Reinvestigation of 1,3,4-thiadiazol-2(3h)-iminium bromide in the two-step synthesis of imidazo[2,1-b][1,3,4]- thiadiazoles

Article abstract of DOI:10.3987/COM-14-12938

The synthesis of 1,3,4-thiadiazol-2(3H)-iminium bromides, which are intermediates in the most commonly used synthetic approach to imidazo[2,1-b][1,3,4]thiadiazoles, and a single crystal X-ray diffraction study of one of these iminium bromides are describe

Full text of DOI:10.3987/COM-14-12938

HETEROCYCLES, Vol. 89, No. 4, 2014
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HETEROCYCLES, Vol. 89, No. 4, 2014, pp. 1041 - 1053. © 2014 The Japan Institute of Heterocyclic Chemistry
Received, 9th January, 2014, Accepted, 30th January, 2014, Published online, 10th February, 2014
DOI: 10.3987/COM-14-12938
REINVESTIGATION OF 1,3,4-THIADIAZOL-2(3H)-IMINIUM BROMIDE
IN THE TWO-STEP SYNTHESIS OF IMIDAZO[2,1-b][1,3,4]-
THIADIAZOLES
Shigeki Sano,* Keisuke Matsuura, Hayato Sumiyoshi, Akira Miki, Syuji
Kitaike, and Michiyasu Nakao
Graduate School of Pharmaceutical Sciences, The University of Tokushima,
Sho-machi, Tokushima 770-8505, Japan
E-mail: ssano@tokushima-u.ac.jp
Abstract – The synthesis of 1,3,4-thiadiazol-2(3H)-iminium bromides, which are
intermediates in the most commonly used synthetic approach to
imidazo[2,1-b][1,3,4]thiadiazoles, and a single crystal X-ray diffraction study of
one of these iminium bromides are described. Cyclization of the resulting
1,3,4-thiadiazol-2(3H)-iminium bromides under microwave irradiation afforded
imidazo[2,1-b][1,3,4]thiadiazoles in 80-100% yields.
Imidazo[2,1-b][1,3,4]thiadiazoles are an important class of fused heterocyclic compounds that have
attracted attention due to their diverse range of biological activities.1 Indeed, these compounds have been
shown to possess crucial effects such as anticancer,2,3 antibacterial,4-7 antitubercular,3,5,8 antifungal,6,7,9,10
antimicrobial,3,7,10,11 analgesic,7,12 anticonvulsant12 and antihyperlipidemic13 activities. In addition,
anti-inflammatory,10,14 antisecretory,15 antiapoptotic,16 anthelmintic,17 diuretic,18 leishmanicidal,19
cardiotonic,20 and herbicidal21 effects have also been reported. Thus, the imidazo[2,1-b][1,3,4]thiadiazoles
are thought to have tremendous potential in medicinal chemistry.
Recently, a novel method for synthesizing imidazo[2,1-b][1,3,4]thiadiazoles by the reaction of
4,5-disubstituted-N-arylaminoimidazole-2-thiones with isocyanides in the presence of azodicarboxylates
has been reported.22 However, the most commonly used method for the preparation of
imidazo[2,1-b][1,3,4]thiadiazole 1 is the one-pot reaction of 5-substituted-2-amino-1,3,4-thiadiazole 2
with appropriate !-haloketone 3. Since 1952, beginning with the work of two-step synthesis of 1 by
Matsukawa and Ban,23 numerous studies on the reaction of 2 and 3 have been reported. A plausible
mechanism involving a 1,3,4-thiadiazol-2(3H)-iminium bromide 4 for the one-pot synthesis is outlined in

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HETEROCYCLES, Vol. 89, No. 4, 2014
Scheme 1. Modified synthetic methods based on the reaction of 2 and 3 have recently been reported by
various authors.24 However, these reactions have not necessarily been optimized to furnish a variety of
imidazo[2,1-b][1,3,4]thiadiazole derivatives. In this context, we planned to reinvestigate the two-step
reactions of 2 and 3 for the preparation of imidazo[2,1-b][1,3,4]thiadiazole 1.
OH
R2
O
O
N
S
N
S
N
S
R2
N
N
N
R1
R1
R1
Br
R2
+
NH2
NH
NH2
H
Br
Br
4
2
3
4'
Br
Br
N
N
N
OH
R2
– H2O
– HBr
N
N
N
OH2
R2
R1
R2
R1
R1
S
N
S
N
H
S
N
1
Scheme 1. Plausible mechanism for the formation of imidazo[2,1-b][1,3,4]thiadiazole 1
First, we synthesized imidazo[2,1-b][1,3,4]thiadiazoles 1a-1d utilizing an ordinary one-pot synthetic
method. Thus, a mixture of 2-amino-1,3,4-thadiazole 2 (R1 = H) and 1mol eq. of !-haloketone 3 [R2 = Ph,
2-thiophenyl, 2-benzofuranyl, and 4-(5-methyl-3-phenylisoxazolyl)] underwent a known reaction under
microwave irradiation25 with a single-mode microwave reactor (InitiatorTM 60; Biotage AB) at 130-150 °C
to afford imidazo[2,1-b][1,3,4]thiadiazoles 1a-1d in 21-56% yields (Scheme 2). The competition between
cyclization and decomposition of 1,3,4-thiadiazol-2(3H)-iminium bromide 4 at elevated reaction
temperatures may be responsible for the lower chemical yields of imidazo[2,1-b][1,3,4]thiadiazole 1.
N
S
N
S
O
N
N
R1
R2
+
H
Br
R2
EtOH
N
NH2
MW (130-150 °C), 30 min
2 (R1 = H)
3a-3d
1a-1d
S
a: R2 = Ph, b: R2 =
,
1a: 56%
1b: 38%
1c: 52%
1d: 21%
Ph
O
N
c: R2 =
, d: R2 =
O
Me
Scheme 2. One-pot synthesis of imidazo[2,1-b][1,3,4]thiadiazoles 1a-1d
We therefore investigated an effective preparation of 1,3,4-thiadiazol-2(3H)-iminium bromide 4, which is
the intermediate in the ordinary one-pot synthesis of imidazo[2,1-b][1,3,4]thiadiazole 1 utilizing

