Pyrimidinthiones (part I): Utility of 2-thioxopyrimidin-6-(1H)ones as ring transformer in the synthesis of fused bi- and tri-cyclic heterocyclic compounds and their potential biological activities

Article abstract of DOI:10.1080/10426500801967963

The pyrimidinethiones have wide biological and pharmaceutical activities, that have attracted considerable interest in recent years especially as antiviral inhibiting production of hepatitis B virus (HBV), and in vitro insulin-mimetic. Activity of the complexes of pyrimidinone derivatives evaluated from 50% inhibitory concentration promoted us to study the transformation of the 2-thioxopyrimidin-6(1H) ones to fused bi- and tri-cyclic heterocyclic compounds having the pyrimidine moieties and screening their biological activity. The reactivity of 2-mercapto-4-aryl-5-cyanopyrimidin-6(1H)ones (1) towards alkylation by different mono and bifunctional halo-organic compounds has been investigated to give S-monoalkylated products 2, 7 and 9; S- and N-dialkylated products 3, 13 and 14. Treatment of 1 and/or 2 with hydrazine hydrate as a nitrogen nucleophile have been investigated to give 4, treatment of 4 with CS2 and sodium nitrite in the presence of acetic acid (0C) produced 1,2,4-triazolopyrimidin-5(1H)one derivatives (5)and tetrazolo[1,5-a]pyrimidin- 5(1H)ones (6), respectively. Also cyclization of 7 and 9 gave [1,3]thiazolo[3,2-a]pyrimidin-5(1H)one and [1,3]thiazolo[3,2-a]pyrimidin-3,5- dione derivatives 8 and 10 respectively, treatment of 10 with aromatic aldehyde produces 11 which reacted with guanidine HCl to give pyrimido[4,5-d]thiazolo[3, 2-a]pyrimidin-6(1H)one derivative 12. Reaction of 14 with o-phenylenediamine was investigated and gave [1,4]quinoxalino[2,3-b][1,3]thiazolo[3,2-a]pyrimidin- 9(1H)one derivative 15.

Full text of DOI:10.1080/10426500801967963

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Phosphorus, Sulfur, and Silicon
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Pyrimidinthiones (Part I):
Utility of 2-Thioxopyrimidin-6-
(1H)ones as Ring Transformer
in the Synthesis of Fused Bi-
and Tri-Cyclic Heterocyclic
Compounds and Their Potential
Biological Activities
M. A. I. Salem a , H. M. F. Madkour a , M. I. Marzouk a
, M. E. Azab a & N. F. H. Mahmoud a
a Chemistry Department, Faculty of Science, Ain
Shams University, Abbassia, Cairo, Egypt
Version of record first published: 26 Sep 2008.
To cite this article: M. A. I. Salem, H. M. F. Madkour, M. I. Marzouk, M. E. Azab &
N. F. H. Mahmoud (2008): Pyrimidinthiones (Part I): Utility of 2-Thioxopyrimidin-6-
(1H)ones as Ring Transformer in the Synthesis of Fused Bi- and Tri-Cyclic Heterocyclic
Compounds and Their Potential Biological Activities, Phosphorus, Sulfur, and Silicon
and the Related Elements, 183:10, 2596-2614
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Phosphorus, Sulfur, and Silicon, 183:2596–2614, 2008
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500801967963
Pyrimidinthiones (Part I): Utility of
2-Thioxopyrimidin-6-(1H)ones as Ring Transformer in the
Synthesis of Fused Bi- and Tri-Cyclic Heterocyclic
Compounds and Their Potential Biological Activities
M. A. I. Salem, H. M. F. Madkour, M. I. Marzouk,
M. E. Azab, and N. F. H. Mahmoud
Chemistry Department, Faculty of Science, Ain Shams University,
Abbassia, Cairo, Egypt
The pyrimidinethiones have wide biological and pharmaceutical activities, that
have attracted considerable interest in recent years especially as antiviral inhibiting
production of hepatitis B virus (HBV), and in vitro insulin-mimetic. Activity of the
complexes of pyrimidinone derivatives evaluated from 50% inhibitory concentration
promoted us to study the transformation of the 2-thioxopyrimidin-6(1H) ones to
fused bi- and tri-cyclic heterocyclic compounds having the pyrimidine moieties and
screening their biological activity.
The reactivity of 2-mercapto-4-aryl-5-cyanopyrimidin-6(1H)ones (1) towards
alkylation by different mono and bifunctional halo-organic compounds has been
investigated to give S-monoalkylated products 2,7 and 9; S- and N-dialkylated
products 3,13 and 14. Treatment of 1 and/or 2 with hydrazine hydrate as a ni-
trogen nucleophile have been investigated to give 4, treatment of 4 with CS2 and
sodium nitrite in the presence of acetic acid (0◦C) produced 1,2,4-triazolopyrimidin-
5(1H)one derivatives (5)and tetrazolo[1,5-a]pyrimidin-5(1H)ones (6), respectively.
Also cyclization of 7 and 9 gave [1,3]thiazolo[3,2-a]pyrimidin-5(1H)one and
[1,3]thiazolo[3,2-a]pyrimidin-3,5-dione derivatives 8 and 10 respectively, treatment
of 10 with aromatic aldehyde produces 11 which reacted with guanidine HCl
to give pyrimido[4,5-d]thiazolo[3,2-a]pyrimidin-6(1H)one derivative 12. Reaction
of 14 with o-phenylenediamine was investigated and gave [1,4]quinoxalino[2,3-
b][1,3]thiazolo[3,2-a]pyrimidin-9(1H)one derivative 15.
Received 12 June 2007; accepted 18 January 2008.
The authors would like to express their appreciation and are grateful to both Prof.
Dr. Sief El-Din Ashour and his assistants in the Microbiology Department, Faculty of
Pharmacy, El-Azhar University for achievement of biological activities evaluation of some
newly synthesized compounds and Professor Dr. K. P. Zeller, Institute fur Organische
Chemie, Tubingen University, Germany for performing some 1H and 13C NMR and mass
spectra.
Address correspondence to M. A. I. Salem, Chemisty Department, Faculty of Science,
Ain Shams University, Abbassia, Cairo, Egypt. E-mail: maisalem1947@yahoo.com
2596

