A one-pot efficient four-component reaction for the synthesis of 2-(arylamino)-2-(5-aryl-1-ethenyl-1,3,4-oxadiazol-2-yl)propyl benzoate (or 4-bromobenzoate) derivatives

Article abstract of DOI:10.3906/kim-1111-45

Reactions of N-isocyaniminotriphenylphosphorane with 2-oxopropyl benzoate (or 2-oxopropyl 4-bromobenzoate) in the presence of 3-phenyl-2-propynoic acid and primary amines proceeded smoothly at room temperature and in neutral conditions to afford sterically congested 1,3,4-oxadiazole derivatives in high yields. The reaction proceeded smoothly and cleanly under mild conditions and no side reactions were observed. TUeBITAK, 2012.

Full text of DOI:10.3906/kim-1111-45

Turk J Chem
36 (2012) , 671 – 681.
¨
˙
c
ꢀ TUBITAK
doi:10.3906/kim-1111-45
A one-pot efficient four-component reaction for the
synthesis of 2-(arylamino)-2-(5-aryl-1-ethenyl-1,3,4-
oxadiazol-2-yl)propyl benzoate (or 4-bromobenzoate)
derivatives
Mohsen VALIZADEH HOLAGH1, Abel Mohammadalioglu MAHARRAMOV1,
Mirza Aliakbaroglu ALLAHVERDIYEV1, Ali RAMAZANI2,∗, Yavar AHMADI3,
Fatemeh ZEINALI NASRABADI2, Ali SOULDOZI4
1Chemistry Department, Baku State University, P O Box AZ 1148, Baku-AZERBAIJAN REPUBLIC
2Department of Chemistry, University of Zanjan, P O Box 45195-313, Zanjan-IRAN
e-mail: aliramazani@gmail.com
3Young Researchers Club, Zanjan Branch, Islamic Azad University, Zanjan-IRAN
4Department of Chemistry, Urmia Branch, Islamic Azad University, P O Box 969, Urmia-IRAN
Received: 26.11.2011
Reactions of N -isocyaniminotriphenylphosphorane with 2-oxopropyl benzoate (or 2-oxopropyl 4-bromo-
benzoate) in the presence of 3-phenyl-2-propynoic acid and primary amines proceeded smoothly at room
temperature and in neutral conditions to afford sterically congested 1,3,4-oxadiazole derivatives in high
yields. The reaction proceeded smoothly and cleanly under mild conditions and no side reactions were
observed.
Key Words: 2-Oxopropyl benzoate, 2-oxopropyl 4-bromobenzoate, 3-phenyl-2-propynoic acid, 1,3,4-oxadiazole,
N -isocyaniminotriphenylphosphorane
Introduction
A multicomponent reaction (MCR) is a chemical reaction in which 3 or more compounds react to form a single
product. By definition, MCRs are those reactions whereby more than 2 reactants combine in a sequential manner
to give highly selective products that retain the majority of the atoms of the starting material. The development
∗Corresponding author
671

A one-pot efficient four-component reaction for the synthesis of..., M. VALIZADEH HOLAGH, et al.
of novel MCRs is receiving growing interest from industrial chemistry research groups and represents a challenge
for organic chemists.1,2 The drive toward the ideal synthesis embracing step count, ideally just one, and yield,
ideally 100%, has been pursued aggressively since scientists began to construct molecules. Of course, there are
many other factors that affect these 2 aspects of synthesis, including cost; starting material availability; safety;
environmental concerns; and overall ease of the process, including work up and purification.3 The nature of
the synthesis project also plays a role. Complex molecule total synthesis is often driven by step count while
showcasing innovative chemistry. Traditional structure-activity relationship evaluations in medicinal chemistry
typically involve the preparation of an advanced intermediate that can be analogued readily to introduce the
molecular diversity necessary to prepare a collection, or library, of structurally related compounds. One strategy
that potentially meets the goals of total synthesis and library production is multicomponent reaction (MCR)
chemistry, in which 3 or more starting materials are brought together in a highly convergent approach to rapidly
build up molecular structure and complexity.4
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 pharmaceu-
tical and biological activities including antimicrobial, antifungal, antiinflammatory, and antihypertensive.5−9
Several methods have been reported in the literature for the synthesis of 1,3,4-oxadiazoles. These
protocols are multi-step in nature.10−15 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 synthesis of 1,3,4-oxadiazoles, especially from readily available carboxylic acids and acid hydrazides.16−21
As part of our ongoing program to develop efficient and robust methods for the preparation of heterocyclic
compounds,22−36 we wish to report the synthesis of sterically congested 2,5-disubstituted 1,3,4-oxadiazoles 7
by a multicomponent reaction between (N -isocyanimino)triphenylphosphorane 6, various primary amines 5,
electron-poor ketones 3 (2-oxopropyl benzoate and 2-oxopropyl 4-bromobenzoate), and 3-phenyl-2-propynoic
acid 4, followed by aza-Wittig cyclization in CH2 Cl2 at ambient temperature in excellent yields (Scheme 1 and
Figure and Table).
