We report a ruthenium-catalyzed hydrodeaminative coupling reaction of nitriles with phenols, enabling the regioselective synthesis of 2-substituted phenol derivatives and coumarins. A cationic Ru−H complex in the presence of a mild base (Cs2CO3) promotes direct C−C bond formation between nitriles and phenols or salicylaldehydes, providing efficient access to structurally diverse alkylated phenols and benzopyranones without the need for reactive reagents or the formation of wasteful byproducts. The analogous deaminative coupling reaction of nitriles with amides led to an efficient synthesis of secondary carbonyl amides. Kinetic isotope effect measurements and Hammett analysis reveal that the electronic nature of the nitrile substrates strongly influences the rate-determining step, shifting between C−C bond formation, hydrogen transfer, and reductive elimination depending on the substituent. Density functional theory calculations, supported by natural population analysis, delineate the full catalytic cycle and account for the substituent-dependent energy profiles of key transition states. Spectroscopic detection of a Ru−iminophenol complex and 13C KIE data further corroborate a mechanistic model involving multiple electronically modulated turnover-limiting steps. The combined kinetic and computational study validates a mechanistically guided approach for the catalytic coupling reaction of nitriles with phenols that underscores modulating electronic effects on controlling reaction pathways.
Thennakoon et al. (Wed,) studied this question.