English

• 1.   Introduction

  Recent decades have witnessed great industrial interests in organic compounds having SCF₃ group incorporated in various aromatics. Pharmaceutical and agrochemical industries are particularly invested in these structural motifs due to enhanced bioavailability, transmembrane permeation and metabolic stability of host molecules by strong electron-withdrawing effect and lipophilicity (Hansch π value=1.44) of SCF₃ group.^[1] Toltrazuril, Losartan, Vaniliprole and Triflorlex are a few prominent examples of biologically active drugs containing SCF₃ group (Figure 1).^[2] Installation of SCF₃ group into smaller molecules for design and discovery of novel bioactive compounds has always been a hot topic of research.^[3] Numerous methodologies have been developed for the introduction of SCF₃ group in different organic compounds over the course of several decades.^[4] Some of the most commonly used methods includes nucleophilic, ^{[2a, 5]} eletrophilic, ^{[4d, 6]} and radical trifluoromethylthiolation, ^[7] trifluoromethylation of sulfur compounds, ^[8] fluorine-halogen exchange reactions.^[9] Rapid growth of transition metal catalyzed protocols has led to the development of more efficient synthetic methods for the direct trifluoromethylthiolation of organic compounds.^[10] Elegant examples include transition metal catalyzed coupling reactions of various SCF₃ sources with different aryl halides, ^[11] diazonium salts, ^[12] arenes, ^[13] and aliphatics.^[14]

  Figure 1

  

  Figure 1.  Examples of SCF₃ containing biologically active compounds

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  Transition metal catalyzed reactions through a metal carbene intermediate has emerged as a powerful tool in organic synthesis.^[15] Among these, the use of diazo compounds as metal carbene precursors for the introduction of SCF₃ group has attracted much attention.^[16-19] Elegant examples include the copper catalyzed coupling reactions of diazo compounds with various nucleophilic SCF₃ sources^[17] and the rhodium^[18] or zinc^[19] catalyzed multicomponent reactions of diazo compounds with SCF₃ sources. Notably, only acyclic diazo compounds like α-diazo esters have been employed in trifluoromethylthiolations giving mostly aliphatic SCF₃ derivatives (Scheme 1a), ^[17] while the use of cyclic diazo compounds for these transformations remains unexplored.

  Scheme 1

  

  Scheme 1.  Trifluoromethylthiolation of acyclic diazo compounds and our work

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  In 2014, we developed practical methods for the preparation of 3-diazoindolin-2-imines, a new class of cyclic α-diazo imidamides, ^[20] and used them as metal carbene precursors for the syntheses of structurally divers indole and indoline derivatives.^[20-21] It was envisioned that 3-diazo- indolin-2-imines could be used for copper-catalyzed trifluoromethylthiolation reactions and would result in important indole embedded aromatic SCF₃ derivatives (Scheme 1b). The results of our effort are described below.

  2.   Results and discussion

  We began our trial by treating 3-diazoindolin-2-imine (1p) with silver trifluoromethylthiolate (AgSCF₃, 2) in the presence of different copper salts (Table 1). In the first attempt, 1p was treated with 1 equiv. AgSCF₃ in the presence of CuI catalyst in 1, 2-dichloroethane (DCE) solvent at room temperature and in ambient air for 1 h as a model reaction. Fortunately, trifluoromethylthiolated product 3p was obtained in 62% yield (Table 1, Entry 1).

  Table 1

  

  Table 1.  Optimization of reaction conditions^a

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  Entry	[Cu]/equiv.	1p/equiv.	Additive (equiv.)	Solvent	Time/h	Yieldb/%
  1	CuI (1.0)	1.0	—	DCE	1	62
  2	CuBr (1.0)	1.0	—	DCE	1	Trace
  3	CuCl (1.0)	1.0	—	DCE	1	Trace
  4 c	CuI (1.0)	1.0	—	DCE	1	53
  5	CuI (1.0)	1.2	—	DCE	1	77
  6	CuI (1.0)	1.4	—	DCE	1	77
  7	CuI (1.0)	1.2	H2O (10)	DCE	1	87
  8	CuI (1.0)	1.2	H2O (20)	DCE	1	67
  9	CuI (1.0)	1.2	H2O (30)	DCE	1	64
  10	CuI (1.0)	1.2	H2O (40)	DCE	1	55
  11	CuI (1.25)	1.2	H2O (10)	DCE	1	66
  12	CuI (0.75)	1.2	H2O (10)	DCE	1	74
  13	CuI (0.50)	1.2	H2O (10)	DCE	1	71
  14	CuI (0.25)	1.2	H2O (10)	DCE	1	30
  15	CuI (1.0)	1.2	H2O (10)	DCM	1	84
  16	CuI (1.0)	1.2	H2O (10)	PhMe	1	87
  17	CuI (1.0)	1.2	H2O (10)	CH3CN	1	trace
  18	CuI (1.0)	1.2	H2O (10)	NMP	1	trace
  19	CuI (1.0)	1.2	H2O (10)	DCE	0.5	85
  20	CuI (1.0)	1.2	H2O (10)	DCE	2	87
  a Reaction conditions: 1a (0.12 mmol), 2 (0.1 mmol), CuI (0.1 mmol), solvent (2 mL), room temperature; b isolated yield; c N2 atmosphere.

