A novel, one-pot, three-component synthesis of 1,2,4-oxadiazoles under microwave irradiation and solvent-free conditions

Article abstract of DOI:10.1055/s-2006-944200

A novel synthesis of 3,5-disubstituted 1,2,4-oxadiazoles is described from a one-pot, three-component reaction between nitriles, hydroxylamine, and Meldrum's acids under microwave irradiation and solvent-free conditions in good to excellent yields. Georg

Full text of DOI:10.1055/s-2006-944200

LETTER
1765
A Novel, One-Pot, Three-Component Synthesis of 1,2,4-Oxadiazoles under
Microwave Irradiation and Solvent-Free Conditions
S
ynthesis of 1,2,4-Oxa
e
diazole
s
hdi Adib,*a Mohammad Mahdavi,a Niusha Mahmoodi,a Hooshang Pirelahi,a Hamid Reza Bijanzadehb
a
School of Chemistry, University College of Science, University of Tehran, Tehran, Iran
Fax +98(21)66495291; E-mail: madib@khayam.ut.ac.ir
b
Department of Chemistry, Tarbiat Modarres University, Tehran, Iran
Received 19 February 2006
As part of our ongoing program to develop efficient
methods for the preparation of biologically interesting
compounds from readily available building blocks, in this
Letter we would like to report a novel synthesis of 3,5-di-
substituted 1,2,4-oxadiazoles via a one-pot three-compo-
nent reaction between nitriles, hydroxylamine, and
Meldrum’s acids. Thus, arylnitriles 1 and hydroxylamine
2 are converted in situ to the corresponding amidoximes
3. Next, the amidoximes react with the Meldrum’s acids 4
under microwave irradiation9 and solvent-free conditions
to produce 1,2,4-oxadiazoles 5 in 81–98% yields
(Scheme 1, Table 1).
Abstract: A novel synthesis of 3,5-disubstituted 1,2,4-oxadiazoles
is described from a one-pot, three-component reaction between
nitriles, hydroxylamine, and Meldrum’s acids under microwave
irradiation and solvent-free conditions in good to excellent yields.
Key words: Meldrum’s acids, nitriles, 1,2,4-oxadiazoles, three-
component reaction, solvent-free synthesis
Five-membered heterocyclic systems containing one oxy-
gen and two nitrogen atoms (positions 1, 2, and 4) are of
synthetic and pharmacological interest because of the
occurrence of the saturated and partially saturated 1,2,4-
oxadiazoles in biologically active compounds and natural
products.1 The rich chemistry of 1,2,4-oxadiazoles has
been repeatedly reviewed.1,2 1,2,4-Oxadiazoles have been
recently described as bioisosteres for amides or esters as a
result of the increased hydrolytic and metabolic stability
of the ring.3 Furthermore, derivatives containing 1,2,4-
oxadiazole ring systems have been employed as anti-
inflammatory and antitumor agents,4a antirhinovirals,4b
serotoninergic (5-HT3) antagonists,4c muscarinic ago-
nists,4d benzodiazepine receptor partial agonists,4e and
growth hormone secretagogues.4f On the other hand some
1,2,4-oxadiazoles have been used as plant protection5 and
liquid crystalline mesophases.6
O
O
(4)
Ar
N
O
O
NH2
AcOH (cat.)
MW, 1 min
N
R
Ar
Ar
N
R
+ NH2OH
MW, 2 min
NOH
O
1
2
3
5
Scheme 1
The reactions were carried out by first mixing the nitrile
and hydroxylamine, proceeding in the presence of a cata-
lytic amount of acetic acid under microwave irradiation.
After a minute and nearly complete conversion to the cor-
responding amidoxime 3, as indicated by TLC monitor-
ing, the Meldrum’s acid 4 was added to the reaction
mixture which was irradiated for a further two minutes.
