Many chiral primary amines derived from acetophenone analogues including (S)-1-[4-(trifuluoromethoxy)phenyl]ethanamine (2) have been attracting increasing attention as chiral building blocks, especially in the pharmaceutical industry. We have developed an efficient asymmetric synthetic method of enantiomerically pure 2 by employing a combination of direct asymmetric reductive amination (DARA) of p-trifluoromethoxy acetophenone (1) and diastereomeric salt formation with (S)-mandelic acid. DARA represents the most straightforward route to enantiomerically enriched primary amines in comparison with a conventional multi-step procedure consisting of formation of a protected imine, followed by asymmetric hydrogenation, and deprotection of the obtained chiral secondary amine. Using the DARA technology, asymmetric synthesis of 1 was achieved in excellent conversion (&gt;99%) and good enantioselectivity (85% ee.) upon treatment with 0.2 mol% of a new catalyst, [RuCl(p-cymene){(S)-da-binap}]Cl, in the presence of NH4Cl as an amine source and NH4HCO3 as an additive to enhance enantioselectivity under 5 MPa of hydrogen atmosphere at 95 oC for 24 h in MeOH. Moreover, enantiomerically pure 2 (99.0% ee.) was obtained through crystallizing 2 as a diastereomeric salt with (S)-mandelic acid (Scheme 1). This new shortcut method is expected to dramatically reduce the time and waste associated with the reaction in the industrial manufacturing process. Scheme 1. Direct Asymmetric Reductive Amination (DARA) of 1 to 2-(S)-mandelate

New practical method for direct asymmetric reductive amination of p-trifluoromethoxy acetophenone

2019 Fall National Meeting

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