Diastereoselective Construction of a-Fluoroalkyl Cycloalkanols via Radical Alkylation of a-Fluoroalkyl Ketones

a-Fluoroalkyl (R-f) alcohols are privileged motifs in drugs and pharmaceutically active compounds. As such, it is highly desirable to develop efficient methods for assembling these scaffolds. Herein, a visible-light-induced cascade radical cyclization of alkenyl fluoroalkyl ketones is developed, producing a variety of decorate a-R-f cycloalkanols in promising yields with up to >20 : 1 dr selectivity. A radical chain mechanism involving an intramolecular radical addition to the a-R-f carbonyl group and a subsequent intermolecular hydrogen atom transfer (HAT) has been proposed. Density functional theory (DFT) calculations indicate that a fluorine effect contributes to the radical addition to carbonyls by lowering the p* (C=O) orbital energy of CORf and energy barrier of the HAT between alkoxy radicals and THF, which may be valuable for controllable transformations of fluorinated molecules.

Automated summary

In this study, a visible-light-induced cascade radical cyclization method was developed for the synthesis of decorated a-fluoroalkyl cycloalkanols. The fluorine effect was found to play a crucial role in this reaction, as supported by density functional theory calculations.