State-of-the-art strategies for Lewis acid-catalyzed strain-release cycloadditions of bicyclo[1.1.0]butanes (BCBs)

Abstract

Due to their low activation energy barriers, small strained carbocyclic systems have always been fascinating building blocks in organic chemistry. Among them, BCBs, as the smallest bicyclic carbocycles, exhibit a molecular structure, bond angles, and orbital hybridization significantly different from those of strain-free hydrocarbons, resulting in unique reactivity. In recent years, Lewis acid-catalyzed strain-release cycloaddition reactions have made BCBs powerful synthetic tools, utilized in various laboratories to expand into other ring systems. This review primarily focuses on the latest developments in Lewis acid-catalyzed strain-release cycloaddition reactions of BCBs, highlighting the applications and limitations of this catalytic system in different types of cycloaddition reactions, providing professionals and non-professionals in the field with valuable insights and new inspiration.

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Xiang Liu

Xiang Liu is an Associate Professor at the School of Chemistry and Chemical Engineering, Guangdong Pharmaceutical University. He received his Ph.D. degree in Organic Chemistry from Sun Yat-sen University under the supervision of Prof. Xiaodan Zhao, where his research focused on asymmetric catalysis and synthesis. After completing his Ph.D. in 2019, he joined Guangdong Pharmaceutical University to start his independent research career. From 2023 to 2024, he was a visiting scholar at the UCSD, USA, where his research focused on the design and synthesis of organic functional molecules. His current research interests include organic synthetic methodology and medicinal chemistry.

Hua Cao

Hua Cao is a Professor at the School of Chemistry and Chemical Engineering, Guangdong Pharmaceutical University. He received his Ph.D. degree in Organic Chemistry from the South China University of Technology under the supervision of Prof. Huanfeng Jiang, where his research focused on organic synthesis and catalysis. Now his current research interests include green chemistry, organic synthetic methodology, and medicinal chemistry.

1. Introduction

The concept of molecular strain has a long history and has developed into a fascinating and unique field, drawing the attention of an increasing number of chemists.¹ Studies on the chemical properties and reactivity of small strained carbocyclic systems have led to numerous new transformations, providing a rapid route for constructing a wide variety of other complex ring systems. BCBs, being the most compact bicyclic carbocycles, are among the most strained carbocycles known. The bridgehead bond in BCBs exhibits olefin-like characteristics, and their weak central carbon–carbon bond readily undergoes various addition, rearrangement, and insertion reactions through strain release.^2,3 It is no exaggeration to say that BCBs have become star molecules in synthetic chemistry laboratories. Moreover, BCBs have shown great potential in medicinal chemistry. They serve not only as core structures in many drug molecules but also display a wide range of biological activities, including anti-inflammatory, antibacterial, and anticancer effects.⁴ These characteristics make BCBs crucial in drug design, further stimulating scientists’ interest in their synthesis and modification.

Strain-release cycloaddition is one of the characteristic reactions of BCBs and has experienced significant growth in recent years, particularly in the last two years, further expanding the chemical space of strained bicyclic carbocycles. Generally, there are three prominent state-of-the-art strategies for the cycloaddition of BCBs: (1) thermally-driven cycloaddition, (2) photochemical radical cycloaddition, and (3) Lewis acid catalyzed polar cycloaddition reactions of BCBs. Photochemical radical cycloaddition represents a key approach for achieving the strain release cycloaddition of BCBs.^5–7 In 2022, Glorius and Brown independently reported the intermolecular [2π + 2σ] cycloaddition of BCBs with coumarins and alkenes via a visible light-mediated energy transfer strategy.^5a,b The Bach group developed the first asymmetric [2π + 2σ] cycloaddition reactions of monosubstituted BCBs with 2(1H)-quinolones under photocatalytic conditions.^7a Apart from radical-based cycloaddition strategies, Lewis acid catalysis has been proven to be a reliable and environmentally friendly activation strategy that can significantly enhance synthetic efficiency, improve reaction selectivity, and increase atom economy (Scheme 1). Various Lewis acid catalysts, such as Sc(OTf)₃, Yb(OTf)₃, BF₃·Et₂O, and so on, have been employed in the cycloaddition reactions of BCBs. Given the rapid developments in this field and the lack of a review focusing on Lewis acid-catalyzed cycloaddition reactions of BCBs, this review is organized according to the types of [n + 3] cycloaddition reactions and provides a comprehensive overview of the cycloaddition patterns of BCBs under Lewis acid catalysis. We focus on the latest advances in this area, emphasizing the scope, limitations, and synthetic applications of the catalytic strategies, offering valuable insights and inspiration for readers in the fields of synthetic chemistry, drug discovery, and materials design.

Scheme 1 Lewis acid-catalyzed strain-release cycloadditions of BCBs.

2. Lewis acid-catalyzed cycloadditions of BCBs

2.1 Lewis acid-catalyzed strain-release (3 + 2) cycloadditions of BCBs

The strain-release (3 + 2) cycloadditions of BCBs, also referred to as [2π + 2σ] cycloaddition reactions, are among the most frequently reported cycloaddition reactions involving BCBs. BCBs can undergo (3 + 2) cycloadditions with coupling partners such as imines, aldehydes, ketenes, indoles, enynes, benzofuran-derived oxa(aza)dienes, vinyl azides, quinoxalin-2(1H)-ones, and enol silyl ethers. These types of cycloaddition reactions predominantly yield bicyclohexanes and azabicyclohexanes, which serve as important bioisosteres of benzene rings.

