Solvent-controlled chemo-selective synthesis of 2-amino-3-(3-(5-hydroxy-1H-pyrazol-4-yl)-2-oxoindolin-3-yl)naphthalene-1,4-diones and 1H-spiro[benzo[6,7]chromeno[2,3-c]pyrazole-4,3'-indoline]-2',5,10-triones

Solvent-controlled chemo-selective synthesis of 2-amino-3-(3-(5-hydroxy-1H-pyrazol-4-yl)-2-oxoindolin-3-yl)naphthalene-1,4-diones and 1H-spiro[benzo[6,7]chromeno[2,3-c]pyrazole-4,3'-indoline]-2',5,10-triones | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Solvent-controlled chemo-selective synthesis of 2-amino-3-(3-(5-hydroxy-1 H -pyrazol-4-yl)-2-oxoindolin-3-yl)naphthalene-1,4-diones and 1 H -spiro[benzo[6,7]chromeno[2,3- c ]pyrazole-4,3'-indoline]-2',5,10-triones Hamed Pezhman, Mohammad Reza Mohammadizadeh, Dariush Saberi This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6693319/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 30 Oct, 2025 Read the published version in Scientific Reports → Version 1 posted 10 You are reading this latest preprint version Abstract In this work, isatins, 2-amino-1,4-naphthoquinone, and 5-methyl-2-phenylpyrazolone reacted to create new derivatives of spiro and non-spiroindolin-2-ones (oxindoles) bearing 2-aminonaphthoquinone and pyrazolone substituents. The solvent regulated the pathway to the aforementioned chemicals. The later compounds were produced in an acetic acid solvent under reflux conditions, whereas the former compounds were made in an ethanol solvent. Nineteen novel oxindole derivatives were synthesized in high yields, and the structures were undoubtedly identified using their NMR data as well as X-ray analysis. Physical sciences/Chemistry Physical sciences/Chemistry/Organic chemistry Physical sciences/Chemistry/Synthesis Isatins 2-Aminonaphthalene-1 4-dione Pyrazolone Spiro compounds Chromeno-oxindoles. Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 1. Introduction Indolin-2-one (2-oxindole) derivatives are very important nitrogen-containing heterocyclic compounds that are of great value in the fields of chemistry and medicinal chemistry due to their unique structure. The possibility of placing various potentially biologically active cyclic and noncyclic moieties on C-3 has given these compounds additional value. However, the groups attached to C-3 may be either non-spiro 1 or spiro 2 (Figure 1). It's interesting to note that different biological actions are displayed by spiro and non-spiroindolin-2-ones. The biological significance of indolin-2-ones has been reported in a number of ways, including anti-cancer, 3 antimicrobial, 4 antifungal, 5 antioxidant, 6 anticonvulsant, 7 anti-inflammatory, 8 anti-tubercular, 8 anti-proliferative activity, 9 antiviral, 10 antimalarial, 11 and anti-HIV-1 12 properties. Therefore, the preparation of new derivatives of indolin-2-ones and the development of methods for the preparation of these compounds continue to be active areas of research in organic chemistry and medicinal chemistry. Although indolin-2-ones can be prepared by various routes, 13 perhaps the most important and widely used method for preparing these compounds is the use of isatin derivatives. A cursory review indicates that more than 3240 papers have been published since the beginning of the present millennium on the two- or multi-component synthesis of various indolin-2-one derivatives using isatins in the presence of numerous nucleophilic compounds and under various conditions. Most of the reported works have been frequently reviewed. 14 Such a variety of biological activities, a large number of studies, and a large volume of reports indicate the extraordinary importance of indoline-2-ones. Therefore, the development of chemical methods that can make the production and conversion of these compounds more practical and convenient remains of great importance. The study of condensation reactions of various nucleophiles on C-3 of isatins indicates that the desired products largely depend on the nitrogen substitution 15 and particularly on the reaction conditions. The diastereoselectively switchable enantioselective Mannich reaction of isatin imines with hydroxyacetone, 16 solvent-controlled chemoselective Friedel–Crafts reactions between isatins and indoles, 17 chemoselective synthesis of spirocyclopropyl and spiropyrazoline oxindoles, 18 solvent-controlled stereo-divergent synthesis of spirocyclopentaneoxindoles, 19 enantiodivergent Friedel-Crafts reaction of 1-naphthols with arylsulfonyl indoles switched by solvents, 20 medium dependent isatin based synthesis of spirooxindoles fused with pyrazolo-tetrahydropyridinone and coumarin-dihydropyridine-pyrazole tetracycles under microwave irradiation conditions, 21 chemo-divergent formation of 1,4-benzoxazepinones and 1,3-benzoxazinones, 22 solvent-controlled access to 3-spirocyclopropyl-2-oxindoles and pyrazoloquinazolinone scaffolds, 23 α-chymotrypsin catalyzed solvent-controlled synthesis of 3-hydroxy-oxindoles/3,3-bis(indol-3-yl)indolin-2-ones, 24 are some methods that have been reported in this area. In this line of research and in continuation of our effort to develop new methods for the synthesis of heterocyclic organic compounds, 25 herein, we report the results of our investigations on the synthesis of oxindoles having 2-amino-1,4-naphthoquinone and 5-methyl-2-phenylpyrazolone substituents ( 4 ) and 1 H -spiro[benzo[6,7]chromeno[2,3- c ]pyrazole-4,3'-indoline]-2',5,10-triones ( 5 ), under switchable solvent conditions. While the three-component reaction of isatins ( 1 ), 2-aminonaphtoquinone ( 2 ), and 5-methyl-2-phenylpyrazolone ( 3 ) in ethanol under reflux conditions produced oxindoles ( 4 ), changing the solvent to acetic acid led to spiro compounds ( 5 ) which were isolated as main products from the reaction mixture (Figure 2). 2. Results and Discussion Our initial studies involved performing the reaction between N -ethylisatin ( 1a ), 2-amino-1,4-naphthoquinone ( 2 ), and 5-methyl-2-phenylpyrazolone ( 3) , under various conditions shown in Table 1, toward synthesis of new oxindole ( 4a ). Solvent screening experiment to identify the best solvent for the reaction showed that the ethanol has the highest yield in a shorter time compared to the other solvents like acetonitrile, methanol, tetrahydrofuran, and water. This choice is justified because ethanol is often preferred in organic synthesis due to its moderate polarity, safety profile, and ability to dissolve a wide range of compounds (Table 1, entries 1-5). All reactions were carried out under reflux conditions of solvents. A decrease in reaction efficiency at lower temperatures suggests that the reaction rate is temperature-dependent. This finding emphasizes the importance of controlling reaction temperature to maintain optimal efficiency (Table 1, entries 6-8). With optimal reaction conditions in hand and the availability of isatin derivatives, several derivatives of 2-amino-3-(3-(5-hydroxy-1 H -pyrazol-4-yl)-2-oxoindolin-3-yl)naphthalene-1,4-diones ( 4 ) were synthesized, the structures of which are shown in Table 2. As