HETEROCYCLES, Vol. 89, No. 4, 2014
1043
2-amino-1,3,4-thiadiazole 2 and !-haloketone 3. As a result, the reaction of 2 (R1 = H, Me, and Et) and
1mol eq. of 3 [R2 = Ph, 2-thiophenyl, 2-benzofuranyl, and 4-(5-methyl-3-phenylisoxazolyl)] in ethanol at
ambient temperature furnished 1,3,4-thiadiazol-2(3H)-iminium bromides 4a-4l in 54-87% yields (Scheme
3, Table 1). The structures of 4a-4l were established by spectroscopic methods. Cyclization of
1,3,4-thiadiazol-2(3H)-iminium bromide 4 to imidazo[2,1-b][1,3,4]thiadiazole 1 did not occur under these
reaction conditions. Unfortunately, the chemical yields of 4 were lower than expected. The solubility of
this compound in organic solvents, which was dependent on substituents R1 and R2, may be one reason
for the disappointing yields. However, the structure of 4l was confirmed for the first time by a single
crystal X-ray diffraction study (an ORTEP view of a single molecule of 4l is given in Figure 1).26
O
N
S
N
S
N
S
O
N
R2
N
N
R1
R1
R2
R1
+
Br
R2
EtOH
rt, 3 d
EtOH
N
NH2
NH2
Br
MW (150 °C)
2
3a-3d
4a-4l
1a-1l
Ph
S
O
N
a: R2 = Ph, b: R2 =
, c: R2 =
, d: R2 =
O
Me
Scheme 3. Two-step synthesis of imidazo[2,1-b][1,3,4]thiadiazoles 1a-1l
Table 1. Synthesis of 1,3,4-thiadiazol-2(3H)-iminium bromides 4a-4l
Entry
R1
H
R2
a
b
c
Yield (%)a
77 (4a)
54 (4b)
61 (4c)
68 (4d)
76 (4e)
66 (4f)
79 (4g)
70 (4h)
74 (4i)
1
2
H
3
H
4
H
d
a
b
c
5
Me
Me
Me
Me
Et
6
7
8
d
a
b
c
9
10
11
Et
69 (4j)
73 (4k)
87 (4l)
Et
12
a Isolated yields.
Et
d

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HETEROCYCLES, Vol. 89, No. 4, 2014
C(13)
C(14)
N(4)
C(12)
O(2)
C(8)
C(11)
C(15)
C(16)
C(9)
C(7)
C(10)
C(6)
O(1)
C(5)
Br(1)
N(2)
N(3)
C(4)
C(1)
C(2)
N(1)
C(3)
S(1)
Figure 1. ORTEP drawing of 1,3,4-thiadiazol-2(3H)-iminium bromide 4l
Having identified suitable conditions for the preparation of 1,3,4-thiadiazol-2(3H)-iminium bromide 4,
we optimized the cyclization reaction of 4 to imidazo[2,1-b][1,3,4]thiadiazole 1 with the use of a
single-mode microwave reactor (InitiatorTM 60; Biotage AB). The cyclization of
1,3,4-thiadiazol-2(3H)-iminium bromides 4a-4l under microwave irradiation at 150 °C in ethanol
consequently afforded the desired cyclized compounds 1a-1l in excellent yields (Scheme 3, Table 2). The
structures of 1a-1l were determined by spectroscopic methods. In addition, the structure of 1l was
independently established by a single crystal X-ray diffraction study as shown in Figure 2.27
Table 2. Synthesis of imidazo[2,1-b][1,3,4]thiadiazoles 1a-1l
Entry
R1
H
R2
a
b
c
Time (min)
Yield (%)a
100 (1a)
80 (1b)
92 (1c)
1
2
4
30
5
H
3
H
4
H
d
a
b
c
5
100 (1d)
100 (1e)
100 (1f)
99 (1g)
93 (1h)
100 (1i)
91 (1j)
5
Me
Me
Me
Me
Et
5
6
10
20
7
7
8
d
a
b
c
9
5
10
11
Et
10
20
5
Et
100 (1k)
94 (1l)
12
a Isolated yields.
Et
d

