English

• Indolizine and pyrrole are basic units that frequently occur in natural products and synthetic pharmaceuticals. Indolizine and pyrrole derivatives have been reported to exhibit a broad spectrum of biological activities including antifungal, anticancer, antitubercular, and hypolipidemic activities.^[1] Recently, the trifluoromethylthiol (CF₃S) group has attracted great attention from academic community and pharmaceutical industry, because of its electron withdrawing effect, good lipophilicity, good bioavailability and good metabolic stability.^[2] Therefore, the development of mild and efficient methods to introduce the trifluoromethylthiol moiety to indolizine and pyrrole derivatives would be highly desirable.

  To the best of our knowledge, only a few methods have been reported to prepare trifluoromethylthiol substituted indolizine or trifluoromethylthiol substituted pyrrole including: (1) trifluoromethylthiolation of indolizine by trifluoromethylsulfenyl chloride (CF₃SCl), ^[3] 2-((trifluoro-methyl)thio)isoindoline-1, 3-dione^[4] or 2-((trifluorome-thyl)thio)benzo[d]isothiazol-3(2H)-one (Scheme 1); ^[5] (2) trifluoromethylthiolation of indolizine and pyrrole by trifluoromethanesulfonyl chloride in the presence of trimethylphosphine (PMe₃) (Scheme 1); ^[6] (3) trifluoromethyl-thiolation of pyrrole by trifluoromethanesulfonyl hypervalent iodonium ylide or N-trifluoromethylthio-dibenzenesul-fonimide (Scheme 1).^[7] However, the toxicity of CF₃SCl as well as the availability of the shelf-stable trifluoromethylthiolation reagents limited their application. Very recently, Cai group did an elegant work to synthesize trifluoromethylthiol substituted pyrrole by using sodium trifluoromethanesulfinate (CF₃SO₂Na) as trifluoromethylthiolation reagent (Scheme 1).^[8] As part of our on-going program to develop efficient methods to construct C—S bonds, ^[9] we recently report direct trifluoromethylthiolation of indoles using trifluoromethanesulfonyl chloride (CF₃SO₂Cl) in the presence of triphenylphosphine.^[10] To broaden the application of this protocol, we herein report a direct trifluoro-methylthiolation of indolizine and pyrrole derivatives by trifluoromethanesulfonyl chloride (CF₃SO₂Cl) in the presence of PPh₃.

  Scheme 1

  

  Scheme 1.  Trifluoromethylthiolation of indolizine and pyrrole

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  1.   Results and discussion

  To probe the trifluoromethylthiolation of indolizine, we employed the reaction of indolizine-1-carbonitrile (1a) and CF₃SO₂Cl (2) as the model reaction in the presence of PPh₃. The reaction in dichloroethane (DCE) at 50 ℃ gave the desired thiolation product 3a, which structure was confirmed by X-ray analysis, ^[11] in 41% yield (Table 1, Entry 1). To optmize the reaction conditions, other solvents such as acetonitrile (CH₃CN), toluene and 1, 4-dioxane were first tested (Table 1, Entry 2~4), and toluene gave the best yield. Then the reaction concentration and temperature effects were examined. When the concentration of 1a was decreased from 0.5 mol•L^-1 to 0.33 mol•L^-1, the yield increased from 53% to 74% (Table 1, Entries 4 and 5). However, further decreasing the concentration of 1a to 0.25 mol•L^-1 led to a diminished yield (Table 1, Entry 6). Decreasing the reaction temperature to 40 ℃ or increasing the reaction temperature to 60 ℃ did not affect much on the yield (Table 1, Entries 7 and 8). However, further increasing the reaction temperature to 70 ℃ led to a diminished yield, because high tempearature led to the decomposition of the product (Table 1, Entry 9). Finally, equivalents of 2 and PPh₃ were investigated. Decreasing the loadings of 2 and PPh₃ to 1.4 and 2.8 equiv., respectively, the yield increased to 80% (Table 1, Entry 10). However, a further decrease in these loadings led to a decreased yield (Table 1, Entry 11). Based on our previous studies, the addition of iodide to the reaction was expected to facilitate this transformation. However, when 0.2 equiv. of potassium iodide (KI) was used as additive, the yield decreased to 60%. Because potassium iodide can accelerate the formation of the CF₃SCl.^{[9f, 10]} CF₃SCl will decompose quickly if the speed of the trifluoromethyl-thiolation reaction can not match the speed of its formation. Thus, the reaction conditions were optimized to be as follows: 1a (0.5 mmol), 2 (0.7 mmol), PPh₃ (1.4 mmol) and toluene (1.5 mL), at 50 ℃.

