Studies on the chemistry of thienoannelated O,N- and S,N-containing heterocycles. 24 [1]. Synthesis of imidazo[1,5-d]thieno[2,3-b][1,4]-thiazine derivatives as potential receptor ligands

Article abstract of DOI:10.1002/jhet.5570390407

A facile synthesis of the imidazo[1,5-d]thieno[2,3-b][1,4]thiazine ring system is described. Reaction of 6- benzyl-2,3-dihydro-1H-thieno[2,3-b][1,4]thiazine-2-one (1) with potassium tert-butoxide and diethylchlorophosphate gave intermediate 2 which resulted in the disired ring system after adding the corresponding isocyanides and potassium tert-butoxide.

Full text of DOI:10.1002/jhet.5570390407

Jul-Aug 2002
Studies on the Chemistry of Thienoannelated O,N- and S,N-Containing
Heterocycles. 24 [1]. Synthesis of Imidazo[1,5-d]thieno[2,3-b][1,4]-
thiazine Derivatives as Potential Receptor Ligands
Thomas Erker* and Norbert Handler
645
Institute of Pharmaceutical Chemistry, University of Vienna
Althanstraße 14, 1090 Wien, Austria
Received September 12, 2001
A facile synthesis of the imidazo[1,5-d]thieno[2,3-b][1,4]thiazine ring system is described. Reaction of 6-
benzyl-2,3-dihydro-1H-thieno[2,3-b][1,4]thiazine-2-one (1) with potassium tert-butoxide and
diethylchlorophosphate gave intermediate 2 which resulted in the disired ring system after adding the corre-
sponding isocyanides and potassium tert-butoxide.
J. Heterocyclic Chem., 39, 645 (2002).
The 1,4-benzothiazine ring system is found in a great
number of substances with pharmaceutical activity. For
example, they posses antimicrobial [2] and growth hor-
mone releasing properties [3]. Furthermore, it is known
from 1,4-benzodiazepine derivatives, that their pharma-
cological profile is enhanced by attachment of a further
heterocyclic ring. The 4H-imidazo[5,1-c][1,4]benzothi-
azine derivatives as shown in Scheme 1 are used as
cyclooxygenase 2 inhibitors and anti-inflammatory
agents [4] or as anticonvulsants, anxiolytics, hypnotics,
and nootropics [5,6].
It is known from various drugs, that pharmacological
activity may be maintained if benzene is exchanged by
a thiophene ring [7]. In course of the studies concern-
ing the synthesis of thienoannelated thiazines, it should
be attempted to link both principles via attachment of a
imidazolo ring to thieno[2,3-b][1,4]thiazines,
respectively.
So we decided to synthesize imidazo[1,5-d]thieno-
[2,3-b][1,4]thiazine derivatives as shown in Scheme 1.
A lipophilic group substituted in the 7-position is meant
to intensify biologic activity and finally the 3-position of
the oxadiazole unit is substituted with various groups as
given in literature [5]. Synthesis of the desired 1,2,4-oxadi-
azolylimidazo[1,5-d]thieno[2,3-b][1,4]thiazine derivatives
is shown in the following Scheme.
Compound 1 [8] was mixed with potassium tert-butox-
ide and diethyl chlorophosphate (beware of the potential
safety hazard of this reagent) under argon to give enol
phosphate ester 2. Reaction of this intermediate, which
was usually not isolated, with various isocyanides in the
presence of additional potassium tert-butoxide yielded
the desired products (3–9). The oxadiazole isocyanides
used in this reaction were synthesized following the
general procedure of Watjen [9].
Starting from compound 3 we also synthesized an
alternative molecule with a methyl 1,3-oxazole-car-
boxylate group in position 3 of the tricyclic ring
system (13). Synthesis of this product is shown in the
following Scheme
.

646
T. Erker and N. Handler
Vol. 39
and 45 minutes, finally the solution was stirred at room tempera-
ture for 45 minutes. The resultant mixture was poured into 120
ml ice-water and the precipitate was recrystallized.
Products 7, 8 and 9 resulted in oils upon pouring them into
water. Therefore, the solutions were partitioned between 100 ml
water (with 2 ml glacial acetic acid added) and dichloromethane
(40 ml) four times, then between pure water and dichloro-
methane. The organic layers were dried over anhydrous sodium
sulfate and evaporated. The residue was recrystallized.
