直接二氟甲硫基化与一氟甲硫基化反应研究进展

含有二氟甲硫基基团(SCF2H)与含有一氟甲硫基基团(SCFH2)的有机化合物具有独特的物理和化学性质,在医药及农药等领域具有潜在的应用价值.这两类化合物的传统制备方法是巯基底物的二氟甲基化与一氟甲基化,但含巯基底物本身种类有限,极大地限制了该类化合物的应用与开发,因此开发新的直接二氟/一氟甲硫基化方法和开拓新型直接二氟/一氟甲硫基化试剂具有重要的意义.综述了直接二氟甲硫基化反应和一氟甲硫基化反应的最新研究进展,并对反应的相关机理进行了论述.     

Visible Light‐Promoted Decarboxylative Di‐ and Trifluoromethylthiolation of Alkyl Carboxylic Acids

Described herein is a new and straightforward decarboxylative di‐ and trifluoromethylthiolation of alkyl carboxylic acids promoted by visible light. This approach enables the synthesis of biologically relevant alkyl SCF₂H and SCF₃ compounds from cheap and abundant carboxylic acids. The method is operationally simple, using irradiation from household light sources, and its mild reaction conditions make it tolerant of a range of functional groups. The strategy employs electrophilic phthalimide‐derived di‐ and trifluoromethylthiolation reagents and exploits the ability of the imidyl radical to carry a radical chain.     

Recent Advances in the Synthesis of SCF2H‐ and SCF2FG‐Containing Molecules

In recent years, much interest has been paid to difluoromethylthiolated molecules as the “SCF₂” moiety is a key motif in drug and agrochemical research. Consequently, the development of versatile strategies for the selective synthesis of SCF₂H‐ and SCF₂FG‐containing molecules (FG=functional group) has attracted a lot of attention and inspired the scientific community to design new tools. This Minireview highlights the major progress made in this field. Particularly, methodologies developed for the difluoromethylation of sulfur‐containing molecules and the direct construction of C?SCF₂ bonds in various classes of compounds are showcased and discussed.     

Direct Electrophilic (Benzenesulfonyl)Difluoromethylthiolation with a Shelf‐Stable Reagent

The (benzenesulfonyl)difluoromethylsulfanyl (PhSO₂CF₂S) group is a valuable substituent with specific properties which can provide access to new applications of fluoroalkylthiolated compounds. Direct introduction of this moiety can be performed by in an electrophilic manner by using a new shelf‐stable reagent, namely a (benzenesulfonyl)difluoromethanesulfenamide. Furthermore, mild magnesium‐mediated reduction of the PhSO₂CF₂S group leads to a facile synthesis of difluoromethylthiolated molecules and their deuterated analogs.     

Exploration of the Synthetic Potential of Electrophilic Trifluoromethylthiolating and Difluoromethylthiolating Reagents

The electrophilicity parameters (E) of some trifluoromethylthiolating and difluoromethylthiolating reagents were determined by following the kinetics of their reactions with a series of enamines and carbanions with known nucleophilicity parameters (N, s_N), using the linear free‐energy relationship log k₂=s_N(N+E). The electrophilic reactivities of these reagents cover a range of 17 orders of magnitude, with Shen and Lu's reagent 1 a being the most reactive and Billard's reagent 1 h being the least reactive electrophile. While the observed electrophilic reactivities (E) of the amido‐derived trifluoromethylthiolating reagents correlate well with the calculated Gibbs energies for heterolytic cleavage of the X?SCF₃ bonds (Tt⁺DA), the cumol‐derived reagents 1 f and 1 g are more reactive than expected from the thermodynamics of the O?S cleavage. The E parameters of the tri/difluoromethylthiolating reagents derived in this work provide an ordering principle for their use in synthesis.     

An Electrophilic Reagent for the Direct Introduction of the SCF2PO(OEt)2 Group to Molecules

An unprecedented electrophilic difluoromethylthiolating reagent (MesNHSCF₂PO(OEt)₂) was designed. Under mild and metal‐free conditions, this new reagent reacted with various nucleophiles, thus offering an efficient and operationally simple tool for the construction of C?SCF₂PO(OR)₂, N?SCF₂PO(OR)₂, and S?SCF₂PO(OR)₂ bonds. Finally, thanks to this new methodology, the synthesis of the non‐stereoidal anti‐inflammatory diflumidone was achieved.     

Synthesis of Difluoromethyl Thioethers from Difluoromethyl Trimethylsilane and Organothiocyanates Generated In Situ

A copper‐CF₂H complex generated in situ from copper thiocyanate and TMS? CF₂H smoothly converts organothiocyanates into valuable difluoromethyl thioethers. This reaction step can be combined with several thiocyanation methods to one‐pot protocols, allowing late‐stage difluoromethylthiolations of widely available alkyl halides and arenediazonium salts. This strategy enables the introduction of difluoromethylthio groups—a largely unexplored substituent with highly promising properties—into drug‐like molecules.