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. 2-Oxopropyl benzoate
(or 4-bromobenzoate) 338 and N -isocyaniminotriphenylphosphorane 612,13 were prepared based on known
procedures.
672

A one-pot efficient four-component reaction for the synthesis of..., M. VALIZADEH HOLAGH, et al.
General procedure for the preparation of compounds 7
A mixture of (N -isocyanimino)triphenylphosphorane 6 (1 mmol), (2-oxopropyl benzoate and 2-oxopropyl 4-
bromobenzoate) 3 (1 mmol), and primary amine 5 (1 mmol) in CH2 Cl2 (5 mL) was added dropwise to a solution
of 3-phenyl-2-propynoic acid 4 (1 mmol) in CH2 Cl2 (5 mL) at room temperature over 15 min. The mixture
was stirred for 6 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:
2-(benzylamino)-2-[5-(2-phenyl-1-ethynyl)-1,3,4-oxadiazol-2-yl]propyl benzoate (7a)
Yellow oil, (Yield 82%). IR (neat): νmax = 3350 (NH), 2920 (C-H), 2230 (C≡C), 1723 (C=O), 1453 (C=C,
aromatic), 1265 (C-O) and 708 (aromatic) cm−1
.
1 H-NMR (250 MHz, CDCl3) δ (ppm): 1.79 (s, 3H, CH3),
2.24 (s, 1H, NH), 3.77 and 3.83 (AB quartet, 2H, J = 12.50 Hz, CH2 of benzyl group), 4.58 and 4.68 (AB
quartet, J = 11.0 Hz, 2H, CH2 aliphatic), 7.27-7.99 (m, 15 H, arom.). 13 C-NMR (62.5 MHz, CDCl3) δ
(ppm): 20.9 (CH3), 47.7 (CH2 of benzyl group), 56.9 (C aliphatic), 69.0 (CH2 aliphatic), 72.8 and 97.2 (2 C,
acetylene), 119.6, 129.4 and 139.5 (3 C, arom.), 127.2, 128.1, 128.4, 128.5, 128.7, 129.7, 130.1, 132.5 and 133.3
(15 CH, arom.), 151.6 and 165.8 (2C of oxadiazole), 168.6 (C of benzoate group). Analysis of C27 H23 N3 O3
(437.50): calcd. C 74.12, H 5.30, N 9.60; found C 74.16, H 5.25, N 9.63. MS, m/z(%): 438 (M+ , 1.85), 392
(2), 332 (3), 302 (33), 284 (18), 211 (30), 179 (70), 148 (100), 135 (89), 114 (64), 91 (63), 77 (98), 51 (57).
2-[(4-methoxybenzyl)amino]-2-[5-(2-phenyl-1-ethynyl]-1,3,4-oxadiazol-2-yl]propyl benzoate (7b)
Yellow oil, (Yield 79%). IR (neat): νmax = 3431 (NH), 2930 (C-H), 2233 (C≡C), 1723 (C=O), 1451 (C=C,
aromatic), 1265 (C-O) and 710 (aromatic) cm−1
.
