Synthesis of pyrimidines, thienopyrimidines, and pyrazolopyrimidines

Article abstract of DOI:10.1080/10426500214894

5-Ethoxycarbonyl-4-methyl-2-phenylpyrimidin-6(1H)-thione (3), which was prepared from the reaction of ethyl β-aminocrotonate 1 with benzoyl isothiocyanate (2) in refluxing acetone, was reacted with a series of halopgenated reagents to give S-alkyl derivatives 4a-g. Upon treatment of compounds 4a-c with sodium ethoxide were cyclized into thienopyrimidine 10a-c. Pyrimidinethione 3 was reacted with hydrazine hydrate to give hydroxypyrazolopyrimidine derivative 6. The later compound was obtained by heating compound 4a with hydrazine hydrate under neat conditions, but when the reaction was carried using hydrazine hydrate in ethanol, the corresponding carbohydrazide 5 was produced.

Full text of DOI:10.1080/10426500214894

This article was downloaded by: [University of Otago]
On: 27 December 2014, At: 01:50
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer House,
37-41 Mortimer Street, London W1T 3JH, UK
Phosphorus, Sulfur, and Silicon and the Related
Elements
Publication details, including instructions for authors and subscription information:
http://www.tandfonline.com/loi/gpss20
Synthesis of Pyrimidines, Thienopyrimidines, and
Pyrazolopyrimidines
Adel M. Kamal El-Dean a & Maisa E. Abdel-Moneam a
a Assiut University , Assiut, Egypt
Published online: 27 Oct 2010.
To cite this article: Adel M. Kamal El-Dean & Maisa E. Abdel-Moneam (2002) Synthesis of Pyrimidines, Thienopyrimidines,
and Pyrazolopyrimidines, Phosphorus, Sulfur, and Silicon and the Related Elements, 177:12, 2745-2751, DOI:
10.1080/10426500214894
To link to this article: http://dx.doi.org/10.1080/10426500214894
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained
in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no
representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the
Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and
are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and
should be independently verified with primary sources of information. Taylor and Francis shall not be liable for
any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever
or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of
the Content.
This article may be used for research, teaching, and private study purposes. Any substantial or systematic
reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any
form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http://
www.tandfonline.com/page/terms-and-conditions

Phosphorus, Sulfur and Silicon, 2002, Vol. 177:2745–2751
C
Copyright 2002 Taylor & Francis
1042-6507/02 $12.00 + .00
DOI: 10.1080/10426500290146749
SYNTHESIS OF PYRIMIDINES,
THIENOPYRIMIDINES, AND PYRAZOLOPYRIMIDINES
Adel M. Kamal El-Dean and Maisa E. Abdel-Moneam
Assiut University, Assiut, Egypt
(Received January 31, 2002; accepted April 12, 2002)
5-Ethoxycarbonyl-4-methyl-2-phenylpyrimidin-6(1H)-thione (3), which
was prepared from the reaction of ethyl -aminocrotonate 1 with ben-
zoyl isothiocyanate (2) in refluxing acetone, was reacted with a series of
halopgenated reagents to give S-alkyl derivatives 4a–g. Upon treatment
of compounds 4a–c with sodium ethoxide were cyclized into thienopy-
rimidine 10a–c. Pyrimidinethione 3 was reacted with hydrazine hy-
drate to give hydroxypyrazolopyrimidine derivative 6. The later com-
pound was obtained by heating compound 4a with hydrazine hydrate
under neat conditions, but when the reaction was carried using hy-
drazine hydrate in ethanol, the corresponding carbohydrazide 5 was
produced.
INTRODUCTION
Thienopyrimidines still attract considerable attention of many research
groups due to their wide applications in the medicinal chemistry. They
were used as analgecics,1 antipyretic,2 and antiinflammatory agents.3,4
In view of the pharmacological importance of thienopyrimidine and in
continuation of our work,5,6 herein we report on the synthesis of some
thienopyrimidines in the hope that in the future they may prove to
exhibit biological activity.
RESULTS AND DISCUSSION
5-Ethoxycarbonyl-4-methyl-2-phenylpyrimidin-6(1H)-thione (3), which
was prepared according to the method reported6 previously, was allowed
Address correspondence to Adel M. Kamal El-Dean, Chemistry Department, Faculty
of Science, Assiut University, Assiut 71516, Egypt. E-mail: a.eldean@aun.eun.eg
2745

