Catalytic Enantioselective Allylic Amination of Unactivated Terminal Olefins Via an Ene Reaction / [2,3]-Rearrangement Hongli Bao & Uttam K. Tambar Guillaume Benoit Charette Group– Literature meeting 02/10/ (This article was featured in the Editors’ Choice section of Science, Synfacts, Synform and Organic Highlights)

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 S N 2 or S N 2’ reactions. 4 Gabriel, S. Ber.1887, 20, Zwierzak, A.; Pilichowska, S. Synthesis 1982, 1982, 922.

Allylic amination : previous work Amination of allyl alcohol : Mitsunobu reaction 5 Mitsunobu, O.; Yamada, M. Bull. Chem. Soc. Jpn 1967, 40, Sen, S. E.; Roach, S. L. Synthesis 1995, 1995, 756

Allylic amination : previous work Amination of allyl alcohol : Overman rearrangement Enantioselective version : 6 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, By addition of Mercury (II) salts, the reaction can be run at rt Catalyst 5 mol% ; DCM (0.6M) ; 38°C ; 18h ­>95% ee for (E)-olefins

Allylic amination : previous work  Amination of allyl halides, acetates, carbonates catalyzed by transition metal complexes Trost : 7 Trost, B. M.; Bunt, R. C. J. Am. Chem. Soc. 1994, 116, Trost, B. M.; Crawley, M. L. Chem. Rev. 2003, 103, Trost, B. M.; Zhang, T.; Sieber, J. D. Chem. Sci. 2010, 1, 427. nYield (%)ee (%)

Allylic amination : previous work  Amination of allyl halides, acetates, carbonates catalyzed by transition metal complexes Hartwig : amination with iridium-phosphoramidite complex 8 Ohmura, T.; Hartwig, J. F. J. Am. Chem. Soc. 2002, 124, Pouy, M. J.; Stanley, L. M.; Hartwig, J. F. J. Am. Chem. Soc. 2009, 131, Hartwig, J. F.; Stanley, L. M. Acc. Chem. Res. 2010, 43, 1461.

Allylic amination : previous work  Amination of allyl halides, acetates, carbonates catalyzed by transition metal complexes Carreira : iridium catalyzed allylic amination of racemic allylic alcohol 9 Defieber, C.; Ariger, M. A.; Moriel, P.; Carreira, E. M. Angew. Chem. Int. Ed. 2007, 46, Lafrance, M.; Roggen, M.; Carreira, E. M. Angew. Chem. Int. Ed. 2012, 51, 3470.

Allylic amination : previous work  Amination based on Ene-reaction followed by [2,3]-sigmatropic rearrangement Kresze ; Sharpless ; Katz 10 Schönberger, N.; Kresze, G. Liebigs Ann. 1975, 1975, ; 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, ; Bruncko, M.; Khuong, T.-A. V.; Sharpless, K. B. Angew. Chem. Int. Ed. 1996, 35, 454.

This Work Author profile : Position : Assistant Professor University of Texas Southwestern Medical Center Educational Background : 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 (James Leighton) 11 Uttam K. Tambar

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, Tandem Catalytic Allylic Amination and [2,3]-Stevens Rearrangement of Tertiary Amines. J. Am. Chem. Soc. 2011, 133,

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 Polyunsaturated terminal olefins Protected Heteroatoms Electrophilic functional groups 17 nyield (%)ee (%) nyield (%)ee (%) nyield (%)ee (%)

Mechanism 18

Vigabatrin synthesis Application of this methodology via Vigabatrin (Sabril ® ; antiepileptic drug) synthesis 19

Benzenesulfonyl sulfurdiimide Commercially available : Synthesis : 20 CAS : Price : $26,60/gr Sigma-Aldrich

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