Preparation of a series of benzothieno[3,2-b]pyridine-3-carbonitriles and benzofuro[3,2-b]pyridine-3-carbonitriles

Article abstract of DOI:10.1002/jhet.5570390425

New and shorter routes to the benzothieno[3,2-b]pyridine-3-carbonitrile and benzofuro[3,2-b]pyridine-3-carbonitrile ring systems are reported. These heterocycles may function as new templates for kinase inhibitors.

Full text of DOI:10.1002/jhet.5570390425

Jul-Aug 2002
Preparation of a Series of Benzothieno[3,2-b]pyridine-3-carbonitriles
and Benzofuro[3,2-b]pyridine-3-carbonitriles
Diane H. Boschelli* and Fei Ye
783
Chemical Sciences, Wyeth Research, 401 N. Middletown Road, Pearl River, NY, 10965
Received December 21, 2001
New and shorter routes to the benzothieno[3,2-b]pyridine-3-carbonitrile and benzofuro[3,2-b]pyridine-3-
carbonitrile ring systems are reported. These heterocycles may function as new templates for kinase
inhibitors.
J. Heterocyclic Chem., 39, 783 (2002).
Introduction.
analogs of 5a-e were prepared as potential EGFr inhibitors. In
addition, various substituted aniline moieties were employed
at C-4 in the hope that these new heterocyclic cores could pro-
vide inhibitors of other kinases.
Protein kinases are enzymes that phosphorylate selective
amino acid residues on proteins resulting in numerous and
diverse cell signaling events, including aberrant cell prolif-
eration. Therefore, small molecule kinase inhibitors can
potentially be used to treat various diseases, including can-
cer. The first potent kinase inhibitor identified was 1, a 4-
anilinoquinazoline, which selectively inhibited the activity
of the epidermal growth factor receptor tyrosine kinase
(EGFr) [1]. Subsequently, it was shown that variation of
the aniline group at C-4 of 1 provided selectivity for other
kinases [2]. The versatility of the quinazoline ring system
as a template for kinase inhibitors is illustrated by the sev-
eral 4-anilinoquinazolines currently in clinical trials for the
treatment of cancer, including the EGFr inhibitor 2 [3] and
the vascular endothelial growth factor receptor tyrosine
kinase (VEGFr) inhibitor 3 [4].
5a:
5b:
5c:
5d:
5e:
4a:
4b:
4c:
1
2
3
Results.
The 3-quinolinecarbonitrile ring system has also been used
as a template for kinase inhibitors. As was seen with the
quinazoline core, varying the aniline group at C-4 of the
3-quinolinecarbonitrile changed the kinase specificity. The
4-anilino-3-quinolinecarbonitriles 4a, 4b and 4c were previ-
ously reported to be potent and selective inhibitors of EGFr
[5], mitogen-activated protein kinase [6] and Src kinase [7],
respectively. Additional heterocyclic systems utilized as tem-
plates for kinase inhibitors include the benzo[b]thieno[3,2-d]-
pyrimidines 5a,c,d and the benzo[b]furo[3,2-d]pyrimidine 5b
which were reported to be inhibitors of EGFr [8]. The acry-
lamide derivative of 5d, namely 5e, was shown to form a
covalent bond with the sulfur atom of a cysteine residue in the
inhibitor binding pocket of EGFr thereby irreversibly inhibit-
ing the enzyme [9]. Since both the quinazoline and 3-quino-
linecarbonitrile groups could be used as templates for kinase
inhibitors, the corresponding benzothieno[3,2-b]pyridine-3-
carbonitrile and benzofuro[3,2-b]pyridine-3-carbonitrile
Methyl 3-aminobenzo[b]thiophene-2-carboxylate (6a)
[10] was converted to the amidine 7a by treatment with
N,N-dimethylformamide dimethyl acetal (DMF-DMA).
Reaction of 7a with the anion of acetonitrile, generated in
situ by the reaction of n-butyl lithium with acetonitrile at
reduced temperature, gave the tricyclic derivative 8a.
Chlorination of 8a with phosphorous oxychloride provided
the key intermediate 9a in an overall yield of 38% from 6a.
