Synthesis of imidazo[2,1-b][2H-1,3,4]thiadiazines and 1,2,4-triazolo[3,4-b][2H-1,3,4]thiadiazines

Article abstract of DOI:10.1002/jhet.2074

Imidazo[2,1-b][2H-1,3,4]thiadiazines were prepared by cyclization of 2-amino-5-(4-chlorophenyl)-6H-1,3,4-thiadiazine with α-haloketones. 1,2,4-Triazolo[3,4-b][2H-1,3,4]thiadiazines were prepared by cyclization of 4-amino-5-sulfanyl-l,2,4-triazoles with ph

Full text of DOI:10.1002/jhet.2074

Month 2014
Synthesis of Imidazo[2,1-b][2H-1,3,4]thiadiazines and
1,2,4-Triazolo[3,4-b][2H-1,3,4]thiadiazines
Stefanie Knak, Wolf-Diethard Pfeiffer, Horst Dollinger, Ashot S. Saghyan, and Peter Langere,f
a
a
b
c,d
*
*
aInstitut für Biochemie, Universität Greifswald, Felix-Hausdorff-Str. 4, 17487 Greifswald, Germany
bBoehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Straße 65, 88397 Biberach/Riss, Germany
cScientific and Production Center “Armbiotechnology” of NAS RA, 14 Gyurjyan Str., 0056 Yerevan, Armenia
dDepartment of Pharmaceutical Chemistry, Yerevan State University, Alex Manoogian Str. 1, 0025 Yerevan, Armenia
eInstitut für Chemie, Universität Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany
fLeibniz-Institut für Katalyse e. V. an der Universität Rostock, Albert-Einstein-Str. 29a, 18059 Rostock, Germany
*
E-mail: wdpfeiffer@googlemail.com and peter.langer@uni-rostock.de
Received March 6, 2013
DOI 10.1002/jhet.2074
Published online 00 Moth 2014 in Wiley Online Library (wileyonlinelibrary.com).
Imidazo[2,1-b][2H-1,3,4]thiadiazines were prepared by cyclization of 2-amino-5-(4-chlorophenyl)-6H-
1,3,4-thiadiazine with α-haloketones. 1,2,4-Triazolo[3,4-b][2H-1,3,4]thiadiazines were prepared by cyclization
of 4-amino-5-sulfanyl-l,2,4-triazoles with phenacyl bromides.
J. Heterocyclic Chem., 00, 00 (2014).
INTRODUCTION
thiadiazines. In preliminary studies, we reported the synthe-
sis of related heterocycles [17l,m]. However, the substitution
pattern was different, and no spectroscopic data were
provided (because of the lack of instruments at that time).
1,3,4-Thiadiazines are of considerable biochemical and
pharmacological relevance. Several 2-amino-1,3,4-thiadiazine
derivatives are important matrix metalloproteinase inhibitors
[1,2]. 2-Alkylimino-1,3,4-thiadiazines and 2-alkyamino-
1,3,4-thiadiazines are used as cardiotonic and spasmolytic
agents [3–8]. 1,3,4-Thiadiazin-2-ones are cardiotonics with
calcium sensitizing activity[9–11]. 3-Phenylazo-1H-4,2,1-
thiadiazine is an agent for the treatment of deficient bone
growth[12]. 3-Nitrobenzyl-5-aryl-1,3,4-thiadiazin-2-ones and
1,3,4-thiadiazin-2-ones are phospho-diesterase IV inhibitors
that can be used for the treatment of tumors and AIDS
[13,14]. 2-Nitrosimino-3,6-dihydro-2H-1,3,4-thiadiazines
[15], N-morpholinyl-1,3,4-thiadiazines, N-thiomorpholinyl-
1,3,4-thiadiazines or N-piperidinyl-1,3,4-thiadiazines [16]
exhibit antithrombotic activities. In continuation of our work
related to the synthesis and reactivity of 1,3,4-thiadiazines
[17], we herein report the synthesis of imidazo[2,1-b]
[2H-1,3,4]thiadiazines and 1,2,4-triazolo[3,4-b][2H-1,3,4]
RESULTS AND DISCUSSION
2-Amino-5-(4-chlorophenyl)-1,3,4-thiadiazine (1a) was
prepared in weakly acidic medium from 4-chlorophenacyl
bromide and thiosemicarbazide. The cyclization of 1a with
α-haloketones afforded the imidazo[2,1-b][2H-1,3,4]
thiadiazines 2a–i (reflux, 8 h, EtOH). After reflux for 4 h,
hydrobromic acid (48%) was added, which supported
the cyclocondensation. The products crystallized from the
reaction mixture in the form of their hydrobromides.
The free bases were obtained by addition of ammonia to
an EtOH solution of the hydrobromides (Scheme 1).
The structures of bicycles 2a–i were confirmed by spec-
1
troscopic methods. The H nmr spectra (DMSO-d6) of the
hydrobromides of 2a–e,g,h exhibit signals of a CH2 group,
© 2014 HeteroCorporation

S. Knak, W.-D. Pfeiffer, H. Dollinger, A. S. Saghyan, and P. Langer
Vol 000
Scheme 1. Synthesis of imidazo[2,1-b][2H-1,3,4]thiadiazines 2a–i.
Scheme 3. Synthesis of l,2,4-triazolo[3,4-b][2H-1,3,4]thiadiazines 3a–c.
which prove that the molecules exist in their 2H tautomeric
form. Although the hydrobromides are rather stable, the
free bases turn from yellow to red in sunlight (Table 1).
