Synthesis and applications of S-(trifluoromethyl)-2,8-bis(trifluoromethoxy)dibenzothiophenium triflate (Umemoto reagent IV)

Abstract

A new, powerful, and easy-to-handle electrophilic trifluoromethylating agent, S-(trifluoromethyl)-2,8-bis(trifluoromethoxy)dibenzothiophenium triflate (Umemoto reagent IV), was developed. Due to the extraordinary electronic effect of trifluoromethoxy group, Umemoto reagent IV was easily synthesized by a one-pot method from readily available 3,3’-bis(trifluoromethoxy)biphenyl. It was shown that Umemoto reagent IV was more powerful than Umemoto reagent II and could trifluoromethylate many kinds of nucleophilic substrates more effectively. In addition, Umemoto reagent IV was successfully utilized for the preparation of trifluoromethyl nonaflate, a useful trifluoromethoxylating agent. The direct conversion of 2,8-bis(trifluoromethoxy)dibenzothiophene to Umemoto reagent IV with triflic anhydride was achieved, albeit in low yield.

Graphical Abstract

1. Introduction

Fluorinated compounds have attracted much attention in the development of new medicines, agrochemicals, and materials because of the unique properties of fluorine element [1]. Among them, trifluoromethyl (CF₃)-containing compounds have occupied an important position because the chemical or biochemical properties of original non-fluorinated compounds can be positively altered by the CF₃ substituent since the CF₃ has high electronegativity, stability, and lipophilicity [2]. Therefore, how to introduce the CF₃ group to an organic compound has been a significant subject in research. Direct trifluoromethylation of target compounds in late stage is considered as an ideal method [3]. In this regard, electrophilic trifluoromethylation is an attractive choice and that is why many kinds of electrophilic trifluoromethylating agents have been developed [4], as described below.

Getting a hint from Yagupolskii’s report [5] in 1984 that (4-chlorophenyl)(2’,4’-dimethyl or 4’-methoxyphenyl)(trifluoromethyl)sulfonium hexafluoroantimonate reacted with sodium 4-nitrophenylthiolate (S-nucleophile) to give 4-nitrophenyl trifluoromethyl sulfide, but could not react with N,N-dimethylaniline even at elevated temperature, in 1990 Umemoto and coworkers reported S- and Se-(trifluoromethyl)dibenzothiophenium salts I as electrophilic trifluoromethylating agents, making possible the first trifluoromethylation of C-nucleophiles [6]. In 1993, they completed a series of power-variable electrophilic trifluoromethylating reagents, reactive and stable S-, Se-, and Te-trifluoromethyl dibenzoheterocyclic salts I, which made possible electrophilic trifluoromethylations on a wide range of C-nucleophilic substrates [7]. In 1995, the Umemoto group reported the zwitterion type reagents series II [8]. A major feature of these reagents was that their power (reactivity) could be tuned by sulfur, selenium, and tellurium atoms and electron-withdrawing and -donating substituents on the heterocyclic rings. Among them, S-(trifluoromethyl)dibenzothiophenium tetrafluoroborate Ia and triflate Ib, which were later called Umemoto reagent, were sold all over the world by a major reagent company at the end of the last century [9].

The commercialization of the Umemoto reagent contributed to the advancement of electrophilic trifluoromethylation reactions. However, the Umemoto reagent was impracticable for actual production of CF₃-containing compounds because it was very expensive due to the many preparation steps needed [10]. Since then, new trifluoromethylating agents [11–28] have been reported, as shown in Figure 1.

Figure 1.

Electrophilic trifluoromethylating agents reported after 1998

However, practically useful electrophilic trifluoromethylating agents were not developed until the appearance of powerful and thermally stable 2,8-difluoro-S-(trifluoromethyl)dibenzothiophenium triflate XVa (Figure 1) in 2017 [23]—readily prepared at large scale and low price by a safe and easy one-pot method from 3,3’-difluorobiphenyl available. XVa was soon commercialized as Umemoto reagent II. As the value of Umemoto reagent I (Ia or Ib) had been amply demonstrated by the large number of published papers [9], the development of the Umemoto reagent II made possible a remarkable progress in practical synthetic fluorine chemistry. Although 2,3,7,8-tetrafluoro-S-(trifluoromethyl)dibenzothiophenium triflate XVb (Umemoto reagent III), reported at the same time, is more powerful than difluoro XVa (Umemoto reagent II), its commercialization was hindered by the costly starting material (3,3’,4,4’-tetrafluorobiphenyl) and a long time reaction process resulting from the low reactivity of the starting tetrafluoro biphenyl [23b]. Since Umemoto reagent II is covered by a patent in major countries [29], its application is limited because it cannot be used on a commercial basis without the patent owner’s approval. Considering these issues, we decided to develop a newer version of Umemoto reagent that is cost-effective and more powerful than Umemoto reagent II. We now wish to report the synthesis and application of S-(trifluoromethyl)-2,8-bis(trifluoromethoxy)dibenzothiophenium triflate (Umemoto reagent IV) (6).

2. Results and Discussion

2.1. Design of S-(trifluoromethyl)-2,8-bis(trifluoromethoxy)dibenzothiophenium triflate (6)

The easy one-pot synthesis of 2,8-difluoro-S-(trifluoromethyl)dibenzothiophenium triflate (XVa) (Umemoto reagent II) from 3,3’-difluorobiphenyl (1) [23a] owes its success to the extraordinarily strong p-activation effect by the fluorine atom located at the 3 or 3’-position despite its electron-withdrawing effect (Hammett constant σ_p = +0.06) [30] (Scheme 1). The strong p-orientation is explained by the unique strong electron-donating effect of the fluorine atom (Hammett constant σ_R = −0.39) [30] on an activated reaction intermediate such as 2. Although a positive σ_p value deactivates the reaction, the negative large σ_R value strongly activates it. This is the reason why the reaction of 1 occurred easily even at low temperature (−20 °C).