  Table 1

  

  Table 1.  Optimization of the trifluoromethylthiolation of 1a with 2 in the presence of PPh₃^a

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  Entry	CF3SO2Cl (equiv.)	PPh3 (equiv.)	Solvent	Volume/mL	Temperature/℃	Yield/%
  1	1.5	3	DCE	1.0	50	41
  2	1.5	3	CH3CN	1.0	50	33
  3	1.5	3	1, 4-Dioxane	1.0	50	50
  4	1.5	3	Toluene	1.0	50	53
  5	1.5	3	Toluene	1.5	50	74
  6	1.5	3	Toluene	2.0	50	64
  7	1.5	3	Toluene	1.5	40	72
  8	1.5	3	Toluene	1.5	60	76
  9	1.5	3	Toluene	1.5	70	70
  10	1.4	2.8	Toluene	1.5	50	80
  11	1.2	2.4	Toluene	1.5	50	67
  12	1.4	2.8	Toluene	1.5	50	60b
  a Reaction conditions: 1a (0.5 mmol), 2 (0.6~0.75 mmol), PPh3 (1.2~1.5 mmol), solvent (1.0~2.0 mL) for 2~4 h. b KI (0.1 mmol) was used as additive.

  The substrate scope of the trifluoromethylthiolation reaction was investigated under the optimized conditions. As shown in Table 2, a series of indolizine-1-carbonitrile (1b and 1c), methyl indolizine-1-carboxylate (1d~1f) and diethyl indolizine-1, 2-dicarboxylate (1g~1i) could be transformed to the corresponding 3-trifluoromethylthioe-thers by in moderate to good yields. Moreover, when the tricyclic methyl pyrrolo[2, 1-a]isoquinoline-1-carboxylate (1j) and diethyl pyrrolo[2, 1-a]isoquinoline-1, 2-dicarboxy-late (1k) were used as substrates, the desired products were obtained in moderate yields.

  Table 2

  

  Table 2.  Trifluoromethylthiolation of indolizine with trifluoromethanesulfonyl chloride in the presence of PPh₃^a

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  Encouraged by these results, trifluoromethylthiolation of pyrrole was investigated. We tried the trifluoromethylthio-lation of 1-benzyl-2, 5-dimethyl-1H-pyrrole by CF₃SO₂Cl in the presence of PPh₃ under the optimized reaction condition previously used for trifluoromethylthiolation of indole. To our delight, the desired product was obtained in 54% yield. Moreover, when the reaction was carried out without using sodium iodide (NaI) as additive, the desired product was obtained in 75% yield. We think that compared with indole, pyrrole is more electron rich heterocyclic. So pyrrole is active enough to get the desired prodcut without the promotion of NaI in this kind of transformation.

  With this information in hand, other pyrroles with electron-donating or electron-withdrawing groups were tested under the optimized condition and the desired products were obtained in moderate to good yields. To get acceptable yield, when 1-(2, 4-dimethyl-1H-pyrrol-3-yl)ethan-1-one (4d) and 2-methyl-5-phenyl-1H-pyrrole (4e) were used as substrates, sodium biscarbonate was used as base to neutrlized the HCl generated during the reaction. Notably, to get full conversion of ethyl 4-tosyl-1H-pyrrole-3-carboxylate (4f), 1-(4-methoxyphenyl)-1H-pyrrole (4g) and 1-(p-tolyl)-1H-pyrrole (4h), 2.4 equiv. of 2 and 4.8 equiv. of PPh₃ were used (Table 3).

  Table 3

  

  Table 3.  Trifluoromethylthiolation of pyrrole with trifluoromethanesulfonyl chloride in the presence of PPh₃^a

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  Based on the experiments and previous reports, ^{[6, 9e]} a plausible mechanism for transformation is proposed (Scheme 2). Initially, aryl CF₃SO₂Cl (2) is reduce to CF₃SCl 6 by PPh₃ via intermediates A~E. Electrophilic trifluoromethylthiolation of indolizine 1 or pyrrole 4 by 6 gives the corresponding trifluoromethylthio substituted indolizine 3 or trifluoromethylthio substituted pyrrole 5, respectively.