HETEROCYCLES, Vol. 89, No. 4, 2014
1045
C(12)
C(13)
C(11)
C(14)
C(10)
C(9)
C(1)
N(1)
C(8)
C(4)
N(2)
C(2)
N(4)
C(3)
C(7)
C(5)
C(6)
O(1)
C(15)
S(1)
N(3)
C(16)
Figure 2. ORTEP drawing of imidazo[2,1-b][1,3,4]thiadiazole 1l
In this work, we have described the preparation of 1,3,4-thiadiazol-2(3H)-iminium bromide 4 in ethanol
and the first example of the single crystal X-ray crystallography of one of these intermediates. The
cyclization of 1,3,4-thiadiazol-2(3H)-iminium bromide 4 is general with respect to all examples and the
products, imidazo[2,1-b][1,3,4]thiadiazole 1, were obtained in excellent yields within minutes under
microwave irradiation. Further investigations to provide more useful insight into the efficient preparation
of 1,3,4-thiadiazol-2(3H)-iminium bromide 4 are currently underway.
EXPERIMENTAL
All melting points were determined on a Yanagimoto micro melting point apparatus and are uncorrected.
1
IR spectra were obtained using a JASCO FT/IR-6200 IR Fourier transform spectrometer. H NMR (500
13
MHz) and C NMR (125 MHz) spectra were recorded on Bruker AV500 spectrometers, respectively.
Chemical shifts are given in ! values (parts per million) using tetramethylsilane (TMS) as an internal
standard. Electron spray ionization mass spectra (ESIMS) were recorded on a Waters LCT Premier
spectrometer. Elemental combustion analyses were performed using a Yanagimoto CHN CORDER MT-5
and a J-SCIENCE LAB JM10. Microwave-assisted reaction was performed utilizing automated
single-mode microwave synthesizer (InitiatorTM 60; Biotage AB). X-Ray crystallographic analysis was
performed using a Rigaku RAXIS-RAPID diffractometer. All reactions were monitored by TLC
employing 0.25-mm silica gel plates (Merck 5715; 60 F254). Column chromatography was carried out on
silica gel [Fuji Silysia Chemical PSQ 60B (spherical)]. All reagents were used as purchased.
Typical Procedure for Preparation of 1,3,4-Thiadiazol-2(3H)-iminium Bromide 4
A solution of 2-amino-5-ethyl-1,3,4-thiadiazole 2 (R1 = H) (129 mg, 1 mmol) and 3d (280 mg, 1mmol) in
EtOH (5 mL) was stirred at rt for 3 days. The reaction mixture was then evaporated in vacuo to afford a

