Iron fluoride: The most efficient catalyst for one-pot synthesis of 4H-pyrimido[2,1-b]benzothiazoles under solvent-free conditions

Article abstract of DOI:10.1016/j.tet.2014.05.094

A new iron fluoride assisted convenient and efficient strategy for the preparation of 4H-pyrimido[2,1-b]benzothiazoles derivatives in solvent-free media is described. The reactions can be performed at low-catalyst loadings with excellent functional group tolerance. The catalyst can be readily recovered and reused for next reaction for at least three runs without any significant impact on the yields of the products. The easy recovery of the catalyst and high yield of the products make the protocol attractive, sustainable, and economic.

Full text of DOI:10.1016/j.tet.2014.05.094

Tetrahedron xxx (2014) 1e7
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Iron fluoride: the most efficient catalyst for one-pot synthesis of
4H-pyrimido[2,1-b]benzothiazoles under solvent-free conditions
*
Amol B. Atar, Yong Seok Jeong, Yeon Tae Jeong
Department of Image Science and Engineering, Pukyong National University, Busan 608-737, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
A new iron fluoride assisted convenient and efficient strategy for the preparation of 4H-pyrimido[2,1-b]
benzothiazoles derivatives in solvent-free media is described. The reactions can be performed at low-
catalyst loadings with excellent functional group tolerance. The catalyst can be readily recovered and
reused for next reaction for at least three runs without any significant impact on the yields of the
products. The easy recovery of the catalyst and high yield of the products make the protocol attractive,
sustainable, and economic.
Received 19 April 2014
Received in revised form 23 May 2014
Accepted 24 May 2014
Available online xxx
Keywords:
4H-Pyrimido[2,1-b]benzothiazoles
Iron fluoride
Ó 2014 Elsevier Ltd. All rights reserved.
One-pot
Solvent-free
Biginelli reaction
1. Introduction
benzothiazoles have been developed in different ways by using
TBAHS,10 kaolin,11 hydrotalcite,12 aluminum trichloride,13 boric
Rapid advances in medicinal chemistry continue to underscore
the need of practical routes for the synthesis of heterocycles, as
a majority of drug-like compounds and natural products contains
a heterocyclic nucleus at their core.1 In recent years, transition-
metal-catalyzed reactions provided a promising algorithm to this
urge, which allow the efficient conversion of simple starting ma-
terials to complex molecules in an iterative manner.2 Among the
various transition metals, iron-catalyzed tandem sequences have
gained considerable attention because of their ability to activate
acid,14 N,N0-dichlorobis(2,4,6-trichlorophenyl)urea,15 and anhy-
drous zinc chloride16 as catalysts. These reported methodologies
produce good results in many instances. However, some of syn-
thetic strategies suffer with certain limitations such as expensive
catalysts, low yields of products, long reaction times, tedious pro-
cedures for preparations of catalysts, and tedious workup condi-
tions. Hence, the development of efficient, simple, easy workup,
and environmentally benign protocol using recyclable catalyst and
solvent-free condition for the synthesis of 4H-pyrimido[2,1-b]
benzothiazoles derivatives is still desirable and in demand.
various p
-systems in mild conditions and at low-catalyst loading.3
Iron catalysts play an important role in organic synthesis because
they are relatively safe, inexpensive, stable, and less hazardous to
the environment when compared to other transition-metal cata-
lysts.4 The combination of transition-metal catalyst and solvent-
free conditions using multicomponent reactions lead to enhanced
reaction rates, higher yields, easier workup, and sometimes to se-
lective conversions, with several advantages of the eco-friendly
approach in the frame work of green chemistry.
4H-Pyrimido[2,1-b]benzothiazoles derivatives are an important
class of fused heterocycles due to their broad range of potential
biological pharmacological activities, as well as the importance in
preparation of drug molecules and natural products.5e9 In recent
years, numerous protocols for preparation of 4H-pyrimido[2,1-b]
In recent decades, fluorine-containing catalytic applications
have undergone rapid growth.17e19 It is evident from the previous
literature that iron fluoride has invoked enormous interest as
a potential green and acid catalyst to construct carbonecarbon and
carboneheteroatom
bonds
in
various
organic
trans-
formations.20e22 In continuation of our research in exploring novel
and practical multicomponent reactions to synthesize useful het-
erocyclic compounds,23,24 we disclosed a novel methodology for
synthesis of 4H-pyrimido[2,1-b]benzothiazoles by ring closure of
substituted 2-aminobenzothiazole with aldehydes and 1,3-dike-
tones in the presence of iron fluoride under solvent-free condition.
To the best of our knowledge, this is the first reported synthesis of
this important class of fused heterocycles from the cheap and easily
available starting materials by employing cheap, recyclable, and
easily available iron fluoride as an efficient catalyst in a green media
(Scheme 1).
* Corresponding author. Tel.: þ82 51 629 6411; fax: þ82 51 629 6408; e-mail
address: ytjeong@pknu.ac.kr (Y.T. Jeong).
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.05.094
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A.B. Atar et al. / Tetrahedron xxx (2014) 1e7
Scheme 1. One-pot synthesis of 4H-pyrimido[2,1-b]benzothiazoles.
2. Result and discussion
In search of effective, eco-friendly, and efficient reusable catalytic
system for this reaction, same test reaction was performed with
different supported metal Lewis acid catalysts such as CueSn (200
mesh, 100 mg), FeCl3, SiO2, CaCl2, Zn(OTf)2, CuCl2, FeF3, Li(OTf),
SnCl2$2H2O, and CuF2. Among all screened catalysts, FeF3 gave the
best result in view of yield and reaction time (Table 1, entry 8). In
contrast CueSn (200 mesh, 100 mg), CaCl2, SiO2, Zn(OTf)2, ZnCl2,
Li(OTf), and SnCl2$2H2O did not afford the desired product in good
yields (Table 1, entries 2e6, 11, and 12). FeF3 was shown to be more
effective than CuF2 in terms of yield and time for completion of the
reaction (Table 1, entries 8 and 14).
