Electrochemical N-Propargylation of N-Heterocycles via Decarboxylation of Allenoic Acids
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Electrochemical N-Propargylation of N-Heterocycles via Decarboxylation of Allenoic Acids
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ACS Organic & Inorganic Au

Cite this: ACS Org. Inorg. Au 2026, XXXX, XXX, XXX-XXX
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https://doi.org/10.1021/acsorginorgau.5c00117
Published March 18, 2026

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Abstract

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Broadly applicable and selective C–N bond formation remains a cornerstone challenge in organic synthesis. Although electrochemical methods have recently emerged as an efficient way for achieving decarboxylative C–N coupling, transforming allenoic acids into N-functionalized products remains elusive. Herein, we report the development of an electrochemical strategy for the decarboxylative N-propargylation of N-heterocycles using readily available 2,3-allenoic acids. By correlating the oxidation potentials of allenoic acids and nucleophilic coupling partners, we derived predictive criteria for anticipating reaction efficiency across a broad substrate scope. Mechanistic studies (cyclic voltammetry, in situ infrared (IR) kinetics, and density functional theory (DFT) calculations) support a two-step sequence involving oxidative decarboxylation to an allenyl radical rapidly oxidized to a highly electrophilic allenyl/propargyl cation and regioselective heterocycle attack yielding N-propargylated products. This work showcases a straightforward method for accessing reactive allenyl cation intermediates and expands the toolkit for sustainable electrosynthetic C–N bond formation.

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Introduction

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Carbon–nitrogen bonds are ubiquitous in natural products, pharmaceuticals, agrochemicals, and functional materials, making their preparation a prime challenge in synthetic chemistry. (1) Many methods for their synthesis exist, involving transition-metal-catalyzed coupling reactions (Buchwald–Hartwig amination, (2) Ullmann coupling, (3) Chan–Lam coupling, (4) etc.) or metal-free routes, (5) such as nucleophilic substitution, reductive amination, (6) the Curtius rearrangement, (7) or the Mitsunobu reaction. (8) Yet, many of these procedures rely on relatively expensive and toxic reagents and generate stoichiometric amounts of hazardous byproducts.
Electrosynthesis offers a powerful, sustainable alternative for challenging bond-forming reactions, relying on electrons as traceless reagents to enable transformations under mild conditions with minimal additives. (9) In this vein, N-centered nucleophiles can be used as substrates in electrosynthetic C–N bond formation, offering both synthetic simplicity and a broad substrate scope. (10) In particular, electrochemical decarboxylative couplings of both C(sp3)- and C(sp2)-hybridized carboxylic acids have emerged as a powerful transformation in organic synthesis. (11) The anodic oxidation of carboxylates, also known as the Kolbe reaction, is among the first reported organic electrosyntheses and is attractive as it generates CO2 as the sole byproduct. (12) This approach has been used by several groups to create C(sp3)–N bonds from sp3 carboxylic acids and N-heterocycles (Scheme 1A). For instance, Wang (13) and Baran (14) independently reported the oxidative decarboxylative C(sp3)–N coupling, proposing the reaction to proceed through a carbocation intermediate trapped by nitrogen-centered nucleophiles (the Hofer–Moest reaction). Later, Zhang described an aerobic decarboxylation of aliphatic carboxylic acids using CF3SO2Na and a cobalt catalyst, suggesting a radical coupling mechanism between an alkyl radical, generated after electrochemical decarboxylation, and a nitrogen-centered radical. (15) By contrast, C(sp2)–N bond formation via electrochemical decarboxylation of α,β-unsaturated carboxylic acids remains unexplored, (16) despite the development of related decarboxylative functionalizations such as sulfonylation, (17) thiocyanation, (18) silylation, (19) phosphorylation, (20) and trifluoromethylation (21) (Scheme 1B). Here, the proposed mechanism involves radical addition to the alkene, generating an alkenyl radical prior to oxidative decarboxylation. In this pursuit, we conducted a similar study on cinnamic acids, but our preliminary results on their oxidative decarboxylation in the presence of pyrazole did not yield the desired C–N coupling product (Scheme 1B). We hypothesize that this is due to the lower oxidation potential of the acid compared to that of the N-heterocycle, leading to the generation of highly reactive vinyl intermediates that undergo decomposition.