Scheme 1.

A successful one-pot reaction of 3,3’-difluorobiphenyl (1) giving Umemoto reagent II

In order to develop a more powerful reagent that can easily be prepared by a one-pot methodology, we designed 2,8-bis(trifluoromethoxy)-S-(trifluoromethyl)dibenzothiophenium triflate (6) and tried its one-pot synthesis from 3,3’-bis(trifluoromethoxy)biphenyl (4), as shown in Scheme 2, because a CF₃O group has a larger Hammett constant σ_p (0.35)[30] than that of F (0.06), but a still negative σ_R value (−0.04) [30]. The σ_p value indicates that CF₃O has a stronger electron-withdrawing effect than F, while the σ_R value indicates that CF₃O has still electron-donating effect in the substitution reaction in the same way as F, though its effect is smaller than F. Actually, a high p-orientation (p/o=9/1) in nitration of CF₃O-C₆H₅ was reported [31], which is close to that of F-C₆H₅ in nitration (p/o = 14.5/1) [32].

Scheme 2.

Planned one-pot synthesis of 2,8-bis(CF₃O)-S-CF₃-dibenzothiophenium triflate 6 from 4

2.2. Preparation of 3,3’-bis(trifluoromethoxy)biphenyl (4)

It had been reported that 3,3’-bis(CF₃O)biphenyl 4 was detected as byproduct in a hetero coupling reaction of 3-(trifluoromethoxy)chlorobenzene and isopropylmagensium chloride [33]. We succeeded in developing a practical FeCl₃-catalyzed homo coupling reaction [34] of 3-(trifluoromethoxy)phenylmagnesium bromide derived from inexpensive 3-(trifluoromethoxy)bromobenzene, furnishing 4 in high yield (79% yield after purification by distillation) (Scheme 3). It is worth noting that, despite its high molecular weight, 4 is a liquid at room temperature.

Scheme 3.

Preparation of 3,3’-bis(trifluoromethoxy)biphenyl (4)

2.3. One-pot synthesis of S-(trifluoromethyl)-2,8-bis(trifluoromethoxy)dibenzothiophenium triflate (6)

We applied the same one-pot method to the synthesis of 6 as for Umemoto reagent II (XVa) using CF₃SO₂Na/(CF₃CO)₂O/CF₃COOH/TfOH. As a result, we found that sulfide 5’ was formed in small amounts (about 10%) in addition to the major sulfoxide 5 by analyzing the ¹⁹F-NMR spectrum of the reaction mixture (S-CF₃ of 5’, −42.0 ppm/DMSO-d₆) (Scheme 4). Intermediate 5’ was not isolated.

Scheme 4.

The first step reaction in the one-pot synthesis of 6 from bis(CF₃O)biphenyl 4

In comparison, the corresponding sulfide was not formed in the reaction with 3,3’-difluorobiphenyl at low temperature (−20 °C) [23a], but a considerable amount of sulfide was formed as a side product in the reaction of the less reactive 3,3’,4,4’-tetrafluorobiphenyl counterpart, after a slow reaction (2–3 days) at the elevated temperature (35–45 °C). We solved that problem by adding an oxidant (35% H₂O₂), and obtained a satisfactory yield of XVb [23b]. We used a similar approach to the one-pot synthesis of 6 by which sulfide 5’ was transformed to sulfoxide 5 and then cyclized to final product 6 (Scheme 5). Thus, as shown in Scheme 5, CF₃SO₂Na (1 eq) was stirred in a mixture of (CF₃CO)₂O (3 eq)/CF₃COOH (2 eq) at 45 °C (oil bath temperature) for 2.5 h and, to the resulting mixture, 3,3’-bis(CF₃O)biphenyl 4 (0.5 eq) was added, followed by triflic acid (2.2 eq) over a period of 1.25 hr at 45 °C. After the resulting mixture was stirred for 20 h, a small amount of 35% H₂O₂ (0.2 eq) in CF₃COOH was slowly added for 2.2 h and the resulting mixture was stirred for 6 h at 45 °C. The solvent in the reaction mixture was evaporated and the resulting residue was washed with a 1:1 mixture of water and toluene. The resulting precipitate was collected by filtration to give final product 6 in 66% isolated yield based on 4. S-CF₃-2,8-bis(CF₃O)dibenzothiophenium triflate 6 is a non-hygroscopic and stable salt having high melting point 157–158 °C (with dec). This isolation method was very simple and easy. Hence, 6 was successfully synthesized in satisfactory yield by the one-pot method. We chose the amount of CF₃SO₂Na necessary to consume the biphenyl 4. Therefore, the actual amount may depend on the purity of CF₃SO₂Na.

Scheme 5.

One-pot procedure for synthesis of S-CF₃-2,8-bis(CF₃O)dibenzothiophenium triflate 6

The reaction mechanism of the one-pot reactions (Scheme 6) should be the same as the one discussed for the synthesis of XVb [23b], namely CF₃SO₂Na reacted with (CF₃CO)₂O to form CF₃SO₂OCOCF₃ in step 1, which then reacted with the biphenyl 4 in the presence of strong acid TfOH to give intermediate sulfoxide 5 in step 2. Sulfoxide 5 was cyclized by the action of the existing (CF₃CO)₂O and TfOH to give final product 6. A small amount of sulfide 5’—possibly formed by the reaction of 4 with a strong CF₃S⁺ reagent 9, generated by ester-exchange reaction of 7 followed by its disproportionation—was oxidized to sulfoxide 5 in step 3 and then cyclized to 6 under the existing conditions.