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HETEROCYCLES, Vol. 89, No. 4, 2014
crude product, which was purified by column chromatography on silica gel [CHCl3—MeOH (20:1)] to
give 4l (355 mg, 87%) as a pale yellow solid.
1
3-(2-Oxo-2-phenylethyl)-1,3,4-thiadiazol-2(3H)-iminium Bromide (4a)23 Colorless solid; H NMR
(500 MHz, DMSO-d6) ! 6.11 (s, 2H), 7.60-7.68 (m, 2H), 7.74-7.81 (m, 1H), 8.02-8.09 (m, 2H), 9.02 (s,
13
1H), 9.96 (brs, 2H); C NMR (125 MHz, DMSO-d6) ! 57.3, 128.3, 128.8, 133.5, 134.4, 145.1, 167.9,
190.1; IR (KBr) 3004, 1635, 1566, 1448, 1418, cm-1; ESI-MS m/z: calcd for C10H10N3OS [M–Br]+,
220.0545; found, 220.0535. Anal. Calcd for C10H10BrN3OS: C, 40.1; H, 3.36; N, 14.00. Found: C, 40.03;
H, 3.53; N, 13.99%.
3-[2-Oxo-2-(thiophen-2-yl)ethyl]-1,3,4-thiadiazol-2(3H)-iminium Bromide (4b)
Yellow plate
(MeOH); 1H NMR (500 MHz, DMSO-d6) ! 6.01 (s, 2H), 7.38 (dd, J = 3.9, 4.8 Hz, 1H), 8.18 (dd, J = 1.0,
3.8 Hz, 1H), 8.20 (dd, J = 0.9, 4.9 Hz, 1H), 9.00 (s, 1H), 9.96 (brs, 2H); 13C NMR (125 MHz, DMSO-d6)
! 56.6, 129.1, 135.1, 136.5, 139.4, 145.0, 168.1, 183.2; IR (KBr) 2994, 1670, 1627, 1562, 1520, 1408,
1249, 1066 cm-1; ESI-MS m/z: calcd for C8H8N3OS2 [M–Br]+, 226.0109; found, 226.0093. Anal. Calcd for
C8H8BrN3OS2: C, 31.38; H, 2.63; N, 13.72. Found: C, 31.29; H, 2.74; N, 13.61%.
3-[2-(Benzofuran-2-yl)-2-oxoethyl]-1,3,4-thiadiazol-2(3H)-iminium Bromide (4c) Pale red needle
1
(MeOH—THF); H NMR (500 MHz, DMSO-d6) ! 6.01 (s, 2H), 7.41–7.48 (m, 1H), 7.59–7.67 (m, 1H),
13
7.78–7.84 (m, 1H), 7.91–7.97 (m, 1H), 8.14 (d, J = 0.7 Hz, 1H), 9.03 (s, 1H), 9.96 (brs, 2H); C NMR
(125 MHz, DMSO-d6) ! 56.6, 112.3, 115.8, 123.9, 124.4, 126.3, 129.2, 145.2, 149.3, 155.0, 168.1, 180.8;
IR (KBr) 2997, 1686, 1627, 1561, 1417, 1343, 1287, 1171, 1142, 1112, 1025 cm-1; ESI-MS m/z: calcd for
C12H10N3O2S [M–Br]+, 260.0494; found, 260.0516. Anal. Calcd for C12H10BrN3O2S: C, 42.37; H, 2.96; N,
12.35. Found: C, 42.16; H, 3.10; N, 12.37%.
3-[2-(5-Methyl-3-phenylisoxazol-4-yl)-2-oxoethyl]-1,3,4-thiadiazol-2(3H)-iminium Bromide (4d)
Colorless solid; 1H NMR (500 MHz, DMSO-d6) ! 2.89 (s, 3H), 5.53 (s, 2H), 7.45–7.61 (m, 5H), 8.95 (s,
13
1H), 9.86 (brs, 2H); C NMR (125 MHz, DMSO-d6) ! 14.3, 58.7, 113.9, 127.9, 128.3, 129.1, 123.0,
144.9, 161.9, 167.8, 176.2, 184.0; IR (KBr) 3023, 1698, 1561, 1416, 1291, 1228, 1139, 1075 cm-1;
ESI-MS m/z: calcd for C14H13N4O2S [M–Br]+, 301.0759; found, 301.0764.
5-Methyl-3-(2-oxo-2-phenylethyl)-1,3,4-thiadiazol-2(3H)-iminium Bromide (4e)23 Colorless solid;
1H NMR (500 MHz, DMSO-d6) ! 2.58 (s, 3H), 6.03 (s, 2H), 7.60–7.68 (m, 2H), 7.74–7.80 (m, 1H),
13
8.01–8.08 (m, 2H), 9.90 (brs, 2H); C NMR (125 MHz, DMSO-d6) ! 15.8, 57.1, 128.3, 128.9, 133.5,

