Synthesis and reactions of some novel nicotinonitrile, thiazolotriazole, and imidazolotriazole derivatives for antioxidant evaluation

Article abstract of DOI:10.1080/00397910903079631

The novel 2-(1H)-pyridone, the lead compound of the pyridone derivative 1, reacted with an electrophilic reagent (ethyl chloroacetate) to give the corresponding ester 2. Condensation of compound 2 with thiosemicarbazide and/or hydrazine hydrate afforded t

Full text of DOI:10.1080/00397910903079631

This article was downloaded by: [Brown University]
On: 22 July 2012, At: 20:52
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered
office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An
International Journal for Rapid
Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and
subscription information:
http://www.tandfonline.com/loi/lsyc20
Synthesis and Reactions of Some Novel
Nicotinonitrile, Thiazolotriazole,
and Imidazolotriazole Derivatives for
Antioxidant Evaluation
Hayam H. Sayed a , Eman M. H. Morsy a & Eman M. Flefel a
a Photochemistry Department, National Research Center, Dokki,
Cairo, Egypt
Version of record first published: 07 Apr 2010
To cite this article: Hayam H. Sayed, Eman M. H. Morsy & Eman M. Flefel (2010): Synthesis and
Reactions of Some Novel Nicotinonitrile, Thiazolotriazole, and Imidazolotriazole Derivatives for
Antioxidant Evaluation, Synthetic Communications: An International Journal for Rapid Communication
of Synthetic Organic Chemistry, 40:9, 1360-1370
To link to this article: http://dx.doi.org/10.1080/00397910903079631
PLEASE SCROLL DOWN FOR ARTICLE
Full terms and conditions of use: http://www.tandfonline.com/page/terms-and-conditions
This article may be used for research, teaching, and private study purposes. Any
substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing,
systematic supply, or distribution in any form to anyone is expressly forbidden.
The publisher does not give any warranty express or implied or make any representation
that the contents will be complete or accurate or up to date. The accuracy of any
instructions, formulae, and drug doses should be independently verified with primary
sources. The publisher shall not be liable for any loss, actions, claims, proceedings,
demand, or costs or damages whatsoever or howsoever caused arising directly or
indirectly in connection with or arising out of the use of this material.

Synthetic Communications1, 40: 1360–1370, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903079631
SYNTHESIS AND REACTIONS OF SOME NOVEL
NICOTINONITRILE, THIAZOLOTRIAZOLE, AND
IMIDAZOLOTRIAZOLE DERIVATIVES FOR
ANTIOXIDANT EVALUATION
Hayam H. Sayed, Eman M. H. Morsy, and Eman M. Flefel
Photochemistry Department, National Research Center, Dokki, Cairo, Egypt
The novel 2-(1H)-pyridone, the lead compound of the pyridone derivative 1, reacted with an
electrophilic reagent (ethyl chloroacetate) to give the corresponding ester 2. Condensation
of compound 2 with thiosemicarbazide and=or hydrazine hydrate afforded the mercaptotria-
zole and the corresponding acetic acid hydrazide derivatives 3 and 4, respectively. The latter
compound reacted with ethyl acetoacetate, ethyl cyanoacetate, and maleic anhydride to give
compounds 5, 6, and 7, respectively. Alkylation of compound 3 with methyl iodide or chlor-
oacetic acid afforded methylsulfanyltriazole and thiazolotriazole derivatives 8 and 9,
respectively. Compound 8 reacted with glycine to afford the imidazotriazole derivative
10. Both compounds 9 and 10 reacted with glucose and benzaldehyde to give compounds
11, 12, 13, and 14, respectively. Some of the prepared products were selected and subjected
to screening for their antioxidant activity.
Keywords: Antioxidant activities; imidazolotriazole; nicotinonitrile; thiazolothione; thiazolotriazole
INTRODUCTION
Pyridinoles have attracted considerable attention because of their wide range of
pharmacological and biological activities. Pyridinole moieties are used in determi-
nation of iron(III) in multivitamins,[1] provide the hepato-protective activity of
coffee.[2] They are used as drugs for angina pectoris[3] and antioxidant agents,[4]
and are used for treatment of ischemic stroke.[5] Also, triazolethiones, thiazolotria-
zoles, imidazolotriazoles, and pyrazoles are useful as centrally acting drugs in mem-
ory deficits[6] and afford mice some protection against radiation and inflammation.[7]
Furthermore, thiazolotriazoles have antibacterial, antifungal, anti-inflammatory,[8]
antimycotic, anti-HIV-1,[9,10] and antihelminthic[11,12] activity. Pyrazole moieties
have bronchodilator, anti-inflammatory,[13] and oxidative hair-dye properties.[14]
This information encouraged us to prepare some new compounds for evaluation
whether they possessed notable chemical and biological properties.
Received April 26, 2009.
Address correspondence to Hayam H. Sayed, Photochemistry Department, National Research
Center, Dokki, Cairo, Egypt. E-mail: Hayamsayed@yahoo.com
1360