  The product 3p was characterized by HRMS, ¹H NMR and ¹³C NMR analysis, and its structure was confirmed by X-ray single crystal analysis.^[22] These results prompted us to further screen the reaction conditions. When CuBr and CuCl were used as catalysts, only a trace amount of 3p was detected on thin-layer chromatography (TLC) (Table 1, Entries 2 and 3). When the reaction was performed under nitrogen atmosphere, 3p was obtained in lower yield (53%) (Table 1, Entry 4). The yield could be increased to 77% when the amount of diazo compound was risen to 1.2 and 1.4 equiv. (Table 1, Entries 5 and 6). When 10 equiv. of water was added to the reaction as additive, the yield of 3p was increased to 87% (Table 1, Entry 7). A gradual decrease in the yield was observed when the amount of water was increased (Table 1, Entries 8~10). Both increase and decrease in the amount of CuI led to a decrease in the yield of 3p (Table 1, Entries 11~14). The solvents were also screened. Dichloromethane (DCM) and toluene gave 84% and 87% yields, respectively (Table 1, Entries 15 and 16), while only trace amount of 3p was observed on TLC when acetonitrile and N-methylpyrrolidone (NMP) were used as solvents (Table 1, Entries 17 and 18). Finally, the reaction time was optimized. Decreasing the reaction time led to a slightly reduction in the yield (85%) (Table 1, Entry 19), while increasing the reaction time did not improve the reaction (Table 1, Entry 20). Thus, the best reaction conditions were determined (Table 1, Entry 7).

  After determining the optimal reaction conditions, the substrate scope of 3-diazoindolin-2-imines 1 was investigated (Table 2). Substituent R¹ at 1-position of diazo component 1 could be varied from methyl to ethyl, isopropyl and benzyl, giving the corresponding products 3a~3d in 78%~86% yields. However, the diazo compound 1e without substituent at 1-position of indole ring (R¹=H) did not undergo this reaction to give the desired product 3e. Substituent at 5-position of 3-diazoindolin-2-imines 1 could be varied from electron-withdrawing groups (F, Cl, Br) to electron-donating groups (Me, OMe). Thus, the corresponding products 3f (89%), 3g (81%), 3h (80%) and 3i (83%) and 3j (93%) were obtained in excellent yields, indicating that the presence of electron-donating groups at phenyl ring of diazo component slightly favors the reaction (Scheme 2). The presence of substituents at 4-, 6- or 7-positions of diazo compounds 1 also tolerated the reaction conditions and the corresponding products 3k (54%), 3l (80%) and 3m (82%) were isolated in moderate to excellent yields. 3-diazoindolin-2-imines 1 with different sulfonyl groups attached (e.g. methylsulfonyl, phenylsulfonyl, (4-chlorophenyl)sulfonyl and (4-fluorophenyl)sulfonyl) were also favorable for these transformations. The corresponding products 3n, 3o, 3p and 3q were isolated in 74%, 75%, 87% and 82% yields, respectively. When the sulfonyl group of diazo compound was changed to 4-nitrophenyl- sulfonyl, the desired product 3r was not formed. On the other hand, diazo compounds 1 bearing 4-methoxyphenyl sulfonyl or naphthalen-2-yl sulfonyl group generated the corresponding products 3s and 3t in 86% and 83% yields, respectively.

  Table 2

  

  Table 2.  Substrate scope of 3-diazoindolin-2-imines^a

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  a Reaction conditions: 1 (0.12 mmol), 2 (0.1 mmol), CuI (0.1 mmol), H2O (1 mmol), DCE (2 mL), room temperature, 1 h; Isolated yield.

