Novel pyridazine fused heterocyclic system: A new route for the synthesis of 2-alkyl/aryl[1,3,4]thiadiazole[2′,3′:2,3] imidazo[4,5-d ]pyridazin-8(7H)-one

Article abstract of DOI:10.1080/00397910600602511

A series of novel imidazo[2,1- b][1,3,4]thiadiazole fused pyridazinones have been synthesized in moderate yields by the reaction of 2-alkyl/ arylimidazo[2,1- b ] [1,3,4]thiadiazole-6-carbohydrazides under Vilsmeier-Haack reaction conditions. This simple m

Full text of DOI:10.1080/00397910600602511

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Novel Pyridazine Fused Heterocyclic
System: A New Route for the Synthesis of
2‐Alkyl/Aryl[1,3,4]Thiadiazole[2′,3′:2,3]
Imidazo[4,5‐d]Pyridazin‐8(7H)‐One
Gundurao Kolavi a , Vinayak Hegde a & Imtiyaz Ahmed Khazi a
a Department of Chemistry, Karnatak University, Dharwad, India
Published online: 18 Aug 2006.
To cite this article: Gundurao Kolavi , Vinayak Hegde & Imtiyaz Ahmed Khazi (2006): Novel Pyridazine
Fused Heterocyclic System: A New Route for the Synthesis of 2‐Alkyl/Aryl[1,3,4]Thiadiazole[2′,3′:2,3]
Imidazo[4,5‐d]Pyridazin‐8(7H)‐One, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 36:13, 1837-1843
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Synthetic Communicationsw, 36: 1837–1843, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910600602511
Novel Pyridazine Fused Heterocyclic
System: A New Route for the Synthesis of
2-Alkyl/Aryl[1,3,4]Thiadiazole[20,30:2,3]
Imidazo[4,5-d]Pyridazin-8(7H)-One
Gundurao Kolavi, Vinayak Hegde, and Imtiyaz Ahmed Khazi
Department of Chemistry, Karnatak University, Dharwad, India
Abstract: A series of novel imidazo[2,1-b][1,3,4]thiadiazole fused pyridazinones have
been synthesized in moderate yields by the reaction of 2-alkyl/arylimidazo[2,1-b]
[1,3,4]thiadiazole-6-carbohydrazides under Vilsmeier–Haack reaction conditions.
This simple methodology has utility for the synthesis of various fused heterocyclic
systems.
Keywords: Imidazo[2,1-b][1,3,4]thiadiazole, pyridazinones, Vilsmeier–Haack reaction
INTRODUCTION
The ring systems 1,3,4-thiadiazole and imidazo[2,1-b][1,3,4]thiadiazoles are
well explored in pharmacological and biological fields.[1–5] Therefore,
several methods have been developed for the preparation of these derivatives.
In view of these facts we have developed a method wherein a pyridazine
nucleus has been incorporated. Although the Vilsmeier–Haack reaction has
mainly been employed in the synthesis of aldehydes, we applied this
reaction to the synthesis of heterocyclic systems by trapping the intermediate
by intramolecular nucleophilic attack. We synthesized a series of 2-alkyl/
aryl[1,3,4]thiadiazole[20,30:2,3]imidazo[4,5-d]pyridazin-8(7H)-ones (5a–f).
The products are characterized by elemental analysis data, IR, NMR, and
mass spectral analysis. See Scheme 1 and 2.
Received in India December 16, 2005
Address correspondence to Imtiyaz Ahmed Khazi, Department of Chemistry,
Karnatak University, Dharwad 580 003, India. E-mail: dr_imk@yahoo.com
1837

1838
G. Kolavi, V. Hegde, and I. A. Khazi
Scheme 1.
DISCUSSION
The required 2-amino-5-alkyl/aryl-1,3,4-thiadiazoles[6] and bromoethyl
pyruvate[7] were prepared as per literature methods. The reaction of 1,3,4-thia-
diazoles (1a–f) with bromoethylpyruvate (2) yielded the corresponding
2-alkyl/aryl imidazothiadiazole-6-carboxylates (3a–f) in moderate yields.
The formation of these compounds is supported by the presence of sharp
band around 1725 cm21 due to ester carbonyl and absence of yNH in IR
1
spectrum. The H NMR displayed characteristic triplet and quartet for ethyl
group of ester around d 1.40 and 4.40, respectively, and the singlet around
d 8.2 was assigned to the imidazole proton (C5-H), confirming the cyclization.
Compounds 3a–f are quantitatively transformed into the corresponding
hydrazides (4a–f) by treatment with hydrazine hydrate. The hydrazides
were established by IR spectra, where yNH bands appeared in the region
3100–3400 cm21 and yCO around 1650 cm21. Decrease in the carbonyl
stretching frequency evidenced the conversion of ester to hydrazide.
The reaction of the hydrazides (4a–f) under Vilsmeier–Haack reaction
conditions did not afford the expected 5-formyl derivatives, but instead it
gave the cyclized products (5a–f) in moderate yields. The IR spectra of these
compounds clearly indicated the absence of two yNH (of NH2) bands,
whereas the and yCO band appeared around 1695 cm21, confirming the
Scheme 2. Mechanism.

