A suitable 1,2,4-oxadiazoles synthesis by microwave irradiation

Article abstract of DOI:10.1016/j.bmcl.2004.06.048

A novel and convenient microwave-assisted synthesis of 1,2,4-oxadiazoles is described. Conventional heating and microwave irradiation of the reactions are compared. Moreover, the importance of some coupling reagents was evaluated. One pot microwave-assisted synthesis of substituted 1,2,4-oxadiazoles in solvent and under solvent free condition was performed exploring the importance of some coupling reagents. Good yields and short reaction times were the main aspects of the methods.

Full text of DOI:10.1016/j.bmcl.2004.06.048

Bioorganic & Medicinal Chemistry Letters 14 (2004) 4491–4493
A suitable 1,2,4-oxadiazoles synthesis by microwave irradiation
*
Vincenzo Santagada, Francesco Frecentese, Elisa Perissutti, Donatella Cirillo,
Sara Terracciano and Giuseppe Caliendo
Dipartimento di Chimica Farmaceutica e Tossicologica, Universit a` di Napoli ‘Federico II’, Via D. Montesano, 49, 80131 Naples, Italy
Received 24 March2004; revised 7 June 2004; accepted 16 June 2004
Available online 17 July 2004
Abstract—One pot microwave-assisted synthesis of substituted 1,2,4-oxadiazoles in solvent and under solvent free condition was
performed exploring the importance of some coupling reagents. Good yields and short reaction times were the main aspects of
the methods.
Ó 2004 Elsevier Ltd. All rights reserved.
2
c
Bioisosteric replacements for the amide moiety represent
an area that is currently the centre of focus because of its
implications in peptide chemistry and the development
of peptidomimetics. Peptide linkages have been replaced
witha wide variety of structural moieties in an attempt
to create chemically stable and orally available mole-
cules. Heterocyclic rings suchas 1,2,4-oxadiazoles and
growt ho hr mone secretagogous.
1,2,4-Oxadiazoles
can be formed by the reaction of an amidoximes with
a carboxylic acid or acid chloride. A wide variety of
reaction conditions have been published for the syn-
thesis of 1,2,4-oxadiazoles in solution, on solid phase
3
or under solvent free conditions. Knowing the impor-
tance of the 1,2,4-oxadiazole ring as pharmacophoric
scaffold, our attention has turned to improve the synthe-
sis of this important nucleus bearing in mind new syn-
thetic methodologies. The application of microwave
energy to organic compounds for conducting synthetic
reactions at highly accelerated rates is an emerging tech-
nique. In fact in later years, microwaves have become
popular among synthetic organic chemists both to im-
prove classical organic reactions, shortening reaction
times and/or improving yields, as well as to promote
1
the amide functionality in biologically active com-
,3,4-oxadiazoles have been used as replacements for
1
pounds. These compounds contain reactive intermedi-
ate functionality, thus allowing easy incorporation into
the parent molecule by a variety of synthetic transfor-
mations. Moreover, the oxadiazole nucleus is a well
studied traditional pharmacophoric scaffold that has
emerged as a core structural unit of various muscarinic
4
,5
2
a
2b
agonists, benzodiazepine receptor partial agonists,
HO
N
N
O
a) coupling reagent, overnight
b) microwawe, 100 ˚C, 30 min
i
COOH
NH
2
N
+ X
H
C
a) coupling reagent, neutral alumina H
b) microwawe, 60 ˚C, 4 min
3
C
X
3
ii
X= H, NO2 OCH CH
,
2 3
i= solution method
ii=solvent free method
Scheme 1. General synthetic procedure of 1,2,4-oxadiazole derivatives.
Keywords: 1,2,4-Oxadiazoles; Microwave irradiation.
