A convenient synthesis and cytotoxic activity of 3-aryl-5-pentyl-1,2,4- oxadiazoles from carboxylic acid esters and arylamidoximes under solvent-free conditions

Article abstract of DOI:10.4067/s0717-97072014000100024

The synthesis of 3-aryl-5-pentyl-1,2,4-oxadiazoles from carboxylic acid esters and arylamidoximes in the presence of potassium carbonate is described. The reaction was carried out in a microwave oven without any solvent in much shorter time and in good yields. The structures of the synthesized compounds were elucidated using IR, 1H and 13C NMR spectroscopy and elemental analysis and their antiproliferative activities was evaluated against three different human cell lines.

Full text of DOI:10.4067/s0717-97072014000100024

J. Chil. Chem. Soc., 59, Nº 1 (2014)
A CONVENIENT SYNTHESIS AND CYTOTOXIC ACTIVITY OF 3-ARYL-5-PENTYL-1,2,4-OXADIAZOLES FROM
CARBOXYLIC ACID ESTERS AND ARYLAMIDOXIMES UNDER SOLVENT-FREE CONDITIONS
CARLOS JONNATAN PIMENTEL BARROS,a ZILYANE CARDOSO DE SOUZA,a JUCLEITON JOSÉ RUFINO DE
FREITAS,a PAULO BRUNO NORBERTO DA SILVA,b GARDENIA CARMEN GADELHA MILITÃO,b,c TERESINHA
GONÇALVES DA SILVA,c JULIANO CARLO RUFINO FREITAS,a,d,* JOÃO RUFINO DE FREITAS FILHOa,*
aDepartamento de Química, Universidade Federal Rural de Pernambuco, Av. Dom Manoel de Medeiros, s/n, 52171-900, Recife, PE, Brazil.
bDepartamento de Fisiologia e Farmacologia, Universidade Federal de Pernambuco, Rua Nelson Chaves, s/n, 50670-901, Recife, PE, Brazil.
cDepartamento de Antibióticos, Universidade Federal de Pernambuco, Av. Artur de Sá, s/n, 50670-901, Recife, PE, Brazil.
dCentro de Educação e Saúde, Universidade Federal de Campina Grande, Olho D’agua da Bica, s/n, 58175-000, Cuité, PB, Brazil.
(Received: August 14, 2013 - Accepted: December 14, 2013)
ABSTRACT
The synthesis of 3-aryl-5-pentyl-1,2,4-oxadiazoles from carboxylic acid esters and arylamidoximes in the presence of potassium carbonate is described. The
reaction was carried out in a microwave oven without any solvent in much shorter time and in good yields. The structures of the synthesized compounds were
elucidated using IR, 1H and 13C NMR spectroscopy and elemental analysis and their antiproliferative activities was evaluated against three different human cell
lines.
Keywords: 1,2,4-Oxadiazoles; Amidoximes; Microwave oven; Cytotoxic Activity.
and thus are hard to store and handle, and only a few acid chlorides are readily
available. Other recently reported methods to obtain 1,2,4-oxadiazoles include
the use of PTSA-ZnCl2 as an efficient and catalytic reagent for the synthesis
of 1,2,4-oxadiazoles 3,5-disubstituted from amidoximes and organic nitriles.25
These reactions, however, require long reaction times, high temperatures,
produce by-products and, in general, the products obtained are difficult to
purify.26,27 Microwave irradiation, an efficient and innocuous technique for
reagent activation in the synthesis of organic compounds, and in particular
heterocyclic compounds, has been applied with success, and was able to
generate products in good to excellent yields.28,29,30,31
The use of microwave irradiation in organic chemistry has being widely
explored over the last few years.32 Two of the main advantages of this
technology are the potential for dramatically shortened reaction times and
access to reaction conditions that are not attainable with conventional thermal
heating.23
INTRODUCTION
The 1,2,4-oxadiazoles (fig. 1) represent a class of heterocyclics with
wide variety of biological activities, especially anti-inflamatory,1,2,3
a
antitumor4,5 and antifungal activities.6 Biologically relevant compounds
