Synthesis and antimicrobial activity of thioxopyrimidines and related derivatives

Article abstract of DOI:10.1080/10426500500272087

The interaction of thiourea with activated cyanoolefins under different reaction conditions were studied, in which a variety of thiopyrimidines (8, 9, 12, 18, 20, & 21) and related derivatives (10, 11, 14, 16, & 17) were obtained respectively. Also, the r

Full text of DOI:10.1080/10426500500272087

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Synthesis and Antimicrobial
Activity of Thioxopyrimidines
and Related Derivatives
Ahmed M. El-Agrody a , Fawzy M. Ali a , Fathy A. Eid
a , Mohammed A. A. El-Nassag a , Gamal El-Sherbeny
b & Ahmed H. Bedair a
a Department of Chemistry , Al-Azhar University ,
Nasr City, Cairo, Egypt
b Department of Botany and Microbiology , Al-Azhar
University , Nasr City, Cairo, Egypt
Published online: 15 Aug 2006.
To cite this article: Ahmed M. El-Agrody , Fawzy M. Ali , Fathy A. Eid , Mohammed
A. A. El-Nassag , Gamal El-Sherbeny & Ahmed H. Bedair (2006) Synthesis
and Antimicrobial Activity of Thioxopyrimidines and Related Derivatives,
Phosphorus, Sulfur, and Silicon and the Related Elements, 181:4, 839-864, DOI:
10.1080/10426500500272087
To link to this article: http://dx.doi.org/10.1080/10426500500272087
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Phosphorus, Sulfur, and Silicon, 181:839–864, 2006
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500500272087
Synthesis and Antimicrobial Activity
of Thioxopyrimidines and Related Derivatives
Ahmed M. El-Agrody
Fawzy M. Ali
Fathy A. Eid
Mohammed A. A. El-Nassag
Department of Chemistry, Al-Azhar University, Nasr City, Cairo, Egypt
Gamal El-Sherbeny
Department of Botany and Microbiology, Al-Azhar University, Nasr City,
Cairo, Egypt
Ahmed H. Bedair
Department of Chemistry, Al-Azhar University, Nasr City, Cairo, Egypt
The interaction of thiourea with activated cyanoolefins under different reaction
conditions were studied, in which a variety of thiopyrimidines (8, 9, 12, 18, 20, &
21) and related derivatives (10, 11, 14, 16, & 17) were obtained respectively. Also,
the reactions of thiopyrimidines (8, 9) with different electrophilic and nucleophilic
1
13
reagents were reported. IR, H NMR, C NMR and mass spectra for the newly syn-
thesized compounds were studied. Most of the obtained compounds were screened
against Gram-postive and Gram-negative bacteria and fungi, for which some of
these derivatives gave promising results.
Keywords Activated nitriles; antimicrobial activities; (1H-pyrazol-1-yl)pyrimidine;
[(pyrimidin-2-yl)disulfanyl] pyrimidine; thiourea; thioxopyrimidines
INTRODUCTION
The importance of the pyrimidine nucleus is well established in the field
of pharmaceutical chemistry and biochemistry.1−3 The pyrimidine-2-
thiol moiety is present in several compounds of biological and medicinal
interest.4−8
Received January 12, 2005; accepted April 7, 2005.
Address correspondence to Ahmed H. Bedair, Al-Azhar University, Department
of Chemistry, Faculty of Science, Nasr City, Cairo 11884, Egypt. E-mail:bedair AH@
yahoo.com
839

840
A. M. El-Agrody et al.
Pyrimidine-5-carboxamides of type (1) are reported to possess an-
ticarcinogenic activity.9 Antiinflammatory,10,11 analgesic, and blood
platelet aggregation inhibitory activity12 was found in a number
of derivatives. 1,4-Dihydropyrimidines (2) (Scheme 1) is useful as
a platelet-activating factor antagonist.13 Also, the 1,4-dihydropyri-
midines have many biological activities. For example, they represent
the largest and most studied class of organic calcium channel blockers
widely used in the management of angina pectoris and hypertension as
some 1,4-dihydropyrimidine (e.g., Nifedipine).14
SCHEME 1
RESULTS AND DISCUSSION
The readily available cyanoolefins are a class of important organic syn-
thones having exciting chemistry.15−17 The obvious route to pyrimidine-
5-carbonitriles is primary synthesis followed by the removal or modifi-
cation of unwanted groups, e.g., ethoxymethylenemalononitrile (3) and
thiourea give 4-amino-2-thioxo-1,2-dihydropyrimidine-5-carbonitrile
(4),18,19 (Scheme 2) which can be desulfurized, S-alkylated, N-acety-
lated, or hydrolyzed to 5-cyanocytosine without affecting the cyano
group.
SCHEME 2
So, we felt it would be valuable to investigate the addition of thiourea
to activated nitriles (5–7),20,21 (Scheme 3) which was previously inten-
sively investigated.22−33
Thus, the piperidine-catalyzed addition of 5 with thiourea in
boiling abs. ethanol gave two reaction products as 4-amino-1,2-
dihydro-2-thioxo-6-(aryl)pyrimidine-5-carbonitrile (8a,b) and 4-amino-

Thioxopyrimidines and Related Derivatives
841
SCHEME 3
2-mercapto-6-(4-methoxyphenyl)pyrimidine-5-carbonitrile (9), respec-
tively (Scheme 4).
SCHEME 4 Synthesis of 8a,b,9, 10a,b & 11 reagents and conditions: (i) piperi-
dine, boiled EtOH, 4 h, 35–57% yield; (ii) Anh. K2CO3, boiled EtOH, 4 h 12–14%
yield.
The structures of 8a,b and 9 have been fully characterized by IR, 1H
NMR, 13C NMR, mass and elementary analysis. In 1H NMR spectra of
8 showed the signals of NH2 at δ (ppm) = 7.909–8.361 (brs), NH as a
singlet signal at δ (ppm) = 12.983–13.091, and 13C NMR for 8a showed
1
δc(ppm) = CS at 180.464, while for compound 9, H NMR showed a

842
A. M. El-Agrody et al.
singlet signal at δ (ppm) = 3.572 (SH) and NH2 protons at δ (ppm) =
7.987 (brs).
Treatment of 5a with thiourea in the presence of boiled alco-
holic K2CO3 solution gave a compound as 3,4,7,8-tetrahydro-4,7-bi
(4-methoxyphenyl)pyrimido[4,5-d]pyrimidine-2,5(1H,6H)-dione (10a)
(Scheme 4), while the treatment of 5b with (NH2)2CS/K2CO3 under sim-
ilar reaction conditions gave two reaction products as 3,4,7,8-tetrahy-
dro-4,7-di(p-tolyl)-pyrimido[4,5-d]pyrimidine-2,5(1H,6H)-dione (10b)
(Scheme 4) and 4-amino-6-(p-tolyl)-2-[2-(4-amino-5-cyano-6-(p-tolyl)py-
rimidine-2-yl)disulfanyl]pyrimidine-5-carbonitrile (11) (Scheme 4).
The establishment of structures 10 and 11 were based on its spectral
analysis. The IR for compound 10 showed N-H at 3465–3268 and CONH
at 1636–1634; 1H NMR (δ ppm). For 10a, 3.726 & 3.755 (2s, 6H, 2CH3O-
Ar), 4.627 (br, s, 2H, H-4 & H-7) and singlet signals at 7.58, 7.963,
9.032, 9.847, 10.112, 10.964 (NH and enolic OH), the mass spectum
gave molecular ion peak at m/z (%): 380 (M+, 10.8) and a base peak
at m/z 121 (100) with other peaks at 259 (14.9), 202 (18.9), 178 (19.8),
1
77 (14.8). For 10b, the H NMR showed absorption signals at 2.233,
2.321 (2s, 6H, 2CH3-Ar), 6.07 (t, 2H, H-4 & H-7, J = 5.1 Hz); and six
absorption peaks at 7.327, 7.719, 7.972, 9.761, 10.043, 10.884 (NH &
enolic OH); the mass spectrum showed a molecular ion peak at m/z (%):
343 (M+, 30.5) and base peak at 105 (100) with other peaks at 288 (14.4),
243 (31.0), 186 (37.3), 262 (39.4). For compound 11, the IR showed NH2
at 3232.1 and 3144.7 and CN at 2218; 1H NMR showed δ (ppm) at 2.302
(s, 6H, 2CH3-Ar) and 6.965 (br, s, 2H, NH2), and the mass spectrum gave
a molecular ion peak at m/z (%): 482 (25.7) and base peak at 241 (100)
corresponding to M+/2 with other peaks at 209 (26.8), 183 (25.6), 141
(7.1), 91 (22.1).
The spectrometric fragmentation of 11 supported the proposed struc-
ture (Scheme 5).
SCHEME 5 Spectrometric fragmentation pattern of compound 11.

