An efficient ultrasonic-assisted synthesis of the thiazolo[2,3-b] quinazoline and thiazolo[3,2-a] pyrimidine derivatives

Article abstract of DOI:10.1007/s13738-012-0169-1

Treatment of cyclohexanone or cyclopentanone (2) with aromatic aldehyde (1) and thiourea (3) in the presence of modified montmorinollite nanostructure or HCl as a catalyst under heating and solvent-free conditions produced 7-benzylidene-4-aryl-3,4,6,7-tetrahydro-1H cyclopenta[d]pyrimidine-2(5H)-thione or 8-benzylidene-4-aryl-3,4,5,6,7,8 hexahydroquinazoline-2(1H)-thione (4). Compound 4 was utilized as a key intermediate for the synthesis of new thiazolo[2,3-b]quinazoline and thiazolo[3,2-a]pyrimidine derivatives (5a-5o) via the reaction with diethyl and dimethyl acetylene dicarboxylate by two different methods: (a) in methanol as a solvent under ultrasonic irradiation at ambient temperature; (b) in methanol as a solvent at ambient temperature (conventional magnetic stirring). Ultrasound-assisted synthesis provides excellent yields (87-95 %) in short reaction times (30-50 min) at room temperature. The chemical structures of the newly synthesized compounds were characterized by UV-Vis, IR and NMR spectral and elemental analysis.

Full text of DOI:10.1007/s13738-012-0169-1

J IRAN CHEM SOC (2013) 10:385–392
DOI 10.1007/s13738-012-0169-1
ORIGINAL PAPER
An efficient ultrasonic-assisted synthesis of the thiazolo[2,3-b]
quinazoline and thiazolo[3,2-a] pyrimidine derivatives
•
Ali Darehkordi Jabber Reentan Mahin Ramezani
•
Received: 12 January 2012 / Accepted: 7 September 2012 / Published online: 5 October 2012
Ó Iranian Chemical Society 2012
Abstract Treatment of cyclohexanone or cyclopentanone
(2) with aromatic aldehyde (1) and thiourea (3) in the
presence of modified montmorinollite nanostructure or
HCl as a catalyst under heating and solvent-free condi-
tions produced 7-benzylidene-4-aryl-3,4,6,7-tetrahydro-1H
cyclopenta[d]pyrimidine-2(5H)-thione or 8-benzylidene-4-
aryl-3,4,5,6,7,8 hexahydroquinazoline-2(1H)-thione (4). Com-
pound 4 was utilized as a key intermediate for the synthesis
of new thiazolo[2,3-b]quinazoline and thiazolo[3,2-a]
pyrimidine derivatives (5a–5o) via the reaction with die-
thyl and dimethyl acetylene dicarboxylate by two different
methods: (a) in methanol as a solvent under ultrasonic
irradiation at ambient temperature; (b) in methanol as a
solvent at ambient temperature (conventional magnetic
stirring). Ultrasound-assisted synthesis provides excellent
yields (87–95 %) in short reaction times (30–50 min) at
room temperature. The chemical structures of the newly
synthesized compounds were characterized by UV–Vis, IR
and NMR spectral and elemental analysis.
great importance in biological chemistry. They exist in
many condensed fused systems that were found to possess
a wide range of activity [1]. Moreover, fused pyrimidines
have drawn the attention of medicinal chemists as che-
motherapeutic agents, where several members of this class
have earned valued places in chemotherapy as effective
agents. Various literature reports displayed numerous fused
pyrimidine ring systems and their chemotherapeutic
activities as anticancer [2], antibacterial [3], antifungal [4],
and antiviral [5] agents. Also, substituted thiazolopyrimi-
dine ring systems were reported to possess antitumor
activity [6].
It is evident from the literature that quinazolines and
condensed quinazolines exhibit potent central nervous
system (CNS) activities, e.g., analgesic and anti-inflam-
matory [7]. Azolopyrimidoquinolines and pyrimidoqui-
nazolines exhibited good anti-oxidant, anti-inflammatory
and analgesic activities [8]. Literature reports show that
thienopyrimidines (bioisostere of quinazoline and con-
densed quinazoline) possess CNS and antibacterial activi-
ties [9]. On the other hand, thiazoles and their derivatives
are found to be associated with various biological activities
[10, 11], such as antibacterial, antifungal and anti-inflam-
matory activities. Furthermore, organic compounds bearing
thiazolopyrimidine and pyrimidothiazolo quinoxaline
nuclei were found to possess potent anti-cancer activity
[12, 13].
Keywords Dihydropyrimidinone ꢀ
Thiazolo[2,3-b]quinazoline ꢀ Thiazolo[3,2-a]pyrimidine ꢀ
Ultrasound assisted ꢀ Dialkyl acetylene dicarboxylate
Introduction
The wide occurrence of the heterocycles in bioactive
natural products made them important synthetic targets.
Thiazoles represent a class of heterocyclic compounds of
Also, thienopyrimidine derivatives have been reported
to possess useful molluscicidal and larvicidal activities
against Biomphalaria alexendra and Schistosoma mansoni
snails [14].
Previously, synthesis and characterization of pyrimidi-
none–peptoid hybrid molecules that modulate Hsp70
activity in vitro and, in some cases, prevent cancer cell
proliferation have been reported [15–18].
A. Darehkordi (&) ꢀ J. Reentan ꢀ M. Ramezani
Department of Chemistry, Faculty of Science, Vali-e-asr
University of Rafsanjan, 77176 Rafsanjan, Iran
e-mail: adarehkordi@yahoo.com; darehkordi@mail.vru.ac.ir
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J IRAN CHEM SOC (2013) 10:385–392
O
Sonochemistry is a unique method in chemical reac-
Ar
modified montmorillonite
tions, because of cavitations, a physical process that cre-
ates, enlarges and implodes gaseous and vaporous cavities
in an irradiated liquid. Cavitations induce very high local
temperatures and pressures inside the bubbles (cavities),
leading to turbulent flow of the liquid and enhanced mass
transfer [19].
