Amberlyst-15 in PEG: A novel catalytic system for the facile and efficient one-pot synthesis of benzothiazolo-[2,3-b]-quinazolinone derivatives

Article abstract of DOI:10.1007/s11426-012-4665-z

A simple and convenient approach for the synthesis of tetraheterocyclic benzothiazolo-[2,3-b]-quinazolin-1-ones has been developed utilizing the MCR methodology, which involves the condensation of 2-aminobenzothiazole, cyclic β-diketones and various aldeh

Full text of DOI:10.1007/s11426-012-4665-z

SCIENCE CHINA
Chemistry
October 2012 Vol.55 No.10: 2154–2160
doi: 10.1007/s11426-012-4665-z
• ARTICLES •
Amberlyst-15® in PEG: A novel catalytic system for the facile and
efficient one-pot synthesis of benzothiazolo-[2,3-b]-quinazolinone
derivatives
MAZAAHIR Kidwai*‡, RITIKA Chauhan & DIVYA Bhatnagar
Green Chemistry Research Laboratory, Department of Chemistry, University of Delhi, Delhi-110007, India
Received November 23, 2011; accepted December 22, 2011; published online July 5, 2012
A simple and convenient approach for the synthesis of tetraheterocyclic benzothiazolo-[2,3-b]-quinazolin-1-ones has been de-
veloped utilizing the MCR methodology, which involves the condensation of 2-aminobenzothiazole, cyclic -diketones and
various aldehydes using Amberlyst-15® in PEG 400 as an environmentally benign and reusable catalyst system. Environmental
benignity, recyclability, cost-effectiveness, easy workup and excellent yields are the major attributes of this one-pot procedure.
Amberlyst-15®, benzothiazolo-[2,3-b]-quinazolinones, multi-component reaction, reusability, PEG (polyethylene glycol),
green chemistry
thetic products that exhibit a wide spectrum of biological
1 Introduction
and pharmacological activities. Thiazoloquinazolines have
also been an important class of heterocycles in drug re-
search, as they incorporate both biodynamic heterosystems
thiazole and quinazoline which have shown significant an-
ticancer activities [6]. Additionally, thiazoloquinazolines
have also been identified as cyclin-dependent kinase (CDK)
and glycogen synthase kinase-3 (GSK-3) inhibitors [7]. In
view of the importance of these polyheterocyclic com-
pounds, several methods have been quoted in the literature
[8–14]. However, these methods suffer from drawbacks
such as prolonged reaction time, use of volatile organic
solvents, harmful catalysts, low yields and harsh reaction
conditions. Therefore, the search of improved catalysts for
the synthesis of benzothiazoloquinazolinone derivatives
using an eco-friendly approach is of prime importance.
Development of efficient and practical catalysts for or-
ganic synthesis is of considerable interest to both academia
and industry [15]. In recent years, a tremendous upsurge of
interest has been observed in carrying out various chemical
transformations under heterogeneous conditions owing to
simplicity in operation, remarkable recyclability and
Multi-component reactions (MCRs), an important subclass
of tandem reactions, are one-pot processes in which three or
more accessible components react to form a single product
that incorporates essentially most or all atoms of the reac-
tants used [1]. One-pot multi-component strategies grant
remarkable advantages over conventional bimolecular reac-
tions owing to their convergence, atom-economy, opera-
tional simplicity, structural diversity and shortness of the
synthetic pathway [2]. MCRs have recently gained a new
dimension in the field of designing methods to produce
elaborate libraries of biologically active compounds [3].
The fusion of biodynamic heterosystems has emerged as
a useful tool for the design of new molecular frameworks
for potential drugs with diverse pharmacological activities
[4]. Quinazolines are very interesting heterocycles [5] as
they serve as building blocks in numerous natural and syn-
*Corresponding author (email: kidwai.chemistry@gmail.com)
‡Presently working as Vice-Chancellor, Jiwaji University, Gwalior (M. P.), India (On
Deputation from Department of Chemistry, University of Delhi, Delhi-110007, India)
© Science China Press and Springer-Verlag Berlin Heidelberg 2012
chem.scichina.com www.springerlink.com

Mazaahir K, et al. Sci China Chem October (2012) Vol.55 No.10
2155
eco-friendly nature [16]. In this regard, Amberlyst-15® pos-
sesses unique features such as environmental compatibility,
non-toxicity, reusability, non-corrosivity, chemical and
physical stability and can be used over a prolonged duration
of time [17]. Owing to the numerous advantages associated
with this cheap and non-hazardous catalyst, Amberlyst-15®
has been explored as a powerful catalyst for a plethora of
organic reactions [18–21]. Recently, polyethylene glycol
(PEG) and its monomethyl ethers have emerged as alterna-
tive green reaction media with unique properties including
thermal stability, commercial availability, non-volatility,
immiscibility with a number of organic solvents, and recy-
clability. On the other hand, PEGs are inexpensive, com-
pletely non-halogenated, easily degradable and possess low
toxicity [22]. The use of PEGs as reaction solvent has re-
ceived great amount of attention in synthetic organic chem-
istry.
