Modular Synthesis of Heterobenzylic Amines via Carbonyl Azinylative Amination

Transformations enabling the synthesis of alpha-alkyl, alpha '-2-azinyl amines by addition of 2-heteroaryl-based nucleophiles to in situ-generated and non-activated alkyl-substituted iminium ions are extremely rare. Approaches involving classical 2-azinyl organometallics, such as the corresponding Grignard reagents, often fail to produce the desired products. Here, we report an operationally straightforward solution to this problem through the development of a multicomponent coupling process wherein a soft 2-azinyl indium nucleophile, generated in situ from the corresponding 2-iodo heteroarene and indium powder, adds to an iminium ion that is also formed directly in the reaction. This modular carbonyl azinylative amination (CAzA) displays a broad scope and only a metal reductant is needed to generate a reactive 2-azinyl nucleophile. Beyond the addition to iminium ions, the 2-azinyl addition to polyfluoromethyl ketones forms the corresponding tertiary alcohols. Together, the products of these reactions possess a high degree of functionality, are typically challenging to synthesize by other methods, and contain motifs recognized as privileged in the context of pharmaceuticals and agrochemicals. An indium metal-mediated carbonyl azinylative amination (CAzA) reaction provides an operationally straightforward protocol for the multicomponent coupling carbonyls, amines and 2-iodo azines to form alpha-alkyl, alpha '-2-azinyl amines. This modular reaction displays a broad scope and only a metal reductant is needed to generate a reactive 2-azinyl nucleophile. These amines possess a high degree of functionality, are challenging to synthesize by other methods, and contain motifs attractive to the design of bioactive molecules. image