  Scheme 2

  

  Scheme 2.  Proposed reaction mechanism

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  Finally, to illustrate the potential practical application of this protocol, the reaction was scaled up using 1 g of the substrate 1a and 4h. As shown in Scheme 3, the desired products 3a and 5 h were obtained in 61% and 62% yields respectively.

  Scheme 3

  

  Scheme 3.  Scale up of the trifluoromethylthiolation reaction

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  2.   Conclusions

  In conclusion, we developed a transition metal-free direct trifluoromethylthiolation of indolizine and pyrrole using CF₃SO₂Cl in the presence of PPh₃. This study broadened the scope for the electrophilic trifluoromethylthiolation by CF₃SO₂Cl/PPh₃ protocol. Moreover, the readily accessable reagents and transition metal-free reaction conditions allowed this protocol applicable for large scales synthesis.

  3.   Experimental section

  3.1   General methods and material

  All solvents were distilled prior to use. Unless otherwise noted, chemicals were used as received without further purification. For chromatography, 200~300 mesh silica gel was employed. ¹H NMR and ¹³C NMR spectra were recorded at 400 and 100 MHz, respectively. Chemical shifts are reported using tetramethylsilane as internal standard. HRMS was performed on an FTMS mass instrument. Melting points are reported as uncorrected.

  3.2   General procedure for trifluoromethylthiolation of indolizine

  Indolizine (0.5 mmol), CF₃SO₂Cl (118 mg, 0.7 mmol), PPh₃ (367 mg, 1.4 mmol) and dry toluene (1.5 mL) were mixed in an oven dried sealed tube. The mixture was stirred at 50 ℃ for 2~4 h. Then, the solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to afford the pure product.

  3.3   General procedure for trifluoromethylthiolation of pyrrole

  Pyrrole (0.5 mmol), CF₃SO₂Cl (101 mg, 0.6 mmol or 202 mg, 0.6 mmol), PPh₃ (314 mg, 1.2 mmol or 618 mg, 2.4 mmol), NaHCO₃ (0 or 42 mg, 0 or 0.5 mmol) and dry MeCN (3.0 mL) were mixed in an oven dried sealed tube. The mixture was stirred at 60 ℃ for 2~46 h. Then, the solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to afford the pure product.

  3-((Trifluoromethyl)thio)indolizine-1-carbonitrile (3a): After purification by silica gel column chromatography [V(PE):V(EA)＝10:1, PE＝petroleum ether, EA＝ethyl acetate], compound 3a was isolated as a pale yellow solid (97 mg, 80%); m.p. 105~107 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 8.56 (d, J＝7.0 Hz, 1H), 7.74~7.77 (m, 1H), 7.51 (s, 1H), 7.35~7.31 (m, 1H), 7.01~7.05 (m, 1H); R_f＝0.3; ¹⁹F NMR (376 MHz, CDCl₃) δ: －44.07 (s, 3F); ¹³C NMR (100 MHz, CDCl₃) δ: 141.08, 129.50, 128.09 (q, J＝311.6 Hz, 1C), 125.31, 124.91, 118.07, 115.07, 114.46, 103.50 (q, J＝2.2 Hz, 1C), 84.39; HRMS (ESI) calcd for C₁₀H₆F₃N₂S [M+H]⁺ 243.0198, found 243.0198.

  7-Methyl-3-((trifluoromethyl)thio)indolizine-1-carboni-trile (3b): After purification by silica gel column chromatography [V(PE):V(EA)＝10:1], compound 3b was isolated as a white solid (71 mg, 55%); m.p. 74~76 ℃; R_f＝0.37; ¹H NMR (400 MHz, CDCl₃) δ: 8.43 (d, J＝7.2 Hz, 1H), 7.50 (s, 1H), 7.44 (s, 1H), 6.85 (dd, J＝7.2, 1.5 Hz, 1H), 2.46 (s, 3H); ¹⁹F NMR (376 MHz, CDCl₃) δ: －44.35 (s, 3F); ¹³C NMR (100 MHz, CDCl₃) δ: 141.57, 136.87, 128.08 (q, J＝312.0 Hz, 1C), 129.49, 124.26, 117.09, 116.57, 115.42, 102.49 (q, J＝2.4 Hz, 1C), 82.81, 21.14; HRMS (ESI) calcd for C₁₁H₈F₃N₂S [M+H]⁺ 257.0355, found 257.0355.

