Synthesis of some new pyrimidine and pyrimido[4,5-d]pyrimidine derivatives

Article abstract of DOI:10.1080/00397910802326596

A convenient synthesis of a series of pyrimidine carbonitrile, thiopyrimidine, and pyrimidopyrimidine derivatives, via the reactions of the versatile, readily accessible 6-aryl-4-oxo-2-thioxo-hexahydro-pyrimidine-5- carbonitrile with the appropriate reagents, is described. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910802326596

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Synthesis of Some New
Pyrimidine and Pyrimido[4,5-
d]pyrimidine Derivatives
Ahmed A. Fadda a , Ehab Abd El-Latif a , Samir
Bondock a & Ahmed Samir a
a Department of Chemistry, Faculty of Science,
Mansoura University, Mansoura, Egypt
Available online: 08 Nov 2008
To cite this article: Ahmed A. Fadda, Ehab Abd El-Latif, Samir Bondock & Ahmed
Samir (2008): Synthesis of Some New Pyrimidine and Pyrimido[4,5-d]pyrimidine
Derivatives, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 38:24, 4352-4368
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Synthetic Communications1, 38: 4352–4368, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802326596
Synthesis of Some New Pyrimidine and
Pyrimido[4,5-d]pyrimidine Derivatives
Ahmed A. Fadda, Ehab Abd El-Latif, Samir Bondock,
and Ahmed Samir
Department of Chemistry, Faculty of Science, Mansoura University,
Mansoura, Egypt
Abstract: A convenient synthesis of a series of pyrimidine carbonitrile, thiopyri-
midine, and pyrimidopyrimidine derivatives, via the reactions of the versatile,
readily accessible 6-aryl-4-oxo-2-thioxo-hexahydro-pyrimidine-5-carbonitrile
with the appropriate reagents, is described.
Keywords: Benzaldehyde, chloroacetic acid, phenyl isothiocyanate, phosphorus
oxychloride, thiourea
INTRODUCTION
The pyrimidine ring system undoubtedly belongs to the most important
heterocycles in nature, as it represent the main structure of many biolo-
gically significant compounds, including nucleosides and nucleotides.
For this reason many analogs and derivatives of pyrimidines have been
synthesized and developed as pharmacologically active compounds or
drugs. Pharmacologically active purine analogs include tricyclic struc-
tures such as imidazo[2,1-i]purinones (e.g., PSB-11, a potent A3 adeno-
sine receptor antagonist), pyrimido[4,5-b]indoles (e.g., APEPI, a potent
A1 adenosine receptor antagonist), and imidazo[2,1-a]purines (e.g., tri-
cyclic ganciclovir analogs, which are potent antiviral agents).[1]
Received May 26, 2008.
Address correspondence to Ahmed A. Fadda, Department of Chemistry,
Faculty of Science, Mansoura University, Mansoura, Egypt. E-mail: afadda2@
yahoo.com
4352

New Pyrimidine Derivatives
4353
RESULTS AND DISCUSSION
Since the isolation of pyrimidine derivatives, considerable attention has
been devoted to their chemistry and biological activity.[2] In recent years,
there has been increasing interest in the synthesis of pyrimidine deriva-
tives, and there are some methods used to synthesize the pyrimidine ring,
allowing access to a large number of multifunctionalized pyrimidine
derivatives.[3] Treatment of different ethyl arylidenecyanoacetates (1a–c)
with thiourea in ethanol–sodium ethoxide at room temperature
affords the corresponding 6-aryl-4-oxo-2-thioxo-hexahydro-pyrimidine-
5-carbonitrile (2a–c). Heating compound 2a in ethanol and in the pre-
sence of potassium hydroxide led to dehydrogenation and afforded 4-
oxo-6-phenyl-2-thioxo-1,2,3,4-tetrahydro-pyrimidine-5-carbonitrile (3).[4]
Compound 3 can be prepared via the one-pot reaction of benzaldehyde
with ethyl cyanoacetate and thiourea in dimethyl formamide at room
temperature, in the presence of potassium hydroxide (Scheme 1).[5]
Boiling pyrimidine derivatives 2a–c in phosphorus oxychloride afforded
the corresponding 6-aryl-4-chloro-2-thioxo-1,2,5,6-tetrahydro-pyrimidine-
5-carbonitrile (4a–c). The IR spectra of these compounds indicate the dis-
appearance of (CO) group. For example, the IR spectrum of compound
(4a) showed characteristic absorption bands at 3152 cmꢀ1 (NH),
2221 cmꢀ1 (CN), 1625 cmꢀ1 (C¼N), and 700 cmꢀ1 (CꢀCl). The mass
spectrum of compound 4a showed the molecular ion peak at m=z 249
(Mþ) (Scheme 1).
In a similar manner, boiling of pyrimidine derivative 3 in phosphorus
oxychloride afforded the corresponding 4-chloro-6-phenyl-2-thioxo-1,2-
dihydro-pyrimidine-5-carbonitrile (5). The IR spectrum of compound 5
indicates the disappearance of (CO) group and showed characteristic
absorption bands at 3420 cmꢀ1 (NH), 2205 cmꢀ1 (CN), 1621 cmꢀ1
(C¼N), and 700 cmꢀ1 (C–Cl). The mass spectrum of compound (5)
showed the molecular ion peak at m=z 247 (Mþ).
An alternative method for the synthesis of compound 5 was achieved
by heating of pyrimidine derivative 4a in dimethyl formamide in the pre-
sence of potassium hydroxide Scheme 1. Pyrimidine derivatives 2a–c
reacted with ethyl chloroacetate in alcoholic potassium hydroxide to
afford (6-aryl-5-cyano-4-oxo-1,4-dihydro-pyrimidin-2-ylsulfanyl)-acetic
acid ethyl ester (6a–c) (Scheme 1). The IR spectrum of compound 6a
showed characteristic absorption bands at 3207 cmꢀ1 (NH), 2223 cmꢀ1
(CN), 1735 cmꢀ1 (COOEt), and 1662 cmꢀ1 (NCO). The mass spectrum
of compound 6b showed the molecular ion peak at m=z 345 (Mþ). The
1H NMR spectrum of compound 6a revealed signals at d 1.23 as triplet
for CH3, d 4.04 as singlet for SCH2, d 4.22 as quartet for CH2, and
7.1–7.8 as multiplets for aromatic protons.