HETEROCYCLES, Vol. 89, No. 4, 2014
1047
134.4, 154.1, 168.4, 190.1; IR (KBr) 3001, 1689, 1582, 1552, 1447, 1411, 1347, 1238, 1123 cm-1;
ESI-MS m/z: calcd for C11H12N3OS [M–Br]+, 234.0701; found, 234.0683. Anal. Calcd for C11H12BrN3OS:
C, 42.05; H, 3.85; N, 13.37. Found: C, 41.75; H, 3.91; N, 13.54%.
5-Methyl-3-[2-oxo-2-(thiophen-2-yl)ethyl]-1,3,4-thiadiazol-2(3H)-iminium Bromide (4f)
Brown
solid; 1H NMR (500 MHz, DMSO-d6) ! 2.56 (s, 3H), 5.94 (s, 2H), 7.38 (dd, J = 3.9, 4.8 Hz, 1H), 8.18 (dd,
13
J = 1.0, 3.8 Hz, 1H), 8.21 (dd, J = 1.0, 4.9 Hz, 1H), 9.93 (brs, 2H); C NMR (125 MHz, DMSO-d6) !
15.8, 56.4, 129.1, 135.1, 136.5, 139.4, 154.2, 168.6, 183.2; IR (KBr) 2997, 1667, 1632, 1554, 1520, 1412,
1254, 1068 cm-1; ESI-MS m/z: calcd for C9H10N3OS2 [M–Br]+, 240.0265; found, 240.0243. Anal. Calcd
for C9H10BrN3OS2: C, 33.76; H, 3.15; N, 13.12. Found: C, 33.60; H, 3.30; N, 13.00%.
3-[2-(Benzofuran-2-yl)-2-oxoethyl]-5-methyl-1,3,4-thiadiazol-2(3H)-iminium
Bromide
(4g)
1
Colorless solid; H NMR (500 MHz, DMSO-d6) ! 2.58 (s, 3H), 5.97 (s, 2H), 7.41–7.48 (m, 1H),
13
7.60–7.66 (m, 1H), 7.79–7.84 (m, 1H), 7.91–7.97 (m, 1H), 8.15 (s, 1H), 10.03 (brs, 2H); C NMR (125
MHz, DMSO-d6) ! 15.8, 56.3, 112.3, 115.8, 124.0, 124.4, 126.4, 129.2, 149.3, 154.3, 155.0, 168.6, 180.8;
IR (KBr) 2992, 1684, 1632, 1556, 1411, 1343, 1287, 1175, 1143, 1029 cm-1; ESI-MS m/z: calcd for
C13H12N3O2S [M–Br]+, 274.0650; found, 274.0655. Anal. Calcd for C13H12BrN3O2S: C, 44.08; H, 3.41; N,
11.86. Found: C, 43.86; H, 3.69; N, 11.64%.
5-Methyl-3-[2-(5-methyl-3-phenylisoxazol-4-yl)-2-oxoethyl]-1,3,4-thiadiazol-2(3H)-iminium Bromide
1
(4h) Colorless needle (MeOH); H NMR (500 MHz, CDCl3) ! 2.34 (s, 3H), 2.77 (s, 3H), 4.81 (s, 2H),
13
7.49–7.59 (m, 3H), 7.59–7.68 (m, 2H), 8.13 (brs, 2H); C NMR (125 MHz, CDCl3) ! 14.1, 16.8, 57.0,
115.0, 128.5, 129.0, 129.3, 130.4, 147.6, 161.4, 165.2, 176.6, 186.7; IR (KBr) 2925, 1694, 1570, 1416,
1292, 1231, 1138, 1075 cm-1; ESI-MS m/z: calcd for C15H15N4O2S [M–Br]+, 315.0916; found, 315.0917.
Anal. Calcd for C15H15BrN4O2S: C, 45.58; H, 3.82; N, 14.17. Found: C, 45.43; H, 3.85; N, 14.05%.
5-Ethyl-3-(2-oxo-2-phenylethyl)-1,3,4-thiadiazol-2(3H)-iminium Bromide (4i)23 Colorless needle
(MeOH); 1H NMR (500 MHz, DMSO-d6) ! 1.25 (t, J = 7.5 Hz, 3H), 2.94 (q, J = 7.5 Hz, 2H), 6.00 (s, 2H),
7.60–7.66 (m, 2H), 7.74–7.80 (m, 1H), 8.02–8.07 (m, 2H), 9.82 (brs, 2H); 13C NMR (125 MHz,
DMSO-d6) ! 12.1, 23.3, 57.1, 128.3, 128.9, 133.5, 134.4, 159.2, 168.2, 190.1; IR (KBr) 2995, 1687, 1580,
1548, 1448, 1409, 1345, 1233, 1122 cm-1; ESI-MS m/z: calcd for C12H13N3NaOS [M–HBr+Na]+,
270.0677; found, 270.0665. Anal. Calcd for C12H14BrN3OS: C, 43.91; H, 4.30; N, 12.80. Found: C, 43.71;
H, 4.23; N, 12.69%.

