Tuning Proton-Electron Synergy for Electrooxidative Alkyne Annulation: Mechanistic Insights and Synthetic Application

Abstract

Electrooxidative catalysis surfaced as a resource-economic and increasingly viable platform toward sustainable organic synthesis. It challenges the paradigm of using stoichiometric chemical reagents with the aid of electricity to enable traceless electron and proton transfers. Thereby, molecular synthesis can be inherently connected to the hydrogen evolution reaction, while avoiding waste formation in the form of stoichiometric by-products. Alkynes represent a widely occurring structural motif of outstanding relevance in molecular synthesis. The direct exploitation of alkynes toward the activation of otherwise inert C─H bonds sets the stage for innovative dehydrogenative annulations, allowing for the rapid construction of structurally complex compounds. Specifically, the merger with earth-abundant metal catalysis constitutes a promising advancement in the light of green chemistry, bearing unique potential to redefine chemical processing.

Keywords

Electrocatalysis - C─H activation - Alkyne annulation - Continuous flow - Hydrogen evolution - Enantioselectivity

1

Introduction

In recent years, organic electrocatalysis gained substantial momentum due to its inherent resource-economic nature, contributing to rising efforts en route to sustainable organic synthesis.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] Stoichiometric redox reagents are replaced in a traceless fashion by heterogeneous electron transfers, obviating the generation of undesired chemical waste, while enabling the use of renewable forms of energy.[6] [7] [11] Besides the circumvention of stoichiometric reagents, the viable chemical space is significantly extended through novel single-electron transfer (SET)-driven pathways. Moreover, tailored selectivities are accessible by the precisely adjustable external potential.[6] [7] Electrooxidative transformations bear the additional advantage of a coupled cathodic hydrogen evolution reaction (HER), merging molecular syntheses with the formation of green hydrogen.[12] [13] [14]

Specifically, the synergistic interaction of organic electrocatalysis with dehydrogenative C─H activation emerged as a uniquely powerful strategy.[15] [16] [17] Thereby, otherwise inert C─H bonds can be leveraged as latent functional groups, thus revolutionizing established molecular chemistry, while circumventing the need for prefunctionalization.[18] [19] [20] [21] [22] In this context, alkynes represent a particularly versatile motif for transition metal-catalyzed C─H activation.[23] [24] Especially their exploitation in dehydrogenative annulation reactions is of topical interest, since it gives rise to structurally complex heterocyclic scaffolds in a resource economical fashion ([Scheme 1]).[25] [26] However, in previous approaches external oxidants as well as harsh reaction conditions are predominantly required for catalytic turnover, substantially compromising the inherent sustainable nature of this approach.[27] Alternatively, molecular oxygen can—in selected cases—be exploited as a terminal oxidant, which we spearheaded in 2015/2016 for ruthenium and cobalt catalysis.[28] [29] Although rendering the synthesis benign, the fixed redox potential and safety hazards associated with the use of molecular oxygen limit its applicability.[30] [31] These hurdles can be efficiently addressed by benefitting from a precisely tuned flow of electrons and protons under mild electrocatalysis conditions.

Scheme 1 Schematic overview of distinct strategies for transition metal-catalyzed C─H activation, utilizing alkynes as multifaceted building block for annulation reactions.

Within our program on inspiring dehydrogenative metallaelectrocatalysis, a broad array of distinct alkyne transformations was realized by means of electrochemistry. This account summarizes our findings on the selective transformation of alkynes in electrooxidative transition metal-catalyzed C─H activations until November 2025.

