Synthesis of some novel fused imidazo [2, 1-b] [1, 3] thiazole and imidazo [2, 1-b] thiazolo [5, 4-d] isoxazole derivatives

Article abstract of DOI:10.1155/2012/896454

In this work we describe the synthesis of some novel fused imidazo [2, 1-b] [1, 3] thiazole derivatives. The reaction of 1, 2-diaminoethane 1 with carbon disulphide in H₂O/ETOH as solvent furnishes 4, 5-dihydro-1H-imidazol- 2-thiol 2 under reflux condition. the reaction of 4, 5-dihydro-1H-imidazol-2- thiol on treatment with ethylchloro acetate and aromatic aldehyde in presence of anhydrous sodium acetate and acetic acid as solvent to give (Z)-2- (arylidene)-5, 6-dihydroimidazo [2, 1-b] [1, 3] thiazol-3 (2H)-one 3a-j. Compounds 3a-j was condensed with hydroxylamine to give 3- (aryl)-2, 3, 6, 7-tetrahydroimidazo [2, 1-b] [1, 3] thiazolo [5, 4-d] isoxazole 4a-j. The structures of the new compounds were established by elemental analyses, IR, ¹H NMR and ¹³C NMR data.

Full text of DOI:10.1155/2012/896454

ISSN: 0973-4945; CODEN ECJHAO
E-Journal of Chemistry
http://www.ejchem.net
2012, 9(3), 1518-1525
Synthesis of Some Novel Fused Imidazo
[2, 1-b] [1, 3] Thiazole and Imidazo [2, 1-b]
Thiazolo [5, 4-d] Isoxazole Derivatives
HAMID REZA JABERI and HADI NOORIZADEH*
Department of Chemistry, Faculty of Sciences
Ilam Branch, Islamic Azad University, Ilam Iran
Hadinoorizadeh@yahoo.com
Received 26 September 2011; Accepted 13 November 2011
Abstract: In this work we describe the synthesis of some novel fused imidazo
[2, 1-b] [1, 3] thiazole derivatives. The reaction of 1, 2-diaminoethane 1 with
carbon disulphide in H2O/ETOH as solvent furnishes 4, 5-dihydro-1H-
imidazol-2-thiol 2 under reflux condition. the reaction of 4,5-dihydro-1H-
imidazol-2-thiol on treatment with ethylchloro acetate and aromatic aldehyde
in presence of anhydrous sodium acetate and acetic acid as solvent to give (Z)-
2-(arylidene)-5,6-dihydroimidazo [2,1-b] [1,3] thiazol-3(2H)-one 3a-j.
Compounds 3a-j was condensed with hydroxylamine to give 3-(aryl)-2, 3, 6,
7-tetrahydroimidazo [2, 1-b] [1,3] thiazolo [5, 4-d] isoxazole 4a-j. The
structures of the new compounds were established by elemental analyses, IR,
1H NMR and 13C NMR data.
Keyword: Imidazole, Condensation, Synthesis, Imidazo [2, 1-b] [1, 3] thiazole, Heterocyclic compounds.
Introduction
In the family of heterocyclic compounds, nitrogen and sulfur containing heterocyles are an
important class of compounds in medicinal chemistry1. Thus, fused heterocyclic derivatives
with thiazole moiety are prospective objects in modern drug discovery. Various biologically
active synthetic compounds have five-membered nitrogen-containing heterocyclic ring in
their structures2. Structural frameworks have been described as privileged structures and in
particular, N-containing polycyclic structures have been reported to be associated with a
wide range of biological activity. In the field of five membered heterocyclic structures
imidazole nucleus shows various properties. The high therapeutic properties of the imidazole
related drugs have encouraged the medicinal chemists to synthesize a large number of novel
chemotherapeutic agents. Imidazole drugs have broadened scope in remedying various
dispositions in clinical medicines. A lot of work on the synthesis and biological activities of the
condensed imidazo [2, 1-b]-thiazoles has been reported. The imidazo [2, 1-b] [1, 3] thiazole
skeleton has been used as anthelmintic agents, anti-hypertensives, anti-inflammatories,
immunosuppressive agents, fungicides, herbicides, antitumor agents and cardiotonic agents3-14
.

Synthesis of Some Novel Fused Imidazo Isoxazole Derivatives 1519
Considering the potent bioactivities of compounds possessing an imidazothiazole core,
synthesizing new imidazo [2, 1-b] [1, 3] thiazole derivatives efficiently attracted our
attention15-18. In this paper we wish to report the synthesis of some novel fused imidazo
[2, 1-b] [1, 3] thiazole derivatives that probably all new synthesized compounds have
Pharmacology activities. The synthetic route is depicted in Figure 1. The structures of the
compounds were supported by elemental and spectral data.