In 2022, Leitch developed an innovative synthetic strategy for the direct synthesis of highly substituted azabicyclohexanes (aza-BCHs) through a Ga(OTf)₃-catalyzed formal (3 + 2) cycloaddition reaction of readily available imines and bicyclobutanes (Scheme 2).⁸ Microscale high-throughput screening identified two distinct reaction pathways: N-aryl imines undergo cycloaddition reactions with BCBs under mild conditions, leading to the formation of various azabicyclohexanes 3. In contrast, N-alkyl imines follow an addition/elimination sequence to yield cyclobutenyl methanamines with relatively high diastereoselectivity 4. Both N-aryl and N-alkyl imines, featuring a range of pharmaceutically relevant substituents, were well tolerated in these transformations. However, both transformations only resulted in moderate yields. In terms of synthetic applications, the practicality of azabicyclohexanes is demonstrated through various functional group transformations, such as oxidative deprotection (5a), ester hydrolysis (5b), and reduction (5c). Notably, the oxidative deprotection of 3b affords secondary amine azabicyclohexane 5a, which can undergo further N-alkylation, arylation, or acylation. This mechanism involves the formation of an enolate intermediate 6a through Lewis acid catalysis, followed by the generation of a carbocation intermediate 6b with the imine. This intermediate 6b can either undergo a nucleophilic attack by nitrogen or undergo an E1 elimination to form the final product. The relative rates of these pathways depend on the nucleophilicity or basicity of the nitrogen atom. For the diastereoselectivity in cyclobutenyl methanamine formation, a stereochemical model suggests that the major and minor diastereomers result from the elimination of specific hydrogen atoms. A clockwise elimination introduces greater torsional strain due to eclipsing interactions, while a counterclockwise elimination minimizes the strain, favoring the formation of the major diastereomer.

Scheme 2 Ga(OTf)₃-catalyzed formal (3 + 2) cycloaddition reaction of imines and BCBs.

The asymmetric version of cycloadditions involving BCBs poses a significant challenge. Prior to this, only Bach and Jiang have independently reported groundbreaking asymmetric cycloadditions of BCBs under photoredox catalysis.⁷ But no reports have been published on the asymmetric Lewis acid-catalyzed cycloadditions of BCBs. In 2024, Wang and Feng developed an efficient method for the synthesis of valuable aza-BCHs via enantioselective zinc-catalyzed (3 + 2) cycloadditions of BCBs with imines.^7d This innovative approach utilizes a novel type of BCB that features a 2-acyl imidazole group and a variety of alkynyl- and aryl-substituted imines. The resulting aza-BCHs, which contain α-chiral amine segments and two quaternary carbon centers, are synthesized with high efficiency and selectivity, affording up to 94% yield with an enantiomeric ratio of 96.5 : 3.5 under mild conditions.

Glorius, as a pioneer in strain-release cycloadditions involving BCBs, has made significant contributions to the innovative transformation of BCBs.^{3a,5a,5d,6a,6b} In 2022, they first reported an intermolecular [2 + 2] photocycloaddition that utilizes BCBs as 2σ-electron components and coumarins as heterocyclic olefin coupling partners. This strain-release-driven [2π + 2σ] photocycloaddition is achieved through visible-light-mediated triplet energy transfer catalysis.^5a After that, a BF₃-catalyzed [2π + 2σ] cycloaddition reaction of BCBs with aldehydes was developed to synthesize highly substituted 2-oxabicyclo[2.1.1]hexanes 9 (Scheme 3).⁹ The chosen BCBs featured an acyl pyrazole group, which not only enhanced the reaction efficiency but also allowed for subsequent diversification transformations. The results showed that a variety of aryl aldehydes, heterocyclic aldehydes, and various aliphatic aldehydes, including simple acetaldehyde and those with aliphatic rings, could smoothly react under mild conditions to give the corresponding 2-oxa-BCHs. BCBs bearing strong electron-withdrawing groups, such as trifluoromethyl, exhibited lower yields in the reaction. This observation further supports the involvement of a benzylic carbocation intermediate in the reaction pathway. Furthermore, aryl and vinyl epoxides could also serve as substrates, undergoing in situ rearrangement to aldehydes before cycloaddition with BCBs. Nonetheless, the reactions proceeded sluggishly when alkyl epoxides were used. The downstream transformations of the acyl pyrazole group highlight the synthetic utility of this method. For instance, hydrolysis affords the free carboxylic acid 10c, reduction of product 9 with NaBH₄ yields the primary alcohol 10b, and nucleophilic substitution with MeOH or amines produces the ester 10e and amide 10a. Additionally, the reaction of compound 9 with a Grignard reagent successfully generates a tertiary alcohol 10b. The BCB substrate initially interacts with the BF₃ catalyst to form intermediate 11a, which subsequently undergoes enolization to produce intermediate 11b. Intermediate 11b then engages in a nucleophilic addition with the aldehyde substrate, potentially activated via coordination with the BF₃ catalyst, leading to the formation of carbocation intermediate 11c. This key intermediate can undergo nucleophilic substitution by the oxygen atom to afford the desired 2-oxa-BCH product or can result in side products through intramolecular elimination reactions. This work provides a novel strategy for synthesizing complex sp³-rich bicyclic frameworks, thereby expanding the scope of BCB-based cycloaddition chemistry.

Scheme 3 BF₃-catalyzed [2π + 2σ] cycloaddition of BCBs with aldehydes.

