Experimental and Computational Studies on the Ruthenium-Catalyzed Dehydrative C–H Coupling of Phenols with Aldehydes for the Synthesis of 2-Alkylphenol, Benzofuran, and Xanthene Derivatives

Pannilawithana, Nuwan; Pudasaini, Bimal; Baik, Mu-Hyun; Yi, Chae S.

Experimental and Computational Studies on the Ruthenium-Catalyzed Dehydrative C–H Coupling of Phenols with Aldehydes for the Synthesis of 2-Alkylphenol, Benzofuran, and Xanthene Derivatives

2021

Pannilawithana, Nuwan | Pudasaini, Bimal | Baik, Mu-Hyun | Yi, Chae S.

The cationic Ru–H complex [(C₆H₆)(PCy₃)(CO)RuH]⁺BF₄– (1) was found to be an effective catalyst for the dehydrative C–H coupling reaction of phenols and aldehydes to form 2-alkylphenol products. The coupling reaction of phenols with branched aldehydes selectively formed 1,1-disubstituted benzofurans, while the coupling reaction with salicylaldehydes yielded xanthene derivatives. A normal deuterium isotope effect was observed from the coupling reaction of 3-methoxyphenol with benzaldehyde and 2-propanol/2-propanol-d₈ (kH/kD = 2.3 ± 0.3). The carbon isotope effect was observed on the benzylic carbon of the alkylation product from the coupling reaction of 3-methoxyphenol with 4-methoxybenzaldehyde (C(3) 1.021(3)) and on both benzylic and ortho-arene carbons from the coupling reaction with 4-trifluorobenzaldehdye (C(2) 1.017(3), C(3) 1.011(2)). The Hammett plot from the coupling reaction of 3-methoxyphenol with para-substituted benzaldehydes p-X-C₆H₄CHO (X = OMe, Me, H, F, Cl, CF₃) displayed a V-shaped linear slope. Catalytically relevant Ru–H complexes were observed by NMR from a stoichiometric reaction mixture of 1, 3-methoxyphenol, benzaldehyde, and 2-propanol in CD₂Cl₂. The DFT calculations provided a detailed catalysis mechanism featuring an electrophilic aromatic substitution of the aldehyde followed by the hydrogenolysis of the hydroxy group. The calculations also revealed a mechanistic rationale for the strong electronic effect of the benzaldehdye substrates p-X-C₆H₄CHO (X = OMe, CF₃) in controlling the turnover-limiting step. The catalytic C–H coupling method provides an efficient synthetic protocol for 2-alkylphenols, 1,1-disubstituted benzofurans, and xanthene derivatives without employing any reactive reagents or forming wasteful byproducts.

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