A unified cobalt-electrocatalytic platform for enantio- and stereo-selective C–H and C–F functionalization of gem-difluoromethylene allenes

Abstract

While the merger of electrochemistry with enantioselective C–H functionalization has opened new avenues for assembling valuable chiral architectures, the simultaneous cleavage of strong C–H and C–F bonds via asymmetric electrocatalysis has remained elusive. Here, we present a unified electrochemical cobalt-catalyzed strategy that enables tandem enantioselective and stereoselective C–H and C–F functionalization with gem-difluoromethylene allenes, paired with hydrogen evolution. This resource-economic approach provides efficient access to a diverse range of enantiopure (Z)-fluoroalkenyl N-heterocycles bearing phosphorus-centered, axial, planar, and inherent chirality. Integrated experimental and computational mechanistic studies collectively support an unconventional Co(III/I/III/I) catalytic cycle, proceeding via sequential C(sp²)–H metalation, allene insertion, reductive elimination, C(sp³)–H metalation, alkene isomerization, and β–F elimination.

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Introduction

Merging electrosynthesis and asymmetric transition-metal catalysis has emerged as a powerful and sustainable platform for constructing chiral molecules.^1–10 This strategy uses electrical current to manipulate catalyst redox states, eliminating the need for stoichiometric sacrificial oxidants or reductants. Within this field, electrochemical enantioselective C–H functionalization is particularly attractive, as it enables the rapid assembly of high-value enantioenriched architectures and allows for late-stage diversification of complex structures, paired with hydrogen evolution as a benign byproduct.^11–14

Electrochemical enantioselective C–H activation was pioneered by Ackermann et al. in 2020 for palladium-catalyzed asymmetric alkenylation/allylation^15–17 and annulation,¹⁸ and was later extended to rhodium catalysis for enantioselective C–H annulation^19–21 and indolization (Scheme 1A).²² The high cost and potential supply constraints of these noble metals, however, have driven the search for earth-abundant 3d transition-metal alternatives. Among them, cobalt stands as the most promising candidate, especially when combined with a chiral salicyloxazoline (Salox) ligand to form a versatile catalytic system.^23,24 This system has enabled electrochemical asymmetric C–H annulation,^25–36 esterification,^37–39 and etherification,⁴⁰ which typically proceed via Co(III/I) or Co(III/IV/II) catalytic manifolds.

Scheme 1 Research background and motivation.

Building upon our prior work on C–H/C–F dual functionalization with gem-difluoromethylene allenes (Scheme 1B),^41,42 and inspired by electrochemical cobalt/Salox-catalyzed asymmetric C–H activation with allenes,^29,31,34 we envisioned this cobalt-electrocatalytic system capable of enantioselective cleavage and functionalization of C–H and C–F bonds using gem-difluoromethylene allenes. A successful implementation would represent the first example of electrocatalytic asymmetric C–H/C–F functionalization.⁴³ However, its realization faced several fundamental mechanistic challenges: (a) the propensity of octahedral Co(III) species to adopt intricate coordination geometries, resulting in geometric and stereoisomerism; (b) complex reaction pathways involving multiple cobalt oxidation and spin states, further complicated by the fluoride anion by-product; (c) the smaller atomic radius of Co(III), which impedes β–F elimination; (d) a potent hard acid/hard base interaction between the Co(III) center and fluoride that may suppress the dissociation of Co–F bond—a step essential for catalytic turnover; (e) electrochemical degradation of chiral Salox ligand or substrates/products. This work details a unified electrochemical cobalt/Salox-catalyzed protocol for enantioselective and stereoselective C–H and C–F functionalization of gem-difluoromethylene allenes (Scheme 1B). This versatile platform enables efficient access to a wide array of enantiopure (Z)-fluoroalkenyl azaheterocycles, integrating phosphorus-centered, N–N and C–N axial, planar, and inherent chirality. Furthermore, combined experimental and computational mechanistic studies reveal an unprecedent Co(III/I/III/I) catalytic pathway, distinct from those of analogous Rh- and Ir-catalyzed systems.^41,42

