thank you for your good vibes and mood! It was sometimes difficult to follow you when you were talking but we always understood each other, and it is the most important thing as friends. Sebastian, thank you for the super nice moments we shared together! This festival in Barcelona and the music of Charlotte de Witte will always stay in my head! Ionna and Ana, you will stay my favorite Master students! Thank you for your patience and thank you for your engagement in the lab! Ana, thank you for the good moments we had together during Santa Tecla! Stay like you are! Julien, I have so many good moments shared with you that I cannot write down everything. How many beers we shared together? How many football matches? How many parties? How many trails and running sessions? How many barbecues on the beach? And a lot of other activities. You were and you are a nice friend to me. We will continue to share nice moments, that’s for sure!! Mario, “el boludo”, the king of the barbecues! First, thank you to have been a precious helper in the lab. I learnt a lot working next to you and with you! Out of the lab, we enjoyed so many moments together! A crazy weekend in Lyon, a football match in Camp Nou, a final of the World Cup in Toulouse! I will always remember what we have done together during these years. And, please, don’t stop the barbecues, it’s an art!
20 Acknowledgements
Anda, thank you for all we did together, the trips in Montpellier, the beers/wines in Paris and in Tarragona of course! Even if Cardiff was not nice to visit, we had a lot of fun there, right? Eric, thank you for having the same passion than me, discovering good beers! Thank you for all the parties and Santa Tecla together, the poker sessions, the barbecues on the beach, the meetings at your flat for the Barcelona matches. I know we will continue to see each other for others good moments!! Eleni, first, thank you for having opened your door when I was in trouble! You were always here for me and this is the definition of a friend! Thank you for listening to me when I was not feeling nice! You were the support I needed at that time. Thank you for the nice moments we shared together! Bafa and Estefi, we did it guys!! We started together and we finished together! So many moments with you! If I have to remember one, I will say Sitges for Estefi! What an amazing conference! We enjoyed a lot there and it was a really nice time together! Also, thank you for being what you are. I will miss the conversion about the “Estefi diet”! Or about food and sports… You are an amazing person, never change! Bafa, do you remember that party in San Sebastian? Me neither… But I know we passed a nice moment together! I know I could count on you during all these years!! We also shared the office for four years!! I remember the fights with Francesca or the conversation about history, or the quiz about the geography!! I enjoyed the discussion with you because you know a lot of things and it is always interesting!! Also, thank you for all the movements you did with me!! Ali, thank you for the good moments we shared together! It started with a concert of Oques Grasses in Plaza De La Font!! Amazing! I wish you the best for your thesis!
Je voudrais également remercier ma famille. Tout d’abords, je remercie mes parents pour m’avoir toujours soutenu dans les moments difficiles. Ils ont toujours été présents pour moi et je leur en suis reconnaissant. Ils ont cru en moi et cela m’a donné la force nécessaire pour finir mes études de doctorat. J’espère que vous serez fiers de moi ! Merci maman et merci papa pour ne jamais avoir douté de moi ! Vous avez fait de moi l’homme que je suis à présent, travailleur et passionné. J’ai, en toute logique, dédicacé cette thèse pour vous car vous le méritez. Vous m’avez donné l’envie d’apprendre, de croire en ses rêves et de ne jamais abandonner quoi qu’il arrive. Vous avez inculqué que tant qu’on le désire, tout est possible. Vous étiez déjà présents lors de mon diplôme d’ingénieur et vous m’avez donné la foi pour aller jusqu’au doctorat. Je ne vous remercierai jamais assez pour cela ! Je vous aime.
21 Acknowledgements
Sarah, ma chère sœur, de même que papa et maman, tu es là quand j’ai besoin de toi ou de me confier. Merci de croire en moi et de me soutenir ! Je t’aime. Je remercie aussi mes grands-parents qui ont toujours cru en moi et qui m’ont donné la force nécessaire pour terminer mes études. Enfin, Marie, ma compagne depuis 10 ans ! Que serait ma vie sans toi ? Je ne me pose même pas la question tellement je ne l’envisage pas ! Je te remercie pour m’avoir soutenu malgré mes nombreux sauts d’humeur. Tu m’as rendu visite tellement de fois que je ne saurai les compter. Tu as été mon pilier toutes ces années. Tu m’as donné la force et la volonté pour vivre loin de toi afin d’accomplir mes études. Tu m’as poussé à partir à l’étranger pour faire mon doctorat an sachant que tu n’allais pas me voir souvent. Tu étais prête à mettre de côté ton bonheur pour le mien et ça je ne l’oublierai jamais J’espère que tu seras fière de moi ! Je ne te dirai jamais assez merci ! Je t’aime.
I also thank the financial support of Institute of Chemical Research of Catalonia (ICIQ).
22 List of publications
List of publications
(7) Duhamel, T.; Martínez, M. D.; Sideri, K. I.; Muñiz, K. 1,3-Diamine Formation from an Interrupted Hofmann-Löffler Reaction: Iodine Catalyst Turn-Over through Ritter Type Amination. ACS Catal. 2019, 9, 7741.
(6) Bosnidou, A. E.; Duhamel, T.; Muñiz, K. Detection of the Elusive Nitrogen-Centered Radicals from Catalytic Hofmann-Löffler Reactions. Eur. J. Org. Chem. 2019, DOI: 10.1002/ejoc.201900497.
(5) Duhamel, T.; Muñiz, K. Cooperative Iodine and Photoredox Catalysis for Direct Oxidative Lactonization of Carboxylic Acids. Chem. Commun. 2019, 55, 933.
(4) Del Castillo, E.; Martínez, M. D.; Bosnidou, A. E.; Duhamel, T.; O’Broin, C. Q.; Zhang, H.; Escudero-Adán, E. C.; Martínez-Belmonte, M.; Muñiz, K. Multiple Halogenation of Aliphatic C-H Bonds within the Hofmann-Löffler Manifold. Chem. Eur. J. 2018, 24, 17225.
(3) Duhamel, T.; Stein, C. J.; Martínez, C.; Reiher, M.; Muñiz, K. Engineering Molecular Iodine Catalysis for Alkyl-Nitrogen Bond Formation. ACS Catal. 2018, 8, 3918.
(2) Becker, P.+; Duhamel, T.+; Martínez, C.; Muñiz, K. Designing Homogeneous Bromine Redox Catalysis for Selective Aliphatic C-H Bond Functionalization. Angew. Chem. Int. Ed. 2018, 57, 5166. + These authors contributed equally to this work.
(1) Becker, P.; Duhamel, T.; Stein, C. J.; Reiher, M.; Muñiz, K. Cooperative Light-Activated Iodine and Photoredox Catalysis for the Amination of Csp3- H Bonds. Angew. Chem. Int. Ed. 2017, 56, 8004.
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24 Table of contents
Table of Contents
Acknowledgments ...... 19 List of publications ...... 23 Table of Contents ...... 25 Abbreviations ...... 31 Part I. General Introduction ...... 35 Concept of direct C(sp3)-H functionalization ...... 37 Abundance and importance of C(sp3)-N bonds ...... 38 Transition metal catalyzed C(sp3)-H activation for amination ...... 41 Directed intramolecular C(sp3)-H amination ...... 41 Palladium catalyzed C(sp3)-H amination ...... 41 First-row transition metal catalyzed C(sp3)-H amination ...... 45 Directed intermolecular C(sp3)-H amination ...... 46 Intermolecular ketoxime-directed C(sp3)-H amination ...... 47 Intermolecular N-heterocycle-directed C(sp3)-H amination ...... 48 Directing group-free C(sp3)-H amination ...... 53 Intramolecular allylic C(sp3)-H amination ...... 53 Intermolecular allylic amination ...... 57 Transition metal catalyzed C(sp3)-H insertion for C(sp3)-H amination ...... 60 First-row transition metal catalyzed C(sp3)-H insertion ...... 62 Manganese and iron as pioneered metals for C(sp3)-H insertion ...... 63 Cobalt-catalyzed C(sp3)-H insertion through metalloradical catalysis ...... 71 Copper-catalyzed C(sp3)-H insertion ...... 79 Second-row transition metal catalyzed C(sp3)-H amination ...... 82 Ruthenium catalysis C(sp3)-H insertion ...... 82 Rhodium catalysis C(sp3)-H insertion ...... 86 Silver catalysis C(sp3)-H insertion ...... 95 Third-row transition metal catalyzed C(sp3)-H amination: the case of iridium and gold ...... 96 Other transition metal mediated C(sp3)-H amination ...... 98 N-F activation for C(sp3)-H amination...... 98 Metal-mediated non-directed amination (free radical generation) ...... 101 Electrochemistry for C(sp3)-H amination ...... 102 N-centered radical directed C(sp3)-H amination via hydrogen atom abstraction ...... 105 Generation of the N-centered radical
25 Table of contents
from photoredox catalyst ...... 105 The Hofmann-Löffler reation ...... 108 Main aims and objectives...... 111 Part II. Engineering bromide catalysis for C(sp3)-H functionalization ...... 113 Introduction ...... 115 Why halogen catalysis? ...... 115 Introduction to the bromine catalysis for amination reaction ...... 116 The Hofmann-Löffler reaction: a possible breakthrough for bromine catalysis?...... 119 Nitrogen-centered radical: the key for the selectivity ...... 119 Sulfonamides: a starting point from Hofmann’s heritage ...... 121 N-X bond cleavage: the case of fluorine and chlorine ...... 123 Stochiometric bromine-mediated C(sp3)-H functionalization ...... 124 Selective C(sp3)-H bromination ...... 124 Selective C(sp3)-H oxygenation ...... 126 Selective C(sp3)-H amination ...... 127 Aims of part II ...... 129 Results and discussion ...... 129 Development of the bromine catalysis for the Hofmann-Löffler reaction ...... 129 Scope of the bromide catalyzed Hofmann-Löffler reaction...... 132 Mechanistic studies for the C(sp3)-H amination reaction ...... 134 Bromine active species investigation ...... 134 Study of the N-Br bond of 3a ...... 138 Quenching experiments ...... 142 Kinetic isotope effect ...... 142 Proposed mechanism for the bromide catalyzed Hofmann-Löffler reaction ...... 143 Application of the method to oxaziridine’s formation ...... 144 Scope of the oxaziridine formation ...... 145 Proposed mechanism ...... 146 Final remarks ...... 148 Experimental section ...... 148 General information ...... 148 Synthesis and characterization of 1 ...... 149 Synthesis and characterization of 2 ...... 150 Synthesis of the substrates 3a-t for the amination reaction ...... 150 Characterization of the substrates 3a-t for the amination reaction ...... 155
26 Table of contents
Synthesis of the pyrrolidines 4a-t (GP3) ...... 162 Characterization of the pyrrolidines 4a-t ...... 162 Synthesis and characterization of 5 ...... 169 Synthesis of the active species I ...... 169 Synthesis and characterization of the intermediate 6 ...... 170 Synthesis of the substrates 7a-o for the oxaziridine formation ...... 170 Characterization of the substrates 7a-o for the oxaziridine formation ...... 172 Synthesis of the oxaziridines 8a-o (GP5) ...... 176 Characterization of the oxaziridines 8a-o ...... 177 Part III. Cooperative iodine and photoredox catalysis for C(sp3)-H functionalization ...... 185 Introduction ...... 187 Iodine-catalyzed C(sp3)-H oxygenation ...... 187 Iodine-mediated C(sp3)-H amination ...... 190 Non-directed amination ...... 190 The Hofmann-Löffler reaction (Stochiometric in iodine) ...... 192 The first iodine-catalyzed Hofmann-Löffler reaction ...... 196 Photoredox catalysis for direct C(sp3)-H functionalization ...... 198 Aims of part III ...... 200 Results and discussion for direct C(sp3)-H amination ...... 200 Study of the N-I bond: calculation ...... 201 Development of the cooperative catalysis for C(sp3)-H amination ...... 202 Scope of the cooperative catalysis for C(sp3)-H amination ...... 206 Mechanistic investigation ...... 209 Quenching experiments ...... 209 Kinetic isotope effect ...... 210 Iodine active species ...... 211 Proposed mechanism ...... 212 Results and discussion for direct C(sp3)-H oxygenation ...... 216 Strategies for direct oxidative C(sp3)-H lactonization ...... 217 Development of the cooperative catalysis for direct oxidative C(sp3)-H lactonization ...... 218 Scope of the cooperative catalysis for C(sp3)-H amination ...... 220 Mechanistic investigation ...... 222 Quenching experiments ...... 223 Kinetic isotope effect ...... 223 Involvement of an O-I bond? ...... 224
27 Table of contents
Cyclic voltammetry experiments ...... 225 Hammett correlation studies ...... 226 Proposed mechanism ...... 228 Final remarks ...... 229 Experimental section ...... 230 General information ...... 230 Synthesis of the substrates 9a-t for the amination reaction ...... 231 Characterization of the substrates 9a-t for the amination reaction ...... 236 Synthesis of the pyrrolidines 10a-t (GP4) ...... 243 Characterization of the pyrrolidines 10a-t ...... 244 Synthesis of the substrates 11a-u for the lactonization ...... 250 Characterization of the substrates 11a-t ...... 255 Synthesis of the lactones 12a-t (GP7) ...... 261 Characterization of the lactones 12a-t ...... 261 Synthesis and characterization of 13 ...... 268 Part IV. Iodine(I/III) catalysis for selective C(sp3)-H amination ...... 269 Introduction ...... 271 Circumvent the limitation ...... 271 Reactivity of alkyliodine(III) ...... 272 The crucial role of the alkyliodine(III) for catalysis ...... 274 Aims of part IV ...... 278 Results and discussion ...... 279 Development of the I(I/III) catalysis for C(sp3)-H amination ...... 279 Scope of the I(I/III) catalysis for selective C(sp3)-H amination ...... 282 Mechanistic investigation ...... 285 Active iodine species ...... 285 Isotope labelling experiment ...... 287 Hammett correlation studies ...... 288 Quantum yield determination ...... 291 Influence of the terminal oxidant for the Hofmann-Löffler reaction ...... 294 Mechanism of the I(I/III) catalysis for the amination reaction...... 295 DFT calculations ...... 297 Final remarks ...... 299 Experimental section ...... 299 General information ...... 299 Synthesis of the substrates 14a-z, 16 and 19a-b for the amination reaction ...... 300
28 Table of contents
Characterization of the substrates 14a-z, 16 and 19a-b for the amination reaction ...... 308 Synthesis of the pyrrolidines 15a-z, 17, 18, 20a-b and 21a-b ...... 318 Characterization of the pyrrolidines 15a-z, 17, 18, 20a-b and 21a-b ...... 319 Part V. Iodine(I/III) catalysis for 1,3-diamine formation ...... 331 Introduction ...... 333 The importance of the 1,3-diamine motif ...... 333 Strategy for the radical-based 1,3-diamine formation ...... 334 Preliminary reactivity exploration ...... 336 Activated benzylic amination ...... 336 Non-activated secondary position ...... 337 A Ritter-type amination at tertiary positions? ...... 339 Strategies for the synthesis of α-tertiary amines ...... 340 Aims of part V ...... 343 Results and discussion on the Ritter-type amination ...... 343 Development of the 1,3-diamine formation ...... 343 Scope of the Ritter-type amination through an interrupted Hofmann-Löffler reaction ...... 345 Deprotection of the protecting groups ...... 349 Mechanistic investigation ...... 350 Isotope labelling experiment ...... 350 Quantum yield determination ...... 355 I(-I/I) or I(I/III) catalysis? ...... 358 Mechanism of the Ritter-type amination through an interrupted Hofmann- Löffler reaction ...... 359 Extension of the Ritter-type amination for oxygenation reaction ...... 360 Final remarks ...... 361 Experimental section ...... 361 General information ...... 361 Synthesis of the substrates 22, 24, 27a-w and 33a-b ...... 362 Characterization of the substrates 22, 24, 27a-x and 33a-b for the amination reaction ...... 373 Synthesis of the products 23, 25, 26, 28a-x, 29, 30, 31, 32 and 34a-b ...... 383 Characterization of the products 23, 25, 26, 28a-x, 29, 30, 31, 32 and 34a-b ...... 386 General conclusion and outlook ...... 403 Conclusiones and perspectivas ...... 405
29 Table of contents
30 Abbreviations
Abbreviations
Ac Acetyl Acac AcetylAcetone ACN Acetonitrile Ad Adamantyl ALAT Alanine Amino Transferase Ar Aryl BBN 9-borabicyclo[3.3.1]nonane BDE Bond Dissociation Energy BHT Butylated HydroxyToluene BQ Benzoquinone Bn Benzyl Bz Benzoyl CAN Ceric Ammonium Nitrate Cbz Benzyl Chloroformate CCE Constant Current Electricity CNS Central Nervous System COD CycloOctaDiene Cp Cyclopentyl DCA DiCyanoAnthracene DCN DiCyanoNapthalene DBDMH 1,3-dibromo-5,5-dimethylhydantoin DCE DiChloroEthane DCM DiChloroMethane DDQ 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone Dfs 2,6-difluorophenyl sulfamate DFT Density Funcional Theory DHBQ DiHydroBenzoQuinone DMA DiMethylAcetamide DMAP 4-DiMethylAminoPyridine DME DiMethylEthane DMF DiMethylFormamide DMQ DiMethoxyQuinoline DMSO DiMethylSulfOxyde DNA DeoxyriboNucleic Acid DTBP DiTertButyl Peroxide dppp 1,3-Bis(diphenylphosphino)propane EDG ElectroDonating Group Et Ethyl EWG ElectroWithdrawing Group
31 Abbreviations
EY Eosyn Y FC Fukuzumi’s Catalyst GP General Procedure HAA Hydrogen Atom Abstraction HAT Hydrogen Atom Transfer Het Heterocycle hfacac Hexafluoroacetylacetonate HFIP HexaFluoroIsoPropanol HRMS High Resolution Mass Spectrometry HSQC Hetronuclear Single Quantum Coherence iPr isopropyl KIE Kinetic Isotope Effect LDA Lithium DiisopropylAmide LED Light-Emitting Diode LUMO Lowest Unoccupied Molecular Orbital mCBA meta-ChloroBenzoic Acid mCPBA meta-ChloroPeroxyBenzoic Acid MA Maleic Acid Me Methyl Mes Mesityl mp melting point MQ MethoxyQuinoline MRC MetalloRadical Catalysis Ms Mesyl MTBE MethylTertButyl Ether NBP N-BromoPhthalimide NBS N-BromoSuccinimide NFSI N-FluorobenzeneSulfonImide NHPI N-HydroxyPhthalImide NIS N-IodoSuccinimide NMR Nuclear Magnetic Resonance Ns Nosyl oct Octyl PA Picolimamide PBE Perdew-Burke-Ernzerhof PCET Proton Coupled Electron Transfer Phen Phenanthroline Ph Phenyl Phth Phthaloyl PIDA (Diacetoxy)Iodobenzene PIFA (Bis(trifluoroacetocy)iodo)benzene PIP 2-(Pyridin-2-yl)IsoPropyl
32 Abbreviations
Piv Pivalate Pr Propyl PTAB PhenylTrimethylAmmonium Bromide PTFE PolyTetraFluoroEthylene Py Pyridine Q Quinoline qpy QuinquePyridine RT Room Temperature RSE Radical Stability Energy SES 2-(Trimethylsilyl)ethanesulfonyl SET Single Electron Transfer SM Starting Material SOX Sulphur Oxides TBAA TetraButyl AcetoAcetate TBAB TetraButyl Ammonium Bromide TBAF TetraButyl Ammonium Fluoride TBAI TetraButyl Ammonium Iodide TBDPS TertButylDiPhenylSilyl TBHP TertButyl HydroPeroxide TBME TertButylMethyl Ether TBS TriButylSilyl tBu tertButyl Tces Trichloroethylsulfamate TFA TriFluoroacetic Acic TFE TriFluoroEthanol TIPS TriIsopropylSilyl TEMPO (2,2,6,6-Tetramethylpiperidin-1-yl)oxyl Tf Triflate TFAA TriFluoroAcetic Anhydride THF TetraHydroFurane TLC Thin Layer Chromatography Tol Toluene TPFPP Tetrakis(pentafluorophenyl)porphyrin TPP TetraPhenylPorphyrin TPT TriphenylPyrylium Tetrafluoroborate Troc 2,2,2-Trichloroethoxycarbonyl chloride Ts Tosyl UV UltraViolet
33
34 34
Part I General Introduction
35
36 36 Part I General Introduction
Part I General Introduction
The main objective of the thesis work was to develop new intramolecular catalytic C(sp3)-H amination reactions under metal-free condition and with the use of halogen as catalyst. We aimed to design mild conditions to be as functional group tolerant as possible to get the final nitrogen-containing heterocycle derivatives. In order to engineer new methodologies, it was crucial to determine whether our ideas were conceptually new and at the cutting-edge of the research. As a result, a preliminary extensive literature search was carried out to gather previous works on C(sp3)-H amination methods.
I.1 Concept of direct C(sp3)-H functionalization
Over the last decades, a new strategy has emerged and represents nowadays an entire field in the synthetic organic chemistry. This new approach consisting in functionalizing an inert C(sp3)-H bond is a terrific advance in organic chemistry since it avoids the pre-installment of functional groups.1 Conceptually, this is a new disconnection in a retrosynthetic approach that can circumvent the use of pre-functionalized group at the targeted carbon center. As a result, it is more atom-economic and reduces consequently the number of steps in a synthesis of natural products. The challenges of the C(sp3)-H functionalization are to overcome the strong stability of such inert chemical bond of saturated hydrocarbons (alkanes) and to activate regio-selectively the desired C(sp3)-H bond.2 The differentiation between C(sp3)-H bonds is not straightforward. However, this strategy revolutionized the way to think methodology development and enabled a plethora of new direct transformations to install functionalities with high regio- and stereo-selectivity such C-C, C-O, C-S, C-N or C-X for instance. These reactions can be achieved by several methods employing
1 a) J. F. Hartwig, M. A. Larsen, ACS Cent. Sci. 2016, 2, 281–292. b) H. M. L. Davies, J. Du Bois, J. Q. Yu, Chem. Soc. Rev. 2011, 40, 1855–1856. 2 R. G. Bergman, Science 2007, 446, 391–393.
37 Part I General Introduction transition metal catalyst for C-H activation or carbene/nitrene insertion,3 radical reactions4 or enzymatic engineering.5 In the last decades, the C(sp3)-H functionalization inspired the synthetic chemists to explore new routes towards challenging natural products synthesis.6 This new tool was bringing forward for the simplification and optimization of the synthesis pathway because of the reduction of steps and atom-economy. Finally, the C(sp3)-H functionalization has demonstrated its utility toward late-stage functionalization of drug candidate. They allow a rapid structural diversification of potential active molecules.7
I.2 Abundance and importance of C(sp3)-N bonds
The group of the Prof. Dr. Kilian Muñiz is focusing on developing new amination reaction starting from non-activated C-H bond. The interest of such functional group is reasonable since they are ubiquitous in natural, bioactive molecules, extremely important for living beings.8 To begin with, they are present in primary metabolites such as amino acids that represent building blocks (monomers) of proteins and enzymes that are responsible of all the biochemistry in Nature (Figure I.1a). The specific chemical properties of the amines play a key role in the smooth running of our body. For instance, the lone pair of the nitrogen atom forms crucial hydrogen bonding between the nucleobases that allow the formation of the double helix of the DNA (Figure I.1b). They allow the replication of the DNA process as well using selective recognition of the nucleobases by hydrogen bonding. They are also crucial for the stability of certain proteins to perform
3 a) P. Gandeepan, T. Müller, D. Zell, G. Cera, S. Warratz, L. Ackermann, Chem. Rev. 2019, 119, 2192–2452. b) R. Giri, B. F. Shi, K. M. Engle, N. Maugel, J. Q. Yu, Chem. Soc. Rev. 2009, 38, 3242–3272. 4 a) J. C. K. Chu, T. Rovis, Angew. Chem. Int. Ed. 2018, 57, 62–101. b) G. Kumar, S. Pradhan, I. Chatterjee, Chem. Asian. J. 2020, 15, 1–23. c) L. M. Stateman, K. M. Nakafuku, D. A. Nagib, Synth. 2018, 50, 1569–1586. 5 J. C. Lewis, P. S. Coelho, F. H. Arnold, Chem. Soc. Rev. 2011, 40, 2003–2021. 6 a) W. R. Gutekunst, R. Gianatassio, P. S. Baran, Angew. Chem. Int. Ed. 2012, 51, 7507– 7510. b) R. R. Karimov, J. F. Hartwig, Angew. Chem. Int. Ed. 2018, 57, 4234–4241. c) Y. Qiu, S. Gao, Nat. Prod. Rep. 2016, 33, 562–581. 7 T. Cernak, K. D. Dykstra, S. Tyagarajan, P. Vachal, S. W. Krska, Chem. Soc. Rev. 2016, 45, 546–576. 8 A. Ricci (Ed.), Amino Group Chemistry: From Synthesis to the Life Sciences; Wiley−VCH, Weinheim, Germany, 2007.
38 38 Part I General Introduction their catalytic activities. It is known as protein folding that enables the obtention of the functional shape of the protein necessary to be active. The sorbitol dehydrogenase is one example of protein that can fall apart if the hydrogen bonding would be absent. Amines play a crucial role in our daily life (mood, health…) as well since they are ubiquitous in secondary metabolites such as the hormones that are involved in the smooth running of our life. Indeed, numerous biogenic amines act as neurotransmitters, responsible of our wellness, our appetite, our motivation, our sexuality such as the dopamine, the serotonin or the melatonin hormone (Figure I.1c).
Figure I.1 Example of primary and secondary nitrogen-containing metabolites such as nucleobases, amino-acids and hormones.
They are also important motifs in drugs.9 The most known molecule’s family is the amphetamine (α-methylphenetylamine) that are used as stimulant for the central nervous system (CNS). For instance, they can be prescribed for the treatment of the attention deficit hyperactivity disorder. Also, the morphine is a worldwide recognized analgesic used for both the acute and chronic pain.
9 E. Vitaku, D. T. Smith, J. T. Mjardarson, J. Med. Chem. 2014, 57, 10257-10274.
39 Part I General Introduction
Since we will be focusing on pyrrolidine formation throughout this thesis, they also represent important building blocks in medicinal chemistry (Figure I.2). They are well-spread in the market for treatments of numerous diseases or symptoms. For instance, the Clemastine, sold by Novartis, is a histamine H1 antagonist (antihistamine family) used for the treatment of allergic rhinitis. The Procyclidine, sold by GSK, is an antipsychotic drug prescribed for patients affected by the Parkinson’s disease.
Figure I.2 Example of pyrrolidine-based drugs.
In Nature, the direct C-H amination reactions do not exist. They are usually installed through an amine condensation reaction at carbonyl compound followed by a reduction process catalyzed by an enzyme. For instance, the synthesis of α-amino acid is done with the use of a transaminase enzyme that can transfer an amino group from an amino acid to a α-keto acid. An example of transaminase (Alanine Amino Transferase) is depicted in Scheme I.1. It allows the transfer of the amine group of the alanine to form the glutamate from the α-keto acid 2-oxoglutarate. Nature is usually performing C-H oxidation for the formation of C-O bond.
40 40 Part I General Introduction
Scheme I.1 Mechanism of the ALanine amino transferase (ALAT) which is part of the transaminase enzyme family. Transfer of the amino group from the Alanine to the 2- oxoglutarate forming the glutamate.
I.3 Transition metal catalyzed C(sp3)-H activation for amination
As organic chemists and as scientific in general, we aim to mimic or outdo Nature developing robust and efficient methodologies that Nature cannot do for C(sp3)-H amination for instance. In order to humbly surpass Nature, we are using different tools and tricks such as directing groups, transition metals to design catalyzes.
I.3.1 Directed intramolecular C(sp3)-H amination Among the plethora of methods developed in the last decades for C(sp3)-H amination reaction, the group-directed transition metal catalyzed strategy has been attracted the organic chemist community. The common issue in direct C(sp3)-H amination is the poor regioselectivity. Indeed, in addition to the high dissociation energy of such C(sp3)-H bond, the difference between these energies is very low from one to another. To tackle these issues, directing groups were installed at proper sites to target the desire C(sp3)-H bond involving five- or six-membered metalacyclic intermediates.
I.3.1.1 Palladium catalyzed C(sp3)-H amination The group of Glorius in 2009 pioneered the group-directed transition metal catalyzed intramolecular C(sp3)-H amination using palladium(II) acetate as catalyst and an acyl moiety as directing group.10 Their were able to synthesize indolines starting with N-(2-tert- butylphenyl)acylamides (Scheme I.2). Regarding the suggested mechanism, after a ligand exchange with the acyl-protected aniline, a six- membered ring palladacycle is proposed. At this stage, either a direct reductive elimination (green pathway) or further oxidation by silver acetate
10 J. J. Neumann, S. Rakshit, T. Droge, F. Glorius, Angew. Chem. Int. Ed. 2009, 48, 6892– 6895.
41 Part I General Introduction to a palladium(IV) species followed by a reductive elimination (orange pathway) take place to yield the indoline product.
Scheme I.2 Intramolecular palladium catalyzed acyl-directed C(sp3)-H amination developed by Glorius et al. Indoline derivatives were formed from a plausible Pd(II/IV) catalysis.
More recently, investigations revealed that the C(sp3)-H bond targeting was more efficient with a chelation-assistance effect. For instance, the group of Daugulis discovered in 2012 that a bidentate picolinamide (PA) group was a suitable chelating moiety for selective C(sp3)-H amination (Scheme I.3a).11 With this methodology, pyrrolidines were obtained as well as indolines. Independently, the group of Chen also developed palladium catalyzed intramolecular amination using PA as directing group (Scheme I.3b).12 Pyrrolidines, azetidines and indolines could be synthesized using this condition. It was assumed that the palladium gets also oxidize to a high-valent palladium(IV) species by a hypervalent iodine(III) PIDA facilitating the reductive elimination leading to the C-N bond formation.
11 E. T. Nadres, O. Daugulis, J. Am. Chem. Soc. 2012, 134, 7–10. 12 G. He, Y. Zhao, S. Zhang, C. Lu, G. Chen, J. Am. Chem. Soc. 2012, 134, 3–6.
42 42 Part I General Introduction
Scheme I.3 Intramolecular palladium catalyzed picolinamide-directed C(sp3)-H amination for the construction of pyrrolidine derivatives.
Other bidentate directing groups were found to be efficient for palladium catalyzed C(sp3)-H amination reaction such as the 2-(pyridine-2- yl)isopropyl (PIP) group. The group of Shi first demonstrated its utility for C-C bond formation and extended the methodology to benzylic C-N bond construction providing -lactams (Scheme I.4).13 The mechanism is relatively close to the aforementioned one since it also involves a palladium(II/IV) catalysis. In this protocol, sodium iodate was used as the preferred oxidant to get the crucial five-membered ring palladacycle(IV) intermediate.
13 Q. Zhang, K. Chen, W. Rao, Y. Zhang, F. J. Chen, B. F. Shi, Angew. Chem. Int. Ed. 2013, 52, 13588–13592.
43 Part I General Introduction
Scheme I.4 Intramolecular palladium catalyzed PIP-directed C(sp3)-H amination developed by Shi et.al. for 4-membered ring lactam formation.
The bidentate quinoline (Q) represents an important directing group for palladium catalyzed functionalization as well. It was first introduced by Daugulis to target non-activated C(sp3)-H bond.14 It was then largely used by the scientific community such as the group of Corey for the design of a novel palladium catalyzed selective β-acetoxylation15 or by the group of Baran in the total synthesis of the Pipercyclobutanamide A. A palladium catalyzed quinoline-directed olefination and arylation was developed to achieve its synthesis.16 Chen et al. reported for the first time a quinoline-assistance for a palladium catalyzed C(sp3)-H amination for the synthesis of -lactams (Scheme I.5).17 A 5-methoxyquinoline (MQ) auxiliary was also designed to be a chelating- assistant and a readily removable directing group. Ceric ammonium nitrate (CAN) can then be used to deprotect such a group. The observed selectivity is due to the key formation of a 6-membered ring palladacyle(IV) intermediate.
14 a) V. G. Zaitsev, D. Shabashov, O. Daugulis, J. Am. Chem. Soc. 2005, 127, 13154–13155. b) L. D. Tran, O. Daugulis, Angew. Chem. Int. Ed. 2012, 51, 5188–5191. c) D. Shabashov, O. Daugulis, J. Am. Chem. Soc. 2010, 132, 3965–3972. 15 B. V. S. Reddy, L. R. Reddy, E. J. Corey, Org. Lett. 2006, 8, 3391–3394. 16 W. R. Gutekunst, R. Gianatassio, P. S. Baran, Angew. Chem. Int. Ed. 2012, 51, 7507– 7510. 17 G. He, S. Y. Zhang, W. A. Nack, Q. Li, G. Chen, Angew. Chem. Int. Ed. 2013, 52, 11124– 11128.
44 44 Part I General Introduction
Scheme I.5 Intramolecular palladium catalyzed Q- or MQ-directed C(sp3)-H amination developed by Chen et.al. The advantage of the MQ is its mild cleavage condition using CAN.
I.3.1.2 First-row transition metal catalyzed C(sp3)-H amination The bidentate directing groups are not restricted to palladium chemistry, they can also be employed with other first-row transition metal catalysts in order to perform selective C(sp3)-H amination reactions. For instance, copper catalyzed aminations were investigated for non-activated C(sp3)-H bond. In 2014, the group of Kanai and Ge developed a quinoline- directed copper catalysis to access β-lactams (Scheme I.6a).18 The reaction plausibly proceeds through a copper(I/III) catalysis with the involvement of a five-membered ring metalacyclic copper(III) intermediate. Either silver acetate or duroquinone was used as oxidant in these systems. Nickel and cobalt appeared to be convenient metals as well for catalysis to install a C-N bond. The group of Ge, also in 2014, published a quinoline- assisted nickel catalysis to obtain β-lactams (Scheme I.6b).19 A nickel(I/III) catalysis was described and the observed selectivity is coming from the five- membered ring nickelacycle intermediate. TEMPO was the proper oxidant for this transformation. As an alternative, a greener cobalt catalysis was developed for such a transformation (Scheme I.6c).20 The reaction
18 a) Z. Wang, J. Ni, Y. Kuninobu, M. Kanai, Angew. Chem. Int. Ed. 2014, 53, 3496–3499. b) X. Wu, Y. Zhao, G. Zhang, H. Ge, Angew. Chem. Int. Ed. 2014, 53, 3706–3710. 19 X. Wu, Y. Zhao, H. Ge, Chem. Eur. J. 2014, 20, 9530–9533. 20 X. Wu, K. Yang, Y. Zhao, H. Sun, G. Li, H. Ge, Nat. Commun. 2015, 6, 6462.
45 Part I General Introduction conditions suggest a cobalt(II/IV) catalysis and the selectivity can be explained as well by the five-membered ring metallacycle key intermediate.
Scheme I.6 Intramolecular transition metal catalyzed Q-directed C(sp3)-H amination for the formation of β-lactam derivatives. Comparison of isolated yield for selected examples obtained using the three different reaction condition are depicted.
Using the same cobalt catalysis, there were also able to perform selective intermolecular amination guided by the quinoline group avoiding the cyclization event. Heptafluorobutanamides were chosen as efficient nitrogen source in this method. In the following subchapter, directed intermolecular C(sp3)-H amination will be presented.
I.3.2 Directed intermolecular C(sp3)-H amination Several methods have been developed by the organic chemist community to selectively perform a directed C(sp3)-H amination with an
46 46 Part I General Introduction external nitrogen source. In order to target the desired non-activated C(sp3)-H bond, various chelating moieties were optimized. Under the chelation-assistance of the directing group, a C(sp3)-H activation through a cyclometallation can occur selectively to form a five-membered ring metallacycle. At this stage, it always involves a nitrenoid species that can insert into the C-M bond of the 5-membered ring metallacycle.
I.3.2.1. Intermolecular ketoxime-directed C(sp3)-H amination Ketoximes can be used as efficient directing groups to target C(sp3)- H bond at the γ-position. Iridium21 as well as rhodium22 or palladium23 catalyzes were developed for selective C(sp3)-H activation / Carbon-Metal nitrene insertion for amination reactions (Scheme I.7). In these methods, primary sulfonamides, trifluoroacetamides, organic azides or 3-subtituted 1,4,2-dioxazol-5-ones can be used as nitrogen sources because of their properties to form the corresponding metal-nitrenoid species either under oxidative or thermal conditions. To enhance the efficiency of the transformation, a dimeric iridium(III) or rhodium(III) catalyst was used in addition with a silver additive to form in- situ a cationic iridium(III) or rhodium(III) species reported more reactive. After a cyclometallation to form the 5-membered ring metallacycle, the metal gets oxidized to yield the corresponding metal nitrenoid. A subsequent insertion into the Carbon-Metal bond occurs to afford the carbon-nitrogen bond formation. A final protonolysis delivers the γ- aminated product.
21 a) T. Kang, Y. Kim, D. Lee, Z. Wang, S. Chang, J. Am. Chem. Soc. 2014, 136, 4141–4144. b) T. Kang, H. Kim, J. G. Kim, S. Chang, Chem. Commun. 2014, 50, 12073–12075. 22 H. Wang, G. Tang, X. Li, Angew. Chem. Int. Ed. 2015, 54, 13049–13052. 23 H. Y. Thu, W. Y. Yu, C. M. Che, J. Am. Chem. Soc. 2006, 128, 9048–9049.
47 Part I General Introduction
Scheme I.7 Intermolecular palladium, iridium or rhodium catalyzed ketoxime-directed C(sp3)-H amination. The key intermediates are depicted regarding the mechanism and examples were selected to illustrate the robustness of this method.
I.3.2.2. Intermolecular N-heterocycle-directed C(sp3)-H amination The group of Muñiz developed in 2012 a palladium catalyzed chelation-assisted intermolecular C(sp3)-H amination using 8-
48 48 Part I General Introduction methylquinoline, 2-tert-butylpyridine or 2-methylanisole, as directing groups (Scheme I.8).24 While putting the starting material in the unique presence of the palladium 3 catalyst Pd(hfacac)2, the C(sp )-H activation already occurs to get the 5- membered ring palladacycle. An X-ray of this intermediate could be obtained with the 8-methylquinoline as starting material. For this transformation, NFSI was used as both oxidant and nitrogen source. It oxidizes the palladium(II) intermediate at the stage of the 5-membered ring palladacycle to a cationic palladium(IV) fluoride species which acts as an excellent nucleofuge. The corresponding bis-benzenesulfonimide anion can perform a nucleophilic substitution at the activated benzylic position to yield the final aminated product. The mechanism was fully substantiated by DFT calculations.
Scheme I.8 Quinoline directed palladium catalyzed intermolecular C(sp3)-H amination designed by Muñiz et.al. using NFSI.
24 Á. Iglesias, R. Álvarez, Á. R. De-Lera, K. Muñiz, Angew. Chem. Int. Ed. 2012, 51, 2225– 2228.
49 Part I General Introduction
Robust catalyzes were designed for iridium21a, cobalt25, rhodium22,26 or ruthenium27 as well to perform selective C(sp3)-H amination of 8- alkylquinoline (Scheme I.9). For all these transformations, a C(sp3)-H activation occurs forming the corresponding 5-membered ring metallacycle intermediate. The nitrogen sources are those which can form a metal- nitrenoid species like organic azides, as well as 3-subtituted 1,4,2-dioxazol- 5-ones or anthranil derivatives. Once the metal-nitrenoid species is formed, a subsequent nitrene insertion is likely to occur affording the C-N bond formation.
25 N. Barsu, M. A. Rahman, M. Sen, B. Sundararaju, Chem. Eur. J. 2016, 22, 9135–9138. 26 a) N. Wang, R. Li, L. Li, S. Xu, H. Song, B. Wang, J. Org. Chem. 2014, 79, 5379–5385. b) C. Tang, M. Zou, J. Liu, X. Wen, X. Sun, Y. Zhang, N. Jiao, Chem. Eur. J. 2016, 22, 11165– 11169. c) S. Yu, G. Tang, Y. Li, X. Zhou, Y. Lan, X. Li, Angew. Chem. Int. Ed. 2016, 55, 8696– 8700. 27 B. Liu, B. Li, B. Wang, Chem. Commun. 2015, 51, 16334–16337.
50 50 Part I General Introduction
Scheme I.9 Rhodium, cobalt, iridium or ruthenium catalyzed quinoline-directed intermolecular C(sp3)-H amination. Various nitrogen sources were exploited as depicted in the scheme. Selected examples were picked from the different methods to display both their efficiency and complementarity.
51 Part I General Introduction
A work published by You and co-workers utilizes a cationic rhodium(III) catalyst and 2-tert-butylpyridine as starting material to complete a intermolecular directed C(sp3)-H activation / nitrene insertion at room temperature (Scheme I.10).28 The difference between the previous mechanism is the necessity to form in-situ an iminoiodinane that can react with the cationic rhodium(III) to provide the desired key metal-nitrenoid intermediate. As a result, the commercially available hypervalent iodine oxidant PIDA is used. Primary sulfonamide as well as primary amide react with the latter to generate the hypervalent iminoiodinane. Therefore, they are the plausible nitrogen sources for this transformation.
Scheme I.10 Rhodium catalyzed pyridine-directed intermolecular C(sp3)-H amination developed by You et. al. R = SO2R’ or COR’.
Finally, Jin-Quan Yu, inspired by the classical mechanism of the cross- coupling reaction installed a palladium(0/II) catalysis where the oxidative addition takes place over a O-benzoyl hydroxylamines (Scheme I.11).29 Under basic conditions, chelation at the directing group and further C(sp3)- H activation occur to get the key intermediate 5-membered ring palladacycle bearing the amine ligand. Then, a reductive elimination takes place to selectively yield β-aminations that provide, after hydrolysis, β- aminoacids. Various O-benzoyl hydroxylamine derivatives could be used for such a reaction. As a result, numerous amines such as morpholine, piperidine or piperazine could be implemented selectively at the β-position.
28 X. Huang, Y. Wang, J. Lan, J. You, Angew. Chem. Int. Ed. 2015, 54, 9404–9408. 29 J. He, T. Shigenari, J. Q. Yu, Angew. Chem. Int. Ed. 2015, 54, 6545–6549.
52 52 Part I General Introduction
Scheme I.11 Intermolecular directed palladium catalyzed C(sp3)-H amination designed by J.Q. Yu et. al. using O-benzoyl hydroxylamine as nitrogen sources. Ar = 3,5- (CF3)2C6H3. Selected examples are displayed to highlight the high diversity of amine that could be implemented.
I.3.3 Directing group-free C(sp3)-H amination As we mentioned previously, the directing groups were installed to selectively target a C(sp3)-H bond and to favor the C-H metalation process. But, the removal of such directing groups is not straightforward. Some efforts have been made by the organic chemist community to overcome both the issue of the regioselectivity and the slow C-H metalation process in the absence of any directing groups.
I.3.3.1. Intramolecular allylic C(sp3)-H amination Among the plethora of strategies for performing C-H amination reaction, the idea is to target a C(sp3)-H bond in allylic position. The regioselectivity is coming from the capacity of certain transition metal to form π-allyl complexes. The group of White developed an intramolecular palladium catalyzed allylic amination without the requirement of a directing group. They identified the key intermediate π-allyl palladium complex by NMR and after its formation,
53 Part I General Introduction a 5-exo cyclization occurs to obtain the corresponding 5-membered ring tosylated carbamate (Scheme I.12a).30 The palladium(II) hydride species then undergoes a reductive elimination to generate the palladium(0) pre- catalyst and the final allyl amine derivative. A quinone is used as oxidant to re-furnish the palladium(II) catalyst. The same group published another article where they extended their work to the formation of 6-membered ring tosylated or nosylated carbamates using the same reaction conditions (Scheme I.12a).31 After a final hydrolysis, syn-amino alcohols could be generated under these conditions. An outstanding application of such palladium catalysis was also developed to perform sequential intramolecular allylic amination followed by an arylation.32 Another terrific contribution of the same group was recently published on an intramolecular non-directed allylic palladium-catalyzed C(sp3)-H amination using SOX ligands.33 What is remarkable about this methodology is the capacity of stereodivergence. While using a SOX ligand bearing either the electronwithdrawing trifluoromethyl group or a methoxy group and slightly tuning the oxidant, the corresponding syn or anti product can be synthesized (Scheme I.12b). The mechanism is the same that afore mentioned with the involvement of the key π-allyl palladium complex intermediate.
30 K. J. Fraunhoffer, M. C. White, J. Am. Chem. Soc. 2007, 129, 7274–7276. 31 G. T. Rice, M. C. White, J. Am. Chem. Soc. 2009, 131, 11707–11711. 32 C. Jiang, D. J. Covell, A. F. Stepan, M. S. Plummer, M. C. White, Org. Lett. 2012, 14, 1386–1389. 33 R. Ma, J. Young, R. Promontorio, F. M. Dannheim, C. C. Pattillo, M. C. White, J. Am. Chem. Soc. 2019, 141, 9468–9473.
54 54 Part I General Introduction
Scheme I.12 Intramolecular palladium catalyzed C(sp3)-H allylic amination by White et. al. .New sulfone ligands were designed for such a transformation (BisSO and SOX) and their structures are displayed. Selected examples are depicted demonstrating the excellent regioselectivity obtained for the allylic position vs propargylic or at α- position of silyl ether.
At the stage of the cyclization process, when the π-allyl palladium complex is installed, an n-exo-trig or a n+2-endo-trig cyclization can occur. To favor the 7-endo-trig versus the 6-exo-trig cyclization, the group of Liu designed a system in which a Pd-N bond is formed under basic conditions after the formation of the π-allyl palladium complex (Scheme I.13).34 Consequently,
34 L. Wu, S. Qiu, G. Liu, Org. Lett. 2009, 11, 2707–2710.
55 Part I General Introduction a palladacycle intermediate is plausibly formed. Primary tosyl-protected amides were cyclized using these conditions to yield the corresponding lactams. Labelling experiments have shown that the rate-limiting step is the reductive elimination leading to the non-favored 7-membered ring compound coming from the 7-endo-trig cyclization process.
Scheme I.13 Intramolecular palladium catalyzed C(sp3)-H allylic amination developed by Liu and co-workers via a 7-endo-trig cyclization. A key Pd-N bond is formed to reach the desired regioselectivity as shown in the selected example.
Pyrrolidine motif could be obtained thanks to transition metal intramolecular allylic amination (Scheme I.14). One of the most interesting work for both tosylamide’s cyclization and subsequent formation of pyrrolidines is coming from the groups of Andersson and Peterson in 1995 and 1996 respectively (Scheme I.14a).35 Indeed, they pioneered the field developing a palladium catalyzed intramolecular allylic amination for the generation of azacycles such as indolines, dihydroquinolines and pyrrolidines. Palladium(II) acetate in DMSO was designed for such a transformation. Presumably, a cationic active Palladium(II) is in-situ generated to form the π-allyl complex. Regarding the mechanism, it has been previously discussed in the above mentioned methodologies since it is following the classical pathway for palladium catalyzed intramolecular allylic amination. The group of Cossy developed a rhodium catalysis as well for the formation of such important pyrrolidine motif (Scheme I.14b).36 The mechanism of
35 a) M. Rönn, J. E. Bäckvall, P. G. Andersson, Tetrahedron Lett. 1995, 36, 7749–7752. b) R. C. Larock, T. R. Hightower, L. A. Hasvold, K. P. Peterson, J. Org. Chem. 1996, 61, 3584– 3585. 36 T. Cochet, V. Bellosta, D. Roche, J. Y. Ortholand, A. Greiner, J. Cossy, Chem. Commun. 2012, 48, 10745–10747.
56 56 Part I General Introduction this transformation was clarified by Tanaka and co-workers and they ensured that it clearly involves a π-allyl rhodium complex.37 The major limitation of this process is the observed olefin migration and isomerization.
Scheme I.14 Intramolecular palladium and rhodium catalyzed C(sp3)-H allylic amination for pyrrolidine formation.
I.3.3.2. Intermolecular allylic amination Non-directed intermolecular palladium-catalyzed allylic aminations were developed as well principally by the groups of White38 and Liu39.
37 Y. Shibata, E. Kudo, H. Sugiyama, H. Uekusa, K. Tanaka, Organometallics 2016, 35, 1547–1552. 38 a) S. A. Reed, A. R. Mazzotti, M. C. White, J. Am. Chem. Soc. 2009, 131, 11701–11706. b) C. C. Pattillo, I. I. Strambeanu, P. Calleja, N. A. Vermeulen, T. Mizuno, M. C. White, J. Am. Chem. Soc. 2016, 138, 1265–1272. c) S. A. Reed, M. C. White, J. Am. Chem. Soc. 2008, 130, 3316–3318. 39 a) G. Yin, Y. Wu, G. Liu, J. Am. Chem. Soc. 2010, 132, 11978–11987. b) G. Liu, G. Yin, L. Wu, Angew. Chem. Int. Ed. 2008, 47, 4733–4736.
57 Part I General Introduction
Starting from the intramolecular amination conditions discussed above, White et al. extended their work to design an intermolecular approach. The major issue of the intermolecular version is the C-N bond formation by a nucleophilic attack. As a result, they developed a heterobimetallic system using chromium(salen) in co-catalysis with palladium(II).sulfoxide (Scheme I.15A). It was proven that the combination of chromium(salen) and benzoquinone helped the nucleophilic attack step. Indeed, the benzoquinone is known to act as a π-acidic ligand facilitating the reductive elimination step. Then, another methodology involves an organic base in combination with the benzoquinone to accelerate the C-N bond formation (Scheme I.15B). Finally, to avoid the counter-productive palladium(II).benzoquinone complex, they designed a system in which DHBQ is used in catalytic amount instead (Scheme I.15C). This heterobimetallic catalysis between palladium and either vanadium or cobalt species uses oxygen as terminal oxidant. Under air, the cobalt or vanadium co-catalyst is getting oxidized by oxygen and enables the oxidation of DHBQ. The group of Liu proposed a methodology in which maleic acid is used instead of benzoquinone to facilitate the nucleophilic attack (Scheme I.15D). Another strategy consists to oxidize the π-allyl complex palladium(II) to a palladium(IV) species with the use of hypervalent iodine(III) (Scheme I.15E). For all these transformations, the N- tosylmethylcarbamate was chosen as the nitrogen source.
58 58 Part I General Introduction
Scheme I.15 Intermolecular palladium catalyzed C(sp3)-H allylic amination using the N- tosylmethylcarbamate as nitrogen source. Selected examples are depicted to both illustrate the functional group tolerance of these methods.and to compare them to each other. The structures of both Cr(III) and Co(II) catalysts are displayed as well.
With all the knowledge acquired, late-stage intermolecular allylic amination could be developed by the group of White.40 The transformation is a coupling reaction between a terminal olefin and a N-trifluorosulfonyl protected aliphatic amine. With this method, two fragments can be coupled together. As demonstrated in the Scheme I.16, a steroid derivative called
40 R. Ma, M. Christina White, J. Am. Chem. Soc. 2018, 140, 3202–3205.
59 Part I General Introduction
Leelamine could be coupled to a tocopherol derivative. This robust and terrific methodology is at the cutting-edge of the non-directed palladium- catalyzed intermolecular amination.
Scheme I.16 Late-stage intermolecular palladium catalyzed C(sp3)-H allylic amination developed by White et. al. Selected examples were chosen to display the efficiency of such transformation. In the first example, a benzyl trifluorosulfonamide was coupled with a tocopherol derivative and in the second example, the Leelamine N- trifluorosulfonyl protected was coupled as well with the tocopherol derivative.
I.4 Transition metal catalyzed C(sp3)-H insertion for C(sp3)-H amination
Another strategy for selective C(sp3)-H aminations is the use of a transition metal to generate in-situ a nitrenoid species. We already discussed previously that such a reactive species can undergo an insertion into a non-activated C(sp3)-H bond. The mechanism of the insertion remains unclear, but two pathways seem reasonable at the first sight (Scheme I.17). Either an ionic route is preferred with a concerted mechanism (Scheme I.17a) or a stepwise radical mechanism is involved with first a hydrogen atom abstraction (HAA) followed by a radical recombination (Scheme I.17b).
60 60 Part I General Introduction
Scheme I.17 Mechanism of the nitrene insertion into a C(sp3)-H bond for C(sp3)-H amination. Either a concerted mechanism or a stepwise HAA/Radical rebound can proceed.
The pioneer for this field is Ronald Breslow in New York. He was inspired by the previous work by Groves on oxygenation reactions developed with iron porphyrin catalysts.41 With such a methodology, oxygenation on cyclohexane could be done using iodosobenzene. Presumably, the iron got oxidized into an oxo-iron species that could undergo the C(sp3)-H insertion. Breslow decided to replace this oxygen by a tosylimide moiety. As a result, he was able to aminate cyclohexane using the porphyrin complexes Mn(TPP)Cl or Fe(TPP)Cl as catalyst and (tosyliminoiodo)benzene as nitrene transfer reagent (Scheme I.18a).42 For the really first time, he demonstrated that an iminoiodinane could be used as a metal-nitrenoid precursor with manganese or iron porphyrin catalysts. In 1983, he published an intramolecular version for this transformation (Scheme I.18b).43 The 2,5- diisopropylbenzylsulfonamide was first converted to the hypervalent iminoiodinane (metal-nitrenoid precursor). Then, the metal-porphyrin complex reacts with the latter to achieve the metal-nitrenoid that can insert via one of the two pathways described above into the C(sp3)-H bond thus providing the aminated product.
41 J. T. Groves, T. E. Nemo, R. S. Myers, J. Am. Chem. Soc. 1979, 101, 1032–1033. 42 R. Breslow, S. H. Gellman, J. Chem. Soc., Chem. Commun. 1982, 1400–1401. 43 R. Breslow, S. H. Gellman, J. Am. Chem. Soc. 1983, 105, 6728–6729.
61 Part I General Introduction
Scheme I.18 Pioneering Breslow’s work on inter- and intramolecular C(sp3)-H nitrene insertion for C(sp3)-H amination using iron or manganese porphyrin and iminoiodinanes as metal-nitrenoid precursor. The structure of the manganese porphyrin catalyst is drawn in the scheme.
In intramolecular reactions, the regioselectivity is governed by the substrate. For instance, geometrically, sulfamate esters or sulfamides are well known to form 5- or 6-membered ring. Carbamates or ureas undergo 5-membered ring cyclization. In intermolecular reactions, the regioselectivity relies on the BDE of the C(sp3)-H bond. The weakest C(sp3)- H bond, the most reactive it will be. Usually, activated benzylic, allylic or propargylic C(sp3)-H bonds are the weakest. Also, the chemoselectivity may sometimes cause issues while working with nitrenoid species. For instance, the most common side-reaction is the aziridination of.44
I.4.1 First-row transition metal catalyzed C(sp3)-H insertion Following the pioneering work of Breslow, other groups started to investigate more in details the development of new methodologies that are more efficient, more applicable, more selective.
44 D. Mansuy, J. P. Mahy, A. Dureault, G. Bedi, P. Battioni, J. Chem. Soc., Chem. Commun. 1984, 1161–1163.
62 62 Part I General Introduction
I.4.1.1 Manganese and iron as pioneered metals for C(sp3)-H insertion The group of Che successfully designed an intermolecular amination using a manganese(III) porphyrin complex. Regarding the formation of the manganese(V)-nitrenoid species, either a preformed iminoiodinane or its in-situ generation by an hypervalent iodine(III) oxidant such as the commercially available PhI(OAc)2 from a primary sulfonamide were used (Scheme I.19a).45 With this conditions in hand, intermolecular selective C(sp3)-H aminations could be performed at non- activated positions as well as at allylic or benzylic positions. Another manganese catalysis was designed by the group of White to perform intramolecular amination (Scheme I.19b).46 The ring-size is coming from the substrate itself because sulfamate esters are well-known to form preferentially 6-membered rings. As a result, the amination takes place regioselectively at the γ-position. The olefin aziridination could be avoided with a careful catalyst design. Indeed, they developed a manganese(III)- phthalocyanine complex to achieve sufficient chemoselectivity towards the nitrene insertion into the C(sp3)-H bond.
45 X. Q. Yu, J. S. Huang, X. G. Zhou, C. M. Che, Org. Lett. 2000, 2, 2233–2236. 46 S. M. Paradine, J. R. Griffin, J. Zhao, A. L. Petronico, S. M. Miller, M. Christina White, Nat. Chem. 2015, 7, 987–994.
63 Part I General Introduction
Scheme I.19 Manganese(III)-complexes as catalysts for inter- or intramolecular nitrene insertion into C(sp3)-H bond. Selected examples are displayed showing the diversity of substrates that can be successfully aminated. THF could be aminated using Che’s protocol. Starting from sulfamate ester derivatives, propargylic amination could be achieved as well as amination at non-activated aliphatic position of highly functionalized molecules. The structures of the manganese catalysts are exhibited as well.
The group of Che designed a chiral porphyrin catalyst to yield chiral amines in an intermolecular amination.47 The porphyrin was tetra-substituted at the position 5, 10, 15 and 20 by a chiral (1,2,3,4,5,6,7,8-octahydro-1,4,5,8- dimethanoanthracen-9-yl). The encountered enantioselectivities were modest. Instead of the use of a manganese(III)-porphyrin catalyst, a Schiff base complex was utilized to install chirality. First, the group of Katsuki was able to design a chiral manganese(III) Schiff base complex catalyst for a selective intermolecular C(sp3)-H amination at benzylic and allylic position (Scheme
47 X. Zhou, X. Yu, J. Huang, C. Che, Chem. Commun. 1999, 2377–2378.
64 64 Part I General Introduction
I.20a).48 This chiral complex induced moderate conversion and enantioselectivity. In this method, since the conversion was already an issue, a preformed nitrene transfer reagent (N-tosyliminophenyliodinane) was preferred. Then, the group of Che developed an intramolecular version of the transformation using sulfamate esters to selectively perform the C(sp3)-H amination at the γ-position or at the β-position when the γ- position is blocked (Scheme I.20b).49 An hypervalent iodine(III) was used to form the nitrene and to reach the key Schiff base manganese(V) complex nitrenoid species. The mechanism of these transformations remain unclear and can follow either a direct insertion or a HAA/Radical recombination pathway.
Scheme I.20 Manganese(III)-Schiff base complex as catalysts for inter- and intramolecular nitrene insertion into activated carbon C(sp3)-H bond. Selected examples from both methods were picked up to illustrate their efficiency. The structures of the Schiff base complex catalysts are exhibited for these methods.
48 Y. Kohmura, T. Katsuki, Tetrahedron Lett. 2001, 42, 3339–3342. 49 J. Zhang, P. W. H. Chan, C. M. Che, Tetrahedron Lett. 2005, 46, 5403–5408.
65 Part I General Introduction
The groups of Che and White extended their discoveries from manganese(III)-porphyrin catalyzes to iron to perform selective C(sp3)-H amination. Che developed an aziridination reaction that can be applicable for C(sp3)-H amination.50 Para-azidonitrobenzene derivatives were used as metal-nitrenoid precursors that allow allylic, benzylic and non-activated aliphatic intermolecular C(sp3)-H amination (Scheme I.21a). The White group extended their knowledge about the manganese(III)- phthalocyanine catalysis to the corresponding iron(III) complex.51 The geometry of the sulfamate ester enables to regioselectively cyclize at the γ- position. Remarkably, as with the close-related manganese catalysis, the direct C(sp3)-H amination is favored and the side-aziridination reaction disfavored while using such a system. An hypervalent iodine(III) oxidant was used to generate the iron-nitrenoid species.(Scheme I.21b).
50 Y. Liu, C. M. Che, Chem. Eur. J. 2010, 16, 10494–10501. 51 S. M. Paradine, M. C. White, J. Am. Chem. Soc. 2012, 134, 2036–2039.
66 66 Part I General Introduction
Scheme I.21 Iron(III) complexes as catalysts for inter- and intramolecular nitrene insertion into C(sp3)-H bond. Selected examples for the intermolecular amination show that both activated and non-activated position can be aminated. For the intramolecular reaction, selected examples displayed the necessity of an activated allylic position. The efficient iron(III) complexes are shown in the scheme for greater clarity.
Nonheme iron(II) complexes were also investigated as potential catalyst for selective C(sp3)-H amination. The group of Betley found out that iron- dipyrromethane complexes could undergo intermolecular amination reaction while using organic azides (Scheme I.22). Amination of toluene (used as solvent) was the starting point of various mechanistic elucidations.52 Later, another iron(II)-dipyrromethane catalyst was elaborated to access allylic and benzylic C(sp3)-H amination using electron-
52 E. R. King, E. T. Hennessy, T. A. Betley, J. Am. Chem. Soc. 2011, 133, 4917–4923.
67 Part I General Introduction poor aryl azide derivatives as nitrogen sources.53 Several experiments were carried out to find out the oxidation state of the iron-nitrenoid species. They identified the involvement of an iron(III) radical imido species that performs a HAA / radical recombination mechanism as the active nitrenoid for the amination.
Scheme I.22 Nonheme iron(II) complexes as catalysts for intermolecular nitrene insertion into C(sp3)-H bond developed by Betley et.al.. This scheme displays selected examples of aminations at activated position. The iron(III) radical imido species as well as the active catalysts are depicted.
With this background in hand, they then developed intramolecular aminations using iron(II) catalysis for pyrrolidine formation (Scheme
53 D. A. Iovan, T. A. Betley, J. Am. Chem. Soc. 2016, 138, 1983–1993.
68 68 Part I General Introduction
I.23).54 They designed a nonheme iron(II) dipyrromethane catalyst which is able to react with aliphatic azides to generate the nitrenoid species. This iron(III) radical imido complex undergoes selectively a 1,5-hydrogen atom abstraction at both activated allylic position and non-activated position to generate a C-centered radical. At this stage, a HAA / radical recombination occurs. The optimized conditions allow a perfect chemoselectivity regarding the C-H amination rather than the aziridination. This work represents the unique contribution of nitrene insertion chemistry for the synthesis of valuable pyrrolidines.
Scheme I.23 Nonheme iron(II) complexes as catalysts by Betley and co-workers for pyrrolidine derivatives formation through C(sp3)-H nitrene insertion. Selected examples are shown and highlight the high efficiency of the amination at both activated allylic position and non-activated tertiary position. The iron(II) catalyst is displayed for greater clarity.
54 a) E. T. Hennessy, T. A. Betley, Science 2013, 340, 591–595. b) D. A. Iovan, M. J. T. Wilding, Y. Baek, E. T. Hennessy, T. A. Betley, Angew. Chem. Int. Ed. 2017, 56, 15599– 15602.
69 Part I General Introduction
A cationic iron(II) complex bearing a quinquepyridine (qpy) as ligand was designed by Che and co-workers to efficiently generate the iron-nitrenoid species starting from an iminoiodinane as nitrogen source.55 This method could be used for intermolecular C(sp3)-H amination at non-activated, benzylic and allylic positions as shown in the selected examples Scheme I.24. Intramolecular version was developed as well from primary sulfamate ester derivatives. The commercially hypervalent iodine(III) PIDA was the suitable oxidant for the generation of the nitrene.
Scheme I.24 Nonheme iron(II) quinquepyridine complex as catalyst designed by Che and co-workers for inter- and intramolecular nitrene insertions into C(sp3)-H bond. Activated as well as non-activated position could be intermolecularly aminated as depicted. Examples of intramolecular amination of complex structures are also displayed. The iron(II) catalyst’s structure is exhibited in the scheme for greater clarity.
55 Y. Liu, X. Guan, E. L. M. Wong, P. Liu, J. S. Huang, C. M. Che, J. Am. Chem. Soc. 2013, 135, 7194–7204.
70 70 Part I General Introduction
At the cutting edge of the manganese catalysis for nitrene transfer chemistry for intermolecular amination, a late-stage amination could be designed by the group of White.56 Generally, one of the limitations of the intermolecular nitrene insertion for C(sp3)-H amination is the sulfonyl protecting groups which is not straightforward to take away. They outwent this issue by choosing an easy-to-remove trichloroethylsulfamate protecting group (Tces). A preformed iminoiodinane was used as a nitrene precursor and a novel perchlorinated manganese phthalocyanine catalyst was developed. The reaction proceeds smoothly, and the mild conditions could be employed for late-stage benzylic amination. Outstandingly, Sulbactam as well as a Leelamine analogue could be synthesized for instance (Scheme I.25).
Scheme I.25 Late-stage intermolecular C(sp3)-H nitrene insertion developed by White et.al. for C(sp3)-H amination catalyzed by a manganese(III)-phthalocyanine complex. The trichloroethoxysulfonyliminoiodinane was the suitable manganese-nitrenoid precursor to achieve amination on complex structures. The structure of the manganese(III) complex is depicted for greater clarity.
I.4.1.2 Cobalt-catalyzed C(sp3)-H insertion through metalloradical catalysis Regarding the cobalt catalysis developed for selective C(sp3)-H amination through C(sp3)-H insertion, Cenini and co-workers pioneered
56 J. R. Clark, K. Feng, A. Sookezian, M. C. White, Nat. Chem. 2018, 10, 583–591.
71 Part I General Introduction the field. They explored intermolecular amination reactions with the use of organic azides as nitrogen sources (nitrenoid precursors). Activated benzylic positions represented the target positions.57 The group of Zhang has provided numerous methods in the last decade for cobalt catalyzed amination. The concept of these catalyzes is based on the metalloradical catalysis (MRC) approach using cobalt(II)-porphyrin complexes. Activated carbonyl, phosphoryl or sulfonyl azides were always used as nitrene precursors and a cobalt(III)-aminyl radical in-situ generated. A subsequent hydrogen atom abstraction (HAA) followed by a radical recombination occur to perform the desired regioselective and chemoselective amination. In 2010, an intermolecular C(sp3)-H benzylic amination could be optimized 58 using [Co(TPP)] as catalyst and TrocN3 as nitrogen source (Scheme I.26a). The following year, certain phosphoryl azides could be used as nitrene precursors for selective intramolecular amination in order to form 6- or 7- membered ring cyclophosphoramidates.59 A cobalt(II)-porphyrin complex was designed for such a transformation and depicted Scheme I.26b. The regioselectivity is coming from the geometry of the phosphoryl azide itself that exclusively enable 1,6 or 1,7-HAT. The angle OPN allows the nitrogen radical to perform a hydrogen atom abstraction passing through a 7- or 8- membered ring intermediate.
57 a) S. Cenini, E. Gallo, A. Penoni, S. Tollari, Chem. Commun. 2000, 2265–2266. b) F. Ragaini, A. Penoni, E. Gallo, S. Tollari, L. Gotti, M. Lapadula, E. Mangioni, S. Cenini, Chem. Eur. J. 2003, 9, 249–259. 58 H. Lu, V. Subbarayan, J. Tao, X. P. Zhang, Organometallics 2010, 29, 389–393. 59 H. Lu, J. Tao, J. E. Jones, L. Wojtas, X. Peter Zhang, Org. Lett. 2010, 12, 1248–1251.
72 72 Part I General Introduction
Scheme I.26 Cobalt(II) porphyrin complex catalysis through MRC designed by Zhang and co-workers for intermolecular C(sp3)-H nitrene insertion and intramolecular formation of cyclophosphoramidate derivatives. The structures of the cobalt porphyrin complex catalysts are depicted.
The group of Zhang designed several methodologies for intramolecular C(sp3)-H amination starting from sulfamoyl azide derivatives. Allylic amination (Scheme I.27a)60 as well as propargylic amination (Scheme I.27b)61 have been developed in mild reaction conditions and through metalloradical catalysis. Remarkably, no olefin isomerization occurs and an
60 H. Lu, H. Jiang, Y. Hu, L. Wojtas, X. P. Zhang, Chem. Sci. 2011, 2, 2361–2366. 61 H. Lu, C. Li, H. Jiang, C. L. Lizardi, X. P. Zhang, Angew. Chem. Int. Ed. 2014, 53, 7028– 7032.
73 Part I General Introduction outstanding chemoselectivity was reached since the aziridination could be completely suppressed. Late stage amination reaction was carried out to demonstrate the robustness and the mildness of the method. In addition, α-amino acid derivatives could be obtained while abstracting electron-deficient C(sp3)-H bond (Scheme I.27c).62 Indeed, the bond dissociation energy (BDE) for the electron-deficient C(sp3)-H bond in alpha to a carbonyl is lower than the electron-rich C(sp3)-H bond for about 10 kcal. The regioselectivity of such a transformation is governed by the sulfamoyl moiety than can undergo geometrically 1,5- or 1,6-hydrogen atom abstraction and by the BDE of the remote C(sp3)-H bond. When the preferred 1,6-hydrogen atom abstraction is not possible and that the unique possibility for the sulfamoyl group is to perform a 1,5-hydrogen atom abstraction, late stage 5-membered ring sulfamides could be synthesized with a proper designed Co(II)-porphyrin complex catalyst (Scheme I.27d).63
62 H. Lu, Y. Hu, H. Jiang, L. Wojtas, X. P. Zhang, Org. Lett. 2012, 14, 5158–5161. 63 H. Lu, K. Lang, H. Jiang, L. Wojtas, X. P. Zhang, Chem. Sci. 2016, 7, 6934–6939.
74 74 Part I General Introduction
Scheme I.27 Cobalt(II) porphyrin complex catalysis through MRC designed by Zhang et.al. for intramolecular C(sp3)-H nitrene insertion using sulfamoyl azide derivatives. Selected examples of various allylic, propargylic intramolecular cyclization are displayed. The reaction is mild, and amination of complex structures could be
75 Part I General Introduction achieved. One example of an amination at α-position of an ester is exhibited as well. Finally, a 5-membered ring example is also depicted. For greater clarity, the structure of the cobalt catalyst used in all these transformations is displayed in the scheme.
The mechanisms of all these transformations follow the classic pathway of the metalloradical catalysis (MRC). The cobalt(II)-porphyrin complex forms the metalloradical species from the corresponding carbonyl, sulfamoyl or phosphoryl azide. A subsequent HAA / rapid radical recombination occurs to yield the corresponding aminated product (Scheme I.28).
Scheme I.28 General mechanism for the metalloradical catalysis (MRC). Example of the formation of a 1,3-diamine starting from a sulfonyl azide derivative.
The group of Zhang explored the possibility to use a Co(II)-porphyrin bearing chiral ligands for asymmetric induction (Scheme I.29). As described in literature, two modes of induction can be involved. The first strategy is to believe that the lifetime of the carbon-centered radical is long- enough and that there is a rapid interconversion between the two pro-chiral faces. One face will react preferentially, and the reaction will be under complete catalyst-control. Two different methods to access chiral 6-
76 76 Part I General Introduction membered ring sulfamides64 or 5-membered ring sulfonamides65 were developed using [Co(P3)] as catalyst Electro-enriched heterocycles for instance are tolerated for this transformation since cyclization at activated α-positions of indole or thiophene process with excellent yield and enantioselectivity. The second strategy is to differentiate one of the two hydrogens during the hydrogen atom abstraction. The catalyst has to be able to perform an enantiodifferentiative hydrogen atom abstraction and the following radical recombination has to be stereorententive. 5-membered ring sulfamides could be obtained using this strategy with the use of the suitable cobalt catalyst [Co(P4)].66 As shown in the selected example, cyclization can process at α-position to a carbonyl with a high yield and enantioselectivity. KIE experiments and calculations were carried out to prove the enantiodifferentiation.
64 C. Li, K. Lang, H. Lu, Y. Hu, X. Cui, L. Wojtas, X. P. Zhang, Angew. Chem. Int. Ed. 2018, 57, 16837–16841. 65 Y. Hu, K. Lang, C. Li, J. B. Gill, I. Kim, H. Lu, K. B. Fields, M. Marshall, Q. Cheng, X. Cui, L. Wojtas, X. P. Zhang, J. Am. Chem. Soc. 2019, 141, 18160–18169. 66 K. Lang, S. Torker, L. Wojtas, X. P. Zhang, J. Am. Chem. Soc. 2019, 141, 12388–12396.
77 Part I General Introduction
Scheme I.29 Chiral cobalt porphyrin complex catalysis through MRC designed by Zhang et.al. for enantioselective intramolecular C(sp3)-H nitrene insertion using sulfamoyl or sulfonyl azide derivatives. The structures of the chiral catalysts are exhibited in the scheme for greater clarity.
The group of Betley displayed a major contribution to the iron-catalyzed amination as mentioned previously but they also described an innovative method for pyrrolidine formation under cobalt catalysis. A close-related cobalt(I) bearing a nonheme dipyrromethane ligand was designed for such a reaction.67 In the presence of an aliphatic azide, a cobalt(III) imido species was identified. It represents the major difference between cobalt and iron
67 Y. Baek, T. A. Betley, J. Am. Chem. Soc. 2019, 141, 7797–7806.
78 78 Part I General Introduction since with the latter an iron(III)-aminyl radical was suggested instead of an iron(IV)-imido species. This cobalt(III) imido species can undergo a HAA and the group found out that it is fasten by the coordination of pyridine derivatives. A radical recombination occurs and as a result, as with the iron catalysis, pyrrolidines could be accessed.
I.4.1.3 Copper-catalyzed C(sp3)-H insertion Copper nitrenoid species can be efficient as well for selective C(sp3)- H amination. In 1967, Kwart and Khan reported amination reactions of cyclohexene while mixing copper powder in excess and benzenesulfonyl azide as nitrogen source.68 Two products could be identified as trace, the typical side-aziridination product and the allylic amination one. Copper nitrenoid species was for the first time reported by the authors as intermediates for the reaction. In 1969, amination of dioxane was reported with the use of copper powder and chloramine-T.69 The authors (Turner et al.) reported the involvement of a copper nitrenoid species as well. Following this idea, the group of Taylor developed a copper(I) chloride catalysis in combination with chloramine-T to perform C(sp3)-H amination of ether derivatives and at other activated benzylic positions (Scheme I.30).70 Nicholas et al. also designed a copper(I) catalysis using chloramine- T.71 The most likely nitrenoid species intermediate for all this transformation is Cu(III)NTs.
68 H. Kwart, A. A. Khan, J. Am. Chem. Soc. 1967, 1950, 1951–1953. 69 D. Carr, T. P. Seden, R. W. Turner, Tetrahedron Lett. 1969, 10, 477–478. 70 D. P. Albone, S. Challenger, A. M. Derrick, S. M. Fillery, J. L. Irwin, C. M. Parsons, H. Takada, C. Taylor, D. J. Wilson, Org. Biomol. Chem. 2005, 3, 107–111. 71 R. Bhuyan, K. M. Nicholas, Org. Lett. 2007, 9, 3957–3959.
79 Part I General Introduction
Scheme I.30 Copper catalysis for intermolecular C(sp3)-H nitrene insertion using chloramine-T designed by Taylor and Nicholas’ group. Selected examples are exhibited for both procedures. Amination of THF and at activated benzylic position were possible and a comparison between the two methods is displayed.
Later, the organic chemist community apply the copper nitrenoid reactivity for aziridination reactions.72 Iminoiodinanes were used as successful nitrene transfer reagents as previously discussed. Evans et al. used oxazolines as ligands to accelerate the aziridination reaction whereas Jacobsen et al. developed Schiff base bis((benzylide)diamino)cyclohexane derivatives. The Pérez group was one of the most active regarding the development of copper nitrenoid catalysis. First, alkene aziridinations were performed using a new class of copper(I) catalyst: the copper(I) tris(pyrazolyl)borates (TpxCu).73 These copper homoscorpionate complexes were really efficient for the olefin aziridinations but could be also used in direct C(sp3)-H amination of cyclohexane (Scheme I.31).74 The method could be extended
72 a) D. A. Evans, M. M. Faul, M. T. Bilodeau, J. Org. Chem. 1991, 56, 6744–6746. b) D. A. Evans, M. M. Faul, M. T. Bilodeau, B. A. Anderson, D. M. Barnes, J. Am. Chem. Soc. 1993, 115, 5328–5329. c) D. A. Evans, M. M. Paul, M. T. Bilodeau, J. Am. Chem. Soc. 1994, 116, 2742–2753. d) C. D. Catalysts, Z. Li, K. R. Conser, E. N. Jacobsen, J. Am. Chem. Soc. 1993, 115, 5326–5327. e) Z. Li, R. W. Quan, E. N. Jacobsen, J. Am. Chem. Soc. 1995, 117, 5889– 5890. f) D. P. Albone, P. S. Aujla, P. C. Taylor, S. Challenger, A. M. Derrick, J. Org. Chem. 1998, 63, 9569–9571. 73 a) P. J. Pérez, M. Brookhart, J. L. Templeton, Organometallics 1993, 12, 261–262. b) M. A. Mairena, M. M. Díaz-Requejo, T. R. Belderraín, M. C. Nicasio, S. Trofimenko, P. J. Pérez, Organometallics 2004, 23, 253–256. 74 M. M. Díaz-Requejo, T. R. Belderraín, M. C. Nicasio, S. Trofimenko, P. J. Pérez, J. Am. Chem. Soc. 2003, 125, 12078–12079.
80 80 Part I General Introduction to amination of ethers and at activated benzylic position with the use of either iminoiodinanes or chloramine-T as nitrene transfer reagents.75
Scheme I.31 Copper(I) tris(pyrazolyl)borates catalysis for intermolecular C(sp3)-H nitrene insertion developed by Pérez et. al. Aminations at non-activated position as well as THF and activated benzylic position could be achieved as depicted in the scheme with the selected examples. The structure of the copper(I) catalyst is displayed for greater clarity.
Other groups such as the group of Warren76 or Stavropoulos77 designed copper(I) catalysts to perform direct C(sp3)-H amination reaction at both activated and non-activated carbon positions. In the work of Warren et al., the azido adamantane represents the nitrogen source and provides in-situ the copper nitrenoid species (Scheme I.32a) whereas the preformed
75 M. R. Fructos, S. Trofimenko, M. M. Díaz-Requejo, P. J. Pérez, J. Am. Chem. Soc. 2006, 128, 11784–11791. 76 a) Y. M. Badiei, A. Dinescu, X. Dai, R. M. Palomino, F. W. Heinemann, T. R. Cundari, T. H. Warren, Angew. Chem. Int. Ed. 2008, 47, 9961–9964. b) S. Wiese, Y. M. Badiei, R. T. Gephart, S. Mossin, M. S. Varonka, M. M. Melzer, K. Meyer, T. R. Cundari, T. H. Warren, Angew. Chem. Int. Ed. 2010, 49, 8850–8855. 77 V. Bagchi, P. Paraskevopoulou, P. Das, L. Chi, Q. Wang, A. Choudhury, J. S. Mathieson, L. Cronin, D. B. Pardue, T. R. Cundari, G Mitrikas, Y. Sanakis, P. Stavropoulos, J. Am. Chem. Soc. 2014, 136, 11362–11381.
81 Part I General Introduction tosyliminoiodinane was used as nitrene transfer for the methodology of Stavropoulos (Scheme I.32b).
Scheme I.32 Copper(I) complexes for intermolecular C(sp3)-H nitrene insertion. Benzylic amination as well as amination at non-activated C(sp3)-H position were carried out as depicted in the selected examples. The structures of the copper(I) catalysts are displayed for greater clarity.
I.4.2 Second-row transition metal catalyzed C(sp3)-H amination
I.4.2.1 Ruthenium catalysis C(sp3)-H insertion The groups of Che and Cenini initiated the development of the ruthenium catalysis for C(sp3)-H amination through nitrene insertion. With the background chemistry of both iron- and manganese-porphyrin catalysts, they successfully tried to transfer the imido group with a
82 82 Part I General Introduction ruthenium(II)-porphyrin catalyst.78 Both groups used a ruthenium(II)- porphyrin complex [Ru(TPFPP)CO] in combination with either tosyliminoiodinane (Scheme I.33a) or 3,5-ditrifluoroazidobenzene (Scheme I.33b) to achieve intermolecular amination of activated benzylic and allylic positions. Later, it was identified that ruthenium(II)-porphyrin complexes could yield bis-nitrene ruthenium(VI)-porphyrin complexes instead of ruthenium(IV).79 Various mechanistic studies have been done to understand the formation and the reactivity of such bis(imido)ruthenium(VI) intermediate that appears to be the active species for the nitrene insertion.80 With this knowledge in hand, intermolecular allylic aminations could be achieved using stoichiometric amount of the preformed bis(imido)ruthenium(VI)-porphyrin complex such as allylic amination of cyclohexene.81
Scheme I.33 Ruthenium(II)-porphyrin complexes for intermolecular C(sp3)-H nitrene insertion at allylic position. The example of the cyclohexene is displayed in the scheme.
78 a) S. Cenini, S. Tollari, A. Penoni, C. Cereda, J. Mol. Catal. A Chemical 1999, 137, 35–146. b) X. Q. Yu, J. S. Huang, X. G. Zhou, C. M. Che, Org. Lett. 2000, 2, 2233–2236. 79 S. Au, J. Huang, W. Yu, W. Fung, C. Che, J. Am. Chem. Soc. 1999, 121, 9120–9132. 80 S. Fantauzzi, E. Gallo, A. Caselli, F. Ragaini, N. Casati, P. Macchi, S. Cenini, Chem. Commun. 2009, 3952–3954. 81 a) S. K. Leung, W. Tsui, J. Huang, C. Che, J. Liang, N. Zhu, J. Am. Chem. Soc. 2005, 127, 16629–16640. b) D. Intrieri, A. Caselli, F. Ragaini, P. Macchi, N. Casati, E. Gallo, Eur. J. Inorg. Chem. 2012, 569–580.
83 Part I General Introduction
Du Bois and co-workers designed a di-ruthenium catalyst that allows intramolecular allylic amination starting from sulfamate esters (Scheme I.34).82 This is a mixed-valent di-ruthenium species bearing a o- hydroxypyridine (hp) ligand. Hypervalent iodine oxidant is used to achieve the in-situ formation of the nitrene. The proposed mechanism, partially elucidated by DFT calculations and control experiments suggested a diruthenium-imidyl diradical species as key intermediate. The optimized conditions allow a remarkable chemoselectivity regarding the olefin aziridination.
Scheme I.34 Mixed-valent diruthenium(II/III) complex for intramolecular C(sp3)-H nitrene insertion designed by Du Bois and co-workers for allylic amination as demonstrated in the selected examples. The structure of the mixed-valent diruthenium(II/III) catalyst is depicted for greater clarity.
Over the last decade, efforts have been made to achieve an enantioselective C(sp3)-H amination using ruthenium catalysis. First, the group of Che developed chiral ruthenium(II)-porphyrin complexes to achieve intermolecular asymmetric amination at benzylic position.47 Unfortunately, the enantioselectivity were modest. Later, Blakey et al. developed an efficient asymmetric intramolecular allylic amination using primary sulfamate esters as nitrene precursors (Scheme I.35a).83 They found out that Pybox was an suitable ligand to transfer chirality yielding chiral sulfamate esters with high enantioselectivities. Therefore, a chiral ruthenium(II) catalyst bearing both Pybox and ethylene as ligands was
82 M. E. Harvey, D. G. Musaev, J. Du Bois, J. Am. Chem. Soc. 2011, 133, 17207–17216. 83 E. Milczek, N. Boudet, S. Blakey, Angew. Chem. Int. Ed. 2008, 47, 6825–6828.
84 84 Part I General Introduction designed for such a reaction. The magnesium oxide added in the reaction mixture is to quench the pivalic acid by-product. Silver triflate was used as co-catalyst probably to in-situ provide a more reactive cationic ruthenium(II) species. An intermolecular version was developed as well by Katsuki et al. with another ruthenium(II) catalyst (Scheme I.35b).84 A chiral salen ligand derivative was designed and implemented at the ruthenium. With such a catalyst, C(sp3)-H amination of activated position such as benzylic or allylic position were carried out. Both the chemoselectivity (no aziridination side- product) and the regioselectivity were completely controlled. As nitrogen source, the (2-trimethylsilyl)ethanesulfonyl azide) (SES-N3) was used. The major advantage of the SES group is its straightforward cleavage. Therefore, using this methodology, chiral primary amines could be synthesized.
84 Y. Nishioka, T. Uchida, T. Katsuki, Angew. Chem. Int. Ed. 2013, 52, 1739–1742.
85 Part I General Introduction
Scheme I.35 Chiral ruthenium(II) complexes for enantioselective intra- and intermolecular C(sp3)-H nitrene insertion. Selected examples have been picked from both methods to highlight their efficiency regarding chiral allylic aminations. The structures of the chiral ruthenium(II) catalysts are depicted for greater clarity.
I.4.2.2 Rhodium catalysis C(sp3)-H insertion Among all the transition metals used for C(sp3)-H nitrene insertion, the methodologies developed with rhodium is by far the most important in terms of scientific contribution. Dirhodium catalysts displayed an outstanding reactivity regarding the transfer of amino group to non- activated C(sp3)-H position.85 The first class of dirhodium catalyst introduced for C(sp3)-H nitrene insertion was the dirhodium tetracarboxylates. The group of Du Bois in 2001 designed an intramolecular amination to yield 5-membered ring carbamate derivatives using dirhodium(II) tetraacetate or triphenyacetate (Scheme I.36a).86 The commercially available hypervalent iodine PIDA was used as oxidant to generate the nitrenoid from the primary carbamate starting materials. Remarkably, both activated benzylic and non-activated aliphatic positions could be targeted and aminated successfully. In the same year, the methodology could be extended to afford cyclic 6-membered ring sulfamate ester derivatives (Scheme I.36b).87 Another dirhodium(II) octanoate was introduced for such a reaction. As in the previous method, both activated and non-activated aliphatic positions could be accessed. Another scientific contribution was published to display the cyclic diatereocontrol of the dirhodium(II) catalysis when a substituent is at the β-position.88 They established models to explain the encountered excellent diastereoselectivities. As an application of this method, the total synthesis of Manzacidin A was successfully achieved where the tertiary enantioretentive C(sp3)-H insertion represents the key step (Scheme I.36c).89 The above methodology was applied as well for the formation of propargylic amines derivatives for instance (Scheme I.36c).90 After a cyclic diastereoselective nitrene insertion
85 a) J. L. Roizen, M. E. Harvey, J. Du Bois, Acc. Chem. Res. 2012, 45, 911–922. b) J. Du Bois, Org. Process Res. Dev. 2011, 15, 758–762. 86 C. G. Espino, J. Du Bois, Angew. Chem. Int. Ed. 2001, 40, 598–600. 87 C. G. Espino, P. M. Wehn, J. Chow, J. Du Bois, J. Am. Chem. Soc. 2001, 123, 6935–6936. 88 P. M. Wehn, J. Lee, J. Du Bois, Org. Lett. 2003, 5, 4823–4826. 89 P. M. Wehn, J. Du Bois, J. Am. Chem. Soc. 2002, 124, 12950–12951. 90 J. J. Fleming, K. W. Fiori, J. Du Bois, J. Am. Chem. Soc. 2003, 125, 2028–2029.
86 86 Part I General Introduction process at α-position of ethers and further activation with a Lewis acid, a subsequent addition of an alkynylzinc reagent yields the corresponding propargylic amine. In all these methods, hypervalent iodine PIDA was used for the oxidative nitrenoid formation and magnesium oxide was added to quench the acid ligand by-product of the dirhodium(II) carboxylate. The crucial feature of these transformations is the possibility of forming in-situ the metal- nitrenoid precursor directly from PIDA. There is no need of any preformation of hypervalent iminoiodinanes. As a result, it is allowing diversification and versatile intramolecular amination.
87 Part I General Introduction
Scheme I.36 Dirhodium(II) catalysis for intramolecular C(sp3)-H nitrene insertion using carboxylate ligands. Carbamates as well as sulfamate esters could be cyclized at both non-activated positions and at benzylic position as depicted in the examples of the scheme. Cyclic diastereocontrol was encountered for such a reaction when the substrate was bearing a substituent at the β-position. Finally, total synthesis of the Manzacidin A could be achieved when the key step is a stereoretentive nitrene insertion. The structures of the dirhodium(II) catalysts are displayed for greater clarity.
88 88 Part I General Introduction
Despite the great reactivity for these systems, the dirhodium(II) carboxylate catalysts suffer from degradation coming from undesirable ligand exchange under the oxidative conditions.91 To improve the stability of such dirhodium(II) catalysts, novel family of ligands were designed. As a result, a new dirhodium(II) complex bearing strapped ligands were developed. For instance, the Bis[rhodium(α,α,α′,α′-tetramethyl-1,3-benzenedipropionic acid)] or simplified [Rh2(esp)2] represents the suitable catalyst for a broader scope and a better catalyst activity (Scheme I.37a). Therefore, further expansion of the substrate scope for dirhodium(II) catalyzed intramolecular C(sp3)-H nitrene insertion could be achieved since cyclization of urea and guanidine derivatives became possible (Scheme I.37b).92 Taking advantage of this new class of catalysts, 1,3-diamine formation could be performed starting from primary sulfamide derivatives.93 Interestingly, the reaction is diastereoselective and enantioretentive. Cyclization of primary carbamates at propargylic position was developed as well with the use of the strap-type ligand by the group of Schomaker.94 Finally and as unique example of azidobenzene as substrate for rhodium catalysis, indolines could be synthesized starting from the azido-2-(tert-butyl)benzene derivatives.95
91 C. G. Espino, K. W. Fiori, M. Kim, J. Du Bois, J. Am. Chem. Soc. 2004, 126, 15378–15379. 92 M. Kim, J. V. Mulcahy, C. G. Espino, J. Du Bois, Org. Lett. 2006, 8, 1073–1076. 93 T. Kurokawa, M. Kim, J. Du Bois, Angew. Chem. Int. Ed. 2009, 48, 2777–2779. 94 R. D. Grigg, J. W. Rigoli, S. D. Pearce, J. M. Schomaker, Org. Lett. 2012, 14, 280–283. 95 Q. Nguyen, K. Sun, T. G. Driver, J. Am. Chem. Soc. 2012, 134, 7262–7265.
89 Part I General Introduction
Scheme I.37 Dirhodium(II) catalysis for intramolecular C(sp3)-H nitrene insertion using the more efficient and robust over oxidative condition [Rh2(esp)2]. The scope could be extended as depicted with the selected examples of urea, guanidine derivative and sulfamide. Example of propargylic amination as well as indoline formation are also displayed in the scheme to show the diversity of reaction that can use [Rh2(esp)2]. The structure of the [Rh2(esp)2] is exhibited for greater clarity.
90 90 Part I General Introduction
Using the dirhodium(II) complex bearing strap-type ligand [Rh2(esp)2], the group of Du Bois96 and Bach97 demonstrated its superiority in terms of catalytic activity and broad substrate scope in intermolecular C(sp3)-H amination as well (Scheme I.38a). 2,2,2-trichloroethoxysulfamide (Tces) or 2,6-difluorophenyl sulfamate (Dfs) (Scheme I.38b) were suitable nitrogen sources for the intermolecular amination. Excellent selectivities were encountered even in the presence of multiple tertiary carbon centres in the case of Du Bois’ method. Recently, Du Bois and co-workers designed a late- stage intermolecular C(sp3)-H amination on complex molecules.98
96 a) K. W. Fiori, J. Du Bois, J. Am. Chem. Soc. 2007, 129, 562–568. b) J. L. Roizen, D. N. Zalatan, J. Du Bois, Angew. Chem. Int. Ed. 2013, 52, 11343–11346. 97 A. Nörder, P. Herrmann, E. Herdtweck, T. Bach, Org. Lett. 2010, 12, 3690–3692. 98 N. D. Chiappini, J. B. C. Mack, J. Du Bois, Angew. Chem. Int. Ed. 2018, 57, 4956–4959.
91 Part I General Introduction
Scheme I.38 Dirhodium catalysis for intermolecular C(sp3)-H nitrene insertion amination using [Rh2(esp)2]. The superiority in terms of catalytic activity of [Rh2(esp)2] has been proved for intermolecular amination. Selected examples have been picked to demonstrate the versatility of such catalyst even for late-stage aminations reaction.
One of the major concerns about nitrene insertion is the regioselectivity prediction in intermolecular reaction. When you offer a tertiary position versus a benzylic position for instance, which of the two will react? Or, will you recover a mixture of the two aminated products? Du Bois and Sigman together were able to predict theoretically the regioselectivity developing a mathematical formula based on computed infrared signals.99 They compared the obtained experimental results with the theoretical and depending on the group attached at the oxygen of the sulfamate ester nitrogen source, the ratio between the benzylic versus the tertiary amination differs. As a result, tuning the nitrogen source yield to either benzylic amination or tertiary amination.