2746
A. M. K. El-Dean and M. E. Abdel-Moneam
SCHEME 1
to react with a series of -halocarbonyl compounds in ethanol and in
the presence of anhydrous sodium acetate to produce the corresponding
S-alkylated pyrimidine derivatives 4.
Ethyl (5-Ethoxycarbonyl-4-methyl-2-phenylpyrimidin-6-yl)thioace-
tate 4a was reacted with hydrazine hydrate in ethanol to afford the
SCHEME 2

Synthesis of Pyrimidines, Thienopyrimidines, and Pyrazolopyrimidines
2747
SCHEME 3
corresponding carbohydrazide 5. But when the reaction was carried
out without solvent, that is, under neat conditions, the mercaptoacetate
group was replaced by the hydrazine group; under this reaction condi-
tion gave pyrazolopyrimidine 6. The latter compound was obtained by
refluxing pyrimidinethione 3 with hydrazine hydrate.
Carbohydrazide 5 was reacted with benzaldehydes, acetyl acetone,
and carbon disulfide in pyridine to afford the corresponding car-
bohydrazone, pyrazolyl derivative, and oxadiazolyl derivatives (7–9)
respectively.
When the alkylmercaptopyrimidine derivatives 4a–c were refluxed
in ethanol in the presence of sodium ethoxide, thienopyrimidines 10a–c
were obtained.
SCHEME 4
EXPERIMENTAL
Melting points were determined on a Kofler melting point apparatus
and are uncorrected. The IR spectra were recorded using potassium

2748
A. M. K. El-Dean and M. E. Abdel-Moneam
bromide disks on a Pye Unicam spectrophotometer using the KBr Wafer
technique. 1H NMR spectra were obtained on Varian 390 90-MHz spec-
trometer in CDCl3. Chemical shift were determined on the scale by
using tetramethylsilan as the internal standard. Elemental analyses
were obtained on Perkin Elmer 240 C microanalyzer.
5-Ethoxycarbonyl-4-methyl-2-phenylpyrimidin-
6(1H)-thione (3)
To a freshly prepared solution of benzoyl isothiocyanate (0.01 mmol) in
dry acetone, a solution of ethyl- -aminocrotonate (0.01 mmol) in acetone
was added. The mixture was stirred at room tempereature for 1 h and
then refluxed on a steam bath for additional 2 h. The solvent was re-
moved and the product was collected and recrystallized from ethanol
as yellow crystals, in 67% yield, m.p. 138 C.
1
1
1
IR: = 3220 cm (NH), 1720 cm (C O), and 1510 cm (C S).
1H NMR (CDCl3): = 1.2–1.5 (t, 3H, CH3 ester), 2.3 (s, 3H, CH3), 4.3–
4.55 (q, 2H, CH2 ester), 7.35–7.7; 7.95–8.15 (2m, 5H, ArH). Anal. Calcd.
for C14H14N2O2S (274.34): C, 61.29; H, 5.14; N, 10.21; S, 11.69%. Found:
C, 61.08; H, 4.92; N, 10.35; S, 11.42%.
5-Ethyl 6-Alkylmercapto-4-methyl-2-phenylpyrimidin-
5-carboxylate (4a---g)
A mixture of compound 3 (2.75 g, 0.01 ml), sodium acetate (0.01 mmol)
and appropriate halo compound (0.01 mmol) in ethanol (20 ml) was
heated under reflux for 2 h, then allowed to cool. The solid product was
collected, washed well with water, and recrystallized from ethanol. The
physical constants and spectral data of compounds 4a–g are listed in
Tables I and II.
2-[5-Ethoxycarbonyl-4-methyl-2-phenylpyrimidin-
6-yl]mercaptoacetichydrazide (5)
A mixture of compound 4 (3.6 g, 0.01 mmol) and hydrazine hydrate
(99%, 0.05 mmol) in ethanol (30 ml) was heated under reflux for one
hour, then allowed to cool. The solid product was collected and recrys-
tallized from ethanol as white crystals in 82% yield, m.p. 180 C.
Anal. Calcd. for C16H18N4O3S (364.40): C, 55.48; H, 5.24; N, 16.17;
S. 9.26%. Found: C, 55.64; H, 5.05; N, 15.98; S. 9.08%. IR: = 3450, 3360,
3300 cm 1 (NHNH2) and, 1700, 1670 cm 1 (2CO). 1H NMR (CDCl3):
1.3–1.5 (t, 3H, CH3), 2.95 (s, 6H, 2CH3), 3.9 (q, 2H, CH2), 4.1 (s, 2H,
CH2) 4.3 (s, 2H, NH2) 7.2–7.5 (m, 5H, Ar H), 9.5 (s, 1H, NH).
=

