Four-component synthesis of 1,3,4-oxadiazole derivatives from N-isocyaniminotriphenylphosphorane, aromatic carboxylic acids, aromatic bis-aldehydes, and secondary amines

Article abstract of DOI:10.3906/kim-1107-19

The 1:1 iminium intermediate generated by the addition of a secondary amine to aromatic bis-aldehydes (isophthalaldehyde and terphthalaldehyde) is trapped by the N-isocyaniminotriphenylphosphorane in the presence of a aromatic carboxylic acid derivative,

Full text of DOI:10.3906/kim-1107-19

Turk J Chem
36 (2012) , 81 – 91.
¨
˙
c
ꢀ TUBITAK
doi:10.3906/kim-1107-19
Four-component synthesis of 1,3,4-oxadiazole derivatives
from N -isocyaniminotriphenylphosphorane, aromatic
carboxylic acids, aromatic bis-aldehydes, and secondary
amines
Ali RAMAZANI1,∗, Zahra KARIMI1, Ali SOULDOZI2, Yavar AHMADI3
1Chemistry Department, Zanjan University, PO Box 45195-313, Zanjan-IRAN
2Chemistry Department, Urmia Branch, Islamic Azad University, PO Box 969, Urmia-IRAN
3Young Researchers Club, Zanjan Branch, Islamic Azad University, Zanjan-IRAN
e-mail: aliramazani@gmail.com
Received: 07.07.2011
The 1:1 iminium intermediate generated by the addition of a secondary amine to aromatic bis-aldehydes
(isophthalaldehyde and terphthalaldehyde) is trapped by the N -isocyaniminotriphenylphosphorane in the
presence of a aromatic carboxylic acid derivative, which leads to the formation of corresponding iminophos-
phorane intermediate. Then disubstituted 1,3,4-oxadiazole derivatives are formed via intramolecular aza-
Wittig reaction of the iminophosphorane intermediates. The reactions were completed in neutral conditions
at room temperature and the corresponding disubstituted 1,3,4-oxadiazole derivatives were produced in
excellent yields.
Key Words: N -isocyaniminotriphenylphosphorane, aromatic carboxylic acid, aromatic bis-aldehydes,
1,3,4-oxadiazole, aza-Wittig reaction, secondary amine
Introduction
In recent years, multicomponent reactions (MCRs) have become important tools in modern preparative synthetic
chemistry because these reactions increase efficiency by combining several operational steps without any isolation
of intermediates or changes in the conditions.1−6 This principle, therefore, is highly efficient in terms of time as
well as resources.7 Among the known multicomponent reactions to date, the most valuable reactions are those
∗Corresponding author
81

Four-component synthesis of 1,3,4-oxadiazole derivatives from..., A. RAMAZANI, et al.
based on isocyanides. Isocyanide-based multicomponent reactions (abbreviated to IMCRs by Ugi and D¨omling),
by virtue of their synthetic potential, their inherent atom efficiency, convergent nature, ease of implementation,
and the generation of molecular diversity, have attracted much attention because of the advantages that they
offer to the field of combinatorial chemistry.8
Iminophosphoranes are a class of special type of zwitterions, which bear a strongly nucleophilic electron
rich nitrogen. The electron distribution around the P+ –N− bond and its consequent chemical implications
have been probed and assessed through theoretical, spectroscopic, and crystallographic investigations.9 The
proton affinity of these iminophosphoranes can be used as a molecular guide to assess their utility as synthetic
reagents and their function as ligands in coordination and organometallic chemistry.9−17
The intramolecular version of the aza-Wittig-type reaction has attracted considerable attention recently
because of its high potential for the synthesis of a wide variety of nitrogen heterocycles, which can be attributed,
in good measure, to the rapid progress in the preparation of functionalized iminophosphoranes. The nucle-
ophilicity at the nitrogen is a factor of essential mechanistic importance in the use of these iminophosphoranes
as aza-Wittig reagents. Iminophosphoranes are important reagents in synthetic organic chemistry, especially
in the synthesis of naturally occurring products, compounds with biological and pharmacological activity.9−20
There are several reports for the use of (N -isocyanimino)triphenylphosphorane 4 in the preparation of metal
complexes.16−21 However, the role of N -isocyaniminotriphenylphosphorane 4 in organic chemistry remains
almost unexplored.16−21 The N -isocyaniminotriphenylphosphorane 4 is expected to have unique synthetic po-
tential because it provides a reaction system in which the iminophosphorane group can react with a reagent
having a carbonyl functionality.20,21 In recent years, we have established a one-pot method for the synthesis of
organophosphorus compounds.18−26 As part of our ongoing program to develop efficient and robust methods for
the preparation of heterocyclic compounds,27−41 we wish to report the synthesis of a new class of disubstituted
1,3,4-oxadiazole derivatives 5 by a novel 4-component condensation of aromatic carboxylic acids 1, bis-aldehydes
(isophthalaldehyde and terphthalaldehyde) 2, a secondary amine 3, and N -isocyaniminotriphenylphosphorane
4 in excellent yields under neutral conditions (Scheme 1).
OHC
CHO
N
N
CH2Cl2
r.t, 5h
(Ph)3 P
+
O
ArCO2H
+
+
N
N
C
+
O
Ar
N
R
(Ph)3P
CHO
1
6
NH
R
2
4
3
5
(meta and para isomers)
Scheme 1. Four-component synthesis of sterically congested 1,3,4-oxadiazole derivatives 5 (see Table).
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, anti-fungal, anti-inflammatory, antihypertensive,
82