Results and discussion

Method development

We initiated our proof-of-concept study by coupling oxidation-sensitive N-(7-azaindole)benzamide 1aa with gem-difluoromethylene allene 2a in an undivided cell equipped with a graphite felt (GF) anode and a platinum cathode (Table 1). Encouragingly, the electrochemical conditions previously established³² for alkyne annulation successfully mediated the desired tandem C–H and C–F functionalization, affording isoquinolinone 3 in a promising 43% yield with 38% enantiomeric excess (ee). The molecular structure of compound 3 was unambiguously determined by X-ray crystallographic analysis, which revealed the (R_a)-configuration around N–N axis and (Z)-configuration within the fluoroalkenyl moiety. Subsequent optimization revealed that NaOPiv·H₂O served as an effective base and supporting electrolyte. While 1 equivalent sharply enhanced enantioselectivity at the expense of yield, increasing the loading to 2 equivalents improved the overall efficiency. The reaction yield was further increased by conducting the reaction under an air atmosphere (entry 4). The cobalt-to-Salox ratio had minimal influence on reaction performance, with an optimum at 1 : 1.5. Consistent with our previous work,³² the catalyst performance was extremely sensitive to ligand design. Only Salox-7 and Salox-8, which feature a bulky ortho-tert-butyl group on the phenol ring, showed moderate-to-good reactivity and enantioselectivity (entry 7). Alternative electrode materials gave much lower yields (entries 8 and 9). This might be rationalized by: (a) large surface area of the GF anode for cobalt contact, and (b) favorable dihydrogen evolution on the Pt surface, which was detected via headspace gas chromatography (GC) analysis. 2,2,2-Trifluoroethanol (TFE) was identified as the optimal solvent, likely due to its dual role in enhancing the solubility of the cobalt salt and acting as a proton shuttle (entry 10). Reaction efficacy diminished at higher current densities, suggesting possible electrochemical decomposition of the substrate or product (entry 11). Both shorter and prolonged reaction times resulted in slightly diminished yields with comparable enantioselectivity (entries 12 and 13). This observation implies that product 3 undergoes decomposition under the current electrochemical conditions. To verify this hypothesis, we resubjected enantiopure 3 to the optimal condition; no erosion of enantioselectivity was observed, but significant decomposition of 3 occurred (Section 4.8 in SI). These findings further underscore the inherent difficulty of employing benzamide 1aa in electrochemical transformations. Control experiments verified that both the cobalt catalyst and an electrical current are essential for this tandem net-oxidation reaction (entries 14 and 15). This electro-oxidative transformation proceeds with a good current efficiency of 57%, underscoring the sustainability of the overall method.

Table 1 Reaction development^a

#	Ligand (mol%)	Base (equiv.)	Air/O2	3, %
				Yield	ee
a Conditions: 1aa (0.08 mmol), 2a (0.096 mmol), Co(OAc)2·4H2O (10 mol%), ligand, base, TFE (2 mL), undivided cell with graphite felt (GF) anode (10 mm × 20 mm × 2 mm) and platinum plate (Pt) cathode (10 mm × 20 mm × 0.3 mm), 1 mA, 80 °C, 6 h. Isolated yields. Enantiomeric excess (ee) determined by HPLC with a chiral stationary phase.
1	Salox-7 (20)	—	O2	43	38
2	Salox-7 (20)	NaOPiv·H2O (1)	O2	14	79
3	Salox-7 (20)	NaOPiv·H2O (2)	O2	47	86
4	Salox-7 (20)	NaOPiv·H2O (2)	Air	70	96
5	Salox-7 (15)	NaOPiv·H2O (2)	Air	80	96
6	Salox-7 (10)	NaOPiv·H2O (2)	Air	60	96

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Further variation from optimal condition (entry 5, condition A)
7	Salox-1–7	As above
8	C as anode	20	91
9	GF as cathode	21	90
10	^tBuOH	31	91
11	2 mA	37	98
12	5 h	70	95
13	7 h	72	96
14	No electricity	10	75
15	No Co(OAc)2·4H2O	<1	—

