One-pot synthesis of fully substituted 1,3,4-oxadiazole derivatives from aromatic carboxylic acids, cyclobutanone and N-isocyaniminotriphenylphosphorane

Article abstract of DOI:10.3906/kim-1102-3

Reactions of N-isocyaniminotriphenylphosphorane with cyclobutanone in the presence of aromatic (or heteroaromatic) carboxylic acids proceeded smoothly at room temperature and in neutral conditions to afford sterically congested 1-(5-aryl-1,3,4-oxadiazol-2

Full text of DOI:10.3906/kim-1102-3

Turk J Chem
36 (2012) , 179 – 188.
¨
˙
c
ꢀ TUBITAK
doi:10.3906/kim-1102-3
One-pot synthesis of fully substituted 1,3,4-oxadiazole
derivatives from aromatic carboxylic acids,
cyclobutanone and N -isocyaniminotriphenylphosphorane
Mohsen VALIZADEH HOLAGH1, Abel Mohammadali oglu MAHARRAMOV1
Mirza Aliakbar oglu ALLAHVERDIYEV1 Ali RAMAZANI2,∗
,
Yavar AHMADI3 and Ali SOULDOZI4
1Chemistry Department, Baku State University, PO Box AZ 1148,
Baku-AZERBAIJAN REPUBLIC
2Chemistry Department, Zanjan University, PO Box 45195-313, Zanjan-IRAN
e-mail: aliramazani@gmail.com
3Young Researchers Club, Zanjan Branch, Islamic Azad University, Zanjan-IRAN
4Chemistry Department, Urmia Branch, Islamic Azad University,
PO Box 969, Urmia-IRAN
Received: 03.02.2011
Reactions of N -isocyaniminotriphenylphosphorane with cyclobutanone in the presence of aromatic (or
heteroaromatic) carboxylic acids proceeded smoothly at room temperature and in neutral conditions to afford
sterically congested 1-(5-aryl-1,3,4-oxadiazol-2-yl)-1-cyclobutanol derivatives in high yields. The reaction
proceeded smoothly and cleanly under mild conditions and no side reactions were observed. The structures
of the products were deduced from their IR, 1 HNMR, and 13 CNMR spectra, and mass spectrometry.
Key Words: N -isocyaniminotriphenylphosphorane, intramolecular aza-Wittig reaction, 1,3,4-oxadiazole,
aromatic carboxylic acid, cyclobutanone
Introduction
Organophosphorus compounds1−4 have been extensively employed in organic synthesis as useful reagents, as
well as ligands, in a number of transition metal catalysts.3 Iminophosphoranes are important synthetic inter-
mediates in organic chemistry, especially in the preparation of naturally occurring products, compounds with
∗Corresponding author
179

One-pot synthesis of fully substituted 1,3,4-oxadiazole..., M. VALIZADEH HOLAGH, et al.
biological and pharmacological activity.5−11 In the last years, several preparative procedures have been reported
for the preparation and synthetic applications of iminophosphoranes.5−13 The unique synthetic potential of
iminophosphoranes results from the presence of electronrich nucleophilic nitrogen atoms and electrophilic phos-
phorus atoms as P+ –N bonds in their structures.5 The structural properties of the P+ –N bond and its chemical
reactivity have been investigated through theoretical, spectroscopic and crystallographic investigations.5,12,13
The presence of the P+ –N bond in the iminophosphoranes’ structures is a factor of essential mechanistic im-
portance in their applications as aza-Wittig reagents.5 The intramolecular aza-Wittig reaction has attracted
attention recently because of its several applications for the preparation of nitrogen-containing heterocyclic com-
pounds, which can result from the rapid progress in the synthesis of iminophosphorane derivatives as starting
materials.5−11 There are several reports on the use of N isocyaniminotriphenylphosphorane 3 in the prepa-
ration of metal complexes12,13 (Scheme 1). However, the role of N -isocyaniminotriphenylphosphorane 3 in
organic chemistry remains almost unexplored.12,13 The N -isocyaniminotriphenylphosphorane 3 is expected to
have unique synthetic potential because it provides a reaction system in which the iminophosphorane group can
react with a reagent having a carbonyl functionality.12,13 In recent years, we have established a one-pot method
for the preparation of organophosphorus compounds.14−22 As part of our ongoing program to develop effi-
cient and robust methods for the synthesis of heterocyclic compounds,23−31 we sought to develop a convenient
preparation of 1-(5-aryl-1,3,4-oxadiazol-2-yl)-1-cyclobutanols 4a-m from N -isocyaniminotriphenylphosphorane
3 cyclobutanone 2 and aromatic (or heteroaromatic) carboxylic acids 1 in excellent yields under neutral condi-
tions (Scheme 1).