The synthesis of 1,2,4-triazolo-[3,4-b][2H-1,3,4]
thiadiazines was next studied. However, our initial at-
tempts were unsuccessful. The reaction of 2-hydrazino-
5,6-diphenyl-1,3,4-thiadiazine (1b) with trimethyl
orthoformate did not result in the formation of the expected
1,2,4-triazolo-[3,4-b][2H-1,3,4]thiadiazine 3a. Under the
conditions employed, this product proved to be unstable
Table 2
Synthesis of l,2,4-triazolo[3,4-b][2H-1,3,4]thiadiazines 3a–c.
Yield (%)a
R1
R2
R3
3
3a
3b
3c
C6H5
H
H
C6H5
4-FC6H4
4-FC6H4
H
H
CH3
85
95
87
aYields of isolated products.
and underwent
a desulfurization reaction to give
pyrazole 4 (Scheme 2). This type of desulfurization
was previously observed for various other 1,3,4-thiadiazine
derivatives [17].
The synthesis of 3a was finally achieved by cyclization
of 2-bromo-1,2-diphenylethan-1-one with 4-amino-5-
sulfanyl-l,2,4-triazole 5a [18] (Scheme 3, Table 2). The
structure of 3a was independently confirmed by X-ray
crystal structure analysis (Fig. 1). Inspection of the crystal
Table 1
Yields of imidazo-2H-[2,1-b][1,3,4]thiadiazines 2a–i.
Figure 1. Ortep plot of 3a [21].
Yield (%)a
Yield (%)a
R1
R2
2·HBr
2
2a
2b
2c
2d
2e
2f
2g
2h
2i
H
H
H
H
H
H
H
C6H5
70
71
65
74
73
—
72
71
—
68
67
61
72
71
70b
71
71
68b
4-BrC6H4
4-ClC6H4
4-FC6H4
4-MeC6H4
4-(MeO)C6H4
4-(NO2)C6H4
C6H5
structure shows that 3a exists in a twisted boat conforma-
tion. Likewise, products 3b,c were prepared by cyclization
of 4-amino-5-sulfanyl-l,2,4-triazole 5a or 4-amino-3-
methyl-5-sulfanyl-l,2,4-triazole 5b [18] with substituted
phenacyl bromides. According to the nmr spectra, the
compounds exist in their 2H tautomeric form. Compounds
3a–c are very stable and, in contrast to simple monocyclic
1,3,4-thiadiazines [17], did not undergo desulfurization by
reaction with triphenylphosphane or by reflux in glacial
acetic acid. Monocyclic 6H-l,3,4-thiadiazines, which are
known to be readily desulfurized, rapidly underwent a deu-
terium exchange of the protons located at position 6 [19]. In
contrast, l,2,4-triazolo[3,4-b][2H-1,3,4]thiadiazines 3a–c
were not deuterated at position 2, not even in the presence
of D2SO4 for several days. The formation of 2-(4-
nitrobenzylidene) derivatives of 3b,c, in analogy to 2-
dialkylamino-1,3,4-thiadiazines[20], was not observed.
In conclusion, we have reported the synthesis of a variety
of imidazo[2,1-b][2H-1,3,4]thiadiazines 2a–i by cyclization
C6H5
CH3
C6H5
aYields of isolated products.
b2f and 2i were immediately converted to their free bases.
Scheme 2. Attempted synthesis of 3a.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
Synthesis of Imidazo[2,1-b][2H-1,3,4]thiadiazines and
1,2,4-Triazolo[3,4-b][2H-1,3,4]thiadiazines
(23), 160 (14), 188 (32), 195 (4), 290 (M+, 1). Anal. Calcd. for
C17H12ClN3S (325.82): C, 62.67; H, 3.71; N, 12.90. Found: C,
62.89; H, 3.70; N, 12.41.
of 2-amino-5-(4-chlorophenyl)-6H-1,3,4-thiadiazine 1a with
α-haloketones. Whereas the reaction 2-hydrazino-5,6-
diphenyl-1,3,4-thiadiazine with trimethyl orthoformate
resulted in desulfurization, 1,2,4-triazolo[3,4-b][2H-1,3,4]
thiadiazines 3a were prepared by cyclization of 4-amino-5-
sulfanyl-l,2,4-triazoles 5a with 2-bromo-1,2-diphenylethan-
1-one.
3-(4-Chlorophenyl)-7-(4-bromophenyl)-imidazo[2,1-b][2H-1,
3,4]thiadiazine (2b).
