Synthesis of new thieno[b]azepinediones from α-methylene ketones

Article abstract of DOI:10.1055/s-2002-31963

New substituted 6,7-dihydro-4H-thieno[3,2-b]azepine-5,8-diones were synthesized in seven steps, starting from substituted α-methylene ketones, via 3-aminothiophene-2-carboxylic acid alkyl esters.

Full text of DOI:10.1055/s-2002-31963

1096
PAPER
Synthesis of New Thieno[b]azepinediones from -Methylene Ketones
S
ynthesis of Thi
v
eno[
b
]
azepin
e
ediones lyne Migianu, Gilbert Kirsch*
Laboratoire d’Ingénierie Moléculaire et Biochimie Pharmacologique, Faculté des Sciences, Université de Metz, Ile du Saulcy,
57045 Metz Cedex, France
Fax +33(3)87315333; E-mail: kirsch@sciences.univ-metz.fr
Received 25 January 2002
Dedicated to Dr. E. Bisagni for his contribution to medicinal chemistry
O
Abstract: New substituted 6,7-dihydro-4H-thieno[3,2-b]azepine-
5,8-diones were synthesized in seven steps, starting from substitut-
ed -methylene ketones, via 3-aminothiophene-2-carboxylic acid
alkyl esters.
NH2
NH
CO2R2
a
R
CO2R1
R
CO2R1
Key words: heterocycles, thieno[b]azepinediones
-methylene
ketones, 3-aminothiophene-2-carboxylic acid alkyl esters
2a R=H
2b R=Br
3a-b
R1, R2=Me, Et
b
Benzoazepinediones and their heterocyclic analogues are
interesting compounds because they are precursors of po-
tential antitumor molecules such as paullones 1, reported
by Kunick and co-workers over the last decade
(Figure 1).1–3
O
O
H
N
H
N
c
R
R
CO2R2
O
H
O
OH
4a-b
N
5a R=H
5b R=Br
R = H, Br, OMe
R
Scheme
Reagents and conditions: (a) ClCO(CH2)2CO2R2,
CaCO3, toluene; (b) KH, toluene, DMF; (c) H2O, DMSO
1
R' = H, hal, OMe,
Me, Et, CF3, NO2
HN
1
R'
O
Figure 1 The structure of paullones 1
HN
In 1991, Kunick4 described for the first time the synthesis
of benzoazepinediones 5 from alkyl 2-aminobenzoates 2
(Scheme 1). Diesters 3 were prepared by the reaction of
amines 2 with a 3-chlorocarbonylpropionic acid alkyl es-
ter. The Dieckmann reaction from 3 using potassium hy-
dride furnished compounds 4. Heating 4 in wet dimethyl
sulfoxide yielded benzoazepinediones 5.
S
O
6
Figure 2 The structure of 5,6,7,8-tetrahydro-4H-thieno[3,2-b]aze-
pine-5,8,dione (6)
To our knowledge, Kunick’s report4 is the only reference
available in the literature regarding the preparation of a
carboxylic acid alkyl esters, prepared from -methylene
ketones.
thieno[b]azepinedione.
The
5,6,7,8-tetrahydro-4H-
thieno[3,2-b]azepine-5,8-dione (6) (Figure 2) was ob-
tained from the 3-aminothiophene-2-carboxylic acid me-
thyl ester in three steps in 33% yield, using the
experimental conditions shown in Scheme 1.
