Benzo[h]thiazolo[2,3-b]quinazolines by an efficient p-toluenesulfonic acid-catalyzed one-pot two-step tandem reaction

Article abstract of DOI:10.1007/s11164-015-2112-4

A highly efficient method has been developed for synthesis of 7,9-disubstituted-6,7-dihydro-5H-benzo[h]thiazolo[2,3-b]quinazolines via multicomponent one-pot two-step tandem reaction involving 1-tetralone, arylaldehydes, thiourea, and 4-chlorophenacyl bromide/(3-bromoacetyl)coumarin utilizing p-toluenesulfonic acid as catalyst in glacial acetic acid under reflux conditions. Analytically pure products are formed with excellent yield and short reaction time. All the synthesized compounds were confirmed by their spectral and elemental analyses. Graphical abstract: [Figure not available: see fulltext.]

Full text of DOI:10.1007/s11164-015-2112-4

Res Chem Intermed
DOI 10.1007/s11164-015-2112-4
Benzo[h]thiazolo[2,3-b]quinazolines by an efficient
p-toluenesulfonic acid-catalyzed one-pot two-step
tandem reaction
B. Sakram1
B. Sonyanaik1 K. Ashok1
•
•
•
S. Rambabu1 S. K. Johnmiya1
•
Received: 24 March 2015 / Accepted: 21 May 2015
Ó Springer Science+Business Media Dordrecht 2015
Abstract A highly efficient method has been developed for synthesis of 7,9-disub-
stituted-6,7-dihydro-5H-benzo[h]thiazolo[2,3-b]quinazolines via multicomponent one-
pot two-step tandem reaction involving 1-tetralone, arylaldehydes, thiourea, and
4-chlorophenacyl bromide/(3-bromoacetyl)coumarin utilizing p-toluenesulfonic acid as
catalyst in glacial acetic acid under reflux conditions. Analytically pure products are
formed with excellent yield and short reaction time. All the synthesized compounds were
confirmed by their spectral and elemental analyses.
Graphical abstract
Keywords Benzo[h]thiazolo[2,3-b]quinazoline Á Coumarin Á Multicomponent
reaction Á Phenacyl bromide Á 1-Tetralone
Electronic supplementary material The online version of this article (doi:10.1007/s11164-015-2112-
4) contains supplementary material, which is available to authorized users.
&
B. Sakram
bschemou@gmail.com
1
Department of Chemistry, Osmania University, Hyderabad 500007, Telangana State, India
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B. Sakram et al.
Introduction
In recent years, increasing interest has been focused on synthesis of thiazolopy-
rimidine and thiazoloquinazoline derivatives owing to their significant biological
activities that include antimicrobial [1, 2], antiviral [3], antioxidant [4], anticancer
[5], antiinflammatory [6], antihypertensive [7], antiparkinsonian [8], anti-human
immunodeficiency virus (HIV) [9], and antibiofilm [10] properties. They have also
been reported as calcium antagonists [11], group 2 metabotropic glutamate receptor
antagonists [12], 5-HT2 receptor antagonists [13, 14], and inhibitors of enzymes
such as xanthine oxidase [15], acetylcholinesterase [16], and CDC25B phosphatise
[17]. Some of the biologically potent thiazolopyrimidine and thiazoloquinazoline
derivatives are given in Fig. 1.
A variety of synthetic methods have been reported for preparation of thiazolopy-
rimidine and thiazoloquinazoline derivatives. One of the commonest methods
involves cyclization of dihydropyrimidinethiones with 1,2-dielectrophiles such as
2-bromoketones [18, 19], chloroacetyl chloride [17], chloroacetic acid [3, 6, 10],
methyl chloroacetate [20], and N-aryl-2-chloroacetamides [21]. Most of these
methods involve two steps: Biginelli reaction as well as cyclization. To the best of our
knowledge, there is no direct route for construction of the thiazolopyrimidine scaffold
in a one-pot procedure. Nowadays, multicomponent reactions have emerged as an
efficient and powerful tool in modern organic chemistry towards generation of highly
diverse and complex products in a single operation without isolation of intermediates
in minimal time with maximum selectivity [22, 23]. Therefore, we envisaged a novel
one-pot two-step tandem reaction for construction of thiazoloquinazoline derivatives
involving 1-tetralone, arylaldehyde, thiourea, and 4-chlorophenacyl bromide/(3-
bromoacetyl)coumarin in presence of p-toluenesulfonic acid as catalyst.
