一种无过渡金属、绿色温和的一锅法合成3-碘代/溴代咪唑并[1,2-a]吡啶类化合物

doi:10.6023/cjoc202509015

摘要/Abstract

以2-氨基吡啶类化合物、甲酰基甲基溴类化合物和碘化钾(KI)为反应物, 建立了一种无过渡金属参与的一锅多步策略, 用于高效合成3-碘代咪唑并[1,2-a]吡啶衍生物. 该方法具有显著优势: 无需过渡金属、反应条件温和(在室温下进行), 且使用绿色无毒的碘化试剂. 值得注意的是, 带有给电子基团和吸电子基团的2-氨基吡啶与甲酰基甲基溴均表现出良好的兼容性, 其中带有给电子基团的底物通常能获得略高的产率. 通过对照实验进行机理研究表明, 该反应遵循两步反应机理: 首先, 2-氨基吡啶与甲酰基甲基溴反应生成咪唑并[1,2-a]吡啶中间体; 随后, 该中间体与KI发生C3位碘化反应. 此外, 该策略可扩展至3-溴代咪唑并[1,2-a]吡啶的合成. 在优化条件(65 ℃, 6 h)下, 以溴化钾(KBr)为溴源, 产物产率可达55%~97%.

关键词: 咪唑并[1,2-a]吡啶衍生物, 一锅多步反应, 碘化反应, 无过渡金属, 碘化钾

A transition-metal-free one-pot multi-step strategy has been established for the efficient synthesis of 3-iodoimida- zo[1,2-a]pyridine derivatives, utilizing 2-aminopyridines, formyl methyl bromides, and potassium iodide (KI) as reactants. This protocol boasts notable advantages: freedom from transition metals, mild reaction conditions (proceeding at room temperature), and employment of green, non-toxic iodinating reagents. Notably, 2-aminopyridines and formyl methyl bromides substituted with both electron-donating groups (EDGs) and electron-withdrawing groups exhibit good compatibility, and substrates substituted with EDGs generally afford slightly higher yields. Mechanistic investigations through control experiments demonstrate that the reaction follows a two-step mechanism: initially, 2-aminopyridine reacts with formyl methyl bromide to form an imidazo[1,2-a]pyridine intermediate, which then undergoes C3-iodination with KI. Furthermore, this strategy is extendable to the synthesis of 3-bromoimidazo[1,2-a]pyridines by using potassium bromide (KBr) as the bromine source under adjusted conditions (65 ℃, 6 h), yielding products with 55%~97% yields.

Key words: imidazo[1,2-a]pyridine, one-pot multi-step reaction, iodination reaction, transition-metal-free, potassium iodide

引用此文

杨利婷, 潘慧茹, 许晓旭, 张益恺, 来姝妤, 曹信誉, 刘国群, 乔辉杰, 焦明立. 一种无过渡金属、绿色温和的一锅法合成3-碘代/溴代咪唑并[1,2-a]吡啶类化合物[J]. 有机化学, 2026, 46(3): 915-924.

Liting Yang, Huiru Pan, Xiaoxu Xu, Yikai Zhang, Shuyu Lai, Xinyu Cao, Guoqun Liu, Huijie Qiao, Mingli Jiao. A Green and Mild One-Pot Protocol for the Synthesis of 3-Iodo-/Bromo-imidazo[1,2-a]pyridines without Transition Metals[J]. Chinese Journal of Organic Chemistry, 2026, 46(3): 915-924.