-Methylene ketones 7 led to -chloroacroleins 8 by a
Vilsmeier–Haack–Arnold reaction, using phosphorus ox-
ychloride and DMF5 (Scheme 2). They were obtained in
good to excellent yields and used without further purifica-
tion in the next step (Table 1). The corresponding oximes
were prepared by reacting 8 with hydroxylamine hydro-
chloride in DMF.6 The oximes were dehydrated by reflux-
ing in acetic anhydride to give the -chloroacrylonitriles 9
in moderate to good yields. Condensation of -chloro-
acrylonitriles 9 with alkyl thioglycolate (R = Me, Et) in a
basic medium, in a mixture of the appropriate alcohol and
tetrahydrofuran yielded 3-aminothiophene-2-carboxylic
acid alkyl esters 10 in moderate to excellent yields.7
We present here the synthesis of new thieno[b]-azepinedi-
ones substituted on the thiophene ring. Starting materials
were the corresponding substituted 3-aminothiophene-2-
Synthesis 2002, No. 8, 04 06 2002. Article Identifier:
1437-210X,E;2002,0,08,1096,1100,ftx,en;Z02102SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

PAPER
Synthesis of New Thieno[b]azepinediones
1097
Table 1 Preparation of -Chloroacroleins 8, -Chloroacrylonitriles 9 and Thiophenes 10
Entry
Ketone 7
Yield (%)
Thiophene 10
Yield (%)
8
9
a
61a
73a
94a
NH2
O
CO2Me
S
b
c
72a
99a
88a
50b
44a
55a
33c
48a
82a
NH2
MeOPh
O
MeOPh
H3C
CO2Et
S
NH2
Ph
O
Ph
CO2Me
NH2
S
d
O
CO2Et
S
a Crude product, analytically pure and used without further purification.
b Product purified by recrystallization in aq EtOH.
c Product purified by chromatography column using CH2Cl2 as eluent.
R2
O
R2
CHO
R2
NH2
R2
HN
a
a
R1
R1
61-99%
O
Cl
R1
CO2R
R1
CO2R
S
CO2CH3
S
62-87%
7a-d
8a-d
11a-d
10a-d
b, c
44-73%
b
35-78%
R2
NH2
R2
CN
Cl
d
O
O
R2
R2
R1
HN
HN
CO2R
S
R1
33-94%
R=Me, Et
10a-d
9a-d
R1
R1
CO2CH3
CO2CH3
S
S
OH
O
Scheme 2 Reagents and conditions: (a) POCl3, DMF, 60 °C, 5 h;
(b) NH2OH HCl, DMF, 110 °C, 8 h; (c) Ac2O, reflux, 18 h; (d)
HSCH2CO2R, K2CO3, ROH, THF, reflux, overnight
12a-d
12'a-d
c
40-98%
The reaction of 3-aminothiophene-2-carboxylic acid alkyl
esters 10 with 3-chlorocarbonylpropionic acid methyl es-
ter in the presence of calcium carbonate or potassium car-
bonate in toluene2,4 yielded the corresponding amides 11
(Scheme 3) in good yields (Table 2). The Dieckmann re-
action of 11 with a large excess of potassium hydride in a
mixture of toluene and DMF gave the cyclized com-
O
R2
HN
R1
S
O
1
pounds 12 in moderate to good yields.2,4 The H NMR
13a-d
spectra indicated that compounds 12 are in equilibrium
with the corresponding enolic forms 12 in DMSO-d6 sol-
ution. The proportion of each form was not determined as
it changes over time. Nevertheless, it was observed that
Scheme 3 Reagents and conditions: (a) ClCO(CH2)2CO2CH3,
CaCO3 or K2CO3, toluene, reflux, 2 h; (b) KH, toluene, DMF, 80 °C,
3 h, argon; (c) H2O, DMSO, 140 °C, 4–8 h
Synthesis 2002, No. 8, 1096–1100 ISSN 0039-7881 © Thieme Stuttgart · New York

1098
E. Migianu, G. Kirsch
PAPER
Table 2 Preparation of Amides 11, Compounds 12 and 12 and
Thienoazepinediones 13
in seven steps from -methylene ketones via 3-ami-
nothiophene-2-carboxylic acid alkyl esters. These
thieno[b]azepinediones and all intermediates of this syn-
thesis, prepared in acceptable yields, were usually ob-
tained analytically pure and no further purification was
needed.
