Mechanistic Studies of the Gas-Phase Cornforth Rearrangement Using Collision-Induced Dissociation and Density Functional Theory

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A mechanistic investigation of the gas-phase Cornforth rearrangement of protonated 2,4,5-trisubstituted oxazoles is presented. Upon collisional activation, these oxazoles undergo a pericyclic ring-opening to generate a nitrile ylide intermediate, which subsequently undergoes a 1,5-dipolar electrocyclization to yield the isomeric thiazole product. An oxygen-to-sulfur replacement was strategically employed as an isosteric labeling approach to probe and monitor the rearranged product ions, [PhCS]+ and [PhC2S]+, in the MS2 spectrum. Quantum chemical calculations at the M06-2X/def2-TZVP level revealed a strong preference for the Cornforth pathway and demonstrated the influence of para-substituents on the phenyl ring, correlating with the intensities of the rearranged product ions. Unlike the condensed-phase reaction, mass spectrometry revealed the potential reversibility of the gas-phase Cornforth rearrangement for trisubstituted oxazoles.