O
Ar
H
NH
catalyst
1
S
Y
or
N
S
H
two drops HCl
Y
Ar
H2N
NH2
2
4
3
Y = CH2, CH2CH2
Ultrasound irradiation has been considered as a clean
and useful protocol in organic synthesis in the last three
decades [20–22]. A large number of organic reactions can
be carried out in higher yield, shorter reaction time or
milder conditions under ultrasonic irradiation compared
with traditional methods [23–25].
Scheme 1 Synthesis of pyrimidinethione derivatives under solvent-
free conditions
drops of HCl was placed in a test tube and heated in oil
bath at 80 °C under solvent-free conditions, for 60–90 min
(Scheme 1). After cooling the reaction mixture, ethanol
was added and the catalyst was removed by filtration. The
filtrate was poured into crushed ice water and the resulting
precipitate recrystallized from hot ethanol to yield the pure
product. All the compounds were characterized by MP,
Several methods are reported for the preparation of
thiazolo quinoxaline and thiazolo quinazolinone deriva-
tives [26–29].
As our continuous endeavor dealing with the design and
preparation of thiazoline compounds [30], we wish to
describe herein a simple and efficient method for synthesis
of ethyl-5-(aryl)-2-(2-alkoxy-2-oxoethylidene)-7-methyl-3-
oxo-3, 5-dihydro-2H-thiazolo[3,2-a] pyrimidine-6-carbox-
ylate derivatives from reaction of dihydropyrimidinone
derivatives with dimethyl and diethyl acetylenedicarbox-
ylate using both ultrasonic irradiation method and a more
conventional magnetic stirring method.
FT-IR, 13C and H-NMR, UV–Vis spectrophotometer and
1
elements analysis.
General procedure for synthesis of the thiazolo
[2,3-b]quinazoline and thiazolo[3,2-a]pyrimidine
derivatives
A solution of DMAD (0.001 mol, 0.140 g) or DEAD
(0.001 mol,0.172 g)in3 mlmethanolwasaddedtoasolution
of pyrimidinethione (0.001 mol) in methanol (10 cc) drop-
wise. The mixture was stirred at ambient temperature for 2 h.
The resulting yellow precipitate was filtered and washed with
cold methanol or ethanol and recrystallized with ethanol. The
product was obtained as yellow powder.
Experimental section
A multivalve ultrasonic generator (Bandlin Sonopuls Gerate-
Typ: UW 3200, Germany) equipped with a converter/trans-
ducer and titanium oscillator (horn), 12.5 mm in diameter,
operating at 50 kHz with a maximum power output of 780 W,
was used for ultrasonic irradiation. The ultrasonic generator
automatically adjusted the power level. Melting points were
determined in open capillary tubes by an Electrothermal IA
9000 melting point apparatus. IR spectra (KBr) were obtained
on a Matson-1000 FT-IR spectrometer. The 1H and 13C-NMR
spectra were recorded with a BRUKER DRX-500 AVANCE
spectrometer at 500 and 125.7 MHz, respectively, with Me4Si
as an internal standard (chemical shifts in d, ppm). Element
analyses (C, H, N and S) were performed with a EURO-
VECTOR EuroEA3000 CHNSO analyzer. UV–Vis spectra
were recorded with a CARY 100 CONC spectrophotometer.
Their results corresponded to the calculated values within
experimental error. TLC was performed on silica gel Poly-
Gram SIL G/UV 254 plates. The starting materials were
purchased from Merck and used without further purification.
All yields refer to isolated products. Pyrimidinethione deriv-
atives were synthesized by the following procedure.
General procedure for synthesis of the thiazolo[2,3-
b]quinazoline and thiazolo[3,2-a]pyrimidine
derivatives under ultrasonic irradiation
A solution of DMAD (0.001 mol, 0.140 g) or DEAD
(0.001 mol, 0.172 g) in 3 ml methanol was added to a
solution of pyrimidinethione derivatives (0.001 mol) in
methanol (4 ml) in small portions. This reaction mixture
was sonicated at 45 kHz. After the completion of reaction
(35–45 min, Table 1) as indicated by TLC, the resulting
yellow precipitate was filtered and recrystallized with
ethanol. The product was obtained as yellow powder.