Entry Yield (%)
Thienoazepinedione 13
Yield
(%)
11
12 and 12
a
b
c
87a
78a
47c
35a
76a
40a
98a
98a
97a
O
HN
KH was purchased from Acros. -Chloroacroleins5 and
-
chloroacrylonitriles6 were prepared according to literature proce-
dures. Melting points were determined on a Stuart SMP3 melting
point apparatus and are uncorrected. IR spectra were performed on
a Mattson 3000 FTIR spectrometer. 1H and 13C NMR spectra were
recorded on a AC Bruker 250 MHz spectrometer in CDCl3 or
DMSO-d6. Mass spectra were performed on a Hewlett-Packard
5971 A GC-MS spectrometer.
S
O
66b
67a
62b
O
HN
3-Aminothiophenes 10; General Procedure
MeOPh
S
-Chloroacrylonitriles 9 (0.109 mol) were dissolved in a mixture of
the appropriate alcohol (MeOH or EtOH, 170 mL) and THF (30
mL). Then, alkyl thioglycolate (methyl thioglycolate or ethyl
thioglycolate, 0.109 mol) was added in one portion with stirring,
followed by K2CO3 (15.15 g, 0.109 mol) and the reaction mixture
was refluxed overnight. After cooling to r.t., the crude mixture was
filtered over Celite and the filtrate evaporated to furnish thiophenes
10.
O
O
HN
H3C
Ph
S
O
S
3-Amino-5-tert-butylthiophene-2-carboxylic Acid Methyl Ester
(10a)
Orange solid; yield: 21.76 g (94%); analytically pure and used with-
out further purification; mp 71–72 °C.
1H NMR (250 MHz, CDCl3): = 1.33 [s, 9 H, C(CH3)3], 3.80 (s, 3
H, CO2CH3), 5.39 (br s, 2 H, NH2, D2O exchangeable), 6.33 (s, 1
Hthiophene).
d
O
HN
O
13C NMR (62.9 MHz, CDCl3): = 31.2 [(CH3)3], 34.4 (C), 50.5
(CH3), 97.4 (C), 114.9 (CH), 153.9 (C), 163.3 (C), 164.6 (C=O).
a Crude product, analytically pure and used without further purifica-
tion.
b Product purified by recrystallization.
GC-MS: m/z (%) = 213 (59), 198 (100).
c Product purified by trituration in hot methanol and filtration.
3-Amino-5-(4-methoxyphenyl)thiophene-2-carboxylic Acid
Ethyl Ester (10b)
Orange solid; yield: 5.01 g (33%); purified by column chromatog-
raphy on silica gel using CH2Cl2 as eluent; mp 148–150 °C.
intermediates 12 are usually the existing major form after
1H NMR (250 MHz, CDCl3): = 1.37 (t, 3 H, J = 7.1 Hz, CH3),
3.84 (s, 3 H, OCH3), 4.31 (q, 2 H, J = 7.1 Hz, CH2), 5.45 (br s, 2 H,
workup of the reaction mixture.
It should be noted that the thiophene ring in the amides
11b and 11d was substituted in position 2 by a carboxylic
acid ethyl ester group, whereas 3-chlorocarbonylpropion-
ic acid methyl ester was always used to prepare the
amides. Hence, the presence of two different ester groups
could involve a transesterification reaction during cy-
clization with potassium hydride. This phenomenon was
NH2, D2O exchangeable), 6.67 (s, 1 Hthiophene), 6.91 (d, 2 Hphenyl
,
J = 8.7 Hz), 7.52 (d, 2 Hphenyl, J = 8.7 Hz).
13C NMR (62.9 MHz, CDCl3): = 14.5 (CH3), 55.3 (OCH3), 60.0
(CH2), 114.3 (2 CH), 114.5 (CH), 116.2 (C), 126.2 (C), 127.2 (2
CH), 149.0 (C), 154.3 (C), 160.3 (C), 164.6 (C=O).
3-Amino-4-methyl-5-phenylthiophene-2-carboxylic Acid Me-
not observed for compounds 12b and 12 b. However, for thyl Ester (10c)
Orange oil; yield: 21.44 g (48%); analytically pure and used without
further purification.
derivatives 12d and 12 d, the presence of other signals
which could correspond to transesterification compounds
1
1H NMR (250 MHz, CDCl3): = 2.21 (s, 3 H, CH3), 3.60 (s, 3 H,
CO2CH3), 7.35–7.44 (m, 5 Hphenyl), NH2 signal not present in the
spectrum.
