Synthesis of thieno[2,3-b][1,5]benzoxazepine derivatives

Article abstract of DOI:10.1002/jhet.5570390124

A new series of 4-(4-methylpiperazin-1-yl)thieno[2,3-b][1,5]benzoxazepines 1a-k has been synthesized from 4-bromo-2-methylthiophene 6 or ethyl 2-amino-4,5-dimethyl-3-thiophencarboxylate 10. Preparation of the key intermediate thieno[2,3-b][1,5]benzoxazepine-4(5H)-ones 4a-i, 4k were carried out by treatment of 2-bromo-N-(2-hydroxyphenyl)-3-thiophencarboxamides 5a-i, 5k with potassium carbonate in DMSO. Compounds 1 are thienoanalogues of loxapine, a potent antipsychotic drug. Of these compounds, the neuroleptic activity of 2-methyl-4-(4-methylpiperazin-1-yl)thieno[2,3-b][1,5]benzoxazepine 1a (R¹, R³=H, R²=CH₃) demonstrated potent antipsychotic activity.

Full text of DOI:10.1002/jhet.5570390124

Jan-Feb 2002
Synthesis of Thieno[2,3-b][1,5]benzoxazepine Derivatives
163
Toshiyuki Kohara* [a], Hiroshi Tanaka [a], Koreichi Kimura [a], Hideki Horiuchi [a],
Kohji Seio [a], Masafumi Arita [a], Tetsuya Fujimoto [b], and Iwao Yamamoto [b]
[a] Research Laboratory I (CNS), Pharmaceuticals Research Division,
Mitsubishi Pharma Corporation, 7-25 Koyata 3-Chome, Iruma, Saitama 358-0026, Japan
[b] Department of Functional Polymer Science, Faculty of Textile Science and Technology, Shinshu University,
15-1, Tokida 3-Chome, Ueda, Nagano 386-8567, Japan
Received July 23, 2001
A new series of 4-(4-methylpiperazin-1-yl)thieno[2,3-b][1,5]benzoxazepines 1a-k has been synthesized
from 4-bromo-2-methylthiophene 6 or ethyl 2-amino-4,5-dimethyl-3-thiophencarboxylate 10. Preparation
of the key intermediate thieno[2,3-b][1,5]benzoxazepine-4(5H)-ones 4a-i, 4k were carried out by treatment
of 2-bromo-N-(2-hydroxyphenyl)-3-thiophencarboxamides 5a-i, 5k with potassium carbonate in DMSO.
Compounds 1 are thienoanalogues of loxapine, a potent antipsychotic drug. Of these compounds, the neu-
1
3
roleptic activity of 2-methyl-4-(4-methylpiperazin-1-yl)thieno[2,3-b][1,5]benzoxazepine 1a (R , R =H,
2
R =CH ) demonstrated potent antipsychotic activity.
3
J. Heterocyclic Chem., 39, 163 (2002).
Benzothiazepine, benzoxazepine and benzodiazepine
derivatives have desirable antipsychotic activities [1-4].
Investigations into the synthesis of these novel compounds
and their biological activities may promote exciting
progress in the medical field. We reported previously that
Y-931 is an effective atypical antipsychotic [5] (Chart 1).
It is well known that a number of 11-piperazinyl deriva-
tives of dibenzo[b,f][1,4]thiazepines (X=S), dibenzo-
[b,f][1,4]oxazepines (X=O) and dibenzo[b,f][1,4]-
diazepines (X=NH) have significant CNS activity. The
most closely related compounds to this series are clothiap-
ine, loxapine and clozapine.
reported that thienobenzoxazepines 2 and 3, which are
thienoanalogues of loxapine, did not have effective
antipsychotic activity [8]. In the course of our approach to
synthesizing novel antipsychotic agents, we designed a
series of the title compounds 1 (X=O) in which the right
side benzene ring of loxapine was replaced by a thiophene
ring. In this report, we describe the synthesis of the
thieno[2,3-b][1,5]benzoxazepine derivatives 1 which
demonstrate potent neuroleptic activities.
We planned the synthesis of the series of compounds 1
from phenols 5 via oxazepines 4 as indicated in Scheme 1.
To our knowledge, there are only a few reports on the syn-
It is reported that the pharmacological activity is main-
tained even though a benzene ring is replaced by an isoster
thiophene ring [6]. Indeed, olanzapine, which is a
thienobenzodiazepine derivative structurally related to
clozapine, has more an effective antipsychotic activity
than clozapine [7]. On the other hand, Laimer and Erker
thesis of 2-aryloxythiophenes that are comprised in
oxazepines 4 [8-10]. We applied an intramolecular
cyclization of the phenols 5 to the synthesis of the
oxazepine derivatives 4.
2
3
Compounds 1a-j (X=O, R =CH , R =H) were synthe-
3
sized from 4-bromo-2-methylthiophene 6 which was pre-

164
T. Kohara, H. Tanaka, K. Kimura, H. Horiuchi, K. Seio,
M. Arita, T. Fujimoto, and I. Yamamoto
Vol. 39
pared according to the method reported by Gronowitz [6]
(Scheme 2). Lithiation of 6 with n-BuLi followed by treat-
ment with dry ice gave thiophene carboxylic acid 7 in 54%
yield. After bromination of 7 at the 2-position, the result-
ing 2-bromo-5-methyl-3-thiophene carboxylic acid 8 was
converted to the acylchloride with thionyl chloride. The
reaction of the acylchloride with 2-aminophenols 9a-i
afforded amides 5a-i in 57-97% yields (Table 1 and 2).
piperazine gave the target compounds 1a-i in 25-91%
yields (Table 5 and 6). Although demethylation of com-
pound 1h by BBr [11], Me SiI [12], or NaI [13] was
3
3
unsuccessful, the phenol derivative 1j was obtained in
39% yield by treating with ethanedithiol in the presence of
AlCl [14,15]. The synthesis of the 2,3-dimethylanalogue
3
1
2
3
1k (X=O, R =H, R , R =CH ) was carried out as shown in
3
Scheme 3. Ethyl 2-amino-4,5-dimethyl-3-thiophenecar-
2-Amino-6-methoxyphenol 9h and 2-amino-6-methylphe-
nol 9i were prepared from 3-methoxysalicylic acid and
3-methylsalicylic acid, respectively (Scheme 4 and 5).
