Parallel Synthesis of a Library of Benzoxazoles and Benzothiazoles Using Ligand-Accelerated Copper-Catalyzed Cyclizations of <i>ortho</i>-Halobenzanilides

TLDR

The approach complements the more commonly used benzoxazole synthesis strategies that rely on 2‑aminophenols as substrates. A general copper‑catalyzed cyclization of ortho‑haloanilides is reported for the formation of benzoxazoles. The reaction proceeds via an intramolecular C–O cross‑coupling that follows a Cu(I)/Cu(III) oxidative‑insertion/reductive‑elimination cycle, with optimal conditions employing CuI and 1,10‑phenanthroline (10 mol %). The method also generates benzothiazoles, benefits from ligand acceleration (e.g., 1,10‑phenanthroline, N,N'-dimethylethylenediamine), enables parallel synthesis of diverse benzoxazole and benzothiazole libraries, works with ortho‑bromo, –iodo, and –chloro substrates, and shows a reaction rate order I > Br > Cl consistent with oxidative addition being rate‑determining.

Abstract

A general method for the formation of benzoxazoles via a copper-catalyzed cyclization of ortho-haloanilides is reported. This approach complements the more commonly used strategies for benzoxazole formation which require 2-aminophenols as substrates. The reaction involves an intramolecular C−O cross-coupling of the ortho-haloanilides and is believed to proceed via an oxidative insertion/reductive elimination pathway through a Cu(I)/Cu(III) manifold. The reaction is also applicable to the formation of benzothiazoles. A variety of ligands including 1,10-phenanthroline and N,N'-dimethylethylenediamine were shown to provide ligand acceleration/stabilization in the reaction. Optimal conditions for cyclization used a catalyst combination of CuI and 1,10-phenanthroline (10 mol %). The method was amenable to a parallel-synthesis approach, as demonstrated by the synthesis of a library of benzoxazoles and benzothiazoles substituted at various positions in the ring. Most examples utilized the cyclization of ortho-bromoanilides, but ortho-iodoanilides and ortho-chloroanilides also undergo a reaction under these conditions. The rate of reaction of the ortho-haloanilides follows the order I > Br > Cl, consistent with oxidative addition being the rate-determining step.