A basic ionic liquid catalyzed reaction of benzothiazole, aldehydes, and 5,5-dimethyl-1,3-cyclohexanedione: Efficient synthesis of tetrahydrobenzo[b] pyrans

Article abstract of DOI:10.1002/jhet.183

(Chemical Equation Presented) A fast, mild, and quantitative procedure for the preparation of tetrahydrobenzo[b]pyran derivatives in the presence of an easily accessible basic ionic liquid - [bmIm]OH(3-butyl-1- methylimidazoliumhydroxide) as the catalyst

Full text of DOI:10.1002/jhet.183

954
A Basic Ionic Liquid Catalyzed Reaction of Benzothiazole,
Aldehydes, and 5,5-Dimethyl-1,3-cyclohexanedione: Efficient
Synthesis of Tetrahydrobenzo[b]pyrans
Vol 46
Li-Rong Wen, Huai-Yuan Xie, and Ming Li*
Key Laboratory of Eco-Chemical Engineering, Ministry of Education, College of Chemistry and
Molecular Engineering, Qingdao University of Science and Technology, Qingdao 266042, China
*E-mail: liming928@qust.edu.cn
Received February 7, 2009
DOI 10.1002/jhet.183
Published online 3 September 2009 in Wiley InterScience (www.interscience.wiley.com).
A fast, mild, and quantitative procedure for the preparation of tetrahydrobenzo[b]pyran derivatives in
the presence of an easily accessible basic ionic liquid—[bmIm]OH(3-butyl-1-methylimidazoliumhydrox-
ide) as the catalyst has been developed. The ionic liquid was stable during the reaction process and
could also be reused at least nine times with consistent activity. This procedure may be a practical alter-
native to the existing procedures to meet the need of academe as well as industries.
J. Heterocyclic Chem., 46, 954 (2009).
INTRODUCTION
Some of these reactions were catalyzed by a plethora of
reagents including solid or molten state [6], sodium bro-
mide under microwave irradiation [7], [bmIm][BF4] [8].
However, despite the potential utility of these catalysts,
many of these methodologies for the synthesis of 4H-
benzo[b]pyrans are associated with several shortcom-
ings, such as, long reaction time, high temperature,
harsh reaction conditions, and using of expensive
reagents. Gaps remain in terms of the search for eco-
nomical and environmentally benign methods.
The exploration of privileged structures in drug dis-
covery is a rapidly emerging theme in medicinal chem-
istry [1]. 4H-Benzopyran derivatives constitute a struc-
tural unit of a number of natural products [2] and are
versatile synthons because of the inherent reactivity of
the pyran ring [3]. In addition, 4H-benzo[b]pyran deriv-
atives are biologically interesting compounds that
possess various pharmacological activities [4], such as,
anticoagulant, spasmolytic, diuretic, anticancer, and anti-
anaphylactin characteristics [5]. These ubiquitous appli-
cations of 4H-benzo[b]pyrans stimulated several groups
[6–8] to develop new and efficient synthetic protocols
for these two bioactive units.
Multicomponent reactions (MCRs), an important sub-
class of tandem reaction [10], are one-pot processes in
which several easily accessible components react to
form a single product. They offer significant advantages
over conventional linear step synthesis, by reducing
time, saving money, energy, and raw materials, thus
resulting in both economical and environmental benefits.
At the same time, diversity can be achieved from build-
ing up libraries by simply varying each component [11].
Recently, ionic liquids have attracted increasing inter-
est in the context of green synthesis [12]. Choline
hydroxide has been used as a basic catalyst for aldol
condensation reactions between several ketones and
aldehydes [13], whereas the basic ionic liquid
Besides, because of the great pharmacological signifi-
cance of benzothiazole, which is of particular interest
especially within the realm of medicinal chemistry,
many useful therapeutic agents also contain the benzo-
thiazole moiety, and these substitution patterns were
introduced with efficiency [9].
Because of the vast utility of these kinds of com-
pounds, a number of synthetic routes have been devel-
oped for the expedition of these structure frameworks.
C
V
2009 HeteroCorporation

September 2009
A Basic Ionic Liquid Catalyzed Reaction of Benzothiazole, Aldehydes, and
5,5-Dimethyl-1,3-cyclohexanedione: Efficient Synthesis of Tetrahydrobenzo[b]pyrans
955
Scheme 1
time was long (Table 1, entry 1). The yields of 4a were
also unsatisfactory when using Et3N or piperidine as cat-
alysts (45.2–52.5%; Table 1, entries 2 and 3). To obtain
the higher yield, inorganic catalysts were studied; how-
ever, the result was disappointing. It turned out that
using KF or KF/Al2O3 (1:1) as the catalyst, only moder-
ate yields of 4a were obtained (52.5–55.0%; Table 1,
entries 4 and 5). Thus, ionic liquids were tried. Utilizing
[bmIm]BF4 and [bmIm]BF4/KOH (1:1), the yields of
the products were not obviously improved (50.2–68.0%;
Table 1, entries 6 and 7), but when the [bmIm]OH was
used as the catalyst, the yield of 4a was dramatically
improved to 83% in 0.5 h. Then, it was observed that
when the quantity of [bmIm]OH increased from 20 to
60 mol %, the yield of 4a improved accordingly to 95%
(Table 1, entries 8–10). However, with increasing the
amount of the catalyst, the yields of 4a were not further
improved but reduced (Table 1, entries 11 and 12).
Therefore, we selected 60 mol % of [bmIm]OH as the
catalyst. It was showed that the basic ionic liquid [bmI-
m]OH plays a significant catalytic role, as well as the
acceleration of the reaction rate and improvement of
selectivity.