O
N
_
C
HO
N
+
CH3CN
ArCO2H
N
N
+
+
r.t., 20h
Ph3PO
+
Ar
PPh3
O
1
2
3
4
5
Scheme 1. Synthesis of sterically congested 2,5-disubstituted 1,3,4-oxadiazoles derivatives from N -isocyaniminotrip-
henylphosphorane 3 cyclobutanone 2 and aromatic (or heteroaromatic) carboxylic acids 1.
1,3,4-Oxadiazoles have attracted interest in medicinal chemistry as surrogates of carboxylic acids, esters,
and carboxamides.32−34 They are an important class of heterocyclic compounds that have a wide range of phar-
maceutical and biological activities including antimicrobial, antifungal, anti-inflammatory, antihypertensive,
analgesic, antibacterial, hypoglycemic, antimalarial, antitubercular and antidepressant.32−34 Several methods
have been reported in the literature for the synthesis of 1,3,4-oxadiazoles. These protocols are multi-step in
nature.35−37 The most general method involves the cyclization of diacylhydrazides with a variety of reagents,
such as thionyl chloride, phosphorous oxychloride, or sulfuric acid, usually under harsh reaction conditions.38
A reliable and simple method has been reported by the Ramazani research group for the one-pot synthesis of
1,3,4-oxadiazole derivatives from carboxylic acids and N -isocyaniminotriphenylphosphorane 324,31
180

One-pot synthesis of fully substituted 1,3,4-oxadiazole..., M. VALIZADEH HOLAGH, et al.
Experimental
Starting materials and solvents were obtained from Merck (Germany) and Fluka (Switzerland) and were used
without further purification. The methods used to follow the reactions were TLC and NMR. TLC and NMR
indicated that there was no side product. Melting points were measured on an Electrothermal 9100 apparatus
and are uncorrected. IR spectra were measured on a Shimadzu IR-460 spectrometer. 1 H and 13 CNMR spectra
were measured (CDCl3 solution) with a BRUKER DRX-250 AVANCE spectrometer at 250.0 and 62.5 MHz,
respectively. Elemental analyses were performed using a Heraeus CHN-O-Rapid analyzer. Mass spectra were
recorded on a FINNIGAN-MATT 8430 mass spectrometer operating at an ionization potential of 20 eV. Flash
chromatography columns were prepared from Merck silica gel powder.
General procedure for the preparation of compounds 4
To a magnetically stirred solution of N -isocyaniminotriphenylphosphorane 3 (1 mmol) and cyclobutanone 2
(1 mmol) in CH3 CN (7 mL) was added dropwise of a solution of aromatic carboxylic acids 1 (1 mmol) in
CH3 CN (5 mL) at room temperature over 15 min. The mixture was stirred for 20 h. The solvent was removed
under reduced pressure and the viscous residue was purified by flash column chromatography (silica gel powder;
petroleum ether–ethyl acetate (3:1)). The solvent was removed under reduced pressure and the products were
obtained. The characterization data of the compounds are given below:
1-(5-phenyl-1,3,4-oxadiazol-2-yl)cyclobutanol (4a)
Yellow oil (Yield: 85%). IR (neat): v = 3276, 2992, 2949, 1548, 1451 and 783 cm−1 1 HNMR (250 MHz, CDCl3)
δ (ppm): 1.95-2.05 (m, 2H, cyclobutane), 2.46-2.58 (m, 2H, cyclobutane), 2.72-2.81 (m, 2H, cyclobutane),
3.48 (s, 1H, OH), 7.41-8.08 (m, 5H, arom). 13 CNMR (62.5 MHz, CDCl3) δ (ppm): 12.8 and 35.5 (2CH2 ,
cyclobutane) 71.2 (C, cyclobutane), 123.7 (C, arom) 127.0 (CH), 129.0 (CH), 131.9 (CH) 165.5 and 169.1 (2C,
oxadiazole). Analysis of C12 H12 N2 O2 (216.24). (% calculation/ found): C: 66.65/66.69, H: 5.59/5.64, N:
12.96/1291 MS, m/z(%): 216 (M+ , 18), 188 (35), 160 (100), 118 (50), 103 (47), 76 (73), 50 (23) and 42 (59).