2

Metallaelectro-Catalyzed C─H Annulation

2.1

Noble-Metal Catalysis

Ruthenium complexes are versatile catalysts for C─H activations, enabling a wide-ranging variety of strategies for the assembly of complex structures.[32] [33] In 2018, distinct electrooxidative approaches were disclosed that showcased the potential of ruthenium catalysis for the elegant construction of heterocyclic scaffolds through either C─H/O─H or C─H/N─H annulation ([Scheme 2a]).[34] [35] [36] Thereby, differently decorated internal alkynes were utilized in H₂O/ ^t AmOH as a sustainable solvent system. Weakly coordinating benzoic acids were found to undergo facile C─H ruthenation, followed by migratory insertion and reductive elimination, furnishing isochromenones 1.[34] [37] The resulting ruthenium(0) intermediate is anodically oxidized to ascertain catalytic turnover through proton and electron transfer ([Scheme 2b]), as evidenced by cyclic voltammetry (CV) studies. Unsymmetrical alkynes delivered the desired products as a single regioisomer. Likewise, weakly coordinating benzamides proved to be amenable substrates to efficiently deliver isoquinolones 2. Shortly after, the strategy was extended to realize unprecedented ruthenaelectro-catalyzed peri C─H activation en route to diverse π-extended heterocyclic scaffolds 3 and 4.[35]

Scheme 2 (a) Selection of distinct ruthenaelectro-catalyzed annulation reactions for the streamlined preparation of different heterocyclic motifs. (b) Electrooxidative conversion of a key ruthenium(0) intermediate.

Subsequently, a mechanistically distinct catalytic platform was established for providing expedient access to bridgehead N-fused [5,6]-bicyclic heteroarenes 6 ([Scheme 3a]).[38] It is noteworthy that azaruthena(II)-bicyclo[3.2.0]heptadiene Ru3 was identified as a key intermediate. After successful isolation and full characterization, it was demonstrated that product release from intermediate Ru3 required anodic oxidation, being suggestive of an oxidation-induced reductive elimination pathway. Mechanistic investigations through computational studies and CV experiments provided further strong support for a ruthenium(II/III/I) regime as an unusual modus operandi.

Scheme 3 (a) Electrooxidative ruthenium-catalyzed synthesis of bridgehead N-fused [5.6]-bicyclic heteroarenes. (b) Domino three-component annulation reaction by ruthenium catalysis for the generation of isoquinoline derivatives. (c) Distinct ruthenacycles established as key intermediates prior to oxidation-induced reductive elimination.

Thereafter, a sophisticated domino three-component annulation reaction was realized for the assembly of isoquinoline motifs 8 from distinct aromatic ketones ([Scheme 3b]).[39] Here, the seven-membered cyclic intermediate Ru4 could be isolated, which was formed by in situ ketimine formation, fast C─H activation, and migratory insertion. This intermediate was proven to be stable in the absence of electricity. Thus, the heterogeneous electron transfer sets the stage for oxidation-induced reductive elimination, releasing the product and ensuring turnover after a second SET.

The versatility of ruthenaelectro-catalyzed C─H annulation was further expanded by Guo, among others, thus enabling the use of nucleosides.[40]

Additionally, the readily tamable reactivity of other noble metals has been leveraged over the years for streamlined C─H annulations as a transformative tool. In 2019, rhodaelectro-catalyzed C─H activation was employed for a twofold alkyne annulation, affording largely π-extended systems 10 ([Scheme 4]).[41] [42] Subsequent electrocatalytic cyclodehydrogenation provided modular access to nonplanar polycyclic aromatic hydrocarbons (PAH), furnishing overall six novel C─C bonds through this versatile double electrocatalysis strategy. Even unsymmetrical alkynes proved to be applicable with high levels of chemoselectivity, as well as challenging iodo-substituted boronic acids, underlining the unique potential of the mild and selective electrocatalysis.

Scheme 4 Modular assembly of π-extended systems via rhodaelectro-catalyzed twofold alkyne annulation.

The implementation of continuous flow chemistry was subsequently demonstrated for diverse intramolecular and intermolecular C─H/N─H annulations with a specially designed porous graphite felt anode ([Scheme 5a]).[43] Continuous flow operation supersedes established batch procedures in terms of efficient mass and heat transfer, viable scale-up, reproducibility, and the possibility of integrating automation and in-line analytics to the synthesis workflow.[44] [45] [46] This enabled the application of in-operando NMR monitoring, which unraveled the modus operandi in conjunction with studies on distinct isolated rhodacycles, CV experiments, and computational studies. Thus, an oxidation-induced reductive elimination was uncovered as part of a rhodium(III/IV/II) regime.[47] [48]

Scheme 5 (a) Continuous flow chemistry for the efficient and scalable build-up of distinct heteroarenes via intermolecular or intramolecular reaction. (b) Electrochemical assembly of aza-PAHs through a domino alkyne annulation.