containing the 1,2,4-oxadiazole moiety also include HIV integrase inhibitors,7
antituberculostatic agents8 and antikinetoplastid agents.9 They are also reported
as inhibitors of tyrosine kinase,10 bacterial and human DNA topoisomerases,11
and human neutrophil elastase.12 Many 1,2,4-oxadiazoles 3,5-disubstituted
have been shown to be bioactive compounds. In the literature it is possible to
find compounds containing the 1,2,4-oxadiazole ring with differing activities
(Figure 1), for example: anti-diabetic (a),13 anti-inflammatory (b),3 antitumor
(c),14 anti-cancer (d)15 and larvicidal and fungicide (e).16
In this report, we describe the synthesis and cytotoxic activity of six 3-aryl-
5-pentyl-1,2,4-oxadiazoles 3a-f under solvent-free conditions employing an
unmodified domestic microwave oven. To the best of our awareness, this
contribution reports a simple and straightforward synthesis of 1,2,4-oxadiazoles
having a alkyl chain attached at C-5 in good yields. Conventionally, syntheses
of this class of compounds have been achieved in 5-18h.30,33
EXPERIMENTAL
General consideration:
All commercially available reagents were used directly without purification
unless otherwise stated. All the solvents used in reactions were distilled for
purity. IR spectra were recorded as KBr films on a Brucker IFFS66 series
Fourier transform spectrophotometer. 1H and 13C NMR spectra were recorded
on a Bruker DPX 400 spectrometer at 400 MHz and 100 MHz, respectively,
using CDCl3 as solvent and Me Si as the internal standard. Chemical shifts
are reported in ppm. Coupling4 constants are reported in Hz. Thin Layer
Chromatography (TLC) was performed using Merck® Silica gel 60 F Plates.
Microwave reactions were performed in a domestic microwave oven, 2S54ANYO,
model EM-300B (220 V; 650 W/2450 MHz). The precise heating area in the
oven was located, and the experiments were repeated several times.29
General Procedure for the Synthesis of ethyl hexanoate (2)
Hexanoic acid (7.00 g, 60.3 mmol), ethanol (65 mL) and sulfuric acid (0.70
mL), were refluxed for 4 hours. The progress of the reaction was monitored
by TLC on 0.2 mm precoated silica gel 60 F254 plates (E. Merck). After the
reaction, the alcohol in excess was removed under reduced pressure and the
residue was extracted with ethyl acetate. The ether extract was washed with a
solution of sodium bicarbonate and subsequently with distilled water, dried over
anhydrous sodium sulfate and concentrated in vacuo to yield the crude product,
which was purified by column chromatography silica gel 60 (Merck® 70–230
mesh) using 9:1 hexanes/EtOAc as eluent, to give the desired carboxylic ester
Figure 1. Examples of biologically active 1,2,4-oxadiazoles.
Generally, 1,2,4-oxadiazoles are synthesized by cyclodehydration of
O-acylamidoximes, promoted by either heat or by bases, such as NaH,
NaOEt or pyridine.17 The use of tetrabutylammonium fluoride (TBAF)
as an activator to promote the cyclization of O-acylamidoximes has been
reported.18 Historically, the preferred method of obtaining O-acylamidoximes
is through the reaction of amidoximes with activated carboxylic acid
derivatives or with carboxylic acids in the presence of a coupling reagent,
such as dicyclohexylcarbodiimide (DCC),19,20,21 1-[3-(dimethylamino)propyl]-
3-ethylcarbodiimide (EDC),11,20,22 2-(dimethylamino)isopropyl chloride
(DIC)/HOBt,11 bis-(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP-Cl),20
2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium
tetrafluoroborate
(TBTU),23 or 1,1’-carbonyldiimidazole (CDI).20,24 However, these methods
have several drawbacks. Acid chlorides are very toxic and reactive chemicals
