Diastereoselective Synthesis of Difluoromethylene—Bridged Cyclopropane‐Cyclobutanes from 2‐(Difluoromethylene)‐cyclobutyl Sulfonium Salt and Cyclopropenes

Comprehensive Summary The difluoromethylene‐bridged cyclopropane‐cyclobutane (CP‐CF₂‐CyBu) motif represents a novel fluorinated scaffold that fuses two privileged strained rings, cyclopropane and cyclobutene, both of which constitute valuable structural elements in medicinal chemistry. This unique bicyclic framework offers attractive opportunities for expanding fluorinated chemical space in pharmaceutical design, particularly as compact, three‐dimensional bioisosteres capable of enhancing metabolic stability and conferring conformational restriction. However, practical synthetic routes to access these strained bicyclic scaffolds remain underdeveloped. Herein, we report an efficient and operationally straightforward method for the diastereoselective synthesis of the CP‐CF 2 ‐CyBu scaffold through copper‐catalyzed hydrodifluoroalkylation of cyclopropenes, employing 2‐(difluoromethylene)cyclobutyl sulfonium salt (CB‐DFAS) as the key fluoroalkylating reagent. This reagent is readily prepared in multigram quantities via a concise three‐step synthesis. The protocol proceeds through in situ generated copper hydride species, involving CuH‐mediated hydrocupration followed by oxidative addition, thereby delivering diverse CP‐CF 2 ‐CyBu products with high efficiency and diastereoselectivity under mild conditions. Notably, the reaction exhibits ligand‐dependent stereodivergence: 1,1‐disubstituted cyclopropenes with triphenylphosphine afford syn ‐diastereomers preferentially via a chelation‐controlled transition state, whereas 1,2‐disubstituted cyclopropenes with a bulky N ‐heterocyclic carbene ligand ( L8 ) furnish anti ‐diastereomers selectively through non‐chelation pathway governed by cage strain effect. Both pathways achieve high diastereoselectivities (up to >20 : 1 dr) and exhibit broad functional group tolerance, accommodating sensitive motifs including boronates, nitriles, halides, and nitro groups that remain compatible for downstream elaboration. The synthetic utility of this method is demonstrated by diverse transformations of the CP‐CF 2 ‐CyBu products, including hydrogenation, reduction, and dihydroxylation, thereby providing streamlined access to complex, medicinally relevant fluorinated bicyclic frameworks previously inaccessible via conventional synthetic strategies. This work establishes a practical platform for expanding fluorinated chemical space in drug discovery.