  8-Bromo-3-((trifluoromethyl)thio)indolizine-1-carboni-trile (3c): After purification by silica gel column chromatography [V(PE):V(EA)＝10:1], compound 3c was isolated as a yellow solid (80 mg, 50%); m.p. 152~154 ℃; R_f＝0.30; ¹H NMR (400 MHz, CDCl₃) δ: 8.55 (d, J＝7.2 Hz, 1H), 7.60 (s, 1H), 7.49 (dd, J＝7.2, 0.7 Hz, 1H), 6.88 (t, J＝7.2 Hz, 1H); ¹⁹F NMR (376 MHz, CDCl₃) δ: －43.63 (s, 3F); ¹³C NMR (100 MHz, CDCl₃) δ: 137.48, 131.60, 128.83, 127.98 (q, J＝311.9 Hz, 1C), 124.22, 115.14, 114.36, 113.20, 105.14 (q, J＝2.3 Hz, 1C), 86.91; HRMS (ESI) calcd for C₁₀H₅BrF₃N₂S [M+H]⁺ 320.9303, found 320.9306.

  Methyl 3-((trifluoromethyl)thio)indolizine-1-carbox-ylate (3d):^[58] After purification by silica gel column chromatography [V(PE):V(EA)＝30:1], compound 3d was isolated as a yellow solid (73 mg, 53%); R_f＝0.26; ¹H NMR (400 MHz, CDCl₃) δ: 8.53 (d, J＝7.0 Hz, 1H), 8.29 (d, J＝9.0 Hz, 1H), 7.71 (s, 1H), 7.30~7.26 (m, 1H), 6.95 (t, J＝7.0 Hz, 1H), 3.91 (s, 3H); ¹⁹F NMR (376 MHz, CDCl₃) δ: －44.44 (s, 3F); ¹³C NMR (100 MHz, CDCl₃) δ: 164.28, 139.34, 129.17, 128.28 (q, J＝311.8 Hz, 1C), 125.03, 124.45, 119.85, 113.82, 105.52, 102.45 (q, J＝2.4 Hz, 1C), 51.15.

  Methyl 6-bromo-3-((trifluoromethyl)thio)indolizine-1-carboxylate (3e): After purification by silica gel column chromatography [V(PE):V(EA)＝30:1], compound 3e was isolated as a yellow solid (125.1 mg, 77%); m.p. 129~131 ℃; R_f＝0.26; ¹H NMR (400 MHz, CDCl₃) δ: 8.64 (s, 1H), 8.19 (d, J＝9.6 Hz, 1H), 7.68 (s, 1H), 7.32 (dd, J＝9.6, 1.6 Hz, 1H), 3.91 (s, 3H); ¹⁹F NMR (376 MHz, CDCl₃) δ: －44.10 (s, 3F); ¹³C NMR (100 MHz, CDCl₃) δ: 163.87, 137.41, 129.22, 128.29, 128.12 (q, J＝311.7 Hz, 1C), 124.59, 120.54, 109.16, 106.60, 103.14 (q, J＝2.5 Hz, 1C), 51.34; HRMS (ESI) calcd for C₁₁H₈BrF₃NO₂S [M+H]⁺ 353.9406, found 353.9404.

  Methyl 8-bromo-3-((trifluoromethyl)thio)indolizine-1-carboxylate (3f): After purification by silica gel column chromatography [V(PE):V(EA)＝10:1], compound 3f was isolated as a yellow solid (107.4 mg, 61%); m.p. 82~84 ℃; R_f＝0.43; ¹H NMR (400 MHz, CDCl₃) δ: 8.56 (d, J＝6.8 Hz, 1H), 7.69 (s, 1H), 7.48~7.50 (m, 1H), 6.77~6.80 (m, 1H), 3.92 (s, 3H); ¹⁹F NMR (376 MHz, CDCl₃) δ: －44.00 (s, 3F); ¹³C NMR (100 MHz, CDCl₃) δ: 163.71, 135.07, 130.42, 129.49, 128.15 (q, J＝311.7 Hz, 1C), 123.82, 113.25, 112.50, 109.06, 103.14 (q, J＝2.4 Hz, 1C), 51.80; HRMS (ESI) calcd for C₁₁H₈BrF₃NO₂S [M+H]⁺ 353.9406, found 353.9407.

