A Convenient Synthesis of Difluoroalkyl Ethers from Thionoesters Using Silver(I) Fluoride

Abstract

Herein we report the mild and rapid fluorodesulfurization of thionoesters using only silver(I) fluoride. This reaction demonstrates excellent functional group tolerance and complements existing strategies for difluoroalkyl ether synthesis, which rely on toxic and often dangerous reagents that demonstrate limited functional group compatibility. We additionally report the translation of this finding to the production of 18F‐labelled difluoroalkyl ethers using fluoride‐derived [18F]AgF. This new process should enable the synthesis of a wide range of difluoroalkyl ethers with applications in medicinal and materials chemistry, and radiotracer production.

Silver-Catalyzed C–H Aryloxydifluoromethylation and Arylthiodifluoromethylation of Heteroarenes

“…Traditional approaches to ArOCF 2 -substituted aromatic compounds include desulfurization–fluorination of thionoesters and fluorination–rearrangement of ketones (see Scheme a). These methods suffer from the use of toxic and/or expensive fluorinating reagents.…”

Fluorodesulfurization of Thionobenzodioxoles with Silver(I) Fluoride

“…Here, conversion of catechols into thionobenzodioxoles using thiophosgene 11 or 1,1′-thiocarbonyldiimidazole (TCDI) 12 is followed by a desulfurative fluorination reaction involving HF and NIS 13 or DBH, 14 Fluolead, 15 and BrF 3 (Figure 1B). 16,17 We have previously described the fluorination of thionoesters with AgF in MeCN, 18 and Schoenebeck has recently demonstrated the fluorination of thiocarbamoyl fluorides using AgF. 19,20 Here, we report the use of AgF for the direct desulfurative fluorination of thionobenzodioxoles.…”

“…We have previously described the fluorination of thionoesters with AgF in MeCN, and Schoenebeck has recently demonstrated the fluorination of thiocarbamoyl fluorides using AgF. , Here, we report the use of AgF for the direct desulfurative fluorination of thionobenzodioxoles. This mild process tolerates a range of functional groups and should enable the late stage conversion of catechols into difluorobenzodioxoles, providing a new route to this important class of compounds.…”

An efficient and straightforward approach for accessing thionoesters via palladium-catalyzed C–N cleavage of thioamides

“…10 Thionoesters are regarded as synthetic isosteres of esters 11–13 and have been readily employed as precursors to construct diverse organic compounds. 14,15 For example, thionoesters fluorinated by DAST or Deoxofluor can directly give access to the corresponding α,α-difluoroethers in good yields under mild conditions, 16–18 attributable to the higher electrophilicity relative to their oxoester counterparts (Scheme 1). It is common and important that α,α-difluoroethers exist in liquid crystal materials.…”