Radical–carbanion relay enabled by earth-abundant titanium: carboxylation of 1°, 2°, and 3° benzyl chlorides with CO2

Abstract

The catalytic conversion of CO2 into arylacetic acids is of significant interest owing to the prevalence of these scaffolds in nonsteroidal anti-inflammatory drugs (NSAIDs) and fine chemicals. However, existing methods remain constrained by limited substrate scope, reliance on precious metals, or the need for stoichiometric additives. Herein, we report an earth-abundant titanium(iii)-catalyzed reductive carboxylation of benzyl halides with CO2 that operates via a radical–carbanion relay mechanism. This protocol accommodates primary, secondary, and tertiary C(sp3)–Cl bonds, benzyl bromides, and allylic chlorides, and proceeds without magnesium salt additives under oxygen-tolerant conditions. The synthetic utility is demonstrated by gram-scale reactions and the direct one-step synthesis of several NSAIDs. Mechanistic studies combining radical trapping, deuterium-labeling, intermediate characterization, and DFT calculations establish that Ti(iii) promotes inner-sphere chlorine-atom abstraction to generate a benzyl radical, which is captured, reduced to a benzyl anion, and subsequently trapped by CO2, thereby circumventing the prohibitive direct activation of CO2 at the metal center.