TLC and 1H NMR analysis of the reaction mixtures clear-
ly indicated the formation of 1,2,4-oxadiazoles 5 in good
to excellent yields. The structures of the isolated products,
5a–n, were corroborated by the comparison of their phys-
ical and spectral data (high-field 1H NMR and 13C NMR
spectra) with those of authentic samples.11
The most common methods recently reported for the
synthesis of 1,2,4-oxadiazoles are cyclization of O-acyl-
amidoximes obtained from acylation of amidoximes by
carboxylic acids or acid chlorides. However, these
methods have several drawbacks. Acid chlorides are very
toxic and reactive chemicals and thus are hard to store and
handle. Carboxylic acids need a coupling regent to react
with amidoximes.7 On the other hand, the reaction times
are relatively long and in some cases the yields of the
reactions are not very high.
Mechanistically, it is reasonable to assume that first the in
situ prepared amidoxime 3 attacks to the Meldrum’s acid
4 to give the O-acylamidoxime intermediate 6 with re-
moval of acetone. This intermediate is cyclized to the
1,2,4-oxadiazole intermediate 7 by removing H2O. The
isolated 1,2,4-oxadiazole 5 is finally formed by decarbox-
ylation of 7 under the reaction conditions (Scheme 2).
The application of microwave irradiation in organic syn-
thesis for conducting reactions at highly accelerated rates
is an emerging technique. In fact, in recent years, the use
of microwaves has become popular among synthetic or-
ganic chemists both to improve classical organic reactions
(shortening reaction times and/or improving yields) as
well as to promote new reactions.8
In conclusion, we have developed a novel, microwave-as-
sisted, one-pot, three-component reaction for the prepara-
tion of 1,2,4-oxadiazoles of potential synthetic and
pharmacological interest. Good to excellent yields, short
SYNLETT 2006, No. 11, pp 1765–1767
1
2
.0
7
.2
0
0
6
Advanced online publication: 04.07.2006
DOI: 10.1055/s-2006-944200; Art ID: D05106ST
© Georg Thieme Verlag Stuttgart · New York

1766
M. Adib et al.
LETTER
O
O
(4)
Ar
N
Ar
N
O
O
O
_ CO2
_ H2O
NOH
NH2
NO
N
O
N
R
O
Ar
Ar
H
R
O
_ (CH3)2CO
O
R
O
NH2
OH
R
3
6
7
5
Scheme 2
(2) Clapp, L. B. Adv. Heterocycl. Chem. 1976, 20, 65.
(3) Vu, C. B.; Corpuz, E. G.; Merry, T. J.; Pradeepan, S. G.;
Bartlett, C.; Bohacek, R. S.; Botfield, M. C.; Lynch, B. A.;
MacNeil, I. A.; Ram, M. K.; van Schravendijk, M. R.;
Violette, S.; Sawyer, T. K. J. Med. Chem. 1999, 42, 4088.
(4) (a) Bezerra, N. M. M.; De Oliveira, S. P.; Srivastava, R. M.;
Da Silva, J. R. Il Farmaco 2005, 60, 955. (b) Diana, G. D.;
Volkots, D. L.; Hitz, T. J.; Bailey, T. R.; Long, M. A.;
Vescio, N.; Aldous, S.; Pevear, D. C.; Dutko, F. J. J. Med.
Chem. 1994, 37, 2421. (c) Swain, C. J.; Baker, R.; Kneen,
C.; Moseley, J.; Saunders, J.; Seward, E. M.; Stevenson, G.;
Beer, M.; Stanton, J.; Watling, K. J. J. Med. Chem. 1991, 34,
140. (d) Orlek, B. S.; Blaney, F. E.; Brown, F.; Clark, M. S.
G.; Hadley, M. S.; Hatcher, J.; Riley, G. J.; Rosenberg, H. E.;
Wadsworth, H. J.; Wyman, P. J. J. Med. Chem. 1991, 34,
2726. (e) Watjen, F.; Baker, R.; Engelstoff, M.; Herbert, R.;
Macleod, A.; Knight, A.; Merchant, K.; Moseley, J.;
Saunder, J.; Swain, C. J.; Wong, E.; Springer, J. P. J. Med.
Chem. 1989, 32, 2282. (f) Ankersen, M.; Peschke, B.;
Hansen, B. S.; Hansen, T. K. Bioorg. Med. Chem. Lett. 1997,
7, 1293.