The synthetic route described here is more efficient than a
recently reported route wherein 9a was obtained in 7 steps
from the potassium salt of the acid corresponding to 6a in
an overall yield of 5% [11]. Reaction of 9a with 3-bro-
moaniline in 2-ethoxyethanol in the presence of pyridine
hydrochloride resulted in 10a. Additional substituted ani-
lines were added under the same conditions to give the
4-anilino-[1]benzothieno[3,2-b]pyridine-3-carbonitriles

784
Vol. 39
D. H. Boschelli and F. Ye
10b-d in yields of 58-66%. Treatment of 9a with 4-chloro-
2-fluorophenol with potassium hydroxide as base provided
the 4-phenoxy derivative 11a in 55% yield.
readily converted to the corresponding amidine, treat-
ment of this amidine with the anion of acetonitrile
resulted only in intractable material. Therefore, 12 was
decarboxylated in refluxing N-methyl-2-pyrrolidinone
(NMP) and N-methylpiperazine [15] to provide 13. This
amine was treated with ethyl (ethoxymethylene)cyano-
acetate and the intermediate was subjected to high tem-
perature to provide the desired tricyclic compound 14 in
an overall yield of 23% from 12. Chlorination of 14
gave 15, which was treated with 3-bromoaniline under
the conditions reported earlier to afford 16. Reduction
of the 8-nitro group of 16 to the amine 17 was accom-
plished by reaction with iron and ammonium chloride in
aqueous methanol. The low yield in this reaction (35%)
may be due to the poor solubility of both 16 and 17.
Treatment of 17 with acrylic acid using 1-[3-(dimethyl-
amino)propyl]-3-ethylcarbodiimide (EDC) as the cou-
pling agent in the presence of N,N-diisopropylethyl-
amine provided 18.
An analogous synthetic sequence was utilized for the
preparation of the benzofuro[3,2-b]pyridine-3-carboni-
triles from 6b [12]. Surprisingly, in the formation of 8b
from the amidine 7b, it was necessary to heat the initially
formed intermediate in acetic acid at reflux in order to
obtain the desired tricyclic product. Chlorination of 8b
readily provided 9b in an overall yield of 40% from 6b.
The synthetic route described here is therefore again more
efficient than a recently reported route wherein 9b was
obtained in 7 steps from the potassium salt of the acid cor-
responding to 6b in an overall yield of 9% [13].
Displacement of the 4-chloro substituent of 9b with vari-
ous substituted anilines provided 10e-g in yields of 35-
42%. The 4-phenoxy compound 11b was obtained in 44%
yield by displacement of the 4-chloro substituent of 9b
with 4-chloro-2-fluorophenol.
6a:
6b:
8a:
8b:
7a:
7b:
9a:
9b:
11a:
11b:
10a:
10b:
10c:
10d:
10e:
10f:
10g:
Attempts to apply the route used for the synthesis of
Conclusion.
8a to the preparation of the corresponding 8-nitro ana-
log was unsuccessful. While methyl 3-amino-5-
nitrobenzo[b]thiophene-2-carboxylate (12) [14] was
In summary, we present here new and shorter routes
to the benzothieno[3,2-b]pyridine-3-carbonitrile and
benzofuro[3,2-b]pyridine-3-carbonitrile ring systems.

Jul-Aug 2002
Preparation of a Series of Benzothieno[3,2-b]pyridine-3-carbonitriles
785
12
13
14
16
15
17
18
3-[[(Dimethylamino)methylene]amino]-benzofuran-2-carboxylic
Acid Ethyl Ester (7b).
In addition, both anilines and phenols can readily
replace the 4-chloro substituent of these heterocycles.
The biological activity of these compounds will be
reported elsewhere.
A mixture of 4.20 g (20.5 mmol) of 6b [12] in 10 ml of N,N-
dimethylformamide dimethyl acetal (DMF-DMA) was heated at
reflux for 1.5 hours then cooled to room temperature and concen-
trated under reduced pressure. The residue was partitioned
between ethyl acetate and water. The organic layer was washed
with water, dried over sodium sulfate, filtered through Celite and
reduced in volume under reduced pressure. The solid was col-
lected by filtration to provide 3.90 g (73%) of 7b as a white solid,
EXPERIMENTAL
General Methods.
Melting points were determined in open capillary tubes on a
1
mp 89-90°C; H nmr: δ 1.30 (t, J = 7 Hz, 3H), 3.04 (s, 3H), 3.06
1
Meltemp melting point apparatus and are uncorrected. H nmr
(s, 3H), 4.25 (t, J = 7 Hz, 2H), 7.38 (t, J = 8 Hz, 1H), 7.49 (t, J =
8 Hz, 1H), 7.57 (d, J = 8 Hz, 1H), 7.68 (d, J = 8 Hz, 1H), 7.99 (s,
spectra were recorded in deuteriodimethylsulfoxide using a NT-
300 WB spectrometer. Chemical shifts (δ) are in parts per million
referenced to tetramethylsilane as an internal standard.
