Iron-catalyzed Synthesis of Unprotected Primary Amines
Dissertation Zur Erlangung des akademischen Grades eines Doktors der Naturwissenschaften
Vorgelegt der Fakultät für Chemie und Biochemie der Ruhr-Universität Bochum
von
Luca Legnani aus Saronno, Italien
Bochum, 2018
"I carried the book a hundred yards into the desolation, towards the southeast. With all my might I threw it far out in the direction she had gone. Then I got into the car, started the engine, and drove back to Los Angeles."
John Fante, Ask the dust
Die vorliegende Arbeit wurde im Zeitraum von Oktober 2014 bis April 2018 am Max- Planck-Institut für Kohlenforschung unter Anleitung von Dr. Bill Morandi angefertigt.
Supervisor: Dr. Bill Morandi
Co-supervisor: Prof. Dr. Wolfram Sander
Acknowledgments i
Acknowledgments
The acknowledgements are going to be the most difficult pages to write.
My sincere gratitude goes in the first place to Bill. In the last four years he passed on a lot of experience and enthusiasm for organic chemistry. However, before being an excellent supervisor, he has been an older brother. Entering his office, I have always found a nice word or a joke and I have never been afraid to discuss with him a reaction mechanism or a concern in private life. I will always be thankful to him for what he taught me and for the nice environment he built. I truly believe he is a wonderful boss and a great person.
I would also like to thank Prof. Sander who agreed to supervise my thesis. His class at the Bochum University has been inspiring and convinced me to pursue my studies in organic chemistry, investigating reaction mechanisms.
I am thankful to Prof. List for sharing the equipment of his group and for the nice activities organized at the Department. I thank the MPI für Kohlenfoschung for the economic and scientific support during these years.
I have had a great time during my PhD thanks to the old and present members of the Morandi group. More than colleagues they have been a group of friends with who you can share ideas, chemicals, stories, fun and laughs. I have been lucky to have met Bastien that made the time in the lab so pleasant. Thanks also for keeping my feet warm with the heat gun. With Nikos, following the tradition of ancient Greek philosophers, I have shared many chats and discussions about life. In case of an issue with DAK I will call your help. Thanks to Gabri, that has been a close friend during these years. I have always counted on him for outdoor activities, a discussion about chemistry or a song to sing together. Thanks also for working with me on the amino chlorination project. I promise I will try my best to support Valentino Rossi and Francesco Totti in the future. I have been lucky to have met Ben. He always had valuable suggestions for any question in lab and his contribution during the proofreading of this thesis has been priceless. The time spent with him has always been pleasant, full of stories, movies and looking-up dogs. The time spent with him has always been pleasant also because I could usually understand half of his words. I will truly miss Peng. He taught me that a different culture ii Iron-catalyzed synthesis of unprotected primary amines
can mean a great friendship. I hope I will soon have the chance to visit China with him. In case of an issue with bureaucracy I am sure you will be ready to help me.
I am sincerely thankful, in a random order, also to: Erhan and his funny videos, Dr. Fang and delicious fishes, Rodeo Rod and his latino intensity, Suzanne and the Dutch directness, Szabo because he is a real NeRD, Tobias for his tough questions, Yong Ho and the tidy glovebox, Eckhard and the google translated emails, Julia that wants to go for lunch at 10:30, Tristan because he can whistle the same song for few days in row, Lin and the Lineneintopf, quick quick Zhong, Sophia, Emrah, Sarah. I am very happy that I had the chance to work with these people because in the morning, on the way to the institute, I have always worn a smile.
During the last years, despite the many kilometers, my Italian friends and I managed to keep a close relationship. Every time I went back to my Alps I have always found a warm welcome, hugs and laughs. I am thankful to them for reminding me that there is no place like home.
I am grateful to my family for having always supported me. They have trusted any decision I have taken during these years and they have never stopped to help me. I am sure Monica and Giuliano will become fantastic grandparents, Anna an incredible aunt, Francesco and Carla wise great-grandparents. I am lucky to have such wonderful uncles and cousins as Walter, Bobo, Giorgio, Roberto, Elga, Francesco. The memories and teachings of nonna Fernanda and nonno Antonio are still vivid in our loud family.
This thesis would have not been written without the constant help, support and love of Tanja. I am incredibly lucky to have met a person that shares with me the same World view. I am thankful to her for deciding to follow me in Mülheim, quitting a ten-year life in Regensburg, friends and jobs. I am sure our next adventure across the ocean will be exciting and will make us even closer. I thank the little kicker for already donating us new and wonderful emotions. I will do the best that I can to make the two of you happy. Table of Contents iii
Table of Contents
1. Introduction: recent progress in the synthesis of unprotected primary amines ...... 1
1.1. About amines ...... 2
1.2. Hydroamination ...... 3
1.3. Reductive amination ...... 6
1.4. Dehydrogenative coupling with alcohols ...... 10
1.5. Allylic amination ...... 13
1.6. Amination of prefunctionalized arenes ...... 16
1.6.1. Amination of halides and pseudohalides...... 16
1.6.2. Amination of boronates ...... 19
1.7. C−H amination ...... 21
1.7.1. Directed C−H amination ...... 22
1.7.2. Innate C−H amination ...... 23
1.8. Aminofunctionalization ...... 27
1.9. Conclusion and project outline ...... 29
2. Direct synthesis of unprotected amino alcohols ...... 31
2.1. Background ...... 32
2.2. Literature precedents ...... 33
2.3. Reaction design and optimization ...... 36
2.4. Scope of the reaction ...... 38
2.5. Extension of the reaction to different nucleophiles ...... 41
2.6. Potential applications in medicinal chemistry ...... 42
2.7. Mechanistic experiments ...... 44
2.8. Extension of the reaction to the synthesis of SLAP reagent ...... 46
2.9. Conclusion and outlooks ...... 48
3. Direct synthesis of primary anilines through C−H amination ...... 51
3.1. Background ...... 52
3.2. Literature precedents in innate C−H amination ...... 52
3.3. A matter of chemoselectivity ...... 56 iv Iron-catalyzed synthesis of unprotected primary amines
3.4. Scope of the reaction ...... 58
3.5. Late stage functionalization ...... 61
3.6. Mechanistic experiments ...... 61
3.7. Conclusion and outlooks ...... 63
4. Direct synthesis of 2-chloroalkylamines from alkenes ...... 67
4.1. Background ...... 68
4.2. Literature precedent ...... 68
4.3. Amino halogens as versatile building blocks...... 71
4.4. Reaction design and optimization...... 72
4.4. Scope of the reaction ...... 74
4.5. Synthetic utility of 2-chloroalkyl-1-amines ...... 78
4.6. Mechanistic experiments ...... 80
4.7. Conclusion...... 82
5. Experimental part ...... 85
5.1. Materials and methods ...... 86
5.2. Experimental part to chapter two (Direct synthesis of unprotected amino alcohols) ...... 87
5.2.1. Synthesis of starting materials ...... 87
5.2.2. Experimental procedures ...... 89
5.2.3. Substrate scope ...... 91
5.2.4. Extension of the reaction to different nucleophiles ...... 101
5.2.5. Potential applications in medicinal chemistry ...... 105
5.2.6. Mechanistic experiments ...... 109
5.2.7. Synthesis of SLAP reagents ...... 112
5.3. Experimental part to chapter three (Direct synthesis of primary anilines through C−H amination) ...... 116
5.3.1. Synthesis of starting materials ...... 116
5.3.2. Experimental procedures ...... 118
5.3.3. Substrate scope ...... 120
5.3.4. Late stage functionalization ...... 134
5.3.5. Mechanistic experiments ...... 138 Table of Contents v
5.4. Experimental part to chapter four (Direct synthesis of 2-chloroalkylamines from alkenes) ...... 142
5.4.1. Synthesis of starting materials ...... 142
5.4.2. Experimental procedures ...... 143
5.4.3. Substrate scope ...... 144
5.4.4. Aminochlorination of complex molecules ...... 155
5.4.5. Derivatizations of 2-chlorododecan-1-amine ...... 158
5.4.6. Mechanistic experiments ...... 163
5.4.7. X-ray structures ...... 167
vi Iron-catalyzed synthesis of unprotected primary amines
Abbreviations vii
Abbreviations
Ac acetyl acac acetylacetonate AIBN azobisisobutyronitrile atm atmosphere binap 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl BINOL 1,1'-bi-2-naphthol Bn benzyl Boc tert -butyloxycarbonyl BPO benzoyl peroxide bpy 2,2′-bipyridine BQ benzoquinone Bz benzoyl Cbz carboxy benzyl cod 1,5-cyclooctadiene coe cyclooctene Cp cyclopentadienyl Cp* 1,2,3,4,5-pentamethylcyclopentadienyl Cy cyclohexyl DABCO 1,4-diazabicyclo[2.2.2]octane DCB 1,2-dichlorobenzene DCE 1,2-dichloroethane DCM dichloromethane DCyB dicyanobenzene DFT density functional theory DG directing group DIBAL diisobutylaluminium hydride DMA dimethylacetamide DMF dimethylformamide viii Iron-catalyzed synthesis of unprotected primary amines dmg dimethylglyoximate DMSO dimethyl sulfoxide DPH O-(2,4-dinitrophenyl)hydroxylamine ee enantiomeric excess equiv equivalent Et ethyl
Fe(NTf 2)2 Fe(II) bis(trifluoromethanesulfonyl)imide h hour HAT hydrogen atom transfer HSA hydroxylamine-O-sulfonic acid i-Pr isopropyl Me methyl Ms mesyl MTBE methyl tert-butyl ether MW microwave Naphth naphthalene NBS N-bromo succinimide NCS N-chloro succinimide Ns nosyl oxidat oxidation Pc phthalocyanine PIFA [bis(trifluoroacetoxy)iodo]benzene Piv pivalyl PNP 2,6-bis(di-tert -butylphosphinomethyl)pyridine RT room temperature SET single electron transfer TAA tert -amyl alcohol TBAA tert -butyl acetoacetate TBAMA tetrabutylammonium acetate Abbreviations ix
TBHP tert -butyl hydroperoxide t-Bu tert-butyl TBHP tert -butyl hydroperoxide TEA triethylamine temp temperature TEMPO (2,2,6,6-tetramethylpiperidin-1-yl)oxyl TFA trifluoroacetic acid TFE 2,2,2-trifluoroethanol Tf trifluoromethanesulfonyl THF tetrahydrofuran TMP 2,2,6,6-tetramethylpiperidido TMS trimethylsilyl tol toluene TPA terephthalic acid TPB triphenylbenzene TPPTS sodium triphenylphosphine trisulfonate Ts tosyl
x Iron-catalyzed synthesis of unprotected primary amines
1. Introduction 1
1. Introduction: recent progress in the synthesis of
unprotected primary amines 2 Iron-catalyzed synthesis of unprotected primary amines
1. Introduction: recent progress in the synthesis of unprotected primary amines 1
1.1. About amines
Amines play an important role in society due to their use as medicines, agrochemicals, materials and dyes. 2 Primary amines represent a large part of this class of compounds and they are often used as intermediates in organic synthesis. Well- known reactions, such as the reduction of nitrile, nitro and imino groups, the Gabriel synthesis or the Curtius rearrangement are commonly used to access this important functional group. 3 Recently, milder approaches have been developed for the transformation of a larger class of functionalities into amines. However, many of these transformations result in the formation of protected amine products. In order to reveal the unprotected amines, subsequent reactions are required, adding further steps to a synthesis. For these reasons, the importance of the introduction of unprotected functionalities is often highlighted as a key challenge in organic chemistry. 4
In many recent reports of amination reactions the authors show the ease and the conditions for the fundamental cleavage of the protecting groups, in order to access the
1 Some of the following contents are based on a work published as “Recent Developments in the Direct Synthesis of Unprotected Primary Amines”, L. Legnani, B. N. Bhawal, B. Morandi, Synthesis 2017 , 49 , 776-789. 2 (a) G. D'Aprano, M. Leclerc, G. Zotti, G. Schiavon, Chem. Mater. 1995 , 7, 33-42. (b) C. Fischer, B. Koenig, Beilstein J. Org. Chem. 2011 , 7, 59-74. (c) T. Kahl, K.-W. Schröder, F. R. Lawrence, W. J. Marshall, H. Höke, R. Jäckh, Aniline in Ullmann's Encyclopedia of Industrial Chemistry , Wiley-VCH Verlag GmbH & Co. KGaA, 2000 . (d) P. Roose, K. Eller, E. Henkes, R. Rossbacher, H. Höke, Amines, Aliphatic in Ullmann's Encyclopedia of Industrial Chemistry , Wiley-VCH Verlag GmbH & Co. KGaA, 2000 . 3 M. B. Smith, J. March, in March's Advanced Organic Chemistry: Reactions, Mechanisms and Structure , 6th ed., John Wiley & Sons, 2007 . 4 (a) N. A. Afagh, A. K. Yudin, Angew. Chem. Int. Ed. 2010 , 49 , 262-310. (b) I. B. Seiple, S. Su, I. S. Young, C. A. Lewis, J. Yamaguchi, P. S. Baran, Angew. Chem. Int. Ed. 2010 , 49 , 1095-1098. (c) B. Trost, Science 1991 , 254 , 1471-1477. (d) P. A. Wender, V. A. Verma, T. J. Paxton, T. H. Pillow, Acc. Chem. Res. 2008 , 41 , 40-49. (e) I. S. Young, P. S. Baran, Nat. Chem. 2009 , 1, 193-205. 1. Introduction 3 final unprotected primary amines. 5 However, beyond the additional steps required, the conditions used are often too harsh for application on complex functionalized molecules.
Ammonia represents the ideal nitrogen source for the installation of unprotected primary amines. 6 In the past few years, other aminating reagents have been reported for the synthesis of this important class of compounds. In this introduction, I will describe current progress in the challenging direct synthesis of unprotected amines, including metal-catalyzed and non-catalyzed methodologies.
1.2. Hydroamination
Hydroamination represents a straightforward method to access primary unprotected amines from alkenes or alkynes. Substrates with multiple C−C bonds, including dienes and allenes, can be obtained from both biomass and fossil fuels and are among the most available chemical feedstock for industry and small scale synthesis.
Alkali metals or zeolites, together with high pressure of ammonia and high temperatures are used in bulk synthesis for the addition of ammonia onto propene and isobutene (Scheme 1). 7 The direct synthesis of the Markovnikov products that follows this approach represents the most atom economical method but finds enormous limitations in small scale synthesis and in the transformation of more functionalized molecules.
5 (a) J. A. Gurak, K. S. Yang, Z. Liu, K. M. Engle, J. Am. Chem. Soc. 2016 , 138 , 5805-5808. (b) H. Kim, G. Park, J. Park, S. Chang, ACS Catal. 2016 , 5922-5929. (c) K. Raghuvanshi, D. Zell, K. Rauch, L. Ackermann, ACS Catal. 2016 , 6, 3172-3175. (d) K. S. Williamson, T. P. Yoon, J. Am. Chem. Soc. 2010 , 132 , 4570-4571. 6 (a) J. Kim, H. J. Kim, S. Chang, Eur. J. Org. Chem. 2013 , 2013 , 3201-3213. (b) J. L. Klinkenberg, J. F. Hartwig, Angew. Chem. Int. Ed. 2011 , 50 , 86-95. (c) J. I. van der Vlugt, Chem. Soc. Rev. 2010 , 39 , 2302- 2322. 7 (a) M. Beller, J. Seayad, A. Tillack, H. Jiao, Angew. Chem. Int. Ed. 2004 , 43 , 3368-3398. (b) T. E. Müller, M. Beller, Chem. Rev. 1998 , 98 , 675-704. 4 Iron-catalyzed synthesis of unprotected primary amines
Scheme 1. Industrial hydroamination of propene and isobutene.
Recently, milder protocols that follow the hydroamination strategy have been developed. However, two-step approaches are normally required to reveal the primary amine moiety and significant limitations remain for highly functionalized molecules (vide infra , chapter four). At this stage, no mild protocols are known for the synthesis of unprotected amines through direct hydroamination of a large set of olefins.
In 2003, Yamashita and coworkers accomplished an example of hydroamination under photosensitized conditions in the presence of 1,2,4-triphenylbenzene as photo sensitizer (Scheme 2).8 A saturated solution of ammonia in MeCN/water was used as the nitrogen source but only a limited number of substrates were shown to tolerate the transformation.
Scheme 2. Photosensitized hydroamination (Yamashita, 2003).
In 2013, the group of Hartwig reported the hydroamination of activated and unactivated olefins (Scheme 3).9 The transformation was realized in a two-step sequence with the formation of a zirconium intermediate that was subsequently aminated by commercially available hydroxylamine-O-sulfonic acid. Also in this case, the
8 M. Yasuda, R. Kojima, H. Tsutsui, D. Utsunomiya, K. Ishii, K. Jinnouchi, T. Shiragami, T. Yamashita, J. Org. Chem. 2003 , 68 , 7618-7624. 9 A. E. Strom, J. F. Hartwig, J. Org. Chem. 2013 , 78 , 8909-8914. 1. Introduction 5 functional group tolerance was limited and the authors demonstrated a larger substrate diversity when the methylated HSA reagent was used.
Scheme 3. Zr-mediated two-steps hydroamination (Hartwig, 2013).
Following a different two-step procedure, the group of Teo accomplished the hydroamination of olefins via a tandem oxidation-reductive amination of olefins (Scheme 4).10 In the first step, a Pd-catalyzed Wacker oxidation installed the carbonyl group on the more substituted carbon and the subsequent Ir-catalyzed reductive amination afforded the desired amine products in good yields. A large set of functionalities tolerated the reaction conditions but the requirement for two distinct metal-catalyzed steps remains a drawback of this transformation.
Scheme 4. Tandem oxidation-reductive amination of olefins (Teo, 2015).
In 2013, the groups of Buchwald and Miura independently reported the Cu- catalyzed hydroamination of alkenes to provide Markovnikov and anti-Markovnikov 11 products (Scheme 5). Silanes and BzONR 2 were used, respectively, as hydrogen and
10 Y. Yang, N. I. Wong, P. Teo, Eur. J. Org. Chem. 2015 , 2015 , 1207-1210. 11 (a) Y. Miki, K. Hirano, T. Satoh, M. Miura, Angew. Chem. Int. Ed. 2013 , 52 , 10830-10834. (b) S. Zhu, N. Niljianskul, S. L. Buchwald, J. Am. Chem. Soc. 2013 , 135 , 15746-15749. (c) M. T. Pirnot, Y.-M. Wang, S. L. Buchwald, Angew. Chem. Int. Ed. 2016 , 55 , 48-57. 6 Iron-catalyzed synthesis of unprotected primary amines nitrogen sources for the transformation. 12 The use of an inexpensive catalyst such as copper in a one-step procedure represents a major progress in the hydroamination of olefins. However, the synthesis of unprotected primary amines via this method has not yet been accomplished.
Scheme 5. Miura-Buchwald hydroamination.
1.3. Reductive amination
An alternative to hydroamination is the reductive amination of aldehydes and ketones. The addition of an ammonia equivalent to the carbonyl group gives an imine intermediate that is reduced to the final primary amine. A common byproduct is obtained through reduction of the carbonyl to the alcohol group. Moreover, the primary amines obtained as products are more prone than ammonia to further react and, for this reason, secondary and tertiary amines can be detected as byproducts. The first reports of reductive amination required, as in the hydroamination strategy, increased temperatures and high pressures of gases.13 Nevertheless, further reports improved the protocols to the use of milder conditions.
In 2002, Beller and coworkers realized the first example of a homogeneously catalyzed reductive amination for the conversion of benzaldehyde to benzylamine (Scheme 6).14 A careful screening of the catalyst/ligand system limited the over- reduction of the aldehyde substrates and led to the desired products with up to 86%
12 X. Dong, Q. Liu, Y. Dong, H. Liu, Chem. Eur. J. 2017 , 23 , 2481-2511. 13 S. Gomez, J. A. Peters, T. Maschmeyer, Adv. Synth. Catal. 2002 , 344 , 1037-1057. 14 T. Gross, A. M. Seayad, M. Ahmad, M. Beller, Org. Lett. 2002 , 4, 2055-2058. 1. Introduction 7 yield. The authors showed that aliphatic aldehydes could also be used as substrates, when a Rh/Ir bimetallic catalyst was used instead of [Rh(cod)Cl] 2.
Scheme 6. Rh-catalyzed reductive amination of benzaldehyde (Beller, 2002).
Shortly after, Kadyrov and Riermeier presented a Ru-catalyzed method for the 15 amination of ketones (Scheme 7). [(( R)-tol-binap)RuCl 2] catalyst also induced enantioselectivity and branched, unprotected primary amines could be obtained with up to 98% ee . The transformation could be performed under milder temperatures than the one used by Beller but the N-formyl products needed an additional acidic deprotection step in order to reveal the unprotected functionality.
Scheme 7. Ru-catalyzed reductive amination of ketones (Kadyrov, 2003).
In 2004, the group of Fukuzumi developed an elegant Ir-catalyzed protocol for the preparation of α-amino acids starting from α-keto acid (Scheme 8). 16 A careful pH control of the aqueous reaction mixture was required to achieve high conversions. When the α-keto acid is protonated, the ketone is more prone to nucleophilic addition with + ammonia. On the other hand, under acidic conditions, the protonated NH 4 cannot undergo the attack onto the carbonyl group and only forms α-hydroxy acids as byproducts.
15 R. Kadyrov, T. H. Riermeier, Angew. Chem. Int. Ed. 2003 , 42 , 5472-5474. 16 S. Ogo, K. Uehara, T. Abura, S. Fukuzumi, J. Am. Chem. Soc. 2004 , 126 , 3020-3021. 8 Iron-catalyzed synthesis of unprotected primary amines
Scheme 8. Ir-catalyzed synthesis of α-amino acids (Fukuzumi, 2004).
In 2010, and in an extension of the substrate scope in 2014, the group of Xiao explored a cyclometalated Ir(III)-catalyzed method for the transformation of aliphatic and aromatic ketones, α-keto acids and β-keto ethers to the corresponding unprotected amines (Scheme 9). 17 Ammonium formate and formic acid served as nitrogen source and reducing agent, enhancing the application of the protocol to small scale laboratory synthesis.
Scheme 9. Ir-catalyzed reductive amination (Xiao, 2010 and 2014).
In 2017, the group of Beller reported an impressive improvement of the reductive amination of aldehydes and ketones under scalable and industrially-relevant conditions
17 (a) C. Wang, A. Pettman, J. Bacsa, J. Xiao, Angew. Chem. Int. Ed. 2010 , 49 , 7548-7552. (b) D. Talwar, N. P. Salguero, C. M. Robertson, J. Xiao, Chem. Eur. J. 2014 , 20 , 245-252. 1. Introduction 9
(Scheme 10). 18 The authors developed a novel heterogeneously-catalyzed protocol for the preparation of cobalt nanoparticles supported on graphite shells. Beller and coworkers, beyond demonstrating the scalability of the reaction up to 50 g, verified the possibility to recycle the catalyst. A scope with more than 140 examples was reported, including highly functionalized molecules. Ammonia, amines and nitro compounds were demonstrated to be suitable nucleophiles for the transformation.
Scheme 10. Co nanoparticles-catalyzed reductive amination (Beller, 2017).
The hydroaminomethylation reaction represents a particular modification of the reductive amination. In this transformation, firstly, the carbonyl group is formed in situ through hydroformylation of an olefin and, subsequently, the nucleophilic attack of ammonia occurs. The first example of hydroaminomethylation was reported by Knifton that explored a Co-catalyzed system. 19 However, the reaction was limited by a poor selectivity of linear versus branched amine products. In 1999, the group of Beller reported a bimetallic Rh/Ir system for the same transformation (Scheme 11). 20 The authors developed a biphasic system in order to avoid the formation of secondary amine byproducts. The primary amine formed during the first cycle of the reaction would migrate to the organic layer, avoiding the competition with ammonia for the nucleophilic attack onto the carbonyl group. The use of aqueous ammonia and pressurized syngas
18 R. V. Jagadeesh, K. Murugesan, A. S. Alshammari, H. Neumann, M.-M. Pohl, J. Radnik, M. Beller, Science 2017 , 358 , 326-332. 19 J. F. Knifton, Catal. Today 1997 , 36 , 305-310. 20 B. Zimmermann, J. Herwig, M. Beller, Angew. Chem. Int. Ed. 1999 , 38 , 2372-2375. 10 Iron-catalyzed synthesis of unprotected primary amines
(CO and H 2 mixture of gases) can represent a limitation for the application of these methods to laboratory scale organic synthesis.
SO 3Na
[Rh(cod)Cl] 2 (0.026 mol%) PAr [Ir(cod)Cl] 2 (0.21 mol%) NaO S 2 BINAS 3 R + NH 3 (1.9 mol%) R NH 2 NaO 3S (in H2O) CO/H (78 bar) PAr 2 75-95% 2 R = alkyl MTBE/H O, 130 °C, 10 h 2 n:iso up to 99:1 BINAS SO 3Na Ar: m-NaSO 3-C 6H4
Scheme 11. Rh/Ir-catalyzed hydroaminomethylation (Beller, 1999).
1.4. Dehydrogenative coupling with alcohols
In the dehydrogenative coupling of amines with alcohols, the carbonyl group that undergoes reductive amination with ammonia is formed in situ from an alcohol substrate. The hydrogenated metal catalyst originated during the oxidation of the alcohol, subsequently reduces the imine to the primary amine product. Therefore, neither H2 nor
H2 surrogates are required for the transformation (Scheme 12).
Scheme 12. Dehydrogenative coupling with alcohols.
This strategy has largely been used in industrial applications because of the availability and stability of the feedstock material and the formation of water as the sole 1. Introduction 11 byproduct of the reaction. 21 The heterogeneous catalysts normally used are based on Al, Co, Ni, Cu and Fe metals and the tuning of the reaction conditions can partially control the selectivity for the formation of primary versus secondary and tertiary amines. The high temperatures and pressures needed for this protocol limit the application of the borrowing hydrogen strategy to small scale laboratories.
In 2008, Gunanathan and Milstein reported the first homogeneously catalyzed example of the synthesis of primary amines via the borrowing hydrogen strategy (Scheme 13). 22 A novel Ru-pincer complex was synthesized and found to catalyze the transformation in the presence of 7.5 atm of NH 3 and under reflux in toluene.
Scheme 13. Ru-catalyzed synthesis of amines via the borrowing hydrogen strategy (Milstein, 2008).
In 2010, Beller and Vogt developed independently a new protocol for the synthesis of amines with secondary alcohols as starting materials (Scheme 14). 23 The two groups used Ru 3(CO) 12 and the phosphine ligand CataCXiumPCy to catalyze the transformation. Subsequently, Beller and coworkers reported an improvement of the reaction using the phosphine ligand Xantphos to improve selectivity and yields.24 The group of Deutsch reported alkyl diphosphine as optimal ligands for the transformation. 25
21 S. Bähn, S. Imm, L. Neubert, M. Zhang, H. Neumann, M. Beller, ChemCatChem 2011 , 3, 1853-1864. 22 C. Gunanathan, D. Milstein, Angew. Chem. Int. Ed. 2008 , 47 , 8661-8664. 23 (a) S. Imm, S. Bähn, L. Neubert, H. Neumann, M. Beller, Angew. Chem. Int. Ed. 2010 , 49 , 8126-8129. (b) D. Pingen, C. Müller, D. Vogt, Angew. Chem. Int. Ed. 2010 , 49 , 8130-8133. 24 S. Imm, S. Bähn, M. Zhang, L. Neubert, H. Neumann, F. Klasovsky, J. Pfeffer, T. Haas, M. Beller, Angew. Chem. Int. Ed. 2011 , 50 , 7599-7603. 25 W. Baumann, A. Spannenberg, J. Pfeffer, T. Haas, A. Köckritz, A. Martin, J. Deutsch, Chem. Eur. J. 2013 , 19 , 17702-17706. 12 Iron-catalyzed synthesis of unprotected primary amines
However, the use of gaseous ammonia in these procedures might limit laboratory scale applications.
Scheme 14. Ru-catalyzed synthesis of amines via the borrowing hydrogen strategy (Beller and Vogt, 2010).
Hofmann and Vogt provided detailed insights into the mechanism of the reaction through DFT calculations, Ru-complex crystal structures and mechanistic experiments. 26 The authors demonstrated that the selectivity-determining step occurs at the imine- reduction step. A control over the ligand-assisted reduction is fundamental to enhance the formation of primary amines as the sole products.
Other authors demonstrated that Cu, 27 Fe, 28 and Ir 29 can also catalyze the transformation. However, secondary amines are usually the major products obtained in these metal-catalyzed protocols.
26 (a) D. Pingen, M. Lutz, D. Vogt, Organometallics 2014 , 33 , 1623-1629. (b) X. Ye, P. N. Plessow, M. K. Brinks, M. Schelwies, T. Schaub, F. Rominger, R. Paciello, M. Limbach, P. Hofmann, J. Am. Chem. Soc. 2014 , 136 , 5923-5929. 27 F. Shi, M. K. Tse, X. Cui, D. Gördes, D. Michalik, K. Thurow, Y. Deng, M. Beller, Angew. Chem. Int. Ed. 2009 , 48 , 5912-5915. 28 R. Martinez, D. J. Ramon, M. Yus, Org. Biomol. Chem. 2009 , 7, 2176-2181. 29 (a) R. Kawahara, K.-i. Fujita, R. Yamaguchi, J. Am. Chem. Soc. 2010 , 132 , 15108-15111. (b) H. Ohta, Y. Yuyama, Y. Uozumi, Y. M. A. Yamada, Org. Lett. 2011 , 13 , 3892-3895. (c) A. Wetzel, S. Wöckel, M. Schelwies, M. K. Brinks, F. Rominger, P. Hofmann, M. Limbach, Org. Lett. 2013 , 15 , 266-269. 1. Introduction 13
1.5. Allylic amination
The metal-catalyzed allylic substitution reaction is a powerful tool in organic chemistry. The metal catalyst, usually Pd or Ir, after coordination with the allyl group, undergoes oxidative addition to form the π-allyl complex intermediate. Substitution with a suitable nucleophile provides the final substituted product. 30 In the field of allylic substitution reactions, despite the numerous methods for the synthesis of N-allylic systems, 31 only the groups of Carreira, Kobayashi and Hartwig established direct protocols for the installation of unprotected amines.
In 2007, Carreira and coworkers reported an Ir-catalyzed protocol for the introduction of the primary amine at the allylic position (Scheme 15). 32 The transformation occurred with perfect regioselectivity and the substrate scope included substrates with alcohols at the benzylic position or linked to an alkyl chain. Full conversion was accomplished with an Ir catalyst in combination with a novel phosphoramidite-olefin ligand. Inexpensive sulfamic acid was used as the nitrogen source.
Scheme 15. Ir-catalyzed amination of allylic alcohols (Carreira, 2007).
Preliminary control experiments suggested that DMF plays an important role in the reaction mechanism, forming a Vilsmeier-type intermediate with sulfamic acid. This
30 N. A. Butt, W. Zhang, Chem. Soc. Rev. 2015 , 44 , 7929-7967. 31 (a) M. Johannsen, K. A. Jørgensen, Chem. Rev. 1998 , 98 , 1689-1708. (b) R. Weihofen, O. Tverskoy, G. Helmchen, Angew. Chem. Int. Ed. 2006 , 45 , 5546-5549. 32 C. Defieber, M. A. Ariger, P. Moriel, E. M. Carreira, Angew. Chem. Int. Ed. 2007 , 46 , 3139-3143. 14 Iron-catalyzed synthesis of unprotected primary amines intermediate might subsequently react with the allylic alcohol and then participate in oxidative addition with the iridium complex (Scheme 16).
Scheme 16. Proposed mechanism for the Ir-catalyzed amination of allylic alcohols (Carreira, 2007).
The Carreira group also reported a stereospecific substitution for the same transformation. 33 The same Ir catalyst was used and lithium iodide and molecular sieves were found to improve the enantiopurity of the products. In 2012, Carreira and coworkers introduced a protocol for the enantioselective amination of racemic allylic alcohols (Scheme 17). 34 In order to induce enantioselectivity the reaction required, in addition to the catalyst [{Ir(coe) 2Cl} 2], the BINOL-derived phosphoramidite-olefin ligand.
Scheme 17. Enantioselective Ir-catalyzed allylic amination of alcohols (Carreira, 2012).
33 M. Roggen, E. M. Carreira, J. Am. Chem. Soc. 2010 , 132 , 11917-11919. 34 M. Lafrance, M. Roggen, E. M. Carreira, Angew. Chem. Int. Ed. 2012 , 51 , 3470-3473. 1. Introduction 15
In 2007, the group of Hartwig reported an Ir-catalyzed transformation for the enantioselective amination of allylic carbonates.35 When a solution of ammonia in EtOH was used as nitrogen source only symmetrical diallylamine products were obtained. The use of potassium trifluoroacetamide as aminating reagent allowed the synthesis of primary amines, but only in a protected form. In a following report, the same group realized the synthesis of primary unprotected amines with a similar protocol and with the use of gaseous ammonia as nitrogen source (Scheme 18).36 The group synthesized and studied in detail an Ir-metallacyclic catalyst that was found to be stable in high concentration of ammonia. The products of the reaction were isolated as chloride salts after HCl quenching or they were protected in situ as amides.
Scheme 18. Ir-catalyzed amination of cinnamyl carbonates (Hartwig, 2009).
Pd-catalysis has been explored by Kobayashi and coworkers to realize the amination of allylic acetates and carbonates (Scheme 19). 37 High selectivity of primary versus secondary amine products was obtained through careful evaluation of the reaction mixture concentration and of the solvent effect. Moreover, the use of gaseous ammonia resulted in negligible conversion of the starting material, whereas an aqueous solution of ammonia was found to give the desired products with good to excellent yields.
35 M. J. Pouy, A. Leitner, D. J. Weix, S. Ueno, J. F. Hartwig, Org. Lett. 2007 , 9, 3949-3952. 36 M. J. Pouy, L. M. Stanley, J. F. Hartwig, J. Am. Chem. Soc. 2009 , 131 , 11312-11313. 37 T. Nagano, S. Kobayashi, J. Am. Chem. Soc. 2009 , 131 , 4200-4201. 16 Iron-catalyzed synthesis of unprotected primary amines
Scheme 19. Pd-catalyzed amination of allylic carbonates and acetates (Kobayashi, 2009).
More recently the group of Mashima demonstrated the use of Pt-catalysis for the amination of allylic alcohols (Scheme 20).38 Also in this case secondary amines were obtained as byproducts but the protocol remains attractive due to the large availability of the substrates and the convenient use of aqueous ammonia as nitrogen source.
Scheme 20. Pt-catalyzed amination of allylic alcohols (Mashima, 2012).
1.6. Amination of prefunctionalized arenes
1.6.1. Amination of halides and pseudohalides
The Chan-Lam 39 and Buchwald-Hartwig 40 cross-coupling reactions are among the most used methods for the synthesis of anilines. Cu, Ni and Pd have been extensively used to catalyze the reaction between halogen functionalized arenes and nitrogen- containing partners.
38 K. Das, R. Shibuya, Y. Nakahara, N. Germain, T. Ohshima, K. Mashima, Angew. Chem. Int. Ed. 2012 , 51 , 150-154. 39 (a) D. M. T. Chan, K. L. Monaco, R.-P. Wang, M. P. Winters, Tetrahedron Lett. 1998 , 39 , 2933-2936. (b) P. Y. S. Lam, C. G. Clark, S. Saubern, J. Adams, M. P. Winters, D. M. T. Chan, A. Combs, Tetrahedron Lett. 1998 , 39 , 2941-2944. 40 (a) A. S. Guram, S. L. Buchwald, J. Am. Chem. Soc. 1994 , 116 , 7901-7902. (b) F. Paul, J. Patt, J. F. Hartwig, J. Am. Chem. Soc. 1994 , 116 , 5969-5970. 1. Introduction 17
Despite the great importance of the cross-coupling protocols in the synthesis of functionalized anilines, it was not until 2006 that Hartwig and coworkers reported the first example for the preparation of primary anilines exploiting Pd catalysis along with the use of ammonia or lithium amide as aminating reagents.41 The groups of Beller, 42 Buchwald 43 and Stradiotto 44 also explored the use of Pd catalysts for the synthesis of primary anilines through the same strategy (Scheme 21).
Scheme 21. Pd-catalyzed general strategy for anilines synthesis.
In 2008, the group of Chang demonstrated the use of a Cu catalyst in the same transformation, a more inexpensive and abundant metal than Pd. 45 Moreover, aqueous ammonia or simple ammonium salts could be used as nitrogen sources, facilitating the application of the procedure in small scale synthesis. Reports with the use of Cu catalysts for the synthesis of primary anilines were also presented by the groups of Fu, 46 Ma, 47 Taillefer, 48 Renaud 49 and Wolf 50 (Scheme 22).
41 Q. Shen, J. F. Hartwig, J. Am. Chem. Soc. 2006 , 128 , 10028-10029. 42 T. Schulz, C. Torborg, S. Enthaler, B. Schäffner, A. Dumrath, A. Spannenberg, H. Neumann, A. Börner, M. Beller, Chem. Eur. J. 2009 , 15 , 4528-4533. 43 D. S. Surry, S. L. Buchwald, J. Am. Chem. Soc. 2007 , 129 , 10354-10355. 44 R. J. Lundgren, A. Sappong-Kumankumah, M. Stradiotto, Chem. Eur. J. 2010 , 16 , 1983-1991. 45 J. Kim, S. Chang, Chem. Commun. 2008 , 3052-3054. 46 H. Rao, H. Fu, Y. Jiang, Y. Zhao, Angew. Chem. Int. Ed. 2009 , 48 , 1114-1116. 47 M. Fan, W. Zhou, Y. Jiang, D. Ma, Org. Lett. 2015 , 17 , 5934-5937. 48 N. Xia, M. Taillefer, Angew. Chem. Int. Ed. 2009 , 48 , 337-339. 49 M. K. Elmkaddem, C. Fischmeister, C. M. Thomas, J.-L. Renaud, Chem. Commun. 2010 , 46 , 925-927. 50 H. Xu, C. Wolf, Chem. Commun. 2009 , 3035-3037. 18 Iron-catalyzed synthesis of unprotected primary amines
Scheme 22. Cu-catalyzed general strategy for anilines synthesis.
In 2015, Stradiotto and Hartwig reported independently a similar Ni-catalyzed strategy for the synthesis of unprotected anilines. The group of Stradiotto demonstrated the transformation of bromo, chloro and tosyl (hetero)arenes to primary anilines when submitted to a solution of ammonia in dioxane and in the presence of Ni(cod) 2/JosiPhos as a catalyst/ligand system (Scheme 23).51 The use of gaseous ammonia, instead of a stock solution of ammonia in dioxane, provided similar results.
X [Ni(cod) 2] (10 mol%) H N JosiPhos (10 mol%) 2 R + NH 3 NaO tBu (3.1 equiv) R (in 1,4-dioxane) Y 1,4-dioxane/toluene, Y X = Br, Cl, OTs 110 °C, 16 h PCy 2 Y = CH, N PCy Fe 2 selected examples H2N N JosiPhos NH 2 Me MeO N NH 2 S MeO 15 16 17 85% 68% 84%
Scheme 23. Ni-catalyzed synthesis of anilines (Stradiotto, 2015).
Hartwig and coworkers exploited the metal complex (Josiphos)Ni( η2-NCPh) to catalyze the conversion of aryl chlorides to unprotected anilines (Scheme 24). 52 Either a solution of ammonia in dioxane or ammonium sulfate could serve as nitrogen sources. Mechanistic experiments ruled out the formation of aryl radicals as intermediates of the catalytic cycle.
51 A. Borzenko, N. L. Rotta-Loria, P. M. MacQueen, C. M. Lavoie, R. McDonald, M. Stradiotto, Angew. Chem. Int. Ed. 2015 , 54 , 3773-3777. 52 R. A. Green, J. F. Hartwig, Angew. Chem. Int. Ed. 2015 , 54 , 3768-3772. 1. Introduction 19
Scheme 24. Ni-catalyzed synthesis of anilines (Hartwig, 2015).
1.6.2. Amination of boronates
Unlike aryl halides, metal catalysts are not required for the amination of boronic acids and esters. Moreover, in addition to aryl boronates, alkyl boronates can also undergo the transformation, providing a powerful methodology for the synthesis of unprotected alkyl amines. In 2012, the group of Morken demonstrated the amination of aryl and alkyl pinacol boronates when 3 equivalents of methoxyamine were used as aminating reagent and n-BuLi as strong base (Scheme 25). 53 Under the reaction conditions, the intermediate boronate complex undergoes a stereo retentive 1,2- rearrangement and affords the aminated product. The subsequent Boc-protection allowed the isolation and full characterization of the major product.
Scheme 25. Amination of aryl and alkyl boronates (Morken, 2012).
53 S. N. Mlynarski, A. S. Karns, J. P. Morken, J. Am. Chem. Soc. 2012 , 134 , 16449-16451. 20 Iron-catalyzed synthesis of unprotected primary amines
In 2012, Kürti and coworkers developed a base free method for the amination of aryl boronic acids via a similar 1,2-migration strategy (Scheme 26). 54 The weak N−O bond of the nitrogen source, DPH, facilitates the departure of the leaving group. Additionally, the aminating reagent, beyond being nucleophilic enough to attack the boronic acid, can also accept the migrating aryl group. Both the methods reported by Kürti and Morken are complementary to cross-coupling reactions and can afford halogen-functionalized anilines otherwise difficult to obtain through amination of (hetero)aryl halides.
