HETEROCYCLES

Short Paper | Regular issue | Vol. 89, No. 4, 2014, pp. 1041-1053
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

Molecular Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokushima, 1-78 Sho-machi, Tokushima 770-8505, Japan

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 α-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 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.

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 α-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.

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 2-amino-1,3,4-thiadiazole 2 and α-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

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

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. IR spectra were obtained using a JASCO FT/IR-6200 IR Fourier transform spectrometer. 1H NMR (500 MHz) and 13C NMR (125 MHz) spectra were recorded on Bruker AV500 spectrometers, respectively. Chemical shifts are given in δ 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 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.

3-(2-Oxo-2-phenylethyl)-1,3,4-thiadiazol-2(3H)-iminium Bromide (4a)23 Colorless solid; 1H NMR (500 MHz, DMSO-d6) δ 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, 1H), 9.96 (brs, 2H); 13C NMR (125 MHz, DMSO-d6) δ 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) δ 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) δ 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 (MeOH—THF); 1H NMR (500 MHz, DMSO-d6) δ 6.01 (s, 2H), 7.41–7.48 (m, 1H), 7.59–7.67 (m, 1H), 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); 13C NMR (125 MHz, DMSO-d6) δ 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) δ 2.89 (s, 3H), 5.53 (s, 2H), 7.45–7.61 (m, 5H), 8.95 (s, 1H), 9.86 (brs, 2H); 13C NMR (125 MHz, DMSO-d6) δ 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) δ 2.58 (s, 3H), 6.03 (s, 2H), 7.60–7.68 (m, 2H), 7.74–7.80 (m, 1H), 8.01–8.08 (m, 2H), 9.90 (brs, 2H); 13C NMR (125 MHz, DMSO-d6) δ 15.8, 57.1, 128.3, 128.9, 133.5, 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) δ 2.56 (s, 3H), 5.94 (s, 2H), 7.38 (dd, J = 3.9, 4.8 Hz, 1H), 8.18 (dd, J = 1.0, 3.8 Hz, 1H), 8.21 (dd, J = 1.0, 4.9 Hz, 1H), 9.93 (brs, 2H); 13C NMR (125 MHz, DMSO-d6) δ 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) Colorless solid; 1H NMR (500 MHz, DMSO-d6) δ 2.58 (s, 3H), 5.97 (s, 2H), 7.41–7.48 (m, 1H), 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); 13C NMR (125 MHz, DMSO-d6) δ 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(4h) Colorless needle (MeOH); 1H NMR (500 MHz, CDCl3) δ 2.34 (s, 3H), 2.77 (s, 3H), 4.81 (s, 2H), 7.49–7.59 (m, 3H), 7.59–7.68 (m, 2H), 8.13 (brs, 2H); 13C NMR (125 MHz, CDCl3) δ 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) δ 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) δ 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%.

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.,23,28 130–132 °C); 1H NMR (500 MHz, CDCl3) δ 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) δ 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, 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) δ 7.07 (dd, J = 3.6, 5.1 Hz, 1H), 7.27 (dd, J = 1.1, 5.1 Hz, 1H), 7.34 (dd, J = 1.1, 3.6 Hz, 1H), 8.01 (s, 1H), 8.51 (s, 1H); 13C NMR (125 MHz, CDCl3) δ 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) δ 7.12 (d, J = 0.7 Hz, 1H), 7.21–7.32 (m, 2H), 7.49–7.54 (m, 1H), 7.58–7.63 (m, 1H), 8.22 (s, 1H), 8.57 (s, 1H); 13C NMR (125 MHz, CDCl3) δ 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 178.0–179.0 °C; 1H NMR (500 MHz, CDCl3) δ 2.68 (s, 3H), 7.38–7.48 (m, 3H), 7.49 (s, 1H), 7.57–7.62 (m, 2H), 8.53 (s, 1H); 13C NMR (125 MHz, CDCl3) δ 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 (lit.,28 135–137 °C, lit.,29 137–139 °C); 1H NMR (500 MHz, CDCl3) δ 2.71 (s, 3H), 7.26–7.31 (m, 1H), 7.38–7.43 (m, 2H), 7.79–7.83 (m, 2H), 7.96 (s, 1H); 13C NMR (125 MHz, CDCl3) δ 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) δ 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) δ 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%.

