无金属条件下烯酰胺的直接硝化反应制备β-氨基硝基烯烃

doi:10.6023/cjoc202412011

摘要/Abstract

β-氨基硝基烯烃是有机合成和医药研究领域中一类重要的生物活性化合物. 目前为止, 虽然已有一些文献报道, 但简单、便捷地合成该类化合物依然是迫切需求的. 此研究发展了一种无金属条件下叔烯酰胺与亚硝酸叔丁酯的直接硝化反应. 基于此反应, 一系列环状和链状的烯酰胺能够被简便易得的非金属试剂进行硝化, 并以优良的产率生成了多种有价值的β-酰氨基硝基烯烃类化合物. 此外, 该反应还具有操作简单、底物范围广、官能团兼容性好等特点.

关键词: 烯酰胺, 硝化反应, β-氨基硝基烯烃, 亚硝酸叔丁酯

β-Amino nitroalkenes are important elements in the medicinal research and organic synthetic chemistry. Despite many documented methods, a facile and convenient synthesis remains desirable so far. Herein, a direct nitration of tertiary enamide with tert-butyl nitrite (^tBuONO) under metal-free conditions is disclosed. A wide array of cyclic and acyclic enamides was nitrated with commercially available nonmetallic reagents, which produced diverse valuable β-acylamino nitroalkenes in excellent yields. Furthermore, this protocol is operationally simple and exhibits broad substrate scope and good functional group compatibility.

Key words: enamide, nitration, β-amino nitroalkenes, tert-butyl nitrite

引用此文

刘菲, 徐鑫明, 王薪, 刘春阳, 陈雪波, 孙凯. 无金属条件下烯酰胺的直接硝化反应制备β-氨基硝基烯烃[J]. 有机化学, 2025, 45(10): 3903-3911.

Fei Liu, Xinming Xu, Xin Wang, Chunyang Liu, Xuebo Chen, Kai Sun. Direct Nitration of Enamide to β-Acylamino Nitroalkenes under Metal-Free Conditions[J]. Chinese Journal of Organic Chemistry, 2025, 45(10): 3903-3911.

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图/表 7

Figure 1. Representative pharmaceuticals with β-amino nitroalkene or 1,2-diamine moiety

Scheme 1. Conventional synthesis of β-amino nitroalkenes and direct nitration of enamides

Entry		Solvent^b	T/℃	t/h	Yield^c^/%
1	K₂S₂O₈	1,4-Dioxane	90	13	63
2	TBHP	1,4-Dioxane	90	13	60
3	DTBP	1,4-Dioxane	90	13	70
4	DCP	1,4-Dioxane	90	13	56
5	TEMPO	1,4-Dioxane	90	13	74
6	BPO	1,4-Dioxane	90	13	58
7	TEMPO	THF	90	14	72
8	TEMPO	DCE	90	12	62
9	TEMPO	Toluene	90	14	61
10	TEMPO	CH₃CN	90	8	88
11	TEMPO	CH₃CN	80	9	73
12	TEMPO	CH₃CN	100	8	78
13	TEMPO	CH₃CN	110	8	75
14^d	TEMPO	CH₃CN	90	12	66
15^e	TEMPO	CH₃CN	90	12	77
16^f	TEMPO	CH₃CN	90	16	64
17^g	TEMPO	CH₃CN	90	16	41
18^h	TEMPO	CH₃CN	90	16	8

Table 1. Reaction condition optimizationa

Scheme 2. Direct nitration of cyclic enamides Reaction conditions: tertiary enamides 1 (0.5 mmol, 1.0 equiv.), tBuONO (1.0 mmol, 2.0 equiv.), TEMPO (0.2 mmol, 0.4 equiv.) and CH3CN (3.0 mL), stirred at 90 ℃ in oil bath for 8 h.

Scheme 3. Direct nitration of acyclic enamides Reaction conditions: tertiary enamides 3 (0.5 mmol, 1.0 equiv.), t-BuONO (1.0 mmol, 2.0 equiv.), TEMPO (0.2 mmol, 0.4 equiv.) and CH3CN (3.0 mL), stirred at 90 ℃ in oil bath for 8 h.

Scheme 4. Gram-scalable synthesis and radical trapping experiments

Scheme 5. Proposed mechanism of this direct nitration reaction

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