The reaction of MND with aryldiazonium chlorides followed by cyclization afforded
the pyridazinimine derivatives. Reaction of the latter with another mole of malononitrile
produce only pyrido[3,2-c]pyridazine derivatives. Reaction of 4-aminopyridazinone-3-
carboxylic acid esters with malononitrile gave only pyridazine-3-carboxylic acid.Fundação para a Ciência e a Tecnologia (FCT) - POCTI-SFA-3-686, SFRH/BPD/31490/2006Fundo Europeu de Desenvolvimento Regional (FEDER

Campos, Ana M. F. Oliveira

Rodrigues, Lígia M.

Salaheldin, Abdellatif M.

Universidade do Minho: RepositoriUM

 1 Heterocyclic synthesis with nitriles: Synthesis of pyridazine and pyridopyridazine derivatives.  Ana M. F. Oliveira-Campos*, Abdellatif M. Salaheldin, Lígia M. Rodrigues Centro de Química, IBQF, Universidade do Minho, Campus de Gualtar, 4710-057 Braga, Portugal amcampos@quimica.uminho.pt Introduction  During the past few decades increasing interest in the synthesis and properties of pyridazines, pyridazinones, pyridopyridazines, and pyridopyridazinones has been observed.  Pyridopyridazines and pyridopyridazinones show wide spectrum of biological activities as described in the literature [1-4]. Both classes of substances are of interest as antiviral and cancer therapies, since their structures and properties resemble those of certain current pteridines and purines. Recently pyridazinone nucleus has been extensively studied in the search for new and selective medicinal agents as drugs acting on the cardiovascular system [5,6]. It has been discovered that several aminopyridazinones showed remarkable biological activities; for example, nootropic (memory-improving) [7]. In contrast to the phthalazinones, their aza analogs, pyridopyridazinones, are as yet relatively little studied their synthesis, chemical properties and further applications. The primary reasons for this are the difficulties associated with the preparation of pyridine starting materials which can easily be transformed into pyridopyridazinones. The only general method for the synthesis of the system pyridopyridazinones involves the cyclization of o-acylpyridinecarboxylic acids [8] and their derivatives (ester [8] and disubstitute amides [9] or of methyl esters of o-cyanopyridinecarboxylic acids [10] with hydrazine and monosubstituted hydrazines). Continuing our interest on the synthesis of pyridazinones [11,12] we present in this work their synthesis applying a method which was previously employed in only a few cases to the preparation of pyridazinones [13].  Results and Discussion The literature showed that, preparation of compounds 1 and 2 could be obtained from cyclocondensation of arylhydrazonomalononitriles with malononitrile, 2-amino-1,1,3-tricycanopropene, and 3-amino-2-cyanopent-2-ene dicarboxylate [14], [15] respectively (Scheme 1). NNNNH2NCR2ArCNR1a, R1 = NH, R2 NH2b, R1 = O, R2 = OH2NNNNH2NCH2N NHArCN1NCNCNNHArCNCNEt3N2 NNHArH2NCNCNNH2NCCN3CNXH2NYa, X = Y = CNb, X = Y = CO2Et45 Scheme 1  2 It was decided to build compounds of type 1 and 2 by both routes, from the reaction of 3-methoxyphenyl hydrazonomalononitrile with two equivalents of malononitrile (MN) and from coupling of arene diazonium chloride with 2-amino-1,1,3-tricycanopropene (MND), and 3-amino-2-cyanopent-2-ene dicarboxylate (ethyl or methyl cyano dimmer) to obtain pyridazine derivatives and further reaction of the latter with another mole of MN to obtain the desired products and confirm the way of cyclization of those compounds when reacted with MN.  