A Facile One-Pot Synthesis of 3-Methylbenzisoxazoles via a Key Intermediate of ortho-Ethoxyvinyl Nitroaryls by Domino Rearrangement and Their Anti- Inflammatory Activity

Author(s): Bashetti Nagaraju, Jagarlapudi V. Shanmukhakumar, Nareshvarma Seelam, Tondepu Subbaiah, Bethanamudi Prasanna*

Journal Name: Current Organic Synthesis

Volume 16 , Issue 8 , 2019

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Background: Recently, there has been a lot of scientific interest in exploring the syntheses of oxygen and nitrogen-containing heterocyclic compounds due to their pharmacological activities. In addition, benzisoxazoles play a very important role in organic synthesis as key intermediates.

Objective: In this paper, we focused on developing a novel synthetic route for biologically active arylisoxazoles under normal conditions, and simplified it to get high purities and yields, and also reported their anti-inflammatory activities.

Methods: An efficient and simple method has been explored for the synthesis of novel 3-methyl arylisoxazoles from o-nitroaryl halides via o-ethoxyvinylnitroaryls, using dihydrated stannous chloride (SnCl2.2H2O) in MeOH / EtOAc (1:1) via Domino rearrangement in one pot synthesis.

Results: We synthesized novel 3-methylarylisoxazoles from o-nitroarylhalides via o-ethoxyvinylnitroaryls, using dihydrated stannous chloride (SnCl2.2H2O) in MeOH / EtOAc (1:1) via domino rearrangement. In this reduction, nitro group and ethoxy vinyl group change to the functional acyl ketones, followed by hetero cyclization. Here, the reaction proceeds without the isolation of intermediates like 2-acylnitroarenes and 2- acylanilines. All the synthesized compounds were completely characterized by the NMR and mass spectra. The compounds were also explored for their anti-inflammatory activity by carrageenan-induced inflammation in the albino rats (150-200 g) of either sex used in this entire study with the use of Diclofenac sodium as the standard drug. The initial evaluations identified leading targets with good to moderate anti-inflammatory activity.

Conclusion: A simple, one-pot and convenient method has been explored for the synthesis of novel 3- methylarylisoxazoles with high purity and reaction yields. All the compounds 3a, 3c, 3d, 3f, 3g and 3h exhibited 51-64% anti-inflammatory activities.

Keywords: Arylisoxazoles, domino rearrangement, SnCl2.2H2O, anti-inflammatory activities, o-ethoxyvinyl nitro aryls, diclofenac.

