Novel one-pot, four-component condensation reaction: An efficient approach for the synthesis of 2,5-disubstituted 1,3,4-oxadiazole derivatives by a ugi-4CR/ aza -wittig sequence

Article abstract of DOI:10.1021/ol100931q

(Figure presented) A novel and efficient method has been developed for the synthesis of 2,5-disubstituted 1,3,4-oxadiazole derivatives using (N-isocyanimino)triphenylphosphorane, a secondary amine, a carboxylic acid, and an aromatic aldehyde in CH₂Cl₂ at ambient temperature in high yields without using any catalyst or activation. The procedure provides an alternative method to the synthesis of fully substituted 1,3,4-oxadiazole derivatives.

Full text of DOI:10.1021/ol100931q

ORGANIC
LETTERS
2010
Vol. 12, No. 12
2852-2855
Novel One-Pot, Four-Component
Condensation Reaction: An Efficient
Approach for the Synthesis of
2,5-Disubstituted 1,3,4-Oxadiazole
Derivatives by a Ugi-4CR/aza-Wittig
Sequence
Ali Ramazani* and Aram Rezaei
Chemistry Department, Zanjan UniVersity, P.O. Box 45195-313, Zanjan, Iran
aliramazani@gmail.com
Received April 27, 2010
ABSTRACT
A novel and efficient method has been developed for the synthesis of 2,5-disubstituted 1,3,4-oxadiazole derivatives using (N-isocyanimino)t-
riphenylphosphorane, a secondary amine, a carboxylic acid, and an aromatic aldehyde in CH2Cl2 at ambient temperature in high yields without
using any catalyst or activation. The procedure provides an alternative method to the synthesis of fully substituted 1,3,4-oxadiazole derivatives.
Multicomponent reactions (MCRs) are important for generat-
ing high levels of diversity, as they allow more than two
building blocks to be combined in a practical, time-saving,
one-pot operation, giving rise to complex structures by
simultaneous formation of two or more bonds.1 As a special
subclass, the isocyanide-based MCRs (IMCRs) offer a
number of advantages originating from the unique reactivity
of an isocyanide, which acts as a nucleophile and an
electrophile at the same time. MCRs contribute to the
requirements of an environmentally friendly process by
reducing the number of synthetic steps, energy consumption,
and waste production.2 MCRs, which lead to interesting
heterocyclic scaffolds, are particularly useful for the con-
struction of diverse chemical libraries of “drug-like” mol-
ecules. Furthermore, the discovery of novel MCRs can be
considered as an interesting topic for academic research,
which also satisfies a practical interest of applied science.3
The aza-Wittig reactions of iminophosphoranes have
attracted much attention in view of their utility in the
synthesis of nitrogen-containing heterocyclic compounds
since they were first prepared in 1919 by Staudinger and
Meyer.4 Several interesting heterocyclization reactions in-
volving iminophosphoranes have been reviewed. These
compounds can easily be converted through an aza-Wittig
reaction with isocyanates, carbon dioxide, or carbon disulfide
into functionalized heterocumulenes which exhibit a rich
(1) (a) Bagley, M. C.; Dale, J. W. J. Chem. Commun. 2002, 1682. (b)
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10.1021/ol100931q  2010 American Chemical Society
Published on Web 05/19/2010