Experimental
Materials and methods
All the reagents and solvents were procured from Aldrich/Merck and used without
further purification. Melting points were recorded using a Cintex melting point
apparatus and are uncorrected. Reaction progress as well as compound purity were
monitored with F254 silica-gel precoated thin-layer chromatography (TLC) plates
using hexane:ethyl acetate (8:3) as eluent, and the developed chromatogram was
Fig. 1 Biologically active thiazolopyrimidine and thiazoloquinazoline derivatives
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Benzo[h]thiazolo[2,3-b]quinazolines by an efficient…
visualized under ultraviolet (UV) light and iodine vapors. Infrared (IR) spectra were
recorded on a Bruker Tensor 27 series Fourier-transform (FT)-IR spectrophotometer
using KBr pellets. Proton nuclear magnetic resonance (1H NMR) spectra were
recorded on a Bruker 400-MHz spectrometer using deuterated dimethyl sulfoxide
(DMSO-d6) as solvent and tetramethylsilane (TMS) as internal standard. Mass spectra
were recorded on a Jeol JMSD-400 spectrometer. Elemental analyses were performed
on a Carlo-Erba model EA1108 analytical unit, and the values are within 0.4 % of
theoretical values.
General procedure for synthesis of 7,9-disubstituted-6,7-dihydro-5H-
benzo[h]thiazolo[2,3-b]quinazolines (4a–f, 5a–f)
p-Toluenesulfonic acid (20 mol%) was added to a mixture of 1-tetralone (1 mmol),
aryl aldehyde (2a–f, 1 mmol), and thiourea (1 mmol) in glacial acetic acid (10 mL),
and refluxed for 30 min. Subsequently, 4-chlorophenacyl bromide/3-(2-bro-
moacetyl)-2H-chromen-2-one (1 mmol) was added to the mixture and further
refluxed for 1–2 h. The progress of the reaction was monitored by TLC. After
completion of the reaction, the mixture was poured into ice-cold water. The solid
separated out was filtered, washed with water, and recrystallized from ethanol.
Spectral data of representative compounds
9-(4-Chlorophenyl)-7-phenyl-6,7-dihydro-5H-benzo[h]thiazolo[2,3-b]quinazoline
(4a)
1
White solid; IR (KBr, mmax, cm-1): 1605 (C=N), 825 (C–Cl); H NMR (400 MHz,
DMSO-d6): d (ppm) 1.76 (t, 1H, J = 7.6 Hz), 2.33 (t, 1H, J = 8.0 Hz), 2.57–2.79
(m, 2H), 6.16 (s, 1H), 6.84 (d, 2H, J = 6.4 Hz), 7.17–7.46 (m, 11H), 7.65 (d, 1H,
J = 6.8 Hz); Mass (ESI) m/z: 426 [M]?; Anal. calcd. for C26H19ClN2S: C, 73.14;
H, 4.49; N, 6.56; Found: C, 73.34; H, 4.62; N, 6.37.
9-(4-Chlorophenyl)-7-(4-methoxyphenyl)-6,7-dihydro-5H-benzo[h]thiazolo[2,3-
b]quinazoline (4d)
Pale-yellow solid; IR (KBr, mmax, cm-1): 1608 (C = N), 1245 (C–O–C), 823 (C–
1
Cl); H NMR (400 MHz, DMSO-d6): d (ppm) 1.75–1.82 (m, 1H), 2.28–2.35 (m,
1H), 2.60 (t, 1H, J = 8.4 Hz), 2.75–2.83 (m, 1H), 3.67 (s, 3H), 6.09 (s, 1H),
6.69–6.75 (m, 4H), 7.26–7.40 (m, 6H), 7.49 (d, 2H, J = 8.4 Hz), 7.63 (d, 1H,
J = 7.6 Hz); Mass (ESI) m/z: 457 [M ? H]?; Anal. calcd. for C27H21ClN2OS: C,
70.96; H, 4.63; N, 6.13; Found: C, 70.71; H, 4.80; N, 6.29.