Scheme 6.

Proposed reaction mechanism of steps 1–3 for the one-pot method of 6

2.4. Reactivity of S-(trifluoromethyl)-2,8-bis(trifluoromethoxy)dibenzothiophenium triflate (6)

We expected that 6 (Umemoto reagent IV) would be more reactive than Umemoto reagent II (XVa) because of the higher electron-withdrawing effect of the CF₃O group compared to the F atom. Their relative reactivity was examined by the reaction with aniline, which produced o-CF₃- and p-CF₃-anilines in good yields. The mixture of 6 (1 eq), XVa (1 eq), and aniline (4 eq) in DMF was stirred at room temperature. As seen in Scheme 7, after 3 h, the conversion of 6 was 50%, while XVa was 31%. After 26 h, the conversion of 6 was 90%, while that of XVa was only 53%. As 6 showed higher conversion in the reaction, it was clear that 6 had higher power (reactivity) compared to Umemoto reagent II (XVa).

Scheme 7.

Controlled reaction of bis(CF₃O) salt 6 and Umemoto reagent II (XVa) with aniline

2.5. Trifluoromethylation of nucleophilic substrates with powerful S-CF₃ reagent 6

Scheme 8 illustrates the trifluoromethylation of various nucleophilic substrates with the powerful 6. Treatment of keto ester salt 10 with 6 in DMF at −20 °C to room temperature provided CF₃-keto ester 11 in 84% yield. It is worth noting that 11 is an important intermediate for the preparation of useful 1-(trifluoromethyl)cyclopropane-1-carboxylic acid [35]. Diketone salt 12 was similarly trifluoromethylated with 6 to give CF₃-diketone 13 in 80% yield. The same treatment of the sodium salt of diethyl 2-methylmalonate 14 gave 2-methyl-2-(trifluoromethyl)malonate 15, but in low yield (38%). Trifluoromethylation of an activated aromatic, p-hydroquinone 16, with 6 in DMF/pyridine at 65 °C produced 2-CF₃-1,4-hydroquinone 17 in 78% yield. Another reactive 4-tert-butylaniline (18) was trifluoromethylated in DMSO at 70 °C to give 19 in 91% yield. Although the thermal trifluoromethylation of 1,3,5-trimethoxybenzene (20) with 6 was difficult, the photo trifluoromethylation of 20 with 6 at 425 nm irradiation was easily conducted without any photo catalyst, giving 2-CF₃ product 21 in very high yield (97%). It is worth noting that the visible 425 nm irradiation gave a higher yield (97%) than the higher energy 365 nm irradiation (89%). It had been reported that the photo reaction of 20 with Umemoto reagent II (XVa) at 365–375 nm could be accomplished, but at 425 nm this was less feasible [36]. This observation meant that the CT complex of 20 and 6 is excited by lower energy than that of 20 and XVa, possibly due to the higher electron-deficiency of 6. The photo reaction with 6 at 425 nm allowed the successful direct trifluoromethylation of caffeine 22, yielding 23 in 71% yield. Similarly, the photo reaction of dimethyluracil 24 with 6 gave 5-CF₃ uracil 25 in 52% yield. The reported yield of the photo reaction of 22 with XVa at 375 nm was only 59% [36]. N-Hydroxylamine 26 was readily trifluoromethylated with 6 in dichloromethane at room temperature in the presence of a base to give N-(trifluoromethoxy)amine 27 [37] in excellent yield (93%). This was a remarkable result that contrasted with the low yield of 39% using Umemoto reagent II (XVa) under the same conditions. Similarly to 26, N-hydroxy-N-benzyl-N-(2-cyanoethyl)amine and N-hydroxy-N,N-bis[2-(ethoxycarbonyl)ethyl]amine were O-trifluoromethylated with 6 in good yields (see SI).

Scheme 8.

Trifluoromethylations of various nucleophilic substrates with 6

2.6. Preparation of trifluoromethyl nonaflate (30) using 6

We have recently reported trifluoromethyl nonaflate (30, TFNf) as an easy-to-handle, stable, and reactive trifluoromethoxylating agent [38]. TFNf was prepared using Umemoto reagent II (XVa). We tried to prepare TFNf using 6, as seen in Scheme 9. The treatment of 6 with tetrabutylammonium chloride afforded chloride 28 in 94% yield (step i), which was then allowed to react with potassium nonaflate to give nonaflate 29 in 89% yield (step ii). The thermolysis of neat nonaflate 29 at 150 °C yielded TFNf in 95% together with 2,8-bis(CF₃O)dibenzothiophene 31 (step iii). The steps i and ii were facile counter anion replacement reactions and the solid products 28 and 29 were easily isolated by simple filtration. In step iii, the liquid product TFNf was easily isolated since TFNf came out from the reactor during the thermolysis. In particular, step iii was more effective than the reported method using Umemoto reagent II, because the thermolysis of 29 occurred smoothly and the directly collected product TFNf was pure, since precursor 29 was a liquid before the thermolysis temperature, and the resulting side product 2,8-bis(CF₃O)dibenzothiophene (31) (mp 93–95 °C) was also a liquid at the thermolysis temperature and served as a good solvent, but it did not sublimate at the thermolysis temperature.

Scheme 9.