shown in this table, despite the presence of various substituents, including ethyl, propyl, and naphthyl methyl, as well as benzyl derivatives with either electron-donating or electron-withdrawing groups, attached to the nitrogen atom of isatin, there was no variation in the reaction rate. All reactions produced the corresponding products with good efficiency. In addition, the 1,1'-(propane-1,3-diyl)bis(indoline-2,3-dione) ( 1k ) was also subjected to the reaction conditions and the corresponding oxindole ( 4k ) was obtained with an efficiency of 86%. The spectral data analysis of products ( 4 ) not only confirms the proposed structure but also reveals an intriguing phenomenon: due to the presence of the pyrazolone moiety, these compounds exist in a dynamic equilibrium between their enol and keto forms when dissolved in an NMR solvent (Figure 3). For instance, in the 1 H‒NMR spectrum of compound ( 4a) , the ethyl group protons appear as a triplet for the methyl protons at δ = 1.28, along with overlapping multiplets for the methylene group in the range of δ = 3.64-3.93, with integrals corresponding to 3H and 2H, respectively. However, the methyl protons of the pyrazolone ring substituent exhibit two distinct peaks at chemical shifts of 1.40 and 2.22 ppm, in a ratio of 2.0:1.0, with a total integral of 3H. The NH 2 protons and those associated with the enol and keto forms of the pyrazolone ring present a broad overlapping pattern in the range of δ = 6.06-6.90, with an integral of 2H, alongside a broad peak between 10.0 and 11.0 ppm, integrating to 1H. Remarkably, the addition of D 2 O results in the disappearance of the broad peak at 10.11-11.29 ppm, while the broad signals around 6 ppm are simplified into a broad peak integrating to 1H. Notably, the methyl protons of the pyrazolone ring continue to manifest as two separate peaks at δ = 1.37 and δ = 2.19 in a 2:1 ratio, with a total integral of 3H. The predicted structure of compounds ( 4 ) was undoubtedly stablished when the X-ray crystallographic analysis of product ( 4c ) was successfully recorded from its appropriate single crystal (Figure 4). As shown in Figure 3, the compound ( 4c ) crystallized in its more stable enol form, which features a diazole ring exhibiting aromatic stability. Further studies on the reaction showed that when the reaction is carried out in acetic acid solvent, new products from the spirochromeno oxindoles family are formed (Figure 2, products ( 5 )). For this purpose, several N -substituted isatins ( 1 ) were subjected to the reaction with 2-amino-1,4-naphthoquinone ( 2 ) in the presence of 5-methyl-2-phenylpyrazolone ( 3 ), and the corresponding 1 H -spiro[benzo[6,7]chromeno[2,3- c ]pyrazole-4,3'-indoline]-2',5,10-triones ( 5a-h ) were obtained in good to excellent yields. The results are collected in Table 3. The close match between the NMR spectra of the compounds formed under the new conditions ( 5 ) and those of products ( 4 ) strongly confirms the formation of 1 H -spiro[benzo[6,7]chromeno[2,3- c ]pyrazole-4,3'-indoline]-2',5,10-triones ( 5 ). While the peaks corresponding to the amine protons and the enol/keto protons of the pyrazolone moiety (specifically the broad signals at δ = 6.0-6.9 and 10.0-11.0 ppm) have disappeared, dynamic equilibrium-related effects—such as peak broadening or multiplicity arising from the enol-keto tautomerism—are no longer observed. Instead, each proton group now exhibits only a single peak corresponding to its specific environment. Finally, the predicted structure of compounds ( 5 ) was unequivocally confirmed when X-ray crystallographic analysis of product ( 5a ) was successfully recorded from its single crystal, as shown in Figure 5. As evident from the results in Tables 2 and 3, the reactions proceeded efficiently to produce products ( 4 ) and spirooxindoles ( 5 ) using various isatin derivatives bearing different substituents on both the aromatic ring and nitrogen atom. The reactions typically completed in 4 hours, yielding the products with good to excellent yields and high purity through simple filtration followed by washing with ethanol. A plausible mechanism is presented for the one-pot three-component synthesis of 2-amino-3-(3-(5-hydroxy-1 H -pyrazol-4-yl)-2-oxoindolin-3-yl)naphthalene-1,4-diones ( 4 ) and 1 H -spiro[benzo[6,7]chromeno[2,3- c ]pyrazole-4,3'-indoline]-2',5,10-triones ( 5 ) (Figure 6). A condensation reaction between isatin ( 1 ) and 2-amino-1,4-naphthoquinone ( 2 ) proceeds via intermediates ( A ) and ( B ), leading to the formation of intermediate ( C ). This intermediate is then attacked by the enolic form of 5-methyl-2-phenylpyrazolone ( 3 ), yielding products ( 4 ). However, under acidic conditions, protonation of the amino group in intermediate ( C ) generates intermediate ( D ), which facilitates nucleophilic attack by the pyrazolone hydroxyl group. This is followed by ammonia elimination to yield products ( 5 ). 3. Conclusion In conclusion, some new derivatives of spiro and non-spirooxindoles were synthesized up to 96% yields from a novel and simple one-pot procedure via the solvent-controlled reaction between isatin derivatives, 2-amino-1,4-naphthoquinone and 5-methyl-2-phenylpyrazolone. The choice of solvent significantly influenced the reaction outcome, with acetic acid favoring the formation of spiro oxindoles and ethanol leading to non-spiro ones. High yields, facile work-up, operational simplicity, and the absence of extraction/chromatography steps are key advantages of these pathways to synthesis of new spiro and non-spirooxindole derivatives. 4. Experimental 4.1. General information: All reagents were purchased from commercial suppliers and used without further purification. All experiments were carried out under air atmosphere. Column chromatography was carried out with Merck silica gel 60 (63-200 mesh). Analytical TLC was performed with Merck silica gel 60 F 254 plates, and the products were visualized by 1 H‒NMR and 13 C‒NMR (400 MHz and 100 MHz, respectively) spectra which recorded in CDCl 3 . Chemical shifts ( δ ) are reported in ppm using TMS as internal standard, and spin-spin coupling constants ( J ) are given in Hz. IR spectra were recorded on a Perkin-Elmer FT/IR 1760 as KBr pellets. MSESI spectra were obtained on Agilent 6450 spectrometer. Melting points were determined using open-end capillary tubes on a Büchi B-540 melting point apparatus and are uncorrected. 