Four-component synthesis of 1,3,4-oxadiazole derivatives from..., A. RAMAZANI, et al.
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 424,31
Experimental
The 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 Jasco 6300 FTIR 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 70 eV. Flash
chromatography columns were prepared from Merck silica gel powder.
General procedure for the preparation of compounds 5
To a stirred solution of N -isocyaniminotriphenylphosphorane 4 (1 mmol), aromatic bis-aldehyde 2 (1 mmol),
and secondary amine 3 (1 mmol) in CH2 Cl2 (5 mL) was added dropwise a solution of aromatic carboxylic acids
1 (1 mmol) in CH2 Cl2 (5 mL) at room temperature over 15 min. The mixture was stirred for 5 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:
4–[[5-(4-Bromophenyl)-1,3,4-oxadiazol-2-yl](dibenzylamino)methyl]benzaldehyde (5a)
Yellow oil, (Yield 90%). IR (neat): νmax = 2980, 1704, 1607, 1482 and 799 cm−1 1 H-NMR (250 MHz, CDCl3)
.
δ (ppm): 3.66 and 3.89 (AB quartet, 4H, J = 13.75 Hz, 2CH2 of dibenzyl group), 5.50 (s, 1H, CH aliphatic),
7.28-7.92 (m, 18H, H-arom), 10.11 (s, 1H, CHO). 13 C-NMR (62.5 MHz, CDCl3) δ (ppm): 54.8 (2CH2 of
benzyl group), 59.5 (CH, aliphatic), 127.5, 128.4, 128.5, 128.8, 129.1, 129.9 and 132.5 (18CH of arom), 122.5,
126.7, 136.2, 138.2 and 143.3 (6C of arom), 164.1 and 164.6 (2C=N of oxadiazole), 191.6 (C=O of aldehyde).
Anal. Calcd for C30 H24 BrN3 O2 (538.4): C 66.92, H 4.49, N 7.80; Found: C 66.86, H 4.42, N 7.88. MS,
m/z(%): 538 (M+ , 3), 342 (6), 314 (53), 222 (4), 196 (100), 132 (6), 91 (93) and 65 (9).
4–{[Benzyl(ethyl)amino][(5-(4-methylphenyl)-1,3,4-oxadiazol-2-yl]methyl}benzaldehyde (5b)
Yellow oil, (Yield 84%). IR (neat) νmax = 3035, 2975, 1704, 1610, 1499, 1211 and 827 cm−1
.
1 H-NMR (250
MHz, CDCl3) δ (ppm): 1.14 (t, 3H, J = 7 Hz, CH3 of Et), 2.43 (s, 3H, CH3), 2.50-2.58 and 2.70-2.81
(2m, 2H, CH2 of Et), 3.58 and 3.90 (AB quartet, 2H, J = 13.75 Hz, CH2 of benzyl group), 5.49 (s, 1H, CH
83

