一种由四卤化碳生成三氯甲基自由基的氧化策略：无过渡金属合成三氯甲基化吲哚酮

doi:10.6023/cjoc202508011

摘要/Abstract

本文报道了一种由四卤化碳的C-X键断裂生成三氯甲基自由基的新型氧化方案。该反应采用过硫酸钾(K₂S₂O₈)与季铵盐(QAS)的组合作为自由基引发体系,从而能够使得通过烯烃的级联环化反应实现三氯甲基化吲哚酮的无过渡金属、无有机过氧化物合成。该方案还实现了较高至优异的产率及良好的官能团兼容性。此外,该组合还应用到了由酮合成α-溴代酮,反应经过了氧化的C(sp³)-H键断裂。

关键词: 自由基, 环化, 氧化, 无过渡金属

A novel oxidative protocol for the generation of trichloromethyl radical from the cleavage of C-X bond of carbon tetrahalides has been reported. This reaction employs the combination of potassium persulfate (K₂S₂O₈) and quaternary ammonium salt (QAS) as a radical triggered system, thereby enabling the transition-metal- and organic-peroxide-free synthesis of trichloromethylated oxindoles through cascade cyclization of alkenes. The protocol delivers both high to excellent yields and good functional group tolerance. Additionally, the combination can be applied to the synthesis of α-bromoketones from ketones via the oxidative cleavage of C(sp³)-H bonds.

Key words: Radicals, Cyclization, Oxidation, Transition-metal-free

引用此文

周可, 王泽涌, 黎亚琳, 张倩, 李馨月, 邹汉芳, 张明忠, 郭圣荣, 陈铁桥. 一种由四卤化碳生成三氯甲基自由基的氧化策略：无过渡金属合成三氯甲基化吲哚酮[J]. 有机化学, doi: 10.6023/cjoc202508011.

Zhou Ke, Wang Ze-Yong, Li Ya-Lin, Zhang Qian, Li Xin-Yue, Zou Han-Fang, Zhang Ming-Zhong, Guo Sheng-Rong, Chen Tieqiao. An Oxidative Strategy for Generating Trichloromethyl Radical from Carbon Tetrahalides: Transition-Metal-Free Synthesis of Trichloromethylated Oxindoles[J]. Chinese Journal of Organic Chemistry, doi: 10.6023/cjoc202508011.

