Recent Progress in Selective C—H Chlorination

doi:10.6023/cjoc202406030

Abstract

The importance of organic chlorides in pharmaceutical, material, and synthetic chemistry has made the constru- ction of C—Cl bonds a significant focus in organic chemistry. The cleavage and functionalization of C—H bonds with high atomic efficiency, leading to direct conversion into desired functional groups, is seen as a promising approach for creating new substances. Recent advancements in C—H bond activation/tranformation have led to the development of C—H chlorination reactions as viable alternatives to traditional halogenation methods. This review provides an overview of the progress made in C—H bond chlorination reactions over the last decade.

Key words: chlorination, C—H bonds, selective, umpolung

Cite this article

Juanjuan Wang, Yan Shi, Yingxian Tian, Bingxian Liu. Recent Progress in Selective C—H Chlorination[J]. Chinese Journal of Organic Chemistry, 2025, 45(2): 574-591.

Export EndNote|Reference Manager|ProCite|BibTeX|RefWorks

share this article

Fig. & Tab. 44

Scheme 1. Conversions of chlorides

Scheme 2. C—H chlorination reaction

Scheme 3. Selective C(sp2)—H chlorination catalyzed by aniline

Scheme 4. Lewis base catalyzed chlorination of aromatic hydrocarbons and heterocyclic C(sp2)—H

Scheme 5. BHT catalyzed chlorination of aromatic hydrocarbons and heterocyclic C(sp2)—H

Scheme 6. Lewis catalyst controlled regioselective C(sp2)—H chlorination of phenol

Scheme 7. High practicality of ammonium salt catalyzed ortho-selective C(sp2)—H chlorination of phenol

Scheme 8. Chlorination reaction of (hetero) aromatic hydrocarbons catalyzed by dimethyl sulfoxide

Scheme 9. Ruthenium catalyzed ortho-selective functionalization of aromatic hydrocarbons with dual C(sp2)—H bonds

Scheme 10. Ru catalyzed C(sp2)—H chlorination reaction

Scheme 11. Copper catalyzed selective remote C(sp2)—H chlorination

Scheme 12. Site selective C(sp2)—H chlorination of (hetero) aromatic hydrocarbons through transient asymmetric iodine

Scheme 13. Iodine(III)/AlCl3 mediated electrophilic C(sp2)—H chlorination of aromatic hydrocarbons

Scheme 14. In situ generation of chlorinated aromatic hydrocarbons using high valent iodine reagents

Scheme 15. Photocatalytic chlorination of aromatic hydrocarbons C(sp2)—H

Scheme 16. In situ bromination oxidation of electron rich aromatic hydrocarbons and C(sp2)—H chlorination

Scheme 17. Visible light catalytic activation of aromatic and heteroaromatic chlorination

Scheme 18. Photoredox catalytic oxidation of C(sp2)—H chlorination

Scheme 19. C(sp2)—H chlorination of (hetero)anilines via photo/organo co-catalysis

Scheme 20. Mechanism and application of selective oxidation of Z-type C(sp2)—H chlorination of acrylamide

Scheme 21. Electrochemical selectivity of thiophene for C(sp2)—H monochlorination and polychlorination

Scheme 22. Pd promoted ortho-C(sp2)—H chlorination of azobenzene

Scheme 23. Pd catalyzed ortho-C(sp2)—H chlorination reaction of benzonitrile

Scheme 24. Regional selectivity of C(sp2)—H chlorination with pyridine as the directing group

Scheme 25. Selective chlorination of 1,2-dichloroethane at the C(sp2)—H position catalyzed by rhodium as a chlorine source

Scheme 26. Targeted C(sp2)—H chlorination using PIP as a removable directing group

Scheme 27. Iridium (III)/l-MPAA catalyzed C(sp2)—H bond chlorination reaction of (hetero) aniline

Scheme 28. Ligands promote directed C(sp2)—H chlorination of aniline and phenol

Scheme 29. Visible light promoted chlorination reaction of tertiary aliphatic C(sp3)—H bonds

Scheme 30. Methylene chlorination reaction under illumination conditions

Scheme 31. Chlorination of C(sp3)—H bonds by Mn mediated atomic transfer

Scheme 32. Photoinduced selective C(sp3)—H chlorination rea- ction of fatty amides

Scheme 33. Chlorination of C(sp3)—H bonds guided by 1,5-HAT initiated by novel alkoxy precursors

Scheme 34. Photoinduced copper charge transfer catalyzed chlorination reaction of amide derivatives

Scheme 35. Aminosulfonic acid ester 1,6-HAT guided chlorination of γ-C(sp3)—H bonds

Scheme 36. Electrochemical chlorination of benzyl C(sp3)—H bond

Scheme 37. Silver catalyzed C(sp3)—H chlorination reaction

Scheme 38. Selective chlorination reaction catalyzed by high fluoride manganese porphyrin

