Microwave-assisted synthesis and antifungal activity of 2,5-Disubstituted-1,3,4-oxadiazoles containing azulene moiety

Article abstract of DOI:10.1080/00397910802654658

Microwave-assisted as well as conventional synthesis of 2,5-disubstituted-1,3,4-oxadiazoles containing the azulene moiety was carried out, and their antifungal activity is also reported.

Full text of DOI:10.1080/00397910802654658

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Microwave-Assisted Synthesis
and Antifungal Activity of
2,5-Disubstituted-1,3,4-
oxadiazoles Containing Azulene
Moiety
Jiao Xu a , Dao-Lin Wang b & Kimiaki Imafuku c
a Cosmetology Department, Heilongjiang University
of Chinese Medicine, Jiamusi Institute, Jiamusi,
China
b College of Chemistry and Chemical Engineering,
Liaoning Key Laboratory of Apple Chemistry, Bohai
University, Jinzhou, China
c Department of Chemistry, Faculty of Science,
Kumamoto University, Kurokami, Kumamoto, Japan
Version of record first published: 13 May 2009.
To cite this article: Jiao Xu , Dao-Lin Wang & Kimiaki Imafuku (2009): Microwave-
Assisted Synthesis and Antifungal Activity of 2,5-Disubstituted-1,3,4-oxadiazoles
Containing Azulene Moiety, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 39:12, 2196-2204
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Synthetic Communications1, 39: 2196–2204, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802654658
Microwave-Assisted Synthesis and Antifungal
Activity of 2,5-Disubstituted-1,3,4-oxadiazoles
Containing Azulene Moiety
Jiao Xu,1 Dao-Lin Wang,2 and Kimiaki Imafuku3
1Cosmetology Department, Heilongjiang University of Chinese Medicine,
Jiamusi Institute, Jiamusi, China
2College of Chemistry and Chemical Engineering, Liaoning Key
Laboratory of Apple Chemistry, Bohai University, Jinzhou, China
3Department of Chemistry, Faculty of Science, Kumamoto University,
Kurokami, Kumamoto, Japan
Abstract: Microwave-assisted as well as conventional synthesis of 2,5-
disubstituted-1,3,4-oxadiazoles containing the azulene moiety was carried out,
and their antifungal activity is also reported.
Keywords: Antifungal activity, azulene derivatives, microwave synthesis,
1,3,4-oxadiazoles
INTRODUTION
Microwave radiation provides an alternative to conventional heating
because it utilizes the ability of liquids or solids to transform electromag-
netic energy into heat. The use of microwave irradiation has introduced
several new concepts in chemistry, because the absorption and transmis-
sion of energy is completely different from the conventional mode of
heating. The microwave technology has been applied to a number of
Received August 30, 2008.
Address correspondence to Jiao Xu, Cosmetology Department, Heilongjiang
University of Chinese Medicine, Jiamusi Institute, Jiamusi, Heilongjiang Province
154007, China. E-mail: xujiao2007@sina.com
2196

2,5-Disubstituted-1,3,4-oxadiazoles
2197
useful research and development processes such as polymer technology,
organic synthesis, application to waste treatment, drug release=targeting,
and ceramic and alkane decomposition.[1,2]
The azulene constituent was the best known of polycyclic nonbene-
noid aromatic compounds and has long fascinated chemists with beauti-
ful colors and unusual electronic properties.[3] Recently, azulenes have
attracted interest in medicine as antiulcer drugs,[4] anticancer agents,[5]
and as antioxidant therapeutics for neurodegenerative conditions.[6]
A variety of heterocycle-fused azulenes with different chemical
properties and physiological activities have been obtained by several
methods.[7] Recently, we reported that 1-cinnamoylazulenes and related
compounds reacted with malononitrile to afford 1-(2-pyridyl)- and
1-(4-pyridyl)azulene derivatives.[8] Bromoacetyl-substituted azulenes
reacted with 2-hydroxy benzaldehydes to yield 1-(2-benzofurancarbonyl)-
azulenes,[9] whereas the reaction with thioureas and thioamides gave
thiazole-substituted azulenes.[10]
Additionally, the substituted oxadiazoles are heterocyclic com-
pounds, which serve as both biomimetic and reactive pharamacophores,
and many of them are key elements with potential biological activities,
such as central nervous system (CNS) stimulant, anti-inflammatory,
antiemetic, diuretic,[11] anti-HIV, and antifungal activities.[12]
This communication describes the synthesis of 1,3,4-oxadiazoles con-
taining the azulene moiety by the condensation of azulene hydrazide with
appropriate carboxylic acids under microwave irradiation and evaluates
the new compounds for their antifungal activity.
RESULTS AND DISCUSSION
The starting material, azulene hydrazide 2, was obtained by refluxing the
starting material 1 with hydrazine hydrate (Scheme 1).
The 5-aryl-2-(3-methylazulen-1-yl)-1,3,4-oxadiazoles 3a–h were pre-
pared by the microwave irradiation of 2 with appropriate carboxylic
acids in the presence of phosphorous oxychloride (Scheme 1). Similarly,
the reaction was also carried out by the conventional method by refluxing
Scheme 1. Preparation of 5-substituted-2-(3-methylazulene-1-yl)-1,3,4-oxadiazoles.

