Convenient Access to meta‐Substituted Phenols by Palladium‐Catalyzed Suzuki–Miyaura Cross‐Coupling and Oxidation

Abstract

We report a new approach to the synthesis of meta-substituted phenols in which a single palladium catalyst accomplishes a Suzuki-Miyaura cross-coupling between a β-chlorocyclohexenone and an arylboronic acid, and oxidation of the resulting cyclohexenone to the corresponding phenol upon introduction of a terminal oxidant and electron transfer mediator. Notably, this method also allows ready access to ortho, meta-disubstituted phenols, sterically congested biaryl phenols, and more highly substituted phenols.

Scalable and Chemoselective Synthesis of γ-Keto Esters and Acids via Pd-Catalyzed Carbonylation of Cyclic β-Chloro Enones

“…These reactions can be carried out at high reaction concentrations on a multigram scale, providing rapid and efficient access to these versatile compounds. − We believe a key element of the carbonylation reactivity observed is coordination of the enone CC bond to Pd prior to oxidative addition, combined with the high electrophilicity of the β-carbon. This propensity of β-chloro enones to add to Pd(0) will likely find application in many other cross-coupling reactions under mild conditions, especially given that the chloro enone moiety can be functionalized in the presence of many other potentially sensitive groups. Evidently, a chloro enone can be more activated toward oxidative addition in comparison to an aryl bromidewhen an appropriate ligand is usedenabling chemoselective functionalization.…”

Phenol-Directed C–H Functionalization

“…In this context, recent work by Fier and Maloney to develop hydroxide surrogates is noteworthy since it has enabled the synthesis of phenols under much milder conditions. − One example is provided in Scheme a, in which Ullmann-type hydroxylation of a base-sensitive substrate is made possible by using oxime as a hydroxide equivalent in conjunction with an elegantly optimized Cu catalyst . The strength of the ortho / para electronic bias makes the synthesis of meta -substituted phenols more difficult, but recent strategies beginning from non-aromatic precursors have alleviated some of these limitations and provide an interesting blueprint for future development (Figure D). − Recent work by Stahl is illustrated in Scheme B, in which oxidative coupling of cyclohexanone and an arylboronic acid affords the corresponding meta -functionalized phenol following aerobic dehydrogenation (Scheme b) . Finally, the synthesis of phenols via direct C–H oxygenation has seen recent development.…”