N-甲基-N-亚硝基脲(MNU)作为重氮甲烷前体参与的“一锅法”选择性甲基化反应研究

doi:10.6023/cjoc202510007

有机化学 ›› 2026, Vol. 46 ›› Issue (3): 907-914.DOI: 10.6023/cjoc202510007 上一篇下一篇

研究论文

N-甲基-N-亚硝基脲(MNU)作为重氮甲烷前体参与的“一锅法”选择性甲基化反应研究

刘轩宇^a, 姚嘉欣^a, 陈宇翔^a, 张天宇^a, 江雨晴^a, 胡智学^a, 孙宏顺^a^,^*(), 褚雪强^a^,^b^,^*()

^a 南京科技职业学院环境与安全工程学院南京 210048
^b 南京工业大学化学与分子工程学院南京 211816

收稿日期:2025-10-12 修回日期:2025-11-19 发布日期:2026-01-06
通讯作者: 孙宏顺, 褚雪强
基金资助:
江苏省高等学校基础科学(自然科学)研究(24KJB150016); 南京科技职业学院科研北斗(NJPIRC-2024-04)

One-Pot Chemoselective Methylation Using N-Methyl-N-nitrosourea (MNU) as Diazomethane Precursor

Xuanyu Liu^a, Jiaxin Yao^a, Yuxiang Chen^a, Tianyu Zhang^a, Yuqing Jiang^a, Zhixue Hu^a, Hongshun Sun^a^,^*(), Xueqiang Chu^a^,^b^,^*()

^a School of Environment and Safety Engineering, Nanjing Polytechnic Institute, Nanjing 210048
^b School of Chemistry and Molecular Engineering, Nanjing Tech University, Nanjing 211816

Received:2025-10-12 Revised:2025-11-19 Published:2026-01-06
Contact: Hongshun Sun, Xueqiang Chu
Supported by:
Basic Science (Natural Science) Research Project of Higher Education Institutions of Jiangsu Province(24KJB150016); Beidou Scientific Research Program of Nanjing Polytechnic Institute(NJPIRC-2024-04)

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摘要/Abstract

以N-甲基-N-亚硝基脲(MNU)作为经济、安全的重氮甲烷前体, 通过“一锅法”原位生成重氮甲烷, 实现了羧酸的效选择性甲基化反应. 该方法避免了高危险性重氮甲烷的分离和转移操作, 显著提升了实验安全性. 反应条件温和, 具备良好的官能团耐受性和广泛的底物适应性, 适用于多种羧酸、氨基酸、多肽及药物分子, 以中等至优良的收率获得相应的甲酯产物. 此外, 该策略还可成功应用于羧酸生物电子等排体苯基四唑的N-甲基化反应, 进一步展示了其在复杂分子后期修饰及药物化学合成中的潜在应用价值.

关键词: N-甲基-N-亚硝基脲, 重氮甲烷, 一锅法反应, 选择性甲基化

An efficient one-pot chemoselective methylation of carboxylic acids is reported using N-methyl-N-nitrosourea (MNU) as an economical and safe precursor for diazomethane. This approach allows in situ generation and consumption of the methylating agent, thereby effectively avoiding the hazardous separation and transfer processes. The reaction was carried out under mild conditions with excellent functional group tolerance. A broad range of substrates including amino acids, peptides, and drug-like molecules were accommodated, and the corresponding methyl esters were obtained in moderate to excellent yields. Furthermore, the methodology was applied successfully to the N-methylation of phenyltetrazole, a common carboxylic acid bioisostere, highlighting its utility for late-stage functionalization in pharmaceutical synthesis.

Key words: N-methyl-N-nitrosourea, diazomethane, one-pot reaction, chemoselective methylation

引用此文

刘轩宇, 姚嘉欣, 陈宇翔, 张天宇, 江雨晴, 胡智学, 孙宏顺, 褚雪强. N-甲基-N-亚硝基脲(MNU)作为重氮甲烷前体参与的“一锅法”选择性甲基化反应研究[J]. 有机化学, 2026, 46(3): 907-914.

