Asymmetric Construction of the C(sp³)–SCF₃ Motif by CuH-Catalyzed Hydrofunctionalizations of 1-SCF₃-Alkenes

Abstract

Trifluoromethylthio (SCF₃)-containing molecules are highly valuable in medicinal chemistry and agrochemistry, and efficient synthetic methods for their preparation have thus been developed. However, the asymmetric construction of the C(sp³)–SCF₃ motif still remains largely underdeveloped. Herein, we summarize our recent work on the CuH-catalyzed hydrofunctionalizations of 1-SCF₃-alkenes, which enable the asymmetric synthesis of nontrivial C(sp³)–SCF₃ compounds that are difficult to prepare by other means.

Keywords

Asymmetric catalysis - Copper - Hydrofunctionalization - Organofluorine molecules - Trifluoromethylthio group

Publication History

Received: 11 April 2025

Accepted after revision: 04 July 2025

Accepted Manuscript online:
04 July 2025

Article published online:
30 July 2025

• References


For selected reviews, see:
• 1a Purser S, Moore PR, Swallow S, Gouverneur V. Chem Soc Rev 2008; 37: 320
• 1b Fujiwara T, O’Hagan D. J Fluorine Chem 2014; 167: 16
• 1c Wang J, Sánchez-Roselló M, Aceña JL. et al. Chem Rev 2014; 114: 2432
• 1d Zhou Y, Wang J, Gu Z. et al. Chem Rev 2016; 116: 422
• 1e Meanwell NA. J Med Chem 2018; 61: 5822
• 1f Inoue M, Sumii Y, Shibata N. ACS Omega 2020; 5: 10633
• 1g Ogawa Y, Tokunaga E, Kobayashi O, Hirai K, Shibata N. iScience 2020; 23: 101467

For selected reviews, see:
• 2a Müller K, Faeh C, Diederich F. Science 1881; 2007: 317
• 2b O’hagan D. Chem Soc Rev 2008; 37: 308
• 2c Gillis EP, Eastman KJ, Hill MD, Donnelly DJ, Meanwell NA. J Med Chem 2015; 58: 8315
• 2d Johnson BM, Shu Y-Z, Zhuo X, Meanwell NA. J Med Chem 2020; 63: 6315
• 3 Hansch C, Leo A, Taft RW. Chem Rev 1991; 91: 165
• 4 Hansch C, Leo A, Unger SH, Kim KH, Nikaitani D, Lien EJ. J Med Chem 1973; 16: 1207
• 5 Wishart DS, Feunang YD, Guo AC. et al. Nucleic Acids Res 2018; 46: D1074

For selected reviews, see:
• 6a Xu X-H, Matsuzaki K, Shibata N. Chem Rev 2015; 115: 731
• 6b Barasta-Vallejo S, Bonesi S, Postigo A. Org Biomol Chem 2016; 14: 7150
• 6c Barthelemy A-L, Magnier E, Dagousset G. Synthesis 2018; 50: 4765
• 6d Ghiazza C, Billard T, Tlili A. Chem Eur J 2019; 25: 6482

For a review, see:
• 7a Hardy MA, Chachignon H, Cahard D. Asian J Org Chem 2019; 8: 591

For recent examples:
• 7b Wang Q, Nilsson T, Eriksson L, Szabó KJ. Angew Chem Int Ed 2022; 61: e202210509
• 7c Zhang W, Tian Y, Liu X-D. et al. Angew Chem Int Ed 2024; 63: e202319850
• 7d Hu D-D, Nie T-M, Xiao X. et al. Angew Chem Int Ed 2024; 63: e202400308
• 8a Kojima Y, Nishii Y, Hirano K. Angew Chem Int Ed 2024; 63: e20240337
• 8b Kojima Y, Suda S, Kanna W, Nishii Y, Maeda S, Hirano K. Chem Eur J. 2025 31. e202501210

For pioneering studies on CuH species, see:
• 9a Mahoney WS, Brestensky DM, Stryker JM. J Am Chem Soc 1988; 110: 291
• 9b Ito H, Ishizuka T, Arimoto K, Miura K, Hosomi A. Tetrahedron Lett 1997; 38: 8887

