Generic placeholder image

Current Organic Chemistry


ISSN (Print): 1385-2728
ISSN (Online): 1875-5348

Review Article

Recent Advances in Transition Metal-Free Halogenation of C(sp2)-H Bonds

Author(s): Tian Luo, Shanghui Tian, Jie-Ping Wan* and Yunyun Liu*

Volume 25, Issue 10, 2021

Published on: 22 January, 2021

Page: [1180 - 1193] Pages: 14

DOI: 10.2174/1385272825666210122094423

Price: $65


C-X (X = halogen) bonds are indispensable functional groups in organic synthesis by mediating a massive number of important organic reactions. While a variety of different catalytic strategies are available for generating C-X bonds, those methods enabling the C-X bond formation under transition metal-free conditions via the C-H bond functionalization are particularly interesting because of the inherent atom economy and environmental friendliness associated with such methods. Herein, the advancements in the transition metal-free halogenation of C(sp2)-H bond are reviewed.

Keywords: C(sp2)-H bond, halogenation, transition metal-free, carbon arene, hereroaryl, non-aromatics.

Graphical Abstract
Guérinot, A.; Cossy, J. Cobalt-catalyzed cross-couplings between alkyl halides and Grignard Reagents. Acc. Chem. Res., 2020, 53(7), 1351-1363.
[] [PMID: 32649826]
Helmecke, L.; Spittler, M.; Baumgarten, K.; Czekelius, C. Metal-free activation of C-I bonds and perfluoroalkylation of alkenes with visible light using phosphine catalysts. Org. Lett., 2019, 21(19), 7823-7827.
[] [PMID: 31532688]
Liu, Z.; Long, J.; Xiao, X.; Lin, J-H.; Zheng, X.; Xiao, J-C.; Cao, Y-C. Ph3P+CF2CO2− as an F− and:CF2 source for trifluoromethylthiolation of alkyl halides. Chin. Chem. Lett., 2019, 30(3), 714-716.
Xu, P.; Duan, X. Recent progress in the Suzuki-Miyaura cross-coupling reactions in water. Chin. J. Org. Chem., 2019, 39(12), 3315-3327.
Heravi, M.M.; Malmir, M.; Moradi, R. Recent advances in the applications of the intramolecular Suzuki cross-coupling reaction in cyclization and heterocyclization: an update. Curr. Org. Chem., 2019, 23(22), 2469-2488.
Ou, W.; Zou, R.; Han, M.; Yu, L.; Su, C. Tailorable carbazolyl cyanobenzene-based photocatalysts for visible light-induced reduction of aryl halides. Chin. Chem. Lett., 2020, 31(7), 1899-1902.
Heravi, M.M.; Ghanbarian, M.; Ghalavand, N.; Nazari, N. Current applications of the Sonogashira reaction in the synthesis of heterocyclic compounds: an update. Curr. Org. Chem., 2018, 22(14), 1420-1457.
Faisal, M.; Saeed, A.; Shahzad, D.; Dar, P.; Larik, F.A. Recent developments and comparison of transformation strategies for organic halides to aldehydes and ketones. Mol. Divers., 2020, 24(2), 571-592.
[] [PMID: 31098859]
Robinson, P.S.D.; Khairallah, G.N.; da Silva, G.; Lioe, H.; O’Hair, R.A.J. Gold-mediated C-I bond activation of iodobenzene. Angew. Chem. Int. Ed. Engl., 2012, 51(16), 3812-3817.
[] [PMID: 22344975]
Hegde, R.V.; Ghosh, A.; Patil, S.A.; Dateer, R.B. Pd-nanoparticles catalyzed denitrogenative coupling of aryl halides with arylhydrazines: greener approach for biaryls synthesis under ligand-free condition. Tetrahedron, 2019, 75(52), 130777.
Liu, X.; Suyama, K.; Shiki, J.; Torikai, K.; Nose, T.; Shimohigashi, M.; Shimohigashi, Y.; Bisphenol, A.F. Bisphenol AF: halogen bonding effect is a major driving force for the dual ERα-agonist and ERβ-antagonist activities. Bioorg. Med. Chem., 2020, 28(3), 115274.
[] [PMID: 31879182]
