Mild Copper-Catalyzed Synthesis of Benzoxazoles

The influence of metals can allow for unprecedented chemical reactions in organic chemistry. Imines, synthesized through the condensation of an aldehyde and primary amine, are known to be inert to alcohol type nucleophiles, hence their traditional preparation in alcohol solvents. The stability of the imine group changes upon coordination of the imine nitrogen to a transition metal where an alcohol can add across the C=N bond. Crystallographic and NMR data show that solvent alcohol can add to coordinated imines to form N,O-aminal or hemiacetal moieties. With this knowledge, the conversion to N,O-aminals was implemented for the synthesis of oxazoles, common substructures in medicinal chemistry, whose previous synthesis from aldehydes necessitated multiple steps and/or unfavorable conditions. The proposed synthesis is facilitated by intramolecular attack of phenol, a poor nucleophile, upon an imine - forming an "oxazoline" N,O-aminal - which then oxidizes to the desired oxazole. The catalytic use of a metal species increases the favorability of this reaction, however previously reported efforts for this approach have still required harsh conditions, including high pressures of O2 in conjunction with heat. Here, we present the use of a Cu(II) triflate catalyst to synthesize a broad substrate scope of benzoxazoles using mild conditions. Full conversion and high isolated yields were obtained by performing the reaction without atmospheric adjustments, low catalyst loadings, and gentle heating. The reaction is largely resistant to steric and electronic impediments to reactivity.