Scheme 26. Base-free amination of aryl boronates (Kürti, 2012).
Recently, McCubbin and coworkers reported a variation of the strategy with the use of HSA as a convenient aminating reagent and NaOH as activator (Scheme 27). 55 Despite showing an extensive substrate scope for the amination of aryl boronic acids, the method failed in the amination of alkyl boronic acids.
Scheme 27. HSA amination of aryl boronates (McCubbin, 2015).
The amination of alkyl boronates, which has not been demonstrated by the groups of Kürti and McCubbin, was achieved by the group of Goswami in 2016 (Scheme 28). 56 In a first step, methoxyamine was activated by PIFA and NBS. A subsequent basic workup in NaOH was required to reveal the unprotected amine. The drawback
54 C. Zhu, G. Li, D. H. Ess, J. R. Falck, L. Kürti, J. Am. Chem. Soc. 2012 , 134 , 18253-18256. 55 S. Voth, J. W. Hollett, J. A. McCubbin, J. Org. Chem. 2015 , 80 , 2545-2553. 56 N. Chatterjee, M. Arfeen, P. V. Bharatam, A. Goswami, J. Org. Chem. 2016 , 81 , 5120-5127. 1. Introduction 21 represented by the poor-atom economy of the transformation is counterbalanced by the metal-free conditions of the methodology.
Scheme 28. Amination of aryl and alkyl boronates (Goswami, 2016).
1.7. C−H amination
C−H functionalization represents one of the most studied classes of reactions in the last decades. 57 In general, this type of reaction is defined as the cleavage of a C−H bond and its replacement with, in most cases, a C−C, a C−N or a C−O bond. For the C−H amination of aromatic molecules, the installation of the amino functional group can occur regioselectively thanks to the presence of a preinstalled directing group on the arene substrate. On the other hand, in the innate C−H amination, arene substrates do not require any prior functionalization with directing groups and more than one isomer is usually obtained (Scheme 29). Since substrate prefunctionalizations are not required, the reaction is also synthetically complementary to the presence of halogens or other coupling partners and represents an important tool for the synthesis of new drugs through late stage functionalization. Despite the numerous recent reports in both directed and innate C−H amination reactions, only scarce examples demonstrated the introduction of the unprotected amino functionality. 58
57 H. M. L. Davies, D. Morton, J. Org. Chem. 2016 , 81 , 343-350. 58 (a) J. Jiao, K. Murakami, K. Itami, ACS Catalysis 2016 , 6, 610-633. (b) Y. Park, Y. Kim, S. Chang, Chem. Rev. 2017 , 117 , 9247-9301. 22 Iron-catalyzed synthesis of unprotected primary amines
Scheme 29. Overview of C−H amination strategies.
1.7.1. Directed C−H amination
In 2014, Zhu and coworkers reported the Cu-mediated amination of arenes (Scheme 30). 59 The authors demonstrated that various N-heterocyclic directing groups could coordinate to the metal mediator and guide the installation of the azide in ortho position. Stoichiometric amounts of TFA were also required in order to transform the azide moiety, introduced during the course of the reaction, into the primary amine.
Scheme 30. Cu-mediated C−H amination (Zhu, 2014).
Shortly after, the group of Uchiyama reported another elegant Cu-mediated protocol for the synthesis of phenols and primary anilines (Scheme 31). 60 Stoichiometric amounts of a TMP-cuprate base were required for the formation of the aryl intermediate through deprotonative cupration at the ortho position. Subsequent oxidation with TBHP or amination with BnONH 2, gave, respectively, phenol and aniline products in good to excellent yields. The authors also demonstrated the use of a catalytic amount of Cu for
59 J. Peng, M. Chen, Z. Xie, S. Luo, Q. Zhu, Org. Chem. Front. 2014 , 1, 777-781. 60 N. Tezuka, K. Shimojo, K. Hirano, S. Komagawa, K. Yoshida, C. Wang, K. Miyamoto, T. Saito, R. Takita, M. Uchiyama, J. Am. Chem. Soc. 2016 , 138 , 9166-9171. 1. Introduction 23 the successful regioselective amination of arenes. However, a stoichiometric amount of t-Bu 2Zn(TMP)Li was still required for the deprotonation of the substrate.
Scheme 31. Cu-mediated synthesis of phenols and anilines (Uchiyama, 2016).
More recently, the groups of Gui and Tan demonstrated the use of Ni as an efficient mediator for the same transformation (Scheme 32). 61 The C−H activation occurred through the complexation of Ni with the 8-amino-quinoline directing group and sodium azide was used as a nitrogen source for the transformation. Reducing agents were not required for the reduction of the azide to the primary amine, but the products yields were greatly increased by the use of phase transfer catalysts, such as TBAMA.
Scheme 32. Ni-mediated C−H amination (Gui and Tan, 2018).
1.7.2. Innate C−H amination
Many authors have demonstrated in the past few decades the synthesis of anilines from arenes but, in general, these protocols are limited by either poor functional groups
61 L. Yu, X. Chen, D. Liu, L. Hu, Y. Yu, H. Huang, Z. Tan, Q. Gui, Adv. Synth. Catal. 2018 , 360 , 1346- 1351. 24 Iron-catalyzed synthesis of unprotected primary amines tolerance, low yields or harsh conditions. In early protocols, Kovacic 62 and Minisci 63 reported this transformation with the use of HSA as the aminating reagent and with AlCl 3 and Fe(II) salts respectively as promoters. More recently, other groups have explored innate C−H amination for the synthesis of anilines with solutions of ammonia or ammonia gas as the ideal aminating reagent. Specifically, Hisao Yoshida studied the 64 65 use of Pt/TiO 2 photocatalyst, Muhler explored DuPont’s NiO/ZrO 2 reactants and Li 66 and Hu employed a Cu/SiO 2 system.
In 2013, Jun-ichi Yoshida and coworkers reported the synthesis of a significant number of anilines through electrochemical oxidation in the presence of pyridine as the aminating reagent (Scheme 33). 67 Neither metal nor organic catalysts were required for the transformation. However, the N-arylpyridinium intermediate needed treatment with an alkylamine, such as piperidine, to reveal the primary aniline.
Scheme 33. Electrochemical oxidation for primary anilines synthesis (J.-i. Yoshida, 2013).
The group of Jun-ichi Yoshida reported a similar protocol in 2015 for the preparation of 2-amino-benzothiazoles and 2-amino-benzoxazoles (Scheme 34).68 In this case, an intramolecular attack of the pyrimidyl moiety under electrochemical oxidation and subsequent cleavage with piperidine provided the final heterocyclic product.
62 P. Kovacic, R. P. Bennett, J. Am. Chem. Soc. 1961 , 83 , 221-224. 63 (a) F. Minisci, Synthesis 1973 , 1973 , 1-24. (b) A. Citterio, A. Gentile, F. Minisci, V. Navarrini, M. Serravalle, S. Ventura, J. Org. Chem. 1984 , 49 , 4479-4482. 64 H. Yuzawa, H. Yoshida, Chem. Commun. 2010 , 46 , 8854-8856. 65 N. Hoffmann, E. Löffler, N. A. Breuer, M. Muhler, ChemSusChem 2008 , 1, 393-396. 66 (a) T. Yu, R. Yang, S. Xia, G. Li, C. Hu, Catalysis Science & Technology 2014 , 4, 3159-3167. (b) T. Yu, Q. Zhang, S. Xia, G. Li, C. Hu, Catalysis Science & Technology 2014 , 4, 639-647. 67 T. Morofuji, A. Shimizu, J.-i. Yoshida, J. Am. Chem. Soc. 2013 , 135 , 5000-5003. 68 T. Morofuji, A. Shimizu, J.-i. Yoshida, Chem. Eur. J. 2015 , 21 , 3211-3214. 1. Introduction 25
Scheme 34. Electrochemical oxidation for 2-amino-benzothiazoles and 2-amino-benzoxazoles synthesis (J.-i. Yoshida, 2015).
In 2016, the group of Tung explored a dual catalytic system with a quinolinium organic photocatalyst and a Co(II) salt for the conversion of benzene to aniline (Scheme 35).69 Phenols were obtained as products, when ammonia was replaced by water and more complex arene substrates could tolerate the transformation.
Scheme 35. Quinolinium/Co(II) dual catalytic system for aniline synthesis (Tung, 2016).
The synthesis of anilines from a larger class of functionalized substrates, although limited to activated ones, was reported by Nicewicz and coworkers in 2015 (Scheme 36).70 A dual catalytic system was also exploited in this protocol in which, firstly, an organic photoredox catalyst was required for the oxidation of the aromatic ring. The subsequent attack of the nitrogen source installed the amine moiety and aromatic oxidation with a catalytic amount of TEMPO provided the final product. An important role was played by oxygen in the regeneration of both the photoredox catalyst and TEMPO. Ammonium carbamate was used as an inexpensive and stable nitrogen source for the reaction.
69 Y.-W. Zheng, B. Chen, P. Ye, K. Feng, W. Wang, Q.-Y. Meng, L.-Z. Wu, C.-H. Tung, J. Am. Chem. Soc. 2016 , 138 , 10080-10083. 70 N. A. Romero, K. A. Margrey, N. E. Tay, D. A. Nicewicz, Science 2015 , 349 , 1326-1330. 26 Iron-catalyzed synthesis of unprotected primary amines
Scheme 36. Photoredox/TEMPO dual catalytic system for anilines synthesis (Nicewicz, 2015).
In 2016, Falck and coworkers reported an additional protocol for the direct synthesis of anilines (Scheme 37).71 DuBois's rhodium catalyst, 72 already employed for 73 the synthesis of unprotected aziridine, in combination with ArSO 2ONHR, enabled the synthesis of diverse N-alkyl arylamines. When ArSO 2ONH 2 was used as aminating reagent, the primary aniline was afforded. However, the authors demonstrated the transformation to the primary aniline only with 1,3,5-trimethylbenzene. Preliminary mechanistic experiments suggested the formation of a nitrene species between the Rh catalyst and the nitrogen source.
71 M. P. Paudyal, A. M. Adebesin, S. R. Burt, D. H. Ess, Z. Ma, L. Kürti, J. R. Falck, Science 2016 , 353 , 1144-1147. 72 C. G. Espino, K. W. Fiori, M. Kim, J. Du Bois, J. Am. Chem. Soc. 2004 , 126 , 15378-15379. 73 (a) J. L. Jat, M. P. Paudyal, H. Gao, Q.-L. Xu, M. Yousufuddin, D. Devarajan, D. H. Ess, L. Kürti, J. R. Falck, Science 2014 , 343 , 61-65. (b) Z. Ma, Z. Zhou, L. Kürti, Angew. Chem. Int. Ed. 2017 , 56 , 9886- 9890. 1. Introduction 27
Scheme 37. Rh-catalyzed synthesis of 2,4,6-trimethylaniline (Falck, 2016).
1.8. Aminofunctionalization
An insight into the use of unprotected functional groups, amines included, has been reported by the group of Yudin. In 2006, they developed a practical approach to access unprotected amino aldehydes (Scheme 38a). 74 Yudin and coworkers demonstrated that aziridine esters, submitted to reductive conditions with DIBAL in toluene at -78 °C, provided products containing both the unprotected aziridine and aldehyde groups. The authors propose that these two functionalities can coexist because the formation of an iminium from an aziridine is highly unfavorable. Two years later, the same group published a protocol to access unprotected amino alcohols (Scheme 39b). 75 Starting from unprotected amino aldehydes and treating them with an allyl indium reagent, prepared in situ , it was possible to achieve, in a stereoselective fashion, the formation of unprotected amino alcohols and sulfanyl amino alcohols when a thiol was subsequently added.
74 R. Hili, A. K. Yudin, J. Am. Chem. Soc. 2006 , 128 , 14772-14773. 75 R. Hili, A. K. Yudin, Angew. Chem. Int. Ed. 2008 , 47 , 4188-4191. 28 Iron-catalyzed synthesis of unprotected primary amines
Scheme 38. Synthesis of unprotected amino aldehydes ((a), Yudin, 2006) and sulfanyl amino alcohols ((b), Yudin, 2008).
In 2014, Kürti and Falck reported a protocol for the synthesis of unprotected aziridines from olefins (Scheme 39).73a Activated and unactivated alkenes afforded the desired products and the reaction showed a good functional group tolerance. Beyond the scope of the reaction, the synthetic utility of the aziridine products was demonstrated through further functionalizations to amino ethers, amino azides and primary amines. The authors, with the support of DFT calculations, suggested that the Rh catalyst employed for the transformation, combined with DPH, could form a reactive nitrene species. In 2017, in an extension of their work, Kürti and coworkers demonstrated the use of commercially available HSA as an inexpensive reagent for the same transformation. 73b The authors also proved that the protocol is oxygen and moisture tolerant.
Scheme 39. Rh-catalyzed synthesis of aziridines and opening to amino ethers (Kürti and Falck, 2014).
1. Introduction 29
1.9. Conclusion and project outline
The attention to the synthesis of primary amines has increased during the past few decades. Primary amines represent a fundamental functional group and are extremely important as synthetic intermediates. Novel methodologies are becoming available for the preparation of this important moiety from diverse substrates.
Despite the progress in the field, significant limitations restrict the applicability of these reactions in organic synthesis. For instance, in some classes of reactions, such as hydroamination reactions, harsh conditions are still required and the functional group tolerance is extremely limited. In other cases, such as the directed C−H amination, stoichiometric amounts of metal are needed. As presented in this introduction, the majority of the protocols required prefunctionalized substrates, affecting the step and atom economy of the synthesis of the target molecules.
The goal of my research work has been the development of new methods that would address some of the limitations listed above for the direct synthesis of primary amines. In chapter two, I will discuss the discovery of a novel Fe catalyzed protocol for the preparation of unprotected 1,2-amino alcohols. Chapter three will present the application of a similar Fe-catalyzed method for the direct synthesis of unprotected anilines via C−H amination. Finally, chapter four will describe the design of a new strategy for the synthesis of a large class of primary amines through the preparation and functionalization of 2-chloroalkylamines. 30 Iron-catalyzed synthesis of unprotected primary amines
2. Aminohydroxylation 31
2. Direct synthesis of unprotected amino alcohols 32 Iron-catalyzed synthesis of unprotected primary amines
2. Direct synthesis of unprotected amino alcohols 76
2.1. Background
Among the various classes of amines, amino alcohols represent a prominent moiety in organic chemistry. Due to the presence of this functionality in the norepinephrine structure, the amino alcohol moiety and, in particular, 2-amino-1- phenylethanols, have been studied. Thousands of bioactive compounds, hundreds of natural products and more than 20 drugs share this structural moiety (Scheme 40). 77 Norepinephrine, also known as noradrenaline, is part of the catecholamine family and plays an important role as a hormone and neurotransmitter in a wide variety of organisms, from protozoa to mammalians. 78
Scheme 40. 2-amino-1-phenylethanol moiety in literature.
In the past few decades, many authors have reported different protocols for the synthesis of this important class of molecules starting from olefins, which are widely available feedstocks. As already discussed in chapter one, the synthesis of amino
76 Some of the following contents are based on a work published as “Direct Catalytic Synthesis of Unprotected 2-Amino-1-Phenylethanols from Alkenes by Using Iron(II) Phthalocyanine”, L. Legnani, B. Morandi, Angew. Chem. Int. Ed. 2016 , 55 , 2248-2251. 77 Number of bioactive compounds, natural products and marketed drugs from the ChEBML, Pubchem and Reaxys database. 78 L. Goodman, A. Gilman, L. Brunton, J. Lazo, K. Parker, Goodman & Gilman's The Pharmacological Basis Of Therapeutics , Mcgraw-Hill, New York, 2006 . 2. Aminohydroxylation 33 alcohols lacks methodologies that are able to furnish this moiety in an unprotected form. Many methods introduce amino alcohols with a protecting group on one of the two functionalities or on both of them.
2.2. Literature precedents
The most established method for the amino hydroxylation of alkenes has been developed by Sharpless and coworkers (Scheme 41). 79 With the use of osmium catalysis and modulating the stereochemistry with simple amino acid derived ligands, the authors demonstrated the enantioselective synthesis of 2-amino-1-phenylethanols. Beyond the toxicity of the metal catalyst, other drawbacks of the transformation include the formation of regioisomers and the introduction of a tosyl protecting group, which is hard to cleave in the presence of other sensitive functionalities.
Scheme 41. Os-catalyzed enanatioselective aminohydroxylation (Sharpless, 2002).
A more recent example for the synthesis of amino alcohols that results in the formation of a protected amine product was reported by Ning Jiao and coworkers 80 (Scheme 42). An easier-to-handle and inexpensive catalyst, MnBr2, was used in combination with trimethylsilyl azide as nitrogen source. The authors demonstrated that the β-azido alcohol products were useful precursors in the synthesis of aziridines and various heterocycles. Amino alcohols could be accessed from β-azido alcohols through subsequent palladium/charcoal reduction.
79 M. A. Andersson, R. Epple, V. V. Fokin, K. B. Sharpless, Angew. Chem. Int. Ed. 2002 , 41 , 472-475. 80 X. Sun, X. Li, S. Song, Y. Zhu, Y.-F. Liang, N. Jiao, J. Am. Chem. Soc. 2015 , 137 , 6059-6066. 34 Iron-catalyzed synthesis of unprotected primary amines
Scheme 42. Mn-catalyzed azidohydroxylation (Ning Jiao, 2015).
The groups of Donohoe, McLeod and Zhu also reported protocols for the synthesis of N-protected amino alcohols starting from olefins. 81
In 2012, the group of Yoon reported an Fe-catalyzed protocol that introduces both the protected O- and N-functionalities (Scheme 43). 82 The amino alcohol moiety was obtained enantioselectively in the presence of an Fe triflimide complex and of a bisoxazoline ligand. Only activated olefins were demonstrated to undergo the transformation.
Scheme 43. Enantioselective Fe-catalyzed aminohydroxylation (Yoon, 2012).
An additional Fe-catalyzed protocol was reported by Xu and coworkers in 2014 (Scheme 44). 83 A hydroxyl amine reagent, in the presence of a tridentate PyBOX ligand, was employed to synthesize alkoxyl oxazoline products. Further acidic and basic treatment with TsOH and LiOH respectively converted the product of the Fe-catalyzed reaction to the final oxazolidinone product.
81 (a) T. J. Donohoe, C. K. A. Callens, A. Flores, S. Mesch, D. L. Poole, I. A. Roslan, Angew. Chem. Int. Ed. 2011 , 50 , 10957-10960. (b) Masruri, A. C. Willis, M. D. McLeod, J. Org. Chem. 2012 , 77 , 8480-8491. (c) Q. Xue, J. Xie, P. Xu, K. Hu, Y. Cheng, C. Zhu, ACS Catalysis 2013 , 3, 1365-1368. 82 K. S. Williamson, T. P. Yoon, J. Am. Chem. Soc. 2012 , 134 , 12370-12373. 83 D.-F. Lu, C.-L. Zhu, Z.-X. Jia, H. Xu, J. Am. Chem. Soc. 2014 , 136 , 13186-13189. 2. Aminohydroxylation 35
Scheme 44. Fe-catalyzed aminohydroxylation (Xu, 2014).
The use of different methods for the introduction of protected O- and N- amino alcohols was also demonstrated by the groups of Dauban, Komatsu and Studer. 84
Protocols for the synthesis of amino alcohols with an unprotected form of the amine are scarce. In 2014, Kürti and coworkers reported the synthesis of unprotected aziridines through Rh-catalysis ( vide supra ). 73a Subsequent opening of the aziridine with camphorsulfonic acid in methanol afforded the 2-methoxy-alkyl-1-amine product.
A report by Minisci and coworkers demonstrated the direct introduction of primary amines with stoichiometric amounts of FeSO 4 and commercially available hydroxylamine-O-sulfonic acid (HSA) as the aminating reagent (Scheme 45). 85 Despite the limited scope and the low conversion, the report of Minisci represents a unique example for the direct synthesis of amines with the use of inexpensive catalysts and hydroxylamine-derived reagents.
Scheme 45. Fe-mediated synthesis of 2-methoxy-2-phenylethan-1-amine (Minisci, 1965).
84 (a) S. Minakata, Y. Morino, T. Ide, Y. Oderaotoshi, M. Komatsu, Chem. Commun. 2007 , 3279-3281. (b) G. Dequirez, J. Ciesielski, P. Retailleau, P. Dauban, Chem. Eur. J. 2014 , 20 , 8929-8933. (c) Y. Li, M. Hartmann, C. G. Daniliuc, A. Studer, Chem. Commun. 2015 , 51 , 5706-5709. 85 F. Minisci, R. Galli, Tetrahedron Lett. 1965 , 6, 1679-1684. 36 Iron-catalyzed synthesis of unprotected primary amines
The reports from Kürti and Minisci are of great interest because amines are introduced in an unprotected fashion. However, these protocols have a limited synthetic utility because the O-protecting groups are hard to cleave under mild conditions.
In conclusion, no reports for the direct introduction of unprotected O- and N- functionalities have been reported in literature. The synthesis of a target molecule that relies on one of these amino hydroxylation methodologies would require, in most cases, a further step in order to reveal the unprotected amine and alcohol moieties.
2.3. Reaction design and optimization
The synthesis of unprotected amino alcohols is recognized as a significant challenge in transition-metal catalysis, due to the possible inhibition of the catalytic cycle via chelation of the metal.86 At the outset of our investigation a report from Minisci attracted our attention ( vide supra ). 85 We reasoned that the radical aminating species suggested by the authors could represent an ideal reactive species (Scheme 46). After attack onto the olefin bond, the formation of the radical at the more substituted position would ensure a high regioselectivity. Next, a single-electron-transfer step would reduce the metal, facilitating the catalytic turnover and delivering a carbocation prone to be trapped by a nucleophile, such as water. Finally, due to the highly electrophilic nature of the reactive species and the protonation of the final product under acidic conditions, we could possibly avoid inhibition of the catalytic cycle by preventing chelation of the metal catalyst.
86 J. F. Hartwig, Organotransition Metal Chemistry: from Bonding to Catalysis , University Science Books, Sausalito, 2010 . 2. Aminohydroxylation 37
Scheme 46. SET mechanism using a protonated amino source.
We started our investigation of the aminohydroxylation reaction using the reagent 87 PivONH 3OTf, as a more stable and soluble hydroxylamine-derived reagent than HSA.
Simple Fe(II) salts, such as FeSO 4, effectively afforded the desired product, whereas Mn and Cu complexes proved to be almost ineffective (Table 1). An important ligand effect was noticed when bidentate nitrogen ligand were used in combination with catalytic amounts of Fe. Fe(II) phthalocyanine, a widely available and inexpensive Fe complex, proved to be the best catalyst for the transformation, giving full conversion of the starting material and 78% yield of the desired product. The formation of a more stable metal complex less prone to decomposition and to product chelation might explain the observed ligand effect.88
A mixture of MeCN/H 2O was able to fully solubilize the reagent and proved to be the best solvent. The work-up of the reaction mixture also required careful optimization. Initially, a basic work-up and the following extraction of the product in the organic phase were attempted. Due to the high polarity of the amino alcohols a significant amount of product was lost in the water phase. The problem was overcome by extracting the reaction mixture with an HCl aqueous solution and evaporating the water phase under vacuum.
87 N. Guimond, S. I. Gorelsky, K. Fagnou, J. Am. Chem. Soc. 2011 , 133 , 6449-6457. 88 (a) J. L. Crossland, D. R. Tyler, Coord. Chem. Rev. 2010 , 254 , 1883-1894. (b) A. Fürstner, ACS Central Science 2016 , 2, 778-789. 38 Iron-catalyzed synthesis of unprotected primary amines
Table 1. Optimization of the reaction conditions. (a)
entry catalyst (5 mol %) ligand (10 mol %) yield (b)
1 Fe(OAc) 2 / 27%
2 Fe(acac) 2 / 55%
3 FeSO 4 / 42%
4 FeSO 4 L7 63%
5 FeSO 4 L8 52%
6 FeSO 4 L9 49%
7 FeSO 4 L10 56%
8 FeSO 4 L11 48% 9 Fe(II)Pc / 78% 10 / Pc 0% 11 / / 0%
12 MnSO 4 / 0%
13 Cu(MeCN) 4PF 6 / 9%
1 (a) MeCN/H 2O, RT, 16 h. (b) H-NMR-yield.
2.4. Scope of the reaction
Functionalized styrenes performed well under the optimized reaction conditions
(Table 2). Electron-donating groups (Me, t-Bu, MeO, −CH 2OH) were well tolerated and electron rich arenes afforded the desired products in good yields. Halogen- functionalized styrenes (Br, Cl) resulted in full conversion and demonstrated that this 2. Aminohydroxylation 39 methodology is compatible with common cross-coupling protocols. On the other hand, stronger electron-withdrawing groups, such as CF 3, did not give full conversion of the styrene substrates and gave the final products in lower yields. α- and β- substituted styrenes performed well under the reaction conditions and, beyond the synthesis of 2- amino-1-phenylethanols, we expanded the scope of the reaction to other activated olefins, such as conjugated dienes and enynes.
Table 2. Scope of the Fe(II)-phthalocyanine catalyzed amino hydroxylation reaction.
entry product yield entry product yield
1 74% (a) 2 61% (50)
3 70% (a) 4 77% (46)
5 77% (67) 6 84% (78)
7 88% (55) 8 73% (41)
9 50% (46) 10 41% (36)
11 66% (55) 12 73% (51)
40 Iron-catalyzed synthesis of unprotected primary amines
OH (b) (a) 13 70% 14 NH 2 54%
55% 73% 15 16 8:1 (c) 1:1 (c)
46% 17 dr 1.3:1
All yields, unless otherwise noted, are 1H-NMR yields of the corresponding amine hydrochloride salts in
D2O. Yields in parentheses are yields of isolated product after Boc protection. (a) Yields of isolated pure amino alcohol products. (b) Yields of isolated product after Boc protection. (c) Ratio of products. dr : diastereomeric ratio.
Electron rich styrenes, such as 4-methoxystyrene, converted to the desired products in limited yields (Table 3). 1H-NMR analysis of the reaction crude revealed the probable formation of polymers under the reaction conditions. Heterocyclic olefins and styrenes functionalized with strong electron-withdrawing groups, such as the nitro group, also represented a limit for the reaction.
Simple unactivated olefins, such as 1-dodecene, failed to convert to the desired amino alcohol products. Traces of the desired products could be observed when 2- methyl-1-nonene and cyclohexene were used as substrates for the reaction.
2. Aminohydroxylation 41
Table 3. Difficult substrates under the Fe(II)-phthalocyanine catalyzed amino hydroxylation reaction.
entry product yield entry product yield
1 25% 2 35%
3 6% 4 8%
5 <5% 6 0%
1 All yields are H-NMR yields of the corresponding amine hydrochloride salts in D 2O.
2.5. Extension of the reaction to different nucleophiles
Different nucleophiles, other than water, could be used to trap the carbocation, which is formed after the attack of the aminating electrophilic species onto the olefin (Table 4). When we submitted the styrene model substrate to the reaction conditions in the presence of MeOH as solvent we observed full conversion of the starting material and we obtained the desired amino methoxylated product in 96% of 1H-NMR yield. i- PrOH, and also a relatively poor nucleophile such as t-BuOH, performed well under the reaction conditions. To our surprise, when MeOH was used as a solvent, unactivated substrates, such as 2-methyl-1-nonene and (2-methyl-propenyl)trimethylsilane, gave the desired amino methoxylated products. These preliminary results suggest that additional nucleophiles could be used in the transformation for the synthesis of more complex molecules. 42 Iron-catalyzed synthesis of unprotected primary amines
Table 4. Use of different nucleophiles than water.
entry product yield entry product yield
1 96% (88) 2 81% (79)
36% 3 64% (61) 4 (3:1) (a)
5 62% (2:1) (a,b) 6 30% (c)
All yields, unless otherwise noted, are 1H-NMR yields of the corresponding amine hydrochloride salts in
D2O. Yields in parentheses are yields of isolated product after Boc protection. (a) Ratio of products. (b) (2- Methyl-propenyl)trimethylsilane as starting material. (c) Camphene as starting material.
2.6. Potential applications in medicinal chemistry
To illustrate the broad applicability of our method to the synthesis of diverse amino alcohol-derived products, the crude, unpurified 2-amino-1-phenylethan-1-ol was transformed into a range of derivatives (Scheme 47). The formation of amides and carbamates was straightforward and gave the corresponding products in high yields. Moreover, the reductive amination of the primary amine was demonstrated, and an anti- malarial product was afforded in 67% yield.89 This practical protocol provides a powerful
89 M. J. Chaparro, J. Vidal, Í. Angulo-Barturen, J. M. Bueno, J. Burrows, N. Cammack, P. Castañeda, G. Colmenarejo, J. M. Coterón, L. de las Heras, E. Fernández, S. Ferrer, R. Gabarró, F. J. Gamo, M. García, M. B. Jiménez-Díaz, M. J. Lafuente, M. L. León, M. S. Martínez, D. Minick, S. Prats, M. Puente, L. Rueda, E. Sandoval, Á. Santos-Villarejo, M. Witty, F. Calderón, ACS Medicinal Chemistry Letters 2014 , 5, 657- 661. 2. Aminohydroxylation 43 strategy for the synthesis of diverse secondary amine groups that are widely present in bioactive compounds.
Scheme 47. Synthetic versatility of 2-amino-1-phenylethan-1-ol.
In order to demonstrate the potential application of our method to the synthesis of bioactive molecules we synthesized (±)-aegoline-O-methylether, a natural product with anti-bacterial properties (Scheme 48).90 The target molecule was afforded in 89% yield over two steps. In the first step, the amino methoxylation of 4-methoxystyrene delivered the intermediate product that subsequently underwent reaction with cinnamoyl chloride to give the final amide product. The application of our methodology to the synthesis of a bioactive molecule demonstrated the potential application to the synthesis of marketed drugs.
Scheme 48. Synthesis of (±)-aegoline-O-methylether.
90 S. Faizi, F. Farooqi, S. Zikr-Ur-Rehman, A. Naz, F. Noor, F. Ansari, A. Ahmad, S. A. Khan, Tetrahedron 2009 , 65 , 998-1004. 44 Iron-catalyzed synthesis of unprotected primary amines
2.7. Mechanistic experiments
In order to gain a deeper insight into the mechanism of the reaction, we performed preliminary mechanistic studies. Initially, the addition of one equivalent of TEMPO, a common radical trap, strongly affected the reactivity of our system, giving only 18% of the desired product. Moreover, the use of enantiopure BOX and PyBOX ligands did not induce enantioselectivity, suggesting the radical nature of our transformation. Despite these results, a common radical clock, α-cyclopropyl-styrene, did not open under the reaction conditions, thus indicating that the putative radical at the benzylic position would be very-short lived (Scheme 49).91
Scheme 49. Radical clock experiment.
When we submitted ( E)- and ( Z)-β-Me-styrene to the amino hydroxylation and amino methoxylation reaction conditions, we observed conservation of the stereo information (Scheme 50). In both cases, the major isomer obtained resulted from anti - addition onto the olefinic bond. The outcome of this experiment, which is very similar in terms of stereoselectivity to an Fe(III)-porphyrin-catalyzed method for the synthesis of Ts-protected aziridines, 92 might suggest the formation of an aziridine intermediate that subsequently opens in the presence of a nucleophile.
91 (a) A. L. J. Beckwith, V. W. Bowry, J. Org. Chem. 1989 , 54 , 2681-2688. (b) E. Shirakawa, X. Zhang, T. Hayashi, Angew. Chem. Int. Ed. 2011 , 50 , 4671-4674. 92 R. Vyas, G.-Y. Gao, J. D. Harden, X. P. Zhang, Org. Lett. 2004 , 6, 1907-1910. 2. Aminohydroxylation 45
Scheme 50. Conservation of stereochemistry with ( E)- and ( Z)-β-Me-styrene.
To verify this hypothesis, we synthesized the unprotected 2-phenylaziridine and we submitted it to the standard reaction conditions (Scheme 51). A clean opening of the aziridine was achieved and 2-amino-1-phenylethan-1-ol was obtained in 88% yield. On the other hand, when styrene was submitted to the standard conditions but in the absence of a nucleophile, we could not observe any formation of the presumed aziridine intermediate. The concomitant presence of a proton shuttle might thus be required for the completion of the transformation.
Scheme 51. Experiments to test the aziridine intermediate formation.
A possible reaction mechanism is depicted in Scheme 52. The hydroxylamine- derived reagent PivONH 3OTf forms the aminyl radical species A, after loss of PivOH. This Fe species, after attack onto the alkene, delivers the carbocationic intermediate C through formation of the radical intermediate B and SET to release Fe(II). Closing to the unprotected aziridine D and further opening via nucleophilic attack provides the final 46 Iron-catalyzed synthesis of unprotected primary amines product E. The formation of an Fe-nitrene reactive species, 93 rather than the radical aminyl intermediate, cannot be excluded. DFT calculations are ongoing and they might help to clarify the exact nature of the Fe reactive species. Additional mechanistic studies could help to collect additional support for the formation of the aziridine intermediate and elucidate the catalytic cycle of the reaction.
PivO NH 3 OTf
Fe(II) OH H N 2 R H H TfOH E PivOH N OTf Fe(III) H2O A OTf H2N R R D Fe(III) OTf Fe(II) Fe(II) OTf H2N H N R 2 R B C SET
Scheme 52. Proposed reaction mechanism.
2.8. Extension of the reaction to the synthesis of SLAP reagent 94
The group of Bode developed in the past few years an elegant method for the synthesis of saturated heterocycles. Sn-containing substrates, called SnAP reagents, formed an imine intermediate after attack to an aldehyde. The imine intermediate, in the presence of stoichiometric amounts of Cu, led to a carbon centered radical that
93 (a) S. M. Paradine, M. C. White, J. Am. Chem. Soc. 2012 , 134 , 2036-2039. (b) E. T. Hennessy, T. A. Betley, Science 2013 , 340 , 591-595. (c) A. I. O. Suarez, V. Lyaskovskyy, J. N. H. Reek, J. I. van der Vlugt, B. de Bruin, Angew. Chem. Int. Ed. 2013 , 52 , 12510-12529. 94 Some of the following contents are based on a work published as “Continuous Flow Synthesis of Morpholines and Oxazepanes with Silicon Amine Protocol (SLAP) Reagents and Lewis Acid Facilitated Photoredox Catalysis”, M. K. Jackl, L. Legnani, B. Morandi, J. W. Bode, Org. Lett. 2017 , 19 , 4696-4699. 2. Aminohydroxylation 47 underwent cyclization to deliver the final substituted heterocyclic product. 95 Further reports from the same research group explored the use of various heteroatoms. Moreover, the formation of the carbon centered radical could be realized under photocatalytic conditions. Finally, the authors provided an alternative to SnAP reagents with the use of SLAP reagents, which are Si-containing substrates (Scheme 53). 96
Scheme 53. General synthesis of substituted heterocycles from SLAP reagents.
The preparation of SLAP reagents relies on a multi-step synthesis and on the use of diols as starting material. The synthesis of a large class of substituted heterocycles is therefore limited by the use of different SLAP reagents that, each time, have to be prepared from the corresponding diol substrate.
Our amino hydroxylation report offered an opportunity to prepare directly in one step different SLAP reagents, some of them previously inaccessible by alkylation of the hindered secondary or tertiary alcohol. The commercially available TMSCH 2OH proved to be a suitable nucleophile for our transformation and a small library of SLAP reagents (Table 5) could be prepared.
Bode and coworkers synthesized various substituted morpholines starting from the SLAP reagents prepared following our protocol. They combined the SLAP reagents with different aldehydes and cyclization under photoredox conditions afforded the final products. The synthesis of some of these trisubstituted morpholines would have been difficult with other protocols.
95 C. V. T. Vo, G. Mikutis, J. W. Bode, Angew. Chem. Int. Ed. 2013 , 52 , 1705-1708. 96 (a) S.-Y. Hsieh, J. W. Bode, Org. Lett. 2016 , 18 , 2098-2101. (b) S.-Y. Hsieh, J. W. Bode, ACS Central Science 2017 , 3, 66-72. 48 Iron-catalyzed synthesis of unprotected primary amines
Table 5. Synthesis of SLAP reagents.
entry product yield entry product yield
1 86% 2 76%
51% 3 77% 4 dr 1:1
All yields, unless otherwise noted, are isolated yields of the aniline products. dr : diastereomeric ratio.
2.9. Conclusion and outlooks
In this chapter, I described the development and the applications of the first reported method for the synthesis of unprotected amino alcohols. This Fe-catalyzed protocol introduces directly the two functionalities and can be extended to the use of alcohols to afford 1,2-amino ethers. Whereas activated olefins, such as styrenes and dienes, performed well as substrates, unactivated terminal and internal alkenes did not convert under the reaction conditions. The primary amine allows for further functionalizations, including the introduction of common protecting groups and reductive amination to give secondary amines. Following protocols already reported in literature, the resolution of the enantiomeric mixture can be easily performed with enzymatic or 2. Aminohydroxylation 49 chemical methods.97 Preliminary mechanistic studies suggest the formation of an aminyl radical species or an Fe nitrene species. We suggested that the mechanism of the reaction includes the formation of an aziridine intermediate and its opening in the presence of a nucleophile. DFT calculations and additional mechanistic experiments are ongoing and will further help to clarify the reaction mechanism.
Additional outlooks include the extension of the discovered reactivity to a broader class of amino functionalization reactions. The carbocation, formed at the benzylic position during the reaction process, can be trapped with a larger class of nucleophiles. The use of cyanides, azides and carbon monoxide has already been explored in transition-metal-catalyzed reactions and can potentially be applied to our transformation. 98 In some preliminary results, we already demonstrated that the synthesis of diaminated products can be achieved when acetamide is added to the reaction mixture. The formation of a diaminated product, with one of the two groups protected as an amide, allows for a plethora of subsequent transformations due to the orthogonal reactivity of the two amino groups (Scheme 54).
Scheme 54. Fe-catalyzed di-amination of olefins.
97 (a) K. Lundell, L. T. Kanerva, Tetrahedron: Asymmetry 1995 , 6, 2281-2286. (b) O. Lohse, C. Spöndlin, Organic Process Research & Development 1997 , 1, 247-249. 98 (a) I. Ryu, N. Sonoda, D. P. Curran, Chem. Rev. 1996 , 96 , 177-194. (b) G. Dagousset, A. Carboni, E. Magnier, G. Masson, Org. Lett. 2014 , 16 , 4340-4343. (c) Y.-T. He, L.-H. Li, Y.-F. Yang, Z.-Z. Zhou, H.-L. Hua, X.-Y. Liu, Y.-M. Liang, Org. Lett. 2014 , 16 , 270-273. 50 Iron-catalyzed synthesis of unprotected primary amines
3. C−H amination 51
3. Direct synthesis of primary anilines through C−H amination 52 Iron-catalyzed synthesis of unprotected primary amines
3. Direct synthesis of primary anilines through C−H amination 99
3.1. Background
Primary anilines are fundamental chemicals and play an important role as final products and synthetic intermediates.2c Traditionally, the synthesis of anilines relies on the nitration of arenes followed by reduction. 3 More recently, protocols based on the amination of aryl halides or pseudohalides have been established, such as the Chan- Lam 39 and Buchwald-Hartwig 40 amination reactions. As already discussed in chapter one, C−H amination protocols allow the use of unfunctionalized arenes as substrates for the transformation. Directed C−H amination, which installs regioselectively the amine group onto the arene, is limited though to the use of stoichiometric amounts of metals and to harsh reaction conditions (vide supra ). On the other hand, the innate C−H amination can provide a useful method for the synthesis of anilines. The installation of the amine moiety can be realized directly without requiring any arene prefunctionalization. This can streamline the discovery of new medicines through late- stage-amination of complex molecules.
3.2. Literature precedents in innate C−H amination
Recently, many research groups have investigated new methods for innate C−H amination. However, most of the protocols afford protected anilines. An additional limitation is the use of arene substrates in excess. In 2003, Pérez and coworkers reported an early example of C−H amination, using the iodine reagent PhINTs as the 100 nitrogen source (Scheme 55). In the presence of the Cu complex TpBr 3Cu(NCMe), a
99 Some of the following contents are based on a work published as “Direct and Practical Synthesis of Primary Anilines through Iron-Catalyzed C −H Bond Amination ”, L. Legnani, G. Prina Cerai, B. Morandi, ACS Catalysis 2016 , 6, 8162-8165. Some of the experiments were performed together with Gabriele Prina Cerai (graduate student in the Morandi group). 100 M. M. Díaz-Requejo, T. R. Belderraín, M. C. Nicasio, S. Trofimenko, P. J. Pérez, J. Am. Chem. Soc. 2003 , 125 , 12078-12079. 3. C−H amination 53 reactive nitrene species was formed and gave tosyl-protected anilines as reaction products. Whereas amination of sp 3 carbons gave the desired products in good yields, the conversion of benzene to aniline was limited.
Scheme 55. Cu-catalyzed innate C −H amination (Pérez, 2003).
The group of DeBoef investigated the amination of arenes with the use of the iodine oxidant PhI(OAc) 2 to mediate the reaction and without requiring an additional metal catalyst (Scheme 56). 101 Phthalimide and other amide derivatives were selected as the best nitrogen sources for this transformation.
Scheme 56. PhI(OAc) 2-mediated innate C−H amination (DeBoef, 2011).
