无过渡金属参与的“一锅法”合成咔啉及其衍生物的新方法

doi:10.6023/cjoc202505007

有机化学 ›› 2025, Vol. 45 ›› Issue (10): 3824-3837.DOI: 10.6023/cjoc202505007 上一篇下一篇

研究论文

无过渡金属参与的“一锅法”合成咔啉及其衍生物的新方法

谢桂玲^a^,^b^,^†, Sudhakar Reddy Mopuri^b^,^†, 李杰^b, 杨元勇^a, 陈铁根^b^,^c^,^*()

^a 贵州医科大学药学院中药功效成分发掘与利用全国重点实验室贵阳 550000
^b 中科中山药物创新研究院广东中山 528400
^c 中国科学院上海药物研究所上海 201203

收稿日期:2025-05-06 修回日期:2025-05-21 发布日期:2025-06-11
作者简介:
^† 共同第一作者.
基金资助:
国家自然科学基金(22371303); 中山市科技局(2021B2014); 中山市科技局(CXTD2022013); 上海市科委“启明星”计划(21QA1411000)

One-Pot Transition-Metal-Free Synthesis of Carboline Derivatives via Dual C—N Bond Formation

Guiling Xie^a^,^b, Sudhakar Reddy Mopuri^b, Jie Li^b, Yuanyong Yang^a, Tie-Gen Chen^b^,^c^,^*()

^a State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang 550000
^b Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, Guangdong 528400
^c Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203

Received:2025-05-06 Revised:2025-05-21 Published:2025-06-11
Contact: * chentiegen@simm.ac.cn
About author:
^† The authors contributed equally to this work.
Supported by:
National Natural Science Foundation of China(22371303); Zhongshan Municipal Bureau of Science and Technology(2021B2014); Zhongshan Municipal Bureau of Science and Technology(CXTD2022013); Shanghai Rising-Star Program(21QA1411000)

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摘要/Abstract

报道了一种以二卤代联芳基吡啶化合物和伯胺为起始原料, 通过构建两个C—N键合成一系列α-、β-、γ-、δ-咔啉及其衍生物的方法. 反应在叔丁醇锂(t-BuOLi)或碳酸铯(Cs₂CO₃)存在下进行, 无需使用任何金属和氧化剂, 具有良好的底物适用性. 该方法可以实现克级规模的制备以及有机材料2,6-CbPy的合成，并进行产物转化.

关键词: 咔啉及其衍生物, 伯胺, 无过渡金属, 双C—N键构建, “一锅法”反应

A transition-metal-free strategy for the synthesis of carboline derivatives via sequential dual C—N bond formation in a one-pot reaction is reported. Using 2,2'-dihalogenated pyridyl biaryls and primary amines as starting materials，this method efficiently constructs a series of α-, β-, γ- and δ-carbolines under alkaline conditions. The reaction proceeds smoothly in the presence of lithium tert-butoxide (t-BuOLi) or cesium carbonate (Cs₂CO₃) without requiring transition metal catalysts, demonstrating good functional group tolerance. This approach enables gram-scale synthesis and has been successfully applied to the preparation of the organic material 2,6-CbPy, achieving high conversion efficiency.

Key words: carboline derivatives, primary amines, transition-metal-free, dual C—N bond formation, one-pot reaction

引用此文

谢桂玲, Sudhakar Reddy Mopuri, 李杰, 杨元勇, 陈铁根. 无过渡金属参与的“一锅法”合成咔啉及其衍生物的新方法[J]. 有机化学, 2025, 45(10): 3824-3837.

Guiling Xie, Sudhakar Reddy Mopuri, Jie Li, Yuanyong Yang, Tie-Gen Chen. One-Pot Transition-Metal-Free Synthesis of Carboline Derivatives via Dual C—N Bond Formation[J]. Chinese Journal of Organic Chemistry, 2025, 45(10): 3824-3837.

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图/表 10

Figure 1. Bioactive compounds with carboline derivatives

Figure 2. Strategies for carboline synthesis

Entry	Base	Solvent	T/℃	Yield^b/%
1	t-BuOK	DMSO	120	30
2	t-BuOLi	DMSO	120	33
3	t-BuONa	DMSO	120	25
4	LiHMDS	DMSO	120	9
5	Cs₂CO₃	DMSO	120	9
6	NaOH	DMSO	120	17
7	NaH	DMSO	120	25
8	DIPEA	DMSO	120	ND
9	t-BuOLi	DMF	120	9
10	t-BuOLi	NMP	120	NR
11	t-BuOLi	PhCH₃	120	ND
12	t-BuOLi	MeCN	120	ND
13^c	t-BuOLi	DMSO	120	60
14^c^,^d	t-BuOLi	DMSO	120	66
15^c^,^d	t-BuOLi	DMSO	100	73
16^c^,^d^,^e	t-BuOLi	DMSO	100	82 (80)^f
17^d^,^e^,^g	t-BuOLi	DMSO	100	70
18^c^,^d^,^e	t-BuOLi	DMSO	80	43
19^d^,^e	—	DMSO	100	NR

Table 1. Optimization of reaction conditionsa

Table 2. Substrate scope with 2,2'-dihalogenated pyridyl biarylsa,b

Table 3. Substrate scope with aromatic aminesa,b

Table 4. Substrate scope with 4-phenylpyridine N-oxides and alkylaminesa,b

Scheme 1. Synthesis of a series of 6-substituted β-carbolines

Scheme 2. Synthesis of 2,6-CbPy

Scheme 3. Mechanistic experiment

Scheme 4. Proposed reaction mechanism

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无过渡金属参与的“一锅法”合成咔啉及其衍生物的新方法

One-Pot Transition-Metal-Free Synthesis of Carboline Derivatives via Dual C—N Bond Formation

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