Preparation of 5-bromo-6-phenylimidazo[2,1-b][1,3,4]thiadiazol-2-ylamines

Article abstract of DOI:10.1002/jhet.5570450138

(Chemical Equation Presented) The reaction of primary or secondary amines with 2,5-dibromo-6-phenylimidazo[2,1-b][1,3,4]-thiadiazole (5) leads to a chemoselective replacement of the 2-Br substituent. The process represents a convenient route to the corresponding 2-ylamines 7a-d. Hydrazine reacts in an analogous fashion (5 → 7e). The structure determinations are based on an X-ray crystal structure analysis and on one- and two-dimensional NMR measurements.

Full text of DOI:10.1002/jhet.5570450138

Jan-Feb 2008
299
Preparation of 5-Bromo-6-
phenylimidazo[2,1-b][1,3,4]thiadiazol-2-ylamines
Saifidin Safarov1*, Rahmonov Rahmon1, Muhamacho Amadovich Kukaniev1, Dieter
Schollmeyer2, Elena Karpuk2 and Herbert Meier2
1
V. I. Nikitin-Institute of Chemistry, Dushanbe, Tajikistan
e-mail: cafi@mail.ru
University of Mainz, Institute of Organic Chemistry, D-55099 Mainz, Germany
2
Received March 8, 2007
R1
Br
Br
H2N
R1
N
S
N
S
R2
N
N
Br
N
R2
N
N
The reaction of primary or secondary amines with 2,5-dibromo-6-phenylimidazo[2,1-b][1,3,4]-
thiadiazole (5) leads to a chemoselective replacement of the 2-Br substituent. The process represents a
convenient route to the corresponding 2-ylamines 7a-d. Hydrazine reacts in an analogous fashion
(5 ꢀ 7e). The structure determinations are based on an X-ray crystal structure analysis and on one- and
two-dimensional NMR measurements.
J. Heterocyclic Chem., 45, 299 (2008).
Scheme 2
INTRODUCTION
O
N
N
During recent years there have been intense investi-
gations on imidazo[2,1-b][1,3,4]thiadiazoles, since many
of which are known to possess interesting pharmacol-
ogical and/or biological properties such as antimicrobial
[1-5], antitubercular [6,7], antiinflammatory [8-10],
anticonvulsive [11,12], antihypertensive [13,14], anti-
cancer [15-17] and antisecretory [18] activities. Many
compounds of structure 1 with different substituents Ri
(i = 1,2,3) are already known (Scheme 1). Nevertheless,
there is a strong need to synthesize new derivatives in
order to optimize their applications. Thus, several new
synthetic strategies appeared in the literature [19-23].
(n-C4H9OH)
+
CH2Br
Br
NH2
S
58%
2
3
Br
N
S
N
Br2
N
N
Br
Br
N
80%
S
N
4
5
Br
R1
R2
R1
N
R2
N
S
N
+
NH
5
60 - 85%
N
6 a-e
R1
7 a-e
Yield [%] m.p. [°C]
Scheme 1
R2
5
7
R2
3
N
4
N
2
R1
R3
a
b
c
d
e
H
CH3
(CH2)5
(CH2)2
CH3
CH3
78
68
60
60
85
186
174
156
173
188
6
S
1
N
7
7a
1
O
(CH2)2
NH2
R1, R2, R3: H, alkyl, aryl, hetaryl, amino, sulfonyl, halogen
H
We report here on the preparation of 2,5-dibromo-6-
phenylimidazo[2,1-b][1,3,4]thiadiazole and its selective
substitution of the 2-Br group by the reaction with
primary and secondary amines or hydrazine.
in acetic acid in the presence of NaOAc the dibromo
compound 5. Treatment of 5 with primary or secondary
amines 6a-d afforded the imidazo[2,1-b][1,3,4]thiadiazol-
2-ylamines 7a-d. Hydrazine (6e) furnished 7e in an analo-
gous process. The nucleophilic replacement of the bromo
substituent in 2-position is highly chemoselective. Even
excess amounts of 6a-e do not provoke an attack on C-5.
The structure determination of 4 was confirmed by a
crystal structure analysis. The target compounds 7a-e
were characterized by their 1H and 13C NMR spectra.