In 2023, Procter first achieved a SmI₂-catalyzed intermolecular coupling between BCB ketones and electron-deficient alkenes for the construction of a variety of substituted BCHs with high efficiency and precise regioselectivity.¹⁰ Following closely behind, the Lewis acid catalyzed (3 + 2) cycloaddition reaction of BCB ketones with a C–C double bond unit was disclosed.

The Studer group has made innovative contributions to the ketenes and DA-cyclopropane chemistry. As a continuation of their work, in 2023, they successfully developed a Lewis acid-catalyzed [3 + 2] cycloaddition reaction of bicyclo-[1.1.0]-butane ketones with disubstituted ketenes for the synthesis of highly substituted bicyclohexan-2-ones 13 under mild and transition-metal-free conditions (Scheme 4).^11a Trimethylsilyl trifluoromethanesulfonate (TMSOTf) was selected as the best catalyst. A range of aryl and alkyl BCB ketones exhibited good performance in [3 + 2] cycloaddition reactions. However, BCB ketones bearing additional substituents at the bridgehead generally resulted in lower yields. Moreover, attempts to employ BCB esters and amides instead of BCB ketones for cycloaddition reactions mostly produced only trace amounts of the desired products, and efforts to generate and utilize ketenes in situ within the reaction were similarly unsuccessful. The authors also explored the potential for further functionalization of the exocyclic ketone groups formed. For instance, BCH 13a was successfully converted to the corresponding naphthyl ester 14avia a Baeyer–Villiger oxidation, achieving a 36% yield. Subsequent hydrolysis of ester 14a under basic conditions led to the formation of carboxylic acid 14b with a 75% yield. The proposed reaction mechanism follows a stepwise ionic pathway. Initially, TMSOTf reacts with the BCB ketone 1, inducing heterolytic cleavage of the BCB bridgehead bond and forming a highly reactive intermediate 15a. Without ketene, BCB 1 rapidly decomposes in the presence of TMSOTf. Intermediate 15a then reacts with ketene to generate silyl enol ether 15b, potentially through a stereoselective (cis) addition. An intramolecular cyclization step follows, yielding the target product, bicyclohexan-2-one 3, and completing the catalytic cycle of TMSOTf. Additionally, the Lewis acid activation of the ketene may facilitate the transformation from intermediate 15a to 15b.

Scheme 4 TMSOTf-catalyzed (3 + 2) cycloaddition reaction of BCBs with disubstituted ketenes.

Very recently, Studer developed a B(C₆F₅)₃-catalyzed stereospecific formal [3 + 3]-cycloaddition of aziridines with BCBs.^11b Through this novel protocol, a variety of enantiopure 2-azabicyclo[3.1.1]heptane derivatives were obtained under simple conditions. Additionally, scale-up reactions, mechanistic experiments, density functional theory (DFT) calculations, and synthetic applications were conducted and discussed.

In 2023, Ni, Deng, and colleagues reported a novel strategy for the direct synthesis of architecturally complex polycyclic indolines 17 from readily available indoles and BCBs via a formal cycloaddition process catalyzed by the Lewis acid Yb(OTf)₃ (Scheme 5).¹² This reaction follows a stepwise mechanism, beginning with the nucleophilic addition of indoles to BCBs, which is subsequently followed by an intramolecular Mannich reaction, leading to the formation of rigid, indoline-fused polycyclic frameworks. These structures closely resemble the core motifs found in polycyclic indole alkaloids. Under optimal conditions, the reaction tolerates N-substituted indoles, including those with N-benzyl, N-allyl, and N-methyl groups. However, indoles with an unprotected N–H group inhibit the reaction. Additionally, unsubstituted indoles, 2-substituted indoles, and 2,3-disubstituted indoles can also participate in the cycloaddition reaction, yielding polycyclic products with contiguous quaternary carbon centers. For BCB substrates, the 2-naphthyl group can be substituted with other aromatic, heteroaromatic, or alkyl groups without adversely affecting the reaction. However, BCB substrates containing Weinreb amides, esters, or sulfonyl groups exhibit lower reactivity due to their relatively poor electrophilicity, which hinders the nucleophilic addition of indoles. In a gram-scale synthesis, using indole 16a and BCB as substrates, the adduct 17a was obtained with a 75% yield. Further derivatization experiments demonstrated that adduct 17a could be transformed into a variety of indoline polycyclic derivatives through reduction, allylation, condensation, and Wittig olefination reactions. The reaction commenced with a nucleophilic addition of indole to a Lewis acid-activated BCB, leading to the formation of an indole iminium intermediate, designated as Int-I. Subsequently, an intramolecular Mannich cyclization involving the tetrasubstituted enolate on cyclobutane and the indole iminium intermediate resulted in the formation of a congested C–C bond.

Scheme 5 Yb(OTf)₃-catalyzed (3 + 2) cycloaddition reaction of BCBs with indoles.

In the same year, Feng independently reported a AgOTf-catalyzed dearomative [2π + 2σ] cycloaddition reaction that effectively converts N-unprotected indoles with BCBs into structurally complex indoline-fused BCHs 20 in moderate to good yields (Scheme 6).¹³ The method was suitable for a variety of 1,3-disubstituted BCB esters, Weinreb amides, and ketones. Complementary to Deng's method, this transformation was mainly applicable to unprotected indoles. For instance, 2-methyl-1H-indoles bearing different substituents at the C4–C6 positions afforded the fused BCHs in 54–85% yields, predominantly forming a single cis-fused diastereomer. The reaction was also compatible with 2,3-disubstituted indoles, enabling the one-step construction of highly substituted polycyclic structures featuring three contiguous all-carbon quaternary centers. In a reaction conducted on a 1.0 mmol scale, the desired product 20a was obtained with a 90% yield. Regarding synthetic applications, the synthesized BCHs, which are rich in functional groups, can be further converted into various compounds through derivatization reactions, such as primary and tertiary alcohols, free carboxylic acids, and aldehydes. Polycyclic pyrrolizidine derivatives and pyrrolizidine alkaloids featuring bridged ring systems can also be synthesized via intramolecular Ley oxidation and Mitsunobu reactions. The proposed mechanism involves the activation of the central bond of BCB by a silver catalyst, facilitating the cycloaddition reaction between indole and BCB, akin to the process outlined in Scheme 5.

