Synthesis of Fluoro-, Monofluoromethyl-, Difluoromethyl-, and Trifluoromethyl-Substituted Three-Membered Rings

This Minireview describes recent advances toward the synthesis of fluoro-, monofluoromethyl-, difluoromethyl-, and trifluoromethyl-substituted three-membered rings such as cyclopropanes, aziridines, epoxides, episulfides, cyclopropenes, and 2 H-azirines. The main synthetic methodologies since 2016 for cyclopropanes and since 2010 for the other three-membered rings are reported.     

Decarboxylative Fluorination of 2-Pyridylacetates

Syntheses of substituted pyridines and fluorinated compounds, which are often pharmaceutical targets, are important objectives in organic chemistry. Herein, we found that decarboxylative fluorination of lithium 2-pyridylacetates occur under catalyst-free conditions. The phenomenon can be applied to one-pot transformation of substituted methyl 2-pyridylacetate to 2-(fluoroalkyl)pyridine by decarboxylative fluorination of the intermediate lithium 2-pyridylacetate. This method was also applied to the syntheses of 2-(difluoroalkyl)pyridines.     

Decarboxylative Trifluoromethylating Reagent [Cu(O2CCF3)(phen)] and Difluorocarbene Precursor [Cu(phen)2][O2CCF2Cl]

This article describes the new economic decarboxylative trifluoromethylating reagent [Cu(phen)(O₂CCF₃)] ( 1 ; phen=1,10‐phenanthroline) and the efficient difluorocarbene precursor [Cu(phen)₂][O₂CCF₂Cl] ( 2 ). Treatment of copper tert‐butoxide with phen and subsequent addition of trifluoroacetic acid or chlorodifluoroacetic acid afforded air‐stable complexes 1 and 2 , respectively, which were characterized by X‐ray crystallography. The copper(I) ion in 1 is coordinated by a bidentate phen ligand, a monodentate trifluoroacetate group, and a molecule of CH₃CN in a distorted tetrahedral coordination geometry. The molecular structure of 2 adopts an ionic form that consists of a [Cu(phen)₂]⁺ cation and a chlorodifluoroacetate anion. Complex 1 reacted with a variety of aryl and heteroaryl halides to form trifluoromethyl (hetero)arenes in good yields. The corresponding Hammett plot exhibited a linear relationship and a reaction parameter (ρ)=+0.56±0.02, which indicated that the trifluoromethylation reaction proceeded via a nucleophilic reactive species. Complex 2 reacts with phenols to produce aryl difluoromethyl ethers in modest‐to‐excellent yields. Mechanistic investigations revealed that the difluoromethylation reaction proceeds by initial copper‐mediated formation of difluorocarbene and subsequent concerted addition of difluorocarbene to the phenol to form a three‐center transition state.     

Copper-Catalyzed Aromatic Trifluoromethylation and the Related Transformations

Trifluoromethylated aromatic compounds (Ar−CF₃) are the substances of considerable interest in various industrial fields. The high lipophilicity, strong electron-withdrawing ability, and characteristic size of trifluoromethyl group are key influences in biologically active molecules. Due to these attractive properties, the benzotrifluoride structural motifs have been widely employed in the design of pharmaceuticals, agrochemicals, dyes, liquid crystals, and polymers. Therefore, the development of highly efficient methodologies for aromatic trifluoromethylation is of significant importance for wide fields of science and technology. Recently, a great deal of attention has been paid to catalytic protocols to introduce fluoroalkyl groups into aromatic rings selectively. This personal account highlights the copper-mediated aromatic trifluoromethylation and the related transformations developed by our research group.