Tabatabaei Dakhili, S.A.; Pérez, D.J.; Gopal, K.; Tabatabaei Dakhili, S.Y.; Ussher, J.R.; Velázquez-Martínez, C.A.; Velázquez-Martínez, C.A. A structure-activity relationship study of Forkhead Domain Inhibitors (FDI): the importance of halogen binding interactions. Bioorg. Chem., 2019, 93, 103269.
[] [PMID: 31654840]
Teles, C.M.; Lammoglia, L.C.; Juliano, M.A.; Ruiz, A.L.T.G.; Candido, T.Z.; de Carvalho, J.E.; Lima, C.S.P.; Abbehausen, C. Novel anticancer PdII complexes: the effect of the conjugation of transferrin binding peptide and the nature of halogen coordinated on antitumor activity. J. Inorg. Biochem., 2019, 199, 110754.
[] [PMID: 31401348]
Dong, M.; Hu, T.; Wang, Y.; Pang, P.; Wang, Y.; Miao, X.; Li, B.; Deng, W. Halogen-bonded building block for 2D self-assembly: triggered by hydrogen-bonding motifs relative to the terminal functions of the side chains. Appl. Surf. Sci., 2020, 515(15), 145983.
Liu, M.; Zhai, W.; Chen, H.; Zhang, H.; Li, C. Halogen effects-induced bright D-π-A fluorophore as scaffold for NIR fluorogenic probes with high contrast. Anal. Chem., 2020, 92(15), 10792-10799.
[] [PMID: 32648733]
Biswas, J.R.; Guin, S.; Maiti, D. Highvalent 3d metal-oxo mediated C–H halogenation: biomimetic approaches. Coord. Chem. Rev., 2020, 408, 213174.
Shi, X.; Shi, D. Recent advances in transition-metal-catalyzed halides formation. Curr. Org. Chem., 2018, 22, 2229-2255.
Liao, G.; Shi, B. Recent advances on transition-metal-catalyzed halogenation of unactivated C-H bonds. Acta Chimi. Sin., 2015, 73(12), 1283-1293.
Chen, J.; Zhou, L. Recent progress in the asymmetric intermolecular halogenation of alkenes. Synthesis, 2014, 46(5), 586-595.
Hao, W.; Liu, Y. C-H bond halogenation catalyzed or mediated by copper: an overview. Beilstein J. Org. Chem., 2015, 11, 2132-2144.
[] [PMID: 26664634]
Arnold, A.M.; Ulmer, A.; Gulder, T. Advances in Iodine(III)-mediated halogenations: a versatile tool to explore new reactivities and selectivities. Chem. Eur. J., 2016, 22(26), 8728-8739.
[] [PMID: 27061937]
Borisova, N.E.; Reshetova, M.D.; Ustynyuk, Y.A. Metal-free methods in the synthesis of macrocyclic schiff bases. Chem. Rev., 2007, 107(1), 46-79.
[] [PMID: 17212470]
Sun, C-L.; Shi, Z-J. Transition-metal-free coupling reactions. Chem. Rev., 2014, 114(18), 9219-9280.
[] [PMID: 25184859]
Bhunia, A.; Yetra, S.R.; Biju, A.T. Recent advances in transition-metal-free carbon-carbon and carbon-heteroatom bond-forming reactions using arynes. Chem. Soc. Rev., 2012, 41(8), 3140-3152.
[] [PMID: 22278415]
Liu, Y.; Xiong, J.; Wei, L. Recent advances in the C(sp2)-S bond formation reactions by transition metal-free C(sp2)-H functionalization. Chin. J. Org. Chem., 2017, 37(7), 1667-1680.
Wan, J-P.; Gao, Y.; Wei, L. Recent advances in transition-metal-free oxygenation of alkene C=C Double bonds for carbonyl generation. Chem. Asian J., 2016, 11(15), 2092-2102.
[] [PMID: 27237866]
Xu, X-M.; Chen, D-M.; Wang, Z-L. Recent advances in sulfenylation of C(sp3)-H bond under transition metal-free conditions. Chin. Chem. Lett., 2020, 31(1), 49-57.
Xu, X.; Chen, D.; Wang, Z. Recent progress in transition metal-free C-heteroatom bond formation by functionalization of C-H bond in imidazole-fused heterocycles. Chin. J. Org. Chem., 2019, 39(12), 3338-3352.
Labinger, J.A.; Bercaw, J.E. Understanding and exploiting C-H bond activation. Nature, 2002, 417(6888), 507-514.
[] [PMID: 12037558]
McMurray, L.; O’Hara, F.; Gaunt, M.J. Recent developments in natural product synthesis using metal-catalysed C–H bond functionalization. Chem. Soc. Rev., 2011, 40(4), 1855-1898.