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

分享此文

参考文献

[1] (a) Steinbiss M.; Maczka M.; Langewald J.; London B.; Vallinayagam R.; Jones P. G.; Bastiaans H.; Schulz, S. J. Nat. Prod.2020, 83, 468.
(b) Nguyen, V.-A.; Willis, C. L.; Gerwick, W. H.Chem. Commun. 2001, 1934.
(c) Butler, A.; Walker, J. V.Chem. Rev. 1993, 93, 1937.
(d) Verhaeghe, P.; Azas, N.; Hutter, S.; Castera-Ducros, C.; Laget, M.; Dumètre, A.; Gasquet, M.; Reboul, J.-P.; Rault, S.; Rathelot, P.; Vanelle, P.Bioorg. Med. Chem. 2009, 17, 4313.
(e) Guo K.-L.; Zhao L.-X.; Wang Z.-W.; Rong S.-Z.; Zhou X.-L.; Gao S.; Fu Y.; Ye F. Biomolecules2019, 9, 438.
(f) Morimoto, H.; Lu, G.; Aoyama, N.; Matsunaga, S.; Shibasaki, M.J. Am. Chem. Soc. 2007, 129, 9588.
(g) Brantley, S. E.; Molinski, T. F.Org. Lett. 1999, 1, 2165.
(h) Kawamura K.; Kato, K. Polym. Adv. Technol.2004, 15, 324.
[2] Galonić D. P.; Vaillancourt, F. H.; Walsh, C. T.J. Am. Chem. Soc. 2006, 128, 3900.
[3] (a) Beaumont S.; llardi E. A.; Monroe L. R.; Zakarian, A. J. Am. Chem. Soc.2010, 132, 1482.
(b) Gu, Z. H.; Herrmann, A. T.; Zakarian, A.Angew. Chem. Int. Ed. 2011, 50, 7136.
[4] (a) Li S.-J.; Wang Y.; Xu J.-K.; Xie D.; Tian S.-K.; Yu Z.-X. Org. Lett.2018, 20, 4545.
(b) Wang H.-Y.; Tian S.-K. Org. Lett.2019, 21, 5675.
(c) Gupta M. K.; Li Z.; Snowden, T. S. J. Org. Chem.2012, 77, 4854.
(d) Henegar K. E.; Lira, R. J. Org. Chem.2012, 77, 2999.
(e) Wang, W.; Lian, X.; Chen, D.; Liu, X.; Lin, L.; Feng, X. Chem. Commun. 2011, 47, 7821.
(f) Li, Y.; Zheng, T.; Wang, W.; Xu, W.; Ma; Y.; Zhang, S.; Wang, H.; Sun, Z.Adv. Synth. Catal. 2012, 354, 308.
(g) Liang, Y.-Y.; Lv, G.-F.; Ouyang, X.-H.; Song, R.-J.; Li, J.-H.Adv. Synth. Catal. 2021, 363, 290.
(h) Huang, G.; Yu, J.-T.; Pan, C.Adv. Synth. Catal. 2021, 363, 305.
[5] (a) Liu, Y.; Zhang, J.-L.; Song, R.-J.; Li, J.-H.Eur. J. Org. Chem. 2014, 1177.
(b) Ueda, M.; Doi, N.; Miyagawa, H.; Sugita, S.; Takeda, N.; Shinada, T.; Miyata, O. Chem. Commun.# 2015, 51#, 4204.
(c) Li, W.-Y.; Wu, C.-S.; Zhou, W.; Yang, L.Chem. Commun. 2018, 54, 11013.
(d) Wu Y.; Liu H.; Liu L.; Yu, J.-T. Org. Biomol. Chem.2023, 21, 7079.
[6] (a) Zhang, Y.; Teng, B.-H.; Wu, X.-F.Chem. Sci. 2024, 15, 1418.
(b) Zhao Y.-L.; Yao Y.; Li W.-T.; Qin J.-H.; Sun Q.; Li J.-H.; Ouyang, X.-H. Org. Chem. Front.2023,10, 4809.
(c) Balili M. N. C.; Pintauer T. Dalton Trans.2011, 40, 3060.
(d) Neff R. K.; Su Y.-L.; Liu S.; Rosado M.; Zhang X.; Doyle, M. P. J. Am. Chem. Soc.2019, 141, 16643.
(e) Chen, C.; Tan, H.; Liu, B.; Yue, C.; Liu, W.Org. Chem. Front. 2018, 5, 3143.