followed by PEG 400 (2 mL) as a solvent. The reaction
mixture was then stirred at 50 °C until the reaction was
complete. The progress of the reaction was monitored using
TLC plates. Upon completion of the reaction, the reaction
mixture was cooled in a dry ice-acetone bath to precipitate
the PEG 400 and was extracted with ether (5 mL × 3) (PEG
400 being insoluble in ether). The ether layer was decanted,
dried over anhydrous Na2SO4 and concentrated under re-
duced pressure to produce the crude product. The recovered
PEG 400 phase along with the catalyst was reused for con-
secutive runs. The crude product, thus obtained was sub-
jected to purification by column chromatography on silica
gel (100–200 mesh size) using hexane/ethyl acetate in var-
ying proportions as eluent which afforded the respective
benzothiazoloquinazolinones, 4(a–q). The structures of all
the products were unambiguously established on the basis
1
of spectral analysis (IR, H NMR, 13C NMR), elemental
As a part of our continuing efforts in laboratory towards
the development of cheap and environmentally benign
methodologies for organic reactions [23], we decided to
couple the heterogeneous catalyst Amberlyst-15® with the
recyclable solvent PEG 400 for the mild and highly efficient
three-component synthesis of benzothiazolo-[2,3-b]-quina-
zolin-1-one derivatives.
analysis and melting point determination [24, 25]. Spectral
data for the synthesized derivatives are described below.
2.3 Regeneration of the catalyst system
After the reaction was complete, the reaction mixture was
cooled in dry-ice acetone bath to precipitate the PEG 400
and was extracted with ether. The ether layer was decanted,
dried over anhydrous Na2SO4 and concentrated under vac-
cuo to produce the crude product. The PEG 400 phase along
with resin (Amberlyst-15®) was used as such for subsequent
runs (four runs) with fresh substrates under the same condi-
tions. The recovered catalyst system showed almost the
same catalytic efficiency as the fresh catalyst.
2 Experimental
2.1 Materials and methods
All chemicals were purchased from Sigma-Aldrich and
were used without further purification. All reactions and the
purity of benzothiazolo-[2,3-b]-quinazolin-1-ones were
monitored by thin-layer chromatography (TLC) using alu-
minum plates coated with silica gel F254 plates (Merck) us-
ing 30% ethyl acetate and 70% petroleum ether (v/v) as an
eluent. The spots were detected either under UV light or by
placing in an iodine chamber. Melting points were deter-
mined in open capilliaries using a Thomas Hoover melting
point apparatus and are uncorrected. IR spectra were rec-
orded on a Perkin-Elmer FTIR-1710 spectrophotometer
2.4 Spectral data of the synthesized compounds
12-Phenyl-2,3,4,12-tetrahydro-benzo[4,5]thiazolo[2,3-b]
quinazolin-1-one (4a)
IR νmax (cm1, nujol): 3317, 2950, 1721, 1589, 1537, 1379,
1
754; H NMR (CDCl3, TMS, 400 MHz) : 1.99–2.05 (m,
2H), 2.38–2.47 (m, 2H), 2.56–2.66 (m, 2H), 5.47 (s, 1H,
ArCH), 7.09–7.20 (m, 5H, Ar–H), 7.28–7.59 (m, 4H, Ar-H);
13C NMR (CDCl3, 100 MHz) δ: 20.0, 29.8, 42.8, 56.2, 112.7,
116.4, 119.1, 120.9, 122.3, 125.8, 126.0, 126.4, 128.1, 130.5,
137.8, 152.4, 165.8, 192.1; Anal calcd. for C20H16N2OS: C,
72.26; H, 4.85; N, 8.43; Found: C, 72.08; H, 4.68; N, 8.27.
1
using KBr pellets per nujol film. H NMR and 13C NMR
spectra were recorded on a JEOL JNM-ECX 400P FT NMR
system using tetramethylsilane (TMS) as an internal stand-
ard and the value of chemical shift is in the  scale and J
value is in hertz (Hz). Elemental analysis was performed on
a Hereaus CHN rapid analyzer. The temperature of the re-
action mixture was measured through a non-contact infrared
mini gun thermometer (AZ minigun type, model 8868).