To optimize the reaction condition, we began our examination
of the reaction of 2-aminobenzothiazole, benzaldehyde, and
dimedone in the presence of different catalysts and solvents
(Table 1). In order to establish the real effectiveness of the catalyst
for the synthesis of 4H-pyrimido[2,1-b]benzothiazole derivatives,
a
test reaction was performed without catalyst using 2-
aminobenzothiazole, benzaldehyde, and dimedone in neat condi-
tion at 100 ꢀC. It was found that only a 22% amount of product was
obtained in the absence of catalyst even after 8 h (Table 1, entry 1).
Table 1
Optimization of catalysts, solvents, and temperature in the synthesis of 4aa
No
Catalyst (10 mol %)
Solvent
Condition
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
d
d
100 ꢀC
Reflux
100 ꢀC
120 ꢀC
80 ꢀC
8
8
6
3
5
4
3
0.5
0.5
3
3
2
3
2
2
3
22
35
38
65
50
55
90
97
94
75
60
65
85
80
80
82
85
82
86
88
85
90
95
FeCl3
SiO2
CaCl2
Ethanol
Neat
Ethylene glycol
Methanol
Ethanol
Ethanol
Neat
Neat
Neat
Neat
Neat
CueSn (200 mesh, 100 mg)
Zn(OTf)2
FeF3
FeF3
FeF3
Reflux
Reflux
100 ꢀC
80 ꢀC
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
CuCl2
80 ꢀC
Li(OTf)
SnCl2$2H2O
FeCl3
CuF2
FeF3
FeF3
FeF3
FeF3
FeF3
FeF3
FeF3
FeF3 (5 mol %)
FeF3 (20 mol %)
80 ꢀC
80 ꢀC
Neat
Neat
80 ꢀC
80 ꢀC
Water
DMF
Methanol
Ethylene glycol
ACN
Toluene
THF
Neat
Reflux
Reflux
Reflux
120 ꢀC
100 ꢀC
100 ꢀC
Reflux
100 ꢀC
100 ꢀC
4
3
2
2.5
2
0.5
0.5
Neat
a
Reaction conditions: benzaldehyde (1 mmol), dimedone (1 mmol), 2-aminobenzothiazole (1 mmol), catalyst (10 mol %).
Isolated yield.
b
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A.B. Atar et al. / Tetrahedron xxx (2014) 1e7
3
To assess the effect of solvents on this reaction, we screened
different solvents such as toluene, EtOH, ACN, DMF, ethylene
glycol, methanol, water, and THF. It was observed that under
solvent condition required longer times (2e4 h) to afford com-
parable yields (Table 1, entries 15e21). When the reaction was
performed under solvent-free conditions, high yield of target
product was obtained (Table 1, entry 8). Moreover, we found that
the yields were affected by the amount of FeF3 loaded. When 5, 10,
and 20 mol % of FeF3 were used, the yields were 90, 97, and 95%,
respectively (Table 1, entries 8, 22, and 23). Therefore, 10 mol % of
FeF3 was sufficient and optimal quantity for the completion of the
reaction.
Thus, we selected the optimized reaction condition to examine
the universality of this catalyst application with different electron
rich and deficient substrates. It was gratifying to observe that most
of the tested substrates exhibited satisfactory reactivity profiles, in
all cases leading to a heterocyclization sequence that readily
afforded the target structures (Table 2). Various substituted alde-
hydes undergo the reaction in the presence of catalytic amount of
FeF3 (10 mol %) in neat condition at 100 ꢀC. As compared to aro-
matic aldehydes, the heteroaromatic aldehyde gave slightly lower
yield. Compared with aromatic aldehydes, aliphatic aldehyde
afforded relatively lower yields of the corresponding 4H-pyrimido
[2,1-b]benzothiazole (Table 2, entry 14).
A possible mechanism of this one-pot reaction is expected on
the basis of reported literature.10 A possible mechanism for the 4H-
pyrimido[2,1-b]benzothiazoles triheterocyclic ring formation is
outlined in (Scheme 2). The cyclization looks to proceed as a dom-
ino sequence of Knoevenagel condensation and Michael type ad-
dition reaction. The well known reaction of dimedone with
benzaldehyde leads to the formation of the standard dimedo-
neebenzaldehyde adducts 5, which then could undergo Michael
type addition reaction with 2-aminobenzothiazole 1 to form an
adduct 6. The adduct 6 formed could then be cyclized in-
tramolecularly to give 7, which could then lose water to afford
tetraheterocyclic 4H-pyrimido[2,1-b]benzothiazoles ring systems.
The asymmetric aspect 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 iso-
meric product via nucleophilic attack of exocyclic amino group is
completely eliminated.
Table 2
a
Synthesis of 4H-pyrimido[2,1-b]benzothiazoles catalyzed by FeF3
No
R
R1
1,3-Diketone
Product
Yieldb (%)
Mp
Reported
1
2
3
4
5
6
7
8
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Ph
Dimedone
Dimedone
Dimedone
Dimedone
Dimedone
Dimedone
Dimedone
Dimedone
Dimedone
Dimedone
Dimedone
Dimedone
Dimedone
Dimedone
2,4-Pentanedione
2,4-Pentanedione
2,4-Pentanedione
2,4-Pentanedione
2,4-Pentanedione
2,4-Pentanedione
2,4-Pentanedione
2,4-Pentanedione
1,3-Cyclohexanedione
1,3-Cyclohexanedione
1,3-Cyclohexanedione
1,3-Cyclohexanedione
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
97
96
97
96
97
93
94
95
96
90
85
91
95
70
94
96
93
91
93
96
92
93
91
94
96
93
205e206
186e188
210e212
202e204
211e212
134e136
210e212
88e89
181e182
170e172
170e172
148e149
125e126
d
205e207[10]
2-MeC6H4
3-MeC6H4
4-MeC6H4
4-OMeC6H4
2-FC6H4
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
3-FC6H4
4-OMeC6H4
4-BrC6H4
2-OH3eOMeC6H3
2-Thiophene
3-BrC6H4
4-OEtC6H4
eCH2CH3
4-MeC6H4
4-ClC6H4
4-(CH3)2CHC6H4
3-BrC6H4
3-FC6H4
4-BrC6H4
2-BrC6H4
4-FC6H4
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
156e158
126e127
174e175
168e170
137e138
145e146
113e114
122e123
130e132
237e238
211e213
180e182
4s
4t
4u
4v
4w
4x
4y
4z
2-FC6H4
4-MeC6H4
4-ClC6H4
4-OEtC6H4
a
Reaction conditions: aldehyde (1 mmol), 1,3-diketone (1 mmol), 2-aminobenzothiazole (1 mmol), FeF3 (10% mol).