[] [PMID: 21390392]
Ma, W.; Gandeepan, P.; Li, J.; Ackermann, L. Recent advances in positional-selective alkenylations: removable guidance for twofold C–H activation. Org. Chem. Front., 2017, 4, 1435-1467.
Wencel-Delord, J.; Glorius, F. C-H bond activation enables the rapid construction and late-stage diversification of functional molecules. Nat. Chem., 2013, 5(5), 369-375.
[] [PMID: 23609086]
Tian, S.; Luo, T.; Zhu, Y.; Wan, J-P. Recent advances in the diversification of chromones and flavones by direct C-H bond activation or functionalization. Chin. Chem. Lett., 2020, 31(12), 3073-3082.
Zhang, C-N.; Zheng, Z-A.; Chang, G.; Xiao, Y-C.; Shen, Y-H.; Li, G.; Zhang, Y-M.; Peng, W-M.; Wang, L.; Xiao, B. Phosphorus-containing groups assisted transition metal catalyzed C-H activation reactions. Curr. Org. Chem., 2019, 23(2), 103-135.
Zhao, B.; Liu, Y. Step-economical C–H activation reactions directed by in situ amidation. Synthesis, 2020, 52(21), 3211-3218.
Wan, J-P.; Gan, L.; Liu, Y. Transition metal-catalyzed C-H bond functionalization in multicomponent reactions: a tool toward molecular diversity. Org. Biomol. Chem., 2017, 15(43), 9031-9043.
[] [PMID: 29075706]
Wan, J-P.; Jing, Y. Recent advances in copper-catalyzed C-H bond amidation. Beilstein J. Org. Chem., 2015, 11, 2209-2222.
[] [PMID: 26664644]
Zhang, Q.; Shi, B-F. From reactivity and regioselectivity to stereoselectivity: an odyssey of designing PIP amine and related directing groups for C—H activation. Chin. J. Chem., 2019, 37(7), 647-656.
Sarkar, S.; Jana, M.; Narender, T. Metal-free directed ortho C-H iodination: synthesis of 2¢-iodobiaryl-2-carbonitriles. Eur. J. Org. Chem., 2013, 6491-6495.
Kamei, T.; Ishibashi, A.; Shimada, T. Metal-free halogenation of arylboronate with N-halosuccinimide. Tetrahedron Lett., 2014, 55(30), 4245-4247.
Maibunkaew, T.; Thongsornkleeb, C.; Tummatorn, J.; Bunrit, A.; Ruchirawat, S. Practical and metal-free electrophilic aromatic halogenation by interhalogen compounds generated in situ from N-halosuccinimide and catalytic TMSCl. Synlett, 2014, 25(12), 1769-1775.
Wang, J.; Chen, S-B.; Wang, S-G.; Li, J-H. A metal-free and ionic liquid-catalyzed aerobic oxidative bromination in water. Aust. J. Chem., 2015, 68, 513-517.
Patil, A.M.; Kamble, D.A.; Lokhande, P.D. A metal-free iodination of aryl ethers and phenols using I2. ChemistrySelect, 2017, 2(27), 8418-8422.
Zhang, J.; Li, S.; Deng, G-J.; Gong, H. Metal-free, oxidant-free, and controllable graphene oxide catalyzed direct iodination of arenes and ketones. ChemCatChem, 2018, 10(2), 376-380.
Tian, C.; Yao, X.; Ji, W.; Wang, Q.; An, G.; Li, G. A para C-H functionalization of aniline derivatives via in situ generated bulky hypervalent iodinium reagents. Eur. J. Org. Chem., 2018, 5972-5979.
Liang, D.; Li, Y.; Gao, S.; Li, R.; Li, X.; Wang, B.; Yang, H. Amide-assisted radical strategy: metal-free direct fluorination of arenes in aqueous media. Green Chem., 2017, 19(14), 3344-3349.
Ma, X.; Yu, J.; Jiang, M.; Wang, M.; Tang, L.; Wei, M.; Zhou, Q. Mild and regioselective bromination of phenols with TMSBr. Eur. J. Org. Chem., 2019, 4593-4596.
Ma, X.; Zhou, K.; Ren, M.; Wang, Y.; Yu, J. Steric hindrance effect leading to regioselective bromination of phenols with HBr. Youji Huaxue, 2019, 39(10), 2796-2801.
Liu, Y.; Yang, J.; Ma, X.; Han, C.; Jiang, Y. Metal-free synthesis of etherified 3-(1H-1,2,3-triazol-1-yl)phenyl iodides through O–H arylation/C–H iodination with diacetoxyiodobenzenes. Eur. J. Org. Chem., 2017, 2017(38), 5769-5775.
