Selective cyclization of S-substituted pyrimidinethione: Synthesis and antimicrobial evaluation of novel polysubstituted thiazolopyrimidine and thiazolodipyrimidine derivatives

Article abstract of DOI:10.1002/jccs.201900199

The synthetic strategy is based on alkylation of 4-aryl-N-(4-chlorophenyl)-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide derivatives IV a–g, with some alkyl halides and α-haloketones, namely, methyl iodide, chloroacetonitrile, and phenacyl bromide to give the corresponding S-substituted derivatives Va–c. Treatment of IVa–c with ethyl bromoacetate in ethanol under reflux in the presence of potassium hydroxide solution led to the formation of N-(4-chlorophenyl)-7-methyl-3-oxo-5-(aryl)-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidine-6-carboxamide derivative VIII a–c in a single-step synthesis. On the other hand, compound IVa reacted with α-halo carbonitriles, namely, chloro acetonitrile, and monobromo malononitrile, to produce directly thiazolo[3,2-a]pyrimidine derivatives Xa and Xb, respectively, Compound Xb also reacted with each of formic acid, formamide, and ammonium thiocyanate to form thiazolodipyrimidine derivatives XI–XIII, respectively. Compound VIIIa–c coupled with arenediazonium salts in pyridine to give the corresponding 2-arylhydrazo derivatives XVIa–e. Compounds IV a–g and VIIIa–c were resynthesized under microwave irradiation. Some of the newly synthesized compounds were tested for their antimicrobial activities.

Full text of DOI:10.1002/jccs.201900199

Received: 19 May 2019
Revised: 17 October 2019
Accepted: 19 October 2019
DOI: 10.1002/jccs.201900199
A R T I C L E
Selective cyclization of S-substituted pyrimidinethione:
Synthesis and antimicrobial evaluation of novel
polysubstituted thiazolopyrimidine and
thiazolodipyrimidine derivatives
Hayat E. Alzahrani1 | Ahmed M. Fouda1 | Ayman M. S. Youssef1,2
1Department of Chemistry, College of
Abstract
Science, King Khalid University, Abha,
Saudi Arabia
The synthetic strategy is based on alkylation of 4-aryl-N-(4-chlorophenyl)-
6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide derivatives IV
a–g, with some alkyl halides and α-haloketones, namely, methyl iodide, chlo-
roacetonitrile, and phenacyl bromide to give the corresponding S-substituted
derivatives Va–c. Treatment of IVa–c with ethyl bromoacetate in ethanol
under reflux in the presence of potassium hydroxide solution led to the forma-
tion of N-(4-chlorophenyl)-7-methyl-3-oxo-5-(aryl)-2,3-dihydro-5H-thiazolo
[3,2-a]pyrimidine-6-carboxamide derivative VIII a–c in a single-step synthesis.
On the other hand, compound IVa reacted with α-halo carbonitriles, namely,
chloro acetonitrile, and monobromo malononitrile, to produce directly
thiazolo[3,2-a]pyrimidine derivatives Xa and Xb, respectively, Compound Xb
also reacted with each of formic acid, formamide, and ammonium thiocyanate
to form thiazolodipyrimidine derivatives XI–XIII, respectively. Compound
VIIIa–c coupled with arenediazonium salts in pyridine to give the
corresponding 2-arylhydrazo derivatives XVIa–e. Compounds IV a–g and
VIIIa–c were resynthesized under microwave irradiation. Some of the newly
synthesized compounds were tested for their antimicrobial activities.
2Chemistry Department, Faculty of
Science, Fayoum University, Fayoum,
Egypt
Correspondence
Ayman M. S. Youssef, Department of
Chemistry, College of Science, King
Khalid University, Abha, Saudi Arabia.
Email: amsyoussef@yahoo.co.uk,
aymsalah@kku.edu.sa
K E Y W O R D S
alkylation, cyclization, multicomponent, pyrimidinethione, thiazolodipyrimidine
1 | INTRODUCTION
Meanwhile, pyrimidopurines are famous for their use as
inhibitors of spontaneous locomotor activity.[5] Some
Fused heterocyclic pyrimidine derivatives have received
considerable attention over the past years due to their
therapeutic and pharmacological properties. Many fused
triazolopyrimidines and tetrazolopyrimidines are well
known for their antibacterial and antifungal activities.[1–3]
The biological importance of pyrimido [4,5-d] pyrimi-
dines includes their use as fungicides and antioxidants.[4]
series of thiazolo[3,2-a]pyrimidine derivatives have been
prepared and investigated for their anti-inflammatory[6]
and anticancer activities.[7] On the other hand,
functionalized 2-thioxopyrimidines are of considerable
importance to chemists as excellent precursors for the
synthesis of fused pyrimidines. They have been exten-
sively utilized to prepare different fused heterocycles,
© 2019 The Chemical Society Located in Taipei & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
J Chin Chem Soc. 2019;1–18.
http://www.jccs.wiley-vch.de
1

2
ALZAHRANI ET AL.
including thiazolo-,[8] triazolo-, pyrazolo-,[9] pyri-
dothiazolo-,[10] and imidazothiazolo-pyrimidines.[11,12]
Condensed pyrimidine derivatives have also been
reported as antimicrobial and hypnotic drugs for the ner-
vous system,[13] with activities including anti-
inflammatory,[14] anti-HIV,[15] antiparasitic,[16] and anti-
tumor and have been used as calcium-sensing receptor
antagonists,[17] antiulceratives,[18] and antimalarial
agents. They are also used as cardiovascular agents[19]
and diuretic drugs.[20]
Alkylation of compound IVa with some alkyl halides
and α-haloketones, namely, methyl iodide, chlo-
roacetonitrile, and phenacyl bromide in refluxing aque-
ous ethanolic potassium carbonate solution gave the
corresponding S-substituted derivatives Va–c, respec-
tively (Scheme 2).
The alkylation awarded at S-atom not the N-
substituted analogue VI. The formation of the S-
substituted derivatives Va–c could be proved via the evo-
lution of methanethiol when Va was treated with hydra-
zine hydrate, forming the sulfur-free hydrazino derivative
VII (Scheme 2). Compounds Va–c and VII gave the
expected values in elemental analysis and spectral data
(Tables 1 and 2).
2 | RESULTS AND DISCUSSION
2.1 | Chemistry
Heating IVa–c,e derivatives with each of ethyl
bromoacetate and chloroacetone under reflux in potas-
sium hydroxide solution led to the formation of VIIIa–c,
respectively, rather than their isomeric structures IXa–d
(Scheme 3).
Prompted by the diverse biological activities associated
with fused heterocyclic annulated pyrimidines, this
work has been dedicated for the synthesis of some S-
substituted and N,S-disubstituted pyrimidine derivatives
as precursors for di- and tricyclic fused pyrimidine
derivatives. Thus, treatment of 4-chloroacetoacetanilide
(I), the appropriate aromatic aldehydes IIa–g and thio-
urea in refluxing ethanol containing catalytic amount of
concentrated hydrochloric acid, Biginelli type re-
Preferring structure VIII over IX was based on the
1
comparison of the H-NMR spectral data for compounds
1
IV and VIII. Thus, the H-NMR spectrum of VIIIb, for
example, revealed, in addition to the methyl group, aro-
matic, and NH proton signals, a singlet (1H) at δ 6.01
assigned to the pyrimidine H-5. The downfield for the
pyrimidine H-5 in VIIIb compared with the pyrimidine
H-4 in IVb, which appeared at δ = 5.36 ppm, indicates
that the moiety nearby H-5 in VIIIb differs from that of
H-4 in IVb. Therefore, structure VIII could be initially
assigned for the reaction products. On the other hand,
actions,[21] afforded (IV a–g) in
a
good yield
(Scheme 1).[22] The progress of reaction was monitored
by TLC. The structures of compounds IV a–g were
established on the basis of analytical and spectral data
(Tables 1 and 2).
1
Compounds IV a–g were resynthesized under micro-
wave irradiation conditions aiming to increase reaction
yields and reduce the reaction times.[23,24] A comparison
between MW and thermal reaction techniques is given in
Table 3. From Table 3, we find that the use of MW tech-
nique improves the yield of the products by 17–23% com-
pared with the conventional methods, and also the
reaction times were considerably reduced.
the H-NMR spectra for methyl group at C-7 in com-
pound VIIIb was not affected; had it been structure IXb,
1
the H-NMR spectra for methyl group at C-5 in com-
pound IX would show a change in the signal position.
Actually, the position of the CH3 group was not affected,
which indicates that the two CH3 groups are not close to
each other, which proves the structure of VIIIb for the
reaction product rather than IXb.
SCHEME 1 Preparation of
compounds IV a-g

