An Environmentally-Benign Synthesis of Spiro-benzo[1,4]diazepines Using Multi Phase Nano-titania as a Highly Efficient Catalyst via MAOS Technique

Author(s): Sharoni Gupta, Pinki B. Punjabi*, Chetna Ameta, Rakshit Ameta

Journal Name: Current Organic Synthesis

Volume 16 , Issue 3 , 2019

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Graphical Abstract:


Aim and Objective: Benzodiazepines and indole fused heterocycles are pharmacologically significant scaffolds. Trivial work on indole fused benzodiazepine compounds is reported in the literature. Hence, it is imperative to explore the synthesis of indole-fused benzodiazepines that may act as a template for biological studies in the future. Hence, in the present work, the synthesis of indole fused benzodiazepine derivatives was undertaken using multi-phase nano-titania as catalyst under microwave irradiation.

Materials and Methods: MAOS technique was used to carry out the synthesis of spiro-benzo [1,4]diazepine derivatives in the presence of multiphase nano-titania as a catalyst. Nano-titania was prepared by sol-gel method and characterized by XRD, FT-IR, FESEM, EDS and thermogravimetric techniques. The synthesized spiro-benzo [1,4] diazepine derivatives were identified by physical and spectral methods.

Results: Synthesized compounds were obtained in excellent yields in a short span of time. The synthesis was also carried out in the presence of conventional catalysts in addition to nano-titania. Among all the catalysts, the best result was obtained with nano-titania. The amount of nano-titania was optimized to be 0.05g giving 93- 95% yield of products. The study of reusability of nano-titania revealed that it could be reused up to four times with a negligible change in efficiency.

Conclusion: The paper reports an efficient, cost-effective and environmentally benign approach for the synthesis of spiro-benzo [1,4] diazepine derivatives in the presence of multiphase nano-titania catalyst under microwave irradiation.

Keywords: Spiro-benzo [1, 4]diazepines, o- phenylenediamine, nano-titania, microwave irradiation, isatin, p-substituted acetophenones.

