Base-Catalyzed Asymmetric α-Functionalization of 2-(Cyanomethyl)azaarene <i>N</i>-Oxides Leading to Quaternary Stereocenters

Abstract

A simple, new strategy for the direct asymmetric α-functionalization of 2-alkyl azaarenes is described. Specifically, a Brønsted base catalyzed conjugate addition of substituted 2-cyanomethylpyridine (and pyrazine) N-oxides to acrylate equivalents to afford hitherto elusive 2-tert-alkyl azaaryl adducts with high enantioselectivity (up to 94% ee) is realized. Extension of the method to the α-amination reaction by using azodicarboxylate esters as electrophiles is also demonstrated. Key for success is the N-oxide functionality of substrates that acts as a removable activating and stereodirecting group. A bifunctional Brønsted base catalyst bearing a squaramide with an attached bulky silyl group is also disclosed.