Four-component synthesis of 1,3,4-oxadiazole derivatives from..., A. RAMAZANI, et al.
aliphatic), 7.22-7.92 (m, 13H, H-arom), 10.01 (s, 1H, CHO). 13 C-NMR (62.5 MHz, CDCl3) δ (ppm): 12.7 and
21.6 (2CH3), 44.6 (CH2 , Ethyl), 54.5 (CH2 of benzyl group), 60.2 (CH, aliphatic), 126.9, 127.2, 128.4, 128.6,
128.8, 129.7 and 129.8 (13CH of arom), 120.8, 130.1, 136.1, 138.7 and 142.5 (5C of arom), 163.9 and 165.5
(2C=N of oxadiazole), 191.6 (C=O of aldehyde). Anal. Calcd for C26 H25 N3 O (411.5): C 75.89, H 6.12, N
10.21; Found: C 75.83, H 6.34, N 10.26. MS, m/z(%): 412 (M+ , 29), 278 (56), 252 (68), 235 (6), 159 (12), 134
(100), 119 (34), 77 (13), 65 (11) and 43 (5).
4–{[Benzyl(ethyl)amino][(5-(4-bromophenyl)-1,3,4-oxadiazol-2-yl]methyl}benzaldehyde (5c)
Yellow oil, (Yield 85%). IR (neat) νmax = 3066, 2979, 1705, 1606, 1482 and 740 cm−1
.
1 H-NMR (250 MHz,
CDCl3) δ (ppm): 1.14 (t, 3H, J = 7 Hz, CH3 of Et), 2.50-2.58 and 2.72-2.77 (2m, 2H, CH2 of Et), 3.59
and 3.89 (AB quartet, 2H, J = 13.75 Hz, CH2 of benzyl group), 5.48 (s, 1H, CH aliphatic), 7.21-7.89 (m,
13H, H-arom), 10.01 (s, 1H, CHO). 13 C-NMR (62.5 MHz, CDCl3) δ (ppm): 12.7 (CH3); 44.7 (CH2 , Ethyl),
54.6 (CH2 of benzyl group), 60.3 (CH, aliphatic), 127.9, 128.3, 128.4, 128.6, 128.8, 129.9 and 132.4 (13CH of
arom), 122.53, 127.2, 136.1, 138.6 and 143.9 (5C of arom), 162.8 and 164.5 (2C=N of oxadiazole), 191.6 (C=O
of aldehyde). Anal. Calcd for C25 H22 BrN3 O2 (476.4): C 63.03, H 4.65, N 8.82; Found: C 63.10, H 4.60, N
8.77. MS, m/z(%): 475 (M+ , 15), 463 (34), 448 (18), 436 (59), 430 (26), 278 (79), 235 (6), 160 (6), 134 (100),
119 (18), 91 (41), 65 (6) and 43 (2).
4–{[Benzyl(methyl)amino][(5-(4-methylphenyl)-1,3,4-oxadiazol-2-yl]methyl}benzaldehyde (5d)
Yellow oil, (Yield 88%). IR (neat) νmax = 2993, 1704, 1613, 1499, 1213 and 828 cm−1
.
1 H-NMR (250 MHz,
CDCl3) δ (ppm): 2.30 and 2.43 (2s, 6H, 2CH3), 3.68 (s, 2H, CH2 of benzyl group), 5.32 (s, 1H, CH aliphatic),
7.29-7.94 (m, 13H, H-arom), 10.02 (s, 1H, CHO). 13 C-NMR (62.5 MHz, CDCl3) δ (ppm): 21.6 and 39.1
(2CH3), 58.9 (CH2 of benzyl group), 63.7 (CH, aliphatic), 126.9, 127.4, 128.4, 128.8, 129.1, 129.8 and 130.0
(13CH of arom), 120.8, 130.1, 136.1, 138.6 and 142.5 (5C of arom), 163.6 and 166.5 (2C=N of oxadiazole), 191.6
(C=O of aldehyde). Anal. Calcd for C25 H23 N3 O2 (397.5): C 75.54, H 5.83, N 10.57; Found: C 75.49, H 5.88,
N 10.64.
3–{[Benzyl(methyl)amino][(5-(4-bromophenyl)-1,3,4-oxadiazol-2-yl]methyl}benzaldehyde (5e)
Yellow oil, (Yield 83%). IR (neat) νmax = 3088, 2969, 1703, 1604, 1482 and 741 cm−1
.
1 H-NMR (250 MHz,
2
CDCl3) δ (ppm): 2.27 (s, 3H, CH3), 3.61 and 3.68 (AB quartet, 2H, JHH = 13.5 Hz, CH2 of benzyl group),
5.29 (s, 1H, CH aliphatic), 7.27-8.04 (m, 13H, H-arom), 10.05 (s, 1H, CHO). 13 C-NMR (62.5 MHz, CDCl3)
δ (ppm): 39.1 (CH3), 58.8 (CH2 of benzyl group), 63.6 (CH, aliphatic), 128.5, 128.7, 128.7, 129.5, 129.7,
130.7 and 132.3 (13CH of arom), 119.5, 127.5, 129.6, 134.3 and 136.8 (5C of arom), 162.8 and 165.0 (2C=N
of oxadiazole), 191.8 (C=O of aldehyde). Anal. Calcd for C24 H20 BrN3 O2 (462.3): C 62.35, H 4.36, N 9.09;
Found: C 62.41, H 4.31, N 9.15.
84

