DESIGN of NEW C(Sp3)-H FUNCTIONALIZATION THROUGH HALOGEN CATALYSIS
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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) 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.