We previously mentioned that the strapped ligand had an important influence on the catalytic activity. One of the reason is that the dirhodium(II) catalyst bearing strap-type ligand is more stable in the presence of hypervalent iodine oxidant. On the contrary, the dirhodium(II) carboxylates suffer from complex degradation in the same condition. + Importantly, formation of the mixed-valent dirhodium(II/III) [Rh2(esp)2] was observed and works as active intermediate in the intermolecular amination reaction.100 Thanks to this discovery, two pathways presumably take place.101 Either a direct traditional formation of the metal nitrenoid intermediate from the iminoiodinane takes place or the oxidized species + [Rh2(esp)2] facilitates the nitrenoid transfer by sequential proton electron transfer (PCET). For the latter, PIDA by a single electron transfer oxidizes + the dirhodium(II) catalyst to the mixed-valent [Rh2(esp)2] . A subsequent addition of the primary sulfonamide and a second PCET process occurs to afford the metal nitrenoid species. The group of Berry developed also a new class of ligand for the dirhodium catalyst. Instead of the carboxylate strap-ligand esp that we explained their plausible weaknesses regarding the oxidative condition, they designed a
99 E. N. Bess, R. J. Deluca, D. J. Tindall, M. S. Oderinde, J. L. Roizen, J. Du Bois, M. S. Sigman, J. Am. Chem. Soc. 2014, 136, 5783–5789. 100 D. N. Zalatan, J. Du Bois, J. Am. Chem. Soc. 2009, 131, 7558–7559. 101 K. P. Kornecki, J. F. Berry, Chem. Eur. J. 2011, 17, 5827–5832.
92 92 Part I General Introduction
more efficient mixed-valent rhodium(II/III) Rh2(espn)2Cl where esp was substituted by the close-related carboxamide espn that often stabilize the high valent metal complexes.102 It results to an increase of the catalyst performance for instance exhibited higher turnover numbers for intramolecular cyclization of primary sulfamate ester derivatives.
Regarding the mechanism of the nitrene insertion into the C-H bond, the community remains unclear even if several investigations were carried out to prove the concerted C-H insertion to be the most plausible pathway.
Efforts have been made towards asymmetric C-H insertion reaction. A bench a chiral carboxylates or carboxamides ligands were designed and installed at the dirhodium(II) catalyst. For both inter- or intramolecular asymmetric amination, the group of Davies and Du Bois developed two efficient chiral catalysts, one based on a chiral carboxylate ligand103 derived from adamantylglycine (Scheme I.39a) and the other from a chiral carboxamide104 derived from 2-piperidonate (Scheme I.39b). The chiral catalyst developed by Davies et at. could be employed as well for intermolecular asymmetric amination. The group of Dauban developed diastereoselective C(sp3)-H amination combining a chiral dirhodium(II) catalyst and a chiral sulfonimidamide moiety (Scheme I.39c).105 They could use their methods for amination of complex molecules putting in evidence the robustness of their protocol.106 Chiral carbamates nitrogen sources were developed as well for diastereoselective intermolecular amination for both allylic and benzylic positions by the group of Lebel.107 Finally, the Bach group designed a chiral rhodium catalyst enabling strong hydrogen bonding with the substrate thus influencing the C-H insertion step.108
102 K. P. Kornecki, J. F. Berry, Chem. Commun. 2012, 48, 12097–12099. 103 R. P. Reddy, H. M. L. Davies, Org. Lett. 2006, 8, 5013–5016. 104 D. N. Zalatan, J. Du Bois, J. Am. Chem. Soc. 2008, 130, 9220–9221. 105 a) C. Liang, F. Robert-Peillard, C. Fruit, P. Müller, R. H. Dodd, P. Dauban, Angew. Chem. Int. Ed. 2006, 45, 4641–4644. b) C. Liang, F. Collet, F. Robert-Peillard, P. Müller, R. H. Dodd, P. Dauban, J. Am. Chem. Soc. 2008, 130, 343–350. 106 C. Lescot, B. Darses, F. Collet, P. Retailleau, P. Dauban, J. Org. Chem. 2012, 77, 7232– 7240. 107 a) H. Lebel, C. Trudel, C. Spitz, Chem. Commun. 2012, 48, 7799–7801. b) H. Lebel, C. Spitz, O. Leogane, C. Trudel, M. Parmentier, Org. Lett. 2011, 13, 5460–5463. 108 T. Höke, E. Herdtweck, T. Bach, Chem. Commun. 2013, 49, 8009–8011.
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Scheme I.39 Asymmetric dirhodium(II) catalysis for inter- and intramolecular C(sp3)-H nitrene insertion. Selected examples were picked to illustrate the excellent enantioselectivities encountered for such reaction conditions. The structures of the chiral dirhodium(II) catalysts are displayed for greater clarity.
94 94 Part I General Introduction
I.4.2.3 Silver catalysis C(sp3)-H insertion Silver catalysis has barely been used for nitrene insertion chemistry, but some methodologies can be found in literature. For instance, the group of He developed a dimeric silver catalyst which is able to dramatically increase the efficiency of the amination reaction (Scheme I.40a).109 Its in- situ formation can be performed from silver nitrate and the corresponding t designed ligand 4,4’,4’’- Bu3tpy. With this catalyst, primary carbamate as well as sulfamate ester derivatives could be cyclized using PIDA as oxidant for the silver-nitrenoid formation. For relative intermolecular nitrene insertion, another dimeric silver(I) catalyst was designed by the same group.110 They found out that bathophenanthroline was the suitable ligand for the effectiveness of the reaction. To circumvent the common chemoselectivity issue in the nitrogen transfer chemistry at allylic positions, the group of Schomaker developed a strategy in which depending on the amount of ligand in the reaction mixture, either olefin aziridination or C-H insertion was favored (Scheme I.40b).111 Using a ratio close to one to one between silver triflate and 1,10-phenanthroline, the aziridination is favored whereas a ratio of one to three exclusively provides the C-H insertion. It was concluded that the silver(I) catalyst is more congested surrounding by two 1,10-phenathroline ligands thus promoting the C-H insertion process.
109 Y. Cui, C. He, Angew. Chem. Int. Ed. 2004, 43, 4210–4212. 110 Z. Li, D. A. Capretto, R. Rahaman, C. He, Angew. Chem. Int. Ed. 2007, 46, 5184–5186. 111 J. W. Rigoli, C. D. Weatherly, J. M. Alderson, B. T. Vo, J. M. Schomaker, , J. Am. Chem. Soc. 2013, 135, 17238–17241.
95 Part I General Introduction
Scheme I.40 Silver(I) catalysis for intramolecular C(sp3)-H nitrene insertion. Selected examples of sulfamate ester and carbamate cyclization are depicted in the scheme. For greater clarity, the structures of the silver(I) catalysts are displayed.
I.4.3 Third-row transition metal catalyzed C(sp3)-H amination: the case of iridium and gold Among all the developed methods for C(sp3)-H nitrene insertion, the third-row transition metals have not received a lot of attention. Examples can be find using iridium or gold catalysis. For intramolecular C(sp3)-H insertion, the group of Driver used the iridium(I) catalyst [(COD)Ir(OMe)]2 that demonstrated to be effective for the formation of the iridium-nitrenoid from aryl azides to form indoline
96 96 Part I General Introduction derivatives (Scheme I.41a).112 Benzylic C(sp3)-H bonds were reactive towards the iridium-nitrenoid intermediate for the C(sp3)-H insertion. The group of Katsuki presented an asymmetric C(sp3)-H amination using a chiral (salen)iridium(III) complex.113 They were inspired by their precedent ruthenium catalysis.84 High enantiomeric excesses were obtained for intramolecular C(sp3)-H insertion at benzylic position starting with both sulfonyl and sulfamoyl azides. Regarding gold catalysis, Feng and co-workers reported a procedure in which an intermolecular C(sp3)-H nitrene insertion using a gold(III) catalyst (Scheme I.41b).114 This procedure represents the unique reactivity of gold species towards C(sp3)-H nitrene insertion reaction. In this method, tosylamide was used a nitrogen source and NBS as oxidant. While reacting together, a N-bromotosylamide is formed in-situ. They proposed that trace of gold(I) may react with the latter for the formation of the gold-nitrogen bond. Subsequent loss of bromide yields the key gold(III)-nitrenoid species enabling benzylic amination. Interestingly, the bipyridine ligand is crucial for the reactivity to be excellent whereas the most common triphenylphosphine was not effective for instance.
112 K. Sun, R. Sachwani, K. J. Richert, T. G. Driver, Org. Lett. 2009, 11, 3598–3601. 113 M. Ichinose, H. Suematsu, Y. Yasutomi, Y. Nishioka, T. Uchida, T. Katsuki, Angew. Chem. Int. Ed. 2011, 50, 9884–9887. 114 Y. Zhang, B. Feng, C. Zhu, Org. Biomol. Chem. 2012, 10, 9137–9141.
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Scheme I.41 Iridium(I), chiral iridium(III) or gold(III) catalysis for inter- and intramolecular C(sp3)-H nitrene insertion. Selected examples have been depicted to show the diversity of the obtained products (cyclic sulfonamide, chiral sulfamide and intermolecular benzylic amination). The structures of the active catalysts are displayed for greater clarity.
I.5 Other transition metal mediated C(sp3)-H amination
Transition metal can be used for C(sp3)-H activation and for C(sp3)- H insertion for amination. In addition, transition metals can also be used to generate N-centered radicals by activation of a N-X bond.
I.5.1 N-F activation for C(sp3)-H amination
98 98 Part I General Introduction
In literature, copper is well-explored regarding its capacity to facilitate the activation of the N-F bond and subsequent formation of the N- centered radical. Its activation is facilitated when an electronwithdrawing group is attached at the nitrogen such as sulfonyl group. The N-centered radical generated can undergo a selective 1,n-hydrogen atom transfer to generate a C-centered radical usually further oxidized by the copper catalyst to a carbocation. Different groups could be implemented at this position 115 116 117 118 such as -CF3, SeCF3, SCF3, Ar (via a cross-coupling reaction), or CN . Our group in collaboration with the group of Pérez designed a copper catalysis for the formation of both pyrrolidines and piperidines (Scheme I.42a).119 A copper(I) tris(pyrazolyl)borate bearing two isopropyl groups at the pyrazole (TpiPr2Cu) was identified as the most efficient catalyst for such a transformation. DFT calculations were performed as well to have evidences of the mechanism. It was strongly believed that there is no oxidative addition from the copper(I) species. Instead, the copper(I) species is reducing the N-F bond to yield the N-centered radical and a copper(II) fluoride species. A subsequent 1,5- or 1,6-HAT (hydrogen atom transfer) occurs to generate the C-centered radical. A concerted radical recombination was proposed at this stage to yield the aminated product. As we discussed previously, copper(I) can activate N-F bond of sulfonamides. For instance, copper(I) chloride in association with phenantroline can activate NFSI for a benzylic intermolecular C(sp3)-H amination (Scheme I.42b).120 The mechanism is relatively close to the intramolecular approach since the copper(I) chloride reduces NFSI to form the bis-sulfonamidyl radical. A HAA occurs at the benzylic position followed by an oxidation to a carbocation by the copper(II) previously formed. Nucleophilic addition of the bis-benzenesulfonamide provides the final aminated product.
115 Z. Liu, H. Xiao, B. Zhang, H. Shen, L. Zhu, C. Li, Angew. Chem. Int. Ed. 2019, 58, 2510– 2513. 116 A. Modak, E. N. Pinter, S. P. Cook, J. Am. Chem. Soc. 2019, 141, 18405–18410. 117 E. Article, Z. Zhang, L. M. Stateman, D. A. Nagib, Chem. Sci. 2019, 10, 1207–1211. 118 a) Z. Zhang, X. Zhang, D. A. Nagib, Chem 2019, 5, 3127–3134. b) H. Zhang, Y. Zhou, P. Tian, C. Jiang, Org. Lett. 2019, 21, 1921–1925. 119 D. Bafaluy, J. M. Muñoz-Molina, I. Funes-Ardoiz, S. Herold, A. J. de Aguirre, H. Zhang, F. Maseras, T. R. Belderrain, P. J. Pérez, K. Muñiz, Angew. Chem. Int. Ed. 2019, 58, 8912– 8916. 120 Z. Ni, Q. Zhang, T. Xiong, Y. Zheng, Y. Li, H. Zhang, J. Zhang, Q. Liu, Angew. Chem. Int. Ed. 2012, 51, 1244–1247.
99 Part I General Introduction
Scheme I.42 Copper(I) catalysis for N-F activation and intra- or intermolecular C(sp3)- H amination. Key intermediates were calculated and depicted in the scheme for the intramolecular amination. Selected examples are displayed to highlight the diversity of the obtained products. The structure of the copper(I) catalyst used is exhibited for greater clarity.
Palladium can also be used for intermolecular benzylic amination in association with NFSI (Scheme I.43).121 After the palladium coordination with an amide directing group placed in para position of the toluene’s methyl targeted group, an oxidative addition with NFSI occurs to reach a palladium(IV) species. The latter being an excellent nucleofuge, a dearomatized intermediate is formed enabling the nucleophilic addition of the bis-benzenesulfonamide at the methylene group. Therefore, an intermolecular benzylic amination product is achieved at the para position of the amide directing group.
121 T. Xiong, Y. Li, Y. Lv, Q. Zhang, Chem. Commun. 2010, 46, 6831–6833.
100 100 Part I General Introduction
Scheme I.43 Palladium(II) catalysis for N-F activation and intermolecular C(sp3)-H amination. Key intermediates are depicted for greater clarity of the mechanism and an example is also displayed.
I.5.2 Metal-mediated non-directed amination (free radical generation) The generation of free-radical is often synonym of regioselectivity issue since the differentiation of inert C(sp3)-H bond is difficult. Nevertheless, if the targeted C(sp3)-H bond is at an activated position meaning that its BDE is lower than the others, the regioselectivity issue can be overcome. The association of certain transition metal with peroxides can provide free radicals. For instance, iron(II) or copper(II) in combination with DTBP was investigated to achieve intermolecular amination at activated benzylic position and of ether derivatives (Scheme I.44).122 Both iron(II) chloride and copper(II) chloride can be oxidized at high temperature by DTBP to the corresponding iron(III) and copper(III) species. DTBP at high temperature forms two free tert-butyl alcohol radicals. One will perform a hydrogen atom abstraction at the most activated position (at the lowest BDE) and the other will oxidize the metal(II) to metal(III) by a single electron transfer. The benzylic radical, oxidized by the metal(III) to a carbocation through a single electron transfer is now a strong electrophile. A subsequent nucleophilic addition occurs to form the C-N bond. Therefore, the encountered selectivity is here explained
122 a) Q. Yang, P. Y. Choy, W. C. Fu, B. Fan, F. Y. Kwong, J. Org. Chem. 2015, 80, 11193– 11199. b) Q. Xia, W. Chen, H. Qiu, J. Org. Chem. 2011, 76, 7577–7582.
101 Part I General Introduction by the fact that the hydrogen abstraction occurs at the weakest C-H bond with the lowest BDE.
Scheme I.44 Mechanism of the iron(II) or copper(II) catalyst in combination with DTBP for free radical generation and intermolecular C(sp3)-H amination. Various nitrogen sources can be employed as demonstrated for the selected examples displayed in the scheme.
I.6 Electrochemistry for C(sp3)-H amination
Another modern approach for selective C(sp3)-H amination reactions is to perform electrochemical aminations. Various strategies inside the electrochemical field can be determined. Without any use of electrochemical mediators, the electrode potential required is quite high.
102 102 Part I General Introduction
For instance, the redox potentials for a phenyl moiety oxidation is about 1.8
V vs. Ag/AgNO3 and for a tosylamide group is around 2 V vs. Ag/AgNO3. Our group designed an electrochemical amination using the strategy of the anodic oxidation of the aryl group (Scheme I.45a).123 A subsequent loss of a benzylic proton generates a benzylic radical. A second anodic oxidation occurs to reach the stabilized benzylic carbocation. After a final cyclization step, sulfonyl-protected pyrrolidines as well as piperidines could be achieved. The two major limitations of this strategy are the requirements of a benzylic position and of a relatively high electrode potential which is not functional-group tolerant. To circumvent the benzylic position restriction, the group of Lei developed an electrochemical proton-coupled electron transfer (PCET) strategy (Scheme I.45b).124 It is relatively easier to oxidize a deprotonated sulfonamide than an aryl group. Therefore, they were able to form a N-centered radical under electrochemical conditions. This crucial intermediate directs the formation of the C-centered radical through a 1,5- HAT. Another anodic oxidation occurs to form the corresponding carbocation. A subsequent cyclization event allows the pyrrolidine derivative formations. One limitation was circumvented but it still remains the issue of the high electrode potential that is not compatible with functional-group tolerance. To overcome the latter, electrochemical mediators can be implemented to the reaction conditions to decrease the electrode potential. Bromide salt125 as well as iodide126 could be used for such a reaction. The bromide or iodide salts mediators are getting oxidized to the anode at lower electrode potential since their oxidation potential are lower (0.7 V vs Fc/Fc+ for bromide and 0.4 V vs Fc/Fc+ for iodide). Therefore, elemental bromine or iodine is formed at the anode electrode. The detailed mechanism of the iodide-mediated electrochemical C(sp3)-H amination will be presented in the chapter III of this thesis.
123 S. Herold, D. Bafaluy, K. Muñiz, Green Chem. 2018, 20, 3191–3196. 124 X. Hu, G. Zhang, F. Bu, L. Nie, A. Lei, ACS Catal. 2018, 8, 9370–9375. 125 a) T. Shono, Y. Matsumura, S. Katoh, K. Takeuchi, K. Sasaki, T. Kamada, R Shimizu, J. Am. Chem. Soc. 1990, 112, 2368–2372. b) S. Zhang, L. Li, M. Xue, R. Zhang, K. Xu, C. Zeng, Org. Lett. 2018, 20, 3443–3446. 126 F. Wang, S. S. Stahl, Angew. Chem. Int. Ed. 2019, 58, 6385–6390.
103 Part I General Introduction
Scheme I.45 Electrochemical processes for intramolecular C(sp3)-H amination. Selected examples have been displayed to show the complementarity of these two methods.
104 104 Part I General Introduction
I.7 N-centered radical directed C(sp3)-H amination via hydrogen atom abstraction
The last strategy that can be employed for C(sp3)-H amination reaction is to guide the amination process through a 1,n-HAT from a N- centered radical.127 In the following paragraph, we will present the plausible pathways to generate such N-centered radicals.
I.7.1. Generation of the N-centered radical from photoredox catalyst In literature, the most common way to obtain the usually non-stable N-centered radical is to use photochemistry.128 To generate such a species, a pre-functionalization is often required to provide under photochemistry conditions the desired N-centered radical (Scheme I.46a). For instance, hydroxylamine derivatives are excellent precursors and commonly used for nitrogen radical generation (Scheme I.46b).129 The N-O bond is relatively weak (BDE of the N-O of about 50 kcal/mol compared with 80 kcal/mol for the BDE of the N-H). To use photochemistry to form the looked-for N- centered radical, an electrophore is implemented at the oxygen atom of the hydroxylamine. After reduction or oxidation of it by single electron transfer from the photoredox catalyst, the generation of the desired N-centered radical is possible. The group of Nagib developed a N-centered radical precursor based on a hydroxylamine for the generation of amidate radical. Reduction of such species by a iridium-based photoredox catalyst leads to the N-centered radical.130 The group of Leonori developed a plethora of methods employing hydroxylamine derivatives to generate in-situ iminyl, amidyl or aminium radical.131 An aromatic electron-withdrawing group moiety (electrophore)
127 a) G. Kumar, S. Pradhan, I. Chatterjee,Chem. Asian. J. 2020, 15, 1–23. b) L. M. Stateman, K. M. Nakafuku, D. A. Nagib, Synthesis 2018, 50, 1569–1586 128 M. D. Kärkäs, ACS Catal. 2017, 7, 4999–5022. 129 J. Davies, S. P. Morcillo, J. J. Douglas, D. Leonori, Chem. Eur. J. 2018, 24, 12154–12163. 130 a) K. M. Nakafuku, S. C. Fosu, D. A. Nagib, J. Am. Chem. Soc. 2018, 140, 11202–11205. b) K. M. Nakafuku, Z. Zhang, E. A. Wappes, L. M. Stateman, A. D. Chen, D. A. Nagib, Nat. Chem. 2020, doi.org/10.1038/s41557-020-0482-8. 131 a) J. Davies, S. G. Booth, S. Essafi, R. A. W. Dryfe, D. Leonori, Angew. Chem. Int. Ed. 2015, 54, 14017–14021. b) J. Davies, T. D. Svejstrup, D. Fernandez Reina, N. S. Sheikh, D.
105 Part I General Introduction was implemented at the hydroxylamine thus facilitating its reduction under photochemistry. Either Eosin Y or Ru(bpy)3Cl2 was used to reduce by single electron transfer (SET) this electron-poor aromatic (electrophore) bearing two nitro groups at the ortho and meta positions. The generated radical anion collapses to homolitically break the N-O bond thus forming iminyl, amidyl or aminium radicals. The driving force of the homolytic cleavage is the formation of stable radical anion of the electrophore. Cristina Nevado and co-workers developed another type of hydroxylamine to generate the desired N-centered radical.132 Another electrophore was used but the mechanism of the formation of the N-centered radical remains equal. Reduction of the electrophore by the Ir(ppy)3 generates iminyl radical. Finally, another type of electrophore was introduced by Leonori et.al. that under oxidative condition forms iminyl or amidyl radicals.133 The α-N- oxyacids require a single electron transfer oxidation to generate the carboxyl radical. A subsequent decarboxylation followed by a β-scission releasing acetone provides the N-centered radical. Another strategy has been developed recently using photoredox chemistry to form amidyl radicals. The group of Rovis and Knowles designed a method in which the proton-coupled electron transfer (PCET) mechanism is used (Scheme I.46c).134 The general reactivity of such nitrogen-centered radical is well-known (Scheme I.46d). First, in the internal presence of an alkene or an alkyne moiety, a 5-exo-trig(dig) cyclization can occur.131c This radical can undergo
Leonori, J. Am. Chem. Soc. 2016, 138, 8092–8095. c) D. F. Reina, E. M. Dauncey, S. P. Morcillo, T. D. Svejstrup, M. V. Popescu, J. J. Douglas, N. S. Sheikh, D. Leonori, Eur J. Org. Chem. 2017, 2108–2111. d) T. D. Svejstrup, A. Ruffoni, F. Juliá, V. M. Aubert, D. Leonori, Angew. Chem. Int. Ed. 2017, 56, 14948–14952. 132 W. Shu, C. Nevado, Angew. Chem. Int. Ed. 2017, 56, 1881–1884. 133 a) J. Davies, N. S. Sheikh, D. Leonori, Angew. Chem. Int. Ed. 2017, 56, 13361–13365. b) S. P. Morcillo, E. M. Dauncey, J. H. Kim, J. J. Douglas, N. S. Sheikh, D. Leonori, Angew. Chem. Int. Ed. 2018, 57, 12945–12949. c) E. M. Dauncey, S. P. Morcillo, J. J. Douglas, N. S. Sheikh, D. Leonori, Angew. Chem. Int. Ed. 2018, 57, 744–748. d) E. M. Dauncey, S. U. Dighe, J. J. Douglas, D. Leonori, Chem. Sci. 2019, 10, 7728–7733. e) L. Angelini, L. Malet Sanz, D. Leonori, Synlett 2020, 31, 37–40. f) J. H. Kim, A. Ruffoni, Y. S. S. Al-Faiyz, N. S. Sheikh, D. Leonori, Angew. Chem. Int. Ed. 2020, 59, 8225–8231. 134 Examples of PCET mechanism for the formation of the N-centered radical. a) J. C. K. Chu, T. Rovis, Nature 2016, 539, 272–275. b) G. J. Choi, Q. Zhu, D. C. Miller, C. J. Gu, R. R. Knowles, Nature 2016, 539, 268–271. c) D. F. Chen, J. C. K. Chu, T. Rovis, J. Am. Chem. Soc. 2017, 139, 14897–14900. d) C. B. Roos, J. Demaerel, D. E. Graff, R. R. Knowles, J. Am. Chem. Soc. 2020, 142, 5974–5979.
106 106 Part I General Introduction a selective 1,n-HAT as well or when a iminyl or amidate radical is formed, a Norrish fragmentation can take place. Also, a nitrogen-centered radical can add to a π-system. In the work of MacMillan for instance, the latter is adding to a chiral enamine moiety.135 They designed a hydroxylamine derivative (N-methyl-N- dinitrophenylsulfonyloxycarbamates) bearing an electrophore that does not need photoredox catalyst to undergo the homolytic cleavage of the N-O bond. The excited state of such species weakens the N-O bond. They proposed a radical chain mechanism in which the initiation step is the light- induced homolytic cleavage of the latter. Then, after the addition of the electrophilic nitrogen-centered radical into the enriched chiral enamine (formed from the condensation between a chiral imidazolidinone and an aldehyde), the newly formed carbon-centered radical can undergo a SET to another hydroxylamine in its excited state providing both the chiral iminium salt and a new nitrogen-centered radical. Final hydrolysis of the iminium affords the corresponding enantioselective α-aminated aldehyde.
135 G. Cecere, C. M. König, J. L. Alleva, D. W. C. MacMillan, J. Am. Chem. Soc. 2013, 135, 11521–11524.
107 Part I General Introduction
Scheme I.46 Presentation of the various nitrogen-centered radicals. Their obtention from either hydroxylamine derivatives or proton-coupled electron transfer mechanism are displayed. The general reactivity of such radicals are depicted as well in the scheme.
I.7.2. The Hofmann-Löffler reation One of the most famous strategy to achieve the nitrogen-centered radical is the homolytic cleavage of a nitrogen-halogen bond. The first chemist who discovered such a feature is August Wilhelm von Hofmann in 1885. He submitted a pre-brominated piperidine starting material to extremely harsh acidic and thermal conditions. He identified the formation of a new product corresponding to a selective amination affording the
108 108 Part I General Introduction
Conine (Scheme I.47a).136 The mechanism of investigated later by Corey and it was suggested a radical chain mechanism.137 The protonation is here playing a double crucial role. First, it destabilizes the N-Br bond which becomes easier to break. Then, the nitrogen-centered radical generated (aminium) is electrophilic and less stable than its close related aminyl radical. Therefore, a selective 1,5-HAT can occur to provide the primary carbon-centered radical that gets brominated. After a basic work-up, further cyclization furnishes the Conine. Later, Löffler applied this new reactivity to the total synthesis of the nicotine (Scheme I.47b).138
Scheme I.47 Origin of the Hofmann-Löffler reaction with the discovery of a new selective amination starting from a brominated amine. Extremely harsh conditions were used. The mechanism was elucidated by Corey in 1960.
As presented above, this reaction requires strong conditions that are not compatible with the modern chemistry. As a result, the so-called Hofmann-Löffler reaction have been attracted the synthetic chemist
136 W. Hofmann, Ber. Dtsch. Chem. Ges. 1885, 18, 5–23. 137 E. J. Corey, W. R. Hertler, J. Am. Chem. Soc. 1960, 82, 1657–1668. 138 K. Löffler, Ber. Dtsch. Chem. Ges. 1910, 43, 2035.
109 Part I General Introduction community for the last decades. Further investigations have been carried out to develop mild reaction condition to be more functional group tolerant. The following chapters will present in their respective introduction part several methods designed over the last years regarding the homolytic cleavage of N-halogen bonds and subsequent amination reaction.
110 110 Main aims and objectives
Main aims and objectives
In the present thesis, we aimed to develop new functionalization reaction using halogen catalysis. To begin with, we aimed to design catalysis for the Hofmann-Löffler reaction to access pyrrolidine formation. To do so, the objective was to find a suitable system in which the pre-formation of the N-X bond is avoided. Then, the aim was to find a suitable protecting group at the nitrogen atom to destabilize the N-X bond under visible light irradiation. After its homolytic cleavage, this protecting group should be helping the 1,5-HAT as well to proceed. Finally, a terminal oxidant should play the role of re-oxidizing the halogen catalyst to close the catalytic cycle. This represents the major difficulty since we do not want to have side-halogenation event due to overoxidation of the halogen catalyst. Also, we aimed to be as green as possible avoiding transition metal and strong oxidant. With this idea in hand, we aimed to install the C-N bond in both activated carbon position and non-activated ones. To circumvent the issue of the leaving group capacity of the halogen that could be an issue for the catalysis to proceed in the case of targeted non- activated carbon, we aimed to design a catalysis in which an hypervalent iodine(III) could be the nucleofuge. Another aim of the thesis was to explore the mechanism and the limitation of such a reaction with experimental control experiments and DFT calculations. Finally, the aim was also to explore intermolecular amination event through the Hoffman-Löffler manifold. The goal was to find a suitable directing group which is not enough nucleophilic to provide a cyclized compound. Thus, an external amination can occur.
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Part II Engineering Bromide Catalysis for C(sp3)-H Functionalization
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114 Part II Engineering Bromide Catalysis for C(sp3)-H Functionalization
Part II Engineering Bromide Catalysis for C(sp3)-H Functionalization
II.1 Introduction
II.1.1 Why halogen catalysis? In the field of C(sp3)-H amination, a plethora of strategies and catalyzes were developed to overcome issues such as the regio- or chemoselectivity or the high BDEs of the C(sp3)-H bonds.139 Myriad of transition metal catalyzed protocols were published so far but some catalysts remains expensive, toxic, non-ecofriendly or even extracted in a non-ethical way (gold for instance). Regarding the prizes, a quick comparison between palladium acetate (mostly used in C-H activation, > 90 € / gr), manganese (> 50 € / gr for the manganese(III)-phthalocyanine catalyst for the nitrene transfer methods of White), rhodium (> 500 € / gr for the Rh2(esp)2 for nitrene transfer chemistry as well) and tert-butylammonium bromide (< 1 € / gr) or molecular iodine (< 6 € / gr) is sufficient to conclude with common sense that the halogen catalysis is more economic that the use of transition metal catalysts. Another issue of transition metal is that some of them are in a rising threat of disappearance because of their increased use such as rhodium, ruthenium, cobalt or iridium. The toxicities of the transition metal are much higher than for the bromide salts or for the molecular iodine. Halogen catalyst are eco-friendlier, less contaminating the environment. In terms of atom-economy also, the designed halogen catalysts are producing less waste in term of weight. The
139 a) H. M. L. Davies, M. S. Long, Angew. Chem. Int. Ed. 2005, 44, 3518–3520. b) J. L. Roizen, M. E. Harvey, J. Du Bois, Acc. Chem. Res. 2012, 45, 911–922. c) H. M. L. Davies, J. Du Bois, J. Yu, F. Collet, C. Lescot, P. Dauban, F. Collet, Chem. Soc. Rev 2011,40, 1926– 1936. d) F. Collet, R. H. Dodd, P. Dauban, Chem. Commun. 2009, 5061–5074. e) Y. Park, Y. Kim, S. Chang, Chem. Rev. 2017, 117, 9247–9301. f) H. M. L. Davies, J. Du Bois, J. Yu, Chem. Soc. Rev. 2011, 40, 1855–1856.
115 Part II Engineering Bromide Catalysis for C(sp3)-H Functionalization molecular weight of the transition metal catalysts with their ligands is higher than the tetrabutylammonium bromide or iodine for instance. Finally, when the product is a potential active molecule that has to be tested on animals, it has to be as pure as possible without any metal contaminants. In a late-stage transition catalyzed amination for instance, it might be an issue that the used catalyst contaminates the final product. The halogen catalysis is less risky in terms of contamination since the catalysts themselves are non-toxic, even inoffensive.
II.1.2 Introduction to the bromine catalysis for amination reaction The bromine catalysis remains in its infancy. In literature, few examples can be found for C(sp2)-H amination such as aziridination of alkenes designed by Sharpless in 1998.140 An ammonium tribromide salt was used as catalyst and chloramine-T as nitrogen source (Scheme II.1). The mechanism was partially investigated regarding for instance the active brominating species. It was supposed that the tribromide is reacting first with the chloramine-T to in-situ generate the N-Br bond which undergo bromination of the alkene forming the corresponding bromonium species. Then, the chloramine-T counter-anion undergoes a nucleophilic substitution to afford the amino-brominated intermediate. A final cyclization occurs to achieve the aziridine’s formation and to close the catalytic cycle.
140 J. U. Jeong, B. Tao, I. Sagasser, H. Henniges, K. B. Sharpless, J. Am. Chem. Soc. 1998, 120, 6844–6845.
116 Part II Engineering Bromide Catalysis for C(sp3)-H Functionalization
Scheme II.1 Aziridination reaction developed by Sharpless et.al. using PTAB in catalytic amount. A plausible mechanism is presented.
Our group, interested in designing new halogen catalysis, developed a bromide catalyzed intramolecular diamination of alkenes (Scheme II.2).141 An hypervalent iodine(III) or hypochlorite were used as oxidant to in-situ generate acyl hypobromite(I) from potassium bromide. This key “Br+” species undergoes the bromination of the sulfamide or urea derivatives. A subsequent intramolecular bromonium formation from the electrophilic N- Br bond occurs. The diaminated product is achieved by a double cyclization event.
141 P. Chávez, J. Kirsch, C. H. Hövelmann, J. Streuff, M. Martínez-Belmonte, E. C. Escudero-Adán, E. Martin, K. Muñiz, Chem. Sci. 2012, 3, 2375–2382.
117 Part II Engineering Bromide Catalysis for C(sp3)-H Functionalization
Scheme II.2 Bromide-catalyzed diamination reaction designed by Muñiz and co- workers.
At the time when this project started, any method for C(sp3)-H amination reaction were developed using bromide catalysis. Since our group was in parallel designing new hypervalent iodine(III) reagent for amination reactions, they found out within the same year that a combination of PhI(NPhth)2 (Phth = Phthaloyl) and an ammonium bromide salt could undergo selective amination on tetrahydrocarbazole derivatives (Scheme II3).142
142 J. Bergès, B. García, K. Muñiz, Angew. Chem. Int. Ed. 2018, 57, 15891–15895.
118 Part II Engineering Bromide Catalysis for C(sp3)-H Functionalization
Scheme II.3 Bromide-catalyzed selective C(sp3)-H amination reaction designed by Muñiz and co-workers on tetrahydrocarbaxole derivatives.
II.1.3 The Hofmann-Löffler reaction: a possible breakthrough for bromine catalysis?
In the general introduction, the mechanism proposed by Corey for the Hofmann-Löffler reaction was presented. A pre-formation of the N-Br bond is required, really harsh acidic and thermal conditions are necessary and a final basic work-up is essential for the final cyclization to occur. All these conditions are at the opposite of the modern requirements of the synthetic chemist community. In order to circumvent all these issues, our objectives were to find a way to in-situ generate the N-Br bond, to develop milder reaction conditions that are functional-group compatible and to cyclize without any basic work-up. Therefore, if we do not need any preformation of the N-Br bond and if the bromine is not ending up to the final product, it is a clear situation where a catalysis can be designed.
II.1.4 Nitrogen-centered radical: the key for the selectivity The nitrogen-centered radical has a key role in the Hofmann-Löffler reaction since it provides a perfect regioselectivity for the amination through a 1,5-HAT. If the nitrogen-centered radical is too unstable, it can affect the selectivity because as it is so reactive it can act as a free-radical and perform HAA at any position. On the contrary, if the nitrogen-centered radical is too stabilized, it becomes unreactive. Zipse and co-workers calculated the stability of several aminyl, aminium, amidyl, and sulfonamidyl radicals (Scheme II.4).143 The radical stabilization energies were calculated in comparison with the unsubstituted aminyl radical. It was found that the less stabilizing electronwithdrawing group is the trifluoroacetamide and that the sulfonamide protecting groups are the most stabilizing.
143 a) D. Šakić, H. Zipse, Adv. Synth. Catal. 2016, 358, 3983–3991. b) J. Hioe, D. Šakić, V. Vrček, H. Zipse, Org. Biomol. Chem. 2015, 13, 157–169.
119 Part II Engineering Bromide Catalysis for C(sp3)-H Functionalization
Highlighting in green are the relative stability energies of the sulfonamidyl radicals that are similar to the aminium radical used in the original Hofmann-Löffler reaction.
Scheme II.4 Radical stabilization energies of various nitrogen-centered radicals computed by Zipse et.al. The trifluoroacetamide group is the most destabilizing and the aminyl radicals are the most stable.
They also computed the BDE of the remote C(sp3)-H bond and of the N-H bond to achieve the enthalpy value for the 1,5-HAT (Scheme II.5). The enthalpy for the 1,5-HAT for the original Hofmann-Löffler reaction is slightly endothermic (+5.6 kJ/mol at 298 K).
120 Part II Engineering Bromide Catalysis for C(sp3)-H Functionalization
The piperidine protonation has a dual role. First, it activates the N-Br bond, which becomes easier to homolitically cleaved under thermal conditions. Then, because it destabilizes the aminyl radical, thus making it more reactive (RSE = -28.9 kJ/mol instead of -55.7 kJ/mol at 298 K, scheme II.4). Hence, it reduces the enthalpy of the 1,5-HAT (+5.6 kJ/mol vs +24 kJ/mol at 298 K).
Scheme II.5 Computed enthalpies for the original Hofmann-Löffler reaction by Zipse and co-workers. This is an evidence of the crucial role of the protonation for the destabilization of the nitrogen-centered radical. The aminium radical is more reactive than its neutral aminyl radical.
With these calculations in hand, we can notice that when using electronwithdrawing protection groups, the enthalpies become negatives and the hydrogen atom abstraction becomes exothermic. As a hypothetic conclusion, a protecting group may have the feature to destabilize the nitrogen-centered radical without the need of a protonation and subsequent use of sulfuric acid. As a result, milder reaction condition could be developed.
II.1.5 Sulfonamides: a starting point from Hofmann’s heritage As the interest was to develop a bromine catalysis for C(sp3)-H amination and having the Hofmann’s heritage in hand, we designed a starting material in which the nitrogen is bearing a tosyl group. As calculated by Zipse et al., the N-centered radical of a N-tosyl sulfonamide is as stabilized as the N-protonated piperidinium radical (-28.9 kJ/mol vs [- 25.1;-30] kJ/mol at 298 K, scheme II.6). Therefore, the N-centered radical is
121 Part II Engineering Bromide Catalysis for C(sp3)-H Functionalization neither too stabilize and consequently unreactive nor too destabilize to be too reactive and consequently unselective for the desired HAT. In this condition, the 1,5-HAT should proceed as in the original Hofmann-Löffler reaction. To fasten the 1,5-HAT and an eventual cyclization, two methyl groups were implemented at β-position to install a Thorpe-Ingold effect. At the δ-position, a phenyl group was added for two reasons. First, at an activated position such as a benzylic position, the BDE of the C-H bond is lower than at a non-activated aliphatic position. Therefore, the 1,5-HAT is clearly favored (-44.7 kJ/mol at 298 K). Then, the cyclization is also favored at activated benzylic position.
Scheme II.6 Comparison between the computed radical stabilization energies for the aminium radical used in the original Hofmann-Löffler reaction and the sulfonamidyl radical we use (top). Calculated enthalpies for the 1,5-HAT of the designed substrate for the development of our methodology (middle). Calculated enthalpies for a substrate bearing a hydrogen at a non-activated position (bottom). In both cases, the enthalpies are negative at room temperature (reaction slightly exothermic). All these calculations were carried out by Zipse and co-workers.
They also calculated the enthalpies for the hydrogen atom abstraction of the common solvents used in the Hofmann-Löffler chemistry. Surprisingly, the computed enthalpies are lower than the intramolecular 1,5-HAT at non- activated positions for instance. Consequently, it seems that the hydrogen
122 Part II Engineering Bromide Catalysis for C(sp3)-H Functionalization atom abstractions at solvents are not kinetically competing with the internal 1,5-HAT. Having this knowledge in hand about the radical stability of such sulfonamidyl radicals, we wondered on how to form them in the medium. We have seen in the general introduction different manners to obtain N- centered radical from homolytic cleavage of a N-Heteroatom bond. Having in mind to design a bromine catalysis for the Hofmann-Löffler reaction, we focused on how to break the N-Br bond.
II.1.6 N-X bond cleavage: the case of fluorine and chlorine In the general introduction, we presented general conditions to cleave the stable N-F bond (67 kcal/mol for a N-F bond where a methyl and a tosyl group are at the nitrogen at 298 K).144 For instance, the N-F bond for compound 1 is fully stable in time. Often, the cleavage of the N-F bond requires the assistance of a transition metal catalyst such as palladium,24,121 iron116 or copper115-120 (Scheme 7a) Regarding the N-Cl bond, its cleavage varies on the electronwithdrawing group attached at the nitrogen (Scheme 7b). For sulfonamides, an iridium- based photoredox catalyst is required145 whereas for sulfamate esters, only the necessity of black light provides the N-centered radical.146 The N- chlorinated compound 2 bearing a tosyl group is stable for few days. Indeed, the half-life of such a species was determined in the lab to be two weeks in the presence of light.
Scheme II.7 N-X stability for N-F and N-Cl bonds and their respective homolytic cleavage conditions.
144 J. Yang, Y. Wang, X. Xue, J. Cheng,J. Org. Chem. 2017, 82, 4129–4135. 145 Q. Qin, S. Yu, Org. Lett. 2015, 17, 1894–1897. 146 M. A. Short, J. M. Blackburn, J. L. Roizen, Angew. Chem. Int. Ed. 2018, 57, 296–299.
123 Part II Engineering Bromide Catalysis for C(sp3)-H Functionalization
As a conclusion, fluorine or chlorine catalysis for such a reaction seems difficult to design since the corresponding N-F or N-Cl bonds are too stable to be rapidly cleaved.
II.1.7 Stochiometric bromine-mediated C(sp3)-H functionalization
II.1.7.1 Selective C(sp3)-H bromination In literature, there are few examples on bromine-mediated C(sp3)-H functionalization. As aforementioned, the trifluoroacetamide group is the less stabilizing group for the N-centered radical (RSE = [14.6;18.8] kJ/mol at 298 K, scheme II.4). As a result, it should be a proper group to implement at the nitrogen to trigger a reactivity. Indeed, Corey and co-workers established a methodology to achieve remote C(sp3)-H bromination of isoleucine and leucine derivatives at the δ-position (Scheme II.8a).147 Starting from the N-brominated-N-trifluoroacetyl(iso)leucine methyl ester and upon light irradiation, the Hofmann-Löffler reaction took place to selectively achieve the bromination at the δ-position. A rhodium catalyzed C(sp3)-H bromination could be designed by Zare and co-workers as well (Scheme II.8b).148 They used sulfamate esters as directing groups and hypobromite HOBr was in-situ generated with a combination of sodium hypochlorite and sodium bromide in stochiometric amounts to afford the N-brominated sulfamate esters. Therefore, in this methodology, the N-Br bond preformation is not required. The rhodium catalyst reduces this intermediate to generate the desired N-centered radical. A subsequent 1,6-HAT occurs followed by a bromination. Here, it is believed that the rhodium catalyst acts as an initiator. It is also important to mention that the reaction is also running with copper(II) bromide. Due to either the poor nucleophilicity of the N-protected amines or the bromine atom feature to not be a sufficient nucleofuge, any cyclization step occurs.
147 L. R. Reddy, B. V. S. Reddy, E. J. Corey, Org. Lett. 2006, 8, 3391–3394. 148 S. Sathyamoorthi, S. Banerjee, J. Du Bois, N. Z. Burns, R. Zare, Chem. Sci. 2018, 9, 100–104.
124 Part II Engineering Bromide Catalysis for C(sp3)-H Functionalization
Scheme II.8 Selective C(sp3)-H bromination from a Hofmann-Löffler reaction using stoichiometric amount of bromide reagents. Selected examples are depicted to highlight the high regioselectivity.
We developed in our group procedures to perform multiple selective brominations within the Hofmann-Löffler reaction.149 Sulfonamides were used as protecting group and DBDMH (1,3-dibromo-5,5- dimethylhydantoin) as bromine source to form in-situ the N-brominated intermediate. Under visible light irradiation, its homolytic cleavage affords the nitrogen-centered radical. As it is disclosed and explained above, the protecting group at the nitrogen plays a crucial role for the stability of the latter. The desired selectivity is linked to this radical stability. As calculated by Zipse et.al., the trifluoroacetamide group is the most destabilizing protecting group for the nitrogen-centered radical.143 We wanted to illustrate this important feature by an easy experiment designing a starting material in which the homo-benzylic position is accessible from a 1,5-HAT. When using a mesyl or a tosyl protecting group which we know they are stabilizing more the nitrogen-centered radicals than the corresponding
149 E. Del Castillo, M. D. Martínez, A. E. Bosnidou, T. Duhamel, C. Q. O’Broin, H. Zhang, E. C. Escudero-Adán, M. Martínez-Belmonte, K. Muñiz, Chem. Eur. J. 2018, 24, 17225– 17229.
125 Part II Engineering Bromide Catalysis for C(sp3)-H Functionalization trifluoroacetamide, we regioselectively performed multiple bromination at the homo-benzylic positions (Scheme II.9a). But, when the reaction was carried out using more electron-withdrawing and therefore more destabilizing protecting groups such as the trifluorosulfonyl or the trifluoroacetyl, undesired unselective multiple benzylic bromination occur (Scheme II.9b). In these cases, the nitrogen-centered radical is formed but not enough stabilized, meaning that the 1,5-HAT cannot proceed selectively. Instead, unselective intermolecular hydrogen atom abstraction at the weakest C(sp3)-H position from free-radicals occur.
Scheme II.9 Multiple selective or unselective C(sp3)-H bromination events depending on the nitrogen protecting group developed by Muñiz and co-workers. Selected examples are displayed to highlight the importance of the nitrogen protecting group for the selectivity.
II.1.7.2 Selective C(sp3)-H oxygenation Other procedures were designed using bromine as mediator for oxygenation chemistry but still using stoichiometric amount of brominating agent (Scheme II.10). The group of Baran employed stoichiometric amount of acylhypobromite(I) to achieve after only five minutes the N-brominated carbamate.150 Upon irradiation, the homolytic cleavage generates the N-centered radical. A subsequent 1,5-HAT followed by a bromination event either by a radical recombination with a bromine radical or by a radical chain mechanism. At this stage, an O-cyclization
150 K. Chen, J. M. Richter, P. S. Baran, J. Am. Chem. Soc. 2008, 130, 7247–7249.
126 Part II Engineering Bromide Catalysis for C(sp3)-H Functionalization event forced by a silver salt and further acidic hydrolysis provides a carbonate establishment. A basic hydrolysis of the obtained carbonate yields the corresponding desired 1,3-diol.
Scheme II.10 1,3-diol formation through Hofmann-Löffler manifold designed by Baran et.al. First, a selectibe bromination occurs followed by an O-cyclization. The mechanism and selected examples are depicted for greater clarity of the method.
II.1.7.3 Selective C(sp3)-H amination The Muñiz group in 2016 published a NIS-promoted Hofmann- Löffler reaction (more details in the next chapter). At that time, they tried to first develop a bromine-promoted amination reaction using NBS, NBP or DBDMH (1,3-dibromo-5,5-dimethylhydantoin).151 Unfortunately, the yields remained really low even with a large excess of brominating agent (Scheme II.11). Moreover, while using such an excess, side-products coming from unselective C(sp3)-H brominations occurred.
151 C. Q. O’Broin, P. Fernández, C. Martínez, K. Muñiz, Org. Lett. 2016, 18, 436–439.
127 Part II Engineering Bromide Catalysis for C(sp3)-H Functionalization
Scheme II.11 Bromine-mediated Hofmann-Löffler reaction developed by Muñiz and co- workers. Large excesses of brominating agents were used. As a result, low yields and side-bromination products were noticed.
Another procedure was developed after the publication of this work without the requirement of the N-Br bond preformation by the group of Nagib (Scheme II.12).152 They developed a stochiometric bromine-mediated formation of 1,2-aminoalcohols through oxazoline formations. An in-situ generation of the N-Br bond and a subsequent generation of the sulfonamidyl radical occurs upon visible light irradiation. The mechanism is similar to the one presented for the 1,3-diols formation of Baran until the
C-Br bond formation. An inorganic base (K2HPO4) was added in the medium to enhance the cyclization step and to afford the oxazoline derivatives. After a mild deprotection, 1,2-aminoalcohol derivatives were obtained.
Scheme II.12 Bromine-mediated selective C(sp3)-H amination developed by Nagib and co-workers. Large excess of NBS was engaged to perform this reaction and a base is required for the cyclization step.
152 K. M. Nakafuku, R. K. Twumasi, A. Vanitcha, E. A. Wappes, K. Namitharan, M. Bekkaye, D. A. Nagib J. Org. Chem. 2019, 84, 13065–13072.
128 Part II Engineering Bromide Catalysis for C(sp3)-H Functionalization
Regarding the bromine-mediated C(sp3)-H functionalization chemistry, these methodologies represents the unique scientific contribution to the field. They all have the limitation to use excesses of brominating agent to provide the key N-Br bond. Moreover, the requirement of a base for the cyclization step represents a limitation as well. The particularly low interest that the organic chemist’s community gives to the bromine catalysis for amination might be due to the limitations usually noticed. The bromine shows a relatively fast catalyst deactivation by overoxidation or disproportionation.
II.2 Aims of part II
With all this data in hand about the sulfonamidyl radical stability, about the calculations on the 1,5-HAT feasibility, about the original Hofmann-Löffler reaction, the formulated hypothesis was that a homogeneous bromine catalysis can be design for selective C(sp3)-H functionalization. Following this hypothesis, we aimed to develop the first bromine catalysis for the Hofmann-Löffler reaction. We aimed to use sulfonamidyl radical to selectively perform the 1,5-HAT. The objective was also to avoid elemental bromine, hazardous reagent, and strong oxidant. The aim was to use a bromide salt instead. It would be more functional group tolerant and it would respect the modern chemistry requirement.
II.3 Results and discussion
II.3.1 Development of the bromine catalysis for the Hofmann- Löffler reaction It was hypothesized with the literature precedence that a bromine(I) active species would be required to achieve the in-situ N-bromination. Hypobromite HOBr could be obtained in solution by either the disproportionation of bromine with water or by the combination of a large excess of both sodium hypochlorite and sodium bromide. These conditions are not suitable for a catalysis design since they often require large excesses of bromine and oxidant to achieve high yields due to the low conversion and stability of the hypobromite. The catalysis design investigation started with 3a as model substrate (Table II.1). The aim was to find suitable bromine source and oxidant to in-situ
129 Part II Engineering Bromide Catalysis for C(sp3)-H Functionalization form the N-brominated species and to re-oxidize the bromide generated after the pyrrolidine’s formation. First, as hypervalent iodine(III) can react with elemental bromine to provide hypobromite species, we screened the commercially available PIFA (entry 1) and the di(3- chlorobenzoyl)iodobenzene (entry 2) that provide 4a in 30% and 22% respectively. Different light sources were assessed but modest conversion (22-33%) were obtained (entries 3-5). As elemental bromine is a relatively toxic liquid that is not easy to handle, we used a cheaper and easier-to-handle-solid ammonium bromide salt. The use of 20 mol% of tetrabutylammonium bromide in combination with hypervalent iodine(III) oxidant did not improve the conversion (entries 6- 7) since PIFA and PhI(mCBA)2 provided 45% and 22% conversion respectively. Changing the solvent from DCE to ACN using PIFA as oxidant and modifying the light sources (entries 8-11) did not affect the conversion (36-40%). At this stage, we focused on using peracids to generate the key hypobromite species. As a result, when 20 mol% of tetrabutylammonium bromide was combined with mCPBA in acetonitrile and under daylight irradiation (entries 12-14), an outstanding improvement was obtained. Indeed, passing from 1.1 to 1.5 and to 2 equivalents of mCPBA enable 69%, 77% and full conversion respectively. 95% of isolated yield for 4a was achieved for the latter (entry 14). Eco-friendlier and more atom economic oxidants such as peracetic acid (entry 15), hydrogen peroxide (entry 16), tert-butylhydroperoxide (entry 17) or hypochlorite (entry 18) did not show any reactivity or provided the corresponding pyrrolidine with a modest 40% conversion in the case of the hypochlorite. Changing the bromide source yields to a dramatic conversion drop (entries 19-20). Indeed, the countercation seems to play an important role since only 26% of conversion was obtained for the tetraphenylphosphonium bromide and 32% for the trimethylsulfonium bromide. Finally, trying to decrease the amount of the bromide catalyst did not successfully yield to a full conversion (entry 21-23). When 10 mol% or 5 mol% were employed, 50% and 40% conversion respectively were recorded. Starting material 3a was fully recovered when using only 2.5 mol%. When the reaction was performed in the darkroom, the starting material was fully recovered (entry 24). The optimal reaction conditions are the following: Tetrabutylammonium bromide and mCPBA are used in 20 mol% and 2 equivalents respectively. The reaction is set-up in purified MeCN, under argon atmosphere and at the concentration of 0.1 M (the reaction still proceeds in an open-air system
130 Part II Engineering Bromide Catalysis for C(sp3)-H Functionalization using unpurified MeCN). The reaction mixture is stirred 18 h at room temperature under daylight irradiation.
Table II.1 Optimization of the bromide catalyzed Hofmann-löffler reaction.
Entry Bromine source Oxidant Solvent Conversion 1 Br2 (10 mol%) PIFA (1.1 eq) DCE 30% 2 Br2 (10 mol%) PhI(mCBA)2 (1.1 eq) DCE 22% a 3 Br2 (10 mol%) PhI(mCBA)2 (1.1 eq) DCE 24% b 4 Br2 (10 mol%) PhI(mCBA)2 (1.1 eq) DCE 33% c 5 Br2 (10 mol%) PhI(mCBA)2 (1.1 eq) DCE 24% 6 NBu4Br (20 mol%) PIFA (1.1 eq) DCE 45% 7 NBu4Br (20 mol%) PhI(mCBA)2 (1.1 eq) DCE 22% a 8 NBu4Br (20 mol%) PIFA (1.1 eq) MeCN 36% b 9 NBu4Br (20 mol%) PIFA (1.1 eq) MeCN 36% c 10 NBu4Br (20 mol%) PIFA (1.1 eq) MeCN 38% 11 NBu4Br (20 mol%) PIFA (1.1 eq) MeCN 40% 12 NBu4Br (20 mol%) mCPBA (1.1 eq) MeCN 69% 13 NBu4Br (20 mol%) mCPBA (1.5 eq) MeCN 77% 14 NBu4Br (20 mol%) mCPBA (2 eq) MeCN 95%* 15 NBu4Br (20 mol%) AcOOH (2 eq) MeCN SM 16 NBu4Br (20 mol%) H2O2 (2 eq) MeCN SM 17 NBu4Br (20 mol%) TBHP (2 eq) MeCN SM 18 NBu4Br (20 mol%) NaOCl (2 eq) MeCN 40% 19 PPh4Br (20 mol%) mCPBA (2 eq) MeCN 26% 20 Me3SBr (20 mol%) mCPBA (2 eq) MeCN 32% 21 NBu4Br (10 mol%) mCPBA (2 eq) MeCN 50% 22 NBu4Br (5 mol%) mCPBA (2 eq) MeCN 40% NBu4Br (2.5 23 mCPBA (2 eq) MeCN SM mol%) d 24 NBu4Br (20 mol%) mCPBA (2 eq) MeCN SM a Experiments carried out using purple LEDs. b Experiments carried using blue LEDs. c Experiments carried using green LEDs. * Isolated yield.
131 Part II Engineering Bromide Catalysis for C(sp3)-H Functionalization
II.3.2 Scope of the bromide catalyzed Hofmann-Löffler reaction With all this information in hand, we then investigated the robustness of the reaction conditions synthesizing numerous pyrrolidines bearing different backbones, sulfonyl groups or aryl groups at the δ-position (Scheme II.13). At the beginning, we prepared starting materials with different substituents at the phenyl moiety placed at the δ-position. Both electron-donating or electron-withdrawing groups are well tolerated at the para-position affording pyrrolidines 4a-e in good to excellent isolated yields (68-95%) and with complete selectivity. A methyl substituent placed at the ortho or meta- position does not interfere with the cyclization step (4f-g) since the latter are obtained with 87% and 92% isolated yield respectively. The reaction conditions are also applicable to starting material bearing various sulfonyl protecting groups. Indeed, mesylated (4h) and nosylated (4i) pyrrolidines could be synthesized in excellent yields (98% and 71% respectively). A cyclopropylsulfonamide (4j) was successfully cyclized with an excellent 82% isolated yield ruling out the potentially competing radical ring opening through a free-radical process. A thiophenylsulfonyl protected pyrrolidine (4k) was smoothly obtained with a respectable yield of 63% without any electrophilic side-bromination reaction observed. Backbone modifications were well tolerated as well since the replacement of the gem di-methyl groups at the β-position by a spiro cyclohexyl group provided the corresponding pyrrolidine 4l with the excellent yield of 94%. Removing one of both methyl groups afforded an inseparable 1:1 diastereoisomeric mixture (4m) with 74% isolated yield. It is noteworthy to mention the importance of the Thorpe-Ingold effect for the effectiveness of the methodology. Indeed, while putting into reaction the substituent-free backbone substrate, only traces of pyrrolidine formation were observed (Scheme II.14). In the case of the ring-annulated product 4n, only one diastereoisomer was formed in 79% isolated yield. Isoindolines (4o-r) could be synthesized as well using this procedure. Remarkably, no imine formation was noticed from a plausible elimination reaction and electron-rich heteroaromatic substituents such as 4-methylbenzyl, thiophenyl, benzothiophenyl or even furanyl did not undergo side-bromination reactions. They could be isolated with 77%, 59%, 48% and 38% isolated yields respectively. In the case of 4r, mCPBA was added in four portions and the yield based on the recovered starting material was 99%. This addition was mandatory to have less amount of hypobromite(I) in solution responsible of undesired side-
132 Part II Engineering Bromide Catalysis for C(sp3)-H Functionalization bromination reactions. Finally, C(sp3)-H amination could be undergone at α-position of heteroatom (4s-t) with excellent isolated yields of 54% and 98% respectively.
Scheme II.13. Scope of the bromide catalyzed Hofmann-Löffler reaction for the formation of numerous pyrrolidine derivatives. a A 1:1-mixture of diastereoisomers was obtained. b Addition of mCPBA in four portions. Yield in parenthesis based on recovering starting material.
133 Part II Engineering Bromide Catalysis for C(sp3)-H Functionalization
Unfortunately, the limitation of this process is that the non-activated aliphatic position could not be accessed (Scheme II.14). While trying to perform the amination reaction, either starting material was recovered or selective bromination was observed. Since bromine is not a good enough nucleofuge to have a rapid cyclization re-generating the halogen catalyst, the catalytic cycle is stopped. Whereas at activated benzylic position, the cyclization is facilitated since the C-Br bond is weaker. In fact, the C-Br bond at benzylic position is always in equilibrium with the dissociative ion pair. It is a fast dissociative-associative equilibrium. 6-membered ring piperidine derivatives could not be accessed using this method. This is also due to the relatively slow cyclization step. Finally, other group than sulfonamide such as amides could not be converted to the corresponding pyrrolidine derivatives.
Scheme II.14. Unsuccessful substrates for the bromide catalysed Hofmann-Löffler reaction.
II.3.3 Mechanistic studies for the C(sp3)-H amination reaction
II.3.3.1 Bromine active species investigation With the optimized conditions in hand, we next investigated the active bromine species. Two hypotheses were expressed at this stage. First, inorganic bromine species could be involved. Then, bromine complexes such as [Br(mCBA)2]NBu4 could also formed under our reaction conditions. We wondered as well which oxidation state has the active bromine catalyst. RAMAN spectroscopy was identified to be the optimum technique to assess the presence or not of inorganic bromine species such as hypobromite(I) HOBr in the media. According to the literature, typical bands from [BrO]-,
134 Part II Engineering Bromide Catalysis for C(sp3)-H Functionalization
- - - - -1 -1 -1 -1 [BrO3] , [BrO2] , [Br3] and [Br5] are 620 cm , 807 cm , 709 cm , 163 cm and 257 cm-1 respectively from their fundamental modes.153 The first spectrum recorded was the one of the solvent: acetonitrile (Scheme II.15a). Two bands could be identified, at 390 cm-1 and 920 cm-1. A second experiment was carried out with the presence of mCPBA and tetrabutylammonium bromide. But as depicted in scheme II.15b., no new bands were observed. Finally, two other spectra were recorded for two different reaction mixtures, one after a reaction time of 5 minutes (Scheme II.15c). and the other after a reaction time of 2 hours (Scheme II.15d). Only the bands related to acetonitrile were identified. As a result, the plausible involvement of inorganic bromine was ruled out since any of the afore-mentioned species were detected.
153 J. C. Evans, G. Y. S. Lo, Inorg. Chem. 1967, 6, 1483–1486.
135 Part II Engineering Bromide Catalysis for C(sp3)-H Functionalization
Scheme II.15 RAMAN spectrum recorded to rule out the involvement of inorganic bromine species as plausible active catalysts.
Then, we investigated the plausible formation of the bromine(I) complex
[Br(mCBA)2]NBu4. In order to synthesize the latter, a similar procedure than for the synthesis of the close-related iodine salt was followed (Scheme II.16).154 The close-related iodine(I) salts are stable and easy to synthesize but we did not expect that the corresponding bromine salts were unstable. After an extensive work trying to synthesize such bromine(I) complexes, it was found that the coutercation of the salt was playing a crucial role for the stabilization of it. As a result, a trimethylsulfonium salt 5 was prepared and fully characterized.
A stochiometric amount of trimethylsulfonium bromide and PhI(mCBA)2 was stirred in dichloromethane at room temperature for 30 min. The freshly obtained bromine(I) salt was characterized and then added to a solution of 3a in acetonitrile at room temperature. After 18h, only starting material was recovered. It was concluded that 5 is not an effective bromine species for the transformation.
Scheme II.16. Trimethylsulfonium salt 5 synthesis and subsequent addition to 3a. The in-situ formation in the medium of such bromine(I) salt was ruled out since only starting material was recovered.
After we ruled out our two initial hypotheses, we thought that the 3- chlorobenzoyl hypobromite(I) I could be involved in this transformation .To confirm our initial hypothesis, the synthesis of the 3-chlorobenzoyl
154 B. García, C. Martínez, A. Piccinelli, K. Muñiz, Chem. Eur. J. 2017, 23, 1539–1545.
136 Part II Engineering Bromide Catalysis for C(sp3)-H Functionalization hypobromite was carried out following the reported synthesis by Glorius et al. from the corresponding commercially and readily available benzoate silver salt (Scheme II.17).155 Treatment of the latter with a stochiometric amount of elemental bromine in deuterated dichloromethane yields the benzoylhypobromite I. The NMR was recorded directly after a quick filtration through a syringe to remove the silver bromide precipitate. An NMR standard (1,2,4,5-tetrachloro-3-nitrobenzene) was added to quantify the yield at 52%. To also quantify the excess of bromine remaining in the NMR tube, another parallel experiment was carried out. Inside a second NMR tube, a large excess of cyclohexene was added to quickly react with the remaining elemental bromine in a dibromination reaction. Only 3.5 % of 1,2-dibromocyclohexane was detected. When a solution of the substrate 3a in acetonitrile was added to the freshly prepared solution of I, formation of the corresponding pyrrolidine was encountered (24% isolated yield based on 3a, 46% based on I) after letting the reaction stirred 18 h (Scheme II.17a). Importantly, when, in a parallel experiment, mCPBA was added in two equivalents, a improved isolated yield of 65% was achieved meaning that the benzoyl hypobromite I is initiating the reaction while mCPBA is the suitable and efficient terminal oxidant (Scheme II.17b).
155 L. Candish, M. Freitag, T. Gensch, F. Glorius, Chem. Sci. 2017, 8, 3618–3622.
137 Part II Engineering Bromide Catalysis for C(sp3)-H Functionalization
Scheme II.17. Synthesis of the 3-chlorobenzoyl hypobromite(I) and subsequent addition to 3a with and without the presence of mCPBA. Conversion to 4a was observed in both cases. An increased isolated yield was noticed when mCPBA was added.
As a conclusion, after an extensive investigation, we found out that the bromine active species for such a transformation is the 3-chlorobenzoyl hypobromite(I) I. Indeed, it is the only reactant that provides the final pyrrolidine 4a.
II.3.3.2 Study of the N-Br bond of 3a After the determination of the active bromine catalyst, we then focused on the isolation and characterization of the N-brominated species 6. As we did not want to use an excess of elemental bromine and because we wanted to avoid work-ups due to the expected instability of the N- brominated compound, we investigated plausible pathways that can fit these restrictive requirements. First, we tried to directly catch the intermediate monitoring the reaction by NMR. We could notice among the NMR peaks of 3a and 4a another product that could have fit with 6. We could not say with complete certitude that those peaks belonged to 6. As a
138 Part II Engineering Bromide Catalysis for C(sp3)-H Functionalization result, we had the idea to find a way to keep it pure in solution just filtrating the reactants and impurities prior to the NMR submission. We started to assess the solubility of various bromide salts and we selected an acetonitrile- insoluble heavy ammonium bromide salt, the dioctadecyldimethylammonium bromide as bromine source. By chance, the solubility of the corresponding dioctadecyldimethylammonium hydroxide and of mCBA (side-product from the reduction of mCPBA) are very low in acetonitrile too. Therefore, their removal from the medium was made by a simple filtration letting the N-brominated species pure in solution. In a dark room, a solution of stochiometric amount of 3a, mCPBA and the dioctadecyldimethylammonium bromide in deuterated acetonitrile was stirred for one hour. After filtration of the salts through a syringe, the NMR recorded showed us the complete conversion of 3a to the N-brominated compound 6 (Scheme II.18). While shinning light on 6, we could recover 4a in 34% isolated yield. Interestingly, 66% of starting material 3a was recovered. We did not expect the major product of the irradiation of 6 to be the starting material 3a. Surprisingly, any plausible benzylic deuterated product was noticed coming from the quenching of the benzylic carbon radical by CD3CN. We postulated that the 1,5-HAT did not proceed as efficient as expected leading to the quenching of the nitrogen-centered radical by CD3CN. As calculated by Zipse et.al., the nitrogen-centered radical can be thermodynamically quenched by acetonitrile.143 After a basic work-up, the deuterium atom at the nitrogen may be replaced by a hydrogen through an acid-base equilibrium (sodium carbonate is used) leading to the formation of 3a.
Scheme II.18. Synthesis and characterization of the N-brominated intermediate 6 and subsequent light irradiation leading to the formation of the desired pyrrolidine 4a.
139 Part II Engineering Bromide Catalysis for C(sp3)-H Functionalization
The species could be fully characterized (1H NMR, 13C NMR, HRMS) and a UV-Vis spectrum was recorded as well (Scheme II.19). A bathochromic shift was noticed while comparing with 3a and the compound starts to absorb at 350 nm. This experiment confirms both the necessity of the daylight and the non-influence of the different LEDs’ irradiation in the table II.1.
140 Part II Engineering Bromide Catalysis for C(sp3)-H Functionalization
Scheme II.19. UV-Vis spectra of 3a and 6. A batochromic shift is noticed for the N- brominated intermediate 6 which starts to absorb at 350 nm.
To study more about the stability of the N-brominated intermediate 6, we assessed its half-life under daylight. By NMR, at 30 min, the ratio between 6 and 3a and 4a is 50 / 50.
141 Part II Engineering Bromide Catalysis for C(sp3)-H Functionalization
II.3.3.3 Quenching experiments Quenching experiments were carried out as well to confirm the involvement of radical species intermediate (Scheme II.20). In the presence of stochiometric amount of BHT, the reaction is not proceeding. The starting material 3a was fully recovered.
Scheme II.20. Quenching experiments using BHT as radical quencher. Starting material 3a fully recovered.
II.3.3.4 Kinetic isotope effect To better understand the mechanism, labelling experiments were carried out. The mono-benzylic-deuterated substrate 3a-D was synthesized and submitted to the optimized reaction conditions (Scheme II.21). After the usual work-up, a crude NMR was taken in order to assess the Kinetic Isotope Effect (KIE) from the intramolecular competition. Therefore, the KIE was calculated from the relative amount of products formed from the C(sp3) amination of the C-H vs the C-D bond. The ratio between the deuterated and the non-deuterated pyrrolidine was determined and provided a KIE of 3 indicating that the rate limiting step might be the C-H bond cleavage (1,5-HAT in the present case).156
Scheme II.21. Isotope labelling experiment carried out with 3a-D. Intramolecular competition provided a KIE of 3 meaning that the hydrogen atom abstraction might be the rate-determining step.
156 E. M. Simmons, J. F. Hartwig, Angew. Chem Int. Ed. 2012, 51, 3066–3072.
142 Part II Engineering Bromide Catalysis for C(sp3)-H Functionalization
II.3.4 Proposed mechanism for the bromide catalyzed Hofmann-Löffler reaction Mechanistically, we identified as aforementioned the active species for such a transformation which is the 3-chlorobenzoyl hypobromite(I) I. The proposed mechanism is the following: First, the tetrabutylammonium bromide pre-catalyst is reacting with mCPBA to in-situ generate the hypobromite active species which undergo the bromination of 3a to afford the N-brominated compound 6 (Scheme II.22). Under daylight irradiation, a subsequent homolytic cleavage of the N-Br bond occurs to provide the key stabilized sulfonamidyl radical. Through a 6-membered ring transition state, a 1,5-HAT takes place to generate the carbon-centered radical III. Without the determination of the quantum yield, we cannot certify that the following bromination forming IV is achieved by a radical chain mechanism or by a radical recombination. At this stage, a rapid cyclization releasing the bromide pre-catalyst and yielding the final pyrrolidine occurs. Unfortunately, we were never able to isolate the intermediate IV from this reaction. Nevertheless, with the precious work done by our group about multiple halogenation through the Hofmann-Löffler reaction149, we can suppose its in-situ formation.
143 Part II Engineering Bromide Catalysis for C(sp3)-H Functionalization
Scheme II.22. Proposed mechanism for the bromide catalyzed Hofmann-Löffler reaction.
II.3.5 Application of the method to oxaziridine’s formation While trying substrate bearing a smaller backbone where the 1,5- HAT was not possible, we wanted to know if we could access azetidine or aziridine derivatives. Although the pyrrolidine formation through the 1,5- HAT pathway is successful, the corresponding 1,3- or 1,4-HAT remains challenging. Since the hydrogen atom abstraction is not geometrically or thermodynamically possible, we wondered what the nature of the new compound was. Obviously, it was not corresponding to the amination reaction. At the beginning, from the NMR spectrum, we hypothesized an O- cyclization from the sulfonamide moiety. Nevertheless, when we received
144 Part II Engineering Bromide Catalysis for C(sp3)-H Functionalization the HRMS, we ruled out this hypothesis and we identified the oxaziridine as the new product.
II.3.5.1 Scope of the oxaziridine formation Investigation over the applicability of the bromide catalysis for oxaziridine formation was carry out (Scheme II.23). First, the N- tosylphenylpropylamide 7a was converted with a good 60% yield to the corresponding oxaziridine 8a. Variation of the para substituent of the phenyl moiety were successfully tolerated providing products 8b and 8c in 59% and 70% yield respectively. Various sulfonyl groups included mesyl (7d), nosyl (7e) and 2-thiophenylsulfonyl (7f) were fruitfully converted into the corresponding oxaziridines 8d-f in 44%, 65% and 64% respectively. A phenyl ether derivative 8g could be achieved with a respectable yield of 68%. Then, N-tosylphenylethylamide 7h and its 2-bromophenyl derivative 7i could be converted in 86% (8h) and 55% yield (8i) respectively. The latter was structurally determined by X-ray analysis. Then, different sulfonyl groups were successfully assessed such as benzylsulfonyl (8j, 72%), cyclopropylsulfonyl (8k, 44%) that remains untouched proving the chemoselectivity in favor of the oxaziridine formation. It proves the non- involvement of free-radicals. 2-naphthylsulfonyl (8l, 71%) as and 4- fluorobenzensulfonyl (8m, 60%) were successfully achieved as well. A neopentyl group at the nitrogen was implemented and proved that the arene moiety is not mandatory for the oxaziridine formation (8n, 85%). Finally, when both the oxaziridine formation and the Hofmann-Löffler reaction can proceed, it was always kinetically in favor of the amination reaction. One example proved that an oxaziridine can be formed instead of the pyrrolidine (8o). Indeed, the increased acidity of the hydrogen atom in α-position to the nitrile prevents the hydrogen atom abstraction from the electrophilic nitrogen-centered radical thus leading to the oxaziridine formation in an excellent yield of 97%.
145 Part II Engineering Bromide Catalysis for C(sp3)-H Functionalization
Scheme II.23. Scope of the bromide catalyzed oxaziridine formation.
II.3.5.2 Proposed mechanism In literature, the classical pathway to synthesize oxaziridines is the use of peracids to the epoxidation of an imine.157 This transformation was discovered unexpectedly since we wanted to prove that both aziridine and
157 K. S. Williamson, D. J. Michaelis, T. P. Yoon, Chem. Rev. 2014, 114, 8016–8036.
146 Part II Engineering Bromide Catalysis for C(sp3)-H Functionalization azetidine’s formation through 1,3- or 1,4-HAT do not constitute viable ways. Thanks to this non-predicted oxaziridine formation, we proved and confirmed that the mechanism for the pyrrolidine’s formation proceeds through a selective 1,5-HAT pathway rather than through a direct benzylic bromination from an intermolecular HAA from a free-radical reaction. Although we did not investigate deeply the mechanism for the oxaziridine formation, we believe that the key N-brominated sulfonamide V is homolytically cleaved under daylight irradiation to generate the nitrogen- centered radical VI (Scheme II.24). A plausible radical elimination might occur at this stage to form the corresponding imine VII which gets oxidize by the excess of mCPBA to the final oxaziridine 8.
Scheme II.24. Mechanism of the bromide catalyzed oxaziridine formation.
147 Part II Engineering Bromide Catalysis for C(sp3)-H Functionalization
II.4 Final remarks
More than 100 years ago, Hofmann discovered the capacity of the N- Br bond to homolitically cleave under certain conditions leading to a selective amination reaction. In this chapter, it was presented the first bromide catalyzed Hofmann-Löffler reaction where a N-Br bond is in-situ generated, cleaved under daylight irradiation, and led to pyrrolidine formation through a selective 1,5-HAT. The developed mild reaction condition allows functional group tolerance and respect the requirements of the modern chemistry challenges. This method allows the formation as well of oxaziridines when the Hofmann-Löffler reaction cannot proceed. This is the first bromide catalyzed oxaziridine formation as well. In the future, it could be interesting to investigate deeply the mechanism of the oxaziridine formation. Is it a radical-based elimination or ionic? Also, more experiments should be done on competition between the Hofmann-Löffler reaction and the oxaziridine formation. Is this linked with the pka of the hydrogen to abstract? If it is the case, what is the exact pka in which the 1,5-HAT does not proceed?
II.5 Experimental section
II.5.1 General information NMR spectra were recorded on a Bruker Avance 400 MHz or 500 MHz spectrometer, respectively. The chemical shifts (δ) for 1H and 13C are reported in ppm relative to residual signals of the solvents (CDCl3 δ = 7.26 and 77.0 ppm, CD3CN δ = 1.94 and 118.26 ppm; DMSO-d6 δ = 2.50 and 39.52 ppm for 1H and 13C NMR respectively). Coupling constants are given in Hz. The following abbreviations are used to indicate the multiplicity: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad. High-resolution mass spectra (HRMS) were obtained from the ICIQ High- Resolution Mass Spectrometry Unit on MicroTOF Focus and Maxis Impact (Bruker Daltonics) with electrospray ionization. X-ray data were obtained from the ICIQ X-Ray Unit using a Bruker-Nonius diffractometer equipped with an APPEX 2 4K CCD area detector. IR spectra were taken in a Bruker Alpha instrument in the solid state. RAMAN spectroscopic investigation was carried out using a Renishaw inVia Raman microscope equipped with a thermoelectrically cooled CCD camera
148 Part II Engineering Bromide Catalysis for C(sp3)-H Functionalization and an optic fibre cable for the excitation. Samples (glass cuvette containing the solution for measurement) were irradiated with a laser beam with a wavelength of 532 nm. For all measurements, the energy of the laser was approximately 100 mW. All reactions were set up under an argon atmosphere in oven- dried glassware using standard Schlenk techniques unless otherwise stated. Synthesis grade solvents as well as reagents were used as purchased. Anhydrous solvents were taken from a commercial solvent purification system (SPS) dispenser. Chromatographic purification of products was accomplished using flash column chromatography (FC) on silica gel (Merck, type 60, 0.063-0.2 mm).
II.5.2 Synthesis and characterization of 1
A solution of 3a (1 equiv.) in CH2Cl2 was added to a stirred mixture of NaH (6 equiv.) in CH2Cl2 (0.1 M) at 25 °C. After 30 min, NFSI (3 equiv.) was added portionwise. The reaction was stirred for 24 h and monitored by
TLC. After 24 h, the reaction was quenched with NH3 (2%)/NaOH (6.5%) solution at 0 °C. The reaction mixture was then extracted three times with
Et2O and the combined organic layers were washed three times with the
NH3/NaOH solution, three times with NaOH (5%) and three times with HCl
(5%), dried over MgSO4, filtered and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel using hexane/ethyl acetate as eluent to get 1 as a white solid in 65% isolated yield.
N-(2,2-Dimethyl-4-phenylbutyl)-N-fluoro-4- methylbenzenesulfonamide (1)
Prepared according to the procedure described above, 1 was isolated as a white solid with a 65% 1 isolated yield. H NMR (400 MHz, CDCl3): δ = 7.88- 7.84 (m, 2H), 7.46-7.42 (m, 2H), 7.33-7.28 (m, 2H), 7.20-7.15 (m, 3H), 3.12 (d, J = 44.4 Hz, 2H), 2.63-2.55 (m, 2H), 2.52 (s, 3H), 13 1.73-1.63 (m, 2H), 1.08 (s, 6H). C NMR (100 MHz, CDCl3): δ = 146.3, 142.7,
130.1, 129.9, 129.6, 128.5, 128.5, 125.9, 62.9 (d, JH-F = 10.6 Hz), 42.4, 34.6, 30.4, 19 -1 25.8, 21.9. F NMR (375 MHz, CDCl3): δ = -36.38. IR ν (cm ): 3028, 2958, + 1954. HRMS (m/z): [M+Na] calculated for C19H24FNNaO2S: 372.1404, found: 372.1402. mp: 72-73 °C.
149 Part II Engineering Bromide Catalysis for C(sp3)-H Functionalization
II.5.3 Synthesis and characterization of 2 A round-bottom flask equipped with a stirrer bar was charged with the 3a (1.0 equiv.). MTBE and tert-butanol (1/1 v/v, 0.05 M) were added. Then, an aqueous solution (14%) of sodium hypochlorite (1 mL for 0.2 mmol of 3a) was added at 0 oC. The reaction mixture was stirred at 0 oC in absence of light for 1 h. The reaction mixture was quenched with water and extracted twice with CH2Cl2. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure, to afford 2 as a colorless oil in 99% isolated yield.
N-Chloro-N-(2,2-dimethyl-4-phenylbutyl)-4- methylbenzenesulfonamide (2)
Prepared according to the procedure described above, 2 was isolated as a colorless oil with a 99% 1 isolated yield. H NMR (400 MHz, CDCl3): δ = 7.84 (d, J = 8.3 Hz, 2H), 7.40 (d, J = 8.1 Hz, 2H), 7.33-7.25 (m, 1H), 7.20 (m, 4H), 3.24 (s, 2H), 2.71-2.56 (m, 2H), 2.48 (s, 3H), 1.73-1.61 13 (m, 2H), 1.10 (s, 6H). C NMR (101 MHz, CDCl3): δ = 145.3, 142.8, 131.0, 129.8, 129.5, 128.5, 128.4, 125.8, 67.0, 42.1, 35.7, 30.4, 25.7, 21.8. IR v(cm-1): 2961, 2930, + 1597. HRMS (m/z): [M+Na] calculated for C19H24ClNNaO2S: 388.1108; found: 388.1098.
II.5.4 Synthesis of the substrates 3a-t for the amination reaction Synthesis of 3a-m and 3t (GP1)
Scheme II.25. Pathway for the synthesis of 3a-m and 3t (GP1).
150 Part II Engineering Bromide Catalysis for C(sp3)-H Functionalization
Step 1. A flame-dried Schlenk tube equipped with a stirrer bar is charged with the corresponding nitrile compound (1.0 equiv.) and THF (50 mL). LDA (2.6 mL, 2M, 1.0 equiv.) is added drop wise at -78 ºC and the solution is stirred for 30 min. After that period, the corresponding alkyl bromide (1.2 equiv.) is added in a single portion and the mixture is stirred at room temperature for 12h. A saturated aqueous solution of NH4Cl is added and the resulting mixture is extracted three times with Et2O. The organic layer is dried over Na2SO4 and the solvent is evaporated under reduced pressure. The crude product is directly engaged in the next step. Step 2. A flame dried Schlenk equipped with a stirrer bar and a reflux condenser is charged with LiAlH4 (3 equiv.), Et2O is added carefully and the mixture is cooled to 0 ºC with an external ice/water cooling bath. The crude nitrile (1 equiv.) is dissolved in a small volume of Et2O and added carefully to the LiAlH4 suspension. The mixture is heated to reflux for 2h and cooled to 0 ºC afterwards. A solution of NaOH (10% in water) is added carefully until a white solid precipitate appears. After filtration over Na2SO4 and evaporation of the solvent, the crude amine is obtained in quantitative yields. Step 3. The crude amine from step 2 (1 equiv.) is dissolved in pyridine (50 mL) and the respective sulfonyl chloride (1.5 equiv.) is added at 0 ºC. The solution is stirred overnight at room temperature. CH2Cl2 is added, and the mixture is washed three times with a hydrochloride solution (10% HCl in water). The organic layer is dried over Na2SO4 and the solvent is evaporated under reduced pressure. The crude product was purified by chromatography (silica gel, hexane/ethyl acetate as eluent) to give the pure product 3a-m and 3t.
Synthesis of 3a-D
Scheme II.26. Pathway for the synthesis of 3a-D.
151 Part II Engineering Bromide Catalysis for C(sp3)-H Functionalization
Step 1. In a flame-dried Schlenk flask, Ni(dppp)Cl2 (48.9 mg, 0.09 mmol, 3% mol) and a 1 M solution of Dibal-H in THF (3.9 mL, 3.9 mmol, 1.3 equiv.) were added. The mixture was then cooled down at 0 ºC before the slow addition of acetylene (0.33 mL, 3 mmol, 1 equiv.). The mixture was stirred 2 h at room temperature before D2O (1.5 mL) was added to quench the reaction at 0 ºC. An usual work up was done to finally get the crude α-D- styrene which was directly used in the following step without any purification. Few crystals of BHT were added to avoid the polymerization of the α-D-styrene. Step 2. In a flame-dried Schlenk flask, the crude α-D-styrene and 9-BBN (0.5 M in THF, 6 mL) were added at 0 ºC and stirred overnight at room temperature. Then, solutions of 3M NaOH (2 mL) and 30% H2O2 (0.9 mL) were added. The mixture was stirred overnight under reflux. An usual work up was done to yield the crude α-D-(2-hydroxyethyl)benzene. A purification by column chromatography was performed prior to the next step.
Step 3. In a flame-dried Schlenk flask, the pure alcohol, CBr4 (995 mg, 3 mmol, 1 equiv.), PPh3 (787 mg, 3 mmol, 1 equiv.) were dissolved in CH2Cl2 (3 mL). The mixture was stirred overnight at room temperature. After an usual work up, the crude α-D-(2-bromoethyl)benzene was obtained and subjected to the general procedure GP1 to get 3a-D as a pale yellow oil in 14% overall yield over 6 steps.
Synthesis of 3n
Scheme II.27. Pathway for the synthesis of 3n.
Step 1. A flame-dried Schlenk tube equipped with a stirrer bar was charged with the trimethylphosphonoacetate (1.62 mL, 10 mmol, 1.0 equiv.) and THF (5 mL/mmol) and the vessel was cooled down to 0º C. n-BuLi (5 mL of a 2
152 Part II Engineering Bromide Catalysis for C(sp3)-H Functionalization
M solution, 10 mmol, 1.0 equiv.) was added dropwise and the reaction was stirred for one hour upon which time the 2-indanone (1.32 g, 10 mmol, 1.0 equiv.) was added and the reaction was then stirred for 18 h at room temperature. A saturated aqueous solution of NH4Cl was added and the resulting mixture extracted three times with Et2O. The organic layer was dried over anhydrous Na2SO4 and the solvent evaporated under reduced pressure. The crude was used for the next step without further purification. Step 2. A flame-dried Schlenk tube equipped with a stirrer bar was charged with the crude from the previous step, Pd/C (20 w%) and ethanol (5 mL/mmol) were added and the reaction was stirred under atmospheric pressure of hydrogen gas overnight. The mixture was filtered through Celite and concentrated to yield the crude ester which was used for the next step without further purification. Step 3. A flame-dried Schlenk tube equipped with a stirrer bar and a reflux condenser was charged with LiAlH4 (2 equiv.). Et2O is added carefully and the mixture was cooled down to 0 ºC. The crude ester (1 equiv.) was added to the LiAlH4/Et2O suspension under argon atmosphere. The mixture was heated to reflux for 2 h and cooled down to 0 ºC afterwards. A solution of NaOH (1 M in water) was added. After filtration of the white precipitate over
Na2SO4 and evaporation of the solvent under reduced pressure, the crude alcohol was obtained in quantitative yield and was used in the following step.
Step 4. The crude alcohol (1 equiv.) was dissolved in dry CH2Cl2 and cooled down to 0 C. NEt3 (2 equiv.) was added and the mixture was stirred for 10 min at 0 C. Mesyl chloride (1.1 equiv.) was added dropwise at 0 C and the reaction mixture was stirred for 30 min at 0 C after which the reaction was quenched by addition of a saturated aqueous solution of NaHCO3. The layers were separated, and the aqueous phase was extracted with CH2Cl2.
The combined organic phases were dried over Na2SO4, filtered and the solvent was removed under reduced pressure to yield the desired mesylate which was used without purification for the next step.
Step 4. The crude from step 3 (1 equiv.) was dissolved in dry DMF and NaN3 (1.5 equiv.) was added. The reaction mixture was stirred overnight at 90 C.
After adding Et2O to the mixture, the organic layer was washed five times with water to remove the DMF prior to be dried over Na2SO4 and evaporated under reduced pressure. The crude product was directly used for the next step without further purification. Step 5. A Schlenk flask equipped with a stirrer bar was charged with the corresponding crude azide from step 4, Pd/C (20 %w/w) and ethyl acetate (5 mL/mmol). The reaction was stirred under hydrogen atmosphere for 12 h
153 Part II Engineering Bromide Catalysis for C(sp3)-H Functionalization using a gas balloon. The mixture was filtered through a pad of Celite and concentrated under reduced pressure to yield the crude amine. The crude product was directly used for the next step without further purification. Step 6. Step 3 of GP1. The crude product was purified by column chromatography (silica gel, hexane/ethyl acetate as eluent) to provide the pure compound 3n as a white solid in 80% overall yield.
Synthesis of 3o-r (GP2)
Scheme II.28. Pathway for the synthesis of 3o-r.
Step 1. In a flame-dried Schlenk tube, Pd(OAc)2 (11.2 mg, 0.049 mmol, 1 mol%), PPh3 (26.2 mg, 0.099 mmol, 2 mol%), the corresponding arylboronic acid (1.5 equiv.) and K3PO4 (4.25 g, 20.0 mmol, 4 equiv.) and toluene (15 mL) were added under argon. Then, the 2-(bromomethyl)benzonitrile (980.3 mg, 5.0 mmol, 1 equiv.) was added. The mixture was stirred at 80 °C until all starting material was consumed (monitored by TLC, 9 h) and then quenched with water. The solution was extracted with Et2O (3x) and the organic phase was washed with water, a 1 N solution of NaOH solution, brine and dried over anhydrous Na2SO4. The solvent was removed and the product isolated by flash column chromatography using hexane and ethyl acetate as eluent. Step 2. Step 2 of GP1. Step 3. Step 3 of GP1. Purification using column chromatography (hexane/ethyl acetate as eluent) afforded 3o-r.
Synthesis of 3s
Scheme II.29. Pathway for the synthesis of 3s.
154 Part II Engineering Bromide Catalysis for C(sp3)-H Functionalization
Step 1. In a flame-dried Schlenk tube, (±)-(1R,2S)-1-amino-2,3-dihydro-1H- inden-2-ol (1.0 equiv.), triethylamine (1.2 equiv.), tosyl chloride (1 equiv.) and CH2Cl2 (3 M) were charged. The reaction was stirred overnight at room temperature. CH2Cl2 is added, and the mixture is washed three times with a hydrochloride solution (10% HCl in water). The organic layer was dried over
Na2SO4 and the solvent evaporated under reduced pressure. A purification by column chromatography was performed prior to the next step. Step 2. In a flame-dried Schlenk tube, the pure alcohol from the precedent step (1.0 equiv.) is added to a suspension of NaH (1.2 equiv.) in THF (3 M) at 0°C. The mixture was stirred for 30 min at 0°C. Then, benzylbromide (1.1 equiv.) was added and the reaction mixture was stirred overnight at room temperature. The mixture was diluted with Et2O and washed with a saturated solution of NH4Cl. The organic layer was dried over Na2SO4 and the solvent evaporated under reduced pressure. The crude was purified by column chromatography using a mixture of ethyl acetate and hexane as eluent to finally get 3s as a colorless oil in 71% overall yield over 2 steps.
II.5.5 Characterization of the substrates 3a-t for the amination reaction N-(2,2-Dimethyl-4-phenylbutyl)-4-methylbenzenesulfonamide (3a)
Prepared according to the general procedure GP1, 3a was isolated as a white solid with an overall yield of 63%. The NMR spectra match those previously 158 1 described in literature. H NMR (400MHz, CDCl3): δ = 7.77 (d, J = 8.3 Hz, 2H), 7.31 (d, J = 8.3 Hz, 2H), 7.30-7.20 (m, 2H), 7.21- 7.18 (m, 1H), 7.17-7.14 (m, 2H), 4.71 (brt, 1H), 2.76 (d, J = 6.9 Hz, 2H), 2.54- 2.49 (m,2H), 2.44 (s, 3H), 1.54-1.50 (m, 2H), 0.95 (s, 6H). 13C NMR (125 MHz,
CDCl3): δ = 143.4, 142.7, 137.1, 129.8, 128.5, 128.4, 127.2, 125.8, 52.9, 41.6, 34.1, 30.4, 25.0, 21.6.
N-(2,2-Dimethyl-4-phenylbutyl-4-D)-4-methylbenzenesulfonamide (3a-D)
158 C. Martínez, K. Muñiz, Angew. Chem. Int. Ed. 2015, 54, 8287–8291.
155 Part II Engineering Bromide Catalysis for C(sp3)-H Functionalization
Prepared according to the procedure described above, 3a-D was isolated as a pale yellow oil with an 1 overall yield of 14%. H NMR (500 MHz, CDCl3): δ = 7.76 (d, J = 8.3 Hz, 2H), 7.35-7.26 (m, 4H), 7.21-7.14 (m, 3H), 4.59-4.44 (m, 1H), 2.77 (d, J = 6.9 Hz, 2H), 2.50 (t, J = 8.9 Hz, 1H), 2.45 13 (s, 3H), 1.54-1.49 (m, 2H), 0.95 (s, 6H). C NMR (125 MHz, CDCl3): δ = 143.3,
142.5, 137.0, 129.7, 128.4, 128.3, 127.1, 125.7, 52.9, 41.5, 34.0, 29.9, 24.9 (t, JC-D = 20Hz), 21.5. IR ν(cm-1): 3267, 3059, 3022, 2947, 2929. HRMS (m/z): [M+Na]+ calculated for C19H24DNNaO2S: 355.1561; found: 355.1563.