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Reaction scope

With the optimized protocols in hand, we sought to evaluate the generality of this electrocatalytic enantioselective C–H/C–F functionalization (Scheme 2). In general, a set of electronically and sterically varied benzamides proceeded smooth tandem C–H and C–F functionalization with gem-difluoromethylene allenes, affording the corresponding products (3–20) in moderate-to-good yields with excellent enantioselectivity and specific stereochemistry. This protocol tolerates diverse functional groups, including chloro (4), methoxy (5), thioether (6), ester (7), keto (8), cyano (9), nitro (10), and trifluoromethyl (11), which provides opportunities for streamlined diversification. Notably, 3-substituted benzamide underwent selective coupling in the less-hindered position (12). Heterocyclic (14) and alkenyl amides (15) were suitable partners. Our electrochemical protocol was also successfully applied to benzamides bearing a C2- or C3-functionalized azaindole moiety (16, 17). In addition to forming N–N atropisomers, the electrochemical protocol was extended to construct C–N axially chiral compounds. This was achieved by coupling gem-difluoromethylene allenes with benzamides (21–23) and sulfonamides (24) derived from 8-aminoquinoline or 2-oxazoline aniline.

Scheme 2 Electrocatalytic asymmetric C–H/C–F functionalization to access axially chiral molecules.^a

We next applied this asymmetric electrolysis to the desymmetrization of phosphinamides under only minimally modified conditions. A suite of diarylphosphinamides underwent enantioselective C–H and C–F functionalization with gem-difluoromethylene allene, furnishing products 25–31 in good yields with excellent enantioselectivity (Scheme 3a). X-ray crystallographic analysis of 26 unambiguously confirmed the (R)-configuration at the phosphine center and the (Z)-configuration of the fluoroalkenyl moiety. This electrocatalytic C–H/C–F functionalization was further extended to construct inherently and planar chiral molecules—valuable skeletons in asymmetric catalysis,^44,45 medicinal chemistry,^46,47 and materials science (Scheme 3b and c).^48,49 For instance, coupling calix[4]arene with gem-difluoromethylene allene afforded product 32, bearing both inherent and axial chirality, in 50% yield with 90% ee and >20 : 1 dr. Kinetic resolution of racemic [2.2]paracyclophane (PCP) using gem-difluoromethylene allene delivered the fluorinated heterocyclic PCP derivative 33 in 50% yield and 90% ee, with recovery of enantiopure substrate (S_p)-1d in good yield and moderate enantiopurity. Taking together, these transformations underscore the robustness and synthetic versatility of our cobalt/Salox catalysis platform for enantioselective C–H/C–F functionalization.

Scheme 3 Electrocatalytic asymmetric C–H/C–F functionalization to access P-centre, inherently, and planar chiral molecules.^a