(Z)-methyl 2-((E)-9-(3-chlorobenzylidene)-5-(3-
chlorophenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-
thiazolo[2,3-b]quinazolin-2-ylidene)acetate (5a)
Yellow powder. IR KBr (tmax, cm-1): 3,067 (C–H, aro-
matic), 1,723, 1,696 (C=O), 1,606, (C=N). 1H-NMR
(DMSO-d6, 500 MHz): d (ppm) = 1.55–1.57 (m, 2H, H7),
A mixture of cyclopentanone or cyclohexanone 2
(1 mmol), appropriate aldehyde 1 (2 mmol), thiourea 3
(1.2 mmol) and montmorillonite catalyst (0.6 g) or a few
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387
Table 1 Structures, yield and conditions of synthesis of thiazolo[2,3-b]quinazoline and thiazolo[3,2-a]pyrimidine derivatives (5a–5o)
Entry
Y
R
R0O
Product
m.p (°C)
Time (min)
Method
Yield %
Method
A
B
A
B
1
CH2CH2
CH2CH2
CH2CH2
CH2CH2
CH2CH2
CH2CH2
CH2CH2
CH2CH2
CH2CH2
CH2CH2
CH2CH2
CH2
3-Cl
Me
Et
5a
5b
5c
5d
5e
5f
167–170
138–140
148–150
157–160
155–156
179–182
115–118
216–219
225–228
145–147
167–170
178–181
208–210
154–157
167–171
150
150
130
130
160
140
140
155
160
145
150
150
140
145
135
45
44
40
45
55
40
43
52
56
50
55
57
50
45
35
84
81
91
92
87
89
90
87
84
86
88
84
87
88
91
89
87
94
95
92
94
93
91
89
90
92
87
92
94
95
2
3-Cl
3
3,4-OMe
3,4-OMe
2,4-Cl2
4-OMe
4-OMe
3-NO2
3-NO2
4-Me
Me
Et
4
5
Me
Me
Et
6
7
5g
5h
5i
8
Me
Et
9
10
11
12
13
14
15
Me
Me
Me
Me
Me
Me
5j
2-Cl
5k
5l
4-Cl
CH2
4-OMe
4-Me
5m
5n
5o
CH2
CH2
3,4-OMe
1.79–1.83 (m, 1H, H6), 2.21–2.24 (m, 1H, H06), 2.49–2.57
(m, 1H, H8), 2.62–2.66 (m, 1H, H08), 3.78 (s, 3H, OCH3),
5.75 (s, 1H, CH-methine), 6.75 (s, 1H, CH-thiazol ring),
7.29-7.44 (m, 8H, Ar–H), 7.47 (s, 1H, H10 vinylic). 13C-
NMR (DMSO-d6, 125.77 MHz): d (ppm) = 22.1 (CH2),
22.2 (CH2), 27.3 (CH2), 53.5 (OCH3), 59.6 (CH–N), 116.3
(CH), 121.2, 124.2, 126.8, 127.3, 128.4, 128.7, 129.5,
130.9, 131.8, 133.8, 133.9, 134.2, 135.4, 140.3, 141.1,
142.3, 150.4 (C=N), 163.8, 166.8 (C=O). Anal. Calcd. For
C26H20Cl2N2O3S: C, 61.06; H, 3.94; N, 5.48, S, 6.27.
Found: C, 60.96; H, 4.02; N, 5.66; S, 6.12 %.
(Z)-methyl 2-((E)-9-(3,4-dimethoxybenzylidene)-5-
(3,4-dimethoxyphenyl)-3-oxo-3,5,6,7,8,9-hexahydro-
2H-thiazolo[2,3-b]quinazolin-2-ylidene)acetate (5c)
Orange powder, IR KBr (tmax, cm-1): 2,999 (C–H, aromatic),
1,718, 1,629 (C=O), 1,605 (C=N). 1H-NMR (DMSO-d6,
500 MHz): d (ppm) = 1.54–1.59 (m, 2H, H7), 1.84–1.90 (m,
1H, H6), 2.17–2.21 (m, 1H, H06) 2.55–2.59 (m, H, H8),
2.62–2.68 (m, 1H, H08), 3.74 (s, 6H, 2OCH3), 3.77–3.79
(m, 9H, 3OCH3), 5.63 (s, 1H, CH-methine), 6.75 (s, 1H,
CH-thiazol ring), 6.80–6.95 (m, 6H, Ar–H), 7.36 (s, 1H,
H10 vinylic). 13C-NMR (DMSO-d6, 125.77 MHz):
d
(ppm) = 21.8 (CH2), 22.2 (CH2), 27.7 (CH2), 57.2, 57.3,
57.5, 57.5, 59.6, (OCH3) 59.1 (CH–N), 116.3, 121.2, 124.2,
126.9, 127.3, 128.4, 128.7, 129.5, 130.7, 131.8, 133.8, 133.9,
134.2, 135.4, 140.3, 141.1, 142.3, 150.4 (C=N), 163.8, 166.8
(C=O). Anal. Calcd. For C30H30N2O7S: C, 64.04; H, 5.37; N,
4.98, S, 5.70. Found: C, 64.23; H, 5.18; N, 5.06; S, 5.46 %.
(Z)-ethyl 2-((E)-9-(3-chlorobenzylidene)-5-(3-
chlorophenyl)-3-oxo-3,5,6,7,8,9-hexa hydro-2H-
thiazolo[2,3-b]quinazolin-2-ylidene)acetate (5b)
Yellow powder, IR KBr (tmax, cm-1): 3,066 (C–H, aro-
matic), 1,721, 1,693 (C=O), 1,605, (C=N). 1H-NMR
(DMSO-d6, 500 MHz): d (ppm) = 1.25 (t, J = 7.0 Hz, 3H,
CH3), 1.57–1.58 (m, 2H, H7), 1.77–1.84 (m, 1H, H6),
2.20–2.24 (m, 1H, H06), 2.50–2.59 (m, 1H, H8), 2.62–2.68
(m, 1H, H08), 4.25 (q, J = 7.0 Hz, 2H, OCH2), 5.75 (s, 1H,
CH-methine), 6.71 (s, 1H, CH-thiazol ring), 7.21–7.44 (m,
8H, Ar–H), 7.46 (s, 1H, H10 vinylic). 13C-NMR (DMSO-
d6, 125.77 MHz): d (ppm) = 14.93 (CH3), 22.2 (CH2),
22.3 (CH2), 27.3 (CH2), 59.6 (CH–N), 62.6 (OCH2),116.5
(CH), 121.2, 124.2, 126.8, 127.3, 128.4, 128.7, 129.5,
130.9, 131.7, 133.8, 133.9, 134.3, 135.4, 141.1, 141.2,
142.4, 150.5 (C=N), 163.9, 166.9 (C=O). Anal. Calcd. For
C27H22Cl2N2O3S: C, 61.72; H, 4.22; N, 5.33, S, 6.10.
Found: C, 61.88; H, 4.31; N, 5.41; S, 6.14 %.