The reaction of compound 4a (MND), with aryldiazonium chlorides followed by cyclization in ethanolic triethylamine afforded the pyridazinimine derivatives 8a,b. Reaction of compounds 8a,b with another mole of malononitrile could takes place in two different pathways to afford pyrido[3,2-c]pyridazine or pyrido[2,3-d]pyridazine derivatives.  It was found that the reaction of pyridazine derivatives 8a,b with malononitrile afforded 1a,b in a good yield. Compound 1a,b could also be obtained from the reaction of 7a,b with malononitrile under refluxing in ethanolic triethylamine solution for 4 h. The data in our hands, IR, mass, 1H and 13C NMR, are in accordance with the structure of pyrido[3,2-c] pyridazines 1 [15, cf. experimental part] (Scheme 2). Moreover, the presence of an NOE enhancement between the NH group and CH aromatic protons in structure 1 and the absence of an NOE between NH and NH2 group for structure 2 allowed establishing the structure 1.  The reaction of 2-(1-amino-2-cyanoethylidene)malonic acid diethyl 4b or dimethyl 4c ester and 4-chlorobenzene diazonium chloride to afford the hydrazo derivative 11a,b which could be cyclised into pyridazinone 12a,b. The reaction of compounds 12a,b with malononitrile produce only pyridazine-3-carboxylic acid 13 which could also be obtained by boiling of compound 11 in ethanolic triethylamine solution for long time to furnish 13 (Scheme 2).  Experimental All melting points were measured on a Gallenkamp apparatus and are uncorrected. IR spectra were determined on a Perkin Elmer FTIR-1600 using Nujol emulsions between NaCl plates. 1HNMR spectra were recorded at 300 MHz and 13C NMR spectra were determined at 75.4 MHz both on Varian Unity plus spectrometer. In the NMR spectra was used TMS as internal reference. Low resolution EI mass spectra were determined on a Unicam GC-MS 120. FAB or high resolution mass spectra were obtained on a VG Ultima or AutoSpec E spectrometers. Elemental analysis data were obtained on a Leco CHNS-932.  General procedure for the preparation of compounds 8a,b and 12a,b To a solution of each of 7a,b and 11a,b (10 mmol) in ethanol (25 ml) was added triethylamine (1ml). The reaction mixture was refluxed for 2-6 h, then allowed to cool, the precipitated solid products formed were collected by filtration, washed with cold water, and recrystalized from ethanol or ethanol/DMF (1:1) to afford 8a,b and 13a,b respectively.   