Direct Regioselective para ‐Fluorination via I(I)/I(III) Catalysis

ABSTRACT Fluorine scanning is an expansive strategy to refine the physicochemical profile of clinically important small molecule drugs. Of the possible regioisomers derived from mono‐substituted benzenes, the para ‐fluorophenyl motif has emerged as a conspicuous chemotype: Lipitor is a compelling exemplar. When considered through this molecular design lens, the development of effective routes to generate this privileged module, without substrate pre‐functionalization, remains very much in focus. Herein, we report a direct, para ‐selective fluorination that operates under the auspices of I(I)/I(III) catalysis. This enabling strategy leverages the venerable Leonard link inherent to phenylpropanoate and phenylpropanamides to promote a spirocyclization/ para ‐selective activation sequence. Aside from biasing regioselectivity, the C 3 ‐side chain of the Leonard link maps onto a range of common drug scaffolds and allows the substrate scope to be extended to amino acids and dipeptides (up to 94% yield). X‐ray crystallographic analyses of selected products reveal intermolecular Dunitz–Diederich‐type interactions between the C(sp 2 )‐F bond and the π* C═O orbital of proximal amides. It is envisaged that this organocatalytic platform to enable direct para ‐fluorination will facilitate the exploration of organo‐fluorine chemical space.