Sc(OTf)3 catalyzed reaction of bicyclobutanes [1.1.0] with isatin to prepare cyclobutane indole ketone intermediate: functionalized cyclobutene indole ketone derivative

Sc(OTf)3 catalyzed reaction of bicyclobutanes [1.1.0] with isatin to prepare cyclobutane indole ketone intermediate: functionalized cyclobutene indole ketone derivative | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 18 December 2025 V1 Latest version Share on Sc(OTf)3 catalyzed reaction of bicyclobutanes [1.1.0] with isatin to prepare cyclobutane indole ketone intermediate: functionalized cyclobutene indole ketone derivative Authors : Ji-Feng Bai , Mostafa Sayed , Shiwei Luo , Pu-Sheng Wang , and Abudu Rexit Abulikemu [email protected] Authors Info & Affiliations https://doi.org/10.22541/au.176604154.46498137/v1 347 views 126 downloads Contents Abstract Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Herein, we report the synthesis of functionalized of bicyclo[1.1.0]butanes (BCBs) enabled by Sc(OTf) 3 catalyst through ring-opening of 1,3-disubstituted bicyclic butane and carbonyl compounds. Interestingly, substituted indoline-2,3-diones were found to be suitable substrates to react with bicyclobutanes under mild reaction conditions, where functionalized cyclobutene products with two consecutive centers successfully obtained in good to high yields (up to 82%). Cite this paper: Chin. J. Chem. 2025 , 43 , XXX—XXX. DOI: 10.1002/cjoc.70XXX Sc(OTf) 3 catalyzed reaction of bicyclobutanes [1.1.0] with isatin to prepare cyclobutane indole ketone intermediate: functionalized cyclobutene indole ketone derivative Ji-Feng Bai, a Mostafa Sayed, b , c Shi-Wei Luo, b Pu-Sheng Wang,* , b Abulikemu Abudu Rexit* , a a Department of Chemistry, Xinjiang Normal University, Urumqi 830054, China b Department of Chemistry, University of Science and Technology of China and Hefei National Research Center for Physical Sciences at the Microscale, Hefei 230026, China c Address Department of Chemistry, Faculty of Science, New Valley University, El-Kharja 72511, Egypt Supporting Information Placeholder Lewis acids | bicyclo[1.1.0]butanes | Alder-Ene | Strain release | Comprehensive Summary Herein, we report the synthesis of functionalized of bicyclo[1.1.0]butanes (BCBs) enabled by Sc(OTf) 3 catalyst through ring-opening of 1,3-disubstituted bicyclic butane and carbonyl compounds. Interestingly, substituted indoline-2,3-diones were found to be suitable substrates to react with bicyclobutanes under mild reaction conditions, where functionalized cyclobutene products with two consecutive centers successfully obtained in good to high yields (up to 82%). Background and Originality Content Cyclobutane–containing compounds exhibit notable biological activity and are commonly found in natural products and pharmaceuticals, also serving as key intermediates in organic synthesis (Scheme 1). [1] Incorporating cyclobutane fragments into bioactive compounds enhances structural rigidity, improving in vivo stability and selectivity. [2] Indolone scaffolds, found in many alkaloid natural products and drugs, show diverse biological activities influenced by the type and configuration of C3 substituents. [3] Constructing novel cyclobutane–indole frameworks by merging rigid cyclobutane units with pharmacologically active fragments offers a promising approach for discovering new bioactive compounds and advancing drug developmenty. Scheme 1 Bioactive drugs containing cyclobutane structure Although several methods exist for cyclobutane synthesis, such as [2+2] cycloaddition [4] , cyclization, [5] and ring contraction or expansion [6] –they often suffer from narrow substrate scope and limited applicability. An alternative approach involves functionalizing preformed four–membered carbocycles, including C–H activation and transformations of cyclobutanones and cyclobutenes. [7] This strategy allows the direct introduction of diverse functional groups into quaternary ring systems in a single step, using readily available starting materials. [8] Incorporating alkenyl groups further enhances synthetic flexibility, making the development of general, modular methods for densely functionalized cyclobutanes highly desirable. [9] As the smallest bicyclic hydrocarbon, bicyclic [1.1.0] butane (BCBs) is a ”spring-loaded” but stable molecule. [10] Strain–release–driven ring–opening reactions of bicyclo[1.1.0]butanes (BCBs) with