Feng-Ling Qing

Oxidative Trifluoromethylation and Trifluoromethylthiolation Reactions Using (Trifluoromethyl)trimethylsilane as a Nucleophilic CF3 Source

The trifluoromethyl group is widely prevalent in many pharmaceuticals and agrochemicals because its incorporation into drug candidates could enhance chemical and metabolic stability, improve lipophilicity and bioavailability, and increase the protein bind affinity. Consequently, extensive attention has been devoted toward the development of efficient and versatile methods for introducing the CF3 group into various organic molecules. Direct trifluoromethylation reaction has become one of the most efficient and important approaches for constructing carbon-CF3 bonds. Traditionally, the nucleophilic trifluoromethylation reaction involves an electrophile and the CF3 anion, while the electrophilic trifluoromethylation reaction involves a nucleophile and the CF3 cation. In 2010, we proposed the concept of oxidative trifluoromethylation: the reaction of nucleophilic substrates and nucleophilic trifluoromethylation reagents in the presence of oxidants. In this Account, we describe our recent studies of oxidative trifluoromethylation reactions of various nucleophiles with CF3SiMe3 in the presence of oxidants. We have focused most of our efforts on constructing carbon-CF3 bonds via direct trifluoromethylation of various C-H bonds. We have demonstrated copper-mediated or -catalyzed or metal-free oxidative C-H trifluoromethylation of terminal alkynes, tertiary amines, arenes and heteroarenes, and terminal alkenes. Besides various C-H bonds, aryl boronic acids proved to be viable nucleophilic coupling partners for copper-mediated or -catalyzed cross-coupling reactions with CF3SiMe3. To further expand the reaction scope, we also applied H-phosphonates to the oxidative trifluoromethylation system to construct P-CF3 bonds. Most recently, we developed silver-catalyzed hydrotrifluoromethylation of unactivated olefins. These studies explore boronic acids, C-H bonds, and P-H bonds as novel nucleophiles in transition-metal-mediated or -catalyzed cross-coupling reactions with CF3SiMe3, opening new viewpoints for future trifluoromethylation reactions. Furthermore, we also achieved the oxidative trifluoromethylthiolation reactions of aryl boronic acids and terminal alkynes to construct carbon-SCF3 bonds by using CF3SiMe3 and elemental sulfur as the nucleophilic trifluoromethylthiolating reagent. These oxidative trifluoromethylation and trifluoromethylthiolation reactions tolerate a wide range of functional groups, affording a diverse array of CF3- and CF3S-containing compounds with high efficiencies, and provide elegant and complementary alternatives to classical trifluoromethylation and trifluoromethylthiolation reactions. Because of the importance of the CF3 and SCF3 moieties in pharmaceuticals and agrochemicals, these reactions would have potential applications in the life science fields.

Copper-mediated oxidative trifluoromethylation of boronic acids.

A copper-mediated oxidative cross-coupling of aryl- and alkenylboronic acids with (trifluoromethyl)trimethylsilane (Me(3)SiCF(3)) under mild conditions has been developed. This method allows a wide range of functional group tolerant trifluoromethylated arenes and alkenes to be easily prepared. This oxidative trifluoromethylation has the potential to introduce trifluoromethyl groups into advanced, highly functionalized organic molecules.

Copper‐Catalyzed Oxidative Trifluoromethylthiolation of Aryl Boronic Acids with TMSCF3 and Elemental Sulfur