e-mails: joaoveronice@yahoo.com.br and juliano.carlo@ufcg.edu.br
2359

J. Chil. Chem. Soc., 59, Nº 1 (2014)
(6.77 g, 78% yield). IR (KBr) nmax 2959, 2869, 1738, 1462, 1373, 1245, 1100,
1035, 735 cm-1. 1H NMR (400 MHz, CDCl ): d 4.13 (q, J = 6.8 Hz, 2H,
OCH2CH ), 2,29 (t, J = 7.2 Hz, 2H, CH2CO), 31.66-1.59 (m, 2H, CH2CH2CO),
1.35-1.283(m, 4H, (CH )2CH3), 1.26 (t, J = 6.8 Hz, 3H, OCH2CH3), 0.89 (t, J =
7.2 Hz, 3H, (CH ) CH2). 13C NMR (100 MHz, (CDCl ): d 173.8, 60.1, 34.3,
31.3, 24.6, 22.3, 2124.2, 313.8. The spectroscopic data of3synthesized compound
match with the reported values in the literature.34
carcinoma), HL-60 (pro-myelocytic leukemia) and HT29 (colon carcinoma)
provided by the Rio de Janeiro Cell Bank (RJ-Brazil). All cancer cells were
maintained in RPMI 1640 medium and DMEN supplemented with 10% fetal
bovine serum, 2mM glutamine, 100 U/mL penicillin, 100mg/mL streptomycin
at 37oC with 5% CO2. The cytotoxicity of all compounds was tested using the
3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H tetrazolium bromide (MTT)
(Sigma Aldrich Co., St. Louis, MO, USA) reduction assay. For all experiments,
tumor cells were plated in 96-well plates (105 cells/mL for adherent cells or
3×105 cells/mL for Leukemia). Tested Compounds (0.1–25 mg/mL) dissolved
in DMSO 1% were added to each well and incubated for 72 h. Control groups
received the same amount of DMSO. After 69h of treatment 25 mL of MTT
(5mg/mL) was added, three hours later, the MTT formazan product was
dissolved in 100 mL of DMSO, and absorbance was measured at 595 nm in
plate spectrophotometer. The IC values and their 95% confidence intervals
for two different experiments we5r0e obtained by nonlinear regression using the
Graphpad Prism program (Intuitive Software for Science, San Diego, CA).
General Procedure for the Synthesis of 3-aryl -5-pentyl-1,2,4-
oxadiazoles (3a-f)
A mixture of ethyl hexanoate 2 (0.22 g, 1.54 mmol), appropriate
arylamidoximes 1a–f (1.00 mmol) and K2CO3 (0.12g, 0.85 mmol) was well
triturated and placed in a small glass test tube followed by irradiation in a
domestic microwave oven (100% potency, 650 W) for 8 min and then cooled.
After that, the crude product was purified by chromatography on silica gel 60
(Merck® 70–230 mesh) using hexanes/EtOAc (9:1) to yield the corresponding
3-aryl-5-pentyl-1,2,4-oxadiazoles, 3a-f.
Compound 5-(pentyl)-3-(phenyl)-1,2,4-oxadiazole (3a): colorless oil,
1
yield 80%. IR (KBr) n 3068, 2917, 2848, 1596, 1446, 1025, 721 cm-1. H
RESULTS AND DISCUSSION
NMR (400 MHz, CDCmla)x: d 8.10-8.07 (m, 2H, H ), 7.52-7.45 (m, 3H, Haryl),
2.94 (t, 2H, J = 7.2 Hz,3Het-CH2), 1.89 (qui, J =ar7yl.2 Hz, 2H, Het-CH2-CH2),
1.46-1.37 (m, 4H, 2 x CH2), 0.93 (t, J = 7.2 Hz, 3H, CH3). 13C NMR (100
MHz, (CDCl3 ): d 179.7, 167.9, 130.7, 128.4, 127.0, 126.7, 30.8, 26.3, 26.0,
21.8, 13.5. Calcd for C13H16ON2: C, 72.19%; H, 7.46%; N, 12.95%. Found
for C13H16ON2: C, 72.08%; H, 7.19 %; N, 12.65%. The spectroscopic data of
synthesized compound match with the reported values in the literature.35
Compound 5-(pentyl)-3-(o-tolyl)- 1,2,4-oxadiazole (3b): colorless oil,
yield 80%. IR (KBr) nmax 3015, 2962, 2870, 1587, 1458, 1028, 745 cm-1. 1H
NMR (400 MHz, CDCl3 ): d 7.98 (d, J = 7.2 Hz, 1H, Haryl), 7.41-7.29 (m, 3H,
Haryl), 2.96 (t, J = 7.6 Hz, 2H, Het-CH ), 2.63 (s, 3H, CH3-Ph), 1.89 (qui, J = 7.6
Hz, Het-CH2-CH2); 1.47-1.37 (m, 4H2, 2 x CH2); 0.94 (t, J = 7.6 Hz, 3H, CH3).
13C NMR (100 MHz, (CDCl ): d 178.9, 168.8, 138.1, 131.3, 130.4, 129.9,
126.2, 125.9, 31.2, 26.5, 26.3,322.0, 13.8. Calcd for C H ON : C, 73.01%; H,
7.88%; N, 12.16%. Found for C14H ON2: C, 72.92%;1H4 ,178.762%; N, 12.13%.
