The reaction of (N-isocyanimino)triphenylphosphorane with anthranilic acid derivatives: One-pot synthesis of 2-substituted 1,3,4-oxadiazoles via intramolecular aza-wittig reaction

Article abstract of DOI:10.1080/10426500802466684

The reaction of anthranilic acid derivatives with (N-isocyanimino) triphenylphosphorane proceeds smoothly at room temperature to afford 2-substituted 1,3,4-oxadiazoles via an intramolecular aza-Wittig reaction in excellent yields under neutral conditions.

Full text of DOI:10.1080/10426500802466684

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The Reaction of (N-
Isocyanimino)triphenylphosphorane
with Anthranilic Acid
Derivatives: One-Pot Synthesis
of 2-Substituted 1,3,4-
Oxadiazoles via Intramolecular
Aza-Wittig Reaction
Ali Ramazani a & Ali Souldozi b
a Chemistry Department , Zanjan University ,
Zanjan, Iran
b Chemistry Department , Islamic Azad University ,
Urmia Branch, Urmia, Iran
Published online: 04 Sep 2009.
To cite this article: Ali Ramazani & Ali Souldozi (2009) The Reaction of (N-
Isocyanimino)triphenylphosphorane with Anthranilic Acid Derivatives: One-Pot
Synthesis of 2-Substituted 1,3,4-Oxadiazoles via Intramolecular Aza-Wittig Reaction,
Phosphorus, Sulfur, and Silicon and the Related Elements, 184:9, 2344-2350
To link to this article: http://dx.doi.org/10.1080/10426500802466684
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Phosphorus, Sulfur, and Silicon, 184:2344–2350, 2009
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500802466684
The Reaction of (N-Isocyanimino)triphenylphosphorane
with Anthranilic Acid Derivatives: One-Pot Synthesis of
2-Substituted 1,3,4-Oxadiazoles via Intramolecular
Aza-Wittig Reaction
Ali Ramazani1 and Ali Souldozi2
1Chemistry Department, Zanjan University, Zanjan, Iran
2Chemistry Department, Islamic Azad University, Urmia Branch,
Urmia, Iran
The reaction of anthranilic acid derivatives with (N-isocyanimino)triphenyl-
phosphorane proceeds smoothly at room temperature to afford 2-substituted 1,3,4-
oxadiazoles via an intramolecular aza-Wittig reaction in excellent yields under
1
neutral conditions. The structures of the products were deduced from their IR,
NMR, and C NMR spectra and mass spectrometry.
H
13
Keywords Anthranilic acid derivatives; iminotriphenylphosphorane; intramolecular
aza-Wittig reaction; (N-isocyanimino)triphenylphosphorane; 1,3,4-oxadiazole
INTRODUCTION
Organophosphorus compounds1−5 have been extensively employed in
organic synthesis as useful reagents, as well as ligands, in a number
of transition metal catalysts.3 Iminophosphoranes are a class of spe-
cial type of zwitterions, which bear a strongly nucleophilic electron-rich
nitrogen. The electron distribution around the P+ –N− bond and its con-
sequent chemical implications have been probed and assessed through
theoretical, spectroscopic, and crystallographic investigations.6−8 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.6−8
Received 4 June 2008; accepted 10 September 2008.
This work was supported by the Iran National Science Foundation: INSF via the
research project number 86053.20.
Address correspondence to Ali Ramazani, Chemistry Department, Zanjan University,
P.O. Box 45195-313, Zanjan, Iran. E-mail: aliramazani@gmail.com
2344