Fluorinated functional groups are key structural units found in various pharmaceuticals and agrochemicals. Approximately 30 % of all agrochemicals and 20% of all pharmaceuticals on the market contain fluorine. Among these substituents, the trifluoromethylthio group (CF3S ), especially as an aromatic substituent, plays an important role because of its strong electron-withdrawing effect and high lipophilicity. These characteristics are similar to those of trifluoromethyl (CF3 ) and trifluoromethoxy (CF3O ) groups. Additionally, aryl trifluoromethyl thioethers (CF3SAr) are also key intermediates in the preparation of trifluoromethyl sulfoxide and sulfone, which are important trifluoromethylation reagents. Although impressive progress has been made in the trifluoromethylation of arenes in the past several years, only a few methods are available for the synthesis of aryl trifluoromethyl thioethers. Generally, aryl trifluoromethyl thioethers are prepared either by a nucleophilic reaction of trifluoromethylthiolate with aryl halides, or by a nucleophilic or radical reaction of aryl sulfides and disulfides with a trifluoromethylation reagent. However, these methods are variously limited by a combination of high temperatures, expensive reagents, and low reactivity with electron-rich aromatic groups. Thus, the development of general, safe, and efficient methods to access aryl trifluoromethyl thioethers is highly desirable. Very recently, Buchwald reported a palladium-catalyzed trifluoromethylthiolation of aryl bromides with CF3SAg. [10] This breakthrough for the preparation of ArSCF3 is highly efficient and compatible with a variety of functional groups. However, from the point view of cost-effectiveness and synthetic convenience, using readily available and inexpensive catalysts and fluorinated reagents, such as copper and (trifluoromethyl)trimethylsilane (the Ruppert–Prakash reagent, TMSCF3), to access aryl trifluoromethyl thioethers would be an attractive alternative. The present study was inspired by our own and Buchwald s recent investigations into the copper mediated oxidative trifluoromethylation of arylboronic acid with TMSCF3, [11] as well as Karlin s observation of the formation of a stable copper disulfide complex from the reaction of elemental sulfur (S8) with a Cu I complex. We hypothesized that a Cu disulfide complex generated in situ (II ; Scheme 1) would

Copper-Catalyzed Direct C–H Oxidative Trifluoromethylation of Heteroarenes

This article describes the copper-catalyzed oxidative trifluoromethylation of heteroarenes and highly electron-deficient arenes with CF(3)SiMe(3) through direct C-H activation. In the presence of catalyst Cu(OAc)(2), ligand 1,10-phenanthroline and cobases tert-BuONa/NaOAc, oxidative trifluoromethylation of 1,3,4-oxadiazoles with CF(3)SiMe(3) proceeded smoothly using either air or di-tert-butyl peroxide as an oxidant to give the corresponding trifluoromethylated 1,3,4-oxadiazoles in high yields. Di-tert-butyl peroxide was chosen as the suitable oxidant for oxidative trifluoromethylation of 1,3-azoles and perfluoroarenes. Cu(OH)(2) and Ag(2)CO(3) were the best catalyst and oxidant for direct oxidative trifluoromethyaltion of indoles. The optimum reaction conditions enable oxidative trifluoromethylation of a range of heteroarenes that bear numerous functional groups. The prepared trifluoromethylated heteroarenes are of importance in the areas of pharmaceuticals and agrochemicals. The preliminary mechanistic studies of these oxidative trifluoromethylations are also reported.

Copper-mediated aerobic oxidative trifluoromethylation of terminal alkynes with Me3SiCF3.

An efficient copper-mediated trifluoromethylation of terminal alkynes with nucleophilic trifluoromethylating reagent (Me(3)SiCF(3)) was developed. Both aromatic alkynes and aliphatic alkynes were effective, and a variety of functionalities such as amino, -OMe, -CO(2)Et, -Br, and -NO(2) were tolerated under the reaction conditions. This reaction provides a general, straightforward, and practically useful method to prepare trifluoromethylated acetylenes.

Metal-Free Oxidative Trifluoromethylthiolation of Terminal Alkynes with CF3SiMe3 and Elemental Sulfur

A metal-free oxidative trifluoromethyl-thiolation of terminal alkynes using readily available CF(3)SiMe(3) and elemental sulfur at room temperature has been developed. This reaction provides an efficient and convenient method for the preparation of alkynyl trifluoromethyl sulfides bearing a wide range of functional groups. Preliminary investigation revealed that elemental sulfur instead of air acted as the oxidant.

Cu(II)-Mediated Methylthiolation of Aryl C−H Bonds with DMSO

An unprecedented Cu(II)-mediated methylthiolation of aryl C-H bonds under oxidative conditions that employs the widely available DMSO as the methylthiolation reagent is described. Various functional groups in the substrates were tolerated, and ethylthiolation was also successfully achieved directly from diethyl sulfoxide under the same reaction conditions.