13C NMR (62.9 MHz, CDCl3): = 18.6 (CH3), 52.6 (CH3), 128.6
(C), 128.9, 129.0, 129.1 (5 CH), 129.8 (C), 130.0 (C), 130.3 (C),
135.1 (C), 161.5 (C=O).
was noticed in the H NMR spectrum. All the isomers
could not be separated in order to be characterized and the
dealkoxycarbonylation was carried out on the mixture. By
heating compounds 12 in dimethyl sulfoxide–water,2,4 the
expected 6,7-dihydro-4H-thieno[3,2-b]azepine-5,8-di-
ones 13 were obtained in moderate to excellent yields.
GC-MS: m/z (%) = 247 (35), 174 (100).
In conclusion, we have described a synthesis of new sub-
stituted 6,7-dihydro-4H-thieno[3,2-b]azepine-5,8-diones
Synthesis 2002, No. 8, 1096–1100 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of New Thieno[b]azepinediones
1099
3-Amino-4,5-dihydronaphtho[1,2-b]thiophene-2-carboxylic
Acid Ethyl Ester (10d)
3-(3-Methoxycarbonylpropionylamino)-4,5-dihydronaph-
tho[1,2-b]thiophene-2-carboxylic Acid Ethyl Ester (11d)
Orange solid; yield: 20.73 g (82%); analytically pure and used with-
out further purification; mp 114–115 °C.
Yellow needles; 2.52 g (62%); purified by recrystallization from
toluene; mp 151–152 °C.
1H NMR (250 MHz, CDCl3): = 1.38 (t, 3 H, J = 7.1 Hz, CH3),
2.60 (m, 2 H, CH2), 3.00 (m, 2 H, CH2), 4.33 (q, 2 H, J = 7.1 Hz,
CH2), 5.43 (br s, 2 H, NH2, D2O exchangeable), 7.22–7.23 (m, 3
Harom), 7.38–7.41 (m, 1 Harom).
13C NMR (62.9 MHz, CDCl3): = 14.5 (CH3), 20.8 (CH2), 28.3
(CH2), 60.0 (CH2), 123.6 (CH), 126.7 (C), 127.1 (CH), 128.1 (CH),
128.4 (CH), 128.5 (C), 130.6 (C), 135.5 (C), 141.2 (C), 151.7 (C),
164.9 (C=O).
1H NMR (250 MHz, CDCl3): = 1.39 (t, 3 H, J = 7.2 Hz, CH3),
2.76–2.78 (m, 6 H, CH2CH2 + CH2), 2.87–2.90 (m, 2 H, CH2), 3.72
(s, 3 H, CO2CH3), 4.35 (q, 2 H, J = 7.2 Hz, CH2), 7.23–7.26 (m, 3
Harom), 7.39–7.40 (m, 1 Harom), 9.21 (br s, 1 H, NH, D2O exchange-
able).
13C NMR (62.9 MHz, CDCl3): = 14.3 (CH3), 24.1 (CH2), 28.8
(CH2), 29.1 (CH2), 31.4 (CH2), 51.8 (CH3), 61.0 (CH2), 113.3 (C),
123.4 (CH), 127.0 (CH), 128.1 (CH), 128.7 (CH), 130.5 (C), 134.0
(C), 136.3 (C), 141.8 (C), 142.1 (C), 163.7 (C=O), 169.8 (C=O),
172.8 (C=O).
GC-MS: m/z (%) = 273 (100), 226 (54).
