Access to spiro-bicyclo[2.1.1]hexanes via BF₃·Et₂O-catalyzed formal [2π + 2σ] cycloaddition of bicyclo[1.1.0]butanes with benzofuran-derived oxa(aza)dienes

Abstract

Herein, we have developed a method for the construction of spiro[benzofuran-2,2′-bicyclo[2.1.1]hexanes] via BF₃·Et₂O-catalyzed formal [2π + 2σ] cycloaddition of bicyclo[1.1.0]butanes with benzofuran-derived oxa(aza)dienes. This transformation allowed for facile access to a variety of functionalized spiro-bicyclo[2.1.1]hexanes in good yields (up to 99% yield) with excellent chemoselectivities and a broad substrate scope (34 examples) under mild reaction conditions. Moreover, the synthetic utility of the cycloadducts was further emphasized through a scale-up experiment and subsequent synthetic transformations.

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Introduction

The scholarly interest in recent decades has been considerable towards the paradigm shift of substituting planar arene moieties with three-dimensional (3D) saturated bicyclic analogues, a concept popularly referred to as “escape from flatland”.¹ Among those 3D skeletons, bicyclo[2.1.1]hexanes (BCHs) have captured the focus of synthetic chemists due to their utility as bioisosteres for ortho- or meta-substituted arenes to enhance both the physicochemical and pharmacokinetic profiles of bioactive drugs.² There has been a heightened emphasis on formulating efficient synthetic methodologies for BCHs,³ and the [2π + 2σ] cycloaddition of bicyclo[1.1.0]butanes (BCBs)⁴ with 2π-synthons emerges as a notable synthetic strategy due to its broad substrate compatibility and effectiveness.^5–7 Blanchard pioneered this approach in 1966 with the inaugural application of thermally driven [2π + 2σ] cycloadditions of BCBs with alkenes to yield captivating mono-BCHs.^5a Very recently, the [2π + 2σ] cycloadditions⁶via a radical pathway between BCBs and alkenes have flourished, pioneered by Glorius^6a and Brown.^6b Furthermore, Leitch's^7a study on Lewis acid catalyzed cycloaddition of imines and BCBs led to a rapid development of [2π + 2σ] dipolar cycloadditions.⁷ These aforementioned elegant studies provided a variety of mono- or fused-BCHs (Scheme 1a). Despite the widespread usage of spirocycles in bioactive natural and synthetic compounds,⁸ the synthesis of BCHs incorporating spirocycles has been constrained. Brown^6b reported the pioneering synthesis of two examples of spiro-BCHs in 2022 through photoinduced cycloaddition of BCBs with 1,1-disubstituted alkenes. Subsequently, Li^6d reported three cases of constructing spiro-BCHs from pyridine BCBs through the selective activation of remote bonds catalyzed by diboron compounds, while Wang^6h also employed a similar strategy to achieve the synthesis of a spiro-BCH (Scheme 1b). These protocols for spiro-BCHs feature exocyclic terminal olefins as the 2π-partner and a radical cycloaddition pathway. Considering that spirocycles bearing unique rigidity and a three-dimensional configuration could lead to potential biological properties,⁹ developing [2π + 2σ] cycloaddition reactions of BCBs to furnish the valuable diversity of spiro-BCHs with a diverse structure is still highly demanded.

Scheme 1 Construction of BCHs from BCBs.

Recently, we reported a Lewis acid-catalyzed [4π + 2σ] cycloaddition of BCBs with nitrones, providing the novel hetero-BCHeps.¹⁰ Hence, we speculated that the intended spiro-BCHs may also be achieved via Lewis acid catalyzed dipolar cycloaddition of BCBs with particular 2π-partners. The benzofuran-derived oxa(aza)dienes, which are widely utilized in the synthesis of important benzofuran-incorporated heterocycles,¹¹ may serve as the ideal choice for constructing the desired spiro-BCHs incorporating the potentially bioactive benzofuran units.¹² To realize the transformation, several issues should be addressed. It is noteworthy that Lewis acid catalyzed dipolar cycloadditions of BCBs with α,β-unsaturated compounds have not been reported, which is presumably due to the mismatch between the in situ formed BCB-dipole and the 2π-partner. Consequently, choosing either a suitable Lewis acid catalyzed system or a 2π-partner is crucial for matching the reactivity of BCB dipoles with that of electron-deficient oxa(aza)dienes. Besides, due to the potential aromatization driving force of benzofuran-derived oxa(aza)dienes, the undesired [4π + 2σ] product may be generated (path b). Additionally, the formation of cyclobutenes from BCBs is also a potential side reaction and needs to be inhibited. Herein, we report a formal [2π + 2σ] cycloaddition of BCBs with benzofuran-derived oxa(aza)dienes promoted by Lewis acids, providing a series of novel spiro-BCHs with a broad substrate scope (Scheme 2, path a).