1 H-NMR (250 MHz, CDCl3) δ (ppm):1.78 (s, 3H, CH3),
2.24 (s, 1H, NH), 3.69 and 3.75 (AB quartet, 2H, J = 12.0 Hz, CH2 of benzyl group), 3.77 (s, 3H, OCH3),
4.57 and 4.66 (AB quartet, J = 11.0 Hz, 2H, CH2 aliphatic), 6.84 (d, J = 8.50 Hz, 2H, CH-Ar), 7.24-7.64 (m,
10 H, arom.), 7.97 (d, J = 7.25 Hz, 2H, CH-Ar). 13 C-NMR (62.5 MHz, CDCl3) δ (ppm): 20.9 (CH3), 47.1
(CH2 of benzyl group), 55.2 (OCH3), 56.8 (C aliphatic), 69.0 (CH2 aliphatic), 72.8 and 96.8 (2 C, acetylene),
119.6, 129.5, 131.5 and 158.8 (4 C, arom.), 113.9, 128.4, 128.6, 129.3, 129.6, 130.7, 132.3 and 133.3 (14 CH,
arom.), 151.3 and 165.8 (2C of oxadiazole), 168.7 (C of benzoate group). Analysis of C28 H25 N3 O4 (467.50):
calcd. C 71.93, H 5.39, N 8.99; found C 71.87, H 5.42, N 9.02. MS, m/z(%): 468 (M+ , 59), 333 (3), 291 (51),
211 (7), 136 (35), 121 (100), 105 (92), 91 (9), 77 (42).
2-[(4-methylbenzyl)amino]-2-[5-(2-phenyl-1-ethynyl]-1,3,4-oxadiazol-2-yl}propyl benzoate (7c)
Yellow oil, (Yield 75%). IR (neat): νmax = 3425 (NH), 2924 (C-H), 2231 (C≡C), 1723 (C=O), 1450 (C=C,
aromatic), 1268 (C-O) and 710 (aromatic) cm−1
.
1 H-NMR (250 MHz, CDCl3) δ (ppm): 1.77 and 2.30 (s,
6H, 2CH3), 2.23 (s, 1H, NH), 3.70 and 3.77 (AB quartet, 2H, J = 12.50 Hz, CH2 of benzyl group), 4.56 and
4.66 (AB quartet, J = 11.0 Hz, 2H, CH2 aliphatic), 7.10 (d, J = 7.75 Hz, 2H, CH-Ar), 7.21 (d, J = 7.75 Hz,
2H, CH-Ar), 7.31-8.10 (m, 10 H, arom.). 13 C-NMR (62.5 MHz, CDCl3) δ (ppm): 20.8 and 21.0 (2 CH3), 47.4
673

A one-pot efficient four-component reaction for the synthesis of..., M. VALIZADEH HOLAGH, et al.
(CH2 of benzyl group), 56.8 (C aliphatic), 69.0 (CH2 aliphatic), 72.8 and 97.1 (2 C, acetylene), 119.6, 129.8,
136.4 and 136.9 (4 C, arom.), 128.1, 128.4, 128.6, 129.1, 129.6, 130.7, 132.3 and 133.3 (14 CH, arom.), 154.5
and 165.8 (2C of oxadiazole), 168.7 (C of benzoate group). Analysis of C28 H25 N3 O3 (451.50): calcd. C 74.48,
H 5.58, N 9.31; found C 74.52, H 5.53, N 9.34. MS, m/z(%): 451 (M+ , 64), 387 (7), 317 (14), 276 (68), 210
(5), 129 (6), 120 (20), 105 (100), 77 (32).
2-[(4-methylbenzyl)amino]-2-[5-(2-phenyl-1-ethynyl]-1,3,4-oxadiazol-2-yl}propyl 4-bromobenzoate
(7d)
Yellow oil, (Yield 73%). IR (neat): νmax = 3445 (NH), 2922 (C-H), 2230 (C≡C), 1722 (C=O), 1538 (C=C,
aromatic), 1264 (C-O) and 753 (aromatic) cm−1
.