Scheme 39. Site selective C(sp3)—H bond chlorination reaction catalyzed by CuOTf

Scheme 40. Site selective benzyl chloride reaction catalyzed by Cu

Scheme 41. Palladium catalyzed chlorination reaction with nitric acid as redox aid

Scheme 42. Pd(II) catalyzed continuous chlorination of α-C(sp3)—H bonds

Scheme 43. Sulfonimide assisted Pd(II) catalytic chlorination of β-C(sp3)—H bonds

Scheme 44. Pd catalyzed directed chlorination reaction of unactivated C(sp3)—H bonds at room temperature

References 76

[1]	Smith, B. R.; Eastman, C. M.; Njardarson, J. T. J. Med. Chem. 2014, 57, 9764.
[2]	Tang, M. L.; Bao, Z. Chem. Mater. 2010, 23, 446.
[3]	Nishii, Y.; Ikeda, M.; Hayashi, Y.; Kawauchi, S.; Miura, M. J. Am. Chem. Soc. 2020, 142, 1621. doi: 10.1021/jacs.9b12672 pmid: 31868360
[4]	Lin, R.; Amrute, A. P.; Perez-Ramirez, J. Chem. Rev. 2017, 117, 4182.
[5]	Petrone, D. A.; Ye, J.; Lautens, M. Chem. Rev. 2016, 116, 8003. doi: 10.1021/acs.chemrev.6b00089 pmid: 27341176
[6]	Ding, L.; Tang, J.; Cui, M.; Bo, C.; Chen, X.; Qiao, X. Ind. Eng. Chem. Res. 2011, 50, 11143.
[7]	Cambeiro, X. C.; Ahlsten, N.; Larrosa, I. J. Am. Chem. Soc. 2015, 137, 15636. doi: 10.1021/jacs.5b10593 pmid: 26645996
[8]	Liu, S.; Zhang, Q.; Li, H.; Yang, Y.; Tian, X.; Whiting, A. Chem.- Eur. J. 2015, 21, 9671.
[9]	Goldsmith, C. R.; Coates, C. M.; Hagan, K.; Mitchell, C. A. J. Mol. Catal. A: Chem. 2011, 335, 24.
[10]	Pu, M.; He, F. Acta Chim. Sinica 2023, 81, 1541 (in Chinese).
	(蒲明瑞, 何凤, 化学学报, 2023, 81, 1541.) doi: 10.6023/A23050245
[11]	Iwasa, E.; Hamashima, Y.; Fujishiro, S.; Higuchi, E.; Ito, A.; Yoshida, M.; Sodeoka, M. J. Am. Chem. Soc. 2010, 132, 4078.
[12]	Ohkita, T.; Tsuchiya, Y.; Togo, H. Tetrahedron 2008, 64, 7247.
[13]	Tay, D. W. P.; Nobbs, J. D.; Romain, C.; White, A. J. P.; Aitipamula, S.; van Meurs, M.; Britovsek, G. J. P. ACS Catal. 2019, 10, 663.
[14]	Kumaran, S.; Parthasarathy, K. J. Org. Chem. 2021, 86, 7987.
[15]	Wang, Q.; Zhang, W. W.; Song, H.; Wang, J.; Zheng, C.; Gu, Q.; You, S. L. J. Am. Chem. Soc. 2020, 142, 15678.
[16]	Yi, J.; Chen, M. Acta Chim. Sinica 2024, 82, 126 (in Chinese).
	(易敬霖, 陈茂, 化学学报, 2024, 82, 126.) doi: 10.6023/A23080387
[17]	Monnier, F.; Taillefer, M. Angew. Chem., Int. Ed. 2009, 48, 6954.
[18]	Cui, C.; Dai, M. Chin. J. Chem. 2023, 41, 3019.
[19]	Su, J.; Li, C.; Hu, X.; Guo, Y.; Song, Q. Angew. Chem., Int. Ed. 2022, 61, e202212740.
[20]	Bhoyare, V. W.; Sosa Carrizo, E. D.; Chintawar, C. C.; Gandon, V.; Patil, N. T. J. Am. Chem. Soc. 2023, 145, 8810.
[21]	Helbert, H.; Visser, P.; Hermens, J. G. H.; Buter, J.; Feringa, B. L. Nat. Catal. 2020, 3, 664.
[22]	Forero-Cortés, P. A.; Haydl, A. M. Org. Process Res. Dev. 2019, 23, 1478. doi: 10.1021/acs.oprd.9b00161