Electrospray (es) mass spectra were recorded on a Micromass
Platform spectrometer. Electron impact (ei) and high resolution
mass spectra were obtained on a Finnigan MAT-90 spectrometer.
Flash chromatography was performed with Baker 40 µM silica
gel. Reactions were carried out under an inert atmosphere of
either nitrogen or argon.
+
1H); ms: m/z 260.9 (M+H) .
Anal. Calcd. for C
H N O : C, 64.60; H, 6.20; N, 10.76.
14 16 2 3
Found: C, 64.45; H, 6.04; N, 10.64.
1,4-Dihydro-4-oxo-[1]benzothieno[3,2-b]pyridine-3-carbonitrile
(8a).
A solution of 1.6 ml (30.6 mmol) of acetonitrile in 10 ml of
tetrahydrofuran was added to a cooled (-78 °C) solution of 12.5 ml
of 2.5 M n-butyl lithium in hexane (31.2 mmol) in 40 ml of tetrahy-
drofuran. After stirring for 10 minutes, a solution of 4.0 g (15.2
mmol) of 7a in 40 ml of tetrahydrofuran was added dropwise over 1
hour. The reaction mixture was stirred at reduced temperature for 30
minutes and then was allowed to warm to room temperature. After
stirring at room temperature for 1 hour, the reaction mixture was
cooled to -50 °C and 2.1 ml of acetic acid was added. The solution
was concentrated under reduced pressure and poured into water.
The aqueous solution was extracted with ethyl acetate and aqueous
HCl was added to the aqueous layer. The product was extracted
into ethyl acetate and the organic layer was dried over magnesium
sulfate, filtered and concentrated under reduced pressure. Ethyl
acetate and hexane were added to the residue and the resulting tan
3-[[(Dimethylamino)methylene]amino]-benzo[b]thiophene-2-
carboxylic Acid Methyl Ester (7a).
A mixture of 3.38 g (16.32 mmol) of 6a [10] in 8 ml of N,N-
dimethylformamide dimethyl acetal (DMF-DMA) was heated at
reflux for 2 hours and then allowed to cool to room temperature.
The solid was collected by filtration and washed with hexane and
ethyl acetate to provide 3.96 g (93%) of 7a as a white solid, mp
1
73-74 °C; H nmr: δ 3.06 (s, 6H), 3.75 (s, 3H), 7.47 (t, J = 8 Hz,
1H), 7.50 (t, J = 8 Hz, 1H), 7.78 (d, J = 8 Hz, 1H), 7.82-7.89 (m,
+
2H); ms: m/z 262.9 (M+H) .
Anal. Calcd. for C
H N O S: C, 59.52; H, 5.38; N, 10.68.
13 14 2 2
Found: C, 59.25; H, 5.32; N, 10.58.

786
Vol. 39
D. H. Boschelli and F. Ye
solid was collected to provide 2.20 g (64%) of 8a. An analytical
and 71 mg (0.61 mmol) of pyridine hydrochloride was heated at
reflux for 4 – 30 hours. The reaction mixture was partitioned
between ethyl acetate and saturated aqueous sodium bicarbonate
and the organic layer was dried over magnesium sulfate, filtered
and concentrated under reduced pressure. Diethyl ether was
added to the residue and the resultant solid was collected by fil-
tration to give the desired product.
sample was obtained by recrystallization from diethyl ether and
1
hexane, mp > 300 °C; H nmr: δ 7.65 (m, 2H), 8.17 (d, J = 7 Hz,
-
1H), 8.44 (d, J = 7 Hz, 1H), 8.84 (s, 1H); ms: m/z 224.9 (M-H) .
Anal. Calcd. for C H N OS x 0.25 H O: C, 62.46; H, 2.84;
12
6
2
2
N, 12.14. Found: C, 62.52; H, 2.93; N, 12.00.
1,4-Dihydro-4-oxo-[1]benzofuro[3,2-b]pyridine-3-carbonitrile
(8b).
4-[(3-Bromophenyl)amino]-[1]benzothieno[3,2-b]pyridine-3-
carbonitrile (10a).
A solution of 1.5 ml (28.6 mmol) of acetonitrile in 30 ml of
tetrahydrofuran was added to a –78 °C solution of 11.4 ml of 2.5
M n-butyl lithium in hexane (29.0 mmol) in 35 ml of tetrahydro-
furan. After stirring for 15 minutes, a solution of 3.7 g (14.2
mmol) of 7b in 50 ml of tetrahydrofuran was added dropwise.