nucleophiles, [11] radicals, [12] electrophiles, [13] and transition-metal catalysts [14] have recently gained widespread attention. These typically proceed via enol-active BCB intermediates to form bicyclo[n.1.1]alkanes (Scheme 2a). [15] However, fewer studies have focused on synthesizing cyclobutenes via this approach. [16] Notably, Feng et al. reported α-selective ring–opening of 1,3–disubstituted BCBs with alkyl radicals, yielding 1,1,3–trisubstituted cyclobutenes with broad scope and good regioselectivity, including single or contiguous all-carbon quaternary centers (Scheme 2b). [17] In 2023, Anderson et al. developed visible light–induced strain–release Alder–Ene reactions of BCBs with cyclopropenes to access cyclobutenes with high stereoselectivity via an asynchronous synergistic pathway (Scheme 2c). [18] More recently, Chang et al. introduced a metal–free umpolung Alder–ene reaction of BCBs with electron–deficient olefins, enabling atom- and step–economical cyclobutene synthesis (Scheme 2d). [19] Concurrently, Yang et al. reported a Pd–catalyzed switchable Alder–Ene/[2π+2σ] cycloaddition of vinyl–BCBs with α–ketoesters, affording cyclobutenes and 2–oxabicyclo[2.1.1]hexanes in good yields and excellent diastereoselectivities (Scheme 2e). [20] Scheme 2 Synthesis of cyclobutenes via ring-opening of BCBs and Our design When we were preparing this manuscript, Han Bo et al reported a Cu(I)/Au(I) –catalyzed chemodivergent reaction of bicyclobutanes[1.1.0] amides with azadienes, enabling access to two valuable product classes: bicyclo[2.1.1]hexanes and cyclobutenes. [21] Despite these advances, most cyclobutene–forming reactions from BCBs rely on radical pathways initiated by photoinduced or single–electron transfer processes. In contrast, Lewis acid–catalyzed strain–release transformations remain underexplored. Herein, we report a Sc(OTf)₃ –catalyzed ring–opening of 1,3–disubstituted BCBs with carbonyl compounds, enabling efficient synthesis of functionalized cyclobutenes. 2,3–Indolediones with various substituents serve as effective substrates, delivering products with two contiguous stereocenters under mild conditions. Mechanistic studies underscore the pivotal role of electronic effects in controlling reactivity and selectivity. Results and Discussion To commence our investigation of the reaction conditions, we selected isatin ( 1a ) and a BCB containing an acyl pyrazole group ( 2a ) as reaction components (Table 1). Gratifyingly, in the presence of 10 mol % of Sc(OTf) 3 as Lewis acid in THF solvent at 40 ℃ for 24 h, the reaction delivered the expected cyclobutene product 3aa in 42% yield along with the formation 16% of spiro–compound 4aa as byproduct (Table 1, entry 1). Investigation of different Lewis acid catalysts, such as Eu(OTF) 3 , Er(OTF) 3 , and Yb(OTF) 3 , showed lower yields of the desired product 3aa (entries 2–5), demonstrating the efficiency of Sc(OTf) 3 as Lewis catalyst. By adjusting the stoichiometric ratio of reactants 1a and 2a , the yield of the desired product 3aa increased to 55%, while the formation of the byproduct 4aa remained essentially unchanged (entry 6). Optimization of different solvents suggested that 1,4–dioxane is the optimal solvent, generating the desired product 3aa in 68 % yield (entries 7–11). Considering that BCBs are known to undergo isomerization under Lewis acid catalysis (a behavior also observed in our study), increasing the loading of 2a led to a significant improvement in the yield of 3aa , affording the product in a 72% isolated yield (entry 12). When the reaction temperature was reduced to 25 °C, the yield of 3aa decreased markedly, and the chemoselectivity significantly deteriorated (entry 13). Moreover, prolonging the reaction time also led to a diminished yield of 3aa (entry 14). Decreasing the loading of the Lewis acid catalyst also led to a reduced yield of 3aa , indicating that 10 mol% is the optimal catalyst loading (entry 15). Performing the reaction under high–concentration conditions resulted in a lower yield of 3aa (entry 16). Overall, the optimization studies revealed that the conditions in entry 12 are optimal for this transformation and were subsequently employed for the evaluation of the substrate scope. Table1 Optimization of the Reaction Conditions a 1 none 42 2.6/1 2 Eu(OTF) 3 instead of Sc(OTf)₃ 25 2.8/1 3 Yb(OTF) 3 instead of Sc(OTf)₃ 34 2.3/1 4 Er(OTF) 3 instead of Sc(OTf)₃ 