Metal-Free Trifluoromethylthiolation of Alkyl Electrophiles via a Cascade of Thiocyanation and Nucleophilic Cyanide–CF₃ Substitution

Abstract

A straightforward synthesis of alkyl trifluoromethyl thioethers was developed that starts from widely available alkyl halides or mesylates and the inexpensive reagents sodium thiocyanate and trimethyl(trifluoromethyl)silane. The alkyl electrophiles are converted in situ into the corresponding thiocyanates, which react with the nucleophilic Ruppert–Prakash reagent to give the corresponding trifluoromethyl thioethers via a Langlois-type CN–CF₃ substitution. This process enables the efficient introduction of the pharmaceutically meaningful trifluoromethylthio groups into functionalized molecules without the need of metal catalysts or expensive preformed trifluoromethylthiolating agents.

Key words

trifluoromethylthiolation - alkyl halides - fluorine - nucleo­philes - sulfur

• References and Notes

• 1a Liang T, Neumann CN, Ritter T. Angew. Chem. Int. Ed. 2013; 52: 8214
• 1b Jeschke P. ChemBioChem 2004; 5: 570
• 1c Wang J, Sánchez-Roselló M, Aceña JL, del Pozo C, Sorochinsky AE, Fustero S, Soloshonok VA, Liu H. Chem. Rev. 2014; 114: 2432
• 1d Müller K, Faeh C, Diederich F. Science 2007; 317: 1881
• 1e Hagmann WK. J. Med. Chem. 2008; 51: 4359
• 1f Purser S, Moore PR, Swallow S, Gouverneur V. Chem. Soc. Rev. 2008; 37: 320
• 2a Tomashenko OA, Grushin VV. Chem. Rev. 2011; 111: 4475
• 2b Furuya T, Kamlet AS, Ritter T. Nature (London, U.K.) 2011; 473: 470
• 2c Wu X.-F, Neumann H, Beller M. Chem. Asian J. 2012; 7: 1744
• 2d Liu X, Xu C, Wang M, Liu Q. Chem. Rev. 2015; 115: 683
• 2e Liu T, Shen Q. Eur. J. Org. Chem. 2012; 6679
• 2f Liang T, Neumann CN, Ritter T. Angew. Chem. Int. Ed. 2013; 52: 8214
• 2g Lantaño B, Torviso MR, Bonesi SM, Barata-Vallejo S, Postigo A. Coord. Chem. Rev. 2015; 285: 76
• 2h Alonso C, Martínez de Marigorta E, Rubiales G, Palacios F. Chem. Rev. 2015; 115: 1847
• 3a Toulgoat F, Alazet S, Billard T. Eur. J. Org. Chem. 2014; 2415
• 3b Boiko VN. Beilstein J. Org. Chem. 2010; 6: 880
• 3c Manteau B, Pazenok S, Vors J.-P, Leroux FR. J. Fluor. Chem. 2010; 131: 140
• 3d Leroux F, Jeschke P, Schlosser M. Chem. Rev. 2005; 105: 827
• 3e Xu X.-H, Matsuzaki K, Shibata N. Chem. Rev. 2015; 115: 731
• 4 Hansch C, Leo A, Unger SH, Kim KH, Nikaitani D, Lien EJ. J. Med. Chem. 1973; 16: 1207
• 5a Counts GW, Gregory D, Zeleznik D, Turck M. Antimicrob. Agents Chemother. 1977; 11: 708
• 5b Aswapokee N, Neu HC. Antimicrob. Agents Chemother. 1979; 15: 444
• 5c Coombs GH, Mottram JC. Antimicrob. Agents Chemother. 2001; 45: 1743
• 5d Sato D, Kobayashi S, Yasui H, Shibata N, Toru T, Yamamoto M, Tokoro G, Ali V, Soga T, Takeuchi T, Suematsu M, Nozaki T. Int. J. Antimicrob. Agents 2010; 35: 56
• 6a Nodiff EA, Lipschutz S, Craig PN, Gordon M. J. Org. Chem. 1960; 25: 60
• 6b Feiring AE. J. Org. Chem. 1979; 44: 2907