N-(2,2-Dimethyl-4-(p-tolyl)butyl)-4-methylbenzenesulfonamide (3b)
Prepared according to the general procedure GP1, 3b was isolated as a white solid with an overall yield of 72%. The NMR spectra match those previously described in literature.158 1H NMR (400 MHz,
CDCl3): δ = 7.77 (d, J = 8.3 Hz, 2H), 7.31 (d, J = 8.3 Hz, 2H), 7.30-7.20 (m, 2H), 7.21-7.18 (m, 1H), 7.17-7.14 (m, 2H), 4.71 (brt, 1H), 2.76 (d, J = 6.9 Hz, 2H), 2.54-2.49 (m, 2H), 2.44 (s, 3H), 1.54-1.50 (m, 2H), 0.95 (s, 6H). 13C NMR (101
MHz, CDCl3): δ = 143.4, 142.7, 137.1, 129.8, 128.5, 128.4, 127.2, 125.8, 52.9, 41.6, 34.1, 30.4, 25.0, 21.6.
N-(4-(4-Methoxyphenyl)-2,2-dimethylbutyl)-4- methylbenzenesulfonamide (3c)
Prepared according to the general procedure GP1, 3c was isolated as a white solid with an overall yield of 81%. The NMR spectra match those previously described in literature.158 1H
NMR (400 MHz, CDCl3): δ = 7.73 (d, J = 8.2 Hz, 2H), 7.29 (d, J = 7.7 Hz, 2H), 7.03 (d, J = 8.6 Hz, 2H), 6.80 (d, J = 8.5 Hz, 2H), 4.54 (t, J = 6.6 Hz, 1H), 3.78 (s, 3H), 2.72 (d, J = 6.8 Hz, 2H), 2.47-2.44 (m, 2H), 2.42 (s, 3H), 1.48-1.44 (m, 13 2H), 0.91 (s, 6H). C NMR (125 MHz, CDCl3): δ = 157.7, 143.4, 137.0, 134.7, 129.8, 129.3, 127.1, 113.9, 55.4, 52.9, 42.0, 34.1, 29.4, 25.2, 21.7.
N-(4-(4-Fluorophenyl)-2,2-dimethylbutyl)-4- methylbenzenesulfonamide (3d)
156 Part II Engineering Bromide Catalysis for C(sp3)-H Functionalization
Prepared according to the general procedure GP1, 3d was isolated as a white solid with an overall yield of 71%. The NMR spectra match those previously described in literature.158 1H NMR (400
MHz, CDCl3): δ = 7.78-7.73 (m, 2H), 7.29 (d, J = 8.1 Hz, 2H), 7.10-7.05 (m, 2H), 6.92 (t, J = 8.6 Hz, 2H), 4.88 (bs, 1H), 2.72 (d, J = 6.9 Hz, 2H), 2.49-2.44 (m, 2H), 2.41 (s, 3H), 1.52-1.42 (m, 2H), 0.91 (s, 6H). 13C NMR (101 MHz, CDCl3): δ = 161.3 (d, JC-F = 243.2 Hz), 143.5, 138.3, 138.2, 137.1, 129.7 (JH-F = 7.8 19 Hz), 127.2, 115.1 (JC-F = 21.1 Hz), 52.9, 41.6, 34.1, 29.6, 25.1, 21.6. F NMR (376
MHz, CDCl3): δ = -118.0.
N-(4-(4-Chlorophenyl)-2,2-dimethylbutyl)-4- methylbenzenesulfonamide (3e)
Prepared according to the general procedure GP1, 3e was isolated as a white solid with an overall yield of 88%. The NMR spectra match those previously described in literature.158 1H NMR (400
MHz, CDCl3): δ = 7.77-7.72 (m, 2H), 7.29 (d, J = 8.0 Hz, 2H), 7.22-7.19 (m, 2H), 7.07-7.04 (m, 2H), 4.68 (brs, 1H), 2.72 (d, J = 7.0 Hz, 2H), 2.50-2.43 (m, 13 2H), 2.42 (s, 3H), 1.50-1.44 (m, 2H), 0.91 (s, 6H). C NMR (101 MHz, CDCl3): δ = 143.5, 141.2, 137.1, 131.5, 129.9, 129.8, 128.5, 127.2, 52.9, 41.4, 34.2, 29.8, 25.1, 21.7.
N-(2,2-Dimethyl-4-(o-tolyl)butyl)-4-methylbenzenesulfonamide (3f)
Prepared according to the general procedure GP1, 3f was isolated as a white solid with an overall yield of 1 36%. H NMR (500 MHz, CDCl3): δ = 7.74 (d, J = 8.2 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), 7.12-7.06 (m, 4H), 4.41 (t, J = 6.9 Hz, 1H), 2.78-2.74 (m, 2H), 2.52-2.45 (m, 2H), 2.42 (s, 3H), 2.27 13 (s, 3H), 1.44-1.39 (m, 2H), 0.95 (s, 6H). C NMR (101 MHz, CDCl3): δ = 143.4, 140.6, 136.9, 135.6, 130.2, 129.7, 128.7, 127.1, 126.1, 126.0, 53.0, 40.3, 34.0, 27.5, 24.8, 21.5, 19.2. IR ν(cm-1): 3272, 2959, 2939, 2870, 1321, 1156, 1093, 1063, 874, + 809, 693, 663, 551. HRMS (m/z): [M+Na] calculated for C20H27NNaO2S: 368.1655; found: 368.1650. mp: 96-97 ºC.
N-(2,2-Dimethyl-4-(m-tolyl)butyl)-4-methylbenzenesulfonamide (3g)
157 Part II Engineering Bromide Catalysis for C(sp3)-H Functionalization
Prepared according to the general procedure GP1, 3g was isolated as a white solid with an overall yield of 1 30%. H NMR (500 MHz, CDCl3): δ = 7.74 (dd, J = 8.4, 2.2 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), 7.15 (t, J = 7.5 Hz, 1H), 6.99 (d, J = 7.6 Hz, 1H), 6.95 (s, 1H), 6.93 (d, J = 7.7 Hz, 1H), 4.51 (s, 1H), 2.73 (d, J = 7.0 Hz, 2H), 2.48-2.43 (m, 2H), 2.42 (s, 13 3H), 2.32 (s, 3H), 1.51-1.47 (m, 2H), 0.92 (s, 6H). C NMR (101 MHz, CDCl3): δ = 143.4, 142.6, 138.1, 137.1, 129.8, 129.2, 128.4, 127.2, 126.6, 125.4, 53.0, 41.7, 34.2, 30.3, 25.1, 21.7, 21.5. IR ν(cm-1): 3263, 2958, 2917, 2867, 1323, 1162, 1095, 1064, 815, 736, 705, 658, 572, 553. HRMS (m/z): [M+H]+ calculated for
C20H28NO2S: 346.1835; found: 346.1836. mp: 108-109 ºC.
N-(2,2-Dimethyl-4-phenylbutyl)methanesulfonamide (3h)
Prepared according to the general procedure GP1, 3h was isolated as a colorless liquid with an overall yield of 80%. The NMR spectra match those previously 158 1 described in literature. H NMR (400 MHz, CDCl3): δ = 7.33-7.28 (m, 2H), 7.24-7.18 (m, 3H), 4.74 (brs, 1H), 2.97 (d, J = 6.8 Hz, 2H), 2.95 (s, 2H), 2.64-2.58 (m, 2H), 1.62-1.56 (m, 2H), 1.02 (s, 6H). 13C NMR
(101 MHz, CDCl3): δ = 142.6, 128.6, 128.4, 126.0, 53.2, 41.7, 40.2, 34.3, 30.5, 25.0.
N-(2,2-Dimethyl-4-phenylbutyl)-4-nitrobenzenesulfonamide (3i)
Prepared according to the general procedure GP1, 3i was isolated as a white solid with an overall yield of 79%. The NMR spectra match those previously 158 1 described in literature. H NMR (400 MHz, CDCl3): δ = 8.34 (d, J = 8.8 Hz, 2H), 8.03 (d, J = 8.8 Hz, 2H), 7.30-7.26 (m, 2H), 7.23- 7.16 (m, 1H), 7.14 (d, J = 6.9 Hz, 2H), 4.80 (s, 1H), 2.83 (d, J = 6.9 Hz, 2H), 13 2.57-2.51 (m, 2H), 1.54-1.47 (m, 2H), 0.96 (s, 6H). C NMR (101 MHz, CDCl3): δ = 150.1, 146.0, 142.4, 128.6, 128.4, 128.3, 126.1, 124.5, 53.3, 41.5, 34.4, 30.4, 25.0.
N-(2,2-Dimethyl-4-phenylbutyl)cyclopropanesulfonamide (3j)
Prepared according to the general procedure GP1, 3j was isolated as a white solid with an overall 1 yield of 69%. H NMR (400 MHz, CDCl3): δ = 7.33- 7.28 (m, 2H), 7.24-7.17 (m, 3H), 4.61 (t, J = 6.8 Hz,
158 Part II Engineering Bromide Catalysis for C(sp3)-H Functionalization
1H), 3.01 (d, J = 6.8 Hz, 2H), 2.66-2.56 (m, 2H), 2.48-2.37 (m, 1H), 1.64-1.55 (m, 2H), 1.22-1.15 (m, 2H), 1.03 (s, 6H), 1.02-0.95 (m, 2H). 13C NMR (101 MHz,
CDCl3): δ = 142.7, 128.5, 128.4, 125.9, 53.2, 41.7, 34.3, 30.5, 30.0, 25.0, 5.4. IR ν(cm-1): 3268, 2951, 2867, 1307, 1152, 1135, 1068, 1045, 892, 724, 698, 566. + HRMS (m/z): [M+Na] calculated for C15H21NNaO2S: 302.1185; found: 302.1193. mp: 59-60 ºC.
N-(2,2-Dimethyl-4-phenylbutyl)thiophene-2-sulfonamide (3k)
Prepared according to the general procedure GP1, 3k was isolated as a yellowish solid with an overall yield of 63%. 1H NMR (400 MHz,
CDCl3): δ = 7.60 (ddd, J = 3.7, 1.4, 0.8 Hz, 1H), 7.57 (dd, J = 5.0, 1.3 Hz, 1H), 7.29-7.24 (m, 2H), 7.20-7.14 (m, 3H), 7.08 (dd, J = 5.0, 3.7 Hz, 1H), 4.61 (s, 1H), 2.85 (d, J = 6.9 Hz, 2H), 2.56-2.50 (m, 2H), 1.56-1.50 13 (m, 2H), 0.96 (s, 6H). C NMR (101 MHz, CDCl3): δ = 142.6, 141.1, 132.1, 131.8, 128.5, 128.4, 127.5, 125.9, 53.3, 41.7, 34.2, 30.4, 25.0. IR ν(cm-1): 3297, 3105, 2954, 2868, 1404, 1332, 1226, 1154, 1060, 1018, 846, 724, 701, 665, 573, 549. - HRMS (m/z): [M-H] calculated for C16H20NO2S2: 322.0941; found: 322.0939. mp: 90-91 ºC.
4-Methyl-N-((1-phenethylcyclohexyl)methyl)benzenesulfonamide (3l)
Prepared according to the general procedure GP1, 3l was isolated as a white solid with an overall yield of 61%. The NMR spectra match those previously 158 1 described in literature. H NMR (400 MHz, CDCl3): δ = 7.75 (d, J = 8.5 Hz, 2H), 7.31-7.28 (m, 2H), 7.28-7.24 (m, 2H), 7.20-7.16 (m, 1H), 7.14 (dt, J = 7.8, 1.2 Hz, 2H), 4.49 (brs, 1H), 2.82 (d, J = 6.9 Hz, 2H), 2.47-2.38 (m, 2H), 2.42 (s, 3H), 1.61-1.54 (m, 2H), 1.46-1.24 13 (m, 10H). C NMR (101 MHz, CDCl3): δ = 143.5, 142.9, 137.1, 129.9, 128.5, 128.5, 127.2, 125.9, 49.3, 37.5, 36.2, 33.6, 29.3, 26.2, 21.7, 21.4.
4-Methyl-N-(2-methyl-4-phenylbutyl)benzenesulfonamide (3m)
Prepared according to the general procedure GP1, 3m was isolated as a white solid with an overall yield of 88%. The NMR spectra match those previously 158 1 described in literature. H NMR (400 MHz, CDCl3):
159 Part II Engineering Bromide Catalysis for C(sp3)-H Functionalization
δ = 7.74 (dd, J = 8.1, 6.0 Hz, 2H), 7.27 (dd, J = 17.6, 8.0 Hz, 4H), 7.20-7.14 (m, 1H), 7.11 (dd, J = 8.1, 1.4 Hz, 2H), 4.56 (brs, 1H), 2.88 (dd, J = 12.6, 5.5 Hz, 1H), 2.78 (dd, J = 12.4, 6.4 Hz, 1H), 2.61 (ddd, J = 13.9, 9.7, 5.7 Hz, 1H), 2.50 (ddd, J = 13.8, 9.9, 6.0 Hz, 1H), 2.42 (s, 3H), 1.72-1.55 (m, 2H), 1.46-1.35 (m, 1H), 0.92 13 (d, J = 6.6 Hz, 3H). C NMR (101 MHz, CDCl3): δ = 143.4, 142.2, 137.2, 129.8, 128.6, 128.5, 127.2, 125.9, 49.0, 35.8, 33.1, 32.9, 21.6, 17.5.
N-(2-(2,3-Dihydro-1H-inden-2-yl)ethyl)-4- methylbenzenesulfonamide (3n)
Prepared according to the procedure described above, 3n was isolated as a white solid with an overall yield of 80%. The NMR spectra match those previously 158 1 described in literature. H NMR (400 MHz, CDCl3): δ = 7.77 (d, J = 8.3 Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H), 7.18-7.07 (m, 4H), 4.73 (brs, 1H), 3.05-2.94 (m, 4H), 2.56-2.45 (m, 3H), 2.43 (s, 3H), 1.67 (q, J = 7.1 Hz, 2H). 13 C NMR (101 MHz, CDCl3): δ = 143.5, 142.9, 137.1, 129.9, 127.2, 126.3, 124.5, 42.3, 39.0, 37.4, 35.5, 21.6.
4-Methyl-N-(2-(4-methylbenzyl)benzyl)benzenesulfonamide (3o)
Prepared according to the procedure GP2, 3o was isolated as a yellowish solid with an overall yield of 69%. 1H NMR (400 MHz, CDCl3): δ = 7.66 (d, J = 8.3 Hz, 2H), 7.32-7.27 (m, 2H), 7.25-7.12 (m, 4H), 7.04 (d, J = 7.8 Hz, 2H), 6.86 (d, J = 7.8 Hz, 2H), 4.26 (brs, 1H), 4.02 (d, J = 6.1 Hz, 2H), 3.89 (s, 2H), 2.45 13 (s, 3H), 2.32 (s, 3H). C NMR (101 MHz, CDCl3): δ = 143.6, 139.5, 137.2, 136.7, 135.9, 134.3, 131.0, 130.0, 129.8, 129.4, 128.5, 128.5, 127.4, 127.1, 45.2, 38.3, 21.7, 21.1. IR ν(cm-1): 3271, 3026, 2920, 1511, 1406, 1449, 1290, 1156, 1093, 1029, 899, 818, 751, 679, 550. HRMS (m/z): [M+Na]+ calculated for C22H23NNaO2S: 388.1342 found: 388.1346. mp: 113-114 ºC.
4-Methyl-N-(2-(thiophen-2-ylmethyl)benzyl)benzenesulfonamide (3p)
Prepared according to the procedure GP2, 3p was isolated as a yellowish solid with an overall yield of 31%. 1H NMR (400 MHz, CDCl3): δ = 7.74 (d, J = 8.3 Hz, 2H), 7.35 (d, J = 7.6 Hz, 2H), 7.33-7.29 (m, 1H), 7.29-7.22 (m, 3H), 7.18 (dd, J = 5.1, 1.2 Hz, 1H), 6.94 (dd, J = 5.1, 3.4 Hz, 1H), 6.66 (dq, J = 3.4, 1.1 Hz,
160 Part II Engineering Bromide Catalysis for C(sp3)-H Functionalization
1H), 4.42 (t, J = 6.1 Hz, 1H), 4.15 (s, 2H), 4.13 (d, J = 6.1 Hz, 2H), 2.50 (s, 3H). 13 C NMR (101 MHz, CDCl3): δ = 143.7, 143.6, 138.9, 136.6, 134.0, 130.5, 130.1, 129.9, 128.7, 127.5, 127.4, 127.0, 125.3, 124.3, 45.1, 33.1, 21.7. IR ν(cm-1): 3248, 2935, 2862, 1436, 1315, 1151, 1092, 1069, 816, 696, 551. HRMS (m/z): [M+Na]+ calculated for C19H19NNaO2S2: 332.0740; found: 332.0753. mp: 111-112 ºC.
N-(2-(benzo[b]thiophen-2-ylmethyl)benzyl)-4- methylbenzenesulfonamide (3q)
Prepared according to the procedure GP2, 3q was isolated as a white solid with an overall yield of 30%. 1H NMR (400 MHz, CDCl3): δ = 7.71 (d, J = 7.7 Hz, 1H), 7.65 (d, J = 8.0 Hz, 2H), 7.62 (d, J = 8.0 Hz, 1H), 7.34-7.21 (m, 8H), 6.80 (d, J = 1.0 Hz, 1H), 4.41 (t, J = 6.1 Hz, 1H), 4.18 (d, J = 1.3 Hz, 2H), 4.11 (d, 13 J = 6.0 Hz, 2H) 2.42 (s, 3H). C NMR (125 MHz, CDCl3): δ = 144.4, 143.6, 139.9 139.6, 138.0, 136.3, 134.2, 130.6, 129.9, 129.7, 128.7, 127.6, 127.2, 124.3, 123.8, 123.0, 122.1 121.6, 45.0, 33.8, 21.6. IR ν(cm-1): 3272, 1454, 1317, 1148, 1080, 744, 540. HRMS (m/z): [M+Na]+ calculated for
C23H21NNaO2S2: 430.0906; found: 430.0908. mp: 148-152 ºC.
N-(2-(furan-2-ylmethyl)benzyl)-4-methylbenzenesulfonamide (3r)
Prepared according to the procedure GP2, 3r was isolated as a brown solid with an overall yield of 36%. 1H NMR (400
MHz, CDCl3): δ = 7.74-7.70 (m, 2H), 7.30 (m, 2H), 7.25-7.15 (m, 5H), 6.27 (dd, J = 3.2, 1.9 Hz, 1H), 5.91-5.87 (m, 1H), 4.47 (s, 1H), 4.16-4.10 (s, 2H), 3.89 (s, 2H), 2.44 (s, 3H). 13C NMR (125 MHz, CDCl3): δ = 153.8, 143.7, 141.8, 136.7, 136.7, 134.1, 130.7, 130.1, 129.9, 128.7, 127.8, 127.4, 110.5, 106.5, 45.2, 31.4, 21.7. IR ν(cm-1): 3255, 1419, 1321, 1154, 1089, 1038, 1015, 705, 549. HRMS (m/z): [M+Na]+ calculated for
C19H19NNaO3S: 364.0978; found: 364.0982. mp: 105-107 ºC.
(±)-N-((1R,2S)-2-(Benzyloxy)-2,3-dihydro-1H-inden-1-yl)-4- methylbenzenesulfonamide (3s)
Prepared according to the procedure described above, 3s was isolated as a colorless oil with an overall yield of 71%. The NMR spectra match those previously described in literature.158 1H NMR (400 MHz, CDCl3): δ = 7.78 (d, J = 8.3 Hz, 2H), 7.36-7.27
161 Part II Engineering Bromide Catalysis for C(sp3)-H Functionalization
(m, 6H), 7.23-7.17 (m, 5H), 5.32 (d, J = 8.9 Hz, 1H), 4.45 (d, J = 11.2 Hz, 1H), 4.39 (d, J = 5.4 Hz, 1H), 4.27 (d, J = 11.3 Hz, 1H), 4.10 (dddd, J = 8.9, 7.9, 7.2, 13 5.4 Hz, 1H), 3.08-2.94 (m, 2H), 2.45 (s, 3H). C NMR (125 MHz, CDCl3): δ = 143.5, 141.4, 139.4, 138.1, 137.6, 130.0, 129.5, 128.5, 128.0, 127.9, 127.4, 126.8, 125.8, 125.4, 79.7, 70.4, 56.4, 37.9, 21.7.
N-(4-Methoxy-2,2-dimethylbutyl)-4-methylbenzenesulfonamide (3t)
Prepared according to the general procedure GP1, 3t was isolated as a white solid with an overall yield of 58%. The NMR spectra match those previously 158 1 described in literature. H NMR (400 MHz, CDCl3): δ = 7.69 (d, J = 8.2 Hz, 2H), 7.29 (d, J = 7.8 Hz, 2H), 5.37 (t, J = 7.1 Hz, 1H), 3.35-3.32 (m, 2H), 3.24 (s, 3H), 2.61 (d, J = 6.8 Hz, 2H), ), 2.41 (s, 3H), 1.48 (dd, J = 6.0, 5.2 Hz, 2H), 0.89 13 (s, 6H). C NMR (125 MHz, CDCl3): δ = 143.1, 137.4, 129.7, 127.1, 69.4, 58.7, 52.9, 39.5, 33.6, 26.4, 21.5.
II.5.6 Synthesis of the pyrrolidines 4a-t (GP3) A Schlenk flask was charged with mCPBA (77% purity, 89.6 mg, 0.4 mmol, 2.0 equiv.), Bu4NBr (12.9mg, 0.04 mmol, 20 mol%) and the corresponding sulfonyl amide 3 (0.2 mmol, 1.0 equiv.). The Schlenk tube was evacuated (2 min) and backfilled with argon, before 2 mL of absolute CH3CN were added. The solution was stirred at room temperature under daylight irradiation for 18 h. After that time, CH2Cl2 was added, the resulting solution was washed with saturated solutions of Na2S2O3 and NaHCO3 and extracted three times with CH2Cl2. The organic phase was dried over Na2SO4 and the solvent was removed under reduced pressure. Column chromatography (silica gel, hexane/ethyl acetate) afforded the corresponding pyrrolidines 4a-t.
II.5.7 Characterization of the pyrrolidines 4a-t 4,4-Dimethyl-2-phenyl-1-tosylpyrrolidine (4a)
Prepared according to the general procedure GP3, 4a was isolated as a white solid with a yield of 95%. The NMR spectra match those previously described in literature.158 1 H NMR (500 MHz, CDCl3): δ = 7.53 (d, J = 8.3 Hz, 2H),
162 Part II Engineering Bromide Catalysis for C(sp3)-H Functionalization
7.24-7.26 (m, 4H), 7.19-7.23 (m, 3H), 4.70 (dd, J = 9.4, 7.3 Hz, 1H), 3.44 (dd, J = 10.4, 1.5 Hz, 1H), 3.34 (d, J = 10.4, Hz, 1H), 2.39 (s, 3H), 2.02 (ddd, J = 12.8, 7.3, 1.5 Hz, 1H), 1.72 (dd, J = 12.8, 9.4 Hz, 1H), 1.05 (s, 3H), 0.77 (s, 3H). 13C NMR (125 MHz, CDCl3): δ = 143.1, 143.0, 135.9, 129.4, 128.4, 127.5, 127.2, 126.6, 63.9, 62.0, 51.7, 38.3, 26.2, 25.8, 21.6.
4,4-Dimethyl-2-(p-tolyl)-1-tosylpyrrolidine (4b)
Prepared according to the general procedure GP3, 4b was isolated as a white solid with a yield of 95%. The NMR spectra match those previously described in 158 1 literature. H NMR (500 MHz, CDCl3): δ = 7.55 (d, J = 8.2 Hz, 2H), 7.21 (d, J = 8.6 Hz, 2H), 7.17 (d, J = 8.1 Hz, 2H), 7.07 (d, J = 8.2 Hz, 2H), 4.65 (dd, J = 9.4, 7.2 Hz, 1H), 3.42 (dd, J = 10.4, 1.4 Hz, 1H), 3.34 (dd, J = 10.3, 0.8 Hz, 1H), 2.40 (s, 3H), 2.32 (s, 3H), 1.99 (ddd, J = 12.8, 7.2, 1.4 Hz, 1H), 1.72 (dd, J = 12.8, 9.4 Hz, 1H), 1.05 (s, 3H), 0.74 (s, 3H). 13C NMR (125
MHz, CDCl3): δ = 143.0, 140.0, 136.7, 135.8, 129.4, 129.0, 127.5, 126.5, 63.7, 61.9, 51.6, 38.1, 26.2, 25.8, 21.6, 21.2.
2-(4-Methoxyphenyl)-4,4-dimethyl-1-tosylpyrrolidine (4c)
Prepared according to the general procedure GP3, 4c was isolated as a white solid with a yield of 94%. The NMR spectra match those previously described in 158 1 literature. H NMR (500 MHz, CDCl3): δ = 7.51 (d, J = 8.2 Hz, 2H), 7.20 (d, J = 8.1 Hz, 2H), 7.18 (d, J = 8.7 Hz, 2H), 6.79 (d, J = 8.7 Hz, 2H), 4.66 (dd, J = 9.4, 7.2 Hz, 1H), 3.78 (s, 3H), 3.43 (dd, J = 10.4, 1.5 Hz, 1H), 3.32 (d, J = 10.4 Hz, 1H), 2.39 (s, 3H), 1.98 (ddd, J = 12.9, 7.3, 1.5 Hz, 1H), 1.71 (dd, J = 12.8, 9.5 Hz, 1H), 1.05 (s, 3H), 0.77 (s, 3H). 13C NMR (125
MHz, CDCl3): δ = 158.8, 142.9, 136.1, 134.9, 129.4, 127.8, 127.4, 113.8, 63.4, 61.9, 55.4, 51.6, 38.0, 26.2, 25.8, 21.6.
2-(4-Fluorophenyl)-4,4-dimethyl-1-tosylpyrrolidine (4d)
Prepared according to the general procedure GP3, 4d was isolated as a white solid with a yield of 76%. The NMR spectra match those previously described in 158 1 literature. H NMR (500 MHz, CDCl3): δ = 7.53 (d, J = 8.1 Hz, 2H), 7.21-7.23 (m, 4H), 6.92-6.96 (m, 2H), 4.68 (ddd, J = 9.1, 7.2 1.8 Hz, 1H), 3.43 (dt, J = 10.5, 1.6 Hz, 1H), 3.33 (d, J = 10.5 Hz, 1H), 2.40 (s, 3H),
163 Part II Engineering Bromide Catalysis for C(sp3)-H Functionalization
2.00 (ddt, J = 13.1, 7.3, 1.5 Hz, 1H), 1.68 (dd, J = 12.8, 9.5 Hz, 1H), 1.05 (d, J = 1.8 13 Hz, 3H), 0.76 (d, J = 3.4 Hz, 3H). C NMR (125 MHz, CDCl3): δ = 162.0 (d,
JC-F = 244.9), 143.3, 138.8, 135.9, 129.5, 129.2, 127.5, 115.2 (d, JC-F = 21.5 Hz), 63.3, 19 61.9, 51.7, 38.2, 26.2, 25.8, 21.6. F NMR (376 MHz, CDCl3): δ = -115.9.
2-(4-Chlorophenyl)-4,4-dimethyl-1-tosylpyrrolidine (4e)
Prepared according to the general procedure GP3, 4e was isolated as a white solid with a yield of 68%. The NMR spectra match those previously described in 158 1 literature. H NMR (500 MHz, CDCl3): δ = 7.54 (d, J = 8.2 Hz, 2H), 7.21-7.24 (m, 6H), 4.65 (dd, J = 9.3, 7.3 Hz, 1H), 3.42 (dd, J = 10.5, 1.4 Hz, 1H), 3.33 (d, J = 10.4 Hz, 1H), 2.41 (s, 3H), 2.00 (ddd, J = 12.8, 7.3, 1.4 Hz, 1H), 1.66 (dd, J = 12.8, 9.4 Hz, 1H), 1.04 (s, 3H), 0.74 (s, 3H). 13C NMR
(125 MHz, CDCl3): δ = 143.4, 141.6, 135.6, 132.8, 129.5, 128.5, 127.9, 127.5, 63.3, 61.9, 51.5, 38.2, 26.2, 25.8, 21.6.
4,4-Dimethyl-2-(o-tolyl)-1-tosylpyrrolidine (4f)
Prepared according to the general procedure GP3, 4f was isolated as a white solid with a yield of 87%. 1H NMR (500 MHz, CDCl3): δ = 7.55 (d, J = 8.3 Hz, 2H), 7.32-7.27 (m, 1H), 7.21 (d, J = 8.0 Hz, 2H), 7.12-7.06 (m, 3H), 5.00 (dd, J = 9.4, 7.4 Hz, 1H), 3.50 (dd, J = 10.5, 1.5 Hz, 1H), 3.35 (d, J = 10.4 Hz, 1H), 2.40 (s, 3H), 2.36 (s, 2H), 2.07 (ddd, J = 12.8, 7.4, 1.5 Hz, 1H), 1.61 (dd, J = 12.8, 9.4 Hz, 13 1H), 1.07 (s, 3H), 0.80 (s, 3H). C NMR (126 MHz, CDCl3): δ = 143.0, 141.1, 136.0, 134.1, 130.2, 129.3, 127.4, 126.7, 126.3, 126.2, 69.7, 61.7, 49.9, 38.3, 26.1, 25.8, 21.5, 19.3. IR ν(cm-1): 2958, 2883, 1566, 1493, 1462, 1343, 1303, 1160, 1089, 1024, 760, 660, 586, 548. HRMS (m/z): [M+Na]+ calculated for C20H25NNaO2S: 366.1498; found: 366.1501. mp: 135-136 ºC.
4,4-Dimethyl-2-(m-tolyl)-1-tosylpyrrolidine (4g)
Prepared according to the general procedure GP3, 4g was isolated as a white solid with a yield of 92%. 1H NMR (400 MHz, CDCl3): δ = 7.55 (d, J = 8.3 Hz, 2H), 7.24-7.20 (m, 2H), 7.20-7.15 (m, 1H), 7.10 (dt, J = 7.8, 1.6 Hz, 1H), 7.05-7.02 (m, 2H), 4.72 (dd, J = 9.5, 7.2 Hz, 1H), 4.23 (t, J = 7.1 Hz, 1H), 3.50 (dd, J = 10.3, 1.5 Hz, 1H), 3.36 (d, J = 10.3 Hz, 1H), 2.42 (s, 3H), 2.30 (s, 3H), 2.04 (ddd, J = 12.7, 7.2, 1.5 Hz, 1H), 1.74 (dd, J = 12.8, 9.5 Hz, 1H), 1.08 (s, 3H), 0.81 (s, 3H).
164 Part II Engineering Bromide Catalysis for C(sp3)-H Functionalization
13 C NMR (101 MHz, CDCl3): δ = 142.9, 142.8, 137.8, 136.1, 129.3, 128.2, 127.9, 127.4, 127.2, 123.8, 63.9, 61.9, 51.7, 38.2, 26.1, 25.7, 21.5, 21.5. IR ν(cm-1): 2961, 2925, 2876, 1598, 1459, 1340, 1156, 1087, 1057, 1028, 965, 800, 700, 661, 575, + 547. HRMS (m/z): [M+Na] calculated for C20H25NNaO2S: 366.1498; found: 366.1502. mp: 85-86 ºC.
4,4-Dimethyl-1-(methylsulfonyl)-2-phenylpyrrolidine (4h)
Prepared according to the general procedure GP3, 4h was isolated as a white solid with a yield of 98%. The NMR spectra match those previously described in literature.158 1 H NMR (400 MHz, CDCl3): δ = 7.39-7.35 (m, 4H), 7.32- 7.26 (m, 1H), 4.93 (dd, J = 9.8, 7.3 Hz, 1H), 3.69 (dd, J = 10.2, 1.7 Hz, 1H), 3.30 (d, J = 10.2 Hz, 1H), 2.55 (s, 3H), 2.22 (ddd, J = 12.8, 7.3, 1.8 Hz, 1H), 1.85 (dd, 13 J = 12.7, 9.8 Hz, 1H), 1.21 (s, 3H), 1.17 (s, 3H). C NMR (101 MHz, CDCl3): δ = 142.6, 128.8, 127.8, 126.9, 63.5, 61.5, 51.7, 40.7, 38.5, 25.8, 25.8.
4,4-Dimethyl-1-((4-nitrophenyl)sulfonyl)-2-phenylpyrrolidine (4i)
Prepared according to the general procedure GP3, 4i was isolated as a white solid with a yield of 71%. The NMR spectra match those previously described in literature.158 1 H NMR (400 MHz, CDCl3): δ = 8.11 (d, J = 8.8 Hz, 2H), 7.57 (d, J = 8.8 Hz, 2H), 7.15-7.20 (m, 3H), 7.09-7.11 (m, 2H), 4.87 (dd, J = 9.8, 7.2 Hz, 1H), 3.66 (dd, J = 9.9, 1.7 Hz, 1H), 3.30 (dd, J = 10.0, 0.9 Hz, 1H), 2.15 (ddd, J = 12.9, 7.3, 1.6 Hz, 1H), 1.79 (ddd, J = 13.1, 9.9, 0.9 Hz, 1H), 1.13 (s, 3H), 13 1.03 (s, 3H). C NMR (125 MHz, CDCl3): δ = 149.6, 145.9, 141.4, 128.5, 128.1, 127.8, 127.2, 123.8, 64.1, 61.9, 51.4, 38.6, 25.8, 25.7.
1-(Cyclopropylsulfonyl)-4,4-dimethyl-2-phenylpyrrolidine (4j)
Prepared according to the general procedure GP3, 4j was isolated as a white solid with a yield of 82%. 1H NMR (400 MHz, CDCl3): δ = 7.41-7.37 (m, 2H), 7.34 (ddd, J = 7.7, 6.6, 1.2 Hz, 2H), 7.29-7.24 (m, 1H), 4.94 (dd, J = 9.7, 7.3 Hz, 1H), 3.68 (dd, J = 10.2, 1.7 Hz, 1H), 3.34 (dd, J = 10.2, 0.8 Hz, 1H), 2.21 (ddd, J = 12.7, 7.3, 1.7 Hz, 1H), 2.01 (tt, J = 8.0, 4.9 Hz, 1H), 1.81 (dd, J = 12.7, 9.7 Hz, 1H), 1.22 (s, 3H), 1.16 (s, 3H), 1.09-1.00 (m, 1H), 0.89-0.76 (m, 2H), 13 0.62-0.55 (m, 1H). C NMR (101 MHz, CDCl3): δ = 143.5, 128.5, 127.4, 126.8, 63.5, 61.9, 51.8, 38.6, 30.5, 25.7, 5.4, 5.0. IR ν(cm-1): 2958, 2871, 1454, 1330,
165 Part II Engineering Bromide Catalysis for C(sp3)-H Functionalization
1307, 1141, 1072, 1042, 15 987, 888, 759, 696, 586, 563, 528. HRMS (m/z): + [M+Na] calculated for C15H21NNaO2S: 302.1185; found: 302.1193. mp: 56-57 ºC.
4,4-Dimethyl-2-phenyl-1-(thiophen-2-ylsulfonyl)pyrrolidine (4k)
Prepared according to the general procedure GP3, 4k was isolated as a yellowish solid with a yield of 63%. 1H NMR
(400 MHz, CDCl3): δ = 7.54 (dd, J = 5.0, 1.3 Hz, 1H), 7.43 (dd, J = 3.7, 1.3 Hz, 1H), 7.36-7.31 (m, 2H), 7.31-7.28 (m, 2H), 7.26-7.21 (m, 1H), 7.06 (dd, J = 5.0, 3.7 Hz, 1H), 4.72 (dd, J = 9.2, 7.3 Hz, 1H), 3.45 (s, 2H), 2.04 (dd, J = 12.8, 7.3 Hz, 1H), 1.78 (dd, J = 12.8, 9.3 Hz, 1H), 1.07 (s, 3H), 0.71 (s, 3H). 13C NMR (101 MHz, CDCl3): δ = 142.9, 138.7, 132.0, 131.5, 128.4, 127.5, 127.3, 126.5, 64.2, 62.2, 51.6, 38.2, 26.3, 25.7. IR ν(cm-1): 2959, 2874, 1466, 1351, 1223, 1152, 1092, 1068, 1053, 1025, 725, 697, 665, 601, 571, 545. HRMS (m/z): [M+Na]+ calculated for
C16H19NNaO2S2: 344.0748; found: 344.0748. mp: 139-140 ºC.
3-Phenyl-2-tosyl-2-azaspiro[4.5]decane (4l)
Prepared according to the general procedure GP3, 4l was isolated as a white foam with a yield of 94%. The NMR spectra match those previously described in literature.158 1 H NMR (500 MHz, CDCl3): δ = 7.59 (d, J = 8.2 Hz, 2H), 7.28-7.30 (m, 4H), 7.22-7.27 (m, 3H), 4.64 (dd, J = 9.4, 7.3 Hz, 1H), 3.64 (dd, J = 10.8, 1.4 Hz, 1H), 3.32 (d, J = 10.8 Hz, 1H), 2.42 (s, 3H), 2.13 (ddd, J = 13.0, 7.4, 1.4 Hz, 1H), 1.67 (dd, J = 13.0, 9.4 Hz, 1H), 1.28-1.45 (m, 13 9H), 1.01-1.05 (m, 1H). C NMR (125 MHz, CDCl3): δ = 143.1, 143.0, 135.5, 129.3, 128.3, 127.4, 127.0, 126.4, 63.1, 59.3, 49.6, 41.9, 36.4, 33.9, 25.9, 23.8, 22.8, 21.5.
(±)-(2S,4S)-4-Methyl-2-phenyl-1-tosylpyrrolidine and (±)-(2R,4S)-4- methyl-2-phenyl-1- tosylpyrrolidine (4m)
Prepared according to the general procedure GP3, 4m was isolated as a non-separable 1:1 mixture of diastereoisomers as a white solid with a yield of 74%. The NMR spectra match those previously described in literature.158 1H NMR (500 MHz, CDCl3): δ = 7.70 (d, J = 8.2 Hz, 4H), 7.63 (d, J = 8.2 Hz, 4H), 7.13- 7.34 (m, 10H), 4.87 (dd, J = 8.4, 2.4 Hz, 1H), 4.67 (dd, J = 9.5, 7.2 Hz, 1H), 3.86 (ddd, J = 11.1, 7.3, 1.4 Hz, 1H), 3.76 (ddd, J = 9.4, 6.9, 0.8 Hz, 1H), 3.11 (t, J =
166 Part II Engineering Bromide Catalysis for C(sp3)-H Functionalization
10.8 Hz, 1H), 2.90 (t, J = 9.3 Hz, 1H), 2.45 (s, 3H), 2.44 (s, 3H), 2.33-2.42 (m, 2H), 1.80-1.94 (m, 2H), 1.61 (ddd, J = 12.3, 10.6, 8.4 Hz, 1H), 1.50 (ddd, J = 12.7, 11.4, 9.5 Hz, 1H), 0.97 (d, J = 6.5 Hz, 3H), 0.90 (d, J = 6.6 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ = 143.4, 143.3, 143.2, 143.1, 135.7, 134.9, 129.6, 128.4, 128.3, 127.6, 127.5, 127.2, 127.0, 126.4, 126.2, 64.7, 63.3, 57.8, 55.9, 45.7, 43.6, 33.5, 31.4, 21.7, 21.6, 16.9, 16.7.
1-Tosyl-1,2,3,3a,4,8b-hexahydroindeno[1,2-b]pyrrole (4n)
Prepared according to the general procedure GP3, 4n was isolated as a white foam with a yield of 79%. The NMR spectra match those previously described in literature.158 1H NMR
(500 MHz, CDCl3): δ = 7.78-7.83 (m, 3H), 7.34 (d, J = 8.0 Hz, 2H), 7.24-7.28 (m, 2H), 7.15-7.17 (m, 1H), 5.15 (d, J = 7.8 Hz, 1H), 3.38 (ddd, J = 10.2, 7.2, 4.4 Hz, 1H), 3.23 (ddd, J = 10.2, 8.7, 6.7 Hz, 1H), 3.03 (dd, J = 16.6, 8.0 Hz, 1H), 2.67-2.75 (m, 2H), 2.44 (s, 3H), 1.84 (dtd, J = 14.2, 7.1, 4.4 Hz, 1H), 13 1.49-1.62 (m, 1H). C NMR (125 MHz, CDCl3): δ = 143.6, 142.0, 141.0, 135.0, 129.8, 128.3, 127.8, 127.4, 126.9, 125.0, 68.8, 49.3, 41.9, 35.9, 31.5, 21.6.
1-(p-Tolyl)-2-tosylisoindoline (4o)
Prepared according to the general procedure GP3, 4o was isolated as a white foam with a yield of 77%. 1H NMR (400 MHz, CDCl3): δ = 7.57 (d, J = 8.2 Hz, 2H), 7.26-7.04 (m, 9H), 6.85 (d, J = 7.9 Hz, 1H) 5.88 (s, 1H), 4.89-4.79 13 (m, 2H), 2.37 (s, 3H), 2.33 (s, 3H). C NMR (101 MHz, CDCl3): δ = 143.3, 141.3, 139.1, 137.6, 135.4, 135.2, 129.5, 129.2, 128.1, 128.0, 127.6, 127.5, 123.8, 122.5, 69.4, 54.1, 21.6, 21.3. IR ν(cm-1): 3029, 2920, 2848, 1485, 1346, 1160, 1093, 1047, 816, + 744, 667, 559. HRMS (m/z): [M+Na] calculated for C22H21NNaO2S: 386.1185; found: 386.1193. mp: 117-118 ºC.
1-(Thiophen-2-yl)-2-tosylisoindoline (4p)
Prepared according to the general procedure GP3, 4p was isolated as a yellowish oil with a yield of 59%. 1H NMR (400 MHz, CDCl3): δ = 7.56 (d, J = 8.3 Hz, 2H), 7.30-7.25 (m, 1H), 7.24-7.20 (m, 2H), 7.21-7.14 (m, 3H), 7.11 (dd, J = 4.0, 1.1 Hz, 1H), 7.09-7.02 (m, 1H), 6.92 (dd, J = 5.1, 3.5 Hz, 1H), 6.32 (d, J = 2.5 Hz, 1H), 4.82 (d, J = 14.6 Hz, 1H), 4.74 (dd, J = 13.6, 2.7 Hz, 1H), 2.36 (s, 3H). 13C NMR (101 MHz, CDCl3): δ = 145.9, 143.4, 140.4, 135.7, 135.3, 129.6, 128.5, 128.1, 127.4,
167 Part II Engineering Bromide Catalysis for C(sp3)-H Functionalization
126.5, 126.5, 126.1, 123.8, 122.6, 64.7, 53.3, 21.6. IR ν(cm-1): 3030, 2923, 2861, 1595, 1462, 1348, 1307, 1293, 1160, 1091, 1035, 820, 745, 669, 559, 540. HRMS + (m/z): [M+Na] calculated for C19H17NNaO2S2: 378.0593; found: 378.0598.
1-(Benzothiophen-2-yl)-2-tosylisoindoline (4q)
Prepared according to the general procedure GP3, 4q was isolated as a yellowish solid with a yield of 48%. 1H
NMR (400 MHz, CDCl3): δ = 7.72 (d, J = 8.0 Hz, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.58 (d, J = 8.0 Hz, 2H), 7.37- 7.20 (m, 6H), 7.10 (d, J = 8.0 Hz, 1H), 7.05 (d, J = 8.0 Hz, 2H), 6.36 (d, J = 2.5 Hz, 1H), 4.90-4.76 (m, 2H), 2.28 (s, 3H). 13C NMR (125
MHz, CDCl3): δ = 146.5, 143.5, 140.4, 139.8, 139.2, 135.5, 135.3, 129.5, 128.7, 128.2, 127.5, 124.5, 124.4, 123.9, 123.8, 123.0, 122.7, 122.5, 65.4, 53.6, 21.5. IR ν(cm-1): 2922, 1338, 1264, 1161, 1102, 813, 743, 725, 660, 508. HRMS (m/z): + [M+Na] calculated for C23H19NNaO2S2: 428.0749; found: 428.0751. mp: 137- 140 ºC.
1-(furan-2-yl)-2-tosylisoindoline (4r)
Prepared according to the general procedure GP3, 4r was isolated as a colorless oil with a yield of 38%. 1H NMR (400
MHz, CDCl3): δ = 7.55 (d, J = 8.3 Hz, 2H), 7.31-7.14 (m, 6H), 7.08-7.03 (m, 1H), 6.37 (dd, J = 3.3, 0.9 Hz, 1H), 6.28 (dd, J = 3.3, 1.8 Hz, 1H), 6.08 (d, J = 2.7 Hz, 1H), 4.86-4.71 (m, 2H), 2.36 (s, 3H). 13C NMR (125 MHz, CDCl3): δ = 153.2, 143.3, 142.7, 138.0, 135.9, 135.8, 129.6, 128.5, 128.0, 127.3, 123.5, 122.7, 110.3, 108.9, 62.5, 53.5, 21.6. IR ν(cm-1): 2964, 2921, 2853, 1344, 1258, 1165, 1097, 1011, 667. HRMS (m/z): [M+Na]+ calculated for
C19H17NNaO3S: 362.0821; found: 362.0817.
(±)-(2R,3aS,8aR/2S,3aR,8aS)-2-Phenyl-3-tosyl-3,3a,8,8a-tetrahydro-2H- indeno[1,2-d]oxazole (4s)
Prepared according to the general procedure GP3, 4s was isolated as a white solid with a yield of 54%. The NMR spectra match those previously described in literature.158 1 H NMR (400 MHz, CDCl3): δ = 7.80 (d, J = 8.2 Hz, 2H), 7.36 (d, J = 8.0 Hz, 2H), 7.22-7.28 (m, 4H), 7.12-7.16 (m, 1H), 7.06-7.10 (m, 3H), 6.97 (d, J = 7.9 Hz, 1H), 6.39 (s, 1H), 5.26 (d, J = 6.8 Hz, 1H), 4.80 (ddd, J = 8.3, 6.8, 3.5 Hz, 1H), 3.31 (dd, J = 17.5, 8.3 Hz, 1H), 3.07 (dd, J = 17.4, 3.4 Hz,
168 Part II Engineering Bromide Catalysis for C(sp3)-H Functionalization
13 1H), 2.47 (s, 3H). C NMR (125 MHz, CDCl3): δ = 144.4, 141.4, 139.2, 138.7, 134.8, 130.0, 129.6, 128.2, 127.9, 127.7, 127.2, 126.7, 125.8, 124.8, 93.3, 86.1, 62.4, 39.1, 21.8.
2-Methoxy-4,4-dimethyl-1-tosylpyrrolidine (4t)
Prepared according to the general procedure GP3, 4t was isolated as a yellowish oil with a yield of 98%. The NMR spectra match those previously described in literature.158 1H NMR (500
MHz, CDCl3): δ = 7.73 (d, J = 8.3 Hz, 2H), 7.29 (d, J = 8.6 Hz, 2H), 5.14 (dd, J = 6.0, 1.9 Hz, 1H), 3.36 (s, 3H), 3.13 (d, J = 9.8 Hz, 1H), 3.06 (d, J = 9.8 Hz, 1H), 2.41 (s, 3H), 1.71 (dd, J = 13.3, 1.9 Hz, 1H), 1.62 (dd, J = 13.3, 6.0 13 Hz, 1H), 1.14 (s, 3H), 0.89 (s, 3H). C NMR (125 MHz, CDCl3): δ = 143.4, 136.6, 129.6, 127.4, 92.9, 60.3, 55.8, 46.7, 38.3, 28.2, 27.9, 21.6.
II.5.8 Synthesis and characterization of 5 5 was synthesised following a procedure reported by Kashyap et al. for a related iodine compound.154
Trimethylsulfonium bis((3-chlorobenzoyl)oxy)bromate(I)(5)
Prepared according to the procedure described above, 5 was isolated as a yellowish solid with a yield of 87%. 1H NMR (500 MHz, DMSO-d6): δ = 7.91-7.84 (m, 4H), 7.60 (ddd, J = 8.0, 2.2, 1.2 Hz, 2H), 7.48 (td, J = 7.7, 0.7 Hz, 2H), 2.89 (s, 9H). 13C NMR (126 MHz, DMSO-d6): δ = 167.0, 136.5, 133.4, 131.8, 130.6, 129.2, 128.2, 26.7. IR ν(cm-1): 1665, 1571, 1418, 1437, 1284, 1239, 1137, 1069, 1040, 751, 709. HRMS (m/z): Decomposition during the ionization. mp: Decomposition at elevated temperature.
II.5.9 Synthesis of the active species I Silver m-chlorobenzoate (52.7 mg, 0.2 mmol, 1 equiv.) was converted with elemental bromine (10.2 µL, 0.2 mmol, 1 equiv.) in anhydrous CD2Cl2 (1 mL) at 0 °C in the absence of light under an inert atmosphere of argon. To be able to quantify the conversion in the upcoming reaction sequences, 1,2,4,5-tetrachloro-3-nitrobenzene (10.4 mg, 0.04 mmol, 0.2 equiv.) was added as an internal standard. After 1 h of stirring, the solution was quickly
169 Part II Engineering Bromide Catalysis for C(sp3)-H Functionalization filtered through a syringe filter and transferred to another light-protected, chilled down (0 °C) Schlenk-tube containing an atmosphere of argon. At this point, 0.25 mL of the solution was submitted to NMR maintaining a temperature of 0 ºC during the measurement to quantify the amount of 3- chlorobenzoyl hypobromite I. Based on the 1H NMR spectra, a 52% yield of the desired 3-chlorobenzoyl hypobromite I was calculated. As another proof-of-concept, the solution in the NMR tube was quenched by the addition of cyclohexene (30.2 µL) and directly submitted to 1H NMR again. While the formation of bromocarboxylate confirmed the presence of the 3- chlorobenzoyl hypobromite again, the remaining elemental bromine from the initial conversion of the silver benzoate could be quantified by the conversion with cyclohexene (3.5% of 1,2-dibromo cyclohexane was detected). Spectroscopic data of the intermediate I obtained in solution in DCM: 1H
NMR (500 MHz, CD2Cl2): δ = 8.13 (t, J = 1.9 Hz, 1H), 8.05 (dt, J = 7.8, 1.4 Hz, 1H), 7.67 (ddd, J = 8.0, 2.2, 1.1 Hz, 1H), 7.51 (t, J = 7.9 Hz, 1H).
II.5.10 Synthesis and characterization of the intermediate 6 In a flame-dried Schlenk tube, the substrate 3a was subjected to a solution of Me2(C18H37)2NBr (1 equiv.) and mCPBA (1 equiv.) in CD3CN (1 M). After 1 h of reaction, the mixture was filtered to remove the insoluble salt of ammonium carboxylate formed during this process. 6 could be isolated and fully characterized.
N-Bromo-N-(2,2-dimethyl-4-phenylbutyl)-4- methylbenzenesulfonamide (6)
Prepared according to the procedure described above, 6 was obtained in solution in acetonitrile. 1H NMR (400 MHz, Acetonitrile-d3): δ = 7.86 (d, J = 8.3 Hz, 2H), 7.48 (d, J = 8.0 Hz, 2H), 7.27 (m, 4H), 7.20 (m, 1H), 3.30 (s, 2H), 2.67-2.60 (m, 2H), 2.48 (s, 3H), 1.68-1.60 (m, 2H), 1.08 13 (s, 6H). C NMR (125 MHz, Acetonitrile-d3): δ = 145.2, 143.3, 132.2, 129.7, 129.1, 128.4, 128.3, 125.6, 67.7, 42.1, 35.7, 30.0, 24.9, 20.7. HRMS (m/z): + + [M+Na] calculated for C19H24BrNNaO2S: 432.0603; found: 432.0597, [M+K] calculated for C19H24BrKNO2S: 448.0343; found: 448.0358.
II.5.11 Synthesis of the substrates 7a-o for the oxaziridine formation
170 Part II Engineering Bromide Catalysis for C(sp3)-H Functionalization
Synthesis of 7a-n (GP4)
From the commercially available primary amines, the corresponding substrates 7a-n were synthesized following the step 3 of GP1 with the correct sulfonyl chloride.
Synthesis of 7o.
Scheme II.30. Pathway for the synthesis of 7o.
Step 1. In a flame-dried Schlenk tube, 2-(2-methylphenyl)acetonitrile (1 mL, 7.7 mmol, 1 equiv.) was dissolved in α,α,α-trifluorotoluene (20 mL). To this solution were added NBS (1.5 g, 1.1 equiv.) and AIBN (14 mg). The mixture was heated under reflux for 2 h. Water was added to quench the reaction and the organic phase was extracted, dried over Na2SO4 and concentrated under reduced pressure. The crude was directly used in the following step. Step 2. A flame-dried Schlenk tube equipped with a stirrer bar was charged with the previous crude material (1.0 equiv.), which was dissolved in DMF. Sodium azide (1.5 equiv.) was added and the reaction was stirred overnight at 90 ºC. H2O was added and the resulting mixture was extracted three times with Et2O. The organic layer was dried over Na2SO4 and the solvent evaporated under reduced pressure to yield the crude azide, which was directly used in the following step without further purification. Step 3. A flame dried Schlenk tube equipped with a stirrer bar was charged with the crude azide, Pd/C (20 w%) and ethanol (5 mL/mmol) and the reaction was stirred under one atmosphere of hydrogen pressure for 12 h. The mixture was then filtered through a plug of Celite and concentrated under reduced pressure to yield the crude amine, which was directly used in the subsequent final step. Step 4. Step 3 (GP1). Purification using a column chromatography and a mixture of ethyl acetate and hexane as eluent was carried out affording 7o as a brown solid with an overall yield of 25%.
171 Part II Engineering Bromide Catalysis for C(sp3)-H Functionalization
II.5.12 Characterization of the substrates 7a-o for the oxaziridine formation 4-Methyl-N-(3-phenylpropyl)benzenesulfonamide (7a)
Prepared according to the general procedure GP4, 7a was isolated as a white solid with a yield of 95%. The NMR spectra match those previously described in 159 1 literature. H NMR (400 MHz, CDCl3): δ = 7.77 (d, J = 8.3 Hz, 2H), 7.32 (d, J = 7.6 Hz, 2H), 7.29-7.27 (m, 2H), 7.23-7.17 (m, 1H), 7.12- 7.08 (m, 2H), 4.69 (brt, J = 6.5 Hz, 1H), 2.99 (q, J = 6.5 Hz, 2H), 2.62 (dd, J = 13 8.4, 6.8 Hz, 2H), 2.45 (s, 3H), 1.87-1.77 (m, 2H). C NMR (125 MHz, CDCl3): δ = 143.5, 141.0, 137.1, 129.8, 128.6, 128.5, 127.2, 126.2, 42.8, 32.8, 31.3, 21.6.
N-(3-(4-Methoxyphenyl)propyl)-4-methylbenzenesulfonamide (7b)
Prepared according to the general procedure GP4, 7b was isolated as a yellowish solid with a yield of 72%. The NMR spectra match those previously described in literature.160 1H NMR (400 MHz,
CDCl3): δ = 7.76-7.70 (m, 2H), 7.33-7.28 (m, 2H), 7.02-6.96 (m, 2H), 6.82- 6.76 (m, 2H), 4.51 (brt, 1H), 3.78 (s, 3H), 2.95 (q, J = 6.7 Hz, 2H), 2.54 (t, J = 7.6 Hz, 2H), 2.43 (s, 3H), 1.74 (dq, J = 8.7, 7.0 Hz, 2H). 13C NMR (125 MHz, CDCl3): δ = 158.1, 143.5, 137.1, 132.9, 129.8, 129.4, 127.2, 114.0, 55.4, 42.7, 31.9, 31.5, 21.7.
N-(3-(4-Chlorophenyl)propyl)-4-methylbenzenesulfonamide (7c)
Prepared according to the general procedure GP4, 7c was isolated as a yellowish solid with a yield of 1 72%. H NMR (400 MHz, CDCl3): δ = 7.73 (d, J = 8.3 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), 7.20 (d, J = 8.3 Hz, 2H), 7.00 (d, J = 8.3 Hz, 2H), 4.68 (t, J = 6.3 Hz, 1H), 2.93 (q, J = 6.7 Hz, 2H), 13 2.66-2.50 (m, 2H), 2.43 (s, 3H), 1.80-1.71 (m, 2H). C NMR (125 MHz, CDCl3): δ = 143.6, 139.4, 136.9, 131.9, 129.9, 128.7, 127.2, 42.5, 32.1, 31.2, 21.7. IR ν(cm-1): 3244, 2928, 2866, 1491, 1437, 1328, 1306, 1287, 1153, 1090, 1061, 811, 706, 664,
159 K. Dong, X. Fang, R Jackstell, M. Beller, Chem. Commun. 2015, 51, 5059–5052. 160 G. C. Tsui, F. Menard, M. Lautens, Org. Lett. 2010, 12, 2456–2459.
172 Part II Engineering Bromide Catalysis for C(sp3)-H Functionalization
+ 550. HRMS (m/z): [M+H] calculated for C16H19ClNO2S: 324.0820; found: 324.0827. mp: = 68-69 ºC.
N-(3-phenylpropyl)methanesulfonamide (7d)
Prepared according to the general procedure GP4, 7d was isolated as a white solid with a yield of 93%. The NMR spectra match those previously described in 161 1 literature. H NMR (400 MHz, CDCl3): δ = 7.33-7.27 (m, 2H), 7.23-7.16 (m, 3H), 4.53 (brt, 1H), 3.14 (t, J = 4.0 Hz, 2H), 2.93 (s, 3H), 13 2.75-2.67 (m, 2H), 1.95-1.87 (m, 2H). C NMR (125 MHz, CDCl3): δ = 140.9, 128.7, 128.5, 126.3, 42.8, 40.4, 32.9, 31.7.
4-Nitro-N-(3-phenylpropyl)benzenesulfonamide (7e)
Prepared according to the general procedure GP4, 7e was isolated as a white solid with a yield of 68%. 1H NMR (400 MHz, CDCl3): δ = 8.41-8.32 (m, 2H), 8.06- 8.02 (m, 2H), 7.28 (tt, J = 6.7, 1.1 Hz, 2H), 7.24-7.18 (m, 1H), 7.13-7.09 (m, 2H), 4.91 (s, 1H), 3.05 (t, J = 7.0 Hz, 2H), 2.64 (t, J = 7.5 Hz, 13 2H), 1.85 (dq, J = 8.5, 7.1 Hz, 2H). C NMR (125 MHz, CDCl3): δ = 150.2, 145.9, 140.5, 128.7, 128.4, 126.4, 124.5, 42.9, 32.7, 31.2. IR ν(cm-1): 3287, 3106, 3062, 2932, 1528, 1429, 1344, 1308, 1153, 1089, 1059, 965, 849, 732, 682, 611, 461. + HRMS (m/z): [M+Na] calculated for C15H16N2NaO4S: 343.0723; found: 343.0730. mp: 71-72 ºC.
N-(3-Phenylpropyl)thiophene-2-sulfonamide (7f)
Prepared according to the general procedure GP4, 7f was isolated as a brownish solid with a yield of 1 72%. H NMR (400 MHz, CDCl3): δ = 7.67-7.57 (m, 2H), 7.33-7.26 (m, 2H), 7.24-7.19 (m, 1H), 7.16-7.08 (m, 3H), 4.89 (s, 1H), 3.09 (t, J = 6.9 Hz, 2H), 2.66 (dd, J = 8.4, 6.9 Hz, 2H), 13 1.86 (dq, J = 8.8, 7.0 Hz, 2H). C NMR (125 MHz, CDCl3): δ =141.0, 140.9, 132.2, 131.9, 128.6, 128.5, 127.5, 126.2, 43.0, 32.8, 31.1. IR ν(cm-1): 3278, 3089, 3025, 2951, 2926, 1468, 1454, 1430, 1403, 1321, 1225, 1149, 1086, 1061, 1031, 1014,
161 S. O’Sullivan, E. Doni, T. Tuttle, J. A. Murphy, Angew. Chem. Int. Ed. 2014, 53, 474– 478.
173 Part II Engineering Bromide Catalysis for C(sp3)-H Functionalization
855, 753, 722, 701, 668, 589, 570, 545. HRMS (m/z): [M+Na]+ calculated for C13H15NNaO2S2: 304.0436; found: 304.0435. mp: 47-48 ºC.
4-Methyl-N-(3-phenoxypropyl)benzenesulfonamide (7g)
Prepared according to the general procedure GP4, 7g was isolated as a colorless oil with a yield of 68%. 1H NMR (400 MHz, CDCl3): δ = 7.77-7.68 (m, 2H), 7.30- 7.22 (m, 4H), 6.95 (tt, J = 7.3, 1.1 Hz, 1H), 6.85-6.80 (m, 2H), 4.82 (brs, 1H), 3.96 (td, J = 5.7, 1.2 Hz, 2H), 3.18 (t, J = 6.4 Hz, 2H), 2.40 13 (s, 3H), 1.99-1.90 (m, 2H). C NMR (125 MHz, CDCl3): δ = 158.5, 143.5, 136.9, 129.8, 129.6, 127.2, 121.2, 114.6, 65.7, 41.2, 29.2, 21.6. IR ν(cm-1): 3327, 3065, 2923, 2888, 1603, 1588, 1492, 1473, 1453, 1423, 1400, 1388, 1328, 1321, 1150, 1101, + 1083, 1042, 812, 755. HRMS (m/z): [M+Na] calculated for C16H19NNaO3S: 328.0978; found: 328.0986.
4-Methyl-N-phenethylbenzenesulfonamide (7h)
Prepared according to the general procedure GP4, 7h was isolated as a yellowish solid with a yield of 92%. The NMR spectra match those previously described in literature 162 1 H NMR (400 MHz, CDCl3): δ = 7.76-7.65 (m, 2H), 7.32- 7.20 (m, 5H), 7.12-7.05 (m, 2H), 4.51 (brt, 1H), 3.21 (t, J = 7.0 Hz, 2H), 2.76 (t, 13 J = 7.0 Hz, 2H), 2.43 (s, 3H). C NMR (125 MHz, CDCl3): δ = 143.5, 137.8, 137.0, 129.8, 128.9, 127.2, 126.9, 44.3, 35.9, 21.6.
N-(2-Bromophenethyl)-4-methylbenzenesulfonamide (7i)
Prepared according to the general procedure GP4, 7i was isolated as a white solid with a yield of 90%. The NMR spectra match those previously described in literature.163 1 H NMR (400 MHz, CDCl3): δ = 7.78-7.69 (m, 2H), 7.50 (dd, J = 7.9, 1.3 Hz, 1H), 7.33-7.26 (m, 2H), 7.20 (dtd, J = 14.6, 7.6, 1.7 Hz, 2H), 7.09 (ddd, J = 8.0, 7.0, 2.1 Hz, 1H), 4.71 (brt, J = 6.2 Hz, 1H), 3.31-3.19 (m, 2H), 13 2.93 (t, J = 7.1 Hz, 2H), 2.43 (s, 3H). C NMR (125 MHz, CDCl3): δ = 143.5, 137.3, 137.0, 133.1, 131.3, 129.8, 128.6, 127.8, 42.7, 36.5, 21.6.
162 K. Laha, N. Dayal, R. Jain, K. Patel, J. Org. Chem. 2014, 79, 10899–10907. 163 E. S. Sherman, P. H. Fuller, D. Kasi, S. R. Chemler, J. Org. Chem. 2007, 72, 3896–3905.
174 Part II Engineering Bromide Catalysis for C(sp3)-H Functionalization
N-Phenethyl-1-phenylmethanesulfonamide (7j)
Prepared according to the general procedure GP4, 7j was isolated as a white solid with a yield of 85%. 1 H NMR (400 MHz, CDCl3): δ = 7.39-7.30 (m, 7H), 7.28-7.24 (m, 1H), 7.19-7.15 (m, 2H), 4.21 (s, 2H), 4.09 (s, 1H), 3.26 (dd, J = 6.7 13 Hz, 2H), 2.80 (t, J = 6.8 Hz, 2H). C NMR (125 MHz, CDCl3): δ = 137.8, 130.7, 129.5, 129.0, 128.9, 128.9, 127.0, 59.0, 45.0, 36.7. IR ν(cm-1): 3299, 3063, 3028, 2932, 1528, 1494, 1454, 1424, 1302, 1156, 1117, 1081, 1030, 747, 694, 604, 546. + HRMS (m/z): [M+Na] calculated for C15H17NNaO2S: 298.0872; found: 298.0875. mp: 95-96 ºC.
N-Phenethylcyclopropanesulfonamide (7k)
Prepared according to the general procedure GP4, 7k was isolated as a yellowish oil with a yield of 78%. 1H
NMR (400 MHz, CDCl3): δ = 7.38-7.33 (m, 2H), 7.30- 7.27 (m, 1H), 7.26-7.22 (m, 2H), 4.24 (s, 1H), 3.46 (dd, J = 6.7 Hz, 2H), 2.91 (t, J = 6.9 Hz, 2H), 2.34 (tt, J = 8.0, 4.8 Hz, 1H), 1.20-1.13 13 (m, 2H), 1.02-0.93 (m, 2H). C NMR (125 MHz, CDCl3): δ = 137.9, 128.9, 127.0, 44.7, 36.8, 30.3, 5.5. IR ν(cm-1): 3284, 3203, 2943, 2882, 1322, 1309, 1144, 1074, + 890, 698. HRMS (m/z): [M+Na] calculated for C11H15NNaO2S: 248.0716; found: 248.0718.
N-Phenethylnaphthalene-2-sulfonamide (7l)
Prepared according to the general procedure GP4, 7l was isolated as a yellowish solid with a 1 yield of 79%. H NMR (400 MHz, CDCl3): δ = 8.45-8.38 (m, 1H), 8.00-7.91 (m, 3H), 7.78 (dd, J = 8.6, 1.9 Hz, 1H), 7.71-7.60 (m, 2H), 7.31-7.18 (m, 3H), 7.11-7.04 (m, 2H), 4.50 (t, J = 6.3 Hz, 1H), 3.30 (td, J = 6.9, 6.2 Hz, 2H), 2.79 (t, J = 6.9 Hz, 2H). 13C
NMR (125 MHz, CDCl3): δ = 137.5, 136.7, 134.8, 132.2, 129.5, 129.2, 128.8, 128.8, 128.7, 128.4, 127.9, 127.6, 126.9, 122.3, 44.2, 35.8. IR ν(cm-1): 3239, 3055, 3026, 2945, 1456, 1310, 1150, 1129, 1076, 1060, 950, 901, 827, 747, 699, 640, 550, 476. + HRMS (m/z): [M+Na] calculated for C18H17NNaO2S: 334.0872; found: 334.0872. mp: 128-129 ºC.
4-Fluoro-N-phenethylbenzenesulfonamide (7m)
175 Part II Engineering Bromide Catalysis for C(sp3)-H Functionalization
Prepared according to the general procedure GP4, 7m was isolated as a yellowish oil with a yield of 1 84%. H NMR (500 MHz, CDCl3): δ = 7.83 (ddt, J = 6.9, 5.0, 2.4 Hz, 2H), 7.33-7.22 (m, 2H), 7.21-7.14 (m, 2H), 7.13-7.08 (m, 2H), 4.49 (bs, 1H), 3.26 (dd, J = 6.7 Hz, 2H), 2.80 (t, J 13 = 6.9 Hz, 2H). C NMR (126 MHz, CDCl3): 165.2 (d, JC-F = 254.6 Hz), 136.9
(d, JC-F = 186.0 Hz), 129.9 (d, JC-F = 9.2 Hz), 129.0, 128.9, 128.8, 127.1, 116.5 (d, 19 - JC-F = 22.5 Hz), 44.3, 35.9. F NMR (376 MHz, CDCl3): δ = -105.47. IR ν(cm 1): 3257, 3020, 2938, 1608, 1489, 1330, 1284, 1150, 1094, 837, 554. HRMS (m/z): + [M+Na] calculated for C14H14FNNaO2S: 302.0621; found: 302.0629.
N-(3,3-Dimethylbutyl)-4-methylbenzenesulfonamide (7n)
Prepared according to the general procedure GP4, 7n was isolated as a colorless oil with a yield of 86%. The NMR spectra match those previously described in literature.164 1H
NMR (400 MHz, CDCl3): δ = 7.85-7.80 (m, 2H), 7.35-7.28 (m, 2H), 4.35 (brt, 1H), 3.02-2.87 (m, 2H), 2.43 (s, 3H), 1.42-1.30 (m, 2H), 0.84 (s, 9H). 13C NMR
(125 MHz, CDCl3): δ = 143.5, 137.1, 129.8, 127.2, 43.5, 40.1, 29.9, 29.4, 21.7.
N-(2-(Cyanomethyl)benzyl)-4-methylbenzenesulfonamide (7o)
Prepared according to the procedure described above, 7o was isolated as a brownish solid with an overall yield of 25%. 1 H NMR (300 MHz, CDCl3): δ = 7.76 (d, J = 8.3 Hz, 2H), 7.46- 7.16 (m, 6H), 4.51 (s, 1H), 4.10 (d, J = 6.2 Hz, 2H), 3.80 (s, 2H), 13 2.46 (s, 3H). C NMR (125 MHz, CDCl3): δ = 144.2, 136.2, 133.5, 130.4, 130.1, 129.7, 129.6, 129.5, 128.8, 127.4, 117.7, 45.6, 21.7, 21.1. IR ν(cm- 1): 3284, 1315, 1158, 1089, 1040, 672, 539. HRMS (m/z): [M+Na]+ calculated for C16H16N2NaO2S: 323.0825; found: 323.0826. mp: 120-124 ºC.
II.5.13 Synthesis of the oxaziridines 8a-o (GP5) A Schlenk flask was charged with mCPBA (77% purity, 89.6 mg, 0.4 mmol, 2.0 equiv.), Bu4NBr (12.9mg, 0.04 mmol, 20 mol%) and the corresponding sulfonyl amide 7 (0.2 mmol, 1.0 equiv.). The Schlenk tube was evacuated (2 min) and backfilled with argon, before 2 mL of absolute CH3CN were added. The solution was stirred at room temperature under daylight
164 M. Zhu, K.-i. Fujita, R. Yamaguchi, Org. Lett. 2010, 12, 1336–1339.
176 Part II Engineering Bromide Catalysis for C(sp3)-H Functionalization
irradiation for 18 h. After that time, CH2Cl2 was added, the resulting solution was washed with saturated solutions of Na2S2O3 and NaHCO3 and extracted three times with CH2Cl2. The organic phase was dried over Na2SO4 and the solvent was removed under reduced pressure. Column chromatography (silica gel, hexane/ethyl acetate) afforded the corresponding pyrrolidines 8a-o. The compounds easily decompose at elevated temperatures (40 ºC). To prevent decomposition, the water bath of the rotary evaporator was kept at room temperature and the crude mixtures as well as the final products were not exposed to higher temperatures that room temperature and were kept in the fridge.
II.5.14 Characterization of the oxaziridines 8a-o 3-Phenethyl-2-tosyl-1,2-oxaziridine (8a)
Prepared according to the general procedure GP5, 8a was isolated as a white solid with a yield of 60%. 1H NMR (400 MHz, CDCl3): δ = 7.85 (d, J = 8.3 Hz, 2H), 7.39 (d, J = 8.5 Hz, 2H), 7.30 (td, J = 6.8, 1.2 Hz, 2H), 7.25-7.16 (m, 3H), 4.67 (t, J = 4.8 Hz, 1H), 2.78 (t, J = 7.9 Hz, 2H), 2.47 (s, 3H), 2.19-2.09 13 (m, 2H). C NMR (125 MHz, CDCl3): δ = 146.4, 139.8, 131.6, 130.1, 129.4, 128.8, 128.4, 126.6, 77.7, 32.6, 29.8, 21.9. IR ν(cm-1): 3063, 3027, 2927, 2856, 1712, 1596, 1454, 1347, 1165, 1089, 699. HRMS (m/z): [M+Na]+ calculated for C16H17NNaO3S: 326.0827; found: 326.0831. mp: 97-98 °C.
3-(4-Methoxyphenethyl)-2-tosyl-1,2-oxaziridine (8b)
Prepared according to the general procedure GP5, 8b was isolated as a colorless oil with a yield of 59%. 1 H NMR (400 MHz, CDCl3): δ = 7.87-7.82 (m, 2H), 7.41-7.35 (m, 2H), 7.12-7.07 (m, 2H), 6.87-6.80 (m, 2H), 4.66 (t, J = 4.8 Hz, 1H), 3.79 (s, 3H), 2.72 (t, J = 7.8 Hz, 2H), 2.47 (s, 3H), 13 2.14-2.03 (m, 2H). C NMR (125 MHz, CDCl3): δ = 158.4, 146.4, 131.8, 131.7, 130.1, 129.4, 129.3, 114.2, 77.8, 55.4, 32.8, 28.9, 21.9. IR ν(cm-1): 3030, 3015, 2957, 2925, 1851, 1720, 1597, 1512, 1454, 1347, 1246, 1165, 1090, 1034, 813, 751, 660, 545. + HRMS (m/z): [M+Na] calculated for C17H19NNaO4S: 356.0927; found: 356.0929.
3-(4-Chlorophenethyl)-2-tosyl-1,2-oxaziridine (8c)
177 Part II Engineering Bromide Catalysis for C(sp3)-H Functionalization
Prepared according to the general procedure GP5, 8c was isolated as a colorless oil with a yield of 70%. 1H NMR (400 MHz, CDCl3): δ = 7.86-7.82 (m, 2H), 7.40- 7.37 (m, 2H), 7.27-7.24 (m, 2H), 7.12-7.09 (m, 2H), 4.66 (t, J = 4.6 Hz, 1H), 2.74 (t, J = 7.9 Hz, 2H), 2.47 (s, 3H), 2.11 (tt, J = 7.7, 13 4.8 Hz, 2H). C NMR (125 MHz, CDCl3): δ = 146.4, 138.2, 132.4, 131.6, 130.1, 129.8, 129.4, 128.9, 77.5, 32.4, 29.1, 21.9. IR ν(cm-1): 2954, 2924, 2854, 1726, 1492, 1348, 1165, 1090, 812. HRMS (m/z): [M+H]+ calculated for
C16H17ClNO3S: 338.0612; found: 338.0626.
2-(Methylsulfonyl)-3-phenethyl-1,2-oxaziridine (8d)
Prepared according to the general procedure GP5, 8d was isolated as a white solid with a yield of 44%. 1H NMR (400 MHz, CDCl3): δ = 7.32 (tt, J = 6.9, 1.0 Hz, 2H), 7.26- 7.19 (m, 3H), 4.73 (t, J = 4.7 Hz, 1H), 3.12 (s, 3H), 2.81 (t, J 13 = 7.9 Hz, 2H), 2.18 (tdd, J = 7.6, 4.7, 2.6 Hz, 2H). C NMR (125 MHz, CDCl3): δ = 139.7, 128.9, 128.4, 126.7, 76.8, 38.4, 32.5, 29.8. IR ν(cm-1): 3063, 3027, 2932, 2855, 1454, 1341, 1324, 1160, 964, 850, 751, 699, 518. HRMS (m/z): [M+Na]+ calculated for C10H13NNaO3S: 250.0508; found: 250.0511. mp: 76-77 °C.
2-[(4-Nitrophenyl)sulfonyl-3-phenethyl-1,2-oxaziridine (8e)
Prepared according to the general procedure GP5, 8e was isolated as a colorless oil with a yield of 65%. 1H
NMR (400 MHz, CDCl3): δ = 8.49-8.42 (m, 2H), 8.24- 8.17 (m, 2H), 7.37-7.30 (m, 2H), 7.29-7.19 (m, 3H), 4.85 (t, J = 4.7 Hz, 1H), 2.83 (t, J = 7.8 Hz, 2H), 2.21 (tt, J = 7.7, 4.4 Hz, 2H). 13C NMR
(125 MHz, CDCl3): δ = 140.7, 139.4, 130.7, 128.9, 128.4, 126.8, 124.6, 78.2, 32.4, 29.7. IR ν(cm-1): 3114, 3027, 1537, 1353, 1312, 1234, 1169, 1086, 855, 739, 554. + HRMS (m/z): [M+Na] calculated for C15H14N2NaO5S: 357.0516; found: 357.0515. mp: 88-89 ºC.
3-Phenethyl-2-(thiophen-2-ylsulfonyl)-1,2-oxaziridine (8f)
178 Part II Engineering Bromide Catalysis for C(sp3)-H Functionalization
Prepared according to the general procedure GP5, 8f was isolated as a colorless oil with a yield of 64%. 1 H NMR (400 MHz, CDCl3): δ = 7.87-7.84 (m, 2H), 7.36-7.31 (m, 2H), 7.27-7.20 (m, 4H), 4.68 (t, J = 4.7 Hz, 1H), 2.82 (t, J = 7.8 Hz, 2H), 2.18 (tt, J = 7.7, 4.8 13 Hz, 2H). C NMR (125 MHz, CDCl3): δ = 139.6, 136.8, 136.4, 133.5, 128.8, 128.4, 128.1, 126.6, 78.7, 32.5, 29.7. IR ν(cm-1): 3094, 2921, 1455, 1399, 1346, 1237, 1164, 1132, 1073, 1018, 859, 746, 731, 697, 543. HRMS (m/z): [M+Na]+ calculated for
C13H13NNaO3S2: 318.0229; found: 318.0233.
3-(2-Phenoxyethyl)-2-tosyl-1,2-oxaziridine (8g)
Prepared according to the general procedure GP5, 8g was isolated as a yellowish oil with a yield of 68%. 1H
NMR (400 MHz, CDCl3): δ = 7.88-7.81 (m, 2H), 7.38- 7.33 (m, 2H), 7.32-7.25 (m, 2H), 6.98 (tt, J = 7.3, 1.1 Hz, 1H), 6.90-6.85 (m, 2H), 4.92 (t, J = 4.8 Hz, 1H), 4.12-4.04 (m, 2H), 2.45 (s, 3H), 2.88 (tdd, J = 5.8, 13 4.7, 3.0 Hz, 2H). C NMR (125 MHz, CDCl3): δ = 158.4, 146.5, 133.1, 131.4, 129.6, 129.4, 121.3, 114.6, 76.6, 62.6, 31.3, 21.9. IR ν(cm-1): 3066, 3041, 2926, 2884, 2854, 1597, 1492, 1347, 1304, 1240, 1165, 1089, 1039, 814, 667. HRMS + (m/z): [M+H] calculated for C16H18NO4S: 320.0951; found: 320.0962.
3-Benzyl-2-tosyl-1,2-oxaziridine (8h)
Prepared according to the general procedure GP5, 8h was isolated as a colorless oil with a yield of 86%. 1H NMR (400
MHz, CDCl3): δ = 7.86-7.81 (m, 2H), 7.37 (d, J = 8.0 Hz, 2H), 7.34-7.28 (m, 3H), 7.25-7.20 (m, 2H), 4.81 (t, J = 5.2 Hz, 1H), 3.10 (dd, J = 14.6, 5.1 Hz, 1H), 3.03 (dd, J = 14.6, 5.3 Hz, 1H), 2.47 (s, 3H). 13C NMR (125 MHz,
CDCl3): δ = 146.4, 133.1, 131.5, 130.1, 129.4, 129.3, 129.0, 127.7, 78.2, 37.9, 21.9. IR ν(cm-1): 3065, 3032, 2925, 2852, 1595, 1494, 1445, 1399, 1347, 1237, 1187, 1165, + 1089, 823, 697, 546. HRMS (m/z): [M+H] calculated for C15H16NO3S: 290.0845; found: 290.0834.
3-(2-Bromobenzyl)-2-tosyl-1,2-oxaziridine (8i)
Prepared according to the general procedure GP5, 8i was isolated as a colorless oil with a yield of 55%. 1H NMR (400
MHz, CDCl3): δ = 7.81 (d, J = 8.1 Hz, 2H), 7.56 (d, J = 8.0 Hz, 1H), 7.36 (d, J = 8.0 Hz, 2H), 7.26-7.21 (m, 2H), 7.17-7.12 (m, 1H), 4.89 (t, J =
179 Part II Engineering Bromide Catalysis for C(sp3)-H Functionalization
13 4.9 Hz, 1H), 3.32-3.20 (m, 2H), 2.46 (s, 3H). C NMR (125 MHz, CDCl3): δ = 146.5, 133.1, 133.0, 131.7, 131.5, 131.4, 130.1, 129.5, 127.9, 124.8, 77.0, 37.8, 21.9. IR ν(cm-1): 3069, 3011, 2960, 2924, 2853, 1594, 1471, 1440, 1345, 1238, 1165, 1086, + 1021, 756, 715, 548. HRMS (m/z): [M+H] calculated for C15H15BrNO3S: 367.9951; found: 367.9949. X-ray crystal structure determination:
______Identification code CCDC 1583024 Empirical formula C15 H14 Br1 N1 O3 S1 Formula weight 368.24 Temperature 100(2) K Wavelength 0.71073 Å Crystal system Monoclinic Space group P2(1)/c Unit cell dimensions a = 14.2315(4)Å α = 90°. b = 13.5852(4)Å β = 94.175(3)°. c = 7.7380(2)Å γ = 90°. 3 Volume 1492.08(7) Å Z 4 3 Density (calculated) 1.639 Mg/m Absorption coefficient 2.903 mm-1 F(000) 744 3 Crystal size 0.2 x 0.1 x 0.1 mm Theta range for data collection 2.870 to 32.439°. Index ranges -21<=h<=21,-20<=k<=13, -11<=l<=7 Reflections collected 14382 Independent reflections 4965[R(int) = 0.0328] Completeness to theta =32.439° 92.3% Absorption correction Multi-scan
180 Part II Engineering Bromide Catalysis for C(sp3)-H Functionalization
Max. and min. transmission 0.760 and 0.585 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 4965/ 0/ 191 Goodness-of-fit on F2 1.047 Final R indices [I>2sigma(I)] R1 = 0.0356, wR2 = 0.0824 R indices (all data) R1 = 0.0467, wR2 = 0.0860 -3 Largest diff. peak and hole 0.949 and -0.560 e.Å
3-Benzyl-2-(benzylsulfonyl)-1,2-oxaziridine (8j)
Prepared according to the general procedure GP5, 8j was isolated as a white solid with a yield of 72%. 1H NMR (400 MHz, CDCl3): δ = 7.50-7.44 (m, 5H), 7.40- 7.32 (m, 3H), 7.27 (dd, J = 8.0, 1.6 Hz, 2H), 4.87 (dd, J = 5.4, 4.6 Hz, 1H), 4.63-4.45 (m, 2H), 3.21-3.02 (m, 2H). 13C NMR (125 MHz,
CDCl3): δ = 132.9, 131.2, 129.5, 129.4, 129.1, 129.0, 127.8, 126.1, 76.9, 57.6, 37.7. IR ν(cm-1): 3061, 3034, 1492, 1456, 1341, 1325, 1244, 1211, 1158, 855, 825, 729, + 695, 617, 550, 509. HRMS (m/z): [M+Na] calculated for C15H15NNaO3S: 312.0665; found: 312.0663. mp: 78-79 ºC.
3-Benzyl-2-(cyclopropylsulfonyl)-1,2-oxaziridine (8k)
Prepared according to the general procedure GP5, 8k was isolated as a colorless oil with a yield of 44%. 1H NMR (400 MHz, CDCl3): δ = 7.41-7.32 (m, 3H), 7.32-7.28 (m, 2H), 4.82 (t, J = 5.2 Hz, 1H), 3.14 (qd, J = 14.6, 5.2 Hz, 2H), 2.64 (tt, J = 8.0, 4.8 Hz, 1H), 1.40-1.34 (m, 2H), 1.25-1.14 (m, 2H). 13C NMR
(125 MHz, CDCl3): δ = 133.1, 129.5, 129.0, 127.8, 76.7, 37.9, 27.9, 6.1, 5.7. IR ν(cm-1): 3061, 3031, 2919, 1455, 1399, 1343, 1303, 1239, 1188, 1154, 1045, 887, 828, + 712, 699, 592, 504. HRMS (m/z): [M+Na] calculated for C11H13NNaO3S: 262.0508; found: 262.0513. mp: 71-72 ºC.
3-Benzyl-2-(naphthalen-2-ylsulfonyl)-1,2-oxaziridine (8l)
181 Part II Engineering Bromide Catalysis for C(sp3)-H Functionalization
Prepared according to the general procedure GP5, 8l was isolated as a white solid with a yield of 71%. 1H
NMR (400 MHz, CDCl3): δ = δ 8.59-8.53 (m, 1H), 8.05-7.92 (m, 4H), 7.70 (dddd, J = 26.2, 8.0, 6.8, 1.3 Hz, 2H), 7.35-7.23 (m, 5H), 4.93 (t, J = 5.2 Hz, 1H), 3.23-3.04 13 (m, 2H). C NMR (125 MHz, CDCl3): δ = 135.9, 133.0, 132.0, 131.7, 131.4, 130.0, 129.7, 129.7, 129.4, 129.0, 128.1, 127.9, 127.7, 123.4, 78.3, 37.8. IR ν(cm-1): 3059, 1455, 1346, 1238, 1165, 1132, 1073, 859, 757, 747, 697, 614, 546, 471. HRMS (m/z): [M+Na]+ calculated for C18H15NNaO3S: 348.0665; found: 348.0660. mp: 111-112 ºC.
3-Benzyl-2-[(4-fluorophenyl)sulfonyl]-1,2-oxaziridine (8m)
Prepared according to the general procedure GP5, 8m was isolated as a colorless oil with a yield of 60%. 1 H NMR (400 MHz, CDCl3): δ = 8.03-7.98 (m, 2H), 7.39-7.31 (m, 3H), 7.31-7.23 (m, 4H), 4.88 (t, J = 5.2 Hz, 13 1H), 3.18-3.05 (m, 2H). C NMR (125 MHz, CDCl3): δ
= 166.8 (d, JC-F = 256.0 Hz), 133.0, 132.4 (d, JC-F = 9.9 19 Hz), 129.3 (d, JC-F = 32.2 Hz), 127.8, 116.9 (d, JC-F = 22.8 Hz), 78.5, 37.9. F NMR -1 (376 MHz, CDCl3): δ = -101.06. IR ν(cm ): 3106, 3067, 3032, 2925, 1590, 1492, 1352, 1236, 1173, 1154, 1088, 836, 698, 545. HRMS (m/z): [M+Na]+ calculated for C14H12FNNaO3S: 316.0414; found: 316.0426.
3-Neopentyl-2-tosyl-1,2-oxaziridine (8n)
Prepared according to the general procedure GP5, 8n was isolated as a yellowish oil with a yield of 85%. 1H NMR (400
MHz, CDCl3): δ = 7.90-7.82 (m, 2H), 7.44-7.34 (m, 2H), 4.70 (t, J = 5.5 Hz, 1H), 2.47 (s, 3H), 1.68 (dd, J = 14.3, 5.3 Hz, 1H), 1.62 (dd, J = 14.2, 5.6 Hz, 1H), 1.04 (s, 9H). 13C NMR (125 MHz, -1 CDCl3): δ = 143, 131.9, 130.1, 129.4, 76.7, 44.6, 30.3, 29.8, 21.9. IR ν(cm ): 2959, 2870, 1596, 1471, 1347, 1234, 1165, 1090, 709, 568. HRMS (m/z): [M+H]+ calculated for C13H20NO3S: 270.1158; found: 270.1155.
2-(2-(2-Tosyl-1,2-oxaziridin-3-yl)phenyl)acetonitrile (8o)
182 Part II Engineering Bromide Catalysis for C(sp3)-H Functionalization
Prepared according to the general procedure GP5, 8o was isolated as a white solid with a yield of 97%. 1H NMR (400
MHz, CDCl3): δ = 7.93 (d, J = 8.4 Hz, 2H), 7.57-7.37 (m, 6H), 5.53 (s, 1H), 3.92 (d, J = 2.0 Hz, 2H), 2.51 (s, 3H). 13C NMR (125
MHz, CDCl3): δ = 147.0, 131.8, 131.1, 130.4, 130.1, 130.1, 129.9, 129.6, 128.8, 128.3, 117.2, 75.9, 22.0, 20.7. IR ν(cm-1): 2926, 2853, 1602, 1352, 1180, 1157, 1084, 566, + 546. HRMS (m/z): [M+Na] calculated for C16H14N2NaO3S: 337.0617; found: 337.0615. mp: 122-125 ºC.
183
184
Part III Cooperative Iodine and Photoredox Catalysis for C(sp3)-H Functionalization
185
186 Part III Cooperative Iodine and Photoredox Catalysis for C(sp3)-H Functionalization Part III Cooperative Iodine and Photoredox Catalysis for C(sp3)-H Functionalization
III.1 Introduction
Iodine was discovered by the French chemist Bernard Courtois from the extraction of sodium and potassium carbonate from the seaweed ash. Once the extraction of the latter was done, the ashes were treated with sulfuric acid. Once, by mistake, Bernard Courtois put too much sulfuric acid and a purple gas escaped. He noticed its condensation in cold metal objects created solid iodine. In the recent years, iodine is mainly extracted in Japan and Chile. Iodine and its relative compounds have emerged since they are environmentally benign, relatively cheap but still are not sufficiently used in industry. Recent achievements regarding the iodine catalysis is the development of new methodologies for C-O, C-N or C-C bond formation proved that is a versatile tool for the organic chemist.
III.1.1 Iodine-catalyzed C(sp3)-H oxygenation Several research groups have investigated iodide catalysis for selective oxygenation reactions. In all the cases, the iodide salt is oxidized by a peracid oxidant to generate in-situ (hypo)iodite species which is the actual catalyst of the transformation. Hypoiodite species are unstable under thermal or irradiation condition providing free radicals which undergo selective hydrogen atom abstraction at the weakest C(sp3)-H bond. Subsequent iodination and oxygenation occur to afford the desired final product. The mechanism is discussed more in details in the following close- related amination reaction (section III.1.2). Ishihara and co-workers established oxygenation reactions under iodide catalysis. Both intra- (Scheme III.1a) or intermolecular (Scheme III.1b) oxygenations were developed using tetrabutylammonium iodide as pre-
187 Part III Cooperative Iodine and Photoredox Catalysis for C(sp3)-H Functionalization catalyst and either hydrogen peroxide or TBHP as oxidant.165 As a result, lactonization could be accessed by cyclization of carboxylic acid derivatives and α-oxygenation of ketones could be developed using carboxylic acid as oxygen source. Remarkably, they also designed chiral ammonium iodide salts for enantioselective cyclization of phenols.166 As application of the latter, they were able to use these chiral ammonium salts to access tocopherol derivatives (Scheme III.1c).167
Scheme III.1. Iodide catalysis for oxygenation reaction developed by Ishihara and co- workers. Lactonization could be performed as well as oxygenation at α-position of ketones. Finally, enantioselective phenol cyclization was designed to afford tocopherol derivatives.
165 a) M. Uyanik, D. Suzuki, T. Yasui, K. Ishihara, Angew. Chem. Int. Ed. 2011, 50, 5331– 5334. b) M. Uyanik, D. Suzuki, M. Watanabe, H. Tanaka, K. Furukawa, K. Ishihara, Chem. Lett. 2015, 44, 387–389. 166 M. Uyanik, H. Okamoto, T. Yasui, K. Ishihara, Science 2010, 328, 1376–1379. 167 M. Uyanik, H. Hayashi, K. Ishihara, Science 2014, 345, 649–652.
188 Part III Cooperative Iodine and Photoredox Catalysis for C(sp3)-H Functionalization
Similarly, the group of Wan was able to perform intermolecular oxygenation at activated allylic position168 and at the α-position of heteroatom (Scheme III.2a).169 Yu et al. designed similar reaction condtions as well to achieve intermolecular benzylic oxygenation (Scheme III.2b).170 Surprisingly, in all these methods, decarboxylation or Hunsdiecker reactions’ side-products were never observed meaning that the formation of the O-I bond is probably not involved.
Scheme III.2. Iodide catalysis for oxygenation reaction of ether derivatives, at allylic and benzylic positions. Carboxylic acids were chosen as the best oxygen sources.
All these transformations were developed with an iodide salt as catalyst. Combination of a hypervalent iodine(III) oxidant and molecular iodine as
168 E. Shi, Y. Shao, S. Chen, H. Hu, Z. Liu, J. Zhang, X. Wan, Org. Lett. 2012, 14, 3384– 3387. 169 L. Chen, E. Shi, Z. Liu, S. Chen, W. Wei, H. Li, K. Xu, X. Wan, Chem. Eur. J. 2011, 17, 4085–4089. 170 J. Feng, S. Liang, S. Y. Chen, J. Zhang, S. Sen Fu, X. Q. Yu, Adv. Synth. Catal. 2012, 354, 1287–1292.
