Mechanochemical synthesis of 7-oxa-4-thia-1-aza-bicyclo[3.2.1]octane-4,4-dioxides via tandem Michael addition-1,3-dipolar cycloaddition and their antibacterial properties

A solvent-free, green and efficient mechanochemical method for the synthesis of a series of bridged bicyclo aza-sulfone derivatives viz. 7-oxa-4-thia-1-aza-bicyclo[3.2.1]octane-4,4-dioxides via 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. It was found that mostly bicyclo aza-sulfones derived from electron rich aromatic aldehydes inhibit the growth of Mycobacterium smegmatis (mc2-155) and that of aliphatic aldehydes inhibit the growth of Escherichia coli (DH5a) in moderate to good effect. However, butyraldehyde derived compound 4r was found to be very effective against both M. smegmatis and E. coli. The key advantages of this mechanochemical method are catalyst- and solvent-free condition, shorter reaction time, and the new series of 7-oxa-4-thia-1-aza-bicyclo[3.2.1]octane-4,4-dioxide derivatives are good antibacterial agents against M. smegmatis and E. coli.

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