Preparation of leukotriene B4 inhibitory active 2- and 3-(2-aminothiazol-4-yl)benzo[b]furan derivatives and their growth inhibitory activity on human pancreatic cancer cells

Article abstract of DOI:10.1039/b803313g

A series of 2-(2-aminothiazol-4-yl)benzo[b]furan and 3-(2-aminothiazol-4- yl)benzo[b]furan derivatives were prepared, and their leukotriene B₄ inhibitory activity and growth inhibitory activity in cancer cell lines were evaluated. Several compounds showed strong inhibition of calcium mobilization in CHO cells overexpressing human BLT₁ and BLT₂ receptors and growth inhibition to human pancreatic cancer cells MIA PaCa-2. 3-(4-Chlorophenyl)-2-[5-formyl-2-[(dimethylamino)methyleneamino]thiazol-4-yl] -5-methoxybenzo[b]furan 8b showed the most potent and selective inhibition for the human BLT₂ receptor, and its IC₅₀ value was smaller than that of the selected positive control compound, ZK-158252. 3-(4-Chlorophenyl)-2-[2-[(dimethylamino)methyleneamino]-5-(2- hydroxyethyliminomethyl)thiazol-4-yl]-5-methoxybenzo[b]furan 9a displayed growth inhibitory activity towards MIA PaCa-2. The Royal Society of Chemistry.

Full text of DOI:10.1039/b803313g

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Preparation of leukotriene B4 inhibitory active 2- and
3-(2-aminothiazol-4-yl)benzo[b]furan derivatives and their growth
inhibitory activity on human pancreatic cancer cells†
Mari Kuramoto,a Yoko Sakata,a Kumi Terai,a Ikuo Kawasaki,a Jun-ichi Kunitomo,a Takahiro Ohishi,b
Takehiko Yokomizo,c Seiichi Takeda,d Shuichi Tanakad and Yoshitaka Ohishi*a
Received 26th February 2008, Accepted 15th April 2008
First published as an Advance Article on the web 29th May 2008
DOI: 10.1039/b803313g
A series of 2-(2-aminothiazol-4-yl)benzo[b]furan and 3-(2-aminothiazol-4-yl)benzo[b]furan derivatives
were prepared, and their leukotriene B4 inhibitory activity and growth inhibitory activity in cancer cell
lines were evaluated. Several compounds showed strong inhibition of calcium mobilization in CHO
cells overexpressing human BLT1 and BLT2 receptors and growth inhibition to human pancreatic
cancer cells MIA PaCa-2. 3-(4-Chlorophenyl)-2-[5-formyl-2-[(dimethylamino)methyleneamino]thiazol-
4-yl]-5-methoxybenzo[b]furan 8b showed the most potent and selective inhibition for the human BLT2
receptor, and its IC50 value was smaller than that of the selected positive control compound,
ZK-158252. 3-(4-Chlorophenyl)-2-[2-[(dimethylamino)methyleneamino]-5-(2-
hydroxyethyliminomethyl)thiazol-4-yl]-5-methoxybenzo[b]furan 9a displayed growth inhibitory activity
towards MIA PaCa-2.
LTB4 have been observed in patients with various inflammatory
Introduction
diseases.3
Leukotriene B4 (LTB4) is known as a potent mediator of the
Although many works have been done to develop LTB4 receptor
antagonists for clinical use as an anti-inflammatory drugs,4 no
antagonist has yet been developed for clinical applications. The
structures of representative reported LTB4 receptor antagonists
are shown in Fig. 1.5 Recently, another LTB4 receptor (BLT2) was
found and its molecular cloning was established.6 This encouraged
new studies to find novel BLT1 and/or BLT2 inhibitors, which
may lead to the development of new clinical drugs for im-
munosuppression of allograft rejection in organ transplantation,7
arteriosclerosis,8 psoriasis,9 cancer,10 and rheumatoid arthritis.11
We have been interested in the preparation of various types
of benzo[b]furan derivatives in order to evaluate their biological
activities, and have reported that several of their derivatives such
as 1, 2 and 3 (Fig. 2) showed selective LTB4 receptor (BLT1,
BLT2) inhibitory activities.12 In an earlier paper, we described the
inflammatory process, playing important physiological roles on
leukocytes trafficking to the site of infection and clearance of
invading microorganisms.2 On the other hand, elevated levels of
aSchool of Pharmaceutical Sciences, Mukogawa Women’s University, 11-
68, Koshien Kyuban-cho, Nishinomiya, 663-8179, Japan. E-mail: ikuo_k@
mukogawa-u.ac.jp; Fax: +81 798 45 9953; Tel: +81 798 45 9953
bScience of Environment and Mathematical Modeling, Graduate School of
Engineering, Doshisha University, Kyotanabe, Kyoto, 610-0394, Japan
cDepartment of Medical Biochemistry, Graduate School of Medical Sciences,
Kyushu University, 3–1-1, Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
dFuso Pharmaceutical Industries, Ltd., 2-3-30, Morinomiya, Joto-ku, Osaka,
536-8523, Japan
† Electronic supplementary information (ESI) available: Growth in-
hibitory activities of 5b, 5c, 5f, 7b, 10a, 12b, 13 and 16 against cancer
cells. See DOI: 10.1039/b803313g
Fig. 1 Structures of representative LTB4 receptor antagonists.
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in constructing the thiazole moiety at the 2-position of the
benzo[b]furan ring.16 The results are shown in Table 1. 2-
(Haloacetyl)benzo[b]furans 4a-4d were prepared according to a
modification of the reported procedure17 and were allowed to react
with thioureas or thiobenzamide to obtain 2-(2-aminothiazol-
4-yl)benzo[b]furans 5a, 5b, 5d, 5e and 2-(2-phenylthiazol-4-
yl)benzo[b]furan 5c in 55–86% yields as shown in Table 1.
Conversion from the 2-(2-aminothiazol-4-yl)benzo[b]furan 5a
to several types of 2-(N-and/or C-substituted-2-aminothiazol-4-
yl)benzo[b]furan derivatives are depicted in Scheme 1.
Acylation of the aminothiazole 5a with acid chloride gave
the corresponding carboxamides 6a–6c in 31–77% yields, and
the morphorinoacetamide 6d and piperazinoacetamide 6e were
derived from 6c in 72 and 38% yields, respectively. Treatment of
the 5-methylisoxazol-4-yl derivative 5b or 6b with Et3N in refluxing
THF afforded the characteristic (Z)-2-cyano-3-hydroxybut-2-
enoyl compound 5f (60% yield) and 7a (50% yield) by a ring
opening reaction of the isoxazole ring followed by enolization
of the a-cyano-b-ketoamide. The structures of 5f and 7a were
supported by the observation of the corresponding enol OH
proton at 15.75 ppm and 14.49 ppm in the 1H NMR spectrum.20
In order to obtain a formylated compound at the 5-position
of the thiazole ring, the reaction of aminothiazole 5a was carried
out with 4 equiv. of POCl3 in DMF at −10 to −5 ◦C, under
Vilsmeier reaction conditions. The reaction proceeded smoothly
and selectively only at the primary amino group of the 2-
position on the thiazole ring to give the N,N-dimethylformimidine
product 8a in 74% yield. On the other hand, the same reaction
using a large excess (8 equiv.) of POCl3 at room temperature
provided Nꢀ-(5-formylthiazol-2-yl)-N,N-dimethylformimidine 8b
in 60% yield as the sole product. However, treatment of 6c with
4 equiv. of POCl3 in DMF gave N-formyl derivative 7b in 34%
yield, probably because the amide bond in 6c was relatively
sensitive to acidic reaction conditions. The condensation reaction
of the aldehyde 8b with 2-aminoethanol or glycine ethyl ester
provided the imine derivatives 9a (73%) and 9b (17%). The
Fig. 2 Structures of the reported LTB4 receptor–inhibitory active
benzo[b]furan derivatives.
preparation of a new class of benzo[b]furan derivatives,13 2-(2-
aminothiazol-4-yl)benzo[b]furans, that selectively showed highly
potent and significant inhibitory activity towards BLT2.1
In 2002, Adrian and co-workers reported that the LTB4 receptor
antagonist, LY293111, inhibited proliferation and induced apop-
tosis in human pancreatic cancer cells.14 In the present study, we
prepared 2- and 3-(2-aminothiazol-4-yl)benzo[b]furan derivatives
showing inhibitory activities for the LTB4 receptor and evaluated
their analogues for growth inhibitory activity by using cancer cell
lines including the human pancreatic cancer cells MIA PaCa-2.