[bmIm]OH has been successfully applied to catalyze
Michael additions of active methylene compounds to
conjugated ketones, carboxylic esters, and nitriles [14].
The synthesis of new and important types of heterocy-
clic compounds using the basic ionic liquid [bmIm]OH
continues to attract wide attention among synthetic
chemists.
Thus, in view of the advantages of MCRs and Tan-
dem reactions, and promoted by our earlier researches
on MCRs [15], herein, we wish to disclose a green pro-
tocol for the synthesis of a variety of biologically im-
portant 4H-Benzo[b]pyrans using the catalyst [bmIm]OH
under reflux condition (Scheme 1).
RESULTS AND DISCUSSION
To extend the scope of this new procedure for the
synthesis of 4H-benzo[b]pyrans, a series of reactions
were carried out under optimized conditions. We were
pleased to find that the reactions proceeded smoothly,
and desired products were afforded in excellent yields
(77–95%) and in short time (30–50 min) (Table 2).
We first studied the effects of a variety of catalysts
on the reaction using m-nitrobenzaldehyde as the sub-
strate in ethanol to develop the optimal reaction condi-
tions. The results are summarized in Table 1. Although
the reaction could take place without any catalyst, the
yield of 4a was relatively low 39.6%, and the reaction
When aromatic aldehydes
2
with more electron-
Table 1
Optimization of reaction conditions for compound 4a.
Entry
Catalyst (equiv)
EtOH (mL)
Time (h)
Yield (%)a
b
1
2
–
15
15
24
10
24
9
39.6
52.5
45.2
52.5
55.0
50.2
68.0
83.0
87.3
95.0
86.6
73.0
Et3N(0.2)
Piperidine(0.2)
KF(0.2)
3
4
15
15
5
KF/Al2O3(0.2)
[bmIm]BF4(0.2)
[bmIm]BF4/KOH(0.2)
[bmIm]OH(0.2)
[bmIm]OH(0.4)
[bmIm]OH(0.6)
[bmIm]OH(0.8)
[bmIm]OH(1.0)
15
15
15
8
6
7
8
8
8
9
3.0
3.0
3.0
3.0
3.0
0.5
0.5
0.5
0.5
0.5
10
11
12
a Isolated.
b No catalyst.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

956
L.-R. Wen, H.-Y. Xie, and M. Li
Vol 46
Table 2
Synthesis of compounds 4 by [bmIm]OH as catalyst.
Entry
Product
R
Time (min)
Yeild (%)a
1
2
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4r
3-NO2C6H4
2,5-Cl2C6H3
2-ClC6H4
30
30
40
30
35
30
30
30
35
30
40
50
40
50
50
40
60
95
90
3
4
88
91
4-ClC6H4
5
2,4-Cl2C6H3
2-BrC6H4
4-BrC6H4
89
94
94
90
89
92
87
80
6
7
8
9
2-FC6H4
3-FC6H4
10
11
12
13
14
15
16
17
4-FC6H4
C6H5
4-CH3C6H4
4-OMeC6H4
4-OHC6H4
3,4(CH3O)2C6H3
Furan
83
77
79
82
4-N(CH3)2C6H4
Trace
a Isolated.
withdrawing substituents or higher electronegativity
were used, the yields of 4 were higher (Table 2, entries
1–10). The heterocyclic aldehyde (furan formaldehyde)
was also used to support this reaction (Table 2, entry
16). In a further study, 4-N(CH3)2C6H4 was used in this
case, however, though the reactions proceeded smoothly,
the 2-(benzo[d]thiazol-2-yl)-3-(4-N,N-dimethyl-phenzyl)-
acrylonitrile instead of the desired product 4r was
observed (Table 2, entry17). Presumably, it was arrested
at the Knoevenagel condensation product stage, as fur-
ther aromatization did not occur due to electronic effect.
We also investigated the reusability and the recycling
of the basic ionic liquid [bmIm]OH, and found that the
catalyst could be easily recovered after completion of
the reaction and reused in subsequent reactions. Using
the reaction of 2-(benzo[d]thiazol-2-yl)acetonitrile 1, 4-
chlorobenzaldehyde 2d and 5,5-dimethyl-1,3-cyclohexa-
nedione 3 as a model reaction, after completion of the
reaction, the mixture was filtrated and the filtrate was
evaporated under reduced pressure, then extracted with
ethyl acetate:ether (1:1). The ionic liquid left in the
reaction vessel was rinsed with ether and dried under
vacuum at 90ꢀC for 8 h to remove water leaving behind
the ionic liquid. The recovered [bmIm]OH was recycled
and reused nine times to carry out the same experiment.
The activity of the catalyst did not show any significant
decrease after nine runs (Fig. 1).
The latter then undergoes Michael addition with 5,5-di-
methyl-1,3-cyclohexanedione 3 tautomer to give the
intermediate [B], followed by a intramolecular O-cycli-
zation to give the products 4H-Benzo[b]pyrans
(Scheme 2).
4
It may be speculated that the difference in basicity of
[bmIm]OH used in this reaction compared with Et3N
and piperidine may play a crucial role in accelerating
the reaction and improving the yield.
In conclusion, this procedure using the task-specific
basic ionic liquid [bmIm]OH as the catalyst provides a
very efficient and convenient methodology for synthesis
of 4H-benzo[b]pyrans through three-component reaction.