Figure 1 shows an PLATON plot of 4. The benzene
ring and the heterocyclic ring are almost coplanar as the
torsion angle C(2)-C(1)-C(9)-C(14) of –12.8° reveals.
RESULTS AND DISCUSSION
The synthesis of 2-bromo-6-phenylimidazo[2,1-b]-
[1,3,4]thiadiazole (4) was carried out by the condensation
of 5-bromo-1,3,4-thiadiazol-2-ylamine (2) with ꢁ-bromo-
acetophenone (3) in boiling n-butanol (Scheme 2) [24].
The initially formed 2-imino-1,3,4-thiadiazole underwent
a spontaneous ring closure and HBr elimination under
these conditions. The reaction of 4 with bromine yielded

300
S. Safarov, R. Rahmon, M. A. Kukaniev, D. Schollmeyer, E. Karpuk and H. Meier
Vol 45
Table 1
The 1H and 13C NMR data of 4,5 and 7a-e are
summarized in the Tables 2 and 3.
Bond lengths, selected bond angles and torsion angles of 2-bromo-6-
phenylimidazo[2,1-b][1,3,4]thiadiazole (4) (the numbering corresponds
to Figure 1 and not to the nomenclature).
Bond lengths [Å]
Bond angles [°]
S(6)—C(5)
S(6)—C(7)
C(5)—Br(1)
C(5)—N(4)
N(4)—N(3)
N(3)—C(7)
N(3)—C(2)
C(2)—C(1)
C(1)—N(8)
N(8)—C(7)
C(1)—C(9)
C(9)—C(10)
1.743(4)
C(7)—S(6)—C(5)
S(6)—C(5)—N(4)
C(5)—N(4)—N(3)
N(4)—N(3)—C(2)
N(3)—C(2)—C(1)
C(2)—C(1)—N(8)
C(1)—N(8)—C(7)
N(8)—C(7)—S(6)
C(2)—C(1)—C(9)
Torsion angles [°]
C(7)—N(3)—N(4)—C(5)
87.0(2)
118.4(3)
107.3(3)
133.9(3)
104.4(3)
111.7(3)
103.5(3)
138.5(3)
127.4(3)
1.741(4)
1.860(4)
1.274(5)
1.362(4)
1.356(5)
1.371(5)
1.372(5)
1.381(5)
1.307(5)
1.474(5)
1.389(6)
–0.8(5)
C(2)—N(3)—N(4)—C(5) –179.3(4)
C(10)—C(11) 1.380(6)
C(11)—C(12) 1.362(6)
C(12)—C(13) 1.371(6)
C(13)—C(14) 1.386(5)
C(7)—N(3)—C(2)—C(1)
N(4)—N(3)—C(2)—C(1)
C(5)—S(6)—C(7)—N(8)
C(1)—N(8)—C(7)—S(6) –178.5(4)
C(2)—C(1)—C(9)—C(14) –12.8(6)
N(8)—C(1)—C(9)—C(10) –14.5(5)
0.3(4)
178.9(4)
179.7(5)
C(14)—C(9)
1.382(5)
Table 2
1H NMR data of the heterobicycles 4,5 and 7a-e (ꢀ values in CDCl3,
TMS as internal standard).
Comp. 2-NR1R2
5-H 6-Phenyl
Figure 1: Upper part: PLATON plot of the crystal structure of 2-bromo-
6-phenylimidazo[2,1-b][1,3,4]thiadiazole (4) (the numbering
corresponds to Table 1 and not to the nomenclature). Lower part:
Elementary cell.
(s) o-H(m) m-H(m) p-H(m)
4
5
7a
8.00 7.78
7.98
7.86
7.40
7.43
7.39
7.29
7.34
7.26
2.49 (br, s, NH)
2.89 (d, 3J = 4.8 Hz, CH3)
3.09 (s, CH3)
The chemoselectivity of the Br/NR1R2 replacement is
documented by the 13C NMR data. The high field shift of
C-5, caused by the bromo substituents, is preserved on
going from 5 to 7a-e, whereas ꢀ (C-2) shows a low-field
shift of more than 30 ppm, when an N atom is attached.