Pyrimidinthiones
2597
Keywords Biological activity; pyrimido[4,5-d]thiazolo[3,2-a]pyrimidinone; quinox-
alino [2,3-b]thiazolo[3,2-a]pyrimidinone; tetrazolo[1,5-a] pyrimidinone; thiazolo[3,2-
a]pyrimidinone
INTRODUCTION
Recently pyrimidinthiones1−7 have received much attention not only
due to their unique physical and chemical properties8,9 but also owing
to their wide biological activities and reported medicinal applications10
as anti-bacterial11,12 anti-tumor,8 anti-biotic,13 anti-microbial,14−16
anti-malarial5 agents and as anti-thyroids17with potential medicinal
interest.18 On the other hand many pyrimidinthiones have proper-
ties potentially useful in stock or crops rising; as insecticides19also
they are used in veterinary medicine.20 This, together with our in-
terest in the synthetic potential of fused hetero bi-and tri-cyclic
systems,21−27encouraged us to investigate the synthesis of some fused
cyanopyrimidinthiones of potential biological activity.
RESULTS AND DISCUSSION
Structurally pyrimidinone is closely related to pyridones, but the char-
acteristic properties of pyridone are considerably enhanced in pyrim-
idinone owing to the presence of two electron-withdrawing ring ni-
trogen. When a hydroxyl group or an amino group is present in
the pyrimidine moiety, the compound no longer behaves entirely as
aromatic derivative, thus 2-thioxo(oxo and/or imino)-4-aryl-5-cyano-
1,2,3,6-tetrahydropyrimidin-6-ones (1) exists in three major tautomeric
forms (A), (B) and (C); the keto form (B) is the predominant one.28 This
phenomenon is confirmed by spectral data29 in addition to our results
of alkylation by mono and bi-functional halo-organic compounds which
afforded S-monoalkylated products and/or S- and N-dialkylated prod-
ucts.
Reaction of 2-thioxo-4-aryl-5-cyano-1,2,3,6-tetrahydropyrimidin-6-
ones (1a,c) with alkylating agents such as methyl iodide, allyl bromide
and/or cyclohexyl bromide using 1:1 and 1:2 molar ratios in ethanolic
NaOH afforded S-alkylated and/or S- and N-dialkylated products 2 and
3 respectively.
A few displacement reactions of the mercapto group in com-
pounds (1a,c) were also investigated, thus treatment of compounds
(1a,c) and/or 2a,b with ammonium acetate by fusion and/or hy-
drazine hydrate (80%) in refluxing n-butanol yielded 2-imino-4-aryl-
5-cyano-1,2,3,6-tetrahydropyrimidin-6-ones (1e,g) and/or 2-hydrazino-
4-aryl-5-cyano-1,6-dihydropyrimidin-6-ones (4a,b) respectively, also

