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Aug 15, 2017 - It has been reported to be a useful trifluoromethylation reagent, which acts via a radical process.13. In 2015, Yi and Zhang reported t...
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Transition-Metal-Free Direct Trifluoromethylthiolation and Trifluoromethylsulfoxidation of Electron-Rich Aromatics with CF3SO2Na in the Presence of PCl3 Xia Zhao,*,† Aoqi Wei,† Bo Yang,† Tianjiao Li,† Quan Li,‡ Di Qiu,† and Kui Lu*,‡ †

College of Chemistry, Tianjin Key Laboratory of Structure and Performance for Functional Molecules, Key Laboratory of Inorganic−Organic Hybrid Functional Material Chemistry, Ministry of Education, Tianjin Normal University, Tianjin 300387, China ‡ College of Biotechnology, Tianjin University of Science & Technology, Tianjin 300457, China S Supporting Information *

ABSTRACT: 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.

C

Scheme 1. Typical Electrophilic Trifluoromethylthiolation Reagents

ompounds bearing SCF3 and SOCF3 groups often comprise pharmaceutical and agrochemical products. For example, Tiflorex, Toltrazuril, and Cefazaflur are fluoroalkylthiolated drugs, and Fipronil is a widely used insecticide (Figure 1).1 Therefore, the development of efficient

Figure 1. Biologically active compounds containing the SCF3 group and the SOCF3 group.

nearly odorless, and stable solid. It has been reported to be a useful trifluoromethylation reagent, which acts via a radical process.13 In 2015, Yi and Zhang reported the direct trifluoromethylthiolation of C(sp2)−H bonds with CF3SO2Na in the presence of CuCl, diethyl phosphonate [(EtO)2P(O)H], and dimethyl sulfoxide (DMSO) (Scheme 2, eq 1).14 Recently, Cai and co-workers reported the triphenylphosphine (PPh3)mediated trifluoromethylthiolation of indoles in the presence of N-chlorophthalimide, which was used as a chlorination reagent (Scheme 2, eq 2).15 During our manuscript preparation, Yi and Zhang reported the (EtO)2P(O)H-mediated trifluoromethylthiolation with CF3SO2Na in the presence of chlorotrimethylsi-

and practical methods for the installation of SCF3 and SOCF3 groups onto desired scaffolds is an active research area in chemistry.2 Recently, considerable progress has been achieved in regard to electrophilic trifluoromethylthiolation reactions, due to the invention of a series of shelf-stable and easy-tohandle electrophilic SCF3 transfer reagents (see compounds 1− 9, Scheme 1).3−12 Among those, trifluoromethanesulfonyl chloride (CF3SO2Cl), which is a commercial available reagent, has been used in transition-metal-free trifluoromethylthiolation and trifluoromethylsulfoxidation of electron-rich aromatics.12 However, the moisture sensitive property of this reagent limited its application. Sodium trifluoromethanesulfinate (CF3SO2Na, 10), known as the Langlois reagent, is a readily accessible, © 2017 American Chemical Society

Received: May 18, 2017 Published: August 15, 2017 9175

DOI: 10.1021/acs.joc.7b01226 J. Org. Chem. 2017, 82, 9175−9181

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The Journal of Organic Chemistry

Next, we optimized the reaction conditions for the production of 13a and identified the optimal reaction conditions as follows: 11a (0.5 mmol), 10 (1.0 mmol), PCl3 (0.3 mmol), CH3CN (1.0 mL) in vessel, CH3CN (1.0 mL) in syringe, adding speed of 0.5 mL/h at 50 °C.19 With the optimized reaction conditions in hand, the substrate scope for the trifluoromethylthiolation and trifluoromethylsulfoxidation reactions was investigated with a series of indole derivatives (Tables 1 and 2). In the trifluoromethylthiolation

Scheme 2. Trifluoromethylthiolation of Indole Using CF3SO2Na as SCF3 Sources

Table 1. Scope of Trifluoromethylthiolation of Indole Derivativesa

lane (TMSCl) (Scheme 2, eq 3).16 However, the abovementioned transformations using CF3SO2Na as a trifluoromethylthiolation reagent either require stoichiometric quantities of the copper salt or lack atom economy. Moreover, the direct trifluoromethylsulfoxidation of electron-rich aromatics by CF3SO2Na was rarely reported.17 It is well-known that PPh3 and EtO2P(O)H are made from PCl3. As we are interested in developing efficient methods to construct C−S bonds,12c,18 we envisioned that if PCl3 could be used as a reductant and chlorination reagent in trifluoromethylthiolation, the atom economy of the reaction would be increased, and the overall cost would be significantly reduced. We found that this was indeed the case and herein report the transition-metal-free direct trifluoromethylthiolation and trifluoromethylsulfoxidation of electron-rich aromatics with CF3SO2Na in the presence of PCl3 (Scheme 2, eq 4). Based on our previous research,12c we initially investigated the treatment of indole 11a with CF3SO2Na (10) in the presence of PCl3 in acetonitrile (CH3CN) at 25 °C. Fortunately, desired products 12a and sulfoxide 13a were obtained in 30% and 34% yields, respectively (Scheme 3).

a

Reaction conditions: 11 (0.5 mmol), 10 (0.6 mmol), PCl3 (0.6 mmol), CH3CN (2.0 mL) in vessel, CH3CN (1.0 mL) in syringe, adding speed (2.0 mL/h) at 60 °C. bAdding speed (3.0 mL/h). c Adding speed (0.5 mL/h). dAdding speed (1.0 mL/h). eAdding speed (0.2 mL/h).

reaction, electron-donating and electron-withdrawing substituents in the 2, 4, 5, 6, and 7 positions (11b−11n) as well as Nsubstituted indoles (11o−11q) were well tolerated, and the desired 3-trifluoromethylthiolation products were obtained in moderate to good yields. However, when 3-methylindole (11r) was used as the substrate, the desired 2-trifluoromethylthiolation product was obtained in a relatively low yield. Notably, when indoles with electron-withdrawing substituents (11d and 11f−11h) were employed as substrates, decreasing the adding speed of PCl3 drastically improved the yields. In the trifluoromethylsulfoxidation of indoles, electrondonating and electron-withdrawing substituents were well tolerated in various positions, and the desired trifluoromethylsulfoxidation products were obtained in moderate-to-good yields. However, when 4-methoxy indoles (11b) were used as substrates, the desired product (13b) was obtained in relatively low yields. Notably, in some cases, this transformation was carried out at 25 °C with 0.8 equiv of PCl3 to obtain acceptable yields. To further expand the substrate scope of the trifluoromethylthiolation and trifluoromethylsulfoxidation reactions, other electron-rich aromatics including indolizine (11t), pyrrole (11u and 11v), 1,3,5-trimethoxybenzene (11w), and 5-methyl-2-

Scheme 3. Reaction of Indole with CF3SO2Na and PCl3

Control experiments revealed that 11a decomposed upon treatment with PCl3. Therefore, we added PCl3 via syringe pump and optimized the reaction conditions by examining the effect of solvent, adding speed of PCl3, substrate loading, reaction temperature, and reaction concentration, which led us to identify the optimal reaction conditions to obtain 12a as follows: 0.5 mmol of 11a, 0.6 mmol of 10, 0.6 mmol of PCl3, 2.0 mL of CH3CN in vessel, 1.0 mL of CH3CN in syringe, adding speed of 2.0 mL/h, and reaction temperature of 60 °C.19 9176

