Direct Nitration of Enamide to β-Acylamino Nitroalkenes under Metal-Free Conditions

doi:10.6023/cjoc202412011

Chinese Journal of Organic Chemistry ›› 2025, Vol. 45 ›› Issue (10): 3903-3911.DOI: 10.6023/cjoc202412011 Previous Articles Next Articles

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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

刘菲^a, 徐鑫明^a^,^*(), 王薪^a, 刘春阳^b^,^*(), 陈雪波^b, 孙凯^a^,^*()

^a 烟台大学化学化工学院山东烟台 264005
^b 烟台先进材料与绿色制造山东省实验室山东烟台 264000

收稿日期:2024-12-15 修回日期:2025-01-05 发布日期:2025-02-07
基金资助:
山东省自然科学基金(ZR2023MB135); 山东省自然科学基金(ZR2024QB086); 山东省青创团队(2023KJ244)

Direct Nitration of Enamide to β-Acylamino Nitroalkenes under Metal-Free Conditions

Fei Liu^a, Xinming Xu^a^,^*(), Xin Wang^a, Chunyang Liu^b^,^*(), Xuebo Chen^b, Kai Sun^a^,^*()

^a College of Chemistry and Chemical Engineering, Yantai University, Yantai, Shandong 264005
^b Shandong Laboratory of Advanced Materials and Green Manufacturing at Yantai, Yantai, Shandong 264000

Received:2024-12-15 Revised:2025-01-05 Published:2025-02-07
Contact: * xuxm18@ytu.edu.cn; sunk468@nenu.edu.cn; liuchy@amgm.ac.cn
Supported by:
Shandong Provincial Natural Science Foundation(ZR2023MB135); Shandong Provincial Natural Science Foundation(ZR2024QB086); Qingchuang Technology Support Program of University in Shandong Province(2023KJ244)

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Abstract

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

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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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Fig. & Tab. 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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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

Direct Nitration of Enamide to β-Acylamino Nitroalkenes under Metal-Free Conditions

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