Aerobic Photocatalytic N-Demethylation of Amides Enabled by a Hydrochloric Acid-Dimethyl Sulfoxide System

doi:10.6023/cjoc202512011

Chinese Journal of Organic Chemistry ›› 2026, Vol. 46 ›› Issue (4): 1713-1721.DOI: 10.6023/cjoc202512011 Previous Articles Next Articles

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盐酸-二甲基亚砜体系促进酰胺的需氧光催化N-脱甲基反应

刘琼^a, 杨修龙^a^,^*(), 李浩源^b^,^c, 沈佳慧^a, 杨硕^a, 孟庆元^b^,^c^,^*(), 牛效莹^a^,^*()

^a 河北大学化学与材料科学学院药物化学与分子诊断教育部重点实验室河北省化学生物学重点实验室河北保定 071002
^b 中国科学院化学研究所分子识别与功能实验室北京分子科学国家研究中心北京 100190
^c 中国科学院大学化学科学学院北京 100049

收稿日期:2025-12-10 修回日期:2026-03-07 发布日期:2026-03-12
通讯作者: 杨修龙, 孟庆元, 牛效莹
基金资助:
国家自然科学基金(22501066); 国家自然科学基金(22271293); 河北省自然科学基金(B2025201045); 及中国科学院稳定支持基础研究领域青年团队计划(YSBR-050)

Aerobic Photocatalytic N-Demethylation of Amides Enabled by a Hydrochloric Acid-Dimethyl Sulfoxide System

Qiong Liu^a, Xiulong Yang^a^,^*(), Haoyuan Li^b^,^c, Jiahui Shen^a, Shuo Yang^a, Qingyuan Meng^b^,^c^,^*(), Xiaoying Niu^a^,^*()

^a Key Laboratory of Chemical Biology of Hebei Province, Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of the Ministry of Education, College of Chemistry and Materials Science, Hebei University, Baoding, Hebei 071002
^b Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory of Molecular Recognition and Function, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190
^c School of Chemical Science, University of Chinese Academy of Sciences, Beijing 100049

Received:2025-12-10 Revised:2026-03-07 Published:2026-03-12
Contact: Xiulong Yang, Qingyuan Meng, Xiaoying Niu
Supported by:
National Natural Science Foundation of China(22501066); National Natural Science Foundation of China(22271293); Natural Science Foundation of Hebei Province(B2025201045); Project for Young Scientists in Basic Research of Chinese Academy of Sciences(YSBR-050)

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Abstract

N-Demethylation represents a significant class of reactions within the metabolic pathways of organisms. This work introduces an innovative photocatalytic protocol for the demethylation of N-methylamides using cost-effective and readily available hydrochloric acid and dimethyl sulfoxide (DMSO), with the process proceeding without the need for exogenous photocatalysts or oxidants. The methodology is characterized by operational simplicity, mild reaction conditions, and does not necessitate inert atmosphere protection, while exhibiting high functional group tolerance. A wide range of substrates, including diverse N-methylamide derivatives, underwent efficient demethylation, yielding the corresponding products in good yields. A scale-up experiment further validates the practicality and environmental benefits of this methodology. This strategy introduces a novel approach for efficient N-demethylation of amides under mild conditions.

Key words: N-demethylation, photocatalytic, C—N bond cleavage

Cite this article

Qiong Liu, Xiulong Yang, Haoyuan Li, Jiahui Shen, Shuo Yang, Qingyuan Meng, Xiaoying Niu. Aerobic Photocatalytic N-Demethylation of Amides Enabled by a Hydrochloric Acid-Dimethyl Sulfoxide System[J]. Chinese Journal of Organic Chemistry, 2026, 46(4): 1713-1721.

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Fig. & Tab. 7

Scheme 1. N-demethylation reactions

Entry	Additive A	Additive B	Solvent	Light /nm	Yield^b/%
1^a	DMSO	HCl	CH₃CN	390	97
2	DMSO	CuCl₂	CH₃CN	390	Trace
3	DMSO	AlCl₃	CH₃CN	390	66
4	DMSO	FeCl₂	CH₃CN	390	Trace
5	DMSO	FeCl₃	CH₃CN	390	57
6	DMSO	HCl	Toluene	390	Trace
7	DMSO	HCl	THF	390	Trace
8	DMSO	HCl	CH₃OH	390	18
9	DMSO	HCl	EtOH	390	9
10	DMSO	HCl	CH₃CN	365	84
11	DMSO	HCl	CH₃CN	405	25
12	DMSO	HCl	CH₃CN	440	Trace
13	DMSO	HCl	CH₃CN	465	Trace
14	—	HCl	CH₃CN	390	39
15	DMSO	—	CH₃CN	390	Trace
16^c	DMSO	HCl	CH₃CN	390	9

Table 1. Optimization of the reaction conditions

Table 2. The scope of substrate

Scheme 2. Scale-up experiment

Scheme 3. Mechanism investigation experiments (A) Light off/on experiment. (B) UV-vis absorption spectra of CH3CN solution of 1a (3.33 mmol/L), 37% HCl (8.33 mmol/L), DMSO (33.3 mmol/L) under LEDs (λ=390 nm) irradiated 0~9 h. 1a (33.33 mmol/L, 333.3 mmol/L) under standard condition unirradiated. (C) Radical quenching experiment. (D) Redox quenching experiment.

Scheme 4. Control experiments

Scheme 5. Proposed mechanism

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盐酸-二甲基亚砜体系促进酰胺的需氧光催化N-脱甲基反应

Aerobic Photocatalytic N-Demethylation of Amides Enabled by a Hydrochloric Acid-Dimethyl Sulfoxide System

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Fig. & Tab. 7

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