Work

Difluoromethylene cyclobutyl sulfonium salts: versatile reagents for chemodivergent synthesis of difluoroalkylated cyclobutenes and cyclobutanes

Year: 2025

Type: article

Abstract: Despite the significant applications of fluorinated cyclobutanes in industrial and diagnostic fields, efficient methods for synthesizing these valuable fluorinated structures remain limited. Here, we report a new difluoroalkylating reagent, 2-(difluoromethylene)cyclobutyl sulfonium salts (CB-DFASs). This reagent can be readily synthesized on a gram scale in three steps from readily available cyclobutanone enol silyl ether. CB-DFASs exhibit high reactivity and enable chemodivergent synthesis of structurally diverse difluoroalkylated cyclobutenes using a wide array of nucleophiles, including those based on carbon, oxygen, nitrogen, and sulfur, under mild conditions. The resulting products serve as versatile linchpins for diverse transformations, thereby enabling the synthesis of a variety of difluoroalkylated cyclobutanes. The synthetic utility of CB-DFASs has been demonstrated through the late-stage modification of complex pharmaceuticals and the rapid synthesis of analogues of bioactive molecules, highlighting their potential in drug discovery.

Source: Chemical Science

DOI: 10.1039/d5sc05409e

Authors: Xiao-Tian Feng, Qiao-Qiao Min, Song-Yu Zhang, Hai-Yang Zhao, Xingang Zhang

Institutions: Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences

Language: English

Topic: Fluorine in Organic Chemistry

Subfield: Pharmaceutical Science

Field: Pharmacology, Toxicology and Pharmaceutics

Domain: Life Sciences

Open Access status: diamond

Funders: National Natural Science Foundation of China, Chinese Academy of Sciences

Awards: G1526392360, G5352599485, G6320157872