Design, microwave assisted synthesis and characterization of substituted 1,2,4-oxadiazole analogues as promising pharmacological agents

Article abstract of DOI:10.14233/ajchem.2017.20626

Microwave assisted synthesis of a series of 3,5-disubstituted-1,2,4-oxadiazole analogues (3a-j) has been achieved between 5-(chloromethyl)-3-substituted phenyl-1,2,4-oxadiazoles (2a-j) and substituted benzophenone in presence of potassium carbonate in ace

Full text of DOI:10.14233/ajchem.2017.20626

Asian Journal of Chemistry; Vol. 29, No. 8 (2017), 1767-1770
ASIAN JOURNAL OF CHEMISTRY
https://doi.org/10.14233/ajchem.2017.20626
Design, Microwave Assisted Synthesis and Characterization of Substituted
1,2,4-Oxadiazole Analogues as Promising Pharmacological Agents
KATHARIGATTA N. VENUGOPALA
Department of Biotechnology and Food Technology, Durban University of Technology, Steve Biko Campus, Durban 4001, South Africa
*Corresponding author: Fax: +27 86 2423534; Tel: +27 31 3734887; E-mail: katharigattav@dut.ac.za
Received: 6 March 2017;
Accepted: 1 May 2017;
Published online: 12 June 2017;
AJC-18439
Microwave assisted synthesis of a series of 3,5-disubstituted-1,2,4-oxadiazole analogues (3a-j) has been achieved between 5-(chloromethyl)-
3-substituted phenyl-1,2,4-oxadiazoles (2a-j) and substituted benzophenone in presence of potassium carbonate in acetone medium. The
structural elucidation of the newly synthesized 1,2,4-oxadiazole analogues was established by means of FT-IR, NMR, LC-MS and
elemental analysis.
Keywords: Microwave assisted synthesis, 1,2,4-Oxadiazoles, Pharmacological properties.
were indicated in parts per million downfield from tetramethyl-
silane and the coupling constants (J) are recorded in Hertz.
Mass spectra were recorded using LC-MS-Agilent 1100 series
with MSD (Ion trap) using 0.1 % aqueous trifluoroacetic acid
in acetonitrile system on C18-BDS column. Elemental analysis
was performed on Thermo Finnigan FLASH EA 1112 CHN
analyzer. c log P of the compounds was calculated using
ChemBioDraw Ultra 13.0v.
INTRODUCTION
The oxadiazole molecular scaffolds are known for various
pharmacological activities such as antitussive, anaesthetic [1],
anthelmintic [2], anti-HIV [3], antiallergic [4], anticancer [5],
anticonvulsant [6], anti-inflammatory [7], antimicrobial [8],
antiplatelet, antithrombotic [9], insecticidal [10], monoamine
oxidase inhibition [11], muscarinic receptor agonists [12] and
selective H3 receptor antagonists [13] properties.
Synthesis of (5-chloro-2-((3-(substituted phenyl)-1,2,4-
oxadiazol-5-yl)methoxy)phenyl)(phenyl)methanone (3a-j):
A mixture of reaction intermediates (2a-j, 5 mmol), substituted
benzophenone (5 mmol), absolute ethanol (25 mL) and K2CO3
(6 mmol) was exposed to microwaves in a microwave reactor
for up to 10 min. After reaction completion, the reaction
medium was allowed to attain room temperature. The reaction
medium was filtered and the filtrate was evaporated to dryness
and the residue obtained was purified by recrystallization
method. The physicochemical characteristics of the charac-
terized title compounds 3a-j are summarized in Table-1 and
details are as follows:
Encouraged by these observations and in continuation of
our research work on the synthesis of novel heterocyclic com-
pounds for pharmacological properties [14-17] and for the
screening of polymorphic properties in heterocyclic com-
pounds [18-20], it was decided to incorporate benzophenone
moiety on 1,2,4-oxadiazole nucleus (Scheme-I) with the
support of microwave method to study the yield and total
reaction time.
