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DOI: 10.1039/D5QO00460H (Research Article) Org. Chem. Front., 2025, Advance Article

Palladium-catalyzed double strain-release (3 + 3) cycloaddition for the synthesis of vinylbicyclo[3.1.1]heptanes†

Xin-Yu Gao‡ , Yuanjiu Xiao‡, Xuan Zhan, Yu-Jie Li, Kun-Ju Wang and Jian-Jun Feng*
State Key Laboratory of Chemo and Biosensing, Advanced Catalytic Engineering Research Center of the Ministry of Education, College of Chemistry and Chemical Engineering, Hunan University, Changsha, Hunan 410082, P. R. China. E-mail: jianjunfeng@hnu.edu.cn

Received 13th March 2025 , Accepted 23rd April 2025

First published on 24th April 2025

Abstract

All-carbon bicyclo[3.1.1]heptanes are important structural motifs in bioactive compounds and serve as bioisosteres for substituted benzenes. However, their synthesis, especially through polar (3 + 3) cycloaddition strategies, remains underexplored. Herein, we present a palladium-catalyzed double strain-release (3 + 3) cycloaddition involving Bicyclo[1.1.0]butanes (BCBs) and vinylcyclopropanes. The reaction tolerates a variety of BCBs and vinylcyclopropane derivatives, including spirovinylcyclopropane oxindoles, providing access to structurally diverse BCHeps with potential applications in drug discovery. The practicality of this method is demonstrated through scale-up reactions and downstream transformations of the cycloadducts.

Introduction

Bicyclo[3.1.1]heptanes (BCHeps) serve as significant scaffolds found in various natural products and biologically active compounds, including α-pinene, massarinolin A and acanthodoral (Scheme 1a).1 Furthermore, the pioneering work of Anderson,2a,b Uchiyama2c and Mykhailiuk2d,e revealed that bridgehead-substituted BCHeps and 3-azabicyclo[3.1.1]heptanes can act as bioisosteres for meta-substituted benzenes and 3,5-disubstituted pyridines, respectively, exhibiting enhanced physicochemical and pharmacokinetic properties. This positions BCHeps and hetero-BCHeps as attractive targets for chemical synthesis. For example, strain-release-driven ring-opening of [3.1.1]propellane,2a–c photochemical formal (4 + 2)-cycloadditions of bicyclo[1.1.1]pentanes and alkenes,3 along with other elegant methods,1 have been developed. Among them, cycloadditions of bicyclo[1.1.0]butanes (BCBs)4–8 are emerging as a reliable method that offers both step and atom economy for the construction of BCHep derivatives (Scheme 1b).8
image file: d5qo00460h-s1.tif
Scheme 1 (3 + 3) cycloadditions of BCBs and its scientific context.

In 2022, Molander's pioneering study of the (3 + 3) cycloaddition reactions of BCBs facilitated the synthesis of trisubstituted bicyclo[3.1.1]heptanes by initiating the reaction via photochemical oxidation of cyclopropylamines.9 Subsequently, Waser introduced a complementary (3 + 3) cycloaddition strategy that involved photocatalyzed homolytic cleavage of aromatic carbonyl cyclopropanes for the synthesis of highly substituted bicyclo[3.1.1]heptanes.10 Additionally, Li reported an elegant pyridine-boryl radical-catalysis strategy for the (3 + 3) cycloaddition reactions of BCBs, aimed at constructing all-carbon BCHeps.11 Very recently, Maity developed an impressive photoredox (3 + 3) reaction involving D–A cyclopropanes12 and monosubstituted BCBs.13 To the best of our knowledge, only the aforementioned four examples of (3 + 3) cycloaddition reactions of BCBs have been developed for the synthesis of bicyclo[3.1.1]heptanes. Furthermore, current research is limited to radical (3 + 3) annulations of BCBs to produce all-carbon BCHep scaffolds (Scheme 1b, middle). In contrast, numerous examples and strategies have been reported for generating hetero-BCHeps. In addition to radical (3 + 3) cycloaddition strategies,14 which include pyridine diboron-catalysis,14a photocatalyzed amidyl radical insertion,14b and TiIII-catalyzed single-electron reduction,14c significant advancements have also been made in polar hetero-(3 + 3) cycloadditions of BCBs. These include Lewis acid catalysis,15 Brønsted acid catalysis,16 palladium-catalyzed (3 + 3) cycloadditions with vinyl oxiranes,17a copper-catalyzed (3 + 3) cycloadditions involving azomethine ylides,18 silver-enabled annulations with isocyanides,19 and base-promoted dearomative cycloadditions with pyridinium ylides over the past two years.20 Consequently, developing new polar (3 + 3) cycloaddition reactions to further expand the novel all-carbon bicyclo[3.1.1]heptane chemical space holds significant value for drug innovation, yet remains largely unexplored.17b,c

