Regiodivergent Lewis acid catalysis of bicyclo[1.1.0]butanes with 2-naphthols

Abstract

Enhancing drug efficacy often involves increasing the proportion of sp³-hybridized carbons. Three-dimensional polycyclic frameworks, such as bicyclo[1.1.1]pentanes (BCPs) and bicyclo[2.1.1]hexanes (BCHs), serve as excellent benzene bioisosteres, improving bioavailability and reducing toxicity while retaining biological activity. However, synthetic routes to 2D/3D-ring-fused BCHs via dearomatization are scarce, previously limited to cycloadditions of bicyclobutanes (BCBs) with indoles, bicyclic aza-arenes, or naphthalenes. Herein, we achieve Lewis acid-catalyzed dearomatization of BCBs with 2-naphthol. Eu(OTf)₃ catalysis provides dearomatized tertiary alcohols, while AgBF₄ promotes dearomatization/aromatization to directly access naphthalene-fused BCHs, showcasing remarkable reaction selectivity. Mechanistic studies definitively identify cyclobutyl carbocations as key intermediates. This strategy is anticipated to accelerate the exploration of fused BCH scaffolds in medicinal and synthetic chemistry.

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Introduction

The benzene ring is a highly significant structural motif in drug molecules, present in approximately 45% of marketed small-molecule drugs, and can be readily transformed into a variety of functionalized two-dimensional (2D) scaffolds.^1–3 However, it has been found that the benzene ring is still associated with limitations in terms of solubility, metabolic liabilities, and stability.⁴ The augmentation of sp³-carbon atoms within the molecular structure of compounds has been demonstrated to be an effective method of enhancing the clinical efficacy.⁵ Three-dimensional polycyclic (3D) frameworks are emerging as attractive non-planar bioisosteric replacements for the benzene ring in medicinal chemistry. Replacement of the benzene ring with its bioisosteres often enables drug molecules to retain their biological activity, while also enhancing bioavailability and reducing inherent toxicity.^6–8 Based on these advantages, it has garnered significant attention from the chemistry community in recent years.

Inspired by the “escape from flatland” concept proposed by Lovering and colleagues,^9–11 three-dimensional (3D) saturated bicyclic scaffolds, such as bicyclo[1.1.1]pentanes (BCPs), bicyclo[2.1.1]hexanes (BCHs) and bicyclo[3.1.1]heptanes (BCHeps), have been developed as novel replacements for arenes (Scheme 1a).¹² Bicyclo[2.1.1]hexanes (BCHs) are a class of highly strained cyclic compounds, which have been extensively studied due to their unique three-dimensional structure and could be used as mimics of meta- or ortho-substituted arenes (Scheme 1b).¹³ Furthermore, fused rings incorporating both 2D and 3D fragments have attracted attention from scientists. Such molecules can enhance biological topological diversity and allow conformational adjustment for improved receptor/ligand complementarity. Consequently, fused rings containing 2D and 3D motifs have become important skeletons in medicinal chemistry (Scheme 1c).¹⁴ Several synthetic methods for constructing BCHs have been developed. However, dearomative cycloaddition reactions involving bicyclo[1.1.0]butanes (BCBs) typically require high activation energy, and consequently, only limited examples have been reported (Scheme 1d). Furthermore, developing dearomative cycloaddition reactions of BCBs to synthesize complex fused rings incorporating both 2D and 3D fragments remains challenging. In 2022, Glorius reported an intermolecular [2π + 2σ]-photocycloaddition that used bicyclo[1.1.0]butanes as 2σ-electron reactants.¹⁵ In 2023, Deng and Feng independently reported Lewis acid-catalyzed [2π + 2σ] cycloadditions of available indoles with BCBs, affording indoline-fused BCHs.^16,17 In the same year, Glorius and Houk reported an ortho-selective intermolecular photocycloaddition of bicyclic aza-arenes including (iso)quinolines, quinazolines, and quinoxalines by utilizing a strain-release approach, enabling the direct assembly of C(sp³)-rich BCHs.¹⁸ In 2025, the You group reported a Gd(III)-catalyzed dearomative [2π + 2σ] photocycloaddition reaction between naphthalene derivatives and BCBs.¹⁹ These reports facilitated the synthesis of fused rings containing 2D/3D motifs. Notably, there was only one example of constructing BCHs from phenol through dearomative cyclization. In 2024, the Glorius group developed photoredox-promoted dearomative [2π + 2σ] cycloaddition of phenolic compounds with BCBs, enabling the synthesis of BCHs fused with cycloalkenones.²⁰ In 2025, Feng and Wang reported a silver-catalyzed cycloaddition reaction of BCBs and naphthol.²¹ Naphthols have been attractive substrates for the syntheses of functionalized benzenes or naphthalene derivatives, demonstrating significant value in the pharmaceutical and agrochemical industries.²² The transformation of planar naphthols into complex polycyclic compounds comprising 2D and 3D fragments is both significant and challenging.