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[13]	Yang, M.; Shao, Y.; Zhang, W.; Wan, Y.; Zhou, P.; Tang, D. Tetrahedron Lett. 2024, 144, 155135.
[14]	Chen, H.; Wang, Y.; Liu, Q.; Guo, Y.; Cao, S.; Zhao, Y. Chin. J. Chem. 2022, 40, 2313.
[15]	Kalari, S.; Balasubramanian, S.; Rode, H. B. Tetrahedron Lett. 2021, 71, 153028.
[16]	Mondal, S.; Samanta, S.; Singsardar, M.; Mishra, S.; Mitra, S.; Hajra, A. Synthesis 2016, 48, 4009.
[17]	Das, D.; Bhutia, Z. T.; Panjikar, P. C.; Chatterjee, A.; Banerjee, M. J. Heterocycl. Chem. 2020, 57, 4099.
[18]	Yang, C.-Y.; Hu, L.-P.; Zhang, D.-R.; Li, X.; Teng, M.-Y.; Liu, B.; Huang, G.-L. New J. Chem. 2022, 46, 10934.
[19]	Neto, J. S. S.; Balaguez, R. A.; Franco, M. S.; Machado, V. C. Saba, S.; Rafique, J.; Galetto, F. Z.; Braga, A. L. Green Chem. 2020, 22, 3410.
[20]	Paul, S.; Das, S.; Choudhuri, T.; Sikdar, P.; Bagdi, A. K. Chem. Asian J. 2025, 20, e202401101.
[21]	Volla, C. M.; Atodiresei, I.; Rueping, M. Chem. Rev. 2014, 114, 2390.
[22]	Chen, D.-F.; Han, Z.-Y.; Zhou, X.-L.; Gong, L.-Z. Acc. Chem. Res. 2014, 47, 2365.
[23]	Zhu, S.; Zhao, X.; Li, H.; Chu, L. Chem. Soc. Rev. 2021, 50, 10836.
[24]	Flores-Reyes, J. C.; Islas-Jácome, A.; González-Zamora, E. Org. Chem. Front. 2021, 8, 5460.
[1]	Bagdi, A. K.; Santra, S.; Monira, K.; Hajra, A. Chem. Commun. 2015, 51, 1555.
[2]	Liu, X.; Fu, H.; Hu, Q.; Cao, H. Chem. Rec. 2024, 24, e202400135.
[3]	Liu, X.; Li, W.; Liu, H.; Cao, H. Chin. J. Org. Chem. 2021, 41, 1759 (in Chinese).
	(刘想, 李文, 刘环宇, 曹华, 有机化学, 2021, 41, 1759.)
[4]	Harrison, T. S.; Keating, G. M. CNS Drugs 2005, 19, 65.
[5]	Wei, C.; Huang, J.; Luo, Y.; Wang, S.; Wu, S.; Xing, Z.; Chen, J. Pestic. Biochem. Physiol. 2021, 175, 104857.
[6]	Yu, W.; Song, L.; Tian, X.; Zhao, T.; Wang, M.; Wu, J.; Qiao, Y.; Chang, J. Chin. J. Org. Chem. 2018, 38, 1530 (in Chinese).
	(于文全, 宋利娜, 田显海, 赵婷, 王漫漫, 武杰, 乔艳, 常俊标, 有机化学, 2018, 38, 1530.)
[25]	Climent, M. J.; Corma, A.; Iborra, S. Chem. Rev. 2011, 111, 1072.
[26]	Chen, L.; Wang, B.; Zhao, Y.; Yan, S.; Lin, J. Chin. J. Org. Chem. 2017, 37, 1433 (in Chinese).
	(陈亮, 王保取, 赵宇澄, 严胜骄, 林军, 有机化学, 2017, 37, 1433.)
[27]	Guan, Y.; Ying, Y.-L.; Wang, B.; Mo, L.-P.; Zhang, Z.-H. J. Catal. 2025, 443, 115938.
[28]	Gao, G.; Wang, P.; Liu, P.; Zhang, W.; Mo, L.; Zhang, Z. Chin. J. Org. Chem. 2018, 38, 846.
[29]	Peng, Q. H.; Li, N. B.; Hou, J. C.; He, C. J.; Yang, Y. X.; Zhuang, C. L.; Ou, L. J.; Yuan, M.; He, W. M. Chin. Chem. Lett. 2025, 36, 111402.
[30]	Meng, X.; Yu, C.; Chen, G.; Zhao, P. Catal. Sci. Technol. 2015, 5, 372.
[7]	Chen, Y.; Lei, H.; Li, T.; Cui, Y.; Wang, X.; Cao, Z.; Wu, H.; Zhai, X. Bioorg. Med. Chem. 2021, 46, 116362.
[8]	Zheng, X.-H.; Zhao, J.-W.; Chen, X.; Cai, R.; Yang, G.-X.; Zhu, J.-J.; Tang, S.-S.; Lin, Z.-H.; Tao, S.-L.; Tong, Q.-X. Chem.-Eur. J. 2020, 26, 8588.
[9]	Shi, L.; Li, T.; Mei, G.-J. Green Synth. Catal. 2022, 3, 227.
[10]	Rostrup, F.; Falk-Petersen, C. B.; Harpsoe, K.; Buchleithner, S.; Conforti, I.; Jung, S.; Gloriam, D. E.; Schirmeister, T.; Wellendorph, P.; Frølund, B. J. Med. Chem. 2021, 64, 4730.
[11]	Zhang, C.-P.; Wang, Z.-L.; Chen, Q.-Y.; Zhang, C.-T.; Gu, Y.-C.; Xiao, J.-C. Angew. Chem., Int. Ed. 2011, 50, 1896.
[12]	Wan, J.; Zheng, C.-J.; Fung, M.-K.; Liu, X.-K.; Lee, C.-S.; Zhang, X.-H. J. Mater. Chem. 2012, 22, 4502.
[31]	Chillal, A. S.; Maurya, C.; Kshirsagar, U. A. Langmuir 2024, 40, 23445.
[32]	Chillal, A. S.; Bhawale, R. T.; Kshirsagar, U. A. RSC Adv. 2024, 14, 13095.
[33]	Indukuri, D. R.; Potuganti, G. R.; Alla, M. Synlett 2019, 30, 1573.
[34]	Semwal, R.; Ravi, C.; Kumar, R.; Meena, R.; Adimurthy, S. J. Org. Chem. 2019, 84, 792.
[35]	Park, J. W.; Kim, Y. H.; Kim, D. Y. Synth. Commun. 2020, 50, 710.
[36]	Qiao, H.; Zhao, K.; Li, Y.; Yang, L.; Yang, F. Green Chem. 2023, 25, 8385.
[37]	Qiao, H.; Yang, L.; Chen, Y.; Wang, J.; Sun, W.; Dong, H.; Wang, Y. Chin. J. Org. Chem. 2022, 42, 1188 (in Chinese).
	(乔辉杰, 杨利婷, 陈雅, 王嘉琳, 孙武轩, 董昊博, 王云威, 有机化学, 2022, 42, 1188.)
[38]	Qiao, H.; Zhao, K.; Wang, S.; Xu, X.; Chen, S.; Kong, X.; Yang, L.; Jiao, M.; Zhai, L. Chem.-Eur. J. 2024, 30, e202402246.
[39]	Qiao, H.; Zhao, K.; Zhu, X.; Xu, X.; Wang, S.; Yang, L.; Wang, C.; Zhong, L.; Ma, B.; Yang, D.; Xing, P.; Liu, G.; Jiao, M. J. Org. Chem. 2024, 89, 7521.
[40]	Xu, X.; Chen, D.; Wang, Z. Chin. J. Org. Chem. 2019, 39, 3338 (in Chinese).
	(徐鑫明, 陈德茂, 王祖利, 有机化学, 2019, 39, 3338.)
[41]	Udavant, R. N.; Yadav, A. R.; Shinde, S. S. Eur. J. Org. Chem. 2018, 2018, 3432.
[42]	Zhang, L.; Wang, B.; Pan, D.; Wang, C.; Zhao, Y.; Chi, H.; Dong, Y.; Wei, W.; Zhang, Z. Chin. J. Org. Chem. 2025, 45, 2923 (in Chinese).
	(张连吉, 王炳福, 潘大龙, 王翠苹, 赵玉辉, 迟海军, 董岩, 魏万国, 张志强, 有机化学, 2025, 45, 2923.)
[43]	Wang, X.; Mu, S.; Sun, T.; Sun, K. Chin. J. Org. Chem. 2019, 39, 2802 (in Chinese).
	(王薪, 穆石强, 孙婷, 孙凯, 有机化学, 2019, 39, 2802.)
[44]	Zhu, S.; Wang, B.; Li, H.; Xiao, W.; Teng, F.; Shen, H.; Gui, Q. W.; Li, Z.; Jiang, H. ChemistrySelect 2020, 5, 12329.
[45]	Xiao, X.; Xie, Y.; Bai, S.; Deng, Y.; Jiang, H.; Zeng, W. Org. Lett. 2015, 17, 3998.
[46]	Zhang, Z.; Guo, Y.; Yang, J.; Wu, D.; Wang, J.; Hong, X.; Cai, P.; Rong, L. C. Chin. J. Org. Chem. 2023, 43, 2104 (in Chinese).
	(张周, 郭钰, 羊静, 吴丹, 王佳昕, 洪欣玥, 蔡佩君, 荣良策, 有机化学, 2023, 43, 2104.)
[47]	He, P.; Liu, C.; Shen, Q.; Xia, J.; Han, Y.; Xiong, W.; Li, Z.; Tang, S.; Liu, Z.; Zhang, F. Lett. Org. Chem. 2023, 20, 72.
[48]	Sen, P. P.; Roy, V. J.; Roy, S. R. J. Org. Chem. 2022, 87, 9551.
[49]	Zhou, Z.; Yuan, Y.; Cao, Y.; Qiao, J.; Yao, A.; Zhao, J.; Zuo, W.; Chen, W.; Lei, A. Chin. J. Chem. 2019, 37, 611.