Similar mechanistic findings paved the way for an intriguing rhodaelectro-catalyzed cascade C─H activation, triggering the formation of aza-PAHs 16 in a single step from simple molecular building blocks ([Scheme 5b]).[49] This unique reactivity was enabled by the design of a multifunctional O-methylamidoxime, whereby the specific order of events was revealed by isolating two potential intermediates. Sensitive functional groups, such as hydroxyl and azide moieties, were fully tolerated by the versatile electrocatalyst, setting the stage for late-stage diversification, and thus potential application to optoelectronics, biomaterials, or energy storage systems.

Additionally, the formation of extended ring sizes was rendered amenable through metallaelectrocatalytic C─H annulation. To this end, the efficient synthesis of benzoxepines 18, as a prominent motif in natural and pharmacological products, was accomplished by rhodaelectro-catalysis ([Scheme 6]).[50] In sharp contrast to the previous strategies, a rhodium(III/I) manifold was identified by detailed mechanistic studies, involving the isolation of the rhodium(I) sandwich complex Rh1.

Scheme 6 Preparation of extended ring sizes in the form of benzoxepines through electrooxidative C─H/O─H annulation.

The merger of C─H activation with enantioselective catalysis constitutes a promising strategy of pronounced topical interest, accessing privileged structures in a resource-economic fashion.[51] [52] [53] [54] In 2022, a diverse array of challenging spirocyclic compounds 20 with all-carbon quaternary stereogenic centers were accessed through enantioselective rhodaelectro-catalyzed C─H activation ([Scheme 7]).[55] [56] Despite the daunting nature of implementing enantioselective catalysis in an electrochemical setting, high enantiomeric ratios of up to 95:5 were obtained, employing the fine-tuned chiral rhodium catalyst Rh2.

Scheme 7 Enantioselective rhodaelectro-catalyzed formation of spirocyclic compounds with all-carbon quaternary stereogenic centers.

Further extension of this strategy toward rhodaelectro-catalyzed dehydrogenative alkyne annulations include vinylic annulation by acrylamides,[57a] a streamlined preparation of pyrroles and lactones,[57f] an enantioselective approach for the synthesis of sultams,[57g] as well as chemo-selective peptide labeling.[57b]

Palladium catalysts were, in contrast, exploited for the dearomatization of 1-aryl-2-naphthols en route to the assembly of a structurally distinct class of spirocyclic compounds 22 ([Scheme 8]).[55] Hence, a broad scope featuring sensitive functional groups and unsymmetrical alkynes was converted in high yields and selectivities.

Scheme 8 Palladaelectro-catalyzed formation of spirocycles.

Generally, metallelectro-catalysis introduces various novel parameters, such as the electrode material, the applied voltage/current, or the supporting electrolyte, that allow the practitioner to steer the reaction’s efficiency and selectivity. This drastically increases the complexity of the chemical space involved in optimization due to the multidimensionality and interaction between the variables. In recent years, machine-learning (ML) gained considerable traction for data-driven prediction and optimization in organic catalysis research, enabling a synergistic interplay with the experimental side.[58] [59] [60] [61] [62] [63] In this context, a workflow was devised that efficiently addressed the multidimensional electrochemical space.[64] The strategy was applied to the ML-guided optimization of an enantioselective palladaelectro-catalyzed C─H annulation ([Scheme 9]). Initially, 16 experiments were carried out, setting the stage for an ML model toward accelerated optimization. Thus, four distinct reactions conditions were proposed for experimental verification, whose results were further implemented to refine the ML model. Based on 12 optimization rounds, ideal conditions were identified out of 8,640 viable options, thereby reducing the required number of experiments to only 68. Overall, our strategy furnished an efficient and selective palladaelectro-catalyst for the assembly of molecules featuring axial chirality through accelerated discovery. This study deliberately portrays the beneficial synergy of organic electrochemistry and data-driven approaches for addressing multidimensional optimization problems in a vastly accelerated manner.

Scheme 9 Enantioselective electrochemical palladium-catalyzed C─H annulation guided by a data-driven workflow.