4354
A. A. Fadda et al.
Scheme 1. (a) Ar ¼ C6H5, (b) Ar ¼ p-OCH3C6H4, and (c) Ar ¼ p-N(CH3)2 C6H4.
On the other hand, refluxing of thioxopyrimidine derivative 3 with
ethyl chloroacetate in alcoholic potassium hydroxide afforded compound
6a (Scheme 1). All attempts to synthesize thiazolo[3,2-a]pyrimidine deri-
vative 7 from 6a under different reaction conditions (refluxing in etha-
nol–sodium ethoxide, refluxing in acetic anhydride,[6] refluxing in
AcOH=H2SO4[7]) failed. The reaction of thiopyrimidine derivative 2a
with chloroacetic acid in ethanol in the presence of potassium hydroxide
gave 2,4-dioxo-6-phenyl-1,2,3,4-tetrahydro-pyrimidine-5-carbonitrile 8,
not the expected S-alkyl derivative 9. Compound 8 was confirmed by
alternative synthesis. Thus, ethyl benzylidenecyanoacetate 1a was reacted
with urea in ethanol–sodium ethoxide at room temperature to afford a
1
compound identical in all respects (mp, mixed mp, IR, H NMR) to 8

New Pyrimidine Derivatives
4355
(Scheme 1). The IR spectrum of compound 8 showed characteristic
absorption bands at 3425 cmꢀ1 (NH), 2230 cmꢀ1 (CN), 1724, and
1683 cmꢀ1 (2CO). The mass spectrum showed the molecular ion peak
at m=z 213 (Mþ).
The reaction of different arylidenemalononitrile derivatives (10a–c)
with thiourea in ethanol–sodium ethoxide at room temperature afforded
the corresponding 6-amino-4-aryl-2-thioxo-1,2,3,4-tetrahydro-pyrimidine-
5-carbonitrile (11a–c). Tetrahydropyrimidine 11a, when heated in ethanol
in the presence of piperidine, underwent auto-oxidation to produce
6-amino-4-phenyl-2-thioxo-1,2-dihydro-pyrimidine-5-carbonitrile (12).
Dihydro-pyrimidine (12) can easily obtained via a one-pot reaction of
malononitrile, benzaldehyde, and thiourea in dimethyl formamide in
the presence of potassium hydroxide at room temperature[4] (Scheme 2).
Compounds 11a–c and 12 were used as precursors for the synthesis
of new pyrimido[4,5-d]pyrimidine derivatives. Thus, reaction of pyrimi-
dines (11a–c) with carbon disulphide in refluxing dimethylformamide
Scheme 2. (a) Ar ¼ C6H5, (b) Ar ¼ p-OCH3C6H4, and (c) Ar ¼ p-CH3C6H4.