DOI: 10.1021/acs.joc.7b01226 J. Org. Chem. 2017, 82, 9175−9181

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The Journal of Organic Chemistry

obtained in 72% yield. At the same time, when 13a was treated with dichloro(hydroxy)phosphane (P(OH)Cl2) (1.0 equiv), generated in situ from PCl3 (1.0 equiv) and H2O (1.0 equiv), in CH3CN at 60 °C, 12a was obtained in 60% yield. Moreover, trifluoromethylthiolation of indole under the optimized reaction conditions at 25 °C was closely monitored by 19F NMR. During the 2 h reaction process, the intensity of the fluorine peak for 13a increased from 15 to 30 min and decreased from 1 to 2 h, while the intensity of the fluorine peak for 12a increased continuously. Notably, when CF3SO2Na (1.0 equiv) was treated with PCl3 (1.0 equiv) or PCl3 (0.3 equiv) in one portion at 60 or 50 °C in CH3CN for 1 h, no fluorine peak for trifluoromethanesulfinic chloride (CF3SOCl) or trifluoromethyl hypochlorothioite (CF3SCl) was observed. Based on the literature20 and above-mentioned results, a plausible reaction mechanism for this transformation was proposed (Scheme 5). CF3SO2Na (10) may react with PCl3

Table 2. Scope of Trifluoromethylsulfoxidation of Indole Derivativesa

Scheme 5. Proposed Reaction Mechanism

a Reaction conditions: 11 (0.5 mmol), 10 (1.0 mmol), PCl3 (0.3 mmol), CH3CN (1.0 mL) in vessel, CH3CN (1.0 mL) in syringe, adding speed (0.5 mL/h) at 50 °C. bThe reaction was carried out at 25 °C. cPCl3 (0.4 mmol) was used. dAdding speed (1.0 mL/h).

phenyl-2,4-dihydro-3H-pyrazol-3-one (11x) were tested. To our delight, these substrates could be transformed into the desired products (12t, 12v, 12w, 12x, 13u, 13v, 13w, and 13x) in moderate to good yields (Scheme 4). To understand the mechanism, 13a was treated with PCl3 (1.0 equiv) in CH3CN at 60 °C. To our surprise, 12a was

to form intermediate A, which is attacked by indole twice to give 13 and intermediate B. Intermediate B reacts with PCl3 to generate P(OH)Cl2 (C). Reduction of 13 by PCl3 and C gives the corresponding indole trifluoromethylthioethers 12. Notably, trifluoromethylsulfoxidation of indole with other species could not be excluded. Finally, to illustrate the practical application of these protocols, the gram-scale reactions for trifluoromethylthiolation and trifluoromethylsulfoxidation of indole were carried out. To our delight, the desired products 12a and 13a were obtained in 78% and 70% yields, respectively. In summary, we developed a new transition-metal-free route for the direct trifluoromethylthiolation and trifluoromethylsulfoxidation of electron-rich aromatics with CF3SO2Na in the presence of PCl3. PCl3 was used as a reducing and chlorination reagent for the first time. 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.

Scheme 4. Trifluoromethylthiolation and Trifluoromethylsulfoxidation of Other Electron-Rich Aromatics

■

a

Reaction conditions: 11 (0.5 mmol), 10 (0.6 mmol), PCl3 (0.6 mmol), CH3CN (2.0 mL) in vessel, CH3CN (1.0 mL) in syringe, adding speed (2.0 mL/h) at 60 °C. bAdding speed (1.0 mL/h). c Adding speed (0.5 mL/h). dPCl3 (1.0 mmol) and 1,4-dioxane (2.0 mL) in vessel, 1,4-dioxane (1.0 mL) in syringe. eReaction conditions: 11 (0.5 mmol), 10 (1.0 mmol), PCl3 (0.3 mmol), CH3CN (1.0 mL) in vessel, CH3CN (1.0 mL) in syringe, adding speed (0.5 mL/h) at 25 °C. fThe reaction was carried out at 50 °C; 10 (1.25 mmol) and PCl3 (0.375 mmol) were used, adding speed (3.0 mL/h). g1,4-Dioxane (1.0 mL) in vessel, 1,4-dioxane (1.0 mL) in syringe at 60 °C.

EXPERIMENTAL SECTION

1. General Experimental Methods. All solvents were distilled prior to use. Unless otherwise noted, chemicals were used as received without further purification. The solvents for the reaction were distilled over Na (for toluene, 1,4-dioxane, and THF) or CaH2 (for DCE and MeCN) under a nitrogen atmosphere. All reactions were carried out in oven-dried glassware under an inert atmosphere (nitrogen or argon). For chromatography, 200−300 mesh silica gel was employed. 1H, 13C{1H}, and 19F{1H}NMR spectra were recorded at 400, 100, and 376 MHz, respectively. Chemical shifts are reported in ppm using tetramethylsilane as internal standard. HRMS was 9177

DOI: 10.1021/acs.joc.7b01226 J. Org. Chem. 2017, 82, 9175−9181

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The Journal of Organic Chemistry