Preparation of trifluoromethyl nonaflate TFNf (30) using 6

With Umemoto reagent II, the side product 2,8-difluorodibenzothiophene (mp ^~150 °C) easily sublimated and contaminated TFNf. These virtues could be the result of the strongly lipophilic nature of the CF₃O groups present, compared to the F atoms present in Umemoto reagent II.

2.7. Attempt to convert 2,8-disubstituted dibenzothiophenes into S-CF₃-dibenzothiophenium triflates

2,7-Bis(CF₃O)dibenzothiophene 31 was quantitatively obtained as a side product by the thermolysis of 29 or by the trifluoromethylation reactions of substrates with 6. Therefore, as seen in Scheme 10, if the side product 31 could be used to regenerate the S-CF₃ reagent 6, the efficiency of the process would be very high. Recently, Ritter and coworkers reported a single step synthesis of another trifluoromethylating agent, trifluoromethyl thianthrenium triflate XX, from thianthrene 32 (Scheme 11, Eq. 1) [28]. However, dibenzothiophene 33 could not be converted to Umemoto reagent Ib (Eq. 2) [28].

Scheme 10.

Direct conversion of dibenzothiophene derivatives to the S-CF₃ reagents

Scheme 11.

One-step synthesis of S-CF₃ reagents

They suggested a reactive S-radical cation species 35 to be a key intermediate for the formation of the product XX (Scheme 12, Eq. 1). Accordingly, the expected key intermediate 37 for Ib could not be formed, or was an extremely short-lived species that decomposed before combining with the CF₃ radical (Eq. 2).

Scheme 12.

Proposed mechanisms of reactions of thianthrene 32 and dibenzothiophene 33 with Tf₂O

We speculated that a 2,8-disubstituted dibenzothiophene such as 1 (R=F) or 31 (R=OCF₃) might undergo the desired reaction to give the corresponding S-CF₃ reagent because F or CF₃O substituents had the capability to stabilize the intermediate key radical cation species long enough to combine with the CF₃ radical (Figure 2).

Figure 2.

Intermediate key radical cation species

As described in detail in the Supporting Information, we first examined the possibility of 1 (R=F) and revealed that, when the reaction of 1 with Tf₂O was carried out in a highly concentrated solution in the presence of a CF₃ radical trap such as benzene, the desired product XVa was obtained in moderate yield (Scheme 13).

Scheme 13.

Reaction of 2,8-diF-dibenzothiophene 1 with Tf₂O

Based on the results of the difluoro 1, we tried the conversion of 31 (R=CF₃O) to the S-CF₃ 6 (Table 1). It needed elevated reaction temperature and excess of Tf₂O (3 eq) because of the lesser reactivity of 31 compared to 1. For this case, the addition of benzene as the radical trap resulted in very low yield of 6 while it formed large amounts of benzotrifluoride and left large amounts of 31 intact (Run 1). Therefore, we used less reactive chlorobenzene without solvent and obtained 6 in 34% yield (Run 2). In Run 3, the reaction was carried out in a tightly closed glassware tube, which gave a better yield (38%). After the reaction, the product was precipitated by adding toluene and water to the reaction mixture and then simply isolated by filtration. The obtained product was contaminated with small amounts of unidentified impurities (see the footnote of Table 1). Unfortunately, the yield of 6 was unsatisfactory because the effect of CF₃O substituents was less than that of F substituents.

Table 1.

Reaction of 2,8-bis(CF₃O)dibenzothiophene 31 with Tf₂O

Run	31	Tf2O	solvent	additive	conditions	Isolated Product 6 (crude)a	31 (unreacted)
1	0.880 g (2.5 mmol)	2.5 eq	DCE 0.5 mL	PhH 4.5 eq	65° C, 44 h	very low yieldc	a lot
2	0.704 g (2 mmol)	3 eq	non	PhCI 4 eq	70° C, 48 h	34%d (19%)e	9%
3b	0.704 g (2 mmol)	3 eq	non	PhCI 4 eq	70° C, 48 h	38%f	4%

DCE=1,2-dichloroethane. PhH=benzene. PhCI=Chlorobenzene. a) Yields were based on 31. b) The reaction was carried out in a tightly closed glass reactor. c) The product could not be isolated because the yield was very low. d) The purity of this crude product was estimated to be around 90% in mol ratio. e) The crude product was recrystallized from CH₃CN/Et₂O (1/4) to give the product of purity 97%, the yield of which was 19% based on 31. f) The purity of this crude product was estimated to be around 87% in mol ratio.

3. Conclusion

Because of the unique properties of the trifluoromethoxy group, we succeeded in finding a new, one-pot preparable and easy-to-handle S-(trifluoromethyl)-2,8-bis(trifluoromethoxy)dibenzothiophenium triflate (6) (Umemoto reagent IV) that is more powerful than Umemoto reagent II. This new reagent was prepared in good yield from readily available 2,8-bis(trifluoromethoxy)biphenyl and was able to trifluoromethylate many nucleophilic substrates more effectively than Umemoto reagent II. We used 6 for the preparation of trifluoromethyl nonaflate, a new trifluoromethoxylating agent. The direct conversion of 2,8-bis(trifluoromethoxy)dibenzothiophene to 6 with Tf₂O was accomplished, albeit in moderate yield.

4. Experimental

4.1. General information

¹H, ¹⁹F, and ¹³C NMR spectra were measured on 400, 376, and 100 MHz spectrometers, respectively. The chemical shifts are reported in δ (ppm) values relative to CHCl₃ (δ 7.26 ppm for ¹H NMR, δ 77.0 ppm for ¹³C NMR) and CFCl₃ (δ 0.00 ppm for ¹⁹F NMR).