Hydrobromide: Starting from 2.26 g
(10 mmoles) of 1a and 2.78 g (10 mmoles) of 4-bromophenacyl
bromide. Yield: 3.45 g (71%), yellow prisms (EtOH), mp 191 °
C; ir (KBr, cmÀ1): 1595 (m), 1464 (m), 1404 (m), 1366 (m),
1285 (m), 1169 (m), 1132 (m), 1091 (m), 1070 (m), 1009 (m),
1
841 (m), 811 (m), 750 (m); H nmr (CDCl3, 300 MHz): δ = 3.98
(s, 2H, 2-CH2), 7.46–7.82 (m, 9H, ArH and H-Hetar); 13C nmr
(DMSO-d6, 50 MHz): δ = 23.38 (2-C, Hetar), 117.01 (6-C,
Hetar), 126.13 (ArH), 127.60 (ArH), 128.69 (ArH), 131.17
(ArH), 132.14 (Ar), 132.48 (Ar), 133.01 (Ar), 135.92 (Ar), 137
(7-C, Hetar), 150.94 (8a-C, Hetar), 151.55 (3-C, Hetar); ms (EI,
70 eV): m/z (%) = 28 (100), 45 (24), 75 (18), 137 (9), 159 (2),
187 (17), 266 (1), 404 (M+, 21). Anal. Calcd. for C17H12Br2Cl
N3S (485.62): C, 42.05; H, 2.49; N, 8.65. Found: C, 42.05; H,
2.49; N, 8.67. Free base: Yield: 2.71 g (67%), yellow prisms
(EtOH), mp 188 °C, ir (KBr, cmÀ1): 1595 (m), 1465 (s), 1404
(m), 1366 (m), 1285 (m), 1169 (m), 1132 (m), 1091 (m), 1070
(m), 1009 (m), 842 (m), 826 (m), 810 (m), 750 (m); 1H nmr
(CDCl3, 300 MHz): δ = 3.99 (s, 2H, 2-CH2), 7.45–9.34 (m, 9H,
ArH and H-Hetar); 13C nmr (CDCl3, 50 MHz): δ = 24.33 (2-C,
Hetar), 116.30 (6-C, Hetar), 121.04 (Ar), 126.32 (ArH), 128
(ArH), 129 (ArH), 131.74 (ArH), 132.03 (Ar), 132.54 (Ar),
137.67 (7-C, Hetar), 139.22 (8a-C, Hetar), 149.26 (3-C, Hetar);
ms (EI, 70 eV): m/z (%) = 28 (59), 44 (10), 101 (27), 137 (14),
155 (4), 187 (59), 238 (1), 266 (7), 343 (4), 359 (2), 405 (M+,
100). Anal. Calcd. for C17H11Br Cl N3S (404,71): C, 50.45; H,
2.74; N, 10.38. Found: C, 50.49; H, 2.74; N, 10.39.
EXPERIMENTAL
2-Amino-5-(4-chlorphenyl)-6H-1,3,4-thiadiazine (1a). Free
base: A mixture of 3.64 g (40 mmoles) of thiosemicarbazide and
4.68 g (40mmoles) of 4-chloro-phenacylbromide in 40mL
ethanol and 8 mL of aq. HBr (48%) was refluxed for 30min. The
precipitated hydrobromide was recrystallized from water. The free
base was obtained by addition of an aqueous solution of ammonia
to the ethanolic solution of the hydrobromide. A precipitate
formed, which was then filtered off. Yield: 2.12 g (94%), yellow
prisms (ethanol), mp 136 °C; ir (KBr, cmÀ1): 3471 (s), 3250 (m),
3075 (m), 1614 (s), 1515 (s), 1490 (m), 1410 (m), 1340 (m), 1318
(m), 1094 (m), 1094 (m), 1009 (m), 816 (m); 1H nmr (DMSO-d6,
300 MHz): δ = 1.03 (s, 2H, NH2), 4.29 (s, 2H, 2-CH2), 7.62–7.94
(m, 4H, ArH); ms (EI, 70 eV): m/z (%) = 28 (90), 51 (23),
60 (82), 77 (7), 102 (62), 117 (4), 137 (100), 162 (4), 185
(16), 196 (7), 225 (M+, 42). Anal. Calcd. for C9H8ClN3S
(225.7): C, 47.89; H, 3.57; N, 18.62. Found: C, 47.91; H,
3.5; 8 N, 18.65.
General procedure for the synthesis of 3-chlorophenyl-7-aryl-
imidazo[2,1-b][2H-1,3,4]thiadiazines (2a–i).
Hydrobromides:
A mixture of 2.26 g (10 mmoles) of 1a and 10 mmoles of
α-haloketones in 15 mL of ethanol was refluxed for 8 h.
After 4 h, 1 mL of aq. HBr (48%) was added. After a short period,
the precipitated hydrobromide was isolated by filtration. The
hydrobromide was dissolved in boiling ethanol. The pure
hydrobromide precipitated when the mixture was added dropwise
to ether. Free bases: The free bases were obtained from the
ethanol solution of the hydrobromides by addition of a diluted
aqueous solution of ammonia until pH8 was reached. A
precipitate formed, which was then filtered off and recrystallized
from ethanol.