Isolated yield.
b
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4
A.B. Atar et al. / Tetrahedron xxx (2014) 1e7
internal standard. The HRMS was recorded on a Jeol JMS-700 mass
spectrometer. Melting points were taken in open capillaries on an
Electrothermal-9100 instrument (Japan).
4.2. General procedure for 4H-pyrimido[2,1-b]benzothiazoles
(4ae4z)
A mixture of aldehydes (1 mmol), 1,3-diketones (1 mmol), and
2-aminobenzothiazole (1 mmol) was heated at 100 ꢀC under
solvent-free conditions using iron fluoride as a catalyst (10 mol %).
The reaction was monitored by TLC. After completion of the re-
action, the reaction mixture was cooled to room temperature, and
the residue was diluted with water. The mixture was filtered and
washed with water. The FeF3 catalyst was dissolved in water and
also recovered by evaporating the aqueous layer under reduced
pressure. The solid crude product was easily purified by column
chromatography over silica gel using hexane and ethyl acetate to
get pure product 4.
Scheme 2. Plausible mechanism for the formation of 4H-pyrimido[2,1-b]benzothia-
zole tricylic ring.
The reusability of the FeF3 catalyst is one of the most important
benefits and makes it useful for commercial applications as well.
Thus, the recovery and reusability of the catalyst were investigated.
The recyclability of the catalyst was checked with model reaction
(Table 3, entries 1e4). The catalyst was recovered after completion
of the first fresh run, the reaction mixture cooled to room tem-
perature, and then water was added. The catalyst was dissolved in
water and product was precipitated out. The precipitated crude
product was separated by simple filtration and FeF3 was recovered
by evaporating the aqueous layer under reduced pressure. The re-
covered FeF3 (10 mol %) was dried at 90e100 ꢀC for 12 h and tested
in up to three more reaction cycles. The same catalyst (10 mol %)
was reused for subsequent reactions (three runs) with fresh sub-
strates under the same conditions. The catalyst showed excellent
recyclability in all these reactions (Table 3), as the reaction times
and yield remained almost the same without having a loss of cat-
alytic activity.
4.2.1. 3,3-Dimethyl-12-phenyl-2,3,4,12-tetrahydro-1H-benzo[4,5]
[1,3]thiazolo[2,3-b]quinazolin-1(2h)-one (4a). Yield 97%; yellow
solid; mp 205e206 ꢀC. 1H NMR (400 MHz,CDCl3):
d 0.94 (s, 3H),1.09
(s, 3H), 2.21 (d, J¼8 Hz, 2H), 2.48 (s, 2H), 6.39 (s, 1H), 7.09 (d, J¼8 Hz,
1H), 7.15e7.19 (m, 2H), 7.21e7.28 (m, 3H), 7.36 (d, J¼8 Hz, 2H), 7.48
(d, J¼8 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3):
d 26.16, 31.59,
44.20, 50.89, 56.32, 111.31, 112.28, 122.56, 124.88, 126.45, 128.76,
128.45, 138.66, 140.89, 158.11, 165.78; 195.67; HRMS (ESI, m/z):
calcd C22H20N2OS (MþHþ) 360.1296. Found: 360.1294.
4.2.2. 3,3-Dimethyl-12-(2-methylphenyl)-2,3,4,12-tetrahydro-1H-
benzo[4,5][1,3]thiazolo[2,3-b]quinazolin-1(2h)-one (4b). Yield 96%;
yellow solid; mp 186e188 ꢀC. 1H NMR (400 MHz, CDCl3):
d 0.94 (s,
3H), 1.08 (s, 3H), 2.17 (d, J¼4 Hz, 2H), 2.50 (s, 2H), 2.76 (s, 3H), 6.57
Table 3
Recycling and reuse of FeF3
(s, 1H), 7.14e7.02 (m, 5H), 7.21 (t, J¼8 Hz, 1H), 7.43 (d, J¼8 Hz,
2H) ppm. 13C NMR (100 MHz, CDCl3):
d 19.48, 27.34, 29.26, 32.53,
Entry
Reaction cycle
Yielda (%)
45.48, 51.00, 111.87, 122.13, 123.42, 124.24, 126.73, 126.93, 128.13,
130.89, 135.23, 135.23,158.46, 165.60, 195.71 ppm. HRMS (ESI, m/z):
calcd for C23H22N2OS (MþHþ) 374.1453, found: 374.1455.