Experimental
Melting points were determined using an electro thermal digital apparatus and are uncorrected.
IR spectra were recorded in film or in potassium bromide disks on a the Mattson Galaxy series
FT‐IR 5000 spectrophotometer (υ max in cm-1) and NMR spectra were recorded on Bruker
spectrophotometer (300 MHz) in DMSO‐d6 or CDCl3 using TMS as an internal standard.
Elemental analysis was performed on an Elemental Analyzer (Vario EL III). The progress of the
reaction was monitored on a ready made silicagel plates (Merck) using n-hexane: ethyl acetate as
a solvent system. Iodine was used as a developing agent. Spectral data (IR, NMR) confirmed the
structures of the synthesized compounds and the purity of these compounds were ascertained by
microanalysis. Elemental (C, H, N) analysis indicated that the calculated and observed values
were within the acceptable limits (±0.4%). Synthetic route is depicted in Figure 1.
Synthesis of 4, 5-dihydro-1H-imidazol-2-thiol (2)
To a solution of compound 1 (0.2 mol, 13.37 mL) in H2O/ETOH (20 mL), CS2 (0.2 mol,
7.31 mL) was added dropwise at (0–5°C), the mixture was refluxed under stirring for about
12 h. Then, the mixture was then cooled to room temperature and the crystalline product
which separated was removed by filtration. The crude product was crystallized from ethanol
to give the corresponding 4, 5-dihydro-1H-imidazol-2-thiol as fine white needles.
General procedure for the synthesis of compounds (3a-j)
A mixture of compound 2 (0.01 mol, 1.02 g), ethylchloro acetate (0.012 mol, 1.05 mL) and
anhydrous sodium acetate (0.025 mol, 2 g) in glacial acetic acid (30 mL), acetic anhydride (10 mL)
mixture and aromatic aldehyde (0.01 mol) was refluxed for 5-7 h, the reaction mixture was
cooled and poured onto cold water (100 mL), the solid formed was filtered off and crystallized
from appropriate solvent to give 3b-i. But for benzaldehyde and furfural (2-furaldehyde)
derivatives the solution was concentrated by evaporation under reduced pressure. Then the
solid was filtered off and crystallized from appropriate solvent to afford compounds 3a and 3j.
General procedure for the synthesis of compounds (4a-j)
A mixture of compound 3a-j (0.005 mol), hydroxylamine hydrochloride (0.005 mol, 0.04 g)
and anhydrous sodium acetate (0.0125 mol, 1 g) was refluxed in glacial acetic acid for 6-9 h.
The reaction mixture was allowed to cool and was poured into water (100 mL). The solid
substance was filtered off and crystallized from appropriate solvent to give compound 4a-j.
4, 5-Dihydro-1H-imidazol-2-thiol (2)
1
Yield 87%, M.p. 196-200 °C IR (KBr, cm-1): υ= 3271 (2NH), 1201(C=S). H NMR (300
MHz, DMSO-d6) δ/ppm: 3.15 (s, 4H, 2CH2), 7.82 (s, 2H, NH, exchangeable with D2O). 13
C
NMR (300 MHz, DMSO-d6) δ/ppm: 43.22, 183.12 Anal.calcd for C3H6N2S: C, 35.27; H,
5.92; N, 27.42; S, 31.39. Found: C, 35.20; H, 5.86; N, 27.45; S, 31.33.
(Z)-2-Benzylidene-5, 6-dihydroimidazo [2, 1-b] thiazol-3(2H)-one (3a)
Yield 63%, M.p. 143-145 °C IR (KBr, cm-1): υ= 3070 (aromatic C-H stretching), 1710
1
(C=O stretching), 1610 (-C=CH stretching), 1214 (C-N). H NMR (300 MHz, DMSO-
d6) δ/ppm: 3.72 (t, J= 5.25 Hz, 2H, CH2), 3.86 (t, J= 5.78 Hz, 2H, CH2), 7.45 (m, 5H,

HADI NOORIZADEH et al.
1520
Harom), 7.76 (s, 1H, Hmethylidene). 13C NMR (300 MHz, DMSO-d6) δ/ppm: 40.13, 46.22,
120.09, 127.85, 127.91, 128.06, 131.13, 138.55, 148.98, 165.25 Anal.calcd for
C12H10N2OS: C, 62.59; H, 4.38; N, 12.16; S, 13.92. Found: C, 62.50; H, 4.31; N, 12.11;
S, 13.88.
