Xinxin Shao

An Electrophilic Hypervalent Iodine Reagent for Trifluoromethylthiolation

[*] X. Shao, X.-Q. Wang, T. Yang, Prof. Dr. L. Lu, Prof. Dr. Q. ShenKey Laboratory of Organofluorine Chemistry, Shanghai Institute ofOrganic Chemistry, Chinese Academy of Sciences345 Lingling Road, Shanghai 200032 (China)E-mail: lulong@sioc.ac.cnshenql@sioc.ac.cn[**] The authors gratefully acknowledge financial support from theNational Basic Research Program of China (2012CB821600,2010CB126103), the Key Program of Natural Science Foundation ofChina (21032006), the National Natural Science Foundation ofChina (21172245/21172244/B020304), Agro-scientific Research inthe Public Interest (201103007), the National Key TechnologiesR&D Program (2011BAE06B05), the Shanghai Scientific ResearchProgram (10XD1405200), and SIOC for financial support.Supporting information for this article is available on the WWWunder http://dx.doi.org/10.1002/anie.201209817.

Highly Selective Trifluoromethylation of 1,3‐Disubstituted Arenes through Iridium‐Catalyzed Arene Borylation

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.

Shelf-Stable Electrophilic Reagents for Trifluoromethylthiolation

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 molecules 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 reagents 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.

Structure–Reactivity Relationship of Trifluoromethanesulfenates: Discovery of an Electrophilic Trifluoromethylthiolating Reagent

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.

Copper-Catalyzed Trifluoromethylthiolation of Primary and Secondary Alkylboronic Acids

A Cu-catalyzed trifluoromethylthiolation of primary and secondary alkylboronic acids with an electrophilic trifluoromethylthiolating reagent is described. Tolerance for a variety of functional groups was observed.

PhSO2SCF2H: A Shelf-Stable, Easily Scalable Reagent for Radical Difluoromethylthiolation

A new shelf-stable and easily scalable difluoromethylthiolating reagent S-(difluoromethyl) benzenesulfonothioate (PhSO2 SCF2 H) was developed. PhSO2 SCF2 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.

Trifluoromethyl-substituted sulfonium ylide: Rh-catalyzed carbenoid addition to trifluoromethylthioether.

A highly efficient Rh-catalyzed carbenoid addition to trifluoromethylthioether for the formation of trifluoromethyl-substituted sulfonium ylide is described. The trifluoromethyl-substituted sulfonium ylide can act as an electrophilic trifluoromethylation reagent, as demonstrated by trifluoromethylation of β-ketoesters and aryl iodides.

CCDC 1054155: Experimental Crystal Structure Determination

Related Article: Yafei Liu, Xinxin Shao, Panpan Zhang, Long Lu, Qilong Shen|2015|Org.Lett.|17|2752|doi:10.1021/acs.orglett.5b01170