Compound 5-(pentyl)-3-(m-to1l8yl)- 1,2,4-oxadiazole (3c): colorless oil,
yield 85%. IR (KBr) nmax 3023, 2968, 2869, 1585, 1465, 1021, 749 cm-1. 1H
NMR (400 MHz, CDCl3 ): d 7.90-7.87 (m, 2H, Haryl), 7.41-7.27 (m, 2H, H ),
2.94 (t, J = 7.2 Hz, 2H, Het-CH2), 2.42 (s, 3H, CH -Ph), 1.88 (qui, J =a7ry.l2
Hz, 2H, Het-CH2-CH2); 1.43-1.36 (m, 4H, 2 x CH2);30.93 (t, J = 7.2 Hz, 3H,
CH3). 13C NMR (100 MHz, (CDCl3 ): d 179.9, 168.3, 138.6, 131.8, 128.7,
127.9, 124.5, 123.2, 31.2, 26.6, 26.3, 22.1, 21.3, 13.8. Calcd for C14H18ON :
C, 73.01%; H, 7.88%; N, 12.16%. Found for C14H18ON2: C, 72.89%; H, 7.729
%; N, 12.09%.
In a typical experimental procedure, the ester or acid was refluxed or heated
to a certain predetermined temperature with the desired amount of alcohol in
the presence of sulfuric acid. The reaction was monitored by TLC and after
completion, the excess alcohol was removed and the residue was extracted
with ether. The ether extract, after being washed with sodium bicarbonate and
subsequently with distilled water, was evaporated to furnish the product with
78% yield.
Arylamidoximes 1a-f were synthesized in excellent yields (85-92%) using
a reaction of arylnitriles with hydroxylamine hydrochloride in the presence of
base under ultrasonic irradiation.36
The 3-aryl-5-pentyl-1,2,4-oxadiazoles 3a-f were synthesized by the
treatment of arylamidoxime 1a-f with ethyl hexanoate 2 for 8 minutes under
microwave irradiation using carbonate as base in solvent-free conditions
(Scheme 1). The solvent-free conditions likely contributed to the high efficiency
of this reaction in two ways: driving the reaction toward the desired oxadiazole
product by removing other volatile products and favored entropy effect by
achieving high concentration of arylamidoxime reactants. The heterocycles
3a-f were obtained in good yields after purification (80-85%).
Compound 5-(pentyl)-3-(p-tolyl)- 1,2,4-oxadiazole (3d): colorless oil,
yield 81%. IR (KBr) nmax 3033, 2958, 2870, 1590, 1465, 1017, 742 cm-1. 1H
NMR (400 MHz, CDCl ): d 7.96 (d, J = 8.4 Hz, 2H, Haryl), 7.28 (d, J = 8.4 Hz,
2H, Haryl), 2.93 (t, J = 7.36 Hz, 2H, Het-CH2), 2.41 (s, 3H, CH3-Ph); 1.88 (qui, J
= 7.6 Hz, 2H, Het-CH2-CH2); 1.43-1.35 (m, 4H, 2 x CH2); 0.92 (t, J = 7.6 Hz,
3H, CH3). 13C NMR (100 MHz, (CDCl3 ): d 179.8, 168.2, 141.3, 129.5, 127.3,
124.1, 31.2, 26.6, 26.3, 22.2, 21.5, 13.8. Calcd for C H ON : C, 73.01%; H,
7.88%; N, 12.16%. Found for C14H18ON2: C, 72.48%;14H,178 .932%; N, 12.01%.
Compound
3-(p-bromophenyl)-5-(pentyl)-1,2,4-oxadiazol
(3e):
Semisolid, yield 83%. IR (KBr) nmax 3060, 2957, 2859, 1588, 1469, 1012, 744
cm-1. 1H NMR (400 MHz, CDCl ): d 7.95 (d, J = 8.0 Hz, 2H, Haryl), 7.61 (d,
J = 8.0 Hz, 2H, Haryl), 2.94 (t, J =37.2 Hz, 2H, Het-CH2), 1.87 (qui, J = 7.2 Hz,
2H, Het-CH2-CH2); 1.43-1.36 (m, 4H, 2 x CH2); 0.93 (t, J = 7.2 Hz, 3H, CH3).