NICOTINONITRILE, THIAZOLOTRIAZOLE, AND IMIDAZOLOTRIAZOLE
1361
RESULTS AND DISCUSSION
2-Oxo-6-thien-2-yl-4-p-tolyl-1,2-dihydro-pyridine-3-carbonitrile (1) was prepared
by refluxing 3-tolyl-1-thien-2-yl-propanone[15,16] with ethyl cyanoacetate in acetic
acid containing anhydrous ammonium acetate.[17] Alkylation of 1 with ethyl chlor-
oacetate in basic conditions afforded acetic acid ethyl ester derivative 2 (Scheme 1).
The infrared (IR) spectrum of compound 2 showed an absorption band at
1
1740 cmꢀ1 characteristic for the carbonyl ester, and its H NMR spectrum showed
the ethoxy group at d 1.3 (t) and 4.1 (q) ppm and CH2O at 4.9 ppm. Cycloconden-
sation of compound 2 with thiosemicarbazide in basic medium afforded 2-(5-
mercapto-1H-[1,2,4]triazol-3-ylmethoxy)-6-thien-2-yl-4-p-tolyl-nicotinonitrile(3).The
IR spectra of compound 3 showed the disappearance of carbonyl ester and the
1
presence of a band at 3175 cmꢀ1 for (NH), and its H NMR spectrum showed
the disappearance of ethoxy group.
When compound 2 condensed with hydrazine hydrate, it afforded acetic acid
hydrazide derivative 4. The treatment of the latter compound 4 with ethyl acetoace-
tate and=or ethyl cyanoacetate afforded pyrazole derivatives 5 and 6, respectively.
When acetic acid hydrazide 4 condensed with maleic anhydride in glacial acetic acid,
it afforded 2-(3-cyano-6-thien-2-yl-4-p-tolyl-pyridin-2-yloxy)-N-(2,5-dioxo-2,5-
dihydro-pyrrol-1-yl)-acetamide (7) (Scheme 2).
However, alkylation of compound 3 with methyl iodide and=or chloroacetic
acid afforded 8 and 9, respectively (Scheme 3). The 1H NMR of compound 8 showed
a signal at 2.52 ppm, which is characteristic for S-CH3, while the IR of compound 9
showed a band at 1703 cmꢀ1, which is characteristic of C O. The latter compound
=
was condensed with glucose and=or benzaldehyde to afford compounds 11 and 12.
The IR of compound 11 showed a band at 1710 cmꢀ1 for C O and at 3400–
=
3410 cmꢀ1, characteristic of the hydroxyl group of the sugar moiety. The H NMR
1
of this compound showed signals at d 3.38–3.68 ppm for 6-CH-glucose, 4.7–4.9 ppm
=
for exchangeable 5-OH-glucose, and at 6.3 ppm for N CH proton.
Scheme 1.

1362
H. H. SAYED, E. M. H. MORSY, AND E. M. FLEFEL
Scheme 2.
Imidazotriazole 10 was achieved by fusion of methyl thiotriazole 8 with
glycine. The reaction may proceed via the formation of insoluble carboxymethylami-
notriazole with evolution of methylmercaptane. Furthermore, compound 10
condensed with glucose and=or benzaldehyde to afford compounds 2-[6-oxo-5-
(2,3,4,5,6-pentahydroxy-hexylidene)-5,6-dihydro-thiazolo[3,2-b][1,2,4]triazol-2-
ylmethoxy]-6-thien-2-yl-4-p-tolyl-nicotinonitrile (13) and 2-(5-benzylidene-6-oxo-
5,6-dihydro-4H-imidazo[1,2-b][1,2,4]triazol-2-ylmethoxy)-6-thien-2-yl-4-p-tolyl-nicotino
nitrile (14), respectively (Scheme 3).
Antioxidant Activity: Free Radical Scavenging Activity
(In Vitro Antioxidant)
The scavenging of diphenyl-1-picryl hydrazide (DPPH) radical was carried out
according to the described method.[18] One ml of various concentrations of each com-
pound in methanol and 5 ml of freshly prepared 0.1 mM methanol solution of DPPH
were thoroughly mixed and kept for 50min in the dark. The absorbance of the reac-
tion mixture at 517 nm was read with a spectrophotometer (UV-1600, Shimazdu)
against a blank. The percentage of free radical scavenging was calculated as follows:
Scavenging effect ¼ ½1 ꢀ ðA517 nm;sample=A517 nm;blankÞꢁ ꢂ 100

