Mild, Stereoselective, and Highly Efficient Synthesis of N‐Acylhydrazones Mediated by CeCl₃·7H₂O in a Broad Range of Solvents

Abstract

In a mild and practical approach, hydrazides and aldehydes underwent condensation reactions that were mediated by cerium(III) chloride to be rapidly converted into N‐acylhydrazones. This method uses a minimal catalytic amount of cerium(III), is stereoselective, and offers several unique features, such as compatibility with aryl, heterocyclic, alkenyl, and sensitive functional groups as well as the ability to prepare N‐acylhydrazones from highly hindered substrates. More strikingly, cerium(III) efficiently mediated the reaction with less reactive substrates such as diaryl and alkyl aryl ketones, when classical protocols without the catalyst were not effective. This method enables the synthesis of a structurally diverse library of N‐acylhydrazones that have applications in synthetic and medicinal chemistry.

Structural design, synthesis and substituent effect of hydrazone-N-acylhydrazones reveal potent immunomodulatory agents

“…This particular behaviour was investigated by Barreiro et al, [27,28] who found out that it is due to the rotamery associated to specific structural features of such molecules, a conclusion in complete accordance with our previous reports. 8,9 The expected stereochemical features of the HAH derivatives could be confirmed by crystallographic data collected for compound SintMed65 (Fig. 2), which is an all-E,E-planar structure, held by the electronic delocalization through the molecule.…”

“…More remarkable is the stereoselectivity observed from the NMR examination of the crude products, which indicates the presence exclusively of the E-isomer. As previously demonstrated, 8,9 the presence of isomeric mixtures of any nature leads to signal splitting on the 1 H NMR spectra, particularly easy to be observed for the hydrazone's amino hydrogen (ANHAN@), the hydrazone's imino (ANAN@CHA), the amido group (ACONHA), and the methyl linked to the imino portion (AN@CCH 3 A) of the NAH. Most compounds of the series HAH exhibited only one signal for each of the mentioned groups, confirming the more stable Eisomer.…”

“…The methyl substituted aryl carboxylates were then converted into hydrazides by reaction with hydrazine hydrate at 70°C, according to current methodologies in use at SintMed Ò . 8,9 The condensation between the aryl hydrazides and the 4-nitrophenyl ketohydrazone 5 was accomplished under mild conditions in the presence of cerium(III) chloride heptahydrate as catalyst. This methodology was recently developed at SintMed Ò , 8 and is essential to the excellent outcomes observed for the HAH series, since the compound 5 is a vinylogous-like ketone, which does not withstand traditional acid conditions.…”

“…8,9 The condensation between the aryl hydrazides and the 4-nitrophenyl ketohydrazone 5 was accomplished under mild conditions in the presence of cerium(III) chloride heptahydrate as catalyst. This methodology was recently developed at SintMed Ò , 8 and is essential to the excellent outcomes observed for the HAH series, since the compound 5 is a vinylogous-like ketone, which does not withstand traditional acid conditions. Reacting both substrates at 65°C in the presence of 10 mol% CeCl 3 Á7H 2 O and ethanol, total conversion was observed in two hours without any decomposition or side products, as confirmed by TLC, and NMR analysis of crude products.…”

“…The N-acylhydrazone group is a unique moiety very often employed into heterocyclic compounds drug design, which endow molecules with a better thermal stability as well as hydrolytic and chemical stability in comparison to amide group [5][6][7] , in addition to the feasibility of varying chemical composition by substituent variation. [8][9][10][11] Among the pharmacological effects of N-acylhydrazonederived compounds, their anticancer and anti-inflammatory effects are well described. 12,13 More specifically, N-acylhydrazone derivatives have been described as potential inhibitors of COX [14][15][16] , iNOS 17 and phosphodiesterases.…”