4356
A. A. Fadda et al.
for 2 h afforded 5-aryl-5,8-dihydro-1H,6H-pyrimido[4,5-d]pyrimidine-
2,4,7-trithione (13a–c), which was converted to 5-phenyl-1H,8H-pyrimido
[4,5-d]pyrimidine-2,4,7-trithione (14) by heating 13a in ethanol in the pre-
sence of a catalytic amount of piperidine. Pyrimido[4,5-d]pyrimidine-
trithione (14) could be also synthesized by refluxing dihydro-pyrimidine
(12) with carbon disulphide in dimethylformamide (Scheme 2). The IR
spectrum of compound 13a showed the absence of the CN absorption
band and revealed the presence of characteristic absorption bands of
(NH) at 3183 cmꢀ1 and (C¼S) at 1238 cmꢀ1. The mass spectrum of com-
pound 13a showed the molecular ion peak at m=z 306 (Mþ). The IR spec-
trum of compound 14 showed the disappearance of the (CN) group and
showed characteristic absorption bands at 3363 cmꢀ1 (NH), 1247 cmꢀ1
(C¼S), and 1617 cmꢀ1 (C¼N). The mass spectrum of compound 14
showed the molecular ion peak at m=z 304 (Mþ).
Prolonged heating of 11a–c with an excess of formic acid afforded
the corresponding 5-aryl-7-thioxo-5,6,7,8-tetrahydro-3H-pyrimido[4,5-d]
pyrimidin-4-one (15a–c), which converted to 5-phenyl-7-thioxo-7,8-dihy-
dro-3H-pyrimido[4,5-d]pyrimidin-4-one (16) by heating in ethanol in the
presence of a catalytic amount of piperidine. Refluxing dihydro-pyrimi-
dine derivative (12) with an excess of formic acid afforded the corre-
sponding dihydro-pyrimido[4,5-d]pyrimidine derivative 16 (Scheme 2).
The IR spectrum of compound 15a showed no absorption band at
2220 cmꢀ1 corresponding to the (CN) group and showed characteristic
absorption bands at 3149 cmꢀ1 (NH), appearance of (C¼O) at
1714 cmꢀ1, and (C¼S) at 1241 cmꢀ1. The mass spectrum of compounds
15a and 15b showed the molecular ion peak at m=z 258 (Mþ) and m=z
288 (Mþ), respectively. The 1H NMR spectrum of compound 15c
revealed signals at d 2.32 as singlet for CH3, at d 5.15 as singlet for
NCH, at d 7.11 as singlet for NCHN, and at d 10.17, 10.46, and 11.76
as singlets for 3NH. The IR spectrum of compound 16 indicates the dis-
appearance of the (CN) group. The mass spectrum of compound 16
showed the molecular ion peak at m=z 256 (Mþ).
An alternative method for the synthesis of compound 15a was
achieved by the reaction of benzylidenecyanoacetamide (17) with thiourea
in ethanol–sodium ethoxide to afford 6-amino-4-phenyl-2-thioxo-1,2,3,4-
tetrahydro-pyrimidine-5-carboxylic acid amide (18). Refluxing compound
18 in an excess of formic acid afforded tetrahydro-pyrimido[4,5-d]pyrimi-
dine (15a) (Scheme 2). Refluxing pyrimido[4,5-d]pyrimidin-4-one deriva-
ꢁ
tive (15a) with phosphorousoxychloride at 100 C afforded the
corresponding 5-chloro-4-phenyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimi-
dine-2-thione (19) (Scheme 2). The IR spectrum of compound 19 showed
no absorption band at 1714 cmꢀ1 corresponding to the (C¼O) group and
showed characteristic absorption bands at 3200 cmꢀ1 (NH) and

New Pyrimidine Derivatives
4357
1614 cmꢀ1 (C¼N). The mass spectrum of compound 19 showed the
molecular ion peak at m=z 276 (Mþ). Boiling compounds 11a–c under
reflux with an excess of formamide afforded the corresponding 5-
amino-4-aryl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidine-2-thione (20a–
c) (Scheme 2). The IR spectrum showed the absence of the CN absorption
band and revealed the presence of characteristic absorption bands at
3259 cmꢀ1 (NH). The mass spectrum of compounds 20a and 20b showed
the molecular ion peaks at m=z 257 (Mþ) and m=z 287 (Mþ), respectively.
On the other hand, when pyrimidine derivatives 10a–c refluxed with
acetic anhydride, they afforded directly 5-aryl-2-methyl-7-thioxo-5,6,7,8-
tetrahydro-3H-pyrimido[4,5-d]pyrimidin-4-one (21a–c) (Scheme 3). The
IR spectrum of compound 21a showed the absence of the CN absorption
band and revealed the presence of characteristic absorption bands
at 3196 cmꢀ1 (NH), 1726 cmꢀ1 (C¼O), 1599 cmꢀ1 (C¼N), and
1229 cmꢀ1 (C¼S). The 1H NMR spectrum of compound 21b revealed sig-
nals at d 2.51 as singlet for CH3, d 3.76 as singlet for OCH3, d 5.16 as singlet
for NCH, and d 10.14, 10.46, and 11.74 as singlets for 3NH. The mass spec-
trum of compound 21b showed the molecular ion peak at m=z 302 (Mþ).
Tetrahydro-thioxopyrimidines (11a–c) were found to afford the 5-
amino-4-aryl-3,4-dihydro-6-phenylpyrimido[4,5-d]pyrimidine-2,7(1H,6H)-
dithione (22a–c), when refluxed with phenyl isothiocyanate in pyridine
Scheme 3. (a) Ar ¼ C6H5, (b) Ar ¼ p-OCH3C6H4, and (c) Ar ¼ p-CH3C6H4.