1-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]cyclobutanol (4b)
Yellow oil (Yield: 85%). IR (neat): v =3265, 2941, 1605, 1406, 1088, 843 cm−1 1 HNMR (250 MHz, CDCl3) δ
.
(ppm): 1.93-2.08 (2CH2 , cyclobutane), 2.45-2.57 (2CH2 , cyclobutane), 2.72-2.82 (2CH2 , cyclobutane), 3.45 (s,
1H, OH), 7.49 (2d, 4H, J = 8.5 Hz, arom) and 7.99 (2d, 4H, J = 8.5 Hz, arom). 13 CNMR (62.5 MHz, CDCl3)
δ (ppm): 12.8 and 35.5 (2CH2 , cyclobutane), 71.1 (C, cyclobutane), 128.2 (CH), 129.4 (CH) 122.1 and 138.2
(2C, arom) 165.1 and 169.3 (2C, oxadiazole). Analysis of C12 H11 ClN2 O2 (250.68). (% calculation/found): C:
57.49/5746, H: 4.42/4.46, N: 11.17/1120. MS, m/z(%): 250 (M+ , 55), 222 (48), 194 (100), 152 (39), 137 (62),
111 (30), 74 (29) and 42 (80).
1-[5-(4-ethylphenyl)-1,3,4-oxadiazol-2-yl]cyclobutanol (4c)
Yellow crystals, (Yield 87%). Mp 77.2-78.3 ◦ C IR (KBr): v =3285, 2938, 1498, 1250, 1074, 838 cm−1 1 HNMR
.
(250 MHz, CDCl3) δ (ppm): 1.26 (t, 3H, J = 7.5 Hz, CH3 of Et), 1.92-2.0 (2CH2 , cyclobutane), 2.02-2.12
181

One-pot synthesis of fully substituted 1,3,4-oxadiazole..., M. VALIZADEH HOLAGH, et al.
(2CH2 , cyclobutane), 2.45-2.57 (2CH2 , cyclobutane), 2.71 (q, 2H, J = 7.5 Hz, CH2 of Et), 2.43 (s, 3H, CH3),
3.60 (s, 1H, OH), 7.31 and 7.96 (2d, 4H, J = 7.5 Hz, arom). 13 CNMR (62.5 MHz, CDCl3) δ (ppm): 12.8 and
35.5 (2CH2 , cyclobutane) 15.2 (CH3 of Et) 28.9 (CH2 of Et), 71.1 (C, cyclobutane), 121.1 and 148.6 (2C, arom)
127.0 (CH), 128.5 (CH) 165.5 and 168.8 (2C, oxadiazole). Analysis of C14 H16 N2 O2 (244.29), (% calculation/
found): C: 68.83/6878, H: 6.60/6.54, N: 11.47/11.51
1-[5-(3,5-dimethylphenyl)-1,3,4-oxadiazol-2-yl]cyclobutanol (4d)
Yellow oil, (Yield: 86%). IR (neat): v = 3212, 2949, 1560, 1429, 1043, 863 cm−1 1 HNMR (250 MHz, CDCl3)
.
δ (ppm): 1.97-2.05 (2CH2 , cyclobutane), 2.46-2.63 (2CH2 , cyclobutane), 2.72-2.82 (2CH2 , cyclobutane), 2.38
(1s, 6H, 2CH3) 3.65 (1s, 1H, OH) 7.15 and 7.66 (2s, 3H, arom). 13 CNMR (62.5 MHz, CDCl3) δ (ppm):
12.8 and 35.4 (2CH2 , cyclobutane) 21.2 (CH3), 71.1 (C, cyclobutane) 123.4 and 138.8 (2C, arom) 124.7 (CH),
133.6 (CH), 165.8 and 170.0 (2C, oxadiazole). Analysis of C14 H16 N2 O2 (244.29). (% calculation/ found): C:
68.83/68.86, H: 6.60/6.56, N: 11.47/11.43
1-[5-(4-methylphenyl)-1,3,4-oxadiazol-2-yl]cyclobutanol (4e)
Yellow crystals, (Yield: 89%). Mp 127.2-128.7 ◦ C. IR (KBr): v =3228, 2928, 1498, 1159, 1085, 823 cm−1
.
