温和条件下苯炔与2-羟基嘧啶加成合成2-芳氧基嘧啶类衍生物

doi:10.6023/cjoc202206011

摘要/Abstract

嘧啶芳基醚衍生物因具有多样的生物活性和药理学特性而受到化学家的广泛关注. 利用2-(三甲基甲硅烷基)苯基三氟甲烷磺酸酯作为苯炔源, 与2-羟基嘧啶发生加成反应, 以中等至良好的产率合成了一系列2-芳氧基嘧啶类衍生物. 与传统的方法相比, 该方法具有无需过渡金属催化, 嘧啶底物易于制备, 底物官能团兼容性强和产物产率高等优点.

关键词: 苯炔, 嘧啶衍生物, 亲核加成, 2-苯氧基嘧啶

Pyrimidine aryl ether derivatives have attracted widespread attention from chemists for their diverse biological activity and pharmacological properties. In this paper, a series of pyrimidine-2-arylether derivatives were synthesized with moderate to good yield by using 2-(trimethylsilyl)phenyl trifluoromethanesulfonate as a source of benzyne to react with 2-hydroxypyrimidine. Compared with the traditional method, this method has the advantages of transition-metal-free, easy preparation of 2-aryloxypyrimidine derivatives, wide functional group compatibility and high yield.

Key words: benzyne, pyrimidine derivatives, nucleophilic addition, 2-phenoxy pyrimidine

引用此文

王文鹏, 杨春红, 刘海超, 王喜存, 权正军. 温和条件下苯炔与2-羟基嘧啶加成合成2-芳氧基嘧啶类衍生物[J]. 有机化学, 2022, 42(11): 3835-3842.

Wenpeng Wang, Chunhong Yang, Haichao Liu, Xicun Wang, Zhengjun Quan. Addition of Benzyne to 2-Hydroxypyrimidine to Synthesize 2-Aryloxypyrimidine Derivatives under Mild Conditions[J]. Chinese Journal of Organic Chemistry, 2022, 42(11): 3835-3842.

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图/表 6

图式1. 2-芳氧基嘧啶化合物的合成方法

Scheme 1. Synthetic method of 2-phenoxypyrimidine compounds

Entry	Additive	Base	Solvent	Yield^b/%
1	KF/18-crown-6	—	CH₃CN	28
2	KF/18-crown-6	—	DCM	11
3	KF/18-crown-6	—	THF	36
4	KF/18-crown-6	—	DME	23
5	KF/18-crown-6	—	DCE	14
6	KF/18-crown-6	—	Dioxane	43
7	KF/18-crown-6	—	Toluene	47
8^c	CsF	—	Toluene	60
9	TBAT	—	Toluene	38
10	TBAF	—	Toluene	45
11	CsF	Cs₂CO₃	Toluene	81
12	CsF	K₂CO₃	Toluene	72
13	CsF	^tBuOK	Toluene	69
14	CsF	Et₃N	Toluene	61
15^d	CsF	Cs₂CO₃	Toluene	81
16^e	CsF	Cs₂CO₃	Toluene	74
17^f	CsF	Cs₂CO₃	Toluene	79
18^g	CsF	Cs₂CO₃	Toluene	71
19^h	CsF	Cs₂CO₃	Toluene	82

表1. 2-羟基嘧啶与苯炔的反应条件优化a

Table 1. Optimization of reaction conditions of 2-hydroxypyrimidine with benzyne

表2. 2-苯氧基嘧啶化合物的底物拓展a

Table 2. Scope of 2-phenoxypyrimidine compoundsa

图式2. 取代苯炔与2-羟基嘧啶的反应性

Scheme 2. Reactivity of substituted benzynes with 2-hydroxypyrimidines

图式3. 3b的克级合成反应

Scheme 3. Gram-scale synthesis of 3b

图式4. 2-羟基嘧啶与苯炔反应的可能机理

Scheme 4. Possible mechanism for the reaction of 2-hydroxypyrimidine with benzyne

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