ALZAHRANI ET AL.
3
TABLE 1 Characterization data of compounds IVa–g, Va–c, VIIIa–d, XIVa–e, and XVIa–e
Analysis
Calcd.
% C
Found
% C
% H
% N
% Cl
% S
% H
% N
% Cl
% S
Compound
IVa
MF (M.Wt.)
Yield %
MP (ꢀC) (solvent)
Color
C18H15Cl2N3OS
(392.30)
63
272–274 (ethanol)
White powder
55.11
3.85
55.01
3.94
10.71
18.07
8.17
10.43
17.83
8.02
IVb
IVc
IVd
IVe
IVf
C18H15BrClN3OS (436.75)
C16H14ClN3OS2 (363.88)
C18H15ClN4O3S (402.85)
C19H18ClN3O2S (387.88)
C18H16ClN3O2S (373.86)
35
48
55
62
34
258–261 (ethanol)
238–240 (ethanol)
248–250 (ethanol)
241–243 (ethanol)
140–142 (ethanol)
White powder
49.50
3.46
9.62
8.11
7.34
49.26
3.27
9.41
8.01
7.11
Beige
Powder
52.81
3.88
11.55
9.74
52.66
3.71
11.42
9.55
17.62
17.38
Yellow powder
Pale yellow powder
White powder
53.67
3.75
13.91
8.79
53.43
3.62
13.74
8.61
5.72
5.55
58.83
4.68
10.83
9.13
58.71
4.56
10.72
8.67
8.26
7.88
57.83
4.31
57.34
4.10
11.24
9.48
10.86
9.21
8.57
8.24
IVg
Va
C19H16ClN3O3S (401.87)
C19H17Cl2N3OS (406.33)
24
97
253–254 (ethanol)
196–198 (ethanol)
White powder
56.79
4.01
10.46
56.63
3.85
10.29
Pale yellow powder
56.16
4.22
55.99
4.08
10.34
17.44
7.89
10.15
17.14
7.47
Vb
C20H16Cl2N4OS (431.34)
65.3
214–216 (ethanol)
Pale brown powder
55.69
3.74
55.62
3.66
12.99
16.43
7.43
12.90
15.86
7.15
(Continues)

4
ALZAHRANI ET AL.
TABLE 1 (Continued)
Analysis
Calcd.
% C
Found
% C
% H
% N
% Cl
% S
% H
% N
% Cl
% S
Compound
Vc
MF (M.Wt.)
Yield %
MP (ꢀC) (solvent)
Color
C26H21Cl2N3O2S (510.43)
C18H17Cl2N5OS (390.27)
C20H15Cl2N3O2S (432.32)
C20H15BrClN3O2S (476.77)
C18H14ClN3O2S2 (403.90)
C20H16Cl2N4OS (431.34)
C21H15Cl2N5OS (456.35)
C22H15Cl2N5O2S (484.36)
C22H16Cl2N6OS (483.37)
62.8
226–230 (ethanol)
Brown powder
61.18
4.15
61.12
4.03
8.23
13.89
6.28
8.14
13.57
6.11
VII
60.1
45
221–225
(DMF)
Yellow crystals
Yellow powder
55.40
4.39
17.95
18.16
8.21
55.11
4.06
17.57
17.79
7.86
VIIIa
VIIIb*
VIIIc
Xa
223–224 (acetic acid)
218–220 (acetic acid)
>300 (acetic acid)
55.57
3.50
9.72
16.39
7.41
55.41
3.39
9.58
15.89
7.13
43
Pale brown
Powder
50.38
3.17
8.81
7.43
6.72
50.20
2.87
8.45
7.13
6.23
52
Orange powder
53.53
3.49
10.40
8.77
53.49
3.38
10.21
8.35
15.87
15.48
73.4
78.5
63.36
50.1
263–265
(ethanol)
Brown powder
55.69
3.74
12.99
16.43
7.43
55.52
3.52
12.83
16.12
7.32
Xb
223–225
(ethanol)
Pale yellow powder
Pale yellow powder
Pale brown powder
55.27
3.31
15.35
15.53
7.02
55.08
3.15
15.21
15.34
6.65
XI
197–200
(ethanol)
54.56
3.12
14.46
14.63
6.61
54.46
2.93
14.28
14.41
6.33
XII
241–243
(ethanol)
54.67
3.34
54.52
3.13
17.39
14.66
6.63
16.89
14.26
6.41
(Continues)

ALZAHRANI ET AL.
5
TABLE 1 (Continued)
Analysis
Calcd.
% C
Found
% C
% H
% N
% Cl
% S
% H
% N
% Cl
% S
Compound
XIII
MF (M.Wt.)
Yield %
MP (ꢀC) (solvent)
Color
C23H17Cl2N7OS3 (574.52)
C27H18Cl3N3O2S (554.87)
C28H21Cl2N3O2S (534.46)
C27H18BrCl2N3O2S (599.32)
C28H21BrClN3O2S (578.91)
C25H17Cl2N3O2S2 (526.45)
C20H17Cl2N3O3S (450.33)
C26H18Cl3N5O2S (570.87)
57.3
210–212
(Dioxane)
Deep brown powder
48.08
2.98
47.38
2.53
17.07
12.34
16.74
16.67
12.13
16.35
XIVa
XIVb
XIVc*
XIVd*
XIVe
XV
70.95
73.66
80.18
62.18
55.46
67.8
268–270 (acetic acid)
279–280 (acetic acid)
276–278 (acetic acid)
273–275 (acetic acid)
225–226 (acetic acid)
Yellow powder
Yellow powder
Yellow powder
Yellow powder
Yellow powder
White crystals
Orange powder
58.45
3.27
7.57
19.16
5.77
58.40
3.11
7.33
18.84
5.46
62.93
3.96
7.86
13.26
5.99
62.82
3.82
7.77
12.97
5.72
54.11
3.03
7.01
11.83
5.34
53.85
2.87
6.68
11.65
5.16
58.09
3.66
7.26
6.12
5.53
58.02
3.58
7.15
5.78
5.31
57.04
3.26
7.98
13.46
12.17
56.86
3.13
7.69
13.25
11.88
271–272
(acetic acid)
53.34
3.81
9.33
15.74
7.11
53.17
3.64
9.07
15.46
7.03
XVIa
88.60
243245 –(acetic acid)
54.70
3.18
54.46
2.96
12.27
18.62
5.61
12.02
18.42
5.38
(Continues)