Thioxopyrimidines and Related Derivatives
843
The base-catalyzed condensation of 5a with thiourea in the pres-
ence of a methoxide ion under different reaction conditions have
also been investigated, where 4-oxo-6-(4-methoxyphenyl)-2-thioxohexa-
hydropyrimidine-5-carbonitr-ile (12a)34 and 2-amino-6-methoxy-4-
(4-methoxyphenyl)pyridine-3,5-dicarbonitrile (15a) were obtained
(Scheme 6).
SCHEME 6 Synthesis of compounds 12–15 reagents and conditions.
(iii) CH3ONa, boiled MeOH, 4 h, 48–50% and 28–30% yield; (iv) excess CH3ONa,
boiled MeOH, 4 h 31% yield.
Similar to the behavior of 5a, olefinic nitrile 5c reacted with
thiourea under the same reaction grounds in the presence of a methox-
ide ion and yielded 4-oxo-6-(4-chlorophenyl)-2-thioxohexahydro-
primidine-5-carbonitrile (12b) and 2-amino-4-(4-chlorophenyl)-6-
methoxypyridine-3,5-dicarbonitrile (15b) (Scheme 6).
The refluxing of activated cyanoolefin 5a with thiourea in the pres-
ence of an excess methoxide ion afforded 4-amino-5-cyano-2-methoxy-
6-(4-methoxyphenyl)pyrimidine (13).
The treatment of 13 with formic acid under reflux afforded the cor-
responding 2-methoxy-4-(4-methoxyphenyl)-6-oxo-1,6-dihydropyrimi-
dine-5-carbonitrile (14) (Scheme 6).

844
A. M. El-Agrody et al.
The structures of 12–15 were established on the basis of spectral
data. Thus, IR for 12 showed CO at 1748–1724; 1H NMR for 12a showed
δ (ppm) at 5.479 (d, 1H, 5-H, J = 11.6 Hz), (5.746–5.621) (m, 1H, 6-H),
10.952, 10.632 (2s, 1H, 1H) and 12.336 (2s, 1H, 3-H). Compound 12b
showed signals at 5.034 (d, 1H, 5-H, J = 11.719 Hz) and 5.247 (d, 1H, H-
6, J = 11.33 Hz) and four absorption signals at 10.198, 10.468, 11.796,
& 11.907 (NH & enolic OH proton). Also, the mass spectrum for 12a,b
showed a very intense molecular ion peak at m/z (%) 269 (M+, 100), &
265 ((M+, 100), respectively. The 13C NMR for 12a showed δc (ppm) at
160.329 (CO) and 178.522 (CS).
For compound 13, the IR showed the absence of υ C O, its 1H NMR
showed δ (ppm) at 3.834 (s, 3H, H3CO-pyrimidine) and 3.824 (s, 3H,
H3CO-Ar), and the mass spectrum showed a molecular ion peak at m/z
(%); 257 (M+, 100).
1
Also, for product 15a, the H NMR showed δ (ppm) at 3.828 (s, 3H,
H3CO-Ar) and 3.953 (s, 3H, H3CO-py); the 13C NMR showed signals at δc
(ppm) 55.454 (C-CH3O-Ar), 56.454 (C-CH3O-py), 166.71 (C-2), 170.078
(C-6) and the mass spectrum showed a very intense molecular ion peak
1
at m/z (%): 280 (M+, 100). For compound 15b, the H NMR showed δ
(ppm) at 3.985 (s, 3H, CH3-O) and mass spectrum at m/z (%): 284 (100).
The formation of products 8–15 could be explained by the proposed
mechanism (Schemes 4 and 6). The formation products 8–15 (Schemes 4
and 6) could be explained by initial Michael addition of thiourea to the
activated double bond (path a 1,4-addition) followed by the cyclization
to the intermediate [A], which hydrolyzed into the corresponding car-
boxamide (CN → CONH2) and then reacted with a molecule of free
aldehyde obtained from retro Michael addition35 to give the product
10. The previous intermediate may be oxidized into 8 and 9, and two
molecules of 9 joined together with the elimination of one molecule of
hydrogen to give the product 11.
Also, the intermediate [A] hydrolyzed into 12 or underwent the nu-
cleophilic substitution of SH− with MeO− followed by aromatization to
give 13.
An alternative path b (1,2–addition) of thiourea to the cyano group
was followed by the addition of a malononitrile molecule obtained from a
retro Michael addition35 to another molecule of cyano olefin, followed by
a ring closure with the elimination of NH3, HCN, and the substitution
¯
of SH by MeO− to give the product 15.36
The interaction of ethoxymethylenemalononitrile (3) with
(NH2)2CS in the presence of boiled alcoholic K2CO3 solution gave
4-amino-2-[2-(4-amino-5-cyanopyrimidine-2-yl)di-sulfanyl]pyrimidine-
5-carbonitrile (16) (Scheme 7) instead of 4-amino-2-thioxo-1,2-dihydro-
pyrimidine-5-carbonitrile (4) previously obtained.18,19

Thioxopyrimidines and Related Derivatives
845
SCHEME 7
1
The H NMR for 16 showed δ (ppm) at 8.252 (br, 4H, 2NH2 disap-
peared by D2O) and 8.499 (s, 2H, H-6 & 6ꢀ), and the mass spectrum
gave a molecular ion peak as an intense peak at m/z (%) 302 (92).
Olefinic 6a was allowed to react with thiourea in the presence
of methanolic methoxide at r.t., which gave rise to three different
reaction products, one assigned as 4-amino-1,2,5,6-tetrahydro-6-(4-
methoxyphenyl)-2-oxopyrimidine-5-carboxamide (17), 4-(4-methoxy-
benzylidine)amino-1,2,5,6-tetrahydro-6-(4-methoxyphenyl)-2-thioxo-
pyrimidine-5-carboxamide (18), and 3,5-dicyano-2,4-di(4-methoxy-
phenyl)-3,4,5,6-tetrahydro-6-oxopyridine-3-carboxamide (19).
The reaction seemed to proceed by the Michael addition of the
thiourea anion to the activated double bond of 6a followed by the cy-
clization of the adduct to give the nonisolated intermediate (B), which
on hydrolysis gave 17 or when added to second mol of 6a under the
reaction conditions formed a acyclic adduct, which underwent a retro
Michael addition to furnish the product 18. The formation of 19 as
a byproduct resulted from the dimerization of 6a under the previous
reaction conditions; a similar finding has been reported previously37
(Schemes 8 and 9).
Refluxing a mixture of 6a and thiourea in methanol-methoxide
afforded
4-amino-1,2,5,6-tetrahydro-6-(4-methoxyphenyl)-2-thioxo-
pyrimidine-5-carboxylic acid (20) as a solo product (Scheme 8).
The structures of 17–20 are substantiated by IR, 1H NMR, and mass
spectra studies. For 18, 1H NMR showed δ (ppm) at 3.738, 3.767 (2s, 6H,
2OCH3), 5.205 (s, 1H, 5-H), 5.551 (s, 1H, 6-H), 6.135 (s, 1H, CH-Ar),
9.553 (s, br, 3H, NH + NH2). Ms for 17 and 18 gave a molecular ion
peak at m/z (%): 262 (M+, 88.9), 396 (M+, 31.5), respectively. Also, the
1H NMR for 19 showed absorption signals at δ (ppm) = 3.695, 3.775 (2s,
6H, 2CH3O-Ar), 4.818, 4.12 (2d, J = 2.734 Hz, 6-H + 5-H), and (8.35–
8.616) (s, br, 2H, CONH2). Its mass spectrum showed a molecular ion
peak at m/z: 402 (M+, 14.7) and a base peak 121 (100) with other peaks
360 (29.3), 294 (13.2), 242 (27.8), 201 (14.1), 162 (26.7), 134 (53.4), 77
(38.8). For 20, IR (υ C O at 1686) with a shoulder at 1704; 1H NMR δ
(ppm) = 4.296 (d, 1H, H-5, J = 12.89 Hz), 4.861 (d, 1H, H-6, J = 12.89
Hz), 5.217 (s, 1H, NH), 7.545 (s, 2H, NH2), 8.797 (s, 1H, CO2H), and mass

846
A. M. El-Agrody et al.
SCHEME 8 Synthesis of compounds 17, 18, and 20 and reagent and condi-
tions, (i) Methanolic CH3O−, r.t. 48h (45 & 20) % yield for 17 and 18; (ii) CH3OH/
CH3O−, refluxed methanol, 4h, 40% yield for compound 20.
spectrum affords an additional support, which showed a molecular ion
peak at (%) 279 (M+, 1.35).
When 7a was stirred with a methanolic methoxide solution
containing thiourea at r.t., it gave 4-oxo-6-(4-methoxyphenyl)-2-
thioxohexahydropyrimidine-5-carbonitrile (12a) previously obtained
from 5a and thiourea (identical IR, 1H NMR, 13C NMR, m.p., and mixed
SCHEME 9 The dimarization of 6a reagent and conditions (i) CH3OH/CH3O−,
r.t., 48 h, 15% yield.