Silver‐Catalyzed Hydrotrifluoromethylation of Unactivated Alkenes with CF3SiMe3

As a result of the strong electron-withdrawing nature and large hydrophobic domain of the trifluoromethyl group (CF3), the incorporation of a trifluoromethyl group into organic molecules can dramatically modify a variety of properties, including lipophilicity, metabolic stability, and bioavailability. Notably, many billion-dollar pharmaceuticals as well as agrochemicals contain a trifluoromethyl group. Therefore, intensive attention has been recently paid to the development of new methods for the introduction of the trifluoromethyl group into organic compounds. Recently, significant advances have been achieved in transition-metal-mediated/ catalyzed trifluoromethylation. For example, in the presence of a palladium 5] or copper 7] catalyst the replacement of a halide, boron, or even C H bond with a trifluoromethyl group can be accomplished under mild reaction conditions. In addition, two rare but interesting examples of silver-mediated direct trifluoromethylation of aryl C H bonds also have been reported. Silver is readily available and silver-mediated/ catalyzed reactions have emerged as versatile synthetic methods for a wide range of organic transformations, including fluorination reactions, trifluoromethylthiolation reactions, and trifluoromethoxylation reactions. The exploration of metal catalysts such as silver, as opposed to palladium and copper, could lead to new opportunities for trifluoromethylation. Despite the pioneering work of Sanford and Br se, current silver-mediated trifluoromethylation reactions are limited to the construction of Caryl CF3 bonds. Furthermore, these transformations require stoichiometric silver salts to generate the reactive intermediate AgCF3. To address these limitations, we herein describe a silver-catalyzed hydrotrifluoromethylation of unactivated alkenes. In contrast to the significant achievements that have been made in the trifluoromethylation of aromatic compounds, the trifluoromethylation of alkenes, especially unactivated alkenes, is still underdeveloped. Recently, copper-catalyzed trifluoromethylation of terminal alkenes or allylsilanes with electrophilic trifluoromethylating reagents has been developed, thus providing a series of trifluoromethylated allylic compounds. Very recently, several groups successfully developed the oxytrifluoromethylation of alkenes using electrophilic trifluoromethylating reagents in the presence or absence of metal catalysts. At the same time, our group also developed a copper-catalyzed oxidative trifluoromethylation of terminal alkenes using the Ruppert–Prakash reagent (CF3SiMe3), thus offering a complementary method to electrophilic allylic trifluoromethylation (Scheme 1). During the course of our investigations, we found that the hydrotrifluoromethylated product 2 was formed as the major

Copper-Catalyzed Oxidative Trifluoromethylation of Terminal Alkynes and Aryl Boronic Acids Using (Trifluoromethyl)trimethylsilane

Trifluoromethylated acetylenes and arenes are widely applicable in the synthesis of pharmaceuticals and agrochemicals. In 2010, our group has reported the copper-mediated oxidative trifluomethylation of terminal alkynes and aryl boronic acids. This method allows a wide range of functional group tolerant trifluoromethylated acetylenes and arenes to be easily prepared. After the preliminary mechanistic studies of the oxidative trifluoromethylation of terminal alkyne, an efficient copper-catalyzed oxidative trifluoromethylation of terminal alkynes and aryl boronic acids has been developed. The catalytic protocol is successfully achieved by adding both the substrate and a portion of CF(3)TMS slowly using a syringe pump to the reaction mixture.

Copper-Catalyzed Oxidative Trifluoromethylation of Terminal Alkenes Using Nucleophilic CF3SiMe3: Efficient C(sp3)–CF3 Bond Formation

An efficient C(sp(3))-CF(3) bond-forming reaction via Cu-catalyzed oxidative trifluoromethylation of terminal alkenes has been developed, which proceeds under mild conditions using readily available, less expensive CF(3)SiMe(3) as the source of the CF(3) group. This method allows access to a variety of trifluoromethylated allylic compounds.