The assignment of the 1H and 13C signals (Tables 2 and 3)
was based on 2D measurements (HMQC and HMBC).
Treatment of 7a with acetic anhydride (8) yielded the
acetamide 9a (Scheme 3), which has a very low solubility
in normal organic solvents.
7b
7c
7.97
7.97
7.39
7.39
7.27
7.27
1.67 (m, 6 H, CH2)
3.45 (m, 4 H, NCH2)
3.46 (m, 4 H, NCH2)
3.80 (m, 4 H, OCH2)
9.43 (br, s, NH)
7d
7.96
7.90
7.40
7.41
7.28
7.26
7e[a]
5.30 (br, s, NH2)
[a] Measurement in CD3SOCD3
Selected bond lengths, bond angles and torsion angles are
listed in Table 1.
Table 3
13C NMR data of the heterobicycles 4,5 and 7a-e (ꢀ values in CDCl3, TMS as internal standard).
Comp.
Heterobicyclic scaffold
6-Phenyl
i-C
2-NR1R2
CH3 / CH2
C-2
C-5
C-6
/
C-7a
o-C
m-C
p-C
4
5
7a[a]
7b
7c
133.1
132.4
162.8
164.2
164.5
109.8
93.4
91.9
91.9
92.0
145.5
142.6
138.3
139.4
139.5
/
146.0
144.4
139.8
140.4
140.2
133.1
133.6
133.4
133.6
135.6
125.1
126.8
125.7
126.3
126.3
128.8
128.6
128.6
128.3
128.3
128.0
128.2
127.2
127.2
127.1
/
/
/
/
30.5
40.0
49.5 (NCH2)
24.9 (CH2)
23.8 (CH2)
65.8 (OCH2)
48.3 (NH2)
7d
164.6
177.3
92.3
91.1
139.9
137.8
/
/
139.9
140.7
133.4
133.6
126.3
125.7
128.4
128.5
127.3
127.1
7e[a]
[a] Measurement in CD3SOCD3

Jan-Feb 2008
Preparation of 5-Bromo-6- phenylimidazo[2,1-b][1,3,4]thiadiazol-2-ylamines
301
Scheme 3
(5-Bromo-6-phenylimidazo[2,1-b][1,3,4]thiadiazol-2-yl)-
dimethylamine (7b). Compound 5 (3.59 g, 10.0 mmol) and an
aqueous solution of dimethylamine (6b) (1.80 g, 40 mmol) were
refluxed in 15 mL 1,4-dioxane/CH3OH (1:1) for 2 h. Work-up,
as described for 7a, and crystallization from 1,4-dioxane/CHCl3
(5:1) yielded 2.20 g (68%) 7b which melted at 174 °C. FD MS:
m/z (%) = 324 (100) [M+, Br pattern]. Anal. Calcd. for
C12H11BrN4S (323.2): C, 44.59; H, 3.43; N, 17.33; S, 9.92.
Found: C, 44.69; H, 3.45; N, 17.23; S, 9.81.
5-Bromo-6-phenyl-2-piperidin-1-ylimidazo[2,1-b][1,3,4]-
thiadiazole (7c). Compound 5 (3.59 g, 10.0 mmol) and 1.70 g
(20.0 mmol) piperidine (6c) were refluxed in 30 mL isopropanol
for 3 h. Work-up and recrystallization as described for 7b
yielded 2.18 g (60%) 7c which melted at 156 °C. FD MS:
m/z (%) = 364 (100) [M+, Br isotope pattern]. Anal. Calcd. for
C15H15BrN4S (363.3): C, 49.59; H, 4.16; N, 15.42; S, 8.83.
Found: C, 49.38; H, 4.25; N, 15.61; S, 8.68.
Br
CH3
AcOAc
8
O
N
S
N
7a
N
72%
N
H3C
9a m.p. 245 °C
Imidazo[2,1-b][1,3,4]thiadiazol-2-ylamines can be
easily prepared by nucleophilic substitution reactions of
the 2-Br derivative and primary and secondary amines (or
hydrazine). The 5-Br group does not disturb this
chemoselective process because it does not show any
reactivity toward amines. Obviously the 1,3,4-thiadiazole
ring is much more prone to this type of replacement
reaction than the imidazole ring.