Synthesis of Pyrimidines, Thienopyrimidines, and Pyrazolopyrimidines
2749
TABLE I Physical Constants of Compounds 4a–g
Analytical data (calcd/found)
m.p.
( C)
Molecular
formula
No.
R
C
H
N
S
4a
COOEt
COPh
85
114
145
150
190
205
C18H20N2O4S
(360.43)
C22H20N2O3S
(392.47)
C22H19ClN2O3S 61.90 4.49
(426.92)
59.98 5.59
60.13 5.42
67.33 5.14
67.52 4.93
7.77
7.93
7.14
6.95
6.56
6.38
5.94
6.14
10.31
10.37
9.51
9.22
9.35
9.47
8.91
9.18
8.09
8.00
7.36
7.30
8.89
9.02
8.17
8.33
7.51
7.71
6.80
6.66
7.87
8.02
7.25
7.42
7.13
7.26
10.20
10.00
9.26
9.44
8.42
8.18
4b
4c
COC6H4Cl-p
COC6H4Br-p
CONHPh
62.09
4.67
4.06
4d
C22H19BrN2O3S 56.06
(471.37)
C22H21N3O3S
(407.49)
55.89 4.13
64.85 5.19
65.03 5.00
4e
4f
CONHC6H4Cl-p
C22H20ClN3O3S 59.79 4.56
(441.93)
C24H23N3O4S
(449.52)
59.92
4.34
4g
CONHC6H4COMe-p 190
64.13 5.16
63.93 5.02
61.13 4.49
60.89 4.66
69.35 4.07
69.15 3.89
10a
10b
CO2Et
COPh
180-2 C16H14N2O3S
(314.36)
205
C20H14N2O2S
(346.40)
C20H13ClN2O2S 63.07 3.44
(380.85) 62.90 3.34
10ca COC6H4Cl
269
a10c: Cl, Calcd = 9.31.
3-Hydroxy-4-methyl-1[H]-
6-phenylpyrazolo[3,4-d]pyrimidin (6)
A mixture of compound 4a (0.01 mmol) or 3 (0.01 mmol) and hydrazine
hydrate (1 ml) was heated under reflux for 4 h, then ethanol (20 ml)
was added and refluxing was continued for an additional 1 h. The solid
product was collected and recrystallized from ethanol as orange crystals
in 67% yield in the using 4a as a starting material and 62% yield when
3 is used, m.p. 298 C, Lit.7 m.p. 297 C.
Anal. Calcd. for C12H10N4O (226.24): C, 63.71; H, 4.46; N, 24.76%.
Found: C, 63.88; H, 4.34; N, 25.00%. IR: = 3450, 3310, cm 1 (NH, OH)
1
and, 1580 cm (C N). 1H NMR (DMSO-d6): = 3.00 (s, 3H, CH3), 4.5
(s, H, OH), 7.2–7.5 (m, 5H, Ar H), 10.5 (s, 1H, NH).
Benzyledine 2-[5-Ethoxycarbonyl-4-methyl-
2-phenylpyrimidin-6-yl]mercaptoacetichydrazone (7)
A mixture of compound 5 (0.01 mmol) and benzaldehyde (0.01 mmol)
in ethanol (20 ml) was heated under reflux for 3 h, then allowed to cool.

