Ultrasound-promoted synthesis of 3-trichloromethyl-5-alkyl(aryl)-1,2,4- oxadiazoles

Article abstract of DOI:10.1016/j.ultsonch.2010.09.016

The alternative synthesis of 12 1,2,4-oxadiazoles using ultrasound irradiation from trichloroacetoamidoxime and acyl chlorides is reported. Seven of them are novel compounds. The 3-trichloromethyl-5alkyl(aryl)-1,2,4- oxadiazoles have been synthesised in b

Full text of DOI:10.1016/j.ultsonch.2010.09.016

Ultrasonics Sonochemistry 18 (2011) 704–707
Contents lists available at ScienceDirect
Ultrasonics Sonochemistry
journal homepage: www.elsevier.com/locate/ultsonch
Ultrasound-promoted synthesis of 3-trichloromethyl-5-alkyl(aryl)-1,2,4-
oxadiazoles
Lizandra C. Bretanha, Vinicius E. Teixeira, Marina Ritter, Geonir M. Siqueira, Wilson Cunico,
⇑
Claudio M.P. Pereira, Rogério A. Freitag
NuQuiA – Núcleo de Química Aplicada, Departamento de Química Orgânica, Universidade Federal de Pelotas/Caixa Postal 354, CEP 96010-900, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 12 April 2010
Received in revised form 16 August 2010
Accepted 30 September 2010
Available online 14 October 2010
The alternative synthesis of 12 1,2,4-oxadiazoles using ultrasound irradiation from trichloroace-
toamidoxime and acyl chlorides is reported. Seven of them are novel compounds. The 3-trichloro-
methyl-5alkyl(aryl)-1,2,4-oxadiazoles have been synthesised in better yields and shorter reaction
times compared to the conventional method. This protocol can be applicable for preparation of 1,2,4-oxa-
diazoles containing aryl or alkyl groups attached at their C-5 side-chain.
Ó 2010 Elsevier B.V. All rights reserved.
Keywords:
1,2,4-Oxadiazoles
Heterocycles
Ultrasonic irradiation
1. Introduction
ticular heterocyclic compounds, has been applied with success, and
generates products in good to excellent yields [18–20].
1,2,4-Oxadiazoles are well-known heterocyclic compounds that
have been given much attention in pharmacological evaluations
[1]. This heterocycle has been utilized as ester or amide bioisosters
[2], and it is being examined as having a role in certain drug sys-
tems, including the potent S1P1 agonist, hemetabotropic glutamate
subtype (mGlu5) receptor, muscarinic receptor for the treatment of
Alzheimer’s disease [3]. Several papers described the use of 1,2,4-
oxdiazole in peptide mimetic synthesis, including the design of
amino acyl-Gly dipeptidomimetics, signal transduction inhibitors,
or cell adhesion inhibitors [3–9]. Recent publications have also
shown their applicability in the field of luminescent liquid crystals,
materials for optical devices, and charge-transporters for organic
light-emitting diodes (OLEDs) [10–13].
The most common protocol for the synthesis of 1,2,4-oxadiaz-
oles involves O-acylation of amidoximes followed by intramolecu-
lar condensation with water elimination [9]. The commonly used
acylating agents are acyl chlorides [9,15], anhydrides, esters
[2,13], and trichloroalkanes and carboxylic acid (with coupling
agents like DCC, DIC or EDC) [14]. However, these reactions re-
quired long reactions times, high temperatures, produce by-prod-
ucts and, in general, have difficult purifications [16,17].