(5) Hagen, H.; Becke, F. Ger. Offen. DE 2,060,082, 1972;
Chem. Abstr. 1972, 77, 88511.
(6) Torgova, S. I.; Karamysheva, L. A.; Geivandova, T. A.;
Strigazzi, A. Mol. Cryst. Liq. Cryst. Sci. Technol., Sect. A
2001, 365, 99.
(7) (a) Wang, Y.; Miller, R. L.; Sauer, D. R.; Djuric, S. W. Org.
Lett. 2005, 7, 925. (b) Evans, M. D.; Ring, J.; Schoen, A.;
Bell, A.; Edwards, P.; Berthelot, D.; Nicewonger, R.;
Baldino, C. M. Tetrahedron Lett. 2003, 44, 9337.
(c) Kaboudin, B.; Navaee, K. Heterocycles 2003, 60, 2287.
(8) Microwaves in Organic Synthesis, 2nd reprint; Loupy, A.,
Ed.; Wiley-VCH: Weinheim, 2004.
(9) The experiments were performed using a microwave oven
(ETHOS 1600, Milestone) with a power of 600 W specially
designed for organic synthesis.
Table 1 Synthesis of 1,2,4-Oxadiazoles 5a–n
5
a
b
c
d
e
f
Ar
R
Mp (reported)
37–39 (41)10a
Colorless oil10b
Colorless oil10b
77–79 (80)10a
Yield (%)a
C6H5
H
98
94
97
98
98
98
95
94
84
81
85
85
87
87
2-CH3C6H4
3-CH3C6H4
4-CH3C6H4
3-ClC6H4
4-ClC6H4
3-BrC6H4
4-BrC6H4
C6H5
H
H
H
H
70–72 (70–72)10c
73–78
H
g
h
i
H
58–61
H
99–100 (103)10a
Colorless oil10d
Colorless oil
Colorless oil
30–32
CH3
CH3
CH3
CH3
CH3
CH3
j
4-CH3C6H4
3-ClC6H4
4-ClC6H4
3-BrC6H4
4-BrC6H4
k
l
m
n
Colorless oil
37–39
a Isolated yields.
reaction times, one-pot and solvent-free conditions and
also using Meldrum’s acids instead of carboxylic acid
derivatives are the main advantages of this method. This
method appears to have broad scope with respect to
variation in the oxadiazole 3- and 5-positions and presents
a straightforward procedure for the synthesis of 1,2,4-
oxadiazoles.
(10) (a) Clarke, K. J. Chem. Soc. 1954, 4251. (b) Srivastava, R.
M.; Mendes e Silva, L. M. J. Chem. Eng. Data 1984, 29,
221. (c) Young, T. E.; Beidler, W. T. J. Org. Chem. 1985,
50, 1182. (d) Chiou, S.; Shine, H. J. J. Heterocycl. Chem.
1989, 26, 125.
(11) Preparation of 5-Methyl-3-phenyl-1,2,4-oxadiazole (5a);
General Procedure.
Acknowledgment
A mixture of benzonitrile (0.21 g, 2 mmol), NH2OH 50%
(0.13 g, 2 mmol), and a catalytic amount of AcOH was
irradiated with microwaves at 100 °C for 1 min. After nearly
complete conversion to the corresponding amidoxime as
was indicated by TLC, Meldrum’s acid (0.29 g, 2 mmol) was
added to the reaction mixture and it was irradiated at 150 °C
for a further 2 min. After cooling to r.t., the solid residue was
sublimated and 5a obtained as colorless crystals. In the case
of the products 5d–h, the obtained crude solid were purified
by recrystallization from 95% EtOH, and the products
5b,c,i–n were purified by column chromatography (4:1 n-
hexane–EtOAc as eluent, Merck silica gel 60 mesh).
This research was supported by the Research Council of the Uni-
versity of Tehran as research project (6102036/1/02).
References and Notes
(1) Jochims, J. C. In Comprehensive Heterocyclic Chemistry II,
Vol. 4; Katritzky, A. R.; Rees, C. W.; Scriven, E. V. F., Eds.;
Pergamon Press: London, 1996, Chap. 4, 179–228; and
references therein.
