Reaction of the title compound I with aromatic aldehydes afforded a,b-unsaturated ketones II, which were allowed to react with cyanoacetamide, ethyl cyanoacetate, hydrazines. Treatment
of I with hydrazines or amines gave V and VI

A. M. Ismail

M. A. Metwally

M. M. EI-Kerdawy

M. Y. Yousif

English

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CROATICA CHEMICA ACTA CCACAA 60 (2) 309-314 (1987)CCA-1730YU ISSN 0011-1643UDe 547.781.1OriginaL Scientific PaperSyntheses of 4-Substi tuted-3- Methyl-2- PhenylimidazolesM. Y. Yousif, A. M. Ismail, M. A. MetwaIly*, and M. M. EI-KerdawyDepartment of Chemistry, FacuUy of Pharmacy and FacuLty of Science+, Universityof Mansaura, Mansaura, EgyptReceived March 24, 1986Reaction of the title compound I with aromatic aldehydesafforded ct.,0-unsaturated ketones II, which were allowed to reactwith cyanoacetamide, ethyl cyanoacetate, hydrazines. Treatmentof I with hydrazines or amines gave V and VI.Imidazo1e nuc1eus constitutes the main part in many pharmaceuticalcompounds possessing variab1e physio1ogica1 activitiesl'". Therefore, 4-acety1--5-methyl-2-phenylimidazo1e (1)10,11was used as the key intermediate in thepreparation of different substituted imidazo1e derivatives.a,/3-unsaturated ketones (Ila-h) were prepared by the interaction of (I)with different aromatic aldehydes in sod. ethoxide. The IR spectra of thesecompounds showed absorption bands at 1680-1660 cm'" (C=O) and a broadone at 3250-3200 cm'" (NH). The lH-NMR (DMSO-d6) of compound Iladisp1ayed signals at 2.2 (s, 3H, methy1 aromatic), 2.55 (s, 3H, CS-CH3),7.5-8.1 (m, 9H, aromatic) and a broad one at o 13 (s, IH, NH), in additionto the appearance of signa1s at 7.15 (d, IH, CO-CH=CH) (J = 15 Hz) and7.35 (d, IH, CO-CH=CH) (J = 15 Hz).Reactivity of II towards base cata1yzed addition of cyanoacetamide wasinvestigated. Thus, the treatment of compounds (Ila-h) with cyanoacetamideafforded 4-(6'-ary 1-3'-cyano-ž[H]- pyridone-4' -y1)-5-methy 1-2-pheny limidazo1es(IIla-h), which were also obtained by treating (II) with ethy1 cyanoacetateand ammonium acetate- Compounds (Ula-h) exhibit characteristic absorptionbands at 2210 crrr ' for conjugated (CN), 3300 crrr" (NH-ring) and 1650 cm?(C=O). 1H-NMR spectra of compound IIle showed signa1s at o 2.5 (s, 3H,CH3), 6.65 (s, IH, pyridone CH), 7.5-8 (m, 9H, ArH, NH,pyridone) and12.5 (broad, NH, imidazo1e).Moreover, the treatment of compounds (U) with hydrazines yie1ded4-(5'-ary1pyrazolin-3'-y1)-5-methyl-2-phenylimidazo1es (IVa-d). The IR spectrumof IVa displayed bands at 1620 cm' (NH) and 1610 crrr! (C=N). The 1H-NMRspectrum of IVa displayed signa1s at o 2.6 (s, 3H, -CH3), 12.8-13 (broad,NH imidazole and pyrazole), 3.2 (broad, 2H, -CH2), 3.81 (s, 3H, -OCH3),and 7.1-7.9 (m, 9H, Ar-H). On the other hand, when hydrazines werefused with compound (I), they afforded 5-methyl-2-pheny1imidazo1e-4-aceto-hydrazones (Va, b). The IR spectrum of Va showed bands at 1620 cm'?