Four-component synthesis of 1,3,4-oxadiazole derivatives from..., A. RAMAZANI, et al.
4–{(Dibenzylamino)[5-(4-ethylphenyl)-1,3,4-oxadiazol-2-yl]methyl}benzaldehyde (5f)
Yellow oil, (Yield 86%). IR (neat) νmax = 3067, 2939, 1705, 1613, 1501 and 753 cm−1
.
1 H-NMR (250 MHz,
CDCl3) δ (ppm): 1.29 (t, J = 7.5 Hz, 3H, CH3 of Et), 2.74 (q, J = 7.5 Hz, 2H, CH2 of Et), 3.61 and 3.89 (AB
quartet, 4H, J = 13.75 Hz, 2CH2 of Benzyl groups), 5.48 (s, 1H, CH aliphatic), 7.28-7.98 (m, 18H, H-arom),
10.03 (s, 1H, CHO). 13 C-NMR (62.5 MHz, CDCl3) δ (ppm): 17.0 (CH3), 28.9 (CH2 , Ethyl), 54.6 (2CH2 of
Benzyl groups), 59.8 (CH, aliphatic), 127.1, 127.4, 128.5, 128.6, 128.8, 129.1 and 129.8 (18CH, arom), 126.82,
134.7, 136.1, 138.3 and 141.9 (3C, arom), 163.4 and 167.1 (2C=N of oxadiazole), 191.9 (C=O of aldehyde).
Anal. Calcd for C32 H29 N3 O2 (487.6): C 78.82, H 5.99, N 8.62; Found: C 78.88, H 5.93, N 8.57.
3–{[Benzyl(methyl)amino][(5-(3,5-dimethylphenyl)-1,3,4-oxadiazol-2-yl]methyl}benzaldehyde (5g)
Yellow oil, (Yield 84%). IR (neat) νmax = 2947, 1707, 1612, 1554, 1456 and 743 cm−1
.
1 H-NMR (250 MHz,
CDCl3) δ (ppm): 2.30 and 2.39 (2s, 9H, 3CH3), 3.60 and 3.68 (AB quartet, 2H, J = 13 Hz, CH2 of benzyl
group), 5.32 (s, 1H, CH aliphatic), 7.17-8.08 (m, 12H, H-arom), 10.04 (s, 1H, CHO). 13 C-NMR (62.5 MHz,
CDCl3) δ (ppm): 21.2 and 39.0 (3CH3), 58.8 (CH2 of benzyl group), 63.5 (CH, aliphatic), 124.7, 128.4, 128.8,
129.5, 129.8, 130.79 and 132.3 (12CH of arom), 123.3, 127.4, 133.7, 136.8 and 138.8 (5C of arom), 161.9 and
165.7 (2C=N of oxadiazole), 191.9 (C=O of aldehyde). Anal. Calcd for C26 H25 N3 O2 (411.5): C 75.89, H
