One-pot efficient synthesis of fully substituted 1,3,4-oxadiazole derivatives from (n-isocyanimino)triphenylphosphorane, carboxylic acids, and aromatic bis-aldehydes

Article abstract of DOI:10.1080/00397911.2010.501480

Reactions of (N-isocyanimino)triphenylphosphorane with aromatic bis-aldehydes (isophthalaldehyde and terphthalaldehyde) in the presence of aromatic (or heteroaromatic) carboxylic acids proceed smoothly at room temperature and in neutral conditions to affo

Full text of DOI:10.1080/00397911.2010.501480

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One-Pot Efficient Synthesis
of Fully Substituted 1,3,4-
Oxadiazole Derivatives from (N-
Isocyanimino)triphenylphosphorane,
Carboxylic Acids, and Aromatic Bis-
Aldehydes
Ali Ramazani a , Yavar Ahmadi b & Amir Mahyari a
a Chemistry Department, Zanjan University, Zanjan, Iran
b Young Researchers Club, Islamic Azad University, Zanjan Branch,
Zanjan, Iran
Version of record first published: 25 May 2011.
To cite this article: Ali Ramazani, Yavar Ahmadi & Amir Mahyari (2011): One-Pot Efficient Synthesis of
Fully Substituted 1,3,4-Oxadiazole Derivatives from (N-Isocyanimino)triphenylphosphorane, Carboxylic
Acids, and Aromatic Bis-Aldehydes, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 41:15, 2273-2282
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Synthetic Communications1, 41: 2273–2282, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.501480
ONE-POT EFFICIENT SYNTHESIS OF FULLY
SUBSTITUTED 1,3,4-OXADIAZOLE DERIVATIVES
FROM (N-ISOCYANIMINO)TRIPHENYLPHOSPHORANE,
CARBOXYLIC ACIDS, AND AROMATIC BIS-ALDEHYDES
Ali Ramazani,1 Yavar Ahmadi,2 and Amir Mahyari1
1Chemistry Department, Zanjan University, Zanjan, Iran
2Young Researchers Club, Islamic Azad University, Zanjan Branch,
Zanjan, Iran
GRAPHICAL ABSTRACT
Abstract Reactions of (N-isocyanimino)triphenylphosphorane with aromatic bis-aldehydes
(isophthalaldehyde and terphthalaldehyde) in the presence of aromatic (or heteroaromatic)
carboxylic acids proceed smoothly at room temperature and in neutral conditions to afford
sterically congested 1,3,4-oxadiazole derivatives in good yields. The reaction proceeds
smoothly and cleanly under mild conditions, and no side reactions were observed.
Keywords Aromatic carboxylic acid; aza-Wittig reaction; heteroaromatic carboxylic
acid; (N-isocyanimino)triphenylphosphorane; 1,3,4-oxadiazole
INTRODUCTION
Organophosphorus compounds[1–4] have been extensively employed in organic
synthesis as useful reagents, as well as ligands, in a number of transition-metal cat-
alysts.[3] Iminophosphoranes are important synthetic intermediates in organic chem-
istry, especially in the preparation of naturally occurring products and compounds
Received May 20, 2010.
Address correspondence to Ali Ramazani, Chemistry Department, Zanjan University, P.O. Box
45195-313, Zanjan, Iran. E-mail: aliramazani@gmail.com
2273