  A gram scale reaction of 3p was performed to evaluate the synthetic potential of this approach. Diazo compound 1p (3.36 mmol) smoothly reacted with 2 (2.8 mmol) under the standard conditions and the corresponding product 3p was isolated in 85% yield (1.008 g).

  Based on our results and previous report, ^[17] a plausible mechanism is proposed for the formation of 3 (Scheme 2). First, AgSCF₃ interacts with CuI and a more reactive specie CuSCF₃ is formed along with the removal of AgI precipitates. This nucleophilic specie then interacts with diazo compound 1 and SCF₃ containing copper carbene intermediate A is formed with the release of nitrogen gas. Subsequently, the Cu carbene A undergoes migratory insertion and the copper complex B is formed. Finally, water assisted protonation results in the formation of SCF₃ containing intermediate C, which undergoes tautomerization to give the final product 3 (path a). Aromatization is the driving force of this step. Alternatively, B tautomerizes to complex D, which gives 3 after hydrolysis.

  Scheme 2

  

  Scheme 2.  Mechanism for the formation of 3-((trifluoromethyl)- thio)-2-aminoindoles (3)

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  3.   Conclusions

  We have developed an efficient cross-coupling reaction between 3-diazoindolin-2-imines 1 and nucleophilic trifluoromethylthiolating reagent AgSCF₃ for the synthesis of novel indole embedded SCF₃ derivatives. It is the first example of trifluoromethylthiolation of cyclic diazo compounds. Readily available starting materials, cheap catalysts, water assisted higher yields and mild reaction conditions are the merits of this reaction. As indole ring system is part of numerous natural products and drugs, these indole embedded SCF₃ derivatives may find applications in medicinal chemistry and be valuable in future.

  4.   Experimental section

  4.1   Instruments and reagents

  ¹H NMR spectra were obtained on 400 MHz in CDCl₃. The chemical shifts were reported referenced to tetramethylsilane (TMS) as an internal standard. ¹³C NMR spectra were recorded on 100 MHz in CDCl₃. The chemical shifts were reported referenced to the internal solvent signals (δ 77.0 for CDCl₃). ¹⁹F NMR chemical shifts were determined relative to CFCl₃ at δ 0.0. Infrared spectra were obtained on an FTIR spectrometer. High-resolution mass spectra (HRMS) data were obtained by using EI ionization on time-of-flight (TOF) mass spectrometer. Melting points were measured with a SGW X-4 micro melting point apparatus. Flash column chromatography was performed employing 300~400 mesh silica gel. Thin layer chromatography (TLC) was performed on silica gel HSGF254. Unless otherwise mentioned, solvents and reagents were purchased from commercial sources and used as received. 3-Diazoindolin-2-imines 1 were prepared according to our published methods.^[20]

  4.2   General procedure for the synthesis of compounds 3

  To an over-dried reaction tube with a magnetic stirring bar were added sequentially 1 (0.12 mmol), 2 (0.1 mmol, 21 mg), CuI (0.1 mmol, 19 mg), H₂O (1 mmol, 18 mg) and dichloromethane (DCE) (2 mL). The mixture was stirred at room temperature for 1 h. After the solvent was evaporated in vacuum, the residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate, V:V=5:1) to give pure products 3.

  4.3   Characterization data for products 3

  4-Methyl-N-(1-methyl-3-((trifluoromethyl)thio)-1H- indol-2-yl)benzenesulfonamide (3a): White solid, yield 78% (31 mg). m.p. 158.2~159.3 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.62 (d, J=8.0 Hz, 1H), 7.49 (d, J=8.4 Hz, 2H), 7.42 (d, J=8.0 Hz, 1H), 7.36 (td, J=7.6 Hz, 1.2 Hz, 1H), 7.29~7.23 (m, 3H), 6.74 (s, 1H), 3.94 (s, 3H), 2.44 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 145.0, 136.7, 135.4, 134.2, 129.8, 129.2 (q, J=309 Hz), 128.0, 127.8, 123.8, 121.9, 119.4, 110.5, 89.3, 31.3, 21.7; ¹⁹F NMR (376 MHz, CDCl₃) δ: -44.06 (s); IR (film) v: 3245, 2959, 1597, 1522, 1479, 1378, 1185, 1124, 849, 738, 672 cm^-1. HRMS (EI) calcd for C₁₇H₁₅F₃N₂O₂S₂ 400.0527; found 400.0525.

