Reaction between N-isocyaniminotriphenylphosphorane, aldehydes, and carboxylic acids: A one-pot and three-component synthesis of 2-aryl-5-hydroxyalkyl-1,3,4-oxadiazoles

Article abstract of DOI:10.1055/s-0029-1217337

A one-pot and three-component synthesis of 2-aryl-5-hydroxyalkyl-1,3,4- oxadiazoles is described. N-Isocyaniminotriphenylphosphorane, an aldehyde, and a carboxylic acid undergo a 1:1:1 addition reaction under mild conditions to afford the title compounds

Full text of DOI:10.1055/s-0029-1217337

LETTER
1575
Reaction between N-Isocyaniminotriphenylphosphorane, Aldehydes, and
Carboxylic Acids: A One-Pot and Three-Component Synthesis of 2-Aryl-5-
hydroxyalkyl-1,3,4-oxadiazoles
S
ynthesis of 2-Aryl-5-h
e
ydroxyalky
h
l-1,3,4-oxad
d
iazoles i Adib,*a Mahdi Riazati Kesheh,a Samira Ansari,a Hamid Reza Bijanzadehb
a
b
Received 22 January 2009
Furthermore, many 1,3,4-oxadiazole derivatives have
been reported as active inhibitors of several enzymes.2,3
Abstract: A one-pot and three-component synthesis of 2-aryl-5-
hydroxyalkyl-1,3,4-oxadiazoles is described. N-Isocyaniminotriph-
enylphosphorane, an aldehyde, and a carboxylic acid undergo a
1:1:1 addition reaction under mild conditions to afford the title com-
pounds in good yields.
N
N
OH
Ar
O
Key words: 2-aryl-5-hydroxyalkyl-1,3,4-oxadiazoles, N-isocyan-
iminotriphenylphosphorane, aldehydes, carboxylic acids, three-
component reactions, cyclizations, heterocycles
1
Figure 1
Some 1,3,4-oxadiazoles have potential applications as
photosensitizers,5 liquid crystals,6 ionic liquid solvents,7
and organic light-emitting devices.8 Some examples have
also photomechanic,9 photoluminescent, and electrochro-
mic properties.10,11
Multicomponent reactions (MCR) have become a signifi-
cant part of today’s arsenal of methods in combinatorial
chemistry due to their valued features such as atom econ-
omy, straightforward reaction design, and the opportunity
to construct target compounds by the introduction of sev-
eral diversity elements in a single chemical event. Typi-
cally, purification of products resulting from MCR is also
simple since all the organic reagents employed are con-
sumed and are incorporated into the target compound.1
Multicomponent reactions, leading to interesting hetero-
cyclic scaffolds, are particularly useful for the construc-
tion of diverse chemical libraries of ‘drug-like’ molecules.
The isocyanide-based MCR are especially important in
this area.1d,e
So far, the most common synthetic methods reported for
the preparation of 1,3,4-oxadiazoles involve: i) transfor-
mation of an existing heterocycle and ii) cyclizations: a)
single-bond formation: cyclodehydration of 1,2-diacyl-
hydrazines, oxidative cyclization of acylhydrazones,
cyclodesulfurization of thiosemicarbazides and b) forma-
tion of two bonds: condensation and then cyclization of
hydrazides with carboxylic acids, acyl chlorides, esters,
amides, trialkyl orthoesters, carbon disulfide, or other
C–S-containing components, cyanogen bromide, potassi-
um isocyanate, trichloromethylarenes, and imidoyl chlo-
rides.2,3,12
Nitrogen–oxygen heterocycles are of synthetic interest
because they constitute an important class of natural and
non-natural products, many of which exhibit useful bio-
logical activities. The interest in five-membered systems
containing one oxygen and two nitrogen atoms (positions
1, 3, and 4) stems from the occurrence of saturated and
partially saturated 1,3,4-oxadiazoles in biologically active
compounds and natural products. Compounds containing
1,3,4-oxadiazole moiety have been shown to possess a
wide range of pharmacological and therapeutic activi-
There are several reports on the use of N-isocyanimino-
triphenylphosphorane (NCNPPh3) 2 (Scheme 1) in the
synthesis of metal complexes.13,14 However, applications
of 2 in organic synthesis are rare. Recently, a synthesis of
1,3,4-oxadiazepines has been reported via a three-compo-
nent reaction between 2, dialkyl acetylenedicarboxylates,
and 1,3-diphenyl-1,3-propanedione.15 A synthesis of 2-
aryl-1,3,4-oxadiazoles from 2 and benzoic acids16 has
been reported.
