Palladium-catalyzed intramolecular C(sp(3))--H functionalization: catalyst development and synthetic applications.

A novel catalytic system, based on a mixture of palladium acetate and tris(5-fluoro-2-methylphenyl)phosphane (F-TOTP), has been designed for the intramolecular C--H functionalization of alkane segments. Among other analogues of tris(2-methylphenyl)phosphane (P(o-tol)(3)), F-TOTP was shown to have the optimal metal-bonding properties for this reaction. This catalytic system operated under milder reaction conditions that allowed the regioselective production of various olefins adjacent to a quaternary benzylic carbon atom, as well as novel bi- and tricyclic molecules. A general mechanism was proposed, with the preferential formation of a six-membered palladium(II) palladacycle after oxidative addition and cyclopalladation. The regioselective C--H functionalization of alkyl groups into olefins was illustrated in the synthesis of the antihypertensive drug verapamil and an analogue. A particularly mild ruthenium-catalyzed direct hydroamidation of the intermediate olefin in this synthesis is also reported.