2274
A. RAMAZANI, Y. AHMADI, AND A. MAHYARI
with biological and pharmacological activity.[5–11] In the fast few years, several
preparative procedures have been reported for the preparations and synthetic appli-
cations of iminophosphoranes.[5–13] The unique synthetic potential of iminopho-
sphoranes results from the presence of electron-rich nucleophilic nitrogen atoms
and electrophilic phosphorus atoms as PþꢀNꢀ bonds in their structures.[5] The
structural properties of the PþꢀNꢀ bond and its chemical reactivity have been inves-
tigated through theoretical, spectroscopic, and crystallographic investigations.[5,12,13]
The presence of the PþꢀNꢀ bond in the iminophosphorane structure is a factor of
essential mechanistic importance in their applications as aza-Wittig reagents.[5] The
intramolecular aza-Wittig reaction has attracted attention recently because of several
applications for the preparation of nitrogen-containing heterocyclic compounds,
which can result from the rapid progress in the synthesis of iminophosphorane
derivatives as starting materials.[5–11] There are several reports for the use of
(N-isocyanimino)triphenylphosphorane 3 in the preparation of metal complexes[12,13]
(Scheme 1). However, the role of (N-isocyanimino)triphenylphosphorane 3 in
organic chemistry remains unexplored.[12,13] The (N-isocyanimino)triphenylpho-
sphorane 3 is expected to have unique synthetic potential because it provides a reac-
tion system in which the iminophosphorane group can react with a reagent having a
carbonyl functionality.[12,13] In recent years, we have established a one-pot method
for the preparation of organophosphorus compounds.[14–22] As part of our ongoing
program to develop efficient and robust methods for the synthesis of heterocyclic
compounds,[23–31] we sought to develop a convenient preparation of 1,3,4-oxadiazole
derivatives 4a–j from (N-isocyanimino)triphenylphosphorane 3, bis-aldehydes
(isophthalaldehyde and terphthalaldehyde) 2, and aromatic (or heteroaromatic)
carboxylic acids 1 in excellent yields under neutral conditions (Scheme 1).
1,3,4-Oxadiazoles have attracted interest in medicinal chemistry as surrogates
of carboxylic acids, esters, and carboxamides.[32–34] They constitute an important
class of heterocyclic compounds with a wide range of pharmaceutical and biological
activities, including antimicrobial, antifungal, anti-inflammatory, antihypertensive,
analgesic, antibacterial, hypoglycemic, antimalarial, antitubercular, and antidepres-
sant activities.[32–34] Several methods have been reported in the literature for the syn-
thesis of 1,3,4-oxadiazoles. These protocols are multistep 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 deri-
vatives from carboxylic acids and (N-isocyanimino)triphenylphosphorane 3.[24,31]
Scheme 1. Three-component synthesis of sterically congested 1,3,4-oxadiazole derivatives 4a–j (see
Table 1).

FULLY SUBSTITUTED 1,3,4-OXADIAZOLES
2275
RESULTS AND DISCUSSION
In recent years, several synthetic methods have been reported for the prep-
aration of (N-isocyanimino)triphenylphosphorane (CNNPPh3) 3 (Scheme 1).[12,13]
There are several reports for the use of (N-isocyanimino)triphenylphosphorane 3
in the synthesis of metal complexes.[12,13] However, application of 3 in the synthesis
of organic compounds is rare.[14–22] As part of our ongoing program to develop
Table 1. Synthesis of sterically congested 1,3,4-oxadiazole derivatives 4a–j from carboxylic acid 1 and
aromatic bis-aldehydes 2 in the presence of (N-isocyanimino)triphenylphosphorane 3 (see Scheme 1)
Carboxylic acid 1
Bis-aldehyde 2
Product 4
Yielda
4a
4b
78
85
4c
4d
80
82
4e
4f
70
72
4g
75
4h
4i
83
80
4j
72
aIsolated yields.

2276
A. RAMAZANI, Y. AHMADI, AND A. MAHYARI
efficient and robust methods for the preparation of heterocyclic compounds,[23–31] we
sought to develop a convenient preparation of sterically congested 1,3,4-oxadiazole
derivatives 4 from (N-isocyanimino)triphenylphosphorane 3, bis-aldehydes (iso-
phthalaldehyde and terphthalaldehyde) 2, and aromatic (or heteroaromatic)
carboxylic acids 1 in excellent yields under neutral conditions (Scheme 1). The car-
boxylic acid derivative 1 with bis-aldehyde (isophthalaldehyde and terphthalalde-
hyde) 2 and (N-isocyanimino)triphenylphosphorane 3 in CH3CN react together in
a 1:1:1 ratio at room temperature to produce sterically congested 1,3,4-oxadiazole
derivatives 4 and triphenylphosphine oxide 5 (Scheme 1, Table 1). The reaction pro-
ceeds smoothly and cleanly under mild conditions, and no side reactions were
observed. (Other aspects of these types multicomponent reactions are currently
under investigation in our laboratory.)
The structures of the products were deduced from their infrared (IR), mass, 1H
1
NMR, and 13C NMR spectra. The H NMR spectrum of 4a consisted of a broad
singlet for the OH (d ¼ 3.26, exchangeable by D2O), a singlet for CH (d ¼ 6.80),
and a singlet for CH of aldehyde group (d ¼ 10.00). The aryl groups exhibited
1
characteristic signals in the aromatic region of the spectrum. The H-decoupled
13C NMR spectrum of 4a showed 12 distinct resonances, and partial assignment
of these resonances is given in the experimental section. The 1H and 13C NMR spec-
tra of compounds 4b–j were similar to those of 4a, except for the aromatic or hetero-
aromatic moieties, which exhibited characteristic signals with appropriate chemical
shifts.
The suggested mechanism for the formation of products 4a–j is illustrated in
Scheme 2. On the basis of the chemistry of isocyanides, it is reasonable to assume
that the first step may involve nucleophilic addition of the (N-isocyanimino)
Scheme 2. Proposed mechanism for the formation of sterically congested 1,3,4-oxadiazole derivatives 4a–j.