The reaction mixture was stirred at -78 °C for 30 minutes then
allowed to warm to 0 °C. The reaction mixture was again cooled
to –78 °C and 3 ml of acetic acid was added. The solution was
allowed to warm to room temperature and the resulting precipi-
tate was collected. This solid was combined with 20 ml of acetic
acid and heated at reflux for 1.5 hours. The mixture was cooled
to room temperature and the solid was collected by filtration
washing with saturated sodium bicarbonate, water, diethyl ether
and ethyl acetate to provide 2.45 g (79%) of 8b as a red solid, mp
Compound 10a was obtained as a white solid in 58% yield,
mp 240-242 °C; H nmr: δ 7.24 (d, J = 8 Hz, 1H), 7.31-7.43
1
(m, 3H), 7.52-7.68 (m, 2H), 8.06 (d, J = 8 Hz, 1H), 8.37 (d, J =
8 Hz, 1H), 8.83 (s, 1H), 9.84 (s, 1H); ms: m/z 379.9, 381.7
+
(M+H) .
Anal. Calcd. for C
H BrN S x 0.5 H O: C, 55.54; H, 2.85;
18 10 3 2
N, 10.79. Found: C, 55.84; H, 2.79; N, 10.73.
4-[(4-Phenoxyphenyl)amino]-[1]benzothieno[3,2-b]pyridine-3-
carbonitrile (10b).
Compound 10b was obtained as a light tan solid in 60% yield,
1
mp 230-233 °C; H nmr: δ 7.06-7.19 (m, 5H), 7.32-7.47 (m, 4H),
7.55-7.86 (m, 2H), 8.05 (d, J = 8 Hz, 1H), 8.34 (d, J = 8 Hz, 1H),
1
+
> 310 °C; H nmr: δ 7.53 (t, J = 7 Hz, 1H), 7.72 (t, J = 7 Hz, 1H),
8.75 (s, 1H), 9.65 (s, 1H); ms: m/z 393.9 (M+H) .
7.86 (d, J = 8 Hz, 1H), 8.13 (d, J = 8 Hz, 1H), 8.80 (s, 1H); ms:
m/z 210.8 (M+H) .
Anal. Calcd. for C
10.44. Found: C, 71.99; H, 3.80; N, 10.56.
H N OS x 0.5 H O: C, 71.62; H, 4.01; N,
24 15 3 2
+
Anal. Calcd. for C H N O x 0.50 H O: C, 65.75; H, 3.22;
N, 12.78. Found: C, 65.51; H, 3.19; N, 12.94.
12
6
2
2
2
4-[(2,4-Dichlorophenyl)amino]-[1]benzothieno[3,2-b]pyridine-
3-carbonitrile (10c).
4-Chloro-[1]benzothieno[3,2-b]pyridine-3-carbonitrile (9a).
Compound 10c was obtained as a yellow solid in 66% yield,
mp 260-262 °C; H nmr: δ 7.55-7.72 (m, 4H), 7.83 (s, 1H), 8.06
1
A mixture of 1.01 g (4.38 mmol) of 8a and 7 ml of phosphorous
oxychloride was heated at reflux for 40 minutes then cooled to
room temperature. Hexane was added and the solid was collected
by filtration, dissolved in ethyl acetate and washed with saturated
aqueous sodium bicarbonate. The organic layer was dried over
magnesium sulfate, filtered and concentrated under reduced pres-
sure to a small volume. The solids were collected by filtration to
(d, J = 8 Hz, 1H), 8.35 (d, J = 8 Hz, 1H), 8.79 (s, 1H), 9.76 (s,
+
1H); ms: m/z 369.8, 371.8 (M+H) .
Anal. Calcd. for C H Cl N S x 0.25 H O: C, 57.68; H, 2.55;
18
9
2
3
2
N, 11.21. Found: C, 57.64; H, 2.48; N, 10.94.
4-[(4-Chloro-2-fluorophenyl)amino]-[1]benzothieno[3,2-b]pyri-
dine-3-carbonitrile (10d).
1
give 696 mg (65%) of 9a, mp 305-308 °C; H nmr: δ 7.70 (t, J = 8
Hz, 1H), 7.80 (t, J = 8 Hz, 1H), 8.26 (d, J = 8 Hz, 1H), 8.45 (d, J =
8 Hz, 1H), 9.20 (s, 1H); ms: m/z 244.6, 246.6 (M+H) .
Compound 10d was obtained as an off-white solid in 66%
yield, mp 250-251 °C; H nmr: δ 7.40 (d, J = 9 Hz, 1H), 7.50-
+
1
7.69 (m, 4H), 8.08 (d, J = 8 Hz, 1H), 8.37 (d, J = 8 Hz, 1H), 8.80
(s, 1H), 9.68 (s, 1H); ms: m/z 353.8, 355.8 (M+H) .