2750
A. M. K. El-Dean and M. E. Abdel-Moneam
TABLE II Physical Constants of Compounds 4a–g
1H NMR
No.
IR
1
4a 1730, 1700 cm (2C O) CDCl3: 1.2–1.7 (2t, 6H, 2CH3), 3.0 (s, 3H, CH3),
3.9–4.3 (m, 4H, 2CH2), 4.4 (s, 2H, CH2),
7.4–7.8 (m, 5H, Ar H)
4b 1720, 1690 cm (2C O) CDCl3: 1.3–1.5 (t, 3H, CH3), 2.95 (s, 3H, CH3),
1
3.9–4.1 (q, 2H, 2CH2), 4.3 (s, 2H, CH2),
7.4–7.8 (m, 10H, Ar H)
4c 1720, 1700 cm (2C O) CDCl3: 1.3–1.5 (t, 3H, CH3), 2.90 (s, 3H, CH3),
1
4.1 (q, 2H, 2CH2), 4.3 (s, 2H, CH2),
7.4–7.8 (m, 9H, Ar H)
4d 1720, 1700 cm (2C O) CDCl3: 1.3–1.5 (t, 3H, CH3), 2.90 (s, 3H, CH3),
1
4.0 (q, 2H, 2CH2), 4.3 (s, 2H, CH2),
7.4–7.8 (m, 9H, Ar H)
1
4e 3260 cm (NH), 1720,
CDCl3: 1.3–1.5 (t, 3H, CH3), 2.95 (s, 3H, CH3),
3.9–4.2 (q, 2H, 2CH2), 4.3 (s, 2H, CH2),
7.4–7.8 (m, 9H, Ar H), 11.3 (s, 1H, NH)
CDCl3: 1.3–1.5 (t, 3H, CH3), 2.95 (s, 3H, CH3),
3.9–4.2 (q, 2H, 2CH2), 4.3 (s, 2H, CH2),
7.4–7.8 (m, 9H, Ar H), 11.3 (s, 1H, NH)
CDCl3: 1.3–1.5 (t, 3H, CH3), 2.95, 3.3 (2s, 6H, 2CH3),
3.9–4.2 (q, 2H, 2CH2), 4.3 (s, 2H, CH2),
7.4–7.8 (m, 9H, Ar H), 11.3 (s, 1H, NH)
CDCl3: 1.5 (t, 3H, CH3), 3.2 (s, 3H, CH3), 3.9–4.2
(q, 2H, CH2), 5.4 (s, 1H, OH), 7.4–7.8 (m, 5H, Ar H)
CDCl3: 3.2 (s, 3H, CH3), 5.6 (s, 1H, OH),
7.4–7.8 (m, 10H, Ar H)
1
1670 cm (2C O)
1
4f 3300 cm (NH), 1720,
1
1670 cm (2C O)
1
4g 3300 cm (NH), 1720,
1
1680, 1670 cm
(3C O)
10a 3420 cm (OH),
1
1
1720 cm (CO)
1
10b 3400 cm (OH),
1
1690 cm (CO)
1
10c 3420 cm (OH),
CDCl3: 3.3 (s, 3H, CH3), 5.6 (s, 1H, OH),
7.4–7.8 (m, 9H, Ar H)
1
1690 cm (CO)
The solid product was collected and recrystallized from ethanol as white
crystals in 77% yield, m.p. 177 C.
Anal. Calcd. for C23H22N4O3S (434.51): C, 63.58; H, 5.10; N, 12.89;
S. 7.38%. Found: C, 63.73; H, 4.95; N, 13.04; S. 7.22%. IR: = 3340
1
1
1
cm (NH) and, 1710–1680 cm (2CO). H NMR (CDCl3): = 1.5 (t,
3H, CH3), 3.00 (s, 3H, CH3), 4.0 (q, 2H, CH2), 4.1 (s, 2H, CH2), 7.1–7.7
(m, 10H, Ar H), 8.1 (s, 1H, CH), 11.2 (s, 1H, NH).
Ethyl 4-Methyl-2-phenyl-6-[3,5-dimethylpyrazol-
1-oxomethylenethio-1-yl]pyrimidin-5-carboxylate (8)
A mixture of compound 5 (0.01 mmol) and acetylacetone (0.01 mmol) in
ethanol (20 ml) was heated under reflux for 5 h, then allowed to cool.
The solid product was collected and recrystallized from ethanol as white
crystals in 72% yield, m.p. 176 C.