Ultrasound irradiation, an efficient and innocuous technique for re-
agent activation in the synthesis of organic compounds, and in par-
Ultrasound-promoted synthesis has attracted much attention
during the past few decades. One advantage of using cavitation
as an energy source to promote organic reactions includes shorter
reaction times [19]. During the rarefaction cycle in the cavitation
process, the molecules of the liquid are separated, generating
bubbles that subsequently collapse in the compression cycle. These
rapid and violent implosions generate short-lived regions with
temperatures of roughly 5000 °C, pressures of about 1000 atm
and heating and cooling rates above 10 billion °C per second. Such
localized hot spots can be thought as micro reactors in which the
energy of sound is transformed into a useful chemical form
[19–21]. This procedure has been considered as a clean and useful
protocol in organic synthesis compared with traditional methods,
and the procedure is, in general, more convenient [19].
In previously work we synthesised 3-trichloromethyl-5-alkyl-
1,2,4-oxadiazoles in good yields using toluene reflux for 20 h [9].
In this context we decided to explore the efficient, simple and fast
synthesis of their corresponding heterocycles using ultrasound
irradiation.
2. Results
The precursor trichloroacetoamidoxime 1 was synthesised in
excellent yields (90%) by reaction of trichloroacetonitrile with
hydroxylamine hydrochloride in water at 25 for 3 h [9].
⇑
In order to optimize the reaction conditions, a small solvent
screen was studied (Table 1). In these experiments, we have
Corresponding author. Tel.: +55 53 3275 7358; fax: +55 53 3275 7354.
E-mail address: freitag@ufpel.edu.br (R.A. Freitag).
1350-4177/$ - see front matter Ó 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.ultsonch.2010.09.016

L.C. Bretanha et al. / Ultrasonics Sonochemistry 18 (2011) 704–707
705
Table 1
Optimization for the synthesis of 3-trichloromethyl-5-phenyl-1,2,4-oxadiazoles 3a.
3.1. General methods
All solvents and reagents were obtained from Aldrich and used
without further purification. The NMR spectra were recorded on a
Bruker DPX 400 (1H at 400.13 MHz and for 13C at 100.63 MHz)
spectrometer, 5 mm sample tubs, 298 K, digital resolution
of 0.01 ppm, 0.5 M in CDCl3, containing TMS as internal standard.
Mass spectra were obtained using an HP 6890 GC connected to an
HP 5973 MSD and interfaced by a Pentium PC. The GC was
equipped with a split-splitless injector, auto sampler, cross-linked
HP-5 capillary column (30 m, 0.32 mm of internal diameter), and
helium was used as the carrier gas.
Entry
Solvent
Time (min)
Yield (%)
1
2
3
4
5
Toluene
Hexane
THF
Ethyl acetate
1,2-Dichloroetane
15
15
15
15
15
76
90
95
92
93
O
OH
O
N
N
N
Cl
Cl3C
NH2
Cl3C
3a
3.2. Synthesis of 3-trichloromethyl-5-alkyl(aryl)-1,2,4-oxadiazoles
)))
15 min
1
2a
To a solution of the trichloroacetoamidoxime 1 (0.003 mol) in
ethyl acetate was added of acyl chloride 2a-l (0.0036 mol). The
reaction mixtures were irradiated with an ultrasound probe for
15 min (the reaction was monitored by TLC). After that time, the
organic layer was washed twice in water, twice in Na2CO3 solution,
and one in water. The organic layer was dried and the solvent was
removed under reduced pressure. Finally, the 5-alkyl(aryl)-3-tri-
chloromethyl-1,2,4-oxadiazoles were obtained in good yields
without any further purification.
Scheme 1.
O
OH
O
N
N
N
R
Cl
R
2
Cl3C
NH2
Cl3C
)))
1
3a-l
3.3. Products data
R = Ph, MePh, 4-nitroPh, 2-fluorPh, 2-MeOPh,
3-bromoPh, 2-iodoPh, Me, Et, ClCH2, Cl2CH
CCl3
3.3.1. 3-Trichloromethyl-5-phenyl-1,2,4-oxadiazole 3a
C9H5Cl3N2O; 263; mp 72 °C; yield (90%); 1H NMR (400 MHz;
CDCl3): d (ppm) 8.20 and 7.26 (m, 5H, Ph); MS CG–MS (EI 70 eV):
m/z (%) 262(9)[M+1], 264 (9), 229(63), 228(9.5), 227(100),
126(22), 124(33), 105(25), 103(35), 77(74), 76(21), 50(21), 51(43).
