Facile Heterocyclic Synthesis and Antibacterial Activity of Substituted Isoxazol-5(4H)-ones

Article abstract of DOI:10.1002/jccs.201700334

An efficient, simple, and green procedure for the synthesis of isoxazol-5(4H)-one derivatives are described here through a convenient one-pot, three-component reaction at room temperature. The title compounds are isolated in high to excellent yields and a

Full text of DOI:10.1002/jccs.201700334

JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
Article
Facile Heterocyclic Synthesis and Antibacterial Activity of Substituted Isoxazol-5
(4H)-ones
a
Ghaniya Ferouani , Amina Nacer,a,b Nawal Ameur ,a,c Redouane Bachira and
*
Chewki Ziani-Cherifa
aLaboratory of Catalysis and Synthesis in Organic Chemistry, University of Tlemcen, Tlemcen BP 119, Algeria
bTechnical and Scientific Research Centre in Physico-Chemical Analysis, Bou-Ismail, Tipaza, Algeria
cEcole Supérieure en Génie Electrique et Energétique (ESG2E), Oran, Algeria
(Received: September 26, 2017; Accepted: November 23, 2017; DOI: 10.1002/jccs.201700334)
An efficient, simple, and green procedure for the synthesis of isoxazol-5(4H)-one derivatives are
described here through a convenient one-pot, three-component reaction at room temperature. The
title compounds are isolated in high to excellent yields and after short reaction times, and are char-
1
acterized by various spectroscopic methods such as IR, H NMR, and 13C NMR. The synthesized
compounds 4a–c and 4e–i were tested for their in vitro activity against a panel of Gram-positive
and Gram-negative bacteria, demonstrating their ability to inhibit microorganisms with a zone of
inhibition ranging from 15 to 30 mm, minimum inhibitory concentration between 250 and 900 μg/
mL, and minimum bacterial concentration between 700 and 1000 μg/mL.
Keywords: 3-Methyl-4-arylmethylene-isoxazol-5(4H)-ones; One-pot synthesis; Aqueous media;
Lithium bromide; Antimicrobial activity.
INTRODUCTION
Heterocyclic compounds are of great importance
ethanol20 pyridine in H2O under ultrasonic irradiation21
and also KHP in H2O at 50 ꢀC.22
Carbon–carbon and carbon–heteroatom bond-
forming reactions are the most important reactions in
organic synthesis; these reactions are simple, fast, and
efficient for chemical synthesis. They have considerable
economic and ecological benefits.23–26 Among the reac-
tions, multicomponent reactions (MCR) are efficient
methods for the synthesis of heterocyclic compounds,
to both medical and organic chemists, and their synthe-
sis continues to represent a challenge from both
academic and industrial perspectives.1,2 Isoxazol-5(4H)-
ones are important five-membered heterocycles charac-
terized by a nitrogen–oxygen bond and are useful in the
syntheses of various other heterocycles such as 1,3-oxa-
zin-6-ones, pyrroles, imidazoles, tetrahydropyridines,
pyridopyrimidines, and 2H-azirines.3–8 Additionally,
isoxazol-5(4H)-one derivatives have attracted much
interest because of their significant pharmaceutical and
therapeutic properties such as antibacterial, anticonvul-
sive, antifungal, and antidiabetic,9–13 anti-androgenic,
anticancer, and hypoglycemic.2,9–12,14 Isoxazol-5(4H)-
one derivatives are described as gamma-aminobutyric
acid (GABA)-A receptors, potent inhibitors of
PTP1B.15,16 They act as inhibitors of the tumor necrosis
factor-alpha.17,18 It has been reported that 3,4-
disubstituted isoxazol-5(4H)-one derivatives can be pre-
pared using sodium sulfide in ethanol at room tempera-
ture19 sodium acetate by visible light in aqueous
which have posed
a real challenge in organic
synthesis.27–32 In the present work, we have developed a
new multicomponent synthesis of arylmethylene-isoxa-
zol-5(4H)-ones using lithium bromide as catalyst.