Synthesis of Pyrimidines, Thienopyrimidines, and Pyrazolopyrimidines
2751
Anal. Calcd. for C21H22N4O3S (410.49): C, 61.45; H, 5.40; N, 13.65;
1
S. 7.81%. Found: C, 61.32; H, 5.25; N, 13.84; S. 8.00%. IR: = 2950 cm
1
1
(CH aliphatic) and, 1710–1680 cm (2CO). H NMR (CDCl3): = 1.5
(t, 3H, CH3), 2.95, 3.1, 3.2, (3s, 9H, 3CH3), 3.9 (q, 2H, CH2), 4.0 (s, 2H,
CH2), 6.1 (s, 1H, CH), 7.2–7.6 (m, 5H, Ar H).
Ethyl 4-Methyl-2-phenyl-6-[2-mercaptooxadiazol-
5-methylenethio-5-yl]pyrimidin-5-carboxylate (9)
A sample of compound 5 (0.01 mmol) and carbon disulfide (1 ml) in
pyridine (10 ml) was heated on a water bath for 12 h, then the solvent
was evaporated under reduced pressure. The solid product was collected
and recrystallized from ethanol as white crystals in 65% yield, m.p.
120 C.
Anal. Calcd. for C17H16N4O3S2 (388.46): C, 52.56; H, 4.15; N, 14.42;
S. 16.51%. Found: C, 52.67; H, 3.98; N, 14.35; S. 16.71%. IR: = 2900–
1
1
2750 cm (SH) and, 1700 cm (CO). 1H NMR (CDCl3): = 1.5 (t, 3H,
CH3), 2.95 3 (s, 3H, CH3), 3.9 (q, 2H, CH2), 4.0 (s, 2H, CH2), 7.2–7.6
(m, 5H, Ar H).
3-Hydroxy-4-methyl-6-phenylthieno[2,3-d]-
2-substitutedpyrimidin (10a---c)
A sample of compound 4a–c (0.005 mmol) in ethanol (20 ml) containing
sodium ethoxide (0.01 mmol) was heated under reflux for 1 h, allowed
to cool, diluted with water (50 ml), and acidified with HCl (0.1 N) to
just acidic. The solid product was collected. The physical properties
and spectral data of compounds 10a–c are listed in Tables I and II.
REFERENCES
[1] C. G. Dave, P. R. Shah, K. C. Dave, and V. J. Patel, J. Indian Chemical Soc., 66, 48
(1989).
[2] E. Bousquet, G. Romero, F. Guerrera, A. Caruso, and M. A. Roxas, Farmaco Ed. Sci.,
40, 869 (1985).
[3] H. Vieweg, S. Leistner, G. Wagner, N. Boehm, U. G. Krasset, R. D. Lohmann, and
G. Loban, East. Ger. Pat. No. DD: 257,830 (1988); C. A. 110, 95262p (1989).
[4] S. Leistner, G. Wagner, M. Guetscharo, and E. Glusa, Pharmazie, 41, 54 (1989).
[5] A. M. Kamal El-Dean, J. Chem. Res., (M), 1401 (1996).
[6] A. M. Kamal El-Dean, Monatsche. fur Chemie, 129, 523 (1998).
[7] J. Goerdeler and D. Wieland, Chem. Ber., 100, 47 (1967).