Asymmetric aza-Henry reaction of hydrazones

Abstract

In this work, the enantioselective organocatalyzed addition of nitroalkanes to N-benzoyl hydrazones has been developed for the first time. In order to find a chiral organocatalyst suitable to promote the reaction under high stereo-control and reaction rates, the catalytic activity of several cinchone-derived Brønsted bases was evaluated. As a result of the study, simple quinine alkaloid was able to catalyze, in the optimal reaction conditions, the synthesis of alkyl substituted betha-nitroalkylhydrazides with good yields (up to 91%) and enantiomeric excesses (up to 77%), while quinidine alkaloid was used to obtain the opposite enantiomer with similar catalytic results. Moreover, the further recrystallization of the corresponding enantio-enriched mixtures led to the obtainment of each enantiomer with ee up to 94%. The scope of the catalytic method was explored (14 examples), and the effect of substitutients present in the substrates was evaluated in terms of activity and selectivity. Additionally, the catalyzed reaction pathway was study ab initio in order to understand the successful chiral induction by the catalyst. Hence, in the transition state of the rate limiting step (RLS), quinine is acting as bifunctional catalyst activating both substrates simultaneously. This step involves the protonation of the hydrazone and the attack of the nitronate anion to the sp2 prochiral center in a concerted process. Experimental kinetic studies support this reaction mechanism.