Green one-pot, four-component synthesis of spiro[indoline-3,4′-pyrano[2,3-c]pyrazole] derivatives using amino-functionalized nanoporous silica SBA-15 under solvent-free conditions J. Serb. Chem. Soc. 80 (10) 1265–1272 (2015) UDC 547.75’81’77:542.913+544.351– JSCS–4794 145.82+546.284–31 Original scientific paper 1265 Green one-pot, four-component synthesis of spiro[indoline-3,4′- -pyrano[2,3-c]pyrazole] derivatives using amino-functionalized nanoporous silica SBA-15 under solvent-free conditions GHODSI MOHAMMADI ZIARANI1*, MAHSHID RAHIMIFARD1, FATEMEH NOURI1 and ALIREZA BADIEI2 1Department of Chemistry, Alzahra University, Vanak Square, P. O. Box 19938939973, Teh- ran, Iran and 2School of Chemistry, College of Science, University of Tehran, Tehran, Iran (Received 30 September 2014, revised 18 May, accepted 24 May 2015) Abstract: Propylamine functionalized nanoporous silica (SBA–Pr-NH2) was used as an efficient heterogeneous solid basic nanoreactor in the synthesis of 6′-amino-1′H-spiro[indoline-3,4′-pyrano[2,3-c]pyrazol]-2-one derivatives 5 through a one-pot, four-component condensation of isatin derivatives 1, acti- vated methylene reagents 2, hydrazine hydrate 3 and β-keto esters 4 under solvent-free conditions at room temperature. Keywords: amino-functionalized nanoporous silica; solvent-free; nanoporous silica; four components; one-pot; spiro indole; pyranopyrazole. INTRODUCTION The indole ring is the core structure of many alkaloids, natural products and medicinal agents.1 Compounds containing this moiety present a variety of anti- bacterial and antifungal activities.2 In addition, it was reported that substitution of the indole ring with heterocycles at the 3-carbon position significantly imp- roves biological properties.3 The resulting spirooxindoles are found in various pharmaceutical components and natural products (Scheme 1).4 Heterocyclic compounds consisting of pyrano[2,3-c]pyrazoles with numer- ous biological properties, such as anticancer,5 antibacterial,6 antimicrobial,7 anti- inflammatory,8 ChK1 kinase inhibitors,9 antifungal10 and molluscicidal acti- vity11 occupy a special place in medicinal chemistry. Thus, considerable attention has been focused on the development of new modified methods for their synthesis. Spiroindoline-pyranopyrazole derivatives can be obtained through various synthetic methods. Shestopalov et al. reported a four-component reaction for their synthesis by condensation of isatin, hydrazine, malononitrile and β-keto * Corresponding author. E-mails: gmziarani@hotmail.com; gmohammadi@alzahra.ac.ir doi: 10.2298/JSC140930045M _________________________________________________________________________________________________________________________ (CC) 2015 SCS. All rights reserved. Available on line at www.shd.org.rs/JSCS/ 1266 ZIARANI et al. esters using triethylamine in ethanol under reflux conditions.12 This reaction can also be affected using different catalysts, such as piperidine,13,14 L-proline,15 [DMBSI]HSO4,16 Mn(bpyo)2/MCM-41,17 Bmim(OH)/chitosan,18 uncapped SnO2 quantum dots,19 4-(dimethylamino)pyridine20 and meglumine.21 Another com- mon synthetic method for the synthesis of this class of compounds is a three- -component condensation of pyrazolone, malononitrile and isatin in the presence of catalysts such as triethylamine,22 ZnS nanoparticles,4 L-proline,23 K2CO3,24 triethanolamine25 and NaHCO3.26 However these methods have some disadvant- ages, such as long reaction times, expensive and non-reusable catalysts and hard work-up or catalyst removal. Scheme 1. Compounds with spirooxindole skeleton. In recent years, mesoporous materials especially mesoporous silica, such as SBA-15 (Santa Barbara Amorphous), have attracted considerable attention. SBA- -15 is a unique inorganic solid support with high surface area, large pore size and high thermal stability.27 Grafting various organic