Chemistry
The literature has only a few examples of the preparation of 2-
(2-aminothiazol-4-yl)benzo[b]furan derivatives.15 We planned the
preparation of a series of 2-(thiazol-4-yl)benzo[b]furan deriva-
tives by applying Hantzsch thiazole synthesis as a key step
Table 1 Preparation of 2-(thiazol-4-yl)benzo[b]furan derivatives 5a–e
Entry
4
X
R1
R2
R3
R4
Yield of 5 (%)
1
2
4a
4b
Cl
Br
4-Cl-C6H4
OMe
Br
H
H
NH2
NH2
5a: 55
5b: 84
3
4b
Br
Br
H
Ph
5c: 86
4
5
4c18
4d
Br
Br
H
H
Br
H
H
OMe
NH2
NH2
5d19: 85
5e: 58
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Scheme 1 Preparation of 3-substituted 2-(2-aminothiazol-4-yl)benzo[b]furan derivatives. Reagents and conditions: (a) CH3COCl, THF, reflux, 77% (6a);
(b) 5-methylisoxazole-4-carbonyl chloride, THF, reflux, 31% (6b); (c) ClCH2COCl, THF, rt, 74% (6c); (d) morphorine, CH3CN, reflux, 72% (6d); (e)
2-(piperazin-1-yl)ethanol, CH3CN, rt, 38% (6e); (f) Et3N, THF, reflux, 50% (7a from 6b); 60% (5f); (g) 4 eqiuv. POCl3, DMF, 34% (rt, 7b from 6c); 74%
◦
˚
(−10 to −5 C, 8a); (h) 8 eqiuv. POCl3, DMF, rt, 60% (8b); (i) NH2CH2CH2OH, EtOH, reflux, 73% (9a); (j) NH2CH2CO2Et. HCl, Et3N, EtOH, 3A
molecular sieves, reflux, 17% (9b); (k) (EtO)2P(O)CH2CONC4H8O, NaH, THF, rt, 63% (10a); (l) (EtO)2P(O)CH2CONHC6H4OMe, NaH, THF, rt, 43%
(10b).
Horner–Wadsworth–Emmons reaction was applied to the alde-
hyde 8b with phosphonoacetamides12b,21 to afford the amides 10a
and 10b in moderate yields (63% and 43%).
Next, we planned the preparation of 3-unsbstituted 2-(2-
amino-5-formylthiazol-4-yl)benzo[b]furan derivatives in order to
compare their activities with 3-(4-chlorophenyl)benzo[b]furan
derivatives (Scheme 2). N-Acylation of the 2-(2-aminothiazol-4-
yl)benzo[b]furan 5d was performed using several acid chlorides
to obtain 2-(acylaminothiazol-4-yl)benzo[b]furan 11a–11d in 49–
68% yields. Formylation reaction of 11a or 5d with POCl3 and
DMF gave the 5-formylated thiazole derivartive 12a and Nꢀ-
(5-formylthiazol-2-yl)-N,N-dimethylformimidine 13 in 41% and
50% yields, respectively. However, applying the same reaction
conditions to the benzamide 11b gave a complex reaction mixture,
and the product obtained was the N-formylthiazolylbenzo[b]furan
12b in 9% isolated yield.22
Scheme 2 Preparation of 3-unsubstituted 2-(2-aminothiazol-4-yl)benzo-
[b]furan derivatives. Reagents and conditions: (a) Me3CCOCl, Et3N, THF,
reflux, 54% (11a); (b) 4-Cl-C6H4COCl, THF, rt, 49% (11b); (c) ClCH2-
COCl, THF, reflux, 68% (11c); (d) Cl(CH2)2COCl, THF, rt, 55% (11d); (e)
POCl3, DMF, rt, 41% (12a); 9% (12b); (f) POCl3, DMF, 60 ◦C, 50% (13).
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Scheme 3 Preparation of 3-(2-aminothiazol-4-yl)benzo[b]furan derivatives. Reagents and conditions: (a) ClCH2COCl, AlCl3, CHCl3, 0 ◦C, 26%; (b)
H2NC(S)NH2, EtOH, reflux, 84%; (c) POCl3, DMF, rt, 33%.
Table 3 In vitro cell growth inhibitory activities of 6c, 6d, 8b, 9a, 11c, 11d
We planned the preparation of the compound with a 2-
aminothiazol-4-yl group attached at the 3-position on the
benzo[b]furan ring as shown in Scheme 3. Hantzsch thiazole
synthesis was also conducted with the 3-chloromethylketone
15, derived from 5-bromo-2-phenylbenzo[b]furan 14,23 to ob-
tain the desired 3-(2-aminothiazol-4-yl)benzo[b]furan 5g in
84% yield. Treatment of 5g with POCl3 and DMF af-
forded 3-[2-[(dimethylamino)methyleneamino]-5-formylthiazol-4-
yl]-2-phenylbenzo[b]furan 16 in 33% yield.
and 5-FU
GI50a/lM
Compound
MIA PaCa-2
PC-3
MCF-7
NHDF
b
b
b
6c
8.64
>10
7.92
4.84
3.68
6.76
7.74
>10
7.59
>10
>10
>10
5.53
>10
>10
9.95
>10
>10
6d
6e
6.99
b
8b
>10
b
9a
4.17
b
11c
11d
5-FU
3.60
7.70
>10
b
Biological study
2.05
a GI50 is the concentration of the compound causing 50% inhibition of cell
growth compared to the negative control. b Not tested.
The results of LTB4 inhibitory activity of 5a, 6a, 6b, 7a, 8a, 8b,
9a and 9b together with 112b by inhibition of calcium mobilization
in both CHO cells overexpressing human BLT1 (CHO-hBLT1)
and human BLT2 (CHO-hBLT1)24 are shown in Table 2.1 Among
the tested compounds, 8b, 9a and 9b, showed potent inhibitory
activity of the LTB4 receptor and inhibited BLT2 more potently
than BLT1. In contrast, ZK-158252 nearly equally inhibited both
BLT1 and BLT2. Compounds 8b, 9a and 9b were more potent than
ZK-158252 in BLT2 inhibition, and showed less inhibition than
ZK-158252 to BLT1.