(Z)-ethyl 2-((E)-9-(3,4-dimethoxybenzylidene)-5-(3,4-
dimethoxyphenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-
thiazolo[2,3-b]quinazolin-2-ylidene)acetate (5d)
Yellow powder, IR KBr (tmax, cm-1): 3,071 (C–H, aro-
matic), 1,717, 1,693 (C=O), 1,604 (C=N). 1H-NMR
(DMSO-d6, 500 MHz): d (ppm) = 1.25 (t, J = 7.0 Hz, 3H,
CH3), 1.56–1.60 (m, 2H, H7), 1.85–1.89 (m, 1H, H6),
2.17–2.21 (m, 1H, H06) 2.57–2.63 (m, 1H, H8), 2.66–2.70
(m, 1H, H08), 3.73 (s, 6H, 2OCH3), 3.76 (s, 6H, 2OCH3),
4.24 (q, J = 7.0 Hz, 2H, OCH2), 5.61 (s, 1H, CH-methine),
6.71 (s, 1H, CH-thiazol ring), 6.80–6.95 (m, 6H, Ar–H),
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7.35 (s, 1H, H10 vinylic). 13C-NMR (DMSO-d6,
125.77 MHz): d (ppm) = 14.9 (CH3), 22.4 (CH2), 27.3
(CH2), 27.6 (CH2), 56.2, 56.3, 56.3, 56.5 (OCH3), 56.9
(CH–N), 62.43 (OCH2), 112.4, 112.9, 114.1, 116.3, 120.4,
122.6, 130.9, 132.6, 134.0, 141.2, 148.5, 149.2, 149.5,
149.8, 163.8, 166.3 (C=O). Anal. Calcd. For C31H32N2O7S:
C, 64.57; H, 5.59; N, 4.86, S, 5.56. Found: C, 64.15; H,
5.71; N, 4.97; S, 5, 42 %.
500 MHz): d (ppm) = 1.26 (t, J = 7.1 Hz, 3H, CH3),
1.53–1.59 (m, 2H, H7), 1.80–1.86 (m, 1H, H6), 2.15–2.20
(m, 1H, H06), 2.51–2.55 (m, 1H, H8), 2.66–2.69 (m, 1H,
H08), 3.74 (s, 3H, OCH3), 3.75 (s, 3H, OCH3), 4.26 (q,
J = 7.1 Hz, 2H, OCH2), 5.63 (s, 1H, CH-methine), 6.71 (s,
1H, CH-thiazol ring), 6.92–6.95 (m, 4H, Ar–H), 7.23–7.26
(m, 2H, Ar–H), 7.30–7.32 (m, 2H, Ar–H),7.35 (s, 1H, H10
vinylic). 13C-NMR (DMSO-d6, 125.77 MHz):
d
(ppm) = 14.9 (CH3), 22.3 (CH2), 27.3 (CH2), 27.5 (CH2),
55.9, 56.0 (OCH3), 59.6 (CH–N), 62.4 (OCH2), 114.6,
115.0, 116.3, 120.4, 124.9, 129.7, 130.6, 131.4, 132.1,
132.3, 134.1, 141.1, 149.9, 158.8, 160.2, 163.8, 166.3
(C=O). Anal. Calcd. For C29H28N2O5S: C, 67.42; H, 5.46;
N, 5.42, S, 6.21. Found: C, 67.63; H, 4.57; N, 5.87; S,
6.33 %.
(Z)-methyl 2-((E)-9-(2,4-dichlorobenzylidene)-5-(2,4-
dichlorophenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-
thiazolo[2,3-b]quinazolin-2-ylidene)acetate (5e)
Yellow powder, IR KBr (tmax, cm-1): 3,067 (C–H, aro-
matic), 1,724, 1,695 (C=O), 1,604, (C=N). 1H-NMR
(DMSO-d6, 500 MHz): d (ppm) = 1.56–164 (m, 2H, H7),
1.75–1.78 (m, 1H, H6), 2.15–2.18 (m, 1H, H06) 2.54, 2.59
(m, H, H8), 2.64–2.67(m, 1H, H08), 3.77 (s, 3H, OCH3),
6.10 (s, 1H, CH-methine), 6.75 (s, 1H, CH-thiazol ring),
7.33–7.59 (m, 6H, Ar–H), 7.65 (s, 1H, H10 vinylic). 13C-
NMR (DMSO-d6, 125.77 MHz): d (ppm) = 22.1 (CH2),
22.3 (CH2), 27.3 (CH2), 55.4 (OCH3), 59.6 (CH–N), 116.8,
121.2, 124.2, 126.8, 127.3, 128.5, 128.8, 129.4, 131.0,
132.1, 133.9, 133.9, 134.3, 135.4, 141.1, 141.2, 142.4,
151.1(C=N), 163.9, 167.1 (C=O). Anal. Calcd. For
C26H18Cl4N2O3S: C, 53.81; H, 3.13; N, 4.83, S, 5.53.
Found: C, 53.61; H, 3.39; N, 5.11; S, 5.67 %.
(Z)-methyl 2-((E)-9-(3-nitrobenzylidene)-5-(3-
nitrophenyl)-3-oxo-3,5,6,7,8,9-hexa hydro-2H-
thiazolo[2,3-b]quinazolin-2-ylidene)acetate (5h)
Yellow powder, IR KBr (tmax, cm-1): 3,069 (C–H, aro-
matic), 1,725, 1,690 (C=O), 1,607, (C=N). 1H-NMR
(DMSO-d6, 500 MHz): d (ppm) = 1.58 (br, 2H, H7),
1.79–1.83 (m, 1H, H6) 2.26–2.29 (m, 1H, H06), 2.51–2.54
(m, 1H, H8), 2.70–2.73 (m, 1H, H08), 3.78 (s, 3H, OCH3),
5.75 (s, 1H, CH-methine), 6.68 (s, 1H, CH-thiazol ring),
7.51 (s, 1H, H10 vinylic), 7.63-7.91 (m, 8H, Ar–H). 13C-
NMR (DMSO-d6, 125.77 MHz): d (ppm) = 22.2 (CH2),
26.2 (CH2), 27.65 (CH2), 58.2 (OCH3) 59.5 (CH–N),
116.9, 122.4, 122.7, 123.3, 123.7, 124.5, 124.5, 129.9,
132.5, 134.2, 135.3, 139.3, 140.2, 142.7, 148.8, 149.7,
150.2, 164.1, 167.2 (C=O). Anal. Calcd. For C26H20N4O7S:
C, 58.64; H, 3.79; N, 10.52, S, 6.02. Found: C, 58.35; H,
3.44; N, 10.68; S, 6.19 %.