189 Part III Cooperative Iodine and Photoredox Catalysis for C(sp3)-H Functionalization catalyst enables direct oxidative cyclization of carboxylic acids as well. The group of Yokohama designed a methodology in which PIFA is used as oxidant (Scheme III.3).171 2-benzylbenzoic acid derivatives were successfully cyclized using this protocol. Indeed, since the pka of benzoic acids are higher than TFA, ligand exchange occurs at the hypervalent iodine(III) PIFA. Further reaction with molecular iodine provides the benzoyl hypoiodite(I) species. At this stage, no decarboxylation reaction was observed since benzoic acid derivatives in mild condition do not decarboxylate. A subsequent homolytic cleavage followed by a selective 1,5- HAT occur. The newly formed C-centred radical is quenched by molevular iodine to provide a benzylic iodide intermediate that is prone to cyclize affording the corresponding lactones.
Scheme III.3. Iodine catalysis for the lactonization of 2-benzylbenzoic acid derivatives developed by Yokohama and co-workers.
III.1.2 Iodine-mediated C(sp3)-H amination
III.1.2.1 Non-directed amination One of the strategies to perform an iodidee-mediated selective C(sp3)-H amination consists of generating free radicals. Once the latter are
171 H. Togo, T. Muraki, Y. Hoshina, K. Yamaguchi, M. Yokoyama, J. Chem. Soc., Perkin Trans. 1 1997, 787–793.
190 Part III Cooperative Iodine and Photoredox Catalysis for C(sp3)-H Functionalization formed, the weakest C-H bond in the molecule will be selectively targeted by the free radical. Usually, the weakest C-H bonds in a molecule is the activated carbon position such as benzylic, allylic, propargylic position… To avoid the presence of metals for such amination involving free radicals, iodide catalyzes were designed in the presence of TBHP as oxidant.172 TBHP oxidizes very quickly an iodide(-I) salt into tert-butylhypoiodite(I) (Scheme III.4). While heating, a homolytic cleavage of this species occurs generating in the media free radicals. The tert-butyl alcohol radical in-situ formed carries out a non-directed but selective hydrogen atom abstraction at the weakest activated C-H bond of the substrate. So far, it is not clear if another oxidation step is necessary to achieve the carbocation. It is more reasonable to assume that an alkyl iodide is formed followed by a nucleophilic substitution at the activated position by various nitrogen sources. The mechanism can be a radical chain mechanism or a radical recombination between the C-centered radical and the iodine radical. TBHP is used in large excess, usually three equivalents, and tert- butylammonium iodide in catalytic amount around 20 mol%. The nucleophiles for these methodologies are nitrogen-containing heterocycles and aniline derivatives.
172 a) X. Zhang, M. Wang, P. Li, L. Wang, Chem. Commun. 2014, 50, 8006–8009. b) W. Liu, C. Liu, Y. Zhang, Y. Sun, A. Abdukadera, B. Wang, H. Li, X. Ma, Z. Zhang, Org. Biomol. Chem. 2015, 13, 7154–7158.
191 Part III Cooperative Iodine and Photoredox Catalysis for C(sp3)-H Functionalization
Scheme III.4. Iodide catalysis for intermolecular amination at activated benzylic and allylic positions through the generation of free radicals.
III.1.2.2 The Hofmann-Löffler reaction (Stochiometric in iodine) These methodologies are robust but the major limitation of them is the predictability of the regioselectivity. As free radicals are involved, it is challenging to selectively target a position unless it is the weakest bond. One strategy to avoid this issue is to direct the C(sp3)-H functionalization at the position we want to tackle. We have seen both in the general introduction and in the first chapter that nitrogen-centered radicals can direct a C(sp3)-H amination by a 1,5-HAT. Also, the so-called Hofmann- Löffler reaction uses this property to direct the amination reaction at the δ- position. We have already seen that an ammonium bromide salt can be suitable to form the nitrogen-centered radical at sulfonamides. However, we were interested whether the iodine could be a appropriate halogen as well for such a reaction. In literature, molecular iodine was already used in stoichiometric amount to perform selective intramolecular C(sp3)-H amination passing through the N-I formation (Hofmann-Löffler reaction).
192 Part III Cooperative Iodine and Photoredox Catalysis for C(sp3)-H Functionalization
First, the group of Suarez in 1980 implemented an electron-withdrawing group at the nitrogen to get milder reaction condition for both the homolytic cleavage and for the 1,5-HAT as discussed in the previous chapter. Also, for the first time, the pre-formation of the N-X bond was not a requirement for the reaction to proceed. They designed a method in which the N-I is in-situ formed. A subsequent homolytic cleavage occurred under visible light irradiation (they used a 100 W tungsten filaments lamp) to generate the nitrogen-centered radical. In 1980, Suarez and co-workers implemented a nitro group at the nitrogen (Scheme III.5a), and they were able to perform intramolecular selective amination at non-activated position on steroid derivatives.173 Stochiometric amount of molecular iodine and really toxic oxidants such as lead tetraacetate or mercury oxide were used. Few years later, they discovered that phosphoramidate radicals were also efficient for selective amination reaction (Scheme III.5b).174 To circumvent the use of extremely toxic lead or mercury-based oxidants, they found out that hypervalent iodine(III) such as PhI(OAc)2 can be a suitable oxidant for such a transformation.175 Cyanamides (Scheme III.5c,d),176 nitroamines177 (Scheme III.5e) or phosphoramidates could be efficiently cyclized on steroid derivatives in milder conditions. Interestingly, transannular aminations could be achieved as well starting with lactams (Scheme III.5f).178 Remarkably, selective intramolecular amination on carbohydrates could be recently developed using carbamates or phosphoramidates as nitrogen source (Scheme III.5g).179 All these protocols require stoichiometric amount of both molecular iodine and oxidant.
173 R. Hernández, A. Rivera, J. A. Salazar, E. Suárez, J. Chem. Soc., Chem. Commun, 1980, 958–959. 174 C. Betancor, J. I. Concepción, J. A. Salazar, E. Suárez, J. Org. Chem. 1983, 48, 4432– 4433. 175 P. De Armas, R Carrau, J. I. Concepción, C. G. Francisco, R. Hernández, E. Suárez, Tetrahedron Letters, 1985, 26, 2493–2496. 176 R. Carrau, R. Hernández, E. Suárez, C. Betancor, J. Chem. Soc. Perkin. Trans 1 1987, 937–943. 177 P. De Armas, C. G. Francisco, R. Hernández, J. A. Salazar, E. Suárez, J. Chem. Soc. Perkin. Trans 1 1988, 3255–3265. 178 R. L. Dorta, C. G. Francisco, E. Suárez, J. Chem. Soc., Chem. Commun. 1989, 1168– 1169. 179 C. G. Francisco, A. J. Herrera, E. Suárez, J. Org. Chem. 2003, 68, 1012–1017.
193 Part III Cooperative Iodine and Photoredox Catalysis for C(sp3)-H Functionalization
Scheme III.5. Iodine mediated Hofmann-Löffler reaction developed by Suárez and co- workers. Various protecting groups were implemented at the nitrogen to destabilize the N-I bond and to activate the nitrogen-centered radical. Selected examples are displayed highlighting the amination of sophisticated molecules.
194 Part III Cooperative Iodine and Photoredox Catalysis for C(sp3)-H Functionalization
In 2007, the group of Wu extended the work of Suárez and co-workers implementing sulfonamide groups at the nitrogen and performing under the exact same reaction conditions the Hofmann-Löffler reaction at less sophisticated molecules (Scheme III.6a).180 By using this procedure, alkyl sulfonamides were cyclized at non-activated aliphatic carbon position. Nevertheless, they are still using stochiometric amount of both molecular iodine and hypervalent iodine oxidant. Our group in 2016 developed a stochiometric iodine-mediated Hofmann- Löffler reaction using NIS as iodine(I) reagent (Scheme III.6b).151 The reaction conditions are easy-to-handle and it proceeds smoothly toward the pyrrolidine’s formation. In the same year, Nagib et al. used large excesses of sodium iodide and hypervalent iodine(III) oxidant to achieve pyrrolidine derivatives (Scheme III.6c).181 The group used the exact same conditions for the generation of amino-alcohols from an imidate radical as well.182 Other applications were designed such as multiple halogenation event or oxazole synthesis for instance.183 All these methodologies require stoichiometric amount of iodine reagent to smoothly proceed.
180 R. Fan, D. Pu, F. Wen, J. Wu, J. Org. Chem. 2007, 72, 8994–8997. 181 E. A. Wappes, S. C. Fosu, T. C. Chopko, D. A. Nagib, Angew. Chem. Int. Ed. 2016, 55, 9974–9978. 182 E. A. Wappes, K. M. Nakafuku, J. Am. Chem. Soc. 2017, 139, 10204–10207. 183 a) E. A. Wappes, A. Vanitcha, D. A. Nagib, Chem. Sci. 2018, 9, 4500–4504. b) A. D. Chen, J. H. Herbort, E. A. Wappes, K. M. Nakafuku, D. N. Mustafa, D. A. Nagib, Chem. Sci. 2020, 11, 2479–2486.
195 Part III Cooperative Iodine and Photoredox Catalysis for C(sp3)-H Functionalization
Scheme III.6. Iodine mediated amination reaction through the Hofmann-Löffler type mechanism. In all the cases, stoichiometric amount of iodine reagent is necessary for the reactions to efficiently proceed.
III.1.2.3 The first iodine-catalyzed Hofmann-Löffler reaction When you have a close look at the equation of the Hofmann-Löffler reaction, there is no iodine atom ending up at the final pyrrolidine. As a result, our group started to investigate a plausible iodine catalysis design for such a transformation. In 2015, the first iodine-catalyzed Hofmann- Löffler reaction was designed.158 Only 2.5 mol% of molecular iodine is necessary for the reaction to proceed smoothly. A hypervalent iodine(III) oxidant PhI(mCBA)2 was found to be the best for the method’s efficiency. With the reaction conditions in hand, a broad scope illustrates the robustness of the methodology. Valuable tert-alkyl amines could also be synthesized as depicted in the Scheme III.7.
196 Part III Cooperative Iodine and Photoredox Catalysis for C(sp3)-H Functionalization
Scheme III.7. First iodine catalyzed Hofmann-Löffler reaction designed by Muñiz et.al. A selected example is displayed that represents a synthetic challenge but could be achieved using this iodine catalysis.
Regarding the mechanism, investigations have been carried out to determine the iodine active species of the reaction. The 3-chlorobenzoyl hypoiodite(I) formed in-situ from molecular iodine and PhI(mCBA)2 was identified to be the active catalyst enabling the formation of the N-I bond (Scheme III.8). Upon visible light irradiation, the nitrogen-centered radical is formed. A subsequent selective 1,5-HAT provides the carbon- centered radical that following a radical chain mechanism (quantum yield of 44) reacts with another N-iodinated molecule. The alkyliodide(I) intermediate is then oxidized by the hypervalent iodine(III) oxidant to the alkyliodide(III) thus allowing the cyclization step to be fast enough to release the iodine catalyst and the product. Right after the publication of all our halogen catalysis regarding the Hofmann-Löffler chemistry, the group of Nagib developed an iodine catalysis for selective C(sp3)-H amination via the imidate radical.184
184 L. M. Stateman, E. A. Wappes, K. M. Nakafuku, K. M. Edwards, D. A. Nagib, Chem. Sci. 2019, 10, 2693–2699.
197 Part III Cooperative Iodine and Photoredox Catalysis for C(sp3)-H Functionalization
Scheme III.8. Mechanism of the first iodine catalyzed Hofmann-Löffler reaction designed by Muñiz et.al.
With this background in hand, we were wondering if we could eradicate the use of a stochiometric amount of a non-commercial hypervalent iodine(III) oxidant. Having this problematic in mind, we were thinking about two possibilities to use only a catalytic amount of oxidant. The first solution was the electrochemistry and our group indeed developed a protocol to achieve pyrrolidine formation with only the use of an anodic oxidation.123 The second solution was to implement a photoredox catalyst to the system.
III.1.3 Photoredox catalysis for direct C(sp3)-H functionalization Direct C(sp3)-H amination or oxygenation are not really developed in the field of photoredox catalysis. Nitrogen-centered radicals can be generated under photoredox catalysis but they are often used for C(sp2)-H
198 Part III Cooperative Iodine and Photoredox Catalysis for C(sp3)-H Functionalization amination.128 Or, these nitrogen-centered radicals are used to guide a C-C bond formation at non-activated position such as in the outstanding work of the groups of Rovis and Knowles.185 For direct amination or oxygenation of C(sp3)-H bond, the strategy employed by the group of Laha was to perform arene oxidations by SET. Using this strategy, the benzylic radical and then the benzylic carbocation can be accessed. Then, interception by an internal or external nucleophile occur. With this new concept in hand, they designed both inter- and intramolecular reactions to achieve both oxygenation and amination transformation (Scheme III.9).186
Scheme III.9. C(sp3)-H functionalization using photoredox catalyst designed by Laha and co-workers. The mechanism consists in oxidizing the arene moiety to generate the benzylic carbocation.
185 a) J. C. K. Chu, T. Rovis, Nature 2016, 539, 272–275. b) G. J. Choi, Q. Zhu, D. C. Miller, C. J. Gu, R. R. Knowles, Nature 2016, 539, 268–271. 186 a) G. Pandey, S. Pal, R. Laha, Angew. Chem. Int. Ed. 2013, 52, 5146–5149. b) G. Pandey, R. Laha, Angew. Chem. Int. Ed. 2015, 54, 14875–14879. c) G. Pandey, R. Laha, P. K. Mondal, Chem. Commun. 2019, 55, 9689–9692
199 Part III Cooperative Iodine and Photoredox Catalysis for C(sp3)-H Functionalization
Finally, the group of Brasholz designed a lactonization reaction using the organic dye DDQ (Scheme III.10).187 First, the arene moiety gets oxidized by SET by DDQ and forms the benzylic radical after a quick benzylic deprotonation. Then, a second oxidation step by SET occurs from the radical DDQH enabling the formation of an activated benzylic carbocation. A subsequent cyclization step occurs to afford the lactone formation. DDQ was used in catalytic amount in combination with tert-butyl nitrite for its re-oxidation.
Scheme III.10. Lactonization designed by Brasholz and co-workers using DDQ as oxidant. A double oxidation event through SET occur generating the benzylic carbocation. A selected example is displayed where the 2-benzylbenzoic acid is cyclized.
III.2 Aims of part III
The objective of this section was to develop an iodine catalysis in combination with an organic dye for the Hofmann-Löffler reaction. We aimed to use a catalytic amount of oxidant. Therefore, the goal was to find a suitable organic dye which can oxidize the iodine catalyst. Another objective was to extend the amination reaction to lactonization using the same cooperative system. We aimed to understand better the N-I bond by investigating theoretically its cleavage conditions.
III.3 Results and discussion for direct C(sp3)-H amination
In the mechanism of the first iodine catalyzed Hofmann-Löffler reaction presented above, an iodide anion is extruded during the cyclization step and re-oxidized by a stochiometric amount of oxidant. Our
187 F. Rusch, J. Schober, M. Brasholz, ChemCatChem 2016, 8, 2881–2884.
200 Part III Cooperative Iodine and Photoredox Catalysis for C(sp3)-H Functionalization idea was to use a photoredox catalyst to carry out this oxidation step. This process would be the first photoredox-catalyzed reoxidation of an iodine - 0 - catalyst. We know that the redox potential of I /I2 at 298 K in water is E (I
/I2) = + 0.54 V vs ESH. As a result, we hypothesized to engage a photoredox catalyst that has a higher redox potential. As our objective was also to design a metal-free protocol, we focused on organic dyes as plausible oxidants.188
III.3.1 Study of the N-I bond: calculation To correctly design our new methodology, we wanted to know more about the N-I bond cleavage’s conditions of the intermediate VIII. Since our trials to isolate this extremely unstable species failed, we did a collaboration with the group of Markus Reiher at ETH Zurich to perform computational studies to obtain more information about the N-I bond. They calculated the ten lowest excited states of VIII for both an open and a close conformation (Scheme III.11). Both structures are close in terms of energy (0.15 kcal/mol). Among the ten lowest exited states, the seven lowest of them correspond to excitations of the LUMO of VIII and therefore facilitate the N-I bond cleavage. The transition energies of these excitation states cover a range of 100 nm with the lowest transition energy being approximately 380 nm. Considering the conformational freedom and the typical error of the calculation methods, the wavelength range for the lowest transition energy is [335;425] nm. It corresponds to the wavelength of the black or blue LEDs.
188 N. A. Romero, D. A. Nicewicz, Chem. Rev. 2016, 116, 10075–10166.
201 Part III Cooperative Iodine and Photoredox Catalysis for C(sp3)-H Functionalization
Scheme III.11. Computed LUMO orbitals for the open and close conformation for the intermediate VIII. The wavelength range for the homolytic cleavage is [335;425] nm.
III.3.2 Development of the cooperative catalysis for C(sp3)-H amination At the beginning of our investigation, we did not know the optimum wavelength to cleave the N-I bond. As a result, we screened three organic dyes, TPT (2,4,6-triphenylpyrylium tetrafluoroborate) and the Fukuzumi’s catalyst (Mes-Acr-M+) that can be exited with blue LEDs and the eosin Y which has its maximal absorption at 539 nm (Scheme III.12).187,189
189 Electrochemical Series of Photocatalysts and Common Organic compounds, D. DiRocco, 2014.
202 Part III Cooperative Iodine and Photoredox Catalysis for C(sp3)-H Functionalization
Scheme III.12. Organic dyes selected for the optimization of the reaction condition.
Then, we optimized the reaction conditions. First, as it is mentioned above, three organic dyes were tested in combination with a catalytic amount of molecular iodine. DCE was selected as solvent in the first trial since it was the optimum solvent for the first iodine-catalyzed Hofmann-Löffler reaction we designed.158 Moreover, we worked in anhydrous condition and under inert argon atmosphere. Under these reaction conditions, only traces of products were NMR detected (Table III.1, entries 1-3). Since we do not have a sacrificial reagent to re-oxidise the organic dye, we thought that oxygen from the air could play this role (E0 = + 0.99 V vs SCE). Unfortunately, only traces were still noticed by NMR (entries 4-6). Carrying out the reaction in an impurified solvent results in traces of products for both the Fukuzumi’s catalyst and the eosin Y (entries 7 and 9) while 20% of isolated yield was achieved using TPT (entry 8). 1 TPT has the extremely important feature to not generate singlet oxygen O2 by energy transfer from its triplet excited state 3TPT* to the oxygen ground 3 state O2 under usual photooxygenation conditions. Also, TPT has the great 3 advantage to not generate from the oxygen ground state O2 the superoxide .- radical anion O2 . Therefore, TPT avoids reactivity that is usually jeopardizing the efficiency of the methodology due to unproductive quenching reactions under aerobic conditions.190 At this stage of the development, we tried all the available solvent in the laboratory without any success and we only got traces or less than 20% conversion. We decided to back up and think what the issue was. We
190 M. A. Miranda, H. Garcia, Chem. Rev. 1994, 94, 1063–1089
203 Part III Cooperative Iodine and Photoredox Catalysis for C(sp3)-H Functionalization decided to assess the maximum wavelength of the LED we were using. We were using at the beginning of the project a single LED which was irradiating from the bottom part of the reactor. We built another type of set-up with several stripes of blue LEDs irradiating from all the sides of the reactor (Scheme 13). Then, we screened again all the possible solvents and when we tried the solvent mixture of DCE and HFIP, the yields dramatically improved. The use of a 1/4 mixture of DCE/HFIP, 72% of yield was achieved (entry 10) whereas a 1/1 mixture provided a slightly better yield of 84% isolated yield (entry 11). Finally, reducing the amount of the non-polar, aprotic solvent DCE or even performing the reaction in only HFIP resulted in a decreased NMR yield of 64% (entry 12) and 57% (entry 13) respectively. We were then interested in reducing the amount of both catalysts. Keeping the amount of molecular iodine at 10 mol%, we first reduced the quantity of TPT from 5 mol% to 2 mol%. We observed a dropping in the isolated yield from 84% to 58% (entry 14). But, while reducing simultaneously both amounts of catalysts (2 mol% of TPT and 5 mol% of molecular iodine (entry 15), the isolated yield increased again to 80%. Indeed, molecular iodine itself is absorbing the blue light at high concentration causing an unproductive absorption of the light and therefore avoiding the excitation of TPT. We assessed the wavelength of the LEDs we were working with and we found that the peak wavelength was at 456 nm (Scheme 13). The blue LEDs start to irradiate at 410 nm. We were surprised to see that the maximum absorption of the TPT was not in perfect adequation with the maximum wavelength of the used blue LEDs. Having already nice isolated yields, we continued with the same set-up.
204 Part III Cooperative Iodine and Photoredox Catalysis for C(sp3)-H Functionalization
Scheme III.13. Irradiation of one LED of the stripes: [410-525] nm.
With only 5 mol% of molecular iodine, the catalyst loading of TPT could be reduced to 1 mol% (entry 16) to afford 90% of isolated products. Decreasing again either the amount of molecular iodine to 2 mol% (entry 17) or the amount of TPT to 0.5 mol% (entry 18) resulted to a dropping NMR yield of 31% and 76% respectively. These results proved the importance of the ratio between both catalysts for the effectiveness and robustness of the reaction. Three control experiments were then carried out to start the investigation of the mechanism and to prove the necessity of both catalysts. In the absence of molecular iodine, with 1 mol% of TPT, 14% NMR yield was achieved (entry 19) with decomposition side-products, this is corresponding to a double oxidation step by TPT (two consecutive SET) to afford the benzylic carbocation followed by a cyclization. When only molecular iodine (5 mol%) was submitted (entry 20), 5% of NMR yield was observed corresponding to a stochiometric reaction of the molecular iodine. Finally, while performing the reaction in the dark-room (entry 21), only starting material was recovered from the reaction mixture. The optimal reaction conditions are the following: Molecular iodine and TPT are used in 5 mol% and 1 mol% respectively. The reaction is set-up in non-purified DCE and HFIP (1/1 ratio) at the concentration of 0.1 M and in an open-air tube. The reaction mixture is stirred 18 h at room temperature under blue LED irradiation.
205 Part III Cooperative Iodine and Photoredox Catalysis for C(sp3)-H Functionalization
Table III.1. Optimization of the cooperative catalysis between molecular iodine and an organic dye for the selective C(sp3)-H amination reaction.
Entry I2 Organic dye Solvent hν Yield 1a 10 mol% FC (5 mol%) DCE Blue LEDs Traceb 2a 10 mol% TPT (5 mol%) DCE Blue LEDs Traceb 3a 10 mol% EY (5 mol%) DCE Green LEDs Traceb 4c 10 mol% FC (5 mol%) DCE Blue LEDs Traceb 5c 10 mol% TPT (5 mol%) DCE Blue LEDs Traceb 6c 10 mol% EY (5 mol%) DCE Green LEDs Traceb 7d 10 mol% FC (5mol%) DCE Blue LEDs Traceb 8d 10 mol% TPT (5 mol%) DCE Blue LEDs 20% 9d 10 mol% EY (5 mol%) DCE Green LEDs Traceb 10d 10 mol% TPT (5 mol%) DCE/HFIP (4/1) Blue LEDs 72%b 11d 10 mol% TPT (5 mol%) DCE/HFIP (1/1) Blue LEDs 84% 12d 10 mol% TPT (5 mol%) DCE/HFIP (1/4) Blue LEDs 64%b 13d 10 mol% TPT (5 mol%) HFIP Blue LEDs 57%b 14d 10 mol% TPT (2 mol%) DCE/HFIP (1/1) Blue LEDs 58% 15d 5 mol% TPT (2 mol%) DCE/HFIP (1/1) Blue LEDs 80% 16d 5 mol% TPT (1 mol%) DCE/HFIP (1/1) Blue LEDs 90% 17d 2 mol% TPT (1 mol%) DCE/HFIP (1/1) Blue LEDs 31%b TPT (0.5 18d 5 mol% DCE/HFIP (1/1) Blue LEDs 76%b mol%) 19d -- TPT (1 mol%) DCE/HFIP (1/1) Blue LEDs 14%b 20d 5 mol% -- DCE/HFIP (1/1) Blue LEDs 5%b 21e 5 mol% TPT (1 mol%) DCE/HFIP (1/1) Blue LEDs SM a Experiments carried out under argon atmosphere and with purified solvents. b 1,3,5-trimethoxybenzene used as internal standard for the determination of the NMR yield. c Experiments carried out open-air and with purified solvents. d Experiments carried out open-air and with unpurified solvents. e Experiment carried out in the dark room.
III.3.3 Scope of the cooperative catalysis for C(sp3)-H amination With the optimized reaction conditions and the calculation of the photolytic cleavage of the N-I bond in hand, we then investigated the
206 Part III Cooperative Iodine and Photoredox Catalysis for C(sp3)-H Functionalization robustness of the methodology applying it at various starting materials (Scheme III.14). We started to study the effect of para-substituents at the phenyl moiety installed at the δ-position. The 4-methyl or 4-fluoro substituents are well tolerated (10b-c) and could be isolated in 88% and 90% yield respectively while the efficiency starts to drop when a chloro- or a bromo-substituted substrate was submitted. The corresponding pyrrolidines 10d and 10e were isolated with 57% and 31% respectively. The reason is that electron-enriched arenes are well-known quenchers for the organic dye TPT.189,191 2- or 3-methyl-substituted arenes were affording products 10f and 10g in excellent (90%) to moderate yield (60%) respectively. The slight drop of yield for the ortho-methyl-substituted substrate is due to steric hindrance. Usual sulfonyl groups such as the mesyl or the nosyl were successfully providing the final products 10h and 10i in 90% and 60% isolated yields. A cyclopropyl radical sensitive group was tolerated as well since it could be isolated in 88% yield (10j). This example is an irrefutable evidence of the high selectivity of the amination reaction since no side-products coming from the cyclopropane ring opening was noticed. An electron-enriched thiophenyl group was untouched after the cyclization reaction which proceeds efficiently since the corresponding pyrrolidine 10k was obtained with 96% yield. This is another key reaction proving that no electrophilic iodination takes place in the mild designed reaction conditions. Finally, regarding the screening of different sulfonyl moieties, the removable 2-(trimethylsilyl)ethanesulfonyl group (SES) was well tolerated and the final product 10l was obtained with a good yield of 52%. The backbone of the alkyl chain was then investigated. Indeed, various substituents at the β-position were assessed such as a spiro-cyclohexyl or a methyl group. The corresponding pyrrolidines 10m and 10n were successfully obtained in 81% and 70% yield respectively. Expectedly, an inseparable mixture of diastereoisomers was achieved for the latter. Even the substituent-free backbone substrate reacted proficiently since the corresponding product 10o was isolated in 81% yield. It was concluded that the Thorpe Ingold effect is not a requirement for the reaction to proceed efficiently. In the case of the ring-annulated product 10p, only one diastereoisomer was obtained in the excellent yield of 82%. Previously inaccessible from the iodine-catalyzed Hofmann-Löffler reaction,158 isoindolines 10q and 10r could be synthesized with the excellent yields of
191 a) R. Akaba, H. Sakuragi, K. Tokumaru, J. Chem. Soc., Perkin. Trans. 2 1991, 291–297. b) S. S. Jayanthi, P. Ramamurthy, J. Phys. Chem. A 1997, 101, 2016–2022. c) P. Jacques, X. Allonas, J. Chem. Soc. Faraday Trans. 1993, 89, 4267–4269.
207 Part III Cooperative Iodine and Photoredox Catalysis for C(sp3)-H Functionalization
94% and 73% respectively. For the first time, other protecting groups than sulfonamides could be employed. Benzamide and trifluoroacetamide group were applicable, leading to the pyrrolidine 10s and 10t in 82% and 70% isolated yield respectively.
Scheme III.14. Scope of the cooperative iodine and photoredox catalysis for the selective C(sp3)-H amination reaction. a A 1:1-mixture of diastereoisomers was
208 Part III Cooperative Iodine and Photoredox Catalysis for C(sp3)-H Functionalization obtained. b The reported yield refers to NMR yield determined using 1,3,5- trimethoxybenzene as internal standard.
6-membered ring piperidine derivatives could be observed as trace while using the optimized conditions for the formation of the pyrrolidines but further optimization would probably lead to better isolated yields. Almost surely, the mechanism involved is different. As a result, we did not continue to investigate in this direction. Another limitation of the methodology is the requirement of an activated benzylic position. Indeed, the reaction involves an alkyliodine(I) intermediate that does not able the cyclization at non-activated aliphatic position. It requires additional activation by the activated benzylic position. Finally, as discussed above, electron-enriched arenes are quenching the organic dye TPT. As a result, starting materials were fully recovered.
Scheme III.15. Unsuccessful substrates for the iodine/photoredox catalysis for the selective C(sp3)-H amination reaction.
III.3.4 Mechanistic investigation
III.3.4.1 Quenching experiments To ensure the involvement of radical species, radical quenchers such as BHT, 1,2-diphenylethene or TEMPO were added to the reaction mixture (Scheme III.16). In all the cases, starting material was recovered. Although we cannot rule out the possibility of the deactivation of the catalytic system prior to radical formations, the effective quenching suggest a radical reaction to be the dominant process.
209 Part III Cooperative Iodine and Photoredox Catalysis for C(sp3)-H Functionalization
Scheme III.16. Quenching experiments by radical quenchers. No reactivity was observed for the selective C(sp3)-H amination reaction.
III.3.4.2 Kinetic isotope effect To investigate the reaction mechanism, isotope labelling experiment was carried out. In order to determine the KIE, the mono- benzylic-deuterated substrate 9o-D was synthesized and submitted to the optimized reaction conditions (Scheme III.17). A crude NMR was recorded to get the ratio between the deuterated and the non-deuterated pyrrolidine. Therefore, the KIE was obtained from the relative amount of products formed from the C(sp3) amination of the C-H vs the C-D bond. A KIE of 2.3 was obtained and suggests that the rate-determining step might be the C- H bond cleavage.156
Scheme III.17. Isotope labelling experiment was carried out with 9o-D. Intramolecular competition provided a KIE of 2.3 meaning that the C-H bond cleavage might be the rate-determining step of the selective C(sp3)-H amination reaction.
Interestingly, this extremely crucial result indicates us that the C-H bond cleavage might be the rate-determining step. This is in favor of a Hofmann- Löffler-type mechanism where a selective 1,5-HAT from the nitrogen- centered radical IX is involved (Scheme III.18a) and disfavors the plausible arene oxidation (Scheme III.18b) by the organic dye (E0(9a/9a.+) = 1.79 V 123 vs Ag/AgNO3). Indeed, the arene oxidation by a SET from the TPT results to the formation of an arene radical cation XI bearing a benzylic C(sp3)-H position. At this stage, the acidity of the benzylic hydrogen atom is dramatically increased192 (the pka is about 10) making it an extremely strong acid that deprotonates readily to afford X. Therefore, the KIE should be closer to 1 in the case of the arene oxidation mechanism. Nevertheless, we cannot completely rule out the fact that even if the deprotonation of the
192 a) M. Schmittel, A. Burghart, Angew. Chem. Int. Ed. Engl. 1997, 36, 2550–2589. b) M. Mella, M. Freccero, A. Albini, Tetrahedron 1996, 52, 5533–5548. c) A. M. de P. Nicholas, R. J. Boyd, D. R. Arnold, Can. J. Chem. 1982, 60, 3011–3018.
210 Part III Cooperative Iodine and Photoredox Catalysis for C(sp3)-H Functionalization benzylic position is supposed to be extremely fast, it does not mean that it is not the rate limiting step of the overall process. As a result, we had the hypothesis that the Hofmann-Löffler-type mechanism is the most probable.
Scheme III.18. Plausible pathways for the cooperative catalysis between molecular iodine and TPT for the selective C(sp3)-H amination reaction.
III.3.4.3 Iodine active species During the optimization process, we noticed that the reaction proceeded better while we were using non-purified solvents. As a result, we hypothesized that water seemed to play a key role in the mechanism. The use of the protic polar solvent HFIP also indicated us the plausible formation of (hypo)iodite species. With all the background on hypoiodite active species catalyst for oxygenation reported for instance by Ishihara and co-workers (see III.1.1), we wondered if (hypo)iodite or iodate species were in-situ generated to provide the N-iodinated intermediate VIII.165,193 In order to prove their formation, we employed RAMAN spectroscopy technique to identify them. The first experiment was to record the RAMAN spectrum of the solvent mixture (Scheme III.19a). Several bands could be identified for the latter. When mixing 5 mol% of molecular iodine in the solvent mixture (Scheme III.19b), two new bands could be observed and
193 J. C. Wren, S. Sunder, J. Paquette,B. L. Ford, Can. J. Chem. 1986, 64, 2284–2296.
211 Part III Cooperative Iodine and Photoredox Catalysis for C(sp3)-H Functionalization assigned to molecular iodine (210 cm-1) and to hypoiodite [OI]- (410 cm-1). - - - - Other inorganic iodine species such as [I3] , [I2OH] , [IO2] or [IO3] were not detected in our experiments (vibrational bands expected at 110 cm-1, 566 cm- 1, 685 cm-1 and 768 cm-1 respectively). A spectrum of the dye (1 mol%) in the solvent mixture was also recorded to identify its own bands (Scheme III.19c). Finally, the spectrum of the reaction mixture was taken as well after 2 h of blue LEDs irradiation (Scheme III.19d). The two bands corresponding to molecular iodine and hypoiodite species are still visible. Although the reaction had been stirred in the dark for 2 h, the exact same spectrum was obtained (Scheme III.19e). These observations agree with the capacity of molecular iodine to perform a disproportionation reaction with water to afford both iodide and hypoiodite species.
Scheme III.19. RAMAN experiments carried to determine whether inorganic iodine species could be detected. A band corresponding to hypoiodite was observed.
III.3.4.4 Proposed mechanism Having all the information in hand, we proposed a mechanism in which the blue LEDs play a dual role in two intertwined individual catalytic cycles (Scheme III.20). As we observed in RAMAN spectroscopy, molecular iodine in the non-purified wet solvent mixture can rapidly disproportionates into hypoiodite. As an assumption, HFIP can also help to the formation of the N-iodinated intermediate VIII from the
212 Part III Cooperative Iodine and Photoredox Catalysis for C(sp3)-H Functionalization hexafluoroisopropyl hypoiodite. Once VIII is generated in-situ, blue LEDs irradiation affords the nitrogen-centered radical IX which undergo a selective 1,5-HAT at the activated benzylic position. This step is assumed to be the rate-determining step of the overall process since the KIE is 2.3. A rapid cyclization enables the pyrrolidine formation and the quick extrusion of the iodide. Under blue LEDs irradiation, TPT gets excited and oxidizes t .- 0 - the iodide (E (TPT*/TPT ) = + 2.3 V vs SCE and E (I /I2) = + 0.54 V vs ESH) into molecular iodine. Oxygen coming from the open-air system re- oxidizes the reduced form of the dye (E0(TPT.-/TPT) = - 0. 35 V vs SCE and 0 E (O2/H2O) = 0.99 V vs SCE).
213 Part III Cooperative Iodine and Photoredox Catalysis for C(sp3)-H Functionalization
Scheme III.20. Mechanism of the cooperative catalysis between molecular iodine and TPT for the Hofmann-Löffler reaction.
214 Part III Cooperative Iodine and Photoredox Catalysis for C(sp3)-H Functionalization
Right after the publication of this work, an outstanding work of Shannon Stahl and co-workers was published where they combined electrochemistry with photochemistry.126 Indeed, they are using an iodide salt as electrochemical mediator for direct C(sp3)-H amination (Scheme III.21). Thanks to this mediator, they could reduce the electrode potential to only 0.7 V vs Fc/Fc+. They identified that the iodide is getting oxidize at the - anode. Indeed, only the oxidation potential of the I /I2 couple is lower than the one of the anode. At the cathode, hydrogen gas evolution was noticed. They conducted cyclic voltammetry and 9o has its oxidation potential at 1.5 V vs Fc/Fc+ (arene oxidation potential) meaning again that only the iodide can be oxidized at the anode. The solvent of the reaction is a mixture of acetonitrile and TFE. In similar condition to us, newly anode-generated molecular iodine disproportionates into hypoiodite. In the presence of TFE, trifluoroethyl hypoiodite is formed from the latter that promotes iodination of the corresponding sulfonamides. At this stage, a Hofmann-Löffler reaction takes place. The iodide extruded is then re-oxidizes at the anode closing the catalytic cycle.
215 Part III Cooperative Iodine and Photoredox Catalysis for C(sp3)-H Functionalization
Scheme III.21. Mechanism of the method developed by Stahl and co-workers where they merge photochemistry (Hofmann-Löffler reaction) and electrochemistry.
III.4 Results and discussion for direct C(sp3)-H oxygenation
We already presented some examples on iodine-mediated reaction and photoredox catalysis for C(sp3)-H oxygenation in the introduction section of this chapter. Having the knowledge in hand for the C(sp3)-H amination reaction, we wondered if we could extend the methodology to direct lactone formation starting from carboxylic acids.
216 Part III Cooperative Iodine and Photoredox Catalysis for C(sp3)-H Functionalization
III.4.1 Strategies for direct oxidative C(sp3)-H lactonization Over the recent years, direct oxidative lactonization has attracted the synthetic chemist community. Various strategies had emerged to form γ-lactones that represent important building blocks in pharmaceutical sciences194 and significant biological activities have also been reported.195 Among them, copper catalysis for lactonization have been developed by Du Bois et al. with the use of sodium persulfate as oxidant (Scheme III.22a).196 After the formation of the stabilized benzylic radical by a hydrogen atom abstraction from the persulfate anion, the copper(II) catalyst oxidizes it to a carbocation. A subsequent cyclization occurs achieving the corresponding γ-lactone derivatives. Since the reaction is running in an open-air system, the copper(I) gets re-oxidize by the oxygen. Another protocol was designed with the use of a cobalt(II) catalyst in combination with DTBP for intermolecular oxygenation (Scheme III.22b).197 The reaction mechanism is similar to the one presented in the section I.5.2. Tert-butyl alcohol free-radicals are generated undergoing a hydrogen atom abstraction of the weakest C(sp3)-H bond such as an allylic or a benzylic position. The cobalt(III) species generated from the reduction of DTBP is oxidizing the stabilized radical to a carbocation. A nucleophilic addition of a carboxylic acid provides the corresponding ester. Electrochemistry processes were designed as well for both lactonization and etherification reactions by our group123 (Scheme III.22c) and by the group of Zeng.198 Following the same mechanism presented in the section I.6, a double anodic oxidations allow the formation of the crucial carbocation species which is trapped by the internal carboxylic acid or alcohol. Finally, hypervalent iodine(III) reagents were successfully used for such transformation as well (Scheme III.22d).199
194 I. Collins, J. Chem. Soc., Perkin. Trans. 1 1998, 1869–1888. 195 J. D. Lambert, J. E. Rice, J. Hong, Z. Hou, C. S. Yang, Bioorg. Med. Chem. Lett. 2005, 15, 873–876. 196 a) S. Sathyamoorthi, J. Du Bois,Org. Lett. 2016, 18, 6308–6311. b) S. Banerjee, S. Sathyamoorthi, J. Du Bois, R. N. Zare, Chem. Sci. 2017, 8, 7003–7008. 197 T. Ren, B. Xu, S. Mahmood, M. Sun, Tetrahedron 2017, 73, 2943–2948. 198 S. Zhang, L. Li, H. Wang, Q. Li, W. Liu, K. Xu, C. Zeng, Org. Lett. 2018, 20, 252–255. 199 .T Dohi, N. Takenaga, A. Goto, A. Maruyama, Y. Kita, Org. Lett 2007, 9, 3129–3132.
217 Part III Cooperative Iodine and Photoredox Catalysis for C(sp3)-H Functionalization
Scheme III.22. Intra- or intermolecular direct oxygenation of C(sp3)-H bond.
III.4.2 Development of the cooperative catalysis for direct oxidative C(sp3)-H lactonization After a careful literature search and having the optimized condition in hand for the close-related amination reaction, we focused on developing a direct oxidative lactonization from carboxylic acids. The first trial we did was with the use of the exact same conditions than the cooperative catalysis for the amination reaction. Using 5 mol% of molecular iodine and 1 mol% of the organic pyrylium dye TPT in a 1 to 1 mixture of unpurified DCE/HFIP in an open-air system, 70% conversion by NMR was observed (Table III.2, entry 1). Modifying the ratio between iodine and TPT (entries 2-6) led to the conclusion that the optimized quantities of molecular iodine and TPT are 5 mol% and 2 mol% respectively. An excellent isolated yield of 94% was obtained under this condition (entry 3). These entries are highlighting the crucial role of the ratio between both catalysts for the effectiveness. We
218 Part III Cooperative Iodine and Photoredox Catalysis for C(sp3)-H Functionalization tried to change the reaction duration from 18 h to 24 h (entry 7) and 48 h (entry 8) but none of them provided better conversion. On the contrary, the longer the reaction was running the most decomposition was observed. After 48 h, only decomposition could be noticed. We investigated the importance of the solvents (entries 9-15). Various solvent mixtures were tested but it was concluded that the mixture HFIP/DCE (1/1) remains the best. To confirm that the water trace is still an important feature for the lactonization to smoothly proceed, two experiments were carried out (entries 16-17) in which the reaction was set up in either dried DCE or dried DCE/HFIP. In both cases, a significant drop was noticed since the conversion obtained were only 30% in dried DCE and 60% in dried DCE/HFIP against 56% and 95% respectively for the non-purified solvents. This is a clear indication that water is playing a role in the reaction process. When the reaction was conducted in the dark room (entry 18), no conversion to the lactone was encountered. As noticed in the amination reaction, while TPT is submitted without the iodine co-catalyst, the reaction still proceeds (entry 19) but a low conversion of 21% was obtained. This result can be explained by the fact that a double SET oxidation event from the dye affords the benzylic carbocation. Subsequent cyclization of the carboxylic acid provides the corresponding lactone. When only molecular iodine (entry 20-21) was used in 5 or even 10 mol%, no trace of lactone formation was noticed. Instead, starting material was fully recovered in these experiments. These results differ from the amination reaction. Indeed, when 5 mol% of molecular iodine was injected without TPT for the amination, a stochiometric reaction occurred since 5% of NMR yield was observed. The optimal reaction conditions are the following: Molecular iodine and TPT are used in 5 mol% and 2 mol% respectively. The reaction is set-up in non-purified DCE and HFIP (1/1 ratio) at the concentration of 0.1 M and in an open-air tube. The reaction mixture is stirred 18 h at room temperature under blue LED irradiation.
Table III.2. Optimization of the cooperative catalysis between molecular iodine and an organic dye for direct selective lactonization reaction.
a a Entry I2 TPT Solvent Time Conversion 1 5 mol% 1 mol% DCE/HFIP 18 h 70%
219 Part III Cooperative Iodine and Photoredox Catalysis for C(sp3)-H Functionalization
2 5 mol% 1.5 mol% DCE/HFIP 18 h 71% 3 5 mol% 2 mol% DCE/HFIP 18 h 94%* 4 5 mol% 2.5 mol% DCE/HFIP 18 h 64% 5 7.5 mol% 2 mol% DCE/HFIP 18 h 53% 6 10 mol% 2 mol% DCE/HFIP 18 h 22% 7 5 mol% 2 mol% DCE/HFIP 24 h 77% 8 5 mol% 2 mol% DCE/HFIP 48 h --b 9 5 mol% 2 mol% DCE 18 h 56% 10 5 mol% 2 mol% DCM 18 h 35% 11 5 mol% 2 mol% HFIP 18 h 44% 12 5 mol% 2 mol% C6H5Cl/HFIP 18 h 52% 13 5 mol% 2 mol% Toluene/HFIP 18 h SM 14 5 mol% 2 mol% MeCN/HFIP 18 h 25% 15 5 mol% 2 mol% THF/HFIP 18 h --b 16c 5 mol% 2 mol% DCE 18 h 30% 17c 5 mol% 2 mol% DCE/HFIP 18 h 60% 18d 5 mol% 2 mol% DCE/HFIP 18 h SM 19 -- 2 mol% DCE/HFIP 18 h 21% 20 5 mol% -- DCE/HFIP 18 h SM 21 10 mol% -- DCE/HFIP 18 h SM a Experiments carried out open-air and with unpurified solvents. b Decomposition c Experiments carried out under open-air and with purified solvents. d Experiment carried out in the dark room. * Isolated yield.
III.4.3 Scope of the cooperative catalysis for C(sp3)-H amination At the starting point, we investigated the functional group tolerance at the para-position of the arene core (Scheme III.23). This position was decorated with various substituents which were well-tolerated since the corresponding lactones 12a-d were isolated in good to excellent yields (51- 94%). For the exact same reason explained above for the amination, only the para-chlorinated lactone 12d showed a decreased yield of 51%. When a γ,γ-diphenylated derivative was submitted to the optimized reaction condition, a modest 21% isolated yield was obtained for 12e which is a consequence of the slow lactone formation. The starting material 11e could be isolated and the yield based on the recovered substrate was 95%. Due to the radical conditions, no stereocontrol was noticed for the formation of 12f which was isolated in 74% yield as a 1:1 mixture of diastereoisomers. Nevertheless, a cyclic stereocontrol was possible for 12g, isolated in 71%
220 Part III Cooperative Iodine and Photoredox Catalysis for C(sp3)-H Functionalization yield. Isobenzofurane derivatives were successfully obtained for this process. Indeed, the reaction time could be reduced to 12 h since the double benzylic radical formed is more stable. Both, the non-decorated and the para-fluorinated isobenzofurane derivatives 12h and 12i were isolated in 74% yield and 73% respectively. When the arene core was implemented by two fluorine atoms at the ortho- and para-position (12j), the yield dropped to 31% due to steric hindrance which affects the cyclization step. While changing a fluorine atom from the ortho- to the meta-position (12k), the product could be isolated with 72% isolated yield. Heteroatoms are well tolerated in this process as noticed from the lactone 12l which bears a thiophene derivative. It was isolated with a respectable yield of 60%. Interestingly, it could be possible to cyclize a benzoic acid derivative onto a fused aliphatic chain. Indeed, 12m represents the main structural unite of the natural product miltiorin D and could be isolated in 21% yield (95% based on recovered starting material). Six-membered ring δ-lactone derivatives could be also obtained. The undecorated substrate 11n could be cyclized with the good yield of 57% providing 12n. Then, different substituents were implemented at the para- position of the arene moiety such as a methyl, a fluorine or a chlorine group which provided the corresponding lactones 12o, 12p and 12q with 35%, 54% and 50% respectively. A slight increase of yield was noticed when gem- dimethyl substituents were implemented at the β-position inducing a Thorpe-Ingold effect. Indeed, the non-decorated lactone 12r was isolated in 59% yield instead of 57% for 12n. The same increase was observed for 12s and 12t which were isolated in 43% and 67% against 54% and 50% respectively for 12o and 12p. Finally, and interestingly, 2-phenetylbenzoic acid 11u exclusively affords the 6-membered ring isochromanone 12u in 96% yield. The non-decorated arene is easier to oxidize than the benzoic acid arene core (more electron-enriched), thus leading exclusively to the formation of the radical benzylic cation in α-position to the non-decorated arene moiety. This is an extremely important feature and control experiment to explore the reaction mechanism.
221 Part III Cooperative Iodine and Photoredox Catalysis for C(sp3)-H Functionalization
Scheme III.22. Scope of the cooperative molecular iodine and photoredox catalyst for direct selective lactonization reaction. a > 95% based on recovering starting material. b Reaction performed 12 h.
III.4.4 Mechanistic investigation
222 Part III Cooperative Iodine and Photoredox Catalysis for C(sp3)-H Functionalization
III.4.4.1 Quenching experiments To have an evidence of the involvement of radical species, radical quenchers such as BHT or TEMPO were added to the reaction mixture (Scheme III.23). In all the cases, starting material was fully recovered. As previously mentioned, we cannot rule out the possibility of the deactivation of the catalytic system prior to radical formations but the effective quenching suggest a radical reaction to be the dominant process.
Scheme III.23. Quenching experiments carried out to prove the involvement of radical species.
III.4.4.2 Kinetic isotope effect The mono-deuterated substrate 11a-D was submitted to the optimized reaction conditions (Scheme III.24). After careful analysis of the crude NMR spectrum, a KIE of 1.0 was calculated from the relative amount of products formed.
Scheme III.24. Isotope labelling experiment leading to a KIE of 1.0 meaning that the C-H bond cleavage is not be the rate-determining step.
It means that the rate-determining step is not the C-H bond cleavage.136 As a result, the plausible benzylic deprotonation or the 1,5-HAT is not the rate- limiting step of the overall process. As we discussed previously for the amination reaction, the benzylic deprotonation (pka of 10) is supposed to be extremely fast and a KIE of 1.0 favors an arene oxidation step by the organic dye through a SET mechanism (Scheme III.25a). Moreover, the
223 Part III Cooperative Iodine and Photoredox Catalysis for C(sp3)-H Functionalization
HAT process often represents the rate-determining step of the overall reaction. Nevertheless, we cannot rule out the plausible pathway in which the HAT would not represent the rate-determining step (Scheme III.25b).
Scheme III.25. Plausible pathways for the cooperative catalysis between molecular iodine and TPT for direct selective lactonization reaction.
III.4.4.3 Involvement of an O-I bond? Having the KIE of 1.0 and 12t as unique product in a competition between the formation of the γ– or δ-lactone, we hypothesized that a mechanism involving an arene oxidation is the most probable. To have another evidence of the reaction mechanism, we synthesized in- situ the O-iodinated intermediate. To do so, hypervalent iodine(III) compound 13 was synthesized prior to its submission to the slightly modified reaction condition in which molecular iodine is added in stochiometric amount (Scheme III.26). After 18 h, no trace of the corresponding lactone was observed. Instead, starting material was recovered in majority. Interestingly, trace of decarboxylation by-product was noticed due to the oxygen-centered radical property to facilitate such a transformation. As a conclusion for this experiment, the acyl hypodiodite intermediate XII is not involved in the reaction mechanism for the lactonization. We never observed decarboxylation side-products and it does not seem to be a efficient pathway to form the final lactone.
224 Part III Cooperative Iodine and Photoredox Catalysis for C(sp3)-H Functionalization
Scheme III.26. Control experiment proving that the O-I bond is not formed under our reaction condition.
III.4.4.4 Cyclic voltammetry experiments From the optimization of the reaction condition, we knew that molecular iodine alone does not provide the lactone 12a. With the control experiments of the KIE and of the non-involvement of O-I bond, we had the hypothesis that the mechanism includes an arene oxidation from the TPT by a SET. To confirm that assumption, we performed cyclic voltammetry experiments. It was carried out in a three-electrode cell. The working electrode was a glassy carbon disk, the counter electrode a platinum wire and the reference electrode a Ag/AgNO3 (silver wire in 0.1 M
Bu4NClO4/MeCN; 0.01 AgNO3). The supporting electrolyte used was
Bu4NBF4. Prior to each experiment, the working electrode was polished with alumina and the electrolyte was purged with argon for 5 min. We used a scan-rate of 50 mV/s. In red, the voltammogram of the solvent mixture was recorded (Scheme III.27). Then, we wondered whether the carboxylic acid or the arene moiety get oxidized first. To determine the oxidation potential of both moieties, the voltammograms of the 4-phenylbutyric acid and of the 4-phenylbutane were recorded. As depicted in scheme III.27, the oxidation potential of the carboxylic acid moiety is about + 2.2 V vs
Ag/AgNO3 whereas the arene has its oxidation potential at + 1.8 V vs Ag/AgNO3. To complete the experiment, the voltammogram of 11a was also recorded. As expected, the first oxidation potential is + 1.8 V vs Ag/AgNO3. The second oxidation potential corresponds to the double oxidation of the
225 Part III Cooperative Iodine and Photoredox Catalysis for C(sp3)-H Functionalization arene moiety (+ 2.1 V vs Ag/AgNO3). This result can explain the plausible double oxidation event from the organic dye to form the benzylic carbocation (Et (TPT*/TPT.-) = + 2.3 V vs SCE).
Scheme III.27. Cyclic voltammetry experiments carried out to prove that the oxidation potential of the arene moiety is lower than the carboxylic acid function.
III.4.4.5 Hammett correlation studies The oxidation potential of the arene moiety varies depending on the substituent type and its position (ortho, meta, or para). For instance, electro-donating groups decrease the oxidation potential whereas electro- withdrawing groups increase it meaning that it is easier to oxidize an electron-enriched arene than an electron-deficient one. Three competition experiments were carried out between 11a and 11b, 11c or 11d (Scheme III.28). A crude NMR was recorded to get the ratio between the corresponding γ-lactones (Table III.3).
226 Part III Cooperative Iodine and Photoredox Catalysis for C(sp3)-H Functionalization
Scheme III.28. Competition experiments between 11a and 11b, 11c or 11d in order to obtain more information about the influence of the para-substituent of the arene on the kinetic of the reaction.
Each substituent has its own Hammett constant σ depending on their position at the arene (Table III.3).
Table III.3. Hammett constants σ for the para-substituents of the arene core. Entry para-X log(kpara-X/kH) σpara-X 1 H 0 0 2 F - 0.061103 0.06 3 Cl - 0.837 0.23 4 Me 0.31803 -0.17
The plot of the Hammett equation is linear, and the negative slope obtained gave us the information that the reaction is accelerated when using electron-donating groups which in agreement with a mechanism involving an arene oxidation by TPT (Scheme III.29). Both the oxidation of the arene core and the cyclization step can be influenced by the substituents. As a result, we cannot exclude that only the cyclization step is influencing the kinetic of the reaction.
227 Part III Cooperative Iodine and Photoredox Catalysis for C(sp3)-H Functionalization
Scheme III.29. Hammett plot showing a negative slope meaning that electron- donating group are accelerating the lactonization reaction.
III.4.4.6 Proposed mechanism Having all these mechanistic studies in hand, we finally proposed a different mechanism than the one previously discussed for the amination. The organic dye TPT is here playing a double role. First, it oxidizes the arene moiety of the substrate and then re-oxidizing the iodide extruded during the cyclization step. The blue LEDs irradiation is necessary to reach the triplet state of the photoredox pyrylium catalyst. At the beginning of the proposed mechanism, TPT oxidizes by a SET the arene moiety of 11a to obtain the arene radical cation intermediate XIII bearing a C(sp3)-H benzylic position. As we mentioned before, the pka of such hydrogen is dramatically enhanced and the deprotonation readily happens affording the benzylic radical species XIV. At this stage, molecular iodine traps it to form the alkyl iodide intermediate XVI. Since the reaction is more efficient in unpurified solvents, we suggested that hypoiodite accelerates somehow the cyclization step providing the corresponding lactone 12a. The released hydrogen iodide is then re-oxidized by a SET by the dye. Finally, oxygen present from the air allows the re-oxidation of TPT.
228 Part III Cooperative Iodine and Photoredox Catalysis for C(sp3)-H Functionalization
Scheme III.30. Mechanism of the cooperative molecular iodine and photoredox catalysts for direct selective lactonization reaction.
III.5 Final remarks
In conclusion, we developed for the first time a cooperative catalysis between molecular iodine and an organic dye. With these methodologies, both amination and oxygenation reactions could be achieved leading to the formation of pyrrolidines and γ– or δ-lactones. Mechanistic investigations were carried out as well to determine with accuracy the mechanism of these transformations. Interestingly, we found out that despite the same reaction conditions, the mechanism of the amination differs from the one of the oxygenation. We did not investigate the crucial role of the HFIP co-solvent but it would have been interesting to know whether the corresponding hypoiodite species is formed in-situ. Also, in the near future, it would be interesting to investigate the exact role of the water in the oxygenation
229 Part III Cooperative Iodine and Photoredox Catalysis for C(sp3)-H Functionalization reaction. Why did the water help the reaction to proceed? Is hypoiodite really oxidizing the alkyliodine(I) intermediate? Or is it halogen bonding?
III.6 Experimental section
III.6.1 General information NMR spectra were recorded on a Bruker Avance 400 MHz or 500 MHz spectrometer, respectively. The chemical shifts (δ) for 1H and 13C are reported in ppm relative to residual signals of the solvents (CDCl3 δ = 7.26 and 77.0 ppm, CD3CN δ = 1.94 and 118.26 ppm; DMSO-d6 δ = 2.50 and 39.52 ppm for 1H and 13C NMR respectively). Coupling constants are given in Hz. The following abbreviations are used to indicate the multiplicity: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad. High-resolution mass spectra (HRMS) were obtained from the ICIQ High- Resolution Mass Spectrometry Unit on MicroTOF Focus and Maxis Impact (Bruker Daltonics) with electrospray ionization. IR spectra were taken in a Bruker Alpha instrument in the solid state. RAMAN spectroscopic investigation was carried out using a Renishaw inVia Raman microscope equipped with a thermoelectrically cooled CCD camera and an optic fibre cable for the excitation. Samples (glass cuvette containing the solution for measurement) were irradiated with a laser beam with a wavelength of 532 nm. For all measurements, the energy of the laser was approximately 100 mW. Cyclic voltammetry was carried out in a three-electrode cell using a Parstat 2273 potentiostat (Princeton Applied Research). As working electrode, a glassy carbon disk (diameter: 3 mm) was used and as counter electrode a platinum wire was utilized. The working electrode was polished using alumina (0.05 µm) prior to each experiment. As reference, an Ag/AgNO3 electrode (silver wire in 0.1 M Bu4NClO4/CH3CN; 0.01 M AgNO3). The reference electrode was separated from the cell with a Vycor frit. 1,1,1,3,3,3- Hexafluoroisopropanole (99%, Fluorochem) and 1,2- dichloroethane (99+%, Alfa Aesar) were used as received. As supporting electrolyte served
Bu4NBF4 (99%, Aldrich). The electrolyte was purged with Argon (5 min) prior to each experiment. All reactions were set up under an argon atmosphere in oven- dried glassware using standard Schlenk techniques unless otherwise stated. Synthesis grade solvents as well as reagents were used as purchased.
230 Part III Cooperative Iodine and Photoredox Catalysis for C(sp3)-H Functionalization
Anhydrous solvents were taken from a commercial solvent purification system (SPS) dispenser. Chromatographic purification of products was accomplished using flash column chromatography (FC) on silica gel (Merck, type 60, 0.063-0.2 mm).
III.6.2 Synthesis of the substrates 9a-t for the amination reaction Synthesis of 9a-n (GP1)
Scheme III.31. Pathway for the synthesis of 9a-n.
Step 1. A flame-dried Schlenk tube equipped with a stirrer bar is charged with the corresponding nitrile compound (1.0 equiv.) and THF (50 mL). LDA (2.6 mL, 2M, 1.0 equiv.) is added drop wise at -78 ºC and the solution is stirred for 30 min. After that period, the corresponding alkyl bromide (1.2 equiv.) is added in a single portion and the mixture is stirred at room temperature for 12h. A saturated aqueous solution of NH4Cl is added and the resulting mixture is extracted three times with Et2O. The organic layer is dried over Na2SO4 and the solvent is evaporated under reduced pressure. The crude product is directly engaged in the next step. Step 2. A flame dried Schlenk equipped with a stirrer bar and a reflux condenser is charged with LiAlH4 (3 equiv.), Et2O is added carefully and the mixture is cooled to 0 ºC with an external ice/water cooling bath. The crude nitrile (1 equiv.) is dissolved in a small volume of Et2O and added carefully to the LiAlH4 suspension. The mixture is heated to reflux for 2h and cooled to 0 ºC afterwards. A solution of NaOH (10% in water) is added carefully until a white solid precipitate appears. After filtration over Na2SO4 and
231 Part III Cooperative Iodine and Photoredox Catalysis for C(sp3)-H Functionalization evaporation of the solvent, the crude amine is obtained in quantitative yields. Step 3. The crude amine from step 2 (1 equiv.) is dissolved in pyridine (50 mL) and the respective sulfonyl chloride (1.5 equiv.) is added at 0 ºC. The solution is stirred overnight at room temperature. CH2Cl2 is added, and the mixture is washed three times with a hydrochloride solution (10% HCl in water). The organic layer is dried over Na2SO4 and the solvent is evaporated under reduced pressure. The crude product was purified by chromatography (silica gel, hexane/ethyl acetate as eluent) to give the pure product 9a-n.
Synthesis of 9o
From the commercially available primary amine, the substrate 9o was synthesized following the step 3 of GP1 using tosyl chloride. 9o was isolated with the excellent isolated yield of 94% as a colorless oil.
Synthesis of 9o-D
Scheme III.32. Pathway for the synthesis of 9o-D.
Step 1. 4-Chlorobutyrophenone (1 equiv.) was dissolved in dry Et2O (0.1 M) and carefully added to a suspension of LiAlH4 (1 equiv.) in diethyl ether at 0 C. The mixture was refluxed for 2 h after which the reaction was cooled down to 0 C and quenched by careful addition of a 2 M aqueous solution of NaOH. The mixture was filtered over Na2SO4 and the solvent was removed under reduced pressure. The crude product was further purified by column chromatography (hexane/ethyl acetate as eluent).
232 Part III Cooperative Iodine and Photoredox Catalysis for C(sp3)-H Functionalization
Step 2. The 4-Chloro-1-phenylbutan-1-ol (1 equiv.) was dissolved in dry
CH2Cl2 and cooled down to 0 C. NEt3 (2 equiv.) was added and the mixture was stirred for 10 min at 0 C. Mesyl chloride (1.1 equiv.) was added dropwise at 0 C and the reaction mixture was stirred for 30 min at 0 C after which the reaction was quenched by addition of a saturated aqueous solution of
NaHCO3. The layers were separated, and the aqueous phase was extracted with CH2Cl2. The combined organic phases were dried over Na2SO4, filtered and the solvent was removed under reduced pressure to yield the desired mesylate which was used without purification for the next step. Note: Due to rapid decomposition of the mesylate, the next step has to be done immediately after the mesylation.
Step 3. The crude mesylate from step 2 was dissolved in dry Et2O and the solution was cooled down to 0 C. Subsequently, LiAlD4 (1 equiv.) was carefully added at 0 C after which the reaction mixture was refluxed for 2 h. The reaction mixture was cooled to 0 C and quenched by careful addition of a 2 M aqueous solution of NaOH. The mixture was filtered over
Na2SO4 and the solvent was removed under reduced pressure. The crude product was further purified by column chromatography using pure hexane as eluent. Step 4. The crude (4-Chlorobutyl-1-D)benzene (1 equiv.) was dissolved in dry DMF and NaN3 (1.5 equiv.) was added. The reaction mixture was stirred overnight at 90 C. After adding Et2O to the mixture, the organic layer was washed five times with water to remove the DMF prior to be dried over
Na2SO4 and evaporated under reduced pressure. The crude product was directly used for the next step without further purification.
Step 5. The crude product from step 4 was dissolved in dry Et2O, the solution was cooled down to 0 C and LiAlH4 (3 equiv.) was added carefully at that temperature. The reaction mixture was refluxed for 2 h after which the mixture was cooled down again to 0 C and quenched by careful addition of a 2 M aqueous solution of NaOH. The mixture was filtered over
Na2SO4 and the solvent was removed under reduced pressure. The crude product was directly used for the next step without purification. Step 6. Step 3 of GP1. The crude product was purified by column chromatography (silica gel, hexane/ethyl acetate as eluent) to provide the pure compound 9o-D as a colorless oil in 15% overall yield.
Synthesis of 9p
233 Part III Cooperative Iodine and Photoredox Catalysis for C(sp3)-H Functionalization
Scheme III.33. Pathway for the synthesis of 9p.
Step 1. A flame-dried Schlenk tube equipped with a stirrer bar was charged with the trimethylphosphonoacetate (1.62 mL, 10 mmol, 1.0 equiv.) and THF (5 mL/mmol) and the vessel was cooled down to 0º C. n-BuLi (5 mL of a 2 M solution, 10 mmol, 1.0 equiv.) was added dropwise and the reaction was stirred for one hour upon which time the 2-indanone (1.32 g, 10 mmol, 1.0 equiv.) was added and the reaction was then stirred for 18 h at room temperature. A saturated aqueous solution of NH4Cl was added and the resulting mixture extracted three times with Et2O. The organic layer was dried over anhydrous Na2SO4 and the solvent evaporated under reduced pressure. The crude was used for the next step without further purification. Step 2. A flame-dried Schlenk tube equipped with a stirrer bar was charged with the crude from the previous step, Pd/C (20 w%) and ethanol (5 mL/mmol) were added and the reaction was stirred under atmospheric pressure of hydrogen gas overnight. The mixture was filtered through Celite and concentrated to yield the crude ester which was used for the next step without further purification. Step 3. A flame-dried Schlenk tube equipped with a stirrer bar and a reflux condenser was charged with LiAlH4 (2 equiv.). Et2O is added carefully and the mixture was cooled down to 0 ºC. The crude ester (1 equiv.) was added to the LiAlH4/Et2O suspension under argon atmosphere. The mixture was heated to reflux for 2 h and cooled down to 0 ºC afterwards. A solution of NaOH (1 M in water) was added. After filtration of the white precipitate over Na2SO4 and evaporation of the solvent under reduced pressure, the crude alcohol was obtained in quantitative yield and was used in the following step.
Step 4. The crude alcohol (1 equiv.) was dissolved in dry CH2Cl2 and cooled down to 0 C. NEt3 (2 equiv.) was added and the mixture was stirred for 10
234 Part III Cooperative Iodine and Photoredox Catalysis for C(sp3)-H Functionalization min at 0 C. Mesyl chloride (1.1 equiv.) was added dropwise at 0 C and the reaction mixture was stirred for 30 min at 0 C after which the reaction was quenched by addition of a saturated aqueous solution of NaHCO3. The layers were separated, and the aqueous phase was extracted with CH2Cl2.
The combined organic phases were dried over Na2SO4, filtered and the solvent was removed under reduced pressure to yield the desired mesylate which was used without purification for the next step.
Step 4. The crude from step 3 (1 equiv.) was dissolved in dry DMF and NaN3 (1.5 equiv.) was added. The reaction mixture was stirred overnight at 90 C.
After adding Et2O to the mixture, the organic layer was washed five times with water to remove the DMF prior to be dried over Na2SO4 and evaporated under reduced pressure. The crude product was directly used for the next step without further purification. Step 5. A Schlenk flask equipped with a stirrer bar was charged with the corresponding crude azide from step 4, Pd/C (20 %w/w) and ethyl acetate (5 mL/mmol). The reaction was stirred under hydrogen atmosphere for 12 h using a gas balloon. The mixture was filtered through a pad of Celite and concentrated under reduced pressure to yield the crude amine. The crude product was directly used for the next step without further purification. Step 6. Step 3 of GP1. The crude product was purified by column chromatography (silica gel, hexane/ethyl acetate as eluent) to provide the pure compound 9p as a white solid in 80% overall yield.
Synthesis of 9q-r (GP2)
Scheme III.34. Pathway for the synthesis of 9q-r.
Step 1. In a flame-dried Schlenk tube, Pd(OAc)2 (11.2 mg, 0.049 mmol, 1 mol%), PPh3 (26.2 mg, 0.099 mmol, 2 mol%), the corresponding arylboronic acid (1.5 equiv.) and K3PO4 (4.25 g, 20.0 mmol, 4 equiv.) and toluene (15 mL) were added under argon. Then, the 2- (bromomethyl)benzonitrile (980.3 mg, 5.0 mmol, 1 equiv.) was added. The mixture was stirred at 80 °C until all starting material was consumed (monitored by TLC, 9 h) and then quenched with water. The solution was
235 Part III Cooperative Iodine and Photoredox Catalysis for C(sp3)-H Functionalization extracted with Et2O (3x) and the organic phase was washed with water, a 1
N solution of NaOH solution, brine and dried over anhydrous Na2SO4. The solvent was removed and the product isolated by flash column chromatography using hexane and ethyl acetate as eluent. Step 2. Step 2 of GP1. Step 3. Step 3 of GP1. Purification using column chromatography (hexane/ethyl acetate as eluent) afforded 9q-r
Synthesis of 9s-t (GP3)
Scheme III.35. Pathway for the synthesis of 9s-t.
Step 1. Step 1 of GP1. Step 2. Step 2 of GP1.
Step 3. The requisite amine was dissolved in DCM (0.5 M) and Et3N (2 equiv.) was added. The solution was cooled to 0 ºC and benzoyl chloride (1.5 equiv.) or trifluoroacetic anhydride (1.5 equiv.) was added dropwise. After 12 h of stirring at room temperature, the solution was diluted with
CH2Cl2 and washed with saturated NaHCO3 solution and water. The organic phase was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The products 9s and 9t were isolated by flash column chromatography using hexane/ethyl acetate as eluent.
III.6.3 Characterization of the substrates 9a-t for the amination reaction N-(2,2-Dimethyl-4-phenylbutyl)-4-methylbenzenesulfonamide (9a)
Prepared according to the general procedure GP1, 9a was isolated as a white solid with an overall yield of 63%. The NMR spectra match those previously 158 1 described in literature. H NMR (400MHz, CDCl3): δ = 7.77 (d, J = 8.3 Hz, 2H), 7.31 (d, J = 8.3 Hz, 2H), 7.30-7.20 (m, 2H), 7.21- 7.18 (m, 1H), 7.17-7.14 (m, 2H), 4.71 (brt, 1H), 2.76 (d, J = 6.9 Hz, 2H), 2.54- 2.49 (m,2H), 2.44 (s, 3H), 1.54-1.50 (m, 2H), 0.95 (s, 6H). 13C NMR (125 MHz,
236 Part III Cooperative Iodine and Photoredox Catalysis for C(sp3)-H Functionalization
CDCl3): δ = 143.4, 142.7, 137.1, 129.8, 128.5, 128.4, 127.2, 125.8, 52.9, 41.6, 34.1, 30.4, 25.0, 21.6.
N-(2,2-Dimethyl-4-(p-tolyl)butyl)-4-methylbenzenesulfonamide (9b)
Prepared according to the general procedure GP1, 9b was isolated as a white solid with an overall yield of 72%. The NMR spectra match those previously described in literature.158 1H NMR (400
MHz, CDCl3): δ = 7.77 (d, J = 8.3 Hz, 2H), 7.31 (d, J = 8.3 Hz, 2H), 7.30-7.20 (m, 2H), 7.21-7.18 (m, 1H), 7.17-7.14 (m, 2H), 4.71 (brt, 1H), 2.76 (d, J = 6.9 Hz, 2H), 2.54-2.49 (m, 2H), 2.44 (s, 3H), 1.54-1.50 (m, 2H), 0.95 (s, 6H). 13C
NMR (101 MHz, CDCl3): δ = 143.4, 142.7, 137.1, 129.8, 128.5, 128.4, 127.2, 125.8, 52.9, 41.6, 34.1, 30.4, 25.0, 21.6.
N-(4-(4-Fluorophenyl)-2,2-dimethylbutyl)-4- methylbenzenesulfonamide (9c)
Prepared according to the general procedure GP1, 9c was isolated as a white solid with an overall yield of 71%. The NMR spectra match those previously described in literature.158 1H NMR (400
MHz, CDCl3): δ = 7.78-7.73 (m, 2H), 7.29 (d, J = 8.1 Hz, 2H), 7.10-7.05 (m, 2H), 6.92 (t, J = 8.6 Hz, 2H), 4.88 (bs, 1H), 2.72 (d, J = 6.9 Hz, 2H), 2.49-2.44 (m, 2H), 2.41 (s, 3H), 1.52-1.42 (m, 2H), 0.91 (s, 6H). 13C NMR (101 MHz, CDCl3): δ = 161.3 (d, JC-F = 243.2 Hz), 143.5, 138.3, 138.2, 137.1, 129.7 (JH-F = 7.8 19 Hz), 127.2, 115.1 (JC-F = 21.1 Hz), 52.9, 41.6, 34.1, 29.6, 25.1, 21.6. F NMR (376 MHz, CDCl3): δ = -118.0.
N-(4-(4-Chlorophenyl)-2,2-dimethylbutyl)-4- methylbenzenesulfonamide (9d)
Prepared according to the general procedure GP1, 9d was isolated as a white solid with an overall yield of 88%. The NMR spectra match those previously described in literature.158 1H NMR
(400 MHz, CDCl3): δ = 7.77-7.72 (m, 2H), 7.29 (d, J = 8.0 Hz, 2H), 7.22-7.19 (m, 2H), 7.07-7.04 (m, 2H), 4.68 (brs, 1H), 2.72 (d, J = 7.0 Hz, 2H), 2.50-2.43 (m, 2H), 2.42 (s, 3H), 1.50-1.44 (m, 2H), 0.91 (s, 6H). 13C NMR (101 MHz,
237 Part III Cooperative Iodine and Photoredox Catalysis for C(sp3)-H Functionalization
CDCl3): δ = 143.5, 141.2, 137.1, 131.5, 129.9, 129.8, 128.5, 127.2, 52.9, 41.4, 34.2, 29.8, 25.1, 21.7.
N-(4-(4-Bromophenyl)-2,2-dimethylbutyl)-4- methylbenzenesulfonamide (9e)
Prepared according to the general procedure GP1, 9e was isolated as a white solid with an overall yield of 68%. The NMR spectra match those previously described in literature.158 1H NMR (400
MHz, CDCl3): δ = 7.76-7.73 (m, 2H), 7.37-7.34 (m, 2H), 7.29 (d, J = 8.1 Hz, 2H), 7.02-6.98 (m, 2H), 4.78 (brs, 1H), 2.72 (d, J = 7.0 Hz, 2H), 2.47-2.42 (m, 13 2H), 2.41 (s, 3H), 1.49-1.43 (m, 2H), 0.91 (s, 6H). C NMR (101 MHz, CDCl3): δ = 143.5, 141.7, 137.1, 131.5, 130.2, 129.9, 127.2, 119.5, 52.9, 41.3, 34.2, 29.8, 25.1, 21.7.
N-(2,2-Dimethyl-4-(o-tolyl)butyl)-4-methylbenzenesulfonamide (9f)
Prepared according to the general procedure GP1, 9f was isolated as a white solid with an overall yield of 1 36%. H NMR (500 MHz, CDCl3): δ = 7.74 (d, J = 8.2 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), 7.12-7.06 (m, 4H), 4.41 (t, J = 6.9 Hz, 1H), 2.78-2.74 (m, 2H), 2.52-2.45 (m, 2H), 2.42 (s, 3H), 2.27 13 (s, 3H), 1.44-1.39 (m, 2H), 0.95 (s, 6H). C NMR (101 MHz, CDCl3): δ = 143.4, 140.6, 136.9, 135.6, 130.2, 129.7, 128.7, 127.1, 126.1, 126.0, 53.0, 40.3, 34.0, 27.5, 24.8, 21.5, 19.2. IR ν(cm-1): 3272, 2959, 2939, 2870, 1321, 1156, 1093, 1063, 874, + 809, 693, 663, 551. HRMS (m/z): [M+Na] calculated for C20H27NNaO2S: 368.1655; found: 368.1650. mp: 96-97 ºC.
N-(2,2-Dimethyl-4-(m-tolyl)butyl)-4-methylbenzenesulfonamide (9g)
Prepared according to the general procedure GP1, 9g was isolated as a white solid with an overall yield of 1 30%. H NMR (500 MHz, CDCl3): δ = 7.74 (dd, J = 8.4, 2.2 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), 7.15 (t, J = 7.5 Hz, 1H), 6.99 (d, J = 7.6 Hz, 1H), 6.95 (s, 1H), 6.93 (d, J = 7.7 Hz, 1H), 4.51 (s, 1H), 2.73 (d, J = 7.0 Hz, 2H), 2.48-2.43 (m, 2H), 2.42 (s, 13 3H), 2.32 (s, 3H), 1.51-1.47 (m, 2H), 0.92 (s, 6H). C NMR (101 MHz, CDCl3): δ = 143.4, 142.6, 138.1, 137.1, 129.8, 129.2, 128.4, 127.2, 126.6, 125.4, 53.0, 41.7,
238 Part III Cooperative Iodine and Photoredox Catalysis for C(sp3)-H Functionalization
34.2, 30.3, 25.1, 21.7, 21.5. IR ν(cm-1): 3263, 2958, 2917, 2867, 1323, 1162, 1095, 1064, 815, 736, 705, 658, 572, 553. HRMS (m/z): [M+H]+ calculated for
C20H28NO2S: 346.1835; found: 346.1836. mp: 108-109 ºC.
N-(2,2-Dimethyl-4-phenylbutyl)methanesulfonamide (9h)
Prepared according to the general procedure GP1, 9h was isolated as a colorless liquid with an overall yield of 80%. The NMR spectra match those previously described in literature.158 1H NMR (400 MHz,
CDCl3): δ = 7.33-7.28 (m, 2H), 7.24-7.18 (m, 3H), 4.74 (brs, 1H), 2.97 (d, J = 6.8 Hz, 2H), 2.95 (s, 2H), 2.64-2.58 (m, 2H), 1.62-1.56 (m, 2H), 1.02 (s, 6H). 13 C NMR (101 MHz, CDCl3): δ = 142.6, 128.6, 128.4, 126.0, 53.2, 41.7, 40.2, 34.3, 30.5, 25.0.
N-(2,2-Dimethyl-4-phenylbutyl)-4-nitrobenzenesulfonamide (9i)
Prepared according to the general procedure GP1, 9i was isolated as a white solid with an overall yield of 79%. The NMR spectra match those previously described in literature.158 1H NMR (400 MHz, CDCl3): δ = 8.34 (d, J = 8.8 Hz, 2H), 8.03 (d, J = 8.8 Hz, 2H), 7.30-7.26 (m, 2H), 7.23-7.16 (m, 1H), 7.14 (d, J = 6.9 Hz, 2H), 4.80 (s, 1H), 2.83 (d, J = 6.9 Hz, 2H), 2.57-2.51 (m, 2H), 1.54-1.47 (m, 2H), 0.96 (s, 6H). 13C NMR (101
MHz, CDCl3): δ = 150.1, 146.0, 142.4, 128.6, 128.4, 128.3, 126.1, 124.5, 53.3, 41.5, 34.4, 30.4, 25.0.
N-(2,2-Dimethyl-4-phenylbutyl)cyclopropanesulfonamide (9j)
Prepared according to the general procedure GP1, 9j was isolated as a white solid with an overall 1 yield of 69%. H NMR (400 MHz, CDCl3): δ = 7.33-7.28 (m, 2H), 7.24-7.17 (m, 3H), 4.61 (t, J = 6.8 Hz, 1H), 3.01 (d, J = 6.8 Hz, 2H), 2.66-2.56 (m, 2H), 2.48-2.37 (m, 1H), 1.64- 1.55 (m, 2H), 1.22-1.15 (m, 2H), 1.03 (s, 6H), 1.02-0.95 (m, 2H). 13C NMR (101 MHz, CDCl3): δ = 142.7, 128.5, 128.4, 125.9, 53.2, 41.7, 34.3, 30.5, 30.0, 25.0, 5.4. IR ν(cm-1): 3268, 2951, 2867, 1307, 1152, 1135, 1068, 1045, 892, 724, 698, + 566. HRMS (m/z): [M+Na] calculated for C15H21NNaO2S: 302.1185; found: 302.1193. mp: 59-60 ºC.
239 Part III Cooperative Iodine and Photoredox Catalysis for C(sp3)-H Functionalization
N-(2,2-Dimethyl-4-phenylbutyl)thiophene-2-sulfonamide (9k)
Prepared according to the general procedure GP1, 9k was isolated as a yellowish solid with an overall yield of 63%. 1H NMR (400 MHz, CDCl3): δ = 7.60 (ddd, J = 3.7, 1.4, 0.8 Hz, 1H), 7.57 (dd, J = 5.0, 1.3 Hz, 1H), 7.29-7.24 (m, 2H), 7.20-7.14 (m, 3H), 7.08 (dd, J = 5.0, 3.7 Hz, 1H), 4.61 (s, 1H), 2.85 (d, J = 6.9 Hz, 2H), 2.56-2.50 (m, 2H), 13 1.56-1.50 (m, 2H), 0.96 (s, 6H). C NMR (101 MHz, CDCl3): δ = 142.6, 141.1, 132.1, 131.8, 128.5, 128.4, 127.5, 125.9, 53.3, 41.7, 34.2, 30.4, 25.0. IR ν(cm-1): 3297, 3105, 2954, 2868, 1404, 1332, 1226, 1154, 1060, 1018, 846, 724, 701, 665, - 573, 549. HRMS (m/z): [M-H] calculated for C16H20NO2S2: 322.0941; found: 322.0939. mp: 90-91 ºC.
N-(2,2-Dimethyl-4-phenylbutyl)-2-(trimethylsilyl)ethane-1- sulfonamide (9l)
Prepared according to the general procedure GP1, 9l was isolated as a yellow foam with an overall yield of 70%. The NMR spectra match those previously described in literature.158 1H NMR (400 MHz, CDCl3): δ = 7.32-7.25 (m, 2H), 7.26-7.13 (m, 3H), 4.63 (t, J = 6.8 Hz, 1H), 2.98- 2.90 (m, 4H), 2.64-2.55 (m, 2H), 1.63-1.54 (m, 2H), 1.05-0.97 (m, 2H), 1.01 (s, 13 6H), 0.06 (s, 9H). C NMR (101 MHz, CDCl3): δ = 142.6, 128.6, 128.4, 125.9, 53.5, 48.7, 41.7, 34.4, 30.5, 25.0, 10.9, -1.8.
4-Methyl-N-((1-phenethylcyclohexyl)methyl)benzenesulfonamide (9m)
Prepared according to the general procedure GP1, 9m was isolated as a white solid with an overall yield of 61%. The NMR spectra match those previously described in literature.158 1H NMR (400 MHz, CDCl3): δ = 7.75 (d, J = 8.5 Hz, 2H), 7.31-7.28 (m, 2H), 7.28-7.24 (m, 2H), 7.20-7.16 (m, 1H), 7.14 (dt, J = 7.8, 1.2 Hz, 2H), 4.49 (brs, 1H), 2.82 (d, J = 6.9 Hz, 2H), 2.47-2.38 (m, 2H), 2.42 (s, 3H), 1.61-1.54 (m, 2H), 13 1.46-1.24 (m, 10H). C NMR (101 MHz, CDCl3): δ = 143.5, 142.9, 137.1, 129.9, 128.5, 128.5, 127.2, 125.9, 49.3, 37.5, 36.2, 33.6, 29.3, 26.2, 21.7, 21.4.
4-Methyl-N-(2-methyl-4-phenylbutyl)benzenesulfonamide (9n)
240 Part III Cooperative Iodine and Photoredox Catalysis for C(sp3)-H Functionalization
Prepared according to the general procedure GP1, 9n was isolated as a white solid with an overall yield of 88%. The NMR spectra match those previously described in literature.158 1H NMR (400 MHz, CDCl3): δ = 7.74 (dd, J = 8.1, 6.0 Hz, 2H), 7.27 (dd, J = 17.6, 8.0 Hz, 4H), 7.20- 7.14 (m, 1H), 7.11 (dd, J = 8.1, 1.4 Hz, 2H), 4.56 (brs, 1H), 2.88 (dd, J = 12.6, 5.5 Hz, 1H), 2.78 (dd, J = 12.4, 6.4 Hz, 1H), 2.61 (ddd, J = 13.9, 9.7, 5.7 Hz, 1H), 2.50 (ddd, J = 13.8, 9.9, 6.0 Hz, 1H), 2.42 (s, 3H), 1.72-1.55 (m, 2H), 1.46-1.35 13 (m, 1H), 0.92 (d, J = 6.6 Hz, 3H). C NMR (101 MHz, CDCl3): δ = 143.4, 142.2, 137.2, 129.8, 128.6, 128.5, 127.2, 125.9, 49.0, 35.8, 33.1, 32.9, 21.6, 17.5.
4-Methyl-N-(4-phenylbutyl)benzenesulfonamide (9o)
Prepared according to the procedure described above, 9o was isolated as a colorless oil with a yield of 94%. The NMR spectra match those previously described in literature.158 1H NMR (400 MHz,
CDCl3): δ = 7.77 (dt, J = 8.3, 1.7 Hz, 2H), 7.34-7.25 (m, 4H), 7.22-7.17 (m, 1H), 7.15-7.11 (m, 2H), 4.58 (brs, 1H), 2.97 (q, J = 6.5 Hz, 2H), 2.57 (t, J = 7.5 Hz, 2H), 2.45 (s, 3H), 1.66-1.57 (m, 2H), 1.55-1.47 (m, 2H). 13C NMR (101 MHz, CDCl3): δ = 143.5, 141.9, 137.1, 129.8, 128.5, 127.2, 126.0, 43.2, 35.4, 29.2, 28.3, 21.6.
4-Methyl-N-(4-phenylbutyl-4-D)benzenesulfonamide (9o-D)
Prepared according to the procedure described above, 9o-D was isolated as a colorless oil with an overall yield of 15%. The NMR spectra match those previously described in literature.158 1H NMR (500
MHz, CDCl3): δ = 7.33 (d, J = 8.3 Hz, 2H), 7.30-7.24 (m, 4H), 7.19-7.15 (m, 1H), 7.11-7.09 (m, 2H), 4.36 (brt, 1H), 2.95 (t, J = 6.9 Hz, 2H), 2.53 (t, J = 7.6 Hz, 1H), 2.42 (s, 3H), 1.62-1.55 (m, 2H), 1.52-1.44 (m, 2H). 13C NMR (125 MHz, CDCl3): δ = 143.5, 137.1, 129.8, 128.5, 127.2, 125.9, 43.2, 34.9 (t, JC-D = 18Hz), 29.2, 28.3, 21.6.
N-(2-(2,3-Dihydro-1H-inden-2-yl)ethyl)-4- methylbenzenesulfonamide (9p)
241 Part III Cooperative Iodine and Photoredox Catalysis for C(sp3)-H Functionalization
Prepared according to the procedure described above, 9p was isolated as a white solid with an overall yield of 80%. The NMR spectra match those previously 158 1 described in literature. H NMR (400 MHz, CDCl3): δ = 7.77 (d, J = 8.3 Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H), 7.18-7.07 (m, 4H), 4.73 (brs, 1H), 3.05-2.94 (m, 4H), 2.56-2.45 (m, 3H), 2.43 (s, 3H), 1.67 (q, J = 7.1 13 Hz, 2H). C NMR (101 MHz, CDCl3): δ = 143.5, 142.9, 137.1, 129.9, 127.2, 126.3, 124.5, 42.3, 39.0, 37.4, 35.5, 21.6.
4-Methyl-N-(2-(4-methylbenzyl)benzyl)benzenesulfonamide (9q)
Prepared according to the procedure GP2, 9q was isolated as a yellowish solid with an overall yield of 69%. 1H NMR (400 MHz, CDCl3): δ = 7.66 (d, J = 8.3 Hz, 2H), 7.32-7.27 (m, 2H), 7.25-7.12 (m, 4H), 7.04 (d, J = 7.8 Hz, 2H), 6.86 (d, J = 7.8 Hz, 2H), 4.26 (brs, 1H), 4.02 (d, J = 6.1 Hz, 2H), 3.89 (s, 13 2H), 2.45 (s, 3H), 2.32 (s, 3H). C NMR (101 MHz, CDCl3): δ = 143.6, 139.5, 137.2, 136.7, 135.9, 134.3, 131.0, 130.0, 129.8, 129.4, 128.5, 128.5, 127.4, 127.1, 45.2, 38.3, 21.7, 21.1. IR ν(cm-1): 3271, 3026, 2920, 1511, 1406, 1449, 1290, 1156, 1093, 1029, 899, 818, 751, 679, 550. HRMS (m/z): + [M+Na] calculated for C22H23NNaO2S: 388.1342 found: 388.1346. mp: 113-114 ºC.
4-Methyl-N-(2-(thiophen-2-ylmethyl)benzyl)benzenesulfonamide (9r)
Prepared according to the procedure GP2, 9r was isolated as a yellowish solid with an overall yield of 31%. 1H NMR (400
MHz, CDCl3): δ = 7.74 (d, J = 8.3 Hz, 2H), 7.35 (d, J = 7.6 Hz, 2H), 7.33-7.29 (m, 1H), 7.29-7.22 (m, 3H), 7.18 (dd, J = 5.1, 1.2 Hz, 1H), 6.94 (dd, J = 5.1, 3.4 Hz, 1H), 6.66 (dq, J = 3.4, 1.1 Hz, 1H), 4.42 (t, J = 6.1 Hz, 1H), 4.15 (s, 2H), 4.13 (d, J = 6.1 Hz, 2H), 2.50 (s, 3H). 13 C NMR (101 MHz, CDCl3): δ = 143.7, 143.6, 138.9, 136.6, 134.0, 130.5, 130.1, 129.9, 128.7, 127.5, 127.4, 127.0, 125.3, 124.3, 45.1, 33.1, 21.7. IR ν(cm-1): 3248, 2935, 2862, 1436, 1315, 1151, 1092, 1069, 816, 696, 551. HRMS (m/z): [M+Na]+ calculated for C19H19NNaO2S2: 332.0740; found: 332.0753. mp: 111-112 ºC.
N-(2,2-Dimethyl-4-phenylbutyl)benzamide (9s)
242 Part III Cooperative Iodine and Photoredox Catalysis for C(sp3)-H Functionalization
Prepared according to the procedure GP3, 9s was isolated as a white solid with an overall 1 yield of 59%. H NMR (400 MHz, CDCl3): δ = 7.77 (d, J = 6.9 Hz, 2H), 7.52-7.47 (m, 4H), 7.33- 7.28 (m, 2H), 7-32-7.26 (m, 2H), 7.24-7.18 (m, 3H), 6.17 (brs, 1H), 3.41 (d, J = 6.3 Hz, 2H), 2.71-2.65 (m, 2H), 1.67-1.60 (m, 2H), 1.07 (s, 6H). 13C NMR (101
MHz, CDCl3): δ = 168.0, 143.0, 135.1, 130.3, 128.7, 128.6, 128.5, 127.0, 125.9, 49.5, 42.4, 35.0, 30.7, 25.3. IR ν(cm-1): 3317, 3027, 2967, 2911, 1683, 1637, 1602, 1546, 1494, 1294, 1209, 693, 666. HRMS (m/z): [M+Na]+ calculated for C19H23NNaO: 304.1672; found: 304.1673. mp: 65-66 ºC.
N-(2,2-Dimethyl-4-phenylbutyl)-2,2,2-trifluoroacetamide (9t)
Prepared according to the procedure GP3, 9t was isolated as a white solid with an overall yield of 1 63%. H NMR (400 MHz, CDCl3): δ = 7.35-7.30 (m, 2H), 7.22 (td, J = 7.3, 6.9, 1.5 Hz, 3H), 6.35 (brs, 1H), 3.30-3.26 (m, 2H), 2.67-2.61 (m, 2H), 1.61-1.55 (m, 2H), 1.03 (s, 6H). 13C
NMR (101 MHz, CDCl3): δ = 157.4, 142.5, 128.6, 128.4, 126.1, 116.1 (q, JC-F = 288.1 Hz), 49.4, 42.0, 34.9, 30.5, 24.9. IR ν(cm-1): 3321, 2966, 2942, 2865, 1720, 1703, 1561, 1469, 1213, 1174, 1147, 1032, 736, 695, 516. HRMS (m/z): + [M+Na] calculated for C14H18F3NNaO: 296.1233; found: 296.1244. mp: 91-92 ºC.
III.6.4 Synthesis of the pyrrolidines 10a-t (GP4) The requisite substrate 9 (0.3 mmol, 1.0 equiv.), molecular iodine (3.8 mg, 0.015 mmol, 5 mol%) and 2,4,6-tetraphenylpyrylium tetrafluoroborate (1,2 mg, 0.003 mmol, 1 mol%) were added to a open-to-air reaction tube. 1.5 mL of DCE and 1.5 mL of 1,1,1,3,3,3-hexafluoroisopropanol were added and the resulting mixture was stirred to form a homogeneous solution. The reaction was then irradiated with blue LEDs for 18 h at room temperature (max. 32 ºC; despite ventilation, a minimal temperature change of the medium could not be ruled out). After 18 h of irradiation, DCM was added and the mixture washed three times with a saturated solution of Na2S2O3 and NaHCO3, dried over Na2SO4 and concentrated. Finally, the product was purified by column chromatography (silica gel, hexane/ethyl acetate as eluent) to give the pure pyrrolidine 10.