A protocol, similar to the one reported by DeBoef and coworkers, was also explored by the group of Hartwig (Scheme 57). 102 The authors demonstrated that, when a Pd-catalyst was added to the system, the regioselectivity could be dictated by steric effects and not by electronic effects. Despite the limited conversion of benzene to aniline, a large set of difunctionalized arenes gave the aniline products with good to excellent yields.
101 A. A. Kantak, S. Potavathri, R. A. Barham, K. M. Romano, B. DeBoef, J. Am. Chem. Soc. 2011 , 133 , 19960-19965. 102 R. Shrestha, P. Mukherjee, Y. Tan, Z. C. Litman, J. F. Hartwig, J. Am. Chem. Soc. 2013 , 135 , 8480- 8483. 54 Iron-catalyzed synthesis of unprotected primary amines
Scheme 57. Pd-catalyzed innate C−H amination (Hartwig, 2013).
Additional protocols for the synthesis of anilines through innate C−H amination and with the use of an excess amount of arene substrates have been reported by the groups of He, Chang, Antonchick, Sanford, Lee and Studer. 103
Recently, the use of arenes as limiting reagents has been explored and several protocols for the innate C−H amination of this class of compounds have become available. In 2013, Ritter and coworkers reported an elegant Pd-catalyzed method for the synthesis of protected anilines (Scheme 58). 104 A large set of arenes and heteroarenes could undergo the transformation and a good functional group tolerance was showed. The authors, in order to prove that the protocol can be used for the synthesis of primary anilines, demonstrated the removal of the sulfonyl group. The same group, in a further development, achieved para -selective C−H amination with the use of a bimetallic Pd/Ru catalytic system and with Selectfluor as the aminating reagent. 105
103 (a) Z. Li, D. A. Capretto, R. O. Rahaman, C. He, J. Am. Chem. Soc. 2007 , 129 , 12058-12059. (b) H. J. Kim, J. Kim, S. H. Cho, S. Chang, J. Am. Chem. Soc. 2011 , 133 , 16382-16385. (c) R. Samanta, J. O. Bauer, C. Strohmann, A. P. Antonchick, Org. Lett. 2012 , 14 , 5518-5521. (d) L. J. Allen, P. J. Cabrera, M. Lee, M. S. Sanford, J. Am. Chem. Soc. 2014 , 136 , 5607-5610. (e) H. Kim, T. Kim, D. G. Lee, S. W. Roh, C. Lee, Chem. Commun. 2014 , 50 , 9273-9276. (f) T. W. Greulich, C. G. Daniliuc, A. Studer, Org. Lett. 2015 , 17 , 254-257. 104 G. B. Boursalian, M.-Y. Ngai, K. N. Hojczyk, T. Ritter, J. Am. Chem. Soc. 2013 , 135 , 13278-13281. 105 G. B. Boursalian, W. S. Ham, A. R. Mazzotti, T. Ritter, Nat. Chemistry 2016 , 8, 810. 3. C−H amination 55
Scheme 58. Arenes as limiting reagents in a Pd-catalyzed C−H amination (Ritter, 2013).
Shortly after the report of Ritter, the group of Itami reported a similar protocol using, instead of a Pd(II) complex, catalytic amounts of inexpensive CuBr.106
In 2014, Baran and coworkers demonstrated the use of ferrocene as a catalyst to realize the innate C−H amination of arenes and heteroarenes (Scheme 59). 107 In a radical process, the succinimidyl moiety was installed onto the aromatic ring. The authors demonstrated that the protecting group can be removed under acidic conditions to reveal the primary aniline as final product.
Scheme 59. Ferrocene-catalyzed innate C−H amination (Baran, 2014).
Kovacic,62 Minisci, 63 Skell 108 and Chow 109 reported early protocols for the C−H amination of arenes, including the synthesis of unprotected anilines. These methods, although representing important proofs of concept, were extremely limited by poor scope and by the use of harsh conditions. More recently, the reports from Nicewicz 70 and Kürti 71 (vide supra ) demonstrated the directed synthesis of unprotected anilines. However, as already discussed, both the methods were limited to the use of electron
106 T. Kawakami, K. Murakami, K. Itami, J. Am. Chem. Soc. 2015 , 137 , 2460-2463. 107 K. Foo, E. Sella, I. Thomé, M. D. Eastgate, P. S. Baran, J. Am. Chem. Soc. 2014 , 136 , 5279-5282. 108 J. C. Day, M. G. Katsaros, W. D. Kocher, A. E. Scott, P. S. Skell, J. Am. Chem. Soc. 1978 , 100 , 1950- 1951. 109 F.-L. Lu, Y. M. A. Naguib, M. Kitadani, Y. L. Chow, Can. J. Chem. 1979 , 57 , 1967-1976. 56 Iron-catalyzed synthesis of unprotected primary amines rich arenes. In conclusion, at the time of our investigations, no general and simple methods were known for the synthesis of primary anilines through innate C−H amination and with the use of arenes as limiting reagents.
3.3. A matter of chemoselectivity
During the evaluation of different aminating reagents and Fe catalysts to tune the amino hydroxylation reactivity, we observed an unexpected result when we subjected β- Me-styrene to the reaction conditions (Scheme 60). Whereas the desired amino methoxylated product was obtained in 21% yield under the standard conditions, in the presence of the novel reagent MsONH 3OTf with FeSO 4 as catalyst, the C−H amination of the arene competed with the expected amination of the double bond.
Scheme 60. Serendipitous discovery of Fe-catalyzed C−H amination.
The reaction conditions found represented an unexplored method for the direct synthesis of unprotected anilines. The use of a protonated aminating reagent increased the electrophilicity of the aminating reactive species 110 and, at the same time, enhanced the amination at the para -position of substituted arene substrates. 105 Additionally, the overamination of the substrates could be avoided due to the formation of protonated
110 S. Z. Zard, Chem. Soc. Rev. 2008 , 37 , 1603-1618. 3. C−H amination 57 anilines under the reaction conditions. The protonated amine, acting as electron withdrawing group, deactivates the aromatic ring.
We then explored different catalytic systems in order to evaluate the role of different metals and potential ligand effects (Table 6). First-row transition metals, other than Fe, such as Mn and Cu, gave a moderate conversion of our model reaction and various Fe(II) salts led to similar results as FeSO4. Nitrogen ligands, which played an important role in our amino hydroxylation reaction, proved to be, at best, ineffective. The commercially available reagent HSA gave a much lower conversion, probably because of the low solubility and stability in aqueous solutions. The hydroxylamine-derived
PivONH 3OTf, used in the amino hydroxylation protocol, performed worse in this case.
Table 6. Optimization of the reaction conditions. (a)
entry catalyst (5 mol %) ligand (10 mol %) reagent yield (b)
1 MnSO 4 / MsONH 3OTf <5%
2 Cu(MeCN) 4PF 6 / MsONH 3OTf 17%
3 FeCl 2 / MsONH 3OTf 63%
4 FeBr 2 / MsONH 3OTf 67%
5 Fe(OAc) 2 / MsONH 3OTf 73%
6 Fe(II)Pc / MsONH 3OTf 23%
7 FeSO 4 L7 MsONH 3OTf 10%
8 FeSO 4 L8 MsONH 3OTf 27%
9 FeSO 4 L12 MsONH 3OTf 75%
10 FeSO 4 L11 MsONH 3OTf 75%
11 FeSO 4 / MsONH 3OTf 76% 58 Iron-catalyzed synthesis of unprotected primary amines
12 FeSO 4 / MsONH 3OTf 82% (1.5 equiv)
13 FeSO 4 / HSA 16%
14 FeSO 4 / PivONH 3OTf 42%
(a) MeCN/H 2O, RT, 16 h. (b) GC-yield.
3.4. Scope of the reaction
A large set of mono-, di- and trisubstituted arenes performed well under the reaction conditions (Table 7). Halogens, acetamides, amines, alcohols, esters and nitriles were well tolerated and the reaction gave good results with both electron withdrawing and donating groups installed onto the arene. In the case of electron poor substrates, an increased amount of reagent was required to achieve higher conversions. Monosubstituted arene with resonance donors, such as halogens, acetamide and methoxy group were converted mostly to the para -aminated product. On the other hand, inductive donors, such as alkyl groups, did not have a strong directing effect.
In the case of 1,4-disubstituted arenes, one regioisomer was usually obtained, with the installation of the amine ortho to the more electron-donating functionality. When 4- methoxyaniline was used as substrate, only the monoaminated product 4- methoxybenzene-1,3-diamine was obtained, thus suggesting that amines are protonated under the reaction conditions and act as electron withdrawing groups.
We then subjected a wide set of heterocycles to the reaction conditions in order to expand the scope of the reaction to this important class of substrates, often found in medicinal chemistry. Only dihydrobenzofuran and dibenzofuran gave good conversions to the aminated products and a monosubstituted indole resulted in a limited yield.
3. C−H amination 59
Table 7. Scope of the Fe(II)-catalyzed C−H amination reaction.
entry product yield entry product yield
83% 1 82% 2 1.1:1:1.9
77% 65% 3 4 1:1.4:3.3 (b) 4:1:14.3
62% 65% 5 6 4.1:1:12.5 1.3:1:2
7 81% 8 78% (a)
9 70% (b) 10 64% (a)
71% (b) 11 55% (b) 12 1:2.1
53% 61% 13 14 1:4.8 1:1.8
71% 88% 15 16 1:2.4 2:13.4:1
60 Iron-catalyzed synthesis of unprotected primary amines
61% 33% 17 18 1:7.3:6:1 1:2.3:1.6
All yields, unless otherwise noted, are isolated yields of the aniline products. Isomeric distribution determined by 1H-NMR analysis of the crude reaction mixture. (a) 2.5 equiv of reagent used. (b) 4.0 equiv of reagent used.
Unprotected phenols and thiols were not tolerated under the reaction conditions (Table 8). This outcome can possibly be explained by the chelation of the Fe catalyst and the subsequent inhibition of the metal's catalytic activity. Thioethers did not give the desired products and, under the oxidizing reaction conditions, were fully oxidized to the corresponding sulfoxides. Very low conversions or decomposition were observed when heterocycles were used as substrates. This represents a limit for the application of the reaction to the late stage amination of heterocyclic-containing medicines.
Table 8. Difficult substrates under the Fe(II)-catalyzed C−H amination reaction.
entry product yield entry product yield
1 0% 2 0%
3 0% 4 0%
5 0% 6 <5%
All yields are 1H-NMR yields of the corresponding aniline products.
3. C−H amination 61
3.5. Late stage functionalization
The amination of complex molecules via innate C−H functionalization offers the potential to prepare large libraries of novel bioactive compounds thus accessing new drug entities.111 Therefore, we were interested in the application of our method to the direct amination of known drug derivatives. The methyl ester form of flurbiprofen, a common nonsteroidal anti-inflammatory drug, underwent the desired transformation and the installation of the amine occurred exclusively on the more electron rich arene (Scheme 61). 17β-Estradiol-3-methyl ether, a member of the gonadocorticoids, could also be aminated and we obtained the two ortho regioisomers. Finally, dextromethorphan, a drug of the morphinan class largely used to treat cough, could be transformed into a single regioisomer. One of the two ortho positions was effectively blocked by the presence of a quaternary carbon at the meta position and, thanks to this steric effect, only one of the two isomers was obtained.
Scheme 61. Late stage functionalization of drugs derivatives.
3.6. Mechanistic experiments
Preliminary mechanistic experiments were performed to obtain relevant information on the mechanism of the reaction. Firstly, a qualitative Hammett study, realized as a competition experiment, confirmed the trend that was already observed during the preparation of the substrate scope of the reaction. A MeO-substituted arene reacted
111 (a) S. L. Schreiber, Nature 2009 , 457 , 153. (b) H.-X. Dai, A. F. Stepan, M. S. Plummer, Y.-H. Zhang, J.- Q. Yu, J. Am. Chem. Soc. 2011 , 133 , 7222-7228. (c) F. O’Hara, D. G. Blackmond, P. S. Baran, J. Am. Chem. Soc. 2013 , 135 , 12122-12134. 62 Iron-catalyzed synthesis of unprotected primary amines faster when compared to p-xylene and the Br-substituted arene, which reacted at a slower rate (Scheme 62). This result is in accordance with the formation of a positive charge at the transition state of the reaction. 112
Scheme 62. Qualitative Hammett study.
In an additional competition experiment, with the use of benzene and d6-benzene as substrates, we obtained the two products in an identical ratio (Scheme 63). This seems to suggest that no primary kinetic isotope effect occurs and that the cleavage of the C−H bond takes place after the rate limiting step of the reaction. 113
Scheme 63. Competitive study for kinetic isotope effect.
Finally, we performed a few control experiments. The use of Fe(III) catalysts gave a very similar result compared to the use of Fe(II) catalysts (Scheme 64a). This suggests that the same reactive species can be formed with the use of Fe metal in both oxidation states. To verify if Fe might play a role in the reaction mechanism as a pure radical initiator, we used common radical initiators, such as peroxides and azonitriles, instead of Fe catalysts (Scheme 64b). However, no desired product was observed in the presence of BPO or AIBN, at room or higher temperatures.
112 C. Hansch, A. Leo, R. W. Taft, Chem. Rev. 1991 , 91 , 165-195. 113 E. M. Simmons, J. F. Hartwig, Angew. Chem. Int. Ed. 2012 , 51 , 3066-3072. 3. C−H amination 63
Scheme 64. Additional control experiments.
A mechanistic model that best accounts for the experimental observations is shown in Scheme 65. Reduction of the N–O bond of MsONH 3OTf by an Fe(II) or Fe(III) species generates the highly electrophilic nitrogen-centered radical A63a,105 that attacks the aromatic ring. Subsequent oxidation of the arene radical B to the intermediate C by the oxidized Fe species, followed by proton loss, regenerates the active catalyst and releases the corresponding amination product. At this stage, we cannot exclude that an alternative pathway proceeding through the attack of an aminyl Fe complex onto the aromatic ring takes place. 76
Scheme 65. Proposed reaction mechanism.
3.7. Conclusion and outlooks
In this chapter, I described the development of the first example of innate C−H amination for the synthesis of primary anilines from a wide set of electron rich and electron poor arenes. A substrate scope with mono, di- and tri-functionalized arenes was performed and last stage amination of drug derivatives was demonstrated. The direct 64 Iron-catalyzed synthesis of unprotected primary amines procedure, using an inexpensive Fe salt and a bench-stable hydroxylamine-derived reagent, makes our protocol a highly practical method for the synthesis of primary anilines. Additionally, the use of unfunctionalized arenes as substrates for the transformation enables our method to complement cross-coupling reactions that require (pseudo)halogenated coupling partners. Information on the mechanism of the reaction was collected through preliminary mechanistic experiments. However, a few questions regarding the catalytic cycle of the reaction still need to be addressed. Specifically, we are interested in investigating in more details the nature of the reactive species, as well as the reason for the different chemoselectivity depicted in Scheme 60.
Possible outlooks of this project include the synthesis of secondary and tertiary anilines via C−H innate amination (Scheme 66). We are interested in preparing and evaluating several aminating reagents with various leaving groups and prefunctionalized with different alkyl groups. With a large set of different reagents in hand, this strategy would possibly lead to the direct synthesis of a wide class of functionalized anilines. Installation of amines in place of C(sp 2)−H bonds could facilitate the synthesis of extended libraries of bioactive compounds of extreme importance in medicinal chemistry. In some preliminary experiments, we evaluated N-methylated and N,N - dimethylated reagents for the amination of benzene with the use of Fe catalysts. At this point, we could observe only low conversions and the reaction conditions, which include refluxing in concentrated sulfuric acid, are still too harsh for being synthetically relevant.
Scheme 66. Synthesis of secondary and tertiary anilines via C−H amination.
As discussed in chapter one, a catalytic and practical method for the synthesis of primary anilines through directed C−H amination has not yet been reported. A directing group installed onto the arene would facilitate the synthesis of unprotected anilines with control over the regioselectivity. Inspired by the many reports in the field of directed C−H amination, we tested the hydroxylamine-derived reagents with different metals, including 3. C−H amination 65
Fe, Pd, Ir, Ru, Rh (Scheme 67). 114 At this stage, we could only observe side reactions and low amounts of the three regioisomers were usually obtained. This seems to indicate that the tested directing groups did not guide the amination through coordination of the metal catalyst.
Scheme 67. Regioselective synthesis of primary amines via directed C−H amination.
However, when we tested the rhodium catalyst [RhCp*Cl 2]2 with MsONH 3OTf reagent and with acetonitrile as solvent, we could observe the formation of a benzimidazole in 40% isolated yield (Scheme 68). The reaction probably proceeds through pyridine directed ortho C−H amination, followed by reaction with acetonitrile. The direct synthesis of benzimidazoles from a larger set of prefunctionalized arenes via C−H amination could avoid the use of 1,2-diamino-substituted arenes, the usual starting materials for the synthesis of these heterocycles. 115 The optimization of this protocol could provide medicinal chemists a valid method for the preparation of this scaffold often found in fungicides and antiparasitic drugs.
Scheme 68. Rh-catalyzed synthesis of benzimidazoles via directed C−H amination.
114 (a) E. J. Yoo, S. Ma, T.-S. Mei, K. S. L. Chan, J.-Q. Yu, J. Am. Chem. Soc. 2011 , 133 , 7652-7655. (b) C. Grohmann, H. Wang, F. Glorius, Org. Lett. 2012 , 14, 656-659. (c) P. Patel, S. Chang, Org. Lett. 2014 , 16 , 3328-3331. (d) M. A. Ali, X. Yao, H. Sun, H. Lu, Org. Lett. 2015 , 17 , 1513-1516. (e) P. Patel, S. Chang, ACS Catalysis 2015 , 5, 853-858. 115 P. Daw, Y. Ben-David, D. Milstein, ACS Catalysis 2017 , 7, 7456-7460. 66 Iron-catalyzed synthesis of unprotected primary amines
4. Aminochlorination 67
4. Direct synthesis of 2- chloroalkylamines from alkenes
68 Iron-catalyzed synthesis of unprotected primary amines
4. Direct synthesis of 2-chloroalkylamines from alkenes 116
4.1. Background
Primary alkyl amines can be prepared following diverse methods that include reduction of nitro group and nitriles, allylic amination, dehydrogenative coupling of alcohols or reductive amination. These protocols rely on the modification of pre-installed functionalities and therefore usually require multi-step synthesis to access the final products. The use of olefins, which are largely available feedstocks, can represent an efficient strategy to directly access primary alkyl amines. In the past few decades many reports of hydroamination or amino functionalization have been presented. However, the amine functionality is usually introduced in a protected form and further manipulations are required to reveal the final unprotected amino group.
4.2. Literature precedent
A general method for the synthesis of primary amines via hydroamination is unknown under mild conditions and with complex molecules as substrates (vide supra ). In more recent reports, the authors have demonstrated improved functional group tolerance but only protected amines were obtained. In the past few years, the groups of Baran, Knowles and Hull reported significant advancements in the field of hydroamination.
In 2015, Baran and coworkers developed a practical Fe-catalyzed method for the hydroamination of alkenes. 117 Nitro(hetero)arenes were used as nitrogen sources and they were reduced in situ by Zn/HCl after attack onto the olefin substrate. A wide substrate scope was demonstrated, as well as the synthesis of small pharmaceutical
116 Some of the following contents are based on a work submitted to a peer reviewed journal as “The Iron- Catalyzed Aminochlorination of Alkenes Provides a Unifying Access to Unprotected Primary Amines”, L. Legnani,† G. Prina Cerai,† B. Morandi, under revision 2018 . Some of the experiments were performed together with Gabriele Prina Cerai (graduate student in the Morandi group). 117 J. Gui, C.-M. Pan, Y. Jin, T. Qin, J. C. Lo, B. J. Lee, S. H. Spergel, M. E. Mertzman, W. J. Pitts, T. E. La Cruz, M. A. Schmidt, N. Darvatkar, S. R. Natarajan, P. S. Baran, Science 2015 , 348 , 886-891. 4. Aminochlorination 69 targets. However, only secondary (hetero)arenes could be prepared following this protocol.
In 2017, the group of Knowles demonstrated the synthesis of tertiary amines via an Ir-photocatalyzed hydroamination (Scheme 69). 118 A thiol cocatalyst was also required to trap the alkyl radical intermediate via HAT. A wide set of olefins and secondary amine substrates were investigated, as well as intramolecular transformations.
Scheme 69. Ir-photocatalyzed hydroamination (Knowles, 2017).
A possible route to the synthesis of unprotected primary amines was reported by Hull and coworkers (Scheme 70). 119 A Pd-catalyzed hydroamination gave phthalimide- protected alkyl amines with anti-Markovnikov selectivity. The fundamental step to reveal the unprotected alkyl amine was also demonstrated.
Scheme 70. Pd-catalyzed anti-Markovnikov hydroamination (Hull, 2018).
Aminohydroxylation reaction could also represent an efficient strategy for the synthesis of functionalized unprotected amines. However, these protocols are limited by the introduction of protected functionalities or by the use of activated olefins. In chapter two I have presented an overview of the most recent examples of aminohydroxylation reactions.
118 A. J. Musacchio, B. C. Lainhart, X. Zhang, S. G. Naguib, T. C. Sherwood, R. R. Knowles, Science 2017 , 355 , 727-730. 119 D. G. Kohler, S. N. Gockel, J. L. Kennemur, P. J. Waller, K. L. Hull, Nat. Chem. 2018 , 10 , 333-340. 70 Iron-catalyzed synthesis of unprotected primary amines
The insertion of azides onto olefins represents a possible strategy for the synthesis of 1,2-diamines. Among the most recent examples, the group of Xu developed an Fe- catalyzed strategy for the synthesis of 1,2-diazo compounds (Scheme 71). 120 The authors suggested that the reaction proceeds via attack of the azidoiodinane formed in situ onto the olefin.
Scheme 71. Fe-catalyzed diazidation of alkenes (Xu, 2016).
In 2017, Lin and coworkers reported a Mn-catalyzed method for the preparation of vicinal amines (Scheme 72). 121 In this transformation, the azidyl radical species which attacked the olefin was formed under electrochemical conditions. On the other hand, the metal catalyst controlled the insertion of the second azide moiety. Preliminary mechanistic experiments seemed to confirm the formation of radical intermediates under the reaction conditions.
Scheme 72. Electrochemical Mn-catalyzed diazidation of alkenes (Lin, 2017).
Additional amino functionalization methods have been reported in recent years. Wang and coworkers developed a Cu-catalyzed intramolecular amino azidation reaction with the use of azidoiodinanes as nitrogen sources.122 The group of Jiao explored
120 Y.-A. Yuan, D.-F. Lu, Y.-R. Chen, H. Xu, Angew. Chem. Int. Ed. 2016 , 55 , 534-538. 121 N. Fu, G. S. Sauer, A. Saha, A. Loo, S. Lin, Science 2017 , 357 , 575-579. 122 K. Shen, Q. Wang, J. Am. Chem. Soc. 2017 , 139 , 13110-13116. 4. Aminochlorination 71 photoredox-catalysis to accomplish azidofluoroalkylation of olefins. 123 The synthesis of azides, despite representing an important strategy for the preparation of vicinal diamines, relies on the use of toxic and explosive reagents and requires further steps to reveal the primary amine moiety.
4.3. Amino halogens as versatile building blocks
A general method that would introduce the ideal primary amine and a versatile electrophile would represent an optimal strategy for the synthesis of 1,2-functionalized amines. 2-halogenalkylamines are amphoteric building blocks and can be transformed into many different amino functionalized molecules. These compounds and their use as strategic intermediates in organic synthesis have rarely been reported in literature.
The preparation of 2-chloroalkylamines has been demonstrated through the opening of aziridines 124 or the chlorination of amino alcohols. 125 The synthesis of this class of compounds from olefins, a widely available feedstock, has been reported in only few examples. In 2011, Feng and coworkers reported a scandium-catalyzed method for the introduction of this moiety.126 The initial chloronium intermediate formed after attack onto the olefin was subsequently opened in the presence of tosylamide to deliver the final product. In 2012, the group of Chemler developed an intramolecular Cu-catalyzed strategy for the amino halogenation of alkenes. 127 However, in both methods, the amine installed onto the olefin is protected as a tosylamide, a protecting group that requires harsh acidic conditions to release the primary amine.
Minisci and coworkers reported the only example for the directed synthesis of unprotected 2-chloroalkylamines.85,128 The method, despite representing an important
123 X. Geng, F. Lin, X. Wang, N. Jiao, Org. Lett. 2017 , 19 , 4738-4741. 124 E. Leemans, S. Mangelinckx, N. De Kimpe, Synlett 2009 , 2009 , 1265-1268. 125 G. Berger, M. Gelbcke, E. Cauët, M. Luhmer, J. Nève, F. Dufrasne, Tetrahedron Lett. 2013 , 54 , 545- 548. 126 Y. Cai, X. Liu, J. Jiang, W. Chen, L. Lin, X. Feng, J. Am. Chem. Soc. 2011 , 133 , 5636-5639. 127 M. T. Bovino, S. R. Chemler, Angew. Chem. Int. Ed. 2012 , 51 , 3923-3927. 128 F. Minisci, R. Galli, M. Cecere, Tetrahedron Lett. 1966 , 7, 3163-3166. 72 Iron-catalyzed synthesis of unprotected primary amines proof of concept, was too limited in scope and yields to be synthetically relevant. Specifically, styrene, 1-hexene and cyclohexene were the only substrates tested. The corresponding products were obtained in 25-45% yield.
Bach and coworkers demonstrated, in an elegant Fe-catalyzed strategy, the synthesis of (2-chloroalkyl)carbamates via a radical mechanism. 129 In their strategy, the unsaturated bond of alkenyloxycarbonyl azides underwent an intramolecular attack of the azide moiety (Scheme 73). The radical species, formed after the intramolecular attack of the olefin, was trapped in situ through Fe-mediated delivery of the chlorine atom.
Scheme 73. Fe-catalyzed synthesis of oxazolidinones (Bach, 2000).
4.4. Reaction design and optimization
Inspired by Bach's reports, we envisioned that the trapping of the carbon-centered radical through a similar Fe-delivered chlorine transfer mechanism would provide an ideal solution for the synthesis of 2-chloroalkylamines (Scheme 74). After delivery of the chlorine atom to the carbon centered radical, the amino-bounded Fe(III) complex would regenerate the Fe(II) catalyst. The direct radical trapping would additionally avoid the usual oxidation of the radical to the carbocation intermediate via a single-electron- transfer step (vide supra , chapter two). This approach could help to expand the scope of the reaction beyond activated olefin substrates. Whereas benzylic radicals undergo SET with ease, the same step is much more challenging with unactivated olefins.
129 (a) T. Bach, B. Schlummer, K. Harms, Chem. Commun. 2000 , 287-288. (b) T. Bach, B. Schlummer, K. Harms, Chem. Eur. J. 2001 , 7, 2581-2594. (c) H. Danielec, J. Klügge, B. Schlummer, T. Bach, Synthesis 2006 , 2006 , 551-556. 4. Aminochlorination 73
Scheme 74. Strategy for 2-aminochlorides synthesis via radical trapping.
We started to evaluate different Fe(II) metal species and reagents to find the best conditions for the intermolecular synthesis of 2-chloroalkylamines (Table 9). A catalytic amount of FeCl 2, used by Minisci and Bach, as mediator and catalyst respectively, was tested. In the presence of a stoichiometric amount of a Cl source, such as TMSCl, the desired product was afforded in good yield (entry 9). Whereas nitrogen ligands had, at best, no effect on modulating the reactivity of Fe, the use of oxygen-containing ligands slightly improved the conversion. Interestingly, Fe(III) salts could convert the substrates to the desired products, albeit in lower yields than Fe(II) salts.
Inorganic chloride salts, much more benign chlorine sources than TMSCl, gave the desired product in good yield. The inexpensive and available NaCl gave the best conversion among the tested chlorine salts.
The reagent PivONH 3OTf, already used for the amino hydroxylation of olefins (vide supra , chapter two), proved to be the best aminating reagent for the transformation, whereas MsONH 3OTf used for the synthesis of anilines ( vide supra , chapter three) gave lower yields. The reagent used by the group of Ning Jiao for the Fe-catalyzed synthesis of primary anilines was tested and gave lower yields (entry 15).130 No conversion to the desired product was obtained when we tested the reagents used by the group of Kürti (entry 16-17).73a The reaction tolerated moisture and oxygen and could be performed in open vials without observing any decrease in yield.
130 J. Liu, K. Wu, T. Shen, Y. Liang, M. Zou, Y. Zhu, X. Li, X. Li, N. Jiao, Chem. Eur. J. 2017 , 23 , 563-567. 74 Iron-catalyzed synthesis of unprotected primary amines
Table 9. Deviation from standard conditions.(a)
entry catalyst (5 mol %) reagent Cl so urce yield (b)
1 Fe(acac) 2 [cat1] reag1 NaCl 72%
2 Fe(acac) 3 [cat2] reag1 NaCl 49%
3 Fe(CF 3acac) 2 [cat3] reag1 NaCl 68%
4 Fe(CF 3acac) 3 reag1 NaCl 45%
5 FeCl 2 reag1 NaCl 70%
6 FeCl 3 reag1 NaCl 63%
7 Fe(OMe) 2 reag1 NaCl 71% 8 Fe(II)Pc reag1 NaCl 0%
9 Fe(acac) 2 [cat1] reag1 TMSCl 43%
10 Fe(acac) 2 [cat1] reag1 KCl 32%
11 Fe(acac) 2 [cat1] reag1 MgCl 2 (0.525 eq.) 50%
12 Fe(acac) 2 [cat1] reag1 CsCl 38%
13 Fe(acac) 2 [cat1] reag1 HCl 0%
14 Fe(acac) 2 [cat1] reag2 NaCl 56%
15 Fe(acac) 2 [cat1] reag3 NaCl 0%
16 Fe(acac) 2 [cat1] reag4 NaCl 0%
(a) MeOH/DCM, RT, 16 h. (b) 1H-NMR-yield.
4.4. Scope of the reaction
With the best conditions in hand, we started exploring the substrate scope of the transformation (Table 10). When terminal olefins were used as substrates, perfect anti- 4. Aminochlorination 75
Markovnikov selectivity was obtained, with the introduction of the unprotected amine at the terminal position and chloride at the internal one. Beyond the use of unfunctionalized alkyl chains, the reaction tolerated various functional groups, including unprotected alcohols, benzyl protected alcohols, halogens and cyanides. Tertiary amines, as in the case of a morpholine derivative, and protected amines, performed well under the reaction conditions. Mono amino chlorination was obtained with substrates containing two, non-conjugated olefin bonds. This effect suggests that the amino group introduced is protonated under the reaction conditions. Therefore, the product, much less soluble in the reaction mixture, results to be unreactive to a second aminochlorination.
Internal olefins underwent the desired transformation as well. Disubstituted 1,1- and 1,2-alkenes, as well as trisubstituted alkenes, gave the desired amino chlorinated products with partial retention of stereoinformation. The successful transformation of an isoprene-derived compound suggested that the aminochlorination protocol can be applied to terpenes for the synthesis of complex natural products.
Styrenes were also submitted to the reaction conditions and gave the desired products in good yields. However, they were transformed and isolated as aziridines through a basic workup, in order to facilitate their purification. Products with chlorines at the benzylic position are less stable and easily form the corresponding aziridine product.
Table 10. Scope of the Fe(II)-catalyzed amino chlorination reaction.
entry product yield entry product yield
1 72% 2 68%
Cl 3 71% 4 64% NH 2 Cl Cl 5 79% 6 58% BnO NH 2 76 Iron-catalyzed synthesis of unprotected primary amines
7 57% 8 75%
Cl 9 55% 10 68% NH 2 t-Bu
11 69% 12 65%
13 56% 14 52%
54% 15 16 61% dr 1:1
60% 73% 17 18 dr 3:1 (a) dr 2.4:1
19 65% (b) 20 75% (b)
21 81% (b) 22 62% (b)
23 76% (b) 24 80% (b)
25 78% (b)
All yields, unless otherwise noted, are isolated yields of the 2-chloroalkylamine products. (a) (E)-alkene isomer used as substrate. (b) Yields refer to the isolated aziridine products after basic workup. (c) Diastereomeric ratio of the isolated aziridine products. dr : diastereomeric ratio. 4. Aminochlorination 77
Secondary amines and thioethers in the allylic position were not tolerated under the reaction conditions (Table 11). Styrenes functionalized with boronic acids did not perform well and neither the corresponding 2-chloroalkylamine nor the aziridine products could be detected.
As in the amino hydroxylation reaction, heterocyclic olefins did not give the desired products. Also in this case, the outcome can be explained by the inhibition of the catalytic activity through Fe chelation.
Table 11. Difficult substrates under the Fe(II)-catalyzed amino chlorination reaction.
entry product yield entry product yield
1 0% 2 0%
3 0% 4 9%
5 15% 6 0%
All yields are 1H-NMR yields of the 2-chloroalkylamine products.
The use of complex molecules as substrates was also demonstrated (Scheme 75). A derivative of isosorbide, a compound obtained through partial hydrogenation of glucose, could be transformed to the desired amino chlorinated compound. Two natural products, a terpene and an alkaloid, were tolerated by the reaction. Camphene, known to be prone to migration upon formation of carbocationic intermediates, did not rearrange, suggesting that the formation of a carbocationic intermediate is unlikely. 78 Iron-catalyzed synthesis of unprotected primary amines
Scheme 75. Aminochlorination of complex molecules.
(a) Yields refer to the isolated aziridine products after basic workup. (b) Diastereomeric ratio of the isolated aziridine products. dr : diastereomeric ratio.
4.5. Synthetic utility of 2-chloroalkyl-1-amines
Beyond the substrate scope of the aminochlorination reaction, we were interested in demonstrating the synthetic utility of 2-chloroalkyl-1-amines as versatile building blocks (Scheme 76). Reduction of 2-chloroalkyl-1-amines could provide a valuable strategy for the synthesis of primary amines, a class of compounds for which preparation remains challenging. The chlorine atom could also be substituted with various moieties to give 1,2-diamines or β-amino acids as final products. After aminochlorination of 1- dodecene and isolation of 2-chlorododecan-1-amine we started exploring various functionalizations. 4. Aminochlorination 79
Scheme 76. Synthetic utility of 2-chloroamines.
When we submitted 2-chlorododecan-1-amine to Raney-nickel reducing conditions we successfully obtained the formal hydroamination product of the terminal olefin, with an anti-Markovnikov selectivity (Table 12). Under different reducing conditions, with
LiAlH 4 in Et 2O, we were surprised to obtain the Markovnikov hydroamination product, a result that likely arises from an in situ formation of an aziridine intermediate followed by reductive opening.
When we added the allyl Grignard reagent to the aminochlorinated product, we could observe the C−C bond formation at the α-position relative to the amine. Elimination of the chlorine atom and formation of an iminium ion intermediate possibly explain this outcome. The formation of unprotected aziridine under basic conditions was also demonstrated and the desired product was obtained in very high yield.
Substitution of the chlorine atom with common nucleophiles, such as cyanides and nitriles, showed that the method could afford as final products masked 1,2-diamines or β-amino acids. The synthesis of secondary anilines was also explored through in situ formation of an aryne and subsequent addition to it. 80 Iron-catalyzed synthesis of unprotected primary amines
Table 12. Derivatizations of 2-chlorododecan-1-amine.
entry reaction conditions product yield (a)
Raney Ni 1 70% t-BuOH, 30°C, 16 h
LiAlH 4 (2.5 equiv) 2 73% Et O, 0 to 80 °C, 16 h 2
allylMgBr (2.5 equiv) 3 71% Et 2O, RT, 16 h
NaOH aq, NaI (5 equiv) 4 95% MeOH, reflux, 16 h
NaN 3 (5 equiv), NaI (5 equiv) 5 66% DMF, 60 °C, 16 h
NaCN (5 equiv), NaI (5 equiv) 6 70% DMF, 60 °C, 16 h
2-(TMS)phenyl-OTf (0.33 equiv) 7 CsF (2 equiv) 71% MeCN, 0 °C to RT, 16 h
(a) Isolated yields.
4.6. Mechanistic experiments
We performed preliminary mechanistic experiments in order to collect additional insight into the mechanism of the reaction. When Z-cyclodecene and E-cyclodecene were submitted to the reaction conditions, we obtained conservation of stereoinformation, with, in both cases, the major diastereomer arising from syn attack onto the olefin (Scheme 77). This result is in accordance with the proposed model in which chloride is delivered by the amine-coordinated Fe(III) complex. On the other hand, when Z-β-methylstyrene and E-β-methylstyrene were used as substrates, the same syn 4. Aminochlorination 81 diastereomer was obtained as the major product. This seemingly divergent outcome can be easily explained by the formation of a long-lived carbocation at the benzylic position and subsequent loss of stereoinformation. Radicals at the benzylic position are known to undergo a fast oxidation to the corresponding carbocation.
Z- cyclodecene 73%, dr 14:1 Z- -Me-styrene 58%, dr 4.5:1 H Cl N Ph Me NH 2 Ph Me 51 81 77 standard 78 standard conditions conditions Cl H Me N
NH 2 Ph Ph Me 79 80 30 82 E- cyclodecene 75%, dr 9:1 E- -Me-styrene 55%, dr 4:1
Scheme 77. Experiments to evaluate the conservation of stereoinformation.
When (trans -2-vinylcyclopropyl)benzene, a commonly used radical clock, was submitted to the standard reaction conditions, we could detect the opening of the cyclopropyl ring, a result that is in accordance with the formation of a radical intermediate (Scheme 78).
Scheme 78. Radical clock experiment with (trans -2-vinylcyclopropyl)benzene as substrate.
The closing of N,N -diallyl-tosylamide to the 5-membered-ring cycle via a radical mechanism could not be detected (Scheme 79). This seems to indicate the formation of an extremely short-lived carbon-centered radical. 82 Iron-catalyzed synthesis of unprotected primary amines
Scheme 79. Radical clock experiment with N,N -diallyl-tosylamide as substrate.
A mechanism that best accounts for our experimental data is depicted in Scheme
80. The reactive aminyl radical species A is formed from the reagent PivONH 3OTf after loss of PivOH. This Fe species, after attack onto the alkene, delivers the carbon centered radical B. The amino-bounded Fe(III) complex delivers the chlorine atom to form the intermediate C and regenerates the Fe(II) catalyst. Loss of the amino-bounded Fe(II) complex gives the final product D.
PivO NH 3 OTf
Fe(II)
Cl PivOH H H H N N OTf 2 R D Fe(III) A R Fe(II) Cl Fe(II) (III)Fe Cl OTf OTf H N H N 2 R 2 R C B trapping
Scheme 80. Proposed reaction mechanism.
4.7. Conclusion
In this chapter, the development of a general method for the synthesis of 2- chloroalkylamines from olefins was discussed. The reaction was performed in an open 4. Aminochlorination 83 flask and uses Fe as catalyst. Simple table salt, NaCl, was the chloride source used for the transformation. Terminal olefins, as well as di- and tri-substituted internal olefins were tolerated in the reaction. Styrenes could also be transformed to the desired products and a good functional group tolerance was demonstrated. The different functionalizations of 2-chloroalkyl-1-amines demonstrated the synthetic utility of this understudied versatile building block. Preliminary mechanistic studies suggested the formation of a radical intermediate and a fast chlorine-atom trapping through an amine- bonded Fe complex.
84 Iron-catalyzed synthesis of unprotected primary amines
5. Experimental part 85
5. Experimental part
86 Iron-catalyzed synthesis of unprotected primary amines
5. Experimental part
5.1. Materials and methods
Commercial materials were used as received. Fe(II) phthalocyanine (CAS #: 132-16-1), Fe(II) sulfate heptahydrate (CAS #: 7782-63-0) and Fe(II) acetylacetonate (CAS #: 14024-17-0) were purchased from Acros Organics and Sigma-Aldrich and they were used without any further purification. Substrates that were not purchased commercially were synthesized following literature conditions and their characterization data were matching the ones found in literature.
1H-NMR and 13 C-NMR spectra were recorded at 300 or 500 MHz and at 75 or 125 MHz, respectively on a spectrometer in CDCl 3 at room temperature (unless otherwise stated). 1H-NMR was reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quadruplet, m = multiplet and br = broad), coupling constant ( J values) in Hz and integration. Chemical shifts (δ) were reported with respect to the corresponding 1 solvent residual peak at 7.26 ppm for CDCl 3 and at 2.50 ppm for DMSO-d6 for H-NMR. 13 C-NMR spectra ( 1H-broadband decoupled) were reported in ppm using the central peak of CDCl 3 (77.2 ppm) and of DMSO-d6 (39.5 ppm). High-resolution mass spectrometric measurements were provided by the Mass Spectrometry Department of the Max-Planck Institut für Kohlenforschung. The molecular ion M +, [M+H] + and [M–X] + respectively or the anion are given in m/z units.
Thin Layer Chromatography analyses were performed on silica gel coated glass plates (0.25 mm) with fluorescence-indicator UV254 (Macherey-Nagel, TLC plates SIL G-25
UV 254 ). For detection of spots, irradiation of UV light at 254 nm, oxidative staining using potassium permanganate solution (KMnO 4) or a solution of ninhydrin in acetone and acetic acid were used. Flash column chromatography was conducted with Silicagel 60 (particle size 40–63 µM, Merck) at room temperature and under elevated pressure (compressed air). Organic solutions were concentrated under reduced pressure on a rotary evaporator. 5. Experimental part 87
5.2. Experimental part to chapter two (Direct synthesis of unprotected amino alcohols)
5.2.1. Synthesis of starting materials
Reagent PivONH 3OTf synthesis procedure
The reagent PivONH 3OTf was synthesized following the above synthetic steps and according to known procedures.83,87 Its characterization data were matching the ones found in literature.
