Synthesis of biologically active [1,5]diazocino[2,1-b]quinazolinones through [4 + 4] cycloaddition of 2-alkynyl quinazolinones with aza-ortho-quinone methides†

We report an atom-economical [4 + 4] cycloaddition of 2-alkynyl quinazolines with aza-ortho-quinone methides (ao-QMs) generated from 2-(bromomethyl)anilines to prepare various [1,5]diazocino[2,1-b]quinazolinones in good to excellent yields in a short reaction time and under mild reaction conditions. Moreover, an estrone-derived [1,5]diazocino[2,1-b]quinazolinone could be easily prepared in 30% total yield over five steps and biological assays reveal that the obtained [1,5]diazocino[2,1-b] quinazolinones significantly inhibited nitric oxide generation in LPS-stimulated RAW264.7 cells. The present method features transition-metal free nature, broad substrate scope, good functional group tolerance, gram-scale preparation, and simple purification operation without flash column chromatography.