1 H-NMR (250 MHz, CDCl3) δ (ppm): 1.77 and 2.31 (s,
6H, 2CH3), 2.23 (s, 1H, NH), 3.70 and 3.77 (AB quartet, 2H, J = 12.25 Hz, CH2 of benzyl group), 4.55 and
4.66 (AB quartet, J = 11.0 Hz, 2H, CH2 aliphatic), 7.10-7.63 (m, 11H, arom.), 7.82 (d, J = 7.25 Hz, 2H,
CH-Ar). 13 C-NMR (62.5 MHz, CDCl3) δ (ppm): 20.8 and 21.0 (2 CH3), 47.4 (CH2 of benzyl group), 56.8
(C aliphatic), 69.2 (CH2 aliphatic), 72.7 and 97.1 (2 C, acetylene), 119.6, 129.3, 129.5, 136.3 and 136.9 (5 C,
arom.), 128.1, 128.5, 129.2, 130.7, 131.1, 131.8 and 132.3 (13 CH, arom.), 151.7 and 165.1 (2C of oxadiazole),
168.5 (C of benzoate group). Analysis of C28 H24 BrN3 O3 (530.4): calcd. C 63.40, H 4.56, N 7.92; found C
63.46, H 4.52, N 7.97.
2-[(2-chlorobenzyl)amino]-2-[5-(2-phenyl-1-ethynyl]-1,3,4-oxadiazol-2-yl]propyl benzoate (7e)
Yellow oil, (Yield 72%). IR (neat): νmax = 3432 (NH), 2926 (C-H), 2231 (C≡C), 1724 (C=O), 1540
(C=C, aromatic), 1269 (C-O), 710 (aromatic) cm−1
.
1 H-NMR (250 MHz, CDCl3) δ (ppm): 1.81 (s, 3H,
CH3), 2.24 (s, 1H, NH), 3.90 (s, 2H, CH2 of benzyl group), 4.60 and 4.70 (AB quartet, J = 10.75 Hz, 2H,
CH2 aliphatic), 7.19-8.11 (m, 14 H, arom.). 13 C-NMR (62.5 MHz, CDCl3) δ (ppm): 20.7 (CH3), 45.1 (CH2
of benzyl group), 56.7 (C aliphatic), 68.8 (CH2 aliphatic), 72.7 and 97.1 (2 C, acetylene), 119.7, 129.4, 129.8
and 133.6 (4 C, arom.), 127.0, 128.4, 128.6, 129.5, 129.7, 130.2, 130.6, 132.3, 133.3 and 136.8 (14 CH, arom.),
151.3 and 165.7 (2C of oxadiazole), 168.4 (C of benzoate group). Analysis of C27 H22 ClN3 O3 (471.9): calcd.
C 68.71, H 4.70, N 8.90; found C 68.77, H 4.65, N 8.94.
2-[(2-furylmethyl)amino]-2-[5-(2-phenyl-1-ethynyl]-1,3,4-oxadiazol-2-yl]propyl 4-bromobenzoate
(7f)
Yellow oil, (Yield 78%). IR (neat): νmax = 3341 (NH), 2926 (C-H), 2231 (C≡C), 1724 (C=O), 1590 (C=C,
aromatic) and 754 (aromatic) cm−1
.
1 H-NMR (250 MHz, CDCl3) δ (ppm): 1.76 (s, 3H, CH3), 2.24 (s, 1H,
NH), 3.84 (s, 2H, CH2 of benzyl group), 4.52 and 4.63 (AB quartet, J = 11.0 Hz, 2H, CH2 aliphatic), 6.13
and 6.27 (s, 2H, CH of furyl), 7.25-7.84 (m, 10H, arom.). 13 C-NMR (62.5 MHz, CDCl3) δ (ppm): 20.6 (CH3),
40.4 (CH2 of benzyl group), 56.3 (C aliphatic), 69.1 (CH2 aliphatic), 72.8 and 96.7 (2 C, acetylene), 119.7,
128.5 , 130.7 and 131.9 (4 C, arom.), 107.2, 110.3, 128.6, 128.7, 131.1, 131.8, 132.3 and 142.0 (12 CH, arom.),
152.6 and 165.7 (2C of oxadiazole), 168.2 (C of benzoate group). Analysis of C25 H20 BrN3 O4 (506.3): calcd.
C 59.30, H 3.98, N 8.30; found C 59.27, H 4.02, N 8.25.
674

A one-pot efficient four-component reaction for the synthesis of..., M. VALIZADEH HOLAGH, et al.
2-[(2-methoxybenzyl)amino]-2-[5-(2-phenyl-1-ethynyl]-1,3,4-oxadiazol-2-yl]propyl 4-bromobenzoa-
te (7g)
Yellow oil, (Yield 70%). IR (neat): νmax = 3340 (NH), 2939 (C-H), 2231 (C≡C), 1724 (C=O), 1538 (C=C,
aromatic), 1269 (C-O) and 711 (aromatic) cm−1
.
