Robert PolliceFluorocarbyne Insertion into Benzene Skeletons
Innovative fluorinated synthons essentially advance the organofluorine chemistry. However, the fundamental fluorocarbon synthon, metal-fluorocarbyne, remains largely unexplored, in contrast to its well-established trifluoromethyl and difluorocarbene counterparts. Here, we report a fluorocarbyne-promoted skeletal editing that transforms simple benzenes into precious monofluorinated cycloheptatrienes. This fluorocarbyne insertion features broad functional-group tolerance, exclusive meta-insertion selectivity, and compatibility with arene substrates ranging from benzene to per-substituted derivatives. The selective benzene activation within polyaromatics and successful applications to late-stage drug modifications further demonstrate its utility. Pharmaceutical application to the antiviral agent tecovirimat yielded a fluorinated derivative with an approximately 3-fold increase in aqueous solubility. Mechanistic studies involving intermediate capture and DFT calculations support the fluorocarbyne intermediate and elucidate the origin of meta-insertion and the ring expansion pathway. This work presents the first application of metal-fluorocarbyne in organic synthesis, enabling concurrent fluorine incorporation and scaffold editing.
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Henrique C. S. Junior