Thioxopyrimidines and Related Derivatives
847
m.p.), while refluxing 7a with thiourea in a methanolic solution con-
taining sodium methoxide gave 4-oxo-2-thioxo-6-(4-methoxyphenyl)-
1,2,3,4-tetrahydropyrimidine-5-carbonitrile (21) besides 12a.
It is assumed that the reaction involved the addition of an anionic
form of thiourea to 7a and a subsequent intramolecular attack at the
carbonyl group of the ester to form the cyclized product 12a, which
underwent oxidation into 21 under the influence of olefinic nitrile upon
reflux (Scheme 10).
SCHEME 10 (i) NaOMe/MeOH, r.t., 48 h, 50% yield; (ii) NaOMe/MeOH, boiled
MeOH, 4 h, 77% yield.
The structure of 21 is inferred from IR (υ C O:1676.7); the 1H NMR
showed a signal at 13.099 (s, 1H, enolic OH), and its mass spectra
added further support, which showed a molecular ion peak m/z (%):
259 (M+, 100).
Compound 15a reacted with (EtO)3CH/Ac2O and gave 2-(E)-etho-
xymethyleneamino-6-methoxy-4-(4-methoxyphenyl)pyridine-3,5-dica-
rbonitrile (22). The IR spectrum showed the disappearance of NH2
1
bands and the appearance of CH N at 3002.8; the H NMR showed δ
at 8.772 (s, 1H, N CH), and its mass spectrum gave a molecular ion
peak at m/z (%): 336 (M+, 100).
When compound 22 was treated with hydrazine hydrate in well-
stirred ethanol at r.t., it lead to the formation of a product, which was
found to be identical in all respects (m.p., mixed m.p., and spectral data)
with 15a (Scheme 11).
The formation of 15a from 22 was assumed to proceed via the addi-
tion of hydrazine as a nucleophile at a N CH site to give the nonisolated
intermediate (C) followed by the elimination of ethyl formatehydrazone
(Scheme 11).
The treatment of 15a with formaline solution in boiling
methanol gave 2-(N-hydroxymethyl)amino-6-methoxy-4-(4-methoxy-
phenyl)pyridine-3,5-dicarbonitrile (23), while the treatment of 15a
with formaline solution in boiling methanol containing an equimo-
lar ratio of ethanolamine gave
a product, which was ana-
lyzed as 2-(N-hydroxymethyl,N-(β-hydroxyethyl))-amino-6-amino-4-(4-
methoxyphenyl)-pyridine-3,5-dicarbonitrile (24) (Scheme 11).

848
A. M. El-Agrody et al.
SCHEME 11
The formation of 24 was assumed by the nucleophilic substitu-
tion of a methoxy group by the β-ethylamino group followed by N-
hydroxymethylation by formaldehyde (Scheme 11).
IR spectrum of 23 showed a broad strong absorption band at 3350
1
(OH, NH), and H NMR δ (ppm) at 3.953 (s, 1H, OH), 4.877 (d, J =
6.4 Hz, CH2), 8.795 (s, br, 1H, NH); its mass spectrum gave a molecular
ion peak at m/z (%) 310 (M+, 12.1).
Also for compound 24, IR [υNH2 as a triplet at 3426, 3334, 3234],1H
NMR [δ (ppm) at 1.113 (t, J = 7Hz, 2H, HOCH2CH2N), 3.543 (q, J =
7Hz, 2H, NCH2CH2OH), 3.928 (s, 1H, OH), 4.006 (s, 1H, OH), 4.919 (d.
J = 6Hz, NCH2OH), 8.772 (s, br, 2H, NH2)], its mass spectrum gave
a molecular ion peak at m/z (%): 339 (M+; 18) and a base peak at 309
(100) with other peaks 393 (80), 280 (72), 59 (42).
The treatment of 9 with boiling formic acid afforded the 4-oxo-2-
thioxo-6-(4-methoxyphenyl)-1,2,3,4-tetrahydroprimidine-5-carbonitrile
(21), (identical IR, 1H NMR, mass, m.p., and mixed m.p.)
Also, the treatment of 9 with CH(OEt)3/Ac2O under reflux
gave the corresponding N-(5-cyano-2-thioxo-6-(4-methoxyphenyl)-1,2-
dihydropyrimidin-4-yl)formamide (25) (Scheme 12). IR spectrum for 25
showed [υ CO at 1726.7 1H NMR gave δ at 9.255 (d, J = 4.688 Hz, 1H,
HN-CHO), 11.565 (br, s, 2H, NH), and mass spectrum gave a molecular
ion peak at m/z (%): 286 (12.8) together with a base peak at 241 (100).
Also, the condensation of 9 with ethyl chloroacetate and/or phenacyl
bromide afforded the corresponding ethyl 2-(4-amino-5-cyano-6-(4-
methoxyphenyl)pyrimidin-2-yl)thioacetate (26) and 4-amino-2-(2-be-
nzoylmethylthio)-6-(4-methoxyphenyl)pyrimidine-5-carbonitrile (27),
respectively (Scheme 12).

Thioxopyrimidines and Related Derivatives
849
SCHEME 12
Spectral data for compounds 26 and 27 support the proposed struc-
ture, thus IR [υCO at 1742.7, 1690], 1H NMR [δ (ppm) at 3.629 (s,
2H, CH2S), 4.781 (s, 2H,CH2S)], and its mass spectrum [m/z (%): 344
(M+, 6.2), 271 (100), 225 (27.4) and 376 (M+, 10.3), 343 (10.9), 271 (27.4),
105 (100), 77 (36.7)] respectively.
The condensation of 9 and 8b with hydrazine hydrate gave prod-
ucts that were identified as 4-amino-6-aryl-2-hydrazinylpyrimidine-
5-carbonitril (28a,b), respectively. Also, the condensation of 28a,b
with an equimolar ratio of aromatic aldehydes in refluxing n-butanol
afforded the corresponding 4-amino-2-((Z)-2-arylidenehydrazinyl)-6-
arylpyrimidine-5-carbonitrile 29a–e (Scheme 12).
The condensation of 2-hydrazinylpyrimidine derivative (28a) with
1,3-dicarbonyl compounds, namely acetylacetone and ethyl acetoac-
etate in boiling ethanol containing a few drops of piperidine, gave 4-
amino-6-(4-methoxyphenyl)-2-[(3,5-dimethyl)-1H-pyrazol-1-yl]pyrimi-
dine-5-carbonitrile (30) and 4-amino-2-(2-ethoxycarbonylisopropy-
lidenehydrazinyl)-6-(4-methoxyphenyl)pyrimidine-5-carbonitrile (31),
respectively (Scheme 13).
1
The H NMR for 30 showed at δ (ppm) = 2.174 (s, 3H, CH3), 2.603
(s, 3H, CH3), and 6.137 (s, 1H, 4-H, pyrazole). Its mass spectrum gave
a molecular ion peak as a base peak at m/z (%): 320 (M+, 100). Also for