EXPERIMENTAL
Commercially available chemicals were obtained from
Aldrich and Merck chemical company. TLC was performed
on Merck 60 F-254 silica gel plates with ethyl acetate and n-hexane
(6:4) as solvent system and visualization with UV-light
and iodine chamber. Reactions were monitored by thin layer
chromatography (TLC). Melting points were determined on a
Buchi melting point B-545 apparatus. The FT-IR spectra were
recorded on a Nicolet 6700 FT-IR spectrometry. 1H NMR and
13C NMR spectra were recorded on Bruker AVANCE III 400
MHz instruments in CDCl3 as a solvent. Chemical shifts (δ)
(5-Chloro-2-((3-(4-(trifluoromethyl)phenyl)-1,2,4-
oxadiazol-5-yl)methoxy)phenyl)(phenyl)methanone (3a):
Brown crystalline compound; FT-IR (KBr, νmax, cm-1): 3064,
1
1655, 1594, 1482, 1451, 1261, 738. H NMR (400 MHz,
CDCl3): δ 8.02-8.06 (m, 2H), 7.82-7.86 (d, J = 7.20 Hz, 2H),
7.55-7.63 (m, 1H), 7.43-7.51 (m, 4H), 7.12-7.22 (m, 2H), 7.07-
7.02 (d, J = 8.61 Hz, 1H), 5.23 (s, 2H, OCH2). 13C NMR (400
MHz, CDCl3): δ 194.18, 173.94, 167.65, 165.97, 163.44,
153.70, 136.99, 133.53, 129.81, 129.74, 129.64, 128.47,

1768 Venugopala
Asian J. Chem.
Cl
O
O
Cl
H2N
R1
N
O
CN
OH
R3
N
N
R1
R3
a
b
c
R1
N
R2
R3
R2
N
O
R2
1a-j
R3
R1
R2
2a-j
3a-j
Scheme-I: Reagents and conditions for the construction of 3,5-disubstituted 1,2,4-oxadiazoles (3a-j): (a) NH2OH.HCl, sodium carbonate,
ethanol; (b) chloroacetyl chloride, N,N-diisopropylethylamine (DIEA), dichloromethene (DCM); (c) potassium carbonate,
2-hydroxy-5-chloro benzophenone, ethanol
127.95, 122.43, 122.38, 116.27, 116.05, 114.90, 62.07. LC-
MS (ESI, Positive): m/z = 459 [M+H]+. CHN analysis calcu-
lated for C23H14N2O3ClF3: C, 60.21; H, 3.08; N, 6.11; Found:
C, 60.22; H, 3.05; N, 6.16.
(5-Chloro-2-((3-(4-fluoro-3-methoxyphenyl)-1,2,4-
oxadiazol-5-yl)methoxy)phenyl)(phenyl)methanone (3e):
Light yellow solid; FT-IR (KBr, νmax, cm-1): 3068, 2981, 1651,
1630, 1498, 1441, 1253, 743. 1H NMR (400 MHz, CDCl3): δ
7.80-7.83 (m, 2H), 7.54-7.65 (m, 3H), 7.42-7.47 (m, 4H), 7.14-
7.21 (m, 1H), 7.03-7.10 (d, J = 8.42 Hz, 1H), 5.27 (s, OCH2),
3.93 (s, OCH3). 13C NMR (400 MHz, CDCl3): δ 193.97, 173.89,
167.67, 167.60, 156.08, 153.69, 152.67, 148.18, 147.92,
136.95, 133.47, 131.58, 131.30, 129.68, 128.42, 127.87,
122.51, 122.41, 120.62, 120.52, 116.52, 116.39, 114.85,
112.19, 112.09, 62.04, 56.21. LC-MS (ESI, Positive): m/z =
440 [M+H]+. CHN analysis calculated for C23H16N2O4ClF: C,
62.95; H, 3.67; N, 6.38. Found: C, 62.98; H, 3.70; N, 6.35.