(Z)-methyl 2-((E)-9-(4-methoxybenzylidene)-5-(4-
methoxyphenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-
thiazolo[2,3-b]quinazolin-2-ylidene)acetate (5f)
Yellow powder, IR KBr (tmax, cm-1): 3,001 (C–H, aro-
matic), 1,719, 1,698 (C=O), 1,605, (C=N). 1H-NMR
(DMSO-d6, 500 MHz): d (ppm) = 1.57–1.63 (m, 2H, H7),
1.78, 1.80 (m, H, H6), 2.20–2.24 (m, 1H, H06), 2.56–2.67
(m, 1H, H8), 2.69–2.72 (m, 1H, H08), 3.73 (s, 6H, OCH3),
3.78 (s, 3H, OCH3), 5.63 (s, 1H, CH-methine), 6.76 (s, 1H,
CH-thiazol ring), 6.95–7.45 (m, 8H, Ar–H), 7.62 (s, 1H,
H10 vinylic). 13C-NMR (DMSO-d6, 125.77 MHz): d
(ppm) = 22.4 (CH2), 27.3 (CH2), 27.5 (CH2), 55.8, 55.9,
56.0 (OCH3), 59.6 (CH–N), 115.1, 115.9, 117.3, 120.7,
125.0, 129.7, 130.9, 131.4, 132.4, 132.5, 134.2, 142.1,
150.0, 158.9, 161.1, 163.9, 167.2 (C=O). Anal. Calcd. For
C28H26N2O5S: C, 66.91; H, 5.21; N, 5.57, S, 6.38. Found:
C, 70.14; H, 5.09; N, 5.45; S, 6.22 %.
(Z)-ethyl 2-((E)-9-(3-nitrobenzylidene)-5-(3-
nitrophenyl)-3-oxo-3,5,6,7,8,9-hexa hydro-2H-
thiazolo[2,3-b]quinazolin-2-ylidene)acetate (5i)
Yellow powder, IR KBr (tmax, cm-1): 3,086 (C–H, aro-
matic), 1,722, 1,691 (C=O), 1,608, (C=N). 1H-NMR
(DMSO-d6, 500 MHz): d (ppm) = 1.25 (t, J = 7.0 Hz, 3H,
CH3), 1.59 (br, 2H, H7), 1.79–1.83 (m, 1H, H6), 2.27–2.30
(m, 1H, H06), 2.55–2.57 (m, 1H, H8), 2.71–2.74 (m, 1H,
H08), 4.25 (q, J = 7.0 Hz, 2H, OCH2), 6.00 (s, 1H, CH-
methine), 6.72 (s, 1H, CH-thiazol ring), 7.52 (s, 1H, H10
vinylic), 7.52 (s, 1H, H10 vinylic), 7.67 (t, J = 5.0 Hz, 1H,
Ar–H) 7.71 (t, J = 5.0 Hz, 1H, Ar–H), 7.82 (t, J = 5.0 Hz,
1H, Ar–H), 8.10 (d, J = 7.9, 1H, Ar–H), 8.15 (s, 1H, Ar–
H), 8.21 (d, J = 8.0 Hz, 1H, Ar–H), 8.23 (s, 1H, Ar–H).
13C-NMR (DMSO-d6, 125.77 MHz): d (ppm) = 14.9
(CH3), 22.1 (CH2), 27.1 (CH2), 27.2 (CH2), 59.3 (CH–N),
62.5 (OCH2), 116.7, 121.4, 122.2, 123.5, 123.6, 124.2,
(Z)-ethyl 2-((E)-9-(4-methoxybenzylidene)-5-(4-
methoxyphenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-
thiazolo[2,3-b]quinazolin-2-ylidene)acetate (5g)
Orange powder, IR KBr (tmax, cm-1): 3,064 (C–H, aro-
matic), 1,693 (C=O), 1,606, (C=N). H-NMR (DMSO-d6,
1
123

J IRAN CHEM SOC (2013) 10:385–392
389
124.5, 130.6, 131.5, 134.1, 134.9, 139.4, 140.9, 141.8,
148.7, 148.8, 150.7, 163.9, 166.3 (2C, C=O). Anal. Calcd.
For C27H22N4O7S: C, 59.33; H, 4.06; N, 10.25, S, 5.87.
Found: C, 59.07; H, 4.16; N, 10.42; S, 6.02 %.
CH-methine), 6.77 (s, 1H, CH-thiazol ring), 7.37–7.73 (m,
8H, Ar–H), 7.74 (s, 1H, H9 vinylic). 13C-NMR (DMSO-d6,
125.77 MHz): d (ppm) = 22.9 (CH2), 28.9 (CH2), 53.4
(OCH3), 57.6 (CH–N), 124.8, 126.9, 128.7, 129.5, 130.9,
132.6, 133.8, 133.8, 134.3, 135.5, 140.2, 141.3, 142.6,
157.0 (C=N), 165.9, 167.7 (C=O). Anal. Calcd. For
C26H20Cl2N2O3S: C, 61.06; H, 3.94; N, 5.48, S, 6.27.
Found: C, 60.89; H, 4.03; N, 5.67; S, 6.30 %.