The use of lithium bromide as a mild Lewis acid
to promote various organic transformations is well
documented in the literature.33–36 In particular, it has
been found that lithium bromide efficiently catalyzes
the Cannizzaro, Tichchenko, and Meerwein–Ponndorf–
Verley reactions.37
In continuation of our work in catalysis, we here
report a one-pot synthesis of 3-methyl-4-arylmethylene-
isoxazol-5-(4H)-ones by a three-component reaction
catalyzed by lithium bromide. This catalyst leads to
*Corresponding author. Email: g-ferouani@live.com
J. Chin. Chem. Soc. 2017
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1

Article
Ferouani et al.
Table 1. First set of optimization experiments: The effect of
the catalyst amount on the synthesis of 4-(4-
efficient yields (70–98%) using different aromatic alde-
hydes. Compared to previously published work,22,38 this
protocol has promising characteristics for the response
of the reaction, such as a shorter reaction time, easy
treatment, ease of separation of the pure product via
simple filtration with high yields, and simplicity of the
experimental procedure. This method is operationally
simple and eco-friendly. In addition, some of the syn-
thesized compounds were evaluated for their antimicro-
bial activity. Three of the compounds tested were
highly promising because they showed very good anti-
bacterial activity against all the three used strains.
methyly-benzylidene)-3-methylisoxazol-5(4H)-one
Catalyst
(mol%)
Yield
(%)2
Entry
T (ꢀC)
Time1
4 h
2 h 30 min
2 h 30 min
2 h
1 h 30 min
1 h 30 min
1 h 30 min
2 h
2 h 30 min
5 h
1
—
1
2.5
5
10
15
20
10
10
10
RT = 23
RT
RT
RT
RT
RT
RT
RT
RT
49
60
80
90
98
98
96
98
98
98
2
3
4
5
6
7
8
9
10
1
RT
RESULTS AND DISCUSSION
Progress of the reaction was monitored by TLC analysis.
Isolated yield of product.
2
3-Methyl-4-arylmethylene-isoxazol-5(4H)-one deriv-
atives were synthesized from substituted aromatic alde-
hydes, mostly with electron-donating (ED) substituents.
Mechanistic insights to the envisioned reaction sug-
gested that high to medium polarity should be the pri-
mary factor contributing to the success of the reaction.
We therefore decided to try lithium bromide, a cheap
inorganic salt, as catalyst in water. The eventual success
of the reaction in those conditions would clearly prove
us right. On this basis, a one-pot reaction was per-
formed using equimolar amounts of ethyl acetoacetate,
hydroxylamine hydrochloride, and p-tolualdehyde in
water, at room temperature (Scheme 1).
In a first set of optimization experiments, various
amounts of LiBr were tried to study the influence of the
catalyst upon the reaction behavior. As shown in
Table 1, when the reaction was performed in the
absence of the catalyst, the isoxazol-one product was
obtained with a modest 49% yield (entry 1). When lith-
ium bromide was used up to 5 mol%, the yield of 4a
increased from 49% to 90% (Table 1, entries 2–4). How-
ever, when the catalyst amount was further raised to
10 mol%, the yield of compound 4a increased to 98%
(Table 1, entry 5). A subsequent increase in the catalyst
amount of up to 20% did not improve the yield, how-
ever (Table 1, entries 6–7). Consequently, 10 mol% of
LiBr was selected as the preferred amount for further
experiments.
In order to investigate the influence of the sol-
vents, the model reaction between ethyl acetoacetate,
hydroxylamine hydrochloride, and p-tolualdehyde was
carried out in various solvents such as polar protic
(EtOH, H2O), polar aprotic (acetone, DMF, CH2Cl2),
and also apolar (pentane, 1,4-dioxane) solvents. As
shown in Table 2, the reaction proceeded well in etha-
nol (Table 2, entry 2) and water (Table 2, entry 1),
whereas in the other solvents the yields varied from
30% to 92%. The general trend was that the yield
improved upon increased solvent polarity, pure water
Table 2. Second set of optimization experiments: The
synthesis of 4-(4-methyly-benzylidene)-3-
methylisoxazol-5(4H)-one using various solvents
Entry
Solvent
H2O
EtOH
Acetone
1,4-Dioxane
Pentane
CH2Cl2
DMF
EtOH–H2O 1:1
EtOH–H2O 1:2
Time
Yield (%)1
1
2
3
4
5
6
7
8
1 h 30 min
1 h 30 min
1 h 30 min
1 h 30 min
1 h 30 min
1 h 30 min
1 h 30 min
1 h 30 min
1 h 30 min
98
80
30
45
44
60
65
86
92
Scheme 1. General operative conditions for the syn-
thesis of arylmethylene-isoxazol-5(4H)-
one derivatives.
