Novel, fast and efficient one-pot sonochemical synthesis of 2-aryl-1,3,4-oxadiazoles

Article abstract of DOI:10.1016/j.ultsonch.2013.06.009

Ultrasound promoted synthesis of 2-aryl-1,3,4-oxadiazoles at ambient temperature is reported. The remarkable features of the new procedure are shorter reaction time, excellent yields, cleaner reaction profile and simple experimental and workup procedure.

Full text of DOI:10.1016/j.ultsonch.2013.06.009

Accepted Manuscript
Novel, fast and efficient one-pot sonochemical synthesis of 2-aryl-1,3,4-oxa‐
diazoles
Morteza Rouhani, Ali Ramazani, Sang Woo Joo
PII:
S1350-4177(13)00147-8
DOI:
http://dx.doi.org/10.1016/j.ultsonch.2013.06.009
ULTSON 2333
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Ultrasonics Sonochemistry
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Revised Date:
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3 November 2012
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11 June 2013
Please cite this article as: M. Rouhani, A. Ramazani, S.W. Joo, Novel, fast and efficient one-pot sonochemical
synthesis of 2-aryl-1,3,4-oxadiazoles, Ultrasonics Sonochemistry (2013), doi: http://dx.doi.org/10.1016/j.ultsonch.
2013.06.009
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Novel, fast and efficient one-pot sonochemical synthesis of 2-aryl-1,3,4-
oxadiazoles
Morteza Rouhani1, Ali Ramazani1,* and Sang Woo Joo2,*
1Department of Chemistry, University of Zanjan, P O Box 45195-313, Zanjan, Iran
*E-mail: aliramazani@gmail.com
2School of Mechanical Engineering, Yeungnam University, Gyeongsan 712-749, Republic of
Korea
*E-mail: swjoo@yu.ac.kr
Abstract
Ultrasound promoted synthesis of 2-aryl-1,3,4-oxadiazoles at ambient temperature is reported.
The remarkable features of the new procedure are shorter reaction time, excellent yields, cleaner
reaction profile and simple experimental and workup procedure.
Keywords:
Ultrasound, 1,3,4-oxadiazoles, N-isocyanoiminotriphenylphosphorane, intramolecular aza-Wittig
reaction, isocyanide.
1.Introduction
During the past decade, isocyanide-based multicomponent reactions (IMCRs) gained significant
interest within the scientific community as an efficient, convenient, time-saving, and atom-
economical approach to a variety of drug-like small heterocyclic molecules [1]. 1,3,4-
oxadiazoles have attracted interest in medicinal chemistry as surrogates of carboxylic acids,
esters, and carboxamides. They are an important class of heterocyclic compounds that have a
1

wide range of pharmaceutical and biological activities including antimicrobial, anti-fungal, anti-
inflammatory, and antihypertensive [2-5]. Several methods have been reported in the literature
for the synthesis of 1,3,4-oxadiazoles [2-6]. These protocols are multi-step in nature [7-12]. The
most general method involves the cyclization of diacylhydrazides with a variety of reagents, such
as thionyl chloride, phosphorusoxychloride or sulfuric acid, usually under harsh reaction
conditions. Few reliable and operationally simple examples have been reported for the one-step
synthesis of 1,3,4-oxadiazoles, especially from readily available carboxylic acids and acid
hydrazides [13].
Iminophosphoranes are important reagents in synthetic organic chemistry, especially in the
synthesis of naturally occurring products-compounds with biological and pharmacological
activity [14]. Recently, we have explored the organic chemistry of N-
isocyanoiminotriphenylphosphorane (2) [15-16]. N-isocyanoiminotriphenylphosphorane (2) has
valuable synthetic potential because it provides a reaction system in which the iminophosphorane
group can react with a reagent having a carbonyl functionality [17-18].
In the last few years, the application of ultrasound in synthetic organic chemistry became more
and more interesting [19-25]. ‘‘Sonochemistry’’ is a new trend in organic chemistry, offering a
versatile and facile pathway for a large variety of syntheses. Thus, a large number of organic
reactions can be carried out under ultrasonic irradiation in high yields, short reaction times and
mild conditions [26-30]. Cavitation is the formation, growth and collapse of bubbles in an
irradiated liquid. This effect induces very high local pressure and temperatures inside the bubbles
and enhances mass transfer and turbulent flow in the liquid. Rayleigh’s early descriptions of a
mathematical model for the collapse of cavities in incompressible liquids predicted enormous
local temperatures and pressures [31]. Ultrasound has been utilized to accelerate a number of
2