ties.2,3 2-Aryl-5-hydroxymethyl-1,3,4-oxadiazoles
1
(Figure 1) have exhibited analgesic, anti-inflammatory,
anticonvulsant, tranquilizing, myorelaxant, antidepres-
sant, vasodilatatory, diuretic, antiulcer, antiarythmic, anti-
serotoninic, spasmolytic, hypotensive, antibroncho-
contrictive, anticholinergic, and antiemetic activities.4
Due to the unique properties of 2,5-disubstituted 1,3,4-ox-
adiazoles, the development of synthetic methods which
enable facile access to these useful entities are desirable.
As part of our current studies on the development of effi-
cient and facile methods for the preparation of biological-
ly active heterocyclic compounds,17 we report herein a
new synthesis of 1,3,4-oxadiazoles. Thus, a mixture of N-
isocyaniminotriphenylphosphorane 2, an excess of an al-
dehyde 3, and a carboxylic acid 4 undergo a 1:1:1 addition
reaction in CH2Cl2 at ambient temperature to produce the
SYNLETT 2009, No. 10, pp 1575–1578
x
x
.x
x
.2
0
0
9
Advanced online publication: 02.06.2009
DOI: 10.1055/s-0029-1217337; Art ID: D02809ST
© Georg Thieme Verlag Stuttgart · New York

1576
M. Adib et al.
LETTER
N
N
CH2Cl2
+
N
–
OH
+
+
ArCO2H
Ar
Ph3P
N
C
RCHO
+ Ph3P
O
O
r.t., 24 h
2
3
4
5
R
H
Scheme 1
N
N
CH2Cl2
+
–
C
ArCO2H
1
RCHO
1
Ph3P
N
N
+
+
Ph
+
RCHO
3P O
+
Ar
r.t., 24 h
O
1
:
:
6 90%
initial ratios:
recovered
unreacted
Scheme 2
corresponding 2-aryl-5-hydroxyalkyl-1,3,4-oxadiazoles 5 for the methyl group (d = 1.53 ppm, J = 6.6 Hz), a multip-
in 80–87% yields (Scheme 1, Table 1).
let for the methine H atom (d = 4.99 ppm), and a doublet
for the hydroxyl group (d = 6.04 ppm, J = 5.6 Hz) due to
coupling with the adjacent methinic H atom, along with
Table 1 Synthesis of 2-Aryl-5-hydroxyalkyl-1,3,4-oxadiazoles 5a–i
1
two doublets for the four aromatic H atoms. The H-
5
R
Ar
Yield (%)a
decoupled 13C NMR spectrum of 5a showed two distinct
resonances at d = 20.87 ppm for the methyl group and
d = 60.33 ppm arising from the methine carbon atom
along with two deshielded characteristic resonances at
d = 163.23 and 168.81 ppm for the two oxadiazoles’ car-
bon atoms, as well as other four signals for the aryl sub-
stituent in agreement with the proposed structure.18
5a
5b
5c
5d
5e
5f
5g
5h
5i
Me
4-BrC6H4
4-MeC6H4
4-ClC6H4
4-ClC6H4
4-Me2NC6H4
4-FC6H4
87
84
85
80
80
84
85
81
80
Me
Me
Ph
EtCH2
4-O2NC6H4
3-O2NC6H4
Ph
A mechanistic rationalization for this reaction is provided
in Scheme 3. On the basis of the chemistry of isocya-
nides,1d,e,19,20 it is reasonable to assume that the first step
may involve nucleophilic addition of the isocyanide 2 to
the aldehyde 3, which facilitates by its protonation with
the acid 4, leading to nitrilium intermediate 7. This inter-
mediate may be attacked by conjugate base of the acid 8
to form 1:1:1 adduct 9. This adduct may undergo intramo-
lecular aza-Wittig reaction of iminophosphorane moiety
with the ester carbonyl to afford the isolated 2-aryl-5-
hydroxyalkyl-1,3,4-oxadiazoles 5 by removal of triphe-
nylphosphine oxide from betaine intermediate 10.
