Radical C(sp3)-S Coupling for the Synthesis of α-Amino Sulfides.

A unique transition-metal-free radical thiolation of 2-azaallyl anions has been developed. Easily accessible thiosulfonates and 2-azaallyls undergo the tandem process of single-electron transfer and radical-radical coupling to construct C(sp3)-S bonds. This robust protocol enables a mild and chemoselective coupling between 2-azaallyl anions and thiosulfonates to access α-amino sulfides in 50-92% yields (25 examples). The scalability of this protocol was demonstrated by telescopic gram-scale experiments. Mechanistic studies provide significant evidence for this radical thiolation reaction.

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

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 ß-functionalized α-amino nitriles from readily available scaffolds, however, remains challenging. Herein is reported a novel dual catalytic photoredox/copper-catalyzed 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.

α-Branched amines through radical coupling with 2-azaallyl anions, redox active esters and alkenes.

α-Branched amines are fundamental building blocks in a variety of natural products and pharmaceuticals. Herein is reported a unique cascade reaction that enables the preparation of α-branched amines bearing aryl or alkyl groups at the ß- or γ-positions. The cascade is initiated by reduction of redox active esters to alkyl radicals. The resulting alkyl radicals are trapped by styrene derivatives, leading to benzylic radicals. The persistent 2-azaallyl radicals and benzylic radicals are proposed to undergo a radical-radical coupling leading to functionalized amine products. Evidence is provided that the role of the nickel catalyst is to promote formation of the alkyl radical from the redox active ester and not promote the C-C bond formation. The synthetic method introduced herein tolerates a variety of imines and redox active esters, allowing for efficient construction of amine building blocks.

Nickel-catalyzed enantioselective vinylation of aryl 2-azaallyl anions.

A unique enantioselective nickel-catalyzed vinylation of 2-azaallyl anions is advanced for the first time. This method affords diverse vinyl aryl methyl amines with high enantioselectivities, which are frequently occurring scaffolds in natural products and medications. This C-H functionalization method can also be extended to the synthesis of enantioenriched 1,3-diamine derivatives by employing suitably elaborated vinyl bromides. Key to the success of this process is the identification of a Ni/chiraphos catalyst system and a less reducing 2-azaallyl anion, all of which favor an anionic vinylation route over a background radical reaction. A telescoped gram scale synthesis and a product derivatization study confirmed the scalability and synthetic potential of this method.

Transition-Metal-Free C(sp3)-H Coupling of Cycloalkanes Enabled by Single-Electron Transfer and Hydrogen Atom Transfer.

Here we report a unique transition-metal-free C(sp3)-H/C(sp3)-H coupling of cycloalkanes at room temperature. Unactivated cycloalkanes and 2-azaallyls underwent the combination process of single-electron transfer (SET) and hydrogen atom transfer (HAT) to deliver a wide variety of cycloalkane-functionalized products. This expedient approach enables C(sp3)-H/C(sp3)-H coupling of cycloalkanes under mild conditions without transition metals, initiators, and oxidants.