Synthesis of pyrimidines, thienopyrimidines and pyrazolopyrimidine

Article abstract of DOI:10.1002/jccs.200200152

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 halo compounds to give S-alkyl derivatives 4a-h. Treatment of compounds 4a-c with sod. ethoxide cyclized into thienopyrimidine 10a-c. Hydrazinolysis of compound 3 gave hydroxypyrazolopyrimidine derivative 6. Also the latter compound was obtained upon heating compound 4a with hydrazine hydrate under neat conditions, but when compound 4a refluxed with hydrazine hydrate in ethanol the corresponding carbohydrazide 5 was produced.

Full text of DOI:10.1002/jccs.200200152

Journal of the Chinese Chemical Society, 2002, 49, 1057-1060
1057
Synthesis of Pyrimidines, Thienopyrimidines and Pyrazolopyrimidine
Adel. M. Kamal El-Dean* and Maisa E. Abdel-Moneam
Chemistry Department, Faculty of Science, Assiut University, Assiut 71516, Egypt
5-Ethoxycarbonyl-4-methyl-2-phenylpyrimidin-6(1H)-thione (3), which was prepared from the reaction
of ethyl -aminocrotonate 1 with benzoyl isothiocyanate (2) in refluxing acetone, was reacted with halo com-
pounds to give S-alkyl derivatives 4a-h. Treatment of compounds 4a-c with sod. ethoxide cyclized into
thienopyrimidine 10a-c. Hydrazinolysis of compound 3 gave hydroxypyrazolopyrimidine derivative 6. Also
the latter compound was obtained upon heating compound 4a with hydrazine hydrate und e r neat conditions,
but when compound 4a refluxed with hydrazine hydrate in ethanol the corresponding carbohydrazide 5 was
produced.
INTRODUCTION
Thienopyrimidines still attract considerable attention
ethanol to afford the corresponding carbohydrazide 5. But
when the reaction was carried out without solvent, i.e. under
neat conditions, the mercaptoacetate group was replaced by
the hydrazine group which und e r the reaction conditions gave
pyrazolopyrimidine 6. The latter compound was obtained by
refluxing pyrimidinethion 3 with hydrazine hydrate.
of many research groups due to their wide applications in me-
dicinal chemistry. They are used as analgecics,1 antipyretics,2
and antiinflammatory agents.3,4
In view of the pharmacological importance of thieno-
pyrimidine and in continuation of our work5-6 herein we re-
port the synthesis of some thienopyrimidines hoping that
they may be biologically active.
CH
CH
3
3
COOEt
COOEt
N
NH NH .H O
N
2
2 2
EtOH
N
SCH COOEt
Ph
N
5
Ph
SCH CONHNH
2
2
2
4a
NH NH .H O
RESULTS AND DISCUSSION
2
2 2
CH
3
5-Ethoxycarbonyl-4-methyl-2-phenylpyrimidin-6(1H)-
thione (3), which was prepared according to the method re-
ported6 previously was allowed to react with -halocarbonyl
compounds in ethanol and in the presence of anhydrous so-
dium acetate to produce the corresponding S-alkylated py-
rimidine derivatives 4.
OH
N
NH NH .H O
2
2 2
N
3
N
N
H
Ph
6
Carbohydrazide 5 was reacted with benzaldehydes,
acetyl acetone, and with carbon disulfide in pyridine to afford
the corresponding carbohydrazone, pyrazolyl derivative and
oxadiazolyl derivatives 7-9, respectively.
CH3
COOEt
N
EtO
Me
NH2
PhCONCS
2
+
N
S
Ph
O
CH3
COOEt
N
H
3
1
CH3
N
7
SCH2 CONHN CHPh
Ph
COOEt
SCH2R
N
ClCH R
2
3
PhCHO
N
4
CH3
Ph
COOEt
S
N
CH3
Me
CH3
N
SH
O
COOEt
COOEt
S
N
9
Ph
N
N
N
N
CS
(MeCO) CH
2
2
2
pyridine
N
N
Ethyl (5-Ethoxycarbonyl-4-methyl-2-phenylpyrimidin-
Ph
N
SCH2CONHNH2
Ph
8
O
Me
5
6-yl)thioacetate 4a was reacted with hydrazine hydrate in
* Corresponding author. E-mail: a.eldean@aun.eun.eg

