A sequential multicomponent reaction (SMCR) strategy: Synthesis of novel pyrazolo-1,4-dioxaspiro[4,5]decane grafted spiro-indenoquinoxaline pyrrolidine heterocycles

References

• (a) Trost, B. M. The Atom Economy-a Search for Synthetic Efficiency. Science 1991, 254, 1471–1477. DOI: 10.1126/science.1962206.
   PubMed Web of Science ®Google Scholar
  (b) Schreiber, S. L. Target-Oriented and Diversity-Oriented Organic Synthesis in Drug Discovery. Science 2000, 287, 1964–1969. DOI: 10.1126/science.287.5460.1964.
   PubMed Web of Science ®Google Scholar
  (c) Trost, B. M. Atom Economy—a Challenge for Organic Synthesis: Homogeneous Catalysis Leads the Way. Angew. Chem. Int. Ed. Engl. 1995, 34, 259–281. DOI: 10.1002/anie.199502591.
   Web of Science ®Google Scholar
• (a) Bonne, D.; Dekhane, M.; Zhu, J.-P. Modulating the Reactivity of alpha-isocyanoacetates: multicomponent synthesis of 5-methoxyoxazoles and furopyrrolones. Angew. Chem. Int. Ed. Engl. 2007, 46, 2485–2488. DOI: 10.1002/ange.200605005. DOI: 10.1002/anie.200605005.
   PubMed Web of Science ®Google Scholar
  (b) Dömling, A.; Ugi, I. Ugi, I. Multicomponent Reactions with Isocyanides. Angew. Chem. Int. Ed. 2000, 39, 3168–3210. DOI: 10.1002/1521-3773(20000915)39:18<3168::AID-ANIE3168>3.0.CO;2-U.
   PubMed Web of Science ®Google Scholar
  (c) Domling, A. Recent Developments in Isocyanide Based Multicomponent Reactions in Applied Chemistry. Chem. Rev 2006, 106, 17–89. DOI: 10.1021/cr0505728.
   PubMed Web of Science ®Google Scholar
  (d) Wang, Q.-F.; Hui, L.; Hou, H.; Yan, C.-G. Synthesis of Zwitterionic Salts of Pyridinium-Meldrum Acid and Barbiturate through Unique Four-component Reactions. J. Comb. Chem. 2010, 12, 260–265. DOI: 10.1021/cc900161z.
   PubMedGoogle Scholar
  (e) Burke, M. D.; Schreiber, S. L. A. A Planning Strategy for Diversity-oriented Synthesis. Angew. Chem. Int. Ed. Engl. 2004, 43, 46–58. DOI: 10.1002/anie.200300626.
   PubMed Web of Science ®Google Scholar
  (f) Tan, D. S. Diversity-Oriented Synthesis: Exploring the Intersections between Chemistry and Biology. Nat. Chem. Biol. 2005, 1, 74–84. DOI: 10.1038/nchembio0705-74.
   PubMed Web of Science ®Google Scholar
• (a) Graebin, C. S.; Ribeiro, F. V.; Rogério, K. R.; Kümmerle, A. E. Multicomponent Reactions for the Synthesis of Bioactive Compounds: A Review. Curr. Org. Synth. 2019, 16, 855–869. DOI: 10.2174/1570179416666190718153703.
   PubMed Web of Science ®Google Scholar
  (b) Cimarelli, C. Multicomponent Reactions. Molecules 2019, 24, 2372. DOI: 10.3390/molecules24132372.
   PubMed Web of Science ®Google Scholar
  (c) Pavlinov, I.; Gerlach, E. M.; Aldrich, L. N. Next Generation Diversity-Oriented Synthesis: A Paradigm Shift from Chemical Diversity to Biological Diversity. Org. Biomol. Chem. 2019, 17, 1608–1623. DOI: 10.1039/c8ob02327a.
   PubMed Web of Science ®Google Scholar
  (d) Liu, T.; Jia, W.; Xi, Q.; Chen, Y.; Wang, X.; Yin, D. Diversity-Oriented Synthesis of Heterocycles: Al(OTf)3-Promoted Cascade Cyclization and Ionic Hydrogenation. J. Org. Chem. 2018, 83, 1387–1393. DOI: 10.1021/acs.joc.7b02894.