Anal. Calcd. for C H ClN S: C, 58.90; H, 2.06; N, 11.45.
Found: C, 58.29; H, 2.13; N, 11.27.
12
5
2
+
Anal. Calcd. for C H ClFN S: C, 61.11; H, 2.56; N, 11.88.
Found: C, 61.50; H, 2.58; N, 11.65.
18
9
3
4-Chlorobenzofuro[3,2-b]pyridine-3-carbonitrile (9b).
A mixture of 2.10 g (9.58 mmol) of 8b in 15 ml of phospho-
rous oxychloride was heated at reflux for 1.5 hours then cooled to
room temperature. Hexane was added and the resulting solid was
collected by filtration, dissolved in ethyl acetate and washed with
cold 1 N aqueous sodium hydroxide. The organic layer was dried
over sodium sulfate, filtered through Celite and concentrated
under reduced pressure to give 1.55 g (71%) of 9b as a red solid,
4-[(3-Bromophenyl)amino]-benzofuro[3,2-b]pyridine-3-carboni-
trile (10e).
Compound 10e was obtained as a light tan solid in 42% yield,
1
mp 242-245 °C; H nmr: δ 7.21-7.57 (m, 5H), 7.70 (d, 2H), 8.18
-
(d, 1H), 8.74 (s, 1H), 9.93 (s, 1H); ms: m/z 361.8, 363.8 (M-H) .
Anal. Calcd. for C
H BrN O: C, 59.36; H, 2.77; N, 11.54.
18 10 3
1
mp 229-231 °C; H nmr: δ 7.64 (t, J = 7 Hz, 1H), 7.87 (t, J = 7
Found: C, 59.01; H, 2.97; N, 11.36.
Hz, 1H), 8.00 (d, J = 8 Hz, 1H), 8.28 (d, J = 8 Hz, 1H), 9.14 (s,
1H); ms: m/z 228.9, 230.6 (M+H) .
4-[(4-Phenoxyphenyl)amino]-benzofuro[3,2-b]pyridine-3-car-
bonitrile (10f).
+
Anal. Calcd. for C H ClN O: C, 63.04; H, 2.20; N, 12.25.
12
5
2
Compound 10f was obtained as a light tan solid in 35% yield,
mp 175-179 °C; H nmr: δ 7.01-7.18 (m, 5H), 7.31-7.45 (m, 4H),
Found: C, 62.83; H, 2.26; N, 12.12.
1
General Procedure for the Reaction of 9a and 9b with Substituted
Anilines to Provide 10a-g.
7.54 (m, 1H), 7.65-7.73 (m, 2H), 8.15 (d, J = 7 Hz, 1H), 8.62 (s,
+
1H), 9.83 (s, 1H); ms: m/z 377.9 (M+H) .
Anal. Calcd. for C
H N O : C, 76.38; H, 4.01; N, 11.13.
A solution of 150 mg (0.61 mmol) of 9a in 3 ml of
24 15 3 2
2-ethoxyethanol containing 0.74 mmol of a substituted aniline
Found: C, 76.13; H, 3.96; N, 11.14.

Jul-Aug 2002
Preparation of a Series of Benzothieno[3,2-b]pyridine-3-carbonitriles
787
4-[(4-Chloro-2-fluorophenyl)amino]-benzofuro[3,2-b]pyridine-
3-carbonitrile (10g).
toluene was heated at reflux for 2 hours. The reaction mixture
was cooled to room temperature and the resulting precipitate was
collected by filtration washing with diethyl ether to provide 11.50
g (78%) of a bright yellow solid. A portion (2.33 g) of this solid
was added to 40 ml of Dowtherm-A and the mixture was heated
at reflux for 4 hours. The mixture was cooled slightly to form a
precipitate which was collected by filtration washing with diethyl
ether and hexane to give 925 mg (46%) of 14 as a brown solid,
Compound 10g was obtained as a light tan solid in 40% yield,
1
mp 259-261 °C; H nmr: δ 7.24-7.39 (m, 2H), 7.43-7.53 (m, 2H),
7.61 (d, J = 4 Hz, 2H), 8.09 (d, J = 7 Hz, 1H), 8.49 (s, 1H), 10.07
+
(s, 1H); ms: m/z 337.8, 339.8 (M+H) .
