title: Shelf-stable electrophilic reagents for trifluoromethylthiolation.
abstract: Fluorine, which is the most electronegative element and has a small atomic radius, plays a key role in pharmaceutical, agrochemical, and materials sciences. One of the fluoroalkyl groups, the trifluoromethylthio group (CF3S-), has been well-recognized as an important structural motif in the design of lead compounds for new drug discovery because of its high lipophilicity (Hansch lipophilicity parameter π = 1.44) and strong electron-withdrawing properties, which could improve the drug molecule's cell-membrane permeability and enhance its chemical and metabolic stability. While classic methods for the preparation of trifluoromethylthiolated compounds typically involve halogen-fluorine exchange reactions of polyhalogenomethyl thioethers or trifluoromethylation of sulfur-containing compounds under harsh reaction conditions, an alternative but more attractive strategy is direct trifluoromethylthiolation of the substrate at a late stage by employing an electrophilic trifluoromethylthiolating reagent. Although several electrophilic trifluoromethylthiolating reagents have been reported previously, these reagents either require a strong Lewis acid/Brønsted acid as an activator or suffer from a toxic nature or limited substrate scope. To address these problems, in late 2011 we initiated a project with the aim to develop new, shelf-stable, and highly reactive electrophilic trifluoromethylthiolating reagents that could easily install the trifluoromethylthio group at the desired positions of the drug molecule at a late stage of drug development. Inspired by the broad reactivity of the hypervalent iodine reagent, we initially discovered a highly reactive trifluoromethylthiolating reagent, trifluoromethanesulfenate 1a. Structure-reactivity studies disclosed that the iodine atom of reagent 1a does not play an important role in this reagent's reactivity. Consequently, a simplified second-generation electrophilic reagent, trifluoromethanesulfenate 1b, was developed. In parallel, we developed another shelf-stable, highly reactive electrophilic reagent with a broad substrate scope, N-trifluoromethylthiosaccharin (2). In this Account, we mainly describe our discovery of these two different types of electrophilic trifluoromethylthiolating reagents, trifluoromethanesulfenates 1a and 1b and N-trifluoromethylthiosaccharin 2. Systematic studies showed that both types of reagents are highly reactive toward a wide range of nucleophiles, yet the substrate scopes of these two different types of reagents are complementary. In particular, reagents 1a and 1b are more reliable in transition-metal-catalyzed reactions such as copper-catalyzed trifluoromethylthiolation of aryl/vinyl/alkylboronic acids and silver-catalyzed decarboxylative trifluoromethylthiolation of aliphatic carboxylic acids as well as in the organocatalytic asymmetric trifluoromethylthiolation of β-keto esters and oxindoles. Reagent 2 is more electrophilic than reagents 1a and 1b and is more efficient for direct trifluoromethylthiolation with nucleophiles such as alcohols, amines, thiols, and electron-rich arenes. The ease in preparation, broad scope, and mild reaction conditions make reagents 1a, 1b, and 2 very attractive as general reagents that allow rapid installation of the trifluoromethylthio group into small molecules.
authors.affiliation: Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China.
authors.forename: Xinxin
authors.initials: X
authors.lastname: Shao
authors.affiliation: Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China.
authors.forename: Chunfa
authors.initials: C
authors.lastname: Xu
authors.affiliation: Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China.
authors.forename: Long
authors.initials: L
authors.lastname: Lu
authors.affiliation: Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China.
authors.forename: Qilong
authors.initials: Q
authors.lastname: Shen
mesh_terms: D006845:Hydrocarbons, Fluorinated / Q000138:chemical synthesis* / Q000737:chemistry*; D015394:Molecular Structure; D013438:Sulfhydryl Compounds / Q000138:chemical synthesis* / Q000737:chemistry*
chemical_list: D006845:Hydrocarbons, Fluorinated; D013438:Sulfhydryl Compounds