A solvent free, four-component synthesis and 1,3-dipolar cycloaddition of 4(H)-pyrans with nitrile oxides: Synthesis and discovery of antimycobacterial activity of enantiomerically pure 1,2,4-oxadiazoles

Four-component reactions of (R)-1-(1-phenylethyl)tetrahydro-4(1H)-pyridinone, aromatic aldehydes and malononitrile in a 1:2:1 molar ratio in the presence of solid sodium ethoxide under solvent free conditions afforded an inseparable mixture of two diastereomeric 4(H)-pyrans in near quantitative yields. These compounds upon 1,3-dipolar cycloaddition with nitrile oxides furnished two enantiomerically pure 1,2,4-oxadiazoles in moderate yields, which were screened for in vitro activity against Mycobacterium tuberculosis H37Rv (MTB) and multi-drug resistant M. tuberculosis (MDR-TB). Among the compounds screened, compound 10h was found to be the most active in vitro with a MIC value of 0.07 and 0.14 μM against MTB and MDR-TB respectively.

Graphical abstract1,3-Dipolar cycloaddition of 4(H)-pyrans with nitrile oxides furnished two enantiomerically pure 1,2,4-oxadiazoles, these compounds were screened for their in vitro activity against H37Rv (MTB) and (MDR-TB).Figure optionsDownload full-size imageDownload as PowerPoint slideHighlights► Diastereomeric 4H-pyrans synthesized in near quantitative yields. ► 1,3-Dipolar cycloaddition of 4H-pyrans with nitrile oxides afforded two enantiomerically pure 1,2,4-oxadiazoles. ► The oxadiazoles displayed excellent in vitro antimycobacterial activity against H37Rv (MTB) and MDR-TB.