Synlett 2006, No. 11, 1765–1767 © Thieme Stuttgart · New York

LETTER
Selected Data.
Synthesis of 1,2,4-Oxadiazoles
1767
Compound 5j: colorless oil. 1H NMR (500.1 MHz, CDCl3):
d = 1.40 (3 H, t, J = 7.6 Hz, CH2CH3), 2.35 (3 H, s, CH3),
2.91 (2 H, q, J = 7.6 Hz, CH2), 7.22 (2 H, d, J = 8.0 Hz, 2 ×
CH), 7.92 (2 H, d, J = 8.0 Hz, 2 × CH). 13C NMR (125.8
MHz, CDCl3): d = 10.78 (CH2CH3), 20.27 (CH2), 21.45
(PhCH3), 124.21 (C), 127.29 and 129.48 (2 × CH), 141.26
(C), 168.22 (NCN), 180.51 (NCO).
Compound 5a: colorless crystals. 1H NMR (500.1 MHz,
CDCl3): d = 2.60 (3 H, s, CH3), 7.45 (3 H, m, 3 × CH), 8.04
(2 H, dd, J = 7.8 Hz and J = 1.7 Hz, 2 × CH). 13C NMR
(125.8 MHz, CDCl3): d = 12.30 (CH3), 124.01 (C), 127.32,
128.80, and 131.05 (3 × CH), 168.38 (NCN), 176.29 (NCO).
Compound 5d: colorless crystals. 1H NMR (500.1 MHz,
CDCl3): d = 2.36 (3 H, s, PhCH3), 2.58 (3 H, s, CH3), 7.23 (2
H, d, J = 7.8 Hz, 2 × CH), 7.92 (2 H, d, J = 7.8 Hz, 2 × CH).
13C NMR (125.8 MHz, CDCl3): d = 12.25 (CH3), 21.44
(PhCH3), 124.00 (C), 127.21 and 129.48 (2 × CH), 141.31
(C), 168.32 (NCN), 176.27 (NCO).
Compound 5l: colorless crystals. 1H NMR (500.1 MHz,
CDCl3): d = 1.42 (3 H, t, J = 7.6 Hz, CH3), 2.94 (2 H, q,
J = 7.6 Hz, CH2), 7.42 (2 H, d, J = 8.5 Hz, 2 × CH), 7.98 (2
H, d, J = 8.5 Hz, 2 × CH). 13C NMR (125.8 MHz, CDCl3):
d = 10.78 (CH3), 20.30 (CH2), 125.51 (C), 128.69 and 129.11
(2 × CH), 137.15 (C), 167.46 (NCN), 180.91 (NCO).
Compound 5n: colorless crystals. 1H NMR (500.1 MHz,
CDCl3): d = 1.44 (3 H, t, J = 7.6 Hz, CH3), 2.97 (2 H, q,
J = 7.6 Hz, CH2), 7.60 (2 H, d, J = 8.5 Hz, 2 × CH), 7.94 (2
H, d, J = 8.5 Hz, 2 × CH). 13C NMR (125.8 MHz, CDCl3):
d = 10.81 (CH3), 20.33 (CH2), 125.59 and 125.98 (2 × C),
128.91 and 132.11 (2 × CH), 167.59 (NCN), 180.98 (NCO).
Compound 5e: colorless crystals. 1H NMR (500.1 MHz,
CDCl3): d = 2.62 (3 H, s, CH3), 7.37 (1 H, t, J = 7.9 Hz, CH),
7.43 (1 H, dd, J = 8.1 Hz and J = 1.1 Hz, CH), 7.91 (1 H, d,
J = 7.7 Hz, CH), 8.03 (1 H, s, CH). 13C NMR (125.8 MHz,
CDCl3): d = 12.30 (CH3), 125.36 and 127.45 (2 × CH),
128.58 (C), 130.11 and 131.09 (2 × CH), 134.92 (C), 167.41
(NCN), 176.78 (NCO).
Synlett 2006, No. 11, 1765–1767 © Thieme Stuttgart · New York