NICOTINONITRILE, THIAZOLOTRIAZOLE, AND IMIDAZOLOTRIAZOLE
1363
Scheme 3.
The extract concentration providing 50% inhibition (IC50) was calculated from the
graph-plotted free radical scavenging percentage against extract concentration; tests
were carried out in triplicate.
RESULTS AND DISCUSSION
Reactive species that initiate reactions that damage organic molecules of
biological importance are considered to be the cause of several health problems
including cancer, heart diseases, and possibly the process of aging itself.[19] Also,

1364
H. H. SAYED, E. M. H. MORSY, AND E. M. FLEFEL
Figure 1. DPPH free radical scavenging effect of compounds.
lipid oxidation by radicals results in food deterioration, especially in high-fat
foods.[20] Synthetic antioxidants such as butylated hydroxyanisole (BHA) and
butylated hydroxytoluene (BHT) are used as antioxidants. However, demand for
natural antioxidants has been increased because of consumer concerns about the
safety of synthetic antioxidants. Antioxidants, either as additives or as pharmaceu-
tical supplements, can terminate radical reactions in vivo.[21]
Many researchers have focused on natural antioxidants such as ascorbic acid
and tocopherol rather than synthetic antioxidants such as BHA and BHT. Synthetic
antioxidants have been widely used in the food industry for extending the shelf life of
foods that are susceptible to lipid oxidation. However, there are some arguments
about the safety and adverse effects of synthetic antioxidants as food additives.[22]
Compounds were subjected to screening for their antioxidant activity by
DPPH free radical scavenging assay (Fig. 1). Compound 13 exhibited a high
scavenging activity against the artificial radical DPPH as compared to the other
compounds. From the chemical point of view, compound 13 contains a hydroxyl
group, which is responsible for the antioxidant potential of compounds 7–12, which
exhibited low scavenging.
Table 1. Free radical scavenging capacities of the compounds
measured in DPPH assay
Compound
IC50 (mmol=ml)
7
8
>1000
>1000
>1000
>1000
>1000
>1000
<1000
9
10
11
12
13

NICOTINONITRILE, THIAZOLOTRIAZOLE, AND IMIDAZOLOTRIAZOLE
1365
CONCLUSION
Some novel 2-O-substituted-pyridine derivatives containing triazole (3, 8),
pyrazole (5, 6), pyrrole (7), thiazolo[3,2-b][1,2,4]triazole (9, 11, 12), and imidazo
[1,2-b][1,2,4]triazole (10, 13, 14) ring systems were prepared. Furthermore, some of
the prepared products were selected and subjected to screening for their antioxidant
activity. In general, compound 13 showed the greatest effect against the artificial
radical DPPH as compared to the other compounds.
EXPERIMENTAL
All melting points are uncorrected and were measured using an Electro-
thermal IA 9100 apparatus, Shimadzu (Japan). IR spectra were recorded as potas-
sium bromide pellets on a Perkin-Elmer 1650 spectrophotometer (Shimadzu),
1
National Research Center, Cairo, Egypt. H NMR spectra were determined on a
Jeol-Ex-300 NMR spectrometer, and chemical shifts are expressed as part per
million (ppm, d values) against tetramethylsilane (TMS) as internal reference
(National Research Center, Cairo, Egypt). Mass spectra (MS) were recorded on a
EI þ Q1 MSLMR UPLR, National Research Center, Cairo, Egypt. Microanalyses
were obtained using a Mario El Mentar apparatus, Organic Microanalysis Unit,
National Research Center, Cairo, Egypt, and the results were within the accepted
range (ꢃ0.20) of the calculated values.
2-Oxo-6-thien-2-yl-4-p-tolyl-1,2-dihydro-pyridine-3-carbonitrile (1)
A mixture of 3-(p-tolyl)-1-thien-2-yl propenol[15,16] (2.28 g, 10 mmol) and ethyl
cyanoacetate (1.13 g, 10 mmol) in 30 ml glacial acetic acid containing anhydrous
ammonium acetate (1.53 g, 20 mmol) was refluxed for 6 h. The reaction mixture was
cooled and poured into water. The formed solid was filtered off, dried, and recrystal-
lized from ethanol to give 1 (2.75 g), 80% yield, mp 280–281ꢄC. IR spectrum (KBr, n,
1
cmꢀ1): 2213 (CN), 1695 (CO); H NMR spectrum (DMSO-d6, d ppm): 9.30 (s, 1H,
NH, D2O exchangeable), 7.00–7.28 (m, 7H, Ar-H), 6.2 (s, 1H, pyridyl ring), 2.37 (s,
3H, CH3); MS, m=z (%): 292.1 (Mþ, 100). Analysis for C17H12N2OS (292.36): required
C, 69.84; H, 4.14; N, 9.58; S, 10.97. Found: C, 69.58; H, 4.00; N, 9.63; S, 11.20.
(3-Cyano-6-thien-2-yl-4-p-tolyl-pyridin-2-yloxy)-acetic
Acid Ethyl Ester (2)
A mixture of compound 1 (2.92 g, 10 mmol) and ethyl chloroacetate (2.44 g,
20 mmol) in 50 ml dry acetone containing sodium carbonate (1.06 g, 10 mmol) was
refluxed for 6 h. The solution was evaporated, and the residue was washed with a
little water and then recrystallized from dioxane to give 2 (4.02 g), 75% yield, mp
137–138ꢄC. IR spectrum (KBr, n, cmꢀ1): 2220 (CN), 1740 (CO); 1H NMR spectrum
(CDCl3, d ppm): 7.00–7.40 (m, 8H, Ar-H), 4.9 (s, 2H, CH2), 4.1 (q, J ¼ 7.5 Hz, 2H,
CH2), 2.35 (s, 3H, CH3), 1.30 (t, J ¼ 7.5 Hz, 3H, CH3); MS, m=z (%): 378.2 (Mþ,
25.7). Analysis for C21H18N2O3S (378.45): required C, 66.65; H, 4.79; N, 7.40; S,
8.47. Found: C, 66.80; H, 4.80; N, 7.55; S, 8.50.

