A Green and Mild One-Pot Protocol for the Synthesis of 3-Iodo-/Bromo-imidazo[1,2-a]pyridines without Transition Metals

doi:10.6023/cjoc202509015

Chinese Journal of Organic Chemistry ›› 2026, Vol. 46 ›› Issue (3): 915-924.DOI: 10.6023/cjoc202509015 Previous Articles Next Articles

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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

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^*()

中原工学院材料电子与储能学院河南省功能盐材料重点实验室河南省功能盐材料重点实验室郑州 450007

收稿日期:2025-09-11 修回日期:2025-12-04 发布日期:2026-01-06
通讯作者: 刘国群, 乔辉杰, 焦明立
基金资助:
国家自然科学基金(52403287); 河南省高校科技创新团队(23IRTSTHN019); 河南省科技攻关(252102230155)

A Green and Mild One-Pot Protocol for the Synthesis of 3-Iodo-/Bromo-imidazo[1,2-a]pyridines without Transition Metals

Liting Yang, Huiru Pan, Xiaoxu Xu, Yikai Zhang, Shuyu Lai, Xinyu Cao, Guoqun Liu^*(), Huijie Qiao^*(), Mingli Jiao^*()

Henan Key Laboratory of Functional Salt Materials, School of Materials Electronics and Energy Storage,Zhongyuan University of Technology, Zhengzhou 450007

Received:2025-09-11 Revised:2025-12-04 Published:2026-01-06
Contact: Guoqun Liu, Huijie Qiao, Mingli Jiao
Supported by:
National Natural Science Foundation of China(52403287); Program for Innovative Research Team (in Science and Technology) in University of Henan Province(23IRTSTHN019); Key Technological Research Project of Henan Province(252102230155)

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Abstract

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

Cite this article

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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Fig. & Tab. 6

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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

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

A Green and Mild One-Pot Protocol for the Synthesis of 3-Iodo-/Bromo-imidazo[1,2-a]pyridines without Transition Metals

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