Entry	Solvent	Oxidant	Yield^b/%
1	DCE	K₂S₂O₈	86
2	PE	K₂S₂O₈	48
3	EA	K₂S₂O₈	<5
4	DMF	K₂S₂O₈	<5
5	1,4-Dioxane	K₂S₂O₈	63
6	EtOH	K₂S₂O₈	67
7	Toluene	K₂S₂O₈	55
8	CH₃CN	K₂S₂O₈	23
9	H₂O	K₂S₂O₈	76
10	CH₃CN/H₂O (V/V=2/1)	K₂S₂O₈	91
11	CH₃CN/H₂O (V/V=1/2)	K₂S₂O₈	88
12	CH₃CN/H₂O (V/V=1/1)	K₂S₂O₈	94
13	CH₃CN/H₂O (V/V=1/1)	TBHP	<5
14	CH₃CN/H₂O (V/V=1/1)	DTBP	<5
15	CH₃CN/H₂O (V/V=1/1)	Na₂S₂O₈	90
16	CH₃CN/H₂O (V/V=1/1)	(NH₄)₂S₂O₈	78
17	CH₃CN/H₂O (V/V=1/1)	KHSO₅	82
18	CH₃CN/H₂O (V/V=1/1)	—	<5
19^c	CH₃CN/H₂O (V/V=1/1)	K₂S₂O₈	94
20^d	CH₃CN/H₂O (V/V=1/1)	K₂S₂O₈	92