1058 J. Chin. Chem. Soc., Vol. 49, No. 6, 2002
Kamal El-Dean and Abdel-Moneam
When alkylmercaptopyrimidine derivatives 4a-c refluxed
in ethanol in the presence of sodium ethoxide, thienopyri-
midines 10a-c were obtained.
2-[5-Ethoxycarbonyl-4-methyl-2-phenylpyrimidin-6-yl]-
mercaptoacetichydrazide (5)
A mixture of compound 4 (3.6 g, 0.01 mL) and hy-
drazine hydrate (99%, 0.05 mol) in ethanol (30 mL) was
heated under reflux for one hour, then allowed to cool. The
solid produ c t was collected and recrystallized from ethanol
as white crystals in 82% yield, m.p. 180 C. Anal. Calcd. for
C16H18N4O3S (346.40): 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).
CH3
CH3
OH
COOEt
EtONa/EtOH
N
N
N
S
Ph
N
4
SCH2COR
Ph
R
10a; R = CO Et
2
10b; R = COPh
10c; R = C H Cl-p
6
4
EXPERIMENTAL
3-Hydroxy-4-methyl-1[H]-6-phenylpyrazolo[3,4-d]-
pyrimidin (6)
Melting points were determined on a Kofler melting
point apparatus and are uncorrected. The IR spectra were re-
corded on potassium bromide disks on a Pye Unicam spectro-
photometer usi n g the KBr Wafer technique. 1H NMR spectra
were obtained on a Varian 390 90-MHz spectrometer in a
suitable deuterated solvent. Chemical shifts were determined
on the scale by usi n g tetramethylsilan as the internal stan-
dard. Elemental analy s e s were obtained on a Perkin Elmer
240 C microanalyzer.
A mixture of compound 4a (0.01 mol) or 3 (0.01 mol)
and hyrdrazine hydrate (1 mL) was heated under reflux for 4
h, then ethanol (20 mL) was added and refluxing was contin-
ued for an additional one hour. The solid product was col-
lected and recrystallized from etha n o l as orange crystals in
67% yield in using 4a as a starting material and 62% yield
when 3 was 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
5-Ethoxycarbonyl-4-methyl-2-phenylpyrimidin-6(1H)-
thione (3)
(NH, OH) and, 1580 cm-1 (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).
To a freshly prepared solution of benzoyl isothiocya-
nate (0.01 mol) in dry acetone, a solution of ethyl- -amino-
crotonate (0.01 mol) in acetone was added. The mixture was
stirred at room temperature for 1 h and then refluxed on a
steam bath for an additional 2 h. The solvent was removed,
and the product was collected and recrystallized from ethanol
as yellow crystals, in 67% yield, m.p. 138 C. IR: = 3220
cm-1 (NH), 1720 cm-1 (C=O), and 1510 cm-1 (C=S). 1H NMR
(CDCl3): = 1.2-15 (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%.
Benzyledine 2-[5-ethoxycarbonyl-4-methyl-2-
phenylpyrimidin-6-yl]mercaptoacetic-hydrazone (7)
A mixture of compound 5 (0.01 mol) and benzaldehyde
(0.01 mol) in ethanol (20 mL) was heated und e r reflux for 3 h,
then allowed to cool. 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 cm-1 (NH) and, 1710-1680
cm-1 (2CO). 1H 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).
5-Ethyl 6-alkylmercapto-4-methyl-2-phenylpyrimidin-5-
carboxylate (4a-h)
Ethyl 4-methyl-2-phenyl-6-[3,5-dimethylpyrazol-1-
oxomethylenethio-1-yl]pyrimidin-5-carboxylate (8)
A mixture of compound 5 (0.01 mol) and acetylacetone
(0.01 mol) in ethanol (20 mL) was heated und e r 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. Anal. Calcd. for C21H22N4O3S (410.49): C,
A mixture of compound 3 (2.75 g, 0.01 mL), sod. ace -
tate (0.01 mol) and an appropriate halo compound (0.01 mol)
in ethanol (20 mL) was heated under reflux for 2 h, then al-
lowed to cool. The solid product was collected, washed well
with water and recrystallized from etha n o l . The physical con-
stants and spectral data of compounds 4a-h are listed in Ta-
bles 1 and 2.