1 H-NMR (250 MHz, CDCl3) δ (ppm): 1.80 (s, 3H, CH3),
2.22 (s, 1H, NH), 3.77 (s, 2H, CH2 of benzyl group), 3.79 (s, 3H, OCH3), 4.61 (s, 2H, CH2 aliphatic), 6.79-7.93
(m, 13 H, arom.). 13 C-NMR (62.5 MHz, CDCl3) δ (ppm): 20.5 (CH3), 43.2 (CH2 of benzyl group), 55.1
(OCH3), 56.4 (C aliphatic), 69.1 (CH2 aliphatic), 72.9 and 96.9 (2 C, acetylene), 119.7, 127.1, 131.5, 131.8 and
157.3 (5 C, arom.), 110.2, 120.6, 128.4, 128.7, 129.8, 130.6, 131.1, 131.8 and 132.2 (13 CH, arom.), 151.1 and
165.0 (2C of oxadiazole), 168.6 (C of benzoate group). Analysis of C28 H24 BrN3 O4 (546.4): calcd. C 61.55, H
4.43, N 7.69; found C 61.58, H 4.37, N 7.73.
2-[(2-methoxybenzyl)amino]-2-[5-(2-phenyl-1-ethyenyl]-1,3,4-oxadiazol-2-yl]propyl benzoate (7h)
Yellow oil, (Yield 71%). IR (neat): νmax = 3433 (NH), 2930 (C-H), 2231 (C≡C), 1724 (C=O), 1569 (C=C,
aromatic), 1267 (C-O) and 709 (aromatic) cm−1
.
1 H-NMR (250 MHz, CDCl3) δ (ppm): 1.82 (s, 3H, CH3),
2.25 (s, 1H, NH), 3.74 and 3.81 (AB quartet, 2H, J = 12.37 Hz, CH2 of benzyl group), 3.79 (s, 3H, OCH3),
4.57 and 4.64 (AB quartet, J = 11.25 Hz, 2H, CH2 aliphatic), 6.79-8.0 (m, 14 H, arom.). 13 C-NMR (62.5
MHz, CDCl3) δ (ppm): 20.5 (CH3), 43.3 (CH2 of benzyl group), 55.1 (OCH3), 56.5 (C aliphatic), 68.96 (CH2
aliphatic), 72.9 and 96.9 (2 C, acetylene), 119.7, 127.2, 129.5 and 157.3 (4 C, arom.), 110.2, 120.6, 128.4, 128.7,
129.1, 129.6, 129.8, 130.6, 132.2 and 133.2 (14 CH, arom.), 151.1 and 165.7 (2C of oxadiazole), 168.7 (C of
benzoate group). Analysis of C28 H25 N3 O4 (467.5): calcd. C 71.93, H 5.39, N 8.99; found C 71.88, H 5.42, N
8.95.
2-[(2-furylmethyl)amino]-2-[5-(2-phenyl-1-ethynyl]-1,3,4-oxadiazol-2-yl]propyl benzoate (7i)
Yellow oil, (Yield 77%). IR (neat): νmax = 3433 (NH), 2925 (C-H), 2231 (C≡C), 1724 (C=O), 1450 (C=C,
aromatic), 1269 (C-O) and 711 (aromatic) cm−1
.
1 H-NMR (250 MHz, CDCl3) δ (ppm): 1.78 (s, 3H, CH3),
2.24 (s, 1H, NH), 3.85 (s, 2H, CH2 of benzyl group), 4.55 and 4.65 (AB quartet, J = 11.50 Hz, 2H, CH2
aliphatic), 6.13-6.27 (m, 2H, CH of furyl), 7.32-7.99 (m, 11H, arom.). 13 C-NMR (62.5 MHz, CDCl3) δ (ppm):
20.6 (CH3), 40.4 (CH2 of benzyl group), 56.4 (C aliphatic), 68.9 (CH2 aliphatic), 119.7, 129.3 and 152.7 (3 C,
arom.), 107.1, 110.3, 128.4, 128.6, 129.6, 130.6, 132.3, 133.3 and 142.0 (13 CH, arom.), 151.3 and 165.7 (2C of
oxadiazole), 168.3 (C of benzoate group). Analysis of C25 H21 N3 O4 (427.50): calcd. C 70.25, H 4.95, N 9.83;
found C 70.28, H 4.91, N 9.89.