Anal. Calcd. for C H ClFN O x 1.0 H O: C, 60.77; H, 3.12;
18
9
3
2
N, 11.81. Found: C, 60.41; H, 2.70; N, 11.60.
1
mp > 305 °C; H nmr: δ 8.43 (s, 2H), 8.95 (s, 1H), 9.45 (s, 1H);
-
4-(4-Chloro-2-fluorophenoxy)-[1]benzothieno[3,2-b]pyridine-3-
carbonitrile (11a).
ms: m/z 270.2 (M-H) .
Anal. Calcd. for C H N O S: C, 53.14; H, 1.86; N, 15.49.
12
5 3 3
Found: C, 52.81; H, 2.07; N, 15.31.
A mixture of 0.59 ml (5.5 mmol) of 4-chloro-2-fluorophenol
and 100 mg (1.78 mmol) of potassium hydroxide was heated to
give a solution. To this solution was added 245 mg (1.00 mmol) of
9a and the mixture was heated for 2 hours. Ethyl acetate was added
and the solution was washed with 1 N aqueous sodium hydroxide.
The organic layer was dried over sodium sulfate, filtered and con-
centrated under reduced pressure. The solid was collected and
recrystallized from ethyl acetate to give 195 mg (55%) of 11a as a
4-Chloro-8-nitro-[1]benzothieno[3,2-b]pyridine-3-carbonitrile
(15).
A mixture of 1.22 g (4.49 mmol) of 14 in 20 ml of phospho-
rous oxychloride was heated at reflux for 3 hours then cooled to
room temperature. The precipitated solid was collected by filtra-
tion, washed with hexane and then saturated aqueous sodium
bicarbonate and water. The solid was dried to give 947 mg (68%)
1
light tan solid, mp 174-175 °C; H nmr: δ 7.49 (m, 1H), 7.64-7.77
1
of 15 as a dark brown solid, mp softens at 270 °C; H nmr: δ 8.59
(s, 2H), 9.09 (s, 1H), 9.34 (s, 1H); ms: m/z 289.0, 291.0 (M+H) .
(m, 3H), 7.86 (m, 1H), 8.15 (d, J = 7 Hz, 1H), 8.46 (d, J = 7 Hz,
+
+
1H), 9.19 (s, 1H); ms: m/z 354.8, 356.8 (M+H) .
Anal. Calcd. for C H ClN O S x 1.0 H O: C, 46.83; H, 1.97;
12
4
3
2
2
Anal. Calcd. for C H ClFN OS x 0.3 H O: C, 60.02; H,
18
8
2
2
N, 13.66. Found: C, 47.10; H, 1.63; N, 13.54.
2.41; N, 7.78. Found: C, 60.32; H, 2.38; N, 7.25.
4-[(3-Bromophenyl)amino]-8-nitro[1]benzothieno[3,2-b]pyri-
dine-3-carbonitrile (16).
4-(4-Chloro-2-fluorophenoxy)-benzofuro[3,2-b]pyridine-3-car-
bonitrile (11b).
A solution of 400 mg (1.30 mmol) of 15, 160 mg (1.38 mmol)
of pyridine hydrochloride and 0.18 ml (1.65 mmol) of 3-bro-
moaniline in 8 ml of 2-ethoxyethanol was heated at reflux for 4
hours. The reaction mixture was filtered while hot and the col-
lected solid was stirred with methanol and ammonium hydroxide.
The mixture was poured into water and the solid was collected,
washing with ethyl acetate to give 363 mg (66%) of 16 as a
A mixture of 0.43 ml (4.1 mmol) of 4-chloro-2-fluorophenol
and 70 mg (1.25 mmol) of potassium hydroxide was heated to
give a solution. To this solution was added 170 mg (0.74 mmol)
of 9b and the mixture was heated for 1 hour. Ethyl acetate was
added and the solution was washed with 1 N aqueous sodium
hydroxide. The organic layer was dried over sodium sulfate, fil-
tered through Celite and reduced in volume under reduced pres-
sure. The solid was collected to give 115 mg (44%) of 11b as a
1
brown solid, mp > 300 °C; H nmr: δ 7.32 (d, J = 8 Hz, 1H), 7.40
(t, J = 8 Hz, 1H), 7.52 (m, 2H), 8.37 (d, J = 8 Hz, 1H), 8.43 (dd, J
= 8, 2 Hz, 1H), 8.92 (s, 1H), 9.01 (d, J = 2 Hz, 1H), 10.03 (s, 1H);
1
light tan solid, mp 138-140 °C; H nmr: δ 7.41 (d, J = 9 Hz, 1H),
7.57-7.85 (m, 5H), 8.25 (d, J = 8 Hz, 1H), 9.10 (s, 1H); ms: m/z
+
ms: m/z 425.0, 427.1 (M+H) .