1366
H. H. SAYED, E. M. H. MORSY, AND E. M. FLEFEL
2-(5-Mercapto-1H-[1,2,4]triazol-3-ylmethoxy)-6-thien-2-yl-4-p-tolyl-
nicotinonitrile (3)
A mixture of compound 2 (3.78 g, 10 mmol) and thiosemicarbazide (1.8 g,
20 mmol) in 30 ml pyridine was refluxed for 4 h. The reaction mixture was cooled
and poured into water. The formed solid was filtered off, dried, and recrystallized
from dioxane to give 3 (3.35 g), 60% yield, mp 298–299ꢄC. IR spectrum (KBr, n,
1
cmꢀ1): 3175 (NH), 2210 (CN); H NMR spectrum (DMSO-d6, d ppm): 11.3 (s,
1H, NH, D2O exchangeable), 9.20 (s, 1H, SH, D2O exchangeable), 7.10–7.50 (m,
8H, Ar-H), 5.3 (s, 2H, CH2), 2.36 (s, 3H, CH3); MS, m=z (%): 405.3 (Mþ, 37.5).
Analysis for C20H15N5OS2 (405.50): required C, 59.24; H, 3.73; N, 17.27; S, 15.82.
Found: C, 59.46; H, 3.76; N, 17.50; S, 16.00.
(3-Cyano-6-thien-2-yl-4-p-tolyl-pyridin-2-yloxy)-acetic
Acid Hydrazide (4)
A mixture of compound 2 (3.78 g, 10 mmol) and hydrazine hydrate 99% (1 mL,
40 mmol) was refluxed in dioxane (50 mL) for 3 h. The reaction mixture was evapo-
rated under reduced pressure. The formed solid was filtered off, dried, and recrystal-
lized from methanol to give 4 (3.13 g), 75% yield, mp 179–180ꢄC. IR spectrum (KBr,
n, cmꢀ1): 3210 (NH), 3250 (NH2), 2221 (CN), 1696 (CO); 1H NMR spectrum
(CDCl3, d ppm): 8.2 (s, 1H, NH, D2O exchangeable), 7.00–7.40 (m, 8H, Ar-H),
4.8 (s, 2H, CH2), 3.8 (s, 2H, NH2, D2O exchangeable); MS, m=z (%): 364 (Mþ,
12). Analysis for C19H16N4O2S (364.42): required C, 62.62; H, 4.43; N, 15.37; S,
8.80. Found: C, 62.80; H, 4.48; N, 15.53; S, 8.91.
2-[2-(3-Methyl-5-oxo-4,5-dihydro-pyrazol-1-yl)-2-oxo-
ethoxy]-6-thien-2-yl-4-p-tolyl-nicotinonitrile (5)
A mixture of compound 4 (0.90 g, 2.25 mmol), ethyl acetoacetate (1.25 mL,
10 mmol), anhydrous NaHCO3 (1 g), and anhydrous Na2SO4 (1 g) in dioxane
(30 mL) was refluxed for 8 h. The mixture was poured into water, and the solid that
formed was filtered off, dried, and recrystallized from methanol to give 5 (1.5 g), 70%
yield, mp 241–242ꢄC. IR spectrum (KBr, n, cmꢀ1): 3150 (NH), 2222 (CN), 1715
(CO), 1700 (CO); 1H NMR spectrum (CDCl3, d ppm): 9.5 (s, 1H, NH, D2O
exchangeable), 7.00–7.43 (m, 8H, Ar-H), 6.5 (s, 1H, CH pyrazole), 4.9 (s, 2H,
CH2), 2.34 (s, 3H, CH3), 1.00 (s, 3H, CH3); MS, m=z (%): 430 (Mþ, 5). Analysis
for C23H18N4O3S (430.48): required C, 64.17; H, 4.21; N, 13.01; S, 7.45. Found:
C, 64.30; H, 4.28; N, 12.82; S, 7.60.
2-[2-(3-Amino-5-hydroxy-pyrazol-1-yl)-2-oxo-ethoxy]-6-thien-2-yl-4-
p-tolyl-nicotinonitrile (6)
A mixture of compound 4 (0.90 g, 2.25 mmol), ethyl cyanoacetate (1.13 mL,
10 mmol), anhydrous NaHCO3 (1 g), and anhydrous Na2SO4 (1 g) in dioxane
(30 mL) was refluxed for 8 h. The mixture was poured into water, and the solid
that formed was filtered off, dried, and recrystallized from benzene to give 6
(1.52 g), 75% yield, mp 209–210ꢄC. IR spectrum (KBr, n, cmꢀ1): 3410–3400

