Ketoketene gem-Dithiols in the Synthesis of Pyrimidine and Pyrazole Derivatives Pyrimidin- und Pyrazol-Derivate aus geminalen Dithiolen eines Ketoketens.код для вставкиСкачать
841 Pyrimidines and Pyrazoles Ketoketene gem-Dithiols in the Synthesis of Pyrimidine and Pyrazole Derivatives Pyrimidin- und Pyrazol-Derivate aus geminalen Dithiolen eines Ketoketens Salem E. Zayed, M. A. Hassan Chemistry Departmen&Faculty ofScience, Assiut University, Qena, Egypt Fatma M. Manhi and Ibrahim A. Hussin National Organization for Drug Control and Research, Cairo, Egypt Received June 12, 1989 The ketoketene dimercaptal 1 prepared from Cacetylbiphenyl and CSz') is a subject of current interest The reaction of a-ketoketene-S,S-mtals and a-cyanoketene-S,S-acetalswith guanidine and thiourea to give pyrimidine derivatives was repo~ted''~'. Here we examine the reaction of 1 with different nucleophiles like thiourea, dicyanodiamide and phenylhydrazine synthesizing various heterocyclic compounds.- Refluxing l a (R= H)with thiourea in the presence of NaOC3H7 gave 2,4dimercapto-6-(4-biphenyl)-pyrimidine (2). HZN /)-SH HN + lb I EtONa/EtOH - W3SH SH I EtoNa - CH3SH - CH3SNa 3 4 Structure 2 was confirmed by elemental analysis, by its irspectrum which shows bands at 2620 cm-' (SH), 1660 cm-' (C=N), and by its 'H-NMR spectrum in CDCl3 which shows signals at 6 (pprn) = 3.6 (s, lH, SH). 3.9 (s, lH, SH), 7.3-8.2 (m,10H. Ar-H + H-5). The synthesis of alkoxy pyrimidines from oxo-pyrimidines in basic medium is rather complicated. since the alkylation can take place either on oxygen or on the basic nitrogen45'. The desired alkoxy pyrimidines were obtained from oxc-pyrimidines via the comsponding chloro-derivatives, which react with alkoxides. Furthermore. the conversion of the oxo-pyrimidines to the comsponding chloroderivatives in the presence of free sulfhydryl group leads to dimerisation6'. We describe the synthetic utility of l b (R = CH3) for the preparation of alkoxy and methylthiopyrirnidines. Treatment of l b with thiourea in ethanolic NaOEt gives 2-mercapto-4-ethoxy-6-(4-(biphenyl) pyrimidine (4). Another product from the same reaction was identified as 2-rnercap to-4-methylthio-6-(4biphenyl)pyrimidine (3). 3 reacts with NaOEt to give 4. Structure 3 was proved by its ir-spectrum which shows bands at 2610 (SH) and 1640 (C=N) cm-', and by its 'H-NMR spectrum in CDCI3 which indicates at 6 (ppm) = 2.3 (s. 3H. SCH,), 3.4 (s. 1H. SH). 7.4-8.1 (m.10H. Ar-H + H-5). The ir-spectrum of 4 shows bands at 2615 (SH) and 1655 (C=N) cm.'