9
1
Isolated yield of product.
2
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JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
Synthesis and Antibacterial Activity of Substituted Isoxazol-5(4H)-ones
offering the best results. This second set of experiments
clearly demonstrated that medium polarity is in fact the
major parameter leading to the success of the reaction.
A three-component one-pot procedure (3-MCR)
was developed to assemble the isoxazol-one nucleus
from commercially available materials. This new meth-
odology affords the desired products in high yields.
The compounds could be obtained in crystalline form
of almost analytical quality from the reaction mixture
and without the use of chromatography. The results of
these reactions are regressed in Scheme 2. It was
observed that aromatic aldehydes containing ED
groups participate in the reaction, giving products in
excellent yields. In addition, reaction with unsaturated
aldehydes such as cinnamaldehyde was carried out,
which resulted in product formation with high yield
(4j). What was surprising, yet very satisfying, was the
case of aromatic aldehydes with electron-withdrawing
groups (EWGs), such as 4-CN (4g), which led to the
corresponding isoxazol-5(4H)-ones derivatives still in
good yields (85–88%). To our knowledge, no other
method has been able to generate this type of yield in
the case of EWGs under simple and inexpensive condi-
tions. Some authors have in fact described the use of
EWGs but could obtain only traces of the desired
compounds.20,22
Finally, we looked at the recovery and recycling
impact of the reaction medium, since all synthesized
compounds were crystalline in nature. Hence, after per-
forming its synthesis on a 12.4 g scale (0.1 mol), com-
pound 4g was filtered off (85% yield), and the obtained
filtrate was directly reused in the synthesis of another
12.4 g batch. The operative conditions were maintained
identical to the previous ones, thus allowing for the iso-
lation of compound 4g with 83% yield in the second
run. Once again, the filtrate was reused a third time,
still using the same conditions and amounts, resulting
in another 85% yield. We therefore believe that these
operative conditions can be very practical and of great
interest for industrial use, owing to the possibility of
medium recycling.
Determination of antibacterial activity
The in vitro antibacterial activity evaluation of our
compounds was carried out by the cup-plate agar diffu-
sion method,39,40 based on the recommendations of the
National Clinical Committee Laboratory Standards
(NCCLS). The strains of pathogenic bacteria used are
responsible for foodborne illness (G+ Clostridium per-
fringens [CECT 486]/G−: Escherichia coli [CECT 515],
Enterococcus faecium [DSM 20477]) and are classified
according to the inhibitory diameter. Gentamicin
(CN 120) and ampicillin (AM 50) were used as standard
drugs for comparing antibacterial activity. The Mueller–
Hinton sterilized agar medium was poured into Petri
dishes and allowed to solidify. On the surface of the
medium, microbial suspensions were spread, and cavities
were hollowed out using a glass cylinder of 6 mm diame-
ter (presterilized) and a micropipette. Fifty microliters of
each of the synthesized compounds (with a final concen-
tration of 1000 μg/mL) was placed serially in the cavities
to diffuse, with dimethyl sulfoxide (DMSO) as the sol-
vent for all compounds and as control. These Petri
ꢀ
dishes were incubated at 37 C for 24 h. The inhibition
zone was observed around the cavities after incubation
and measured.
The antibacterial activity of the various com-
pounds was examined against the selected bacterial
strains (E. coli [CECT 515], C. perfringens [CECT 486],
and E. faecium [DSM 20477]) using the cup-plate agar
diffusion method. The diameters of the inhibition zone
were compared, and the results are grouped in the
Table 3. Compounds 4-F, 4-CH3, and 2-OH showed a
Scheme 2. Synthesis of isoxazol-5(4H)-one deriva-
tives 4a–j using various aldehydes.
J. Chin. Chem. Soc. 2017
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Article
Ferouani et al.
Table 4. MIC (μg/mL) and MBC (μg/mL) results of
compounds
very good antibacterial activity against all the tree used
strains. They also showed better activity when com-
pared with standard drug (CN120) and AM50. The rest
of the compounds showed moderate to good antibacter-
ial activity except 4-N(CH3)2 which showed complete
resistance to all the strains. The compound 4-CN
showed the same antibacterial activity against E. coli
and E. faecium, whereas compound 2-F and 4-OMe
were found to be effective against only one strain
(E. faecium and C. perfringens, respectively).