   PubMed Web of Science ®Google Scholar
  (e) Guarnieri-Ibanez, A.; Medina, F.; Besnard, C.; Kidd, S. L.; Spring, D. R.; Lacour, J. Diversity-Oriented Synthesis of Heterocycles and Macrocycles by Controlled Reactions of Oxetanes with α-Iminocarbenes. Chem. Sci. 2017, 8, 5713–5720. DOI: 10.1039/C7SC00964J.
   PubMed Web of Science ®Google Scholar
  (f) Spandl, R. J.; Bender, A.; Spring, D. R. Diversity-Oriented Synthesis; a Spectrum of Approaches and Results. Org. Biomol. Chem. 2008, 6, 1149–1158. DOI: 10.1039/b719372f.
   PubMed Web of Science ®Google Scholar
  (g) Spring, D. R. Diversity-Oriented Synthesis; a Challenge for Synthetic Chemists. Org. Biomol. Chem. 2003, 1, 3867–3870. DOI: 10.1039/B310752N.
   PubMed Web of Science ®Google Scholar
  (h) Burke, M. D.; Berger, E. M.; Schreiber, S. L. Generating Diverse Skeletons of Small Molecules Combinatorially. Science 2003, 302, 613–618. DOI: 10.1126/science.1089946.
   PubMed Web of Science ®Google Scholar
• (a) Lledo, D.; Grindlay, G.; Sansano, J. M. 1,3-Dipolar Cycloadditions of Stabilized Azomethine Ylides and Electrophilic Alkenes Mediated by a Recyclable TSIL·AgOAc Catalyst. Eur. J. Org. Chem. 2019, 25, 4095–4100. DOI: 10.1002/ejoc.201900724;
   Web of Science ®Google Scholar
  (b) Gulevskaya, A. V.; Nelina-Nemtseva, J. I. 1,3-Dipolar Cycloaddition Reactions of Azomethine Ylides and Alkynes. Chem. Heterocycl. Comp. 2018, 54, 1084–1107. DOI: 10.1007/s10593-019-02398-5.
   Web of Science ®Google Scholar
  (c) Hashimoto, T.; Maruoka, K. Recent Advances of Catalytic Asymmetric 1,3-Dipolar Cycloadditions. Chem. Rev. 2015, 115, 5366–5412. DOI: 10.1021/cr5007182.
   PubMed Web of Science ®Google Scholar
  (d) Pandey, G.; Banerjee, P.; Gadre, S. R. Construction of Enantiopure Pyrrolidine Ring System via Asymmetric [3 + 2]-Cycloaddition of Azomethine Ylides. Chem. Rev. 2006, 106, 4484–4517. DOI: 10.1021/cr050011g.
   PubMed Web of Science ®Google Scholar
• (a) O’Hagan, D. Pyrrole, Pyrrolidine, Pyridine, Piperidine, Andtropane Alkaloids. Nat. Prod. Rep. 2000, 17, 435–446. DOI: 10.1039/a707613d.
   PubMed Web of Science ®Google Scholar
  (b) Chupakhin, E.; Babich, O.; Prosekov, A.; Asyakina, L.; Krasavin, M. Spirocyclic Motifs in Natural Products. Molecules 2019, 24, 4165. DOI: 10.3390/molecules24224165.
   Web of Science ®Google Scholar
• (a) Kumar, A.; Gupta, G.; Srivastava, S.; Bishnoi, A. J.; Saxena, R.; Kant, R.; Khanna, R. S.; Maulik, P. R.; Dwivedi, A. Novel Diastereoselective Synthesis of Spiropyrrolidine-Oxindole Derivatives as Anti-Breast Cancer Agents. RSC Adv. 2013, 3, 4731–4735. DOI: 10.1039/c3ra21595d.
   Web of Science ®Google Scholar
  (b) Abou-Gharbia, M. A.; Doukas, P. H. Synthesis of Tricyclic Aryl Spiro Compounds as Potential Antileukemic and Anticonvulsant Agents. Heterocycles 1979, 12, 637–640. DOI: 10.3987/R-1979-05-0637.