2-[(4-methoxybenzyl)amino]-2-[5-(2-phenyl-1-ethynyl]-1,3,4-oxadiazol-2-yl]propyl 4-bromoben-
zoate (7j)
Yellow oil, (Yield 78%). IR (neat): νmax = 3434 (NH), 2931 (C-H), 2230 (C≡C), 1724 (C=O), 1590 (C=C,
aromatic), 1267 (C-O) and 755 (aromatic) cm−1
.
1 H-NMR (250 MHz, CDCl3) δ (ppm): 1.77 (s, 3H, CH3),
2.24 (s, 1H, NH), 3.69 and 3.73 (AB quartet, 2H, J = 11.50 Hz, CH2 of benzyl group), 3.77 (s, 3H, OCH3),
4.56 and 4.67 (AB quartet, J = 11.25 Hz, 2H, CH2 aliphatic), 6.84 (d, J = 8.5 Hz, 2H, CH-Ar), 7.23-7.64
675

A one-pot efficient four-component reaction for the synthesis of..., M. VALIZADEH HOLAGH, et al.
(m, 9 H, arom.), 7.82 (d, J = 8.5 Hz, 2H, CH-Ar). 13 C-NMR (62.5 MHz, CDCl3) δ (ppm): 20.8 (CH3), 47.1
(CH2 of benzyl group), 55.2 (OCH3), 56.8 (C aliphatic), 69.1 (CH2 aliphatic), 72.8 and 96.8 (2 C, acetylene),
119.7, 129.4, 130.7, 132.4 and 158.8 (5 C, arom.), 113.9, 128.1, 129.4, 131.1, 131.2, 131.8 and 132.3 (13 CH,
arom.), 151.4 and 165.8 (2C of oxadiazole), 168.7 (C of benzoate group). Analysis of C28 H24 BrN3 O4 (546.40):
calcd. C 61.55, H 4.43, N 7.69; found C 61.51, H 4.46, N 7.67.
2-[(1-naphthylmethyl)amino]-2-[5-(2-phenyl-1-ethynyl]-1,3,4-oxadiazol-2-yl]propyl benzoate (7k)
Yellow oil, (Yield 70%). IR (neat): νmax = 3435 (N-H), 2921 (C-H), 2241 (C≡C), 1723 (C=O), 1450 (C=C,
aromatic), 1281 (C-O) and 711 (aromatic) cm−1
.
1 H-NMR (250 MHz, CDCl3) δ (ppm): 1.88 (s, 3H, CH3),
2.23 (s, 1H, NH), 4.21 and 4.27 (AB quartet, 2H, J = 12.25 Hz, CH2 of benzyl group), 4.63 and 4.76 (AB
quartet, J = 10.75 Hz, 2H, CH2 aliphatic), 7.41-8.14 (m, 17 H, arom.). 13 C-NMR (62.5 MHz, CDCl3) δ
(ppm): 21.0 (CH3), 45.5 (CH2 of benzyl group), 57.0 (C aliphatic), 68.8 (CH2 aliphatic), 72.8 and 97.2 (2
C, acetylene), 119.7, 129.4, 131.7, 133.8 and 134.9 (5 C, arom.), 123.7, 125.4, 125.7, 126.2, 126.6, 128.2, 128.4,
128.7, 129.7, 130.7, 132.3 and 133.3 (17 CH, arom.), 151.4 and 165.8 (2C of oxadiazole), 168.6 (C of benzoate
group). Analysis of C31 H25 N3 O3 (487.5): calcd. C 76.37, H 5.17, N 8.62; found C 76.40, H 5.22, N 8.68.