Scheme 6 AgOTf-catalyzed (3 + 2) cycloaddition reaction of BCBs with indoles.

In 2024, Chen and Zhou successfully developed a Sc(OTf)₃-catalyzed (3 + 2) cycloaddition reaction to synthesize polysubstituted 2-amino-bicyclo[2.1.1]hexenes 24 from BCBs and ynamides (Scheme 7).¹⁴ Under optimal conditions, using only 1 mol% of the Sc(OTf)₃ catalyst in toluene at 35 °C, the target compounds were obtained in 99% yield. The substrates involved various substituted BCB ketones, including those with 2-naphthyl, phenyl, vinyl, cyclohexyl, allyl, n-butyl, and t-butyl groups. Unfortunately, BCBs bearing thienyl, furyl, and Weinreb amide groups exhibited no reactivity in this reaction, likely due to their relatively low electrophilicity. Additionally, methyl 3-phenylbicyclo[1.1.0]butane-1-carboxylate led to the formation of only an elimination side product. Regarding ynamide esters, N-alkyl-substituted ynamides, N-phenyl-N-tosyl, and N-Ns ynamides were investigated. A series of synthetic transformations, including hydrogenation, reduction, bromination, hydrolysis, oxidation, and Wittig reactions, were performed, demonstrating the versatility and practicality of these synthesized compounds. For example, compound 24 was hydrogenated to produce 2-amino-BCH 25d with an 85% yield, while selective reduction of 24 with NaBH₄ afforded alcohol 25e in a 73% yield. A scaled-up cycloaddition reaction under optimized conditions, employing 1 mol% of Sc(OTf)₃ as the catalyst, afforded the target compound 24a in 91% yield (0.9 g). The proposed reaction mechanism involves the initial activation of BCB 1 by Sc(OTf)₃ to form complex 26a. Subsequently, the electron-rich ynamide 23a undergoes a nucleophilic attack on complex 26avia an SN₂-like mechanism, leading to the formation of enolate and keteniminium intermediates (26b). Finally, an intramolecular cyclization results in the formation of the desired bicyclohexene 24a, with the Lewis acid being regenerated.

Scheme 7 Sc(OTf)₃-catalyzed cycloaddition reactions of BCBs with ynamides.

In 2024, Li, Zheng, and Deng reported a BF₃·Et₂O-catalyzed formal [2π + 2σ] cycloaddition to successfully synthesize a series of spiro-bicyclo[2.1.1]hexanes (Scheme 8).¹⁵ This method utilized BCBs and benzofuran-derived oxa(aza)dienes as substrates, achieving the synthesis of functionalized spiro-bicyclo[2.1.1]hexanes 28 with yields up to 99% and excellent chemoselectivity. Benzofuran-derived oxadienes with various substituents such as methyl, halogens, and trifluoromethyl at different positions of the phenyl ring were tolerated. By adjusting the reaction conditions, benzofuran-derived azadienes could also react efficiently. Scaling up the [2π + 2σ] cycloaddition reaction of BCB 1c with benzofuran-derived oxadiene 27a to a 2.0 mmol scale resulted in the desired spiro-bicyclo[2.1.1]hexane 28a with an 81% yield. Several transformations of 28a were further investigated, including the reaction with MeMgBr to afford tertiary alcohol 32a, reduction of the carbonyl and ester groups of 28a to hydroxyl groups using DIBAL-H to yield compound 32b, and hydrolysis of the ester group of 28a to produce carboxylic acid 32c. Additionally, the imine moiety of 30a was reduced with NaBH₄, yielding amine 31a. The study also proposed a plausible reaction mechanism involving coordination of BCB 1c with the BF₃ catalyst to form species 33a, followed by enolization to intermediate 33b, nucleophilic addition to benzofuran-derived oxadiene 27a resulting in carbocation species 33c, and finally intramolecular cyclization to generate the desired adduct 28a, with regeneration of the BF₃ catalyst.

Scheme 8 BF₃·Et₂O-catalyzed (3 + 2) cycloaddition of BCBs with benzofuran-derived oxa(aza)dienes.