Scheme 1 (a) Escaping from flatland: from 2D rings to 3D scaffolds; (b) BCHs as bio-isosteres of meta- or ortho-substituted arenes; (c) examples of bioactive compounds and natural products with fused 2D/3D rings; (d) dearomative cycloadditions of aromatics to construct BCHs; (e) this work: catalyst directed selective reactions of BCBs with 2-naphthols.

In this work, we outline the Lewis acid-catalyzed [2π + 2σ] cycloaddition reaction of BCBs with 2-naphthols (Scheme 1e). This transformation exhibits high tunability, yielding distinct fused rings incorporating 2D/3D motifs, which are selectively synthesized dictated by Lewis acid catalysts. When Eu(OTf)₃ is used as the catalyst, dearomatized products can be obtained. The reaction follows a dearomatization/aromatization strategy catalyzed by AgBF₄, yielding alternative naphthalene-fused bicyclic[2.1.1]hexanes (BCHs).

Results and discussion

To explore the feasibility of the dearomative [2π + 2σ] cycloaddition reaction, we preliminarily selected keto-substituted BCBs (1a; Table 1; see the SI for details) and 2-naphthol (2a) as standard substrates. We initially investigated the effect of Lewis acids on the [2π + 2σ] cycloaddition reaction of BCBs with 2-naphthol. Pleasingly, the desired BCH containing tertiary alcohol (3a) was obtained with Sc(OTf)₃ as the catalyst, exhibiting excellent regioselectivity, despite the moderate yield (46%, entry 1). At the same time, another product bearing the naphthalene-fused BCH (4a) could be obtained from the reaction with low yield (19%, entry 1). Encouraged by this result, we further screened other Lewis acid catalysts and observed that Yb(OTf)₃ and Bi(OTf)₃ could also afford compounds 3a and 4a (entries 2–3). More remarkably, In(OTf)₃ failed to produce 3a, whereas Tm(OTf)₃ was able to catalyze the reaction more effectively and synthesize 3a in 26% yield with high chemoselectivity (entries 4–5). Following further screening, we were pleased to observe that Eu(OTf)₃ emerged as optimal, affording 3a in moderate yield (53%) with high selectivity (entry 6). In addition, AgBF₄ proved highly effective for synthesizing 4a in 78% yield with excellent chemoselectivity (entry 8). These results demonstrated that Lewis acid played a critical role in governing the chemoinductive effect of the reaction (entries 1–8). Next, the effect of solvents on the reaction was investigated (entries 9–12). When Eu(OTf)₃ was used as a catalyst in this reaction, the polarity of the solvent had a significant effect on this reaction. As solvent polarity decreased, the yield of 3a progressively increased, with hexane identified as the optimal solvent that significantly elevated the yield to 88%. When AgBF₄ was employed as the catalyst, attempts to promote the cyclization of keto-substituted BCB 1a using various solvents (DCM, toluene and DMF) proved futile (entries 13–15). Furthermore, adjusting the ratio of 1a to 2a to 1.5 : 1 further enhanced the reaction efficiency, affording 3a in 90% yield and 4a in 80% yield (entries 16–17). The optimized conditions for synthesizing 3a were established as: 1a (1.5 equiv.), 2a (1.0 equiv.), Eu(OTf)₃ (10 mol%), hexane (0.1 M), 25 °C. Conversely, the optimal conditions for 4a were determined to be 1a (1.5 equiv.), 2a (1.0 equiv.), AgBF₄ (10 mol%), DCE (0.1 M), 25 °C.