(C=N), 1640 cm? (CH3C=N), 3225 crn? (NH) and two sharp bands at 3300,l310 M. Y. YOUSIF ET AL.3320 cm " (NH2). The lH-NMR spectrum of Vb displayed signals at o 2.4(s, 3H, -CH3), 2.65 (s, 3H, -CH3), 12.8 (s, IH, NH-imidazole), 8.35 (s, IH,NH-N=C) and 7.3-8.1 (m, lOH, ArH).Treatment of (Va) with m-chlorobenzaldehyde or pyridine-4-carboxyal-dehydes yielded the corresponding mixed azines (VIla, b). The IR spectraof these compounds showed bands at 1630 crrr" (C=N) and 3220 cm! (NE).Fusion of compound (I) with benzylamine and toluidines gave the cor-responding alkylazomethines (Vla-c). The IR spectra of compounds VI showedabsorption bands at 1640-1610 cm"! (C=N) and a broad band at 3250-3200cm-loEXPERIMENTALMelting points are uncorrected, IR spectra were measured on a Unicam sp1000 infrared spectrophotometer (max in cm ") in KBr disc., 1H-NMR spectra ona Varian EM-390 90 MHz NMR spectrometer.a,/3-Unsaturated Ketones (IIa-h)To a solution of (I) (0.01 mol) in ethanolic sodium ethoxide (0.3 g sodium metalin 20 ml ethanol), the appropriate aldehyde (0.01 mol) was added, and the reactionmixture was heated under reflux for 2-5 hrs. After cooling, the" reaction mixturewas diluted with water and neutralized with hydrochloric acid. The precipitatedproduct was filtered off, dried and crystallized from the appropriate solvent(Table I).TABLE Ia,/I-Unsaturated Ketones (IIa-h)Analyses/? /o,Compd. R Cryst, m.p. YieldMol. Calc.!FoundNo. solv. °c % formulaC H NIla C6H4CH3-P E+W 214 75 C20HlSN20 79.4 6.0 9.379.2 6.0 9.7b C6H40CH3-p E 235 30 C2UHlSN202 75.4 5.6 8.875.0 5.5 9.0c C6H4CI-o E+W 160 65 C1»Hl5CIN20 70.7 4.7 8.769.9 5.2 7.9d C6H4CI-m E 152 80 C19H15CIN2O 70.7 4.7 8.770.6 4.5 8.9e C6H4CI-p E+W 225 75 Cl9HvlCIN20 70.7 4.7 8.771.2 5.2 8.4f C6H4N(CH3h-p E 247 65 C2lH2lNsO 76.1 6.3 12.776.1 6.0 12.5g 2-thiopheno E 238 80 Cl7H14N20S 69.3 4.7 9.569.2 5.0 9.6h 4-pyridino D+E 275 75 ClsHl5NsO 74.7 5.2 14.574.6 5.4 14.3E = Ethanoi, D = DMF and W = Water.4-(6'-Aryl-3'-Cyano-2'{1H]-Pyridon-4'-yl)-5-Methyl-2-Phenylimidazoles (IIIa-h)A mixture of a,,8-unsaturated ketones (IIa-h) (0.05 mol), cyanoacetamide (0.05mol) and a few drops of piperidine was heated under reflux on an oil bath at140-150oC for 6 hrs. On cooling, the reaction mixture was triturated with water,then filtered off and triturated with hot ethanol. The undissolved solid was filtered,dried and crystallized from DMF (Table II).4-SUBSTITUTED-3-METHYL-2-PHENYLIMIDAZOLES 