A Convenient, Highly Stereoselective, Metal-Free Synthesis of Chiral Amines

Abstract

A low cost, efficient, metal-free highly stereoselective reduction of ketimines to chiral amines was developed. Different imines bearing a very cheap and removable chiral auxiliary were reduced simply by trichlorosilane in the presence of N,N-dimethyl­formamide, often in quantitative yield and complete control of the absolute stereochemistry, to afford highly enantiomerically enriched amines.

Key words

imine reduction - Lewis base - trichlorosilane - chiral auxiliary - chiral amine

References and Notes

• Reviews:
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• See also:
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• Reviews:
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• For two recent contributions about the enantioselective synthesis of β-amino acids involving the use of trichloro-silane, see:
• 6a Malkov AV. Stoncius S. Vrankova K. Arndt M. Kocovsky P. Chem. Eur. J.  2008,  14:  8082 
• 6b Zheng H.-J. Chen W.-B. Wu Z.-J. Deng J.-G. Lin W.-Q. Yuan W.-C. Zhang X.-M. Chem. Eur. J.  2008,  14:  9864 ; and references cited therein
• For a recent contribu-tion in the field, see:
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• 7b Guizzetti S, and Benaglia M. inventors; EP  2008/010079. 
• 7c Guizzetti S, and Benaglia M. inventors; EP  07023240.0. 
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• 10 By ^¹H NMR analysis on the crude reaction mixture and then confirmed after purification only one product was detected; HPLC analysis showed the presence of the other diastereomer to be <0.5%, see Supporting Information. For a recent contribution on the analytical aspect, see: Claridge TDW. Davies SGM. Polywka EC. Roberts PM. Russell AJ. Savory ED. Edward D. Smith AD. Org. Lett.  2008,  10:  5433 
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• 12b

  In our hands the deprotection required hydrogenation for 12 h at 25 ˚C and 9.9 bar, with catalytic amounts of Pd/C.

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15

Typical Experimental Procedure for the Reduction of Ketimines
To a stirred solution of the imine (1 mmol/equiv, for the imine synthesis see Supporting Information) in CH₂Cl₂ (2 mL), DMF (6 mmol/equiv) was added. The mixture was then cooled to -50 ˚C and HSiCl₃ (3 mmol/equiv) was added dropwise by means of a syringe. The reaction was quenched by the addition of NaHCO₃ sat. soln (2 mL). The mixture was allowed to warm up to r.t. and H₂O (2 mL) and CH₂Cl₂ (5 mL) were added. The organic phase was separated and the combined organic phases were dried over Na₂SO₄, filtered, and concentrated under vacuum to afford the crude product.