1
2
3
4
First (fresh run)
Second cycle
Third cycle
97
96
95
95
Fourth cycle
4.2.3. 3,3-Dimethyl-12-(3-methylphenyl)-2,3,4,12-tetrahydro-1H-
a
Isolated yield.
benzo[4,5][1,3]thiazolo[2,3-b]quinazolin-1(2h)-one (4c). Yield 97%;
yellow solid; mp 210e212 ꢀC. 1H NMR (400 MHz, CDCl3):
d 0.94 (s,
3. Conclusion
3H),1.07 (s, 3H), 2.29e2.25 (m, 5H), 2.49 (s, 2H), 6.45 (s,1H), 6.97 (d,
J¼4 Hz, 1H), 7.16e7.10 (m, 3H), 7.26e7.21 (m, 3H), 7.46 (d, J¼4 Hz,
In this work, we have described a successful strategy for the
efficient and convenient preparation of substituted 4H-pyrimido
[2,1-b]benzothiazoles using iron fluoride as catalyst in neat condi-
tion by ring closure of substituted 2-aminobenzothiazole with al-
dehydes and 1,3-diketones. It was suggested that iron fluoride
shows high catalytic activity. Moreover, the catalyst can be readily
recovered and reused for at least three runs without any significant
impact on the yield of the products.
The current strategy offers several advantages such as high
yields and purity of products, low amount of catalyst, safe, cheap
and environmentally benign, and an easy experimental workup
procedure. Furthermore, we are trying our best to develop more
reaction by using iron fluoride as a catalyst in an environmental
way, and the related work is underway in our laboratory.
1H) ppm. 13C NMR (100 MHz, CDCl3):
d 20.54, 26.42, 28.28, 30.46,
31.72, 44.39, 49.95, 55.15, 111.37, 121.17, 123.15, 123.24, 125.97,
126.62, 127.54, 128.07, 137.33, 139.65, 157.56, 164.64, 194.53 ppm.
HRMS (ESI, m/z): calcd for C23H22N2OS (MþHþ) 374.1453, found:
374.1455.
4.2.4. 3,3-Dimethyl-12-(4-methylphenyl)-2,3,4,12-tetrahydro-1H-
benzo[4,5][1,3]thiazolo[2,3-b]quinazolin-1(2h)-one (4d). Yield 96%;
yellow solid; mp 202e204 ꢀC. 1H NMR (400 MHz, CDCl3):
d 0.94 (s,
3H), 1.08 (s, 3H), 2.29e2.16 (m, 5H), 2.48 (s, 2H), 6.46 (s, 1H), 7.05 (d,
J¼8 Hz, 2H), 7.17e7.14 (m, 2H), 7.27e7.23 (m, 1H), 7.32 (d, J¼8 Hz,
2H), 7.48e7.46 (m, 1H) ppm. 13C NMR (100 MHz, CDCl3):
d 21.17,
27.43, 29.33, 32.70, 45.40, 50.96, 55.97,110.57,112.37,122.16,123.73,
124.21, 126.94, 129.38, 137.86, 137.95, 138.44, 158.45, 165.58 ppm.
HRMS (ESI, m/z): calcd for C23H22N2OS (MþHþ) 374.1453, found:
374.1455.
4. Experimental section-
4.1. General
4.2.5. 3,3-Dimethyl-12-(4-methoxyphenyl)-2,3,4,12-tetrahydro-1H-
6methylbenzo[4,5][1,3]thiazolo[2,3-b]quinazolin-1(2h)-one
(4e). Yield 97%; yellow solid; mp 211e212 ꢀC. 1H NMR (400 MHz,
Chemicals were purchased from Aldrich and Alfa Aesar chemical
companies and used as it is. The NMR spectra were recorded in
CDCl3 on a Jeol JNMECP 400NMR instrument using TMS as an
CDCl3):
d 0.93 (s, 3H), 1.07 (s, 3H), 2.35e2.15 (m, 5H), 2.47 (s, 2H),
3.67 (s, 3H), 6.42 (s, 1H), 6.74 (d, J¼8 Hz, 2H), 7.02 (s, 2H), 7.24 (s,
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A.B. Atar et al. / Tetrahedron xxx (2014) 1e7
5
1H), 7.34 (d, J¼8 Hz, 2H) ppm. 13C NMR (100 MHz, CDCl3):
d
21.05,
(m, 1H), 7.35e7.29 (m, 2H), 7.50 (d, J¼8 Hz, 1H) ppm. 13C NMR
27.22, 29.31, 32.55, 45.21, 50.80, 55.02, 55.62, 110.28, 112.04, 113.85,
122.26, 123.61, 127.75, 128.14, 133.15, 134.26, 136.09, 158.42, 159.16,
165.36, 195.46 ppm. HRMS (ESI, m/z): calcd for C24H24N2O2S
(MþHþ) 404.1558, found: 404.1556.
(100 MHz, CDCl3): d 27.37, 29.38, 32.65, 45.17, 50.76, 109.92, 112.13,
122.30, 125.54, 125.67,126.55,126.93,137.98,143.22,158.96,165.08,
195.46 ppm. HRMS (ESI, m/z): calcd for C20H18N2OS2 (MþHþ)
366.0861, found: 366.0863.
4.2.6. 3,3-Dimethyl-12-(2-fluorophenyl)-2,3,4,12-tetrahydro-1H-
benzo[4,5][1,3]thiazolo[2,3-b]quinazolin-1(2h)-one (4f). Yield 93%;
4.2.12. 3,3-Dimethyl-12-(3-bromophenyl)-2,3,4,12-tetrahydro-1H-
benzo[4,5][1,3]thiazolo[2,3-b]quinazolin-1(2h)-one (4l). Yield 91%;
yellow solid; mp 134e136 ꢀC. 1H NMR (400 MHz, CDCl3):
d
0.97 (s,
yellow solid; mp 148e149 ꢀC. 1H NMR (400 MHz, CDCl3):
d 0.94 (s,
3H), 1.10 (s, 3H), 2.35 (d, J¼4 Hz, 2H), 2.51 (s, 2H), 6.69 (s, 1H), 6.88
(d, J¼8 Hz, 1H), 7.00e6.93 (m, 2H), 7.12e7.04 (m, 1H), 7.21e7.15 (m,
2H), 7.28 (s, 1H), 7.50 (d, J¼8 Hz, 1H) ppm. 13C NMR (100 MHz,
3H), 1.25 (s, 3H), 2.24 (d, J¼4 Hz, 2H), 2.49 (s, 2H), 6.46 (s, 1H), 7.01
(d, J¼8 Hz, 1H), 7.14e7.08 (m, 2H), 7.22 (s, 1H), 7.36 (d, J¼8 Hz, 2H),
7.50 (t, J¼8 Hz, 1H), 7.57 (m, 1H) ppm. 13C NMR (100 MHz, CDCl3):
CDCl3):
d
27.38, 28.93, 32.70, 45.53, 50.18, 50.73, 109.44, 112.29,
d 27.33, 31.38, 32.62, 45.23, 46.95, 50.73, 55.57, 109.75, 112.10,
121.75, 122.09, 123.45, 124.28, 124.71, 125.96, 128.96, 129.57, 137.93,
115.00, 122.28, 125.37, 128.86, 130.08, 131.36, 137.94, 142.66, 158.86,
165.57, 195.40 ppm. HRMS (ESI, m/z): calcd for C22H19BrN2OS
(MþHþ) 438.0401, found: 438.0404.