Scheme 2 BF₃-catalyzed formal [2π + 2σ] cycloaddition of benzofuran-derived oxa(aza)dienes with BCBs for synthesis of spiro-BCHs.

Results and discussion

We initiated our studies by employing bicyclo[1.1.0]butane 1a (0.20 mmol, 2.0 equiv.) and benzofuran-derived oxadiene 2a (0.10 mmol, 1.0 equiv.) as model substrates in the presence of BF₃·Et₂O (0.01 mmol, 10 mol%) in toluene (2.0 mL) at 25 °C (Table 1, entry 1). Gratifyingly, the desired spiro-BCH 3a was obtained in 54% yield, and 2a was recovered in a yield of 29%. Simultaneously, the decomposed product cyclobutene 4a derived from BCB 1a was obtained in 67% yield. Encouraged by the result, various Lewis acids were assessed to improve the conversion of 2a and reduce the formation of cyclobutene. Most selected Lewis acids demonstrated inefficacy in producing the target product 3a (entries 2–10). Among them, Eu(OTf)₃, Er(OTf)₃, Ni(OTf)₂, and Zn(OTf)₂ failed to cleave the ring of BCB 1a, even when the reaction time was extended to 24 hours (entries 6–9). The utilization of In(OTf)₃ and AgOTf gave inferior outcomes (<5% yield, 23% yield) (entries 11 and 12). Consequently, BF₃·Et₂O demonstrated optimal reactivity. Subsequently, other solvents were also examined, but lower yields of 3a were obtained (entries 13–17), ultimately highlighting toluene as the preeminent solvent. Furthermore, the slow addition of 1a to the reaction mixture gave a comparable result (Table 1, entry 18), while the retrieval of 2a was sustained at a 30% yield. Elevating the loading of bicyclo[1.1.0]butane 1a from 0.20 mmol to 0.30 mmol resulted in the formation of 3a with an 83% yield, accompanied by the complete conversion of 2a (Table 1, entry 19). However, the reaction was impeded in the presence of 20 mol% water (entry 20). Notably, no [4π + 2σ] product was detected during the process of condition screening. Control experiments showed that the Lewis acid catalyst is crucial for this transformation (Table 1, entry 21). Ultimately, the optimum conditions identified were based on the use of bicyclo[1.1.0]butanes 1 (3.0 equiv.) and benzofuran-derived oxadienes 2 (1.0 equiv.) in toluene (0.05 M) at 25 °C in the presence of BF₃·Et₂O (10 mol%).

Table 1 Optimization of the reaction conditions^a

Entry	Lewis acid	Solvent	Yield of 3a ^b (%)	Yield of 4a ^b^,^c (%)
a Reaction conditions: 1a (0.20 mmol), 2a (0.10 mmol), Lewis acid (0.01 mmol, 10 mol%), solvent (2.0 mL), N2 atmosphere, 25 °C, 10 min. b Isolated yield. c The yield of 4a was calculated based on BCB 1a as one equivalent. d Toluene (1.5 mL) and a solution of 1a (0.40 M in toluene, 0.20 mmol) was added dropwise within 5 min. e With 1a (0.30 mmol). f With 20 mol% H2O. Abbreviation: THF = tetrahydrofuran, DMF = N,N-dimethylformamide.
1	BF3·Et2O	Toluene	54	67
2	TMSOTf	Toluene	—	92
3	Ga(OTf)3	Toluene	—	91
4	Sc(OTf)3	Toluene	—	87
5	Bi(OTf)3	Toluene	—	88
6	Eu(OTf)3	Toluene	—	—
7	Er(OTf)3	Toluene	—	—
8	Ni(OTf)2	Toluene	—	—
9	Zn(OTf)2	Toluene	—	—
10	Yb(OTf)3	Toluene	—	<5
11	In(OTf)3	Toluene	<5	85
12	AgOTf	Toluene	23	75
13	BF3·Et2O	THF	—	82
14	BF3·Et2O	DMF	—	85
15	BF3·Et2O	CH2Cl2	21	81
16	BF3·Et2O	EtOAc	36	72
17	BF3·Et2O	MeCN	14	83
18^d	BF3·Et2O	Toluene	56	64
19^e	BF3·Et2O	Toluene	83	62
20^f	BF3·Et2O	Toluene	—	—
21	—	Toluene	—	—