4358
A. A. Fadda et al.
(Scheme 3). The IR spectrum of compound 22a showed the absence of the
CN absorption band and revealed the presence of characteristic absorption
bands at 3206 cmꢀ1 (NH2), 3034 cmꢀ1 (NH), 1624 cmꢀ1 (C¼N), and
1241 cmꢀ1 (C¼S). The mass spectrum of compound 22a showed the mole-
cular ion peak at m=z 366 (Mþ ꢀ 1).
Treatment of 11a with carbon disulphide and methyl iodide at
room temperature in dimethylformamide (DMF) in the presence of
potassium hydroxide gives (dimethyl-5-cyano-6-phenyl-2-thioxo-1,2,3,6-
tetrahydropyrimidin-4-yldithioimidocarbonate)pyrimidine (23) (Scheme
3). The IR spectrum of compound 23 showed the absence of the NH2
and NH absorption bands and revealed the presence of characteristic
absorption bands at 2224 cmꢀ1 (CN), 1579 cmꢀ1 (C¼N), and
1
1230 cmꢀ1 (C¼S). The H NMR spectrum of compound 22 revealed sig-
nals at d 2.38 as singlet for 2SCH3, d 3.69 as singlet for 2NCH3, and d
4.76 as singlet for CH. The mass spectrum of compound 23 showed the
molecular ion peak at m=z 362 (Mþ).
Refluxing thioxopyrimidine derivatives 11a–c with ethyl chloroace-
tate in alcoholic potassium hydroxide afforded (4-amino-6-aryl-5-
cyano-pyrimidin-2-ylsulfanyl)-acetic acid ethyl ester (24a–c). On the other
hand, when dihydro-pyrimidine derivative 12 reacted with ethyl chloroa-
cetate in alcoholic potassium hydroxide, it afforded (4-amino-5-cyano-6-
phenyl-pyrimidin-2-ylsulfanyl)-acetic acid ethyl ester (24a) (Scheme 3).
The IR spectrum of compound 24a showed characteristic absorption
bands at 3336 cmꢀ1 (NH), 3454 cmꢀ1 (NH) 2187 cmꢀ1 (CN), 1740 cmꢀ1
1
carbonyl ester, 1659 cmꢀ1 (C¼N). The H NMR spectrum of compound
24a revealed signals at d 1.39 as triplet for CH3, d 4.01 as singlet for SCH2,
d 4.35 as quartet for OCH2, and d 10.19 as singlet for NH2. Compound
24a underewent esting for reactivity of b-enaminonitrile moiety by
prolonged heating with an excess of formic acid to afford the correspond-
ing (5-oxo-4-phenyl-5,6-dihydro-pyrimido[4,5-d]pyrimidin-2-ylsulfanyl)-
acetic acid ethyl ester (25) (Scheme 3). The IR spectrum of compound
25 showed no absorption band at 2220 cmꢀ1 corresponding to the (CN)
group aꢀn1d revealed the presence of characteristic absorption bands at
3086 cm
(NH), appearance of (C¼O) at 1712 cmꢀ1, (COOEt) at
1735 cmꢀ1, and (C¼N) at 1616 cmꢀ1. The mass spectrum of compound
25 showed the molecular ion peak at m=z 342 (Mþ).
EXPERIMENTAL
All melting points are recorded on a Gallenkamp electric melting-point
apparatus and are uncorrected. The IR spectra n cmꢀ1 (KBr) were
recorded on Perkin-Elmer infrared spectrophotometer model 157,

Table 1. Characterization data of newly prepared compounds
Analytical data calc., % (Found, %)
Compound
Formula
Mol. weight
C
H
N
Yield (%)
Mp (ꢁC)
2a[4]
2b[4]
2c[4]
3[5]
4a
C11H9N3OS
C12H11N3O2S
C13H14N4OS
C11H7N3OS
C11H8ClN3S
C12H10ClN3OS
C13H13ClN4S
C11H6ClN3S
C15H13N3O3S
C16H15N3O4S
C17H18N4O3S
C11H7N3O2
C11H10N4S
C12H12N4OS
C12H12N4S
C11H8N4S
C12H10N4S3
C13H12N4OS3
C13H12N4S3
C12H8N4S3
231.27
261.30
274.34
229.26
249.72
279.75
292.79
247.7
57.13 (57.21)
55.16 (55.11)
56.91 (56.82)
57.63 (57.51)
52.91 (52.83)
51.52 (51.27)
53.33 (53.18)
53.34 (53.37)
57.13 (57.11)
55.64 (55.73)
56.97 (57.01)
61.97 (62.16)
57.37 (57.34)
55.37 (55.32)
58.99 (58.92)
57.88 (57.92)
47.03 (47.05)
46.41 (46.34)
48.27 (48.54)
47.35 (47.65)
55.80 (56.02)
3.92 (3.98)
4.24 (4.20)
5.14 (5.09)
3.08 (3.01)
3.23 (3.29)
3.60 (3.48)
4.48 (4.51)
2.44 2.49)
4.16 (4.13)
4.38 (4.44)
5.06 (5.15)
3.31 (3.29)
4.38 (4.32)
4.65 (4.58)
4.95 (4.89)
3.53 (3.58)
3.29 (3. 39)
3.59 (3.66)
3.77 (3.67)
2.65 (2.88)
3.90 (4.18)
18.17 (18.23)
16.08 (16.01)
20.42 (20.38)
18.33 (18.27)
16.83 (16.75)
15.02 (15.22)
19.14 (19.06)
16.96 (16.90)
13.33 (13.21)
12.17 (12.23)
15.63 (15.62)
19.71 (19.69)
24.33 (24.28)
21.52 (21.46)
22.93 (22.88)
24.54 (24.61)
18.28 (18.30)
16.65 (16.64)
17.48 (17.10)
18.40 (18.73)
21.69 (21.75)
Lit.[4] mp)
Lit.[4] mp)
Lit.[4] mp)
Lit.[4] mp)
257
280
285
> 280
240
70
65
4b
4c
75
A, 60; B, 70
5
6a
315.35
345.37
358.4
85
80
85
40
6b
6c
200
215
285
8
213.19
230.29
260.31
244.32
228.27
306.43
336.46
320.46
304.41
258.3
11a[4]
11b[4]
11c[4]
12[4]
13a
13b
13c
14
Lit.[4] mp)
Lit.[4] mp)
Lit.[4] mp)
Lit.[4] mp)
250
82
75
73
68
90
260
> 280
> 280
251
15a
C12H10N4OS
(Continued )