(f) Chen, C.; Li, Y.; Pan, Y.; Duan, L.; Liu, W.Org. Chem. Front. 2019, 6, 2032.
(g) Kumar, V.; Bisoyi, A.; Beevi V, F.; Yatham, V. R.J. Org. Chem. 2024, 89, 16964.
(h) Kusakabe M.; Nagao K.; Ohmiya H. Org. Lett.2021, 23, 7242.
[7] (a) Murai S.; Sugise R.; Sonoda, N. Angew. Chem. Int. Ed.1981, 20, 475.
(b) Chen B.; Fang C.; Liu P.; Ready, J. M. Angew. Chem. Int. Ed.2017, 56, 8780.
(c) Nikitas, N. F.; Voutyritsa, E.; Gkizis, P. L.; Kokotos, C. G.Eur. J. Org. Chem. 2021, 2021, 96.
[8] (a) Wu, N.; Wahl, B.; Woodward, S.; Lewis, W.Chem.—Eur. J. 2014, 20, 7718.
(b) Wahl, B.; Lee, D. S.; Woodward, S.Eur. J. Org. Chem. 2015, 2015, 6033.
[9] Kamijo S.; Yokosaka S.; Inoue M.Tetrahedron 2012, 68, 5290.
[10] (a) Wang Q.; Wang M.; Wu Q.; Ma M.; Zhao B. Org. Lett.2022, 24, 4772.
(b) Pal, B.; Sahoo, S.; Mal, P.J. Org. Chem. 2024, 89, 1784.
(c) Kontara, I. I.; Panagiotari, V. A.; Mountanea, O. G.; Mantzourani, C.; Gkizis, P. L.; Kokotos, G.Eur. J. Org. Chem. 2024, 27, e202400733.
[11] (a) Pothoczki S.; Temleitner L.; Pusztai L. Chem. Rev.2015, 115, 13308.
(b) Drago, R. S. J. Phys. Chem.1991, 95, 9800.
[12] Mandal S.; Bera T.; Dubey G.; Saha J.; Laha, J. K. ACS Catal.2018, 8, 5085.
[13] (a) Zhu, X.; Shi, Y.; Mao, H.; Cheng, Y.; Zhu, C.Adv. Synth. Catal. 2013, 355, 3558.
(b) Hu, B.; Zhou, P.; Zhang, Q.; Wang, Y.; Zhao, S.; Lu, L.; Yan, S.; Yu, F.J. Org. Chem. 2018, 83, 14978.
(c) Yang, X.; Zhao, L.; Yuan, B.; Qi, Z.; Yan, R.Adv. Synth. Catal. 2017, 359, 3248.
(d) Hu, B.; Zhang, Q.; Zhao, S.; Wang, Y.; Xu, L.; Yan, S.; Yu, F.Adv. Synth. Catal. 2019, 361, 49.
(e) Tong, C.; Gan, B.; Yan, Y.; Xie, Y.-Y.Synth. Commun. 2017, 47, 1927.
(f) More, S. G.; Kamble, R. B.; Suryavanshi, G.J. Org. Chem. 2021, 86, 2107.
(g) Chen H.; Chen L.; He Z.; Zeng Q. Green Chem.2021, 23, 2624.
[14] (a) Ji P.-Y.; Zhang M.-Z.; Xu J.-W.; Liu Y.-F.; Guo, C.-C. J. Org. Chem.2016, 81, 5181.
(b) Zhang, M.-Z.; Luo, N.; Long, R.-Y.; Gou, X.-T.; Shi, W.-B.; He, S.-H.; Jiang, Y.; Chen, J.-Y.; Chen, T.J. Org. Chem. 2018, 83, 2369.
(c) Zhang M.-Z.; Li W.-T.; Li Y.-Y.; Wang Q.; Li C.; Liu Y.-H.; Yin J.-X.; Yang X.; Huang H.; Chen, T. J. Org. Chem.2021, 86, 15544.
[15] (a) Wang, Z.-Y.; Wang, S.; Dai, N.-N.; Xiao, Y.; Zhou, Y.; Tian, W.-C.; Sun, D.; Li, Q.; Wang, Y.; Wei, W.-T.Nat. Commun. 2025, 16, 993.
(b) Zhou Y.; Yang W.-H.; Dai N.-N.; Feng J.-Y.; Yang M.-Q.; Gao W.; Li Q.; Deng C.; Lu Z.; Wei W.-T. Org. Lett.2024, 26, 5074.
(c) Dai N.-N.; Lu Y.-J.; Wu Z.-Q.; Zhou Y.; Tong Y.; Tang K.; Li Q.; Zhang J.-Q.; Liu Y.; Wei W.-T. Org. Lett.2024, 26, 3014.
