Formal [4 + 2] combined ionic and radical approach of vinylogous enaminonitriles to access highly substituted sulfonyl pyridazines

Abstract

Pyridazine derivatives hold significant interest due to their broad applications in pharmaceuticals and materials science, where they serve as valuable scaffolds for bioactive compounds and functional materials. Here, we report a formal [4 + 2] reaction for the synthesis of 5’-sulfonyl-4’-aryl-3-cyano substituted pyridazine compounds from the reaction between vinylogous enaminonitriles and sulfonyl hydrazides. The key features of our pyridazine synthesis include the transamidation of vinylogous enaminonitriles with sulfonyl hydrazide, radical sulfonylation of the resulting intermediate, and subsequent 6-endo-trig radical cyclization. This reaction proceeds smoothly to deliver a series of pyridazine derivatives in good to high yields. We also found that the sulfonyl group of the synthesized pyridazines can be transformed into C-, O-, or N-containing functional groups. A gram-scale experiment and a diverse transformation of synthesized pyridazines were also performed to validate the practicality of our developed process. In the synthesis of sulfonyl-substituted pyridazines, a 6-endo-trig cyclization via a radical pathway is both kinetically and thermodynamically favored over the cyclization via an ionic pathway, as supported by DFT calculations. Pyridazine is an aromatic heterocyclic compound that is utilized as a bioisostere for benzene or pyridine, and is found in the core scaffold of various drug molecules, making synthetic methods to access pyridazine scaffolds of high interest. Here, the authors report the synthesis of 5’-sulfonyl-4’-aryl-3-cyano substituted pyridazine compounds from a formal [4 + 2] reaction between vinylogous enaminonitriles and sulfonyl hydrazides.