  N-(1-Ethyl-3-((trifluoromethyl)thio)-1H-indol-2-yl)-4- methylbenzenesulfonamide (3b): White solid, yield 85% (35 mg). m.p. 129.2~130.1 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.62 (d, J=8.0 Hz, 1H), 7.51 (d, J=8.0 Hz, 2H), 7.46 (d, J=8.4 Hz, 1H), 7.35 (td, J=7.6, 1.2 Hz, 1H), 7.27~7.24 (m, 3H), 6.71 (s, 1H), 4.52 (d, J=7.6 Hz, 2H), 2.44 (s, 3H), 1.49 (t, J=3.2 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ: 145.0, 136.0, 134.4, 134.2, 129.8, 129.2 (q, J=309 Hz), 128.3, 127.9, 123.8, 121.8, 119.6, 110.9, 90.0, 39.4, 21.7, 14.5; ¹⁹F NMR (376 MHz, CDCl₃) δ: -44.00 (s); IR (film) v: 3252, 2979, 2929, 1598, 1525, 1383, 1343, 1230, 1186, 1105, 1018, 813, 749, 672 cm^-1. HRMS (EI) calcd for C₁₈H₁₇F₃N₂O₂S₂ 414.0684; found 414.0684.

  N-(1-Isopropyl-3-((trifluoromethyl)thio)-1H-indol-2-yl)-4-methylbenzenesulfonamide (3c): White solid, yield 82% (35 mg). m.p. 158.2~159.1 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.68 (d, J=8.4 Hz, 1H), 7.63 (d, J=8.0 Hz, 1H), 7.51 (d, J=8.4 Hz, 2H), 7.31 (td, J=8.0 Hz, 0.8 Hz, 1H), 7.26~7.21 (m, 3H), 6.68 (s, 1H), 5.39~5.32 (m, 1H), 2.44 (s, 3H), 1.72 (s, 3H), 1.70 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 145.0, 135.8, 134.1, 133.1, 129.8, 129.2 (q, J=309 Hz), 129.0, 127.9, 123.2, 121.3, 119.8, 113.2, 89.8, 48.8, 21.7, 21.1; ¹⁹F NMR (376 MHz, CDCl₃) δ: -43.99 (s); IR (film) v: 3253, 2977, 2940, 1598, 1527, 1456, 1377, 1168, 1102, 1019, 909, 813, 672 cm^-1. HRMS (EI) calcd for C₁₉H₁₉F₃N₂O₂S₂ 428.0840; found 428.0839.

  N-(1-Benzyl-3-((trifluoromethyl)thio)-1H-indol-2-yl)-4-methylbenzenesulfonamide (3d): White solid, yield 86% (41 mg). m.p. 134.0~135.0 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.66~7.64 (m, 1H), 7.53 (d, J=8.4 Hz, 2H), 7.27~7.25 (m, 8H), 7.00 (d, J=6.4 Hz, 2H), 6.72 (s, 1H), 5.69 (s, 2H), 2.45 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 145.0, 136.6, 136.5, 135.0, 134.3, 129.8, 129.2 (q, J=309 Hz), 128.7, 128.2, 127.9, 127.5, 126.3, 124.1, 122.0, 119.6, 115.5, 91.2, 47.9, 21.7; ¹⁹F NMR (376 MHz, CDCl₃) δ: -43.92 (s); IR (film) v: 3255, 3032, 2929, 1597, 1528, 1384, 1167, 1105, 971, 909, 813, 735 cm^-1. HRMS (EI) calcd for C₂₃H₁₉F₃N₂O₂S₂ 476.0840; found 476.0841.

  N-(5-Fluoro-1-methyl-3-((trifluoromethyl)thio)-1H-in- dol-2-yl)-4-methylbenzenesulfonamide (3f): White solid, yield 89% (37 mg). m.p. 213.0~214.0 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.58 (d, J=8.4 Hz, 2H), 7.35 (dd, J=8.8 Hz, 4.0 Hz, 2H), 7.28~7.25 (m, 3H), 7.10 (td, J=9.2 Hz, 2.4 Hz, 2H), 6.78 (s, 1H), 3.93 (s, 3H), 2.45 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 159.0 (d, J=237.2 Hz), 145.2, 137.9, 134.1, 131.9, 129.9, 129.2 (q, J=309 Hz), 128.7 (d, J=10.4 Hz), 127.7, 112.5 (d, J=22.1 Hz), 111.7 (d, J=9.5 Hz), 104.6 (d, J=10.2 Hz), 89.4, 31.5, 21.7; ¹⁹F NMR (376 MHz, CDCl₃) δ: -44.06 (s, 3F), -120.62~-120.67 (m, 1F); IR (film) v: 3232, 2959, 2916, 1383, 1489, 1333, 1169, 1104, 986, 863, 674 cm^-1. HRMS (EI) calcd for C₁₇H₁₄- F₄N₂O₂S₂ 418.0433; found 418.0433.

