One-pot synthesis of 3,5-diaryl substituted-1,2,4-oxadiazoles using gem -dibromomethylarenes

Article abstract of DOI:10.1139/cjc-2018-0333

1,2,4-Oxadiazole is one of the most promising heterocyclic ring systems in medicinal chemistry. In the present paper, we report the method for an efficient one-pot synthesis of 3,5-diaryl substituted 1,2,4-oxadiazoles using a two-component reaction of gem-dibromomethylarenes with amidoximes in good yields. In this method, gem-dibromomethylarenes are used as benzoic acid equivalents for the efficient synthesis of aryl-substituted 1,2,4-oxadiazoles. It is anticipated that this methodology will have versatile applications in the practical syntheses of various molecules of both medicinal and material chemistry importance.

Full text of DOI:10.1139/cjc-2018-0333

Page 1 of 22
One pot synthesis of 3,5-diaryl substituted-1,2,4-oxadiazoles using gem-dibromomethylarenes
Kambappa Vinaya,a,* Ganganahalli K. Chandrashekara,a Prasanna D. Shivaramub,*
[a] Kambappa Vinaya
Department of Chemistry
Government First Grade College, Kadur-577 548, India.
E-mail: vinaymphally@gmail.com
[a] Ganganahalli K. Chandrashekara
Department of Chemistry
Government First Grade College, Kadur-577 548, India.
E-mail: gk.chandu7486@gmail.com
[b] Prasanna D. Shivaramu
Department of Nanotechnology, Visvesvaraya Technological University, Bengaluru Region,
Muddenahalli, Chikkaballapur - 562101, India.
E-mail: prasuds@gmail.com

Page 2 of 22
Abstract: 1,2,4-oxadiazole is one of the most promising heterocyclic ring systems in medicinal
chemistry. In the present paper, we are reporting the method for efficient one-pot synthesis of of 3,5-
diaryl substituted 1,2,4-oxadiazoles using two-component reaction of gem-dibromomethylarenes with
amidoximes in good yields. In this method, gem-dibromomethylarenes are used as benzoic acid
equivalent for the efficient synthesis of aryl substituted 1,2,4-oxadiazoles. It is anticipated that this
methodology will have versatile applications in the practical syntheses of various molecules of both
medicinal and material chemistry importance.
Keywords: Gem-dibromomethylarene ; oxadiazole ; amidoxime.

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Introduction
1,2,4-Oxadiazoles are being considered as one of the most important structural motifs in the research
area for drug discovery programme. They are often considered as ester and amide bioisosteres and have
been used in the design of dipeptidomimetics.1 These N- and O- containing heterocyclic compounds are
integral part of many drugs such as pleconaril,2 verucerfont3,4 and drug leads5 (Figure 1) including the
potent S1P1 agonist,6,7 mGlu5 receptor,8 and cortical muscarinic receptor9 for the treatment of
Alzheimer’s disease. They have also shown interesting biological activities such as GABA
modulators,10 anti-prostate cancer agents,11 5HT3 receptor antagonists,12 anticonvulsant activity,13 CNS
depressant,14 tumor-selective and apoptosis-inducing,15 antiviral,16 diuretic,17 analgesic, anti-
inflammatory agents, inhibitiors of cytosolic hCA II and membrane-bound hCA IX isoforms.18
In addition to medicinal importance, they have drawn considerable attention researchers working in the
area of material science due to their exceptional electrical, thermal and optical properties. Recent
reports reveals that 1,2,4-oxadiazoles are used as fabrication materials for organic solar cells19 and light-
emitting diodes.20,21 In view of wide spread applications of 1,2,4-oxadiazoles, development of
improved synthetic methodology for the synthesis of substituted 1,2,4-oxadiazoles is of prime interest.
Many synthetic methods have been reported for the preparation of 1,2,4-oxadiazole ring system.22-27 Of
the many methods reported, cyclocondensation of amidoximes, 1,3-dipolar cycloaddition of nitriles to
nitrile oxides and rearrangement from other heterocycles are important methods. The most familiar
method for the synthesis of 1,2,4-oxadiazoles is cyclization of amidoximes with acid
chlorides/carboxylic acids and esters 28-30. Coupling reagent such as CDI, DCC, EDC, HBTU, HOBt or
TBTU are being used for their synthesis using carboxylic acids.31 This method, although it works well
fairly on straightforward substrates, it is incompatible with many functional groups. There are many
other reports which arrived at synthesis of oxadiazoles using acid chlorides.32-37 Acid chlorides are toxic,
hard to store and require essential knowledge to handle. These methods suffer from drawbacks such as
reactions take more time, usually reactions have to be conducted under harsh conditions, purification of

Page 4 of 22
synthesized compounds are very difficult and tend to low yields accompanied with multiple by-product
and high toxicity.
N
O
NH
N
N
N
O
N
O
N
N
O
F3C
N
O
Verucefont
Pleconaril
CN
N
N
N
N
N
O
O
N
HOOC
mGlu5 receptor
S1P1 agonist
N
O
N
N
Muscarinic receptor
Figure-1: N and O containing heterocyclic drug molecules
Gem-dibromomethylarenes are very interesting and important starting materials in the field of synthetic
organic chemistry. By using gem-dibromomethylarenes as synthetic carbonyl compound equivalents,
various applications have been explored in synthetic organic chemistry.38-43 In recent days, gem-
dibromomethylarene moiety is occupying its own importance in pharmaceutical and medicinal
industries. To the best of our knowledge, there is no literature available on the synthesis of 1,2,4-
oxadiazoles starting from gem-dihalomethylarenes. Though the synthesis of 1,2,4-oxadiazoles has been
extensively documented, substitution of the carboxylic acid and their derivatives component with an
alternative functional group has not been documented. Therefore, development of a simple and stable
substitute by using inexpensive and readily available reagents would extend the scope of 1,2,4-
oxadiazoles in organic synthesis.
Experimental
General procedure for the synthesis of gem-dibromomethylarenes 1(a-j)
To a solution of substituted methyl analogues (1.0 eq) in CCl4 was added NBS (2.0 eq) followed by
catalytic amount of benzoylperoxide (0.2 eq). The mixture was gradually heated to reflux for 8 h.
Progress of the reaction was monitored by TLC. Upon completion, the reaction mixture was cooled to
room temperature, the succinimide was filtered off and the filtrate was concentrated under reduced