6.12, N 10.21; Found: C 75.81, H 6.19, N 10.25.
4–{[Benzyl(methyl)amino][(5-(2,5-dimethylphenyl)-1,3,4-oxadiazol-2-yl]methyl}benzaldehyde (5h)
Yellow oil, (Yield 82%). IR (neat) νmax = 2943, 1706, 1614 and 834 cm−1
.
1 H-NMR (250 MHz, CDCl3) δ
(ppm): 2.29, 2.38 and 2.66 (3s, 9H, 3CH3), 3.66 (s, 2H, CH2 of benzyl group), 5.31 (s, 1H, CH aliphatic),
7.11-7.92 (m, 12H, H-arom), 10.01 (s, 1H, CHO). 13 C-NMR (62.5 MHz, CDCl3) δ (ppm): 21.4, 22.0 and 39.2
(3CH3), 58.9 (CH2 of benzyl group), 63.7 (CH, aliphatic), 119.9, 126.9, 127.4, 128.4, 128.7, 129.0, 130.0 and
132.5 (12CH of arom), 124.4, 127.6, 132.5, 136.2, 138.7 and 142.0 (6C of arom), 163.5 and 164.68 (2C=N of
oxadiazole), 191.7 (C=O of aldehyde). Anal. Calcd for C26 H25 N3 O2 (411.5): C 75.89, H 6.12, N 10.21; Found:
C 75.83, H 6.18, N 10.16.
3–{[Benzyl(ethyl)amino][(5-(3,4-dimethylphenyl)-1,3,4-oxadiazol-2-yl]methyl}benzaldehyde (5i)
Yellow oil, (Yield 86%). IR (neat) νmax = 2977, 1702, 1606, 1495, 1143 and 740 cm−1
.
1 H-NMR (250 MHz,
CDCl3) δ (ppm): 1.13 (t, 3H, CH3 of Et), 2.33 (s, 6H, 2CH3), 2.55 and 2.76 (2q, 2H, CH2 of Et), 3.58
and 3.90 (AB quartet, 2H, J = 13.75 Hz, CH2 of Benzyl groups), 5.49 (s, 1H, CH aliphatic), 7.28-8.01 (m,
12H, H-arom), 10.0 (s, 1H, CHO). 13 C-NMR (62.5 MHz, CDCl3) δ (ppm): 12.7, 19.7 and 19.9 (3CH3), 44.5
(CH2 , Ethyl), 54.5 (CH2 of Benzyl groups), 59.9 (CH); 134.2, 136.6, 137.6, 137.6, 138.1 and 141.2 (6C, arom),
121.1, 124.52, 127.2, 127.9, 128.4, 128.6, 129.1, 129.2, 129.6 and 130.2 (12CH, arom), 164.8 and 165.6 (2C=N of
oxadiazole), 191.9 (C=O of aldehyde). Anal. Calcd for C27 H27 N3 O2 (425.5): C 76.21, H 6.40, N 9.87; Found:
C 76.28, H 6.35, N 9.82.
85