152.90, 162.05, 166.73, 197.88 ppm. 19F NMR (376 MHz, CDCl3):
d
ꢁ113.35 (m, 1F) ppm. HRMS (ESI, m/z): calcd for C22H19FN2OS
(MþHþ) 378.1202, found: 378.1200.
4.2.13. 3,3-Dimethyl-12-(4-ethoxyphenyl)-2,3,4,12-tetrahydro-1H-
4.2.7. 3,3-Dimethyl-12-(3-fluorophenyl)-2,3,4,12-tetrahydro-1H-
benzo[4,5][1,3]thiazolo[2,3-b]quinazolin-1(2h)-one (4g). Yield 94%;
benzo[4,5][1,3]thiazolo[2,3-b]quinazolin-1(2h)-one (4m). Yield 95%;
brown solid; mp 125e126 ꢀC. 1H NMR (400 MHz, CDCl3):
d 0.94 (s,
yellow solid; mp 210e212 ꢀC. 1H NMR (400 MHz, CDCl3):
d
0.93 (s,
3H), 1.07 (s, 3H), 1.31 (t, J¼12 Hz, 3H), 2.29e2.16 (m, 2H), 2.49 (s,
2H), 3.93e3.89 (m, 2H), 6.43 (s, 1H), 6.75 (d, J¼4 Hz, 2H), 7.14 (d,
J¼8 Hz, 2H), 7.23 (t, J¼8 Hz,1H), 7.34 (d, J¼8 Hz, 2H), 7.44 (d, J¼8 Hz,
3H), 1.08 (s, 3H), 2.32e2.19 (m, 2H), 2.51 (s, 2H), 6.52 (s, 1H),
6.89e6.84 (m, 1H), 7.29e7.10 (m, 6H), 7.50 (d, J¼8 Hz, 1H) ppm. 13
C
NMR (100 MHz, CDCl3):
d
27.27, 29.26, 32.63, 45.11, 50.80, 55.60,
1H) ppm. 13C NMR (100 MHz, CDCl3):
d 14.73, 27.24, 29.28, 32.57,
109.90, 112.23, 113.86, 114.08, 115.14, 115.35, 122.31, 122.55, 123.68,
124.52, 127.07, 130.29, 138.01, 142.92, 158.74, 165.66, 195.53 ppm.
45.21, 50.82, 55.57, 63.22, 110.52, 112.31, 114.37, 122.07, 123.61,
124.12, 126.80, 128.14, 132.84, 138.27, 158.23, 158.61, 165.39,
195.53 ppm. HRMS (ESI, m/z): calcd for C24H24N2O2S (MþHþ)
404.1558, found: 404.1557.
19F NMR (376 MHz, CDCl3):
d
ꢁ112.54 (m, 1F) ppm. HRMS (ESI, m/z):
calcd for C22H19FN2OS (MþHþ) 378.1202, found: 378.1200.
4.2.8. 3,3-Dimethyl-12-(4-methoxyphenyl)-2,3,4,12-tetrahydro-1H-
4.2.14. 3,3-Dimethyl-12-(propyl)-2,3,4,12-tetrahydro-1H-benzo[4,5]
benzo[4,5][1,3]thiazolo[2,3-b]quinazolin-1(2h)-one (4h). Yield 95%;
[1,3]thiazolo[2,3-b]quinazolin-1(2h)-one (4n). Yield 70%; sticky
yellow solid; mp 88e89 ꢀC. 1H NMR (400 MHz, CDCl3):
d
0.92 (s,
brown liquid. 1H NMR (400 MHz, CDCl3):
d
0.77 (t, J¼8 Hz, 3H), 1.12
3H), 1.05 (s, 3H), 2.30e2.16 (m, 2H), 2.49 (s, 2H), 3.61 (s, 3H), 6.43 (s,
1H), 6.73 (d, J¼8 Hz, 2H), 7.22e7.06 (m, 2H), 7.37 (d, J¼8 Hz, 2H),
(d, J¼8 Hz, 6H), 1.77e1.75 (m, 1H), 1.95e1.93 (m, 1H), 2.32 (s, 2H),
2.45 (d, J¼4 Hz, 2H), 5.76 (t, J¼8 Hz, 1H), 7.29e7.22 (m, 2H), 7.39 (t,
J¼12 Hz, 1H), 7.53 (d, J¼4 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3):
7.48e7.45 (m, 2H) ppm. 13C NMR (100 MHz, CDCl3):
d 27.11, 29.29,
32.50, 45.05, 50.71, 54.95, 55.60, 110.41, 112.29, 113.86, 118.37,
120.69, 121.72, 122.03, 125.71, 126.76, 128.19, 132.94, 151.64, 159.16,
167.16, 195.65 ppm. HRMS (ESI, m/z): calcd for C23H22N2O2S
(MþHþ) 390.1402, found: 390.1402.
d 7.61, 25.44, 27.50, 29.51, 32.52, 45.28, 51.03, 52.80, 107.37, 111.65,
122.39, 123.90, 124.14, 126.94, 138.19, 161.41, 166.61, 196.08 ppm.