2198
J. Xu, D.-L. Wang, and K. Imafuku
a mixture of hydrazide 2 with the appropriate carboxylic acid in phos-
phorous oxychloride in an oil bath. The physical constants, yield, and
analytical data of 5-substituted-2-(3-methylazulen-1-yl)-1,3,4-oxadiazoles
3a–h are given in Table 1.
To establish the general validity of our newly developed method,
several one-pot, microwave-assisted syntheses were carried out. This
method appeared to be rapid and economical, with a wide range of appli-
cations. The reaction was found to proceed smoothly under microwave
irradiation within 10–15 min, whereas under refluxing conditions,
5–15 h were required (Table 1). The products were isolated by simple,
cold, aqueous workup followed by either solvent extraction or precipita-
tion and were finally purified by column chromatography wherever
necessary to afford pure 2,5-disubstituted-1,3,4-oxadiazole.
The antifungal activity studies of the newly synthesized oxadiazole
derivatives were carried out against fungi such as Aspergillus flavus, A.
fumigatus, Penicillium, and Trichophyton by the cup–plate method.[13]
The results of the antifungal studies are shown in Table 2. Among
the compounds tested, 3c showed good activity against all the fungi.
Compounds 3a, 3b, and 3e showed good activity against the fungus
A. flavus and moderate activity against Penicillium, whereas compounds
3d, 3f, 3g, and 3h showed moderate activity against the fungi Penicillium
and Trichophyton.
In conclusion, this method provides an excellent approach for the
safe, rapid, inexpensive, and simple synthesis of medicinally important
2,5-disubstituted-1,3,4-oxadiazoles containing the azulene moiety in a
single step. The compound 2 will be a valuable synthon for the prepara-
tion of a variety of heterocycle-fused azulenes.
Table 1. Comparison between microwave-assisted and convention methods of
synthesis of 5-substituted-2-(3-methylazulene-1-yl)-1,3,4-oxadiazoles in terms of
yield and time
Microwave
Conventional
Compound
R
Time (min) Yield (%) Time (h) Yield (%)
3a
3b
3c
3d
3e
3f
C6H5
4-MeC6H4
4-ClC6H4
4-OHC6H4
2-BrC6H4
2-OHC6H4
12
10
12
12
12
10
15
12
87
85
82
81
88
83
82
84
10
7
12
8
15
5
6
77
79
67
68
75
78
63
66
3g
3h
C6H5CH¼CH
4-MeC6H5CH¼CH
8

