Efficient one-pot, four-component synthesis of N,N-dibenzyl-1-(5-aryl-1,3, 4-oxadiazol-2-yl)cyclobutylamine derivatives from the reaction of (isocyanoimino)triphenylphosphorane, dibenzylamine, an aromatic carboxylic acid and cyclobutanone

Article abstract of DOI:10.2298/JSC111014024S

The four-component reaction of cyclobutanone, dibenzylamine and (isocyanoimino)triphenylphosphorane in the presence of aromatic carboxylic acids proceeds smoothly at room temperature under neutral conditions to afford N,N-dibenzyl-1-(5-aryl-1,3,4-oxadiazo

Full text of DOI:10.2298/JSC111014024S

J. Serb. Chem. Soc. 77 (9) 1175–1180 (2012)
UDC 547.239+542.9+547.857.8+547.78:547.7
JSCS–4342
Original scientific paper
Efficient one-pot, four-component synthesis of N,N-dibenzyl-
-1-(5-aryl-1,3,4-oxadiazol-2-yl)cyclobutylamine derivatives
from the reaction of (isocyanoimino)triphenylphosphorane,
dibenzylamine, an aromatic carboxylic acid and cyclobutanone
*
NAHID SHAJARI , ALI REZA KAZEMIZADEH and ALI RAMAZANI
Research Laboratory of MCRs, Department of Chemistry, Zanjan Branch,
Islamic Azad University, P. O. Box 49195-467, Zanjan, Iran
(Received 14 October 2011)
Abstract: The four-component reaction of cyclobutanone, dibenzylamine and
(isocyanoimino)triphenylphosphorane in the presence of aromatic carboxylic
acids proceeds smoothly at room temperature under neutral conditions to afford
N,N-dibenzyl-1-(5-aryl-1,3,4-oxadiazol-2-yl)cyclobutylamine derivatives in
high yields.
Keywords: multicomponent reaction; isocyanide; 1,3,4-oxadiazole; heterocycles.
INTRODUCTION
There is increasing interest in the chemistry of heterocyclic compounds
because of their vast distribution in natural compounds, their applications in
pharmaceuticals, agrochemicals, and industrial chemicals, etc. 1,3,4-Oxadiazole
derivatives are an important class of heterocycles, which possess pharmaceutical
1-3
4
and biological activities, such as antimicrobial,
antimycobacterial, anti-in-
5
6
7
flammatory, anti-allergic, antifungal and genotoxic activities. Nowadays,
many organic compounds can be synthesized in multicomponent reactions
(MCRs). An important class of MCRs are the isocyanide-based multicomponent
8
reactions (IMCRs). IMCRs are especially interesting because they are more
9–18
diverse and versatile than non-IMCRs.
Several methods have been reported
in the literature for the synthesis of 1,3,4-oxadiazoles. These protocols are multi-
19–21
step in nature.
In recent years, a one-pot method for the synthesis of 1,3,4-
-oxadiazole derivatives from (isocyanoimino)triphenylphosphorane has been es-
22–26
27–30
tablished.
In connection with interest in the synthesis of heterocycles,
the synthesis of N,N-dibenzyl-1-(5-aryl-1,3,4-oxadiazol-2-yl)cyclobutylamine
derivatives via a four-component reaction of cyclobutanone, dibenzylamine, and
*Corresponding author. E-mail: n_shajari120@yahoo.com
doi: 10.2298/JSC111014024S
1175

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SHAJARI, KAZEMIZADEH and RAMAZANI
(isocyanoimino)triphenylphosphorane in the presence of aromatic carboxylic
acids, in high yields and fairly mild reaction conditions, is reported herein (Sche-
me 1).
Scheme 1. Four-component reaction of carboxylic acids, cyclobutanone,
dibenzylamine and (isocyanoimino)triphenylphosphorane.
RESULTS AND DISCUSSION
The four-component reactions of cyclobutanone (2), dibenzylamine (3) and
(isocyanoimino)triphenylphosphorane (4) in the presence of aromatic carboxylic
acids (1) led to N,N-dibenzyl-1-(5-aryl-1,3,4-oxadiazol-2-yl)cyclobutylamine
derivatives (5) in high yields, under fairly mild reaction conditions (Scheme 1
and Table I). A mechanistic rationalization for this reaction is provided in Sche-
me 2. The imine intermediate generated by the reaction of cyclobutanone (2) and
dibenzylamine (3) is protonated with aromatic carboxylic acid (1) to produce
iminium intermediate (7). Nucleophilic addition of the (isocyanoimino)triphenyl-
phosphorane (4) to the iminium ion (7) leads to a nitrilium intermediate (9). The
intermediate 9 may be attacked by the carboxylate anion (8) to form adduct 10.
The adduct 10 may undergo an intramolecular aza-Wittig reaction of an
iminophosphorane moiety with the ester carbonyl group to afford the 1,3,4-
oxadiazole derivatives (5) by the removal of triphenylphosphine oxide (6) from
intermediate (11).
1
13
The structures of the products were deduced from their H-NMR, C-NMR,
1
mass, IR spectra, and elemental analysis. For example the H-NMR spectrum of
5a exhibited distinct signals at δ 1.71–1.92, 2.17–2.38 and 2.40–2.61 ppm (6H,
H
3m) arising from the 3CH groups of cyclobutane, δ 3.65 ppm (4H, s) from the
2
H
2CH groups of benzyl and at δ 7.12–8.18 ppm (15H, m) of the aromatic CH
2
H
13
groups. The C-NMR spectrum of 5a showed 14 distinct resonances arising
from the 3CH of cyclobutane (δ 14.47 and 33.05 ppm), the 2CH of benzyl (δ
2
c
2
c
53.85 ppm), C
of cyclobutane (δ 62.66 ppm), aromatic carbons (δ 124.09,
ipso
c c
126.88, 126.95, 128.01, 129.00, 129.12, 131.74 and 139.65 ppm), 2C=N (δ
c