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Upon establishing the optimized reaction conditions, exploration of the substrate scope was undertaken. First, various BCBs 1 were reacted with benzofuran-derived oxadiene 2a. As summarized in Table 2, BCBs 1b–1d and 1f bearing electron-donating groups (o-Me, m-OMe, m-Me, p-Me) furnished the corresponding products (3b–3d and 1f) in high yields (83%–86%). However, BCBs 1e and 1g bearing electron-withdrawing groups (m-Cl, p-F) reduced the yields (69%). However, the BCB substituted with p-CF₃ provided only a trace amount of the desired product. Notably, the methyl-substituted BCB 1h also yielded the desired cycloadduct 3h, albeit with low yield (16%). Moreover, the ethyl-substituted BCB 1i can also maintain high yield (84%). Apart from BCB esters, N,N-dimethyl-3-phenylbicyclo[1.1.0]butane-1-carboxamide, monosubstituted BCB sulfones and monosubstituted BCB ketone were evaluated, but no reaction occurred. Moreover, disubstituted BCB ketone and BCB containing an acyl pyrazole group gave complex reaction mixtures (details are shown in the ESI†). Attention was then paid to benzofuran-derived oxadienes. An array of benzofuran-derived oxadienes 2b–2h, bearing either electron-donating or electron-withdrawing groups on the ortho (o-Me, o-Br), meta (m-Me, m-F), and para positions (p-Me, p-I, p-CF₃) of phenyl rings (R⁴), gave products 3j–3p in good yields (72%–78%). It was noteworthy that 3,5-diMe and 3,4-diCl substituted substrates 2i and 2j underwent the reaction smoothly, affording the target products 3q (70% yield) and 3r (68% yield), respectively. Benzofuran-derived oxadienes 2k and 2l, featuring a heteroaryl R⁴ group (2-furyl) and a fused-ring R⁴ group (α-naphthyl), also reacted smoothly, producing 3s and 3t in yields of 64% and 60%. Significantly, styrenyl benzofuran-derived oxadiene 2m also showed good reactivity in this reaction, giving product 3u in reasonable yield (41%). However, benzofuran-derived oxadiene with an aliphatic R⁴ group (cyclohexyl) gave a complex reaction mixture (details are shown in the ESI†). The influence of the R³ group on the benzofuran-derived oxadienes was also investigated, and the reactions of benzofuran-derived oxadienes 2n and 2p–2r bearing various substituents (5-Br, 6-F, 7-OMe, and 7-Br) on the benzofuran ring also effciently proceeded to afford the target products 3v and 3x–3z in 65–87% yields. It is worth noting that the methoxyl group on the C6 position failed to give the desired product, and BCB 1a was completely decomposed into cyclobutene (details are shown in the ESI†). Nevertheless, 2o bearing a methyl group at the C6 position could engage in the reaction to produce 3w, albeit with reduced yield (44%). The structure of 3a was unambiguously determined by X-ray single crystal diffraction, and the configurations of other products were assigned by analogy.

Table 2 Substrate scope investigation^a,b

a Reaction conditions: 1 (0.60 mmol), 2 (0.20 mmol), BF₃·Et₂O (0.02 mmol, 10 mol%), toluene (4.0 mL), N₂ atmosphere, 25 °C. b Isolated yields.

