Discovery of 4-tert-Butyl-2,6-dimethylphenylsulfur Trifluoride as a Deoxofluorinating Agent with High Thermal Stability as Well as Unusual Resistance to Aqueous Hydrolysis, and Its Diverse Fluorination Capabilities Including Deoxofluoro-Arylsulfinylation with High Stereoselectivity

Abstract

Versatile, safe, shelf-stable, and easy-to-handle fluorinating agents are strongly desired in both academic and industrial arenas, since fluorinated compounds have attracted considerable interest in many areas, such as drug discovery, due to the unique effects of fluorine atoms when incorporated into molecules. This article describes the synthesis, properties, and reactivity of many substituted and thermally stable phenylsulfur trifluorides, in particular, 4-tert-butyl-2,6-dimethylphenylsulfur trifluoride (Fluolead, 1k), as a crystalline solid having surprisingly high stability on contact with water and superior utility as a deoxofluorinating agent compared to current reagents, such as DAST and its analogues. The roles of substituents on 1k in thermal and hydrolytic stability, fluorination reactivity, and the high-yield fluorination mechanism it undergoes have been clarified. In addition to fluorinations of alcohols, aldehydes, and enolizable ketones, 1k smoothly converts non-enolizable carbonyls to CF(2) groups, and carboxylic groups to CF(3) groups, in high yields. 1k also converts C(=S) and CH(3)SC(=S)O groups to CF(2) and CF(3)O groups, respectively, in high yields. In addition, 1k effects highly stereoselective deoxofluoro-arylsulfinylation of diols and amino alcohols to give fluoroalkyl arylsulfinates and arylsulfinamides, with complete inversion of configuration at fluorine and the simultaneous, selective formation of one conformational isomer at the sulfoxide sulfur atom. Considering the unique and diverse properties, relative safety, and ease of handling of 1k in addition to its convenient synthesis, it is expected to find considerable use as a novel fluorinating agent in both academic and industrial arenas.

Arylsulfur trifluorides: Improved method of synthesis and use as in situ deoxofluorination reagents

“…This is consistent with Umemoto's finding that PhSF 3 is considerably less effective than Fluolead in its reactions in DCE [14]. The interesting thing about the current results, however, is that PhSF 3 , under our in situ reaction conditions in acetonitrile, appears to be essentially untouched by the added benzaldehyde reactant.…”

“…Benzaldehyde (0.75 equiv.) was then added and the mixture allowed to stir at room temperature with no significant amount of product being observed after 24 h. Umemoto had shown that the reaction of Fluolead with aldehydes is complete at room temperature after 20 h when the reaction is carried out in 1,2-dichloroethane (DCE) (Scheme 1) [14]. Thus the mixture of in situ-generated Fluolead in acetonitrile is less reactive than that of pure Fluolead in DCE.…”

“…Mesityl disulfide (2c) was prepared in 70% yield via the sulfonyl chloride [28], using the method of Umemoto [10,14].…”

Fluorine Compounds, Organic

“…Sulfur tetrafluoride and the following compounds can be used for the controlled introduction of fluorine into organic compounds: Dialkylaminosulfur(IV) fluorides (R 2 NSF 3 ) [44][45][46], arylsulfurtrifluorides [47], fluoroalkylamines (e.g., 2-chloro-1,1,2-trifluoroethyldiethylamine or 1,1,2,3,3,3-hexafluoropropyldiethylamine), tetra-n-butylammonium fluoride, amine hydrofluorides, nitrosyl fluoride, perchloryl fluoride, fluoroxyfluoroalkanes (e.g., CF 3 OF) [48], xenon difluoride [49], CH 3 COOF [50], N-fluoropyridinium salts [51], N-fluorosulfonimides [52], and Selectfluor [53]. They are of commercial value for the fluorination of complex organic compounds, such as pharmaceuticals.…”

Fluolead

“…2 When the replacement is carried out with DAST 8a or Deoxo-Fluor™, 8b 11:89 and 28:72 mixtures of α-and β-isomers are obtained.…”