(Z)-methyl 2-((E)-9-(4-methylbenzylidene)-3-oxo-5-p-
tolyl-3,5,6,7,8,9-hexahydro-2H-thiazolo[2,3-
b]quinazolin-2-ylidene)acetate (5j)
Orange powder, IR KBr (tmax, cm-1): 3,001, 3,063 (C–H,
(Z)-methyl 2-((E)-8-(4-methylbenzylidene)-5-p-tolyl-
7,8-dihydrocyclopenta[d] thiazolo[3,2-a]pyrimidin-
2(3H,5H,6H)-ylidene)acetate (5n)
aromatic), 1,717 (2C=O), 1,605, (C=C). 1H-NMR (DMSO-
d6, 500 MHz):
d (ppm) = 1.55–158 (m, 2H, H7),
1.82–1.86 (m, 1H, H6), 2.10–2.17 (m, 1H, H06), 2.53–2.54
(m, 1H, H8), 2.68–2.71 (m, 1H, H08), 3.78 (s, 6H, CH3),
3.81 (s, 3H, OCH3), 5.63 (s, 1H, CH-methine), 6.74 (s, 1H,
CH-thiazol ring), 6.93 (d, J = 7.0 Hz, 2H, Ar–H), 6.94 (d,
J = 7.0 Hz, 2H, Ar–H), 7.24 (d, J = 8.7 Hz, 2H, Ar–H),
7.31 (d, J = 8.7 Hz, 2H, Ar–H), 7.35 (s, 1H, H10 vinylic).
13C-NMR (DMSO-d6, 125.77 MHz): d (ppm) = 22.2
(CH2), 27.1 (CH2), 27.5 (CH2), 55.9 (CH3), 56.0 (CH2,
OCH3), 59.6 (CH–N), 114.6, 115.1, 116.1, 124.9, 129.7,
130.5, 131.4, 141.3, 149.8, 158.8, 160.2, 166.8 (C=O).
Anal. Calcd. For C28H26N2O3S: C, 71.46; H, 5.57; N, 5.95,
S, 6.81. Found: C, 71.67; H, 5.69; N, 6.22; S, 6.70 %.
Orange powder, IR KBr (tmax, cm-1): 3,020 (C–H, aro-
matic), 1,720, 1,673 (2C=O), 1,607, (C=N). 13C-NMR
(DMSO-d6, 125.77 MHz): d (ppm) = 21.1 (CH3) 22.9
(CH2), 29.1 (CH2), 53.6 (OCH3), 56.9 (CH–N), 124.7,
127.2, 128.7, 129.6, 131.2, 132.8, 133.5, 133.6, 134.2,
135.4, 140.1, 141.3, 142.7, 156.1 (C=N), 165.8, 167.7
(C=O). Anal. Calcd. For C27H24N2O3S: C, 71.03; H, 5.30;
N, 6.14, S, 7.02. Found: C, 70.97; H, 5.17; N, 6, 38; S,
7.13 %.
(Z)-methyl 2-((E)-8-(3,4-dimethoxybenzylidene)-5-
(3,4-dimethoxyphenyl)-7,8-dihydro
(Z)-methyl 2-((E)-9-(2-chlorobenzylidene)-5-(2-
chlorophenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-
thiazolo[2,3-b]quinazolin-2-ylidene)acetate (5k)
cyclopenta[d]thiazolo[3,2-a]pyrimidin-2(3H,5H,6H)-
ylidene)acetate(5o)
Yellow powder, IR KBr (tmax, cm-1): 3,057, 3,067 (C–H,
Yellow powder, IR KBr (tmax, cm-1): 3,066 (C–H, aro-
matic), 1,723, 1,699 (2C=O), 1,605, (C=N). 1H-NMR
(DMSO-d6, 500 MHz): d (ppm) = 1.57 (br, 2H, H7),
1.79–1.82 (m, 1H, H6) 2.20–2.24 (m, 1H, H06), 2.52–2.55
(m, 1H, H8), 2.66–2.69 (m, 1H, H08), 3.78 (s, 3H, OCH3),
5.74 (s, 1H, CH-methine), 6.74 (s, 1H, CH-thiazol ring),
7.29–7.31 (m, 4H, Ar–H), 7.38–7.39 (m, 2H, Ar–H),
7.40–7.42 (m, 2H, Ar–H), 7.47 (s, 1H, H10 vinylic). 13C-
NMR (DMSO-d6, 125.77 MHz): d (ppm) = 22.2 (CH2),
22.3 (CH2), 27.4 (CH2), 55.9 (OCH3), 59.6 (CH–N), 117.4
(CH), 122.1, 124.3, 126.8, 127.2, 128.7, 128.8, 129.6,
130.8, 131.9, 133.6, 133.9, 134.5, 135.4, 141.1, 141.14,
142.6, 151.1 (C=N), 164.7, 166.9 (2C=O). Anal. Calcd. For
C26H20Cl2N2O3S: C, 61.06; H, 3.94; N, 5.48, S, 6.27.
Found: C, 61.33; H, 3.79; N, 5.64; S, 6.13 %.
aromatic), 1,721 (2C=O), 1,612, (C=N). 1H-NMR (DMSO-
d6, 500 MHz):
d (ppm) = 2.23–2.29 (m, 2H, H6),
2.37–2.40 (m, 2H, H7), 3.77–3.79 (s, 15H, OCH3), 5.96 (s,
1H, CH-methine), 6.85 (s, 1H, CH-thiazol ring), 7.16–7.43
(m, 6H, Ar–H), 7.48 (s, 1H, H9 vinylic). 13C-NMR
(DMSO-d6, 125.77 MHz): d (ppm) = 22.0 (CH2), 28.5
(CH2), 53.6 (OCH3), 55.3, 56.7 (OCH3) 56.9 (CH–N),
111.1, 112.7, 112.9, 119.7, 120.4, 122.6, 131.7, 132.8,
134.5, 141.4, 148.3, 149.7, 149.7, 158.3, 160.5 (C=N),
164.6, 167.7 (C=O). Anal. Calcd. For C29H28N2O7S: C,
63.49; H, 5.14; N, 5.11, S, 5.84. Found: C, 63.24; H, 5.17;
N, 5.23; S, 5.78 %.