3-(7-(4-Chlorophenyl)-6,7-dihydro-5H-benzo[h]thiazolo[2,3-b]quinazolin-9-yl)-
2H-chromen-2-one (5c)
White solid; IR (KBr, mmax, cm-1): 1741 (C=O), 1635 (C=N), 840 (C–Cl); 1H NMR
(400 MHz, DMSO-d6): d (ppm) 1.73–1.78 (m, 1H), 2.27–2.35 (m, 1H), 2.60–2.66
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B. Sakram et al.
(m, 1H), 2.76–2.81 (m, 1H), 6.26 (s, 1H), 7.23–7.27 (m, 5H), 7.34–7.51 (m, 5H),
7.64–7.75 (m, 3H), 7.94 (s, 1H); Mass (ESI) m/z: 495 [M ? H]?; Anal. calcd. for
C29H19ClN2O2S: C, 70.37; H, 3.87; N, 5.66; Found: C, 70.61; H, 3.66; N, 5.89.
3-(7-(3,4-Dimethoxyphenyl)-6,7-dihydro-5H-benzo[h]thiazolo[2,3-b]quinazolin-9-
yl)-2H-chromen-2-one (5e)
1
White solid; IR (KBr, mmax, cm-1): 1734 (C=O), 1636 (C=N), 1261 (C–O–C); H
NMR (400 MHz, DMSO-d6): d (ppm) 1.76–1.83 (m, 1H), 2.29 (t, 1H, J = 8.0 Hz),
2.61–2.66 (m, 1H), 2.76–2.80 (m, 1H), 3.26 (s, 3H), 3.59 (s, 3H), 6.15 (s, 1H), 6.68
(s, 1H), 6.75 (s, 2H), 7.25–7.50 (m, 6H), 7.66–7.65 (m, 3H), 7.88 (s, 1H); Mass
(ESI) m/z: 521 [M ? H]?; Anal. calcd. for C31H24N2O4S: C, 71.52; H, 4.65; N,
5.38; Found: C, 71.35; H, 4.80; N, 5.51.
Results and discussion
A schematic for the formation of 7,9-disubstituted-6,7-dihydro-5H-benzo[h]thia-
zolo[2,3-b]quinazoline derivatives (4a–f, 5a–f) via one-pot two-step tandem
reaction catalyzed by p-toluenesulfonic acid is shown in Scheme 1. 4-Aryl-
3,4,5,6-tetrahydrobenzo[h]quinazoline-2(1H)-thiones, which were obtained in situ
by reaction of 1-tetralone (1), aromatic aldehydes (2a–f), and thiourea (3) in glacial
acetic acid in presence of catalytic p-toluenesulfonic acid under reflux conditions,
on condensation with 4-chlorophenacyl bromide/3-(2-bromoacetyl)-2H-chromen-2-
one resulted in the formation of desired products 4a–f, 5a–f in good yields
(86–94 %). One of the starting materials, 3-(2-bromoacetyl)-2H-chromen-2-one,
was prepared following the literature procedure [24].