243 Part III Cooperative Iodine and Photoredox Catalysis for C(sp3)-H Functionalization
III.6.5 Characterization of the pyrrolidines 10a-t 4,4-Dimethyl-2-phenyl-1-tosylpyrrolidine (10a)
Prepared according to the general procedure GP4, 10a was isolated as a white solid with a yield of 90%. The NMR spectra match those previously described in literature.158 1 H NMR (500 MHz, CDCl3): δ = 7.53 (d, J = 8.3 Hz, 2H), 7.24-7.26 (m, 4H), 7.19-7.23 (m, 3H), 4.70 (dd, J = 9.4, 7.3 Hz, 1H), 3.44 (dd, J = 10.4, 1.5 Hz, 1H), 3.34 (d, J = 10.4, Hz, 1H), 2.39 (s, 3H), 2.02 (ddd, J = 12.8, 7.3, 1.5 Hz, 1H), 1.72 (dd, J = 12.8, 9.4 Hz, 1H), 1.05 (s, 3H), 0.77 (s, 3H). 13C
NMR (125 MHz, CDCl3): δ = 143.1, 143.0, 135.9, 129.4, 128.4, 127.5, 127.2, 126.6, 63.9, 62.0, 51.7, 38.3, 26.2, 25.8, 21.6.
4,4-Dimethyl-2-(p-tolyl)-1-tosylpyrrolidine (10b)
Prepared according to the general procedure GP4, 10b was isolated as a white solid with a yield of 88%. The NMR spectra match those previously described in 158 1 literature. H NMR (500 MHz, CDCl3): δ = 7.55 (d, J = 8.2 Hz, 2H), 7.21 (d, J = 8.6 Hz, 2H), 7.17 (d, J = 8.1 Hz, 2H), 7.07 (d, J = 8.2 Hz, 2H), 4.65 (dd, J = 9.4, 7.2 Hz, 1H), 3.42 (dd, J = 10.4, 1.4 Hz, 1H), 3.34 (dd, J = 10.3, 0.8 Hz, 1H), 2.40 (s, 3H), 2.32 (s, 3H), 1.99 (ddd, J = 12.8, 7.2, 1.4 Hz, 1H), 1.72 (dd, J = 12.8, 9.4 Hz, 1H), 1.05 (s, 3H), 0.74 (s, 3H). 13C NMR (125 MHz, CDCl3): δ = 143.0, 140.0, 136.7, 135.8, 129.4, 129.0, 127.5, 126.5, 63.7, 61.9, 51.6, 38.1, 26.2, 25.8, 21.6, 21.2.
2-(4-Fluorophenyl)-4,4-dimethyl-1-tosylpyrrolidine (10c)
Prepared according to the general procedure GP4, 10c was isolated as a white solid with a yield of 90%. The NMR spectra match those previously described in 158 1 literature. H NMR (500 MHz, CDCl3): δ = 7.53 (d, J = 8.1 Hz, 2H), 7.21-7.23 (m, 4H), 6.92-6.96 (m, 2H), 4.68 (ddd, J = 9.1, 7.2 1.8 Hz, 1H), 3.43 (dt, J = 10.5, 1.6 Hz, 1H), 3.33 (d, J = 10.5 Hz, 1H), 2.40 (s, 3H), 2.00 (ddt, J = 13.1, 7.3, 1.5 Hz, 1H), 1.68 (dd, J = 12.8, 9.5 Hz, 1H), 1.05 (d, J = 13 1.8 Hz, 3H), 0.76 (d, J = 3.4 Hz, 3H). C NMR (125 MHz, CDCl3): δ = 162.0 (d, JC-F = 244.9), 143.3, 138.8, 135.9, 129.5, 129.2, 127.5, 115.2 (d, JC-F = 21.5 Hz), 19 63.3, 61.9, 51.7, 38.2, 26.2, 25.8, 21.6. F NMR (376 MHz, CDCl3): δ = -115.9.
244 Part III Cooperative Iodine and Photoredox Catalysis for C(sp3)-H Functionalization
2-(4-Chlorophenyl)-4,4-dimethyl-1-tosylpyrrolidine (10d)
Prepared according to the general procedure GP4, 10d was isolated as a white solid with a yield of 57%. The NMR spectra match those previously described in 158 1 literature. H NMR (500 MHz, CDCl3): δ = 7.54 (d, J = 8.2 Hz, 2H), 7.21-7.24 (m, 6H), 4.65 (dd, J = 9.3, 7.3 Hz, 1H), 3.42 (dd, J = 10.5, 1.4 Hz, 1H), 3.33 (d, J = 10.4 Hz, 1H), 2.41 (s, 3H), 2.00 (ddd, J = 12.8, 7.3, 1.4 Hz, 1H), 1.66 (dd, J = 12.8, 9.4 Hz, 1H), 1.04 (s, 3H), 0.74 (s, 3H). 13C NMR
(125 MHz, CDCl3): δ = 143.4, 141.6, 135.6, 132.8, 129.5, 128.5, 127.9, 127.5, 63.3, 61.9, 51.5, 38.2, 26.2, 25.8, 21.6.
2-(4-Bromophenyl)-4,4-dimethyl-1-tosylpyrrolidine (10e)
Prepared according to the general procedure GP4, 10e was isolated as a white solid with a yield of 31%. The NMR spectra match those previously described in 158 1 literature. H NMR (500 MHz, CDCl3): δ = 7.54 (d, J = 8.2 Hz, 2H), 7.37 (d, J = 8.4 Hz, 2H), 7.23 (d, J = 8.1 Hz, 2H), 7.15 (d, J = 8.4 Hz, 2H), 4.63 (dd, J = 9.3, 7.3 Hz, 1H), 3.41 (d, J = 10.5 Hz, 1H), 3.33 (d, J = 10.4 Hz, 1H), 2.40 (s, 3H), 1.99 (ddd, J = 12.9, 7.3, 1.5 Hz, 1H), 1.66 (dd, J = 12.7, 9.4 13 Hz, 1H), 1.04 (s, 3H), 0.73 (s, 3H). C NMR (125 MHz, CDCl3): δ = 143.4, 142.2, 135.5, 131.4, 129.5, 128.3, 127.5, 120.9, 63.3, 61.9, 51.4, 38.2, 26.2, 25.7, 21.6.
4,4-Dimethyl-2-(o-tolyl)-1-tosylpyrrolidine (10f)
Prepared according to the general procedure GP4, 10f was isolated as a white solid with a yield of 60%. 1H NMR (500
MHz, CDCl3): δ = 7.55 (d, J = 8.3 Hz, 2H), 7.32-7.27 (m, 1H), 7.21 (d, J = 8.0 Hz, 2H), 7.12-7.06 (m, 3H), 5.00 (dd, J = 9.4, 7.4 Hz, 1H), 3.50 (dd, J = 10.5, 1.5 Hz, 1H), 3.35 (d, J = 10.4 Hz, 1H), 2.40 (s, 3H), 2.36 (s, 2H), 2.07 (ddd, J = 12.8, 7.4, 1.5 Hz, 1H), 1.61 (dd, J = 12.8, 9.4 Hz, 13 1H), 1.07 (s, 3H), 0.80 (s, 3H). C NMR (126 MHz, CDCl3): δ = 143.0, 141.1, 136.0, 134.1, 130.2, 129.3, 127.4, 126.7, 126.3, 126.2, 69.7, 61.7, 49.9, 38.3, 26.1, 25.8, 21.5, 19.3. IR ν(cm-1): 2958, 2883, 1566, 1493, 1462, 1343, 1303, 1160, 1089, 1024, 760, 660, 586, 548. HRMS (m/z): [M+Na]+ calculated for
C20H25NNaO2S: 366.1498; found: 366.1501. mp: 135-136 ºC.
4,4-Dimethyl-2-(m-tolyl)-1-tosylpyrrolidine (10g)
245 Part III Cooperative Iodine and Photoredox Catalysis for C(sp3)-H Functionalization
Prepared according to the general procedure GP4, 10g was isolated as a white solid with a yield of 90%. 1H NMR (400
MHz, CDCl3): δ = 7.55 (d, J = 8.3 Hz, 2H), 7.24-7.20 (m, 2H), 7.20-7.15 (m, 1H), 7.10 (dt, J = 7.8, 1.6 Hz, 1H), 7.05-7.02 (m, 2H), 4.72 (dd, J = 9.5, 7.2 Hz, 1H), 4.23 (t, J = 7.1 Hz, 1H), 3.50 (dd, J = 10.3, 1.5 Hz, 1H), 3.36 (d, J = 10.3 Hz, 1H), 2.42 (s, 3H), 2.30 (s, 3H), 2.04 (ddd, J = 12.7, 7.2, 1.5 Hz, 1H), 1.74 (dd, J = 12.8, 9.5 Hz, 1H), 1.08 (s, 3H), 0.81 (s, 13 3H). C NMR (101 MHz, CDCl3): δ = 142.9, 142.8, 137.8, 136.1, 129.3, 128.2, 127.9, 127.4, 127.2, 123.8, 63.9, 61.9, 51.7, 38.2, 26.1, 25.7, 21.5, 21.5. IR ν(cm-1): 2961, 2925, 2876, 1598, 1459, 1340, 1156, 1087, 1057, 1028, 965, 800, 700, 661, + 575, 547. HRMS (m/z): [M+Na] calculated for C20H25NNaO2S: 366.1498; found: 366.1502. mp: 85-86 ºC.
4,4-Dimethyl-1-(methylsulfonyl)-2-phenylpyrrolidine (10h)
Prepared according to the general procedure GP4, 10h was isolated as a white solid with a yield of 92%. The NMR spectra match those previously described in literature.158 1 H NMR (400 MHz, CDCl3): δ = 7.39-7.35 (m, 4H), 7.32- 7.26 (m, 1H), 4.93 (dd, J = 9.8, 7.3 Hz, 1H), 3.69 (dd, J = 10.2, 1.7 Hz, 1H), 3.30 (d, J = 10.2 Hz, 1H), 2.55 (s, 3H), 2.22 (ddd, J = 12.8, 7.3, 1.8 Hz, 1H), 1.85 (dd, 13 J = 12.7, 9.8 Hz, 1H), 1.21 (s, 3H), 1.17 (s, 3H). C NMR (101 MHz, CDCl3): δ = 142.6, 128.8, 127.8, 126.9, 63.5, 61.5, 51.7, 40.7, 38.5, 25.8, 25.8.
4,4-Dimethyl-1-((4-nitrophenyl)sulfonyl)-2-phenylpyrrolidine (10i)
Prepared according to the general procedure GP4, 10i was isolated as a white solid with a yield of 60%. The NMR spectra match those previously described in literature.158 1 H NMR (400 MHz, CDCl3): δ = 8.11 (d, J = 8.8 Hz, 2H), 7.57 (d, J = 8.8 Hz, 2H), 7.15-7.20 (m, 3H), 7.09-7.11 (m, 2H), 4.87 (dd, J = 9.8, 7.2 Hz, 1H), 3.66 (dd, J = 9.9, 1.7 Hz, 1H), 3.30 (dd, J = 10.0, 0.9 Hz, 1H), 2.15 (ddd, J = 12.9, 7.3, 1.6 Hz, 1H), 1.79 (ddd, J = 13.1, 9.9, 0.9 Hz, 1H), 1.13 (s, 3H), 13 1.03 (s, 3H). C NMR (125 MHz, CDCl3): δ = 149.6, 145.9, 141.4, 128.5, 128.1, 127.8, 127.2, 123.8, 64.1, 61.9, 51.4, 38.6, 25.8, 25.7.
1-(Cyclopropylsulfonyl)-4,4-dimethyl-2-phenylpyrrolidine (10j)
246 Part III Cooperative Iodine and Photoredox Catalysis for C(sp3)-H Functionalization
Prepared according to the general procedure GP4, 10j was isolated as a white solid with a yield of 88%. 1H NMR (400
MHz, CDCl3): δ = 7.41-7.37 (m, 2H), 7.34 (ddd, J = 7.7, 6.6, 1.2 Hz, 2H), 7.29-7.24 (m, 1H), 4.94 (dd, J = 9.7, 7.3 Hz, 1H), 3.68 (dd, J = 10.2, 1.7 Hz, 1H), 3.34 (dd, J = 10.2, 0.8 Hz, 1H), 2.21 (ddd, J = 12.7, 7.3, 1.7 Hz, 1H), 2.01 (tt, J = 8.0, 4.9 Hz, 1H), 1.81 (dd, J = 12.7, 9.7 Hz, 1H), 1.22 (s, 3H), 1.16 (s, 3H), 1.09-1.00 (m, 1H), 0.89-0.76 (m, 13 2H), 0.62-0.55 (m, 1H). C NMR (101 MHz, CDCl3): δ = 143.5, 128.5, 127.4, 126.8, 63.5, 61.9, 51.8, 38.6, 30.5, 25.7, 5.4, 5.0. IR ν(cm-1): 2958, 2871, 1454, 1330, 1307, 1141, 1072, 1042, 15 987, 888, 759, 696, 586, 563, 528. HRMS (m/z): + [M+Na] calculated for C15H21NNaO2S: 302.1185; found: 302.1193. mp: 56-57 ºC.
4,4-Dimethyl-2-phenyl-1-(thiophen-2-ylsulfonyl)pyrrolidine (10k)
Prepared according to the general procedure GP4, 10k was isolated as a yellowish solid with a yield of 96%. 1H NMR (400 MHz, CDCl3): δ = 7.54 (dd, J = 5.0, 1.3 Hz, 1H), 7.43 (dd, J = 3.7, 1.3 Hz, 1H), 7.36-7.31 (m, 2H), 7.31-7.28 (m, 2H), 7.26-7.21 (m, 1H), 7.06 (dd, J = 5.0, 3.7 Hz, 1H), 4.72 (dd, J = 9.2, 7.3 Hz, 1H), 3.45 (s, 2H), 2.04 (dd, J = 12.8, 7.3 Hz, 1H), 1.78 (dd, J = 12.8, 9.3 Hz, 1H), 1.07 (s, 3H), 0.71 (s, 3H). 13C NMR (101 MHz,
CDCl3): δ = 142.9, 138.7, 132.0, 131.5, 128.4, 127.5, 127.3, 126.5, 64.2, 62.2, 51.6, 38.2, 26.3, 25.7. IR ν(cm-1): 2959, 2874, 1466, 1351, 1223, 1152, 1092, 1068, 1053, 1025, 725, 697, 665, 601, 571, 545. HRMS (m/z): [M+Na]+ calculated for C16H19NNaO2S2: 344.0748; found: 344.0748. mp: 139-140 ºC.
4,4-Dimethyl-2-phenyl-1-{[2- (trimethylsilyl)ethyl]sulfonyl}pyrrolidine (10l)
Prepared according to the general procedure GP4, 10l was isolated as a white solid with a yield of 72%. The NMR spectra match those previously described in literature.158 1 H NMR (400 MHz, CDCl3): δ = 7.39-7.33 (m, 4H), 7.31- 7.26 (m, 1H), 4.95 (dd, J = 10.2, 7.2 Hz, 1H), 3.77 (dd, J = 10.2, 1.8 Hz, 1H), 3.28 (d, J = 10.3 Hz, 1H), 2.49 (td, J = 13.9, 4.1 Hz, 1H), 2.30 (td, J = 13.9, 4.5 Hz, 1H), 2.20 (ddd, J = 12.7, 7.2, 1.8 Hz, 1H), 1.86 (dd, J = 12.5, 10.3 Hz, 1H), 1.21 (s, 13 3H), 1.17 (s, 3H), 0.93-0.75 (m, 2H), -0.11 (s, 9H). C NMR (101 MHz, CDCl3): δ = 142.7, 128.8, 127.9, 127.2, 63.4, 62.3, 51.6, 50.4, 38.7, 25.6, 25.4, 10.1, -2.0.
247 Part III Cooperative Iodine and Photoredox Catalysis for C(sp3)-H Functionalization
3-Phenyl-2-tosyl-2-azaspiro[4.5]decane (10m)
Prepared according to the general procedure GP4, 10l was isolated as a white foam with a yield of 81%. The NMR spectra match those previously described in 158 1 literature. H NMR (500 MHz, CDCl3): δ = 7.59 (d, J = 8.2 Hz, 2H), 7.28-7.30 (m, 4H), 7.22-7.27 (m, 3H), 4.64 (dd, J = 9.4, 7.3 Hz, 1H), 3.64 (dd, J = 10.8, 1.4 Hz, 1H), 3.32 (d, J = 10.8 Hz, 1H), 2.42 (s, 3H), 2.13 (ddd, J = 13.0, 7.4, 1.4 Hz, 1H), 1.67 (dd, J = 13.0, 9.4 Hz, 13 1H), 1.28-1.45 (m, 9H), 1.01-1.05 (m, 1H). C NMR (125 MHz, CDCl3): δ = 143.1, 143.0, 135.5, 129.3, 128.3, 127.4, 127.0, 126.4, 63.1, 59.3, 49.6, 41.9, 36.4, 33.9, 25.9, 23.8, 22.8, 21.5.
(±)-(2S,4S)-4-Methyl-2-phenyl-1-tosylpyrrolidine and (±)-(2R,4S)-4- methyl-2-phenyl-1- tosylpyrrolidine (10n)
Prepared according to the general procedure GP4, 10n was isolated as a non-separable 1:1 mixture of diastereoisomers as a white solid with a yield of 70%. The NMR spectra match those previously described in literature.158 1H NMR
(500 MHz, CDCl3): δ = 7.70 (d, J = 8.2 Hz, 4H), 7.63 (d, J = 8.2 Hz, 4H), 7.13- 7.34 (m, 10H), 4.87 (dd, J = 8.4, 2.4 Hz, 1H), 4.67 (dd, J = 9.5, 7.2 Hz, 1H), 3.86 (ddd, J = 11.1, 7.3, 1.4 Hz, 1H), 3.76 (ddd, J = 9.4, 6.9, 0.8 Hz, 1H), 3.11 (t, J = 10.8 Hz, 1H), 2.90 (t, J = 9.3 Hz, 1H), 2.45 (s, 3H), 2.44 (s, 3H), 2.33-2.42 (m, 2H), 1.80-1.94 (m, 2H), 1.61 (ddd, J = 12.3, 10.6, 8.4 Hz, 1H), 1.50 (ddd, J = 12.7, 11.4, 9.5 Hz, 1H), 0.97 (d, J = 6.5 Hz, 3H), 0.90 (d, J = 6.6 Hz, 3H). 13C
NMR (125 MHz, CDCl3): δ = 143.4, 143.3, 143.2, 143.1, 135.7, 134.9, 129.6, 128.4, 128.3, 127.6, 127.5, 127.2, 127.0, 126.4, 126.2, 64.7, 63.3, 57.8, 55.9, 45.7, 43.6, 33.5, 31.4, 21.7, 21.6, 16.9, 16.7.
2-Phenyl-1-tosylpyrrolidine (10o)
Prepared according to the general procedure GP4, 10o was isolated as a yellow solid with a yield of 81%. The NMR spectra match those previously described in literature.158 1H NMR (400 MHz, CDCl3): δ = 7.70 (d, J = 8.3 Hz, 2H), 7.34- 7.24 (m, 7H), 4.81 (dd, J = 7.9, 3.6 Hz, 1H), 3.69-3.60 (m, 1H), 3.45 (dt, J = 10.2, 7.2 Hz, 1H), 2.45 (s, 3H), 2.05-1.96 (m, 1H), 1.93-1.80 (m, 2H), 1.72-1.65 13 (m, 1H). C NMR (125 MHz, CDCl3): δ = 143.4, 143.1, 135.2, 129.7, 128.4, 127.6, 127.1, 126.2, 63.4, 49.5, 35.9, 24.1, 21.6.
248 Part III Cooperative Iodine and Photoredox Catalysis for C(sp3)-H Functionalization
1-Tosyl-1,2,3,3a,4,8b-hexahydroindeno[1,2-b]pyrrole (10p)
Prepared according to the general procedure GP4, 10p was isolated as a white foam with a yield of 82%. The NMR spectra match those previously described in literature.158 1H
NMR (500 MHz, CDCl3): δ = 7.78-7.83 (m, 3H), 7.34 (d, J = 8.0 Hz, 2H), 7.24-7.28 (m, 2H), 7.15-7.17 (m, 1H), 5.15 (d, J = 7.8 Hz, 1H), 3.38 (ddd, J = 10.2, 7.2, 4.4 Hz, 1H), 3.23 (ddd, J = 10.2, 8.7, 6.7 Hz, 1H), 3.03 (dd, J = 16.6, 8.0 Hz, 1H), 2.67-2.75 (m, 2H), 2.44 (s, 3H), 1.84 (dtd, J = 14.2, 7.1, 4.4 13 Hz, 1H), 1.49-1.62 (m, 1H). C NMR (125 MHz, CDCl3): δ = 143.6, 142.0, 141.0, 135.0, 129.8, 128.3, 127.8, 127.4, 126.9, 125.0, 68.8, 49.3, 41.9, 35.9, 31.5, 21.6.
1-(p-Tolyl)-2-tosylisoindoline (10q)
Prepared according to the general procedure GP4, 10q was isolated as a white foam with a yield of 94%. 1H NMR (400 MHz, CDCl3): δ = 7.57 (d, J = 8.2 Hz, 2H), 7.26-7.04 (m, 9H), 6.85 (d, J = 7.9 Hz, 1H) 5.88 (s, 1H), 13 4.89-4.79 (m, 2H), 2.37 (s, 3H), 2.33 (s, 3H). C NMR (101 MHz, CDCl3): δ = 143.3, 141.3, 139.1, 137.6, 135.4, 135.2, 129.5, 129.2, 128.1, 128.0, 127.6, 127.5, 123.8, 122.5, 69.4, 54.1, 21.6, 21.3. IR ν(cm-1): 3029, 2920, 2848, 1485, 1346, 1160, 1093, 1047, 816, 744, 667, 559. HRMS (m/z): [M+Na]+ calculated for C22H21NNaO2S: 386.1185; found: 386.1193. mp: 117-118 ºC.
1-(Thiophen-2-yl)-2-tosylisoindoline (10r)
Prepared according to the general procedure GP4, 10r was isolated as a yellowish oil with a yield of 73%. 1H NMR (400 MHz, CDCl3): δ = 7.56 (d, J = 8.3 Hz, 2H), 7.30-7.25 (m, 1H), 7.24-7.20 (m, 2H), 7.21-7.14 (m, 3H), 7.11 (dd, J = 4.0, 1.1 Hz, 1H), 7.09-7.02 (m, 1H), 6.92 (dd, J = 5.1, 3.5 Hz, 1H), 6.32 (d, J = 2.5 Hz, 1H), 4.82 (d, J = 14.6 Hz, 1H), 4.74 (dd, J = 13.6, 2.7 Hz, 1H), 2.36 (s, 3H). 13C NMR (101 MHz, CDCl3): δ = 145.9, 143.4, 140.4, 135.7, 135.3, 129.6, 128.5, 128.1, 127.4, 126.5, 126.5, 126.1, 123.8, 122.6, 64.7, 53.3, 21.6. IR ν(cm-1): 3030, 2923, 2861, 1595, 1462, 1348, 1307, 1293, 1160, 1091, 1035, 820, 745, 669, 559, 540. HRMS + (m/z): [M+Na] calculated for C19H17NNaO2S2: 378.0593; found: 378.0598.
(4,4-Dimethyl-2-phenylpyrrolidin-1-yl)(phenyl)methanone (10s)
249 Part III Cooperative Iodine and Photoredox Catalysis for C(sp3)-H Functionalization
Prepared according to the general procedure GP4, 10s was isolated as a white solid with a yield of 82%. 1H NMR (400
MHz, CDCl3): δ = 7.64 (dd, J = 7.7, 1.9 Hz, 2H), 7.44 (td, J = 5.9, 2.7 Hz, 3H), 7.38-7.33 (m, 5H), 5.36 (dd, J = 10.2, 7.7 Hz, 1H), 3.61 (d, J = 10.4 Hz, 1H), 3.40 (dd, J = 10.4, 1.9 Hz, 1H), 2.26 (ddd, J = 12.8, 7.7, 1.9 Hz, 1H), 1.80 (dd, J = 12.7, 10.2 Hz, 1H), 1.13 (s, 13 3H), 1.06 (s, 3H). C NMR (101 MHz, CDCl3): δ = 170.2, 143.6, 136.7, 130.3, 128.5, 128.2, 127.8, 126.8, 125.7, 64.1, 60.8, 49.3, 39.0, 25.6, 25.4. IR ν(cm-1): 3318, 2966, 2912, 2912, 1637, 1546, 1493, 1303, 1209, 693. HRMS (m/z): [M+H]+ calculated for C19H22NO: 280.1696; found: 280.1703. mp: 84-85 ºC.
1-(4,4-Dimethyl-2-phenylpyrrolidin-1-yl)-2,2,2-trifluoroethan-1-one (10t)
Prepared according to the general procedure GP4, 10t was isolated as a white solid with a yield of 43%. 1H NMR (500
MHz, CDCl3): δ = 7.33 (t, J = 7.6 Hz, 2H), 7.26-7.22 (m, 1H), 7.21-7.18 (m, 2H), 5.11 (t, J = 8.8 Hz, 1H), 3.71 (dt, J = 10.8, 2.0 Hz, 1H), 3.51 (d, J = 10.9 Hz, 1H), 2.23 (ddd, J = 13.0, 7.8, 1.7 Hz, 1H), 1.74 (dd, J = 13.0, 9.8 Hz, 1H), 1.19 (s, 3H), 1.12 (s, 3H). 13C NMR
(126 MHz, CDCl3): δ = 156.0, 141.7, 128.9, 127.5, 125.7, 116.4 (q, JC-F = 288.0 Hz), 62.7, 60.6, 48.6, 39.0, 25.6, 25.5. IR ν(cm-1): 2967, 1677, 1447, 1240, 1194, 1146, 1030, 747, 700, 536. HRMS (m/z): [M+Na]+ calculated for C14H16F3NNaO: 294.1076; found: 294.1082. mp: 78-79 ºC.
III.6.6 Synthesis of the substrates 11a-u for the lactonization 11a, 11h, 11m and 11n are commercially available and were purchased and used as received.
Synthesis of 11b-d and 11o-q (GP5)
Scheme III.36. Pathway for the synthesis of 11b-d and 11o-q.
250 Part III Cooperative Iodine and Photoredox Catalysis for C(sp3)-H Functionalization
Step 1. In a flame-dried Schlenk flask were added the corresponding substituted benzene (10 mL), which was used as solvent, and anhydrous aluminium chloride (4 g, 30 mmol, 3 equiv.). The mixture was stirred at room temperature for 30 min. To this mixture, succinic anhydride (1.0 g, 10 mmol, 1 equiv.) was added in portions with continuous stirring. Vigorous reaction started with the evolution of HCl gas. Stirring was continued overnight at 80°C. Hydrolysis by HCl (1M) was then carried out and the reaction was extracted with EtOAc. The combined organic layers were washed with an aqueous solution of 10 % NaOH. To the combined aqueous layers were added a 6 N HCl solution to adjust the pH to 1-2. The aqueous phase was then extracted again with EtOAc and dried over Na2SO4 before to be concentrated. The crude compound was used in the next step without any purifications. Step 2. Hydrazine hydrate (4 equiv.) and KOH pellets (4 equiv.) were added to a solution of the crude from the step 1 (1 equiv.) in ethylene glycol (0.1 M), and the reaction mixture was heated to 180 °C for 10 h. The reaction mixture was cooled down to room temperature and diluted with water. The aqueous layer was washed with Et2O, acidified with an aqueous solution of
6 N HCl and then extracted twice with Et2O. The organic layer was then dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography using hexane/ethyl acetate and 1 % of acetic acid as eluent to provide 11b-d and 11o-q.
Synthesis of 11e
In a flame-dried Schlenk flask was added benzene (10 mL), which was used as solvent, and anhydrous aluminium chloride (245 mg, 1.8 mmol, 1.5 equiv.). The mixture was stirred at room temperature for 30 min. To this mixture, 12a (Synthetized by GP-7, 200 mg, 1.23 mmol, 1 equiv.) was added in portions with continuous stirring overnight at 80°C. Hydrolysis by HCl (1M) was then carried out and the reaction was extracted with EtOAc. The combined organic layers were washed with an aqueous solution of 10 % NaOH. To the combined aqueous layers were added a 6 N HCl solution to adjust the pH to 1-2. The aqueous phase was then extracted again with
EtOAc and dried over Na2SO4 before to be concentrated. The crude acid was purified by column chromatography using hexane/ethyl acetate and 1 % of acetic acid as eluent to finally get 11e as a white solid in 36% isolated yield.
251 Part III Cooperative Iodine and Photoredox Catalysis for C(sp3)-H Functionalization
Synthesis of 11f
A Schlenk tube equipped with a stirrer bar was charged with the commercially available 11a (1.64 g, 10 mmol, 1 equiv.) and THF (20 mL). The vessel was then cooled down to 0ºC. LDA (2M solution, 12.5 mL, 25 mmol, 2.5 equiv.) was added dropwise and the mixture was stirred 30 min at 0ºC. At this point, MeI (1.37 mL, 22 mmol, 2.2 equiv.) was added dropwise and the reaction could reach room temperature overnight. A saturated aqueous solution of NH4Cl was added and the reaction was extracted with Et2O. The combined organic layers were washed with an aqueous solution of 10 % NaOH. To the combined aqueous layers were added a 6 N HCl solution to adjust the pH to 1-2. The aqueous phase was then extracted again with Et2O and dried over Na2SO4 before to be concentrated. The crude acid was purified by column chromatography using hexane/ethyl acetate and 1 % of acetic acid as eluent to finally get 11f as a yellow oil in 80% isolated yield.
Synthesis of 11g
Scheme III.37. Pathway for the synthesis of 11g.
Step 1. A flame-dried Schlenk tube equipped with a stirrer bar was charged with the trimethylphosphonoacetate (1.62 mL, 10 mmol, 1.0 equiv.) and THF (5 mL/mmol) and the vessel was cooled down to 0º C. n-BuLi (5 mL of a 2 M solution, 10 mmol, 1.0 equiv.) was added dropwise and the reaction was stirred for one hour upon which time the 2-indanone (1.32 g, 10 mmol, 1.0 equiv.) was added and the reaction was then stirred for 18 h at room temperature. A saturated aqueous solution of NH4Cl was added and the resulting mixture extracted three times with Et2O. The organic layer was dried over anhydrous Na2SO4 and the solvent evaporated under reduced pressure. The crude was used for the next step without further purification.
252 Part III Cooperative Iodine and Photoredox Catalysis for C(sp3)-H Functionalization
Step 2. A flame-dried Schlenk tube equipped with a stirrer bar was charged with the crude from the previous step, Pd/C (20 w%) and ethanol (5 mL/mmol) were added and the reaction was stirred under atmospheric pressure of hydrogen gas overnight. The mixture was filtered through Celite and concentrated to yield the crude ester which was used for the next step without further purification.
Step 3. The crude ester from the previous step was stirred with LiOH.H2O
(840 mg, 20 mmol, 2 equiv.) in a mixture of THF/H2O (1/1) overnight. The reaction was washed with Et2O and the aqueous layer was acidified with an aqueous solution of 6 N HCl to adjust the pH to 1-2. The aqueous phase was then extracted again with Et2O and dried over anhydrous Na2SO4 before to be concentrated. The crude acid was purified by column chromatography using hexane/ethyl acetate and 1 % of acetic acid as eluent to finally get 11g as a white solid in 61% overall yield.
Synthesis of 11a-D, 11i-l and 11r-t (GP6)
Scheme III.38. Pathway for the synthesis of 11a-D, 11i-l and 11r-t.
Step 1. In a flame-dried Schlenk flask were added the corresponding substituted benzene (10 mL), which was used as solvent, and anhydrous aluminium chloride (4 g, 30 mmol, 3 equiv.). The mixture was stirred at room temperature for 30 min. To this mixture, the corresponding anhydride (1.0 g, 10 mmol, 1 equiv.) was added in portions with continuous stirring. Vigorous reaction started with the evolution of HCl gas. Stirring was continued overnight at 80°C. Hydrolysis by HCl (1M) was then carried out and the reaction was extracted with EtOAc. The combined organic
253 Part III Cooperative Iodine and Photoredox Catalysis for C(sp3)-H Functionalization layers were washed with an aqueous solution of 10 % NaOH. To the combined aqueous layers were added a 6 N HCl solution to adjust the pH to 1-2. The aqueous phase was then extracted again with EtOAc and dried over Na2SO4 before to be concentrated. The crude compound was used in the next step without any purifications. Step 2. In a flame-dried Schenk flask, trifluoroacetic acid (4.1 mL) was added dropwise to a solution of the crude of the previous step (4.1 mmol, 1.0 equiv.) and of triethylsilane (12.3 mmol, 3.0 equiv.) in chloroform (4.1 mL) at 0 ºC. The solution was then heated at reflux for 18 h. After cooling down to room temperature, the reaction was diluted with Et2O and washed twice with brine, dried over anhydrous Na2SO4 and concentrated. The intermediate lactones were used without any purifications. Note: For the compound 11a-D, deuterated triethylsilane was used instead. Step 3. A flame-dried Schlenk tube equipped with a stirrer bar was charged with the crude from the previous step, Pd/C (20 w%) and ethyl acetate (5 mL/mmol) were added and the reaction was stirred under atmospheric pressure of hydrogen gas overnight. The mixture was filtered through Celite and concentrated to yield the crude acid which was purified by column chromatography using hexane/ethyl acetate and 1 % of acetic acid as eluent providing the products 11a-D, 11i-l and 11r-t.
Synthesis of 11u
Scheme III.39. Pathway for the synthesis of 11u.
Step 1. A flame-dried Schlenk tube equipped with a stirrer bar was charged with the (Phenylmethyl)triphenylphosphonium bromide (2.8 g, 6.5 mmol, 1.3 equiv.) and THF (15 mL) and the vessel was cooled down to 0ºC. n-BuLi (5.2 mL of a 2.5 M solution, 13 mmol, 2.6 equiv.) was added dropwise and the reaction was stirred for 1 h to form the ylide. Then, the 2- carboxybenzaldehyde (750 mg, 5 mmol, 1 equiv.) was added portion wise and the mixture was stirred for 18 h at room temperature. An aqueous solution of 1 M HCl was added and the resulting mixture extracted three times with Et2O. The organic layer was dried over Na2SO4 and the solvent
254 Part III Cooperative Iodine and Photoredox Catalysis for C(sp3)-H Functionalization evaporated under reduced pressure. The crude acid was purified by column chromatography using hexane/ethyl acetate and 1 % of acetic acid as eluent. Step 2. A flame dried Schlenk tube equipped with a stirrer bar was charged with the purified compound from the previous step, Pd/C (20 w%) and ethanol (5 mL/mmol) were added and the reaction was stirred under atmospheric pressure of hydrogen gas overnight. The mixture was filtered through Celite to yield 11u as a white solid in 80% overall yield.
III.6.7 Characterization of the substrates 11a-t 4-Phenylbutanoic-4-D acid (11a-D)
Prepared according to the general procedure GP6, 11a- D was isolated as a white solid with an overall yield of 72%. The NMR spectra match those previously 195 1 described in literature. H NMR (400 MHz, CDCl3): δ = 7.33-7.27 (m, 2H), 7.23-7.17 (m, 3H), 2.71-2.64 (m, 1H), 2.39 (t, J = 7.5 Hz, 13 2H), 2.03-1.94 (m, 2H). C NMR (101 MHz, CDCl3): δ = 179.9, 141.2 (d, JH-D
= 4.3 Hz), 128.5 (d, JH-D = 6.8 Hz), 126.1, 35.0, 34.6 (t, JH-D = 19.6 Hz), 33.3 (d,
JH-D = 3.3 Hz), 26.2 (d, JH-D = 9.8 Hz).
4-(p-Tolyl)butanoic acid (11b)
Prepared according to the general procedure GP5, 11b was isolated as a white solid with an overall yield of 66%. The NMR spectra match those previously described in literature.191 1H NMR (400 MHz, CDCl3): δ = 7.16-7.08 (m, 4H), 2.70-2.64 (m, 2H), 2.43-2.32 (m, 5H), 2.04- 13 1.92 (m, 2H). C NMR (101 MHz, CDCl3): δ = 180.2, 137.9, 135.3, 129.0, 128.2, 34.4, 33.2, 26.2, 20.9.
4-(4-Fluorophenyl)butanoic acid (11c)
191 C. E. Dumelin, S. Trüssel, F. Buller, E. Trachsel, Bootz, F. Bootz, Y. Zhang, L. Mannocci, S. C. Beck, M. Drumea-Mirancea, M. W. Seeliger, C. Baltes, T. Müggler, F. Kranz, M. Rudin, S. Melkko, J. Scheuermann, D Neri, Angew. Chem. Int. Ed. 2008, 47, 3196–3201.
255 Part III Cooperative Iodine and Photoredox Catalysis for C(sp3)-H Functionalization
Prepared according to the general procedure GP5, 11c was isolated as a white solid with an overall yield of 64%. The NMR spectra match those previously described in literature.192 1H NMR (400 MHz,
CDCl3): δ = 7.18-7.14 (m, 2H), 7.02-6.97 (m, 2H), 2.68 (t, J = 7.6 Hz, 2H), 2.40 13 (t, J = 7.4 Hz, 2H), 2.03-1.90 (m, 2H). C NMR (101 MHz, CDCl3): δ = 179.9,
161.4 (d, JC–F = 243.7 Hz), 136.8 (d, JC–F = 3.2 Hz), 129.8 (d, JC–F = 7.8 Hz), 115.17 19 (d, JC–F = 21.1 Hz), 34.16, 33.2, 26.3 (d, JC–F = 1.2 Hz). F NMR (376 MHz,
CDCl3): δ = -117.5.
4-(4-Chlorophenyl)butanoic acid (11d)
Prepared according to the general procedure GP5, 11d was isolated as a white solid with an overall yield of 54%. The NMR spectra match those previously described in literature.193 1H NMR (400
MHz, CDCl3): δ = 7.34-7.21 (m, 2H), 7.17-7.12 (m, 2H), 2.68 (t, J = 7.6 Hz, 13 2H), 2.40 (t, J = 7.4 Hz, 2H), 2.03-1.92 (m, 2H). C NMR (101 MHz, CDCl3): δ = 180.0, 139.6, 131.8, 129.8, 128.5, 34.3, 33.2, 26.1.
4,4-Diphenylbutanoic acid (11e)
Prepared according to the procedure described above, 11e was isolated as a white solid with a yield of 36%. The NMR spectra match those previously described in 194 1 literature. H NMR (400 MHz, CDCl3): δ = 7.39-7.29 (m, 8H), 7.29-7.21 (m, 2H), 4.02 (t, J = 7.6 Hz, 1H), 2.52-2.43 (m, 2H), 2.43- 13 2.35 (m, 2H). C NMR (101 MHz, CDCl3): δ = 178.6, 143.9, 128.6, 127.8, 126.4, 50.3, 32.3, 30.3.
2-Methyl-4-phenylbutanoic acid (11f)
192 M. S. Newman, R. Chatterji, S. Seshadri, J. Org. Chem. 1961, 26, 2667–2669. 193 I. T. Crosby, J. K. Shin, B. Capuano, Aust. J. Chem. 2010, 63, 211–226. 194 L. M. Ferreira, M. M. B. Marques, P. M. C. Glória, H. T. Chaves, J-P. P. Franco, I. Mourato, J-R T. Antunes, H. S. Rzepa, A. M. Lobo, S. Prabhakar, Tetrahedron 2008, 64, 7759–7770.
256 Part III Cooperative Iodine and Photoredox Catalysis for C(sp3)-H Functionalization
Prepared according to the procedure described above, 11f was isolated as a yellow oil with a yield of 80%. The NMR spectra match those previously described in 195 1 literature. H NMR (400 MHz, CDCl3): δ = 7.34-7.27 (m, 2H), 7.24-7.18 (m, 3H), 2.73-2.68 (m, 2H), 2.59-2.49 (m, 1H), 2.14-2.03 (m, 1H), 1.83-1.72 (m, 1H), 1.27 (dd, J = 7.0, 0.7 Hz, 3H). 13C NMR (101 MHz,
CDCl3): δ = 180.0, 148.9, 138.1, 128.1, 125.3, 34.4, 33.4, 31.4, 26.2.
2-(2,3-Dihydro-1H-inden-2-yl)acetic acid (11g)
Prepared according to the procedure described above, 11f was isolated as a white solid with an overall yield of 85%. The NMR spectra match those previously 196 1 described in literature. H NMR (400 MHz, CDCl3): δ = 7.27-7.13 (m, 4H), 3.25-3.15 (m, 2H), 3.00-2.85 (m, 1H), 2.75-2.65 (m, 2H), 13 2.62-2.55 (m, 2H). C NMR (101 MHz, CDCl3): δ = 179.7, 142.5, 126.4, 124.5, 39.8, 38.9, 35.9.
2-(4-Fluorobenzyl)benzoic acid (11i)
Prepared according to the general procedure GP6, 11i was isolated as a white solid with an overall yield of 58%. The NMR spectra match those previously 197 1 described in literature. H NMR (400 MHz, CDCl3): δ = 8.13-8.08 (m, 1H), 7.52 (td, J = 7.5, 1.3 Hz, 1H), 7.36 (t, J = 7.6 Hz, 1H), 7.25 (d, J = 7.7 Hz, 1H), 7.14 (ddd, J = 8.2, 5.5, 1.8 Hz, 2H), 13 6.97 (td, J = 8.6, 1.5 Hz, 2H), 4.44 (s, 2H). C NMR (101 MHz, CDCl3): δ =
172.8, 161.3 (d, JC–F = 243.9 Hz), 143.3, 136.4 (d, JC–F = 3.2 Hz), 133.1, 131.8, 131.7, 19 130.4 (d, JC–F = 7.8 Hz), 128.3, 126.5, 115.1 (d, JC–F = 21.2 Hz), 38.9. F NMR (376 MHz, CDCl3): δ = -117.5.
2-(2,4-Difluorobenzyl)benzoic acid (11j)
195 T. Fujita, S. Watanabe, K. Suga, H. Nakayama, Synthesis 1979, 4, 310–311. 196 M. P. Hay, K. O. Hicks, K. Pchalek, H. H. Lee, A. Blaser, F. B. Pruijn, R. F. Anderson, S. S. Shinde, W. R. Wilson, W. A. Denny, J. Med. Chem. 2008, 51, 6853–6865. 197 K. M. Khan, S. Hayat, Z. Ullah, A-U. Rahman, M. I. Choudhary, G. M. Maharvi, E. Bayer, Synth. Commun. 2003, 33, 3435–3453.
257 Part III Cooperative Iodine and Photoredox Catalysis for C(sp3)-H Functionalization
Prepared according to the general procedure GP6, 11j was isolated as a white solid with an overall yield of 1 48%. H NMR (400 MHz, CDCl3): δ = 8.11 (dt, J = 7.8, 1.5 Hz, 1H), 7.50 (td, J = 7.6, 1.5 Hz, 1H), 7.36 (td, J = 7.6, 1.3 Hz, 1H), 7.20 (d, J = 7.8 Hz, 1H), 7.00 (td, J = 8.5, 6.5 Hz, 1H), 6.84-6.74 13 (m, 2H), 4.44 (s, 2H). C NMR (101 MHz, CDCl3): δ = 173.0, 161.5 (dd, JC–F =
249.0, 12.3 Hz), 161.0 (dd, JC–F = 248.5, 12.1 Hz), 142.1, 133.4, 132.0, 131.5 (dd, JC–
F = 10.7, 6.2 Hz), 131.5, 128.5, 126.8, 123.7 (dd, JC–F = 15.9, 3.8 Hz), 111.1 (dd, JC–F 19 = 20.9, 3.8 Hz), 103.7 (t, JC–F = 25.7 Hz), 32.4 (d, JC–F = 2.7 Hz). F NMR (376 - MHz, CDCl3): δ = -113.17 (d, JF–F = 7.0 Hz), -113.32 (d JF–F = 6.7 Hz). IR v(cm 1): 2961, 1678, 1620, 1574, 1505, 1413, 1266, 1137, 1096, 731. HRMS (m/z): [M- - H] calculated for C14H9F2O2: 247.0577; found: 247.0576. mp: 106-110 ºC.
2-(3,4-Difluorobenzyl)benzoic acid (11k)
Prepared according to the general procedure GP6, 11k was isolated as a white solid with an overall yield of 1 52%. H NMR (400 MHz, CDCl3): δ = 8.10 (dd, J = 7.9, 1.5 Hz, 1H), 7.53 (td, J = 7.5, 1.5 Hz, 1H), 7.37 (td, J = 7.6, 1.3 Hz, 1H), 7.23 (dd, J = 7.8, 1.2 Hz, 1H), 7.04 (dt, J = 10.3, 8.3 Hz, 1H), 6.95 (ddd, J = 11.5, 7.6, 2.2 Hz, 1H), 6.92-6.85 (m, 1H), 4.40 13 (s, 2H). C NMR (101 MHz, CDCl3): δ = 172.7, 150.2 (dd, JC–F = 247.5, 12.6
Hz), 149.6 (dd, JC–F = 245.9, 12.6 Hz), 142.6 (d, JC–F = 0.8 Hz), 137.9 (dd, JC–F =
5.4, 3.9 Hz), 133.4, 132.1, 131.9, 128.3, 127.0, 124.8 (dd, JC–F = 6.0, 3.5 Hz), 117,8 19 (d, JC–F = 17.1 Hz), 117.0 (dd, JC–F = 17.0, 0.8 Hz), 39.0 (d, JC–F = 1.3 Hz). F NMR (376 MHz, CDCl3): δ = -138.41 (d, JF–F = 21.2 Hz), -142.11 (d, JF–F = 21.4 Hz). IR v(cm-1): 2927, 1676, 1521, 1434, 1409, 1270, 1208, 1118, 732. HRMS - (m/z): [M-H] calculated for C14H9F2O2: 247.0575; found: 247.0576. mp: 127- 128 ºC.
2-(Thiophen-2-ylmethyl)benzoic acid (11l)
Prepared according to the general procedure GP6, 11l was isolated as a yellow oil with an overall yield of 24%. The NMR spectra match those previously described in 198 1 literature. H NMR (400 MHz, CDCl3): δ = 8.11 (dd, J = 8.1, 1.5 Hz, 1H), 7.52 (td, J = 7.5, 1.5 Hz, 1H), 7.38-7.32 (m, 2H), 7.14 (dd, J =
198 M. L. Tedjamulia, Y. Tominaga, R. N. Castle, J. Heterocyclic. Chem. 1983, 20, 1143– 1148.
258 Part III Cooperative Iodine and Photoredox Catalysis for C(sp3)-H Functionalization
5.2, 1.2 Hz, 1H), 6.92 (dd, J = 5.2, 3.4 Hz, 1H), 6.82 (dq, J = 3.4, 1.1 Hz, 1H), 13 4.66 (s, 2H). C NMR (101 MHz, CDCl3): δ =173.0, 143.5, 143.1, 133.3, 131.9, 131.3, 127.9, 126.8, 126.7, 125.4, 123.9, 34.1.
5-(p-Tolyl)pentanoic acid (11o)
Prepared according to the general procedure GP5, 11o was isolated as a pale-yellow solid with an overall yield of 56%. The NMR spectra match those previously described in literature.199 1H
NMR (500 MHz, CDCl3): δ = 7.12-7.05 (m, 4H), 2.64-2.57 (m, 2H), 2.41-2.35 13 (m, 2H), 2.32 (s, 3H), 1.72-1.62 (m, 4H). C NMR (101 MHz, CDCl3): δ = 180.2, 139.1, 135.4, 129.2, 128.4, 35.2, 34.1, 31.0, 24.4, 21.1.
5-(4-Fluorophenyl)pentanoic acid (11p)
Prepared according to the general procedure GP5, 11p was isolated as a pale-yellow solid with an overall yield of 54%. The NMR spectra match 200 1 those previously described in literature. H NMR (500 MHz, CDCl3): δ = 7.14-7.07 (m, 2H), 6.98-6.93 (m, 1H), 6.86-6.83 (m, 1H), 2.63-2.56 (m, 2H), 13 2.40-2.35 (m, 2H), 1.71-1.61 (m, 4H). C NMR (101 MHz, CDCl3): δ = 180.2,
161.4 (d, JC-F = 243.4 Hz), 137.7 (d, JC-F = 3.2 Hz), 129.8 (d, JC-F = 7.7 Hz), 115.2 19 (d, JC-F = 21.1 Hz), 34.8, 34.0, 31.0, 24.3. F NMR (376 MHz, CDCl3): δ = - 117.9.
5-(4-Chlorophenyl)pentanoic acid (11q)
Prepared according to the general procedure GP5, 11q was isolated as a pale-yellow solid with an overall yield of 54%. The NMR spectra match those previously described in literature.201 1H
NMR (500 MHz, CDCl3): δ = 7.26-7.22 (m, 2H), 7.12-7.07 (m, 2H), 2.64-2.57 13 (m, 2H), 2.40-2.34 (m, 2H), 1.71-1.59 (m, 4H). C NMR (101 MHz, CDCl3): 180.0, 140.5, 131.7, 129.8, 128.6, 35.0, 33.9, 30.8, 24.3.
199 L. Jin, J. Qian, N. Sun, B. Hu, Z. Shen, X. Hu, Chem. Commun. 2018, 54, 5752–5755. 200 P. Shao, S. Wang, C. Chen, C. Xi, Org. Lett. 2016, 18, 2050–2053. 201 E. Shirakawa, D. Ikeda, S. Masui, M. Yoshida, T. Hayashi, J. Am. Chem. Soc. 2012, 134, 272–279.
259 Part III Cooperative Iodine and Photoredox Catalysis for C(sp3)-H Functionalization
3,3-Dimethyl-5-phenylpentanoic acid (11r)
Prepared according to the general procedure GP6, 11r was isolated as a colorless oil with an overall yield 1 of 65%. H NMR (400 MHz, CDCl3): δ = 7.33-7.27 (m, 2H), 7.23-7.17 (m, 3H), 2.68-2.58 (m, 2H), 2.34 (s, 2H), 13 1.73-1.64 (m, 2H), 1.14 (s, 6H). C NMR (101 MHz, CDCl3): δ = 179.0, 142.9, 128.5, 128.5, 125.8, 45.9, 44.5, 33.5, 30.9, 27.4. IR v(cm-1): 3026, 2959, 1700, - 1454, 1408, 1248, 795, 697. HRMS (m/z): [M-H] calculated for C13H17O2: 205.1234; found: 205.1236.
3,3-Dimethyl-5-(p-tolyl)pentanoic acid (11s)
Prepared according to the general procedure GP6, 11s was isolated as a white solid with an overall 1 yield of 45%. H NMR (400 MHz, CDCl3): δ = 7.12- 7.08 (m, 4H), 2.63-2.54 (m, 2H), 2.33 (s, 3H), 2.32 13 (s, 2H), 1.70-1.60 (m, 2H), 1.12 (s, 6H). C NMR (101 MHz, CDCl3): δ = 178.8, 139.8, 135.3, 129.2, 128.4, 45.9, 44.7, 33.5, 30.4, 27.4, 21.1. IR v(cm-1): 2963, - 1693, 1319, 1280, 1249, 808. HRMS (m/z): [M-H] calculated for C14H19O2: 219.1391; found: 219.1390. mp: 65-67 ºC.
5-(4-Fluorophenyl)-3,3-dimethylpentanoic acid (11t)
Prepared according to the general procedure GP6, 11t was isolated as a white solid with an overall 1 yield of 52%. H NMR (400 MHz, CDCl3): δ = 7.16- 7.10 (m, 2H), 6.98-6.92 (m, 2H), 2.62-2.55 (m, 2H), 13 2.32 (s, 2H), 1.66-1.59 (m, 2H), 1.11 (s, 6H). C NMR (101 MHz, CDCl3): δ =
178.4, 161.3 (d, JC–F = 243.1 Hz), 138.5 (d, JC–F = 3.2 Hz), 129.8 (d, JC–F = 7.7 Hz), 19 115.2 (d, JC–F = 21.1 Hz), 45.7, 44.5, 33.5, 30.1, 27.5. F NMR (376 MHz, CDCl3): δ = -117.7. IR v(cm-1): 2964, 2932, 1694, 1509, 1320, 1287, 1214, 822. HRMS - (m/z): [M-H] calculated for C13H16FO2: 223.1140; found: 223.1142. mp: 76.2- 78.2 ºC.
2-Phenethylbenzoic acid (11u)
260 Part III Cooperative Iodine and Photoredox Catalysis for C(sp3)-H Functionalization
Prepared according to the procedure described above, 11u was isolated as a white solid with an overall yield of 81%. The NMR spectra match those previously 202 1 described in literature. H NMR (400 MHz, CDCl3): δ = 8.13 (dq, J = 7.9, 1.5 Hz, 1H), 7.50 (tt, J = 7.5, 1.6 Hz, 1H), 7.38-7.18 (m, 7H), 13 3.41-3.35 (m, 2H), 3.04-2.92 (m, 2H). C NMR (101 MHz, CDCl3): δ = 173.5, 145.0, 142.1, 133.2, 132.0, 131.7, 128.7, 128.5, 128.2, 126.4, 126.1, 38.3, 37.3.
III.6.8 Synthesis of the lactones 12a-t (GP7) The requisite carboxylic acid 1 (0.3 mmol, 1.0 equiv.), molecular iodine (3.8 mg, 0,015 mmol, 5 mol%) and 2,4,6- tetraphenylpyrylium tetrafluoroborate (2.4 mg, 0,003 mmol, 2 mol%) were added to a reaction tube. 1.5 mL of DCE and 1.5 mL of 1,1,1,3,3,3-hexafluoroisopropanol were added and the resulting mixture was stirred to form a homogeneous solution. Then, the reaction was irradiated with blue LEDs for 18 h at room temperature. After 18 h of irradiation, DCM was added and the mixture washed three times with a saturated solution of Na2S2O3 and NaHCO3, dried over Na2SO4 and concentrated. The residue was purified by column chromatography over silica gel using a mixture of hexane and ethyl acetate as eluent to provide the pure product 12a-t.
III.6.9 Characterization of the lactones 12a-t 5-Phenyldihydrofuran-2(3H)-one (12a)
Prepared according to the general procedure GP7, 12a was isolated as a pale-yellow oil with a yield of 94%. The NMR spectra match those previously described in literature.203 1H
NMR (400 MHz, CDCl3): δ = 7.42-7.32 (m, 5H), 5.52 (dd, J = 7.99, 6.14 Hz, 1H), 2.71-2.62 (m, 3H), 2.26-2.14 (m, 1H). 13C NMR
(101 MHz, CDCl3): δ = 177.0, 139.5, 128.9, 128.6, 125.4, 81.3, 31.1, 29.1.
5-(p-Tolyl)dihydrofuran-2(3H)-one (12b)
202 M. Lamani, R. S. Guralamata, K. R. Prabhu, Chem. Commun. 2012, 48, 6583–6585. 203 L. Huang, H. Jiang, C. Qi, X. Liu, J. Am. Chem. Soc. 2010, 132, 17652–17654.
261 Part III Cooperative Iodine and Photoredox Catalysis for C(sp3)-H Functionalization
Prepared according to the general procedure GP7, 12b was isolated as a white solid with a yield of 65%. The NMR spectra match those previously described in literature.202 1H NMR (400 MHz, CDCl3): δ = 7.23-7.19 (m, 4H), 5.48 (dd, J = 8.07, 6.21 Hz, 1H), 2.67-2.59 (m, 3H), 2.36 (s, 3H), 2.23-2.15 13 (m, 1H). C NMR (101 MHz, CDCl3): δ = 177.1, 138.5, 136.5, 129.5, 125.5, 81.5, 31.1, 29.2, 21.3.
5-(4-Fluorophenyl)dihydrofuran-2(3H)-one (12c)
Prepared according to the general procedure GP7, 12c was isolated as a white solid with a yield of 86%. The NMR spectra match those previously described in literature.202 1H NMR (400 MHz, CDCl3): δ = 7.34-7.28 (m, 2H), 7.10-7.04 (m, 2H), 5.48 (dd, J = 8.37, 5.83 Hz, 1H), 2.69-2.60 (m, 3H), 2.22- 13 2.10 (m, 1H). C NMR (101 MHz, CDCl3): δ = 176.7, 162.8 (d,
JC–F = 247.2 Hz), 135.2 (d, JC–F = 3.23 Hz), 127.3 (d, JC–F = 8.26 Hz), 115.8 (d, JC– 19 F = 21.7 Hz), 80.8, 31.1, 29.1. F NMR (376 MHz, CDCl3): δ = -113.5.
5-(4-Chlorophenyl)dihydrofuran-2(3H)-one (12d)
Prepared according to the general procedure GP7, 12d was isolated as a pale yellow oil with a yield of 51%. The NMR spectra match those previously described in literature.202 1H
NMR (400 MHz, CDCl3): δ = 7.37-7.33 (m, 2H), 7.28-7.24 (m, 2H), 5.47 (dd, J = 8.21, 6.13 Hz, 1H), 2.70-2.59 (m, 3H), 13 2.20-2.08 (m, 1H). C NMR (101 MHz, CDCl3): δ = 176.6, 138.0, 134.4, 129.1, 126.8, 80.5, 31.1, 29.0
5,5-Diphenyldihydrofuran-2(3H)-one (12e)
Prepared according to the general procedure GP7, 12e was isolated as a white solid with a yield of 21%. The NMR spectra match those previously described in literature.198 1H NMR
(400 MHz, CDCl3): δ = 7.44-7.40 (m, 4H), 7.37-7.32 (m, 4H), 7.30-7.26 (m, 2H), 2.91 (t, J = 7.7 Hz, 2H), 2.58 (t, J = 7.8 Hz, 13 2H). C NMR (101 MHz, CDCl3): δ = 176.2, 143.2, 128.7, 128.0, 125.5, 89.9, 35.8, 29.2.
3-Methyl-5-phenyldihydrofuran-2(3H)-one (12f)
262 Part III Cooperative Iodine and Photoredox Catalysis for C(sp3)-H Functionalization
Prepared according to the general procedure GP7, 12f was isolated as a yellow oil with a yield of 74%. The NMR spectra match those previously described in literature.198 1 H NMR (400 MHz, CDCl3): δ = 7.41-7.30 (m, 10H), 5.57 (dd, J = 7.8, 4.6 Hz, 1H), 5.36 (m, 1H), 2.86-2.78 (m, 2H), 2.78-2.71 (m, 1H), 2.47-2.42 (m, 1H), 2.39-2.33 (m, 1H), 1.9-1.81 (m, 1H), 1.34 (s, 3H), 1.33 (s, 3H). 13 C NMR (101 MHz, CDCl3): δ = 180.0, 179.3, 139.9, 139.3, 128.9, 128.8, 128.6, 128.3, 125.6, 125.1, 79.3, 78.4, 40.1, 38.5, 36.5, 33.7, 15.5, 15.1.
3,3a,4,8b-Tetrahydro-2H-indeno[1,2-b]furan-2-one (12g)
Prepared according to the general procedure GP7, 12g was isolated as a pale yellow oil with a yield of 71%. The NMR spectra match those previously described in literature.204 1H NMR (400 MHz, CDCl3): δ = 7.48 (d, J = 7.5 Hz, 1H), 7.37-7.26 (m, 3H), 5.89 (d, J = 7.0 Hz, 1H), 3.41-3.29 (m, 2H), 2.94-2.86 13 (m, 2H), 2.42-2.36 (m, 1H). C NMR (101 MHz, CDCl3): δ = 177.0, 142.6, 138.9, 130.1, 127.7, 126.5, 125.5, 87.8, 38.0, 37.5, 35.8.
3-Phenylisobenzofuran-1(3H)-one (12h)
Prepared according to the general procedure GP7, 12h was isolated as a white solid with a yield of 74%. The NMR spectra match those previously described in literature.205 1 H NMR (400 MHz, CDCl3): δ = 7.96 (d, J = 7.7 Hz, 1H), 7.65 (td, J = 7.5, 1.2 Hz, 1H), 7.55 (tt, J = 7.5, 0.9 Hz, 1H), 7.39-7.36 (m, 3H), 7.33 (dd, J = 7.6, 0.9 Hz, 1H), 7.29-7.27 (m, 2H), 6.40 (s, 13 1H). C NMR (101 MHz, CDCl3): δ = 170.6, 149.8, 136.6, 134.4, 129.5, 129.4, 129.1, 127.1, 125.8, 125.7, 123.0, 82.8.
3-(4-Fluorophenyl)isobenzofuran-1(3H)-one (12i)
204 W. E. Fristad, J. R. Peterson, J. Org. Chem. 1985, 50, 10–18. 205 J. Karthikeyan, K. Parthasarathy, C-H. Cheng, Chem. Commun. 2011, 47, 10461– 10463.
263 Part III Cooperative Iodine and Photoredox Catalysis for C(sp3)-H Functionalization
Prepared according to the general procedure GP7, 12i was isolated as a white solid with a yield of 73%. The NMR spectra match those previously described in 206 1 literature. H NMR (400 MHz, CDCl3): δ = 8.00 (d, J = 7.6 Hz, 1H), 7.68 (td, J = 7.5, 1.2 Hz, 1H), 7.58 (tt, J = 7.5, 0.8 Hz, 1H), 7.33 (dd, J = 7.7, 0.9 Hz, 1H), 7.28-7.25 (m, 13 2H), 7.10-7.06 (m, 2H), 6.40 (s, 1H). C NMR (101 MHz, CDCl3): δ = 170.4,
164.6 (d, JC–F = 248.9 Hz), 149.5, 134.5, 132.4 (d, JC–F = 3.2 Hz), 129.7, 129.2 (d, 19 JC–F = 8.4 Hz), 125.9, 125.8, 123.0, 116.1 (d, JC–F = 21.9 Hz), 82.1. F NMR (376
MHz, CDCl3): δ = -111.9.
3-(2,4-Difluorophenyl)isobenzofuran-1(3H)-one (12j)
Prepared according to the general procedure GP7, 12j was isolated as a white solid with a yield of 31%. 1H NMR (400 MHz, CDCl3): δ = 7.94 (d, J = 7.7 Hz, 1H), 7.68 (dd, J = 7.6, 1.2 Hz, 1H), 7.57 (tt, J = 7.5, 0.8 Hz, 1H), 7.40 (dt, J = 7.7, 0.9 Hz, 1H), 7.10 (td, J = 8.4, 6.2 Hz 1H), 6.92-6.82 (m, 13 2H), 6.68 (s, 1H). C NMR (101 MHz, CDCl3): δ = 170.2,
163.4 (dd, JC–F = 251.4, 12.1 Hz), 160.9 (dd, JC–F = 251.1, 12.2 Hz), 148.9 134.7,
129.8, 129.2 (dd, JC–F = 10.0, 4.9 Hz), 125.9, 125.6, 122.8 (d, JC–F = 2.1 Hz), 120.3
(dd, JC–F = 13.3, 3.8 Hz), 112.1 (dd, JC–F = 21.6, 3.7 Hz), 104.6 (t, JC–F = 25.3 Hz), 19 76.3 (d, JC–F = 3.6 Hz). F NMR (376 MHz, CDCl3): δ = -108.0 (d, JF–F = 8.3 -1 Hz), -114.2 (d, JF–F = 8.3 Hz). IR v(cm ): 1754, 1600, 1508, 1288, 1207, 1143, 1101, + 973, 738. HRMS (m/z): [M+H] calculated for C14H9F2O2: 247.0565; found: 247.0569. mp: 88-90 ºC.
3-(3,4-Difluorophenyl)isobenzofuran-1(3H)-one (12k)
Prepared according to the general procedure GP7, 12k was isolated as a white solid with a yield of 72%. 1H NMR (400 MHz, CDCl3): δ = 8.00 (d, J = 7.6 Hz, 1H), 7.68 (td, J = 7.5, 1.2 Hz, 1H), 7.59 (tt, J = 7.5, 0.8 Hz, 1H), 7.34 (dd, J = 7.6, 0.9 Hz, 1H), 7.21-7.16 (m, 1H), 7.09-7.06 13 (m, 2H), 6.35 (s, 1H). C NMR (101 MHz, CDCl3): δ = 170.1, 151.8 (dd, JC–F =
250.8, 11.9 Hz), 149.8 (dd, JC–F = 247.6, 10.7 Hz), 149.0 134.7, 133.6 (dd, JC–F =
5.4, 4.2 Hz), 129.9, 126.0, 125.6, 123.5 (dd, JC–F = 6.6, 3.7 Hz), 122.9, 118.1 (d, JC–
206 Z. Ye, G. Lv, W. Wang, M. Zhang, J. Cheng, Angew. Chem. Int. Ed. 2010, 49, 3671– 3674.
264 Part III Cooperative Iodine and Photoredox Catalysis for C(sp3)-H Functionalization
19 F = 17.6 Hz), 116.3 (d, JC–F = 18 Hz), 81.4 (d, JC–F = 1.5 Hz). F NMR (376 MHz, -1 CDCl3): δ = -135.8 (d, JF–F = 21.1 Hz), -136.2 (d, JF–F = 21.0 Hz). IR v(cm ): 1759, 1516, 1465, 1285, 1105, 1060, 1017, 942, 732. HRMS (m/z): [M+H]+ calculated for C14H9F2O2: 247.0565; found: 247.0573. mp: 80-83 ºC.
3-(Thiophen-2-yl)isobenzofuran-1(3H)-one (12l)
Prepared according to the general procedure GP7, 12l was isolated as a pale yellow oil with a yield of 60%. 1H NMR
(400 MHz, CDCl3): δ = 7.96 (dt, J = 7.6, 1.0 Hz, 1H), 7.71 (td, J = 7.5, 1.1 Hz, 1H), 7.60 (tt, J = 7.5, 0.8 Hz, 1H), 7.48-7.46 (m, 1H), 7.37 (dd, J = 5.1, 1.2 Hz, 1H), 7.15 (ddd, J = 3.6, 1.2, 0.7 Hz, 13 1H), 7.02 (dd, J = 5.1, 3.6 Hz, 1H), 6.67 (s, 1H). C NMR (101 MHz, CDCl3): δ =169.9, 148.8, 139.0, 134.5, 129.9, 128.0, 127.7, 127.2, 126.1, 125.8, 123.3, 78.0. IR v(cm-1): 1746, 1465, 1285, 1212, 1066, 938, 694. HRMS (m/z): [M+H]+ calculated for C12H9O2S: 217.0320; found: 217.0318.
6,7,8,8a-Tetrahydro-2H-naphtho[1,8-bc]furan-2-one (12m)
Prepared according to the general procedure GP7, 12m was isolated as a yellow oil with a yield of 21%. 1H NMR (400 MHz, CDCl3): δ = 7.68-7.66 (m, 1H), 7.44 (td, J = 7.5, 0.7 Hz, 1H), 7.38 (dq, J = 7.5, 1.0 Hz, 1H), 5.23 (dd, J = 11.7, 5.3 Hz, 1H), 3.04 (dddd, J = 17.8, 8.2, 2.3, 1.2 Hz, 1H), 2.78-2.71 (m, 1H), 2.52 (ddt, J = 11.6, 5.3, 3.8 Hz, 1H), 2.22-2.17 (m, 1H), 1.99-1.94 (m, 1H), 1.41 (dtd, J = 13.1, 11.7, 4.3 13 Hz, 1H). C NMR (101 MHz, CDCl3): δ = 170.8, 149.6, 134.2, 132.4, 130.0, 124.6, 122.9, 78.3, 27.6, 24.9, 19.8. IR v(cm-1): 2920, 1754, 1482, 1448, 1355, + 1254, 1088, 982, 733. HRMS (m/z): [M+H] calculated for C11H11O2: 175.0747; found: 175.0754.
6-Phenyltetrahydro-2H-pyran-2-one (12n)
Prepared according to the general procedure GP7, 12n was isolated as a pale yellow oil with a yield of 57%. The NMR spectra match those previously described in literature.207 1H NMR (400 MHz, CDCl3): δ = 7.43-7.29 (m, 5H), 5.36 (dd, J = 10.4, 3.4 Hz, 1H), 2.71 (dtd, J = 17.8, 6.3, 1.1 Hz, 1H), 2.58 (dt, J = 17.8, 7.8 Hz,
207 J-L. Hsu, J-M. Fang, J. Org. Chem. 2001, 66, 8573–8584.
265 Part III Cooperative Iodine and Photoredox Catalysis for C(sp3)-H Functionalization
1H), 2.22-2.12 (m, 1H), 2.04-1.94 (m, 2H), 1.93-1.80 (m, 1H). 13C NMR (101 MHz, CDCl3): δ = 171.4, 139.9, 128.7, 128.4, 125.8, 81.8, 30.6, 29.6, 18.7.
6-(p-Tolyl)tetrahydro-2H-pyran-2-one (12o)
Prepared according to the general procedure GP7, 12o was isolated as a white solid with a yield of 35%. The NMR spectra match those previously described in literature.208 1 H NMR (400 MHz, CDCl3): δ = 7.25-7.16 (m, 4H), 5.33 (dd, J = 10.4, 3.3 Hz, 1H), 2.70 (dt, J = 17.6, 6.3 Hz, 1H), 2.57 (dt, J = 17.8, 7.8 Hz, 1H), 2.35 (s, 3H), 2.20-2.10 (m, 1H), 2.03-1.93 (m, 2H), 1.93-1.80 (m, 1H). 13 C NMR (101 MHz, CDCl3): δ = 171.5, 138.1, 136.8, 129.3, 125.7, 81.6, 30.5, 29.5, 21.1, 18.6.
6-(4-Fluorophenyl)tetrahydro-2H-pyran-2-one (12p)
Prepared according to the general procedure GP7, 12p was isolated as a white solid with a yield of 54%. The NMR spectra match those previously described in 209 1 literature. H NMR (400 MHz, CDCl3): δ = 7.36-7.29 (m, 2H), 7.10-7.02 (m, 2H), 5.32 (dd, J = 10.7, 3.3 Hz, 1H), 2.71 (dtd, J = 17.8, 6.3, 1.1 Hz, 1H), 2.57 (dt, J = 17.8, 7.9 Hz, 1H), 2.20-2.11 (m, 1H), 2.04-1.95 (m, 13 2H), 1.90-1.77 (m, 1H). C NMR (101 MHz, CDCl3): δ = 171.3, 162.7 (d, JC–F =
246.9 Hz), 135.7 (d, JC–F = 3.2 Hz), 127.7 (d, JC–F = 8.4 Hz), 115.7 (d, JC–F = 21.5 19 Hz), 81.2, 30.7, 29.6, 18.8. F NMR (376 MHz, CDCl3): δ = -113.8.
6-(4-Chlorophenyl)tetrahydro-2H-pyran-2-one (12q)
Prepared according to the general procedure GP7, 12q was isolated as a white solid with a yield of 50%. The NMR spectra match those previously described in 208 1 literature. H NMR (400 MHz, CDCl3): δ = 7.37-7.33 (m, 2H), 7.30-7.26 (m, 2H), 5.32 (dd, J = 10.7, 3.3 Hz, 1H), 2.71 (dtd, J = 17.8, 6.3, 1.1 Hz, 1H), 2.57 (dt, J = 17.8, 7.9 Hz, 1H), 2.20-2.11 (m, 1H), 2.03-1.93 (m, 13 2H), 1.89-1.75 (m, 1H). C NMR (101 MHz, CDCl3): δ = 171.2, 138.4, 134.2, 128.9, 127.2, 81.0, 30.7, 29.6, 18.7.
208 L. Zhou, X. Liu, J. Jie, Y. Zhang, W. Wu, Y. Liu, L. Lin, X. Feng, Org. Lett. 2014, 16, 3938–3941. 209 V. Valerio, D. Petkova, C. Madelaine, N. Maulide, Chem. Eur. J. 2013, 19, 2606–2610.
266 Part III Cooperative Iodine and Photoredox Catalysis for C(sp3)-H Functionalization
4,4-Dimethyl-6-phenyltetrahydro-2H-pyran-2-one (12r)
Prepared according to the general procedure GP7, 12r was isolated as a pale yellow oil with a yield of 59%. 1H NMR (400 MHz, CDCl3): δ = 7.41-7.29 (m, 5H), 5.38 (dd, J = 12.1, 3.6 Hz, 1H), 2.51 (dd, J = 16.6, 1.8 Hz, 1H), 2.35 (d, J = 16.7 Hz, 1H), 1.92 (ddd, J = 14.3, 3.6, 1.7 Hz, 1H), 1.76 (dd, J = 14.3, 12.1 Hz, 1H), 1.22 13 (s, 3H), 1.11 (s, 3H). C NMR (101 MHz, CDCl3): δ = 171.7, 139.8, 128.7, 128.4, 125.9, 79.1, 45.2, 44.1, 31.2, 30.3, 27.6. IR v(cm-1): 2956, 1734, 1234, 1153, 1026, + 753, 698. HRMS (m/z): [M+H] calculated for C13H17O2: 205.1234; found: 205.1236.
4,4-Dimethyl-6-(p-tolyl)tetrahydro-2H-pyran-2-one (12s)
Prepared according to the general procedure GP7, 12s was isolated as a pale colorless oil with a yield of 43%. 1 H NMR (400 MHz, CDCl3): δ = 7.28-7.22 (m, 2H), 7.20- 7.15 (m, 2H), 5.35 (dd, J = 12.1, 3.6 Hz, 1H), 2.50 (dd, J = 16.6, 1.8 Hz, 1H), 2.35 (s, 3H), 2.34 (d, J = 16.3 Hz), 1.89 (ddd, J = 14.3, 3.7, 1.8 Hz, 1H), 1.75 (dd, J = 14.3, 12.1 Hz, 1H), 1.21 (s, 3H), 1.11 (s, 3H). 13C NMR (101 MHz, CDCl3): δ = 171.8, 138.2, 136.9, 129.4, 125.9, 79.1, 45.2, 44.1, 31.2, 30.3, 27.6, 21.3. IR v(cm-1): 2955, 1735, 1370, 1269, 1234, 1154, 1076, 1030, 796. HRMS + (m/z): [M+H] calculated for C14H19O2: 219.1391; found: 219.1390.
6-(4-Fluorophenyl)-4,4-dimethyltetrahydro-2H-pyran-2-one (12t)
Prepared according to the general procedure GP7, 12t was isolated as a pale white solid with a yield of 67%. 1 H NMR (400 MHz, CDCl3): δ = 7.36-7.29 (m, 2H), 7.09-7.02 (m, 2H), 5.35 (dd, J = 12.2, 3.5 Hz, 1H), 2.50 (dd, J = 16.6, 1.7 Hz, 1H), 2.34 (d, J = 16.7 Hz, 1H), 1.90 (ddd, J = 14.3, 3.6, 1.7 Hz, 1H), 1.73 (dd, J = 14.2, 12.2 Hz, 1H), 1.21 (s, 3H), 1.11 (s, 3H). 13C NMR (101 MHz, CDCl3): δ = 171.5, 162.7 (d, JC-F = 246.9 Hz), 135.6 (d, JC-F = 3.1 Hz), 127.8 (d, JC- 19 F = 8.2 Hz), 115.6 (d, JC-F = 21.6 Hz), 78.4, 45.2, 44.0, 31.2, 30.3, 27.6. F NMR + (376 MHz, CDCl3): δ = -113.4. HRMS (m/z): [M+H] calculated for -1 C13H16FO2: 223.1140; found: 223.1142. IR v(cm ): 2958, 1724, 1604, 1513, 1371, 1237, 1151, 1075, 1026, 1012, 803. mp: 45.6-48.6 ºC.
3-Phenylisochroman-1-one (12u)
267 Part III Cooperative Iodine and Photoredox Catalysis for C(sp3)-H Functionalization
Prepared according to the general procedure GP7, 12u was isolated as a yellow oil with a yield of 96%. The NMR spectra match those previously described in 210 1 literature. H NMR (400 MHz, CDCl3): δ = 8.15 (dd, J = 7.9, 1.4 Hz, 1H), 7.57 (td, J = 7.5, 1.4 Hz, 1H), 7.51-7.33 (m, 7H), 7.29 (d, J = 7.6 Hz, 1H), 5.55 (dd, J = 12.0, 3.2 Hz, 1H), 3.34 (dd, J = 16.5, 12.0 Hz, 1H), 3.13 13 (dd, J = 16.5, 3.2 Hz, 1H). C NMR (101 MHz, CDCl3): δ = 165.4, 139.1, 138.7, 134.0, 130.5, 128.8, 128.8, 128.0, 127.5, 126.2, 125.2, 80.1, 35.7.
III.6.10 Synthesis and characterization of 13 In an open-to-air flask, a solution of the substrate 11a (328 mg, 2 mmol, 1 equiv.) and PIDA (322 mg, 1 mmol, 0.5 equiv.) in chlorobenzene (10 mL) was stirred 10 min. Then, the solvent was removed under vacuum to wipe out the acetic acid from the ligand dissociation from PIDA displacing the equilibrium towards the formation of 13. We repeated another time this procedure to finally get 13 as a colorless oil in 98 % yield.
[Bis(4-phenylbutanoxy)iodo]benzene (13)
Prepared according to the procedure described above, 13 was isolated as a colorless oil with a yield of 98%. 1H NMR (400 MHz, CDCl3): δ = 8.06 (dd, J = 8.5, 1.2 Hz, 2H), 7.60-7.56 (m, 1H), 7.48 (ddd, J = 8.3, 6.9, 1.2 Hz, 2H), 7.28-7.23 (m, 4H), 7.19-7.15 (m, 2H), 7.13-7.10 (m, 4H), 2.58 (t, J = 7.6 Hz, 4H), 2.28 (t, J = 7.4 Hz, 4H), 1.91-1.84 (m, 4H). 13C NMR (101 MHz, CDCl3): δ = 178.6, 141.7, 135.1, 131.8, 131.0, 128.6, 128.4, 126.0, 122.0, 35.3, 33.5, 27.4. HRMS (m/z): not stable under usual ionization conditions. IR v(cm-1): 3025, 2928, 1646, 1496, 1443, 1225, 994, 735, 698.
210 X. Yang, X. Jin, C. Wang, Adv. Synth. Catal. 2016, 358, 2436–2442.
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Part IV Iodine(I/III) Catalysis for Selective C(sp3)-H Amination
269
270 Part IV Iodine(I/III) Catalysis for Selective C(sp3)-H Amination
Part IV Iodine(I/III) Catalysis for Selective C(sp3)-H Amination
IV.1 Introduction
IV.1.1 Circumvent the limitation Both developed bromide and cooperative iodine and photoredox catalyzes have the same limitation which is the requirement of an activated carbon position at the δ-position. It can be a benzylic position or an α- position of a heteroatom. This limitation can be due to two reasons. First, it can be a thermodynamic issue that makes the 1,5-HAT impossible. Or, the cyclization step does not proceed due to either the lack of nucleophilicity of the protected nitrogen or the halogen is not a good enough nucleofuge. As we presented in the previous chapter, calculation by Zipse et al. indicated a slightly endothermic 1,5-HAT in the case of a non- activated carbon position.143 In the first iodine-catalyzed Hofmann-Löffler developed in our group in 2015, the activated position was not a requirement for the reaction to proceed.158 Although the calculation rejected the idea that the 1,5-HAT could be the issue to access non-activated positions, the results from our previous work neglected it definitively. We previously explained in the section II that the sulfonamide moiety is crucial for both the stabilization of the nitrogen-centered radical inducing the selectivity (1,5-HAT) and the destabilization of the N-X bond. Therefore, to facilitate the cyclization step, we need to enhance the leaving group capacity to access the C-N bond formation at non-activated position. Although it is underestimated and not sufficiently developed, alkyliodine in high oxidation state can act as an outstanding nucleofuge.211 As a result, we needed to design a synthesis in which an extra oxidation step from the alkyliodine(I) intermediate to an alkyliodine(III) occurred (Scheme IV.1).
211 A. E. Bosnidou, K. Muñiz, Chem. Eur. J. 2019, 25, 13654–13664.
271 Part IV Iodine(I/III) Catalysis for Selective C(sp3)-H Amination
Scheme IV.1. Necessity of an alkyliodine(III) intermediate to accelerate the cyclization step and access non-activated position.
IV.1.2 Reactivity of alkyliodine(III) Hypervalent aryliodine(III) compounds have been broadly used as oxidant in modern synthesis,212 in radical chemistry213 or in combination with photoredox catalyst.214 On the contrary, alkyliodine(III) compounds remains underestimated and unemployed maybe because of their lower stability in comparison with their arene counterpart. Thiele and Peter pioneered the field, they oxidized for the first time alkyliodine(I) with elemental chlorine or bromine. They observed an enhanced reactivity in
212 V. V. Zhdankin, Hypervalent Iodine Chemistry: Preparation, Structure and Synthetic Applications of Polyvalent Iodine Compounds,.2014, John Wiley & Sons, Ltd. 213 X. Wang, A. Studer, Acc. Chem. Res. 2017, 50, 1712–1724. 214 L. Wang, J. Liu, Euro J. Org. Chem. 2016, 2016, 1813–1824.
272 Part IV Iodine(I/III) Catalysis for Selective C(sp3)-H Amination
comparison with the alkyliodine(I) and isolated MeICl2 at low temperature.215 In literature, the oxidation of alkyliodine(I) is generally performed in-situ providing an alkyliodine(III) intermediate that acts as an exceptional nucleofuge. Therefore, this chemistry was employed to direct nucleophilic substitutions,158,216 elimination reactions217 or rearrangements218 for instance. Various oxidants could be employed in order to reach the oxidation state of III at the iodine atom such as elemental fluorine,219 chlorine220 or bromine,221 xenon difluoride222 or preformed hypervalent iodine(III).158,211,223 All these oxidants afford the T-shaped alkyliodine(III) alkyl-IX2 that bears three substituents in which two are coming from the oxidant. In contrast, peracids are employed oxidants for the formation of alkyliodine(III) but they lead to the formation of iodoso derivatives alkyl- IO.216d-e,217,224 These alkyliodine(III) intermediates react differently whether they bear two labile substituents X or they are iodoso derivatives (Scheme IV.2). In the case of the iodoso derivative alkyl-IO, nucleophilic displacement by a nucleophile can proceed (SN1 or SN2) releasing hypoiodite. They can also undergo undesired elimination reaction (syn-elimination or E1) or rearrangement by a dissociation/re-association of the hypodiodite to form an alcohol. The T-shaped trisubstituted alkyl-IX2 can undergo various reactions. Nucleophilic displacement by a nucleophile (SN1 or SN2) has been
215 a) J. Thiele, W. Peter, Chem. Ber. 1905, 38, 2842–2846. b) J. Thiele, W. Peter, Liebigs Ann. Chem. 1909, 369, 147–149. 216 a) A. E. Bosnidou, K. Muñiz, Angew. Chem. Int. Ed. 2019, 58, 7485–7489. b) K. Kiyokawa, K. Takemoto, S. Minakata, Chem. Commun. 2016, 52, 13082–13085. c) W. Guo, O. Vallcorba, A. Vallribera, A. Shafir, R. Pleixats, J. Rius, ChemCatChem 2014, 6, 468–472. d) D. B. Damon, D. J. Hoover, J. Am. Chem. Soc. 1990, 112, 6439–6442. e) R. R. Sicinski, W. J. Szczepek, Tetrahedron Lett. 1987, 28, 5729–5732. 217 a) S. Knapp, A. B. J. Naughton, T. G. Murali Dhar, Tetrahedron Lett. 1992, 33, 1025– 1028. b) S. Kim, P. L. Fuchs, Tetrahedron Lett. 1994, 35, 7163–7166. 218 T. B. Patrick, S. Qian, Org. Lett. 2000, 2, 3359–3360. 219 S. Rozen, M. Brand, J. Org. Chem. 1981, 46, 733–736. 220 E. J. Corey, W. J. Wechter, J. Am. Chem. Soc. 1954, 76, 6040–6042. 221 K. B. Wiberg, W. E. Pratt, M. G. Matturro, J. Org. Chem. 1982, 47, 2720–2722. 222 E. W. Della, N. J. Head, W. K. Janowski, C. H. Schiesser, J. Org. Chem. 1993, 58, 7876– 7882. 223 K. Kiyokawa, K. Takemoto, S. Minakata, Chem. Commun. 2016, 52, 13082–13085. 224 a) Y. Ogata, K. Aoki, J. Org. Chem. 1969, 34, 3974–3977. b) Y. Ogata, K. Aoki, J. Org. Chem. 1969, 34, 3978–3980.
273 Part IV Iodine(I/III) Catalysis for Selective C(sp3)-H Amination identified and this reaction was used in our previous work on inter- and intramolecular amination.158,211 The dissociation of one substituent X from the iodine atom can induce a direct nucleophilic substitution by the anion - - X . Also, the dissociation of the anion IX2 can disproportionate into IX and X- which can undergo a nucleophilic substitution too. Both scenario afford the formation of the undesired C-X bond where X was a substituent of the hypervalent alkyliodine(III). Elimination side-reaction remains plausible as well.
Scheme IV.2. Plausible reactions pathways of the alkyliodine(III) intermediates.
IV.1.3 The crucial role of the alkyliodine(III) for catalysis In the first iodine-catalyzed Hofmann-Löffler reaction published by our group in 2015, a hypervalent aryliodine(III) was used as terminal oxidant.158 As aforementioned, hypervalent aryliodine(III) can oxidize an alkyliodine(I) to a T-shaped trisubstituted alkyliodine(III) where two
274 Part IV Iodine(I/III) Catalysis for Selective C(sp3)-H Amination substituents are coming from the aryliodine(III) oxidant (Scheme IV.3). The mechanism was presented in the section III.1.2.3. The key step highlighted in the scheme IV.3 is the oxidation of the alkyliodine(I) to the alkyliodine(III) intermediate by a hypervalent aryliodine(III) compounds. Importantly, the catalysis shuts down in the case of targeting non-activated position if this oxidation does not proceed because the cyclization is not fast enough to release the iodine catalyst. The alkyliodine(III) accelerates the catalyst turn-over.
Scheme IV.3. Mechanism of the first iodine catalysis for the Hofmann-Löffler reaction highlighting the key oxidation step providing the alkyliodine(III) intermediate.
We recently developed an intermolecular selective C(sp3)-H amination as well using a combination of molecular iodine and a hypervalent iodine(III) 211 oxidant PhI(pBBA)2 (Scheme IV.4). Trifluorosulfonamide was used as the external nucleophile. The mechanism remains similar enrolling benzoyl hypoiodite species that affords the iodination of the trifluorosulfonamide. Subsequent homolytic cleavage provides the nitrogen-centered radical. The
275 Part IV Iodine(I/III) Catalysis for Selective C(sp3)-H Amination triflylsulfonyl protecting group enhances the reactivity of the radical since it is more destabilizing than the close-related aryl- or alkylsulfonyl groups. As a result, intermolecular selective HAT occurs at the weakest C(sp3)-H bond followed by an iodination. The same oxidation step than in the intramolecular version occurs to get the T-shaped trisubstituted alkyliodine(III) intermediate. An external nucleophilic substitution by the trifluorosulfonamide itself provides the final aminated product. Both the final substitution and the catalyst turn-over are possible thanks to the involvement of the alkyliodine(III) intermediate that enables a fast amination event.
276 Part IV Iodine(I/III) Catalysis for Selective C(sp3)-H Amination
Scheme IV.4. Presentation of the iodine catalysis for intermolecular amination. The oxidation step from the alkyliodine(I) to the alkyliodine(III) is highlighted.
In our previous work, alkyliodine in high oxidation state accelerates the catalyst turn-over thanks to the its capacity to be a better nucleofuge accelerating the amination step. In order to demonstrate this capacity, control experiments were carried out in these two projects. As displayed in the scheme IV.5a, the primary alkyliodine(I) does not cyclize at room temperature in DCM. But, the cyclization becomes possible when a hypervalent aryliodine(III) oxidant was engaged. The primary alkyliodine(I) gets oxidize into alkyliodine(III), enhancing its leaving group
277 Part IV Iodine(I/III) Catalysis for Selective C(sp3)-H Amination capacity and enabling the cyclization to occur at room temperature. For the intermolecular version (Scheme IV.5b), α-iodoethylbenzene was synthesized. While putting the latter in the presence of one equivalent of trifluorosulfonamide, the amination product was not detected. In contrast, in the presence of the hypervalent iodine(III) oxidant, the nucluophilic substitution proceeds leading to the aminated product. In the present case, the low nucleophilicity of the trifluorosulfonamide represents the issue which is circumvented by the high leaving group capacity of hypervalent alkyliodine(III).
Scheme IV.5. Control experiments carried out to highlight the crucial role of the alkyliodine(I) oxidation to alkyliodine(III) for the amination reaction to proceed.
IV.2 Aims of part IV
In this chapter, the aim was to design a iodine catalysis for the Hofmann-Löffler reaction that would allow the amination of non-activated carbon position. As a protocol was already developed by our group using an hypervalent iodine(III), we aimed to circumvent the use of a non-
278 Part IV Iodine(I/III) Catalysis for Selective C(sp3)-H Amination commercial oxidant and to use greener solvent than DCE. Reading literature, we had the goal to use a peroxide to oxidize the alkyliodine(I) intermediate to the corresponding hypervalent alkyliodine(III), better nucleofuge. With this in hand, the objective was also to compare both intermediate in terms of leaving group capacity and to explore the differences between the functional group tolerance.
IV.3 Results and discussion
For this procedure, we aimed to design a catalysis in which the oxidant is commercially available, easy to handle and the most functional- group tolerant possible. Having this challenge in mind, we eliminated some strong oxidant incompatible with our expectations to be mild and functional-group tolerant. Xenon difluoride, molecular fluorine, chlorine and bromine and hypervalent aryliodine(III) oxidants were banned. We decided to investigate peracids as oxidant to reach the in-situ generation of the key alkyliodoso(III) intermediate. Moreover, toxic solvent was used in the previous amination protocols. In order to be eco-friendlier, we aimed to design a reaction which require non-chlorinated solvents.
IV.3.1 Development of the I(I/III) catalysis for C(sp3)-H amination To start our investigation to find the optimized reaction condition, 14a was submitted into reaction with molecular iodine as catalyst (15 mol%) and peracetic acid as oxidant (3 equiv.). The reactions were set up either in DCE (Table IV.1, entry 1) or MeCN (entry 2) and stirred for 12 h. 12% conversion was observed by NMR in DCE whereas starting material was fully recovered for the reaction set up in MeCN. Using the commercially available and relatively cheap mCPBA as terminal oxidant, we screened various solvents. In DCE, the conversion increases to 52% (entry 3) meaning that mCPBA seemed to be a better peracid oxidant. In the slightly more polar acetonitrile, the reached conversion was of 60% (entry 4). To try to in-situ generate hypoiodite, we set up the reaction in a mixture of MeCN/AcOH (1/1). The reaction did not improve since 52% conversion was obtained (entry 5). Other solvents such as benzonitrile (entry 6), acetic acid (entry 7), TFE (entry 8), MeOH (entry 9) or ethyl acetate (entry 10) were assessed without any successful results since 38%, 32%, 37%, 26% and 56% conversion were observed respectively. Then, an ammonium iodide
279 Part IV Iodine(I/III) Catalysis for Selective C(sp3)-H Amination was assessed as iodine catalyst source (entry 11) but only starting material was recovered after 12 h of reaction time. At this stage, we noticed that elimination side-product was always formed in few amounts due to the high living group capacity of the plausible hypervalent alkyliodine(III) intermediate. To counter this non-wished elimination side-product, we reduced the quantity of mCPBA from 3 equivalents to 1 equivalent. After 12 h (entry 12), a small drop to 44% conversion was noticed. Increasing the reaction time to 24 h (entry 13) and 48 h (entry 14) led to 51% and 60% conversion respectively. To enhance our chance to get hypoiodite in the media, tBuOH was used as co-solvent in a 1 to 1 mixture (entry 15). Under this condition, 90% isolated yield was obtained. While MeCN was replaced by EtOAc (entry 16), the conversion dropped back to 50%. We aimed at this point to assess the importance of the iodine catalyst loading. Decreasing the amount of molecular iodine from 15 mol% to 10 mol% (entry 17), 5 mol% (entry 18) or even 2.5 mol% (entry 19) led to a small drop of isolated yields since 85%, 70% and 56% was obtained respectively. We tried to keep 2.5 mol% for the catalyst loading optimizing again the amount of oxidant. Unfortunately, while using 2.2 (entry 20) or 3 equivalents (entry 21) of mCPBA, the isolated yield did not improve (56% and 60% respectively). Also, when 5 mol% of molecular iodine was combined with 2.2 equivalents of oxidant, the isolated yield was not as good as expected since 70% was obtained (entry 22). We then came back to the initial catalyst loading of 15 mol% and investigated the influence of the amount of oxidant. 1.5 (entry 23), 2.2 (entry 24) and 3 equivalents (entry 25) were assessed affording the pyrrolidine 15a in 97%, 98% and 98% isolated yield respectively. Our ambition to be as eco-friendly as possible, we tested whether hydrogen peroxide could be the oxidant. An acid additive was implemented to help for the formation of hypoiodite species. Despite the screening of additive (PivOH or TFA) and solvent (DCE or MeCN/tBuOH (1/1)), only starting material was recovered (entries 26, 27 and 28) or trace of pyrrolidine was observed (7%, entry 29). TBHP was submitted as well in combination with molecular iodine (15 mol%) but unreacted starting material was fully recovered (entry 30). Finally, while performing the reaction in the darkroom, the final pyrrolidine was not formed (entry 31). The optimal reaction conditions are the following: Molecular iodine and mCPBA are used in 15 mol% and 2.2 equivalents respectively. The reaction is set-up in non-purified MeCN and tBuOH (1/1 ratio) under argon at the concentration of 0.22 M (the reaction still proceeds in an open-air system).