Four-component synthesis of 1,3,4-oxadiazole derivatives from..., A. RAMAZANI, et al.
4–{[Benzyl(ethyl)amino][(5-(4-ethylphenyl)-1,3,4-oxadiazol-2-yl]methyl}benzaldehyde (5j)
Yellow oil, (Yield 83%). IR (neat) νmax = 2971, 1704, 1612, 1501, 1212 and 844 cm−1
.
1 H-NMR (250 MHz,
CDCl3) δ (ppm): 1.11 and 1.27 (2t, J = 7.5 Hz, 6H, CH3 of Et), 2.52 and 2.69 (2q, J = 7.5 Hz, 4H, CH2 of
Et), 3.57 and 3.91 (AB quartet, 4H, J = 13.75 Hz, 2CH2 of Benzyl groups), 5.49 (s, 1H, CH aliphatic), 7.29-
8.01 (m, 13H, H-arom), 10.01(s, 1H, CHO). 13 C-NMR (62.5 MHz, CDCl3) δ (ppm): 12.6 and 15.2 (2CH3),
28.9 and 44.6 (2CH2 , Ethyl), 54.5 (CH2 of Benzyl groups), 60.1 (CH, aliphatic), 121.2, 127.7, 136.1, 140.0 and
148.81 (5C, arom), 127.0, 128.4, 128.6, 128.8, 129.4, 129.9 and 130.1 (13CH, arom), 163.4 and 165.2 (2C=N of
oxadiazole); 191.4 (C=O of aldehyde). Anal. Calcd for C27 H27 N3 O2 (425.5): C 76.21, H 6.40, N 9.87; Found:
C 76.26, H 6.37, N 9.91.
3–{[Dibenzylamino][(5-(4-methylphenyl)-1,3,4-oxadiazol-2-yl]methyl}benzaldehyde (5k)
Yellow oil, (Yield 85%). IR (neat) νmax = 3068, 2951, 1707, 1619, 1498 and 700 cm−1
.
1 H-NMR (250 MHz,
CDCl3) δ (ppm): 2.45 (s, 3H, CH3), 3.61 and 3.89 (AB quartet, 4H, J = 13.5 Hz, 2CH2 of dibenzyl group),
5.48 (s, 1H, CH aliphatic), 7.34-8.01 (m, 18H, H-arom), 10.02 (s, 1H, CHO). 13 C-NMR (62.5 MHz, CDCl3) δ
(ppm): 21.6 (CH3), 54.6 (2CH2 of benzyl group), 59.0 (CH, aliphatic), 126.9, 127.4, 128.5, 128.8, 128.9, 129.3,
129.4, 129.7 and 129.8 (18CH of arom), 121.5, 134.4, 136.5, 138.3, 142.9 (6C of arom), 163.6 and 165.6 (2C=N
of oxadiazole), 191.9 (C=O of aldehyde). Anal. Calcd for C31 H27 N3 O2 (473.6): C 78.62, H 5.75, N 8.87;
Found: C 78.57, H 5.79, N 8.83.
3 –{[benzyl(isopropyl)amino][(5-(3,4-dimethylphenyl)-1,3,4-oxadiazol-2-yl]methyl}benzaldehyde
(5l)
Yellow oil, (Yield 87%). IR (neat) νmax = 2976, 1703, 1611, 1485 and 768 cm−1 1 H-NMR (250 MHz, CDCl3)
.
δ (ppm): 0.95 (d, 3H,J = 6.25 Hz, CH3 amin), 1.17 (d, 3H, J = 6.25 Hz, CH3 amin), 2.32 (s, 6H, 2CH3),
3.15-3.20 (m, 1H, CH amin), 3.82 and 3.91 (AB quartet, 2H, J = 15 Hz, CH2 of dibenzyl group), 5.51 (s, 1H,
CH aliphatic), 7.05-8.03 (m, 12H, H-arom), 9.99 (s, 1H, CHO). 13 C-NMR (62.5 MHz, CDCl3) δ (ppm): 18.8,
19.2, 19.7 and 19.9 (4CH3), 53.4 (CH2 of benzyl group), 50.0 and 58.7 (CH, aliphatic), 124.4, 126.8, 127.8,
128.1, 128.3, 129.2, 129.6, 129.9, 130.1 and 131.0 (12CH of arom), 134.2, 134.6, 136.6, 136.98, 137.42 and 141.0
(6C of arom), 161.2 and 163.4 (2C=N of oxadiazole), 191.0 (C=O of aldehyde). Anal. Calcd for C28 H29 N3 O2
(439.5): C 76.51, H 6.65, N 9.56; Found: C 76.55, H 6.59, N 9.61.
Results and discussion
The 1:1 imine intermediate generated by the addition of secondary amine 3 with bis-aldehydes (isophtha-
laldehyde and terphthalaldehyde) 2 is trapped by the N -isocyaniminotriphenylphosphorane in the presence
of aromatic carboxylic acid derivatives 1, which leads to the formation of 1,3,4-oxadiazole derivative 5 and
triphenylphosphine oxide 6 (Scheme 1 and Table). The reaction proceeds smoothly and cleanly under mild
conditions and no side reactions were observed.
86