2598
M. A. I. Salem et al.
cyclization of compound
4
via reaction of 4a with CS2
in presence of ethanolic KOH (10%), and also reaction of
4a,b with NaNO2 in presence of acetic acid at 0◦C were
carried out to afford 3-mercapto-6-cyano-7-(3,4-methylenedioxy-
phenyl)[1,2,4]triazolo[3,4-a]pyrimidin-5(1H)-one (5) and 7-cyano-8-
(3,4-methylendioxylphenyl)tetrazolo[1,5-a]pyrimidin-6(5H)-one (6a,b)
respectively.
Alkylation of 1a with α-haloketones such as mono-bromoacetone8
depends upon the reaction conditions and the used base; if the re-
action is carried out in refluxing ethanol and piperidine, the ob-
tained products are 2-substituted thio-4-(3,4-methylenedioxyphenyl)-
5-cyanopyrimidin-6(1H)-ones (7), while if it done in DMF and
ethanolic NaOH (10%) it yielded 3-substituted 6-cyano-7-(3,4-
methylenedioxyphenyl)-[1,3]thiazolo[3,2-a]pyrimidine-5-ones (8), also
compounds (7) underwent cyclization by refluxing with a mixture of
acetic anhydride/pyridine (1:1) to afford (8).
The products of alkylation of (1a,c) with α-haloacid and/or
α-halo-ester such as mono-chloroacetic acid is dependent upon
the reaction conditions30; if the reaction is carried out in reflux-
ing ethanol/piperidine and/or dry acetone/anhydrous potassium
carbonate, the isolated products are 4-aryl-5-cyanopyrimidin-6(1H)-
one-2-thioglycollic acid derivatives (9a,b), while if it done in DMF
and ethanolic NaOH (10%), the products are identified as the bicyclic

Pyrimidinthiones
2599
system 6-cyano-7-aryl[1,3]thiazolo[3,2-a]pyrimidin-3,5-dione deriva-
tives (10a,b), which are obtained also on treatment of (9a,d) with
a refluxing mixture of glacial acetic acid-anhydrous AcONa. On the
other hand treatment of the title compounds (1a,c) with chloroacetyl
chloride9 as bi-functional halo-organic compound in DMF afforded the
same products 10a,b. The presence of an active methylene group in
10a was established by its condensation with p-chlorobenzaldehyde in
the presence of glacial acetic acid-anhydrous AcONa mixture9 to afford
2[(p-chlorophenyl)methylene]-6-cyano-7-(3,4-methylenedioxyphenyl)-
[1,3]thiazolo[3,2-a]pyrimidin-3,5-diones (11). Utilizing the aryli-
dene derivative 11 in hetero- tricycle system synthesis, was via
its reaction with guanidine HCl in n-butanol with a few drops
of piperidine to afford1-(p-chlorophenyl)-3-amino-7-cyano-8(3,4-
SCHEME 1

2600
M. A. I. Salem et al.
SCHEME 2
methylenedioxyphenyl)-pyrimidino [4,5-d][1,3] thiazolo[3,2-a]pyrimi-
din-6(1H)-one (12).
The synthesis of 2,2,3,3-tetrahydro-6-cyano-7-aryl-[1,3]thiazolo[3,2-
a] pyrimidin-5(1H)-ones (13a,b) was accomplished by reacting the title
compounds (1a,c) with 1,2-dibromoethane in DMF and ethanolic NaOH
(10%); also compounds (13a,b) were synthesized authentically in a one-
pot reaction by reacting (1a,c) with 2-chloroethanol8,31 with a mixture
of acetic anhydride/pyridine (1:1).
On the other hand, treatment of equimolar amounts of 1a with oxa-
lyl chloride in THF at room temperature in the presence of triethy-
lamine afforded 2,3-dihydro-6-cyano-7-(3,4-methylenedioxyphenyl)
[1,3]thiazolo[3,2-a] pyrimidin-2,3,5-trione derivative (14) which is
condensed with o-phenylene-diamine to produce 7-(3,4-methylenedi-
oxyphenyl)-[1,4]quinoxalino[2,3-b] [1,3] thiazolo[3,2-a]pyrimidin-9(1H)
-one (15) as hetero tricycle system.
The characterization of newly synthesized compounds 1–15 are
listed in Table I, while the spectroscopic data32 are listed in Tables
II and III. Also the biological activities of some products are listed in
Table IV.
EXPERIMENTAL
All melting points are uncorrected. The infrared absorption spectra
were measured on a Pye Unicam SP 2000 Infrared spectrophotometer
as KBr Wafer Technique. The G.C-mass spectra were determined on