Page 5 of 22
pressure. The residue was purified by column chromatography (hexane:ethyl acetate 10%) to afford
gem-dibromomethylarenes. All the products were isolated and were well characterized by physical and
spectral data which are in good agreement with the structure of the reported products.
General procedure for the synthesis of amidoximes 2(a-c)
Hydroxylamine hydrochloride (2.5 eq) and sodiumcarbonate (1.6 eq) was taken in water and stirred to
complete dissolution. Substituted benzonitrile (1.0 eq) were dissolved in ethanol and added to the
reaction mixture. The reaction mixture is allowed to stir for 5-6 h at 60 0C. Progress of the reaction was
monitored by TLC. Upon completion, the solvent was removed under reduced pressure and residue was
taken in water and extracted with ethyl acetate. The organic layer was dried with anhydrous sodium
sulphate, the solvent was evaporated to get amidoximes. All the products were isolated in good yields
and were well characterized by physical and spectral data which are in good agreement with the
structure of the reported products.
General procedure for the synthesis of 3,5-diphenyl-1,2,4-oxadiazole derivatives 3(a-ad)
Substituted gem-dibromomethylarenes 1(a-j) and substituted (Z)-N'-hydroxybenzimidamides 2(a-c) was
taken in pyridine which acts as both base and solvent. Then potassium tert-butoxide and iodine was
added. The reaction mixture was allowed to stir for 8-10 h at 80 0C. Progress of reaction was monitored
by TLC. Upon completion, the solvent was removed under reduced pressure and residue was taken in
water and extracted with ethyl acetate. The organic layer was dried with anhydrous sodium sulphate, the
solvent was evaporated and crude was purified by column chromatography (hexane and ethyl acetate)
to get 3,5-diphenyl-1,2,4-oxadiazole 3(a-ad) derivatives.
3,5-Diphenyl-1,2,4-oxadiazole (3a)
The product was obtained from (dibromomethyl)benzene (0.1 g, 0.400 mmol) (1a), (Z)-N'-
hydroxybenzimidamide (0.052 g, 0.400 mmol) (2a), potassium tert-butoxide (0.022 g, 0.200 mmol)
1
and iodine (0.020 g, 0.080 mmol). Mp 105–108 °C (lit22 106-108 °C); H NMR (400 MHz, CDCl3): δ 8.21
(2H, d, J = 7.8 Hz, Ar-H), 8.20 (2H, dd, J = 7.5 and J = 1.5 Hz, Ar-H), 7.62 (1H, t, J = 7.1 Hz, Ar-H), d
7.51–7.58 (5H, m, Ar-H). 13C NMR (100.6 MHz, DMSO-d6): δ 175.92, 169.13, 132.82, 131.96, 129.11,

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129.04, 128.70, 127.89, 127.10, 124.83. IR (KBr) ν/cm-1: 1611, 1563, 1412, 1359. MS (ESI) m/z:
223.241 (100.0%).
5-Phenyl-3-(p-tolyl)-1,2,4-oxadiazole (3b)
The product was obtained from (dibromomethyl)benzene (0.1 g, 0.400 mmol) (1a), (Z)-N'-hydroxy-4-
methylbenzimidamide (0.060 g, 0.400 mmol) (2b), potassium tert-butoxide (0.022 g, 0.200 mmol) and
1
iodine (0.020 g, 0.080 mmol). Mp 114–116 °C (lit22 113–115 °C). H NMR (400 MHz, CDCl3): δ 8.24 (2H,
dd, J = 7.3 and J = 1.9 Hz, Ar-H), 8.11 (2H, d, J = 8.0 Hz, Ar-H), 7.50–7.69 (3H, m, Ar-H), 7.32 (2H, d,
J = 8.0 Hz, Ar-H), 2.41 (3H, s, -CH3). 13C NMR (100.6 MHz, CDCl3): δ 175.80, 168.84, 143.41, 131.09,
129.79, 128.81, 128.11, 127.48, 127.13, 121.59, 21.70. IR (KBr) ν/cm-1: 2883, 1609, 1571, 1418, 1351.
MS (ESI) m/z: 237.255 (100.0%).
3-(4-Methoxyphenyl)-5-phenyl-1,2,4-oxadiazole (3c)
The product was obtained from (dibromomethyl)benzene (0.1 g, 0.400 mmol) (1a), (Z)-N'-hydroxy-4-
methoxybenzimidamide (0.066 g, 0.400 mmol) (2c), potassium tert-butoxide (0.022 g, 0.200 mmol) and
1
iodine (0.020 g, 0.080 mmol). Mp 93–96 °C (lit22 94–96 °C). H NMR (400 MHz, CDCl3): δ 8.19 (2H, dd, J
= 8.4 and J = 1.7 Hz, Ar-H), 8.15 (2H, d, J = 8.8 Hz, Ar-H), 7.49–7.58 (3H, m, Ar-H), 7.03 (2H, d, J =
8.7 Hz, Ar-H), 3.85 (3H, s, -OCH3). 13C NMR (100.6 MHz, CDCl3): δ 175.79, 168.91, 163.29, 131.13,
130.02, 128.79, 127.51, 127.19, 116.88 114.49, 55.47. IR (KBr) ν/cm-1: 1611, 1563, 1412, 1359, 1237,
1048. MS (ESI) m/z: 253.25 (100.0%).
5-(4-Chlorophenyl)-3-phenyl-1,2,4-oxadiazole (3d)
The product was obtained from 1-chloro-4-(dibromomethyl)benzene (0.1 g, 0.351 mmol) (1b), (Z)-N'-
hydroxybenzimidamide (0.047 g, 0.351 mmol) (2a), potassium tert-butoxide (0.019 g, 0.175 mmol)
and iodine (0.017 g, 0.070 mmol). Mp 118–120 °C (lit22 118–119 °C) 1H NMR (400 MHz, CDCl3): δ 8.23
(2H, d, J = 7.8 Hz, Ar-H), 8.18 (2H, dd, J = 7.5 and J = 1.5 Hz, Ar-H), 7.49-7.56 (5H, m, J = 8.7 Hz, Ar-
13
H). C NMR (100.6 MHz, CDCl3): δ 175.81, 168.71, 134.68, 131.45, 129.68, 129.14, 128.55, 127.04,
126.22, 122.03. IR (KBr) ν/cm-1: 1601, 1550, 1411, 1352, 1091, 810. MS (ESI) m/z: 257.681 (100.0%).
5-(4-Chlorophenyl)-3-(p-tolyl)-1,2,4-oxadiazole (3e)

