[2,3]-Rearrangement

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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
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Allylamines compounds
Allylamines compounds are key building blocks in organic chemistry
2
Allylic amination : previous work
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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.
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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
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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.
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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
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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.
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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.
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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.
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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)
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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.
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This Work
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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
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Optimization
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Palladium source, solvent, T°C :
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Optimization
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Ligand screening :
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Optimization
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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
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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
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Mechanism
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Vigabatrin synthesis
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Application of this methodology via Vigabatrin (Sabril ® ; antiepileptic drug)
synthesis
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Benzenesulfonyl sulfurdiimide
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Commercially available :
CAS : 667-20-9
Price : $26,60/gr Sigma-Aldrich
•
Synthesis :
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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
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Hartwig Ir
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Carreira Ir
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