1 HNMR (250 MHz, CDCl3) δ (ppm): 1.92-2.06 (2CH2 , cyclobutane), 2.48-2.57 (2CH2 , cyclobutane), 2.72-2.82
(2CH2 , cyclobutane), 2.43 (s, 3H, CH3) 3.60 (s, 1H, OH) 7.30 and 7.95 (2d, 4H, J = 8 Hz, arom). 13 CNMR
(62.5 MHz, CDCl3) δ (ppm): 12.8 and 35.5 (2CH2 , cyclobutane) 21.7 (CH3) 71.2 (C, cyclobutane); 120.9
and 142.4 (2C, arom) 126.9 (CH), 129.7 (CH), 165.5 and 169.0 (2C, oxadiazole). Analysis of C13 H14 N2 O2
(230.26). (% calculation/ found): C: 67.81/67.85, H: 6.13/6.17, N: 12.17/1214
1-[5-(2-Bromophenyl)-1,3,4-oxadiazol-2-yl]cyclobutanol (4f)
Yellow oil (Yield: 87%). IR (neat): v =3284, 2939, 1523, 1454, 1094, 897, 754 cm−1
.
1 HNMR (250
MHz, CDCl3) δ (ppm): 1.92-2.2.05 (2CH2 , cyclobutane), 2.48-2.60 (2CH2 , cyclobutane), 2.72-2.83 (2CH2 ,
cyclobutane), 3.40 (s, 1H, OH) 7.36-7.49 (m, 2H, arom) 7.75 (d, J = 7.75 Hz, 1H, arom) 7.95 (d, J = 7.5 Hz,
1H, arom). 13 CNMR (62.5 MHz, CDCl3) δ (ppm): 12.7 and 35.6 (2CH2 , cyclobutane) 71.3 (C, cyclobutane)
121.7 and 125.9 (2C, arom) 127.6 (CH), 131.8 (CH), 132.6 (CH), 134.5 (CH) 164.5 and 170.8 (2C, oxadiazole).
Analysis of C12 H11 BrN2 O2 (295.13). (% calculation/ found): C: 4884/4879, H: 376/373, N: 949/953.
4-[5-(1-hydroxycyclobutyl)-1,3,4-oxadiazol-2-yl]benzonitrile (4g)
Yellow oil, (Yield: 86%). IR (neat): v =3289, 2915, 2229, 1489, 1158, 1083, 854 cm−1
.
1 HNMR (250 MHz,
CDCl3) δ (ppm): 1.91-2.10 (2CH2 , cyclobutane), 2.46-2.59 (2CH2 , cyclobutane), and 2.74-2.83 (3m, 6H,
cyclobutane) 3.42 (s, 1H, OH) 7.82 and 8.20 (2d, 4H, J = 8.5 Hz, arom). 13 CNMR (62.5 MHz, CDCl3)
δ (ppm): 12.8 and 35.6 (2CH2 , cyclobutane) 71.2 (C, cyclobutane) 127.5 (CH), 132.9 (CH) 115.4 and 138.2
(2C, arom) 165.2 and 169.2 (2C, oxadiazole). Analysis of C13 H11 N3 O2 (241.25). (% calculation/ found): C:
6472/6477, H: 460/456, N: 1742/1746.
182

One-pot synthesis of fully substituted 1,3,4-oxadiazole..., M. VALIZADEH HOLAGH, et al.