2601

2602

2603

2604

2605

2606
M. A. I. Salem et al.
TABLE III 13C-NMR Data for the Newly Synthesized Compounds
Structure
13C-NMR
106.16 (C1), 138.9 (C2), 130.20 (C3) 132.1 (C4),
132.1 (C5), 130.2 (C6), 137.39 (C7), 156.4 (C8),
110.7 (C9), 117.6 (C10), 161.2 (C11) and 155.6
(C12
)
55.5 (C1), 56.0 (C2), 163.5 (C3) 131.1 (C4), 133.6
(C5), 133.6 (C6), 131.1 (C7), 159.8 (C8), 152.8
(C9), 112.2 (C10), 116.9 (C11) 161.2 (C12) and
155.6 (C13
)
105.92 (C1), 138.62 (C2), 129.6 (C3) 131.8 (C4),
131.8 (C5), 129.6 (C6), 137.4 (C7), 143.4 (C8),
111.6 (C9), 114.2 (C10), 160.1 (C11) and 123.1
(C12
)
55.1 (C1), 55.7 (C2), 163.3 (C3) 132.6 (C4), 133.8
(C5), 133.8 (C6), 142.8 (C7), 161.7 (C8), 142.8
(C9), 111.8 (C10), 116.2 (C11), 159.8 (C12) and
121.9 (C13
)
56.1 (C1), 54.9 (C2), 162.8 (C3) 131.8 (C4), 134.6
(C5), 134.6 (C6), 131.8 (C7), 161.7 (C8), 154.9
(C9), 112.2 (C10), 117.8 (C11), 158.7 (C12),
162.6 (C13) and 30.4 (C14
)
107.2 (C1), 138.2 (C2), 131.97 (C3), 131.5 (C4),
131.5 (C5), 131.97 (C6), 137.6 (C7), 153.5 (C8),
113.7 (C9), 118.2 (C10), 166.2 (C11), 64.8(C12
and 160.4 (C13
)
)

Pyrimidinthiones
2607
TABLE IV Biological Activity of the Newly Synthesized Compounds
Inhibition
Asperigillus
Candida
E-Coli
St. aur
A*
Compd no.
A*
MIC
A*
MIC
A*
MIC
MIC
1a
1c
1d
2a
2c
4b
5
6a
7
8
9a
10b
11
12
14
15
+
+
100
100
100
—
100
100
100
—
+
+
100
100
100
—
—
—
100
—
—
100
100
100
50
—
—
50
25
100
100
50
—
25
50
50
50
50
100
50
100
25
—
++
+ + +
+
—
50
25
100
100
40
—
25
50
50
50
50
100
—
100
25
++
+
+
+ + +
+
—
+
—
—
—
+
+
+
+
++
++
+
—
—
—
—
+
—
—
+
+ + +
++
++
++
++
+
++
++
++
++
++
+
—
100
100
100
50
100
—
+
+
+
+
++
+
++
—
—
++
—
—
50
+
—
—
++
+
+
50
+ + +
+ + +
The width of the zone of inhibition indicates the potency of antibacterial activity;
(−) no antibacterial activity; (+) mild activity with the diameter of the zones equal to
0.6−0.8 cm; (++) moderate activity with the diameter of the zones equal to 1.2-1.3 cm;
(+ + +) marked activity with the diameter of the zones equal to 1.8–1.2 cm. E. coli is
Gram-negative and St. aur is a gram-positive bacteria and Asperigllus flavus and
Candida albicans as fungi.38−40
AE1 MS.902 mass spectrometer, while the mass fragmentations were
scanned on Shimadzu MS-1000 Ex instruments. The 1H NMR spectra
were determined on a Varian Gemini 200 and 400 NMR spectropho-
tometer using DMSO-d6 and CDCl3 as solvents, (chemical shifts in δ,
ppm) and TMS as internal standard. Characterization data of the new
synthesized products are given in Table I.
Reaction of Arylidene Ethyl Cyanoacetate with Thiourea,
and/or Guanidine Hydrochloride; Formation of 1a-h
The appropriate arylidene ethyl cyanoacetate (2.7 g, 0.01 moles) was
condensed with thiourea (0,6 g, 0.01 moles), and/or guanidine hy-
drochloride (0.95 g, 0.01 moles) in the presence of sodium ethoxide
(0.23 g of sodium metal in 10 mL of absolute ethanol). The reaction
mixture was heated under reflux for 4 h, then cooled and poured onto
ice/HCl. The solid, which separated out, was filtered off, dried and