Intramolecular cyclizations of the amides 5 were achieved
by potassium carbonate in DMSO (Table 3 and 4). After
conversion of the oxazepinones 4 into the iminochloride
by phosphoryl chloride, treatment with excess 1-methyl-
boxylate 10 was prepared according to the method
described by Gewald [16]. Reaction of 10 with sodium
nitrite followed by treatment with sodium hypophosfite
gave 11 in 27% yield. Hydrolysis of 11 with potassium
hydroxide and treatment with bromine in acetic acid
afforded compound 12 in 80% yield. 2-Bromothiophene
12 was converted to the acylchloride with thionyl chloride.

Jan-Feb 2002
Synthesis of Thieno[2,3-b][1,5]benzoxazepine Derivatives
165
Table 1
Synthetical and Analytical Data of 2-Bromo-N-(2-hydroxyphenyl)-3-thiophenecarboxamides 5a-i, 5k
-1
Cmpd
Mp
(°C)
Yield
(%)[b]
IR(cm ;
MS
(m/z)
Molecular
Formula
Analysis %
Calcd. / Found
KBr disk)
5a
5b
5c
5d
5e
5f
183-186
164-167
173-175
232-235
183-184
210-212
225-228
169-172
108-111
185-188
82
84
97
76
57
77
65
89
80
82
1633(amide)
1633(amide)
1637(amide)
1631(amide)
1637(amide)
1641(amide)
1640(amide)
1651(amide)
1628(amide)
1649(amide)
312
326
326
346
342
326
346
342
326
326
C
C
C
H
Br NO S
46.17 3.23
4.49
4.43
4.29
4.26
4.29
4.29
4.04
4.10
4.09
4.11
4.29
4.27
4.04
4.02
3.99
4.12
4.29
4.23
4.29
4.21
12 10
2
46.45 3.24
47.86 3.71
47.58 3.72
47.86 3.71
48.20 3.75
41.58 2.62
41.95 2.81
45.63 3.53
45.51 3.51
47.86 3.71
47.92 3.66
41.58 2.62
41.22 2.58
44.46 3.73
44.74 3.44
47.86 3.71
47.54 3.66
47.86 3.71
47.52 3.32
H
Br NO S
2
13 12
H
Br NO S
2
13 12
C
H BrCl NO S
9 2
12
C
C
H
Br NO S
13 12 3
H
Br NO S
2
13 12
5g
5h
5i
C H BrCl NO S
12 9 2
C
C
C
H
Br NO S
13 12 3
1/2H O
2
H
Br NO S
13 12
2
5k
[a]
H
Br NO S
13 12 2
[a] See Scheme 3; [b] Isolated yield.

166
T. Kohara, H. Tanaka, K. Kimura, H. Horiuchi, K. Seio,
M. Arita, T. Fujimoto, and I. Yamamoto
Vol. 39
Table 2
1
H-NMR Data of 2-Bromo-N-(2-hydroxyphenyl)-3-thiophenecarboxamides 5a-i, 5k
Cmpd
pmr(δ: dimethylsulfoxide-d )
6
5a
10.27 (s, 1H), 9.71 (s, 1H), 7.84 (d, J = 7.8 Hz, 1H), 7.12 (s, 1H), 7.00 (ddd, J = 1.5, 7.8 and 7.8 Hz, 1H), 6.91 (dd, J = 1.5 and 7.8Hz,
1H), 6.81 (ddd, J = 1.5, 7.8 and 7.8Hz, 1H), 2.42 (s, 3H)
5b
9.24 (s, 1H), 9.22 (s, 1H), 7.11 (s, 1H), 7.00 (dd, J = 7.3 and 7.8 Hz, 1H), 6.72 (d, J = 7.8 Hz, 1H), 6.69 (d, J = 7.3 Hz, 1H), 2.43 (s, 3H),
2.14 (s, 3H)
5c
5d
5e
5f
5g
5h
9.62 (s, 1H), 9.16 (s, 1H), 7.67 (s, 1H), 7.11 (s, 1H), 6.78 (m, 2H), 2.42 (s, 3H), 2.20 (s, 3H)
10.31 (s, 1H), 9.22 (s, 1H), 7.99 (s, 1H), 7.12 (s, 1H), 7.03 (dd, J = 2.5 and 8.8 Hz, 1H), 6.90 (d, J = 8.8 Hz, 1H), 2.42 (s, 3H)
9.84 (s, 1H), 9.17 (s, 1H), 7.57 (d, J = 8.8 Hz, 1H), 7.11(s, 1H), 6.46 (s, 1H), 6.40 (d, J = 8.8 Hz, 1H), 3.69 (s, 3H), 2.41 (s, 3H)
9.74 (s, 1H), 9.17 (s, 1H), 7.57 (d, J = 7.9 Hz, 1H), 7.11 (s, 1H), 6.71 (s, 1H), 6.62 (d, J = 7.9 Hz, 1H), 2.42 (s, 3H), 2.21 (s, 3H)
10.22 (s, 1H), 9.94 (s, 1H), 7.42 (s, 1H), 7.29 (d, J = 8.0 Hz, 1H), 7.16 (d, J = 8.0 Hz, 1H), 6.72 (s, 1H), 2.31 (s, 3H)
8.62 (br.s, 1H), 7.83 (d, J = 8.3 Hz, 1H), 7.09 (s, 1H), 6.86 (dd, J = 8.3 and 8.3 Hz, 1H), 6.86 (d, J = 8.3 Hz, 1H), 6.27 (s, 1H), 3.81 (s,
3H), 2.41 (s, 3H)
5i
9.71 (s, 1H), 8.95 (s, 1H), 7.41 (d, J = 7.8 Hz, 1H), 7.14 (s, 1H), 6.96 (d, J = 7.8 Hz, 1H), 6.74 (dd, J = 7.8 and 7.8 Hz, 1H), 2.37 (s, 3H),
2.19 (s, 3H)
5k
[a]
9.77 (s, 1H), 9.43 (s, 1H). 7.77 (d, J = 8.3 Hz, 1H), 7.00 (dd, J=7.8 and 7.8 Hz, 1H), 6.88 (d, J = 8.1 Hz, 1H), 6.80 (d, J = 6.8 and
8.2 Hz, 1H), 2.29 (s, 3H), 2.11 (s, 3H)
[a] See Scheme 3.