Experimental mechanistic investigations

To gain insight on this electrocatalytic C–H/C–F functionalization, we performed a series of mechanistic investigations (Scheme 4). Negligible H/D scrambling was observed in the presence of D₂O, both with and without gem-difluoromethylene allene 2a, pointing toward an irreversible C–H metalation step (Scheme 4A). Kinetic isotope experiments revealed a primary KIE value of 1.11 (Scheme 4B), which suggests that C–H bond cleavage is likely not involved in the rate-determining step—a conclusion consistent with our density functional theory (DFT) calculations. An intermolecular competition experiment between benzamides containing electron-rich and electron-deficient aromatic rings showed a preference for electron-deficient substrates (Scheme 4C). This finding implies a base-assisted concerted metalation deprotonation (CMD) pathway operating for C–H activation, followed by the formation of a stable C–Co bond. In support of this, the cyclometalated Co(III) species Co-I was isolated and characterized. This intermediate was stabilized by the neutral ligand 4-methoxypyridine and synthesized by treating 1aa with an equimolar amount of Co(OAc)₂·4H₂O and Salox-2 (Scheme 4E). This complex Co-I was found to be catalytically competent, affording product 3 in 45% yield and 88% ee, thereby strongly supporting its role as a key intermediate in the catalytic cycle. The use of either monofluoroallene 2f or allenone 2g as coupling partner gave unsatisfactory results, underscoring the essential role of gem-difluoromethylene functionality in achieving high reactivity and enantiocontrol (Scheme 4D). To probe the electrochemical landscape of the reaction, cyclic voltammetry (CV) was performed (all potentials vs. Ag/AgCl, Scheme 4F). Benzamide 1aa displayed an irreversible oxidation peak at +0.78 V (curve b), confirming its susceptibility to anodic oxidation. While a mixture of Co(OAc)₂·4H₂O and NaOPiv·H₂O in TFE remained electrochemically silent across the scanned range, the introduction of Salox-7 produced a reversible redox couple with an oxidation potential of +0.84 V (curve d/e). This value is notably anodically shifted relative to the oxidation of unbound Salox-7 (+0.73 V, curve c). This comparison demonstrates that in situ complexation of Salox-7 to the Co(II) centre not only protects the ligand from irreversible oxidative decay but also facilitates the Co(II)/Co(III) redox process.

Scheme 4 Mechanistic insights.

Computational mechanistic studies

To understand the rationale behind the regio-, enantio-, and stereoselectivity in this electrocatalytic C–H and C–F functionalization, we conducted DFT calculations using Gaussian 16 at the B3LYP level in the reaction solvent (TFE). The Gibbs free energy profile of the most favorable pathway is depicted in Fig. 1A, with its spin-state evolution highlighted (a full comparison of alternative pathways is provided in SI). Initially, we examined the formation of the diastereoselective, chiral-at-cobalt complex INT-0, generated by C–H cyclometallation of benzamide 1aa. Consistent with literature precedents, the cobalt center preferentially adopts the meridional, pseudo-octahedral geometry [mer-(S_L)-ΔCo], which is stabilized by 6.3 kcal mol⁻¹ over the ΛCo isomer in the singlet state (Fig. 1B). Subsequently, coordination and migratory insertion of gem-difluoroallene 2a proceeds via intermediate INT-1. This allene 1,2-insertion features a spin-crossover event (i.e., ³INT-1 → ¹INT-1 → ¹TS-1 → ¹INT-2 → ³INT-2) and proceeds with a low free energy barrier of 21.5 kcal mol⁻¹ (from ³INT-0 to ¹TS-1). Afterwards, the reaction proceeds exclusively through the spin-triplet state. In the C–N reductive elimination, the triplet transition state ³TS-2 is more favorable than its singlet counterpart, ¹TS-2, both kinetically (5.3 vs. 31.8 kcal mol⁻¹) and thermodynamically (−24.9 vs. −5.9 kcal mol⁻¹). Subsequent intramolecular allylic C(sp³)–H oxidative addition proceeds via a triplet transition state (³TS-3) with a lower free energy barrier by 15.5 kcal mol⁻¹ than its singlet counterpart ¹TS-3, leading to intermediate ³INT-5. The selective β–F elimination was calculated and revealed that the product bearing a Z-type configuration was more favorable dynamically, which was in good agreement with our experimental results. H–F reductive elimination at the metal center requires a 21.7 kcal mol⁻¹ energy barrier via triplet transition state ³TS-5, leading to the Co(I) complex ³INT-7, which is facilitated by electrochemistry to generate the active Co(III) catalyst together with product 3 and dihydrogen in the presence of HOPiv.

Fig. 1 DFT calculations.

To elucidate the origin of enantioselectivity, we located and compared the transition states for C–N reductive elimination. The free energy of ³TS-2_R was calculated to be 4.4 kcal mol⁻¹ lower than that of its diastereomer, ³TS-2_S, corresponding to an enantiomeric excess of >98% (Fig. 1C). This computational result aligns well with our experimental observation of (R)-selective products being obtained in excellent enantioselectivity. Independent gradient model based on Hirshfeld partition (IGMH) analysis revealed that this energy difference arises because ³TS-2_R is stabilized by both C–H⋯O hydrogen bonding and π⋯π interactions. These stabilizing forces are significantly stronger than the lone C–H⋯π interaction present in ³TS-2_S, leading to a lower energy barrier for the pathway involving ³TS-2_R.