4-MeOC6H4
4-BrC6H4
9-anthryl
2-naphthyl
a Isolated yields.
When the reaction was performed using equivalent ratios
of the three components, TLC and 1H NMR analysis of the
reaction mixture indicated formation of the corresponding
2-aryl-1,3,4-oxadiazole 6 in nearly 90% yield along with
triphenylphosphine oxide, as has been previously report-
ed,16 and the aldehyde was recovered unreacted at the end
of the reaction (Scheme 2). The best results were obtained
when the reactions were carried out using the three com-
ponents in a ratio of 1:4:1, respectively.18
O
OH
R
O
+
N
Ph3P
N
C
+
N
HO
Ar
–
C
Ph3P
N
R
H
4
7
O
2
3
O–
Ar
8
All the reactions went to completion within 24 hours. The
1H NMR analysis of the reaction mixtures clearly indicat-
ed the formation of the corresponding 2-aryl-5-hydroxy-
alkyl-1,3,4-oxadiazoles 5 and triphenylphosphine oxide.18
Ph3P
Ph3P
N
N
OH
N
N
N
N
O
OH
R
O–
Ar
Ar
OH
O
O
R
O
5
R
Ar
Ph3P
O
+
9
10
The structures of the isolated products 5 were deduced by
means of IR, 1H NMR and 13C NMR spectroscopy, mass
spectrometry, and elemental analysis. The IR spectrum of
5a showed absorption at 3252 cm–1 indicating the pres-
ence of hydroxyl group. The mass spectrum of 5a dis-
played the molecular ion [M+] peaks at m/z = 270 [81Br]
and 268 [79Br], which is consistent with the 1:1:1 adduct
of N-isocyaniminotriphenylphosphorane, 4-bromobenzo-
ic acid, and acetaldehyde losing triphenylphosphine ox-
Scheme 3
In conclusion, we have developed a one-pot, three-com-
ponent reaction between N-isocyanimino-triphenylphos-
phorane, aldehydes, and carboxylic acids for the
preparation of 2-aryl-5-hydroxyalkyl-1,3,4-oxadiazoles
which are of potential synthetic and pharmacological in-
terest. Good yields of the products and mild reaction con-
ditions are the main advantages of this method. The
1
ide. The H NMR spectrum of 5a consisted of a doublet
Synlett 2009, No. 10, 1575–1578 © Thieme Stuttgart · New York

LETTER
Synthesis of 2-Aryl-5-hydroxyalkyl-1,3,4-oxadiazoles
1577
(17) (a) Adib, M.; Sheibani, E.; Bijanzadeh, H. R.; Zhu, L. G.
Tetrahedron 2008, 64, 10681. (b) Adib, M.; Sayahi, M. H.;
Ziyadi, H.; Zhu, L. G.; Bijanzadeh, H. R. Synthesis 2008,
3289. (c) Adib, M.; Sheibani, E.; Zhu, L. G.; Bijanzadeh,
H. R. Synlett 2008, 2941. (d) Adib, M.; Mohammadi, B.;
Bijanzadeh, H. R. Synlett 2008, 3180. (e) Adib, M.;
Mohammadi, B.; Bijanzadeh, H. R. Synlett 2008, 177.
(f) Adib, M.; Sayahi, M. H.; Ziyadi, H.; Bijanzadeh, H. R.;
Zhu, L. G. Tetrahedron 2007, 63, 11135. (g) Adib, M.;
Aali Koloogani, S.; Abbasi, A.; Bijanzadeh, H. R. Synthesis
2007, 3056. (h) Adib, M.; Sheibani, E.; Abbasi, A.;
Bijanzadeh, H. R. Tetrahedron Lett. 2007, 48, 1179.