4.2. General procedure for one-pot synthesis of 2-amino-3-(3-(5-hydroxy-1H-pyrazol-4-yl)-2-oxoindolin-3-yl)naphthalene-1,4-diones ( 4a-k ) : 2-Amino-1,4-naphthoquinone ( 2 ) (1 mmol) was added to a round bottom flask containing EtOH (3 mL), isatin ( 1 ) (1 mmol) and 5-methyl-2-phenylpyrazolone ( 3 ) (1 mmol) and the resulting mixture stirred for 4 hours at 80 ℃. Reaction progress was monitored by TLC. After completion, the resulting mixture was filtered and the precipitate obtained washed with warm EtOH (2 mL) and dried at 50 °C until the products ( 4a-k ) obtained in pure form. No additional operations were required for further purification. Similar procedure was used for the synthesis of products ( 5a-h ), except that acetic acid was used as the solvent instead of ethanol. Declarations Author Contribution Hamzeh PezhmanMethodologyMohammad Reza MohammadizadehSupervision; Writing - review & editingDariush Saberi:Writing - original draft Acknowledgments The authors wish to acknowledge the research council of Persian Gulf University. Data availability All data generated or analyzed during this study are included in this published article [and its supplementary information file]. References Pellissier, H. Beilstein J. Org. Chem. 2018 , 14 , 1349–1369. Santos, M. M. M. Tetrahedron 2014 , 70 , 9735‒9757. a) Mohan, M.; Gilbert, G.; Sandhya, K. S.; Nair, A. S. Vishwakarma, A.; Deepthi, A. J. Mol. Struct. 2025, 1321, 139870; b) Khanum, A.; Afzal Pasha, M. Tetrahedron 2024 , 158 , 133980; c) Zhu, H.-P.; Chai, J.; Qin, R.; Leng, H.-J.; Wen, X.; Peng, C.; He, G.; Han, B. Eur. J. Med. Chem. 2023 , 246 , 115009; d) Marques, C. S.; González-Bakker, A.; Padrón, J. M. Beilstein J. Org. Chem. 2024 , 20 , 1213‒1220. a)Guo, H. Eur. J. Med. Chem. 2019 , 164 , 678-688; b) Bonvicini, F.; Locatelli, A.; Morigi, R.; Leoni, A.; Gentilomi, G. A. Molecules 2022 , 27 , 5781; c) Periyasami, G.; Raghunathan, R.; Surendiran, G.; Mathivanan, N. Eur. J. Med. Chem. 2009 , 44 , 959–966; d) Nieto, M. J.; Lupton, H. K. Curr. Med. Chem. 2021 , 28 , 4828‒4844. a) Ma, J.; Jiang, Y.; Zhuang, X.; Chen, H.; Shen, Y.; Mao, Z.; Rao, G.; Wang, R. Bioorg. Med. Chem. Lett. 2022 , 71 , 128826; b) Konechnyi, Y. T.; Lozynskyi, A. V.; Horishny, V. Y.; Konechna, R. T.; Vynnytska, R. B.; Korniychuk, O. P.; Lesyk, R. B. Biopolymers and Cell 2020 , 36 , 381‒391. a) Aboul-Enein, H.Y.; Kładna, A.; Kruk, I.; Lichszteld, K.; Michalska, T.; Olgen, S. Biopolymers 2005 , 78 , 171‒178; b) Camcı-Eren, M.; Cinek, T.; Cihan-Üstündağ, G.; Özen-Eroğlu, G.; Yıldırım, M.; Genç-Akar, Ö.; Erol-Bozkurt, A.; Sancar, S.; Öztay, F.; Soylu-Eter, Ö.; Bolkent, Ş. Bioorg. Chem. 2025 , 120 , 108203. Fayed, E. A.; Ragab, A.; Eldin, R. R. E.; Bayoumi, A. H.; Ammar, Y. A. Bioorg. Chem. 2021 , 116 , 105300. a) Jähne, E. A.; Eigenmann, D. E.; Culot, M.; Cecchelli, R.; Walter, F. R.; Deli, M. A.; Tremmel, R.; Fricker, G.; Smiesko, M.; Hamburger, M.; Oufir, M. J. pharm. Biomed. Anal. 2014 , 98 , 235‒246; b) Kim, S. J.; Lee, S. H.; Lee, H.; Shin, M. S.; Lee, J. W. Int. J. Mol. Sci. 2023 , 24 , 2066. a) Eldehna, W. M.; El Kerdawy, A. M.; Al-Ansary, G. H.; Al-Rashood, S. T.; Ali, M. M. Mahmoud, A. E. Eur. J. Med. Chem. 2019 , 163 , 37‒53. b) Shiri, F.; Rakhshani-morad, S.; Samzadeh-kermani, A.; Karimi, P. Med. Chem. Res. 2016 , 25 , 2643‒2665. Xu, F.; Wang, Y.; He, F.; Li, Z.; Guo, S.; Xie, Y.; Luo, D.; Wu, J.; Green Chem. Lett. Rev. 2022 , 15 ,139‒152. Yeung, B. K. S.; Zou, B.; Rottmann, M.; Lakshminarayana, S. B.; Ang, S. H.; Leong, S. Y.; Tan, J.; Wong, J.; Keller-Maerki, S.; Fischli, C.; Goh, A.; Schmitt, E. K.; Krastel, P.; Francotte, E.; Kuhen, K.; Plouffe, D.; Henson, K.; Wagner, T.; Winzeler, E. A.; Petersen, F.; Brun, R.; Dartois, V.; Diagana, T. T.; Keller, T. H. J. Med. Chem. 2010 , 53 , 5155‒5164. Chander, S.; Tang, C. R.; Penta, A.; Wang, P.; Bhagwat, D. P.; Vanthuyne, N.; Albalat, M.; Patel, P.; Sankpal, S.; Zheng, Y. T.; Sankaranarayanan, M. Bioorg. Chem. 2018 , 79 , 212‒222. Bariwal, J.; Voskressensky, L. G.; Van der Eycken, E. V. Chem. Soc. Rev. 2018 , 47 , 3831‒3848. a) Xia, M.; Ma, R.-Z. J. Heterocycl. Chem. 2014 , 51 , 539‒554; b) Nasri, S.; Bayat, M.; Mirzaei, F. Top. Curr. Chem. 2021, 379, 25; c) Gataullin, R. R. Helv. Chim. Acta 2020 , 103 , e2000137; d) Alshammari, M. B.; Aly, A. F.; Ahmad, A.; Brown, A. B.; Mohamed, A. H. RSC Adv . 2023 , 13 , 32786‒32823; e) Singh, G. S.; Desta, Z. Y. Chem. Rev. 2012 , 112 , 6104−6155; f) Miankooshki, F. R.; Bayat, M.; Shima Nasri, S.; Habibi Samet, N. Mol. Divers. 2023 , 27 , 2365‒2397. Arizavi, M.; Mohammadizadeh, M. R.; Saberi, D.; Ghodrati, A. Hashemi, S. F. ChemistrySelect 2024 , 9 , e202402162. Guo, Q.-X.; Liu, Y.-W.; Li, X.-C.; Zhong, L.-Z.; Peng, Y.G. J. Org. Chem. 2012 , 77 , 3589‒3594. a) Xue, J.‐W.; Guo, J. T.; He, Y. H.; Guan, Z. Asian J. Org. Chem. 2017 , 6 , 297‒304; b) Jun, T.; Li, Y.‐W.; Xu, D.‐Z. ChemistrySelect 2017 , 2 , 3799‒3803. Xie, D.‐X.; Huang, Y.-M.; Lin, X.-M.; Kang, Z.-H.; Ni, C.-C.; Fu, Y.-T.; Ren, Z.; Liu, Y.-L. Chem. Eur. J. 2024 , 30 , e202402654. Ramu, G.; Krishna, N. H.; Pawar, G.; Visweswara Sastry, K. N.; Nanubolu, J. B.; Babu, B. N. ACS Omega 2018 , 3 , 12349‒12360. Chang, C.‐H.; Nadaraj, S.; Yu-Ting, L.; Hsin-Tsung, C.; Jeng-Liang, H. Adv. Synth. Catal. 2020 , 362 , 903‒912. Mishra, R.; Jana, A.; Panday, A. K.; Choudhury, L. H. New J. Chem. 2019 , 43 , 2920‒2932. Chen, Q.; Wu, Y.; Hua, R. Molecules 2019 , 24 , 3773. Ramu, G.; Hari Krishna, N.; Pawar, G.; Visweswara Sastry, K. N.; Nanubolu, J. B.; Nagendra Babu, B. ACS Omega 2018 , 3 , 12349-12360. Shi, H.; Wang, L.; Li, S.-S.; Liu, Y.; Xu, L. Org. Chem. Front. 2020 , 7 , 747‒755. a) Firoozi, N.; Roshan, Z.; Mohammadizadeh, M. R. Appl. Organomet. Chem. 2017 , 32 , e3963; b) Mohammadizadeh, M. R.; Saberi, D.; Taghavi, S. Z. Tetrahedron Lett. 2016 , 57 , 264‒267; c) Mahdavinia, G. H.; Mohammadizadeh, M. R.; Ariapour, N.; Alborz, M. Tetrahedron Lett. 2014 , 55 , 1967‒1970. Tables Tables 1 to 3 are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files Supportinginformation.docx Tables.docx Cite Share Download PDF Status: Published Journal Publication published 30 Oct, 2025 Read the published version in Scientific Reports → Version 1 posted Editorial decision: Revision requested 02 Jul, 2025 Reviews received at journal 25 Jun, 2025 Reviews received at journal 20 Jun, 2025 Reviewers agreed at journal 18 Jun, 2025 Reviewers agreed at journal 04 Jun, 2025 Reviewers invited by journal 04 Jun, 2025 Editor assigned by journal 04 Jun, 2025 Editor invited by journal 04 Jun, 2025 Submission checks completed at journal 03 Jun, 2025 First submitted to journal 18 May, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6693319","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":467140304,"identity":"9598d1bd-bcb7-4a14-8434-6e9006b3758d","order_by":0,"name":"Hamed Pezhman","email":"","orcid":"","institution":"Persian Gulf University","correspondingAuthor":false,"prefix":"","firstName":"Hamed","middleName":"","lastName":"Pezhman","suffix":""},{"id":467140305,"identity":"91f8caff-92b9-420b-9cff-41b9a83a6c67","order_by":1,"name":"Mohammad Reza Mohammadizadeh","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABA0lEQVRIiWNgGAWjYJACZjB5GIh5GA7IwUR5iNZiTIKWAxAtiQ2EHKU7+3Ti44KabfJ8x9kffnhTcSd9O/8aA4YfNQwy5jg0m53L3Ww849htw5mHGZIl55x5lrtzxhsDxp5jDDwyB3BoOcO7TZqH7TbjhsMMB6R52w7nbrhxxoCBt4GBRwKHwyBa/t2233CYsfk377/D6QZALYx/CWnhbbuduOEwM5s0b8PhBIPzPQbMBGzZbMzbdzt55mE2Nss5xw4b7pzBVnBY5pgEPi0bH/N8u23bd/744xtvag7Lm/Mf3vjwTY2NPS4tmMBAIgEUR8RrAGrhP0CC6lEwCkbBKBgJAAArfV+BqEYsfwAAAABJRU5ErkJggg==","orcid":"","institution":"Persian Gulf