311TABLE II4-(6' -Aryl-3' -Cyano-2' [1H]-Pyridon-4' -yl)-5 -Methyl-2- Phenylimidazoles (III a-h)Analyses/? /0,Compd. R m.p. YieldMol. calc'!foundNo. °c % formula C H N!Ila C6H4Ch-p > 280 60 C23H1SN40 75.9 4.9 15.275.6 5.3 15.5b C6H40CHa-P > 280 60 C23H1SN402 72.2 4.8 14.472.2 4.9 14.0c C6H4CI-o > 280 45 C22H15CIN40 68.3 3.9 14.568.0 4.0 14.2d C6H4CI-m > 280 50 C22H15CIN40 68.3 3.9 14.568.2 3.8 14.3e C6H4CI-p > 280 50 C22H15CIN40 68.3 3.9 14.567.9 4.1 14.6f C6H4N(CH3h-p > 280 55 C24H21N50 72.9 5.3 17.773.0 5.3 17.5g 2-thiopheno > 280 65 C20H14N40S 67.0 3.9 15.666.8 4.1 15.2h 4-pyridino > 280 60 C21H15N50 71.4 4.2 19.871.0 4.1 20.04-(5' -AryLpyrazoLin-3' -yL)-5-MethyL-2-PhenyLim.idazoLes (IVa-d)a) A mixture of (!Ib) ar (!Ih) (0.01 mol) and hydrazine hydrate (0.015 mol) inethanol-acetic acid mixture (30 ml) was heated under reflux for 10 hrs. After312 M. Y. YOUSIF ET AL.cooling, the separated solid was filtered, dried and crystallized from aq. ethanolto give compounds (IVa, b) (c. f. Table III).b) A mixture of (Ile) ar (Ile) (0.01 mol) and phenylhydrazine (0.01 mol) inglacial acetic acid (30 ml) was heated under reflux for 10 hrs. After cooling, theseparated soild product was filtered off, dried and crystallized from aq. ethanol togive compounds (IVc, d) (c. f. Table III).TABLE III4-(5' -Arylpyrazolin-3' -yl)-5 -Methyl-2- Phenylimidazoles (IVa-d)Analyses/Ofo,Compd. R R' Yield m.p.Mol. calc.lfoundNo. ofo °c formulaC H NIVa 4-pyridino H 213 50 C1SH17N5 71.3 5.6 23.171.5 5.5 23.0b C6H40CH3-P H 80 45 C20H20N40 .72.3 6.0 16.972.0 6.1 17.0c C6H4CI-o CGH5 141 45 C25H21CIN1 72.7 5.1 13.672.5 4.9 14.0d C6H4CI-p C6H5 162 45 C25H21CIN4 72.7 5.1 13.672.6 5.0 13.55-Methyl-2-Phenylimidazole-4-Aeetohydrazones (Va, b)A mixture of (I) (0.01 mol) and excess hydrazine hydrate (0.1 mol) ar phenyl-hydrazine (0.03 mol) was fused on an oil-bath at 150° under reflux for 4 hrs. Aftercooling the content was washed with pet. ether (60-80). The obtained solid pro-duct was filtered off, dried and crystallized from ethanol, (Table IV).TABLE IV5-Methyl-2-Phenylimidazole-4-acetohydrazones (Va, b)bAnalyses/? 1o,R m.p. YieldMol. calc.lfound°c 0/0 formulaC H NH > 280 70 C12H14N4 67.0 6.6 26.166.5 6.5 25.7C6H5 160 40 C18H1SN4 74.5 6.2 19.374.2 6.0 19.5Compd.No.Va4-(a-Methyl-N-Aralkylazomethin)-5-Methyl-2-Phenylimidazoles (VIa-e)A mixture of I (0.01 mol) and benzylamine, o-toluidine or m-toluidine (0.05mol) was fused in an oil-bath at 1500C for 5 hrs. After cool ing the residue was tri-tura ted with pet. ether (60-80), then filtered off, dried and recrystallized from aq,ethanol to give compounds (Vla-c) (c. f., Table Vj.4-SUBSTITUTED-3-METHYL-2-PHENYLIMIDAZOLES 