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Radical C(sp3)–H functionalization and cross-coupling reactions

Abstract

C–H functionalization reactions are playing an increasing role in the preparation and modification of complex organic molecules, including pharmaceuticals, agrochemicals and polymer precursors. In recent years, there have been many reports of radical C–H functionalization reactions initiated by hydrogen-atom transfer and proceeding via open-shell radical intermediates. These methods introduce strategic opportunities to functionalize C(sp3)–H bonds. Examples include synthetically useful advances in radical-chain reactivity and biomimetic radical-rebound reactions. A growing number of reactions, however, have been found to proceed via radical relay, whereby hydrogen-atom transfer generates a diffusible radical that is functionalized by a separate reagent or catalyst. The latter methods provide the basis for versatile C–H cross-coupling methods with diverse partners. In this Review, we highlight recent examples of radical-chain and radical-rebound methods to provide context for a survey of emerging radical-relay methods, which greatly expand the scope and utility of intermolecular C(sp3)–H functionalization and cross coupling.

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Fig. 1: Mechanisms and components of radical-chain, radical-rebound and radical-relay reactions.
Fig. 2: Late-stage C(sp3)–H functionalization reactions via radical chain and radical rebound.
Fig. 3: Radical relay involving radical addition to trapping reagents.
Fig. 4: Timeline of representative Kharasch–Sosnovsky-type reactions.
Fig. 5: Summary of Cu/NFSI-catalysed radical-relay functionalization, functionalization/diversification and cross-coupling reactions of benzylic C(sp3)–H bonds.
Fig. 6: Catalytic cycle and radical functionalization mechanisms for Cu/NFSI-catalysed radical-relay reactions.
Fig. 7: Radical-relay C–H functionalization and cross-coupling reactions with catalysts other than copper.
Fig. 8: Photoredox C(sp3)–H functionalization/cross coupling via radical relay.
Fig. 9: Different methods for radical-relay C(sp3)–H functionalization and cross coupling using carbon-centred radicals access via photoredox methods.
Fig. 10: Nickel-catalysed arylation of C(sp3)–H bonds of inexpensive (co)solvents enabled by in situ generation of HAT reagents.
Fig. 11: Radical-relay reactions involving electrochemistry.

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Acknowledgements

This work was supported by funding from the NIH (R35 GM134929).

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D.L.G. and S.-E.S. contributed equally to all aspects of the Review. D.L.G., S.-E.S. and S.S.S. wrote, edited and reviewed the manuscript.

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Correspondence to Shannon S. Stahl.

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Golden, D.L., Suh, SE. & Stahl, S.S. Radical C(sp3)–H functionalization and cross-coupling reactions. Nat Rev Chem 6, 405–427 (2022). https://doi.org/10.1038/s41570-022-00388-4

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