12-(4-Chloro-phenyl)-2,3,4,12-tetrahydro-benzo[4,5]thiazolo
[2,3-b]quinazolin-1-one (4b)
IR νmax (cm1, nujol): 3318, 2950, 1719, 1588, 1534, 1376,
1
544; H NMR (CDCl3, TMS, 400 MHz) : 1.98–2.05 (m,
2.2 General procedure for the synthesis of benzothia-
zolo-[2,3-b]-quinazolin-1-one derivatives
2H), 2.34–2.48 (m, 2H), 2.54–2.65 (m, 2H), 5.40 (s, 1H,
ArCH), 7.01–7.22 (m, 4H, Ar–H), 7.29–7.83 (m, 4H, Ar–H);
13C NMR (CDCl3, 100 MHz) : 20.0, 33.4, 41.6, 112.4,
116.1, 120.9, 126.0, 127.9, 128.2, 129.4, 130.2, 130.9,
136.5, 140.8, 145.6, 165.8, 192.3; Anal calcd. for
A 50 mL round-bottom flask was filled with 2-amino-ben-
zothiazole 1 (1 mmol), aldehyde 2(a–p) (1 mmol), cyclic
-diketone 3(a–b) (1 mmol) and Amberlyst-15® (100 mg)

2156
Mazaahir K, et al. Sci China Chem October (2012) Vol.55 No.10
C20H15ClN2OS: C, 65.48; H, 4.12; N, 7.64; Found: C, 65.28;
H, 3.96; N, 7.48.
2H), 2.41–2.47 (m, 2H), 2.56–2.67 (m, 2H), 5.45 (s, 1H,
ArCH), 7.10–7.56 (m, 4H, Ar–H), 7.68–8.00 (m, 4H, Ar–H);
13C NMR (CDCl3, 100 MHz) : 19.9, 33.4, 37.1, 52.6,
114.2, 115.5, 119.0, 121.7, 122.2, 125.9, 129.0, 130.2,
131.8, 132.7, 143.5, 144.6, 148.3, 151.6, 163.0, 192.7; Anal
calcd. for C20H15N3O3S: C, 63.65; H, 4.01; N, 11.13; Found:
C, 63.46; H, 3.89; N, 11.01.
12-(4-Methoxy-phenyl)-2,3,4,12-tetrahydro-benzo[4,5]thiazolo
[2,3-b]quinazolin-1-one (4c)
IR νmax (cm1, nujol): 3308, 2952, 1722, 1588, 1537, 1377,
1243, 752; 1H NMR (CDCl3, TMS, 400 MHz) : 1.99–2.05
(m, 2H), 2.33–2.48 (m, 2H), 2.55–2.65 (m, 2H), 3.77 (s, 3H,
OCH3), 5.41 (s, 1H, ArCH), 6.79–7.01 (m, 4H, Ar–H),
7.13–7.60 (m, 4H, Ar-H); 13C NMR (CDCl3, 100 MHz) :
20.1, 33.5, 41.2, 55.2, 112.2, 113.5, 116.7, 119.4, 126,
127.5, 129.8, 130.2, 136.7, 145.2, 151.9, 157.5, 165.7,
192.1; Anal calcd. for C21H18N2O2S: C, 69.59; H, 5.01; N,
7.73; Found: C, 69.45; H, 4.91; N, 7.56.
12-(4-Methyl-phenyl)-2,3,4,12-tetrahydro-benzo-[4,5]-thia-
zolo-[2,3-b]-quinazolin-1-one (4h)
IR νmax (cm1, KBr): 3336, 2941, 1722, 1637, 1603, 1372,
1
752; H NMR (CDCl3, TMS, 400 MHz) : 1.98–2.05 (m,
2H), 2.28 (s, 3H, CH3), 2.35–2.47 (m, 2H), 2.54–2.65 (m,
2H), 5.41 (s, 1H, ArCH), 6.95–7.06 (m, 4H, Ar–H), 7.12–
7.78 (m, 4H, Ar–H); 13C NMR (CDCl3, 100 MHz) : 20.1,
20.9, 33.5, 40.5, 50.3, 113.2, 116.5, 119.1, 126.3, 128.9,
130.3, 134.6, 138.7, 144.3, 151.6, 166.0, 192.0; Anal calcd.
for C21H18N2OS: C, 72.80; H, 5.24; N, 8.09; Found: C,
72.64; H, 5.05; N, 7.93.