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5-Ethyl-3-[2-oxo-2-(thiophen-2-yl)ethyl]-1,3,4-thiadiazol-2(3H)-iminium Bromide (4j)
Colorless
1
solid; H NMR (500 MHz, DMSO-d6) ! 1.23 (t, J = 7.5 Hz, 3H), 2.94 (q, J = 7.5 Hz, 2H), 5.95 (s, 2H),
7.38 (dd, J = 3.9, 4.9 Hz, 1H), 8.18 (dd, J = 1.0, 3.9 Hz, 1H), 8.21 (dd, J = 1.0, 4.9 Hz, 1H), 9.93 (brs,
2H); 13C NMR (125 MHz, DMSO-d6) ! 12.1, 23.3, 56.5, 129.1, 135.1, 136.5, 139.4, 159.3, 168.3, 183.2;
IR (KBr) 2989, 1676, 1630, 1552, 1515, 1408, 1250, 1066 cm-1; ESI-MS m/z: calcd for C10H11N3NaOS2
[M–HBr+Na]+, 276.0241; found, 276.0267. Anal. Calcd for C10H12BrN3OS2: C, 35.93; H, 3.62; N, 12.57.
Found: C, 35.68; H, 3.78; N, 12.54%.
3-[2-(Benzofuran-2-yl)-2-oxoethyl]-5-ethyl-1,3,4-thiadiazol-2(3H)-iminium Bromide (4k) Colorless
1
solid; H NMR (500 MHz, DMSO-d6) ! 1.25 (t, J = 7.5 Hz, 3H), 2.95 (q, J = 7.5 Hz, 2H), 5.94 (s, 2H),
7.41–7.47 (m, 1H), 7.60–7.66 (m, 1H), 7.78–7.84 (m, 1H), 7.91–7.96 (m, 1H), 8.13 (d, J = 0.8 Hz, 1H),
13
9.93 (brs, 2H); C NMR (125 MHz, DMSO-d6) ! 12.1, 23.3, 56.4, 112.3, 115.8, 123.9, 124.4, 126.4,
129.2, 149.3, 155.0, 159.4, 168.4, 180.8; IR (KBr) 2979, 1685, 1633, 1552, 1413, 1347, 1290, 1176, 1144,
1115, 1031 cm-1; ESI-MS m/z: calcd for C14H14N3O2S [M–Br]+, 288.0807; found, 288.0821. Anal. Calcd
for C14H14BrN3O2S: C, 45.66; H, 3.83; N, 11.41. Found: C, 45.39; H, 3.66; N, 11.43%.
5-Ethyl-3-[2-(5-methyl-3-phenylisoxazol-4-yl)-2-oxoethyl]-1,3,4-thiadiazol-2(3H)-iminium Bromide
(4l) Colorless column (MeOH); 1H NMR (500 MHz, CDCl3) ! 1.29 (t, J = 7.6 Hz, 3H), 2.79 (q, J = 7.5
Hz, 2H), 2.80 (s, 3H), 5.23 (s, 2H), 7.51–7.57 (m, 3H), 7.69–7.75 (m, 2H), 9.87 (brs, 2H); 13C NMR (125
MHz, CDCl3) ! 12.3, 14.5, 24.1, 59.6, 114.6, 128.1, 129.0, 129.6, 130.5, 159.8, 161.4, 168.3, 177.3,
183.9; IR (KBr) 2979, 1695, 1633, 1579, 1417, 1292 cm-1; ESI-MS m/z: calcd for C16H17N4O2S [M–Br]+,
329.1072; found, 329.1043.
Typical Procedure for Preparation of Imidazo[2,1-b][1,3,4]thiadiazole 1
A solution of 4a (30 mg, 0.1 mmol) in EtOH (0.5 mL) was irradiated at 150 °C for 4 min utilizing a
Biotage Initiator® microwave synthesizer. After being concentrated in vacuo, the residue was treated with
0.2N Na2CO3 aq (0.5 mL) and then extracted with CHCl3 (30 mL x 2). The extract was dried over
anhydrous MgSO4, filtered, and concentrated in vacuo to afford 1a (20 mg, 100%) as a pale orange solid.
6-Phenylimidazo[2,1-b][1,3,4]thiadiazole (1a)23,28 Orange needle (EtOH), mp 128.5–129.0 °C (lit.,23,28
1
130–132 °C); H NMR (500 MHz, CDCl3) ! 7.29–7.34 (m, 1H), 7.39–7.45 (m, 2H), 7.81–7.86 (m, 2H),
8.10 (s, 1H), 8.52 (s, 1H); 13C NMR (125 MHz, CDCl3) ! 109.5, 125.2, 127.7, 128.7, 133.8, 144.3, 146.4,
147.6; IR (KBr) 3138, 3055, 1490, 1439, 1336, 1255, 1168, 1070 cm-1; ESI-MS m/z: calcd for C10H8N3S
[M+H]+, 202.0439; found, 202.0443. Anal. Calcd for C10H7N3S: C, 59.68; H, 3.51; N, 20.88. Found: C,