Therefore ethylester 3 was hydrolized with 5% aqueous
sodiumhydroxide to give compound 10. Reaction with D,L-
serine methyl ester gave intermediate 11 which was cyclized
by adding Burgess Reagent to yield 12 [10]. Finally dehy-
drogenation of 12 was carried out with tert-butyl perben-
zoate and copper-(I)-bromide following the reaction of
Kharasch-Sosnovsky to get the desired product 13 [11].
EXPERIMENTAL
Ethyl 7-Benzyl-4H-imidazo[1,5-d]thieno[2,3-b][1,4]thiazine-3-
carboxylate (3).
Melting ranges were determined on a Kofler-hot stage appara-
Prepared from 1 (1.31 g, 5 mmoles). After crystallisation from
1
13
tus and are uncorrected. The H-nmr and C-nmr spectra were
recorded on a Varian Unity Plus 300 spectrometer (using TMS as
internal reference, δ values in ppm). The MS spectra were
obtained using a Shimadzu GC/MS QP 1000 EX or a HP-5890
spectrometer. Analytical TLC was performed on Merck silica gel
F254 plates. Column chromatography was performed on Merck
silica gel 60, 0.063-0.200 mm. Evaporation refers to evaporation
under reduced pressure, and drying of solutions refers to the use
of anhydrous sodium sulfate.
1
ethanol 1.00 g (56%) 3 was obtained, mp 165 °C; H nmr (deu-
teriochloroform): δ 7.73 (s, 1H, imidazole-H), 7.39-7.20 (m, 5H,
phenyl H), 6.89 (s, 1H, thiophene H), 4.44 (s, 2H, benzyl-CH ),
2
4.39 (q, 2H, J = 7.2 Hz, CH ), 4.09 (s, 2H, S-CH ), 1.41 (t, 3H, J
2
2
13
= 7.2 Hz, CH ); C nmr (deuteriochloroform): δ 162.8, 143.6,
3
138.6, 130.8, 128.7, 128.4, 128.2, 127.3, 127.0, 117.5, 115.6,
+
60.6, 36.2, 24.6, 14.3; ms: m/z 356 (M ), 311, 282 (100%), 230,
+
+
154, 115, 91 (tropylium ), 77 (phenylium ), 45.
Anal. Calcd. for C N O S : C, 60.65; H, 4.52; N, 7.86.
H
18 16
2 2 2
General Procedure for the Synthesis of Compounds (3-9).
Found: C, 60.44; H, 4.64; N, 7.63.
All the following reactions were carried out under an argon
atmosphere. A solution of 5 mmol 1.31 g (5 mmoles) of com-
pound 1 in 10 ml absolute tetrahydrofuran was cooled to –40 °C
and 5.5 ml (1.0 M in tetrahydrofuran, 5.5 mmoles) potassium
tert-butoxide was added drop for drop over 5 minutes. The mix-
ture was warmed to room temperature over 30 minutes, and then
cooled to –50 °C. Within 4 minutes 0.94 ml (6.5 mmoles)
diethylchlorophosphate was added into the flask, then the solu-
tion was warmed to –30 °C over 1 hour and finally to room tem-
perature over 30 minutes. Afterwards it was cooled again to –78
°C and 0.69 ml (6.0 mmoles) corresponding isocyanide was
added. Within 10 minutes 6 ml (1.0 M in tetrahydrofuran, 6.0
mmoles) potassium tert-butoxide was added drop by drop to the
mixture. The solution was allowed to warm to –20 °C over 1 hour
3-(7-Benzyl-4H-imidazo[1,5-d]thieno[2,3-b][1,4]thiazine-3-yl)-
5-cyclopropyl-1,2,4-oxadiazole (4).