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The product was obtained from 1-chloro-4-(dibromomethyl)benzene (0.1 g, 0.351 mmol) (1b), (Z)-N'-
hydroxy-4-methylbenzimidamide (0.052 g, 0.351 mmol) (2b), potassium tert-butoxide (0.019 g, 0.175
1
mmol) and iodine (0.017 g, 0.070 mmol). Mp 137–140 °C (lit22 138–140 °C). H NMR (400 MHz, CDCl3):
δ 8.28 (2H, d, J = 7.8 Hz, Ar-H), 8.21 (2H, dd, J = 7.5 and J = 1.5 Hz, Ar-H), 7.65 (2H, d, Ar-H), 7.58
(2H, d, 2H), 2.32 (s, 3H, -CH3). 13C NMR (100.6 MHz, CDCl3): δ 175.83, 168.91, 134.43, 131.90,
129.88, 129.08, 128.40, 125.62, 123.54, 122.35, 21.44. IR (KBr) ν/cm-1: 1612, 1546, 1418, 1342, 828.
MS (ESI) m/z: 271.704, (100.0%).
5-(4-Chlorophenyl)-3-(4-methoxyphenyl)-1,2,4-oxadiazole (3f)
The product was obtained from 1-chloro-4-(dibromomethyl)benzene (0.1 g, 0.351 mmol) (1b), (Z)-N'-
hydroxy-4-methoxybenzimidamide (0.058 g, 0.351 mmol) (2c), potassium tert-butoxide (0.019 g, 0.175
45
mmol) and iodine (0.017 g, 0.070 mmol). Mp 138–140 °C (lit 138–139 °C) 1H NMR (400 MHz, CDCl3):
δ 8.25 (2H, d, J = 7.8 Hz, Ar-H), 8.18 (2H, dd, J = 7.5 and J = 1.5 Hz, Ar-H), 7.71 (2H, d, Ar-H), 7.65
13
(2H, d, 2H), 3.83 (s, 3H, -OCH3). C NMR (100.6 MHz, CDCl3): δ 175.93, 168.78, 160.84, 134.58,
129.96, 129.01, 125.67, 122.38, 118.52, 114.96, 55.88. IR (KBr) ν/cm-1: 2893, 1620, 1559, 1410, 1352,
819, 741. MS (ESI) m/z: 287.724 (100.0%).
5-(4-Bromophenyl)-3-phenyl-1,2,4-oxadiazole (3g)
The product was obtained from 1-bromo-4-(dibromomethyl)benzene (0.1 g, 0.304 mmol) (1c), (Z)-N'-
hydroxybenzimidamide (0.041 g, 0.304 mmol) (2a), potassium tert-butoxide (0.017 g, 0.152 mmol)
45
and iodine (0.015 g, 0.068 mmol). Mp 113–114 °C (lit 112–114 °C). 1H NMR (400 MHz, CDCl3): δ 8.18
(2H, d, J = 7.8 Hz, Ar-H), 8.12 (2H, dd, J = 7.5 and J = 1.5 Hz, Ar-H), 7.57-7.52 (3H, m, Ar-H), 7.38
(2H, d, Ar-H). 13C NMR (100.6 MHz, CDCl3): δ 175.90, 168.92, 132.18, 131.03, 129.98, 129.04,
127.84, 126.39, 123.32. IR (KBr) ν/cm-1: 1606, 1555, 1408, 1355, 734. MS (ESI) m/z: 302.128,
(100.0%).
5-(4-Bromophenyl)-3-(p-tolyl)-1,2,4-oxadiazole (3h)
The product was obtained from 1-bromo-4-(dibromomethyl)benzene (0.1 g, 0.304 mmol) (1c), (Z)-N'-
hydroxy-4-methylbenzimidamide (0.045 g, 0.304 mmol) (2b), potassium tert-butoxide (0.017 g, 0.152

Page 8 of 22
46
1
mmol) and iodine (0.015 g, 0.068 mmol). Mp 118–120 °C (lit not given). H NMR (400 MHz, CDCl3): δ
8.20 (2H, d, J = 7.8 Hz, Ar-H), 8.14 (2H, dd, J = 7.5 and J = 1.5 Hz, Ar-H), 7.57 (2H, d, Ar-H), 7.45
(2H, d, Ar-H), 2.32 (s, 3H, -CH3). 13C NMR (100.6 MHz, CDCl3): δ δ 175.89, 168.79, 132.55, 131.71,
129.96, 129.15, 128.40, 125.71, 123.04, 21.38. IR (KBr) ν/cm-1: 2892, 1601, 1550, 1411, 1352, 738.
MS (ESI) m/z: 316.209, (100.0%).
5-(4-Bromophenyl)-3-(4-methoxyphenyl)-1,2,4-oxadiazole (3i)
The product was obtained from 1-bromo-4-(dibromomethyl)benzene (0.1 g, 0.304 mmol) (1c), (Z)-N'-
hydroxy-4-methoxybenzimidamide (0.050 g, 0.304 mmol) (2c), potassium tert-butoxide (0.017 g, 0.152
46
1
mmol) and iodine (0.015 g, 0.068 mmol). Mp 110–112 °C (lit not given). H NMR (400 MHz, CDCl3): δ
8.29 (2H, d, J = 7.8 Hz, Ar-H), 8.15 (2H, dd, J = 7.5 and J = 1.5 Hz, Ar-H), 7.55 (2H, d, Ar-H), 7.47
(2H, d, Ar-H), 3.79 (s, 3H, -OCH3). 13C NMR (100.6 MHz, CDCl3): δ 175.84, 168.81, 160.62, 132.38,
129.87, 125.58, 123.77, 118.63, 114.79, 55.92. IR (KBr) ν/cm-1: 2884, 1608, 1561, 1407, 1350, 1125,
732. MS (ESI) m/z: 331.164, (100.0%).
5-(4-Fluorophenyl)-3-phenyl-1,2,4-oxadiazole (3j)
The product was obtained from 1-(dibromomethyl)-4-fluorobenzene (0.1 g, 0.373 mmol) (1d), (Z)-N'-
hydroxybenzimidamide (0.050 g, 0.373 mmol) (2a), potassium tert-butoxide (0.020 g, 0.186 mmol) and
47
1
iodine (0.018 g, 0.074 mmol). Mp 116–118 °C (lit 116-117 °C). H NMR (400 MHz, CDCl3): δ 8.26 (2H,
13
d, J = 7.8 Hz, Ar-H), 8.18 (2H, dd, J = 7.5 and J = 1.5 Hz, Ar-H), 7.42-7.49 (5H, m, Ar-H). C NMR
(100.6 MHz, CDCl3): δ 175.88, 168.82, 163.05, 131.25, 129.28, 129.10, 127.22, 126.22 119.82, 116.13.
IR (KBr) ν/cm-1: 1625, 1571, 1421, 1371, 1210. MS (ESI) m/z: 241.239, (100.0%).
5-(4-Fluorophenyl)-3-(p-tolyl)-1,2,4-oxadiazole (3k)
The product was obtained from 1-(dibromomethyl)-4-fluorobenzene (0.1 g, 0.373 mmol) (1d), (Z)-N'-
hydroxy-4-methylbenzimidamide (0.056 g, 0.373 mmol) (2b), potassium tert-butoxide (0.020 g, 0.186
1
mmol) and iodine (0.018 g, 0.074 mmol). Mp 122–124 °C H NMR (400 MHz, CDCl3): δ 8.22 (2H, d, J
= 7.8 Hz, Ar-H), 8.13 (2H, dd, J = 7.5 and J = 1.5 Hz, Ar-H), 7.49 (2H, d, Ar-H), 7.38 (2H, d, Ar-H),
13
2.38 (3H, s, -CH3). C NMR (100.6 MHz, CDCl3): δ 175.94, 168.82, 163.07, 131.75, 129.98, 129.08,