1-[5-(4-Bromorophenyl)-1,3,4-oxadiazol-2-yl]cyclobutanol (4h)
Yellow crystals, (Yield: 83%). Mp 117-118.9 ◦ C. IR (KBr): v =3286, 2941, 1525, 1458, 1098, 891 cm−1
1 HNMR (250 MHz, CDCl3) δ (ppm): 1.87-2.05 (2CH2 , cyclobutane), 2.45-2.57 (2CH2 , cyclobutane), 2.75-
2.78 (2CH2 , cyclobutane), 3.36 (s, 1H, OH), 7.64 and 7.91 (2d, 4H, J = 7.5 Hz, arom). 13 CNMR (62.5 MHz,
CDCl3) δ (ppm): 12.8 and 35.5 (2CH2 , cyclobutane), 71.2 (C, cyclobutane), 128.4 (CH), 132.4 (CH), 122.2
and 138.3 (2C, arom), 165.0 and 166.8 (2C, oxadiazole). Analysis of C12 H11 BrN2 O2 (295.13). (% calculation/
found): C: 4884/4888, H: 376/3.80, N: 9.49/944.
1-[5-(3,4-dimethylphenyl)-1,3,4-oxadiazol-2-yl]cyclobutanol (4i)
Yellow crystals, (Yield 84%). Mp 90.4-91.9 ◦ C IR (KBr): v =3213, 2947, 1562, 1494, 1045, 827 cm−1 1 HNMR
.
(250 MHz, CDCl3) δ (ppm): 1.84-2.04 (2CH2 , cyclobutane), 2.44-2.56 (2CH2 , cyclobutane), 2.73-2.78 (2CH2 ,
cyclobutane), 2.30 (s, 6H, 2CH3), 3.91 (s, 1H, OH), 7.19-7.78 (m, 3H, arom). 13 CNMR (62.5 MHz, CDCl3) δ
(ppm): 12.8 and 35.4 (2CH2 , cyclobutane), 19.6 and 19.9 (2CH3) 71.0 (C, cyclobutane) 121.1, 137.5 and 141.1
(3C, arom), 124.5 (CH), 127.9 (CH), 129.2 (CH); 165.5 and 168.9 (2C, oxadiazole). Analysis of C14 H16 N2 O2
(244.29). (% calculation/ found): C: 6883/6880, H: 6.60/665, N: 11.47/1144.
1-(5-(2-Thienyl)-1,3,4-oxadiazol-2-yl)cyclobutanol (4j)
Yellow oil (Yield: 81%). IR (neat): v = 3289, 2995, 2938, 1587, 1491 and 855 cm−1
.
1 HNMR (250
MHz, CDCl3) δ (ppm): 1.85-2.05 (2CH2 , cyclobutane), 2.44-2.56 (2CH2 , cyclobutane), 2.71-2.75 (2CH2 ,
cyclobutane), 3.62 (s, 1H, OH), 7.15-7.76 (m, 3H, arom. 13 CNMR (62.5 MHz, CDCl3) δ (ppm): 12.8 and
35.4 (2CH2 , cyclobutane), 71.1 (C, cyclobutane), 124.9 (C, arom), 128.1 (CH), 130.0 (CH), 130.3 (CH) 164.5
and 168.5 (2C, oxadiazole). Analysis of C10 H10 N2 O2 S (222.26). (% calculation/ found): C: 5404/5409, H:
4.53/4.50, N: 1260/1256.
1-[5-(2,4-dimethylphenyl)-1,3,4-oxadiazol-2-yl]cyclobutanol (4k)
Yellow crystals (Yield 85%). Mp 82.2-83.7 ◦ C IR (KBr): v =3215, 2951, 1564, 1495, 1059, 826 cm−1 1 HNMR
.
(250 MHz, CDCl3) δ (ppm): 1.91-2.10 (2CH2 , cyclobutane), 2.43-2.54 (2CH2 , cyclobutane), 2.69-2.90 (2CH2 ,
cyclobutane), 2.37 and 2.65 (2s, 6H, 2CH3) 3.90 (s, 1H, OH) 7.09-7.92 (m, 3H, arom). 13 CNMR (62.5 MHz,
CDCl3) δ (ppm): 12.8 and 35.5 (2CH2 , cyclobutane), 21.4 and 21.9 (2CH3), 71.1 (C, cyclobutane) 120.0,
138.3 and 141.7 (3C, arom) 126.9 (CH), 129.0 (CH), 132.5 (CH) 165.7 and 168.9 (2C, oxadiazole). Analysis of
C14 H16 N2 O2 (244.29). (% calculation/ found): C: 6883/6886, H: 6.60/664, N: 11.47/11.44.