synthetically useful reactions, especially in heterocyclic chemistry. The literature reports the
sonochemistry synthesis of 1,2,4-oxadiazoles [32], benzoxazoles [33], pyrazoles [34], thiazoles
[35], isoxazoles [36], imidazolines [37], thiazolidinones [38], triazoles [39], pyrimidines [40],
pyrazolopyridines [41], thiazinanones [42]. Motivated by the afore-mentioned findings, and in a
continuation of our interest in synthesis of a wide range of heterocyclic systems, for biological
screening programme in our laboratory [43–46], and as a part of our growing interest in
sonochemistry [47], we describe here a facile sonochemical synthesis of some novel 1,3,4-
oxadiazoles (5) from benzoic acid derivatives (1) and N-isocyanoiminotriphenylphosphorane (2)
in excellent yields under ultrasonic irradiation (Scheme 1).
Scheme 1
2. Experimental
2.1 General
All reagents were obtained from commercial sources and used without further purification. N-
isocyanoiminotriphenylphosphorane (2) was prepared based on a reported procedure [48].
Reactions were monitored by TLC carried out on precoated glass-backed plates Merck 60 HF254
(0.25 mm) with UV light. Melting points were determined by Electrothermal 9100 apparatus and
1
13
are uncorrected. IR spectra were taken on a Jasco 6300 FT-IR spectrometer. H and C NMR
spectra were measured (CDCl3 solution) with a Bruker DRX-250 Avance spectrometer at 250.0
and 62.5 MHz, respectively. MS were determined on Esquire Finnigan-Matt 8430 mass
spectrometer operating at an ionization potential of 20 eV. Sonication was performed in a
Bandelin SONOPULS ultrasonic homogenizers (made in Germany) with 20 kHz processing
frequency, a nominal power 250 W, uniform sonic waves and constant sound radiation.
3

2.2 Classical procedure for the synthesis of 2-aryl-1,3,4-oxadiazoles.
The classical procedure was operated based on our previous work [16]. To a magnetically stirred
solution of N-isocyanoiminotriphenylphosphorane (2) (0.302 g, 1 mmol) in dry CH2Cl2 (4 mL), a
solution of 2-aryl-benzoic acid derivatives (1) (1 mmol) in dry CH2Cl2 (4 mL) was added. The
mixture was stirred for 12 h at room temperature. The solvent was removed under reduced
pressure, and the viscous residue was purified by precoated glass-backed plates [silica gel;
petroleum ether/ethyl acetate (10:2)]. The solvent was removed under reduced pressure, and the
product (5) was obtained.
2.3 Ultrasound-promoted synthesis of 2-aryl-1,3,4-oxadiazoles.
To a solution of N-isocyanoiminotriphenylphosphorane (2) (0.302 g, 1 mmol) in dry CH2Cl2 (4
mL), a solution of 2-aryl-benzoic acid derivatives (1) (1 mmol) in dry CH2Cl2 (4 mL) was added
and the mixture was sonicated in an ultrasonic cleaner at room temperature. The solvent was
removed under reduced pressure, and the viscous residue was purified by precoated glass-backed
plates [silica gel; petroleum ether/ethyl acetate (10:2)]. The solvent was removed under reduced
pressure, and the product (5) was obtained.
2.4 Data spectra of products
2.4.1 Compound 5a
2-phenyl-1,3,4-oxadiazole. White crystal; m.p:143.6°C; Yield: 97%. IR(KBr) (νmax,cm-1):
1
3007.69, 1692.31, 1661.54, 1530.77, 723.08. H NMR (CDCl3) δH: 8.42(s, 1H, oxadiazole );
8.10-8.06(m, 2H, arom); 7.59-7.48(m, 3H, arom). 13C NMR (CDCl3) δC: 164.79(1C, oxadiazole);
4