  Diethyl 3-((trifluoromethyl)thio)indolizine-1, 2-dicarb-oxylate (3g): After purification by silica gel column chromatography [V(PE):V(EA)＝10:1], compound 3g was isolated as a white solid (108.9 mg, 60%); m.p. 49~51 ℃; R_f＝0.26; ¹H NMR (400 MHz, CDCl₃) δ: 8.54 (d, J＝7.0 Hz, 1H), 8.32 (dd, J＝8.2, 0.9 Hz, 1H), 7.36~7.32 (m, 1H), 7.02 (t, J＝7.0 Hz, 1H), 4.48 (q, J＝7.2 Hz, 2H), 4.36 (q, J＝7.2 Hz, 2H), 1.44~1.36 (m, 6H); ¹⁹F NMR (376 MHz, CDCl₃) δ:－43.06 (s, 3F); ¹³C NMR (100 MHz, CDCl₃) δ: 164.61, 162.67, 138.43, 134.66, 128.17 (q, J＝313.1 Hz, 1C), 126.06, 124.42, 120.33, 114.80, 103.79, 101.45 (q, J＝2.5 Hz, 1C), 61.97, 60.30, 14.30, 14.09; HRMS (ESI) calcd for C₁₅H₁₅F₃NO₄S [M+H]⁺ 362.0668, found 362.0668.

  Diethyl 7-methyl-3-((trifluoromethyl)thio)indolizine-1, 2-dicarboxylate (3h): After purification by silica gel column chromatography [V(PE):V(EA)＝10:1], compound 3h was isolated as a white solid (83 mg, 44%); m.p. 66~68 ℃; R_f＝0.26; ¹H NMR (400 MHz, CDCl₃) δ: 8.41 (d, J＝7.2 Hz, 1H), 8.10 (s, 1H), 6.85 (dd, J＝7.2, 1.6 Hz, 1H), 4.47 (q, J＝7.2 Hz, 2H), 4.35 (q, J＝7.2 Hz, 2H), 2.45 (s, 3H), 1.42 (t, J＝7.2 Hz, 3H), 1.37 (t, J＝7.2 Hz, 3H); ¹⁹F NMR (376 MHz, CDCl₃) δ: －43.31 (s, 3F); ¹³C NMR (100 MHz, CDCl₃) δ: 164.76, 162.83, 138.91, 137.59, 134.68, 128.15 (q, J＝313.2 Hz, 1C), 123.77, 118.73, 117.44, 102.42, 100.59 (q, J＝2.4 Hz, 1C), 61.89, 60.15, 21.37, 14.29, 14.08; HRMS (ESI) calcd for C₁₆H₁₇F₃NO₄S [M+H]⁺ 376.0825, found 376.0824.

  Diethyl 8-bromo-3-((trifluoromethyl)thio)indolizine-1, 2-dicarboxylate (3i): After purification by silica gel column chromatography [V(PE):V(EA)＝10:1], compound 3i was isolated as a yellow solid (139 mg, 70%); m.p. 40~42 ℃; R_f＝0.23; ¹H NMR (400 MHz, CDCl₃) δ: 8.57 (d, J＝7.2 Hz, 1H), 7.36 (d, J＝7.2 Hz, 1H), 6.78 (t, J＝7.2 Hz, 1H), 4.47~4.39 (m, 4H), 1.42 (t, J＝7.2 Hz, 3H), 1.39 (t, J＝7.2 Hz, 3H); ¹⁹F NMR (376 MHz, CDCl₃) δ: －42.63 (s, 3F); ¹³C NMR (100 MHz, CDCl₃) δ: 165.01, 162.04, 131.45, 128.20 (q, J＝312.6 Hz, 1C), 127.25, 127.19, 123.40, 113.99, 112.80, 112.75, 104.33 (q, J＝2.6 Hz, 1C), 61.92, 61.46, 13.93; HRMS (ESI) calcd for C₁₅H₁₄-BrF₃NO₄S [M+H]⁺ 439.9774, found 439.9774.