(q, J = 307.5 Hz, 1C), 126.7, 123.4, 123.4, 109.7, 95.0 (q, J = 2.6 Hz, 1C), 19.4; 19F NMR (376 MHz, CDCl3): δ −45.88 (s). 5-Chloro-3-((trifluoromethyl)thio)-1H-indole (12d).12c After purification by silica gel column chromatography (PE:EA = 7:1), compound 12d was isolated as a brown solid (77 mg, 61%); Rf (PE:EA = 5:1) = 0.27; 1H NMR (400 MHz, CDCl3): δ 8.55 (s, 1H), 7.76 (d, J = 1.6 Hz, 1H), 7.55 (d, J = 2.8 Hz, 1H), 7.34 (dd, J = 8.6 Hz, 0.3 Hz, 1H), 7.24 (dd, J = 8.6 Hz, 2.0 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 134.3, 134.0, 130.6, 129.2 (q, J = 308.1 Hz, 1C), 127.6, 123.9, 118.9, 112.8, 95.4 (q, J = 2.3 Hz, 1C); 19F NMR (376 MHz, CDCl3): δ −44.47 (s). 5-Bromo-3-((trifluoromethyl)thio)-1H-indole (12e).12c After purification by silica gel column chromatography (PE:EA = 5:1), compound 12e was isolated as a pink solid (111 mg, 75%); Rf (PE:EA = 5:1) = 0.21; 1H NMR (400 MHz, CDCl3): δ 8.57 (s, 1H), 7.93 (d, J = 1.3 Hz, 1H), 7.55 (d, J = 2.8 Hz, 1H), 7.39 (dd, J = 8.6 Hz, 1.8 Hz, 1H), 7.31 (d, J = 8.6 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 134.7, 133.8, 131.2, 129.2 (q, J = 307.9 Hz, 1C), 126.5, 122.0, 115.2, 113.1, 95.4 (q, J = 2.4 Hz, 1C); 19F NMR (376 MHz, CDCl3): δ −44.49 (s). 5-Fluoro-3-((trifluoromethyl)thio)-1H-indole (12f).12c After purification by silica gel column chromatography (PE:EA = 7:1), compound 12f was isolated as a brown solid (89 mg, 76%); Rf (PE:EA = 5:1) = 0.30; 1H NMR (400 MHz, CDCl3): δ 8.54 (s, 1H), 7.58 (d, J = 2.8 Hz, 1H), 7.44 (dd, J = 9.1 Hz, 2.4 Hz, 1H), 7.36 (dd, J = 8.8 Hz, 4.2 Hz, 1H), 7.05 (td, J = 9.0 Hz, 2.5 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 159.0 (d, J = 236.1 Hz, 1C), 134.4, 132.4, 130.3 (d, J = 10.3 Hz, 1C), 129.3 (q, J = 308.0 Hz, 1C), 112.6 (d, J = 9.5 Hz, 1C), 112.0 (d, J = 26.4 Hz, 1C), 104.4 (d, J = 24.5 Hz, 1C), 95.6 (q, J = 1.9 Hz, 1C); 19F NMR (376 MHz, CDCl3): δ −44.56 (s), −121.61(s). Methyl 3-((Trifluoromethyl)thio)-1H-indole-5-carboxylate (12g).12c After purification by silica gel column chromatography (PE:EA = 3:1), compound 12g was isolated as a white solid (66 mg, 48%); Rf (PE:EA = 2:1) = 0.40; 1H NMR (400 MHz, d6-DMSO): δ 12.4 (s, 1H), 8.34 (s, 1H), 8.14 (d, J = 2.8 Hz, 1H), 7.89 (dd, J = 8.6 Hz, 1.6 Hz, 1H), 7.64 (d, J = 8.6 Hz, 1H), 3.90 (s, 3H); 13C NMR (100 MHz, DMSO): δ 166.8, 139.1, 137.1, 129.4 (q, J = 308.1 Hz, 1C), 128.7, 123.5, 122.6, 120.3, 112.8, 92.9 (q, J = 2.3 Hz, 1C), 52.0; 19 F NMR (376 MHz, CDCl3): δ −44.20 (s). 5-Nitro-3-((trifluoromethyl)thio)-1H-indole (12h).12c After purification by silica gel column chromatography (PE:EA = 3:1), compound 12h was isolated as a yellow solid (59 mg, 45%); Rf (PE:EA = 2:1) = 0.35; 1H NMR (400 MHz, d6-DMSO): δ 12.7 (s, 1H), 8.50 (d, J = 1.0 Hz, 1H), 8.29 (d, J = 2.5 Hz, 1H), 8.14 (dd, J = 9.0 Hz, 2.0 Hz, 1H), 7.73 (d, J = 9.0 Hz, 1H); 13C NMR (100 MHz, d6-DMSO): δ 142.3, 139.7, 139.1, 129.2 (q, J = 308.1 Hz, 1C), 128.6, 117.9, 114.6, 113.6, 94.3 (q, J = 2.4 Hz, 1C); 19F NMR (376 MHz, CDCl3): δ −44.07 (s). 6-Fluoro-3-((trifluoromethyl)thio)-1H-indole (12i).12c After purification by silica gel column chromatography (PE:EA = 10:1), compound 12i was isolated as a brown solid (68 mg, 58%); Rf (PE:EA = 10:1) = 0.21; 1H NMR (400 MHz, CDCl3): δ 8.51 (s, 1H), 7.71 (dd, J = 8.7 Hz, 5.2 Hz, 1H), 7.53 (d, J = 2.7 Hz, 1H), 7.12 (dd, J = 9.2 Hz, 2.2 Hz, 1H), 7.04 (tdd, J = 9.1 Hz, 2.2 Hz, 0.6 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 160.5 (d, J = 238.8 Hz, 1C), 135.9 (d, J = 12.5 Hz, 1C), 133.1 (d, J = 2.2 Hz, 1C), 129.3 (q, J = 308.1 Hz, 1C), 127.8, 120.4 (d, J = 10.1 Hz, 1C), 110.6 (d, J = 24.4 Hz, 1C), 98.1 (d, J = 26.3 Hz, 1C), 95.9 (q, J = 2.5 Hz, 1C); 19F NMR (376 MHz, CDCl3): δ −44.51 (s), −119.05 (s). 6-Chloro-3-((trifluoromethyl)thio)-1H-indole (12j).12c After purification by silica gel column chromatography (PE:EA = 10:1), compound 12j was isolated as a brown solid (75 mg, 59%); Rf (PE:EA = 10:1) = 0.21; 1H NMR (400 MHz, CDCl3): δ 8.50 (s, 1H), 7.70 (d, J = 8.5 Hz, 1H), 7.54 (d, J = 2.8 Hz, 1H), 7.43 (d, J = 1.6 Hz, 1H), 7.25 (dd, J = 8.5 Hz, J = 1.8 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 136.3, 133.3, 129.3 (q, J = 308.0 Hz, 1C), 129.4, 128.0, 122.5, 120.3, 111.6, 96.0 (q, J = 2.3 Hz, 1C); 19F NMR (376 MHz, CDCl3): δ −44.43 (s). 6-Methoxy-3-((trifluoromethyl)thio)-1H-indole (12k).12c After purification by silica gel column chromatography (PE:EA = 5:1), compound 12k was isolated as a pale yellow solid (73 mg, 59%); Rf