Prepared from 1 (1.83 g, 7 mmoles). After crystallization from
1
ethanol 1.29 g (47%) 4 was obtained, mp 172 °C; H nmr (deu-
teriochloroform): δ 7.81 (s, 1H, imidazole-H), 7.40-7.17 (m, 5H,
phenyl-H), 6.90 (s, 1H, thiophene-H), 4.45 (s, 2H, benzyl-CH ),
2
4.10 (s, 2H, S-CH ), 2.28-2.19 (m, 1H, cylcopropyl-CH), 1.40-
2
13
1.17 (m, 4H, cyclopropyl-CH ); C nmr (deuteriochloroform): δ
2
181.7, 164.0, 143.5, 138.7, 131.1, 128.7, 128.5, 127.0, 124.4,
+
123.6, 117.1, 115.7, 36.3, 24.7, 10.1, 7.6; ms: m/z 392 (M ), 323,
+
+
220, 154, 115, 91 (tropylium ), 77 (phenylium ), 69, 45 (100%).
Anal. Calcd. for C N OS : C, 61.20; H, 4.11; N, 14.27.
H
20 16
4
2
Found: C, 61.33; H, 4.27; N, 14.04.

Jul-Aug 2002
Studies on the Chemistry of Thienoannelated O,N- and S,N-Containing Heterocycles
647
3-(7-Benzyl-4H-imidazo[1,5-d]thieno[2,3-b][1,4]thiazine-3-yl)-
5-isopropyl-1,2,4-oxadiazole (5).
(deuteriochloroform): δ 7.83 (s, 1H, imidazole-H), 7.41-7.16 (m,
5H, phenyl-H), 6.92 (s, 1H, thiophene-H), 4.48 (s, 2H, benzyl-
13
CH ), 4.09 (s, 2H, S-CH ), 1.46 (s, 9H, tert-butyl-H); C nmr
2
2
Prepared from 1 (1.31 g, 5 mmoles). After crystallisation from
(deuteriochloroform): δ 185.9, 163.8, 143.4, 138.6, 131.0, 128.7,
1
diluted ethanol 0.651 g (33%) 5 was obtained, mp 135 °C; H
128.4, 126.9, 124.4, 123.5, 117.1, 115.7, 36.2, 33.5, 28.3, 24.7;
nmr (deuteriochloroform): δ 7.83 (s, 1H, imidazole-H), 7.40-7.17
(m, 5H, J = 7.05, phenyl-H), 6.91 (s, 1H, thiophene-H), 4.48 (s,
+
+
ms: m/z 408 (M ), 323, 261, 232, 115, 91 (tropylium ), 77
+
+
(phenylium ), 57 (tert-butylium ), 45 (100%).
Anal. Calcd. for C N OS : C, 61.74; H, 4.93; N, 13.71.
2H, benzyl-CH ), 4.09 (s, 2H, S-CH ), 3.27 (septett, 1H, J = 7.1
2
2
H
13
21 20
4
2
Hz, CH), 1.45 (d, 6H, J = 7.1 Hz, CH ); C nmr (deuteriochloro-
3
Found: C, 61.96; H, 5.00; N, 13.50.
form): δ 183.5, 163.9, 143.4, 138.6, 131.0, 128.7, 128.5, 126.9,
124.4, 123.5, 117.1, 115.7, 36.2, 27.3, 24.7, 20.0; ms: m/z 394
(M ), 323, 308, 154, 115, 91 (tropylium ), 77 (phenylium ), 69,
58 (100%), 45.
7-Benzyl-4H-imidazo[1,5-d]thieno[2,3-b][1,4]thiazine-3-car-
boxylic Acid (10).
+
+
+
A solution of 3 (2.00 g, 5.6 mmoles) in 55 ml absolute
ethanol and 22 ml 5% aqueous sodium hydroxide was refluxed
at 85 °C for 2 hours. The mixture was cooled to room tempera-
ture and the solvent was removed by evaporation. The residue
was suspended in 60 mL water, acidified with concentrated
hydrochloric acid and stirred for 1 hour at 10 °C. The precipi-
Anal. Calcd. for C
H N OS : C, 60.89; H, 4.60; N, 14.20.
20 18 4 2
Found: C, 60.93; H, 4.65; N, 13.99.
3-(7-Benzyl-4H-imidazo[1,5-d]thieno[2,3-b][1,4]thiazine-3-yl)-
5-phenyl-1,2,4-oxadiazole (6).
