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

Abstract

The first asymmetricc atalyzed aza-Henry reaction of hydrazones is presented. In this process, quininew as used as the catalyst to synthesize different alkyl substituted b-nitrohydrazides with ee up to 77 %. This ee wasi mproved up to 94 %b yafurther recrystallization and the opposite enantiomer can be obtained by using quinidinea st he catalyst, opening exciting possibilities in fields in which the control of chirality is vital, such as the pharmaceutical industry. Additionally,e xperimental and ab initio studies were per-formed to understand the reaction mechanism. The experimental resultsr evealed an unexpected secondary kinetic isotope effect (KIE) that is explained by the calculated reaction pathway, which showst hat the protonation of the initial hydrazone and the CÀCb ond forming reaction occur during a concerted process. This concerted mechanism makes the catalysis conceptually different to traditionalb ase-promoted Henrya nd aza-Henry reactions.Supporting information and the ORCID identification number(s) for the author(s) of this articlecan be found under: https://doi.Scheme2.Catalysts tested in the asymmetricaddition of nitromethane(2a)t oN-acylhydrazone 1a.DCM = dichloromethane; n.r. = no reaction;n.d. = not determined; rac. = racemic mixture;r .t. = roomtemperature.Scheme4.Proposed catalytic cycle for the asymmetric organocatalyzed addition of nitromethane 2a to hydrazones 1.

Asymmetric aza-Henry reaction of hydrazones

“…Finally, under the optimized reaction conditions, the desired product 3aa was obtained with unprecedented yield and enantioselectivity. This procedure let us synthetize a great number of enantio-enriched alkyl β-nitroalkylhydrazides (up to 14 examples) with moderate to excellent yields (18-91%) and moderate to good enantioselectivities (39-77% ee) starting from different N-benzoyl hydrazones and nitroalkanes (Scheme 3) [12]. For those reactions carried out at room temperature, different substrates provided, in general, similar results of enantioselectivity.…”

“…The absolute configuration of each enantiomer was studied through its X-ray structure after grown single crystals in ethyl acetate/toluene mixtures. Hence, quinine catalyst led to the obtainment of the (S)-adduct, whereas the use of quinidine afforded the (R)-isomer [12].…”

“…In an initial study, we explored the catalytic activity of different cinchone alkaloid derivatives in the addition of nitromethane (2a) to the N-p-nitrobenzoyl hydrazone 1a (Scheme 2). In addition to cinchone derivatives 4a-d, other interesting bifunctional basic and acid organocatalysts were tested [12].…”

“…To acquire a better understanding on the activation of substrates by the catalyst as well as the origin of the enantioselection in the catalytic process, the full catalytic pathway was study using ab initio calculations [12]. As a result of the study, some conclusions can be deduced:…”

“…In contrast, at the present work, we have developed a method for the efficient asymmetric synthesis of alkyl β-nitroalkylhydrazides. To achieve this goal, we have carried out the enantioselective catalyzed addition of nitroalkanes to hydrazones for the first time (Scheme 1) [12]. Scheme 1.…”