This method offers remarkable improvements with
A plausible mechanism for the reaction is outlined in
Scheme 2. The initial event can be considered as a
Knoevenagel condensation of aldehydes 2 with benzo-
thiazole 1 to form the intermediate [A], followed by the
elimination to afford the 2-(benzo[d]thiazol-2-yl)-3-(ary-
l)acrylonitrile under the basic ionic liquid [bmIm]OH.
Figure 1. Recycling times of [bmIm]OH and the isolated yields of
product 4d.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2009
A Basic Ionic Liquid Catalyzed Reaction of Benzothiazole, Aldehydes, and
5,5-Dimethyl-1,3-cyclohexanedione: Efficient Synthesis of Tetrahydrobenzo[b]pyrans
957
NMR, and 13C NMR spectroscopy. 1H NMR (500 MHz,
CDCl3): d ¼ 10.24 (s, 1 H), 7.62 (t, J ¼ 1.7 Hz, 1 H), 7.50 (t,
J ¼ 1.7, 1 H), 4.34 (t, J ¼ 7.4 Hz, 2 H), 4.12 (s, 3 H), 3.32–
3.25 (br s, 1H), 1.93–1.87 (m, 2 H), 1.40–1.36 (m, 2 H), 0.96
ppm (t, J ¼ 7.4 Hz, 3 H); 13C NMR (125 MHz, CDCl3): d ¼
137.2, 123.8, 122.1, 49.7, 36.7, 32.1, 19.4, 13.4 ppm; IR (neat)
Scheme 2
t: 3422, 3079, 1571, 1169 cmꢁ1
.
General procedure for the synthesis of 2-amino-3-(ben-
zo[d]thiazol-2-yl)-4-aryl-7,7-dimethyl–5–carbonyl-5,6,7,8-4H-
benzo[b]pyrans (4). To a mixture of 2-(benzo[d]thiazol-2-
yl)acetonitrile 1 (1 mmol), aromatic aldehydes 2 (1 mmol),
5,5-dimethyl-1,3-cyclohexanedione 3 (1 mmol) dissolved in a
minimum amount (3.0 mL) of ethanol, the basic ionic liquid,
[bmIm]OH (60 mol %) was added, and the mixture was
refluxed for appropriate time. The progress of reaction was
monitored by TLC. After completion of reaction aqueous, the
mixture was allowed to cool to room temperature, and filtered
to give the crude products, which was further purified by
recrystallization (THF/ethanol) to give pure products 4.
2-Amino-3-(benzo[d]thiazol-2-yl)-4-(3-nitrophenyl)-7,7-dimethyl-
5-carbonyl-5,6,7,8-4H-benzo[b]pyran (4a). mp 218–219ꢀC. IR
(KBr) t: 3429, 1679, 1624, 1525, 1473, 822, 696 cmꢁ1 1H
;
NMR (500 MHz, DMSO-d6) d: 0.67 (s, 3H, CH3), 0.92 (s, 3H,
CH3), 2.07 (d, J ¼ 16.5 Hz, 1H), 2.29 (d, J ¼ 16.0 Hz, 1H),
2.50 (d, J ¼ 17.5 Hz, 1H), 2.59 (d, J ¼ 17.5 Hz, 1H), 4.70 (s,
1H) 7.14–8.09 (m, 8H, ArH), 8.52 ppm (s, 2H, NH2); 13C
NMR (125 MHz, DMSO-d6) d: 25.5, 25.6, 26.6, 29.0, 32.4,
37.4, 50.2, 67.4, 80.5, 114.4, 120.6, 121.9, 122.2, 123.4, 126.6,
130.1, 131.7, 135.3, 147.0, 147.9, 154.6, 162.8, 168.3, 196.3
ppm; ms (ESI) m/z: 448.4 [M þH]þ. Anal. calcd. for
C24H21N3O4S: C, 64.42; H, 4.73; N, 9.40. Found: C, 64.49; H,
4.75; N, 9.42.
regard to operational simplicity, reaction time, reaction
conditions, general applicability, and greenness of proce-
dure, especially high isolated yields of products and the
selectivity. Thus, we believe that this simple and green
procedure will be a practical alternative to the existing
procedures to cater the need of academe as well as
industries.
2-Amino-3-(benzo[d]thiazol-2-yl)-4-(2,5-dichlorophenyl)-7,7-
dimethyl-5-carbonyl-5,6,7,8-4H-benzo[b]pyran (4b). mp 217–
218ꢀC. IR (KBr) t: 3446, 1679, 1661, 1626, 1477, 820, 669
cmꢁ1 1H NMR (500 MHz, CDCl3) d: 1.007 (s, 3H, CH3),
;
1.09 (s, 3H, CH3), 2.23 (d, J ¼ 16.0 Hz, 1H), 2.29 (d, J ¼
16.0 Hz, 1H), 2.50 (d, J ¼ 17.5 Hz, 1H), 2.59 (d, J ¼ 17.5
Hz, 1H), 5.07 (s, 1H) 7.04–7.30 (m, 7H, ArH), 7.35 ppm (s,
2H, NH2); 13C NMR (125 MHz, CDCl3) d: 26.6, 29.2, 32.2,
36.8, 50.5, 79.7, 112.7, 120.5, 121.9, 123.4, 126.6, 128.8,
131.3, 132.2, 142.5, 153.0, 154.8, 163.1, 168.4, 196.1 ppm; ms
(47 eV) m/z: 493.40 (100%, M þNa). Anal. calcd. for
C24H21N2O2SCl2: C, 61.02; H, 4.48; N, 5.93. Found: C, 60.89;
H, 4.47; N, 5.95.