chemistry of unusual synthetic promise.5 The nucleophilicity
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 phar-
macological activity.5 There are several reports for the use
of (N-isocyanimino)triphenylphosphorane 4 in the synthesis
of metal complexes. However, the organic chemistry of 4
remains almost unexplored. The (N-isocyanimino)triph-
enylphosphorane 4 is expected to have synthetic potential
because it provides a reaction system in which the imino-
phosphorane group can react with a reagent having a
carbonyl functionality (Scheme 1).6
analgesic, anticonvulsive, antiemetic, diuretic,11 tyrosinase
inhibitor,12 growth hormone secretagogues,13 benzodiazepine
receptor partial agonists,14 dopamine transporters,15 and 5-HT
agonists16 (Figure 1).
Figure 1. Examples of some biologically active 2,5-disubstituted
1,3,4-oxadiazole derivatives.
Several methods have been reported in the literature for
the synthesis of 1,3,4-oxadiazole heterocycles which are
multistep in nature. 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.17 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.18
Therefore, development of a synthetic method that could be
used to prepare a variety of these templates remains an
important task.
Scheme 1
.
Synthesis of 2,5-Disubstituted 1,3,4-Oxadiazole
Derivatives 5a-o
As part of our ongoing program to develop efficient and
robust methods for the preparation of heterocyclic com-
pounds,19 herein we wish to report a fundamentally new
approach to the synthesis of 2,5-disubstituted 1,3,4-oxadia-
Oxadiazoles have often been described as bioisoesteres
for amides and esters. Due to the increased hydrolytic and
metabolic stability of the oxadiazole ring, improved phar-
macokinetic and in vivo performance is often observed,
which make this heterocycle an important structural motif
to the pharmaceutical industry.7 As a consequence of these
characteristics, 1,3,4-oxadiazoles have impacted numerous
drug discovery programs, including CNS stimulant, antiin-
flammatory, hypotensive,8 insecticidal,9 hypoglycemic,10
(11) Thomas, J. Ger. Pat. 2,403, 357/1974 [Chem. Abstr., 1974, 81,
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Tetrahedron Lett. 2009, 50, 5625. (b) Souldozi, A.; Ramazani, A.;
Bouslimani, N.; Welter, R. Tetrahedron Lett. 2007, 48, 2617. (c) Souldozi,
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179, 1615. (f) Ramazani, A.; Kazemizadeh, A. R.; Ahmadi, E. Phosphorus,
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Org. Lett., Vol. 12, No. 12, 2010
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Table 1. Synthesis of 2,5-Disubstituted 1,3,4-Oxadiazole Derivatives 5a-o from Benzaldehyde 1, Secondry Amine 2, and Carboxylic
Acid 3 in the Presence of (N-Isocyanimino)triphenylphosphorane 4
aldehyde 1
secondry amine 2
carboxylic acid 3
product
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
benzaldehyde
benzaldehyde
benzaldehyde
benzaldehyde
benzaldehyde
benzaldehyde
benzaldehyde
benzaldehyde
dibenzylamine
N-methylbenzyl amine
dibenzylamine
N-methylbenzyl amine
dibenzylamine
N-methylbenzyl amine
dibenzylamine
N-methylbenzyl amine
dibenzylamine
dibenzylamine
N-methylbenzyl amine
dibenzylamine
piperidine
benzoic acid
benzoic acid
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
4-fluorobenzoic acid
4-fluorobenzoic acid
3-fluorobenzoic acid
3-fluorobenzoic acid
4-bromobenzoic acid
4-bromobenzoic acid
4-bromobenzoic acid
4-bromobenzoic acid
3-bromobenzoic acid
4-chlorobenzoic acid
4-iodobenzoic acid
4-iodobenzoic acid
biphenyl-4-carboxylic acid
4-chloro benzaldehyde
3-chloro benzaldehyde
benzaldehyde
benzaldehyde
4-chloro benzaldehyde
4-chloro benzaldehyde
benzaldehyde
diethylamine
N-methylbenzyl amine
zoles by the multicomponent reaction between (N-isocyan-
imino)triphenylphosphorane, secondary amine, benzaldehyde
derivatives, and various carboxylic acids, followed by an aza-
Wittig cyclization in CH2Cl2 at ambient temperature in high
yields (Scheme 1).20
temperature, and no undesirable byproducts were observed.