Pyridazine Fused Heterocyclic Systems
1839
conversion of hydrazide (yCO 1650 cm21) to pyridazine. The 1H NMR spectra
showed the absence of C5-H/aldehydic proton as well as NH2 protons of
hydrazide. However, the presence of signals around d 12.2 (1H, NH) and 8.5
(s, 1H, CH55N) confirmed the formation of pyridazine. They were further
characterized by mass spectra. The proposed mechanism for the formation of
the pyridazine derivative is given later. It can be noted that during the
formation of the pyridazine derivative the formyl compound was not formed.
EXPERIMENTAL
Melting points were determined in open capillaries and are uncorrected. The
IR spectra were recorded on Nicolet Impact 410 FT IR spectrophotometer
1
using KBr pellets. H and 13C NMR were recorded on Bruker 300-MHz FT
NMR spectrometer in CDCl3 and DMSO-d6 with TMS as internal standard.
Mass spectrum was recorded on Micromass Walter instrument by the
electron-impact technique, and elemental analysis was carried out using a
Heraus CHN rapid analyzer.
Preparation of ethyl-2-alkyl/arylimidazo[2,1-b][1,3,4]thiadiazole-
6-carboxylate (3a–f), General Method
2-Alkyl/aryl-1,3,4-thiadiazole (0.02 mol) and bromoethylpyruvate (3.9 g,
0.02 mol) were refluxed in dry ethanol (25 mL) for 6 h. The solvent was
removed under reduced pressure, the residual sticky mass was suspended in
water and neutralized with sodium carbonate solution (pH 7), and the
separated solid was extracted with chloroform (3 ꢀ 25 mL), washed with
water, and dried over sodium sulphate. The solvent was removed under dimin-
ished pressure to yield the sticky mass, which was purified by column chrom-
atography using an appropriate solvent.
Data
Ethyl 2-ethylimidazo[2,1-b][1,3,4]thiadiazole-6-carboxylate (3a): Yield
35%; colorless solid (hexane); mp 52–548C; Rf 0.53 (benzene); IR (KBr)
1
ycm21 1722, 1588, 1523, 1443; H NMR (C6D6) d 1.43 (t, J ¼ 6 Hz, 3H,
CH3, ethyl), 1.49 (t, 3H, J ¼ 6.3 Hz, CH3, ester), 3.19 (q, J ¼ 6 Hz, 2H,
CH2, ethyl), 4.43 (q, J ¼ 6.3 Hz, 2H, CH2, ester), 8.25 (s, 1H, C5-H,
imidazole). Anal. calcd. for C9H11N3O2S: C, 47.99; H, 4.92; N, 18.65;
found: C, 48.10; H, 4.98; N, 18.81%.
Ethyl 2-propylimidazo[2,1-b][1,3,4]thiadiazole-6-carboxylate (3b): Yield
38%; colorless solid (benzene); mp 124–1268C; Rf 0.61 (benzene); IR
(KBr) ycm21 2871, 1720, 1637, 1534; 1H NMR (CDCl3) d 1.07