Li, L.; Li, Y.; Zhao, Z.; Luo, H.; Ma, Y.N. Facial syntheses of bromobenzothiazines via catalyst-free tandem C-H amination/bromination in water. Org. Lett., 2019, 21(15), 5995-5999.
[] [PMID: 31339322]
Wang, Y.; Wang, Y.; Jiang, K.; Zhang, Q.; Li, D. Transition-metal-free oxidative C5 C-H-halogenation of 8-aminoquinoline amides using sodium halides. Org. Biomol. Chem., 2016, 14(43), 10180-10184.
[] [PMID: 27753444]
Jiao, J-Y.; Mao, Y-J.; Feng, A-W.; Li, X-F.; Li, M-T.; Zhang, X-H. The regioselective C5 halogenation of quinolines using sodium halides under transition metal-free conditions. Tetrahedron, 2017, 73(11), 1482-1488.
Sen, C.; Sahoo, T.; Ghosh, S.C. Regio-selective C-H halogenation of 8-amido-quinolines under transition metal free conditions. ChemistrySelect, 2017, 2(9), 2745-2749.
Chen, J.; Wang, T.; Liu, Y.; Wang, T.; Lin, A.; Yao, H.; Xu, J. Metal-free C5-selective halogenation of quinolines under aqueous conditions. Org. Chem. Front., 2017, 4(4), 622-626.
Hao, W.; Wang, Y.; Liu, Y. Catalyst-free selective C5-H bromination and chlorination of 8-amido quinolines. Chin. J. Org. Chem., 2018, 38(12), 3198-3203.
Li, Y.; Zhu, L.; Cao, X.; Au, C-T.; Qiu, R.; Yin, S-F. Metal-free C5-H bromination of quinolines for one-pot C−X (X=C, O, S) bond formations. Adv. Synth. Catal., 2017, 359(16), 2864-2873.
Dutta, H.S.; Khan, B.; Khan, A.A. Raziullah, Ahmad, A.; Kant, R.; Koley, D. Halogenations to aminoquinolines at room temperature using N-halosaccharins. ChemistrySelect, 2017, 2(22), 6488-6492.
Motati, D.R.; Uredi, D.; Watkins, E.B. A general method for the metal-free, regioselective, remote C-H halogenation of 8-substituted quinolines. Chem. Sci. (Camb.), 2018, 9(7), 1782-1788.
[] [PMID: 29675222]
Du, Y.; Liu, Y.; Wan, J-P. Copper-catalyzed one-pot N-acylation and C5-H halogenation of 8-aminoquinolines: the dual role of acyl halides. J. Org. Chem., 2018, 83(6), 3403-3408.
[] [PMID: 29498525]
Li, D.; Jia, Z.; Jiang, Y.; Jia, J.; Zhao, X.; Li, Z.; Xu, Z. One-pot functionalization of 8-aminoquinolines through the acylation and regioselective C5-H halogenation under transition-metal-free conditions. ChemistrySelect, 2019, 4(47), 13964-13967.
Xiong, J.; Liu, Y. Transition-metal-free C5, C7-dihalogenation and the switchable C5 halogenation of 8-hydroxyquinolines. ChemistrySelect, 2019, 4(2), 693-697.
Zhang, Y.; Wen, C.; Li, J. C5-Regioselective C-H fluorination of 8-aminoquinoline amides and sulfonamides with Selectfluor under metal-free conditions. Org. Biomol. Chem., 2018, 16(11), 1912-1920.
[] [PMID: 29487929]
Chen, H.; Li, P.; Wang, M.; Wang, L. Transition-metal-free regioselective C-H bond fluorination of 8-amidoquinolines with selectfluor. Eur. J. Org. Chem., 2018, 2018, 2091-2097.
Chen, Q.; Yang, Y.; Wang, X.; Zhang, Q.; Li, D. Hypervalent iodine reagent-mediated C(5) C-H nucleophilic fluorination of 8-aminoqunolines. Chin. J. Org. Chem., 2020, 40(2), 454-461.
Shi, L.; Zhang, D.; Lin, R.; Zhang, C.; Li, X.; Jiao, N. The direct C–H halogenations of indoles. Tetrahedron Lett., 2014, 55(14), 2243-2245.
Sun, L.; Zhang, X.; Li, Z.; Ma, J.; Zeng, Z.; Jiang, H. A versatile C-H halogenation strategy for indole derivatives under electrochemical catalyst- and oxidant-free conditions. Eur. J. Org. Chem., 2018, 2018(35), 4949-4952.
Li, J.; Tang, J.; Wu, Y.; He, Q.; Yu, Y. Transition-metal-free regioselective C–H halogenation of imidazo[1,2-a]pyridines: sodium chlorite/bromite as the halogen source. RSC Advances, 2018, 8(8), 5058-5062.