   Web of Science ®Google Scholar
• (a) Maurya, R. A.; Nayak, R.; Reddy, C. N.; Kapure, J. S.; Nanubolu, J. B.; Singarapu, K. K.; Ajitha, M.; Kamal, A. Regio- and Stereoselective Synthesis of Novel Spiropyrrolidines through 1,3-Dipolar Cycloaddition Reactions of Azomethine Ylides and 2-Styrylquinazolin-4(3H)-Ones. RSC Adv. 2014, 4, 32303–32311. DOI: 10.1039/C4RA03508A.
   Web of Science ®Google Scholar
  (b) Obniska, J.; Zagorska, A. Synthesis and Anticonvulsant Properties of New N-[(4-Arylpiperazin-1-yl)-Methyl] Derivatives of 3-Aryl Pyrrolidine-2,5-Dione and 2-Aza-Spiro[4.4]Nonane-1,3-Dione. Farmaco 2003, 58, 1227–1234. DOI: 10.1016/S0014-827X(03)00187-3.
   PubMedGoogle Scholar
• (a) De Clercq, E. Antiviral Agents Active against Influenza a Viruses. Nat Rev Drug Discov. 2006, 5, 1015–1025. DOI: 10.1038/nrd2175.
   PubMed Web of Science ®Google Scholar
  (b) Stylianakis, I.; Kolocouris, A.; Kolocouris, N.; Fytas, G.; Foscolos, G. B.; Padalko, E.; Neyts, J.; De Clercq, E. Spiro[Pyrrolidine-2,2′-Adamantanes]: Synthesis, Anti-Influenza Virus Activity and Conformational Properties. Bioorg. Med. Chem. Lett. 2003, 13, 1699–1703. DOI: 10.1016/S0960-894X(03)00231-2.
   PubMed Web of Science ®Google Scholar
• (a) Buciova, L.; Cizmarik, J.; Sedlarova, E.; Racanska, E. Preparation, Local Anaesthetic and Antiarrhythmic Activity of Pyrrolidinomethylcyclohexyl Esters of Alkoxysubstituted Phenyl Carbamic Acids. Pharmazie 1995, 50, 566–567.
   PubMed Web of Science ®Google Scholar
  (b) Kornet, M. J.; Thio, A. P. Oxindole-3-Spiropyrrolidines and -Piperidines. Synthesis and Local Anesthetic Activity. J. Med. Chem. 1976, 19, 892–898. DOI: 10.1021/jm00229a007.
   PubMed Web of Science ®Google Scholar
• Hussein, E. M.; Abdel-Monem, M. I. Regioselective Synthesis and anti-Inflammatory Activity of Novel Dispiro[Pyrazolidine-4,3′-Pyrrolidine-2′,3″-Indoline]-2″,3,5-Triones. Arkivoc 2011, 2011, 85–98. DOI: 10.3998/ark.5550190.0012.a07.
   Web of Science ®Google Scholar
• (a) Montana, M.; Montero, V.; Khoumeri, O.; Vanelle, P. Quinoxaline Derivatives as Antiviral Agents. A Systematic Review. Molecules 2020, 25, 2784–2803. DOI: 10.3390/molecules25122784.
   PubMed Web of Science ®Google Scholar
  (b) Janus, S. L.; Magdif, A. Z.; Erik, B. P.; Claus, N. Synthesis of Triazenopyrazole Derivatives as Potential Inhibitors of HIV-1. Monatsh. Chem. 1999, 130, 1167–1173. DOI: 10.1007/PL00010295.
   Web of Science ®Google Scholar
  (c) Singh Jadav, S.; Nayan Sinha, B.; Pastorino, B.; de Lamballerie, X.; Hilgenfeld, R.; Jayaprakash, V. Identification of Pyrazole Derivative as an Antiviral Agent against Chikungunya through HTVS. Lddd. 2015, 12, 292–301. DOI: 10.2174/1570180811666141001005402.
