三氟甲氧基化反应研究进展

doi:10.6023/cjoc202604036

摘要/Abstract

含氟有机化合物在制药、农用化学品及材料科学领域的重要性日益凸显. 其中, 三氟甲氧基(OCF₃)结构单元因其良好的代谢稳定性、适中的亲脂性以及独特的电子效应备受青睐并得到广泛应用. 近年来, 已成功开发了一系列用于构建含OCF₃有机分子的创新性合成策略. 汤平平课题组长期致力于三氟甲氧基化试剂与方法的研究. 重点论述了2021~2026年间该小组在三氟甲氧基化反应领域取得的研究成果, 并评述了这些方法在功能分子构建中的应用.

关键词: 三氟甲氧基, 苯磺酸三氟甲酯(TFMS), N-OCF₃双功能试剂

Fluorinated organic compounds are playing an increasingly vital role in pharmaceuticals, agrochemicals, and materials science. With superior metabolic stability, moderate lipophilicity, and unique electronic effects, the trifluoromethoxy (OCF₃) group is a highly valued structural motif. In recent years, a variety of innovative synthetic strategies have been developed for the efficient construction of OCF₃-containing organic molecules. Tangʼs group has long been dedicated to the development of novel trifluoromethoxylation reagents and methodologies. The recent progress of Tangʼs group in the field of trifluoromethoxylation reactions achieved between 2021 and 2026 is summarized, with a particular focus on the application of these methods in the synthesis of functional molecules.

Key words: trifluoromethoxylation, trifluoromethyl aryl sulfonate (TFMS), bifunctional N-OCF₃ reagent

引用此文

马占彩, 汤平平. 三氟甲氧基化反应研究进展[J]. 有机化学, 2026, 46(9): 3559-3577.

Zhancai Ma, Pingping Tang. Advances in Trifluoromethoxylation Reactions[J]. Chinese Journal of Organic Chemistry, 2026, 46(9): 3559-3577.

导出引用 EndNote|Reference Manager|ProCite|BibTeX|RefWorks

分享此文

图/表 19

图1. 含有三氟甲氧基的代表性医药和农药分子

Figure 1. Representative pharmaceutical and agrochemical molecules containing trifluoromethoxy group

图2. 代表性三氟甲氧基试剂

Figure 2. Representative trifluoromethoxylating reagents

图式1. 导向基辅助的芳基C—H三氟甲氧基化

Scheme 1. Directing-group-assisted aryl C—H trifluoromethoxylation

图式2. 芳基卤化物的三氟甲氧基化

Scheme 2. Trifluoromethoxylation of aryl halides

图式3. 苯酚的三氟甲氧基化

Scheme 3. Trifluoromethoxylation of phenols

图式4. 四氟硼酸二芳基碘鎓的三氟甲氧基化

Scheme 4. Trifluoromethoxylation of diaryliodonium tetrafluoroborates

图式5. 末端炔烃二溴三氟甲氧基化

Scheme 5. Dibromotrifluoromethoxylation of terminal alkynes

图式6. 丙炔磺酸盐的对映选择性三氟甲氧基化

Scheme 6. Enantioselective trifluoromethoxylation of propargyl sulfonates

图式7. 三氯乙酰亚胺烯丙基酯的对映选择性三氟甲氧基化

Scheme 7. Enantioselective trifluoromethoxylation of allylic trichloroacetimidates

图式8. 芳香烯烃的对映选择性氢三氟甲氧基化

Scheme 8. Enantioselective hydrotrifluoromethoxylation of aromatic alkenes

图式9. 氮丙啶的三氟甲氧基化

Scheme 9. Trifluoromethoxylation of aziridines

图式10. 吲哚的脱芳香三氟甲氧基化

Scheme 10. Dearomative trifluoromethoxylation of indoles

图式11. 联烯基三氯乙酰亚胺酯的三氟甲氧基化

Scheme 11. Trifluoromethoxylation of allenylic trichloroacetimidates

图式12. 联烯的溴代三氟甲氧基化

Scheme 12. Bromotrifluoromethoxylation of allenes

图式13. Pummerer重排法构建α-三氟甲氧基硫醚

Scheme 13. Construction of α‑trifluoromethoxy sulfides via Pummerer rearrangement

图式14. 双环[1.1.0]丁烷的顺式立体选择性三氟甲氧基化

Scheme 14. syn-Stereoselective trifluoromethoxylation of bicyclo[1.1.0]butanes

图式15. 芳环丙烷的1,3-双三氟甲氧基化和1,3-氟三氟甲氧基化

Scheme 15. 1,3-Ditrifluoromethoxylation and 1,3-fluorotrifluoromethoxylation of arylcyclopropanes