Encouraged by these results, we planned the evaluation of the
growth inhibitory activity in cancer cell lines. Fourteen compounds
5b, 5c, 5f, 6c, 6d, 6e, 7b, 8b, 9a, 10a, 11c, 11d, 12b, 13 and 16 were
assayed for activity in vitro against human pancreatic carcinoma
(MIA PaCa-2), breast cancer (MCF-7, MDA-MB-231), human
prostate carcinoma (PC-3) and normal human dermal fibroblast
(NHDF) cells, and the results are summarized in Table 3 and
Fig. 3.25 Compounds 5b, 5c, 5f and 7b, N-unsubstituted 2-
aminothiazole derivatives, had no inhibitory effect in MIA PaCa-
2. However, compounds 10a, 12b, 13 and 16 which are fully
Fig. 3 Effects of 8b and 9a on MIA Paca-2. * P<0.05, **P<0.01 V.S. 5-FU
(Tukey’s test). Each data point represents the mean (% growth) S.E. for
6 cultures.
Table 2 Evaluation of prepared compounds for LTB4 receptor (BLT1,
BLT2) inhibitory activitiesa
substituted at both the N- and C-positions in the 2-aminothiazol-
4-yl group at the 2- or 3-position of the benzo[b]furan skeleton
showed an inhibitory effect on cancer cell lines. Compound 10a,
% Inhibition (10 lM)
IC50/lM
Compound CHO-hBLT1 CHO-hBLT2 CHO-hBLT1 CHO-hBLT2
in particular, inhibited MIA PaCa-2 (79.3
at 10 lM) more potently than 5-FU (81.2
inhibitory potency in NHDF was less than that of 5-FU (84.5
1.0% vs 48.0 2.0).25
Among the tested compounds, we found 6c, 6e, 8b, 9a, 11c,
and 11d showed potent inhibitory activity on cell growth in
MIA PaCa-2. Their GI50 values against MIA PaCa-2, PC-3,
MCF-7 and NHDF cells are given in Table 3. The GI50 values
of 2-[2-[(dimethylamino)methyleneamino]-5-substituted-thiazol-
4-yl]benzo[b]furans 8b and 9a against MIA PaCa-2 were 4.84 and
3.68 lM, respectively, which were less than half the concentration
2.2% cell growth
1.8%), while its
5a
4.8
70.6
68.7
N.I.b
82.1
72.0
97.9
100
88.3
100
—
—
—
—
—
—
—
—
3.29
—
0.19
0.20
0.35
0.48
1.18
6a
11.2
N.I.b
13.6
11.6
24.4
51.3
49.4
69.9
—
6b
7a
8a
—
8b
3.55
3.19
6.81
2.88
1.70
9a
9b
1
ZK-158252
a Effect of calcium mobilization by LTB4 (300 nM) in CHO-hBLT1 and
CHO-hBLT2 cells. b Not inhibited.
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of 5-FU (Fig. 3, Table 3). Inhibitory activity of 8b and 9a against
NHDF was very low (GI50>10). From the viewpoint of reducing
the risk of side effects in therapeutic treatment, such selective
activity is a promising feature.
Ar-H); Anal. Calcd for C17H12Cl2O3: C, 60.92; H, 3.61 found: C,
60.97; H, 3.45%.
5-Bromo-2-bromoacetyl-3-(5-methylisoxazole-4-carboxamido)-
benzo[b]furan 4b. A solution of Br2 (0.72 g, 4.51 mmol) in
CHCl3 (15 mL) was added to a solution of 2-acetyl-5-bromo-
3-(5-methylisoxazole-4-carboxamido)benzo[b]furan27 (1.50 g,
4.14 mmol) in CHCl3 (30 mL). After stirring for 1.5 h at room
temperature, saturated NaHCO3 aqueous solution (10 mL) was
added to the mixture, and the products were extracted with
CHCl3. The organic layer was washed with saturated NaCl
aqueous solution, dried over anhydrous MgSO4 and evaporated
to give a solid, which was purified by column chromatography
(CHCl3) and recrystallized from AcOEt to give 4b (1.28 g, 70%)
Conclusions
We have developed a method for preparing N-substituted 3-
and 2-(2-aminothiazol-4-yl)benzo[b]furans. Compounds 8b and
9a showed potent and selective inhibitory activities for the BLT2
receptor and inhibited cell growth of human pancreatic cancer
cells. A common structural feature of the active compounds is the
2-[(dimethylamino)methyleneamino]thiazole having substituent
groups at the 5-position. Their inhibitory potencies toward BLT2
were 6.2–3.4 times more active than ZK-158252, and their activ-
ities against MIA PaCa-2 were more potent than 5-FU. Further
studies with in vivo experiments and on their mechanism to confirm
these preliminary results are in progress with the ultimate aim of
developing them as agents for clinical purposes.
◦
as colorless crystals; mp, 195–196 C; dH (CDCl3, 60 MHz) 2.87
(3H, s, CH3), 4.48 (2H, s, CH2Br), 7.19–7.46 (1H, m, 6-H), 7.71
(1H, d, J = 10.2 Hz, 7-H), 8.64 and 8.85 (1H each, each s, 4-H
and isoxazole-H), 10.57 (1H, br s, NH); Anal. Calcd for C15H10Br2
N2O4: C, 40.75; H, 2.28; N, 6.34 found: C, 40.66; H, 2.13; N,
6.35%.
2-Bromoacetyl-6-methoxybenzo[b]furan 4d.
A solution of
Experimental
chloroacetone (2.01 mL, 25 mmol) in CH3CN (8 mL) and
K2CO3 (8.58 g, 62 mmol) were added to a solution of 4-
methoxysalicylaldehyde (3.20 g, 21 mmol) in CH3CN (45 mL).
After stirring for 2 h under reflux, the reaction mixture was filtered
and the solvent was evaporated. H2O and CHCl3 were added to
the residue. The products were extracted with CHCl3. The organic
layer was washed with saturated NaCl aqueous solution, dried
over anhydrous MgSO4 and evaporated to give a brown solid,
which was recrystallized from AcOEt–n-hexane to give 2-acetyl-
6-methoxybenzo[b]furan (2.76 g, 69%) as slightly brown crystals;
mp, 77–79 ◦C; dH (CDCl3, 60 MHz) 2.56 (3H, s, COCH3), 3.87
(3H, s, OCH3), 6.85–7.63 (4H, m, 3-, 4-, 5-, 7-H); Anal. Calcd for
C11H10O3·0.05H2O: C, 69.14; H, 5.33 found: C, 69.13; H, 5.35%.
Compound 4d was prepared under similar reaction
conditions to the synthesis of 4b starting from 2-acetyl-
6-methoxybenzo[b]furan instead of 2-acetyl-5-bromo-3-(5-
methylisoxazole-4-carboxamido)benzo[b]furan, and obtained as
yellow crystals after recrystallization from AcOEt–n-hexane;
yield, 62%; mp, 72–74 ◦C; dH (CDCl3, 60 MHz) 3.90 (3H, s,
OCH3), 4.39 (2H, s, CH2Br), 6.91–7.60 (4H, m, 3-, 4-, 5-, 7-H);
Anal. Calcd for C11H9BrO3 C, 49.10; H, 3.37 found: C, 48.98; H,
3.24%.
Chemistry
Melting point was measured with a Yanaco MP micro-melting-
point apparatus and are uncorrected. 1H NMR spectra were
measured with JEOL JNM-ECP500 (500 MHz) or JEOL JNM-
ECP400 (400 MHz) spectrometers, with chemical shifts expressed
in parts per million (ppm) downfield from tetramethylsilane as the
internal standard. Mass spectra were measured on a JEOL JMS
DX-303 EIMS spectrometer. Elemental analyses were performed
with a CHN CORDER MT-3 (Yanaco).
