| The design and preparation of new palladium complexes that afford C--F bond formation is described. Aryl fluorides are valuable compounds as pharmaceuticals, agrochemicals, and tracers for positron-emission tomography. Conventional fluorination reactions, however, exhibit a limited substrate scope with respect to the electronic structure of the arene and the functional groups tolerated, and are therefore typically not applicable to late-stage introduction of fluorine into complex functionalized molecules. An arylpalladium(II) complex with a bidentate pyridyl-sulfonamide ligand was identified as a suitable C--F bond formation precursor. The arylpalladium(II) complex was prepared by transmetalation between an arylboronic acid and the corresponding palladium(II) acetate complex, and upon treatment with the electrophilic fluorinating agent, F-TEDA-BF 4, resulted in C--F bond formation with functional group tolerance that surpasses traditional nucleophilic or electrophilic aromatic substitution. Study on the reaction mechanism revealed new features including: (1) the intermediacy of a palladium(IV) fluoride complex that was unambiguously confirmed by X-ray crystallography, (2) the facial kappa3 coordination mode of the pyridyl-sulfonamide ligand that stabilizes the high-valent palladium center, and (3) facile C--F bond formation from the palladium(IV) fluoride complex via C--F reductive elimination.;Guided by the hypothesis that transition metals can yield aryl fluorides more efficiently than main group organometallics because of redox participation of the metal and subsequent C--F reductive elimination from a high-valent metal fluoride, silver(I) was identified as another suitable transition metal for C--F bond formation. A variety of fuctionalized arylstannanes synthesized from the corresponding aryl bromides, iodides, or triflates were fluorinated in the presence of AgOTf and F-TEDA-BF4 in 63--83% yield. The presented fluorination reaction enabled us to access functionalized aryl fluorides including fluoro-deoxy-camptothecin, fluoro-quinine, and fluoro-estrone in three steps from the corresponding phenols, which are otherwise laborious to synthesize. The silver-mediated fluorination was further extended to fluorination of arylboronic acids after discovery of unprecedented transmetalation from an arylboronic acid to silver(I). Analysis of the side reaction, hydrodestannylation, that competes with the desired fluorination thereby hampering catalysis with high turnover, led to the development of a silver-catalyzed fluorination of arylstannanes. The utility of the silver-catalyzed fluorination was demonstrated in the late-stage introduction of fluorine into functionalized molecules including strychnine, ezetimibe, and a rifamycin and taxol derivative. |