850
A. M. El-Agrody et al.
SCHEME 13
1
compound 31, the IR showed υCO at 1732, H NMR: δ (ppm) = 1.978
(s, 3H, CH3C ), 3.297 (s, 2H, CH2C O), 7.4 (s, br, 2H, NH2 cancelled
by D2O) 9.907 (s, 1H, NH cancelled by D2O). Its mass spectrum gave
m/z (%) at 368 (M+, 5.08) and a base peak at 281 (100).
The condensation of 8 with piperidine afforded 1,6-dihydro-4-(4-
methoxyphenyl)-6-oxo-2-(piperidin-1-yl)pyrimidine-5-carbonitrile (32)
(Scheme 12). The 1H NMR for 32 showed absorption signals in the form
of a complex pattern at δ (ppm) = (1.506–1.591) (10 H, piperidine–H), its
mass spectrum showed a molecular ion peak at m/z (%): 310 (M+, 18.7).
together with a base peak at 280 (M+-CH2O).
IR, 1H NMR, 13C NMR, and mass spectra for the newly synthesized
pyrimidine derivatives were studied (Table I).
ANTIMICROBIAL ACTIVITIES
Some selected compounds were screened for their antimicrobial ac-
tivity using Bacillus subtilis (ATCC 7972) (BS), Staphylococcus au-
rous (NCTC 7447) (SA) (Gram-positive), Escherichia coli (NCTC
10416) (EC), Pseudomonas aeuroginosa (ATCC 10415) (PA), Can-
dida albican (IMRU 3669) (CA) (Gram-negative), and Aspergillus
niger (ATCC 6275) (AN) (fungi) microorganisms. The activities of
these compounds were tested using disc diffusion method.38,39 The
tested compound were dissolved in N,N-dimethylformamide (DMF)
to get a solution of mg mL−1. The inhibition zones were measured
in millimeters at the end of incubation period of 48 h at 28◦C. N,N-
dimethylformamide showed no inhibition zones. The area of the zone
of inhibition was measured using neomycin (30 mg) as a standard
antibiotic.
Compound 26 showed the highest antibacterial activity (+++,
the inhibition zone was between 12–15 mm), against BS, SA, EC,

Thioxopyrimidines and Related Derivatives
851
TABLE I Spectral Data for the Newly Prepared Compounds
Compound
IR (ν
cm−1
)
1HNMR/13CNMR (δ ppm)/MS (m/z %)
max
8a
3405.8, 3345, 3233.6,
3163.9 (NH2, NH),
2213.3 (CN), 1639.2
(C N), 1392 (C S)
2.386 (s, 3H, CH3-Ar), 7.351, 7.570 (2d,
J = 8.203 Hz, 4H, Ar-H), 7.909, 8.361
(2brs, 2H, NH2), 12.983 (s, 1H, NH)
21.057, 68.275, 115.069, 128.792, 128.967,
142.16, 163.796, 180.464
242 (75.9), 241 (100), 209 (15.7), 184 (32.5),
140 (12.5), 118 (12.6), 91 (13.6), 65 (19.6)
7.599, 7.826 (2d, 4H, Ar-H, J = 8.203 Hz),
8.112 (brs, 2H, NH2), 13.091 (s, 1H, NH)
262 (85.2), 261 (100), 229 (24), 204 (40),
187 (12), 162 (14.5), 138 (22.4), 111 (14.3),
92 (17.6), 75 (34.4), 67 (29.3), 51 (29.6)
3.572 (s, 1H, SH), 3.831 (s, 3H, CH3O-Ar),
7.057, 7.840 (2d, J = 8.984 Hz, 4H, Ar-H)
and 7.987 (brs, 2H, NH2)
8b
3471.3, 3329.8, 3226.3
(NH2, NH), 2221.5
(CN), 1392 (C S)
9
3434, 3333.4, 3229.5
(NH2), 2218 (CN)
10a
3465.3, 3268.9 (NH),
1634.3 (CONH)
3.726, 3.755 (2s, 6H, 2CH3O-Ar), 4.627 (br,
s, 2H, H-4 & H-7), (6.907–6.948) (br, s,
4H, Ar-H), 7.05 & 7.18 (2d, 4H, Ar-H,
J = 8.5 Hz), 7.58, 7.963, 9.032 (hump),
9.847 (broad), 10.112 (broad), 10.964 (NH
and enolic OH protons)
380 (10.8), 121 (100), 259 (14.9), 202 (18.9),
178 (19.8), 77 (14.8)
10b
3460.5, 3404.1, 3326.1
(NH), 2986.2 , 2903.7
(CH), 1636.1 (CONH)
2.233 (s, 3H, CH3-Ar), 2.321 (s, 3H,
CH3-Ar), 6.07 (t, 2H, H-4 & H-7, J = 5.1
Hz), 7.019 & 7.171 (2m, 8H, Ar-H), 7.327
& 7.719 & 7.972 & 9.761 & 10.043 &
10.884 (NH and enolic OH protons)
348 (30.5), 105 (100), 288 (14.4), 243 (31.0),
186 (37.3), 162 (39.4)
11
3232.1, 3144.7 (NH2),
2218.6 (CN)
2.302 (s, 6H, 2CH3-Ar), 6.965 (br, s, 2H,
NH2), 7.049 (m, 8H, Ar-H)
482 (25.7), 241 (100), 209 (26.8), 184 (23.4),
183 (25.6), 142 (13.2), 141 (7.1), 140 (16.3),
91 (22.1), 65 (35.1)
12a
3431, 3137.9 (NH),
2267.4, (CN), 1724.1
(CO)
4.262 (s, 3H, OCH3), 5.479 (d, J = 11.6 Hz,
1H, 5-H), (5.746–5.621) (m, 1H, 6-H),
7.869, 7.498 (2d, J = 8.2 Hz, 4H, Ar-H),
10.952 & 10.632 (2s, 1H, 1-H), 12.337,
12.336 (2s, 1H, 3-H)
39.667 (C-5), 40.669 (C-6), 55.189 (OCH3),
114.128, 114.280 (C-3ꢀ, 5ꢀ), 114.575 (CN),
127.374 (C1ꢀ), 127.928, 129.096 (C2ꢀ, 6ꢀ),
159.806 (C4ꢀ), 160.329 (CO), 178.522 (CS)
261 (100), 186 (68.1), 178 (75.7), 158 (21.8),
134 (73.9), 121 (33.6), 89 (25.4), 77 (22.3),
51 (22.6)
(Continued on next page)

852
A. M. El-Agrody et al.
TABLE I Spectral Data for the Newly Prepared Compounds
(Continued)
1
Compound
IR (ν
cm−1
)
HNMR/13CNMR (δ ppm)/MS (m/z %)
max
12b
3302, 3162 (NH), 2940,
2902 (CH), 2245 (CN),
1748 (CO)
5.034 (d, 1H, H-5; J = 11.719 Hz), 5.247
(d, 1H, H-6; J = 11.328 Hz), 7.456 & 7.536
(2d, 4H, Ar-H, J = 8.594 Hz), 10.198,
10.468, 11.796, 11.907 (NH and enolic
OH)
265 (100), M + 2 (39.37), 182 (55.37), 138
(38.47), 28.1 (36,93), 101 (9.76), 86 (7.14),
75 (16.04), 59 (20.76)
13
14
3.923 (s, 3H, CH3O-Ar), 4.051 (s, 3H,
CH3O-pyrimidine), 7.352, 7.546 (2d, 4H,
Ar-H, J = 9.0 Hz), 7.934 (br, s, 2H, NH2)
3.834 (s, 3H, OCH3-py), 3.824 (s, 3H,
OCH3-Ar), 7.100 & 7.625 (2d, 4H, Ar-H),
12.931, 13.081 (s, br, 2H, 2NH).
257 (M+, 100), 200 (18.9), 199 (25.2),
134 (20.9), 63 (13.2)
3451.1 (NH), 3062.4 (C-H
arom.), 2964 (C-H
aliph.), 2214.8 (CN),
1673.4 (CO), 1603
(C N)
15a
3424, 3330, 3234 (NH2),
2942 ( aliph. C-H),
2224, 2210 (CN)
3.828 (s, 3H, CH3O-Ar), 3.953 (s, 3H,
CH3O-Py), 7.096 & 7.473 (2d, 4H, Ar-H;
J = 8.985 Hz), 7.936 (s, br, 2H, NH2)
55.454 (C-CH3O-Ar), 56.454 (C-CH3O-Py),
82.811 (C-3, C-5), 113.938 (C-3ꢀ, C-5ꢀ),
116.267 (2CN), 127.571 (C-2ꢀ, C-6ꢀ),
130.393 (C-1ꢀ), 161.885 (C-4ꢀ), 164.107
(C-4), 166.710 (C-2), 170.078 (C-6)
280 (100), 238 (2.8), 157 (2), 127 (2.3),
100 (2.9)
15b
16
3481, 3346, 3227.2 (NH2),
2955 (aliph. C-H), 2217
(CN)
3.985 (s, 3H, CH3O ), 7.544 & 7.654 (2d,
4H, Ar-H; J = 6.6 Hz) and at 7.967 (br, s,
2H, NH2)
284 (100), M + 2 (33.4), 255 (24.2),
249 (42.2), 165 (12.7)
3421.6, 3308, 3205.6
(NH2), 2224.4 (CN)
8.252 (br, 4H, 2NH2, disappeared by D2O),
8.499 (s, 1H, 2H, 2H-6).
302 (92), 94 (100), 270 (8), 238 (45), 185 (20),
152 (64),119 (45), 93 (53), 66 (60)
262 (M+, 88.9), 261 (100), 204 (33.2), 134
(19.2), 99 (20.7), 67 (40.4)
3.738, 3.767 (2s, 6H, 2OCH3), 5.205 (s, 1H,
5-H), 5.551 (s, 1H, 6-H), 6.135 (s, 1H,
=CH-Ar), 6.90, 6.972 (2d, J = 7 Hz, 4H,
Ar-H), 7.237, 7.455 (2d, J = 7 Hz, 4H,
Ar-H), 9.553 (s, br, 3H, NH + NH2)
396 (31.51), 134 (100), 394 (47.8), 353 (41.3),
287 (90.7), 178 (38.5), 119 (33.1), 77 (57.6)
17
18
3372, 3172 (NH2), 3075.2
(C-H arom.), 2932 (C-H
aliph.), 1668.3 (CO)
(Continued)