17 2.8/1 5 Sn(OTF) 3 instead of Sc(OTf)₃ 5 0.3/1 6 d 1.5 equiv of 2a 55 3.2/1 7 CH 3 CN instead of THF 27 1.6/1 8 EA instead of THF 32 1.2/1 9 DCE instead of THF 30 2.7/1 10 MTBE instead of THF 21 1.5/1 11 1.4-dioxane instead of THF 68 3.8/1 12 e 2.0 equiv of 2a 90(82 c ) 4.6/1 13 25 °C instead of 40 °C 48 1.5/1 14 28 h instead of 24 h 63 3.2/1 15 5 mol% Sc(OTf) 3 40 2.7/1 16 0.125 M1.4-dioxane equiv of 0.1 M1.4-dioxane 53 2.7/1 a Reaction conditions: 2a (0.1 mmol, 1.0 equiv), 1a (0.15 mmol), Sc(OTf) 3 (10 mol%), THF (0.1 M), 40℃, N 2 , 24 h. b Yields were determined by 1 H NMR. c Isolated yields. d 2a (0.15 mmol,), 1a (0.1 mmol,1.0 equiv), Sc(OTf) 3 (10 mol%), THF (0.1 M), 40℃ N 2 , 24 h. e 2a (0.2 mmol), 1a (0.1 mmol,1.0 equiv.), Sc(OTf) 3 (10 mol%), 1.4-dioxane (0.1 M), 40℃ for 24 h. With the optimized reaction conditions in hand, we next explored the scope of this Lewis acid catalyzed reaction between isatin and 1,3–disubstituted BCBs (Scheme 3). Initially, a series of 1,3–disubstituted BCBs containing acylpyrazole moiety was investigated. BCBs with different groups in the phenyl substituent (including electron withdrawing and electron donating groups) were smoothly tolerated with isatin to furnish the corresponding products 3ab–3ah in good to high yields (up to 82%). Furthermore, BCBs with disubstituted groups in the phenyl substituent also exhibited a good reaction efficiency to deliver the corresponding products 3ai and 3aj . In addition to the previously examined 1,3–disubstituted BCBs bearing acyl pyrazole groups, 1,3–disubstituted BCBs containing 2–naphthyl, Weinreb amide, or ester functionalities also reacted smoothly with isatin. However, the majority of BCBs being isomerized into corresponding cyclobutene derivatives, the main product yield is very low. Therefore, the corresponding products could not be isolated under the standard reaction conditions. In contrast, monosubstituted BCBs failed to afford the desired products. The main reason may be that monosubstituted BCBs cannot form a stable coordination environment with Lewis acids (see Supporting Information for details). Next, isatin bearing either electron–donating or electron—withdrawing substituents on the aromatic ring were efficiently explored. It is gratifying that various isatin bearing different groups (such as F, Cl, Br, NO 2 ,CH 3 O etc.) at different positions in the benzene ring were proved to be appropriate candidates generating the desired products 3ak–3at in moderate yields. Moreover, the effect of electron–donating substituents at position C 5 on benzene ring was investigated. According to the previous reports, it was found that the presence of elec-tron-rich groups in the benzene ring of isatin, could provide better levels of yields compared to the electron-withdrawing groups at the same position. In our case we found that the existence of electron donating groups such as methyl and isopropyl exhibited a little effect on the reaction providing the corresponding products 3au–3av in moderate yield. Furthermore, isatin bearing two substituted groups in the aromatic core, was investigated in this reaction to deliver the products 3aw–3az in good yields. It is worth noting that the presence of two opposite electrical groups in the benzene core led to the formation of products 3aw–3ax in better yield than that of the same group nature like 3az . Installing different protecting groups such as Boc, Me, Ph and Bn turned out to be not effective, and the desired product couldn’t be detected which reflects the necessity of NH group in isatin derivative (see Supporting Information for details). To evaluate the synthetic utility of this ring-opening addition reaction, a scale–up experiment was successfully conducted, affording the desired product in 72% yield (Scheme 4a). Moreover, to gain insight into the reaction pathway and underlying mechanism, a series of mechanistic experiments were performed (Scheme 4b). First, the reaction proceeded smoothly in the presence of TEMPO, suggesting that a radical pathway is unlikely (Equation A). Second, under the standard conditions, product 3aa was found to decompose into cyclo-butene and isatin. However, when cyclobutene and isatin were subjected to the standard conditions, the formation of 3aa was not observed (Equation B). Furthermore, as shown in Equation D, treatment of 3aa under the standard conditions did not lead to the