Amides 11; General Procedure
Compounds 12 and 12 ; General Procedure
A solution of 3-chlorocarbonylpropionic acid methyl ester (17.33 g,
0.115 mol) in toluene (50 mL) was added dropwise to a stirred and
cooled (0 °C) suspension of the appropriate substituted 3-ami-
nothiophene-2-carboxylic acid alkyl ester 10 (0.096 mol) and
CaCO3 (19.19 g, 0.192 mol) or K2CO3 (26.50 g, 0.192 mol) in tolu-
ene (200 mL). The reaction mixture was allowed to stand at that
temperature for an additional 15 min. After warmimg to r.t. gradu-
ally, the mixture was refluxed for 2–3 h (progress of the reaction
was monitored by TLC) and then filtered to remove the inorganic
salts. The filtrate was evaporated to give amides 11.
A solution of the appropriate amide 11 (15.5 mmol) in anhyd tolu-
ene (40 mL) and DMF (6 mL) was added dropwise to a stirred and
cooled (0 °C) suspension of potassium hydride (3.73 g, 93.1 mmol)
in anhyd toluene (30 mL) under argon, and the reaction mixture was
allowed to stand at that temperature for an additional 30 min. After
warming to r.t. gradually, the mixture was heated at 80 °C for 3 h
(progress of the reaction was monitored by TLC). The mixture was
hydrolysed slowly at 0 °C with AcOH (7 mL) and filtered after ad-
dition of H2O (60 mL).
For compounds 12b and 12 b: the obtained residue constituted a
mixture of the two isomers 12b and 12 b.
5-tert-Butyl-3-(3-methoxycarbonylpropionylamino)thiophene-
2-carboxylic Acid Methyl Ester (11a)
Orange solid; yield: 27.24 g (87%); analytically pure and used with-
out further purification; mp 66–68 °C.
1H NMR (250 MHz, CDCl3): = 1.37 [s, 9 H, C(CH3)3], 2.74 (br s,
4 H, CH2CH2), 3.71 (s, 3 H, CO2CH3), 3.86 (s, 3 H, CO2CH3), 7.91
(s, 1 Hthiophene), 10.23 (br s, 1 H, NH, D2O exchangeable).
13C NMR (62.9 MHz, CDCl3): = 28.9 (CH2), 31.7 (CH2), 31.8
[(CH3)3], 35.2 (C), 51.7 (CH3), 51.9 (CH3), 107.0 (C), 117.6 (CH),
144.4 (C), 164.5 (C), 164.9 (C=O), 168.9 (C=O), 172.8 (C=O).
For the rest: the filtrate was extracted with Et2O (3 50 mL). The
organic layers were combined, washed with brine (100 mL), dried
(Na2SO4) and evaporated to give a mixture of the two isomers 12
and 12 .
2-tert-Butyl-5,8-dioxo-5,6,7,8-tetrahydro-4H-thieno[3,2-b]-
azepine-7-carboxylic Acid Methyl Ester (12a) and 2-tert-Butyl-
8-hydroxy-5-oxo-5,6-dihydro-4H-thieno[3,2-b]azepine-7-car-
boxylic Acid Methyl Ester (12 a)
Orange paste; yield: 11.50 g (78%); used without further purifica-
tion. A small sample was purified by trituration in hot MeOH and
filtration to give a beige solid; mp 194–195 °C.
3-(3-Methoxycarbonylpropionylamino)-5-(4-methoxyphe-
nyl)thiophene-2-carboxylic Acid Ethyl Ester (11b)
Orange crystals; yield: 3.45 g (66%); purified by recrystallization
from MeOH; mp 112–113 °C.
IR (KBr): 1563 (C=O), 1603 (C=O), 1634 (C=O), 1687 (C=O)
cm–1.
1H NMR (250 MHz, CDCl3): = 1.40 (t, 3 H, J = 7.1 Hz, CH3),
2.77 (s, 4 H, CH2CH2), 3.72 (s, 3 H, CO2CH3), 3.84 (s, 3 H, OCH3),
4.36 (q, 2 H, J = 7.1 Hz, CH2), 6.92 (d, 2 Hphenyl, J = 8.9 Hz), 7.60
(d, 2 Hphenyl, J = 8.9 Hz), 8.26 (s, 1 Hthiophene), 10.30 (br s, 1 H, NH,
D2O exchangeable).