performed on an ion trap mass instrument. Melting points are reported as uncorrected. 2. General Procedure for Trifluoromethylthiolation of an Electron-Rich Aromatic by CF3SO2Na in the Presence of PCl3. To a flame-dried Schlenk tube was added an electron-rich aromatic (0.5 mmol), CF3SO2Na (94 mg, 0.6 mmol), and dry CH3CN (2 mL). The mixture was heated to 60 °C by a preheated oil bath. PCl3 (82 mg, 0.6 mmoL) in dry CH3CN (1 mL) was added slowly by syringe pump with the indicated adding speed. The reaction mixture was stirred at 60 °C for the indicated time. Then the reaction mixture was cooled to room temperature. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to afford the pure product. 3. General Procedure for Trifluoromethylsulfoxidation of an Electron-Rich Aromatic by CF3SO2Na in the Presence of PCl3. To a flame-dried Schlenk tube was added an electron-rich aromatic (0.5 mmol), CF3SO2Na (156 mg, 1.0 mmol or 195 mg, 1.25 mmol), and dry CH3CN (1 mL). The mixture was heated to 25 or 50 °C by a preheated oil bath. PCl3 (41 mg, 0.3 mmoL or 51 mg, 0.375 mmoL or 55 mg, 0.4 mmoL) in dry CH3CN (1 mL) was added slowly by syringe pump with the indicated adding speed. The reaction mixture was stirred at 25 or 50 °C for the indicated time. Then the reaction mixture was cooled to room temperature. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to afford the pure product. 4. Large Scale Trifluoromethylthiolation of Indole by CF3SO2Na in the Presence of PCl3. To a flame-dried Schlenk tube was added indole (1.17 g, 10 mmol), CF3SO2Na (1.87 g, 12 mmol), and dry CH3CN (40 mL). The mixture was heated to 60 °C by a preheated oil bath. PCl3 (1.65 g, 12 mmol) in dry CH3CN (20 mL) was added slowly by syringe pump with 40 mL/h. The reaction mixture was stirred at 60 °C for 0.5 h. Then the reaction mixture was cooled to room temperature. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to afford compound 12a (1.69 g, 78%). 5. Large Scale Trifluoromethylsulfoxidation of Indole by CF3SO2Na in the Presence of PCl3. To a flame-dried Schlenk tube was added indole (1.17 g, 10 mmol), CF3SO2Na (3.12 g, 20 mmol), and dry CH3CN (20 mL). PCl3 (824 mg, 6 mmol) in dry CH3CN (20 mL) was added slowly by syringe pump with 10 mL/h at 20 °C. After addition, the reaction mixture was stirred at 20 °C for another 1 h. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to afford compound 13a (1.63 g, 70%). 6. Characteristic data for 12a−12r, 12t, 12v, 12w, and 12x. 3((Trifluoromethyl)thio)-1H-indole (12a).12c After purification by silica gel column chromatography (PE:EA = 10:1), compound 12a was isolated as a pale yellow solid (94 mg, 86%); Rf (PE:EA = 10:1) = 0.21; 1H NMR (400 MHz, CDCl3): δ 8.50 (s, 1H), 7.82−7.80 (m, 1H), 7.54 (d, J = 2.7 Hz, 1H), 7.44−7.42 (m, 1H), 7.32−7.26 (m, 1H), 7.33−7.27 (m, 1H); 13C NMR (100 MHz, CDCl3): δ 136.0, 132.8, 129.5 (q, J = 308.2 Hz, 1C), 129.4, 123.4, 121.6, 119.3, 111.7, 95.4 (q, J = 2.4 Hz, 1C); 19F NMR (376 MHz, CDCl3): δ −44.45 (s). 4-Methoxy-3-((trifluoromethyl)thio)-1H-indole (12b).12c After purification by silica gel column chromatography (PE:EA = 10:1), compound 12b was isolated as a yellow solid (100 mg, 81%); Rf (PE:EA = 10:1) = 0.20; 1H NMR (400 MHz, CDCl3): δ 8.48 (s, 1H), 7.36−7.34 (m, 1H), 7.17 (t, J = 8.0 Hz, 1H), 6.98 (dd, J = 8.2 Hz, 3.2 Hz, 1H), 6.63 (d, J = 7.6 Hz, 1H), 3.94 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 154.4, 137.9, 132.4, 129.4 (q, J = 307.5 Hz, 1C), 124.3, 118.5, 104.9, 102.1, 94.3 (q, J = 2.5 Hz, 1C), 55.5 (q, J = 2.0 Hz, 1C); 19 F NMR (376 MHz, CDCl3): δ −45.41 (s). 4-Methyl-3-((trifluoromethyl)thio)-1H-indole (12c).12c After purification by silica gel column chromatography (PE:EA = 10:1), compound 12c was isolated as a pink solid (70 mg, 61%); mp = 167−168 °C; Rf (PE:EA = 10:1) = 0.24; 1H NMR (400 MHz, CDCl3): δ 8.52 (s, 1H), 7.53 (d, J = 2.8 Hz, 1H), 7.27 (d, J = 8.2 Hz, 1H), 7.17 (t, J = 7.7 Hz, 1H), 6.99 (dt, J = 7.2 Hz, 0.8 Hz, 1H), 2.83 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 136.3, 134.0, 131.6, 129.1 9178

DOI: 10.1021/acs.joc.7b01226 J. Org. Chem. 2017, 82, 9175−9181

Note

The Journal of Organic Chemistry (PE:EA = 5:1) = 0.20; 1H NMR (400 MHz, CDCl3): δ 8.38 (s, 1H), 7.66 (d, J = 8.7 Hz, 1H), 7.43 (d, J = 2.7 Hz, 1H), 6.94 (dd, J = 8.7 Hz, 2.2 Hz, 1H), 6.90 (d, J = 2.1 Hz, 1H), 3.86 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 157.5, 136.9, 131.6, 129.4 (q, J = 308.1 Hz, 1C), 123.7, 120.0, 111.7, 95.7 (q, J = 2.3 Hz, 1C), 95.0, 55.7 (q, J = 1.8 Hz, 1C); 19F NMR (376 MHz, CDCl3): δ −44.62 (s). 7-Methyl-3-((trifluoromethyl)thio)-1H-indole (12l).12c After purification by silica gel column chromatography (PE:EA = 10:1), compound 12l was isolated as a pale yellow solid (83 mg, 72%); Rf (PE:EA = 10:1) = 0.24; 1H NMR (400 MHz, CDCl3): δ 8.46 (s, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.55 (d, J = 2.8 Hz, 1H), 7.20 (t, J = 7.5 Hz, 1H), 7.10 (d, J = 7.1 Hz, 1H), 2.52 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 135.6, 132.4, 129.4 (q, J = 308.2 Hz, 1C), 129.1, 123.9, 121.8, 120.8, 117.0, 96.0 (q, J = 2.5 Hz, 1C), 16.3; 19F NMR (376 MHz, CDCl3): δ −44.55 (s). 2-Methyl-3-((trifluoromethyl)thio)-1H-indole (12m).12c After purification by silica gel column chromatography (PE:EA = 10:1), compound 12m was isolated as a pink solid (76 mg, 66%); Rf (PE:EA = 10:1) = 0.24; 1H NMR (400 MHz, CDCl3): δ 8.31 (s, 1H), 7.71− 7.69 (m, 1H), 7.33−7.30 (m, 1H), 7.24−7.19 (m, 2H), 2.58 (s, 3H); 13 C NMR (100 MHz, CDCl3): δ 143.6, 135.0, 130.5, 129.8 (q, J = 309.0 Hz, 1C), 122.6, 121.3, 118.7, 110.8, 92.5 (q, J = 2.2 Hz, 1C), 12.0; 19F NMR (376 MHz, CDCl3): δ −44.39 (s). 2-Phenyl-3-((trifluoromethyl)thio)-1H-indole (12n).12c After purification by silica gel column chromatography (PE:EA = 10:1), compound 12n was isolated as a brown solid (98 mg, 67%); Rf (PE:EA = 10:1) = 0.27; 1H NMR (400 MHz, CDCl3): δ 8.58 (s, 1H), 7.86−7.84 (m, 1H), 7.78−7.76 (m, 2H), 7.54−7.47 (m, 3H), 7.45− 7.41 (m, 1H), 7.33−7.27 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 144.4, 135.3, 131.4, 130.6, 129.7 (q, J = 309.4 Hz, 1C), 129.2, 128.8, 128.7, 123.7, 121.8, 119.8, 111.2, 92.4 (q, J = 2.3 Hz, 1C); 19F NMR (376 MHz, CDCl3): δ −44.55 (s). 1-Methyl-3-((trifluoromethyl)thio)-1H-indole (12o).12c After purification by silica gel column chromatography (PE:EA = 20:1), compound 12o was isolated as a pale yellow solid (83 mg, 72%); Rf (PE:EA = 10:1) = 0.50; 1H NMR (400 MHz, CDCl3): δ 7.79 (d, J = 7.6 Hz, 1H), 7.38−7.36 (m, 2H), 7.32 (td, J = 6.8 Hz, 1.2 Hz, 1H), 7.27 (td, J = 7.3 Hz, 1.6 Hz, 1H), 3.82 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 137.2, 136.9, 130.2, 129.4 (q, J = 308.2 Hz, 1C), 122.9, 121.3, 119.4, 109.9, 93.0 (q, J = 2.3 Hz, 1C), 33.2; 19F NMR (376 MHz, CDCl3): δ −44.88 (s). 1,2-Dimethyl-3-((trifluoromethyl)thio)-1H-indole (12p).12c After purification by silica gel column chromatography (PE:EA = 10:1), compound 12p was isolated as a pale yellow solid (82 mg, 67%); Rf (PE:EA = 10:1) = 0.50; 1H NMR (400 MHz, CDCl3): δ 7.73−7.71 (m, 1H), 7.33−7.31 (m, 1H), 7.28−7.21 (m, 2H), 3.74 (s, 3H), 2.57 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 145.1, 136.8, 130.1, 129.7 (q, J = 309.1 Hz, 1C), 122.1, 121.1, 118.6, 109.2, 91.0 (q, J = 2.2 Hz, 1C), 30.3, 10.8; 19F NMR (376 MHz, CDCl3): δ −44.89 (s). 1-Phenyl-3-((trifluoromethyl)thio)-1H-indole (12q).12c After purification by silica gel column chromatography (PE), compound 12q was isolated as a white solid (64 mg, 43%); Rf (PE) = 0.67; 1H NMR (400 MHz, CDCl3): δ 7.87−7.85 (m, 1H), 7.66 (s, 1H), 7.58−7.50 (m, 5H), 7.44 (tt, J = 7.2 Hz, 1.5 Hz, 1H), 7.35−7.29 (s, 2H); 13C NMR (100 MHz, CDCl3): δ 138.4, 136.6, 135.9, 130.6, 129.8, 129.5 (q, J = 308.6 Hz, 1C), 127.7, 124.6, 123.7, 122.1, 119.7, 111.1, 96.3 (q, J = 2.5 Hz, 1C); 19F NMR (376 MHz, CDCl3): δ −44.24 (s). 3-Methyl-2-((trifluoromethyl)thio)-1H-indole (12r).12c After purification by silica gel column chromatography (PE:EA = 20:1), compound 12r was isolated as a pale yellow solid (41 mg, 35%); Rf (PE:EA = 10:1) = 0.33; 1H NMR (400 MHz, CDCl3): δ 8.09 (s, 1H), 7.61 (dd, J = 8.0 Hz, 0.6 Hz, 1H), 7.34 (d, J = 8.2 Hz, 1H), 7.32−7.28 (m, 1H), 7.18−7.14 (m, 1H), 2.44 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 137.3, 128.7 (q, J = 309.8 Hz, 1C), 127.9, 124.7, 123.6, 120.0, 119.9, 113.0 (q, J = 2.2 Hz, 1C), 111.1, 9.4; 19F NMR (376 MHz, CDCl3): δ −43.07 (s). 3-((Trifluoromethyl)thio)indolizine-1-carbonitrile (12t). After purification by silica gel column chromatography (PE:EA = 10:1), compound 12t was isolated as a yellow solid (76 mg, 63%); mp = 105−107 °C; Rf (PE:EA = 10:1) = 0.36; 1H NMR (400 MHz,

