Electroredox carbene organocatalysis with iodide as promoter

The study addresses the challenge of developing a general and efficient electrochemical oxidation platform for N-heterocyclic carbene (NHC) organocatalysis. While oxidative carbene organocatalysis is well established with chemical oxidants (e.g., diphenoquinone) and increasingly with photoredox systems, analogous electroredox methods have lagged, historically limited to thiazolium-catalyzed (thio)esterifications. Drawing inspiration from biological oxidative activation (Vitamin B1/TPP and PFOR-mediated oxidation of the Breslow intermediate en route to acetyl-CoA) and prior electrochemical concepts of coupled electrolysis, the authors aim to enable anodic single-electron oxidation of the Breslow intermediate broadly across activation modes (α-, β-, γ-, δ-, and carbonyl) using iodide as a promoter. The purpose is to replace stoichiometric chemical oxidants with electricity (a greener oxidant), expand reaction scope and enantioselective variants, and clarify mechanistic underpinnings of SET pathways in NHC catalysis.

The paper situates its work within: (1) classical oxidative esterifications from aldehydes (Corey, 1968) and subsequent developments using thiazolium, imidazolium, and triazolium NHC catalysts with diverse oxidants, where diphenoquinone (DQ) became a standard; (2) expansion of oxidative NHC catalysis beyond α- to β-, γ-, and δ-activation modes enabling annulations and remote functionalizations; (3) emergence of radical/SET modes via chemical redox and photoredox co-catalysis; and (4) electrochemistry as a green oxidant, including prior organocatalyzed anodic oxidations (Boydston) limited to (thio)esterifications. The authors also reference theoretical and experimental studies on the Breslow intermediate and radical cation species, iodine-mediated electrochemical oxidative couplings, and the concept of anodically coupled electrolysis. This context underscores the unmet need for a general electrochemical system compatible with multiple NHC catalysts, activation modes, and asymmetric synthesis.

• Reaction design: Merge NHC catalysis with electrochemistry using iodide as a promoter for anodic SET oxidation of the Breslow intermediate. Proposed mechanism involves anodic generation of (i) a Breslow radical cation and (ii) iodine radical; rapid coupling at the anode surface affords an intermediate that eliminates iodide to the acyl azolium.
• Electrochemical setup: Undivided cells (IKA ElectraSyn 2.0), constant current electrolysis; electrode materials varied by transformation (Pt anode/cathode for γ- and α-activation, graphite anode/Pt cathode for β-activation). Typical currents: 0.8–1.0 mA.
• Electrolyte/base/catalyst system: n-Bu4NI (1.0 equiv) as electrolyte/promoter; bases included K2CO3, Cs2CO3, DIEA depending on transformation; chiral NHC precatalysts A, B, C employed for different activation modes and enantioselective outcomes. Solvents tailored per reaction (e.g., CH2Cl2, DCE, THF, CH3CN, DMF, t-BuOH, xylene mixtures).
• Optimization: Explored solvent, electrolyte (iodide vs BF4−), base, electrode materials, showing necessity of both electricity and iodide. Direct anodic oxidation without iodide (using n-Bu4NBF4) was inefficient.
• Scope studies: Four modules were established: (i) γ-activation formal [4+2] annulation of enals with hydrazones (NHC A, Pt/Pt, CH2Cl2); (ii) β-activation [3+3] annulation of enals with 1,3-dicarbonyls under two condition sets (B: NHC B, CH2Cl2/t-BuOH; C: NHC C, CH3CN/t-BuOH; graphite/Pt); (iii) α-activation formal [4+2] benzannulation of aldehydes with chalcone enones (NHC A, DMF/DCE; Pt/Pt); (iv) asymmetric acylation of hydroxyphthalides via dynamic kinetic resolution (NHC A, THF; Pt/Pt). Gram-scale synthesis of a γ-annulation product was demonstrated.
• Mechanistic studies: (a) Control with I2 as a chemical oxidant (50 mol%) under standard conditions failed (0% product). (b) Poisoning tests showed I2 reduces activity; iodinated NHCs D/E formed under electrochemical conditions with iodide, confirmed by isolation and subsequent inactivity. (c) Test for γ-iodination pathway gave no iodinated product. (d) Radical clock experiments with cis-2-phenylcyclopropane-1-carbaldehyde indicated reversible ring opening and formation of trans-ester under electrochemical SET, contrasting with DQ (two-electron) conditions that gave cis products. (e) Cyclic voltammetry in CH2Cl2 with n-Bu4NBF4 supporting electrolyte established oxidation events attributable to iodide and Breslow adduct, supporting anodic radical coupling near the electrode due to concentration gradients/electrical double layer effects.
• General procedures: Detailed stepwise protocols provided for each transformation (charge ratios, volumes, currents, times, workup, purification).