(Z)-2-(2-Hydroxybenzylidene)-5, 6-dihydroimidazo [2, 1-b] thiazol-3(2H)-one (3b)
Yield 58%, M.p. 258-260 °C IR (KBr, cm-1): υ= 3228 (-OH stretching), 3062 (aromatic
C-H stretching), 2938 (aliphatic C-H stretching), 1711 (C=O stretching), 1606 (-C=CH
1
stretching), 1237 (C-N). H NMR (300 MHz, DMSO-d6) δ/ppm: 3.52 (t, J= 4.65 Hz, 2H,
CH2), 3.70 (t, J= 5.28 Hz, 2H, CH2), 6.94-7.34 (m, 4H, Harom), 7.91 (s, 1H, Hmethylidene),
9.56 (bs, 1H, OH). 13C NMR (300 MHz, DMSO-d6) δ/ppm: 40.38, 46.49, 118.12,
118.20, 120.21, 120.64, 122.04, 122.22, 140.12, 150.02, 151.86, 165.50 Anal.calcd for
C12H10N2O2S: C, 58.52; H, 4.09; N, 11.37; S, 13.02. Found: C, 58.44; H, 3.95; N, 11.28;
S, 12.98.
(Z)-2-(4-Methylbenzylidene) - 5, 6-dihydroimidazo [2, 1-b] thiazol-3(2H)-one (3c)
Yield 68%, M.p. 165-167 °C IR (KBr, cm-1): υ= 2998 (aromatic C-H stretching), 1707 (C=O
stretching), 1619 (-C=CH stretching), 1216 (C-N). 1H NMR (300 MHz, CDCl3) δ/ppm: 2.37
(s, 3H, CH3), 3.66 (t, J= 4.92 Hz, 2H, CH2), 3.77 (t, J= 5.73 Hz, 2H, CH2), 7.24 (d, J= 7.70
Hz, 2H, Harom), 7.36 (d, J= 7.80 Hz, 2H, Harom), 7.65 (s, 1H, Hmethylidene). 13C NMR (300
MHz, CDCl3) δ/ppm: 21.46, 40.44, 46.80, 120.33, 129.60, 129.66, 129.79, 131.04, 139.83,
149.92, 165.15 Anal.calcd for C13H12N2OS: C, 63.91; H, 4.95; N, 11.47; S, 13.12. Found: C,
63.85; H, 4.89; N, 11.41; S, 13.07.
(Z)-2-(3-Methoxybenzylidene) - 5, 6-dihydroimidazo [2, 1-b] thiazol-3(2H)-one (3d)
Yield 65%, M.p. 137-139 °C IR (KBr, cm-1): υ= 3056 (aromatic C-H stretching), 2933
(aliphatic C-H stretching), 1708 (C=O stretching), 1617(-C=CH stretching), 1226 (C-N). 1H
NMR (300 MHz, CDCl3) δ/ppm: 2.18 (t, J= 4.85 HZ, 2H, CH2), 3.69 (t, J= 5.25 HZ, 2H,
CH2), 3.82 (s, 3H, OCH3), 6.94 (d, J= 7.84, 1H, Harom), 7.02 (s, 1H, Harom), 7.10 (d, J= 7.26,
1H, Harom), 7.37 (t, J= 7.78, 1H, Harom), 7.68 (s, 1H, Hmethylidene). 13C NMR (300 MHz,
CDCl3) δ/ppm: 40.19, 46.22, 57.33, 117.06, 118.42, 120.16, 120.78, 131.22, 132.63, 139.56,
149.17, 160.18, 165.28 Anal.calcd for C13H12N2O2S: C, 59.98; H, 4.65; N, 10.76; S, 12.32.
Found: C, 59.92; H, 4.62; N, 10.69; S, 12.29.
(Z)-2-(3-Bromobenzylidene) - 5, 6-dihydroimidazo [2, 1-b] thiazol-3(2H)-one (3e)
Yield 56%, M.p. 170-172 °C IR (KBr, cm-1): υ= 3057 (aromatic C-H stretching), 2957
(aliphatic C-H stretching), 1702 (C=O stretching), 1643 (-C=CH stretching), 1226 (C-N). 1H
NMR (300 MHz, CDCl3) δ/ppm: 3.69 (t, J= 5.19 Hz, 2H, CH2), 3.82 (t, J= 5.81 Hz, 2H,
CH2), 7.32 (t, J= 7.76 Hz, 1H, Harom), 7.41 (d, J= 7.57 Hz, 1H, Harom), 7.49(d, J= 7.68 Hz,
1H, Harom), 7.59(d, 2H, Harom + Hmethylidene). 13C NMR (300 MHz, CDCl3) δ/ppm: 40.23,
45.89, 119.95, 127.22, 128.15, 128.38, 129.53, 130.84, 133.24, 140.08, 150.10, 165.11
Anal.calcd for C12H9N2OSBr: C, 46.62; H, 2.93; N, 9.06; S, 10.37.Found: C, 46.66; H, 2.87;
N, 8.98; S, 10.34.