HRMS (ESI, m/z): calcd for C18H20N2OS (MþHþ) 312.1296, found:
312.1295.
4.2.9. 3,3-Dimethyl-12-(4-bromophenyl)-2,3,4,12-tetrahydro-1H-
4.2.15. 2-Methyl-4-(4-methylphenyl)-4H-pyrimido[2,1-b][1,3]benzo-
benzo[4,5][1,3]thiazolo[2,3-b]quinazolin-1(2h)-one (4i). Yield 96%;
thiazole-3-ethanone (4o). Yield 94%; brown solid; mp 156e158 ꢀC.
yellow solid; mp 181e182 ꢀC. 1H NMR (400 MHz, CDCl3):
d
0.91 (s,
1H NMR (400 MHz, CDCl3):
d 2.20 (s, 3H), 2.37 (s, 3H), 2.44 (s, 3H),
3H),1.07 (s, 3H), 2.29e2.20 (m, 2H), 2.47 (s, 2H), 6.45 (s,1H), 7.06 (d,
J¼8 Hz, 1H), 7.18 (d, J¼8 Hz, 1H), 7.36e7.29 (m, 5H), 7.46 (d, J¼8 Hz,
6.51 (s, 1H), 7.02 (d, J¼8 Hz, 2H), 7.11e7.07 (m, 1H), 7.22e7.15 (m,
2H), 7.30 (d, J¼8 Hz, 2H), 7.40 (d, J¼8 Hz, 1H) ppm. 13C NMR
1H) ppm. 13C NMR (100 MHz, CDCl3):
d
27.17, 29.23, 32.54, 45.14,
(100 MHz, CDCl3): d 21.05, 25.13, 31.82, 56.73, 111.99, 114.25, 122.12,
50.69, 55.52, 109.81, 112.11, 122.23, 124.42, 126.96, 128.54, 130.13,
131.05, 131.76, 139.51, 158.75, 162.48, 195.46 ppm. HRMS (ESI, m/z):
calcd for C22H19BrN2OS (MþHþ) 438.0401, found: 438.0404.
123.87, 124.00, 126.73, 127.01, 129.27, 137.92, 138.12, 138.37, 154.16,
163.57, 195.34 ppm. HRMS (ESI, m/z): calcd for C20H18N2OS (MþHþ)
334.1140, found: 334.1145.
4.2.10. 3,3-Dimethyl-12-(2-hydroxy 3-methoxyphenyl)-2,3,4,12-
4.2.16. 2-Methyl-4-(4-chlorophenyl)-4H-pyrimido[2,1-b][1,3]benzo-
tetrahydro
(4j). Yield 90%; yellow solid; mp 170e172 ꢀC. 1H NMR (400 MHz,
CDCl3): 0.95 (s, 3H), 1.09 (s, 3H), 2.36e2.22 (m, 2H), 2.49 (s, 2H),
1H-benzo[4,5][1,3]thiazolo[2,3-b]quinazolin-1(2h)-one
thiazole-3-ethanone (4p). Yield 96%; brown solid; mp 126e127 ꢀC.
1H NMR (400 MHz, CDCl3):
d
2.37 (s, 3H), 2.43 (s, 3H), 6.52 (s, 1H),
7.11e7.04 (m, 3H), 7.24 (d, J¼8 Hz, 2H), 7.34 (d, J¼8 Hz, 1H),
7.53e7.47 (m, 2H) ppm. 13C NMR (100 MHz, CDCl3):
25.20, 31.94,
d
3.82 (s, 3H), 6.70e6.66 (m, 3H), 6.72 (s, 1H), 7.24e7.12 (m, 3H), 7.30
d
(s, 1H), 7.47 (d, J¼8 Hz,1H) ppm. 13C NMR (100 MHz, CDCl3):
d
27.33,
60.44, 111.91, 118.77, 120.83, 121.99, 124.31, 126.89, 128.46, 128.77,
131.31, 139.69, 151.98, 166.71, 195.27 ppm. HRMS (ESI, m/z): calcd
for C19H15ClN2OS (MþHþ) 354.0594, found: 354.0597.
29.05, 32.65, 45.36, 50.59, 55.79, 109.36, 110.80, 112.34, 118.55,
121.06, 121.99, 123.34, 124.51, 127.24, 128.53, 138.14, 142.22, 148.81,
161.07, 166.29, 197.11 ppm. HRMS (ESI, m/z): calcd for C23H22N2O3S
(MþHþ) 406.1351, found: 406.1354.
4.2.17. 2-Methyl-4-(4-isopropylphenyl)-4H-pyrimido[2,1-b][1,3]ben-
zothiazole-3-ethanone (4q). Yield 93%; pale yellow solid; mp
4.2.11. 3,3-Dimethyl-12-(2-thiophenyl)-2,3,4,12-tetrahydro-1H-
174e175 ꢀC. 1H NMR (400 MHz, CDCl3):
d
1.16 (d, J¼4 Hz, 6H), 2.06
benzo[4,5][1,3]thiazolo[2,3-b]quinazolin-1(2h)-one (4k). Yield 85%;
(s, 3H), 2.16 (s, 3H), 2.83e2.80 (m, 1H), 5.67 (s, 1H), 7.04 (t, J¼12 Hz,
1H), 7.13 (d, J¼8 Hz, 2H), 7.25e7.21 (m,1H), 7.33 (d, J¼8 Hz, 2H), 7.50
pale yellow solid; mp 170e172 ꢀC. 1H NMR (400 MHz, CDCl3):
d 1.02
(S, 3H), 1.10 (s, 3H), 2.29 (d, J¼4 Hz, 2H), 2.51 (s, 2H), 6.82e6.81 (m,
(t, J¼12 Hz, 2H) ppm. 13C NMR (100 MHz, CDCl3):
d 23.79, 29.60,
1H), 6.84 (s, 1H), 7.01 (d, J¼4 Hz, 1H), 7.12 (d, J¼4 Hz, 1H), 7.22e7.18
30.70, 33.64, 58.41, 72.84, 119.10, 12.083, 121.79, 125.84, 126.89,
Please cite this article in press as: Atar, A. B.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.05.094

6
A.B. Atar et al. / Tetrahedron xxx (2014) 1e7
136.00, 148.73, 201.89 ppm. HRMS (ESI, m/z): calcd for C22H22N2OS
(MþHþ) 362.1453, found: 362.1455.