6
ALZAHRANI ET AL.
TABLE 1 (Continued)
Analysis
Calcd.
% C
Found
% C
% H
% N
% Cl
% S
% H
% N
% Cl
% S
Compound
XVIb
MF (M.Wt.)
Yield %
MP (ꢀC) (solvent)
Color
C27H21Cl2N5O2S (550.46)
C26H18BrCl2N5O2S (615.33)
C27H21BrClN5O2S (594.91)
C24H17Cl2N5O2S2 (542.45)
71.26
185–188 (acetic acid)
Bright orange powder
58.91
3.85
12.72
12.88
5.82
58.82
3.75
12.61
12.67
5.53
XVIc*
XVId*
XVIe
60.42
68.70
65.06
184–186 (acetic acid)
194–195 (acetic acid)
182–186 (acetic acid)
Orange powder
Orange powder
Brown powder
50.75
2.95
11.38
11.52
5.21
50.53
2.77
11.22
11.28
5.10
54.51
3.56
11.77
5.95
54.27
3.31
11.57
5.81
5.38
5.16
53.14
3.16
52.97
3.02
12.91
13.07
11.82
12.74
12.79
11.58
* IVb: Calc; Br, 18.29; found; 18.06.
* VIIIb: Calc; Br, 16.75; found; 16.48.
* XIVc: Calc; Br, 13.33; found; 13.10.
* XIVd: Calc; Br, 13.80; found; 13.56.
* XVIc: Calc; Br, 12.98; found; 12.59.
* XVId: Calc; Br, 13.43; found; 13.11.
Another conclusive evidence for structure VIII has
been made, by carrying out earlier studies, which rev-
ealed that B3LYP is one of the best functionals that
reproduce the experimental geometries among various
standard DFT functionals.[25] Formerly, a number of
functional properties were studied by B3LYP functional
(ICT). The ICT from HOMOs to LUMOs has been
observed in both compounds.
Compounds VIIIa–c could be resynthesized using
microwave-assisted reaction conditions. Comparing
compounds produced by the traditional methods with
those prepared by the microwave-assisted conditions
indicates that the reaction time is reduced to 10 min
instead of overnight standing in the latter. Also the reac-
tion yields were improved from 40–53% to 68–85%
(Table 3).
On the other hand, Compound IVa reacted with
α-halo carbonitriles, namely chloro acetonitrile and
monobromo malononitrile, in refluxing ethanol con-
taining potassium hydroxide solution to produce directly
3-amino-N,5-bis(4-chlorophenyl)-7-methyl -5H-thiazolo
[3,2-a]pyrimidine-6-carboxamide (Xa) and 3-amino-
N,5-bis(4-chlorophenyl)-2-cyano-7-methyl-5H-thiazolo
[3,2-a] pyrimidine-6-carboxamide (Xb), respectively
(Scheme 4).
[26–28]
and 6-31G** basis set.[29–33] In the current study,
the ground-state (S0) geometries of two representative
compounds were optimized at DFT/B3LYP/6-31G**
level. The stability calculations of representative com-
pounds VIIIa and IXa were performed at B3LYP/6-31G*
level of theory. The total energy for Compound VIIIa
was HF = -2,404.431331, while for Compound IXa,
HF = -2,404.4191378. It was found that Compound VIIIa
is 31.7 kJ/mol more stable than Compound IXa. Also,
the charge density distribution of highest occupied
molecular orbitals (HOMOs) and lowest unoccupied
molecular orbitals (LUMOs) has been illustrated in
Figure 1 to understand the intermolecular charge transfer

ALZAHRANI ET AL.
7
TABLE 2 Spectral data for compounds IVa-g, Va-c, VIIIa-c, XIVa–e, and XVIa–e
Compound
IR (KBr) cm−1
1H NMR (δ Valeus)
13C NMR (δ Valeus)
IVa
3,300–3,200 (NH),
2,981 (C-H, aliph.),
1,676 (C=O), 1,632
(C=C), 1,241 (C=S)
2.06 (s, 3H, CH3), 5.37 (s, 1H, CH), 7.25–7.27 (d,
2H, Ar-H, J = 8.5 Hz), 7.31–7.33 (d, 2H, Ar-H,
J = 8.9 Hz), 7.43–7.44 (d, 2H, Ar-H, J = 8.5 Hz),
7.56–7.58 (d, 2H, Ar-H, J = 9 Hz), 9.49 (s, 1H,
NH, D2O exchangeable), 9.87 (s, 1H, NH, D2O
exchangeable), 10.08 (s, 1H,NH amide, D2O
exchangeable)
16.59 (CH3), 54.43 (CH), 106.54,
121.25, 127.04, 128.31, 128.55,
128.70, 132.41, 136.38, 137.87,
141.92 (Ar–C), 164.95 (C=O),
174.23 (C=S)
IVb
IVc
3,300–3,180 (NH),
3,006 (C-H, aliph.),
1,679 (C=O), 1,636
(C=C), 1,268 (C=S)
2.06 (s, 3H, CH3), 5.36 (s, 1H, CH), 7.18–7.19 (d,
2H, Ar-H, J = 8.5 Hz), 7.31–7.33 (d, 2H, Ar-H,
J = 8.5 Hz), 7.56–7.57 (m, 4H, Ar-H), 9.49 (s,
1H, NH, D2O exchangeable), 9.87 (s, 1H, NH,
D2O exchangeable), 10.08 (s, 1H, NH, D2O
exchangeable)
16.58 (CH3), 54.49 (CH), 106.48,
120.95, 121.25, 127.04, 128.54,
128.63, 131.61, 136.35, 137.84142.30
(Ar–C), 164.94 (C=O), 174.22 (C=S)
3,265–3,180 (NH),
2,989 (C-H aliph.),
1,676 (C=O), 1,636,
1,591, 1,575 (C=C),
1,205 (C=S)
2.10 (s, 3H, CH3), 5.65 (s, 1H, CH), 6.93–6.97 (d,
1H, Ar-H, J = 3.4 Hz), 6.96–6.98 (dd, 1H, Ar-H,
J = 3.57, 1.44 Hz), 7.33–7.32 (d, 2H, Ar-H,
J = 8 Hz), 7.42–7.43 (dd, 1H, Ar-H, J = 6.8,
1.7 Hz), 7.60 (d, 2H, Ar-H, J = 8.5 Hz), 9.64 (s,
1H, NH, D2O exchangeable), 9.85 (s, 1H, NH,
D2O exchangeable), 10.167 (s, 1H, NH amide,
D2O exchangeable)
16.64 (CH3), 50.33 (CH), 106.81,
121.31, 124.34, 125.73, 126.84,
126.95, 128.49, 137.22, 137.96,
146.91 (Ar–C), 164.65 (C=O),
174.29 (C=S)
IVd
IVe
IVf
3,300–3,200 (NH str.), 2.09 (s, 3H, CH3), 5.49 (s, 1H, CH), 7.31–7.32 (d,
16.70 (CH3), 54.57 (CH), 105.94,
121.32, 124.07, 127.14, 127.74,
128.56, 137.04, 137.78, 147.04,
149.98 (Ar–C), 164.79 (C=O),
174.54 (C=S)
2,900 (C-H
2H, Ar-H, J = 8.5 Hz), 7.50–7.52 (d, 2H, Ar-H,
J = 8.5 Hz), 7.56–7.57(d, 2H, Ar-H, J = 8.5 Hz),
8.24–8.25 (d, 2H, Ar-H, J = 8.5 Hz), 9.60 (s, 1H,
NH, D2O exchangeable), 9.93 (s, 1H, NH, D2O
exchangeable), 10.20 (s, 1H, NH amide, D2O
exchangeable)
aliphatic), 1,682
(C=O), 1,629 (C=C),
1,209 (C=S)
3,260–3,100 (NH str.), 2.07 (s, 3H, CH3), 3.33 (s, 3H, OCH3), 5.34 (s, 1H, 18.3 (CH3), 53.7 (OCH3), 56.70 (CH),
3,000 (C-H aliph.),
1,676 (C=O), 1,634
(C=C), 1,245 (C=S)
CH), 6.88–6.89 (d, 2H, Ar-H, J = 8.7 Hz),
7.15–7.17 (d, 2H, Ar-H, J = 8.7 Hz), 7.29 (d, 2H,
Ar-H, J = 9 Hz), 7.57–7.58 (d, 2H, Ar-H,
J = 9 Hz), 9.39 (s, 1H, NH, D2O exchangeable),
9.78 (s, 1H, NH, D2O exchangeable), 9.95 (s, 1H,
NH, D2O exchangeable)
106.54, 116.4, 121.34, 125.13, 128.14,
129.96, 134.50, 136.04, 156.44
(Ar–C), 163.78 (C=O), 174.52 (C=S)
3,300–3,188 (NH and
OH), 1,663 (C=O),
1,617 (C=C), 1,261
(C=S)
2.05 (s, 3H, CH3), 5.29 (s, 1H, CH), 6.70–6.72 (d,
2H, Ar-H, J = 8.5 Hz), 7.04–7.06 (d, 2H, Ar-H,
J = 8.5 Hz), 7.32–7.33 (d, 2H, Ar-H, J = 8.5 Hz),
7.57–7.58 (d, 2H, Ar-H, J = 8.5 Hz), 9.36 (s, 1H,
NH, D2O exchangeable), 9.44 (s, 1H, OH, D2O
exchangeable), 9.79 (s, 1H, NH, D2O
16.49 (CH3), 54.62 (CH), 107.24,
115.25, 121.16, 126.86, 127.75,
128.48, 133.55, 135.59, 137.97, 157.0
(Ar–C), 165.15 (C=O), 173.69 (C=S)
exchangeable), 9.93 (s, 1H, -NH, D2O
exchangeable)
IVg
3,430–3,320 (NH),
1,673 (C=O), 1,619
(C=C), 1,250 (C=S),
1,135 (CO)
2.08 (s, 3H, CH3), 5.322 (d, 1H, CH, J = 3 Hz),
5.99 (s, 2H, CH2), 6.72–6.73 (dd, 1H, Ar-H,
J = 8, 1.5 Hz), 6.78–6.79 (d, 1H, Ar-H,
J = 1.5 Hz), 6.87–6.89 (d, 1H, Ar-H, J = 8 Hz),
7.31–7.32 (d, 2H, Ar-H, J = 9 Hz) 7.58–7.60 (d,
2H, Ar-H, J = 9 Hz), 9.41 (s, 1H, NH), 9.81 (s,
1H, NH), 10 (s, 1H, NH amide).
16.93 ppm (CH3), 55.13 (CH), 101.49,
107.22, 107.33, 108.59, 120.22,
121.58, 127.34, 128.87, 136.45,
137.38, 138.32, 147.21, 147.88
(Ar–C), 165.41 (C=O) and 174.34
(C=S).
Va*
3,500–3,350 (NH),
2.18 (s, 3H, CH3), 2.73 (s, 3H, S-CH3), 5.85 (s, 1H, 13.98 (CH3), 16.53 (CH3), 55.11 (CH),
2,849 (C-H aliph.),
CH), 7.32–7.48 (m, 6H, Ar-H), 7.61–7.63 (d, 2H,
Ar-H, J = 9 Hz), 10.47 (s, 1H, NH, D2O
121.47, 127.63, 128.67, 128.92,
(Continues)

