Iron-Catalyzed Cross-Electrophile Coupling for the Formation of All-Carbon Quaternary Centers.

Quaternary carbon centers are desirable targets for drug discovery and complex molecule synthesis, yet the synthesis of these motifs within traditional cross-coupling paradigms remains a significant challenge due to competing β-hydride elimination pathways. In contrast, the bimolecular homolytic substitution (S2) mechanism offers a unique and attractive alternative pathway. Metal porphyrin complexes have emerged as privileged catalysts owing to their ability to selectively form primary metal-alkyl complexes, thereby eliminating the challenges associated with tertiary alkyl complexation with a metal center.

Tandem C/N-Difunctionalization of Nitroarenes: Reductive Amination and Annulation by a Ring Expansion/Contraction Sequence.

A synthetic method for the reductive transformation of nitroarenes into -aminated and -annulated products is reported. The method operates via the exhaustive deoxygenation of nitroarenes by an organophosphorus catalyst and a mild terminal reductant to access aryl nitrenes, which after ring expansion, are trapped by amine nucleophiles to give dearomatized 2-amino-3-azepines. Treatment of these ring-expanded intermediates with acyl electrophiles triggers 6π electrocyclization to extrude the nitrogen atom and restore aromaticity of the phenyl ring, which delivers via C-H functionalization 2-aminoanilide and benzimidazole products.

Metallaphotoredox: The Merger of Photoredox and Transition Metal Catalysis.

The merger of photoredox catalysis with transition metal catalysis, termed metallaphotoredox catalysis, has become a mainstay in synthetic methodology over the past decade. Metallaphotoredox catalysis has combined the unparalleled capacity of transition metal catalysis for bond formation with the broad utility of photoinduced electron- and energy-transfer processes. Photocatalytic substrate activation has allowed the engagement of simple starting materials in metal-mediated bond-forming processes.

A biomimetic S2 cross-coupling mechanism for quaternary sp-carbon formation.

Bimolecular homolytic substitution (S2) is an open-shell mechanism that is implicated across a host of biochemical alkylation pathways. Surprisingly, however, this radical substitution manifold has not been generally deployed as a design element in synthetic C–C bond formation. We found that the S2 mechanism can be leveraged to enable a biomimetic sp-sp cross-coupling platform that furnishes quaternary sp-carbon centers, a long-standing challenge in organic molecule construction.

HARC as an open-shell strategy to bypass oxidative addition in Ullmann-Goldberg couplings.

The copper-catalyzed arylation of unsaturated nitrogen heterocycles, known as the Ullmann-Goldberg coupling, is a valuable transformation for medicinal chemists, providing a modular disconnection for the rapid diversification of heteroaromatic cores. The utility of the coupling, however, has established limitations arising from a high-barrier copper oxidative addition step, which often necessitates the use of electron-rich ligands, elevated temperatures, and/or activated aryl electrophiles. Herein, we present an alternative aryl halide activation strategy, in which the critical oxidative addition (OA) mechanism has been replaced by a halogen abstraction-radical capture (HARC) sequence that allows the generation of the same Cu(III)-aryl intermediate albeit via a photoredox pathway.