Catalytic Enantioselective Allylic Amination of Unactivated Terminal Olefins Via an Ene Reaction / [2,3]-Rearrangement Hongli Bao & Uttam K. Tambar (This article was featured in the Editors’ Choice section of Science, Synfacts, Synform and Organic Highlights) Guillaume Benoit Charette Group– Literature meeting 02/10/2013 1 Allylamines compounds Allylamines compounds are key building blocks in organic chemistry 2 Allylic amination : previous work 3 Allylic amination : previous work Amination of allyl halides : Gabriel reaction Historically one of the first reaction to syntheses amines via a SN2 or SN2’ reactions. Gabriel, S. Ber.1887, 20, 2224. Zwierzak, A.; Pilichowska, S. Synthesis 1982, 1982, 922. 4 Allylic amination : previous work Amination of allyl alcohol : Mitsunobu reaction Mitsunobu, O.; Yamada, M. Bull. Chem. Soc. Jpn 1967, 40, 2380. Sen, S. E.; Roach, S. L. Synthesis 1995, 1995, 756 5 Allylic amination : previous work Amination of allyl alcohol : Overman rearrangement By addition of Mercury (II) salts, the reaction can be run at rt Enantioselective version : Catalyst 5 mol% ; DCM (0.6M) ; 38°C ; 18h >95% ee for (E)-olefins Overman, L. E. J. Am. Chem. Soc. 1974, 96, 597. Watson, M. P.; Overman, L. E.; Bergman, R. G. J. Am. Chem. Soc. 2007, 129, 5031. 6 Allylic amination : previous work Amination of allyl halides, acetates, carbonates catalyzed by transition metal complexes Trost : n 5 6 7 Trost, B. M.; Bunt, R. C. J. Am. Chem. Soc. 1994, 116, 4089. Trost, B. M.; Crawley, M. L. Chem. Rev. 2003, 103, 2921. Trost, B. M.; Zhang, T.; Sieber, J. D. Chem. Sci. 2010, 1, 427. Yield (%) 87 95 84 ee (%) 94 97 98 7 Allylic amination : previous work Amination of allyl halides, acetates, carbonates catalyzed by transition metal complexes Hartwig : amination with iridium-phosphoramidite complex Ohmura, T.; Hartwig, J. F. J. Am. Chem. Soc. 2002, 124, 15164. Pouy, M. J.; Stanley, L. M.; Hartwig, J. F. J. Am. Chem. Soc. 2009, 131, 11312. Hartwig, J. F.; Stanley, L. M. Acc. Chem. Res. 2010, 43, 1461. 8 Allylic amination : previous work Amination of allyl halides, acetates, carbonates catalyzed by transition metal complexes Carreira : iridium catalyzed allylic amination of racemic allylic alcohol Defieber, C.; Ariger, M. A.; Moriel, P.; Carreira, E. M. Angew. Chem. Int. Ed. 2007, 46, 3139. Lafrance, M.; Roggen, M.; Carreira, E. M. Angew. Chem. Int. Ed. 2012, 51, 3470. 9 Allylic amination : previous work Amination based on Ene-reaction followed by [2,3]-sigmatropic rearrangement Kresze ; Sharpless ; Katz Schönberger, N.; Kresze, G. Liebigs Ann. 1975, 1975, 1725. ; Sharpless, K. B.; Hori, T. J. Org. Chem. 1976, 41, 176. Sharpless, K. B.; Hori, T.; Truesdale, L. K.; Dietrich, C. O. J. Am. Chem. Soc. 1976, 98, 269. ; Kresze, G.; Muensterer, H. J. Org. Chem. 1983, 48, 3561. ; Bruncko, M.; Khuong, T.-A. V.; Sharpless, K. B. Angew. Chem. Int. 10 Ed. 1996, 35, 454. This Work • Author profile : Position : Assistant Professor University of Texas Southwestern Medical Center Educational Background : • • • Uttam K. Tambar A.B. Magna Cum Laude in Chemistry & Physics, Harvard University 2000 (Cynthia Friend and Stuart Schreiber) Ph.D., California Institute of Technology 2006 (Brian Stoltz) NIH Postdoctoral Fellow, Columbia University 2006-2009 (James Leighton) 11 This Work Research Interests : Complex molecule synthesis ; new synthetic methodology ; medicinal chemistry • Selected Publications : Catalytic Enantioselective [2,3]-Rearrangements of Amine N-Oxides. J. Am. Chem. Soc. 2011, 133, 1206-1208. • Tandem Catalytic Allylic Amination and [2,3]-Stevens Rearrangement of Tertiary Amines. J. Am. Chem. Soc. 2011, 133, 12956-12959. 12 This Work • Allylic amination of terminal olefins : 2 steps reaction : - Ene reaction with benzenesulfonyl sufurdiimide to provide the stable zwitterionic Ene-adduct (4) (isolated and purified by a simple filtration) - Palladium catalyzed [2,3]-rearrangement to provide eniantioenriched allylic amine 13 Optimization • Palladium source, solvent, T°C : 14 Optimization • Ligand screening : 15 Optimization • Optimal conditions summary : Catalyst : Pd(TFA)2 (10 mol%) Ligand : Bisoxazoline 6 (12 mol%) Solvent : MeOH (0.13M) T°C : -15°C Time : 2 days 16 Scope Linear hydrocarbon chains Branched hydrocarbons n yield (%) ee (%) 1 89 97 2 89 96 3 88 98 Polyunsaturated terminal olefins n 5 3 Protected Heteroatoms yield (%) ee (%) 97 96 82 96 Electrophilic functional groups n 2 3 7 yield (%) ee (%) 85 97 87 94 94 98 17 Mechanism 18 Vigabatrin synthesis • Application of this methodology via Vigabatrin (Sabril ® ; antiepileptic drug) synthesis 19 Benzenesulfonyl sulfurdiimide • Commercially available : CAS : 667-20-9 Price : $26,60/gr Sigma-Aldrich • Synthesis : 20 Summary Improvement of the Kresze & Sharpless reaction : - 2 separated steps process which allows an enantioselective [2,3] sigmatropic rearrangement Practical method to convert terminal olefins into chiral allylic amines Compatible with a broad range of functional groups 21 Hartwig Ir 22 Carreira Ir 23