2,5-Disubstituted-1,3,4-oxadiazoles
2199
Table 2. Antifungal screening for compounds 3: diameter of zone of inhibition
(mm) at 10 mg=mL concentration
Compound
A. flavus A. fumigatus Penicillium Trichophyton
3a
3b
24
24
26
—
20
—
—
—
22
—
—
—
25
—
—
—
—
—
22
—
14
18
24
10
18
12
10
16
20
—
—
—
26
12
14
10
12
14
20
—
3c
3d
3e
3f
3g
3h
Ciclopiroxolamine (std)a
Solvent control (DMF)
astd ¼ standard.
EXPERIMENTAL
All melting points were determined with a Yanaco MP JP-3 apparatus
and are uncorrected. The infrared (IR) spectra were measured on a Jasco
A-102 IR spectrophotometer. The NMR spectra were recorded with a
Jeol JNM-EX 300 spectrometer. Mass spectra (MS) were recorded on a
HP 1100. The reactions were carried out under microwave irradiation
at 360 W. Thin-layer chromatography (TLC) was used to monitor the
progress of the reaction. Elemental analyses were performed at the
Center for Instrumental Analysis, Beijing University.
Preparation of 3-Methyazulen-1-carboxyhydrazide (2)
A mixture of methyl 3-methylazulene-1-carboxylate (1[14]) (2.0 g, 0.01 mol)
and hydrazine hydrate (80%, 2.0 g, 0.05 mol) in ethanol (100 mL) was
refluxed for 8 h. On cooling, the solution gave a solid mass of hydra-
zide 2, which was collected by filtration and recrystallized from
ethanol. Mp: 151–152ꢀC; yield 1.74 g (87%). IR (KBr): 3311 (NH2),
1
1618 (C¼O) cmꢁ1; H NMR (CDCl3, 300 MHz) d (ppm): 2.61 (s, 3H,
CH3), 4.09 (br s, 2H, NH2), 7.28 (dd, 1H, J ¼ 9.9, 9.6 Hz, 5-H), 7.36
(dd, 1H, J ¼ 10.0, 10.8 Hz, 7-H), 7.52 (br s, 1H, NH), 7.70 (t, 1H,
J ¼ 9.6, 9.6 Hz, 6-H), 7.84 (s, 1H, 2-H), 8.29 (d, 1H, J ¼ 9.6 Hz, 4-H),
9.52 (d, 1H, J ¼ 9.6 Hz, 8-H). MS (FAB) m=z (%): 200. Anal. calcd. for
C2H12N2O: C, 71.98; H, 6.04; N, 13.99%. Found: C, 71.72; H, 6.21; N,
14.14%.

2200
J. Xu, D.-L. Wang, and K. Imafuku
Preparation of 5-Substituted-2-(3-methylazulen-1-yl)-1,3,4-oxadiazoles
(3a–h)
Method 1
A mixture of substituted carboxylic acid (0.01 mol) and azulenehydrazide
(2) (0.01 mol) was ground in a mortar using a pestle for uniform mixing.
This mixture was taken in a 50-mL beaker, and five to six drops of phos-
phorous oxychloride were added. The beaker was kept inside a micro-
wave oven operating at 360 W for about 15 min. The completion of the
reaction was checked by thin-layer chromatography (TLC). The product
was poured to crushed ice. It was then neutralized by 5% sodium bicar-
bonate. The solid obtained was filtered, dried, and crystallized from a
mixture of ethanol–DMF or finally purified by column chromatography
wherever necessary to give 3a–h.
Method 2
Phosphorous oxychloride (5 mL) was added to a mixture of substituted
carboxylic acid (0.01 mol) and azulenehydrazide 2 (0.01 mol). The reac-
tion mixture was refluxed for 5–9 h on an oil bath; the contents were
cooled to room temperature and poured onto crushed ice. They were then
neutralized by 5% sodium bicarbonate solution. The solid that separated
was collected by filtration through a Buchner funnel and dried. Further
¨
purification was done by crystallization from a mixture of ethanol–
DMF to give 3a–h. A few typical compounds are described.
2-(3-Methylazulen-1-yl)-5-phenyl-1,3,4-oxadiazoles (3a)
1
Green needles; mp: 95–96ꢀC; IR (KBr): 3061, 1641, 1575, 1518 cmꢁ1; H
NMR (CDCl3, 300MHz) d (ppm): 2.66 (s, 3H, CH3), 7.39 (dd, 1H,
J¼ 9.6, 9.6 Hz, 5- or 7-H), 7.85 (dd, 1H, J ¼ 9.9, 9.0 Hz, 7- or 5-H), 7.73 (t,
1H, J ¼ 9.6 Hz, 6-H), 7.51–7.55 (m, 3H, 30,40,50-H, Ph), 8.03 (s, 1H, 2-H),
8.13–8.15 (m, 2H, 20,60-H, Ph) 8.37 (d, 1H, J ¼ 9.6 Hz, 4-H), 9.53 (d, 1H,
J¼ 9.6 Hz, 8-H); MS (FAB) m=z (%): 286. Anal. calcd. for C19H14N2O: C,
79.70; H, 4.93; N, 9.78%. Found: C, 79.84; H, 4.83; N, 9.91%.
2-(3-Methylazulen-1-yl)-5-(4-methylphenyl)-1,3,4-oxadiazoles (3b)
Green needles; mp: 136–138ꢀC; IR (KBr): 3064, 1647, 1579, 1525 cmꢁ1
1H NMR (CDCl3, 300 MHz) d (ppm): 2.43 (s, 3H, CH3), 2.67 (s, 3H,
;