152.67(1CH, oxadiazole) ; 132.03, 129.127 and 127.10(5Ch, arom), 123.42(1C, arom). Chemical
Formula: C8H6N2O. MS m/z (%): 51(27) 77(80), 105(100),146(2).
2.4.2 Compound 5b
2-m-tolyl-1,3,4-oxadiazole. White crystal; m.p:64.4°C; Yield: 96%. IR(KBr) (νmax,cm-1):
1
3107.69, 2984.62, 2407.69, 2276.92, 1553.85, 1500.12, 1115.38, 730.77. H NMR (CDCl3) δH:
8.46(s, 1H, oxadiazole); 7.96-7.83(m, 1H, arom); 7.43-7.34(m, 3H, arom); 2.429(s, 3H,CH3). 13C
NMR (CDCl3) δC: 164.90(1C, oxadiazole); 152.56(1CH, oxadiazole); 132.80, 129.01, 127.61,
124.21(4CH, arom); 139.02, 123.33(2C, arom); 21.32(1C, CH3). Chemical Formula: C9H8N2O.
MS m/z (%): 41(40), 43(83), 51(74), 65(52), 77(84), 91(55), 104(35), 119(92), 160(100).
2.4.3 Compound 5c
2-p-tolyl-1,3,4-oxadiazole. White crystal; m.p:86.9°C; Yield: 97%. IR(KBr) (νmax,cm-1):
1
3123.08, 2915.38, 1615.38, 1500.06, 1100.10, 953.85, 830.77, 738.46. H NMR (CDCl3) δH:
3
3
8.44(s, 1H, oxadiazole), 7.97(d, 2H, JHH=8.25 Hz, arom), 7.32(d, 2H, JHH=8.00Hz, arom),
2.43(s, 3H, CH3). 13C NMR (CDCl3) δC: 164.89(1C, oxadiazole); 152.37(1CH, oxadiazole);
142,58 and 120.70(2C, arom), 129.81 and 127.03(4CH, arom), 21.65(1C, CH3). Chemical
Formula: C9H8N2O. MS m/z (%): 41(17), 51(24), 57(26), 77(35), 91(31), 104(22), 119(79),
149(67), 160(100).
2.4.4 Compound 5d
2-(3-chlorophenyl)-1,3,4-oxadiazole. White crystal; m.p:115.3°C; Yield: 91%. IR(KBr) (νmax,cm-
1): 3030.77, 2923.08, 1553.85, 1123.08, 776.92. H NMR (CDCl3) δH: 8.50(s, 1H, oxadiazole);
1
8.08(d, 1H, 4JHH=1.5Hz, arom); 8.02-7.97(m, 1H, arom); 7.57-7.53(m, 1H, arom); 7.50-7.45(m,
1H, arom). 13C NMR (CDCl3) δC: 163.17(1C, oxadiazole), 152.84(1CH, oxadiazole), 135.28 and
5

125.07(2C, arom), 132.09, 130.52, 127.11 and 125.20(4CH, arom). Chemical Formula:
C8H5ClN2O. MS m/z (%): 51(29), 65(25), 77(85), 105(100), 149(58), 181(31).
2.4.5 Compound 5e
2-(4-chlorophenyl)-1,3,4-oxadiazole. White crystal; m.p: 127.1-128.4°C; Yield: 92%. IR(KBr)
1
(νmax,cm-1): 3076.92, 1607.69, 1484.62, 1092.31, 838.46, 738.40. H NMR (CDCl3) δH: 8.49(s,
3
3
1H, oxadiazole); 8.03(d, 2H, JHH=8.5Hz, arom); 7.50(d, 2H, JHH=8.25Hz, arom). 13C NMR
(CDCl3) δC: 164.01(1C, oxadiazole), 152.73(1CH, oxadiazole), 138.36 and 121.92(2C, arom);
129.55 and 128.38 (4CH, arom). Chemical Formula: C8H5ClN2O MS m/z (%): 41(57), 43(89),
57(76), 71(39), 89(20), 111(15), 113(16), 139(34), 49(100), 167(36), 180(32).
2.4.6 Compound 5f
2-(4-fluorophenyl)-1,3,4-oxadiazole. White crystal; m.p:142.1°C; Yield: 91%. IR(KBr) (νmax,cm-
1): 3071.86, 2931.56, 1615.38, 1500.02, 1238.46, 846.15, 746.15. H NMR (CDCl3) δH: 8.47(s,
1
1H, oxadiazole); 8.13-8.06(m, 2H, arom); 7.26-7.18(m, 2H, arom). 13C NMR (CDCl3) δC:
1
166.94(1C, oxadiazole); 163.43(d, 1C, JCF=66.87Hz, arom); 152.61(1CH, oxadiazole),
3
2
129.41(d, 2CH, JCF=8.75Hz, arom) 119.78(s,1C, arom), 116.5(d, 2CH, JCF=22.5Hz arom).
Chemical Formula: C8H5FN2O. MS m/z (%): 43(86), 57(31), 77(94), 105(100), 149( 56),
164(10).
2.4.7 Compound 5g
2-(4-bromophenyl)-1,3,4-oxadiazole. White crystal; m.p: 140.2°C; Yield: 96%. IR(KBr)
1
(νmax,cm-1): 3146.15, 3092.31, 2930.77, 1600.01, 1476.92, 1107.69, 830.77. H NMR (CDCl3)
3
3
13
δH: 8.47(s, 1H, oxadiazole); 7.96(d, 2H, JHH=8.75Hz,arom); 7.67(d, 2H, JHH=8.75, arom). C
NMR (CDCl3) δC: 164.11(1C, oxadiazole) ; 152.74(1CH, oxadiazole), 126.82 and 122.35(2C,
6

