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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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