. The 'H-NMR spectrum in CDCIJ reveales signals at 6 (ppm) = 1.2 (f, 3H, CH3),3.4 (4.2H. CH3,3.5 (s, IH,SH), 7.4-8.2 (m, IOH, ArH + H-5). Arch. Pharm. (Weinheim) 322.841 -842 (1989) Treatment of equirnolar quantities of la and dicyanodiamide in boiling ethanol gave 2-cyanamino4mercapto-6-(4bipheny1)pyrimidine (5). whereas in the presence of triethylamine gave 2,4-diaminc+5-(4-phenylbenzoyl)-6-mercaptopyrimidine(6). v-CN I la + Hy-CN 5 H2N ,~NH-CN HN The ir-spectrum of 5 shows absorption at 3380 (NH), 2610 (SH), 2220 (CN) and 1625 (C=N) cm". 'H-NMRanalysis in CDCl3 indicates signals at 6 (ppm) = 3.2 (s. lH, SH),4.8 (broad, 1H.NH),and 7.3-8.0 (m,10H, Ar-H + H3.-Structure 6 was confirmed by its ir-spectrum which shows bands at 3400; 3350; 3200 (NH2); 2590 (SH);1690 (C=O), and 1640 (C=N) crn-'. 'H-NMR in DMSO shows OVCH Verlagsgesellschaft mbH. D-6940 Weinheim, 1989 0365-6233/89/1 I 1 1-0841 $02.50/0 842 Harsan and cow- signals at 6 @pm) = 3.5 (s, lH, SH), 4.9 (broad,2H, NHd, 5.3 (broad, 2H, NH2). and 7.3-8.1 (m, 9H,Ar-H). Condensation of l b with phenylhydrazine at room temp. afforded the acyclic product 7 whereas in boiling butanol3(4-biphenyl)-I-phenylJ-methylthio pyrazole (8) was obtained. When 7 was refluxed in butanol, 8 was formed in 90% yield. for 5 h. On cooling. the solid product was f i l t e d and crystallized from EtOH to give 4 (1.29 g. 42%) m.p. 92-93. C18Hl$IflS (308.3) Calc. C 70.1H5.23N9.1 S 10.4FoundC70.3H5.26N9.1 S 10.4.Neutralization of the filtrate with 10% HCI gave a solid which was crystallized from benzene to afford3 (250 mg. 8%) m.p. 114-116. CI7HI4N2S* (310.3) Calc. C 65.8 H 4.54 N 9.0 S 20.6 Found C 65.8 H4.60 N 9.1 S 20.5. 2-Cyanamino4-mercapto-6-(4-biphenyl) pyrimidine (5) f SCH, 7 n-butanol rdlux n-butonol reflux I Ph CH3 A mixture of l a (2.72 g. 0.01 mol) and dicyanodiamide (0.84 g. 0.01 mol) in absol. EtOH (100 ml) was refluxed for 4 h (until development of H2S had ceased). After cooling, the separated product was recrystallized from EtOH to give 5 (2.3 g. 76%) m.p. 184-186. Ci7H12N4S(304.3) Calc. C67.1 H3.97N 18.4s 10.5FoundC67.0H3.94N 18.4s 10.7. 2.4-Diornino-5-(~-phcnylbcnzoyl)-6-mcrcapro-pyrimidine (6) An equimolar ratio of l a and dicyanodiamide (0.01 mol) and triethylamine in catalytic amount in absol. EtOH (100 ml) was heated under nflux for 5 h. After cooling. the solid product was crystallized frombenzene to give 6 (2.22 g, 69%) m.p. 246-248. C17H1.,NlOS (322.3) Calc. C 63.3 H 4.38 N 17.4 S 9.9 Found C 63.1 H 4.32 N 17.4 S 10.0. 8 1,1-bis(me~hylthio)-2-(4-phenylben:oylphenylhydrazone)-e1~le~ (7) It is thus probable that the pyrazole 8 is formed via elimination of water prior to the elimination of methylthiol. The u-specof 7 shows swng bands at 3450 (NH) and 1640 (C=N). The 'H-NMR spectrum reveals signals at 6 (ppm) = 2.4 (s. 6H. 2 SCH3), 5.4 (s, 1H, NH), 7.1 (s, lH, CH=C), and 7.4-8.2 (m, 14H, Ar-H). The 'HNMR of compound 8 shows absorption at 6 (ppm) = 2.5 (s, 3H. (331). 