solid; mp 237e238 ꢀC. 1H NMR (400 MHz, CDCl3):
d 1.98e1.92 (m,
2H), 2.23 (s, 3H), 2.39e2.34 (m, 2H), 2.62e2.60 (m, 2H), 6.49 (s, 1H),
7.04 (d, J¼8 Hz, 2H), 7.15e7.10 (m, 2H), 7.25e7.21 (m, 1H), 7.30 (d,
J¼8 Hz, 2H), 7.46 (d, J¼8 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3):
4.2.18. 2-Methyl-4-(3-bromophenyl)-4H-pyrimido[2,1-b][1,3]benzo-
thiazole-3-ethanone (4r). Yield 91%; brown solid; mp 168e170 ꢀC. 1H
d 21.15, 21.36, 31.58, 37.24, 55.74, 111.73, 112.36, 122.17, 123.17,
NMR (400 MHz, CDCl3):
d
2.41 (s, 3H), 2.46 (s, 3H), 6.53 (s, 1H),
123.67, 124.22, 126.87, 126.94, 129.39, 137.93, 138.11, 138.38, 160.27,
165.44,195.80 ppm. HRMS (ESI, m/z): calcd for C21H18N2OS (MþHþ)
346.1140, found: 346.1143.
7.15e7.07 (m, 3H), 7.29e7.26 (m, 2H), 7.35 (d, J¼8 Hz, 1H), 7.46 (d,
J¼8 Hz,1H), 7.56 (s,1H) ppm.13C NMR (100 MHz, CDCl3):
d25.26, 31.94,
111.84, 113.70, 122.28, 122.77, 123.83, 124.30, 125.74, 126.93, 129.96,
130.08, 131.28, 137.75, 143.30, 154.83, 163.69, 195.00 ppm. HRMS (ESI,
m/z): calcd for C19H15BrN2OS (MþHþ) 398.0088, found: 398.0087.
4.2.25. 10-Methyl-12-(4-chlorophenyl)-2,3,4,12-tetrahydrobenzo-
[4,5]-thiazolo-[2,3-b]-quinazolin-1-one (4y). Yield 96%; yellow
solid; mp 211e212 ꢀC. 1H NMR (400 MHz, CDCl3):
d 1.99e1.92 (m,
4.2.19. 2-Methyl-4-(3-fluorophenyl)-4H-pyrimido[2,1-b][1,3]benzo-
thiazole-3-ethanone (4s). Yield 93%; brown solid; mp 137e138 ꢀC.
2H), 2.38e2.33 (m, 2H), 2.63e2.56 (m, 2H), 6.51 (s, 1H), 7.11e7.04
(m, 2H), 7.23 (t, J¼8 Hz, 1H), 7.37 (d, J¼8 Hz, 1H), 7.56e7.47 (m,
1H NMR (400 MHz, CDCl3):
d
2.41 (s, 3H), 2.45 (s, 3H), 6.58 (s, 1H),
6.87e6.83 (m, 1H), 7.25e7.14 (m, 5H), 7.55e7.44 (m, 2H) ppm. 13
NMR (100 MHz, CDCl3): 25.22, 31.89, 56.30, 111.91, 113.79, 115.22,
122.02, 124.30, 126.91, 130.04, 137.83, 143.56, 154.84, 163.74,
4H) ppm. 13C NMR (100 MHz, CDCl3):
d 21.24, 31.47, 37.09, 55.35,
C
112.19, 118.90, 120.85, 122.08, 124.45, 125.88, 127.02, 128.26, 128.89,
133.91, 137.97, 139.31, 151.98, 160.68, 166.44, 195.88 ppm. HRMS
(ESI, m/z): calcd for C20H15ClN2OS (MþHþ) 366.0594, found:
366.0596.
d
195.17 ppm. 19F NMR (376 MHz, CDCl3):
d
ꢁ111.14 (m, 1F) ppm.
HRMS (ESI, m/z): calcd for C19H15FN2OS (MþHþ) 338.0889, found:
338.0892.
4.2.26. 10-Methyl-12-(4-ethoxyphenyl)-2,3,4,12-tetrahydrobenzo-
[4,5]-thiazolo-[2,3-b]-quinazolin-1-one (4z). Yield 93%; yellow
4.2.20. 2-Methyl-4-(4-bromophenyl)-4H-pyrimido[2,1-b][1,3]benzo-
solid; mp 180e182 ꢀC. 1H NMR (400 MHz, CDCl3):
d
1.32 (t, J¼12 Hz,
thiazole-3-ethanone (4t). Yield 96%; brown solid; mp 145e146 ꢀC.