2,5-Disubstituted-1,3,4-oxadiazoles
2201
CH3), 7.27 (d, 2H, J ¼ 9.6 Hz, 30, 50-H, ArH), 7.34 (dd, 1H, J ¼ 9.6,
8.0 Hz, 7- or 5-H), 7.45 (t, 1H, J ¼ 9.6 Hz, 6-H), 7.73 (dd, 1H, J ¼ 9.6,
9.6 Hz, 5- or 7-H), 8.01 (d, 2H, J ¼ 9.6 Hz, 30, 50-H, ArH), 8.26 (s, 1H,
2-H), 8.34 (d, 1H, J ¼ 9.6 Hz, 4-H), 9.56 (d, J ¼ 9.6 Hz, 1H, 8-H); MS
(FAB) m=z (%): 300. Anal. calcd. for C20H16N2O: C, 79.97; H, 5.37;
N, 9.33 %, Found: C, 79.84; H, 4.83; N, 9.53%.
5-(4-Chlorophenyl)-2-(3-methylazulen-1-yl)-1,3,4-oxadiazoles (3c)
Green needles; mp: 83–85ꢀC; IR (KBr): 3061, 1658, 1565, 1521 cmꢁ1; 1H
NMR (CDCl3, 300 MHz) d (ppm): 2.64 (s, 3H, CH3), 7.21 (d, 2H,
J ¼ 9.6 Hz, 30, 50-H, ArH), 7.27 (d, 2H, J ¼ 9.6 Hz, 20, 60-H, ArH), 7.36
(dd, 1H, J ¼ 9.6, 8.0 Hz, 7- or 5-H), 7.52 (t, 1H, J ¼ 9.6 Hz, 6-H), 7.71
(dd, 1H, J ¼ 9.6, 9.6 Hz, 5- or 7-H), 8.07 (s, 1H, 2-H), 8.32 (d, 1H,
J ¼ 9.6 Hz, 4-H), 9.43 (d, 1H, J ¼ 9.6 Hz, 8-H); MS (FAB) m=z (%):
320. Anal. calcd. for C19H13ClN2O: C, 71.13; H, 4.08; N, 8.73%, Found:
C, 71.34; H, 4.23; N, 8.92%.
5-(4-Hydroxyphenyl)-2-(3-methylazulen-1-yl)-1,3,4-oxadiazoles (3d)
Green needles; mp: 200–201ꢀC; IR (KBr): 3328, 3056, 1643, 1569,
1
1528 cmꢁ1; H NMR (CDCl3, 300 MHz) d (ppm): 2.70 (s, 3H, CH3),
6.91 (d, 2H, J ¼ 8.8 Hz, 30, 50-H, ArH), 7.29 (dd, 1H, J ¼ 9.6, 8.0 Hz,
7- or 5-H), 7.43 (t, 1H, J ¼ 9.6 Hz, 6-H), 7.52 (dd, 1H, J ¼ 9.6, 9.6 Hz,
5- or 7-H), 7.91 (d, 2H, J ¼ 9.6 Hz, 20, 60-H, ArH), 8.30 (s, 1H, 2-H),
8.33 (d, 1H, J ¼ 9.6 Hz, 4-H), 9.57 (d, 1H, J ¼ 9.6 Hz, 8-H); MS (FAB)
m=z (%): 302. Anal. calcd. for C19H14N2O2: C, 75.48; H, 4.67; N,
9.27%. Found: C, 75.53; H, 4.73; N, 9.54%.
5-(4-Bromophenyl)-2-(3-methylazulen-1-yl)-1,3,4-oxadiazoles (3e)
Green needles; mp: 108–110ꢀC; IR (KBr): 3071, 1647, 1558, 1537 cmꢁ1
;
1H NMR (CDCl3, 300 MHz) d (ppm): 2.70 (s, 3H, CH3), 7.27–7.30
(m, 2H, 30, 40-H, ArH), 7.30 (dd, 1H, J ¼ 9.6, 8.0 Hz, 7- or 5-H), 7.43
(t, 1H, J ¼ 9.6 Hz, 6-H), 7.11 (d, 1H, J ¼ 7.6 Hz, 60-H, ArH), 7.62
(dd, 1H, J ¼ 9.6, 9.6 Hz, 5- or 7-H), 7.80 (d, 1H, J ¼ 7.6 Hz, 30-H,
ArH), 8.26 (s, 1H, 2-H), 8.33 (d, 1H, J ¼ 9.6 Hz, 4-H), 9.57 (d, 1H,
J ¼ 9.6 Hz, 8-H); MS (FAB) m=z (%): 365. Anal. calcd. for
C19H13BrN2O: C, 62.48; H, 3.59; N, 7.67%, Found: C, 62.54; H, 3.68;
N, 7.87%.

