Metolachlor, asymmetric reductive amination

Reductive amination is a well-known methodology in organic synthesis as is evident from the literature reviews. There are a large number of reports available in the literature that deal with the asymmetric imine reduction, but there are few reports available on asymmetric reductive amination. The asymmetric version of this brilliant methodology was introduced in 1999 when Blaser et al. reported on the first asymmetric reductive amination for the synthesis of metolachlor. ... 

After taking up the challenge for the synthesis of (5)-metolachlor on an industrial scale, Blaser reported on the very first example of asymmetric reductive amination and succeeded to synthesize the desired (5)-enantiomer of metolachlor 77 up to 78% ee ° Blaser optimized the reaction condition where the 2-methyl-5-ethylaniline (MEA, 79) was treated with 1.2 equivalents of dry methoxyacetone (MOA, 78), 0.01 mol% Ir-xyliphos catalyst 81 in the presence of tetrabutylammonium iodide (TBAI), and a small amount of trifluoroacetic acid in cyclohexane as the solvent under 80 bar hydrogen pressure at 50 °C. Within 16 hours, almost complete conversion was reached furnishing the chiral amine 80 with 99% conversion and 78% ee. Upon chloroa-cetylization, 80 afforded the desired compound metolachlor 77 without any loss of enantioselectivity (Scheme 39.20). 

SCHEME 39.20. Synthetic route toward metolachlor 77 first breakthrough in asymmetric reductive amination. 

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