University","correspondingAuthor":true,"prefix":"","firstName":"Mohammad","middleName":"Reza","lastName":"Mohammadizadeh","suffix":""},{"id":467140306,"identity":"134d84f1-6b75-460d-8b61-8a46a9080f5c","order_by":2,"name":"Dariush Saberi","email":"","orcid":"","institution":"Persian Gulf University","correspondingAuthor":false,"prefix":"","firstName":"Dariush","middleName":"","lastName":"Saberi","suffix":""}],"badges":[],"createdAt":"2025-05-18 18:53:08","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6693319/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6693319/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41598-025-21805-w","type":"published","date":"2025-10-30T15:57:52+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":84221187,"identity":"f1f67ae9-027a-4304-a203-2d3390445f09","added_by":"auto","created_at":"2025-06-09 11:45:27","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":14492,"visible":true,"origin":"","legend":"\u003cp\u003eThe structure of spiro (left) and non-spiroindolin-2-ones (right)\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-6693319/v1/ab246b2b0b95c70199fc39f9.png"},{"id":84221192,"identity":"d64f4cb8-187c-4dc8-a06b-5f0707c15aff","added_by":"auto","created_at":"2025-06-09 11:45:27","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":43845,"visible":true,"origin":"","legend":"\u003cp\u003eSolvent-controlled synthesis of substituted oxindoles (\u003cstrong\u003e4\u003c/strong\u003e) and spirooxindoles (\u003cstrong\u003e5\u003c/strong\u003e) \u003cem\u003evia\u003c/em\u003eone-pot three-component reaction of isatins (\u003cstrong\u003e1\u003c/strong\u003e), 2-amino-1,4-naphthoquinone (\u003cstrong\u003e2\u003c/strong\u003e) and 5-methyl-2-phenylpyrazolone (\u003cstrong\u003e3\u003c/strong\u003e).\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-6693319/v1/d98e3118f2c55cb153dfb486.png"},{"id":84221188,"identity":"444422ce-a5e0-430d-8090-30b48416dc77","added_by":"auto","created_at":"2025-06-09 11:45:27","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":34843,"visible":true,"origin":"","legend":"\u003cp\u003eEnol-keto tautomerization equilibrium of product (\u003cstrong\u003e4a\u003c/strong\u003e)\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-6693319/v1/a2e57f5b7b09e76f76146bf3.png"},{"id":84222090,"identity":"109c48bf-a467-4e7b-bae3-66963775d83c","added_by":"auto","created_at":"2025-06-09 12:01:27","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":146018,"visible":true,"origin":"","legend":"\u003cp\u003eSingle crystal X-ray structure of (\u003cstrong\u003e4c\u003c/strong\u003e) (CCDC 2447689).\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-6693319/v1/f36292c8df5a9195700e0d4f.png"},{"id":84221538,"identity":"b00b7653-5e37-40ab-9669-50b9812c88a5","added_by":"auto","created_at":"2025-06-09 11:53:27","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":118547,"visible":true,"origin":"","legend":"\u003cp\u003eSingle crystal X-ray structure of (\u003cstrong\u003e5a)\u003c/strong\u003e (CCDC 2447690).\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-6693319/v1/ab14c7e5eacadcb8839e231d.png"},{"id":84221194,"identity":"87961f5f-a744-4651-8dce-a67beda28162","added_by":"auto","created_at":"2025-06-09 11:45:27","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":93751,"visible":true,"origin":"","legend":"\u003cp\u003ePlausible mechanism for the one-pot three-component synthesis of products (\u003cstrong\u003e4\u003c/strong\u003e) and (\u003cstrong\u003e5\u003c/strong\u003e)\u003c/p\u003e","description":"","filename":"6.png","url":"https://assets-eu.researchsquare.com/files/rs-6693319/v1/b5763c0db981cf256183560d.png"},{"id":95039963,"identity":"d09cc04b-f9d5-4b2a-a13b-1fe1326917a6","added_by":"auto","created_at":"2025-11-03 16:06:36","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1016882,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6693319/v1/1fae5d22-1682-4faf-8d6f-1bd7fac55418.pdf"},{"id":84221543,"identity":"3792ee1a-8590-4882-9214-aa1258cec4d7","added_by":"auto","created_at":"2025-06-09 11:53:27","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":3001210,"visible":true,"origin":"","legend":"","description":"","filename":"Supportinginformation.docx","url":"https://assets-eu.researchsquare.com/files/rs-6693319/v1/402ced5bbb3138f9544330f4.docx"},{"id":84221189,"identity":"633d7441-b9c6-4ffa-991e-1faf3c4d00ea","added_by":"auto","created_at":"2025-06-09 11:45:27","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":192617,"visible":true,"origin":"","legend":"","description":"","filename":"Tables.docx","url":"https://assets-eu.researchsquare.com/files/rs-6693319/v1/ddf694909a7c45347330fbb0.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eSolvent-controlled chemo-selective synthesis of 2-amino-3-(3-(5-hydroxy-1\u003cem\u003eH\u003c/em\u003e-pyrazol-4-yl)-2-oxoindolin-3-yl)naphthalene-1,4-diones and 1\u003cem\u003eH\u003c/em\u003e-spiro[benzo[6,7]chromeno[2,3-\u003cem\u003ec\u003c/em\u003e]pyrazole-4,3'-indoline]-2',5,10-triones\u003c/p\u003e","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eIndolin-2-one (2-oxindole) derivatives are very important nitrogen-containing heterocyclic compounds that are of great value in the fields of chemistry and medicinal chemistry due to their unique structure. The possibility of placing various potentially biologically active cyclic and noncyclic moieties on C-3 has given these compounds additional value. However, the groups attached to C-3 may be either non-spiro\u003csup\u003e1\u003c/sup\u003e or spiro\u003csup\u003e2\u003c/sup\u003e (Figure 1). It\u0026apos;s interesting to note that different biological actions are displayed by spiro and non-spiroindolin-2-ones. The biological significance of indolin-2-ones has been reported in a number of ways, including anti-cancer,\u003csup\u003e3\u003c/sup\u003e antimicrobial,\u003csup\u003e4\u003c/sup\u003e antifungal,\u003csup\u003e5\u003c/sup\u003e antioxidant,\u003csup\u003e6\u003c/sup\u003e anticonvulsant,\u003csup\u003e7\u003c/sup\u003e anti-inflammatory,\u003csup\u003e8\u003c/sup\u003e anti-tubercular,\u003csup\u003e8\u003c/sup\u003e anti-proliferative activity,\u003csup\u003e9\u003c/sup\u003e antiviral,\u003csup\u003e10\u003c/sup\u003e antimalarial,\u003csup\u003e11\u003c/sup\u003e and anti-HIV-1\u003csup\u003e12\u003c/sup\u003e properties. Therefore, the preparation of new derivatives of indolin-2-ones and the development of methods for the preparation of these compounds continue to be active areas of research in organic chemistry and medicinal chemistry.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAlthough indolin-2-ones can be prepared by various routes,\u003csup\u003e13\u003c/sup\u003e perhaps the most important and widely used method for preparing these compounds is the use of isatin derivatives. A cursory review indicates that more than 3240 papers have been published since the beginning of the present millennium on the two- or multi-component synthesis of various indolin-2-one derivatives using isatins in the presence of numerous nucleophilic compounds and under various conditions. Most of the reported works have been frequently reviewed.