(2-Vinylphenyl)methanol, Table 2, Entry 7SM
was prepared following literature conditions 131 and its characterization data were 132 1 matching the ones found in literature. H-NMR (500 MHz, CDCl 3): δ = 7.54 (dd, J = 7.4, 1.6 Hz, 1H), 7.36 (ddd, J = 7.4, 1.6, 0.4 Hz, 1H), 7.32 – 7.27 (m, 2H), 7.05 (dd, J = 17.4, 11.0 Hz, 1H), 5.71 (dd, J = 17.4, 1.2 Hz, 1H), 5.36 (dd, J = 11.0, 1.2 Hz, 1H), 4.75 13 (s, 2H), 1.76 (s, 1H). C-NMR (125 MHz, CDCl 3): δ = 137.6, 136.8, 133.9, 128.5, 128.3, 128.1, 126.1, 116.6, 63.5.
131 P. Cheng, D. L. J. Clive, J. Org. Chem. 2012 , 77 , 3348-3364. 132 H. Konishi, T. Ueda, T. Muto, K. Manabe, Org. Lett. 2012 , 14 , 4722-4725. 88 Iron-catalyzed synthesis of unprotected primary amines
(1-Cyclopropylvinyl)benzene, Table 2, Entry 14SM
was prepared following literature conditions and its characterization data were matching 133 1 the ones found in literature. H-NMR (500 MHz, CDCl 3): δ = 7.61 (dd, J = 8.2, 1.2 Hz, 2H), 7.45 – 7.33 (m, 2H), 7.32 – 7.27 (m, 1H), 5.29 (d, J = 1.2 Hz, 1H), 4.95 (s, 1H), 1.73 13 – 1.61 (m, 1H), 0.89 – 0.79 (m, 2H), 0.69 – 0.57 (m, 2H). C-NMR (125 MHz, CDCl 3): δ = 149.5, 141.8, 128.3, 127.6, 126.2, 109.1, 15.8, 6.8.
(E)-Buta-1,3-dien-1-ylbenzene, Table 2, Entry 16SM
was prepared following literature conditions and its characterization data were matching 134 1 the ones found in literature. H-NMR (500 MHz, CDCl 3): δ = 7.48 – 7.40 (m, 2H), 7.33 (dd, J = 8.4, 7.0 Hz, 2H), 7.29 – 7.17 (m, 1H), 6.81 (dd, J = 15.6, 10.4 Hz, 1H), 6.67 – 6.36 (m, 2H), 5.35 (dd, J = 17.0, 1.6 Hz, 1H), 5.19 (dd, J = 10.0, 1.6 Hz, 1H). 13 C-NMR
(125 MHz, CDCl 3): δ = 137.3, 137.3, 133.0, 129.8, 128.7, 127.8, 126.6, 117.7.
2-Phenylaziridine, Scheme 51, 52
NH
133 T. W. Liwosz, S. R. Chemler, Chem. Eur. J. 2013 , 19 , 12771-12777. 134 X.-J. Wei, D.-T. Yang, L. Wang, T. Song, L.-Z. Wu, Q. Liu, Org. Lett. 2013 , 15 , 6054-6057. 5. Experimental part 89 was prepared following literature conditions 135 and its characterization data were 136 1 matching the ones found in literature. H-NMR (500 MHz, CDCl 3): δ = 7.37 – 7.18 (m, 5H), 3.01 (dd, J = 6.0, 3.4 Hz, 1H), 2.20 (d, J = 6.0 Hz, 1H), 1.79 (s, 1H), 0.87 (br s, 1H). 13 C-NMR (125 MHz, CDCl 3): δ = 140.5, 128.6, 127.2, 125.8, 32.2, 29.4.
1-(trimethylsilyl)Ethan-1-ol, Table 5, alcohol used to synthesize entry 4SM
was prepared from commercially available acetyltrimethylsilane according to a literature procedure. 137
5.2.2. Experimental procedures
General procedure (A): evaluation of reaction conditions, Table 1
A screw-cap vial was charged with a metal catalyst (0.01 mmol), a ligand (0.02 mmol) and a stirring bar, was evacuated and refilled 3x with Ar, and was finally equipped with an Ar-filled balloon. A second vial was charged with reagent PivONH 3OTf (133.6 mg, 0.5 mmol) and a mixture of MeCN/H 2O (0.6 mL, MeCN/H 2O 2:1) was added. After purging the solution with Ar for 20 minutes, commercially available styrene (0.2 mmol) and the degassed solution of the reagent were simultaneously injected in the vial containing the metal catalyst and the ligand and the reaction mixture was stirred at 25 °C. After 16 h the reaction mixture was diluted with MTBE (8 mL) and extracted with an aqueous solution of HCl 1.0 M (3 x 8 mL). The combined water phases were then concentrated in vacuo to afford the crude product as the free amine salt. The yields of the corresponding product were determined by 1H-NMR analysis of the crude reaction mixture using DMSO and 1,4-dioxane as analytical standards in D 2O.
135 J.-L. Hsu, J.-M. Fang, J. Org. Chem. , 2001 , 66 , 8573-8584. 136 D. A. Alonso, P. G. Andersson, J. Org. Chem. , 1998 , 63 , 9455-9461. 137 M. Parasram, P. Chuentragool, D. Sarkar, V. Gevorgyan, J. Am. Chem. Soc. , 2016 , 138 , 6340-6343. 90 Iron-catalyzed synthesis of unprotected primary amines
General procedure (B): substrate scope, Table 2
A screw-cap vial was charged with Fe(II) phthalocyanine (14.2 mg, 0.025 mmol) and a stirring bar, was evacuated and refilled 3x with Ar, and was finally equipped with an Ar- filled balloon. A second vial was charged with a solution of reagent PivONH 3OTf (334.0 mg, 1.25 mmol) and a mixture of MeCN/H 2O (1.5 mL, MeCN/H 2O 2:1) was added. After purging the solution with argon for 20 minutes, the corresponding olefin (0.5 mmol) and the solution were simultaneously injected in the vial containing the Fe(II) catalyst and the reaction mixture was stirred at 25 °C. After 16 h the reaction mixture was diluted with MTBE (15 mL) and extracted with an aqueous solution of HCl 1.0 M (3 x 15 mL). The combined water phases were concentrated in vacuo to afford the crude product as the free amine salt.
The yields of the corresponding products were determined by 1H-NMR analysis of the crude reaction mixture using DMSO and 1,4-dioxane as analytical standards in D 2O. After analysis, the crude products were directly used in the following Boc-protection prior to isolation.
General procedure (C) for Boc protection and purification
The corresponding crude product from procedure (B), dissolved in DCM (5 mL) and TEA (139 µL, 1.0 mmol), was stirred 10 minutes at 25 °C. The reaction mixture was then cooled to 0 °C in an ice bath and Boc 2O (218.2 mg, 1.0 mmol) was added dropwise. After allowing the mixture to reach room temperature, it was stirred for 2 h. The reaction mixture was then quenched by addition of water (5 mL) and diluted with DCM (15 mL), the two phases were separated and the organic layer washed with saturated aqueous
NaHCO 3 (1 x 20 mL) and brine (1 x 20 mL). The combined water phases were extracted with DCM (3 x 30 mL) and the combined organic phases were dried over Na 2SO 4, filtered, and concentrated in vacuo . The crude product was purified via flash column chromatography (pentane-EtOAc as eluent) to afford the desired products.
5. Experimental part 91
General procedure for direct purification (D)
The corresponding crude product from procedure (B), dissolved in DCM (2 mL) and TEA (139 µL, 1.0 mmol), was loaded on silica gel and purified via flash column chromatography (DCM-MeOH-TEA 100:15:1.5 as eluent) to afford the desired product.
5.2.3. Substrate scope
2-Amino-1-phenylethanol, Table 2, Entry 1
was prepared from commercially available styrene according to general procedure (B) to afford the crude product as the free amine salt with 78% of 1H-NMR yield (DMSO as internal standard). Following general purification procedure (D) the desired product was then afforded as a solid with 74% isolated yield (51.0 mg, 0.372 mmol) based on 1 styrene. H-NMR (500 MHz, CDCl 3): δ = 7.26 – 7.17 (m, 5H), 4.60 (dd, J = 8.2, 3.8 Hz, 1H), 3.07 (br s, 3H), 2.89 (br dd, J = 12.8, 3.8 Hz, 1H), 2.74 (dd, J = 12.8, 8.2 Hz, 1H). 13 C-NMR (125 MHz, CDCl 3): δ = 142.5, 128.5, 127.7, 126.0, 73.9, 49.0. HR-MS (ESI+) + calc. for C 8H11 N1O1Na 1 [M+Na] 160.073283, found 160.073320. Its characterization data were matching the ones found in literature. 138
tert -Butyl (2-hydroxy-2-(naphthalen-2-yl)ethyl)carbamate, Table 2, Entry 2Boc
was prepared from commercially available 2-vinylnaphtalene according to general procedure (B), in a solvent mixture of MeCN/H 2O 3:1 and charging the vial containing
138 S. Selvakumar, D. Sivasankaran, V. K. Singh, Org. Biomol. Chem. 2009 , 7, 3156-3162. 92 Iron-catalyzed synthesis of unprotected primary amines
Fe(II) phthalocyanine with 2-vinylnaphtalene, to afford the crude product as the free amine salt with 61% of 1H-NMR yield (DMSO as internal standard). Following general procedure (C) the desired product was then afforded as a solid with 50% isolated yield 1 (71.3 mg, 0.248 mmol) based on 2-vinylnaphtalene. H-NMR (500 MHz, CDCl 3): δ = 7.83 – 7.81 (m, 4H), 7.50 – 7.44 (m, 3H), 4.99 (br s, 2H), 3.59 – 3.54 (br m, 1H), 3.45 (br 13 s, 1H), 3.35 – 3.30 (m, 1H), 1.44 (s, 9H). C-NMR (125 MHz, CDCl 3): δ = 157.2, 139.3, 133.4, 133.2, 128.4, 128.1, 127.8, 126.3, 126.1, 124.9, 124.0, 80.1, 74.2, 48.5, 28.5. + HR-MS (ESI+) calc. for C 17 H21 N1O3Na 1 [M+Na] 310.141362, found 310.141290. Its characterization data were matching the ones found in literature. 139
2-Amino-1-(3-methoxyphenyl)ethan-1-ol, Table 2, Entry 3
was prepared from commercially available 3-vinylanisole according to general procedure (B) to afford the crude product as the free amine salt with 74% of 1H-NMR yield (DMSO as internal standard). Following general purification procedure (D) the desired product was then afforded as a solid with 70% isolated yield (58.6 mg, 0.350 mmol) based on 3- 1 vinylanisole. H-NMR (500 MHz, CDCl 3): δ = 7.26 – 7.20 (m, 1H), 6.91 – 6.88 (m, 2H), 6.78 (ddd, J = 8.2, 2.6, 1.0 Hz, 1H), 4.65 (dd, J = 8.0, 3.8 Hz, 1H), 3.77 (s, 3H), 3.15 (br s, 3H), 2.97 (dd, J = 13.0, 3.8 Hz, 1H), 2.81 (dd, J = 13.0, 8.0 Hz, 1H). 13 C-NMR (125
MHz, CDCl 3): δ = 159.8, 144.2, 129.6, 118.3, 113.1, 111.5, 73.7, 55.3, 48.9. HR-MS + (ESI+) calc. for C 9H14 N1O2 [M+H] 168.101904, found 168.102010. Its characterization data were matching the ones found in literature. 140
139 P. O’Brien, S. A. Osborne, D. D. Parker, J. Chem. Soc. Perk. T. 1, 1998 , 2519-2526. 140 G. Shang, D. Liu, S. E. Allen, Q. Yang, X. Zhang, Chem.-Eur. J. , 2007 , 13 , 7780-7784. 5. Experimental part 93 tert -Butyl (2-hydroxy-2-(3-methoxyphenyl)ethyl)carbamate, Table 2, Entry 3Boc
was prepared from commercially available 3-vinylanisole according to general procedure (B) to afford the crude product as the free amine salt with 74% of 1H-NMR yield (DMSO as internal standard). Following general procedure (C) the desired product was then afforded as an oil with 62% isolated yield (83.3 mg, 0.312 mmol) based on 3- 1 vinylanisole. H-NMR (500 MHz, CDCl 3): δ = 7.27 – 7.24 (m, 1H), 6.92 (d, J = 6.8 Hz, 2H), 6.83 – 6.81 (m, 1H), 4.98 (br s, 1H), 4.80 – 4.78 (br m, 1H), 3.80 (s, 3H), 3.49 – 13 3.46 (br m, 1H), 3.26 – 3.21 (br m, 2H), 1.44 (s, 9H). C-NMR (125 MHz, CDCl 3): δ = 159.9, 157.2, 143.7, 129.7, 118.3, 113.6, 111.3, 80.0, 74.1, 55.4, 48.5, 28.5. HR-MS + (ESI+) calc. for C 14 H21 N1O4Na 1 [M+Na] 290.136278, found 290.136540.
tert -Butyl (2-hydroxy-2-(o-tolyl)ethyl)carbamate, Table 2, Entry 4Boc
was prepared from commercially available 2-methylstyrene according to general procedure (B) to afford the crude product as the free amine salt with 77% of 1H-NMR yield (DMSO as internal standard). Following general procedure (C) the desired product was then afforded as a solid with 46% isolated yield (57.7 mg, 0.230 mmol) based on 2- 1 methylstyrene. H-NMR (500 MHz, CDCl 3): δ = 7.49 (d, J = 7.6 Hz, 1H), 7.26 – 7.12 (m, 3H), 5.04 – 5.03 (br m, 2H), 3.46 – 3.42 (br m, 1H), 3.19 – 3.15 (br m, 2H), 2.35 (s, 3H), 13 1.45 (s, 9H). C-NMR (125 MHz, CDCl 3): δ = 157.1, 139.9, 134.7, 130.5, 127.7, 126.4, + 125.6, 79.9, 70.8, 47.2, 28.5, 19.1. HR-MS (ESI+) calc. for C 14 H21 N1O3Na 1 [M+Na] 274.141363, found 274.141170.
94 Iron-catalyzed synthesis of unprotected primary amines tert -Butyl (2-hydroxy-2-(m-tolyl)ethyl)carbamate, Table 2, Entry 5Boc
was prepared from commercially available 3-methylstyrene according to general procedure (B) to afford the crude product as the free amine salt with 77% of 1H-NMR yield (DMSO as internal standard). Following general procedure (C) the desired product was then afforded as a solid with 67% isolated yield (84.2 mg, 0.335 mmol) based on 3- 1 methylstyrene. H-NMR (500 MHz, CDCl 3): δ = 7.25 – 7.08 (m, 4H), 4.99 (br s, 1H), 4.78 – 4.76 (br m, 1H), 3.48 – 3.44 (br m, 1H), 3.22 (ddd, J = 13.8, 8.0, 5.2 Hz, 1H), 3.18 (br 13 s, 1H), 2.35 (s, 3H), 1.44 (s, 9H). C-NMR (125 MHz, CDCl 3): δ = 157.1, 141.9, 138.3, 128.7, 128.5, 126.7, 123.0, 79.9, 74.1, 48.5, 28.5, 21.6. HR-MS (ESI+) calc. for + C14 H21 N1O3Na 1 [M+Na] 274.141363, found 274.141500.
tert -Butyl (2-hydroxy-2-(p-tolyl)ethyl)carbamate, Table 2, Entry 6Boc
was prepared from commercially available 4-methylstyrene according to general procedure (B) to afford the crude product as the free amine salt with 84% of 1H-NMR yield (DMSO as internal standard). Following general procedure (C) the desired product was then afforded as a solid with 78% isolated yield (98.1 mg, 0.390 mmol) based on 4- 1 methylstyrene. H-NMR (500 MHz, CDCl 3): δ = 7.24 (d, J = 8.0 Hz, 2H), 7.16 (d, J = 8.0 Hz, 2H), 4.99 (br s, 1H), 4.78 – 4.76 (br m, 1H), 3.46 – 3.44 (br m, 1H), 3.25 – 3.20 (br 13 m, 1H), 2.84 (br s, 1H), 2.34 (s, 3H), 1.44 (s, 9H). C-NMR (125 MHz, CDCl 3): δ = 157.1, 139.0, 137.6, 129.3, 126.0, 79.9, 73.9, 48.4, 28.5, 21.3. HR-MS (ESI+) calc. for 5. Experimental part 95
+ C14 H21 N1O3Na 1 [M+Na] 274.141363, found 274.141260. Its characterization data were matching the ones found in literature. 141
tert -Butyl (2-hydroxy-2-(2-(hydroxymethyl)phenyl)ethyl)carbamate, Table 2, Entry 7Boc
was prepared from (2-vinylphenyl)methanol according to general procedure (B) at 0 °C, to afford the crude product as the free amine salt with 88% of 1H-NMR yield (DMSO as internal standard). Following general procedure (C) the desired product was then afforded as a solid with 55% isolated yield (73.9 mg, 0.276 mmol) based on (2- 1 vinylphenyl)methanol. H-NMR (500 MHz, CDCl 3): δ = 7.47 – 7.25 (m, 4H), 5.19 (br s, 1H), 5.09 – 5.08 (br m, 1H), 4.74 – 4.61 (m, 2H), 3.68 (br s, 1H), 3.61 (br s, 1H), 3.50 – 3.46 (m, 1H), 3.28 (ddd, J = 14.0, 8.2, 5.6 Hz, 1H), 1.42 (s, 9H). 13 C-NMR (125 MHz,
CDCl 3): δ = 157.3, 140.4, 137.9, 130.1, 128.6, 128.1, 126.5, 80.3, 71.2, 63.6, 48.0, 28.5. + HR-MS (ESI+) calc. for C 14 H21 N1O4Na 1 [M+Na] 290.136278, found 290.136230.
tert -Butyl (2-(4-(tert -butyl)phenyl)-2-hydroxyethyl)carbamate, Table 2, Entry 8Boc
was prepared from commercially available 4-tert -butylstyrene according to general procedure (B) at 0 °C, to afford the crude product as the free amine salt with 73% of 1H- NMR yield (DMSO as internal standard). Following general procedure (C) the desired product was then afforded as a solid with 41% isolated yield (59.8 mg, 0.204 mmol)
141 A. Russo, A. Lattanzi, Adv. Synth. Catal., 2008 , 350 , 1991-1995. 96 Iron-catalyzed synthesis of unprotected primary amines
1 based on 4-tert -butylstyrene. H-NMR (500 MHz, CDCl 3): δ = 7.38 (d, J = 8.2 Hz, 2H), 7.29 (d, J = 8.2 Hz, 2H), 4.97 (br s, 1H), 4.80 – 4.78 (br m, 1H), 3.49 – 3.45 (br m, 1H), 3.29 – 3.23 (m, 1H), 2.94 (br s, 1H), 1.44 (s, 9H), 1.31 (s, 9H). 13 C-NMR (125 MHz,
CDCl 3): δ = 157.0, 150.9, 138.9, 125.8, 125.6, 79.9, 73.9, 48.3, 34.7, 31.5, 28.5. HR-MS + (ESI+) calc. for C 17 H27 N1O3Na 1 [M+Na] 316.188313, found 316.188480.
tert -Butyl (2-(2-bromophenyl)-2-hydroxyethyl)carbamate, Table 2, Entry 9Boc
was prepared from commercially available 2-bromostyrene according to general procedure (B) with an increased amount of reagent PivONH 3OTf (427.6 mg, 1.60 mmol), to afford the crude product as the free amine salt with 50% of 1H-NMR yield (DMSO as internal standard). Following general procedure (C) the desired product was then afforded as an oil with 46% isolated yield (72.7 mg, 0.230 mmol) based on 2- 1 bromostyrene. H-NMR (500 MHz, CDCl 3): δ = 7.61 – 7.60 (m, 1H), 7.51 (dd, J = 8.0, 1.2 Hz, 1H), 7.34 (td, J = 7.6, 1.2 Hz, 1H), 7.14 (td, J = 7.6, 1.8 Hz, 1H), 5.16 – 5.14 (br m, 1H), 4.95 (br s, 1H), 4.11 (br s, 1H), 3.53 (ddd, J = 14.6, 6.4, 3.0 Hz, 1H), 3.37 – 3.32 13 (br m, 1H), 1.44 (s, 9H). C-NMR (125 MHz, CDCl 3): δ = 158.0, 140.8, 132.7, 129.2,
128.1, 127.7, 121.8, 80.4, 73.9, 46.8, 28.5. HR-MS (ESI+) calc. for C 13 H18 Br 1N1O3Na 1 [M+Na] + 338.036238, found 338.036110. Its characterization data were matching the ones found in literature. 142
142 R. Viswanathan, E. N. Prabhakaran, M. A. Plotkin, J. N. Johnston, J. Am. Chem. Soc. 2003 , 125 , 163- 168. 5. Experimental part 97 tert -Butyl (2-hydroxy-2-(4-(trifluoromethyl)phenyl)ethyl)carbamate, Table 2, Entry 10Boc
was prepared from commercially available 4-(trifluoromethyl)styrene according to general procedure (B) with an increased amount of reagent PivONH 3OTf (668.1 mg, 2.50 mmol) and Fe(II) phthalocyanine (28.4 mg, 0.05 mmol), to afford the crude product as the free amine salt with 41% of 1H-NMR yield (DMSO as internal standard). Following general procedure (C) the desired product was then afforded as a solid with 36% isolated yield (55.5 mg, 0.182 mmol) based on 4-(trifluoromethyl)styrene. 1H-NMR (500
MHz, CDCl 3): δ = 7.60 (d, J = 8.2 Hz, 2H), 7.48 (d, J = 8.2 Hz, 2H), 4.97 (br s, 1H), 4.90 – 4.89 (br m, 1H), 3.67 (br s, 1H), 3.51 – 3.46 (br m, 1H), 3.27 – 3.21 (m, 1H), 1.43 (s, 13 9H). C-NMR (125 MHz, CDCl 3): δ = 157.5, 146.0, 130.1 (d, J = 33.0 Hz), 126.4, 125.5 (d, J = 3.7 Hz), 124.2 (d, J = 271.9 Hz), 80.4, 73.8, 48.6, 28.4. 19 F-NMR (282 MHz, + CDCl 3): δ = -62.54. HR-MS (ESI+) calc. for C 14 H18 F3N1O3Na 1 [M+Na] 328.113098, found 328.113400.
tert -Butyl (2-(4-chlorophenyl)-2-hydroxyethyl)carbamate, Table 2, Entry 11Boc
was prepared from commercially available 4-chlorostyrene according to general procedure (B) to afford the crude product as the free amine salt with 66% of 1H-NMR yield (DMSO as internal standard). Following general procedure (C) the desired product was then afforded as a solid with 55% isolated yield (74.6 mg, 0.275 mmol) based on 4- 1 chlorostyrene. H-NMR (500 MHz, CDCl 3): δ = 7.32 – 7.28 (m, 4H), 4.96 (br s, 1H), 4.80 (dd, J = 7.6, 2.8 Hz, 1H), 3.46 – 3.42 (m, 1H), 3.20 (dd, J = 14.2, 7.6 Hz, 1H), 3.06 (br s, 13 1H), 1.43 (s, 9H). C-NMR (125 MHz, CDCl 3): δ = 157.3, 140.4, 133.6, 128.7, 127.4, 98 Iron-catalyzed synthesis of unprotected primary amines
+ 80.3, 73.6, 48.5, 28.5. HR-MS (ESI+) calc. for C 13 H18 Cl 1N1O3Na 1 [M+Na] 294.086741, found 294.086560.
tert -Butyl (2-(4-bromophenyl)-2-hydroxyethyl)carbamate, Table 2, Entry 12Boc
was prepared from commercially available 4-bromostyrene according to general procedure (B) with an increased amount of reagent PivONH 3OTf (427.6 mg, 1.60 mmol), to afford the crude product as the free amine salt with 73% of 1H-NMR yield (DMSO as internal standard). Following general procedure (C) the desired product was then afforded as a solid with 51% isolated yield (80.5 mg, 0.255 mmol) based on 4- 1 bromostyrene. H-NMR (500 MHz, CDCl 3): δ = 7.47 (d, J = 8.4 Hz, 2H), 7.24 (d, J = 8.4 Hz, 2H), 4.93 (br s, 1H), 4.81 – 4.78 (br m, 1H), 3.46 – 3.43 (br m, 1H), 3.23 – 3.18 (m, 13 2H), 1.44 (s, 9H). C-NMR (125 MHz, CDCl 3): δ = 157.3, 141.0, 131.7, 127.8, 121.7, + 80.3, 73.7, 48.5, 28.5. HR-MS (ESI+) calc. for C 13 H18 Br 1N1O3Na 1 [M+Na] 338.036238, found 338.036040. Its characterization data were matching the ones found in literature. 143
tert -Butyl (2-hydroxy-2-phenylpropyl)carbamate, Table 2, Entry 13Boc
was prepared from commercially available α-methylstyrene according to general procedure (B) using the following modified workup after the amino hydroxylation reaction. After 16 h of stirring at 25 °C the reaction mixture was diluted with an aqueous solution of NaOH 1.0 M (15 mL) and extracted with MTBE (3 x 15 mL). The combined
143 G. Bartoli, M. Bosco, A. Carlone, M. Locatelli, P. Melchiorre, L. Sambri, Org. Lett. 2004 , 6, 3973-3975. 5. Experimental part 99
organic phases were dried over Na 2SO 4, filtered, and concentrated in vacuo to afford the crude product as the free amine salt. Following general procedure (C) the desired product was then afforded as a solid with 70% isolated yield (87.4 mg, 0.348 mmol) 1 based on α-methylstyrene. H-NMR (500 MHz, CDCl 3): δ = 7.46 – 7.24 (m, 5H), 4.82 (br s, 1H), 3.51 (dd, J = 14.0, 7.2 Hz, 1H), 3.32 (dd, J = 14.0, 5.4 Hz, 1H), 3.26 (br s, 1H), 13 1.53 (s, 3H), 1.40 (s, 9H). C-NMR (125 MHz, CDCl 3): δ = 157.4, 145.9, 128.4, 127.1, + 125.2, 80.0, 75.1, 52.1, 28.4, 27.6. HR-MS (ESI+) calc. for C 14 H21 N1O3Na 1 [M+Na] 274.141363, found 274.141430. Its characterization data were matching the ones found in literature. 144
2-Amino-1-cyclopropyl-1-phenylethan-1-ol, Table 2, Entry 14Boc
was prepared from (1-cyclopropylvinyl)benzene (0.250 mmol) according to general procedure (B) using the following modified workup after the amino hydroxylation reaction. After 16 h of stirring at 25 °C the reaction mixture was diluted with an aqueous solution of NaOH 1.0 M (15 mL) and extracted with MTBE (3 x 15 mL). The combined organic phases were dried over Na 2SO 4, filtered, and concentrated in vacuo to afford the crude product as the free amine salt. Following general purification procedure (D) the desired product was then afforded as a solid with 54% isolated yield (23.8 mg, 0.134 1 mmol) based on (1-cyclopropylvinyl)benzene. H-NMR (500 MHz, CDCl 3): δ = 7.47 – 7.45 (m, 2H), 7.36 – 7.33 (m, 2H), 7.26 – 7.23 (m, 1H), 3.16 (d, J = 12.6 Hz, 1H), 2.97 (d, J = 12.6 Hz, 1H), 2.32 (br s, 3H), 1.15 (tt, J = 8.4, 5.4 Hz, 1H), 0.54 (dtd, J = 9.6, 5.4, 13 4.2 Hz, 1H), 0.46 – 0.41 (m, 1H), 0.34 – 0.25 (m, 2H). C-NMR (125 MHz, CDCl 3): δ = 145.5, 128.2, 126.8, 125.8, 73.5, 51.8, 19.8, 1.1, -0.1. HR-MS (ESI+) calc. for + C11 H16 N1O1 [M+H] 178.122639, found 178.122870.
144 W. Masruri, M. D. McLeod, J. Org. Chem. 2012 , 77 , 8480-8491. 100 Iron-catalyzed synthesis of unprotected primary amines
1-Amino-2-methylhex-3-yn-2-ol and 2-methylenehex-3-yn-1-amine , Table 2, Entry 15a, 15b
were prepared from commercially available 2-methyl-1-hexen-3-yne (0.250 mmol) according to general procedure (B) to afford the products as the free amine salts with 49% and 6% of 1H-NMR yield respectively (DMSO as internal standard). 1H-NMR (500
MHz, D 2O): δ = 5.49 (d, J = 19.0 Hz, 2H minor product ), 3.58 (s, 2H minor product ), 3.09 – 2.99 (m, 2H), 2.29 – 2.24 (m, 2H minor product ), 2.15 (q, J = 7.6 Hz, 2H), 1.45 (s, 3H), 13 1.05 (t, J = 7.6 Hz, 3H minor product ), 1.02 (t, J = 7.6 Hz, 3H). C-NMR (125 MHz, D 2O) major and minor product : δ = 125.7, 121.5, 119.0, 116.5, 90.0, 78.7, 65.6, 49.8, 44.5, + 27.5, 26.9, 13.4, 12.9, 12.2. HR-MS (ESI+) calc. for C 7H14 N1O1Na 1 [M+H] 128.106989, + found 128.107110. HR-MS (ESI+) calc. for C 7H12 N1 [M+H] 110.096424, found 110.096550.
tert -Butyl ( E)-(2-hydroxy-4-phenylbut-3-en-1-yl)carbamate and tert -butyl ( E)-(4- hydroxy-4-phenylbut-2-en-1-yl)carbamate , Table 2, Entry 16aBoc, 16bBoc
were prepared from ( E)-buta-1,3-dien-1-ylbenzene according to general procedure (B) to afford the crude products as the free amine salts with 39% and 34% of 1H-NMR yield respectively (DMSO as internal standard). Following general procedure (C) the crude products were Boc protected and only the major product was isolated as an oil with 24% isolated yield (31.9 mg, 0.121 mmol) based on ( E)-buta-1,3-dien-1-ylbenzene. 1H-NMR
(500 MHz, CDCl 3): δ = 7.38 – 7.23 (m, 5H), 6.67 (d, J = 16.0 Hz, 1H), 6.19 (dd, J = 16.0, 6.0 Hz, 1H), 4.97 (br s, 1H), 4.42 (br s, 1H), 3.46 – 3.41 (br m, 1H), 3.22 – 3.17 (m, 1H), 13 2.76 (br s, 1H), 1.44 (s, 9H). C-NMR (125 MHz, CDCl 3): δ = 157.0, 136.5, 131.6, 5. Experimental part 101
129.2, 128.7, 128.0, 126.7, 80.0, 72.6, 46.7, 28.5. HR-MS (ESI+) calc. for + C15 H21 N1O3Na 1 [M+Na] 286.141363, found 286.141480.
tert -Butyl (1-hydroxy-2,3-dihydro-1H-inden-2-yl)carbamate, Table 2, Entry 17Boc
was prepared from commercially available indene (0.5 mmol) according to general procedure (B) to afford the crude product as the free amine salt with 46% (57:43 mixture of two diastereomers) of 1H-NMR yield (DMSO as internal standard). Following general procedure (C) the desired product, as a mixture of diastereomers, was then afforded as an oil with 21% isolated yield (25.8 mg, 0.104 mmol) based on indene. 1H-NMR (500
MHz, CDCl 3): δ = 7.42 (s, 1H minor diastereomer ), 7.40 (s, 1H), 7.30 – 7.23 (m, 2H minor and 3H major diastereomer ), 7.18 (d, J = 6.2 Hz, 1H minor diastereomer ), 5.22 (br s, 1H minor diastereomer ), 5.07 – 5.03 (m, 2H), 4.47 (br s, 1H minor diastereomer ), 4.37 (br s, 1H), 4.11 – 4.05 (m, 1H minor diastereomer ), 3.30 (dd, J = 15.2, 8.2 Hz, 1H minor diastereomer ), 3.22 (dd, J = 15.8, 7.2 Hz, 1H), 2.87 (dd, J = 15.8, 7.2 Hz, 1H), 2.69 (dd, J = 15.2, 9.0 Hz, 1H minor diastereomer ), 2.27 (br s, 1H minor diastereomer ), 1.73 (br s, 13 1H), 1.48 (s, 9H minor diastereomer ), 1.47 (s, 9H). C-NMR (125 MHz, CDCl 3) mixture of two diastereomers : δ = 157.4, 156.2, 142.6, 142.3, 141.2, 138.4, 129.3, 128.4, 127.6, 127.4, 125.3, 125.3, 124.5, 82.0, 80.5, 78.5, 74.9, 61.9, 54.7, 37.0, 36.1, 28.5, 28.5. HR- + MS (ESI+) calc. for C 14 H19 N1O3Na 1 [M+Na] 272.125713, found 272.125540.
5.2.4. Extension of the reaction to different nucleophiles tert -Butyl (2-methoxy-2-phenylethyl)carbamate, Table 4, Entry 1Boc
102 Iron-catalyzed synthesis of unprotected primary amines was prepared from commercially available styrene according to general procedure (B) and performing the reaction in MeOH (1.5 mL), to afford the crude product as the free amine salt with 96% of 1H-NMR yield (DMSO as internal standard). Following general procedure (C) the desired product was then afforded as a solid with 88% isolated yield 1 (110.3 mg, 0.439 mmol) based on styrene. H-NMR (500 MHz, CDCl 3): δ = 7.38 – 7.29 (m, 5H), 4.96 (br s, 1H), 4.26 – 4.24 (br m, 1H), 3.46 – 3.42 (br m, 1H), 3.25 (s, 3H), 13 3.20 – 3.15 (m, 1H), 1.44 (s, 9H). C-NMR (125 MHz, CDCl 3): δ = 156.0, 139.4, 128.7,
128.2, 126.9, 82.8, 79.4, 57.0, 47.1, 28.5. HR-MS (ESI+) calc. for C 14 H21 N1O3Na 1 [M+Na] + 274.141363, found 274.141320.
tert -Butyl (2-isopropoxy-2-phenylethyl)carbamate, Table 4, Entry 2Boc
was prepared from commercially available styrene according to general procedure (B) and performing the reaction in iPrOH (1.5 mL), to afford the crude product as the free amine salt with 81% of 1H-NMR yield (DMSO as internal standard). Following general procedure (C) the desired product was then afforded as a solid with 79% isolated yield 1 (110.1 mg, 0.394 mmol) based on styrene. H-NMR (500 MHz, CDCl 3): δ = 7.34 – 7.27 (m, 5H), 4.94 (br s, 1H), 4.51 – 4.49 (br m, 1H), 3.56 – 3.49 (m, 1H), 3.44 – 3.39 (br m, 1H), 3.10 – 3.05 (br m, 1H), 1.44 (s, 9H), 1.15 (d, J = 6.0 Hz, 3H), 1.11 (d, J = 6.0 Hz, 13 3H). C-NMR (125 MHz, CDCl 3): δ = 156.1, 140.8, 128.5, 127.9, 126.8, 79.3, 77.9, + 69.5, 47.5, 28.6, 23.5, 21.4. HR-MS (ESI+) calc. for C 16 H26 N1O3 [M+H] 280.190719, found 280.190770.
tert -Butyl (2-(tert -butoxy)-2-phenylethyl)carbamate, Table 4, Entry 3Boc
5. Experimental part 103 was prepared from commercially available styrene according to general procedure (B), performing the reaction in tBuOH (1.5 mL) and using the following modified workup. After 16 h of stirring at 25 °C the reaction mixture was diluted with an aqueous solution of NaOH 1.0 M (15 mL) and extracted with MTBE (3 x 15 mL). The combined organic phases were dried over Na 2SO 4, filtered, and concentrated in vacuo to afford the crude 1 product as the free amine salt with 64% of H-NMR yield (MeNO 2 as internal standard). Following general procedure (C) the desired product was then afforded as a solid with 1 61% isolated yield (90.1 mg, 0.307 mmol) based on styrene. H-NMR (500 MHz, CDCl 3): δ = 7.37 – 7.21 (m, 5H), 4.91 (br s, 1H), 4.64 – 4.62 (br m, 1H), 3.38 – 3.33 (br m, 1H), 13 2.94 – 2.89 (br m, 1H), 1.44 (s, 9H), 1.13 (s, 9H). C-NMR (125 MHz, CDCl 3): δ = 156.2, 143.5, 128.3, 127.2, 126.3, 79.3, 74.8, 73.0, 48.4, 28.7, 28.6. HR-MS (ESI+) calc. + for C 17 H28 N1O3 [M+H] 294.206369, found 294.206510.
tert -Butyl (2-methoxy-2-methylnonyl)carbamate and tert -butyl (2- methylenenonyl)carbamate , Table 4, Entry 4aBoc, 4bBoc
were prepared from commercially available 2-methyl-1-nonene (0.250 mmol) according to general procedure (B) and performing the reaction in MeOH (0.75 mL) to afford the crude products as the free amine salts with 27% and 9% of 1H-NMR yield respectively (DMSO as internal standard). Following general procedure (C) the crude products were Boc protected and only the major product was isolated as an oil with 23% isolated yield 1 (16.8 mg, 0.058 mmol) based on 2-methyl-1-nonene. H-NMR (500 MHz, CDCl 3): δ = 4.75 (br s, 1H), 3.18 – 3.01 (br m, 5H), 1.44 (s, 9H), 1.26 (s, 12H), 1.10 (s, 3H), 0.87 (d, 13 J = 6.8 Hz, 3H). C-NMR (125 MHz, CDCl 3): δ = 156.3, 79.2, 76.5, 49.2, 46.2, 35.9,
32.0, 30.3, 29.4, 28.6, 23.6, 22.8, 20.5, 14.3. HR-MS (ESI+) calc. for C 16 H33 N1O3Na 1 [M+Na] + 310.235262, found 310.235190.