1-[5-(2-methylphenyl)-1,3,4-oxadiazol-2-yl]cyclobutanol (4l)
Yellow oil, (Yield 82%). IR (neat): v =3230, 2925, 1489, 1155, 1089, 827 cm−1
.
1 HNMR (250 MHz, CDCl3)
δ (ppm): 1.91-2.05 (2CH2 , cyclobutane), 2.45-2.58 (2CH2 , cyclobutane), 2.69-2.73 (2CH2 , cyclobutane), 2.67
(s, 3H, CH3) 3.44 (s, 1H, OH) 7.18-8.00 (m, 4H, arom). 13 CNMR (62.5 MHz, CDCl3) δ (ppm): 12.8 and 35.5
(3CH2 , cyclobutane), 22.0 (CH3), 71.1 (C, cyclobutane) 122.8 and 138.4 (2C, arom) 126.1 (CH), 129.0 (CH),
183

One-pot synthesis of fully substituted 1,3,4-oxadiazole..., M. VALIZADEH HOLAGH, et al.
131.3 (CH), 131.7 (CH) 165.0 and 168.5 (2C, oxadiazole). Analysis of C13 H14 N2 O2 (230.26). (% calculation/
found): C: 67.81/6777, H: 6.13/616, N: 1217/1213.
1-[5-(2-chlorophenyl)-1,3,4-oxadiazol-2-yl]cyclobutanol (4m)
Yellow oil, (Yield: 81%). IR (neat): v =3269, 2948, 1604, 1409, 1084, 847, 755 cm−1
.
1 H-NMR (250
MHz, CDCl3) δ (ppm): 1.95-2.06 (2CH2 , cyclobutane), 2.46-2.55 (2CH2 , cyclobutane), 2.72-2.77 (2CH2 ,
cyclobutane), 3.87 (s, 1H, OH), 7.29-8.00 (m, 4H, arom). 13 C-NMR (62.5 MHz, CDCl3) δ (ppm): 12.6 and
35.6 (2CH2 , cyclobutane), 71.2 (C, cyclobutane), 121.8 and 126.2 (2C, arom), 127.7 (CH), 131.3 (CH), 132.5
(CH), 134.4 (CH), 165.0 and 168.9 (2C, oxadiazole). Analysis of C12 H11 ClN2 O2 (250.68). (% calculation/
found): C: 57.49/57.54, H: 4.42/4.38, N: 11.17/11.20.
Results and discussion
In recent years, several synthetic methods have been reported for the preparation of N -isocyaniminotriphenylp-
hosphorane (CNNPPh3) 3 (Scheme 1).12,13 There are several reports on the use of N -isocyaniminotriphenylp-
hosphorane 3 in the synthesis of metal complexes.12,13 However, application of 3 in the synthesis of organic
compounds has been fairly rare.23−28 As part of our ongoing program to develop efficient and robust methods
for the preparation of heterocyclic compounds,23−31 we sought to develop a convenient preparation of 1-
(5-aryl-1,3,4-oxadiazol-2-yl)-1-cyclobutanols 4 from aromatic (or heteroaromatic) carboxylic acids 1 and N -
isocyaniminotriphenylphosphorane 3 in excellent yields under neutral conditions (Scheme 1).