\u003csup\u003e14\u003c/sup\u003e Such a variety of biological activities, a large number of studies, and a large volume of reports indicate the extraordinary importance of indoline-2-ones. Therefore, the development of chemical methods that can make the production and conversion of these compounds more practical and convenient remains of great importance.\u003c/p\u003e\n\u003cp\u003eThe study of condensation reactions of various nucleophiles on C-3 of isatins indicates that the desired products largely depend on the nitrogen substitution\u003csup\u003e15\u003c/sup\u003e and particularly on the reaction conditions. The diastereoselectively switchable enantioselective Mannich reaction of isatin imines with hydroxyacetone,\u003csup\u003e16\u003c/sup\u003e solvent-controlled chemoselective Friedel\u0026ndash;Crafts reactions between isatins and indoles,\u003csup\u003e17\u003c/sup\u003e chemoselective synthesis of spirocyclopropyl and spiropyrazoline oxindoles,\u003csup\u003e18\u003c/sup\u003e solvent-controlled stereo-divergent synthesis of spirocyclopentaneoxindoles,\u003csup\u003e19\u003c/sup\u003e enantiodivergent Friedel-Crafts reaction of 1-naphthols with arylsulfonyl indoles switched by solvents,\u003csup\u003e20\u003c/sup\u003e medium dependent isatin based synthesis of spirooxindoles fused with pyrazolo-tetrahydropyridinone and coumarin-dihydropyridine-pyrazole tetracycles under microwave irradiation conditions,\u003csup\u003e21\u003c/sup\u003e chemo-divergent formation of 1,4-benzoxazepinones and 1,3-benzoxazinones,\u003csup\u003e22\u003c/sup\u003e solvent-controlled access to 3-spirocyclopropyl-2-oxindoles and pyrazoloquinazolinone scaffolds,\u003csup\u003e23\u003c/sup\u003e \u0026alpha;-chymotrypsin catalyzed solvent-controlled synthesis of 3-hydroxy-oxindoles/3,3-bis(indol-3-yl)indolin-2-ones,\u003csup\u003e24\u003c/sup\u003e are some methods that have been reported in this area. In this line of research and in continuation of our effort to develop new methods for the synthesis of heterocyclic organic compounds,\u003csup\u003e25\u003c/sup\u003e herein, we report the results of our investigations on the synthesis of\u0026nbsp;oxindoles having 2-amino-1,4-naphthoquinone and 5-methyl-2-phenylpyrazolone substituents (\u003cstrong\u003e4\u003c/strong\u003e) and\u0026nbsp;1\u003cem\u003eH\u003c/em\u003e-spiro[benzo[6,7]chromeno[2,3-\u003cem\u003ec\u003c/em\u003e]pyrazole-4,3\u0026apos;-indoline]-2\u0026apos;,5,10-triones (\u003cstrong\u003e5\u003c/strong\u003e), under switchable solvent conditions. While the three-component reaction of isatins (\u003cstrong\u003e1\u003c/strong\u003e), 2-aminonaphtoquinone (\u003cstrong\u003e2\u003c/strong\u003e), and 5-methyl-2-phenylpyrazolone (\u003cstrong\u003e3\u003c/strong\u003e) in ethanol under reflux conditions produced oxindoles (\u003cstrong\u003e4\u003c/strong\u003e), changing the solvent to acetic acid led to spiro compounds (\u003cstrong\u003e5\u003c/strong\u003e) which were isolated as main products from the reaction mixture (Figure 2).\u003c/p\u003e"},{"header":"2. Results and Discussion","content":"\u003cp\u003eOur initial studies involved performing the reaction between \u003cem\u003eN\u003c/em\u003e-ethylisatin (\u003cstrong\u003e1a\u003c/strong\u003e), 2-amino-1,4-naphthoquinone (\u003cstrong\u003e2\u003c/strong\u003e), and\u0026nbsp;5-methyl-2-phenylpyrazolone (\u003cstrong\u003e3)\u003c/strong\u003e, under various conditions shown in Table 1, toward synthesis of new oxindole\u0026nbsp;(\u003cstrong\u003e4a\u003c/strong\u003e). Solvent screening experiment to identify the best solvent for the reaction showed that the ethanol has the highest yield in a shorter time compared to the other solvents like acetonitrile, methanol, tetrahydrofuran, and water. This choice is justified because ethanol is often preferred in organic synthesis due to its moderate polarity, safety profile, and ability to dissolve a wide range of compounds (Table 1, entries 1-5). All reactions were carried out under reflux conditions of solvents. A decrease in reaction efficiency at lower temperatures suggests that the reaction rate is temperature-dependent. This finding emphasizes the importance of controlling reaction temperature to maintain optimal efficiency (Table 1, entries 6-8).\u003c/p\u003e\n\u003cp\u003eWith optimal reaction conditions in hand and the availability of isatin derivatives, several derivatives of 2-amino-3-(3-(5-hydroxy-1\u003cem\u003eH\u003c/em\u003e-pyrazol-4-yl)-2-oxoindolin-3-yl)naphthalene-1,4-diones (\u003cstrong\u003e4\u003c/strong\u003e) were synthesized, the structures of which are shown in Table 2. As shown in this table, despite the presence of various substituents, including ethyl, propyl, and naphthyl methyl, as well as benzyl derivatives with either electron-donating or electron-withdrawing groups, attached to the nitrogen atom of isatin, there was no variation in the reaction rate. All reactions produced the corresponding products with good efficiency. In addition, the 1,1\u0026apos;-(propane-1,3-diyl)bis(indoline-2,3-dione) (\u003cstrong\u003e1k\u003c/strong\u003e) was also subjected to the reaction conditions and the corresponding oxindole (\u003cstrong\u003e4k\u003c/strong\u003e) was obtained with an efficiency of 86%.\u003c/p\u003e\n\u003cp\u003eThe spectral data analysis of products (\u003cstrong\u003e4\u003c/strong\u003e) not only confirms the proposed structure but also reveals an intriguing phenomenon: due to the presence of the pyrazolone moiety, these compounds exist in a dynamic equilibrium between their enol and keto forms when dissolved in an NMR solvent (Figure 3). For instance, in the \u003csup\u003e1\u003c/sup\u003eH‒NMR spectrum of compound (\u003cstrong\u003e4a)\u003c/strong\u003e, the ethyl group protons appear as a triplet for the methyl protons at \u003cem\u003e\u0026delta;\u003c/em\u003e = 1.28, along with overlapping multiplets for the methylene group in the range of \u003cem\u003e\u0026delta;\u003c/em\u003e = 3.64-3.93, with integrals corresponding to 3H and 2H, respectively. However, the methyl protons of the pyrazolone ring substituent exhibit two distinct peaks at chemical shifts of 1.40 and 2.22 ppm, in a ratio of 2.0:1.0, with a total integral of 3H. The NH\u003csub\u003e2\u003c/sub\u003e protons and those associated with the enol and keto forms of the pyrazolone ring present a broad overlapping pattern in the range of \u003cem\u003e\u0026delta;\u003c/em\u003e = 6.06-6.90, with an integral of 2H, alongside a broad peak between 10.0 and 11.0 ppm, integrating to 1H. Remarkably, the addition of D\u003csub\u003e2\u003c/sub\u003eO results in the disappearance of the broad peak at 10.11-11.29 ppm, while the broad signals around 6 ppm are simplified into a broad peak integrating to 1H. Notably, the methyl protons of the pyrazolone ring continue to manifest as two separate peaks at \u003cem\u003e\u0026delta;\u003c/em\u003e = 1.37 and \u003cem\u003e\u0026delta;\u003c/em\u003e = 2.19 in a 2:1 ratio, with a total integral of 3H.