104 Iron-catalyzed synthesis of unprotected primary amines tert -Butyl (2-methoxy-2-methylpropyl)carbamate and tert -butyl (2- methylallyl)carbamate, Table 4, Entry 5aBoc, 5bBoc
were prepared from commercially available (2-methyl-propenyl)trimethylsilane (0.250 mmol) according to general procedure (B) and performing the reaction in MeOH (0.75 mL) to afford the crude products as the free amine salts with 41% and 21% of 1H-NMR yield respectively (DMSO as internal standard). Following general procedure (C) the crude products were Boc protected and only the major product was isolated as an oil with 32% isolated yield (16.3 mg, 0.080 mmol) based on (2-methyl- 1 propenyl)trimethylsilane. H-NMR (500 MHz, CDCl 3): δ = 4.82 (br s, 1H), 3.17 (s, 3H), 13 3.13 (d, J = 5.8 Hz, 2H), 1.44 (s, 9H), 1.14 (s, 6H). C-NMR (125 MHz, CDCl 3): δ =
156.3, 79.1, 74.4, 49.4, 48.4, 28.4, 22.4. HR-MS (ESI+) calc. for C 10 H21 N1O3Na 1 [M+Na] + 226.141363, found 226.141520.
tert -Butyl (((1 R*,2 R*,4 R*)-2-methoxy-7,7-dimethylbicyclo[2.2.1]heptan-1- yl)methyl)carbamate , Table 4, Entry 6aBoc, 6bBoc
was prepared from commercially available camphene (0.250 mmol) according to general procedure (B) and performing the reaction in MeOH (0.75 mL) to afford the crude product as the free amine salt with 30% of 1H-NMR yield (DMSO as internal standard). Following general procedure (C) the desired product was then Boc protected and 1 isolated for characterization. H-NMR (500 MHz, CDCl 3): δ = 4.85 (s, 1H), 3.33 – 3.24 (m, 3H), 3.22 (s, 3H), 1.82 – 1.79 (m, 1H), 1.73 – 1.68 (m, 2H), 1.64 – 1.60 (m, 1H), 1.57 – 1.53 (m, 1H), 1.44 (s, 9H), 1.11 – 0.99 (m, 5H), 0.89 (s, 3H). 13 C-NMR (125 MHz,
CDCl 3): δ = 156.4, 87.2, 78.8, 55.8, 52.7, 46.6, 46.0, 40.0, 37.3, 31.4, 28.6, 27.0, 20.9, + 20.5. HR-MS (ESI+) calc. for C 16 H30 N1O3 [M+H] 284.222019, found 284.221960. 5. Experimental part 105
5.2.5. Potential applications in medicinal chemistry
Functionalizations of 2-amino-1-phenylethan-1-ol tert -Butyl (2-hydroxy-2-phenylethyl)carbamate, Scheme 47, 43
was prepared from commercially available styrene according to general procedure (B) to afford the crude product as the free amine salt with 78% of 1H-NMR yield (DMSO as internal standard). Following general procedure (C) the desired product was then afforded as a solid with 72% isolated yield (85.1 mg, 0.359 mmol) based on styrene. 1H-
NMR (500 MHz, CDCl 3): δ = 7.37 – 7.27 (m, 5H), 4.96 (br s, 1H), 4.82 (dd, J = 8.0, 3.2 Hz, 1H), 3.49 – 3.46 (br m, 1H), 3.24 (dd, J = 13.6, 8.0 Hz, 1H), 2.89 (br s, 1H), 1.44 (s, 13 9H). C-NMR (125 MHz, CDCl 3): δ = 157.2, 141.9, 128.6, 127.9, 126.0, 80.0, 74.1, + 48.5, 28.5. HR-MS (ESI+) calc. for C 13 H19 N1O3Na 1 [M+Na] 260.125713, found 260.125730. Its characterization data were matching the ones found in literature. 145
2-(Benzylamino)-1-phenylethanol, Scheme 47, 44
was prepared from commercially available styrene according to general procedure (B) to afford the crude product as the free amine salt with 78% of 1H-NMR yield (DMSO as internal standard). The crude mixture, dissolved in EtOH (5 mL) and TEA (279 µL, 2.0 mmol), was stirred 10 minutes at 25 °C. Benzaldehyde (203 µL, 2.0 mmol) was then added and the mixture was stirred for 2 h, cooled afterwards at 0 °C in an ice bath and
145 L. Harris, S. P. H. Mee, R. H. Furneaux, G. J. Gainsford, A. Luxenburger, J. Org. Chem. 2011 , 76, 358- 372. 106 Iron-catalyzed synthesis of unprotected primary amines
treated slowly with NaBH 4 (79.4 mg, 2.1 mmol). After 1 h of stirring at 0 °C, the reaction mixture was quenched by addition of water (5 mL), concentrated in vacuo , and finally redissolved in DCM (30 mL). The organic phases were washed with saturated aqueous
NaHCO 3 (1 x 30 mL) and the aqueous solution of NaHCO 3 was extracted with DCM (3 x
30 mL). The combined organic phases were dried over Na 2SO 4, filtered, and concentrated in vacuo . The crude product was purified via flash column chromatography (DCM-MeOH 100:5 as eluent) to afford the desired product as a solid with 67% isolated 1 yield (75.9 mg, 0.334 mmol) based on styrene. H-NMR (500 MHz, CDCl 3): δ = 7.37 – 7.25 (m, 10H), 4.74 (dd, J = 9.0, 3.6 Hz, 1H), 3.87 – 3.80 (m, 2H), 2.93 (dd, J = 12.2, 3.6 13 Hz, 1H), 2.76 (dd, J = 12.2, 9.0 Hz, 1H), 2.59 (br s, 2H). C-NMR (125 MHz, CDCl 3): δ = 142.6, 140.0, 128.6, 128.5, 128.2, 127.6, 127.3, 126.0, 71.9, 56.7, 53.7. HR-MS (ESI+) + calc. for C 15 H17 N1O1Na 1 [M+Na] 250.120233, found 250.120280. Its characterization data were matching the ones found in literature. 146
Benzyl (2-hydroxy-2-phenylethyl)carbamate, Scheme 47, 45
was prepared from commercially available styrene according to general procedure (B) to afford the crude product as the free amine salt with 78% of 1H-NMR yield (DMSO as internal standard). The crude mixture, dissolved in DCM (5 mL) and TEA (279 µL, 2.0 mmol), was stirred 10 minutes at 25 °C. The reaction mixture was then cooled at 0 °C in an ice bath and CbzCl (79 µL, 0.55 mmol) was added. After allowing the mixture to reach room temperature, it was stirred for 16 h. The reaction mixture was then quenched by saturated aqueous NH 4Cl (5 mL) and diluted with DCM (15 mL), the two phases separated and the organic layer washed with saturated aqueous NaHCO 3 (1 x 20 mL) and brine (1 x 20 mL). The combined aqueous solution of NaHCO 3 and brine was extracted with DCM (3 x 30 mL) and all the combined organic phase was dried over
Na 2SO 4, filtered, and concentrated in vacuo . The crude product was purified via flash
146 W. Kawamoto, J. Chem. Soc. Perk. T. 1 2001 , 16 , 1916-1928. 5. Experimental part 107 column chromatography (pentane-EtOAc 3:1 as eluent) to afford as a solid the desired product with 71% isolated yield (95.7 mg, 0.353 mmol) based on styrene. 1H-NMR (500
MHz, CDCl 3): δ = 7.38 – 7.28 (m, 10H), 5.22 (br s, 1H), 5.11 (s, 2H), 4.83 (dd, J = 8.0, 3.6 Hz, 1H), 3.56 (ddd, J = 14.0, 7.0, 3.6 Hz, 1H), 3.31 (ddd, J = 14.0, 8.0, 4.8 Hz, 1H), 13 2.60 (br s, 1H). C-NMR (125 MHz, CDCl 3): δ = 157.3, 141.6, 136.5, 128.7, 128.7,
128.3, 128.3, 128.1, 126.0, 73.8, 67.1, 48.6. HR-MS (ESI+) calc. for C 16 H17 N1O3Na 1 [M+Na] + 294.110063, found 294.109940. Its characterization data were matching the ones found in literature. 146
2-Acetamido-1-phenylethyl acetate, Scheme 47, 46
was prepared from commercially available styrene according to general procedure (B) to afford the crude product as the free amine salt with 78% of 1H-NMR yield (DMSO as internal standard). The crude mixture, dissolved in DCM (5 mL) and pyridine (404 µL, 5.0 mmol), was stirred 10 minutes at 25 °C. Acetic anhydride (473 µL, 5.0 mmol) was added and the mixture was stirred for 16 h at 25 °C. The reaction mixture was then diluted with DCM (15 mL) and washed with saturated aqueous NaHCO 3 (1 x 20 mL). The water phase was extracted with DCM (3 x 20 mL) and all the combined organic phase was dried over Na 2SO 4, filtered, and concentrated in vacuo . The crude product was purified via flash column chromatography (pentane-EtOAc 1:5 as eluent) to afford the desired product as an oil with 63% isolated yield (69.9 mg, 0.316 mmol) based on 1 styrene. H-NMR (500 MHz, CDCl 3): δ = 7.37 – 7.29 (m, 5H), 5.83 (dd, J = 8.2, 4.2 Hz, 1H), 5.83 (br s, 1H), 3.68 (ddd, J = 14.2, 6.2, 4.2 Hz, 1H), 3.57 (ddd, J = 14.2, 8.2, 5.6 13 Hz, 1H), 2.10 (s, 3H), 1.95 (s, 3H). C-NMR (125 MHz, CDCl 3): δ = 170.5, 170.3, 137.8,
128.8, 128.6, 126.5, 74.7, 44.6, 23.4, 21.3. HR-MS (ESI+) calc. for C 12 H15 N1O3Na 1 108 Iron-catalyzed synthesis of unprotected primary amines
[M+Na] + 244.094413, found 244.094300. Its characterization data were matching the ones found in literature. 147
Synthesis of (±)-aegoline-O-methylether
N-(2-Methoxy-2-(4-methoxyphenyl)ethyl)cinnamamide, Scheme 48, 48
was prepared according to the following procedure. A screw cap vial was charged with Fe(II) phthalocyanine (14.2 mg, 0.025 mmol) and a stirring bar, was evacuated and refilled 3x with Ar, and was finally equipped with an Ar-filled balloon. A second vial was charged with a solution of reagent PivONH 3OTf (334.0 mg, 1.25 mmol) and MeOH (1.5 mL) was added. After purging the solution with argon for 20 minutes, commercially available 4-methoxystyrene (67 µL, 0.5 mmol) and the solution were simultaneously injected in the vial containing the Fe(II) catalyst and the reaction mixture was stirred at 25 °C. After 16 h the reaction mixture was diluted with an aqueous solution of NaOH 1.0 M (15 mL) and extracted with MTBE (3 x 15 mL). The combined organic phase was dried over Na 2SO 4, filtered, and concentrated in vacuo to afford the crude product as the 1 free amine salt with 99% of H-NMR yield (MeNO 2 as internal standard). The crude mixture, dissolved in DCM (5 mL) and TEA (209 µL, 1.5 mmol), was stirred 10 minutes at 25 °C. The reaction mixture was then cooled at 0 °C in an ice bath and cinnamoyl chloride (166.6 mg, 1.0 mmol) was added dropwise. After allowing the mixture to reach room temperature, it was stirred for 2 h. The reaction mixture was then quenched by addition of water (5 mL) and diluted with DCM (15 mL), the two phases were separated and the organic layer washed with saturated aqueous NaHCO 3 (1 x 20 mL). The aqueous solution of NaHCO 3 was extracted with DCM (3 x 30 mL) and all the combined organic phases were dried over Na 2SO 4, filtered, and concentrated in vacuo . The crude product was purified via flash column chromatography (pentane-EtOAc 6:4 as eluent) to
147 P. Chen, J. Qu, J. Org. Chem. 2011 , 76 , 2994-3004. 5. Experimental part 109 afford as a solid the desired product with 89% isolated yield (137.9 mg, 0.443 mmol) 1 based on 4-methoxystyrene. H-NMR (500 MHz, CDCl 3): δ = 7.66 (d, J = 15.6 Hz, 1H), 7.53 (dd, J = 7.6, 2.0 Hz, 2H), 7.38 – 7.36 (m, 3H), 7.28 – 7.26 (m, 2H), 6.94 – 6.91 (m, 2H), 6.45 (d, J = 15.6 Hz, 1H), 6.20 (dd, J = 8.0, 3.8 Hz, 1H), 4.30 (dd, J = 9.0, 4.0 Hz, 1H), 3.87 – 3.84 (m, 1H), 3.83 (s, 3H), 3.33 (ddd, J = 13.8, 9.0, 4.0 Hz, 1H), 3.28 (s, 3H). 13 C-NMR (125 MHz, CDCl 3): δ = 165.9, 159.6, 141.2, 135.0, 131.1, 129.8, 128.9, 128.1,
127.9, 120.8, 114.1, 82.0, 56.7, 55.4, 45.9. HR-MS (ESI+) calc. for C 19 H21 N1O3Na 1 [M+Na] + 334.141363, found 334.141430. Its characterization data were matching the ones found in literature. 148
5.2.6. Mechanistic experiments
Use of TEMPO as radical inhibitor
A screw-cap vial was charged with Fe(II) phthalocyanine (5.7 mg, 0.01 mmol) and a stirring bar, was evacuated and refilled 3x with Ar, and was finally equipped with an Ar- filled balloon. A second vial was charged with reagent PivONH 3OTf (133.6 mg, 0.5 mmol), TEMPO (31.3 mg, 0.2 mmol) and a mixture of MeCN/H 2O (0.6 mL, MeCN/H 2O 2:1) was added. After purging the solution with Ar for 20 minutes, commercially available styrene (0.2 mmol) and the degassed solution of the reagent and TEMPO were simultaneously injected in the vial containing the Fe(II) catalyst and the reaction mixture was stirred at 25 °C. After 16 h the reaction mixture was diluted with MTBE (8 mL) and extracted with an aqueous solution of HCl 1.0 M (3 x 8 mL). The combined water phases were then concentrated in vacuo to afford the crude product as the free amine salt with 18% of 1H-NMR yield (DMSO as internal standard).
Aminomethoxylation and aminohydroxylation of cis and trans -β-methylstyrene, Scheme 50
148 S. Faizi, F. Farooqi, S. Zikr-Ur-Rehman, A. Naz, F. Noor, F. Ansari, A. Ahmad, S. A. Khan, Tetrahedron 2009 , 65 , 998-1004. 110 Iron-catalyzed synthesis of unprotected primary amines
A screw-cap vial was charged with Fe(II) phthalocyanine (5.7 mg, 0.01 mmol) and a stirring bar, was evacuated and refilled 3x with Ar, and was finally equipped with an Ar- filled balloon. A second vial was charged with reagent PivONH 3OTf (133.6 mg, 0.5 mmol) and MeOH (0.6 mL) was added. After purging the solution with Ar for 20 minutes, commercially available ( cis or trans )-β-methylstyrene styrene (0.2 mmol) and the degassed solution of the reagent were simultaneously injected in the vial containing the Fe(II) catalyst and the reaction mixture was stirred at 25 °C. After 16 h the reaction mixture was diluted with MTBE (8 mL) and extracted with an aqueous solution of HCl 1.0 M (3 x 8 mL). The combined water phases were then concentrated in vacuo to afford the crude product as the free amine salt. The yields and the ratio of the corresponding products were determined by 1H-NMR analysis of the crude reaction mixture using
DMSO and 1,4-dioxane as analytical standards in D 2O. Using commercially available cis -β-methylstyrene the two diastereomers were obtained as the free amine salts with 33% of overall 1H-NMR yield (DMSO as internal standard) and with a ratio of 1.5:1.0 between, respectively, (1 R*,2 R*)-1-methoxy-1-phenylpropan-2-amine and (1 R*,2 S*)-1- methoxy-1-phenylpropan-2-amine. Using commercially available trans -β-methylstyrene the two diastereomers were obtained as the free amine salts with 56% of overall 1H- NMR yield (DMSO as internal standard) and with a ratio of 1.0:5.0 between, respectively, (1 R*,2 R*)-1-methoxy-1-phenylpropan-2-amine and (1 R*,2 S*)-1-methoxy-1- phenylpropan-2-amine. Characterization data used for assignment and for characterization of the crude products were matching the ones found in literature ( 1H- NMR in DMSO). 149
The same experiment was repeated using a mixture of MeCN/H 2O (0.6 mL, MeCN/H 2O 2:1) instead of methanol to afford 2-amino-1-phenylpropan-1-ol as the free amine salt. Using commercially available cis -β-methylstyrene the two diastereomers were obtained as the free amine salts with 16% of overall 1H-NMR yield (DMSO as internal standard) and with a ratio of 1.2:1.0 between, respectively, (1 R*,2 R*)-2-amino-1-phenylpropan-1-ol and (1 R*,2 S*)-2-amino-1-phenylpropan-1-ol. Using commercially available trans -β-
149 M. Osorio-Olivares, M. C. Rezende, S. Sepulveda-Boza, B. K. Cassels, A. Fierro, Bioorgan. Med. Chem. 2004 , 12 , 4055-4066. 5. Experimental part 111 methylstyrene the two diastereomers were obtained as the free amine salts with 26% of overall 1H-NMR yield (DMSO as internal standard) and with a ratio of 1.0:3.0 between, respectively, (1 R*,2 R*)-1-methoxy-1-phenylpropan-2-amine and (1 R*,2 S*)-1-methoxy-1- phenylpropan-2-amine. Characterization data used for assignment and for characterization of the crude products were matching the ones found in literature. 150
Opening of 2-phenylaziridine under reaction conditions, Scheme 51
2-Phenylaziridine (0.250 mmol) was submitted to reaction conditions according to general procedure (B). After 16 h the crude reaction mixture was analyzed by TLC and GC, using diethylenglycoldimethylether and tridecane as analytical standards. Complete conversion of 2-phenylaziridine was observed and the reaction mixture, without intermediate workup, was directly purified following general purification procedure (D). 2- Amino-1-phenylethanol was afforded as a solid with 88% isolated yield (30.4 mg, 0.222 mmol).
Styrene under dry reaction conditions, Scheme 51
Commercially available styrene (0.250 mmol) was submitted to reaction conditions according to general procedure (B) and performing the reaction in dry MeCN (0.75 mL). After 16 h the crude reaction mixture was analyzed by TLC and GC, using diethylenglycoldimethylether and tridecane as analytical standards. No formation of 2- phenylaziridine was observed and 80% of unreacted styrene (0.200 mmol) was observed in the crude reaction mixture.
Use of chiral ligands under reaction conditions
Commercially available styrene (0.250 mmol) was submitted to reaction conditions according to general procedure (B) and performing the reaction using FeSO 4 · 7H 2O
150 M. Thunhorst, U. Holzgrabe, Magn. Reson. Chem. 1998 , 36 , 211-216. 112 Iron-catalyzed synthesis of unprotected primary amines
(3.5 mg, 0.013 mmol) as metal catalyst and 2,6-bis[(4 R)-phenyl-2-oxazolin-2-yl]pyridine (9.2 mg, 0.025 mmol) or (-)-2,2-bis[(4 S)-4-phenyl-2-oxazolin-2-yl]propane (8.4 mg, 0.025 mmol) as chiral ligands. After 16 h the crude reaction mixture, without intermediate workup, was directly purified following general purification procedure (D). Using 2,6- bis[(4 R)-phenyl-2-oxazolin-2-yl]pyridine as a ligand, 2-amino-1-phenylethanol was afforded as a solid with 36% isolated yield (12.3 mg, 0.090 mmol). The enantiomeric ratio of the product was determined to be 50.99:49.01 by chiral HPLC analysis of the isolated 2-amino-1-phenylethanol (150 mm Chiralpak AD-RH, 4.6 mm i.D., MeCN (+ 0.1% ethanolamine), 1.0 mL/min, 4.7 MPa, 25°C, 220 nm, retention time: 3.89 min (enantiomer 1), 4.32 min (enantiomer 2)). Using (-)-2,2-bis[(4 S)-4-phenyl-2-oxazolin-2- yl]propane as a ligand, 2-amino-1-phenylethanol was afforded as a solid with 50% isolated yield (17.3 mg, 0.126 mmol). The enantiomeric ratio of the product was determined to be 50.98:49.02 by chiral HPLC analysis of the isolated 2-amino-1- phenylethanol.
5.2.7. Synthesis of SLAP reagents
General procedure (E): synthesis of SLAP reagents through Fe(II)-catalyzed amino etherification of olefins, Table 5
An oven dried Schlenk flask under Ar flow was charged with a stirring bar and a mixture of MeCN (15.0 mL, degassed through Ar purging) and (trimethylsilyl)methanol (6.3 mL, 50 mmol, degassed through Ar purging). The corresponding olefin (5.0 mmol), the reagent PivONH 3OTf (3.34 g, 12.5 mmol) and Fe(II) phthalocyanine (142.1 mg, 0.25 mmol) were subsequently added in this order, the flask was equipped with an Ar-filled balloon and the reaction mixture was stirred at 25 °C. After 16 h the reaction mixture was quenched with an aqueous solution of NaOH (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic phases were dried over Na 2SO 4, filtered, and concentrated in vacuo . The crude product was purified via flash column chromatography (DCM/MeOH as eluent) to afford the desired products.
5. Experimental part 113
2-Phenyl-2-((trimethylsilyl)methoxy)ethan-1-amine, Table 5, Entry 1
was prepared from commercially available styrene according to general procedure (E) to afford the desired product as an oil in 86% isolated yield (962.8 mg, 4.310 mmol) after flash column chromatography (DCM/MeOH = 100/5 to 100/10). 1H-NMR (500 MHz,
CDCl 3): δ = 7.37 – 7.33 (m, 2H), 7.31 – 7.23 (m, 3H), 4.13 (dd, J = 7.2, 4.6 Hz, 1H), 3.08 (d, J = 12.6 Hz, 1H), 2.93 (d, J = 12.6 Hz, 1H), 2.89 – 2.77 (m, 2H), 2.19 (br s, 2H), 0.05 13 (s, 9H). C-NMR (125 MHz, CDCl 3): δ = 140.8, 128.5, 127.8, 126.9, 87.5, 62.9, 49.2, -
2.9. HR-MS (ESI+) calc. for C 12 H22 N1O1Si 1 [M+H] = 224.146517; found = 224.146350.
2-Phenyl-2-((trimethylsilyl)methoxy)propan-1-amine, Table 5, Entry 2
was prepared from commercially available α-methylstyrene according to general procedure (E) to afford the desired product as an oil in 76% isolated yield (899.8 mg, 3.790 mmol) after flash column chromatography (DCM/MeOH = 100/5 to 100/10). 1H-
NMR (500 MHz, CDCl 3): δ = 7.37 – 7.31 (m, 4H), 7.29 – 7.22 (m, 1H), 2.89 (d, J = 12.4 Hz, 1H), 2.82 – 2.79 (m, 2H), 2.75 (d, J = 12.4 Hz, 1H), 1.51 (br s, 2H), 1.51 (s, 3H), 13 0.07 (s, 9H). C-NMR (125 MHz, CDCl 3): δ = 144.1, 128.3, 127.0, 126.6, 80.1, 54.3,
53.3, 20.7, -2.8. HR-MS (ESI+) calc. for C 13 H24 N1O1Si 1 [M+H] = 238.162167; found = 238.161980.
114 Iron-catalyzed synthesis of unprotected primary amines
2-(4-Bromophenyl)-2-((trimethylsilyl)methoxy)ethan-1-amine, Table 5, Entry 3
was prepared from commercially available 4-bromostyrene according to general procedure (E) to afford the desired product as an oil in 77% isolated yield (1169.0 mg, 3.867 mmol) after flash column chromatography (DCM/MeOH = 100/5 to 100/10). 1H-
NMR (500 MHz, CDCl 3): δ = 7.48 – 7.46 (m, 2H), 7.15 – 7.12 (m, 2H), 4.10 – 4.07 (m, 1H), 3.04 (d, J = 12.6 Hz, 1H), 2.92 (d, J = 12.6 Hz, 1H), 2.84 – 2.76 (m, 2H), 2.11 (br s, 13 2H), 0.04 (s, 9H). C-NMR (125 MHz, CDCl 3): δ = 140.0, 131.7, 128.6, 121.6, 87.1,
63.1, 49.1, -2.9. HR-MS (ESI+) calc. for C 12 H21 N1O1Br 1Si 1 [M+H] = 302.057043; found = 302.057090.
2-Phenyl-2-(1-(trimethylsilyl)ethoxy)ethan-1-amine, Table 5, Entry 4
was prepared from commercially available styrene and 1-(trimethylsilyl)ethan-1-ol (50 mmol) according to general procedure (E) to afford the desired products A diastereomer and B diastereomer as oils in respectively 25% (298.1 mg, 1.256 mmol) and 26% (312.3 mg, 1.315 mmol) isolated yields after flash column chromatography (DCM/MeOH = 1 100/5 to 100/10). A diastereomer: H-NMR (500 MHz, CDCl 3): δ = 7.35 – 7.25 (m, 5H), 4.32 – 4.30 (m, 1H), 3.25 (q, J = 7.2 Hz, 1H), 2.89 (br s, 2H), 2.58 (br s, 2H), 1.01 (d, J = 13 7.2 Hz, 3H), 0.08 (s, 9H). C-NMR (125 MHz, CDCl 3): δ = 142.5, 128.3, 127.6, 126.8,
84.2, 69.3, 49.0, 16.9, -3.3. HR-MS (ESI+) calc. for C 13 H24 N1O1Si 1 [M+H] = 238.162167; 1 found = 238.162040. B diastereomer: H-NMR (500 MHz, CDCl 3): δ = 7.35 – 7.26 (m, 5H), 4.44 (dd, J = 8.0, 4.0 Hz, 1H), 3.03 (q, J = 7.2 Hz, 1H), 2.86 – 2.79 (br m, 2H), 1.63 5. Experimental part 115
13 (br s, 2H), 1.19 (d, J = 7.2 Hz, 3H), -0.02 (s, 9H). C-NMR (125 MHz, CDCl 3): δ = 141.1,
128.3, 127.7, 127.5, 80.4, 64.6, 49.4, 14.2, -3.7. HR-MS (ESI+) calc. for C 13 H24 N1O1Si 1 [M+H] = 238.162167; found = 238.162050.
116 Iron-catalyzed synthesis of unprotected primary amines
5.3. Experimental part to chapter three (Direct synthesis of primary anilines through C−H amination)
5.3.1. Synthesis of starting materials
Reagent MsONH 3OTf synthesis procedure
tert -Butyl ((methylsulfonyl)oxy)carbamate
was prepared from commercially available N-Boc-hydroxylamine according to literature and its characterization data were matching the ones found in literature. 81b,151
O-(Methylsulfonyl)hydroxylamine trifluoromethanesulfonate, 62
was prepared from tert -butyl ((methylsulfonyl)oxy)carbamate according to the following procedure: tert -butyl ((methylsulfonyl)oxy)carbamate (5.28 g, 25.0 mmol) was dissolved in diethylether (50 mL) and triflic acid (2.21 mL, 25.0 mmol) was added dropwise at 0 °C. The reaction mixture was allowed to reach 25 °C, stirred for additional 1 h at 25 °C and diluted with pentane (75 mL) to precipitate the product. The mixture was filtered and dried to afford the desired product as a white solid with 94% isolated yield (6.13 g, 23.47 1 mmol). H-NMR (500 MHz, DMSO-d6): δ = 10.85 (br s, 1H), 9.27 (br s, 2H), 2.46 (s, 3H).
151 J. A. Stafford, S. S. Gonzales, D. G. Barrett, E. M. Suh, P. L. Feldman, J. Org. Chem. 1998 , 63 , 10040- 10044. 5. Experimental part 117
13 19 C-NMR (125 MHz, DMSO-d6): δ = 120.7 (d, J = 322.6 Hz), 39.7. F-NMR (470 MHz, + DMSO-d6): δ = -77.74. HR-MS calc. for C 2H6F3NO 6S2 [M] 260.95886, Not found. ESI- - calc. for C1F3O3S1 [TfO] 149.0, found 149.0.
Methyl 2-(2-fluoro-[1,1'-biphenyl]-4-yl)propanoate, Scheme 61, 63SM
was prepared from commercially available flurbiprofen (( RS )-2-(2-fluoro-[1,1'-biphenyl]- 4-yl)propanoic acid) according to literature and its characterization data were matching the ones found in literature. 152
17β-Estradiol-3-methyl ether, Scheme 61, 64SM
was prepared from commercially available estrone according to literature and its characterization data were matching the ones found in literature. 153
152 P. Çıkla, E. Tatar, İ. Küçükgüzel, F. Şahin, D. Yurdakul, A. Basu, R. Krishnan, D. B. Nichols, N. Kaushik-Basu, Ş. G. Küçükgüzel, Med. Chem. Res. 2013 , 22 , 5685-5699. 153 P. C. B. Page, J. P. G. Moore, I. Mansfield, M. J. McKenzie, W. B. Bowlerb, J. A. Gallagher, Tetrahedron 2001 , 57 , 1837-1847. 118 Iron-catalyzed synthesis of unprotected primary amines
Dextromethorphan, Scheme 61, 65SM
was prepared from commercially available dextromethorphan hydrobromide according to the following procedure: a flask was charged with dextromethorphan hydrobromide
(1000.0 mg, 2.7 mmol) and stirred at 25 °C in a saturated solution of NaHCO 3 (50 mL). After 1 h (gas evolution is no more evident) the reaction mixture was diluted with DCM (50 mL) and extracted with DCM (3 x 50 mL). The combined organic phases were dried over Na 2SO 4, filtered, and concentrated in vacuo . The product was used directly in the next step without further purification.
5.3.2. Experimental procedures
Comparison between different protocols, Scheme 60
A screw-cap vial charged with Fe(II) phthalocyanine (5.7 mg, 0.01 mmol), PivONH 3OTf (53.4 mg, 0.20 mmol) and a stirring bar, was evacuated and refilled 3 times with Ar, and was finally equipped with an Ar-filled balloon. MeOH (0.6 mL, degassed through Ar purging) was subsequently added to the vial, followed by trans -β-methylstyrene (129.7 µL, 1.0 mmol). After stirring for 16 h at 25 °C, a small aliquot was collected, diluted with
EtOAc, washed with a saturated solution of NaHCO 3 and analyzed at GC and GC/MS using tetradecane as analytical standard. The remaining reaction mixture was diluted with MTBE (8 mL) and extracted with an aqueous solution of HCl 1.0 M (3 x 8 mL). The combined water phases were then concentrated in vacuo to afford the crude product as the free amine salt. The yields of the corresponding products were determined by 1H- NMR analysis of the crude reaction mixture using DMSO and 1,4-dioxane as analytical standards in D 2O.
5. Experimental part 119
A screw-cap vial charged with Fe(II) sulfate heptahydrate (2.8 mg, 0.01 mmol),
MsONH 3OTf (52.2 mg, 0.20 mmol) and a stirring bar, was evacuated and refilled 3 times with Ar, and was finally equipped with an Ar-filled balloon. MeCN/H 2O (0.6 mL,
MeCN/H 2O = 2/1, degassed through Ar purging) was subsequently added to the vial, followed by trans -β-methylstyrene (129.7 µL, 1.0 mmol). After stirring for 16 h at 25 °C, a small aliquot was collected, diluted with EtOAc, washed with a saturated solution of
NaHCO 3 and analyzed at GC and GC/MS using tetradecane as analytical standard. The remaining reaction mixture was diluted with MTBE (8 mL) and extracted with an aqueous solution of HCl 1.0 M (3 x 8 mL). The combined water phases were then concentrated in vacuo to afford the crude product as the free amine salt. The yields of the corresponding products were determined by 1H-NMR analysis of the crude reaction mixture using DMSO and 1,4-dioxane as analytical standards in D 2O.
General procedure (A): evaluation of reaction conditions, Table 6
A screw-cap vial charged with a metal catalyst (0.01 mmol), a ligand (0.02 mmol), a reagent (0.24 mmol) and a stirring bar, was evacuated and refilled 3 times with Ar, and was finally equipped with an Ar-filled balloon. MeCN/H 2O (0.6 mL, MeCN/H 2O = 2/1, degassed through Ar purging) was subsequently added to the vial, followed by commercially available benzene (17.9 µL, 0.2 mmol). After stirring for 16 h at 25 °C, the reaction mixture was diluted with an aqueous solution of NaOH 1.0 M (3 mL) and extracted directly in the vial with EtOAc (4 mL). The yields of the corresponding products were determined by GC analysis of the organic layer using tetradecane as analytical standard.
General procedure (B): substrate scope and late stage functionalization, Table 7 and Scheme 61
A screw-cap vial charged with Fe(II) sulfate heptahydrate (7.0 mg, 0.025 mmol),
MsONH 3OTf (195.9 mg, 0.75 mmol) and a stirring bar, was evacuated and refilled 3 times with Ar, and was finally equipped with an Ar-filled balloon. MeCN/H 2O (1.5 mL, 120 Iron-catalyzed synthesis of unprotected primary amines
MeCN/H 2O = 2/1, degassed through Ar purging) was subsequently added to the vial, followed by the corresponding arene substrate (0.5 mmol). After stirring for 16 h at 25 °C, the reaction mixture was diluted with an aqueous solution of NaOH 1.0 M (15 mL) and extracted with DCM (3 x 15 mL). The combined organic phases were dried over
Na 2SO 4, filtered, and concentrated in vacuo . The isomers distribution of the corresponding products was determined by 1H-NMR analysis of the crude reaction mixture using nitromethane as analytical standard in CDCl 3. After analysis, the crude mixtures were directly purified via flash column chromatography to afford the desired products. Some of the regio-isomers resulting after the amination reaction could be separated via column chromatography. The separable regio-isomers are specified in the descriptions below.
5.3.3. Substrate scope
Aniline, Table 7, Entry 1
was prepared from commercially available benzene according to general procedure (B) to afford the desired product as an orange oil in 82% isolated yield (38.3 mg, 0.411 mmol) after flash column chromatography (eluting solvent: pentane/MTBE = 3/1). 1H-
NMR (300 MHz, CDCl 3): δ = 7.20 – 7.12 (m, 2H), 6.81 – 6.73 (m, 1H), 6.72 – 6.67 (m, 13 2H), 3.53 (br s, 2H). C-NMR (75 MHz, CDCl 3): δ = 146.5, 129.4, 118.7, 115.3. Its characterization data were matching the ones found in literature. 154
154 O. Kreye, S. Wald, M. A. R. Meier, Adv. Synth. Catal. 2013 , 355 , 81-86. 5. Experimental part 121 o-Toluidine ( A isomer), m-toluidine ( B isomer), p-toluidine ( C isomer), Table 7, Entry 2
were prepared from commercially available toluene according to general procedure (B) to afford the desired products as an orange oil in 83% isolated yield (44.5 mg, 0.416 mmol, mixture of isomers: 1.1:1.0:1.9) after flash column chromatography (eluting solvent: pentane/MTBE = 3/1). Isomeric distribution was determined by 1H-NMR analysis of the crude reaction mixture by integration of the methyl group signal (s signals at 2.18 ppm, 2.27 ppm, 2.25 ppm, respectively for A isomer, B isomer, C isomer). A 1 isomer: H-NMR (300 MHz, CDCl 3): δ = 7.06 – 7.01 (m, 2H), 6.75 – 6.65 (m, 2H), 3.41 13 (br s, 2H), 2.18 (s, 3H). C-NMR (75 MHz, CDCl 3): δ = 144.7, 130.6, 127.1, 122.4, 1 118.8, 115.1, 17.5. B isomer: H-NMR (300 MHz, CDCl 3): δ = 7.10 – 7.06 (m, 1H), 6.65 – 6.56 (m, 1H), 6.54 – 6.48 (m, 2H), 3.41 (br s, 2H), 2.27 (s, 3H). 13 C-NMR (75 MHz, 1 CDCl 3): δ = 146.5, 139.2, 129.3, 119.6, 116.1, 112.4, 21.6. C isomer: H-NMR (300
MHz, CDCl 3): δ = 7.01 – 6.93 (m, 2H), 6.65 – 6.56 (m, 2H), 3.41 (br s, 2H), 2.25 (s, 3H). 13 C-NMR (75 MHz, CDCl 3): δ = 143.9, 129.9, 127.9, 115.4, 20.6. Theirs characterization data were matching the ones found in literature. 155
2-Bromoaniline ( A isomer), 3-bromoaniline ( B isomer), 4-bromoaniline ( C isomer), Table 7, Entry 3
NH 2
Br
155 T. Maejima, Y. Shimoda, K. Nozaki, S. Mori, Y. Sawama, Y. Monguchi, H. Sajiki, Tetrahedron 2012 , 68 , 1712-1722. 122 Iron-catalyzed synthesis of unprotected primary amines were prepared from commercially available bromobenzene according to general procedure (B) and with an increased amount of MsONH3OTf (522.4 mg, 2.0 mmol) to afford the desired products as an orange oil in 77% isolated yield (66.3 mg, 0.385 mmol, mixture of isomers: 1.0:1.4:3.3) after flash column chromatography (eluting solvent: pentane/MTBE = 2/1). Isomeric distribution was determined by 1H-NMR analysis of the crude reaction mixture by integration of the aromatic signals (dd signal at 7.40 ppm, t signal at 7.00 ppm, m signal at 7.25 – 7.20 ppm, respectively for A isomer, B isomer, C isomer). A isomer could be easily separated from the mixture via column chromatography. In this case the three isomers were isolated in a single fraction. A 1 isomer: H-NMR (300 MHz, CDCl 3): δ = 7.40 (dd, J = 8.0, 1.4 Hz, 1H), 7.10 (ddd, J = 8.0, 7.2, 1.4 Hz, 1H), 6.76 (dd, J = 8.0, 1.4 Hz, 1H), 6.65 – 6.58 (m, 1H), 3.69 (br s, 2H). 13 1 C-NMR (75 MHz, CDCl 3): δ = 144.2, 132.7, 128.5, 119.6, 115.90, 109.5. B isomer: H-
NMR (300 MHz, CDCl 3): δ = 7.00 (t, J = 7.8 Hz, 1H), 6.87 (ddd, J = 7.8, 2.0, 1.0 Hz, 1H), 13 6.83 (t, J = 2.0 Hz, 1H), 6.65 – 6.58 (m, 1H), 3.69 (br s, 2H). C-NMR (75 MHz, CDCl 3): 1 δ = 147.9, 130.7, 123.2, 121.5, 118.0, 113.8. C isomer: H-NMR (300 MHz, CDCl 3): δ = 13 7.25 – 7.20 (m, 2H), 6.58 – 6.52 (m, 2H), 3.69 (br s, 2H). C-NMR (75 MHz, CDCl 3): δ = 145.5, 132.2, 116.9, 110.4. Theirs characterization data were matching the ones found in literature. 156
2-Methoxyaniline ( A isomer), 3-methoxyaniline ( B isomer), 4-methoxyaniline ( C isomer), Table 7, Entry 4
were prepared from commercially available anisole according to general procedure (B) to afford the desired products as an orange solid in 65% isolated yield (40.4 mg, 0.328
156 (a) S. M. Kelly, B. H. Lipshutz, Org. Lett. , 2014 , 16 , 98-101 ( A isomer). (b) U. Sharma, P. Kumar, N. Kumar, V. Kumar, B. Singh, Adv. Synth. Catal. 2010 , 352 , 1834-1840 (B isomer). (c) J. H. Kim, J. H. Park, Y. K. Chung, K. H. Park, Adv. Synth. Catal. 2012 , 354 , 2412-2418 (C isomer). 5. Experimental part 123 mmol, mixture of isomers: 4.0:1.0:14.3) after flash column chromatography (eluting solvent: pentane/MTBE = 3/1). Isomeric distribution was determined by 1H-NMR analysis of the crude reaction mixture by integration of the methoxy group signal (s signals at 3.85 ppm, 3.76 ppm, 3.75 ppm, respectively for A isomer, B isomer, C 1 isomer). A isomer: H-NMR (500 MHz, CDCl 3): δ = 6.82 – 6.77 (m, 2H), 6.73 – 6.71 (m, 13 2H), 3.85 (s, 3H), 3.41 (br s, 2H). C-NMR (125 MHz, CDCl 3): δ = 147.5, 136.3, 121.2, 1 118.6, 115.2, 110.6, 55.6. B isomer: H-NMR (500 MHz, CDCl 3): δ = 7.06 (t, J = 8.0 Hz, 1H), 6.33 (ddd, J = 8.0, 2.4, 0.8 Hz, 1H), 6.30 (ddd, J = 8.0, 2.4, 0.8 Hz, 1H), 6.25 (t, J = 13 2.4 Hz, 1H), 3.76 (s, 3H), 3.41 (br s, 2H). C-NMR (125 MHz, CDCl 3): δ = 157.9, 147.5, 1 130.2, 108.1, 104.1, 101.2, 55.2. C isomer: H-NMR (500 MHz, CDCl 3): δ = 6.77 – 6.73 13 (m, 2H), 6.68 – 6.64 (m, 2H), 3.75 (s, 3H), 3.41 (br s, 2H). C-NMR (125 MHz, CDCl 3): δ = 153.0, 139.9, 116.6, 115.0, 55.9. Theirs characterization data were matching the ones found in literature. 157
N-(2-Aminophenyl)acetamide ( A isomer), N-(3-aminophenyl)acetamide (B isomer), N-(4-aminophenyl)acetamide ( C isomer), Table 7, Entry 5
were prepared from commercially available N-phenylacetamide according to general procedure (B) and weighing the starting material into the vial containing Fe(II) sulfate heptahydrate and the reagent MsONH 3OTf to afford the desired products as an orange solid in 62% isolated yield (46.2 mg, 0.308 mmol, mixture of isomers: 4.1:1.0:12.5, isomers distribution determined on the isolated products) after flash column chromatography (eluting solvent: EtOAc). Isomeric distribution was determined by 1H-
157 (a) G. D. Vo, J. F. Hartwig, J. Am. Chem. Soc. 2009 , 131 , 11049-11061 ( A, B, C isomer). (b) Y. Wang, J. Ling, Y. Zhang, A. Zhang, Q. Yao, Eur. J. Org. Chem. 2015 , 2015 , 4153-4161 ( B isomer). (c) H.-L. Qi, D.-S. Chen, J.-S. Ye, J.-M. Huang, J. Org. Chem. 2013 , 78 , 7482-7487 ( C isomer). 124 Iron-catalyzed synthesis of unprotected primary amines
NMR analysis of the crude reaction mixture by integration of the –NHCO CH 3 signal (s signals at 2.03 ppm, 1.99 ppm, 1.95 ppm, respectively for A isomer, B isomer, C 1 isomer). A isomer: H-NMR (500 MHz, DMSO-d6): δ = 9.10 (br s, 1H), 7.15 (dd, J = 7.8, 1.6 Hz, 1H), 6.90 – 6.87 (m, 1H), 6.70 (dd, J = 7.8, 1.6 Hz, 1H), 6.54 – 6.51 (m, 1H), 13 4.83 (br s, 2H), 2.03 (s, 3H). C-NMR (125 MHz, DMSO-d6): δ = 168.2, 141.9, 125.7, 1 125.3, 123.5, 116.1, 115.8, 23.3. B isomer: H-NMR (500 MHz, DMSO-d6): δ = 9.58 (br s, 1H), 6.92 (t, J = 2.0 Hz, 1H), 6.90 – 6.87 (m, 1H), 6.67 – 6.62 (m, 1H), 6.26 – 6.19 (m, 13 1H), 4.98 (br s, 2H), 1.99 (s, 3H). C-NMR (125 MHz, DMSO-d6): δ = 167.9, 148.9, 1 139.9, 128.8, 109.1, 106.9, 104.7, 24.1. C isomer: H-NMR (500 MHz, DMSO-d6): δ = 9.46 (br s, 1H), 7.21 – 7.16 (m, 2H), 6.50 – 6.46 (m, 2H), 4.79 (br s, 2H), 1.95 (s, 3H). 13 C-NMR (125 MHz, DMSO-d6): δ = 167.2, 144.6, 128.6, 120.8, 113.8, 23.7. Theirs characterization data were matching the ones found in literature. 158
2-(2-Aminophenyl)ethan-1-ol ( A isomer), 2-(3-aminophenyl)ethan-1-ol ( B isomer), 2-(4-aminophenyl)ethan-1-ol ( C isomer), Table 7, Entry 6
were prepared from commercially available 2-phenylethan-1-ol according to general procedure (B) to afford the desired products as a yellow solid in 65% isolated yield (44.3 mg, 0.323 mmol, mixture of isomers: 1.3:1.0:2.0) after flash column chromatography (eluting solvent: pentane/MTBE = 1/3). Isomeric distribution was determined by 1H-NMR analysis of the crude reaction mixture by integration of the –CH 2OH signal (t signals at
158 (a) H. Zhao, H. Fu, R. Qiao, J. Org. Chem. 2010 , 75 , 3311-3316 ( A isomer). (b) J. Ungvarsky, J. Plsikova, L. Janovec, J. Koval, J. Mikes, L. Mikesová, D. Harvanova, P. Fedorocko, P. Kristian, J. Kasparkova, V. Brabec, M. Vojtickova, D. Sabolova, Z. Stramova, J. Rosocha, J. Imrich, M. Kozurkova, Bioorg. Chem. 2014 , 57 , 13-29 ( B isomer). (c) D. Wang, Q. Cai, K. Ding, Adv. Synth. Catal. 2009 , 351 , 1722-1726 ( C isomer). 5. Experimental part 125
3.88 ppm, 3.82 ppm, 3.78 ppm, respectively for A isomer, B isomer, C isomer). A 1 isomer: H-NMR (300 MHz, CDCl 3): δ = 7.14 – 7.06 (m, 2H), 6.76 (td, J = 7.4, 1.2 Hz, 1H), 6.70 (d, J = 7.4 Hz, 1H), 3.88 (t, J = 6.2 Hz, 2H), 2.98 (br s, 3H), 2.81 – 2.73 (m, 13 2H). C-NMR (75 MHz, CDCl 3): δ = 145.2, 130.7, 127.8, 124.4, 119.4, 116.4, 63.7, 1 34.9. B isomer: H-NMR (300 MHz, CDCl 3): δ = 7.06 – 6.97 (m, 1H), 6.68 – 6.59 (m, 1H), 6.58 – 6.54 (m, 2H), 3.82 (t, J = 6.4 Hz, 2H), 2.98 (br s, 3H), 2.81 – 2.73 (m, 2H). 13 C-NMR (75 MHz, CDCl 3): δ = 146.7, 139.8, 129.7, 119.3, 115.9, 113.5, 63.4, 39.3. C 1 isomer: H-NMR (300 MHz, CDCl3): δ = 7.06 – 6.97 (m, 2H), 6.68 – 6.59 (m, 2H), 3.78 13 (t, J = 6.6 Hz, 2H), 2.98 (br s, 3H), 2.81 – 2.73 (m, 2H). C-NMR (75 MHz, CDCl 3): δ = 145.0, 130.0, 128.4, 115.6, 64.0, 38.4. Theirs characterization data were matching the ones found in literature. 159
2,5-Dimethylaniline, Table 7, Entry 7
was prepared from commercially available p-xylene according to general procedure (B) to afford the desired product as a yellow oil in 81% isolated yield (48.8 mg, 0.403 mmol) after flash column chromatography (eluting solvent: pentane/MTBE = 3/1). 1H-NMR (300
MHz, CDCl 3): δ = 6.94 (d, J = 7.4 Hz, 1H), 6.56 – 6.52 (m, 2H), 3.46 (br s, 2H), 2.26 (s, 13 3H), 2.14 (s, 3H). C-NMR (75 MHz, CDCl 3): δ = 144.5, 136.7, 130.4, 119.6, 119.5, 115.9, 21.2, 17.0. Its characterization data were matching the ones found in literature. 160
159 X. Guo, Z. Peng, S. Jiang, J. Shen, Synth. Commun. 2011 , 41 , 2044-2052 ( A isomer). E. Moreau, S. Fortin, M. Desjardins, J. L. C. Rousseau, E. Petitclerc, R. C.-Gaudreault, Bioorg. Med. Chem. 2005 , 13 , 6703-6712 ( B isomer). B. S. Bodnar, P. F. Vogt, J. Org. Chem. 2009 , 74 , 2598-2600 ( C isomer). 160 R. A. Green, J. F. Hartwig, Org. Lett. 2014 , 16 , 4388-4391. 126 Iron-catalyzed synthesis of unprotected primary amines
5-Bromo-2-methoxyaniline, Table 7, Entry 8
was prepared from commercially available 1-bromo-4-methoxybenzene according to general procedure (B) and with an increased amount of MsONH 3OTf (326.5 mg, 1.25 mmol) to afford the desired product as an orange oil in 78% isolated yield (78.4 mg, 0.388 mmol) after flash column chromatography (eluting solvent: pentane/MTBE = 3/1). 1 H-NMR (300 MHz, CDCl 3): δ = 6.93 – 6.76 (m, 2H), 6.69 – 6.57 (m, 1H), 3.83 (s, 3H), 13 3.83 (br s, 2H). C-NMR (75 MHz, CDCl 3): δ = 146.6, 137.7, 121.0, 117.6, 113.4, 111.9, 55.8. Its characterization data were matching the ones found in literature. 161
4-Methoxybenzene-1,3-diamine, Table 7, Entry 9
NH 2 MeO
NH 2 was prepared from commercially available 4-methoxyaniline according to general procedure (B), weighing the starting material into the vial containing Fe(II) sulfate heptahydrate and an increased amount of MsONH 3OTf (522.4 mg, 2.0 mmol) to afford the desired product as an orange solid in 70% isolated yield (48.7 mg, 0.352 mmol) after flash column chromatography (eluting solvent: pentane/EtOAc = 1/2 to EtOAc). 1H-NMR
(300 MHz, CDCl 3): δ = 6.61 (d, J = 8.4 Hz, 1H), 6.13 (d, J = 2.6 Hz, 1H), 6.06 (dd, J = 13 8.4, 2.6 Hz, 1H), 3.77 (s, 3H), 3.46 (br s, 4H). C-NMR (75 MHz, CDCl 3): δ = 141.0, 140.8, 137.2, 112.4, 104.9, 103.5, 56.4. Its characterization data were matching the ones found in literature. 162
161 H. Y. Choi, D. Y. Chi, J. Am. Chem. Soc. 2001 , 123 , 9202-9203. 162 B.-S. Liao, S.-T. Liu, J. Org. Chem. 2012 , 77 , 6653-6656. 5. Experimental part 127
Methyl 3-amino-4-methoxybenzoate, Table 7, Entry 10
was prepared from commercially available methyl 4-methoxybenzoate according to general procedure (B), weighing the starting material into the vial containing Fe(II) sulfate heptahydrate and an increased amount of MsONH 3OTf (326.5 mg, 1.25 mmol) to afford the desired product as a white solid in 64% isolated yield (58.0 mg, 0.320 mmol) after flash column chromatography (eluting solvent: pentane/MTBE = 3/1 to 2/1). 1H-
NMR (300 MHz, DMSO-d6): δ = 7.27 (d, J = 2.2 Hz, 1H), 7.21 (dd, J = 8.4, 2.2 Hz, 1H), 6.87 (d, J = 8.4 Hz, 1H), 4.98 (br s, 2H), 3.83 (s, 3H), 3.77 (s, 3H). 13 C-NMR (75 MHz,
DMSO-d6): δ = 166.5, 150.1, 137.6, 122.0, 118.3, 113.8, 109.7, 55.4, 51.5. Its characterization data were matching the ones found in literature. 104
3-Amino-4-methoxybenzonitrile, Table 7, Entry 11
was prepared from commercially available 4-methoxybenzonitrile according to general procedure (B), weighing the starting material into the vial containing Fe(II) sulfate heptahydrate and an increased amount of MsONH 3OTf (522.4 mg, 2.0 mmol) to afford the desired product as a white solid in 55% isolated yield (40.4 mg, 0.273 mmol) after flash column chromatography (eluting solvent: pentane/MTBE = 3/1 to 1/1). 1H-NMR
(300 MHz, CDCl 3): δ = 7.04 (dd, J = 8.2, 2.0 Hz, 1H), 6.90 (d, J = 2.0 Hz, 1H), 6.78 (d, J 13 = 8.2 Hz, 1H), 3.94 (br s, 2H), 3.89 (s, 3H). C-NMR (75 MHz, CDCl 3): δ = 150.5, 137.1, + 123.5, 119.8, 116.8, 110.3, 104.2, 55.8. HR-MS (ESI+) calc. for C 8H8N2O1Na 1 [M+Na] 171.052882, found 171.052790.
