氧膦对吲哚炔串联加成和环化合成二芳基膦酰基吲哚并[1,2-a]喹啉

doi:10.6023/A25080283

摘要/Abstract

首次以二芳基氧化膦(含膦酸酯)为原料, 与吲哚炔反应合成非共平面的二芳基膦酰基吲哚并[1,2-a]喹啉. 该方法涉及银介导的串联加成和环化过程, 包括具有显著位阻的二芳基膦酰基自由基的生成和后续吲哚炔的自由基环化. 该方案具有反应条件比较温和及操作简便等显著优势, 可合成多种非共平面二芳基膦酰基吲哚并[1,2-a]喹啉, 产率中等到良好. 这些化合物在医药和材料科学领域具有重要的应用潜力.

关键词: 串联反应, 加成反应, 自由基环化反应, 银介导反应, 吲哚炔, 二芳基氧化膦

Nitrogen-containing heterocyclic compounds, especially indolo[1,2-a]quinolines with unique tetracyclic frameworks, are widely present in natural products, bioactive substances, and functional materials, exhibiting significant potential in pharmaceuticals and materials science. Meanwhile, heterocyclic organophosphorus compounds have attracted considerable attention due to their extensive applications in organic synthesis, medicinal chemistry, and materials science, and modifying organophosphorus functionalities can enhance biological activities. Herein, a highly efficient and innovative synthetic methodology for the preparation of non-coplanar diarylphosphinoyl indolo[1,2-a]quinolines from indoloalkynes and secondary diarylphosphine oxides has been successfully developed. This approach entails a silver-mediated cascade process, involving the generation of diarylphosphinoyl radicals with significant steric hindrance via the reaction of silver salts (AgOAc as the optimal oxidant) with secondary diarylphosphine oxides, followed by the addition of these radicals to indoloalkynes to form alkenyl radical intermediates, and subsequent intramolecular radical cyclization, oxidation, and deprotonation to construct C—P and C—C bonds. The optimized reaction conditions are determined as: indoloalkynes (1.0 equiv.), secondary diarylphosphine oxides (2.0 equiv.), AgOAc (3.0 equiv.), K₃PO₄ (2.5 equiv.) as the base, MeCN as the solvent, reaction at 100 ℃ under a nitrogen atmosphere for 24 h. Notably, this protocol exhibits excellent substrate compatibility. Electron-rich, electron-deficient, and ortho-substituted aryl groups on indoloalkynes are well-tolerated, yielding corresponding products in 55%~81% yields. Secondary diarylphosphine oxides with electron-withdrawing groups (F), electron-donating groups (Me, OMe), and even alkyl substituents can also participate in the reaction, giving products with moderate to good yields (51%~79%). A gram-scale experiment under optimized conditions still affords the desired product with a 68% yield, demonstrating its potential for large-scale synthesis. Control experiments with the free radical inhibitor 2,2,6,6-tetramethylpiperidinooxy (TEMPO) confirm that the reaction proceeds via a free radical mechanism. Single-crystal X-ray diffraction analysis of the product reveals that the four aromatic rings are non-coplanar (with a 14.899° angle between the normals of two internal aromatic rings) due to steric hindrance from the diarylphosphinoyl group, while maintaining intact aromaticity and stability. Overall, this method features mild reaction conditions, simplicity in operation, broad substrate scope, and the ability to yield diverse non-coplanar diarylphosphinoyl indolo[1,2-a]quinolines, holding considerable potential for applications in pharmaceuticals and materials science, and representing a substantial advancement in the synthesis of such compounds.

Key words: cascade reaction, addition, radical cyclization, silver-mediated reaction, indoloalkyne, diarylphosphine oxide

引用此文

王禾林, 曾庆乐. 氧膦对吲哚炔串联加成和环化合成二芳基膦酰基吲哚并[1,2-a]喹啉[J]. 化学学报, 2026, 84(2): 189-195.

Helin Wang, Qingle Zeng. Cascade Addition and Cyclization of Indoloalkynes with Phosphine Oxides for the Synthesis of Diarylphosphinoyl Indolo[1,2-a]quinolines[J]. Acta Chimica Sinica, 2026, 84(2): 189-195.

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图/表 9

图1. 吲哚并[1,2-a]喹啉的代表性分子

Figure 1. Selected examples of indolo[1,2-a]quinolines

图式1. 吲哚并[1,2-a]喹啉衍生物的合成方法

Scheme 1. Synthetic methods of indolo[1,2-a]quinoline derivatives

Entry	Oxidant	Base	Solvent	Temp./℃	Yield^b/%
1	K₂S₂O₈	K₂CO₃	MeCN	100	32
2	TBHP	K₂CO₃	MeCN	100	42
3	Mn(OAc)₂•4H₂O	K₂CO₃	MeCN	100	36
4	Ag₂CO₃	K₂CO₃	MeCN	100	40
5	AgOAc	K₂CO₃	MeCN	100	53
6	—	K₂CO₃	MeCN	100	0
7	AgOAc	NaH	MeCN	100	46
8	AgOAc	K₃PO₄	MeCN	100	73
9	AgOAc	Na₂CO₃	MeCN	100	59
10	AgOAc	t-BuOK	MeCN	100	42
11	AgOAc	Et₃N	MeCN	100	45
12	AgOAc	K₃PO₄	Toluene	100	52
13	AgOAc	K₃PO₄	DMSO	100	27
14	AgOAc	K₃PO₄	1,4-Dioxane	100	30
15	AgOAc	K₃PO₄	MeCN	80	56
16	AgOAc	K₃PO₄	MeCN	120	47
17^c	AgOAc	K₃PO₄	MeCN	100	14
18^d	AgOAc	K₃PO₄	MeCN	100	78
19^e	AgOAc	K₃PO₄	MeCN	100	62

表1. 反应条件优化a

Table 1. Optimization of reaction conditions

图式2. 3-甲基-1-[2-(芳基乙炔基)苯基]-1H-吲哚的底物适用范围

Scheme 2. Substrate scope of 3-methyl-1-[2-(arylethynyl) phenyl]-1H-indoles

图式3. 芳基氧化膦(含膦酸酯)的底物范围

Scheme 3. Substrate scope of arylphosphine oxides (including phosphinates)

图式4. 克级制备

Scheme 4. Gram-scale preparation

图式5. 控制实验

Scheme 5. Control experiments

图式6. 可能的反应机理

Scheme 6. A plausible mechanism

图2. 产物3ag的单晶X射线衍射图(CCDC 2403895)

Figure 2. Diagram of the single crystal X-ray diffraction of product 3ag (CCDC 2403895)

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