Asymmetric Organocatalyzed Aza-Henry Reaction of Hydrazones: Experimental and Computational Studies

Abstract

The first asymmetric catalyzed aza-Henry reaction of hydrazones is presented. In this process, quinine was used as the catalyst to synthesize different alkyl substituted β-nitrohydrazides with ee up to 77 %. This ee was improved up to 94 % by a further recrystallization and the opposite enantiomer can be obtained by using quinidine as the catalyst, opening exciting possibilities in fields in which the control of chirality is vital, such as the pharmaceutical industry. Additionally, experimental and ab initio studies were performed to understand the reaction mechanism. The experimental results revealed an unexpected secondary kinetic isotope effect (KIE) that is explained by the calculated reaction pathway, which shows that the protonation of the initial hydrazone and the C-C bond forming reaction occur during a concerted process. This concerted mechanism makes the catalysis conceptually different to traditional base-promoted Henry and aza-Henry reactions.

Keywords: aza-Henry reaction; computational calculations; hydrazones; nitroalkanes; synthetic methods.