(5-Chloro-2-((3-(2,5-difluoro-4-methylphenyl)-1,2,4-
oxadiazol-5-yl)methoxy)phenyl)(phenyl)methanone (3f):
Yellow crystalline compound; FT-IR (KBr, νmax, cm-1): 3055,
2938, 1659, 1598, 1481, 1459, 1260, 743. 1H NMR (400 MHz,
CDCl3): δ 7.83-7.89 (d, J = 7.20 Hz, 2H), 7.55-7.68 (m, 2H),
7.44-7.49 (m, 4H), 7.04-7.12 (m, 2H), 5.29 (s, 2H, OCH2),
2.33 (s, 3H, CH3). 13C NMR (400 MHz, CDCl3): δ 194.11,
173.58, 164.73, 164.69, 164.65, 164.61, 158.28, 158.23,
157.59, 157.54, 155.88, 155.83, 155.08, 154.88, 153.61,
136.98, 133.57, 131.67, 131.38, 130.87, 130.81, 130.69,
130.60, 129.79, 128.49, 127.97, 119.32, 119.28, 119.11,
119.02, 116.37, 116.33, 116.09, 116.01, 114.76, 112.83,
112.78, 112.72, 112.63, 61.86, 14.92, 14.81. LC-MS (ESI,
Positive): m/z = 442 [M+H]+. CHN analysis calculated for
C23H15N2O3ClF2: C, 62.67; H, 3.43; N, 6.35. Found: C, 62.62;
H, 3.51; N, 6.39.
(5-Chloro-2-((3-(4-fluorophenyl)-1,2,4-oxadiazol-5-
yl)methoxy)phenyl)(phenyl)methanone (3b): Light yellow
solid; FT-IR (KBr, νmax, cm-1): 3063, 1651, 1592, 1482, 1451,
1264, 742. 1H NMR (400 MHz, CDCl3): δ 8.00-8.05 (m, 2H),
7.82-7.84 (d, J = 7.24 Hz, 2H), 7.53-7.58 (m, 1H), 7.41-7.48
(m, 4H), 7.13-7.22 (m, 2H), 7.06-7.08 (d, J = 8.42 Hz, 1H),
5.25 (s, 2H, OCH2). 13C NMR (400 MHz, CDCl3): δ 194.14,
173.97, 167.61, 165.98, 163.42, 153.70, 136.99, 133.53,
131.62, 131.41, 129.78, 129.71, 129.67, 128.42, 127.91,
122.42, 122.38, 116.25, 116.04, 114.89, 62.01. LC-MS (ESI,
Positive): m/z = 410 [M+H]+. CHN analysis calculated for
C22H14N2O3ClF: C, 64.64; H, 3.45; N, 6.85; Found: C, 64.61;
H, 3.47; N, 6.81.
(5-Chloro-2-((3-(3-chloro-4-fluorophenyl)-1,2,4-
oxadiazol-5-yl)methoxy)phenyl)(phenyl)methanone (3c):
Light yellow crystalline compound; FT-IR (KBr, νmax, cm-1):
3058, 1662, 1594, 1480, 1443, 1261, 742. 1H NMR (400 MHz,
CDCl3): δ 8.06-8.10 (m, 1H), 7.91-7.97 (m, 1H), 7.79-7.84
(m, 2H), 7.54-7.58 (m, 1H), 7.30-7.46 (m, 4H), 7.21-7.28 (m,
1H), 7.04-7.09 (d, J = 8.42 Hz, 1H), 5.24 (s, 2H, OCH2). 13C
NMR (400 MHz, CDCl3): δ 194.07, 174.25, 166.81, 161.27,
158.74, 153.63, 133.97, 131.66, 131.43, 130.05, 129.79,
128.48, 128.05, 127.57, 127.49, 123.44, 123.38, 122.12,
121.96, 117.42, 117.19, 114.92, 62.05. LC-MS: (ESI, Positive)
m/z = 444 [M+H]+. CHN analysis calculated for C22H13N2O3Cl2F:
C, 59.61; H, 2.96; N, 6.32. Found C, 59.58; H, 3.02; N, 6.30.