12-(4-Hydroxy-phenyl)-2,3,4,12-tetrahydro-benzo[4,5]thia-
zolo [2,3-b]quinazolin-1-one (4d)
IR νmax (cm1, nujol): 3448, 2987, 2251, 1647, 1376, 1249,
1
1053, 760; H NMR (DMSO-d6, TMS, 400 MHz) : 1.98–
2.04 (m, 2H), 2.12–2.19 (m, 2H), 2.22–2.30 (m, 2H), 5.34 (s,
1H, ArCH), 6.55–6.69 (m, 4H, Ar-H), 6.85–7.06 (m, 4H,
Ar–H), 8.86 (br s, 1H, OH); 13C NMR (DMSO-d6, 100 MHz)
: 20.0, 33.5, 40.8, 54.6, 112.2, 115.4, 116.1, 117.2, 126.0,
128.4, 129.6, 131.3, 135.5, 143.8, 152.7, 157.4, 164.2,
192.3; Anal calcd. for C20H16N2O2S: C, 68.94; H, 4.63; N,
8.04; Found: C, 68.78; H, 4.48; N, 7.86.
12-(4-Dimethylamino-phenyl)-3,3-dimethyl-2,3,4,12-tetra-
hydro-benzo[4,5]thiazolo[2,3-b]quinazolin-1-one (4i)
IR νmax (cm1, nujol): 3367, 2950, 1694, 1642, 1540, 1377,
1236, 753; 1H NMR (CDCl3, TMS, 400 MHz) : 1.96–2.02
(m, 2H), 2.26–2.38 (m, 2H), 2.52–2.60 (m, 2H), 3.05 (s, 6H,
2 × CH3), 5.38 (s, 1H, ArCH), 6.76–6.94 (m, 4H, Ar–H),
7.12–7.40 (m, 4H, Ar–H); 13C NMR (CDCl3, 100 MHz) :
19.6, 27.8, 32.5, 46.3, 49.8, 112.6, 115.7, 118.2, 119.7,
124.5, 128.0, 129.6, 129.8, 130.7, 137.5, 140.5, 145.3,
161.2, 192.4; Anal calcd. for C22H21N3OS: C, 70.37; H, 5.64;
N, 11.19; Found: C, 70.13; H, 5.50; N, 11.06.
12-(4-Nitro-phenyl)-2,3,4,12-tetrahydro-benzo[4,5]thiazolo
[2,3-b]quinazolin-1-one (4e)
IR νmax (cm1, nujol): 3321, 3193, 2951, 2252, 1722, 1604,
1346, 754; 1H NMR (CDCl3, TMS, 400 MHz) : 1.98–2.07
(m, 2H), 2.36–2.52 (m, 2H), 2.57–2.69 (m, 2H), 5.47 (s, 1H,
ArCH), 7.11–7.60 (m, 4H, Ar–H), 7.87–8.41 (m, 4H, Ar–H);
13C NMR (CDCl3, 100 MHz) : 20.0, 33.4, 41.6, 49.6, 112.3,
115.7, 116.4, 119.3, 123.4, 126.0, 127.4, 130.0, 130.9,
144.1, 146.0, 148.7, 151.7, 162.8, 192.6; Anal calcd. for
C20H15N3O3S: C, 63.65; H, 4.01; N, 11.13; Found: C, 63.47;
H, 3.88; N, 10.97.
3,3-Dimethyl-12-phenyl-2,3,4,12-tetrahydro-benzo[4,5]thia-
zolo[2,3-b]quinazolin-1-one (4j)
IR νmax (cm1, KBr): 3024, 2962, 1594, 1374, 1249, 777; 1H
NMR (CDCl3, TMS, 400 MHz) : 1.07 (s, 6H, 2 × CH3),
2.36 (s, 2H), 2.31 (AB-q J = 16.48 Hz, 2H, CH2), 5.51 (s,
1H, ArCH), 7.06–7.16 (m, 5H, Ar–H), 7.22–7.58 (m, 4H,
Ar–H); 13C NMR (CDCl3, 100 MHz) δ: 17.5, 27.3, 29.6,
46.4, 47.0, 53.4, 112.6, 115.5, 119.1, 125.8, 126.7, 127.1,
128.2, 130.0, 130.7, 140.7, 145.4, 162.6, 190.5; Anal calcd.
for C22H20N2OS: C, 73.30; H, 5.59; N, 7.77; Found: C,
73.12; H, 5.41; N, 7.63.
