Native functionality in triple catalytic cross-coupling: sp3 C–H bonds as latent nucleophiles

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Science  10 Jun 2016:
Vol. 352, Issue 6291, pp. 1304-1308
DOI: 10.1126/science.aaf6635

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A tip of the HAT to C-C bond formation

Iridium and nickel are already a proven team for forging carbon-carbon bonds. The iridium harvests blue light from a simple light-emitting diode and orchestrates the coupling by the nickel. Shaw et al. now add a third player to the team, a hydrogen atom transfer (HAT) catalyst (see the Perspective by Fruit). Together, the trio of catalysts can link bromo- or chloroaryl rings directly to C-H sites adjacent to nitrogen or oxygen, with no need for prior modification. The reaction is highly selective across a broad range of substrates.

Science, this issue p. 1304; see also p. 1277


The use of sp3 C–H bonds—which are ubiquitous in organic molecules—as latent nucleophile equivalents for transition metal–catalyzed cross-coupling reactions has the potential to substantially streamline synthetic efforts in organic chemistry while bypassing substrate activation steps. Through the combination of photoredox-mediated hydrogen atom transfer (HAT) and nickel catalysis, we have developed a highly selective and general C–H arylation protocol that activates a wide array of C–H bonds as native functional handles for cross-coupling. This mild approach takes advantage of a tunable HAT catalyst that exhibits predictable reactivity patterns based on enthalpic and bond polarity considerations to selectively functionalize α-amino and α-oxy sp3 C–H bonds in both cyclic and acyclic systems.

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