+
338.8, 340.8 (M+H) .
Anal. Calcd. for C H BrN O S: C, 50.84; H, 2.13; N, 13.17.
18
9
4 2
Anal. Calcd. for C H ClFN O x 0.5 H O: C, 62.16; H, 2.61;
18
8
2
2
2
Found: C, 50.77; H, 2.47; N, 13.01.
N, 8.06. Found: C, 62.00; H, 2.34; N, 7.71.
8-Amino-4-[(3-bromophenyl)amino]-[1]benzothieno[3,2-b]pyri-
dine-3-carbonitrile (17).
5-Nitrobenzo[b]thiophen-3-amine (13).
A solution of 23.0 g (91.3 mmol) of 12 [14] in 100 ml of N-
methyl-2-pyrrolidinone (NMP) and 30 ml N-methylpiperazine
was heated at 180 °C for 2 hours. The reaction was cooled to
room temperature and poured into water. The resultant solid was
collected by filtration, washing with water. The solid was dis-
solved in a mixture of ethyl acetate and diethyl ether and the solu-
tion was washed twice with water. The organic layer was dried
over magnesium sulfate, filtered and concentrated under reduced
pressure. Diethyl ether and hexane were added to the residue and
the dark red solid was collected by filtration to provide 11.17 g
A mixture of 436 mg (1.03 mmol) of 16, 291 mg (5.19 mmol)
of iron powder and 416 mg (7.77 mmol) of ammonium chloride
in 160 ml of methanol and 110 ml of water was heated at reflux
for 5.5 hours. The reaction mixture was filtered hot and the solid
residue was extracted with several portions of hot ethyl acetate
followed by hot methanol. The organic layers were combined,
washed with water, dried over magnesium sulfate, filtered and
concentrated under reduced pressure. Diethyl ether and hexane
were added and the solid was collected by filtration to provide 87
mg (21%) of 17. The filtrate was concentrated and purified by
flash chromatography eluting with a gradient of 1:1 hexane:ethyl
acetate to all ethyl acetate to give an additional 56 mg (14%) of
1
(63%) of 13, mp 155-158 °C; H nmr: δ 5.67 (s, 2H), 6.39 (s,
+
1H), 8.05-8.14 (m, 2H), 8.88 (s, 1H); ms: m/z 194.9 (M+H) .
Anal. Calcd. for C H N O S: C, 49.48; H, 3.11; N, 14.42.
8
6 2 2
1
17 as a bright yellow solid, mp 295-300 °C dec; H nmr: δ 5.43
Found: C, 49.73; H, 3.25; N, 14.13.
(s, 2H), 6.95 (dd, J = 8, 2 Hz, 1H), 7.21 (m, 1H), 7.29-7.40 (m,
3H), 7.51 (d, J = 2 Hz, 1H), 7.64 (d, J = 8 Hz, 1H), (8.77 (s, 1H),
1,4-Dihydro-8-nitro-4-oxo-[1]benzothieno[3,2-b]pyridine-3-car-
bonitrile (14).
+
9.67 (s, 1H); ms: m/z 395.2, 397.2 (M+H) .
Anal. Calcd. for C H BrN S: C, 54.69; H, 2.80; N, 14.17.
A mixture of 9.00 g (46.34 mmol) of 13 and 8.65 g (51.12
18 11
4
Found: C, 54.37; H, 2.85; N, 13.98.
mmol) of ethyl (ethoxymethylene)cyanoacetate in 100 ml of

788
Vol. 39
D. H. Boschelli and F. Ye
[3] A. J. Barker, K. H. Gibson, W. Grundy, A. A. Godfrey, J.
J. Barlow, M. P. Healy, J. R. Woodburn, S. E. Ashton, B. J. Curry, L.
Scarlett, L. Henthorn and L. Richards, Bioorg. Med. Chem. Lett., 11,
1911 (2001).
N-[4-[(3-Bromophenyl)amino]-3-cyano[1]benzothieno[3,2-
b]pyridin-8-yl]-2-propenamide (18).