CDCl3): δ 8.56 (d, J = 7.0 Hz, 1H), 7.75 (d, J = 8.9 Hz, 1H), 7.51 (s, 1H), 7.33 (ddd, J = 8.8 Hz, 6.8 Hz, 0.8 Hz, 1H), 7.03 (td, J = 7.0 Hz, 1.0 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 141.1, 129.5, 128.1 (q, J = 311.9 Hz, 1C), 125.3, 124.9, 118.1, 115.0, 114.5, 103.5 (q, J = 2.9 Hz, 1C), 84.5; 19F NMR (376 MHz, CDCl3): δ −44.07 (s); HRMS (ESI) m/e calcd for C10H6F3N2S+ (M+H)+ 243.0198, found 243.0198. Ethyl 2,4-Dimethyl-5-((trifluoromethyl)thio)-1H-pyrrole-3-carboxylate (12v).12c After purification by silica gel column chromatography (PE:EA = 10:1), compound 12v was isolated as a brown solid (50 mg, 36%); Rf (PE:EA = 10:1) = 0.37; 1H NMR (400 MHz, CDCl3): δ 8.26 (s, 1H), 4.29 (q, J = 7.2 Hz, 2H), 2.53 (s, 3H), 2.36 (s, 3H), 1.36 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 165.2, 140.0, 133.8, 128.5 (q, J = 310.3 Hz, 1C), 113.3, 104.5 (q, J = 2.3 Hz, 1C), 59.6, 14.4, 14.2 (q, J = 1.4 Hz, 1C), 12.0 (q, J = 1.1 Hz, 1C); 19F NMR (376 MHz, CDCl3): δ −44.92 (s). (Trifluoromethyl)(2,4,6-trimethoxyphenyl)sulfane (12w).12b After purification by silica gel column chromatography (PE:EA = 30:1), compound 12w was isolated as a white solid (94 mg, 70%); Rf (PE:EA = 10:1) = 0.38; 1H NMR (400 MHz, CDCl3): δ 6.16 (s, 2H), 3.88 (s, 6H), 3.86 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 164.5, 163.5, 129.5 (q, J = 308.6 Hz, 1C), 91.8 (q, J = 1.4 Hz, 1C), 91.1, 56.2 (q, J = 2.2 Hz, 1C), 55.4 (q, J = 1.9 Hz, 1C); 19F NMR (376 MHz, CDCl3): δ −43.50 (s). 3-Methyl-1-phenyl-4-((trifluoromethyl)thio)-1H-pyrazol-5-ol (12x).12a After purification by silica gel column chromatography (CH2Cl2:MeOH = 30:1), compound 12x was isolated as a white solid (31 mg, 23%); Rf (CH2Cl2:MeOH = 30:1) = 0.31; 1H NMR (400 MHz, d6-DMSO): δ 7.69 (d, J = 7.8 Hz, 2H), 7.48 (t, J = 7.9 Hz, 2H), 7.31 (t, J = 7.4 Hz, 1H), 2.24 (s, 3H); 13C NMR (100 MHz, d6DMSO): δ 157.8, 152.4, 137.7, 129.4 (q, J = 309.0 Hz, 1C), 129.1, 126.3, 121.2, 80.3, 12.1; 19F NMR (376 MHz, d6-DMSO): δ −44.79 (s). 7. Characteristic Data for 13a, 13b, 13d−13g, 13i−13p, 13r, 13s, and 13u−13x. 3-((Trifluoromethyl)sulfinyl)-1H-indole (13a). After purification by silica gel column chromatography (PE:EA = 2:1), compound 13a was isolated as a pink solid (102 mg, 88%); mp = 115−116 °C; Rf (PE:EA = 2:1) = 0.32; 1H NMR (400 MHz, CDCl3): δ 10.08 (s, 1H), 7.94 (d, J = 7.8 Hz, 1H), 7.68 (d, J = 3.2 Hz, 1H), 7.44 (d, J = 7.8 Hz, 1H), 7.32−7.23 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 136.9, 131.1, 125.6 (q, J = 332.4 Hz, 1C), 124.5, 124.1, 122.7, 120.1 (q, J = 1.7 Hz, 1C), 112.7, 107.9 (q, J = 2.0 Hz, 1C); 19F NMR (376 MHz, CDCl3): δ −72.85 (s); HRMS (ESI) m/z calcd for C9H7F3NOS+ (M+H)+ 234.0195, found 234.0196. 3-((Trifluoromethyl)sulfinyl)-1H-indole (13b). After purification by silica gel column chromatography (PE:EA = 2:1), compound 13b was isolated as a gray solid (53 mg, 40%); mp = 137−139 °C; Rf (PE:EA = 2:1) = 0.31; 1H NMR (400 MHz, CDCl3): δ 9.69 (s, 1H), 7.79 (d, J = 3.0 Hz, 1H), 7.22 (t, J = 8.0 Hz, 1H), 7.09 (d, J = 8.2 Hz, 1H), 6.65 (d, J = 7.9 Hz, 1H), 3.93 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 152.9, 137.9, 127.4, 125.2 (q, J = 333.8 Hz, 1C), 124.9, 115.6, 109.1 (q, J = 2.1 Hz, 1C), 105.4, 102.0, 55.5 (q, J = 2.0 Hz, 1C); 19F NMR (376 MHz, CDCl3): δ −75.60 (s); HRMS (ESI) m/z calcd for C10H9F3NO2S+ (M+H)+ 264.0301, found 264.0300. 5-Chloro-3-((trifluoromethyl)sulfinyl)-1H-indole (13d). After purification by silica gel column chromatography (PE:EA = 2:1), compound 13d was isolated as a yellow solid (91 mg, 68%); mp = 135−138 °C; Rf (PE:EA = 2:1) = 0.22; 1H NMR (400 MHz, CDCl3): δ 9.88 (s, 1H), 7.92 (s, 1H), 7.77 (d, J = 3.1 Hz, 1H), 7.39 (d, J = 8.7 Hz, 1H), 7.28 (dd, J = 8.8 Hz, 2.0 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 135.1, 131.5, 128.7, 125.4 (q, J = 332.4 Hz, 1C), 125.1, 125.1, 119.8 (q, J = 1.8 Hz, 1C), 113.5, 108.2; 19F NMR (376 MHz, CDCl3): δ −72.97 (s); HRMS (ESI) m/z calcd for C9H6ClF3NOS+ (M+H)+ 267.9805, found 267.9806. 5-Bromo-3-((trifluoromethyl)sulfinyl)-1H-indole (13e). After purification by silica gel column chromatography (PE:EA = 2:1), compound 13e was isolated as a white solid (103 mg, 66%); mp = 154−157 °C; Rf (PE:EA = 2:1) = 0.22; 1H NMR (100 MHz, d6DMSO): δ 12.68 (s, 1H), 8.45 (d, J = 2.6 Hz, 1H), 7.99 (s, 1H), 7.61 (d, J = 8.7 Hz, 1H), 7.48 (dd, J = 8.7 Hz, 1.9 Hz, 1H); 13C NMR (100 MHz, d6-DMSO): δ 135.9, 134.9, 126.4, 125.8 (q, J = 334.6 Hz, 1C), 9179

