English

• 1.   Introduction

  Aryl triflates have found widespread applications in organic synthesis^[1] and medicinal chemistry^[2]. They have served as versatile coupling partners in transition metal-catalyzed cross-coupling reactions.^[1] Aryl triflates bearing a trimethylsilyl group at the ortho position have proved to be convenient aryne precursors.^[3] Furthermore, the trifluoromethyl group could increase the lipophilicity of organic compounds, and thus aryl triflate moiety can be present as an important structural motif in medicinal chemistry.^[2] Therefore, significant efforts have been directed towards the development of efficient methods for the synthesis of aryl triflates. Although C—H triflation is a step-economy strategy, it suffers from a limited substrate scope or the need for the installation of a directing group into substrates (Scheme 1, a).^[4] The Sandmeyer triflation may deliver products which are difficult to obtain by other routes, but the arenediazonium substrates are explosive and high triflation temperatures may be required (Scheme 1, b).^[5] Trifluoromethanesulfonylation of phenols, the most commonly used protocol, is quite straightforward and attractive.^[6]

  Scheme 1

  

  Scheme 1.  Synthesis of aryl triflates

  下载: 全尺寸图片 幻灯片

  Various trifluoromethanesulfonylation reagents, such as TfCl (Tf＝CF₃SO₂), ^[7] Tf₂O, ^[8] Im-Tf (Im＝imidazole), ^[9] PhNTf₂, ^[10] and ArOTf, ^[11] have been developed for the synthesis of aryl triflates from phenols (Scheme 1, c). The good reactivity of PhNTf₂ has stimulated the development of polymer-supported reagents, polymer-C₆H₄NTf₂, whose byproduct, polymer-C₆H₄NHTf, generated in the trifluoromethane- sulfonylation reactions, could be recovered and reused to generate polymer-C₆H₄NTf₂.^[12] Although these reagents are quite efficient, some drawbacks still remain. For instance, TfCl and Tf₂O are highly volatile and may lead to inconvenient operations. Tedious procedures are required for the synthesis and the reuse of the polymer-supported reagents. The desired products usually have to be isolated by flash column chromatography. Therefore, the development of efficient trifluoromethanesulfonylation reagents is desirable.

  Although the trifluoromethanesulfonyl pyridinium salt, 1, is a known compound, ^[13] it has never been used as trifluoromethanesulfonylation reagent. We found that this compound could smoothly convert phenols into aryl triflates under mild conditions (Scheme 1, d). More importantly, the pure triflate products could be isolated simply by washing. The preliminary results are described herein.

  2.   Results and discussion

  Pyridinium salt 1 could be readily produced from the reaction of pyridine with trifluoromethanesulfonic anhydride, and the pure product could be obtained via a simple washing procedure (please see experimental section). It is a solid and stable under dry atmosphere. Our initial attempts at trifluoromethanesulfonylation of substrate 2a with salt 1 revealed that almost a quantitative yield could be obtained by using organic or inorganic base (Table 1, Entries 1~6). Decreasing the loading of DMAP did not lower the yield (Entries 7~9). Interestingly, the desired product was also obtained in 99% ¹⁹F NMR yield when using 0.1 equiv. of other base such as Et₃N or DBU. 0.1 equiv. of NaHCO₃ gave the desired product only in 33% ¹⁹F NMR yield. However, no desired product was generated and salt 1 remained intact if no base was used (Entry 10). The reaction proceeded smoothly in various reaction solvents (Entry 9 and Entries 11~13). The yield was not decreased by shortening the reaction time (Entries 14).

  Table 1

  