128 Iron-catalyzed synthesis of unprotected primary amines
2-Bromo-5-methylaniline ( A isomer), 5-bromo-2-methylaniline ( B isomer), Table 7, Entry 12
were prepared from commercially available 1-bromo-4-methylbenzene according to general procedure (B), weighing the starting material into the vial containing Fe(II) sulfate heptahydrate and an increased amount of MsONH 3OTf (522.4 mg, 2.0 mmol) to afford the desired products as an orange solid in 71% isolated yield (66.5 mg, 0.357 mmol, mixture of isomers: 1.0:2.1) after flash column chromatography (eluting solvent: pentane/MTBE = 4/1). Isomeric distribution was determined by 1H-NMR analysis of the crude reaction mixture by integration of the methyl group signal (s signals at 2.23 ppm, 1 2.10 ppm, respectively for A isomer, B isomer). A isomer: H-NMR (300 MHz, CDCl 3): δ = 7.27 (d, J = 8.0 Hz, 1H), 6.59 (dd, J = 2.0, 0.8 Hz, 1H), 6.44 (ddd, J = 8.0, 2.0, 0.8 Hz, 13 1H), 3.73 (br s, 2H), 2.23 (s, 3H). C-NMR (75 MHz, CDCl 3): δ = 143.9, 138.5, 132.3, 1 120.6, 116.6, 106.3, 21.2. B isomer: H-NMR (300 MHz, CDCl 3): δ = 6.92 – 6.87 (m, 13 1H), 6.85 – 6.77 (m, 2H), 3.73 (br s, 2H), 2.10 (s, 3H). C-NMR (75 MHz, CDCl 3): δ = 146.0, 131.8, 121.4, 121.2, 120.2, 117.5, 17.1. Assignment of 13 C-NMR signals through + HSQC, HMBC spectra. HR-MS (ESI+) calc. for C 7H9N1Br 1 [M+H] 185.991299, found 185.991350. GC-MS analysis showed presence of two distinct peaks, both with mass of 185.0 [M] +. Theirs characterization data were matching the ones found in literature. 163
5-Methoxy-2-methylaniline ( A isomer), 2-methoxy-5-methylaniline ( B isomer), Table 7, Entry 13
163 M. R. Pitts, J. R. Harrison, C. J. Moody, J. Chem. Soc ., Perkin Trans. 1 2001 , 955-977 ( B isomer). 5. Experimental part 129 were prepared from commercially available 1-methoxy-4-methylbenzene according to general procedure (B) to afford the desired products as a yellow solid in 53% isolated yield (36.1 mg, 0.263 mmol, mixture of isomers: 1.0:4.8) after flash column chromatography (eluting solvent: pentane/MTBE = 4/1). Isomeric distribution was determined by 1H-NMR analysis of the crude reaction mixture by integration of the methyl group signal (s signals at 2.11 ppm, 2.23 ppm, respectively for A isomer, B 1 isomer). A isomer: H-NMR (300 MHz, CDCl 3): δ = 6.94 (d, J = 7.8 Hz, 1H), 6.30 – 6.26 13 (m, 2H), 3.75 (s, 3H), 3.51 (br s, 2H), 2.11 (s, 3H). C-NMR (75 MHz, CDCl 3): δ = 159.1, 145.6, 131.1, 114.9, 103.8, 101.1, 55.3, 16.6. B isomer: 1H-NMR (300 MHz,
CDCl 3): δ = 6.69 (d, J = 8.0 Hz, 1H), 6.60 – 6.44 (m, 2H), 3.82 (s, 3H), 3.51 (br s, 2H), 13 2.23 (s, 3H). C-NMR (75 MHz, CDCl 3): δ = 145.5, 136.0, 130.7, 118.8, 116.1, 110.6, + 55.8, 20.8. HR-MS (APPI+) calc. for C 8H11 N1O1 [M] 137.083514, found 137.083460. GC-MS analysis showed presence of two distinct peaks, both with mass of 137.0 [M] +. Theirs characterization data were matching the ones found in literature. 160
4-Bromo-2,6-dimethoxyaniline ( A isomer), 2-bromo-4,6-dimethoxyaniline ( B isomer), Table 7, Entry 14
were prepared from commercially available 1-bromo-3,5-dimethoxybenzene according to general procedure (B), weighing the starting material into the vial containing Fe(II) sulfate heptahydrate and the reagent MsONH 3OTf to afford the desired products as a yellow solid in 61% isolated yield (71.1 mg, 0.306 mmol, mixture of isomers: 1.0:1.8) after flash column chromatography (eluting solvent: pentane/MTBE = 4/1). Isomeric distribution was determined by 1H-NMR analysis of the crude reaction mixture by integration of the aromatic signals (s signal at 6.65 ppm, d signals at 6.59 ppm and 6.40 1 ppm, respectively for A isomer, B isomer). A isomer: H-NMR (300 MHz, CDCl 3): δ = 13 6.65 (s, 2H), 3.83 (s, 6H), 3.76 (br s, 2H). C-NMR (75 MHz, CDCl 3): δ = 147.9, 124.7, 130 Iron-catalyzed synthesis of unprotected primary amines
1 108.8, 107.8, 56.2. B isomer: H-NMR (300 MHz, CDCl 3): δ = 6.59 (d, J = 2.6 Hz, 1H), 6.40 (d, J = 2.6 Hz, 1H), 3.83 (s, 3H), 3.76 (br s, 2H), 3.73 (s, 3H). 13 C-NMR (75 MHz,
CDCl 3): δ = 152.5, 148.5, 129.0, 108.5, 107.6, 99.0, 56.0, 56.0. HR-MS (ESI+) calc. for + C8H11 N1O2Br 1 [M+H] 231.996779, found 231.996810. GC-MS analysis showed presence of two distinct peaks, both with mass of 231.0 [M] +. Theirs characterization data were matching the ones found in literature. 164
5,6,7,8-Tetrahydronaphthalen-1-amine ( A isomer), 5,6,7,8-tetrahydronaphthalen-2- amine ( B isomer), Table 7, Entry 15
were prepared from commercially available 1,2,3,4-tetrahydronaphthalene according to general procedure (B) to afford the desired products as an orange oil in 71% isolated yield (52.5 mg, 0.357 mmol, mixture of isomers: 1.0:2.4) after flash column chromatography (eluting solvent: pentane/MTBE = 3/1). Isomeric distribution was determined by 1H-NMR analysis of the crude reaction mixture by integration of the aromatic signals (t signal at 6.96 ppm, d signal at 6.88 ppm, respectively for A isomer, B 1 isomer). A isomer: H-NMR (300 MHz, CDCl 3): δ = 6.96 (t, J = 7.7 Hz, 1H), 6.61 – 6.51 (m, 2H), 3.43 (br s, 2H), 2.77 (d, J = 6.4 Hz, 2H), 2.47 (t, J = 6.4 Hz, 2H), 1.95 – 1.82 (m, 13 2H), 1.81 – 1.73 (m, 2H). C-NMR (75 MHz, CDCl 3): δ = 144.4, 138.2, 126.0, 121.9, 1 119.7, 113.3, 30.1, 24.2, 23.2, 22.9. B isomer: H-NMR (300 MHz, CDCl 3): δ = 6.88 (d, J = 8.0 Hz, 1H), 6.49 (dd, J = 8.0, 2.4 Hz, 1H), 6.44 (d, J = 2.4 Hz, 1H), 3.43 (br s, 2H), 13 2.73 – 2.65 (m, 4H), 1.81 – 1.73 (m, 4H). C-NMR (75 MHz, CDCl 3): δ = 144.0, 138.0, 130.0, 127.5, 115.6, 112.2, 29.6, 28.7, 23.7, 23.4. Theirs characterization data were matching the ones found in literature. 165
164 S. Samanta, A. A. Beharry, O. Sadovski, T. M. McCormick, A. Babalhavaeji, V. Tropepe, G. A. Woolley, J. Am. Chem. Soc. 2013 , 135 , 9777-9784 (A isomer). 165 (a) F. Nador, Y. Moglie, C. Vitale, M. Yus, F. Alonso, G. Radivoy, Tetrahedron 2010 , 66 , 4318-4325 ( A isomer). (b) L. M. Stock, M. R. Wasielewski, J. Am. Chem. Soc. 1977 , 99 , 50-59 ( B isomer). 5. Experimental part 131
2,3-Dihydrobenzofuran-7-amine ( A isomer), 2,3-dihydrobenzofuran-5-amine ( B isomer), 2,3-dihydrobenzofuran-4-amine ( C isomer), Table 7, Entry 16
were prepared from commercially available 2,3-dihydrobenzofuran according to general procedure (B) to afford the desired products separated in column chromatography (eluting solvent: pentane/MTBE = 2/1 to 1/1): A isomer (orange solid, 11% isolated yield, 7.3 mg, 0.054 mmol), B isomer (orange solid, 72% isolated yield, 48.4 mg, 0.358 mmol), C isomer (orange solid, 5% isolated yield, 3.6 mg, 0.027 mmol). Isomeric distribution was determined on the amount of the isolated products. A isomer, B isomer and C isomer could be separated from the mixture via column chromatography. A isomer: 1H-
NMR (300 MHz, CDCl 3): δ = 6.76 – 6.62 (m, 2H), 6.61 – 6.47 (m, 1H), 4.57 (t, J = 8.6 13 Hz, 2H), 3.42 (br s, 2H), 3.20 (t, J = 8.6 Hz, 2H). C-NMR (75 MHz, CDCl 3): δ = 130.6, + 130.1, 126.8, 121.2, 115.1, 114.8, 71.3, 30.7. HR-MS (ESI+) calc. for C 8H10 N1O1 [M+H] 1 136.075689, found 136.075620. B isomer: H-NMR (300 MHz, CDCl 3): δ = 6.65 – 6.55 (m, 2H), 6.49 – 6.43 (m, 1H), 4.49 (t, J = 8.6 Hz, 2H), 3.27 (br s, 2H), 3.13 (t, J = 8.6 Hz, 13 2H). C-NMR (75 MHz, CDCl 3): δ = 153.3, 140.0, 127.9, 114.8, 112.9, 109.5, 71.0, + 30.4. HR-MS (ESI+) calc. for C 8H10 N1O1 [M+H] 136.075689, found 136.075590. C 1 isomer: H-NMR (300 MHz, CDCl 3): δ = 6.95 (dt, J = 8.4, 1.0 Hz, 1H), 6.29 – 6.12 (m, 2H), 4.53 (t, J = 8.6 Hz, 2H), 3.70 (br s, 2H), 3.13 – 3.06 (m, 2H). 13 C-NMR (125 MHz,
CDCl 3): δ = 161.2, 146.8, 125.1, 116.8, 107.2, 97.1, 71.7, 29.1. HR-MS (ESI+) calc. for + C8H10 N1O1 [M+H] 136.075689, found 136.075660. Theirs characterization data were matching the ones found in literature. 166
166 (a) Novartis AG; Novartis Pharma GMBH. Patent: WO2004/80980 A1, 2004 ( A isomer). (b) R. A. Hartz, V. T. Ahuja, M. Rafalski, W. D. Schmitz, A. B. Brenner, D. J. Denhart, J. L. Ditta, J. A. Deskus, E. W. Yue, A. G. Arvanitis, S. Lelas, Y.-W. Li, T. F. Molski, H. Wong, J. E. Grace, K. A. Lentz, J. Li, N. J. Lodge, R. Zaczek, A. P. Combs, R. E. Olson, R. J. Mattson, J. J. Bronson, J. E. Macor, J. Med. Chem. 2009 , 52 , 4161-4172 ( B isomer). (c) Kyoto University; National University Corporation Tokyo Medical and Dental 132 Iron-catalyzed synthesis of unprotected primary amines
Dibenzo[ b,d ]furan-4-amine ( A isomer), dibenzo[ b,d ]furan-1-amine ( D isomer), dibenzo[ b,d ]furan-3-amine ( B isomer), dibenzo[ b,d ]furan-2-amine ( C isomer), Table 7, Entry 17
were prepared from commercially available dibenzo[ b,d]furan according to general procedure (B), weighing the starting material into the vial containing Fe(II) sulfate heptahydrate and the reagent MsONH 3OTf and using a mixture of MeCN/H 2O = 4/1 (1.5 mL), to afford the desired products separated in column chromatography (eluting solvent: pentane/EtOAc = 3/1 to 1/1): A isomer and D isomer (white solid, 8% isolated yield, 7.4 mg, 0.040 mmol, mixture of isomers: 1.0:1.0), B isomer (white solid, 29% isolated yield, 26.7 mg, 0.146 mmol), C isomer (white solid, 24% isolated yield, 22.0 mg, 0.120 mmol). Isomeric distribution was determined on the amount of the isolated products. A isomer and D isomer distribution was determined by 1H-NMR analysis by integration of the m signal at 7.94 – 7.90 ppm and of the ddd signal at 7.84 ppm, respectively. A isomer and D isomer were isolated as a single fraction. B isomer and C isomer could be separated from the mixture via column chromatography. A isomer: 1H-
NMR (500 MHz, CDCl 3): δ = 7.94 – 7.90 (m, 1H), 7.58 – 7.54 (m, 1H), 7.48 – 7.32 (m, 3H), 7.16 (t, J = 7.6 Hz, 1H), 6.83 (dd, J = 7.6, 1.0 Hz, 1H), 4.19 (br s, 2H). 13 C-NMR
(125 MHz, CDCl 3): δ = 156.1, 145.0, 132.0, 127.0, 125.1, 124.7, 123.6, 122.7, 121.1, 1 113.1, 111.8, 110.7. D isomer: H-NMR (500 MHz, CDCl 3): δ = 7.84 (ddd, J = 7.6, 1.4, 0.8 Hz, 1H), 7.58 – 7.54 (m, 1H), 7.48 – 7.32 (m, 2H), 7.29 – 7.24 (m, 1H), 7.02 (dd, J = 8.1, 0.8 Hz, 1H), 6.64 (dd, J = 7.8, 0.8 Hz, 1H), 4.19 (br s, 2H). 13 C-NMR (125 MHz,
CDCl 3): δ = 157.5, 155.6, 142.6, 128.2, 126.9, 125.9, 124.0, 122.8, 120.8, 111.5, 109.2, + 102.1. HR-MS (ESI+) calc. for C 12 H10 N1O1 [M+H] 184.075689, found 184.075600. GC- MS analysis showed presence of two distinct peaks, both with mass of 183.0 [M] +. B
University; Kinopharma, Inc.; HAGIWARA, Masatoshi; ONOGI, Hiroshi; KII, Isao; HOSOYA, Takamitsu; SUMIDA, Yuto. Patent: EP2881397 A1, 2015 ( C isomer). 5. Experimental part 133
1 isomer: H-NMR (500 MHz, CDCl 3): δ = 7.79 (ddd, J = 7.4, 1.4, 0.6 Hz, 1H), 7.69 (dd, J = 8.2, 0.6 Hz, 1H), 7.48 (dt, J = 8.0, 0.8 Hz, 1H), 7.32 (ddd, J = 8.2, 7.4, 1.4 Hz, 1H), 7.26 (s, 1H), 6.85 (dd, J = 2.0, 0.6 Hz, 1H), 6.69 (dd, J = 8.2, 2.0 Hz, 1H), 3.91 (br s, 13 2H). C-NMR (125 MHz, CDCl 3): δ = 158.1, 156.1, 146.9, 125.3, 125.0, 122.7, 121.4, + 119.4, 115.8, 111.4, 111.3, 97.6. HR-MS (ESI+) calc. for C 12 H10 N1O1 [M+H] 1 184.075689, found 184.075600. C isomer: H-NMR (500 MHz, CDCl 3): δ = 7.86 (d, J = 7.6 Hz, 1H), 7.53 – 7.49 (m, 1H), 7.42 (ddd, J = 8.4, 7.2, 1.4 Hz, 1H), 7.36 (d, J = 8.6 Hz, 1H), 7.29 (td, J = 7.6, 1.0 Hz, 1H), 7.24 (d, J = 2.4 Hz, 1H), 6.83 (dd, J = 8.6, 2.4 Hz, 13 1H), 3.62 (br s, 2H). C-NMR (125 MHz, CDCl 3): δ = 156.9, 150.5, 142.2, 127.1, 125.0,
124.5, 122.4, 120.7, 115.9, 112.1, 111.8, 106.1. HR-MS (ESI+) calc. for C 12 H10 N1O1 [M+H] + 184.075689, found 184.075650. Assignment of isomers and of 13 C-NMR signals through COSY, HSQC, HMBC spectra. Theirs characterization data were matching the ones found in literature. 46,167
Methyl 7-amino-1H-indole-3-carboxylate ( A isomer), methyl 6-amino-1H-indole-3- carboxylate ( B isomer), methyl 5-amino-1H-indole-3-carboxylate ( C isomer), Table 7, Entry 18
were prepared from commercially available methyl 1H-indole-3-carboxylate according to general procedure (B), weighing the starting material into the vial containing Fe(II) sulfate heptahydrate and the reagent MsONH 3OTf to afford the desired products as an orange solid in 33% isolated yield (31.1 mg, 0.164 mmol, mixture of isomers: 1.0:2.3:1.6) after flash column chromatography (eluting solvent: pentane/EtOAc = 2/1 to EtOAc). Isomeric distribution was determined by 1H-NMR analysis of the isolated products
167 (a) W. Li, J. Li, Y. Wu, J. Wu, R. Hotchandani, K. Cunningham, I. McFadyen, J. Bard, P. Morgan, F. Schlerman, X. Xu, S. Tam, S. J. Goldman, C. Williams, J. Sypek, T. S. Mansour, J. Med. Chem. 2009 , 52 , 1799-1802 ( B isomer). (b) L. W. Deady, R. M. D. Sette, Aust. J. Chem. 2001 , 54 , 177-180 (C isomer). 134 Iron-catalyzed synthesis of unprotected primary amines mixture by integration of the d signal at 8.01 ppm, of the d signal at 7.73 ppm and of the d signal at 7.83 ppm, respectively for A isomer, B isomer, C isomer. A isomer: 1H-NMR
(300 MHz, DMSO-d6): δ = 11.49 (br s, 1H), 8.01 (d, J = 3.2 Hz, 1H), 7.27 – 7.22 (m, 1H), 6.89 (t, J = 7.6 Hz, 1H), 6.42 (dd, J = 7.6, 1.0 Hz, 1H), 4.90 (br s, 2H), 3.78 (s, 3H). 13 C-
NMR (75 MHz, DMSO-d6): δ = 165.0, 134.3, 131.0, 126.5, 125.7, 108.6, 105.9, 122.4, 1 106.6, 50.5. B isomer: H-NMR (300 MHz, DMSO-d6): δ = 11.32 (br s, 1H), 7.73 (d, J = 3.0 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H), 6.62 (dd, J = 2.0, 0.8 Hz, 1H), 6.59 – 6.51 (m, 1H), 13 4.90 (br s, 2H), 3.75 (s, 3H). C-NMR (75 MHz, DMSO-d6): δ = 165.0, 144.9, 138.1, 1 129.7, 120.6, 117.0, 111.7, 106.4, 95.5, 50.4. C isomer: H-NMR (300 MHz, DMSO-d6): δ = 11.49 (br s, 1H), 7.83 (d, J = 3.0 Hz, 1H), 7.19 (d, J = 2.0 Hz, 1H), 7.15 (dd, J = 8.6, 0.6 Hz, 1H), 6.59 – 6.51 (m, 1H), 4.90 (br s, 2H), 3.76 (s, 3H). 13 C-NMR (75 MHz,
DMSO-d6): δ = 165.0, 143.4, 131.4, 129.5, 127.0, 112.6, 112.4, 104.9, 103.5, 50.3. HR- + MS (APPI+) calc. for C 10 H10 N2O2 [M] 190.073677, found 190.073420. GC-MS analysis showed presence of three distinct peaks, all of them with mass of 190.0 [M] +. Assignment of isomers and of 13 C-NMR signals through COSY, HSQC, HMBC spectra. Theirs characterization data were matching the ones found in literature. 168
5.3.4. Late stage functionalization
Methyl 2-(2'-amino-2-fluoro-[1,1'-biphenyl]-4-yl)propanoate ( A isomer), methyl 2- (3'-amino-2-fluoro-[1,1'-biphenyl]-4-yl)propanoate ( B isomer), methyl 2-(4'-amino-2- fluoro-[1,1'-biphenyl]-4-yl)propanoate ( C isomer), Scheme 61, 63
168 S. Castellano, A. Spannhoff, C. Milite, F. Dal Piaz, D. Cheng, A. Tosco, M. Viviano, A. Yamani, A. Cianciulli, M. Sala, V. Cura, J. Cavarelli, E. Novellino, A. Mai, M. T. Bedford, G. Sbardella, J. Med. Chem. 2012 , 55 , 9875-9890 ( C isomer). 5. Experimental part 135 were prepared from methyl 2-(2-fluoro-[1,1'-biphenyl]-4-yl)propanoate according to general procedure (B), in 0.45 mmol scale, to afford the desired products separated in column chromatography (eluting solvent: pentane/MTBE = 3/1 to 1/1): A isomer (yellow oil, 2% isolated yield, 1.9 mg, 0.007 mmol), B isomer and C isomer (yellow oil, 58% isolated yield, 71.4 mg, 0.261 mmol, mixture of isomers: 1.0:3.0). Isomeric distribution was determined on the amount of the isolated products. B isomer and C isomer distribution was determined by 1H-NMR analysis by integration of the aromatic signals (ddd signal at 6.70 ppm, m signal at 6.81 – 6.72 ppm, respectively for B isomer, C isomer). A isomer could be separated from the mixture via column chromatography. A 1 isomer: H-NMR (300 MHz, CDCl 3): δ = 7.33 (t, J = 7.8 Hz, 1H), 7.23 – 7.08 (m, 4H), 6.87 – 6.76 (m, 2H), 3.77 (q, J = 7.2 Hz, 1H), 3.71 (s, 3H), 3.66 (br s, 2H), 1.54 (d, J = 13 7.2 Hz, 3H). C-NMR (75 MHz, CDCl 3): δ = 174.6, 160.0 (d, J = 247.0 Hz), 144.1, 142.4 (d, J = 7.5 Hz), 132.2 (d, J = 4.2 Hz), 131.2, 129.3, 125.5 (d, J = 16.7 Hz), 123.9 (d, J = 3.4 Hz), 121.5, 118.8, 116.0, 115.3 (d, J = 23.4 Hz), 52.4, 45.1, 18.6. 19 F-NMR (280 + MHz, CDCl 3): δ = -113.85. HR-MS (APPI+) calc. for C 16 H16 N1O2F1 [M] 273.115957, 1 found 273.115920. B isomer: H-NMR (300 MHz, CDCl 3): δ = 7.43 – 7.29 (m, 1H), 7.25 – 7.18 (m, 1H), 7.17 – 7.02 (m, 2H), 6.92 (dtd, J = 7.6, 1.6, 1.0 Hz, 1H), 6.88 – 6.84 (m, 1H), 6.70 (ddd, J = 8.0, 2.4, 1.0 Hz, 1H), 3.84 – 3.71 (m, 1H), 3.70 (s, 3H), 3.70 (br s, 13 2H), 1.53 (d, J = 7.2 Hz, 3H). C-NMR (75 MHz, CDCl 3): δ = 174.6, 159.8 (d, J = 247.4 Hz), 146.5, 141.8 (d, J = 7.8 Hz), 136.7, 130.9 (d, J = 4.0 Hz), 129.5, 128.0 (d, J = 13.4 Hz), 123.5 (d, J = 3.2 Hz), 119.6, 115.9, 115.6 (d, J = 27.4 Hz), 114.7, 52.3, 45.0, 18.6. 19 1 F-NMR (280 MHz, CDCl 3): δ = -117.09. C isomer: H-NMR (300 MHz, CDCl 3): δ = 7.43 – 7.29 (m, 3H), 7.17 – 7.02 (m, 2H), 6.81 – 6.72 (m, 2H), 3.84 – 3.71 (m, 1H), 3.70 (s, 13 3H), 3.70 (br s, 2H), 1.52 (d, J = 7.2 Hz, 3H). C-NMR (75 MHz, CDCl 3): δ = 174.7, 159.8 (d, J = 247.4 Hz), 146.1, 140.8 (d, J = 7.8 Hz), 130.5, 130.4 (d, J = 4.2 Hz), 130.0 (d, J = 3.2 Hz), 125.7 (d, J = 1.2 Hz), 119.5, 115.3 (d, J = 24.0 Hz), 115.1, 52.3, 45.0, 19 18.6. F-NMR (280 MHz, CDCl 3): δ = -117.79. HR-MS (APPI+) calc. for C 16 H16 N1O2F1 [M] + 273.115957, found 273.116060. GC-MS analysis showed presence of two distinct peaks, both with mass of 273.0 [M] +. Assignment of isomers and of 13 C-NMR signals 136 Iron-catalyzed synthesis of unprotected primary amines through COSY, HSQC, HMBC spectra. Theirs characterization data were matching the ones found in literature. 169
4-Amino-17β-estradiol-3-methyl ether ( A isomer), 2-amino-17ß-estradiol-3-methyl ether ( B isomer), Scheme 61, 64
Me OH
H H2N H H MeO were prepared from 17β-estradiol-3-methyl ether according to general procedure (B), in 0.40 mmol scale, weighing the starting material into the vial containing Fe(II) sulfate heptahydrate and an increased amount of MsONH 3OTf (261.2 mg, 1.0 mmol) to afford the desired products separated in column chromatography (eluting solvent: pentane/EtOAc = 4/1 to 1/1): A isomer (white solid, 16% isolated yield, 19.6 mg, 0.065 mmol), B isomer (white solid, 28% isolated yield, 34.3 mg, 0.114 mmol). Isomeric distribution was determined on the amount of the isolated products. A isomer and B isomer could be separated from the mixture via column chromatography. A isomer: 1H-
NMR (300 MHz, CDCl 3): δ = 6.75 (dd, J = 8.4, 1.0 Hz, 1H), 6.69 (d, J = 8.4 Hz, 1H), 3.84 (s, 3H), 3.73 (t, J = 8.0 Hz, 1H), 3.63 (br s, 3H), 2.63 (dd, J = 16.4, 5.6 Hz, 1H), 2.55 – 2.43 (m, 1H), 2.35 – 1.91 (m, 5H), 1.76 – 1.67 (m, 1H), 1.55 – 1.23 (m, 7H), 0.77 (s, 3H). 13 C-NMR (75 MHz, CDCl 3): δ = 145.1, 133.5, 133.5, 121.8, 114.7, 107.9, 82.1, 55.8, 50.2, 44.3, 43.3, 38.3, 36.9, 30.8, 27.2, 26.6, 24.8, 23.3, 11.1. HR-MS (ESI+) calc. for + 1 C19 H28 N1O2 [M+H] 302.211454, found 302.211180. B isomer: H-NMR (300 MHz,
CDCl 3): δ = 6.69 (s, 1H), 6.51 (s, 1H), 3.82 (s, 3H), 3.71 (t, J = 8.0 Hz, 1H), 2.88 – 2.70 (m, 2H), 2.80 (br s, 3H), 2.27 – 2.05 (m, 3H), 1.96 – 1.83 (m, 2H), 1.74 – 1.64 (m, 1H), 13 1.54 – 1.13 (m, 7H), 0.78 (s, 3H). C-NMR (75 MHz, CDCl 3): δ = 145.8, 133.8, 132.6, 126.7, 112.6, 111.2, 82.1, 55.7, 50.2, 44.2, 43.4, 39.1, 36.9, 30.8, 29.4, 27.7, 26.6, 23.3,
169 M. Migliore, D. Habrant, O. Sasso, C. Albani, S. M. Bertozzi, A. Armirotti, D. Piomelli, R. Scarpelli, Eur. J. Med. Chem. 2016 , 109 , 216-237 ( B isomer). 5. Experimental part 137
+ 11.2. HR-MS (ESI+) calc. for C 19 H28 N1O2 [M+H] 302.211454, found 302.211150. Theirs characterization data were matching the ones found in literature. 170
4-Amino-dextromethorphan, Scheme 61, 65
was prepared from dextromethorphan according to general procedure (B), weighing the starting material into the vial containing Fe(II) sulfate heptahydrate and an increased amount of MsONH 3OTf (326.5 mg, 1.25 mmol) to afford the desired product as a white solid in 51% isolated yield (73.1 mg, 0.255 mmol) after flash column chromatography 1 (eluting solvent: DCM/MeOH/TEA = 100/10/1). H-NMR (500 MHz, CDCl 3): δ = 6.62 (s, 1H), 6.46 (s, 1H), 3.80 (s, 3H), 3.66 (br s, 2H), 2.87 (d, J = 18.2 Hz, 1H), 2.81 (dd, J = 5.8, 3.2 Hz, 1H), 2.55 (dd, J = 18.0, 6.6 Hz, 1H), 2.47 (ddd, J = 11.8, 5.0, 2.0 Hz, 1H), 2.40 (s, 3H), 2.31 – 2.25 (m, 1H), 2.19 – 2.13 (m, 1H), 1.83 (dt, J = 12.8, 3.2 Hz, 1H), 1.73 (td, J = 12.8, 4.8 Hz, 1H), 1.65 – 1.60 (m, 1H), 1.52 – 1.47 (m, 1H), 1.39 – 1.28 (m, 13 5H), 1.19 – 1.11 (m, 1H). C-NMR (125 MHz, CDCl 3): δ = 146.7, 133.8, 129.9, 129.7, 114.3, 107.4, 58.5, 55.8, 47.6, 45.3, 42.8, 41.9, 36.8, 36.6, 26.7, 26.7, 23.8, 22.3. HR- + MS (ESI+) calc. for C 18 H27 N2O1 [M+H] 287.211787, found 287.211960.
170 M. D. Hylarides, A. A. Leon, F. A. Mettler, D. S. Wilbur, J. Org. Chem. 1984 , 49 , 2744-2745. 138 Iron-catalyzed synthesis of unprotected primary amines
5.3.5. Mechanistic experiments
Intermolecular competition experiment, Scheme 62
A screw-cap vial charged with Fe(II) sulfate heptahydrate (7.0 mg, 0.025 mmol),
MsONH 3OTf (130.6 mg, 0.50 mmol) as limiting reagent and a stirring bar, was evacuated and refilled 3 times with Ar, and was finally equipped with an Ar-filled balloon.
MeCN/H 2O (1.5 mL, MeCN/H 2O = 2/1, degassed through Ar purging) was subsequently added to the vial, followed by a R 1-4-methylarene (2.5 mmol) and a R2-4-methylarene (2.5 mmol). After stirring for 16 h at 25 °C, the reaction mixture was diluted with an aqueous solution of NaOH 1.0 M (15 mL) and extracted with DCM (3 x 15 mL). The combined organic phases were dried over Na 2SO 4, filtered, and concentrated in vacuo . The ratio of the corresponding products was determined by 1H-NMR analysis of the st crude reaction mixture using nitromethane as analytical standard in CDCl 3. 1 experiment: 1-methoxy-4-methylbenzene (R1: MeO, 305.4 mg, 2.5 mmol) vs p -xylene nd (R2: Me, 265.4 mg, 2.5 mmol) resulted in a products mixture ratio of 2.1/1.0. 2 experiment: p-xylene (R1: Me, 265.4 mg, 2.5 mmol) vs 1-bromo-4-methylbenzene (R2: Br, 427.6 mg, 2.5 mmol) resulted in a products mixture ratio of 16.7/1.0. 3rd experiment:
1-methoxy-4-methylbenzene (R1: MeO, 305.4 mg, 2.5 mmol) vs 1-bromo-4- methylbenzene (R2: Br, 427.6 mg, 2.5 mmol) only products arising from amination of 1- methoxy-4-methylbenzene were detected.
5. Experimental part 139
Intermolecular competition experiment between benzene and benzene-d6, Scheme 63
A screw-cap vial charged with Fe(II) sulfate heptahydrate (7.0 mg, 0.025 mmol),
MsONH 3OTf (130.6 mg, 0.50 mmol) as limiting reagent and a stirring bar, was evacuated and refilled 3 times with Ar, and was finally equipped with an Ar-filled balloon.
MeCN/H 2O (1.5 mL, MeCN/H 2O = 2/1, degassed through Ar purging) was subsequently added to the vial, followed by benzene (390.6 mg, 5.0 mmol) and benzene-d6 (420.4 mg, 5.0 mmol). After stirring for 16 h at 25 °C, the reaction mixture was diluted with an aqueous solution of NaOH 1.0 M (15 mL) and extracted with DCM (3 x 15 mL). The combined organic phases were dried over Na 2SO 4, filtered, and concentrated in vacuo .
To the crude mixture, dissolved in DCM (1.5 mL), Ac2O (473 µL, 5.0 mmol) was added and the mixture was stirred for 2 h at 25 °C until full conversion was obtained as verified by TLC. The reaction mixture was then diluted with saturated aqueous NaHCO 3 (15 mL) and extracted with DCM (3 x 15 mL). The combined organic phases were dried over
Na 2SO 4, filtered, and concentrated in vacuo . The crude product was purified via flash column chromatography (eluting solvent: pentane/EtOAc = 2/1 to 1/1) to afford the desired products as a mixture of N-phenylacetamide/ N-phenylacetamide-d5 = 1.0/1.0. The amount of the two products were determined by 1H-NMR analysis of the isolated products mixture by integration of the aromatic signals (m signals at 7.53 – 7.45 ppm, 7.37 – 7.21 ppm, 7.15 – 7.03 ppm) and compared with the integrated signal of –
NHCO CH 3 (s signal at 2.16 ppm). The products mixture ratio resulted as an average of 1 three runs of the same experiment. H-NMR (300 MHz, CDCl 3): δ = 7.62 (br s, 2H), 7.53 – 7.45 (m, 2H), 7.37 – 7.21 (m, 2H), 7.15 – 7.03 (m, 1H), 2.16 (s, 6H). 13 C-NMR (75 140 Iron-catalyzed synthesis of unprotected primary amines
MHz, CDCl 3): δ = 168.7, 138.1, 129.1, 124.4, 120.1, 24.7. Characterization data of products were matching the ones found in literature. 171
Mechanistic control experiments – use of Fe 2(SO 4)3 as catalyst, Scheme 64a
A screw-cap vial charged with Fe(III) sulfate (2.0 mg, 0.005 mmol), MsONH 3OTf (62.7 mg, 0.24 mmol) and a stirring bar, was evacuated and refilled 3 times with Ar, and was finally equipped with an Ar-filled balloon. MeCN/H 2O (0.6 mL, MeCN/H 2O = 2/1, degassed through Ar purging) was subsequently added to the vial, followed by commercially available benzene (17.9 µL, 0.2 mmol). After stirring for 16 h at 25 °C, the reaction mixture was diluted with an aqueous solution of NaOH 1.0 M (3 mL) and extracted directly in the vial with EtOAc (4 mL). The yields of the corresponding products were determined by GC analysis of the organic layer using tetradecane as analytical standard.