8
ALZAHRANI ET AL.
TABLE 2 (Continued)
Compound
IR (KBr) cm−1
1H NMR (δ Valeus)
13C NMR (δ Valeus)
1,685 (C=O), 1,595
(C=N)
exchangeable), 11.93 (s, 1H, NH, D2O
exchangeable)
129.06, 133.46, 137.33 (Ar–C),
163.60 (C=O)
Vb
3,420–3,340 (NH),
2,849 (C-H aliph.),
2,220 (CN), 1,680
2.03 (s, 3H, CH3), 4.11 (s, 2H, S-CH2), 5.38 (s, 1H, 17.12 (CH2), 22.86 (CH3), 54.46 (CH),
CH), 7.27–7.57 (m, 8H, Ar-H), 8.81 (s, 1H, NH,
114.55, 121.15, 126.75, 128.19,
128.46, 128.51, 128.60, 131.94,
138.10, 139.31, 143.18, 152.30
(Ar–C), 165 (C=O)
D2O exchangeable), 9.70
(C=O), 1,595 (C=N) (s, 1H, NH, D2O exchangeable)
Vc
3,396, 3,250 (NH),
1,675 (C=O), 1,632
(C=N)
2.07 (s, 3H, CH3), 4.10 (s, 2H,S-CH2), 5.41 (s, 1H, 19.22 (CH3), 32.85 (CH2), 49.48 (CH),
CH), 7.15 (s, 1H, NH, D2O exchangeable),
7.24–7.52 (m, 6H, Ar-H), 7.84–8.10 (m, 7 H,
Ar-H), 9.84 (s, 1H, NH, D2O exchangeable)
121.15, 125.33, 126.75, 128.11,
129.46, 132.95, 136.10, 139.73,
152.30 (Ar–C), 164.50 (C=O),
166.21 (CS), 192.10 (C=O)
VII
3,048–2,997 (NH),
2,943 (C-H aliph.),
1,625 (C=O), 1,593
(C=N).
2.07 (s, 3H,CH3), 5.38 (s, 1H, CH), 7.25–7.58 (m,
8H, Ar-H), 8.72 (s, 2H, NH2, D2O
exchangeable), 9.50 (s, 1H, NH, D2O
exchangeable), 9.87 (s, 1H, NH, D2O
exchangeable), 10.09 (s, 1H, NH, D2O
exchangeable)
16.57 (CH3), 54.39 (CH), 106.51,
121.21, 126.99, 128.27, 128.67,
129.12, 130.05, 132.35,
132.61,136.06, 136.36, 137.85, 141.89
(Ar–C), 164.91 (C=O)
VIIIa
3,310 (NH), 1,730,
1,645 (2C=O), 1,586
(C=N)
2.06 (s, 3H, CH3), 4.10 (s, 2H, CH2), 6.02 (s, 1H,
CH), 7.24–7.25 (d, 2H, Ar-H, J = 8.5 Hz),
7.33–7.34 (d, 2H, Ar-H, J = 8.5 Hz), 7.41 7.42 (d,
2H, Ar-H, J = 8.5 Hz), 7.55–7.56 (d, 2H, Ar-H,
J = 8.5 Hz), 10.07 (s, 1H, -NH, D2O
exchangeable)
21.24 (CH3), 31.96 (CH2), 55.15 (CH),
112.83, 121.25, 127.31, 128.59,
128.81, 128.87, 133.03, 137.53,
138.60, 141.19 (Ar–C), 157.61
(C=N), 165.09, 171.06 (2C=O)
VIIIb*
VIIIc
Xa
3,448 (NH), 1,732,
1,646 (2C=O), 1,585
(C=N)
2.06 (s, 3H, CH3), 4.10 (s, 2H, CH2), 6.01 (s, 1H,
CH), 7.17–7.18 (d, 2H, Ar-H, J = 8.5 Hz),
7.33–7.34 (d, 2H, Ar-H, J = 8.5 Hz), 7.54–7.56
(m, 4H, Ar-H), 10.07 (s, 1H, -NH, D2O
exchangeable)
21.24 (CH3), 31.96 (CH2), 55.23 (CH),
112.77, 121.25, 121.67, 127.31,
128.59, 129.16, 131.74, 137.53,
139.01, 141.20 (Ar–C), 157.62
(C=N), 165.08, 171.05 (2C=O)
3,287 (NH), 1,733,
1,646 (2C=O), 1,585
(C=N)
2.12 (s, 3H, CH3), 2.17 (s, 2H, CH2), 6.41 (s, 1H,
CH), 7.01–7.70 (m, 7H, Ar-H), 10.40 (s, 1H, NH,
D2O exchangeable)
21.11 (CH3), 32.06 (CH2), 55.20 (CH),
112.86, 121.27, 127.33, 128.59,
128.81, 128.93, 133.07, 137.53,
138.52, 140.89 (Ar–C), 157.9 (C=N),
165, 171 (2C=O)
3,404 (NH),
2.06 (s, 3H, CH3), 5.49 (s, 1H,CH), 6.01 (s, 1H,
CH), 7.22–7.57 (m, 8H, Ar-H), 8.19 (s, 2H, NH2,
D2O exchangeable), 10.08 (s, 1H, NH, D2O
exchangeable);
19.54 (CH3), 59.76, 69.97 (2 CH),
121.37, 126.43, 126.45, 128.65,
132.51, 133.89, 136.21, 140.62,
151.62, 156.88, 158.32 (Ar–C),
163.13 (C=O)
3,271–3,105 (NH2),
1,708 (C=O), 1,650
(C=N),
Xb
3,338 (NH),
2.15 (s, 3H, CH3), 6.75 (s, 1H, CH), 7.32–7.33 (d,
2H, Ar-H, J = 8.5 Hz), 7.37–7.39 (d, 2H, Ar-H,
J = 9 Hz), 7.47–7.48 (d, 2H, Ar-H, J = 8.5 Hz),
7.62–7.65 (d, 2H, Ar-H, J = 9 Hz), 8.01 (s, 2H,
NH2, D2O exchangeable), 10.24 (s, 1H, NH, D2O
exchangeable)
18.52 (CH3), 56.76 (CH), 109.93,
112.99, 121.37, 127.65, 128.25,
128.65, 129.18, 133.89, 136.70,
137.22, 151.20 (12 Ar–C), 159.40 (C
−NH2), 163.13 (C=O)
3,150–3,050 (NH2),
2,206 (CN), 1,643
(C=O), 1,595 (C=N)
XI
3,286 (NH), 1,691,
1,644 (2C=O), 1,592
(C=N)
2.07 (s, 3H, CH3), 6.52 (s, 1H, CH), 7.24–7.25 (d,
2H, Ar-H, J = 8.5 Hz), 7.33–7.35 (d, 2H, Ar-H,
J = 8.8 Hz), 7.38–7.39 (d, 2H, Ar-H, J = 8.5 Hz),
7.59–7.61 (d, 2H, Ar-H, J = 9 Hz), 8.02 (s, 1H,
NH, D2O exchangeable), 10.08 (s, 1H, NH, D2O
exchangeable), 13.06 (s, 1H, OH, D2O
exchangeable)
21.55 (CH3), 56.31 (CH), 101.04,
109.93, 121.25, 127.17, 128.14,
128.61, 128.99, 133.01, 137.81,
139.67, 143.03, 150.19 (12 Ar–C),
153.54, 155.51, 158.22 (3C=N),
165.68 (C=O)
(Continues)