Thioxopyrimidines and Related Derivatives
853
TABLE I Spectral Data for the Newly Prepared Compounds
(Continued)
1
Compound
IR (ν
cm−1
)
HNMR/13CNMR (δ ppm)/MS (m/z %)
max
19
3240.5 (NH2), 2215 (CN),
1663.4 (CO)
3.695 (s, 3H, OCH3), 3.775 (s, 3H, OCH3),
4.818, 4.12 (2d, J = 2.734 Hz, 6-H + 5-H),
7.515, 7.122, 6.995, 6.87 (4d, 8H, Ar H),
(8.35–8.616) (s, br, 2H, CONH2)
402 (M+, 14.7), 121 (100), 360 (29.3), 294
(13.2), 242 (27.8), 201 (14.1), 162 (26.7),
134 (53.4), 77 (38.8)
20
3454, 3350 (NH2), 1704,
1686 (CO)
3.746 (s, 3H, OCH3), 4.296 (d, 1H, H-5,
J = 12.89 Hz), 4.861 (d, 1H, H-6,
J = 12.89 Hz), 5.217 (s, 1H, NH), three set
of multiples at (6.922–7.424) (m, 4H,
Ar-H), 7.545 (s, 2H, NH2), 8.797 (s, 1H,
CO2H)
279 (M+, 1.35), 268 (7.7), 211 (24.79), 196
(29.62), 161 (9.16), 149 (12.47), 135 (6.75),
97 (10.08), 85 (15.21), 71 (23.1), 45 (100)
3.843 (s, 3H, OCH3), 7.103 & 7.651 (2d,
J = 9.0 Hz, 4H, Ar-H), 13.099 (s, 1H, OH)
259 (M+, 100), 231 (19.7), 201 (27),
158 (16.2), 134 (63.5), 91 (13.8), 63 (13.8)
1.352 (t, J = 7.0 Hz, 3H, CH3), 3.848 (s, 3H,
OCH3), 4.088 (s, 3H, OCH3); 4.424 (q,
J = 7.0 Hz, 2H, CH2) 7.147, 7.565 (2d,
J = 8.6 Hz, 4H, Ar-H), 8.772 (s, 1H,
N=CH)
21
22
3470.9 (NH), 2212.1 (CN),
1676.7, (CO)
3002.8 (C-H arom.),
2966.2 (C-H aliph.)
2226.2 (CN)
336 (M+, 100), 280 (98.40), 249 (24.9), 195
(12.0), 114 (11.3)
23
24
Strong broad at 3350 (OH
& NH), 2214 (CN )
3.836 (s, 3H, OCH3-Ar), 3.953 (s, 1H, OH),
4.010 (s, 3H, OCH3-Py), 4.877 (d,
J = 6.4 Hz, CH2), 7.112, 7.499 (2d,
J = 8.59, 4H, Ar-H), 8.795 (s, br, 1H, NH).
310 (M+, 12.1), 309 (13.2), 292 (100),
280 (83.8), 195 (20), 152 (18.2), 114 (16.2),
63 (13.2)
3426, 3334, 3234 (NH2),
2944 (CH-aliph.),
2212 (CN)
1.113 (t, J = 7 Hz, 2H, HOCH2CH2N), 3.543
(q, J = 7 Hz, 2H, NCH2CH2OH), 3.83 (s,
3H, OCH3), 3.928 (s, 1H, OH), 4.006 (s,
1H, OH), 4.919 (d. J = 6Hz, NCH2OH),
7.104, 7.484 (2d, J = 8.6 Hz, 4H, Ar-H),
8.772 (s, br, 2H, NH2)
339 (M+; 18), M-1 (68), 309 (100), 293 (80),
280 (72), 59(42)
25
3329, 3228 (NH ), 2219.4
(CN), 1726.7 (CO)
3.826 (s, 3H, OCH3), 7.089, 7.889 (2d,
J = 9.0 Hz, 4H, Ar-H), 9.255 (d, J = 4.688
Hz, 1H, HN-CHO), 11.565 (br, s, 2H, NH).
(Continued on next page)

854
A. M. El-Agrody et al.
TABLE I Spectral Data for the Newly Prepared Compounds
(Continued)
1
Compound
IR (ν
cm−1
)
HNMR/13CNMR (δ ppm)/MS (m/z %)
max
286 (12.8), 241 (100), 257 (64.2), 199 (41.7),
157 (11.2), 92 (11.4), 64 (20)
26
3354.8, 3327, 3150.7
(NH2), 2217.1 (CN),
1742.7 (CO)
2.074 (s, 3H, CH3), 3.629 (s, 2H, CH2S),
3.838 (s, 3H, OCH3), 4.01 (s, CH2CH3)
(7.071–7.893) (m, 6H, Ar-H + NH2)
344 (M+, 6.2), 271 (100), 225 (27.4)
3.777 (s, 3H, OCH3), 4.781 (s, 2H, CH2);
6.868, 7.559 (2d, J = 8.5 Hz, 4H-ArH),
(7.634-8.061) (m, 7H, Ar-H + NH2)
376 (M+, 10.3), 343 (10.9), 271 (27.4),
105 (100), 77 (36.7)
27
3354, 3164 (NH2), 2222
(CN), 1690 (CO), 1666
(C N)
28a
3454.2, 3301.8, 3238.3
(NH2), 3153.4 (NH),
2193.7 (CN)
3.809 (s, 3H, OCH3); 4.375 (s, 2H, NH2),
7.039 (d, J = 8.985, 4H, ArH), 7.834,
8.661 (2s, br, 3H, NH2+ NH)
256 (M+, 100), 227 (26), 225 (30), 184 (10)
260 (M+, 100), M + 2 (34.4), 231 (42.2), 230
(16.1), 204 (15.91), 138 (14.4), 67 (16.1)
360 (M+, 25.43), 343 (20.15), 241 (100),
240 (61.29), 225 (27.35), 200 (28.39), 199
(28.52), 157 (15.37), 134 (24.02), 119
(42.89), 105 (38), 91 (70.17), 77 (60.34)
2.335 (s, 3H, CH3), 3.848 (s, 3H, OCH3),
7.092–7.246 (2d, J = 8.4 Hz, 4H, Ar-H),
7.42 (s, br, 2H, NH2, cancelled by D2O)
7.566, 7.867 (2d, J = 8.7 Hz, 4H, Ar-H),
8.167 (s, 1H, N = CH), 11.29 (s, br, 1H,
NH, cancelled by D2O)
28b
29a
3414, 3342 (NH2), 3250
(NH), 2214 (CN)
3475, 3372 (NH2), 3298
(NH), 2200 (CN)
29b
3470, 3350, 3294 (NH2),
3148 (NH), 2202 (CN)
358 (M+, 8), 276 (16), 241 (100) 199 (28),
134 (16), 117 (44), 91 (68), 65 (40)
3.795 (s, 3H, OCH3), 3.84 (s, 3H, OCH3),
6.100, 7.083 (2d, J = 8.7 Hz, 4H, Ar-H),
7.394 (s, br, 2H, NH2 cancelled by D2O),
7.631, 7.856 (2d, J = 8.4 Hz, 4H, Ar-H),
8.14 (s, 1H, N=CH), 11.227 (s, br, 1H, NH,
cancelled by D2O)
29c
3476, 3290 (NH2), 3112
(NH), 2196 (CN)
374 (M+, 3.36), 241 (100), 199 (27.3),
157 (12.84), 133 (37.4), 91(35), 77 (44.74)
6.881 (m, 4H, Ar-H), 7.244 (hump, 2H,
NH2), (7.629–7.885) (m, 4H, Ar-H), 8.413
(s, 1H, N=CH), 11.052, (11.702–11.903)
(br signals, OH + NH)
29d
29e
3402 (br), 3254 (NH2,
NH), 2210 (CN)
3470, 3346, 3292 (NH2),
3158 (NH), 2206 (CN)
2.32 (s, 3H, CH3), 7.232, 7.547 (2d,
J = 8.203 Hz, 4H, Ar-H), 7.610, 7.843 (2d,
J = 8.6 Hz, 4H, Ar-H), 8.155 (s, 1H,
N=CH), 7.598 (s, br, 2H, NH2), 11.434 (s,
br, 1H, NH)
(Continued)