Table 3
Synthetical and Analytical Data of Methylthieno[2,3-b][1,5]benzoxazepine-4(5H)-ones 4a-i, 4k
-1
Cmpd
IR(cm ;
MS
(m/z)
Molecular
Formula
Analysis %
Calcd. / Found
KBr disk)
4a
4b
4c
4d
4e
4f
1676(amide)
1201(ArOAr)
1670(amide)
1203(ArOAr)
1678(ArOAr)
1209(ArOAr)
1670(amide)
1203(ArOAr)
1672(amide)
1200(ArOAr)
1676(amide)
1207(ArOAr)
1677(amide)
1200(ArOAr)
1676(amide)
1204(ArOAr)
1678(amide)
1205(ArOAr)
1672(amide)
1207(ArOAr)
231
245
245
265
261
245
265
261
245
245
C
H NO S
231.03540
231.03094
245.05123
245.05018
264.99528
261.04145
245.05131
264.99522
261.04295
245.05076
245.05052
12
9
2
C
C
H
NO S
245.05105
245.05105
264.99643
261.04597
245.05105
264.99643
261.04597
245.05105
245.05105
13 11
2
H
NO S
2
13 11
C
H ClNO S
8 2
12
C
C
H NO S
13 11 3
H
NO S
2
13 11
4g
4h
4i
C H ClNO S
12 8 2
C
C
C
H NO S
13 11 3
H
NO S
2
13 11
4k
[a]
H NO S
13 11 2
[a] See Scheme 3.
Table 4
H-NMR Data of Methylthieno[2,3-b][1,5]benzoxazepine-4(5H)-ones 4a-i, 4k
pmr(δ:dimethylsulfoxide-d )
1
Cmpd
6
4a
4b
4c
4d
4e
4f
10.12 (s, 1H), 7.09-7.23 (m, 4H), 6.72 (s, 1H), 2.31 (s, 3H)
9.45 (s, 1H), 7.05-7.09 (m, 3H), 6.70 (s, 1H), 2.32 (s, 3H), 2.31 (s, 3H)
10.05 (s, 1H), 7.09 (d, J = 8.3 Hz, 1H), 6.94 (s, 1H), 6.90 (d, J = 8.3 Hz, 1H), 6.71 (s, 1H), 2.30 (s, 3H), 2.20 (s, 3H)
10.28 (s, 1H), 7.28 (d, J = 8.8 Hz, 1H), 7.13-7.21 (m, 2H), 6.73 (s, 1H), 2.32 (s, 3H)
9.95 (s, 1H), 7.06 (d, J = 8.8 Hz, 1H), 6.83 (d, J = 2.9 Hz, 1H), 6.80 (dd, J = 2.9 and 8.3 Hz, 1H), 6.70 (s, 1H), 3.73 (s, 3H), 2.31 (s, 3H)
10.02 (s, 1H), 7.01-7.04 (m, 3H), 6.71 (s, 1H), 2.31 (s, 3H), 2.24 (s, 3H)
4g
4h
4i
10.17 (s, 1H), 7.36 (s, 1H), 7.23 (d, J = 8.3 Hz, 1H), 7.11 (d, J = 8.3 Hz, 1H), 6.67 (s, 1H), 2.26 (s, 3H)
10.09 (s, 1H), 7.10 (dd, J = 8.3 and 8.3 Hz, 1H), 6.86 (d, J = 8.3 Hz, 1H), 6.72 (d, J = 8.3 Hz, 1H), 6.71 (s, 1H), 3.81 (s, 3H), 2.31 (s, 3H)
10.08 (s, 1H), 6.99-7.09 (m, 3H), 6.72 (s, 1H), 2.32 (s, 3H), 2.29 (s, 3H)
4k
[a]
10.17 (s, 1H), 7.11-7.22 (m, 4H), 2.21 (s, 3H), 2.13 (s, 3H)
[a] See Scheme 3.

Jan-Feb 2002
Synthesis of Thieno[2,3-b][1,5]benzoxazepine Derivatives
167
The reaction of the acylchloride with 2-aminophenol
afforded smoothly amide 5k in 82% yield (Table 1 and 2).
Furthermore, the resulting 5k was heated at 140° for 2
hours in the presence of potassium carbonate in DMSO to
provide 4k in 55% yield (Table 3 and 4). After the activa-
tion of 4k to an iminochloride by phosphoryl chloride, the
reaction of the iminochloride with 1-methylpiperazine
gave the desired amine 1k in good yield (Table 5 and 6).
high affinity for dopamine D receptors (IC =36 nmol/L)
2 50
and antagonized locomotor hyperactivity induced by apo-
morphine in vivo (ED =0.04 mg/kg, mice).
50
In conclusion, we have synthesized a new series of 4-(4-
methylpiperazin-1-yl)thieno[2,3-b][1,5]benzoxazepines 1
from 4-bromo-2-methylthiophene 6 or ethyl 2-amino-4,5-
dimethyl-3-thiophencarboxyate 10. Of these compounds, 1a
showed potent antipsychotic activity. The detailed pharma-
Table 5
Synthetical and Analytical Data of 4-(4-Methylpiperazin-1-yl)thieno[2,3-b][1,5]benzoxazepines 1a-k
-1
Cmpd
Mp
(°C)
Yield
(%)[c]
IR(cm ;
MS
(m/z)
Molecular
Formula
Analysis %
Calcd. / Found
KBr disk)
1a
1b
1c
1d
1e
1f
132-133
114-117
146-148
227-228
219-222
149-150
96-100
52
43
25
55
63
65
49
91
54
39
91
1195(ArOAr)
1194(ArOAr)
1180(ArOAr)
1203(ArOAr)
1197(ArOAr)
1195(ArOAr)
1195(ArOAr)
1201(ArOAr)
1197(ArOAr)
313
327
327
347
343
327
347
343
327
329
327
C
C
C
H
N OS
65.15
6.11
6.15
6.46
6.44
6.46
6.48
4.78
4.70
5.54
5.60
6.46
6.48
5.22
5.22
5.53
5.51
6.46
6.40
5.81
5.89
6.99
6.89
13.41
17 19
3
65.10
66.02
65.77
66.02
65.81
54.37
54.16
56.94
56.96
66.02
65.75
58.70
58.68
57.06
57.06
66.02
65.97
61.98
61.81
61.09
60.92
13.34
12.83
12.61
12.83
12.63
9.06
9.00
9.06
8.93
12.83
12.76
12.08
12.09
9.07
H
N OS
3
18 21
H
N OS
3
18 21
C
H ClN OS
17 18 3
fumalate 1/4H O
2
C
H
N O S
18 21
3 2
fumalate 1/5H O
2
C
H
N OS
18 21
3
1g
1h
1i
C H ClN OS
17 18 3
239-241
149-150
200-204
102-103
C H N O S
18 21 3 2
fumalate 1/5H O
9.08
2
C
H
N OS
12.83
12.71
12.76
12.52
9.91
18 21
3
1j
2837(OH)
1195(ArOAr)
1198(ArOAr)
C H N O S
17 19 3 2
[a]
1k
[b]
C
H N OS EtOH
18 21 3
1/2fumalate
1/4 H O
9.62
2
[a] See Scheme 2; [b] See Scheme 3; [c] Isolated yield.