(Z)-methyl 2-((E)-8-(4-methoxybenzylidene)-5-(4-
methoxyphenyl)-7,8-dihydro cyclopenta-
[d]thiazolo[3,2-a]pyrimidin-2(3H,5H,6H)-
ylidene)acetate (5m)
(Z)-methyl 2-((E)-8-(4-chlorobenzylidene)-5-(4-
chlorophenyl)-7,8-dihydro cyclopenta[d] thiazolo[3,2-
a]pyrimidin-2(3H,5H,6H)-ylidene)acetate (5l)
Orange powder, IR KBr (tmax, cm-1): 3,043 (C–H, aro-
matic), 1,722, 1,670 (2C=O), 1,606, (C=N). 1H-NMR
(DMSO-d6, 500 MHz): d (ppm) = 2.20–2.24 (m, 2H, H6),
2.34–2.38 (m, 2H, H7), 3.75 (s, 6H, 2OCH3), 3.82 (s, H,
OCH3), 5.94 (s, 1H, CH-methine), 6.87 (s, 1H, CH-thiazol
ring), 7.12–7.52 (m, 8H, Ar–H), 7.51 (s, 1H, H9 vinylic).
Yellow powder, IR KBr (tmax, cm-1): 3,036 (C–H, aro-
matic), 1,732, 1,700 (2C=O), 1,609, (C=N). 1H-NMR
(DMSO-d6, 500 MHz): d (ppm) = 2.76–2.83 (m, 2H, H6),
2.89–294 (m, 2H, H7), 3.80 (s, 3H, OCH3), 6.06 (s, 1H,
123

390
J IRAN CHEM SOC (2013) 10:385–392
13C-NMR (DMSO-d6, 125.77 MHz): d (ppm) = 22.1
(CH2), 28.7 (CH2), 53.2 (OCH3), 56.1, 56.1 (OCH3) 56.93
(CH–N), 114.1, 114.5, 124.4, 131.8, 132.9, 134.4, 137.9,
139.2, 140.3, 158.3, 159.5, 159.8, 160.5 (C=N), 165.1,
167.2 (C=O). Anal. Calcd. For C27H24N2O5S: C, 66.38; H,
4.95; N, 5.73, S, 6.56. Found: C, 66.15; H, 5.02; N, 5.83; S,
6.47 %.
The formation of compound 5a was confirmed by the
absence of amino group absorptions in the IR spectra,
absence of the signals one of the COOR and the (N1), (N3)
protons, which were present in the spectra of the starting
materials in the 1H-NMR spectra and appear as signals of
the protons of the C=CH unit in the thiazol ring as a singlet
around 6.70 ppm in the 1H-NMR spectra.
Compound 5a also reveals C–H absorption of the aro-
matic ring at 3,067 cm-1, carbonyl groups at 1,723,
1,696 cm-1 and C=N, C=C at 1,606, 1,474 cm-1 respec-
Results and discussion
1
tively, in the FT-IR spectra. The H-NMR spectrum of 5a
The preparation of quinazoline and pyrimidine compounds
has been developed over the years. Continuing from our
synthesis of five-membered S, N-heterocyclic thiazoline
[30], we wish to report another heterocyclic compound
from pyrimidinone derivatives. In our earlier studies, we
have reported the reaction of thiosemicarbazone deriva-
tives with DAMAD and DEAD at ambient temperature.
Herein, we have reacted DMAD and DEAD with a dif-
ferent dihydropyrimidinethione using both ultrasonic irra-
diation method and a conventional method. In this pursuit,
we examined the reaction of pyrimidinone derivative 4a
with dialkyl acetylenedicarboxylate in methanol at ambient
temperature. This led to excellent yield (84–92 %) of
thiazolo[2,3-b]quinazoline and thiazolo[3,2-a]pyrimidine
derivatives 5a–o at 130–160 min (Scheme 2).
indicates one singlet at d 7.46 ppm, related to the protons
of HC=C H9 vinylic, (d 5.75) which is related to
CH-methaine, (d 3.78) which in turn is related to the pro-
tons of the –CH3 methoxy group. The 13C-NMR spectrum
of 5a indicates carbonyl group carbons (C=O, NC=O) and
imino group (C=N) at 166.85 and 163.83 ppm. The mass
spectral data and elemental analyses are also in accordance
with the proposed structure. In general, all of the spectral
data support the structures for all of the compounds
(5a–5o). The structure of all the thiazole derivatives,
reaction conditions and product yields are given in Table 1.
To improve our studies, the synthesis of the same
compounds 5a–o was performed using ultrasound irradia-
tion at room temperature for short reaction times. We
examined the reaction of pyrimidinethione derivative 4
with dialkyl acetylenedicarboxylate promoted by ultra-
sound in methanol to give the corresponding thiazolo[2,3-
b]quinazoline and thiazolo[3,2-a]pyrimidine derivatives
5a–o in excellent yield (87–95 %) only in 35–57 min
(Table 1). Ultrasonic irradiation displays dramatically
reduced reaction times compared to conventional magnetic
stirring method and also affords the desired products in
high yields and purity (Scheme 2; Table 1).
The structures of target compounds were appropriately
1
characterized by spectral data. For example, the H-NMR
of spectra of thiazolo[2,3-b]quinazoline derivatives show
that these compounds are chiral.
For example, the 1H-NMR spectrum of compound 5a
shows two multiple signals at 2.48 and 2.66 ppm, which
belong to H1 and H2 of C8, and two multiples at 1.81,
2.22 ppm, which belong to H1 and H2 of C6 in compound
5a. The other methylene group appeared at 1.56 ppm in the
1H-NMR spectrum.
