Triphosgene/Sodium Organosulfinate System: A General and Efficient Electrophilic Thiolation of Silylenol Ethers and Electron-Rich Heteroaromatics

Abstract

An efficient and practical approach to electrophilic thiolation was developed by using commercially available triphosgene as a reductant and the appropriate alkyl- or arylsulfinates, which were transformed in situ into electrophilic RSCl intermediates in the presence of triphosgene. This procedure represents a general and powerful approach for the synthesis of α-(trifluoromethyl)thio-substituted ketones and thiolated electron-rich heteroaromatic compounds.

Key words

drifluoromethylthiolation - difluoromethylthiolation - triphosgene - silylenol ethers - indoles

Publication History

Received: 30 July 2020

Accepted after revision: 31 August 2020

Article published online:
08 October 2020

• References and Notes

• 1a Uneyama K. Organofluorine Chemistry . Blackwell; Oxford: 2006
• 1b O’Hagan D. Chem. Soc. Rev. 2008; 37: 308
• 1c Wang J, Sánchez-Roselló M, Aceña JL, del Pozo C, Sorochinsky AE, Fustero S, Soloshonok VA, Liu H. Chem. Rev. 2014; 114: 2432
• 2a Landelle G, Panossian A, Leroux FR. Curr. Top. Med. Chem. (Sharjah, United Arab Emirates) 2014; 14: 941
• 2b Lawton G, Witty DR. Progress in Medicinal Chemistry. Elsevier Science; 2015
• 2c Xiong H.-Y, Pannecoucke X, Besset T. Chem. Eur. J. 2016; 22: 16734
• 2d Ni C, Hu M, Hu J. Chem. Rev. 2015; 115: 765
• 2e Diaferia M, Veronesi F, Morganti G, Nisoli L, Fioretti DP. Parasitol. Res. 2013; 112: 163
• 2f Xu X.-H, Matsuzaki K, Shibata N. Chem. Rev. 2015; 115: 731
• 3a Zheng H, Huang Y, Weng Z. Tetrahedron Lett. 2016; 57: 1397
• 3b Shao X, Xu C, Lu L, Shen Q. Acc. Chem. Res. 2015; 48: 1227
• 3c Li S.-G, Zard SZ. Org. Lett. 2013; 15: 5898
• 3d Huang Y, He X, Li H, Weng Z. Eur. J. Org. Chem. 2014; 7324
• 3e Huang Y, He X, Lin X, Rong M, Weng Z. Org. Lett. 2014; 16: 3284
• 4a Bootwicha T, Liu X, Pluta R, Atodiresei I, Rueping M. Angew. Chem. Int. Ed. 2013; 52: 12856
• 4b Rueping M, Liu X, Bootwicha T, Pluta R, Merkens C. Chem. Commun. 2014; 50: 2508
• 5a Alazet S, Ismalaj E, Glenadel Q, Le Bars D, Billard T. Eur. J. Org. Chem. 2015; 4607
• 5b Wu W, Zhang X, Liang F, Cao S. Org. Biomol. Chem. 2015; 13: 6992
• 5c Liu Q, Huang T, Zhao X, Wu J, Cao S. ACS Omega 2017; 2: 7755
• 6a Xu C, Ma B, Shen Q. Angew. Chem. Int. Ed. 2014; 53: 9316
• 6b Alazet S, Zimmer L, Billard T. Chem. Eur. J. 2014; 20: 8589
• 7 Arimori S, Takada M, Shibata N. Org. Lett. 2015; 17: 1063
• 8 Saravanan P, Anbarasan P. Adv. Synth. Catal. 2018; 360: 2894
• 9 He X.-l, Swarup M, Wu J, Jin C.-d, Guo S.-r, Guo Z.-p, Yang M. Org. Chem. Front. 2019; 6: 2435
• 10a Liu C, Lu Q, Huang Z, Zhang J, Liao F, Peng P, Lei A. Org. Lett. 2015; 17: 6034
