Facile synthesis of chiral alpha-difluoromethyl amines from N-(tert-butylsulfinyl)aldimines.

Fluorinated amines are important synthetic building blocks in the design of antimetabolites and drugs because fluorine causes minimal structural changes and maximal shifts in electron distribution. Fluorine lowers the basicity of amines and improves oral absorption, suppresses metabolism, and thus increases the bioavailability of a target drug. Among the fluorinated amines, a-difluoromethyl amines are of particular interest as the CF2H functionality is isosteric to a carbinol (CH2OH) unit and also, as a lipophilic group, it shares much of the dipolar nature of the latter. Therefore, a-difluoromethyl amines can be regarded as more lipophilic bioisosteres of corresponding a-aminocarbinols (or b-amino alcohols), which may feature some significant properties within biologically active molecules. Despite its importance for applications related to life sciences, the synthesis of a-difluoromethyl amines has not been well explored. The few knownmethods are mainly based on the use of difluoromethyl carbonyl compounds or their imine derivatives as precursors. Pey and Schirlin reported the multistep synthesis of a-difluoromethyl amines from substituted malonate esters with CHF2Cl followed by a Curtius rearrangement. However, the general and efficient asymmetric synthesis of a-difluoromethyl amines still remains a challenge although it has drawn many synthetic endeavors. 14] The asymmetric hydrogenation of fluorinated imines are usually difficult, and recently Uneyama and coworkers reported that the palladium-catalyzed asymmetric hydrogenation of difluoromethyl imino esters proceeded with poor enantioselectivity (30% ee). Hydride reduction of the C=N bond of chiral difluoromethyl b-sulfinyl-N-arylimine only gave 82% diastereomeric excess. Difluoropyruvaldehyde N,S-ketal was synthesized in three steps from difluoroacetic esters and chiral methyl p-tolyl sulfoxide in only 72% enantiomeric excess. Conversion of optically pure b-