  Table 1.  Optimization of reaction conditions ^a

  下载: 导出CSV

  Entry	Base (mmol)	Solvent	Time/h	Yieldb/%
  1	Et3N (1.5)	DCM	3	99
  2	DBU (1.5)	DCM	3	99
  3	Pyridine (1.5)	DCM	3	99
  4	DMAP (1.5)	DCM	3	99
  5	NaHCO3 (1.5)	DCM	3	99
  6	Na2CO3 (1.5)	DCM	3	99
  7	DMAP (1.0)	DCM	3	99
  8	DMAP (0.5)	DCM	3	99
  9	DMAP (0.1)	DCM	3	99
  10	—	DCM	3	ND
  11	DMAP (0.1)	EA	3	99
  12	DMAP (0.1)	n-Hexane	3	99
  13	DMAP (0.1)	Acetone	3	99
  14	DMAP (0.1)	DCM	0.5	99
  a Reaction conditions: Substrate 2a (1 mmol), reagent 1 (1.9 mmol), base, and solvent (5 mL) at room temperature under air atmosphere; DBU＝1, 8- Diazabicyclo[5.4.0]undec-7-ene; DMAP＝4-dimethylaminopyridine; EA＝ethyl acetate; ND＝not detected; b The yields were determined by 19F NMR spectroscopy by using PhOCF3 as an internal standard.

  With the optimal reaction conditions in hand (Table 1, Entry 14), we then investigated the substrate scope of the trifluoromethanesulfonylation of phenols with salt 1. As shown in Scheme 2, various electron-rich, electron-neutral and electron-deficient phenols were all converted smoothly into the desired products in high yields. Estrone, a female sex hormone, could also be transformed into its corresponding triflate under these conditions (3n). It is worth noting that all of these products were purified simply by washing without the use of chromatography. Increasing the reaction scale to 10 mmol, product 3a was still afforded in high isolated yield (89%), further demonstrating the synthetic utility of this protocol.

  Scheme 2

  

  Scheme 2.  Synthesis of vinyl triflates

  下载: 全尺寸图片 幻灯片

  Table 2

  

  Table 2.  Trifluoromethanesulfonylation of phenols^a

  下载: 导出CSV

  Vinyl triflates are also valuable coupling partners in transition metal-catalyzed cross-coupling reactions.^[6b] β-Ketoesters could also be transformed into vinyl triflates by using salt 1 as a trifluoromethanesulfonylation reagent (Scheme 2). The one-pot two-step reaction gave the desired products in high yields.

  3.   Conclusions

  In summary, the trifluoromethanesulfonylation of phenols with pyridinium salt 1 under mild conditions to give the desired aryl triflates in high yields have been described. All triflate products were purified simply by washing without the use of chromatography. Vinyl triflates were also synthesized from β-ketoesters by using salt 1 as reagent. The trifluoromethanesulfonylation protocol is quite attractive due to the easy accessibility of the reagent and the convenient operations for product purification.

  4.   Experimental section

  4.1   General information

  ¹H NMR and ¹⁹F NMR spectra were detected on a 500, 400 or 300 MHz NMR spectrometer. Mass spectra were obtained on GC-MS. Unless otherwise noted, all reagents were obtained commercially and used without further purification.

  4.2.1   Procedure for the synthesis of pyridinium salt 1

  Into the solution of DMAP (0.1 mol, 12.2 g, 1.0 equiv.) in DCM (40 mL) was added Tf₂O (0.15 mol, 42.3 g, 1.5 equiv) slowly at 0 ℃. The resulting mixture was warmed to room temperature and stirred for 1 h. The precipitate was washed with DCM, and the solid was dried under vacuum to afford 4-dimethylamino-1-(trifluoromethyl)- sulfonylpyridin-1-ium trifluoromethanesulfonate (1)^[13] (34.3 g, 85% yield). ¹H NMR (400 MHz, CD₃CN) δ: 8.28 (d, J＝8.2 Hz, 2H), 7.13 (d, J＝8.3 Hz, 2H), 3.41 (s, 6H); ¹⁹F NMR (376 MHz, CD₃CN) δ: －74.59 (s, 3F), －79.36 (s, 3F).

  4.2.2   Typical procedure for the trifluoromethanesulfonylation of phenols

  Into a 15 mL Schlenk tube were added substrate 2 (1.0 mmol), pyridinium salt 1 (1.9 mmol, 756.0 mg), DMAP (0.1 mmol, 12.2 mg) and DCM (5 mL). The tube was sealed and the resulting mixture was stirred at room temperature for 0.5 h. The reaction was quenched by water. The organic phase was washed with water (10 mL×3), and the water phase was further extracted with DCM. The combined organic phase was concentrated and the solvent was removed to afford the pure product 3.

