Catalytic Carbon-Carbon Bond Activation of Saturated and Unsaturated Carbonyl Compounds via Chelate-Assisted Coupling Reaction with Indoles

The chelate assistance strategy was devised to promote a highly regioselective catalytic C-C bond activation reaction of saturated and unsaturated carbonyl compounds. The cationic Ru-H complex 1 was found to be an effective catalyst for mediating the coupling reaction of 1,2-disubstituted indoles with alpha,beta-unsaturated aldehydes and ketones, in which the regioselective C-alpha-C-beta activation of the carbonyl substrates has been achieved in forming the 3-alkylindole products. The analogous coupling reaction of indoles with saturated aldehydes and ketones directly led to the C-alpha- C-beta cleavage of the carbonyl substrates in forming the 3-allcylindole products. The coupling reaction of 1,2-dimethylinole with (E)-3-nonen-2-one and 2-propanol-d(8) showed 20-22% of deuterium incorporation to both alpha- and beta-CH2 of the 3-alkylindole product. The coupling reaction of 1,2-dimethylinole with (E)-3-nonen-2-one exhibited the most significant carbon kinetic isotope effect on the alpha-carbon of the product (C-alpha = 1.046). The Hammett plot constructed from the reaction of 1,2-dimethylinole with a series of para-substituted enones p-X-C6H4CH=CHCOCH3 (X = OMe, Me, H, Cl, CF3) showed a modest promotional effect by an electron-donating group (rho = -0.2 +/- 0.1). Several catalytically relevant Ru-H species were detected by NMR from a stoichiometric reaction mixture of the Ru-H complex 1 with 1,2-dimethylindole and (E)-3-nonen-2-one in CD2Cl2. These results support a mechanism of the catalytic coupling reaction via conjugate addition of indoles to enones followed by the C-C bond activation and hydrogenolysis steps.