For recent examples, see:
• 9c Romero EA, Olsen PM, Jazzar R, Soleilhavoup M, Gembicky M, Bertrand G. Angew Chem Int Ed 2017; 56: 4024
• 9d Jang WJ, Song SM, Moon JH, Lee JY, Yun J. J Am Chem Soc 2017; 139: 13660
• 9e Speelman AL, Tran BL, Erickson JD, Vasiliu M, Dixon DA, Bullock RM. Chem Sci 2021; 12: 11495
• 9f Carroll TG, Ryan DE, Erickson JD, Bullock RM, Tran BL. J Am Chem Soc 2022; 144: 13865
• 9g Kutateladze DA, Mai BK, Dong Y, Zhang Y, Liu P, Buchwald SL. J Am Chem Soc 2023; 145: 17557

For a review, see:
• 10a Fichez J, Dupommier D, Besset T. Synthesis 2022; 54: 3761

Selected examples:
• 10b Zhang C-P, Vicic DA. Chem Asian J 2012; 7: 1756
• 10c Glenadel Q, Alazet S, Tlili A, Billard T. Chem Eur J 2015; 21: 14694
• 10d Arimori S, Takada M, Shibata N. Dalton Trans 2015; 44: 19456
• 10e Zhang P, Li M, Xue X-S. et al. J Org Chem 2016; 81: 7486
• 10f King ER, Tarrago M, Ghosh A. Catal Sci Technol 2023; 13: 7059
• 11a Rueping M, Tolstoluzhsky N, Nikolaienko P. Chem Eur J 2013; 19: 14043
• 11b Huang Y, Ding J, Wu C, Zheng H, Weng Z. J Org Chem 2015; 80: 2912
• 12a Yagupolskii LM, Kondratenko NV, Sambur VP. Synthesis 1975; 721
• 12b Yang Y, Xu L, Yu S, Liu X, Zhang Y, Vicic DA. Chem Eur J 2016; 22: 858

For a review on (bpy)CuSCF3 reagent, see:
• 13 Huang Y, Zhang M, Lin Q, Weng Z. Synlett 2021; 32: 109
• 14a Pan S, Huang Y, Qing F-L. Chem Asian J 2016; 11: 2854
• 14b Cheng Z-F, Tao T-T, Feng Y-S. et al. J Org Chem 2018; 83: 499
• 14c Zheng C, Huang S, Liu Y. et al. Org Lett 2020; 22: 4868
• 14d Zheng C, Ma M, Huang S. et al. Tetrahedron Lett 2022; 103: 153982
• 14e Kojima Y, Hirano K. Chem Lett 2023; 52: 791
• 15a Noguchi H, Hojo K, Suginome M. J Am Chem Soc 2007; 129: 758
• 15b Wood JL, Marciasini LD, Vaultier M, Pucheault M. Synlett 2014; 25: 551
• 16 Xi Y, Hartwig JF. J Am Chem Soc 2017; 139: 12758

We consider that epimerization of the α-SCF₃ alkyl copper intermediate proceeds via stereoinvertive transmetalation with another copper complex. Related reactions via stereoinvertive Cu/Pd transmetalation:
• 17a Logan KM, Smith KB, Brown MK. Angew Chem Int Ed 2015; 54: 5228
• 17b Semba K, Akiyama K, Zheng H, Kameyama R, Sakaki S, Nakao Y. Angew Chem Int Ed 2016; 55: 6275
• 17c Schuppe AW, Knippel JL, Borrajo-Calleja GM, Buchwald SL. J Am Chem Soc 2021; 143: 5330
• 18a Ohmiya H, Yokoi U, Makida Y, Sawamura M. J Am Chem Soc 2010; 132: 2895
• 18b Nagao K, Yokobori U, Makida Y, Ohmiya H, Masaya S. J Am Chem Soc 2012; 134: 8982
• 19a Bäckvall J-E, Sellén M, Grant B. J Am Chem Soc 1990; 112: 6615
• 19b Bäckvall J-E, Persson ESM, Bombrun A. J Org Chem 1994; 59: 4126
• 19c Yoshikai N, Zhang S-L, Nakamura E. J Am Chem Soc 2008; 130: 12862
• 20a Matsui H, Kojima Y, Hirano K. Chem Lett 2024; 53: upae076
• 20b Matsui H, Kojima Y, Yasui K, Nishii Y, Hirano K. Org Lett 2005; 2025: 27