Integrating I(I)/I(III) catalysis in reaction cascade design enables the synthesis of gem-difluorinated tetralins from cyclobutanols.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 37268631.
- Also identified by DOI 10.1038/s41467-023-38957-w and PMC identifier 10238417.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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(sp<sup>3</sup>)-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.