compounds on the surface of SBA-15 could improve the catalytic activity of the silica surface. Amino func- tionalized SBA-15 (SBA–Pr-NH2) was proved to be an efficient heterogeneous mesoporous solid base catalyst that could be used in the synthesis of various heterocyclic compounds.28–30 In this work, an attempt was made to develop a modified methodology in the synthesis of spiro[indoline-3,4′-pyrano[2,3-c]pyr- azole] derivatives 5 using the green solid heterogeneous base nanocatalyst SBA– –Pr-NH2 under solvent free conditions at room temperature via a one-pot four- -component condensation of isatin derivatives 1, activated methylene reagents 2, hydrazine hydrate 3 and β-keto esters 4. RESULTS AND DISCUSSION This report is devoted to the study of the four component condensation of isatin derivatives 1, activated methylene reagents (malononitrile or ethyl cyano- acetate) 2, hydrazine hydrate 3 and β-keto esters 4 catalyzed by nanoporous base catalyst of SBA–Pr-NH2 under solvent-free conditions at room temperature (Scheme 2). In initiation of this study, various conditions employing different solvents, such as ethanol or water, and a solvent-free system with or without cat- alyst at room temperature were evaluated. Among the tested conditions, the best _________________________________________________________________________________________________________________________ (CC) 2015 SCS. All rights reserved. Available on line at www.shd.org.rs/JSCS/ SYNTHESIS OF SPIRO[INDOLINE-3,4′-PYRANO[2,3-c]PYRAZOLE] USING SBA–PR-NH2 1267 result was obtained in the presence of SBA–Pr-NH2 using the solvent-free sys- tem at room temperature (Table I). Scheme 2. Synthesis of 6′-amino-1′H-spiro[indoline-3,4′-pyrano[2,3-c]pyrazol]-2-one derivatives 5 in the presence of SBA–Pr-NH2. TABLE I. The optimization of the reaction conditions in the synthesis of 5a at room tem- perature Yield, % t / h Solvent Catalyst Entry 50 8 EtOH – 1 50 3 H2O – 2 70 2 EtOH SBA–Pr-NH2 3 80 0.25 – SBA–Pr-NH2 4 Under the optimized conditions, various 6′-amino-1′H-spiro[indoline-3,4′- -pyrano[2,3-c]pyrazol]-2-one derivatives 5a–f were synthesized in the presence of SBA–Pr-NH2 using several isatin derivatives 1a–d, activated methylene reagents 2a and b, hydrazine hydrate 3 and β-keto esters 4a–c. Results are sum- marized in Table II. Under these conditions, the reactions were realized easily to produce spiroindoline-pyranopyrazole derivatives in good yields. It should be noted that the presence of halogens on the reacting isatins (Entries 3 and 5) dec- reased the reaction time in comparison to that for to isatin (Entry 1). It may be related to inductive withdrawing effects of halogens on the carbonyl group of isatin. On the other hand, replacing malononitrile with ethyl cyanoacetate inc- reased the reaction time, which was attributed to the competing formation of the Knoevenagel adduct of isatin and the activated methylene reagents. TABLE II. Four-component synthesis of spiro[indoline-3,4′-pyrano[2,3-c]pyrazole] deri- vatives 5a–f in the presence of SBA–Pr-NH2 Literature m.p., °C M.p. range, °C Yield % t min Product R5 R4 R3 R2 R1 Entry 279–28026 278–280 80 15 5a MeEt CN H H 1 279–28026 278–280 87 15 5a MeMe CN H H 2 282–28326 281–283 85 10 5b MeEt CN H Br 3 Not reported 268–270 78 15 5c MeEt CN CH2Ph H 4 297–29815 296–298 83 10 5d MeEt CN H Cl 5 280–28113 279–281 85 15 5e Ph Et CN H H 6 281–28231 280–282 80 20 5f MeEt CO2Et H H 7 281–28231 280–282 83 25 5f MeMeCO2Et H H 8 _________________________________________________________________________________________________________________________ (CC) 2015 SCS. All rights reserved. Available on line at www.shd.org.rs/JSCS/ 1268 ZIARANI et al. The reusability of the catalyst was investigated under the optimized con- ditions for the synthesis of the model compound 5a. As shown in Table III, the recycling process was completed four times