1H NMR (250 MHz, DMSO-d6): = 1.32 [s, C(CH3)3 12a], 1.35 [s,
C(CH3)3 12 a], 2.98–3.05 (m, CH2 12a + CH2 12 a), 3.66 (s,
CO2CH3 12a), 3.81 (s, CO2CH3 12 a), 4.06 (m, CH 12a), 6.69 (s,
Hthiophene 12 a), 6.70 (s, Hthiophene 12a), 10.73 (br s, NH 12a + NH
12 a, D2O exchangeable), 12.22 (br s, OH 12 a, D2O exchangeable).
13C NMR (62.9 MHz, CDCl3): = 14.3 (CH3), 28.9 (CH2), 31.9
(CH2), 51.8 (CH3), 55.3 (OCH3), 60.9 (CH2), 108.2 (C), 114.4
(2CH), 117.1 (CH), 126.0 (C), 127.5 (2CH), 145.0 (C), 149.8 (C),
160.5 (C), 164.4 (C=O), 169.0 (C=O), 172.8 (C=O).
2-(4-Methoxyphenyl)-5,8-dioxo-5,6,7,8-tetrahydro-4H-thi-
eno[3,2-b]azepine-7-carboxylic Acid Methyl Ester (12b) and 8-
Hydroxy-2-(4-methoxyphenyl)-5-oxo-5,6-dihydro-4H-thieno-
[3,2-b]azepine-7-carboxylic Acid Methyl Ester (12 b)
Yellow solid; yield: 1.35 g (47%); purified by trituration in hot
MeOH and filtration; mp 226–228 °C.
3-(3-Methoxycarbonylpropionylamino)-4-methyl-5-phenylth-
iophene-2-carboxylic Acid Methyl Ester (11c)
Orange oil; yield: 1.87 g (67%); analytically pure and used without
further purification.
IR (KBr): 1567 (C=O), 1605 (C=O), 1630 (C=O), 1697 (C=O)
cm–1.
1H NMR (250 MHz, CDCl3): = 2.16 (s, 3 H, CH3), 2.61–2.70 (m,
2 H, CH2), 2.88–2.97 (m, 2 H, CH2), 3.68 (s, 3 H, CO2CH3), 3.85 (s,
3 H, CO2CH3), 7.41–7.51 (m, 5 Hphenyl), NH signal not present in the
spectrum.
13C NMR (62.9 MHz, CDCl3): = 12.1 (CH3), 28.6 (CH2), 33.1
(CH2), 51.8 (CH3), 52.3 (CH3), 126.0 (C), 128.8, 128.9, 129.1
(5CH), 133.2 (C), 133.3 (C), 140.9 (C), 144.3 (C), 161.3 (C=O),
172.8 (C=O), 173.7 (C=O).
1H NMR (250 MHz, DMSO-d6): = 3.03–3.10 (m, CH2 12b + CH2
12 b), 3.68 (s, CO2CH3 12b), 3.82 (s, CO2CH3 12 b + OCH3 12b +
OCH3 12 b), 4.12 (m, CH 12b), 7.04–7.10 (m, 2 Hphenyl 12b + 2 Hphe-
nyl 12 b + Hthiophene 12b + Hthiophene 12 b), 7.61–7.65 (m, 2 Hphenyl 12b
+ 2 Hphenyl 12 b), 10.88 (br s, NH 12 b, D2O exchangeable), 10.90
(br s, NH 12b, D2O exchangeable), OH 12 b signal not present in
the spectrum.
Synthesis 2002, No. 8, 1096–1100 ISSN 0039-7881 © Thieme Stuttgart · New York

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E. Migianu, G. Kirsch
PAPER
3-Methyl-5,8-dioxo-2-phenyl-5,6,7,8-tetrahydro-4H-thieno[3,2-
b]azepine-7-carboxylic Acid Methyl Ester (12c) and 8-Hydroxy-
3-methyl-5-oxo-2-phenyl-5,6-dihydro-4H-thieno[3,2-b]azepine-
7-carboxylic Acid Methyl Ester (12 c)
Yellow solid; yield: 242 mg (35%); analytically pure and used with-
out further purification; mp 202–203 °C.