Mechanistic control experiments – use of azobisisobutyronitrile (AIBN) as radical initiator, Scheme 64b
A screw-cap vial charged with azobisisobutyronitrile (AIBN) (1.6 mg, 0.01 mmol),
MsONH 3OTf (62.7 mg, 0.24 mmol) and a stirring bar, was evacuated and refilled 3 times with Ar, and was finally equipped with an Ar-filled balloon. MeCN/H 2O (0.6 mL,
MeCN/H 2O = 2/1, degassed through Ar purging) was subsequently added to the vial, followed by commercially available benzene (17.9 µL, 0.2 mmol). After stirring for 16 h at 85 °C, the reaction mixture was diluted with an aqueous solution of NaOH 1.0 M (3 mL) and extracted directly in the vial with EtOAc (4 mL). The yields of the corresponding products were determined by GC analysis of the organic layer using tetradecane as analytical standard.
171 W. Zhou, W. Fan, Q. Jiang, Y.-F. Liang, N. Jiao, Org. Lett. 2015 , 17 , 2542-2545. 5. Experimental part 141
Mechanistic control experiments – use of benzoyl peroxide (BPO) as radical initiator, Scheme 64b
A screw-cap vial charged with benzoyl peroxide (BPO) (2.4 mg, 0.01 mmol),
MsONH 3OTf (62.7 mg, 0.24 mmol) and a stirring bar, was evacuated and refilled 3 times with Ar, and was finally equipped with an Ar-filled balloon. MeCN/H 2O (0.6 mL,
MeCN/H 2O = 2/1, degassed through Ar purging) was subsequently added to the vial, followed by commercially available benzene (17.9 µL, 0.2 mmol). After stirring for 16 h at 85 °C, the reaction mixture was diluted with an aqueous solution of NaOH 1.0 M (3 mL) and extracted directly in the vial with EtOAc (4 mL). The yields of the corresponding products were determined by GC analysis of the organic layer using tetradecane as analytical standard.
142 Iron-catalyzed synthesis of unprotected primary amines
5.4. Experimental part to chapter four (Direct synthesis of 2- chloroalkylamines from alkenes)
5.4.1. Synthesis of starting materials
4-(But-3-en-1-yl)morpholines , Table 10, Entry 16SM
was synthesized from morpholine and 4-brom-1-butene according to a known procedure. 172 Its characterization data were matching the ones found in literature. 173
(3 R,3a R,6 R,6a R)-3,6-Bis(pent-4-en-1-yloxy)hexahydrofuro[3,2-b]furan , Scheme 75, 73SM
was synthesized starting from 1,4:3,6-dianhydro-D-mannitol and 5-bromo-1-pentene 174 1 according to a known procedure. HNMR (500 MHz, CDCl 3): δ = 5.80 (ddt, J = 17.0, 10.2, 6.6 Hz, 2H), 5.04 – 4.94 (m, 4H), 4.53 (dd, J = 3.4, 1.6 Hz, 2H), 4.04 (dd, J = 8.2, 7.0 Hz, 2H), 4.01 – 3.97 (m, 2H), 3.70 – 3.62 (m, 4H), 3.46 (dt, J = 9.2, 6.8 Hz, 2H), 2.15 13 – 2.10 (m, 4H), 1.72 (dt, J = 8.0, 6.8 Hz, 4H). CNMR (125 MHz, CDCl 3): δ = 138.3, + 114.9, 80.8, 80.6, 71.2, 70.3, 30.3, 29.1. HR-MS (ESI+) calc. C16 H26 O4Na 1 [M+Na] 305.172329, found 305.172250.
172 Y. Liu, A. Maden, W. V. Murray, Tetrahedron 2002 , 58 , 3159-3170. 173 Patent: Isis Innovation Limited; N. Araujo, A. Ferreira Da Silva, Y. Qing, M. Lufino, A. J. Russell, B. Small, R. Wade-Martins, G. M. Wynne, - WO2015/4485, 2015, A1. Patent Family Members: GB201312499 D0; WO2015/4485 A1. 174 T. K. M. Shing, Y.-L. Zhong, Synlett 2006 , 8, 1205-1208. 5. Experimental part 143
((1 R* ,2 S* )-2-Vinylcyclopropyl)benzene , Scheme 78, 83
was synthesized starting from trans -2-phenylcyclopropane-1-carboxylic acid according to a known procedure. 121 Its characterization data were matching the ones found in literature.
N,N-Diallyl-4-methylbenzenesulfonamide , Scheme 79, 85
was synthesized from diallylamine and 4-toluenesulfonyl chloride according to a known procedure. 121 Its characterization data were matching the ones found in literature.
5.4.2. Experimental procedures
General procedure (A): deviation from standard conditions, Table 9
A screw-cap vial was charged with Fe(acac) 2 (2.5 mg, 0.01 mmol), NaCl (12.3 mg, 0.21 mmol), PivONH 3OTf (133.6 mg, 0.50 mmol) and a stirring bar. MeOH/DCM (200 µL, MeOH/DCM 3:1) was subsequently added to the vial, followed by commercially available dodecene (44.4 µL, 0.20 mmol). After stirring for 16 h at 25 °C, the reaction mixture was diluted with an aqueous solution of NaOH 1.0 M (1 mL) and stirred for 10 min. The water phase was then extracted directly in the vial with DCM (4 x 2 mL). The combined organic phases were dried over Na 2SO 4, filtered, and concentrated in vacuo . The yields of the corresponding products were determined by 1H-NMR analysis of the crude reaction mixture using nitromethane as an analytical standard.
144 Iron-catalyzed synthesis of unprotected primary amines
General procedure (B): substrate scope, Table 10
A screw-cap vial was charged with Fe(acac) 2 (6.4 mg, 0.025 mmol), NaCl (30.7 mg,
0.525 mmol), PivONH 3OTf (334.0 mg, 1.25 mmol) and a stirring bar. MeOH/DCM (500 µL, MeOH/DCM 3:1) was subsequently added to the vial, followed by the corresponding alkene substrate (0.50 mmol). After stirring for 16 h at 25 °C, the reaction mixture was diluted with an aqueous solution of NaOH 1.0 M (2.5 mL) and stirred for 10 min. The water phase was then extracted directly in the vial with DCM (4 x 5 mL). The combined organic phases were dried over Na 2SO 4, filtered, and concentrated in vacuo . The crude mixtures were directly purified via flash column chromatography to afford the desired products.
General procedure (C): substrate scope – isolation of aziridine products, Table 10
A screw-cap vial was charged with Fe(acac) 2 (6.4 mg, 0.025 mmol), NaCl (30.7 mg,
0.525 mmol), PivONH 3OTf (334.0 mg, 1.25 mmol) and a stirring bar. MeOH/DCM (500 µL, MeOH/DCM 3:1) was subsequently added to the vial, followed by the corresponding alkene substrate (0.50 mmol). After stirring for 16 h at 25 °C, the reaction mixture was diluted with an aqueous solution of NaOH 1.0 M (2.5 mL) and stirred for 1 h at 45 °C. The water phase was then extracted directly in the vial with DCM (4 x 5 mL). The combined organic phases were dried over Na 2SO 4, filtered, and concentrated in vacuo . The crude mixtures were directly purified via flash column chromatography to afford the desired products.
5.4.3. Substrate scope
2-Chlorododecan-1-amine , Table 10, Entry 1
was prepared from commercially available dodecene according to general procedure (B) on a 0.20 mmol scale to afford the desired product in 72% isolated yield (31.5 mg, 0.143 5. Experimental part 145 mmol) after flash column chromatography (DCM/MeOH 95:5). 1H-NMR (500 MHz,
CDCl 3): δ = 3.88 (tdd, J = 8.2, 5.3, 3.6 Hz, 1H), 2.98 (dd, J = 13.7, 3.6 Hz, 1H), 2.84 (dd, J = 13.7, 7.8 Hz, 1H), 1.77 – 1.63 (m, 4H), 1.59 – 1.46 (m, 1H), 1.44 – 1.35 (m, 1H), 13 1.32 – 1.24 (m, 14H), 0.87 (t, J = 6.9 Hz, 3H). C-NMR (125 MHz, CDCl 3): δ = 67.2, 49.0, 35.8, 32.0, 29.7, 29.7, 29.6, 29.5, 29.3, 26.6, 22.8, 14.2. HR-MS (ESI+) calc. for + C12 H27 Cl 1N1 [M+H] 220.182652, found 220.182790.
6-Amino-5-chlorohexan-1-ol, Table 10, Entry 2
was prepared from commercially available hex-5-en-1-ol according to general procedure (B), using only MeOH as solvent, to afford the desired product in 68% isolated yield (51.5 mg, 0.340 mmol) after flash column chromatography (DCM/MeOH 95:5 to 80:20). 1 H-NMR (500 MHz, CDCl 3): δ = 3.89 (tt, J = 8.4, 4.3 Hz, 1H), 3.64 (t, J = 6.2 Hz, 2H), 2.98 (dd, J = 13.7, 3.7 Hz, 1H), 2.85 (dd, J = 13.7, 7.7 Hz, 1H), 1.76 – 1.71 (m, 4H), 1.66 13 – 1.46 (m, 5H). C-NMR (125 MHz, CDCl 3): δ = 66.9, 62.5, 48.9, 35.5, 32.3, 22.9. HR- + MS (ESI+) calc. for C 6H15 Cl 1N1O1 [M+H] 152.083667, found 152.083680.
2,6-Dichlorohexan-1-amine, Table 10, Entry 3
Cl NH Cl 2 was prepared from commercially available 6-chlorohex-1-ene according to general procedure (B) to afford the desired product in 71% isolated yield (60.0 mg, 0.353 mmol) 1 after flash column chromatography (DCM/MeOH 95:5). H-NMR (500 MHz, CDCl 3): δ = 3.89 (tt, J = 8.2, 4.1 Hz, 1H), 3.54 (t, J = 6.5 Hz, 2H), 3.00 (dd, J = 13.7, 3.7 Hz, 1H), 2.86 (dd, J = 13.7, 7.8 Hz, 1H), 1.87 (s, 2H), 1.83 – 1.69 (m, 5H), 1.62 – 1.53 (m, 1H). 13 C-NMR (125 MHz, CDCl 3): δ = 66.4, 48.9, 44.8, 35.0, 32.2, 24.0. HR-MS (ESI+) calc. + for C 6H14 Cl 2N1 [M+H] 170.049780, found 170.049770.
146 Iron-catalyzed synthesis of unprotected primary amines
6-Bromo-2-chlorohexan-1-amine, Table 10, Entry 4
was prepared from commercially available 6-bromohex-1-ene according to general procedure (B) to afford the desired product in 64% isolated yield (69.0 mg, 0.322 mmol) after flash column chromatography (DCM/MeOH 95:5). 1H-NMR (500 MHz, Methylene
Chloride-d2): δ = 3.89 (tt, J = 8.1, 4.1 Hz, 1H), 3.44 (t, J = 6.7 Hz, 2H), 2.96 (dd, J = 13.8, 3.8 Hz, 1H), 2.83 (dd, J = 13.7, 7.5 Hz, 1H), 1.94 – 1.64 (m, 7H), 1.60 – 1.52 (m, 13 1H). C-NMR (125 MHz, Methylene Chloride-d2): δ = 67.4, 49.4, 35.2, 34.2, 32.9, 25.7. + HR-MS (ESI+) calc. for C 6H14 N1Br 1Cl 1 [M+H] 213.999277, found 213.999510.
7-Amino-6-chloroheptanenitrile, Table 10, Entry 5
was prepared from commercially available 6-heptenenitrile according to general procedure (B) to afford the desired product in 79% isolated yield (63.0 mg, 0.393 mmol) 1 after flash column chromatography (DCM/MeOH 95:5). H-NMR (500 MHz, CDCl 3): δ = 3.93 – 3.84 (m, 1H), 3.00 (dd, J = 14.0, 3.8 Hz, 1H), 2.88 (dd, J = 13.7, 7.7 Hz, 1H), 2.37 13 (t, J = 6.8 Hz, 2H), 1.82 – 1.67 (m, 7H), 1.63 – 1.55 (m, 1H). C-NMR (125 MHz, CDCl 3): + δ = 119.5, 66.0, 48.9, 34.9, 25.8, 25.1, 17.3. HR-MS (ESI+) calc. for C7H14 Cl 1N2 [M+H] 161.084000, found 161.084020.
3-(Benzyloxy)-2-chloropropan-1-amine, Table 10, Entry 6
Cl BnO NH 2 was prepared from commercially available allyl-benzyl-ether according to general procedure (B) to afford the desired product in 58% isolated yield (58.0 mg, 0.290 mmol) 1 after flash column chromatography (DCM/MeOH 95:5). H-NMR (500 MHz, CDCl 3): δ = 5. Experimental part 147
7.38 – 7.28 (m, 5H), 4.57 (s, 2H), 4.04 (tdd, J = 6.9, 5.5, 3.9 Hz, 1H), 3.73 – 3.61 (m, 2H), 3.13 (d, J = 13.9 Hz, 1H), 2.97 (dd, J = 14.2, 6.9 Hz, 1H), 1.53 (br, 2H). 13 C-NMR
(125 MHz, CDCl 3): δ = 137.8, 128.6, 128.0, 127.8, 73.5, 71.7, 62.8, 45.9. HR-MS (ESI+) + calc. for C 10 H15 Cl 1N1O1 [M+H] 200.083667, found 200.083660.
2-Chloro-3-ethoxypropan-1-amine, Table 10, Entry 7
was prepared from commercially available allyl-ethylether according to general procedure (B) to afford the desired product in 57% isolated yield (39.0 mg, 0.283 mmol) 1 after flash column chromatography (DCM/MeOH 93:7). H-NMR (500 MHz, CDCl 3): δ = 4.00 (tdd, J = 6.9, 5.5, 3.9 Hz, 1H), 3.66 – 3.59 (m, 2H), 3.53 (qd, J = 7.0, 2.2 Hz, 2H), 3.11 (dd, J = 13.9, 3.9 Hz, 1H), 2.93 (dd, J = 13.9, 7.0 Hz, 1H), 1.63 (br, 2H), 1.20 (t, J = 13 7.0 Hz, 3H). C-NMR (125 MHz, CDCl 3): δ = 72.4, 67.1, 62.7, 46.0, 15.2. HR-MS (ESI+) + calc. for C 5H13 Cl 1N1O1 [M+H] 138.068017, found 138.068040.
2-Chloro-2-cyclohexylethan-1-amine, Table 10, Entry 8
was prepared from commercially available ethenylcyclohexane according to general procedure (B) to afford the desired product in 75% isolated yield (61.0 mg, 0.377 mmol) 1 after flash column chromatography (DCM/MeOH 94:6). H-NMR (500 MHz, CDCl 3): δ = 3.76 (ddd, J = 8.7, 5.5, 3.4 Hz, 1H), 3.00 (dd, J = 13.7, 3.4 Hz, 1H), 2.90 (dd, J = 13.8, 8.6 Hz, 1H), 1.87 – 1.82 (m, 1H), 1.78 – 1.70 (m, 5H), 1.68 – 1.62 (m, 2H), 1.29 – 1.09 13 (m, 5H). C-NMR (125 MHz, CDCl 3): δ = 73.1, 46.4, 42.3, 30.3, 29.0, 26.3, 26.3, 26.1.
HR-MS (EI) calc. for C 8H16 Cl 1N1 [M] 161.096577, found 161.096577.
148 Iron-catalyzed synthesis of unprotected primary amines
2-Chloro-3,3-dimethylbutan-1-amine, Table 10, Entry 9
Cl NH t-Bu 2 was prepared on a 0.20 mmol scale from commercially available 3,3-dimethylbut-1-ene according to general procedure (B) to afford the desired product in 55% isolated yield (15.0 mg, 0.111 mmol) after flash column chromatography (DCM/MeOH 95:5). 1H-NMR
(500 MHz, CDCl 3): δ = 3.70 (dd, J = 10.6, 2.3 Hz, 1H), 3.12 (d, J = 13.5 Hz, 1H), 2.78 13 (dd, J = 13.5, 10.6 Hz, 1H), 1.85 (br, 2H), 1.03 (s, 9H). C-NMR (125 MHz, CDCl 3): δ =
78.9, 44.8, 35.5, 27.1. HR-MS (EI) calc. for C 6H14 Cl 1N1 [M] 135.080927, found 135.080910.
2-Chloro-3-phenylpropan-1-amine, Table 10, Entry 10
was prepared from commercially available allylbenzene according to general procedure (B) to afford the desired product in 68% isolated yield (58.0 mg, 0.342 mmol) after flash 1 column chromatography (DCM/MeOH 94:6). H-NMR (500 MHz, CDCl 3): δ = 7.33 – 7.30 (m, 2H), 7.27 – 7.21 (m, 3H), 4.11 (qd, J = 7.3, 3.5 Hz, 1H), 3.06 (dd, J = 7.1, 1.8 Hz, 2H), 3.02 (dd, J = 13.8, 3.5 Hz, 1H), 2.85 (dd, J = 13.8, 7.7 Hz, 1H), 1.76 (br, 2H). 13 C-
NMR (125 MHz, CDCl 3): δ = 137.6, 129.4, 128.7, 127.0, 66.8, 48.0, 42.3. HR-MS (ESI+) + calc. for C 9H13 Cl 1N1 [M+H] 170.073102, found 170.073330.
2-Chloro-3-(4-fluorophenyl)propan-1-amine, Table 10, Entry 11
was prepared from commercially available 1-allyl-4-fluorbenzene according to general procedure (B) to afford the desired product in 69% isolated yield (65.0 mg, 0.346 mmol) 1 after flash column chromatography (DCM/MeOH 93:7). H-NMR (500 MHz, CDCl 3): δ = 5. Experimental part 149
7.20 – 7.15 (m, 2H), 7.03 – 6.97 (m, 2H), 4.05 (tdd, J = 7.7, 6.2, 3.6 Hz, 1H), 3.09 – 2.96 13 (m, 3H), 2.85 (dd, J = 13.7, 7.6 Hz, 1H), 1.51 (br, 2H). C-NMR (125 MHz, CDCl 3): 162.0 (d, J = 245.2 Hz), 133.3 (d, J = 3.2 Hz), 130.9 (d, J = 7.9 Hz), 115.5 (d, J = 21.2 + Hz), 66.8, 48.1, 41.4. HR-MS (ESI+) calc. for C 9H12 Cl 1N1F1 [M+H] 188.063680, found 188.063660.
3-(2-bromophenyl)-2-chloropropan-1-amine, Table 10, Entry 12
was prepared from commercially available 1-allyl-2-bromobenzene according to general procedure (B) to afford the desired product in 65% isolated yield (80.3 mg, 0.325 mmol) 1 after flash column chromatography (DCM/MeOH 95:5). H-NMR (500 MHz, CDCl 3): δ 7.55 (dd, J = 7.9, 1.1 Hz, 1H), 7.31 – 7.24 (m, 2H), 7.13 (ddd, J = 7.9, 7.0, 2.2 Hz, 1H), 4.23 (tdd, J = 7.9, 5.9, 3.6 Hz, 1H), 3.27 (dd, J = 14.1, 5.9 Hz, 1H), 3.14 – 3.03 (m, 2H), 13 2.91 (dd, J = 13.8, 7.5 Hz, 1H), 1.42 (br, 2H). C-NMR (125 MHz, CDCl 3): δ 137.1, 133.1, 132.1, 128.8, 127.5, 124.8, 65.3, 48.4, 42.4. HR-MS (ESI+) calc. for + C9H12 Cl 1N1Br 1 [M+H] 247.983627, found 247.983710.
2-chloro-3-(p-tolyl)propan-1-amine, Table 10, Entry 13
was prepared from commercially available 4-allyl-toluene according to general procedure (B) to afford the desired product in 56% isolated yield (51.3 mg, 0.280 mmol) after flash column chromatography (DCM/MeOH 95:5). 1H-NMR (500 MHz, CDCl3): δ 7.15 – 7.08 (m, 4H), 4.08 (qd, J = 7.3, 3.5 Hz, 1H), 3.06 – 2.99 (m, 3H), 2.84 (dd, J = 13.8, 7.6 Hz, 1H), 2.33 (s, 3H), 1.46 (br, 2H). 13 C-NMR (125 MHz, CDCl3): δ 136.6, + 134.6, 129.4, 129.3, 67.1, 48.1, 41.9, 21.2. HR-MS (ESI+) calc. for C 10 H15 Cl 1N1 [M+H] 184.088752, found 184.088730. 150 Iron-catalyzed synthesis of unprotected primary amines
7-Amino-6-chlorohept-3-yn-1-ol, Table 10, Entry 14
was prepared from commercially available 6-hepten-3-in-1-ol according to general procedure (B) to afford the desired product in 52% isolated yield (42.0 mg, 0.260 mmol) 1 after flash column chromatography (DCM/MeOH 90:10). H-NMR (500 MHz, CDCl 3): δ = 3.98 (tdd, J = 7.2, 5.8, 4.0 Hz, 1H), 3.69 (t, J = 6.2 Hz, 2H), 3.13 (dd, J = 13.8, 4.0 Hz, 1H), 2.97 (dd, J = 13.8, 7.2 Hz, 1H), 2.75 – 2.61 (m, 2H), 2.47 – 2.40 (m, 2H), 1.83 (br, 13 3H). C-NMR (125 MHz, CDCl 3): δ = 80.2, 77.5, 62.9, 61.2, 47.6, 26.2, 23.3. HR-MS + (ESI+) calc. for C 7H13 Cl 1N1O1 [M+H] 162.068017, found 162.068180.
7-Amino-6-chlorohept-1-en-4-ol, Table 10, Entry 15
was prepared from commercially available 1,6-heptadien-4-ol according to general procedure (B) to afford the desired product in 54% isolated yield (44.0 mg, 0.269 mmol) after flash column chromatography (DCM/MeOH/EtOAc 80:10:10). Analysis of the crude 1 1 H NMR revealed a 1:1 diastereomeric mixture of products. H-NMR (500 MHz, CDCl 3): δ = 5.87 – 5.78 (m, 1H), 5.15 – 5.10 (m, 2H), 4.27 (p, J = 5.0 Hz, 0.5 H, isomer 1), 4.20 (ddt, J = 9.0, 7.1, 4.3 Hz, 0.5 H, isomer 2), 3.95 – 3.90 (m, 1H), 3.19 (dd, J = 13.3, 4.3 Hz, 0.5H, isomer 1), 3.03 (dd, J = 13.6, 4.4 Hz, 0.5 H, isomer 2), 2.97 – 2.92 (m, 1H), 2.70 (br, 3H), 2.30 – 2.19 (m, J = 7.5, 6.7 Hz, 2H), 2.05 – 1.75 (m, 2H). 13 C-NMR (125
MHz, CDCl 3): δ = 134.9, 134.5, 118.4 (d, J = 2.6 Hz), 118.0, 67.7, 66.4, 63.1, 62.4, 49.1, + 47.4, 43.4, 43.2, 42.5, 41.8. HR-MS (ESI+) calc. for C 7H15 Cl 1N1O1 [M+H] 164.083667, found 164.083660.
5. Experimental part 151
2-Chloro-4-morpholinobutan-1-amine, Table 10, Entry 16
was prepared on a 0.20 mmol scale from 4-(but-3-en-1-yl)morpholine according to general procedure (B), with the use of an increased amount of PivONH 3OTf (213.8 mg, 4.0 equiv, 0.8 mmol) and of MeOH as solvent (300 µL). The desired product was afforded in 61% isolated yield (23.5 mg, 0.122 mmol) after flash column chromatography 1 (DCM/MeOH 100:10 to DCM/MeOH/TEA 100:10:1). H-NMR (500 MHz, CDCl 3): δ = 4.09 – 4.04 (m, 1H), 3.71 (t, J = 4.8 Hz, 4H), 3.03 (dd, J = 13.8, 4.2 Hz, 1H), 2.94 (br s, 2H), 2.92 (dd, J = 13.8, 7.4 Hz, 1H), 2.56 – 2.39 (m, 6H), 2.00 – 1.94 (m, 1H), 1.92 – 13 1.84 (m, 1H). C-NMR (125 MHz, CDCl 3): δ = 67.1, 64.3, 55.6, 53.9, 48.8, 32.8. HR-MS + (ESI+) calc. C 8H18 N2O1Cl 1 [M+H] 193.110216, found 193.110320.
5-Chlorooctan-4-amine, Table 10, Entry 17
was prepared from commercially available ( E)-oct-4-ene according to general procedure (B) to afford the desired product in 62% isolated yield (50.6 mg, 0.309 mmol) after flash column chromatography (DCM/MeOH 100:5). The major diastereomer was assigned via X-ray structure ( vide infra ) and resulted to be (4 R*,5 R*)-5-chlorooctan-4-amine. Analysis of the crude 1H-NMR revealed a 3:1 diastereomeric mixture between, respectively, (4 R*,5 R*)-5-chlorooctan-4-amine and (4 R*,5 S*)-5-chlorooctan-4-amine. (4 R*,5 R*)-5- 1 Chlorooctan-4-amine (major isomer): H-NMR (500 MHz, CDCl 3): δ = 3.90 (ddd, J = 9.4, 4.4, 3.2 Hz, 1H), 2.84 (ddd, J = 7.4, 5.4, 3.2 Hz, 1H), 2.27 (br s, 2H), 1.80 – 1.34 (m, 8H), 0.95 – 0.91 (m, 6H). 13 C-NMR (125 MHz, CDCl3): δ = 68.8, 55.4, 37.6, 37.4, 20.2, 19.6, 14.2, 13.7. (4 R*,5 S*)-5-Chlorooctan-4-amine (minor isomer): 1H-NMR (500 MHz, CDCl3): δ = 3.99 (dt, J = 10.2, 3.4 Hz, 1H), 2.98 (dt, J = 8.8, 3.4 Hz, 1H), 2.27 (br s, 2H), 13 1.80 – 1.34 (m, 8H), 0.95 – 0.91 (m, 6H). C-NMR (125 MHz, CDCl 3): δ = 69.4, 56.2, 152 Iron-catalyzed synthesis of unprotected primary amines
+ 35.4, 34.6, 20.3, 19.7, 14.2, 13.7. HR-MS (ESI+) calc. C 8H19 N1Cl 1 [M+H] 164.120052, found 164.120180.
2-Chlorocyclohexan-1-amine, Table 10, Entry 18
was prepared from commercially available cyclohexene according to general procedure (B) to afford the desired product in 73% isolated yield (49.0 mg, 0.367 mmol) after flash column chromatography (DCM/MeOH 95:5). The major diastereomer, after isolation via column chromatography, was assigned via X-ray structure ( vide infra ) and resulted to be (1 R*,2 R*)-2-chlorocyclohexan-1-amine. Analysis of the crude 1H-NMR revealed revealed a 2.4:1 diastereomeric mixture between, respectively, (1 R*,2 R*)-2- chlorocyclohexan-1-amine and (1 R*,2 S*)-2-chlorocyclohexan-1-amine. (1 R*,2 R*)-2- 1 Chlorocyclohexan-1-amine (major isomer): H-NMR (500 MHz, CDCl 3): δ = 3.57 (ddd, J = 11.8, 9.7, 4.3 Hz, 1H), 2.71 (ddd, J = 11.1, 9.7, 4.2 Hz, 1H), 2.23 – 2.18 (m, 1H), 2.01 – 1.96 (m, 1H), 1.88 (br, 2H), 1.76 – 1.70 (m, 2H), 1.68 – 1.59 (m, 1H), 1.38 – 1.24 (m, 13 2H), 1.22 – 1.14 (m, 1H). C-NMR (125 MHz, CDCl 3): δ = 69.2, 57.5, 36.2, 34.7, 26.3, + 24.8. HR-MS (ESI+) calc. for C 6H13 Cl 1N1 [M+H] 134.073102, found 134.073140. 1 (1 R*,2 S*)-2-Chlorocyclohexan-1-amine (minor isomer): H-NMR (500 MHz, CDCl 3): δ = 4.33 (dt, J = 5.5, 3.0 Hz, 1H), 2.95 – 2.91 (m, 1H), 2.09 – 2.03 (m, 1H), 1.87 (br, 2H), 1.82 – 1.75 (m, 1H), 1.72 – 1.65 (m, 2H), 1.62 – 1.58 (m, 2H), 1.46 – 1.41 (m, 1H), 1.34 13 – 1.28 (m, 1H). C-NMR (125 MHz, CDCl 3) δ = 67.3, 53.0, 32.9, 30.6, 23.6, 20.5. HR- + MS (ESI+) calc. for C 6H13 Cl 1N1 [M+H] 134.073102, found 134.073120.
3-Isopentyl-2,2-dimethylaziridine, Table 10, Entry 19
was prepared from commercially available 2,6-dimethyl-2-heptene according to general procedure (C) to afford the desired product in 65% isolated yield (46.0 mg, 0.326 mmol) 5. Experimental part 153
1 after flash column chromatography (DCM/MeOH 95:5). H-NMR (500 MHz, CDCl 3): δ = 1.73 (br, 2H), 1.55 – 1.47 (m, 1H), 1.42 – 1.27 (m, 3H), 1.22 – 1.17 (m, 1H), 1.20 (s, 3H), 13 1.12 (s, 3H), 0.83 (d, J = 6.6 Hz, 6H). C-NMR (125 MHz, CDCl 3): δ = 44.2, 37.2, 36.3, + 28.1, 27.7, 27.2, 22.8, 22.7, 19.6. HR-MS (ESI+) calc. for C 9H20 N1 [M+H] 142.159024, found 142.159050.
2-Phenylaziridine, Table 10, Entry 20
was prepared from commercially available styrene according to general procedure (C) and stirring in aqueous NaOH solution at 60 °C for 1 h during the work-up, to afford the desired product in 75% isolated yield (44.9 mg, 0.377 mmol) after flash column 1 chromatography (DCM/MeOH 100:2). H-NMR (500 MHz, CDCl 3): δ = 7.33 – 7.29 (m, 2H), 7.28 – 7.19 (m, 3H), 3.02 (dd, J = 6.2, 3.4 Hz, 1H), 2.21 (d, J = 6.2 Hz, 1H), 1.80 (d, 13 J = 3.4 Hz, 1H), 1.13 (br s, 1H). C-NMR (125 MHz, CDCl 3): δ = 140.4, 128.5, 127.1, 125.7, 32.1, 29.3. Its characterization data were matching the ones found in literature. 136
2-(4-Bromophenyl)aziridine, Table 10, Entry 21
was prepared from commercially available 4-bromostyrene according to general procedure (C) and stirring in aqueous NaOH solution at 60 °C for 1 h during the work- up, to afford the desired product in 81% isolated yield (80.5 mg, 0.407 mmol) after flash 1 column chromatography (DCM/MeOH 100:2). H-NMR (500 MHz, CDCl 3): δ = 7.42 (d, J = 8.4 Hz, 2H), 7.12 (d, J = 8.4 Hz, 2H), 2.99 (dd, J = 6.2, 3.4 Hz, 1H), 2.23 (d, J = 6.2 13 Hz, 1H), 1.71 (d, J = 3.4 Hz, 1H), 1.15 (br s, 1H). C-NMR (125 MHz, CDCl 3): δ = 139.8, + 131.6, 127.6, 120.8, 31.6, 29.6. HR-MS (ESI+) calc. C 8H9N1Br1 [M+H] 197.991299, found 197.991560.
154 Iron-catalyzed synthesis of unprotected primary amines
2-(3-Methoxyphenyl)aziridine, Table 10, Entry 22
was prepared from commercially available 3-methoxystyrene according to general procedure (C) and stirring in aqueous NaOH solution at 60 °C for 1 h during the work- up, to afford the desired product in 62% isolated yield (46.3 mg, 0.310 mmol) after flash 1 column chromatography (DCM/MeOH 100:2). H-NMR (500 MHz, CDCl 3): δ = 7.25 – 7.18 (m, 1H), 6.83 (dt, J = 7.7, 1.3 Hz, 1H), 6.79 – 6.77 (m, 2H), 3.80 (s, 3H), 3.00 (dd, J = 6.0, 3.4 Hz, 1H), 2.19 (d, J = 6.0 Hz, 1H), 1.78 – 1.77 (m, 1H), 1.00 (br s, 1H). 13 C-
NMR (125 MHz, CDCl 3): δ = 160.0, 142.3, 129.6, 118.2, 112.8, 111.1, 55.3, 32.2, 29.4. + HR-MS (ESI+) calc. C 9H12 N1O1 [M+H] 150.091339, found 150.091430.
2-(3-(Trifluoromethyl)phenyl)aziridine, Table 10, Entry 23
was prepared from commercially available 3-(trifluoromethyl)styrene according to general procedure (C) and stirring in aqueous NaOH solution at 60 °C for 1 h during the work-up, to afford the desired product in 76% isolated yield (70.9 mg, 0.379 mmol) after 1 flash column chromatography (DCM/MeOH 100:2). H-NMR (500 MHz, CDCl 3): δ = 7.53 – 7.38 (m, 4H), 3.10 (dd, J = 6.2, 3.4 Hz, 1H), 2.29 (d, J = 6.2 Hz, 1H), 1.74 (d, J = 3.4 13 Hz, 1H), 1.21 (br s, 1H). C-NMR (125 MHz, CDCl 3): δ = 141.8, 130.9 (q, J = 32.6 Hz), 129.3, 129.0, 124.3 (q, J = 272.2 Hz), 123.9 (q, J = 3.8 Hz), 122.8 (q, J = 3.8 Hz), 31.5, 19 + 29.8. F-NMR (470 MHz, CDCl 3) δ = -62.66. HR-MS (ESI+) calc. C 9H9N1F3 [M+H] 188.068159, found 188.068190.
2-(3-Nitrophenyl)aziridine, Table 10, Entry 24
5. Experimental part 155 was prepared from commercially available 3-nitrostyrene according to general procedure (C) and stirring in aqueous NaOH solution at 60 °C for 1 h during the work-up, to afford the desired product in 80% isolated yield (66.0 mg, 0.402 mmol) after flash column 1 chromatography (DCM/MeOH 100:2). H-NMR (500 MHz, CDCl 3): δ = 8.19 – 8.02 (m, 2H), 7.58 (dt, J = 7.8, 1.4 Hz, 1H), 7.47 (t, J = 7.8 Hz, 1H), 3.15 (br s, 1H), 2.34 (d, J = 13 6.2 Hz, 1H), 1.72 (s, 1H), 1.03 (br s, 1H). C-NMR (125 MHz, CDCl 3): δ = 148.6, 143.2, + 132.1, 129.4, 122.1, 121.1, 31.1, 30.1. HR-MS (ESI+) calc. C 8H9N2O2 [M+H] 165.065852, found 165.065810.
2-(o-Tolyl)aziridine, Table 10, Entry 25
was prepared from commercially available 2-methylstyrene according to general procedure (C) and stirring in aqueous NaOH solution at 60 °C for 1 h during the work- up, to afford the desired product in 78% isolated yield (52.2 mg, 0.392 mmol) after flash 1 column chromatography (DCM/MeOH 100:2). H-NMR (500 MHz, CDCl 3): δ = 7.22 – 7.14 (m, 4H), 3.09 (dd, J = 6.0, 3.6 Hz, 1H), 2.44 (s, 3H), 2.21 (d, J = 6.0 Hz, 1H), 1.72 13 (d, J = 3.6 Hz, 1H), 1.12 (br s, 1H). C-NMR (125 MHz, CDCl 3): δ = 138.4, 137.2, 129.8, + 127.0, 126.1, 125.2, 30.5, 27.7, 19.2. HR-MS (ESI+) calc. C 9H12N1 [M+H] 134.096424, found 134.096480.
5.4.4. Aminochlorination of complex molecules
2-Chloro-5-(((3 R,3a R,6 R,6a R)-6-(pent-4-en-1-yloxy)hexahydrofuro[3,2-b]furan-3- yl)oxy)pentan-1-amine, Scheme 75, 73
was prepared on a 0.20 mmol scale from (3 R,3a R,6 R,6a R)-3,6-bis(pent-4-en-1- yloxy)hexahydrofuro[3,2-b]furan according to general procedure (B), with the use of an 156 Iron-catalyzed synthesis of unprotected primary amines
increased amount of PivONH 3OTf (213.8 mg, 4.0 equiv, 0.8 mmol) and of MeOH as solvent (300 µL). The desired product was afforded in 57% isolated yield (38.0 mg, 0.114 mmol) after flash column chromatography (DCM/MeOH 100:7). Analysis of the 13 C-NMR (150.94 MHz, CDCl 3, relaxation delay = 300 ms, scans number = 200) revealed a 1:1 diastereomeric mixture between ( R)-2-Chloro-5-(((3 R,3a R,6 R,6a R)-6- (pent-4-en-1-yloxy)hexahydrofuro[3,2-b]furan-3-yl)oxy)pentan-1-amine and ( S)-2-Chloro- 5-(((3 R,3a R,6 R,6a R)-6-(pent-4-en-1-yloxy)hexahydrofuro[3,2-b]furan-3-yl)oxy)pentan-1- 1 amine. HNMR (500 MHz, CDCl 3): δ = 5.80 (ddt, J = 17.0, 10.2, 6.6 Hz, 1H), 5.03 – 4.93 (m, 2H), 4.55 – 4.52 (m, 2H), 4.04 – 3.97 (m, 4H), 3.96 – 3.90 (m, 1H), 3.69 – 3.62 (m, 4H), 3.52 – 3.43 (m, 2H), 2.99 (dd, J = 13.8, 3.8 Hz, 1H), 2.85 (dd, J = 13.8, 7.7 Hz, 1H), 2.14 – 2.09 (m, 2H), 1.93 – 1.83 (m, 2H), 1.76 – 1.69 (m, 6H). 13 CNMR (125 MHz,
CDCl 3): δ = 138.3, 115.0, 80.7, 80.6, 80.6, 80.6, 80.5, 71.3, 71.3, 71.2, 71.2, 70.4, 70.2, 69.9, 66.8, 66.7, 49.0, 49.0, 32.4, 32.3, 30.3, 29.1, 26.9, 26.9. HR-MS (ESI+) calc. + C16 H29 N1O4Cl 1 [M+H] 334.177962, found 334.177980.
((1 S,4 S,5 R)-5-(2-Amino-1-chloroethyl)quinuclidin-2-yl)methanol, Scheme 75, 74
A screw-cap vial was charged with Fe(acac) 2 (2.5 mg, 0.05 equiv, 0.01 mmol), NaCl
(12.3 mg, 1.05 equiv, 0.21 mmol), PivONH 3OTf (133.6 mg, 2.5 equiv, 0.50 mmol) and a stirring bar. MeOH (250 µL) was subsequently added to the vial, followed by commercially available quincoridine (QCD) (33.5 mg, 1.0 equiv, 0.20 mmol). After stirring for 16 h at 25 °C, the reaction mixture was diluted with an aqueous solution of NaOH 1.0 M (2 mL) and stirred for 10 min. The water phase was then extracted directly in the vial with CHCl 3 (4 x 6 mL). The combined organic phases were concentrated in vacuo until 1 mL of solution was remaining. The mixture was then acidified with an aqueous solution of HCl 1.0 M solution (2 mL), the two phases were separated and the organic phase was then further extracted with H 2O (2 x 2 mL). The combined aqueous phases were basified to pH > 10 with an aqueous solution of NaOH 1.0 M and they were 5. Experimental part 157
extracted with CHCl 3 (4 x 10 mL). The combined organic phases were dried over
Na 2SO 4, filtered, and concentrated in vacuo . This procedure afforded 36.2 mg of clean material containing the desired product ((1 S,4 S,5 R)-5-(2-amino-1- chloroethyl)quinuclidin-2-yl)methanol in a 1.85:1 diastereomeric mixture and minor amounts of unreacted starting material (ratio products/starting material 62:38; 57% calculated yield of the desired product). The major isomer was separated and fully 1 characterized. H-NMR (500 MHz, CDCl 3): δ = 3.96 (ddd, J = 10.5, 7.6, 2.7 Hz, 1H), 3.51 (t, J = 10.7 Hz, 1H), 3.45 (dd, J = 11.2, 5.0 Hz, 1H), 3.08 (br d, J = 13.7 Hz, 1H), 2.98 – 2.74 (m, 6H), 1.92 (q, J = 9.6 Hz, 1H), 1.85 – 1.79 (m, 1H), 1.71 – 1.53 (m, 4H), 1.53 – 1.44 (m, 1H), 1.07 – 1.02 (m, 1H), 0.85 – 0.81 (m, 1H). 13 C-NMR (125 MHz,
CDCl 3): δ = 62.0, 56.9, 48.6, 46.8, 46.7, 40.2, 29.7, 27.3, 24.9, 23.5. HR-MS (ESI+) calc. + for C 10 H20 Cl 1N2O1 [M+H] 219.125865, found 219.125810.
