Recent Advances in the Functionalization of para C(sp²)-H Bonds of Anilines

doi:10.6023/cjoc202511017

Abstract

The direct functionalization of the para C(sp²)-H bond of anilines represents a significant research direction in organic synthesis. Conventionally, achieving selective functionalization at this position has predominantly relied on the pre-protection and activation of the amino group, a process that is not only step-intensive but also severely limits synthetic efficiency and step economy. In recent years, revolutionary progress has been made in this field. The development of diverse strategies, such as transition metal catalysis, organic photoredox catalysis, electrochemical synthesis, and metal-free catalysis, has successfully enabled the direct and highly selective modification of the para C-H bond of anilines, fundamentally overcoming the limitations of traditional approaches. This review aims to systematically outline the research trajectory in this area, providing a detailed summary of the reaction design, mechanistic characteristics, and applications of these catalytic modalities in constructing carbon-carbon and carbon-heteroatom bonds, thereby offering a comprehensive account of the current development and key achievements in this pivotal synthetic transformation.

Key words: Anilines, C-H Functionalization, Site-Selectivity, Transition Metal Catalysis, Photoredox Catalysis

Cite this article

Lewei Dai, Jianling Wang, Dong Zou. Recent Advances in the Functionalization of para C(sp²)-H Bonds of Anilines[J]. Chinese Journal of Organic Chemistry, doi: 10.6023/cjoc202511017.

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References

[1] (a) Lyons T. W.; Sanford, M. S.Chem. Rev.2010,110, 1147
(b) Vanjari R.; Singh, K. N.Chem. Soc. Rev.2015,44, 8062.
[2] Sambiagio C.; Schönbauer D.; Blieck R.; Dao-Huy T.; Pototschnig G.; Schaaf P.; Wiesinger T.; Zia M. F.; Wencel-Delord J.; Besset T.; Maes B. U. W.; Schnürch, M.Chem. Soc. Rev.2018,47, 6603.
[3] (a) Engle K. M.; Mei T.-S.; Wasa M.; Yu, J.-Q.Acc. Chem. Res.2012,45, 788;
(b) Sharma, R.; Thakur, K.; Kumar, R.; Kumar, I.; Sharma, U.Catal. Rev.2015,57, 345;, 5671.
[4] (a) Tsukano, C.Chem. Pharm. Bull.2017,65, 409;
(b) Cai, C.; Zou, D.Chin. J. Org. Chem.2022,42, 1586(in Chinese);
(c) Doraghi F.; Aghanour Ashtiani M. M.; Ameli M.; Larijani B.; Mahdavi M.Chem. Rec.2024,24, e202400116;
(d) Liu, C.-X.; Yin, S.-Y.; Zhao, F.; Yang, H.; Feng, Z.; Gu, Q.; You, S.-L.Chem. Rev.2023,123, 10079.
[5] (a) Gandeepan, P.; Müller, T.; Zell, D.; Cera, G.; Warratz, S.; Ackermann, L.Chem. Rev.2019,119, 2192
(b) Su L.; Yu Z.; Ren P.; Luo Z.; Hou W.; Xu, H.Org. Biomol. Chem.2018,16, 7236;
(c) Zhang, X.; Bai, R.; Xiong, H.; Xu, H.; Hou, W.Bioorg. Med. Chem. Lett.2020,30, 126916.
[6] (a) Zhang J.; Bellomo A.; Creamer A. D.; Dreher S. D.; Walsh, P. J.J. Am. Chem. Soc.2012,134, 13765;
(b) Bellomo, A.; Zhang, J.; Trongsiriwat, N.; Walsh, P. J.Chem. Sci.2013,4, 849;, 6276
(d) Cao X.; Sha S.-C.; Li M.; Kim B.-S.; Morgan C.; Huang R.; Yang X.; Walsh, P. J.Chem. Sci.2016,7, 611;
(e) Li, J.; Wu, C.; Zhou, B.; Walsh, P. J.J. Org. Chem.2018,83, 2993;, 3854.