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59.64; H, 3.64; N, 20.76%.
6-(Thiophen-2-yl)imidazo[2,1-b][1,3,4]thiadiazole (1b) Colorless needle (CHCl3—n-hexane), mp
124.0–125.0 °C; 1H NMR (500 MHz, CDCl3) ! 7.07 (dd, J = 3.6, 5.1 Hz, 1H), 7.27 (dd, J = 1.1, 5.1 Hz,
13
1H), 7.34 (dd, J = 1.1, 3.6 Hz, 1H), 8.01 (s, 1H), 8.51 (s, 1H); C NMR (125 MHz, CDCl3) ! 108.9,
122.9, 124.6, 127.7, 137.3, 142.6, 144.2, 146.5; IR (KBr) 3142, 3062, 1800, 1476, 1363, 1318, 1258,
1208, 1159, 1017 cm-1; ESI-MS m/z: calcd for C8H6N3S2 [M+H]+, 208.0003; found, 208.0015.
6-(Benzofuran-2-yl)imidazo[2,1-b][1,3,4]thiadiazole (1c) Brown needle (EtOH), mp 188.0–190.0 °C;
1H NMR (500 MHz, CDCl3) ! 7.12 (d, J = 0.7 Hz, 1H), 7.21–7.32 (m, 2H), 7.49–7.54 (m, 1H), 7.58–7.63
13
(m, 1H), 8.22 (s, 1H), 8.57 (s, 1H); C NMR (125 MHz, CDCl3) ! 102.1, 110.9, 111.1, 121.0, 123.0,
124.4, 128.9, 139.3, 145.1, 147.1, 150.9, 154.6; IR (KBr) 3093, 1632, 1486, 1444, 1258, 1171, 1058 cm-1;
ESI-MS m/z: calcd for C12H7N3NaOS [M+Na]+, 264.0208; found, 264.0195.
4-(Imidazo[2,1-b][1,3,4]thiadiazol-6-yl)-5-methyl-3-phenylisoxazole (1d) Yellow needle (EtOH), mp
1
178.0–179.0 °C; H NMR (500 MHz, CDCl3) ! 2.68 (s, 3H), 7.38–7.48 (m, 3H), 7.49 (s, 1H), 7.57–7.62
13
(m, 2H), 8.53 (s, 1H); C NMR (125 MHz, CDCl3) ! 12.3, 109.4, 112.2, 128.6, 128.7, 129.3, 129.6,
137.4, 143.8, 146.7, 161.3, 168.2; IR (KBr) 3159, 3111, 2921, 1640, 1487, 1226, 1168 cm-1; ESI-MS m/z:
calcd for C14H10N4NaOS [M+Na]+, 305.0473; found, 305.0455. Anal. Calcd for C14H10N4OS: C, 59.56; H,
3.57; N, 19.85. Found: C, 59.43; H, 3.82; N, 19.56%.
2-Methyl-6-phenylimidazo[2,1-b][1,3,4]thiadiazole (1e)28,29 Yellow plate (EtOH), mp 140.0–141.0 °C
1
(lit.,28 135–137 °C, lit.,29 137–139 °C); H NMR (500 MHz, CDCl3) ! 2.71 (s, 3H), 7.26–7.31 (m, 1H),
13
7.38–7.43 (m, 2H), 7.79–7.83 (m, 2H), 7.96 (s, 1H); C NMR (125 MHz, CDCl3) ! 17.8, 109.1, 125.0,
127.5, 128.7, 134.0, 145.7, 146.1, 159.2; IR (KBr) 3117, 1604, 1478, 1258, 1200, 1062 cm-1; ESI-MS
m/z: calcd for C11H9N3NaS [M+Na]+, 238.0415; found, 238.0408. Anal. Calcd for C11H9N3S: C, 61.37; H,
4.21; N, 19.52. Found: C, 61.27; H, 4.13; N, 19.48%.
2-Methyl-6-(thiophen-2-yl)imidazo[2,1-b][1,3,4]thiadiazole (1f)
Yellow column (EtOH), mp
169.0–170.0 °C; 1H NMR (500 MHz, CDCl3) ! 2.71 (s, 3H), 7.06 (dd, J = 3.6, 5.0 Hz, 1H), 7.25 (dd, J =
1.1, 5.1 Hz, 1H), 7.32 (dd, J = 1.1, 3.6 Hz, 1H), 7.87 (s, 1H); 13C NMR (125 MHz, CDCl3) ! 17.8, 108.5,
122.5, 124.2, 127.6, 137.6, 141.0, 145.5, 159.4; IR (KBr) 3142, 3060, 2918, 1796, 1542, 1476, 1268,
1196, 1045 cm-1; ESI-MS m/z: calcd for C9H8N3S2 [M+H]+, 222.0160; found, 222.0170. Anal. Calcd for
C9H7N3S2: C, 48.85; H, 3.19; N, 18.99. Found: C, 48.69; H, 3.28; N, 18.84%.

