Recent Progress on Direct Trifluoromethylthiolating Reagents and Methods

Abstract

With a significantly high Hansch's hydrophobicity parameter (π＝1.44), electron-withdrawing trifluoromethylthio group (CF 3 S-) has been considered as one of the most lipophilic substituents and privileged fragments that are able to improve drug molecules' pharmacokinetic and physicochemical properties such as lipophilicity and metabolic stability. It is well-known that incorporation of the trifluoromethylthio group into small molecules greatly enhances its ability to cross lipid membranes and in vivo absorpotion rate. In addition, the high electronegativity of the trifluoromethylthio group significantly improves the small molecule's stablity in acidic environments. Not surprisingly, the trifluoromethylthio group has been of special attention not only from the academia but also from pharmaceutical and agrochemical industry for their use in isostere-based drug design. Development of highly efficient methods for the introduction of the trifluoromethylthio group into small molecules, thereafter, has become a subject of recent focus in the field of organic chemistry. In the early 1960s, a few methods for the formation of trifluoromethylthioethers were reported, which typically involved halogen exchange of the trichloromethyl-substituted compounds and trifluoromethylation of thiolated substrates. However, the conditions of these methods were harsh and incompatible with many common functional groups. Since 2008, new reagents and methods that were able to efficiently incorporate the trifluoromethylthio group under mild conditions have emerged, that pave the way for the facile introduction of trifluoromethylthio group into site-specific positions of the target molecules. In this review, we will first briefly introduce the indirect strategies for trifluoromethylthiolation including halogen exchange and trifluoromethylation of thiolated substrates, and then focus on the direct trifluoromethylthiolation strategies including the transition metal-catalyzed trifluoromethylthiolation reactions, electrophilic trifluoromethylthiolation reactions with electrophilic trifluoromethylthiolating reagents and radical trifluoromethylthiolations. These methods represent the most straightforward and promising approaches for the incorporation of the trifluoromethylthio group into small molecules. At the end, we will discuss the remaining problems and challenges in this particular field.

Exploration of the Synthetic Potential of Electrophilic Trifluoromethylthiolating and Difluoromethylthiolating Reagents

“…The electrophilicities of Shen and Lu's first‐ ( 1 g ) and second‐generation ( 1 f ) O−SCF 3 reagents are very similar to each other, which is in line with Shen and Lu's report that cumyl trifluoromethanesulfenates with or without a substituent at the aromatic ring show similar reactivity towards a variety of nucleophiles . Billard's first‐generation reagent 1 h ( E : −23.32) is by far the least electrophilic reagent studied, but can be efficiently activated by Brønsted and Lewis acids . Shen and Lu's difluoromethylthiolating reagent 1 i ( E : −11.86) is only slightly more electrophilic than its SCF 3 analogue 1 c , suggesting that replacement of one F by H might also have little effect on the electrophilicities of the other SCF 3 reagents listed in Figure .…”

Selenium speciation in tea by dispersive liquid–liquid microextraction coupled to high‐performance liquid chromatography after derivatization with 2,3‐diaminonaphthalene

“…In recent years, many methods have been developed for the determination of selenium such as HPLC with inductively coupled plasma MS (ICP-MS) [10][11][12][13][14][15][16], inductively coupled plasma optical emission spectrometry [17], graphite furnace atomic absorption spectrometry (GF-AAS) [18][19][20], hydride generation-atomic fluorescence spectrometry [4,21], electrothermal atomic absorption spectrometry [22,23], GC-MS [24,25], and HPLC with fluorescence detection [26], etc. Generally, some selenium species cannot be directly analyzed and that are often converted into Se(IV) with UV irradiation and thermoreduction in hydride generation procedure.…”

Fluorination and Fluoroalkylation Reactions Mediated by Hypervalent Iodine Reagents

“…By incorporating the right fluoroalkyl groups to the specific positions of molecules, medicinal chemists can desirably finetune the pharmacological and pharmacokinetic properties of drug candidates, and streamline the drug discovery process. [96] Among many fluoroalkyl groups, the fluoroalkylthio functionalities (SR fn ) such as trifluoromethylthio (SCF 3 ), pentafluoroethylthio (SC 2 F 5 ), difluoromethylthio (SCF 2 H) and monofluoromethylthio (SCH 2 F) moieties have attracted great interest because of their tunable lipophilicity, metabolic stability, and strong electron-withdrawing ability. [96] In the past several years, many SR fn reagents and methods for CÀ SCF 3 , CÀ SC 2 F 5 , CÀ SCF 2 H, and CÀ SCH 2 F bonds formation have emerged, providing a portfolio of tools for preparation of fluoroalkylthiolated compounds.…”

“…[96] Among many fluoroalkyl groups, the fluoroalkylthio functionalities (SR fn ) such as trifluoromethylthio (SCF 3 ), pentafluoroethylthio (SC 2 F 5 ), difluoromethylthio (SCF 2 H) and monofluoromethylthio (SCH 2 F) moieties have attracted great interest because of their tunable lipophilicity, metabolic stability, and strong electron-withdrawing ability. [96] In the past several years, many SR fn reagents and methods for CÀ SCF 3 , CÀ SC 2 F 5 , CÀ SCF 2 H, and CÀ SCH 2 F bonds formation have emerged, providing a portfolio of tools for preparation of fluoroalkylthiolated compounds. Oxidative fluoroalkylthiolation using hypervalent iodine(III) reagent as an oxidant has also been harnessed.…”