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125.70, 123.09, 116.07, 119.83, 21.41. IR (KBr) ν/cm-1: 2891, 1610, 1542, 1412, 1371, 1219, 761. MS
(ESI) m/z: 255.263, (100.0%).
5-(4-Fluorophenyl)-3-(4-methoxyphenyl)-1,2,4-oxadiazole (3l)
The product was obtained from 1-(dibromomethyl)-4-fluorobenzene (0.1 g, 0.373 mmol) (1d), (Z)-N'-
hydroxy-4-methoxybenzimidamide (0.062 g, 0.373 mmol) (2c), potassium tert-butoxide (0.020 g, 0.186
48
1
mmol) and iodine (0.018 g, 0.074 mmol). Mp 150–152 °C (lit 151-152 °C). H NMR (400 MHz, CDCl3): δ
8.20 (2H, d, J = 7.8 Hz, Ar-H), 8.15 (2H, dd, J = 7.5 and J = 1.5 Hz, Ar-H), 7.51 (2H, d, Ar-H), 7.36
(2H, d, Ar-H), 3.84 (3H, s, -OCH3). 13C NMR (100.6 MHz, CDCl3): δ 175.90, 168.79, 163.01, 160.85,
129.19, 125.89, 119.79, 118.03, 116.12, 114.99, 55.95. IR (KBr) ν/cm-1: 1612, 1548, 1412, 1363, 1253,
1217, 1048. MS (ESI) m/z: 271.264, (100.0%).
5-(2-Chloro-6-fluorophenyl)-3-phenyl-1,2,4-oxadiazole (3m)
The product was obtained from 1-chloro-2-(dibromomethyl)-3-fluorobenzene (0.1 g, 0.330 mmol) (1e),
(Z)-N'-hydroxybenzimidamide (0.045 g, 0.330 mmol) (2a), potassium tert-butoxide (0.018 g, 0.165
1
mmol) and iodine (0.016 g, 0.066 mmol). Mp 120–122 °C. H NMR (400 MHz, CDCl3): δ 8.11 (2H, dd, J
= 7.5 and J = 1.5 Hz, Ar-H), 7.50 (2H, t, Ar-H), 7.45 (1H, t, Ar-H), 7.37 (1H, d, Ar-H), 7.30 (1H, d, Ar-
H), 7.25 (1H, t, Ar-H). 13C NMR (100.6 MHz, CDCl3): δ 175.93, 166.79, 159.95, 133.91, 131.92,
131.02, 129.31, 127.42, 126.18, 124.92, 123.95, 112.93. IR (KBr) ν/cm-1: 1624, 1581, 1430, 1363, 1273,
1095, 827. MS (ESI) m/z: 275.682, (100.0%).
5-(2-Chloro-6-fluorophenyl)-3-(p-tolyl)-1,2,4-oxadiazole (3n)
The product was obtained from 1-chloro-2-(dibromomethyl)-3-fluorobenzene (0.1 g, 0.330 mmol) (1e),
(Z)-N'-hydroxy-4-methylbenzimidamide (0.049 g, 0.330 mmol) (2b), potassium tert-butoxide (0.018 g,
0.165 mmol) and iodine (0.016 g, 0.066 mmol). Mp 119–121 °C. 1H NMR (400 MHz, CDCl3): δ 8.15
(2H, dd, J = 7.5 and J = 1.5 Hz, Ar-H), 7.52 (2H, t, Ar-H), 7.40 (1H, d, Ar-H), 7.34 (1H, d, Ar-H), 7.28
13
(1H, t, Ar-H), 2.36 (3H, s, -CH3). C NMR (100.6 MHz, CDCl3): δ 175.80, 168.91, 159.84, 133.92,
131.87, 129.66, 125.93, 124.95, 123.98, 123.12, 112.91, 21.55. IR (KBr): 2907, 1613, 1560, 1454, 1371,
1265, 1089, 840, 769. MS (ESI) m/z ν/cm-1: 289.904, (100.0%).