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe predicted structure of compounds (\u003cstrong\u003e4\u003c/strong\u003e) was undoubtedly stablished when the X-ray crystallographic analysis of product (\u003cstrong\u003e4c\u003c/strong\u003e) was successfully recorded from its appropriate single crystal (Figure 4).\u0026nbsp;As shown in Figure 3, the compound (\u003cstrong\u003e4c\u003c/strong\u003e) crystallized in its more stable enol form, which features a diazole ring exhibiting aromatic stability.\u003c/p\u003e\n\u003cp\u003eFurther studies on the reaction showed that when the reaction is carried out in acetic acid solvent, new products from the spirochromeno oxindoles family are formed (Figure 2, products (\u003cstrong\u003e5\u003c/strong\u003e)). For this purpose, several \u003cem\u003eN\u003c/em\u003e-substituted isatins (\u003cstrong\u003e1\u003c/strong\u003e) were subjected to the reaction with 2-amino-1,4-naphthoquinone (\u003cstrong\u003e2\u003c/strong\u003e) in the presence of 5-methyl-2-phenylpyrazolone (\u003cstrong\u003e3\u003c/strong\u003e), and the corresponding\u0026nbsp;1\u003cem\u003eH\u003c/em\u003e-spiro[benzo[6,7]chromeno[2,3-\u003cem\u003ec\u003c/em\u003e]pyrazole-4,3\u0026apos;-indoline]-2\u0026apos;,5,10-triones (\u003cstrong\u003e5a-h\u003c/strong\u003e) were obtained in good to excellent yields. The results are collected in Table 3.\u003c/p\u003e\n\u003cp\u003eThe close match between the NMR spectra of the compounds formed under the new conditions (\u003cstrong\u003e5\u003c/strong\u003e) and those of products (\u003cstrong\u003e4\u003c/strong\u003e) strongly confirms the formation of 1\u003cem\u003eH\u003c/em\u003e-spiro[benzo[6,7]chromeno[2,3-\u003cem\u003ec\u003c/em\u003e]pyrazole-4,3\u0026apos;-indoline]-2\u0026apos;,5,10-triones (\u003cstrong\u003e5\u003c/strong\u003e). While the peaks corresponding to the amine protons and the enol/keto protons of the pyrazolone moiety (specifically the broad signals at \u003cem\u003e\u0026delta;\u003c/em\u003e = 6.0-6.9 and 10.0-11.0 ppm) have disappeared, dynamic equilibrium-related effects\u0026mdash;such as peak broadening or multiplicity arising from the enol-keto tautomerism\u0026mdash;are no longer observed. Instead, each proton group now exhibits only a single peak corresponding to its specific environment. Finally, the predicted structure of compounds (\u003cstrong\u003e5\u003c/strong\u003e) was unequivocally confirmed when X-ray crystallographic analysis of product (\u003cstrong\u003e5a\u003c/strong\u003e) was successfully recorded from its single crystal, as shown in Figure 5.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAs evident from the results in Tables 2 and 3, the reactions proceeded efficiently to produce products (\u003cstrong\u003e4\u003c/strong\u003e) and spirooxindoles (\u003cstrong\u003e5\u003c/strong\u003e) using various isatin derivatives bearing different substituents on both the aromatic ring and nitrogen atom. The reactions typically completed in 4 hours, yielding the products with good to excellent yields and high purity through simple filtration followed by washing with ethanol.\u003c/p\u003e\n\u003cp\u003eA plausible mechanism is presented for the one-pot three-component synthesis of\u0026nbsp;2-amino-3-(3-(5-hydroxy-1\u003cem\u003eH\u003c/em\u003e-pyrazol-4-yl)-2-oxoindolin-3-yl)naphthalene-1,4-diones\u0026nbsp;(\u003cstrong\u003e4\u003c/strong\u003e) and 1\u003cem\u003eH\u003c/em\u003e-spiro[benzo[6,7]chromeno[2,3-\u003cem\u003ec\u003c/em\u003e]pyrazole-4,3\u0026apos;-indoline]-2\u0026apos;,5,10-triones (\u003cstrong\u003e5\u003c/strong\u003e)\u0026nbsp;(Figure 6). A condensation reaction between isatin (\u003cstrong\u003e1\u003c/strong\u003e) and 2-amino-1,4-naphthoquinone (\u003cstrong\u003e2\u003c/strong\u003e) proceeds \u003cem\u003evia\u003c/em\u003e intermediates (\u003cstrong\u003eA\u003c/strong\u003e) and (\u003cstrong\u003eB\u003c/strong\u003e), leading to the formation of intermediate (\u003cstrong\u003eC\u003c/strong\u003e). This intermediate is then attacked by the enolic form of 5-methyl-2-phenylpyrazolone (\u003cstrong\u003e3\u003c/strong\u003e), yielding products (\u003cstrong\u003e4\u003c/strong\u003e). However, under acidic conditions, protonation of the amino group in intermediate (\u003cstrong\u003eC\u003c/strong\u003e) generates intermediate (\u003cstrong\u003eD\u003c/strong\u003e), which facilitates nucleophilic attack by the pyrazolone hydroxyl group. This is followed by ammonia elimination to yield products (\u003cstrong\u003e5\u003c/strong\u003e).\u003c/p\u003e"},{"header":"3. Conclusion","content":"\u003cp\u003eIn conclusion, some new derivatives of spiro and non-spirooxindoles were synthesized up to 96% yields from a novel and simple one-pot procedure \u003cem\u003evia\u003c/em\u003e the solvent-controlled reaction between isatin derivatives, 2-amino-1,4-naphthoquinone and 5-methyl-2-phenylpyrazolone. The choice of solvent significantly influenced the reaction outcome, with acetic acid favoring the formation of spiro oxindoles and ethanol leading to non-spiro ones. High yields, facile work-up, operational simplicity, and the absence of extraction/chromatography steps are key advantages of these pathways to synthesis of new spiro and non-spirooxindole derivatives.\u003c/p\u003e"},{"header":"4. Experimental","content":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003e4.1.\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cem\u003eGeneral information:\u003c/em\u003e\u003c/strong\u003e All reagents were purchased from commercial suppliers and used without further purification. All experiments were carried out under air atmosphere. Column chromatography was carried out with Merck silica gel 60 (63-200 mesh). Analytical TLC was performed with Merck silica gel 60 F\u003csub\u003e254\u003c/sub\u003e plates, and the products were visualized by \u003csup\u003e1\u003c/sup\u003eH‒NMR and \u003csup\u003e13\u003c/sup\u003eC‒NMR (400 MHz and 100 MHz, respectively) spectra which recorded in CDCl\u003csub\u003e3\u003c/sub\u003e. Chemical shifts (\u003cem\u003e\u0026delta;\u003c/em\u003e) are reported in ppm using TMS as internal standard, and spin-spin coupling constants (\u003cem\u003eJ\u003c/em\u003e) are given in Hz. IR spectra were recorded on a Perkin-Elmer FT/IR 1760 as KBr pellets. MSESI spectra were obtained on Agilent 6450 spectrometer. Melting points were determined using open-end capillary tubes on a B\u0026uuml;chi B-540 melting point apparatus and are uncorrected.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003e4.2.