3 CNCNN N ClXCNCNNNHXCNCN2NNHXH2N CNCNNH2CNNCCNCNH2NNCCNCNN N ClXCNCNH2NNCN NHXNNXH2N CNNCNNH2HNCNH2NNCN NXNHCNCNH2NNCCNCNCNCNCNNNH NH2NC CNCNH2NCNNN NCNH2NHNNH2CNNH2N NNHH2NNCCNXH2NNCN NNHNH2NCCNXOrEtOH/TEA1a,b234 4567a,b8a,b910EtOH/TEAEtOH/TEAa, X = 3-OCH3b, X = 4-ClX = 3-OCH3X = Ha, X = 3-OCH3b, X = 4-ClNOEHNOENOE7.92.2  CNXH2NY+N=N ClEtOHAcONaCNXH2NYN NHNN OCNNH2Y/ 3 hCNNCEtOH/TEA 2ml/ 7 hEtOH/TEA 1ml11124 b, X = Y = CO2Etc, X = Y = CO2Mea, Y = CO2Etb, Y = CO2MeClClClNN OCNNH2HOOC13ClEtOH/TEA 2ml / 7 h Scheme 2   4 4-Amino-6-imino-1-(3-methoxyphenyl)-1,6-dihydro-pyridazine-3,5-dicarbonitrile (8a). Red powder, Yield 92 %, mp > 300oC ethanol/DMF (1:1), 1H NMR (300 MHz, DMSO-d6) δ, 3.77 (s, 3H, CH3), 7.04-7.08 (m, 3H, Ar-H), 7.41-(s, 1H, NH), 7.43 (s, 1H, Ar-H), 7.48 (br, 2H, NH2). Anal. Calcd. for (C13H10N6O): C, 58.64; H, 3.79; N, 31.56. Found C, 58.51, H, 4.01, N, 30.99. 4-Amino-1-(4-chlorophenyl)-6-imino-1,6-dihydro-pyridazine-3,5-dicarbonitrile (8b). Red powder, Yield 90 %, mp > 300oC ]Lit. mp mp > 300oC 16], ethanol/DMF (1:1), 1H NMR (300 MHz, DMSO-d6) δ, 6.82 (s, 1H, NH), 7.7 (d, 2H, J = 9 Hz, Ar-H), 7.99 (d, 2H, J = 9 Hz, Ar-H), 8.68 (s, 2H, NH2).  4-Amino-1-(4-chloro-phenyl)-5-cyano-6-oxo-1,6-dihydro-pyridazine-3-carboxylic acid ethyl ester (12a) Yellow powder, Yield 92 %, mp 290-292oC ethanol/DMF (1:1), MS (EI), m/z = 318 [M+, 24.8 %], 320 [(M+2)+, 5 %] 1H NMR (300 MHz, DMSO-d6) δ, 1.26 (t, 3H, J = 7Hz, CH3), 4.33 (q, 2H, J = 7Hz, CH2), 7.51-7.60 (m, 4H, Ar-H), 8.20 (brs, 2H, NH2).  4-Amino-1-(4-chloro-phenyl)-5-cyano-6-oxo-1,6-dihydro-pyridazine-3-carboxylic acid methyl ester (12b) Yellow powder, Yield 80 %, mp 279-280oC ethanol/DMF (1:1),  1H NMR (300 MHz, DMSO-d6) δ, 3.83 (s, 3H, CH3), 7.51-7.60 (m, 4H, Ar-H), 8.10 (s, 1H, NH), 8.42 (s, 1H, NH). Anal. Calcd. for (C13H9ClN4O3): C, 51,25; H, 2,98; N, 18,39. Found C, 51.24; H, 3.03; N, 18.39. General procedure for preparation of compounds 1a,b To a solution of each of 7a,b and 8a,b (10 mmol), malononitrile (10 mmol) in ethanol (25 ml) was added triethylamine (1ml). The reaction mixture was refluxed for 3 h, then allowed to cool, the precipitated solid products formed were collected by filtration, washed with ethanol, and recystalized from ethanol/DMF (1:2) to afford 1a,b  6,8-Diamino-3-imino-2-(3-methoxyphenyl)-2,3-dihydropyrido[3,2-c]pyridazine-4,7-dicarbonitrile (1a) Red powder, Yield 94 %, mp > 300oC ethanol/DMF (1:1), (Lit. mp > 360oC, 15), IR, 2217 (CN), 3355, 3457(NH, NH2)   1H NMR (300 MHz, DMSO-d6) δ, 3.79 (s, 3H, CH3), 6.29 (brs, 1H, NH, exchangeable D2O), 7.03 (dd, 1H, J = 9 Hz, 2.1 Hz, Ar-H), 7.15 (m, 2H, Ar-H), 7.43 (t, 1H, J = 9Hz, Ar- H), 7.63 (brs, 1H, NH, exchangeable D2O), 8.08 (s, 2H, NH2, exchangeable D2O), 8.26 (brs, 1H, NH, exchangeable D2O). 13C NMR (75.4 MHz, DMSO-d6) δ  56.4 (CH3), 70.9 (C-7), 89.8 (C-4), 112.4 (C-2´), 114.7 (CN), 114.8 (C-4´), 115.9 (CN), 118.5 (C-6´), 126.2 (C-9), 129.8 (C-5´), 141.8 (C-1´), 148.9 (C-9a), 154.3 (C-3), 155.4 (C-8), 159.7 (C-3´), 161.4 (C-6). MS (FAB) m/z 333 (M+ + 1, 100%), Anal. Calcd. for (C16H12N8O): C, 57.83; H, 3.64; N, 33.72. Found C, 57.49, H, 4.02, N, 33.95. 6,8-Diamino-2-(4-chlorophenyl)-3-imino-2,3-dihydropyrido[3,2-c]pyridazine-4,7-dicarbonitrile (1b) Red powder, Yield 90 %, mp > 300oC ethanol/DMF (1:1), 1H NMR (300 MHz, DMSO-d6) δ, 6.50 (s, 1H, NH), 7.57 (d, 2H, J = 9 Hz, Ar-H), 7.68 (d, 2H, J = 9 Hz, Ar-H), 7.69(s, 1H, NH), 8.10 (s, 2H, NH2), 7.69, 8.29 (s, 1H, NH).   