2-(1,7a-Dimethyloctahydro-4H-2,4-methanoinden-4-yl)-2-methylaziridine, Scheme 75, 75
was prepared from the corresponding alkene starting material according to general procedure (B) to afford the desired product in 51% isolated yield (56.0 mg, 0.255 mmol) after flash column chromatography (DCM/MeOH 95:5). Analysis of 1H-NMR revealed a 1 2:1 diastereomeric ratio of products. H-NMR (500 MHz, CDCl 3): δ = 1.71 (dt, J = 3.4, 1.7 Hz, 1H), 1.68 – 1.52 (m, 3H), 1.50 – 1.38 (m, 8H), 1.28 (s, 1H), 1.22 (s, 2H), 1.19 (s, 1H), 1.14 – 0.98 (m, 2H), 0.95 – 0.87 (m, 1H), 0.84 (s, 3H), 0.82 (dd, J = 7.3, 2.0 Hz, 3H = dd signal arising from 2 different doublets with integration ratio 2:1 ). 13 C-NMR (125
MHz, CDCl 3): δ = 51.2, 51.1, 45.6, 45.3, 43.3, 43.1, 41.7, 39.8, 39.8, 39.1, 36.4, 36.3, 35.0, 34.5, 34.4, 32.8, 31.7, 31.5, 29.8, 25.6, 25.5, 21.8, 18.0, 17.8, 16.3(d). HR-MS + (ESI+) calc. for C 15 H26 N1 [M+H] 220.205974, found 220.205940.
3',3'-Dimethylspiro[aziridine-2,2'-bicyclo[2.2.1]heptane], Scheme 75, 76 158 Iron-catalyzed synthesis of unprotected primary amines
was prepared from commercially available camphene according to general procedure (C) to afford the desired product in 31% isolated yield (23.1 mg, 0.153 mmol) after flash column chromatography (DCM/MeOH 100:5). 1H-NMR analysis of the crude reaction mixture did not show any formation of the product arising from the tandem 1 aminochlorination–rearrangement of camphene. H-NMR (500 MHz, CDCl 3): δ = 3.36 (br s, 1H), 2.02 – 1.92 (m, 2H), 1.77 – 1.68 (m, 2H), 1.60 – 1.52 (m, 2H), 1.42 – 1.34 (m, 13 2H), 1.24 – 1.20 (m, 2H), 0.89 (s, 3H), 0.84 (s, 3H). C-NMR (125 MHz, CDCl 3): δ =
53.8, 49.6, 47.8, 36.1, 29.9, 27.5, 26.1, 25.6, 24.5, 24.2. HR-MS (ESI+) calc. C 10 H18 N1 [M+H] + 152.143374, found 152.143430.
5.4.5. Derivatizations of 2-chlorododecan-1-amine
Dodecan-1-amine, Table 12, Entry 1
A screw-cap vial under Ar atmosphere was charged with Raney-nickel (800 mg), tBuOH (800 µL, degassed through Ar purging) and a stirring bar. 2-Chlorododecan-1-amine (44.0 mg, 0.200 mmol) was subsequently added to the vial. After stirring for 16 h at 30 °C, the reaction mixture was diluted with an aqueous solution of NaOH 1.0 M (2.5 mL) and stirred for 10 min. The water phase was then extracted directly in the vial with DCM
(4 x 5 mL). The combined organic phases were dried over Na 2SO 4, filtered, and concentrated in vacuo . The crude mixture was directly purified via flash column chromatography (DCM/MeOH 100:10 to DCM/MeOH/TEA 100:10:1) to afford the desired product in 70% isolated yield (25.7 mg, 0.139 mmol). 1H-NMR (500 MHz,
CDCl 3): δ = 2.73 (br s, 2H), 2.63 (br s, 2H), 1.52 – 1.46 (m, 2H), 1.32 – 1.25 (m, 18H), 13 0.87 (t, J = 7.0 Hz, 3H). C-NMR (125 MHz, CDCl 3): δ = 41.9, 32.9, 32.1, 29.8, 29.8, + 29.8, 29.7, 29.6, 29.5, 27.0, 22.8, 14.3. HR-MS (ESI+) calc. for C 12 H28 N1 [M+H] 5. Experimental part 159
186.221624, found 186.221690. Its characterization data were matching the ones found in literature. 175
Dodecan-2-amine, Table 12, Entry 2
A screw-cap vial under Ar atmosphere was charged with LiAlH 4 (19.0 mg, 0.5 mmol), dry
Et 2O (600 µL) and a stirring bar. At 0 °C, 2-chlorododecan-1-amine (44.0 mg, 0.200 mmol) was added to the vial and the mixture was allowed to reach room temperature. After stirring for 16 h at 80 °C, the reaction mixture was diluted with an aqueous solution of NaOH 1.0 M (2.5 mL) and stirred for 10 min. The water phase was then extracted directly in the vial with DCM (4 x 5 mL). The combined organic phases were dried over
Na 2SO 4, filtered, and concentrated in vacuo . The crude mixture was directly purified via flash column chromatography (DCM/MeOH 100:10 to DCM/MeOH/TEA 100:10:1) to afford the desired product in 73% isolated yield (27.1 mg, 0.146 mmol). 1H-NMR (500
MHz, CDCl 3): δ = 2.96 – 2.90 (m, 1H), 2.51 (br s, 2H), 1.39 – 1.25 (m, 18H), 1.10 (d, J = 13 6.4 Hz, 3H), 0.88 (t, J = 7.0 Hz, 3H). C-NMR (125 MHz, CDCl 3): δ = 47.4, 39.5, 32.1,
29.8, 29.8, 29.8, 29.7, 29.5, 26.4, 23.2, 22.8, 14.3. HR-MS (ESI+) calc. for C 12 H28 N1 [M+H] + 186.221624, found 186.221740.
Pentadec-1-en-4-amine, Table 12, Entry 3
A screw-cap vial under Ar atmosphere was charged with 500 µL of a 1.0 M solution of allylmagnesium bromide in Et 2O (0.5 mmol) and a stirring bar. 2-Chlorododecan-1- amine (44.0 mg, 0.200 mmol) was subsequently added to the vial. After stirring for 16 h
175 M. Szostak, B. Sautier, M. Spain, D. J. Procter, Org. Lett. 2014 , 16 , 1092-1095. 160 Iron-catalyzed synthesis of unprotected primary amines at 25 °C, the reaction mixture was diluted with an aqueous solution of NaOH 1.0 M (2.5 mL) and stirred for 10 min. The water phase was then extracted directly in the vial with
DCM (4 x 5 mL). The combined organic phases were dried over Na 2SO 4, filtered, and concentrated in vacuo . The crude mixture was directly purified via flash column chromatography (DCM/MeOH 100:5 to DCM/MeOH/TEA 100:10:1) to afford the desired 1 product in 71% isolated yield (31.8 mg, 0.142 mmol). H-NMR (500 MHz, CDCl 3): δ = 5.80 (ddt, J = 17.2, 10.2, 7.2 Hz, 1H), 5.22 – 5.08 (m, 2H), 3.54 (br s, 2H), 2.96 (ddd, J = 12.8, 7.2, 5.6 Hz, 1H), 2.38 – 2.30 (m, 1H), 2.23 – 2.17 (m, 1H), 1.55 – 1.46 (m, 2H), 13 1.36 – 1.24 (m, 18H), 0.88 (t, J = 7.0 Hz, 3H). C-NMR (125 MHz, CDCl3): δ = 134.3, 118.7, 51.4, 40.3, 35.5, 32.1, 29.8, 29.8, 29.8, 29.7, 29.7, 29.5, 26.0, 22.8, 14.3. HR-MS + (ESI+) calc. C 15 H32 N1 [M+H] 226.252924, found 226.253050.
2-Decylaziridine, Table 12, Entry 4
A screw-cap vial was charged with NaI (149.9 mg, 1.0 mmol), 500 µL of a 4.0 M aqueous solution of NaOH (2.0 mmol), MeOH (500 µL) and a stirring bar. 2- Chlorododecan-1-amine (44.0 mg, 0.200 mmol) was subsequently added to the vial. After stirring for 16 h at 90 °C, the reaction mixture was diluted with distilled water (2.5 mL) and the water phase was then extracted directly in the vial with DCM (4 x 5 mL).
The combined organic phases were dried over Na 2SO 4, filtered, and concentrated in vacuo . The crude mixture was directly purified via flash column chromatography (DCM/MeOH 100:5) to afford the desired product in 95% isolated yield (34.8 mg, 0.190 1 mmol). H-NMR (500 MHz, CDCl 3): δ = 1.96 – 1.91 (m, 1H), 1.75 (d, J = 5.8 Hz, 1H), 1.46 – 1.25 (m, 19H), 1.03 (br s, 1H), 0.87 (t, J = 7.0 Hz, 3H). 13 C-NMR (125 MHz,
CDCl 3): δ = 34.7, 32.1, 30.5, 29.8, 29.8, 29.8, 29.6, 29.5, 27.7, 25.3, 22.8, 14.3. HR-MS + (ESI+) calc. C 12 H26 N1 [M+H] 184.205974, found 184.206070. Its characterization data were matching the ones found in literature. 176
176 I. C. Stewart, C. C. Lee, R. G. Bergman, F. D. Toste, J. Am. Chem. Soc. 2005 , 127 , 17616-17617. 5. Experimental part 161
2-Azidododecan-1-amine, Table 12, Entry 5
A screw-cap vial under Ar atmosphere was charged with NaN 3 (65.0 mg, 1.0 mmol), NaI (149.9 mg, 1.0 mmol), dry DMF (800 µL) and a stirring bar. 2-Chlorododecan-1-amine (44.0 mg, 0.200 mmol) was subsequently added to the vial. After stirring for 16 h at 60 °C, the reaction mixture was diluted with an aqueous solution of NaOH 1.0 M (2.5 mL) and stirred for 10 min. The water phase was then extracted directly in the vial with DCM
(4 x 5 mL). The combined organic phases were dried over Na 2SO 4, filtered, and concentrated in vacuo . The crude mixture was directly purified via flash column chromatography (DCM/MeOH 100:5) to afford the desired product in 66% isolated yield 1 (30.0 mg, 0.132 mmol). H-NMR (500 MHz, CDCl 3): δ = 3.37 (dd, J = 12.0, 4.0 Hz, 1H), 3.15 (dd, J = 12.0, 7.6 Hz, 1H), 2.90 (tt, J = 7.6, 4.0 Hz, 1H), 1.62 (br s, 2H), 1.43 – 1.25 13 (m, 18H), 0.88 (t, J = 7.0 Hz, 3H). C-NMR (125 MHz, CDCl 3): δ = 58.4, 51.3, 35.1, + 32.0, 29.8, 29.7, 29.7, 29.7, 29.5, 26.2, 22.8, 14.3. HR-MS (ESI+) calc. C 12 H27 N4 [M+H] 227.223020, found 227.223040.
2-(Aminomethyl)dodecanenitrile, Table 12, Entry 6
A screw-cap vial under Ar atmosphere was charged with NaCN (49.0 mg, 1.0 mmol), NaI (149.9 mg, 1.0 mmol), dry DMF (800 µL) and a stirring bar. 2-Chlorododecan-1- amine (44.0 mg, 0.200 mmol) was subsequently added to the vial. After stirring for 16 h at 60 °C, the reaction mixture was diluted with an aqueous solution of NaOH 1.0 M (2.5 mL) and stirred for 10 min. The water phase was then extracted directly in the vial with
DCM (4 x 5 mL). The combined organic phases were dried over Na 2SO 4, filtered, and concentrated in vacuo . The crude mixture was directly purified via flash column chromatography (DCM/MeOH 100:3) to afford the desired product in 70% isolated yield 1 (29.6 mg, 0.140 mmol). H-NMR (500 MHz, CDCl 3): δ = 3.12 – 3.07 (m, 1H), 2.48 (dd, J 162 Iron-catalyzed synthesis of unprotected primary amines
= 16.6, 5.0 Hz, 1H), 2.36 (dd, J = 16.6, 6.8 Hz, 1H), 1.60 (br s, 2H), 1.48 – 1.24 (m, 13 18H), 0.88 (t, J = 7.0 Hz, 3H). C-NMR (125 MHz, CDCl 3): δ = 118.3, 48.6, 37.2, 32.0, + 29.7, 29.7, 29.6, 29.5, 29.5, 27.0, 26.2, 22.8, 14.3. HR-MS (ESI+) calc. C 13 H27 N2 [M+H] 211.216872, found 211.216890.
N-(2-Chlorododecyl)aniline, Table 12, Entry 7
Me N H Cl
A screw-cap vial under Ar atmosphere was charged with 2-(trimethylsilyl)phenyl trifluoromethanesulfonate (59.7 mg, 0.200 mmol), 2-chlorododecan-1-amine (131.9 mg, 0.600 mmol), dry MeCN (2.0 mL) and a stirring bar. At 0 °C, cesium fluoride (60.8 mg, 0.400 mmol) was added to the vial and the reaction mixture was stirred for 6 h at 0 °C and for an additional 16 h at 25 °C. The reaction mixture was then filtered on a short plug of silica gel, eluting with EtOAc (4 x 5 mL). The combined organic phases were concentrated in vacuo and the crude mixture was purified via flash column chromatography (pentane/EtOAc 100:5) to afford the desired product in 71% isolated 1 yield (42.0 mg, 0.142 mmol). H-NMR (500 MHz, CDCl 3): δ = 7.25 – 7.15 (m, 2H), 6.74 (tt, J = 7.4, 1.2 Hz, 1H), 6.68 – 6.56 (m, 2H), 4.15 – 4.10 (m, 1H), 4.08 (br s, 1H), 3.50 (dd, J = 13.6, 4.2 Hz, 1H), 3.28 (dd, J = 13.6, 8.0 Hz, 1H), 1.88 – 1.71 (m, 2H), 1.60 – 1.54 (m, 1H), 1.47 – 1.39 (m, 1H), 1.32 – 1.27 (m, 14H), 0.89 (t, J = 7.0 Hz, 3H). 13 C-
NMR (125 MHz, CDCl 3): δ = 147.6, 129.5, 118.2, 113.4, 62.6, 50.7, 36.2, 32.1, 29.7, + 29.7, 29.6, 29.5, 29.3, 26.6, 22.8, 14.3. HR-MS (ESI+) calc. C 18 H31 N1Cl 1 [M+H] 296.213952, found 296.214010.
5. Experimental part 163
5.4.6. Mechanistic experiments
(1 R*,2 S*)-2-Chlorocyclodecan-1-amine and (1 R*,2 R*)-2-chlorocyclodecan-1-amine, Scheme 77, 78 and 80
Reaction of commercially available ( Z) -cyclodecene according to general procedure (B) afforded the desired product in 73% isolated yield (69.1 mg, 0.364 mmol) after flash column chromatography (DCM/MeOH 100:5). Analysis of the crude 1H-NMR and of NOESY-NMR revealed a 14:1 diastereomeric mixture between, respectively, (1 R*,2 S*)- 2-chlorocyclodecan-1-amine and (1 R*,2 R*)-2-chlorocyclodecan-1-amine. (1 R*,2 S*)-2- 1 Chlorocyclodecan-1-amine: H-NMR (500 MHz, CDCl 3): δ = 4.37 – 4.31 (m, 1H), 3.31 (br s, 1H), 2.89 (br s, 2H), 2.17 – 2.11 (m, 1H), 1.94 – 1.87 (m, 1H), 1.86 – 1.75 (m, 1H), 13 1.68 – 1.39 (m, 13H). C-NMR (125 MHz, CDCl 3): δ = 68.9, 54.3, 31.5, 30.3, 25.0, 24.9, + 24.2, 24.2, 24.1, 23.8. HR-MS (ESI+) calc. C 10 H21 N1Cl 1 [M+H] 190.135702, found 190.135870.
Reaction of commercially available ( E) -cyclodecene according to general procedure (B) afforded the desired product in 75% isolated yield (71.0 mg, 0.374 mmol) after flash column chromatography (DCM/MeOH 100:2). Analysis of the crude 1H-NMR and of NOESY-NMR revealed a 1:9 diastereomeric mixture between, respectively, (1 R*,2 S*)-2- chlorocyclodecan-1-amine and (1 R*,2 R*)-2-chlorocyclodecan-1-amine. (1 R*,2 R*)-2- 1 Chlorocyclodecan-1-amine: H-NMR (500 MHz, CDCl 3): δ = 4.15 (dt, J = 8.8, 5.0 Hz, 1H), 3.22 (dt, J = 9.2, 4.8 Hz, 1H), 2.16 – 2.09 (m, 1H), 2.05 – 1.97 (m, 1H), 1.83 – 1.71 13 (m, 2H), 1.65 – 1.46 (m, 14H). C-NMR (125 MHz, CDCl 3): δ = 70.2, 54.5, 32.9, 31.6, + 25.1, 25.0, 24.5, 24.3, 23.2, 23.1. HR-MS (ESI+) calc. C 10 H21 N1Cl 1 [M+H] 190.135702, found 190.135850.
164 Iron-catalyzed synthesis of unprotected primary amines
2-Methyl-3-phenylaziridine, Scheme 77, 81 and 82
NH
Me
was prepared on a 0.20 mmol scale from commercially available ( Z) -β-methylstyrene according to general procedure (C) and stirring in aqueous NaOH solution at 60 °C for 1 h during the work-up, to afford the desired product in 58% isolated yield (15.4 mg, 0.116 mmol) after flash column chromatography (DCM/MeOH 100:2). Analysis of the crude 1H- NMR revealed a 4.5:1 diastereomeric mixture between, respectively, cis -2-methyl-3- phenylaziridine and trans -2-methyl-3-phenylaziridine. Its characterization data were matching the ones found in literature. 177, 178
2-Methyl-3-phenylaziridine was also prepared on a 0.20 mmol scale from commercially available ( E) -β-methylstyrene according to general procedure (C) and stirring in aqueous NaOH solution at 60 °C for 1 h during the work-up, to afford the desired product in 55% isolated yield (14.6 mg, 0.110 mmol) after flash column chromatography (DCM/MeOH 100:2). Analysis of the crude 1H-NMR revealed a 4:1 diastereomeric mixture between, respectively, cis -2-methyl-3-phenylaziridine and trans -2-methyl-3- phenylaziridine. cis -2-Methyl-3-phenylaziridine (major isomer): 1H-NMR (500 MHz,
CDCl 3): δ = 7.35 – 7.18 (m, 5H), 3.25 (d, J = 6.6 Hz, 1H), 2.44 – 2.40 (m, 1H), 1.24 (br s, 13 1H), 0.92 (d, J = 5.7 Hz, 3H). C-NMR (125 MHz, CDCl 3): δ = 137.7, 128.0, 127.9, 126.8, 37.3, 32.3, 13.8. trans -2-Methyl-3-phenylaziridine (minor isomer): 1H-NMR (500
MHz, CDCl 3): δ = 7.35 – 7.18 (m, 5H), 2.66 (d, J = 3.0 Hz, 1H), 2.16 – 2.11 (m, 1H), 1.37 13 (d, J = 5.4 Hz, 3H), 1.24 (br s, 1H). C-NMR (125 MHz, CDCl 3): δ = 140.6, 128.6, 127.1, + 125.7, 40.6, 37.2, 19.8. HR-MS (ESI+) calc. C 9H12 N1 [M+H] 134.096424, found 134.096480.
177 A. Cruz, I. I. Padilla-Martínez, E. V. García-Báez, Tetrahedron-Asymmetry 2010 , 21 , 909-913. 178 L. Dahlenburg, R. Götz, J. Organomet. Chem. 2001 , 619 , 88-98. 5. Experimental part 165 tert -Butyl-(E)-(5-chloro-5-phenylpent-2-en-1-yl)carbamate and tert -butyl-(E)-(5- methoxy-5-phenylpent-2-en-1-yl)carbamate, Scheme 78, 84a and 84b
were prepared from ((1 R* ,2 S* )-2-vinylcyclopropyl)benzene according to general procedure (B) to afford ( E)-5-chloro-5-phenylpent-2-en-1-amine and ( E)-5-methoxy-5- phenylpent-2-en-1-amine in 55% isolated yield (53.1 mg of products mixture, 0.203 mmol of ( E)-5-chloro-5-phenylpent-2-en-1-amine and 0.070 mmol of ( E)-5-methoxy-5- phenylpent-2-en-1-amine) after flash column chromatography (DCM/MeOH 100:7 to DCM/MeOH/TEA 100/10/1).
For the full characterization and separation of the two products, they were Boc protected according to the following procedure: the product mixture, dissolved in DCM (2.5 mL) and TEA (77 µL, 0.550 mmol), was stirred 10 minutes at 25 °C. The reaction mixture was then cooled to 0 °C in an ice bath and Boc 2O (120.0 mg, 0.550 mmol) was added dropwise. After allowing the mixture to reach room temperature, it was stirred for 2 h. The reaction mixture was then quenched by addition of water (4 mL) and diluted with DCM (4 mL), the two phases were separated and the organic layer washed with saturated aqueous NaHCO 3 (1 x 4 mL). The combined water phases were extracted with DCM (4 x 8 mL) and the combined organic phases were dried over Na 2SO 4, filtered, and concentrated in vacuo . The crude product was purified via flash column chromatography (pentane/EtOAc 6:1) to afford the desired products in 50% (30.2 mg, 0.102 mmol) and 22% (4.4 mg, 0.015 mmol) isolated yields for, respectively, tert -butyl- (E)-(5-chloro-5-phenylpent-2-en-1-yl)carbamate and tert -butyl-(E)-(5-methoxy-5- phenylpent-2-en-1-yl)carbamate. tert -Butyl-(E)-(5-chloro-5-phenylpent-2-en-1- 1 yl)carbamate: H-NMR (500 MHz, CDCl 3): δ = 7.37 – 7.28 (m, 5H), 5.59 – 5.51 (m, 2H), 4.84 (dd, J = 8.2, 6.4 Hz, 1H), 4.51 (br s, 1H), 3.68 – 3.66 (m, 2H), 2.85 – 2.73 (m, 2H), 13 1.44 (s, 9H). C-NMR (125 MHz, CDCl 3): δ = 155.8, 141.3, 130.7, 128.8, 128.5, 127.7, + 127.1, 79.5, 63.0, 42.7, 42.4, 28.5. HR-MS (ESI+) calc. C 16 H22 N1O2Cl 1Na 1 [M+Na] 166 Iron-catalyzed synthesis of unprotected primary amines
318.123126, found 318.123160. tert -Butyl-(E)-(5-methoxy-5-phenylpent-2-en-1- 1 yl)carbamate: H-NMR (500 MHz, CDCl 3): δ = 7.37 – 7.25 (m, 5H), 5.59 – 5.53 (m, 1H), 5.46 (dt, J = 15.4, 6.0 Hz, 1H), 4.46 (br s, 1H), 4.13 (dd, J = 7.6, 5.6 Hz, 1H), 3.67 – 3.65 (m, 2H), 3.21 (s, 3H), 2.52 (dddd, J = 14.4, 7.6, 6.8, 1.2 Hz, 1H), 2.36 (dddd, J = 14.4, 13 6.8, 5.6, 1.2 Hz, 1H), 1.44 (s, 9H). C-NMR (125 MHz, CDCl 3): δ = 155.8, 141.7, 129.1, 128.8, 128.5, 127.8, 126.8, 83.8, 79.4, 56.8, 42.6, 41.1, 28.6. HR-MS (ESI+) calc. + C17 H25 N1O3Na 1 [M+Na] 314.172663, found 314.172530.
N-Allyl-N-(3-amino-2-chloropropyl)-4-methylbenzenesulfonamide, Scheme 79, 86
Me O O S Cl N NH 2 was prepared on a 0.20 mmol scale from N,N-diallyl-4-methylbenzenesulfonamide according to general procedure (B) to afford the desired product in 61% isolated yield (36.8 mg, 0.122 mmol) after flash column chromatography (DCM/MeOH 100:5). 1H-NMR analysis of the crude reaction mixture did not show any formation of the product arising from the tandem aminochlorination–cyclization of N,N-diallyl-4- 1 methylbenzenesulfonamide. H-NMR (500 MHz, CDCl 3): δ = 7.72 – 7.68 (m, 2H), 7.35 – 7.30 (m, 2H), 5.58 (ddt, J = 16.8, 10.2, 6.6 Hz, 1H), 5.21 – 5.14 (m, 2H), 4.17 (dtd, J = 8.4, 6.0, 3.4 Hz, 1H), 3.89 (dd, J = 15.4, 6.6 Hz, 1H), 3.77 (dd, J = 15.4, 6.6 Hz, 1H), 3.57 (dd, J = 14.6, 8.4 Hz, 1H), 3.17 (dd, J = 14.6, 6.0 Hz, 1H), 3.16 – 3.10 (m, 1H), 3.01 13 – 2.96 (m, 1H), 2.67 (br s, 2H), 2.43 (s, 3H). C-NMR (125 MHz, CDCl 3): δ = 144.0, 136.2, 132.7, 130.0, 127.5, 120.2, 62.5, 52.7, 50.7, 45.1, 21.7. HR-MS (ESI+) calc. + C13 H20 N2O2Cl 1S1 [M+H] 303.092853, found 303.092930.
5. Experimental part 167
5.4.7. X-ray structures
X-ray structure of compound 17AMIDE, Table 10
5-Chlorooctan-4-amine was transformed to 4-bromo-N-(5-chlorooctan-4-yl)benzamide following the procedure below and in order to facilitate diastereomers separation and further crystallization. A screw-cap vial was charged with 4-bromobenzoyl chloride (109.7 mg, 0.500 mmol), DCM (2.0 mL), TEA (76.7 µL, 0.550 mmol) and a stirring bar. A solution of 5-chlorooctan-4-amine (81.8 mg, 0.500 mmol) in DCM (200 µL) was added dropwise at 0 °C and the reaction mixture was allowed to reach room temperature. After stirring for 16 h at room temperature, the reaction mixture was diluted with an aqueous solution of HCl 1.0 M (2.5 mL). The water phase was then extracted directly in the vial with DCM (4 x 5 mL). The combined organic phases were dried over Na 2SO 4, filtered, and concentrated in vacuo . The crude mixtures were directly purified via flash column chromatography (pentane/EtOAc 10:1) to afford the desired product in 47% isolated yield (82.2 mg, 0.237 mmol).
The major and minor diastereomers were isolated via preparative liquid chromatography (250 mm YMC PVA-Sil 5 µm, 4.6 mm i.D.; n-heptan/2-propanol 95:5; 1.0 mL/min, 8.6 MPa, 35 °C; UV 220 nm; retention time: 4.95 min (major diastereomer), 5.85 min (minor diastereomer)). Crystals of the major diastereomer (Figure S1) were obtained by vapor diffusion method, from MeCN/Et 2O. The X-ray data was collected to establish the relative stereochemistry. Atoms C1-C2, C4-C5, C7-C8, C9, Cl1, N1 were found disordered. The structure was refined to convergence and indicated 4-bromo-N- ((4 R*,5 R*)-5-chlorooctan-4-yl)benzamide as the major isomer. 168 Iron-catalyzed synthesis of unprotected primary amines
Figure S1. Molecular conformational of 4-bromo-N-((4 R*,5 R*)-5-chlorooctan-4-yl)benzamide in crystals.
5. Experimental part 169
Table S1. Crystal data and structure refinement.
Identification code 11425
Empirical formula C15 H21 Br Cl N O Color colourless Formula weight 346.68 g · mol -1 Temperature 100(2) K Wavelength 0.71073 Å Crystal system ORTHORHOMBIC
Space group Pna21, (no. 33) Unit cell dimensions a = 19.078(5) Å α= 90°. b = 16.218(4) Å β= 90°. c = 5.2135(14) Å γ = 90°. Volume 1613.1(7) Å 3 Z 4 Density (calculated) 1.428 Mg · m -3 Absorption coefficient 2.707 mm -1 F(000) 712 e Crystal size 0.091 x 0.023 x 0.023 mm 3 θ range for data collection 1.648 to 30.532°. Index ranges -27 ≤ h ≤ 27, -23 ≤ k ≤ 23, -7 ≤ l ≤ 7 Reflections collected 36249
Independent reflections 4926 [R int = 0.1515] Reflections with I>2σ(I) 3107 Completeness to θ = 25.242° 99.9 % Absorption correction Gaussian Max. and min. transmission 0.95 and 0.85 Refinement method Full-matrix least-squares on F 2 Data / restraints / parameters 4926 / 1 / 168 Goodness-of-fit on F 2 1.089 2 Final R indices [I>2σ(I)] R1 = 0.0663 wR = 0.1405 2 R indices (all data) R1 = 0.1242 wR = 0.1757 Absolute structure parameter 0.64(3) Extinction coefficient 0.035(4) Largest diff. peak and hole 1.6 and -0.7 e · Å -3
170 Iron-catalyzed synthesis of unprotected primary amines
Table S2. Bond lengths [Å] and angles [°]. Br(1)-C(13) 1.896(7) Cl(1A)-C(4A) 1.818(12) Cl(1B)-C(5B) 1.86(3) O(1A)-C(9A) 1.229(16) O(1B)-C(9B) 1.21(3) N(1A)-H(1A) 0.8800 N(1A)-C(5A) 1.461(13) N(1A)-C(9A) 1.355(14) N(1B)-H(1B) 0.8800 N(1B)-C(4B) 1.49(3) N(1B)-C(9B) 1.32(3) C(1A)-H(1AA) 0.9800 C(1A)-H(1AB) 0.9800 C(1A)-H(1AC) 0.9800 C(1A)-C(2A) 1.50(2) C(1B)-H(1BA) 0.9800 C(1B)-H(1BB) 0.9800 C(1B)-H(1BC) 0.9800 C(1B)-C(2B) 1.51(5) C(2A)-H(2AA) 0.9900 C(2A)-H(2AB) 0.9900 C(2A)-C(3) 1.601(13) C(2B)-H(2BA) 0.9900 C(2B)-H(2BB) 0.9900 C(2B)-C(3) 1.46(2) C(3)-H(3AA) 0.9900 C(3)-H(3AB) 0.9900 C(3)-H(3BC) 0.9900 C(3)-H(3BD) 0.9900 C(3)-C(4A) 1.491(13) C(3)-C(4B) 1.57(3) C(4A)-H(4A) 1.0000 C(4A)-C(5A) 1.535(15) C(4B)-H(4B) 1.0000 C(4B)-C(5B) 1.49(3) C(5A)-H(5A) 1.0000 C(5A)-C(6) 1.574(13) C(5B)-H(5B) 1.0000 C(5B)-C(6) 1.46(3) C(6)-H(6AA) 0.9900 C(6)-H(6AB) 0.9900 C(6)-H(6BC) 0.9900 C(6)-H(6BD) 0.9900 C(6)-C(7A) 1.520(13) C(6)-C(7B) 1.72(3) C(7A)-H(7AA) 0.9900 C(7A)-H(7AB) 0.9900 C(7A)-C(8A) 1.509(19) C(7B)-H(7BA) 0.9900 C(7B)-H(7BB) 0.9900 C(7B)-C(8B) 1.41(4) C(8A)-H(8AA) 0.9800 C(8A)-H(8AB) 0.9800 C(8A)-H(8AC) 0.9800 C(8B)-H(8BA) 0.9800 C(8B)-H(8BB) 0.9800 C(8B)-H(8BC) 0.9800 C(9A)-C(10) 1.487(13) C(9B)-C(10) 1.55(2) C(10)-C(11) 1.380(10) C(10)-C(15) 1.409(10) C(11)-H(11) 0.9500 C(11)-C(12) 1.376(11) C(12)-H(12) 0.9500 C(12)-C(13) 1.379(11) C(13)-C(14) 1.369(10) C(14)-H(14) 0.9500 C(14)-C(15) 1.383(9) C(15)-H(15) 0.9500
C(5A)-N(1A)-H(1A) 120.2 C(9A)-N(1A)-H(1A) 120.2 C(9A)-N(1A)-C(5A) 119.6(8) C(4B)-N(1B)-H(1B) 119.2 C(9B)-N(1B)-H(1B) 119.2 C(9B)-N(1B)-C(4B) 121.5(19) H(1AA)-C(1A)-H(1AB) 109.5 H(1AA)-C(1A)-H(1AC) 109.5 H(1AB)-C(1A)-H(1AC) 109.5 C(2A)-C(1A)-H(1AA) 109.5 C(2A)-C(1A)-H(1AB) 109.5 C(2A)-C(1A)-H(1AC) 109.5 H(1BA)-C(1B)-H(1BB) 109.5 H(1BA)-C(1B)-H(1BC) 109.5 H(1BB)-C(1B)-H(1BC) 109.5 C(2B)-C(1B)-H(1BA) 109.5 C(2B)-C(1B)-H(1BB) 109.5 C(2B)-C(1B)-H(1BC) 109.5 C(1A)-C(2A)-H(2AA) 109.9 C(1A)-C(2A)-H(2AB) 109.9 C(1A)-C(2A)-C(3) 109.1(11) H(2AA)-C(2A)-H(2AB) 108.3 C(3)-C(2A)-H(2AA) 109.9 C(3)-C(2A)-H(2AB) 109.9 C(1B)-C(2B)-H(2BA) 109.3 C(1B)-C(2B)-H(2BB) 109.3 H(2BA)-C(2B)-H(2BB) 107.9 C(3)-C(2B)-C(1B) 112(3) C(3)-C(2B)-H(2BA) 109.3 C(3)-C(2B)-H(2BB) 109.3 C(2A)-C(3)-H(3AA) 109.5 C(2A)-C(3)-H(3AB) 109.5 C(2B)-C(3)-H(3BC) 108.9 C(2B)-C(3)-H(3BD) 108.9 C(2B)-C(3)-C(4B) 113.4(17) H(3AA)-C(3)-H(3AB) 108.1 5. Experimental part 171
H(3BC)-C(3)-H(3BD) 107.7 C(4A)-C(3)-C(2A) 110.8(8) C(4A)-C(3)-H(3AA) 109.5 C(4A)-C(3)-H(3AB) 109.5 C(4B)-C(3)-H(3BC) 108.9 C(4B)-C(3)-H(3BD) 108.9 Cl(1A)-C(4A)-H(4A) 108.1 C(3)-C(4A)-Cl(1A) 111.7(7) C(3)-C(4A)-H(4A) 108.1 C(3)-C(4A)-C(5A) 113.3(9) C(5A)-C(4A)-Cl(1A) 107.4(8) C(5A)-C(4A)-H(4A) 108.1 N(1B)-C(4B)-C(3) 113.8(19) N(1B)-C(4B)-H(4B) 107.2 N(1B)-C(4B)-C(5B) 104(2) C(3)-C(4B)-H(4B) 107.2 C(5B)-C(4B)-C(3) 117(2) C(5B)-C(4B)-H(4B) 107.2 N(1A)-C(5A)-C(4A) 108.9(9) N(1A)-C(5A)-H(5A) 107.5 N(1A)-C(5A)-C(6) 111.7(8) C(4A)-C(5A)-H(5A) 107.6 C(4A)-C(5A)-C(6) 113.4(9) C(6)-C(5A)-H(5A) 107.5 Cl(1B)-C(5B)-H(5B) 108.4 C(4B)-C(5B)-Cl(1B) 106.0(18) C(4B)-C(5B)-H(5B) 108.4 C(6)-C(5B)-Cl(1B) 113.5(16) C(6)-C(5B)-C(4B) 112(2) C(6)-C(5B)-H(5B) 108.4 C(5A)-C(6)-H(6AA) 109.0 C(5A)-C(6)-H(6AB) 109.0 C(5B)-C(6)-H(6BC) 108.8 C(5B)-C(6)-H(6BD) 108.8 C(5B)-C(6)-C(7B) 113.7(14) H(6AA)-C(6)-H(6AB) 107.8 H(6BC)-C(6)-H(6BD) 107.7 C(7A)-C(6)-C(5A) 112.8(8) C(7A)-C(6)-H(6AA) 109.0 C(7A)-C(6)-H(6AB) 109.0 C(7B)-C(6)-H(6BC) 108.8 C(7B)-C(6)-H(6BD) 108.8 C(6)-C(7A)-H(7AA) 109.1 C(6)-C(7A)-H(7AB) 109.1 H(7AA)-C(7A)-H(7AB) 107.8 C(8A)-C(7A)-C(6) 112.6(10) C(8A)-C(7A)-H(7AA) 109.1 C(8A)-C(7A)-H(7AB) 109.1 C(6)-C(7B)-H(7BA) 109.1 C(6)-C(7B)-H(7BB) 109.1 H(7BA)-C(7B)-H(7BB) 107.8 C(8B)-C(7B)-C(6) 113(2) C(8B)-C(7B)-H(7BA) 109.1 C(8B)-C(7B)-H(7BB) 109.1 C(7A)-C(8A)-H(8AA) 109.5 C(7A)-C(8A)-H(8AB) 109.5 C(7A)-C(8A)-H(8AC) 109.5 H(8AA)-C(8A)-H(8AB) 109.5 H(8AA)-C(8A)-H(8AC) 109.5 H(8AB)-C(8A)-H(8AC) 109.5 C(7B)-C(8B)-H(8BA) 109.5 C(7B)-C(8B)-H(8BB) 109.5 C(7B)-C(8B)-H(8BC) 109.5 H(8BA)-C(8B)-H(8BB) 109.5 H(8BA)-C(8B)-H(8BC) 109.5 H(8BB)-C(8B)-H(8BC) 109.5 O(1A)-C(9A)-N(1A) 122.6(11) O(1A)-C(9A)-C(10) 121.8(10) N(1A)-C(9A)-C(10) 115.5(9) O(1B)-C(9B)-N(1B) 123(2) O(1B)-C(9B)-C(10) 120.3(18) N(1B)-C(9B)-C(10) 116.8(17) C(11)-C(10)-C(9A) 115.5(7) C(11)-C(10)-C(9B) 123.0(10) C(11)-C(10)-C(15) 118.8(6) C(15)-C(10)-C(9A) 125.6(7) C(15)-C(10)-C(9B) 116.7(10) C(10)-C(11)-H(11) 119.3 C(12)-C(11)-C(10) 121.5(7) C(12)-C(11)-H(11) 119.3 C(11)-C(12)-H(12) 120.7 C(11)-C(12)-C(13) 118.6(7) C(13)-C(12)-H(12) 120.7 C(12)-C(13)-Br(1) 119.6(6) C(14)-C(13)-Br(1) 118.8(6) C(14)-C(13)-C(12) 121.7(7) C(13)-C(14)-H(14) 120.1 C(13)-C(14)-C(15) 119.8(6) C(15)-C(14)-H(14) 120.1 C(10)-C(15)-H(15) 120.2 C(14)-C(15)-C(10) 119.6(6) C(14)-C(15)-H(15) 120.2
172 Iron-catalyzed synthesis of unprotected primary amines
X-ray structure of compound 18HCl, Table 10
Crystals of the major diastereomer (Figure S2) were obtained by evaporation from
DCM/MeOH/HCl in Et 2O. The X-ray data was collected to establish the relative stereochemistry. The structure indicated (1 R*,2 R*)-2-chlorocyclohexan-1-aminium chloride as the major isomer.
Figure S2. Molecular conformational of (1 R*,2 R*)-2-chlorocyclohexan-1-aminium chloride in crystals.
5. Experimental part 173
Table S3. Crystal data and structure refinement.
Identification code 11378
Empirical formula C12 H24 Cl 3 N2 Color colourless Formula weight 302.68 g · mol -1 Temperature 100(2) K Wavelength 1.54178 Å Crystal system MONOCLINIC
Space group P2 1/c, (no. 14) Unit cell dimensions a = 5.4638(2) Å α= 90°. b = 6.1305(2) Å β= 92.609(2)°. c = 22.4628(7) Å γ = 90°. Volume 751.63(4) Å 3 Z 2 Density (calculated) 1.337 Mg · m -3 Absorption coefficient 5.364 mm -1 F(000) 322 e Crystal size 0.184 x 0.174 x 0.060 mm 3 θ range for data collection 7.490 to 63.628°. Index ranges -6 ≤ h ≤ 6, -7 ≤ k ≤ 7, -26 ≤ l ≤ 25 Reflections collected 10589
Independent reflections 1235 [R int = 0.0493] Reflections with I>2σ(I) 1211 Completeness to θ = 63.628° 99.3 % Absorption correction Gaussian Max. and min. transmission 0.82 and 0.60 Refinement method Full-matrix least-squares on F 2 Data / restraints / parameters 1235 / 0 / 87 Goodness-of-fit on F 2 1.061 2 Final R indices [I>2σ(I)] R1 = 0.0447 wR = 0.1092 2 R indices (all data) R1 = 0.0452 wR = 0.1095 Largest diff. peak and hole 1.0 and -0.6 e · Å -3
174 Iron-catalyzed synthesis of unprotected primary amines
Table S4. Bond lengths [Å] and angles [°]. Cl(1)-C(2) 1.811(3) N(1)-C(1) 1.485(3) C(1)-C(2) 1.524(4) C(1)-C(6) 1.532(4) C(2)-C(3) 1.527(4) C(3)-C(4) 1.527(4) C(4)-C(5) 1.521(4) C(5)-C(6) 1.534(4)
N(1)-C(1)-C(2) 113.5(2) N(1)-C(1)-C(6) 109.5(2) C(2)-C(1)-C(6) 108.3(2) C(1)-C(2)-Cl(1) 110.08(17) C(1)-C(2)-C(3) 111.4(2) C(3)-C(2)-Cl(1) 109.44(18) C(2)-C(3)-C(4) 110.4(2) C(5)-C(4)-C(3) 111.3(2) C(4)-C(5)-C(6) 111.5(2) C(1)-C(6)-C(5) 111.1(2)