Scheme 1

Scheme 1. Synthesis of Propargylic N-Heterocycles and Reactivity of Carboxylic Acids
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With allenoic acids as substrates, electrochemical decarboxylation is expected to initially yield C(sp)-hybridized allenyl radicals, which may undergo further oxidation, thus unlocking the ability to engage in both propargylation and allenylation reactions. Despite this pathway being, in principle, ideally suited for the controlled generation of allenyl/propargyl cations, it remains synthetically unexplored. However, the implementation of the electrochemical generation of allenyl radicals from allenoic acids faces three primary challenges: (a) the complex reactivity of allenyl radicals due to the presence of multiple π bonds, associated with a low radical stability; (b) the control of the regioselectivity, as nucleophiles may react at the propargylic or allenic position, leading to a mixture of allenic and acetylenic products; (22) and (c) the presence of the carboxylic acid that may act as a competing nucleophile. In fact, 2,3-allenoic acids have been mostly engaged as substrates in Pd- or Rh-catalyzed coupling reactions (23,24) and metal- or photoredox-catalyzed radical cyclization (25) to access γ-butyrolactone derivatives (Scheme 1C). Thus, allenoic acids have neither been utilized as precursors in decarboxylation reactions nor have they been utilized in the context of electrosynthesis. Further, the direct propargylation of N-heterocycles, key scaffolds in numerous therapeutic agents with antimicrobial, anticancer, analgesic, and anti-inflammatory properties, (26) remains relatively underdeveloped. Existing methods are largely restricted to pyrazoles, (27) benzo(triazoles), (28) carbazoles, and indoles (29) and often rely on metal catalysts or elevated temperatures. Although these methods represent notable advances, their limitations leave room for complementary strategies that achieve general and regioselective propargylation under mild and sustainable conditions.
Herein, we report an electrochemical strategy for the construction of propargylic C–N(heterocycle) bonds through the decarboxylation of 2,3-allenoic acids, followed by trapping with N-heterocycles (Scheme 1D). 2,3-Allenoic acids are particularly well suited for the anodic generation of cations, as oxidative decarboxylation furnishes a delocalized allenyl/propargyl radical that is readily oxidized in a second electron transfer step. In this way, highly electrophilic allenyl/propargyl cations are obtained in a controlled way under mild constant-current conditions. Moreover, this method provides access to products featuring a quaternary stereogenic carbon center at the propargylic position. By correlating the oxidation potentials of both coupling partners, we rationally guided the selection of substrates. To gain a deeper insight into the reaction mechanism and the observed regioselectivity, we conducted electrochemical analysis, kinetic studies, and density functional theory (DFT) computations.

Results and Discussion

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Verification of the Hypothesis and Optimization

Initially, cyclic voltammetry (CV) measurements were performed to test whether 4-phenylhexa-2,3-dienoic acid 1a has a lower oxidation potential than that of a potential N-heterocyclic coupling partner such as pyrazole 2a. This is a prerequisite for ensuring that a radical or a cation intermediate generated from the oxidative decarboxylation of 1a can be accessed while leaving 2a intact. For 1a, CV indicates a single irreversible oxidation wave at 1.77 V (vs Ag/AgNO3), whereas 2a exhibits an irreversible oxidation peak at 2.01 V (Figure 1A, gray curve). Encouraged by these numbers, we initially subjected a mixture of 1a and 2a (1.5 equiv) to electrolysis under the conditions reported by Baran for the C(sp3)–N coupling of N-heterocycles, (14) adding 2,4,6-collidine as a base (1.5 equiv) and nBu4NPF6 as a supporting electrolyte in DCM, which may act as an electron sink (30) (Figure 1A). The electrolysis was conducted under a constant current of 5 mA in an undivided cell equipped with an inexpensive graphite anode and a nickel cathode at room temperature. Encouragingly, under these unoptimized conditions, target product 3 was obtained in a 68% yield (entry 1, Figure 1B). Decreasing the excess of 2a to 1.0 equiv resulted in a lower isolated yield (entry 2). A slight increase in the yield was observed when running the reaction at 10 mA (entry 3), albeit a degradation of the graphene anode was observed. Replacing the material of the cathode from nickel (Ni) to graphite (C) or platinum (Pt) did not have a positive impact on the reaction outcome (entries 4 and 5). Subsequently, other common organic solvents were examined, with MeCN and THF leading to lower yields of 3 (entries 6 and 7). A slight decrease in the yield was observed when changing the supporting electrolyte (entries 8 and 9). Various bases were tested, in most cases leading to an incomplete conversion or lower yields (see the SI for details, Table S5). To our surprise and in contrast with the conditions required by Baran, we observed the highest yield (78%) without any externally added base (entry 10). Finally, a control reaction without current was conducted, and no product was observed (entry 11). Under the optimized conditions, the Faradaic efficiency of the reaction was determined as 71%, showing the minimal loss of current in this transformation.

Figure 1

Figure 1. Identification of reaction conditions based on cyclic voltammetry. [a]Cyclic voltammogram of allenoic acid 1a (purple curve) and pyrazole 2a (blue curve) in MeCN with nBu4NPF6 (0.1 M) as the electrolyte using a platinum disk (d = 2 mm) as the working electrode, a platinum wire as the counter electrode, and a nonaqueous Ag/AgNO3 electrode (3.0 M in MeCN) as the reference. All cyclic voltammetry experiments scan from 0.0 V vs the Ag/Ag+ reference electrode in the anodic direction at a scan rate of 50 mV/s. The cyclic voltammetry traces were presented with the IUPAC convention. [b]Initial conditions: 1a (0.2 mmol), pyrazole 2a (1.5 equiv), 2,4,6-collidine (1.5 equiv), nBu4NPF6 (0.05 M), DCM (3.0 mL), undivided cell, C-SK-50 anode, Ni cathode, CCE = 5 mA, 2.2 F/mol. [c]Isolated yield. [d]Surface degradation of the C anode was observed. [e]Faradaic efficiency.

