Hantzsch synthesis of substituted dihydropyridines and pyridines using a benign approach

Abstract

The Hantzsch synthesis is a multicomponent reaction which is known for its ease in obtaining the respective 1,4-dihydropyridines. Studies have shown that it is amongst the most complicated multicomponent reactions yet studied due to its potential to undergo different pathways in obtaining the desired adduct. One of the main limitations which lie in this method of preparation of these compounds is the fact that the structural diversity of compounds has been limited to symmetrical dihydropyridines about the ring. A benign approach has been adopted in order to develop an alternative route for obtaining substituted pyridines. This approach has been taken by screening a number of heterogeneous catalysts, optimizing the reaction conditions and then alternating the reagents to analyse the versatility of the method. Two main model reactions have been tested: the 3-component reaction between benzaldehyde, ethyl acetoacetate and ammonium acetate and the 4-component reaction between the before mentioned reagents and dimedone. The optimal conditions occurred when using 40% w/w phosphotungstic acid loaded on neutral alumina support. The results obtained include the formation of the unsymmetrical substituted 1,2-dihydropyridine in just 2.3-5 h at relatively high yields since most were higher than 75%. The conditions developed for the model reactions mentioned have been tested on a variety of substituted benzaldehyde and aliphatic aldehydes. Both classes of aldehydes gave successful results. More over a temperature study was conducted which suggested that this factor has a direct effect on the regioisomerism of the product obtained. The oxidation of the final product to obtain the pyridine occurred in situ while the reaction was carried out under nitrogen. The catalyst chosen has been characterized via X-ray fluorescence spectroscopy and the reusability tests have shown that it could be used up to eight consecutive cycles. Moreover, it has also passed the heterogeneity test.