To a cooled (0 °C) solution of 164 mg (0.42 mmol) of 17 and
120 mg (0.63 mmol) of 1-[3-(dimethylamino)propyl]-3-ethylcar-
bodiimide hydrochloride (EDC) in 2 ml of N,N-dimethylfor-
mamide and 2 ml of tetrahydrofuran was added 0.045 ml (0.66
mmol) of acrylic acid followed by 0.110 ml (0.63 mmol) of N,N-
diisopropylethylamine. The reaction mixture was stirred at room
temperature for 4 hours then partitioned between methylene
choride and water. The aqueous layer was extracted with addi-
tional methylene chloride and the organic layers were combined,
dried over magnesium sulfate, filtered and concentrated under
reduced pressure. The residue was purified by flash chromatogra-
phy eluting with a gradient of 5% methanol in methylene chlo-
ride to 10% methanol in methylene chloride to provide 69 mg
[4] L. F. Hennequin, E. S. E. Stokes, A. P. Thomas, C.
Johnstone, P. A. Ple, D. J. Oglivie, M. Dukes, S. R. Wedge, J.
Kendrew and J. O. Curwen, J. Med. Chem., 45, 1300 (2002).
[5] A. Wissner, D. M. Berger, D. H. Boschelli, M. B. Floyd,
L. M. Greenberger, B. C. Gruber, B. D. Johnson, N. Mamuya, R.
Nilakatan, M. F. Reich, R. Shen, H. R. Tsou, E. Upeslacis, Y. F.
Wang, B. Wu, F. Ye and N. Zhang, J. Med. Chem., 43, 3244 (2000).
[6] N. Zhang, B. Wu, D. Powell, A. Wissner, M. B. Floyd, E.
D. Kovacs, L. Toral-Barza and C. Kohler, Bioorg. Med. Chem. Lett.,
10, 2825 (2000).
[7] D. H. Boschelli, D. Y. Wang, F. Ye, B. Wu, N. Zhang, M.
Dutia, D. W. Powell, A. Wissner, K. Arndt, J. M. Weber and F.
Boschelli, J. Med. Chem., 44, 822 (2001).
1
(37%) of 18 as a light tan solid, mp >300 °C dec; H nmr: δ 5.81
(dd, J = 10, 2 Hz, 1H), 6.32 (dd, J = 17, 2 Hz, 1H), 6.49 (dd, J =
17, 10 Hz, 1H), 7.25 (m, 1H), 7.30-7.47 (m, 2H), 7.80 (dd, J = 9,
2 Hz, 1H), 8.00 (d, J = 9 Hz, 1H), 8.84 (s, 1H), 8.90 (d, J = 2 Hz,
[8]
H. D. H. Showalter, A. J. Bridges, H. Zhou, A. D. Sercel,
A. McMichael and D. W. Fry, J. Med. Chem. 42, 5464 (1999).
[9] A. J. Bridges, W. A. Denny, E. M. Dobrusin, A. M.
Doherty, D. W. Fry, D. J. McNamara, H. D. H. Showalter, J. B.
Smaill and H. Zhou, WO 9738983 (1997); Chem. Abstr., 1997: 3695;
and H. Zhou, A. J. Bridges, S. Trumpp-Kallmeyer, D. Fry and J. M.
Nelson, National Meeting of American Chemical Society, Boston,
1998; Chem. Abstr., 1998:529753.
+
1H), 9.81 (s, 1H), 10.46 (s, 1H); ms: m/z 449.1, 451.2 (M+H) .
Anal. Calcd. for C
H BrN OS: C, 56.13; H, 2.92; N, 12.47.
21 13 4
Found: C, 55.91; H, 3.08; N, 12.18.
Acknowledgments.
[10] J. Beck, J. Org. Chem., 37, 3224 (1972).
[11] K. Gorlitzer, C. Kramer and C. Boyle, Pharmazie, 55, 595
(2000).
We thank the members of the Wyeth Analytical Chemistry
Department for the spectral data and elemental analyses.
[12] S. S. Sangapure and Y. S. Agasimundin, Indian J. Chem.,
Sect. B, 14, 688 (1976).
REFERENCES AND NOTES
[13] K. Gorlitzer, C. Kramer and C. Boyle, Pharmazie, 55, 651
(2000).
[14] A. J. Bridges and H. Zhou, J. Heterocyclic Chem., 34,
1163 (1997).
[1] D. W. Fry, A. J. Kraker, A. McMichael, L. A. Ambroso, J.
M. Nelson, W. R. Leopold, R. W. Connors and A. J. Bridges, Science,
265, 1093 (1994).
[15] M. H. Norman and F. Navas, WO 9316073 (1993); Chem.
Abstr., 1994: 409406.
[2] Reviewed in D. H. Boschelli, Drugs Future, 24, 515
(1999).