6.9 (s. 1H. H-4). and 7.3-8.2 (m,14H. Ar-H). To a stirred solution of l b (3.0 g. 0.01 mol) in EtOH (150 ml). phenylhydrazine (0.01 mol) in EtOH (50 ml)was given in portions during 30 min. The mixture was stimd for 2 h and left at m m temp. overnight The separated crystals were washed twice with EtOH to give 7 (3.4 g. 87%) m.p. 133-134. CUHUNZS2(390.4) Calc. C 70.8 H 5.68 N 7.2 S 16.4 Found C 70.9 H 5.46 N 7.2 S 16.4. 3-(4-Biphenyl)-l-phenyl-5-merhylrhio pyrazole (8) Experimental Part Mps. are uncorrected (electrothermal apparatus).- IX-spectra. Unicam SP lo00 spectrometer, KBr.- 'H-NMR: 90 MHz spectrometer, TMS as int standard. 2.4-Dimercapto-6-(4-bipheny1)pyrimidine (2) The a-oxoketene gem-dithiol l a (2.72 g, 0.01 mol) and the thiourea (0.76 g. 0.01 mol) were heated under reflux with NaOC3H7 (0.82 g. 0.01 mol) in n-propanol(100ml) for 2 h. After cooling, the mixture was filtered and the filhate was neutralized with 10% HCI. The reddish solid was filtered off and recrystallized from EtOH to give 2 (1.54 g. 52%) m.p. 128129°C.- C&I~NZSZ(296.3) Calc. C 64.9 H 4.08 N 9.4 S 21.6 Found C 64.8 H 4.1 I N 9.4 S 21.5. An quimolar ratio of phenylhydrazine and l b (0.01 rnol) in n-butanol (100 mI) was heated under nflux for 14 h. 'Ihe mixture was cooled and the solid was n n y s W i from benzene to afford 8 (2.46 g. 72%) m.p. 185186. C ~ H I ~ N (342.4) ~ S Calc. C 77.2 H 5.30 N 8.2 S 9.3 Found C 77.0 H 5.36 N 8.2 S 9.4. References 1 2 3 4 2-Mercap~o4-mthylrhio-6-(4-biphenyl) pyrimidine (3) and 2-mrcapro4-erhoxy-6-(4-biphenyl) pyrimidine (4) 5 The a-ketoketene-S,S-acetall b (3.0 g. 0.01 mol) and thiourea (0.76 g. 0.01 mol) in ethanolic NaOEt (0.52 g. 0.01 moUl00 ml) were- refluxed 6 a) L. Dargad and S. 0.Lawesson. Tetrahedron 28. 205 1 (1972). b) F. C. V. Larsson and S. 0. Lawesson, Tetrahedron28,5431 (1972). c) A. Marei and M. M.A. Sukkary, Egypt J. Chem. 14,101 (1971); C.A. 77. 126473(1972). S. M.S. Chauhan and H. Junjappa, Tetrahedron32.1779 (1976). E. Soderlack, Acta. Chem.S a d . 17.362 (1963). D. J. Brown, The Pyrimidines (Ed.A. Weissbtrger), p. 359, Intersdence, New York 1962. B. S. Thyagarajan. Advances in Heterocyclic Chemistry, Vol. 8, p. 143, Academic press, New York 1967. see4,page 164. m i 3 1 0 VCH Verligsgedlschaft mbH. D-6940 Weinheim. 1989 -Printed in the Federal Republic of Gemany Veranhvottlich Hir die Rcdaktion: Prof. Dr. W. Wiegrebe. PharmazeutischesInstitut der Universitat Regensburg. Universiulustde 3 I , Posdach 397. D-840Regensburg.-Anzeigcnleitung:R J. Roth. D-6940Weinhcim -VCH Vcrlagrgesellschaft mbH (GcschllfufUlucrHans DiA KOhler). Postfach 101161. D-6940Wcinheim - M e Rcchtc. insbesondcrc die der CIberseuung in fremde Spmchen. vorbehalten. 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