  N-(5-Chloro-1-methyl-3-((trifluoromethyl)thio)-1H- indol-2-yl)-4-methylbenzenesulfonamide (3g): White solid, yield 81% (35 mg). m.p. 181.2~182.3 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.58 (s, 1H), 7.47 (d, J=8.0 Hz, 2H), 7.35~7.29 (m, 2H), 7.27~7.25 (m, 2H), 6.76 (s, 1H), 3.93 (s, 3H), 2.45 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 145.2, 137.8, 134.0, 133.8, 129.9, 129.02, 129.01 (q, J=309 Hz), 128.0, 127.7, 124.3, 118.9, 111.8, 89.1, 31.5, 21.7; ¹⁹F NMR (376 MHz, CDCl₃) δ: -44.09 (s); IR (film) v: 3224, 3054, 2954, 1598, 1525, 1373, 1332, 1142, 1116, 907, 713 cm^-1. HRMS (EI) calcd for C₁₇H₁₄ClF₃N₂O₂S₂ 434.0137; found 434.0138.

  N-(5-Bromo-1-methyl-3-((trifluoromethyl)thio)-1H-indol-2-yl)-4-methylbenzenesulfonamide (3h): White solid, yield 80% (38 mg). m.p. 234.6~235.6 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.73 (d, J=1.2 Hz, 1H), 7.48~7.43 (m, 3H), 7.29 (d, J=8.8 Hz, 1H), 7.27~7.25 (m, 2H), 6.76 (s, 1H), 3.93 (s, 3H), 2.45 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 145.3, 137.7, 134.1, 134.0, 129.9, 129.6, 129.0 (q, J=309 Hz), 127.7, 126.9, 122.0, 115.6, 112.1, 89.0, 31.5, 21.7; ¹⁹F NMR (376 MHz, CDCl₃) δ: -43.95 (s); IR (film) v: 3229, 2959, 2912, 1598, 1472, 1372, 1188, 1117, 1052, 809, 675 cm^-1; HRMS (ESI) calcd for C₁₇H₁₄BrF₃N₂- O₂S₂Na⁺ [M+Na]⁺: 500.9524; found 500.9537.

  N-(1, 5-Dimethyl-3-((trifluoromethyl)thio)-1H-indol-2- yl)-4-methylbenzenesulfonamide (3i): White solid, yield 83% (34 mg). m.p. 165.2~166.3 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.48 (d, J=8.0 Hz, 2H), 7.39 (s, 1H), 7.30 (d, J=8.4 Hz, 1H), 7.25~7.22 (m, 2H), 7.18 (dd, J=8.4 Hz, 1.2 Hz, 1H), 6.74 (s, 1H), 3.91 (s, 3H), 2.47 (s, 3H), 2.44 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 144.9, 136.5, 134.2, 133.8, 131.5, 129.8, 129.2 (q, J=309 Hz), 128.2, 127.8, 125.5, 118.9, 110.3, 88.6, 31.2, 21.7, 21.5; ¹⁹F NMR (376 MHz, CDCl₃) δ: -44.13 (s); IR (film) v: 3253, 3028, 2923, 1598, 1491, 1343, 1306, 1186, 1122, 909, 795, 674 cm^-1. HRMS (EI) calcd for C₁₈H₁₇F₃N₂O₂S₂ 414.0684; found 414.0686.

