Research Progress in the Synthesis of α-Tertiary Amines via Radical Strategies

doi:10.6023/cjoc202406040

Abstract

α-Tertiary amines are a class of amine compounds with a tertiary carbon center at the α-position of the nitrogen atom. The presence of the tertiary carbon center significantly alters the lipid solubility and metabolic stability of α-tertiary amines in biological systems, making them valuable in pharmaceutical development. Traditional methods for the synthesis of α-tertiary amines include nucleophilic addition of ketimines, electrophilic amination of carbonyl compounds, allylic amination of tertiary allyl electrophiles, and rearrangement reactions. Due to the high reactivity, mild reaction conditions, and good functional group tolerance of the radical, radical reactions exhibit unique advantages in the synthesis of α-tertiary amines. Given the importance of α-tertiary amines and the advantages of radical reactions, various methods have been developed, including radical amination/hydroamination of alkenes, radical C—N cross-coupling, radical addition of imines, and C—H bond activation of alkanes. The radical-mediated intermolecular synthesis of α-tertiary amines over the past decade is summarized and the characteristics of each method is discussed in detail.

Key words: α-tertiary amine, radical, imine

Cite this article

Jiaheng Fang, Runyan Tian, Jijun Chen, Xinyuan Liu. Research Progress in the Synthesis of α-Tertiary Amines via Radical Strategies[J]. Chinese Journal of Organic Chemistry, 2025, 45(1): 22-41.

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Fig. & Tab. 36

Figure 1. Structures of α-tertiary amines and radical involved α-tertiary amines synthesis

Scheme 1. Carboazidation of 1,1-disubstituted alkenes

Scheme 2. Photoredox catalyzed amidoazidation of 1,3-dienes

Scheme 3. Iron-catalyzed asymmetric carboazidation of 1,1-di- substituted alkenes

Scheme 4. Iron-catalyzed asymmetric carboazidation of 1,1-di- substituted alkenes with alkane

Scheme 5. Copper-catalyzed asymmetric carboazidation of 1,1- disubstituted alkenes

Scheme 6. Copper-catalyzed three-component carboamination of alkenes with arylamines

Scheme 7. Iron-catalyzed olefin hydroamination with nitro- arenes

Scheme 8. Photoredox catalyzed three-component hydroaminoalkylation of alkenes

Scheme 9. Photoredox catalyzed olefin hydroaminoalkylation with protected alkyl amines

Scheme 10. Photoredox catalyzed olefin hydroaminoalkylation with unprotected alkyl amines

Scheme 11. Electro-catalyzed three-component hydroaminoalkylation of alkenes

Scheme 12. Copper-catalyzed cross coupling of hydroxylamines with α-bromocarbonyls

Scheme 13. Photoredox-copper dual catalyzed radical asymmetric C—N bond cross coupling of tertiary chloride with indole/carbazole

Scheme 14. Palladium-catalyzed radical C—N cross coupling

Scheme 15. Photoredox-copper dual catalyzed radical asymmetric C—N bond cross coupling of tertiary halides with arylamines

Scheme 16. Copper-catalyzed radical asymmetric C—N cross coupling with sulfoximines/arylamines

Scheme 17. Copper-catalyzed asymmetric Hoffman N-alkylation

Scheme 18. Copper-catalyzed radical cross coupling of hetero/aromatic amines

Scheme 19. Photoredox catalyzed β-Mannich reaction of ketimines with cyclohexanone

Scheme 20. Photoredox-catalyzed radical-radical cross coupling of tertiary bromines with PhI=NNs/PhI=NT

Scheme 21. Photoredox-catalyzed radical-radical cross coupling of DHPs with imines

Scheme 22. Photoredox-catalyzed radical cross coupling of ammonia with ketone

Scheme 23. Photoredox-catalyzed radical-radical cross coupling of oximes/imines with 4-cyanopyridine

Scheme 24. Photoredox-catalyzed radical-radical cross coupling of NHP ester with 4-cyanopyridine

Scheme 25. Photoredox-catalyzed radical-radical cross coupling of alkanes with imines

Scheme 26. Radical addition of trimethyltin protected imines with alkyl iodides

Scheme 27. Photoredox-copper dual catalyzed radical addition of imines with alkyl trifluoroborate

Scheme 28. Photoredox-copper dual catalyzed radical addition of imines with alkanes

Scheme 29. Photoredox-catalyzed three component reaction of alkyl amines, ketone and iodides

Scheme 30. Zinc-Lewis acid catalyzed three component reaction of alkyl amines, ketone and iodides

Scheme 31. Photoredox-chiral phosphoric acid dual catalyzed radical addition of imines with DHPs

Scheme 32. Cobalt-catalyzed asymmetric aza-Barbier reaction

Scheme 33. Iron-catalyzed C—H bond azidation of tertiary unactivated alkanes

Scheme 34. Electrophotocatalytic/manganese-catalyzed C(sp3)—H bonds azidation of unactivated alkanes

Scheme 35. Photoredox-cerium dual catalyzed C—H bond amination of chain alkanes

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