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Ligand-Enabled Reactivity and Selectivity in a Synthetically Versatile Aryl C–H Olefination

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Science  15 Jan 2010:
Vol. 327, Issue 5963, pp. 315-319
DOI: 10.1126/science.1182512

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Heck of an Alternative

The Mizoroki-Heck reaction is widely used in organic synthesis to link together unsaturated carbon fragments such as olefins and arenes. However, one of its drawbacks is the need to append a reactive group such as a halogen to one of the reagents beforehand. Wang et al. (p. 315, published online 26 November) present an alternative palladium-catalyzed reaction that links olefins directly to aryl acids. Oxygen added to the reaction medium concurrently oxidizes the aryl C-H bond at the linkage site, eliminating the need for prior halogenation. Introducing amino acid–derived ligands tunes the aryl site at which the reaction takes place, and efficient reactivity can be achieved across a diverse range of substrates.

Abstract

The Mizoroki-Heck reaction, which couples aryl halides with olefins, has been widely used to stitch together the carbogenic cores of numerous complex organic molecules. Given that the position-selective introduction of a halide onto an arene is not always straightforward, direct olefination of aryl carbon-hydrogen (C–H) bonds would obviate the inefficiencies associated with generating halide precursors or their equivalents. However, methods for carrying out such a reaction have suffered from narrow substrate scope and low positional selectivity. We report an operationally simple, atom-economical, carboxylate-directed Pd(II)-catalyzed C–H olefination reaction with phenylacetic acid and 3-phenylpropionic acid substrates, using oxygen at atmospheric pressure as the oxidant. The positional selectivity can be tuned by introducing amino acid derivatives as ligands. We demonstrate the versatility of the method through direct elaboration of commercial drug scaffolds and efficient syntheses of 2-tetralone and naphthoic acid natural product cores.

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