Table 1. Continued
Analytical data calc., % (Found, %)
Compound
Formula
Mol. weight
C
H
N
Yield (%)
Mp (ꢁC)
15b
15c
16
C13H12N4O2S
C13H12N4OS
C12H8N4OS
C11H12N4OS
C12H9ClN4S
C12H11N5S
288.32
272.33
256.28
248.3
276.74
257.31
287.34
271.34
272.33
302.35
286.35
379.5
54.15 (54.54)
57.34 (57.23)
56.24 (56.43)
53.21 (53.68)
52.08 (51.87)
56.01 (56.34)
54.34 (54.69)
57.54 (57.93)
57.34 (57.85)
55.61 (55.25)
58.72 (59.12)
59.15 (59.78)
57.70 (58.03)
60.13 (60.56)
53.01 (52.66)
57.31 (57.89)
55.80 (55.48)
58.52 (58.88)
56.13 (56.76)
4.20 (4.37)
4.44 (4.12)
3.15 (3.47)
4.87 (4.45)
3.28 (3.48)
4.31 (4.68)
4.56 (4.27)
4.83 (5.03)
4.44 (4.97)
4.67 (4.99)
4.93 (5.41)
4.14 (4.66)
4.33 (4.78)
4.52 (4.74)
5.00 (5.14)
4.49 (4.21)
4.68 (4.23)
4.91 (5.24)
4.12 (4.59)
19.43 (19.71)
20.57 (20.35)
21.86 (22.10)
22.56 (22.13)
20.24 (20.42)
27.22 (27.75)
24.37 (24.11)
25.81 (25.98)
20.57 (20.92)
18.53 (18.83)
19.57 (19.95)
19.16 (19.52)
17.71 (18.09)
18.45 (18.61)
15.45 (15.52)
17.82 (17.65)
16.27 (15.84)
17.06 (17.32)
16.36 (16.73)
92
87
71
65
62
69
65
60
72
79
82
57
62
58
30
87
77
81
67
220
150
249
196
18
19
240
20a
20b
20c
21a
21b
21c
22a
22b
22c
23
> 280
220
215
> 280
220
150
C13H13N5OS
C13H13N5S
C13H12N4OS
C14H14N4O2S
C14H14N4OS
C18H15N5S2
C19H17N5OS2
C19H17N5S2
C16H18N4S3
C15H14N4O2S
C16H16N4O3S
C16H16N4O2S
C16H14N4O3S
250
200
190
185
280
248
210
230
395.5
379.5
362.54
314.36
344.39
328.39
342.37
24a
24b
24c
25

New Pyrimidine Derivatives
4361
1
grating. The H NMR spectra were run on a Varian spectrophotometer
at 200 MHz. using TMS as an internal reference and DMSO-d6 as sol-
vent. The mass spectra (EI) were recorded at 70 eV with Kratos MS
equipment and=or a Varian MAT 311 A spectrometer. Elemental ana-
lyses (C, H, and N) were carried out at the microanalytical center of
Cairo University Giza, Egypt. The results were found to be in good
agreement (ꢂ0.3%) with the calculated values. Compounds (2),[4] (3),[5]
(11),[4] and (12),[4] were prepared according to literature procedures.
The barbituric and dimethylbarbituric acids were purchased by Fluoka
Company.
General Procedure for Synthesis of 6-Aryl-4-chloro-2-thioxo-1,2,5,6-
tetrahydro-pyrimidine-5-carbonitrile (4a–c)
Compounds 2a (1.16 g, 5 mmol), 2b (1.30 g, 5 mmol), or 2c (1.37 g,
5 mmol) were added to phosphorus oxychloride 30 cm3 and refluxed on
a water bath at 95 ꢁC for 4 h. The mixture was poured onto ice-cold
water. The precipitate formed and was filtered off, dried, and crystallized
from ethanol to afford 4a–c, respectively (cf. Tables 1 and 2).
Synthesis of 4-Chloro-6-phenyl-2-thioxo-2,5-dihydropyrimidine-5-
carbonitrile (5)
Method A
Compound 3 (1.15 g, 5 mmol) was added to phosphorus oxychloride
30 cm3 and refluxed on a water bath at 95 ꢁC for 5 h. The reaction mixture
was left to cool and then poured onto ice-cold water. The precipitate
formed and was filtered off, dried, and crystallized from a mixture of
ethanol=chloroform.
Method B
A mixture of compound 4a (1.24 g, 5 mmol), potassium hydroxide (0.28 g,
5 mmol), and 25 cm3 dimethylformamide was refluxed for 2 h. The
reaction mixture was left to cool and then poured onto ice-cold water.
The precipitate formed and was filtered off, dried, and crystallized
from a mixture of ethanol=chloroform to give compound 5. (cf. Tables
1 and 2).