All target compounds (1a-k) were screened for neurolep-
cological activity of 4-(4-methylpiperazin-1-yl)thieno-
[2,3-b][1,5]benzoxazepines will be reported in due course.
1
3
2
tic activity. Compound 1a (R , R =H, R =CH ) showed a
3

168
T. Kohara, H. Tanaka, K. Kimura, H. Horiuchi, K. Seio,
M. Arita, T. Fujimoto, and I. Yamamoto
Vol. 39
Table 6
1
H-NMR Data of 4-(4-Methylpiperazin-1-yl)thieno[2,3-b][1,5]benzoxazepines 1a-k
Cmpd
solvent
pmr(δ)
1a
1b
deuteriochloroform
deuteriochloroform
6.95-6.99 (m, 4H), 6.29 (s, 1H), 3.58 (br.t, 4H), 2.48 (t, J = 4.0 Hz, 4H), 2.33 (s, 3H), 2.32 (s, 3H)
6.95-7.01 (m, 1H), 6.83-6.88 (m, 2H), 6.30 (s, 1H), 3.59 (t, J = 4.9 Hz, 4H), 2.49 (t, J = 4.9 Hz, 4H), 2.34 (s, 3H),
2.32 (s, 3H), 2.29 (s, 3H)
1c
deuteriochloroform
6.91 (d, J = 1.9 Hz, 1H), 6.87 (d, J = 8.3 Hz, 1H), 6.76 (dd, J = 1.9 and 8.3 Hz, 1H), 6.28 (s, 1H), 3.57 (t, J = 4.9 Hz,
4H), 2.48 (t, J = 4.9 Hz, 4H), 2.32 (s, 3H), 2.31 (s, 3H), 2.23 (s, 3H)
1d
1e
dimethylsulfoxide-d
dimethylsulfoxide-d
6.99 (m, 3H), 6.60 (s, 2H), 6.54 (s, 1H), 3.53 (br.t, 4H), 2.43 (br.t, 4H), 2.34 (s, 3H), 2.24 (s, 3H)
6.95 (d, J = 8.8 Hz, 1H), 6.70 (d, J = 8.8 Hz, 1H), 6.68 (d, J = 2.5 Hz, 1H), 6.60 (s, 2H), 6.49 (s, 1H), 3.70 (s,
3H), 3.47 (br.t, 4H), 2.62 (br.t, 4H), 2.33 (s, 3H), 2.26 (s, 3H)
6
6
1f
deuteriochloroform
deuteriochloroform
6.98 (d, J = 7.8 Hz, 1H), 6.86 (d, J = 7.8 Hz, 1H), 6.80 (s, 1H), 6.28 (s, 1H), 3.56 (br.t, 4H), 2.43 (t, J = 4.9 Hz,
4H), 2.33 (s, 3H), 2.32 (s, 3H), 2.25 (s, 3H)
7.02-7.04 (m, 3H), 6.31 (s, 1H), 3.60 (br.t, 4H), 2.50 (t, J = 4.0Hz, 4H), 2.36 (s, 3H), 2.35 (s, 3H)
6.98 (dd, J = 7.8 and 8.3 Hz, 1H), 6.74 (d, J = 8.3 Hz, 1H), 6.60 (s, 2H), 6.58 (d, J = 7.8 Hz, 1H), 6.51 (s, 1H), 3.78 (s,
3H), 2.50-4.50 (br.s, 8H), 2.33 (s, 3H), 2.28 (s, 3H)
1g
1h
dimethylsulfoxide-d
6
1i
dimethylsulfoxide-d
6.96 (dd, J = 7.4 and 7.8 Hz, 1H), 6.88 (d, J = 7.4 Hz, 1H), 6.84 (d, J = 7.4 Hz, 1H), 6.51 (s, 1H), 3.47 (br.t, 4H), 2.38
(br.t, 4H), 2.33 (s, 3H), 2.26 (s, 3H), 2.21 (s, 3H)
6
1j
deuteriochloroform
dimethylsulfoxide-d
6.91 (dd, J = 7.8 and 8.3 Hz, 1H), 6.64 (d, J = 8.3 Hz, 1H), 6.63 (d, J = 8.3 Hz, 1H), 6.30 (s, 1H), 5.60 (br.s, 1H), 3.59
(br.t, 4H), 2.50 (t, J = 4.9 Hz, 4H), 2.33 (s, 6H)
7.09-6.98 (m, 4H), 6.60 (br.s, 1H), 7.00-4.50 (br.s, 1H), 4.00-2.10 (m, 8H), 3.45 (q, 2H), 2.28 (s, 3H), 2.21 (s, 3H),
2.03 (s, 3H), 1.06 (t, 3H)
[a]
1k
[b]
6
[a] See Scheme 2; [b] See Scheme 3.
EXPERIMENTAL
To a solution of 9-methoxy-2-methyl-4-(4-methylpiperazin-1-
yl)thieno[2,3-b][1,5]benzoxazepine 1h (0.51 g, 1.49 mmoles) and
1,2-ethanedithiol (2.4 ml, 28.6 mmoles) in dichloromethane (30 ml)
was added aluminum chloride (3.0 g, 22.0 mmoles). The mixture
was stirred at room temperature for 2 hours followed by addition of
1 N NaOH (100 ml), and the mixture was extracted with ethyl
acetate. The extract was washed with brine, dried over sodium sul-
fate, and evaporated. The residue was purified by column chro-
matography (chloroform-methanol 10:1) to give 9-hydroxy-2-
methyl-4-(4-methylpiperazin-1-yl)thieno[2,3-b][1,5]benzoxa-
zepine 1j (0.19 g, 39%) as colorless crystals (Table 5 and 6).
Silica gel chromatography was performed on a Merck
Kieselgel 60. Melting points were obtained on a Büchi 535
melting point apparatus and are uncorrected. H NMR spectra
1
were recorded on a JEOL α400 spectrometer (400 MHz) or a
HITACHI R-90H spectrometer (90 MHz) using tetramethylsi-
lane (TMS) as an internal standard. Mass spectra were mea-
sured on a JEOL-JMS-DX300 instrument. Infrared spectra were
recorded on a JASCO FT/IR-5300 spectrometer. Element analy-
ses were performed on a Yanako CHN coder MT-5, and the
results indicated by element symbols are within ±0.4% of the
calculated values.