4.2. Materials

CF₃SO₂Na was purchased and dried at 80 °C for 1 h by a vacuum pump before use. 3-(Trifluoromethoxy)bromobenzene, CF₃COOH, (CF₃CO)₂O, CF₃SO₃H (TfOH), (CF₃SO₂)₂O (Tf₂O), potassium nonafluorobutanesulfonate (nonflate), and other commercial reagents were used without further purification. Solvents like tetrahydrofuran (THF), dimethylformamide (DMF), dimethylsulfoxide (DMSO), acetonitrile (ACN), and dichloromethane (DCM) were dried by the standard methods. 2,8-Difluorodibenzothiophene was prepared by the reported thermolysis of S-(trifluoromethyl)-2,8-dibenzothiophenium nonaflate [38].

4.3. Preparation of 3,3’-bis(trifluoromethoxy)biphenyl 4

Into a 1 L-three necked flask equipped with a dropping funnel (200–300 mL), a thermometer, a condenser, a magnetic stirrer, an argon inlet and outlet cock, and purged with argon, were added 16.6 g (685 mmol, 1.1 eq) of Mg, 500 mL of dry THF (commercially bought), and a trace amount (about 0.2 g) of I₂. 3-(CF₃O)-bromobenzene (150 g, 622 mmol, 1 equiv) was placed in the dropping funnel. Small amount of 3-(CF₃O)-bromobenzene (about 1/8 part) was added to the 1 L-flask, the reaction mixture was stirred and the Grignard reaction started soon. After that, the remaining 3-(CF₃O)-bromobenzene in the dropping funnel was added dropwise over 80 min (maximum temp was 42 °C during addition). After the addition, the reaction mixture was stirred for 50 min at room temperature (rt) and then for 2 h in an oil bath at 45 °C. Simultaneously, but in another setup, into a 1 L-two necked flask equipped with a dropping funnel, a thermometer, a magnetic stirrer, an argon inlet and outlet cock, and purged with argon, were added 30 mL (37.7 g, 381 mmol, 0.6 eq) of dry ClCH₂CH₂Cl, 3.0 g (18.7 mmol, 3 mol%) of anhydrous FeCl₃, and 190 mL of dry THF. The resulting Grignard reagent solution was transferred to the dropping funnel through a fluoropolymer tube by argon pressure and added dropwise to the solution of ClCH₂CH₂Cl and FeCl₃ in THF for 70 min under water bath cooling. After the addition, the reaction mixture was stirred at rt overnight (15 h). The liquid layer of the reaction mixture was transferred to a flask and the solvent was evaporated using a rotary evaporator. The precipitate layer of the reaction mixture was extracted three times with diethyl ether (100–200 mL x 3). The collected diethyl ether layer was mixed with the above residue and the resulting organic layer was washed with brine (50 ml x 3), dried with anhydrous MgSO₄, and filtered. The filtrate was evaporated using a rotary evaporator and the residue was distilled under reduced pressure, giving 78.94 g (79%) of 4 as pure product. 4: B.p. 97–101 °C/14–16 mmHg; ¹H NMR (400 MHz, CDCl₃) δ 7.51 (m, 4H), 7.43 (d, J = 2.4 Hz, 2H), 7.27 (m, 2H). ¹³C NMR (100 MHz, CDCl₃) δ 149.80, 141.76, 130.32, 125.50, 120.53 (q, J = 257.4 Hz) 120.27, 119.79. ¹⁹F NMR (376 MHz, CDCl₃) δ −57.70. HRMS (EI method): Chemical Formula C₁₄H₈F₆O₂ (M); theoretical mass for M: 322.0428. Found: (M)⁺ = 322.0427.

4.4. Synthesis of 2,8-bis(trifluoromethoxy)-S-(trifluoromethyl)dibenzothiophenium triflate 6

CF₃SO₂Na (7.56 g, 48.5 mmol) was placed in a flask (reactor) and dried in vacuum at 80 °C (oil bath temp) for 1 h. After that, the reactor was cooled to rt and equipped with a dropping funnel, a magnetic stirrer, and a condenser connected with a drying tube (CaCl₂). A mixture of (CF₃CO)₂O (20.2 ml, 146 mmol) and CF₃COOH (7.4 mL, 97 mmol) was then added under stirring over 18 min through the dropping funnel to the reactor on a water bath. Then the reaction mixture in the reactor was stirred in an oil bath at 45 °C for 2.5 h and 3,3’-bis(CF₃O)biphenyl (4) (7.80 g, 24.2 mmol) was added through a dropping funnel (Note: after the dropping, 2 mL of (CF₃CO)₂O was used for washing the dropping funnel and added to the reaction mixture). Triflic acid (TfOH, 9.0 mL, 30.1 mmol) was dropwise added through the dropping funnel into the stirred reaction mixture in the oil bath (45 °C) for 1.25 h (Note: after the dropping, 2 mL of (CF₃CO)₂O was used for washing the dropping funnel and dropped to the reaction mixture). The reaction mixture was stirred at 45 °C for 20.3 h. After that, a mixture of 35% H₂O₂ (470 mg) and CF₃COOH (4 mL) was dropwise added through the dropping funnel to the stirred reaction mixture in the oil bath (45 °C) for 2.2 h and then the reaction mixture was stirred for 6 h at 45 °C. The reaction mixture was evaporated using a rotary evaporator. Toluene (30 mL) was added to the residue and toluene was evaporated. This process (the addition and evaporation of toluene) was repeated three times. To the resulting residue, water (100 mL) and toluene (100 mL) were added and the mixture was stirred vigorously at rt for 4 h. The resulting precipitate was filtered and washed with water (10 mL x 2) and then with toluene (25 mL x 3) to give white solid of the product 6 (9.07 g, 66% yield). M.p. 157–158 °C (with dec) (recrystallized from CH₃CN/Et₂O). ¹H NMR (400 MHz, DMSO-d₆) δ 8.76 (d, J = 8.9 Hz, 2H), 8.68 (d, J = 2.6 Hz, 2H), 7.85 (ddd, J = 8.9, 2.5, 1.2 Hz, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ 153.40, 142.64, 132.14, 125.63, 124.17, 122.82 (q, J = 332 Hz), 120.64 (q, J = 321 Hz) 119.75 (q, J = 259.8 Hz), 118.09. ¹⁹F NMR (376 MHz, DMSO-d₆) δ −51.61 (3F, s, SCF₃), −56.34 (6F, s, 2xOCF₃), −77.35 (3F, s, SO₂CF₃). HRMS (ESI method): Chemical Formula C₁₆H₆F₁₂O₅S₂ (M); theoretical mass for (M-CF₃SO₃)⁺: 420.9939. Found: 420.9941.