Prepared from 1 (1.31 g, 5 mmoles). After crystallization
tate was collected, washed with cold water and dried to yield
1
from ethanol 1.20 g (56%) 6 was obtained, mp 206 °C; H nmr
1
1.75 g (95%) 10, mp 204 °C; H nmr (dimethylsulfoxide-d ): δ
6
(dimethylsulfoxide-d ): δ 8.55 (s, 1H, imidazole-H), 8.31 (d,
6
8.34 (s, 1H, imidazole-H), 7.54 (s, 1H, thiophene-H), 7.46-
2H, J = 7.1 Hz, phenyl-H), 7.87-7.69 (m, 3H, phenyl-H), 7.62 (s,
1H, thiophene-H), 7.48-7.30 (m, 5H, phenyl-H), 4.80 (s, 2H,
7.24 (m, 5H, phenyl-H), 4.59 (s, 2H, benzyl-CH ), 4.20 (s, 2H,
2
13
S-CH ); C nmr (dimethylsulfoxide-d ): δ 164.2, 142.7,
+
2
6
benzyl-CH ), 4.25 (s, 2H, S-CH ); ms: m/z 408 (M ), 323, 308,
2
2
139.4, 131.2, 128.5, 128.4, 128.2, 127.1, 126.6, 117.2, 116.0,
+
+
282,154, 115, 105 (C H -CO ), 91 (tropylium ), 77
6
5
+
35.4, 24.4;ms: m/z 328 (M ), 282 (100%), 230, 171, 154, 115,
+
(phenylium , 100%), 45.
Anal. Calcd. for C
+
+
91 (tropylium ), 77 (phenylium ), 69, 45.
Anal. Calcd. for C N O S x 0.5 H O: C, 56.96; H, 3.88;
H
N OS : C, 64.47; H, 3.76; N, 13.07.
4 2
23 16
H
16 12
2
2
2
2
Found: C, 64.21; H, 3.85; N, 12.87.
N, 8.30. Found: C, 56.87; H, 3.81; N, 8.22.
3-(7-Benzyl-4H-imidazo[1,5-d]thieno[2,3-b][1,4]thiazine-3-yl)-
5-cyclohexyl-1,2,4-oxadiazole (7).
Methyl 2-{[(7-Benzyl-4H-imidazo[1,5-d]thieno[2,3-b][1,4]-
thiazine-3yl)carbonyl]amino}-3-hydroxypropanoate (11).
Prepared from 1 (1.31 g, 5 mmoles). After crystallization from
1
Compound 10 (1.90 g, 5.8 mmoles) was suspended in 30 ml
absolute N,N-dimethylformamide under argon atmosphere. Then
carbonyldiimidazole (1.033 g, 6.3 mmoles) was added and the
mixture was stirred for 1 hour at room temperature, then another
2 hours at 55 °C. After cooling the suspension to 0-5 °C (0.99 g,
7.1 mmoles) D,L-serinemethylester hydrochloride and absolute
triethylamine (0.89 ml, 6.4 mmoles) was added and stirred for 96
hours at room temperature. The solvent was evaporated, and the
residue was dissolved in hot water and extracted with ethylac-
etate. The oily product was purified by column with ethylacetate
ethanol 1.00 g (46%) 7 was obtained, mp 147 °C; H nmr (deuterio-
chloroform): δ 7.82 (s, 1H, imidazole-H), 7.39-7.18 (m, 5H,
phenyl-H), 6.91 (s, 1H, thiophene-H), 4.47 (s, 2H, benzyl-CH ),
2
4.09 (s, 2H, S-CH ), 3.03-2.93 (m, 1H, cyclohexyl-CH), 2.15-1.16
2
13
(m, 10H, cyclohexyl-CH ); C nmr (deuteriochloroform): δ 182.5,
2
163.7, 143.4, 138.6, 131.0, 128.6, 128.4, 126.9, 124.4, 123.5, 117.0,
+
115.7, 36.2, 36.1, 30.0, 25.3, 25.2, 24.6; ms: m/z 434 (M ), 323,
+
+
261, 184, 154, 127, 91 (tropylium ), 83 (cyclohexylium ), 77
+
+
(phenylium ), 68 (oxydiazolylium ), 55, 45 (100%).
Anal. Calcd. for C N OS : C, 63.57; H, 5.10; N, 12.89.