NICOTINONITRILE, THIAZOLOTRIAZOLE, AND IMIDAZOLOTRIAZOLE
1367
1
(OH), 3115–3110 (NH), 1697 (CO); H NMR spectrum (CDCl3, d ppm): 8.9 (s,
1H, OH), 6.90–7.30 (m, 8H, Ar-H), 6.2 (s, 1H, CH pyrazole), 5.0 (s, 2H, CH2),
4.3 (s, 2H, NH2, D2O exchangeable), 2.34 (s, 3H, CH3). Analysis for
C22H17N5O3S (431.47): required C, 61.24; H, 3.97; N, 16.23; S, 7.43. Found: C,
61.35; H, 4.00; N, 16.33; S, 7.23.
2-(3-Cyano-6-thien-2-yl-4-p-tolyl-pyridin-2-yloxy)-N-
(2,5-dioxo-2,5-dihydro-pyrrol-1-yl)-acetamide (7)
A mixture of compound 4 (0.90 g, 2.25 mmol) and maleic anhydride (0.03 g,
2.25 mmol) was refluxed in glacial acetic acid (30 mL) for 6 h. The reaction mixture
was cooled and poured in water, and the solid that formed was filtered off, dried, and
recrystallized from n-butanol to give 7 (0.47 g), 50% yield, mp 273–274ꢄC. IR
spectrum (KBr, n, cmꢀ1): 3110 (NH), 2222 (CN), 1720 (CO), 1707 (CO), 1700
1
(CO); H NMR spectrum (CDCl3, d ppm): 6.90–7.30 (m, 10H, Ar-H), 4.8 (s, 2H,
CH2), 2.34 (s, 3H, CH3), 1.7 (s, 1H, NH, D2O exchangeable); MS, m=z (%): 444.5
(Mþ, 9). Analysis for C23H16N4O4S (444.46): required C, 62.15; H, 3.63; N, 12.61;
S, 7.21. Found: C, 62.25; H, 3.60; N, 12.72; S, 7.15.
2-(5-Methylsulfanyl-1H-[1,2,4]triazol-3-ylmethoxy)-6-thien-2-yl-4-p-
tolyl-nicotinonitrile (8)
A mixture of compound 3 (4.01 g, 10 mmol) and methyl iodide (1.2 ml,
30 mmol) was refluxed in dioxane containing sodium hydroxide (0.4 g, 1 mmol)
for 8 h. Then the reaction mixture was cooled and poured into water. The preci-
pitates that formed were filtered off, dried, and recrystallized from ethanol to give
8 (3.13 g), 60% yield, mp 213–214ꢄC. IR spectrum (KBr, n, cmꢀ1): 3230 (NH),
1
2218 (CN); H NMR spectrum (CDCl3, d ppm): 10.3 (s, 1H, NH, D2O exchange-
able), 7.10–7.43 (m, 8H, Ar-H), 5.0 (s, 2H, CH2), 2.34 (s, 3H, CH3), 2.52 (s, 3H,
SCH3); MS, m=z (%): 419.2 (Mþ, 33.5). Analysis for C21H17N5OS2 (419.52):
required C, 60.12; H, 4.08; N, 16.69; S, 15.29. Found: C, 60.00; H, 4.10; N,
16.72; S, 15.33.
2-(6-Oxo-5,6-dihydro-thiazolo[3,2-b][1,2,4]triazol-2-ylmethoxy)-6-
thien-2-yl-4-p-tolyl-nicotinonitrile (9)
A mixture of compound 3 (2.02 g, 5 mmol) and chloroacetic acid (0.28 g,
5 mmol) was refluxed in a mixture of glacial acetic acid=acetic anhydride (3:1)
containing anhydrous sodium acetate (0.25 g, 5 mmol) for 3 h. The reaction mix-
ture was cooled and poured into water. The formed solid was filtered off, dried,
and recrystallized from methanol to give 9 (1.27 g), 55% yield, mp 183–184ꢄC. IR
spectrum (KBr, n, cmꢀ1): 2221 (CN), 1703 (CO); 1H NMR spectrum (CDCl3,
d ppm): 7.10–7.50 (m, 8H, Ar-H), 5.2 (s, 2H, CH2), 4.00 (s, 2H, thiazole), 2.37
(s, 3H, CH3); MS, m=z (%): 445.3 (Mþ, 17.3). Analysis for C22H15N5O2S2
(445.52): required C, 59.31; H, 3.39; N, 75.72; S, 14.39. Found: C, 59.59; H,
3.40; N, 75.83; S, 14.50.