Neto, J.S.S.; Balaguez, R.A.; Franco, M.S.; de Sá Machado, V.C.; Saba, S.; Rafique, J.; Galetto, F.Z.; Braga, A.L. Trihaloisocyanuric acids in ethanol: an eco-friendly system for the regioselective halogenation of imidazo-heteroarenes. Green Chem., 2020, 22(11), 3410-3415.
Dannenberg, C.A.; Bizet, V.; Zou, L-H.; Bolm, C. Transition-metal-free oxidative iodination of 1,3,4-oxadiazoles. Eur. J. Org. Chem., 2015, 77-80.
Liu, X.; Zhao, X.; Liang, F.; Ren, B. t-BuONa-mediated direct C-H halogenation of electron-deficient (hetero)arenes. Org. Biomol. Chem., 2018, 16(6), 886-890.
[] [PMID: 29340407]
Rogers, D.A.; Brown, R.G.; Brandeburg, Z.C.; Ko, E.Y.; Hopkins, M.D.; LeBlanc, G.; Lamar, A.A. Organic dye-catalyzed, visible-light photoredox bromination of arenes and heteroarenes using N-bromosuccinimide. ACS Omega, 2018, 3(10), 12868-12877.
[] [PMID: 31458011]
Sato, K.; Sanford, G.; Shimizu, K.; Akiyama, S.; Lancashire, M.; Yufit, D.S.; Tarui, A.; Omote, M.; Kumadaki, I.; Harusawa, S.; Ando, A. Synthesis of fluorinated isoxazoles using Selectfluor™: preparation and characterization of 4-fluoroisoxazole, 4,4,5-trifluoroisoxazoline and 4,4-difluoro-5-hydroxyiso-xazoline systems from one-pot and multi-step processes. Tetrahedron, 2016, 72(13), 1690-1698.
Xie, Y.; Zhong, J.; Li, Y.; Xiao, X.; Zou, L.; Liu, Y.; Zhang, K.; He, J. Iodination and O-Arylation of 2-arylquinolin-4(1H)-one with PhI(OAc)2 under metal-free conditions. ChemistrySelect, 2018, 3(6), 1655-1657.
Sosnovskikh, V.Y. New data on the reactivity of 2-unsubstituted 3-halochromones. Chem. Heterocycl. Compd., 2020, 56, 243-254.
Luo, T.; Wan, J-P.; Liu, Y. Toward C2-nitrogenated chromones by copper-catalyzed β-C(sp2)-H N-heteroarylation of enaminones. Org. Chem. Front., 2020, 7(9), 1107-1112.
Wan, J-P.; Tu, Z.; Wang, Y. Transient and Recyclable Halogenation Coupling (TRHC) for isoflavonoid synthesis with site-selective arylation. Chem. Eur. J., 2019, 25(28), 6907-6910.
[] [PMID: 30958593]
Fu, L.; Wan, J-P. Recent advances in the C3‐functionalized chromones synthesis by the featured tandem C-H elaboration and chromone annulation of enaminones. Asian J. Org. Chem., 2019, 8(6), 767-776.
Tian, S.; Luo, T.; Zhu, Y.; Wan, J-P. Recent advances in the diversification of chromones and flavones by direct C-H bond activation or functionalization. Chin. Chem. Lett., 2020, 31(12), 3073-3082.
Zhao, Q-L.; Xia, P-J.; Zheng, L.; Xie, Z-Z.; Hu, Y-Z.; Chen, G-J.; Chen, X-Q.; Xiang, H-Y.; Yang, H. A BHT-regulated chemoselective access to monofluorinated chromones. Tetrahedron, 2020, 76(8), 130833.
Wang, Y.; Hu, B.; Zhang, Q.; Zhao, S.; Zhao, Y.; Zhang, B.; Yu, F. Selectfluor- triggered fluorination/cyclization of o-hydroxylenaminones: a facile access to 3-fluoro-chromones. J. Chem. Rec, 2020.
Lin, Y.; Wan, J-P.; Liu, Y. Synthesis of 3-halochromones with simple KX halogen sources enabled by in situ halide oxidation. New J. Chem., 2020, 44(19), 8120-8124.
Xu, H.; Zhou, P.; Hang, R.; Zhou, J.; Lu, L-L.; Shen, Y.; Yu, F-C. Direct copper(II)-mediated regioselective α-halogenation of N-aryl enaminones. Tetrahedron Lett., 2016, 57(45), 4965-4968.
Sorabad, G.S.; Maddani, M.R. Metal-free, green and efficient oxidative α halogenation of enaminones by halo acid and DMSO. New J. Chem., 2019, 43(17), 6563-6568.

Rights & Permissions Print Export Cite as
© 2022 Bentham Science Publishers | Privacy Policy