The search for more effective and highly selective C–H bond oxidation of accessible hydrocarbons and biomolecules is a greatly attractive research mission. The elucidating of mechanism and controlling factors will, undoubtedly, help to broaden scope of these synthetic protocols, and enable discovery of more efficient, environmentally benign, and highly practical new C–H oxidation reactions. Here, we reveal the stepwise intramolecular SN2 nucleophilic substitution mechanism with the rate-limiting C–O bond formation step for the Pd(II)-catalyzed C(sp3)–H lactonization in aromatic 2,6-dimethylbenzoic acid. We show that for this reaction, the direct C–O reductive elimination from both Pd(II) and Pd(IV) (oxidized by O2oxidant) intermediates is unfavorable. Critical factors controlling the outcome of this reaction are the presence of the η3-(π-benzylic)–Pd and K+–O(carboxylic) interactions. The controlling factors of the benzylic vs ortho site-selectivity of this reaction are the: (a) difference in the strains of the generated lactone rings; (b) difference in the strengths of the η3-(π-benzylic)–Pd and η2-(π-phenyl)–Pd interactions, and (c) more pronounced electrostatic interaction between the nucleophilic oxygen and K+cation in the ortho-C–H activation transition state. The presented data indicate the utmost importance of base, substrate, and ligand in the selective C(sp3)–H bond lactonization in the presence of C(sp2)–H.
Ligand-enabled ortho -C–H olefination of phenylacetic amides with unactivated alkenes
Although chelation-assisted C–H olefination has been intensely investigated, Pd( ii )-catalyzed C–H olefination reactions are largely restricted to acrylates and styrenes. Here we report a quinoline-derived ligand that enables the Pd( ii )-catalyzed olefination of the C(sp 2 )–H bond with simple aliphatic alkenes using a weakly coordinating monodentate amide auxiliary. Oxygen is used as the terminal oxidant with catalytic copper as the co-oxidant. A variety of functional groups in the aliphatic alkenes are tolerated. Upon hydrogenation, the ortho -alkylated product can be accessed. The utility of this reaction is also demonstrated by the late-stage diversification of drug molecules.
- Award ID(s):
- Publication Date:
- NSF-PAR ID:
- Journal Name:
- Chemical Science
- Page Range or eLocation-ID:
- 1311 to 1316
- Sponsoring Org:
- National Science Foundation
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Unconventional mechanism and selectivity of the Pd-catalyzed C–H bond lactonization in aromatic carboxylic acid
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