General Procedure for the Preparation of Thieno[2,3-b][1,5]ben-
zoxazepin-4(5H)-ones 4a-i, 4k.
General Procedure for the Preparation of 4-(4-Methylpiperazin-
1-yl)thieno[2,3-b][1,5]benzoxazepines 1a-i, 1k.
To a solution of 2-bromo-N-(2-hydroxyphenyl)-5-methyl-3-
thiophene carboxamide derivative 5a-i, 5k (48 mmoles) in
dimethylsulfoxide (100 ml) was added potassium carbonate (13
g) and the mixture was stirred at 140° for 2 hours. The reaction
system was cooled to room temperature and the mixture was
poured into water (800 ml). After neutralization with hydrochlo-
ric acid (37 wt. % in water), the mixture was extracted twice with
chloroform and washed with aqueous sodium hydrogencarbon-
ate. The organic layer was dried over sodium sulfate and the sol-
vent was evaporated under reduced pressure. To the residue was
added chloroform and the crystals were collected by filtration to
give the thieno[2,3-b][1,5]benzoxazepine-4(5H)-ones 4a-i, 4k.
The products are shown in Table 3 and 4.
2-Methylthieno[2,3-b][1,5]benzoxazepine-4(5H)-one deriva-
tive 4a-i, 4k (4.3 mmoles) was suspended in phosphorus oxy-
chloride (6.4 ml) and N,N-dimethylaniline (240 mg) was added.
The mixture was stirred under reflux for 1 hour. The solvent was
completely evaporated azeotropically with toluene under reduced
pressure, and 1-methylpiperazine (25 ml) was added to the
residue. The mixture was stirred under reflux for 40 minutes.
The reaction system was cooled to room temperature and the sol-
vent was evaporated under reduced pressure. The residue was
extracted twice with chloroform and washed with water and
brine. The organic layer was dried over sodium sulfate and the
solvent was evaporated under reduced pressure. The residue was
purified by silica gel column chromatography (chloroform-
methanol 100:1). The obtained compound was recrystallized
from diisopropyl ether to give the 2-methyl-4-(4-methylpiper-
azin-1-yl)thieno[2,3-b][1,5] benzoxazepines 1a-i, 1k. The prod-
ucts are shown in Table 5 and 6.
General Procedure for the Preparation of 2-Bromo-N-(2-hydrox-
yphenyl) -5-methyl-3-thiophenecarboxamides 5a-i, 5k.
2-Bromo-5-methyl-3-thiophenecarboxylic acid 8 or 2-bromo-
4,5-dimethyl-3-thiophenecarboxylic acid 12 (22.6 mmoles) was
suspended in thionyl chloride (20 ml) and the mixture was stirred
under reflux for 75 minutes. Thionyl chloride was evaporated
under reduced pressure and the residue was dissolved in toluene (5
ml). This toluene solution was added dropwise to a solution of 2-
9-Hydroxy-2-methyl-4-(4-methylpiperazin-1-yl)thieno[2,3-
b][1,5]benzoxazepine (1j).

Jan-Feb 2002
Synthesis of Thieno[2,3-b][1,5]benzoxazepine Derivatives
169
aminophenol derivatives 9a-i (33 mmoles) in pyridine (30 ml) at 0°.
The mixture was stirred at room temperature for 6 hours and the sol-
vent was evaporated under reduced pressure. The residue was dis-
solved in ethyl acetate. It was washed with diluted hydrochloric
acid and saturated aqueous sodium hydrogencarbonate, and dried
over sodium sulfate. The solvent was evaporated under reduced
pressure and diisopropyl ether was added. The precipitated crystals
were collected by filtration and washed with hexane to give
2-bromo-N-(2-hydroxyphenyl)-5-methyl-3-thiophene carboxam-
ides 5a-i, 5k. The products are shown in Table 1 and 2.
was filtrated, washing with diisopropyl ether gave the 2-methyl-
6-aminophenol hydrochloride 9i (4.85 g, 81%) as colorless crys-
tals, mp 250°; ir (potassium bromide): 3314, 2937, 1453, 1479,
-1
+
1
1203 cm ; ms: m/z 123 (M ); H nmr (dimethylsulfoxide-d ): δ
6
9.86 (br.s, 3H), 9.58 (br.s, 1H), 7.12-7.17 (m, 2H), 6.82 (dd, J =
7.8 and 7.9 Hz, 1H), 2.23 (s, 3H).
Anal. Calcd. for C H NO•HCl•H O: C, 47.33; H, 6.81; N,
7
9
2
7.89. Found: C, 47.71; H, 6.66; N, 8.02.
Ethyl 4,5-Dimethyl-3-thiophencarboxylate (11).
To a solution of ethyl 2-amino-4,5-dimethyl-3-thiophenecar-
boxylate 10 (11.5 g, 58.6 mmoles) and hydrochloric acid (30%,
60 ml) in ethanol (60 ml) a solution of sodium nitrate (22 wt. % in
water, 15 ml) was added dropwise at -2°. After stirring at -2° for
1 hour, sodium hypophosphite (38 wt. % in water, 50 ml) was
added. The reaction mixture was partitioned between ethyl
acetate and water. The combined organic layers were washed
with brine. After it was dried over sodium sulfate, the solvent
was removed to give a residue. Silica gel column chromatogra-
phy, eluting with hexane-ethyl acetate (95:5), gave the ethyl 4,5-
dimethyl-3-thiophencarboxylate 11 (2.9 g, 27%) as a colorless
5-Methyl-3-thiophencarboxylic Acid (7).
To a solution of 4-bromo-2-methylthiophene 6 (35.9 g, 202
mmoles) in dimethyl ether at -70° was added 1.6 M n-BuLi
hexane solution (133 ml, 212 mmoles). After stirring at -70° for
1 hour, crushed dry ice (24 g, 545 mmoles) was added and the
reaction mixture was stirred for 30 minutes. Water (200 ml) and
hydrochloric acid (37 wt. % in water, 30 ml) were added and the
mixture was extracted with ethyl acetate. The extract was
washed with brine and dried over sodium sulfate. The solvent
was evaporated under reduced pressure. Silica gel column chro-
matography, eluting with chloroform-methanol (20:1), gave
5-methyl-3-thiophencarboxylic acid 7 (15.49 g, 54%) as yellow
crystals, mp 126-128°; ir (potassium bromide): 2860, 1680, 1271
-1
oil, ir (potassium bromide): 1732, 1452, 1269 cm ; ms: m/z 184
+
1
(M ); H nmr (deuteriochloroform): δ 7.19 (s, 1H), 4.16 (q, J =
7.3 Hz, 2H), 2.29 (s, 3H), 2.25 (s, 3H), 1.30 (t, J = 7.3 Hz, 3H).
-1
+
1
cm ; ms: m/z 142 (M ); H nmr (deuteriochloroform): δ 7.98 (s,
2-Bromo-4,5-dimethyl-3-thiophencarboxylic Acid (12).