4.5. Controlled trifluoromethylation of aniline with 6 and Umemoto reagent II (XVa)

Into a vial reactor were added 6 (0.2 mmol, 1 eq), Umemoto reagent II (0.2 mmol, 1 eq), dry DMF (0.8 mL), and aniline (0.8 mmol, 4 eq) (note: 2 eq of aniline acted as a base). The reaction mixture was stirred at rt under argon atmosphere. 4-(Trifluoromethyl)chlorobenzene (0.2 mmol) as a reference was added to the reaction mixture after 3 h. ¹⁹F NMR analysis of the reaction mixture was made after 3 h and 26 h. The results are shown in Scheme 7.

4.6. Trifluoromethylation of nucleophilies 10, 12, and 14 with 6

Typical procedure: Under an argon atmosphere, NaH (1 mmol, 60% in oil) was added to a stirred solution of 1-acetyl-γ-butyrolactone (1 mmol, 1 eq) in 3 mL of dry DMF cooled on an ice bath. Then the mixture was stirred at rt for 20 min. After the mixture was cooled to −45° C, 6 (1.2 mmol, 1.2 eq) was added and the reaction mixture was stirred for 20 min and then warmed to rt over a period of ca. 1 h. The reaction mixture was analyzed by ¹⁹F NMR using an internal standard to get the yield of the product (the results are shown in Scheme 8). The reaction mixture was then quenched with water and extracted with ethyl acetate (3 × 10 ml), washed with brine, and dried over sodium sulfate and filtered. It was then evaporated using a rotary evaporator under reduced pressure to get the crude product, which was then purified by flash chromatography.

1-Acetyl-1-(trifluoromethyl)-γ-butyrolactone (11): Colorless oil (150 mg, 77%) (Eluent, EtOAc:hexane 1:5 v/v). Rf (EtOAc:hexane 1:5 v/v) = 0.55 (UV). The NMR data of the title compound were in agreement with the reported data [35].

2-Methyl-2-(trifluoromethyl)cyclopentan-1,3-dione (13): Colorless oil (135 mg, 75%) (Eluent, EtOAc:hexane 1:5 v/v). Rf (EtOAc:hexane 1:5 v/v) = 0.4 (UV). The NMR data of the title compound were in agreement with the literature reference [7].

Diethyl 2-methyl-2-(trifluoromethyl)malonate (14): Colorless oil (75 mg, 31%) (Eluent, EtOAc:hexane 1:10 v/v). Rf (EtOAc:hexane 1:10 v/v) = 0.48 (UV). The NMR data of the title compound were in agreement with the literature reference [7].

4.7. Trifluoromethylation of 1,4-hydroquinone (16) with 6

A solution of 6 (285 mg, 0.5 mmol, 1 eq) in dry DMF (1.1 mL) was added dropwise to a stirred solution of 1,4-hydroquinone (110 mg, 1 mmol, 2 eq) in pyridine (0.4 mL) for 1–2 min under argon atmosphere. The reaction mixture was stirred in an oil bath at 65 °C for 7 h. ¹⁹F NMR analysis of the reaction mixture showed that 2-trifluoromethyl-1,4-hydroxyquinone (17) was formed in 78% yield. The product was identified by ¹⁹F NMR and GC-Mass by comparison with the reported data [39].

4.8. Trifluoromethylation of 4-tert-butylaniline (18) with 6

An 8 mL-glass vial was charged with 4-tert-butylaniline (17) (1.5 mmol, 3.0 eq) and 6 (0.5 mmol, 1 eq) under argon atmosphere, followed by addition of 0.5 ml of dry DMSO. The resulting solution was heated under stirring at 70 °C for 3 h. The reaction mixture was analyzed by ¹⁹F NMR using an internal standard and it was found that product 19 was produced in 91% yield. Then it was quenched with water. The resulting mixture was then extracted with ethyl acetate (3 × 10 mL) and dried over sodium sulfate and evaporated under reduced pressure to get the crude product, which was then purified by flash chromatography to get 4-tert-butyl-2-(trifluoromethyl)aniline (19) as colorless oil in (80 mg, 74%) (Eluent, EtOAc:hexane 3:7 v/v). Rf (EtOAc:hexane 3:7 v/v) = 0.39 (UV). The NMR data of the title compound were in agreement with the literature reference [13].

