カチオン性イリジウム/Me-BIPAM触媒を用いたC-H結合活性化を伴う不斉ヒドロアリール化反応

抄録

In this article, we have summarized our recent efforts to use chiral bidentate phosphoramidites for asymmetric hydroarylation. Asymmetric intramolecular hydroarylation of α-ketoamides gave various types of optically active 3-substituted 3-hydroxy-2-oxindoles in high yields with complete regioselectivity and high enantioselectivities (84—98% ee). This asymmetric hydroarylation was realized by the use of the cationic iridium complex [Ir(cod)₂](BAr^F₄) and the chiral O-linked bidentate phosphoramidite (R,R)-Me-BIPAM. A catalytic cycle involving C-H bond cleavage to give an Ar-[Ir]⁺ intermediate, insertion of a carbonyl group into the aryl-iridium bond, giving iridium alkoxide, and finally reductive elimination to reproduce active [Ir]⁺ species was proposed. The mechanistic insight for the iridium hydride species indicated that the C-H bond cleavage is caused in a reversible manner. Because the kinetic isotope effect was determined that k_H/k_D was 1.85, the C-H bond cleavage step was not included in the turnover-limiting step. In addition, Hammett studies of substrates (ρ=−0.99) demonstrated that electron-donating groups at the para position to the reactive C-H bond accelerate the reaction rate. This linear relationship obtained in the Hammett plot indicated that the nucleophilicity of the aryl-iridium intermediate is an important factor in this reaction. All of the data indicated that carbonyl insertion into aryl-iridium was included in the turnover-limiting step of the catalytic cycle. Meanwhile, highly enantioselective cationic iridium-catalyzed hydroarylation of bicycloalkenes, by carbonyl-directed C-H bond cleavage, was accomplished using a newly synthesized sulfur-linked bis(phosphoramidite) ligand (S-Me-BIPAM). The reaction provided alkylated acetophenone or benzamide derivatives in moderate to excellent yields and good to excellent enantioselectivities. Notably, the hydroarylation reaction of 2-norbornene with N,N-dialkylbenzamide proceeded with excellent enantioselectivity (up to 99% ee) and high selectivity for the mono-ortho-alkylation product. Deuterium incorporation experiments indicated that C-H bond cleavage occurs in a non-reversible manner prior to the alkene insertion. A kinetic isotope effect (KIE) of 2.08 indicated that the turnover-limiting step included the C-H bond cleavage step.