(5-Chloro-2-((3-(4-fluoro-3-methylphenyl)-1,2,4-
oxadiazol-5-yl)methoxy)phenyl)(phenyl)methanone (3d):
Light yellow solid; FT-IR (KBr, νmax, cm-1): 3051, 2935, 1659,
1617, 1484, 1450, 1258, 748. 1H NMR (400 MHz, CDCl3): δ
7.81-7.89 (m, 4H), 7.54-7.58 (m, 1H), 7.41-7.45 (m, 4H), 7.03-
7.12 (m, 2H), 5.26 (s, 2H, OCH2), 2.32 (s, 3H, CH3). 13C NMR
(400 MHz, CDCl3): δ 194.15, 173.80, 167.79, 164.59, 162.05,
153.72, 136.98, 133.51, 131.41, 131.33, 130.88, 130.83,
129.79, 128.44, 127.89, 127.02, 126.93, 125.95, 125.77,
121.98, 121.94, 115.83, 115.62, 114.87, 62.05, 14.52. LC-MS
(ESI, Positive): m/z = 424 [M+H]+. CHN analysis calculated
for C23H16N2O3ClF: C, 65.33; H, 3.81; N, 6.63. Found C, 65.30;
H, 3.89; N, 6.58.
(5-Chloro-2-((3-(4-iodophenyl)-1,2,4-oxadiazol-5-
yl)methoxy)phenyl)(phenyl)methanone (3g): Light brown
crystalline compound; FT-IR (KBr, νmax, cm-1): 3056, 1650,
1
1591, 1476, 1452, 1268, 747, 521. H NMR (400 MHz,
CDCl3): δ 7.76-7.85 (m, 6H), 7.55-7.58 (m, 1H), 7.42-7.48
(m, 4H), 7.05-7.08 (d, J = 8.42 Hz, 1H), 5.22 (s, 2H, OCH2).
13C NMR (400 MHz, CDCl3): δ 194.11, 174.12, 167.94,
153.66, 138.22, 136.95, 133.57, 131.62, 131.43, 129.81,
128.96, 128.47, 128.06, 125.63, 114.94, 98.33, 62.05. LC-
MS (ESI, Positive): m/z = 518 [M+H]+. CHN analysis
calculated for C22H14N2O3ClI: C, 51.14; H, 2.73; N, 5.42.
Found: C, 51.17; H, 2.71; N, 5.49.
(5-Chloro-2-((3-phenyl-1,2,4-oxadiazol-5-yl)methoxy)-
phenyl)(phenyl)methanone (3h):White amorphous compound;

Vol. 29, No. 8 (2017)
Design, Microwave Assisted Synthesis of Substituted 1,2,4-Oxadiazole Analogues 1769
FT-IR (KBr, νmax, cm-1): 3061, 1655, 1591, 1484, 1451, 1247,
738. 1H NMR (400 MHz, CDCl3): δ 7.89-8.06 (m, 2H), 7.71-
7.78 (m, 2H), 7.28-7.58 (m, 8H), 7.04-7.08 (d, J = 8.42 Hz,
1H), 5.23 (s, 2H, OCH2). 13C NMR (400 MHz, CDCl3): δ
194.10, 174.08, 167.94, 153.71, 138.25, 136.81, 133.50,
131.59, 131.38, 129.81, 128.91, 128.51, 128.12, 125.63,
125.60, 114.93, 98.36, 62.09. LC-MS (ESI, Positive): m/z =
392 [M+H]+. CHN analysis calculated for C22H15N2O3Cl: C,
67.61; H, 3.87; N, 7.17; Found: C, 67.62; H, 3.91; N, 7.22.