2202
J. Xu, D.-L. Wang, and K. Imafuku
5-(2-Hydroxyphenyl)-2-(3-methylazulen-1-yl)-1,3,4-oxadiazoles (3f)
Green needles; mp: 159–160ꢀC; IR (KBr): 3334, 3063, 1652, 1567,
1
1521 cmꢁ1; H NMR (CDCl3, 300 MHz) d (ppm): 2.70 (s, 3H, CH3),
7.03 (dd, 1H, J ¼ 8.0, 8.0 Hz, 50-H, ArH), 7.15 (d, 1H, J ¼ 8.4 Hz, 60-H,
ArH), 7.38 (dd, 1H, J ¼ 9.6, 9.6 Hz, 7- or 5-H), 7.44 (dd, 1H, J ¼ 8.0,
8.0 Hz, 40-H, ArH), 7.45 (t, 1H, J ¼ 9.6 Hz, 6-H), 7.77 (dd, 1H, J ¼ 9.6,
9.6 Hz, 5- or 7-H), 7.91 (d, 1H, J ¼ 8.0 Hz, 30-H, ArH), 8.27 (s, 1H, 2-
H), 8.36 (d, 1H, J ¼ 9.6 Hz, 4-H), 9.53 (d, 1H, J ¼ 9.6 Hz, 8-H); MS
(FAB) m=z (%): 302. Anal. calcd. for C19H14N2O2: C, 75.48; H, 4.67;
N, 9.27%, Found: C, 75.61; H, 4.54; N, 9.36%.
2-(3-Methylazulen-1-yl)-5-styryl-1,3,4-oxadiazoles (3g)
1
Green needles, mp 95–96ꢀC; IR (KBr): 3076, 1653, 1572, 1523 cmꢁ1; H
NMR (CDCl3, 300MHz) d (ppm): 2.68 (s, 3H, CH3), 7.14 (d, 1H,
J¼ 16.8 Hz, CH¼CH-), 7.34 (dd, 1H, J ¼ 9.6, 9.6Hz, 7- or 5-H), 7.43 (t,
1H, J ¼ 9.6 Hz, 6-H), 7.41–7.46 (m, 3H, 30,40,50-H, ArH) 7.59–7.61 (m, 2H,
20, 60-H, ArH), 7.61 (d, 1H, J ¼ 16.8 Hz, CH ¼ CH-), 7.73 (dd, 1H, J ¼ 9.6,
9.6 Hz, 5- or 7-H), 8.23 (s, 1H, 2-H), 8.33 (d, 1H, J ¼ 9.6 Hz, 4-H), 9.54 (d,
1H, J ¼ 9.6 Hz, 8-H); MS (FAB) m=z (%): 312. Anal. calcd. for
C21H16N2O: C, 80.75; H, 5.16; N, 8.97%. Found: C, 80.54; H, 5.35; N, 9.11%.
2-(3-Methylazulen-1-yl)-5-(4-methylstyryl)-1,3,4-oxadiazoles (3h)
Green needles; mp: 127–128ꢀC; IR (KBr): 3077, 1658, 1564, 1529 cmꢁ1; 1H
NMR (CDCl3, 300 MHz) d (ppm): 2.39 (s, 3H, CH3), 2.68 (s, 3H, CH3), 7.09
(d, 1H, J ¼ 16.4 Hz, CH¼CH-), 7.23 (d, 2H, J ¼ 8.0 Hz, 30, 50-H, ArH), 7.33
(dd, 1H, J ¼ 9.6, 9.6 Hz, 7- or 5-H), 7.43 (t, 1H, J ¼ 9.6 Hz, 6-H), 7.53 (d,
2H, J ¼ 8.0 Hz, 20, 60-H, ArH), 7.58 (d, 1H, J ¼ 16.4 Hz, CH¼CH-), 7.58
(d, 1H, J ¼ 16.8 Hz, CH¼CH-), 7.73 (dd, 1H, J ¼ 9.6, 9.6 Hz, 7- or 5-H),
8.23 (s, 1H, 2-H), 8.33 (d, 1H, J ¼ 9.6 Hz, 4-H), 9.54 (d, 1H, J ¼ 9.6 Hz,
8-H); MS (FAB) m=z (%): 326. Anal. calcd. for C22H18N2O: C, 80.96; H,
5.56; N, 8.58%. Found: C, 80.84; H, 5.45; N, 8.76%.
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