3.7-(4-Dichlorophenyl)-imidazo[2,1-b][2H-1,3,4]thiadiazine
(2c). Hydrobromide: Starting from 2.26 g (10 mmoles) of 1a
and 2.34 g (10 mmoles) of 4-chlorophenacyl bromide. Yield:
2.87g (65%), yellow prisms (EtOH), mp 191 °C; ir (KBr, cmÀ1):
1598 (m), 1483 (s), 1465 (s), 1407 (m), 1366 (m), 1309 (m), 1286
(m), 1171 (m), 1133 (m), 1091 (s), 1010 (m), 843 (m), 809 (m),
750 (m); 1H nmr (CDCl3, 300 MHz): δ = 3.98 (s, 2H, 2-CH2),
7.34–7.83 (m, 9H, ArH und H-Hetar); 13C nmr (DMSO-d6,
50MHz): δ = 23.44 (2-C, Hetar), 117.29 (6-C, Hetar), 125.99
(ArH), 128.55 (ArH), 128.92 (ArH), 128.95 (ArH), 131.42 (Ar),
131.53 (Ar), 132.52 (Ar), 133.39 (Ar), 136.19 (7-C, Hetar),
137.16 (8a-C, Hetar), 151.42 (3-C, Hetar); ms (EI, 70 eV):
m/z (%) = 28 (3), 58 (1), 75 (8), 102 (19), 137 (45), 162
(10), 187 (100), 222 (54), 324 (4), 359 (M+, 20). Anal. Calcd. for
C17H12Br Cl2N3S (441,17): C, 46.28 H, 2.74 N, 9.52. Found: C,
46.32 H, 2.75 N, 9.51. Free base: Yield: 2.20 g (61%), yellow
prisms (EtOH), mp 198 °C; ir (KBr, cmÀ1): 1598 (m), 1482 (s),
1463 (s), 1407 (m), 1366 (m), 1285 (m), 1168 (m), 1132 (m),
3-(4-Chlorophenyl)-7-phenyl-imidazo[2,1-b][2H-1,3,4]thiadiazine
(2a). Hydrobromide: Starting from 2.26 g (10 mmoles) of 1a and
1.99 g (10mmoles) of phenacyl bromide. Yield: 2.85g (70%),
yellow prisms (EtOH), mp 173 °C, ir (KBr, cmÀ1): 1594 (m),
1488 (m), 1468 (m), 1442 (m), 1405 (m), 1362 (m), 1169 (m),
1094 (m), 814 (m), 747 (s), 690 (m); 1H nmr (CDCl3, 300 MHz):
δ = 3.97 (s, 2H, 2-CH2), 7.36–8.03 (m, 10H, ArH und H-Hetar);
ms (EI, 70eV): m/z (%) = 28 (100), 91 (10), 102 (7), 160 (2), 187
(9), 271 (3), 325 (M+, 49), 405 (1). Anal. Calcd. for
C17H13BrClN3S (406.73): C, 50.20 H, 3.22 N, 10.33. Found: C,
50.31 H, 3.21 N, 10.35. Free base: Yield: 2.22 g (68%), yellow
prisms (EtOH), mp 172 °C; ir (KBr, cmÀ1): 1595 (m), 1488 (m),
1468 (m), 1442 (m), 1405 (m), 1362 (m), 1169 (m), 1094 (m),
1
1090 (s), 1011 (m), 841 (m), 813 (m), 751 (m). H nmr (CDCl3,
300 MHz): δ = 4.01 (s, 2H, 2-CH2), 7.35–9.34 (m, 9H, ArH und
H-Hetar). 13C nmr (CDCl3, 50 MHz): δ = 24.31 (2-C, Hetar),
116.24 (6-C, Hetar), 126.00 (ArH), 128.20 (ArH), 128.80 (ArH),
129.24 (ArH), 131.55 (Ar), 132.52 (Ar), 132.92 (Ar), 137.65
(7-c, Hetar), 139 (8a-C, Hetar), 149.23 (3-C, Hetar); ms (EI,
70eV): m/z (%)= 28 (100), 32 (26), 70 (1), 101 (3), 155 (2), 359
(M+, 66). Anal. Calcd. for C17H11Cl2N3S (360.26): C, 56.68; H,
3.08; N, 11.66. Found: C, 56.85; H, 3.09; N, 11.69.
1
849 (m), 814 (m), 747 (s), 691 (m); H nmr (CDCl3, 300 MHz):
δ = 3.99 (s, 2H, 2-CH2), 7.30–7.84 (m, 10H, ArH und H-Hetar);
13C nmr (CDCl3, 50 MHz): δ = 24.29 (2-CH2, Hetar), 116.09
(6-C, Hetar), 124.74 (ArH), 127.33 (ArH), 128.18 (ArH),
128.62 (ArH), 129.23 (ArH), 132.53 (Ar), 132.60 (Ar), 132.96
(Ar), 137.48 (7-C, Hetar), 140 (8a-C, Hetar), 149.02 (3-C,
Hetar); ms (EI, 70 eV): m/z (%) = 28 (18), 76 (9), 102 (26), 116
3-(4-Chlorophenyl)-7-(4-fluorophenyl)-imidazo[2,1-b][2H-1,
3,4]thiadiazine (2d).
Hydrobromide: Starting from 2.26 g
(10 mmoles) of 1a and 2.17 g (10 mmoles) of 4-fluorophenacyl
bromide. Yield: 3.15 g (74%), yellow needles (EtOH), mp 201 °
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

S. Knak, W.-D. Pfeiffer, H. Dollinger, A. S. Saghyan, and P. Langer
Vol 000
C; ir (KBr, cmÀ1): 1497 (m), 1464 (m), 1412 (m), 1365 (m), 1222
(m), 1158 (m), 1090 (m), 1009 (m), 843 (m), 810 (m), 749 (m).