12-Benzo[1,3]dioxol-5-yl-2,3,4,12-tetrahydro-benzo[4,5]
thiazolo[2,3-b]quinazolin-1-one (4f)
IR νmax (cm1, KBr): 3301, 2964, 1720, 1603, 1484, 1375,
1241, 777; 1H NMR (CDCl3, TMS, 400 MHz) : 2.01–2.06
(m, 2H), 2.46–2.50 (m, 2H), 2.54–2.60 (m, 2H), 5.37 (s, 1H,
ArCH), 5.92 (s, 2H, CH2), 6.54–6.71 (m, 4H, Ar–H), 6.78–
7.57 (m, 3H, Ar-H); 13C NMR (CDCl3, 100 MHz) : 20.0,
33.5, 42.6, 51.7, 100.8, 112.6, 113.6, 114.3, 116.6, 119.4,
120.9, 126.0, 130.8, 131.7, 132.0, 144.4, 145.6, 147.5,
151.9, 161.5, 192.0; Anal calcd. for C21H16N2O3S: C, 67.00;
H, 4.28; N, 7.44; Found: C, 66.84; H, 4.15; N, 7.32.
3,3-Dimethyl-12-(thiophen-2-yl)-2,3,4,12-tetrahydro-benzo
[4,5]thiazolo[2,3-b]quinazolin-1-one (4k)
IR νmax (cm1, nujol): 2958, 2638, 1594, 1376, 1261, 733;
1H NMR (CDCl3, TMS, 400 MHz) : 1.08 (s, 6H, 2 × CH3),
2.35 (s, 2H), 3.69 (AB-q J = 20.84 Hz, 2H, CH2), 5.61 (s,
1H, ArCH), 6.61–7.09 (m, 3H, thienyl), 7.30–7.54 (m, 4H,
Ar–H); 13C NMR (CDCl3, 100 MHz) : 17.4, 26.7, 30.0,
46.2, 46.9, 53.4, 112.6, 115.9, 119.1, 123.5, 124.5, 126.0,
126.3, 128.3, 131.2, 139.4, 143.6, 151.7, 166.0, 189.9; Anal
calcd. for C20H18N2OS2: C, 65.54; H, 4.95; N, 7.64; Found:
12-(3-Nitro-phenyl)-2,3,4,12-tetrahydro-benzo[4,5]thiazolo
[2,3-b]quinazolin-1-one (4g)
IR νmax (cm1, KBr): 3311, 2965, 1721, 1600, 1520, 1351,
1
751; H NMR (CDCl3, TMS, 400 MHz) : 1.94–2.05 (m,

Mazaahir K, et al. Sci China Chem October (2012) Vol.55 No.10
2157
C, 65.40; H, 4.82; N, 7.49.
12-(4-Bromo-phenyl)-3,3-dimethyl-2,3,4,12-tetrahydro-benzo
[4,5]thiazolo[2,3-b]quinazolin-1-one (4p)
12-(2-Hydroxy-phenyl)-3,3-dimethyl-2,3,4,12-tetrahydro-
IR νmax (cm1, nujol): 2961, 2928, 1701, 1593, 1487, 1373,
benzo[4,5]thiazolo[2,3-b]quinazolin-1-one (4l)
1
1242, 734; H NMR (CDCl3, TMS, 400 MHz) : 1.06 (s,
IR νmax (cm1, nujol): 3180, 2953, 1642, 1593, 1375, 1260,
6H, 2 × CH3), 2.36 (s, 2H), 4.09 (AB-q J = 20.52 Hz, 2H,
CH2), 5.42 (s, 1H, ArCH), 6.92–7.12 (m, 4H, Ar–H), 7.33–
7.73 (m, 4H, Ar–H); 13C NMR (CDCl3, 100 MHz) : 19.7,
27.2, 28.3, 46.3, 49.8, 112.3, 115.1, 118.1, 120.8, 126.0,
129.6, 130.0, 130.8, 131.1, 137.2, 143.3, 150.4, 165.0,
191.0; Anal calcd. for C22H19N2BrOS: C, 60.14; H, 4.36; N,
6.38; Found: C, 60.03; H, 4.20; N, 6.26.
1
755; H NMR (CDCl3, TMS, 400 MHz) : 0.97 (s, 6H, 2 ×
CH3), 2.31 (s, 2H), 3.71 (AB-q J = 22.0 Hz, 2H, CH2), 4.71
(br s, 1H, OH), 6.70 (s, 1H, ArCH), 7.13–7.30 (m, 4H,
Ar–H), 7.49–7.55 (m, 4H, Ar-H); 13C NMR (CDCl3, 100
MHz) : 17.6, 27.1, 29.1, 41.4, 45.4, 53.9, 110.9, 115.6,
116.4, 118.2, 120.8, 126, 127.4, 127.9, 129.5, 130.0, 131.2,
145.6, 150.8, 154.5, 166.8, 196.5; Anal calcd. for
C22H20N2O2S: C, 70.19; H, 5.35; N, 7.44; Found: C, 70.03;
H, 5.23; N, 7.30.