• 10b Yang Y.-D, Iwamoto K, Tokunaga E, Shibata N. Chem. Commun. 2013; 49: 5510
• 10c Hang Z, Li Z, Liu Z.-Q. Org. Lett. 2014; 16: 3648
• 10d Zhu L, Wang L.-S, Li B, Fu B, Zhang C.-P, Li W. Chem. Commun. 2016; 52: 6371
• 10e Liu Z.-Q, Liu D. J. Org. Chem. 2017; 82: 1649
• 10f Jiang L, Qian J, Yi W, Lu G, Cai C, Zhang W. Angew. Chem. Int. Ed. 2015; 54: 14965
• 10g Bu M.-j, Lu G.-p, Cai C. Org. Chem. Front. 2017; 4: 266
• 10h Zhao X, Wei A, Yang B, Li T, Li Q, Qiu D, Lu K. J. Org. Chem. 2017; 82: 9175
• 11 Electrophilic Trifluoromethylthiolation of Silyl Enol Ethers; General Procedure A 10 mL Schlenk tube equipped with a magnetic stirring bar was charged with F₃CSO₂Na (0.4 mmol), the appropriate silyl enol ether (0.2 mmol), and MeCN (1 mL), and the mixture was stirred at –78 °C for the initial time. A solution of triphosgene (0.4 mmol) in MeCN (1 mL) was then added slowly from a syringe. After 1 h at –78 °C, the mixture was warmed to rt over 1 h, then diluted with CH₂Cl₂ (20 mL). The mixture was washed 5% aq NaHCO₃ (10 mL), and the combined organic phase was dried (Na₂SO₄) and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel). 1-Phenyl-2-[(trifluoromethyl)sulfanyl]ethanone (2a) Yellow oil; yield: 40.9 mg (93%). ¹H NMR (300 MHz, CDCl₃): δ = 7.96 (d, J = 6.8 Hz, 2 H), 7.65 (t, J = 6.8 Hz, 1 H), 7.54 (t, J = 6.8 Hz, 2 H), 4.53 (s, 2 H). ¹³C NMR (75 MHz, CDCl₃): δ = 192.1 (s), 134.7 (s), 134.3 (d, J = 1.5 Hz), 130.7 (q, J = 306.4 Hz), 129.0 (s), 128.5 (s), 38.5 (q, J = 1.8 Hz). HRMS (EI-TOF): m/z [M]+ calcd for C₉H₇F₃OS: 220.0170; found: 220.0162. Electrophilic Thiolation of Indoles or N-Methylpyrrole; General Procedure A 10 mL Schlenk tube equipped with a magnetic stirring bar was charged with RSO₂Na (0.4 mmol) and the appropriate indole or N-methylpyrrole (0.2 mmol). The tube was then evacuated and backfilled with dry N₂ (this operation was repeated three times), and the mixture was stirred at –78 °C for the initial time. A solution of triphosgene (0.4 mmol) in MeCN (1 mL) was added slowly from a syringe, and the mixture was stirred at –78 °C for 1 h. When the reaction was complete, the mixture was warmed to rt and diluted with CH₂Cl₂ (20 mL). The mixture was then washed with 5% aq NaHCO₃ (10 mL), and the combined organic phase was dried (Na₂SO₄) and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel). 3-[(Difluoromethyl)sulfanyl]-1-methyl-1H-indole (4a) Yellow oil; yield: 37.9 mg (89%). ¹H NMR (300 MHz, CDCl₃): δ = 7.80 (d, J = 7.8 Hz, 1 H), 7.42–7.20 (m, 4 H), 6.67 (t, J = 57.7 Hz, 1 H), 3.83 (s, 3 H). ¹³C NMR (75 MHz, DMSO-d ₆): δ = 137.31, 136.14, 130.50, 122.82, 121.15 (t, J = 275 Hz), 120.98, 119.47, 109.82, 94.28, 33.23. MS (EI): m/z = 213.1 [M]⁺. HRMS (EI-TOF): m/z [M]⁺ calcd for C₁₀H₉F₂NS: 213.0424; found: 213.042.