Table 2. Spectral data of newly prepared compounds
Compound
Spectral data
4a
4b
4c
5
IR, n=cmꢀ1: 3152 (NH), 2221 (C ꢃ N), 1625 (C ¼ N), 1150 (C–Cl) MS, m=z (%): 249 (21) (Mþ)
IR, n=cmꢀ1: 3160 (NH), 2222 (C ꢃ N), 1620 (C ¼ N), 1153 (C–Cl)
IR, n=cmꢀ1: 3149 (NH), 2220 (C ꢃ N), 1630 (C ¼ N), 1152 (C–Cl)
IR, n=cmꢀ1: 3420 (NH), 2205 (C ꢃ N), 1621 (C ¼ N), 1178 (C–Cl) MS, m=z (%): 247 (100) (Mþ)
1
6a
IR, n=cmꢀ1: 3207 (NH), 2223 (C ꢃ N), 1735 (COOEt), 1662 (CON) H NMR (CDCl3), d: 1.23 (t, 3H,
CH3), 4.04 (s, 2H, SCH2), 4.22 (q, 2H, OCH2), 7.26–8.07 (m, 5H, Ar–H)
IR, n=cmꢀ1: 3200 (NH), 2225 (C ꢃ N), 1738 (COOEt), 1660 (CON) MS, m=z (%): 245 (28) (Mþ)
IR, n=cmꢀ1: 3209 (NH), 2224 (C ꢃ N), 1740 (COOEt), 1665 (CON)
IR, n=cmꢀ1: 3425 (NH), 2230 (C ꢃ N), 1724, 1683 (2CON) MS, m=z (%): 213 (44) (Mþ)
IR, n=cmꢀ1: 3183 (NH), 1238 (C ¼ S) MS, m=z (%): 306 (100 ) (Mþ)
IR, n=cmꢀ1: 3180 (NH), 1245 (C ¼ S)
6b
6c
8
13a
13b
13c
14
IR, n=cmꢀ1: 3185 (NH), 1240 (C ¼ S)
IR, n=cmꢀ1: 3363 (NH), 1617 (C ¼ N) MS, m=z (%): 304 (30 ) (Mþ)
IR, n=cmꢀ1: 3149 (NH), 1714 (C ¼ O), 1614 (C ¼ N), 1241 (C ¼ S) MS, m=z (%): 258 (47) (Mþ)
IR, n=cmꢀ1 : 3150 (NH), 1712 (C ¼ O), 1610 (C ¼ N), 1240 (C ¼ S) MS, m=z (%): 288 (27) (Mþ)
15a
15b
15c
1
IR, n=cmꢀ1 : 3156 (NH), 1716 (C ¼ O), 1618 (C ¼ N), 1248 (C ¼ S) H NMR (DMSO-d6), d: 2.32
(s, 3H, CH3), 5.15 (s, 1H, NCH), 7.15–7.35 (m, 4H, Ar-H), 7.11 (s, 1H, NCHN), 10.17, 10.46, 11.7 (s, 3H, 3NH)
16
IR, n=cmꢀ1 : 3164 (NH), 1712 (C ¼ O), 1617 (C ¼ N), 1241 (C ¼ S) MS, m=z (%): 256 (100) (Mþ)

18
19
IR, n=cmꢀ1 : 3340 (NH), 3325 (NH2), 1662 (CONH2), 1238 (C ¼ S) MS, m=z (%): 248 (18) (Mþ)
IR, n=cmꢀ1 : 3200 (NH), 1614 (C ¼ N), 1050 (C–Cl) MS, m=z (%): 276 (42) (Mþ)
IR, n=cmꢀ1 : 3316 (NH2), 3259 (NH), 1626 (C ¼ N), 1240 (C ¼ S) MS, m=z (%): 257 (86) (Mþ)
IR, n=cmꢀ1 : 3318 (NH2), 3263 (NH), 1630 (C ¼ N), 1242 (C ¼ S) MS, m=z (%): 287 (11) (Mþ)
IR, n=cmꢀ1 : 3320 (NH2), 3298 (NH), 1629 (C ¼ N), 1240 (C ¼ S)
20a
20b
20c
21a
21b
IR, n=cmꢀ1 : 3196 (NH), 1726 (C ¼ O), 1599 (C ¼ N), 1229 (C ¼ S) MS, m=z (%): 287 (11) (Mþ)
1
IR, n=cmꢀ1 : 3200 (NH), 1730 (C ¼ O), 1601 (C ¼ N), 1230 (C ¼ S) H NMR (DMSO-d6), d: 2.51 (s, 3H, CH3), 3.76
(s, 3H, OCH3), 5.16 (s, 1H, NCH), 6.98–7.39 (m, 4H, Ar–H), 10.14, 10.46, 11.74 (s, 3H, 3NH) MS, m=z (%): 302
(27) (Mþ)
21c
22a
22b
22c
23
IR, n=cmꢀ1 : 3195 (NH), 1725 (C ¼ O), 1603 (C ¼ N), 1227 (C ¼ S)
IR, n=cmꢀ1 : 3206 (NH2), 3034 (NH), 1624 (C ¼ N), 1241 (C ¼ S) MS, m=z (%): 366 (32) (Mþ ꢀ 1)
IR, n=cmꢀ1 : 3200 (NH2), 3025 (NH), 1620 (C ¼ N), 1240 (C ¼ S)
IR, n=cmꢀ1 : 3205 (NH2), 3035 (NH), 1628 (C ¼ N), 1242 (C ¼ S)
1
IR, n=cmꢀ1 : 2224 (C ꢃ N), 1579 (C ¼ N), 1230 (C ¼ S) H NMR (DMSO-d6), d: 2.38 (s, 6H, 2SCH3), 2.69 (s, 6H,
2NCH3), 4.76 (s, 1H, NCH), 7.29–7.6 (m, 5H, Ar–H) MS, m=z (%): 362 (100) (Mþ)
1
24a
IR, n=cmꢀ1 : 3454 (NH2), 3336 (NH), 2187 (C ꢃ N), 1740 (COOEt), 1659 (C ¼ N) H NMR (DMSO-d6), d: 1.39 (t, 3H,
CH3), 4.01 (s, 2H, SCH2), 4.35 (q, 2H, OCH2), 7.16–7.41 (m, 5H, Ar–H), 10.19 (s, 2H, NH2)
IR, n=cmꢀ1 : 3328 (NH2), 3461 (NH), 2190 (C ꢃ N), 1742 (COOEt), 1655 (C ¼ N)
IR, n=cmꢀ1 : 3330 (NH2), 3458 (NH), 2184 (C ꢃ N), 1746 (COOEt), 1654 (C ¼ N)
IR, n=cmꢀ1 : 3086 (NH), 1712 (C ¼ O), 1735 (COOEt), 1616 (C ¼ N) MS, m=z (%): 342 (45) (Mþ)
24b
24c
25