12-(3-Hydroxy-phenyl)-3,3-dimethyl-2,3,4,12-tetrahydro-
benzo[4,5]thiazolo[2,3-b]quinazolin-1-one (4q)
IR νmax (cm1, nujol): 3320, 2960, 1718, 1642, 1581, 1376,
1
3,3-Dimethyl-12-(naphthalen-1-yl)-2,3,4,12-tetrahydro-
benzo[4,5]thiazolo[2,3-b]quinazolin-1-one (4m)
1248, 756; H NMR (CDCl3, TMS, 400 MHz) : 1.04 (s,
6H, 2 × CH3), 2.32 (s, 2H), 3.48 (AB-q J = 18.24 Hz, 2H,
CH2), 5.36 (s, 1H, ArCH), 6.45–6.74 (m, 4H, Ar–H), 6.96–
7.42 (m, 4H, Ar–H), 9.64 (br s, 1H, OH); 13C NMR (CDCl3,
100 MHz) δ: 18.6, 28.5, 36.7, 48.5, 52.4, 110.7, 112.6,
114.7, 116.2, 118.3, 118.9, 124.8, 129.7, 131.2, 132.3,
139.6, 144.5, 147.2, 156.8, 160.2, 190.4; Anal calcd. for
C22H20N2O2S: C, 70.19; H, 5.35; N, 7.44; Found: C, 70.02;
H, 5.20; N, 7.26.
IR νmax (cm1, KBr): 3100, 1645, 1470, 1177, 1126, 752; 1H
NMR (CDCl3, TMS, 400 MHz) : 1.07 (s, 6H, 2 × CH3),
2.34 (s, 2H), 3.46 (AB-q J = 23.52 Hz, 2H, CH2), 6.14 (s,
1H, ArCH), 7.08–7.36 (m, 4H, Ar-H), 7.49–8.09 (m, 7H,
Ar–H); 13C NMR (CDCl3, 100 MHz) : 17.6, 27.9, 30.9,
46.6, 51.8, 56.2, 109.9, 116.9, 117.6, 123.8, 124.6, 124.7,
125.1, 126.5, 126.6, 128.2, 128.7, 130.7, 132.5, 133.4,
134.0, 147.8, 149.6, 167.5, 196.8; Anal calcd. for
C26H22N2OS: C, 76.07; H, 5.40; N, 6.82; Found: C, 75.93;
H, 5.24; N, 6.66.
3 Results and discussions
In order to achieve the most suitable conditions for the pre-
sent reaction, we first investigated the model reaction using
1 equiv each of 2-aminobenzothiazole 1, benzaldehyde 2a
and cyclohexane-1,3-dione 3a. These were stirred at ambi-
ent temperature in ethanol. The reaction did not proceed to
completion even after 10 h with only 36% of the product 4a
being isolated. In order to improve the yield and optimize the
reaction conditions, the same reaction was carried out in the
presence of Amberlyst-15®
Surprisingly, a significant improvement was observed and the
yield of the product 4a was enhanced to 70% after stirring the
reaction mixture for 3 h. To further enhance the yield, we
chose PEG 400 as solvent for the model reaction and
achieved 92% isolated yield in 30 min at 50 °C (Scheme 1).
Next, we optimized the catalyst loading for this reaction
and we noted that although the product could be formed
with low catalyst loading (20 mg/mmol of the reactant), the
best outcome, in terms of yield and the reaction time, was
obtained with 100 mg/mmol of Amberlyst-15® (Table 1).
3,3-Dimethyl-12-styryl-2,3,4,12-tetrahydro-benzo[4,5]thia-
zolo[2,3-b]quinazolin-1-one (4n)
IR νmax (cm1, KBr): 3445, 2956, 1622, 1455, 1391, 1238,
1
751; H NMR (CDCl3, TMS, 400 MHz) : 0.99 (s, 3H,
CH3), 1.09 (s, 3H, CH3), 2.30 (AB-q J = 16.38 Hz, 2H,
CH2), 2.48 (s, 2H), 6.02 (m, 1H, ArCH), 7.11 (m, 1H), 7.16
(d, 1H, J = 14.6 Hz), 7.29–7.58 (m, 9H, Ar–H); 13C NMR
(CDCl3, 100 MHz) : 18.4, 28.3, 29.6, 42.7, 49.8, 55.0,
111.8, 113.2, 117.2, 123.4, 126.0, 126.4, 127.4, 127.7,
128.2, 128.8, 130.5, 138.2, 142.4, 149.5, 165.3, 197.0; Anal
calcd. for C24H22N2OS: C, 74.58; H, 5.74; N, 7.25; Found:
C, 74.42; H, 5.64; N, 7.13.
catalyst under similar conditions.
