The unique chemical properties of aryl trifluoromethyl sulfides (ArSCF3) have been known for over 60 years.[1] The capacity of SCF3 to act as a lipophilic electron-withdrawing group has resulted in the incorporation of ArSCF3 components into a number of pharmaceutical and agrochemical agents.[2] Unfortunately, direct access to this important class of compounds is complicated by a lack of efficient, safe and general methods.[1a, 3]

Significant advances in Pd-catalyzed cross-coupling processes have allowed for efficient access to a diverse array of functionalized aromatic products, including aryl sulfides.[4] While the coupling of many aromatic or aliphatic thiols with aryl halides has been achieved with very high efficiency,[5] the analogous transformation to form aryl trifluoromethyl sulfides has not been reported. As gaseous CF3SH (b.p. = -36 °C)[6] can be difficult to handle in a laboratory setting, several SCF3 salts have been developed, however, most of these decompose under standard cross-coupling conditions.[3c]

It has been postulated that reductive elimination of Ar–SR from a palladium center is initiated via a nucleophilic attack on the electrophilic hydrocarbyl group by the metal-bound thiolate.[7] Thus, metal-catalyzed Ar–SCF3 coupling might be complicated by the reduced nucleophilicity of the SCF3 anion[2b] as compared to a standard thiolate.

Recent reports from our group regarding novel ligands including BrettPhos (1), t-BuBrettPhos (2), XPhos (3) and 3,4,5,6-tetramethyl(t-Bu)XPhos (4) (Scheme 1), have allowed for the successful coupling of weak nucleophiles traditionally thought to be reluctant participants in the transmetalation or reductive elimination steps of a typical Pd(0)/Pd(II) catalytic cycle. Specifically, using these catalyst systems has allowed for the direct formation of diaryl ether,[8] aryl fluoride,[9] aryl trifluoromethyl,[10] and aryl nitro compounds[11] from their corresponding aryl halides or pseudo halides. In light of these results, we hypothesized that a similar Pd-based system might allow for the formation of an aromatic C–SCF3 bond.



Scheme 1

Various ligands used in Pd-catalyzed cross-coupling reactions.



As we suspected that reductive elimination from putative intermediate 11 would be rate limiting in any catalytic process, we began our investigation by attempting its preparation from oxidative addition complex 10 via treatment with AgSCF3 (Scheme 2). We were surprised when this procedure did not provide the expected transmetalation complex but instead led directly to the Ar–SCF3 product 12 (presumably via 11).



Scheme 2

Formation of ArSCF3 via transmetalation and reductive elimination from an isolated LPdAr(Br) complex.



Given this finding, we attempted to convert 4-(4-bromophenyl)morpholine to the corresponding trifluoromethyl sulfide using AgSCF3 and a catalytic quantity of 1 and (COD)Pd(CH2TMS)2 (Table 1). However, under these conditions, none of 13 was observed. We surmised that failure to observe the coupled product might be due to the inefficient transfer of ⊖SCF3 to 10 under catalytic conditions. Thus, we elected to examine the use of a number of alternative previously reported ⊖SCF3 sources (Table 1).[3c, e]



Table 1

Examination of different SCF3 sources.[a]



Clark’s[3d] work on the use of (Bu)4NI and AgSCF3 for SNAr reactions with aryl halides indicated to us that the addition of a quaternary ammonium salt might be beneficial. Consistent with this hypothesis, the addition of 1 equivalent of (Bu)4NI to the reaction mixture increased the yield of 13 from 0 % to 55 % (Table 1). Further examination of different ammonium salts revealed that Ph(Me)3NI was more effective than (Bu)4NI and that switching to a more soluble ammonium salt, Ph(Et)3NI, provided a nearly quantitative yield of the desired product (Table 1). Based on work done by Clark, it is presumed that the iodide anion binds to AgSCF3 in order generate an anionic “ate” complex. We hypothesize that a large diffuse cation further aids in the solubility of this complex. It is worth noting that while the use of quaternary ammonium iodides and bromides allowed for catalytic turnover, the corresponding chloride analogs were ineffective.