IR (KBr): 1632 (C=O), 1672 (C=O) cm–1.
1H NMR (250 MHz, DMSO-d6): = 2.79 (m, 4 H, CH2CH2), 3.82
(s, 3 H, OCH3), 7.06 (d, 2 Hphenyl, J = 8.7 Hz), 7.09 (s, 1 Hthiophene),
7.62 (d, 2 Hphenyl, J = 8.7 Hz), 10.77 (br s, 1 H, NH, D2O exchange-
able).
13C NMR (62.9 MHz, DMSO-d6): = 30.3 (CH2), 35.1 (CH2), 55.5
(OCH3), 114.9 (2CH), 117.6 (CH), 121.8 (C), 124.8 (C), 127.3
(2CH), 142.5 (C), 150.5 (C), 160.6 (C), 172.9 (C=O), 190.6 (C=O).
IR (KBr): 1589 (C=O), 1639 (C=O), 1655 (C=O), 1673 (C=O)
cm–1.
1H NMR (250 MHz, DMSO-d6): = 2.18 (s, CH3 12c), 2.22 (s, CH3
12 c), 3.08 (m, CH2 12c + CH2 12 c), 3.70 (s, CO2CH3 12c), 3.83 (s,
CO2CH3 12 c), 4.15 (m, CH 12c), 7.52 (m, 5 Hphenyl 12c + 5 Hphenyl
12 c), 10.40 (br s, NH 12c + NH 12 c, D2O exchangeable), OH 12 c
signal not present in the spectrum.
3-Methyl-2-phenyl-6,7-dihydro-4H-thieno[3,2-b]azepine-5,8-
dione (13c)
Brown solid; yield: 124 mg (98%); analytically pure without further
purification; mp 219–220 °C.
IR (KBr): 1634 (C=O), 1682 (C=O) cm–1.
8,11-Dioxo-5,7,8,9,10,11-hexahydro-6H-12-thia-7-azanaphtho-
[2,1-a]azulene-10-carboxylic Acid Methyl Ester (12d) and 11-
Hydroxy-8-oxo-5,7,8,9-tetrahydro-6H-12-thia-7-azanaphtho-
[2,1-a]azulene-10-carboxylic Acid Methyl Ester (12 d)
Yellow solid; yield: 4.19 g (76%); analytically pure and used with-
out further purification; mp 178–179 °C.
1H NMR (250 MHz, DMSO-d6): = 2.18 (s, 3 H, CH3), 2.80–2.85
(m, 4 H, CH2CH2), 7.51 (m, 5 Hphenyl), 9.99 (br s, 1 H, NH, D2O ex-
changeable).
13C NMR (62.9 MHz, DMSO-d6): = 13.0 (CH3), 30.3 (CH2), 36.0
(CH2), 124.1 (C), 127.9 (C), 128.9 (2 CH), 129.1 (CH), 129.2 (2
CH), 133.3 (C), 140.9 (C), 145.5 (C), 173.2 (C=O), 191.4 (C=O).
IR (KBr): 1560 (C=O), 1601 (C=O), 1644 (C=O), 1681 (C=O)
cm–1.
5,6,9,10-Tetrahydro-7H-12-thia-7-azanaphtho[2,1-a]azulene-
8,11-dione (13d)
Yellow solid; 3.30 g (97%); analytically pure without further puri-
fication; mp 281–283 °C.
1H NMR (250 MHz, DMSO-d6): = 2.80 (m, CH2 12d + CH2 12 d),
2.93 (m, CH2 12d + CH2 12 d), 3.08 (m, CH2 12d + CH2 12 d), 3.69
(s, CO2CH3 12d), 3.83 (s, CO2CH3 12 d), 4.14 (m, CH 12d), 7.32
(m, 3 Harom 12d + 3 Harom 12 d), 7.45 (m, 1 Harom 12d + 1 Harom 12 d),
10.31 (br s, NH 12 d, D2O exchangeable), 10.56 (br s, NH 12d, D2O
exchangeable), 12.34 (br s, OH 12 d, D2O exchangeable).