   Google Scholar
• (a) Kaushal, T.; Srivastava, G.; Sharma, A.; Negi, A. S. An Insight into Medicinal Chemistry of Anticancer Quinoxalines. Bioorg. Med. Chem. 2019, 27, 16–35. DOI: 10.1016/j.bmc.2018.11.021.;
   PubMed Web of Science ®Google Scholar
  (b) Bennani, F. E.; Doudach, L.; Cherrah, Y.; Ramli, Y.; Karrouchi, K.; Ansar, M.; Faouzi, M. E. Overview of Recent Developments of Pyrazole Derivatives as an Anticancer Agent in Different Cell Line. Bioorg. Chem. 2020, 97, 103470–103470. DOI: 10.1016/j.bioorg.2019.103470.
   PubMed Web of Science ®Google Scholar
• (a) Shen, Q.-K.; Gong, G.-H.; Li, G.; Jin, M.; Cao, L.-H.; Quan, Z.-S. Discovery and Evaluation of Novel Synthetic 5-Alkyl-4-Oxo-4,5-Dihydro-[1,2,4]Triazolo[4,3-a]Quinoxaline-1-Carbox-Amide Derivatives as anti-Inflammatory Agents. J. Enzyme. Inhib. Med. Chem. 2020, 35, 85–95. DOI: 10.1080/14756366.2019.1680658.
   PubMed Web of Science ®Google Scholar
  (b) Bekhit, A. A.; Hymete, A.; Bekhit, A. A.-D. A.; Damtew, A.; Aboul-Enein, H.-Y. Pyrazoles as Promising Scaffold for the Synthesis of anti-Inflammatory and/or Antimicrobial Agent: A Review. Mini Rev. Med. Chem. 2010, 10, 1014–1033. DOI: 10.2174/1389557511009011014. DOI: 10.2174/1389557511009011014.;
   PubMed Web of Science ®Google Scholar
  (c) Arán, V. J.; Ochoa, C.; Boiani, L.; Buccino, P.; Cerecetto, H.; Gerpe, A.; González, M.; Montero, D.; Nogal, J. J.; Gómez-Barrio, A.; et al. Synthesis and Biological Properties of New 5-Nitroindazole Derivatives. Bioorg. Med. Chem. 2005, 13, 3197–3207. DOI: 10.1016/j.bmc.2005.02.043.
   PubMed Web of Science ®Google Scholar
  (d) Hassan, G. S.; Rahman, D. E. A.; Abdelmajeed, E. A.; Refaey, R. H.; Salem, M. A.; Nissan, Y. M. New Pyrazole Derivatives: Synthesis, anti-Inflammatory Activity, Cycloxygenase Inhibition Assay and Evaluation of mPGES. Eur. J. Med. Chem. 2019, 171, 332–342. DOI: 10.1016/j.ejmech.2019.03.052.
   PubMed Web of Science ®Google Scholar
• (a) Wang, T.; Tang, Y.; Yang, Y.; An, Q.; Sang, Z.; Yang, T.; Liu, P.; Zhang, T.; Deng, Y.; Luo, Y. Discovery of Novel anti-Tuberculosis Agents with Pyrrolo[1,2-a]Quinoxaline-Based Scaffold. Bioorg. Med. Chem. Lett. 2018, 28, 2084–2090. DOI: 10.1016/j.bmcl.2018.04.043.;
   PubMed Web of Science ®Google Scholar
  (b) Pandit, U.; Dodiya, A. Synthesis and Antitubercular Activity of Novel Pyrazole–Quinazolinone Hybrid Analogs. Med. Chem. Res. 2013, 22, 3364–3371. DOI: 10.1007/s00044-012-0351-0.
   Web of Science ®Google Scholar
• (a) Cogo, J.; Cantizani, J.; Cotillo, I.; Sangi, D. P.; Corrêa, A. G.; Ueda-Nakamura, T.; Filho, B. P. D.; Martín, J. J.; Nakamura, C. V. Quinoxaline Derivatives as Potential Antitrypanosomal and Antileishmanial Agents. Bioorg. Med. Chem. 2018, 26, 4065–4072. DOI: 10.1016/j.bmc.2018.06.033.;
   PubMed Web of Science ®Google Scholar
  (b) Razzaghi-Asl, N.; Sepehri, S.; Ebadi, A.; Karami, P.; Nejatkhah, N.; Johari-Ahar, M. Insights into the Current Status of Privileged N-Heterocycles as Antileishmanial Agents. Mol. Divers. 2020, 24, 525–569. DOI: 10.1007/s11030-019-09953-4.