ALZAHRANI ET AL.
9
TABLE 2 (Continued)
Compound
IR (KBr) cm−1
1H NMR (δ Valeus)
13C NMR (δ Valeus)
XII
3,399 (NH),
2.15 (s, 3H, CH3), 5.38 (s, 1H, CH), 7.26–7.61 (m, 16.91 (CH3), 32.78 (CH), 52.35 (CH),
3,300–3,100 (NH2),
1,665 (C=O), 1,574
(C=N), 1,470 (C=C)
9H, Ar-H), 9.28 (s, 2H, NH2, D2O
exchangeable), 10.08 (s, 1H, NH, D2O
exchangeable)
110.14, 121.24, 127.27, 128.09,
128.54, 128.74, 128.82, 132.67,
134.91, 137.57, 140.75, 156.22 (16
Ar–C), 164.28 (C=O)
XIII
3,399 (NH),
2.08 (s, 3H, CH3), 5.40 (s, 1H, CH), 7.27–7.59 (m, 16.56 (CH3), 54.38 (CH), 91.74,
3,300–3,172 (NH2),
1,664 (C=O), 1,622
(C=N), 1,468 (C=C),
1,333 (C=S)
8H, Ar-H), 9.11 (s, 2H, NH2, D2O
exchangeable), 9.49 (s, 1H, NH, D2O
exchangeable), 9.89 (s, H, NH, D2O
exchangeable), 10.08 (s, 1H, NH, D2O
exchangeable)
106.48, 121.21, 126.96, 128.28,
128.43, 128.60, 132.31, 136.32,
137.80, 141.84, 151.16 (12 Ar–C),
160.11, 164.88 (C=N), 172.87
(C=O), 174.17, 175.12 (2C=S)
XIVa*
3,306 (NH), 1,715,
1,645 (2C=O), 1,585
(C=N), 1,518 (C=C)
2.12 (s, 3H, CH3), 6.27 (s, 1H, CH), 7.32–7.35 (d,
2H, Ar-H, J = 9 Hz), 7.40–7.41 (d, 2H, Ar-H,
J = 8.5 Hz), 7.60–7.64 (m, 6H, Ar-H), 7.76 (s,
1H, CH), 10.42 (s, 1H, NH, D2O exchangeable)
21.27 (CH3), 55.69 (CH), 114.45,
120.40, 121.34, 127.36, 128.55,
128.71, 128.76, 128.84, 129.02,
129.19, 129.47, 130.78, 131.60,
131.86, 133.19, 135.08, 137.56,
137.99, 140.79 (Ar–C), 152.15
(C=N), 164.21, 164.74 (2C=O)
XIVb*
XIVc
XIVd*
XIVe*
XV
3,276 (NH), 1,709,
1,646 (2C=O), 1,624
(C=N), 1,586 (C=C)
2.13 (s, 3H, CH3), 2.35 (s, 3H, CH3), 6.29 (s, 1H,
CH), 7.32–7.36 (m, 6H, Ar-H), 7.39–7.40 (d, 2H,
Ar-H, J = 8.5 Hz), 7.49–7.51 (d, 2H, Ar-H,
J = 9 Hz), 7.63–7.64 (d, 2H, Ar-H, J = 8.5 Hz),
7.72 (s, 1H, CH), 10.46 (s, 1H, NH, D2O
exchangeable)
21.08, 21.26 (2CH3), 55.57 (CH),
114.24, 118.33, 121.32, 126.33,
127.29, 128.47, 128.77, 129.15,
129.98, 130.15, 132.18, 133.12,
137.59, 138.10, 140.87, 140.94,
(Ar–C), 152.44 (C=N), 164.36,
164.79 (2C=O)
3,303 (NH), 1,715,
1,645 (2C=O), 1,607
(C=N), 1,585 (C=C)
2.13 (s, 3H, CH3), 6.29 (s, 1H, CH), 7.27–7.28 (d,
2H, Ar-H, J = 8.5 Hz), 7.32–7.35 (d, 2H, Ar-H,
J = 9 Hz), 7.53–7.54 (d, 2H, Ar-H, J = 8 Hz),
7.61–7.65 (m, 6H, Ar-H), 7.75 (s, 1H, CH); 10.49
(s, 1H, NH, D2O exchangeable)
21.25 (CH3), 55.76 (CH), 114.37,
120.38, 121.34, 121.79, 127.31,
128.48, 129.42, 129.49, 130.73,
131.54, 131.70, 131.83, 135.04,
137.57, 138.36, 140.80 (Ar–C),
152.05 (C=N), 164.15, 164.70
(2C=O)
3,273 (NH), 1,709,
1,645 (2C=O), 1,624
(C=N), 1,586 (C=C)
2.12 (s, 3H, CH3), 2.36 (s, 3H, CH3), 6.27 (s, 1H,
CH), 7.26–7.27 (d, 2H, Ar-H, J = 8.5 Hz),
7.32–7.34 (d, 2H, Ar-H, J = 9), 7.35–7.36 (d, 2H,
Ar-H, J = 8 Hz), 7.49–7.50 (d, 2H, Ar-H,
J = 8 Hz), 7.53–7.54 (d, 2H, Ar-H, J = 8.5 Hz),
7.63–7.65 (d, 2H, Ar-H, J = 9 Hz), 7.72 (s, 1H,
CH); 10.460 (s, 1H, NH, D2O exchangeable)
21.59, 21.75 (2CH3), 56.15 (CH),
114.68, 118.82, 121.82, 122.26,
127.79, 128.99, 129.92, 130.50,
130.65, 132.21, 132.71, 138.08,
139.02141.39, 141.42 (Ar–C), 152.96
(C=N), 164.86, 165.28 (2C=O)
3,335 (NH), 1,716,
1,655 (2C=O), 1,606
(C=N), 1,569, 1,517
(C=C)
2.19 (s, 3H, CH3), 6.60 (s, 1H, CH), 6.96–6.97 (dd, 21.08 (CH3), 50.64 (CH), 114.09,
1H, J = 5.3 Hz), 7.15–7.16 (d, 1H, J = 3 Hz),
7.34–7.44 (d, 2H, Ar-H, J = 8.5 Hz), 7.49–7.51
(dd, 1H, J = 5, 1.5 Hz), 7.60–7.70 (m, 6H, Ar-H)
7.86 (s, 1H,CH) 10.53 (s, 1H, NH, D2O
exchangeable)
120.40, 121.38, 126.98, 127.06,
127.23, 127.27, 128.48, 129.43,
131.13, 131.62, 131.79, 135.13,
137.71, 141.37, 142.28 (Ar–C),
151.77 (C=N), 164.14, 164.69
(2C=O)
3,300–3,100 (OH),
3,224 (NH), 1,717,
1,685 (2C=O)
1.90 (s, 2H, CH2), 2.06 (s, 3H, CH3), 5.37–5.38 (d, 16.59 (SCH2), 21.11 (CH3), 54.43
1H, CH, J = 3 Hz), 7.24–7.32 (m, 4H, Ar-H),
7.41–7.44 (d, 2H, Ar-H, J = 9 Hz), 7.55–7.57 (d,
2H, Ar-H, J = 9 Hz), 9.83 (s, 1H, NH, D2O
exchangeable), 10.05 (s, 1H, NH, D2O
exchangeable), 11.92 (s, exchangeable) 1H, OH,
D2O
(CH), 106.55, 121.26, 127.05, 128.31,
128.55, 128.70, 132.39, 136.36,
137.85, 141.90 (Ar–C), 164.95,
172.11 (2C=O),174.23 (C-S)
(Continues)