Thioxopyrimidines and Related Derivatives
855
TABLE I Spectral Data for the Newly Prepared Compounds
(Continued)
1
Compound
IR(ν
cm−1
)
HNMR/13CNMR (δ ppm)/MS (m/z %)
max
362 (4.89), M + 2 (2.21), 271 (4.4), 245 (100),
229 (2.56), 205 (11), 203 (24.74), 162
(2.12), 138 (4.6), 91 (6.18)
30
3477.4, 3274.1 (NH2),
3140.9, 2208.7 (CN ),
1649.1 (C N)
2.174 (s, 3H, CH3), 2.603 (s, 3H, CH3),
3.842 (s, 3H, OCH3), 6.137 (s, 1H, 4-H,
pyrazole), 7.117, 7.944 (2d, J = 9 Hz, 4H,
Ar-H), 7.922–7.965 (s, br, 2H, NH2)
320 (100), 305 (21.4), 278 (11.8), 225 (11.7),
121 (10.2), 95 (11.7)
31
3484, 3294, 3152 (NH2,
NH), 2202 (CN), 1732
(CO)
1.202 (t, J = 5.1 Hz, 3H, CH3), 1.978 (s, 3H,
CH3C=), 3.297 (s, 2H, CH2C=O), 3.835
(s, 3H, OCH3), 4.118 (q, J = 5.1 Hz,
CH2CH3), 7.008, 7.819 (2d, J = 8.7 Hz,
4H, Ar-H), 7.4 (s, br, 2H, NH2 cancelled by
D2O) 9.907 (s, 1H, NH cancelled by D2O)
368 (5.08), 281 (100), 353 (2.51), 322 (12.74),
254 (9.56), 225 (18.91), 183 (10.86),
158 (7.42), 134 (10.11), 77 (5.86), 68 (10)
(1.506–1.591) (complex pattern, 10 H,
piperidine–H), 3.812 (s, 3H, OCH3),
7.041, 7.816 (2d, J = 8.6 Hz, 4H, Ar-H),
7.131 (s, br, 1H, NH)
32
3258.6 (NH), 2947.9,
28471 (C-H aliph.),
229.8 (CN), 1730.8 (CO)
310 (18.7), 180 (100), 309 (89.2), 294 (30.2),
281 (26.3), 266 (39), 254 (42.8), 226 (37.0),
225 (38.5), 183 (10.7), 84 (81.3)
and PA, while compound 12a showed the same effect against BS,
SA, and PA, and compound 24 gave the same effect against BS
and SA. Compound 26 showed moderate inhibition (++, inhibition
zone ≈ 8–12 mm) against CA and AN, while compounds 17, 18, 27,
29a, and 30 showed moderate inhibition against BS, SA, EC, and
PA, compound 8 gave a moderate effect against BS, and SA, Com-
pound 24 gave a moderate effect against EC, and PA, compound 12a
also gave a moderate effect against EC. The remaining tested com-
pounds showed weak (+) to poor (−) activities against all the tested
microorganisms.
It was observed that the compounds containing pyridine nucleus sub-
stituted by two carbonitriles (3,5-) and two amino groups (2,6-) (com-
pound 24) that contained a pyrimidine moiety with poly functional sub-
stituted groups (compounds 12a, 26) showed a promising effect against
most of the tested microorganisms (Table II).

856
A. M. El-Agrody et al.
TABLE II Antimicrobial Activity of Some Newly
Synthesized Compounds. −ve ( no activity); +ve (when
inhibition zone up to 8 mm); ++ve (when inhibition zone
was between 8–12 mm); +++ve (when inhibition zone was
between 12–15 mm); ++++ve (when inhibition zone was
over 15 mm); −MIC 50 mg/mL.
Gram-positive
Gram-negative
Fungi
AN
Compound
BS SA
EC
−ve
PA
CA
8a
9
12a
15a
15b
17
18
19
21
22
24
26
27
29a
30
−ve
−ve
−ve
−ve
−ve
−ve
+ve
−ve
+ve
−ve
−ve
−ve
+ve
−ve
−ve
++ve
+ve
−ve
−ve
−ve
−ve
++ve
+++ve
+ve
++ve
+++ve
+ve
−ve
−ve
+ve
−ve
−ve
−ve
−ve
−ve
−ve
−ve
−ve
++ve
−ve
−ve
−ve
−ve
++ve
+ve
+++ve
+ve
+ve
+ve
+
+ve
++ve
++ve
+ve
++ve
++ve
+ve
++ve
++ve
+ve
++ve
++ve
+ve
+ve
+ve
+ve
+ve
+ve
+ve
+ve
+ve
+++ve
+++ve
++ve
++ve
++ve
++++ve
+++ve
+++ve
++ve
++ve
++ve
++++ve
++ve
+++ve
++ve
++ve
++ve
+++ve
++ve
+++ve
++ve
++ve
++ve
+++ve
Neomycin
EXPERIMENTAL SECTION
Melting points were measured using the melting point apparatus (Stu-
art Scientific Co., UK), and remained uncorrected. The IR spectra were
recorded on a Shimadzu IR 440 spectrophotometer (Shimadzu, Japan)
1
in KBr. H and 13C NMR spectra were recoded on a Varian Gemini
200 NMR spectrometer at 200 and 50 MHz with a chemical shift calcu-
lated from deuterated solvent residues. Microanalytical data (Table II)
were obtained from the Microanalytical Unit of the Cairo University
(Cairo, Egypt).
4-Amino-1,2-dihydro-2-thioxo-6-arylpyrimidine-5-carbonitrile
(8a, b) 4-Amino-2-mercapto-6-(4-methoxyphenyl)pyrimidine-
5-carbonitrile (9)
A solution of thiourea (760 mg, 10 mmol) in ethanol (15 mL) containing
three drops of piperidine and the corresponding benzylidenemalonon-
itrile (5) (10 mmol) dissolved in ethanol (15 mL), were successively