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Scope and Limitations

After identifying suitable reaction conditions, we set out to explore the versatility of this reaction based on the oxidation potential of various allenoic acids with pyrazole (2a) as the nucleophile (Scheme 2). Good yields were obtained with electron-donating and weakly electron-withdrawing substituents at the para position (4: 70% yield and 5: 63% yield). The presence of an electron-withdrawing CF3 group led to an incomplete conversion and a low yield of 28% (6). This drop in efficiency can be attributed to the Eox of 1d becoming higher than that of 2a and thus preventing the formation of the oxidized intermediate. The reactivity can be fully restored by introducing an ethyl substituent on allenoic acid that generates a quaternary propargylic product with a 60% yield (7), in line with the oxidation potential of 1e being increased to 1.95 V. Other quaternary propargylic alkynes were synthesized in 49–64% yields (8–10), highlighting that, in a single step, a quaternary center is efficiently installed at the propargylic position. Changing the methyl substituent to p-bromobenzyl lowered the yield (11: 40% yield), while no reaction occurred with a hydrogen atom (12). However, the terminal propargylic alkyne was synthesized in a 43% yield when using γ-disubstituted allenoic acid (13). Replacing the phenyl group with an alkyl substituent led to no conversion, demonstrating the critical role of the substituted groups on allenoic acid for this transformation. In line with these results, no oxidation peak was observed in the CV measurements of 1l.

Scheme 2

Scheme 2. Electrochemical Propargylation of Pyrazole with Various Allenoic Acids
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[a] Two major oxidation peaks were observed on the CV of 1i (see the SI for CV graphs). [b] A broad, ill-defined oxidation wave was observed, which precluded the determination of an oxidation potential for 1j.

Next, we examined the scope of the reaction of N-heterocycles with 2,3-allenoic acids 1a and 1f (Scheme 3). We first examined substituted pyrazoles and found that various substitution patterns are compatible with our method. Pyrazoles with bromo, chloro, and ethoxycarbonyl substituents reacted regioselectively with 1a and 1f to furnish a single isomer of the corresponding product (15–24) in 32–70% yields. (31) A second set of reaction conditions was developed for deactivated pyrazoles, which are virtually insoluble in DCM and, consequently, cannot be utilized under the original conditions (Cond. B). We achieved the desired reactivity by adding HFIP as a polar protic cosolvent (DCM/HFIP, 9:1, v/v) and including 2,4,6-collidine as a base (see the SI). The inclusion of HFIP promoted cathodic H2 evolution and increased the solubility of the azoles. Condition B enabled C–N propargylation of pyrazoles bearing several relevant functional groups such as formyl, cyano, trifluoromethyl, and nitro (25–32, 25–59% yields).

Scheme 3

Scheme 3. Scope of N-Heterocycles for the Electrochemical Propargylation of Allenoic Acids and Extension to Other Nucleophiles
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[a]22 was observed in the crude reaction mixture with a similar conversion as 21, but it could not be isolated in the pure form, presumably due to decomposition. [b] 3 equiv of the nucleophile was used. [c] The reaction was performed in a 9:1 (v/v) mixture of DCM/alcohol.

Other aromatic N-heterocycles, such as 4,5,6,7-tetrahydro-1H-indazole, benzotriazoles, and triazole and tetrazole derivatives, reacted smoothly and led to the desired N-alkylated products 33–48 in up to an 87% yield. It should be noted that a low N-site selectivity is observed, resulting in a mixture of N1-/N2- or N2-/N3-alkylated products, which can be attributed to the loss of selectivity during diffusion-controlled trapping (cf. the computational section and Figure 3D). Nevertheless, the regioisomers can be effectively separated through chromatography, extending the range of propargylated N-heterocycles accessible from allenoic acids. Indazole and benzimidazole could not be coupled under the reaction conditions as their calculated oxidation potentials are lower than those of allenoic acid 1a (see the SI for DFT computations and the complete list of unsuccessful nucleophiles). Moreover, this reaction was successfully expanded to benzamide (49), carboxylic acids (50 and 51), and alcohols (52–54) as nucleophiles, thus opening a new synthetic entry to valuable propargylic compounds. Of note, the reaction displays a high Faradaic efficiency, as it proceeds via two sequential oxidations of allenoic acids and requires only a slight excess of charge (2.2 F/mol) relative to the theoretical value of 2.0 F/mol (see Table S8 in the Supporting Information for Faradaic yields and Figure 3 for mechanistic details). Additionally, the reaction exhibits very good atom economy, typically around ∼80–85% (see Table S8 in the Supporting Information for atom economy values), which makes it attractive from a sustainability perspective.
Next, we tested the synthetic utility of our protocol (Scheme 4). From a practical point of view, upscaling the reaction (2.0 mmol) allowed a larger-scale synthesis of propargylated compound 3 in a 59% yield. The slight reduction in the isolated yield can be attributed to the increased solution concentration caused by material limitations in achieving a larger-scale experiment. The synthetic versatility of 3 was further explored in divergent hydrogenation protocols employing a Pd/C catalyst and a poisoned Pd/C catalyst with quinoline to afford the reduction products 55 and 56, respectively.