[7] (a) Yang F.; Zou D.; Chen S.; Wang H.; Zhao Y.; Zhao L.; Li L.; Li J.; Walsh, P. J.Adv. Synth. Catal.2020,362, 3423
(b) Zou D.; Gan L.-S.; Yang F.; Wang J.-M.; Li L.-L.; Li J.Tetrahedron Lett.2020,61, 152532;
(c) Wang, H.; Mao, J.; Shuai, S.; Chen, S.; Zou, D.; Walsh, P. J.; Li, J.Org. Chem. Front.2021,8, 6000.
[8] Huang Y.; Zou, D.Sci. Sin. Chim.2023,53, 932.
[9] Mary A.; Kanagathara N.; Baby Suganthi, A. R.Mater. Proceed.2020,33, 4751.
[10] Arıkan C. C.; Kulabaş N.; Küçükgüzel, İ.J. Pharmaceut. Biomed.2023,223, 115123.
[11] Ni Y.; Liao J.; Qian Z.; Wu C.; Zhang X.; Zhang J.; Xie Y.; Jiang, S.Bioorgan. Med. Chem.2022,53, 116523.
[12] Wang Z.; Wang Y.; Pasangulapati J. P.; Stover K. R.; Liu X.; Schier S.; Weaver, D. F.Eur. J. Med. Chem.2021,222, 113565.
[13] Khan S.; Yaqoob M.; Asad M. H. H. B.; Falak R.; Ashraf Z.; Mannan A.; Bukhari S. M.; Alam F.; Rashid, U.Future Med. Chem.2025,17, 2429.
[14] Li J.-F.; Huang R.-Z.; Yao G.-Y.; Ye M.-Y.; Wang H.-S.; Pan Y.-M.; Xiao, J.-T.Eur. J. Med. Chem.2014,86, 175.
[15] (a) Tomkins P.; Gebauer-Henke E.; Leitner W.; Müller, T. E.ACS Catal.2015,5, 203;
(b) Orlandi, M.; Brenna, D.; Harms, R.; Jost, S.; Benaglia, M.Org. Process Res. Dev.2018,22, 430;, 4530
(d) Zou D.; Wang W.; Hu Y.; Jia, T.Org. Biomol. Chem.2023,21, 2254.
[16] (a) Wang X.; Li Y.; Wang M.; Gao Y.; Ma Z.; Lei A.; Li, W.Chin. J. Catal.2025,72, 392;
(b) Popov, Y. V.; Mokhov, V. M.; Latyshova, S. E.; Nebykov, D. N.; Panov, A. O.; Pletneva, M. Y.Russ. J. Gen. Chem.2017,87, 2276
(c) Ding Y.; Luo S.; Weng C.; An, J.J. Org. Chem.2019,84, 15098.
[17] (a) Wu J.; Darcel C.ChemCatChem2022,14, e202101874;
(b) Doan, S. H.; Nguyen, T. V.Green Chem.2022,24, 7382
(c) Bhunia M.; Sahoo S. R.; Das A.; Ahmed J.; P S.; Mandal, S. K.Chem. Sci.2020,11, 1848.
[18] Zou. D.; Wang W.; Ying, J.Adv. Synth. Catal.2024,366, 1450.
[19] Zou D.; Ying, J.Org. Biomol. Chem.2025, 10.1039/D5OB01461A.
[20] Paras N. A.; MacMillan, D. W. C.J. Am. Chem. Soc.2002,124, 7894.
[21] (a) Leitch J. A.; McMullin C. L.; Paterson A. J.; Mahon M. F.; Bhonoah Y.; Frost, C. G.Angew. Chem. Int. Ed.2017,56, 15131;
(b) Tian, C.; Wang, Q.; Wang, X.; An, G.; Li, G.J. Org. Chem.2019,84, 14241;, 5683.
[22] Brand J. P.; Waser J.Org. Lett.2012,14, 744.
[23] Liang S.; Bolte M.; Manolikakes, G.Chem. Eur. J.2017,23, 96.
[24] Tian C.; Yao X.; Ji W.; Wang Q.; An G.; Li, G.Eur. J. Org. Chem.2018,2018, 5972.
