Application of Dimethyl Sulfoxide as Methylating Reagent in Organic Synthesis

doi:10.6023/cjoc202211026

Abstract

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

Cite this article

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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Fig. & Tab. 24

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

Figure 2. Source of methyl

Scheme 1. Methyl formation process by Fenton reagent and DMSO

Scheme 2. Pd-catalyzed methylation of isoquinoline nitrogen oxides

Scheme 3. C(5) methylation of cytosine deoxynucleotide

Scheme 4. Methylation or methylchlorination of alkene with DMSO

Scheme 5. Methylation of isocyanates and DMSO

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

Scheme 7. Photocatalytic methylation of aromatic heterocycles

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

Scheme 9. Photocatalytic methylation of 1,8-naphthylpyrimidine

Scheme 10. N-methylation of aromatic nitro compounds

Scheme 11. Synthesis route of the antipyretic alkaloid galipinine

Scheme 12. S-Methylation reaction and mechanism

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

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

Scheme 15. Cascade trideuterium methylation of acrylamide

Scheme 16. Fe-mediated radical cascade trideuteromethylation of isocyanides

Scheme 17. Iron-mediated azidotrideuteriummethylation

Scheme 18. Ir-photoredox-catalyzed trideuteromethylation of heteroarenes

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

Scheme 20. Trideuteromethylation of active methylenes with DMSO-d6

Scheme 21. N-trideuteromethylation of various amines

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

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