(Z)-2-(3-Chlorobenzylidene) - 5, 6-dihydroimidazo [2, 1-b] thiazol-3(2H)-one (3f)
Yield 54%, M.p. 161-162 °C IR (KBr, cm-1): υ= 3050 (aromatic C-H stretching), 2955
(aliphatic C-H stretching), 1698 (C=O stretching), 1632 (-C=CH stretching), 1219 (C-N). 1H
NMR (300 MHz, CDCl3) δ/ppm: 3.62 (t, J= 5.13 Hz, 2H, CH2), 3.78 (t, J= 5.87 Hz, 2H,
CH2), 7.37-7.52 (m, 4H, Harom), 7.56 (s, 1H, Hmethylidene). 13C NMR (300 MHz, CDCl3)
δ/ppm: 40.44, 46.07, 120.15, 126.88, 127.17, 127.36, 129.23, 131.30, 133.14, 139.88,

Synthesis of Some Novel Fused Imidazo Isoxazole Derivatives 1521
150.23, 165.32 Anal.calcd for C12H9N2OSCl: C, 46.62; H, 2.93; N, 9.06; S, 10.37.Found: C,
46.57; H, 2.86; N, 9.11; S, 10.32.
(Z)-2-(2-Nitrobenzylidene) - 5, 6-dihydroimidazo [2, 1-b] thiazol-3(2H)-one (3g)
Yield 55%, M.p. 114-116 °C IR (KBr, cm-1): υ= 3048 (aromatic C-H stretching), 2987
(aliphatic C-H stretching), 1713 (C=O stretching), 1623 (-C=CH stretching), 1524 (NO2
1
asym), 1231(C-N). H NMR (300 MHz, CDCl3) δ/ppm: 3.70 (t, J= 4.95 Hz, 2H, CH2), 3.87
(t, J= 5.50 Hz, 2H, CH2), 7.57 (t, J= 7.35 Hz, 1H, Haromat), 7.71 (m, 2H, Harom), 8.07 (s, 1H,
Hmethylidene), 8.14 (d, J= 8.04 Hz, 1H, Harom). 13C NMR (300 MHz, CDCl3) δ/ppm: 40.80,
46.75, 120.28, 125.70, 127.30, 127.41, 129.63, 131.43, 139.10, 141.18, 150.05, 165.42
Anal.calcd for C12H9N3O3S: C, 52.36; H, 3.30; N, 15.26; S, 11.65. Found: C, 52.29 H, 3.26;
N, 15.21; S, 11.61.
(Z)-2-(3-nitrobenzylidene) - 5, 6-dihydroimidazo [2, 1-b] thiazol-3(2H)-one (3h)
Yield 60%, M.p. 199-201 °C IR (KBr, cm-1): υ= 3061 (aromatic C-H stretching), 1709 (C=O
1
stretching), 1614 (-C=CH stretching), 1515 (NO2 asym), 1225 (C-N). H NMR (300 MHz,
CDCl3) δ/ppm: 3.72 (t, J= 5.15 Hz, 2H, CH2), 3.86 (t, J= 5.70 Hz, 2H, CH2), 7.66 (t, J= 7.99
Hz, 1H, Harom), 7.72 (s, 1H, Hmethylidene), 7.81 (d, J= 7.49 Hz ,1H, Harom), 8.23 (d, J= 7.86 Hz
1H, Harom), 8.35 (s, 1H, Harom). 13C NMR (300 MHz, CDCl3) δ/ppm: 41.06, 46.13, 120.36,
121.12, 122.55, 124.42, 129.62, 132.43, 138.82, 142.25, 149.22, 165.37 Anal.calcd for
C12H9N3O3S: C, 52.36; H, 3.30; N, 15.26; S, 11.65. Found: C, 52.31; H, 3.33; N, 15.21; S,
11.60.