Reaction of Anthranilic Acid Derivatives
2345
The intramolecular version of the aza-Wittig-type reaction has at-
tracted 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 prepara-
tion of functionalized iminophosphoranes. Several interesting heterocy-
clization reactions involving iminophosphoranes have been reviewed.6
These compounds can easily be converted through aza-Wittig reac-
tion with isocyanates, carbon dioxide, or carbon disulfide into func-
tionalized heterocumulenes that exhibit a rich chemistry of unusual
synthetic promise.6 The nucleophilicity at the nitrogen is a factor
of essential mechanistic importance in the use of these iminophos-
phoranes as aza-Wittig reagents. Iminophosphoranes are important
reagents in synthetic organic chemistry, especially in the synthe-
sis of naturally occurring products, and compounds with biological
and pharmacological activity.6 However, the organic chemistry of (N-
isocyanimino)triphenylphosphorane 2 remains almost unexplored.7,8
(N-isocyanimino)triphenylphosphorane 2 is expected to have syn-
thetic potential because it provides a reaction system in which the
iminophosphorane group can react with a reagent having a car-
bonyl functionality.7,8 In recent years, we have established a one-
pot method for the synthesis of organophosphorus compounds (Ali
Ramazani reaction).9−18 As part of our ongoing program to de-
velop efficient and robust methods for the preparation of heterocyclic
compounds,19−21 we sought to develop a convenient preparation of 2-
substituted 1,3,4-oxadiazoles 5 from anthranilic acid derivatives 1 and
(N-isocyanimino)triphenylphosphorane 2 in excellent yields under neu-
tral conditions (Scheme 1).
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 pharmaceutical and biological activities including an-
timicrobial, antifungal, antiinflammatory, and antihypertensive.22−26
Several methods have been reported in the literature for the
synthesis of 1,3,4-oxadiazoles. These protocols are multistep in
nature.27−32 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. 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.33−37

2346
A. Ramazani and A. Souldozi
SCHEME 1
RESULTS AND DISCUSSION
In the last years, several synthetic methods have been reported for
the preparation of (N-isocyanimino)triphenylphosphorane (CNNPPh3)
2 (Scheme 1).7,8 There are several reports for the use of (N-
isocyanimino)triphenylphosphorane 2 in the synthesis of metal
complexes.7,8 However, application of 2 in the synthesis of organic com-
pounds has not been reported. As part of our ongoing program to de-
velop efficient and robust methods for the preparation of heterocyclic
compounds,19−21 we sought to develop a convenient preparation of 2-
substituted 1,3,4-oxadiazoles 5 from anthranilic acid derivatives 1 and
(N-isocyanimino)triphenylphosphorane 2 (Scheme 1).
The anthranilic acid derivatives 1 and (N-isocyanimino)triphenyl-
phosphorane 2 in dry CHCl3 react together in a 1:1 ratio at
room temperature to produce 2-substituted 1,3,4-oxadiazoles 5 and
triphenylphosphine oxide 6 (Scheme 1). The reaction proceeds
smoothly and cleanly under mild conditions. The mechanism of
the reaction between the anthranilic acid derivatives 1 and (N-
isocyanimino)triphenylphosphorane 2 has not been established experi-
mentally. However, a possible explanation is proposed in Scheme 1. On