Bridged bicyclic scaffolds have emerged as bioisosteres of planar aromatic rings. However, incorporating nitrogen atoms into these bridged bicyclic structures presents a challenge, despite the potential of this strategy to aid in the development of pyridine bioisosteres. In 2024, Zheng achieved catalyst-controlled annulation reactions from readily available vinyl azides and BCBs for the divergent synthesis of 2- and 3-azabicyclo[3.1.1]heptenes (aza-BCHepes), potential bioisosteres of pyridine (Scheme 9).¹⁶ The Ti^(III)-catalyzed single-electron reductive generation of C-radicals from BCBs enables a concise (3 + 3) annulation with vinyl azides, yielding novel 2-aza-BCHepe scaffolds. In contrast, Sc(OTf)₃ catalysis facilitates an efficient dipolar (3 + 2) annulation with vinyl azides, leading to the formation of 2-azidobicyclo[2.1.1]hexanes, which subsequently undergo chemoselective rearrangement to produce 3-aza-BCHepes. Both strategies effectively deliver unique azabicyclo[3.1.1]heptene scaffolds with high functional group tolerance. Stability tests demonstrated that compound 35a remained stable under both acidic and basic conditions, whereas compound 37a was stable under basic conditions but underwent hydrolysis under acidic conditions. The synthetic utility of these methods has been further demonstrated by scale-up reactions and diverse post-catalytic transformations, yielding valuable azabicyclic compounds, including 2- and 3-azabicyclo[3.1.1]heptanes and rigid bicyclic amino esters. For example, the selective reduction of compound 35a efficiently produced 38a and 38b, while the ketone group in 35a was smoothly transformed into alkene 38cvia a Wittig reaction. Beckmann and Baeyer–Villiger rearrangements were successfully employed to synthesize the corresponding amides and esters, respectively. Additionally, the selective reduction of compound 37a afforded 3-azabicyclo[3.1.1]heptane 39b and the imidazole group in 40a was converted into ester 35b, which was subsequently reduced to yield the bicyclic α-amino ester 40b. Moreover, the presence of an sp²-hybridized nitrogen atom and the geometric similarity between pyridines and the corresponding aza-BCHepes suggest that these compounds are promising bioisosteres of pyridines. In Ti catalysis, a γ-carbonyl radical generated by Ti^(III)-catalyzed ring opening of BCB 1 reacts with vinyl azide to form an iminyl radical, which subsequently reacts with a Ti(IV) enolate to produce 2-azabicyclo[3.1.1]heptene, thereby completing the catalytic cycle. In the case of scandium catalysis, coordination of Sc(OTf)₃ to the carbonyl group activates the BCB, which is then attacked by vinyl azide to generate an imino diazonium ion. This intermediate undergoes transannular cyclization to form 2-azidobicyclo[2.1.1]hexanes. Under thermal conditions, a less sterically hindered secondary carbon migrates, leading to the formation of 3-azabicyclo[3.1.1]heptene upon the release of dinitrogen.

Scheme 9 Sc(OTf)₃-catalyzed dipolar (3 + 2) annulation of BCBs with vinyl azides.

In 2024, Guo, Li, and co-workers reported a Sc(OTf)₃-catalyzed intermolecular (3 + 2) cycloaddition of BCBs with quinoxalin-2(1H)-ones, effectively synthesizing quinoxaline-fused azabicyclo[2.1.1]hexanes 43 with multiple quaternary carbon centers (Scheme 10).¹⁷ 1,3-Disubstituted BCB esters reacted efficiently with quinoxalin-2(1H)-ones to produce the desired aza-BCHs. Additionally, BCBs containing amide groups proved to be effective 2σ units in the reaction. However, the reaction efficiency of monosubstituted BCBs was lower, attributed to the absence of the stabilizing effect provided by an aromatic ring on the carbocation within the zwitterionic enolate intermediate. Pyridine-substituted BCBs were found to be incompatible, likely due to potential coordination with the Lewis acid. The substrate scope of quinoxalin-2(1H)-ones was also broad, encompassing derivatives with both electron-donating and electron-withdrawing groups that successfully participated in the reaction. The presence of a protecting group was essential for the reaction's success. Notably, certain drug molecules, such as derivatives of ibuprofen and aspirin, were also able to yield products in this reaction, albeit with lower conversion rates. The reaction system's compatibility extended to other N-heterocycles containing an imine moiety, such as benzoxazin-2-ones and dibenzoxazepine. However, compounds like quinazolin-4(3H)-one and quinolones remained inert under the transformation conditions. On a gram scale, the reaction produced aza-BCH 43a with an 85% isolated yield. Further derivatization studies demonstrated that compound 43a could undergo various transformations to yield different derivatives.

Scheme 10 Sc(OTf)₃-catalyzed (3 + 2) cycloaddition of BCBs with quinoxalin-2(1H)-ones.

The proposed reaction mechanism begins with the strain-release-driven carbon–carbon bond cleavage of the BCB in the presence of a Lewis acid, resulting in the formation of a zwitterionic intermediate 45a. Subsequently, the imine moiety acts as a nucleophile, attacking the zwitterionic intermediate 45a to form intermediate 45b, which then undergoes cyclization to yield the target aza-BCH 43. Key challenges in this process include the isomerization of the BCB under Lewis acid catalysis and the intramolecular E1 elimination of intermediate 45b.

Very recently, Li achieved a Yb(OTf)₃-catalyzed (3 + 2) cycloaddition between enol silyl ethers and BCBs, efficiently synthesizing a series of bicyclo[2.1.1]hexanes 47 (Scheme 11).¹⁸ A variety of cyclic enol silyl ethers and acyclic enol silyl ethers can participate in the reaction. However, BCBs containing functional groups like Weinreb amides, esters, and sulfur-containing cyclic enol silyl ethers showed poor reactivity under the standard reaction conditions. Additionally, substrates with bulky substituents, such as tert-butyl groups, failed to undergo the reaction due to significant steric hindrance. A gram-scale reaction afforded the target product 47a with an 80% yield and an enantiomeric ratio of >20 : 1. Product 47a can be efficiently transformed into polycyclic tertiary alcohols and polycyclic derivatives through subsequent TBAF deprotection, allylation, and Wittig reactions. A possible reaction mechanism was proposed: under the activation of the Lewis acid Yb(OTf)₃, the BCB becomes highly reactive and is readily attacked by the enol silyl ether to form intermediate 49b, which then undergoes cycloaddition to yield the final product 49c. In this process, Yb(OTf)₃ is regenerated, allowing the catalytic cycle to continue. This mechanism accounts for the high efficiency of the reaction and its broad substrate tolerance.