10
ALZAHRANI ET AL.
TABLE 2 (Continued)
Compound
IR (KBr) cm−1
1H NMR (δ Valeus)
13C NMR (δ Valeus)
XVIa*
3,408 (NH), 2,920 (C-H 2.11 (s, 3H, CH3), 6.17 (s, 1H, CH), 7.22–7.24 (d,
20.91 (CH3), 55.28 (CH), 114.72,
115.73, 121.07, 121.34, 126.03,
127.41, 128.54, 128.80, 129.05,
129.17, 133.17, 137.43, 138.04,
140.20, 142.12, 151.47 (Ar–C),
160.34, 164.54 (2C=O)
aliph.), 1,738, 1,676
(2C=O), 1,640, 1,569
(C=N), 1,519 (C=C)
2H, Ar-H, J = 8.57 Hz), 7.29–7.31 (d, 2H, Ar-H,
J = 9.35 Hz), 7.34–7.44 (d, 2H, Ar-H,
J = 8.57 Hz), 7.36–7.38 (d, 2H, Ar-H,
J = 9.35 Hz), 7.42–7.44 (d, 2H, Ar-H, J = 9 Hz),
7.56–7.57 (d, 2H, Ar-H, J = 9 Hz), 10.16 (s, 1H,
NH, D2O exchangeable), 10.96 (s, 1H, NH, D2O
exchangeable)
XVIb
XVIc
XVId
3,401 (NH), 2,900 (C-H 2.31 (s, 3H, CH3), 3.12 (s, 3H, CH3), 6.14 (s, 1H,
21.32 (CH3), 59.53 (CH), 115.67,
121.41, 124.35, 126.44, 127.38,
128.64, 129.63, 131.77, 132.81,
136.41, 140.67, 142.11, 151.93,
155.45 (Ar–C), 163.78, 168.64
(2C=O)
aliph.), 1,767, 1,654
(2C=O), 1,616, 1,593
(C=N)
CH), 7.23–7.42 (m, 10 H, Ar-H), 7.76–7.77 (d,
2H, Ar-H, J = 9 Hz), 9.78 (s, 1H, NH, D2O
exchangeable), 11.36 (s, 1H, NH, D2O
exchangeable)
3,404 (NH), 1,685,
1,654 (2C=O), 1,591,
1,573 (C=N), 1,490
(C=C)
2.11 (s, 3H, CH3), 6.164 (s, 1H, CH), 7.18–7.58 (m, 21.21 (CH3), 55.33 (CH), 115.72,
12H, Ar-H), 10.20 (s, 1H, NH, D2O
exchangeable), 11.04 (s, 1H, NH, D2O
exchangeable)
121.13, 121.38, 121.47, 126.03,
127.38, 127.50, 128.66, 129.30,
131.76, 131.83, 137.46, 138.62,
138.92, 140.73, 142.17, 150.93
(Ar–C), 164.74, 165 (2C=O)
3,404 (NH), 2,900 (C-H 2.31 (s, 3H, CH3), 3.12 (s, 3H, CH3), 6.14 (s, 1H,
21.53 (CH3), 60.52 (CH), 116.67,
121.45, 125.43, 126.41, 127.78,
128.77, 130.52, 131.76, 133.68,
136.41, 141.35, 142.14, 152.96,
155.44 (Ar–C), 163.74, 169.21
(2C=O)
aliph.), 1,750, 1,690
(2C=O), 1,654, 1,593
(C=N), 1,529 (C=C)
CH), 7.20–7.23 (d, 2H, Ar-H, J = 8.54 Hz),
7.41–7.43 (d, 2H, Ar-H, J = 9.33 Hz), 7.45–7.46
(d, 2H, Ar-H, J = 8.54 Hz), 7.49–7.50 (d, 2H,
Ar-H, J = 9.33 Hz), 7.84–7.86 (d, 2H, Ar-H,
J = 9 Hz), 7.86–7.88 (d, 2H, Ar-H, J = 9 Hz),
9.77 (s, 1H, NH, D2O exchangeable), 11.34 (s,
1H, NH, D2O exchangeable)
XVIe
3,422 (NH), 3,100 (C-H 2.17 (s, 3H, CH3), 6.50 (s, 1H, CH), 7.25–7.63 (m, 21.32 (CH3), 50.22 (CH), 114.46,
aliph.), 1,719, 1,685
(2C=O), 1,654, 1,594
(C=N), 1,569 (C=C)
11H, Ar-H), 10.24 (s, 1H, NH, D2O
exchangeable), 11.05 (s, 1H, NH, D2O
exchangeable)
115.80, 121.37, 121.44, 126.54,
126.83, 127.10, 127.24, 128.61,
128.65, 129.31, 137.61, 141.67,
142.05, 142.12, 142.32, 150.54
(Ar–C), 164.7, 165 (2C=O)
* Va: MS (m/z; %), 408 (M+2; 6.5), 406 (M
+ H; 9.1), 360 (1.5), 318 (0.5).
* XIVb: MS (m/z; %), 537 (M+4; 1.04), 535 (M+2; 4.44), 533 (M+; 5.92), 409 (M+2–126;
41.10), 407 (M+-126; 100), 165 (M+2–370; 17.88), 163 (M+-370; 50.43), 67 (38.86)
* XIVd: MS (m/z; %), 581 (M+4; 2.74), 579 (M+2; 8.71), 577 (M+; 6.37), 453 (M+2–126;
100),451 (M+ − 126; 94.10), 209 (M+2–370; 32.40), 207 (M+-370; 31.63), 128 (15.89), 67
(27.48)
* VIIIb: MS (m/z; %), 479 (M+4; 2.51), 477
(M+2; 8.40), 475 (M+; 6.18), 351 (M+2 - 126;
100), 349 (M+ − 126; 98.42), 323 (M+2–154;
7.76), 321 (M+ − 154; 7.65)
* XIVe: MS (m/z; %), 529 (M+4; 1.86), 527 (M+2; 7.32), 525 (M+; 9.35), 401 (M+2–126;
* Xb: MS (m/z), 459 (M+4; 2.89%), 457 (M+2
;
44.62), 399 (M+-126; 99.46), 135 (100), 67 (56.65)
12.59%), 455 (M+; 18.14%), 331 (M+2–126; * XVIa: MS (m/z; %), 575 (M+6; 0.77), 573 (M+4; 4.48), 571 (M+2; 11.77), 569 (M+; 11.51),
36.71%), 329 (M+-126; 98.36%), 318 (M+2
–
447 (M+4–126; 15.74), 445 (M+2–126; 72.96), 443 (M+-126; 100), 359 (M+2212; 9.71), 357
139; 20.43%), 316 (M+; 30.75%), 165 (100%)
* XIVa: MS (m/z; %), 559 (M+6; 0.43), 557
(M+4; 2.61), 555 (M+2; 6.70), 553 (M+;
6.57), 429 (M+2–126; 69.34), 427 (M+-126;
100), 165 (M+2–390; 13.82), 163 (M+-390;
37.53), 67 (28.93)
(M+-212; 14.43), 67 (58.20)
Compound Xa could also be synthesized stepwise by
refluxing Vb in ethanol in the presence of sodium ethoxide
solution. Compounds Xa and b gave the expected values
in elemental analyses and spectral data (Tables 1 and 2).
Compound Xb, as typical enaminonitriles, allowed
heterocyclic annelations performing access to more fused
pyrimidines. They could be used as precursors for the
preparation of thiazolodipyrimidine, pyrazolothiazolo-