with no significant decrease in the catalyst activity. The yields for the four runs were found to be 80, 78, 78 and 76 %, respectively. TABLE III. Synthesis of the spiroindoline–pyranopyrazole 5a with recycled SBA–Pr-NH2 Parameter 1st run 2nd run 3rd run 4th run Time, min 15 15 20 20 Yield, % 80 78 78 76 A possible mechanism for synthesis of 6′-amino-1′H-spiro[indoline-3,4′-pyr- ano[2,3-c]pyrazol]-2-one derivatives 5 is presented in Scheme 3. The initiation step begins with the two-component condensation of hydrazine hydrate 3 and β-keto esters 4 to afford the 5-alkyl-2,4-dihydro-3H-pyrazol-3-one 7, which was deprotonated by SBA–Pr-NH2. Then a fast Knoevenagel condensation occurred Scheme 3. Plausible mechanism. _________________________________________________________________________________________________________________________ (CC) 2015 SCS. All rights reserved. Available on line at www.shd.org.rs/JSCS/ SYNTHESIS OF SPIRO[INDOLINE-3,4′-PYRANO[2,3-c]PYRAZOLE] USING SBA–PR-NH2 1269 between isatin derivatives 1 and activated methylene reagents 2. Michael addi- tion of 8 to 10 afforded compound 11, which was followed by enol–keto tauto- merization to yield intermediate 12. Addition of hydroxyl to cyano group pro- vided compound 13. Tautomerization of compound 13 yielded the desired pro- duct 5 (Scheme 3). Several varying conditions have been reported in the literature for the syn- thesis of 6′-amino-1′H-spiro[indoline-3,4′-pyrano[2,3-c]pyrazol]-2-one derivat- ives 5, as given in Table IV. TABLE IV. Comparison of several conditions Year Yield, % t / min ConditionsSolvent Catalyst Entry 200912 76–85 5–30 Reflux EtOH N(Et)3 1 201014 80-97 300 r.t. H2O Piperidine 2 201213 73–93 60 UltrasoundEtOH Piperidine 3 201416 88–96 1–2 60 °C – [DMBSI]HSO4 4 201517 89–92 18–24 Reflux H2O Mn(bpyo)2/MCM-41 5 201418 89–93 150–210r.t. Bmim(OH)/Chitosan 6 201419 90–93 120–150r.t. H2O Uncapped SnO2 quantum dot7 201420 75–85 60 60 °C EtOH 4-(Dimethylamino)pyridine 8 201321 90–93 27–35 r.t. EtOH/H2OMeglumine 9 201315 83–92 10–30 80 °C H2O L-proline 10 Present work 78–87 10–25 r.t. – SBA–Pr-NH2 11 In the current method, the basic nanoreactor with hexagonal platelet mor- phology, several reusabilities, ease of handling and removal from the reaction medium could make it an economic and efficient green solid heterogeneous nanocatalyst for this synthesis. Furthermore, the short reaction time, solvent-free conditions, room temperature and simple procedure are other advantages of this method. Structure of the catalyst The surface of the catalyst was analyzed by different methods, such as TGA, FT-IR and others, which demonstrated that the organic groups (propylamine) were immobilized into the pores.29 The same ordered mesoscopic structured silica with (100), (110) and (200) reflections in the low-angle XRD patterns of SBA-15 and SBA–Pr-NH2 indi- cated a two-dimensional hexagonal symmetrical array of nano-channels. This means that the structural integrity of SBA-15 was not affected during the func- tionalization reaction. Moreover, the TEM image of SBA–Pr-NH2 confirmed the parallel channels were similar to the configuration of the pores in SBA-15. This indicated that during grafting of the aminopropyl-triethoxysilane (APTES) groups, the pores of SBA-15 did not collapse.29 _________________________________________________________________________________________________________________________ (CC) 2015 SCS. All rights reserved. Available on line at www.shd.org.rs/JSCS/ 1270 ZIARANI et al. Fig. 1. Functionalized SBA-15. EXPERIMENTAL Materials and methods The chemical compounds used in this work were all obtained from Merck and were employed without further purification. The IR spectra were recorded from KBr disks using a Fourier-transform (FT)-IR Bruker Tensor 27 instrument. The melting points were measured using the capillary tube method with an Electrothermal 9200 apparatus. 