\u003c/em\u003e\u003c/strong\u003e \u003cstrong\u003e\u003cem\u003eGeneral\u003c/em\u003e\u003c/strong\u003e \u003cstrong\u003e\u003cem\u003eprocedure for one-pot synthesis of 2-amino-3-(3-(5-hydroxy-1H-pyrazol-4-yl)-2-oxoindolin-3-yl)naphthalene-1,4-diones\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003cem\u003e(\u003cstrong\u003e4a-k\u003c/strong\u003e)\u003c/em\u003e: 2-Amino-1,4-naphthoquinone (\u003cstrong\u003e2\u003c/strong\u003e) (1 mmol) was added to a round bottom flask containing EtOH (3 mL), isatin (\u003cstrong\u003e1\u003c/strong\u003e) (1 mmol) and 5-methyl-2-phenylpyrazolone (\u003cstrong\u003e3\u003c/strong\u003e) (1 mmol) and the resulting mixture stirred for 4 hours at 80 ℃. Reaction progress was monitored by TLC. After completion, the resulting mixture was filtered and the precipitate obtained washed with warm EtOH (2 mL) and dried at 50 \u0026deg;C until the products (\u003cstrong\u003e4a-k\u003c/strong\u003e) obtained in pure form. No additional operations were required for further purification. Similar procedure was used for the synthesis of products (\u003cstrong\u003e5a-h\u003c/strong\u003e), except that acetic acid was used as the solvent instead of ethanol.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eHamzeh PezhmanMethodologyMohammad Reza MohammadizadehSupervision; Writing - review \u0026amp; editingDariush Saberi:Writing - original draft\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eAcknowledgments\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors wish to acknowledge the research council of\u0026nbsp;Persian Gulf University.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;All data generated or analyzed during this study are included in this published article [and its supplementary information file].\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003ePellissier, H. \u003cem\u003eBeilstein J. Org. Chem.\u003c/em\u003e\u003cstrong\u003e2018\u003c/strong\u003e, \u003cem\u003e14\u003c/em\u003e, 1349\u0026ndash;1369.\u003c/li\u003e\n\u003cli\u003eSantos, M. M. M. \u003cem\u003eTetrahedron\u003c/em\u003e\u003cstrong\u003e2014\u003c/strong\u003e, \u003cem\u003e70\u003c/em\u003e, 9735‒9757.\u003c/li\u003e\n\u003cli\u003ea) Mohan, M.; Gilbert, G.; Sandhya, K. S.; Nair, A. S. Vishwakarma, A.; Deepthi, A. J. Mol. Struct. 2025, 1321, 139870; b) Khanum, A.; Afzal Pasha, M. \u003cem\u003eTetrahedron\u003c/em\u003e\u003cstrong\u003e2024\u003c/strong\u003e, \u003cem\u003e158\u003c/em\u003e, 133980; c) Zhu, H.-P.; Chai, J.; Qin, R.; Leng, H.-J.; Wen, X.; Peng, C.; He, G.; Han, B. \u003cem\u003eEur. J. Med. Chem.\u003c/em\u003e\u003cstrong\u003e2023\u003c/strong\u003e, \u003cem\u003e246\u003c/em\u003e, 115009; d) Marques, C. S.; Gonz\u0026aacute;lez-Bakker, A.; Padr\u0026oacute;n, J. M. \u003cem\u003eBeilstein J. Org. Chem. \u003c/em\u003e\u003cstrong\u003e2024\u003c/strong\u003e, \u003cem\u003e20\u003c/em\u003e, 1213‒1220.\u003c/li\u003e\n\u003cli\u003ea)Guo, H. \u003cem\u003eEur. J. Med. Chem. \u003c/em\u003e\u003cstrong\u003e2019\u003c/strong\u003e, \u003cem\u003e164\u003c/em\u003e, 678-688; b) Bonvicini, F.; Locatelli, A.; Morigi, R.; Leoni, A.; Gentilomi, G. A. \u003cem\u003eMolecules\u003c/em\u003e\u003cstrong\u003e2022\u003c/strong\u003e, \u003cem\u003e27\u003c/em\u003e, 5781; c) Periyasami, G.; Raghunathan, R.; Surendiran, G.; Mathivanan, N. \u003cem\u003eEur. J. Med. Chem.\u003c/em\u003e\u003cstrong\u003e2009\u003c/strong\u003e, \u003cem\u003e44\u003c/em\u003e, 959\u0026ndash;966; d) Nieto, M. J.; Lupton, H. K. \u003cem\u003eCurr. Med. Chem.\u003c/em\u003e\u003cstrong\u003e2021\u003c/strong\u003e, \u003cem\u003e28\u003c/em\u003e, 4828‒4844.\u003c/li\u003e\n\u003cli\u003ea) Ma, J.; Jiang, Y.; Zhuang, X.; Chen, H.; Shen, Y.; Mao, Z.; Rao, G.; Wang, R. \u003cem\u003eBioorg. Med. Chem. Lett.\u003c/em\u003e\u003cstrong\u003e2022\u003c/strong\u003e, \u003cem\u003e71\u003c/em\u003e, 128826; b) Konechnyi, Y. T.; Lozynskyi, A. V.; Horishny, V. Y.; Konechna, R. T.; Vynnytska, R. B.; Korniychuk, O. P.; Lesyk, R. B. \u003cem\u003eBiopolymers and Cell\u003c/em\u003e\u003cstrong\u003e2020\u003c/strong\u003e, \u003cem\u003e36\u003c/em\u003e, 381‒391.\u003c/li\u003e\n\u003cli\u003ea) Aboul-Enein, H.Y.; Kładna, A.; Kruk, I.; Lichszteld, K.; Michalska, T.; Olgen, S. \u003cem\u003eBiopolymers\u003c/em\u003e\u003cstrong\u003e2005\u003c/strong\u003e, \u003cem\u003e78\u003c/em\u003e, 171‒178; b) Camcı-Eren, M.; Cinek, T.; Cihan-\u0026Uuml;st\u0026uuml;ndağ, G.; \u0026Ouml;zen-Eroğlu, G.; Yıldırım, M.; Gen\u0026ccedil;-Akar, \u0026Ouml;.; Erol-Bozkurt, A.; Sancar, S.; \u0026Ouml;ztay, F.; Soylu-Eter, \u0026Ouml;.; Bolkent, Ş. \u003cem\u003eBioorg. Chem.\u003c/em\u003e\u003cstrong\u003e2025\u003c/strong\u003e, \u003cem\u003e120\u003c/em\u003e, 108203.\u003c/li\u003e\n\u003cli\u003eFayed, E. A.; Ragab, A.; Eldin, R. R. E.; Bayoumi, A. H.; Ammar, Y. A. \u003cem\u003eBioorg. Chem.\u003c/em\u003e\u003cstrong\u003e2021\u003c/strong\u003e, \u003cem\u003e116\u003c/em\u003e, 105300.\u003c/li\u003e\n\u003cli\u003ea) J\u0026auml;hne, E. A.; Eigenmann, D. E.; Culot, M.; Cecchelli, R.; Walter, F. R.; Deli, M. A.; Tremmel, R.; Fricker, G.; Smiesko, M.; Hamburger, M.; Oufir, M. \u003cem\u003eJ. pharm. Biomed. Anal.\u003c/em\u003e\u003cstrong\u003e2014\u003c/strong\u003e, \u003cem\u003e98\u003c/em\u003e, 235‒246; b) Kim, S. J.; Lee, S. H.; Lee, H.; Shin, M. S.; Lee, J. W. \u003cem\u003eInt. J. Mol. Sci.\u003c/em\u003e\u003cstrong\u003e2023\u003c/strong\u003e, \u003cem\u003e24\u003c/em\u003e, 2066. \u003c/li\u003e\n\u003cli\u003ea) Eldehna, W. M.; El Kerdawy, A. M.; Al-Ansary, G. H.; Al-Rashood, S. T.; Ali, M. M. Mahmoud, A. E. \u003cem\u003eEur. J. Med. Chem.\u003c/em\u003e\u003cstrong\u003e2019\u003c/strong\u003e, \u003cem\u003e163\u003c/em\u003e, 37‒53. b) Shiri, F.; Rakhshani-morad, S.; Samzadeh-kermani, A.; Karimi, P. \u003cem\u003eMed. Chem. Res.\u003c/em\u003e\u003cstrong\u003e2016\u003c/strong\u003e, \u003cem\u003e25\u003c/em\u003e, 2643‒2665.\u003c/li\u003e\n\u003cli\u003eXu, F.; Wang, Y.; He, F.; Li, Z.; Guo, S.; Xie, Y.; Luo, D.; Wu, J.; \u003cem\u003eGreen Chem. Lett. Rev.\u003c/em\u003e\u003cstrong\u003e2022\u003c/strong\u003e, \u003cem\u003e15\u003c/em\u003e,139‒152.\u003c/li\u003e\n\u003cli\u003eYeung, B. K. S.; Zou, B.; Rottmann, M.; Lakshminarayana, S. B.; Ang, S. H.; Leong, S. Y.; Tan, J.; Wong, J.; Keller-Maerki, S.; Fischli, C.; Goh, A.; Schmitt, E. K.; Krastel, P.; Francotte, E.; Kuhen, K.; Plouffe, D.; Henson, K.; Wagner, T.; Winzeler, E. A.; Petersen, F.; Brun, R.; Dartois, V.; Diagana, T. T.; Keller, T. H. \u003cem\u003eJ. Med. Chem.\u003c/em\u003e\u003cstrong\u003e2010\u003c/strong\u003e, \u003cem\u003e53\u003c/em\u003e, 5155‒5164.\u003c/li\u003e\n\u003cli\u003eChander, S.; Tang, C. R.; Penta, A.; Wang, P.; Bhagwat, D. P.; Vanthuyne, N.; Albalat, M.; Patel, P.; Sankpal, S.; Zheng, Y. T.; Sankaranarayanan, M. \u003cem\u003eBioorg. Chem.\u003c/em\u003e\u003cstrong\u003e2018\u003c/strong\u003e, \u003cem\u003e79\u003c/em\u003e, 212‒222.\u003c/li\u003e\n\u003cli\u003eBariwal, J.; Voskressensky, L. G.; Van der Eycken, E. V. \u003cem\u003eChem. Soc. Rev.\u003c/em\u003e\u003cstrong\u003e2018\u003c/strong\u003e, \u003cem\u003e47\u003c/em\u003e, 3831‒3848. \u003c/li\u003e\n\u003cli\u003ea) Xia, M.; Ma, R.-Z. \u003cem\u003eJ. Heterocycl. Chem.