1840
G. Kolavi, V. Hegde, and I. A. Khazi
(t, J ¼ 7.2 Hz, 3H, CH3, propyl); 1.41 (t, 3H, J ¼ 6.9 Hz, CH3, ester); 1.90
(sextet, JCH CH ¼ 7.2 Hz, JCH CH ¼ 7.5 Hz, 2H, CH2, propyl); 2.98
2
3
2
2
(t, J ¼ 7.5 Hz, 2H, CH2, propyl); 4.42 (q, J ¼ 7.2 Hz, 2H, CH2, ester); 8.28
(s, 1H, C5-H, imidazole); 13C NMR (CDCl3) d 13.72 (CH3, propyl), 14.67
(CH3, ester), 22.34 (CH2, propyl), 34.35 (CH2, propyl), 61.24 (CH2, of
ester), 118.53, 137.43, 146.36, 162.77, 167.83. Anal. calcd. for
C10H13N3O2S: C, 50.19; H, 5.48; N, 17.56; found: C, 50.52; H, 5.33; N,
17.77%.
Ethyl 2-cyclohexylimidazo[2,1-b][1,3,4]thiadiazole-6-carboxylate (3c):
Yield 41%; colorless solid (hexane–ethylacetate); mp 88–908C; Rf. 0.4
(9:1 v/v hexane–EtOAc); IR(KBr) ycm21 2981, 2930, 1703, 1577, 1522;
1H NMR (C6D6) d 1.04–1.81 (m, 13H, cyclohexyl and CH3), 2.50 (m, 1H,
C1-H, cyclohexyl), 4.33 (q, 2H, J ¼ 7.2 Hz, CH2), 8.22 (s, 1H, C5-H,
imidazole); 13C NMR (C6D6) d 14.57 (CH3, ester), 14.58 (C4 cyclohexyl),
25.78 (C3, C5 cyclohexyl), 32.44 (C2, C6 cyclohexyl), 41.36 (C1 cyclohexyl),
60.60 (CH2 ester), 118.51, 138.34, 145.87, 162.64, 172.25 (C55O). Anal.
calcd. for C13H17N3O2S: C, 55.89; H, 6.13; N, 15.04; found: C, 55.98; H,
6.19; N, 15.32%.
Ethyl 2-benzylimidazo[2,1-b][1,3,4]thiadiazole-6-carboxylate (3d): Yield
40%; colorless solid (hexane–ethylacetate); mp 142–1448C; Rf 0.5 (8:2 v/v
1
hexane–EtOAc); IR (KBr) ycm21 1706, 1569, 1527; H NMR (C6D6) d
1.17 (t, J ¼ 7.2 Hz, 3H, CH3, ester), 3.72 (s, 2H, CH2), 4.31 (q, J ¼ 6.9 Hz,
2H, CH2, ester); 7.00–7.15 (m, 5H, phenyl), 8.16 (s, 1H, C5-H imidazole);
13C NMR (C6D6) d 14.55 (CH3 ester), 38.06 (CH2), 60.72 (CH2CO),
127.86, 128.18, 129.31, 129.36, 135.40, 138.31, 146.52, 162.64, 166.69
(C55O). Anal. calcd. for C14H13N3O2S: C, 58.52; H, 4.56; N, 14.62; found:
C, 58.81; H, 4.71; N, 14.88%.
Ethyl 2-thien-2-ylimidazo[2,1-b][1,3,4]thiadiazole-6-carboxylate (3e):
Yield 48%; colorless solid (hexane–ethylacetate); mp 148–1508C; Rf 0.6
(7:3 v/v hexane–EtOAc); IR (KBr) ycm21 1725, 1547, 1511, 1469;
1H NMR (CDCl3) d 1.44 (t, J ¼ 6.9 Hz, 3H, CH3), 4.45 (q, J ¼ 6.9 Hz, 2H,
CH2), 7.19 (dd, J ¼ 3 Hz and 3.3 Hz, 1H, C4-H, thienyl), 7.52–7.61
(m, 2H, C3, C5-H, thienyl), 8.34 (s, 1H, C5-H, imidazole). Anal. calcd. for
C11H9N3O2S2: C, 47.30; H, 3.25; N, 15.04; found: C, 47.39; H, 3.32; N,
15.41%.
Ethyl 2-(2-furyl)imidazo[2,1-b][1,3,4]thiadiazole-6-carboxylate (3f): Yield
43%; pale yellow solid (hexane–ethylacetate); mp 152–1548C; Rf 0.54
(7:3 v/v hexane–EtOAc); IR (KBr) ycm21 1718, 1542, 1535; 1H NMR
(CDCl3) d 1.43 (t, J ¼ 7.2 Hz, 3H, CH3, ester), 4.45 (q, J ¼ 6.9 Hz, 2H,
CH2, ester), 6.67 (dd, JH H ¼ 3 Hz, JH H ¼ 3 Hz, 1H, C4-H, furyl), 7.12
3
4
4
5
(d, J ¼ 3 Hz, 1H, C3-H, furyl), 7.54 (d, J ¼ 3 Hz, 1H, C5-H, furyl), 8.31
(s, 1H, C5-H, imidazole). Anal. calcd. for C11H9N3O3S: C, 50.18; H, 3.45;
N, 15.96; found: C, 50.25; H, 3.27; N, 16.09%.