2-Chloroacetyl-3-(4-chlorophenyl)-5-methoxybenzo[b]furan
4a.
A
solution of 1-(4-chlorophenyl)-2-(4-methoxyphenoxy)etha-
none26 (1.00 g, 3.62 mmol) in polyphosphoric acid (10 mL) was
stirred for 30 min at 140 ◦C. The reaction mixture was poured
into ice water, and the products were extracted with AcOEt. The
organic layer was washed with saturated NaCl aqueous solution,
dried over anhydrous MgSO4 and evaporated to give a solid,
which was recrystallized from AcOEt to give 3-(4-chlorophenyl)-
5-methoxybenzo[b]furan (0.93 g, 99%) as colorless crystals; mp,
◦
77–78 C; dH (CDCl3, 500 MHz) 3.86 (3H, s, OCH3), 6.97 (1H,
dd, J = 9.2, 2.7 Hz, 6-H), 7.20 (1H, d, J = 2.8 Hz, 4-H), 7.42–7.46
(3H, m, J = 8.7 Hz, 7- and Ar-H), 7.54 (2H, d, J = 8.3 Hz, Ar-H),
7.74 (1H, s, 2-H); Anal. Calcd for C15H11ClO2: C, 69.64; H, 4.29
found: C, 69.67; H, 4.19%.
General procedure for the synthesis of the 2-(2-aminothiazol-
4-yl)benzo[b]furans 5—synthesis of 2-(2-aminothiazol-4-yl)-3-(4-
chlorophenyl)-5-methoxybenzo[b]furan 5a as an example. A so-
lution of 4a (0.31 g, 0.92 mmol) and thiourea (0.085 g, 1.12 mmol)
in EtOH (20 mL) was refluxed for 2 h. The reaction mixture
was poured into ice water, and powdered products were extracted
with CHCl3. The organic layer was washed with saturated NaCl
aqueous solution, dried over anhydrous MgSO4 and evaporated to
give a solid, which was recrystallized fro◦m AcOEt to give 5a (0.18 g,
55%) as yellow crystals; mp, 196–198 C; dH (CDCl3, 400 MHz)
3.80 (3H, s, OCH3), 4.98 (2H, s, NH2), 6.63 (1H, s, Th-H), 6.86
(1H, d, J = 2.6 Hz, 4-H), 6.93 (1H, dd, J = 8.8, 2.5 Hz, 6-H), 7.45
(1H, d, J = 8.8 Hz, 7-H), 7.45–7.51 (4H, m, Ar-H); Anal. Calcd
for C18H13ClN2O2S: C, 60.59; H, 3.67; N, 7.85 found: C, 60.43; H,
3.57; N, 7.80%.
A
solution of 3-(4-chlorophenyl)-5-methoxybenzo[b]furan
(300 mg, 1.16 mmol) in CHCl3 (10 mL) was added to a mixture of
the AlCl3(0.16 g, 1.20 mmol) and chloroacetyl chloride (0.11 m l,
1.40 mmol) in CHCl3 (5 mL) at 0 ◦C. After stirring for 2.5 h at 0 ◦C,
the reaction mixture was poured into ice water, and the products
were extracted with CHCl3. The organic layer was washed with
saturated NaCl aqueous solution, dried over anhydrous MgSO4
and evaporated to give a solid, which was recrystallized from
AcOEt–n-hexane to give 4a (310 mg, 80%) as yellow crystals;
mp, 138–139 ◦C; dH (CDCl3, 500 MHz) 3.81 (3H, s, OCH3), 4.72
(2H, s, CH2), 6.95 (1H, d, J = 2.7 Hz, 4-H), 7.18 (1H, dd, J = 9.1,
2.3 Hz, 6-H), 7.50–7.57 (3H, m, 7- and Ar-H), 7.55–7.57 (2H, m,
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2-(2-Aminothiazol-4-yl)-5-bromo-3-(5-methylisoxazole-4-carbo-
xamido)benzo[b]furan 5b. The title compound was synthesized
according to the general procedure for 5a by using 4b instead of
evaporated to give crude isoxazolecarboyl chloride as a residue,
which was dissolved in THF (20 mL). The compound 5a (0.3 g,
0.84 mmol) was added to the solution, and the mixture was
refluxed for 2 h. THF was evaporated and the product was
extracted using AcOEt by adding a 5% HCl aqueous solution.
The organic layer was washed with saturated NaCl aq. solution,
dried over anhydrous MgSO4 and evaporated to give a yellow
solid, which was recrystallized from AcOEt to give 6b (0.12 g,
31%) as pale yellow crystals; mp, 217–219 ◦C; dH (CDCl3,
400 MHz) 2.66 (3H, s, CCH3), 3.79 (3H, s, OCH3), 6.81 (1H,
d, J = 2.5 Hz, 4-H), 6.92 (1H, dd, J = 8.8, 2.6 Hz, 6-H), 7.13
(1H, s, Th-H), 7.33 (1H, d, J = 9.1 Hz, 7-H), 7.42 (4H, br s,
Ar-H), 8.19 (1H, s, isoxazole-H), 11.06 (1H, s, NH); Anal. Calcd
for C23H16ClN3O4S·0.5H2O: C, 58.17; H, 3.61; N, 8.85 found: C,
58.14; H, 3.44; N, 8.87%.
◦
4a; yield, 84%; mp, 203–205 C (recrystallized from MeOH); dH
(CDCl3, 400 MHz) 2.75 (3H, s, CH3), 7.09 (1H, s, Th-H), 7.35
(2H, s, NH2), 7.48 (1H, dd, J = 8.8, 2.2 Hz, 6-H), 7.56 (1H, d, J =
8.7 Hz, 7-H), 7.97 (1H, d, J = 1.8 Hz, 4-H), 9.10 (1H, s, isoxazole-
H), 10.27 (1H, s, NHCO); Anal. Calcd for C16H11BrN4O3S: C,
45.84; H, 2.64; N, 13.36 found: C, 45.89; H, 2.51; N, 13.10%.
5-Bromo-3-(5-methylisoxazole-4-carboxamido)-2-(2-phenylthia-
zol-4-yl)benzo[b]furan 5c. The title compound was synthesized
according to the general procedure for 5a by using 4b and
thiobenzamide instead of 4a and thiourea; yield, 86%; mp, 231–
235 ◦C; dH (CDCl3, 400 MHz) 2.82 (3H, s, CH3), 7.34 (1H, d, J =
8.7 Hz, 7-H), 7.45 (1H, dd, J = 8.7, 2.0 Hz, 6-H), 7.51–7.54 (3H,
m, Ar-H), 7.68 (1H, s, thiazole-H), 7.85–7.87 (2H, m, Ar-H), 8.46
(1H, d, J = 2.0 Hz, 4-H), 8.63 (1H, s, isoxazole-H), 10.42 (1H, s,
NH); Anal. Calcd for C22H14BrN3O3S: C, 55.01; H, 2.94; N, 8.75
found: C, 54.81; H, 2.91; N, 8.63%.
