Linear paired electrolysis enabled dearomative [3 + 2] cycloadditions of indoles and benzofurans with vinyl azides

Abstract

Linear paired electrolysis is an ideal yet relatively rare electrochemical approach that offers significant advantages for constructing fused heterocyclic frameworks. Herein, we report an efficient protocol for dearomative [3 + 2] cycloadditions of indoles and benzofurans with vinyl azides via linear paired electrolysis under redox-neutral conditions. This method enables the formation of both rare benzofuro[3,2-b]pyrrolines, indolo[3,2-b]pyrrolines and conventional indolo[2,3-b]pyrrolines with excellent regio- and stereo-selectivity. Notably, this electrochemical approach shows good functional group tolerance and broad substrate scope, making it valuable for synthetic applications and molecular modification in pharmaceutical research.

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Green foundation

1. A general linear paired electrolysis-driven dearomative [3 + 2] cycloaddition reaction was carried out under metal- and oxidant-free conditions.

2. The electrochemical method shows excellent functional group compatibility and a wide substrate applicability range, enabling the construction of various fused compounds with high regio- and stereo-selectivity.

3. The linear paired electrolysis circumvents sacrificial half-reactions on the electrodes, greatly improving energy efficiency and providing a new direction for the synthesis of fused heterocyclic compounds.

Introduction

2,3-Indoline- and 2,3-dihydrobenzofuran-fused cyclic compounds are widely present in natural products and pharmaceutical molecules,¹ and exhibit broad biological activities.² Among them, indolo[2,3-b]pyrrolidines, as a common class of heterocyclic fused structures, have attracted extensive attention from the organic chemistry community, and numerous synthetic methods have been developed.³ In contrast, indolo- and benzofuro-[3,2-b]pyrrolidines are exceptionally rare in natural products. To date, aristone and phalarine have been reported in the literature as the only natural products containing these two structural frameworks, respectively (Scheme 1a).⁴ Owing to their distinctive and novel fusion architectures, there have been only a few reports on the synthesis of indolo- and benzofuro-[3,2-b]pyrrolidines over the past decades.⁵ Notably, the current synthetic approaches for both types of fused-ring compounds often face certain challenges such as lengthy reaction sequences and poor substrate generality. Therefore, establishing a highly efficient protocol for the synthesis of indolo- and benzofuro-[3,2-b]pyrrolidines under mild conditions holds substantial significance for advancing both organic synthesis methodologies and medicinal chemistry research.

Scheme 1 Background and project design. (a) 2,3-Indoline- and 2,3-dihydrobenzofuran-fused cyclic compounds. (b) Lei's work on the electrooxidative [3 + 2] annulation of β-ketonitriles and indoles. (c) This work: linear paired electrolysis synthesis of diverse indole- and benzofuran-fused pyrrolines.

Electrosynthesis has garnered increasing attention as a powerful tool in organic chemistry due to its ability to utilize sustainable green energy to generate highly reactive radical intermediates via single-electron transfer,⁶ typically without the need for external oxidants or reductants, thereby offering a green and sustainable synthetic pathway.⁷ Despite electrosynthesis having made great progress in various research fields like C–H activation,⁸ cross-coupling reactions,⁹ and alkene difunctionalization,¹⁰ among others,¹¹ these methods often need to be coupled with another sacrificial half-reaction (e.g., proton reduction to form hydrogen) at the counter electrode,¹² which greatly reduces energy efficiency. Interestingly, linear paired electrolysis,¹³ where both electrodes actively participate in the redox transformation, provides an effective and practical strategy to circumvent sacrificial half-reactions. However, its application in the synthesis of fused heterocyclic compounds remains largely underexplored.¹⁴ With the rapid development of organic electrochemistry, electrochemical oxidative dearomative [3 + 2] cycloaddition of indoles has emerged as a concise and efficient synthetic method for constructing 2,3-indoline-fused five-membered heterocyclic compounds.¹⁵ In 2023, Lei's group reported that electrochemical oxidative coupling between β-ketonitriles and indoles affords furo[3,2-b]indolines via radical cation/nucleophile coupling (Scheme 1b).¹⁶ Although this method requires coupling with another sacrificial half-reaction at the counter electrode, it represents the first electrochemical synthesis of furo[3,2-b]indolines. To the best of our knowledge, the electrochemical synthesis of indolo- and benzofuro-[3,2-b]pyrrolines has not been reported yet.