Since the pioneering work by Tsuji's research group in 1985 on the synthesis of cyclopentanes through (3 + 2) cycloadditions of vinylcyclopropanes (VCPs) with electron-deficient olefins,21 transition-metal-catalyzed cycloadditions of VCPs with 2π components, involving π-allyl-metal complexes, have become a versatile platform for accessing mono-, fused-, and spiro-carbocyclic compounds as well as heterocycles.22 However, there are currently no reports on the (3 + 3) cycloadditions of vinylcyclopropanes. Furthermore, the application of (3 + n) and (5 + n) cycloadditions of vinylcyclopropanes for the synthesis of bridged bicyclic scaffolds remains is still rare in the literature.23

As part of our ongoing program to discover new cycloaddition reactions involving strained rings,24 we present our design for a palladium-catalyzed (3 + 3) reaction between BCBs and vinylcyclopropanes. This reaction represents the first polar cycloaddition involving BCBs for constructing all-carbon BCHep scaffolds (Scheme 1c).

Results and discussion

We initiated the optimization of the reaction utilizing BCB 1a and VCP 2a as model substrates (Table 1, see ESI† for detailed optimization data). After screening of various reaction parameters, we discovered that the desired (3 + 3) cycloaddition occurred using Pd2(dba)3·CHCl3/L2 as the catalyst in THF at room temperature; the desired BCHep 3aa was obtained in 86% NMR yield, accompanied by a trace amount of the (5 + 3) cycloadduct 4aa (conditions A, entry 1). The bisphosphine ligands L1–L6 with varying bite angles significantly influence the yield of the (3 + 3) cycloaddition reaction, while having minimal impact on regioselectivity (entries 2–6). While the dppb ligand L4 produced the 3aa with a yield of 77%, the electron-rich bulky phosphine ligand L7 resulted in a relatively lower yield (entry 4 versus entry 7). Other bisphosphine ligands L8–L12 with different backbones were tested; however, no enhancement compared to ligand L2 was observed (entries 8–12). The monodentate phosphine ligand L13 was tested, yielding the desired product with a 12% NMR yield (entry 13). Subsequently, a solvent survey revealed that THF was the most suitable candidate (entry 1 versus entries 14–16). Notably, the non-polar solvent produced only a trace amount of 3aa. Replacing Pd2(dba)3·CHCl3 with other commonly used palladium catalysts, including Pd(PPh3)4, Pd(OAc)2, and CpPd(η3-C3H5), resulted in a reduced yield. Additionally, the temperatures were examined (entries 20 and 21), and 25 °C was determined to be the most suitable temperature for this transformation. Finally, we conducted condition-based sensitivity screening, which revealed that this reaction is sensitive to oxygen levels and concentrations.25
Table 1 Deviation from the standard reaction conditionsa

image file: d5qo00460h-u1.tif
Entry Variation from the standard conditions Yield of 3aa[thin space (1/6-em)]b (%) Yield of 4aa[thin space (1/6-em)]b (%)
a Reaction optimization: 1a (0.10 mmol), 2a (0.12 mmol), catalyst (5 mol%) and ligand (10 mol%), solvent (1 mL), 25 °C, under N2 for 12 h.b NMR yield with CH2Br2 as an internal standard.c Pd2(dba)3 served as the catalyst.
1 None 86 <5
2c L1 instead of L2 5 0
3c L3 instead of L2 49 <5
4c L4 instead of L2 77 <5
5c L5 instead of L2 29 <5
6c L6 instead of L2 15 <5
7c L7 instead of L2 60 <5
8c L8 instead of L2 64 <5
9c L9 instead of L2 16 0
10c L10 instead of L2 15 0
11c L11 instead of L2 68 6
12c L12 instead of L2 33 0
13c L13 instead of L2 12 <5
14c Toluene instead of THF 6 0
15c CH2Cl2 instead of THF 74 <5
16c CH3CN instead of THF 60 <5
17 Pd(PPh3)4 was used 79 7
18 Pd(OAc)2 was used 53 0
19 CpPd(η3-C3H5) was used 62 0
20 Run at 0 °C 31 0
21 Run at 40 °C 79 0