EXPERIMENTAL
General remarks. Melting points were measured by using
a RY-1 apparatus and were uncorrected. IR spectra were
recorded on a Nicolet 510P FTIR spectrophotometer as KBr
pellets. 1H and 13C NMR were recorded in DMSO-d6 and
CDCl3 on a Bruker AC-500 instrument and TMS as internal
standard. Mass spectra were performed on a Bruker Esquire
Hct spectrometer with an ESI source. Elemental analyses were
carried out on a Vario EL III analyzer. All chemicals were
purchased and used without further purification.
2-Amino-3-(benzo[d]thiazol-2-yl)-4-(2-chlorophenyl)-7,7-
dimethyl-5-carbonyl-5,6,7,8-4H-benzo[b]pyran
204–205ꢀC. IR (KBr) t: 3445, 1678, 1658, 1624, 1475, 748,
666 cmꢁ1 1H NMR (500 MHz, DMSO-d6) d: 0.83 (s, 3H,
(4c). mp
;
CH3), 0.99 (s, 3H, CH3), 2.01 (d, J ¼ 16.0 Hz, 1H), 2.23 (d, J
¼ 16.0 Hz, 1H), 2.40 (d, J ¼ 17.5 Hz, 1H), 2.57(d, J ¼17.5
Hz, 1H), 4.82 (s, 1H), 7.06–7.83 (m, 8H, ArH), 8.48 ppm (s,
2H, NH2); 13C NMR (125 MHz, DMSO-d6) d: 26.6, 29.3,
32.1, 36.4, 39.4, 50.5, 80.4, 113.4, 120.4, 121.7, 123.2, 126.4,
127.0, 128.7, 126.6, 131.9, 133.1, 133.3, 140.5, 153.0, 154.7,
162.6, 168.6, 195.9 ppm; ms (ESI) m/z: 437.8 [M þH]þ. Anal.
calcd. for C24H21N2O2SCl: C, 65.97; H, 4.84; N, 6.41. Found:
C, 66.11; H, 4.85; N, 6.43.
The synthesis of 2-cyanomethy-1ꢁ,31-benzothiazloe [16]. mp
101–102ꢀC; IR (KBr) t: 2250 cm
;
1H NMR (500 MHz,
DMSO-d6) d: 7.80–8.27 (m, 2H), 7.00–7.80 (m, 2H), 4.72 (s,
2H, CH2). Anal. calcd. for C9H2N2S: C, 62.07; H, 3.47; N,
16.09; found: C, 62.16; H, 3.44; N, 16.11.
General procedure for the synthesis of basic ionic
liquid. The basic ionic liquid [bmIm]OH was prepared by
anion change of [bmIm]Br using 1 mol equivalent KOH. The
ionic liquid was dried under vacuum for 24 h and stored in
desiccators. The ionic liquid was characterized by IR, 1H
2-Amino-3-(benzo[d]thiazol-2-yl)-4-(4-chlorophenyl)-7,7-
dimethyl-5-carbonyl-5,6,7,8-4H-benzo[b]pyran
173–174ꢀ. IR (KBr) t: 3451, 1667, 1618, 1531, 1469, 835,
672 cmꢁ1 1H NMR (500 MHz, DMSO-d6) d: 0.85 (s, 3H,
(4d). mp
;
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DOI 10.1002/jhet

958
L.-R. Wen, H.-Y. Xie, and M. Li
Vol 46
CH3), 1.12 (s, 3H, CH3), 2.18 (d, J ¼ 16.5 Hz, 1H), 2.25 (d, J
¼ 16.0 Hz, 1H), 2.41 (d, J ¼ 17.5 Hz, 1H), 2.46 (d, J ¼ 17.5
Hz, 1H), 4.76 (s, 1H), 7.24–7.77 (m, 8H, ArH), 7.79 ppm (s,
2H, NH2); 13C NMR (125 MHz, DMSO-d6) d: 26.7, 29.2,
32.4, 36.9, 50.4, 81.2, 115.1, 120.6, 121.9, 123.4, 126.6, 128.5,
130.5, 131.5, 131.9, 143.8, 153.3, 154.5, 162.4, 168.7, 196.3
ppm; ms (ESI) m/z: 437.5 [M þH]þ. Anal. calcd. for
C24H21N2O2SCl: C, 65.97; H, 4.84; N, 6.41. Found: C, 65.89;
H, 4.83; N, 6.39.
182ꢀC. IR (KBr) t: 3427, 1679, 1663, 1616, 1480, 1452 cmꢁ1
;
1H NMR (500 MHz, DMSO-d6) d: 0.85 (s, 3H, CH3), 1.05 (s,
3H, CH3), 2.10 (d, J ¼ 16.0 Hz, 1H), 2.31 (d, J ¼ 16.5 Hz,
1H), 2.53 (d, 1H), 2.60 (d, J ¼ 17.5 Hz,1H), 4.61 (s, 1H),
6.94–7.89 (m, 8H, ArH), 8.46 ppm (s, 2H, NH2); 13C NMR
(125 MHz, DMSO-d6) d: 26.6, 29.1, 32.4, 37.2, 50.4, 81.0,
99.9, 113.8, 113.9, 114.9, 115.2, 115.4, 120.6, 121.9, 123.4,
124.5, 126.5, 130.4, 130.5, 131.9, 147.7, 147.8, 153.3, 154.6,
161.3, 162.5, 163.3, 168.6, 196.2 ppm; ms (ESI) m/z: 421.2
[M þH]þ. Anal. calcd. for C24H21FN2O2S: C, 68.55; H, 5.03;
N, 6.66. Found: C, 68.75; H, 5.04; N, 6.65.
