Catalytic Chemo‐ and Regioselective Radical Carbocyanation of 2‐Azadienes for the Synthesis of α‐Amino Nitriles

Abstract

α-Amino nitriles are versatile structural motifs in a variety of biologically active compounds and pharmaceuticals and they serve as valuable building blocks in synthesis. The preparation of α-and βfunctionalized α-amino nitriles from readily available scaffolds, however, remains challenging. Herein is reported a novel dual catalytic photoredox/coppercatalyzed chemo-and regioselective radical carbocyanation of 2-azadienes to access functionalized α-amino nitriles by using redox-active esters (RAEs) and trimethylsilyl cyanide. This cascade process employs a broad scope of RAEs and provides the corresponding α-amino nitrile building blocks in 50-95 % yields (51 examples, regioselectivity > 95 : 5). The products were transformed into prized α-amino nitriles and α-amino acids. Mechanistic studies suggest a radical cascade coupling process.

Recent Advances in Radical Coupling Strategies Enabled by 2‐Azaallyl Anions as Super‐Electron‐Donors

“…Despite the initial progress in the domain of radical coupling strategies enabled by 2-azaallyl anions as SEDs, there is still a broad scope for further development in terms of applying newer nonstabilized ketimines as substrates, application of more clean and efficient energy sources (photocatalytic and electrocatalytic) as catalytic conditions. Similarly, the relatively recent discovery of transition-metal-catalyzed, [57,59] photoredoxcatalyzed, [59][60] and electro-catalyzed [61] CÀ H activation to generate 2-azaallyl radical species finally provides a more diverse protocol for these intriguing reactive species. In summary, the development of sustainable technologies to achieve more types of functionalization reactions using 2-azaallyl anions as SEDs and coupling partners still has a promising future.…”

Nickel-Catalyzed Enantioselective Hydrophosphinylation of 2-Azadienes to Access Enantioenriched α-Aminophosphine Oxides

“…Inspired by Malcolmson’s elegant studies, we investigated the radical carbocyanation of 2-azadienes. In that study, 2-azadienes acted as radical acceptors to capture alkyl radicals and generate 2-azaallyl radical intermediates. Oxidative capture by a L n Cu–CN and subsequent reductive elimination produced rac -α-aminonitriles (Scheme b) .…”

“…In that study, 2-azadienes acted as radical acceptors to capture alkyl radicals and generate 2-azaallyl radical intermediates. Oxidative capture by a L n Cu–CN and subsequent reductive elimination produced rac -α-aminonitriles (Scheme b) . Based on these studies, we were curious if 2-azadienes could be hydrofunctionalized in the presence of an enantioenriched metal catalyst toward the synthesis of enantioenriched α-aminophosphine oxides.…”

Ti-Catalyzed Formal [2π + 2σ] Cycloadditions of Bicyclo[1.1.0]butanes with 2-Azadienes to Access Aminobicyclo[2.1.1]hexanes

“…Pioneered by the Malcolmson group, 2-azadienes have served as enamine umpolung synthons in two-electron-mediated reactions and found great applications in generating acyclic amines. Inspired by these advances, we envisioned that the polarity-reversed reactivity of 2-azadienes might also be employed in the transformations involving open-shell species.…”