[25] Yin Q.; Klare H. F. T.; Oestreich, M.Angew. Chem. Int. Ed.2016,55, 3204.
[26] Yin Q.; Klare H. F. T.; Oestreich, M.Angew. Chem. Int. Ed.2017,56, 3712.
[27] Doraghi F.; Kalooei Y. M.; Darban N. M. Z.; Larijani B.; Mahdavi, M.J. Organomet. Chem.2024,1019, 123313.
[28] Jacob C.; Annibaletto J.; Maes B. U. W.; Evano G.Synthesis2023,55, 1799.
[29] (a) Tischler M. O.; Tóth M. B.; Novák Z.Chem. Rec.2017,17, 184;
(b) Al Mamari, H. H.Reactions2024,5, 318.
[30] (a) Gillis E. P.; Eastman K. J.; Hill M. D.; Donnelly D. J.; Meanwell, N. A.J. Med. Chem.2015,58, 8315
(b) Meanwell, N. A.J. Med. Chem.2018,61, 5822.
[31] Yang Z.; Pei C.; Koenigs, R. M.Org. Lett.2020,22, 7234.
[32] Nie X.-D.; Mao Z.-Y.; Guo J.-M.; Si C.-M.; Wei B.-G.; Lin, G.-Q.J. Org. Chem.2022,87, 2380.
[33] (a) Chatupheeraphat A.; Rueping M.; Magre M.Org. Lett.2019,21, 9153
(b) Manikandan R.; Jeganmohan M.Org. Lett.2014,16, 912.
[34] Lichte D.; Pirkl N.; Heinrich G.; Dutta S.; Goebel J. F.; Koley D.; Gooßen, L. J.Angew. Chem. Int. Ed.2022,61, e202210009.
[35] (a) Chen Y.-L.; Fang K.-C.; Sheu J.-Y.; Hsu S.-L.; Tzeng, C.-C.J. Med. Chem.2001,44, 2374
(b) Hegab M. I.; Abdel-Fattah A.-S. M.; Yousef N. M.; Nour H. F.; Mostafa A. M.; Ellithey M.Arch. Pharm.2007,340, 396;
(c) Mallick, S.; Dutta, A.; Ghosh, J.; Maiti, S.; Mandal, A. K.; Banerjee, R.; Bandyopadhyay, C.; Pal, C.Chemotherapy2011,57, 388;, 16.
[36] Shen G.; Wang Z.; Huang X.; Hong M.; Fan S.; Lv X.Org. Lett.2020,22, 8860.
[37] Jana S.; Empel C.; Pei C.; Aseeva P.; Nguyen T. V.; Koenigs, R. M.ACS Catal.2020,10, 9925.
[38] (a) Arredondo V.; Hiew S. C.; Gutman E. S.; Premachandra I. D. U. A.; VanβVranken, D. L.Angew. Chem. Int. Ed.2017,56, 4156
(b) Shen H.-Q.; Wu B.; Xie H.-P.; Zhou Y.-G.Org. Lett.2019,21, 2712;
(c) Shen, H.-Q.; Xie, H.-P.; Sun, L.; Zhou, Y.-G.Organometallics2019,38, 3902.
[39] Gao L.; Liu S.; Wang Z.-C.; Mao Y.; Shi, S.-L.Asian J. Org. Chem.2022,11, e202100723.
[40] Zhu D.-X.; Xia H.; Liu J.-G.; Chung L. W.; Xu, M.-H.J. Am. Chem. Soc.2021,143, 2608.
[41] (a) Chen D.; Zhang X.; Qi W.-Y.; Xu B.; Xu, M.-H.J. Am. Chem. Soc.2015,137, 5268
(b) Chen D.; Zhu D.-X.; Xu, M.-H.J. Am. Chem. Soc.2016,138, 1498.
[42] Li Z.-Y.; Zhang J.-P.; Ying Y.-Y.; Yan D.; Jiao L.; Hao E.Org. Lett.2022,24, 7888.
[43] Akritopoulou-Zanze, I.; Patel, J. R.; Hartandi, K.; Brenneman, J.; Winn, M.; Pratt, J. K.; Grynfarb, M.; Goos-Nisson, A.; von Geldern, T. W.; Kym, P. R.Bioorg. Med. Chem. Lett.2004,14, 2079.