1368
H. H. SAYED, E. M. H. MORSY, AND E. M. FLEFEL
2-(6-Oxo-5,6-dihydro-4H-imidazo[1,2-b][1,2,4]triazol-2-ylmethoxy)-6-
thien-2-yl-4-p-tolyl-nicotinonitrile (10)
A mixture of compound 8 (4.10 g, 10 mmol) and glycine (0.228 ml, 30 mmol)
was heated at 190ꢄC on oil bath for 3 h. The reaction mixture was treated with water,
and the precipitates that formed were filtered off, dried, and recrystallized from
n-butanol to give 10 (2.17 g), 50% yield, mp 305–306ꢄC. IR spectrum (KBr, n,
cmꢀ1): 3150 (NH), 2218 (CN), 1703 (CO); 1H NMR spectrum (DMSO-d6, d
ppm): 8.7 (s, 1H, NH, D2O exchangeable), 7.00–7.42 (m, 8H, Ar-H), 5.2 (s, 2H,
CH2), 3.8 (s, 2H, imidazole), 2.34 (s, 3H, CH3); MS, m=z (%): 428.5 (Mþ, 32). Analy-
sis for C22H16N6O2S (428.47): required C, 61.67; H, 3.76; N, 19.61; S, 7.48. Found:
C, 61.90; H, 3.80; N, 19.80; S, 7.50.
2-[6-Oxo-5-(2,3,4,5,6-pentahydroxy-hexylidene)-5,6-dihydro-thiazolo
[3,2-b][1,2,4] triazol-2-ylmethoxy]-6-thien-2-yl-4-p-tolyl-
nicotinonitrile (11)
A solution of compound 9 (1.11 g, 2.5 mmol) was mixed with ethanol=DMF
(4:1) and a few drops of acetic acid treated with a solution of glucose (1.8 g, 10 mmol)
in water (1 ml), and then the mixture was refluxed for 5 h. The product that separated
out on cooling was filtered off, washed with water, and recrystallized from methanol
to give 11 (1.75 g), 60% yield, mp 163–164ꢄC. IR spectrum (KBr, n, cmꢀ1):
3400–3410 (OH), 2213 (CN), 1710 (CO); 1H NMR spectrum (CDCl3, d ppm):
7.00–7.40 (m, 8H, Ar-H), 6.3 (s, 1H, methylene), 5.7 (s, 2H, CH2), 4.90–4.7 (br,
5H, OH, D2O exchangeable), 3.68–3.38 (m, 7H, CH and CH2 of glucose). Analysis
for C28H25N5O7S2 (607.66): required C, 55.35; H, 4.15; N, 11.53; S, 10.55. Found: C,
55.50; H, 4.20; N, 11.33; S, 10.35.
2-(5-Benzylidene-6-oxo-5,6-dihydro-thiazolo[3,2-b][1,2,4]triazol-
2-ylmethoxy)-6-thien-2-yl-4-p-tolyl-nicotinonitrile (12)
A mixture of compound 9 (1.11 g, 2.25 mmol) and benzaldehyde (0.3 ml,
2.25 mmol) was refluxed in glacial acetic acid containing anhydrous sodium acetate
(0.35 g, 4 mmol) for 3 h. The reaction mixture was cooled and poured into water. The
formed solid was filtered off, dried, and recrystallized from dioxane to give 12 (1.0 g),
70% yield, mp 258–259ꢄC. IR spectrum (KBr, n, cmꢀ1): 2210 (CN), 1715 (CO);
1H NMR spectrum (DMSO-d6, d ppm): 7.10–7.60 (m, 14H, Ar-H þ aryl methylene),
5.1 (s, 2H, CH2), 2.32 (s, 3H, CH3); MS, m=z (%): 533 (Mþ, 18.2). Analysis for
C29H19N5O2S2 (533.63): required C, 65.27; H, 3.59; N, 13.13; S, 12.02. Found: C,
65.32; H, 3.60; N, 13.00; S, 11.90.
2-[6-Oxo-5-(2,3,4,5,6-pentahydroxy-hexylidene)-5,6-dihydro-4H-
imidazo[1,2-b][1,2,4]triazol-2-ylmethoxy]-6-thien-2-yl-4-p-tolyl-
nicotinonitrile (13)
A solution of compound 10 (1.07 g, 2.25 mmol) in DMF containing a few drops
of acetic acid was treated with a solution of glucose (0.45 g, 2.25 mmol) in water