12-(2-Hydroxy-3-methoxy-phenyl)-3,3-dimethyl-2,3,4,12-
tetrahydro-benzo[4,5]thiazolo[2,3-b]quinazolin-1-one (4o)
IR νmax (cm1, KBr): 3385, 3199, 2953, 1641, 1584, 1540,
1381, 1229, 757; 1H NMR (CDCl3, TMS, 400 MHz) : 0.96
(s, 6H, 2 × CH3), 2.34 (s, 2H), 2.58 (AB-q J = 18.16 Hz, 2H,
CH2), 3.86 (s, 3H, OCH3), 5.78 (s, 1H, ArCH), 6.55–6.92
(m, 3H, Ar–H), 7.13–7.52 (m, 4H, Ar–H), 9.90 (br s, 1H,
OH); 13C NMR (CDCl3, 100 MHz) : 18.6, 27.1, 29.1, 41.5,
45.0, 55.8, 56.0, 110.3, 113.5, 116.7, 119.0, 120.8, 122.2,
126.0, 130.0, 130.3, 131.1, 142.2, 145.6, 148.7, 151.4,
161.1, 197.0; Anal calcd. for C23H22N2O3S: C, 67.96; H,
5.46; N, 6.89; Found: C, 67.77; H, 5.26; N, 6.76.
Scheme 1 Optimized reaction conditions of the model reaction for the
synthesis of benzothiazolo-[2,3-b]-quinazolinones.

2158
Mazaahir K, et al. Sci China Chem October (2012) Vol.55 No.10
We also examined the effect of temperature on this reac-
erivatives are well illustrated with structurally diverse alde-
hydes (Scheme 2) and the results are summarized in Table 3.
The reaction proceeded smoothly and equally well for elec-
tron-withdrawing as well as electron-donating aldehydes to
afford the corresponding benzothiazolo-[2,3-b]-quinazo-
linones in good to excellent yields.
tion (Figure 1). It was found that the optimum temperature
was 50 °C from the point of view of yield and reaction time.
At higher temperatures, no further improvement on yield
and reaction time was observed. On the other hand, the re-
action did not proceed at room temperature. At 50 °C, the
reaction proceeded smoothly and almost complete conver-
sion of the reagent was observed. Also, the model reaction
was carried out in various solvents commonly used in or-
ganic synthesis (Table 2) and the best result was obtained in
solvent PEG 400 at 50 °C.
The scope and generality of this three-component,
one-pot synthesis of benzothiazolo-[2,3-b]-quinazolin-1-one
Scheme
multi-component reaction.
2
Synthesis of benzothiazolo-[2,3-b]-quinazolin-1-ones via
Table 1 Optimization of the amount of the catalyst a)
We also investigated the recyclability of the catalyst sys-
tem (Amberlyst-15® in PEG 400) (Table 4). The model re-
action was carried out under the optimized conditions. After
complete conversion of the starting materials, the reaction
mixture was cooled in dry-ice acetone bath to precipitate the
PEG 400 and was extracted with ether (PEG being insoluble
in ether). The ether layer was decanted, dried over anhy-
drous Na2SO4 and concentrated under reduced pressure to
produce the products. The PEG 400 phase along with resin
was used as such for subsequent runs (four runs) with fresh
substrates under the same conditions. The recycled catalyst
and solvent exhibited excellent recyclability in this reaction
as the reaction time and yield remained almost the same.
As far as the mechanism of the above transformation
(Scheme 2) is concerned, a reasonable possibility is pro-
posed in Scheme 3. The reaction presumably proceeds via
two steps: reaction of aldehyde 2(a–p) and cyclic -diketone
3(a–b) by Knoevenagel condensation to produce ,-un-
saturated ketone (5), which then could undergo Michael-
type addition reaction with 2-aminobenzothiazole (1) to
form an adduct (6). The adduct formed could then be cy-
clized intramolecularly to give (7) which could then lose
water to afford tetraheterocyclic benzothiazolo-[2,3-b]-
quinazolin-1-one ring systems 4(a–q). The asymmetric as-
pect of the reaction, i.e.; the regioselectivity of the reaction
is confirmed by theoretical studies according to which the
endocyclic nitrogen is more nucleophilic as compared to the
exocyclic amino group. Thus, the possibility of formation of
isomeric product via nucleophilic attack of exocyclic amino
group is completely eliminated [12].