Page 10 of 22
5-(2-Chloro-6-fluorophenyl)-3-(4-methoxyphenyl)-1,2,4-oxadiazole (3o)
The product was obtained from 1-chloro-2-(dibromomethyl)-3-fluorobenzene (0.1 g, 0.330 mmol) (1e),
(Z)-N'-hydroxy-4-methoxybenzimidamide (0.054 g, 0.330 mmol) (2c), potassium tert-butoxide (0.018 g,
0.165 mmol) and iodine (0.016 g, 0.066 mmol). Mp 108–110 °C. 1H NMR (400 MHz, CDCl3): δ 8.13
(2H, dd, J = 7.5 and J = 1.5 Hz, Ar-H), 7.54 (2H, t, Ar-H), 7.39 (1H, d, Ar-H), 7.34 (1H, d, Ar-H), 7.27
13
(1H, t, Ar-H), 3.78 (3H, s, -OCH3). C NMR (100.6 MHz, CDCl3): δ 175.91, 168.93, 160.71, 159.81,
133.85, 131.88, 125.99, 124.99, 123.95, 118.81, 114.91, 112.99, 55.92. IR (KBr) ν/cm-1: 1608, 1574,
1423, 1358, 1260, 1243, 1088, 1066, 841. MS (ESI) m/z: 305.724, (100.0%).
4-(3-Phenyl-1,2,4-oxadiazol-5-yl)benzonitrile (3p)
The product was obtained from 4-(dibromomethyl)benzonitrile (0.1 g, 0.363 mmol) (1f), (Z)-N'-
hydroxybenzimidamide (0.049 g, 0.363 mmol) (2a), potassium tert-butoxide (0.020 g, 0.181 mmol) and
49
1
iodine (0.018 g, 0.072 mmol). Mp 160–162 °C (lit 161-162 °C). H NMR (400 MHz, CDCl3): δ 8.20 (2H,
d, J = 7.8 Hz, Ar-H), 8.13 (2H, dd, J = 7.5 and J = 1.5 Hz, Ar-H), 7.92 (2H, d, Ar-H), 7.50 (2H, t, J =
13
7.1 Hz, Ar-H), 7.42 (1H, d, Ar-H). C NMR (100.6 MHz, CDCl3): δ 175.95, 168.91, 132.88, 131.15,
129.38, 128.99, 128.03, 127.62, 126.13, 118.91, 112.79. IR (KBr) ν/cm-1: 2236, 1622, 1570, 1424, 1367.
MS (ESI) m/z: 248.241, (100.0%).
4-(3-(p-Tolyl)-1,2,4-oxadiazol-5-yl)benzonitrile (3q)
The product was obtained from 4-(dibromomethyl)benzonitrile (0.1 g, 0.363 mmol) (1f), (Z)-N'-
hydroxy-4-methylbenzimidamide (0.054 g, 0.363 mmol) (2b), potassium tert-butoxide (0.020 g, 0.181
46
1
mmol) and iodine (0.018 g, 0.072 mmol). Mp 128–130 °C (lit not reportedI ). H NMR (400 MHz,
CDCl3): δ 8.22 (2H, d, J = 7.8 Hz, Ar-H), 8.09 (2H, dd, J = 7.5 and J = 1.5 Hz, Ar-H), 7.92 (2H, d, Ar-
H), 7.35 (2H, t, J = 7.1 Hz, Ar-H), 2.32 (3H, s, -CH3). 13C NMR (100.6 MHz, CDCl3): δ 175.89, 168.93,
132.84, 131.81, 130.00, 128.39, 128.59, 125.89, 123.27, 118.74, 112.63, 21.55. IR (KBr) ν/cm-1: 2877,
2242, 1610, 1559, 1437, 1356, 761. MS (ESI) m/z: 262.50, (100.0%).
4-(3-(4-Methoxyphenyl)-1,2,4-oxadiazol-5-yl)benzonitrile (3r)

Page 11 of 22
The product was obtained from 4-(dibromomethyl)benzonitrile (0.1 g, 0.363 mmol) (1f), (Z)-N'-
hydroxy-4-methoxybenzimidamide (0.060 g, 0.363 mmol) (2c), potassium tert-butoxide (0.020 g, 0.181
46
1
mmol) and iodine (0.018 g, 0.072 mmol). Mp 108–110 °C (lit not reported). H NMR (400 MHz, CDCl3): δ
8.21 (2H, d, J = 7.8 Hz, Ar-H), 8.13 (2H, dd, J = 7.5 and J = 1.5 Hz, Ar-H), 7.90 (2H, d, Ar-H), 7.38
(2H, t, J = 7.1 Hz, Ar-H), 3.83 (3H, s, -OCH3). 13C NMR (100.6 MHz, CDCl3): δ 175.97, 168.83,
160.79, 132.89, 128.99, 128.03, 125.77, 119.00, 118.01, 114.91, 112.71, 55.85. IR (KBr) ν/cm-1: 2241,
1634, 1561, 1430, 1353, 1246, 1038. MS (ESI) m/z: 278.267, (100.0%).
3-Phenyl-5-(4-(trifluoromethyl)phenyl)-1,2,4-oxadiazole (3s)
The product was obtained from 1-(dibromomethyl)-4-(trifluoromethyl)benzene (0.1 g, 0.314 mmol)
(1g), (Z)-N'-hydroxybenzimidamide (0.042 g, 0.314 mmol) (2a), potassium tert-butoxide (0.017 g,
46
1
0.157 mmol) and iodine (0.016 g, 0.062 mmol). Mp 130–132 °C (lit not reported). H NMR (400 MHz,
CDCl3): δ 8.24 (2H, d, J = 7.8 Hz, Ar-H), 8.11 (2H, dd, J = 7.5 and J = 1.5 Hz, Ar-H), 7.85 (2H, d, Ar-
H), 7.53 (2H, t, J = 7.1 Hz, Ar-H), 7.45 (1H, d, Ar-H). 13C NMR (100.6 MHz, CDCl3): δ 175.88, 168.93,
131.90, 131.02, 129.99, 127.97, 127.01, 127.00, 126.22, 125.89, 124.32. IR (KBr) ν/cm-1: 1619, 1549,
1424, 1351, 1317, 1273, 1142, 641. MS (ESI) m/z: 291.252, (100.0%).
3-(p-Tolyl)-5-(4-(trifluoromethyl)phenyl)-1,2,4-oxadiazole (3t)
The product was obtained from 1-(dibromomethyl)-4-(trifluoromethyl)benzene (0.1 g, 0.314 mmol)
(1g), (Z)-N'-hydroxy-4-methylbenzimidamide (0.047 g, 0.314 mmol) (2b), potassium tert-butoxide
1
(0.017 g, 0.157 mmol) and iodine (0.016 g, 0.062 mmol). Mp 132–134 °C. H NMR (400 MHz, CDCl3): δ
8.21 (2H, d, J = 7.8 Hz, Ar-H), 8.13 (2H, dd, J = 7.5 and J = 1.5 Hz, Ar-H), 7.87 (2H, d, Ar-H), 7.50
(2H, t, J = 7.1 Hz, Ar-H), 2.36 (3H, s, -CH3). 13C NMR (100.6 MHz, CDCl3): δ 175.91, 168.90, 131.98,
131.01, 129.97, 127.89, 127.01, 125.94, 125.12, 124.32, 123.12, 21.41. IR (KBr) ν/cm-1: 2886, 1624,
1557, 1432, 1363, 1321, 1278, 1151, 742, 636. MS (ESI) m/z: 305.272, (100.0%).
3-(4-Methoxyphenyl)-5-(4-(trifluoromethyl)phenyl)-1,2,4-oxadiazole (3u)
The product was obtained from 1-(dibromomethyl)-4-(trifluoromethyl)benzene (0.1 g, 0.314 mmol)
(1g), (Z)-N'-hydroxy-4-methoxybenzimidamide (0.052 g, 0.314 mmol) (2c), potassium tert-butoxide