Thioxopyrimidines and Related Derivatives
857
added, and the reaction mixture was refluxed for 4 h. The reaction mix-
ture was precipitated with dil. HCl; the solid product so formed was
collected by filtration, washed several times by water, and then recrys-
tallized from the appropriate solvent (Table III).
3,4,7,8-Tetrahydro-4,7-bis(4-methoxyphenyl)pyrimido[4,5-d]-
pyrimidine-2,5(1H, 6H)-dione (10a), 3,4,7,8-Tetrahydro-4,7-bi-
(p-tolyl)pyrimido[4,5-d]-pyrimidine-2,5(1H, 6H)-Dione (10b),
4-Amino-6-(p-tolyl)-2-[2-(4-amino-5-cyano-6-(p-tolyl))pyrimid-
in-2-yl)-disulfanyl]pyrimidine-5-carbonitrile (11) and 4-Amino-
2- [2-(4-amino-5-cyanopyrimidin-2-yl) disulfanyl]-pyrimidine-5-
carbonitrile (16)
To a solution of respective benzylidenemalononitrile (5) or ethoxymeth-
ylenemalononitrile (3) (10 mmol) in (10 mL) absolute ethanol and
(760 mg, 10 mmol) of thiourea in ethanol (10 mL) containing anhy-
drous K2CO3 (1.380 g, 10 mmol) were added. The reaction mixture was
refluxed for 4 h. The potassium salt, which precipitated during the reac-
tion, was collected. The crude salt was stirred in water at 80◦C; stirring
was continued until a clear solution was obtained. After cooling, the
solution was acidified with dil. HCl; the solid product so formed was
collected by filtration, washed several times by water, and then recrys-
tallized from the appropriate solvent (Table III). In the case of 5b, the
reaction product was a mixture of 10b and 11 and was separated by
gas–liquid chromatography.
4-Oxo-6-(4-methoxyphenyl)-2-thioxohexahydropyrimidine-5-
carbonitrile (12a), 2-Amino-6-methoxy-4-(4-methoxyphenyl)-
pyridine-3,5-dicarbonitrile (15a), and 4-Oxo-6(4-chlorophenyl)-
2-thioxohexahydroprimidine-5-carbonitrile (12b) and
2-Amino-4-(4-chlorophenyl)-6-methoxypyridine-3,5-
dicarbonitrile (15b)
To a solution of sodium (230 mg, 10 mmol) in methanol (50 mL), thiourea
(760 mg, 10 mmol) was added. When it became dissolved, (10 mmol) of
the corresponding benzylidenemalononitrile (5) dissolved in methanol
was added. The resulting mixture was refluxed for 4 h. The reaction
mixture was poured onto ice water and neutralized by dil. hydrochlo-
ric acid (10%); the solid product so formed was collected by filtration,
washed several times with water, and then recrystallized from the ap-
propriate solvent (Table III).

858
A. M. El-Agrody et al.
TABLE III Physical and Analytical Data for the Newly Prepared
Compounds
Calcd/(found)
M.P.◦C
(solvent)
Color
(yield %)
M. formula
(m. wt.)
Compound
C
H
N
8a
.265–267
(D)
Colorless
(57)
C12H10N4S
(242.23)
59.48
4.16
23.12
(59.38) (4.08) (23.03)
50.29 2.69 21.33
(50.18) (2.53) (21.25)
55.80 3.90 21.69
(55.79) (3.74) (21.57)
63.15 5.30 14.73
(62.96) (5.18) (14.56)
68.95 5.79 16.08
(68.84) (5.67) (16.08)
59.73 3.76 23.22
(59.67) (3.63) (23.11)
4.24 16.08
(54.98) (4.28) (15.30)
C11H8ClN3OS 49.72 3.03 15.81
(49.28) (2.96) (15.04)
60.93 4.72 21.86
(60.84) (4.61) (21.72)
60.70 4.31 16.33
(60.61) (4.22) (16.22)
64.28 4.32 19.99
(64.17) (4.23) (19.86)
59.06 3.19 19.68
(58.92) (3.02) (19.53)
39.73 2.00 37.06
(39.62) (1.91) (36.93)
54.96 5.38 21.36
(54.82) (5.18) (21.12)
5.08 14.13
(60.42) (4.98) (14.6)
65.66 4.51 13.92
(65.58) (4.43) (13.81)
4.69 15.04
(51.49) (4.53) (14.92)
55.59 3.50 16.21
(55.49) (3.39) (16.15)
64.28 4.79 16.66
(64.18) (4.70) (16.58)
61.93 4.55 18.06
(61.82) (4.47) (17.94)
60.17 5.05 20.64
(60.8) (4.96) (20.58)
3.52 19.57
8b
9
268–270
(D)
258–260
(DMF)
206–208
(Et)
Colorless
(53)
Colorless C12H10N4OS
(35)
Brown
(12)
Yellow
(14)
Yellow
(14)
Yellow
(50)
Yellow
(48)
Colorless
(31)
Yellow
(92)
Colorless C15H12N4O2
(30)
Colorless
(28)
Yellow
(53)
C
11H7CIN4S
(262.72)
(258.23)
20H20N4O4
(380.40)
20H20N4O2
(348.40)
10a
10b
11
C
C
Mixed 230–234
(Et)
Mixed 230–234
(Et)
C24H18N8S2
(482.58)
C12H11N3O2S 55.16
(261.30)
12a
12b
13
226–228∗
(Et)
216–218
(B)
250–252
(E/B)
(265.72)
13H12N4O2
(256.26)
13H11N3O3
(257.24)
C
C
14
268–270
(GAA)
15a
15b
16
280–282∗∗
(D)
(280.28)
14H9ClN4O
(284.7)
282–284
(D)
314–316
(DMF)
C
C10H6N8S2
(302.40)
C
17
Mixed 248–252 Colorless
(Et) (45)
Mixed 248–252 Colorless
12H14N4O3
(262.26)
18
C20H20N4O3S 60.59
(Et)
272–174
(DMF)
252–254
(D)
280–282
(Et)
188–190
(B)
184–186
(Et)
178–180
(Et)
226–228
(D)
(20)
Green
(15)
Colorless
(40)
(396.46)
22H18N4O4
(402.40)
19
C
20
C
12H13N3O3S 51.60
(279.31)
21
Colorless C12H9N3O2S
(77)
Colorless
(80)
Colorless
(67.7)
Colorless
(69.9)
Colorless
(60)
(259.28)
18H16N4O3
(336.12)
16H14N4O3
(310.31)
22
C
C
C
23
24
17H17N5O3
(339.35)
25
C13H10N4O2S 54.54
(286.31)
(54.43) (3.51) (19.48)
(Continued on next page)

Thioxopyrimidines and Related Derivatives
859
TABLE III Physical and Analytical Data for the Newly Prepared
Compounds (Continued)
Calcd/(found)
M.P.◦C
(solvent)
Color
(yield%)
M. formula
(m. wt.)
Compound
C
H
N
26
180–182
(Et)
174–176
(Et)
280–282
(D)
258–260
(D)
216–218
(Et)
218–220
(Et)
234–236
(Et/B)
246–248
(Et)
230–232
(Et)
Yellow
(72)
Colorless
(80)
Colorless
(81)
Colorless
(76)
Colorless
(68)
Colorless
(69)
Yellow
(73)
Colorless
(70)
Colorless
(66)
Colorless
(80)
Yellow
(76)
Colorless
(72)
C16H16N4O3S
(344.39)
55.80
(55.69)
63.81
(63.72)
56.24
(56.16)
50.68
(50.79)
63.32
(63.22)
67.02
(66.93)
64.16
(64.8)
59.27
(59.18)
62.90
(62.87)
63.74
(63.66)
58.69
(58.59)
65.79
(65.66)
4.68
(4.56)
4.28
(4.21)
4.72
(4.64)
3.48
(3.41)
4.48
(4.41)
5.06
(4.96)
4.85
(4.78)
3.59
(3.49)
4.17
16.27
(16.18)
14.88
(14.79)
32.79
(32.79)
32.24
(32.17)
23.32
(23.21)
23.45
(23.38)
22.45
(22.35)
23.04
(22.96)
23.16
(23.7)
26.23
(26.13)
22.81
(22.69)
18.05
(17.96)
27
C
20H16N4O2S
(376.43)
28a
28b
29a
29b
29c
29d
29e
30
C12H12N6O
(256.26)
C
11H9ClN6
(260.68)
C
19H16N6O2
(360.37)
C20H18N6O
(358.40)
C
20H18N6O2
(374.40)
C18H13ClN6O
(364.79)
C
19H15ClN6
(362.82)
(4.9)
5.03
(4.96)
5.47
(5.41)
5.85
255–256
(Et/B)
160–161
(Et)
260–262
(Et/B)
C
17H16N6O
(320.35)
31
C
C
18H20N6O3
(368.39)
17H18N4O2
(310.35)
32
(5.78)
∗(lit.34 m.p. 231–232).
∗∗(lit.37 m.p. 279–280).
B, Benzene; D, Dioxan; DMF, Dimethylformamide; Et, Etanol; GAA, Glacial acetic
acid.
2-Methoxy-5-cyano-4-amino-6-(4-methoxyphenyl)-
pyrimidine (13)
To a solution of sodium (230 mg, 10 mmol) in methanol (30 mL),
thiourea (380 mg, 5 mmol) was added. When it became dissolved,
(920 mg, 5 mmol) of p-methoybenzylidenemalononitrile (5a) dissolved
in methanol (10 mL) were added. The resulting mixture was refluxed
for 4 h. The reaction mixture was poured onto ice water and neutral-
ized by dil. hydrochloric acid (15%) up to pH 6; the solid product so
formed was collected by filtration and washed several times by water
(Table III).

