Thierry Billard

Formation of CSCF3 Bonds through Direct Trifluoromethylthiolation

For a long time, the SCF3 moiety has attracted the interest of chemists because of its intrinsic properties, including its high lipophilicity. However, until recently, the direct introduction of the SCF3 group into organic molecules has been poorly investigated, favoring indirect strategies, including the trifluoromethylation of sulfur compounds or the formation of a CF3 moiety from a precursor group that was already present in the molecule by halogen–fluorine exchange reactions. The development of new methods for the formation of C SCF3 bonds has very recently attracted the interest of several research groups. The most general and efficient methods for the attachment of SCF3 groups to carbon centers are highlighted herein. A transition-metal-free oxidative trifluoromethylthiolation of alkynes was presented by Qing and co-workers (Scheme 1). The reaction of elemental sulfur with the Ruppert–Prakash reagent (CF3SiMe3) generated the “CF3S ” species in situ, and allowed the formation of the C SCF3 bond at room temperature under air. This system supplies the products with good to excellent yields and exhibits a broad tolerance toward electron-rich and electron-poor aryl acetylene derivatives. Recently, reagent R1, which is an airand moisture-stable reagent, was successfully synthesized and used for the trifluoromethylthiolation of Grignard or Lithium reagents with good to excellent yields (Scheme 2).

Electrophilic Trifluoromethanesulfanylation of Organometallic Species with Trifluoromethanesulfanamides

More and more applications for fluorinated molecules are being found in various fields, in particular in the fields of medicinal chemistry and agrochemistry. In recent years, there has been growing interest in the association of the trifluoromethyl group with heteroatoms such as CF3O or CF3S. The CF3S moiety is of particular interest, because it has a high hydrophobicity parameter (pR = 1.44). [2] Consequently, compounds bearing this group are potentially important targets for applications in pharmaceuticals and agrochemicals. 3] Numerous methods for the introduction of this group onto organic substrates are described in literature. The main strategies are indirect methods, wherein the CF3S moiety can be constructed from a precursor already present in the molecule by halogen–fluorine exchange reactions. Another way is through the trifluoromethylation of sulphur-containing compounds. Examples include the nucleophilic and radical trifluoromethylation of disulfides, thiocyanates, and thiols, as well as the electrophilic trifluoromethylation of thiolates. Such strategies may be of interest, but require the preparation of sulfur-precursors, must be fluorinated or trifluoromethylated. A more elegant approach is the direct trifluoromethanesulfanylation of substrates. However, this method is still limited. Some radical and electrophilic reactions have been performed with CF3SCl. [9] However, this species is gaseous and highly toxic. Some nucleophilic reactions have previously been realized through the use of stabilized forms of the unstable CF3S anion, but apart from CF3SCu the reactivity of these species is relatively limited; such reagents are generally not stable enough to be stored for extended periods. Most recently, metal-catalyzed coupling reactions with CF3SAg [11] or CF3SNMe4 [12] have been described. However, the reagents are not very stable and must be prepared before use. Qing et al. have circumvented this main drawback by generating the CF3SCu reagent in situ from Ruppert s reagent, S8 and copper salts. [13] Nevertheless, these recent direct trifluoromethanesulfanylations are essentially limited to aromatic compounds. Furthermore, whereas researchers have shown renewed interest in nucleophilic strategies, electrophilic methods remain underdeveloped. We have, recently, described an easy synthesis of a family of reagents that are stable and easy to handle, namely the trifluoromethanesulfanamides. These reagents have already demonstrated their potential in the electrophilic trifluoromethanesulfanylations of alkenes, alkynes, and electron-rich aromatic compounds. Herein, we will extend the application of these reagents to organometallic nucleophiles. In previous papers, the use of Lewis or protic acids has been required to activate the trifluoromethanesulfanamides. However, when the same strategy (with BF3·Et2O as an activator) has been applied to the reaction of 1a and phenylmagnesium chloride (2a), no reaction was been observed. This was probably due to reaction between the Grignard reagent and the Lewis acid. Supposing that magnesium could play the role of a Lewis acid, the same reaction was performed without additional activator (Table 1). With this change, the expected product 3 a was obtained in good yield, but with a long reaction time at 13 8C (entries 1 and 2). Increasing the temperature appears to be deleterious for the reaction, probably owing to the thermal degradation of a reaction intermediate. To increase the kinetic reaction, the reacting medium was concentrated. Although temper-

PREPARATION OF TRIFLUOROMETHYL SULFIDES OR SELENIDES FROM TRIFLUOROMETHYL TRIMETHYLSILANE AND THIOCYANATES OR SELENOCYANATES

Abstract Trifluoromethyl sulfides (or selenides) are easily obtained in one pot at 0°C from thiocyanates (or selenocyanates), commerical trifluoromethyl trimethylsilane and catalytic amounts of tetrabutylammonium fluoride (TBAF).