1H), 7.19 (s, 1H), 2.48 (s, 3H).
Anal. Calcd. for C H O S: C, 50.69; H, 4.25. Found: C, 50.31;
H, 4.19.
To a solution of ethyl 4,5-dimethyl-3-thiophencarboxylate 11
(2.9 g, 17.2 mmoles) in ethanol (100 ml) and water (14 ml) potas-
sium hydroxide (1.44 g, 25.7 mmoles) was added at room temper-
ature. After stirring at 40° for 5 hours, hydrochloric acid (35 wt. %
in water) was added dropwise. The precipitate was collected and
washed with n-hexane to give 4,5-dimethyl-3-thiophencarboxylic
acid. To a solution of 4,5-dimethyl-3-thiophenecarboxylic acid
(2.4 g, 15.4 mmoles) in acetic acid (10 ml) bromine (2.7 g,
17.1 mmoles) was added at room temperature. After stirring at
room temperature for 3 hours, the precipitated solids were col-
lected by filtration and washed with water to give 2-bromo-4,5-
dimethyl-3-thiophenecarboxylic acid 12 (2.9 g, 80%) as a colorless
solid, mp 178-180°; ir (potassium bromide): 2926, 2600, 1674,
6
6 2
2-Bromo-5-methyl-3-thiophencarboxylic Acid (8).
To a suspension of 5-methyl-3-thiophencarboxylic acid 7 (13.7
g, 96.5 mmoles) in acetic acid (120 ml) was added bromine (5.5
ml, 106 mmoles). The mixture was stirred at room temperature
for 3 hours and poured into water. The mixture was extracted
with ethyl acetate and the combined organic layers were washed
with brine. After it was dried over sodium sulfate, the solvent
was removed to give a residue. Recrystallization from ethyl
acetate/n-hexane gave 2-bromo-5-methyl-3-thiophene carboxylic
acid 8 (15.4 g, 72%) as colorless crystals, mp 191-195°; ir (potas-
-1
-1
+
1
sium bromide): 2864, 1676, 1475, 1269, 729 cm ; ms: m/z 221
1452, 1269, 729 cm ; ms: m/z 234, 236 (M ); H nmr (dimethyl-
+
1
(M ); H nmr (deuteriochloroform): δ 6.82 (s, 1H), 2.40 (s, 3H).
Anal. Calcd. for C H BrO S: C, 32.60; H, 2.28. Found: C,
sulfoxide-d ): δ 13.14 (br. s, 1H), 2.29 (s, 3H), 2.24 (s, 3H).
6
Anal. Calcd. For C H BrO S: C, 35.76; H, 3.00. Found: C,
6
5
2
7
7
2
32.97; H, 2.26.
35.81; H, 3.10.
2-Methoxy-6-aminophenol Hydrochloride (9h).
2-Ethoxycarbonyloxy-3-methoxycarbonylaminoanisole (13).
A suspension of 3-t-butyloxycarbonylamino-2-hydroxyanisole
16 (3.1 g, 12.9 mmoles) in 4 N HCl (in dioxane, 35 ml) was
stirred at room temperature for 1 hour. The reaction mixture was
filtrated, washing with diisopropyl ether gave 2-methoxy-6-
aminophenol hydrochloride 9h (1.85 g, 81%) as colorless crys-
tals, mp 180°; ir (potassium bromide): 2849, 1504, 1485, 1282,
To a solution of 3-methoxysalicylic acid (25 g, 148 mmoles) and
triethylamine (30 g, 297 mmoles) in acetone (50 ml) ethyl chlorofor-
mate (28 ml, 297 mmoles) was added at 0°. The mixture was stirred
for 1 hour at 0° and a solution of sodium azide (12 wt. % in water, 75
ml) was added. The mixture was stirred for 2 hours at 0°, poured
into water and extracted with chloroform. After it was dried over
sodium sulfate, the solvent was removed to give a residue. The
residue in benzene (200 ml) was heated for 1 hour at 70°. After cool-
ing, methanol (120 ml) was added and the mixture was heated for
1 hour at 55°. The solvent was removed to give a residue and it was
washed by n-hexane to give 2-ethoxycarbonyloxy-3-methoxycar-
bonylaminoanisole 13 (32.83 g, 82%) as colorless crystals, mp 85-
-1
+
1
1221 cm ; ms: m/z 139 (M ); H nmr (dimethylsulfoxide-d ): δ
6
9.83 (br.s, 4H), 6.99 (d, J = 7.8 Hz, 1H), 6.93 (d, J = 7.8 Hz, 1H),
6.83 (dd, J = 8.3 and 8.3 Hz, 1H), 3.83 (s, 3H).
Anal. Calcd. for C H NO •HCl: C, 47.88; H, 5.74; N, 7.98.
7
9
2
Found: C, 47.59; H, 5.81; N, 7.90.
2-Methyl-6-aminophenol Hydrochloride (9i).
-1
87°; ir (potassium bromide): 3319, 1761, 1712, 1234 cm ; ms: m/z
+
1
A suspension of 3-t-butyloxycarbonylamino-2-hydroxy-
toluene 20 (8.78 g, 39.3 mmoles) in 4 N HCl (in dioxane, 80 ml)
was stirred at room temperature for 1 hour. The reaction mixture
269 (M ); H nmr (deuteriochloroform): δ 7.72 (br.d, 1H), 7.17 (dd,
J = 8.3 and 8.3 Hz, 1H), 6.87 (br.s, 1H), 6.67 (d, J = 8.3 Hz, 1H), 4.34
(q, J = 7.3 Hz, 2H), 3.84 (s, 3H), 3.78 (s, 3H), 1.40 (t, J = 7.3 Hz, 3H).

170
T. Kohara, H. Tanaka, K. Kimura, H. Horiuchi, K. Seio,
M. Arita, T. Fujimoto, and I. Yamamoto
Vol. 39
Anal. Calcd. For C
Found: C, 53.50; H, 5.57; N, 5.26.