Scheme 2.
observed that the reaction between trichloroacetoamidoxime 1
with benzoyl chloride 2a under ultrasonic irradiation was solvent
dependent (Scheme 1, Table 1). Although the reaction time was
shorter than in the literature, the procedure could be improved,
and thus other solvent were tested. We found that the ethyl ace-
tate was the appropriated solvent for these reactions. Though the
reaction in THF showed goods yields (95%), the reaction require
two steps for extraction of the final product. Thus, ethyl acetate
was the better solvent for the reaction, since the solvent of reaction
was the same as used in the extraction in the latter case.
The important points of this reaction process include the easier
work-up, shorter reaction time, and higher yields than the conven-
tional method.
3.3.2. 3-Trichloromethyl-5-[4-methylphenyl]-1,2,4-oxadiazoles 3b
C
10H7Cl3N2O; 275; mp 163; yield (93%); 1H NMR (400 MHz;
CDCl3): d (ppm) 8.12–7.82 (m, 4H, aryl), 2.42 (s, 3H, CH3); MS
CG–MS (EI 70 eV): m/z (%) 275 [M+1] (1), 272(20), 271(71),
269(100),126(6), 119(20), 117(26), 108(15), 91(10).
3.3.3. 3-Trichloromethyl-5-[4-nitrophenyl]-1,2,4-oxadiazole 3c
C9H4Cl3N3O3; 306; mp 110; yield (94%); 1H NMR (400 MHz;
CDCl3): d (ppm) 8.95–8.46 (m, 4H, aryl); 13C NMR (100 MHz;
CDCl3): d (ppm) 177.1 (C5), 169.7 (C3), 148.3–125.2 (aryl), 99.9
(CCl3); MS CG–MS (EI, 70 eV): m/z (%) 306 [M+], 307(10), 273(66),
272(12), 271(100), 126(29), 124(44), 120(7), 118 (7), 117(6).
The 5-alkyl(aryl)-3-trichloromethyl-1,2,4-oxadiazoles 3a-l
were synthesised by treatment of trichloroacetamidoxime 1 with
acyl chlorides 2a-l for 15 min under ultrasonic irradiation using
ethyl acetate as solvent (Scheme 2). The heterocycles 3a-l were ob-
tained in good yields without purification (84–98%). The scope and
generality of this process is illustrated by a series of twelve com-
pounds and the results are presented in Table 2. The compounds
2a-j were synthesised by conventional method according to the lit-
erature [9]. The products were identified using both analytical and
spectral data (1H and 13C NMR) and all compounds are in full
agreement with the proposed structure.
3.3.4. 3-Trichloromethyl-5[2-fluorphenyl]-1,2,4-oxadiazole 3d
C9H4Cl3FN2O; 279; mp 53; yield (95%); 1H NMR (400 MHz;
CDCl3): d (ppm) 8.09–7.13 (m, 4H, aryl); 13C NMR (100 MHz;
CDCl3): d (ppm) 174.7 (C5), 170.5 (C3), 157.2–116.9 (aryl), 91.0
(CCl3); MS CG–MS (EI 70 eV): m/z (%) 280 [M+1] (11), 282(10),
249(11), 247(66), 246(11), 245(100), 126(27), 124(46), 123(23),
121(31).
3.3.5. 3-Trichloromethyl-5-[2-metoxiphenyl]-1,2,4-oxadiazole 3e
C
10H7Cl3N2O2; 291; yield (84%); 1H NMR (400 MHz; CDCl3): d
(ppm) 9.25–8.34 (m, 4H, aryl), 4.63 (s, 3H, OCH3); 13C NMR
(100 MHz; CDCl3): d (ppm) 177.2 (C5), 170.1 (C3), 158.4–110.9
(aryl), 85.4 (CCl3); MS CG–MS (EI 70 eV): m/z (%) 291[M+] (7),
292(6), 133(100), 132(12), 126(10), 124(16), 121(38), 119(10),
105(19), 104(14), 77(32).