Table 1 Optimization of the reaction conditions^a

Entry	LA	Solvent	Yield of^b3a	Yield of^b4a
a 1a (0.1 mmol, 1.0 equiv.), 2a (0.1 mmol, 1.0 equiv.), Lewis Acid (10 mol%), solvent (0.1 M), 30 °C, 48 h. b NMR yield with CH2Br2 as an internal standard. c reaction was carried out using a 1.5 : 1 ratio of 1a and 2a. LA = Lewis acid, DCE = dichloroethane, DCM = dichloromethane, DMF = N,N-dimethylformamide, CyH = cyclohexane.
1	Sc(OTf)3	DCE	46%	19%
2	Yb(OTf)3	DCE	47%	20%
3	Bi(OTf)3	DCE	28%	52%
4	In(OTf)3	DCE	nd	57%
5	Tm(OTf)3	DCE	26%	nd
6	Eu(OTf)3	DCE	53%	nd
7	AgPF6	DCE	nd	57%
8	AgBF4	DCE	nd	78%
9	Eu(OTf)3	DCM	43%	nd
10	Eu(OTf)3	CCl4	45%	nd
11	Eu(OTf)3	CyH	67%	nd
12	Eu(OTf)3	Hexane	88%	nd
13	AgBF4	DCM	nd	76%
14	AgBF4	Toluene	nd	44%
15	AgBF4	DMF	nd	17%
16^c	Eu(OTf)3	Hexane	90%	nd
17^c	AgBF4	DCE	nd	80%

