Divergent synthesis of coumarin-heterocycle hybrids via isoxazole ring opening

Abstract

Dedication: Dedicated to the memory of Prof. Dr. Volodymyr S. Brovarets, Corresponding Member of the National Academy of Sciences of Ukraine. While his enduring devotion to science left an indelible mark, it was his extraordinary nobility of spirit, wisdom, and deep humanity that truly defined him. He remains an exceptional example of a professor and a human being, continuing to inspire our team and the scientific community. A novel, atom-economical divergent protocol for the synthesis of advanced coumarin-heterocycle hybrids has been developed, leveraging a strategic isoxazole ring opening cascade. Initially, the reaction of starting 6- and 8-(isoxazol-5-yl)coumarins with N,N-dimethylformamide dimethyl acetal (DMFDMA) triggered a tandem ring-cleavage, condensation, and O-methylation sequence, providing highly reactive multi-electrophilic cyanoenaminone building blocks. Subsequent cyclocondensation cascades of these intermediates with 1,2-N,N- and 1,2-N,O-binucleophiles (hydrazines and hydroxylamine hydrochloride) exhibited remarkable, microenvironment-controlled chemoselectivity. In refluxing ethanol, the reaction cleanly afforded preserved carbonyl-linked 5-aminopyrazole and 5-aminoisoxazole derivatives via a sequential addition-elimination and nitrile cyclization pathway. Conversely, conducting the reaction in refluxing acetic acid or pyridine redirected the cyclization exclusively toward the hard carbonyl center, inducing a dehydration-deamination cascade that leaves the nitrile function intact to deliver direct ring-to-ring bound pyrazole-coumarin and isoxazole-coumarin conjugates in excellent yields (up to 96%). The strict regioselectivity and absolute structural connectivity of the resulting 24-membered library were definitively assigned using 1D and 2D NMR spectroscopy (HMBC and NOESY).