Thereby, L-tert-leucine served a triple role, namely: (i) providing means for site-selectivity as a transient directing group, (ii) enabling C─H activation via a carboxylate-assisted pathway, and (iii) setting the stage for highly enantioselective electrocatalysis.[65] [66] Based on previous studies,[65] [67] sequential C─H activation and migratory alkyne insertions were suggested to be operative, leading to a twofold C─H alkenylated intermediate. Reductive elimination and anodic reoxidation of palladium(0) ensure product formation and catalytic turnover.

Osmium catalysis was successfully employed in C─H/O─H annulation reactions under iodide-mediated electrooxidative conditions, relying on weak O-coordination of benzoic acid derivatives 26 ([Scheme 10a]).[68] Decisive intermediates were isolated and fully characterized, which fostered the mechanistic understanding in combination with, among other, in-operando NMR spectroscopy and high-resolution mass spectrometry. Thus, a modus operandi based on osmium(II/0) was unraveled, including a facile C─H activation, occurring through a base-assisted internal electrophilic-type substitution (BIES) mechanism. The synthetic utility was further demonstrated by performing an enantioselective electrochemical bishydroxylation in a one-pot fashion following initial alkyne annulation, underlining the versatility of osmaelectrooxidative catalysis ([Scheme 10b]).

Scheme 10 (a) Osmaelectro-catalyzed annulation with benzoic acids through weak O-coordination. (b) One-pot osmaelectro-catalyzed annulation and enantioselective electrooxidative dihydroxylation.

2.2

Earth-Abundant 3d Transition-Metal Catalysis

The choice of metal is clearly a decisive factor in influencing the overall sustainability of catalytic reactions.[53] [69] On this premise, cobalt was repeatedly demonstrated to be a promising and efficient surrogate for its noble congeners due to the earth-abundance and diminished toxicity.[70] Based on the first cobaltaelectro-catalysis for C─H oxygenations,[71] an unprecedented electrochemical alkyne annulation via cobalt-catalyzed C–H/N–H activation proved viable ([Scheme 11a]).[72] Notably, H₂O was employed as the solvent under ambient conditions, demonstrating the tolerance of cobaltaelectro-catalyzed C–H activation under environmentally benign conditions. Based on detailed mechanistic studies, a plausible catalytic cycle was proposed ([Scheme 11b]). The catalytically active cobalt(III) carboxylate species A is generated through initial anodic oxidation. Subsequent carboxylate-assisted C–H activation provides intermediate B, which undergoes migratory insertion to form the cobalt(III) metallacycle C. Thereafter, reductive elimination delivers the desired product 31 and the putative cobalt(I) species D. The latter upon anodic oxidation leads to the regeneration of the catalytically active cobalt(III) carboxylate complex.

Scheme 11 (a) Cobaltaelectro-catalyzed C–H/N–H alkyne annulation with terminal alkynes. (b) A plausible catalytic cycle for cobaltaelectro-catalyzed C–H/N–H alkyne annulation.

Subsequently, the outstanding potential of electro-oxidative C–H activation concerning sustainable synthesis was showcased by the efficiency of cobaltaelectro-catalyzed C–H activation in biomass-derived glycerol. Furthermore, the transformation was powered by electricity generated directly from renewable energy sources such as sunlight ([Scheme 12a]) or wind ([Scheme 12b]).[73] [74] [75] [76] [77] Notably, this proof-of-concept study underscores the feasibility of utilizing renewable energy to drive sustainable and resource-economical electrocatalysis, further illustrating the robustness and practicality of this approach. A comprehensive description of the electrolytic cell design for the cobaltaelectro-catalysis was provided, detailing readily accessible electrode materials and electrode holders.[78]

Scheme 12 Cobaltaelectro-catalyzed C–H activation driven by natural sunlight (a) or wind (b) as a renewable source of energy.