Entry	Solvent	Oxidant	Yield^b/%
1	DCE	K₂S₂O₈	86
2	PE	K₂S₂O₈	48
3	EA	K₂S₂O₈	<5
4	DMF	K₂S₂O₈	<5
5	1,4-Dioxane	K₂S₂O₈	63
6	EtOH	K₂S₂O₈	67
7	Toluene	K₂S₂O₈	55
8	CH₃CN	K₂S₂O₈	23
9	H₂O	K₂S₂O₈	76
10	CH₃CN/H₂O (V/V=2/1)	K₂S₂O₈	91
11	CH₃CN/H₂O (V/V=1/2)	K₂S₂O₈	88
12	CH₃CN/H₂O (V/V=1/1)	K₂S₂O₈	94
13	CH₃CN/H₂O (V/V=1/1)	TBHP	<5
14	CH₃CN/H₂O (V/V=1/1)	DTBP	<5
15	CH₃CN/H₂O (V/V=1/1)	Na₂S₂O₈	90
16	CH₃CN/H₂O (V/V=1/1)	(NH₄)₂S₂O₈	78
17	CH₃CN/H₂O (V/V=1/1)	KHSO₅	82
18	CH₃CN/H₂O (V/V=1/1)	—	<5
19^c	CH₃CN/H₂O (V/V=1/1)	K₂S₂O₈	94
20^d	CH₃CN/H₂O (V/V=1/1)	K₂S₂O₈	92