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Integrating I(I)/I(III) catalysis in reaction cascade design enables the synthesis of gem-difluorinated tetralins from cyclobutanols

Author

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  • Joel Häfliger

    (Westfälische Wilhelms-Universität (WWU) Münster)

  • Louise Ruyet

    (Westfälische Wilhelms-Universität (WWU) Münster)

  • Nico Stübke

    (Westfälische Wilhelms-Universität (WWU) Münster)

  • Constantin G. Daniliuc

    (Westfälische Wilhelms-Universität (WWU) Münster)

  • Ryan Gilmour

    (Westfälische Wilhelms-Universität (WWU) Münster)

Abstract

Partially saturated, fluorine-containing rings are ubiquitous across the drug discovery spectrum. This capitalises upon the biological significance of the native structure and the physicochemical advantages conferred by fluorination. Motivated by the significance of aryl tetralins in bioactive small molecules, a reaction cascade has been validated to generate novel gem-difluorinated isosteres from 1,3-diaryl cyclobutanols in a single operation. Under the Brønsted acidity of the catalysis conditions, an acid-catalysed unmasking/fluorination sequence generates a homoallylic fluoride in situ. This species serves as the substrate for an I(I)/I(III) cycle and is processed, via a phenonium ion rearrangement, to an (isolable) 1,3,3-trifluoride. A final C(sp3)-F bond activation event, enabled by HFIP, forges the difluorinated tetralin scaffold. The cascade is highly modular, enabling the intermediates to be intercepted: this provides an expansive platform for the generation of structural diversity.

Suggested Citation

  • Joel Häfliger & Louise Ruyet & Nico Stübke & Constantin G. Daniliuc & Ryan Gilmour, 2023. "Integrating I(I)/I(III) catalysis in reaction cascade design enables the synthesis of gem-difluorinated tetralins from cyclobutanols," Nature Communications, Nature, vol. 14(1), pages 1-8, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-38957-w
    DOI: 10.1038/s41467-023-38957-w
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    References listed on IDEAS

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    1. Paul A. Wender & Benjamin L. Miller, 2009. "Synthesis at the molecular frontier," Nature, Nature, vol. 460(7252), pages 197-201, July.
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