6-(Benzofuran-2-yl)-2-methylimidazo[2,1-b][1,3,4]thiadiazole (1g)30 Orange needle (EtOH), mp 178.0–179.0 °C (lit.,30 >250 °C); 1H NMR (500 MHz, CDCl3) δ 2.74 (s, 3H), 7.07 (d, J = 0.7 Hz, 1H), 7.21–7.30 (m, 2H), 7.48–7.52 (m, 1H), 7.57–7.61 (m, 1H), 8.09 (s, 1H); 13C NMR (125 MHz, CDCl3) δ 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 (EtOH), mp 174.5–175.5 °C; 1H NMR (500 MHz, CDCl3) δ 2.66 (s, 3H), 2.70 (s, 3H), 7.35 (s, 1H), 7.37–7.48 (m, 3H), 7.55–7.63 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 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 (lit.,23 127–128 °C); 1H NMR (500 MHz, CDCl3) δ 1.44 (t, J = 7.6 Hz, 3H), 3.03 (q, J = 7.6 Hz, 2H), 7.26–7.31 (m, 1H), 7.38–7.43 (m, 2H), 7.79–7.84 (m, 2H), 7.96 (s, 1H); 13C NMR (125 MHz, CDCl3) δ 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) δ 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) δ 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) δ 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) δ 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%.

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) δ 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) δ 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.