(Z)-2-(4-Nitrobenzylidene) - 5, 6-dihydroimidazo [2, 1-b] thiazol-3(2H)-one (3i)
Yield 58%, M.p. 228-230 °C IR (KBr, cm-1): υ= 3050 (aromatic C-H stretching), 2973
(aliphatic C-H stretching), 1712 (C=O stretching), 1605 (-C=CH stretching), 1505 (NO2
1
asym), 1227 (C-N). H NMR (300 MHz, CDCl3) δ/ppm: 3.73 (t, J= 5.25 Hz, 2H, CH2)
3.86 (t, J= 5.81 Hz, 2H, CH2), 7.65 (d, 2H, J= 8.57 Hz, Harom), 7.73 (s, 1H, Hmethylidene),
8.32 (d, J= 8.52 Hz, 2H, Harom). 13C NMR (300 MHz, CDCl3) δ/ppm: 40.24, 46.38,
120.14, 126.25, 126.34, 132.74, 139.83, 145.73, 149.50, 165.31 Anal.calcd for
C12H9N3O3S: C, 52.36; H, 3.30; N, 15.26; S, 11.65. Found: C, 52.39; H, 3.26; N, 15.29;
S, 11.59.
(Z)-2-(Furan-2-ylmethylene) - 5, 6-dihydroimidazo [2, 1-b] thiazol-3(2H)-one (3j)
Yield 56%, M.p. 145-147 °C IR (KBr, cm-1) υ= 2982 (aromatic C-H stretching), 1709
1
(C=O stretching), 1618 (-C=CH stretching), 1231 (C-N). H NMR (300 MHz, DMSO-d6)
δ/ppm: 3.52 (t, 2H, J= 5.20 Hz, CH2), 3.68 (t, 2H, J= 5.71 Hz, CH2), 6.71 (t, 1H, Harom),
6.97 (d, 1H, Harom), 7.48 (s, 1H, Hmethylidene), 8.00 (d, 1H, Harom). 13C NMR (300 MHz,
DMSO-d6) δ/ppm: 40.32, 45.95, 116.08, 118.11, 122.26, 139.71, 144.44, 149.25, 150.51,
165.11 Anal.calcd for C10H8N2O2S: C, 54.53; H, 3.66; N, 12.72; S, 14.56. Found: C,
54.48; H, 3.69; N, 12.67; S, 14.51.
3-Phenyl-2, 3, 6, 7-tetrahydroimidazo [2, 1-b] thiazolo [5, 4-d] isoxazole (4a)
Yield 62%, M.p. 162-164 °C IR (KBr, cm-1): υ= 3170 (NH), 3024 (aromatic C-H stretching),
2985 (aliphatic C-H stretching), 1218(C-N). 1H NMR (300 MHz, DMSO-d6) δ/ppm: 3.62 (t, J=
5.35 Hz, 2H, CH2), 3.81 (t, J= 5.97 Hz, 2H, CH2), 4.67(s, 1H, C3-H), 7.38 (m, 5H, Harom), 10.45
(s, 1H, NH, exchangeable with D2O). 13C NMR (300 MHz, DMSO-d6) δ/ppm: 41.73, 46.91,
71.18, 96.12, 127.10, 127.26, 127.65, 131.27, 150.42, 169.12 Anal.calcd for C12H11N3OS: C,
58.76; H, 4.52; N, 17.13; S, 13.07.Found: C, 58.68; H, 4.47; N, 17.07; S, 13.12.

HADI NOORIZADEH et al.
1522
3-(2-Hydroxyphenyl)-2, 3, 6, 7-tetrahydroimidazo [2, 1-b] thiazolo [5, 4-d]
isoxazole (4b)
Yield 53%, M.p. 271-273 °C IR (KBr, cm-1): υ= 3320 (-OH), 3184 (NH), 3064 (aromatic C-
H stretching), 1219 (C-N). 1H NMR (300 MHz, DMSO-d6) δ/ppm: 3.49 (t, J= 4.85 Hz, 2H,
CH2), 3.68 (t, J= 5.47 Hz, 2H, CH2), 4.71(s, 1H, C3-H), 7.11-7.39 (m, 4H, Harom), 9.49 (bs,
1H, OH), 10.41 (s, 1H, NH, exchangeable with D2O). 13C NMR (300 MHz, DMSO-d6)
δ/ppm: 42.09, 46.89, 66.58, 95.76, 118.66, 120.83, 121.05, 125.55, 125.91, 149.78, 151.13,
170.02 Anal.calcd for C12H11N3O2S: C, 55.16; H, 4.24; N, 16.08; S, 12.27.Found: C, 55.09;
H, 4.27; N, 15.98; S, 12.22.