With the optimal combination of Ph(Et)3NI and AgSCF3 realized, we re-examined various other previously reported ligands, which have enjoyed a measure of success in Pd-catalyzed cross-coupling reactions.[12] Our survey revealed that only dialkylbiarylphosphine based ligands were successful carrying out this transformation, while other ligands such as 5 or 6 did not perform well even with higher catalyst loadings.

Accordingly, we were successful in converting electron-rich, -neutral and -deficient aryl bromides to their respective aryl trifluoromethyl sulfides in 2 hours at 80 °C using 1.5 - 3.5 mol % of Pd and 1.65 – 3.85 mol % of 1. Electron-neutral and electron-rich substrates were coupled more efficiently than their electron-poor analogs. This effect has previously been noted in the coupling of aryl halides with NaNO2.[11] Substrates containing acid-sensitive functional groups, such as BOC-protected anilines and nitriles, were tolerated and coupled in high yield along with substrates containing ketones, esters, and free NH groups of anilines (Table 3). Aryl bromides containing bulky ortho-groups, e.g., o-cyclohexyl and o-phenyl groups, could also be coupled successfully, although they required the use of the smaller ligand XPhos (3) (Table 3).



Table 3

Pd-catalyzed coupling of aryl bromides.[a]



Heteroaryl bromides such as those containing indoles, pyridines, quinolines, thiophenes and furans, were also viable substrates (Table 4). Unfortunately, attempts to extend this methodology to the coupling of aryl chlorides or aryl triflates were unsuccessful. We are currently working to understand and overcome these limitations.



Table 4

Pd-catalyzed formation of heteroaryl–SCF3 compounds.[a]



Finally, to demonstrate the utility of this method, we prepared an intermediate in the reported synthesis of Toltrazuril,[13] an antiprotozoal agent. Intermediate 14 can be assembled from readily available starting materials in an overall yield of 88%. The key C–SCF3 bond-forming process proceeded in 95% yield (Scheme 3).



Scheme 3

Synthesis of Toltrazuril intermediate.



In summary, we have developed a general method for the Pd-catalyzed Ar–SCF3 bond-forming reaction. Using this method, a wide range of aryl bromides were converted into their corresponding aryl trifluoromethyl sulfides. Additionally, we have been successful in generating a variety of heterocyclic aryl trifluoromethyl sulfides from heteroaryl bromide precursors. Due to the utility of Ar–SCF3 compounds as biologically active agents, and the mild reaction conditions employed, we expect this method to be immediately implemented in the discovery of novel compounds with pharmaceutical and agrochemical applications.

Pd-Catalyzed Synthesis of Ar-SCF3 Compounds under Mild Conditions

Fluorinated pyrazoles play an important role in medicinal chemistry, drug discovery, agrochemistry, coordination chemistry, and organometallic chemistry. Since the early 1990s, their popularity has grown exponentially. Moreover, more than 50% of all contributions on the topic have been published in the last 5 years. In this review, analysis of novel synthetic approaches to fluorinated pyrazoles that appeared in recent years is performed. A particular emphasis is devoted to a detailed consideration of reaction mechanisms. In addition, the reasons that have led to the ever-increasing popularity of fluorinated pyrazoles in various areas of science are discussed. At the end of the review, several potentially interesting but yet mostly unknown classes of fluorinated pyrazoles are outlined.

Fluorinated Pyrazoles: From Synthesis to Applications.

A general and practical strategy for remote site-selective functionalization of unactivated aliphatic C-H bonds in various amides by radical chemistry is introduced. C-H bond functionalization is achieved by using the readily installed N-allylsulfonyl moiety as an N-radical precursor. The in situ generated N-radical engages in intramolecular 1,5-hydrogen atom transfer to generate a translocated C radical which is subsequently trapped with various sulfone reagents to afford the corresponding C-H functionalized amides. The generality of the approach is documented by the successful remote C-N3 , C-Cl, C-Br, C-SCF3 , C-SPh, and C-C bond formation. Unactivated tertiary and secondary C-H bonds, as well as activated primary C-H bonds, can be readily functionalized by this method.