Entry
Catalyst (mg)
Time (min)
420
Yield (%) b)
1
2
3
4
5
20
40
58
67
74
80
92
270
60
240
80
120
100
30
a) Reaction conditions: 2-Aminobenzothiazole 1 (1 mmol), benzalde-
hyde 2a (1 mmol), cyclohexane-1,3-dione 3a (1 mmol); catalyst: Amber-
lyst-15® (mg); temp: 50 °C; solvent : PEG (2 mL). b) Isolated yields.
Figure 1 Effect of temperature on the synthesis of benzothiazolo-[2,3-
b]quinazoline-1-ones. Reaction conditions: 2-Aminobenzothiazole 1 (1
mmol), benzaldehyde 2a (1 mmol), cyclohexane-1,3-dione 3a (1 mmol);
catalyst: Amberlyst-15® (100 mg); temp: (°C); solvent: PEG 400 (2 mL). b)
Isolated yields.
Table 2 Effect of solvents on the synthesis of benzothiazolo-[2,3-b]
quinazoline-1-onesa)
S.No.
Solvent (mL)
MeOH
Time (min)
Yield (%) b)
1
2
3
4
5
6
7
8
50
50
90
45
180
35
78
80
70
78
65
92
92
60
EtOH
THF
4 Conclusion
CH3CN
toluene
PEG 200
PEG 400
DMF
In summary, Amberlyst-15® has been demonstrated as an
efficient and environmentally benign catalyst for the multi-
component synthesis of benzothiazolo-[2,3-b]-quinazolin-
1-ones. This protocol further demonstrates the values of
PEG-promoted synthesis in avoiding hazardous organic
30
200
a) Reaction conditions: 2-Aminobenzothiazole 1 (1 mmol), benzalde-
hyde 2a (1 mmol), cyclohexane-1,3-dione 3a (1 mmol); catalyst: Amber-
lyst-15® (100 mg); temp: 50 °C; solvent: 2 mL. b) Isolated yields.

Mazaahir K, et al. Sci China Chem October (2012) Vol.55 No.10
Table 3 Amberlyst-15® mediated synthesis of benzothiazolo-[2,3-b]-quinazolin-1-ones a)
2159
Entry
1
R
C6H5
R1
H
Product
4a
M.P. (°C)
230–234 [24]
212–214
186–190
224–228
218–222
216–220
160–164
146–150
250–252
224–226 [25]
134–138
166–170
286–290
164–168
168–172
176–180
234–236
Time (min)
Yield (%) b)
30
30
30
30
45
30
40
30
45
30
40
30
50
40
35
35
40
92
92
92
90
90
88
90
92
90
92
89
92
87
88
85
92
91
2
4-Cl-C6H4
4-MeO-C6H4
4-HO-C6H4
4-NO2-C6H4
piperonyl
H
4b
4c
3
H
4
H
4d
4e
5
H
6
H
4f
7
3-NO2-C6H4
4-Me-C6H4
4-(CH3)2N-C6H4
C6H5
H
4g
8
H
4h
4i
9
H
10
11
12
13
14
15
16
17
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
4j
2-thienyl
4k
4l
2-HO-C6H4
1-naphthyl
cinnamyl
4m
4n
4o
2-HO-3-MeO-C6H3
4-Br-C6H4
3-HO-C6H4
4p
4q
a) Reaction conditions: 2-Aminobenzothiazole 1 (1 mmol), aldehyde 2(a–p) (1 mmol), cyclic -diketone 3(a–b) (1 mmol); catalyst: Amberlyst-15® (100
mg); temp: 50 °C; solvent: PEG 400 (2 mL). b) Isolated yields.
Table 4 Recycling studies of the catalyst system a)
The author (Ritika Chauhan) is thankful to the UGC (University Grants
Commission) for providing the junior research fellowship and also to the
Director of University Science and Instrumentation Centre, University of
Delhi, Delhi for providing the spectral analysis data.
No. of cycles a)
Yield (%) b)
Time (min)
Fresh
92
Run 1
92
Run 2
92
Run 3
91
Run 4
90
30
30
30
30
30
a) Reaction conditions: 2-Aminobenzothiazole 1 (1 mmol), benzalde-
hyde 2a (1 mmol), cyclohexan-1,3-dione 3a (1 mmol); catalyst: Amber-
lyst-15® (100 mg); temp: 50 °C; solvent: PEG 400 (2 mL). b) Isolated yields.
1
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