Chikhale, R.V.; Khedekar, P.B. Ultrasound assisted one-pot synthesis of some 1, 5-benzodiazepine derivatives. Curr. Catal., 2013, 2(2), 1-5.
Wang, L.Z.; Li, X.Q.; An, Y.S. 1,5-Benzodiazepine derivatives as potential antimicrobial agents: design, synthesis, biological evaluation, and structure-activity relationships. Org. Biomol. Chem., 2015, 13(19), 5497-5509.
Bhat, I.; Kumar, A. Synthesis and anti-inflammatory activity of some novel 1,5 benzodiazepine derivatives. Asian J. Pharm. Clin. Res., 2016, 9(4), 63-66.
Pavlovsky, V.I.; Tsymbalyuk, O.V.; Martynyuk, V.S.; Kabanova, T.A.; Semenishyna, E.A.; Khalimova, E.I.; Andronati, S.A. Analgesic effects of 3- substituted derivatives of 1,4-benzodiazepines and their possible mechanisms. Neurophysiology, 2013, 45(5,6), 427-432.
Kamal, A.; Srikanth, Y.V.V.; Janaki Ramaiah, M. Khan. M.N.A.; Reddy, M.K.; Ashraf, Md.; Lavanya, A.; Pushpavalli, S.N.C.V.L.; Pal-Bhadra, M. Synthesis, anticancer activity and apoptosis inducing ability of bisindole linked pyrrolo[2,1-c][1,4]benzodiazepine conjugates. Bioorg. Med. Chem. Lett., 2012, 22(1), 571-578.
Pandeya, S.N.; Rajput, N. Synthesis and anticonvulsant activity of various Mannich and Schiff bases of 1,5-benzodiazepines. Int. J. Med. Chem., 2012, 2012, Article ID 237965.
Chinnasamy, G.; Subramani, K.; Srinivasan, V. Green synthesis, characterization and anxiolytic, sedative and hypnotic activity of pyrimidine based diazepine derivatives. Biomed. Res., 2017, 28(2), 525-531.
Sangshetti, J.N.; Chouthe, R.S.; Jadhav, M.R.; Sakle, N.S.; Chabukswar, A.; Gonjari, I.; Darandale, S.; Shinde, D.B. Green synthesis and anxiolytic activity of some new dibenz-[1,4] diazepine-1-one analogues. Arab. J. Chem., 2017, 10(1), 1356-1363.
Cheng, P.; Zhang, Q.; Ma, Y-B.; Jiang, Z-Y.; Zhang, X-M.; Zhang, F-X.; Chen, J-J. Synthesis and in vitro anti-hepatitis B virus activities of 4-aryl-6-chloro-quinolin-2-one and 5-aryl-7-chloro-1,4-benzodiazepine derivatives. Bioorg. Med. Chem. Lett., 2008, 18(13), 3787-3789.
Zhang, L.; Deng, X-S.; Meng, G-P.; Zhang, C.; Liu, C-C.; Chen, G-Z.; Jiang, X-L.; Zhao, Q-C.; Hu, C. Design, synthesis and biological evaluation of a novel series of indole-3-carboxamide derivatives for cancer treatment as EGFR inhibitors. Lett. Drug Des. Discov., 2018, 15(1), 70-83.
Schuck, D.C.; Jordao, A.K.; Nakabashi, M.; Cunha, A.C.; Ferreira, V.F.; Garcia, C.R. Synthetic indole and melatonin derivatives exhibit antimalarial activity on the cell cycle of the human malaria parasite plasmodium falciparum. Eur. J. Med. Chem., 2014, 78, 375-382.
Olgen, S. Recent development of new substituted indole and azaindole derivatives as anti-HIV agents. Mini Rev. Med. Chem., 2013, 13(12), 1700-1708.
Hong, W.; Jingyang, L.; Chang, Z.; Tan, X.; Yang, H.; Ouyang, Y.; Yang, Y.; Kaur, S.; Paterson, I.C.; Ngeow, Y.F.; Wang, H. Synthesis and biological evaluation of indole core-based derivatives with potent antibacterial activity against resistant bacterial pathogens. J. Antibiot., 2017, 70, 832-844.
Atluntas, T.G.; Yilmaz, N.; Coban, T.; Olgen, S. Synthesis and antioxidant activity of indole derivatives containing 4-substituted piperazine moieties. Lett. Drug Des. Discov., 2017, 14(4), 380-386.
Thikekar, T.U.; Selvaraju, M.; Sun, C-M. Skeletally diverse synthesis of indole-fused diazocine and diazepine frameworks by one-pot, two-component cascade reaction. Org. Lett., 2016, 18(2), 316-319.
Biradar, J.S.; Somappa, S.B. Synthesis of novel indolyl benzo[b][1,4]diazepins as potent antimicrobial and antioxidant agents. Arab. J. Chem., 2016, 9(2), S1063-S1068.
Kharate, R.M.; Deohate, P.P.; Berad, B.N. Microwave assisted synthesis, characterization and antimicrobial study of substituted benzo-(5,6-e)-[1,3]-diazepine-4,7-dione derivatives. Chem. Sci. Trans., 2013, 2(1), 65-68.
Zhu, X-T.; Jia-Yan, Liu. J-Y.; Jiang, B.; Tu, S-J. Microwave-assisted aqueous reactions: An efficient route to benzodiazepines. J. Heterocyclic. Chem., 2015, 52(1), 92-96.
Chan, C-K.; Tsai, Y-L.; Chan, Y-L.; Chang, M-Y. Synthesis of substituted 2,3-benzodiazepines. J. Org. Chem., 2016, 81(20), 9836-9847.
Sibous, S.; Ghailane, T.; Houda, S.; Ghailane, R.; Boukhris, S.; Souizi, A. Green and efficient method for the synthesis of 1,5-benzodiazepines using phosphate fertilizers as catalysts under solvent-free conditions. Mediterr. J. Chem., 2017, 6(2), 53-59.
Polshettiwar, V.; Asefa, T. Eds., Introduction to Nanocatalysis. In: Nanocatalysis Synthesis and Applications, 1st ed; John Wiley & Sons, Inc.: Hoboken, NJ, USA, 2013; pp. 1-9.
Sheldon, R.A.; Downing, R.S. Heterogeneous catalytic transformations for environmentally friendly production. Appl. Catal. A, 1999, 189(2), 163-183.
Cole-Hamilton, D.J. Homogeneous catalysis—New approaches to catalyst separation, recovery, and recycling. Science, 2003, 299(5613), 1702-1706.
Chaturvedi, S.; Dave, P.N.; Shah, N.K. Application of nano-catalyst in new era. J. Saudi Chem. Soc., 2012, 16(3), 307-325.
Hemalatha, K.; Madhumitha, G.; Kajbafvala, A.; Anupama, N.; Sompalle, R.; Roopan, S.M. Function of nanocatalyst in chemistry of organic compounds revolution: an overview. J. Nanomater., 2013, Article ID 341015.
Vellaisamy, K.; Li, G.; Ko, C-N.; Zhong, H-J.; Fatima, S.; Kwan, H-Y.; Wong, W-J.; Kwong, C-Y.; Tan, W.; Leung, C-H.; Ma, D-L. Cell imaging of dopamine receptor using agonist labeling iridium(III) complex. Chem. Sci., 2018, 9(5), 1119-1125.
Lu, L.; Chan, D.S-H.; Kwong, D.W.J.; He, H-Z.; Leung, C-H.; Ma, D-L. Detection of nicking endonuclease activity using a G-quadruplex-selective luminescent switch-on probe. Chem. Sci., 2014, 5(12), 4561-4568.
Burke, C.S.; Byrne, A.; Keyes, T.E. Targeting photoinduced DNA destruction by Ru(II) tetraazaphenanthrene in live cells by signal peptide. J. Am. Chem. Soc., 2018, 140(22), 6945-6955.
Boyle, K.M.; Barton, J.K. A family of rhodium complexes with selective toxicity toward mismatch repair-deficient cancers. J. Am. Chem. Soc., 2018, 140(16), 5612-5624.
Lin, S.; Wei, G.; Yang, C.; Lu, L.; Mergny, J-L.; Leung, C-H.; Ma, D-L. Luminescence switch-on detection of protein tyrosine kinase-7 using a G-quadruplex-selective probe. Chem. Sci., 2015, 6(7), 4284-4290.
Liu, J-B.; Yang, C.; Ko, C-N.; Vellaisamy, K.; Yang, B.; Lee, M-Y.; Leung, C-H.; Ma, D-L. A long lifetime iridium(III) complex as a sensitive luminescent probe for bisulfite detection in living zebrafish. Sens. Actuators B Chem., 2017, 243, 971-976.
Jindakun, C.; Hsieh, S-Y.; Bode, J.W. Iridium-catalyzed synthesis of saturated N-heterocycles from aldehydes and SnAP reagents with continuous flow photochemistry. Org. Lett., 2018, 20(7), 2071-2075.
Chen, W-W.; Xu, M-H. Recent advances in rhodium-catalyzed asymmetric synthesis of heterocycles. Org. Biomol. Chem., 2017, 15(5), 1029-1050.
Wan, K.Y.; Roelfes, F.; Lough, A.J.; Hahn, F.E.; Morris, R.H. Iridium and rhodium complexes containing enantiopure primary amine-tethered N-heterocyclic carbenes: synthesis, characterization, reactivity, and catalytic asymmetric hydrogenation of ketones. Organometallics, 2018, 37(3), 491-504.
Selvaganapathy, M.; Raman, N. Pharmacological activity of anfew transition meta complexes: a rshort review. J. Chem. Biol. Ther., 2016, 1(2), 108.
Elhakim, H.K.A.; Azab, S.M.; Fekry, A.M. A novel simple biosensor containing silver nanoparticles/propolis (bee glue) for microRNA let-7a determination. Mater. Sci. Eng. C, 2018, 92, 489-495.
Wang, Y.; Sun, C.; Zhao, X.; Cui, B.; Zeng, Z.; Wang, A.; Liu, G.; Cui, H. The application of nano-TiO2 photo semiconductors in agriculture. Nanoscale Res. Lett., 2016, 11(1), 529.
Su, H.; Liu, D-D.; Zhao, M.; Hu, W-L.; Xue, S-S.; Cao, Q. Le, X-Y.; Ji, L-N.; Mao, Z-W. Dual-Enzyme characteristics of polyvinylpyrrolidone-capped iridium nanoparticles and their cellular protective effect against H2O2-induced oxidative damage. ACS Appl. Mater. Interfaces, 2015, 7(15), 8233-8242.
