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

Abstract

The cationic Ru−H complex [(C 6 H 6 )(PCy 3 )(CO)-RuH] + BF 4 − (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-d 8 (k H /k D = 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-C 6 H 4 CHO (X = OMe, Me, H, F, Cl, CF 3 ) 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 CD 2 Cl 2 . 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-C 6 H 4 CHO (X = OMe, CF 3 ) 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.

Parametrization of Catalytic Organic Reactions with Convex Hammett Plots

“…The first one consists of Mn­(V) complexes to catalyze hydride and oxygen atom transfer reactions, and the other makes use of Ru with differently substituted phenol ligands to catalyze the hydrogenolysis of ketones . The latter incidentally describes but does not claim to parametrize the effect proposed here, i.e., the use of different catalysts to modulate the Hammett plot from linear to V-shaped, and shows that the V-shaped effect also occurs when the phenol compound is used as a reactant during the Ru-catalyzed coupling reaction with aldehydes …”

“…11 The latter incidentally describes but does not claim to parametrize the effect proposed here, i.e., the use of different catalysts to modulate the Hammett plot from linear to V-shaped, and shows that the V-shaped effect also occurs when the phenol compound is used as a reactant during the Ru-catalyzed coupling reaction with aldehydes. 12 Figure 1B also shows our proposal here, which consists of catalysts able to generate V-shaped Hammett plots by changing the reaction mechanism, after interacting with substrates of opposed electronics. For instance, it is known 13,14 that the hydrogenation reaction proceeds either by populating the 1σ* antibonding orbital of the H−H bond with electron density coming from electron-rich substrate−catalyst intermediates or, on the contrary, by extracting electron density from the 1σ bonding orbital of the same adduct with electron-withdrawing substrates, provided that the catalyst can manifold both mechanisms.…”

Scope and Mechanistic Studies on the Ruthenium-Catalyzed Multicomponent Deaminative C–H Coupling Reaction of Phenols with Aldehydes and Enamines for the Formation of Xanthene and Dioxacyclic Derivatives

“…We previously discovered that both the tetranuclear Ru–H complex [(PCy 3 )­(CO)­RuH] 4 (μ-O)­(μ-OH) 2 ( 1 ) and the cationic Ru–H complex [(η 6 -C 6 H 6 )­(PCy 3 )­(CO)­RuH] + BF 4 – ( 2 ) with a redox-active 3,4,5,6-tetrachloro-1,2-benzoquinone ( L1 ) exhibited uniquely high catalytic activity for the deaminative coupling reactions of ketones with simple amines to form α-alkylated ketone products . We also devised a highly efficient dehydrative C–H coupling reaction of phenols with carbonyl compounds to synthesize oxygen heterocyclic core structures by using the same catalytic system 1 / L1 . We reasoned that merging these two C–H coupling and deaminative coupling methods might lead to a step-efficient synthetic strategy for a variety of heterocyclic compounds.…”

Ruthenium(0)-catalyzed cross-coupling of aryl methyl ethers with organoboranes by selective C–O cleavage

“…Likewise, few studies have been reported on the kinetic and thermodynamic selectivity of C–OMe bond activation vs. other inert bonds. 14…”