Synthesis of Trifluoromethanesulfinamidines and -sulfanylamides

Fluorinated moieties constitute important substituents used in many applications to modify the properties of molecules. The action of DAST onto Rupperts reagent yields to a not isolable intermediate that can then react with various primary amines to give trifluoromethanesulfinamidines and trifluoromethanesulfanylamides. Such compounds were unknown until now and constitute interesting new families of fluorinated molecules.

Base‐Catalyzed Electrophilic Trifluoromethylthiolation of Terminal Alkynes

[*] S. Alazet, Dr. T. BillardInstitute of Chemistry and Biochemistry (ICBMS—UMR CNRS5246), Universit de Lyon, Universit Lyon 1, CNRS43 Bd du 11 novembre 1918, 69622 Lyon (France)E-mail: Thierry.billard@univ-lyon1.frS. Alazet, Prof. L. Zimmer, Dr. T. BillardCERMEP—in vivo imaging, Groupement Hospitalier Est59 Bd Pinel, 69003 Lyon (France)Prof. L. ZimmerLyon Neuroscience Research Center (UMR CNRS 5292, UMRINSERM 1028), Groupement Hospitalier Est59 Bd Pinel, 69003 Lyon (France)[**] We thank the CNRS and the French Ministry of Research for theirfinancial supports. The French Fluorine Network is also thanked forits support.Supporting information for this article is available on the WWWunder http://dx.doi.org/10.1002/anie.201305179.

A new simple access to trifluoromethyl thioethers or selenoethers from trifluoromethyl trimethylsilane and disulfides or diselenides

Abstract Trifluoromethyl thioethers (or selenoethers) are easily obtained in one pot at 0°C from disulfides (or diselenides), commercial trifluoromethyl trimethyl silane and TBAF.

Electrophilic Trifluoromethylthiolation of Carbonyl Compounds

A general method for the α-trifluoromethylthiolation of carbonyl compounds, without prefunctionalization, has been developed. Aldehydes, ketones, esters, amides, keto-esters, alkaloids, and steroids have been trifluoromethylthiolated with good yields. This work, proposing a new reagent for electrophilic trifluoromethylthiolation, provides a route towards the original synthesis of various trifluoromethylthiolated molecules for further applications.

New stable reagents for the nucleophilic trifluoromethylation. Part 4: Trifluoromethylation of disulfides and diselenides with hemiaminals of trifluoroacetaldehyde

Abstract Hemiaminals of fluoral and derivatives have been previously described as efficient new reagents for the nucleophilic trifluoromethylation of carbonyl compounds. Their use has been extended to the synthesis of trifluoromethyl sulfides and selenides from disulfides and diselenides.

Synthetic Approaches to Trifluoromethoxy-Substituted Compounds.

Because of the unique properties of the trifluoromethoxy group, molecules bearing this moiety will find applications in various fields, particularly in the life sciences. However, despite the great interest in this functional group, only a small number of trifluoromethoxylated molecules are currently synthetically accessible. Over the last few years, several innovative and promising strategies for the synthesis of trifluoromethoxylated compounds have been described. This Minireview discusses these existing methods with a particular focus on more recent advances.

Tetrakis(dimethylamino)ethylene (TDAE) mediated addition of difluoromethyl anions to heteroaryl thiocyanates. A new simple access to heteroaryl–SCF2R derivatives

Abstract New heteroaryl–SCF2R derivatives 8–13 are easily obtained in one-pot from the tetrakis(dimethylamino)ethylene (TDAE) mediated reduction of halogenodifluoromethyl substrates RCF2X 1–4 in the presence of heteroaryl–thiocyanates 5–7 .