1H- and 13C-NMR were run on a Bruker DPX at 400 or 250 MHz using TMS as an internal standard. The mass spectra were obtained on an Agilent 5973 MS detector. The physical, analytical and spectral data of compounds 5a–f are given in the Sup- plementary material to this paper. Synthesis and functionalization of SBA-15 The nanoporous compound SBA-15 was synthesized and functionalized according to a previous report. The triblock copolymer Pluronic P126 was used as the directing agent for the preparation of SBA-15 as nanoporous silica.32,33 Functionalization of SBA-15 was performed through post-grafting of calcined SBA-15 with (3-aminopropyl)triethoxysilane (APTES, Fig. 1).29 General procedure for the synthesis of the 6′-amino-1'H-spiro[indoline-3,4′-pyrano[2,3-c]- pyrazol]-2-one derivatives A suspension of SBA–Pr-NH2 (0.02 g), isatin derivatives 1 (1 mmol), methylene reagent (malononitrile or ethyl cyanoacetate) 2 (1 mmol), hydrazine hydrate (80 %) 3 (1.4 mmol, 0.07 g) and β-keto ester 4 (1 mmol) was stirred at room temperature under solvent-free conditions for an appropriate time as indicated in Table II. Upon completion of the reaction as monitored by TLC (thin layer chromatography), the solid product was dissolved in hot ethyl acetate and the insoluble catalyst was removed by filtration. The filtrate was cooled to room temperature to yield pure crystals of a spiro[indoline-3,4′-pyrano[2,3-c]pyrazole] derivative 5. CONCLUSION In conclusion, amino-functionalized SBA-15 could serve as an effi- cient heterogeneous solid basic nanocatalyst for the synthesis of 6′-amino- 1′H-spiro[indoline-3,4′-pyrano[2,3-c]pyrazol]-2-one derivatives 5 at room _________________________________________________________________________________________________________________________ (CC) 2015 SCS. All rights reserved. Available on line at www.shd.org.rs/JSCS/ SYNTHESIS OF SPIRO[INDOLINE-3,4′-PYRANO[2,3-c]PYRAZOLE] USING SBA–PR-NH2 1271 temperature and under solvent-free conditions. This procedure offers several advantages, such as short reaction times, mild reaction conditions, high yield of products, easy workup procedure, and reusability of the cat- alyst. SUPPLEMENTARY MATERIAL Physical, analytical and spectral data of compounds 5a–f are available electronically from http://www.shd.org.rs/JSCS/, or from the corresponding author on request. Acknowledgement. We gratefully acknowledge the financial support from the Research Council of Alzahra University and the University of Tehran. И З В О Д ЗЕЛЕНА СИНТЕЗА ДЕРИВАТА СПИРО[ИНДОЛИН-3,4'-ПИРАНО[2,3-c]ПИРАЗОЛА], У ЈЕДНОМ РЕАКЦИОНОМ КОРАКУ, УПОТРЕБОМ АМИНО ФУНКЦИОНАЛИЗОВАНИХ НАНО-ЧЕСТИЦА СИЛИКА-ГЕЛА БЕЗ РАСТВАРАЧА GHODSI MOHAMMADI ZIARANI1, MAHSHID RAHIMIFARD1, FATEMEH NOURI1 и ALIREZA BADIEI2 1 Department of Chemistry, Alzahra University, Vanak Square, P. O. Box No. 19938939973, Tehran, Iran и 2 School of Chemistry, College of Science, University of Tehran, Tehran, Iran Нано-честице силика-гела функционализоване пропиламином употребљене су као ефикасан хетерогени нанореактор у синтези деривата 6'-амино-1'H-спиро[индолин-3,4'- пирано[2,3-c]пиразол]-2-она 5 у четворокомпонентној реакцији кондензације деривата изатина 1, активних метиленских реагенаса 2, хидразин-хидрата 3 и β-кeтo-естара 4 без присуства растварача, на собној температури. (Примљено 30. септембра 2014, ревидирано 18. маја, прихваћено 24. маја 2015) REFERENCES 1. R. Sundberg, The Chemistry of Indoles, Vol. 18, Elsevier, New York, USA, 2012, p. 431 2. T. C. Leboho, J. P. Michael, W. A. van Otterlo, S. F. van Vuuren, C. B. de Koning, Bioorg. Med. Chem. 19 (2009) 4948 3. A. Abdel-Rahman, E. Keshk, M. Hanna, S. M. El-Bady, Bioorg. Med. Chem. 12 (2004) 2483 4. A. Dandia, V. Parewa, A. K. Jain, K. S. Rathore, Green Chem. 13 (2011) 2135 5. J.-L. Wang, D. Liu, Z.-J. Zhang, S. Shan, X. 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