   PubMed Web of Science ®Google Scholar
• (a) Kumar, G.; Tanwar, O.; Kumar, J.; Akhter, M.; Sharma, S.; Pillai, C. R.; Alam, M. M.; Zama, M. S. Pyrazole-Pyrazoline as Promising Novel Antimalarial Agents: A Mechanistic Study. Eur. J. Med. Chem. 2018, 149, 139–147. DOI: 10.1016/j.ejmech.2018.01.082.
   PubMed Web of Science ®Google Scholar
  (b) Bonilla-Ramirez, L.; Rios, A.; Quiliano, M.; Ramirez-Calderon, G.; Beltrán-Hortelano, I.; Franetich, J. F.; Corcuera, L.; Bordessoulles, M.; Vettorazzi, A.; López de Cerain, A.; et al. Novel Antimalarial Chloroquine- and Primaquine-Quinoxaline 1,4-di-N-Oxide Hybrids: Design, Synthesis, Plasmodium Life Cycle Stage Profile, and Preliminary Toxicity Studies. Eur. J. Med. Chem. 2018, 158, 68–81. DOI: 10.1016/j.ejmech.2018.08.063.
   PubMed Web of Science ®Google Scholar
• (a) Gupta, D.; Radhakrishnan, M.; Thangaraj, D.; Kurhe, Y. Antidepressant and Anti-anxiety Like Effects of 4i (N-(3-chloro-2-methylphenyl) Quinoxalin-2-carboxamide), a Novel 5-HT3 Receptor Antagonist in Acute and Chronic Neurobehavioral Rodent Models. Eur. J. Pharmacol. 2014, 735, 59–67. DOI: 10.1016/j.ejphar.2014.04.008.
   PubMed Web of Science ®Google Scholar
  (b) Mohammed, A. A.; Gamal, E. A. A.; Alaa, A. H. Synthesis of Novel Pyrazole Derivatives and Evaluation of Their Antidepressant and Anticonvulsant Activities Euro. J. Med. Chem. 2009, 44, 3480–3487. DOI: 10.1016/j.ejmech.2009.01.032.
   Web of Science ®Google Scholar
• Danylkova, N. O.; Alcala, S. R.; Pomeranz, H. D.; McLoon, L. K. Neuroprotective Effects of Brimonidine Treatment in a Rodent Model of Ischemic Optic Neuropathy. Exp. Eye Res. 2007, 84, 293–301. DOI: 10.1016/j.exer.2006.10.002.
   PubMed Web of Science ®Google Scholar
• Mohanasundaram, U. M.; Chitkara, R.; Krishna, G. Smoking Cessation Therapy with Varenicline. Int. J. Chron. Obstruct. Pulmon. Dis. 2008, 3, 239–251. DOI: 10.2147/copd.s1848.
   PubMedGoogle Scholar
• (a) Gavaskar, D.; Suresh Babu, A. R.; Raghunathan, R.; Dharani, M.; Balasubramanian, S. An Expedient Sequential One-Pot Four Component Synthesis of Novel Steroidal Spiro-Pyrrolidine Heterocycles in Ionic Liquid. Steroids 2016, 109, 1–6. DOI: 10.1016/j.steroids.2016.02.010.
   PubMed Web of Science ®Google Scholar
  (b) Gavaskar, D.; Suresh Babu, A. R.; Raghunathan, R.; Dharani, M.; Balasubramanian, S. Ionic Liquid Accelerated Multicomponent Sequential Assembly of Ferrocene Grafted Spiro-Heterocycles. J. Organomet. Chem. 2014, 768, 128–135. DOI: 10.1016/j.jorganchem.2014.06.015.
   Web of Science ®Google Scholar
  (c) Babu, A. R. S.; Raghunathan, R.; Kumaresan, K.; Raaman, N. Synthesis, Characterization and anti-Microbial Activity of Novel Dispirooxindolopyrrolizidines. Curr. Chem. Biol. 2009, 3, 112–123. DOI: 10.2174/2212796810903010112.
   Google Scholar
  (d) Suresh Babu, A. R.; Raghunathan, R.; Madhivanan, R.; Ompraba, G.; Velmurugan, D. Raghu, R Synthesis, Characterization, anti-Microbial Activity and Docking Studies of Novel Dispirooxindolopyrrolidines. Curr. Chem. Biol. 2008, 2, 312–320. DOI: 10.2174/187231308785739729.
