Solvent-Free Microwave-Assisted Preparation of N-(2-(Pyridin-2-yl)-ethyl)sulfonamides

Abstract

Although nitrogen-containing heterocycles and sulfonamides both play crucial roles in the chemical and pharmaceutical industries, surprisingly little research exists that examines the bifunctional N-(2-(pyridin-2-yl)ethyl)sulfonamide scaffold for any potential applications. Retrosynthetic analysis indicates that this skeleton would be well suited for a conjugate addition reaction. However, the ability of 2-vinylpyridine to behave as an acceptor, and of sulfonamides to behave as donors, has very limited literature precedent, and thus required some preliminary investigations into their mutual reactivity. Herein outlines our laboratory's discovery of a novel and efficient solvent-free 1,4-aza-conjugate addition reaction between sulfonamides and 2-vinylpyridines that provides expedient access to various N-(2-(pyridin-2-yl)ethyl)sulfonamide derivatives. The products, possessing multiple sites of Brønsted acidity and basicity in close proximity, could display a wide array of valuable host–guest properties and should thus be investigated for potent pharmaceutical or agrochemical properties.

[Supplementary materials are available for this article. Go to the publisher's online edition of Synthetic Communications® for the following free supplemental resource(s): Full experimental and spectral details.]

GRAPHICAL ABSTRACT

Keywords:

• Conjugate addition
• microwave-assisted synthesis
• sulfonamide
• 2-vinylpyridine

ACKNOWLEDGMENTS

We thank Gregory Schaaf (Seachaid Pharmaceuticals) and Matthias McIntosh (University of Arkansas) for their helpful discussions throughout this project, and CEM Corporation for their temporary loan of a Discover microwave system. This project was significantly funded via Rider University Faculty Development Grants.

Notes

^a Ratios of 1a:2a and 1a:4a determined by ¹H NMR integration analysis.

^a All reactions displayed minimal, if any, by-product via ¹H NMR integration analysis.

^b Ratios of 1:2 determined by ¹H NMR integration analysis.

^c Isolated product yield.

^d Yield based on recovered sulfonamide 3.

^e 0.25 equivalents of Cs₂CO₃ was added.