(i) Adib, M.; Sheibani, E.; Mostofi, M.; Ghanbary, K.;
Bijanzadeh, H. R. Tetrahedron 2006, 62, 3435. (j) Adib,
M.; Mahdavi, M.; Mahmoodi, N.; Pirelahi, H.; Bijanzadeh,
H. R. Synlett 2006, 1765.
reactions were performed under neutral conditions, and
the starting materials and reagents were simply mixed
without any activation or modification. The simplicity of
this method makes it an interesting alternative to other
1,3,4-oxadiazole syntheses. This approach is an extension
of the previously described method which leads to oxa-
diazoles of type 6, unsubstituted at C-5. The 2-aryl-5-
hydroxyalkyl-1,3,4-oxadiazoles prepared in the present
study may find useful applications in synthetic organic,
bioorganic, and medicinal chemistry.
Acknowledgment
This research was supported by the Research Council of University
of Tehran (research project 6102036/1/03).
(18) Procedure for the Preparation of 2-(4-Bromophenyl)-5-
(1-hydroxyethyl)-1,3,4-oxadiazole (5a)
A mixture of N-isocyaniminotriphenylphosphorane (0.302
g, 1 mmol), acetaldehyde (0.176 g, 4 mmol), 4-bromobenz-
oic acid (0.201 g, 1 mmol) in CH2Cl2 (4 mL) was stirred at
ambient temperature for 24 h. Then, the solvent was
removed, and the residue was purified by column
References and Notes
(1) (a) Multicomponent Reactions; Zhu, J.; Bienaymé, H., Eds.;
Wiley: Weinheim, 2005. (b) Basso, A.; Banfi, L.; Riva, R.;
Guanti, G. J. Org. Chem. 2005, 70, 575. (c) Ramón, D. J.;
Yus, M. Angew. Chem. Int. Ed. 2005, 44, 1602.
(d) Dömling, A. Chem. Rev. 2006, 106, 17. (e) Dömling,
A.; Ugi, I. Angew. Chem. Int. Ed. 2000, 39, 3169.
(2) Hill, J. In Comprehensive Heterocyclic Chemistry II, Vol. 4;
Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V., Eds.;
Pergamon: London, 1996, Chap. 6, 267–287; and references
therein.
(3) Suwiński, J.; Szczepankiewicz, W. In Comprehensive
Heterocyclic Chemistry III, Vol 5; Katritzky, A. R.;
Ramsden, C. A.; Scriven, E. F. V.; Taylor, R. J. K., Eds.;
Elsevier Science: Oxford, 2008, Chap. 6, 396–458; and
references therein.
(4) Huguet, G. J.; Fauran, C. P.; Douzon, C. A.; Raynaud, G. M.;
Thomas, J. M. US 3912747 (A), 1975; Chem. Abstr. 1975,
82, p156324n.
(5) Schinzel, E.; Martini, T.; Spatzier, W.; Probst, H. DE
3126464, 1983 Chem. Abstr. 1983, 98, 199850.
(6) Chudgar, N. K.; Shah, S. N.; Vora, R. A. Mol. Cryst. Liq.
Cryst. 1989, 172, 51.