arom), 131.83 and 128.51(4CH, arom). Chemical Formula: C8H5BrN2O. MS m/z (%): 41(53),
50(71), 62(58), 75(56), 89(100), 119(39), 183(54), 224(67).
2.4.8 Compound 5h
2-(4-Iodophenyl)-1,3,4-oxadiazole. White crystal; m.p: 149.5°C; Yield: 96%. IR(KBr) (νmax,cm-
1): 3461.54, 1684.62, 1592.31, 1323.08, 761.52. H NMR (CDCl3) δH: 8.47 (s, 1H, oxadiazole);
1
7.88 (d, 2H, 3JHH=8.5 Hz, arom); 7.79(d, 2H, 3JHH=7.00Hz, arom). 13C NMR (CDCl3) δC: 164.23
(1C, oxadiazole); 152.77 (1CH, oxadiazole); 138.43 and 128.41 (4CH, arom); 122.87 and 99.04
(2C, arom). Chemical Formula: C8H5IN2O. MS m/z (%): 50(37), 63(26), 76(36), 89(32), 105(22),
149(14), 203(13), 231(56), 272(100).
2.4.9 Compound 5i
2-(3,5-Dimethoxy-phenyl)-[1,3,4]oxadiazole. White crystals; m.p: 113.3-114.1 °C; Yield: 86%.
IR(KBr) (νmax,cm-1): 3146.15, 3115.38, 2969.23, 2938.46, 1607.69, 1561.54, 1469.23, 1361.54,
1
1215.38, 1161.54, 1046.15, 838.46. H NMR (CDCl3) δH: 8.48 (s, 1H, oxadiazole), 7.21 (s, 2H,
13
arom); 6.63(s, 1H, arom); 3.86 (2s, 6H, CH3). C NMR (CDCl3) δC: 164.70(1C, oxadiazole);
161.17(1CH, oxadiazole); 152.65 (2CH, arom), 124.89(1C, arom); 104.81 and 104.49(3CH,
arom); 55.60 (2CH, OCH3). Chemical Formula: C10H10N2O3. MS m/z (%): 41(45), 43(100),
57(44), 75(40), 91(10), 105(12), 122(11), 149(53), 167(18), 206(23).
2.4.10 Compound 5j
2-Naphthalen-2-yl-[1,3,4]oxadiazole. White crystals; m.p: 149.8-150.0°C ; Yield: 83%. IR(KBr)
1
(νmax,cm-1): 3007.69, 1661.54, 1530.77, 1269.23, 1207.69, 1030.77. H NMR (DMSO-d6) δH:
4
8.48 (s, 1H, oxadiazole); 8.15(d, 1H, JHH= 2Hz, arom); 8.04-7.90(m, 4H, arom); 7.62-7.59(m,
2H, arom). 13C NMR (DMSO-d6) δC: 167.83(1C, oxadiazole); 160.44(1CH, oxadiazole); 134.82,
7

130.00, 128.42(3C, arom); 132.47, 129,39, 128.58, 128.51, 128.11, 127.37, 124.44(7CH, arom).
Chemical Formula: C12H8N2O. MS m/z (%): 41(4), 51(30), 69(10), 127(81), 155(100), 186(5),
196(34).
2.4.11 Compound 5k
2-Styryl-[1,3,4]oxadiazole. Vicose oil; Yield: 72%. IR(KBr) (νmax,cm-1): 307.69, 1638.46,
1
1523.08, 1100.32, 976.92. H NMR (CDCl3) δH: 8.38 (s, 1H, oxadiazole); 7.58-7.55 (m, 2H,
3
3
arom); 7.45-7.41(m, 3H, arom); 7.09(d, 1H, JHH=16.5Hz, vinylic); 7.62 (d, 1H, JHH=16.5 Hz,
vinylic). 13C NMR (CDCl3) δC: 164.28(1C, oxadiazole); 152.00(1CH, oxadiazole), 139.85(1CH,
vinylic); 134.53(1C, arom); 130.14, 129.03, 127.57(5CH, arom); 109.53(1CH, vinylic).
Chemical Formula: C10H8N2O. MS m/z (%): 51(7), 63(7), 77(8), 89(10), 103(7), 115(22),
171(100) 172(37).
2.4.12 Compound 5l
°
2-(1,3,4-oxadiazol-2-yl)aniline. Yellow crystal; m.p:145.3 C; Yield: 96%. IR(KBr) (νmax,cm-1):
3430.77and 3338.46(NH2), 3038.46, 2938.46, 2930.77, 2930.77, 2561.54, 1623.08, 1269.23,
1
1107.69, 753.85. H NMR (CDCl3) δH: 8.41(s, 1H, oxadiazole); 7.78-7.75(m, 1H, arom), 7.32-
7.25(m,1H, arom); 6.79(t, 1H, 3JHH=7.5Hz, arom); 6.73(s, 1H, arom), 5.69(2H, NH2). 13C NMR
(CDCl3) δC: 164.62(1C, oxadiazole); 150.91(1CH, oxadiazole); 147.01 and 105.38(2C, arom);
132.79, 127.99, 116,91 and 116.28(4CH, arom). Chemical Formula: C8H7N3O. MS m/z (%):
41(21), 51(32), 65(28), 77(35), 92(26), 105(21), 120(51), 161(100).
2.4.13 Compound 5m
2-Biphenyl-4-yl-[1,3,4]oxadiazole. White crystals; m.p: 154.7-155.1°C; Yield: 91%. IR(KBr)
1
(νmax,cm-1): 3107.69, 3007.69, 1638.46, 1484.62, 1415.38, 1115.38, 1107.69, 738.46. H NMR
8

(CDCl3) δH: 8.49 (s, 1H, oxadiazole); 8.15(d, 3JHH=8.5Hz, 2H, arom); 7.75 (d, 3JHH=8.75Hz, 2H,
arom); 7.66-7.62(m, 2H, arom); 7.52-7.40(m, 3H, arom). 13C NMR (CDCl3) δC: 164.43(1C,
oxadiazole); 152.61(1CH, oxadiazole); 144.74, 139.668, 122.22(3C, arom); 129.00, 128.25,
127.74; 127.56, 127.15(9CH, arom). Chemical Formula:C14H10N2O. MS m/z (%): 41(5), 43(8),
57(10), 115(8), 152(31), 181(100), 221(12).
2.4.14 Compound 5n
2-Biphenyl-2-yl-[1,3,4]oxadiazole Viscose oil; Yield: 93%. IR(KBr) (νmax,cm-1): 3030.77;
1640.23; 1469.23; 1284.62; 1123.08. 8.21 (s, 1H, oxadiazole); 8.00-7.93 (m, 1H, arom); 7.65-
7.59(m, 1H, arom); 7.55-7.50 (m, 1H, arom); 7.49-7.43 (m, 2H, arom); 7.37-7.34 (m,2H, arom),
7.27-7.21 (m, 2H, arom). 13C NMR (CDCl3) δC: 165.39 (1C, oxadiazole); 152.85 (1CH,
oxadiazole); 142.21, 140.14, 122.48 (3C, arom); 131.61, 131.03, 130.67, 128.60, 128.33, 127.70,
127.66(9CH, arom). Chemical Formula: C14H10N2O. MS m/z (%): 41(3), 43(4), 57(3), 77(5),
115(2), 152( 41), 181(100), 221(10).
3. Results and discussion
To achieve suitable conditions for the synthesis of 2-aryl-1,3,4-oxadiazoles (5), various reaction
conditions have been investigated in the reaction of benzoic acid (1a) and N-
isocyanoiminotriphenylphosphorane (2) as a model reaction.
3.1. Effect of solvent on the product yield
9

We examined the effects of the solvent through some experiments. To search for the optimal
solvent, the ultrasonic-assisted reaction of benzoic acid (1a) and N-
isocyanoiminotriphenylphosphorane (2) was examined using acetonitrile (CH3CN),
dichloromethane (CH2Cl2), chloroform (CHCl3), ethanol (C2H5OH) and methanol (CH3OH) as
solvent respectively. The results were summarized in Table 1. As can be seen in Table 1, the
reaction between benzoic acid (1a) with N-isocyanoiminotriphenylphosphorane (2) under
ultrasonic irradiation at room temprature was solvent dependent. The reaction could be
efficiently carried out in solvents such as dichloromethane and chloroform (Table 1, entries 2
and 3). The reaction using dichloromethane as the solvent resulted in higher yields and shorter
reaction time than those using C2H5OH, CH3OH and CH3CN as solvents (product was obtained
in 97% yield in 10 min). So, dichloromethane was chosen as the solvent for all further reactions.
Table 1
3.2. Influence of ultrasound power on product yield
As shown in Table 2, the product yield was affected by ultrasonic power. The highest product
yield of 97% was obtained when ultrasonic power was 200 W. The reaction time and yield of 1a
did not change from 200 to 250 W, therefore, 200W of ultrasonic irradiation was sufficient to
push the reaction forward. The best yield for (1a) was obtained by ultrasonic irradiation for 10
min at room temperature and 200 W. Decreased yields were observed outside the optimum
ultrasonic power. The reaction could not carry out completely because it had no enough energy
when ultrasonic power was lower than 200 W. Without ultrasonic irradiation, the reaction
needed at least 12 h with stirring and gained lower yield (91%).
10

Table 2
3.3. High efficiency and generality of synthesis by ultrasound irradiation
After detecting more efficient solvent (CH2Cl2), and power (200 W) to delineate the role of
ultrasound, this method was examined by the reaction of several substituted benzoic acids, and
N-isocyanoiminotriphenylphosphorane with and without ultrasonic irradiation at the same
temperature in CH2Cl2 as solvent (Table 3-Figure).
Table 3
Figure
Table 4
When the reaction was carried out under conventional method it gave comparatively low yields
of products and took longer reaction time, while the same reaction carried in the influence of
ultrasonic irradiation gave excellent yields of product in short reaction time (Table 4). As is
known, the influence of ultrasound on the reaction is that it can markedly shorten the reaction
time compared with conventional conditions. The similar effect was also observed in our
experiments. It is apparent that ultrasound irradiation can accelerate the reaction significantly to
give better yield. The results in Table 4 show that ultrasound is much more efficient than
magnetic stirring. Thus, ultrasonic irradiation was found to have beneficial effect on the
11

synthesis of 2-aryl-1,3,4-oxadiazoles derivatives. To the best of our knowledge, this new
procedure provides the first example of an efficient and ultrasound-promoted one-pot three-
component approach for the synthesis of disubstituted 1,3,4-oxadiazole derivatives.
3.4. The study of acceleration mechanism under irradiation of ultrasound
The benzoic acid derivative (1) and N-isocyanoiminotriphenylphosphorane (2) in
dichloromethane (CH2Cl2) as solvent under ultrasonic irradiation at room temperature afforded
one product and triphenylphosphine oxide (6) as byproduct in each case (as evidenced by TLC)
(Scheme 1). The reaction proceeds very fast and cleanly under ultrasonic irradiation and no side
reactions were observed. The mechanism of the reaction between the benzoic acid derivative (1)
and N-isocyanoiminotriphenylphosphorane (2) has not been established experimentally.
However, a possible explanation is proposed in Scheme 2. On the basis of the well established
chemistry of isocyanides [46], it is reasonable to assume that the protonation of (2) by carboxylic
acid (1) followed by quenching of the cationic center by the conjugate base of the carboxylic
acid can generate iminophosphorane (4) [14]. Intramolecular aza-Wittig [14] reaction of
iminophosphorane (4) would lead to the formation of 2-aryl-1,3,4- oxadiazoles (5) and
triphenylphosphine oxide (6) (Scheme 2, Table 3).
Scheme 2
Cavitation is the origin of sonochemistry. As ultrasound passes through a liquid, the liquid can
produce bubbles. These bubbles can undergo a violent collapse, which generates very high
pressures and temperatures, inducing molecular fragmentation, and highly reactive species are
12

locally produced. The implosion of cavities reportedly established an unusual environment for
reactions. The gases and vapors inside the cavity are compressed, generating intense heat that
raises the temperature of the liquid immediately surrounding the cavity and the high temperature
and pressure produced during cavitation break their chemical bonds, short-lived chemical species
are returned to the bulk liquid at room temperature, thus reacting with other species [49]. With
this case in mind, we turned our attention to the reaction mechanism and the role of ultrasound
irradiation played in the reaction. We believed that there were two main reasons for the
acceleration in present system. One was the physical aspect of ultrasound which leaded N-
isocyanoiminotriphenylphosphorane to dissolve faster in dichloromethane; another was the
chemical aspect of ultrasound which accelerated the reaction. As is known in our previous work
[16], in these type of reactions, deprotonation of the acid and the formation of O-centered
nucleophiles occurred very slowly in the absence of ultrasound conditions. The ultrasonic
irradiation played an important role in the formation of O-centered nucleophile while this may be
the rate-determining step in the reaction. It has been observed that the yield of 5a in the absence
of ultrasound irradiation was only 12% after 10 minutes. After 3h, 6h, 9h and 12h the yields was
obtained 41%, 65%, 80% and 91% respectively. The yield of the reaction does not efficiently
vary after 12h [16]. Based on the present work and the our previous work [16], the 12h is the
shortest reaction time for this reaction to provide the yields of silent conditions. In the presence
of ultrasound irradiation, localized ‘‘hot spots’’ generated from a violent collapse of the bubbles
creates a transient high temperature and pressures, inducing molecular fragmentation, and highly
reactive species are locally produced. In the presence of ultrasound irradiation, producing of the
conjugate base of acid 1 goes more faster. Furthermore we believed that ultrasound waves
disturbances
the
CH2Cl2
layer
around
benzoic
acid
derivative
and
N-
13

isocyanoiminotriphenylphosphorane and thus accelerates deprotonation speed in rate
determining step. From the Table 4, it is indicated that the obvious difference in the reaction
efficiencies with or without sonication suggests again that the reaction under ultrasound
condition proceeded in not the same, but in more efficient way than did the reaction under the
heating conditions. For example the yield of the related reaction to synthesize 5a is up to 97%
under ultrasound condition at the room temperature, whereas the yield of the reaction without
sonication is 91%, and the reaction time under sonication is reduced from 12 h to 10 min. Thus,
ultrasound was found to have beneficial effect on the synthesis of 2-aryl-1,3,4-oxadiazoles 5a–n
(Figure) in which decrease time of above reactions from 12 h in conventional procedure to less
than 20 min, also, a noticeable improvement in yields of reactions under ultrasonic irradiations
(Figure-Table 3).
In Summary, under ultrasound irradiation; the reaction is simple to execute and the products are
isolated in good yields. The work-up is very simple. The reaction time is short (less than 20 min)
and the products are obtained in excellent purity.
To the best of our knowledge, this new procedure provides the first example of an efficient and
two-component method for the synthesis of 2-aryl-1,3,4-oxadiazoles under ultrasound
irradiation. This method, based on two-component free-catalyst reaction under ultrasonic
irradiation, is the most simple and convenient and would be applicable for the synthesis of
different types of oxadiazoles.
4. Conclusion
In this work, we have developed a mild, highly efficient and improved protocol for the
preparation of a series of 2-aryl-1,3,4-oxadiazoles. Our sonochemical method offers several
14

advantages over existing methods, including improved yields, cleaner reactions, simple work-up
and very short reaction times, which makes it a useful and environmentally attractive strategy for
the synthesis of oxadiazole derivatives.
Acknowledgements
This work is funded by the World Class University Grant No. R32-2008-000-20082-0 of the
National Research Foundation of Korea. The authors thank Yeungnam and Zanjan universities
and the “Iran National Science Foundation: INSF.”for the support and guidance.
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19

Scheme 1: One-pot two-component synthesis of 2-aryl-1,3,4-oxadiazoles under ultrasound
irradiation.
Z
N
N
Z
O
X
Y
X
Y
)))
O
Ph3PO
OH
+
C
N N PPh3
+
r.t.,
CH2Cl2
W
W
Scheme 2: Proposed mechanism for the formation of 2-phenyl-1,3,4-oxadiazole derivatives 5a-
n.
Z
O
X
Y
)))
OH
C
N N PPh3
+
r.t.,
CH2Cl2
1
2
W
N
Ph3P
O
Z
O
Z
N
X
Y
X
Y
)))
O
O
H
HC
N
N
PPh3
W
W
3
4
Z
N
N
X
Y
)))
O
Ph3PO
+
6
5
W
Figure: Two-component synthesis of 2-aryl-1,3,4-oxadiazoles derivatives 5a-n (See Table and
Text).
20

N
N
N
N
N
N N
N
O
O
O
O
Cl
5d
H3C
CH3
5c
5b
5a
N
N
N
N
N
N
N
N
O
O
O
O
Br
Cl
I
F
5g
5h
5e
5f
N
N
N
N
N
N
N
N
H
H3CO
O
O
O
O
H
NH2
OCH3
5i
5j
5l
5k
N
N
N
N
O
O
5m
5n
21

Table 1: Synthesis of 2-phenyl-1,3,4-oxadiazole (5a) in different solvent systems under
ultrasonic irradiation at room temperature.
Entry
Solvent
Acetonitrile
CH2Cl2
Time (min)
Yielda(%)
1
2
3
4
5
6
13
10
12
18
21
30
63
97
91
78
71
21
CHCl3
Ethanol
Methanol
Solvent free
a Isolated yield.
Table 2: Effect of the ultrasonic power in the synthesis of 2-phenyl-1,3,4-oxadiazole (5a)
Entry
Power (W)
Time (min)
Yielda(%)
1
2
3
4
100
150
200
250
35
20
10
10
41
54
97
97
a Isolated yield.
Table 3: Synthesis of 1,3,4-oxadiazole derivatives 5.
Compound
Z
X
Y
W
5a
5b
H
H
H
-CH3
H
H
H
H
5c
H
H
-CH3
H
22

5d
5e
5f
5g
5h
5i
H
H
H
H
H
H
Cl
H
H
Cl
F
H
H
H
H
H
Br
I
H
H
H
-OCH3
H
-OCH3
O
5j
N
N
O
5k
N
H
N
H
5l
5m
5n
-NH2
H
H
H
H
H
-Ph
H
H
H
H
-Ph
Table 4: Comparison of the times and yields of the reactions with or without sonication for the
synthesis of 1,3,4-oxadiazole derivatives.
Compound
With sonicationa
Without sonicationb
Yieldc (%)
Time (min)
Yieldc (%)
Time (min)
5a
5b
5c
5d
5e
5f
5g
5h
5i
97
96
97
91
92
91
96
96
86
10
13
15
15
15
14
10
11
16
91
91
92
85
82
84
92
91
72
720
720
720
720
720
720
720
720
720
23

5j
5k
5l
5m
5n
83
72
96
91
93
16
16
14
15
15
72
32
85
80
80
720
720
720
720
720
a Reaction condition: Reaction of benzoic acid derivatives and N-isocyanoiminotriphenylphosphorane in CH2Cl2 under
ultrasound irradiation.
b Reaction condition: Reaction of benzoic acid derivatives and N-isocyanoiminotriphenylphosphorane in CH2Cl2 at room
temprature under high stirring condition.
c
Yields of isolated products.
24