5-Bromo-2-morpholin-4-yl-6-phenylimidazo[2,1-b][1,3,4]-
thiadiazole (7d). The reaction of 3.59 g (10.0 mmol) 5 and
1.74 g (20.0 mmol) morpholine (6d) was carried out as
described for 7c. The residue, obtained after the evaporation of
the volatile parts, was dissolved in CHCl3, extracted with 15 mL
1% HCl and 2 x 15 mL H2O. The organic layer was dried with
CaCl2 and concentrated. Crystallization from CHCl3 yielded
2.20 g (60%) 7d which melted at 173 °C. FD MS: m/z (%) = 366
(100) [M+, Br isotope pattern]. Anal. Calcd. for C14H13BrN4OS
(365.3): C, 46.04; H, 3.59; N, 15.34; S, 8.78. Found: C, 46.12;
H, 3.45; N, 15.39; S, 8.71.
EXPERIMENTAL
Melting points were determined on a Boetius apparatus and
1
are uncorrected. H and 13C NMR spectra were measured with
the Bruker machines AM 400 and AMX 400 using CDCl3 or
CD3SOCD3 as solvent and TMS as internal standard. Mass
spectra were recorded on a Finnigan MAT 95 applying the field
desorption (FD) technique.
5-Bromo-1,3,4-thiadiazol-2-ylamine (2) was generated
according to reference [25,26].
(5-Bromo-6-phenylimidazo[2,1-b][1,3,4]thiadiazol-2-yl)-
hydrazine (7e). To 3.59 g (10.0 mmol) 5, dissolved in 20 mL
EtOH/DMF (5:1), 0.75 g (15.0 mmol) hydrazine hydrate was
added dropwise under stirring within 20 min. After further
40 min. at room temperature, the generated precipitate was
filtered, washed with water (3 x 15 mL) and recrystallized from
EtOAc/1,4-dioxane (10:3). Yield 2.64 g (85%), m.p. 187 °C. FD
MS: m/z (%) = 311 (100) [M+, Br isotope pattern]. Anal. Calcd.
for C10H8BrN5S (310.2): C, 38.72; H, 2.60; N, 22.58; S, 10.34.
Found: C, 38.59; H, 2.45; N, 22.43; S, 10.27.
2-Bromo-6-phenylimidazo[2,1-b][1,3,4]thiadiazole (4). 1.80 g
(10.0 mmol) of 2 and 1.99 g (10.0 mmol) of ꢀ-bromoaceto-
phenone [27] were refluxed in 50 mL of n-butanol for 8 h. The
reaction mixture was cooled to 20 °C, the formed precipitate
filtered and washed three times with 7 mL H2O each.
Recrystallization from 1,4-dioxane/CHCl3 (5:1) gave 1.62 g
(58%) crystals which melted at 195 °C. FD MS: m/z (%) = 281
(100) [M+, Br isotope pattern]. Anal. Calcd. for C10H6BrN3S
(280.2): C, 42.87; H, 2.16; N, 15.00; S, 11.45. Found: C, 42.65;
H, 2.05; N, 15.15; S, 11.32.
N-(5-Bromo-6-phenylimidazo[2,1-b][1,3,4]thiadiazol-2-yl)-
N-methylacetamide (9a). Compound 7a (3.09 g, 10.0 mmol) was
refluxed in 35 mL (38.04 g, 373.0 mmol) acetic anhydride (8) for
1 h. The formed precipitate was filtered, washed with H2O (3 x
15 mL) and recrystallized from DMF. Yield 2.53 g (72%), m.p.
245 °C. FD MS: m/z (%) = 352 (100) [M+, Br isotope pattern]. 1H
NMR (CD3SOCD3): ꢁ = 2.44 (s, 3 H, CH3), 3.63 (s, 3 H, NCH3),
7.33 (m, 1 H, p-H, phenyl), 7.46 (m, 2 H, m-H, phenyl), 7.95 (m,
2 H, o-H, phenyl). 13C NMR (CD3SOCD3): ꢁ = 22.8 (CH3), 35.5
(NCH3), 91.8 (C-5), 126.2 (o-CH, phenyl), 127.7 (p-CH, phenyl),
128.7 (m-CH, phenyl), 132.8 (i-C, phenyl), 172.3 (CO); the
solubility of 9a is so low that the signals of the remaining
quaternary carbon atoms C-2, C-6 and C-7a are not clearly visible
within the level of the electronic noise. Anal. Calcd. for
C13H11BrN4OS (351.2): C, 44.46; H, 3.16; N, 15.95; S, 9.13.