DOI: 10.1021/acs.joc.7b01226 J. Org. Chem. 2017, 82, 9175−9181

Note

The Journal of Organic Chemistry

2-Methyl-3-((trifluoromethyl)sulfinyl)-1H-indole (13m). After purification by silica gel column chromatography (PE:EA = 2:1), compound 13m was isolated as a pink solid (88 mg, 71%); mp = 176− 178 °C; Rf (PE:EA = 2:1) = 0.3; 1H NMR (400 MHz, d6-DMSO): δ 12.36 (s, 1H), 7.78 (d, J = 7.8 Hz, 1H), 7.48 (d, J = 7.9 Hz, 1H), 7.24 (td, J = 7.5 Hz, 1.2 Hz, 1H), 7.19 (td, J = 7.5 Hz, 1.2 Hz, 1H), 2.58 (s, 3H); 13C NMR (100 MHz, d6-DMSO): δ 144.9, 135.8, 126.2 (q, J = 335.1 Hz, 1C), 124.9, 122.9, 121.6, 119.2, 112.1, 102.2 (q, J = 2.7 Hz, 1C), 11.8; 19F NMR (376 MHz, d6-DMSO): δ −72.37 (s); HRMS (ESI) m/z calcd for C10H9F3NOS+ (M+H)+ 248.0352, found 248.0351. 2-Phenyl-3-((trifluoromethyl)sulfinyl)-1H-indole (13n). After purification by silica gel column chromatography (PE:EA = 2:1), compound 13n was isolated as a yellow solid (107 mg, 70%); mp = 176−178 °C; Rf (PE:EA = 2:1) = 0.3; 1H NMR (400 MHz, d6DMSO): δ 12.83 (s, 1H), 7.98 (d, J = 7.9 Hz, 1H), 7.67−7.58 (m, 6H), 7.37 (t, J = 7.3 Hz, 1H), 7.29 (t, J = 7.6 Hz, 1H); 13C NMR (100 MHz, d6-DMSO): δ 146.0, 136.5, 130.3, 129.4, 129.1, 128.8, 126.5 (q, J = 336.4 Hz, 1C), 125.2, 124.0, 122.1, 120.5 (q, J = 2.3 Hz, 1C), 112.8, 103.2 (q, J = 2.2 Hz, 1C); 19F NMR (376 MHz, d6-DMSO): δ −70.73 (s); HRMS (ESI) m/z calcd for C15H11F3NOS+ (M+H)+ 310.0508, found 310.0506. 1-Methyl-3-((trifluoromethyl)sulfinyl)-1H-indole (13o). After purification by silica gel column chromatography (PE:EA = 2:1), compound 13o was isolated as a yellow solid (94 mg, 76%); mp = 119−122 °C; Rf (PE:EA = 2:1) = 0.43; 1H NMR (400 MHz, CDCl3): δ 7.95 (d, J = 8.0 Hz, 1H), 7.65 (s, 1H), 7.42−7.36 (m, 2H), 7.32− 7.28 (m, 1H), 3.86 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 137.7, 133.8, 125.6 (q, J = 333.1 Hz, 1C), 125.1, 124.0, 122.5, 120.5 (q, J = 1.3 Hz, 1C), 110.5, 107.3 (q, J = 2.1 Hz, 1C), 33.7 (q, J = 2.0 Hz, 1C); 19 F NMR (376 MHz, CDCl3): δ −73.51 (s); HRMS (ESI) m/z calcd for C10H9F3NOS+ (M+H)+ 248.0352, found 248.0351. 1,2-Dimethyl-3-((trifluoromethyl)sulfinyl)-1H-indole (13p). After purification by silica gel column chromatography (PE:EA = 2:1), compound 13p was isolated as a pink solid (78 mg, 60%); mp = 157− 158 °C; Rf (PE:EA = 2:1) = 0.42; 1H NMR (400 MHz, CDCl3): δ 7.98 (d, J = 7.6 Hz, 1H), 7.34−7.23 (m, 3H), 3.68 (s, 3H), 2.55 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 143.8, 137.2, 126.1 (q, J = 333.6 Hz, 1C), 124.8, 123.2, 122.3, 120.2 (q, J = 1.9 Hz, 1C), 109.7, 103.5 (q, J = 2.1 Hz, 1C), 29.9, 11.0; 19F NMR (376 MHz, CDCl3): δ −72.52 (s); HRMS (ESI) m/z calcd for C11H11F3NOS+ (M+H)+ 262.0508, found 262.0509. 3-Methyl-2-((trifluoromethyl)sulfinyl)-1H-indole (13r). After purification by silica gel column chromatography (PE:EA = 20:1), compound 13r was isolated as a white solid (61 mg, 49%); mp = 157−159 °C; Rf (PE:EA = 10:1) = 0.44; 1H NMR (400 MHz, CDCl3): δ 9.36 (s, 1H), 7.65 (d, J = 8.1 Hz, 1H), 7.47 (d, J = 8.4 Hz, 1H), 7.40 (td, J = 7.6 Hz, 0.8 Hz, 1H), 7.21 (t, J = 7.2 Hz, 1H), 2.49 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 138.3, 127.6, 126.5, 125.1 (q, J = 334.2 Hz, 1C), 122.7 (q, J = 1.1 Hz, 1C), 122.3, 120.7, 120.4, 112.4, 8.8; 19F NMR (376 MHz, CDCl3): δ −72.77 (s); HRMS (ESI) m/z calcd for C10H9F3NOS+ (M+H)+ 248.0352, found 248.0351. 5-Methyl-3-((trifluoromethyl)sulfinyl)-1H-indole (13s). After purification by silica gel column chromatography (PE:EA = 2:1), compound 13s was isolated as a yellow solid (91 mg, 73%); mp = 125−128 °C; Rf (PE:EA = 2:1) = 0.3; 1H NMR (400 MHz, CDCl3): δ 10.12 (s, 1H), 7.72 (s, 1H), 7.63 (d, J = 3.2 Hz, 1H), 7.32 (d, J = 8.4 Hz, 1H), 7.11 (dd, J = 8.4 Hz, 0.9 Hz, 1H), 2.39 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 135.2, 132.4, 131.3, 126.1, 125.6 (q, J = 332.3 Hz, 1C), 124.2, 119.6 (q, J = 1.5 Hz, 1C), 112.3, 106.8, 21.4; 19F NMR (376 MHz, CDCl3): δ −72.48 (s); HRMS (ESI) m/z calcd for C10H9F3NOS+ (M+H)+ 248.0352, found 248.0351. 2,5-Dimethyl-1-phenyl-3-((trifluoromethyl)sulfinyl)-1H-pyrrole (13u). After purification by silica gel column chromatography (PE:EA = 10:1), compound 13u was isolated as a pink solid (94 mg, 66%); mp = 125−129 °C; Rf (PE:EA = 5:1) = 0.48; 1H NMR (400 MHz, d6DMSO): δ 7.63−7.55 (m, 3H), 7.42−7.40 (m, 2H), 6.43 (s, 1H), 2.15 (s, 3H), 2.01 (s, 3H); 13C NMR (100 MHz, d6-DMSO): δ 136.3, 136.0, 132.1, 129.8, 129.2, 127.9, 125.3 (q, J = 332.8 Hz, 1C), 111.6 (q, J = 2.1 Hz, 1C), 104.1, 12.5, 10.9; 19F NMR (376 MHz, d6-