Page 12 of 22
50
1
(0.017 g, 0.157 mmol) and iodine (0.016 g, 0.062 mmol). Mp 120–122 °C (lit not reported). H NMR (400
MHz, CDCl3): δ 8.18 (2H, d, J = 7.8 Hz, Ar-H), 8.10 (2H, dd, J = 7.5 and J = 1.5 Hz, Ar-H), 7.83 (2H, d,
13
Ar-H), 7.47 (2H, t, J = 7.1 Hz, Ar-H), 3.78 (3H, s, -OCH3). C NMR (100.6 MHz, CDCl3): δ 175.86,
168.93, 160.71, 131.09, 127.99, 127.02, 125.68, 125.50, 124.30, 118.51, 114.96, 55.89. IR (KBr) ν/cm-
1: 1615, 1542, 1428, 1357, 1310, 1278, 1197, 1145, 1046, 648. MS (ESI) m/z: 321.233, (100.0%).
3-Phenyl-5-(thiophen-2-yl)-1,2,4-oxadiazole (3v)
The product was obtained from 2-(dibromomethyl)thiophene (0.1 g, 0.390 mmol) (1h), (Z)-N'-
hydroxybenzimidamide (0.053 g, 0.390 mmol) (2a), potassium tert-butoxide (0.023 g, 0.195 mmol) and
51
1
iodine (0.019 g, 0.078 mmol). Mp 108–110 °C (lit not reported). H NMR (400 MHz, CDCl3): δ 8.14 (2H,
dd, J = 7.5 and J = 1.5 Hz, Ar-H), 7.53 (2H, d, Ar-H), 7.40 (1H, t, J = 7.1 Hz, Ar-H), 7.35–7.33 (1H, d, J
= 7.8 Hz, Ar-H), 7.22–7.20 (1H, d, Ar-H), 7.13 (1H, t, Ar-H). 13C NMR (100.6 MHz, CDCl3): δ 168.72,
164.69, 132.23, 131.53, 131.02, 129.62, 128.72, 128.06, 127.88, 126.25. IR (KBr) ν/cm-1: 1622, 1570,
1527, 1423, 1384, 1366, 1236, 847. MS (ESI) m/z: 229.327, (100.0%).
5-(Thiophen-2-yl)-3-(p-tolyl)-1,2,4-oxadiazole (3w)
The product was obtained from 2-(dibromomethyl)thiophene (0.1 g, 0.390 mmol) (1h), (Z)-N'-hydroxy-
4-methylbenzimidamide (0.058 g, 0.390 mmol) (2b), potassium tert-butoxide (0.023 g, 0.195 mmol)
51
1
and iodine (0.019 g, 0.078 mmol). Mp 112–114 °C (lit not reported). H NMR (400 MHz, CDCl3): δ 8.10
(2H, dd, J = 7.5 and J = 1.5 Hz, Ar-H), 7.48 (2H, d, Ar-H), 7.36–7.34 (1H, d, J = 7.8 Hz, Ar-H), 7.25–
13
7.23 (1H, d, Ar-H), 7.15 (1H, t, Ar-H), 2.31 (3H, s, -CH3). C NMR (100.6 MHz, CDCl3): δ 168.94,
164.72, 132.45, 131.95, 131.08, 129.71, 128.96, 128.11, 125.93, 21.31. IR (KBr) ν/cm-1: 2858, 1620,
1575, 1521, 1420, 1389, 1371, 1242, 840, 746. MS (ESI) m/z: 243.384, (100.0%).
3-(4-Methoxyphenyl)-5-(thiophen-2-yl)-1,2,4-oxadiazole (3x)
The product was obtained from 2-(dibromomethyl)thiophene (0.1 g, 0.390 mmol) (1h), (Z)-N'-hydroxy-
4-methoxybenzimidamide (0.064 g, 0.390 mmol) (2c), potassium tert-butoxide (0.023 g, 0.195 mmol)