3. Conclusions
In conclusion, we have described the simple and rapid prepara-
tion of 1,2,4-oxadiazoles under ultrasound irradiation. The final
products were obtained in short times and excellent yields (84–
98%), better than through the use of the conventional process
(60–90%), which required significantly longer reaction times.
3.3.6. 3-Trichloromethyl-5-[3-bromophenyl]-1,2,4-oxadiazole 3f
C9H4BrCl3N2O; 339; mp 185; yield (96%); 1H NMR (400 MHz;
CDCl3): d (ppm) 8.36–7.46 (m, 4H, aryl); 13C NMR (100 MHz;
CDCl3): d (ppm) 170.7 (C5), 165.9 (C3), 136.1–121.8 (aryl), 91.2

706
L.C. Bretanha et al. / Ultrasonics Sonochemistry 18 (2011) 704–707
Table 2
Synthesis of 3-trichloromethyl-5-alkyl(aryl)-1,2,4-oxadiazoles 3a-l under ultrasound irradiation.
Product
MF/WM
Conventional method
Time (hour)
20
Ultrasound irradiation
Yields (%)
70
Time (min)
15
Yields (%)
92
3a
3b
3c
3d
C9H5Cl3N2O (261,95)
O
N
N
O
Cl3C
Cl3C
Cl3C
Cl3C
C10H7Cl3N2O (275,96)
C9H4Cl3N3O3 (306,93)
C9H4Cl3FN2O (279,94)
20
20
20
90
64
78
15
15
15
93
94
95
N
N
N
N
O
NO2
N
O
N
F
3e
3f
C10H7Cl3N2O2 (291,96)
C9H4BrCl3N2O (339,86)
C9H4Cl3IN2O (387,84)
20
20
20
80
74
85
15
15
15
84
96
98
O
N
N
N
N
Cl3C
Cl3C
Cl3C
MeO
O
N
Br
3ga
O
N
I
3ha
3ia
3ja
3ka
3la
C4H3Cl3N2O (199,93)
C5H5Cl3N2O (213,95)
C4H2Cl4N2O (233,89)
C4HCl5N2O (267,85)
C4Cl6N2O (301,8)
20
20
20
20
20
61
60
80
74
90
15
15
15
15
15
86
90
89
88
90
O
N
N
N
N
N
N
O
Cl3C
Cl3C
Cl3C
Cl3C
Cl3C
N
O
N
O
Cl
Cl
N
O
Cl
CCl3
N
a
Ref. [9].
(CCl3); MS CG–MS (EI 70 eV): m/z (%) 343[M+ 4] (11), 342(13),
341(22), 308(45), 306(100), 304(61), 156(23), 154(25), 126(34),
124(53).
References
[1] J.C. Jochims, In comprehensive heterocyclic chemistry II, in: A.R. Katritzky,
C.W. Rees, E.F.D. Scriven (Eds.), Elsevier Science, Oxford, 1996, pp. 179–228.
[2] J.K. Agustine, V. Akabote, S.G. Hegde, P. Alagarsamy, J. Org. Chem. 74 (2009)
5640.
3.3.7. 3-Trichloromethyl-5-[2-iodophenyl]-1,2,4-oxadiazole 3g
C9H4ICl3N2O; 387; mp 115; yield (98%); 1H NMR (400 MHz;
CDCl3): d (ppm) 9.31–8.39 (m, 4H, aryl); 13C NMR (100 MHz;
CDCl3): d (ppm) 170.4 (C5), 163.6 (C3), 94.1–140.5 (aryl), 91.1
(CCl3); MS CG–MS (EI 70 eV): m/z (%) 387 [M+] (31), 388(34),
354(66), 353(100), 288(13), 126(24), 124(35), 77(4), 76(52).