1H nmr (CDCl3, 300 MHz): δ = 3.98 (s, 2H, 2-CH2), 7.05–7.83
(m, 9H, ArH and H-Hetar); 13C nmr (DMSO-d6, 50 MHz):
δ = 23.54 (2-C, Hetar), 115.13 (6-C, Hetar), 127.89 (ArH),
128.05 (ArH), 128.96 (ArH), 129.03 (ArH), 132.29 (Ar),
132.53 (Ar), 135.19 (Ar), 136.19 (Ar), 136.42 (7-C, Hetar),
151.58 (8a-C, Hetar), 163.91 (3-C, Hetar); ms (EI, 70 eV): m/z
(%) = 28 (100), 32 (20), 75 (9), 120 (15), 134 (84), 179 (21),
206 (59), 308 (3), 342 (M+, 63). Anal. Calcd. for
C17H11BrClFN3S (424.72): C, 48.07; H. 2.85; N, 9.80. Found:
C, 48.07; H, 2.84; N, 9.91. Free base: Yield: 2,48 g (72%),
yellow needles (EtOH), mp 180 °C; ir (KBr, cmÀ1): 1561 (m),
1495 (m), 1463 (m), 1410 (m), 1363 (m), 1340 (m), 1292 (m),
of 1a and 2.44 g (10mmoles) of 4-nitrophenacyl bromide. Yield:
3.25g (72%), yellow prisms (EtOH), mp 257 °C; ir (KBr, cmÀ1):
3434 (m), 1599 (s), 1556 (m), 1511 (s), 1464 (m), 1340 (s), 1286
1
(m), 1172 (m), 1110 (m), 1091 (m), 856 (m), 745 (m) H nmr
(CDCl3, 300 MHz): δ = 3.65 (s, 2H, 2-CH2), 7.19–8.37 (m, 9H,
ArH and H-Hetar), ms (EI, 70eV): m/z (%) = 28 (16), 51 (5), 76
(15), 101 (22), 137 (24), 159 (5), 187 (13), 233 (30), 335 (3), 340
(4), 370 (M+, 100). Anal. Calcd. for C17H12BrClN4O2S (451.73):
C, 45.20; H, 2.68; N, 12.40. Found: C, 45.19; H, 2.67; N, 12.40.
Free base: Yield: 2.63g (71%), yellow prisms (EtOH), mp 253°
C; ir (KBr, cmÀ1): 3431 (m), 1599 (s), 1511 (m), 1464 (m), 1410
(m), 1374 (m), 1339 (s), 1285 (m), 1172 (m), 1110 (m), 1092 (m),
856 (m), 744 (m); 1H nmr (DMSO-d6, 300MHz): δ = 4.44 (s, 2H,
2-CH2), 7.64À8.58 (m, 9H, ArH and H-Hetar); 13C nmr (CDCl3,
50 MHz): δ = 24.29 (2-C, Hetar), 118.35 (6-C, Hetar), 124.23
(ArH), 125.01 (ArH), 128.23 (ArH), 129.39 (ArH), 137.5 (Ar),
134.2 (Ar), 137.98 (7-C, Hetar), 146.5 (8a-C, Hetar), 150.14 (3-C,
Hetar); ms (EI, 70eV): m/z (%) = 28 (49), 45 (15), 81 (32), 137
(37), 149 (10), 233 (17), 370 (M+, 100). Anal. Calcd. for
C17H11ClN4O2S (370.81): C, 55.06; H, 2.99; N, 15.11. Found: C,
55.05; H, 2.99; N, 15.10.
1
1222 (m), 1158 (m), 1091 (m), 843 (m), 811 (m), 750 (m); H
nmr (CDCl3, 300 MHz): δ = 3.99 (s, 2H, 2-CH2), 7.05–7.92
(m, 9H, ArH and H-Hetar); ms (EI, 70 eV): m/z (%) = 28 (51),
32 (10), 70 (2), 101 (14), 134 (1), 155 (3), 199 (1), 343 (M+, 100).
Anal. Calcd. for C17H11ClF N3S (343.81): C, 59.39; H, 3.22; N,
12.22. Found: C, 59.40; H, 3.22; N, 12.23.
3-(4-Chlorophenyl)-7-tolyl-imidazo[2,1-b][2H-1,3,4]thiadiazine
(2e). Hydrobromide: Starting from 2.26 g (10 mmoles) of 1a and
2.13 g (10 mmoles) of 4-methylphenacyl bromide. Yield: 3.07 g
(73%), yellow prisms (EtOH), mp 185°C; ir (KBr, cmÀ1): 3029
(m), 3983 (m), 2915 (m)2817 (m), 2694 (m), 2616 (m), 1591 (m),
3-(4-Chlorophenyl)-6,7-diphenyl-imidazo[2,1-b][2H-1,3,4]
thiadiazine (2h).