NICOTINONITRILE, THIAZOLOTRIAZOLE, AND IMIDAZOLOTRIAZOLE
1369
(1 ml), and then the mixture was refluxed for 3 h. The product that separated out on
cooling was filtered off, washed with water, and recrystallized from ethanol to give
13 (0.91 g), 60% yield, mp 233–234ꢄC. IR spectrum (KBr, n, cmꢀ1): 3390–3400 (OH),
1
3155 (NH), 2220 (CN), 1710 (CO); H NMR spectrum (CDCl3, d ppm): 9.1 (s, 1H,
NH, D2O exchangeable), 7.10–7.50 (m, 8H, Ar-H), 5.9 (s, 1H, methylene) 5.2 (s, 2H,
CH2), 4.80–4.60 (br, 5H, OH, D2O exchangeable), 4.00–3.40 (m, 7H, CH and CH2 of
glucose). Analysis for C28H26N6O7S (590.61): required C, 56.94; H, 4.44; N, 14.23; S,
5.43. Found: C, 57.00; H, 4.50; N, 14.00; S, 5.50.
2-(5-Benzylidene-6-oxo-5,6-dihydro-4H-imidazo[1,2-b][1,2,4]triazol-
2-ylmethoxy)-6-thien-2-yl-4-p-tolyl-nicotinonitrile (14)
A mixture of compound 10 (1.07 g, 2.25 mmol) and benzaldehyde (0.3 ml,
2.25 mmol) was refluxed in glacial acetic acid containing anhydrous sodium acetate
(0.35 g, 4 mmol) for 3 h. The reaction mixture was cooled and poured into water. The
formed solid was filtered off, dried, and recrystallized from DMF to give 14 (1.1 g),
80% yield, mp 334–335ꢄC. IR spectrum (KBr, n, cmꢀ1): 3160 (NH), 2222 (CN), 1719
1
(CO); H NMR spectrum (DMSO-d6, d ppm): 9.3 (s, 1H, NH, D2O exchangeable),
6.90–7.40 (m, 14H, Ar-H þ aryl methylene), 5.2 (s, 2H, CH2), 2.35 (s, 3H, CH3); MS,
m=z (%): 516.5 (Mþ, 12.6). Analysis for C29H20N6O2S (516.57): required C, 67.43; H,
3.90; N, 16.27; S, 6.21. Found: C, 67.62; H, 3.95; N, 16.18; S, 6.11.
ACKNOWLEDGMENT
We are thankful to Dr. Sahar R. Abd El-Hamid, Medicinal and Aromatic
Plants Department, National Research Center, for antioxidant evaluation.
REFERENCES
1. Hashem, E.; AbuBakr, M. S. Complex formation equilibria of iron (III) with
2-hydroxy-3-pyridinol and 2-mercapto-3-pyridinol: Spectrophotometry determination of
iron (III) in multivitamins. Anal. Lett. 2000, 33, 691–707.
2. Kurakane, S.; Igarashi, K. A radical scavenging compound, 3-pyridinol, in instant coffee
and its hepatoprotective activity. Food Sci. Tech. 2006, 12, 148–151.
3. David, T. N. A study of the effects of pyridinol carbamate (P-23) on angina pectoris.
J. Clin. Pharm. 1968, 8, 259–267.
4. Masashi, H.; Kyoko, T.; Shigeo, N.; Tadahiko, M. Preparation and antioxidant activity
of a-pyridoin and its derivatives. Bioorg Med. Chem. 2005, 13, 6763–6770.
5. Zhang, Y.; Fan, X.; Chakaravarty, D.; Xiang, B.; Hecht, S. R. 1-Hydroxy-2-pyridinone-
based MMP inhibitors: Synthesis; and biological evaluation for the treatment of ischemic
stroke. Bioorg Med. Chem. Lett. 2008, 18, 409–413.
6. Finke, P. E.; Meurer, L. C.; Debenham, J. S.; Toupence, R. B.; Walsh, T. F. Cannabinoid
CB1 receptor antagonists therapeutic and structural perspectives. US Patent, codv.
200790153, 2007.
`
7. Gold-Aubert, P.; Melkonain, D.; Toribio, L. Syntheses de nouvelles phenyl-1-triazoline-
1,2,4-ones-5 substituees en 3 et 4. 2 communication. Helv. Chim. Acta 1964, 47,
´
e
´
2068–2071.