[3] M. Adib, A.H. Jahromi, N. Tavoosi, M. Mahdavia, H.R. Bijanzadeh, Tetrahedron
Lett 47 (2006) 2965.
[4] R.F. Poulain, A.L. Tartar, B.P. Deprez, Tetrahedron Lett. 42 (2001) 1495.
[5] A.C.L. Leite, R.F. Vieira, A.R. Faria, A.G. Wanderley, P. Afiatpour, E.C. Ximenes,
R.M. Srivastava, C.F. Oliveira, M.V. Medeiros, E. Antunes, D.J. Brindani, IL
Farmaco 55 (2000) 719.
[6] M.L. Boys, L.A. Schretzman, N.S. Chandrakumar, M.B. Tollefson, S.B. Mohler, V.L.
Downs, T.D. Penning, M.A. Russell, J.A. Wendt, B.B. Chen, H.G. Stenmark, H. Wu,
D.P. Spangler, M. Clare, B.N. Desai, I.K. Khanna, M.N. Nguyen, T. Duffin, W.
Englemn, J.L. Keene, M. Westlin, W. Westlin, Y.X. Yu, Y. Wang, C.R. Dalton, S.
Norring, Bioorg. Med. Chem. Lett. 16 (2006) 839.
[7] V.V. Sureshbabu, H.P. Hemantha, S.A. Naik, Tetrahedron Lett. 49 (2008) 5133.
[8] A. Hamze, J.F. Hernandez, P. Fulcrand, J. Martinez, J. Org. Chem. 68 (2003) 7316.
[9] L.C. Bretanha, D. Venzke, P.T. Campos, A. Duarte, M.A.P. Martins, G.M. Siqueira,
R.A. Freitag. Arkivoc xii (2009) 1–7.
Acknowledgment
The authors would like to thanks the CNPq (Project 476769/
2004-3) and CAPES for financial support.

L.C. Bretanha et al. / Ultrasonics Sonochemistry 18 (2011) 704–707
707
[10] R.A.W.N. Filho, N.M.M. Bezerra, J.M. Guedes, R.M. Srivastava, J. Braz. Chem. Soc.
[16] R. Lenaers. Patent, 1965, US 3211742 19651012.
20 (2009) 1365.
[17] L. Pizzuti, P.L.G. Martins, B.A. Ribeiro, F.H. Quina, E. Pinto, A.F.C. Flores, D.
Venzke, C.M.P. Pereira, Ultrason. Sonochem. 17 (2010) 34.
[18] J.T. Li, Y. Yin, L. Li, M.X. Sun, Ultrason. Sonochem. 17 (2010) 11.
[19] R.M. Srivastava, R.A.W.N. Filho, C.A. Silva, A. Bortoluzzi, Ultrason. Sonochem.
16 (2009) 737.
[11] S. Buscemi, V. Frenna, N. Vivona, G. Petrillo, D. Spinelli, Tetrahedron Lett. 51
(1995) 5133.
[12] S. Buscemi, A. Pace, A.P. Piccionello, N. Vivona, J. Fluorine Chem. 127 (2006)
1601.
[13] N.M.M. Bezerra, S.P. Oliveira, R.M. Srivastava, J.R. Silva, IL Fármaco 60 (2005)
955.
[20] A. Duarte, W. Cunico, C.M.P. Pereira, A.F.C. Flores, R.A. Freitag, G.M. Siqueira,
Ultrason. Sonochem. 17 (2010) 281.
[14] G.B. Liang, D.D. Feng, Tetrahedron Lett 37 (1996) 662.
[15] A.D. Gutman. Patent, U.S. 1968 US 4279638 19810721.
[21] H.A. Stefani, C.M.P. Pereira, R.B. Almeida, R.C. Braga, K.P. Guzenb, R. Cellac,
Tetrahedron Lett 46 (2005) 6833.