2-Amino-3-(benzo[d]thiazol-2-yl)-4-(2,4-dichlorophenyl)-7,7-
dimethyl-5-carbonyl-5,6,7,8-4H-benzo[b]pyran (4e). mp 209–
210ꢀC. IR (KBr) t: 3454, 1681, 1618, 1468, 1454, 855, 672
2-Amino-3-(benzo[d]thiazol-2-yl)-4-(4-fluorophenyl)-7,7-dimethyl-
5-carbonyl-5,6,7,8-4H-benzo[b]pyran (4j). mp 192–193ꢀC. IR
;
(KBr) t: 3423, 1664, 1617, 1480, 1453 cmꢁ1 1H NMR (500
cmꢁ1 1H NMR (500 MHz, DMSO-d6) d: 0.85 (s, 3H, CH3),
;
1.02 (s, 3H, CH3), 2.05 (d, J ¼ 16.5 Hz, 1H), 2.29 (d, J ¼
16.5 Hz, 1H), 2.46 (d, J ¼ 17.5 Hz, 1H), 2.60 (d, J ¼ 17.5
Hz,1H), 4.832 (s, 1H), 7.14–7.85 (m, 7H, ArH), 8.53 ppm (s,
2H, NH2); 13C NMR (125 MHz, DMSO-d6) d: 26.6, 29.2,
32.2, 36.7, 50.4, 79.9, 113.0, 120.4, 121.7, 123.3, 126.5, 127.3,
129.6, 130.3, 132.3, 134.0, 139.8, 152.9, 154.7, 162.9, 168.4,
196.0 ppm; ms (ESI) m/z: 472.2 [M þH]þ. Anal. calcd. for
C24H20N2O2SCl2: C, 61.15; H, 4.28; N, 5.94. Found: C, 61.45;
H, 4.27; N, 5.91.
MHz, CDCl3) d: 0.96 (s, 3H, CH3), 1.13 (s, 3H, CH3), 2.20 (d,
J ¼ 16.5 Hz, 1H), 2.27 (d, J ¼ 16.0 Hz, 1H), 2.44(d, J ¼ 17.5
Hz, 1H), 2.52 (d, J ¼ 17.5 Hz, 1H), 4.81 (s, 1H), 6.90–7.81
(m, 8H, ArH), 8.45 ppm (s, 2H, NH2); 13C NMR (125 MHz,
CDCl3) d: 27.3, 29.2, 32.3, 36.6, 40.8, 50.8, 83.4, 114.8,
115.0, 116.1, 120.5, 121.2, 123.2, 125.9, 130.1, 130.2, 132.5,
139.6, 152.9, 160.6, 161.2, 162.6, 168.7, 196.4 ppm; ms (ESI)
m/z: 421.3 [M þH]þ. Anal. calcd. for C24H21FN2O2S: C,
68.55; H, 5.03; N, 6.66. Found: C, 68.28; H, 5.04; N, 6.67.
2-Amino-3-(benzo[d]thiazol-2-yl)-4-phenyl-7,7-dimethyl-5-
carbonyl-5,6,7,8-4H-benzo[b]pyran (4k). mp 185–186ꢀC. IR
2-Amino-3-(benzo[d]thiazol-2-yl)-4-(2-bromophenyl)-7,7-
dimethyl-5-carbonyl-5,6,7,8-4H-benzo[b]pyran
(4f). mp
177–178ꢀC. IR (KBr) t: 3446, 1677, 1658, 1475, 1454 cmꢁ1
;
1H NMR (500 MHz, DMSO-d6) d: 0.90 (s, 3H, CH3), 1.05 (s,
3H, CH3), 2.06 (d, J ¼ 16.0 Hz, 1H), 2.29 (d, J ¼ 16.0 Hz,
1H), 2.45 (d, 1H), 2.60 (d, J ¼ 17.5 Hz, 1H), 4.87 (s, 1H),
7.03–7.88 (m, 8H, ArH), 8.53 ppm (s, 2H, NH2); 13C NMR
(125 MHz, DMSO-d6) d:26.8, 29.3, 32.2,38.4, 50.6, 80.6, 80.7,
113.6, 115.7, 120.5, 121.7, 123.3, 126.5, 127.7, 129.0, 132.1,
133.8, 142.1, 147.2, 152.9, 154.8, 162.6, 168.7, 196.0 ppm; ms
(ESI) m/z: 483.2 [M þH]þ. Anal. calcd. for C24H21BrN2O2S:
C, 59.88; H, 4.40; N, 5.82. Found: C, 59.70; H, 4.39; N, 5.83.
2-Amino-3-(benzo[d]thiazol-2-yl)-4-(4-bromophenyl)-7,7-
(KBr) t: 3428, 1654, 1620, 1532, 1474, 833, 672 cmꢁ1 1H
;
NMR (500 MHz, DMSO-d6) d: 0.897 (s, 3H, CH3), 1.021 (s,
3H, CH3), 2.055 (d, J ¼ 16.0 Hz, 1H), 2.274 (d, J ¼ 16.0 Hz,
1H), 2.47 (d, J ¼ 17.5 Hz, 1H), 2.58 (d, J ¼ 17.0 Hz, 1H),
4.53 (s, 1H), 7.04–7.85 (m, 9H, ArH), 8.519 ppm (s, 2H,
NH2); 13C NMR (125 MHz, DMSO-d6) d: 26.6, 29.2, 32.3,
37.4, 50.4, 81.7, 115.5, 120.5, 121.8, 123.2, 126.4, 126.9,
128.4, 128.56, 131.9, 144.8, 153.2, 162.1, 168.8, 196.1 ppm;
ms (47 eV) m/z: 425.20 (100%, M þNa). Anal. calcd. for
C24H22N2O2S: C, 71.62; H, 5.51; N, 6.96. Found: C, 71.55; H,
5.49; N, 6.94.
