7‐Oxa‐4‐thia‐1‐aza‐bicyclo[3.2.1]octane 4,4‐Dioxides: Mechanochemical Synthesis by Tandem Michael Addition–1,3‐Dipolar Cycloaddition of Aldoximes and Evaluation of Antibacterial Activities

Abstract

A solvent‐free, green, and efficient mechanochemical method for the synthesis of a series of bridged bicyclo aza‐sulfone derivatives, namely 7‐oxa‐4‐thia‐1‐aza‐bicyclo[3.2.1]octane 4,4‐dioxides through tandem Michael addition–1,3‐dipolar cycloaddition of aldoximes was developed. Mechanochemical grinding/milling facilitates quick formation of aldoximes from corresponding aldehydes and hydroxylamine, which upon reaction with divinyl sulfone in a mixer mill affords 7‐oxa‐4‐thia‐1‐aza‐bicyclo[3.2.1]octane 4,4‐dioxide derivatives in good overall yields. The newly synthesized bicyclo aza‐sulfone derivatives 4 were screened for antibacterial activities. Mostly bicyclo aza‐sulfones derived from electron‐rich aromatic aldehydes inhibit the growth of Mycobacterium smegmatis (mc 2 155) and those from aliphatic aldehydes the growth of Escherichia coli (DH5α) in moderate to good effect. However, butyraldehyde‐derived compound 4r was very effective against both M. smegmatis and E. coli . The key advantages of this mechanochemical method are catalyst‐ and solvent‐free conditions, shorter reaction time, and formation of a new series of 7‐oxa‐4‐thia‐1‐aza‐bicyclo[3.2.1]octane 4,4‐dioxide derivatives, which are good antibacterial agents against M. smegmatis and E. coli .