• Established an iodide-promoted electroredox NHC organocatalysis platform that enables efficient SET oxidation of the Breslow intermediate and diverse downstream transformations across α-, β-, γ-, δ- or carbonyl activation modes.
• Necessity of iodide promoter: Replacing n-Bu4NI with n-Bu4NBF4 shut down or diminished reactions; a mixed electrolyte (20% n-Bu4NI/80% n-Bu4NBF4) gave reduced yield (55% vs 79% for model), indicating direct anodic two-electron oxidation to acyl azolium is inefficient without iodide. Iodide promotes via anodic iodine radical generation and coupling.
• γ-Activation [4+2] annulation (enal + hydrazone): Model product 3a obtained in 79% isolated yield, 97% ee (Pt/Pt, 1 mA, CH2Cl2, NHC A, K2CO3, n-Bu4NI). Broad scope including various aryl hydrazones and ester variants gave 45–80% yields with 92–98% ee; complex molecule derivatives (isoniazid, probenecid, febuxostat, indometacin, dehydrocholic acid) were tolerated, including a dehydrocholic acid derivative 3q (50%, 98% de). Gram-scale: 3a isolated as 1.12 g (62%, 96% ee).
• β-Activation [3+3] annulation (enal + 1,3-dicarbonyl): Under Conditions B (NHC B) or C (NHC C), products 6a–6i obtained in 46–86% yields depending on substrate and condition, demonstrating flexibility of catalyst/base/solvent.
• α-Activation formal [4+2] benzannulation (aldehyde + chalcone enone): Products 9a–9i delivered in 42–76% yields with high diastereoselectivity (up to >20:1 dr) and excellent enantioselectivity (96–99% ee) under 0.8 mA, DMF/DCE, NHC A, Cs2CO3, n-Bu4NI.
• Dynamic kinetic resolution/acylation of hydroxyphthalides: Products 12a–12d obtained in 38–84% yields with 92–96% ee under 1 mA in THF with NHC A and DIEA.
• Mechanistic evidence for anodic radical coupling pathway: (i) I2 as a chemical oxidant abolishes reactivity (0%), and I2 partially poisons NHCs (lower yields; isolated iodinated NHCs D/E inactive). (ii) Radical clock with cis-cyclopropyl aldehyde affords trans-21 (15%) under electrochemical iodide-promoted conditions, indicating reversible radical ring opening; under DQ (two-electron) conditions, cis-21 formed in 91–92% yield, highlighting a mechanistic divergence. (iii) CV shows anodic oxidation features consistent with iodide and Breslow adduct, supporting coupled anodic events and near-electrode radical capture preventing catalyst poisoning.
• Green and modular: Reactions proceed without stoichiometric chemical oxidants, at room temperature, and are compatible with multiple NHC catalysts and activation modes.

The findings directly address the goal of creating a general electrochemical oxidative system for NHC organocatalysis. Iodide serves as a crucial promoter by forming iodine radicals at the anode, which couple with the anodically generated Breslow radical cation to forge an intermediate that collapses to the acyl azolium, enabling downstream reactivity. This coupled anodic radical coupling circumvents the inefficiency of direct two-electron anodic oxidation to acyl azoliums and mitigates iodine-induced catalyst poisoning by restricting iodine radical reactions to the anode vicinity before diffusion. Mechanistic probes (poisoning controls, iodinated NHC isolation, radical clock divergence vs DQ, and CV) substantiate the SET/radical coupling pathway, contrasting with conventional chemical two-electron oxidations. The platform’s breadth across α-, β-, γ-activations and dynamic kinetic resolution, with high stereocontrol and tolerance of complex substrates, demonstrates its relevance and potential impact as a greener, scalable alternative to chemical oxidants in oxidative NHC catalysis. It also broadens access to NHC-enabled radical processes by providing a general electrochemical handle.

The study introduces a modular, iodide-promoted electroredox NHC organocatalysis system that replaces stoichiometric chemical oxidants with electricity to effect SET oxidation of the Breslow intermediate. It enables diverse transformations (cyclizations, benzannulations, dynamic kinetic resolutions) across multiple activation modes, delivering good to excellent yields and high stereoselectivities, and is scalable. Mechanistic experiments support a distinctive anodic radical coupling pathway between iodine radicals and Breslow-derived radicals, differentiating it from traditional two-electron oxidations. This green approach enhances feasibility for large-scale synthesis and opens new avenues in NHC-catalyzed radical chemistry. Future directions include extending electroredox activation to deoxy-Breslow and other NHC-bound intermediates and further expanding reaction classes and enantioselective variants.

• The system requires iodide as a promoter; attempts with non-iodide electrolytes (e.g., n-Bu4NBF4) significantly reduce or abolish reactivity, indicating limited efficacy of direct anodic two-electron oxidation.
• Iodine can poison NHC catalysts: added I2 shuts down the model reaction (0%), and iodinated NHC species form under certain electrochemical conditions, which are catalytically inactive; performance depends on controlling near-electrode processes to avoid catalyst deactivation.
• Reaction performance is sensitive to solvent, base, electrolyte counterions, and electrode materials (Pt anodes superior to graphite in some cases), requiring tailored optimization per transformation.
• Some substrates provide only moderate yields, and in β-activation different condition sets (B vs C) are needed to balance yields across substrates.
• The mechanistic rationale relies on coupled electrolysis and near-electrode concentration gradients; deviations in cell geometry or stirring/mass transport may impact outcomes and scalability parameters.