C-NUCLEOPHILIC MODIFICATION OF 2-(4-OXO-3,4-DIHYDRO-2-QUINAZOLINYL)-2-(TETRAHYDRO-2-FURANYLIDENE)ACETORINTHRILES
DOI: https://doi.org/10.17721/1728-2209.2025.1(60).12
Keywords:
heterocycles, condensed heterocycles, 2-(4-oxo-3,4-dihydro-2-quinazolinyl)-2-(tetrahydro-2-furanylidene)acetonitriles, acrylonitriles, cyanopyridines, 2-hetaryl-3-(hetarylidene)acrylonitriles, recyclizationAbstract
Background. Nitrogen-containing heterocycles are important objects of both fundamental and applied research. They are used in the creation of fine organic synthesis products, pharmaceuticals, agrochemicals, dyes, and more. Functionalized azaheterocycles are promising research targets due to their potential application as efficient building blocks for the synthesis of new heterocyclic derivatives and their broad spectrum of biological activity. Therefore, the search for new approaches and reagents for the construction of such heterocyclic systems is an urgent task. The aim of the present study was to expand the synthetic potential of 2-(2-hetaryl)-2-(tetrahydro-2-furanylidene)acetonitriles for the design of condensed heterocyclic derivatives.
Methods. Organic synthesis of new functionalized derivatives based on 2-(4-oxo-3,4-dihydro-2-quinazolinyl)-2-(tetrahydro-2-furanylidene)acetonitriles; structural elucidation and characterization of the synthesized compounds using IR spectroscopy, 1H and 13C NMR spectroscopy, and mass spectrometry.
Results. The interaction features of 2-(4-oxo-3,4-dihydro-2-quinazolinyl)-2-(tetrahydro-2-furanylidene)acetonitriles with malononitrile have been established, and the influence of structural factors on the regioselectivity of intramolecular heterocyclizations has been demonstrated. A possibility of forming a mixture of regioisomers – 9-amino-7-(3-hydroxypropyl)-11-oxo-11H-pyrido[2,1-b]quinazoline-6,8-dicarbonitriles and 1-amino-3-(3-hydroxypropyl)-6-oxo-6H-pyrido[1,2-a]quinazoline-2,4-dicarbonitriles, as well as the pathway for their directed transformation into 9-amino-7-(3-hydroxypropyl)-2,4-disubstituted-11-oxo-11H-pyrido[2,1-b]quinazoline-6,8-dicarbonitriles, has been shown. A method has been proposed for the stepwise formation of 2-(6-amino-3,5-dicyano-4-(3-hydroxypropyl)-2-oxopyridin-1(2H)-yl)-N-methylbenzamide and 3-(3-hydroxypropyl)-1,6-dioxo-5,6-dihydro-1H-pyrido[1,2-a]quinazoline-2,4-dicarbonitrile starting from N-substituted furanilideneacetonitrile and malononitrile.
Conclusions. Based on the C-nucleophilic modification of 2-(4-oxo-3,4-dihydro-2-quinazolinyl)-2-(tetrahydro-2-furanylidene)acetonitriles, methods for the directed synthesis of 9-amino-7-(3-hydroxypropyl)-2,4-disubstituted-11-oxo-11H-pyrido[2,1-b]quinazoline-6,8-dicarbonitriles, 2-(6-amino-3,5-dicyano-4-(3-hydroxypropyl)-2-oxopyridin-1(2H)-yl)-N-methylbenzamide, and 3-(3-hydroxypropyl)-1,6-dioxo-5,6-dihydro-1H-pyrido[1,2-a]quinazoline-2,4-dicarbonitrile have been developed.