Hydrobromide: Starting from 2.26 g
(10 mmoles) of 1a and 2.75 g (10 mmoles) of 2-bromo-1,2-
diphenylethan-1-one. Yield: 3.43 g (71%), yellow needles (EtOH),
mp 207°C; ir (KBr, cmÀ1): 1602 (m), 1504 (m), 1492 (m), 1484
(m), 1459 (m), 1442 (m), 1337 (m), 1090 (m), 1010 (m), 846 (m),
1
1515 (s), 1493 (m), 1407 (m), 1348 (m), 1094 (m), 819 (s); H
nmr (DMSO-d6, 300 MHz): δ = 2.32 (s, 3H,Mc), 4.43 (s, 2H,
2-CH2), 7.21–8.27 (m, 9H, ArH and H-Hetar); ms (EI,
70 eV): m/z (%) = 29 (10), 43 (13), 91 (50), 120 (32), 147
(100), 194 (28), 210 (3), 300 (4), 340 (M+, 2). Anal. Calcd. for
C18H15BrClN3S (420.75): C, 51.38; H, 3.59; N, 9.99. Found: C,
51.48; H, 3.58; N, 9.97. Free base: Yield: 2.41g (71%), yellow
needles (EtOH), mp 195°C; ir (KBr, cmÀ1): 1594 (m), 1494 (m),
1464 (s), 1405 (s), 1364 (m), 1288 (m), 1168 (m), 1131 (m), 1094
(m), 1011 (m), 847 (m), 824 (s), 755 (s), 512 (m); 1H nmr
(CDCl3, 300 MHz): δ = 1.25 (s,3H, Mc), 4.00 (s, 2H, 2-CH2),
7.30–8.05 (m, 9H, ArH and H-Hetar); 13C nmr (CDCl3, 50MHz):
δ = 24.29 (3-C, Hetar), 115.64 (6-C, Hetar), 124.66 (ArH), 128.16
(ArH), 129.20 (ArH), 129.31 (ArH), 130.18 (Ar), 132.35 (Ar),
132.65 (Ar), 137.09 (Ar), 137.41 (7-C, Hetar), 140.28 (8a-C,
Hetar), 148.81 (3-C, Hetar); ms (EI, 70 eV): m/z (%)= 28 (15), 39
(2), 91 (74), 116 (13), 135 (14), 163 (8), 202 (17), 300 (5), 339
(M+, 100). Anal. Calcd. for C18H14ClN3S (339.84): C, 63.62; H,
4.15; N, 12.36. Found: C, 63.62; H, 4.1; 5 N, 12.37.
1
816 (m), 798 (m), 771 (m), 696 (s); H nmr (CDCl3, 300MHz):
δ = 3.98 (s, 2H, 2-CH2), 7.30–7.57 (m, 14H, ArH); ms (EI,
70eV): m/z (%) = 58 (2), 103 (25), 137 (21), 161 (21), 178 (50),
231 (19), 263 (68), 401 (M+, 100). Anal. Calcd. for
C23H17BrClN3S (482.82): C, 57.21; H, 3.55; N, 8.70. Found: C,
57.18; H, 3.54; N, 8.69. Free base: Yield: 2.85g (71%), yellow
needles (EtOH), mp 171 °C; ir (KBr, cmÀ1): 3428 (m), 1600 (m),
1487 (m), 1460 (m), 1442 (m), 1334 (m), 1307 (m), 1092 (m),
1
816 (m), 797 (m), 770 (m), 697 (m); H nmr (CDCl3, 300MHz):
δ = 3.98 (s, 2H, 2-CH2), 7.22–7.73 (m, 14H, ArH); 13C nmr
(DMSO-d6, 50 MHz): δ = 22.70 (2-C, Hetar), 126.51 (ArH),
126.88 (ArH), 128.14 (ArH), 128.23 (ArH), 128.30 (ArH), 128.74
(ArH), 128.91 (ArH), 130.05 (6-C, Hetar), 130.18 (Ar), 133.62
(Ar), 133.72 (Ar), 135.45 (7-C, Hetar), 135.93 (8a-C, Hetar),
150.75 (3-C, Hetar); ms (EI, 70eV): m/z (%) = 28 (100), 58 (4),
103 (7), 137 (2), 178 (7), 263 (10), 401/403 (M+, 53/17). Anal.
Calcd. for C23H16Cl N3S (401,91): C, 68.73; H, 4.01; N, 10.46.
Found: C, 68.75; H, 4.02; N, 10.47
3-(4-Chlorophenyl)-7-(4-methoxyphenyl)-imidazo[2,1-b][2H-
1.3.4]thiadiazine (2f).
Free base: Starting from 2.26 g
3-(4-Chlorophenyl)-6-methyl-7-phenyl-imidazo[2,1-b][2H-
(10 mmoles) of 1a and 2.29 g (10 mmoles) of 4-methoxyphenacyl
bromide. Yield: 2.49 g (70%), yellow prisms (EtOH), mp 198°C;
ir (KBr, cmÀ1): 3438 (m), 1613 (m), 1592 (m), 1564 (m), 1498
(m), 1459 (m), 1412 (m), 1365 (m), 1245 (m), 1175 (m), 1093
1,3,4]thiadiazine (2i).
Free base: Starting from 2.26 g
(10 mmoles) of 1a and 2.13 g (10 mmoles) of α-
bromopropiophenone. Yield: 2.31 g (68%), yellow prisms
(EtOH), mp 158°C; ir (KBr, cmÀ1): 3431 (m), 3170 (m), 1625
(m), 1600 (m), 1492 (m), 1465 (m), 1445 (m), 1405 (m), 1331 (s),
1091 (m), 1010 (m), 844 (m), 814 (m), 769 (m), 697 (m), 1H nmr
(CDCl3, 300MHz): δ = 2.57 (2s, 3H, Me), 3.95 (s, 2H, 2-CH2),
7.30–8.01 (m, 9H, ArH); 13C nmr (CDCl3, 50 MHz): δ = 9.89
(Me), 23.75 (2-C, Hetar), 125.37 (6-C, Hetar), 126.61 (ArH),
128.12 (ArH), 128.40 (ArH), 129.12 (ArH), 130.93 (Ar),
132.95 (Ar), 134.26 (Ar), 135.77 (7-C, Hetar), 137.20 (8a-C,
Hetar), 148.00 (3-C, Hetar); ms (EI, 70 eV): m/z (%) = 28 (24),
61 (45), 91 (69), 102 (38), 137 (95), 163 (8), 201 (25), 225
(45), 300 (6), 339 (M+, 100). Anal. Calcd. for C18H14Cl N3S
(339.84): C, 63.62; H, 4.15; N, 12.36. Found: C, 63.63; H,
4.15; N, 12.37.