In 2018, a cobaltaelectro-catalyzed oxidative C–H/N–H activation annulation of hydrazides with internal alkynes was reported ([Scheme 13a]).[79] Thereby, the hydrazide directing group in the annulation product 33 was efficiently removed in 90% yield via cathodic electroreduction catalyzed by samarium iodide in an operationally advantageous undivided cell ([Scheme 13b]). Hence, it highlights the practical utility of this versatile electrochemical strategy. Furthermore, the approach was extended to 1,3-diynes ([Scheme 13c]).[80] Intermolecular competition experiments revealed that electron-rich hydrazides exhibit higher reactivity, indicating that the C–H activation likely proceeds via a BIES mechanism.

Scheme 13 (a) Cobaltaelectro-catalyzed C–H/N–H annulation of hydrazides with internal alkynes. (b) Electroreductive cleavage of the directing group. (c) Extension of the cobaltaelectro-catalyzed approach to 1,3-diynes.

Further examples of cobaltaelectro-catalyzed C─H annulation include the application of sulfonamides for the synthesis of sultams, as well as the use of gaseous ethyne, as reported by Lei.[81] [82]

Additionally, copper-catalyzed C─H annulation was realized in the form of a decarboxylative cupraelectro-catalyzed domino reaction with broad functional group tolerance and ample scope ([Scheme 14]).[83] [84] [85] Economically desirable and widely available Cu(OAc)₂ was utilized for the strategic construction of isoindolones 38, whereby successful scale-up was demonstrated. Thorough mechanistic studies involving isotope-labeling and CV experiments suggested facile C─H activation mediated by copper(III) with an ensuing alkynylation through reductive elimination. While copper is anodically reoxidized to copper(III), the alkynlated product undergoes cyclization affording the desired compound 38.

Scheme 14 Cupraelectro-catalyzed alkyne annulation.

Enantioselective catalysis has surfaced as a transformative platform in molecular sciences,[86] rendering the combination with earth-abundant transition metals highly desirable. The synergism between high-valent cobalt-catalyzed C─H activation and enantioselective catalysis was identified by Ackermann,[87] [88] Cramer,[89] Matsunaga,[90] and later Shi.[91] In 2023, a major advance was achieved in terms of an unprecedented merger of enantioselective cobalt-catalyzed C─H activation and electrocatalysis.[92] Thereby, the Salox ligand L1 was applied, belonging to a ligand class developed by Bolm[93] that is readily accessible from the corresponding amino alcohol. The asymmetric C–H annulation of arylphosphinic amides 39 with distinct alkynes afforded P-chiral cyclic phosphinic amides 41 with excellent enantioselectivities and broad substrate compatibility ([Scheme 15a]). Remarkably, this cobaltaelectro-catalyzed strategy was not limited to simple alkynes; a cascade annulation involving alkynoates 40 was also successfully realized. Moreover, this study demonstrated that enantioselective cobaltaelectro-catalysis could be directly powered by natural sunlight via a solar panel, showcasing the seamless integration of sustainable C–H functionalization with renewable energy. In addition to P-stereogenic products, this cobaltaelectro-catalyzed C–H annulation platform was successfully extended to the construction of C–N axial chirality, delivering atropostable products 44 with excellent levels of enantioselectivity ([Scheme 15b]).

Scheme 15 Enantioselective cobaltaelectro-catalyzed C–H/N–H alkyne annulation for P-central chirality (a) and C–N axial chirality (b).

Further findings on enantioselective cobaltaelectro-catalyzed annulation were elegantly extended by Shi and Niu, showcasing the broad applicability of this strategy.[94] [95] [96] [97] [98]

A novel ligand design enabled highly efficient, atroposelective cobaltaelectro-catalyzed C–H/N–H annulation of benzamides 45 with 2-substituted 1-alkynylindoles 46 ([Scheme 16]).[99] [100] Thus, κ²-N,O-oxazoline ligand L3 allowed for the construction of two remote C–N chiral axes in a single step. In this study, the isolation of an octahedral cyclometalated cobalt(III) complex revealed an N,O-coordination pattern. DFT calculations further identified the migratory insertion as the rate-determining step, with the N,O-coordination mode being energetically preferred over the N,N-mode. As to the energy efficiency, qualitative and quantitative gas evolution analysis unraveled a Faradaic efficiency of ~80% for the cathodic HER. These findings are in good agreement with previous studies on related systems.[101]

Scheme 16 Enantioselective cobaltaelectro-catalyzed C–H/N–H alkyne annulation for double remote C–N axial chirality.