  Naphthalen-2-yl trifluoromethanesulfonate (3a):^[14] 94% yield. ¹H NMR (400 MHz, CDCl₃) δ: 7.93~7.81 (m, 3H), 7.76 (d, J＝2.2 Hz, 1H), 7.62~7.51 (m, 2H), 7.38 (dd, J＝9.0, 2.4 Hz, 1H); ¹⁹F NMR (376 MHz, CDCl₃) δ: －72.88 (s, 3F); GC-MS m/z: 276.0.

  (1, 1'-Biphenyl)-4-yl trifluoromethanesulfonate (3b):^[14] 85% yield. ¹H NMR (400 MHz, CDCl₃) δ: 7.65 (d, J＝8.8 Hz, 2H), 7.58 (d, J＝7.1 Hz, 2H), 7.53~7.40 (m, 3H), 7.37 (d, J＝8.8 Hz, 2H); ¹⁹F NMR (376 MHz, CDCl₃) δ: －72.88 (s, 3F); GC-MS m/z: 302.0.

  4-(2-Phenylpropan-2-yl)phenyl trifluoromethanesulfona- te (3c):^[15] 92% yield. ¹H NMR (400 MHz, CDCl₃) δ: 7.38~7.34 (m, 4H), 7.32~7.26 (m, 3H), 7.25~7.20 (m, 2H), 1.76 (s, 6H); ¹⁹F NMR (376 MHz, CDCl₃) δ: －73.01 (s, 3F); GC-MS m/z: 344.1.

  3-Methyl-4-(methylthio)phenyl  trifluoromethanesulfo- nate (3d):^[14] 82% yield. ¹H NMR (400 MHz, CDCl₃) δ: 7.13 (d, J＝8.6 Hz, 1H), 7.11~7.03 (m, 2H), 2.45 (s, 3H), 2.32 (s, 3H); ¹⁹F NMR (376 MHz, CDCl₃) δ: －73.06 (s, 3F); GC-MS m/z: found 286.0.

  4-Allyl-2-methoxyphenyl  trifluoromethanesulfonate (3e):^[16] 90% yield. ¹H NMR (400 MHz, CDCl₃) δ: 7.12 (d, J＝8.3 Hz, 1H), 6.86 (d, J＝1.5 Hz, 1H), 6.79 (dd, J＝8.3, 1.4 Hz, 1H), 6.02~5.87 (m, 1H), 5.18~5.07 (m, 2H), 3.88 (s, 3H), 3.39 (d, J＝6.7 Hz, 2H); ¹⁹F NMR (376 MHz, CDCl₃) δ: －74.06 (s, 3F); GC-MS m/z: found 296.0.

  3, 4, 5-Trimethoxyphenyl  trifluoromethanesulfonate (3f):^[14] 83% yield. ¹H NMR (400 MHz, CDCl₃) δ: 6.44 (s, 2H), 3.79 (s, 6H), 3.77 (s, 3H); ¹⁹F NMR (376 MHz, CDCl₃) δ: －73.06 (s, 3F); GC-MS m/z: 316.0.

  1, 3-Phenylene bis(trifluoromethanesulfonate) (3g):^[17] 80% yield. ¹H NMR (400 MHz, CDCl₃) δ: 7.56 (t, J＝8.4 Hz, 1H), 7.35 (dd, J＝8.4, 2.3 Hz, 2H), 7.26 (t, J＝2.2 Hz, 1H); ¹⁹F NMR (376 MHz, CDCl₃) δ: －72.88 (s, 6F); GC-MS m/z: 373.9.

  4-Cyanophenyl trifluoromethanesulfonate (3h):^[10b] 93% yield. ¹H NMR (400 MHz, CDCl₃) δ: 7.77 (d, J＝8.9 Hz, 2H), 7.40 (d, J＝8.9 Hz, 2H); ¹⁹F NMR (376 MHz, CDCl₃) δ: －72.79 (s, 3F); GC-MS m/z: 251.0.

  2-Nitrophenyl trifluoromethanesulfonate (3i):^[18] 85% yield. ¹H NMR (400 MHz, CDCl₃) δ: 8.14 (dd, J＝8.2, 1.6 Hz, 1H), 7.76 (td, J＝8.3, 1.7 Hz, 1H), 7.59 (td, J＝8.2, 1.2 Hz, 1H), 7.45 (d, J＝8.3 Hz, 1H); ¹⁹F NMR (376 MHz, CDCl₃) δ: －73.29 (s, 3F); GC-MS m/z: 270.9.