   Google Scholar
• (a) Suresh Babu, A. R.; Gavaskar, D.; Raghunathan, R. An Expedient Ultrasonic Assisted One-Pot Four Component Synthesis of Novel Ferrocene Grafted Pyrrolidine Heterocycles via [3 + 2]- Cycloaddition of Azomethine Ylides. J. Organomet. Chem. 2013, 745–746, 409–416. DOI: 10.1016/j.jorganchem.2013.08.014.
   Web of Science ®Google Scholar
  (b) Sureshbabu, A. R.; Raghunathan, R.; Satiskumar, B. K. A Facile Synthesis of Ferrocene Grafted N-Methyl-Spiropyrrolidines through 1,3-Dipolar Cycloaddition of Azomethine Ylides. Tetrahedron Lett. 2009, 50, 2818–2821. DOI: 10.1016/j.tetlet.2009.03.175.
   Web of Science ®Google Scholar
  (c) Suresh Babu, A. R.; Raghunathan, R.; Baskaran, S. An Expedient Synthesis of Ferrocene Grafted Spirooxindolopyrrolizidines via [3 + 2]-Cycloaddition of Azomethine Ylides. Tetrahedron 2009, 65, 2239–2243. DOI: 10.1016/j.tet.2009.01.044.
   Web of Science ®Google Scholar
• Ghalib, R. M.; Hashim, R.; Sulaiman, O.; Hemamalini, M.; Fun, H. K. 11H-Indeno-[1,2-b]Quinoxalin-11-One. Acta Cryst. 2010, E 66, o1494. DOI: 10.1107/s1600536810019252.
   Google Scholar
• Suresh Babu, A. R.; Gavaskar, D.; Raghunathan, R. A Facile Synthesis of Novel Ferrocene Grafted Spiro-Indeoquinoxaline Pyrrolizidines via One Pot Multicomponent [3 + 2] Cycloaddition of Azomethine Ylide. Tetrahedron Lett. 2012, 53, 6676–6681. DOI: 10.1016/j.tetlet.2012.09.104.
   Web of Science ®Google Scholar
• Gavaskar, D.; Suresh Babu, A. R. An Easy Access to Highly Substituted Trispiroheterocycles – Synthesis of Novel Pyrazolo-1,4-Dioxa-Spiro[4,5]Decane Grafted Spiro-Oxindolopyrrolidines via a Sequential Multicomponent Reaction. Synth. Commun. 2021, 51, 1066–1075.  DOI: 10.1080/00397911.2020.1866613.
   Web of Science ®Google Scholar
• (a) Rappe, A. K.; Casewit, C. L. Molecular Mechanics across Chemistry; University Science Books: Sausalito, CA, 1997. http://www.chm.colostate.edu/mmac;
   Google Scholar
  (b) Leach, A. R. Molecular Modelling, Principles and Applications; chapter 3; Addison Wesley Longman: Essex, 1996.;
   Google Scholar
  (c) Burkert, U.; Allinger, N. L. “Molecular Mechanics,” ACS Monograph 177; American Chemical Society: Washington, DC, 1982.
   Google Scholar
• Almansour, A. I.; Arumugam, N.; Kumar, R. S. An Efficient, Sustainable Approach to the Chemo and Regioselective Synthesis of Novel Spiroindenoquinoxaline Grafted Piperidone Hybrid Heterocycles. J. King. Saud. Univ-Sci. 2020, 32, 3059–3064. DOI: 10.1016/j.jksus.2020.08.013.
   Web of Science ®Google Scholar
• Dimmock, J. R.; Padmanilayam, M. P.; Zello, G. A.; Nienaber, K. H.; Allen, T. M.; Santos, C. L.; De Clercq, E.; Balzarini, J.; Manavathu, E. K.; Stables, J. P. Cytotoxic Analogues of 2,6-Bis(Arylidene)Cyclohexanones. Eur. J. Med. Chem. 2003, 38, 169–177. DOI: 10.1016/s0223-5234(02)01444-7.
   PubMed Web of Science ®Google Scholar