Site‐Selective Remote Radical C−H Functionalization of Unactivated C−H Bonds in Amides Using Sulfone Reagents

Aryl diazonium salts are versatile building blocks in organic synthesis In light of the ever-increasing importance of aryl diazonium salts spanning most disciplines of the chemical sciences, we review the recent development of aryl diazonium chemistry over the past seven years (2013-2020) Special emphasis is put on various new transformations involving the generation of radical intermediates via thermal, photochemical, and electrochemical means Recent advances in the development of transition metal-catalyzed reactions using aryl diazonium salts are also reviewed Together, these newly developed transformations significantly expand the synthetic chemist's repertoire of aromatic carbon-carbon and carbon-heteroatom bond forming methods using aryl diazonium precursors, providing powerful tools for the synthesis and modification of complex molecular scaffolds

Recent Development of Aryl Diazonium Chemistry for the Derivatization of Aromatic Compounds

The synthetic strategies towards thiosulfonates (RSO2SR1) are comprehensively reviewed from their original discovery to recent advances. Incorporation of the green credentials of the synthetic procedures towards thiosulfonates allows one to judge the merits of the state of the art, beyond the typical yield of a product and availability of the reactants. As reactant for organic transformations, thiosulfonates are particularly interesting given their possibility to react with nucleophiles, electrophiles and radicals. This review aims to give researchers, not familiar with the field, a good understanding of the general applications of thiosulfonates, while not skipping the recent important advances. The related, but less explored, selenosulfonates (RSO2SeR1) are also covered. (Figure presented.).

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Thiosulfonates as Emerging Reactants : Synthesis and Applications

A new transition-metal-free route for the direct trifluoromethylthiolation and trifluoromethylsulfoxidation of electron-rich aromatics with CF3SO2Na in the presence of PCl3 was developed. Notably, PCl3 was used as a reducing and chlorination reagent. The transition-metal-free protocol utilized cheap and readily available reagents and exhibited good atom economy; therefore, it will serve as an alternative and practical strategy for the trifluoromethylthiolation and trifluoromethylsulfoxidation of electron-rich aromatics.

Transition-Metal-Free Direct Trifluoromethylthiolation and Trifluoromethylsulfoxidation of Electron-Rich Aromatics with CF3SO2Na in the Presence of PCl3.

Ferric chloride-promoted direct trifluoromethylselenolation of nitrogen-containing heterocyclic compounds by Se-(trifluoromethyl) 4-methylbenzenesulfonoselenoate in water

A novel visible-light photocatalytic difluoromethylselenolation of aryl amines via in situ generation of aryldiazonium salts was achieved using Se-(difluoromethyl) 4-methylbenzenesulfonoselenoate, which was synthesized for the first time. The reagent is readily accessible and shelf-stable. The metal-free reaction conditions and the broad substrate scope provide a green protocol for the efficient and rapid introduction of the difluoromethylselenylether group.

Metal-Free Difluoromethylselenolation of Arylamines Under Visible-Light Photocatalysis.

Silver-mediated radical aryltrifluoromethylthiolation of activated alkenes by S-trifluoromethyl 4-methylbenzenesulfonothioate

In this study, we developed the first copper-catalyzed direct trifluoromethylthiolation of indoles using TfNHNHBoc as a trifluoromethylthiolation reagent Due to the cheap and readily accessible reagents, as well as its mild reaction conditions and good atom economy, this method is as an alternative and practical strategy for trifluoromethylthiolation of indoles

Quan Li

Papers

Transition-Metal-Free Direct Trifluoromethylthiolation and Trifluoromethylsulfoxidation of Electron-Rich Aromatics with CF3SO2Na in the Presence of PCl3.

Ferric chloride-promoted direct trifluoromethylselenolation of nitrogen-containing heterocyclic compounds by Se-(trifluoromethyl) 4-methylbenzenesulfonoselenoate in water

Metal-Free Difluoromethylselenolation of Arylamines Under Visible-Light Photocatalysis.

Silver-mediated radical aryltrifluoromethylthiolation of activated alkenes by S-trifluoromethyl 4-methylbenzenesulfonothioate

Copper-catalyzed direct trifluoromethylthiolation of indoles by tert-butyl 2-((trifluoromethyl)sulfonyl)hydrazine-1-carboxylate