formation of the byproduct 4aa , ruling out its possible interconversion. Scheme 4 Scale-up synthesis and control experiments To explore the temporal evolution of product distribu-tion, we monitored the reaction progress at various time intervals (Scheme 5). No detectable product formation was observed within the first 10 minutes. After 30 minutes, com-pound 3aa and 4aa were isolated in 21% and 14% yields, respectively. At the 50–minute mark, a trace amount (approx-imately 1%) of 5aa was observed. As the reaction proceeded, a marked increase in the yields of both 3aa and 4aa was noted. Notably, the yield of 3aa peaked at 80% after 24 hours, while the yield of 4aa plateaued at around 20% beyond 8 hours of reaction time. However, when the reaction time exceeded 24 hours, a decline in the yield of 3aa was accom-panied by a significant increase in the amount of 5aa . These results, together with control experiments, suggest that pro-longed reaction time facilitates the decomposition of 3aa into 5aa and isatin. Scheme 5 Scale-up synthesis and control experiments To confirm the proposed reaction mechanism, theoreti-cal calculations were carried out. The computational results revealed that the transition states corresponding to 3aa and 4aa (TS–G) exhibit similar structural and energetic character-istics. These findings, in conjunction with previous reports, [22] support the proposed mechanistic pathway, as indicated in Scheme 6b. Initially, the BCB substrate coordinates with the Lewis acid catalyst to form intermediate I . This intermediate undergoes enolization to yield intermediate II . The nucleophilic intermediate II then attacks the carbonyl group of ketone substrate (isatin) potentially activated via coordination to the same Lewis acid, forming carbocation intermediate III . From here, intermediate III can follow two distinct pathways: in-tramolecular elimination leads to the formation of product 3aa , while an alternative oxygen–mediated nucleophilic attack results in the formation of 4aa . Scheme 6 DFT calculation and Proposed mechanism Conclusions In summary, we have developed a Lewis acid catalyzed Alder-Ene reaction of bicyclo[1.1.0]butanes and isatin. Under optimized conditions, a wide range of cyclobutene derivatives were successfully obtained in moderate yields. This method-ology features broad substrate scope, good functional group tolerance, and mild conditions. this approach can be used for the synthesis of novel cyclobutane indole frameworks with potential applications in the realm of drug synthesis. These findings highlight the potential of Lewis acid catalysis in accessing structurally distinct molecular scaffolds, facilitating the synthesis of cyclobutenes, a valuable framework in bioisosteric design and medicinal chemistry. Experimental To a flame-dried and N 2 -purged Schlenk tube were added isatin 1a (0.1mmol), 2a (0.2 mmol). This Schlenk tube were taken inside the glovebox, Sc(OTf) 3 (10mol%) and 1,4-dioxane(0.1M) were added to Schlenk tube. Removing the resulting reaction mixture from the glove box，Then resulting reaction mixture was subjected to stirring 40℃ for 24 hours. After 24 hours, removal of the solvents under reduced pressure. The crude mixture was purified by silica gel column chromatography to afford analytically pure products 3aa . Supporting Information The supporting information for this article is available on the WWW under https://doi.org/10.1002/cjoc.70XXX. Acknowledgement The authors acknowledge the financial support from National Natural Science Foundation of China (NO.22161046). References 1. (a)Hui,C. G.; Liu, Y.; Jiang, M.; Wu, P. Cyclobutane−containing scaffolds in bioactive small molecules. Trends Chem. 2022 , 4, 677−681; (b) van der Kolk, M. R.; Janssen, M.; Rutjes, F.; Blanco-Ania, D. Cyclobutanes in Small−Molecule Drug Candidates. ChemMedChem. 2022 , 17, e202200020. 2. (a) Levterov, V. V.; Panasyuk, Y.; Pivnytska, V. O.; Mykhailiuk, P. K. Water−Soluble Non−Classical Benzene Mimetics. Angew. Chem. Int. Ed. 2020 , 59, 7161−7167; (b)Denisenko, A.; Garbuz, P.; Voloshchuk, N. M.; Holota, Y.; Al-Maali, G.; Borysko, P.; Mykhailiuk, P. K. 2−Oxabicyclo[2.1.1]hexanes as saturated bioisosteres of the ortho−substituted phenyl ring. Nat. Chem. 2023 , 15, 1155−1163; (c) Dibchak, D.; Snisarenko, M.; Mishuk, A.; Shablykin, O.; Bortnichuk, L.; Klymenko−Ulianov, O.; Kheylik, Y.; Sadkova, I. V.; Rzepa, H. S.; Mykhailiuk, P. K. General Synthesis of 3−Azabicyclo[3.1.1]heptanes and Evaluation of Their Properties as Saturated Isosteres. Angew. Chem. Int. Ed. 2023 , 62, 1−8; (d) Levterov, V. V.; Panasiuk, Y.; Sahun, K.; Stashkevych, O.; Badlo, V.; Shablykin, O.; Sadkova, I.; Bortnichuk, L.; Klymenko−Ulianov, O.; Holota, Y.; Lachmann, L.; Borysko, P.; Horbatok, K.; Bodenchuk, I.; Bas, Y.; Dudenko, D.; Mykhailiuk, P. K. 2−Oxabicyclo[2.2.2]octane as a new bioisostere of the phenyl ring. Nat. Commun. 