Moradi, L.; Tadayon, M. Green synthesis of 3,4-dihydropyrimidinones using nano Fe3O4@meglumine sulfonic acid as a new efficient solid acid catalyst under microwave irradiation. J. Saudi Chem. Soc., 2018, 22, 66-75.
Rao, G.B.D.; Nagakalyanb, S.; Prasad, G.K. Solvent-free synthesis of polyhydroquinoline derivatives employing mesoporous vanadium ion doped titania nanoparticles as a robust heterogeneous catalyst via the Hantzsch reaction. RSC Adv, 2017, 7, 3611-3616.
Luo, X.; Chidchob, P.; Rahbani, J.F.; Sleiman, H.F. Encapsulation of gold nanoparticles into DNA minimal cages for 3D-anisotropic functionalization and assembly. Small, 2018, 14(5)
Castro, L.; Blázquez, M.L.; Muñoz, J.A.; González, F.G.; Ballester, A. Mechanism and applications of metal nanoparticles prepared by bio-mediated process. Rev. Adv. Sci. Eng., 2014, 3(3), 199-216.
Haghighi, M.; Nikoofar, K. Nano TiO2/SiO2: An efficient and reusable catalyst for the synthesis of oxindole derivatives. J. Saudi Chem. Soc., 2016, 20(1), 101-106.
Abdolmohammadi, S. Solvent-free synthesis of 4,5-dihydropyrano[c]chro-mene derivatives over TiO2 nanoparticles as an economical and efficient catalyst. Curr. Catal., 2013, 2(2), 116-121.
Bajpai, S.; Singh, S.; Srivastava, V. Multi phase nano-TiO2 as an effective heterogeneous catalyst for condensation reaction of isatin derivatives with 1,2-diaminobenzene under solvent free conditions: A greener “NOSE”approach. Arab. J. Chem., 2014, 2014, 1-8.
Bahramia, K.; Khodaeia, M.M.; Naalia, F. TiO2 nanoparticles catalysed synthesis of 2-arylbenzimidazoles and 2-arylbenzothiazoles using hydrogen peroxide under ambient light. J. Exp. Nanosci., 2016, 11(2), 148-160.
Fatahpour, M.; Sadeh, F.M.; Hazeri, N.; Maghsoodlou, M.T.; Hadavi, M.S.; Mahnaei, S. Ag/TiO2 nano-thin films as robust heterogeneous catalyst for one-pot, multi-component synthesis of bis (pyrazol-5-ol) and dihydropyrano[2,3-c]pyrazole analogs. J. Saudi Chem. Soc., 2017, 21(8), 998-1006.
Vijayalakshmi, R.; Rajendran, K.V. Synthesis of Nano-TiO2 by Sol-Gel route: Effect of solvent and temperature on the optical properties. Int. J. Pure Appl. Phys., 2011, 7(1), 105-115.
Perumal, S.; Sambandam, C.G.; Prabu, K.M.; Ananthakumar, S. Synthesis and charecterization studies of nano TiO2 prepared via sol-gel method. Int. J. Res. Eng. Technol, 2014, 3(4), 651-657.
Ramazani, M.; Farahmandjou, M.; Firoozabadi, T.P. Effects of nitric acid on particle morphology of nano- TiO2. Int. J. Nanosci. Nanotechnol., 2015, 11(2), 115-122.
Phonkhokkong, T.; Thongtem, T.; Thongtem, S.; Phurvangrat, A.; Promnopas, W. Synthesis and characterization of TiO2 nanopowders for fabrication of dye sensitized solar cells. Dig. J. Nanomater. Bios., 2016, 11(1), 81-90.
Wongkaew, A.; Jansome, W.; Khemchan, S.; Sawaengmit, N.; Mitpapan, S. Synthesis of nanoparticles of mixed oxides containing titanium, cerium, silver and silicon: phase transformation. Energy Rec. J., 2010, 1(2), 73-77.
Cenovar, A.; Paunovic, P.; Grozdavov, A.; Makreski, P.; Fidancevska, E. Preparation of nano-crystalline TiO2by sol-gel method using titanium tetraisopropoxide (TTIP) as a precursor. Adv. Nat. Sci.: Theory Appl, 2012, 1(2), 133-142.
Kalaivani, T.; Anilkumar, P. Role of temperature on the phase modification of TiO2 nanoparticles synthesized by the precipitation method. Silicon, 2018, 10(4), 1679-1686.
Avci, N.; Smet, F. Poelman, de Velde, N.V.; Buysser, K.D.; Driessche, I.V.; Poelman, D. Characterization of TiO2 powders and thin films prepared by non-aqueous sol-gel techniques. J. Sol-Gel Sci. Technol., 2009, 52, 424.

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Article Details

Year: 2019
Published on: 17 June, 2019
Page: [435 - 443]
Pages: 9
DOI: 10.2174/1570179415666181109095849
Price: $65

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