Sulfur and friends: A new electrophilic hypervalent iodine reagent 1 has been developed for direct trifluoromethylthiolation. A variety of nucleophiles, including β‐ketoesters, aldehydes, amides, aryl or vinyl boronic acids, and alkynes, reacted with 1 under mild conditions to give the corresponding trifluoromethylthiolated compounds in good to excellent yields.

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,...

Here we report highly efficient and chemoselective azadiene-imine reductive couplings catalyzed by (Ph-BPE)Cu-H that afford anti-1,2-diamines. In all cases, reactions take place with either aldimine or ketimine electrophiles to deliver a single diastereomer of product in >95:5 er. The products' diamines are easily differentiable, facilitating downstream synthesis.

A family of electrophilic trifluoromethanesulfenates was prepared. Structure-reactivity relationship studies showed that the substituted groups on the aryl ring of the trifluoromethylthiolating reagent did not have an obvious influence on their reactivities. A simplified electrophilic trifluoromethylthiolating reagent 1c was then identified that can react with a wide range of nucleophiles such as Grignard reagents, arylboronic acids, alkynes, indoles, β-ketoesters, oxindoles, and sodium sulfinates under mild reaction conditions. A variety of functional groups were tolerated under these conditions.

The old one two: A sequential iridium-catalyzed borylation and copper-catalyzed trifluoromethylation of arenes is described (see scheme; Pin = pinacol). The reaction is conducted under mild reaction conditions and tolerates a variety of functional groups. The advantages of this tandem procedure are demonstrated by the late-stage trifluoromethylation of a number of biologically active molecules.

A new shelf-stable and easily scalable difluoromethylthiolating reagent S-(difluoromethyl) benzenesulfonothioate (PhSO SCF H) was developed. PhSO SCF H is a powerful reagent for radical difluoromethylthiolation of aryl and alkyl boronic acids, decarboxylative difluoromethylthiolation of aliphatic acids, and a phenylsulfonyl-difluoromethylthio difunctionalization of alkenes under mild reaction conditions.

We introduce a new strategy for synthesis of chiral amines: couplings of α-aminoalkyl nucleophiles generated by enantioselective migratory insertion of 2-azadienes to a Cu-H. In this report, we demonstrate its application in catalytic reductive coupling of 2-azadienes and ketones to furnish 1,2-amino tertiary alcohols with vicinal stereogenic centers.

A silver-catalyzed decarboxylative trifluoromethylthiolation of secondary and tertiary carboxylic acids under mild conditions tolerates a wide range of functional groups. The reaction was dramatically accelerated by its performance in an aqueous emulsion, which was formed by the addition of sodium dodecyl sulfate to water. It was proposed that the radical, which was generated from the silver-catalyzed decarboxylation in the "oil-in-water" droplets, could easily react with the trifluoromethylthiolating reagent to form the product.