Pyridazine Fused Heterocyclic Systems
1841
Preparation of 2-alkyl/arylimidazo[2,1-b][1,3,4]thiadiazole-6-
carbohydrazide (4a–f)
2-Alkyl/arylimidazo[2,1-b][1,3,4]thiadiazole-6-carboxylate (4a–f, 0.01 mol)
was refluxed in ethanol (25 mL) with hydrazine hydrate (1.5 mL) for 6 h.
The colorless solid that separated was collected by filtration, washed with
alcohol, dried, and the crude product was recrystallized from ethanol.
Data
2-Ethylimidazo[2,1-b][1,3,4]thiadiazole-6-carbohydrazide (4a): Yield 77%;
colorless solid (ethanol); mp 188–1908C; IR (KBr) ycm21 3346, 3256, 3179,
1648, 1542. Anal. calcd. for C7H9N5OS: C, 39.80; H, 4.29; N, 33.15; found:
C, 39.73; H, 4.42; N, 33.47%.
2-Propylimidazo[2,1-b][1,3,4]thiadiazole-6-carbohydrazide (4b): Yield 84%;
colorless prisms (ethanol); mp 196–1988C; IR (KBr) ycm21 3255, 3105, 3094,
1661, 1541, 1435. Anal. calcd. for C8H11N5OS: C, 42.65; H, 4.92; N, 31.09;
found: C, 42.78; H, 5.03; N, 31.26%.
2-Cyclohexylimidazo[2,1-b][1,3,4]thiadiazole-6-carbohydrazide (4c): Yield
84%; colorless needles (ethanol); mp 168–1708C; IR (KBr) ycm21 3333,
3315, 3197, 1663, 1584, 1559. Anal. calcd. for C11H15N5OS: C, 49.79; H,
5.70; N, 26.39; found: C, 49.91; H, 5.78; N, 26.54%.
2-Benzylimidazo[2,1-b][1,3,4]thiadiazole-6-carbohydrazide (4d): Yield 79%;
colorless crystalline solid (ethanol); mp 186–1888C; IR (KBr) ycm21 3351
(broad), 3173, 1648, 1555. Anal. calcd. for C12H11N5OS: C, 52.73; H, 4.06; N,
25.62; found: C, 52.85; H, 4.19; N, 25.80%.
2-Thien-2-ylimidazo[2,1-b][1,3,4]thiadiazole-6-carbohydrazide (4e): Yield
90%; colorless solid (ethanol); mp 198–2008C; IR (KBr) ycm21 3311, 3285,
3196, 1645, 1548, 1458. Anal. calcd. for C9H7N5OS2: C, 40.74; H, 2.66; N,
26.40; found: C, 40.90; H, 2.49; N, 26.71%.
2-(2-Furyl)imidazo[2,1-b][1,3,4]thiadiazole-6-carbohydrazide (4f): Yield
90%; pale yellow solid (ethanol); mp 206–2088C; IR (KBr) ycm21 3420,
3315 (broad), 1648, 1541. Anal. calcd. for C9H7N5O2S: C, 43.37; H, 2.83;
N, 28.10; found: C, 43.46; H, 2.99; N, 28.29%.
Preparation of 2-alkyl/aryl[1,3,4]thiadiazolo[20,30:2,3]
imidazo[4,5-d]pyridazin-8(7H)-one (5a–f)
Vilsmeier reagent was prepared by adding phosphorylchloride (1.5 mL) to
dimethylformamide (10 mL) at 08C with stirring. Then appropriately
substituted 2-alkyl/arylimidazo[2,1-b][1,3,4]thiadiazole-6-carbohydrazide

