Sustainable Organic Synthesis and Catalysis
Pro-aromatic heterocycles constitute a privileged class of redox-active reagents in which the thermodynamic driving force for rearomatization enables the controlled release of a hydride, an electron, or a radical. Nicotinamide adenine dinucleotide (NADH) and the Hantzsch ester exemplify this design principle in biological and synthetic chemistry, respectively. Building on this precedent, our group develops new pro-aromatic heterocycles engineered for the single-electron-triggered release of alkyl radicals, and anticipates applications for this reagent class both within and beyond classical synthetic organic chemistry.
A central application lies in the generation of alkyl radicals for alkyl cross-coupling. Alkyl groups remain notoriously challenging in cross-coupling chemistry, owing to sluggish oxidative addition and competing β-hydride elimination; by generating the requisite alkyl radical independently of a metal-mediated oxidative-addition or transmetalation step, our heterocyclic precursors circumvent this limitation.
Pro-Aromaticity as a Design Principle
The release of a hydride, electron, or radical from a pro-aromatic heterocycle is thermodynamically driven by rearomatization, the same principle underlying hydride transfer from NADH and the Hantzsch ester. We extend this concept to heterocycles engineered for single-electron and radical release.
A Structurally Encoded Trigger for Radical Release
Systematic variation of the substitution pattern on our dihydropyrimidine (DHPym) platform modulates the aromatization driving force and, correspondingly, the redox potential required to trigger irreversible C−C bond homolysis, affording precise control over radical release.
Alkyl Radical Precursors for Nickel-Catalyzed Cross-Coupling
By generating alkyl radicals, our heterocyclic precursors enable efficient radical capture and C−C bond formation under nickel catalysis, circumventing the classical bottleneck of alkyl electrophile activation.
Enantioselective Synthesis of Radical Precursors
N-Hydroxyphthalimide (NHPI) esters have become pivotal precursors for the generation of alkyl radicals in modern synthesis. We develop organocatalytic methods, employing chiral N-heterocyclic carbenes (NHC) and isothioureas (ITU), for the enantioselective synthesis of these redox-active esters.
A Toolbox for Sustainable Catalysis
Our heterocyclic radical platform is combined with photoredox, electrochemical, transition metal and organocatalysis to access complex targets from renewable, biogenic feedstocks, obviating the need for precious-metal catalysts.
Probing Reactivity by Electrochemistry and Spectroscopy
Cyclic voltammetry, UV/Vis, and fluorescence spectroscopy give direct access to the redox potentials of our pro-aromatic heterocycles, allowing their rational optimization for radical generation and downstream synthetic application.