Based on experimental and computational evidence alongside literature precedent,³² we proposed a plausible mechanism for the electrochemical cobalt-catalyzed enantioselective C–H/C–F functionalization (Scheme 5). The cycle is initiated begins with the single-electron oxidation of the cobalt(II) salt by the anode or air in the presence of Salox-7 and NaOPiv·H₂O, forming the active chiral octahedral Co(III) species, Cat. Ligand exchange with benzamide 1aa followed by base-assisted N–H and C–H activation generates a five-membered cobaltacycle INT-0. This intermediate coordinates to gem-difluoromethylene allene 2a, and undergoes migratory 1,2-insertion to yield the seven-membered cobaltacycle INT-2. A C–N reductive elimination furnishes a Co(I) intermediate, INT-4, which then undergoes an intramolecular allylic C(sp³)–H oxidative addition to form INT-5. Subsequent stereoselective β-F elimination and reductive elimination produces Co(I) species INT-7. Finally, anodic oxidation of INT-7 releases product 3 and regenerates the active Co(III) catalyst. Concurrently, protons are reduced at the cathode to evolve dihydrogen.

Scheme 5 Proposed mechanism.

Conclusions

In summary, we have established a general cobalt electrocatalysis platform for enantioselective and stereoselective C–H and C–F functionalization with gem-difluoromethylene allenes. This approach provides efficient access to diverse enantioenriched (Z)-fluoroalkenyl N-heterocyclic frameworks containing phosphorus stereocenters, C–N and N–N axial chirality, planar chirality, and inherent chirality. This work expands the reaction paradigms of asymmetric cobalt electrocatalysis, and is poised to inspire further methodological advances and applications in synthetic and medicinal chemistry.

Author contributions

J. C.: data curation, formal analysis, investigation, validation, writing – original draft; X. G.: data curation, formal analysis, investigation, validation, writing – review & editing; C. W.: data curation, formal analysis, investigation, validation; Y. L.: data curation, formal analysis, investigation, validation; X. T.: investigation, validation; L. L.: investigation, validation; S. Q.: investigation, validation; M. Y.: investigation, validation; Q. L.: investigation, validation; W. W.: investigation, validation; L. M.: investigation, validation; M. W.: formal analysis, funding acquisition, project administration, resources, validation, writing – review & editing; S.-Y. L.: resources, writing – review & editing; Y. H.: resources, writing – review & editing; X. Z.: resources, writing – review & editing; S.W.: writing – review & editing; Z. Zhou: funding acquisition, resources, writing – review & editing; H. G.: funding acquisition, resources, writing – review & editing; W. Y.: formal analysis, funding acquisition, project administration, resources, supervision, validation, writing – review & editing; Z. Zeng: conceptualization, data curation, formal analysis, funding acquisition, investigation, project administration, resources, supervision, validation, writing – original draft, writing – review & editing.

Conflicts of interest

There are no conflicts to declare.

Data availability

CCDC 2502352, 2502550 and 2502688 contain the supplementary crystallographic data for this paper.^50a–c

The authors confirm that all the data supporting the findings of this study are available within the article and its supplementary information (SI). Supplementary information: experimental procedures, compound characterization, and copies of NMR spectra and HPLC traces. See DOI: https://doi.org/10.1039/d6sc02228f.

Acknowledgements

We acknowledge the financial support from National Natural Science Foundation of China (No. 22201051, 82273795, 42407581), Guangdong Basic and Applied Basic Research Foundation (No. 2024A1515030179, 2024A1515010260), and Plan on Enhancing Scientific Research at GMU.

Notes and references

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Footnote

† These authors contributed equally to this work.

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