1370
H. H. SAYED, E. M. H. MORSY, AND E. M. FLEFEL
8. Kulkarnatak, M. V.; Patil, V. D.; Biradar, V. N.; Nanjappa, S. Synthesis and biological
properties of some 3-heterocyclic substituted coumarins. Arch. Pharm. Chem. Life Sci.
1981, 314, 435–439.
9. Wujec, M.; Pitucha, M.; Dobosz, M.; Kosikowska, U.; Malm, A. Synthesis and potential
antimycotic activity of 4-substituted-3-(thiophene-2-yl-methyl)-dalta2-1,2,4-triazoline-5-
thiones. Acta Pharm. 2004, 54, 251–260.
10. Sayed, H. H.; Ali, M. A. Synthesis of 3-[(4-chloro-phenyl) oxiranyl]thiophen-2-
yl-propanone and their reactions with some nucleophilles for antiviral evaluations.
Phosphorus, Sulfur Silicon Relat. Elem. 2008, 183, 156–167.
11. Kamal, A.; Shankaraiah, N.; Devaiah, V.; Reddy, K. L.; Juvekar, A.; Sen, S.; Kurian, N.;
Zingde, S. Synthesis of 1,2,3-triazole-linked pyrrolobenzodiazepine conjugates employing
‘‘click’’ chemistry: DNA-binding affinity and anticancer activity. Bioorg Med. Chem. Lett.
2008, 18, 1468–1473.
12. Habernickel, V. J. Alkyl-5-heterocyclic-benzimidazolyl-carbamate derivatives. Drugs Ger.
1992, 35, 97–100.
13. Boschelli, D. H.; Connor, D. T.; Bornemeier, D. A.; Dyer, R. D.; Kennedy, J. A.;
Kuipers, P. J.; Okonkwo, G. C.; Schrier, D. J.; Wright, C. D. 1,3,4-Oxadiazole, 1,3,4-thia-
diazole, and 1,2,4-triazole analogs of the fenamates: In vitro inhibition of cyclooxygenase
and 5-lipoxygenase activities. J. Med. Chem. 1993, 36, 1802–1810.
14. Martin, C.; Go¨ggel, R.; Dal Piaz, V.; Vergelli, C.; Giovannoni, P.; Ernst, M.; Uhlig, S.
Airway relaxant and anti-inflammatory properties of a PDE4 inhibitor with low affinity
for the high-affinity rolipram binding site. Naunyn-Schmiedeberg’s Arch. Pharmacol.
2002, 365(4), 284–289.
15. Amr, A. E.; Sayed, H. H.; Abdulla, M. A. Synthesis and reactions of some new substituted
pyridine and pyrimidine derivatives as analgesic, anticonvulsant, and anti-Parkinsonian
agents. Arch. Pharm. Chem. Life Sci. 2005, 338, 433–440.
16. Rashad, A. E.; Sayed, H. H.; Shamroukh, A. H. Preparation of some fused pyridopyrimi-
dine and pyridothienotriazine derivatives for biological evaluation. Phosphorus, Sulfur
Silicon Relat. Elem. 2005, 180, 2767–2777.
17. Blankley, C. J.; Bennett, L. R.; Fleming, R. W.; Smith, R. D.; Tessman, D. K.; Kaplan, H. R.
Antihypertensive activity of 6-arylpyrido[2,3-d]pyrimidin-7-amine derivatives, 2: 7-Acyl
amide analogs. J. Med. Chem. 1983, 26, 403–411.
18. Hsu, C. L.; Chen, W.; Weng, Y. M.; Tseng, C. Y. Chemical compositions, physical
properties, and antioxidant activities of yam flours as affected by different drying
methods. Food Chem. 2003, 83(1), 85–92.
19. Halliwell, B.; Gutteridge, J. M. C. Free Radicals in Biology and Medicine, 2nd ed.;
Clarendon Press: Oxford, 1989; pp. 416–508.
20. Kanner, J. Oxidative process in meat and meat products: Quality implications. Meatt Sci.
1994, 36, 169–189.
21. Hudson, B. J. F. The mechanism of antioxidant action in vitro. In Food Antioxidants;
Elsevier Applied Science: London, 1990.
22. Inatani, R.; Nakatani, N.; Fuwa, H. Antioxidative effect of the constituents of rosemary
(Rosmarinus officinalis L.) and their derivatives. Agric. Biol. Chem. 1983, 47, 521–528.