图式16. 苯乙烯的光氧化还原酰胺基三氟甲氧基化

Scheme 16. Photoredox amido-trifluoromethoxylation of styrenes

图式17. 三氟甲氧基化反应研究进展(2021~2026)

Scheme 17. Advances in trifluoromethoxylation reactions (2021~2026)

参考文献 42

[1]	(a) Kalita, S. J.; Qi, J.; Xiao, L.; Saha, D.; Huang, Y. Y.; Shibata, N. Chem. Rev. 2025, 125, 8477. doi: 10.1021/acs.chemrev.5c00177
	(b) Zhang, C.; Yan, K.; Fu, C.; Peng, H.; Hawker, C. J.; Whittaker, A. K. Chem. Rev. 2022, 122, 167. doi: 10.1021/acs.chemrev.1c00632
	(c) Han, J.; Kiss, L.; Mei, H.; Remete, A. M.; Ponikvar-Svet, M.; Sedgwick, D. M.; Roman, R.; Fustero, S.; Moriwaki, H.; Soloshonok, V. A. Chem. Rev. 2021, 121, 4678. doi: 10.1021/acs.chemrev.0c01263
[2]	(a) Leo, A.; Hansch, C.; Elkins, D. Chem. Rev. 1971, 71, 525. doi: 10.1021/cr60274a001
	(b) Hansch, C.; Leo, A.; Taft, R. W. Chem. Rev. 1991, 91, 165. doi: 10.1021/cr00002a004
[3]	(a) Federsel, D.; Herrmann, A.; Christen, D.; Sander, S.; Willner, H.; Oberhammer, H. J. Mol. Struct. 2001, 567-568, 127. doi: 10.1016/S0022-2860(01)00541-5
	(b) Klocker, J.; Karpfen, A.; Wolschann, P. Chem. Phys. Lett. 2003, 367, 566. doi: 10.1016/S0009-2614(02)01786-4
	(c) Manteau, B.; Genix,, P.; Brelot, L.; Vors, J. P.; Pazenok, S.; Giornal, F.; Leuenberger, C.; Leroux, F. R. Eur. J. Org. Chem. 2010, 2010, 6043. doi: 10.1002/ejoc.v2010:31
[4]	(a) Manteau, B.; Pazenok, S.; Vors, J. P.; Leroux, F. R. J. Fluorine Chem. 2010, 131, 140. doi: 10.1016/j.jfluchem.2009.09.009
	(b) Landelle, G.; Panossian, A.; Leroux, R. F. Curr. Top. Med. Chem. 2014, 14, 941. doi: 10.2174/1568026614666140202210016
	(c) Chen, Y.; Zhang, A. F.; Wang, W. X.; Zhang, Y.; Gao, T. C. Ann. Appl. Biol. 2012, 161, 247. doi: 10.1111/aab.2012.161.issue-3
	(d) Meanwell, N. A. J. Med. Chem. 2018, 61, 5822. doi: 10.1021/acs.jmedchem.7b01788
[5]	(a) Besset, T.; Jubault,, P.; Pannecoucke, X.; Poisson, T. Org. Chem. Front. 2016, 3, 1004. doi: 10.1039/C6QO00164E
	(b) Yagupol'skii, L. M. Dokl. Akad. Nauk SSSR 1955, 105, 100.
	(c) Mathey, F.; Bensoam, J. Tetrahedron Lett. 1973, 25, 2253. doi: 10.1016/S0040-4039(01)80225-2
	(d) Kuroboshi, M.; Kanie, K.; Hiyama, T. Adv. Synth. Catal. 2001, 343, 235. doi: 10.1002/(ISSN)1615-4169
	(e) Shimizu, M.; Hiyama, T. Angew. Chem., Int. Ed. 2005, 44, 214. doi: 10.1002/anie.v44:2
[6]	(a) Si, Y. F.; Tang, P. P. Chin. J. Chem. 2023, 41, 2179. doi: 10.1002/cjoc.v41.17
	(b) Zheng, W.; Liu, F. X.; Zhao, H. Q.; Xu, Y.; Chen, N.; Liu, Y. J. Chin. J. Org. Chem. 2024, 44, 3321 (in Chinese). doi: 10.6023/cjoc202403011
	(郑威, 刘凤雪, 赵红琼, 许颖, 陈宁, 刘颖杰, 有机化学, 2024, 44, 3321.) doi: 10.6023/cjoc202403011
[7]	(a) Noftle, R. E.; Cady, G. H. Inorg. Chem. 1965, 4, 1010. doi: 10.1021/ic50029a019
	(b) Ran, L. Y.; Zhang, C. P. Chin. J. Org. Chem. 2022, 42, 2045 (in Chinese). doi: 10.6023/cjoc202202025
	(冉龙玉, 张成潘, 有机化学, 2022, 42, 2045.) doi: 10.6023/cjoc202202025
[8]	Kolomeitsev, A. A.; Vorobyev, M.; Gillandt, H. Tetrahedron Lett. 2008, 49, 449. doi: 10.1016/j.tetlet.2007.11.105
[9]	Marrec, O.; Billard, T.; Vors, J. P.; Pazenok, S.; Langlois, B. R. Adv. Synth. Catal. 2010, 352, 2831. doi: 10.1002/adsc.v352:16
[10]	Zhang, C. P.; Vicic, D. A. Organometallics 2012, 31, 7812. doi: 10.1021/om3002747
[11]	Chen, S. X.; Huang, Y. J.; Fang, X.; Li, H. L.; Zhang, Z. X.; Hor, T. S. A.; Weng, Z. Q. Dalton Trans. 2015, 44, 19682. doi: 10.1039/C5DT02078F
[12]	(a) Koller, R.; Huchet, Q.; Battaglia,, P.; Welch, J. M.; Togni, A. Chem. Commun. 2009, 5993.
	(b) Guo, S.; Cong, F.; Guo, R.; Wang, L.; Tang, P. P. Nat. Chem. 2017, 9, 546. doi: 10.1038/nchem.2711
[13]	Zhou, M.; Ni, C. F.; Zeng, Y. W.; Hu, J. B. J. Am. Chem. Soc. 2018, 140, 6801. doi: 10.1021/jacs.8b04000 pmid: 29787259
[14]	Chen, D. Q.; Lu, L.; Shen, Q. L. Org. Chem. Front. 2019, 6, 1801. doi: 10.1039/C9QO00278B
[15]	Li, Y.; Yang, Y.; Xin, J. R.; Tang, P. P. Nat. Commun. 2020, 11, 755. doi: 10.1038/s41467-020-14598-1 pmid: 32029731
[16]	Newton, J. J.; Jelier, B. J.; Meanwell, M.; Martin, R. E.; Britton, R.; Friesen, C. M. Org. Lett. 2020, 22, 1785. doi: 10.1021/acs.orglett.0c00099
[17]	Lu, Z. C.; Kumon, T.; Hammond, G. B.; Umemoto, T. Angew. Chem., Int. Ed. 2021, 60, 16171. doi: 10.1002/anie.202104975 pmid: 34010513
[18]	(a) Duran-Camacho, G.; Ferguson, D. M.; Kampf, J. W.; Bland, D. C.; Sanford, M. S. Org. Lett. 2021, 23, 5138. doi: 10.1021/acs.orglett.1c01664
	(b) Bonnefoy, C.; Chefdeville, E.; Panosian, A.; Hanquet, G.; Leroux, F. R.; Toulgoat, F.; Billard, T. Chem.-Eur. J. 2021, 27, 15986. doi: 10.1002/chem.v27.64
[19]	Yuan, W. J.; Tong, C. L.; Xu, X. H.; Qing, F. L. J. Org. Chem. 2023, 88, 4434. doi: 10.1021/acs.joc.2c03031
[20]	Chen, D. Q.; Luo, Y. R.; Lu, L.; Shen, Q. L. Organometallics. 2024, 43, 3132.
[21]	Zhang, K. X.; Zhao, M. X.; Guo, J. X.; Luan, Y. X.; Tang, P. P. CCS Chem. 2026, 8, 1276. doi: 10.31635/ccschem.025.202506759
[22]	Kellogg, K. B.; Cady, G. H. J. Am. Chem. Soc. 1948, 70, 3986. doi: 10.1021/ja01192a006
[23]	(a) Porter, R. S.; Cady, G. H. J. Am. Chem. Soc. 1957, 79, 5628. doi: 10.1021/ja01578a013
	(b) Roberts, H. L. J. Chem. Soc. 1964, 4538.
[24]	(a) Zheng, W. J.; Morales-Rivera, C. A.; Lee, J. W.; Liu, P.; Ngai, M.-Y. Angew. Chem., Int. Ed. 2018, 57, 9645. doi: 10.1002/anie.v57.31
	(b) Zheng, W. J.; Lee, J. W.; Morales-Rivera, C. A.; Liu, P.; Ngai, M.-Y. Angew. Chem., Int. Ed. 2018, 57, 13795. doi: 10.1002/anie.v57.42
[25]	Jelier, B. J.; Tripet, P. F.; Pietrasiak, E.; Franzoni, I.; Jeschke, G.; Togni, A. Angew. Chem., Int. Ed. 2018, 57, 13784. doi: 10.1002/anie.v57.42
[26]	Guo, L.; Fang, R. J.; Liu, Y.; Zhao, Z. B.; Ye, N. C.; Deng, Z. J.; Altaf, M. B.; Tang, P. P. Org. Biomol. Chem. 2025, 23, 9336. doi: 10.1039/D5OB01162K
[27]	Zhou, J. Y.; Chen, L. H.; Miao, Z. A. Li, J. J.; Luan, Y. X.; Chen, L.; Tang, P. P. J. Am. Chem. Soc. 2025, 147, 38979. doi: 10.1021/jacs.5c11167
[28]	Zhou, J. Y.; Li, J. Y.; Su, C. J.; Luan, Y. X.; Huang, Q. Y.; Tang, P. P. J. Am. Chem. Soc. 2026, 148, 8087. doi: 10.1021/jacs.6c00511
[29]	Li, J. J.; Zhao, M. X.; Huang, Q. Y.; Tang, P. P. J. Org. Chem. 2026, 91, 3031. doi: 10.1021/acs.joc.5c03177
[30]	Wang, F.; Guo, Y. C.; Zhang, Y. T.; Tang, P. P. ACS Catal. 2021, 11, 3218. doi: 10.1021/acscatal.1c00090
[31]	Altaf, M. B.; Zhao, M. X.; Guo, L.; Luan, Y. X.; Tang, P. P. J. Org. Chem. 2025, 90, 10748. doi: 10.1021/acs.joc.5c01052
[32]	Altaf, M. B.; Huang, Q. Y.; Tang, P. P. Org. Chem. Front. 2026, 13, 2817. doi: 10.1039/D6QO00025H
[33]	Hou, Y. D.; Zhang, Z.; Sun, X. Y.; Yang, Z.; Luan, Y. X.; Tang, P. P. Angew. Chem., Int. Ed. 2023, 62, e202218919. doi: 10.1002/anie.v62.18
[34]	Wang, L. Y.; Si, Y. F.; Luan, Y. X.; Tang, P. P. CCS Chem. 2024, 6, 1885. doi: 10.31635/ccschem.024.202404011
[35]	Si, Y. F.; Liu, Y. T.; Zhou, F.; Fang, L.; Wu, K.; Luan, Y. X.; Chen, L.; Tang, P. P. Angew. Chem., Int. Ed. 2025, 64, e202501680. doi: 10.1002/anie.v64.24
[36]	Xin, J. R.; Deng, X. Y.; Tang, P. P. Org. Lett. 2022, 24, 881. doi: 10.1021/acs.orglett.1c04226
[37]	Deng, Z. J.; Meng, L. D.; Bing, X.; Niu, S. X.; Zhang, X. F.; Peng, J. Q.; Luan, Y. X.; Chen, L.; Tang, P. P. J. Am. Chem. Soc. 2024, 146, 2325. doi: 10.1021/jacs.3c11653
[38]	Hou, Y. D.; Luo, Y. C.; Tang, P. P. Org. Lett. 2024, 26, 9764. doi: 10.1021/acs.orglett.4c03676
[39]	Liu, R. Hou, Y. D.; Tang, P. P. Org. Chem. Front. 2025, 12, 3960. doi: 10.1039/D4QO02426E
[40]	Zhao, M. X.; Zhou, Z. Y.; Tang, P. P. Org. Biomol. Chem. 2025, 23, 6127. doi: 10.1039/D5OB00673B
[41]	Yang, P. F.; Chen, S. H.; Lu, J. X.; Ning, P. F.; Zhao, W. Q.; Luan, Y. X.; Chen, L.; Xu, X. F.; Tang, P. P. Org. Lett. 2025, 27, 7679. doi: 10.1021/acs.orglett.5c02396
[42]	Zhou, F.; Fang, L.; Si, Y. F.; Huang, Q. Y.; Tang, P. P. Org. Lett. 2026, 28, 224. doi: 10.1021/acs.orglett.5c04608