  4-Acetylphenyl trifluoromethanesulfonate (3j):^[14] 86% yield. ¹H NMR (400 MHz, CDCl₃) δ: 8.00 (d, J＝8.9 Hz, 2H), 7.32 (d, J＝8.8 Hz, 2H), 2.56 (s, 3H); ¹⁹F NMR (376 MHz, CDCl₃) δ: －73.02 (s, 3F); GC-MS m/z: 268.0.

  4-Formylphenyl trifluoromethanesulfonate (3k):^[19] 92% yield. ¹H NMR (400 MHz, CDCl₃) δ: 10.00 (s, 1H), 7.96 (d, J ＝8.8 Hz, 2H), 7.42 (d, J ＝8.7 Hz, 2H); ¹⁹F NMR (376 MHz, CDCl₃) δ: －72.94 (s, 3F); GC-MS m/z: 254.0.

  4-Bromophenyl trifluoromethanesulfonate (3l)^[19]: 82% yield. ¹H NMR (400 MHz, CDCl₃) δ: 7.62~7.52 (m, 2H), 7.19~7.12 (m, 2H); ¹⁹F NMR (376 MHz, CDCl₃) δ: －72.77 (3F); GC-MS m/z: 303.9.

  2-Nitropyridin-3-yl trifluoromethanesulfonate (3m):^[20] 85% yield. ¹H NMR (400 MHz, CDCl₃) δ: 8.58 (dd, J＝4.5, 1.3 Hz, 1H), 7.95 (dd, J＝8.3, 1.1 Hz, 1H), 7.82 (dd, J＝8.3, 4.5 Hz, 1H); ¹⁹F NMR (376 MHz, CDCl₃) δ: －73.08 (s, 3F); GC-MS m/z: 271.9.

  (8R, 9S, 13S, 14S)-13-Methyl-17-oxo-7, 8, 9, 11, 12, 13, 14, 15, 16, 17-decahydro-6H-cyclopenta[a]phenanthren-3-yltrifluoromethanesulfonate (3n):^[14] 91% yield. ¹H NMR (400 MHz, CDCl₃) δ: 7.29 (d, J＝8.6 Hz, 1H), 7.02~6.89 (m, 2H), 2.91~2.88 (m, 2H), 2.45 (dd, J＝18.5, 8.7 Hz, 1H), 2.39~2.30 (m, 1H), 2.29~2.19 (m, 1H), 2.16~1.96 (m, 3H), 1.95~1.88 (m, 1H), 1.68~1.34 (m, 6H), 0.86 (s, 3H); ¹⁹F NMR (376 MHz, CDCl₃) δ: －73.12 (s, 3F); GC-MS m/z: 402.1.

  4.2.3   Procedure for the 10 mmol-scale reaction

  Into a mixture of 2a (10.0 mmol, 1.44 g), pyridinium salt 1 (19 mmol, 7.56 g), DMAP (1 mmol, 122 mg) and DCM (40 mL). The resulting mixture was stirred at room temperature for 0.5 h. The reaction was quenched by water. The organic phase was washed with water (20 mL×3), and the water phase was further extracted with DCM. The combined organic phase was concentrated to remove the solvent to afford the pure product 3a (2.45 g, 89%).

  4.2.4   Typical procedure for the synthesis of vinyl triflates

  Into the solution of substrate 4 (1.0 mmol) in dry THF (10 mL) was added LDA (0.5 mL, 2 mol/L) at －78 ℃. The mixture was stirred at the same temperature for 1 h. Pyridinium salt 1 (1.9 mmol, 756.0 mg) was added. The reaction mixture was warmed to room temperature and stirred at room temperature for 12 h. Products 5 were isolated by flash column chromatography.

  2-(((Trifluoromethyl)sulfonyl)oxy)cyclopent-1-ene-1-carboxylate (5a):^[21] 86% yield. ¹H NMR (400 MHz, CDCl₃) δ: 4.21 (q, J＝7.2 Hz, 2H), 2.72~2.63 (m, 4H), 2.00~1.93 (m, 2H), 1.27 (t, J＝7.1 Hz, 3H); ¹⁹F NMR (376 MHz, CDCl₃) δ: －74.79 (s, 3F); GC-MS m/z: 288.0.