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6-(Benzofuran-2-yl)-2-methylimidazo[2,1-b][1,3,4]thiadiazole (1g)30 Orange needle (EtOH), mp
1
178.0–179.0 °C (lit.,30 >250 °C); H NMR (500 MHz, CDCl3) ! 2.74 (s, 3H), 7.07 (d, J = 0.7 Hz, 1H),
13
7.21–7.30 (m, 2H), 7.48–7.52 (m, 1H), 7.57–7.61 (m, 1H), 8.09 (s, 1H); C NMR (125 MHz, CDCl3) !
17.9, 101.5, 110.6, 111.0, 120.9, 123.0, 124.2, 129.0, 137.8, 146.5, 151.2, 154.6, 160.0; IR (KBr) 3142,
1632, 1444, 1255, 1171, 1063 cm-1; ESI-MS m/z: calcd for C13H9N3NaOS [M+Na]+, 278.0364; found,
278.0354. Anal. Calcd for C13H9N3OS: C, 61.16; H, 3.55; N, 16.46. Found: C, 61.02; H, 3.71; N, 16.21%.
5-Methyl-4-(2-methylimidazo[2,1-b][1,3,4]thiadiazol-6-yl)-3-phenylisoxazole (1h) Colorless needle
1
(EtOH), mp 174.5–175.5 °C; H NMR (500 MHz, CDCl3) ! 2.66 (s, 3H), 2.70 (s, 3H), 7.35 (s, 1H),
13
7.37–7.48 (m, 3H), 7.55–7.63 (m, 2H); C NMR (125 MHz, CDCl3) ! 12.3, 17.8, 109.5, 111.9, 128.5,
128.7, 129.3, 129.5, 135.7, 145.2, 159.6, 161.2, 168.0; IR (KBr) 3113, 1637, 1468, 1277, 1194, 1055
cm-1; ESI-MS m/z: calcd for C15H12N4NaOS [M+Na]+, 319.0630; found, 319.0632.
2-Ethyl-6-phenylimidazo[2,1-b][1,3,4]thiadiazole (1i)23 Colorless plate (EtOH); mp 129.0–130.0 °C
1
(lit.,23 127–128 °C); H NMR (500 MHz, CDCl3) ! 1.44 (t, J = 7.6 Hz, 3H), 3.03 (q, J = 7.6 Hz, 2H),
13
7.26–7.31 (m, 1H), 7.38–7.43 (m, 2H), 7.79–7.84 (m, 2H), 7.96 (s, 1H); C NMR (125 MHz, CDCl3) !
12.9, 25.7, 109.1, 125.0, 127.4, 128.7, 134.0, 145.3, 146.0, 165.7; IR (KBr) 3139, 2964, 1605, 1526, 1478,
1192 cm-1; ESI-MS m/z: calcd for C12H12N3S [M+H]+, 230.0752; found, 230.0752. Anal. Calcd for
C12H11N3S: C, 62.86; H, 4.84; N, 18.33. Found: C, 62.85; H, 4.90; N, 18.35%.
2-Ethyl-6-(thiophen-2-yl)imidazo[2,1-b][1,3,4]thiadiazole (1j)
Colorless needle (EtOH), mp
124.0–125.5 °C; 1H NMR (500 MHz, CDCl3) ! 1.43 (t, J = 7.6 Hz, 3H), 3.03 (q, J = 7.6 Hz, 2H), 7.06 (dd,
J = 3.6, 5.1 Hz, 1H), 7.25 (dd, J = 1.1, 5.1 Hz, 1H), 7.32 (dd, J = 1.1, 3.6 Hz, 1H), 7.87 (s, 1H); 13C NMR
(125 MHz, CDCl3) ! 13.0, 25.7, 108.5, 122.5, 124.1, 127.6, 137.7, 141.0, 145.2, 165.9; IR (KBr) 3138,
3064, 1791, 1465, 1268, 1198, 1049 cm-1; ESI-MS m/z: calcd for C10H10N3S2 [M+H]+, 236.0316; found,
236.0302. Anal. Calcd for C10H9N3S2: C, 51.04; H, 3.85; N, 17.86. Found: C, 50.94; H, 4.06; N, 17.56%.
6-(Benzofuran-2-yl)-2-ethylimidazo[2,1-b][1,3,4]thiadiazole (1k)
Brown needle (EtOH), mp
129.0–130.0 °C; 1H NMR (500 MHz, CDCl3) ! 1.46 (t, J = 7.6 Hz, 3H), 3.05 (q, J = 7.6 Hz, 2H), 7.07 (d,
J = 0.7 Hz, 1H), 7.20–7.30 (m, 2H), 7.47–7.53 (m, 1H), 7.57–7.62 (m, 1H), 8.08 (s, 1H); 13C NMR (125
MHz, CDCl3) ! 12.9, 25.8, 101.5, 110.6, 111.0, 120.9, 123.0, 124.1, 129.0, 137.7, 146.2, 151.3, 154.6,
166.4; IR (KBr) 3131, 2973, 2937, 2917, 1632, 1444 cm-1; ESI-MS m/z: calcd for C14H12N3OS [M+H]+,
270.0701; found, 270.0676. Anal. Calcd for C14H11N3OS: C, 62.43; H, 4.12; N, 15.60. Found: C, 62.28; H,
4.42; N, 15.53%.

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4-(2-Ethylimidazo[2,1-b][1,3,4]thiadiazol-6-yl)-5-methyl-3-phenylisoxazole (1l)
Colorless needle
(EtOH), mp 132.0–133.5 °C; 1H NMR (500 MHz, CDCl3) ! 1.43 (t, J = 7.6 Hz, 3H), 2.66 (s, 3H), 3.02 (q,
J = 7.6 Hz, 2H), 7.35 (s, 1H), 7.38–7.47 (m, 3H), 7.57–7.65 (m, 2H); 13C NMR (125 MHz, CDCl3) ! 12.3,
13.0, 25.7, 109.6, 111.8, 128.6, 128.7, 129.4, 129.5, 135.8, 144.9, 161.3, 166.0, 168.0; IR (KBr) 3115,
2972, 1641, 1528, 1468, 1241, 1185, 1056 cm-1; ESI-MS m/z: calcd for C16H14N4NaOS [M+Na]+,
333.0786; found, 333.0785. Anal. Calcd for C16H14N4OS: C, 61.92; H, 4.55; N, 18.05. Found: C, 61.88; H,
4.63; N, 17.99%.
ACKNOWLEDGEMENTS
This work was supported in part by a Grant for the Regional Innovation Cluster Program (Global Type)
promoted by MEXT.
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10.039(1) Å, c = 16.092(2) Å, " = 93.953(3) °, V = 1936.5(4) Å3, Z = 4, Dcalc = 1.404 g/cm3,
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27. Crystal data for 1l: C16H14N4OS, M = 310.37, triclinic, P-1 (No. 2), a = 5.6466(3) Å, b = 11.1503 (6)

HETEROCYCLES, Vol. 89, No. 4, 2014
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Å, c = 12.9232(9) Å, ! = 66.584(3) °, " = 82.763(3) °, $ = 89.608(2) °, V = 739.87(8) Å3, Z = 2, Dcalc
= 1.393 g/cm3, #(Mo-K!) = 2.26 cm-1. Deposition number CCDC-980272 for compound 1l contains
the supplementary crystallographic data. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
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