H
NO : C, 53.53; H, 5.62; N, 5.20.
at 70°. After cooling, methanol (150 ml) was added and the mix-
ture was heated for 1 hour at 55°. The solvent was removed to give
a residue and it was washed by n-hexane to give 2-ethoxycarbony-
loxy-3-methoxycarbonylaminotoluene 17 (42.1 g, 97%), mp 67-
71°; ir (potassium bromide): 3354, 1739, 1622, 1483, 1273, 1224,
1178 cm ; ms: m/z 253 (M ); H nmr (deuteriochloroform): δ
7.88 (br.s, 1H), 7.13 (dd, J = 7.8 and 7.8 Hz, 1H), 6.92 (d, J = 7.3
Hz, 1H), 6.77 (br.d, 1H), 4.32 (q, J = 7.3 Hz, 2H), 3.76 (s, 3H), 2.18
(s, 3H), 1.38 (q, J = 7.3 Hz, 3H).
12 15
6
2-Hydroxy-3-methoxycarbonylaminoanisole (14).
To a solution of 2-ethoxycarbonyloxy-3-methoxycarbony-
laminoanisole 13 (32.8 g, 122.0 mmoles) in methanol (150 ml),
tetrahydrofuran (300 ml) and water (225 ml) lithium hydroxyde
monohydrate (20.5g, 487.0 mmol) was added. After stirring at
60° for 4 hours, the reaction mixture was concentrated, and parti-
tioned between ethyl acetate and water. The organic layer was
separated, and washed with brine. The solution was dried over
sodium sulfate, and evaporated. Silica gel column chromatogra-
phy, eluting with hexane-ethyl acetate (2:1), gave the 2-hydroxy-
3-methoxycarbonylaminoanisole 14 (8.1 g, 31%) as colorless
crystals, mp 84-86°; ir (potassium bromide): 3530, 3383, 1734,
-1
+
1
Anal. Calcd. for C
H NO : C, 56.91; H, 5.97; N, 5.53.
12 15 5
Found: C, 57.05; H, 5.88; N, 5.64.
2,3-Dihydro-7-methyl-3H-benzoxazole-2-one (18).
To a solution of 2-ethoxycarbonyloxy-3-methoxycarbony-
laminotoluene 17 (20.0 g, 79.0 mmoles) in methanol (100 ml),
tetrahydrofuran (200 ml) and water (150 ml) lithium hydroxide
monohydrate (13.3 g, 315.9 mmoles) was added. After stirring at
60° for 3 hours, the reaction mixture was concentrated, and parti-
tioned between ethyl acetate and water. The organic layer was
separated, and washed with brine. The solution was dried over
sodium sulfate, and evaporated. Silica gel column chromatogra-
phy, eluting with hexane-ethyl acetate (3:1), gave 2,3-dihydro-7-
methyl-3H-benzoxazole-2-one 18 (6.2 g, 53%) as brown crystals,
mp 155-159°; ir (potassium bromide): 3244, 1765, 1645, 1585,
-1
+
1
1248 cm ; ms: m/z 211 (M ); H nmr (deuteriochloroform): δ
7.56 (br.d, 1H), 6.96 (br.s, 1H), 6.77 (dd, J = 8.3 and 8.3 Hz, 1H),
6.53 (d, J = 8.3 Hz, 1H), 5.77 (s, 1H), 4.16(q, J = 7.3 Hz, 2H),
3.81 (s, 3H), 1.23 (t, J = 7.3 Hz, 3H).
Anal. Calcd. for C
H NO : C, 56.86; H, 6.20; N, 6.63.
10 13 4
Found: C, 56.55; H, 6.15; N, 6.64.
2-t-Butyloxycarbonyl-3-ethoxycarbonylaminoanisole (15).
To a solution of 2-hydroxy-3-methoxycarbonylaminoanisole
14 (5.6 g, 26.5 mmoles), triethylamine (3.22 g, 31.8 mmoles),
and 4-dimethylaminopyridine (1.3 g, 10.6 mmoles) in tetrahydro-
furan (190 ml) di-tert-butyl dicarbonate (6.94 g, 31.8 mmoles)
was added. After stirring at room temperature for 2 hours, the
reaction mixture was concentrated. Silica gel column chro-
matography, eluting with hexane-ethyl acetate (3:1), gave the 2-t-
butyloxycarbonyl-3-ethoxycarbonylaminoanisole 15 (5.0 g,
61%) as a colorless oil, ms: m/z 311 (M ); H nmr (deuteriochlo-
roform): δ 7.71 (br.d, 1H), 7.12 (dd, J = 8.3 and 8.3 Hz, 1H), 6.82
(br.s, 1H), 6.64 (d, J = 8.3 Hz, 1H), 4.19 (q, J = 7.3 Hz, 2H), 3.82
(s, 3H), 1.38 (s, 9H), 1.30 (t, J = 7.3 Hz, 3H).
-1
+
1
1466 cm ; ms: m/z 149 (M ); H nmr (dimethylsulfoxide-d ): δ
6
8.54 (br.s, 1H), 7.26 (d, J = 7.8 Hz, 1H), 6.83 (d, J = 7.8 Hz, 1H),
6.67 (dd, J = 8.3 and 8.3 Hz, 1H), 2.16 (s, 3H).
Anal. Calcd. for C H NO •1/2H O: C, 60.75; H, 5.10; N, 8.86.
8
7
2
2
Found: C, 60.53; H, 4.70; N, 8.83.
3-t-Butyloxycarbonyl-2,3-dihydro-7-methyl-3H-benzoxazole-2-
one (19).
+
1
To a solution of 2,3-dihydro-7-methyl-3H-benzoxazole-2-one
18 (6.2 g, 41.5 mmoles), triethylamine (5.04 g, 49.8 mmoles),
and 4-dimethylaminopyridine (1.0 g, 8.3 mmoles) in tetrahydro-
furan (300 ml) di-tert-butyl dicarbonate (11.8 g, 54.0 mmoles)
was added. After stirring at room temperature for 2 hours, the
reaction mixture was concentrated. Silica gel column chro-
matography, eluting with hexane-ethyl acetate (5:1), gave 3-t-
butyloxycarbonyl-2,3-dihydro-7-methyl-3H-benzoxazole-2-one
19 (10.5 g, 99%) as colorless crystals, mp 118-119°; ir (potas-
3-t-Butyloxycarbonylamino-2-hydroxyanisole (16).