(5-Chloro-2-((3-(4-ethoxyphenyl)-1,2,4-oxadiazol-5-
yl)methoxy)phenyl)(phenyl)methanone (3i): Light yellow
crystalline compound; FT-IR (KBr, νmax, cm-1): 3088, 2978,
(ESI, Positive): m/z = 434 [M+H]+. CHN analysis calculated
for C25H21N2O3Cl: C, 69.36; H, 4.89; N, 6.47. Found: C, 69.42;
H, 4.99; N, 6.51.
RESULTS AND DISCUSSION
Synthetic route for the formation of 1,2,4-oxadiazole
analogues (3a-j) by microwave method is depicted in Scheme-I.
The title compounds 3a-j were synthesized from substituted
benzophenone and reaction intermediates 5-(chloromethyl)-
3-substituted phenyl-1,2,4-oxadiazoles (2a-j) in absolute ethanol
medium. Intermediates 2a-j were synthesized from equimolar
ratios of N’-hydroxybenzimidamides (1a-j) and chloroacetyl
chloride in presence of DIPEA in dichloro methanol medium.
The synthesis of N'-hydroxybenzimidamides (1a-j) was accompl-
ished from the corresponding hydroxylamine hydrochloride
and substituted benzonitriles in presence of sodium carbonate
in methanol medium. The reaction intermediates 1a-j and 2a-
j were synthesized and characterized by FT-IR, 1H NMR, LC-
MS and the characterization details matched with our previous
communication [8]. The title compounds 3a-j were characterized
by FT-IR, NMR, LC-MS and CHN analysis. The yields of
intermediates 1a-j and 2a-j were in the range of 58-79 and
56-75 %, respectively. The yield of title compounds 3,5-disubst-
ituted 1,2,4-oxadiazoles (3a-j) was 87-93 % and the physico-
chemical constants of the title compounds are summarized in
Table-1.
1
1652, 1591, 1482, 1449, 1272, 745. H NMR (400 MHz,
CDCl3): δ 7.91-7.96 (m, 2H), 7.83-7.94 (m, 2H), 7.54-7.57
(m, 1H), 7.40-7.45 (m, 4H), 7.03-7.06 (d, J = 8.42 Hz, 1H),
6.92-6.98 (m, 2H), 5.29 (s, 2H, OCH2), 4.05-4.14 (q, 2H,
OCH2), 1.42-1.48 (t, 3H, CH3). 13C NMR (400 MHz, CDCl3):
δ 194.07, 173.52, 168.08, 161.51, 153.61, 136.94, 133.41,
131.54, 131.32, 129.82, 129.68, 129.11, 128.39, 127.75,
119.00, 114.74, 114.67, 63.60, 61.90, 14.63. LC-MS (ESI,
Positive): m/z = 436 [M+H]+. CHN analysis calculated for
C24H19N2O4Cl: C, 66.29; H, 4.40; N, 6.44. Found: C, 66.32;
H, 4.39; N, 6.47.
(5-Chloro-2-((3-(4-isopropylphenyl)-1,2,4-oxadiazol-5-
yl)methoxy)phenyl)(phenyl)methanone (3j): Light yellow
crystalline compound; FT-IR (KBr, νmax, cm-1): 3051, 2972,
1
In the FT-IR spectra of 3,5-disubstituted 1,2,4-oxadiazole
analogues (3a-j), carbon-chlorine and carbonyl group (C=O)
peaks were found in the ranges of 725-760 and 1646-1668
cm-1, respectively. In the 1H NMR spectra singlet peak in the
range of 5.22-5.31 corresponds to -OCH2- group in molecular
scaffolds 3a-j. In 13C NMR spectra, alkyl carbon (-CH2-) and
carbonyl carbon peaks are observed in the range of δ 61.86-
62.09 and 193.97-194.18, respectively. In LC-MS spectra,
1657, 1598, 1481, 1453, 1268, 747. H NMR (400 MHz,
CDCl3): δ 7.95-7.99 (m, 2H), 7.80-7.87 (m, 2H), 7.51-7.59
(m, 1H), 7.44-7.48 (m, 4H), 7.34-7.36 (d, J = 8.16 Hz, 2H),
7.05-7.09 (m, 1H), 5.31 (s, 2H, OCH2), 2.95-2.97 (q, J = 6.84
Hz, 1H), 1.27-1.31 (d, 6H, 2 X CH3). 13C NMR (400 MHz,
CDCl3): δ 194.18, 173.57, 168.40, 153.69, 152.81, 137.08,
133.55, 131.72, 131.29, 129.98, 129.82, 128.61, 127.84,
127.61, 127.09, 123.64, 114.83, 62.00, 34.26, 23.71. LC-MS
TABLE-1
PHYSICO-CHEMICAL CHARACTERISTICS OF 3,5-DISUBSTITUTED 1,2,4-OXADIAZOLES (3a-j)
R1
O
R2
R3
N
Cl
O
N
O
m.p.