2608
M. A. I. Salem et al.
recrystallized yielding the products 1a–h. Some of the products were
previously prepared by other methodologies33−37 (Table I).
Reaction of 1a, c with Methyl Iodide, and/or 1a with Allyl
Bromide and Cyclohexyl Bromide; Formation of 2a–d
An equimolar mixture of 1a,c (2.7 g, 0.01 moles) and methyl iodide
(1.4 g, 0.01 moles) and/or 1a (2.7g, 0.01 moles) with allylbromide (1.2
g, 0.01 moles) & cyclohexyl bromide (1.6 g, 0.01 moles) in ethanolic
sodium hydroxide 10% (2.5 g NaOH in 25 mL EtOH 96%) was refluxed
for 1 h, the reaction mixture was cooled and neutralized by pouring
onto ice/HCl. The precipitated solid was collected by filtration, washed
with water, dried and crystallized affording 2a-d respectively (Table 1).
Reaction of 1a, c with Methyl Iodide and/or 1a with Allyl
Bromide and Cyclohexyl Bromide; Formation of 3a–d
A mixture of 1a, c (2.7 g, 0.01 moles) and organohalo compounds namely
methyl iodide (1.4 g, 0.02 moles), and/or 1a (2.7 g, 0.01 moles) with allyl
bromide (1.2 g, 0.02 moles) and cyclohexyl bromide (1.6 g,0.02 moles)
in alcoholic sodium hydroxide 20% (5 g of NaOH in 25 mL EtOH)
was heated under reflux for 2 h. The reaction mixture was left to cool,
acidified by cold HCl (2N) after pouring onto ice; the solid that separated
out was filtered by suction and recrystallized to give 3a–d respectively.
Action of Ammonium Acetate on 2a–d; Formation of 1e, g
The mixture of 2a-b (2.09 g, 0.01 moles) and ammonium acetate (2.31 g,
0.03 moles) was fused at a temperature of not more than 210◦C for 2 h,
cooled, washed well with water several times and collect the solid that
separated out by filtration, followed by recrystallisation to furnish the
products named 1e,g respectively.
Preparation of Authentic Sample
The fusion of pryimidine derivatives 1a,c (2.7 g,0.01 moles) with am-
monium acetate (0.03 mol, 2.31 g) at temperature not more than 200◦C
for 2 h afforded the authentic products 1e,g which were identified by
m.p., mixed m.p., I.R. comparison and TLC.