3134-( a-Methyl- N-Aralkylazomethin)-5- Methyl-2- Phenylimidazoles (VI a-e)TABLE VCompd. m.p. Yield Mol.No. °c % formulaVIa -CH2C2H5 115 75 C19H19Nzb -C6H4CH3-0 > 280 60 C19C19N3e -C6H4CH3-m 210 45 C19H19N3Analyses/Ofoeale'!foundC H N78.9 6.6 14.579.0 6.4 14.278.9 6.6 14.578.6 6.5 14.478.9 6.6 14.579.2 6.3 14.5Preparation of Mixed Azines (VIla, b)To a solution of Va (0.01 mol) in glacial acetic acid (30 ml), pyridine-4-carbo-xyaldehyde or m-chlorobenzaldehyde (0.01 mol) was added and the reaction mixturewas heated under reflux for 6 hrs. After cooling, a sufficient amount of water wasadded. The solid product that separated was filtered off, dried and recrystallizedfrom the appropriate solvent, (Table VI).TABLE VIAnalyses/? /o,Compd. R' Cryst. m.p. Yield Mol. calc'!foundNo. solv. °c ~/o formula C H NVIra 4-pyridino ethan ol 105 65 C1SH17N5 71.3 5.6 23.170.9 5.3 23.4b C6H4CI-m benzene 90 70 C19H17ClN4 67.8 5.1 16.668.0 5.0 16.5REFERENCE S1. A. C. C u c k 1e r, L. R. C h a p i n, C. M. Ma I a n g a, E. F. Rog e r s,H. J. B e c k e r, L. L. Cl ark, W. J. Lea n z a, A. A. P e s s o 1a n o, T. Y.S h e n, and L. H. Sa r e t t, Proe. Soc. Exptl. Biol. Med., 98 (1958) 167.2. L. Bauer, C. N. V. Nambury, and D. Dhawan, J. Heterocyclic Chem.1 (1964) 275.3. J. Nematollahi, W. Guess, and J. Autian, J. iaea; Chem. 9 (1966)660.4. J. J. BI a d w i n and F. C. N ove Il o, German Offen. 2,322,561 (1973); Chem.Abstr. 80 27253y (1974).5. J. R. N u I u and Ne mat o Il ahi, J. Med. Chem. 12 (1969) 804.6. E. Belgodere, R. Bossio, V. Parrini, and R. Pepino, Arzneim-Forseh. 30 (1980) 1051.7. E. Belgodere, R. Bossio, V. Parrini, and R. Pepino, J. Hetero-eyclie Chem. 19 (1982) 561.8. N. Yasuda, H. Lw a g a m i, E. Nakanishi, T. Nakamiya, Y. Sa-sa k i, and T. Ura t a, J. Antibiot. 36 (1983) 242.9. N. Y a s uda, J. Heteroeyelie Chem. 22 (1985) 413.314 M. Y. YOUSIF ET AL.10. A. C. Ver o n e s e, G. C avi ceh i ati, G. Ser v a d i o, and G. Vec ehi a-ti, J. Heterocyclic Chem. 17 (1980) 1723.11. A. C. Ver o n e s e, F. D. An g eli, G. Za n o t ti, and A. Del Pra, J.Chem. Soc., Chem. Commun. (1977) 443.12. M. A. El - H ash ash and M. E 1- Kad y, Revue Roumaire de Chimie, 23(1978) 1581.SAZETAKSinteza 4-supstituiranih-3-metil-2-fenilinidazolaM. Y. Yousif, A. M. IsmaiL, M. A. MetwaHy i M. M. El-KerdawyReakcijom naslovnog spoja s aromatskim aldehidima pripravljeni su (l,~-neza-sićeni alkil-imidazolil-4-ketoni. Njihovom kondenzacijom s cijanoacetamidom, etil-cijanoacetatom i hidrazinom pripravljeni su 4-pirazolil-4-pirimidonil-imidazoli, tehidrazo- i amino-derivati spoja I (spojevi V i VI»

Syntheses of 4-Substituted-3-Methyl-2-Phenylimidazoles

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