dimethyl-5-carbonyl-5,6,7,8-4H-benzo[b]pyran
175–176ꢀC. IR (KBr) t: 3418, 1676, 1652, 1621, 1477, 1456
cmꢁ1 1H NMR (500 MHz, DMSO-d6) d: 0.84 (s, 3H, CH3),
(4g). mp
2-Amino-3-(benzo[d]thiazol-2-yl)-4-p-tolyl-7,7-dimethyl-5-
carbonyl-5,6,7,8-4H-benzo[b]pyran (4l). mp 189–190ꢀC. IR
;
(KBr) t: 3430, 1658, 1628, 1542, 1470, 822, 692 cmꢁ1 1H
;
1.03 (s, 3H, CH3), 2.08 (d, J ¼ 16.0 Hz, 1H), 2.29 (d, J ¼ 16.0
Hz, 1H), 2.46 (d, J ¼ 18.0 Hz, 1H), 2.59 (d, J ¼ 17.5 Hz,1H),
4.56 (s, 1H), 7.17–7.86 (m, 8H, ArH), 8.45 ppm (s, 2H, NH2);
13C NMR (125 MHz, DMSO-d6) d: 26.7, 29.2, 32.4, 37.1, 50.4,
81.2, 115.0, 120.0, 120.1, 121.9, 123.4, 126.6, 130.9, 131.4,
131.9, 144.2, 153.3, 154.5, 162.4, 168.7, 196.3 ppm; ms (ESI)
m/z: 483.2 [M þH]þ. Anal. calcd. for C24H21BrN2O2S: C,
59.88; H, 4.40; N, 5.82. Found: C, 59.64; H, 4.41; N, 5.83.
2-Amino-3-(benzo[d]thiazol-2-yl)-4-(2-fluorophenyl)-7,7-
NMR (500 MHz, DMSO-d6) d: 0.79 (s, 3H, CH3), 0.98 (s, 3H,
CH3), 2.03 (d, J ¼ 16.0 Hz, 1H), 2.11 (s, 3H) 2.24 (d, J ¼
16.5 Hz, 1H), 2.42 (d, J ¼ 17.5 Hz, 1H), 2.58(d, J ¼ 17.5 Hz,
1H), 4.46 (s, 1H), 6.95–7.82 (m, 8H, ArH), 8.32 ppm (s, 2H,
NH2); 13C NMR (125 MHz, DMSO-d6) d: 20.9, 26.6, 29.2,
32.3, 36.9, 50.4, 66.8, 81.8, 115.6, 117.6, 121.8, 123.2, 126.4,
128.5, 128.9, 131.9, 135.9, 141.8, 153.2, 154.7, 161.9, 168.9,
196.2 ppm; ms (47 eV) m/z: 439.24 (100%, M þNa). Anal.
calcd. for C24H24N2O2S: C, 71.26; H, 5.98; N, 6.92. Found: C,
71.39; H, 5.99; N, 6.94.
dimethyl-5-carbonyl-5,6,7,8-4H-benzo[b]pyran
173–174ꢀC. IR (KBr) t: 3429, 1674, 1652, 1614, 1476, 1453
cmꢁ1 1H NMR (500 MHz, DMSO-d6) d: 0.88 (s, 3H, CH3),
(4h). mp
;
2-Amino-3-(benzo[d]thiazol-2-yl)-4-(4-methoxyphenyl)-7,7-
1.06 (s, 3H, CH3), 2.06 (d, J ¼ 15.5 Hz, 1H), 2.30 (d, J ¼
16.0 Hz, 1H), 2.46 (d, 1H), 2.64 (d, J ¼ 18.0 Hz,1H), 4.75 (s,
1H), 7.02–7.91 (m, 8H, ArH), 8.46 ppm (s, 2H, NH2); 13C
NMR (125 MHz, DMSO-d6) d: 26.5, 29.2, 32.1, 32.3, 50.4,
80.5, 99.9, 113.7, 115.9, 120.4, 121.7, 123.3, 124.4, 126.5,
128.9,129.0, 131.0, 131.1, 131.6, 131.8, 153.2, 154.5, 159.6,
161.6, 168.7, 195.9 ppm; ms (ESI) m/z: 421.2 [M þH]þ. Anal.
calcd. for C24H21FN2O2S: C, 68.55; H, 5.03; N, 6.66. Found:
C, 68.34; H, 5.02; N, 6.67.
dimethyl-5-carbonyl-5,6,7,8-4H-benzo[b]pyran
177–178ꢀC. IR (KBr) t: 3396, 1675, 1656, 1621, 1474, 754,
665 cmꢁ1 1H NMR (500 MHz, DMSO-d6) d: 0.85 (s, 3H,
(4m). mp
;
CH3), 1.03 (s, 3H, CH3), 2.06 (d, J ¼ 16.0 Hz, 1H), 2.28 (d, J
¼ 16.0 Hz, 1H), 2.48 (d, J ¼ 17.5 Hz, 1H), 2.58(d, J ¼ 17.5
Hz, 1H), 3.63(s 3H), 4.49 (s, 1H), 6.75–7.86 (m, 8H, ArH),
8.35 ppm (s, 2H, NH2); 13C NMR (125 MHz, DMSO-d6) d:
26.2, 28.7, 31.9, 36.0, 49.9, 54.9, 81.5, 113.3, 115.2, 119.9,
121.9, 123.8, 125.9, 129.1, 131.5, 136.2, 152.7, 153.9, 157.7,
162.5, 168.4, 195.7 ppm; ms (ESI) m/z: 433.4 [M þH]þ. Anal.