Vinyl azides serve as versatile three-atom synthons, exhibiting both nucleophilic and radical-accepting properties, and have been widely utilized in the synthesis of high-value nitrogen-containing heterocycles.¹⁷ However, in the field of electrochemistry, the use of vinyl azides to synthesize nitrogen-containing fused rings remains largely unexplored.¹⁸ According to this, we envisioned that the [3 + 2] annulation of indoles and benzofurans with vinyl azides could provide efficient access to indole- and benzofuran-fused pyrrolines under appropriate electrochemical conditions. Herein, we report a linear paired electrolysis strategy for the controlled synthesis of diverse indole- and benzofuran-fused pyrroline scaffolds via a radical cation-mediated dearomative [3 + 2] annulation reaction of indoles and benzofurans with vinyl azides (Scheme 1c). This protocol enables the efficient synthesis of benzofuro[3,2-b]pyrrolines, indolo[3,2-b]pyrrolines and indolo[2,3-b]pyrrolines under mild conditions, with excellent regio- and stereo-selectivity. Importantly, the transformation proceeds in the absence of external oxidants and catalysts, offering a sustainable and practical approach for the construction of structurally complex heterocycles with potential bioactivity.

Results and discussion

To probe the feasibility of this method, we initially selected 3-phenylbenzofuran (1aa) and α-tolyl vinyl azide (2a) as the model substrates to test the reaction conditions (Table 1). Utilizing ⁿBu₄NBF₄ as the electrolyte and 1,1,1,3,3,3-hexafluoroisopropyl alcohol (HFIP)/MeCN as co-solvents, the dearomative [3 + 2] annulation product 3aa could be obtained in 82% yield under 3.0 mA constant current for 6 h in an undivided cell (entry 1). Poor efficiency for the [3 + 2] annulation reaction was obtained when HFIP or MeCN was used as the sole solvent (entries 2 and 3). The ratio of solvent affects the yield of the reaction to some extent (entry 4). In addition, increasing or decreasing the current reduced the yield of the reaction (entries 5 and 6). As for the electrolyte used, ⁿBu₄NPF₆ and ⁿBu₄NClO₄ have a significant detrimental effect (entries 7 and 8). When evaluating different electrode materials, the use of a graphite rod or platinum plate as the anode decreased the yield (entries 9 and 10). Similarly, using a platinum plate as the cathode caused a moderate decrease in the yield (entry 11), possibly due to its lower hydrogen evolution potential. However, replacing the carbon felt cathode with a Ni form cathode led to lower reaction yield (entry 12). Notably, the reaction could be conducted under atmospheric conditions in 70% yield (entry 13). Obviously, no reaction took place without electric current as indicated by the residue of almost all of the starting materials (entry 14).

Table 1 Optimization of reaction conditions^a

Entry	Variations	Yield^b/%
a Reaction conditions: carbon felt electrodes (15 mm × 10 mm × 2.0 mm, distance: 10 mm), 1aa (0.20 mmol), 2a (2.0 equiv.), ^nBu4NBF4 (1.0 equiv.), solvent (MeCN/HFIP = 2 mL/4 mL), undivided cell, N2, room temperature, constant current = 3.0 mA, 6 h. b Isolated yields are shown. HFIP: hexafluoroisopropanol. n.r.: no reaction.
1	None	82
2	Without MeCN	35
3	Without HFIP	23
4	MeCN/HFIP (4/2)	65
5	2 mA, 10 h instead of 3 mA, 6 h	72
6	5 mA, 3.5 h instead of 3 mA, 6 h	81
7	^nBu4NPF6 instead of ^nBu4NBF4	74
8	^nBu4NClO4 instead of ^nBu4NBF4	48
9	C rod (+) instead of C felt (+)	45
10	Pt (+) instead of C felt (+)	32
11	Pt (−) instead of C felt (−)	65
12	Ni form (−) instead of C felt (−)	23
13	Under air	70
14	No electric current	n.r.

