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Studies on Polyfunctionalised Heteroaromatics: a Novel Synthesis of Polyfunctionalised Pyridine, Pyridazine and Pyrido[2,3-c]pyridazine Derivatives

 

作者: Mohamed Hilmy Elnagdi,  

 

期刊: Journal of Chemical Research, Synopses  (RSC Available online 1998)
卷期: Volume 0, issue 1  

页码: 26-27

 

ISSN:0308-2342

 

年代: 1998

 

DOI:10.1039/a703978f

 

出版商: RSC

 

数据来源: RSC

 

摘要:

Me R O NNHAr X CN Ar¢ 1 a bc d Ar Ph C6H4Me- p Ph C6H4Me- p R CO2Et CO2Et COMe COMe 2 a b c def Ar¢ Ph C6H4Cl- p C6H4OMe- p Ph C6H4Cl- p C6H4OMe- p X CN CN CN CO2Et CO2Et CO2Et Ar¢ CO2Et X CNO N HN Ar 1a,b + 2a,f O NNHAr O Ar¢ NC NC N N O CO2Et Ar¢ Ar O N OH Ar¢ N N O CO2Et Ar¢ Ar NC N Ar N N O CO2H Ar¢ Ar Route a Route b X = CN –EtOH X = CO2Et –CH2(CN)CO2Et 3 4 6 5 7 8 5,8 abcdef Ar Ph Ph Ph C6H4Me- p C6H4Me- p C6H4Me- p Ar¢ Ph C6H4Cl- p C6H4OMe- p Ph C6H4Cl- p C6H4OMe- p –HCN CN X H2N CN R Me CN X H2N NNHAr CN NC HN N N Me COMe Ar NH2 X 9a X = CN b X = CO2Et 11 NH O ArHNN Me X CN CN 13a Ar = Ph, X = CN b Ar = C6H4Me- p, X = CN N N N Me CO2Et NH2 Ar X HN N N N Me COMe NH2 Ar X HN 14 12 Ar Ph C6H4Me- p Ph C6H4Me- p X CN CN CO2Et CO2Et N N N Me CO2Et NH2 Ar HO2C HN 16 N N N Me CO2Et NH2 Ar H2NOC HN 15 1c,d R = COMe 1a,b –EtOH R = CO2Et X = CO2Et X = CN Ar = Ph Ar = C6H4Me- p 1 + abcd 26 J.CHEM. RESEARCH (S), 1998 J. Chem. Research (S), 1998, 26–27 J.Chem. Research (M), 1998, 0188–0197 Studies on Polyfunctionalised Heteroaromatics: a Novel Synthesis of Polyfunctionalised Pyridine, Pyridazine and Pyrido[2,3-c]pyridazine Derivatives Mohamed Hilmy Elnagdi,*a Magda Abdel-aziz Barsy,b Fawi Mohamed Abdel-Latifb and Kamal Usef Sadek*c aDepartment of Chemistry, Faculty of Science, University of Kuwait, P.O. Box 5969, Safat 13060, Kuwait bDepartment of Chemistry, Faculty of Science, South Valley University, Aswan, Egypt cDepartment of Chemistry, Faculty of Science, Minia University, 61519, Minia, Egypt Ethyl 2-arylhydrazono-3-oxobutyrates react with a,b-unsaturated nitriles to afford either pyridopyridazine or pyridine derivatives depending on the structure of the unsaturated nitrile.As a part of our programme aimed at synthesising pyridazinones with substitution patterns required for a biological chemistry programme, we report here a novel synthesis of several pyridazines and condensed pyridazines which are difficult to obtain through established synthetic routes.11–13 Ethyl 3-oxo-2-phenylhydrazonobutyrate (1a) (Ar=Ph, R=CO2Et) reacted with 2a in the presence of ammonium acetate to yield 3,5-dihydroxy-4-phenylazobiphenyl-2-carbonitrile (5a).The formation of 5a is assumed to proceed through a Michael-type addition of the methyl function in 1a to the activated double bond in 2a, affording the acyclic adducts 3 which then cyclises via loss of ethanol and then aromatise via elimination of HCN to yield 5 (Scheme 1, route a).Similarly 1a reacted with 2b,c and 1b reacted with 2a–c to afford 5b–f, the 1H NMR spectrum for the reaction products revealed in each case a multiplet for aromatic and pentasubstituted benzene protons and two one-proton signals for OH