Scheme 11 Yb(OTf)₃-catalyzed (3 + 2) cycloaddition of BCBs with enol silyl ethers.

2.2 Lewis acid-catalyzed strain-release (3 + 3) cycloadditions of BCBs

In contrast to the strain-release (3 + 2) cycloadditions of BCBs, there are fewer documented instances of (3 + 3) cycloadditions involving BCBs. These types of cycloaddition reactions, also known as [4π + 2σ] cycloaddition reactions, predominantly yield bicyclo[3.1.1]heptanes and azabicyclo[3.1.1]heptanes.

In 2024, Zhang and Deng developed a novel Eu(OTf)₃-catalyzed formal dipolar [4π + 2σ] cycloaddition reaction between BCBs and nitrones to synthesize multifunctional 2-oxa-3-azabicyclo[3.1.1]heptanes 51 (Scheme 12).¹⁹ Through this strategy, multiple heteroatoms have been efficiently introduced into the bicycloheptane framework for the first time, demonstrating its potential for constructing complex molecular structures. The disubstituted BCB ketone with phenyl or methyl substituents afforded the corresponding products in good to high yields, whereas the monosubstituted BCB ketone resulted in a lower yield. Additionally, the monosubstituted BCB sulfone and N,N-dimethyl-3-phenylbicyclo[1.1.0]butane-1-carboxamide did not produce the desired cycloadducts. A series of nitrones with various electron-donating or electron-withdrawing groups positioned at different sites on the phenyl ring were also evaluated, affording the corresponding products in yields ranging from 48% to 99%. Notably, the reaction remained efficient on a 2.0 mmol scale, achieving an 87% yield even when the catalyst loading was reduced to 5 mol%. Furthermore, several derivatization reactions were conducted on product 51a. These included the nucleophilic substitution of the acyl pyrazole unit with an alcohol to form ester 52a (98% yield), the reaction with MeMgBr to produce tertiary alcohol 52b (85% yield), the reduction of the acyl pyrazole group with NaBH₄ to generate hydroxyl compound 52c (95% yield), and the cleavage of the N–O bond in the presence of Pd/C and H₂ to yield functionalized cyclobutane 52d (88% yield). Importantly, the 2-oxa-3-azabicyclo[3.1.1]heptane moiety was successfully integrated into the structure of the antihistamine drug Rupatadine, allowing for the synthesis of a Rupatadine analog from 51b in just three steps with an overall yield of 29%. Two possible reaction pathways were proposed: the first involves a nucleophilic attack of activated BCBs on nitrones, followed by ring closure (Path A); the second pathway entails the nucleophilic attack of BCBs on nitrones under Lewis acid activation and subsequent enolization, leading to ring closure (Path B). Experimental data indicated that electron-rich nitrones exhibited higher reaction efficiency, supporting Path B as the more plausible initial step of the reaction. DFT calculations revealed that Eu(OTf)₃ coordinates with the acyl pyrazole group, thereby activating BCB 1f. This activation facilitates the nucleophilic attack of nitrone 50a on the activated 1f, leading to the formation of intermediate Int2, which subsequently undergoes intramolecular cyclization to yield the target compound 51a.

Scheme 12 Eu(OTf)₃-catalyzed cycloaddition reactions of BCBs with nitrones.

Pyridinium 1,4-zwitterionic thiolate derivatives demonstrate exceptional versatility in organic synthesis, serving as valuable precursors for the construction of a wide range of cyclic compounds.²⁰ In 2024, Wang and Feng developed two innovative cycloaddition reactions from BCBs and pyridinium 1,4-zwitterionic thiolate derivatives. Sc(OTf)₃-catalyzed (3 + 3) cycloaddition of BCBs with pyridinium 1,4-zwitterionic thiolates produced thia-norpinanes, representing the first synthesis of 2-thiabicyclo[3.1.1]heptanes (thia-BCHeps) 57 (Scheme 13).²¹ In contrast, by using Ni(ClO₄)₂ as a catalyst, they achieved (5 + 3) cycloaddition with quinolinium 1,4-zwitterionic thiolates, yielding uncommon 2-thia-5-azabicyclo[5.1.1]nonenes 56. A preliminary example of a Lewis acid-catalyzed asymmetric polar (5 + 3) cycloaddition of BCBs, utilizing a zinc/Ph-Pybox catalytic system to construct 56a with excellent yield, has been reported with 90.5 : 9.5 er. Various substituents, such as methyl, trifluoromethyl, halogens, and different groups on the BCB ketone, all provided good yields ranging from 70% to 93% under optimized reaction conditions. Additionally, this strategy was successfully employed for the rapid synthesis of a 3D analog of the bioactive molecule Pitofenone 58. The (3 + 3) cycloaddition process involves an initial acid-activated nucleophilic addition/ring-opening, followed by a subsequent intramolecular cyclization. For (5 + 3) cycloaddition, the process begins with the generation of a Lewis acid/BCB complex 59a. This adduct can engage in a concerted nucleophilic addition/ring-opening process to form a zwitterionic intermediate 59c. Subsequently, intermediate 59c undergoes intramolecular cyclization (via59d), yielding a (5 + 3)-type intermediate 59e. 59e further undergoes a ligand exchange reaction to afford the desired product.