\u003c/em\u003e\u003cstrong\u003e2014\u003c/strong\u003e, \u003cem\u003e51\u003c/em\u003e, 539‒554; b) Nasri, S.; Bayat, M.; Mirzaei, F. Top. Curr. Chem. 2021, 379, 25; c) Gataullin, R. R. \u003cem\u003eHelv. Chim. Acta\u003c/em\u003e\u003cstrong\u003e2020\u003c/strong\u003e, \u003cem\u003e103\u003c/em\u003e, e2000137; d) Alshammari, M. B.; Aly, A. F.; Ahmad, A.; Brown, A. B.; Mohamed, A. H. \u003cem\u003eRSC Adv\u003c/em\u003e. \u003cstrong\u003e2023\u003c/strong\u003e, \u003cem\u003e13\u003c/em\u003e, 32786‒32823; e) Singh, G. S.; Desta, Z. Y. \u003cem\u003eChem. Rev.\u003c/em\u003e\u003cstrong\u003e2012\u003c/strong\u003e, \u003cem\u003e112\u003c/em\u003e, 6104\u0026minus;6155; f) Miankooshki, F. R.; Bayat, M.; Shima Nasri, S.; Habibi Samet, N. \u003cem\u003eMol. Divers.\u003c/em\u003e\u003cstrong\u003e2023\u003c/strong\u003e, \u003cem\u003e27\u003c/em\u003e, 2365‒2397.\u003c/li\u003e\n\u003cli\u003eArizavi, M.; Mohammadizadeh, M. R.; Saberi, D.; Ghodrati, A. Hashemi, S. F. \u003cem\u003eChemistrySelect \u003c/em\u003e\u003cstrong\u003e2024\u003c/strong\u003e, \u003cem\u003e9\u003c/em\u003e, e202402162.\u003c/li\u003e\n\u003cli\u003eGuo, Q.-X.; Liu, Y.-W.; Li, X.-C.; Zhong, L.-Z.; Peng, Y.G. \u003cem\u003eJ. Org. Chem.\u003c/em\u003e\u003cstrong\u003e2012\u003c/strong\u003e, \u003cem\u003e77\u003c/em\u003e, 3589‒3594.\u003c/li\u003e\n\u003cli\u003ea) Xue, J.‐W.; Guo, J. T.; He, Y. H.; Guan, Z. \u003cem\u003eAsian J. Org. Chem.\u003c/em\u003e\u003cstrong\u003e2017\u003c/strong\u003e, \u003cem\u003e6\u003c/em\u003e, 297‒304; b) Jun, T.; Li, Y.‐W.; Xu, D.‐Z. \u003cem\u003eChemistrySelect\u003c/em\u003e\u003cstrong\u003e2017\u003c/strong\u003e, \u003cem\u003e2\u003c/em\u003e, 3799‒3803.\u003c/li\u003e\n\u003cli\u003eXie, D.‐X.; Huang, Y.-M.; Lin, X.-M.; Kang, Z.-H.; Ni, C.-C.; Fu, Y.-T.; Ren, Z.; Liu, Y.-L. \u003cem\u003eChem. Eur. J.\u003c/em\u003e\u003cstrong\u003e2024\u003c/strong\u003e, \u003cem\u003e30\u003c/em\u003e, e202402654.\u003c/li\u003e\n\u003cli\u003eRamu, G.; Krishna, N. H.; Pawar, G.; Visweswara Sastry, K. N.; Nanubolu, J. B.; Babu, B. N. \u003cem\u003eACS Omega\u003c/em\u003e\u003cstrong\u003e2018\u003c/strong\u003e, \u003cem\u003e3\u003c/em\u003e, 12349‒12360.\u003c/li\u003e\n\u003cli\u003eChang, C.‐H.; Nadaraj, S.; Yu-Ting, L.; Hsin-Tsung, C.; Jeng-Liang, H. \u003cem\u003eAdv. Synth. Catal. \u003c/em\u003e\u003cstrong\u003e2020\u003c/strong\u003e, \u003cem\u003e362\u003c/em\u003e, 903‒912.\u003c/li\u003e\n\u003cli\u003eMishra, R.; Jana, A.; Panday, A. K.; Choudhury, L. H. \u003cem\u003eNew J. Chem.\u003c/em\u003e\u003cstrong\u003e2019\u003c/strong\u003e, \u003cem\u003e43\u003c/em\u003e, 2920‒2932.\u003c/li\u003e\n\u003cli\u003eChen, Q.; Wu, Y.; Hua, R. \u003cem\u003eMolecules\u003c/em\u003e\u003cstrong\u003e2019\u003c/strong\u003e, \u003cem\u003e24\u003c/em\u003e, 3773.\u003c/li\u003e\n\u003cli\u003eRamu, G.; Hari Krishna, N.; Pawar, G.; Visweswara Sastry, K. N.; Nanubolu, J. B.; Nagendra Babu, B. \u003cem\u003eACS Omega\u003c/em\u003e\u003cstrong\u003e2018\u003c/strong\u003e, \u003cem\u003e3\u003c/em\u003e, 12349-12360. \u003c/li\u003e\n\u003cli\u003eShi, H.; Wang, L.; Li, S.-S.; Liu, Y.; Xu, L. \u003cem\u003eOrg. Chem. Front.\u003c/em\u003e\u003cstrong\u003e2020\u003c/strong\u003e, \u003cstrong\u003e\u003cem\u003e7\u003c/em\u003e\u003c/strong\u003e, 747‒755.\u003c/li\u003e\n\u003cli\u003ea) Firoozi, N.; Roshan, Z.; Mohammadizadeh, M. R. \u003cem\u003eAppl. Organomet. Chem.\u003c/em\u003e\u003cstrong\u003e2017\u003c/strong\u003e, \u003cem\u003e32\u003c/em\u003e, e3963; b) Mohammadizadeh, M. R.; Saberi, D.; Taghavi, S. Z. \u003cem\u003eTetrahedron Lett.\u003c/em\u003e\u003cstrong\u003e2016\u003c/strong\u003e, \u003cem\u003e57\u003c/em\u003e, 264‒267; c) Mahdavinia, G. H.; Mohammadizadeh, M. R.; Ariapour, N.; Alborz, M.\u003cem\u003e Tetrahedron Lett.\u003c/em\u003e\u003cstrong\u003e2014\u003c/strong\u003e, \u003cem\u003e55\u003c/em\u003e, 1967‒1970.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 3 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Isatins, 2-Aminonaphthalene-1,4-dione, Pyrazolone, Spiro compounds, Chromeno-oxindoles. ","lastPublishedDoi":"10.21203/rs.3.rs-6693319/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6693319/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eIn this work, isatins, 2-amino-1,4-naphthoquinone, and 5-methyl-2-phenylpyrazolone reacted to create new derivatives of spiro and non-spiroindolin-2-ones (oxindoles) bearing 2-aminonaphthoquinone and pyrazolone substituents. The solvent regulated the pathway to the aforementioned chemicals. The later compounds were produced in an acetic acid solvent under reflux conditions, whereas the former compounds were made in an ethanol solvent. Nineteen novel oxindole derivatives were synthesized in high yields, and the structures were undoubtedly identified using their NMR data as well as X-ray analysis.\u003c/p\u003e","manuscriptTitle":"Solvent-controlled chemo-selective synthesis of 2-amino-3-(3-(5-hydroxy-1H-pyrazol-4-yl)-2-oxoindolin-3-yl)naphthalene-1,4-diones and 1H-spiro[benzo[6,7]chromeno[2,3-c]pyrazole-4,3'-indoline]-2',5,10-triones","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-06-09 11:45:23","doi":"10.21203/rs.3.rs-6693319/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-07-03T03:40:57+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-06-26T03:48:03+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-06-20T14:01:44+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"5804537424557653263354814023921029502","date":"2025-06-18T16:58:57+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"25711629436894618013528882323204544669","date":"2025-06-04T21:13:45+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-06-04T20:03:22+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-06-04T18:25:09+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-06-04T18:14:41+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-06-04T03:40:30+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2025-05-18T18:39:17+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"5266a72f-02d6-44ac-bbec-09c52b3ff97c","owner":[],"postedDate":"June 9th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":49746058,"name":"Physical sciences/Chemistry"},{"id":49746059,"name":"Physical sciences/Chemistry/Organic chemistry"},{"id":49746060,"name":"Physical sciences/Chemistry/Synthesis"}],"tags":[],"updatedAt":"2025-11-03T16:01:35+00:00","versionOfRecord":{"articleIdentity":"rs-6693319","link":"https://doi.org/10.1038/s41598-025-21805-w","journal":{"identity":"scientific-reports","isVorOnly":false,"title":"Scientific Reports"},"publishedOn":"2025-10-30 15:57:52","publishedOnDateReadable":"October 30th, 2025"},"versionCreatedAt":"2025-06-09 11:45:23","video":"","vorDoi":"10.1038/s41598-025-21805-w","vorDoiUrl":"https://doi.org/10.1038/s41598-025-21805-w","workflowStages":[]},"version":"v1","identity":"rs-6693319","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6693319","identity":"rs-6693319","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}