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Ketoketene gem-Dithiols in the Synthesis of Pyrimidine and Pyrazole Derivatives Pyrimidin- und Pyrazol-Derivate aus geminalen Dithiolen eines Ketoketens.

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Pyrimidines and Pyrazoles
Ketoketene gem-Dithiols in the Synthesis of Pyrimidine and Pyrazole
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).
- W3SH
- CH3SNa
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).
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
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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.
pyrimidine (5)
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.
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.
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
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
~ 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.
pyrimidine (3) and
2-mrcapro4-erhoxy-6-(4-biphenyl) pyrimidine (4)
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
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.
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
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