With the optimized reaction conditions in hand, the reaction scope of the (3 + 3) cycloaddition was then explored (Scheme 2). In addition to VCP 2a, which contains a methyl ester group, substrates 2b and 2c, featuring more sterically hindered ethyl and benzyl moieties, were also compatible, although they produced lower yields. Subsequently, we investigated the range of BCB substrates. In addition to naphthyl-substituted BCB ketones (1a and 1b), the phenyl (1c–1e), thienyl (1f), and furanyl (1g) substituted BCB ketones effectively participated in the reaction, yielding the corresponding BCHeps in moderate to good yields. Notably, Malins's BCB 1h containing an alkynyl group can selectively form the desired (3 + 3) cycloadduct 3ha with a yield of 75%.26 Unfortunately, the alkyl-substituted BCB ketone 1i is prone to undergoing several side reactions, and the corresponding cycloadduct was not observed. Similarly, the cycloaddition reactions of 1,3-disubstituted acyl BCBs (1j and 1k) failed to afford the desired products, likely due to their lower reactivity in the cycloaddition process. Given that no asymmetric cycloaddition reaction of BCBs has been developed for the synthesis of chiral all-carbon BCHeps, we further attempted the catalytic asymmetric version of the current (3 + 3) annulation. The reaction utilizing chiral ligand L14 resulted in a yield of 87% for 3aa; however, the enantioselectivity was low. In contrast, when ligand L15 was used, 3aa was produced with an enantiomeric excess of 58%, but the yield was poor. Further attempts to improve the yield and enantioselectivity of the BCHep product were unsuccessful (see Table S3 in the ESI†).


image file: d5qo00460h-s2.tif
Scheme 2 Scope of the (3 + 3) cycloaddition between BCBs and VCPs. Conditions A: 1 (0.20 mmol), 2 (0.24 mmol), Pd2(dba)3·CHCl3 (5 mol%), and L2 (10 mol%) in THF (2 mL) at 25 °C for 12 h. Isolated yield.

Spirooxindole is a significant heterocyclic compound known for its extensive biological activities and its potential applications in pharmaceutical lead discovery.27 Developed by Carreira,28a Xiao,28b–d Punniyamurthy,28e Du,28f and Miao,28g the (3 + 2)28a–f and (4 + 3)28g cycloadditions of spirovinylcyclopropane oxindoles (SVCPs) represent an efficient method for accessing three-dimensional spirooxindole architectures. However, the corresponding (3 + 3) cycloadditions of SVCPs have not been documented in the literature. Consequently, we conducted the (3 + 3) cycloaddition of BCB 1a and SVCP cis-5a under conditions A. Unfortunately, the desired cycloaddition products 6aa and 7aa were not detected. Instead, cis-5a was fully converted to its diastereomer trans-5a. After re-optimization of the reaction conditions (see Table S4 in the ESI†), the (3 + 3) cycloaddition reaction of 1a and cis-5a produced the cycloadduct 6aa and its diastereoisomer in 78% NMR yield, which contains two chiral centers, including a spiro quaternary carbon stereocenter, using Pd(PPh3)4/L4 in CH2Cl2 at 30 °C for 12 h (conditions B). When trans-5a was employed as the reaction substrate instead of cis-5a, nearly identical product distributions were observed under conditions B (Scheme 3). Scheme 4 illustrates the exploration of the reaction scope for the cross-dimerization reactions of BCBs with SVCPs, which generally exhibited moderate diastereoselectivity and acceptable regioselectivity.


image file: d5qo00460h-s3.tif
Scheme 3 Study of the (3 + 3) cycloaddition of 1a and 5a under conditions A and B.

image file: d5qo00460h-s4.tif
Scheme 4 Scope of the (3 + 3) cycloaddition between BCBs and SVCPs. Conditions B: 1 (0.20 mmol), cis-5 (0.24 mmol), Pd(PPh3)4 (10 mol%), and L4 (15 mol%) in CH2Cl2 (2 mL) at 30 °C for 12 h. Isolated yield of the major diastereomer of 6; values in parentheses are combined NMR yield of the diastereomers. The ratio r.r. represents the proportion of (3 + 3) product to (5 + 3) cycloadduct, as determined by crude 1H NMR spectroscopy.

The reactions employing various N-protected SVCP substrates, such as those bearing methyl, allyl, benzyl, and phenyl groups, proceeded smoothly, affording the corresponding major diastereomers of the cycloadducts in yields ranging from 42% to 57%. The method demonstrated broad substrate tolerance, being amenable to a series of SVCPs bearing different R3 substituents, including alkyl (e.g., 6ae and 6aj), methoxy (6af), halogen (e.g., 6ag and 6ai), and CF3 (6ah) groups at the C5–C7 positions of the oxindole moieties. The relative configuration of compound 6ai was determined via X-ray diffraction analysis.29 We subsequently investigated the reactivities of diverse BCBs in this reaction. The results indicate that, in addition to various phenyl-substituted BCB ketones (6ca–6da, 6la), BCB 1f possessing a thienyl group was identified as a suitable reaction partner (6fa).