860
A. M. El-Agrody et al.
6-Amino-1,2,3,4-tetrahydro-4-(4-methoxyphenyl)-2-thioxopyr-
imidine-5-carboxamide (17), 6-(4-Methoxybenzylidine)
amino-1,2,3,4-tetrahydro-4-(4-methoxyphenyl)-2-thioxopyri-
midine-5-carboxamide (18), and 3,5-Di-cyano-4,6-di(4-methox-
yphenyl)-2,3,4,5-tetrahydropyridine-2-one (19)
Thiourea (760 mg, 10 mmol) and (E)-3-(4-methoxyphenyl)-2-cyanoprop-
enamide (6a) (2.02 g, 10 mmol) were added to a solution of sodium
methoxide (230 mg, 10 mmol) in dry methanol (40 mL). The mixture
was stirred at r.t. for 48 h, and the solvent was removed in vacuo. By
the addition of water (60 mL) and then adicified with 10% hydrochlo-
ric acid, a precipitate was formed that was collected and washed with
water. The product thus obtained was boiled with ethanol and filtered.
The remaining solid was recrystallized from DMF to give 19. The boiled
ethanol gave a solid, which was separated by gas–liquid chromatogra-
phy into 17 and 18 (Table III).
6-Amino-1,2,3,4-tetrahydro-4-(4-methoxyphenyl)-2-
thioxopyrimidine-5-carboxylic acid (20)
Thiourea (760 mg, 10 mmol) and (E)-3-(4-methoxyphenyl)-2-cyanoprop-
enamide (6a) (2.02 g, 10 mmol) were added to a solution of sodium
methoxide (230 mg, 10 mmol) in dry methanol (40 mL). The mixture
was refluxed for 4 h. The reaction mixture was poured onto ice water
and acidification with (10%) hydrochloric acid; a precipitate was formed
that was collected and washed with water (Table III).
5-Cyano-4-oxo-6-(4-methoxyphenyl)-
2-thioxotetrahydro-pyrimidine (21)
Method A
To a solution of sodium (230 mg, 10 mmol) in methanol (50 mL),
thiourea (760 mg, 10 mmol) was added. When it became dissolved, (2.31
g, 10 mmol) of ethyl p-methoybenzylidenecyanoacetate (7a) was added
the resulting mixture was refluxed for 4 h. The reaction mixture was
poured onto ice water and neutralized by dil. hydrochloric acid (10%) the
solid product so formed was collected by filtration and washed several
times by water (Table III).
Method B for Compound 21 and 14
A mixture of 8 or 13 (1 mmol) and formic acid (10 mL) was refluxed
for 3 h; the solvent was evaporated in vacuo, and the solid so obtained

Thioxopyrimidines and Related Derivatives
861
was washed by dil. ethanol; the obtained solid was recrystallized from
a suitable solvent.
(E)-Ethoxymethyleneamino-6-methoxy-4-(4-
methoxyphenyl)pyridine-3,5-dicarbonitrile (22) and
N-(5-Cyano-2-thioxo-6-(4-methoxyphenyl)-1,2-di-
Hydropyrimidin-4-yl)formamide (25)
A mixture of 13a or 8 (1 mmol), triethylorthoformate (148 mg, 1 mmol),
and acetic anhydride (10 mL) was refluxed for 3–5 h then cooled, and
the solid product was collected by filtration, washed by pet. ether, and
recrystallized from an appropriate solvent (Table III).
2-(N-Hydroxymethyl)amino-6-methoxy-4-(4-
methoxyphenylpyridine-3,5-di-carbonitrile (23)
A mixture of 13a (280 mg, 1 mmol) and formaline solution (1 mL) in
ethanol (10 mL) was refluxed for 2 h; the solid product was collected by
filtration and washed by dil. ethanol (Table III).
2-(N-Hydroxymethyl,N-(β-hydroxyethyl))amino-6-amino-4-
(4-methoxyphenyl)pyridine-3,5-dicarbonitrile (24)
A mixture of 13a (560 mg, 2 mmol), formaline solution (1 mL), and
ethanolamine (122 mg, 2 mmol) in ethanol (10 mL) was refluxed for
2 h; the solid product was collected by filtration and washed by dil.
ethanol (Table III).
2-(4-Amino-5-cyano-6-(4-methoxyphenyl)pyrimidin-
2-yl)thioethylacetate (26)
A solution of 4-amino-2-mercapto-6-(4-methoxyphenyl)pyrimidine-5-
carbonitrile (8) (258 mg, 1 mmol), ethyl chloroacetate (122 mg, 1 mmol),
and 2 drops of sodium methoxide were added. The mixture was refluxed
for 3 h in dioxane (30 mL). The reaction mixture was poured onto ice
water and neutralized by dil. hydrochloric acid (10%); the solid product
so formed was collected by filtration and washed several times by water
(Table III).
2-(2-Benzoylmethylthio)-4-amino-6-(4-
methoxyphenyl)pyrimidine-5-carbonitrile (27)
A solution of 4-amino-2-mercapto-6-(4-methoxyphenyl)pyrimidine-5-
carbonitrile (8) (516 mg, 2 mmol) and phenacylbromide (384 mg

862
A. M. El-Agrody et al.
2 mmol). The mixture was refluxed for 1 h in ethanol (30 mL); the
solid product so formed was collected by filtration and washed by dil.
ethanol (Table III).
4-Amino-6-(4-methoxyphenyl)-2-hydrazinylpyrimidine-
5-carbonitrile (28a) and 4-Amino-6-(4-chlorophenyl)-
2-hydrazinylpyrimidine-5-carbonitrile (28b)
A suspension of 8 or 9b (10 mmol) and hydrazine hydrate (320 mg,
10 mmol) in n-butanol (30 mL) was refluxed for 3 h. The solvent was
evaporated in vacuo; the residue was triturated with dil. ethanol and
the solid, which separated, was filtered off (Table III).
2-((Z)-2-Arylidenehydrazinyl)-4-amino-6-(aryl)pyrimidine-
5-carbonitrile 29a–e
A mixture of 28a,b (1 mmol) and aromatic aldehyde (1 mmol) in n-
butanol (10 mL) was refluxed for 30 min. The solvent was evaporated
in vacuo; the solid product was collected by filtration, washed by dil.
ethanol, and recrystallized from an appropriate solvent (Table III).
4-Amino-6-(4-methoxyphenyl)-2-[(3,5-dimethyl)-1H-pyrazol-
1-yl)pyrimidine-5-carbonitrile (30) and 2-(2-
Ethoxycarbonylisopropylidenehydrazinyl)-4-amino-
6-(4-methoxyphenyl)pyrimidine-5-carbonitrile (31)
A
suspension of 4-amino-6-(4-methoxyphenyl)-2-hydrazinylpyri-
midine-5-carbonitril (28a) (256 mg, 1 mmol), acetyl acetone and/or
ethyl aceto-acetate (1 mmol) in ethanol (30 mL) and 2 drops of piperi-
dine was added. The mixture was refluxed for 3 h; the solid obtained
was collected by filtration, washed by dil. ethanol, and recrystallized
from a suitable solvent (Table III).
1,6-Dihydro-4-(4-methoxyphenyl)-6-oxo-2-(piperidin-1-yl)-
pyrimidine-5-carbonitrile (32)
A suspension of 4-amino-2-mercapto-6-(4-methoxyphenyl)-pyrimidine-
5-carbonitrile (8) (516 mg, 2 mmol) and piperidine (168 mg, 2 mmol) was
refluxed in ethanol (30 mL) for 3 h. The solid obtained was collected by
filtration and washed by dil. ethanol (Table III).
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