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Apart from benzofuran-derived oxadienes, benzofuran-derived azadienes were also evaluated. With the simple adjustment of the feeding method and substrate equivalent, target product 6a could be obtained in excellent yield (99%) under the optimized conditions, indicating that benzofuran-derived azadienes exhibit higher reactivities than the benzofuran-derived oxadienes 2 (details are shown in the ESI†). The structure of 6a was determined by X-ray crystallography (see the ESI†). Subsequently, the generality of this reaction was investigated by testing various benzofuran-derived azadienes (Table 3). A wide range of monosubstituents on the benzofuran-derived azadienes 5 were well tolerated in the reaction and 6b–6f, 6i–6j bearing various substituents (o-Cl, m-OMe, m-Br, p-OMe, p-F, 5-Me, 5-Cl) were isolated in high to excellent yields (83%–99%). The reaction has also demonstrated compatibility with a substrate containing the 2-thiophene moiety, which furnished the desired product with acceptable result (6g, 67% yield). Moreover, when β-naphthyl benzofuran-derived azadiene 5h was utilized, the reaction furnished product 6h in high yield (90%). It is noteworthy that furan-derived azadiene 5k also effciently proceeded to afford the target product 6k in 84% yield. In addition, acyclic oxadiene afforded the ideal product 7 in 9% yield. Encouragingly, monocyclic oxadiene without the dearomatization driving force was investigated, but no target product was observed. Moreover, several other α,β-unsaturated compounds were tested in our protocol and they failed to furnish more spiro-BCHs (details are shown in the ESI†).

Table 3 (Benzo)furan-derived azadiene scope investigation^a,b

a Reaction conditions: 5 (0.20 mmol), BF₃·Et₂O (0.02 mmol, 10 mol%), toluene (3.0 mL), a solution of 1a (0.30 M in toluene, 0.30 mmol) added dropwise within 5 min, N₂ atmosphere, 25 °C. b Isolated yields. c 1a (0.40 mmol), 5 (0.20 mmol), BF₃·Et₂O (0.02 mmol, 10 mol%), toluene (4.0 mL), N₂ atmosphere, 25 °C.

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To demonstrate the synthetic potential of the current protocol, scale-up synthesis and several transformations were performed as illustrated in Scheme 3. The [2π + 2σ] cycloaddition of BCB 1a and benzofuran-derived oxadiene 2a could be scaled up to the 2.0 mmol scale almost without loss in efficiency, furnishing the desired product 3a in 81% yield (Scheme 3a). Subsequently, several transformations of 3a were conducted (Scheme 3b). The reaction of 3a with MeMgBr produced the tertiary alcohol 8 (dr > 20 : 1) in a high yield (83%). The carbonyl and ester groups of 3a were reduced to the hydroxyl group with DIBAL-H with high efficiency (9, 90% yield, CCDC 2356085, more details are shown in the ESI†). Hydrolysis of the ester group of 3a afforded the carboxylic acid 10 in excellent yield (93%). Furthermore, the imine moiety of 6a underwent reduction by NaBH₄ to generate amine 11 in 91% yield.

Scheme 3 Scale-up synthesis and synthetic transformations.

A plausible mechanism is proposed in Scheme 4 by utilizing the formation of 3a as an example. Initially, the BCB 1a coordinates to the BF₃ catalyst to afford species A, which undergoes enolization to intermediate B. The subsequent nucleophilic addition of B to the benzofuran-derived oxadiene 2a (which might also be activated by coordination to the BF₃ catalyst) leads to the formation of carbocation species C. This key intermediate then undergoes intramolecular cyclization to form the desired adduct 3a along with the regeneration of the BF₃ catalyst.

Scheme 4 Proposed catalytic cycle.

Conclusions

In summary, we have developed a BF₃·Et₂O-catalyzed formal [2π + 2σ] cycloaddition of benzofuran-derived oxa(aza)dienes with bicyclo[1.1.0]butanes. A series of diverse and meaningful spiro[benzofuran-2,2′-bicyclo[2.1.1]hexanes] were obtained in an efficient (up to 99% yield) and economical way. The reaction proceeds under mild conditions with high functional group tolerance and broad substrate scope. We anticipate that the synthesized benzofuran-fused spiro-bicycles can be instrumental in the discovery of pharmaceutical molecules, and further studies of construction of spiro-bicycles by dipolar cycloaddition of bicyclo[1.1.0]butanes are currently underway in our laboratory.

Data availability

The data supporting this article have been included as part of the ESI.†

Crystallographic data for compounds 3a, 6a and 9 have been deposited at the CCDC under 2331074, 2331076 and 2356085, and can be obtained from https://www.ccdc.cam.ac.uk/?locale=zh_CN.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

This work was supported by the Leading Innovative and Entrepreneur Team Introduction Program of Zhejiang (No. 2022R01007), the National Key Research and Development Program of China (2021YFA0804900), and the Start-up Research Grant from Zhejiang Normal University.

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Footnotes

† Electronic supplementary information (ESI) available. CCDC 2331074 (3a) and 2331076 (6a). For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d4qo00511b

‡ These authors contributed equally to this work.

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