• 7a Wakselman C, Tordeux M. J. Org. Chem. 1985; 50: 4047
• 7b Kieltsch I, Eisenberger P, Togni A. Angew. Chem. Int. Ed. 2007; 46: 754
• 7c Harsányi A, Dorkó É, Csapó Á, Bakó T, Peltz C, Rábai J. J. Fluorine Chem. 2011; 132: 1241
• 7d Billard T, Langlois BR. Tetrahedron Lett. 1996; 37: 6865
• 7e Billard T, Large S, Langlois BR. Tetrahedron Lett. 1997; 38: 65
• 7f Wakselman C, Tordeux M, Clavel J.-L, Langlois B. J. Chem. Soc., Chem. Commun. 1991; 993
• 7g Quiclet-Sire B, Saicic RN, Zard SZ. Tetrahedron Lett. 1996; 37: 9057
• 7h Roques N. J. Fluorine Chem. 2001; 107: 311
• 7i Blond G, Billard T, Langlois BR. Tetrahedron Lett. 2001; 42: 2473
• 7j Pooput C, Medebielle M, Dolbier WR. Org. Lett. 2004; 6: 301
• 7k Pooput C, Dolbier William R, Médebielle M. J. Org. Chem. 2006; 71: 3564
• 7l Potash S, Rozen S. J. Fluorine Chem. 2014; 168: 173
• 8a Baert F, Colomb J, Billard T. Angew. Chem. Int. Ed. 2012; 51: 10382
• 8b Shao X, Wang X, Yang T, Lu L, Shen Q. Angew. Chem. Int. Ed. 2013; 52: 3457
• 8c Pluta R, Nikolaienko P, Rueping M. Angew. Chem. Int. Ed. 2014; 53: 1650
• 8d Xu C, Ma B, Shen Q. Angew. Chem. Int. Ed. 2014; 53: 9316
• 8e Yang Y.-D, Azuma A, Tokunaga E, Yamasaki M, Shiro M, Shibata N. J. Am. Chem. Soc. 2013; 135: 8782
• 9a Teverovskiy G, Surry DS, Buchwald SL. Angew. Chem. Int. Ed. 2011; 50: 7312
• 9b Zhang C.-P, Vicic DA. J. Am. Chem. Soc. 2012; 134: 183
• 9c Weng Z, He W, Chen C, Lee R, Tan D, Lai Z, Kong D, Yuan Y, Huang K.-W. Angew. Chem. Int. Ed. 2013; 52: 1548
• 10 Tran LD, Popov I, Daugulis O. J. Am. Chem. Soc. 2012; 134: 18237
• 11a Chen C, Xie Y, Chu L, Wang R.-W, Zhang X, Qing F.-L. Angew. Chem. Int. Ed. 2012; 51: 2492
• 11b Chen C, Chu L, Qing F.-L. J. Am. Chem. Soc. 2012; 134: 12454
• 11c Zhang C.-P, Vicic DA. Chem. Asian J. 2012; 7: 1756
• 11d Zhu S.-Q, Xu X.-H, Qing F.-L. Eur. J. Org. Chem. 2014; 4453
• 12a Man EH, Coffman DD, Muetterties EL. J. Am. Chem. Soc. 1959; 81: 3575
• 12b Harris JF. J. Org. Chem. 1966; 31: 931
• 12c Kolomeitsev AA, Chabanenko KY, Röschenthaler G.-V, Yagupolskii YL. Synthesis 1994; 145
• 12d Ferry A, Billard T, Langlois BR, Bacqué E. Angew. Chem. Int. Ed. 2009; 48: 8551
• 13a Wang X, Zhou Y, Ji G, Wu G, Li M, Zhang Y, Wang J. Eur. J. Org. Chem. 2014; 3093
• 13b Hu M, Rong J, Miao W, Ni C, Han Y, Hu J. Org. Lett. 2014; 16: 2030
• 13c Lefebvre Q, Fava E, Nikolaienko P, Rueping M. Chem. Commun. 2014; 50: 6617
• 14a Liu J.-B, Xu X.-H, Chen Z.-H, Qing F.-L. Angew. Chem. Int. Ed. 2015; 54: 897
• 14b Nikolaienko P, Pluta R, Rueping M. Chem. Eur. J. 2014; 20: 9867
• 15a Munavalli S, Rossman DI, Rohrbaugh DK, Ferguson CP, Durst HD. J. Fluorine Chem. 1996; 76: 7
• 15b Zhang K, Liu J.-B, Qing F.-L. Chem. Commun. 2014; 50: 14157
• 15c Kong D, Jiang Z, Xin S, Bai Z, Yuan Y, Weng Z. Tetrahedron 2013; 69: 6046
• 15d Zhong W, Liu X. Tetrahedron Lett. 2014; 55: 4909