2023 , 14, 1−10. 3. For selected reviews on indoles and their derivatives, see: (a) Kochanowska−Karamyan, A. J.; Hamann,M. T. Marine Indole Alkaloids: Potential New Drug Leads for the Control of Depression and Anxiety. Chem. Rev. 2010 , 110, 8, 4489−4497; (b) Dalpozzo, R. Strategies for the asymmetric functionalization of indoles: an update. Chem. Soc. Rev. 2015 , 44, 742−778; (c) Ping, L.; Chung, D. S.; Bouffard, J.; Lee, S. g. Transition metal−catalyzed site− and regio−divergent C−H bond functionalization. Chem. Soc. Rev. 2017 , 46, 4299−4328; (d) Bariwal, J.; Voskressensky, L. G.; Van der Eycken, E. V. Recent advances in spirocyclization of indole derivatives. Chem. Soc. Rev . 2018 , 47, 3831−3848; (e) Li, L.; Chen, Z.; Zhang, X.; Jia, Y. Divergent Strategy in Natural Product Total Synthesis. Chem. Rev. 2018 , 118, 3752−3832; (f) Yang, Y.; Shi, Z. Regioselective direct arylation of indoles on the benzenoid moiety. Chem. Commun. 2018 , 54, 1676−1685; 4. (a) Xu, Y.; Conner, M. L.; Brown, M. K. Cyclobutane and Cyclobutene Synthesis: Catalytic Enantioselective [2+2] Cycloadditions. Angew. Chem. Int. Ed. 2015 , 54, 11918−11928; (b) Pagar, V. V.; RajanBabu, T. V. Tandem catalysis for asymmetric coupling of ethylene and enynes to functionalized cyclobutanes. Science. 2018 , 361, 68−72; (c) Brimioulle, R.; Bach, T. Enantioselective Lewis Acid Catalysis of Intramolecular Enone [2+2] Photocycloaddition Reactions. Science. 2013 , 342, 840−843. 5. (a) Du, J.; Skubi, K. L.; Schultz, D. M.; Yoon, T. P. A Dual−Catalysis Approach to Enantioselective [2+2] Photocycloadditions Using Visible Light. Science. 2014 , 344, 392−396; (b) García−Morales, C.; Ranieri, B.; Escofet, I.; López−Suarez, L.; Obradors, C.; Konovalov, A. I.; Echavarren, A. M. Enantioselective Synthesis of Cyclobutenes by Intermolecular [2+2] Cycloaddition with Non−C 2 Symmetric Digold Catalysts. J. Am. Chem. Soc. 2017, 139, 13628−13631. 6. (a) Wang, M. Y. ; Bruno,N. C. ; Placeres, Á. L. ; Zhu S. L. ; Buchwald,S. L. Enantioselective Synthesis of Carbo− and Heterocycles through a CuH−Catalyzed Hydroalkylation Approach. J. Am. Chem. Soc. 2015 , 137, 10524−10527; (b) Kim, D. K.; Riedel, J.; Kim, R. S.; Dong, V. M., Cobalt Catalysis for Enantioselective Cyclobutanone Construction. J. Am. Chem. Soc. 2017 , 139, 10208−10211. 7. Lee-Ruff, E.; Mladenova, G. Enantiomerically Pure Cyclobutane Derivatives and Their Use in Organic Synthesis. Chem. Rev. 2003 , 103, 1449−1484. 8. (a) Audisio, D.; Gopakumar, G.; Xie, L. G.; Alves, L. G.; Wirtz, C.; Martins, A. M.; Thiel, W.; Farès, C.; Maulide, N. Palladium-Catalyzed Allylic Substitution at Four−Membered−Ring Systems: Formation of η1−Allyl Complexes and Electrocyclic Ring Opening. Angew. Chem. Int. Ed. 2013 , 52, 6313−6316; (b) Zhong, C. X.; Huang, Y. C.; Zhang, H. C.; Zhou, Q.; Liu, Y.; Lu, P. Enantioselective Synthesis of 3−Substituted Cyclobutenes by Catalytic Conjugate Addition/Trapping Strategies. Angew. Chem. Int. Ed. 2020 , 59, 2750−2754. 9. Xiao, K. J.; Lin, D. W.; Miura, M.; Zhu, R. Y.; Gong, W.; Wasa, M.; Yu, J. Q. Palladium(II) −Catalyzed Enantioselective C(sp3)–H Activation Using a Chiral Hydroxamic Acid Ligand. J. Am. Chem. Soc. 2014 , 136, 8138−8142. 10. For selected reviews on bicyclo[1.1.0]butanes (BCBs), see: (a) Walczak, M. A. A.; Krainz, T.; Wipf, P., Ring-Strain-Enabled Reaction Discovery: New Heterocycles from Bicyclo[1.1.0]butanes. Acc. Chem. Res. 2015 , 48, 1149-1158; (b)Turkowska, J.; Durka, J.; Gryko, D., Strain release – an old tool for new transformations. Chem. Commun. 2020 , 56, 5718-5734; (c) Kelly, C. B.; Milligan, J. A.; Tilley, L. J.; Sodano, T. M., Bicyclobutanes: from curiosities to versatile reagents and covalent warheads. Chem. Sci. 2022 , 13, 11721-11737; (d) Golfmann, M.; Walker, J. C. L., Bicyclobutanes as unusual building blocks for complexity generation in organic synthesis. Commun. Chem. 2023 , 6, 9; (e) Meiboom, S.; Snyder, L. C., Nuclear magnetic resonance spectra in liquid crystals and molecular structure. Acc. Chem. Res. 1971 , 4, 81-87; (f) Hu, Q. Q.; Chen, J.; Yang, Y.; Yang, H.; Zhou, L. Strain-release transformations of bicyclo[1.1.0]butanes and [1.1.1]propellanes. Tetrahedron Chem 2024 , 9, 100070. 