Silver(I) Oxide Catalyzed C/S–H Trifluoromethylation of Arenes and Heteroarenes with Sodium Trifluoromethanesulfinate

Abstract

We present a general and scalable approach for the C(sp²)–H or S–H trifluoromethylation of arenes and heteroarenes. This method employs bench-stable CF₃SO₂Na as the CF₃ source, with Ag₂O serving as the catalyst and K₂S₂O₈ as the oxidant. Notably, the protocol features broad functional-group compatibility, mild conditions, and high regioselectivity. Furthermore, it is applicable to biologically relevant molecules such as caffeine, pentoxifylline, ganciclovir triacetate, and mercaptopurine.

Key words

silver catalysis - trifluoromethylation - sodium trifluoromethanesulfinate - late-stage functionalization

• References and Notes

• 1 Mandal D, Maji S, Pal T, Sinha SK, Maiti D. Chem. Commun. 2022; 58: 10442
• 2 Huang Y, Zhang M, Lin Q, Weng Z. Synlett 2021; 32: 109
• 3 Chen P, Liu G. Synthesis 2013; 45: 2919
• 4 Inoue M, Sumii Y, Shibata N. ACS Omega 2020; 5: 10633
• 5 Mei H, Han J, Fustero S, Medio-Simon M, Sedgwick DM, Santi C, Ruzziconi R, Soloshonok VA. Chem. Eur. J. 2019; 25: 11797
• 6 Zhou X.-Y, Zhang M, Liu Z, He J.-H, Wang X.-C. J. Am. Chem. Soc. 2022; 144: 14463
• 7 Zhou Y, Wang J, Gu Z, Wang S, Zhu W, Aceña JL, Soloshonok VA, Izawa K, Liu H. Chem. Rev. 2016; 116: 422
• 8 Xiao H, Zhang Z, Fang Y, Zhu L, Li C. Chem. Soc. Rev. 2021; 50: 6308
• 9 Barata-Vallejo S, Lantaño B, Postigo A. Chem. Eur. J. 2014; 20: 16806
• 10 Wu X.-F, Neumann H, Beller M. Chem. Asian J. 2012; 7: 1744
• 11 Furuya T, Kamlet AS, Ritter T. Nature 2011; 473: 470
• 12 Nagib DA, MacMillan DW. C. Nature 2011; 480: 224
• 13 Guyon H, Chachignon H, Cahard D. Beilstein J. Org. Chem. 2017; 13: 2764
• 14 Kaboudin B, Ghashghaee M, Bigdeli A, Farkhondeh A, Eskandari M, Esfandiari H. ChemistrySelect 2021; 6: 12998
• 15 Langlois BR, Laurent E, Roidot N. Tetrahedron Lett. 1991; 32: 7525
• 16 Ji Y, Brueckl T, Baxter RD, Fujiwara Y, Seiple IB, Su S, Blackmond DG, Baran PS. Proc. Natl. Acad. Sci. U.S.A. 2011; 108: 14411
• 17 Kumawat S, Natte K. J. Catal. 2024; 434: 115506
• 18 Shen J, Xu J, He L, Liang C, Li W. Chin. Chem. Lett. 2022; 33: 1227
• 19 Lefebvre Q. Synlett 2017; 28: 19
• 20 Li L, Mu X, Liu W, Wang Y, Mi Z, Li C.-J. J. Am. Chem. Soc. 2016; 138: 5809
• 21 Kumawat S, Natte K. Chem. Commun. 2024; 60: 13935
• 22 Tan X, Liu Z, Shen H, Zhang P, Zhang Z, Li C. J. Am. Chem. Soc. 2017; 139: 12430
• 23 Seo S, Taylor JB, Greaney MF. Chem. Commun. 2013; 49: 6385
• 24 Shi G, Shao C, Pan S, Yu J, Zhang Y. Org. Lett. 2015; 17: 38
• 25 Liu J.-B, Xu X.-H, Qing F.-L. Org. Lett. 2015; 17: 5048
• 26 Brochetta M, Borsari T, Gandini A, Porey S, Deb A, Casali E, Chakraborty A, Zanoni G, Maiti D. Chem. Eur. J. 2019; 25: 750
• 27 Liu J, Zhuang S, Gui Q, Chen X, Yang Z, Tan Z. Eur. J. Org. Chem. 2014; 3196
• 28 Yin J, Li Y, Zhang R, Jin K, Duan C. Synthesis 2014; 46: 607
• 29 Guillemard L, Kaplaneris N, Ackermann L, Johansson MJ. Nat. Rev. Chem. 2021; 5: 522
• 30 Castellino NJ, Montgomery AP, Danon JJ, Kassiou M. Chem. Rev. 2023; 123: 8127
• 31 Trifluoromethylation of C–H and S–H Bonds of (Hetero)arenes; General Procedure An oven-dried 20 mL borosilicate glass vial equipped with a magnetic stirrer bar was charged with the appropriate substrate 1 (0.5 mmol), Ag₂O (10 mol%), CF₃CO₂Na (2.0 equiv.), K₂S₂O₈ (3.0 equiv.), and DMSO (4 mL), and the resulting mixture was stirred at r.t. (28 °C) for 24 h. When the reaction was complete, ice-cold H₂O (30 mL) was added and the mixture was extracted with EtOAc (2 × 30 mL). The combined organic phase was washed with sat. brine (2 × 10 mL), dried (Na₂SO₄), filtered, and concentrated in vacuo. The residue was purified by column chromatography [silica gel (230–400 or 60–200 mesh)]. 1,3,7-Trimethyl-8-(trifluoromethyl)-3,7-dihydro-1H-purine-2,6-dione [8-(Trifluoromethyl)caffeine] (2a)¹⁷ Prepared by the general procedure from 1a (0.5 mmol, 97.1 mg) and purified by column chromatography [silica gel (60–200 mesh), hexane–EtOAc (3:1)] to give a white solid; yield: 102.2 mg (78%). ¹H NMR (400 MHz, CDCl₃): δ = 4.14 (s, 3 H), 3.57 (s, 3 H), 3.40 (s, 3 H). ¹⁹F NMR (376 MHz, CDCl₃): δ = –62.41 (s, CF₃). ¹³C NMR (151 MHz, CDCl₃): δ = 155.6, 151.4, 146.6, 139.0 (q, J _C–F = 40.8 Hz), 118.3 (q, J _C–F = 270.3 Hz), 109.8, 33.3, 30.0, 28.3.