References

1. B. A. Bhongade, S. Talath, R. A. Gadad, and A. K. Gadad, J. Saudi Chem. Soc., 2014, in press.
2. G. Tegginamath, R. R. Kamble, T. Taj, P. P. Kattimani, and G. Y. Meti, Med. Chem. Res., 2013, 22, 4367; CrossRef M. N. Noolvi, H. M. Patel, S. Kamboj, A. Kaur, and V. Mann, Eur. J. Med. Chem., 2012, 56, 56; CrossRef M. N. Noolvi, H. M. Patel, N. Singh, A. K. Gadad, S. S. Cameotra, and A. Badiger, Eur. J. Med. Chem., 2011, 46, 4411; CrossRef S. S. Karki, K. Panjamurthy, S. Kumar, M. Nambiar, S. A. Ramareddy, K. K. Chiruvella, and S. C. Raghavan, Eur. J. Med. Chem., 2011, 46, 2109; CrossRef N. Terzioglu and A. Gürsoy, Eur. J. Med. Chem., 2003, 38, 781. CrossRef
3. T. M. Gireesh, R. R. Kamble, and T. Taj, Pharm. Chem. J., 2011, 45, 313. CrossRef
4. K. F. M. Atta, O. O. M. Farahat, A. Z. A. Ahmed, and M. G. Marei, Molecules, 2011, 16, 5496; CrossRef A. K. Gadad, C. S. Mahajanshetti, S. Nimbalkar, and A. Raichurkar, Eur. J. Med. Chem., 2000, 35, 853. CrossRef
5. S. D. Joshi, K. Manish, and A. Badiger, Med. Chem. Res., 2013, 22, 869. CrossRef
6. B. Chandrakantha, A. M. Isloor, P. Shetty, H. K. Fun, and G. Hegde, Eur. J. Med. Chem., 2014, 71, 316. CrossRef
7. V. K. Bhovi and Y. D. Bodke, Curr. Chem. Biol., 2010, 4, 145.
8. S. G. Alegaon, K. R. Alagawadi, P. V. Sonkusare, S. M. Chaudhary, D. H. Dadwe, and A. S. Shah, Bioorg. Med. Chem. Lett., 2012, 22, 1917; CrossRef G. Kolavi, V. Hegde, I. A. Khazi, and P. Gadad, Bioorg. Med. Chem., 2006, 14, 3069; CrossRef A. K. Gadad, M. N. Noolvi, and R. V. Karpoormath, Bioorg. Med. Chem., 2004, 12, 5651. CrossRef
9. C. S. Andotra, T. C. Langer, and A. Kotha, J. Indian Chem. Soc., 1997, 74, 125.
10. P. Kumar, Chin. J. Chem., 2010, 28, 250. CrossRef
11. S. G. Alegaon and K. R. Alagawadi, Eur. J. Chem., 2011, 2, 94; CrossRef F. A. Ashour, N. S. Habib, M. El Taibbi, S. El Dine, and A. S. El Dine, Il Farmaco, 1990, 45, 1341.
12. I. A. Khazi, C. S. Mahajanshetti, A. K. Gadad, A. D. Tarnalli, and C. M. Sultanpur, Arzneim. Forsch., 1996, 46, 949.
13. H. M. Patel, M. N. Noolvi, A. Goyal, and B. S. Thippeswamy, Eur. J. Med. Chem., 2013, 65, 119. CrossRef
14. V. B. Jadhav, M. V. Kulkarni, V. P. Rasal, S. S. Biradar, and M. D. Vinay, Eur. J. Med. Chem., 2008, 43, 1721. CrossRef
15. A. Andreani, A. Leoni, A. Locatelli, R. Morigi, M. Rambaldi, W. A. Simon, and J. Senn-Bilfinger, Arzneim. Forsch., 2000, 50, 550.
16. A. H. Salehi, S. J. Morris, W.-C. Ho, K. M. Dickson, G. Doucet, S. Milutinovic, J. Durkin, J. W. Gillard, and P. A. Barker, Chem. Biol., 2006, 13, 213. CrossRef
17. A. Marin, N. Valls, F. J. Berenguer, M. T. Alonso, A. Ramon Martínez, M. Mercedes Martínez, and J. Elguero, Il Farmaco, 1992, 47, 63.
18. A. Andreani, M. Rambaldi, A. Locatelli, S. Malandrino, and G. Pifferi, Arzneim. Forsch., 1994, 44, 618.
19. V. J. Ram and N. Haque, Indian J. Chem., Sec B, 1996, 35B, 238.
20. A. Andreani, M. Rambaldi, A. Locatelli, R. Bossa, G. Salvatore, and I. Galatulas, Eur. J. Med. Chem., 1994, 29, 339. CrossRef
21. K. Ohta, S. Itoh, Y. Kandou, H. Yoshikawa, and Y. Ishida, J. Pesticide Sci., 1994, 19, 137. CrossRef
22. T. Zarganes-Tzitzikas, C. G. Neochoritis, J. Stephanidou-Stephanatou, C. A. Tsoleridis, G. Buth, and G. E. Kostakis, Tetrahedron, 2013, 69, 5008. CrossRef
23. T. Matsukawa and S. Ban, Yakugaku Zasshi, 1952, 72, 610.
24. M. Kidwai, D. Bhatnagar, and R. Chauhan, J. Heterocycl. Chem., 2013, 50, E234; CrossRef S. Dhepe, S. Kumar, R. Vinayakumar, S. A. Ramareddy, and S. S. Karki, Med. Chem. Res., 2012, 21, 1550; CrossRef K. Tiwari, P. K. Verma, S. B. Singh, and J. Singh, Synth. Commun., 2012, 42, 3021; CrossRef C. Copin, N. Henry, F. Buron, and S. Routier, Eur. J. Org. Chem., 2012, 3079; CrossRef I. A. M. Khazi, A. K. Gadad, R. S. Lamani, and B. A. Bhongade, Tetrahedron, 2011, 67, 3289. CrossRef
25. X. Wang, M. Wang, Z. Quan, and Z. Li, Synth. Commun., 2005, 35, 2881; CrossRef X.-C. Wang, M.-G. Wang, Z. Yang, Z.-J. Quan, F. Wang, and Z. Li, J. Chem. Res., 2005, 11, 744. CrossRef
26. Crystal data for 4l: C16H17BrN4O2S, M = 409.30, monoclinic, P21/a (No. 14), a = 12.015(1) Å, b = 10.039(1) Å, c = 16.092(2) Å, β = 93.953(3) °, V = 1936.5(4) Å3, Z = 4, Dcalc = 1.404 g/cm3, μ(Mo-Kα) = 22.51 cm-1. Deposition number CCDC-980273 for compound 4l 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.
27. Crystal data for 1l: C16H14N4OS, M = 310.37, triclinic, P-1 (No. 2), a = 5.6466(3) Å, b = 11.1503 (6) Å, c = 12.9232(9) Å, α = 66.584(3) °, β = 82.763(3) °, γ = 89.608(2) °, V = 739.87(8) Å3, Z = 2, Dcalc = 1.393 g/cm3, μ(Mo-Kα) = 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.
28. M. Kidwai and S. Rastogi, Indian J. Chem., Sec B, 2006, 45B, 2321; M. Kidwai and S. Rastogi, Lett. Org. Chem., 2006, 3, 149. CrossRef
29. S. Ban, Yakugaku Zasshi, 1954, 74, 1044.
30. R. Rani and J. K. Makrandi, Indian J. Heterocycl. Chem., 2008, 18, 121.