125.6, 121.9 (q, J = 1.8 Hz, 1C), 115.3, 114.5, 105.9 (q, J = 2.4 Hz, 1C); 19F NMR (376 MHz, d6-DMSO): δ −73.02 (s); HRMS (ESI) m/z calcd for C9H6BrF3NOS+ (M+H)+ 311.9300, found 311.9301. 5-Fluoro-3-((trifluoromethyl)sulfinyl)-1H-indole (13f). After purification by silica gel column chromatography (PE:EA = 2:1), compound 13f was isolated as a brown solid (83 mg, 66%); mp = 109−111 °C; Rf (PE:EA = 2:1) = 0.22; 1H NMR (400 MHz, CDCl3): δ 9.71 (s, 1H), 7.78 (d, J = 3.2 Hz, 1H), 7.61 (d, J = 8.3 Hz, 1H), 7.41 (dd, J = 9.0 Hz, 4.3 Hz, 1H), 7.08 (td, J = 9.0 Hz, 2.4 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 159.1 (d, J = 238.3 Hz, 1C), 133.3, 132.2, 125.5 (q, J = 332.3 Hz, 1C), 124.6 (q, J = 11.1 Hz, 1C), 113.6 (d, J = 9.6 Hz, 1C), 113.3 (d, J = 26.3 Hz, 1C), 108.0, 105.6 (dq, J = 1.6 Hz, J = 25.4 Hz, 1C); 19F NMR (376 MHz, CDCl3): δ −72.79 (s), δ −119.49 (s); HRMS (ESI) m/z calcd for C9H6F4NOS+ (M+H)+ 252.0101, found 252.0101. Methyl 3-((Trifluoromethyl)sulfinyl)-1H-indole-5-carboxylate (13g). After purification by silica gel column chromatography (PE:EA = 2:1), compound 13g was isolated as a pale yellow solid (68 mg, 47%); mp = 162−165 °C; Rf (PE:EA = 1:1) = 0.36; 1H NMR (400 MHz, d6-DMSO): δ 12.79 (s, 1H), 8.55 (s, 1H), 8.52 (d, J = 3.0 Hz, 1H), 7.95 (dd, J = 8.6 Hz, 1.6 Hz, 1H), 7.71 (d, J = 8.6 Hz, 1H), 3.89 (s, 3H); 13C NMR (100 MHz, d6-DMSO): δ 166.5, 139.8, 135.7, 125.8 (q, J = 334.6 Hz, 1C), 124.5, 123.6, 123.4, 122.0 (q, J = 1.3 Hz, 1C), 113.4, 107.6 (q, J = 2.1 Hz, 1C), 52.1; 19F NMR (376 MHz, d6DMSO): δ −72.89 (s); HRMS (ESI) m/z calcd for C11H9F3NO3S+ (M+H)+ 292.0250, found 292.0249. 6-Fluoro-3-((trifluoromethyl)sulfinyl)-1H-indole (13i). After purification by silica gel column chromatography (PE:EA = 2:1), compound 13i was isolated as a yellow solid (80 mg, 64%); mp = 97−100 °C; Rf (PE:EA = 2:1) = 0.31; 1H NMR (400 MHz, CDCl3): δ 10.05 (s, 1H), 7.87 (dd, J = 8.8 Hz, 5.2 Hz, 1H), 7.74 (d, J = 3.0 Hz, 1H), 7.12 (dd, J = 9.0 Hz, 2.2 Hz, 1H), 7.03 (td, J = 9.2 Hz, 2.2 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 160.8 (d, J = 241.1 Hz, 1C), 137.2 (d, J = 12.4 Hz, 1C), 131.5, 125.5 (q, J = 332.4 Hz, 1C), 121.3 (q, J = 8.2 Hz, 1C), 120.4, 111.8 (d, J = 24.6 Hz, 1C), 108.4 (q, J = 1.9 Hz, 1C), 99.1 (d, J = 26.4 Hz, 1C); 19F NMR (376 MHz, CDCl3): δ −72.70 (s), δ −116.70 (s); HRMS (ESI) m/z calcd for C9H6F4NOS+ (M+H)+ 252.0101, found 252.0100. 6-Chloro-3-((trifluoromethyl)sulfinyl)-1H-indole (13j). After purification by silica gel column chromatography (PE:EA = 2:1), compound 13j was isolated as a yellow solid (77 mg, 58%); mp = 125−127 °C; Rf (PE:EA = 2:1) = 0.28; 1H NMR (400 MHz, d6DMSO): δ 12.59 (s, 1H), 8.43 (d, J = 3.1 Hz, 1H), 7.85 (d, J = 8.6 Hz, 1H), 7.68 (d, J = 1.8 Hz, 1H), 7.31 (dd, J = 8.6 Hz, 1.9 Hz, 1H); 13C NMR (100 MHz, d6-DMSO): δ 137.6, 134.8, 128.4, 125.7 (q, J = 334.6 Hz, 1C), 122.7, 122.4, 121.1 (q, J = 1.6 Hz, 1C), 112.9, 106.7 (q, J = 2.2 Hz, 1C); 19F NMR (376 MHz, d6-DMSO): δ −72.89 (s); HRMS (ESI) m/z calcd for C9H6ClF3NOS+ (M+H)+ 267.9805, found 267.9805. 6-Methoxy-3-((trifluoromethyl)sulfinyl)-1H-indole (13k). After purification by silica gel column chromatography (PE:EA = 2:1), compound 13k was isolated as a pink solid (79 mg, 60%); mp = 136− 140 °C; Rf (PE:EA = 2:1) = 0.19; 1H NMR (400 MHz, CDCl3): δ 9.86 (s, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.59 (d, J = 3.0 Hz, 1H), 6.91 (dd, J = 8.8 Hz, 2.2 Hz, 1H), 6.88 (d, J = 2.0 Hz, 1H), 3.77 (s, 3H); 13 C NMR (100 MHz, CDCl3): δ 157.8, 138.0, 130.3, 125.5 (q, J = 332.4 Hz, 1C), 120.9 (q, J = 1.7 Hz, 1C), 117.8, 112.9, 108.0, 95.4, 55.5; 19F NMR (376 MHz, CDCl3): δ −72.65 (s); HRMS (ESI) m/z calcd for C10H9F3NO2S+ (M+H)+ 264.0301, found 264.0301. 7-Methyl-3-((trifluoromethyl)sulfinyl)-1H-indole (13l). After purification by silica gel column chromatography (PE:EA = 2:1), compound 13l was isolated as a green solid (102 mg, 82%); mp = 132−136 °C; Rf (PE:EA = 2:1) = 0.38; 1H NMR (400 MHz, CDCl3): δ 9.94 (s, 1H), 7.76 (d, J = 7.9 Hz, 1H), 7.68 (d, J = 3.2 Hz, 1H), 7.17 (t, J = 7.6 Hz, 1H), 7.11 (d, J = 7.2 Hz, 1H), 2.48 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 136.4, 130.6, 125.5 (q, J = 332.5 Hz, 1C), 124.9, 123.8, 122.8, 122.0, 117.7 (q, J = 1.4 Hz, 1C), 108.5, 16.5; 19F NMR (376 MHz, CDCl3): δ −72.87 (s); HRMS (ESI) m/z calcd for C10H9F3NOS+ (M+H)+ 248.0352, found 248.0352. 9180