1842
G. Kolavi, V. Hegde, and I. A. Khazi
(4a–f, 0.005 mol) was added to the reagent and stirred at 08C for 30 min. The
mixture was further stirred for 2 h at room temperature and at 608C for additional
2 h. The reaction mixture was then poured in sodium carbonate solution
and stirred at 908C for 2 h. After cooling, the mixture was diluted with water.
The solid separated was collected by filtration, washed with water, dried, and
recrystallized from an appropriate solvent as pale yellow solids.
Data
2-Ethyl[1,3,4]thiadiazole[20,30:2,3]imidazo[4,5-d]pyridazin-8(7H)-one
(5a): Yield 56%; pale yellow solid (ethanol); mp 182–1848C; IR (KBr)
1
ycm21 3172, 1696, 1564, 1513; H NMR (CDCl3) d 1.44 (t, J ¼ 6 Hz, 3H,
CH3), 3.21 (q, J ¼ 6.3 Hz, 2H, CH2), 8.75 (s, 1H, CH55N), 12.52 (br s, 1H,
NH, D2O exchangeable). Anal. calcd. for C8H7N5O S: C, 43.43; H, 3.19; N,
31.66; found: C, 43.31; H, 3.28; N, 31.84%.
2-Propyl[1,3,4]thiadiazole[20,30:2,3]imidazo[4,5-d]pyridazin-8(7H)-one
(5b): Yield, 52%; pale yellow solid (ethanol); mp 176–1788C; IR (KBr)
d 1.05
ycm21 3221, 1694, 1556, 1504, 1467; 1H NMR (CDCl3)
(t, J ¼ 7.2 Hz, 3H, CH3), 1.90 (sextet, JCH CH ¼ 7.2 Hz, JCH CH ¼ 7.2 Hz,
2
3
2
2
2H, CH2), 2.98 (t, J ¼ 7.2 Hz, 2H, CH2), 8.68 (s, 1H, CH55N), 12.61 (br s,
1H, NH, D2O exchangeable). Anal. calcd. for C9H9N5OS: C, 45.95; H,
3.86; N, 29.77; found: C, 45.99; H, 3.97; N, 29.92%.
2-Cyclohexyl[1,3,4]thiadiazole[20,30:2,3]imidazo[4,5-d]pyridazin-8(7H)-
one (5c): Yield, 41%; pale yellow solid (ethanol); mp 174–1768C; IR (KBr)
ycm21 3301, 1692, 1545; 1H NMR (DMSO-d6) d 1.30–2.36 (m, 10H, cyclo-
hexyl), 3.25 (m, 1H, C1-H, cyclohexyl), 8.57 (s, 1H, CH55NH), 12.02 (br s,
1H, NH, D2O exchangeable). Anal. calcd. for C12H13N5OS: C, 52.35; H,
4.76; N, 25.44; found: C, 52.21; H, 4.89; N, 25.63%.
2-Benzyl[1,3,4]thiadiazole[20,30:2,3]imidazo[4,5-d]pyridazin-8(7H)-one
(5d): Yield, 51%; pale yellow solid (ethanol); mp 196–1988C;
1
IR(KBr)ycm21 3291, 1695, 1535; H NMR (CDCl3) d 3.78 (s, 1H, CH2,
benzyl), 7.01–7.16 (m, 5H, phenyl), 8.88 (s, 1H, CH55N), 12.62 (br s, 1H,
NH, D2O exchangeable). Anal. calcd. for C13H9N5OS: C, 55.11; H, 3.20;
N, 24.72; found: C, 55.02; H, 3.29; N, 24.98%.
2-Thien-2-yl[1,3,4]thiadiazole[20,30:2,3]imidazo[4,5-d]pyridazin-8(7H)-
one (5e): Yield, 58%; pale yellow solid (methanol); mp 178–1808C; IR (KBr)
1
ycm21 3147, 1700, 1546, 1518; H NMR (DMSO-d6) d 7.29 (dd, JH H
¼
3
4
4.2 Hz, JH H ¼ 4.8 Hz, 1H, C4-H, thienyl), 7.93 (d, J ¼ 3.3 Hz, 1H, C3-H,
4
5
thienyl), 7.99 (d, J ¼ 4.8 Hz, 1H, C5-H, thienyl), 8.77 (s, 1H, CH55N),
12.76 (br s, 1H, NH, D2O exchangeable). Anal. calcd. for C10H5N5OS2:
C, 43.63; H, 1.83; N, 25.44; found: C, 43.75; H, 2.09; N, 25.73%; Mass,
m/z (%) Mþ, 275 (100).

Pyridazine Fused Heterocyclic Systems
1843
2-(2-Furyl)[1,3,4]thiadiazole[20,30:2,3]imidazo[4,5-d]pyridazin-8(7H)-one
(5f): Yield 39%; pale yellow solid (methanol); mp 178–1808C; IR (KBr)
1
ycm21 3186, 1694, 1573, 1522; H NMR (DMSO-d6) d 6.82 (dd, JH H
¼
3
4
3 Hz, JH H ¼ 3.3 Hz, 1H, C4-H, furyl), 7.35 (d, J ¼ 3 Hz, 1H, C3-H, furyl),
4
5
7.62 (d, J ¼ 3.3 Hz, 1H, C5-H, furyl), 8.69 (s, 1H, CH ¼ N), 12.12 (br s,
1H, NH, D2O exchangeable). Anal. calcd. for C10H5N5O2S: C, 46.33; H,
1.94; N, 27.01; found: C, 46.45; H, 1.33; N, 27.39%.
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