IR (KBr): 1631 (C=O), 1678 (C=O) cm–1.
1H NMR (250 MHz, DMSO-d6): = 2.81 (m, 6 H, 3 CH2), 2.92 (m,
2 H, CH2), 7.33 (m, 3 Harom), 7.49 (m, 1 Harom), 10.16 (br s, 1 H, NH,
D2O exchangeable).
Thienoazepinediones 13; General Procedure
The cyclized compounds 12 and 12 (11 mmol) were dissolved in
DMSO (40 mL) and the solution was heated at 90 °C. H2O (0.11
mol, 2 mL) was added in one portion and the reaction mixture was
heated at 140 °C for 4–8 h (progress of the reaction was monitored
by TLC). At r.t., the mixture was poured into iced H2O (50 mL). If
a precipitate appeared (compounds 13a, 13b and 13d), it was fil-
tered off to give the expected thienoazepinediones 13. Otherwise,
the mixture was extracted with EtOAc (3 100 mL). The organic
layers were combined, washed with H2O (50 mL) and brine (50
mL), dried (Na2SO4) and evaporated to give the expected
thienoazepinedione 13c.
13C NMR (62.9 MHz, DMSO-d6): = 21.1 (CH2), 27.7 (CH2), 30.4
(CH2), 35.7 (CH2), 123.6 (C), 123.7 (CH), 127.4 (CH), 128.5 (CH),
129.5 (CH), 129.8 (C), 131.1 (C), 135.8 (C), 139.7 (C), 142.9 (C),
173.2 (C=O), 191.2 (C=O).
Acknowledgement
We are grateful to the Ligue contre le Cancer de la Région Lorraine
for financial support.
References
2-tert-Butyl-6,7-dihydro-4H-thieno[3,2-b]azepine-5,8-dione
(13a)
(1) Kunick, C. Arch. Pharm. (Weinheim) 1992, 325, 297.
(2) Schultz, C.; Link, A.; Leost, M.; Zaharevitz, D. W.; Gussio,
R.; Sausville, E. A.; Meijer, L.; Kunick, C. J. Med. Chem.
1999, 42, 2909.
Brown solid; 3.58 g (40%), analytically pure without further purifi-
cation; mp 248–249 °C.
IR (KBr): 1643 (C=O), 1679 (C=O) cm–1.
(3) Kunick, C.; Schultz, C.; Lemcke, T.; Zaharevitz, D. W.;
Gussio, R.; Jalluri, R. K.; Sausville, E. A.; Leost, M.; Meijer,
L. Bioorg. & Med. Chem. Lett. 2000, 10, 567.
(4) Kunick, C. Arch. Pharm. (Weinheim) 1991, 324, 579.
(5) Arnold, Z.; Zemlicka, J. Collect. Czech. Chem. Commun.
1959, 24, 2385.
(6) Sampath Kumar, H. M.; Subba Reddy, B. V.; Tirupathi
Reddy, P.; Yadav, J. S. Synthesis 1999, 586.
(7) Wang, Z.; Neidlein, R.; Krieger, C. Synthesis 2000, 255.
1H NMR (250 MHz, DMSO-d6): = 1.32 [s, 9 H, C(CH3)3], 2.74 (s,
4 H, CH2CH2), 6.70 (s, 1 Hthiophene), 10.65 (br s, 1 H, NH, D2O ex-
changeable).
13C NMR (62.9 MHz, DMSO-d6): = 30.4 (CH2), 31.5 [(CH3)3],
34.9 (C), 35.2 (CH2), 118.5 (CH), 121.1 (C), 141.7 (C), 165.5 (C),
173.0 (C=O), 190.8 (C=O).
2-(4-Methoxyphenyl)-6,7-dihydro-4H-thieno[3,2-b]azepine-5,8-
dione (13b)
Pale brown solid; yield: 980 mg (98%); analytically pure without
further purification; mp 282–284 °C.
Synthesis 2002, No. 8, 1096–1100 ISSN 0039-7881 © Thieme Stuttgart · New York