(d) Yan, Z.; Ye, J.; Wang, H.; Chen, T.; Xu, Z.-F.; Yu, M.; Li, C.-Y.Org. Lett. 2024, 26, 6647.
(e) Zhao, D.; Wang, X.; Huang, J.; Yu, T.; Hao, E.; Ni, S.; Sun, K.Org. Lett. 2025, 27, 1030.
(f) Shi T.; Tian M.; Sun Z.; Zou R.; Zhang Z.; Xie N.; Hao E.; Xu X.; Sun K. Chem. Commun.2025, 61, 4066.
(g) Xu Y.-D.; Xing Y.-M.; Ji H.-T.; Ou L.-J.; He W.-B.; Peng J.; Wang J.-S.; Jiang J.; He, W.-M. J. Org. Chem.2024, 89, 17701.
(h) Ji, H.-T.; Peng, Q.-H.; Wang, J.-S.; Lu, Y.-H.; Dai, H.; Luo, Q.-X.; He, W.-M. Green Chem. 2024, 26, 12084.
(i) Xu H.; Li X.; Wang Y.; Song X.; Shi Y.; Lv J.; Yang D. Org. Lett.2024, 26, 1845.
(j) Wu Q.; Li X.; Ma J.; Shi Y.; Lv J.; Yang D. Org. Lett.2024, 26, 7949.
(k) Tan Y.; Zhao J.; Deng G.-J.; Ji X.; Huang H. Org. Lett.2024, 26, 2398.
(l) Zhu, M.; Wang, Q.-L.; Huang, H.; Mao, G.; Deng, G.-J.J. Org. Chem. 2024, 89, 12591.
(m) Chen T.; Zhang W.; Yan Z.; Xu Z.-F.; Li, C.-Y. Org. Chem. Front.2024, 11, 299.
(n) Niu C.; Yang J.; Yan K.; Su Z.; Li B.; Wen, J. J. Org. Chem.2024, 89, 13284.
[16] For selected latest examples, see:
(a) Wang Q.-L.; Zhou Q.; Liao J.; Chen Z.; Xiong B.-Q.; Deng G.-J.; Tang K.-W.; Liu, Y. J. Org. Chem.2021, 86, 2866.
(b) Xian, N.; Yin, J.; Ji, X.; Deng, G.-J.; Huang, H.Org. Lett. 2023, 25, 1161.
(c) Liu Z.; Zhong S.; Ji X.; Deng G.-J.; Huang H. ACS Catal.2021, 11, 4422.
(d) Zhong L.-J.; Chen H.; Shang X.; Xiong B.-Q.; Tang K.-W.; Liu, Y. J. Org. Chem.2024, 89, 5409.
(e) Zhong L.-J.; Chen H.; Shang X.; Fan J.-H.; Tang K.-W.; Liu Y.; Li, J.-H. J. Org. Chem.2024, 89, 8721.
(f) Wang X.-S.; Zhang Y.-J.; Cao J.; Xu, L.-W. J. Org. Chem.2024, 89, 12848.
(g) Wu, Z.-L.; Liu, J.-T.; Zhou, R.-W.; Deng, M.-Q.; Li, X.; Ji, H.-T.; He, W.-M.J. Org. Chem. 2024, 89, 12693.
(h) Hou H.; Ou W.; Su, C. J. Org. Chem.2024, 89, 4120.
(i) Han, S; Liu, L.; Meng, J.; Li, M.; Cao, Q.; Shen, Z.J. Org. Chem. 2025, 90, 7062.
(j) Cao Y.; Wei Y.; Hu Y.; Liu D.; Liu M.; Wang J.; Li C.; Wang P.; Hu L.; Li, F. Org. Biomol. Chem.2025, 23, 5106.
[17] (a) Lu, M.-Z.; Loh, T.-P.Org. Lett. 2014, 16, 4698.
(b) Li, X.; Xu, J.; Gao, Y.; Fang, H.; Tang, G.; Zhao, Y.J. Org. Chem. 2015, 80, 2621.
(c) Li D.; Shen X. Tetrahedron Lett.2020, 61, 152316.
(d) Zhu M.; Fu W. Heterocycl. Commun.2015, 21, 387.
[18] Su L.; Sun H.; Liu J.; Wang C.Org. Lett. 2021, 23, 4662.
[19] An example of converting arylacrylamide with CCl₄ into a trichloromethylated oxindole was also demonstrated in a metal-free phenol/Cs₂CO₃-promoted cascade cyclization ofN-arylacrylamides with unactivated aryl and alkyl chlorides, see: Jha, A. K.; Nair, D. P.; Arif, M.; Yedase, G. S.; Kuniyil, R.; Yatham, V. R. J. Org. Chem. 2023, 88, 15389.
