The Paal-Knorr reaction in the synthesis of 1,2-annulated pyrroles

Abstract

An original effective protocol for the synthesis of 1,2-annulated pyrroles has been developed. This new process features the simultaneous formation of both pyrrole and diazepine cores as a result of intramolecular Paal-Knorr reaction of 1,4-dicarbonyl compounds forming during an acid-catalyzed hydrolysis of the corresponding furans 1. A wide variety of pyrrolo[1,2-a][1,4]diazepines 3 and pyrrolo[1,2-d][1,4]diazepines 4, prospective pharmacological agents, was synthesized (path a) [1]. In addition to this, a simple and effective methods for the synthesis of substituted (het)arene-annulated pyrrolo[1,2-d][1,4]diazepines 5 and pyrrolo[1,2-a]quinoxalines 6. The developed approach is based on the acid-catalyzed hydrolysis of substituted furans 2 with the formation of the corresponding 1,4-diketones followed by the key reductive cyclization with the formation of a broad range of nitrogen heterocycles 5, 6 (path b) [2, 3]. The optimal reaction conditions were found, the scope and limitations of the developed method were defined. Cytotoxicity of synthesized 1,2-annulated pyrroles against cell lines HEK293T, VA13, MCF7, A549 and MCF10A was investigated. Research results will be presented in the report.