• 15e Lin Q, Chen L, Huang Y, Rong M, Yuan Y, Weng Z. Org. Biomol. Chem. 2014; 12: 5500
• 16 Hu F, Shao X, Zhu D, Lu L, Shen Q. Angew. Chem. Int. Ed. 2014; 53: 6105
• 17a Wu H, Xiao Z, Wu J, Guo Y, Xiao J.-C, Liu C, Chen Q.-Y. Angew. Chem. Int. Ed. 2015; 54: 4070
• 17b Chen C, Xu X.-H, Yang B, Qing F.-L. Org. Lett. 2014; 16: 3372
• 17c Bootwicha T, Liu X, Pluta R, Atodiresei I, Rueping M. Angew. Chem. Int. Ed. 2013; 52: 12856
• 17d Guo S, Zhang X, Tang P. Angew. Chem. Int. Ed. 2015; 54: 4065
• 18 Tyrra W, Naumann D, Hoge B, Yagupolskii YL. J. Fluorine Chem. 2003; 119: 101
• 19a Matheis C, Jouvin K, Goossen LJ. Org. Lett. 2014; 16: 5984
• 19b Danoun G, Bayarmagnai B, Grünberg MF, Gooßen LJ. Angew. Chem. Int. Ed. 2013; 52: 7972
• 19c Bayarmagnai B, Matheis C, Risto E, Goossen LJ. Adv. Synth. Catal. 2014; 356: 2343
• 20a Danoun G, Bayarmagnai B, Gruenberg MF, Goossen LJ. Chem. Sci. 2014; 5: 1312
• 20b Bayarmagnai B, Matheis C, Jouvin K, Goossen LJ. Angew. Chem. Int. Ed. 2015; 54 in press; doi: 10.1002/anie.201500899
• 21 Ishizaki M, Hoshino O. Tetrahedron 2000; 56: 8813
• 22 General Procedure for the Trifluoromethylthiolation of Alkyl Thiocyanates Generated in situ An oven-dried 20 mL crimp-cap vessel with Teflon-coated stirrer bar was charged with Cs₂CO₃ (652 mg, 1.00 mmol) and NaSCN (100 mg, 1.20 mmol). MeCN (2 mL), TMSCF₃ (537 mg, 0.60 mL, 1.20 mmol), and the alkyl halide or mesylate (1.00 mmol) were added via syringe. The suspension was heated to the following temperatures, depending on the leaving group: primary alkyl bromides and iodides 60 °C; secondary alkyl bromides and primary chlorides 90 °C, and alkyl mesylates 110 °C. Stirring was continued until completion of the reaction was determined by GC and GC–MS. The resulting mixture was allowed to cool to r.t., diluted with Et₂O (20 mL), washed with H₂O (2 × 10 mL) and brine (10 mL). The organic layer was dried over MgSO₄, filtered, and concentrated under reduced pressure (700 mbar, 40 °C). Most compounds were obtained in pure form, for products with aromatic substituents the residue was purified by column chromatography (SiOH, Et₂O–pentane gradient). [(Trifluoromethyl)thio]methylbenzene [CAS No.: 351-60-0] (2) ¹H NMR (400 MHz, CDCl₃): δ = 7.38–7.36 (m, 5 H), 4.15 (s, 2 H) ppm. ¹⁹F NMR (375 MHz, CDCl₃): δ = –41.47 ppm. ¹³C NMR (101 MHz, CDCl₃): δ = 135.0, 130.6 [q, ¹ J(C,F) = 307.0 Hz], 128.9 (2 C), 128.8 (2 C), 128.0, 34.2 [q, ³ J(C,F) = 2.7 Hz] ppm. IR (neat): ν = 2922, 2853, 1463, 1378 cm^–1. MS (ion trap, EI, 70 eV): m/z (%) = 192 (23) [M ⁺ ], 91 (100), 69 (13). HRMS (EI-TOF): m/z calcd for C₈H₇F₃S: 192.0221; found: 192.0224. 