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After establishing the optimal reaction conditions, we next investigated the substrate scope of the Lewis acid-catalyzed [2π + 2σ] cycloaddition reaction of BCBs with 2-naphthols (Table 2). First, we investigated substrate suitability for the dearomatization reaction catalyzed by Eu(OTf)₃. Initially, a series of BCBs featuring aryl ketone substituents with various groups on the benzene ring were investigated. Electron-donating groups (Ar′ = 4-Me-phenyl, 4-^tBu-phenyl, 4-OMe-phenyl) and electron-withdrawing groups (Ar′ = 4-Cl-phenyl, 4-F-phenyl) afforded dearomatized BCHs containing tertiary alcohols (3b–3f) in good to excellent yields. The biphenyl BCB (Ar′ = 4-Ph-phenyl), which had a larger conjugated and more delocalized system, also afforded compound 3g in 65% yield. Furthermore, meta-substituents on the benzene ring of the aryl ketone substituent, such as Me and Cl, also demonstrated good compatibility (3h–3i). When two substituents were present on the benzene ring of the aryl ketone substituent, a satisfactory result was obtained (3j). However, the BCB with ortho-tolyl ketone substitution failed to afford the dearomatized product, probably due to the influence of the steric effect and Lewis acid. BCBs substituted with Cl at the para- or meta-position proved to be suitable substrates, affording the desired BCHs 3k–3l in 87% and 85% yields, respectively. Notably, the alkyl ketone-substituted BCB could also react with 2-naphthol under standard conditions to form 3m with good yield (71%). Subsequently, we turned our attention to examining the compatibility of 2-naphthol. Various substituents at position 6 of 2-naphthol were well tolerated in the reaction, affording the desired products (3n–3p) in 70–82% yields, regardless of whether they were electron-donating or electron-withdrawing groups. Halogen-substituted substrates at positions 7 and 8 were compatible with the reaction, generating the corresponding cyclization products (3q–3s), despite the reaction yields being low, presumably due to steric hindrance. Next, we explored the substrate tolerance of the AgBF₄-catalyzed dearomatization-aromatization reaction. A series of structurally and electronically diverse BCBs participated in the cycloaddition reaction, thus affording naphthalene-fused BCHs in good yields. For instance, BCBs featuring aryl ketone substituents exhibited good tolerance toward both electron-donating and electron-withdrawing groups on the aromatic ring (4b–4i), although the yields of meta-substituted substrates were slightly lower than those of para-substituted substrates. BCBs bearing two substituents on the benzene ring of the aryl ketone group afforded the target compound 4j. Notably, even an ortho-methyl substituent on the aryl ketone's benzene ring did not significantly interfere with the reaction, delivering 4k in 51% yield. When the groups on the benzene ring of the aryl ketone substituent were replaced with thiophene or methyl, the target products 4l and 4m were obtained in good yields. Encouraged by these results, we further evaluated the electronic and steric influences produced by substituents on the aromatic ring of 2-naphthol associated with this transformation. BCBs equipped with 4-Cl and 3-Cl phenyl groups also reacted with 2-naphthol, affording satisfactory results (4n–4o). When methyl was introduced at the C3 position of 2-naphthol, the dearomatization-aromatization product was obtained in 73% yield (4p). The introduction of electron-donating or electron-withdrawing substituents at the C6 or C7 position of 2-naphthol had little impact on the reaction, delivering products in moderate to good yields (45–84%, 4q–4w). However, no reaction occurred when 1-methyl-2-naphthol was employed. Both anthracenol and sesamol also participated in the reaction, albeit with lower yields (4x–4y). Additionally, the structures of compounds 3a, 4a and 4y were confirmed by X-ray diffraction (see the SI for details). BCBs featuring pyrazole amide, an ester group and a sulfonyl group, unsubstituted BCB ketones and BCB with a methyl substituent were investigated, none of which afforded the corresponding target BCHs (see the SI for details). The reactivity of 1-naphthol has been investigated. When AgBF₄ was used as the catalyst, 4a′ could be obtained in 37% yield, which was lower than that of 2-naphthol. Dearomative (3 + 2) cycloaddition product 5 could be afforded in 78% yield catalyzed by Eu(OTf)_3.

Table 2 Substrate scope investigation^a

a Reaction conditions for synthesis of 3: 1 (0.15 mmol, 1.5 equiv.), 2 (0.1 mmol, 1.0 equiv.), Eu(OTf)₃ (10 mol%), hexane (0.1 M), 30 °C, 48 h. Reaction conditions for synthesis of 4: 1 (0.15 mmol, 1.5 equiv.), 2 (0.1 mmol, 1.0 equiv.), AgBF₄ (10 mol%), DCE (0.1 M), 30 °C, 48 h. b 1-Naphthol instead of 2-naphthol. The reaction procedure was based on the synthesis of 4. c 1-Naphthol instead of 2-naphthol. The reaction procedure was based on the synthesis of 3.