H
23 22
4
2
1
to obtain 1.49 g (60%) 11, mp 56 °C; H nmr (deuteriochloro-
Found: C, 63.47; H, 5.32; N 12.66.
form): δ 7.91 (d, J = 7.9, 1H, NH), 7.59 (s, 1H, imidazole-H),
7.40-7.17 (m, 5H, phenyl-H), 6.79 (s, 1H, thiophene-H), 4.87-
3-(7-Benzyl-4H-imidazo[1,5-d]thieno[2,3-b][1,4]thiazine-3-yl)-
5-ethyl-1,2,4-oxadiazole (8).
4.73 (m, 1H, CH), 4.43 (s, 2H, benzyl-CH ), 4.33 (s, 1H, OH),
2
4.12 (m, 2H, CH -OH), 4.05 (s, 2H, S-CH ), 3.77 (s, 3H,
Prepared from 1 (1.31 g, 5 mmoles). After crystallization from
diluted ethanol 1.10 g (58%) 8 was obtained, mp 155 °C; H nmr
(deuteriochloroform): δ 7.83 (s, 1H, imidazole-H), 7.40-7.18 (m,
5H, phenyl-H), 6.91 (s, 1H, thiophene-H), 4.47 (s, 2H, benzyl-
2
2
13
1
COOCH ); C nmr (deuteriochloroform): δ 170.8, 162.2, 143.4,
3
138.7, 130.6, 128.7, 128.5, 127.0, 125.8, 117.7, 115.6, 63.1, 54.4,
+
52.6, 36.22, 24.4; ms: m/z 429 (M ), 310, 282 (100%), 230, 171,
+
+
154, 115, 91 (tropylium ), 77 (phenylium ), 69, 57.
Anal. Calcd. for C N O S : C, 55.93; H, 4.46; N, 9.78.
CH ), 4.09 (s, 2H, S-CH ), 2.95 (q, 2H, J = 7.7, CH ), 1.43 (t,
2
2
2
13
H
3H, J = 7.7, CH ); C nmr (deuteriochloroform): δ 180.3, 163.9,
20 19
3 4 2
3
Found: C, 55.63; H, 4.33; N, 9.49.
143.4, 138.6, 131.0, 128.6, 128.4, 126.9, 124.3, 123.5, 117.0,
+
115.7, 36.2,24.6, 20.1, 10.6; ms: m/z 380 (M ), 323, 310, 282,
Methyl 2-(7-Benzyl-4H-imidazo[1,5-d]thieno[2,3-b][1,4]-
thiazine-3yl)-4,5-dihydro-1,3-oxazole-4-carboxylate (12).
+
+
154, 115, 91 (tropylium ), 77 (phenylium ), 57, 45 (100%).
Anal. Calcd. for C N OS : C, 59.98; H, 4.24; N, 14.73.
H
19 16
4
2
A solution of 11 (0.816 g, 1.9 mmoles) in 10 ml absolute
tetrahydrofurane was mixed with (methoxycarbonylsulfamoyl)-
triethylammonium hydroxide, inner salt (Burgess Reagent)
(0.500 g, 2.1 mmoles) under an argon atmosphere and refluxed
for 1 hour. The mixture was cooled to room temperature and the
solvent was evaporated. The oily residue was dissolved in
Found: C, 60.02; H, 4.40; N, 14.54.
3-(7-Benzyl-4H-imidazo[1,5-d]thieno[2,3-b][1,4]thiazine-3-yl)-
5-tert-butyl-1,2,4-oxadiazole (9).
Prepared from 1 (1.31 g, 5 mmoles). After crystallization from
diluted ethanol 1.49 g (73%) 9 was obtained, mp 146 °C; H nmr
1

648
T. Erker and N. Handler
Vol. 39
dichloromethane and separated by column chromatography (sil-
ica gel, ethylacetate/ethanol 9+1). If necessary the product can be
recrystallized from ethanol to yield 0.368 g (47%) 12, mp 157
°C; H nmr (deuteriochloroform): δ 7.73 (s, 1H, imidazole-H),
7.40-7.20 (m, 5H, phenyl-H), 6.88 (s, 1H, thiophene-H), 4.99-
Anal. Calcd. for C H N O S : C, 58.66; H, 3.69; N, 10.26.