3H), 1.99e1.96 (m, 2H), 2.39e2.34 (m, 2H), 2.68e2.51 (m, 2H), 6.46
(s, 1H), 6.74 (d, J¼8 Hz, 2H), 7.15e7.10 (m, 2H), 7.22 (d, J¼8 Hz, 1H),
7.32 (d, J¼8 Hz, 2H), 7.45 (d, J¼8 Hz, 1H) ppm. 13C NMR (100 MHz,
1H NMR (400 MHz, CDCl3):
d 2.09 (s, 3H), 2.17 (s, 3H), 6.42 (s, 1H),
7.05 (t, J¼8 Hz, 1H), 7.23 (d, J¼8 Hz, 1H), 7.29 (d, J¼8 Hz, 2H), 7.38 (d,
J¼8 Hz, 2H), 7.52e7.48 (m, 2H) ppm. 13C NMR (100 MHz, CDCl3):
CDCl3):
d 14.75, 21.33, 31.47, 37.17, 55.43, 63.27, 111.74, 112.36,
d
29.49, 30.70, 57.68, 119.10, 120.88, 122.05, 125.95, 128.77, 131.87,
114.42, 122.10, 123.61, 124.15, 126.85, 128.13, 133.10, 138.30, 158.64,
160.06, 165.27, 195.81 ppm. HRMS (ESI, m/z): calcd for C22H20N2O2S
(MþHþ) 376.1245, found: 376.1247.
151.97, 166.13,196.51 ppm. HRMS (ESI, m/z): calcd for C19H15BrN2OS
(MþHþ) 398.0088, found: 398.0087.
4.2.21. 2-Methyl-4-(2-bromophenyl)-4H-pyrimido[2,1-b][1,3]benzo-
Supplementary data
thiazole-3-ethanone (4u). Yield 92%; brown solid; mp 113e114 ꢀC.
1H NMR (400 MHz, CDCl3):
d 2.36 (s, 3H), 2.44 (s, 3H), 6.72 (s, 1H),
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2014.05.094.
6.96e6.92 (m, 1H), 7.08e7.00 (m, 1H), 7.15 (t, J¼12 Hz, 1H), 7.22 (t,
J¼12 Hz, 1H), 7.33 (d, J¼8 Hz, 1H), 7.40 (d, J¼8 Hz, 1H), 7.48 (t,
J¼8 Hz, 1H), 7.58 (d, J¼8 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3):
References and notes
d
24.91, 31.90, 57.16, 112.49, 114.31, 118.61, 120.73, 121.77, 121.94,
123.71, 124.15, 125.71, 126.78, 128.45, 129.69, 130.09, 133.09, 138.22,
1. Davis, C. S. J. Pharm. Sci. 1962, 51, 1111.
140.93, 153.57, 163.42, 195.98 ppm. HRMS (ESI, m/z): calcd for
2. (a) D’Souza, D. M.; Muller, T. J. J. Chem. Soc. Rev. 2007, 36, 1095; (b) Walsh, D. P.;
Chang, Y. T. Chem. Rev. 2006, 106, 2476; (c) Arya, P.; Chou, D. T. H.; Baek, M. G.
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H. Angew. Chem., Int. Ed. 2013, 52, 3638.
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R. M.; Lai, A. G.; Carter, T. A.; Velasco, A. M.; Gunawardane, R. N.; Cramer, M. D.;
Gardner, M. F.; James, J.; Zarrinkar, P. P.; Patel, H. K.; Bhagwat, S. S. J. Med. Chem.
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744.
C
19H15BrN2OS (MþHþ) 398.0088, found: 398.0087.
4.2.22. 2-Methyl-4-(4-fluorophenyl)-4H-pyrimido[2,1-b][1,3]benzo-
thiazole-3-ethanone (4v). Yield 93%; brown solid; mp 122e123 ꢀC.
1H NMR (400 MHz, CDCl3):
d
7.46e7.38 (m, 3H), 7.24 (d, 8 Hz, 1H),
7.16e7.07 (m, 2H), 6.92e6.87 (m, 2H), 6.55 (s, 1H), 2.45 (s, 3H), 2.40
(s, 3H) ppm. 13C NMR (100 MHz, CDCl3):
25.19, 31.92, 56.24,111.94,
d
114.18, 115.40, 115.61, 122.15, 123.90, 124.24, 125.95, 126.85, 128.80,
128.88, 137.89, 154.56, 163.69, 195 ppm. 19F NMR (376 MHz, CDCl3):
d
ꢁ117.42 (m, 1F) ppm. HRMS (ESI, m/z): calcd for C19H15FN2OS
(MþHþ) 338.0889, found: 338.0892.
4.2.23. 10-Methyl-12-(2-fluorophenyl)-2,3,4,12-tetrahydrobenzo-
[4,5]-thiazolo-[2,3-b]-quinazolin-1-one (4w). Yield 91%; Brown
solid; mp 130e132 ꢀC. 1H NMR (400 MHz, CDCl3):
d 2.03e1.98 (m,
2H), 2.36e2.35 (m, 2H), 2.68e2.59 (m, 2H), 6.69 (s, 1H), 6.98e6.93
(m, 1H), 7.06e7.02 (m, 1H), 7.15e7.13 (m, 2H), 7.23 (d, J¼4 Hz, 1H),
7.43 (d, J¼8 Hz, 1H), 7.53e7.49 (m, 2H) ppm. 13C NMR (100 MHz,
6. (a) Wade, J. J.; Toso, C. B.; Matson, C. J.; Stelzer, V. L. J. Med. Chem. 1983, 26, 608;
(b) Yevich, J. P.; Temple, D. L., Jr.; Covington, R. R.; Owens, D. A.; Seidehamel, R.
J.; Dungan, K. W. J. Med. Chem. 1982, 25, 864.
CDCl3):
d 21.38, 31.45, 37.04, 50.79, 110.23, 111.64, 115.75, 122.11,
7. (a) Bhosale, V. N.; Vartale, S. P.; Deshmukh, V. K.; Kuberkar, S. V. J. Chem. Pharm.
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123.39, 124.65, 126.99, 129.87, 130.21, 138.14, 158.38, 160.90, 165.24,
195.55 ppm. 19F NMR (376 MHz, CDCl3):
d
ꢁ117.17 (m, 1F) ppm.
HRMS (ESI, m/z): calcd for C20H15FN2OS (MþHþ) 350.0889, found:
350.0892.
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[4,5]-thiazolo-[2,3-b]-quinazolin-1-one (4x). Yield 94%; yellow
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