chromatography using n-hexane–EtOAc (5:1) as eluent. The
solvent was removed, and the product was obtained as
colorless crystals. Yield 0.23 g (87%); mp 98 °C. IR (KBr):
3252 (OH), 1609, 1585, 1563, 1551, 1487, 1408, 1375,
1238, 1124, 1092, 1043, 1007, 841, 727 cm–1. 1H NMR
(500.1 MHz, DMSO-d6): d = 1.53 (d, J = 6.6 Hz, 3 H, CH3),
4.99 (m, 1 H, CHCH3), 6.04 (d, J = 5.6 Hz, 1 H, OH), 7.65
(d, J = 8.5 Hz, 2 H, 2 × CH), 7.98 (d, J = 8.5 Hz, 2 H, 2 ×
CH). 13C NMR (125.8 MHz, DMSO-d6): d = 20.87 (CH3),
60.33 (CH), 122.29 (C), 128.29 and 129.61 (2 × CH), 136.71
(C), 163.23 and 168.81 (2 × OC=N). MS: m/z (%) = 270 (2)
[M+ 81Br], 268 (2) [M+ 79Br], 244 (16), 224 (97), 209 (24),
181 (72), 152 (40), 139 (100), 125 (20), 111 (56), 89 (18), 75
(36). Anal. Calcd for C10H9BrN2O2 (269.10): C, 44.63; H,
3.37; N, 10.41. Found: C, 44.5; H, 3.5; N, 10.2.
2-[4-(Dimethylamino)phenyl]-5-(1-hydroxypropyl)-
1,3,4-oxadiazole (5e)
Yield 0.21 g (80%); colorless crystals; mp 118 °C. IR (KBr):
3219 (OH), 1610, 1582, 1553, 1502, 1433, 1371, 1198,
1173, 1128, 1085, 1014, 968, 810 cm–1. 1H NMR (500.1
MHz, DMSO-d6): d = 0.89 (t, J = 7.4 Hz, 3 H, CH2CH3),
1.27–1.47 (m, 2 H, CH2), 1.78–1.84 (m, 2 H, CH2), 2.98 [s,
6 H, N(CH3)2], 4.75–4.80 (m, 1 H, CH), 5.93 (d, J = 5.7 Hz,
1 H, OH), 6.80 (d, J = 8.9 Hz, 2 H, 2 × CH), 7.76 (d, J = 8.9
Hz, 2 H, 2 × CH). 13C NMR (125.7 MHz, DMSO-d6):
d = 13.55 (CH3), 17.98 and 36.57 (2 × CH2), 39.56
[N(CH3)2], 63.87 (CH), 109.89 (C), 111.72 and 127.65 (2 ×
CH), 152.20 (C), 164.48 and 166.79 (2 × OC=N). MS: m/z
(%) = 261 (100) [M+], 218 (24), 188 (3), 160 (8), 146 (54),
132 (6), 118 (5), 105 (4), 91 (3), 77 (5). Anal. Calcd for
C14H19N3O2 (261.32): C, 64.35; H, 7.33; N, 16.08. Found: C,
64.2; H, 7.4; N, 16.0.
(7) Lozinskaya, E. I.; Shaplov, A. S.; Kotseruba, M. V.;
Komarova, L. I.; Lyssenko, K. A.; Antipin, M. Y.;
Golovanov, D. G.; Vygodskii, Y. S. J. Polym. Sci., Part A:
Polym. Chem. 2006, 44, 380.
(8) Zhang, H.; Huo, C.; Zhang, J.; Zhang, P.; Tian, W.; Wang,
Y. Chem. Commun. 2006, 281.
(9) Ikeda, T.; Mamiya, J.; Yu, Y. Angew. Chem. Int. Ed. 2007,
46, 506.
(10) Liou, G. S.; Huang, N. K.; Yang, Y. L. Eur. Polym. J. 2006,
42, 2283.
(11) Liou, G. S.; Hsiao, S. H.; Chen, W. C.; Yen, H.-J.
Macromolecules 2006, 39, 6036.
(12) Polshettiwar, V.; Varma, R. S. Tetrahedron Lett. 2008, 49,
879.
(13) Stolzenberg, H.; Weinberger, B.; Fehlhammer, W. P.;
Pühlhofer, F. G.; Weiss, R. Eur. J. Inorg. Chem. 2005, 21,
4263.
(14) Chiu, T. W.; Liu, Y. H.; Chi, K. M.; Wen, Y. S.; Lu, K. L.
Inorg. Chem. 2005, 44, 6425.
(15) Souldozi, A.; Ramazani, A.; Bouslimani, N.; Welter, R.
Tetrahedron Lett. 2007, 48, 2617.
