<i>meta</i> -Chloroperbenzoic-Acid-Promoted Oxidative Annulations of Alkynes and Nitriles into Oxazoles via Putative β-Hydroxy Vinyl Cations

Electrophile-promoted alkyne transformations are fundamental to organic synthesis, yet the utilization of oxygen-centered electrophiles compared to carbon- or other heteroatom-centered ones has remained challenging due to the fundamental mismatch between the low nucleophilicity and electron density of alkynes and the high electronegativity of oxygen which hinders the formation of oxygen-centered cations or highly polarized oxy-electrophiles. Herein, we address this long-standing challenge by reporting the DFT-supported electrophilic hydroxylation of alkynes using meta -chloroperbenzoic acid as an electrophilic hydroxyl donor, generating the proposed β-hydroxy vinyl cations. These putative intermediates were efficiently trapped by nitriles, yielding biologically relevant oxazoles (35–95% yields). This protocol tolerated diverse substituent patterns on both the alkyne and nitrile partners and enabled a concise two-step synthesis of the nonsteroidal anti-inflammatory drug oxaprozin (30% overall yield). Mechanistic investigations via DFT calculations and control experiments not only supported the proposed key elementary step of direct electrophilic hydroxylation of alkynes but also shed light on the intermediacy of the envisioned transient and traditionally elusive β-hydroxy vinyl cations.