1
(m), 1026 (m), 1015 (m), 836 (m); H nmr (CDCl3, 300 MHz):
δ = 3.89 (s, 3H, Mc), 3.98 (s, 2H, 2-CH2) 6.92–8.04 (m, 9H, ArH
and H-Hetar); 13C nmr (CDCl3, 50 MHz): δ = 24.31 (2-C, Hetar),
55.27 (OMe), 114.04 (6-C, Hetar), 114.04 (6-C, Hetar), 125.82
(ArH), 126.05 (ArH), 128.15 (ArH), 129.22 (ArH), 132.67 (Ar),
137.41 (Ar), 140.13 (7-C, Hetar), 148.67 (8a-C, Hetar), 159.03
(3-C, Hetar); ms (EI, 70eV): m/z (%)= 28 (33), 44 (14), 91 (100),
101 (3), 135 (26), 163 (16), 209 (1), 300 (8), 355 (M+, 45). Anal.
Calcd. for C18H14Cl N3OS (355,84): C, 60.75; H, 3.97; N, 11.81.
Found: C, 60.75; H, 3.97; N, 11.82.
3-(4-Chlorophenyl)-7-(4-nitrophenyl)-imidazo[2,1-b][2H-1,3,4]
thiadiazine (2g). Hydrobromide: Starting from 2.26 g (10 mmoles)
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
Synthesis of Imidazo[2,1-b][2H-1,3,4]thiadiazines and
1,2,4-Triazolo[3,4-b][2H-1,3,4]thiadiazines
[4] Pfeiffer, W. D.; Bulka, E.; Fermum, R. German East Patent
209 196, 1984; Chem Abstr 1984, 101, 191974.
[5] Pfeiffer, W. D.; Bulka, E. German East Patent 220 311, 1985;
Chem Abstr 1986, 104, 68891.
[6] Pfeiffer, W. D.; Bulka, E. German East Patent 280 760, 1990;
Chem. Abstr. 1991, 114, 81896.
[7] Pfeiffer, W. D.; Bulka, E. German East Patent 289 272, 1991;
Chem Abstr 1991, 115, 232298.
[8] Pfeiffer, W. D., Bulka, E. German East Patent 293 351, 1991;
Chem Abstr 1992, 116, 41490.
[9] Ravens, U.; Fluss, M. O.; Li, Qi.; Himmel, H. M.; Wettwer, E.;
Klockow, M.; Lues, I. Naunyn-Schmiedeberg's Arch Pharma 1997, 355,
733; Chem Abstr 1997, 127, 104094.
2,3-Diphenyl-1, 2, 4-triazolo[3,4-b][2H-1,3,4]thiadiazine (3a). Free
base: 1.16 g (10mmoles) of 4-amino-5-sulfanyl-l,2,4-triazole 5a
and 2-bromo-1,2-diphenylethan-1-one (2.72 g, 10mmoles) in
60mL of ethanol was first stirred for 1 h at 20°C. The mixture
was refluxed subsequently for 4 h. After cooling, a diluted
aqueous solution of ammonia was added until pH8 was reached,
and the precipitate was filtered. Yield: 2.48g (85%), colorless
lamella (ethanol). Anal. Calcd. for C16H12N4S (292.36): C, 65.73;
H, 4.14; N, 19.16. Found: C, 65.81; H, 4.23; N, 19.08.
3-(4-Fluorophenyl)-1,2,4-triazolo[3,4-b][2H-1,3,4]thiadiazine
(3b). Free base: Starting from 1.16g (10 mmoles) of 4-amino-5-
sulfanyl-l,2,4-triazole 5a and 2.17g (10 mmoles) of 4-
fluorophenacyl bromide as described for 3a. Yield: 2.22 g (95%),
colorless needles (EtOH), mp 203°C; ir (KBr, cmÀ1): 511 (m),
812 (s), 855 (s), 942 (m), 1173 (s), 1227 (s), 1286 (m), 1359 (m),
[10] Sugawara, H.; Endoh, M. Jpn J Pharmacol 1999, 80, 55; Chem
Abstr 1999, 131, 111182.
[11] Himmel, M. H.; Amos, G. J.; Wettwer, E.; Ravens, U. J
Cardiovas Pharmacol 1999, 33, 301; Chem Abstr 1999, 131, 443.
[12] Petrie, C.; Orme, M. W.; Baindur, N.; Robbins, K. G.; Harris,
S. M.; Kontoyianni, M.; Hurley, L. H.; Kerwin, S. M.; Mundy, G. R. PCT
Int Appl WO 9 715 308, 1997; Chem Abstr 1997, 127, 17703.
[13] Eggenweiler, H. M.; Wolf, M. German Patent 10 150 517,
2003; Chem Abstr 2003, 138, 297702.
[14] Warner, J. M. PCT Int Appl WO 2 004 067 006, 2004; Chem
Abstr 2004, 141, 185092.
[15] Rese, R.; Brümmer, U.; Unsöld, E. Pharmazie 1998, 53, 820.
[16] Chupakhin, O. N.; Sidorova, L. P.; Perova, N. M.; Charushin,
V. N.; Rusinov, V. L.; Mulyar, A. G. Russ Patent 2259371, 2005; Chem
Abstr 2005, 143, 229887.
