Aromatic molecules are key constituents of many pharmaceuticals, electronic materials and commodity plastics. The utility of these molecules directly reflects the identity and pattern of substituents on the aromatic ring. Here, we report the discovery of a palladium(II) catalyst system, incorporating an unconventional ortho-dimethylaminopyridine ligand, for the conversion of substituted cyclohexanones to the corresponding phenols. The reaction proceeds via successive dehydrogenation of two saturated carbon-carbon bonds of the six-membered ring and uses molecular oxygen as the hydrogen acceptor. This reactivity demonstrates a versatile and efficient strategy for the synthesis of substituted aromatic molecules with fundamentally different selectivity constraints from the numerous existing synthetic methods that rely on substitution of a pre-existing aromatic ring.

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Pd-catalyzed aerobic oxidative coupling of arenes provides efficient access to biaryl compounds. The biaryl product forms via C–H activation of two arenes to afford a PdIIArAr′ intermediate, which then undergoes C–C reductive elimination. The key PdIIArAr′ intermediate could form via a “monometallic” pathway involving sequential C–H activation at a single PdII center, or via a “bimetallic” pathway involving parallel C–H activation at separate PdII centers, followed by a transmetalation step between two PdII–aryl intermediates. Here, we investigate the oxidative coupling of o-xylene catalyzed by a PdX2/2-fluoropyridine catalyst (X = trifluoroacetate, acetate). Kinetic studies, H/D exchange experiments and kinetic isotope effects provide clear support for a bimetallic/transmetalation mechanism.

An improved method for direct oxidative coupling of o-xylene could provide streamlined access to an important monomer used in polyimide resins. The use of 2-fluoropyridine as a ligand has been found to enable unprecedented levels of chemo-and regioselectivity in this Pd-catalyzed aerobic oxidative coupling reaction. Preliminary insights have been obtained into the origin of the effectiveness of 2-fluoropyridine as a ligand. KeywordsC-H activation; palladium; oxidation; oxidative coupling; aerobic oxidation; industrial chemistryThe synthesis of biaryls via direct oxidative coupling of arenes [Eq. (1)] is a prominent contemporary challenge in organic chemistry, and significant recent efforts have been directed toward homocoupling [1] and cross-coupling [2] (1) methods. Reactions of this type first emerged in the mid-1960s, when the oxidative homocoupling of simple arenes was reported by van Helden and Verberg using stoichiometric Pd II salts, [3] and later by Davidson and Triggs using catalytic Pd II . [4] Homocoupling reactions of simple substituted arenes (e.g., toluene, anisole, o-xylene) typically suffer from low regioselectivity, and therefore such reactions have limited utility in organic synthesis. An important exception is the oxidative coupling of dimethyl-o-phthalate. This Pd-catalyzed coupling reaction is an important step in the commercial synthesis of 4,4′-biphthalic anhydride (2), [5,6] a monomer used in the high-performance polyimide resin, Upilex ® (Scheme 1, Route A), [7] and is the basis for recent industrial interest in the development of improved arene homocoupling methods.[8] Production of the bisanhydride monomer 2 could be streamlined significantly by carrying out direct homocoupling of oxylene, followed by aerobic oxidation of the benzylic methyl groups of 4,4′-bixylyl 3 (Scheme 1, Route B).[9] A major barrier to implementing this improved synthetic route is the poor selectivity obtained in the homocoupling of o-xylene. Selectivity challenges include The oxidative coupling of dimethyl-o-phthalate and o-xylene has been the subject of numerous investigations, and the best reported results are presented in Eqs. (3) and (4), respectively.[10] Large-scale reactions of this type are typically stopped at low conversion (≤ 10%) to avoid overoxidation and formation of oligomeric byproducts. The starting materials are recycled to ensure efficient feedstock utilization. In such reactions, product selectivity often becomes a more important measure of the success of the reaction than the single-pass yield. The oxidative coupling of dimethyl-o-phthalate proceeds with sufficient chemo-and regioselectivity [88% and 91%, respectively; Eq. (3)] to be used in the commercial production of 4,4′-biphthalic anhydride 2. In contrast, the oxidative coupling of o-xylene exhibits poor selectivity [40% and 77%, respectively; Eq. (4)].(3)We speculated that the o-xylene coupling reaction could proceed with higher selectivity improved by carrying out the reaction under milder reaction conditions, and that ...

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