Scheme 1 Synthesis of 7,9-disubstituted-6,7-dihydro-5H-benzo[h]thiazolo[2,3-b]quinazolines
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Benzo[h]thiazolo[2,3-b]quinazolines by an efficient…
Table 1 Optimizing the reaction conditionsa
Entry
Amount of PTSA (mol%)
Solvent
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
9
a
–
Ethanol
12
12
12
6
–
–
Acetic acid
Acetonitrile
Ethanol
14
–
–
10
10
10
15
20
25
19
46
21
78
93
93
Acetic acid
Acetonitrile
Acetic acid
Acetic acid
Acetic acid
3
6
2
1.5
1.5
1-Tetralone (1 mmol), benzaldehyde (1 mmol), thiourea (1 mmol), 4-chlorophenacyl bromide
(1 mmol), solvent (10 mL), reflux
b
Isolated yields
Table 2 Synthesis of benzo[h]thiazolo[2,3-b]quinazoline derivatives (4a–f, 5a–f)
Producta
Aldehyde
Time (h)
Yieldb (%)
Melting point (°C)
Observed
Literature [19]
4a
4b
4c
4d
4e
4f
Benzaldehyde
1.5
1.5
1.0
1.5
1.5
2.0
1.5
1.5
1.0
1.0
1.5
1.5
93
89
94
91
92
86
92
92
93
90
91
88
320–322
300–302
319–321
260–262
231–232
290–293
290–292
280–281
282–283
275–276
270–272
294–296
319–320
301–303
317–318
260–262
233–236
292–294
290–291
277–279
280–282
275–277
267–269
293–294
4-Fluorobenzaldehyde
4-Chlorobenzaldehyde
4-Methoxybenzaldehyde
3,4-Dimethoxybenzaldehyde
4-Hydroxybenzaldehyde
Benzaldehyde
5a
5b
5c
5d
5e
5f
4-Fluorobenzaldehyde
4-Chlorobenzaldehyde
4-Methoxybenzaldehyde
3,4-Dimethoxybenzaldehyde
4-Hydroxybenzaldehyde
a
Reaction conditions: 1-tetralone (1, 1 mmol), arylaldehyde (2a–f, 1 mmol), thiourea (3, 1 mmol),
4-chlorophenacyl bromide/(3-bromoacetyl)coumarin (1 mmol), glacial acetic acid (10 mL), PTSA
(20 mol%), reflux
b
Isolated yields
Recently, Janardhan et al. [19] reported synthesis of thiazolopyrimidines in a
two-step manner, in which the first step is the formation of Biginelli product and the
second step is cyclization with various 2-bromoketones. To develop a one-pot
method, we carried out the model reaction of 1-tetralone (1), benzaldehyde (2a),
thiourea (3), and 4-chlorophenacyl bromide (4) in different solvents such as ethanol,
acetic acid, and acetonitrile under reflux conditions. Without catalyst, product
formation (4a) was not observed in ethanol or acetonitrile, whereas only 14 % was
123

B. Sakram et al.
Scheme 2 Plausible mechanism for formation of benzo[h]thiazolo[2,3-b]quinazolines
observed in acetic acid even after 12 h. Later, the same reaction was carried out in
presence of 10 mol% p-toluenesulfonic acid (PTSA), observing maximum yield
(46 %) of the product (4a) in acetic acid within 3 h. To improve the yield of the
product and to reduce the reaction time, we tested the reaction with 15, 20, and
25 mol% PTSA, and observed the maximum yield (93 %) of the product with
20 mol% PTSA in shorter reaction time (Table 1). Under these reaction conditions
(PTSA 20 mol%, acetic acid, reflux), we synthesized a series of substituted
benzo[h]thiazolo[2,3-b]quinazolines (4a–f, 5a–f) by varying the aromatic aldehyde
(2a–f) and 2-bromoketone in good to excellent yields (Table 2).
All the synthesized compounds were confirmed by IR, 1H NMR, and mass
spectral data as well as elemental analysis studies (Electronic Supplementary
Material). The melting points were also compared with literature values, showing
good agreement. The proposed mechanism for formation of the title compounds is
shown in Scheme 2. In the presence of PTSA, 4-aryl-3,4,5,6-tetrahy-
drobenzo[h]quinazoline-2(1H)-thiones were obtained through Biginelli reaction,
which on cyclization with 4-chlorophenacyl bromide/(3-bromoacetyl)coumarin
resulted in formation of corresponding benzo[h]thiazolo[2,3-b]quinazoline deriva-
tives (4a–f, 5a–f).
Conclusions
A novel and efficient method is described for construction of benzo[h]thiazolo[2,3-
b]quinazoline derivatives in a one-pot two-step manner without isolating the
Biginelli product. This methodology is high yielding in shorter reaction times and
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Benzo[h]thiazolo[2,3-b]quinazolines by an efficient…
applicable for industrial preparation of various thiazoloquinazoline derivatives in a
single step.
Acknowledgments The authors would like to thank the Head, Department of Chemistry, Osmania
University for providing research facilities. B. Sonyanaik thanks the University Grant Commission
(UGC), New Delhi for financial assistance.
Conflict of interest The authors report no conflicts of interest. The authors alone hereby stand
responsible for the contents of this scientific paper.
Ethical standard This article does not contain any studies with human participants or animals per-
formed by any of the authors.
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