ALZAHRANI ET AL.
11
TABLE 3 The difference in the outcome of the MW-assisted and thermal reactions for the synthesis of compounds IVa–g and VIIIa–c
Reaction yield %
Reaction time/min
Compound
IVa
Microwave
Conventional method
Microwave
Conventional method
88
74
87
83
82
76
55
88
74
87
63
35
48
55
62
34
24
45
43
52
11
14
10
15
15
13
15
10
14
9
1,440
180
IVb
IVc
360
IVd
1,440
1,500
1,440
2,540
1,440
1,440
1,440
IVe
IVf
IVg
VIIIa
VIIIb
VIIIc
pyrimidine, and pyridothiazolopyrimidine derivatives.
Thus, a mixture of Xb with each of formic acid, formam-
ide in formic acid/DMF mixture and an excess of ammo-
nium thiocyanate in acetic acid to yield N,9-bis
(4-chlorophenyl)-7-methyl-4-oxo-1,4-dihydro-9H-thiazolo
[3,2-a:4,5-d’]dipyrimi-dine-8-carboxamide (XI), 4-amino-
N,9-bis(4-chlorophenyl)-7-methyl-9H-thiazolo[3,2-a:4,5-d’]
dipyrimidine-8-carboxamide derivative(XII) and N,9-bis
(4-chloro- phenyl)-7-methyl-4-thioureido-2-thioxo-1,2-
dihydro-9H-thiazolo[3,2-a:4,5-d’]dipyrimidine-8-carbo-
xamide (XIII), respectively (Scheme 5). Compounds XI,
XII, and XIII gave the expected values in elemental
analyses and spectral data (Tables 1 and 2).
An extension of alkylation and cycloalkylation, Com-
pounds IVa–c were heated under reflux with a mixture
of chloroacetic acid, aromatic aldehyde and fused sodium
acetate in acetic acid/acetic anhydride solution to give
5-(Aryl)-N-(4-chlorophenyl)-7-methyl-2-(Arylidene)-
3-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidine-
Compound XV gave the expected values in elemental
analyses and spectral data (Tables 1 and 2). Furthermore,
Compounds VIIIa–c coupled with arenediazonium salts in
pyridine to give the corresponding 2-arylhydrazo derivatives
XVIa–e (Scheme 8). Compounds XVI gave agreeable values
in elemental analyses and spectral data (Tables 1 and 2).
2.2 | Antimicrobial evaluation
Most of the newly synthesized compounds were screened
for their in vitro antimicrobial activity against different
microorganisms representing gram-positive (Staphylococ-
cus aureus, Bacillus subtilis, and Staphylococcus mutants)
and gram-negative bacteria (Enterobacter cloacae, Proteus
vulgaris, and Escherichia coli) using the standard antibiotic
gentamycin (4 μg/ml) as reference drugs and fungi (Asper-
gillus fumigates, Aspergillus flavus, and Candida albicans)
using the standard antibiotic ketoconazole (100 μg/ml).
The compounds were tested for their activities with the
same concentration of the standard using inhibition zone
diameter (in millimeters) as a criterion for the antimicro-
bial activity,[34,35] and the results are shown in (Table 4).
The antimicrobial activity of the synthesized com-
pounds was carried out by the mean zone of inhibition
method. The ketoconazole was the antifungal control of
this study with a concentration of 100 μg/ml, while gen-
tamycin was used as gram-positive and gram-negative
control with a concentration of 4 μg/ml, while the syn-
thesized compounds were used with the same concentra-
tion as the control compounds. The antifungal activity of
the newly synthesized compounds was tested against
Aspergillus flavus, Aspergillus fumigatus, and Candida
albicans. The inhibition activities showed that five of the
tested compounds exhibited antifungal activity more than
the ketoconazole.
6-carboxamide XIVa–e, in good yields (Scheme 6). Com-
pounds XIVa–e gave the expected values in elemental
analyses and spectral data (Tables 1 and 2).
In support of structure XIV, compound XIVa, as an
example, could be synthesized step wisely. Thus, when
compound IVa was heated under reflux with chloroacetic
acid and fused sodium acetate in acetic acid, it gave the
2-carboxymethylthio derivative XV. The latter compound
could be cyclized by heating with acetic acid/acetic anhy-
dride solution at 100ꢀC to give Compound VIIIa
(Scheme 7), which could also be obtained from IVa in one
step by heating under reflux with a mixture of chloroacetic
acid and fused sodium acetate in acetic acid / acetic anhy-
dride solution. Compound VIIIa condensed with p-chloro
benzaldehyde in refluxing acetic acid/acetic anhydride
solution and gave XIVa, which was identical in all aspects
with XIVa produced by one-pot synthesis.

12
ALZAHRANI ET AL.
SCHEME 2 Alkylation of
compound IV a
SCHEME 3 Synthesis of
compounds VIII a-c
The active antifungal compounds from the highest to
(ketoconazole) and antibacterial drugs (gentamycin). The
highest inhibition activity that exceeds the inhibition activity
of the control drugs may be due to the presence of pyrimi-
dine, carboxamide, and thiazole groups, which are well
known to act as antibacterial and antifungal drugs. [36–38]
the lowest against Aspergillus flavus were XIVb, XVIb,
VIIIb, XVIe, and IVb, respectively. Furthermore, com-
pounds VIIIb, XVIa, and XVIe, respectively, had the
highest activity against Aspergillus fumigates, while the
activity of tested compounds against Candida albicans
ranged from moderate to undetectable.
Compound Xb had inhibition activity against Aspergillus
fumigatus and Streptococcus mutants similar to ketoconazole
and gentamycin activities, respectively. The inhibition activity
of Compound Va against the Streptococcus mutants (gram-
positive) and the Proteus vulgaris (gram-negative) was similar
to the inhibition activity of gentamycin. All of the synthesized
compounds that exerted high antifungal or antibacterial activ-
ity were mostly due to the presence of pyrimidine and carbox-
amide units (XIVb, XVIb, VIIIb, XVIc, and IVb).
Compounds (Xb, VIIIb, XVIe, XIVb and XVIa) containing
thiazol moiety beside the pyrimidine and carboxamide groups
were with higher inhibition activity of some fungi and bacte-
ria compared with the broad specificity antifungal
2.3 | Experimental
All melting points were determined with a Stuart Digital
Melting Point apparatus SMP10 and are uncorrected. The
elemental analyses were performed on a Perkin-Elmer
240 microanalyzer, PE 2400 Series II CHNS/O Analyzer,
carried out at the regional center for mycology and bio-
technology, Al-Azhar University, Egypt. IR spectra were
determined as KBr pellets on a Thermo Nicolet apparatus
(Thermo Scientific, Madison, WI) at Postgraduate cam-
pus for Girls at Lassan, King Khalid University, Abha.
The NMR spectra were recorded on a Varian Mercury
300 MHz NMR spectrometer at Faculty of Science, Cairo

ALZAHRANI ET AL.
13
FIGURE 1 Ground state frontier molecular orbitals (HOMOs) and (LUMOs) of Compounds VIIIa and IXa, contour value 0.05
University, Egypt; Bruker NMR spectrometer 500 MHz at
King Khalid University, Abha and Bruker NMR spec-
trometer 850 MHz, at King Abdul-Aziz, Jeddah, respec-
tively, using tetramethyl silane as internal standard
(TMS) in DMSO-d6, as solvent. The chemical shifts were
recorded in (δ) units. Mass spectra on GC/MS-QP5 spec-
trometer and the antimicrobial activity were measured at
regional center for mycology and biotechnology, Al-
Azhar University, Egypt.
2.4 | General procedures for the
synthesis of N-(4-chlorophenyl)-4-(aryl)-
6-methyl-2-thioxo-
1,2,3,4-tetrahydropyrimidine-5-carboxamide
IVa–g
A mixture of thiourea III (0.01 mol, 0.76 g), p-chloro
Acetoacetanilide I (0.01 mol, 2.11 g) and aromatic
aldehyde derivatives IIa–g (0.01 mol) in ethanol in the