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With the optimized reaction conditions in hand, we first turned to explore the substrate scope of α-substituted vinyl azides amenable for the dearomative [3 + 2] annulation with benzofuran derivatives (Scheme 2). The reaction of the electron-neutral parent α-phenyl vinyl azide produced the cycloadduct 3aa in 82% isolated yield. Moreover, aryl vinyl azides bearing electron-donating (e.g., Me, ⁿBu, OMe, ^tBu, and Ph) or electron-withdrawing (e.g., F, Br, and CO₂Me) functional groups at the para-position of the aromatic ring were all well tolerated, giving the corresponding products (3ab–3ai) in generally good yields. As seen in the reactions, regulation of the substitution patterns and steric hindrance at the meta- or ortho-positions of the aromatic ring had no adverse effect on the reaction efficiency, and the expected cycloadducts (3aj–3aq) were isolated in good yields. Naphthyl vinyl azides reacted well to provide 3ar with satisfactory results. Excitedly, thiophenyl and alkyl vinyl azides also participated in the reaction (3as, 3at and 3au).

Scheme 2 Reaction conditions: carbon felt electrodes (15 mm × 10 mm × 2.0 mm, distance: 10 mm), 1 (0.20 mmol), 2 (2.0 equiv.), ⁿBu₄NBF₄ (1.0 equiv.), solvent (MeCN/HFIP = 2 mL/4 mL), undivided cell, N₂, room temperature, constant current = 3.0 mA, 6 h. Isolated yields are shown.

We then examined the effects of substituents on the benzofuran ring. Introducing various substituents at the C-5 position of the benzofuran ring could provide the corresponding products (3ba–3bd) in moderate to good yields. Additionally, C-6 or C-7 methoxy substituted benzofuran also worked smoothly to provide the relative products (3be and 3bf). Naphthofuran was successfully coupled with the vinyl azide to build larger heterocyclic systems (3bg and 3bh). The structure of 3bh was further confirmed through X-ray crystallography (see the SI for details). Electron-donating substrates at the C-3 phenyl position exhibited higher reactivity (3bi and 3bj). In contrast, phenyl groups of electron-deficient substrates could not react, likely due to their higher oxidation potential. Other aryl groups at the C-3 position of benzofuran, such as naphthyl and methyl, also participated effectively in the reaction (3bk and 3bl). Moreover, a C-3 methyl substituted benzofuran derivative provided the product 3bm. Intriguingly, when benzofurans with C-2/C-3 fused cyclohexane or cycloheptane rings were employed as substrates, three-dimensional bridged products possessing a turbine-blade-like architecture were obtained with excellent regio- and stereo-selectivity (3bn–3bp). The structure of 3bn was also confirmed by X-ray crystallographic analysis (see the SI for details). Our mechanistic studies (Scheme 5c) confirmed that the reaction proceeds via a radical addition mechanism. The C-3 substituted benzofuran radical cation, generated through anodic oxidation, undergoes radical addition preferentially at the C-2 position, which rationalizes the high regioselectivity observed (3aa–3bp). This regioselectivity is further supported by DFT calculations from Lei's work.¹⁹

