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.

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

References and Notes

Reviews:

<A NAME="RG34209ST-1A">1a</A> Dalko PI. Moisan L. Angew. Chem. Int. Ed.  2004,  43:  5138 

<A NAME="RG34209ST-1B">1b</A> Dondoni A. Massi A. Angew. Chem. Int. Ed.  2008,  47:  4638 

<A NAME="RG34209ST-1C">1c</A> Melchiorre P. Marigo M. Carlone A. Bartoli G. Angew. Chem. Int. Ed.  2008,  47:  6138 

<A NAME="RG34209ST-2A">2a</A> Blaser H.-U. Pugin B. Spindler F. Thommen M. Acc. Chem. Res.  2007,  40:  1240 ; and references cited therein

See also:

<A NAME="RG34209ST-2B">2b</A> Kadyrov R. Riermeier TH. Angew. Chem. Int. Ed.  2003,  42:  5472 

<A NAME="RG34209ST-2C">2c</A> Li C. Villa-Marcos B. Xiao J. J. Am. Chem. Soc.  2009,  131:  6967 

<A NAME="RG34209ST-3">3</A> Ouellet SG. Walji A. MacMillan DWC. Acc. Chem. Res.  2007,  40:  1327 ; and references cited therein

Reviews:

<A NAME="RG34209ST-4A">4a</A> Benaglia M. Guizzetti S. Pignataro L. Coord. Chem. Rev.  2008,  252:  492 

<A NAME="RG34209ST-4B">4b</A> Denmark SE. Beutner GL. Angew. Chem. Int. Ed.  2008,  47:  1560 

<A NAME="RG34209ST-5A">5a</A> Iwasaki F. Onomura O. Mishima K. Maki T. Matsumura Y. Tetrahedron Lett.  1999,  40:  7507 

<A NAME="RG34209ST-5B">5b</A> Iwasaki F. Onomura O. Mishima K. Kanematsu T. Maki T. Matsumura Y. Tetrahedron Lett.  2001,  42:  2525 

For two recent contributions about the enantioselective synthesis of β-amino acids involving the use of trichloro-silane, see:

<A NAME="RG34209ST-6A">6a</A> Malkov AV. Stoncius S. Vrankova K. Arndt M. Kocovsky P. Chem. Eur. J.  2008,  14:  8082 

<A NAME="RG34209ST-6B">6b</A> 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:

<A NAME="RG34209ST-6C">6c</A> Malkov AV. Figlus M. Prestly MR. Rabami G. Cooke G. Kocovsky P. Chem. Eur. J.  2009,  15:  9651 

<A NAME="RG34209ST-7A">7a</A> Guizzetti S. Benaglia M. Cozzi F. Rossi S. Celentano G. Chirality  2009,  21:  233 

<A NAME="RG34209ST-7B">7b</A> Guizzetti S, and Benaglia M. inventors; EP  2008/010079. 

<A NAME="RG34209ST-7C">7c</A> Guizzetti S, and Benaglia M. inventors; EP  07023240.0. 

<A NAME="RG34209ST-7D">7d</A> Guizzetti S. Benaglia M. Cozzi F. Annunziata R. Tetrahedron  2009,  65:  6354 

<A NAME="RG34209ST-8">8</A> Guizzetti S. Benaglia M. Rossi S. Org. Lett.  2009,  11:  2928 

<A NAME="RG34209ST-9">9</A> See: Alexakis A. Gille S. Prian F. Rosset S. Ditrich K. Tetrahedron Lett.  2004,  45:  1449 ; and references cited therein

<A NAME="RG34209ST-10">10</A> 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 

<A NAME="RG34209ST-11">11</A> For the diastereoselective reduction of these chiral substrates through hydrogenation with different catalytic systems, see: Nugent TC. El-Shazly M. Wachaure VN. J. Org. Chem.  2008,  73:  1297 ; and references cited therein

<A NAME="RG34209ST-12A">12a</A> For selective debenzylation reactions, see: Kanai M. Yasumoto M. Kuriyama Y. Inomiya K. Katsuhara Y. Higashiyama K. Ishii A. Org. Lett.  2003,  5:  1007 

<A NAME="RG34209ST-12B">12b</A>

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

<A NAME="RG34209ST-13">13</A> Wakchaure VN. Mohanty RR. Shaikh AJ. Nugent TC. Eur. J. Org. Chem.  2007,  959 

<A NAME="RG34209ST-14">14</A> Chen ZY. Coates RM. J. Org. Chem.  1990,  55:  3464 

<A NAME="RG34209ST-15">15</A>

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.