The bioisosteric properties of both pyridine rings and sulfonamides have allowed these two functionalities to separately reign high in the agrochemical and pharmaceutical industries, respectively. A convergent synthetic protocol designed to marry these two moieties in close proximity would provide facile access to a litany of structurally diverse molecules promising far more than the established chemical and pharmacological properties of the individual pharmacophores themselves. Such strategic placement of two heteroatomic functional groups with orthogonal Brønsted donor/acceptor properties additionally confers predictable tunability of acid/base, chelation, and solubility properties, further expanding the potential of these molecular scaffolds in organocatalysis, pharmaceuticals, and water purification. Our laboratory previously reported access to the N-(2-(pyridin-2-yl)-ethyl)sulfonamide scaffold via the 100% atom-economical microwave-assisted aza-conjugate addition of sulfonamides to derivatized 2-vinylpyridines; however, the substrate scope was practically limited to electron-poor 2-vinylpyridine derivatives, and the general reaction suffered from an unavoidable equilibration precluding reaction completion. We have accordingly shifted our approach to uniting these two moieties via a unique palladium-catalyzed hydrosulfonamidation reaction. This presentation outlines the overall methodological development of the green microwave-promoted anti-Markovnikov hydrosulfonamidation reaction, its proposed mechanistic pathway and rationale, synthetic protocols and characterization of the catalyst and substituted 2-vinylpyridine derivatives, and full characterization data for the resultant N-(2-(pyridin-2-yl)-ethyl)sulfonamide products possessing varying electronic & steric properties.

General reaction scheme for the microwave-assisted anti-Markovnikov hydrosulfonamidation of 2-vinylpyridine derivatives.

Timothy Maxfield

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