Overcoming Challenges in Small‐Ring Transfer: Direct Decarboxylative Hydroalkylation of Alkenes via Iron‐Thiol Catalysis

Cyclopropanes, especially those substituted with trifluoromethyl (CF₃) groups, are valuable scaffolds in medicinal chemistry. Their enhanced bioavailability contributes to the widespread presence of this motif in a variety of bioactive compounds. Despite the development of multiple synthetic strategies, a direct method for transferring CF₃-containing small rings from their most abundant carboxylic acid surrogates remains a significant challenge. In this work, we overcome the challenging decarboxylation of CF₃-cyclopropyl and CF₃-cyclobutyl carboxylic acids while leveraging the ligand-to-metal charge transfer (LMCT) excited state of photochemically activated iron complexes. The resulting radicals were then engaged in radical addition to alkenes, followed by a timely hydrogen atom transfer (HAT) process mediated by a thiol donor. This efficient iron-thiol cooperative catalysis enables, for the first time, facile hydroalkylation of alkenes with highly reactive CF₃-containing cyclopropyl and cyclobutyl radicals. Synergistic experimental, spectroscopic, and density functional theory (DFT) studies support the proposed reaction mechanism. Additionally, we employed the radical stabilization energy (RSE) scale, developed using isodesmic equations computed at the DFT level, aiming to provide a better understanding of the reluctant radical decarboxylation of small-strained cycloalkanes.