Page 13 of 22
and iodine (0.019 g, 0.078 mmol). Mp 108–110 °C. 1H NMR (400 MHz, CDCl3): δ 8.13 (2H, dd, J = 7.5
and J = 1.5 Hz, Ar-H), 7.50 (2H, d, Ar-H), 7.34–7.31 (1H, d, J = 7.8 Hz, Ar-H), 7.25–7.23 (1H, d, Ar-
H), 7.15 (1H, t, Ar-H), 3.83 (3H, s, -OCH3). 13C NMR (100.6 MHz, CDCl3): δ 168.82, 164.80, 160.58,
132.05, 131.12, 129.00, 128.22, 125.77, 118.52, 114.91, 55.91. IR (KBr): 1614, 1563, 1531, 1430, 1365,
1351, 1244, 1231, 1042, 840. MS (ESI) m/z ν/cm-1: 258.375, (100.0%).
5-(5-Bromothiophen-2-yl)-3-phenyl-1,2,4-oxadiazole (3y)
The product was obtained from 2-bromo-5-(dibromomethyl)thiophene (0.1 g, 0.298 mmol) (1i), (Z)-N'-
hydroxybenzimidamide (0.040 g, 0.298 mmol) (2a), potassium tert-butoxide (0.016 g, 0.149 mmol) and
1
iodine (0.015 g, 0.059 mmol). Mp 112–114 °C. H NMR (400 MHz, CDCl3): δ 8.17 (2H, dd, J = 7.5 and J
= 1.5 Hz, Ar-H), 7.56 (2H, d, Ar-H), 7.40 (1H, t, Ar-H) 7.38–7.35 (1H, d, J = 7.8 Hz, Ar-H), 7.25–7.23
(1H, d, Ar-H). 13C NMR (100.6 MHz, CDCl3): δ 168.81, 164.82, 134.93, 131.22, 129.92, 127.78,
126.23, 111.79. IR (KBr) ν/cm-1: 1618, 1564, 1534, 1423, 1372, 1351, 1225, 841, 805. MS (ESI) m/z:
307.631, (100.0%).
5-(5-Bromothiophen-2-yl)-3-(p-tolyl)-1,2,4-oxadiazole (3z)
The product was obtained from 2-bromo-5-(dibromomethyl)thiophene (0.1 g, 0.298 mmol) (1i), (Z)-N'-
hydroxy-4-methylbenzimidamide (0.044 g, 0.298 mmol) (2b), potassium tert-butoxide (0.016 g, 0.149
1
mmol) and iodine (0.015 g, 0.059 mmol). Mp 114–116 °C. H NMR (400 MHz, CDCl3): δ 8.12 (2H, dd, J
= 7.5 and J = 1.5 Hz, Ar-H), 7.53 (2H, d, Ar-H), 7.34–7.31 (1H, d, J = 7.8 Hz, Ar-H), 7.23–7.21 (1H, d,
13
Ar-H), 2.33 (3H, s, -CH3). C NMR (100.6 MHz, CDCl3): δ 168.74, 164.55, 134.85, 131.99, 131.12,
129.94, 129.13, 125.82, 123.21, 111.88, 21.42. IR (KBr) ν/cm-1: 2864, 1623, 1571, 1541, 1432, 1363,
1351, 1217, 838, 801, 732. MS (ESI) m/z: 321.233, (100.0%).
5-(5-Bromothiophen-2-yl)-3-(4-methoxyphenyl)-1,2,4-oxadiazole (3aa)
The product was obtained from 2-bromo-5-(dibromomethyl)thiophene (0.1 g, 0.298 mmol) (1i), (Z)-N'-
hydroxy-4-methoxybenzimidamide (0.049 g, 0.298 mmol) (2c), potassium tert-butoxide (0.016 g, 0.149
1
mmol) and iodine (0.015 g, 0.059 mmol). Mp 100–102 °C. H NMR (400 MHz, CDCl3): δ 8.19 (2H, dd, J
= 7.5 and J = 1.5 Hz, Ar-H), 7.56 (2H, d, Ar-H), 7.33–7.30 (1H, d, J = 7.8 Hz, Ar-H), 7.22–7.19 (1H, d,

Page 14 of 22
Ar-H), 3.79 (3H, s, -OCH3). 13C NMR (100.6 MHz, CDCl3): δ 168.91, 164.81, 160.81, 134.79, 131.22,
129.08, 125.75, 118.55, 114.88, 111.71, 55.88. IR (KBr) ν/cm-1: 1614, 1571, 1540, 1423, 1365, 1350,
1262, 1218, 1044, 835, 808. MS (ESI) m/z: 337.299, (100.0%).
3-Phenyl-5-(pyridin-4-yl)-1,2,4-oxadiazole (3ab)
The product was obtained from 4-(dibromomethyl)pyridine (0.1 g, 0.398 mmol) (1j), (Z)-N'-
hydroxybenzimidamide (0.054 g, 0.398 mmol) (2a), potassium tert-butoxide (0.022 g, 0.199 mmol) and
1
iodine (0.020 g, 0.079 mmol). Mp 154–157 °C (lit47 155-157 °C). H NMR (400 MHz, CDCl3): δ 8.56 (2H, d,
Ar-H), 8.21 (2H, d, J = 7.8 Hz, Ar-H), 8.14 (2H, dd, J = 7.5 and J = 1.5 Hz, Ar-H), 7.60 (1H, t, J = 7.1
Hz, Ar-H), 7.53–7.56 (2H, dd, Ar-H). 13C NMR (100.6 MHz, CDCl3): δ 175.91, 168.86, 150.01, 131.22,
129.32, 12781, 126.18, 121.65, 143.78. IR (KBr) ν/cm-1: 1628, 1575, 1521, 1424, 1354. MS (ESI) m/z:
224.367, (100.0%).
5-(Pyridin-4-yl)-3-(p-tolyl)-1,2,4-oxadiazole (3ac)
The product was obtained from 4-(dibromomethyl)pyridine (0.1 g, 0.398 mmol) (1j), (Z)-N'-hydroxy-4-
methylbenzimidamide (0.059 g, 0.398 mmol) (2b), potassium tert-butoxide (0.022 g, 0.199 mmol) and
1
iodine (0.020 g, 0.079 mmol). Mp 157–159 °C. H NMR (400 MHz, CDCl3): δ 8.51 (2H, d, Ar-H), 8.24
(2H, d, J = 7.8 Hz, Ar-H), 8.08 (2H, dd, J = 7.5 and J = 1.5 Hz, Ar-H), 7.50–7.53 (2H, dd, Ar-H), 2.45
(3H, s, -CH3). 13C NMR (100.6 MHz, CDCl3): δ 175.91, 168.79, 149.91, 143.95, 131.81, 129.81,
125.78, 123.29, 121.45, 21.49. IR (KBr) ν/cm-1: 2931, 1612, 1576, 1535, 1518, 1358, 763. MS (ESI)
m/z: 238.273, (100.0%).
3-(4-Methoxyphenyl)-5-(pyridin-4-yl)-1,2,4-oxadiazole (3ad)
The product was obtained from 4-(dibromomethyl)pyridine (0.1 g, 0.398 mmol) (1j), ), (Z)-N'-hydroxy-
4-methoxybenzimidamide (0.066 g, 0.398 mmol) (2c), potassium tert-butoxide (0.022 g, 0.199 mmol)
1
and iodine (0.020 g, 0.079 mmol). Mp 148–150 °C. H NMR (400 MHz, CDCl3): δ 8.58 (2H, d, Ar-H),
8.25 (2H, d, J = 7.8 Hz, Ar-H), 8.13 (2H, dd, J = 7.5 and J = 1.5 Hz, Ar-H), 7.52–7.55 (2H, dd, Ar-H),
3.85 (3H, s, -OCH3). 13C NMR (100.6 MHz, CDCl3): δ 175.89, 168.82, 160.71, 149.94, 143.81, 125.88,