2-[2-(2-Chloroacetamido)thiazol-4-yl)]-3-(4-chlorophenyl)-5-
methoxybenzo[b]furan 6c. Chloroacetyl chloride (0.10 mL,
1.26 mmol) was added to a solution of 5a (0.30 g, 0.84 mmol)
in THF (25 mL). After stirring for 8 h at room temperature,
the reaction mixture was poured into ice water, and the mixture
was neutralized by addition of NaHCO3. The products were
extracted with AcOEt, and the organic layer was washed with
saturated NaCl aqueous solution, dried over anhydrous MgSO4
and evaporated to give an orange solid, which was recrystallized
from AcOEt to give 6c (0.27 g, 74%) as yellow crystals; mp, 181–
182 ◦C; dH (CDCl3, 400 MHz) 3.81 (3H, s, CH3), 4.25 (2H, s, CH2),
6.88 (1H, d, J = 2.5, 4-H), 6.97 (1H, dd, J = 8.8, 2.5 Hz, 6-H),
7.08 (1H, s, Th-H), 7.47–7.50 (5H, m, 7-H and, Ar-H), 9.83 (1H,
br s, NH); Anal. Calcd for C20H14Cl2N2O3S: C, 55.44; H, 3.26; N,
6.47 found: C, 55.62; H, 3.24; N, 6.25%.
2-(2-Aminothiazol-4-yl)-5-bromobenzo[b]furan 5d19. The title
compound was synthesized according to the general procedure
for 5a by using 4c18 instead of 4a; yield, 85%; mp, 234–236 ◦C; dH
(CDCl3, 400 MHz) 6.95 and 7.10 (1H each, each s, Th-H and 3-H),
7.21 (2H, s, NH2), 7.42 (1H, dd, J = 8.8, 2.2 Hz, 6-H), 7.54 (1H,
d, J = 8.4 Hz, 7-H), 7.84 (1H, d, J = 1.9 Hz, 4-H); Anal. Calcd
for C11H7BrN2OS: C, 44.76; H, 2.39; N, 9.49 found: C, 44.85; H,
2.36; N, 9.54%.
2-(2-Aminothiazol-4-yl)-6-methoxybenzo[b]furan 5e. The title
compound was synthesized according to the general procedure
for 5a by using 4d instead of 4a; yield, 58%; mp, 190–191 ◦C
(recrystallized from CHCl3); dH (CDCl3, 400 MHz) 3.81 (3H, s,
OCH3), 6.868 (1H, s, 3-H or Th-H), 6.871 (1H, dd, J = 8.4, 2.2 Hz,
5-H), 6.91 (1H, s, 3-H or Th-H), 7.15 (2H, s, NH2), 7.18 (1H, d,
J = 1.8 Hz, 7-H), 7.49 (1H, d, J = 8.8 Hz, 4-H); Anal. Calcd for
C12H10N2O2S: C, 58.52; H, 4.09; N, 11.37 found: C, 58.32; H, 4.06;
N, 11.15%.
3-(4-Chlorophenyl)-5-methoxy-2-[2-[2-(morpholin-4-yl)aceta-
mido]thiazol-4-yl]benzo[b]furan 6d. Morphorine (0.05 mL,
0.56 mmol) was added to a solution of 6c (0.20 g, 0.46 mmol)
in CH3CN (30 mL). After stirring for 3 h under reflux, the solvent
was evaporated to give a white solid, which was recrystallized from
AcOEt to give 6d (0.16 g, 72%) as yellow crystals; mp, 111–116 ◦C;
dH (CDCl3, 400 MHz) 2.62 (4H, t, J = 4.8 Hz, 2 × NCH2CH2),
3.26 (2H, s, COCH2N), 3.79 (4H, t, J = 4.8 Hz, 2 × OCH2CH2),
3.81 (3H, s, OCH3), 6.88 (1H, d, J = 2.5 Hz, 4-H), 6.96 (1H, dd,
J = 9.0, 2.8 Hz, 6-H), 6.99 (1H, s, Th-H), 7.45–7.52 (4H, m, Ar-
H), 7.50 (1H, d, J = 7.0, 7-H), 10.31 (1H, br s, NH); Anal. Calcd
for C24H22ClN3O4S·0.5H2O: C, 58.47; H, 4.70; N, 8.52 found C,
58.64; H, 4.65; N, 8.30%.
2-(2-Acetamidothiazol-4-yl)-3-(4-chlorophenyl)-5-methoxybenzo-
[b]furan 6a. Acetyl chloride (0.24 mL, 3.36 mmol) was added
to a solution of 5a (0.50 g, 1.40 mmol) in THF (15 mL). After
stirring for 2 h under refluxing, the reaction mixture was poured
into ice water, and the mixture was acidified by adding of 5%
HCl aqueous solution. The products were extracted with AcOEt,
and the organic layer was washed with saturated NaCl aqueous
solution, dried over anhydrous MgSO4 and evaporated to give a
brown solid, which was recrystallized from MeOH–CCl4 to give
3-(4-Chlorophenyl)-2-[2-[2-[4-(2-hydroxyethyl)piperazin-1-yl]-
acetamido]thiazol-4-yl]-5-methoxybenzo[b]furan 6e. Compound
6e was prepared under similar reaction conditions to the synthesis
of 6d by using 2-(piperazin-1-yl)ethanol instead of morphorine,
and the reaction was conducted at room temperature; yield,
◦
6a (0.43 g, 77%) as yellow crystals; mp, 217–218 C; dH (CDCl3,
400 MHz) 2.09 (3H, s, COCH3), 3.81 (3H, s, OCH3), 6.89 (1H,
d, J = 2.6 Hz, 4-H), 6.96 (1H, dd, J = 8.8, 2.6 Hz, 6-H), 7.17
(1H, s, Th-H), 7.42 (2H, d, J = 8.6 Hz, Ar-H), 7.45 (1H, d, J =
9.1 Hz, 7-H), 7.49 (2H, d, J = 8.6 Hz, Ar-H), 9.87 (1H, s, NH);
Anal. Calcd for C20H15ClN2O3S: C, 60.22; H, 3.79; N, 7.02 found:
C, 60.24; H, 3.69; N, 6.92%.
◦
38%; mp, 101–105 C (recrystallized from MeOH–n-hexane); dH
(CDCl3, 400 MHz) 1.88 (1H, br s, OH), 2.62–2.65 (10H, m, CH2
in piperazine and NCH2CH2OH), 3.26 (2H, s, COCH2N), 3.66
(2H, t, J = 5.5 Hz, CH2OH), 3.81 (3H, s, OCH3), 6.88 (1H, d, J =
2.5 Hz, 4-H), 6.96 (1H, dd, J = 8.8, 2.6 Hz, 6-H), 7.03 (1H, s, Th-
H), 7.46–7.52 (4H, m, Ar-H), 7.49 (1H, d, J = 7.0 Hz, 7-H), 10.35–
3-(4-Chlorophenyl)-5-methoxy-2-[2-(5-methylisoxazole-4-carbo-
xamido)thiazol-4-yl]benzo[b]furan 6b. A solution of 5-methyl-4-
isoxazolecarboxylic acid (0.08 g, 0.63 mmol) and thionyl chloride
(0.46 mL, 6.3 mmol) was refluxed for 2 h, and the solvent was
1
3
10.36 (1H, br s, NH); Anal. Calcd for C26H27ClN4O4S· H2O: C,
58.58; H, 5.23; N, 10.51 found C, 58.72; H, 5.16; N, 10.34%.