3-(4-Methylphenyl)-2, 3, 6, 7-tetrahydroimidazo [2, 1-b] thiazolo [5, 4-d] isoxazole
(4c)
Yield 57%, M.p. 180-182 °C IR (KBr, cm-1): υ= 3165 (NH), 3045 (aromatic C-H
1
stretching), 1229 (C-N). H NMR (300 MHz, CDCl3) δ/ppm: 2.57 (s, 3H, CH3), 3.68 (t, J=
5.10 Hz, 2H, CH2), 3.79 (t, J= 5.85 Hz , 2H, CH2), 4.65 (s, 1H, C3-H), 7.10 (d, J= 7.65 Hz,
2H, Harom), 7.26 (d, J= 7.70 Hz, 2H, Harom), 10.45 (s, 1H, NH, exchangeable with D2O). 13C
NMR (300 MHz, CDCl3) δ/ppm: 21.35, 42.21, 46.71, 67.83, 95.63, 127.70, 127.81, 128.13,
130.70, 149.85, 169.91 Anal.calcd for C13H13N3OS: C, 60.21; H, 5.05; N, 16.20; S,
12.36.Found: C, 60.17; H, 4. 98; N, 16.15; S, 12.31.
3-(3-Methoxyphenyl)-2, 3, 6, 7-tetrahydroimidazo [2, 1-b] thiazolo [5, 4-d]
isoxazole (4d)
Yield 52%, M.p. 151-152 °C IR (KBr, cm-1): υ= 3154 (NH), 3014 (aromatic C-H
1
stretching), 2933 (aliphatic C-H stretching), 1217 (C-N). H NMR (300 MHz, CDCl3)
δ/ppm: 2.41 (t, J= 4.70 Hz, 2H, CH2), 3.65 (t, J= 5.20 Hz, 2H, CH2), 3.75 (s, 3H, OCH3),
4.55 (s, 1H, C3-H), 6.75-6.89 (m, 3H, Harom), 7.15 (t, J= 7.55 Hz, 1H, Harom), 10.38 (s, 1H,
NH, exchangeable with D2O). 13C NMR (CDCl3) δ/ppm: 42.85, 46.73, 56.32, 70.12, 96.22,
116.88, 117.13, 119.14, 128.13, 131.24, 149.93, 152.23, 170.05 Anal.calcd for
C13H13N3O2S: C, 56.71; H, 4.76; N, 15.26; S, 11.65.Found: C, 56.65; H, 4.79; N, 15.21; S,
11.59.
3-(3-Bromophenyl)-2, 3, 6, 7-tetrahydroimidazo [2, 1-b] thiazolo [5, 4-d] isoxazole
(4e)
Yield 56%, M.p. 193-195 °C IR (KBr, cm-1): υ= 3162 (NH), 3067 (aromatic C-H
stretching), 2936 (aliphatic C-H stretching), 1234(C-N). 1H NMR (300 MHz, CDCl3)
δ/ppm: 3.62 (t, J= 5.21 Hz, 2H, CH2), 3.75 (t, J= 5.71 Hz, 2H, CH2), 4.61 (s, 1H, C3-H),
7.15-7.42 (m, 4H, Harom), 10.47 (s, 1H, NH, exchangeable with D2O). 13C NMR (CDCl3)
δ/ppm: 42.67, 46.65, 68.17, 96.38, 125.22, 126.10, 127.28, 129.53, 130.04, 138.71, 149.68,
171.03 Anal.calcd for C12H10N3OSBr: C, 44.46; H, 3.11; N, 12.96; S, 9.89. Found: C, 44.39;
H, 3.07; N, 12.91; S, 9.93.
3-(3-Chlorophenyl)-2, 3, 6, 7-tetrahydroimidazo [2, 1-b] thiazolo [5, 4-d] isoxazole
(3f)
Yield 53%, M.p. 183-185 °C IR (KBr, cm-1): υ= 3159 (NH), 3047 (aromatic C-H
stretching), 1228 (C-N). 1H NMR (300 MHz, CDCl3) δ/ppm: 3.65 (t, J= 5.05 Hz, 2H, CH2),
3.73(t, J= 5.64 Hz, 2H, CH2), 4.70 (s, 1H, C3-H), 7.23-7.49 (m, 4H, Harom), 10.41 (s, 1H,
NH, exchangeable with D2O). 13C NMR (CDCl3) δ/ppm: 42.74, 46.69, 70.15, 96.09, 126.15,
126.53, 126.78, 128.98, 130.12, 135.68, 149.16, 170.58 Anal.calcd for C12H10N3OSCl: C,
51.52; H, 3.60; N, 15.02; S, 11.46. Found: C, 51.56; H, 3.55; N, 14.97; S, 11.41.