  N-(5-Methoxy-1-methyl-3-((trifluoromethyl)thio)-1H- indol-2-yl)-4-methylbenzenesulfonamide (3j): White solid, yield 93% (40 mg). m.p. 190.1~191.2 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.49 (d, J=8.4 Hz, 2H), 7.30 (d, J=8.8 Hz, 1H), 7.25 (d, J=7.2 Hz, 2H), 7.03 (d, J=2.0 Hz, 1H), 7.00 (dd, J=8.8 Hz, 2.4 Hz, 1H), 6.77 (s, 1H), 3.90 (s, 3H), 3.86 (s, 3H), 2.44 (s, 3H), 2.44 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 155.8, 144.9, 136.6, 134.3, 130.3, 129.8, 129.3 (q, J=309 Hz), 128.8, 114.3, 111.5, 100.6, 88.8, 55.7, 31.3, 21.7; ¹⁹F NMR (376 MHz, CDCl₃) δ: -44.16 (s); IR (film) v: 3218, 3004, 2965, 1623, 1598, 1378, 1291, 1221, 1120, 1029, 952, 794, 697 cm^-1. HRMS (EI) calcd for C₁₈H₁₇F₃- N₂O₃S₂ 430.0633; found 430.0635.

  N-(4-Bromo-1-methyl-3-((trifluoromethyl)thio)-1H- indol-2-yl)-4-methylbenzenesulfonamide 3k: White solid, yield 56% (27 mg). m.p. 157~159 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.51 (d, J=8.4 Hz, 2H), 7.44~7.38 (m, 2H), 7.27 (d, J=8.0 Hz, 2H), 7.18 (t, J=7.6 Hz, 1H), 6.87 (s, 1H), 3.95 (s, 3H), 2.46 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 145.3, 138.9, 136.6, 134.2, 129.9, 128.9 (q, J=309 Hz), 127.8, 127.1, 124.9, 124.2, 114.2, 110.1, 89.7, 31.8, 21.7; ¹⁹F NMR (376 MHz, CDCl₃) δ: -44.74 (s); IR (film) v: 3254, 3051, 2948, 1624, 1514, 1343, 1285, 1186, 1122, 909, 795, 674 cm^-1. HRMS (EI) calcd for C₁₇H₁₄Br- F₃N₂O₂S₂ 477.9632; found 477.9635.

  N-(6-Chloro-1-methyl-3-((trifluoromethyl)thio)-1H-in- dol-2-yl)-4-methylbenzenesulfonamide (3l): White solid, yield 80% (35 mg). m.p. 159~161 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.53~7.47 (m, 3H), 7.42 (d, J=1.6 Hz, 1H), 7.26~7.21 (m, 3H), 6.80 (s, 1H), 3.90 (s, 3H), 2.45 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 145.1, 137.3, 135.8, 134.1, 129.89, 129.86, 129.0 (q, J=309 Hz), 127.8, 126.4, 122.8, 120.5, 110.6, 89.9, 31.4, 21.7; ¹⁹F NMR (376 MHz, CDCl₃) δ: -43.92 (s); IR (film) v: 3236, 3032, 2956, 1598, 1491, 1343, 1306, 1186, 1122, 909, 795, 674 cm^-1. HRMS (EI) calcd for C₁₇H₁₄ClF₃N₂O₂S₂ 434.0137; found 434.0138.

  N-(1, 7-Dimethyl-3-((trifluoromethyl)thio)-1H-indol-2- yl)-4-methylbenzenesulfonamide (3m): White solid, yield 82% (34 mg). m.p. 170.1~171.2 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.41 (d, J=8.0 Hz, 2H), 7.37 (d, J=7.6 Hz, 1H), 7.16 (d, J=8.4 Hz, 2H), 7.03 (t, J=3.6 Hz, 1H), 6.97(d, J=7.2 Hz, 1H), 6.69 (s, 1H), 4.09 (s, 3H), 2.74 (s, 3H), 2.36 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 145.0, 137.1, 134.6, 134.3, 129.8, 129.2 (q, J=309 Hz), 128.9, 127.8, 126.6, 122.5, 121.8, 117.4, 89.5, 34.6, 21.7, 20.0; ¹⁹F NMR (376 MHz, CDCl₃) δ: -44.02 (s); IR (film) v: 3253, 3028, 2923, 1598, 1491, 1343, 1306, 1186, 1122, 909, 795, 674 cm^-1. HRMS (EI) calcd for C₁₈H₁₇F₃N₂O₂S₂ 414.0684; found 414.0686.