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(Z)-3-(4-Chlorophenyl)-2-[2-(2-cyano-3-hydroxybut-2-enamido)-
thiazol-4-yl]-5-methoxybenzo[b]furan 7a. Et3N (0.30 mL,
2.15 mmol) was added to a solution of 6b (0.10 g, 0.22 mmol)
in THF (6 mL), and the mixture was refluxed for 4.5 h. After
the reaction, THF was evaporated. The product was extracted
using AcOEt by addition of 5% HCl aqueous solution, and the
organic layer was washed with saturated NaCl aq. solution, dried
over anhydrous MgSO4 and evaporated to give a brown solid,
which was recrystallized from EtOH to give 7a (0.05 g, 50%) as
pale yellow crystals; mp, 227–229 ◦C; dH (CDCl3, 400 MHz) 3.21
(3H, s, CCH3), 3.75 (3H, s, OCH3), 6.87 (1H, d, J = 2.5 Hz, 4-H),
6.96 (1H, dd, J = 8.7, 2.5 Hz, 6-H), 7.08 (1H, s, Th-H), 7.46 (1H,
d, J = 8.7 Hz, 7-H), 7.47 (4H, br s, Ar-H), 9.66 (1H, br s, NH),
14.49 (1H, br s, OH); Anal. Calcd for C23H16ClN3O4S: C, 59.29;
H, 3.46; N, 9.02 found: C, 59.07; H, 3.40; N, 8.93%.
The solvent was evaporated to give a yellow residue, which
was dissolved in AcOEt, washed with H2O and saturated NaCl
aqueous solution. The organic layer was dried over anhydrous
MgSO4 and evaporated to give an orange solid, which was
recrystallized from AcOEt to give 9a (0.24 g, 73%) as red crystals;
mp, 168–169 ◦C; dH (CDCl3, 400 MHz) 2.04 (1H, br s, OH), 3.06
(6H, s, N (CH3)2), 3.60–3.62 (2H, m, OCH2CH2N), 3.80–3.83
(2H, m, OCH2CH2N), 3.83 (3H, s, OCH3), 6.98 (1H, d, J =
1.8 Hz, 4-H), 6.99 (1H, dd, J = 8.7, 2.3 Hz, 6-H), 7.41 (2H, d,
J = 8.7 Hz, Ar-H), 7.45 (2H, d, J = 8.7 Hz, Ar-H), 7.46 (1H,
=
=
d, J= 8.7 Hz, 7-H), 8.03 (1H, s, N CH), 8.64 (1H, s, N CH);
m/z 484 (6), 482 (M+, 14), 385 (17), 371 (100); Anal. Calcd for
C24H23ClN4O3S: C, 59.68; H, 4.80; N, 11.60 found: C, 59.49; H,
4.77; N, 11.35%.
3-(4-Chlorophenyl)-2-[5-[(2-ethoxy-2-oxoethylimino)methyl]-2-
[(dimethylamino)methyleneamino]thiazol-4-yl]-5-methoxybenzo-
[b]furan 9b. A mixture of 8b (0.50 g, 1.13 mmol), glycine
ethyl ester hydrochloride (0.19 g, 1.36 mmol), Et3N (0.31 mL,
General procedure for Vilsmeier reaction—synthesis of 2-(2-
amino-5-formylthiazol-4-yl)-3-(4-chlorophenyl)-5-methoxybenzo-
[b]furan 7b as an example. A solution of 6c (0.30 g, 0.69 mmol)
in DMF (10 mL) was added to a solution of POCl3 (0.26 mL,
2.78 mmol) in DMF (10 mL) at 0 ◦C. After stirring for 30 h at room
temperature, the reaction mixture was poured into 5% NaOH
aqueous solution, and the resulting precipitate was collected by
filtration and washed with H2O to give a red solid, which was
recrystallized from AcOEt–n-hexane to give 7b (0.09 g, 34%) as
red crystals; mp, 217–220 ◦C; dH (DMSO-d6, 400 MHz) 3.80 (3H, s,
OCH3), 7.05 (1H, d, J = 2.2 Hz, 4-H), 7.09 (1H, dd, J = 8.8, 2.2 Hz,
6-H), 7.52 (2H, d, J = 8.8 Hz, Ar-H), 7.56 (2H, d, J = 8.8 Hz,
Ar-H), 7.66 (1H, d, J = 9.1, 7-H), 8.21 (2H, s, NH2), 9.85 (1H, s,
CHO); Anal. Calcd for C19H13ClN2O3S: C, 59.30; H, 3.40; N, 7.28
found: C, 59.44; H, 3.34; N, 7.24%.
˚
2.22 mmol) and molecular sieves (3A, 0.1 g) in EtOH (10 mL)
was refluxed for 1 h. The solvent was evaporated to give a yellow
residue, which was dissolved in AcOEt, washed with H2O and
saturated NaCl aqueous solution. The organic layer was dried
over anhydrous MgSO4 and evaporated to give an orange solid,
which was recrystallized from AcOEt to give 9b (0.10 g, 17%) as
red crystals; mp, 162–165 ◦C; dH (CDCl3, 500 MHz) 1.29 (3H, t,
J = 7.4, CH2CH3), 3.05 (3H, s, NCH3), 3.06 (3H, s, NCH3), 3.82
(3H, s, OCH3), 4.21 (2H, q, J = 7.4 Hz, CH2CH3), 4.23 (2H, s,
NCH2CO), 6.97–7.00 (2H, m, 4- and 6-H), 7.41 (2H, d, J = 8.7 Hz,
=
Ar-H), 7.44–7.48 (3H, m, 7- and Ar-H), 8.01 (H, s, N CH), 8.62
+
=
(H, s, N CH); m/z 526 (10), 524 (M , 25), 427 (23), 413 (100), 356
(12), 354 (31); Anal. Calcd for C26H25ClN4O4S·0.2H2O: C, 59.07;
3-(4-Chlorophenyl)-5-methoxy-2-[2-[(dimethylamino)methylene-
amino]thiazol-4-yl]benzo[b]furan 8a. This compound was
synthesized according to the general procedure for 7b by using 5a
instead of 6c. The reaction was conducted at −10 to −5 ◦C; yield,
74%; mp, 145–147 ◦C (recrystallized from EtOH); dH (CDCl3,
400 MHz) 3.05 and 3.07 (3H each, each s, NCH3 × 2), 3.30 (3H, s,
OCH3), 6.90 (1H, d, J = 2.5 Hz, 4-H), 6.92 (1H, dd, J = 8.8,
2.6 Hz, 6-H), 7.00 (1H, s, Th-H), 7.43 (1H, d, J = 8.8 Hz, 7-H),
H, 4.84; N, 10.60 found: C, 59.25; H, 4.80; N, 10.34%.
(E)-3-(4-Chlorophenyl)-5-methoxy-2-[-2-[(dimethylamino)me-
thyleneamino]-5-[3-(morpholin-4-yl)-3-oxoprop-1-enyl]thiazol-4-
yl]benzo[b]furan 10a. A solution of 8b (0.47 g, 1.07 mmol) in
THF (30 mL) was added to a mixture of [2-(4-morpholinyl)-2-
oxoethyl]phosphonic acid ethyl ester12b (0.34 g, 1.28 mmol) and
NaH (60% in oil, 0.051 g, 1.28 mmol) in THF (10 mL) at 0 ◦C. After
stirring for 42 h at room temperature, the reaction mixture was
poured into saturated NH4Cl aqueous solution. The products were
extracted with AcOEt, and the organic layer was washed with
sat. NaCl aqueous solution, dried over anhydrous MgSO4 and
evaporated to give a yellow solid, which was recrystallized from
AcOEt to give 10a (0.37 g, 63%) as yellow crystals; mp, 142–
=
7.42–7.55 (4H, m, Ar-H), 8.16 (1H, s, N CH); Anal. Calcd for
C21H18ClN3O2S: C, 61.23; H, 4.40; N, 10.20 found: C, 61.12; H,
4.27; N, 10.14%.