Pyrimidinthiones
2609
Reaction of 1a, c and/or 2a, b with Hydrazine Hydrate;
Formation of 4a, b
To a solution of 1a,c (2.7 g, 0.01 moles) and/or 2a,b (2.09 g, 0.01 moles)
in n-butanol (30 mL), hydrazine hydrate (80%) (0.02 mol; 1.0 mL) was
added and the reaction mixture was heated under reflux for 6 h, most of
the solvent was distilled off using a rotatory evaporator and left to cool.
The solid product that deposited was collected by filtration, washed
with water, dried and then recrystallized to give the monohydrazino
derivative 4a,b respectively.
Action of Carbon Disulphide on 4a; Formation of 5
A mixture of 4a (2.71 g, 0.01 moles, in 25 mL ethanol) and ethanolic
solution of potassium hydroxide (1 g/10 mL H2O and 25 mL ethanol)
was stirred at room temperature for 1 h, then carbon disulphide (2 mL)
was added drop wise with continuous stirring for additional 1 h. The
reaction mixture was heated under reflux on water bath for 6 h fol-
lowed by concentrating the resultant solution to its half volume using
a rotatory evaporator. The reaction mixture was left to cool at room
temperature then kept overnight in the refrigerator. The solid that
separated out was filtered off, dried, washed with L.P 60-80◦C several
times and then recrystallized to afford the desired product 5.
Action of Nitrous Acid (NaNO2/AcOH) on 4a, b; Formation of
6a, b Respectively
Hydrazino derivatives 4a,b (2.7 g, 0.01 moles) was dissolved in acetic
acid (30 mL) and the solution was cooled to 0◦C in an ice/salt bath
then an aqueous solution of sodium nitrite (0.8 g) in water (10 mL) was
added simultaneously with stirring, the reaction mixture was left at
0◦C with additional stirring for another 3 h. The reaction mixture was
kept overnight in a refrigerator, then poured onto ice/water. The solid
that collected by filtration was crystallized from the proper solvent to
afford 6a,b respectively.
Reaction of 1a with Bromoacetone; Formation of 7
When compound 1a (2.7 g , 0.01 moles) was allowed to react with mono-
bromoacetone (1.36 g, 0.01 moles) in cold ethanol (30 mL), a few drops
of piperidine (1 mL) was added during stirring for 30 min. at room
temperature, then the mixture was refluxed for 6 h. The volume of the
mixture was reduced to half, and then it was left to cool, poured onto

2610
M. A. I. Salem et al.
ice/HCl. The solid product that precipitated was filtered off, dried, and
then recrystallized to give the product 7.
Reaction of Pyrimidine 1a with Bromoacetone; Formation of 8
A solution of 1a (2.7 g, 0.01 moles) in dimethyl formamide (30 mL)
was immersed in ice, then bromoacetone (5.6 g, 0.01 moles) was added
drop wise with vigorously stirring during 30 min. ethanolic sodium
hydroxide 10% (2.5 g NaOH in 25 mL ethanol) also was added drop wise
with continuous stirring for additional 30 min. The reaction mixture
was heated under reflux for 3 h, most of the solvent was distilled off and
left to cool, poured onto ice/HCl and the solid product that separated
out was filtered off, dried and recrystallized to yield the products 8,
respectively.
Cyclization of 7: Formation of 8
A mixture of compound 7 (3.29 g, 0.01 moles) in 50 mL of acetic anhy-
dride –dry pyridine mixture (1:1) was heated under reflux for 6 h., then
the reaction mixture was cooled followed by dilution with ice/water. The
solid that obtained was filtered off, dried and recrystallized to afford
the cyclized product 8, respectively, which were identified by m.p., and
mixed m.p., IR comparison and TLC.
Reaction of 1a, c with Chloroacetic Acid; Formation of 9a, b
An equimolar mixture of 1a,c (2.7g, 0.01 moles) and chloroacetic acid
(0.95 mL, 0.01 moles) in ethanol (30 mL) and piperidine (1 mL) was
added, and then the reaction mixture was heated under reflux for 6 h.
The reaction mixture was concentrated to its half volume, left to cool
and pour onto ice/HCl. The solid that separated out was recovered by
filtration and recrystallized to yield the thioglycollic acid derivatives
9a,b, respectively.
Reaction of 1a, c with Chloroacetic Acid; Formation of 10a, b
An equimolar mixture of 1a,c (2.7 g, 0.01 moles) and mono-chloroacetic
acid (0.95 mL, 0.01 moles) in dimethyl formamide (30 mL) was stirred
at room temperature for 30 min. Ethanolic sodium hydroxide 10% (2.5
g NaOH in 25 mL ethanol) was added with good stirring for another 30
min., then the reaction mixture was heated under reflux for 6 h. The
volume of the mixture was reduced to half using a rotatory evaporator