The UV–visible absorption of 5a–5n demonstrates
major absorption in wavelength ranges of 272.15–362.19 nm
Scheme 2 Synthesis of the
thiazolo[2,3-b]quinazoline and
thiazolo[3,2-a]pyrimidine
R
derivatives under ultrasonic
irradiation
R
O
Y
N
R
N
S
CO2R'
5a
NH
MeOH
3
Y
R'O2C
C C CO2R'
R
1
N
S
)))))
H
R
4
O
Y
R' =CH3, CH2CH3
N
Y = CH2, CH2CH2
R
N
S
CO2R'
6a
no isolated
123

J IRAN CHEM SOC (2013) 10:385–392
391
only the desired products of cyclization 5a were isolated in
87–95 % yield.
Table 2 UV–Vis absorption of 5a–5i in DMSO at 25 °C
Entry
Product
kmax (nm)
Two types of cyclic products could be obtained in the
reaction media (5 and 6, Scheme 2). As a result of the
conjugate addition of the sulfur center and intermolecular
N-acylation, the corresponding thiazolone (5a) was iso-
lated as a major product, stabilized by S–O and S–N close
contact interactions involving the other carbomethoxy
group in a double conjugate addition, followed by spon-
taneous dehydrogenation. Methyl-[1, 3]thiazin-4-one-6-
carboxylate (6a) can be interpreted to be formed by the
conjugate addition of the sulfur center and alternative
N-acylation, presumably furnishing a six-membered ring.
As the product ratio 5a/6a increases with longer reaction
time, thiazinone (6a) seems to be an unstable kinetic
product undergoing ring isomerization to 5a, catalyzed by
methanol, which is released in the reaction mixture and
can cleave the six-membered lactame at elevated tem-
perature [35, 36]. The recyclization of the resulting
intermediate, involving the methoxycarbonyl group sep-
arated by one carbon from the sulfur atom, leads to the
final product.
1
5a
5b
5c
5d
2e
5f
314.86
2
315.44
3
326.41
4
323.52
5
279.07, 313.71
362.19
6
7
5g
5h
5i
317.17
8
272.15
9
275.61
10
11
12
5j
317.17
5k
5n
313.70, 317.17
335.64
in DMSO solvent at room temperature, as indicated in
Table 2.
As revealed therein, using conventional magnetic stir-
ring, the resulting product was obtained with 84–92 %
yield after 130–160 min (Table 1). However, under ultra-
sonic irradiation, with the power 360 W, irradiation fre-
quency of 47 kHz and reaction temperature of 30–35 °C,
excellent product yield (87–95 %) was obtained after only
35–57 min (Table 1).
The reaction is mainly condensation, followed by
cyclization. Initially, the sulfur atom from pyrimidinethi-
one attacks the carbon triplet bond of acetylenic ester
compound, which is prone to nucleophilic attack. Then
cyclization proceeds on to the esteric (CO2R) function to
give products 5 and 6 in excellent yield (Scheme 3). A
plausible mechanism has been proposed for the reactions of
pyrimidinone derivatives with DMAD and DEAD to yield
ethyl-5-(aryl)-2-(2-alkoxy-2-oxoethylidene)-7-methyl-3-
oxo-3, 5-dihydro-2H thiazolo[3,2a]pyrimidine-6-car-
boxylate derivatives as shown in Scheme 3.
In these reactions, compound 4 contains two nucleophile
nitrogens. Because of the more nucleophilic nature of N3
compared to N1 (Scheme 2), compound 5a (N3 regioi-
somers) were isolated as the main product, whereas other
products (N3 regioisomers) were not isolated. Therefore in
each of the examples studied, the formation of products of
N3 or N1 cyclization was possible [31–34], but in all cases
Scheme 3 Suggested
R
R
mechanism for synthesis of the
thiazolo[2,3-b]quinazoline and
thiazolo [3,2-a]pyrimidine
derivatives
O
OR'
CO2R'
H
S
NH
N
Y
Y
R'O2C
C C CO2R'
N
S
N
H
R
R
R
O
N
Y
S
CO2R'
N
R
major product
123

392
J IRAN CHEM SOC (2013) 10:385–392
10. N. Hans, Swiss Patent, 592103, 1977
11. N. Hans, Chem. Abstr. 88, 22886 (1978)
Conclusion
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Zhu, S. Werner, D.M. Huryn, J.M. Pipas, B.W. Day, P. Wipf, J.L.
Brodsky, Bioorg. Med. Chem. 16, 329 (2008)
This successful synthesis of thiazolo[2,3-b]quinazoline and
thiazolo[3,2-a]pyrimidine demonstrated that addition of
pyrimidinone to alkylacetylenic ester and then cyclization
of intermediate compounds is a feasible method for the
synthesis of fused oxo-thiazoles.
The synthesized thiazolo[2,3-b]quinazoline and pyr-
ido[4,3-d]thiazolo[3,2-a]pyrimidine analogs could be con-
sidered as useful templates in future to obtain more potent
antitumor agents.
16. S.W. Fewell, C.M. Smith, M.A. Lyon, T.P. Dumitrescu, P. Wipf,
B.W. Day, J.L. Brodsky, J. Biol. Chem. 279, 51131 (2004)
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P. Wipf, J. Massague, X. Jiang, J.L. Brodsky, G.W. Krystal,
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(2010)
In conclusion, we have developed two different simple
synthetic methods to prepare thiazolo[2,3-b]quinazoline
and thiazolo[3,2-a]pyrimidine derivatives, conventional
magnetic stirring and ultrasonic irradiation. Both the
methods led to excellent yield. Ultrasonic irradiation dis-
plays dramatically reduced reaction times compared to
conventional magnetic stirring method and also provides
the desired products in high yields and purity.
23. R.R. Deshmukh, R. Rajagopal, K.V. Srinivasan, Chem. Commun.
17, 1544 (2001)
Acknowledgments We gratefully acknowledge the financial sup-
port for this project of Vali-e-Asr University of Rafsanjan Faculty
Research Grant.
24. R. Rajagopal, D.V. Jarikote, K.V. Srinivasan, Chem. Commun.
65, 616 (2002)
´
´
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