(°C)
reported
[Ref. 8]
–
Reaction
time
(min)
m.p.
(°C)
found
Compd.
No.
Yield
(%)
Crystal
solvent
R1
R2
R3
m.f.
m.w.
c log Pb
H
H
H
H
H
F
CF3
F
H
H
Cl
C23H14N2O3ClF3
C22H14N2O3ClF
C22H13N2O3Cl2F
C23H16N2O3ClF
C23H16N2O4ClF
C23H15N2O3ClF2
C22H14N2O3ClI
C22H15N2O3Cl
C24H19N2O4Cl
C25H21N2O3Cl
458
408
442
422
438
440
516
390
434
432
4
6
5
6
7
5
6
8
7
8
91
88
93
84
89
92
87
83
88
86
102-103 Ethanol
6.2627
3a
3b
3c
3d
3e
3f
96-97
85-86
73-74
84-85
87-89
97-98
86-87
73-74
85-86
88-89
Methanol 5.5197
Methanol 6.2332
F
F
CH3
OCH3
F
Ethanol
Ethanol
Ethanol
6.0187
5.4184
6.1622
F
CH3
H
H
H
H
I
H
124-126 125-126 Methanol 6.4997
108-110 109-110 Methanol 5.3727
3g
3h
3i
H
H
OC2H5
H
80-82
81-82
Ethanol
5.9437
6.7997
CH(CH3)2
H
110-112 111-112 Ethanol
3j
aAll the yields are on isolated basis. Compound purification is by recrystallization method.
bc log P of the compounds is calculated by ChemBioDraw Ultra 13.0v.

1770 Venugopala
Asian J. Chem.
molecular ion peaks (M+1) of the tittle compounds 3a-j were in
good agreement with proposed molecular weight. The elemen-
tal analysis results were within 0.05 % of the calculated
values of the 3,5-disubstituted 1,2,4-oxadiazole analogues
(3a-j). The ChemBioDraw calculated partition coefficient
values of the title compounds 3a-j were in the range of p =
5.3727-6.7997. Compound with aliphatic group (isopropyl)
on phenyl ring which is on third place of 1,2,4-oxadiazole nucleus
exhibited highest partition value of p = 6.7997 compared to
other analogoues in the series.
5. R. Hamdy, N.I. Ziedan, S. Ali, C. Bordoni, M. El-Sadek, E. Lashin, A.
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Conclusion
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In the present investigation, synthesis of 3,5-disubstitued
1,2,4-oxadiazole molecular scaffolds was achieved by micro-
wave method. The functional groups such as halogens and
alkoxy groups on 1,2,4-oxadiazole moiety favoured good
yields and were found in the range of 87-93 % after purification
by recrystallization method. It was confirmed from the present
investigation that, microwave method favoured to enhance the
yield of the product and reduce the reaction time to obtain the
title compounds 3a-j. The Title compounds are proposed to
test for suitable pharmacological properties.
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ACKNOWLEDGEMENTS
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The author is grateful to Durban University of Technology,
and National Research Foundation, South Africa for facilities
and support.
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