We further applied this method to indoles, enabling their coupling with vinyl azides to form indole-fused pyrrolines (Scheme 3). A series of 2-substituted N-Boc indoles were selectively transformed into indolo[2,3-b]pyrrolines (5aa–5ac), featuring fully substituted carbon centers at the C-2 position in good yields. The structure of 5ab was confirmed by X-ray crystallographic analysis (see the SI for details). Interestingly, when substituents were introduced at the C-3 position of indoles, the reaction proceeded with excellent regioselectivity to afford indolo[3,2-b]pyrrolines bearing a fully substituted carbon center at the C-3 position. Regarding the regioselectivity originating from different substituent positions on the indole ring, our mechanistic studies (Scheme 5b) confirm that the substrate initially forms a radical cation upon anodic oxidation. Subsequently, the conclusions derived from the DFT calculations in Lei's study¹⁶ provide an explanation for the high regioselectivity achieved in our work. When the indole nitrogen is substituted with an electron-withdrawing group, the indole radical cation generated through anodic oxidation exhibits similar radical characteristics at both the C-2 and C-3 positions. Consequently, the regioselectivity is primarily governed by the steric effects at the C-2 and C-3 positions, rather than by electronic effects. We initially evaluated a series of N-Boc indoles bearing diverse substituents on the benzene ring. Notably, indole substrates containing either halogen atoms or electron-donating groups (e.g., Me and OMe) at various positions underwent efficient annulation to provide the corresponding products (5ad–5aj) in consistently high yields. Among them, the structure of 5ag was further confirmed through X-ray crystallography (see the SI for details). The [3 + 2] annulation reaction showed moderate efficiency regardless of the substituents at the indole C-3 position, including phenyl, cyclohexyl, and various functionalized alkyl groups (5ak–5an). Additionally, the reaction between diverse functionalized vinyl azides and N-tosylindoles successfully afforded the desired cycloadducts. This encompassed not only various aryl vinyl azides with different substituents (5ao–5aw) but also the more challenging alkyl vinyl azides (5ay–5be). Furthermore, a cyclohexenyl-substituted vinyl azide (5ax) was tolerated.

Scheme 3 Reaction conditions: carbon felt electrodes (15 mm × 10 mm × 2.0 mm, distance: 10 mm), 4 (0.20 mmol), 2 (2.0 equiv.), ⁿBu₄NBF₄ (1.0 equiv.), solvent (MeCN/HFIP = 2 mL/4 mL), undivided cell, N₂, room temperature, constant current = 3.0 mA, 6 h. Isolated yields are shown.

To further show the use of this protocol for synthesizing polycyclic fused indole and benzofuran compounds, we conducted gram-scale synthesis studies on α-tolyl vinyl azide (2a) with 3-phenylbenzofuran (1be) and N-Boc indole (4ad), respectively. The results confirmed the scalability of the reaction, delivering compounds 3be (75% yield) and 5ad (81% yield) under the optimized conditions (Scheme 4a). The two distinct gram-scale protocols showed acceptable green chemistry metrics: E-factors of 48.46 and 43.67, PMI values of 49.46 and 44.67, atom economies of 92.4% and 92.6%, atom efficiencies of 69.3% and 75.0%, carbon efficiencies reaching 100% and 100%, and reaction mass efficiencies of 49.6% and 54.2%, respectively.²⁰ Furthermore, compounds 3be and 5ad were subjected to further transformations. First, the compound 3be with a cyclic imine group could be further utilized for cyclization reactions, enabling the synthesis of both 2,3-dihydrobenzofuran-fused carbapenem analog 6a and oxaziridine 6b. Then, the NaBH₃CN-mediated reduction of the C=N bonds in 3be and 5ad afforded densely functionalized benzofuro[3,2-b]pyrrolidine 6c and indolo[3,2-b]pyrrolidine 7a, respectively, each as a single diastereomer (>20 : 1 dr). Lastly, deprotection of the N-Boc group in 5ad with TFA/DCM at room temperature provided compound 7b in 80% yield (Scheme 4b) (see the SI for the detailed synthesis process).

Scheme 4 Synthetic applications. (a) Gram scale synthesis. (b) Cycloaddition product diversification. Reaction conditions are as follows: (i) 2-methoxyacetyl chloride, Et₃N, CH₂Cl₂, 50 °C; (ii) m-CPBA, Et₃N, CH₂Cl₂, r.t.; (iii) NaBH₃CN, MeOH/AcOH, 0 °C to r.t.; (iv) NaBH₃CN, MeOH/AcOH, 0 °C to r.t.; and (v) TFA, CH₂Cl₂, r.t.