280 Part IV Iodine(I/III) Catalysis for Selective C(sp3)-H Amination
The reaction mixture is stirred 12 h at room temperature under fluorescent light irradiation.
Table IV.1. Optimization of the reaction condition for the I(I/III) catalysis for the selective C(sp3)-H amination (Hofmann-Löffler reaction).
Conve Entry Iodine source Oxidant Solvent rsion 1 I2 (15 mol%) AcOOH (3 equiv.) DCE 12% 2 I2 (15 mol%) AcOOH (3 equiv.) MeCN SM 3 I2 (15 mol%) mCPBA (3 equiv.) DCE 52% 4 I2 (15 mol%) mCPBA (3 equiv.) MeCN 60% 5 I2 (15 mol%) mCPBA (3 equiv.) MeCN/AcOH (1/1) 52% 6 I2 (15 mol%) mCPBA (3 equiv.) PhCN 38% 7 I2 (15 mol%) mCPBA (3 equiv.) AcOH 32% 8 I2 (15 mol%) mCPBA (3 equiv.) TFE 37% 9 I2 (15 mol%) mCPBA (3 equiv.) MeOH 26% 10 I2 (15 mol%) mCPBA (3 equiv.) EtOAc 56% NBu4I (30 11 mCPBA (3 equiv.) MeCN SM mol%) 12 I2 (15 mol%) mCPBA (1 equiv.) MeCN 44% a 13 I2 (15 mol%) mCPBA (1 equiv.) MeCN 51% b 14 I2 (15 mol%) mCPBA (1 equiv.) MeCN 60% t 15 I2 (15 mol%) mCPBA (1 equiv.) MeCN/ BuOH (1/1) 90%* t 16 I2 (15 mol%) mCPBA (1 equiv.) EtOAc/ BuOH (1/1) 50% t 17 I2 (10 mol%) mCPBA (1 equiv.) MeCN/ BuOH (1/1) 85%* t 18 I2 (5 mol%) mCPBA (1 equiv.) MeCN/ BuOH (1/1) 70%* t 19c I2 (2.5 mol%) mCPBA (1 equiv.) MeCN/ BuOH (1/1) 56%* t 20 I2 (2.5 mol%) mCPBA (2.2 equiv.) MeCN/ BuOH (1/1) 56%* t 21 I2 (2.5 mol%) mCPBA (3 equiv.) MeCN/ BuOH (1/1) 60%* t 22 I2 (5 mol%) mCPBA (2.2 equiv.) MeCN/ BuOH (1/1) 70%* t 23 I2 (15 mol%) mCPBA (1.5 equiv.) MeCN/ BuOH (1/1) 97%* t 24 I2 (15 mol%) mCPBA (2.2 equiv.) MeCN/ BuOH (1/1) 98%* t 25 I2 (15 mol%) mCPBA (3 equiv.) MeCN/ BuOH (1/1) 98* c 26 I2 (15 mol%) H2O2 (1.5 equiv.) DCE SM d 27 I2 (15 mol%) H2O2 (1.5 equiv.) DCE 7% c t 28 I2 (15 mol%) H2O2 (1.5 equiv.) MeCN/ BuOH (1/1) SM d t 29 I2 (15 mol%) H2O2 (1.5 equiv.) MeCN/ BuOH (1/1) SM
281 Part IV Iodine(I/III) Catalysis for Selective C(sp3)-H Amination
t 30 I2 (15 mol%) TBHP (3 equiv.) MeCN/ BuOH (1/1) SM e t 31 I2 (15 mol%) mCPBA (2.2 equiv.) MeCN/ BuOH (1/1) SM * Isolated yield. a Experiment carried out for 24 h. b Experiment carried out for 48 h. c Experiment carried out with PivOH (1.5 equiv.) as additive. d Experiment carried out with TFA (1.5 equiv.) as additive. e Experiment carried out in the dark room.
IV.3.2 Scope of the I(I/III) catalysis for selective C(sp3)-H amination Having the optimized reaction condition in hand, we wondered if it could be employed to different starting material bearing various backbones and functionalities (Scheme IV.6). As in our previous work, cyclization of the linear sulfonamides at activated benzylic position where the arene contains different electron-donating or electron-withdrawing para-substituents occurs smoothly (15a-f, 73-99%). A new pyrrolidine bearing an acetylenic group could be obtained in good yield (15g, 58%). The variation of the nitrogen protecting group as well as the modification of the backbone at the β-position does not affect the effectiveness of the reaction (15h, 63% and 15i-l, [54-99%] respectively). For substrate 14k, an internal competition between a secondary non-activated position and an activated benzylic position takes place but the reaction exclusively proceeded at the weakest C-H bond thus providing 15k in an unseparated 1/1 diastereoisomeric mixture in 67% yield. The Thorpe-Ingold effect seems to play an important role in the present system since 15l was isolated in only 54% yield compared with the 98% of its β-gem-dimethyl close-related 15a. Extremely important α-tertiary alkyl amines could be synthesized straightforward using DCE as solvent (15m-n, 36-84%).225 It represents a non-canonical synthetic pathway to this crucial family of compound that are ubiquitous in natural alkaloids. Cyclic stereocontrol with very high diastereoselectivities were encountered when synthesizing 15o and 15p. They could be isolated with the excellent isolated yields of 96% and 85% respectively. When the 1,5-HAT remains impossible, a 1,6 HAT occurs smoothly to get 15q in 40% isolated yield. It represents a rare case of 1,6- HAT in the Hofmann-Löffler chemistry. New class of substrates were cyclized under the present conditions in decent isolated yield (15r-s, 63- 85%) whereas they were unreactive in all the other protocols. Transannular
225 A. Hager, N. Vrielink, D. Hager, J. Lefranc, D. Trauner, Nat. Prod. Rep. 2016, 33, 491– 522.
282 Part IV Iodine(I/III) Catalysis for Selective C(sp3)-H Amination amination was also possible since 15t was synthesized in the good yield of 70%. The reaction still proceeds at α-position of heteroatom as illustrated with 15u which was isolated in 60% yield. All these examples are cyclizing at activated position but the aim of introducing an alkyliodine(III) intermediate was to access non-activated aliphatic position. While submitting substrates 14v and 14w in the optimized reaction condition, the pyrrolidines 15v and 15w were isolated in 58% and 54% yield respectively. Thus, the cyclization occurs at non- activated homobenzylic positions. The reaction also proceeds at non- activated aliphatic secondary position (15x-y, 65-69%). In the case of 14y, there is a competition between a non-activated primary and secondary position. Obviously, the C-H amination occurs at the secondary C-H bond. First, the BDE of a hydrogen at a secondary position is usually weaker than a primary hydrogen meaning that the 1,5-HAT is slightly thermodynamically favored.226 Also, the radical is more stabilized at a secondary position. As we mentioned it previously, the α-tertiary alkyl amines represent an important class of compounds and 15z could be synthesized in 61% yield using DCE as solvent.
226 G. Laudalio, Y. Deng, K. Van der Wal, D. Ravelli, M. Nuño, M. Fagnoni, D. Guthrie, Y. Sun, T. Noël, Science 2020, 369, 92–96.
283 Part IV Iodine(I/III) Catalysis for Selective C(sp3)-H Amination
Scheme IV.6. Scope of the I(I/III) catalysis for selective C(sp3)-H amination (Hofmann- Löffler reaction. a Reaction performed in DCE. b A 1:1-mixture of diastereoisomers was obtained. c Reaction performed with 3 equivalents of mCPBA.
284 Part IV Iodine(I/III) Catalysis for Selective C(sp3)-H Amination
IV.3.3 Mechanistic investigation
IV.3.3.1 Active iodine species Having the optimized condition in hand, we then investigated the active iodine species. In the precedent iodine(I/III) catalysis for C(sp3)-H amination, benzyl hypoiodite ArCO2I (Ar= 3-chlorobenzyl) was determined to be the active species. As a result, we started our investigation synthesizing the I(I) species [I(mCBA)2]NBu4 that is in equilibrium in 158 solution with ArCO2I by losing one acid ligand. While submitting the latter in catalytic amount in combination with mCPBA under the optimized reaction condition, starting material was fully recovered (Scheme IV.7a). To force the displacement of the equilibrium towards the hypoiodite species, we submitted the exact same reaction but in the presence of an excess of the free 3-chlorobenzoic acid. Under this condition, the reaction did not proceed (Scheme IV.7b). Finally, to definitively neglect the idea of the involvement of the benzoyl hypoiodite, an experiment combining tetrabutyl ammonium iodide with mCPBA was carried out (Scheme IV.7c). According to our previous work on the bromide catalysis (section II), benzyl hypoiodite should be formed in-situ. Expectedly, the pyrrolidine formation did not occur.
285 Part IV Iodine(I/III) Catalysis for Selective C(sp3)-H Amination
Scheme IV.7. Control experiments ruling out the involvement of the I(I) species ArCO2I (Ar = 3-chlorobenzyl).
During the optimization, we noticed the positive effect of the tBuOH as co- solvent. We already hypothesized that the protic solvent HFIP could play this role in the mechanism of the amination in section III.2.4.4 but we did not prove it because we could not synthesize it. We became intrigued by the plausible participation of tert-butyl hypoiodite tBuOI. Thanks to the Wirth’s procedure to synthesize such unstable species, we managed to freshly prepare it.227 Then, a stochiometric reaction was carried out. Despite the relatively unstable tBuOI, the reaction proceeded with a good 53% isolated yield (Scheme IV.8a). Another key experiment was performed using a catalytic amount of the freshly prepared tert-butyl hypoiodite combined with mCPBA. Outstandingly, an excellent 83% of isolated yield was obtained (Scheme IV.8b). In our optimized reaction condition,
227 R. Montoro, T. Wirth, Org. Lett. 2003, 5, 4729–4731.
286 Part IV Iodine(I/III) Catalysis for Selective C(sp3)-H Amination molecular iodine in the presence of water, can disproportionate into hypoiodite HOI. The protic solvent tBuOH can react with the latter to form a more stable hypoiodite species tBuOI. The crucial information obtained with all these experiments is that mCPBA enables the catalyst turn-over but is not enrolled in the obtention of the tert-butyl hypoiodite tBuOI. It means that the productive oxidation for the catalyst turn over occurs at the stage of the alkyliodine intermediate.
Scheme IV.8. Control experiments proving that tBuOI is the iodine active species for the I(I/III) catalysis for the selective C(sp3)-H amination reaction.
IV.3.3.2 Isotope labelling experiment An intramolecular competition experiment was carried out for the benzylic mono-deuterated substrate 14l-D. The reaction was set up using the optimized conditions. A crude 1H-NMR was then recorded and a KIE of 2.5 was obtained (Scheme IV.9a). Intermolecular competition experiment between the benzylic double-deuterated substrate 14l-D2 and 14l was also performed to determine a KIE of 1.5 (Scheme IV.9b). These two kinetic experiments provide us the information that the C-H bond cleavage (1,5- HAT) may be the rate-determining step.136
287 Part IV Iodine(I/III) Catalysis for Selective C(sp3)-H Amination
Scheme IV.9. Isotope labelling experiments were carried out with 14l-D and 14l-D2. Intramolecular competition provided a KIE of 2.5 and intermolecular competition a KIE of 1.5 meaning that the C-H bond cleavage might be the rate-determining step of the selective C(sp3)-H amination reaction.
IV.3.3.3 Hammett correlation studies Hammett studies had been carried out in our first iodine-catalyzed Hofmann-Löffler reaction and it was found that the substituents at the arene core slightly affected the kinetic of the reaction (ρ = -0.2).158 Indeed, it was concluded that the high leaving group capacity of the trisubstituted alkyliodine(III) intermediate accelerates the relative rate of the C-N bond formation. As a result, the parasubstituents at the arene core have little influence on the kinetic of the reaction. Five competition experiments were carried out between 14a and 14b, 14c, 14d, 14e or 14f (Scheme IV.10). A crude NMR was recorded to get the ratio between the corresponding pyrrolidines (Table IV.2).
288 Part IV Iodine(I/III) Catalysis for Selective C(sp3)-H Amination
Scheme IV.10. Competition experiments between 14a and 14b, 14c, 14d, 14e or 14f in order to obtain more information about the influence of the para-substituent of the arene on the kinetic of the reaction.
Each substituent has its own Hammett constant σ depending on their position at the arene (Table IV.2).
Table IV.2. Hammett constants σ for the para-substituents of the arene core. Entry para-X log(kpara-X/kH) σpara-X 1 H 0 0 2 F 0 0.06 3 Cl - 0.1 0.23 4 Br - 0.081 0.23 5 Me 0.14 -0.17 6 OMe 0.24 -0.27
In the present procedure, a negative slope was encountered while drawing the Hammett plot (ρ = -0.63). It means that an electron-enriched arene accelerates the formation of the final pyrrolidine (Scheme IV.11). A comparison between the Hammett plot obtained with the method employing molecular iodine and PhI(mCBA)2 and the present procedure was done. We hypothesized that the alkyliodoso(III) was a weaker leaving group than its close-related T-shaped alkyliodine(III) bearing two benzoyl ligands.
289 Part IV Iodine(I/III) Catalysis for Selective C(sp3)-H Amination
Scheme IV.11. Hammett plot showing a negative slope meaning that electron- donating group are accelerating the amination reaction.
At this stage, we wondered whether the alkyliodine(I) oxidation by mCPBA, the cyclization step or the 1,5-HAT was affected by the presence of substituents at the arene core. In order to better understand the influence of the para-substituent, we performed a control experiment in which 14a and 14h are in competition. Despite the absence of substituent in para position, the ratio between 15a and 15h was found to be 1.7 (Scheme IV.12). The less nucleophilic nosyl group displays a decreased reactivity. The 1,5- HAT process for 14a has a reaction enthalpy of - 44.7 kJ/mol whereas the one of 14h is about- 50 kJ/mol.143 In conclusion, the 1,5-HAT is thermodynamically more favorable for 14h bearing a nosyl group but our experiment showed us an opposite result. Also, with the absence of substituent at the arene core, we know that the alkyliodine(I) oxidation is the same for both substrates. In conclusion, the obtained ratio is exclusively because the nosyl group is less nucleophilic making the cyclization slower and the alkyliodoso(III) is not a sufficient leaving group since the cyclization step is influenced by the nucleophilicity of the nitrogen. Indeed, in an ideal case of an excellent nucleofuge, the ratio between 15a and 15h would have been 1. With this competition experiment, we know that the cyclization step may be affected by the presence of para-substituent at the arene core since we demonstrated that the leaving group capacity of the
290 Part IV Iodine(I/III) Catalysis for Selective C(sp3)-H Amination alkyliodoso(III) is not high enough. Doing the hypothesis that in the compared methods, the 1,5-HAT process is thermodynamically the same for the substrates (even though the methods use different solvents for instance) and that the alkyliodine(I) oxidation is not influenced, we can claim that the alhyliodoso(III) leaving group capacity is lower than its close- related T-shaped alkyliodine(III) bearing two benzoyl ligands. We are conscious that this information requires more control experiments to uncontestably be proved.
Scheme IV.12. Competition experiment between 14a and 14h proving that the alkyliodoso(III) is not a sufficient leaving group allowing the cyclization step to not be influenced by the nucleophilicity of the nitrogen.
IV.3.3.4 Quantum yield determination To determine whether the mechanism is a radical chain mechanism, or it involves a radical recombination step, we determined the quantum yield. It corresponds to the number of molecules of product formed with one photon. If the latter is more than one, it necessarily proves that there is a radical chain mechanism. All the experiments were carried out in the dark laboratory following an adapted protocol published by Melchiorre et al.228 Both a ferrioxalate actinometer solution alongside the reaction mixture were irradiated by a 300 W Xenon lamp (50% intensity) at 400 nm for specified intervals of time. These irradiation times were chosen to reach at the maximum 20% conversion to be on the linear part of the kinetic profile (time of irradiation of 12.5, 15 and 17.5 min). In the actinometer solution and upon irradiation, ferric ions are converted to ferrous ions. After irradiation, the ferrous ions
228 S. R. Kandukuri, A. Bahamonde, I. Chatterjee, I. D. Jurberg, E. C. Escudero-Adán, P. Melchiorre, Angew. Chem. Int. Ed. 2015, 54, 1485–1489.
291 Part IV Iodine(I/III) Catalysis for Selective C(sp3)-H Amination are complexed with the 1,10-phenanthroline. Finally, to determine the moles of ferrous ions formed with time, UV-Vis spectra were recorded for each interval of time and the absorbance monitored at 510 nm. The absorbance at 510 nm of a non-irradiated but complexed with 1,10- phenanthroline was recorded as well. The moles of ferrous ions is calculated following the Beer-Lambert’s law (Equation IV.1) where ΔA represents the difference between the absorption of the irradiated sample with the non-irradiated one at 510 nm, ε the absorption coefficient of the 2+ -1 -1 complex ferrous ions Fe(phen)3 at 510 nm (11100 L.mol .cm ) and l the width of the quartz cuvette (1 cm). 0.01 L is the volume of the final ferrous complexed solution.
훥퐴(510푛푚) Equation IV.1.푚표푙푒푠 Calculation (퐹푒 of2 +the) =mole 0,01 of iron(II)(퐿) ∗ thanks to the absorbance at 510nm. 휀(510 푛푚) ∗ 푙 (푐푚) Having this result in hand, we could access the mole of incident photons 0 by unit of time called q n,p thanks to the following equation (Equation IV.2) where dx/dt represents the slope of the mole of complexed ferrous ions with time (Scheme IV.13), Φ(Fe2+ at 510 nm) the quantum yield of the 2+ complexed Fe(phen)3 at 510 nm (1.13) and A(400 nm) is the absorbance at 400 nm of the actinometer solution non-complexed and non-irradiated (0.124).
푑푥 0 Equation IV.2푞0푛,. Calculation 푝 = of the mole of incident푑푡 photon q n,p−퐴. (400푛푚) 훷(퐹푒2 + 푎푡 510 푛푚) ∗ [1 − 10 ] 0 -1 Having the data in hand, q n,p was calculated to be 3.559E-9 einstein.s . This value corresponds to a flow of photon.
292 Part IV Iodine(I/III) Catalysis for Selective C(sp3)-H Amination
Scheme IV.13. Plot of the mole of iron(II) formed vs time.
The moles of products formed during the different reaction time were determined by 1H-NMR. We plotted (Scheme IV.14) the moles of products 0 formed versus the number of photon in Einstein (determined by q n,p * t (s)).
Scheme IV.14. Plot of the mole of product formed vs the mol of photon.
0 The slope of the linear function corresponds to dx/(q n,p *dt) in the following equation and equals 3.1063 (Equation IV.3). The absorbance is the one of the reaction mixture at 400 nm. To be more precise, the reaction mixture was diluted by 10 and the absorbance found at 400 nm was 0.289. The multiplication factor was considered in the following formula. As a
293 Part IV Iodine(I/III) Catalysis for Selective C(sp3)-H Amination result, A(400 nm) equals 2.89 and the quantum yield was determined to be 3.1.
푑푥 Equation IV.3. Calculation of the quantum yield at 400푞0푛, nm for 푝 ∗ the 푑푡 amination reaction. 훷(푟푒푎푐푡푖표푛 푎푡 400 푛푚) = −퐴(400 푛푚) 1 − 10 In conclusion, the quantum yield of the reaction is higher than one and proves that the reaction mechanism follows a radical chain mechanism with an initiation step, propagation steps and a termination.
IV.3.3.5 Influence of the terminal oxidant for the Hofmann- Löffler reaction To further demonstrate the differences between the two procedures involving an alkyliodine(III) intermediate, we performed various experiments to determine the influence of the terminal oxidant on certain substrates. For instance, the benzyl methyl ether derivative 16 was submitted to both procedures (Scheme IV.15a). Regarding the iodine/hypervalent iodine oxidant system, the C-H amination occurs as expected providing 17 in 89% isolated yield. But, while mCPBA was used, overoxidation to the corresponding lactam was observed. 18 was isolated with the excellent yield of 99%. Then, we investigated the tolerance of the substrates 19a and 19b bearing a remote tertiary alcohol (Scheme IV.15b). In the case of the iodine/mCPBA, clean conversion to the final pyrrolidine products 20 a and 20b was obtained. In contrast, while using hypervalent iodine(III) as terminal oxidant, concomitant radical opening of the tertiary alcohols forming the corresponding iodo-ketones 21a and 21b occurs. Previous works were published for such a reaction by the group of Barluenga where they use a cationic iodonium reagent.229 This is due to the activation of the remote tertiary alcohol with the iodine(I) active species leading to the formation of the O-centered radical that collapses to form the ketone and the carbon-centered radical that recombines with molecular iodine. Since the incorporation of an atom of iodine in the carbon framework, it prevents the progress of the catalytic version of the Hofmann-Löffler reaction. Thus, only traces of products were obtained.
229 J. Barluenga, F. González-Bobes, S. R. Ananthoju, M. A. Garca-Martn, J. M. González, Angew. Chem. Int. Ed. 2001, 40, 3389–3392.
294 Part IV Iodine(I/III) Catalysis for Selective C(sp3)-H Amination
While performing the reaction with stochiometric amount of molecular iodine, the isolated yields dramatically increased.
Scheme IV.15. Influence of the terminal oxidant for certain substrates for the amination reaction.
IV.3.3.6 Mechanism of the I(I/III) catalysis for the amination reaction Having all the data in hand regarding the mechanistic investigations, we proposed the following mechanism (Scheme IV.16).
295 Part IV Iodine(I/III) Catalysis for Selective C(sp3)-H Amination
Molecular iodine as we presented before can disproportionate in the presence of water (contained in the non-purified solvents) into hypoiodite species. We have the evidence that tert-butyl hypoiodite is the iodine active species in the system. As a result, we supposed that hypoiodite HOI can in- situ generates the latter since tert-butanol is used as co-solvent. The N- iodination occurs from the reaction of 14a and tert-butyl hypoiodite. An homolytic cleavage of the N-iodinated intermediate XVII takes place under fluorescent light irradiation providing the key nitrogen-centered radical XVIII as the initiation step. The 1,5-HAT affords the formation of the carbon-centered radical XIX through a 6-membered ring transition state. At this stage, another N-iodinated intermediate XVII reacts with the latter in a propagation chain to provide the alkyliodine(I) intermediate XX. The latter is then oxidized by mCPBA towards the alkyliodoso(III) intermediate XXI. As alkyliodine(III) increased the leaving group capacity, a subsequent rapid cyclization occurs generating the final pyrrolidine 15a and the hypoiodite active species to close the catalytic cycle.
296 Part IV Iodine(I/III) Catalysis for Selective C(sp3)-H Amination
Scheme IV.16. Mechanism of the iodine(I/III) catalysis for selective C(sp3)-H amination (Hofmann-Löffler reaction).
IV.3.3.7 DFT calculations To truly understand the reaction mechanism and the crucial step of the alkyliodine oxidation, DFT calculations were carried out. As in the section III.2.1, the closed conformation was chosen for all the structures and the relative energy barriers between the open and the close structure are about 2 kcal/mol. We depicted below the energy profile of the reaction following a radical recombination mechanism calculated with either PBE functional or PBE0 hybrid functional with or without dispersion correction D3 (Scheme IV.17).
Scheme IV.17. Energy profile of the iodine(I/III) catalysis for the amination reaction.
The formation of the N-iodinated intermediate XVII is slightly endothermic (+ 1.37 kcal/mol) and its homolytic cleavage leads to the nitrogen-centered radical XVIII, destabilized by about 35 kcal/mol. Obviously, the light is providing enough energy to reach it. The hydrogen atom abstraction to form the more stable carbon-centered radical XIX (by
297 Part IV Iodine(I/III) Catalysis for Selective C(sp3)-H Amination
10 kcal/mol compared with the nitrogen-centered radical XVIII) is almost barrierless (4 kcal/mol). The intermediate XX formed by a recombination with an iodine radical is dramatically stabilized (-40 kcal/mol). At this stage, the crucial mCPBA oxidation of the alkyliodine(I) occurs and was computed. The barrier was found to be between 4.7 and 11.6 kcal/mol taking or not into account the dispersion correction. The corresponding transition state for this step was elucidated and displayed in Scheme IV.18.
Scheme IV.18. Transition state for the alkyliodine(I) intermediate oxidation by mCPBA.
Interestingly, the direct conversion of intermediate XX to the final pyrrolidine is slightly endothermic with energies ranging from 1.3 to 5.1 kcal/mol taking or not into account the dispersion correction. This key calculation is the evidence of the necessity of the alkyliodine(I) oxidation with mCPBA. It was also interesting to note that the transition state of the oxidation of XX with TBHP is significantly increased by 20 kcal/mol. Kinetically, the alkyliodine(I) oxidation by TBHP is not competing. Another information could be extracted from the DFT calculations since the higher transition state of the overall process is the one of the 1,5-HAT
298 Part IV Iodine(I/III) Catalysis for Selective C(sp3)-H Amination indicating us that it may be the rate-determining step as indicated by the KIE. It was demonstrated the necessity to have an I(III) intermediate in order to have a kinetically competent pyrrolidine formation. To illustrate the obtention of a low quantum yield, radical quenching by a molecule of solvent was also calculated. For the most stable carbon-centered radical intermediate XIX, a hydrogen atom abstraction from either acetonitrile or tert-butanol is exothermic (+ 12 kcal/mol and + 19 kcal/mol respectively). These reactions are competing but do not affect the reaction yield because they lead to the regeneration of the starting material. Unfortunately, they contribute to the low quantum yield obtained for the radical chain mechanism.
IV.4 Final remarks
In this chapter, a I(I/III) catalysis was displayed for the formation of pyrrolidine derivatives. Non-activated position could be achieved thanks to the involvement of a key hypervalent alkyliodine(III) intermediate. Mechanistic investigations were carried out as well to propose the most accurate mechanism. Further investigations must be done about the minimum leaving group capacity required to be able to access non- activated aliphatic position. A scale of leaving group capacity can be built as well to better understand the crucial role of the nucleofuge. We started to compare the T-shaped hypervalent trisubtituted alkyliodine(III) intermediate and the hypervalent alkyliodoso(III) species leaving group capacity but since the reactions are not performed under the same conditions, we cannot surely confirm our hypothesis.
IV.5 Experimental section
IV.5.1 General information NMR spectra were recorded on a Bruker Avance 400 MHz or 500 MHz spectrometer, respectively. The chemical shifts (δ) for 1H and 13C are reported in ppm relative to residual signals of the solvents (CDCl3 δ = 7.26 and 77.0 ppm, CD3CN δ = 1.94 and 118.26 ppm; DMSO-d6 δ = 2.50 and 39.52 ppm for 1H and 13C NMR respectively). Coupling constants are given in Hz.
299 Part IV Iodine(I/III) Catalysis for Selective C(sp3)-H Amination
The following abbreviations are used to indicate the multiplicity: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad. High-resolution mass spectra (HRMS) were obtained from the ICIQ High- Resolution Mass Spectrometry Unit on MicroTOF Focus and Maxis Impact (Bruker Daltonics) with electrospray ionization. IR spectra were taken in a Bruker Alpha instrument in the solid state. All reactions were set up under an argon atmosphere in oven- dried glassware using standard Schlenk techniques unless otherwise stated. Synthesis grade solvents as well as reagents were used as purchased. Anhydrous solvents were taken from a commercial solvent purification system (SPS) dispenser. Chromatographic purification of products was accomplished using flash column chromatography (FC) on silica gel (Merck, type 60, 0.063-0.2 mm). For the intermolecular KIE, 5 equivalents of substrate 14l and 5 equivalents of 14l-D2. The reaction was run to full conversion, which accounts for a 10% total conversion of the starting materials. For the Hammett correlation studies, the solution was stirred for 1 h resulting in less than 15% overall conversion.
IV.5.2 Synthesis of the substrates 14a-z, 16 and 19a-b for the amination reaction Synthesis of 14a-f, 14h-k, 14m-n and 14u-z (GP1)
Scheme IV.19. Pathway for the synthesis of 14a-f, 14h-k, 14m-n and 14u-z.
Step 1. A flame-dried Schlenk tube equipped with a stirrer bar is charged with the corresponding nitrile compound (1.0 equiv.) and THF (50 mL). LDA (2.6 mL, 2M, 1.0 equiv.) is added drop wise at -78 ºC and the solution
300 Part IV Iodine(I/III) Catalysis for Selective C(sp3)-H Amination is stirred for 30 min. After that period, the corresponding alkyl bromide (1.2 equiv.) is added in a single portion and the mixture is stirred at room temperature for 12h. A saturated aqueous solution of NH4Cl is added and the resulting mixture is extracted three times with Et2O. The organic layer is dried over Na2SO4 and the solvent is evaporated under reduced pressure. The crude product is directly engaged in the next step. Step 2. A flame dried Schlenk equipped with a stirrer bar and a reflux condenser is charged with LiAlH4 (3 equiv.), Et2O is added carefully and the mixture is cooled to 0 ºC with an external ice/water cooling bath. The crude nitrile (1 equiv.) is dissolved in a small volume of Et2O and added carefully to the LiAlH4 suspension. The mixture is heated to reflux for 2h and cooled to 0 ºC afterwards. A solution of NaOH (10% in water) is added carefully until a white solid precipitate appears. After filtration over Na2SO4 and evaporation of the solvent, the crude amine is obtained in quantitative yields. Step 3. The crude amine from step 2 (1 equiv.) is dissolved in pyridine (50 mL) and the respective sulfonyl chloride (1.5 equiv.) is added at 0 ºC. The solution is stirred overnight at room temperature. CH2Cl2 is added, and the mixture is washed three times with a hydrochloride solution (10% HCl in water). The organic layer is dried over Na2SO4 and the solvent is evaporated under reduced pressure. The crude product was purified by chromatography (silica gel, hexane/ethyl acetate as eluent) to give the pure product 14a-f, 14h-k, 14m-n and 14u-z.
Synthesis of 14g
A flame-dried Schlenk tube equipped with a stirrer bar was charged with 14e (500 mg, 1.22 mmol, 1.0 equiv.), PdCl2(PPh3)2 (86 mg, 0.12 mmol, 10 mol%), CuI (30 mg, 0.16 mmol, 13 mol%), phenylacetylene (250 mg, 2.44 mmol, 2.0 equiv.) and 22 mL of a mixture of DMF/Et3N (4/1, v/v). The mixture was stirred for 12h at 90 ºC. After cooling down to room temperature, a saturated aqueous solution of NH4Cl was added and the mixture extracted three times with CH2Cl2. The organic layers were dried over Na2SO4 and solvents evaporated under reduced pressure. The crude product was purified by column chromatography (silica gel, hexane/ethyl acetate as eluent) to give the pure compound 14g as brownish oil in 76% isolated yield.
Synthesis of 14l
301 Part IV Iodine(I/III) Catalysis for Selective C(sp3)-H Amination
From the commercially available primary amine, the substrate 14l was synthesized following the step 3 of GP1 using tosyl chloride. 14l was isolated with the excellent isolated yield of 94% as a colorless oil.
Synthesis of 14l-D and 14l-D2
Scheme IV.20. Pathway for the synthesis of 14l-D and 14l-D2.
Step 1. 4-Chlorobutyrophenone (1 equiv.) was dissolved in dry Et2O (0.1 M) and carefully added to a suspension of LiAlH4 (1 equiv.) in diethyl ether at 0 C. The mixture was refluxed for 2 h after which the reaction was cooled down to 0 C and quenched by careful addition of a 2 M aqueous solution of NaOH. The mixture was filtered over Na2SO4 and the solvent was removed under reduced pressure. The crude product was further purified by column chromatography (hexane/ethyl acetate as eluent).
Note: LiAlD4 was used instead for the synthesis of 14l-D2. Step 2. The crude from the previous step (1 equiv.) was dissolved in dry
CH2Cl2 and cooled down to 0 C. NEt3 (2 equiv.) was added and the mixture was stirred for 10 min at 0 C. Mesyl chloride (1.1 equiv.) was added dropwise at 0 C and the reaction mixture was stirred for 30 min at 0 C after which the reaction was quenched by addition of a saturated aqueous solution of
NaHCO3. The layers were separated, and the aqueous phase was extracted with CH2Cl2. The combined organic phases were dried over Na2SO4, filtered and the solvent was removed under reduced pressure to yield the desired mesylate which was used without purification for the next step. Note: Due to rapid decomposition of the mesylate, the next step has to be done immediately after the mesylation.
Step 3. The crude mesylate from step 2 was dissolved in dry Et2O and the solution was cooled down to 0 C. Subsequently, LiAlD4 (1 equiv.) was
302 Part IV Iodine(I/III) Catalysis for Selective C(sp3)-H Amination carefully added at 0 C after which the reaction mixture was refluxed for 2 h. The reaction mixture was cooled to 0 C and quenched by careful addition of a 2 M aqueous solution of NaOH. The mixture was filtered over
Na2SO4 and the solvent was removed under reduced pressure. The crude product was further purified by column chromatography using pure hexane as eluent. Step 4. The crude product from the previous step (1 equiv.) was dissolved in dry DMF and NaN3 (1.5 equiv.) was added. The reaction mixture was stirred overnight at 90 C. After adding Et2O to the mixture, the organic layer was washed five times with water to remove the DMF prior to be dried over
Na2SO4 and evaporated under reduced pressure. The crude product was directly used for the next step without further purification.
Step 5. The crude product from step 4 was dissolved in dry Et2O, the solution was cooled down to 0 C and LiAlH4 (3 equiv.) was added carefully at that temperature. The reaction mixture was refluxed for 2 h after which the mixture was cooled down again to 0 C and quenched by careful addition of a 2 M aqueous solution of NaOH. The mixture was filtered over
Na2SO4 and the solvent was removed under reduced pressure. The crude product was directly used for the next step without purification. Step 6. Step 3 of GP1. The crude product was purified by column chromatography (silica gel, hexane/ethyl acetate as eluent) to provide the pure compound 14l-D and 14l-D2.
Synthesis of 14o-p (GP2)
Scheme IV.21. Pathway for the synthesis of 14o-p.
303 Part IV Iodine(I/III) Catalysis for Selective C(sp3)-H Amination
Step 1. A flame-dried Schlenk tube equipped with a stirrer bar was charged with the trimethylphosphonoacetate (1.62 mL, 10 mmol, 1.0 equiv.) and THF (5 mL/mmol) and the vessel was cooled down to 0º C. n-BuLi (5 mL of a 2 M solution, 10 mmol, 1.0 equiv.) was added dropwise and the reaction was stirred for one hour upon which time the corresponding ketone (1.32 g, 10 mmol, 1.0 equiv.) was added and the reaction was then stirred for 18 h at room temperature. A saturated aqueous solution of NH4Cl was added and the resulting mixture extracted three times with Et2O. The organic layer was dried over anhydrous Na2SO4 and the solvent evaporated under reduced pressure. The crude was used for the next step without further purification. Step 2. A flame-dried Schlenk tube equipped with a stirrer bar was charged with the crude from the previous step, Pd/C (20 w%) and ethanol (5 mL/mmol) were added and the reaction was stirred under atmospheric pressure of hydrogen gas overnight. The mixture was filtered through Celite and concentrated to yield the crude ester which was used for the next step without further purification. Step 3. A flame-dried Schlenk tube equipped with a stirrer bar and a reflux condenser was charged with LiAlH4 (2 equiv.). Et2O is added carefully and the mixture was cooled down to 0 ºC. The crude ester (1 equiv.) was added to the LiAlH4/Et2O suspension under argon atmosphere. The mixture was heated to reflux for 2 h and cooled down to 0 ºC afterwards. A solution of NaOH (1 M in water) was added. After filtration of the white precipitate over Na2SO4 and evaporation of the solvent under reduced pressure, the crude alcohol was obtained in quantitative yield and was used in the following step.
Step 4. The crude alcohol (1 equiv.) was dissolved in dry CH2Cl2 and cooled down to 0 C. NEt3 (2 equiv.) was added and the mixture was stirred for 10 min at 0 C. Mesyl chloride (1.1 equiv.) was added dropwise at 0 C and the reaction mixture was stirred for 30 min at 0 C after which the reaction was quenched by addition of a saturated aqueous solution of NaHCO3. The layers were separated, and the aqueous phase was extracted with CH2Cl2.
The combined organic phases were dried over Na2SO4, filtered and the solvent was removed under reduced pressure to yield the desired mesylate which was used without purification for the next step.
Step 4. The crude from step 3 (1 equiv.) was dissolved in dry DMF and NaN3 (1.5 equiv.) was added. The reaction mixture was stirred overnight at 90 C.
After adding Et2O to the mixture, the organic layer was washed five times with water to remove the DMF prior to be dried over Na2SO4 and
304 Part IV Iodine(I/III) Catalysis for Selective C(sp3)-H Amination evaporated under reduced pressure. The crude product was directly used for the next step without further purification. Step 5. A Schlenk flask equipped with a stirrer bar was charged with the corresponding crude azide from step 4, Pd/C (20 %w/w) and ethyl acetate (5 mL/mmol). The reaction was stirred under hydrogen atmosphere for 12 h using a gas balloon. The mixture was filtered through a pad of Celite and concentrated under reduced pressure to yield the crude amine. The crude product was directly used for the next step without further purification. Step 6. Step 3 of GP1. The crude product was purified by column chromatography (silica gel, hexane/ethyl acetate as eluent) to provide the pure compound 14o-p.
Synthesis of 14q and 16 (GP3)
Scheme IV.22. Pathway for the synthesis of 14q and 16.
A flame-dried Schlenk tube equipped with a stirrer bar was charged with the N-(2- bromophenethyl)-4-methylbenzenesulfonamide (1 equiv.) and dissolved in THF (0.1 M). The solution was cooled down to -78 ºC and a solution of MeLi in Et2O (1.2 equiv.) was added. The mixture was stirred for 10 min, then t BuLi (2.5 equiv.) was added and the mixture stirred for 15 min. Benzyl bromide or the bromo(methoxy)methane (4 equiv.) was added and the solution was stirred at room temperature for 12 h. A saturated aqueous solution of NH4Cl was added and the resulting mixture extracted three times with CH2Cl2. The organic layer was dried over Na2SO4 and the solvent evaporated under reduced pressure. The crude product was purified by column chromatography (silica gel, hexane/ethyl acetate as eluent) to provide 14q and 16.
Synthesis of 14r-s (GP4)
305 Part IV Iodine(I/III) Catalysis for Selective C(sp3)-H Amination
Scheme IV.23. Pathway for the synthesis of 14r-s.
Step 1. A flame-dried Schlenk tube equipped with a stirrer bar was charged with benzenesulfonyl chloride (1 equiv.) in CHCl3 (0.1 M) and the respective primary amine (3 equiv.) was added at 0 ºC. The solution was stirred overnight at room temperature. The solvent was then evaporated under reduced pressure. The crude product was purified by column chromatography (silica gel, hexane/ethyl acetate as eluent) to provide the pure intermediate. Step 2. A flame-dried Schlenk tube equipped with a stirrer bar was charged with the corresponding starting material from step 1 (1 equiv.) and dissolved in THF (10 mL). The mixture was cooled down to -78 ºC and n-BuLi (2.1 equiv.) was added. The mixture was then stirred for 30 min at -78 ºC. ZnCl2 (2.5 equiv.) was added and the mixture stirred for another 15 min and allowed to reach 0 ºC. Then benzyl bromide (1.2 equiv.) and Pd(PPh3)4 (5 mol%) were added. The mixture was heated at 50 ºC for 12 h. The crude was poured into an aqueous 2 M solution of HCl and extracted three times with
CH2Cl2. The solvent was evaporated under reduced pressure and the crude product purified by column chromatography (silica gel, hexane/ethyl acetate as eluent) to provide 14r-s.
Synthesis of 14t
306 Part IV Iodine(I/III) Catalysis for Selective C(sp3)-H Amination
Scheme IV.24. Pathway for the synthesis of 14t.
Step 1. Step 1 of GP4. Step 2. A flame-dried Schlenk tube equipped with a stirrer bar was charged with the pure intermediate from the precedent step (1 equiv.) diluted in
Et2O (0.02 M). t-BuLi (3.6 equiv.) was added carefully at -78 ºC and the mixture was stirred for 30 minutes, while warming to -40 ºC. At this point,
Cu(SMe2)Br (1.2 equiv.) and allyl bromide (1.4 equiv.) were added successively. The reaction temperature was raised to room temperature over the next 12 h. A saturated aqueous solution of NH4Cl was added and the mixture extracted three times with CH2Cl2. The combined organic layers were dried over Na2SO4 and the solvent evaporated under reduced pressure. The crude product was purified by column chromatography (silica gel, hexane/ethyl acetate as eluent) to provide the pure intermediate. Step 3. A flame-dried Schlenk tube equipped with a stirrer bar was charged with the intermediate from the previous step (1.0 equiv.), with the Grubbs nd 2 generation catalyst (5 mol%) and CH2Cl2 (0.1 M). The mixture was heated at 37 ºC for 12h. The crude reaction residue was then cooled down to room temperature, and immediately filtered through Celite. The solvent was then evaporated under reduced pressure and the crude compound used in the next step without further purification. Step 4. A flame-dried Schlenk equipped with a stirrer bar was charged with the crude from the previous step, with Pd/C (5 w%) and EtOH (10 mL). The mixture was heated at 40 ºC for 12 h under one atmosphere of hydrogen gas. The residue was filtered through Celite and all volatile solvent was evaporated under reduced pressure. The crude product was purified by column chromatography (silica gel, hexane/ethyl acetate as eluent) to provide 14t as a white solid in 74% overall yield.
Synthesis of 19a-b
A flame-dried Schlenk tube equipped with a stirrer bar was charged with 14e (1.0 equiv.) and dissolved in THF (0.1 M). n-BuLi (3.0 equiv.) was added dropwise at -78 ºC and the solution was stirred for 30 min. After that period, the corresponding cycloketone (3.0 equiv.) was added in a single portion and the mixture stirred at room temperature for 12 h. A saturated aqueous solution of NH4Cl was added and the resulting mixture extracted three times with CH2Cl2. The organic layer was dried over Na2SO4 and the solvent evaporated under reduced pressure. The crude product was purified by
307 Part IV Iodine(I/III) Catalysis for Selective C(sp3)-H Amination column chromatography (silica gel, hexane/ethyl acetate as eluent) to provide 19a-b.
IV.5.3 Characterization of the substrates 14a-z, 16 and 19a-b for the amination reaction N-(2,2-Dimethyl-4-phenylbutyl)-4-methylbenzenesulfonamide (14a)
Prepared according to the general procedure GP1, 14a was isolated as a white solid with an overall yield of 63%. The NMR spectra match those previously 158 1 described in literature. H NMR (400MHz, CDCl3): δ = 7.77 (d, J = 8.3 Hz, 2H), 7.31 (d, J = 8.3 Hz, 2H), 7.30-7.20 (m, 2H), 7.21- 7.18 (m, 1H), 7.17-7.14 (m, 2H), 4.71 (brt, 1H), 2.76 (d, J = 6.9 Hz, 2H), 2.54- 2.49 (m,2H), 2.44 (s, 3H), 1.54-1.50 (m, 2H), 0.95 (s, 6H). 13C NMR (125 MHz, CDCl3): δ = 143.4, 142.7, 137.1, 129.8, 128.5, 128.4, 127.2, 125.8, 52.9, 41.6, 34.1, 30.4, 25.0, 21.6.
N-(2,2-Dimethyl-4-(p-tolyl)butyl)-4-methylbenzenesulfonamide (14b)
Prepared according to the general procedure GP1, 14b was isolated as a white solid with an overall yield of 72%. The NMR spectra match those previously described in literature.158 1H NMR (400 MHz, CDCl3): δ = 7.77 (d, J = 8.3 Hz, 2H), 7.31 (d, J = 8.3 Hz, 2H), 7.30-7.20 (m, 2H), 7.21-7.18 (m, 1H), 7.17-7.14 (m, 2H), 4.71 (brt, 1H), 2.76 (d, J = 6.9 Hz, 2H), 2.54-2.49 (m, 2H), 2.44 (s, 3H), 1.54-1.50 (m, 2H), 0.95 (s, 6H). 13C
NMR (101 MHz, CDCl3): δ = 143.4, 142.7, 137.1, 129.8, 128.5, 128.4, 127.2, 125.8, 52.9, 41.6, 34.1, 30.4, 25.0, 21.6.
N-(4-(4-Fluorophenyl)-2,2-dimethylbutyl)-4- methylbenzenesulfonamide (14c)
Prepared according to the general procedure GP1, 14c was isolated as a white solid with an overall yield of 71%. The NMR spectra match those previously described in literature.158 1H NMR (400
MHz, CDCl3): δ = 7.78-7.73 (m, 2H), 7.29 (d, J = 8.1 Hz, 2H), 7.10-7.05 (m,
308 Part IV Iodine(I/III) Catalysis for Selective C(sp3)-H Amination
2H), 6.92 (t, J = 8.6 Hz, 2H), 4.88 (bs, 1H), 2.72 (d, J = 6.9 Hz, 2H), 2.49-2.44 (m, 2H), 2.41 (s, 3H), 1.52-1.42 (m, 2H), 0.91 (s, 6H). 13C NMR (101 MHz,
CDCl3): δ = 161.3 (d, JC-F = 243.2 Hz), 143.5, 138.3, 138.2, 137.1, 129.7 (JH-F = 7.8 19 Hz), 127.2, 115.1 (JC-F = 21.1 Hz), 52.9, 41.6, 34.1, 29.6, 25.1, 21.6. F NMR (376
MHz, CDCl3): δ = -118.0.
N-(4-(4-Chlorophenyl)-2,2-dimethylbutyl)-4- methylbenzenesulfonamide (14d)
Prepared according to the general procedure GP1, 14d was isolated as a white solid with an overall yield of 88%. The NMR spectra match those previously described in literature.158 1H NMR (400 MHz, CDCl3): δ = 7.77-7.72 (m, 2H), 7.29 (d, J = 8.0 Hz, 2H), 7.22-7.19 (m, 2H), 7.07-7.04 (m, 2H), 4.68 (brs, 1H), 2.72 (d, J = 7.0 Hz, 2H), 2.50-2.43 (m, 2H), 2.42 (s, 3H), 1.50-1.44 (m, 2H), 0.91 (s, 6H). 13C NMR (101 MHz,
CDCl3): δ = 143.5, 141.2, 137.1, 131.5, 129.9, 129.8, 128.5, 127.2, 52.9, 41.4, 34.2, 29.8, 25.1, 21.7.
N-(4-(4-Bromophenyl)-2,2-dimethylbutyl)-4- methylbenzenesulfonamide (14e)
Prepared according to the general procedure GP1, 14e was isolated as a white solid with an overall yield of 68%. The NMR spectra match those previously described in literature.158 1H NMR (400
MHz, CDCl3): δ = 7.76-7.73 (m, 2H), 7.37-7.34 (m, 2H), 7.29 (d, J = 8.1 Hz, 2H), 7.02-6.98 (m, 2H), 4.78 (brs, 1H), 2.72 (d, J = 7.0 Hz, 2H), 2.47-2.42 (m, 13 2H), 2.41 (s, 3H), 1.49-1.43 (m, 2H), 0.91 (s, 6H). C NMR (101 MHz, CDCl3): δ = 143.5, 141.7, 137.1, 131.5, 130.2, 129.9, 127.2, 119.5, 52.9, 41.3, 34.2, 29.8, 25.1, 21.7.
N-(4-(4-Methoxyphenyl)-2,2-dimethylbutyl)-4- methylbenzenesulfonamide (14f)
Prepared according to the general procedure GP1, 14f was isolated as a white solid with an overall yield of 81%. The NMR spectra match those previously described in literature.158 1H NMR (400 MHz, CDCl3): δ = 7.73 (d, J = 8.2 Hz, 2H), 7.29 (d, J = 7.7 Hz,
309 Part IV Iodine(I/III) Catalysis for Selective C(sp3)-H Amination
2H), 7.03 (d, J = 8.6 Hz, 2H), 6.80 (d, J = 8.5 Hz, 2H), 4.54 (t, J = 6.6 Hz, 1H), 3.78 (s, 3H), 2.72 (d, J = 6.8 Hz, 2H), 2.47-2.44 (m, 2H), 2.42 (s, 3H), 1.48-1.44 13 (m, 2H), 0.91 (s, 6H). C NMR (125 MHz, CDCl3): δ = 157.7, 143.4, 137.0, 134.7, 129.8, 129.3, 127.1, 113.9, 55.4, 52.9, 42.0, 34.1, 29.4, 25.2, 21.7.
N-(2,2-Dimethyl-4-(4-(phenylethynyl)phenyl)butyl)-4- methylbenzenesulfonamide (14g)
Prepared according to the procedure described above, 14g was isolated as a brownish oil with a yield of 76%. The NMR spectra match those previously described in literature.158 1H NMR (400 MHz, CDCl3): δ = 7.73 (d, J = 8.3 Hz, 2H), 7.54-7.52 (m, 2H), 7.42 (d, J = 8.1 Hz, 2H), 7.37-7.32 (m, 3H), 7.30 (d, J = 7.7 Hz, 2H), 7.11 (d, J = 8.1 Hz, 2H), 4.49 (t, J = 6.9 Hz, 1H), 2.74 (d, J = 6.9 Hz, 2H), 2.53-2.50 (m, 2H), 2.42 (s, 3H), 1.52-1.48 (m, 2H), 0.93 (s, 6H). 13C NMR (125 MHz, CDCl3): δ = 143.5, 143.1, 137.1, 131.8, 131.7, 129.9, 128.4, 128.3, 127.2, 123.6, 120.8, 89.6, 89.0, 52.9, 41.3, 34.2, 30.4, 25.1, 21.7.
N-(2,2-Dimethyl-4-phenylbutyl)-4-nitrobenzenesulfonamide (14h)
Prepared according to the general procedure GP1, 14h was isolated as a white solid with an overall yield of 79%. The NMR spectra match those previously described in literature.158 1H NMR (400 MHz,
CDCl3): δ = 8.34 (d, J = 8.8 Hz, 2H), 8.03 (d, J = 8.8 Hz, 2H), 7.30-7.26 (m, 2H), 7.23-7.16 (m, 1H), 7.14 (d, J = 6.9 Hz, 2H), 4.80 (s, 1H), 2.83 (d, J = 6.9 Hz, 2H), 2.57-2.51 (m, 2H), 1.54-1.47 (m, 2H), 0.96 (s, 6H). 13C NMR (101 MHz, CDCl3): δ = 150.1, 146.0, 142.4, 128.6, 128.4, 128.3, 126.1, 124.5, 53.3, 41.5, 34.4, 30.4, 25.0.
4-Methyl-N-((1-phenethylcyclohexyl)methyl)benzenesulfonamide (14i)
Prepared according to the general procedure GP1, 14i was isolated as a white solid with an overall yield of 61%. The NMR spectra match those previously described in literature.158 1H NMR (400 MHz, CDCl3): δ = 7.75 (d, J = 8.5 Hz, 2H), 7.31-7.28 (m, 2H), 7.28-7.24 (m, 2H),
310 Part IV Iodine(I/III) Catalysis for Selective C(sp3)-H Amination
7.20-7.16 (m, 1H), 7.14 (dt, J = 7.8, 1.2 Hz, 2H), 4.49 (brs, 1H), 2.82 (d, J = 6.9 Hz, 2H), 2.47-2.38 (m, 2H), 2.42 (s, 3H), 1.61-1.54 (m, 2H), 1.46-1.24 (m, 10H). 13 C NMR (101 MHz, CDCl3): δ = 143.5, 142.9, 137.1, 129.9, 128.5, 128.5, 127.2, 125.9, 49.3, 37.5, 36.2, 33.6, 29.3, 26.2, 21.7, 21.4.
4-Methyl-N-(2-methyl-4-phenylbutyl)benzenesulfonamide (14j)
Prepared according to the general procedure GP1, 14j was isolated as a white solid with an overall yield of 88%. The NMR spectra match those previously described in literature.158 1H NMR (400 MHz, CDCl3): δ = 7.74 (dd, J = 8.1, 6.0 Hz, 2H), 7.27 (dd, J = 17.6, 8.0 Hz, 4H), 7.20- 7.14 (m, 1H), 7.11 (dd, J = 8.1, 1.4 Hz, 2H), 4.56 (brs, 1H), 2.88 (dd, J = 12.6, 5.5 Hz, 1H), 2.78 (dd, J = 12.4, 6.4 Hz, 1H), 2.61 (ddd, J = 13.9, 9.7, 5.7 Hz, 1H), 2.50 (ddd, J = 13.8, 9.9, 6.0 Hz, 1H), 2.42 (s, 3H), 1.72-1.55 (m, 2H), 1.46-1.35 13 (m, 1H), 0.92 (d, J = 6.6 Hz, 3H). C NMR (101 MHz, CDCl3): δ = 143.4, 142.2, 137.2, 129.8, 128.6, 128.5, 127.2, 125.9, 49.0, 35.8, 33.1, 32.9, 21.6, 17.5.
4-Methyl-N-(2-phenethylhexyl)benzenesulfonamide (14k)
Prepared according to the general procedure GP1, 14k was isolated as a pale yellow oil with an overall yield 1 of 65%. H NMR (400 MHz, CDCl3): δ = 7.77 (d, J = 8.3 Hz, 2H), 7.35-7.25 (m, 4H), 7.22-7.17 (m, 1H), 7.15- 7.10 (m, 2H), 4.51 (t, J = 6.4 Hz, 1H), 2.92 (td, J = 6.1, 1.3 Hz, 2H), 2.58-2.51 (m, 2H), 2.45 (s, 3H), 1.67-1.44 (m, 1H), 1.34-1.13 (m, 13 6H), 0.87 (t, J = 7.1 Hz, 3H). C NMR (101 MHz, CDCl3): δ = 143.3, 142.1, 137.0, 129.7, 128.4, 128.3, 127.1, 125.8, 46.0, 37.4, 33.2, 32.8, 31.0, 28.6, 22.9, 21.5, 14.0. IR ν(cm-1): 3284, 2927, 2859, 1454, 1322, 1157, 1093, 544. HRMS (m/z): - [M-H] calculated for C21H28NO2S: 358.1846; found: 358.1842.
4-Methyl-N-(4-phenylbutyl)benzenesulfonamide (14l)
Prepared according to the procedure described above, 14l was isolated as a colorless oil with a yield of 94%. The NMR spectra match those previously 158 1 described in literature. H NMR (400 MHz, CDCl3): δ = 7.77 (dt, J = 8.3, 1.7 Hz, 2H), 7.34-7.25 (m, 4H), 7.22-7.17 (m, 1H), 7.15-7.11 (m, 2H), 4.58 (brs, 1H), 2.97 (q, J = 6.5 Hz, 2H), 2.57 (t, J = 7.5 Hz, 2H), 2.45 (s, 3H), 1.66-1.57 (m,
311 Part IV Iodine(I/III) Catalysis for Selective C(sp3)-H Amination
13 2H), 1.55-1.47 (m, 2H). C NMR (101 MHz, CDCl3): δ = 143.5, 141.9, 137.1, 129.8, 128.5, 127.2, 126.0, 43.2, 35.4, 29.2, 28.3, 21.6.
4-Methyl-N-(4-phenylbutyl-4-D)benzenesulfonamide (14l-D)
Prepared according to the procedure described above, 14l-D was isolated as a colorless oil with an overall yield of 15%. The NMR spectra match those previously described in literature.158 1H NMR (500
MHz, CDCl3): δ = 7.33 (d, J = 8.3 Hz, 2H), 7.30-7.24 (m, 4H), 7.19-7.15 (m, 1H), 7.11-7.09 (m, 2H), 4.36 (brt, 1H), 2.95 (t, J = 6.9 Hz, 2H), 2.53 (t, J = 7.6 Hz, 1H), 2.42 (s, 3H), 1.62-1.55 (m, 2H), 1.52-1.44 (m, 2H). 13C NMR (125 MHz,
CDCl3): δ = 143.5, 137.1, 129.8, 128.5, 127.2, 125.9, 43.2, 34.9 (t, JC-D = 18Hz), 29.2, 28.3, 21.6.
4-Methyl-N-(4-phenylbutyl-4,4-D2)benzenesulfonamide (14l-D2)
Prepared according to the procedure described
above, 14l-D2 was isolated as a colorless oil with an overall yield of 13%. The NMR spectra match those previously described in literature.158 1H NMR (500 MHz, CDCl3): δ = 7.75 (d, J = 8.3 Hz, 2H), 7.32-7.25 (m, 4H), 7.22-7.16 (m, 1H), 7.13-7.10 (m, 2H), 4.39 (brt, J = 6.3 Hz, 1H), 2.97 (q, J = 6.4 Hz, 2H), 2.44 13 (s, 3H), 1.62-1.44 (m, 4H). C NMR (125 MHz, CDCl3): δ = 143.5, 141.8, 137.1, 129.8, 128.5, 127.2, 125.9, 43.2, 34.6 (m), 29.2, 28.2, 21.7.
4-Methyl-N-(4-phenylpentyl)benzenesulfonamide (14m)
Prepared according to the general procedure GP1, 14m was isolated as a yellow oil with an overall yield of 61%. The NMR spectra match those previously described in literature.158 1H NMR (400 MHz,
CDCl3): δ = 7.70 (d, J = 8.3 Hz, 2H), 7.29-7.24 (m, 4H), 7.23-7.12 (m, 1H), 7.11- 7.09 (m, 2H), 4.29 (t, J = 6.3 Hz, 1H), 2.88 (q, J = 6.7 Hz, 2H), 2.60 (q, J = 7.0 Hz, 1H), 2.42 (s, 3H), 1.61-1.46 (m, 2H), 1.46-1.37 (m, 1H), 1.35-1.23 (m, 1H), 13 1.19 (d, J = 6.9 Hz, 3H). C NMR (125 MHz, CDCl3): δ = 146.9, 143.5, 137.1, 129.8, 128.5, 127.2, 127.0, 126.2, 43.4, 39.7, 35.2, 27.9, 22.5, 21.7.
N-(4,4-Diphenylbutyl)-4-methylbenzenesulfonamide (14n)
312 Part IV Iodine(I/III) Catalysis for Selective C(sp3)-H Amination
Prepared according to the general procedure GP1, 14n was isolated as a white solid with an overall yield of 71%. The NMR spectra match those previously described in literature.158 1H NMR (400 MHz,
CDCl3): δ = 7.74 (d, J = 8.2 Hz, 2H), 7.30-7.26 (m, 6H), 7.20-7.17 (m, 6H), 4.58 (t, J = 6.0 Hz, 1H), 3.82 (t, J = 7.9 Hz, 1H), 2.97 (q, J = 6.8 Hz, 2H), 2.44 (s, 3H), 2.06-2.00 (m, 2H), 1.47-1.40 (m, 2H). 13C NMR (125 MHz, CDCl3): δ = 144.6, 143.4, 137.0, 129.8, 128.6, 127.8, 127.2, 126.3, 50.9, 43.2, 32.6, 28.2, 21.6.
N-(2-(2,3-Dihydro-1H-inden-2-yl)ethyl)-4- methylbenzenesulfonamide (14o)
Prepared according to the general procedure GP2, 14o was isolated as a white solid with an overall yield of 80%. The NMR spectra match those previously 158 1 described in literature. H NMR (400 MHz, CDCl3): δ = 7.77 (d, J = 8.3 Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H), 7.18-7.07 (m, 4H), 4.73 (brs, 1H), 3.05-2.94 (m, 4H), 2.56-2.45 (m, 3H), 2.43 (s, 3H), 1.67 (q, J = 7.1 13 Hz, 2H). C NMR (101 MHz, CDCl3): δ = 143.5, 142.9, 137.1, 129.9, 127.2, 126.3, 124.5, 42.3, 39.0, 37.4, 35.5, 21.6.
4-Methyl-N-(2-(1,2,3,4-tetrahydronaphthalen-2- yl)ethyl)benzenesulfonamide (14p)
Prepared according to the general procedure GP2, 14p was isolated as a white solid with an overall yield of 88%. The NMR spectra match those previously 158 1 described in literature. H NMR (400 MHz, CDCl3): δ = 7.77 (d, J = 8.3 Hz, 2H), 7.30 (d, J = 8.2 Hz, 2H), 7.09-7.03 (m, 3H), 7.00- 6.98 (m, 1H), 4.56 (t, J = 6.9 Hz, 1H), 3.07 (q, J = 6.9 Hz, 2H), 2.76-2.71 (m, 3H), 2.42 (s, 3H), 2.35 (dd, J = 16.7, 10.1 Hz, 1H), 1.86-1.80 (m, 1H), 1.78-1.69 (m, 1H), 1.52 (qd, J = 7.0, 1.6 Hz, 2H), 1.34 (dtd, J = 12.8, 10.5, 6.4 Hz, 1H). 13C NMR (125 MHz, CDCl3): δ = 143.6, 137.0, 136.5, 135.9, 129.9, 129.2, 128.9, 127.2, 125.8, 125.7, 41.1, 36.1, 35.8, 31.6, 29.2, 28.9, 21.7.
N-(2-Butylphenethyl)-4-methylbenzenesulfonamide (14q)
313 Part IV Iodine(I/III) Catalysis for Selective C(sp3)-H Amination
Prepared according to the general procedure GP3, 14q was isolated as a yellow oil with an overall yield of 55%. 1H
NMR (400 MHz, CDCl3): δ = 7.81 (d, J = 8.1 Hz, 1H), 7.30- 7.22 (m, 3H), 7.12-7.07 (m, 4H), 4.30 (brt, J = 6.7 Hz, 1H), 3.19 (q, J = 6.7 Hz, 2H), 2.82-2.73 (m, 4H), 2.38 (s, 3H), 1.61- 1.49 (m, 2H), 1.41-1.31 (m, 2H), 0.92 (t, J = 7.3 Hz, 3H). 13C NMR (125 MHz,
CDCl3): δ = 143.4, 142.1, 137.8, 134.5, 132.1, 129.9, 128.9, 128.8, 126.9, 126.6, 44.2, 35.9, 33.5, 32.6, 23.0, 21.5, 14.1. IR ν(cm-1): 3292, 2956, 2945, 2870, 1434, 1317, + 1156, 1139, 656. HRMS (m/z): [M+H] calculated for C19H26NO2S: 332.1679; found: 332.1676.
2-Benzyl-N-methylbenzenesulfonamide (14r)
Prepared according to the general procedure GP4, 14r was isolated as a yellow solid with an overall yield of 67%. 1H NMR (400 MHz, CDCl3): δ = 8.02 (dd, J = 7.9, 1.5 Hz, 1H), 7.55 (td, J = 7.5, 1.5 Hz, 1H), 7.40 (ddd, J = 15.9, 8.0, 1.4 Hz, 2H), 7.34-7.28 (m, 2H), 7.26-7.22 (m, 1H), 7.16 (d, J = 6.8 Hz, 2H), 4.47 (s, 2H), 3.40 (d, J = 5.6 Hz, 1H), 2.20 (d, J = 5.4 Hz, 2H). 13C NMR
(125 MHz, CDCl3): δ = 139.8, 139.2, 136.5, 133.5, 132.9, 131.1, 128.9, 128.8, 126.9, 39.1, 29.3. IR ν(cm-1): 3304, 3063, 3058, 3028, 2961, 2936, 1475, 1441, 1317, 1299, + 1155, 1083, 692, 588. HRMS (m/z): [M+Na] calculated for C14H15NNaO2S: 284.0716; found: 284.0710. mp: 76-77 ºC.
2-Benzyl-N-ethylbenzenesulfonamide (14s)
Prepared according to the general procedure GP4, 14s was isolated as a brownish oil with an overall yield of 50%. 1H
NMR (400 MHz, CDCl3): δ = 8.02 (dd, J = 8.2, 1.3 Hz, 1H), 7.55 (td, J = 7.6, 1.5 Hz, 1H), 7.42-7.38 (m, 2H), 7.34-7.30 (m, 2H), 7.27-7.25 (m, 1H), 7.20-7.17 (m, 2H), 4.48 (s, 2H), 3.32 (t, J = 6.0 Hz, 1H), 2.54 (qd, J = 7.2, 6.0 Hz, 2H), 0.66 (t, J = 13 7.2 Hz, 3H). C NMR (125 MHz, CDCl3): δ = 139.9, 138.9, 137.6, 133.6, 132.9, 130.9, 129.1, 128.9, 127.1, 126.9, 39.1, 38.1, 14.4. IR ν(cm-1): 3308, 3063, 3027, 2979, 2936, 2876, 1452, 1319, 1155, 750, 690, 589. HRMS (m/z): [M-H]- calculated for C15H16NO2S: 274.0907; found: 274.0898.
3,4,5,6-Tetrahydro-2H-benzo[g][1,2]thiazocine 1,1-dioxide (14t)
314 Part IV Iodine(I/III) Catalysis for Selective C(sp3)-H Amination
Prepared according to the procedure described above, 14t was isolated as white solid with an overall yield of 45%. The NMR spectra match those previously described in 158 1 literature. H NMR (400 MHz, CDCl3): δ = 8.01 (dd, J = 7.9, 1.4 Hz, 1H), 7.47 (td, J = 7.5, 1.5 Hz, 1H), 7.33-7.29 (m, 2H), 4.40 (t, J = 7.0 Hz, 1H), 3.45-3.41 (m, 2H), 3.38-3.27 (m, 2H), 1.88 (p, J = 6.7 Hz, 13 2H), 1.52 (dddd, J = 10.0, 6.2, 4.9, 1.8 Hz, 2H). C NMR (125 MHz, CDCl3): δ = 142.2, 140.0, 132.8, 132.1, 128.1, 126.6, 41.8, 30.8, 29.5, 27.5.
N-(4-Methoxy-2,2-dimethylbutyl)-4-methylbenzenesulfonamide (14u)
Prepared according to the general procedure GP1, 14u was isolated as a white solid with an overall yield of 58%. The NMR spectra match those previously 158 1 described in literature. H NMR (400 MHz, CDCl3): δ = 7.69 (d, J = 8.2 Hz, 2H), 7.29 (d, J = 7.8 Hz, 2H), 5.37 (t, J = 7.1 Hz, 1H), 3.35-3.32 (m, 2H), 3.24 (s, 3H), 2.61 (d, J = 6.8 Hz, 2H), ), 2.41 (s, 3H), 1.48 (dd, J = 6.0, 5.2 Hz, 13 2H), 0.89 (s, 6H). C NMR (125 MHz, CDCl3): δ = 143.1, 137.4, 129.7, 127.1, 69.4, 58.7, 52.9, 39.5, 33.6, 26.4, 21.5.
N-(2,2-Dimethyl-5-phenylpentyl)-4-methylbenzenesulfonamide (14v)
Prepared according to the general procedure GP1, 14v was isolated as a yellow oil with an overall yield of 89%. The NMR spectra match those previously 158 1 described in literature. H NMR (400 MHz, CDCl3): δ = 7.74 (d, J = 8.2 Hz, 2H), 7.30 (d, J = 8.3 Hz, 2H), 7.27-7.26 (m, 2H), 7.19-7.16 (m, 1H), 7.14- 7.13 (m, 2H), 4.48 (t, J = 6.9 Hz, 1H), 2.67 (d, J = 6.8 Hz, 2H), 2.53 (t, J = 7.7 Hz, 2H), 2.42 (s, 3H), 1.52-1.45 (m, 2H), 1.25-1.21 (m, 2H), 0.83 (s, 6H). 13C
NMR (125 MHz, CDCl3): δ = 143.4, 142.5, 137.2, 129.8, 128.4, 127.2, 125.9, 53.0, 39.1, 36.6, 33.9, 25.9, 25.0, 21.6.
4-Methyl-N-((3- Phenylpropyl)cyclohexyl)methyl)benzenesulfonamide (14w)
Prepared according to the general procedure GP1, 14w was isolated as a colorless oil with an overall yield of 78%. The NMR spectra match those
315 Part IV Iodine(I/III) Catalysis for Selective C(sp3)-H Amination
230 1 previously described in literature. H NMR (300 MHz, CDCl3): δ = 7.76 (d, J = 8.4 Hz, 2H), 7.35-7.24 (m, 4H), 7.24-7.19 (m, 1H), 7.18-7.12 (m, 2H), 4.37 (bs, 1H), 2.75 (d, J = 6.4 Hz, 2H), 2.53 (t, J = 7.3 Hz, 2H), 2.43 (s, 3H), 13 1.49-1.16 (m, 14H). C NMR (75 MHz, CDCl3): δ = 143.4, 142.6, 137.1, 129.8, 128.4, 128.5, 127.2, 125.9, 49.1, 36.6, 35.9, 34.9, 33.6, 26.2, 24.7, 21.7, 21.4.
N-(2,2-Dimethylhexyl)-4-methylbenzenesulfonamide (14x)
Prepared according to the general procedure GP1, 14x was isolated as a yellow oil with an overall yield of 60%. The NMR spectra match those previously described in 158 1 literature. H NMR (400 MHz, CDCl3): δ = 7.75 (d, J = 8.3 Hz, 2H), 7.30 (d, J = 8.2 Hz, 2H), 4.67 (6.8 Hz, 1H), 2.66 (d, J = 6.8 Hz, 2H), 2.42 (s, 3H), 1.25-1.16 (m, 2H), 1.13-1.06 (m, 4H), 0.84 (t, J = 7.3 Hz, 3H), 0.82 (s, 6H). 13C
NMR (125 MHz, CDCl3): δ = 14.2, 21.6, 23.5, 25.0, 25.9, 33.8, 39.4, 53.1, 127.2, 129.8, 137.2, 143.4.
N-(2-Ethyl-7-phenylheptyl)-4-methylbenzenesulfonamide (14y)
Prepared according to the general procedure GP1, 14y was isolated as a white solid with an overall yield of 58%. 1H NMR (400 MHz,
CDCl3): δ = 7.75-7.71 (m, 2H), 7.27-7.23 (m, 4H), 7.17-7.13 (m, 3H), 4.63 (brs, 1H), 2.80 (t, J = 6.1 Hz, 2H), 2.54 (dd, J = 7.6 Hz, 2H), 2.38 (s, 3H), 1.59-1.47 (m, 2H), 1.37-1.11 (m, 9H), 0.75 (t, J = 7.3 Hz, 3H). 13C NMR (125 MHz,
CDCl3): δ = 143.4, 142.8, 137.1, 129.8, 128.5, 128.4, 127.2, 125.7, 45.9, 39.3, 36.0, 31.5, 31.0, 29.6, 26.5, 24.0, 21.6, 10.8. IR (cm-1): 3260, 2965, 2925, 2874, 2851, 1416, 1321, 1305, 1163, 1093, 703, 553. HRMS (m/z): [M+H]+ calculated for
C22H32NO2S: 374.2148; found: 374.2139. mp: 83-85ºC.
4-Methyl-N-(2,2,4-trimethylpentyl)benzenesulfonamide (14z)
Prepared according to the general procedure GP1, 14z was isolated as a white solid with an overall yield of 70%. The NMR spectra match those previously 158 1 described in literature. H NMR (400 MHz, CDCl3): δ = 7.74 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 7.8 Hz, 2H), 4.40 (brt, J = 6.9 Hz, 1H), 2.67 (d, J = 6.8 Hz, 2H), 2.42 (s, 3H), 1.59 (dddd, J = 9.6, 6.7, 4.8, 3.5 Hz, 1H), 1.10 (d, J = 5.5
230 H. Zhang, K. Muñiz, ACS Catal. 2017, 7, 4122–4125.
316 Part IV Iodine(I/III) Catalysis for Selective C(sp3)-H Amination
13 Hz, 2H), 0.87-0.85 (m, 12H). C NMR (125 MHz, CDCl3): δ = 143.4, 137.2, 129.8, 127.2, 54.0, 48.5, 34.6, 25.4, 24.1, 21.7.
N-(2-(Methoxymethyl)phenethyl)-4-methylbenzenesulfonamide (16)
Prepared according to the general procedure GP3, 16 was isolated as a yellow solid with an overall yield of 38%. 1H NMR (400 MHz, CDCl3): δ = 7.53 (d, J = 8.3 Hz, 2H), 7.27- 7.25 (m, 1H), 7.20-7.14 (m, 4H), 7.05- 7.01 (m, 1H), 5.63 (t, J = 5.1 Hz, 1H), 4.40 (s, 2H), 3.43 (s, 3H), 3.20 (td, J = 6.5, 5.1 Hz, 2H), 2.82 (t, 13 J = 6.5 Hz, 2H), 2.38 (s, 3H). C NMR (125 MHz, CDCl3): δ = 142.9, 137.9, 136.9, 135.8, 130.6, 130.0, 129.6, 129.1, 127.1, 126.8, 73.3, 58.3, 44.2, 31.8, 21.6. IR ν(cm-1): 3253, 2971, 2945, 2925, 2852, 1434, 1320, 1150, 1060, 814, 747, 665, 547. + HRMS (m/z): [M+Na] calculated for C17H21NNaO3S. 342.1134; found: 342.1128. mp: 72-73 ºC.
N-(4-(4-(1-Hydroxycyclododecyl)phenyl)-2,2-dimethylbutyl)-4- methylbenzenesulfonamide (19a)
Prepared according to the general procedure GP5, 19a was isolated as a white solid with a yield of 60%. 1H NMR
(400 MHz, CDCl3): δ = 7.74 (d, J = 8.2 Hz, 2H), 7.36 (d, J = 8.2 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), 7.09 (d, J = 8.2 Hz, 2H), 4.42 (t, J = 6.9 Hz, 1H), 2.74 (d, J = 7.0 Hz, 2H), 2.50-2.45 (m 2H), 2.42 (s, 3H), 1.87-1.83 (m, 4H), 1.51-1.47 (m, 2H), 1.39-1.28 13 (m, 18H), 0.92 (s, 6H). C NMR (125 MHz, CDCl3): δ = 146.0, 143.5, 140.9, 137.1, 129.9, 127.9, 127.2, 125.4, 76.4, 53.0, 41.6, 35.6, 34.2, 29.9, 26.5, 26.2, 25.0, 22.7, 22.4, 21.7, 20.1. IR ν(cm-1): 3286, 2927, 2862, 1470, 1324, 1160, 1076, 813, + 661, 551. HRMS (m/z): [M+Na] calculated for C31H47NNaO3S: 536.3169; found: 536.3155. mp: 72-73 ºC.
N-(4-(4-(1-Hydroxycyclopentadecyl)phenyl)-2,2-dimethylbutyl)-4- methylbenzenesulfonamide (19b)
317 Part IV Iodine(I/III) Catalysis for Selective C(sp3)-H Amination
Prepared according to the general procedure GP5, 19a was isolated as a yellow oil with a yield of 55%. 1H NMR (400 MHz, CDCl3): δ = 7.73 (d, J = 8.3 Hz, 2H), 7.37 (d, J = 8.3 Hz, 2H), 7.31- 7.29 (m, 2H), 7.10 (d, J = 6.9 Hz, 2H), 4.33 (t, J = 6.9 Hz, 1H), 2.74 (d, J = 6.9 Hz, 2H), 2.50-2.46 (m, 2H), 2.42 (s, 3H), 1.92-1.85 (m, 2H), 1.80-1.72 (m, 2H), 1.52-1.48 (m, 2H), 1.37-1.34 (m, 20H), 13 1.25-1.20 (m, 4H), 0.92 (s, 6H). C NMR (125 MHz, CDCl3): δ = 145.9, 145.5, 140.9, 137.2, 129.9, 128.0, 127.2, 125.5, 76.5, 53.1, 41.6, 39.4, 34.2, 29.9, 27.9, 27.2, 26.9, 26.8, 26.6, 25.0, 22.2, 21.7. IR ν(cm-1): 3492, 3282, 2926, 2855, 1458, 1324, 1158, 1072, 813, 661. HRMS (m/z): [M+Na]+ calculated for
C34H53NNaO3S: 578.3638; found: 578.3648.
IV.5.4 Synthesis of the pyrrolidines 15a-z, 17, 18, 20a-b and 21a-b Synthesis of 15a-z, 18 and 20a-b (GP6)
A tube equipped with a stirrer bar was charged with mCPBA (0.44 mmol, 2.2 equiv.), molecular iodine (0.03 mmol, 15 mol%) and the corresponding substrate 14a-z or 16 or 19a-b (0.2 mmol, 1.0 equiv.). Then 1.0 mL of a 1:1 mixture of absolute CH3CN and t-BuOH was added. The solution was stirred at room temperature for 12 h under visible light irradiation. CH2Cl2 was then added and the residue washed with saturated aqueous solutions of Na2SO3 and NaHCO3 and extracted three times with CH2Cl2. The organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude product was purified by column chromatography (silica gel, hexane/ethyl acetate as eluent) to provide 15a-z, 18 or 20a-b.
Synthesis of 17 and 21a-b (GP7)
A flame-dried Schlenk tube equipped with a stirrer bar was charged with
PhI(mCBA)2 (0.4 mmol, 2.0 equiv.), molecular iodine (0.2 mmol, 1.0 equiv.) and the corresponding substrate 16 or 19a-b (0.2 mmol, 1.0 equiv.), evacuated, and backfilled with argon. 1.5 mL of absolute DCE were added. The solution was stirred at room temperature for 12 h under visible light irradiation. CH2Cl2 was added and the resulting solution washed with saturated aqueous solutions of Na2SO3 and NaHCO3 and extracted three
318 Part IV Iodine(I/III) Catalysis for Selective C(sp3)-H Amination
times with CH2Cl2. The combined organic layers were dried over anhydrous
Na2SO4 and solvents were evaporated under reduced pressure. The crude product was purified by column chromatography (silica gel, hexane/ethyl acetate as eluent) to provide 21a-b. Note: 15 mol% of molecular iodine was used instead for the synthesis of 17.
IV.5.5 Characterization of the pyrrolidines 15a-z, 17, 18, 20a-b and 21a-b 4,4-Dimethyl-2-phenyl-1-tosylpyrrolidine (15a)
Prepared according to the general procedure GP6, 15a was isolated as a white solid with a yield of 98%. The NMR spectra match those previously described in literature.158 1 H NMR (500 MHz, CDCl3): δ = 7.53 (d, J = 8.3 Hz, 2H), 7.24-7.26 (m, 4H), 7.19-7.23 (m, 3H), 4.70 (dd, J = 9.4, 7.3 Hz, 1H), 3.44 (dd, J = 10.4, 1.5 Hz, 1H), 3.34 (d, J = 10.4, Hz, 1H), 2.39 (s, 3H), 2.02 (ddd, J = 12.8, 7.3, 1.5 Hz, 1H), 1.72 (dd, J = 12.8, 9.4 Hz, 1H), 1.05 (s, 3H), 0.77 (s, 3H). 13C
NMR (125 MHz, CDCl3): δ = 143.1, 143.0, 135.9, 129.4, 128.4, 127.5, 127.2, 126.6, 63.9, 62.0, 51.7, 38.3, 26.2, 25.8, 21.6.
4,4-Dimethyl-2-(p-tolyl)-1-tosylpyrrolidine (15b)
Prepared according to the general procedure GP6, 15b was isolated as a white solid with a yield of 96%. The NMR spectra match those previously described in 158 1 literature. H NMR (500 MHz, CDCl3): δ = 7.55 (d, J = 8.2 Hz, 2H), 7.21 (d, J = 8.6 Hz, 2H), 7.17 (d, J = 8.1 Hz, 2H), 7.07 (d, J = 8.2 Hz, 2H), 4.65 (dd, J = 9.4, 7.2 Hz, 1H), 3.42 (dd, J = 10.4, 1.4 Hz, 1H), 3.34 (dd, J = 10.3, 0.8 Hz, 1H), 2.40 (s, 3H), 2.32 (s, 3H), 1.99 (ddd, J = 12.8, 7.2, 1.4 Hz, 1H), 1.72 (dd, J = 12.8, 9.4 Hz, 1H), 1.05 (s, 3H), 0.74 (s, 3H). 13C NMR (125
MHz, CDCl3): δ = 143.0, 140.0, 136.7, 135.8, 129.4, 129.0, 127.5, 126.5, 63.7, 61.9, 51.6, 38.1, 26.2, 25.8, 21.6, 21.2.
2-(4-Fluorophenyl)-4,4-dimethyl-1-tosylpyrrolidine (15c)
Prepared according to the general procedure GP6, 15c was isolated as a white solid with a yield of 83%. The NMR spectra match those previously described in
319 Part IV Iodine(I/III) Catalysis for Selective C(sp3)-H Amination
158 1 literature. H NMR (500 MHz, CDCl3): δ = 7.53 (d, J = 8.1 Hz, 2H), 7.21- 7.23 (m, 4H), 6.92-6.96 (m, 2H), 4.68 (ddd, J = 9.1, 7.2 1.8 Hz, 1H), 3.43 (dt, J = 10.5, 1.6 Hz, 1H), 3.33 (d, J = 10.5 Hz, 1H), 2.40 (s, 3H), 2.00 (ddt, J = 13.1, 7.3, 1.5 Hz, 1H), 1.68 (dd, J = 12.8, 9.5 Hz, 1H), 1.05 (d, J = 1.8 Hz, 3H), 0.76 (d, J = 13 3.4 Hz, 3H). C NMR (125 MHz, CDCl3): δ = 162.0 (d, JC-F = 244.9), 143.3, 138.8, 135.9, 129.5, 129.2, 127.5, 115.2 (d, JC-F = 21.5 Hz), 63.3, 61.9, 51.7, 38.2, 19 26.2, 25.8, 21.6. F NMR (376 MHz, CDCl3): δ = -115.9.
2-(4-Chlorophenyl)-4,4-dimethyl-1-tosylpyrrolidine (15d)
Prepared according to the general procedure GP6, 15d was isolated as a white solid with a yield of 82%. The NMR spectra match those previously described in 158 1 literature. H NMR (500 MHz, CDCl3): δ = 7.54 (d, J = 8.2 Hz, 2H), 7.21-7.24 (m, 6H), 4.65 (dd, J = 9.3, 7.3 Hz, 1H), 3.42 (dd, J = 10.5, 1.4 Hz, 1H), 3.33 (d, J = 10.4 Hz, 1H), 2.41 (s, 3H), 2.00 (ddd, J = 12.8, 7.3, 1.4 Hz, 1H), 1.66 (dd, J = 12.8, 9.4 Hz, 1H), 1.04 (s, 3H), 0.74 (s, 3H). 13C NMR (125 MHz, CDCl3): δ = 143.4, 141.6, 135.6, 132.8, 129.5, 128.5, 127.9, 127.5, 63.3, 61.9, 51.5, 38.2, 26.2, 25.8, 21.6.
2-(4-Bromophenyl)-4,4-dimethyl-1-tosylpyrrolidine (15e)
Prepared according to the general procedure GP6, 15e was isolated as a white solid with a yield of 73%. The NMR spectra match those previously described in 158 1 literature. H NMR (500 MHz, CDCl3): δ = 7.54 (d, J = 8.2 Hz, 2H), 7.37 (d, J = 8.4 Hz, 2H), 7.23 (d, J = 8.1 Hz, 2H), 7.15 (d, J = 8.4 Hz, 2H), 4.63 (dd, J = 9.3, 7.3 Hz, 1H), 3.41 (d, J = 10.5 Hz, 1H), 3.33 (d, J = 10.4 Hz, 1H), 2.40 (s, 3H), 1.99 (ddd, J = 12.9, 7.3, 1.5 Hz, 1H), 1.66 (dd, J = 12.7, 9.4 13 Hz, 1H), 1.04 (s, 3H), 0.73 (s, 3H). C NMR (125 MHz, CDCl3): δ = 143.4, 142.2, 135.5, 131.4, 129.5, 128.3, 127.5, 120.9, 63.3, 61.9, 51.4, 38.2, 26.2, 25.7, 21.6.
2-(4-Methoxyphenyl)-4,4-dimethyl-1-tosylpyrrolidine (15f)
Prepared according to the general procedure GP6, 15f was isolated as a white solid with a yield of 99%. The NMR spectra match those previously described 158 1 in literature. H NMR (500 MHz, CDCl3): δ = 7.51 (d, J = 8.2 Hz, 2H), 7.20 (d, J = 8.1 Hz, 2H), 7.18 (d, J = 8.7 Hz, 2H), 6.79 (d, J = 8.7 Hz, 2H), 4.66 (dd, J = 9.4, 7.2 Hz, 1H), 3.78 (s, 3H), 3.43 (dd, J = 10.4,
320 Part IV Iodine(I/III) Catalysis for Selective C(sp3)-H Amination
1.5 Hz, 1H), 3.32 (d, J = 10.4 Hz, 1H), 2.39 (s, 3H), 1.98 (ddd, J = 12.9, 7.3, 1.5 Hz, 1H), 1.71 (dd, J = 12.8, 9.5 Hz, 1H), 1.05 (s, 3H), 0.77 (s, 3H). 13C NMR (125
MHz, CDCl3): δ = 158.8, 142.9, 136.1, 134.9, 129.4, 127.8, 127.4, 113.8, 63.4, 61.9, 55.4, 51.6, 38.0, 26.2, 25.8, 21.6.
4,4-Dimethyl-2-(4-(phenylethynyl)phenyl)-1-tosylpyrrolidine (15g)
Prepared according to the general procedure GP6, 15g was isolated as a colorless oil with a yield of 77%. The NMR spectra match those previously described in literature.158 1H NMR (400 MHz, CDCl3): δ = 7.56-7.52 (m, 4H), 7.42 (d, J = 8.2 Hz, 2H), 7.38-7.34 (m, 3H), 7.25-7.22 (m, 4H), 4.72 (dd, J = 9.3, 7.3 Hz, 1H), 3.45 (d, J = 10.5 Hz, 1H), 3.34 (d, J = 10.4 Hz, 1H), 2.41 (s, 3H), 2.02 (ddd, J = 12.8, 7.3, 1.5 Hz, 1H), 1.70 (dd, J = 12.8, 9.3 Hz, 1H), 1.06 (s, 3H), 0.78 (s, 3H). 13C NMR (125 MHz, CDCl3): δ = 143.4, 135.9, 131.7, 131.6, 131.5, 129.5, 128.5, 128.3, 127.5, 126.2, 123.5, 122.1, 89.5, 89.3, 63.7, 61.9, 51.4, 38.4, 26.2, 25.8, 21.7.
4,4-Dimethyl-1-((4-nitrophenyl)sulfonyl)-2-phenylpyrrolidine (15h)
Prepared according to the general procedure GP6, 15h was isolated as a white solid with a yield of 63%. The NMR spectra match those previously described in literature.158 1 H NMR (400 MHz, CDCl3): δ = 8.11 (d, J = 8.8 Hz, 2H), 7.57 (d, J = 8.8 Hz, 2H), 7.15-7.20 (m, 3H), 7.09-7.11 (m, 2H), 4.87 (dd, J = 9.8, 7.2 Hz, 1H), 3.66 (dd, J = 9.9, 1.7 Hz, 1H), 3.30 (dd, J = 10.0, 0.9 Hz, 1H), 2.15 (ddd, J = 12.9, 7.3, 1.6 Hz, 1H), 1.79 (ddd, J = 13.1, 9.9, 0.9 Hz, 1H), 1.13 (s, 3H), 13 1.03 (s, 3H). C NMR (125 MHz, CDCl3): δ = 149.6, 145.9, 141.4, 128.5, 128.1, 127.8, 127.2, 123.8, 64.1, 61.9, 51.4, 38.6, 25.8, 25.7.
3-Phenyl-2-tosyl-2-azaspiro[4.5]decane (15i)
Prepared according to the general procedure GP6, 15i was isolated as a white foam with a yield of 99%. The NMR spectra match those previously described in 158 1 literature. H NMR (500 MHz, CDCl3): δ = 7.59 (d, J = 8.2 Hz, 2H), 7.28-7.30 (m, 4H), 7.22-7.27 (m, 3H), 4.64 (dd, J = 9.4, 7.3 Hz, 1H), 3.64 (dd, J = 10.8, 1.4 Hz, 1H), 3.32 (d, J = 10.8 Hz, 1H), 2.42 (s, 3H), 2.13 (ddd, J = 13.0, 7.4, 1.4 Hz, 1H), 1.67 (dd, J = 13.0, 9.4 Hz, 13 1H), 1.28-1.45 (m, 9H), 1.01-1.05 (m, 1H). C NMR (125 MHz, CDCl3): δ =
321 Part IV Iodine(I/III) Catalysis for Selective C(sp3)-H Amination
143.1, 143.0, 135.5, 129.3, 128.3, 127.4, 127.0, 126.4, 63.1, 59.3, 49.6, 41.9, 36.4, 33.9, 25.9, 23.8, 22.8, 21.5.
(±)-(2S,4S)-4-Methyl-2-phenyl-1-tosylpyrrolidine and (±)-(2R,4S)-4- methyl-2-phenyl-1- tosylpyrrolidine (15j)
Prepared according to the general procedure GP6, 15j was isolated as a non-separable 1:1 mixture of diastereoisomers as a white solid with a yield of 94%. The NMR spectra match those previously described in literature.158 1H NMR
(500 MHz, CDCl3): δ = 7.70 (d, J = 8.2 Hz, 4H), 7.63 (d, J = 8.2 Hz, 4H), 7.13- 7.34 (m, 10H), 4.87 (dd, J = 8.4, 2.4 Hz, 1H), 4.67 (dd, J = 9.5, 7.2 Hz, 1H), 3.86 (ddd, J = 11.1, 7.3, 1.4 Hz, 1H), 3.76 (ddd, J = 9.4, 6.9, 0.8 Hz, 1H), 3.11 (t, J = 10.8 Hz, 1H), 2.90 (t, J = 9.3 Hz, 1H), 2.45 (s, 3H), 2.44 (s, 3H), 2.33-2.42 (m, 2H), 1.80-1.94 (m, 2H), 1.61 (ddd, J = 12.3, 10.6, 8.4 Hz, 1H), 1.50 (ddd, J = 12.7, 11.4, 9.5 Hz, 1H), 0.97 (d, J = 6.5 Hz, 3H), 0.90 (d, J = 6.6 Hz, 3H). 13C
NMR (125 MHz, CDCl3): δ = 143.4, 143.3, 143.2, 143.1, 135.7, 134.9, 129.6, 128.4, 128.3, 127.6, 127.5, 127.2, 127.0, 126.4, 126.2, 64.7, 63.3, 57.8, 55.9, 45.7, 43.6, 33.5, 31.4, 21.7, 21.6, 16.9, 16.7.