Owing to the great diversity of substitution patterns, this
reaction may be used in the production of combinatorial
libraries.
This route permits us to introduce great molecular diversity
under mild reaction conditions, including substitution and
scaffold diversity. A large number of derivatives can be
rapidly synthesized in excellent purity and high yield by
using this method.
The structures of the products were deduced from their
IR, Mass, 1H NMR, and 13C NMR spectra. The mass spectra
of these compounds displayed molecular ion peaks at the
appropriate m/z values. The 1H NMR spectrum of 5a
consisted of an AB-quartet for 2 CH2 of benzyl groups at δ
) 3.65 and 3.90 (2JHH ) 13.8 Hz), a singlet at δ ) 5.5 for
CH, and a multiplet at δ ) 7.21-7.72 and 8.03-8.07 for
H-aromatic. The 1H-decoupled 13C NMR spectrum of 5a is
in agreement with the proposed structure. In view of the
success of the above-mentioned reaction, we explored the
scope of this promising reaction by varying the structure of
the benzaldehyde, amine, and carboxylic acid component
(Table 1).
As indicated in Figure 2 and Scheme 1, the reaction
proceeds very cleanly under mild reaction conditions at room
(20) Representative experimental procedure and spectral data: To
a magnetically stirred solution of dibenzylamine (1 mmol), benzaldehyde
(1 mmol), and (N-isocyanimino)triphenylphosphorane (1 mmol) in CH2Cl2
(5 mL) was added dropwise a solution of benzoic acid (1 mmol) in CH2Cl2
(5 mL) at room temperature over 15 min. The mixture was stirred for 2 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 (2:1)) to afford 5a (93%) as a colorless oil. IR (KBr)
(νmax/cm-1): 3471, 3028, 2925, 1551, 1492, 1451, 1070, and 747. 1H NMR
(CDCl3, 250 MHz): δH (ppm) 3.65 and 3.90 (AB quartet, 4 H, 2JHH ) 13.8
Hz, 2 CH2 of Benzyl groups), 5.45 (s, 1 H, CH), 7.21-7.72, and 8.03-8.07
(m, 20 H, arom). 13C NMR (CDCl3, 62.5 MHz): δC (ppm) 54.55 (2 CH2 of
Benzyl groups), 59.62 (CH), 127.00, 127.23, 128.17, 128.41, 128.59, 128.85,
129.07, and 131.79 (20 CH of arom), 123.83, 136.71, and 138.84 (4 Cipso(CdC)
of 4 C6H5), 164.73 and 165.15 (2 CdN). Anal. Calcd for C33H33N3O: C,
81.28; H, 6.82; N, 8.62. Found: C, 81.20; H, 6.77; N, 8.58.
Figure 2. Synthesis of 2,5-disubstituted 1,3,4-oxadiazole deriva-
tives.
A mechanistic rationalization for this reaction is provided
in Scheme 2. It is conceivable that the initial event is the
condensation of the benzaldehyde 1, secondary amine 2, and
carboxylic acid 3 entities to an intermediate iminium ion 7.
Nucleophilic addition of the (N-isocyanimino)triphe-
nylphosphorane 4 to the intermediate iminium ion 7 leads
2854
Org. Lett., Vol. 12, No. 12, 2010

to nitrilium intermediate 8. This intermediate may be
attacked by conjugate base of the acid 3 to form 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.
To the best of our knowledge, this is the first report in
which (N-isocyanimino)triphenylphosphorane 4 was used in
a four-component condensation and followed by an intramo-
lecular aza-Wittig22 ring closure of the iminophosphorane
moiety with the ester carbonyl.
In conclusion, we are reporting a new MCR, yielding 2,5-
disubstituted 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 the potential in synthesis of
various 2,5-disubstituted 1,3,4-oxadiazoles, which are of
considerable interest as potential biologically active com-
pounds or pharmaceuticals.
Scheme 2
.
Possible Mechanism for the Formation of Products
5a-o
Acknowledgment. This research was supported by the
“Zanjan University”.
Supporting Information Available: Experimental pro-
cedures and full spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL100931Q
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an intramolecular aza-Wittig reaction after the formation of
the imino-anhydride intermediate typical of the Ugi reaction.
The use of a secondary amine is vital as the Mumm
rearrangement is no longer possible.21
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