  Methyl 3-((trifluoromethyl)thio)pyrrolo[2, 1-a]isoquino-line-1-carboxylate (3j): After purification by silica gel column chromatography [V(PE):V(EA)＝30:1], compound 3j was isolated as a yellow solid (74 mg, 46%); m.p. 134~136 ℃; R_f＝0.35; ¹H NMR (400 MHz, CDCl₃) δ: 9.81 (dd, J＝6.6, 0.4 Hz, 1H), 8.34 (d, J＝7.4 Hz, 1H), 7.76 (s, 1H), 7.70~7.56 (m, 3H), 7.14 (d, J＝7.4 Hz, 1H), 3.94 (s, 3H); ¹⁹F NMR (376 MHz, CDCl₃) δ: －44.43 (s, 3F); ¹³C NMR (100 MHz, CDCl₃) δ: 164.77, 136.51, 129.98, 129.45, 128.81, 128.15 (q, J＝311.3 Hz, 1C), 128.03, 127.55, 126.84, 125.15, 121.52, 114.77, 110.02, 104.48 (q, J＝2.4 Hz, 1C), 51.70; HRMS (ESI) calcd for C₁₅H₁₁F₃NO₂S [M+H]⁺ 326.0457, found 326.0459.

  Diethyl 3-((trifluoromethyl)thio)pyrrolo[2, 1-a]isoquino-line-1, 2-dicarboxylate (3k): After purification by silica gel column chromatography [V(PE):V(EA)＝10:1], compound 3k was isolated as a yellow solid (100 mg, 49%); m.p. 85~87 ℃; R_f＝0.31; ¹H NMR (400 MHz, CDCl₃) δ: 8.90~8.86 (m, 1H), 8.38 (d, J＝7.2 Hz, 1H), 7.72~7.69 (m, 1H), 7.63~7.57 (m, 2H), 7.18 (d, J＝7.6 Hz, 1H), 4.50~4.41 (m, 4H), 1.44 (t, J＝7.2 Hz, 3H), 1.41 (t, J＝7.2 Hz, 3H); ¹⁹F NMR (376 MHz, CDCl₃) δ: －42.96 (s, 3F); ¹³C NMR (100 MHz, CDCl₃) δ: 165.31, 163.62, 133.18, 130.27, 129.12, 128.82, 128.43, 128.10 (q, J＝312.4 Hz, 1C), 127.30, 125.33, 124.61, 121.22, 115.46, 110.85, 105.00 (q, J＝2.3 Hz, 1C), 61.57, 61.55, 14.10, 14.02; HRMS (ESI) calcd for C₁₉H₁₇F₃NO₄S [M+H]⁺ 412.0825, found 412.0825.

  1-Benzyl-2, 5-dimethyl-3-((trifluoromethyl)thio)-1H-py-rrole (5a):^[12] After purification by silica gel column chromatography (PE), compound 5a was isolated as a colorless liquid (107.6 mg, 75%); R_f＝0.31; ¹H NMR (400 MHz, CDCl₃) δ: 7.33~7.23 (m, 3H), 6.86 (d, J＝7.6 Hz, 2H), 6.10 (s, 1H), 5.04 (s, 2H), 2.23 (s, 3H), 2.12 (s, 3H); ¹⁹F NMR (376 MHz, CDCl₃) δ: －45.65 (s, 3F); ¹³C NMR (100 MHz, CDCl₃) δ: 137.12, 136.05, 129.71 (q, J＝307.2 Hz, 1C), 128.89, 128.80, 127.38, 125.48, 112.81, 97.04 (q, J＝2.1 Hz, 1C), 47.71, 12.12, 10.34.

  2, 5-Dimethyl-1-phenyl-3-((trifluoromethyl)thio)-1H-py-rrole (5b): After purification by silica gel column chromatography (PE), compound 5b was isolated as a brown solid (70 mg, 52%); m.p. 62~64 ℃; R_f＝0.47; ¹H NMR (400 MHz, CDCl₃) δ: 7.52~7.42 (m, 3H), 7.21~7.19 (m, 2H), 6.12 (s, 1H), 2.10 (s, 3H), 1.99 (s, 3H); ¹⁹F NMR (376 MHz, CDCl₃) δ: －45.31 (s, 3F); ¹³C NMR (100 MHz, CDCl₃) δ: 138.25, 136.58, 129.75 (q, J＝307.5 Hz, 1C), 129.47, 129.36, 128.46, 128.01, 112.57, 97.52 (q, J＝2.2 Hz, 1C), 12.70, 11.10. HRMS (ESI) calcd for [M+H]⁺ 272.07208, found 272.07187.