The applicability of this methodology was further demonstrated by a scale-up experiment and the transformations of multifunctionalized vinylbicyclo[3.1.1]heptanes. When the reaction of 1a and 2a was conducted on a 1.0 mmol scale, the product 3aa was obtained in 80% yield, maintaining its efficiency. The hydrolysis of the diester groups in compound 3aa afforded the corresponding acid 8 in 76% yield. Additionally, subjecting diester 3aa to a reaction with LiCl in DMSO/H2O at 130 °C afforded the selective decarboxylation product 9 in satisfactory yield. The ester and ketone in 3aa were readily converted to alcohol (10) using LiAlH4. Upon reduction with NaBH4 in methanol, cycloadduct 6aa was converted to the secondary alcohol 11 in 85% yield, with a diastereomeric ratio of 85[thin space (1/6-em)]:[thin space (1/6-em)]15. Upon treatment of 6aa with DIBAL-H, both the lactam and carbonyl groups underwent reduction, affording compound 12 in good yield, and excellent d.r. value. Hydrogenation of the terminal olefin moiety of 6aa occurred smoothly using Pd/C as catalyst, affording product 13 in 85% yield. In the presence of 9-BBN, 6aa underwent hydroboration followed by oxidation, yielding the primary alcohol 14 in acceptable yield.

Based on prior research and experimental findings, a plausible mechanism is proposed, exemplified by the reaction involving BCB 1 and SVCP 5 (Scheme 5).17a,28 Initially, the selective oxidative addition of a Pd(0) complex to SVCP cis-5 generates the π-allylpalladium dipole intermediate INT-I. This intermediate INT-I can undergo intramolecular cyclization to form the thermodynamically stable diastereomer trans-5. Alternatively, BCB 1 can intercept intermediate INT-I through an intermolecular nucleophilic ring-opening reaction, leading to the formation of intermediate INT-II. Ultimately, intramolecular cyclization via path a yields the (3 + 3) cycloadduct 6 and its diastereoisomer, while concurrently releasing the Pd catalyst to complete the catalytic cycle. Alternatively, (5 + 3) cycloadduct 7 is generated through path b (Scheme 6).


image file: d5qo00460h-s5.tif
Scheme 5 Scale-up and derivatization.

image file: d5qo00460h-s6.tif
Scheme 6 Proposed mechanism.

Conclusions

In summary, we have developed a palladium-catalyzed formal cross-dimerization of BCBs and vinylcyclopropanes (VCPs) to synthesize pharmaceutically valuable all-carbon bicyclo[3.1.1]heptanes. This method addresses a significant gap in the synthesis of all-carbon BCHep scaffolds via polar (3 + 3) cycloaddition strategies, providing a modular and atom-economical approach under mild conditions. The reaction exhibits broad substrate scope, including spirovinylcyclopropane oxindoles (SVCPs), and demonstrates excellent functional group tolerance. Mechanistic insights suggest a Pd(0)-mediated pathway involving oxidative addition, nucleophilic ring-opening, and intramolecular regioselective cyclization. The synthetic utility of this strategy is further highlighted by scale-up experiments and versatile downstream transformations of the cycloadducts. We also demonstrate the achievability of an asymmetric cross-dimerization of BCB and VCP using a chiral palladium catalyst, as exemplified by the enantioselective formal (3 + 3) cycloaddition of 1a and 2a.30 This work not only enriches the toolbox for strain-release-driven cycloadditions but also opens new avenues for the synthesis of multi-functionalized BCHep frameworks with potential applications in medicinal chemistry.

Author contributions

X.-Y. G., Y. X., X. Z., Y.-J. L., and K.-J. W. performed all of the experiments and analysed their results. Y. X. and J.-J. F. wrote the manuscript. J.-J. F. conceived the catalytic system and directed the project.

Data availability

The data supporting this article have been included as part of the ESI.† All detailed procedures, characterization data and NMR spectra are available in the ESI.†

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

We are grateful to the National Natural Science Foundation of China (22471068) and Fundamental Research Funds for the Central Universities for financial support. The 1H, 13C NMR spectra, HRMS (ESI) and single crystal X-ray diffraction were performed at Analytical Instrumentation Center of Hunan University.

References

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Footnotes

† Electronic supplementary information (ESI) available. CCDC 2417046. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d5qo00460h
‡ These authors contributed equally.
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