  N-(1-Methyl-3-((trifluoromethyl)thio)-1H-indol-2-yl)- methanesulfonamide (3n): White solid, yield 74% (24 mg). m.p. 158.2~159.3 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.77 (d, J=8.0 Hz, 1H), 7.42~7.36 (m, 2H), 7.34~7.30 (m, 1H), 6.84 (s, 1H), 3.87 (s, 3H), 3.14 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 136.4, 135.4, 129.2 (q, J=309 Hz), 128.1, 124.2, 122.3, 119.4, 89.0, 40.4, 31.2; ¹⁹F NMR (376 MHz, CDCl₃) δ: -43.64 (s); IR (film) v: 3256, 2075, 2936, 1528, 1477, 1382, 1162, 973, 746 cm^-1. HRMS (EI) calcd for C₁₁H₁₁F₃N₂O₂S₂ 324.0214; found 324.0215.

  N-(1-Methyl-3-((trifluoromethyl)thio)-1H-indol-2-yl)- benzenesulfonamide (3o): White solid, yield 75% (29 mg). m.p. 200.1~201.1 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.67~7.61 (m, 4H), 7.49~7.44 (m, 3H), 7.37 (td, J=8.4, 1.2 Hz, 1H), 7.29~7.26 (m, 1H), 6.78 (s, 1H), 3.95 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 137.1, 136.5, 135.4, 133.9, 129.3, 129.1 (q, J=309 Hz), 128.0, 127.8, 123.9, 122.0, 119.4, 89.5, 31.3; ¹⁹F NMR (376 MHz, CDCl₃) δ: -44.08 (s); IR (film) v: 3232, 3062, 2929, 1526, 1385, 1238, 1171, 1121, 1012, 847, 751, 686 cm^-1. HRMS (EI) calcd for C₁₆H₁₃F₃N₂O₂S₂ 386.0371; found 386.0372.

  4-Chloro-N-(1-methyl-3-((trifluoromethyl)thio)-1H- indol-2-yl)benzenesulfonamide (3p): White solid, yield 87% (37 mg). m.p. 199.8~200.8 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.64 (d, J=8.0 Hz, 1H), 7.58~7.55 (m, 2H), 7.46~7.43 (m, 3H), 7.38 (td, J=7.2, 1.2 Hz, 1H), 7.31~7.27 (m, 1H), 6.83 (s, 1H), 3.95 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 140.7, 136.1, 135.8, 135.5, 129.5, 129.2, 129.1 (q, J=309 Hz), 127.9, 124.1, 122.1, 119.5, 110.6, 89.7, 31.3; ¹⁹F NMR (376 MHz, CDCl₃) δ: -43.94 (s); IR (film) v: 3250, 3062, 2959, 1574, 1475, 1379, 1172, 1092, 1016, 848, 668 cm^-1. HRMS (EI) calcd for C₁₆H₁₂Cl- F₃N₂O₂S₂ 419.9981; found 419.9981.

  4-Fluoro-N-(1-methyl-3-((trifluoromethyl)thio)-1H- indol-2-yl)benzenesulfonamide (3q): White solid, yield 82% (33 mg). m.p. 156.9~157.8 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.66~7.63 (m, 3H), 7.43 (d, J=8.4 Hz, 1H), 7.40~7.36 (m, 1H), 7.29~7.26 (m, 1H), 7.27 (t, J=7.2 Hz, 1H), 7.15 (t, J=8.4 Hz, 1H), 6.78 (s, 1H), 3.95 (s, 3H), 3.87 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 165.9 (J=255.6 Hz), 136.2, 135.5, 133.3, 130.6 (J=9.6 Hz), 129.1 (q, J=308 Hz), 127.9, 124.1, 122.1, 119.5, 116.5 (J=22.6 Hz), 110.6, 89.5, 31.3; ¹⁹F NMR (376 MHz, CDCl₃) δ: -43.99 (s); IR (film) v: 3255, 3067, 2959, 1593, 1527, 1386, 1157, 1014, 949, 838, 735 cm^-1. HRMS (EI) calcd for C₁₆H₁₂F₄N₂O₃S₂ 404.0276; found 404.0277.

  4-Methoxy-N-(1-methyl-3-((trifluoromethyl)thio)-1H- indol-2-yl)benzenesulfonamide (3s): White solid, yield 86% (36 mg). m.p. 143.0~144.1 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.62 (d, J=8.0 Hz, 1H), 7.55~7.52 (m, 2H), 7.42 (d, J=8.0 Hz, 1H), 7.39~7.37 (m, 1H), 7.29~7.26 (m, 1H), 6.90 (d, J=8.8 Hz, 2H), 6.71 (s, 1H), 3.95 (s, 3H), 3.87 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 163.9, 136.9, 135.5, 130.0, 129.2 (q, J=309 Hz), 128.7, 128.0, 123.8, 121.9, 119.4, 114.4, 110.5, 89.2, 55.7, 31.3; ¹⁹F NMR (376 MHz, CDCl₃) δ: -43.99 (s, 3F), -102.60~-102.66 (m, 1F); IR (film) v: 3253, 2946, 1596, 1527, 1386, 1264, 1162, 1121, 1026, 943, 833, 675 cm^-1. HRMS (EI) calcd for C₁₇H₁₅F₃N₂O₃S₂ 416.0476; found 416.0478.