  Ethyl 2, 4-dimethyl-5-((trifluoromethyl)thio)-1H-pyrrole-3-carboxylate (5c):^[12] After purification by silica gel column chromatography [V(PE):V(EA)＝10:1], compound 5c was isolated as a yellow solid (100 mg, 75%); R_f＝0.14; ¹H NMR (400 MHz, CDCl₃) δ: 8.30 (br, 1H), 4.29 (q, J＝7.2 Hz, 2H), 2.53 (s, 3H), 2.36 (s, 3H), 1.36 (t, J＝7.1 Hz, 3H); ¹⁹F NMR (376 MHz, CDCl₃) δ: －44.93 (s, 3F); ¹³C NMR (100 MHz, CDCl₃) δ: 164.22, 140.30, 132.17, 128.56 (q, J＝310.0 Hz), 111.98, 102.98 (q, J＝2.2 Hz, 1C), 58.91, 14.27, 13.52, 11.70.

  1-(2, 4-Dimethyl-5-((trifluoromethyl)thio)-1H-pyrrol-3-yl)ethanone (5d):^[13] After purification by silica gel column chromatography [V(PE):V(EA)＝5:1], compound 5d was isolated as a white solid (72 mg, 61%); R_f＝0.29; ¹H NMR (400 MHz, CDCl₃) δ: 8.58 (br, 1H), 2.55 (s, 3H), 2.46 (s, 3H), 2.40 (s, 3H); ¹⁹F NMR (376 MHz, CDCl₃) δ: －44.79 (s, 3F); ¹³C NMR (100 MHz, CDCl₃) δ: 193.89, 139.89, 131.77, 128.67 (q, J＝310.2 Hz, 1C), 122.16, 103.40 (q, J＝2.4 Hz, 1C), 30.88, 14.62, 12.54.

  2-Phenyl-3-((trifluoromethyl)thio)-1H-pyrrole (5e):^[8] After purification by silica gel column chromatography [V(PE):V(EA)＝30:1], compound 5e was isolated as a pink solid (47.2 mg, 78%); R_f＝0.39; ¹H NMR (400 MHz, CDCl₃) δ: 8.57 (br, 1H), 7.51~7.49 (m, 2H), 7.42~7.38 (m, 2H), 7.31~7.28 (m, 1H), 6.71~6.70 (m, 1H), 6.57~6.55 (m, 1H); ¹⁹F NMR (376 MHz, CDCl₃) δ: －45.04 (s, 3F); ¹³C NMR (100 MHz, CDCl₃) δ: 137.84, 131.32, 129.06, 128.30 (q, J＝309.5 Hz, 1C), 127.64, 124.38, 123.01, 108.25, 108.22 (q, J＝2.1 Hz, 1C).

  Ethyl 4-(tosylmethyl)-5-((trifluoromethyl)thio)-1H-py-rrole-3-carboxylate (5f): After purification by silica gel column chromatography [V(PE):V(EA)＝5:1], compound 5f was isolated as a white solid (146.4 mg, 72%); m.p. 154~156 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 8.91 (br, 1H), 7.61~7.56 (m, 3H), 7.26~7.29 (m, 2H), 4.81 (s, 2H), 4.11 (q, J＝7.2 Hz, 2H), 2.43 (s, 3H), 1.27 (q, J＝7.2 Hz, 3H); ¹⁹F NMR (376 MHz, CDCl₃) δ: －43.68 (s, 3F); ¹³C NMR (100 MHz, CDCl₃) δ: 163.12, 144.69, 135.71, 129.55, 128.65, 128.59, 128.23 (q, J＝310.0 Hz, 1C), 121.26, 117.29, 112.94 (q, J＝2.4 Hz, 1C), 60.10, 52.54, 21.57, 14.22. HRMS (ESI) calcd for C₁₆H₁₇F₃NO₄S₂ [M+H]⁺ 408.0546, found 408.0546.

