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Functionalization of C(sp3)–H bonds using a transient directing group

Science  15 Jan 2016:
Vol. 351, Issue 6270, pp. 252-256
DOI: 10.1126/science.aad7893

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Amino acids can lend palladium a hand

Metals such as rhodium and palladium (Pd) are adept at activating otherwise inert carbon-hydrogen bonds toward useful reactivity. To get properly oriented, they often require some help from oxygen or nitrogen groups nearby. Appending and removing these directing groups, however, detracts from the efficiency of chemical synthesis. Zhang et al. show that amino acids can act as temporary directing groups in the Pd-catalyzed coupling of arenes with aldehydes or ketones. By reversibly binding to these latter substrates just long enough for the Pd catalysis to ensue, the amino acids eliminate the need for more laborious directing group manipulations.

Science, this issue p. 252

Abstract

Proximity-driven metalation has been extensively exploited to achieve reactivity and selectivity in carbon–hydrogen (C–H) bond activation. Despite the substantial improvement in developing more efficient and practical directing groups, their stoichiometric installation and removal limit efficiency and, often, applicability as well. Here we report the development of an amino acid reagent that reversibly reacts with aldehydes and ketones in situ via imine formation to serve as a transient directing group for activation of inert C–H bonds. Arylation of a wide range of aldehydes and ketones at the β or γ positions proceeds in the presence of a palladium catalyst and a catalytic amount of amino acid. The feasibility of achieving enantioselective C–H activation reactions using a chiral amino acid as the transient directing group is also demonstrated.

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