  N-(1-Methyl-3-((trifluoromethyl)thio)-1H-indol-2-yl)- naphthalene-2-sulfonamide (3t): White solid, yield 83% (36 mg). m.p. 205.8~206.6 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.93~7.89 (m, 2H), 7.83 (d, J=8.0 Hz, 1H), 7.67~7.62 (m, 1H), 7.62~7.56 (m, 3H), 7.43 (d, J=8.4 Hz, 1H), 7.39~7.35 (m, 1H), 7.25 (td, J=8.0, 1.2 Hz, 1H), 6.94 (s, 1H), 3.97 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 136.5, 135.5, 135.2, 134.4, 132.0, 129.5, 129.42, 129.35, 129.34, 129.1 (q, J=309 Hz), 128.0, 127.7, 123.9, 122.5, 122.0, 119.5, 89.7, 31.3; ¹⁹F NMR (376 MHz, CDCl₃) δ: -44.02 (s); IR (film) v: 3236, 3057, 2943, 1625, 1525, 1240, 1169, 1103, 1013, 939, 816, 670 cm^-1. HRMS (EI) calcd for C₂₀H₁₅F₃N₂O₃S₂ 436.0527; found 436.0526.

  Supporting Information  The copies of NMR of newly synthesized products 3. The Supporting Information is available free of charge via the Internet at http://sioc-journal.cn/.

  
  Dedicated to Professor Henry N. C. Wong on the occasion of his 70th birthday.
  
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• 

  Figure 1  Examples of SCF₃ containing biologically active compounds

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  Scheme 1  Trifluoromethylthiolation of acyclic diazo compounds and our work

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  Scheme 2  Mechanism for the formation of 3-((trifluoromethyl)- thio)-2-aminoindoles (3)

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  Table 1.  Optimization of reaction conditions^a

  Entry	[Cu]/equiv.	1p/equiv.	Additive (equiv.)	Solvent	Time/h	Yieldb/%
  1	CuI (1.0)	1.0	—	DCE	1	62
  2	CuBr (1.0)	1.0	—	DCE	1	Trace
  3	CuCl (1.0)	1.0	—	DCE	1	Trace
  4 c	CuI (1.0)	1.0	—	DCE	1	53
  5	CuI (1.0)	1.2	—	DCE	1	77
  6	CuI (1.0)	1.4	—	DCE	1	77
  7	CuI (1.0)	1.2	H2O (10)	DCE	1	87
  8	CuI (1.0)	1.2	H2O (20)	DCE	1	67
  9	CuI (1.0)	1.2	H2O (30)	DCE	1	64
  10	CuI (1.0)	1.2	H2O (40)	DCE	1	55
  11	CuI (1.25)	1.2	H2O (10)	DCE	1	66
  12	CuI (0.75)	1.2	H2O (10)	DCE	1	74
  13	CuI (0.50)	1.2	H2O (10)	DCE	1	71
  14	CuI (0.25)	1.2	H2O (10)	DCE	1	30
  15	CuI (1.0)	1.2	H2O (10)	DCM	1	84
  16	CuI (1.0)	1.2	H2O (10)	PhMe	1	87
  17	CuI (1.0)	1.2	H2O (10)	CH3CN	1	trace
  18	CuI (1.0)	1.2	H2O (10)	NMP	1	trace
  19	CuI (1.0)	1.2	H2O (10)	DCE	0.5	85
  20	CuI (1.0)	1.2	H2O (10)	DCE	2	87
  a Reaction conditions: 1a (0.12 mmol), 2 (0.1 mmol), CuI (0.1 mmol), solvent (2 mL), room temperature; b isolated yield; c N2 atmosphere.

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  Table 2.  Substrate scope of 3-diazoindolin-2-imines^a

  a Reaction conditions: 1 (0.12 mmol), 2 (0.1 mmol), CuI (0.1 mmol), H2O (1 mmol), DCE (2 mL), room temperature, 1 h; Isolated yield.

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•