*
0
Corresponding author. Tel.: +39-81-678648; fax: +39-81-678649; e-mail: santagad@unina.it
960-894X/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2004.06.048

4492
V. Santagada et al. / Bioorg. Med. Chem. Lett. 14 (2004) 4491–4493
new reactions. This paper describes a facile synthesis of
,2,4-oxadiazole derivatives by application of micro-
1
wave energy in the presence of solvents and under sol-
vent free condition. At first we investigated, in the
presence of solvent, the O-acylation of an amidoxime
witha few carboxylic acids mediated by some peptide
coupling reagents and the subsequent cyclization reac-
tion (Scheme 1, i).
Conventional heating (oil bath) and microwave irradia-
tion of the reactions were compared (Table 1). The
synthetic procedure, summarized in Scheme 1, was
performed using a microwave oven (ETHOS 1600, Mile-
stone) especially designed for organic synthesis. The
experimental conditions used during microwave applica-
tion were similar, witht he same concentration of start-
ing material and volume of solvent, to those used by
conventional heating. All reactions were performed in
standard Pyrex glassware and were performed by micro-
wave program, which was composed by appropriate
ramping and holding steps. Identification of the opti-
mum profile power/time and temperature for the synthe-
sis was reported in Table 1. The temperature of the
stirred reaction mixture was monitored directly by a
microwave-transparent fluoroptic probe inserted into
the solution. The general procedure for the synthesis
of 1,2,4-oxadiazole derivatives in solution, reported in
6
Scheme 1, is as follows: p-toluene amidoxime and the
carboxylic acid were dissolved in the solvent in the pres-
ence of the coupling reagents. The reaction mixture was
stirred overnight and then transferred, according to our
procedure, in the microwave oven. A starting tempera-
ture of 50°C for the acylation step was used with
EDC in order to facilitate the dissolution of this cou-
pling reagent in diglyme or in DMF; botht he se condi-
tions are necessary in the conventional synthetic
method than in the microwave procedure proposed by
us. The main advantage to this synthetic route is that
a short time of irradiation of the mixture reaction pro-
vided the 1,2,4-oxadiazole derivatives as the major prod-
uct. If the application of microwave energy was
performed for a longer time (>30min, Table 1) the rea-
gents were not completely transformed in the corre-
sponding 1,2,4-oxadiazole derivatives. The results
obtained withthe considered coupling reagents are sum-
marized in Table 1. For compounds 4–9 we obtained
higher yields (68–94%) using TBTU/HOBt and DCC/
HOBt, while with DCC, EDC and CDI the yields were
lower (27–50%, compd 1–3). Instead, reactions per-
formed under conventional heating always gave the de-
sired 1,2,4-oxadiazoles in lower yields. We have also
investigated the electronic effects on the overall reaction
using different substituted benzoic acids. Compounds 8
and 9, withelectron donor substituent (OEt) gave lower
yields (75–68%) withrespect to compounds 6 and 7,
characterized by electronic withdraw substituent (NO2,
9
4–91%), or unsubstituted acid 4 and 5 (93–88%).
When the reactions were performed under solvent free
7
conditions, in the presence of neutral alumina as sup-
port, (Scheme 1, ii) the time of reaction was greatly re-
duced (4min). Yields were always lower respect the
solution microwave method except for compound 2

V. Santagada et al. / Bioorg. Med. Chem. Lett. 14 (2004) 4491–4493
4493
(
EDC activation), while were comparable (compd 9) or
higher (compd 1–3) respect the conventional heating
Table 1). Even in the solvent free method the presence
Compd. (NY) 1999, 35, 630; (h) Ooi, N. S.; Wilson, D. A. J.
Chem. Soc., Perkin Trans. 2 1980, 1792; (i) Anderseen, K.
E.; Lundt, B. F.; Joergensen, A. S.; Braestrup, C. Eur. J.
Med. Chem. 1996, 31, 417; (j) Gangloff, A. R.; Litvack, J.;
Shelton, J. E. J.; Sperandio, D.; Wang, V. R.; Rice, K. D.
Tetrahedron Lett. 2001, 42, 1441; (k) Hebert, N.; Hannah,
A. L.; Sutton, S. C. Tetrahedron Lett. 1999, 40, 8547; (l)
Oussaid, B.; Moeini, L.; Martin, B.; Villemin, D.; Garri-
gues, B. Synth. Commun. 1995, 25, 1451.