Thienopyrimidines and Pyrazolopyrimidines
J. Chin. Chem. Soc., Vol. 49, No. 6, 2002 1059
Table 1. Physical Constants of Compounds 4a-h
No.
R
M.P.
C
Molecular
Formula
Analytical Data (Calcd/Found)
C
H
N
S
4a
COOEt
COPh
85
114
145
150
190
205
190
180-2
205
269
C18H20N2O4S
(360.43)
C22H20N2O3S
(392.47)
C22H19ClN2O3S
(426.92)
C22H19BrN2O3S
(471.37)
C22H21N3O3S
(407.49)
C22H20ClN3O3S
(441.93)
C24H23N3O4S
(449.52)
C16H14N2O3S
(314.36)
59.98
60.13
67.33
67.52
61.90
62.09
56.06
55.89
64.85
65.03
59.79
59.92
64.13
63.93
61.13
60.89
69.35
69.15
63.07
62.90
5.59
5.42
5.14
4.93
4.49
4.67
4.06
4.13
5.19
5.00
4.56
4.34
5.16
5.02
4.49
4.66
4.07
3.89
3.44
3.34
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
4d
4e
4f
CONHC6H4Cl-p
CONHC6H4COMe-p
CO2Et
4g
10a
10b
10c
COPh
C20H14N2O2S
(346.40)
C20H13ClN2O2S
(380.85)
COC6H4Cl
10c: Cl, Calcd = 9.31
Table 2. Spectral Data of Compounds 4a-h
No.
IR
1H NMR
4a
1730, 1700 cm-1 (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).
CDCl3: 1.3-1.5 (t, 3H, CH3), 2.95 (s, 3H, CH3), 3.9-4.1 (q, 2H, 2CH2),
4.3 (s, 2H, CH2), 7.4-7.8 (m, 10H, Ar-H).
CDCl3: 1.3-1.5 (t, 3H, CH3), 2.90 (s, 3H, CH3), 4.1 (q, 2H, 2CH2), 4.3
(s, 2H, CH2), 7.4-7.8 (m, 9H, Ar-H).
CDCl3: 1.3-1.5 (t, 3H, CH3), 2.90 (s, 3H, CH3), 4.0 (q, 2H, 2CH2), 4.3
(s, 2H, CH2), 7.4-7.8 (m, 9H, Ar-H).
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).
4b
4c
1720, 1690 cm-1 (2C=O)
1720, 1700 cm-1 (2C=O)
1720, 1700 cm-1 (2C=O)
4d
4e
3260 cm-1 (NH), 1720,
1670 cm-1 (2C=O)
4f
3300 cm-1 (NH), 1720,
1670 cm-1 (2C=O)
4g
10a
3300 cm-1 (NH), 1720,
1680, 1670 cm-1 (3C=O)
3420 cm-1 (OH), !720 cm-1 (CO)
10b
10c
3400 cm-1 (OH), !690 cm-1 (CO)
3420 cm-1 (OH), !690 cm-1 (CO)
CDCl3: 3.2 (s, 3H, CH3), 5.6 (s, 1H, OH), 7.4-7.8 (m, 10H, Ar-H).
CDCl3: 3.3 (s, 3H, CH3), 5.6 (s, 1H, OH), 7.4-7.8 (m, 9H, Ar-H).
61.45; H, 5.40; N, 13.65; S. 7.81%. Found: C, 61.32; H, 5.25;
N, 13.84; S. 8.00%. IR: = 2950 cm-1 (CH aliphatic) and,
Ethyl 4-methyl-2-phenyl-6-[2-mercaptooxadiazol-5-
methylenethio-5-yl]pyrimidin-5-carboxylate (9)
1
1710-1680 cm-1 (2CO). H NMR (CDCl3): = 1.5 (t, 3H,
A sample of compound 5 (0.01 mol) and carbon disul-
fide (1 mL) in pyridine (10 mL) was heated on a water bath
for 12 h, then the solvent was evaporated und e r reduced pres-
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).

1060 J. Chin. Chem. Soc., Vol. 49, No. 6, 2002
Kamal El-Dean and Abdel-Moneam
sure. 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: = 2900-2750 cm-1 (SH) and, 1700 cm-1 (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).
Key Words
Synthesis; Pyrimidines; Thienopyrimidines and
pyrazolopyrimidines.
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3-Hydroxy-4-methyl-6-phenylthieno[2,3-d]-2-substituted-
pyrimidin (10a-c)
A sample of compound 4a-c (0.005) in ethanol (20 mL)
containing sod. ethoxide (0.01 mol) was heated und e r reflux
for 1 h, then allowed to cool, diluted with water (50 mL) and
acidified with HCl (0.1 N) to just acidic. The solid product
was collected. The physi c a l properties and spectral data of
compounds 10a-c are listed in Tables 1 and 2.
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Received November 12, 2001.