(±)-(2S,4S)/(2R,4S)-4-Methyl-N-(2- phenethylhexyl)benzenesulfonamide (2z/2z’) (15k)
Prepared according to the general procedure GP6, 15k was isolated as a non-separable 1:1 mixture of diastereoisomers as a pale yellow oil with a yield of 1 67%. H NMR (400 MHz, CDCl3): δ = 7.70 (d, J = 8.3 Hz, 4H), 7.62 (d, J = 8.3 Hz, 4H), 7.35-7.19 (m, 10H), 4.86 (dd, J = 8.5, 2.3 Hz, 1H), 4.64 (dd, J = 9.6, 7.2 Hz, 1H), 3.89 (ddd, J = 11.1, 7.3, 1.3 Hz, 1H), 3.78 (dd, J = 9.4, 7.0 Hz, 1H), 3.13 (t, J = 10.8 Hz, 1H), 2.93 (t, J = 9.3 Hz, 1H), 2.45 (s, 3H), 2.44 (s, 3H), 2.43-2.37 (m, 1H), 2.25 (d, J = 10.8 Hz, 1H), 1.92 (ddd, J = 12.3, 6.0, 2.3 Hz, 1H), 1.75 (td, J = 6.9, 3.5 Hz, 1H), 1.68-1.41 (m, 2H), 1.39-1.11 13 (m, 12H), 0.86 (dt, J = 8.7, 6.9 Hz, 6H). C NMR (125 MHz, CDCl3): δ = 143.4, 143.3, 143.2,143.2, 143.1, 143.0, 64.4, 63.0, 55.4, 54.5, 44.0, 41.8, 38.8, 36.8, 32.4, 32.0, 30.4, 30.3, 22.7, 22.6, 21.5, 13.9. IR ν(cm-1): 2923, 1345, 1157, 1092, + 699, 588, 544. HRMS (m/z): [M+H] calculated. for C21H28NO2S: 358.1835; found: 358.1840.
2-Phenyl-1-tosylpyrrolidine (15l)
322 Part IV Iodine(I/III) Catalysis for Selective C(sp3)-H Amination
Prepared according to the general procedure GP6, 15l was isolated as a yellow solid with a yield of 54%. The NMR spectra match those previously described in literature.158 1H NMR (400 MHz, CDCl3): δ = 7.70 (d, J = 8.3 Hz, 2H), 7.34- 7.24 (m, 7H), 4.81 (dd, J = 7.9, 3.6 Hz, 1H), 3.69-3.60 (m, 1H), 3.45 (dt, J = 10.2, 7.2 Hz, 1H), 2.45 (s, 3H), 2.05-1.96 (m, 1H), 1.93-1.80 (m, 2H), 1.72-1.65 13 (m, 1H). C NMR (125 MHz, CDCl3): δ = 143.4, 143.1, 135.2, 129.7, 128.4, 127.6, 127.1, 126.2, 63.4, 49.5, 35.9, 24.1, 21.6.
2-Methyl-2-phenyl-1-tosylpyrrolidine (15m)
Prepared according to the general procedure GP6, 15m was isolated as a colorless oil with a yield of 36%. The NMR spectra match those previously described in literature.158 1H
NMR (500 MHz, CDCl3): δ = 7.58 (d, J = 8.3 Hz, 2H), 7.41- 7.38 (m, 2H), 7.32-7.27 (m, 2H), 7.24- 7.21 (m, 3H), 3.70 (ddd, J = 9.1, 6.9, 5.4 Hz, 1H), 3.55 (dt, J = 9.1, 7.3 Hz, 1H), 2.41 (s, 3H), 2.18-2.10 (m, 1H), 2.04-1.93 13 (m, 1H), 1.89 (s, 3H), 1.87-1.80 (m, 2H). C NMR (125 MHz, CDCl3): δ = 146.6, 142.7, 138.6, 129.4, 128.1, 127.2, 126.7, 125.9, 70.0, 49.9, 45.9, 26.5, 22.6, 21.6.
2,2-Diphenyl-1-tosylpyrrolidine (15n)
Prepared according to the general procedure GP6, 15n was isolated as a white solid with a yield of 84%. The NMR spectra match those previously described in literature.158 1H NMR (500 MHz, CDCl3): δ = 7.35-7.32 (m, 4H), 7.27-7.23 (m, 6H), 6.99-6.97 (m, 2H), 6.86 (d, J = 8.3 Hz, 2H), 3.82 (t, J = 6.8 Hz, 2H), 2.60 (t, J = 6.7 Hz, 2H), 2.35 (s, 3H), 1.83 (q, J = 6.8 Hz, 2H). 13C
NMR (125 MHz, CDCl3): δ = 142.8, 142.1, 138.3, 129.6, 128.9, 127.6, 127.1, 126.7, 76.1, 50.5, 46.3, 22.8, 21.6.
1-Tosyl-1,2,3,3a,4,8b-hexahydroindeno[1,2-b]pyrrole (15o)
Prepared according to the general procedure GP6, 15o was isolated as a white foam with a yield of 96%. The NMR spectra match those previously described in literature.158 1H
NMR (500 MHz, CDCl3): δ = 7.78-7.83 (m, 3H), 7.34 (d, J = 8.0 Hz, 2H), 7.24-7.28 (m, 2H), 7.15-7.17 (m, 1H), 5.15 (d, J = 7.8 Hz, 1H), 3.38 (ddd, J = 10.2, 7.2, 4.4 Hz, 1H), 3.23 (ddd, J = 10.2, 8.7, 6.7 Hz, 1H), 3.03 (dd, J = 16.6, 8.0 Hz, 1H), 2.67-2.75 (m, 2H), 2.44 (s, 3H), 1.84 (dtd, J = 14.2, 7.1, 4.4
323 Part IV Iodine(I/III) Catalysis for Selective C(sp3)-H Amination
13 Hz, 1H), 1.49-1.62 (m, 1H). C NMR (125 MHz, CDCl3): δ = 143.6, 142.0, 141.0, 135.0, 129.8, 128.3, 127.8, 127.4, 126.9, 125.0, 68.8, 49.3, 41.9, 35.9, 31.5, 21.6.
1-Tosyl-2,3,3a,4,5,9b-hexahydro-1H-benzo[g]indole (15p)
Prepared according to the general procedure GP6, 15p was isolated as a white solid with a yield of 85%. The NMR spectra match those previously described in literature.158 1H
NMR (500 MHz, CDCl3): δ = 7.94 (d, J = 7.8 Hz, 1H), 7.78 (d, J = 8.2 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 7.29-7.25 (m, 1H), 7.19-7.15 (m, 1H), 7.04 (dd, J = 7.7, 1.5 Hz, 1H), 4.82 (d, J = 7.5 Hz, 1H), 3.42-3.29 (m, 2H), 2.77- 2.69 (m, 1H), 2.58 (dt, J = 16.1, 5.4 Hz, 1H), 2.45 (s, 3H), 2.04-1.90 (m, 2H), 1.77-1.70 (m, 1H), 1.66-1.61 (m, 1H), 1.58-1.52 (m, 1H). 13C NMR (125 MHz, CDCl3): δ = 143.6, 137.6, 135.8, 135.3, 129.9, 129.8, 127.9, 127.7, 127.0, 126.7, 60.7, 48.0, 31.2, 29.0, 25.8, 24.2, 21.7.
1-Propyl-2-tosyl-1,2,3,4-tetrahydroisoquinoline (15q)
Prepared according to the general procedure GP6, 15q was isolated as a colorless oil with a yield of 40%. 1H NMR (400
MHz, CDCl3): δ = 7.58 (d, J = 8.3 Hz, 2H), 7.13-7.02 (m, 5H), 6.86 (d, J = 7.0 Hz, 1H), 4.97 (dd, J = 9.5, 4.9 Hz, 1H), 3.91- 3.76 (m, 1H), 3.47 (ddd, J = 14.3, 9.1, 7.1 Hz, 1H), 2.51 (dd, J = 8.9, 5.6 Hz, 2H), 2.31 (s, 3H), 1.81 (dtd, J = 14.0, 9.6, 5.3 Hz, 1H), 1.72-1.63 (m, 1H), 1.56-1.46 (m, 13 2H), 0.95 (t, J = 7.3 Hz, 3H). C NMR (125 MHz, CDCl3): δ = 143.0, 138.1, 137.1, 132.8, 129.4, 128.9, 127.1, 127.0, 126.6, 126.1, 56.7, 40.0, 38.9, 26.3, 21.5, 19.8, 13.9. IR ν(cm-1): 2957, 2932, 2871, 1333, 1158, 1089, 756, 660. HRMS + (m/z): [M+H] calculated for C19H24NO2S: 330.1522; found: 330.1519.
2-Methyl-3-phenyl-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (15r)
Prepared according to the general procedure GP6, 15r was isolated as a white solid with a yield of 63%. 1H NMR (400 MHz, CDCl3): δ = 7.89-7.79 (m, 1H), 7.55-7.45 (m, 2H), 7.42-7.35 (m, 3H), 7.33 (dd, J = 7.3, 2.4 Hz, 2H), 7.07-6.99 (m, 1H), 13 5.19 (s, 1H), 2.77 (s, 3H). C NMR (125 MHz, CDCl3): δ = 138.5, 136.7, 134.1, 133.1, 129.4, 129.3, 129.2, 128.2, 125.1, 121.1, 67.1, 27.5. IR ν(cm-1): 3069, 3029, 2925, 2853, 2820, 1455, 1290, 1163, 1125, 978, + 748, 659, 564. HRMS (m/z): [M+Na] calculated for C14H13NNaO2S: 282.0559; found: 282.0553. mp: 132-133 ºC.
324 Part IV Iodine(I/III) Catalysis for Selective C(sp3)-H Amination
2-Ethyl-3-phenyl-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (15s)
Prepared according to the general procedure GP6, 15s was isolated as a white solid with a yield of 85%. 1H NMR (400 MHz, CDCl3): δ = 7.84-7.80 (m, 1H), 7.51-7.48 (m, 2H), 7.41- 7.34 (m, 5H), 7.05-7.03 (m, 1H), 5.40 (s, 1H), 3.09 (dq, J = 14.7, 7.4 Hz, 1H), 3.17 (qd, J = 14.2, 7.1 Hz, 1H), 1.25 (t, J = 7.2 13 Hz, 3H). C NMR (125 MHz, CDCl3): δ = 138.3, 137.4, 134.2, 132.9, 129.3, 129.2, 129.0, 128.0, 125.0, 120.9, 64.7, 36.9, 13.5. IR ν(cm-1): 2976, 2927, 2875, 1452, + 1288, 1128, 767, 696, 564. HRMS (m/z): [M+H] calculated for C15H16NO2S: 274.0896; found: 274.0889. mp: 127-128 ºC.
1,2,3,9b-Tetrahydrobenzo[d]pyrrolo[1,2-b]isothiazole 5,5-dioxide (15t)
Prepared according to the general procedure GP6, 15t was isolated as a colorless oil with a yield of 70%. The NMR spectra match those previously described in literature.158 1H NMR
(400 MHz, CDCl3): δ = 7.75 (d, J = 8.4 Hz, 1H), 7.60 (td, J = 7.6, 1.2 Hz, 1H), 7.51 (t, J = 7.5 Hz, 1H), 7.36 (d, J = 8.6 Hz, 1H), 5.04-4.95 (m, 1H), 3.84-3.78 (m, 1H), 3.37 (dt, J = 10.9, 6.5 Hz, 1H), 2.47-2.42 (m, 1H), 2.02-1.85 13 (m, 3H). C NMR (125 MHz, CDCl3): δ = 140.1, 136.3, 133.2, 129.4, 124.0, 121.6, 65.2, 48.4, 32.5, 26.2.
2-Methoxy-4,4-dimethyl-1-tosylpyrrolidine (15u)
Prepared according to the general procedure GP6, 15u was isolated as a yellowish oil with a yield of 60%. The NMR spectra match those previously described in literature.158 1H NMR (500 MHz, CDCl3): δ = 7.73 (d, J = 8.3 Hz, 2H), 7.29 (d, J = 8.6 Hz, 2H), 5.14 (dd, J = 6.0, 1.9 Hz, 1H), 3.36 (s, 3H), 3.13 (d, J = 9.8 Hz, 1H), 3.06 (d, J = 9.8 Hz, 1H), 2.41 (s, 3H), 1.71 (dd, J = 13.3, 1.9 Hz, 1H), 1.62 (dd, J = 13.3, 6.0 Hz, 1H), 1.14 (s, 3H), 0.89 (s, 3H). 13C NMR (125 MHz, CDCl3): δ = 143.4, 136.6, 129.6, 127.4, 92.9, 60.3, 55.8, 46.7, 38.3, 28.2, 27.9, 21.6.
2-Benzyl-4,4-dimethyl-1-tosylpyrrolidine (15v)
325 Part IV Iodine(I/III) Catalysis for Selective C(sp3)-H Amination
Prepared according to the general procedure GP6, 15v was isolated as a white foam with a yield of 58%. The NMR spectra match those previously described in literature.158 1 H NMR (400 MHz, CDCl3): δ = 7.79 (d, J = 8.2 Hz, 2H), 7.33 (d, J = 8.0 Hz, 2H), 7.31-7.28 (m, 2H), 7.23-7-20 (m, 3H), 3.79 (dtd, J = 9.8, 7.8, 3.6 Hz, 1H), 3.58 (dd, J = 13.1, 3.6 Hz, 1H), 3.12 (s, 2H), 2.77 (dd, J = 13.1, 9.8 Hz, 1H), 2.43 (s, 3H), 1.52-1.43 (m, 2H), 0.98 (s, 3H), 0.46 (s, 3H). 13C NMR (125 MHz, CDCl3): δ = 143.4, 138.6, 135.4, 129.7, 129.6, 128.5, 127.6, 126.5, 61.8, 61.7, 45.9, 43.0, 37.3, 26.6, 25.9, 21.7.
3-Benzyl-2-tosyl-2-azaspiro[4.5]decane (15w)
Prepared according to the general procedure GP6, 15w was isolated as a white solid with a yield of 54%. 1H NMR
(400 MHz, CDCl3): δ = 0.77-0.57 (m, 2H), 1.54-1.01 (m, 10H), 2.43 (s, 3H), 2.77 (dd, J = 13.2, 9.7 Hz, 1H), 3.11-3.04 (m, 1H), 3.30 (d, J = 10.8 Hz, 1H), 3.54 (dd, J = 13.2, 3.5 Hz, 1H), 3.72 (ddd, J = 17.3, 8.0, 3.6 Hz, 1H), 7.24- 7.21 (m, 3H), 7.34-7.27 (m, 4H), 13 7.81-7.78 (m, 2H). C NMR (125 MHz, CDCl3): δ = 143.4, 138.7, 129.7, 128.5, 127.7, 126.5, 125.5, 60.8, 43.2, 41.3, 36.6, 34.3, 26.0, 23.8, 23.0, 21.7. IR ν(cm-1): 2924, 2852, 1451, 1339, 1157, 1088, 1033, 817, 660, 585, 549. HRMS (m/z): + [M+H] calculated for C23H30NO2S: 384.1992; found: 384.1982. mp: 87-90 ºC.
2-Ethyl-4,4-dimethyl-1-tosylpyrrolidine (15x)
Prepared according to the general procedure GP6, 15x was isolated as a white solid with a yield of 65%. The NMR spectra match those previously described in literature.158 1H NMR (400
MHz, CDCl3): δ = 7.73 (d, J = 8.2 Hz, 2H), 7.31 (d, J = 8.4 Hz, 2H), 3.55 (tdd, J = 9.1, 7.2, 3.3 Hz, 1H), 3.17-3.10 (m, 2H), 2.43 (s, 3H), 2.12 (dqd, J = 13.3, 7.6, 3.3 Hz, 1H), 1.75-1.67 (m, 1H), 1.64-1.53 (m, 1H), 1.44 (dd, J = 12.6, 8.8 Hz, 1H), 1.03 (s, 3H), 0.86 (t, J = 7.5 Hz, 3H), 0.54 (s, 3H). 13C NMR
(125 MHz, CDCl3): δ = 143.1, 135.9, 129.6, 127.5, 61.6, 45.7, 37.4, 29.1, 26.6, 26.0, 21.6, 9.8.
(±)-(2S,4S)/(2R,4S)-4-Ethyl-2-(3-phenylpropyl)-1-tosylpyrrolidine (15y)
326 Part IV Iodine(I/III) Catalysis for Selective C(sp3)-H Amination
Prepared according to the general procedure GP6, 15y was isolated as a non-separable 1:1 mixture of diastereoisomers as colorless oil with a yield of 69%. 1H NMR (400 MHz, CDCl3): δ = 7.73-7.68 (m, 4H), 7.34- 7.24 (m, 10H), 7.22-7.15 (m, 4H), 3.71- 3.56 (m, 4H), 2.86-2.80 (m, 1H), 2.70-2.58 (m, 4H), 2.43 (s, 6H), 2.18-1.80 (m, 4H), 1.73-1.58 13 (m, 6H), 1.37-1.18 (m, 6H), 0.91-0.79 (m, 9H). C NMR (125 MHz, CDCl3): δ = 143.3, 143.3, 142.6, 142.6, 135.8, 134.8, 129.8, 129.7, 128.6, 128.5, 128.2, 128.2, 127.7, 127.5, 125.9, 125.9, 61.1, 60.5, 54.6, 54.2, 40.1, 39.0, 38.5, 36.7, 36.6, 36.5, 36.1, 36.0, 28.9, 28.4, 27.8, 26.1, 25.6, 21.7, 12.7, 12.6. IR ν(cm-1): 2959, 2925, 1342, 1156, 1093, 1029, 662, 585, 549. HRMS (m/z): [M+Na]+ calculated for C22H29NNaO2S: 394.1811; found: 394.1796.
2,2,4,4-Tetramethyl-1-tosylpyrrolidine (15z)
Prepared according to the general procedure GP6, 15z was isolated as a colorless oil with a yield of 61%. The NMR spectra match those previously described in literature.158 1H NMR
(400 MHz, CDCl3): δ = 7.73 (d, J = 8.2 Hz, 2H), 7.27 (d, J = 7.7 Hz, 2H), 3.06 (s, 2H), 2.41 (s, 3H), 1.69 (s, 2H), 1.48 (s, 6H), 1.01 (s, 6H). 13C
NMR (125 MHz, CDCl3): δ = 142.7, 138.4, 129.4, 127.5, 65.7, 61.4, 57.1, 36.3, 29.9, 27.6, 21.6.
1-Methoxy-2-tosyl-1,2,3,4-tetrahydroisoquinoline (17)
Prepared according to the general procedure GP7, 17 was isolated as a colorless oil with a yield of 89%. 1H NMR (400 MHz, CDCl3): δ = 7.64 (d, J = 8.3 Hz, 2H), 7.31-7.28 (m, 1H), 7.23-7.16 (m, 4H), 7.00-6.96 (m, 1H), 5.96 (s, 1H), 3.76 (dddd, J = 13.7, 5.9, 3.0, 1.1 Hz, 1H), 3.54 (ddd, J = 13.7, 11.2, 4.9 Hz, 1H), 3.48 (s, 3H), 13 2.66-2.48 (m, 2H), 2.36 (s, 3H). C NMR (125 MHz, CDCl3): δ = 143.5, 137.9, 133.7, 133.3, 129.7, 128.8, 128.7, 128.5, 127.1, 126.6, 84.6, 55.7, 38.6, 26.9, 21.6. IR ν(cm-1): 3065, 3028, 2931, 2830, 1334, 1159, 1067, 917, 762, 660, 585. HRMS + (m/z): [M+Na] calculated for C17H19NNaO3S: 340.0978; found: 340.0972.
2-Tosyl-3,4-dihydroisoquinolin-1(2H)-one (18)
327 Part IV Iodine(I/III) Catalysis for Selective C(sp3)-H Amination
Prepared according to the general procedure GP6, 18 was isolated as a white solid with a yield of 99%. The NMR spectra match those previously described in literature.231 1H NMR (400 MHz, CDCl3): δ = 8.05-7.93 (m, 3H), 7.47 (td, J = 7.5, 1.4 Hz, 1H), 7.33-7.30 (m, 3H), 7.21 (d, J = 7.6 Hz, 1H), 4.23 (t, J = 6.2 Hz, 13 2H), 3.12 (t, J = 6.2 Hz, 2H), 2.41 (s, 3H). C NMR (125 MHz, CDCl3): δ = 163.5, 144.9, 139.4, 136.3, 133.6, 129.5, 129.3, 128.7, 128.3, 127.5, 127.3, 44.9, 29.1, 21.8.
1-(4-(4,4-Dimethyl-1-tosylpyrrolidin-2-yl)phenyl)cyclododecanol (20a)
Prepared according to the general procedure GP6, 20a was isolated as a colorless oil with a 1 yield of 60%. H NMR (400 MHz, CDCl3): δ = 7.52 (d, J = 8.3 Hz, 2H), 7.34 (d, J = 8.4 Hz, 2H), 7.21-7.17 (m, 4H), 4.71 (dd, J = 9.4, 7.2 Hz, 1H), 3.46 (d, J = 10.4 Hz, 1H), 3.33 (d, J = 10.4 Hz, 1H), 2.38 (s, 3H), 2.01 (ddd, J = 12.8, 7.2, 1.5 37 Hz, 1H), 1.89-1.81 (m, 4H), 1.71 (dd, J = 12.8, 9.4 Hz, 2H), 13 1.42-1.33 (m, 17H), 1.05 (s, 3H), 0.78 (s, 3H). C NMR (125 MHz, CDCl3): δ = 147.3, 143.0, 141.3, 136.2, 129.4, 127.5, 126.2, 125.3, 76.4, 63.6, 61.9, 51.6, 38.3, 35.7, 35.5, 26.5, 26.2, 26.1, 25.8, 22.6, 22.3, 21.6, 20.1. IR ν(cm-1): 3538, 2928, 2861, 2844, 1328, 1150, 1065, 1007, 710, 755, 671, 580. HRMS (m/z): [M+Na]+ calculated for C31H45NNaO3S: 534.3012; found: 534.3035.
1-(4-(4,4-Dimethyl-1-tosylpyrrolidin-2-yl)phenyl)cyclopentadecanol (20b)
Prepared according to the general procedure GP6, 20b was isolated as a colorless oil with a yield of 50%. 1H NMR (400 MHz, CDCl3): δ = 7.51 (d, J = 8.3 Hz, 2H), 7.35 (d, J = 8.4 Hz, 2H), 7.20 (d, J = 8.3 Hz, 2H), 7.18 (d, J = 8.1 Hz, 2H), 4.73 (dd, J = 9.4, 7.3 Hz, 1H), 3.46 (d, J = 10.4 Hz, 1H), 3.33 (d, J = 10.4 Hz, 1H), 2.38 (s, 3H), 2.01 (ddd, J = 12.8, 7.3, 1.5 Hz, 1H), 1.94-1.82 (m, 2H), 1.78-1.69 (m, 3H), 13 1.45-1.31 (m, 24H), 1.05 (s, 3H), 0.78 (s, 3H). C NMR (125 MHz, CDCl3): δ = 147.2, 142.9, 141.3, 136.2, 129.4, 127.5, 126.3, 125.3, 76.5, 63.6, 61.9, 51.6, 39.5,
231 W. Rao, H. W. P. Chan, Chem. Eur. J. 2008, 14, 10486–10495.
328 Part IV Iodine(I/III) Catalysis for Selective C(sp3)-H Amination
39.4, 38.3, 27.9, 27.1, 26.9, 26.8, 26.6, 26.2, 25.8, 22.2, 22.1, 21.6. IR ν(cm-1): 3521, 2926, 2855, 1334, 1156, 1092, 1056, 754, 662, 580, 546. + HRMS (m/z): [M+Na] calculated for C34H51NNaO3S: 576.3482; found: 576.3490.
1-(4-(4,4-Dimethyl-1-tosylpyrrolidin-2-yl)phenyl)-12-iodododecan-1- one (21a)
Prepared according to the general procedure GP7, 21a was isolated as a colorless oil with a 1 yield of 53%. H NMR (400 MHz, CDCl3): δ = 7.88 (d, J = 8.3 Hz, 2H), 7.58 (d, J = 8.2 Hz, 2H), 7.38 (d, J = 8.3 Hz, 2H), 7.24 (d, J = 7.9 Hz, 2H), 4.72 (dd, J = 9.3, 7.3 Hz, 1H), 3.43- 3.35 (m, 2H), 3.19 (t, J = 7.1 Hz, 2H), 2.93 (t, J = 7.4 Hz, 2H), 2.41 (s, 3H), 2.05-2.00 (m, 1H), 1.82 (p, J = 7.0 Hz, 2H), 1.76- 1.66 (m, 4H), 1.38-1.29 (m, 13H), 1.05 (s, 3H), 0.72 (s, 3H). 13C NMR (125 MHz, CDCl3): δ = 200.2, 148.5, 145.5, 136.2, 135.4, 129.6, 128.4, 127.6, 126.7, 63.7, 62.1, 51.4, 38.7, 38.5, 33.7, 30.7, 29.9, 29.7, 29.6, 29.5, 29.4, 28.7, 26.2, 25.8, 24.6, 21.7, 7.5. IR ν(cm-1): 2915, 2849, 1681, 1608, 1467, 1344, 1153, 1092, 1054, 668, + 545. HRMS (m/z): [M+H] calculated for C31H44INNaO3S: 660.1979; found: 660.1963.
1-(4-(4,4-Dimethyl-1-tosylpyrrolidin-2-yl)phenyl)-15- iodopentadecan-1-one (21b)
Prepared according to the general procedure GP7, 21b was isolated as a colorless oil with a yield of 79%. 1H NMR (400 MHz, CDCl3): δ = 7.87 (d, J = 8.1 Hz, 2H), 7.58 (d, J = 7.9 Hz, 2H), 7.38 (d, J = 8.0 Hz, 2H), 7.24 (d, J = 8.0 Hz, 2H), 4.72 (dd, J = 9.2, 7.3 Hz, 1H), 3.45-3.33 (m, 2H), 3.18 (t, J = 7.0 Hz, 2H), 2.93 (t, J = 7.4 Hz, 2H), 2.40 (s, 3H), 2.04-1.99 (m, 1H), 1.85-1.78 (m, 2H), 1.74-1.65 (m, 4H), 1.38-1.26 (m, 19H), 1.04 13 (s, 3H), 0.72 (s, 3H). C NMR (125 MHz, CDCl3): δ = 200.2, 148.5, 143.5, 136.1, 135.4, 129.6, 128.4, 125.6, 120.6, 63.6, 62.0, 51.3, 38.7, 38.4, 33.7, 30.6, 29.8, 29.7, 29.6, 29.6, 29.6, 29.5, 28.7, 26.2, 25.7, 24.6, 21.6, 7.5. IR ν(cm-1): 2914, 2849, 1682, 1472, 1337, 1155, 1092, 732, 669. HRMS (m/z): [M+H]+ calculated for C34H51INO3S: 680.2629; found: 680.2632.
329
330
Part V Iodine(I/III) Catalysis for 1,3- Diamine Formation
331
332 Part V Iodine(I/III) Catalysis for 1,3-Diamine Formation
Part V Iodine(I/III) Catalysis for 1,3- Diamine Formation
V.1 Introduction
V.1.1 The importance of the 1,3-diamine motif In contrast with the 1,2-diamine motif, the corresponding 1,3- diamine’s family remains at its early stage regarding the methodology development. Nevertheless, they represent crucial structural unit since they are ubiquitous in natural product such as the bromopyrrole alkaloid manzacidin’s family,232 the carfentanil233 or the Nankakurine A.234 Additionally, they are also key building blocks in synthetic organic chemistry235 and used as chiral ligands for transition metal asymmetric catalysis (Scheme V.1).236
232 S. H. Kang, S. Y. Kang, H. S. Lee, A. J. Buglass, Chem. Rev. 2005, 105, 4537– 4558. 233 N. Misailidi, I. Papoutsis, P. Nikolaou, A. Dona, C. Spiliopoulou, S. Athanaselis, Forensic Toxicol. 2018, 36, 12–32. 234 Y. Hirasawa, H. Morita, J. Kobayashi, Org. Lett. 2004, 6, 3389–3391. 235 a) J. Halli, M. Bolte, J. Bats, G. Manolikakes, Org. Lett. 2017, 19, 674–677. b) S. K. Liew, Z. He, J. D. St. Denis, A. K. Yudin, J. Org. Chem. 2013, 78, 11637–11645. 236 G. Facchetti, R. Gandolfi, M. Fusè, D. Zerla, E. Cesarotti, M. Pellizzoni, I. Rimoldi, New J. Chem. 2015, 39, 3792–3800.
333 Part V Iodine(I/III) Catalysis for 1,3-Diamine Formation
Scheme V.1. Examples of natural products and ligands containing a 1,3-diamine moiety.
In the last decades, various strategies have been developed to reach the 1,3- diamine motif. Among them, we presented in the general introduction that nitrenes can insert into a C(sp3)-H bond. With the use of transition metal catalyst such as rhodium or cobalt in combination with primary sulfamides or sulfonylazides, selective and direct C(sp3)-H amination occurs. Also, allylic amination under palladium catalysis could be designed for such a reaction starting from ureas.237 Despite the effort of the synthetic chemist community toward the methodology development for the C-N bond instalment, the canonical pathway for their formation remains the C-C bond formation through a Mannich-type reaction for instance.238 To the best of our knowledge, metal-free radical-based reaction for the direct instalment of the 1,3-diamine through C(sp3)-H amination has never been developed so far.
V.1.2 Strategy for the radical-based 1,3-diamine formation Our strategy was based on the Hofmann-Löffler chemistry that enables selective C(sp3)-H amination through 1,n-HAT. In the precedent chapters, we presented various combination of halogen catalyst and oxidant that can smoothly and effectively performed amination reaction. Keeping the main strategy for the selective amination through 1,n-HAT, the
237 M. Morgen, S. Bretzke, P. Li, D. Menche, Org. Lett. 2010, 12, 4494–4497. 238 X. Ji, H. Huang, Org. Biomol. Chem. 2016, 14, 10557–10566.
334 Part V Iodine(I/III) Catalysis for 1,3-Diamine Formation
1,3-diamine formation can either require a challenging 1,4-HAT followed by an external amination event or require the instalment of a tether moiety (Scheme V.2).
Scheme V.2. Retrosynthetic analysis for the obtention of the 1,3-diamine motif through a radical pathway.
We were inspired by the outstanding works of numerous research groups on sulfamide tether that guide amination reaction through nitrene insertion and were wondering whether the Hofmann-Löffler could proceed using this motif. Calculation by Zipse et al. proved that the nitrogen- centered radical from a cyclic close-related sulfamate ester is as stabilized as the sulfonamidyl radical.143 As a result, the 1,6-HAT should thermodynamically proceed in smooth condition. Experimentally, in our previous work on multiple halogenation through the Hofmann-Löffler manifold, we used the close-related sulfamate ester which destabilizes the corresponding N-X bond thus providing the nitrogen-centered radical under visible light irradiation.149 A subsequent 1,6-HAT occurs while using this tether group. Indeed, sulfamate ester cannot geometrically performed 1,5-HAT. Instead, a 1,6-HAT through a 7-membered ring intermediate occurs. Other examples of radical C(sp3)-H functionalization through 1,6- HAT using sulfamate esters could be found in literature as well.239 As a result, we decided to install a sulfamide tether group that would a priori both destabilize the corresponding N-X bond generating the nitrogen- centered radical and guide a 1,6-HAT process and. Subsequent cyclization from the external nitrogen of the sulfamide would generate the desired C(sp3)-N bond. Moreover, this tether group is labile and can be removed easily after the reaction generating the corresponding free 1,3-diamine.
239 a) S. Sathyamoorthi, S. Banerjee, J. Du Bois, N. Z. Burns, R. N. Zare, Chem. Sci. 2017, 9, 100–104. b) D. N. Zalatan, J. Du Bois, Synlett 2009, 143–146. c) S. K. Ayer, J. L. Roizen, J. Org. Chem. 2019, 84, 3508–3523. d) A. L. G. Kanegusuku, T. Castanheiro, S. K. Ayer, J. L. Roizen, Org. Lett. 2019, 21, 6089–6095.e) M. A. Short, J. M. Blackburn, J. L. Roizen, Angew. Chem. Int. Ed. 2018, 57, 296–299.
335 Part V Iodine(I/III) Catalysis for 1,3-Diamine Formation
So far, the Hofmann-Löffler reaction had never been developed with the use of sulfamides as directing groups.
V.1.3 Preliminary reactivity exploration
V.1.3.1 Activated benzylic amination To start our initial exploration, we investigated the substrate 22 that bears an activated benzylic position. We initiated our exploration using 5 mol% of molecular iodine as catalyst and 1.2 equivalent of PhI(mCBA)2 as hypervalent aryliodine(III) oxidant. In DCE, 32% of NMR conversion was observed (Table V.1, entry 1). Two others hypervalent aryliodine(III) oxidants were screened (entries 2-4). The commercially available PIDA afforded only 29% conversion (entry 2) whereas PhI(oFBA)2 provided 48% (entry 3).The more reactive PIFA was also assessed without any success (entry 4) since only decomposition was observed. When using NIS as iodine source (entry 5), the reaction is still proceeding, and 39% conversion was obtained after 16 h of reaction time. At this stage, we decided to continue our investigation with PhI(oFBA)2 as oxidant since no side- oxygenation product coming from ligand insertion of the alkyliodine(III) intermediate was noticed (mechanism of this side-reaction presented in the section IV.1.2). Increasing slightly the amount of molecular iodine catalyst to 10 mol% led to 71% conversion (entry 6). Various LEDs were tested for the irradiation of the reaction mixture. While irradiation with blue LEDs (entry 7) led to 70% conversion, the use of black LEDs seemed to decrease the efficiency of the reaction since only 40% conversion was obtained (entry 8). Finally, purple LEDs were found to be the most efficient for the reaction to procced (entry 9). Under purple LEDs irradiation, 90% of isolated yield was obtained. Changing DCE by MeCN (entry 10) led to a decrease efficiency (71% conversion).
Table V.1. Optimization of the first iodine catalysis for the Hofmann-Löffler reaction involving a 1,6-HAT for amination at activated benzylic position.
Entry Iodine source Oxidant Conversion
336 Part V Iodine(I/III) Catalysis for 1,3-Diamine Formation
1 I2 (5 mol%) PhI(mCBA)2 (1.2 equiv.) 32% 2 I2 (5 mol%) PIDA (1.2 equiv.) 29% 3 I2 (5 mol%) PhI(oFBA)2 (1.2 equiv.) 48%
4 I2 (5 mol%) PIFA (1.2 equiv.) Decomposition
5 NIS (10 mol%) PhI(oFBA)2 (1.2 equiv.) 39% 6 I2 (10 mol%) PhI(oFBA)2 (1.2 equiv.) 71% a 7 I2 (10 mol%) PhI(oFBA)2 (1.2 equiv.) 70% b 8 I2 (10 mol%) PhI(oFBA)2 (1.2 equiv.) 40% c c 9 I2 (10 mol%) PhI(oFBA)2 (1.2 equiv.) 90% d 10 I2 (10 mol%) PhI(oFBA)2 (1.2 equiv.) 71% a Experiment carried out using blue LEDs. b Experiment carried out using black LEDs. c Experiment carried out using purple LEDs. d Experiment carried out using acetonitrile as solvent * Isolated yield.
Apart from the hypervalent iodine(III) oxidant bearing a fluorine atom at the ortho-position PhI(oFBA)2, we observed that in all the reaction mixture, side-product from C-O bond formation was noticed. Our hypothesis was that the cyclization step is rather slow and competing ligand insertion mechanism occurs. The sulfamide tether is presumably a weaker nucleophile than the corresponding sulfonamide. The heterocycle 23 was formed as a single diastereoisomer where the two phenyl substituents are in equatorial position (confirmed by X-ray analysis).
V.1.3.2 Non-activated secondary position When we attempted to move from the activated benzylic position to a non-activated secondary position 24, we did not observe the corresponding cyclized product 25. Surprisingly, the corresponding alkyliodine(I) 26 was identified and purified. It results from a stochiometric iodination reaction. After screening of various iodine sources, solvents and oxidants (Table V.2, entries 1-10), we could reach in an excellent isolated yield of 40% (corresponding to 99% calculated from the iodine source) the C-iodinated product 26. The reaction was carried out in either MeCN or DCE using the commercially available PIDA and 20 mol% of molecular iodine. Diverse light sources were screened as well without any improvement of yields. Compound 26 was isolated as an inseparable 1:1 mixture of diastereoisomers. Interestingly, the reaction shut down when more than 20 mol% of molecular iodine was used in either DCE or acetonitrile (entries
337 Part V Iodine(I/III) Catalysis for 1,3-Diamine Formation
11-12). This may be due to the strong light absorption from iodine quenching the overall transformation. Attempts for the direct cyclization of 24 to provide the corresponding 1,3- diamine 25 were unsuccessful. Various additive such as inorganic (entry 13) or organic (entry 14) bases were ineffective. The use of either the Lewis acid BF3.OEt2 or HFIP as co-solvent did not lead to the cyclized product 25 (entry 15-16 respectively).
Table V.2. Optimization reaction to access the alkyliodine(I) product and unsuccessful trials to get the cyclized heterocycle.
Iodine Convers Entry Oxidant Solvent source ion 1 I2 (20 mol%) PhI(oFBA)2 (1.2 equiv.) DCE 26: 34% 2 I2 (20 mol%) PhI(oFBA)2 (1.2 equiv.) MeCN 26: 37% a 3 I2 (20 mol%) PIDA (1.2 equiv.) DCE 26: 40%*
a 4 I2 (20 mol%) PIDA (1.2 equiv.) MeCN 26: 40%*
b 5 I2 (20 mol%) PIFA (1.2 equiv.) DCE -- 6 I2 (20 mol%) PhI(mClBA)2 (1.2 equiv.) DCE 26: 35%
7 NIS (20 mol%) PhI(oFBA)2 (1.2 equiv.) DCE 26: 18% 8 I2 (20 mol%) PhI(oFBA)2 (1.2 equiv.) MeNO2 26: 35% 10 I2 (20 mol%) PhI(oFBA)2 (1.2 equiv.) DMA 26: 30% 11 I2 (30 mol%) PIDA (1.2 equiv.) DCE 26: trace 12 I2 (30 mol%) PIDA (1.2 equiv.) MeCN 26: trace Attempts for the cyclization of 24- c,d 13 I2 (20 mol%) PIDA (1.2 equiv.) MeCN -- d,e 14 I2 (20 mol%) PIDA (1.2 equiv.) MeCN -- d,f 15 I2 (20 mol%) PIDA (1.2 equiv.) MeCN -- MeCN/HFIP 16 I2 (20 mol%) PIDA (1.2 equiv.) -- (1/1) a Experiment carried out using blue, purple or black LEDs. b Decomposition. c d Experiment carried out with K2CO3 (2 equiv.) as additive. Experiment carried out e f using purple LEDs. Experiment carried out with NEt3 (2 equiv.) as additive. Experiment carried out with BF3OEt2 (1 equiv.) as additive. * Isolated yield.
After putting all our effort toward the direct conversion of 24 to 25, we step back to rationalize this unexpected result. We wondered why the
338 Part V Iodine(I/III) Catalysis for 1,3-Diamine Formation alkyliodine(I) intermediate could be isolated and the reaction stopped. Three possibilities were hypothesized. First, the alkyliodine(I) intermediate is not getting oxidized by the oxidant to the alkyliodine(III) species. Then, it could be that the sulfamide is not a good enough nucleophile or the leaving group capacity of the alkyliodine(III) intermediate is not sufficient. We sometimes observe oxygenation coming from a ligand dissociation of the oxidant or elimination side-products. As a result, although it was not completely resolved, it seems that the alkyliodine(I) intermediate is getting oxidized by the hypervalent aryliodine(III) oxidant. Since we know that the alkyliodine(III) are really efficient nucleofuges, the relatively low nucleophilicity of the sulfamide tether appeared to be the major issue. To enhance the leaving group capacity of the iodine(III) intermediate that would a priori accelerate the cyclization step. As a result, it would counter the relatively low nucleophilic capacity of the sulfamide tether group. Thus, a stronger hypervalent aryliodine(III) oxidant (PhICl2) was added to the purified alkyliodine(I) 26 (Scheme V.3). Cyclization event occurred to generate the corresponding heterocycle 25 as a single diastereoisomer where both the methyl and the phenyl substituents are positioned in equatorial (confirmed by X-ray analysis).
Scheme V.3. Synthesis of the 1,3-diamine 25 by using a stronger hypervalent iodine(III) oxidant PhI(Cl)2.
The major issue regarding the stronger oxidant PhICl2 is its incompatibility with smooth catalytic reaction conditions.
V.1.3.3 A Ritter-type amination at tertiary positions? At this stage, we speculated if we could arrive to a synthetic useful amination reaction and we wondered whether we could take advantage of the sulfamide incapacity to undergo a cyclization event.
339 Part V Iodine(I/III) Catalysis for 1,3-Diamine Formation
The group of Minakata published in 2017 a decarboxylative Ritter-type amination using PIDA as oxidant.240 Starting from tertiary carboxylic acid, a mild iodine catalyzed decarboxylation proceeds followed by an iodination event (Scheme V.4). The newly tertiary alkyliodine(I) gets oxidized by PIDA to the corresponding tertiary trisubstituted alkyliodine(III) intermediate. Therefore, with the use of acetonitrile as solvent, a Ritter- type amination occurs selectively through the displacement of the I(III) nucleofuge. The limitation of this methodology is the necessity of the pre- instalment of the carboxylic acid.
Scheme V.4. Decarboxylative iodine catalyzed Ritter-type amination developed by Minakata et.al.
Considering this terrific work, we decided to tackle tertiary non-activated position to investigate a plausible Hofmann-Löffler-guided Ritter-type amination reaction. Thanks to this strategy, 1,3-α-tertiary diamines could be achieved.
V.1.4 Strategies for the synthesis of α-tertiary amines The α-tertiary amines (i.e. a tetrasubstituted carbon atom surrounded by three carbons and one nitrogen) represents ubiquitous moiety in alkaloids and drugs (Scheme V.5).241
240 K. Kiyokawa, T. Watanabe, L. Fra, T. Kojima, S. Minakata, J. Org. Chem. 2017, 82, 11711–11720. 241 G. A. Cordell, The Alkaloids, Elsevier, London, 1998.
340 Part V Iodine(I/III) Catalysis for 1,3-Diamine Formation
Scheme V.5. Examples of molecules containing a α-tertiary amine moiety.
Numerous strategies have been developed in the last decades for the formation of such C-N bond from a sp3 hybridized carbon atom. Among them, numerous molecular rearrangement reactions such as Overman, Curtius, Hofmann, Schmidt, Stieglitz or Beckmann rearrangements can form the desired C-N bond from a pre-functionalized carbon atom.242 This interesting motif has been challenging the organic chemists for the last decades.243 The fascinating and under-estimated Ritter reaction can be used as well for the construction of α-tertiary amines.244 Indeed, activated alcohols in the presence of either Lewis or Brønsted acid lead to the formation of a stabilized carbocation. Subsequent addition of a nitrile moiety occurs (commonly coming from the nitrile derivative solvent). Ritter-type reactions were designed for ethers, esters and alkenes in presence of Lewis or Brønsted acid as well. As we previously mentioned, a decarboxylative Ritter-type amination was also introduced by Minakata et al. employing iodine catalysis.239 All these reactions require a pre-functionalization of the sp3 hybridized carbon to afford the desired amination reaction. Regarding direct C(sp3)-H amination at non-activated tertiary position, nitrene insertion remains the most exploited tool so far. Though, Olah et al. first introduced in 1980 a Ritter-type amination on adamantane derivatives in the presence of nitrosonium species (Scheme V.6a). It
242 J. Clayden, M. Donnard, J. Lefranc, D. J. Tetlow, Chem. Commun. 2011, 47, 4624–4639. 243 a) A. Hager, N. Vrielink, D. Hager, J. Lefranc, D. Trauner, Nat. Prod. Rep. 2016, 33, 491–522. b) G. Dake, Tetrahedron 2006, 62, 3467–3492. c) S. A. A. El Bialy, H. Braun, L. F. Tietze, Synthesis 2004, 2249–2262. d) S. H. Kang, S. Y. Kang, H. S. Lee, A. J. Buglass, Chem. Rev. 2005, 105, 4537–4558. 244 D. Jiang, T. He, L. Ma, Z. Wang, RSC Adv. 2014, 4, 64936–64946.
341 Part V Iodine(I/III) Catalysis for 1,3-Diamine Formation represents the first Ritter-type amination on non-activated alkanes.245 Then, the group of Baran developed a cooperative bimetallic copper and zinc catalysis providing direct intermolecular amination of non-activated tertiary C(sp3)-H bond (Scheme V.6b).246 Finally, the group of Minakata in 2016 designed a Ritter-type amination using iodic acid as oxidant (Scheme V.6c).247 The mechanism relies on the formation of free radicals from a combination of NHPI and iodic acid. Nitroxide radicals are formed in this condition and can perform a hydrogen atom abstraction at the weakest C(sp3)-H bond of the targeted molecule. Since the tertiary carbon represents the most thermodynamically stable position, the C-H functionalization smoothly proceeds followed by an iodination event. Then, the hypervalent iodic acid oxidizes the alkyliodine(I) intermediate into the tertiary alkyliodine(III) species. The increased leaving group capacity of the latter enables the Ritter-type amination from the acetonitrile to occur. The limitation of this procedure is the regioselectivity issue due to the free-radical generation.
Scheme V.6. Ritter-type amination from direct conversion of C(sp3)-H bond to C(sp3)- N bond using acetonitrile as solvent and nitrogen source.
245 G. A. Olah, B. G. B. Gupta, J. Org. Chem. 1980, 45, 3532–3533. 246 Q. Michaudel, D. Thevenet, P. S. Baran, J. Am. Chem. Soc. 2012, 134, 2547– 2550. 247 K. Kiyokawa, K. Takemoto, S. Minakata, Chem. Commun. 2016, 52, 13082– 13085.
342 Part V Iodine(I/III) Catalysis for 1,3-Diamine Formation
V.2 Aims of part V
We aimed in this section to develop the first interrupted Hofmann- Löffler reaction. Therefore, the objective was to find a suitable directing group which is a bad nucleophile, but which is efficient to perform a selective hydrogen atom abstraction. With the preliminary results described above, the sulfamide moiety seemed to suit the the requirement. Once the iodine is installed at the desired carbon position, an external nucleophile can enter and perform the amination reaction. With the literature in hand and with perseverance, we aimed to use the famous Ritter reaction using acetonitrile as both solvent and nitrogen source. So far, no metal-free guided Ritter-type amination have never been designed.
V.3 Results and discussion on the Ritter-type amination
V.3.1 Development of the 1,3-diamine formation We started our investigation screening various hypervalent iodine oxidants in combination with molecular iodine in acetonitrile. We used 27 as starting material for the optimization. While performing the reaction using PhI(mCBA)2, 81% of isolated yield for 28 was already obtained (Table V.3, entry 1). While modifying the meta-chloro substituent at the benzoate ligands of the hypervalent iodine oxidant by a fluorine atom at the ortho position, the yield increased slightly to reach 90% (entry 2). The commercially available PIDA provided the good isolated yield of 73% (entry 3). Thanks to our strong background on setting-up reactions with molecular iodine as catalyst, we envisaged that its use in relatively high amount might have a negative effect due to its strong absorption in visible light. As a result, reducing both its quantity and the equivalent of oxidant resulted in an increased of isolated yield since 95% of obtained (entry 4). When we tried to decrease again the amount of iodine catalyst, the efficiency dramatically dropped to 48% (entry 5) and 30% (entry 6) when 5 mol% and 2.5 mol% were used respectively. NIS was also a successful iodine source catalyst since 95% of isolated yield was obtained (entry 7) while the use of tetrabutylammonium iodide salt did not afford the desired 1,3-diamine (entry 8). All these reactions were carried out using a
343 Part V Iodine(I/III) Catalysis for 1,3-Diamine Formation fluorescent lightbulb. Having in mind the calculations performed for the close-related sulfonamide (section III.2.1), we tried to irradiate under blue LEDs the reaction mixture. A minor drop of yield was observed and 80% of product was obtained (entry 9). The best result we got was when we irradiated the reaction vessel with purple LEDs (entry 10) since 99% of isolated yield could be reached. The optimal reaction conditions are the following: Molecular iodine and PIDA are used in 10 mol% and 1.2 equivalents respectively. The reaction is set-up in non-purified MeCN and at the concentration of 0.05 M. The reaction mixture is stirred 16 h at room temperature under purple LEDs irradiation. When the acetonitrile was purified prior to use, the isolated yield dropped to 30% (entry 11). On the contrary, when water was used in large excess, the reaction was quenched (entry 12). To be reproductible, we explored the amount of water contained in the used acetonitrile. As a result, three Karl- Fischer titrations were carried out for both the purified and the used non- purified batches. For the dried acetonitrile, a median of 7.5 μg/g was encountered corresponding to 0.655 μmol (0.7 mol%) of water in the reaction mixture. The batch used for the optimized Ritter-type amination contained 209 μg/g corresponding to 18.3 μmol (20 mol% of water). These results proved that the addition of water at the nitrilium ion mostly comes from the work-up. Various attempts for the direct cyclization of 27 to provide the corresponding 1,3-diamine XXII were carried out. Additives such as the inorganic K2CO3 (entry 13) or the organic NEt3 (entry 14) bases were unsuccessful. The use of the Lewis acid BF3.OEt2 did not lead to the cyclized product (entry 15). The protic and polar solvent HFIP was used as co- solvent of the reaction in combination with acetonitrile (1/1 mixture) but decomposition was obtained (entry 16).
Table V.3. Optimization reaction of the Ritter-type amination from an interrupted Hofmann-Löffler reaction. Unsuccessful trials of cyclization are also presented.
Entry Iodine source Oxidant Yield 1 I2 (20 mol%) PhI(mCBA)2 (2 equiv.) 81% 2 I2 (20 mol%) PhI(oFBA)2 (2 equiv.) 90% 3 I2 (20 mol%) PIDA (2 equiv.) 73%
344 Part V Iodine(I/III) Catalysis for 1,3-Diamine Formation
4 I2 (10 mol%) PIDA (1.2 equiv.) 95% 5 I2 (5 mol%) PIDA (1.2 equiv.) 48% 6 I2 (2.5 mol%) PIDA (1.2 equiv.) 30% 7 NIS (20 mol%) PIDA (1.2 equiv.) 95% 8 Bu4NI (20 mol%) PIDA (1.2 equiv.) -- a 9 I2 (10 mol%) PIDA (1.2 equiv.) 80% b 10 I2 (10 mol%) PIDA (1.2 equiv.) 99% c 11 I2 (10 mol%) PIDA (1.2 equiv.) 30% d d 12 I2 (10 mol%) PIDA (1.2 equiv.) -- Attempts for the cyclization of 27 b,e f 13 I2 (10 mol%) PIDA (1.2 equiv.) -- b,g 14 I2 (10 mol%) PIDA (1.2 equiv.) -- b,h 15 I2 (10 mol%) PIDA (1.2 equiv.) -- b,i f 16 I2 (10 mol%) PIDA (1.2 equiv.) -- a Experiment carried out using blue LEDs. b Experiment carried out using purple LEDs. c Experiment carried out with purified MeCN. d Experiment carried out using e MeCN/H2O as solvent. Experiment carried out with K2CO3 (2 equiv.) as additive. f g h Decomposition Experiment carried out with NEt3 (2 equiv.) as additive. i Experiment carried out with BF3OEt2 (1 equiv.) as additive. MeCN/HFIP (1/1) used as solvent.
V.3.2 Scope of the Ritter-type amination through an interrupted Hofmann-Löffler reaction While having the optimized reaction condition for the Ritter-type amination, we aimed to prove the robustness and the applicability of the method (Scheme V.7). As presented previously, the standard substrate 27a was converted to 28a in the excellent yield of 99%. Removing the methyl group at the α-position of the tether group did not affect the efficiency of the reaction since 90% isolated yield was obtained for 28b. As a result, the Thorpe-Ingold effect is not a essential parameter for the reaction to proceed. Aryls groups were implemented at the α-position as well and the corresponding 1,3-diamines 28c-i could be isolated from good to excellent isolated yields (62-99%). Importantly, we assessed the influence of para- substituents at the arene core, but we did not observe any impact on the isolated yield. Mostly, the small observed drop of yield came from isolation issues for the compounds 28g, 28h and 28i. Interestingly, the isopropyl group placed at the arene moiety for the substrate 27i remains untouched meaning that the regioselectivity is high and driven by the tether sulfamide group. No free radicals are generated thus undergoing non-selective reactions. Then, we modified the targeted tertiary position. For compounds
345 Part V Iodine(I/III) Catalysis for 1,3-Diamine Formation
28j and 28k, a non-separable 1:1 mixture of diastereoisomers was isolated in 64% and 50% yield respectively. The remote benzylic or tertiary position of these two compounds remains untouched meaning that the regioselectivity is high as well. Another example illustrates the high regioselectivity of the present method. 27l was aminated exclusively at the desired tertiary position providing 28l in 72% yield letting the remote tertiary C(sp3)-H bond intact. The reaction proceeds efficiently as well in cyclic position as demonstrated for compounds 28m and 28n. After a slight reaction time increase, 28m was isolated in 72% yield. Outstandingly, 27n was converted regioselectively in 28n where the amination exclusively proceeds at a tertiary homobenzylic position. 45% of isolated yield was obtained but unreactive starting material could be recovered leading to a 95% yield based on starting material recovering. While using isopropionitrile as solvent, the corresponding Ritter-type aminated product 28o was isolated in 83% of yield.
Scheme V.7. Scope of the Ritter-type amination from direct conversion of C(sp3)-H 3 a bond to C(sp )-N bond (Part I). [N] = NMeSO2NHMe. Reaction performed with 15
346 Part V Iodine(I/III) Catalysis for 1,3-Diamine Formation
b c mol% of I2 and 1.3 equiv. of PIDA. A 1:1-mixture of diastereoisomers was obtained. Reaction performed 24 h. d Yield in parenthesis based on recovered starting material. e Isopropionitrile used as solvent. Reaction performed with 20 mol% of I2 and 1.5 equiv. of PIDA.
We assessed the influence of alkyl substituents at the internal nitrogen of the sulfamide moiety. We implemented a propyl (27p) and a butyl (27q) group in order to put in competition a primary or a secondary position vs the targeted tertiary position (Scheme V.8). We did not notice any side- products coming from the functionalization of the corresponding primary or secondary position. Thermodynamically, the carbon-centered radical is more stable at tertiary position and the BDEs of tertiary C(sp3)-H bond are usually lower. It can explain the observed complete regioselectivity towards the amination at the tertiary position for compounds 28p and 28q that were isolated in 82% and 60% respectively. A cyclopropyl and a removable benzyl group were assessed as well providing 28r and 28s in 70% and 65% respectively. When the reaction was performed on larger scale, the reaction still proceeded effectively since 62% of isolated yield was obtained for 28s. A tert-butyl group was implemented at the external nitrogen of the sulfamide and submitted to the optimized reaction condition. 28t was isolated in 65% yield after 40 h of reaction time. We then hypothesized that the hindered tert-butyl group slows down the kinetic of the reaction. More complex molecules were then investigated for this reaction. A proline derivative could be aminated providing 28u in 70% of isolated yield. The structure was confirmed by X-ray analysis. Substrates bearing a cyano and an acetate group could be converted in the corresponding 1,3-diamines 28v and 28w in 42% and 65% of isolated yields respectively demonstrating the functional group tolerance of the present methodology. Also, a steroid derivative could be aminated providing 28x in 65% of yield. Unexpectedly, the Ritter-type amination came from the β–face leading to a trans decaline isomer form. We managed to confirm the structure by single crystal X-ray diffraction, and we claimed that the benzyl group is shielding the α-face at the stage of the acetonitrile attack.
347 Part V Iodine(I/III) Catalysis for 1,3-Diamine Formation
Scheme V.8. Scope of the Ritter-type amination from direct conversion of C(sp3)-H 3 a bond to C(sp )-N bond (Part II). Reaction performed with 15 mol% of I2 and 1.3 equiv. of PIDA. b Yield in parenthesis refers to the reaction performed with 1 mmol of 28s. c Reaction performed 40 h. d Reaction performed with 2 equiv. of AcOH. e Starting from the 5α-androsterone isomer.
As in all methods, limitations could be observed while carrying out the scope. Fist of all, we noticed that unprotected sulfamides (at the internal or external nitrogen) did not provide any reactivity since only starting material was recovered. While changing from alkyl groups to carbamates such as implementing a Boc or Cbz group, the reaction shut down. This may be due to the non-formation of the N-I bond because of the increased acidity of the hydrogen at the external nitrogen. We tried whether the reaction could proceed at allylic position as well, but decomposition was observed instead. This is probably due to the high over reaction of the olefin with PIDA. While implementing a hindered group such as the isopropyl group at the α-position of the targeted tertiary position, both decomposition and starting material were observed by NMR. Finally, and surprisingly, the close-related sulfamate esters are not reacting under the
348 Part V Iodine(I/III) Catalysis for 1,3-Diamine Formation optimized conditions. Only starting materials were recovered without any side-products formation meaning that the 1,6-HAT might not take place.
Scheme V.9. Unsuccessful substrates for the iodine catalyzed Ritter-type amination through an interrupted Hofmann-Löffler reaction.
V.3.3 Deprotection of the protecting groups In order to obtain the free 1,3-diamine, we developed an orthogonal procedure in which either the tether sulfamide group or the acetamide group could be removed (Scheme V.10). Thanks to this orthogonal approach, each nitrogen may be individually functionalized after its deprotection leading to plausible diversification products. Sodium hydroxide was used for the hydrolysis of the acetamide group providing 29 in 87% yield. 1,3-propanediamine was employed for the nucleophilic removal of the sulfamide moiety affording 30 in 82% isolated yield. The same procedures were applied to 29 and 30 to get the free 1,3-diamine 31 in 46% or 98% isolated yields respectively.
349 Part V Iodine(I/III) Catalysis for 1,3-Diamine Formation
Scheme V.10. Deprotection procedures for 28s. An orthogonal deprotection of both the tether sulfamide and the acetamide is displayed.
V.3.4 Mechanistic investigation
V.3.4.1 Isotope labelling experiment To investigate deeper the reaction mechanism, we performed isotope labelling experiment to determine the KIE (Scheme V.11). We encountered a lot of troubles for the synthesis of the proper starting material 27a-D. As a result, not only the tertiary C-H bond was deuterated but also other undesired positions. Although the latter were not important for the KIE determination, they complicated the NMR spectra.
Scheme V.11. Isotope labelling experiment was carried out with 27a-D. Intramolecular competition provided a KIE of 5.5 meaning that the C-H bond cleavage might be the rate-determining step of the Ritter-type amination.
350 Part V Iodine(I/III) Catalysis for 1,3-Diamine Formation
Prior to engage 27a-D in the optimized reaction conditions, we needed to know the percentage of deuteration at the targeted tertiary position. Due to the complicated mixture of several deuterated compounds, 13C NMR was determined to be the most useful tool to assess the ratio between the non- deuterated and the deuterated tertiary carbon position of the substrate. To correctly identify the carbon peak of the targeted tertiary carbon position, a HSQC experiment of 27a was carried out (more details in the experimental section). After its identification (peak at 24.9 ppm), we performed a T1 experiment in order to be able to integrate the carbon NMR (Scheme V.12).
Scheme V.12. T1 experiment for the targeted tertiary carbon position at 24.9 ppm.
The T1 value was found to be 3.56 s. As a result, we recorded a 13C NMR (Scheme V.13a) of 27a-D in a 125 MHz spectrometer equipped with a cryoprobe to reduce the noise with a relaxation time of 30 s > 7T1 (after 7T1 the magnetization has recovered 99.9% of its original size). After integration of the corresponding non-deuterated tertiary carbon and the deuterated one, a ratio of C(H)/C(D) = 64/36 was obtained (Scheme V.13b) for 27a-D. Then, we set up the reaction and quenched it after 15 min. By
351 Part V Iodine(I/III) Catalysis for 1,3-Diamine Formation
NMR, it was found out that 40% of 27a-D was converted of which 25% was providing the corresponding 1,3-diamine 28a-D.
Scheme V.13. 13C NMR for the determination of the ratio between the non-deuterated and the deuterated tertiary carbon position of 27a-D before the Ritter-type amination.
352 Part V Iodine(I/III) Catalysis for 1,3-Diamine Formation
A new 13C NMR of the crude was recorded using a relaxation time of 20 s > 5T1 (after 5T1 the magnetization has recovered 99.5% of its original size) and the window of [20-26] ppm to be more precise in the integration (Scheme V.14a). The new ratio between the non-deuterated tertiary carbon and the deuterated one was C(H)/C(D) = 50/50 (Scheme V.14b). The obtained ratio after the reaction is only mathematically making sense if we consider the total conversion of 40% (If 25% is considered, the KIE becomes negative). Following the equation 1, we calculated a KIE of 5.5. As a result, the C-H bond cleavage might be the rate determining step of the overall reaction.136
(64% − (1 − 40%) ∗ 50%) Equation V.1. Calculation퐾퐼퐸 of= the KIE for the Ritter-type amination through the Hofmann-Löffler reaction. (36% − (1 − 40%) ∗ 50%)
353 Part V Iodine(I/III) Catalysis for 1,3-Diamine Formation
Scheme V.14. 13C NMR for the determination of the ratio between the non-deuterated and the deuterated tertiary carbon position of 27a-D after the Ritter-type amination.
354 Part V Iodine(I/III) Catalysis for 1,3-Diamine Formation
V.3.4.2 Quantum yield determination As previously described in section IV.2.3.4, we determined the quantum yield of the reaction in order to prove the type of mechanism. A quantum yield higher than one means that a radical chain mechanism is involved. The procedure still follow the adapted protocol published by Melchiorre et al.228 In the dark room, both a ferrioxalate actinometer solution alongside the reaction mixture were irradiated by a 300 W Xenon lamp (100% intensity) at 400 nm for specified intervals of time. These irradiation times were chosen to reach at the maximum 20% conversion to be on the linear part of the kinetic profile (time of irradiation of 30, 60, 90 and 120 s). In the actinometer solution and upon irradiation, ferric ions are converted to ferrous ions. After irradiation, the ferrous ions are complexed with the 1,10- phenanthroline. Finally, to determine the moles of ferrous ions formed with time, UV-Vis spectra were recorded for each interval of time and the absorbance monitored at 510 nm. The absorbance at 510 nm of a non- irradiated but complexed with 1,10-phenanthroline was recorded as well. The moles of ferrous ions is calculated following the Beer-Lambert’s law (Equation V.2) where ΔA represents the difference between the absorption of the irradiated sample with the non-irradiated one at 510 nm, ε the 2+ absorption coefficient of the complex ferrous ions Fe(phen)3 at 510 nm (11100 L.mol-1.cm-1) and l the width of the quartz cuvette (1 cm). 0.01 L is the volume of the final ferrous complexed solution.
훥퐴(510푛푚) Equation V.2.푚표푙푒푠 Calculation (퐹푒 of2 +the) mole= 0, 01of iron(II) (퐿) ∗ thanks to the absorbance at 510nm. 휀(510 푛푚) ∗ 푙 (푐푚) Having this result in hand, we could access the mole of incident photons 0 by unit of time called q n,p thanks to the following equation (Equation V.3) where dx/dt represents the slope of the mole of complexed ferrous ions with time (Scheme V.15), Φ(Fe2+ at 510 nm) the quantum yield of the 2+ complexed Fe(phen)3 at 510 nm (1.13) and A(400 nm) is the absorbance at 400 nm of the actinometer solution non-complexed and non-irradiated (2.565).
푑푥 푞0푛, 푝 = 푑푡 −퐴(400푛푚) 훷(퐹푒2 + 푎푡 510 푛푚) ∗ [1 − 10 ] 355 Part V Iodine(I/III) Catalysis for 1,3-Diamine Formation
0 Equation V.3. Calculation of the mole of incident photon q n,p.
0 -1 Having the data in hand, q n,p was calculated to be 9.961E-9 einstein.s . This value corresponds to a flow of photon.
Scheme V.15. Plot of the mole of iron(II) formed vs time.
The moles of products formed during the different reaction time were determined by 1H-NMR using an internal standard. We plotted (Scheme V.16) the moles of products formed versus the number of photon in 0 Einstein (determined by q n,p * t (s)).
356 Part V Iodine(I/III) Catalysis for 1,3-Diamine Formation
Scheme V.16. Plot of the mole of product formed vs the mol of photon.
0 The slope of the linear function corresponds to dx/(q n,p *dt) in the following equation and equals 90.855 (Equation V.4). The absorbance is the one of the reaction mixture at 400 nm. To be more precise, the reaction mixture was diluted by 2 and the absorbance found at 400 nm was 0.308. The multiplication factor was considered in the following formula. As a result, A(400 nm) equals 0.615 and the quantum yield was determined to be 120.
푑푥 Equation V.4. Calculation of the quantum yield at푞0푛, 400 푝 ∗nm 푑푡 for the Ritter-type 훷(푟푒푎푐푡푖표푛 푎푡 400 푛푚) = −퐴(400 푛푚) amination through an interrupted Hofmann-Löffler1 −reaction.10
In conclusion, the quantum yield of the reaction is higher than one and proves that the reaction mechanism follows a radical chain mechanism with an initiation step, propagation steps and a termination.
357 Part V Iodine(I/III) Catalysis for 1,3-Diamine Formation
V.3.4.3 I(-I/I) or I(I/III) catalysis? We hypothesized the plausible involvement of an alkyliodine(III) intermediate as in the precedent I(I/III) mechanism presented in section IV.2.3.6. To prove the necessity of this key intermediate for the Ritter-type amination to occur, we performed a reaction in which only NIS is used in stoichiometric amount (Table V.4, entry 1). Surprisingly, 33% of conversion was already observed. When PIDA was implemented in the reaction mixture in combination with 1 equivalent of NIS, the conversion doubled (entry 2) to 68%. While trying to decrease the amount of NIS to 20 mol% without the presence of oxidant, only trace of 28a was observed (entry 3). Finally, full conversion leading to 95% of isolated yield (entry 4) was reached when NIS was used as catalyst (20 mol%) in combination with PIDA (1.2 equiv.). This is a clue that PIDA is not oxidizing an inorganic iodine reagent generated after the Ritter-type amination on the alkyliodine(I) species. Since a catalytic amount of NIS in association with PIDA provides an excellent isolated yield, while alone does not lead to completion means that an alkyliodine(III) species may be involved in the Ritter-type amination. To further convince on the crucial role of this intermediate, Minakata et.al. carried out a control experiment proving the necessity of reaching the alkyliodine(III) intermediate for the Ritter-type amination to proceed.239
Table V.4. Reaction performed with NIS as iodine source to investigate the role of the terminal oxidant.
Entry NIS (x equiv.) PIDA (y equiv.) Conversion 1 1 equiv. -- 33% 2 1 equiv. 1.2 equiv. 68% 3 0.2 equiv. -- trace 4 0.2 equiv. 1.2 equiv. 100% (95%)* * Isolated yield.
358 Part V Iodine(I/III) Catalysis for 1,3-Diamine Formation
V.3.5 Mechanism of the Ritter-type amination through an interrupted Hofmann-Löffler reaction As previously displayed in the mechanism of the first iodine catalyzed Hofmann-Löffler reaction (section III.1.2.3),158 molecular iodine comproportionates with hypervalent iodine reagent leading to the formation of hypoiodite species. As PIDA was used in the present method, acylhypoiodite was generated in the medium providing the in-situ formation of XXIII from 27a. As we calculated a quantum yield of 120 > 1, a radical chain mechanism is involved. XXIII upon light irradiation forms the nitrogen-centered radical intermediate XIV. A subsequent 1,6-HAT through a 7-menbered ring transition state occurs providing the carbon- centered radical XV. In a radical chain mechanism, XV reacts with another molecule of XXIII leading to the formation of the carbon-iodine bond in the intermediate XVI. At this stage, the hypervalent iodine oxidant PIDA oxidizes the alkyliodine(I) intermediate XVI into the corresponding alkyliodine(III) species XVII. A molecule of acetonitrile can perform the Ritter-type amination reaction selectively. After hydrolysis either with the presence of water in the medium or during the work-up, the 1,3-α-tertiary- diamine 28a is obtained.
359 Part V Iodine(I/III) Catalysis for 1,3-Diamine Formation
Scheme V.17. Mechanism of the Ritter-type amination through an interrupted Hofmann-Löffler reaction.
V.4 Extension of the Ritter-type amination for oxygenation reaction
With this methodology, 1,3-diamine derivatives could be synthesized but we wondered if other nucleophiles than acetonitrile could be used as well. We presented that we did not manage to have the Ritter- type amination working with sulfamate ester derivatives (section V.2.2) that could provide 1,3-aminoalcohols. In some cases, insertion of an acetate ligand from the alkyliodine(III) intermediate XVII leading to an oxygenation reaction was identified as side-products of the Ritter-type amination. Nevertheless, we decided to generate the latter from a guided oxygenation reaction through an interrupted Hofmann-Löffler reaction using sulfamide as tether group. As a result, we did a quick solvent optimization in order to get a clean oxygenation reaction (Table V.5). In chlorinated solvents such as DCE (entry 1) or DCM (entry 2), only trace of 32 was noticed. When we used the polar solvent nitromethane, 42% of isolated yield was obtained. Since the oxygen source was exclusively coming from PIDA, we decided to add more acetic acid in order to increase the insertion rate. Unfortunately, when 2 extra equivalents were implemented in the reaction medium (entry 4), the isolated yield did not improve since 45% was obtained. Finally, when performing the reaction in a 1 /1 mixture of acetic acid and nitromethane, 32 could be isolated with 90% of yield.
Table V.5. Optimization of the oxygenation reaction through an interrupted Hofmann-Löffler reaction.
Entry Solvent Conversion 1 DCE trace 2 DCM trace 3 MeNO2 50% (42%)* 4 MeNO2 + AcOH (2 equiv.) 50% (45%)* 5 MeNO2 / AcOH (1/1) 90%* * Isolated yield.
360 Part V Iodine(I/III) Catalysis for 1,3-Diamine Formation
A close-related intramolecular oxygenation reaction was obtained as well with Leucine derivatives 33a and 33b having lateral ester and ether substituents respectively. In the present case, the alkyliodine(III) intermediate is intercepted by the internal oxygenated functional group to provide the lactone 34a and the THF derivative 34b in 50% and 82% isolated yields respectively. These examples are demonstrating the absent nucleophilicity of the sulfamide moiety.
Scheme V.18. Internal oxygenation reaction through an interrupted Hofmann-Löffler reaction.
V.5 Final remarks
In this chapter, an iodine catalyzed interrupted Hofmann-Löffler reaction was presented. It is the first time that the Hofmann-Löffler reaction is used to selectively guide through a 1,6-HAT an iodination using sulfamide. Due to the lack of nucleophilicity of the latter, a Ritter-type amination occurs instead. Oxygenation can also be done using the sulfamide moiety. It demonstrates that other reaction than amination can be developed using iodine catalysis. Other nucleophiles might be tested in the close future. Also, it could be interesting to apply this methodology for the synthesis of a natural product. For instance, the Manzacidin A might be synthesized using the present method as a key step.
V.6 Experimental section
V.6.1 General information NMR spectra were recorded on a Bruker Avance 400 MHz or 500 MHz spectrometer, respectively. The chemical shifts (δ) for 1H and 13C are reported in ppm relative to residual signals of the solvents (CDCl3 δ = 7.26
361 Part V Iodine(I/III) Catalysis for 1,3-Diamine Formation
and 77.0 ppm, CD3CN δ = 1.94 and 118.26 ppm; DMSO-d6 δ = 2.50 and 39.52 ppm for 1H and 13C NMR respectively). Coupling constants are given in Hz. The following abbreviations are used to indicate the multiplicity: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad. High-resolution mass spectra (HRMS) were obtained from the ICIQ High- Resolution Mass Spectrometry Unit on MicroTOF Focus and Maxis Impact (Bruker Daltonics) with electrospray ionization. IR spectra were taken in a Bruker Alpha instrument in the solid state. All reactions were set up under an argon atmosphere in oven- dried glassware using standard Schlenk techniques unless otherwise stated. Synthesis grade solvents as well as reagents were used as purchased. Anhydrous solvents were taken from a commercial solvent purification system (SPS) dispenser. Chromatographic purification of products was accomplished using flash column chromatography (FC) on silica gel (Merck, type 60, 0.063-0.2 mm).
V.6.2 Synthesis of the substrates 22, 24, 27a-w and 33a-b Synthesis of 22, 24, 27a-b and 27p-t (GP1)
Scheme V.19. Pathway for the synthesis of 22, 24, 27a-b, 27p-s and 27t (GP1).
Step 1. In a flame-dried Schlenk tube, titanium(IV) isopropoxide (2 mL, 6.6 mmol) was added to a commercially available solution of methylamine in methanol (2 M, 7.5 mL) followed by the addition of the starting aldehyde (5 mmol). The reaction mixture was stirred at ambient temperature for 5 h, after which sodium borohydride (0.2 g, 5 mmol) was added and the resulting mixture was further stirred for another period of 2 h. The reaction was then quenched by the addition of water (1 mL), the resulting inorganic
362 Part V Iodine(I/III) Catalysis for 1,3-Diamine Formation
precipitate was filtered and washed with Et2O (20 mL). The organic layer was separated and the aqueous part was further extracted twice with Et2O (20 mL). The combined ether extracts were dried over anhydrous Na2SO4 and HCl in Et2O (1.1 equiv.) was added to form the salt. The solvent was removed in vacuo to provide the chloride salt which was used directly in the next step without further purification. Step 2. In a flame-dried Schlenk tube, a mixture of the crude from the previous step (1 equiv.) in CH2Cl2 (0.1 M) was added the freshly prepared methylsulfamoyl chloride (1.1 equiv.). To the resulting solution was added dropwise Et3N (1.1 equiv.). After stirring for 2 h, the reaction was quenched by slow addition of 10 mL of 1.0 M aqueous HCl. After extraction, the organic layer was collected and the aqueous fraction was extracted twice with CH2Cl2. The combined organic fractions were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. Purification using a column chromatography (hexane/ethyl acetate as eluent) provided the pure compounds 22, 24, 27a-b and 27p-s. Note: Synthesis of the methylsulfamoyl chloride: A flame-dried Schlent flask was charged with methylsulfamic acid (1 equiv.), PCl5 (1.1 equiv.) and toluene (2 mL/mmol). The mixture was stirred at 80 °C for 5 h. After cooling to room temperature, the reaction contents were filtered through a small plug of cotton under argon. The cotton plug was rinsed with an additional 10 mL of CH2Cl2, and the combined filtrates were concentrated under reduced pressure to a light brown oil. This material was used immediately without further purification in the subsequent sulfamoylation reaction. Step 3. A flame dried Sclenk tube was charged with the N-(tert-butyl)-2- oxooxazolidine-3-sulfonamide (1 equiv.) and DMAP (20 mol%). Anhydrous acetonitrile (5 mL/mmol) and NEt3 (3 equiv.) were added and the resulting mixture was heated to 80 °C with stirring for 15 min. A solution of the crude from step 1 (1 equiv.) in anhydrous acetonitrile (1.5 mL/mmol) was added dropwise, and the mixture was stirred at 80 °C for 6 h. The mixture was then cooled to room temperature, the solvent was removed under reduced pressure, and the crude product was purified by column chromatography on silica gel (hexane/ethyl acetate as eluent) to afford 27t as a white solid in 53% isolated yield.
Synthesis of 27a-D
363 Part V Iodine(I/III) Catalysis for 1,3-Diamine Formation
Scheme V.20. Pathway for the synthesis of 27a-D.
Step 1. In a flame-dried Schlenk tube was charged the α,β-unsaturated ketone (1 equiv.) and triethylsilane (2 equiv.) in 10 ml of absolute deuterated ethanol. Then, a catalytic amount of palladium(II) chloride (10 mol%) under an argon atmosphere was added. The resulting mixture was refluxed for 6 h. After filtration on Celite, the solvent was dried over anhydrous
Na2SO4 and removed under reduced pressure. The crude was then purified on column chromatography using hexane and ethyl acetate as eluent to provide the pure intermediate ketone. Step 2. Step 1 of GP1. Step 3. Step 2 of GP1. The crude product was purified by column chromatography (silica gel, hexane/ethyl acetate as eluent) to provide the pure compound 27a-D as a colorless oil in 24 % overall yield.
Synthesis of 27c-i (GP2)
Scheme V.21. Pathway for the synthesis of 27c-i (GP2).
Step 1. In a flame-dried Schlenk tube was charged the tosylhydrazine (1.0 equiv.) in MeOH (0.5 M). Then, the corresponding aldehyde (1.0 equiv.) was added. The reaction mixture was stirred at room temperature until complete conversion was observed by TLC. Solvents were removed in vacuo and the crude was used without further purification in the next step.
364 Part V Iodine(I/III) Catalysis for 1,3-Diamine Formation
Step 2. In a flame-dried Schlenk flask, the crude tosylhydrazone from the previous step (1.0 equiv.), Cs2CO3 (1.5 equiv.). The tube was backfilled with argon and evacuated (3 cycles), before addition of 1,4-dioxane (4 mL/mmol) under an argon atmosphere, followed by the addition of the aldehyde (1.0 equiv.). The tube was sealed with a silicone/PTFE cap and heated to 110 °C for 6 h. The mixture was cooled to room temperature, quenched with
NH4Cl and extracted three times with CH2Cl2. The combined organic phases were dried over MgSO4 and solvents removed in vacuo to give a residue which was purified by flash column chromatography (hexane/ethyl acetate as eluent) to provide the intermediate ketone. Step 3. Step 1 of GP1. Step 4. Step 2 of GP1. The crude product was purified by column chromatography (silica gel, hexane/ethyl acetate as eluent) to provide the pure compound 27c-i.
Synthesis of 27j-k (GP3)
Scheme V.22. Pathway for the synthesis of 27j-k (GP3).
Step 1. In a flame-dried Schlenk tube equipped with septum and stirring bar, CuI (1 equiv.) was dissolved in THF (0.1 M). The corresponding α,β- unsaturated ketone (1 equiv.) was then added and after stirring for 5 min at that temperature the mixture was cooled to 0 °C. The corresponding Grignard reagent (1.1 equiv.) was added dropwise during 5 min and the resulting mixture was further stirred at that temperature for 2 h. Then, aqueous NH4Cl solution (1 M) was added to the mixture. The organic phase was separated, and the resulting aqueous layer was extracted three times with Et2O. The combined organic phases were dried and concentrated under reduced pressure. The crude was purified by flash column chromatography (hexane/ethyl acetate as eluent) to yield the corresponding intermediate ketone. Step 2. Step 1 of GP1. Step 3. Step 2 of GP1. The crude product was purified by column chromatography (silica gel, hexane/ethyl acetate as eluent) to provide the pure compound 27j-k.
365 Part V Iodine(I/III) Catalysis for 1,3-Diamine Formation
Synthesis of 27l
Scheme V.23. Pathway for the synthesis of 27I.
Step 1. A flame dried Schlenk flask equipped with a stirrer bar was charged with citronellal (1.0 equiv.), Pd/C (20 % w/w) and ethyl acetate (5 mL/mmol). The reaction was stirred under 1 atm of hydrogen using a balloon overnight. The mixture was filtered through a pad of Celite and concentrated under reduced pressure to yield the crude amine, which was used without any further purification for the next step. Step 2. Step 1 of GP1. Step 3. Step 2 of GP1. The crude product was purified by column chromatography (silica gel, hexane/ethyl acetate as eluent) to provide the pure compound 27l as a colorless oil in 65% overall yield.
Synthesis of 27m-n (GP4)
Scheme V.24. Pathway for the synthesis of 27m-n (GP4).
Step 1. A flame and dried Schlenk tube equipped with a stirrer bar was charged with trimethyl phosphonoacetate (1.0 equiv.) and THF (5 mL/mmol). The mixture was cooled to 0 ºC and n-BuLi (2.0 M solution in cyclohexane, 1.0 equiv.) was added dropwise under an argon atmosphere. The reaction mixture was stirred for 1 h and the appropriate ketone (1.0
366 Part V Iodine(I/III) Catalysis for 1,3-Diamine Formation equiv.) was added. The mixture was stirred overnight at room temperature.
A saturated aqueous solution of NH4Cl was added and the resulting mixture was extracted three times with Et2O. The organic layer was dried over anhydrous Na2SO4 and the solvents were evaporated under reduced pressure. The crude product was filtered through a silica pad and was used in the next step without further purification. Step 2. A Schlenk flask equipped with a stirrer bar was charged with the corresponding crude ester from the previous step (1.0 equiv.), Pd/C (20 % w/w) and ethyl acetate (5 mL/mmol). The reaction was stirred under hydrogen atmosphere using a balloon for 12 h. The mixture was filtered through a pad of Celite and concentrated under reduced pressure to yield the crude material which was used in the next step without further purification. Step 3. A flame dried Schlenk flask equipped with a stirrer bar and a reflux condenser was charged with LiAlH4 (2.0 equiv.). Et2O (5 mL/mmol) was added carefully and the mixture was cooled to 0 ºC. The appropriate crude ester (1.0 equiv.) was added to the LiAlH4/Et2O suspension under an argon atmosphere. The mixture was heated to reflux for 2 h and cooled to 0 ºC afterwards. A solution of NaOH (1 M in water) was added. After filtration over anhydrous Na2SO4 and evaporation of the solvent under reduced pressure, the crude alcohol was obtained and directly used for the next step without further purification. Step 4. A flame dried Schlenk flask equipped with a stirrer bar was added dry DCM (10 mL/mmol) and oxalyl chloride (2.0 equiv.) under an argon atmosphere. The solution was cooled at -78 ºC and DMSO (4.0 equiv.) was added. The mixture was stirred for 1 h. After that, a solution of the crude alcohol from the previous step (1.0 equiv.) in dry DCM (1 mL/mmol) was added and the reaction mixture was stirred for another extra hour. NEt3 (6.0 equiv.) was added dropwise and the reaction temperature was increased until 0 ºC and stirred for another hour. A saturated aqueous solution of NH4Cl was added and the resulting mixture was extracted three times with DCM. The organic layer was dried over anhydrous Na2SO4 and the solvents were evaporated under reduced pressure. The crude aldehyde was directly used in the following step without further purification. Step 5. Step 1 of GP1. Step 6. Step 2 of GP1. The crude product was purified by column chromatography (silica gel, hexane/ethyl acetate as eluent) to provide the pure compound 27m-n.
Synthesis of 27u
367 Part V Iodine(I/III) Catalysis for 1,3-Diamine Formation
Scheme V.25. Pathway for the synthesis of 27u.
Step 1. A Flame dried Schlenk flask equipped with a magnetic stirrer bar was charged with iso-propyltriphenylphosphonium iodide (1.0 equiv.). After purging with argon, dry THF was added (5 mL/mmol). The flask was cooled at 0 °C, and n-BuLi (2.0 M solution in cyclohexane, 1.3 equiv.) was slowly injected by syringe over 5 min. The scarlet-red suspension was stirred for 1 h under an argon atmosphere. In another round-bottom flask, the corresponding proline derivative (1.0 equiv.) was dissolved in dry THF (2 mL/mmol) and added dropwise to the separately prepared mixture. The mixture was stirred at room temperature overnight. A saturated aqueous solution of NH4Cl was added and the resulting mixture was extracted three times with Et2O. The organic layer was dried over anhydrous Na2SO4 and the solvents were evaporated under reduced pressure. The crude product was filtered through a silica pad and was used without further purification for the following step. Step 2. A Schlenk flask equipped with a stirrer bar was charged with the corresponding crude alkene from the previous step (1.0 equiv.), Pd/C (20 % w/w) and ethyl acetate (5 mL/mmol). The reaction was stirred under hydrogen atmosphere using a balloon for 12 h. The mixture was filtered through a pad of Celite and concentrated under reduced pressure to yield the crude material which was used in the next step without further purification. Step 3. In a round-bottomed flask equipped with a magnetic stirrer bar, the crude from the previous step (1.0 equiv.) was dissolved in DCM (10 mL/mmol). The solution was cooled to 0 ºC and TFA (1 mL/mmol) was added. The reaction mixture was stirred at room temperature for 2 h. The reaction was quenched with water, neutralized with NaOH (1 M) and extracted twice with CH2Cl2. The combined organic layers were dried over anhydrous Na2SO4. HCl (1 M in Et2O, 1.1 equiv.) was added and the solvent was evaporated under reduced pressure. The crude hydrochloride salt was directly used in the following step.
368 Part V Iodine(I/III) Catalysis for 1,3-Diamine Formation
Step 4. Step 2 of GP1. The crude product was purified by column chromatography (silica gel, hexane/ethyl acetate as eluent) to provide the pure compound 27u as colorless oil in 68% overall yield.
Synthesis of 27v-w and 33a-b (GP5)
Scheme V.26. Pathway for the synthesis of 27v-w and 33a-b (GP4).
Step 1. A round-bottomed flask equipped with a magnetic stirrer bar was charged with the (L)-leucine (1.0 equiv.) and tert-butylacetate (2.5 mL/mmol). HClO4 (70% in water, 2.0 equiv.) was added and the mixture was stirred at room temperature overnight. A saturated aqueous solution of Na2CO3 was added and the resulting mixture was extracted three times with Et2O. The organic layer was dried over anhydrous Na2SO4 and the solvents were evaporated under reduced pressure to afford the amino ester, which was used in the next step without any further purification. Step 2. A flame-dried Schlenk flask equipped with a stirrer bar was charged with the crude amine (1.0 equiv.), benzaldehyde (1.5 equiv.) and methanol
369 Part V Iodine(I/III) Catalysis for 1,3-Diamine Formation
(2 mL/mmol). The mixture was stirred 2 h at room temperature. Then,
NaBH4 (4.0 equiv.) was added and the mixture was stirred for another 2 h at room temperature. The reaction was quenched with water and extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4. Purification by flash chromatography using a mixture of ethyl acetate/hexane as eluent was performed. Step 3. Step 2 of GP1. The crude product was purified by column chromatography (silica gel, hexane/ethyl acetate as eluent) to provide the pure compound 33a as white solid in 35% overall yield. Step 1. A round-bottomed flask equipped with a magnetic stirrer bar was charged with the (L)-leucine (1.0 equiv.) and MeCN (2 mL/mmol). Boc2O (1.5 equiv.) was added and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure. Purification over silica gel using a mixture of ethyl acetate/hexane as eluent afforded the pure Boc-protected (L)-leucine intermediate. Step 2. A flame dried Schlenk flask equipped with a stirrer bar and a reflux condenser was charged with LiAlH4 (2.0 equiv.), and Et2O (5 mL/mmol) was added carefully and the mixture was cooled at 0 ºC. The Boc-protected (L)-Leucine from the previous step (1.0 equiv.) was added to the
LiAlH4/Et2O suspension under an argon atmosphere. The mixture was heated to reflux for 2 h and cooled to 0 ºC afterwards. A solution of NaOH
(1 M in water) was added. After filtration over Na2SO4 and evaporation of the solvent under reduced pressure, the crude alcohol was obtained in quantitative yield. The crude alcohol was used in the next step without further purification. Step 3. A flame dried Schlenk flask equipped with a stirrer bar was charged with the freshly prepared crude alcohol (1.0 equiv.), imidazole (1.2 equiv.), DMAP (10 mol%), TBSCl (1.2 equiv.) and THF (2 mL/mmol). The mixture was stirred overnight at room temperature. A saturated aqueous solution of NH4Cl was added and the resulting mixture was extracted three times with Et2O. The organic layer was dried over anhydrous Na2SO4 and the solvents were evaporated under reduced pressure. Purification by flash chromatography using a mixture of ethyl acetate/hexane as eluent provided the pure silyl ether intermediate. Step 4. A flame dried Schlenk flask equipped with a stirrer bar was charged with the freshly prepared protected silyl ether (1.0 equiv.), 2,6-lutidine (2.0 equiv.) and DCM (2 mL/mmol). TBSOTf (1.2 equiv.) was added dropwise and the resulting mixture was stirred for 15 min at room temperature. A saturated aqueous solution of NH4Cl was added and the resulting mixture was extracted three times with CH2Cl2. The organic layer was dried over
370 Part V Iodine(I/III) Catalysis for 1,3-Diamine Formation
anhydrous Na2SO4 and the solvents were evaporated under reduced pressure. THF (2 mL/mmol) was added followed by TBAF (1 M solution in THF, 1.0 equiv.). The solution was stirred for 1 h at room temperature. A saturated aqueous solution of NH4Cl was added and the resulting mixture was extracted three times with Et2O. The organic layer was dried over anhydrous Na2SO4 and the solvents were evaporated under reduced pressure. The crude was directly used for the following step without any purification. Step 5. Step 2 of GP5. Step 6. Step 2 of GP1. Step 7. A round-bottomed flask equipped with a magnetic stirrer bar was charged with the corresponding sulfamide (1.0 equiv.) and THF (2 mL/mmol). TBAF (1 M solution in THF, 1.2 equiv.) was added and the mixture was stirred at room temperature for 1 h. A saturated aqueous solution of NH4Cl was added and the resulting mixture was extracted three times with Et2O. The organic layer was dried over anhydrous Na2SO4 and the solvents were evaporated under reduced pressure to afford the crude alcohol. Purification over silica gel using a mixture of ethyl acetate/hexane as eluent afforded 33b as a colorless oil with 15% overall yield. Step 8. A flame dried Schlenk flask equipped with a stirrer bar was charged with the previous purified alcohol 33a (1.0 equiv.), DMAP (5 mol%) and DCM (2 mL/mmol). Ac2O (1.0 equiv.) was added dropwise at 0 ºC and the resulting mixture could reach room temperature and stirred overnight. A saturated aqueous solution of NH4Cl was added and the resulting mixture was extracted three times with CH2Cl2. The organic layer was dried over anhydrous Na2SO4 and the solvents were evaporated under reduced pressure. Purification over silica gel using a mixture of ethyl acetate/hexane as eluent afforded 27w as colorless oil with 12 % overall yield. Step 1. Step 1 of GP5. Step 2. A flame dried Schlenk flask equipped with a stirrer bar was charged with the Boc-protected (L)-Leucine (1.0 equiv.), N-methylmorpholine (1.5 equiv.) and THF (5 mL/mmol). Methylchloroformate (1.2 equiv.) was added at 0 ºC and the resulting solution was stirred for 20 min. Then, ammonia (30% in water, 5.0 equiv.) was added and the mixture was stirred at room temperature for 4 h. A saturated aqueous solution of NH4Cl was added and the resulting mixture was extracted three times with ethyl acetate. The organic layer was dried over anhydrous Na2SO4 and the solvents were evaporated under reduced pressure. The crude amide was obtained in quantitative yield and was directly used in the following step without further purification.
371 Part V Iodine(I/III) Catalysis for 1,3-Diamine Formation
Step 3. A flame dried Schlenk flask equipped with a stirrer bar was charged with the freshly prepared amide from the previous step (1.0 equiv.), pyridine (1.5 equiv.) and THF (2 mL/mmol). TFAA (1.5 equiv.) was added at 0 ºC and the resulting mixture was stirred for 2 h. A saturated aqueous solution of NH4Cl was added and the resulting mixture was extracted three times with CH2Cl2. The organic layer was dried over anhydrous Na2SO4 and the solvents were evaporated under reduced pressure. The crude nitrile was directly used in the following step without any further purification. Step 4. In a round-bottomed flask equipped with a magnetic stirrer bar, the N-Boc derivative from the previous step (1.0 equiv.) was dissolved in DCM (10 mL/mmol). The solution was cooled to 0 ºC and TFA (1 mL/mmol) was added. The reaction mixture was stirred at room temperature for 2 h. The reaction was quenched with water, neutralized with NaOH (1 M) and extracted twice with CH2Cl2. The combined organic layers were dried over anhydrous Na2SO4. HCl (1 M in Et2O, 1.1 equiv.) was added and the solvent was evaporated under reduced pressure. The crude hydrochloride salt was directly used in the following step without further purification. Step 5. Step 2 of GP5. Step 6. Step 2 of GP1. The crude product was purified by column chromatography (silica gel, hexane/ethyl acetate as eluent) to provide the pure compound 27v as colorless oil in 26% overall yield.
Synthesis of 27x
Scheme V.27. Pathway for the synthesis of 27x.