20 15 3 3 2
Found: C, 58.83; H, 3.84; N 10.01.
REFERENCES AND NOTES
Author to whom correspondence should be sent:
1
4.86 (m, 1H, N-CH), 4.71-4.50 (m, 2H, CH ), 4.43 (s, 2H, ben-
2
*
13
zyl-CH ), 4.08 (s, 2H, S-CH ), 3.78 (s, 3H, OCH ); C nmr
2
2
3
thomas.erker@univie.ac.at
[1] Part 23: M. E. Galanski, N. Böhler, and T. Erker, Sci.
Pharm., 69, 321 (2001).
(deuteriochloroform): δ 171.5, 161.7, 143.4, 138.6, 128.7, 128.4,
126.9, 125.8, 124.4, 117.3, 115.6, 69.0, 68.3, 52.5, 36.2, 24.7;
+
+
ms: m/z 411 (M ), 310, 282, 230, 171, 154, 115, 91 (tropylium ),
[2] D. Armenise, G. Trapani, V. Arrivo, E. Laraspata, and F.
Morlacchi, J. Heterocyclic Chem., 37,1611 (2000).
[3] J. R. De Vita, W. R. Schoen, G. A: Doldouras, M. H.
Fisher, M. J. Wyvratt, K. Cheng, W. W.-S. Chan, B. S. Bridget, and
R. G. Smith, Bioorg. Med. Chem. Lett., 5, 1281 (1995).
[4] T. Yaegashi, H. Nishiyama, T. Itsumi, and S. Sawada,
Japan Patent 99-295214; Chem. Abstr., 134, 288850 (2001).
[5] F. Waetjen and M. Engelstoft, EP 220845, Chem. Abstr.,
105, 515590 (1987).
[6] R. I. Fryer, R. F. Lauer, E. J. Trybulski, s. Vittone, A.
Walser, and G. Zenchoff, , J. Heterocyclic Chem., 20,1605 (1983).
[7] S. Gronowitz, Thiophene and its Derivatives, Part I, John
Wiley and Sons, 1985.
+
77 (phenylium ), 57, 55 (100%).
Anal. Calcd. for C
H N O S : C, 58.38; H, 4.16; N, 10.21.
20 17 3 3 2
Found: C, 58.17; H, 4.22; N 10.02.
Methyl 2-(7-Benzyl-4H-imidazo[1,5-d]thieno[2,3-b][1,4]thi-
azine-3yl)-1,3-oxazole-4-carboxylate (13).
Under an argon atmosphere 12 (0.296 g, 0.72 mmol) in boiling
benzene was mixed with (0.133 g, 0.79 mmol) copper-(I)-bro-
mide and stirred for 5 minutes. Then tert-butylperbenzoate (0.21
g, 1.08 mmoles) was added drop by drop and then the solution
was refluxed for 1.5 hours. After cooling to room temperature 20
ml water was added and extracted with benzene. The organic
layer was evaporated and separated by column chromatography
[8] I. Puschmann and T. Erker, Monatsh. Chem., 126, 569
(1995).
1
(silica gel, ethylacetate) to give 32 mg (11%) 13; H nmr (deu-
[9] F. Watjen, R. Baker, M. Engelstoff, R. Herbert, A.
MacLeod, A. Knight, K. Merchant, J. Moseley, J. Saunders, C. J.
Swain, E. Wong, and J. P. Springer, J. Med. Chem., 32, 2282 (1989).
[10] P. Wipf and C. P. Miller, Tetrahedron Lett., 33, 907 (1992).
[11] A. I. Meyers and F. Tavares, Tetrahedron Lett., 35, 2481
(1994).
teriochloroform + dimethylsulfoxide-d ): δ 8.29 (s, 1H, oxazole-
6
H), 7.83 (s, 1H, imidazole-H), 7.37-7.26 (m, 5H, phenyl-H), 6.92
(s, 1H, thiophene-H), 4.58 (s, 2H, benzyl-CH ), 4.12 (s, 2H,
2
+
S-CH ), 3.92 (s, 3H, OCH ); ms: m/z 409 (M ), 347, 287, 259,
2
3
+
154, 122, 105 (100%), 77 (phenylium ), 69, 57, 51, 45.