A highly efficient metal-free selective 1,4-addition of difluoroenoxysilanes to chromones

Abstract

A highly efficient metal-free selective 1,4-addition reaction of difluoroenoxysilanes to chromones was developed using the low-cost and readily available HOTf as the catalyst, which is a facile and straightforward method to access valuable C2-difluoroalkylated chroman-4-one derivatives. Interestingly, the products could be readily converted to the difluorinated bioisostere of the natural product (S)-2,6-dimethylchroman-4-one and a difluorinated benzo-seven-membered heterocycle via the Schmidt rearrangement reaction. In addition, the in vitro anti-proliferative activities of these synthesized derivatives against human colon carcinoma cells (HCT116) revealed that compound 3g exhibited potent inhibitory effect on HCT116 cancer cells with an IC₅₀ value of 6.37 μM, representing a novel lead compound for further structural optimization and biological evaluation.