To elucidate the mechanism of the linear paired electrolysis process, we conducted a series of mechanistic studies. Cyclic voltammetry experiments revealed distinct oxidation peaks at 1.91 V (vs. Hg/Hg₂Cl₂) for 1aa and 1.83 V (vs. Hg/Hg₂Cl₂) for 4ad. In contrast, no obvious oxidation peak was observed for compound 2a, suggesting that either 1aa or 4ad is preferentially oxidized in the reaction mixture (Scheme 5a). Further evidence was provided by radical cation trapping experiments; when two equivalents of triethyl phosphite were added to the standard reaction, the desired [3 + 2] annulation product was not observed. Instead, the benzofuran phosphorylation product 8a was detected by HRMS, and the indole phosphorylation product 9a was isolated in 58% yield (Scheme 5b). These results confirm the existence of both indole and benzofuran radical cation intermediates. Moreover, the addition of the radical scavenger butylated hydroxytoluene (BHT) completely suppressed the reaction, and HRMS detected the two radical intermediates (10a and 11a) that were trapped by BHT, clearly supporting the involvement of radical species (Scheme 5c). To gain deeper insights into the redox-neutral reaction mechanism, we conducted the experiment in divided cells. The cycloaddition product was not observed, indicating that both anodic oxidation and cathodic reduction are critical to the reaction (Scheme 5d).

Scheme 5 Mechanistic studies. (a) Cyclic voltammograms on a glassy carbon electrode (∅ 3 mm) at 0.05 V s⁻¹ under nitrogen. Black line, 3-phenylbenzofuran (1aa); red line, 3-methyl N-Boc indole (4ad); blue line, α-tolyl vinyl azide (2a); green line, background. (b) Radical cation trapping experiment of 3-phenylbenzofuran (1aa) and 3-methyl N-Boc indole (4ad) by P(OEt)₃. (c) Radical trapping experiment of 3-phenylbenzofuran (1aa) by BHT. (d) Control experiment in divided cells.

Based on experimental results and literature reports,^15,16,19,21 we proposed a possible reaction mechanism (Scheme 6). Under electrochemical conditions, indoles and benzofurans were oxidized to form the radical cation intermediate A. This reactive intermediate then could participate in a regioselective radical addition reaction with vinyl azide 2, affording intermediate B, which then underwent intramolecular denitrogenative cyclization to produce intermediate C. Finally, the cyclization intermediate C could be further reduced at the cathode to afford the target product 3.

Scheme 6 Proposed mechanism for the dearomative [3 + 2] annulation of indoles and benzofurans.

Conclusions

In summary, we have developed a linear paired electrolysis method that enables the [3 + 2] cycloaddition of indoles and benzofurans with vinyl azides under mild reaction conditions. This electrochemical approach enables the controlled synthesis of both rare benzofuro[3,2-b]pyrrolines, indolo[3,2-b]pyrrolines and conventional indolo[2,3-b]pyrrolines with excellent regio- and stereo-selectivity. This linear paired electrolysis method provides an efficient platform for synthesizing diverse fused heterocyclic compounds, holding significant importance for advancing both organic synthesis methodologies and medicinal chemistry research.

Author contributions

H. Z. and J. C. conceived the project. S. Y. and Y. Z. designed and performed the experimental work. E. P., P. J. and X. L. contributed to the analysis and interpretation of data. J. C., S. Y. and Y. Z. wrote the manuscript. All authors contributed to or approved the final version of the paper.

Conflicts of interest

There are no conflicts to declare.

Data availability

Data supporting the findings of this study are available within the article and its supplementary information (SI). Supplementary information is available. See DOI: https://doi.org/10.1039/d5gc04148a.

CCDC 2457376–2457379 contain the supplementary crystallographic data for this paper.^22a–d

Acknowledgements

This work was supported by the National Natural Science Foundation of China (22361051 and U24A20802), the Yunnan Fundamental Research Projects (202301BF070001-022), Yunnan Science and Technology Plan (202449CE340027) and The 2025 Central Government Project for Supporting the Reform and Development of Local Universities – Special Project for the Construction of an Interdisciplinary “Comprehensive Health” Medical-Education Integration Innovation Platform.

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Footnote

† These authors contributed equally to this work.

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