Results and discussion
Recently, 1,3,4-oxadiazoles have been the object of intense research in organic synthesis and medicinal chemistry,
and several procedures have been reported for the synthesis of these heterocyclic compounds, which are multi-
step in nature.22 Accordingly, development of a synthetic procedure that could be used to prepare a diversity of
these templates remains a significant task. Over the last few years, several synthetic methods have been reported
for the preparation of N−isocyaniminotriphenylphosphorane (CNNPPh3) 6.12,13 There are several reports
on the use of N -isocyaniminotriphenylphosphorane (CNNPPh3) 6 in the synthesis of metal complexes.12,13
O
O
O
°
DMF, 100 C, 21 h
CH3
+
H3C
CH2Cl
Ar 1
ONa
Ar 1
O
2
1
O
3
O
OH
C
N
N
N
O
NH2
CH2Cl2
3
Ar2
+
+
H3C
+
O
N
r. t., 6 h
Ar 1
O
Ph3PO
+
5
(Ph)3P
N
8
7
H
6
Ar2
4
Scheme 1. Synthesis of 2-oxopropyl benzoate (or 2-oxopropyl 4-bromobenzoate) and 4-component synthesis of disub-
stituted 1,3,4-oxadiazole derivatives 7a-k (see Figure and Table and Text).
676

A one-pot efficient four-component reaction for the synthesis of..., M. VALIZADEH HOLAGH, et al.
However, application of 6 in the synthesis of organic compounds is fairly rare.28−37 In recent years, we have
established a one-pot method for the synthesis of organophosphorus compounds.14−21,37 As part of our ongoing
program to develop efficient and robust methods for the preparation of heterocyclic compounds,22−36 we
wish to report the synthesis of sterically congested 2,5-disubstituted 1,3,4-oxadiazoles 7 by a multicomponent
reaction between (N -isocyanimino)triphenylphosphorane 6, various primary amines 5, electron-poor ketones 3
(2-oxopropyl benzoate and 2-oxopropyl 4-bromobenzoate), and 3-phenyl-2-propynoic acid 4, followed by aza-
Wittig cyclization in CH2 Cl2 at ambient temperature in excellent yields (Scheme 1 and Figure and Table).
N
N
H3C
O
N
N
H3C
O
O
O
N
HN
N
H3C
O
O
O
HN
O
O
HN
OMe
CH3
N
N
H3C
O
N
N
H3C
O
O
O
HN
N
N
H3C
O
O
HN
Cl
O
O
O
HN
Br
O
CH3
Br
Br
N
N
H3C
O
N
N
H3C
O
N
N
O
O
H3C
HN
O
O
O
HN
O
O
HN
H3CO
H3CO
Br
O
N N
O
H3C
HN
N N
H3C
HN
O
O
O
O
O
Br
OCH3
Product
Yield (%)
5a 5b 5c 5d 5e 5f
82 79 75 73 72 78
5g 5h 5i 5j 5k
70 71 77 78 70
Figure. Four-component synthesis of disubstituted 1,3,4-oxadiazole derivatives 7a-k (see Table and Text).
A mechanistic rationalization for this reaction is provided in Scheme 2. It is conceivable that the
initial event is the condensation reaction of the 3-phenyl-2-propynoic acid 4, 2-oxopropyl benzoate (or 4-
bromobenzoate) 3, and primary amine 5 that leads to an intermediate iminium ion 9. Nucleophilic addition of
677

A one-pot efficient four-component reaction for the synthesis of..., M. VALIZADEH HOLAGH, et al.
the N -isocyaniminotriphenylphosphorane 6 to the intermediate iminium ion 9 leads to nitrilium intermediate
10. This intermediate may be attacked by the conjugate base of the acid 4 to form 1:1:1 adduct 11. This
adduct may undergo an intramolecular aza-Wittig reaction of an iminophosphorane moiety with the ester
carbonyl group to afford the isolated disubstituted 1,3,4-oxadiazole 7 by removal of triphenylphosphine oxide 8
from intermediate 12. We also used acetone and acetophenone instead of electron-poor ketones 3 (2-oxopropyl
benzoate and 2-oxopropyl 4-bromobenzoate) 2 in this reaction, but no corresponding products 7 were observed,
and the acetone and acetophenone were recovered unreacted at the end of the reaction. As indicated in the
Table, the reactions proceeded efficiently with an electron-poor ketone 3 and electron-rich ketones such as
acetone and acetophenone are not suitable starting materials in these reactions (Scheme 1).
Table. Synthesis of disubstituted 1,3,4-oxadiazole derivatives 7 (see Scheme 1 and Figure).