  1-(4-Methoxyphenyl)-2-((trifluoromethyl)thio)-1H-pyr-role (5g):^[8] After purification by silica gel column chro-matography (PE), compound 5g was isolated as a yellow oil (103.7 mg, 76%); R_f＝0.28; ¹H NMR (400 MHz, CDCl₃) δ: 7.21 (dd, J＝6.8 Hz, 2.4 Hz, 2H), 7.06 (dd, J＝2.8 Hz, 2.0 Hz, 1H), 6.96 (dd, J＝6.8 Hz, 2.4 Hz, 2H), 6.81 (dd, J＝3.6 Hz, 2.0 Hz, 1H), 6.34 (dd, J＝3.6 Hz, 2.8 Hz, 2H), 3.86 (s, 3H); ¹⁹F NMR (376 MHz, CDCl₃) δ: －45.28 (s, 3F); ¹³C NMR (100 MHz, CDCl₃) δ: 159.35, 131.92, 128.93, 128.29, 128.23 (q, J＝309.0 Hz, 1C), 123.46, 114.00, 110.00 (q, J＝2.0 Hz, 1C), 109.74, 55.50 (q, J＝3.0 Hz, 1C).

  1-(p-Tolyl)-2-((trifluoromethyl)thio)-1H-pyrrole (5h):^[8] After purification by silica gel column chromatography (PE), compound 5h was isolated as a colorless oil (82.2 mg, 64%); R_f＝0.55; ¹H NMR (400 MHz, CDCl₃) δ: 7.25 (d, J＝7.6 Hz, 2H), 7.18 (dd, J＝6.4, 2.0 Hz, 2H), 7.08 (dd, J＝2.8, 2.0 Hz, 1H), 6.82 (dd, J＝3.6, 2.0 Hz, 1H), 6.35 (dd, J＝3.6, 2.8 Hz, 1H), 2.42 (s, 3H); ¹⁹F NMR (376 MHz, CDCl₃) δ: －45.28 (s, 3F); ¹³C NMR (100 MHz, CDCl₃) δ: 138.05, 136.43, 129.69, 128.77, 128.14 (q, J＝309.0 Hz, 1C), 126.86, 123.68, 110.68, 109.85, 21.08 (q, J＝2.0 Hz, 1C).

  Supporting Information ¹H NMR, ¹³C NMR and ¹⁹F NMR spectra for the products. The Supporting Information is available free of charge via the Internet at http://sioc-journal.cn.

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• 

  Scheme 1  Trifluoromethylthiolation of indolizine and pyrrole

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  Scheme 2  Proposed reaction mechanism

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  Scheme 3  Scale up of the trifluoromethylthiolation reaction

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  Table 1.  Optimization of the trifluoromethylthiolation of 1a with 2 in the presence of PPh₃^a

  Entry	CF3SO2Cl (equiv.)	PPh3 (equiv.)	Solvent	Volume/mL	Temperature/℃	Yield/%
  1	1.5	3	DCE	1.0	50	41
  2	1.5	3	CH3CN	1.0	50	33
  3	1.5	3	1, 4-Dioxane	1.0	50	50
  4	1.5	3	Toluene	1.0	50	53
  5	1.5	3	Toluene	1.5	50	74
  6	1.5	3	Toluene	2.0	50	64
  7	1.5	3	Toluene	1.5	40	72
  8	1.5	3	Toluene	1.5	60	76
  9	1.5	3	Toluene	1.5	70	70
  10	1.4	2.8	Toluene	1.5	50	80
  11	1.2	2.4	Toluene	1.5	50	67
  12	1.4	2.8	Toluene	1.5	50	60b
  a Reaction conditions: 1a (0.5 mmol), 2 (0.6~0.75 mmol), PPh3 (1.2~1.5 mmol), solvent (1.0~2.0 mL) for 2~4 h. b KI (0.1 mmol) was used as additive.

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  Table 2.  Trifluoromethylthiolation of indolizine with trifluoromethanesulfonyl chloride in the presence of PPh₃^a

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  Table 3.  Trifluoromethylthiolation of pyrrole with trifluoromethanesulfonyl chloride in the presence of PPh₃^a

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•