  2-(((Trifluoromethyl)sulfonyl)oxy)cyclohex-1-ene-1-carboxylate (5b):^[22] 83% yield. ¹H NMR (400 MHz, CDCl₃) δ: 4.23 (q, J＝7.1 Hz, 2H), 2.50~2.40 (m, 2H), 2.40~ 2.31 (m, 2H), 1.78~1.72 (m, 2H), 1.66~1.60 (m, 2H), 1.29 (t, J＝7.5 Hz, 3H); ¹⁹F NMR (376 MHz, CDCl₃) δ: －74.91 (s, 3F); GC-MS m/z: 302.0.

  Supporting Information ¹H NMR and ¹⁹F NMR spectra of salt 1, products 3a~3n and 5a~5b. The Supporting Information is available free of charge via the Internet at http://sioc-journal.cn/.

  
  
• 1. [1]

     (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
     (b) Hartwig, J. F. Angew. Chem., Int. Ed. 1998, 37, 2046.
     (c) Zhang, M.; Chen, B.; Ge, C.; Liu, R.; Gao, J.; Jia, Y. Chin. J. Org. Chem. 2016, 36, 1636 (in Chinese).
     (张鸣頔, 陈斌, 葛晨, 刘人荣, 高建荣, 贾义霞, 有机化学, 2016, 36, 1636.)

  2. [2]

     (a) Moriconi, A.; Bigogno, C.; Bianchini, G.; Caligiuri, A.; Resconi, A.; Dondio, M. G.; D'Anniballe, G.; Allegretti, M. ACS Med. Chem. Lett. 2011, 2, 768.
     (b) Broccatelli, F.; Mannhold, R.; Moriconi, A.; Giuli, S.; Carosati, E. Mol. Pharm. 2012, 9, 2290.

  3. [3]

     (a) Tadross, P. M.; Stoltz, B. M. Chem. Rev. 2012, 112, 3550.
     (b) Bhunia, A.; Yetra, S. R.; Biju, A. T. Chem. Soc. Rev. 2012, 41, 3140.
     (c) Dubrovskiy, A. V.; Markina, N. A.; Larock, R. C. Org. Biomol. Chem. 2013, 11, 191.

  4. [4]

     (a) Pialat, A.; Liegault, B.; Taillefer, M. Org. Lett. 2013, 15, 1764.
     (b) Yang, Z.-W.; Zhang, Q.; Jiang, Y.-Y.; Li, L.; Xiao, B.; Fu, Y. Chem. Commun. 2016, 52, 6709.
     (c) Nakazawa, H.; Sako, M.; Masui, Y.; Kurosaki, R.; Yamamoto, S.; Kamei, T.; Shimada, T. Org. Lett. 2019, 21, 6466.

  5. [5]

     Norihiko, Y.; Tsuyoshi, F.; Takao, M.; Akira, S. Chem. Lett. 1991, 20, 459. doi: 10.1246/cl.1991.459

  6. [6]

     (a) Stang, P. J.; Hanack, M.; Subramanian, L. R. Synthesis 1982, 85.
     (b) Ritter, K. Synthesis 1993, 735.

  7. [7]

     Seganish, W. M.; DeShong, P. J. Org. Chem. 2004, 69, 1137. doi: 10.1021/jo035309q

  8. [8]

     (a) Qing, F.-L.; Fan, J.; Sun, H.-B.; Yue, X.-J. J. Chem. Soc., Perkin Trans. 1 1997, 3053.
     (b) Frantz, D. E.; Weaver, D. G.; Carey, J. P.; Kress, M. H.; Dolling, U. H. Org. Lett. 2002, 4, 4717.
     (c) Gill, D.; Hester, A. J.; Lloyd-Jones, G. C. Org. Biomol. Chem. 2004, 2, 2547.

  9. [9]

     Effenberger, F.; Mack, K. E. Tetrahedron Lett. 1970, 11, 3947. doi: 10.1016/S0040-4039(01)98633-2

  10. [10]

      (a) Hendrickson, J. B.; Bergeron, R. Tetrahedron Lett. 1973, 14, 4607.
      (b) Bengtson, A.; Hallberg, A.; Larhed, M. Org. Lett. 2002, 4, 1231.