3-(4-Chlorophenyl)-2-[5-formyl-2-[(dimethylamino)methylene-
amino]thiazol-4-yl]-5-methoxybenzo[b]furan 8b. This compound
was synthesized according to the general procedure for 7b by using
5a instead of 6c, and 8 equiv. of POCl3 was used; yield, 60%;
mp, 196–198 ◦C (recrystallized from MeOH–AcOE); dH (CDCl3,
400 MHz) 3.07 (6H, s, N(CH3)2), 3.82 (3H, s, OCH3), 6.94 (1H,
d, J = 2.8 Hz, 4-H), 7.03 (1H, dd, J = 9.0, 2.6 Hz, 6-H), 7.42–
◦
144 C; dH (CDCl3, 500 MHz) 3.06 (6H, s, N(CH3)2), 3.70–3.72
(8H, m, 2 × CH2CH2), 3.82 (3H, s, OCH3), 6.27 (1H, d, J =
=
15.1 Hz, CH CHCO), 6.95 (1H, dd, J = 8.5, 2.6 Hz, 6-H), 6.98
(1H, d, J = 2.3 Hz, 4-H), 7.37–7.39 (2H, m, Ar-H), 7.42–7.45 (2H,
=
m, Ar-H), 7.50 (1H, d, J = 9.1 Hz, 7-H), 8.01 (1H, s, N CH),
=
7.55 (5H, m, 7- and Ar-H), 7.96 (1H, s, CH N), 10.43 (1H, s,
CHO); m/z 441 (40), 439 (M+, 100), 410 (17), 395 (18), 380 (18),
283 (14), 235 (16), 208 (16), 115 (20), 98 (15); Anal. Calcd for
C22H18ClN3O3S: C, 60.07; H, 4.12; N, 9.55 found: C, 59.99; H,
3.99; N, 9.57%.
8.19 (1H, d, J = 15.1 Hz, CH=CHCO); m/z 552 (M + 2, 42), 551
(M + 1, 33), 550 (M+, 100), 464 (39), 332 (48).
(E)-3-(4-Chlorophenyl)-5-methoxy-2-[5-[3-(4-methoxyphenyl-
amino)-3-oxoprop-1-enyl]-2-[(dimethylamino)methyleneamino]thi-
azol-4-yl]benzo[b]furan 10b. Compound 10b was prepared under
similar reaction conditions to the synthesis of 10a by using [2-[(4-
methoxyphenyl)amino]-2-oxoethyl]phosphonic acid ethyl ester21
instead of [2-(4-morpholinyl)-2-oxoethyl]phosphonic acid ethyl
3-(4-Chlorophenyl)-2-[5-(2-hydroxyethylimino)methyl]-2-[(dime-
thylamino)methyleneamino]thiazol-4-yl]-5-methoxybenzo[b]furan
9a. A solution of 8b (0.30 g, 0.68 mmol) and ethanolamine
(0.06 mL, 1.03 mmol) in EtOH (5 mL) was refluxed for 0.5 h.
2778 | Org. Biomol. Chem., 2008, 6, 2772–2781
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ester; yield, 43%; mp, 224–227 ◦C; dH (CDCl3, 400 MHz) 3.06
(6H, s, 2 × NCH3), 3.80 (3H, s, OCH3), 3.81 (3H, s, OCH3), 6.00
4-, 6-, 7-H), 7.73 (1H, s, Th-H), 9.72 (1H, brs, NH); Anal. Calcd
for C13H8BrClN2O2S: C, 42.01; H, 2.17; N, 7.54 found: C, 42.29;
H, 2.13; N, 7.51%.
=
(1H, d, J = 15.0 Hz, CH CHCO), 6.85–6.89 (2H, m, Ar-H), 6.94
(1H, d, J = 2.2 Hz, 4-H), 6.97 (1H, dd, J = 8.8, 2.5 Hz, 6-H),
7.08 (1H, br s, NH), 7.37–7.47 (6H, m, Ar-H), 7.51 (1H, d, J =
5-Bromo-2-[2-(3-chloropropanamido)thiazol-4-yl]benzo[b]furan
11d. Compound 11d was prepared under similar reaction condi-
tions to the synthesis of 11b by using 3-chloropropionyl chloride
instead of p-chlorobenzoyl chloride, and obtained as pale yellow
crystals after recrystallization from MeOH; yield, 55%; mp, 210–
212 ◦C; dH (DMSO-d6, 400 MHz) 2.99 (2H, t, J = 6.2 Hz, COCH2),
3.92 (2H, t, J = 6.3 Hz, CH2Cl), 7.12 (1H, s, 3-H), 7.47 (1H, dd,
J = 8.7, 2.1 Hz, 6-H), 7.60 (1H, d, J = 8.4 Hz, 7-H), 7.71 (1H, s,
Th-H), 7.89 (1H, d, J = 1.8 Hz, 4-H), 12.65 (1H, s, NH); Anal.
Calcd for C14H10BrClN2O2S: C, 43.60; H, 2.61; N, 7.26 found: C,
43.67; H, 2.66; N, 7.12%.
=
8.8 Hz, 7-H), 8.01 (1H, s, N CH), 8.22 (1H, d, J = 15.0 Hz,
CH=CHCO); Anal. Calcd for C31H27ClN4O4S: C, 63.42; H, 4.64;
N, 9.54 found: C, 63.45; H, 4.57; N, 9.45%.
(Z)-2-(2-Aminothiazol-4-yl)-5-bromo-3-(2-cyano-3-hydroxybut-
2-enamido)benzo[b]furan 5f. Compound 5f was prepared under
similar reaction conditions to the synthesis of 7a by using 5b
instead of 6b, and obtained as yellow crystals after r◦ecrystallization
from AcOEt–n-hexane; yield, 60%; mp, 228–230 C; dH (CDCl3,
400 MHz) 2.38 (3H, s, CCH3), 5.59 (2H, s, NH2), 6.85 (1H, s, Th-
H), 7.28 (1H, d, J = 8.7 Hz, 7-H), 7.91 (1H, dd, J = 8.7, 2.0 Hz,
6-H), 8.54 (1H, d, J = 2.0 Hz, 4-H), 11.76 (1H, s, NHCO), 15.75
(1H, s, OH); Anal. Calcd for C16H11BrN4O3S: C, 45.84; H, 2.64;
N, 13.36 found: C, 45.92; H, 2.52; N, 13.25%.
5-Bromo-2-[5-formyl-2-(2,2-dimethylpropanamido)thiazol-4-yl-
]benzo[b]furan 12a. This compound was synthesized according
to the general procedure for 7b by using 11a instead of 6c; yield,
41%; mp, 244–245 ◦C (recrystallized from MeOH–AcOEt); dH
(CDCl3, 400 MHz) 1.38 (9H, s, C(CH3)3), 7.30 (1H, s, 3-H), 7.42
(1H, d, J = 8.8 Hz, 7-H), 7.48 (1H, dd, J = 8.8, 1.9 Hz, 6-H),
7.80 (1H, d, J = 1.8 Hz, 4-H), 9.03 (1H, br s, NH), 10.70 (1H, s,
CHO); Anal. Calcd for C17H15BrN2O3S·0.2H2O: C, 49.69; H,
3.78; N, 6.82 found: C, 49.82; H, 3.71; N, 6.72%.