4.9. Photo-trifluoromethylation of 20, 22, and 24 with 6

General procedure: An 8 mL-glass vial was charged with the substrate (0.6 mmol, 3.0 eq), 7 (0.2 mmol, 1 eq) and sodium bicarbonate (0.24 mmol, 1.2 eq) under argon atmosphere followed by addition of 2 ml of dry DMSO or acetonitrile. The solution was sparged with argon via submerged needle for 5 min. Then the stirred reaction mixture was subjected to photo-irradiation at 425 nm (HeptaChem Inc HCK1012–01-012 P207–18-1 425nm) at rt until the CF₃ reagent was consumed completely (1–3 h). After completion of the reaction, the reaction mixture was analyzed by ¹⁹F NMR using an internal standard to get the yield of the product (the results are shown in Scheme 8). Then it was quenched with water. The resulting mixture was then extracted with ethyl acetate (3 × 10 mL) and dried over sodium sulfate and evaporated under reduced pressure to get crude mass which was then purified by flash chromatography to get the product 21, 23, or 25.

1,3,5-Trimethoxy-2-(trifluoromethyl)benzene (21): White solid (40 mg, 85%) (Eluent, EtOAc:hexane 1:9 v/v). Rf (EtOAc:hexane 1:9 v/v) = 0.45 (UV). The NMR data of the title compound were in agreement with the literature reference [36].

1,3,7-Trimethyl-8-(trifluoromethyl)-1H-purine-2,6(3H,7H)-dione (23): White solid (33 mg, 63%) (Eluent, EtOAc:hexane 1:3 v/v). Rf (EtOAc:hexane 1:3 v/v) = 0.34 (UV). The NMR data of the title compound were in agreement with the literature reference [28].

N,N’-Dimethyl-5-(trifluoromethyl)uracil (25): Colorless liquid (19 mg, 46 %) (Eluent, EtOAc:hexane, 1:3 v/v). Rf (EtOAc:hexane, 1:3 v/v) = 0.3 (UV). The NMR data of the title compound were in agreement with the literature reference [40].

4.10. O-Trifluoromethylation of N,N-dibenzyl-N-hydroxyamine (26) with 6

An 8 mL-glass vial was charged with 26 (0.4 mmol, 1.0 eq) and 6 (0.5 mmol, 1.25 eq) under argon atmosphere, and 1 ml of dry dichloromethane (DCM) was added. After five minutes of stirring, a solution of diisopropylethylamine (DIPES) (0.7 mmol, 1.75 eq) in 1 ml of dry DCM was added to the stirred reaction mixture over 1 minute and stirred further at rt for 2 h. After that, 0.5 ml of sat. aq. NaHCO₃ was added into the reaction mixture and stirred for 10 minutes. The reaction mixture was analyzed by ¹⁹F NMR using an internal standard (C₆H₅CF₃) and it was found that product 26 was produced in 93% yield. The organic layer was separated, and the aqueous layer was extracted twice with DCM. The combined organic layer was dried over sodium sulfate, filtered, and evaporated under reduced pressure to get crude mass, which was then purified by HPLC to get N,N-dibenzyl-N-(trifluoromethoxy)amine (26): Colorless oil (73 mg, 65%) (Eluent, 100 % acetonitrile, purified by Prep HPLC). Rf (EtOAc:hexane, 0.5:10 v/v) = 0.41 (UV). ¹H NMR (400 MHz, CDCl₃) δ 7.33 (m, 10H), 4.07 (s, 4H). ¹³C NMR (100 MHz, CDCl₃) δ 135.14, 129.82, 128.36, 127.95, 62.40. ¹⁹F NMR (376 MHz, CDCl₃) δ −63.30 (s, CF₃). The NMR data of the title compound were in agreement with the literature reference [37].

4.11. Preparation of trifluoromethyl nonaflate (30, NFTf) using 6

Step 1: Preparation of S-(trifluoromethyl)-2,8-bis(trifluoromethoxy)dibenzothiophenium chloride (28)

Into a solution of Bu₄NCl 13.35 g (43.9 mmol) in 40 mL of CH₃CN, was added a solution of 6 (25.0 g, 43.9 mmol) in 70 mL of CH₃CN portionwise (with a pipet) for 5 min under vigorous stirring. After the reaction mixture was stirred for 3 h, the resulting precipitate was collected by filtration and washed with cold CH₃CN (10 mL x 2), giving 18.79 g (94%) of chloride 28: M.p. 189–190 °C (with dec) (recrystallized from CH₃CN). ¹H NMR (400 MHz, DMSO-d₆) δ 8.90 (d, J = 8.8 Hz, 2H), 8.75 (d, J = 2.5 Hz, 2H), 7.90 (d, J = 8.9 Hz, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ 152.98, 142.64, 131.49, 128.93, 124.64, 124.11, 119.99 (q, J = 257 Hz), 119.60 (CF_3, q, J = 336 Hz)118.13. ¹⁹F NMR (376 MHz, DMSO-d₆) δ −52.08 (s, CF₃), −56.26 (s, 2xOCF₃). HRMS (ESI method): Chemical Formula C₁₅H₆ClF₉O₂S (M); theoretical mass for (M-Cl)⁺: 420.9939. Found: 420.9940.

