Electrochemically driven strain-release dearomative (3 + 2) cyclization for the synthesis of bicyclo[2.1.1]hexane-fused polycyclic spiroindolines

Abstract

Spiroindolines are ubiquitous structural motifs in natural products and biologically active compounds, making the development of reliable synthetic methods for their construction highly important to the synthetic chemistry community. Moreover, the synthesis of polycyclic compounds featuring C(sp³)-rich and complex three-dimensional (3D) architectures and multiple contiguous quaternary carbon centers in a single step remains a formidable challenge. Herein, we report an efficient and environmentally friendly electrochemical strategy for a dearomative (3 + 2) cyclization reaction of C3-bicyclo[1.1.0]butane (BCB)-substituted indoles. This method enables the efficient assembly of structurally complex and novel bicyclo[2.1.1]hexane (BCH)-fused polycyclic spiroindolines in high yields, featuring four contiguous stereogenic centers, two of which are spirocyclic all-carbon quaternary carbon centers. This new methodology provides a series of valuable spiroindolines under mild reaction conditions in a practical and atom-economic manner without the need for external oxidants, and the products can be further transformed into more complex spiroindolines. Notably, these C(sp³)-rich products exhibit significant potential in the field of medicinal chemistry.

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Introduction

Dearomatization represents a powerful strategy for the efficient construction of sp³-rich, three-dimensional, and structurally complex polycyclic architectures from readily accessible aromatic feedstocks.^1–4 Owing to the broad spectrum of biological activities associated with indole derivatives,^5,6 the development of indole dearomatization reactions has emerged as an area of significant interest in synthetic chemistry.⁷ In particular, spiroindoline derivatives are privileged and valuable scaffolds that are prevalent in a great number of natural products and biologically active molecules, such as (+)-alstonlarsine A,^8,9 ajmaline,¹⁰ (+)-koumine^11,12 and anticancer agent (Scheme 1a).¹³ In drug structure optimization, the introduction of spirocycles and cyclobutane moieties significantly enhances the three-dimensional character of molecules and restricts bond stretching and rotation within molecular conformations, thereby stabilizing the presentation of a single pharmacophore conformation upon target binding, mediating desired pharmacological effects, and substantially reducing off-target effects and toxic side effects.^14–19 Over the past decade, remarkable progress has been made in indole dearomative spiroannulation, driven primarily by transition-metal catalysis and visible-light catalysis,^7,20,21 thereby enabling the efficient construction of spiroindolines and spiroindolenines. Notably, Tang and co-workers reported the preparation of a class of tetracyclic cyclopenta-fused spiroindoline skeletons through Cu(II)-catalyzed intramolecular (3 + 2) annulation reactions of donor–acceptor cyclopropanes with indoles.²² However, the single-step synthesis of polycyclic spiroindolines with C(sp³)-rich complex three-dimensional (3D) structures and multiple contiguous quaternary carbon centers represents the most rapid and efficient approach, yet it remains a formidable challenge.

Scheme 1 Overview of the work. (a) Representative natural products and bioactive molecules with a spiroindoline moiety. (b) Existing dearomatization reactions of indoles with BCBs. (c) This work: electrochemically driven dearomative (3 + 2) cyclization of C3-BCB-substituted indoles.

In recent years, bicyclo[1.1.0]butanes (BCBs) have gained widespread recognition as useful synthetic tools in (3 + n) cycloaddition reactions,^23–38 enabling the formation of C(sp³)-rich bicyclic hydrocarbons that serve as bioisosteres of aromatic rings in medicinal chemistry, due to their improved pharmacokinetic and physicochemical properties.^39–42 Benefiting from their distinctive ring strain and unique σ-bond framework, numerous BCB-based cycloaddition reactions have been developed, demonstrating exceptional reactivity and broad application potential in both polar and radical reaction systems. Among them, BCBs have been employed in the dearomatization cyclization reactions of indoles to access BCH-fused indolines. In 2022, Glorius et al. reported a representative photochemical [2π + 2σ] cycloaddition between indoles and monosubstituted BCBs, leading to the formation of BCHs with limited substrate scope.⁴³ In 2023, Deng and co-workers developed a Yb(OTf)₃ catalyzed intermolecular atom-economical cycloaddition of indoles with BCBs to provide a direct construction of polycyclic indoline skeletons.⁴⁴ In the same year, Feng et al. developed a silver-catalyzed dearomative [2π + 2σ] cycloaddition of N-unprotected 2-substituted indoles and bicyclobutanes for the synthesis of indoline fused BCHs with opposite regioselectivity compared to the classical pathway.⁴⁵ Very recently, Dong and coworkers investigated photocycloadditions of indole derivatives with monosubstituted BCBs by photoinduced chiral N,N′-dioxide/metal complex Lewis acid catalysis (Scheme 1b).⁴⁶ Despite these achievements, the synthesis of polycyclic spiroindolines with more intricate 3D configurations remains an exceptionally intriguing and highly valuable frontier for researchers, and the development of environmentally friendly and sustainable methodologies to construct such structures holds significant importance for both synthetic and medicinal chemistry.