Four-component synthesis of 1,3,4-oxadiazole derivatives from..., A. RAMAZANI, et al.
Table. Synthesis of disubstituted 1,3,4-oxadiazole derivatives 5 (See Scheme 1).
Yield
5
a
Ar
R
Bis-aldehyde
Product
(%)a
OHC
N
N
N
4-BrC6H4
C6H5
90
O
Br
CHO
OHC
CH3
OHC
N
N
N
O
CH3
b
c
4-MeC6H4
4-BrC6H4
CH3CH2
CH3CH2
84
85
CHO
OHC
OHC
CH3
N
N
N
O
CHO
Br
OHC
OHC
CH3
N
N
N
d
e
4-MeC6H4
4-BrC6H4
CH3
CH3
O
88
83
CH3
CHO
OHC
OHC
OHC
CH3
N
N
N
O
Br
OHC
OHC
N
N
N
N
f
4-EtC6H4
C6H5
CH3
O
86
84
CHO
H3C
OHC
OHC
OHC
CH3
N
CH3
N
g
3,5-diMeC6H4
O
CH3
OHC
87

Four-component synthesis of 1,3,4-oxadiazole derivatives from..., A. RAMAZANI, et al.
Table. Continued.
Yield
(%)a
5
h
Ar
R
Bis-aldehyde
Product
CH3
H3
C
OHC
N
N
N
O
2,4-diMeC6H4
CH3
82
CH3
CHO
OHC
CH3
OHC
OHC
CH3
CH3
N
N
N
i
j
3,4-diMeC6H4
4-EtC6H4
CH3CH2
CH3CH2
86
O
OHC
OHC
CH3
N
N
N
83
O
CHO
H3C
OHC
OHC
OHC
N
N
N
k
l
4-MeC6H4
C6H5
85
87
O
CH3
OHC
H3
CH3
C
OHC
OHC
CH3
CH3
N
N
N
3,4-diMeC6H4
(CH3)CH
O
OHC
a Yield of isolated 5.
The suggested mechanism for this reaction is provided in Scheme 2. It is conceivable that the initial
event is the condensation of the bis-aldehyde 2, secondary amine 3, and aromatic carboxylic acid 1 entities
to an intermediate iminium ion 7. Nucleophilic addition of the N -isocyaniminotriphenylphosphorane 4 to
the intermediate iminium ion 7 leads to nitrilium intermediate 8. This intermediate may be attacked by the
conjugate base of the acid 1 to form 1:1:1:1 adduct 9. This adduct may undergo an intramolecular aza-Wittig
reaction of an iminophosphorane moiety with the ester carbonyl group to afford the isolated 2,5-disubstituted
1,3,4-oxadiazole 5 by removal of triphenylphosphine oxide 6 from intermediate 10.
The structures of the products 5a-l were deduced from their IR, 1 HNMR, and 13 CNMR spectra. For
example the IR spectrum of 5a showed strong absorptions at 2980 (CH), 1704 (C=O, aldehyde) 1482 (C=C,
aromatic) and 799 (aromatic) cm−1 . The 1 HNMR spectrum of 5a consisted of an AB-quartet for 2 CH2 of
the benzyl group (δ = 3.66 and 3.89 ppm, J = 13.75 Hz), a singlet for the CH aliphatic (δ = 5.50 ppm), a
88

Four-component synthesis of 1,3,4-oxadiazole derivatives from..., A. RAMAZANI, et al.
CHO
O
R
N
- H2O
ArCO2H
+
+
O
Ar
N
H
NH
R
CHO
1
3
2
C
N
P(Ph)3
(meta and para isomers)
7
OHC
4
O
R
C
O
Ar
N
R
N
N
Ar
O
N
8
N
OHC
O
9
P(Ph)3
N
OHC
P(Ph)3
OHC
N
O
N
P(Ph)3
Ar
R
N
N
N
(Ph) P
O
3
+
O
6
O
N
Ar
R
5
OHC
10
Scheme 2. Proposed mechanism for the formation of sterically congested 1,3,4-oxadiazole derivatives 5a-l.
multiplet for H-Ar (7.28-7.92 ppm), and a singlet for CH of the aldehyde group (δ = 10.11 ppm). The 1 H
decoupled 13 CNMR spectrum of 5a showed 17 distinct resonances [δ = 54.8 (2 CH2 , benzyl group); 595 (1 CH,
aliphatic); 122.5, 126.7, 136.2, 138.2 and 143.3 (6 C, arom.); 127.5, 128.4, 128.5, 128.8, 129.1, 129.9 and 132.5
(18 CH, arom.); 1641 and 1646 (2 C, oxadiazole); 191.6 (1 C=O, aldehyde)] that are in agreement with the
formula and structure of 5a. Partial assignment of these resonances is given in the spectral analysis section (see
Experimental section). The 1 H and 13 CNMR spectra of compounds 5bl were similar to those of 5a, except
for the aromatic or heteroaromatic moieties, which exhibited characteristic signals with appropriate chemical
shifts.
89

Four-component synthesis of 1,3,4-oxadiazole derivatives from..., A. RAMAZANI, et al.
Conclusions
In summary, the previously developed method was extended to bis-aldehyde for the preparation of sterically
congested 2,5-disubstituted 1,3,4-oxadiazole derivatives 5 from aromatic carboxylic acids 1, bis-aldehyde 2,
secondary amine 3, and N -isocyaniminotriphenylphosphorane 4 in excellent yields under neutral conditions.
Its ease of work-up and reaction conditions make it a useful addition to modern synthetic methodologies.
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 availability of the synthetic approach and the neutral ring closure conditions,
this new synthetic approach discussed here has potential in the synthesis of various 2,5-disubstituted 1,3,4-
oxadiazoles, which are of considerable interest as potential biologically active compounds or pharmaceuticals.
Other aspects of this process are under investigation.
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