[44] Zhang F.-L.; Hong K.; Li T.-J.; Park H.; Yu J.-Q.Science2016,351, 252.
[45] (a) Rej S.; Chatani, N.J. Am. Chem. Soc.2021,143, 2920
(b) Song H.; Li Y.; Yao Q.-J.; Jin L.; Liu L.; Liu Y.-H.; Shi, B.-F.Angew. Chem. Int. Ed.2020,59, 6576.
[46] Chen Q.; Huang T.; Shao Y.; Tang S.; Sun, J.J. Org. Chem.2023,88, 3308.
[47] Ge Z.; Lu B.; Teng H.; Wang, X.Chem. Eur. J.2023,29, e202202820.
[48] Zhou J.; Li Z.-H.; Wang L.; Kang J.-C.; Wang X.-H.; Zhang S.-Y.Org. Lett.2021,23, 9353.
[49] Choi S.; Choi Y.; Kim Y.; Lee J.; Lee, S. Y.J. Am. Chem. Soc.2023,145, 24897.
[50] Wang X.-J.; Cheng Y.-H.; Lv X.-Y.; Liang L.-Y.; An G.-H.; Li G.-M.Chin. Chem. Lett. 2025, doi: https://doi.org/10.1016/j.cclet.2025.112154.
[51] Xiong B.; Xu S.; Xu W.; Liu Y.; Zhang L.; Tang K.-W.; Yin S.-F.; Wong, W.-Y.Org. Chem. Front.2022,9, 3807.
[52] Ghosh S.; Saha S. N.; Baidya M.Org. Lett.2023,25, 5073.
[53] Luo R.; Liang Y.; Wang S.; Liao J.; Ouyang L.J. Catal.2023,428, 115184.
[54] Yuan C.; Zhang W.; Zang W.; Zhu L.; Yu Y.; Han X.Org. Lett. 2025, doi.org/10.1021/acs.orglett.5c04333.
[55] (a) Montero Bastidas J. R.; Oleskey T. J.; Miller S. L.; Smith, M. R., III; Maleczka, R. E., Jr.J. Am. Chem. Soc.2019,141, 15483;
(b) Mihai, M. T.; Williams, B. D.; Phipps, R. J.J. Am. Chem. Soc.2019,141, 15477.
[56] Haldar C.; Bisht R.; Chaturvedi J.; Guria S.; Hassan M. M. M.; Ram B.; Chattopadhyay B.Org. Lett.2022,24, 8147.
[57] Tanemura, K.Tetrahedron2025,176, 134544.
[58] (a) Yuan Y.; Cao Y.; Qiao J.; Lin Y.; Jiang X.; Weng Y.; Tang S.; Lei, A.Chin. J. Chem.2019,37, 49;
(b) Hua, J.; Fang, Z.; Xu, J.; Bian, M.; Liu, C.; He, W.; Zhu, N.; Yang, Z.; Guo, K.Green Chem.2019,21, 4706
(c) Zhao Z.; Yan H.; Zhou Y.; Xue W.; Gu L.; Zhang, S.Chin. J. Chem.2024,42, 2049;
(d) Zhang, C.; Han, Z.; Zhao, Z.; Zhou, Y.; Gu, L.Org. Lett.2025,27, 9121.
[59] Luo M.-J.; Li Y.; Ouyang X.-H.; Li J.-H.; He D.-L.Chem. Commun.2020,56, 2707.
[60] (a) Matsumoto K.; Yoshida M.; Shindo, M.Angew. Chem. Int. Ed.2016,55, 5272
(b) Matsumoto K.; Takeda S.; Hirokane T.; Yoshida M.Org. Lett.2019,21, 7279.
[61] Liu X.; Cai T.-C.; Guo D.; Wang B.-B.; Ying S.; Wang H.; Tang S.; Shen Q.; Gui Q.-W.Tetrahedron Lett.2021,70, 153021.
[62] Zhang C.; Zhou Y.; Zhao Z.; Xue W.; Gu L.Chem. Commun.2022,58, 13951.
[63] Yu J.; Li T.; Sun Q.; Wang Z.RSC Adv.2025,15, 12042.
[64] Lv X.; Cheng Y.; Zong Y.; Wang Q.; An G.; Wang J.; Li G.ACS Catal.2023,13, 7310.
[65] (a) Cheng Y.; He Y.; Zheng J.; Yang H.; Liu J.; An G.; Li, G.Chin. Chem. Lett.2021,32, 1437
(b) Fan W.-T.; Li Y.; Wang D.; Ji S.-J.; Zhao, Y.J. Am. Chem. Soc.2020,142, 20524.
[66] Cheng Y.; Zhang X.; An G.; Li G.; Yang, Z.Chin. Chem. Lett.2023,34, 107625.
[67] Das B.; Sahoo S. R.; Das A.; Pathak B.; Sarkar D.Org. Lett.2023,25, 7733.
[68] Liu R.;Tong, H. e.; Li, Y.; Shi, W.-Y.; Guo, H.; Zhou, R.J. Org. Chem. 2025, doi.org/10.1021/acs.joc.5c02448.
[69] Jiang Y.; Li B.; Ma N.; Shu S.; Chen Y.; Yang S.; Huang Z.; Shi D.; Zhao, Y.Angew. Chem. Int. Ed.2021,60, 19030.
[70] Motiwala H. F.; Fehl C.; Li S.-W.; Hirt E.; Porubsky P.; Aubé, J.J. Am. Chem. Soc.2013,135, 9000.
[71] Tian Y.; Xu X.; Zhang L.; Qu J.Org. Lett.2016,18, 268.
[72] Zhu Y.; Colomer I.; Thompson A. L.; Donohoe, T. J.J. Am. Chem. Soc.2019,141, 6489.
[73] Champagne P. A.; Benhassine Y.; Desroches J.; Paquin, J.-F.Angew. Chem. Int. Ed.2014,53, 13835.
[74] Nielsen C. D. T.; White A. J. P.; Sale D.; Bures J.; Spivey, A. C.J. Org. Chem.2019,84, 14965.
[75] Colomer, I.ACS Catal.2020,10, 6023.
[76] Corral Suarez C.; Colomer I.Chem. Sci.2023,14, 12083.
[77] Winfrey L.; Yun L.; Passeri G.; Suntharalingam K.; Pulis, A. P.Chem. Eur. J.2024,30, e202303130.
[78] Kumar G.; Qu Z.-W.; Grimme S.; Chatterjee I.Org. Lett.2021,23, 8952.
[79] Li X.; Zhu Y.; Gong Z.; Li J.; Xie J.; Zhao Z.; Li J.; Jia C.Green Chem.2024,26, 10969.
[80] (a) Li L.; Liu J.; Zhu L.; Cutler S.; Hasegawa H.; Shan B.; Medina, J. C.Bioorg. Med. Chem. Lett.2006,16, 1638
(b) Cheng J.-F.; Chen M.; Wallace D.; Tith S.; Haramura M.; Liu B.; Mak C. C.; Arrhenius T.; Reily S.; Brown S.; Thorn V.; Harmon C.; Barr R.; Dyck J. R. B.; Lopaschuk G. D.; Nadzan, A. M.J. Med. Chem.2006,49, 1517;
(c) Nishiyama, Y.; Mori, S.; Makishima, M.; Fujii, S.; Kagechika, H.; Hashimoto, Y.; Ishikawa, M.ACS Med. Chem. Lett.2018,9, 641.
[81] Li X.; Wu Y.; Li J.; Xie J.; Liu J.; Wen Z.; Zhao Z.; Jia C.Green Chem.2025,27, 7234.
[82] Yang J.; Liu S.; Gui J.; Xiong D.; Li J.; Wang Z.; Ren, J.J. Org. Chem.2022,87, 6352.
[83] Teli Y. A.; Reetu R.; Chanu S. A.; Kant K.; Keremane K. S.; Almeer R.; Singh V.; Malakar, C. C.Chem Asian J.2024,19, e202400635.
[84] Teli Y. A.; Reetu R.; Gujjarappa R.; Banerjee S.; Ghanta S.; Patel M. J.; Singh V.; Al-Zaqri N.; Sengupta R.; Malakar, C. C.Eur. J. Org. Chem.2024,27, e202301086.
[85] Zhu L.; Ren Y.; Liu X.; Xu S.; Li T.; Xu W.; Li Z.; Liu Y.; Xiong, B.Chem Asian J.2023,18, e202300792.
[86] Huang P.; Jiang X.; Gao D.; Wang C.; Shi D.-Q.; Zhao, Y.Org. Chem. Front.2023,10, 2476.
[87] Hu H.-L.; Chen P.; Niu Y.-D.; Li M.-Y.; Shi J.; Jiang Y.-J.Synlett2024,36, 739.
[88] (a) Bai H.-Y.; Tan F.-X.; Liu T.-Q.; Zhu G.-D.; Tian J.-M.; Ding T.-M.; Chen Z.-M.; Zhang S.-Y.Nat. Commun.2019,10, 3063
(b) Akiyama T.; Itoh J.; Yokota K.; Fuchibe, K.Angew. Chem. Int. Ed.2004,43, 1566.
[89] Liu C.; Tan F.-X.; Zhou J.; Bai H.-Y.; Ding T.-M.; Zhu G.-D.; Zhang S.-Y.Org. Lett.2020,22, 2173.
[90] Li Z.-H.; Zhou J.; Liu C.; Tan F.-X.; Wang L.; Zhu G.-D.; Zhang S.-Y.Chem Catal.2024,4, 100918.
[91] Zhang M.; Qu X.-Y.; Li R.-R.; Lin B.; Liu X.-L.; Zhao, J.-Q.J. Org. Chem.2025,90, 10702.
[92] Zhang R.-L.; Liu B.; Qiu K.-X.; Li H.-T.; Zhang H.-N.; Shen B.-C.; Sun Z.-W.Org. Lett.2023,25, 1711.
[93] Parida C.; Granda J. M.Org. Lett. 2025, doi.org/10.1021/acs.orglett.5c04100.
[94] Albert-Soriano M.; Hernández-Martínez L.; Pastor, I. M.ACS Sustainable Chem. Eng.2018,6, 14063.
[95] Gisbert P.; Albert-Soriano M.; Pastor, I. M.Eur. J. Org. Chem.2019,2019, 4928.
[96] Albert-Soriano M.;M. Pastor,I.Adv. Synth. Catal.2020,362, 2494.
[97] Ponpao N.; Senapak W.; Saeeng R.; Jaratjaroonphong J.; Sirion U.RSC Adv.2021,11, 22692.
[98] Jiang X.; Shen Z.; Zheng C.; Fang L.; Chen K.; Yu C.Tetrahedron Lett.2020,61, 152141.
[99] (a) Yang D.; Yan K.; Wei W.; Zhao J.; Zhang M.; Sheng X.; Li G.; Lu S.; Wang, H.J. Org. Chem.2015,80, 6083
(b) Wang H.-H.; Shi T.; Gao W.-W.; Wang Y.-Q.; Li J.-F.; Jiang Y.; Hou Y. S.; Chen C.; Peng X.; Wang, Z.Chem. Asian J.2017,12, 2675.
[100] Zhao W.; Zhang F.; Deng, G.-J.J. Org. Chem.2021,86, 291.
[101] Das M.; Kumar V.; Venkatesh C.; Gandeepan P.J. Org. Chem. 2025, doi.org/10.1021/acs.joc.5c01976.
[102] Xu J.; Huang L.; He L.; Liang C.; Ouyang Y.; Shen J.; Jiang M.; Li W.Green Chem.2021,23, 6632.
[103] Bovonsombat P.; Hocks A.; Kittithanaluk P.; We J. T.; Khanthapura P.; Choosakoonkriang S.; Srikamhom N.; Ploymanee F.ChemistrySelect2025,10, e202500544.
[104] Zhou Y.; Jones A. M.Molecules2024,29, 1445.

芳胺对位C(sp²)-H键官能团化研究进展