4364
A. A. Fadda et al.
General Procedure for Synthesis of (6-Aryl-5-cyano-4-oxo-1,4-dihydro-
pyrimidin-2-ylsulfanyl)-acetic Acid Ethyl Ester (6a–c)
An equimolar amount of 2a (1.16 g, 5 mmol), 2b (1.30 g, 5 mmol), or 2c
(1.37 g, 5 mmol) and 3 (1.15 g, 5 mmol), potassium hydroxide (0.28 g,
5 mmol), ethyl chloroacetate (0.53 ml, 5 mmol), and 25 cm3 absolute etha-
nol was refluxed for 3 h. The reaction mixture was left to cool and then
poured onto ice-cold water. The precipitate formed and was filtered
off, dried, and crystallized from ethanol to give 6a–c, respectively (cf.
Tables 1 and 2).
Synthesis of 2,4-Dioxo-6-phenyl-1,2,3,4-tetrahydro-pyrimidine-5-
carbonitrile (8)
Method A
A mixture of 2a (1.16 g, 5 mmol), potassium hydroxide (0.28 g, 5 mmol),
chloroacetic acid (0.3 ml, 5 mmol), and 25 cm3 absolute ethanol was
refluxed for 3 h. The reaction mixture was left to cool and then poured
onto ice-cold water. The precipitate formed and was filtered off, dried,
and crystallized from ethanol.
Method B
To a solution of sodium ethoxide [sodium metal 0.11 g in absolute etha-
nol 20 cm3], 1a (1.01 gm, 5 mmol) and urea (0.3 g, 5 mmol) were added.
The mixture was stirred at room temperature for 24 h. Then the mixture
was poured onto ice-cold water and neutralized by adding dilute HCl.
The precipitate formed and was filtered off, dried, and crystallized from
ethanol to give compound 8 (cf. Tables 1 and 2).
General Procedure for Synthesis of 5-Aryl-5,8-dihydro-1H,6H-
pyrimido[4,5-d]pyrimidine-2,4,7-trithione (13a–c)
A mixture of compound 11a (1.15 g, 5 mmol), 11b (1.30 g, 5 mmol),
and=or 11c (1.2 g, 5 mmol), carbon disulfide (0.42 ml, 7 mmol), and
dimethylformamide 25 cm3 was refluxed for 3 h. The reaction mixture
was left to cool and then poured onto ice-cold water. The precipitate
formed and was filtered off, dried, and crystallized from ethanol to afford
13a–c, respectively (cf. Tables 1 and 2).

New Pyrimidine Derivatives
4365
Synthesis of 5-Phenyl-1H,8H-pyrimido[4,5-d]pyrimidine-2,4,7-trithione (14)
Method A
A mixture of compound 13a (1.53 g, 5 mmol) and a catalytic amount of
piperidine (3 drops) in ethanol 30 cm3 was refluxed for 3 h. The reaction
mixture was left to cool, then poured onto ice water; the solid product
that had formed was collected by filtration and crystallized from ethanol.
Method B
A mixture of compound 12 (1.14 g, 5 mmol), carbon disulfide (0.42 ml,
7 mmol), and dimethylformamide 25 cm3 was refluxed for 3 h. The
reaction mixture was left to cool and then poured onto ice-cold water.
The precipitate formed and was filtered off, dried, and crystallized from
ethanol to give compound 14 (cf. Tables 1 and 2).
General Procedure for Synthesis of 5-Aryl-7-thioxo-5,6,7,8-tetrahydro-3H-
pyrimido[4,5-d]pyrimidin-4-one (15a–c)
Compound 11a (1.15 g, 5 mmol), 11b (1.30 g, 5 mmol), or 11c (1.20 g,
5 mmol) and 18 (1.24 g, 5 mmol) were added to formic acid (85%, 5 mmol),
and the mixture was refluxed for 2 h. The reaction mixture was left to cool,
and then the formed precipitate was filtered off and washed with cold
ethanol 10 cm3 to afford 15a–c, respectively (cf. Tables 1 and 2).
Synthesis of 5-Phenyl-7-thioxo-7,8-dihydro-3H-pyrimido[4,5-d] pyrimidin-
4-one (16)
Method A
A mixture of compound 15a (1.29 g, 5 mmol) and a catalytic amount of
piperidine (3 drops) in ethanol 30 cm3 was refluxed for 3 h. The reaction
mixture was left to cool and then poured onto ice water. The solid product
that had formed was collected by filtration and crystallized from ethanol.
Method B
Compound 12 (1.14 g, 5 mmol) was added to formic acid (85%), and the
mixture was refluxed for 3 h. The reaction mixture was left to cool, and