groups. In contrast, the reaction of 1a with 2d afforded a compound of molecular formula C17H12N2O3 [m/z 293 [M+)]. The 1H NMR spectrum of the reaction product revealed only a multiplet at d 7.12–7.77 integrating for aromatic protons.Moreover, we could detect by TLC the presence of ethyl cyanoacetate in the reaction mixture. Structure 8a was suggested for the reaction product. The formation of 8a is assumed to proceed through the intermediacy of the Michael *To receive any correspondence. Scheme 1 Scheme 2J. CHEM. RESEARCH (S), 1998 27 adduct 3 which loses ethyl cyanoacetate via an SN2 displacement into dihydropyridazinone (6) which undergoes hydrolysis and autooxidation under the reaction conditions affording the acid 8a.Similarly, the reaction of 1a with 2e,f and of 1b with 2d–f afforded 8b–f. Compounds 1c,d reacted with 2-amino-1,1,3-tricyanopropene (9a) via a Knoevenagel condensation to yield the intermediate 11, which then cyclised into pyridopyridazines 12a,b. In the reaction of 1c,d with 9b the formed esters were hydrolysed to give the corresponding acids 12c,d by the water eliminated during the condensation step (see Scheme 2).The reaction of 9a with the ethyl arylhydrazonoacetoacetate 1a afforded a mixture (1.2:1) of two products of molecular formulae C16H10N6O (M+=302) and C18H18N6O3 (M+=365), respectively. The former was identified as the pyridine derivative 13a and the latter as the pyridazinecarboxamide 15a. Structural assignments were based on analytical and spectral data. Thus, compound 13a is coloured due to the presence of the hydrazone chromophore which is indicated by a strong UV band at 380 nm.The IR spectrum revealed the presence of a ring CO band at 1680 cmµ1, as well as two cyano bands at 2225 cmµ1. The 1H NMR spectrum of 13a indicated the expected aromatic multiplets, as well as signals at d 8.22 for an NH proton and d 2.35 for a methyl group. The IR spectrum of 15a indicated the presence of bands for amide CO and NH2 groups. The 1H NMR spectrum was also in accordance with the proposed structure. A possible mechanism for the formation of both 13 and 15 is depicted in Scheme 2: in each case a Knoevenagel condensation would yield an intermediate 10, cyclisation of which via the elimination of an ethanol molecule would afford 13, while intramolecular cyclisation and hydrolysis would give 15. Similarly, 13b and 15b were formed from the reaction of 1b with 9a. The reaction of 1a,b with ethyl 3-amino-2,4-dicyanoprop- 2-enoate (9b) afforded only the carboxylic acids 16a,b which are believed to be formed via hydrolysis of the esters 14c,d. Techniques used: 1H NMR, MS References: 13 Received, 9th June 1997; Accepted, 1st October 1997 Paper E/7/03978F References cited in this synopsis 11 M. H. Elnagdi, A. M. Negm and K. U. Sadek, Synlett., 1994, 27 and references cited therein. 12 M. H. Elnagdi, N. S. Ibrahim, K. U. Sadek and M. H. Mohamed, Liebigs Ann. Chem., 1988, 1005. 13 H. A. Awadhi, F. Al-Omran, M. H. Elnagdi, L. Infantes, C. F. Foces, N. Jagerovic and J. Elguero, Tetrahedron, 1955, 12 745.

 



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