References
Anwara, H. F., Elnagdi, M. H. (2009). Recent developments in aminopyrazole chemistry. ARKIVOC. 1, 198–250. https://doi.org/10.3998/ark.5550190.0010.107
Erian A. W. (1993). The chemistry of β-enaminonitriles as versatile reagents in heterocyclic synthesis. Chem. Rev. 93(6), 1991-2005. https://doi.org/10.1021/cr00022a002
Ge, Yan- Qing, Jia, Jiong, Yang, He, Tao, Xu Tang, Wang, Jian-Wu. (2011). The synthesis, characterization and optical properties of novel pyrido[1,2-a]benzimidazole derivatives Dyes Pigm., 88, 344–349. https://doi.org/10.1016/j.dyepig.2010.08.005
Hranjec, M., Horak, E., Tireli, M., Pavlović, G. (2012). Synthesis, crystal structure and spectroscopic study of novel benzimidazoles and benzimidazo[1,2-a]quinolines as potential chemosensors for different cations. Dyes Pigm. 95, 644–656. https://doi.org/10.1016/j.dyepig.2012.05.024
Jardosh, H. H., Sangani, C. B., Patel, M. P., Patel, R. G. (2013). One step synthesis of pyrido[1,2-a]benzimidazole derivatives of aryloxypyrazole and their antimicrobial evaluation. Chin. Chem. Lett. 24(2), 123–126. https://doi.org/10.1016/j.cclet.2013.01.021
Khilya O.V., Milokhov D.S., Postupalenko V.Yu., Turov A.V., Volovenko Y.M. (2013). A ring opening reaction of 2-hetaryl-2-(tetrahydro-2-furanylidene)acetonitriles with amino acids. Monatsh. Chem., 144, 1071–1079. https://doi.org/10.1007/s00706-013-0967-x (b)
Khilya, O. V., Volovnenko, T. A., Turov, A. V., Zubatyuk, R. I., Shishkin, O. V., Volovenko, Yu. M. (2013). Synthesis of 2-(2-hetaryl)-6-hydroxy-3-(R-amino)-2-hexenenitriles. Chem. Heterocycl. Compd., 48(12), 1770–1780. https://doi.org/10.1007/s10593-013-1208-2 (a)
Khilya, O.V., Volovnenko, T.A., Turov, A.V., Zubatyuk, R.I., Shishkin, O.V., Volovenko, Yu.M. (2011). Synthesis of 2-hetaryl-2-(tetrahydrofuran-2-ylidene)acetonitriles. Chem. Heterocycl. Comp., 47(9), 1141–1154. https://doi.org/10.1007/s10593-011-0885-y
Khilya, Olga V., Milokhov, Demyd S., Kononets, Lyudmyla A., Kobzar, Oleksandr L., Vovk, Andriy I., Volovenko, Yulian M. (2018). Synthesis and evaluation of new 2,6-diamino-5-hetarylpyrimidines as inhibitors of dihydrofolate reductase. Monatsh. Chem., 149, 813–822. https://doi.org/10.1007/s00706-017-2032-7
Lyons, D. M., Huttunen, K. M., Browne, K. A., Ciccone, A., Trapani, J. A, Denny, W. A, Spicer, J. A. (2011). Inhibition of the cellular function of perforin by 1-amino-2,4-dicyanopyrido[1,2-a]benzimidazoles. Bioorg. Med. Chem. 19, 4091–4100. https://doi.org/10.1016/j.bmc.2011.05.013
Manfroni, G., Meschini, F., Barreca, M. L., Leyssen, P., Samuele, A., Iraci, N., Sabatini, S., Massari, S., Maga, G., Neyts, J., Cecchetti, V. (2012). Pyridobenzothiazole derivatives as new chemotype targeting the HCV NS5B polymerase. Bioorg. Med. Chem. 20, 866–876. https://doi.org/10.1016/j.bmc.2011.11.061
Milokhov, D. S., Khilya, O. V., Turov, A. V., Zubatyuk, R. I., Palamarchuk, G. V., Shishkin, O. V., Chekotilo, A. A., Volovenko, Yu. M. (2013). Reactions of 2-(2-hetaryl)-2-(tetrahydrofuran-2-ylidene)acetonitriles with tertiary amines. Chem. Heterocycl. Compd., 48, 1761–1769. https://doi.org/10.1007/s10593-013-1207-3