Electrochemistry, as a powerful and environmentally friendly platform for synthetic organic chemistry, is gaining increasing attention due to its inherent scalability, the ability to avoid harmful chemical oxidants and reductants, and the high tunability of reaction parameters.^47–57 Furthermore, this strategy has also been successfully employed in dearomatization of indole to provide three-dimensional indolines of high-added value by Lei,^58–61 Ling,⁶² Zhao,^63,64 Guo,⁶⁵et al.^66–70 Nonetheless, reports on the application of BCBs in electrochemical systems remain very limited.^37,71,72 To the best of our knowledge, the methods for obtaining polycyclic spiroindolines with two or more spirocenters through indole-based dearomatization reactions have not been reported. Moreover, to date, there have been no studies on the use of BCBs in electrocatalytic indole dearomatization reactions for the construction of polycyclic spiroindole derivatives. Based on previous literature and our research on indole dearomatization reactions,⁷³ we speculate that the radical cation-mediated strain-release intramolecular (3 + 2) cycloaddition reaction may be achieved under mild and sustainable electrochemical conditions. Herein, we report a highly efficient and environmentally friendly electrochemical strategy for the intramolecular (3 + 2) dearomatization reaction of C3-BCB-substituted indoles, providing access to structurally complex and novel BCH-fused spiroindolines (Scheme 1c). This oxidant-free protocol enables the practical and atom-economic synthesis of a wide range of valuable spirocyclic indolines that bear four contiguous stereogenic centers, including two spiro quaternary carbon stereocenters in generally good yields with broad substrate scope and functional group compatibility.

Results and discussion

To validate the design strategy for constructing polycyclic spiroindolines, we selected the C3-BCB-substituted indole derivative 1a as the model substrate and explored a radical cation-mediated strain-release (3 + 2) cyclization reaction by the electrochemical method. Following systematic optimization, the polycyclic spiroindoline product 2a was successfully synthesized at a constant current of 1 mA in an undivided cell equipped with a graphite felt anode (GF) and a platinum plate cathode, using acetonitrile as the solvent. The reaction was conducted at room temperature, yielding 2a in 93% yield (see Table 1, entry 1). First, the screening of solvents indicated the importance of CH₃CN in the reaction (see Table 1, entries 2 and 3). Additionally, replacing ⁿBu₄NBF₄ with ⁿBu₄NBF₆ or ⁿBu₄NI all resulted in diminished yield (see entries 4 and 5). The electrode screening results indicated that carbon cloth, carbon rod, and Pt plate anodes demonstrated inferior performance compared to the graphite felt anode (see entries 6–8). Considering the crucial role of current in the reaction, increasing the current did not lead to an improvement in yield (see entries 9 and 10). Control experiments confirmed the essential role of electricity, as no reaction was observed in the absence of current (see Table 1, entry 11). Notably, the transformation exhibits low sensitivity to ambient atmospheric conditions, delivering a comparable yield even in the presence of air (entry 12), which underscores the practical value of this protocol. Remarkably, control experiments conducted under conditions adapted from Lewis acid-catalyzed intermolecular reactions demonstrate that the transformation proceeds smoothly with 10 mol% In(OTf)₃ as a Lewis acid catalyst, affording the desired product 2a in 71% yield (see Table S5 in the SI for more details).