3

Conclusion

In recent years, metallaelectro-catalysis was identified as an increasingly versatile toolbox in molecular synthesis by leveraging proton-coupled electron transfers for traceless redox transformations. Thus, stoichiometric chemical redox reagents can be replaced, and novel reaction pathways are rendered accessible through SET. Specifically, metallaelectrocatalysis enabled the effective annulation of user-friendly alkynes by means of activation of otherwise inert C─H bonds. Salient features include (i) dehydrogenative alkyne annulations with weakly coordinating amides and acids by precious metal catalysis and (ii) the use of earth-abundant cobalt and copper electrocatalysts for chemo-, regio-, and even enantioselective alkyne annulations. With regard to the current societal energy transition, it is noteworthy that all these electrooxidative transformation were coupled with the cathodic proton reduction in terms of a green HER.

Given the practical importance of metallaelectrocatalysis for practitioners in material sciences as well as chemical and pharmaceutical industries, further exciting advances are expected in this rapidly evolving area. Thus, data-enabled accelerated optimization and discovery in electrocatalysis is in its infancy and needs to be explored, particularly with respect to effective upscaling of processes.[44] [45] [46] [59] [102] [103] [104] Further future advances should also include the identification of scalable electrooxidations with outstanding societal demand to be coupled with the HER,[105] as well as the efficient use of less-toxic electrocatalysts based on nickel[106] or iron.[107]

Sven Erik Peters

Sven Erik Peters was born in Hamburg, Germany. He studied chemistry at the Georg-August-Universität Göttingen, where he completed his MSc under the supervision of Prof. Lutz Ackermann. There, he continued his research for his PhD, with a specific focus on selectivity-control in electrochemical and thermal C─H activations. In 2024, he received the Kekulé-fellowship from the Fonds der Chemischen Industrie (FCI).

Yang Xu

Yang Xu received his MSc from Zhengzhou University. In February 2022, he joined the research group of Prof. Lutz Ackermann at Georg-August-Universität Göttingen as a PhD candidate. His current research focuses on the development of photo- and electro-oxidative asymmetric C–H activation reactions.

Felix Gerlich

Felix Gerlich was born in Würzburg, Germany. He obtained his BSc from the University of Applied Sciences in Aachen. Over the course of his master’s studies at the Georg-August-Universität Göttingen, he shifted his focus to synthetic organic chemistry. Receiving his MSc in 2025, he subsequently joined the research group of Prof. Dr. Lutz Ackermann as a PhD student, further concentrating on developing sustainable, enantioselective, and electrocatalytic approaches.

Lutz Ackermann

Lutz Ackermann studied Chemistry at the Christian-Albrechts-Universität zu Kiel (Germany) and performed his PhD with Prof. Alois Fürstner at the Max-Planck-Institut für Kohlenforschung (Mülheim/Ruhr, 2001). After a postdoctoral stay at UC Berkeley with Prof. Robert G. Bergman, he initiated his independent research career in 2003 at the Ludwig-Maximilians-Universität München. In 2007, he became a Full Professor (W3) at the Georg-August-Universität Göttingen. His recent awards and distinctions include an ERC Consolidator Grant (2012), a Gottfried-Wilhelm-Leibniz-Preis (2017), an ERC Advanced Grant (2021), the French–German Prize “Georg Wittig–Victor Grignard” (2022), the Otto Roelen Medal (2024), and the Hansen Family Award from the Bayer Foundation (2025). The development and application of novel concepts for sustainable catalysis constitutes his major current research interests, with a topical focus on electrocatalysis and bond activation.

Contributors’ Statement

S.E.P.: Conceptualization, Writing – original draft, Writing – review & editing. Y.X.: Conceptualization, Writing – original draft, Writing – review & editing. F.G.: Writing – original draft, Writing – review & editing. L.A.: Conceptualization, Funding acquisition, Project administration, Resources, Supervision, Writing – original draft, Writing – review & editing.

Conflict of Interest

The authors declare that they have no conflict of interest.

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Publication History

Received: 27 November 2025

Accepted after revision: 23 December 2025

Article published online:
22 January 2026