  11. [11]

      Zhu, J.; Bigot, A.; Elise, M.; Dau, T. H. Tetrahedron Lett. 1997, 38, 1181. doi: 10.1016/S0040-4039(97)00024-5

  12. [12]

      Wentworth, A. D.; Wentworth, P.; Mansoor, U. F.; Janda, K. D. Org. Lett. 2000, 2, 477.
      (b) Chung, C. W. Y.; Toy, P. H. Tetrahedron 2005, 61, 709.

  13. [13]

      (a) White, K. L.; Mewald, M.; Movassaghi, M. J. Org. Chem. 2015, 80, 7403.
      (b) Yogendra, S.; Hennersdorf, F.; Bauzá, A.; Frontera, A.; Fischer, R.; Weigand, J. J. Chem. Commun. 2017, 53, 2954.

  14. [14]

      Wu, J.; Lu, C.; Lu, L.; Shen, Q. Chin. J. Chem. 2018, 36, 1031. doi: 10.1002/cjoc.201800306

  15. [15]

      Takeshi, K.; Hideki, K.; Takeshi, F.; Rieko, T.; Takashi, T.; Koji, S.; Naokid, T. US 2011/112103, 2011.

  16. [16]

      Ma, X.; Dang, H.; Rose, J. A.; Rablen, P.; Herzon, S. B. J. Am. Chem. Soc. 2017, 139, 5998. doi: 10.1021/jacs.7b02388

  17. [17]

      James M. B.; Daniel C. B.; Timothy, B.; Allen, B. WO 2017/218922, 2017.

  18. [18]

      Qin, L.; Ren, X.; Lu, Y.; Li, Y.; Zhou, J. Angew. Chem., Int. Ed. 2012, 51, 5915. doi: 10.1002/anie.201201806

  19. [19]

      Scheidt, F.; Neufeld, J.; Schäfer, M.; Thiehoff, C.; Gilmour, R. Org. Lett. 2018, 20, 8073. doi: 10.1021/acs.orglett.8b03794

  20. [20]

      Chao, J.; Istvan J. E.; Kevin, G.; Richard, H. WO 2014/8214, 2014.

  21. [21]

      Su, N.; Theorell, J. A.; Wink, D. J.; Driver, T. Angew. Chem., Int. Ed. 2015, 54, 12942. doi: 10.1002/anie.201505993

  22. [22]

      Picado, A; Li, S.; Dieter, R. K. J. Org. Chem. 2016, 81, 1391. doi: 10.1021/acs.joc.5b02350

• 

  Scheme 1  Synthesis of aryl triflates

  下载: 全尺寸图片 幻灯片
  

  Scheme 2  Synthesis of vinyl triflates

  下载: 全尺寸图片 幻灯片

  Table 1.  Optimization of reaction conditions ^a

  Entry	Base (mmol)	Solvent	Time/h	Yieldb/%
  1	Et3N (1.5)	DCM	3	99
  2	DBU (1.5)	DCM	3	99
  3	Pyridine (1.5)	DCM	3	99
  4	DMAP (1.5)	DCM	3	99
  5	NaHCO3 (1.5)	DCM	3	99
  6	Na2CO3 (1.5)	DCM	3	99
  7	DMAP (1.0)	DCM	3	99
  8	DMAP (0.5)	DCM	3	99
  9	DMAP (0.1)	DCM	3	99
  10	—	DCM	3	ND
  11	DMAP (0.1)	EA	3	99
  12	DMAP (0.1)	n-Hexane	3	99
  13	DMAP (0.1)	Acetone	3	99
  14	DMAP (0.1)	DCM	0.5	99
  a Reaction conditions: Substrate 2a (1 mmol), reagent 1 (1.9 mmol), base, and solvent (5 mL) at room temperature under air atmosphere; DBU＝1, 8- Diazabicyclo[5.4.0]undec-7-ene; DMAP＝4-dimethylaminopyridine; EA＝ethyl acetate; ND＝not detected; b The yields were determined by 19F NMR spectroscopy by using PhOCF3 as an internal standard.

  下载: 导出CSV

  Table 2.  Trifluoromethanesulfonylation of phenols^a

  下载: 导出CSV
•