Scheme 13 Sc(OTf)₃-catalyzed cycloaddition reactions of BCBs with pyridinium 1,4-zwitterionic thiolate derivatives.

2.3 Lewis acid-catalyzed strain-release (4 + 3) cycloadditions of BCBs

In 2024, Wang and Feng reported the first Zn(OTf)₂-catalyzed hetero-(4 + 3) cycloaddition of BCBs with 3-benzylideneindoline-2-thione derivatives for the synthesis of thiabicyclo[4.1.1]octanes (S-BCOs) 62 (Scheme 14).²² In contrast, the less electrophilic BCB ester participates in a Sc(OTf)₃-catalyzed [2π + 2σ] reaction with 1,1,2-trisubstituted alkenes, producing highly substituted BCHs that feature a spirocyclic quaternary carbon center. A variety of BCB substrates, including BCB ketones with phenyl, furanyl, thiophenyl, and alkyl substitutions, as well as 1,3-disubstituted BCB ketones were explored, all of which showed good compatibility in the reaction. In addition, 3-benzylideneindoline-2-thione derivatives with different N-substituents, including allyl, alkyl, benzyl, and aryl groups were compatible. The successful application of these substrates further proves the versatility and practicality of the reaction. Two scaled-up cycloaddition reactions of BCBs with 3-benzylideneindoline-2-thione derivatives were performed, resulting in the formation of compounds 62a and 63a with yields of 86% and 68%, respectively. Further product derivatizations, including oxidation, reduction, and rearrangement reactions, were also achieved, expanding the scope of this method's application. Additionally, the highly substituted BCH unit was successfully incorporated into the structure of the lipid-lowering drug Lomitapide in just two steps, underscoring the potential utility of these synthetic strategies in medicinal chemistry.

Scheme 14 Lewis acid-catalyzed cycloaddition reactions of BCBs with 3-benzylideneindoline-2-thione.

The proposed mechanism involves two distinct Lewis acid-catalyzed cycloaddition reactions of BCBs with 3-benzylideneindoline-2-thione derivatives. The hetero-(4 + 3) cycloaddition reaction is hypothesized to proceed via a concerted nucleophilic ring-opening mechanism, where the sulfur atom attacks the BCB ring to form a nucleophilic intermediate 66f, which is then followed by an intramolecular Michael addition. The [2π + 2σ] cycloaddition reaction likely involves a concerted process between a zwitterionic intermediate and E-1,1,2-trisubstituted alkenes. In this mechanism, the BCB ester generates an enolate intermediate 66b under the influence of the Lewis acid, which then forms a complex with the trisubstituted alkene, culminating in a concerted cycloaddition reaction to produce the final product.

In 2024, Nicolai and Waser reported an Al(OTf)₃-catalyzed [4 + 3] cycloaddition protocol that efficiently converts naphthoyl BCBs with silyl dienol ethers into structurally rigid bicyclic [4.1.1]octane (BCO) diketones 68 (Scheme 15).²³ Aromatic BCB ketones with various electron-donating and electron-withdrawing substituents, as well as those with alkyl or phenyl groups at the bridgehead position, were found to be compatible with the reaction conditions. However, BCB Weinreb amides required a longer reaction time to achieve full conversion. Both unsubstituted and 1-methyl-substituted silyl dienol ethers successfully produced the corresponding BCO derivatives. Further synthetic applications, such as reduction and cross-coupling reactions, were also demonstrated.

Scheme 15 Al(OTf)₃-catalyzed cycloaddition reactions of BCBs with silyl dienol ethers.

Under Lewis acid catalysis, the BCB ketone and silyl dienol ether form an activated intermediate (70a), which undergoes a nucleophilic attack by the enolate moiety of the dienol ether at the bridgehead position, resulting in the formation of a key C–C bond. This is followed by a conjugated intramolecular addition, where the enolate anion adds to the enone, generating a silyl-protected enol intermediate (70c). Subsequent acid hydrolysis transforms this intermediate into the BCO diketone product (68). Moreover, the reaction's sensitivity to the substituent at the C4 position of the silyl dienol ether is consistent with the proposed mechanism, where steric hindrance may slow down the second step of the cyclization process, providing theoretical support for this synthetic approach.

In 2024, Biju reported a Bi(OTf)₃-catalyzed (4 + 3) annulation reaction of BCBs with para-quinone methides (p-QMs) to prepare oxabicyclo[4.1.1]octanes 72 (Scheme 16).²⁴ Catalyzed by 5 mol% Bi(OTf)₃, the reaction exhibited excellent regioselectivity and compatibility with a range of functional groups, effectively accommodating p-QM derivatives and BCBs with various electronic properties and substituents. The oxabicyclo[4.1.1]octane derivative 72a demonstrated significant potential for synthetic applications. For example, reduction of the ester group and C–O bond cleavage of 72a using LiAlH₄ yielded tetrasubstituted cyclobutane 73a; selective reduction with DIBAL-H gave the mono-substituted product 73c; and in the presence of NaH, 72a underwent O-alkylation with iodomethane and allyl bromide to produce the O-alkylated products 73b and 73d, respectively. The proposed mechanism involves the simultaneous activation of p-QM and BCB by the Lewis acid, followed by a 1,6-addition of the BCB enolate to the p-QM to form a diaryl cyclobutylmethane intermediate 74a. A selective nucleophilic addition from the C2 carbon of the phenol moiety to the carbocation center then forms the key bicyclic intermediate 74b, where C-addition is favored over O-addition. Cleavage of the carbon–carbon bond in the spirocyclohexadienone fragment releases strain, generating phenol intermediate 74c, and a second 1,6-addition by the phenol moiety may lead to the formation of the desired product 72a.

