Green Light-Driven, Diastereoselective Synthesis of Pentasubstituted α-Trifluoromethylated Pyrrolidines via a Singlet Carbene Process

Abstract

Trifluoromethylated heterocycles represent privileged structural motifs in pharmaceuticals and agrochemicals, as the incorporation of a CF₃ group significantly enhances metabolic stability, lipophilicity, and bioactivity. Among these, α-trifluoromethyl pyrrolidines have garnered considerable interest; however, stereoselective access to polysubstituted variants remains a persistent synthetic challenge. To tackle this, we report a green light-driven, three-component reaction of α,β-unsaturated ketones, trifluoromethyl diazo compounds, and alkyl nitriles under metal- and photosensitizer-free conditions. This atom-economical and operationally simple protocol, followed by a sequential one-pot NaBH₄/AlCl₃ reduction, efficiently delivers pentasubstituted α-trifluoromethyl pyrrolidines with excellent yields (up to 99%) and exclusive diastereoselectivity (all >20 : 1 d.r.). Mechanistic studies elucidate a concise cascade initiated by photoinduced singlet carbene generation. These electrophilic species are captured by alkyl nitriles, which serve as both solvent and nitrogen donor, to form key fluoroalkyl ylides. Subsequent stereoselective 1,3-dipolar cycloaddition with α,β-unsaturated ketones, followed by reduction, constructs the complex skeleton. This work not only provides a highly practical and green route to valuable fluorinated heterocycles but also advances the fundamental understanding of singlet carbene reactivity, showcasing the remarkable utility of long-wavelength photochemistry in complex molecule synthesis.