[23]	Liu, Y.; Fang, Y.; Zhang, L.; Jin, X.; Li, R.; Zhu, S.; Gao, H.; Fang, J.; Xia, Q. Chin. J. Org. Chem. 2014, 34, 1523 (in Chinese).
	(刘雨燕, 方烨汶, 张莉, 金小平, 李瑞丰, 朱帅汝, 高浩其, 房江华, 夏勤波, 有机化学, 2014, 34, 1523.) doi: 10.6023/cjoc201403003
[24]	Ziegler, D. S.; Wei, B.; Knochel, P. Chem. Eur. J. 2019, 25, 2695.
[25]	Das, R.; Kapur, M. Asian J. Org. Chem. 2018, 7, 1524.
[26]	Chen, J.; Lin, J. H.; Xiao, J. C. Org. Lett. 2018, 20, 3061. doi: 10.1021/acs.orglett.8b01058 pmid: 29741387
[27]	Samanta, R. C.; Yamamoto, H. Chem.-Eur. J. 2015, 21, 11976. doi: 10.1002/chem.201502234 pmid: 26185028
[28]	Maddox, S. M.; Nalbandian, C. J.; Smith, D. E.; Gustafson, J. L. Org. Lett. 2015, 17, 1042. doi: 10.1021/acs.orglett.5b00186 pmid: 25671756
[29]	Werf, A.; Selander, N. Org. Lett. 2015, 17, 6210.
[30]	Maddox, S. M.; Dinh, A. N.; Armenta, F.; Um, J.; Gustafson, J. L. Org. Lett. 2016, 18, 5476. pmid: 27754679
[31]	Xiong, X.; Yeung, Y.-Y. ACS Catal. 2018, 8, 4033.
[32]	Song, S.; Li, X.; Wei, J.; Wang, W.; Zhang, Y.; Ai, L.; Zhu, Y.; Shi, X.; Zhang, X.; Jiao, N. Nat. Catal. 2019, 3, 107.
[33]	Li, G.; Zhu, B.; Ma, X.; Jia, C.; Lv, X.; Wang, J.; Zhao, F.; Lv, Y.; Yang, S. Org. Lett. 2017, 19, 5166.
[34]	Fan, Z.; Lu, H.; Cheng, Z.; Zhang, A. Chem Commun. 2018, 54, 6008.
[35]	Zhang, H.; Xu, M.; Liu, N.; Yang, F. ChemistrySelect 2021, 6, 2319. doi: 10.1002/slct.202100030
[36]	Fosu, S. C.; Hambira, C. M.; Chen, A. D.; Fuchs, J. R.; Nagib, D. A. Chem 2019, 5, 417.
[37]	Segura-Quezada, A.; Satkar, Y.; Patil, D.; Mali, N.; Wrobel, K.; González, G.; Zárraga, R.; Ortiz-Alvarado, R.; Solorio-Alvarado, C. R. Tetrahedron Lett. 2019, 60, 1551. doi: 10.1016/j.tetlet.2019.05.019
[38]	Granados, A.; Jia, Z.; del Olmo, M.; Vallribera, A. Eur. J. Org. Chem. 2019, 2019, 2812. doi: 10.1002/ejoc.201900237
[39]	Hering, T.; König, B. Tetrahedron 2016, 72, 7821.
[40]	Düsel, S. J. S.; König, B. Eur. J. Org. Chem. 2019, 2020, 1491.
[41]	Rogers, D. A.; Gallegos, J. M.; Hopkins, M. D.; Lignieres, A. A.; Pitzel, A. K.; Lamar, A. A. Tetrahedron 2019, 75, 130498.
[42]	Zhang, L.; Hu, X. Chem. Sci. 2017, 8, 7009. doi: 10.1039/c7sc03010j pmid: 29147528
[43]	Xie, W. C.; Wang, M.; Yang, S.; Chen, Y. D.; Feng, J.; Huang, Y. T. Org. Biomol. Chem. 2022, 20, 5319.
[44]	Harnedy, J.; Hareram, M. D.; Tizzard, G. J.; Coles, S. J.; Morrill, L. C. Chem. Commun. 2021, 57, 12643.
[45]	Liu, T.; Lu, H. K.; Shi, Z.; Yan, H.; Li, Z.; Ye, K. Y. Eur. J. Org. Chem. 2024, 27, e202300880.
[46]	Fahey, D. R. Chem. Commun. 1970, 7, 417a.
[47]	Du, B.; Jiang, X.; Sun, P. J. Org. Chem. 2013, 78, 2786.
[48]	Mo, S.; Zhu, Y.; Shen, Z. Org. Biomol. Chem. 2013, 11, 2756.
[49]	Qian, G.; Hong, X.; Liu, B.; Mao, H.; Xu, B. Org. Lett. 2014, 16, 5294.
