Pd(II)-Catalyzed ortho- or meta-C–H Olefination of Phenol Derivatives

Abstract

A combination of weakly coordinating auxiliaries and ligand acceleration allows for the development of both ortho- and meta-selective C–H olefination of phenol derivatives. These reactions demonstrate the feasibility of directing C–H functionalizations when functional groups are distal to target C–H bonds. The meta-C–H functionalization of electron-rich phenol derivatives is unprecedented and orthogonal to previous electrophilic substitution of phenols in terms of regioselectivity. These methods are also applied to functionalize α-phenoxyacetic acids, a fibrate class of drug scaffolds.

Accessing Remote meta‐ and para‐C(sp2)−H Bonds with Covalently Attached Directing Groups

“…[12] This approach enabled the highly regioselective meta-olefination of phenols to be achieved (12 a,b). This was aremarkable undertaking since the meta-position of phenol is the least activated towards attack by electrophiles and all attempts at its selective functionalization failed.…”

Transition Metal‐Catalyzed Directing‐Group‐Assisted C−H Activation of Phenols

“…In comparison with examples of ortho CÀHa ctivation of phenol,m ethods for transition-metal-catalyzed meta-o rpara-CÀHa ctivation of phenols is far less common. Notably,o wing to the well-known ortho/para-directing ability of the electrondonating hydroxy group, meta-CÀHf unctionalization of phenols was not reported until 2013, when Yu and co-workersr eported ab reakthrough for CÀHo lefination [50] and arylation [51] of phenol derivatives assisted by an end-on template. These methods override the intrinsic ortho/para selectivity,c oupling with phenolsa tt he meta position.I na ddition, these seminal examples of meta-CÀHf unctionalizations demonstrate the feasibility of activation of the remote CÀHb onds refer to the functional group.…”

Distant C-H Activation/Functionalization: A New Horizon of Selectivity Beyond Proximity

“…Using different templates arylation of hydrocinnamic and phenylpropanoic acid derivatives (Scheme 26), and meta C-H olefination of electron rich alcohols and phenols derivatives were carried out (Scheme 27) (66,67). Mechanism for meta C-H activation was proposed based on the KIE study (Scheme 28) and DFT calculations (Fig.…”