Roles of Ligand and Oxidant in Pd(II)-Catalyzed and Ligand-Enabled C(sp3)-H Lactonization in Aliphatic Carboxylic Acid: Mechanistic Studies

The mechanism of Pd(II)-catalyzed, mono-Nprotected amino acid (MPAA) ligand and TBHP oxidant-mediated lactonization of beta-C(sp(3))-H bond in aliphatic carboxylic acid has been studied. We have shown that the combination of TBHP oxidant and MPAA ligand is very critical: the reaction proceeds via MPAA ligand-mediated Pd(II)/Pd(IV) oxidation by TBHP, followed by C-O reductive elimination from the Pd(IV) intermediate. While Pd(II)/Pd(IV) oxidation is a rate-limiting step, C-H bond activation is the regioselectivity-controlling step. MPAA ligand acts not only as an auxiliary ligand to stabilize the catalytic active species but also as a proton acceptor in C-H bond deprotonation and as a proton donor during Pd(II)/Pd(IV) oxidation by TBHP. The use of a peroxide-based oxidant with the hydroxyl group is required: in the rate-limiting Pd(II)/Pd(IV) oxidation transition state, the H-atom of the OH group participates in the 1,2-hydrogen shift to facilitate proton-shuttling between MPAA ligand and peroxide. Thus, lactonization of the C(sp(3))-H bond in aliphatic carboxylic acid occurs via the Pd(II)/Pd(IV) catalytic cycle, unlike the previously reported Pd(II)-catalyzed pyridone ligand and O-2 oxidant-assisted benzylic C-H lactonization in aromatic o-methyl benzoic acid, which occurs via the Pd(II)/Pd(0) catalytic cycle and an intramolecular S(N)2 nudeophilic substitution mechanism. A comparison of these findings for C(sp(3))-H bond lactonization in aliphatic and aromatic carboxylic acids enabled us to identify the roles of catalyst, substrate, ligand, and oxidant.