Scheme 4

Scheme 4. Synthetic Utility of the Electrochemical Propargylation of N-Heterocycles
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Mechanistic Studies

First, we set out to ascertain the hypothesized oxidation of allenoic acid 1a as the first step of the mechanism (Figure 2). In divided-cell electrolysis experiments, the product formed only when the reactants were placed in the anodic chamber, supporting the idea that an oxidation process is responsible for product formation (Figure 2A). The anodic oxidation of 1a was further confirmed to be critical for effective product formation by constant-potential electrolysis (Figure 2B). In fact, with the amount of total charge remaining unchanged, tuning the potential between 1.5 and 2.0 V (vs Ag/AgCl in 3.0 M KCl) led to a variation of the yield of 3 with a maximum yield observed at an applied potential of 1.7 V. This result aligns with the cyclic voltammetry (CV) of 1a, suggesting that the oxidation reaction only becomes effective when the cell potential surpasses a critical threshold.

Figure 2

Figure 2. Overview of the mechanistic experiments. (A) Divided-cell experiments were carried out in IKA Pro-Divide equipment that includes two PTFE cells separated from each other by a glass frit (pore size 10–16 μm) equipped with an O-ring. A graphite SK-50 electrode (8 mm wide, 50 mm length, 1 mm thickness) was used as the anode, and a nickel electrode (8 mm wide, 50 mm length, 1 mm thickness) was used as the cathode. (B) Constant-potential electrolysis experiments were performed using IKA ElectraSyn equipment equipped with graphite as the working electrode, nickel as the counter electrode, and Ag/AgCl wire in 3.0 M KCl as the reference electrode. Constant-potential electrolysis was conducted at various potentials and terminated once a total charge of 1.0 F/mol had passed through the circuit. The reaction yield was determined by NMR using mesitylene as an internal standard. (C) Chirality transfer experiments using standard conditions. (D) IR kinetics were followed using a Mettler-Toledo ReactIR 15 system and a 6.3 mm AgX Fiber probe with 78 scans per spectrum. Data was acquired and processed with Mettler-Toledo iC IR software with solvent subtraction of DCM and electrolyte subtraction of nBu4NPF6. The absorbance at 1689 cm–1 was recorded.

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Oxidation of 1a may yield different intermediates involved in product formation, including carboxylic radicals, allenyl/propargyl radicals, and allenyl/propargyl cations. The C–N propargylation of the enantiopure substrate (S)-1a with 2a was evaluated to obtain insights into the nature of the intermediates (Figure 2C). Here, we observed a complete loss of stereochemical information, which supports the involvement of planarized propargyl or allenyl species (radicals or cations) for C–N bond formation rather than carboxylic radicals. (32) Of note, radical trapping experiments using TEMPO or BHT are not conclusive for the investigated system due to the lower oxidation potential of these reagents compared to that of allenoic acids or pyrazole, thus leading to inconclusive results. (33) A radical clock experiment was considered as an alternative, but we were unable to prepare an allenoic acid bearing a cyclopropyl moiety.
Next, kinetic studies were performed by in situ IR spectroscopy (Figure 2D). To establish the time-dependent concentration of 1a during the kinetic measurement, the linear relationship of the IR absorbance at 1689 cm–1, which corresponds to the C═O band of 1a, and the concentration of 1a was used. The disappearance of 1a over time was then applied to determine initial reaction rates k, which was experimentally measured with different initial concentrations of 1a and 2a. The initial rates of k were independent of the concentrations of 1a and 2a, suggesting the reaction to be of zero partial order in both allenoic acid 1a and pyrazole 2a. Yet, the initial rate exhibits a linear correlation with the applied current, indicating that the anodic electron transfer process constitutes the rate-limiting step.
Finally, we applied DFT computations to quantitatively explore the different mechanistic options (Figure 3). Structures were optimized at the SMD(CH2Cl2)/ωB97XD/def2-SVP level of theory and combined with single-point energy corrections at the SMD(CH2Cl2)/ωB97XD/def2-TZVPP level (for details, see the Supporting Information). (34−37) Without any external base, as used under our standard conditions, carboxylic radicals derived from 1a can form via three pathways: (I) oxidation of the carboxylic acid followed by proton transfer to 2a (Figure 3A, states A→C→D), (II) proton transfer from 1a to 2a followed by oxidation of the carboxylate anion (Figure 3A, states A→B→D), (38) or (III) a combined proton-coupled electron transfer (PCET). Although the carboxylate anion of 1a has a significantly lower computed oxidation potential (+0.67 vs +1.55 V; both vs SCE), 2a is not a sufficiently strong base in dichloromethane to deprotonate 1a (ΔG0 = +112.6 kJ mol–1). This aligns with experimental acidity measurements from Leito and co-workers in CH2Cl2 for 2a-H+ (pKa,DCM = 9.1) and the related carboxylic acid benzoic acid (pKa,DCM = 21.5). (39) Accordingly, scenarios (I) or (III) are most likely to occur under our conditions, where the radical cation of the carboxylic acid C becomes sufficiently acidic so that proton transfer can occur (ΔG0 = +27.7 kJ mol–1). In line with the experimental observation that an aryl substitution is important for the oxidation to occur, inspection of the HOMO of 1a shows a direct conjugation of the aryl ring with the adjacent C═C double bond of the allenyl system (Figure S16).

