p-(Dimethylamino)benzaldehyde modification of the Hantzsch reaction: Synthesis of 3-(1H-benzimidazol-2-yl)-5,7-dimethoxyquinolines

Abstract

The Hantzsch synthesis of pyridines usually consists of two stages: a three component cyclocondensation of aldehydes with acetoacetic ester and ammonia (or ammonium acetate) and subsequent oxidation of the 1,4-dihydropyridines formed [1]. Exchange of acetoacetic ester for dimedone similarly gives acridine compounds with an aromatic pyridine ring (including those not containing a substituent at position 10) but the first stage of the reaction involving formaldehyde (or paraformaldehyde) occurs with very low selectivity and in only 41% yield [2]. As we reported earlier [3] the same acridine compound is obtained in 85% yield by replacing formaldehyde by p-(dimethylamino)benzaldehyde 1 in the starting three component system. In this case the reaction of the reagents in refluxing acetic acid does not stop at the formation of the corresponding 10-aryl-1,10-dihydroacridine but is accompanied by a previously unknown aromatization via fission of N,N-dimethylaniline. Such a modification of the Hantzsch reaction has clear advantages: 1) the aldehyde 1 is available and, in contrast to formaldehyde, stable on storage and readily measured out; 2) the use of an oxidant is not required; 3) the N,Ndimethylaniline formed in the reaction has a high solubility and does not hinder the separation of the product from the reaction mixture; 4) the process is single stage and efficient. In our opinion this variation of the Hantzsch reaction can be efficiently used as a novel and convenient method for preparation of compounds with a γ-unsubstituted pyridine ring which we have also demonstrated in our work on the synthesis of novel quinoline compounds.

Synthesis of methyl 6-aryl-5-(1H-benzimidazol-2-yl)-2-methylnicotinates

“…It does not remain as the 1,4-dihydropyridine structure product but readily undergoes aromatization via desarylation (loss of N,N-dimethylaniline). On this basis we have proposed a convenient single-stage method for the synthesis of γ-unsubstituted pyridines condensed with other rings leading to a series of quinoline [2], acridine [3], pyrazolo [3,4-b]pyridine [4], and pyrido [2,3-d]pyrimidine [5] derivatives. In this work the method is extended to the synthesis of previously unknown functionalized pyridines.…”