Table 1 Optimization of reaction conditions^a

Entry	Deviation from standard conditions	Yield%^b
a Reaction condition: undivided cell, graphite felt anode (GF), Pt plate cathode, 1a (0.20 mmol), ^nBu4NBF4 (0.20 mmol), CH3CN (4 mL), room temperature, constant current = 1 mA, 1 h, Ar. b Isolated yields.
1	None	93
2	DCM instead of CH3CN	86
3	HFIP instead of CH3CN	N.D.
4	^nBu4NBF6 instead of ^nBu4NBF4	88
5	^nBu4NI instead of ^nBu4NBF4	56
6	Carbon cloth as an anode	53
7	Carbon rod as an anode	Trace
8	Pt as an anode	Trace
9	3 mA instead of 1 mA	92
10	5 mA instead of 1 mA	90
11	No electricity	N.R.
12	Under air	85

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With the optimized reaction conditions established, the substrate scope of this electrocatalytic (3 + 2) cycloaddition reaction was subsequently explored. As illustrated in Scheme 2, initially, both unprotected and benzyl-protected BCB-substituted indole compounds 1a and 1b could be smoothly transformed into the corresponding spiroindolines 2a and 2b in 93% and 86% yields, respectively. Next, we investigated the influence of different substituents on the arene moiety of the aromatic ketone. Under optimal reaction conditions, a range of aromatic ketones bearing both electron-withdrawing (such as F, Cl, and CF₃) and electron-donating (such as Me, OMe and OEt) substituents at different positions of the aromatic ring can efficiently undergo the reaction, producing the desired products 2c–2m in 76–91% yields. The structure of compound 2k was unambiguously verified by crystallographic analysis. In addition, a disubstituted aromatic ketone was applied to the reaction, successfully affording the corresponding polycyclic spiroindoline 2n in 75% yields. Subsequently, we turned our attention to the R³ moieties on the bridgehead bond in the BCBs. The cycloaddition reaction demonstrated remarkable tolerance toward both electron-deficient and electron-rich substituents at the ortho-, meta- and para-positions of the aromatic ring, including halogen (F, Cl, Br), methyl, tert-butyl, methoxy, trifluoromethoxy, and trifluoromethyl groups. These transformations delivered the desired products 2o–2aa in 68–92% yields. Replacing the R³ with a 2-naphthyl group was investigated and produced the desired product 2ab in 82% yield. However, when R³ was a vinyl group, the yield decreases significantly, with the desired 2ac obtained only in 33% yield. When R³ was a methyl group, the reaction proceeds smoothly, affording the target compound 2ad in 76% yield. Notably, the reaction of indole derivatives containing a C5-substituent (Me, OMe, F, CF_3, Cl) was also tolerated, producing BCH-fused spiroindolines 2ae–2ai in 66–92% yields. Furthermore, a variety of functional groups on R² moieties, including an H (as in 2aj), a silyl ether (as in 2ak) and a phenyl (as in 2al) were well tolerated, providing the desired cycloadducts 2aj–2al in good yields (80–89%). The experimental results indicate that the R² on the indole ring has no significant effect on the reaction efficiency. More importantly, the homologous substrate with more than one carbon atom also exhibits good compatibility under the optimized reaction conditions, leading to the spirocycloheptane indoline 2am in decent yield (78%). Interestingly, an amide-linked BCB 1an was also well tolerated, affording the desired product 2an in 72% yield.

Scheme 2 Scope of C3-BCB-substituted indoles. ^aReaction conditions: undivided cell, graphite felt anode (GF), Pt plate cathode, 1a (0.20 mmol), ⁿBu₄NBF₄ (0.20 mmol), CH₃CN (4 mL), room temperature, constant current = 1 mA, 1 h, Ar. ^bYield of isolated products 2. ^cThe reaction time is 5 h.

To showcase the potential application of this protocol, a scale-up synthesis of 2a was conducted. Under the standard reaction conditions, 4.0 mmol of BCB 1a reacted smoothly, resulting in the desired product 2a in 78% yield (Scheme 3a). Subsequently, we carried out additional late-stage transformations using BCH-fused polycyclic spiroindolines 2 to demonstrate the synthetic utility of these products. First, the carbonyl group of 2b was reduced to the hydroxyl group with NaBH₄, affording alcohol 3 in high efficiency (95% yield, dr 1.2 : 1). Furthermore, the spiroindoline 2a was subsequently elaborated into 4 and 5via electrophilic aromatic bromination. Interestingly, starting from 2ac, the carbonyl group and double bond were fully reduced to 6 by Pd/C-catalyzed hydrogenolysis in 81% yield. Next, the silyl group of 2ak could be removed with TBAF to give the primary alcohol 7. Alcohol 7 can undergo esterification with indomethacin to afford the complex derivative 8. Importantly, spiroindoline 7 can also undergo an intramolecular Ley oxidation reaction to access a complex polycyclic spiroindoline 9 containing three spiro carbon stereocenters. The structure of the 9 was unambiguously determined by X-ray crystallographic analysis (Scheme 3b).