11-[(Trifluoromethyl)thio]undecanoic Acid (14) ¹H NMR (400 MHz, CDCl₃): δ = 2.88 (t, ³ J = 7.5 Hz, 2 H), 2.35 (t, ³ J = 7.5 Hz, 2 H), 1.72–1.60 (m, 4 H), 1.44–1.29 ppm (m, 12 H) ppm. ¹⁹F NMR (375 MHz, CDCl₃): δ = –41.3 ppm. ¹³C NMR (101 MHz, CDCl₃): δ = 180.5, 131.2 [q, ¹ J(C,F) = 305.2 Hz], 34.1, 29.83 [q, ³ J(C,F) = 2.4 Hz], 29.34, 29.27, 29.25, 29.1, 29.0, 28.9, 28.5, 24.6 ppm. IR (neat): ν = 2927, 2856, 1709, 1464, 1414, 1113, 938, 756 cm^–1. MS (ion trap, EI, 70 eV): m/z (%) = 287 (12) [M⁺ + H], 199 (73), 129 (44), 117 (91), 101 (9), 69 (24). HRMS (EI-TOF): m/z calcd for: C₁₂H₂₁F₃O₂S: 286.1214; found: 286.1230. 3-[(Trifluoromethyl)thio]propyltrimethoxysilane (16) ¹H NMR (400 MHz, CDCl₃): δ = 3.55 (s, 9 H), 2.88 (t, ³ J = 7.3 Hz, 2 H), 1.79 (qi, ³ J = 7.8 Hz, 2 H), 0.73 (t, ³ J = 8.3 Hz, 2 H) ppm. ¹⁹F NMR (375 MHz, CDCl₃): δ = –41.2 ppm. ¹³C NMR (101 MHz, CDCl₃): δ = 131.2 [q, ¹ J(C,F) = 305.9 Hz], 50.5 (3 H), 32.5 [q, ³ J(C,F) = 1.5 Hz], 23.2, 8.3 ppm. IR (neat): ν = 2945, 2843, 1759, 1077, 809, 754 cm^–1. MS (ion trap, EI, 70 eV): m/z (%) = 264 (1) [M⁺], 233 (12), 195 (63), 121 (13), 93 (100). HRMS (EI-TOF): m/z calcd for C₇H₁₅O₃SiF₃S: 264.0463; found: 264.0468. N-{2-[(Trifluoromethyl)thio]ethyl}-N,N-dibutylamine (17) ¹H NMR (400 MHz, CDCl₃): δ = 3.30 (t, ³ J = 7.1 Hz, 2 H), 2.74 (t, ³ J = 7.0 Hz, 2 H), 2.42 (t, ³ J = 7.2 Hz, 4 H), 1.43–1.37 (m, 4 H), 1.34–1.28 (m, 4 H), 0.92 (t, ³ J = 7.3 Hz, 6 H) ppm. ¹⁹F NMR (375 MHz, CDCl₃): δ = –41.4 ppm. ¹³C NMR (101 MHz, CDCl₃): δ = 131.6 [q, ¹ J(C,F) = 306.8 Hz], 53.6 (2 C), 52.8, 29.3 (2 C), 28.8, 20.5 (2 C), 14.0 (2 C) ppm. IR (neat): ν = 2959, 2934, 2874, 1739, 1460, 1366, 1217, 1119, 748 cm^–1. MS (ion trap, EI, 70 eV): m/z (%) = 257 (3), 214 (44), 172 (66), 142 (100), 58 (41). HRMS (EI-TOF): m/z calcd for C₁₁H₂₂NF₃S: 257.1425; found: 257.1420. 1-Trimethylsilyl-5-(trifluoromethyl)thiopent-1-yne (19) ¹H NMR (400 MHz, CDCl₃): δ = 3.01 (t, ³ J = 7.1 Hz, 2 H), 2.38 (t, ³ J = 6.8 Hz, 2 H), 1.90 (qi, ³ J = 7.0 Hz, 2 H), 0.15 (s, 9 H) ppm. ¹⁹F NMR (375 MHz, CDCl₃): δ = –41.1 ppm. ¹³C NMR (101 MHz, CDCl₃): δ = 131.0 [q, ¹ J(C,F) = 306.1 Hz], 104.8, 86.2, 28.7 [q, ³ J(C,F) = 1.8 Hz], 28.3, 18.6, 0.0 (3 C) ppm. IR (neat): ν = 2960, 2176, 1685, 1432, 1250, 1107, 838, 758, 699 cm^–1. MS (ion trap, EI, 70 eV): m/z (%) = 240 (11) [M⁺], 171 (97), 129 (100). HRMS (EI-TOF): m/z calcd for C₉H₁₅SiF₃S: 240.0616; found: 240.0614. (1R,5S)-[(Trifluoromethyl)thio]-2-{6,6-dimethylbicyclo[3.1.1]-hept-2-en-2-yl}ethylene (21) ¹H NMR (400 MHz, CDCl₃): δ = 5.31 (m, 1 H), 2.93–2.89 (m, 2 H), 2.41–2.38 (m, 1 H), 2.37–2.32 (m, 2 H), 2.26–2.23 (m, 2 H), 2.11–2.09 (m, 1 H), 2.02–1.99 (m, 1 H), 1.29 (s, 3 H), 1.16 (d, ³ J = 8.5 Hz, 1 H), 0.84 (s, 3 H) ppm. ¹⁹F NMR (375 MHz, CDCl₃): δ = –41.2 ppm. ¹³C NMR (101 MHz, CDCl₃): δ = 145.2, 132.2 [q, ¹ J(C,F) = 306.1 Hz], 118.8, 40.6, 38.0, 36.6, 31.6, 31.2, 27.8 [q, ³ J(C,F) = 1.8 Hz], 26.2, 21.1 ppm. IR (neat): ν = 2917, 1434, 1366, 1104, 887, 794, 756 cm^–1. MS (ion trap, EI, 70 eV): m/z (%) = 250 (14) [M⁺], 105 (100), 121 (10). HRMS (EI-TOF): m/z calcd for C₁₂H₁₇F₃S: 250.1003; found: 250.0987; [α]_D ²⁰ –25.9 (c 1.00, Et₂O).