2-Amino-3-(benzo[d]thiazol-2-yl)-4-(3-fluorophenyl)-7,7-di-
methyl-5-carbonyl-5,6,7,8-4H-benzo[b]pyran (4i). mp 181–
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2009
A Basic Ionic Liquid Catalyzed Reaction of Benzothiazole, Aldehydes, and
5,5-Dimethyl-1,3-cyclohexanedione: Efficient Synthesis of Tetrahydrobenzo[b]pyrans
959
[2] (a) Cingolant, M. G.; Pigini, M. J Med Chem 1988, 12,
531; (b) Hatakeyama, S.; Ochi, N.; Numata, H.; Takano, S. J Chem
Soc Chem Commun 1988, 1202.
calcd. for C25H24N2O3S: C, 69.42; H, 5.59; N, 6.48. Found: C,
69.34; H, 5.61; N, 6.46.
2-Amino-3-(benzo[d]thiazol-2-yl)-4-(4-hydroxyphenyl)-7,7-
dimethyl-5-carbonyl-5,6,7,8-4H-benzo[b]pyran (4n). mp 200–
201ꢀC. IR (KBr) t: 3451, 1677, 1652, 1616, 1474, 757, 538
[3] (a) Martins, M. A. P.; Frizzo, C. P.; Moreira, D. N.;
Zanatta, N.; Bonacorso, H. G. Chem Rev 2008, 108, 2015; (b) O’Call-
aghan, C. N.; McMarry, T. B. H. J Chem Res (S)1995, 214.
[4] Bloxham, J.; Dell, C. P.; Smith, C. W. Heterocycles 1994,
38, 399.
cmꢁ1 1H NMR (500 MHz, DMSO-d6) d: 0.82 (s, 3H, CH3),
;
1.02 (s, 3H, CH3), 2.06 (d, J ¼ 16.0 Hz, 1H), 2.26 (d, J ¼
16.0 Hz, 1H), 2.44 (d, J ¼ 17.5 Hz, 1H), 2.53 (d, J ¼ 17.0
Hz, 1H), 4.42 (s, 1H), 6.55–7.84 (m, 8H, ArH), 8.30 (s, 2H,
NH2), 9.15 ppm (s, 1H); 13C NMR (125 MHz, DMSO-d6) d:
18.9, 26.3, 29.2, 32.3, 36.5, 50.5, 56.5, 81.5, 115.1, 115.9,
120.4, 123.2, 126.4, 129.5, 132.0, 135.0, 153.2, 154.3, 156.2,
169.1, 196.1 ppm; ms (ESI) m/z: 419.2 [M þH]þ. Anal. calcd.
for C24H22N2O3S: C, 68.88; H, 5.30; N, 6.69. Found: C,
68.75; H, 5.29; N, 6.72.
[5] (a) Gianluca, S.; Francesca, C.; Andrea, G. Org Lett 2005,
7, 725; (b) Singh, K.; Singh, J.; Singh, H. Tetrahedron 1996, 52,
14273; (c) Foye, W. O. Prinicipi di Chimica Farmaceutica; Piccin:
Padova, Italy, 1991, p 416; (d) Andreani, L. L.; Lapi, E. Boll Chim
Farm 1960, 99, 583; (e) Zhang, Y.-L.; Chen, B.-Z.; Zheng, K.-Q.; Xu,
M.-L.; Lei, X.-H. YaoXueXuebao 1982, 17, 17; (f) Bonsignore, L.;
Loy, G.; Secci, D.; Calignano, A. Eur J Med Chem 1993, 28, 517; (g)
Wang, X.-S.; Shi, D.-Q.; Tu, S.-J.; Yao, C.-S.Synth Commun 2003,
33, 119.
2-Amino-3-(benzo[d]thiazol-2-yl)-4-(3,4-dimethoxyphenyl)-7,7-
dimethyl-5-carbonyl-5,6,7,8-4H-benzo[b]pyran (4o). mp 191–
192ꢀC. IR (KBr) t: 3443, 1662, 1624, 1615, 1560, 838, 669
[6] Kaupp, G.; Naimi-Zamal, M. R.; Schmeyers, J.Tetrahedron
2003, 59, 3753.
cmꢁ1 1H NMR (500 MHz, CDCl3) d: 1.20 (s, 3H, CH3),
;
[7] Ipsita, D.; Pulak, J. B. Tetrahedron Lett 2004, 45, 8625.
[8] Yang, G.-F. Adv Synth Catal 2006, 348, 1826.
1.216 (s, 3H, CH3), 2.19 (d, J ¼ 16.0 Hz, 1H), 2.24 (d, J ¼
16.5 Hz, 1H), 2.39 (d, J ¼ 17.5 Hz, 1H), 2.44 (d, J ¼ 17.5
Hz, 1H), 3.75 (s, 3H, OCH3), 3.85 (s, 3H, OCH3), 4.74 (s,
1H), 6.24–7.67 (m, 7H, ArH), 7.67 ppm (s, 2H, NH2); 13C
NMR (125 MHz, CDCl3) d: 26.7, 29.3, 33.4, 36.9, 32.4, 55.9,
55.9, 81.9, 111.9, 112.7, 115.7, 120.5, 120.7, 121.8, 123.3,
126.5, 132.1, 137.2, 147.9, 148.6, 153.3, 154.5, 161.9, 196.1,
196.3 ppm; ms (ESI) m/z: 463.8 [M þH]þ. Anal. calcd. for
C26H26N2O4S: C, 67.51; H, 5.67; N, 6.06. Found: C, 67.49; H,
5.68; N, 6.05.
