二甲亚砜作为甲基化试剂在有机合成中的应用

doi:10.6023/cjoc202211026

摘要/Abstract

在药物分子中引入甲基可改变其药代动力学特性与药理特性, 这种“神奇的甲基效应”使得甲基化成为有机合成与药物化学领域十分重要的一类反应. 近年来, 过渡金属催化的偶联反应以及光或电促进的有机反应成为甲基化反应的新策略, 并相继开发了系列廉价易得、低毒高效、适用性广的甲基化试剂. 其中, 二甲亚砜(DMSO)作为一种来源广泛、性能优良的溶剂与多功能反应试剂, 受到研究者们越来越多的关注. 基于此, 聚焦交叉偶联反应与自由基反应, 系统阐述DMSO/DMSO-d₆作为甲基化/三氘甲基化试剂在有机合成中的应用, 并探讨相关的反应机理、发展趋势以及合成过程所面临的挑战.

关键词: 二甲亚砜(DMSO), 氘代二甲亚砜, 甲基化, 三氘甲基化, 自由基反应

The introduction of methyl groups into drug molecules can change their pharmacokinetic and pharmacological properties. This “magical methyl effectˮ makes methylation a very important reaction in the field of organic synthesis and pharmaceutical chemistry. In recent years, the transition metal-catalyzed coupling reaction and the organic reaction promoted by light or electricity have become the new strategies for methylation reaction. A series of cheap, low toxicity, high efficiency and wide applicability of methylating reagents have been developed. Among them, dimethyl sulfoxide (DMSO), as a kind of solvent with wide sources, excellent performance and multi-functional reagent, has been paid more and more attention by researchers. Based on this, by focusing on the cross-coupling reaction and free radical reaction, the application of DMSO/ DMSO-d₆ as methylation/trideuterium methylating reagent in organic synthesis is systematically described, and the relevant reaction mechanism, development trend and challenges in the synthesis process are discussed.

Key words: dimethyl sulfoxide (DMSO), DMSO-d₆, methylation, (trideuterium) methylation, radical-mediated reaction

引用此文

田钰, 张娟, 高文超, 常宏宏. 二甲亚砜作为甲基化试剂在有机合成中的应用[J]. 有机化学, 2023, 43(7): 2391-2406.

Yu Tian, Juan Zhang, Wenchao Gao, Honghong Chang. Application of Dimethyl Sulfoxide as Methylating Reagent in Organic Synthesis[J]. Chinese Journal of Organic Chemistry, 2023, 43(7): 2391-2406.

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图/表 24

图1. 药物结构中“神奇的甲基效应”

Figure 1. “Magic methyl effect” in the structure of drugs

图2. 甲基来源示意图

Figure 2. Source of methyl

图式1. Fenton试剂与DMSO作用产生甲基的过程

Scheme 1. Methyl formation process by Fenton reagent and DMSO

图式2. 钯催化的异喹啉氮氧化物的甲基化反应

Scheme 2. Pd-catalyzed methylation of isoquinoline nitrogen oxides

图式3. 胞嘧啶脱氧核苷酸的C(5)甲基化

Scheme 3. C(5) methylation of cytosine deoxynucleotide

图式4. 烯烃与二甲亚砜的甲基化或甲基氯化反应

Scheme 4. Methylation or methylchlorination of alkene with DMSO

图式5. 异氰化物与二甲亚砜的甲基化

Scheme 5. Methylation of isocyanates and DMSO

图式6. 可见光诱导和铁催化的N-芳烯酰胺的甲基化

Scheme 6. Visible light induced and Fe-catalyzed methylation of N-arylamide

图式7. 光催化芳杂环的甲基化

Scheme 7. Photocatalytic methylation of aromatic heterocycles

图式8. 铁介导活性烯烃、叠氮三甲基硅烷和二甲亚砜的叠氮甲基化

Scheme 8. Iron-mediated the azide methylation of active alkenes, trimethylazide silane and DMSO

图式9. 光催化1,8-萘基嘧啶的甲基化

Scheme 9. Photocatalytic methylation of 1,8-naphthylpyrimidine

图式10. 芳香硝基化合物的N-甲基化反应

Scheme 10. N-methylation of aromatic nitro compounds

图式11. 生物碱galipinine的合成路线

Scheme 11. Synthesis route of the antipyretic alkaloid galipinine

图式12. S-甲基化反应及机理

Scheme 12. S-Methylation reaction and mechanism

图式13. 钯催化异喹啉N-氧化物的C—H三氘甲基化反应

Scheme 13. Pd-catalyzed C—H trideuteromethylation of isoquinoline N-oxide

图式14. (异)喹啉的C—H三氘甲基化反应

Scheme 14. C—H trideuterium methylation of (iso)quinoline

图式15. 丙烯酰胺的级联三氘甲基化

Scheme 15. Cascade trideuterium methylation of acrylamide

图式16. 铁介导的异氰化物的自由基级联三氘甲基化

Scheme 16. Fe-mediated radical cascade trideuteromethylation of isocyanides

图式17. 铁介导的叠氮三氘甲基化反应

Scheme 17. Iron-mediated azidotrideuteriummethylation

图式18. 铱-光氧化还原催化的异芳烃三氘甲基化反应

Scheme 18. Ir-photoredox-catalyzed trideuteromethylation of heteroarenes

图式19. 光诱导1,8-萘嘧啶的α-三氘甲基化反应

Scheme 19. Light-induced α-trideuteromethylation of 1,8-naphthyridines

图式20. 活性亚甲基与DMSO-d6的三氘甲基化反应

Scheme 20. Trideuteromethylation of active methylenes with DMSO-d6

图式21. 多种胺的N-三氘甲基化

Scheme 21. N-trideuteromethylation of various amines

图式22. 4-硝基苯甲酸的亲电O-三氘甲基化反应

Scheme 22. Electrophilic O-trideuteriummethylation of 4-nitrobenzoic acid

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