DOI: 10.1021/acs.joc.7b01226 J. Org. Chem. 2017, 82, 9175−9181

Note

The Journal of Organic Chemistry DMSO): δ −73.79 (s); HRMS (ESI) m/z calcd for C13H13F3NOS+ (M+H)+ 288.0665, found 288.0661. Ethyl 2,4-Dimethyl-5-((trifluoromethyl)sulfinyl)-1H-pyrrole-3-carboxylate (13v). After purification by silica gel column chromatography (PE:EA = 10:1), compound 13v was isolated as a dark yellow solid (98 mg, 69%); mp = 134−138 °C; Rf (PE:EA = 10:1) = 0.19; 1H NMR (400 MHz, d6-DMSO): δ 12.67 (s, 1H), 4.20 (q, J = 7.1 Hz, 0.6 Hz, 2H), 2.48 (s, 3H), 2.33 (s, 3H), 1.28 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, d6-DMSO): δ 163.9, 143.8, 132.2, 124.9 (q, J = 335.3 Hz, 1C), 115.9 (q, J = 1.9 Hz, 1C), 112.5, 59.3, 14.2, 13.6, 11.0; 19F NMR (376 MHz, d6-DMSO): δ −72.92 (s); HRMS (ESI) m/e calcd for C10H13F3NO3S+ (M+H)+ 284.0563, found 284.0562. 1,3,5-Trimethoxy-2-((trifluoromethyl)sulfinyl)benzene (13w). After purification by silica gel column chromatography (PE:EA = 3:1), compound 13w was isolated as a brown solid (51 mg, 36%); mp = 69−73 °C; Rf (PE:EA = 3:1) = 0.17; 1H NMR (400 MHz, CDCl3): δ 6.13 (s, 2H), 3.87 (s, 6H), 3.87 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 166.5, 162.5, 125.8 (q, J = 336.3 Hz, 1C), 103.7 (q, J = 2.6 Hz, 1C), 91.1, 56.1, 55.5; 19F NMR (376 MHz, CDCl3): δ −68.45 (s); HRMS (ESI) m/z calcd for C10H12F3O4S+ (M+H)+ 285.0403, found 285.0403. 3-Methyl-1-phenyl-4-((trifluoromethyl)sulfinyl)-1H-pyrazol-5-ol (13x). After purification by silica gel column chromatography (CH2Cl2:MeOH = 20:1), compound 13x was isolated as a pale pink solid (74 mg, 51%); mp = 178−182 °C; Rf (CH2Cl2:MeOH = 10:1) = 0.24; 1H NMR (400 MHz, d6-DMSO): δ 8.00 (d, J = 8.0 Hz, 2H), 7.27 (t, J = 7.9 Hz, 2H), 6.96 (t, J = 7.3 Hz, 1H), 2.12 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 164.3, 146.5, 140.8, 128.1, 126.2 (q, J = 336.6 Hz, 1C), 122.0, 117.5, 87.2 (q, J = 2.8 Hz, 1C), 14.3; 19F NMR (376 MHz, d6-DMSO): δ −72.35 (s). HRMS (ESI) m/e calcd for C11H10F3N2O2S+ (M+H)+ 291.0410, found 291.0406.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b01226. Optimization of trifluoromethylthiolation and trifluoromethylsulfoxidation reactions, spectra of compounds 12a−12r, 12t, 12v−12x, 13a, 13b, 13d−13g, 13i−13p, 13r, 13s, and 13u−13x (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Xia Zhao: 0000-0001-9477-5912 Author Contributions

A.W. and B.Y. contributed equally to this work. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors are sincerely thankful for the financial support from the National Science Foundation of China (Grants 21572158). We thank Dr. Guojiao Wu for the helpful discussions about the mechanism. We thank Prof. Zhenhua Zhang (China Agricultural University) for providing several heterocyclic compounds (synthesized in the National Key Technologies R&D Program of China, 2015BAK45B01, CAU).

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REFERENCES

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DOI: 10.1021/acs.joc.7b01226 J. Org. Chem. 2017, 82, 9175−9181