5 4-Amino-1-(4-chlorophenyl)-5-cyano-6-oxo-1,6-dihydro-pyridazine-3-carboxylic acid 13 To a solution of each of 11a,b and 12a,b (10 mmol) in ethanol (25 ml) was added triethylamine (1ml). The reaction mixture was refluxed for 7 h, then allowed to cool, the precipitated solid product formed was collected by filtration, washed with ethanol, and recystalized from ethanol/DMF (1:1) to afford 13. Reddish brown powder, mp 244-246oC (EtOH), in  74% yield.  1H NMR (300 MHz, DMSO-d6) δ, 7.52 (m, 5H, 4Ar-H, 1H, NH), 8.16 (s, 1H, NH), 10.47 (s, 1H, COOH).  Acknowledgements We thank Fundação para a Ciência e Tecnologia and FEDER (POCTI-SFA-3-686) and post-Doctoral grant for A. Salaheldin (SFRH/BPD/31490/2006) and Miss Elisa Pinto for obtaining the NMR, and elemental analyses data. References 1. Oka, Y.; Omura, K.; Miyake, A.; Itoh, K.; Tomimoto, M.; Tada, N.; Yurugi, S. Chem. Pharm. Bull. 1975, 23, 2239 and references within. 2. Matsuura, I.; Yoneda, F; Nitta, Y. Chem. Pharm. Bull. 1966, 14, 1010. 3. Tigler, M.; Stanovnik, B. Azolo- and Azinopyridazines and Some Oxa and Thia Analogs. In Condensed Pyridazines Including Cinnolines and Phthalazines; Castle, R. N. Ed.; John Wiley & Sons, Inc.: New York, 1973; pp. 968-1012 and references within. 4. Kricka, L. Pure Appl. Chem., 1996,68 (I 0). 1825- 1830. 5. Frank, H.; Heinisch, G. Pharmacologically Active Pyridazines Part I. In Progress in Medicinal Chemistry, Ellis, G.P., West, G. B., Eds.; Elsevier: Amsterdam, 1990; Vol 27, 1. 6. Frank, H.; Heinisch, G. Pharmacologically Active Pyridazines Part II. In Progress in Medicinal Chemistry, Ellis, G.P., Luscombe, D.K., Eds.; Elsevier: Amsterdam, 1992; Vol 29, 141. 7. Matyus, P. 3(2H)-Pyridazinones: Some recent aspects of synthetic and medicinal chemistry. J. Heterocycl. Chem. 1998, 35, 1075-1089. 8. Tigler, M.; Stanovnik, B. Azolo- and Azinopyridazines and Some Oxa and Thia Analogs. In Condensed Pyridazines Including Cinnolines and Phthalazines; Castle, R. N. Ed.; John Wiley & Sons, Inc.: New York, 1973; pp. 968-1012 and references within. 9. Epsztajn, J.; Brzezifiski, J. Z.; Czech, K Monatsh. Chem. 1993, 124, 549. 10. Kormendy, K.; Kovfics, T.; Szulfigyi, J.; Ruff, F.; K6vesdi, I. Acta Chim. Hung. 1981, 108, 167. 11. Abdellatif M. Salah El-Din, Heteroatom chem. 2003, 14, 612. 12. Fathy M. Abdelrazek, Abdel-latif M. Salah El Din, and Ahmed E. Makky, Tetrahedron 2001, 57/9, 1813. 13. Fahmy, S. M.; Abded, N. M.; Mohareb, R. M.; Elnagdi, M. H. Synthesis, 1982, 490. 14. Kandeel, Z. E.; Abdelrazek, F. M.; Elnagdi, M. H.; Et-Torgoman, A. M. Heterocycles, 1982, 24, 2455. 15. Schäfer, H.; Gewald, K.; Gruner, M. J. Prakt. Chemie, 1989, 331, 878. 16. Hafez, E. A.; Khalifa, M. A.; Guda, S. K.; Elnagdi, M. H. Z. Naturforsch. 1981 35b, 485. 

Heterocyclic synthesis with nitriles: synthesis of pyridazine and pyridopyridazine derivatives

Crossref

Heterocyclic Synthesis with Nitriles: Synthesis of Pyridazine and Pyridopyridazine Derivatives

http://repositorium.sdum.uminho.pt/bitstream/1822/10487/1/Studies%20to%20ECSOC.pdf

Heterocyclic synthesis with nitriles: synthesis of pyridazine and pyridopyridazine derivatives

Abstract

Similar works

Full text

Available Versions

Universidade do Minho: RepositoriUM

Crossref