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To demonstrate the practicality of the reaction, we performed a mmol-scale [2π + 2σ] cycloaddition experiment under standard reaction conditions using 1a and 2a, yielding 3a and 4a in 82% yield and 75% yield, respectively. Subsequently, several transformations were performed on compounds 3a and 4a to highlight the application potential of 2D/3D ring fused BCHs (Scheme 2a). The epoxidation of 3a was achieved using meta-chloroperoxybenzoic acid (m-CPBA), affording epoxidized BCH 6 in 76% yield. The carbonyl group of 3a was efficiently reduced to secondary alcohol 7 using NaBH₄ (85% yield). Nucleophilic addition of 4a with the allyl Grignard reagent afforded tertiary alcohol 8. 4a underwent nucleophilic addition with phosphorus ylide (Wittig reaction) to afford alkene product 9. In order to gain deeper insights into the reaction mechanism, a series of mechanistic investigations were conducted. Initially, when the radical scavenger BHT was introduced to the standard reaction system, product formation was not completely suppressed, indicating that the reaction does not proceed via a radical pathway (Scheme 2b). We attempted to use 3a as a substrate in the AgBF₄-catalyzed reaction and found that it was almost completely converted to 4a, indicating that 3a serves as an intermediate in the formation of 4a (Scheme 2c). The reaction of 1a with AgBF₄ or Eu(OTf)₃ at 30 °C led to the formation of cyclobutene product 10, indicating the generation of a cyclobutyl carbocation intermediate along the reaction pathway. When methanol was employed as an external nucleophile in the reaction between BCB 1a and 2-naphthol 2a, nucleophilic addition product 11 was obtained. In contrast, cyclobutene product 10 with methanol did not afford nucleophilic addition product 11. These observations strongly supported the carbocation mechanism and excluded the possibility of cyclobutene serving as an intermediate (Scheme 2d). Additionally, deuterium labeling experiments were conducted to deepen the understanding of the reaction mechanism. Subjecting naphthol 12 with 50% deuterium incorporation to the Eu(OTf)₃-catalyzed dearomative [2π+2σ] reaction afforded deuterated product 13 with 27% deuterium retention (Scheme 2e). This deuterium labeling study confirmed the critical role of the naphthol hydroxyl group in the dearomative cycloaddition. Finally, 3.0 equiv. of water was added to the reaction and significant inhibition of the reaction was observed (Scheme 2f).

Scheme 2 Synthetic derivatizations and mechanistic studies.

Based on mechanistic studies and previous literature reports,^21,23 a feasible mechanism is proposed (Scheme 3). In the initial stage, the coordination between Eu(OTf)₃ and 1a forms the intermediate A. 2-Naphthol 2a then coordinates with intermediate A to generate the cationic intermediate B. The carbocation moiety in B is attacked by the C1 position of naphthol, yielding intermediate C. Subsequent intramolecular electrophilic addition and cyclization of C affords intermediate D, which is then protonated to deliver the dearomatized tertiary alcohol product 3a, completing one catalytic cycle. In addition, AgBF₄ coordinates with bicyclobutane 1a to form intermediate E. E undergoes 1,3-silver migration to generate the zwitterionic intermediate F. Intramolecular nucleophilic attack of F then forms intermediate G. Cyclization of G yields intermediate H, which undergoes dehydration via β-hydride elimination to afford the dearomatized/aromatized product 4a.

Scheme 3 Proposed mechanism.

Conclusions

In summary, we have integrated two types of Lewis acid to catalyze the [2π + 2σ] cycloaddition reactions between BCBs and 2-naphthol ingeniously, yielding dearomatized tertiary alcohols and dearomatized/aromatized naphthalene-fused BCHs, respectively. These products enrich fused rings containing both 2D and 3D structural fragments. Serving as potential bioisosteres of meta-substituted arenes, these frameworks exhibit broad substrate scope and excellent functional group tolerance. We foresee that these mild and highly efficient catalytic methods will open new avenues for developing dearomatization of phenolic compounds while enabling access to sp³-rich architectures, showing promising applications in drug discovery.

Author contributions

L. Fan carried out most of the experiments and wrote the initial manuscript draft. G.-F. Zhong directed the project and finalized the manuscript. All the authors discussed the results and commented on the manuscript.

Conflicts of interest

There are no conflicts to declare.

Data availability

Crystallographic information files (CIF) have been deposited with the Cambridge Crystallographic Data Centre.

CCDC 2416986 2416987 and 2481133 contain the supplementary crystallographic data for this paper.²⁴

General information, detailed experimental procedures, characterization data for compounds and NMR spectra are available in the SI.

Supplementary information: supplementary methods, tables, experimental procedures, NMR figures and X-ray structure. See DOI: https://doi.org/10.1039/d5sc05468k.

Acknowledgements

Financial support was provided by the Start-Up Funding for scientific research of EIT and the 2024 Ningbo Yongjiang Talent Program.

Notes and references

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