铜催化2-氨基苯甲酸与异硫氰酸酯脱硫环化合成2-氨基苯并-1,3-噁嗪-4-酮

doi:10.6023/cjoc202601010

摘要/Abstract

2-氨基取代的苯并噁嗪酮衍生物因其显著的药理活性而备受关注, 在药物研发中具有重要地位. 此研究发展了一种廉价铜催化策略, 以氧气为氧化剂, 实现了2-氨基苯甲酸与异硫氰酸酯的脱硫环化反应, 高效合成2-氨基苯并-1,3-噁嗪-4-酮衍生物. 机理研究表明, 反应通过铜脱硫环化机制过程, 促进硫脲中间体的脱硫及分子内C—O键的构建. 该方法避免了贵金属催化剂和外源氧化剂的使用, 条件温和、操作简便, 为苯并噁嗪酮类化合物的绿色合成提供了新思路.

关键词: 铜催化, 苯并噁嗪酮, 氧气, 异硫氰酸酯, 脱硫环化

2-Amino-substituted benzoxazinone derivatives have attracted considerable attention due to their remarkable pharmacological activities and play an important role in drug discovery. In this work, an inexpensive copper-catalyzed strategy that utilizes oxygen as a green oxidant to achieve desulfative cyclization of 2-aminobenzoic acids with isothiocyanates has been developed, enabling the efficient synthesis of 2-amino-1,3-benzoxazin-4-one derivatives. Mechanistic studies reveal that the reaction proceeds via a copper-mediated desulfative cyclization mechanism, facilitating the desulfurization of thiourea intermediates and the construction of intramolecular C—O bonds. This approach avoids the use of precious metal catalysts and external oxidants, features mild reaction conditions and simple manipulation, and thus provides a new avenue for the green synthesis of benzoxazinone derivatives.

Key words: copper catalysis, benzoxazinone, molecular oxygen, isothiocyanates, desulfurative cyclization

引用此文

高鹰鹏, 张林军, 宋基懿, 钟品勇, 刘晋彪. 铜催化2-氨基苯甲酸与异硫氰酸酯脱硫环化合成2-氨基苯并-1,3-噁嗪-4-酮[J]. 有机化学, 2026, 46(7): 2808-2815.

Yingpeng Gao, Linjun Zhang, Jiyi Song, Pinyong Zhong, Jinbiao Liu. Catalytic Synthesis of 2-Aminobenz-1,3-oxazin-4-ketone by Copper-Catalyzed Desulfurization and Cyclization of 2-Aminobenzoic Acid and Isothiocyanate[J]. Chinese Journal of Organic Chemistry, 2026, 46(7): 2808-2815.

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图/表 8

图1. 含有苯并噁嗪酮类化合物分子

Figure 1. Molecules containing benzoxazinone compounds

图式1. 2-氨基-1,3-苯并噁嗪-4-酮的合成方法

Scheme 1. Synthesis of 2-amino-1,3-benzoxazin-4-one

Entry	Photocatalyst	Solvent	Base	Yield/%
1	CuSO₄•5H₂O	DMF	DMAP	84
2	FeCl₃	DMF	DMAP	42
3	AlCl₃	DMF	DMAP	14
4	CoCl₂	DMF	DMAP	52
5	CuI	DMF	DMAP	79
6	CuCl₂	DMF	DMAP	96
7	－	DMF	DMAP	25
8	CuCl₂	DMSO	DMAP	92
9	CuCl₂	DCE	DMAP	83
10	CuCl₂	EtOH	DMAP	17
11	CuCl₂	MeCN	DMAP	18
12	CuCl₂	Toluene	DMAP	23
13	CuCl₂	1,4-Dioxane	DMAP	20
14	CuCl₂	DMF	DBU	10
15	CuCl₂	DMF	DBN	ND
16	CuCl₂	DMF	NaOH	33
17	CuCl₂	DMF	t-BuOK	21
18	CuCl₂	DMF	Na₂CO₃	21
19	CuCl₂	DMF	Et₃N	27
20	CuCl₂	DMF	Na₃PO₄	32

表1. 2-氨基苯并-1,3-噁嗪-4-酮合成反应条件的优化a

Table 1. Optimization of the reaction conditions for the synthesis of 2-aminobenz-1,3-oxazin-4-ketone

表2. 2-氨基苯甲酸的适用范围a

Table 2. Scope of 2-aminobenzoic acid

表3. 芳基异硫氰酸酯的适用范围a

Table 3. Scope of aromatic isothiocyanates

图式2. 2-(苯基氨基)-5,6-二氢-1,3-氧氮杂䓬-7(4H)-酮的合成

Scheme 2. Synthesis of 2-(phenylamino)-5,6-dihydro-1,3-oxazepin-7(4H)-one

图式3. 对照试验

Scheme 3. Control experiments

图式4. 可能的反应机理

Scheme 4. Proposed mechanism

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