Reaction of Anthranilic Acid Derivatives
2347
the basis of the well-established chemistry of isocyanides,19,20 it is rea-
sonable to assume that protonation of 2 by the anthranilic acid deriva-
tives 1 followed by a quenching of the cationic center by the conjugate
base of the carboxylic acid can generate the iminophosphorane 4.6 An
intramolecular aza-Wittig6 reaction of the iminophosphorane 4 would
lead to formation of the 2-substituted 1,3,4-oxadiazoles 5 and triph-
enylphosphine oxide 6 (Scheme 1). The structures of the products 5a–c
were deduced from their IR, 1H NMR, and 13C NMR spectra. The mass
spectra of these compounds displayed molecular ion peaks at the appro-
priate m/z values. The IR spectrum of 5a showed strong adsorptions at
3431 and 3339 (NH2); 3039 (CH, aromatic); 1623 (C C, aromatic); 1108
and 754 (oxadiazole and aromatic parts) cm−1 indicating the presence
of the mentioned functionalities in its formula. The 1H NMR spectrum
of 5a compound exhibited six signals readily recognized as arising from
amino group (δ = 5.69 [br. s, 2 H, NH2]), aromatic moiety (δ = 6.73 [d,
3
1 H,3JHH = 7.0 Hz, arom], 6.79 [t, 1 H, JHH = 7.5 Hz, arom.], 7.75 [t,
1 H, 3JHH Hz, arom.], 7.76 [d, 1 H,3JHH = 6.0 Hz, arom.]), and a CH of
oxadiazole ring (δ = 8.41, s, 1 H). The 1H decoupled 13C NMR spectrum
of 5 showed eight distinct resonances (δ = 116.28, 116.91, 127.99 and
132.79 [4 CH, arom.]; 105.38 and 147.01 [2 C, arom.]; 150.91 [1 CH,
oxadiazole]; 164.62 [1 C, oxadiazole]) that are in agreement with the
formula and structure of 5. Partial assignment of these resonances is
given in the spectral analysis section (see the Experimental section).
We have also used other carboxylic acids (acetic acid, phthalic acid,
maleic acid, chloroacetic acid, trichloroacetic acid, benzylic acid, 3,5-
dinitrosalicylic acid, (2-hydroxyphenyl)acetic acid, 4-hydroxybenzoic
acid, 3-hydroxybenzoic acid, salicylic acid, 4-aminobenzenesulfonic
acid, 5-sulfosalicylic acid, nicotinic acid, 3-methoxyphenylacetic acid,
4-methoxyphenylacetic acid, diphenylacetic acid, 4-fluorobenzeneacetic
acid, 3-phenylpropanoic acid, 4-chlorobenzeneacetic acid, benzenesul-
fonic acid, acetylenedicarboxylic acid, and methyl red) in this reaction,
but no products were observed after 24 h. TLC indicated that the solu-
tion contained starting materials and some minor colored products.
CONCLUSION
In summary, we have found a new method for the preparation of 2-
substituted 1,3,4-oxadiazoles 5 from anthranilic acid derivatives 1 and
(N-isocyanimino)triphenylphosphorane 2 in excellent yields under neu-
tral conditions. We believe that the reported method offers a mild and
simple route for the preparation of these derivatives. Its ease of workup

2348
A. Ramazani and A. Souldozi
and reaction conditions make it a useful addition to modern synthetic
methodologies. Other aspects of this process are under investigation.
EXPERIMENTAL
1H (250 MHz) and 13C (62.5 MHz) NMR measurements were recorded
on a Bruker 250 spectrometer in CDCl3 with tetramethylsilane as
internal standard. IR spectra were measured on a Shimadzu IR-460
spectrometer. Elemental analyses for C and H 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. Melting points were measured on an Electrothermal
9100 apparatus and are uncorrected. (N-Isocyanimino) triphenylphos-
phorane 2 was prepared based on a reported procedure.7,8 Other start-
ing materials and solvents were obtained from Merck (Germany) and
Fluka (Switzerland) and were used without further purification. Flash
chromatography columns were prepared from Merck silica gel powder.
General Procedure for the Preparation of Compounds 4 and 5
To a magnetically stirred solution of (N-isocyanimino)triphenyl-
phosphorane7,8 2 (0.302 g, 1 mmol) in dry CHCl3 (4 mL) was added
drop-wise a solution of anthranilic acid derivative 1 (1 mmol) in dry
CHCl3 (4 mL) over 15 min. The mixture was stirred for 6 h at room
temperature. The solvent was removed under reduced pressure and
the viscous residue was purified by flash column chromatography (sil-
ica gel; petroleum ether-ethyl acetate [10:2]). The solvent was removed
under reduced pressure and the product 5 was obtained. The charac-
terization data of the compounds are given below.
2-(1,3,4-Oxadiazol-2-yl)Aniline 5a
Light yellow crystals; Yield: 140 mg (86%); mp 145.3–145.4◦C. IR
(KBr): ν = 3431, 3339, 3039, 2939, 2931, 2931, 1623, 1269, 1108, 754
cm−1. 1H NMR (CDCl3): δ = 5.69 (br. s, 2 H, NH2), 6.73 (s, 1 H, arom.),
6.79 (t, 1 H, 3JHH = 7.5 Hz, arom.), 7.75 (t, 1 H, 3JHH = 7.8 Hz, arom.),
7.76 (d, 1 H,3JHH = 6.0 Hz, arom.), 8.41 (s, 1 H, oxadiazole).13C NMR
(CDCl3): δ = 116.28, 116.91, 127.99 and 132.79 (4 CH, arom.); 105.38
and 147.01 (2 C, arom.); 150.91 (1 CH, oxadiazole); 164.62 (1 C, oxa-
diazole). MS: m/z (%) 161 (M+, 100%), 120 (50%), 105 (22), 92 (25), 90
(15), 78 (15), 77 ( 34), 65 (28), 63 (21), 58 (22), 55 (11), 52 (20), 51 (31),
50 (18), 43 (28), 41 (21). C8H7N3O (161.06): Calcd (%): C 59.62, H 4.38,
N 26.07; Found (%): C 59.57, H 4.34, N 26.14.