Hasagawa, H. Utilization of zonisamide in patients with chronic pain orepilepsyrefractory to other treatments, a retrospective, open label, uncontrolled studying a VA hospital. Curr. Med. Res. Opin., 2004, 20(5), 577-580.
Masuda, Y.; Utsui, Y.; Sharashi, Y.; Karasawa, T.; Yoshida, K.; Shimizu, M. Relationships between plasma concentrations of diphenylhydantoin, phenobarbital, carbamazepine, and 3-sulfamoylmethyl-1,2-benzisoxazole (AD-810), a new anticonvulsant agent, and their anticonvulsant or Neurotoxic effects in experimental animals. Epilepsia, 1979, 20(6), 623-633.
Uno, H.; Kurukova, M.; Masuda, Y.; Nishimura, H. Studies on 3-substituted 1,2-benzisoxazole derivatives. 6. Syntheses of 3-(sulfamoylmethyl)-1,2-benzisoxazole derivatives and their anticonvulsant activities. J. Med. Chem., 1979, 22(2), 180-183.
Liu, Y.; Cui, Z.; Bin, L.; Cai, B.; Li, Y.; Wang, Q. Design, synthesis, and herbicidal activities of novel 2-cyanoacrylates containing isoxazole moieties. J. Agric. Food Chem., 2010, 58, 2685-2689.
Hwang, I.T.; Kim, H.R.; Jeon, D.J.; Hong, K.S.; Song, J.H.; Cho, K.Y. 5-(2,6-Difluorobenzyl)oxymethyl-5-methyl-3-(3-methylthiophen-2-yl)-1,2-isoxazoline as a useful rice herbicide. J. Agric. Food Chem., 2005, 53, 8639-8643.
Jain, M.; Kwon, C.H. 1,2-Benzisoxazole phosphorodiamidates as novel anticancer prodrugs requiring bioreductive activation. J. Med. Chem., 2003, 46(25), 5428-5436.
Thakar, K.A.; Bhawal, B.M. Synthesis and antimicrobial screening of amino-1,2-binzisoxazoles andsulphanilamido-1,2-benzisoxazoles. Curr. Sci., 1978, 47, 950-952.
Ji, Z.; Ahmed, A.A.; Albert, D.H.; Bouska, J.J.; Bousquet, P.F.; Cunha, G.A.; Diaz, G.; Glaser, K.B.; Guo, J.; Harris, C.M.; Li, J.; Marcotte, P.A.; Moskey, M.D.; Oie, T.; Pease, L.; Soni, N.B.; Stewart, K.D.; Davidsen, S.K.; Michaelides, M.R. 3-Amino-benzo[d]isoxazoles as novel multitargeted inhibitors of receptor tyrosine kinases. J. Med. Chem., 2008, 51, 1231-1241.
Thon, V.; Harle, P.; Scholmerich, J.; Kuklinek, P.; Lokaj, J.; Straub, R.H. Allergy, 2007, 2017, 1320-1325.
Cullen, M.D.; Deng, B.L.; Hartman, T.L.; Watson, K.M.; Buckheit, R.W., Jr; Pannecouque, C.; De Clercq, E.; Cushman, M. Synthesis and biological evaluation of alkenyldiarylmethane hiv-1 non-nucleoside reverse transcriptase inhibitors that possess increased hydrolytic stability. J. Med. Chem., 2007, 50, 4854-4867.
Barcelo, M.; Ravina, E.; Masaguer, C.F.; Dominguez, E.; Areias, F.M.; Brea, J.; Loza, M.I. Synthesis and binding affinity of new pyrazole and isoxazole derivatives as potential atypical antipsychotics. Bioorg. Med. Chem. Lett., 2007, 17, 4873-4877.
Severance, D.L.; Gardiner, E.M.M.; Noble, S.A.; Lou, B.; Borchardt, A.J.; Kahraman, M.; Roppe, J.R.; Siegel, D.L.; Scranton, S.A. Design, synthesis, and biological evaluation of a library of 1-(2-thiazolyl)-5-(trifluoro-methyl)pyrazole-4-carboxamides. J. Comb. Chem., 2006, 4, 23-32.
Donohue, B.A.; Michelotti, E.L.; Reader, J.C.; Reader, V.; Stirling, M.; Tice, C.M. Design, synthesis, and biological evaluation of a library of 1-(2-thiazolyl)-5-(trifluoromethyl)pyrazole-4-carboxamides. J. Comb. Chem., 2002, 4, 23-32.
Forood, B. New 3-substituted-2,1-benzoxazoles: Synthesis and antimicrobial activities. Arab. J. Chem., 2000, 10(2), S2464-S2470.
Chaker, A.; Najahi, E.; Chatriant, O.; Valentino, A.; Tene, N.; Treilhour, M.; Chabchoub, F.; Nepveu, F. New 3-substituted-2,1-benzoxazoles: synthesis and antimicrobial activities. Arab. J. Chem., 2017, 10(2), S2464-S2470.
Elguero, J. The cleavage of 1-amino-2-nitrobenzylphosphonates in a basic medium formation of the 3-amino-2,1-benzoxazole derivatives. Tetrahedron, 1984, 53, 11399-11410.
Boduszek, B.; Halama, A.; Zon, J. The cleavage of 1-amino-2-nitrobenzylphosphonates in a basic medium formation of the 3-amino-2,1-benzoxazole derivatives. Tetrahedron, 1997, 53, 11399-11410.
Altaf-ur-Rahman. Boulton, A. J. Electrophillic substitution in anthranils. Tetrahedron, 1966, 7, 49-56.
Han, R.; Son, K.I.; Ahn, G.H.; Jun, Y.M.; Lee, B.M.; Park, Y.; Kim, B.H. Reductive heterocyclizations via indium/iodine-promoted one-pot conversion of 2-nitroaryl aldehydes, ketones, and imines. Tetrahedron Lett., 2006, 47, 7295-7299.
Kim, B.H.; Jin, Y.; Jun, Y.M.; Han, R.; Baik, W.; Lee, B.M. Indium mediated reductive heterocyclization of 2-nitroacylbenzenes or 2-nitroiminobenzenes toward 2,1-benzisoxazoles in aqueous media. Tetrahedron Lett., 2000, 41, 2137-2140.
Stokes, B.J.; Vogel, C.V.; Urnezis, L.K.; Pan, M.; Driver, T.G. Intramolecular Fe(II)-catalyzed N−O or N−N bond formation from aryl azides. Org. Lett., 2010, 12, 2884-2887.
Winter, C.A.; Risley, E.A.; Nuss, G.N. Carrageenin-induced edema in hind paw of the rat as an assay for anti-inflammatory drugs. Proc. Soc. Exp. Biol., 1962, 111, 544-547.
Moussa, G.; Alaaedddine, R.; Alaeddine, L.M.; Nassra, R.; Belal, A.S.F.; Ismail, A. EI-Yazbi, A.F.; Abdel-Ghany, Y.S. Novel click modifiable thioquinazolinones as anti-inflammatory agents: Design, synthesis, biological evaluation and docking study. Eur. J. Med. Chem., 2018, 144, 635-650.
Ahmed, M.; Qadir, M.A.; Hameed, A.; Imran, M.; Muddassar, M. Screening of curcumin-derived isoxazole, pyrazoles, and pyrimidines for their anti-inflammatory, antinociceptive, and cyclooxygenase-2 inhibition. Chem. Biol. Drug Des., 2018, 91(1), 338-343.

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Article Details

Year: 2019
Page: [1161 - 1165]
Pages: 5
DOI: 10.2174/1570179416666190925125450
Price: $65

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