Figure 3

Figure 3. Computational exploration of the reaction mechanism at the SMD(CH2Cl2)/ωB97XD/def2-TZVPP//SMD(CH2Cl2)/ωB97XD/def2-SVP level of theory. (A) Competing pathways for electrochemical oxidation; all Gibbs energies are reported in kJ mol–1. Electrochemical steps are highlighted with blue arrows, and the oxidation potentials are calculated vs the saturated calomel electrode (SCE). (B, C) Evaluation of addition of 2a to radical intermediates D and E. (D) Gibbs energy profile for the reaction of cation F as allenyl vs propargyl cations with nucleophile 2a.

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Once radical D is generated, decarboxylation to yield the propargyl radical E occurs (Figure 3A). Radical D is located in a flat region on the potential energy surface, and decarboxylation proceeds without any barrier in a highly exergonic reaction (ΔG0 = −167.7 kJ mol–1). The potential for the further oxidation of the delocalized propargyl radical E (see Figure 3A for the spin density and key bond lengths) to a propargyl cation F is calculated to be +0.43 V (vs SCE), which is significantly lower than that for the initial oxidation. Accordingly, under conditions where oxidation from A to D can occur, the oxidation of E to F should also take place. Although F is thus the most likely intermediate for the C–N coupling step, we first evaluated the possibility of C–N coupling through radical intermediates.
The addition of 2a to radical D could lead to the radical species IM-B that is stabilized by intramolecular hydrogen bonding and that, after deprotonation, leads to the thermochemically unfavorable IM-A. (Figure 3B) Although we could optimize the structure IM-B, attempts to localize a transition state for its formation lead, in all cases, to the decarboxylation and formation of E. The loss of stereochemical information (cf. above) is consistent with this mechanism being implausible. Adding 2a to the delocalized propargyl radical E is similarly not a viable option for thermochemical reasons (Figure 3C).
In contrast to potential radical pathways, the propargyl cation F is a highly electrophilic species. It has been discussed previously that, for cations such as F, reaction via the propargyl cation is kinetically preferred, whereas reaction via the allenyl cation is thermodynamically more favorable. (40) Our computations for the addition of 2a to F are in line with such an analysis (Figure 3D). However, the addition of 2a to F to yield the propargylic system G proceeds as a barrierless process and is thus suggested to proceed with close to a diffusion-controlled rate. The computational prediction of diffusion-controlled reactivity to G, in combination with the reaction being irreversible, is in line with experimental observations that suggest the formation of product mixtures with azoles, i.e., the loss of selectivity. (41) In contrast, a barrier of ΔG‡ = +30 kJ mol–1 was computed for the reaction to yield the allene I. Yet, the thermochemistry for forming I is more favorable compared to G by 19 kJ mol–1. However, given the high Lewis acidity of F, reactions with most types of coupling partners are likely irreversible and the propargylation product is observed, in line with our experimental findings that exclusively lead to such products.

Conclusion

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In conclusion, we reported an electrochemical strategy for the propargylation of N-heterocycles with 2,3-allenoic acids. The energy-efficient transformation with a Faradaic efficiency typically in the 40–70% range utilizes a straightforward reaction setup that involves an inexpensive carbon-based productive anode and no external additives such as oxidants, bases, or dehydrating agents. Under these conditions, 43 N-propargylated products were successfully synthesized in yields ranging from 25 to 82%. In addition, the scope of the reaction was further extended to include amides, carboxylic acids, and alcohols as nucleophiles. Experimental and computational analyses of the mechanisms suggest the involvement of an allenyl radical intermediate that is further oxidized to the corresponding allenyl/propargyl cation. The C–N coupling reaction is governed by the reaction of the highly electrophilic cation under kinetic control to yield the propargylation products. We will continue to explore the concept of a quantitative mechanistic approach to explore the electrochemical generation of reactive intermediates for energy-efficient syntheses.