372 Part V Iodine(I/III) Catalysis for 1,3-Diamine Formation
Step 1. A flame dried Schlenk flask equipped with a stirrer bar was charged with the 3β-acetoxy-13α-androst-5-en-17-one (1.0 equiv.), K2CO3 (2.0 equiv.) and MeOH (10 mL/mmol). The mixture was stirred at room temperature for 16 h. Water was added, and the resulting mixture was extracted three times with Et2O. The organic layer was dried over anhydrous Na2SO4 and the solvents were evaporated under reduced pressure. The crude product was used without further purification for the following step. Step 2. In a flame dried Schlenk flask equipped with a stirrer bar, the crude alcohol from the previous (1.0 equiv.) was dissolved in dry THF (10 mL/mmol) under an argon atmosphere. Diisopropyl azodicarboxylate (2.0 equiv.), triphenylphosphine (2.0 equiv.) and a solution of diphenyl phosphoryl azide (2.0 equiv.) in dry THF (1 mL/mmol) were added. The reaction mixture was stirred at room temperature for 16 h. After that, the solvent was removed under reduced pressure and the crude mixture was purified by column chromatography using a gradient of ethyl acetate and hexane to afford the azido derivative intermediate. Step 3. The pure azido alkene derivative from the previous step (1.0 equiv.) was hydrogenated using Pd/C (20 % w/w) and ethanol (5 mL/mmol) in a Parr apparatus at 4 bars of hydrogen gas pressure. After 48 h, the mixture was filtered through a pad of Celite and concentrated under reduced pressure to yield the crude amine derivative, which was used for the following step without any further purification. Step 4. A flame dried Schlenk flask equipped with a stirrer bar was charged with the benzylamine androstane derivative from the previous step (1.0 equiv.), MeOH (5 mL/mmol), benzaldehyde (1.0 equiv.), NaBH3CN (1.0 equiv.) and acetic acid (2.0 equiv.). The reaction mixture was stirred at room temperature for 72 h. After that, water was added, and the resulting mixture was extracted twice with ethyl acetate. The organic layer was dried over anhydrous Na2SO4 and the solvents were evaporated under reduced pressure. The crude mixture was directly used for the following step without any further purification. Step 5. Step 2 of GP1. The crude product was purified by column chromatography (silica gel, hexane/ethyl acetate as eluent) to provide the pure compound 27x as yellow solid in 16% overall yield.
V.6.3 Characterization of the substrates 22, 24, 27a-x and 33a- b for the amination reaction 1,3-Diphenyl-1-(methyl(N-methylsulfamoyl)amino)propane (22)
373 Part V Iodine(I/III) Catalysis for 1,3-Diamine Formation
Prepared according to the general procedure GP1, 22 was isolated as a colorless oil with an overall yield of 82%. 1H NMR (400 MHz, CDCl3): δ = 7.42-7.27 (m, 7H), 7.24-17 (m, 3H), 5.05 (t, J = 7.7 Hz, 1H), 3.88 (bq, J = 5.6 Hz, 1H), 2.77- 2.61 (m, 2H), 2.69 (s, 3H), 2.55 (d, J = 5.4 Hz, 3H), 2.33-2.23 (m, 2H). 13C NMR
(101 MHz, CDCl3): δ = 141.5, 138.6, 128.8, 128.6, 128.5, 128.3, 128.2, 126.2, 60.6, 33.1, 33.1, 29.4, 29.2. IR v(cm-1): 3304, 2942, 1453, 1311, 1146, 933, 698. HRMS - (m/z): [M-H] calculated for C17H21N2O2S: 317.1327; found: 317.1330.
1-Phenyl-1-(methyl(N-methylsulfamoyl)amino)butane (24)
Prepared according to the general procedure GP1, 24 was isolated as a yellowish oil with an overall yield of 76%. 1H
NMR (400 MHz, CDCl3): δ = 7.41-7.27 (m, 5H), 5.00 (t, J = 7.8 Hz, 1H), 3.91 (bq, J = 5.7 Hz, 1H), 2.64 (s, 3H), 2.55 (d, J = 5.4 Hz, 3H), 1.98-1.88 (m, 2H), 1.51-1.30 (m, 2H), 0.98 (t, J = 7.4 Hz, 3H). 13C
NMR (101 MHz, CDCl3): δ = 139.1, 128.7, 128.3, 128.0, 60.5, 33.1, 29.3, 29.0, 20.0, 14.0. IR v(cm-1): 3313, 2961, 1315, 1139. HRMS (m/z): [M-H]- calculated for C12H19N2O2S: 255.1173; found: 255.1172.
2-Methyl-4-(methyl(N-methylsulfamoyl)amino)pentane (27a)
Prepared according to the general procedure GP1, 27a was isolated as a colorless oil with an overall yield of 65%. 1H NMR (400 MHz, CDCl3): δ = 4.09-3.96 (m, 1H), 3.94 (bs, 1H), 2.66 (s, 3H), 2.66 (s, 3H), 1.69-1.53 (m, 1H), 1.46 (ddd, J = 14.3, 8.9, 5.6 Hz, 1H), 1.20 (ddd, J = 14.2, 8.4, 6.2 Hz, 1H), 1.16 (d, J = 6.7 Hz, 3H), 13 0.94 (d, J = 6.5 Hz, 3H), 0.92 (d, J = 6.6 Hz, 3H). C NMR (101 MHz, CDCl3): δ = 51.3, 43.7, 29.4, 27.7, 24.9, 23.1, 22.3, 18.3. IR v(cm-1): 3308, 2956, 1300, 1134, 1073, 927, 885, 568. HRMS (m/z): [M+Na]+ calculated for C8H20N2NaO2S: 231.1138; found: 231.1136. Determination of the carbon peak of the tertiary C(sp3)-H bond for the KIE experiment by HSQC: The targeted tertiary C-H bond is the multiplet at 1.69-1.53 by 1H NMR. By HSQC, the corresponding carbon peak is the one at 24.9 ppm.
374 Part V Iodine(I/III) Catalysis for 1,3-Diamine Formation
Scheme V.28. HSQC experiment of 27a to find out the related carbon peak of the targeted tertiary C(sp3)-H bond.
2-Methyl-4-(methyl(N-methylsulfamoyl)amino)butane (27b)
Prepared according to the general procedure GP1, 27b was isolated as a colorless oil with an overall yield of 66%. 1H
NMR (500 MHz, CDCl3): δ = 4.02 (bs, 1H), 3.21-3.15 (m, 2H), 2.80 (s, 3H), 2.69 (s, 3H), 1.66-1.56 (m, 1H), 1.51-1.43 (m, 2H), 13 0.92 (d, J = 6.6 Hz, 6H). C NMR (126 MHz, CDCl3): δ = 49.1, 36.7, 34.8, 29.6, 25.8, 22.6. IR v(cm-1): 3304, 2956, 1314, 1145. HRMS (m/z): [M+Na]+ calculated for C7H18N2NaO2S: 217.0981; found: 217.0972.
2-Methyl-4,4-phenyl-(methyl(N-methylsulfamoyl)amino)butane (27c)
Prepared according to the general procedure GP2, 27c was isolated as a colorless oil with an overall yield of 26%. 1H NMR (400 MHz, CDCl3): δ = 7.42-7.27 (m, 5H), 5.09 (t, J = 7.9 Hz, 1H), 3.90 (bs, 1H), 2.64 (s, 3H), 2.54 (s, 3H), 1.90-1.75 (m, 2H), 1.68-1.54 (m, 1H), 1.00 (d, J = 6.6 Hz, 3H), 0.96 (d, 13 J = 6.6 Hz, 3H). C NMR (101 MHz, CDCl3): δ = 139.1, 128.7, 128.3, 128.0, 58.7,
375 Part V Iodine(I/III) Catalysis for 1,3-Diamine Formation
40.1, 29.3, 29.0, 25.0, 22.8, 22.6. IR v(cm-1): 3304, 2955, 1315, 1133, 933, 705. + HRMS (m/z): [M+Na] calculated for C13H22N2NaO2S: 293.1294; found: 293.1287.
2-Methyl-4,4-p-methoxyphenyl-(methyl(N- methylsulfamoyl)amino)butane (27d)
Prepared according to the general procedure GP2, 27d was isolated as a colorless oil with an overall yield 1 of 18%. H NMR (500 MHz, CDCl3): δ = 7.33-7.28 (m, 2H), 6.91-6.85 (m, 2H), 5.05 (t, J = 7.9 Hz, 1H), 3.86 (q, J = 5.5 Hz, 1H), 3.81 (s, 3H), 2.61 (s, 3H), 2.55 (d, J = 5.4 Hz, 3H), 1.89-1.71 (m, 2H), 1.63-1.49 (m, 1H), 0.98 (d, J = 6.6 Hz, 3H), 0.95 (d, 13 J = 6.6 Hz, 3H). C NMR (126 MHz, CDCl3): δ = 159.3, 131.1, 129.5, 113.9, 58.2, 55.4, 40.2, 29.3, 28.9, 25.0, 22.7, 22.6. IR v(cm-1): 3313, 2961, 1521, 1309, 1251, + 1130. HRMS (m/z): [M+Na] calculated for C14H24N2NaO3S: 323.1400; found: 323.1403.
2-Methyl-4,4-p-fluorophenyl-(methyl(N- methylsulfamoyl)amino)butane (27e)
Prepared according to the general procedure GP2, 27e was isolated as a yellowish oil with an overall yield of 1 23%. H NMR (400 MHz, CDCl3): δ = 7.40-7.33 (m, 2H), 7.08-7.01 (m, 2H), 5.08 (t, J = 7.9 Hz, 1H), 3.95 (bs, 1H), 2.60 (s, 3H), 2.56 (s, 3H), 1.89-1.70 (m, 2H), 1.66-1.52 (m, 1H), 0.99 (d, J = 6.6 Hz, 3H), 0.96 (d, J = 6.6 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ = 162.4 (d, JC-F = 246.6 Hz), 134.9 (d, JC-F = 3.1 Hz), 129.9 (d, JC-F = 19 8.0 Hz), 115.5 (d, JC-F = 21.3 Hz), 57.9, 40.2, 29.3, 28.8, 24.9, 22.8, 22.5. F -1 NMR (376 MHz, CDCl3): δ = -114.4. IR v(cm ): 3316, 2970, 1509, 1321, 1139. + HRMS (m/z): [M+Na] calculated for C13H21FN2NaO2S: 311.1200; found: 311.1205.
2-Methyl-4,4-p-chlorophenyl-(methyl(N- methylsulfamoyl)amino)butane (27f)
376 Part V Iodine(I/III) Catalysis for 1,3-Diamine Formation
Prepared according to the general procedure GP2, 27f was isolated as a colorless oil with an overall yield of 1 54%. H NMR (500 MHz, CDCl3): δ = 7.33 (m, 4H), 5.07 (dd, J = 8.2, 7.5 Hz, 1H), 4.04 (bs, 1H), 2.60 (s, 3H), 2.56 (bs, 3H), 1.87-1.70 (m, 2H), 1.60 (m, 1H), 0.99 (d, J = 6.6 Hz, 3H), 0.96 (d, J = 6.6 Hz, 3H). 13C NMR (126 MHz,
CDCl3): δ = 137.7, 133.9, 129.7, 128.8, 58.0, 40.0, 29.3, 28.9, 25.0, 22.8, 22.5. IR v(cm-1): 3313, 2961, 2922, 1512, 1136, 1093, 936, 824, 587. HRMS (m/z): + [M+Na] calculated for C13H21ClN2NaO2S: 327.0904; found: 327.0908.
2-Methyl-4,4-p-bromophenyl-(methyl(N- methylsulfamoyl)amino)butane (27g)
Prepared according to the general procedure GP2, 27g was isolated as a colorless oil with an overall yield of 1 46%. H NMR (500 MHz, CDCl3): δ = 7.50-7.46 (m, 2H), 7.28-7.25 (m, 2H), 5.06 (t, J = 7.9 Hz, 1H), 2.60 (s, 3H), 2.57 (s, 3H), 1.85-1.71 (m, 2H), 1.62-1.56 (m, 1H), 13 0.99 (d, J = 6.5 Hz, 3H), 0.96 (d, J = 6.7 Hz, 3H). C NMR (126 MHz, CDCl3): δ = 138.2, 131.8, 130.0, 122.0, 58.1, 40.0, 28.9, 27.1, 25.0, 22.8, 22.5. IR v(cm-1): 3307, 2955, 1306, 1136. HRMS (m/z): [M+Na]+ calculated for C13H21BrN2NaO2S: 371.0399; found: 371.0404.
2-Methyl-4,4-(4-trifluomethylphenyl)-(methyl(N- methylsulfamoyl)amino)butane (27h)
Prepared according to the general procedure GP2, 27h was isolated as a colorless oil with an overall yield of 1 31%. H NMR (400 MHz, CDCl3): δ = 7.62 (d, J = 8.2 Hz, 2H), 7.51 (d, J = 8.2 Hz, 2H), 5.15 (t, J = 7.9 Hz, 1H), 4.01 (bs, 1H), 2.62 (d, J = 0.8 Hz, 3H), 2.58 (s, 3H), 1.92- 1.73 (m, 2H), 1.68-1.54 (m, 1H), 1.01 (d, J = 6.6 Hz, 3H), 13 0.97 (d, J = 6.6 Hz, 3H). C NMR (101 MHz, CDCl3): δ = 143.3 (q, JC-F = 1.2 Hz), 130.2 (q, JC-F = 32.5 Hz), 128.6, 125.6 (q, JC-F = 3.7 Hz), 124.2 (q, JC-F = 272.0 19 Hz), 58.1, 39.9, 29.3, 28.9, 24.9, 22.8, 22.4. F NMR (376 MHz, CDCl3): δ = - 62.7. IR v(cm-1): 3307, 2958, 1330, 1130, 1064. HRMS (m/z): [M+Na]+ calculated for C14H21F3N2NaO2S: 361.1168; found: 361.1180.
2-Methyl-4,4-(4-isopropylphenyl)-(methyl(N- methylsulfamoyl)amino)butane (27i)
377 Part V Iodine(I/III) Catalysis for 1,3-Diamine Formation
Prepared according to the general procedure GP2, 27i was isolated as a colorless oil with an overall yield of 1 30%. H NMR (500 MHz, CDCl3): δ = 7.33-7.24 (m, 2H), 7.23-7.17 (m, 2H), 5.05 (t, J = 7.9 Hz, 1H), 2.89 (hept, J = 6.9 Hz, 1H), 2.61 (s, 3H), 2.53 (s, 3H), 1.88-1.73 (m, 2H), 1.67-1.55 (m, 1H), 1.24 (d, J = 7.0 Hz, 6H), 0.98 13 (d, J = 6.6 Hz, 3H), 0.95 (d, J = 6.6 Hz, 3H). C NMR (126 MHz, CDCl3): δ = 148.5, 136.4, 128.2, 126.6, 58.4, 40.0, 33.8, 29.2, 28.8, 24.9, 24.0, 24.0, 22.8, 22.5. IR v(cm-1): 3316, 2961, 1315, 1136. HRMS (m/z): [M+Na]+ calculated for
C16H28N2NaO2S: 335.1764; found: 335.1757.
6-Phenethyl-8-(methyl(N-methylsulfamoyl)amino)nonane (27j)
Prepared according to the general procedure GP3, 27j was isolated as a non-separable 1:1 mixture of diastereoisomers as a colorless oil with an overall 1 yield of 35%. H NMR (400 MHz, CDCl3): δ = 7.31- 7.24 (m, 4H), 7.22-7.14 (m, 6H), 4.09-3.99 (m, 2H), 3.93 (bs, 1H), 3.88 (bs, 1H), 2.67 (s, 3H), 2.65 (s, 3H), 2.62 (bs, 3H), 2.62 (bs, 3H), 2.60-2.51 (m, 4H), 1.80-1.61 (m, 2H), 1.60-1.49 (m, 6H), 1.49-1.35 (m, 2H), 1.38-1.23 (m, 16H), 1.15 (d, J = 6.7 Hz, 3H), 1.14 (d, J = 6.7 Hz, 3H), 0.90 (t, J = 13 6.9 Hz, 3H), 0.89 (t, J = 6.9 Hz, 3H). C NMR (101 MHz, CDCl3): δ = 143.0, 142.9, 128.6, 128.5, 128.5, 128.4, 125.8, 125.8, 51.0, 51.0, 38.9, 38.8, 35.5, 35.4, 34.2, 34.0, 33.5, 33.1, 33.0, 32.9, 32.5, 32.4, 29.4, 29.4, 27.8, 27.8, 26.2, 25.9, 22.8, 22.8, 18.4, 18.3, 14.2, 14.2. IR v(cm-1): 2925, 2856, 1319, 1133, 698. HRMS - (m/z): [M-H] calculated for C19H33N2O2S: 353.2268; found: 353.2282.
6-isobutyl-8-(methyl(N-methylsulfamoyl)amino)nonane (27k)
Prepared according to the general procedure GP3, 27k was isolated as a non-separable 1:1 mixture of diastereoisomers as a colorless oil with an overall yield 1 of 32%. H NMR (500 MHz, CDCl3): δ = 4.08-3.89 (m, 2H), 2.67 (s, 3H), 2.66 (s, 3H), 2.66 (s, 6H), 1.69-1.56 (m, 2H), 1.52-1.37 (m, 4H), 1.33-1.18 (m, 18H), 1.16 (d, J = 6.7 Hz, 3H), 1.15 (d, J = 6.6 Hz, 3H), 1.19-1.07 (m, 3H), 1.06-0.98 (m, 1H), 0.90-0.86 (m, 18H). 13C NMR (101 MHz, CDCl3): δ = 51.2, 51.0, 43.8, 43.8, 39.6, 39.3, 33.5, 33.5, 32.5, 32.5, 32.1, 31.9, 29.5, 29.4, 27.9, 27.8, 25.9, 25.7, 25.5, 25.2, 23.5, 23.2, 23.1, 22.9,
378 Part V Iodine(I/III) Catalysis for 1,3-Diamine Formation
22.9, 22.6, 18.4, 18.3, 14.3, 14.3. IR v(cm-1): 3310, 2928, 1312, 1136. HRMS + (m/z): [M+Na] calculated for C15H34N2NaO2S: 329.2233; found: 329.2230.
2-Methyl-6-methyl-8-(methyl(N-methylsulfamoyl)amino)octane (27l)
Prepared according to the procedure described above, 27l was isolated as a colorless oil with an 1 overall yield of 65%. H NMR (500 MHz, CDCl3): δ = 3.99 (bs, 1H), 3.25-3.11 (m, 2H), 2.81 (s, 3H), 2.69 (s, 3H), 1.66-1.56 (m, 1H), 1.58-1.48 (m, 1H), 1.50-1.41 (m, 1H), 1.44-1.34 (m, 1H), 1.36-1.19 (m, 3H), 1.20-1.08 (m, 3H), 0.90 (d, J = 6.5 Hz, 3H), 0.87 (d, J = 6.7 13 Hz, 3H), 0.86 (d, J = 6.6 Hz, 3H). C NMR (126 MHz, CDCl3): δ (ppm) = 48.9, 39.4, 37.3, 34.9, 34.8, 30.6, 29.6, 28.1, 24.8, 22.8, 22.7, 19.6. IR v(cm-1): - 3310, 2928, 1318, 1142. HRMS (m/z): [M-H] calculated for C12H27N2O2S: 263.1799; found: 263.1810.
N-(1-(2-(methyl(N- methylsulfamoyl)amino)ethyl)cyclohexyl)acetamide (27m)
Prepared according to the general procedure GP4, 27m was isolated as a colorless oil with an overall yield of 1 48%. H NMR (400 MHz, CDCl3): δ = 3.99 (bs, 1H), 3.24- 3.11 (m, 2H), 2.80 (s, 3H), 2.69 (d, J = 5.4 Hz, 3H), 1.78- 1.60 (m, 5H), 1.53-1.42 (m, 2H), 1.37-1.06 (m, 4H), 1.02-0.84 (m, 2H). 13C NMR - (101 MHz, CDCl3): δ = 48.6, 35.3, 35.3, 34.8, 33.3, 29.6, 26.7, 26.4. IR v(cm 1): 3313, 2928, 2849, 1321, 1145. HRMS (m/z): [M+H]+ calculated for C10H23N2O2S :235.1475; found: 235.1484.
N-(2-(2-(methyl(N-methylsulfamoyl)amino)ethyl)-2,3-dihydro-1H- inden-2-yl)acetamide (27n)
Prepared according to the general procedure GP4, 27n was isolated as a colorless oil with an overall yield of 1 36%. H NMR (400 MHz, CDCl3): δ = 7.21-7.16 (m, 2H), 7.16-7.10 (m, 2H), 4.06 (bq, J = 5.4 Hz, 1H), 3.31-3.24 (m, 2H), 3.10 (dd, J = 15.3, 7.7 Hz, 2H), 2.84 (s, 3H), 2.71 (d, J = 5.4 Hz, 3H), 2.63 (dd, J = 15.4, 8.0 Hz, 2H), 2.55-2.42 (m, 1H), 1.86-1.78 (m, 13 2H). C NMR (101 MHz, CDCl3): δ = 143.1, 126.4, 124.6, 49.7, 39.2, 37.4, 35.0,
379 Part V Iodine(I/III) Catalysis for 1,3-Diamine Formation
33.8, 29.6. IR v(cm-1): 3313, 2920, 1320, 1124. HRMS (m/z): [M+Na]+ calculated for C13H20N2NaO2S: 291.1138; found: 291.1132.
2-Methyl-4-(propyl(N-methylsulfamoyl)amino)butane (27p)
Prepared according to the general procedure GP1, 27p was isolated as a colorless oil with an overall yield of 89%. 1H NMR (500 MHz, CDCl3): δ = 3.96 (bs, 1H), 3.22-3.17 (m, 2H), 3.16-3.11 (m, 2H), 2.67 (s, 3H), 1.66-1.53 (m, 3H), 1.53- 1.44 (m, 2H), 0.92 (d, J = 6.5 Hz, 6H), 0.92 (t, J = 7.4 Hz, 3H). 13C NMR (126 -1 MHz, CDCl3): δ = 49.7, 46.5, 37.3, 29.4, 26.1, 22.6, 21.7, 11.4. IR v(cm ): 3305, + 2958, 2873, 1313, 1142. HRMS (m/z): [M+Na] calculated for C9H22N2NaO2S: 245.1294; found: 245.1287.
2-Methyl-4-(butyl(N-methylsulfamoyl)amino)butane (27q)
Prepared according to the general procedure GP1, 27q was isolated as a yellowish oil with an overall yield of 78%. 1H
NMR (500 MHz, CDCl3): δ = 3.22-3.14 (m, 4H), 2.67 (s, 3H), 1.63-1.52 (m, 3H), 1.52-1.45 (m, 2H), 1.38-1.29 (m, 2H), 0.95 13 (t, J = 7.4 Hz, 3H), 0.92 (d, J = 6.6 Hz, 6H). C NMR (126 MHz, CDCl3): δ = 47.7, 46.4, 37.2, 31.1, 30.6, 29.4, 26.1, 22.6, 20.2, 13.9. IR v(cm-1): 2957, 2872, - 1311, 1142. HRMS (m/z): [M-H] calculated for C10H23N2O2S: 235.1486; found: 235.1486.
2-Methyl-4-(cyclohexyl(N-methylsulfamoyl)amino)pentane (27r)
Prepared according to the general procedure GP1, 27r was isolated as a white solid with an overall yield of 45%. 1H NMR (400 MHz, CDCl3): δ = 3.91 (bs, 1H), 3.65-3.49 (m, 1H), 3.21-3.08 (m, 1H), 2.67 (s, 3H), 1.81-1.70 (m, 6H), 1.67- 1.53 (m, 3H), 1.50-1.39 (m, 1H), 1.35-1.20 (m, 2H), 1.26 (d, J = 6.8 Hz, 3H), 1.19-1.03 (m, 1H), 0.93 (d, J = 6.3 Hz, 3H), 0.90 (d, J = 6.4 Hz, 13 3H). C NMR (101 MHz, CDCl3): δ = 57.4, 51.7, 45.3, 32.6, 32.4, 29.2, 26.7, 26.7, 25.5, 25.5, 23.6, 22.1,19.7. IR v(cm-1): 3313, 2919, 1318, 1133. HRMS (m/z): + [M+Na] calculated for C13H28N2NaO2S: 299.1764; found: 299.1752. mp: 84- 86 ºC.
2-Methyl-4-(benzyl(N-methylsulfamoyl)amino)pentane (27s)
380 Part V Iodine(I/III) Catalysis for 1,3-Diamine Formation
Prepared according to the general procedure GP1, 27s was isolated as a colorless oil with an overall yield of 58%. 1H
NMR (400 MHz, CDCl3): δ = 7.44-7.23 (m, 5H), 4.34 (d, J = 15.4 Hz, 1H), 4.24 (d, J = 15.4 Hz, 1H), 3.96 (m, 1H), 3.67 (bs, 1H), 2.53 (s, 3H), 1.66-1.50 (m, 1H), 1.49 (ddd, J = 13.9, 7.5, 6.4 Hz, 1H), 1.24 (dt, J = 13.6, 7.2 Hz, 1H), 1.22 (d, J = 6.7 Hz, 3H), 0.89 (d, J = 6.5 Hz, 3H), 0.78 13 (d, J = 6.6 Hz, 3H). C NMR (101 MHz, CDCl3): δ = 138.5, 128.6, 128.6, 127.7, 53.3, 47.7, 44.7, 29.4, 25.0, 22.7, 22.5, 19.4. IR v(cm-1): 3319, 2964, 1315, 1142. + HRMS (m/z): [M+Na] calculated for C14H24N2NaO2S: 307.1451; found: 307.1448.
2-Methyl-4-(methyl(N-tert-butylsulfamoyl)amino)pentane (27t)
Prepared according to the general procedure GP1, 27t was isolated as a white solid with an overall yield of 53%. 1H NMR (400 MHz, CDCl3): δ = 4.14-3.96 (m, 1H), 3.80 (bs, 1H), 2.64 (s, 3H), 1.66-1.51 (m, 1H), 1.48-1.36 (m, 1H), 1.32 (s, 9H), 1.27-1.16 (m, 1H), 1.14 (d, J = 6.7 Hz, 3H), 0.93 (d, J = 6.5 Hz, 3H), 0.91 (d, 13 J = 6.6 Hz, 3H). C NMR (101 MHz, CDCl3): δ = 54.3, 51.3, 43.8, 30.1, 27.7, 25.0, 22.8, 22.7, 17.8. IR v(cm-1): 3264, 2962, 1306, 1136. HRMS (m/z): [M- - H] calculated for C11H25N2O2S: 249.1642; found: 249.1653. mp: 54-56 ºC.
(S)-2-Isobutyl-N-methylpyrrolidine-1-sulfonamide (27u)
Prepared according to the procedure described above, 27u was isolated as a colorless oil with an overall yield of 68%. 1 H NMR (500 MHz, CDCl3): δ = 3.99 (bs, 1H), 3.90-3.82 (m, 1H), 3.40 (dt, J = 10.1, 7.3 Hz, 1H), 3.23 (dt, J = 10.1, 6.1 Hz, 1H), 2.72 (d, J = 5.3 Hz, 3H), 2.07-1.96 (m, 1H), 1.93-1.85 (m, 2H), 1.70-1.56 (m, 3H), 1.33-1.24 (m, 1H), 0.93 (d, J = 5.7 Hz, 3H), 0.92 (d, J = 5.6 Hz, 3H). 13C NMR
(126 MHz, CDCl3): δ = 59.1, 48.6, 45.1, 31.3, 29.7, 25.7, 24.7, 23.8, 21.8. IR v(cm-1): 3196, 2955, 1311, 1148, 590. HRMS (m/z): [M-H]- calculated for
C9H19N2O2S: 219.1173; found: 219.1179.
1-Cyano-3-methyl-1-(benzyl(N-methylsulfamoyl)amino)butane (27v)
Prepared according to the general procedure GP5, 27v was isolated as a colorless oil with an overall yield of 26%. 1H
NMR (400 MHz, CDCl3): δ = 7.46-7.42 (m, 2H), 7.40-7.29 (m, 3H), 4.80 (t, J = 7.9 Hz, 1H), 4.73 (d, J = 15.4 Hz, 1H), 4.28
381 Part V Iodine(I/III) Catalysis for 1,3-Diamine Formation
(d, J = 15.4 Hz, 1H), 4.02 (bq, J = 5.8 Hz, 1H), 2.71 (d, J = 5.4 Hz, 3H), 1.68-1.57 (m, 1H), 1.57-1.53 (m, 2H), 0.88 (d, J = 6.5 Hz, 3H), 0.70 (d, J = 6.5 Hz, 3H). 13 C NMR (101 MHz, CDCl3): δ = 136.4, 128.9, 128.6, 128.5, 118.1, 50.8, 49.6, 41.4, 29.8, 24.5, 21.9, 21.8. IR v(cm-1): 3325, 2955, 2928, 1342, 1154. HRMS + (m/z): [M+Na] calculated for C14H21N3NaO2S: 318.1247; found: 318.1255.
1-Acetoxy-4-methyl-2-(S)-(benzyl(N- methylsulfamoyl)amino)pentane (27w)
Prepared according to the general procedure GP5, 27w was isolated as a colorless oil with an overall yield of 12%. 1H NMR (400 MHz, CDCl3): δ = 7.42-7.27 (m, 5H), 4.34 (d, J = 15.2 Hz, 1H), 4.28 (d, J = 15.2 Hz, 1H), 4.19-4.00 (m, 3H), 3.85 (bq, J = 5.6 Hz, 1H), 2.58 (d, J = 5.4 Hz, 3H), 2.02 (s, 3H), 1.73-1.60 (m, 1H), 1.56-1.46 (m, 1H), 1.36-1.27 (m, 1H), 0.89 (d, J = 6.5 Hz, 3H), 0.84 (d, J = 13 6.6 Hz, 3H). C NMR (101 MHz, CDCl3): δ = 170.8, 137.5, 128.8, 128.7, 128.1, 64.8, 56.3, 49.0, 39.5, 29.4, 24.9, 22.7, 22.5, 21.0. IR v(cm-1): 3313, 2961, 1745, - 1330, 1239, 1139. HRMS (m/z): [M-H] calculated for C16H25N2O4S: 315.1541; found: 341.1539.
(3,5)-3-(Benzyl(N-methylsulfamoyl)amino)-androstane-17-one (27x)
Prepared according to the procedure described above, 27x was isolated as a yellow solid with an overall yield of 16%. 1H NMR
(400 MHz, CDCl3): δ = 7.40-7.35 (m, 2H), 7.34-7.29 (m, 2H), 7.26-7.21 (m, 1H), 4.55 (s, 2H), 4.05 (bs, 1H), 3.98 (tt, J = 8.9, 4.4 Hz, 1H), 2.61 (s, 3H), 2.41 (ddd, J = 19.1, 8.9, 1.1 Hz, 1H), 2.05 (dt, J = 19.2, 9.0 Hz, 1H), 1.96-1.83 (m, 2H), 1.79-1.73 (m, 2H), 1.73-1.63 (m, 2H), 1.63-1.52 (m, 2H), 1.50- 1.38 (m, 3H), 1.30-1.07 (m, 7H), 0.82 (s, 3H), 0.90-0.69 (m, 1H), 0.76 (s, 3H), 13 0.60-0.48 (m, 1H). C NMR (75 MHz, CDCl3): δ = 221.5, 139.0, 128.5, 127.5, 127.3, 55.2, 53.2, 51.5, 50.4, 47.9, 40.4, 35.9, 35.2, 35.1, 35.0, 32.8, 31.7, 30.7, 29.4, 28.2, 26.0, 21.8, 20.2, 13.9, 13.3. IR v(cm-1): 2924, 1737, 1318, 1154. HRMS - (m/z): [M-H] calculated for C27H39N2O3S: 471.2687; found: 471.2676. mp: 77 -79 ºC.
Tert-butyl N-benzyl-N-(N-methylsulfamoyl)-L-leucinate (33a)
382 Part V Iodine(I/III) Catalysis for 1,3-Diamine Formation
Prepared according to the general procedure GP5, 33a was isolated as a white solid with an overall yield of 35%. 1H
NMR (300 MHz, CDCl3): δ = 7.47-7.40 (m, 2H), 7.36-7.27 (m, 3H), 4.64 (d, J = 15.7 Hz, 1H), 4.32 (t, J = 7.2 Hz, 1H), 4.31 (d, J = 15.7 Hz, 1H), 4.20 (bs, 1H), 2.68 (s, 3H), 1.60-1.51 (m, 3H), 1.49 (s, 9H), 0.83 (d, J = 6.2 Hz, 3H), 0.63 (d, J = 6.3 Hz, 3H). 13C
NMR (75 MHz, CDCl3): δ = 171.9, 137.8, 128.7, 128.6, 127.8, 82.4, 60.5, 50.5, 39.5, 29.6, 28.2, 24.8, 22.6, 21.7. IR v(cm-1): 3316, 2961, 1724, 1330, 1145. HRMS + (m/z): [M+Na] calculated for C18H30N2NaO4S: 393.1818; found: 393.1817. mp: 85-88 ºC.
1-Hydroxy-4-methyl-2-(S)-(benzyl(N- methylsulfamoyl)amino)pentane (33b)
Prepared according to the general procedure GP5, 33b was isolated as a colorless oil with an overall yield of 15%. 1H
NMR (400 MHz, CDCl3): δ = 7.46-7.42 (m, 2H), 7.37-7.28 (m, 3H), 4.44 (d, J = 15.5 Hz, 1H), 4.34 (d, J = 15.5 Hz, 1H), 4.17 (bs, 1H), 4.01-3.90 (m, 1H), 3.72-3.55 (m, 2H), 2.67 (s, 3H), 2.03 (bs, 1H), 1.64-1.57 (m, 1H), 1.39 (ddd, J = 13.9, 8.0, 5.8 Hz, 1H), 1.17 (ddd, J = 14.1, 7.9, 6.2 Hz, 1H), 0.87 (d, J = 6.5 Hz, 3H), 0.75 (d, J = 6.6 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ = 138.1, 128.8, 128.6, 128.0, 63.7, 59.6, 48.9, 39.1, 29.6, 24.8, 22.7, 22.4. IR v(cm-1): 3492, 3304, 2955, 1306, 1139. HRMS (m/z): [M-H]- calculated for C14H23N2O3S: 299.1435; found: 299.1429.
V.6.4 Synthesis of the products 23, 25, 26, 28a-x, 29, 30, 31, 32 and 34a-b Synthesis of 23
A flame dried Schlenk tube equipped with a stirrer bar was charged with 22
(0.10 mmol, 1.0 equiv.) and backfilled with argon. DCE (2 mL), PhI(oFBA)2 (0.12 mmol, 1.2 equiv.) and molecular iodine (0.01 mmol, 10 mol%) were added. The reaction mixture was stirred at room temperature under purple LEDs irradiation for 16 h. The reaction mixture was quenched with a 1/1- mixture of saturated aqueous solutions of Na2S2O3 and Na2CO3 and extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude mixture was purified by column chromatography over silica gel
383 Part V Iodine(I/III) Catalysis for 1,3-Diamine Formation using a mixture of ethyl acetate/hexane as eluent to yield 23 as a white solid in 90% isolated yield.
Synthesis of 25
A flame dried Schlenk tube equipped with a stirrer bar was charged with 26
(0.04 mmol, 1.0 equiv.) and backfilled with argon. DCE (2 mL) and PhICl2 (0.04 mmol, 1.0 equiv.) were added. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with a 1/1- mixture of saturated aqueous solutions of Na2S2O3 and Na2CO3 and extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude was purified by column chromatography using a mixture of ethyl acetate/hexane as eluent to finally get 25 as a white solid in 52% isolated yield.
Synthesis of 26 A flame dried Schlenk tube equipped with a stirrer bar was charged with 24 (0.10 mmol, 1.0 equiv.) and backfilled with argon. DCE or MeCN (2 mL), PIDA (0.12 mmol, 1.2 equiv.) and molecular iodine (0.02 mmol, 20 mol%) were added. The reaction mixture was stirred at room temperature under purple LEDs irradiation for 16 h. The reaction mixture was quenched with a 1/1-mixture of saturated aqueous solutions of Na2S2O3 and Na2CO3 and extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude mixture was purified using a preparative TLC and a mixture of ethyl acetate/hexane as eluent to provide 26 as a yellow oil in 40% isolated yield.
Synthesis of 28a-x and 34a-b (GP6)
A tube equipped with a stirrer bar was charged with the corresponding starting material 27a-x (0.10 mmol, 1.0 equiv.) and backfilled with argon. Acetonitrile (2 mL), PIDA (0.12 mmol, 1.2 equiv.) and molecular iodine (0.01 mmol, 10 mol%) were added. The reaction mixture was stirred at room temperature under purple LED irradiation for 16 h. The reaction mixture was quenched with a 1/1- mixture of saturated aqueous solutions of Na2S2O3 and Na2CO3 and extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude mixture was purified by reverse phase column
384 Part V Iodine(I/III) Catalysis for 1,3-Diamine Formation
chromatography (RPC18) using a mixture of methanol/water (80/20, v/v) to provide 28a-x.
Synthesis of 29
A tube equipped with a stirrer bar was charged with 28s (0.10 mmol) and ethylene glycol (1 mL). NaOH (80 mg) was added to the solution and the tube was sealed with a cap and heated at 200 ºC for 6 h. After that, the reaction mixture was cooled down to room temperature and diluted with a
2 M solution of NaOH and extracted three times with Et2O. The combined organic layers were dried over anhydrous Na2SO4 before the addition of HCl (100 L of a 1 M solution in dioxane). The mixture was then concentrated under reduced pressure to provide the pure ammonium salt 29 as a yellowish oil in 87% isolated yield.
Synthesis of 30
A tube equipped with a stirrer bar was charged with 28s (0.10 mmol) and 1,3-propanediamine (1 mL). The tube was sealed with a cap and heated at 150 ºC for 3 h. After that, the reaction mixture was cooled down to room temperature and diluted with water and extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to provide 30 as a colorless oil in 82% isolated yield.
Synthesis of 31 from 29
A tube equipped with a stirrer bar was charged with 29 (0.05 mmol) and 1,3-propanediamine (0.5 mL). The tube was sealed with a cap and heated at 150 ºC for 48 h. After that, the reaction mixture was cooled down to room temperature and diluted with a 2 M solution of NaOH and extracted three times with Et2O. The combined organic layers were dried over anhydrous
Na2SO4 before the addition of HCl (100 L of a 1 M solution in dioxane). The mixture was then concentrated under reduced pressure to provide the crude ammonium salt. The crude mixture was purified by reverse phase column chromatography (RPC18) using a mixture of methanol/water (30/70, v/v) to afford 31 as a yellowish oil in 46% isolated yield.
Synthesis of 31 from 30
385 Part V Iodine(I/III) Catalysis for 1,3-Diamine Formation
A tube equipped with a stirrer bar was charged with 30 (0.05 mmol) and ethylene glycol (0.5 mL). NaOH (40 mg) was added to the solution and the tube was sealed with a cap and heated at 200 ºC for 6 h. After that, the reaction mixture was cooled down to room temperature and diluted with a
2 M solution of NaOH and extracted three times with Et2O. The combined organic layers were dried over anhydrous Na2SO4 before the addition of HCl (100 L of a 1 M solution in dioxane). The mixture was then concentrated under reduced pressure to provide the crude ammonium salt. The crude mixture was purified by reverse phase column chromatography (RPC18) using a mixture of methanol/water (30/70, v/v) to afford 31 as a yellowish oil in 98% isolated yield.
Synthesis of 32
A flame dried Schlenk tube equipped with a stirrer bar was charged with 27a (0.10 mmol, 1.0 equiv.) and backfilled with argon. Nitromethane (1 mL), AcOH (1 mL), PIDA (0.14 mmol, 1.4 equiv.) and molecular iodine (0.02 mmol, 0.02 equiv.) were added. The reaction mixture was stirred at room temperature under purple LED irradiation for 16 h. The reaction mixture was then quenched with a 1/1-mixture of saturated aqueous solutions of
Na2S2O3 and Na2CO3 and extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude mixture was purified by column chromatography over silica gel using a mixture of ethyl acetate/hexane as eluent to provide 32 as a yellow oil in 90% isolated yield.
V.6.5 Characterization of the products 23, 25, 26, 28a-x, 29, 30, 31, 32 and 34a-b 2,6-Dimethyl-3,5-diphenyl-1,2,6-thiadiazinane-1,1-dioxide (23)
Prepared according to the procedure described above, 23 was isolated as a white solid with a yield of 90%. 1H NMR (400 MHz, CDCl3): δ = 7.43-7.31 (m, 10H), 4.81 (dd, J = 12.3, 2.9 Hz, 2H), 2.57 (s, 6H), 2.51 (dt, J = 14.2, 12.4 Hz, 1H), 2.08 13 (dt, J = 14.2, 2.9 Hz, 1H). C NMR (101 MHz, CDCl3): δ = 138.6, 129.1, 128.6, 127.6, 63.3, 32.7, 32.1. IR v(cm-1): 1451, 1317, 1151, 1101, 914, 792, 768, 699. + HRMS (m/z): [M+H] calculated for C17H21N2O2S: 317.1318; found: 317.1326. mp: 145-147 ºC. X-ray crystal structure determination:
386 Part V Iodine(I/III) Catalysis for 1,3-Diamine Formation
______Identification code CCDC 1909453 Empirical formula C17 H20 N2 O2 S Formula weight 316.41 Temperature 100(2)K Wavelength 0.71073 Å Crystal system monoclinic Space group P 21/n Unit cell dimensions a = 10.2981(14)Å α = 90°. b = 7.0578(9)Å β = 94.024(4)° c = 21.651(3)Å γ = 90°. 3 Volume 1569.7(3) Å Z 4 3 Density (calculated) 1.339 Mg/m Absorption coefficient 0.215 mm-1 F(000) 672 3 Crystal size 0.550 x 0.250 x 0.150 mm Theta range for data collection 1.886 to 33.764°. Index ranges -16<=h<=15, -11<=k<=10, -29<=l<=32 Reflections collected 21566 Independent reflections 6146[R(int) = 0.0429] Completeness to theta =33.764° 97.8% Absorption correction Multi-scan Max. and min. transmission 0.74 and 0.57 Refinement method Full-matrix least-squares on F2
387 Part V Iodine(I/III) Catalysis for 1,3-Diamine Formation
Data / restraints / parameters 6146/ 0/ 201 Goodness-of-fit on F2 1.046 Final R indices [I>2sigma(I)] R1 = 0.0417, wR2 = 0.1051 R indices (all data) R1 = 0.0566, wR2 = 0.1135 -3 Largest diff. peak and hole 0.534 and -0.491 e.Å
2,6-Dimethyl-3-methyl-5-phenyl-1,2,6-thiadiazinane-1,1-dioxide (25)
Prepared according to the procedure described above, 25 was isolated as a white solid with a yield of 52%. 1H NMR (400 MHz, CDCl3): δ = 7.46-7.30 (m, 5H), 4.28 (dd, J = 12.0, 3.3 Hz, 1H), 4.24-4.15 (m, 1H), 2.88 (s, 3H), 2.47 (s, 3H), 2.09-1.96 (m, 1H), 1.67 (dt, J = 14.5, 3.0 Hz, 1H), 1.27 (d, J = 6.7 Hz, 3H). 13C NMR (101 MHz, - CDCl3): δ = 139.8, 129.1, 128.5, 127.4, 65.7, 53.7, 35.5, 32.8, 29.9, 19.3. IR v(cm 1): 2922, 1721, 1466, 1327, 1278, 1148. HRMS (m/z): [M+Na]+ calculated for C12H18N2NaO2S: 277.0981; found: 277.0983. mp: 53-56 ºC. X-ray crystal structure determination:
______Identification code CCDC 1923112 Empirical formula C12 H18 N2 O2 S Formula weight 254.34 Temperature 100(2)K Wavelength 0.71073 Å Crystal system orthorhombic Space group P b c a Unit cell dimensions a = 17.0285(7) Å α = 90°.
388 Part V Iodine(I/III) Catalysis for 1,3-Diamine Formation
b = 6.9101(3) Å β = 90°. c = 21.3006(9) Å γ = 90°. 3 Volume 2506.40(18) Å Z 8 3 Density (calculated) 1.348 Mg/m Absorption coefficient 0.251 mm-1 F(000) 1088 3 Crystal size 0.200 x 0.200 x 0.120 mm Theta range for data collection 1.912 to 34.468∞. Index ranges -26<=h<=19, -10<=k<=10, -33<=l<=25 Reflections collected 29390 Independent reflections 5074[R(int) = 0.0168] Completeness to theta =34.468° 96.0% Absorption correction Multi-scan Max. and min. transmission 1.00 and 0.57 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 5074/ 0/ 157 Goodness-of-fit on F2 1.056 Final R indices [I>2sigma(I)] R1 = 0.0304, wR2 = 0.0862 R indices (all data) R1 = 0.0326, wR2 = 0.0874 -3 Largest diff. peak and hole 0.579 and -0.307 e. Å
1-phenyl-3-iodo-1-(methyl(N-methylsulfamoyl)amino)butane (26)
Prepared according to the procedure described above, 26 was isolated as a non-separable 1:1 mixture of diastereoisomers as a yellow oil with a yield of 40%. 1H NMR (400 MHz, CDCl3): δ = 7.52-7.30 (m, 10H), 5.21-5.11 (m, 2H), 4.26-4.15 (m, 1H), 4.06-3.94 (m, 3H), 2.71 (s, 3H), 2.69 (s, 3H), 2.67- 2.63 (m, 1H), 2.62 (d, J = 5.4 Hz, 3H), 2.59 (d, J = 5.4 Hz, 3H), 2.55-2.48 (m, 1H), 2.43-2.30 (m, 2H), 2.03 (d, J = 3.9 Hz, 3H), 2.02 (d, J = 3.9 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ = 137.7, 137.1, 129.0, 128.9, 128.6, 128.5, 128.4, 128.3, 60.8, 60.7, 44.7, 44.2, 30.1, 30.0, 29.5, 29.4, 28.9, 28.7, 24.1, 23.8. IR v(cm-1): + 3310, 2958, 1321, 1139. HRMS (m/z): [M+Na] calculated for C12H19IN2NaO2S: 405.0104; found: 405.0101.
389 Part V Iodine(I/III) Catalysis for 1,3-Diamine Formation
N-(2-Methyl-4-(methyl(N-methylsulfamoyl)amino)pentan-2- yl)acetamide (28a)
Prepared according to the general procedure GP6, 28a was isolated as a yellow oil with a yield of 99%. 1H NMR (400 MHz, CDCl3): δ = 5.74 (bs, 1H), 4.38 (bq, J = 5.3 Hz, 1H), 4.10-4.01 (m, 1H), 2.70 (s, 3H), 2.69 (d, J = 5.2 Hz, 3H), 2.19 (dd, J = 14.8, 7.7 Hz, 1H), 1.93 (s, 3H), 1.59 (dd, J = 14.8, 4.4 Hz, 1H), 1.37 (s, 13 3H), 1.33 (s, 3H), 1.18 (d, J = 6.8 Hz, 3H). C NMR (101 MHz, CDCl3): δ = 170.7, 53.0, 50.2, 42.7, 29.6, 28.5, 28.4, 27.6, 24.6, 20.0. IR v(cm-1): 3294, 2971, 1653, 1540, 1369, 1127, 871, 565. HRMS (m/z): [M+Na]+ calculated for C10H23N3NaO3S: 288.1352; found: 288.1345.
N-(2-Methyl-4-(methyl(N-methylsulfamoyl)amino)butan-2- yl)acetamide (27b)
Prepared according to the general procedure GP6, 28b was isolated as a yellow oil with a yield of 90%. 1H NMR (400 MHz, CDCl3): δ = 5.39 (s, 1H), 4.31 (s, 1H), 3.24-3.20 (m, 2H), 2.83 (s, 3H), 2.70 (bs, 3H), 2.10-2.06 (m, 2H), 1.94 (s, 3H), 13 1.32 (s, 6H). C NMR (101 MHz, CDCl3): δ = 170.4, 53.0, 46.8, 36.4, 35.2, 29.8, 29.7, 27.7, 24.6. IR v(cm-1): 3305, 2969, 1654, 1541, 1370, 1307, 1144, 952, 724, + 566. HRMS (m/z): [M+Na] calculated for C9H21N3NaO3S: 274.1196; found: 274.1188.
N-(2-Methyl-4-(methyl(N-methylsulfamoyl)amino)-4-phenylbutan- 2-yl)acetamide (28c)
Prepared according to the general procedure GP6, 28c was isolated as a colorless oil with a yield of 99%. 1H NMR (500 MHz, CDCl3): δ = 7.41-7.28 (m, 5H), 5.50 (s, 1H), 5.14 (dd, J = 7.0, 6.0 Hz, 1H), 4.27 (bq, J = 5.7 Hz, 1H), 2.67 (s, 3H), 2.66 (dd, J = 14.6, 6.0 Hz, 1H), 2.54 (d, J = 5.3 Hz, 3H), 2.29 (dd, J = 14.6, 7.2 Hz, 1H), 1.88 (s, 3H), 1.43 (s, 3H), 1.19 (s, 3H). 13C NMR (126 MHz, CDCl3): δ = 170.9, 139.2, 128.7, 128.5, 128.2, 57.9, 53.2, 38.9, 29.7, 29.5, 28.4, 28.1, 24.6. IR v(cm-1): 2970, 1645, 1315, 1127. HRMS (m/z): [M-H]- calculated for C15H24N3O3S: 326.1544; found: 326.1554.
N-(4-(4-Methoxyphenyl)-2-methyl-4-(methyl(N- methylsulfamoyl)amino)butan-2-yl)acetamide (28d)
390 Part V Iodine(I/III) Catalysis for 1,3-Diamine Formation
Prepared according to the general procedure GP6, 28d was isolated as a pale yellow oil with a yield of 1 84%. H NMR (500 MHz, CDCl3): δ = 7.35-7.28 (m, 2H), 6.91-6.84 (m, 2H), 5.55 (bs, 1H), 5.09 (dd, J = 7.4, 5.7 Hz, 1H), 4.33 (bq, J = 5.3 Hz, 1H), 3.80 (s, 3H), 2.64 (s, 3H), 2.62 (dd, J = 14.6, 5.7 Hz, 1H), 2.55 (d, J = 5.4 Hz, 3H), 2.24 (dd, J = 14.6, 7.4 Hz, 1H), 1.89 (s, 3H), 1.42 (s, 3H), 1.18 (s, 3H). 13C NMR (101 MHz, CDCl3): δ = 170.9, 159.4, 131.3, 129.7, 114.0, 57.4, 55.4, 53.3, 39.2, 29.6, 29.5, 28.4, 28.0, 24.6. IR v(cm-1): 3307, 2919, 1518, 1315, 1251. HRMS (m/z): [M-H]- calculated for C16H26N3O4S : 356.1650; found: 356.1661.
N-(4-(4-Fluorophenyl)-2-methyl-4-(methyl(N- methylsulfamoyl)amino)butan-2-yl)acetamide (28e)
Prepared according to the general procedure GP6, 28e was isolated as a white solid with a yield of 92%. 1H NMR (400 MHz, CDCl3): δ = 7.40-7.34 (m, 2H), 7.08- 6.99 (m, 2H), 5.49 (s, 1H), 5.13 (dd, J = 7.4, 5.6 Hz, 1H), 4.41 (bq, J = 5.2 Hz, 1H), 2.66 (dd, J = 14.7, 5.6 Hz, 1H), 2.63 (s, 3H), 2.56 (d, J = 5.3 Hz, 3H), 2.27 (dd, J = 14.6, 13 7.4 Hz, 1H), 1.89 (s, 3H), 1.42 (s, 3H), 1.17 (s, 3H). C NMR (101 MHz, CDCl3): δ = 170.9, 162.4 (d, JC-F = 247.2 Hz), 135.1 (d, JC-F = 3.4 Hz), 130.2 (d, JC-F = 8.0 19 Hz), 115.6 (d, JC-F = 21.3 Hz), 57.1, 53.2, 38.9, 29.6, 29.5, 28.4, 28.2, 24.6. F -1 NMR (376 MHz, CDCl3): δ = -114.0. IR v(cm ): 3310, 2973, 1654, 1512, 1309, - 1218, 1142. HRMS (m/z): [M-H] calculated for C15H23FN3O3S : 344.1450; found: 344.1443. mp: 52-56 ºC.
N-(4-(4-Chlorophenyl)-2-methyl-4-(methyl(N- methylsulfamoyl)amino)butan-2-yl)acetamide (28f)
Prepared according to the general procedure GP6, 28f was isolated as a yellow solid with a yield of 93%. 1H NMR (400 MHz, CDCl3): δ = 7.38-7.30 (m, 4H), 5.53 (s, 1H), 5.11 (dd, J = 7.4, 5.5 Hz, 1H), 4.48 (bq, J = 5.3 Hz, 1H), 2.65 (dd, J = 14.5, 5.4 Hz, 1H), 2.62 (s, 3H), 2.56 (d, J = 5.3 Hz, 3H), 2.27 (dd, J = 14.6, 7.4 Hz, 1H), 1.89 (s, 3H), 1.41 (s, 3H), 1.16 13 (s, 3H). C NMR (101 MHz, CDCl3): δ = 171.0, 137.8, 134.0, 129.9, 128.9, 57.2, 53.2, 38.7, 29.6, 29.5, 28.4, 28.2, 24.6. IR v(cm-1): 3298, 2937, 1657, 1309, 1139. + HRMS (m/z): [M+Na] calculated for C15H24ClN3NaO3S: 384.1119; found: 384.1115. mp: 66-68 ºC.
391 Part V Iodine(I/III) Catalysis for 1,3-Diamine Formation
N-(4-(4-Bromophenyl)-2-methyl-4-(methyl(N- methylsulfamoyl)amino)butan-2-yl)acetamide (28g)
Prepared according to the general procedure GP6, 28g was isolated as a white solid with a yield of 62%. 1 H NMR (500 MHz, CDCl3): δ = 7.51-7.45 (m, 2H), 7.30-7.26 (m, 2H), 5.51 (s, 1H), 5.10 (dd, J = 7.4, 5.5 Hz, 1H), 4.47 (bq, J = 5.3 Hz, 1H), 2.65 (dd, J = 14.5, 5.4 Hz, 1H), 2.62 (s, 3H), 2.56 (d, J = 5.3 Hz, 3H), 2.26 (dd, J = 14.6, 7.4 Hz, 1H), 1.89 (s, 3H), 1.41 (s, 3H), 1.16 (s, 3H). 13C NMR (126 MHz, CDCl3): δ = 171.0, 138.3, 131.8, 130.2, 122.2, 57.2, 53.2, 38.7, 29.6, 29.5, 28.4, 28.2, 24.6. IR v(cm-1): 3307, 2976, 1660, 1309, 1145. HRMS (m/z): [M-H]- calculated for C15H23BrN3O3S : 404.0649; found: 404.0631. mp: 65-67 ºC.
N-(2-Methyl-4-(methyl(N-methylsulfamoyl)amino)-4-(4- (trifluoromethyl)phenyl)butan-2-yl)acetamide (28h)
Prepared according to the general procedure GP6, 28h was isolated as a yellow oil with a yield of 70%. 1 H NMR (400 MHz, CDCl3): δ = 7.62 (d, J = 8.2 Hz, 2H), 7.53 (d, J = 8.2 Hz, 2H), 5.49 (s, 1H), 5.20 (dd, J = 7.4, 5.5 Hz, 1H), 4.51 (bq, J = 5.3 Hz, 1H), 2.69 (dd, J = 14.7, 5.4 Hz, 1H), 2.64 (s, 3H), 2.57 (d, J = 5.3 Hz, 3H), 2.34 (dd, J = 14.6, 7.4 Hz, 1H), 1.89 (s, 3H), 1.42 (s, 3H), 1.16 (s, 3H). 13C NMR (101 MHz, CDCl3): δ = 171.0, 143.3 (q, JC-F = 1.2 Hz), 130.4 (q, JC-F = 32.5 Hz), 128.9, 125.6 (q, JC-F = 3.8 Hz), 124.1 (q, JC-F = 272.1 Hz), 57.4, 53.2, 38.5, 29.6, 19 -1 29.5, 28.4, 28.3, 24.5. F NMR (376 MHz, CDCl3): δ = -62.7. IR v(cm ): 2928, 1324, 1115, 1078. HRMS (m/z): [M+Na]+ calculated for C16H24F3N3NaO3S: 418.1383; found: 418.1380.
N-(4-(4-Isopropylphenyl)-2-methyl-4-(methyl(N- methylsulfamoyl)amino)butan-2-yl)acetamide (28i)
Prepared according to the general procedure GP6, 28i was isolated as a yellow solid with a yield of 71%. 1 H NMR (500 MHz, CDCl3): δ (ppm) = 7.33-7.27 (m, 2H), 7.23-7.17 (m, 2H), 5.49 (s, 1H), 5.10 (dd, J = 7.1, 6.0 Hz, 1H), 4.25 (bq, J = 5.3 Hz, 1H), 2.89 (hept, J = 6.9 Hz, 1H), 2.67 (s, 3H), 2.62 (dd, J = 14.6, 5.8 Hz, 1H), 2.54 (d, J = 5.3 Hz, 3H), 2.27 (dd, J = 14.6, 7.2 Hz, 1H), 1.85 (s, 3H), 1.42 (s, 3H), 1.23 (d, J = 6.9 Hz, 3H), 1.23 (d, J = 6.9 Hz, 3H), 1.21 (s, 3H). 13C NMR (126 MHz, CDCl3): δ = 170.8, 148.9, 136.5, 128.5, 126.7, 57.7, 53.2, 39.1, 33.9,
392 Part V Iodine(I/III) Catalysis for 1,3-Diamine Formation
29.7, 29.5, 28.4, 28.1, 24.6, 24.1. IR v(cm-1): 3310, 2955, 1651, 1309, 1145. HRMS - (m/z): [M-H] calculated for C18H30N3O3S : 368.2013; found: 368.2031. mp: 53-57 ºC.
N-(2-(Methyl(N-methylsulfamoyl)amino)-4-phenethylnonan-4- yl)acetamide (28j)
Prepared according to the general procedure GP6, 28j was isolated as a non-separable 1:1 mixture of diastereoisomers as a yellow oil with a 1 yield of 64%. H NMR (500 MHz, CDCl3): δ = 7.32-7.23 (m, 4H), 7.22-7.14 (m, 6H), 5.36 (bs, 1H), 5.33 (bs, 1H), 4.23 (q, J = 5.5 Hz, 1H), 4.19 (q, J = 5.4 Hz, 1H), 4.16-4.07 (m, 2H), 2.73 (s, 3H), 2.72 (s, 3H), 2.70 (d, J = 5.4 Hz, 3H), 2.69 (d, J = 5.4 Hz, 3H), 2.59-2.44 (m, 4H), 2.38 (m, J = 15.0, 7.6 Hz, 2H), 2.23 (m, J = 15.0, 7.8 Hz, 2H), 1.95 (s, 3H), 1.93 (s, 3H), 1.90-1.80 (m, 4H), 1.78-1.68 (m, 2H) 1.71 (dd, J = 14.9, 4.4 Hz, 1H), 1.52 (dd, J = 15.1, 4.2 Hz, 1H), 1.39-1.21 (m, 12H), 1.20 (d, J = 6.8 Hz, 3H), 1.19 (d, J = 6.8 Hz, 3H), 0.91 (t, J = 7.0 Hz, 3H), 0.90 (t, J 13 = 7.0 Hz, 3H). C NMR (126 MHz, CDCl3): δ = 170.5, 170.4, 142.3, 141.9, 128.6, 128.6, 128.5, 128.5, 126.1, 125.9, 58.4, 58.4, 49.9, 49.7, 38.4, 38.2, 36.9, 36.7, 35.1, 34.8, 32.2, 32.2, 29.8, 29.8, 29.7, 29.7, 28.7, 28.7, 24.7, 24.6, 22.9, 22.8, 22.8, 22.8, 20.1, 20.0, 14.2, 14.2. IR v(cm-1): 2931, 1651, 1540, 1454, 1371, 1309, 1129, - 699. HRMS (m/z): [M-H] calculated for C21H36N3O3S: 410.2483; found: 410.2477.
N-(4-Isobutyl-2-(methyl(N-methylsulfamoyl)amino)nonan-4- yl)acetamide (28k)
Prepared according to the general procedure GP6, 28k was isolated as a non-separable 1:1 mixture of diastereoisomers as a yellow oil with a yield of 50%. 1H NMR (500 MHz, CDCl3): δ = 5.33 (bs, 1H), 5.26 (bs, 1H), 4.37 (q, J = 5.5 Hz, 1H), 4.16 (q, J = 5.4 Hz, 1H), 4.12-4.02 (m, 2H), 2.74-2.70 (m, 12H), 2.44 (dd, J = 15.0, 7.1 Hz, 1H), 2.12 (dd, J = 15.0, 8.2 Hz, 1H), 2.07-1.99 (m, 2H), 1.93 (s, 3H), 1.93 (s, 3H), 1.81 (dd, J = 14.4, 7.2 Hz, 1H), 1.75-1.61 (m, 7H), 1.49-1.20 (m, 14H), 1.18 (d, J = 6.9 Hz, 3H), 1.17 (d, J = 6.8 Hz, 3H), 0.95 (d, J = 6.6 Hz, 3H), 0.93 (d, J = 6.7 Hz, 3H), 0.92 (d, J = 6.7 Hz, 3H), 0.91 (d, J = 6.7 Hz, 3H), 0.89 (t, J = 7.0 Hz, 3H), 0.88 (t, J = 7.1 13 Hz, 3H). C NMR (126 MHz, CDCl3): δ = 170.7, 170.2, 58.8, 58.7, 49.9, 49.6, 43.1, 42.7, 38.8, 38.7, 35.5, 35.3, 32.2, 32.2, 29.8, 29.7, 28.7, 28.7, 25.1, 25.1, 24.9, 24.8, 24.1, 23.9, 23.8, 23.7, 23.2, 23.1, 22.8, 22.8, 20.3, 19.7, 14.2, 14.2. IR v(cm-
393 Part V Iodine(I/III) Catalysis for 1,3-Diamine Formation
1): 3298, 2968, 1655, 1541, 1370, 1304, 1133, 563. HRMS (m/z): [M-H]- calculate. for C17H36N3O3S: 362.2483; found: 362.2484.
N-(3,7-Dimethyl-1-(methyl(N-methylsulfamoyl)amino)octan-3- yl)acetamide (28l)
Prepared according to the general procedure GP6, 28l was isolated as a colorless oil with a yield of 72%. 1 H NMR (400 MHz, CDCl3): δ = 5.29 (s, 1H), 4.40 (bs, 1H), 3.24-3.17 (m, 2H), 2.83 (s, 3H), 2.70 (bs, 3H), 2.24-2.14 (m, 1H), 2.02-1.90 (m, 1H), 1.94 (s, 3H), 1.79-1.72 (m, 1H), 1.57-1.48 (m, 2H), 1.25 (s, 3H), 1.30-1.11 (m, 4H), 0.86 (d, J = 6.6 Hz, 6H). 13C NMR (126 MHz, CDCl3): δ = 170.3, 55.7, 46.5, 39.5, 39.3, 35.3, 35.0, 29.7, 28.0, 24.6, 24.6, 22.7, 22.7, 21.4. IR v(cm-1): 3295, 2934, 1654, 1315, 1148. HRMS (m/z): + [M+Na] calculated for C14H31N3NaO3S: 344.1978; found: 344.1969.
N-(1-(2-(methyl(N- methylsulfamoyl)amino)ethyl)cyclohexyl)acetamide (28m)
Prepared according to the general procedure GP6, 28m was isolated as a colorless oil with a yield of 72%. 1H NMR (400 MHz, CDCl3): δ = 5.15 (bs, 1H), 4.24 (bs, 1H), 3.26-3.17 (m, 2H), 2.82 (s, 3H), 2.71 (d, J = 4.7 Hz, 3H), 2.15-2.07 (m, 2H), 2.05-1.98 (m, 2H), 1.99 (s, 3H), 1.54-1.21 (m, 8H). 13C NMR (101 MHz, CDCl3): δ = 170.4, 55.3, 46.1, 35.2, 35.2, 29.8, 25.7, 24.6, 21.8, 21.8. IR v(cm-1): 3343, 2931, 2854, 1654, 1315, 1133. HRMS (m/z): [M+Na]+ calculated for C12H25N3NaO3S : 314.1509; found: 314.1508.
N-(2-(2-(methyl(N-methylsulfamoyl)amino)ethyl)-2,3-dihydro-1H- inden-2-yl)acetamide (28n)
Prepared according to the general procedure GP6, 28n was isolated as a colorless oil with a yield of 45%. 1H NMR (500 MHz, CDCl3): δ = 7.22-7.14 (m, 4H), 5.66 (s, 1H), 4.16 (q, J = 5.2 Hz, 1H), 3.32 (d, J = 16.2 Hz, 2H), 3.30 (t, J = 7.2, 6.6 Hz , 2H), 3.07 (d, J =16.3 Hz, 2H), 2.84 (s, 3H), 2.72 (d, J = 5.4 Hz, 3H), 2.36 (dd, J = 7.6, 6.4 Hz, 13 2H), 1.92 (s, 3H). C NMR (126 MHz, CDCl3): δ = 171.0, 141.0, 126.9, 125.0, 64.1, 47.5, 45.3, 35.2, 33.6, 29.8, 24.4. IR v(cm-1): 3328, 2925, 1657, 1548, 1318, + 1124. HRMS (m/z): [M+Na] calculated for C15H23N3NaO3S : 348.1352; found: 348.1338.
394 Part V Iodine(I/III) Catalysis for 1,3-Diamine Formation
N-(2-Methyl-4-(methyl(N-methylsulfamoyl)amino)pentan-2- yl)isobutyramide (28o)
Prepared according to the general procedure GP6, 28o was isolated as a pale yellow oil with a yield of 83%. 1H NMR (400 MHz, CDCl3): δ = 5.61 (bs, 1H), 4.21 (q, J = 5.5 Hz, 1H), 4.11-3.98 (m, 1H), 2.72 (s, 3H), 2.70 (d, J = 5.4 Hz, 3H), 2.30 (hept, J = 6.8 Hz, 1H), 2.14 (dd, J = 14.7, 7.2 Hz, 1H), 1.72 (dd, J = 14.7, 4.9 Hz, 1H), 1.36 (s, 3H), 1.35 (s, 3H), 1.20 (d, J = 6.8 Hz, 3H), 1.13 13 (d, J = 6.9 Hz, 3H), 1.12 (d, J = 6.8 Hz, 3H). C NMR (101 MHz, CDCl3): δ = 177.4, 52.8, 50.2, 43.1, 36.4, 29.7, 28.6, 28.4, 27.8, 20.1, 20.0, 19.5. IR v(cm-1): - 2969, 1651, 1532, 1313, 1129. HRMS (m/z): [M-H] calculated for C12H26N3O3S: 292.1700; found: 292.1694.
N-(2-Methyl-4-((N-methylsulfamoyl)(propyl)amino)butan-2- yl)acetamide (28p)
Prepared according to the general procedure GP6, 28p was isolated as a yellow oil with a yield of 82%. 1H NMR (400 MHz, CDCl3): δ = 5.45 (s, 1H), 4.42 (bq, J = 5.4 Hz, 1H), 3.25-3.19 (m, 2H), 3.18-3.12 (m, 2H), 2.67 (d, J = 5.4 Hz, 3H), 2.10-2.02 (m, 2H), 1.94 (s, 3H), 1.66-1.52 (m, 2H), 1.31 13 (s, 6H), 0.91 (t, J = 7.4 Hz, 3H). C NMR (101 MHz, CDCl3): δ = 170.4, 53.0, 49.9, 43.5, 37.6, 29.5, 27.5, 24.6, 21.7, 11.3. IR v(cm-1): 3298, 2968, 1655, 1541, - 1370, 1304, 1133, 563. HRMS (m/z): [M-H] calculated for C11H24N3O3S: 278.1544; found: 278.1545.
N-(4-(Butyl(N-methylsulfamoyl)amino)-2-methylbutan-2- yl)acetamide (28q)
Prepared according to the general procedure GP6, 28q was isolated as a yellow oil with a yield of 60%. 1H NMR (400 MHz, CDCl3): δ = 5.42 (s, 1H), 4.35 (bq, J = 5.4 Hz, 1H), 3.27-3.14 (m, 4H), 2.68 (d, J = 5.4 Hz, 3H), 2.10-2.03 (m, 2H), 1.94 (s, 3H), 1.61-1.49 (m, 2H), 1.39-1.26 (m, 2H), 13 1.31 (s, 6H), 0.93 (t, J = 7.3 Hz, 3H). C NMR (101 MHz, CDCl3): δ = 170.4, 53.0, 47.9, 43.4, 37.6, 30.5, 29.5, 27.5, 24.6, 20.1, 13.9. IR v(cm-1): 3300, 2964, - 1655, 1315, 1132, 924. HRMS (m/z): [M-H] calculated for C12H26N3O3S: 292.1700; found: 292.1710.
N-(4-(Cyclohexyl(N-methylsulfamoyl)amino)-2-methylpentan-2- yl)acetamide (28r)
395 Part V Iodine(I/III) Catalysis for 1,3-Diamine Formation
Prepared according to the general procedure GP6, 28r was isolated as a white solid with a yield of 90%. 1H NMR (500 MHz, CDCl3): δ = 5.96 (s, 1H), 4.24 (bq, J = 5.4 Hz, 1H), 3.80-3.71 (m, 1H), 3.08-2.99 (m, 1H), 2.68 (d, J = 5.4 Hz, 3H), 2.08 (dd, J = 14.4, 2.9 Hz, 1H), 1.90 (s, 3H), 1.88- 1.76 (m, 6H), 1.64-1.57 (m, 1H), 1.37 (s, 3H), 1.35 (s, 3H), 1.46-1.21 (m, 3H), 1.31 13 (d, J = 6.8 Hz, 3H), 1.18-1.06 (m, 1H). C NMR (126 MHz, CDCl3): δ = 170.4, 57.8, 53.4, 51.0, 47.4, 33.1, 33.0, 29.3, 28.3, 26.9, 26.8, 26.8, 25.4, 24.6, 22.2. IR v(cm-1): 3299, 2928, 1651, 1309, 1133. HRMS (m/z): [M-H]- calculated for C15H30N3O3S: 332.2013; found: 332.2005. mp: 57-59 ºC.
N-(4-(Benzyl(N-methylsulfamoyl)amino)-2-methylpentan-2- yl)acetamide (28s)
Prepared according to the general procedure GP6, 28s was isolated as a yellow oil with a yield of 70%. 1H NMR (400 MHz, CDCl3): δ = 7.45-7.38 (m, 2H), 7.38-7.25 (m, 3H), 5.84 (bs, 1H), 4.37 (d, J = 15.5 Hz, 1H), 4.24 (d, J = 15.5 Hz, 1H), 4.10-3.96 (m, 2H), 2.55 (d, J = 5.4 Hz, 3H), 2.23 (dd, J = 14.5, 3.9 Hz, 1H), 1.92 (s, 3H), 1.69 (dd, J = 14.5, 6.8 Hz, 1H), 1.33 (s, 3H), 1.31 (s, 3H), 1.27 (d, J = 6.9 13 Hz, 3H). C NMR (75 MHz, CDCl3): δ = 170.7, 138.2, 128.7, 128.6, 127.8, 53.3, 51.8, 48.1, 46.0, 29.5, 28.4, 27.1, 24.6, 22.5. IR v(cm-1): 3304, 2970, 1660, 1309, - 1145. HRMS (m/z): [M-H] calculated for C16H26N3O3S: 340.1700; found: 340.1716.
N-(4-((N-(tert-Butyl)sulfamoyl)(methyl)amino)-2-methylpentan-2- yl)acetamide (28t)
Prepared according to the general procedure GP6, 28t was isolated as a colorless oil with a yield of 65%. 1H NMR (500 MHz, CDCl3): δ = 5.82 (s, 1H), 4.11-4.03 (m, 1H), 4.03 (bs, 1H), 2.67 (s, 3H), 2.19 (dd, J = 14.7, 6.5 Hz, 1H), 1.93 (s, 3H), 1.55 (dd, J = 14.6 Hz, 5.1, 1H), 1.37 (s, 3H), 1.33 (s, 9H), 1.32 (s, 13 3H), 1.17 (d, J = 6.8 Hz, 3H). C NMR (126 MHz, CDCl3): δ = 170.8, 54.6, 53.0, 50.0, 43.3, 30.2, 28.4, 28.3, 27.4, 24.6, 19.9. IR v(cm-1): 3285, 2979, 1657, 1312, + 1133. HRMS (m/z): [M+Na] calculated for C13H29N3NaO3S: 330.1822; found: 330.1822.
(S)-N-(2-Methyl-1-(1-(N-methylsulfamoyl)pyrrolidin-2-yl)propan-2- yl)acetamide (28u)
396 Part V Iodine(I/III) Catalysis for 1,3-Diamine Formation
Prepared according to the general procedure GP6, 28u was isolated as a white solid with a yield of 70%. 1H NMR (400 MHz, CDCl3): δ = 6.10 (s, 1H), 4.50 (bs, 1H), 3.93-3.84 (m, 1H), 3.38-3.21 (m, 2H), 2.73 (s, 3H), 2.19 (dd, J = 14.6, 2.1 Hz, 1H), 2.17-2.05 (m, 1H), 1.94 (s, 3H), 1.98-1.88 (m, 2H), 1.75- 13 1.54 (m, 2H), 1.37 (s, 3H), 1.34 (s, 3H). C NMR (101 MHz, CDCl3): δ = 171.0, 56.7, 53.2, 48.8, 48.2, 34.6, 29.6, 28.1, 26.2, 24.8, 24.7. IR v(cm-1): 3341, 3249, 2975, 1660, 1547, 1292, 1133, 1042. HRMS (m/z): [M+Na]+ calculated for C11H23N3NaO3S : 300.1352; found: 300.1352. mp: 70-72 ºC. X-ray crystal structure determination:
______Identification code CCDC 1909452 Empirical formula C11 H23 N3 O3 S Formula weight 277.38 Temperature 100(2)K Wavelength 0.71073 Å Crystal system orthorhombic Space group P 21 21 21 Unit cell dimensions a = 8.3707(3)Å α = 90°. b = 11.4502(4)Å β = 90°. c = 14.6387(5)Å γ = 90°. 3 Volume 1403.06(9) Å Z 4 3 Density (calculated) 1.313 Mg/m Absorption coefficient 0.236 mm-1 F(000) 600
397 Part V Iodine(I/III) Catalysis for 1,3-Diamine Formation
3 Crystal size 0.300 x 0.300 x 0.100 mm Theta range for data collection 2.258 to 27.779°. Index ranges -10<=h<=10, -11<=k<=13, -14<=l<=19 Reflections collected 6662 Independent reflections 2631[R(int) = 0.0275] Completeness to theta =27.779° 88.6% Absorption correction Multi-scan Max. and min. transmission 1.00 and 0.51 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 2631/ 0/ 168 Goodness-of-fit on F2 1.067 Final R indices [I>2sigma(I)] R1 = 0.0292, wR2 = 0.0719 R indices (all data) R1 = 0.0320, wR2 = 0.0733 -3 Largest diff. peak and hole 0.234 and -0.345 e.Å
N-(2-Methyl-4-(S)-cyano-4-(benzyl(N- methylsulfamoyl)amino)butan-2-yl)acetamide (28v)
Prepared according to the general procedure GP6, 28v was isolated as a white solid with a yield of 42%. 1H NMR (500 MHz, CDCl3): δ = 7.48-7.44 (m, 2H), 7.41-7.30 (m, 3H), 5.34 (bs, 1H), 4.83 (dd, J = 9.2, 4.1 Hz, 1H), 4.57 (d, J = 15.0 Hz, 1H), 4.37 (d, J = 15.1 Hz, 1H), 4.29 (bs, 1H), 2.66 (d, J = 5.3 Hz, 3H), 2.37 (dd, J = 14.3, 9.2 Hz, 1H), 2.29 (dd, J = 14.2, 4.2 Hz, 1H), 1.94 (s, 3H), 1.32 (s, 3H), 13 1.29 (s, 3H). C NMR (101 MHz, CDCl3): δ = 170.9, 135.8, 129.1, 128.9, 128.6, 118.7, 52.6, 51.0, 47.0, 41.3, 29.7, 27.8, 27.8, 24.5. IR v(cm-1): 3349, 3082, 2925, + 1654, 1548, 1315, 1142. HRMS (m/z): [M+H] calculated for C16H25N4O3S: 353.1642; found: 353.1639. mp: 115-117 ºC.
N-(2-Methyl-5-(S)-acetoxy-4-(benzyl(N- methylsulfamoyl)amino)pentan-2-yl)acetamide (28w)
Prepared according to the general procedure GP6, 28w was isolated as a colorless oil with a yield of 64%. 1H NMR (500 MHz, CDCl3): δ = 7.43 (d, J = 7.1 Hz, 2H), 7.37- 7.28 (m, 3H), 5.69 (bs, 1H), 4.40 (d, J = 15.5 Hz, 1H), 4.26 (d, J = 15.5 Hz, 1H), 4.18-4.13 (m, 2H), 4.11 (dd, J = 11.5, 4.3 Hz, 1H), 3.92 (dd, J = 11.6, 9.2 Hz, 1H), 2.60 (d, J = 5.3 Hz, 3H), 2.28 (dd, J = 14.7, 3.3 Hz, 1H),
398 Part V Iodine(I/III) Catalysis for 1,3-Diamine Formation
2.01 (s, 3H), 1.95 (s, 3H), 1.77 (dd, J = 14.7, 6.9 Hz, 1H), 1.36 (s, 3H), 1.33 (s, 13 3H). C NMR (126 MHz, CDCl3): δ = 171.0, 170.9, 137.4, 128.7, 128.7, 128.1, 65.1, 54.8, 53.0, 48.8, 40.3, 29.5, 28.3, 27.6, 24.6, 21.0. IR v(cm-1): 2925, 1739, + 1366, 1151. HRMS (m/z): [M+Na] calculated for C18H29N3NaO5S: 422.1720; found: 422.1725.
(3,5)-3-(Benzyl(N-methylsulfamoyl)amino)-5-(N- acetyl)aminoandrostane-17-one (28x)
Prepared according to the general procedure GP6, 28x was isolated as a white solid with a 1 yield of 65%. H NMR (500 MHz, CDCl3): δ = 7.41-7.21 (m, 5H), 5.23 (s, 1H), 4.59 (d, J = 15.6 Hz, 1H), 4.44 (bq, J = 5.3 Hz, 1H), 4.33 (d, J = 15.5 Hz, 1H), 3.78 (tt, J = 11.8, 3.6 Hz, 1H), 2.84- 2.77 (m, 1H), 2.70 (d, J = 5.4 Hz, 3H), 2.53-2.38 (m, 2H), 2.21-2.06 (m, 2H), 2.01-1.90 (m, 1H), 1.94 (s, 3H), 1.81-1.75 (m, 1H), 1.69-1.43 (m, 10H), 1.41-1.15 13 (m, 4H), 0.87 (s, 3H), 0.82 (s, 3H). C NMR (126 MHz, CDCl3): δ = 220.6, 170.2, 138.9, 128.7, 128.3, 127.8, 61.2, 54.7, 51.6, 49.2, 47.6, 42.2, 38.6, 36.0, 34.3, 31.7, 31.5, 31.3, 29.7, 29.6, 26.4, 26.0, 25.3, 21.8, 20.2, 16.9, 13.8. IR v(cm-1): 3325, 2922, 1739, 1324, 1151, 827. HRMS (m/z): [M+Na]+ calculated for C29H43N3NaO4S : 552.2866; found: 552.2869. mp: 140-145 ºC. X-ray crystal structure determination:
______Identification code CCDC 1909451 Empirical formula C29 H47 N3 O6 S Formula weight 565.75 Temperature 100(2) K Wavelength 0.71073 Å
399 Part V Iodine(I/III) Catalysis for 1,3-Diamine Formation
Crystal system Triclinic Space group P1 Unit cell dimensions a = 7.0841(2) Å α = 98.320(3)°. b = 14.1779(5) Å β = 100.672(3)°. c = 15.2277(7) Å γ = 103.356(3)°. 3 Volume 1433.94(10) Å Z 2 3 Density (calculated) 1.310 Mg/m Absorption coefficient 0.160 mm-1 F(000) 612 Theta range for data collection 1.837 to 27.905°. Index ranges -8<=h<=9, -18<=k<=18, -19<=l<=19 Reflections collected 16813 Independent reflections 16813[R(int) = ?] Completeness to theta =27.905° 83.200005% Absorption correction Multi-scan Max. and min. transmission 0.992 and 0.763 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 16813/ 10/ 760 Goodness-of-fit on F2 0.970 Final R indices [I>2sigma(I)] R1 = 0.0437, wR2 = 0.1018 R indices (all data) R1 = 0.0555, wR2 = 0.1047 Flack parameter x =0.07(4) -3 Largest diff. peak and hole 0.397 and -0.347 e. Å
N-(4-(Benzyl(N-methylsulfamoyl)amino)-2-methylpentan-2- yl)ammonium chloride (29)
Prepared according to the procedure described above, 29 was isolated as a yellowish oil with a yield of 87%. 1H NMR (300 MHz, CDCl3): δ = 11.57 (s, 1H), 7.49-7.30 (m, 5H), 7.14- 7.08 (m, 2H), 4.82 (d, J = 16.9 Hz, 1H), 4.57 (d, J = 17.0 Hz, 1H), 2.62 (s, 3H), 1.92 (dd, J = 13.7, 4.4 Hz, 1H), 1.77 (dd, J = 14.1, 10.5 Hz, 1H), 13 1.57 (s, 3H), 1.40 (s, 3H), 1.32 (d, J = 6.3 Hz, 3H). C NMR (101 MHz, CDCl3):
400 Part V Iodine(I/III) Catalysis for 1,3-Diamine Formation
δ = 161.2, 134.0, 129.7, 128.8, 126.0, 50.6, 50.4, 48.5, 42.0, 29.2, 28.5, 19.5, 19.1. IR v(cm-1): 3384, 2974, 2925, 1618, 1452, 726.
N-(4-(benzylamino)-2-methylpentan-2-yl)acetamide (30)
Prepared according to the procedure described above, 30 was isolated as a colorless oil with a yield of 82%. 1H NMR (500 MHz, CDCl3): δ = 8.97 (s, 1H), 7.35-7.25 (m, 5H), 3.94 (d, J = 12.5 Hz, 1H), 3.65 (d, J = 12.5 Hz, 1H), 3.02-2.94 (m, 1H), 1.80 (s, 3H), 1.51 (dd, J = 14.7, 10.3 Hz, 1H), 1.41 (s, 3H), 1.34 (s, 3H), 1.30 (dd, J = 14.7, 1.6 13 Hz, 1H), 1.19 (d, J = 6.3 Hz, 3H). C NMR (101 MHz, CDCl3): δ = 169.7, 140.0, 128.7, 128.3, 127.4, 53.6, 51.1, 50.1, 50.0, 28.5, 24.8, 24.4, 22.0. IR v(cm-1): 3314, + 2987, 1678. HRMS (m/z): [M+H] calculated for C15H25N2O: 249.1961; found: 249.1966.
N2-benzyl-4-methylpentane-2,4-diaminium dichloride (31)
Prepared according to the procedure described above (from 29), 31 was isolated as a yellowish oil with a yield of 46%. Prepared according to the procedure described above (from 30), 31 was isolated as a yellowish oil with an isolated yield of 98%. 1H NMR (500 MHz, CD3OD): δ = 7.59-7.54 (m, 2H), 7.52-7.44 (m, 3H), 4.28 (s, 2H), 3.61-3.53 (m, 1H), 2.30 (d, J = 14.3 Hz, 1H), 2.01 (dd, J = 14.4, 9.3 Hz, 1H), 1.54 13 (d, J = 6.4 Hz, 3H), 1.46 (s, 3H), 1.43 (s, 3H). C NMR (101 MHz, CD3OD): δ = 132.4, 131.0, 130.8, 130.4, 54.6, 51.9, 44.2, 40.7, 25.9, 25.7, 19.5. IR v(cm-1): - 3398, 2973, 1616. HRMS (m/z): [M-H-2Cl] calculated for C13H23N2: 207.1856; found: 207.1853.
O-(2-Methyl-4-(methyl(N-methylsulfamoyl)amino)pentan-2- yl)acetate (32)
Prepared according to the procedure described above, 32 was isolated as a yellow oil with a yield of 90%. 1H NMR (400 MHz, CDCl3): δ = 4.22-4.12 (m, 1H), 4.08 (bs, 1H), 2.69 (s, 3H), 2.68 (d, J = 5.4 Hz, 3H), 2.13 (dd, J = 14.7, 6.6 Hz, 1H), 1.99 (s, 3H), 1.86 (dd, J = 14.7, 6.1 Hz, 1H), 1.49 (s, 6H), 1.22 (d, 13 J = 6.8 Hz, 3H). C NMR (101 MHz, CDCl3): δ = 170.9, 81.4, 50.0, 44.3, 29.5, 28.4, 26.9, 26.5, 22.7, 19.6. IR v(cm-1): 3294, 2971, 1726, 1322, 1150. HRMS + (m/z): [M+Na] calculated for C10H22N2NaO4S: 289.1192; found: 289.1199.
3-(S)-(benzyl-(N-methylsulfamoyl)amino)-5,5- dimethyldihydrofuran-2(3H)-one (34a)
401 Part V Iodine(I/III) Catalysis for 1,3-Diamine Formation
Prepared according to the procedure described above, 34a was isolated as a brown solid with a yield of 82%. 1 H NMR (500 MHz, CDCl3): δ = 7.44-7.40 (m, 2H), 7.39-7.29 (m, 3H), 4.61 (bs, 1H), 4.54 (d, J = 15.2 Hz, 1H), 4.54 (t, J = 11.2, 9.7 Hz, 1H), 4.38 (d, J = 15.4 Hz, 1H), 2.83 (s, 3H), 2.17-2.06 13 (m, 2H), 1.38 (s, 3H), 1.29 (s, 3H). C NMR (126 MHz, CDCl3): δ = 174.2, 136.5, 129.0, 128.3, 128.3, 82.7, 59.4, 52.1, 39.9, 29.7, 29.1, 27.5. IR v(cm-1): 3313, + 1779, 1315, 1154. HRMS (m/z): [M+Na] calculated for C14H20N2NaO4S: 335.1036; found: 335.1048. mp: 101-103 ºC.
3-(S)-(benzyl-(N-methylsulfamoyl)amino)-5,5- dimethyltetrahydrofuran (34b)
Prepared according to the procedure described above, 34b was isolated as a colorless oil with a yield of 50%. 1 H NMR (500 MHz, CDCl3): δ = 7.40-7.27 (m, 5H), 4.68-4.59 (m, 1H), 4.42 (s, 2H), 3.99 (dd, J = 9.8, 7.7 Hz, 1H), 3.80 (dd, J = 9.8, 6.2 Hz, 1H), 2.57 (s, 3H), 2.10 (dd, J = 12.9, 8.7 Hz, 1H), 1.82 (dd, J = 12.9, 8.4 Hz, 1H), 1.31 (s, 3H), 1.18 (s, 3H). 13C NMR (101 MHz, CDCl3): δ = 138.5, 128.8, 127.7, 127.5, 80.5, 68.3, 59.5, 48.4, 42.1, 29.5, 28.6, 27.2. IR v(cm-1): 3292, 2916, 1321, 1151. HRMS (m/z): [M+Na]+ calculated for
C14H22N2NaO3S: 321.1243; found: 321.1245.
402 General conclusion and outlook
General conclusion and outlook
In the present thesis, new C(sp3)-H functionalization have been developed using halogen catalysis. First, a bromide assisted Hofmann- Löffler reaction has been designed to afford the formation of pyrrolidines and oxaziridines. Then, a cooperative iodine and organic dye catalysis was established to generate pyrrolidines and lactones. Finally, regarding intramolecular amination, another iodine catalysis was designed in which the installment of new C-N bond was possible at non-activated carbon position. As the last discovery, it was possible to use the Hofmann-Löffler reaction to selectively direct an intermolecular amination using a Ritter reaction. To understand the mechanisms of each procedures, mechanistic investigations were carried out. Control experiments were performed such as kinetic isotope effect, Hammett correlation, RAMAN spectroscopy, quantum yield, quenching experiments, cyclic voltammetry… Also, DFT calculations were used as well when it was not possible to experimentally design control experiments. Regarding the outlook about the halogen-catalyzed Hofmann-Löffler reaction, an enantioselective reaction is still missing. The major issue remains the capacity of the halogen to dissociate and re-associate thus leading to a racemization at activated benzylic position. As a result, the chirality transfer should be at the cyclization step. Therefore, it seems difficult to develop a metal-free procedure for an enantioselective amination reaction. Since copper can perform N-F activation thus leading to amination reaction, screening of chiral ligands seems to be the best option at the moment. Regarding the outlook about the halogen catalysis, I think the developed methodologies are robust enough to be implemented in industry. The reactions are water-tolerant, oxygen-tolerant, reproductible… I am also positive about halogen catalysis for developing new reactivity since an iodine catalyzed nucleophilic fluorination has been developed in our group using sulfamide as directing group right after the publication of the Ritter- type amination. Also, as presented in chapter III, Shannon Sthal used iodine as an electrochemical mediator to perform an iodine catalyzed Hofmann- Löffler reaction just after the developed cooperative iodine and organic dye catalysis. Also, to overcome the low leaving group capacity of the halogen, maybe a halogen bonding donor catalyst could be implemented to the system.
403 General conclusion and outlook
Therefore, we would avoid the necessity of the alkyliodine(I) intermediate oxidation for the cyclization at non-activated position. In my personal point of view, the domain of the halogen catalysis is promising and should continue to grow.
404 Conclusiones y perspectivas
Conclusiones y perspectivas
En la presente tesis doctoral, nuevas metodologías de funcionalización C(sp3)-H basadas en catálisis de halógenos han sido desarrolladas. En primer lugar, hemos diseñado una variación de la reacción de Hormann-Löffler basada en bromo para la formación de pirrolidinas y oxaziridinas. A continuación, se ha desarrollado un sistema catalítico cooperativo empleando yodo y un colorante orgánico como catalizadores para la síntesis de pirrolidinas y lactonas. Por último, en el contexto de aminación intramolecular, otro sistema catalítico de yodo ha sido diseñado para instalar nuevos enlaces C-N en posiciones alifáticas no activadas. Como en el último caso, ha sido posible usar la reacción de Hofmann-Löffler para dirigir la aminación intermolecular de forma selectiva en una reacción de aminación de tipo Ritter. Para comprender los mecanismos de los diferentes procedimientos, se llevaron a cabo una serie de investigaciones mecanísticas. En dicho contexto, diferentes experimentos de control fueron estudiados, como el efecto cinético isotópico, correlación de Hammett, espectroscopía Raman, rendimiento cuático, experimentos quenching o voltametría cíclica entre otros. Además, cálculos DFT fueron empleados cuando no era posible diseñar experimentos de control. En cuanto a la perspectiva de la catálisis de halógenos en la reacción de Hofmann-Löffler, la correspondiente variante enantioselectiva aún no ha sido desarrollada. El principal problema concierne a la capacidad del halógeno para disociarse y reasociarse a las posiciones alifáticas activadas, conllevando a la correspondiente racemización. Por tanto, la inducción de la quiralidad debe llevarse a cabo en la etapa de ciclación. Consecuentemente, la adaptación de un procedimiento metal free para la reacción de aminación enantioselectiva se presenta muy problemática. Teniendo en cuenta que la catálisis de cobre puede activar enlaces N-F en una reacción final de aminación, la exploración de ligandos quirales parece la mejor opción por el momento. En cuanto a la perspectiva de la catálisis de halógenos, creo que las metodologías descritas en la presente tesis son lo suficientemente robustas para ser implementadas en la industria. Las reacciones toleran la presencia de agua y oxígeno, además de ser reproducibles. También soy optimistas en cuanto al potencial de la catálisis de halógenos para desarrollar nueva reactividad, ya que un nuevo protocolo catalizado con yodo molecular para fluorinación nucleófila usando sulfamidas como grupos directores ha sido desarrollado en nuestro grupo tras la publicación de la aminación tipo
405 Conclusiones y perspectivas
Ritter. Además, como indicado en el capítulo III, Shannon Stahl usó yodo molecular como mediador electroquímico para la reacción de Hofmann- Löffler tras la publicación de nuestro protocolo de catálisis cooperativa de yodo y pigmento orgánico. Asimismo, para mejorar la capacidad del halógeno como grupo saliente, la catálisis de puentes de halógeno podría implementarse en el sistema. En este sentido, evitaríamos la oxidación del intermedio alquil-ioduro(I) necesaria para la ciclación en posiciones no activadas. Desde mi punto de vista personal, el campo de la catálisis de halógeno tiene un futuro prometedor y continuará en su expansión.
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