5-Bromo-2-[2-(2,2-dimethylpropanamido)thiazol-4-yl]benzo[b]-
furan 11a. Trimethylacetyl chloride (0.19 mL, 1.53 mmol) was
added to a solution of 5d (0.30 g, 1.02 mmol) and Et3N (0.40 mL,
2.87 mmol) in THF (10 mL). After stirring for 23 h under reflux,
the reaction mixture was poured into ice water. The products were
extracted with CHCl3, and the organic layer was washed with
saturated NaCl aqueous solution, dried over anhydrous MgSO4
and evaporated to give a white solid, which was recrystallized
from AcOEt to give 11a (0.21 g, 54%) as colorless crystals; mp,
184–185 ◦C; dH (DMSO-d6, 400 MHz) 1.27 (9H, s, C(CH3)2), 7.13
(1H, s, 3-H), 7.46 (1H, dd, J = 8.7, 2.1 Hz, 6-H), 7.60 (1H, d,
J = 8.7 Hz, 7-H), 7.69 (1H, s, Th-H), 7.90 (1H, d, J = 2.0, 4-H),
12.05 (1H, s, NH); m/z 380 (M + 2, 42), 378 (M+, 41), 296 (33),
294 (32), 57 (100); HRMS Calcd for C16H15BrN2O2S: 378.0038;
found: 378.0033.
5-Bromo-2-(2-formamido-5-formylthiazol-4-yl)benzo[b]furan
12b. This compound was synthesized according to the general
procedure for 7b by using 11b instead of 6c; yield, 9%; mp, 250–
254 ◦C; dH ((CD3)2CO, 400 MHz) 7.46 (1H, s, 3-H), 7.59 (1H, dd,
J = 8.8, 2.2 Hz, 6-H), 7.70 (1H, d, J = 8.8 Hz, 7-H), 7.95 (1H, d,
J = 2.2 Hz, 4-H), 8.79 (1H, br s, NCHO), 10.74 (1H, s, CCHO),
11.66 (1H, br s, NH); m/z 352 (M + 2, 100), 350 (M+, 99), 324
(38), 322 (37), 280 (28), 278 (27), 254 (62), 252 (62), 145 (33), 144
(30).
5-Bromo-2-[2-(4-chlorobenzamido)thiazol-4-yl]benzo[b]furan
5-Bromo-2-[5-formyl-2-[(dimethylamino)methyleneamino]thia-
zol-4-yl]benzo[b]furan 13. This compound was synthesized ac-
cording to the general procedure for 7b by using 5d instead of 6c,
and the reaction was conducted at 60 ◦C; yield, 50%; mp, 187 ◦C
(recrystallized from AcOEt); dH (CDCl3, 500 MHz) 3.17 and 3.21
(3H each, each s, N(CH3)2), 7.37 (1H, s, 3-H), 7.40 (1H, d, J =
8.7 Hz, 7-H), 7.46 (1H, dd, J = 8.9, 2.1 Hz, 6-H), 7.78 (1H, d, J =
11b.
A solution of p-chlorobenzoyl chloride (1.97 mL,
15.4 mmol) in THF (50 mL) was added to a solution of 5d (0.30 g,
1.02 mmol) in THF (100 mL). After stirring for 47 h at room
temperature, the reaction mixture was poured into water, and the
mixture was acidified by addition of 10% HCl aqueous solution.
The products were extracted with AcOEt, and the organic layer
was washed with saturated NaCl aqueous solution, dried over
anhydrous MgSO4 and evaporated to give a yellow solid, which
was recrystallized from MeOH to give 11b (2.15 g, 49%) as pale
=
1.8, 4-H), 8.35 (1H, s, N CH), 10.61 (1H, s, CHO); Anal. Calcd
for C15H12BrN3O2S: C, 47.63; H, 3.20; N, 11.11 found: C, 47.47;
H, 2.98; N, 10.91%.
◦
yellow crystals; mp, 234–249 C; dH (DMSO-d6, 400 MHz) 7.18
(1H, s, 3-H), 7.48 (1H, dd, J = 8.7, 2.0 Hz, 6-H), 7.54–7.58 (2H,
m, Ar-H), 7.62 (1H, d, J = 9.7 Hz, 7-H), 7.63–7.66 (2H, m, Ar-H),
7.79 (1H, s, Th-H), 7.91 (1H, d, J = 2.1 Hz, 4-H), 13.0 (1H, s,
NH); m/z 436 (M + 4, 9), 434 (M + 2, 31), 432 (M+, 22), 141 (32),
111 (23); HRMS Calcd for C18H10BrClN2O2S: 431.9336; found:
431.9335.
5-Bromo-3-(2-chloroacetyl)-2-phenylbenzo[b]furan 15. A solu-
tion of 1423 (1.00 g, 3.67 mmol) in CHCl3 (18 mL) was added
to a solution of AlCl3 (1.94 g, 15 mmol) and chloroacetyl
chloride (0.35 mL, 4.42 mmol) at 0 ◦C. After stirring for 2 h
at 0 ◦C, the reaction mixture was poured into ice water, and
the products were extracted with AcOEt. The organic layer
was washed with saturated NaCl aqueous solution, dried over
anhydrous MgSO4 and evaporated to give a yellow solid, which
was purified by column chromatography (AcOEt–n-hexane = 3 : 7)
and recrystallized from AcOEt–n-hexane to give 15 (0.33 g, 26%)
as pale yellow crystals; mp, 104–106 ◦C; dH (CDCl3, 400 MHz) 4.28
(2H, s, CH2), 7.41 (1H, d, 7-H, J = 8.8 Hz), 7.52 (1H, dd, 6-H, J =
8.4, 1.9 Hz), 7.54–7.63 (3H, m, Ar-H), 7.71–7.74 (2H, m, Ar-H),
5-Bromo-2-[2-(2-chloroacetamido)thiazol-4-yl]benzo[b]furan
11c. Compound 11c was prepared under similar reaction condi-
tions to the synthesis of 11b by using chloroacetyl chloride instead
of p-chlorobenzoyl chloride. The reaction mixture was refluxed
for 46 h and obtained as yellow crystals after recrystallization
from AcOEt–n-hexane; yield, 68%; mp, 211 ◦C; dH ((CD3)2CO,
400 MHz) 4.31 (2H, s, CH2), 7.01 (1H, s, 3-H), 7.39–7.42 (3H, m,
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8.24 (1H, d, 4-H, J = 1.8 Hz); Anal. Calcd for C16H10BrClO2: C,
Acknowledgements
54.97; H, 2.88 found: C, 54.85; H, 2.79%.
This research was financially supported in part by a grant from the
Ministry of Education, Culture, Sports, Science and Technology of
Japan for a ‘University–Industry Joint Research’ Project (2004–
2008). The authors thank the staff of the Instrument Analysis
Center of Mukogawa Women’s University for the H NMR and
MS measurements and element analyses.
3-(2-Aminothiazol-4-yl)-5-bromo-2-phenylbenzo[b]furan
5g.
This compound was synthesized according to the general
procedure for 5a by using 15 instead of 4a; yield, 84%; mp, 203–
205 ◦C (recrystallized from AcOEt–n-hexane); dH (DMSO-d6,
400 MHz) 6.73 (1H, s, Th-H), 7.12 (2H, br s, NH2), 7.42–7.49
(3H, m, Ar-H), 7.51 (1H, dd, J = 8.6, 2.1 Hz, 6-H), 7.63 (1H,
d, J = 8.8 Hz, 7-H), 7.81–7.83 (2H, m, Ar-H), 7.92 (1H, d, J =
2.2 Hz, 4-H); Anal. Calcd for C17H11BrN2OS: C, 55.00; H, 2.99;
N, 7.55 found: C, 54.94; H, 2.93; N, 7.48%.
1
Notes and references
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