[17] (a) Pfeiffer, W. D.; Dilk, E.; Roßberg, H.; Langer, P. Synlett
2003, 2392; (b) Bodtke, A.; Pfeiffer, W. D.; Ahrens, N.; Langer, P. Tetra-
hedron 2005, 61, 10926; (c) Bodtke, A.; Pfeiffer, W. D.; Ahrens, N.;
Langer, P. Bioorg Med Chem Lett 2004, 1509; (d) Pfeiffer, W. D.; Dilk,
E.; Rossberg, H.; Langer, P. Synlett 2003, 2392; (e) Pfeiffer, W. D. In
Houben-Weyl, Methoden der organischen Chemie, Hetarene IV, E9c;
Schaumann, E., Ed.; Thieme-Verlag: Stuttgart 1998, pp 483–529; (f) Jira,
Th.; Stelzer, A.; Pfeiffer, W. D.; Schopplich, Ch.; Siegert, S.;
Kindermann, M. Pharmazie 1997, 52, 11; (g) Jira, Th.; Pfeiffer, W.
D.; Lachmann, K.; Epperlein, U. Pharmazie 1994, 49, 401; (h)
Szulzewsky, K.; Pfeiffer, W. D.; Bulka, E.; Rossberg, H.; Schulz, B.
Acta Chem Scand 1993, 47, 302; (i) Pfeiffer, W. D.; Dilk, E.; Bulka,
E. Wiss Zeitschrift der Ernst-Moritz-Arndt-Universität Greifswald
1978, 27, 135; (j) Pfeiffer, W. D.; Buhrow, J.; Bulka, E. Wiss Zeitschrift
der Ernst-Moritz-Arndt-Universität Greifswald 1988, 37, 38; (k) Bulka,
E.; Pfeiffer, W. D.; Tröltsch, C.; Dilk, E.; Gärtner, H.; Daniel, D. Collect
Czech Chem Commun 1978, 28, 577; (l) Bulka, E.; Pfeiffer, W. D. Z
Chem 1975, 15, 482; (m) Pfeiffer, W. D.; Dilk, E.; Bulka, E. Z Chem
1977, 17, 15.
1
1415 (m), 1452 (s), 1480 (s), 1511 (s), 1600 (s), 3057 (m); H
nmr (300 MHz, CDCl3): δ = 4.02 (s, 2H, 6-CH2), 7.19–7.99 (m,
4H, ArH), 8.59 (s, 1H, 3H, Hetar); 13C nmr (50MHz, DMSO-d6):
δ = 115.79, 129.81, 130.03, 140.04, 142.96, 154.53, 161.65,
166.63; ms (EI, 70 eV): m/z = 234 (M+, 100), 135 (49), 121 (42),
112 (33), 101 (25), 95 (22), 85 (14), 75 (13), 58 (12). Anal.
Calcd. for C10H7N4S (234.25): C, 51.27; H, 3.01; N, 23.92.
Found: C, 51.31; H, 3.21; N 23.81.
3-(4-Fluorophenyl)-6-methyl)-1,2,4-triazolo[3,4-b][2H-1,3,4]
thiadiazine (3c). Free base: Starting from 1.30 g (10 mmoles)
of 4-amino-3-methyl-5-sulfanyl-l,2,4-triazole 5b and from 2.17g
(10 mmoles) of 4-fluoro-phenacylbromide as described for 3a.
Yield: 2.16 g (87%), colorless rods (EtOH), mp 217 °C; ir (KBr,
cmÀ1): 846 (m), 1169 (m), 1308 (s), 1366 (s), 1469 (s), 1509 (s),
1
1600 (s), 3002 (s); H nmr (300MHz, CDCl3): δ = 2.59 (s, 3H,
Me), 3.95 (s, 2H, 6-CH2), 7.19–7.94 (m, 4H, ArH); ms (EI,
70 eV): m/z = 248 (M+, 100), 135 (47), 121 (83), 101 (58), 95 (42),
75 (42), 58 (86), 28 (47). Anal. Calcd. for C11H9N4SF (248.28):
C, 53.21; H, 3.65; N 22.57. Found: C, 53.24; H, 3.81; N 22.67.
Acknowledgment. We are grateful to Boehringer Ingelheim Pharma
GmbH & Co. KG for the financial support.
REFERENCES AND NOTES
[18] Beyer, H., Kröger, C.-F. Liebigs Ann Chem 1960, 637, 135.
[19] Schmidt, R. R.; Huth, H. Tetrahedron Lett 1975, 49, 33.
[20] Beyer, H.;Honeck, H.;Reichelt, L. Liebigs AnnChem1970, 741, 45.
[21] CCDC 941615 contains all crystallographic details of this pub-
lication and is available free of charge at www.ccdc.cam.ac.uk/conts/re-
trieving.html or can be ordered from the following address: Cambridge
Crystallographic Data Centre, 12 Union Road, GB-Cambridge CB21EZ;
Fax: (+44)1223-336-033; or deposit@ccdc.cam.ac.uk.
[1] Tschesche, H.; Schröder, J. Euro Patent 1191024, 2002; Chem
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[2] Schröder, J.; Henke, A.; Wenzel, H.; Brandstetter, H.;
Stammler, H. G.; Stammler, A.; Pfeiffer, W. D.; Tschesche, H. J Med
Chem 2001, 44, 3231.
[3] Pfeiffer, W. D.; Dilk, E.; Bulka, E. German East Patent 204
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet