Ultrasonics in isocyanide-based multicomponent reactions: A new, efficient and fast method for the synthesis of fully substituted 1,3,4-oxadiazole derivatives under ultrasound irradiation

Article abstract of DOI:10.1016/j.ultsonch.2014.06.017

A fast and convenient approach to the synthesis of fully substituted 1,3,4-oxadiazoles via three-component reaction of aromatic carboxylic acids, acenaphthoquinone, and (N-isocyanimino)triphenylphosphorane under ultrasound irradiation is described. Furthe

Full text of DOI:10.1016/j.ultsonch.2014.06.017

Accepted Manuscript
Ultrasonics in isocyanide-based multicomponent reactions: A new, efficient and
fast method for the synthesis of fully substituted 1,3,4-oxadiazole derivatives
under ultrasound irradiation
Morteza Rouhani, Ali Ramazani, Sang Woo Joo
PII:
S1350-4177(14)00203-X
DOI:
http://dx.doi.org/10.1016/j.ultsonch.2014.06.017
ULTSON 2640
Reference:
Ultrasonics Sonochemistry
To appear in:
Received Date:
Revised Date:
Accepted Date:
5 July 2013
16 May 2014
23 June 2014
Please cite this article as: M. Rouhani, A. Ramazani, S.W. Joo, Ultrasonics in isocyanide-based multicomponent
reactions: A new, efficient and fast method for the synthesis of fully substituted 1,3,4-oxadiazole derivatives under
ultrasound irradiation, Ultrasonics Sonochemistry (2014), doi: http://dx.doi.org/10.1016/j.ultsonch.2014.06.017
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Ultrasonics in isocyanide-based multicomponent reactions: A new, efficient
and fast method for the synthesis of fully substituted 1,3,4-oxadiazole
derivatives under ultrasound irradiation
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
A fast and convenient approach to the synthesis of fully substituted 1,3,4-oxadiazoles via three-
component reaction of aromatic carboxylic acids, acenaphthoquinone, and (N-
isocyanimino)triphenylphosphorane under ultrasound irradiation is described. Furthermore, a
series of compounds were synthesized and characterized by melting point, IR, NMR and MS.
Utilization of easy reaction conditions, very high to excellent yields, and short reaction times
makes this manipulation potentially very useful.
Keywords
Ultrasound, 1,3,4-oxadiazoles, (N-isocyanimino)triphenylphosphorane, aromatic carboxylic
acids, acenaphthoquinone, intramolecular aza-Wittig reaction, isocyanide.
1.Introduction
Multicomponent reactions (MCRs) [1-2] are referred to as the one-pot processes, where multiple
bonds are formed among starting materials to furnish the product with essentially all of the atoms
1

of the reactants. Among the known multicomponent reactions, isocyanide based MCRs (IMCRs)
are particularly valuable [3-4]. In addition to the added diversity of bond formation and
functional group tolerance, the outstanding position of IMCRs can also be traced back to the
exceptional reactivity of isocyanide. As we know, no other functional group reacts with
nucleophiles and electrophiles at the same atom [5]. Consequently, MCRs involving isocyanides
have been widely applied to organic synthesis, especially in drug discovery [6]. The aza-Wittig-
type reaction has attracted much attention recently because of its high potential for the synthesis
of a wide variety of nitrogen heterocycles, which can be attributed in the preparation of
functionalized iminophosphoranes [7]. Through aza-Wittig reaction, iminophosphoranes with
isocyanates, carbon dioxide, or carbon disulfide can easily be converted into functionalized
hetero-cumulenes [7]. The nucleophilicity at the nitrogen is an important factor in the use of
these iminophosphoranes as aza-Wittig reagents. Iminophosphoranes are important reagents in
organic chemistry, especially in the producing of naturally occurring products, compounds with
biological and pharmacological activity [7-8]. In recent years, we have confirmed a one-pot
method for the preparation of organophosphorus compounds [9-15].
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 wide range of pharmaceutical and biological activities including antimicrobial, antifungal,
antiinflammatory, and antihypertensive [16-20]. Several methods have been reported in the
literature for the synthesis of 1,3,4-oxadiazoles. These protocols are multistep in nature [21-26].
The most general method involves the cyclization of diacylhydrazides with a variety of reagents,
such as thionyl chloride, phosphorus oxychloride, or sulfuric acid, usually under harsh reaction
conditions. Few reliable and operationally simple examples have been reported for the one-step
2

synthesis of 1,3,4-oxadiazoles, especially from readily available carboxylic acids and acid
hydrazides [27-32].
Ultrasound irradiation, an efficient and innocuous technique for reagent activation in the
synthesis of inorganic compounds [33-38], organic compounds and in particular heterocyclic
compounds, has been applied with success, milder reaction condition, and higher yields in
comparison to the classical methods [39–41]. Ultrasound-promoted synthesis has attracted much
attention during the past few decades. One advantage of using cavitation as an energy source to
promote organic reactions includes shorter reaction times [42]. During the rarefaction cycle in
the cavitation process, the molecules of the liquid are separated, generating bubbles that
subsequently collapse in the compression cycle. These rapid and violent implosions generate
°
short-lived regions with temperatures of roughly 5000 C, pressures of about 1000 atm and
heating and cooling rates above 10 billion °C/s. Such localized hot spots can be thought as micro
reactors in which the energy of sound is transformed into a useful chemical form [42,45,46]. This
procedure has been considered as a clean and useful protocol in organic synthesis compared with
traditional methods, and the procedure is in general, more convenient [42].
There are very few reports in literature about application of ultrasound irradiation in Isocyanide-
based multicomponent reactions. In continuation of our research program to find the effect of
ultrasound irradiation on isocyanide-based multicomponent reactions [43,44], we wish to report
a novel and efficient method for the synthesis of 1,3,4-oxadiazole derivatives (4) via an efficient
condensation
of
aromatic
carboxylic
acids,
acenaphthoquinone,
and
(N-
isocyanimino)triphenylphosphorane under ultrasound irradiation (Scheme 1).
Scheme 1
3

2. Experimental
2.1. Apparatus, materials and measurements
(N-Isocyanimino)triphenylphosphorane (3) was prepared based on reported procedures [8,47].
Other starting materials and solvents were purchased from Merck (Germany) and Fluka
(Switzerland) and were used without further purification. The methods used to monitor the
reactions are TLC and NMR. Melting points were determined on an Electrothermal 9100
apparatus. IR spectra (νmax, cm-1) were recorded on a Jasco 6300 FTIR spectrophotometer using
KBr technique. 1H and 13C NMR spectra (CDCl3) were recorded on a Bruker DRX- 250 Avance
spectrometer at 250.0 and 62.5 MHz, respectively. Mass analyses were carried out using a
Finnigan MAT-8430 mass spectrometer operating at an ionization potential of 70 eV.
Preparative layer chromatography (PLC) plates were prepared from Merck silica gel (F254)
powder. 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.
2.2. General procedure for the synthesis of the title compounds in CH3CN
A mixture of (N-isocyanimino)triphenylphosphorane (302 mg, 1.0 mmol), acenaphthoquinone
(182 mg, 1.0 mmol), and aromatic carboxylic acid (1.0 mmol) in CH3CN (10 mL) was stirred at
for 24 h in room temperature. The solvent was removed under reduced pressure, and the viscous
residue was purified by PLC [silica gel (F254) powder; petroleum ether/ethyl acetate 4:1].
2.3. Ultrasound-promoted typical procedure for synthesis of title compounds
The carboxylic acid derivatives (1.0 mmol), acenaphthoquinone (182 mg, 1.0 mmol), (N
isocyanimino)triphenylphosphorane (302 mg, 1.0 mmol) and CH3CN (10 mL) were added into a
4

25 mL round bottomed flask. During the ultrasound irradiation, the temperature of the mixture
was controlled with ice bath (temperature was maintained in room temperature). The reaction
mixture was sonicated under 100 W for the period of time (The reaction was monitored by TLC)
and the . The solvent was removed under reduced pressure, and the viscous residue was purified
by PLC [silica gel (F254) powder; petroleum ether/ethyl acetate 4:1]. The authenticity of the
samples (4a-4p) was established by their 1H NMR, 13C NMR and MS.
2.4. Data spectra of products
2.4.1. Compound 4a
2-Hydroxy-2-(5-phenyl-1,3,4-oxadiazol-2-yl)-1(2H)-acenaphthylenone (4a, C20H12N2O3)
°
Yellow powder; yield 80%; Rf = 0.36 (petroleum ether/ethyl acetate 4:1); m.p.: 162–164 C; H
1
13
NMR (250.13 MHz, CDCl3): d = 4.59 (br s, OH), 7.40–8.30 (m, 11CHarom) ppm; C NMR
(62.53 MHz, CDCl3): d= 87.74 (C–OH), 122.56, 123.88, 126.97, 127.13, 128.79, 128.96,
129.07, 132.02, 132.85 (11CH of arom), 123.22, 127.80, 129.60, 135.12, 142.96 (5C of arom),
161.05, 166.13 (2C=N of oxadiazole), 198.51 (C=O) ppm; IR (KBr): νmax= 3,366, 3,073, 1,718,
1,603, 1,448, 1,012 cm-1; MS (EI, 20 eV): m/z (%) = 328 (M+), 198 (16), 182 (34), 154 (83), 126
(100), 98 (28), 85 (28), 76 (39), 62 (38), 43 (45).
2.4.2. Compound 4b
2-[5-(4-Bromophenyl)-1,3,4-oxadiazol-2-yl]-2-hydroxy-1(2H)-acenaphthylenone(4b,
C20H11BrN2O3)
°
Yellow powder; yield 78%; Rf = 0.33(petroleum ether/ ethyl acetate 4:1); m.p.: 151–153 C; 1H
3
NMR (250.13 MHz, CDCl3): d= 4.57 (br s, OH), 7.57 (d, JHH =8.3 Hz, 2CHarom), 8.03 (d,
5

3JHH= 8.3 Hz, 2CHarom), 7.69–7.86, 8.09–8.30 (m, 6CHarom) ppm; 13C NMR (62.53 MHz,
CDCl3): d= 86.50 (C–OH), 122.59, 123.96, 127.03, 128.51, 128.83, 129.08, 132.33, 132.94
(10CH of arom), 122.12, 126.80, 129.50, 130.98, 134.22, 140.25 (6C of arom), 164.02, 165.03
(2C=N of oxadiazole), 202.02 (C=O) ppm; IR (KBr): νmax = 3,204, 3,077, 1,733, 1,600, 1,481,
1,007 cm-1; MS (EI, 20 eV): m/z (%) = 407 (M+), 198 (8), 182 (37), 154 (78), 126 (100), 98 (22),
85 (22), 75 (55), 62 (45), 50 (18).
2.4.3. Compound 4c
4-[5-(1,2-Dihydro-1-hydroxy-2-oxo-1-acenaphthylenyl)-1,3,4-oxadiazol-2-yl]benzonitrile (4c,
C21H11N3O3)
°
1
Yellow powder; yield 73%; Rf= 0.30 (petroleum ether/ethyl acetate 4:1); m.p.: 161–163 C; H
NMR (250.13 MHz,CDCl3): d= 3.63 (s, OH), 7.71–8.33 (m, 10CHarom) ppm; 13C NMR (62.53
MHz, CDCl3): d = 77.31 (C–OH), 122.07, 127.13, 127.60, 128.45, 129.09, 132.62, 132.75
(10CH of arom), 109.98, 115.51, 124.00, 128.90, 133.02, 135.05, 143.03 (7C of arom), 161.03,
165.13 (2C=N of oxadiazole), 192.21 (C=O) ppm; IR (KBr): νmax = 3,439, 3,209, 1,729, 1,604,
1,495, 1,014 cm-1; MS (EI, 20 eV): m/z (%) = 353 (M+), 197 (17), 182 (32), 154 (73), 130 (100),
126 (85), 101 (90), 75 (86), 62 (47), 50 (48), 42 (30).
2.4.4. Compound 4d
2-Hydroxy-2-[5-(3-methylphenyl)-1,3,4-oxadiazol-2-yl]-1(2H)-acenaphthylenone(4d,
C21H14N2O3)
°
Yellow powder; yield 83%; Rf = 0.36 (petroleum ether/ ethyl acetate 4:1); m.p.: 169–171 C; 1H
NMR (250.13 MHz, CDCl3): d = 2.37 (s, CH3), 4.50 (br s, OH), 7.26–8.30 (m, 10CHarom) ppm;
6

13C NMR (62.53 MHz, CDCl3): d = 21.21 (CH3), 76.57 (C–OH), 122.06, 122.55, 124.29,
126.84, 127.58, 128.44, 128.78, 129.07, 132.60, 132.86 (10CH of arom),123.82, 128.81, 129.10,
130.91, 134.80, 143.35 (6C of arom), 164.18, 166.75 (2C=N of oxadiazole), 198.87 (C=O) ppm;
IR(KBr): νmax = 3,399, 3,073, 1,723, 1,603, 1,490, 1,073 cm-1; MS (EI, 20 eV): m/z (%) = 342
(M+), 198 (6), 182 (24), 154 (54), 126 (60), 105 (100), 91 (18), 76 (54), 62 (23), 50 (24).
2.4.5. Compound 4e
2-[5-(4-tert-Butylphenyl)-1,3,4-oxadiazol-2-yl]-2-hydroxy-1(2H)-acenaphthylenone(4e,
C24H20N2O3)
°
Yellow powder; yield 85%; Rf = 0.33 (petroleum ether/ ethyl acetate 4:1); m.p.: 176–178 C; 1H
3
NMR (250.13 MHz, CDCl3): d = 1.30 (s, 3CH3), 5.30 (br s, OH), 7.41 (d, JHH = 8.3 Hz,
3
13
2CHarom), 7.98 (d, JHH = 8.3 Hz, 2CHarom), 7.71–7.86, 8.05–8.20 (m, 6CHarom) ppm; C
NMR (62.53 MHz, CDCl3): d = 31.03 (3CH3), 35.03 (C), 76.60 (C–OH), 122.53, 123.74,
125.89, 126.79, 126.98, 128.70, 129.03, 132.73 (10CH of arom), 122.04, 128.43, 129.75, 130.88,
135.51, 142.33 (6C of arom), 164.28, 166.00 (2C=N of oxadiazole), 198.17 (C=O) ppm; IR
(KBr): νmax = 3,209, 2,965, 1,738, 1,614, 1,495, 1,010 cm-1; MS (EI, 20 eV): m/z (%) = 384
(M+), 182 (11), 163 (25), 148 (14), 120 (38), 103 (17), 91 (73), 76 (35), 57 (18), 43 (100).
2.4.6. Compound 4f
2-[5-(3-Chlorophenyl)-1,3,4-oxadiazol-2-yl]-2-hydroxy-1(2H)-acenaphthylenone(4f,
C20H11ClN2O3)
°
Yellow powder; yield 76%; Rf = 0.30 (petroleum ether/ ethyl acetate 4:1); m.p.: 174–176 C; 1H
13
NMR (250.13 MHz, CDCl3): d = 4.06 (br s, OH), 7.33–8.29 (m, 10CHarom) ppm; C NMR
7

(62.53 MHz, CDCl3):d = 77.25 (C–OH), 122.06, 123.98, 125.24, 127.02, 128.44, 129.09,
130.34, 132.09, 132.62, 132.94 (10CH of arom), 122.59, 128.83, 129.50, 133.82, 135.12, 148.62
(6C of arom), 158.50, 164.82 (2C=N of oxadiazole), 198.27 (C=O) ppm; IR (KBr): νmax = 3,379,
3,080, 1,718, 1,602, 1,551, 1,068 cm-1; MS (EI, 20 eV): m/z (%) = 362 (M+), 197 (18), 182 (44),
154 (95), 126 (100), 98 (23), 85 (19), 75 (47), 62 (34), 50 (17).
2.4.7. Compound 4g
2-Hydroxy-2-[5-(3-phenoxyphenyl)-1,3,4-oxadiazol-2-yl]-1(2H)-acenaphthylenone(4g,
C26H16N2O4)
°
Yellow powder; yield 72%; Rf = 0.26 (petroleum ether/ ethyl acetate 4:1); m.p.: 153–155 C; 1H
13
NMR (250.13 MHz, CDCl3): d = 4.81 (br s, OH), 6.96–8.29 (m, 15CHarom) ppm; C NMR
(62.53 MHz, CDCl3):d = 85.02 (C–OH), 117.19, 119.14, 121.80, 122.05, 123.88, 123.97,
126.95, 128.77, 129.04, 129.95, 130.45, 130.92, 132.84 (15CH of arom), 122.52, 128.44, 129.62,
135.22, 145.30, 156.20, 157.85 (7C of arom), 165.45, 164.71 (2C=N of oxadiazole), 198.17
(C=O) ppm; IR(KBr): νmax = 3,307, 3,082, 1,743, 1,563, 1,485, 1,225 cm-1; MS (EI, 20 eV): m/z
(%) = 420 (M+), 214 (27), 197 (29), 182 (80), 154 (80), 126 (100), 98 (21), 85 (15), 76 (29), 62
(29), 50 (22).
2.4.8. Compound 4h
2-[5-[4-(Bromomethyl)phenyl]-1,3,4-oxadiazol-2-yl]-2-hydroxy-1(2H)-acenaphthylenone (4h,
C21H13BrN2O3)
°
Yellow powder; yield 82%; Rf = 0.33 (petroleum ether/ ethyl acetate 4:1); m.p.: 163–165 C; 1H
3
NMR (250.13 MHz, CDCl3): d = 4.46 (s, CH2), 4.98 (br s, OH), 7.43 (d, JHH = 8.3 Hz,
8

3
13
2CHarom), 7.90 (d, JHH = 8.3 Hz, 2CHarom), 7.70–7.86, 7.99–8.29 (m, 6CHarom) ppm; C
NMR (62.53 MHz, CDCl3):d = 32.09 (CH2), 76.77 (C–OH), 122.56, 123.89, 126.95, 127.55,
129.07, 129.61, 132.62, 132.87 (10CH of arom), 123.10, 128.44, 128.79, 130.92, 135.24, 141.80
(6C of arom), 165.12, 166.22 (2C=N of oxadiazole), 198.15 (C=O) ppm; IR (KBr): νmax = 3,343,
3,072, 1,717, 1,603, 1,486, 1,012 cm-1.
2.4.9. Compound 4i
2-Hydroxy-2-[5-(1-naphthalenyl)-1,3,4-oxadiazol-2-yl]-1(2H)-acenaphthylenone(4i,
C24H14N2O3)
°
Yellow powder; yield 75%; Rf = 0.36 (petroleum ether/ ethyl acetate 4:1); m.p.: 154–156 C; 1H
13
NMR (250.13 MHz, CDCl3): d = 4.84 (br s, OH), 7.42–9.07 (m, 13CHarom) ppm; C NMR
(62.53 MHz, CDCl3):d = 76.39 (C–OH), 122.60, 124.67, 125.95, 126.71, 126.96, 128.22,
128.59, 128.75, 128.79, 129.08, 132.88 (13CH of arom), 123.91, 128.35, 129.90, 131.92, 133.80,
135.22, 142.26 (7C of arom), 162.32, 166.25 (2C=N of oxadiazole), 198.17 (C=O) ppm; IR
(KBr): νmax = 3,433, 3,186, 1,741, 1,604, 1,538, 1,089 cm-1.
2.4.10. Compound 4j
2-[5-(4-Chlorophenyl)-1,3,4-oxadiazol-2-yl]-2-hydroxy-1(2H)-acenaphthylenone(4j,
C20H11ClN2O3)
°
Yellow powder; yield 72%; Rf = 0.30 (petroleum ether/ ethyl acetate 4:1); m.p.: 169–171 C; 1H
3
NMR (250.13 MHz, CDCl3): d = 4.58 (br s, OH), 7.77 (d, JHH = 8.3 Hz, 2CHarom), 8.24 (d,
3JHH = 8.3 Hz, 2CHarom), 7.40–7.73, 7.83–8.13 (m, 6CHarom) ppm; C NMR (62.53 MHz,
13
CDCl3): d = 83.23 (C–OH), 122.07, 122.58, 128.40, 128.45, 129.09, 129.37, 132.63, 132.94
9

(10CH of arom), 123.95, 127.02, 128.83, 135.02, 137.52, 138.45 (6C of arom), 164.12, 165.23
(2C=N of oxadiazole), 202.12 (C=O) ppm; IR (KBr): νmax = 3,227, 3,022, 1,732, 1,604, 1,486,
1,078 cm-1.
2.4.11. Compound 4k
2-[5-(4-Fluorophenyl)-1,3,4-oxadiazol-2-yl]-2-hydroxy-1(2H)-acenaphthylenone(4k,
C20H11FN2O3)
°
Yellow powder; yield 75%; Rf = 0.33 (petroleum ether/ ethyl acetate 4:1); m.p.: 156–158 C; 1H
NMR (250.13 MHz, CDCl3): d = 4.40 (s, OH), 7.10–8.31 (m, 10CHarom) ppm; 13C NMR (62.53
2
MHz, CDCl3):d = 82.65 (C–OH), 116.38 (d, JCF = 20.1 Hz, 2CH of arom), 122.06, 122.55,
128.44, 129.09, 132.62 (6CH of arom), 129.53 (d, 3JCF = 12.5 Hz, 2CH of arom), 123.93, 127.00,
1
128.94, 135.02, 140.74 (5C of arom), 160.52 (d, JCF = 252.0 Hz, C of arom), 164.48, 166.53
(2C=N of oxadiazole), 189.51 (C=O) ppm; IR (KBr): νmax = 3,375, 3,082, 1,725, 1,606, 1,497,
1,013 cm-1.
2.4.12. Compound 4l
2-Hydroxy-2-[5-(4-methylphenyl)-1,3,4-oxadiazol-2-yl]-1(2H)-acenaphthylenone(4l,
C21H14N2O3)
°
Yellow powder; yield 80%; Rf = 0.36 (petroleum ether/ ethyl acetate 4:1); m.p.: 170–172 C; 1H
NMR (250.13 MHz, CDCl3): d = 2.37 (s, CH3), 4.30 (br s, OH), 7.20–8.29 (m, 10CHarom) ppm;
13C NMR (62.53 MHz, CDCl3): d = 21.61 (CH3), 76.64 (C–OH), 122.05, 123.81, 127.07,
128.44, 129.05, 129.64, 132.61, 132.80 (10CH of arom), 122.52, 128.60, 128.75, 126.89, 135.22,
10

142.85 (6C of arom), 162.08, 164.13 (2C=N of oxadiazole), 198.10 (C=O) ppm; IR (KBr): νmax
= 3,355, 3,068, 1,725, 1,603, 1,498, 1,012 cm-1.
2.4.13. Compound 4m
2-Hydroxy-2-[5-(4-methoxyphenyl)-1,3,4-oxadiazol-2-yl]-1(2H)-acenaphthylenone(4m,
C21H14N2O4)
°
Yellow powder; yield 68%; Rf = 0.26 (petroleum ether/ ethyl acetate 4:1); m.p.: 195–197 C; 1H
NMR (250.13 MHz, CDCl3): d = 3.84 (s, CH3), 4.33 (s, OH), 6.85–8.31 (m, 10CHarom) ppm;
13C NMR (62.53 MHz, CDCl3): d = 55.55 (OCH3), 77.55 (C–OH), 114.40, 122.54, 123.92,
126.92, 128.93, 128.95, 132.50, 132.89 (10CH of arom), 122.54, 128.86, 131.04, 135.22, 140.04,
158.82 (6C of arom), 164.08, 166.53 (2C=N of oxadiazole), 194.51 (C=O) ppm; IR (KBr): νmax
= 3,244, 3,083, 1,739, 1,614, 1,500, 1,185 cm-1.
2.4.14. Compound 4n
2-[5-(3,5-Dimethoxyphenyl)-1,3,4-oxadiazol-2-yl]-2-hydroxy-1(2H)-acenaphthylenone(4n,
C22H16N2O5)
°
Yellow powder; yield 67%; Rf = 0.20 (petroleum ether/ ethyl acetate 4:1); m.p.: 168–170 C; 1H
NMR (250.13 MHz, CDCl3): d = 3.80 (s, 2OCH3), 4.43 (s, OH), 6.56–8.30 (m, 9CHarom) ppm;
13C NMR (62.53 MHz, CDCl3): d = 55.64 (2OCH3), 87.00 (C–OH), 105.00, 107.05, 122.04,
123.94, 128.43, 132.59, 132.84 (9CH of arom), 124.75, 127.00, 131.04, 135.03, 142.10, 162.15
(7C of arom), 164.02, 166.43 (2C=N of oxadiazole), 189.51 (C=O) ppm; IR (KBr): νmax = 3,380,
3,094, 1,725, 1,604, 1,463, 1,162 cm-1.
11

2.4.15. Compound 4o
2-Hydroxy-2-[5-(2-methylphenyl)-1,3,4-oxadiazol-2-yl]-1(2H)-acenaphthylenone(4o,
C21H14N2O3)
°
Yellow powder; yield 72%; Rf = 0.34 (petroleum ether/ ethyl acetate 4:1); m.p.: 154–156 C; 1H
NMR (250.13 MHz, CDCl3): d = 2.57 (s, CH3), 4.09 (br s, OH), 7.06–8.64 (m, 10CHarom) ppm;
13C NMR (62.53 MHz, CDCl3): d = 22.32 (CH3), 77.70 (C–OH), 122.06, 126.06, 126.98,
128.44, 129.09, 129.13, 131.50, 132.61, 132.80 (10CH of arom), 123.82, 128.60, 131.65, 132.00,
138.62, 140.35 (6C of arom), 164.18, 166.73 (2C=N of oxadiazole), 198.03 (C=O) ppm; IR
(KBr): νmax = 3,416, 3,072, 1,725, 1,604, 1,491, 1,014 cm-1.
2.4.16. Compound 4p
2-[5-(3,4-Dimethylphenyl)-1,3,4-oxadiazol-2-yl]-2-hydroxy-1(2H)-acenaphthylenone(4p,
C22H16N2O3)
°
Yellow powder; yield 70%; Rf = 0.32 (petroleum ether/ ethyl acetate 4:1); m.p.: 167–169 C; 1H
NMR (250.13 MHz, CDCl3): d = 2.26, 2.28 (s, 2CH3), 4.42 (br s, OH), 7.07–8.75 (m, 9CHarom)
13
ppm; C NMR (62.53 MHz, CDCl3): d = 19.65, 19.93 (2CH3), 80.00 (C–OH), 122.05, 122.54,
126.89, 128.43, 128.59, 128.85,130.16, 132.61, 132.75 (9CH of arom), 122.05, 123.92, 127.50,
128.05, 129.02, 135.32, 145.90 (7C of arom), 164.18, 166.33 (2C=N of oxadiazole), 188.07
(C=O) ppm; IR (KBr): νmax = 3,376, 3,083, 1,721, 1,603, 1,494, 1,184 cm-1.
3. Results and Discussion
12

To achieve suitable conditions for the synthesis of disubstituted 1,3,4-oxadiazole derivatives (4),
various reaction conditions have been investigated in the reaction of benzoic acid (1a),
acenaphthoquinone (2), (N-isocyanimino)triphenylphosphorane (3) as a model reaction.
3.1. Effects of the solvents under ultrasound irradiation
To optimize the reaction conditions using different solvents (DMF, CH2Cl2, CH3CN, CH3OH,
C2H5OH and 1,4-dioxane), were variably investigated in the synthesis of (4a) as model
compound. The best result was obtained by the reaction of benzoic acid (1 mmol),
acenaphthoquinone (1 mmol), (N-isocyanimino)triphenylphosphorane (1 mmol) in CH3CN by
ultrasound irradiation (100 W) to produce (4a) in 15 minutes with 93% yield (Table 1, entry 3).
Dichloromethane, methanol and ethanol afforded moderate yields of desired products but took
comparatively longer reaction time (Table 1, entries 2, 4 and 5). When the reaction was
performed in DMF, and dioxane, unfortunately, the desired product was only obtained in 47%
and 54% yield, respectively (Table 1, entries 1 and 6).
In order to verify the effect of ultrasound irradiation, the reaction was also performed in
mentioned solvents by high stirring alone under silent condition (Table 1). As shown in Table 1,
in all cases, the experimental results show that the yields of the products are lower than
sonication within very longer time. Based on the results of this study, it’s clear that the
ultrasound improves the yields of products. With these results in hand, CH3CN was chosen as
solvent of reaction.
Table 1
3.2. Comparison of ultrasonic irradiation power
13

In order to verify the effect of irradiation power, the reaction was also performed in 50, 100, and
150 W. When the power was 100 W, the yield of 4a (93%) (Table 2, entry 2) was better than that
with 50 W irradiation within 15 min (71%, Table 2, entry 1). With increase of irradiation power
from 100 to 150 W (Table 2, entries 2, 3), the reaction yield did not change a considerable
amount (93% in the similar time). The results are shown that there is an optimum power for
effective synthesis of 4a in the power of 100 W.
Table 2
3.3. High efficiency and generality of synthesis by ultrasound irradiation
After detecting more efficient solvent (CH3CN), and power (100 W) to delineate the role of
ultrasound, this method was examined by the reaction of several substituted benzoic acids,
acenaphthoquinone and (N-isocyanimino)triphenylphosphorane with and without ultrasonic
irradiation at the same temperature in CH3CN (Table 3). 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. The results in
Table 3 show that ultrasound is much more efficient than magnetic stirring. Clearly, sluggish
reactions were observed under conventional conditions and longer reaction time was required to
achieve better yield. However, to our delight, ultrasound irradiation efficiently accelerated the
reaction and markedly shortened the reaction time. Thus, ultrasonic irradiation was found to have
beneficial effect on the synthesis of disubstituted 1,3,4-oxadiazoles which was superior to the
traditional method with respect to yield, reaction time. To the best of our knowledge, this new
14

procedure provides the first example of an efficient and ultrasound-promoted three-component
approach for the synthesis of disubstituted 1,3,4-oxadiazole derivatives.
3.4. Aspects of acceleration mechanism under irradiation of ultrasound
Sonochemistry can be defined as chemistry in a liquid medium in presence of pressure waves.
The increasing interest for sonochemistry is due to the positive chemical and mechanical effects
that can be observed when ultrasonic waves propagate in a liquid medium. Collapsing bubbles
are generated, localized ‘‘hot spots” with a transient high temperature and pressures are formed,
inducing molecular fragmentation, and highly reactive species are locally produced, which are
responsible for the chemical effects of ultrasound on homogeneous solutions. In the some case,
sonication can probably provide more efficient stirring [48-49]. All of these can cause the
reaction to take place rapidly. With this case in mind, we turned our attention to the role of
ultrasound irradiation in reaction mechanism. The suggested mechanism for the formation of
products (4a–4p) is illustrated in Scheme 2. On the basis of the chemistry of isocyanides under
ultrasonic irradiation condition, it is reasonable to assume that the first step may involve
nucleophilic addition of (N-isocyanimino)triphenylphosphorane (3) to acenaphthoquinone (2),
which is facilitated by its protonation with
Table 3
Scheme 2
15

the acid (1), leading to nitrilium intermediate (6). This intermediate may be attacked by the
conjugate base of acid 1 to form 1:1:1 adduct (7). This adduct may undergo intramolecular aza-
Wittig reaction of the iminophosphorane moiety with the ester carbonyl to afford the isolated
sterically congested 1,3,4-oxadiazole derivatives (4) by elimination of triphenylphosphine oxide
(5) from intermediate (8). 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. We believed that 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. As is known, deprotonation of the acid and the formation of O-
centered nucleophiles occurred very slowly in the absence of ultrasound conditions. Moreover,
the use of ultrasonic irradiation enabled the reaction to proceed smoothly under mild conditions
even without the use of inert atmosphere.
Table 2
To the best of our knowledge, this new procedure provides the first example of an efficient and
ultrasound-promoted approach for the synthesis of disubstituted 1,3,4-oxadiazole derivatives.
This method is the most simple and convenient and would be applicable for the synthesis of
different types of 1,3,4-oxadiazoles. The structures of all the synthesized compounds were
established by their IR, Mass, 13C NMR and 1H NMR.
4. Conclusion
16

In conclusion, we have developed a new general and convenient method for synthesis of a series
of 1,3,4-oxadiazole derivatives in high yields under ultrasound irradiation. To the best of our
knowledge, this new procedure provides the first example of an efficient method for the
synthesis of fully substituted 1,3,4-oxadiazole derivatives under ultrasound irradiation. The
method leads to a series of disubstituted 1,3,4-oxadiazole bearing different aryl groups.
Ultrasounds induce a remarkable acceleration for these reactions, the reaction times decreasing
dramatically and the yields increasing considerably.
Acknowledgments
This work is funded by the Grant 2011-0014246 of the National Research Foundation of Korea. The
authors thank Zanjan university for the support and guidance.
References
[1] (a) G.H. Posner, Chem. Rev. 86 (1986) 831;
(b) C.O. Kappe, Acc. Chem. Res. 33 (2000) 879;
(c) R.A.V. Orru, M. de Greef, Synthesis (2003) 1471.
[2] (a) L. Weber, Curr. Med. Chem. 9 (2002) 2085;
(b) C. Hulme, V. Gore, Curr. Med. Chem. 10 (2003) 51;
(c) J. Zhu, Eur. J. Org. Chem. (2003) 1133;
(d) D.J. Ramon, M. Yus, Angew. Chem., Int. Ed. 44 (2005) 1602;
(e) A. Domling, Chem. Rev. 106 (2006) 17.
[3] A. Ramazani, A. Rezaei, A. Tofangchi Mahyari, M. Rouhani, M. Khoobi, Helv. Chim . Acta
93 (2010) 2033.
17

[4] A. Ramazani, A. Mahyari, A. Farshadi, M. Rouhani, Helv. Chim. Acta 94 (2011) 1831.
[5] A. Ramazani, K. Dastanra, F. Zeinali Nasrabadi, Z. Karimi, M. Rouhani, M. Hosseini, Turk.
J. Chem. 36 (2012) 476.
[6] A. Ramazani, A. Tofangchi Mahyari, M. Rouhani, A. Rezaei, Tetrahedron Lett. 50 (2009)
5625.
[7] F. Palacios, D. Aparicio, G. Rubiales, C. Alonso, J.M. de los Santos, Curr. Org. Chem. 13
(2009) 810.
[8] H. Stolzenberg, B. Weinberger, W.P. Fehlhammer, F.G. Pühlhofer, R. Weiss, Eur. J. Inorg.
Chem. 21 (2005) 4263.
[9] A. Ramazani, A. Bodaghi, Tetrahedron Lett. 41 (2000) 567.
[10] P. Pakravan, A. Ramazani, N. Noshiranzadeh, A. Sedrpoushan, Phosphorus Sulfur 182
(2007) 545.
[11] A. Ramazani, M. Rahimifard, A. Souldozi, Phosphorus Sulfur 182 (2007) 1.
[12] A. Ramazani, M. Rahimifard, N. Noshiranzadeh, A. Souldozi, Phosphorus Sulfur 182
(2007) 413.
[13] A. Ramazani, E. Ahmadi, A.R. Kazemizadeh, L. Dolatyari, N. Noshiranzadeh, I. Eskandari,
A. Souldozi, Phosphorus Sulfur 180 (2005) 2419.
[14] A. Ramazani, N. Shajari, F. Gouranlou, Phosphorus Sulfur 174 (2001) 223.
[15] A. Ramazani, I. Amini, A. Massoudi, Phosphorus Sulfur 181 (2006) 2225.
[16] W.R. Tully, C.R. Gardner, R.J. Gillespie, R. Westwood, J. Med. Chem. 34 (1991) 2060.
[17] C. Chen, C.H. Senanayake, T.J. Bill, R.D. Larsen, T.R. Verhoeven, P.J. Reider, J. Org.
Chem. 59 (1994) 3738.
[18] B.S. Holla, R. Gonsalves, S. Shenoy, Eur. J. Med. Chem. 35 (2000) 267.
18

[19] M.J. Crimmin, P.J. O-Hanlon, N.H. Rogers, G. Walker, J. Chem. Soc. Perkin Trans 1
(1989) 2047.
[20] U.V. Laddi, S.R. Desai, R.S. Bennur, S.C. Bennur, Ind. J. Heterocycl. Chem. 11 (2002) 319.
[21] I.R. Baxendale, S.V. Ley, M. Martinelli, Tetrahedron 61 (2005) 5323.
[22] S. Liras, M.P. Allen, B.E. Segelstein, Synth. Commun. 30 (2000) 437.
[23] B.J. Brown, I.R. Clemens, J.K. Neesom, Synlett. 1 (2000) 131.
[24] F.T. Coppo, K.A. Evans, T.L. Graybill, G. Burton, Tetrahedron Lett. 45 (2004) 3257.
[25] C.T. Brain, S.A. Brunton, Synlett. 3 (2001) 382.
[26] V.K. Tandon, R.B. Chhor, Synth. Commun. 31 (2001) 1727.
[27] A. Ramazani, A. Souldozi, Phosphorus Sulfur Silicon Relat. Elem. 184 (2009) 2344.
[28] A. Ramazani, A. Souldozi, Arkivoc xvi (2008) 235.
[29] A. Ramazani, S. Salmanpour, A. Souldozi, Phosphorus Sulfur Silicon Relat. Elem. 185
(2010) 97.
[30] A. Souldozi, A. Ramazani, K. Slepokura, T. Lis, Z. Naturforsch 62b (2007) 835.
[31] A. Ramazani, A. Rezaei, Org. Lett. 12 (2010) 2852.
[32] P. Molina, M.J. Vilaplana, Synthesis (1994) 1197.
[33] D.J. Casadonte Jr, J.D. Sweet, M.S. Vedamuthu, Ultrasonics 32 (1994) 477.
[34] J.D. Sweet, D.J. Casadonte Jr, Ultrason. Sonochem. 8 (2001) 97.
[35] K.S. Suslick, D.J. Casadonte, S.J. Doktycz, R. Shojate, Solid State Ionics 26 (1988) 176.
[36] K.S. Suslick, D.J. Casadonte, S.J. Doktycz, Solid State Ionics 32-33 (1989) 444.
[37] K.S. Suslick, D.J. Casadonte, M.L.H. Green, M.E. Thompson, Ultrasonics, 25 (1987) 56.
19

[38] L.C. Bretanha, V.E. Teixeira, M. Ritter, G.M. Siqueira, W. Cunico, C.M.P. Pereira, R.A.
Freitag, Ultrason. Sonochem. 18 (2007) 704.
[39] K.S. Suslick, Ultrasound, Its Chemical, Physical, and Biological Effects, Verlag Chemie,
New York, 1988
.
[40] T.J. Mason, J.L. Luche, in: R. Van Eldik, C.D. Hubband (Eds.), Chemistry Under Extreme
or Non-Classical Conditions, Wiley and Spectrum, New York and Heidelberg, 1997, p. 317.
[41] J.P. Lorimer, T.J. Mason, Chem. Soc. Rev. 16 (1987) 239.
[42] R.M. Srivastava, R.A.W.N. Filho, C.A. Silva, A. Bortoluzzi, Ultrason. Sonochem. 16
(2009) 737.
[43] M. Rouhani, A. Ramazani, S.W. Joo, Y. Hanifehpour, Bull. Korean Chem. Soc. 33 (2012)
4127.
[44] M. Rouhani, A, Ramazani, S.W. Joo, Ultrason. Sonochem. 21 (2014) 262.
[45] A. Duarte, W. Cunico, C.M.P. Pereira, A.F.C. Flores, R.A. Freitag, G.M. Siqueira,
Ultrason. Sonochem. 17 (2010) 281.
[46] H.A. Stefani, C.M.P. Pereira, R.B. Almeida, R.C. Braga, K.P. Guzenb, R. Cellac,
Tetrahedron Lett. 46 (2005) 6833.
[47] T.W. Chiu, Y.H. Liu, K.M. Chi, Y.S. Wen, K.L. Inorg. Chem. 44 (2005) 6425.
[48] J.T. Li, S. Wang, L.J. Li, J. Org. Chem. 15 (1995) 558.
[49] O. Dahlem, J. Reisse, V. Halloin, Chem. Eng. Sci. 54 (1999) 2829.
20

Scheme 1: Synthesis of disubstituted 1,3,4-oxadiazole derivatives under ultrasound irradiation.
N
N
OH
O
O
Ar
O
O
CH3CN, )))
r.t., 15 min
ArCO2H
1
+
C
N
N
PPh3
+
+
Ph3PO
5
3
2
4
Scheme 2. Probable mechanism for synthesis of disubstituted 1,3,4-oxadiazole derivatives.
O
O
HO
Ar
1
OH
O
O
O
Ar
O
Ph3P
N
N
C
)))
Ph3P
N
3
N
C
2
6
Ph3P
O
N
N
OH
Ph3P
O
N
O
N
OH
O
O
)))
)))
Ar
O
Ar
7
8
N
N
OH
O
)))
+
Ph3PO
5
Ar
O
4
21

Table 1
The effect of reaction condition on the synthesis of 4a under various conditions.
Entry
Solvent
With sonicationa
Without sonicationb
Time (min )
Yieldc (%)
Time (h ) Yieldc (%)
DMF
CH2Cl2
115
120
15
47
75
93
62
78
54
24
24
24
24
24
24
31
59
80
41
62
38
1
2
3
4
5
6
CH3CN
Methanol
Ethanol
135
125
110
1,4-dioxane
a Reaction conditions: Reaction of (N-isocyanimino)triphenylphosphorane (1.0 mmol), acenaphthoquinone (1.0 mmol), and
benzoic acid (1.0 mmol) in different solvents and ultrasonic power of 100 W for various times.
b
Reaction condition: Reaction of (N-isocyanimino)triphenylphosphorane (1.0 mmol), acenaphthoquinone (1.0 mmol), and
benzoic acid in different solvents at room temprature under high stirring condition for 24 hours.
c Isolated yields.
Table 2
The synthesis of 4a under ultrasound irradiation in various frequencies.
Entry
Power (W)
Time (min)
Yield (%)
50
15
15
15
71
93
93
1
2
3
100
150
Table 3
Synthesis of 4a–4p in CH3CN with or without ultrasound irradiation.
Entry
Product
Ar
With sonicationa
Yieldc (%)
93
Without sonicationb
Yieldc (%)
4a
4b
4c
C6H5
80
1
2
3
4-BrC6H4
4-CNC6H4
91
88
78
73
22

4d
4e
4f
3-MeC6H4
4-t-BuC6H4
3-ClC6H4
96
98
92
89
96
91
92
90
94
85
89
93
91
83
85
76
72
82
75
72
75
80
68
67
72
70
4
5
6
4g
4h
4i
3-PhOC6H4
4-Br-CH2C6H4
C10H7
7
8
9
4j
4-Cl-C6H4
10
11
12
13
14
15
16
4k
4l
4-FC6H4
4-MeC6H4
4-MeOC6H4
3,5-diMeOC6H3
2-MeC6H4
3,5-diMeC6H3
4m
4n
4o
4p
a Reaction condition: Reaction of (N-isocyanimino)triphenylphosphorane (302 mg, 1.0 mmol), acenaphthoquinone (182 mg, 1.0
mmol), and aromatic carboxylic acid (1.0 mmol) in CH3CN under ultrasound irradiation for 15 minutes.
b Reaction condition: Reaction of (N-isocyanimino)triphenylphosphorane (302 mg, 1.0 mmol), acenaphthoquinone (182 mg, 1.0
mmol), and aromatic carboxylic acid (1.0 mmol) in CH3CN at room temperature in high stirring condition for 24 hours.
c Yields of isolated products.
23

• The best results were obtained in CH3CN by ultrasound (100 W) in 15 minutes.
• The results show that ultrasound is much more efficient than magnetic stirring.
• The products were synthesized and characterized by melting point, IR, NMR and MS.
• We have developed a convenient method for synthesis of 1,3,4-oxadiazoles.
24