4366
A. A. Fadda et al.
then the precipitate was formed, filtered, and washed with cold ethanol to
give compound 16 (cf. Tables 1 and 2).
Synthesis of 6-Amino-4-phenyl-2-thioxo-1,2,3,4-tetrahydro-pyrimidine-5-
carboxylic Acid Amide (18)
A mixture of 17 (0.86 g, 5 mmol), sodium ethoxide (sodium metal 0.11 gm
in absolute ethanol 20 cm3), and thiourea (0.38 g, 5 mmol) was added.
The mixture was stirred at room temperature for 24 h. The mixture was
poured onto ice-cold water and neutralized by adding dilute HCl. The
precipitate formed and was filtered off, dried, and crystallized from
ethanol to give compound 18 (cf. Tables 1 and 2).
Synthesis of 5-Chloro-4-phenyl-3,4-dihydro-1H-pyrimido[4,5-d]
pyrimidine-2-thione (19)
Compound 15a (1.29 g, 5 mmol) was added to phosphorus oxychloride
30 cm3 and refluxed on a water bath at 95 ꢁC for 4 h. The mixture was
poured onto ice-cold water. The precipitate formed and was filtered
off, dried, and crystallized from ethanol to give compound 19 (cf. Tables
1 and 2).
General Procedure for Synthesis of 5-Amino-4-aryl-3,4-dihydro-1H-
pyrimido[4,5-d]pyrimidine-2-thione (20a–c)
A solution of 11a (1.15 g, 5 mmol), 11b (1.30 g, 5 mmol), or 11c (1.20 g,
5 mmol) in 20 cm3 of formamide was heated under reflux for 2 h, at which
time the color darkened after cooling at room temperature. The mixture
was poured onto ice-cold water. The precipitate formed and was filtered
off, dried, and crystallized from ethanol to give 20a–c, respectively (cf.
Tables 1 and 2).
General Procedure for Synthesis of 5-Aryl-2-methyl-7-thioxo-5,6,7,8-
tetrahydro-3H-pyrimido[4,5-d]pyrimidin-4-one (21a–c)
Compound 11a (1.15 g, 5 mmol), 11b (1.30 g, 5 mmol), or 11c (1.20 g,
5 mmol) was added to 20 cm3 of acetic anhydride. The reaction mixture
was heated under reflux for 3 h after cooling to room temperature.
The mixture was poured onto ice-cold water and let stand for 24 h. The

New Pyrimidine Derivatives
4367
precipitate formed and was filtered off, dried, and crystallized from
ethanol to afford 21a–c, respectively (cf. Tables 1 and 2).
General Procedure for Synthesis of 5-Amino-4-aryl-3,4-dihydro-6-
phenylpyrimido[4,5-d]pyrimidine-2,7(1H,6H)-dithione (22a–c)
A mixture of 11a (1.15 g, 5 mmol), 11b (1.30 g, 5 mmol), or 11c (1.20 g,
5 mmol) and phenylisothiocyanate (0.60 ml, 5 mmol) in pyridine 20 cm3
was refluxed for 6 h. The reaction mixture was cooled, poured onto
ice=water, and neutralized with diluted HCl. The solid product that
formed was collected by filtration and crystallized from ethanol to afford
22a–c, respectively (cf. Tables 1 and 2).
Synthesis of (Dimethyl-5-cyano-6-phenyl-2-thioxo-1,2,3,6-
tetrahydropyrimidin-4-yldithioimidocarbonate)-pyrimidine (23)
A mixture of compound 11a (1.15 g, 5 mmol), potassium hydroxide
(0.56 g, 10 mmol), carbon disulfide (0.42 g, 7 mmol), and dimethylforma-
mide 25 cm3 was stirred for 24 h. Then methyl iodide was added (0.62 g,
10 mmol), and the mixture was stirred for another 24 h. The reaction mix-
ture was poured onto ice=water and neutralized with diluted HCl. The
precipitate formed and was filtered off and crystallized from a mixture
of ethanol=chloroform to give compound 23 (cf. Tables 1 and 2).
General Procedure for Synthesis of (4-Amino-6-aryl-5-cyano-pyrimidin-2-
ylsulfanyl)-acetic Acid Ethyl Ester (24a–c)
A mixture of compound 11a (1.15 g, 5 mmol), 11b (1.30 g, 5 mmol), 11c
(1.20 g, 5 mmol), or 12 (1.14 g, 5 mmol), potassium hydroxide (0.82 g,
5 mmol), ethyl chloroacetate (0.53 ml, 5 mol), and 25 cm3 absolute ethanol
was refluxed for 3 h. The reaction mixture was left to cool and then poured
onto ice-cold water. The precipitate solid was filtered off and crystallized
from ethanol to afford 24a–c, respectively (cf. Tables 1 and 2).
Synthesis of (5-Oxo-4-phenyl-5,6-dihydro-pyrimido[4,5-d]pyrimidin-2-
ylsulfanyl)-acetic Acid Ethyl Ester (25)
Compound 24a (1.57 g, 5 mmol) was added to formic acid (85%, 5 mmol),
and the mixture was refluxed for 3 h. The reaction mixture was left to

4368
A. A. Fadda et al.
cool and then poured onto ice-cold water. The precipitate formed and
was filtered off, dried, and crystallized from ethanol to give compound
25 (cf. Tables 1 and 2).
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