11. (a) Gianatassio,R.; Lopchuk, J. M.; Wang, J. ; Pan, C. M. ; Malins, L. R.; Prieto,L. T.; Brandt, A.; Collins,M. R.; Gallego,G. M.; Sach, N. W.; Spangler, J. E.; Zhu H.; Zhu, J. J.; Baran,P. S. Strain−release amination. Science. 2016 , 351, 241–246; (b) Lopchuk, J. M.; Fjelbye, K.; Kawamata, Y.; Malins, L. R.; Pan, C. M.; Gianatassio, R.; Wang, J.; Prieto, L.; Bradow, J.; Brandt, T. A.; Collins, M. R.; Elleraas, J.; Ewanicki, J.; Farrell, W.; Fadeyi, O. O.; Gallego, G. M.; Mousseau, J. J.; Oliver, R.; Sach, N. W.; Smith, J. K.; Spangler, J. E.; Zhu, H.; Zhu, J.; Baran, P. S. Strain−Release Heteroatom Functionalization: Development, Scope, and Stereospecificity. J. Am. Chem. Soc. 2017 , 139, 3209−3226; (c) Tokunaga, K.; Sato, M.; Kuwata, K.; Miura, C.; Fuchida, H.; Matsunaga, N.; Koyanagi, S.; Ohdo, S.; Shindo, N.; Ojida, A. Bicyclobutane Carboxylic Amide as a Cysteine−Directed Strained Electrophile for Selective Targeting of Proteins. J. Am. Chem. Soc. 2020 , 142, 18522−18531. 12. (a) William R. M.; Taylor K.G.; Müller P.; Stan S.; Zalman L.F. The synthesis and some reactions of 1,2,2−trimethylbicyclobutane, Tetrahedron Lett. 1970, 11, 2365—2368. (b) Dauben, W. G.; Smith, J. H.; Saltiel, J. Mass spectra of cyclobutyl and cyclopropylcarbinyl methyl ethers and the methanolysis of bicyclobutane. J. Org. Chem .1969, 34, 261-266. 13. Wu, X. Y.; Hao, W.; Ye, K. Y.; Jiang, B. Y.; Pombar, G.; Song, Z. D.; Lin, S. Ti−Catalyzed Radical Alkylation of Secondary and Tertiary Alkyl Chlorides Using Michael Acceptors. J. Am. Chem. Soc. 2018 , 140, 14836−14843. 14. (a) Ociepa, M.; Wierzba, A. J.; Turkowska, J.; Gryko, D. Polarity−Reversal Strategy for the Functionalization of Electrophilic Strained Molecules via Light−Driven Cobalt Catalysis. J. Am. Chem. Soc. 2020 , 142, 5355−5361; (b) Noyori, R. On the nature of carbenoids generated from bicyclo[1.1.0]butanes and transition metal complexes. Tetrahedron Lett. 1973 , 14, 1691−1696. 15. (a)Tang, S. Y.; Wang, Z. J.; Wu, J. J.; Xing, Z. X.; Du, Z. Y.; Huang, H. M. Photocatalytic synthesis of 2−oxabicyclo[2.1.1]hexanes: cobalt−enhanced efficiency. Chem. Sci. 2025 , 16, 11908−11917; (b) Liao, H. J.; Dong, J. Y.; Zhou, X. C.; Jiang, Q.; Lv, Z. S.; Lei, F.; Xue, D. Silver−mediated formal [4π+2σ] cycloaddition reactions of bicyclobutanes with nitrile imines: access to 2,3−diazobicyclo[3.1.1]heptenes. Chem. Sci. 2025 , 16, 4654−4660; (C) Zhu, S. J.; Tian, X.; Li, S. W. Intermolecular Formal [2π+2σ] Cycloaddition of Enol Silyl Ethers with Bicyclo[1.1.0]butanes Promoted by Lewis Acids. Org. Lett. 2024 , 26, 30, 6309−6313; (d) Zhou, J. L.; Xiao, Y.; He, L.; Gao, X. Y.; Yang, X. C.; Wu, W. B.; Wang, G.; Zhang, J.; Feng, J. J. Palladium−Catalyzed Ligand−Controlled Switchable Hetero− (5+3) / Enantioselective [2σ+2σ] Cycloadditions of Bicyclobutanes with Vinyl Oxiranes. J. Am. Chem. Soc. 2024 , 146, 19621−19628; (e) Zheng, L.; Yang, Y. M.; Liu, Z. P.; Wang, W.; Liang, W. J.; Jiang, H. L.; Yang, L.; Lin, C.; Su, W.; Xiao, J. A. Palladium−Catalyzed Strain−Enabled [2π + 2σ] Cycloadditions of Vinyl Bicyclo[1.1.0]butanes with Methyleneindolinones. Org. Lett. 2024 , 27, 229−234; (f) Zhang, X. G.; Zhou, Z. Y.; Li, J. X.; Chen, J. J.; Zhou, Q. L. Copper−Catalyzed Enantioselective [4π + 2σ] Cycloaddition of Bicyclobutanes with Nitrones. J. Am. Chem. Soc. 2024 , 146, 27274−27281; (g) Zhang, J.; Su, J. Y.; Zheng, H.; Li, H.; Deng, W. P. Eu(OTf) 3 −Catalyzed Formal Dipolar [4π+2σ] Cycloaddition of Bicyclo[1.1.0]butanes with Nitrones: Access to Polysubstituted 2−Oxa−3−azabicyclo[3.1.1]heptanes. Angew. Chem. Int. Ed. 2024 , 63, e202318476; (h)Xiao, Y. J.; Wu, F.; Tang, L.; Zhang, X.; Wei, M. R.; Wang, G. Q.; Feng, J. J. Divergent Synthesis of Sulfur−Containing Bridged Cyclobutanes by Lewis Acid Catalyzed Formal Cycloadditions of Pyridinium 1,4−Zwitterionic Thiolates and Bicyclobutanes. Angew. Chem.Int. Ed. 2024 ,63, e202408578; (i) Wu, W. B.; Xu, B.; Yang, X. C.; Wu, F.; He, H. X.; Zhang, X.; Feng, J. J. Enantioselective formal (3 + 3) cycloaddition of bicyclobutanes with nitrones enabled by asymmetric Lewis acid catalysis. Nat Commun 15, 15 ( 2024 ). https://doi.org/10.1038/s41467-023-44578-0; (j) Wu, F.; Wu, W. B.; Xiao, Y. J.; Li, Z. X.; Tang, L.; He, H. X.; Yang, X. C.; Wang, J. J.; Cai, Y.; Xu, T. T.; Tao, J. H.; Wang, G.; Feng, J. J. Zinc−Catalyzed Enantioselective Formal (3+2) Cycloadditions of Bicyclobutanes with Imines: Catalytic Asymmetric Synthesis of Azabicyclo[2.1.1]hexanes. Angew. Chem.Int. Ed. 2024 , 63, e202406548; (k) Wang, X. H.; Gao, R. K; Li, X. X. Catalytic Asymmetric Construction of Chiral Polysubstituted 3-−Azabicyclo[3.1.1]heptanes by Copper−Catalyzed Stereoselective Formal [4π+2σ] Cycloaddition. J. Am. Chem. Soc. 2024 , 146, 21069-21077; (l)Ren, H. S.; Li, T. X.; Xing, J. P.; Li, Z. Y.; Zhang, Y. X.; Yu, X. H.; Zheng, J. Ti−Catalyzed Formal [2π + 2σ] Cycloadditions of Bicyclo[1.1.0]butanes with 2−Azadienes to Access Aminobicyclo[2.1.1]hexanes. Org. Lett. 2024 , 26, 1745−1750; (m) Qin, T. Z.; He, M. Y.; Zi, W. W. Palladium−catalysed [2σ + 2π] cycloaddition reactions of bicyclo[1.1.0]butanes with aldehydes. Nat. Synth. 2024 , 4, 124−133; (n) Lin, Z. R.; Ren, H. S.; Lin, X. B.; Yu, X. H.; Zheng, J. Synthesis of Azabicyclo[3.1.1]heptenes Enabled by Catalyst−Controlled Annulations of Bicyclo[1.1.0]butanes with Vinyl Azides. J. Am. Chem. Soc. 2024 , 146, 18565−18575; (o)Liang, Y. J.; Nematswerani, R.; Daniliuc, C. G.; Glorius, F. Silver−Enabled Cycloaddition of Bicyclobutanes with Isocyanides for the Synthesis of Polysubstituted 3−Azabicyclo[3.1.1]heptanes. Angew. Chem. Int. Ed. 2024 , 63, e202402730; (p)Li, T. X.; Wang, Y.; Xu, Y.; Ren, H. S.; Lin, Z. R.; Li, Z. Y.; Zheng, J. Zwitterionic π−Allyl−Pd Species Enabled [2σ+2π] Cycloaddition Reactions of Vinylbicyclo[1.1.0]butanes (VBCBs) with Alkenes, Carbonyls, and Imines. ACS Catalysis. 2024 , 14, 18799-18809; (q)Fu, Q. Q.; Cao, S. S.; Wang, J. H.; Lv, XX.; Wang, H.; Zhao, X. W.; Jiang, Z. Y. Enantioselective [2π+2σ] Cycloadditions of Bicyclo[1.1.0]butanes with Vinylazaarenes through Asymmetric Photoredox Catalysis. J. Am. Chem. Soc. 2024 , 146, 8372−8380; (r)Dutta, S.; Lee, D.; Ozols, K.; Daniliuc, C. G.; Shintani, R.; Glorius, F. Photoredox−Enabled Dearomative [2π + 2σ] Cycloaddition of Phenols. J. Am. Chem. Soc. 2024 , 146, 2789−2797; (s) Deswal, S.; Guin, A.; Biju, A. T. Lewis Acid-Catalyzed Unusual (4+3) Annulation of para−Quinone Methides with Bicyclobutanes: Access to Oxabicyclo[4.1.1]Octanes. Angew. Chem. Int. Ed. 2024 , 63, e202408610; (t) Deswal, S.; Das, R. C.; Sarkar, D.; Biju, A. T., Lewis Acid-Catalyzed 1,3-Dipolar Cycloaddition of Bicyclobutanes with Isatogens: Access to Tetracyclic 2-Oxa-3-azabicyclo[3.1.1]heptanes. JACS Au . 2025, 5, 136-143;(u) Hu, Q. Q.; Geng, Z. X.; Bai, X.; Chen, J.; Zhou, L., Lewis Acid Catalyzed Divergent Reaction of Bicyclo[1.1.0]Butanes With Quinones for the Synthesis of Diverse Polycyclic Molecules. Angew. Chem. Int. Ed. 2025 , 64. e202506228. 16. Lin, S. L.; Chen, Y. H.; Liu, H. H.; Xiang, S. H.; Tan, B. Enantioselective Synthesis of Chiral Cyclobutenes Enabled by Brønsted Acid-Catalyzed Isomerization of BCBs. J. Am. Chem. Soc. 2023 , 145, 21152-21158. 17. Xiao, Y.; Xu, T. T.; Zhou, J. L.; Wu, F.; Tang, L.; Liu, R. Y.; Wu, W. B.; Feng, J. J. Photochemical α−selective radical ring−opening reactions of 1,3−disubstituted acyl bicyclobutanes with alkyl halides: modular access to functionalized cyclobutenes. Chem. Sci. 2023 , 14, 13060−13066 . 18. Dasgupta, A.; Bhattacharjee, S.; Tong, Z. X.; Guin, A.; McNamee, R. E.; Christensen, K. E.; Biju, A. T.; Anderson, E. A., Stereoselective Alder-Ene Reactions of Bicyclo[1.1.0]butanes: Facile Synthesis of Cyclopropyl− and Aryl− Substituted Cyclobutenes. J. Am. Chem. Soc. 2024 , 146, 1196−1203. 19. Bai, D. C.; Guo, X. L.; Wang, X. H.; Xu, W. J.; Cheng, R. S.; Wei, D. H.; Lan, Y.; Chang, J. B. Umpolung reactivity of strained C–C σ−bonds without transition-metal catalysis. Nat .Commun. 2024 , 15, 2833. 20. Wang, W.; Xiao, J. A.; Zheng, L.; Liang, W. J.; Yang, L.; Huang, X. X.; Lin, C.; Chen, K.; Su, W.; Yang, H. Structure-Dependent, Switchable Alder-Ene/[2π+2σ] Cycloadditions of Vinyl Bicyclo[1.1.0]butanes with α-Ketoesters Enabled by Palladium Catalysis. Org. Lett. 2024 , 26, 10645–10650. 21. Lu, R.; Yang, J.; Jiang, J. M.; Wang, J.; Huang, W.; Peng, C.; Zhan, G.; Han, B. Catalyst-Controlled Divergent Synthesis of Bicyclo[2.1.1]hexanes and Cyclobutenes: The Unique Effect of Au(I). JACS Au. 2025 , 5, 2738−27480. 