Step 2: Preparation of S-(trifluoromethyl)-2,8-bis(trifluoromethoxy)dibenzothiophenium nonaflate (29)

A solution of chloride 28 (1.00 g, 2.19 mmol) in 6 mL of MeOH was added in one-portion into a stirred solution of C₄F₉SO₃K (0.741 g, 2.19 mmol) in 4 mL of MeOH heated on an oil bath (60 °C) (Note: 1 mL of MeOH was used to wash the vessel and added to the reaction mixture). After the addition, the reaction mixture was stirred in the oil bath (60 °C) for 5 min and the reaction mixture was cooled to rt. The reaction mixture was evaporated in a rotary evaporator and 16 mL of water was added to the residue. Copious amount of solid matter formed. After the reaction mixture was stirred for 1 h, the solid matter was collected by filtration and washed with water (3 mL x 3) and then toluene (3 mL x 3) and dried, giving 1.41 g (89%) of nonaflate 29: M.p. 127–128 °C (recrystallized from CH₃CN/Et₂O). ¹H NMR (399 MHz, DMSO-d₆) δ 8.85 (d, J = 8.9 Hz, 2H), 8.79 (d, J = 2.5 Hz, 2H), 7.97 (m, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ 153.94, 143.15, 132.63, 126.07, 124.58, 123.32 (q, J = 330.2 Hz), 120.25 (q, J = 259.6 Hz), 118.56, 116.67 (d, J = 33.8 Hz), 116.27 (d, J = 21.5 Hz), 113.78 (q, J = 33.7, 33.1 Hz), 111.1–110.6 (m), 108.98 (d, J = 37.7 Hz). ¹⁹F NMR (376 MHz, DMSO-d₆) −51.59 (3F, s, SCF₃), −56.34 (6F, s, 2xCF₃O), −80.03 (3F, t, J=10 Hz, CF₃), −114,37 (2F, br, CF₂), −120.93 (2F, br, CF₂), −125.23 (2F, t, J=13 Hz, CF₂). HRMS (ESI method): Chemical Formula C₁₉H₆F₁₈O₅S₂ (M); theoretical mass for (M-C₄F₉SO₃)⁺: 420.9939. Found: 420.9940.

Step 3: Thermolysis of S-(trifluoromethyl)-2,8-bis(trifluoromethoxy)dibenzothiophenium nonaflate (29)

In a 20 mL-glass flask (reactor) connecting to a distillation apparatus having a condenser and a collector, was placed nonaflate 29 (7.20 g, 10 mmol). The reactor was heated in an oil bath. The solid 29 melted at 140 °C (oil bath temperature). The thermolysis of 29 started to occur at 149 °C (oil bath) and product 30 (bp 87–89 °C) came out of the reactor and moved to the collector cooled in an ice bath. Most of the thermolysis of 29 was completed soon. The oil bath was heated to 160 °C and then argon gas was slowly flowed through the reactor in order to completely transfer the product 30 (CF₃ONf) left in the reactor part to the collector vessel. The obtained amount of CF₃ONf was 3.48 g (95%). The NMR data were in agreement with those of an authentic sample [38].

Another product, 2,8-bis(trifluoromethoxy)dibenzothiophene (31) was left in the reactor. The yield of 31 was 3.47 g (99%). 31: M.p. 93–95 °C (recrystallized from methanol). ¹H NMR (400 MHz, CDCl₃) δ 7.95 (s, 2H), 7.85 (d, J=8.8 Hz), 7.38 (d, J=8.8 Hz). ¹⁹F NMR (376 MHz, CDCl₃) δ −58.47 (s, CF₃O). ¹³C NMR (100 MHz, CDCl₃) δ 146.88, 138.68, 135.86, 123.93, 120.88, 120.66 (q, J = 257.4 Hz), 114.38. HRMS (EI method): Chemical Formula C₁₄H₆F₆O₂S (M); Theoretical mass for M⁺: 351.9993. Found: M⁺ = 351.9989

4.12. Conversion of 2,8-bis(trifluoromethoxy)dibenzothiophene (31) to S-(trifluoromethyl)-2,8-bis(trifluoromethoxy)dibenzothiophenium triflate (6) with Tf₂O

Experimental procedure (from run 3 in Table 1): Under an argon atmosphere, 31 (0.704 g, 2 mmol, 1 eq) was placed in a pressure reactor (glassware), and then 0.81 mL (8 mmol, 4 eq) of dry chlorobenzene and 1.0 mL (6 mmol, 3 eq) of Tf₂O were added. The reactor was tightly closed and stirred in an oil bath (70 °C) for 48 h. After the reaction mixture was stirred at rt overnight (17 h), the reactor was opened. Toluene (8 mL) and then water (8 mL) were added to the reaction mixture cooled in an ice bath and then the mixture was stirred vigorously at rt for 5 h. The resulting precipitate was filtered and washed with water (3 mL) and then toluene (5 mL x 3) to give 0.433 g (38%) of crude 6. This purity was estimated to be around 87% in mol ratio by ¹⁹F NMR. To get the pure product, the crude product needed to be purified by recrystallization or other methods. The crude product (ca 90%) of Run 2 in Table 1 was recrystallized from CH₃CN/Et₂O (1/4) to give the product 6 (ca purity 97%) in 19% yield based on 31. In runs 1 and 2, the reactions were carried out in the same way as in run 3 under the conditions described in Table 1, except under a very slow flow of argon at atmospheric pressure.

Highlight.

• S-CF₃-2,8-bis(CF₃O)dibenzothiophenium triflate (6) was developed as a new CF₃ reagent.

• Reagent 6 was easily synthesized by a one-pot method from 3,3’-bis(CF₃O)biphenyl.

• Reagent 6 was easy-to-handle and more powerful than Umemoto reagent II.

• Reagent 6 effectively trifluoromethylated many nucleophilic substrate.

• Trifluoromethyl nonaflate was effectively prepared using 6 through 3 steps.

• Reagent 6 was recovered from 2,8-bis(CF₃O)dibenzothiophene with Tf₂O, but in low yield.