SYNTHESIS OF N,N-DIBENZYLCYCLOBUTYLAMINE DERIVATIVES
1177
165.47 and 168.55 ppm). The mass spectrum of 5a displayed a molecular ion
peak at m/z = 395. The analytic and spectral data for all the synthesized com-
pounds are given in the Supplementary material to this paper.
TABLE I. Synthesis of N,N-dibenzyl-1-(5-aryl-1,3,4-oxadiazol-2-yl)cyclobutylamine deriva-
tives
Entry
Ar
Product
1
2
3
4
5
6
7
8
C6H5
5a
5b
5c
5d
5e
5f
2-Thienyl
4-ClC6H4
3-ClC6H4
4-BrC6H4
4-FC6H4
4-MeC6H4
3-MeC6H4
5g
5h
O
Ar
O
O
_
(8)
N
Ph
Ph
H2O
ArCO2H
+
+
Ph
N
H
Ph
N N C
(2)
(3)
(1)
Ph3P
(7)
(4)
Ph3P
N N C
N N
Ph3P
N
O
O
_
O
Ph
N
Ar
Ph
(9)
Ph
(10)
Ar
O
(8)
Ph
Ph3P
N N
O
Ph
O
Ar
Ph
N
N
N
N
Ph3PO
+
Ph
O
Ar
Ph
(5)
(6)
(11)
Scheme 2. The proposed mechanism for the formation of 5.
EXPERIMENTAL
The starting materials and solvents were obtained from Merck (Germany) and Fluka
(Switzerland) and were used without further purification. The melting points were measured

1178
SHAJARI, KAZEMIZADEH and RAMAZANI
on an electrothermal 9100 apparatus and are uncorrected. The IR spectra were recorded on a
1
Jasco FT-IR 6300 spectrometer. The H- and 13C-NMR spectra were measured (CDCl3 solu-
tion) with a Bruker DRX-250 Avance spectrometer at 250.0 and 62.5 MHz, respectively. The
mass spectra were recorded on a HP (Agilent Technologies) 5937 mass selective detector at
an ionization potential of 70 eV. The elemental analyses were realized using a Heraeus CHN-
-O-rapid analyzer.
General procedure
To a magnetically stirred solution of cyclobutanone (2, 1 mmol), dibenzylamine (3, 1
mmol) and an aromatic carboxylic acid (1, 1 mmol) in CH3CN (5 mL) was added dropwise a
solution of (isocyanoimino)triphenylphosphorane (4, 1 mmol) in CH3CN (5 mL) at room
temperature over 15 min. The mixture was stirred for 24 h. The solvent was removed under
reduced pressure and the viscous residue was purified by preparative layer chromatography
(silica gel; petroleum ether–ethyl acetate (10:3)). The solvent was removed under reduced
pressure and the products 5a–h were obtained.
CONCLUSIONS
The reported method offers a mild, simple, and efficient route for the prepa-
ration of N,N-dibenzyl-1-(5-aryl-1,3,4-oxadiazol-2-yl)cyclobutylamine derivati-
ves via a four-component reaction of cyclobutanone, dibenzylamine and (isocy-
anoimino)triphenylphosphorane in the presence of an aromatic carboxylic acid in
high yields and under fairly mild reaction conditions.
SUPPLEMENTARY MATERIAL
Analytical and spectral data of the synthesized compounds are available electronically
from http://www.shd.org.rs/JSCS/, or from the corresponding author on request.
Acknowledgment. The authors are thankful to the Zanjan Branch, Islamic Azad Uni-
versity for partial support of this work.
И З В О Д
ЕФИКАСНА СИНТЕЗА ДЕРИВАТА N,N-ДИБЕНЗИЛ-1-(5-АРИЛ-1,3,4-ОКСА-
ДИАЗОЛ-2-ИЛ)ЦИКЛОБУТИЛАМИНА У ЈЕДНОМ РЕАКЦИОНОМ КОРАКУ
ЧЕТВОРОКОМПОНЕНТНЕ РЕАКЦИОНЕ СМЕШЕ – (ИЗОЦИЈАНО-
ИМИНО)ТРИФЕНИЛФОСФОРАН, ДИБЕНЗИЛАМИН, АРОМАТИЧНА
КАРБОКСИЛНА КИСЕЛИНА И ЦИКЛОБУТАНОН
NAHID SHAJARI, ALI REZA KAZEMIZADEH и ALI RAMAZANI
Research Laboratory of MCRs, Department of Chemistry, Zanjan Branch,
Islamic Azad University, P O Box 49195-467, Zanjan, Iran
Реакциона смеша која садржи (изоцијаноимино)трифенилфосфоран, дибензиламин
и циклобутанон, у присуству ароматичних карбоксилних киселина, при собној темпера-
тури, као производ даје деривате N,N-дибензил-1-(5-арил-1,3,4-оксадиазол-2-ил)цикло-
бутиламина у високом приносу.
(Примљено 14. октобра 2011)

SYNTHESIS OF N,N-DIBENZYLCYCLOBUTYLAMINE DERIVATIVES
1179
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