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The development of a Pd(II)-catalyzed C-H activation/C-O cyclization reaction directed by a proximate hydroxyl group is described. The reaction provides a new pathway to construct dihydrobenzofurans, including a spirocyclic analogue which is a process that could find potential application in natural product synthesis.

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. [ABSTRACT FROM AUTHOR]

A Pd(II)-catalyzed trifluoromethylation of ortho C-H bonds with an array of N-arylbenzamides derived from berizoic acids is reported. N-Methylforma-mide has been identified as a crucial promoter of C∔CF3 bond formation from the Pd center. X-ray characterization of the C∔H insertion intermediate has revealed a rare coordination mode of acidic amides as directing groups and the origin of their capacity in directing C∔H activation. [ABSTRACT FROM AUTHOR]

The development of a Pd-catalyzed oxidative ortho-C-H borylation with N-arylbenzamides is reported. A modified dibenzylideneacetone (dba) ligand, a weak base, and a strong oxidant are critical for obtaining good yields. The reaction is tolerant of electron-deficient and electron-rich benzamides derived from readily available benzoic acids. The borylated products can be converted to various synthons via diverse transformations. [ABSTRACT FROM AUTHOR]

Modern drug discovery is contingent on identifying lead compounds and rapidly synthesizing analogues. The use of a common pharmacophore to direct multiple and divergent C-H functionalizations of lead compounds is a particularly attractive approach. Herein, we demonstrate the viability of late-stage diversification through the divergent C-H functionalization of sulfonamides, an important class of pharmacophores found in nearly 200 drugs currently on the market, induding the non-steroidal anti-inflammatory blockbuster drug celecoxib. We developed a set of six categorically different sulfonamide C-H functionalization reactions (olefination, arylation, alkylation, halogenation, carboxylation, and carbonylation), each representing a distinct handle for further diversification to reach a large number of analogues. We then performed late-stage, site-selective diversification of a sulfonamide drug candidate containing multiple potentially reactive C-H bonds to synthesize directly novel celecoxib analogues as potential cyclooxygenase-II (COX-2)-specffic inhibitors. Together with other recently developed practical directing groups, such as CONHOMe and CONHC6F5, sulfonamide directing groups demonstrate that the auxiliary approach established in asymmetric catalysis can be equally effective in developing broadly useful C-H activation reactions. [ABSTRACT FROM AUTHOR]