Carbon-carbon formation at N-α-carbon is an essential transformation in the synthesis of nitrogen-containing compounds. N-α-Carbocations (iminium ions), N-α-carbanions, and N-α-aminoalkyl radicals constitute three major classes of intermediates for this goal. The carbon-carbon forming reactions based on N-α-aminoalkyl radicals is advantageous over other two classes of intermediates for being able to run the reactions under mild neutral conditions. Moreover, because N-α-aminoalkyl radicals are umpolung of N-α-carbocations (iminium ions), the approaches based on these intermediates are complementary. In this regard, Kagan reagent (samarium diiodide, SmI₂), a mild single-electron reductant, has emerged as a versatile reagent for the generation and coupling of N-α-aminoalkyl radicals. In this review, recent progresses on the carbon-carbon forming reactions at N-α-carbon via Kagan reagent is summarized. A number of nitrogen-containing substrates including imines, nitrones, hemiaminals, imides and amides have been shown to be valuable precursors to generate α-aminoalkyl radicals. The in situ coupling reactions of the latter with aldehydes/ketones, or electron-deficient alkenes lead to the formation of N-α-C—C bonds. These methods allow flexible access to diverse N-α-C functionalized compounds. To overcome some limitations of Kagan reagent, methods based on the titanocene-catalyzed generation of N-α-aminoalkyl radicals have also been developed. Many of these methods have been applied to the concise syntheses of medicinal-relevant compounds, alkaloids or key intermediates.
Contents
1 Introduction
2 SmI₂-mediated radical coupling of imines
3 SmI₂-mediated radical coupling of nitrones
3.1 Methodology research
3.2 Synthetic application
4 SmI₂-mediated radical coupling of chiral N-tert-butanesulfinyl imines
4.1 Methodology research
4.2 Synthetic application
5 SmI₂-mediated radical coupling of hemiaminal
5.1 Methodology research
5.2 Synthetic application
6 SmI₂-mediated radical coupling of imides, amides and nitriles
6.1 Radical coupling of imides
6.2 Radical coupling of amides
6.3 Radical coupling of nitriles
7 An extension research:titanocene-catalyzed radical coupling reactions
8 Conclusion and outlook