The carboxylic acid derivative 1 with cyclobutanone 2 and N - isocyaniminotriphenylphosphorane 3 in
CH3 CN react together in a 1:1:1 ratio at room temperature to produce sterically congested 2,5-disubstituted
1,3,4-oxadiazoles 4 and triphenylphosphine oxide 5 (Scheme 1 and Table). The reaction proceeds smoothly
and cleanly under mild conditions. The suggested mechanism for this reaction is provided in Scheme 2. On
the basis of the chemistry of isocyanides, it is reasonable to assume that the first step may involve nucleophilic
addition of the N -isocyaniminotriphenylphosphorane 3 to cyclobutanone 2, which facilitates by its protonation
with the acid 1, leading to nitrilium intermediate 6. This intermediate may be attacked by conjugate base
of the acid 1 to form 1:1:1 adduct 7. This adduct may undergo an intramolecular aza-Wittig23−29 reaction
of iminophosphorane moiety with the ester carbonyl to afford the isolated sterically congested 1,3,4-oxadiazole
derivatives 4 by removal of triphenylphosphine oxide 5 from intermediate 8 (Scheme 2). The structures of the
products 4a-m were deduced from their IR, 1 HNMR, and 13 CNMR spectra. For example the IR spectrum of
4a showed strong absorptions at 3276 (OH), 2992 (CH), 1548 (C=C, aromatic) 1451 (C=C, aromatic) and 783
(aromatic) cm−1 . The 1 HNMR spectrum of 4a exhibited 3 multiplets for the cyclobutane (δ = 1.95-2.05, 2.46-
2.58 and 2.72-2.81 ppm), a singlet for OH (δ = 3.48 ppm), and a multiplet for H-Ar (7.41-8.08 ppm). The 1 H
decoupled 13 CNMR spectrum of 4a showed 9 distinct resonances [δ = 12.8 and 35.5 (2 CH2 , cyclobutane); 71.2
(1 C, cyclobutane); 123.7 (1 C, arom.); 127.0, 129.0 and 131.9 (3 CH, arom.); 165.5 and 169.1 (2 C, oxadiazole)]
that are in agreement with the formula and structure of 4a. Partial assignment of these resonances is given
in the spectral analysis section (see Experimental section). The 1 H and 13 CNMR spectra of compounds 4bm
were similar to those of 4a, except for the aromatic or heteroaromatic moieties, which exhibited characteristic
signals with appropriate chemical shifts.
184

One-pot synthesis of fully substituted 1,3,4-oxadiazole..., M. VALIZADEH HOLAGH, et al.
Table. Synthesis of disubstituted 1,3,4-oxadiazole derivatives 4 (see Scheme 1).
4
a
Ar
Product
Yield (%)a
N
N
HO
C6H5
85
O
N
N
HO
O
Cl
4-ClC6H4
85
b
N
N
N
HO
HO
HO
4-EtC6H4
87
86
c
O
Et
CH3
N
3,5-diMeC6H4
d
O
CH3
N
N
4-MeC6H4
2-BrC6H4
4-CNC6H4
9
e
f
O
CH3
N
N
HO
87
86
O
Br
N
N
N
N
HO
HO
HO
g
O
CN
Br
N
4-BrC6H4
83
h
O
CH3
CH3
N
i
j
3,4-diMeC6H4
84
81
85
O
N
N
HO
O
C4H3S
S
N
N
HO
2,4-diMeC6H4
k
O
CH3
H3C
185

One-pot synthesis of fully substituted 1,3,4-oxadiazole..., M. VALIZADEH HOLAGH, et al.
Table. Continued.
4
l
Ar
Product
Yield (%)a
N
N
HO
HO
2-MeC6H4
82
O
H3C
N
N
2-ClC6H4
81
O
m
Cl
aYield of isolated 4.
O
OH
+
O
HO
Ar
_
C
+
N
N
C
N
N
Ph3P
O
1
Ph3P
3
_
Ar
O
2
Ph3P
6
+
Ph3P
OH
N
N
HO
N
O
N
N
OH
_
N
+
O
Ph3PO
O
Ar
O
O
Ar
Ar
5
8
4
7
Scheme 2. Proposed mechanism for the formation of disubstituted 1,3,4-oxadiazole derivatives 4.
In summary, we have found a new method for the preparation of sterically congested 2,5-disubstituted
1,3,4-oxadiazole derivatives 4 from aromatic (or heteroaromatic) carboxylic acids 1, cyclobutanone 2 and N -
isocyaniminotriphenylphosphorane 3 in excellent yields under neutral conditions. We think that the reported
method offers a mild and simple route for the preparation of these derivatives. Its ease of work-up and reaction
conditions make it a useful addition to modern synthetic methodologies. Other aspects of this process are under
investigation.
Conclusions
We think that the reported method offers a mild, simple, and efficient route for the preparation of sterically
congested 1,3,4-oxadiazole derivatives, by a sequence of multicomponent reactions and an intramolecular aza-
Wittig closure. Due to the easy availabilityof the synthetic approach and the neutral ring closure conditions, this
186

One-pot synthesis of fully substituted 1,3,4-oxadiazole..., M. VALIZADEH HOLAGH, et al.
new synthetic approach discussed here has potential in synthesis of various 2,5-disubstituted 1,3,4-oxadiazoles,
which are of considerable interest as potential biologically active compounds or pharmaceuticals.
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