Entry
Ketone 3
Amine 5
Acid 4
Product
7a
1
2
2-oxopropyl benzoate
benzylamine
3-phenyl-2-propynoic acid
2-oxopropyl benzoate
4-methoxybenzylamine 3-phenyl-2-propynoic acid
7b
7c
2
2-oxopropyl benzoate
4-methylbenzylamine
4-methylbenzylamine
2-chlorobenzylamine
2-furylmethanamine
3-phenyl-2-propynoic acid
3-phenyl-2-propynoic acid
3-phenyl-2-propynoic acid
3-phenyl-2-propynoic acid
4
2-oxopropyl 4-bromobenzoate
2-oxopropyl 4-bromobenzoate
2-oxopropyl 4-bromobenzoate
7d
7e
5
6
7f
7
2-oxopropyl 4-bromobenzoate 2-methoxybenzylamine 3-phenyl-2-propynoic acid
7g
8
2-oxopropyl benzoate
2-oxopropyl benzoate
2-methoxybenzylamine 3-phenyl-2-propynoic acid
2-furylmethanamine 3-phenyl-2-propynoic acid
7h
7i
9
10
11
2-oxopropyl 4-bromobenzoate 4-methoxybenzylamine 3-phenyl-2-propynoic acid
2-oxopropyl benzoate 1-naphthylmethanamine 3-phenyl-2-propynoic acid
7j
7k
The structures of the products 7a-k were deduced from their IR, 1 HNMR, and 13 CNMR spectra. For
example the IR spectrum of 7a showed strong absorptions at 3350 (NH), 2920 (CH), 2230 (C≡C), 1723 (C=O),
1453 (C=C, aromatic) and 708 (aromatic) cm1 The 1 HNMR spectrum of 7a consisted of a singlet for the CH3
(δ = 1.79 ppm), a singlet for the NH of amine (δ = 2.24 ppm), a AB-quartet for CH2 of the benzyl group
(δ = 3.77 and 3.83 ppm, J = 12.50 Hz), a AB-quartet for CH2 aliphatic (δ = 4.58 and 4.68 ppm, J = 11.0
Hz), and a multiplet for H-Ar (7.27-7.99 ppm). The 1 H decoupled 13 CNMR spectrum of 7a showed 21 distinct
resonances [δ= 20.9 (CH3); 477 (CH2 , benzyl group); 56.9 (C, aliphatic); 69.0 (CH2 , aliphatic); 72.8 and 97.2
(2 C, acetylene); 119.6, 129.4, and 139.5 (3 C, arom.); 127.2, 128.1, 128.4, 128.5, 128.7, 129.7, 130.1, 132.5, and
133.3 (15 CH, arom.); 151.6 and 165.8 (2 C, oxadiazole); 168.6 (C of benzoate group)] that are in agreement
with the formula and structure of 7a. Partial assignment of these resonances is given in the spectral analysis
section (see Experimental section). The 1 H and 13 CNMR spectra of compounds 7b–k were similar to those of
7a, except for the aromatic or heteroaromatic moieties, which exhibited characteristic signals with appropriate
chemical shifts.
In summary, we have found a new method for the preparation of sterically congested 2,5-disubstituted
1,3,4-oxadiazole derivatives 7 from 3-phenyl-2-propynoic acid 4, 2-oxopropyl benzoate (or 4-bromobenzoate) 3,
primary amine 5, and N -isocyaniminotriphenylphosphorane 6 in excellent yields under neutral conditions. We
678

A one-pot efficient four-component reaction for the synthesis of..., M. VALIZADEH HOLAGH, et al.
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.
O
O
Ar2
Ar2
O
H
C
H
N
O
N
- H2O
H3C
3
4
+
5
+
CH3
N
O
C
N
N
P(Ph)3
O
O
N
O
9
6
10
Ar1
P(Ph)3
Ar1
Ar2
P(Ph)3
O
H
N
N
N
Ar2
O
CH3
H
N
O
8
7
+
N
O
O
O
O
N
Ar 1
H3C
11
O
Ar 1
12
P(Ph)3
Scheme 2. Proposed mechanism for the formation of disubstituted 1,3,4-oxadiazole derivatives 7a-k.
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 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.
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