Photochemical generation of radicals from alkyl electrophiles using a nucleophilic organic catalyst

Abstract

Chemists extensively use free radical reactivity for applications in organic synthesis, materials science, and life science. Traditionally, generating radicals requires strategies that exploit the bond dissociation energy or the redox properties of the precursors. Here, we disclose a photochemical catalytic approach that harnesses different physical properties of the substrate to form carbon radicals. We use a nucleophilic dithiocarbamate anion catalyst, adorned with a well-tailored chromophoric unit, to activate alkyl electrophiles via an SN2 pathway. The resulting photon-absorbing intermediate affords radicals upon homolytic cleavage induced by visible light. This catalytic SN2-based strategy, which exploits a fundamental mechanistic process of ionic chemistry, grants access to open-shell intermediates from a variety of substrates that would be incompatible with or inert to classical radical-generating strategies. We also describe how the method’s mild reaction conditions and high functional group tolerance could be advantageous for developing C–C bond-forming reactions, for streamlining the preparation of a marketed drug, for the late-stage elaboration of biorelevant compounds and for enantioselective radical catalysis.

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Fig. 1: Strategies for generating radicals.
Fig. 2: Design plan and reaction development.
Fig. 3: Reaction scope.
Fig. 4: Synthetic applications of the method.
Fig. 5: Application in enantioselective radical catalysis.

Data availability:

The data supporting the findings of this study are available within the paper and its Supplementary InformationCrystallographic data for Br-11, an analogue of the major diastereoisomer of compound 11, have been deposited with the Cambridge Crystallographic Data Centre, accession number CCDC 1839232.

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Acknowledgements

We thank ICIQ and the European Research Council (ERC 681840 - CATA-LUX) for financial support. E.P.B. thanks MINECO (CTQ2016-75520-P) for a predoctoral fellowship.

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Authors

Contributions

B.S.-C. was involved in the discovery and initial development of the radical generation strategy. B.S.-C., M.A.H., and E.P.B. performed the experiments. All the authors analyzed the data and designed the experiments. P.M directed the project and wrote the manuscript with contributions from all the authors.

Corresponding author

Correspondence to Paolo Melchiorre.

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Supplementary information

Supplementary information

General information, catalyst synthesis, experimental set-up, mechanistic studies, synthetic procedures, additional references and chemical compound characterization data

Crystallographic data

CIF for Br-11, an analogue of the major diastereoisomer of compound 11; CCDC reference: 1839232

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Schweitzer-Chaput, B., Horwitz, M.A., de Pedro Beato, E. et al. Photochemical generation of radicals from alkyl electrophiles using a nucleophilic organic catalyst. Nature Chem 11, 129–135 (2019). https://doi.org/10.1038/s41557-018-0173-x

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