Xuanyu Liu, Jiaxin Yao, Yuxiang Chen, Tianyu Zhang, Yuqing Jiang, Zhixue Hu, Hongshun Sun, Xueqiang Chu. One-Pot Chemoselective Methylation Using N-Methyl-N-nitrosourea (MNU) as Diazomethane Precursor[J]. Chinese Journal of Organic Chemistry, 2026, 46(3): 907-914.

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Entry	CH₂N₂ precursor	Yield^b/%
1	NMU	43
2	MNNG	26
3	Diazald	17
4	STZ	12
5	TMZ	Trace

Entry	CH₂N₂ precursor	Yield^b/%
1	NMU	43
2	MNNG	26
3	Diazald	17
4	STZ	12
5	TMZ	Trace

Entry	Base (Dosage/equiv.)	Solvent	Yield^b/%
1	KOH (5)	Dioxane/H₂O	43
2	NaOH (5)	Dioxane/H₂O	37
3	NaHCO₃ (5)	Dioxane/H₂O	82
4	Na₂CO₃(5)	Dioxane/H₂O	87
5	K₂CO₃ (5)	Dioxane/H₂O	83
6	K₃PO₄ (5)	Dioxane/H₂O	79
7	Et₃N (5)	Dioxane/H₂O	10
8	DBU (5)	Dioxane/H₂O	23
9	None	Dioxane/H₂O
10	Na₂CO₃ (5)	CH₃CN/H₂O	52
11	Na₂CO₃ (5)	THF/H₂O	35
12	Na₂CO₃ (5)	CH₂Cl₂/H₂O	21
13	Na₂CO₃ (5)	CH₂Cl₂	8
14	Na₂CO₃ (5)	Dioxane	48
15	Na₂CO₃ (5)	H₂O	6
16^c	Na₂CO₃ (5)	Dioxane/H₂O	65
17	Na₂CO₃ (3)	Dioxane/H₂O	91
18	Na₂CO₃ (2)	Dioxane/H₂O	98
19^d	Na₂CO₃ (2)	Dioxane/H₂O	98
20^e	Na₂CO₃ (2)	Dioxane/H₂O	40
21^f	Na₂CO₃ (2)	Dioxane/H₂O	53
22^g	Na₂CO₃ (2)	Dioxane/H₂O	98

Entry	Base (Dosage/equiv.)	Solvent	Yield^b/%
1	KOH (5)	Dioxane/H₂O	43
2	NaOH (5)	Dioxane/H₂O	37
3	NaHCO₃ (5)	Dioxane/H₂O	82
4	Na₂CO₃(5)	Dioxane/H₂O	87
5	K₂CO₃ (5)	Dioxane/H₂O	83
6	K₃PO₄ (5)	Dioxane/H₂O	79
7	Et₃N (5)	Dioxane/H₂O	10
8	DBU (5)	Dioxane/H₂O	23
9	None	Dioxane/H₂O
10	Na₂CO₃ (5)	CH₃CN/H₂O	52
11	Na₂CO₃ (5)	THF/H₂O	35
12	Na₂CO₃ (5)	CH₂Cl₂/H₂O	21
13	Na₂CO₃ (5)	CH₂Cl₂	8
14	Na₂CO₃ (5)	Dioxane	48
15	Na₂CO₃ (5)	H₂O	6
16^c	Na₂CO₃ (5)	Dioxane/H₂O	65
17	Na₂CO₃ (3)	Dioxane/H₂O	91
18	Na₂CO₃ (2)	Dioxane/H₂O	98
19^d	Na₂CO₃ (2)	Dioxane/H₂O	98
20^e	Na₂CO₃ (2)	Dioxane/H₂O	40
21^f	Na₂CO₃ (2)	Dioxane/H₂O	53
22^g	Na₂CO₃ (2)	Dioxane/H₂O	98

N-甲基-N-亚硝基脲(MNU)作为重氮甲烷前体参与的“一锅法”选择性甲基化反应研究

One-Pot Chemoselective Methylation Using N-Methyl-N-nitrosourea (MNU) as Diazomethane Precursor

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