Scheme 3 Gram-scale synthesis and further transformations of the products.

To elucidate the reaction mechanism, we conducted a series of mechanistic investigations (see the SI for details). Upon the introduction of TEMPO (2,2,6,6-tetramethylpiperidoxy) or BHT (butyl-hydroxytoluene) as a radical scavenger, the formation of the product was almost entirely suppressed. Furthermore, mass spectrometric analysis identified adducts between compound 1a and both TEMPO and BHT. These findings suggest that the reaction mechanism likely involves a radical pathway. Similarly, when C2-unsubstituted 1an was used as the substrate and P(OEt)₃ was used as a trapping reagent, the desired product 2an was obtained in 38% yield. Meanwhile, an indole phosphorylation product was detected by HRMS, indicating the presence of a radical cation intermediate in the reaction (see the SI for details). Furthermore, according to cyclic voltammetry (CV) experiments, the oxidation peaks of 1a and its decomposition product, 2,3-dimethylindole 10, with BCB 11 were observed at +1.14 V, +1.22 V, and +1.66 V (vs. SCE), respectively (Scheme 4a). These results indicate that the oxidation potential of compound 1a is primarily attributed to the indole moiety, further suggesting that the reaction is likely initiated from the indole. Notably, the results from the divided-cell experiment revealed that the target product 2a, with a 12% yield, was detected in the anode compartment during substrate decomposition, whereas no reactions occurred in the cathode compartment (Scheme 4b). Importantly, the faradaic efficiency reveals that only 0.2 equiv. of charge is sufficient to achieve complete conversion (see the SI for details). This finding indicates that the reaction not only involves cathodic reduction but may also undergo chain propagation reactions.

Scheme 4 Mechanistic studies and the proposed mechanism.

According to the above studies and literature reports,^58–61 a possible mechanism for the electrochemical dearomative (3 + 2) annulation of indole derivatives is proposed in Scheme 4d. To begin with, compound 1a undergoes anodic oxidation to generate the radical cation intermediate I. Subsequently, the intramolecular radical promotes the ring-opening of BCB, converting I into the benzyl radical species II. To validate the proposed intermediate, spin density analysis of radical cation II was performed. The results show that the unpaired electron is highly localized at the C6 position (Mulliken spin population of 0.61), while the spin density at C5a is negligible (0.08), indicating that intermediate II is a C6-localized radical, consistent with our hypothesis (Scheme 4c). Then, intermediate II undergoes an intramolecular radical addition cyclization to afford radical cation III. Ultimately, cathodic reduction or chain propagation of intermediate III delivers the target polycyclic spiroindolines.

Conclusions

In conclusion, we have developed a highly efficient and environmentally friendly electrochemical-driven radical cation-mediated strain-release dearomative (3 + 2) cyclization of C3-BCB-substituted indoles. Through this methodology, a series of structurally novel and densely functionalized BCH-fused spiroindolines were successfully synthesized as single diastereomers with good yields. This method involves mild conditions and produces BCH-fused spiroindolines with broad substrate scope, functional group compatibility and potential application, as demonstrated by late-stage synthetic transformations. Mechanistic studies provided strong evidence for a radical process. This practical and sustainable method is anticipated to see broader applications in organic synthesis and medicinal chemistry.

Author contributions

Y. Zhu, E. Pu and S. Yang designed and performed the experimental work. D. Zhao performed calculations. Q. Xu, P. Jiang, and X. Li contributed to the analysis and interpretation of data. H. Zhang and J. Chen conceived the project. J. Chen and Y. Zhu 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

CCDC 2517829 and 2517830 contain the supplementary crystallographic data for this paper.^74a,b

Supplementary information (SI): experimental procedures, crystallographic data, compound characterization data, and copies of NMR spectra of the products. See DOI: https://doi.org/10.1039/d6sc01271j.

Acknowledgements

This work was supported by the National Natural Science Foundation of China (22361051 and U24A20802), the Yunnan Fundamental Research Projects (202301BF070001-022), and the Yunnan Key Laboratory of Crystalline Porous Organic Functional Materials (202449CE340024). D. Zhao was supported by the High-Level Talent Special Support Plan.

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