Pyrimidinthiones
2611
followed by cooling; the reaction mixture was neutralized by pouring
onto ice/HCl. The solid that separated out was recovered by filtration
and recrystallized to yield the cyclic adducts 10a,b, respectively.
Authentic Proofs for the Formation of 10a, b
Cyclization of 9a, b; Formation of 10a, b
A mixture of 9a,b (3.3 g, 0.01 moles), glacial acetic acid (30 mL) and
anhydrous sodium acetate (freshly prepared; 2 g) was refluxed for 4
h., cooled and/then poured onto crushed-ice, to yield the solid products
10a,b, respectively.
Reaction of Pyrimidine 1a, c with Chloroacetyl Chloride;
Formation of 10a,b
The solution of 1a,c (2.7 g, 0.01 moles) in dimethylformamide (30
mL) was heated under reflux for 6 h with chloroacetyl chloride (1.13
mL, 0.01 moles). The reaction mixture was left to cool after evapor-
ization most of the solvent. The solid product that precipitated down
was filtered off, dried and recrystallized to afford the desired products
10a,b, respectively.
The desired products 10a,b either from method A or B were identified
by m.p., mixed m.p., IR comparison and TLC.
Reaction of 10a with p-Chlorobenzaldehyde; Formation of 11
A mixture of 10a (3.1 g, 0.01 moles), p-chlorobenzaldehyde (1.4 g,
0.01 moles) and anhydrous sodium acetate (2 g) in glacial acetic acid
(30 mL) was heated under reflux for 6 h, cooled, then poured onto
crushed ice. The resultant solid was filtered off, dried and recrystal-
lized to yield 11.
Reaction of 11 with Guanidine Hydrochloride; Formation of 12
A mixture of an equimolar amount of 11 and guanidine hydrochloride
in n-butanol (40 mL) with few drops of piperidine (0.5–1.0 mL) was
stirred at room temperature for 30 min. followed by heating under
reflux with continuous stirring for 6 h. The reaction mixture was con-
centrated to its half volume. The separated solid was filtered off, dried
and recrystallized to give 12 as the only product.

2612
M. A. I. Salem et al.
Reaction of 1a, c with 1,2–dibromoethane; Formation of 13a, b
A mixture of 1a,c (2.7 g, 0.01 moles) and 1,2-dibromoethane (0.01 mol)
and ethanolic NaOH 10% (2.5 g NaOH in 25 mL ethanol) in dimethyl
formamide (40 mL) was heated under reflux for 4 h. The reaction mix-
ture was concentrated to its half volume, then left to cool, poured onto
ice/HCl to acidify the solution. The solid that separated out was fil-
tered off, washed, dried and recrystalized to yield the products 13a, b,
respectively.
Synthesis of 13a, b Authentically
In one-pot reaction a mixture of 1a,c (2.7 g, 0.01 moles) and 2-
chloroethanol (0.8 g, 0.01 moles) in dry pyridine (20 mL) was stirred for
1 h at room temperature, then 40 mL of dry pyridine/acetic anhydride
mixture (1:1) was added, stirring was continued for another 1 h at room
temperature. The reaction mixture was refluxed for 6 h, concentrated
to its half volume, cooled and neutralized by conc HCl then poured onto
crushed ice. The solid products obtained were identified to be 13a, b
respectively by m.p., mixed m.p., IR comparison and TLC.
Reaction of 1a with Oxalyl Chloride; Formation of 14
A solution of 1a (2.73 g, 0.01 moles) in least amount of dry tetrahy-
drofuran (15 mL) and triethyl amine (1-2 mL) was stirred at room
temperature for 10 min. then the solution of oxalyl chloride (1.27 g,
0.01 moles) in dry tetrahydrofuran (15 mL) was cooled by immersing
in ice for 10 min. then it was added drop wise during 30 min. with stir-
ring. The mixture was stirred for additional 4 h and then left overnight.
The solid product that precipitated down was collected by filtration and
recrystallized to afford 14.
Reaction of 14 with o-Phenylenediamine; Formation of 15
A mixture of 14 (3.2 g, 0.01 moles), o-phenylene diamine (1.1 g, 0.01
moles) and anhydrous ZnCl2 (3 g) was mixed well then fused at 140–
150◦C for 2 h. The desired product 15 was obtained after pouring the
reaction mixture over hot water, washing with water several times
during the filtration process and recrystallization.

Pyrimidinthiones
2613
CONCLUSION
Bi- and tri-acyclic heterocyclic compounds having the pyrimidine moi-
eties are an important class of compounds in medicinal chemistry.
From Table III it can be seen that compounds 1d, 6a, and 15 were the
most effective against both gram-negative and gram-positive bacterial
strains whereas some other compounds have moderate effect on the
tested bacteria, while compounds 11b and 15 were the most effective
against the test fungi. We can conclude that compounds 1d, 6a, 15 can
be used as antibacterial agents both gram-negative and gram-positive
bacteria, while compounds 11b, and 15 can be used as moderate anti-
fungal agents against Asperigillus flavus and Candida albicans.
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