[50]	Li, B.; Liu, B.; Shi, B. F. Chem. Commun. 2015, 51, 5093.
[51]	Zhan, B. B.; Liu, Y. H.; Hu, F.; Shi, B. F. Chem. Commun. 2016, 52, 4934.
[52]	Kathiravan, S.; Nicholls, I. A. Chem.-Eur. J. 2017, 23, 7031. doi: 10.1002/chem.201700280 pmid: 28221698
[53]	Zhu, Y.; Huang, J.; Yang, X. Chin. J. Org. Chem. 2019, 39, 1665 (in Chinese).
	(朱晔, 黄金文, 杨先金, 有机化学, 2019, 39, 1665.) doi: 10.6023/cjoc201903037
[54]	Shi, H.; Wang, P.; Suzuki, S.; Farmer, M. E.; Yu, J. Q. J. Am. Chem. Soc. 2016, 138, 14876.
[55]	Wang, Y.; Li, G. X.; Yang, G.; He, G.; Chen, G. Chem. Sci. 2016, 7, 2679.
[56]	Zhao, M.; Lu, W. Org Lett. 2017, 19, 4560.
[57]	Xiang, M.; Zhou, C.; Yang, X. L.; Chen, B.; Tung, C. H.; Wu, L. Z. J. Org. Chem. 2020, 85, 9080. doi: 10.1021/acs.joc.0c01000 pmid: 32434320
[58]	He, Q.; Cao, Z.; Zhang, Y.; Chen, G.; Wang, Y. Adv. Synth. Catal. 2023, 365, 2711.
[59]	McMillan, A. J.; Sienkowska, M.; Di Lorenzo, P.; Gransbury, G. K.; Chilton, N. F.; Salamone, M.; Ruffoni, A.; Bietti, M.; Leonori, D. Angew. Chem., Int. Ed. 2021, 60, 7132.
[60]	Liu, R. Z.; Li, J.; Sun, J.; Liu, X. G.; Qu, S.; Li, P.; Zhang, B. Angew. Chem., Int. Ed. 2020, 59, 4428.
[61]	Zhu, Y.; Shi, J.; Yu, W. Org. Lett. 2020, 22, 8899.
[62]	Herron, A. N.; Liu, D.; Xia, G.; Yu, J. Q. J. Am. Chem. Soc. 2020, 142, 2766.
[63]	He, Y.; Tian, C.; An, G.; Li, G. Chin. Chem. Lett. 2024, 35, 108546.
[64]	Short, M. A.; Blackburn, J. M.; Roizen, J. L. Angew. Chem., Int. Ed. 2018, 57, 296.
[65]	Zhao, J.; Zhang, J.; Fang, P.; Wu, J.; Wang, F.; Liu, Z.-Q. Green Chem. 2024, 26, 507.
[66]	Ozawa, J.; Kanai, M. Org. Lett. 2017, 19, 1430. doi: 10.1021/acs.orglett.7b00367 pmid: 28256138
[67]	Li, G.; Dilger, A. K.; Cheng, P. T.; Ewing, W. R.; Groves, J. T. Angew. Chem., Int. Ed. 2018, 57, 1251.
[68]	Jin, J.; Zhao, Y.; Kyne, S. H.; Farshadfar, K.; Ariafard, A.; Chan, P. W. H. Nat. Commun. 2021, 12, 4065.
[69]	Lopez, M. A.; Buss, J. A.; Stahl, S. S. Org. Lett. 2022, 24, 597.
[70]	Stowers, K. J.; Kubota, A.; Sanford, M. S. Chem. Sci. 2012, 3, 3192. pmid: 23050075
[71]	Li, B.; Wang, S.-Q.; Liu, B.; Shi, B.-F. Org. Lett. 2015, 17, 1200.
[72]	Liu, W.; Tan, L.; Zhou, P.; Chen, C.; Zhang, Q. Synthesis 2013, 45, 2600.
[73]	Su, Y.; Shi, Y.; Chang, B.; Wu, L.; Chong, S.; Zhang, W.; Huang, D.; Wang, K.; Hu, Y. Chin. J. Org. Chem. 2018, 38, 1454 (in Chinese).
	(苏瀛鹏, 石娅, 常兵兵, 吴丽丽, 种思颖, 张为钢, 黄丹凤, 王克虎, 胡雨来, 有机化学, 2018, 38, 1454.) doi: 10.6023/cjoc201712042
[74]	Rit, R. K.; Yadav, M. R.; Ghosh, K.; Shankar, M.; Sahoo, A. K. Org. Lett. 2014, 16, 5258.
[75]	Xiong, H. Y.; Cahard, D.; Pannecoucke, X.; Besset, T. Eur. J. Org. Chem. 2016, 2016, 3625.
[76]	Yang, X.; Sun, Y.; Sun, T. Y.; Rao, Y. Chem. Commun. 2016, 52, 6423.

选择性C—H键氯化反应进展