Found: C, 44.34; H, 2.95; N, 15.86; S, 9.05.
2,5-Dibromo-6-phenylimidazo[2,1-b][1,3,4]thiadiazole (5).
To 2.80 g (10.0 mmol) 4 dissolved in 30 mL acetic acid, 1.59 g
(10.0 mmol) Br2, dissolved in 3 mL acetic acid, was dropped at
ambient temperature within 15 min. The reaction was vigorously
stirred for 75 min. A saturated aqueous solution of 0.82 g
(10.0 mmol) NaOAc was slowly added under cooling. The
formed precipitate was collected by filtration and washed with
H2O (4 x 15 mL). Recrystallization from 1,4-dioxane yielded
2.87 g (80%) 5 which melted at 132 °C. FD MS: m/z (%) = 359
(100) [M+, Br2 isotope pattern]. Anal. Calcd. for C10H5Br2N3S
(359.1): C, 33.45; H, 1.40; N, 11.70; S, 8.93. Found: C, 33.25;
H, 1.32; N, 11.85; S, 9.05.
(5-Bromo-6-phenylimidazo[2,1-b][1,3,4]thiadiazol-2-yl)-
methylamine (7a). Compound 5 (3.59 g, 10.0 mmol, in 28 mL
CH3OH) and an aqueous solution of methylamine (6a) (0.62 g,
20.0 mmol, in 1.86 g H2O) was refluxed for 3 h. After
evaporation of the volatile parts, the residue was suspended in
4 mL H2O and extracted with CHCl3 (3 x 30 mL). The organic
phase was dried over Na2SO4 and evaporated. Crystallization of
the residue from 1,4-dioxane/CHCl3 (10:1) afforded 2.41 g
(78%) 7a which melted at 186 °C. FD MS: m/z (%) = 310 (100)
[M+, Br pattern]. Anal. Calcd. for C11H9BrN4S (309.2): C,
42.73; H, 2.93; N, 18.12; S, 10.37. Found: C, 42.61; H, 2.77; N,
18.21; S, 10.35.
Crystal structure analysis of compound 4. Structure
solution, refinement and data output were carried out with
SHELX-97 program package [28]. H atoms were placed in
geometrically calculated positions using a riding model. Details
of the X-ray crystal structure analysis are summarized in
Table 4.
Crystallographic data for 4 have been deposited with the
Cambridge Crystallographic Data Centre as supplementary

302
S. Safarov, R. Rahmon, M. A. Kukaniev, D. Schollmeyer, E. Karpuk and H. Meier
Vol 45
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Table 4
Details of X-ray crystal structure analysis of 4
Formula
C10H6N3SBr
280.15
0.1 x 0.2 x 0.3
Mr [g mol-1]
Crystal size [mm3]
Space group
Cell constants
a [Å]
P
21 / n (monoclinic)
5.561(2)
13.400(5)
13.891(5)
83.87(1)
b [Å]
c [Å]
ꢀ [°]
V [Å3]
1029.3(10)
Z
4
Dx [Mgm-3]
Diffractometer
Radiation
Scan type
Scan width [°]
Range [°]
1.808
Smart CCD
Mo–Kꢀ (ꢁ = 0.71073 Å), graphite monochromator
CCD
0.3
2 ꢁ ꢂ ꢁ 29
–6 ꢁ h ꢁ 7, –17 ꢁ k ꢁ 17, –18 ꢁ l ꢁ 18
F (000)
T [°C]
552
25
No. of refl. measured 13880
indep.
observed
Rꢂ
2626
1705 (F
0.0773
/ ꢂ(F) > 4.0
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Acknowledgements. We are grateful to the Volkswagen
Foundation for a grant for S. S. and to the Fonds der
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