13C NMR (100 MHz, (CDCl3 ): d 180.3, 167.5, 132.1, 128.8, 125.9, 125.5,
31.1, 26.6, 26.3, 22.1, 13.8. Calcd for C13H15BrON : C, 52.90%; H, 5.12%;
N, 9.49%. Found for C13H BrON2: C, 52.82%; H,25.08 %; N, 9.23%. The
spectroscopic data of synth1e5sized compound match with the reported values
in the literature.35
Scheme 1. Synthesis 3-(aryl)-5-(n-penthyl)-1,2,4-oxadiazoles 3a-f.
Compound
3-(p-chlorophenyl)-5-(pentyl)-1,2,4-oxadiazol
(3f):
Semisolid, yield 85%. IR (KBr) nmax 3070, 2957, 2871, 1594, 1446, 1015, 721
cm-1. 1H NMR (400 MHz, CDCl3 ): d 8.02 (d, J = 8.4 Hz, 2H, H ), 7.46 (d, J
= 8.4 Hz, 2H, H ), 2.94 (t, J = 7.2 Hz, 2H, Het-CH2), 1.88 (qui, Ja=ryl7.2 Hz, 2H,
Het-CH2-CH2); a1ry.l44-1.36 (m, 4H, 2 x CH ); 0.93 (t, J = 7.2 Hz, 3H, CH ). 13C
NMR (100 MHz, (CDCl ): d 180.6, 167.28, 137.5, 129.9, 129.4, 129.0, 3125.8,
31.5, 26.9, 26.6, 22.5, 143.1. Calcd for C13H15ClON2: C, 62.28%; H, 6.03%; N,
11.17%. Found for C13H15ClON2: C, 62.41%; H, 6.13 %; N, 11.29%.
Scheme 2. Proposal for mechanism of formation of 3-(aryl)-5-(n-penthyl)-
1,2,4-oxadiazoles 3.
Pharmacology
Cytotoxicity assay
The scope and generality of this process is illustrated by a series of seven
compounds and the results are presented in Table 1.
The antiproliferative activities 3-aryl-5-pentyl-1,2,4-oxadiazoles 3a-f
were evaluated in the following human cancer cells lines: NCI H292 (lung
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J. Chil. Chem. Soc., 59, Nº 1 (2014)
Table 1. Synthesis of 3-aryl-5-penthyl-1,2,4-oxadiazoles 3a-f under
microwave irradiation.
3e and 3f exhibited moderate activity.
Table 2. IC50 values µM for compounds 3a-f.
Entry
ROH
Product
Yield(%)a
NH2
N
N
1
1a
1b
3a
3b
80
N
H
O
O
4
e
M
e
M
NH2
N
2
3
80
85
N
N
O
H
O
Compound
HL-60
>115.6
>108.6
42.1
NCI-H292
>115.6
>108.6
>108.6
>108.6
>85
HT29
>115.6
>108.6
>108.6
>108.6
>85
4
e
M
e
M
3a
3b
1c
1d
1e
1f
3c
3d
3e
3f
NH2
N
3c
N
N
O
H
O
4
3d
>108.6
19.0
e
M
e
M
3e
NH2
3f
28.0
>100
>100
4
5
6
81
83
85
N
N
DOXa
0.04
0.4
0.8
N
H
O
O
4
r
B
aDoxorubicin (DOX) was the positive control.
r
B
CONCLUSION
NH2
N
N
N
N
N
H
O
In summary, we have described the simple and rapid preparation of
1,2,4-oxadiazoles in under microwave irradiation. The final products were
obtained in short times and with good yields (80-85%). The compounds 3a-f
were tested against three human cell lines where only of compounds 3c, 3e and
3f exhibited moderate antiproliferative activity against HL-60 cancer cell lines
with IC values of 42.1, 19.0 and 28 μM, respectively. Additional reactions
conduct5i0ng to new structures are required because the synthesis of related
oxadiazole structures can lead to better cytotoxic activities.
O
4
l
C
l
C
NH2
N
H
O
O
4
aIsolated yield.
ACKNOWLEDGMENTS
A proposed reaction mechanism for the formation the 1,2,4-oxadiazole is
outlined in scheme 2. Initially the removal of the acidic37proton of 1 with a
suitable base create an anion at the oxygen atom which attacks the carbonyl
carbon of 2 to furnish an unstable tetrahedral species I with subsequent
loss of ethanol to give II. Then, this intermediate is cyclized to furnish III,
suffering elimination of water by heating (intermediate IV and V) to produce
1,2,4-oxadiazole 3.
The authors are grateful to the Brazilian National Research Council
(CNPq), FACEPE APQ 1257-106/10.” and CAPES for financial support.
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Pharmacology
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