14
ALZAHRANI ET AL.
SCHEME 4 Synthesis of
compounds Xa,b
presence of catalytic amount of HCl was refluxed
(monitored by TLC), The precipitate that formed after
cooling was filtered off, then dried, and recrystallized
from ethanol to afford IVa–g.
2.5 | General procedures for the
synthesis of N,6-bis(4-chlorophenyl)-
4-methyl-2-(alkylthio)-
1,6-dihydropyrimidine-5-carboxamide Va–c
In alcoholic potassium carbonate (0.28 g) IVa was added
(5 mmol, 2 g) after 1 hr of reflux (5 mmol) the alkyl halide
was added, the mixture continued to reflux and was moni-
tored by TLC. The reaction was cooled and poured onto ice-
water acidified by drops of HCl, the formed precipitate was
filtered, washed with water repeatedly, dried, and rec-
rystallized from ethanol.
2.6 | Synthesis of N,6-Bis
(4-chlorophenyl)-2-hydrazineyl-4-methyl-
1,6-dihydropyrimidine-5-carboxamide VII
A mixture of Va (2.4 mmol, 1 g) and hydrazine hydrate
(3 ml) in 15 ml dioxane was refluxed for 5 hr. The reaction
mixture was left to cool to room temperature and then poured
onto ice water, the formed precipitate was filtered off, washed
thoroughly with water, dried, and recrystallized from DMF.
2.7 | Synthesis of N-(4-Chlorophenyl)-
5-(4-methoxyphenyl)-3,7-dimethyl-5H-
thiazolo[3,2-a] pyrimidine-6-carboxamide
VIIIa-c
2.7.1 | Method (A)
A solution of 2-thioxopyrimidine derivatives IVa–c
(5 mmol, 1.93 g) and each of chloroacetone (5 mmol,
0.5 ml), ethyl bromoacetate (5 mmol, 0.56 ml), in ethanol
(30 ml) in the presence of potassium hydroxide (5 mmol,
0.34 g) was refluxed for 2 hr. The reaction mixture was
left to cool to room temperature, poured onto ice water,
SCHEME 5 Preparation of compounds XI, XII and XIII

ALZAHRANI ET AL.
15
SCHEME 6 Preparation of compounds XIVa-e
SCHEME 7 The step wise
synthesis of compound VIIIa
SCHEME 8 Tautomeric form of compounds XVIa-e

16
ALZAHRANI ET AL.

ALZAHRANI ET AL.
17
and acidified with HCl. The formed precipitate was fil-
tered off, washed with water, dried, and recrystallized
from the proper solvent.
2.11 | Synthesis of N,9-bis
(4-chlorophenyl)-7-methyl-4-thioureido-
2-thioxo-1,2-dihydro-9H-thiazolo
[3,2-a:4,5-d’]dipyrimidine-
8-carboxamide XIII
2.7.2 | Method (B)
A mixture of Xb (2 mmol, 1 g), Acetic Acid (10 ml) and
excess ammonium thiocyanate (0.5 g) was refluxed over-
night then left to cool, poured onto ice water, the formed
precipitate was filtered off, dried, and recrystallized.
A
mixture of 2-thioxopyrimidine derivatives IVa–c
(5 mmol), fused sodium acetate (5 mmol, 0.41 g) and chlo-
roacetic acid (5 mmol, 0.47 g) in 30 ml AcOH and 15 ml
Ac2O was refluxed for 12 hr. The reaction mixture was left
to cool, poured onto ice-water; the formed precipitate was
filtered off, washed thoroughly with water, dried, and rec-
rystallized from acetic acid to afford compounds VIIIa–c.
2.12 | General procedures for the
synthesis of 5-(aryl)-N-(4-chlorophenyl)-
7-methyl-2-(Arylidene)-3-oxo-2,3-dihydro-
5H-thiazolo[3,2-a]pyrimidine-
2.8 | General procedures for the
synthesis of 3-amino-N,5-bis
(4-chlorophenyl)-2-alkyl-7-methyl-5H-
thiazolo[3,2-a]pyrimidine-
6-carboxamide XIVa–e
Equimolar amounts of IVa–c (5 mmol), an aromatic
aldehyde (5 mmol), fused sodium acetate (5 mmol,
0.41 g) and chloroacetic acid (5 mmol, 0.47 g) in 30 ml of
AcOH and 15 ml Ac2O were refluxed for (5–12 hr) then
left to cool and poured onto ice water. The separated pre-
cipitate formed was filtered off, washed with water, dried,
and recrystallized from AcOH.
6-carboxamide Xa,b
A
mixture of 2-thioxopyrimidine derivative IVa
(2.5 mmol, 2 g), chloro acetonitrile or monobromo malo-
nonitrile (2.5 mmol) in ethanolic potassium hydroxide
solution was refluxed for 1 hr. The precipitate was col-
lected by filtration, washed with cold ethanol, dried, and
recrystallized from ethanol.
2.13 | Synthesis of
2-((6-(4-chlorophenyl)-5-((4-chlorophenyl)
carbamoyl)-4-methyl-1,6-dihydropyrimidin-
2-yl)thio)acetic acid XV
2.9 | Synthesis of N,9-bis
(4-chlorophenyl)-7-methyl-4-oxo-
1,4-dihydro-9H-thiazolo[3,2-a:4,5-d’]
dipyrimidine-8-carboxamide XI
A mixture of IVa (6 mmol, 2 g), fused sodium acetate
(6 mmol, 0.5 g) and chloroacetic acid (6 mmol, 0.56 g) in
30 ml of AcOH were refluxed for 6 hr. The reaction mixture
left to cool, poured onto cold water. The precipitate formed
was filtered off, washed with water, dried, and recrystallized.
A mixture of thiazolo[3,2-a]pyrimidine-6-carboxamide
Xb (2 mmol, 1.0 g) and formic acid (20 ml) was
refluxed for 20 hr. The reaction mixture was left to
cool and poured onto ice water, and the separated pre-
cipitate was filtered off, washed with water, dried, and
recrystallized.
2.14 | General procedures for the
synthesis of N-(4-chlorophenyl)-2-(2-(aryl)
hydrazineylidene)-7-methyl-3-oxo-5-(aryl)-
2,3-dihydro-5H-thiazolo[3,2-a]pyrimidine-
6-carboxamide XVI a–e
2.10 | Synthesis of 4-amino-N,9-bis
(4-chlorophenyl)-7-methyl-9H-thiazolo
[3,2-a:4,5-d’]dipyrimidine-
The appropriate aromatic amine (2.5 mmol) was dissolved
in 10 ml of concentrated HCl the solution was then cooled
to 0–5ꢀC in an ice bath. A solution of sodium nitrite
(2.5 mmol, 0.1 g) in water (5 ml) was then added drop wise
with continues stirring. The diazonium solution was added
portion wise to a solution prepared by mixing a suspension
of VIIIa–c (2.5 mmol) in 10 ml of ethanol with sodium
acetate (0.12 g), the temperature was maintained at 0–5ꢀC
8-carboxamide XII
A mixture of Xb (1 mmol, 0.5 g), formic acid (5 ml),
formamide (10 ml), and DMF (5 ml) was refluxed for
6 hr, left to cool, poured onto ice water, the formed pre-
cipitate was filtered off, washed with water, dried, and
recrystallized.

18
ALZAHRANI ET AL.
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Ayman M. S. Youssef https://orcid.org/0000-0001-9611-
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How to cite this article: Alzahrani HE,
Fouda AM, Youssef AMS. Selective cyclization of
S-substituted pyrimidinethione: Synthesis and
antimicrobial evaluation of novel polysubstituted
thiazolopyrimidine and thiazolodipyrimidine
derivatives. J Chin Chem Soc. 2019;1–18. https://
doi.org/10.1002/jccs.201900199