Regioselective synthesis of 3-halo-2H-chromenes via decarboxylative halogenation of oxygenated 3-carboxy-2H-chromenes: Application to isoflavonoid synthesis

A practical and regioselective method has been developed for 3-halo-2H-chromene synthesis via decarboxylative halogenation. These chromenes are key intermediates in synthesizing isoflavene derivatives and related bioactive compounds, including molecules of interest in agrochemical research. In this study, 3-carboxy-2H-chromenes, prepared from salicylaldehyde-derived cyanochromenes, were subjected to decarboxylative halogenation under mild conditions. Systematic evaluation of halogen sources, bases, solvents, and other reaction parameters revealed that combining tetrabutylammonium tribromide with sodium-containing bases in acetonitrile promotes decarboxylative bromination with high regioselectivity. This method was designed for chromene substrates bearing oxygen-containing functional groups, which are often difficult to synthesize due to competing electrophilic aromatic substitutions. The optimized protocol, demonstrated on gram scale, afforded the corresponding 3-bromo-2H-chromene as the sole isolable species without requiring column chromatography. The resulting 3-bromo-2H-chromene was converted into an isoflavene derivative via Suzuki–Miyaura coupling, accomplishing its first convergent synthesis as well as formal total synthesis of an isoflavan natural product.