FULLY SUBSTITUTED 1,3,4-OXADIAZOLES
2277
triphenylphosphorane 3 to bis-aldehyde 2, which facilitates its protonation with the
acid 1, leading to nitrilium intermediate 6. This intermediate may be attacked by
conjugate base of the acid 1 to form 1:1:1 adduct 7. This adduct may undergo intra-
molecular aza-Wittig[23–29] reaction of iminophosphorane moiety with the ester
carbonyl to afford the isolated sterically congested 1,3,4-oxadiazole derivatives 4
by removal of triphenylphosphine oxide 5 from intermediate 8.
CONCLUSION
We believe that the reported method offers a mild, simple, and efficient route
for the preparation of sterically congested 1,3,4-oxadiazole derivatives 4 from
(N-isocyanimino) triphenylphosphorane 3, bis-aldehydes (isophthalaldehyde and
terphthalaldehyde) 2 and aromatic (or heteroaromatic) carboxylic acids 1. Its ease
of workup, good yields, and fairly mild reaction conditions make it a useful addition
to modern synthetic methodologies.[39–49]
EXPERIMENTAL
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 are thin-layer chromatography (TLC). TLC and NMR
indicated that there is no side product. Melting points were measured on an Electro-
thermal 9100 apparatus and are uncorrected. IR spectra were measured on a Jasco
Fourier transform 6300 (FT)–IR spectrometer. 1H and 13C NMR spectra were mea-
sured (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 20 eV. Flash chromatography
columns were prepared from Merck silica-gel powder.
General Procedure
A mixture of (N-isocyanimino)triphenylphosphorane 3 (1.0 mmol), aromatic
bis-aldehyde 2 (1.0 mmol), and carboxylic acid 1 (1.0 mmol) in CH3CN (5 mL) was
stirred at room temperature for 20 h. Then, the solvent was removed under reduced
pressure, and the viscous residue was purified by flash column chromatography
[silica-gel powder; petroleum ether–ethyl acetate (4:1)]. The solvent was removed
under reduced pressure to give the products 4. The characterization data of the
compounds are given.
Selected Data
4-(Hydroxy(5-phenyl-1,3,4-oxadiazol-2-yl)methyl)benzaldehyde
(4a).
White crystals, mp 76–78 ꢁC, yield 78%. IR (KBr) (tmax, cmꢀ1): 3401, 2919, 1700,
1606, 1449, 1204, 1079. Anal. calcd. for C16H12N2O3: C,68.56; H, 4.32; N, 9.99%.
Found: C, 68.51; H, 4.37; N, 9.92. 1H NMR (250.13 MHz, DMSO-d6) d: 3.26
(1H, br s, OH), 6.80 (1H, s, CH), 7.25–8.05 (9H, m, H-Ar), 10.00 (1H, s, CHO).

