Titanium-catalyzed Cross-coupling of Aryl Boronate Derivatives and Aryl Halides en Route to Biaryl Backbones

Abstract

Developing sustainable and low-toxicity catalytic systems for carbon–carbon cross-coupling reactions remains highly desirable in synthetic chemistry. Herein, we report a titanium-catalyzed Suzuki–Miyaura cross-coupling of aryl halides with arylboronic acid derivatives. This protocol provides efficient access to a wide range of biaryl (hetero) frameworks in up to 98% yield across 60 examples with promising functional group tolerance. Its practical utility is highlighted by a gram-scale reaction and late-stage modifications, including the synthesis of an Orelabrutinib core intermediate. Preliminary mechanistic experiments, including radical-trapping, isotope-labeling, electrochemical, Hammett, and crossover studies, reveal reactivity features distinct from those commonly observed in conventional Suzuki–Miyaura cross-coupling. These observations provide experimental constraints for future mechanistic investigations of this titanium-catalyzed transformation.