Scheme 16 Bi(OTf)₃-catalyzed (4 + 3) cycloaddition of BCBs with para-quinone methides.

2.4 Lewis acid-catalyzed strain-release (5 + 3) and (6 + 3) cycloadditions of BCBs

In 2024, Peng and colleagues reported the first B(C₆F₅)₃-catalyzed formal (n + 3) (n = 5 and 6) cycloaddition reaction between BCBs and imidazolidines/hexahydropyrimidines (Scheme 17).²⁵ This reaction strategy was successfully applied to the synthesis of challenging medium-bridged ring systems, specifically 2,5-diazabicyclo[5.1.1]nonanes 77 and 2,6-diazabicyclo[6.1.1]decanes 78 in moderate to good yields. The substrate scope of BCBs was thoroughly examined, revealing that a wide range of aryl, alkyl, alkenyl, and alkynyl BCBs could effectively participate in the reaction to afford the desired products. It is worth noting that BCB esters, amides, and sulfones did not undergo the reaction under standard conditions. In contrast, the reaction with BCB Weinreb amide proceeded slowly under these conditions, achieving a yield of less than 10%. However, the yield improved significantly to 42% when Sc(OTf)₃ was employed as a catalyst instead of B(C₆F₅)₃. The scope of imidazolidines was also extensively explored. Both symmetrical and unsymmetrical imidazolidines, including N-aryl, N-alkyl, and N-benzyl derivatives, provided the desired products in good yields. Furthermore, hexahydropyrimidines were identified as suitable substrates, enabling the formation of structurally challenging bridged ring systems. Scaling up the reaction using 2-naphthyl BCB ketone 1a and imidazolidine 75a to a gram scale maintained a high yield of 85% for product 78a. Additionally, the synthesized product 78a was utilized in various downstream transformations to access a range of medium-bridged ring systems through condensation, allylation, Wittig olefination, and reduction reactions. Selective deprotection was also achieved, allowing for further modification of the nitrogen atom with diverse N-pharmacophores such as sulfonyl, triazole, and peptide groups. Mechanistic investigations indicated that the B(C₆F₅)₃ catalyst activates BCB 1 rather than the imidazolidine or hexahydropyrimidine substrates. The proposed mechanism involves the initial complexation of the Lewis acidic B(C₆F₅)₃ catalyst with BCB 1 to form species 81a, which undergoes enolization to produce intermediate 81b. Subsequent nucleophilic addition of imidazolidine or hexahydropyrimidine to the carbocation center of intermediate 81b results in the formation of ammonium species 81c, followed by aminal ring opening to yield zwitterionic iminium species 81d. Finally, an intramolecular cyclization occurs, generating the target product 77/78 and releasing the B(C₆F₅)₃ catalyst.

Scheme 17 B(C₆F₅)₃-catalyzed (n + 3) (n = 5 and 6) cycloaddition reaction between BCBs and imidazolidines/hexahydropyrimidines.

3. Conclusions and outlook

BCBs have evolved from marginal structures to star components in modern organic synthesis, particularly in the construction of complex polycyclic frameworks. The synthesis strategies of BCBs are crucial for creating three-dimensional bioisosteres of planar aromatic rings; they serve as saturated bioisosteres of benzene rings, which is particularly significant in medicinal chemistry. In recent years, especially in the past two years, strain-release (n + 3) (n = 2–6) cycloaddition reactions catalyzed by Lewis acids have made BCBs powerful synthetic tools, successfully applied in the synthesis of various quaternary polycyclic compounds. BCBs can react with a diverse range of coupling partners, such as imines, disubstituted ketenes, electron-deficient alkenes, indoles, aldehydes, ynamides, 3-benzylideneindoline-2-thione, nitrones, pyridinium 1,4-zwitterionic thiolate derivatives, silyl dienol ethers, vinyl azides, quinolines, benzofuran-derived oxa(aza)dienes, imidazolidines/hexahydropyrimidines, enol silyl ethers, and para-quinone methides, demonstrating broad synthetic applicability and stereoselectivity.

Despite the growing applications of BCBs in synthetic chemistry, several challenges remain in their practical use: (1) the reactivity of BCBs can be influenced by the electronic and stereochemical properties of the substrates, necessitating precise control of reaction conditions; (2) in attempts to construct more complex molecular structures, the conversion of BCBs may encounter side reactions and low yields; and (3) current cycloaddition reactions involving BCBs are predominantly non-chiral, with enantioselective transformations being quite rare and in need of improvement. Nonetheless, this presents new opportunities for the development of diverse asymmetric variants of these reactions in the future.

Despite these challenges, the future prospects of BCBs in synthetic chemistry remain promising. With the continuous development of novel catalysts and synthetic strategies, BCBs are expected to play an increasingly important role in synthetic chemistry, medicinal chemistry, materials science, and other fields. Future research may focus on developing more efficient and selective synthetic methods and exploring new applications of BCBs, further expanding their scope in chemical synthesis.

Author contributions

X. L., J. H., K. L., X. W. and H. C. conceived the idea and contributed to the writing, reviewing and editing of the manuscript. All authors have given approval to the final version of the manuscript.

Data availability

No primary research results, software or code have been included and no new data were generated or analysed as part of this review.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

This work was supported by a Start-up Grant from Guangdong Pharmaceutical University (grant no. 51304043005) and the Guangdong Cosmetics Engineering & Technology Research Center.

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