Synthesis of Some Novel Fused Imidazo Isoxazole Derivatives 1523
3-(2-Nitrophenyl)-2, 3, 6, 7-tetrahydroimidazo [2, 1-b] thiazolo [5, 4-d] isoxazole
(4g)
Yield 55%, M.p. 132-134 °C IR (KBr, cm-1): υ= 3168 (NH), 3014 (aromatic C-H
1
stretching), 1549 (NO2 asym), 1213 (C-N). H NMR (300 MHz, CDCl3) δ/ppm: 3.61
(t, J= 4.83 Hz, 2H, CH2), 3.77 (t, J= 5.45 Hz, 2H, CH2), 4.63 (s, 1H, C3-H), 7.72-8.05 (m,
4H, Harom), 10.38 (s, 1H, NH, exchangeable with D2O). 13C NMR (CDCl3) δ/ppm: 42.07,
46.81, 65.83, 97.23, 125.14, 126.23, 126.36, 130.21, 132.21, 137.39, 150.02, 171.11
Anal.calcd for C12H10N4O3S: C, 49.65; H, 3.47; N, 19.30; S, 11.05. Found: C, 49.57; H,
3.39; N, 19.23; S, 10.98.
3-(3-Nitrophenyl)-2, 3, 6, 7-tetrahydroimidazo [2, 1-b] thiazolo [5, 4-d] isoxazole
(4h)
Yield 60%, M.p. 214-216 °C IR (KBr, cm-1): υ= 3171 (NH), 3074 (aromatic C-H
1
stretching), 2947 (aliphatic C-H stretching), 1537 (NO2 asym), 1216 (C-N). H NMR (300
MHz, CDCl3) δ/ppm: 3.66(t, J= 5.20 Hz, 2H, CH2), 3.74 (t, J= 5.73 Hz, 2H, CH2), 4.58 (s,
1H, C3-H), 7.57-7.69 (m, 2H, Harom), 8.04 (d, J= 7.65 Hz, 1H, Harom), 8.21 (s, 1H, Harom),
10.29 (s, 1H, NH, exchangeable with D2O). 13C NMR (CDCl3) δ/ppm: 42.61, 46.64, 66.12,
98.89, 123.03, 124.18, 126.68, 129.28, 130.89, 144.26, 150.23, 169.92 Anal.calcd for
C12H10N4O3S: C, 49.65; H, 3.47; N, 19.30; S, 11.05. Found: C, 49.60; H, 3.41; N, 19.25; S,
11.09.
3-(4-Nitrophenyl)-2, 3, 6, 7-tetrahydroimidazo [2, 1-b] thiazolo [5, 4-d] isoxazole
(4i)
Yield 63%, M.p. 240-242 °C IR (KBr, cm-1): υ= 3168 (NH), 3012 (aromatic C-H
1
stretching), 1510 (NO2 asym), 1222 (C-N). H NMR (300 MHz, CDCl3) δ/ppm: 3.66(t, J=
5.15 Hz, 2H, CH2), 3.72 (t, J= 5.60 Hz, 2H, CH2), 4.61 (s, 1H, C3-H), 7.49 (d, J= 8.45 Hz,
2H, Harom), 7.89 (d, J= 8.40 Hz, 2H, Harom), 10.25 (s, 1H, NH, exchangeable with D2O). 13C
NMR (CDCl3) δ/ppm: 42.53, 46.43, 68.11, 97.18, 126.08, 128.18, 141.26, 144.06, 149.73,
170.19 Anal.calcd for C12H10N4O3S: C, 49.65; H, 3.47; N, 19.30; S, 11.05. Found: C, 49.69;
H, 3.41; N, 19.23; S, 10.97.
3-(Furan-2-yl)-2, 3, 6, 7-tetrahydroimidazo [2, 1-b] thiazolo [5, 4-d] isoxazole (4j)
Yield 51%, M.p. 155-157 °C IR (KBr, cm-1) υ= 3173 (NH), 3019 (aromatic C-H stretching),
2942 (aliphatic C-H stretching), 1237 (C-N). 1H NMR (300 MHz, DMSO-d6) δ/ppm: 3.61 (t, J=
5.07 Hz, 2H, CH2), 3.78 (t, J= 5.56 Hz, 2H, CH2), 4.64 (s, 1H, C3-H), 6.61-67.15 (m, 3H, Harom),
10.37 (s, 1H, NH, exchangeable with D2O) 13C NMR (DMSO-d6) δ/ppm: 41.89, 46.13,
69.02, 95.84, 112.21, 113.37, 139.88, 148.13, 150.42 170.21 Anal.calcd for C10H9N3O2S: C,
51.05; H, 3.86; N, 17.86; S, 13.63. Found: C, 50.97; H, 3.80; N, 17.79; S, 13.57.