Experimental Methods

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General Information

All commercial materials were purchased from Sigma-Aldrich, TCI, Fischer Scientific, and BLDPharm and were used as received without further purification. Reactions were monitored by thin-layer chromatography (TLC) performed on aluminum plates coated with silica gel F254 with a 0.2 mm thickness. Chromatograms were visualized by fluorescence quenching with UV light at 254 nm or by staining using vanillin. Flash column chromatography (FC) was performed using silica gel (50 μm, irregular, FlashPure Ecoflex, Buchi). Yields refer to chromatographically and spectroscopically pure compounds. 1H NMR, 13C NMR, and 19F NMR spectra were recorded using Bruker 300 or 400 MHz spectrometers at 300 K. 1H NMR chemical shifts are reported in ppm using the residual solvent peak as a reference (CDCl3: δ = 7.26 ppm). Data for 1H NMR are presented as follows: chemical shift δ (ppm), multiplicity (s = singlet, d = doublet, t = triplet, m = multiplet, br = broad), coupling constant J (Hz), and integration; 13C NMR spectra were recorded at 75 and 100 MHz using broadband proton decoupling and chemical shifts are reported in ppm using residual solvent peaks as the reference (CDCl3: δ = 77.16 ppm). Multiplicity was defined by recording 13C NMR spectra using an attached proton test (APT). 19F NMR spectra were recorded at 376 MHz at ambient temperature. High-resolution mass spectrometry (HRMS) analysis was performed on a Waters LCT Premier (ESI-TOF) instrument or an Agilent QTOF 6500 spectrometer.
All of the electrochemical reactions were conducted on an IKA ElectraSyn 2.0 equipment. The electrodes used in the N-propargylation are a graphite SK-50 anode and a nickel cathode (dimensions (W × H × D): 8 × 52.5 × 2 mm3) purchased from IKA and used as received without any treatment.

General Procedure for the N-Alkylation of Heterocycles with Allenoic Acids (Cond. A)

Under air, a 5 mL ElectraSyn vial equipped with a Teflon-coated magnetic stir bar was charged with allenoic acid 1 (0.20 mmol, 1.0 equiv), N-heterocycle 2 (0.30 mmol, 1.5 equiv), and nBu4NPF6 (58.0 mg, 0.05 M). Then, DCM (3.0 mL, 0.07 M) was added, and the ElectraSyn vial was equipped with two electrodes (a graphite anode and a nickel cathode, 8 mm wide, 50 mm length, 1 mm thickness) and sealed. The reaction mixture was electrolyzed under DC conditions (electrolysis parameters: constant current: 5 mA, amount of charge: 2.2 F/mol). Upon completion, the electrodes were rinsed with DCM. The liquid from washing the electrodes was combined with the crude mixture, which was quenched with HCl 1 M (10 mL) and then extracted with DCM (10 mL × 2). The combined organic layers were washed with brine (10 mL), dried over MgSO4, and concentrated under reduced pressure. The crude mixture was purified by flash column chromatography (FC) over silica gel to furnish the target products 3–24 and 33–36.

General Procedure for the N-Alkylation of Heterocycles with Allenoic Acids (Cond. B)

Under air, a 5 mL vial equipped with a Teflon-coated magnetic stir bar was charged with allenoic acid 1 (0.20 mmol, 1.0 equiv), N-heterocycle 2 (0.30 mmol, 1.5 equiv), and nBu4NPF6 (58.0 mg, 0.05 M). Then, DCM/HFIP (9:1, 3.0 mL, 0.07 M) and 2,4,6-collidine (40.0 μL, 0.30 mmol, 1.5 equiv) were added, and the ElectraSyn vial was equipped with two electrodes (a graphite anode and a nickel cathode, 8 mm wide, 50 mm length, 1 mm thickness) and sealed. The reaction mixture was electrolyzed under DC conditions (electrolysis parameters: constant current: 5 mA, amount of charge: 2.2 F/mol). Upon completion, the electrodes were rinsed with DCM. The liquid from washing the electrodes was combined with the crude mixture, which was quenched with HCl 1 M (10 mL) and then extracted with DCM (10 mL × 2). The combined organic layers were washed with brine (10 mL), dried over MgSO4, and concentrated under reduced pressure. The crude mixture was purified by flash column chromatography (FC) over silica gel to furnish the target products 25–32 and 37–48.