Page 15 of 22
121.68, 118.59, 114.92, 55.96. IR (KBr) ν/cm-1: 1620, 1554, 1534, 1435, 1340, 1263, 1023. MS (ESI)
m/z: 254.283, (100.0%).
Results and Discussion
In connection with above studies and in continuation of our previous research works, the present paper
reports the new, rapid and efficient method for the one-pot synthesis of 3,5-aryl substituted 1,2,4-
oxadiazoles from gem-dibromomethylarenes/ gem-dibromomethyl-hetero-arenes and amidoximes
(Scheme 1). In this synthetic approach, gem-dibromomethylarenes were generated starting from the
easily accessible methyl analogs using radical bromination.31 The obtained gem-dibromomethylarenes
were treated with different amidoximes44 in presence of potassium tert-butoxide and iodine in pyridine
to yield 3,5-aryl substituted-1,2,4-oxadiazoles. As mentioned above, various coupling reagents are used
for the synthesis of 3,5-substituted-1,2,4-oxadiazoles to achieve a good yield and purity of the obtained
products. Of which pyridine catalyzed reaction ended up with good expected yield in 8 h, whereas the
other bases did not promote this reaction.
Conditions were optimized for synthesis of 1,2,4-oxadiazoles by varying reaction temperature and time
to get good yield. The obtained results showed that the reaction using a 1:1 ratio of gem-
dibromomethylarene 1 and amidaoxime 2 in a one-pot reaction proceeded with highest yield in shorter
reaction times (Table 1, entry 9). One equivalent of pyridine with respect to the gem-
dibromomethylarene is sufficient for complete conversion of the starting materials.
Br
N
N
H2N
N
O
t-BuOK/ I2
R2
R1
R2
Pyridine, 80 C
Br
HO
R1
1(a-j)
2(a-c)
3a-3ad
Scheme 1. Scheme for synthesis of 3,5-substituted-1,2,4-oxadiazoles 3a-3ad

Page 16 of 22
Table 1. Optimization of the synthesis of 3,5-substituted-1,2,4-oxadiazoles.
Time(h)
Temperature (oC)
Yield (%)
Sl.Noa
1
2
3
4
5
6
7
8
9
6
7
8
6
7
8
6
7
8
6
7
8
30
30
30
55
55
55
80
80
80
26
38
31
44
58
78
70
81
93
72
77
85
10
11
12
100
100
100
A wide variety of base catalysts including DBU, triethylamine, DABCO, K2CO3, Cs2CO3, and
piperidine were employed to improve the yield for the synthesis of 3,4-dihydropyrimidin-2-ones/thiones.
While pyridine catalysed the reaction in presence of potassium tert-butoxide (t-BuOK) and iodine to
give quantitative yield in 8-10 h, the other bases did not promote this reaction. Under the above reaction
conditions, gem-dibromomethylarene proved to be an excellent substrate for the synthesis of 1,2,4-
oxadiazoles and various functional groups like fluro, chloro, bromo, cyano, trifluromethyl, methoxy
groups are survived in this reaction (Table 2).
Gem-dibromomethylarenes being stable and readily accessible alternates for noncommercial and some
of the unstable carboxylic acid and its derivatives, this transformation would extend the scope in
organic synthesis. In addition, it is fascinating to note that aromatic gem-dibromomethylarenes bearing
various functionalities such as chloro, bromo, nitrile, methoxy and trifluoromethyl groups survived the
reaction and provided high yields of corresponding products.

Page 17 of 22
Table 2. 3,5-substituted-1,2,4-oxadiazoles results
Time
(h)
Yield (3)
a,b (%)
Entry
R1
R2
Product (3a-3ad)
1
1a
1a
1a
1b
1b
1b
1c
1c
1c
1d
1d
1d
1e
1e
1e
1f
-H
-CH3
-OCH3
-H
3a
3b
3c
8
10
10
8
8922
8822
9122
8522
8722
9245
9045
8746
9146
9047
93
2
3
4
3d
3e
5
-CH3
-OCH3
-H
9
6
3f
9
7
3g
3h
3i
8
8
-CH3
-OCH3
-H
9
9
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
3j
8
-CH3
-OCH3
-H
3k
3l
9
9
8848
86
3m
3n
3o
3p
3q
3r
8
-CH3
-OCH3
-H
9
93
9
94
8
8849
8946
8446
8546
88
1f
-CH3
-OCH3
-H
9
1f
10
8
1g
1g
1g
1h
1h
1h
1i
3s
-CH3
-OCH3
-H
3t
8
3u
3v
3w
3x
3y
3z
9
9050
8951
9051
85
9
-CH3
-OCH3
-H
10
10
8
88
1i
-CH3
-OCH3
-H
9
84
1i
3aa
3ab
3ac
3ad
10
9
86
1j
8747
89
1j
-CH3
-OCH3
10
10
1j
90
a Isolated yields of product. b Literature reported compounds.

Page 18 of 22
Conclusion
In summary, gem-dibromomethylarenes have been identified and exploited as excellent starting material
substrate for the cyclocondensation in the synthesis of 1,2,4-oxadiazoles in high yield. Accessibility of a
large number of gem-dibromomethylarenes for synthesis of substituent varied 1,2,4-oxadiazoles
synthesis is one of the main advantages of this method compared to the other methods for the synthesis
of title compounds. More importantly, this improved method is compatible with many functional groups.
It is anticipated that this methodology will have versatile applications in the practical syntheses of
medicinal and material science important molecules.
Acknowledgments
The authors are grateful to UGC, Govt. of India for financial support to K.V. under the UGC vide no. F.
39-810⁄2010 (SR) and the Principal, Government First Grade College, Kadur for providing the
laboratory facilities to carry out this work successfully. The authors are also grateful to Vision Group on
Science and Technology, Government of Karnataka (VGST/SMYSR/(2014-15)/GRD-432/2015-16) and
Science and Engineering Research Board (SERB), Department of Science and Technology (DST)
Government of India for Financial Assistance (YSS/2015/001930).
Supporting Information
Supplementary information is available with the article through the journal Web site.
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