(
of a withdrawing group provided higher reaction yields.
In contrast to that observed in both the solution meth-
ods, the activation by DCC/HOBt represents the opti-
mal condition. No further yield increasing was
evidenced when the irradiation time was prolonged for
over 4min; this is related to the decomposition of the
starting materials. Finally, neat reaction was not suc-
cessful (we did not noticed the presence of the final com-
pound even if heating was prolonged for over 30min).
4. (a) Santagada, V.; Perissutti, E.; Fiorino, F.; Vivenzio, B.;
Caliendo, G. Tetrahedron Lett. 2001, 42, 2397; (b) Santa-
gada, V.; Fiorino, F.; Perissutti, E.; Severino, B.; De
Filippis, V.; Vivenzio, B.; Caliendo, G. Tetrahedron Lett.
2001, 42, 5171; (c) Caliendo, G.; Fiorino, F.; Perissutti, E.;
Severino, B.; Gessi, S.; Cattabriga, E.; Borea, P. A.;
Santagada, V. Eur. J. Med. Chem. 2001, 36(11–12), 873;
(d) Santagada, V.; Perissutti, E.; Caliendo, G. Curr. Med.
Chem. 2002, 9, 1251.
. (a) Loupy, A.; Petit, A.; Hamelin, J.; Texier-Boullet, F.;
Jacquault, P.; Mathe, D. Synthesis 1998, 1213–1234; (b)
Galema, S. A. Chem. Soc. Rev. 1997, 26, 233–238; (c)
Caddick, S. Tetrahedron 1995, 51, 10403; (d) Larhed, M.;
Hallberg, A. Drug Discov. Today 2001, 6, 406.
. General procedure of 1,2,4-oxadiazole derivatives in solu-
tion: Commercially available (Aldrich) p-toluene amidoxi-
me (1mmol) and 1equiv of carboxylic acid were dissolved
in 10mL of the solvent (diglyme or DMF) in the presence of
the coupling reagents (1equiv). An opportune quantity of
base (N-ethyldiisopropylamine) was added when TBTU/
HOBt was used. The reaction mixture was kept at room
temperature, under nitrogen atmosphere, overnight.
Then the vessel containing reaction mixture was transferred
in the microwave oven and was heated at 100°C by
application of microwave energy for 30min. The desired
parameters (microwave power, temperature and time) were
set as reported in Table 1. The reaction was monitored by
TLC. After irradiation, the solvent was removed and the
In conclusion, we have shown that the application of
microwave irradiation in to the solution method in pres-
ence of a peptide coupling reagent improves the yields of
1
,2,4-oxadiazole derivatives and significantly reduces
5
6
reaction times. Furthermore, when the cyclization was
performed under solvent free condition, reaction times
were strongly reduced although yields were not so satis-
factory.
Abbreviations and symbols. We have followed the recom-
mendations of the IUPAC-IUB Joint Commission on
Biochemical Nomenclature (Eur. J. Biochem. 1984,
1
TBTU,
38, 9). In addition the following abbreviations are used:
0 0
O-(1H-benzotriazol-1-yl)-N,N,N ,N -tetrame-
thyluronium tetrafluoroborate; HOBt, 1,2,3-benzotrial-
ole-1-hydroxide; DCC, dicyclohexyl-carbodiimide;
EDC, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
0
hydrochloride; CDI, 1,1 -carbonyldiimidazole.
References and notes
crude residue was purified by silica gel chromatography.