[20] Chen C.; Liu R.-X.; Xiong F.; Li Z.-H.; Kang J.-C.; Ding T.-M.; Zhang S.-Y. Chem. Commun.2022, 58, 9230.
[21] The α-bromination of ketones is a straightforward method for producing α-bromoketones, which are versatile intermediates in organic synthesis. Commonly used brominating systems in the reported reactions include liquid bromine (Br₂), HBr/H₂O₂, CuBr₂, CuBr, NH₄Br/H₂SO₄, NBS, dibromohydantoin (DBH), etc. However, these bromination systems exhibit at least one of the following drawbacks:(1) unsafe;
(a) Li Z.; B.; Wang C.; Zhang, Lo W. Y.; Yang L.; Sun, J. J. Am. Chem. Soc.2024, 146, 2779.
(b) Podgoršek A.; Stavber S.; Zupan M.; Iskra J. Green Chem.2007, 9, 1212.
(c) Zampieri, D.; Calabretti, A.; Romano, M.; Fortuna, S.; Collina, S.; Amata, E.; Dichiara, M.; Marrazzo, A.; Mamolo, M. G.Molecules 2023, 28, 3431.
(d) Moon D. Y.; An S.; Park B. S. Tetrahedron2019, 75, 130684.
(e) Dong, Y.; Yang, G.; Sun, Z.; Wei, G.; Zhu, X. CN115093374 A, 2022.
(f) Jagatheesan R.; Raj K. J. S.; Lawrence S.; Christopher, C. Int. J. Res. Pharm. Chem.2016, 6, 843.
(g) Wang J.; Wang X.; Niu Z.-Q.; Wang J.; Zhang M.; Li J. Synth. Commun.2016, 46, 165.
(h) Reddy B. M.; Kumar V. V. R.; Reddy N. C. G.; Rao, S. M. Chin. Chem. Lett.2014, 25, 179.
(i) Lee J. C.; Park, H. J. Synth. Commun.2007, 37, 87.
(j) NicDaéid, N.; Meier-Augenstein, W.; Kemp, H. F.; Sutcliffe, O. B.Anal. Chem. 2012, 84, 8691.
(k) Bartroli, J.; Turmo, E.; Alguero, M.; Boncompte, E.; Vericat, M. L.; Garcia-Rafanell, J.; Fom, J.J. Med. Chem. 1995, 38, 3918.
(l) Meltzer P. C.; Butler D.; Deschamps J. R.; Madras, B. K. J. Med. Chem.2006, 49, 1420.
(m) Chai Y.-M.; Zou Q.; Guo Z.-X.; Qin Y.-J.; Zhang P. Tetrahedron Lett.2023, 122, 154517.
[22] The use of tetrabutylammonium tribromide (n-Bu₄NBr₃) as a source of Br₂ in the α-bromination reaction is also documented in the literature, see: Kondoh, A.; Tasato N.; Aoki T.; Terada M. Org. Lett.2020, 22, 5170(in SI file).
[23] Jiang Q.; Sheng W.; Guo C.Green Chem. 2013, 15, 2175.
[24] More optimizations can be found in the Supporting Information.
[25] Zhang M.-Z.; Ji P.-Y.; Liu Y.-F.; Xu J.-W.; Guo, C.-C. Adv. Synth. Catal.2016, 358, 2976.
[26] Xu B.; Zhao H.; Chen H.; Sun D.; Qin M.; Gong P. ChemistrySelect2022, 7, e202201602.
[27] (a) Mu X.; Wu T.; Wang H.-Y.; Guo Y.-L.; Liu, G.-S. J. Am. Chem. Soc. 2012, 134, 878. (b) Fabry D. C.; Stodulski M.; Hoerner S.; Gulder T. Chem.-Eur. J.2012, 18, 10834.