22. Li, M. M.; Xiao, T. F.; Geng, Y. X.; Xu, G. Q.; Xu, P. F., Precise Modulation of BCB Reactive Sites via Lewis/Brønsted Acid Switching for the Synthesis of Spirocycles and Bridged Frameworks. Org. Lett. 2025 , 27, 7633−7638. Manuscript received: XXXX, 2024 Manuscript revised: XXXX, 2024 Manuscript accepted: XXXX, 2024 Version of record online: XXXX, 2024 Left to Right: Ji-Feng Bai, Mostafa Sayed, Shi-Wei Luo, Pu-Sheng Wang, Abulikemu Abudu Rexit You will be invited to submit the most recent photos of all the authors upon acceptance of the manuscript Information & Authors Information Version history V1 Version 1 18 December 2025 Copyright This work is licensed under a Non Exclusive No Reuse License. Keywords alder-ene bicyclo[1.1.0]butanes lewis acids strain release Authors Affiliations Ji-Feng Bai Xinjiang Normal University View all articles by this author Mostafa Sayed New Valley University View all articles by this author Shiwei Luo University of Science and Technology of China Hefei National Research Center for Microscale Physical Sciences View all articles by this author Pu-Sheng Wang University of Science and Technology of China Hefei National Research Center for Microscale Physical Sciences View all articles by this author Abudu Rexit Abulikemu [email protected] Xinjiang Normal University View all articles by this author Metrics & Citations Metrics Article Usage 347 views 126 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Ji-Feng Bai, Mostafa Sayed, Shiwei Luo, et al. Sc(OTf)3 catalyzed reaction of bicyclobutanes [1.1.0] with isatin to prepare cyclobutane indole ketone intermediate: functionalized cyclobutene indole ketone derivative. Authorea . 18 December 2025. DOI: https://doi.org/10.22541/au.176604154.46498137/v1 If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download. For more information or tips please see 'Downloading to a citation manager' in the Help menu . Format Please select one from the list RIS (ProCite, Reference Manager) EndNote BibTex Medlars RefWorks Direct import Tips for downloading citations document.getElementById('citMgrHelpLink').addEventListener('click', function() { popupHelp(this.href); return false; }); $(".js__slcInclude").on("change", function(e){ if ($(this).val() == 'refworks') $('#direct').prop("checked", false); $('#direct').prop("disabled", ($(this).val() == 'refworks')); }); View Options View options PDF View PDF Figures Tables Media Share Share Share article link Copy Link Copied! Copying failed. Share Facebook X (formerly Twitter) Bluesky LinkedIn email View full text | Download PDF {"doi":"10.22541/au.176604154.46498137/v1","type":"Article"} Now Reading: Share Figures Tables Close figure viewer Back to article Figure title goes here Change zoom level Go to figure location within the article Download figure Toggle share panel Toggle share panel Share Toggle information panel Toggle information panel Go to previous graphic Go to next graphic Go to previous table Go to next table All figures All tables View all material View all material xrefBack.goTo xrefBack.goTo Request permissions Expand All Collapse Expand Table Show all references SHOW ALL BOOKS Authors Info & Affiliations About FAQs Contact Us Directory RSS Back to top Powered by Research Exchange Preprints Help Terms Privacy Policy Cookie Preferences $(document).ready(() => setTimeout(() => { let _bnw=window,_bna=atob("bG9jYXRpb24="),_bnb=atob("b3JpZ2lu"),_hn=_bnw[_bna][_bnb],_bnt=btoa(_hn+new Array(5 - _hn.length % 4).join(" ")); $.get("/resource/lodash?t="+_bnt); },4000)); (function(){function c(){var b=a.contentDocument||a.contentWindow.document;if(b){var d=b.createElement('script');d.innerHTML="window.__CF$cv$params={r:'a00d6441f8cc0708',t:'MTc3OTYzNzE1MQ=='};var a=document.createElement('script');a.src='/cdn-cgi/challenge-platform/scripts/jsd/main.js';document.getElementsByTagName('head')[0].appendChild(a);";b.getElementsByTagName('head')[0].appendChild(d)}}if(document.body){var a=document.createElement('iframe');a.height=1;a.width=1;a.style.position='absolute';a.style.top=0;a.style.left=0;a.style.border='none';a.style.visibility='hidden';document.body.appendChild(a);if('loading'!==document.readyState)c();else if(window.addEventListener)document.addEventListener('DOMContentLoaded',c);else{var e=document.onreadystatechange||function(){};document.onreadystatechange=function(b){e(b);'loading'!==document.readyState&&(document.onreadystatechange=e,c())}}}})();