(16) Souldozi, A.; Ramazani, A. Tetrahedron Lett. 2007, 48,
1549.
5-[1-Hydroxy-1-(3-nitrophenyl)methyl-2-(4-methoxy-
phenyl)-1,3,4-oxadiazole (5g)
Yield 0.28 g (85%); colorless crystals; mp 148 °C. IR (KBr):
3190 (OH), 1614, 1591, 1537, 1504, 1477, 1442, 1350,
1265, 1174, 1049, 1022, 833, 800, 732 cm–1. 1H NMR (500.1
MHz, DMSO-d6): d = 3.82 (s, 3 H, OCH3), 6.29 (d, J = 6.2
Hz, 1 H, CH), 7.11 (d, J = 8.7 Hz, 2 H, 2 × CH), 7.12 (d,
J = 6.2 Hz, 1H, OH), 7.71 (t, J = 7.9 Hz, 1 H, CH), 7.90 (d,
J = 8.7 Hz, 2 H, 2 × CH), 7.97 (d, J = 7.6 Hz, 1 H, CH), 8.21
(d, J = 8.0 Hz, 1 H, CH), 8.41 (s, 1 H, CH). 13C NMR (125.8
MHz, DMSO-d6): d = 55.46 (OCH3), 65.32 (CH), 114.87
(CH), 115.39 (C), 121.23, 123.03, 128.38, 129.97 and
Synlett 2009, No. 10, 1575–1578 © Thieme Stuttgart · New York

1578
M. Adib et al.
LETTER
133.27 (5 × CH), 141.59 and 147.80 (2 × C), 162.11 (CO),
164.36 and 166.18 (2 × OC=N). MS: m/z (%) = 327 (54)
[M+], 175 (91), 150 (13), 133 (100), 104 (15), 92 (14), 76
(28). Anal. Calcd for C16H13N3O5 (327.30): C, 58.72; H,
4.00; N, 12.84. Found: C, 58.7; H, 3.9; N, 12.8.
2-(9-Anthryl)-5-[1-hydroxy-1-(2-naphthyl)methyl]-
1,3,4-oxadiazole (5i)
Yield 0.32 g (80%); colorless crystals; mp 176 °C. IR (KBr):
3250 (OH), 1601, 1566, 1550, 1508, 1454, 1415, 1375,
1269, 1175, 1142, 1082, 1003, 991, 889, 727 cm–1. 1H NMR
(500.1 MHz, DMSO-d6): d = 6.44 (d, J = 4.4 Hz, 1 H, CH),
7.06 (d, J = 4.4 Hz, 1 H, OH), 7.48–7.60 (m, 6 H, 6 × CH),
7.73 (d, J = 8.4 Hz, 1 H, CH), 7.79 (d, J = 8.3 Hz, 2 H, 2 ×
CH), 7.91–8.00 (m, 3 H, 3 × CH), 8.15 (s, 1 H, CH), 8.20 (d,
J = 8.0 Hz, 2 H, 2 × CH), 8.92 (s, 1 H, CH). 13C NMR (125.8
MHz, DMSO-d6): d = 66.77 (CH), 116.40 (C), 124.25,
124.55, 125.38, 125.89, 126.34, 126.41, 127.58, 127.97,
128.12, 128.13, 128.89 and 130.42 (12 × CH), 130.44,
131.66, 132.72, 132.75 and 136.99 (5 × C), 162.47 and
168.64 (2 ×°C=N). MS: m/z (%) = 402 (89) [M+], 246 (7),
218 (7), 203 (100), 190 (16), 177 (16), 157 (54), 129 (49).
Anal. Calcd for C27H18N2O2 (402.45): C, 80.58; H, 4.51; N,
6.96. Found: C, 80.7; H, 4.3; N, 6.8.
(19) Ugi, I. Isonitrile Chemistry; Academic Press: London, 1971.
(20) Ugi, I. Angew. Chem., Int. Ed. Engl. 1982, 21, 810.
Synlett 2009, No. 10, 1575–1578 © Thieme Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not
be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.