Results and Discussion
In this study we have prepared new imidazo [2, 1- b] [1, 3] thiazole derivatives from 4,
5-dihydro-1H-imidazol-2-thiol. The initial step in the synthetic method involved the
synthesis of 4, 5-dihydro-1H-imidazol-2-thiol 2 by refluxing 1, 2-diaminoethane and
carbon disulphide. The synthesis route of compounds is outlined in Figure 1. In the
second step, 4,5-dihydro-1H-imidazol-2-thiol 2 was refluxed with ethyl chloroacetate
and benzaldehyde derivatives in the presence of sodium acetate in acetic acid as solvent
to give (Z)-2-(arylidene)- 5,6-dihydroimidazo [2, 1-b] [1,3] thiazol-3(2H)-one 3a-j, The
presence of active methylene group in intermediate compound could be confirmed by
condensation with benzaldehyde derivatives in the presence of sodium acetate in a
mixture of glacial acetic acid/acetic anhydride to yield arylmethylene. The IR spectra of

HADI NOORIZADEH et al.
1524
the latter compounds showed the presence of C=O group. In the last step 3-(aryl)-2,
3, 6, 7-tetrahydroimidazo [2, 1-b] thiazolo [5, 4-d] isoxazole 4a-j were prepared
separately from (Z)-2-(arylidene)- 5,6-dihydroimidazo [2, 1-b] [1,3] thiazol-3(2H)-one
3a-j and hydroxylamine hydrochloride in glacial acetic acid and anhydrous sodium
acetate (Figure 1), according to reported methods15-18. No evidences for the presence of
C=O group in IR spectra. In addition, 1H NMR spectrum clearly shows the loss of
Hmethylidene leading to compounds 4a-j. In the present work the formulas of compounds
3a-j, 4a-j were found by elemental analysis and their structures were determined by IR,
1H-NMR and 13C-NMR spectra data.
H
N
SH
ClCH2COOEt,CH3COO Na
CS2
NH2(CH2)2NH2
1
H2O/ETOH
Ar CHO,CH3COOH, AC2O
N
2
O
O
NH
H
C
N
N
NH2OH,CH3COO Na
CH3COOH
Ar
Ar
N
S
N
H
S
3a-j
4a-j
Ar, 3a, 4a: C6H5, 3b, 4b: 2-OHC6H4, 3c,4c: 4-CH3C6H4, 3d, 4d: 3-OCH3C6H4, 3e, 4e: 3-BrC6H4, 3f,
4f: 3-ClC6H4, 3g, 4g: 2-NO3C6H4; 3h, 4h: 3- NO2C6H4, 3i, 4i: 4- NO2C6H4, 3j, 4j: C4H3O
Figure 1. Synthetic pathway for preparation of 4a-j.
The IR data were very informative and provided evidence for the formation of the
expected structures. The compounds were isolated in satisfactory yields (50-87%) and
purified by crystallization, using from appropriate solvent. In the IR spectra of 3a-j and
4a-j showed an absorption bond at 1214-1231 cm–1 for C-N, 3150-3185 cm–1 due to
NH and 1698-1713 cm–1 characteristic (C=O) of α,β-unsaturated ketone [this shift to
1
lower frequency is due to conjugation with exocyclic double bond]. Also, the H NMR
spectrum in DMSO-d6 and CDCl3 of compounds 3a-j and 4a-j is in agreement with its
structure, which revealed at 3.52-3.88 ppm due to aliphatic proton and all the aromatic
protons were observed at expected regions. The signal of NH groups appears as a broad
signal in the same range as those of the aromatic protons and OH proton was observed
as a broad at 9.50 ppm.
Conclusion
In conclusion, we have presented a facile route for the synthesis of new imidazo [2, 1- b] [1, 3]
thiazole derivatives using 4, 5-dihydro-1H-imidazol-2-thiol, This compound was used as a key
compound for this study and for further syntheses of other fused heterocyclic. Compound 2
was treated with ethyl chloroacetate and benzaldehyde derivatives to afford compound 3a-j.
These compounds were used to synthesize a series of new other compounds 4a-j by
condensation reaction with hydroxylamine hydrochloride. Because of the compounds 4a-j
having –NH– factors can be used for the synthesis of newer compounds. As it is mentioned
above probably all new synthesized compounds have Pharmacology activities.

Synthesis of Some Novel Fused Imidazo Isoxazole Derivatives 1525
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