Reaction of Anthranilic Acid Derivatives
2349
Methyl-(2-[1,3,4]Oxadiazol-2-yl-Phenyl)-Amine 5b
Yellow crystals; Yield: 90%, mp: 76.5–76.9◦C. IR (KBr): ν = 3353.85,
3107.69, 2930.77, 1623.08, 1523.08, 1284.62, 1176.92, 1115.38, 746.15
cm−1. 1H NMR (CDCl3) δH: 8.41 (s, 1H, oxadiazole); 7.81 (d, 1H, 3JHH
=
3
8.0 Hz, arom); 7.53 (1H, NH of amine); 7.42 (t, 1H, JHH = 7.8 Hz,
arom); 6.82–6.72 (m,2H, arom); 3.04 (s, 3H, CH3).13C NMR (CDCl3)δC:
164.77 (1C, oxadiazole); 150.75 (1CH, oxadiazole); 148.50 (1C, arom);
133.20, 128.24, 16.62, 115.12 (4CH, arom); 104.89 (1C, arom). MS: m/z
(%) 175 (M+ , 10%), 167 (19), 149 (52), 105 (32), 91 (47), 75 (100), 57 (
65), 43 (91), 41 (70). C9H9N3O (175.07): Calcd (%): C 61.70, H 5.18, N
23.99; Found (%): C 61.59, H 5.11, N 24.10.
N-(2-[1,3,4]Oxadiazol-2-yl-Phenyl)-Acetamide 5c
Yellow crystals; Yield: 91%. mp: 134.5–135.2◦C. IR (KBr): ν =
3130.77, 2930.77, 1715.38, 1623.08, 1553.85, 1438.46, 1307.69,
1107.69 cm−1
.
1H NMR (CDCl3)δH: 10.91 (s, 1H, NH); 8.78 (d, 1H,
3
3JHH = 8.0 Hz, arom); 8.50 (s, 1H, oxadiazole); 7.91 (d, 1H, JHH
=
8 Hz, arom); 7.55–7.49 (m, 1H, arom); 7.20–7.14 (m, 1H, arom); 2.31
(s, 3H, CH3)13C NMR (CDCl3)δC: 169.39 (1C, C = O, amide); 164.03
(1C, oxadiazole); 151.64 (1CH, oxadiazole); 138.56 (1C, arom); 133.28,
127.65, 123.09 and 120.61 (4 CH, arom); 109.67 (1C, arom). MS: m/z (%)
203 (M+, 29%), 161 (100), 120 (24), 43 (17). C10H9N3O2 (203.20): Calcd
(%): C 59.11, H 4.46, N 20.68; Found (%): C 59.11, H 4.46, N 20.68.
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