General Procedure for the Propargylation of Other Nucleophiles from Allenoic Acid 1a

Under air, a 5 mL ElectraSyn vial equipped with a Teflon-coated magnetic stir bar was charged with allenoic acid 1a (0.20 mmol, 1.0 equiv), the nucleophile (1.5–3.0 equiv), and nBu4NPF6 (58.0 mg, 0.05 M). Then, DCM (3.0 mL, 0.07 M) was added, and the ElectraSyn vial was equipped with two electrodes (a graphite anode and a nickel cathode, 8 mm wide, 50 mm length, 1 mm thickness) and sealed. The reaction mixture was electrolyzed under DC conditions (electrolysis parameters: constant current: 5 mA; amount of charge: 2.2 F/mol). Upon completion, the electrodes were rinsed with DCM. The liquid from washing the electrodes was combined with the crude mixture, which was quenched with 1 M HCl (10 mL) and then extracted with DCM (10 mL × 2). The combined organic layers were washed with brine (10 mL), dried over MgSO4, and concentrated under reduced pressure. The crude mixture was purified by flash column chromatography (FC) over silica gel to furnish target products 49–54.

Data Availability

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The data underlying this study are available in the published article and its Supporting Information.

Supporting Information

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The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsorginorgau.5c00117.

  • Experimental procedures and characterization data, additional experimental details, and 1H, 13C, and 19F NMR spectra (PDF)

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Author Information

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  • Corresponding Authors
  • Authors
    • Sarah Abdoun - Biomolécules: Conception, Isolement, Synthèse (BioCIS), CNRS UMR 8076, Université Paris-Saclay, 17 avenue des Sciences, 91400 Orsay, France
    • Christophe Bour - Institut de Chimie Moléculaire et des Matériaux d’Orsay (ICMMO), CNRS UMR 8182, Université Paris-Saclay, 17 avenue des Sciences, 91400 Orsay, France;  Orcidhttps://orcid.org/0000-0001-6733-5284
  • Author Contributions

    The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.

  • Notes
    The authors declare no competing financial interest.

Acknowledgments

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Financial support for this work was provided by the French National Research Agency (ANR-24-CE07-3221), the ANR PIA funding (ANR-20-IDEES-0002), and as part of the France 2030 program ANR11-IDEX-0003, awarded by the Graduate School Chemistry of the Université Paris-Saclay. M.V. thanks the CNRS. R.J.M. thanks the Fonds der Chemischen Industrie and the Emmy-Noether Program of the DFG (553844165) for financial support. Computations were performed on resources provided by the Leibniz Supercomputing Centre (LRZ). C.B. thanks the French National Research Agency (ANR-21-CE07-0027). Dr. Laurence Grimaud is acknowledged for helpful discussions.

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Cite this: ACS Org. Inorg. Au 2026, XXXX, XXX, XXX-XXX
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https://doi.org/10.1021/acsorginorgau.5c00117
Published March 18, 2026

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  • Abstract

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    Scheme 1

    Scheme 1. Synthesis of Propargylic N-Heterocycles and Reactivity of Carboxylic Acids
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    Figure 1

    Figure 1. Identification of reaction conditions based on cyclic voltammetry. [a]Cyclic voltammogram of allenoic acid 1a (purple curve) and pyrazole 2a (blue curve) in MeCN with nBu4NPF6 (0.1 M) as the electrolyte using a platinum disk (d = 2 mm) as the working electrode, a platinum wire as the counter electrode, and a nonaqueous Ag/AgNO3 electrode (3.0 M in MeCN) as the reference. All cyclic voltammetry experiments scan from 0.0 V vs the Ag/Ag+ reference electrode in the anodic direction at a scan rate of 50 mV/s. The cyclic voltammetry traces were presented with the IUPAC convention. [b]Initial conditions: 1a (0.2 mmol), pyrazole 2a (1.5 equiv), 2,4,6-collidine (1.5 equiv), nBu4NPF6 (0.05 M), DCM (3.0 mL), undivided cell, C-SK-50 anode, Ni cathode, CCE = 5 mA, 2.2 F/mol. [c]Isolated yield. [d]Surface degradation of the C anode was observed. [e]Faradaic efficiency.

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    Scheme 2

    Scheme 2. Electrochemical Propargylation of Pyrazole with Various Allenoic Acids
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    [a] Two major oxidation peaks were observed on the CV of 1i (see the SI for CV graphs). [b] A broad, ill-defined oxidation wave was observed, which precluded the determination of an oxidation potential for 1j.

    Scheme 3

    Scheme 3. Scope of N-Heterocycles for the Electrochemical Propargylation of Allenoic Acids and Extension to Other Nucleophiles
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    [a]22 was observed in the crude reaction mixture with a similar conversion as 21, but it could not be isolated in the pure form, presumably due to decomposition. [b] 3 equiv of the nucleophile was used. [c] The reaction was performed in a 9:1 (v/v) mixture of DCM/alcohol.