Milokhov, Demyd S., Khilya, Olga V., Turov, Alexander V., Medviediev, Volodymyr V., Shishkin, Oleg V., Volovenko, Yulian M. (2014). Hydroxypropyl substituted nitrogen bridgehead fused cyanopyridines. Tetrahedron, 70, 1214-1222. https://doi.org/10.1002/chin.201429186
Milokhov, Demyd S., Khilya, Olga V., Volovenko, Yulian M., Palamarchuk, Gennady V., Shishkin, Oleg V. (2012). The reaction of 2-hetaryl-2-(tetrahydro-2-furanyliden)acetonitriles with 1,3-N,N-binucleophiles. Synlett, 23(14), 2063-2068. https://doi.org/10.1055/s-0031-1290435
Ndakala, A. J., Gessner, R. K., Gitari, P. W., October, N., White, K. L, Hudson, A., Fakorede, F., Shackleford, D. M., Kaiser, M., Yeates, C., Charman, S. A., Chibale, K. (2011). Antimalarial Pyrido[1,2-a]benzimidazoles. J. Med. Chem. 54, 4581–4589. https://doi.org/10.1021/jm200227r
Pätzel, M., Liebscher, J. (1995). Ring Transformation Reactions of Bridged 1,3-Dicarbonyl Heteroanalogs as a Versatile Entry to Side Chain Functionalized Alkylheterocycles. Synthesis. 8, 879–894. https://doi.org/10.1055/s-1995-4432
Pieroni, M., Tipparaju, S. K., Lun, S., Song, Y., Sturm, A. W., Bishai, W. R,, Kozikowski, A. P. (2011). Pyrido[1,2-a]benzimidazole-Based Agents Active Against Tuberculosis (TB), Multidrug-Resistant (MDR) TB and Extensively Drug-Resistant (XDR) TB. ChemMedChem. 6(2), 334–342. https://doi.org/10.1002/cmdc.201000490
Rakesh, K. P., Darshini, N., Shubhavathi, T., Mallesha, N. (2017). Biological Applications of Quinazolinone Analogues: A Review. Organic & Medicinal Chem IJ. 2(2), 41-45. https://doi.org/10.19080/OMCIJ.2017.02.555585
Refaat H. M. (2012). Synthesis of potential anticancer derivatives of pyrido[1,2-a]benzimidazoles. Med. Chem. Res. 21(7), 1253–1260. https://doi.org/10.1007/s00044-011-9636-y
Rörsch, F., Buscató, E., Deckmann, K., Schneider, G., Schubert-Zsilavecz, M., Geisslinger, G., Proschak, E., Grösch, S. (2012). Structure−Activity Relationship of Nonacidic Quinazolinone Inhibitors of Human Microsomal Prostaglandin Synthase 1 (mPGES1). J. Med. Chem. 55(8), 3792-3803. https://doi.org/10.1021/jm201687d
Saad, I., Hafiz, A., Ramiz, M. M. M., Mahmoud, F. F., Darwish, E. S. (2008). β-Enaminonitriles in heterocylic synthesis: Synthesis of new tetrahydropyridinethione, pyridopyrimidines, pyridotriazines and dihydropyridines. J. Chem. Sci. 120(3), 339-345. https://doi.org/10.1007/s12039-008-0057-5
Takeshita, H., Watanabe, J., Kawakami, K., Takahashi, H., Takemura, M., Kitamura, A., Someya, K., Nakajima, R. (2010). Novel pyridobenzimidazole derivatives exhibiting antifungal activity by the inhibition of b-1,6-glucan synthesis. Bioorg. Med. Chem. Lett. 20, 3893–3896. https://doi.org/10.1016/j.bmcl.2010.05.024
Yang, He, Ge, Yan-Qing, Jia, Jiong, Wang, Jian-Wu (2011). Synthesis andopticalpropertiesofnovelpyrido[1,2-a]benzimidazole-containing 1,3,4-oxadiazole derivatives J. Lumin., 131, 749–755. https://doi.org/10.1016/j.jlumin.2010.11.030
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