2278
A. RAMAZANI, Y. AHMADI, AND A. MAHYARI
13C NMR (62.53 MHz, DMSO-d6) d: 71.56 (CH); 131.58, 131.99, 133.97, 134.65,
136.77 (9CH of arom); 128.30, 140.99, 150.51 (3C of arom); 162.30 and 169.08
=
(2C N, oxadiazole); 191.67 (C O of aldehyde).
=
4-(Hydroxy(5-p-tolyl-1,3,4-oxadiazol-2-yl)methyl)benzaldehyde
(4b).
Yellow crystals, mp 91–93 ꢁC, yield 85%. IR (KBr) (tmax, cmꢀ1): 3389, 2922, 1700,
1607, 1480, 1202, 1068. Anal. calcd. for C17H14N2O3: C, 69.38; H, 4.79; N, 9.52%.
1
Found: C, 69.45; H, 4.74; N, 9.45. H NMR (250.13 MHz, CDCl3) d: 2.39 (3H, s,
CH3), 4.25 (1H, br s, OH), 6.23 (1H, s, CH), 7.25–7.92 (8H, m, H-Ar), 10.02 (1H,
s, CHO). 13C NMR (62.53 MHz, CDCl3) d: 21.66 (CH3); 67.79 (CH); 126.99,
127.15, 129.78, 130.21 (8CH of arom); 129.18, 136.61, 142.86, 144.03 (4C of arom);
=
=
164.85 and 166.20 (2C N of oxadiazole); 191.72 (C O of aldehyde). MS m=z: 294
(Mþ, 60), 159 (100), 133 (27), 119 (54), 105 (15), 91 (67), 77 (47), 57 (20), and 43 (24).
4-((5-(4-Ethylphenyl)-1,3,4-oxadiazol-2-yl)(hydroxy)methyl)benzaldehyde
(4c). Yellow crystals, mp 77–79 ꢁC, yield 80%. IR (KBr) (tmax, cmꢀ1): 3396, 2919,
1699, 1607, 1498, 1206, 1048. Anal. calcd. for C18H16N2O3: C, 70.12; H, 5.23; N,
1
9.09%. Found: C, 70.08; H, 5.20; N, 9.05. H NMR (250.13 MHz, CDCl3) d: 1.22
3
3
(3H, t, JHH ¼ 7.2 Hz, CH3 of Et); 2.66 (2H, q, JHH ¼ 7.2 Hz, CH2 of Et), 5.35
(1H, br s, OH), 6.23 (1H, s, CH); 7.24–7.86 (8H, m, H-Ar), 9.98 (1H, s, CHO).
13C NMR (62.53 MHz, CDCl3) d: 15.16 (CH3 of Et); 28.89 (CH2 of Et); 67.53
(CH); 127.08, 127.14, 128.23, 130.13 (8CH of arom); 124.49, 136.46, 144.35,
=
=
149.02 (4C of arom); 165.78 and 166.13 (2C N of oxadiazole); 191.80 (C O of
aldehyde).
4-((5-(4-Chlorophenyl)-1,3,4-oxadiazol-2-yl)(hydroxy)methyl)benzalde-
hyde (4d). Yellow oil, yield 82%. IR (KBr) (tmax, cmꢀ1): 3403, 2918, 1699, 1604,
1480, 1204, 1089. Anal. calcd. for C16H11ClN2O3: C, 61.06; H, 11.26; N, 8.90%.
1
Found: C, 61.11; H, 11.19; N, 8.95. H NMR (250.13 MHz, CDCl3) d: 4.70 (1H,
br s, OH), 6.25 (1H, s, CH), 7.27–7.90 (8H, m, H-Ar), 10.01 (1H, s, CHO). 13C
NMR (62.53 MHz, CDCl3) d: 67.66 (CH); 127.12, 128.28, 129.50, 130.23 (8CH of
=
arom); 121.53, 136.66, 138.59, 143.86 (4C of arom); 164.90 and 166.39 (2C N of
þ
=
oxadiazole); 191.70 (C O of aldehyd). MS m=z: 314 (M , 22), 294 (20), 179 (24),
156 (60), 139 (100), 111 (60), 91 (60), 69 (53), 57 (54) and 43 (59).
4-fHydroxy[5-(2-naphthyl)-1,3,4-oxadiazol-2-ylgmethyl]benzaldehyde
(4e). Yellow crystals, mp 99–100 ꢁC, yield 70%. IR (neat) (tmax, cmꢀ1): 3412, 2920,
1694, 1607, 1458, 1205, 1069. Anal. calcd. for C24H14N2O3: C, 72.72; H, 4.27; N,
1
8.48%. Found: C, 72.66; H, 4.34; N, 8.41. H NMR (250.13 MHz, CDCl3) d: 4.83
(1H, br s, OH), 6.31 (1H, s, CH), 7.37–9.03 (11H, m, H-Ar), 10.00 (1H, s, CHO).
13C NMR (62.53 MHz, CDCl3) d: 67.88 (CH); 124.75, 126.81, 127.19, 128.32,
128.73, 130.22 (11CH of arom); 125.83, 133.07, 133.72, 136.60, 144.04 (5C of arom);
=
162.20 and 169.80 (2C N of oxadiazole); 191.74 (C O of aldehyde).
=
4-fHydroxyl[5-(2-thienyl)-1,3,4-oxadiazol-2-yl]methylgbenzaldehyde
(4f). Yellow oil, yield 72%. IR (neat) (tmax, cmꢀ1): 3407, 2919, 1698, 1606, 1457,
1205, 1048. Anal. calcd. for C14H10N2O3S: C, 58.73; H, 3.52; N, 9.78%. Found:
1
C, 58.77; H, 3.55; N, 9.70. H NMR (250.13 MHz, CDCl3) d: 4.82 (1H, br s, OH),
6.22 (1H, s, CH), 7.16–7.95 (7H, m, H-Ar), 10.08 (1H, s, CHO). 13C NMR