1,2,4-Oxadiazole derivatives were characterized by
NMR and MS and the data were consistent with the
considered structures. NMR spectra were recorded on a
Bruker WM 500 spectrometer using tetramethylsilane as an
internal standard. For the H-substituted derivatives (1–5):
1
H
1
. (a) 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;
(b) Street, L. J.; Baker, R.; Castro, J. L.; Chambers, M. S.;
Guiblin, A. R.; Hobbs, S. C.; Matassa, V. G.; Reeve, A. J.;
Beer, M. S.; Middlemiss, D. N. J. Med. Chem. 1993, 36,
1529; (c) Clithirow, J. W.; Beswick, P.; Irving, W. J.;
Scopes, D. I. C.; Barnes, J. C.; Clapham, J.; Brown, J. D.;
Evans, D. J.; Hayes, A. G. Bioorg. Med. Chem. Lett. 1996,
6, 833; (d) Swain, C. J.; Baker, R. A.; Kneen, C.; Mosely, J.;
mp 98–100°C, ESI: calcd for C15
H
N
O 237.26, found
): d 8.21 (d, 2H), d 8.08 (d,
2H), d 7.64 (dd, 1H), d 7.58 (d, 2H), d 7.37 (d, 2H), d 2.42 (s,
3H). NO
-substituted derivatives (6,7): mp 167–169°C,
ESI: calcd for C15
12
2
+
1
237.27 (MH ); H NMR (CDCl
3
2
+
H
N
O
282.27, found 287.26 (MH );
): d 8.41 (d, 4H), d 8.07 (d, 2H), d 7.34 (d,
2H), d 2.44 (s, 3H); OEt-substituted derivatives (8,9): mp
119–121°C, ESI: calcd for C17 281.31, found
3
281.32 (MH ); H NMR (CDCl ): d 8.13 (d, 2H), d 8.05
11
3
3
1
H NMR (CDCl
3
Saunders, J.; Seward, E. M.; Stevenson, G.; Beer, M.;
Stanton, J.; Watling, K. J. Med. Chem. 1991, 34, 140.
. (a) Orlek, B. S.; Balaney, F. E.; Braun, F.; Clark, M. S. G.;
Hadley, M. S.; Hatcher, J.; Riley, G. J.; Rosenberg, H. E.;
Wadsworth, H. J.; Wyman, P. J. Med. Chem. 1991, 34,
H N O
16 2 2
+
1
2
(d, 2H), d 7.31 (d, 2H), d 7.02 (d, 2H), d 4.11 (q, 2H), d 2.42
(s, 3H), d 1.46 (t, 3H).
2
726; (b) Watjen, F.; Baker, R.; Engelstoff, M.; Herbert, R.;
7. Synthesis of 1,2,4-oxadiazole derivatives under solvent free
conditions: p-Toluene amidoxime (1mmol), benzoic substi-
tuted acid (1equiv) and coupling reagents (1equiv) were
mixed with the neutral alumina in a 4:1 ratio. The mixture
was shacked for 5min. To have a complete mixing in the
powder, dichloromethane was added in small quantity to
solubilize the reagents and then the solvent was evaporated.
The reaction mixture was then irradiated by microwave for
4min. The desired parameters (microwave power, temper-
ature and time) were set as reported in Table 1. After
irradiation the solid was extracted in dichloromethane
MacLeod, A.; Knight, A.; Merchant, K.; Moseley, J.;
Saunders, J.; Swain, J.; Wong, E.; Springer, J. P. J. Med.
Chem. 1989, 32, 2282; (c) Ankersen, M.; Peschke, B.;
Hansen, B. S.; Hansen, T. K. Biorg. Med. Chem. Lett. 1997,
7
, 1293.
. (a) Kaboudin, B.; Navaee, K. Heterocycles 2003, 60, 2287;
b) Liang, G. B.; Feng, D. D. Tetrahedron Lett. 1996, 37,
3
(
6627; (c) Rice, K. D.; Nuss, J. M. Bioorg. Med. Chem. Lett.
2001, 11, 753; (d) Clapp, L. B. Adv. Heterocycl. Chem. 1976,
20, 65; (e) Korbonits, D.; Horvath, K. Heterocycles 1994,
37, 2051; (f) Chiou, S.; Shine, H. J. J. Heterocycl. Chem.
1989, 26, 125; (g) Kayukova, L. A.; Praliev, K. D.;
1
and purified by silica gel chromatography. H NMR
spectra and MS data were consistent witht he considered
structures.
Zhumadildaeva, I. S.; Klepikova, S. G. Chem. Heterocycl.