Cooperative NHC and Photoredox Catalyzed Radical Aminoacylation of Alkenes to Tetrahydropyridazines.

Tetrahydropyridazines constitute an important structural motif found in numerous natural products and pharmaceutical compounds. Herein, we report an aminoacylation reaction of alkenes that enables the synthesis of 1,4,5,6-tetrahydropyridazines through cooperative N-heterocyclic carbene (NHC) and photoredox catalysis. This approach involves the 6-endo-trig cyclization of N-centered hydrazonyl radicals, generated via single-electron oxidation of hydrazones, followed by a radical-radical coupling step. The mild process tolerates a wide range of common functional groups and affords a variety of tetrahydropyridazines in moderate to high yields. Preliminary investigations using chiral NHC catalysts demonstrate the potential of this protocol for asymmetric radical reactions.

Synthesis of γ-Oxo-phosphonates via N-Heterocyclic Carbene-Catalyzed Acylphosphorylation of Alkenes.

In this study, we present an N-heterocyclic carbene-catalyzed method for the radical acylphosphorylation of alkenes. Electrochemical investigations were employed to identify an appropriate class of oxime phosphonates capable of undergoing a single-electron transfer (SET) with Breslow enolates. The resulting phosphoryl radicals were effectively coupled with diverse styrenes and aldehydes to yield a variety of γ-oxo-phosphonates. Both radical clock experiments and electrochemical studies support our reaction design, and a plausible mechanism for the organocatalytic transformation is proposed.

Synthesis of Pyrroloindolines via N-Heterocyclic Carbene Catalyzed Dearomative Amidoacylation of Indole Derivatives.

Pyrroloindoline is a privileged heterocyclic motif that is widely present in many natural products and pharmaceutical compounds. Herein, we report an amidyl radical-mediated dearomatization for synthesizing a series of pyrroloindolines via N-heterocyclic carbene catalysis. In this organocatalytic process, the Breslow enolate served as both a single electron donor and an acyl radical equivalent to assemble C3a-acyl pyrroloindolines with a broad substrate scope. Sequential reduction of the indole derivatives provided the analogues of (±)-desoxyeseroline, which exhibited potential anticancer activity.

Photoredox Catalytic Phosphine-Mediated Deoxygenation of Hydroxylamines Enables the Construction of N-Acyliminophosphoranes.

The chemistry of phosphoranyl radicals has received increasing attention in recent years. Here, we report the generation of amidyl radicals through photocatalytic deoxygenation of hydroxylamines with triphenylphosphine. This methodology offers a novel and convenient route to a diverse range of N-acyliminophosphoranes in moderate to good yields under visible-light photoredox conditions. Fluorescence quenching experiments suggest that the excited-state of the organic photocatalyst (4CzIPN) was oxidatively quenched by a Cu(II) salt.

Generation of Oxyphosphonium Ions by Photoredox/Cobaloxime Catalysis for Scalable Amide and Peptide Synthesis in Batch and Continuous-Flow.

Phosphine-mediated deoxygenative nucleophilic substitutions, such as the Mitsunobu reaction, are of great importance in organic synthesis. However, the conventional protocols require stoichiometric oxidants to trigger the formation of the oxyphosphonium intermediates for the subsequent nucleophilic additions. Through dual catalysis of photoredox and cobaloxime, we realized a radical strategy for the catalytic formation of acyloxyphosphonium ions that enables direct amidation. The deoxygenative protocol exhibits a broad scope and has been used in the late-stage amidation of drug molecules. In addition to batch reactions, a continuous-flow reactor was developed, enabling rapid peptide synthesis on gram scale. The successful assembly of a tetrapeptide on the solid support further demonstrated the versatility of this photocatalytic system. Moreover, experimental and computational studies are consistent with the hypothesis of acyloxyphosphonium ions being formed as the key intermediates.

The Asymmetric A³(Aldehyde⁻Alkyne⁻Amine) Coupling: Highly Enantioselective Access to Propargylamines.

The recent developments in asymmetric A³ (aldehyde⁻alkyne⁻amine) coupling has been summarized in this review. Several interesting modifications of the ligands enabled the highly enantioselective synthesis of chiral propargylamines, which are further used in the construction of nitrogen-containing chiral building blocks.

Regiospecific Three-Component Aminofluorination of Olefins via Photoredox Catalysis.

Direct visible-light-mediated aminofluorination of styrenes has been developed with high regioselectivity. Shelf-stable N-Ts-protected 1-aminopyridine salt was used as the nitrogen-radical precursor, and the commercially available hydrogen fluoride-pyridine was used as the nucleophilic fluoride source. The synthesis of an analogue of LY503430 was performed to demonstrate the synthetic value of this strategy.

Direct Decarboxylative-Decarbonylative Alkylation of α-Oxo Acids with Electrophilic Olefins via Visible-Light Photoredox Catalysis.

The decarbonylation of primary, secondary, and tertiary alkyl-substituted acyl radicals has been investigated through photoredox catalysis. A series of quaternary carbons and γ-ketoesters have been directly constructed by the photoredox 1,4-conjugate addition of the corresponding alkyl ketoacids with electrophilic alkenes. And, the tertiary alkyl ketoacids have proved to be good precursors of tertiary alkyl radicals.