To a solution of 2-t-butyloxycarbonyl-3-ethoxycarbony-
laminoanisole 15 (5.0 g, 16.0 mmoles) in methanol (20 ml),
tetrahydrofuran (40 ml) was added lithium hydroxide monohy-
drate (2.7 g, 64.2 mmoles). The mixture was stirred at 45° for 1
hour and concentrated under reduced pressure. The mixture was
extracted with ethyl acetate and the combined organic layers were
washed with brine. After the solution was dried over sodium sul-
fate, the solvent was removed to give a residue. Silica gel column
chromatography, eluting with hexane-ethyl acetate (2:1), gave 3-t-
butyloxycarbonylamino-2-hydroxyanisole 16 (3.1 g, 80%) as a
-1
sium bromide): 1828, 1319, 1290, 1257, 1157 cm ; ms: m/z 249
+
1
(M ); H nmr (deuteriochloroform): δ 7.49 (d, J = 7.8 Hz, 1H),
7.09 (dd, J = 7.8 and 8.3 Hz, 1H), 7.01 (d, J = 7.8 Hz, 1H), 2.35
(s, 3H), 1.65 (s, 9H).
Anal. Calcd. for C
H NO : C, 62.64; H, 6.07; N, 5.62.
13 15 4
Found: C, 62.55; H, 6.20; N, 5.45.
-1
red oil, ir (neat): 3433, 2978, 1730, 1533, 1467, 1249, 1157 cm ;
3-t-Butyloxycarbonylamino-2-hydroxytoluene (20).
+
1
ms: m/z 239 (M ); H nmr (deuteriochloroform): δ 7.58 (br.d,
1H), 6.87 (br.s, 1H), 6.82 (dd, J = 8.3 and 8.3 Hz, 1H), 6.59 (d, J =
8.3 Hz, 1H), 5.81 (s, 1H), 3.88 (s, 3H), 1.52 (s, 9H).
To a solution of 3-t-butyloxycarbonyl-2,3-dihydro-7-methyl-
3H-benzoxazole-2-one 19 (9.54 g, 38.3 mmoles) in methanol (400
ml) and tetrahydrofuran (50 ml) cesium carbonate (12.5 g, 38.3
mmoles) was added at room temperature. After stirring at 60° for
2 hours, citric acid (8.04 g, 38.3 mmoles) was added and the sol-
vents removed in vacuo. Silica gel column chromatography, elut-
ing with hexane-ethyl acetate (3:1), gave 3-t-butyloxycarbony-
lamino-2-hydroxytoluene 20 (8.78 g, 99%) as a colorless oil, ir
2-Ethoxycarbonyloxy-3-methoxycarbonylaminotoluene (17).
To a solution of 3-methylsalicylic acid (30.0 g, 197.2 mmoles)
and triethylamine (39.9 g, 394.4 mmoles) in acetone (700 ml) was
added ethyl chloroformate (37 ml, 394.4 mmoles) at 0°. The mix-
ture was stirred at 0° for 1 hour and a solution of sodium azide (12
wt. % in water, 100 ml) was added. The mixture was stirred for
2 hours at 0°, poured into water, and extracted with chloroform.
The extract was washed with brine, dried over sodium sulfate, and
evaporated. The residue in benzene (300 ml) was heated for 1 hour
-1
(neat): 3324, 2980, 1682, 1531, 1485, 1369, 1249, 1159 cm ; ms:
+
1
m/z 223 (M ); H nmr (deuteriochloroform): δ 8.10 (br.s, 1H),
6.93 (d, J = 7.3 Hz, 1H), 6.83 (d, J = 7.3 Hz, 1H), 6.73 (dd, J = 7.3
and 7.8 Hz, 1H), 6.55 (br.s, 1H), 2.26 (s, 3H), 1.45 (s, 9H).

Jan-Feb 2002
Synthesis of Thieno[2,3-b][1,5]benzoxazepine Derivatives
171
REFERENCES AND NOTES
Sanger and S. Hamilton, Neuropsychopharmacology, 14, 111 (1996).
[8] I. Laimer and T. Erker, J. Heterocyclic. Chem., 31, 1053
(1994).
[9] J. Sice, J. Am. Chem. Soc., 75, 3697 (1953).
[10] S. Katou, M. Ishizaki (Tokuyama Soda KK), Jpn. Kokai
Tokkyo Koho JP 62106029 (1987); Chem. Abstr., 108, 93811b
(1987).
[11] M. Demuynck, P. D. Clercq and M. Vandewalle, J. Org.
Chem., 44, 4863 (1979).
[12] M. E. Jung and M. A. Lyster, J. Org. Chem., 42, 3761
(1977).
[1] J. K. Chakrabarti, T. M. Hotten, I. A. Pullar and D. J.
Steggles, J. Med. Chem., 32, 2375 (1989).
[2] J. B. Press, C. M. Hofmann, N. H. Eudy, I. P. Day, E. N.
Greenblatt and S. R. Safir, J. Med. Chem., 24, 154 (1981).
[3] Y. Lieo, B. J. Venhuis, N. Rodenhuis, W. Timmerman and
H. Wikströn, J. Med. Chem., 42, 2235 (1999).
[4] J-F. F. Liégeois, F. A. Rogister, J. Bruhwyler, J. Damas, T.
P. Nguyen, M-O. Inarejos, E. M. G. Chleide, M. G. A. Mercier and J.
E. Delarge, J. Med. Chem., 37, 519 (1994).
[13] T. Tsunoda, M. Amaike, U. S. F. Tambunan, Y. Fujise, S.
Ito and M. Kodama, Tetrahedron Lett., 28, 2537 (1987).
[14] G. Vidari, S. Ferrino and P. A. Grieco, J. Am. Chem. Soc.,
106, 3539 (1984).
[15] M. Node, H. Hori and E. Fujita, J. Chem. Soc., Perkin
Trans. 1, 2237 (1976).
[5] H. Tanaka, K. Kimura, H. Horiuchi, T. Kohara, M.
Fujimura, K. Hashimoto, H. Yasumatsu, T. Morimoto, K. Yamagami,
and M. Arita, "16 International Symposium on Medicinal
Chemistry", Bologna, Italy, September 18-22, 2000, pp 404.
[6] S. Gronowitz, Thiophene and Its Derivatives, Part IV, John
Wiely and Sons. (1985).
th
[16] K. Gewald, Z. Chem., 2, 305 (1962).
[7] C. M. Beasley, G. Tollefson, P. Tran, W. Satterlee, T.