[9] (a) Tale, R. H. Org Lett 2002, 4, 1641; (b) Bradshaw, T.
D.; Wrigley, S.; Shi, D. F.; Schulz, R. J.; Paull, K. D.; Stevens, M. F.
G. Br J Cancer 1998, 77, 745; (c) Moderhack, D.; Jan-Christoph, S. J
Heterocycl Chem 2007, 44, 393; (d) Chande, M. S.; Barve, P. A.; Sur-
anarayan, V. J Heterocycl Chem 2007, 44, 49.
¨
[10] Domling, A.; Ugi, I. Angew Chem Int Ed Engl 2000, 39,
3168.
¨
[11] (a) Domling, A. Chem Rev 2006, 106, 17; (b) Ngouansa-
vanh, T.; Zhu, J.-P. Angew Chem Int Ed Engl 2007, 46, 5775; (c)
Chao, G.-Y.; Xiao, K.-S.; Qi, F.-W.; Jing, S.; Siemeling, U.; Bruhn, C.
Chem Commun 2008, 10, 1440.
2-Amino-3-(benzo[d]thiazol-2-yl)-4-(furan-2-yl)-7,7-dimethyl-
5-carbonyl-5,6,7,8-4H-benzo[b]pyran (4p). mp 201–202ꢀC. IR
[12] (a) Dzyuba, S. V.; Li, S.; Bartsch, R. A. J Heterocycl Chem
2007, 44, 223; (b) Ranu, B. C.; Jana, R. J Org Chem 2005, 70, 8621;
(c) Zhu, A.-L.; Jiang, T.; Wang, D.; Han, B.-X.; Liu, L.; Huang, J.;
Zhang, J.-C.; Sun, D.-H. Green Chem 2005, 7, 514; (d) Song, C.-E.;
Jung, D.-U.; Choung, S.-Y.; Roh, E. J.; Lee, S. G. Angew Chem Int
Ed Engl 2004, 43, 6183.
1
(KBr) t: 3458, 1684, 1668, 1621, 1477, 1454 cmꢁ1; H NMR
(500 MHz, DMSO-d6) d: 0.95 (s, 3H, CH3), 1.06 (s, 3H,
CH3), 2.16 (d, J ¼ 16.0 Hz, 1H), 2.33 (d, J ¼ 16.0 Hz, 1H),
2.48 (d, 1H), 2.59 (d, J ¼ 17.5 Hz,1H), 4.73 (s, 1H), 6.18 (s,
1H), 6.27 (s, 1H), 7.20 (s, 1H), 7.22–7.92 (m, 4H, ArH), 8.39
ppm (s, 2H, NH2); 13C NMR (125 MHz, DMSO-d6) d: 26.7,
29.2, 32.4, 50.4, 79.2, 107.1, 110.8, 112.6, 120.6, 121.9, 123.4,
126.5, 131.9, 142.1, 153.4, 154.8, 155.5, 163.6, 168.7, 195.9
ppm; ms (ESI) m/z: 393.2 [M þH]þ. Anal. calcd. for
C22H20N2O3S: C, 67.33; H, 5.14; N, 7.14. Found: C, 67.53; H,
5.13; N, 7.15.
[13] Abello, S.; Medina, F.; Rodriguez, X.; Cesteros, Y.; Sala-
gre, P.; Sueiras, J. E.; Tichit, D.; Coq, B. Chem Commun 2004, 10,
1096.
[14] (a) Ranu, B. C.; Banerjee, S. Org Lett 2005, 7, 3049; (b)
Xu, J.-M.; Liu, B.-K.; Wu, W.-B.; Qian, C.; Wu, Q.; Lin, X.-F. J Org
Chem 2006, 71, 3991; (c) Ranu, B. C.; Jana, R.; Sowmiah, S. J Org
Chem 2007, 72, 3152; (d) Yang, L.; Xu, L.-W.; Zhou, W.; Li, L.; Xia,
C.-G. Tetrahedron Lett 2006, 47, 7723; (e) Sun, H.; Zhang, D.-J.;
Wang, F.; Li, C.-B. J Phys Chem A 2007, 111, 4535; (f) Lee, S.-G.
Chem Commun 2006, 1049.
Acknowledgments. Financial supports for this research by the
National Nature Science Foundation of China (No. 20572057 and
20872074) and Nature Science Foundation of Shandong province
(Y2006B11 and Z2008B03).
[15] (a) Wen, L.-R.; Sun, J.-H.; Li, M.; Sun, E.-T.; Zhang, S.-S.
J Org Chem 2008, 73, 1852; (b) Li, M.; Guo, W.-S.; Wen, L.-R.; Li,
Y.-F.; Yang, H.-Z. J Mol Catal A Chem 2006, 258, 133; (c) Li, M.;
Sun, E.-T.; Wen, L.-R.; Sun, J.-H.; Li, Y.-F.; Yang, H.-Z. J Comb
Chem 2007, 9, 903; (d) Li, M.; Zuo, Z.-Q.; Wen, L.-R.; Wang, S.-W.
J. Comb Chem 2008, 10, 436; (e) Li, M.; Yang, W.-L.; Wen, L.-R.;
Li, F.-Q. Eur J Org Chem 2008, 16, 2751.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet