Incorporation of transition-metal catalyzed C-H functionalization into synthesis is a powerful strategy for increasing molecular complexity due to the ubiquity of the carbon-hydrogen bond. However, selectively functionalizing the desired C-H bond, and overcoming the lack of reactivity at these sites, ultimately pose problems. These obstacles have been addressed by employing a coordinating functionality to direct metalation of proximal C–H bonds. The nitrile functionality, found in several bioactive molecules, is an attractive synthetic tool too to employ, as harnessing the versatile chelating ability and modifiability of these groups could offer a powerful approach to C–H functionalization. Thus, a nitrile-directed, palladium-catalyzed remote C-H acetoxylation methodology has been developed. By utilizing the weakly chelating property of the nitrile group’s end-on coordination with palladium (σ-donation) unique <i>meta</i>-selective acetoxylation of distal arenes within a molecule is achieved. Additionally, coordination of the nitrile to the metal through donation from the π-system of the carbon-nitrogen triple bond, can be used for directing C–H activation to the <i>ortho-</i>position of the nitrile-containing aromatic ring. Methoxylation and halogenation through this chelation mode has been demonstrated. Employing biaryl substrates afforded by a copper-catalyzed cascade cyanoborylation and Suzuki-type coupling, this transformation is a robust approach to rapid increases in synthetic complexity beginning from simple styrenes.

Cyanoborylation and nitrile-directed C-H activation as a versatile combined approach to C-H functionalization

255th National Meeting (2018)

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