FULLY SUBSTITUTED 1,3,4-OXADIAZOLES
2279
(62.53 MHz, CDCl3) d: 67.84 (CH); 127.13, 128.21, 130.25, 130.42, 130.76 (7CH of
=
arom); 124.87, 136.90, 143.81 (3C of arom); 160.50 and 165.95 (2C N of oxadia-
=
zole); 191.60 (C O of aldehyde).
4-fHydroxyl[5-(3-thienyl)-1,3,4-oxadiazol-2-yl]methylgbenzaldehyde
(4g). Yellow oil, yield 75%. IR (neat) (tmax, cmꢀ1): 3380, 2922, 1698, 1603, 1206,
1057. Anal. calcd. for C14H10N2O3S: C, 58.73; H, 3.52; N, 9.78%. Found: C,
1
58.80; H, 3.47; N, 9.72. H NMR (250.13 MHz, CDCl3) d: 4.86 (1H, br s, OH),
6.23 (1H, s, CH), 7.25–8.05 (7H, m, H-Ar), 10.0 (1H, s, CHO). 13C NMR
(62.53 MHz, CDCl3) d: 67.55 (CH); 125.87, 127.13, 127.66, 128.14, 130.19 (7CH of
=
arom); 124.34, 136.55, 145.07 (3C of arom); 162.30 and 166.30 (2C N of oxadia-
=
zole); 191.79 (C O of aldehyde).
3-(Hydroxy(5-p-tolyl-1,3,4-oxadiazol-2-yl)methyl)benzaldehyde
(4h).
Yellow crystals, mp 10–105 ꢁC, yield 83%. IR (KBr) (tmax, cmꢀ1): 3384, 2918,
1700, 1608, 1499, 1049. Anal. calcd. for C17H14N2O3 (294.30): C, 69.38; H, 4.79;
1
N, 9.52%. Found: C, 69.33; H, 4.85; N, 9.46. H NMR (250.13 MHz, CDCl3) d:
2.39 (3H, s, CH3), 4.34 (1H, br s, OH), 6.23 (1H, s, CH), 7.25–8.09 (8H, m,
H-Ar), 10.03 (1H, s, CHO). 13C NMR (62.53 MHz, CDCl3) d: 21.66 (CH3); 67.68
(CH); 126.99, 127.86, 129.62, 129.77, 130.03, 132.50 (8CH of arom); 127.30,
=
129.48, 136.82, 142.79 (4C of arom); 162.30 and 171.25 (2C N of oxadiazole);
=
191.85 (C O of aldehyde).
3-((5-(4-Bromophenyl)-1,3,4-oxadiazol-2-yl)(hydroxy)methyl)benzalde-
hyde (4i). Yellow crystals, mp 133–135 ꢁC, yield 80%. IR (KBr) (tmax, cmꢀ1): 3408,
2919, 1700, 1604, 1466, 1204, 1059. Anal. calcd. for C16H11BrN2O3: C, 53.50; H,
1
3.09; N, 7.80%. Found: C, 53.55; H, 3.15; N, 7.73. H NMR (250.13 MHz, CDCl3)
d: 4.60 (1H, br s, OH), 6.25 (1H, s, CH), 7.59–8.09 (8H, m, H-Ar), 10.02 (1H, s,
CHO). 13C NMR (62.53 MHz, CDCl3) d: 67.60 (CH); 127.62, 128.40, 129.69,
129.83, 132.45 (8CH of arom); 122.04, 126.97, 136.84, 138.89 (4C of arom); 165.00
=
and 166.57 (2C N of oxadiazole); 191.82 (C O of aldehyde).
=
3-fHydroxyl[5-(3-thienyl)-1,3,4-oxadiazol-2-yl]methylgbenzaldehyde (4j).
Yellow oil, yield 72%. IR (KBr) (tmax, cꢀ1): 3399, 2920, 1698, 1605, 1437, 1057. Anal.
calcd. for C14H10N2O3S: C, 58.73; H, 3.52; N, 9.78%. Found: C, 58.67; H, 3.45; N,
1
9.75. H NMR (250.13 MHz, CDCl3) d: 2.70 (1H, br s, OH), 6.20 (1H, s, CH),
7.25–8.35 (7H, m, H-Ar), 9.95 (1H, s, CHO). 13C NMR (62.53 MHz, CDCl3) d:
66.96 (CH); 125.87, 127.13, 12.66, 130.19 (7CH of arom); 129.18, 136.61, 144.03
=
(3C of arom); 160.01 and 169.80 (2C N of oxadiazole); 192.05 (C O of aldehyde).
=
ACKNOWLEDGMENTS
This research was supported by Zanjan University and the Iranian National
Science Foundation (INSF).
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´
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