    Scheme 4

    Scheme 4. Synthetic Utility of the Electrochemical Propargylation of N-Heterocycles
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    Figure 2

    Figure 2. Overview of the mechanistic experiments. (A) Divided-cell experiments were carried out in IKA Pro-Divide equipment that includes two PTFE cells separated from each other by a glass frit (pore size 10–16 μm) equipped with an O-ring. A graphite SK-50 electrode (8 mm wide, 50 mm length, 1 mm thickness) was used as the anode, and a nickel electrode (8 mm wide, 50 mm length, 1 mm thickness) was used as the cathode. (B) Constant-potential electrolysis experiments were performed using IKA ElectraSyn equipment equipped with graphite as the working electrode, nickel as the counter electrode, and Ag/AgCl wire in 3.0 M KCl as the reference electrode. Constant-potential electrolysis was conducted at various potentials and terminated once a total charge of 1.0 F/mol had passed through the circuit. The reaction yield was determined by NMR using mesitylene as an internal standard. (C) Chirality transfer experiments using standard conditions. (D) IR kinetics were followed using a Mettler-Toledo ReactIR 15 system and a 6.3 mm AgX Fiber probe with 78 scans per spectrum. Data was acquired and processed with Mettler-Toledo iC IR software with solvent subtraction of DCM and electrolyte subtraction of nBu4NPF6. The absorbance at 1689 cm–1 was recorded.

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    Figure 3

    Figure 3. Computational exploration of the reaction mechanism at the SMD(CH2Cl2)/ωB97XD/def2-TZVPP//SMD(CH2Cl2)/ωB97XD/def2-SVP level of theory. (A) Competing pathways for electrochemical oxidation; all Gibbs energies are reported in kJ mol–1. Electrochemical steps are highlighted with blue arrows, and the oxidation potentials are calculated vs the saturated calomel electrode (SCE). (B, C) Evaluation of addition of 2a to radical intermediates D and E. (D) Gibbs energy profile for the reaction of cation F as allenyl vs propargyl cations with nucleophile 2a.

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      Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Petersson, G. A.; Nakatsuji, H.; Li, X.; Caricato, M.; Marenich, A. V.; Bloino, J.; Janesko, B. G.; Gomperts, R.; Mennucci, B.; Hratchian, H. P.; Ortiz, J. V.; Izmaylov, A. F.; Sonnenberg, J. L.; Williams-Young, D.; Ding, F.; Lipparini, F.; Egidi, F.; Goings, J.; Peng, B.; Petrone, A.; Henderson, T.; Ranasinghe, D.; Zakrzewski, V. G.; Gao, J.; Rega, N.; Zheng, G.; Liang, W.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Throssell, K.; Montgomery, J. A., Jr.; Peralta, J. E.; Ogliaro, F.; Bearpark, M. J.; Heyd, J. J.; Brothers, E. N.; Kudin, K. N.; Staroverov, V. N.; Keith, T. A.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A. P.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Millam, J. M.; Klene, M.; Adamo, C.; Cammi, R.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Farkas, O.; Foresman, J. B.; Fox, D. J. Gaussian 16, Revision C.01; Gaussian, Inc.: Wallingford CT, 2016.
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    38. 38

      A similar situation has been discussed computationally in:

      Wei, Q.; Lee, Y.; Liang, W.; Chen, X.; Mu, B.-S.; Cui, X.-Y.; Wu, W.; Bai, S.; Liu, Z. Photocatalytic Direct Borylation of Carboxylic Acids. Nat. Commun. 2022, 13, 7112  DOI: 10.1038/s41467-022-34833-1
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    39. 39
      (a) Tshepelevitsh, S.; Kütt, A.; Lõkov, M.; Kaljurand, I.; Saame, J.; Heering, A.; Plieger, P. G.; Vianello, R.; Leito, I. On the Basicity of Organic Bases in Different Media. Eur. J. Org. Chem. 2019, 2019, 6735– 6748,  DOI: 10.1002/ejoc.201900956
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      (b) Kütt, A.; Tshepelevitsh, S.; Saame, J.; Lõkov, M.; Kaljurand, I.; Selberg, S.; Leito, I. Strengths of Acids in Acetonitrile. Eur. J. Org. Chem. 2021, 2021, 1407– 1419,  DOI: 10.1002/ejoc.202001649
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    40. 40

      For a discussion of competing kinetic vs thermodynamic product formation of allenyl/propargyl cations, see:

      Mayr, H.; Schneider, R. Ab-initio-MO-Studie Methyl- und Phenyl-substituierter Allenyl-Kationen. Chem. Ber. 1982, 115, 3470– 3478,  DOI: 10.1002/cber.19821151103
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    41. 41

      For a discussion of the loss of selectivity upon reaching diffusion control, see:

      Mayr, H.; Ofial, A. R. The Reactivity–Selectivity Principle: An Imperishable Myth in Organic Chemistry. Angew. Chem., Int. Ed. 2006, 45, 1844– 1854,  DOI: 10.1002/anie.200503273
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