CECT 515
CECT 486
DSM 20477
4a
4g
4c
4h
4i
MIC
MBC
MIC
MBC
MIC
MBC
MIC
MBC
MIC
MBC
MIC
MBC
MIC
MBC
700
1000
500
900
—
250
700
—
500
900
500
900
—
—
900
500
—
—
—
—
900
500
250
900
—
—
—
The evaluation of the antibacterial activity of the
various compounds tested against the three bacterial
strains showed good antibacterial activity.
250
900
500
900
700
1000
250
900
500
900
500
900
4b
4e
The minimum inhibitory concentration (MIC)
and the minimum bactericidal concentration (MBC)
were determined in a liquid medium (Mueller–Hinton
broth)41 on compounds inhibiting the growth of one or
more microorganisms tested in the medium diffusion
method. The technique consists of inoculating the
same amount of bacteria in a series of tubes filled with
the tested compounds dissolved in DMSO and then
diluted in Mueller–Hinton broth at concentrations
ranging from 50 to 1000 μg/mL. After 24 h of incuba-
tion at 37 ꢀC, the first tube in which no microbial
growth is observed gives by definition the MIC in μg/
mL. MBC was found out by taking samples in the
tubes without visible growth, which were then seeded
—
700
1000
MBC, minimum bactericidal concentration; MIC, minimum
inhibitory concentration.
EXPERIMENTAL
A mixture of ethyl acetoacetate (10 mmol),
hydroxylamine hydrochloride (10 mmol), aromatic
aldehyde (10 mmol), and 10% of lithium bromide was
stirred in water (5 mL) at room temperature. After the
completion of the reaction (monitored by thin-layer
chromatography [TLC]), the solid obtained was fil-
tered off and washed with diethyl ether. The desired
product was isolated in high yields in the essentially
pure form.
(Z)-4-(4-Methylbenzylidene)-3-methylisoxazol-5
(4H)-one (4a). Yield: 98%, m.p. 132–133 ꢀC; 1H
NMR (400 MHz, CDCl3): δppm 8.21–8.19 (2H, d,
J = 8.00 Hz, Haromatic); 7.3245 (1H, s, CH); 7.25–7.23
(2H, d, J = 8.00 Hz, Haromatic); 2.37 (3H, s, CH3); 2.21
(3H, s, CH3) ppm. 13C NMR (400 MHz, CDCl3): δppm
168.22; 161.23; 149.98; 145.73; 134.15; 129.95; 129.89;
118.41; 22.06; 11.63 ppm. IR (neat/cm−1): 1730.40;
1698.34; 1169.28.
(Z)-4-(3-Methylbenzylidene)-3-methylisoxazol-5
(4H)-one (4b). Yield: 97%; m.p. 141–142 ꢀC; 1H
NMR (400 MHz, CDCl3): δppm 8.13 (1H, br, Haro-
matic); 8.05 (1H, s, CH); 7.32 (3H, br, Haromatic); 2.35 (3H, s,
CH3); 2.21 (3H, s, CH3) ppm. 13C NMR (400 MHz,
CDCl3): δppm 167.94; 161.19; 150.28; 138.83; 134.99;
134.41; 132.32; 131.04; 128.80; 119.35; 21.29;
11.64 ppm. IR (neat/cm−1): 1728.36; 1693.32; 1165.36.
ꢀ
in an agar medium. After 24 h of incubation at 37 C,
the values of the MBC obtained are given in Table 4.
Compound 4i was found to have a broad antimicrobial
spectrum with MIC of 250 μg/mL and MBC of
900 μg/mL.
Table 3. Antibacterial activity of isoxazol-ones (the inhibition
zone is in mm)
Compounds
CECT 515
CECT 486
DSM 20477
4a
4g
4c
4h
20
15
(−) R
(−) R
30
20
(−) R
15
(−) R
20
25
15
(−) R
20
4i
25
4b
4e
15
15
20
20
(−) R
20
4f
(−) R
25
(−) R
26
12
(−) R
30
15
(CN120)
(AM50)
20
(−) R: resistance.
4
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Synthesis and Antibacterial Activity of Substituted Isoxazol-5(4H)-ones
(Z)-4-(4-Methoxybenzylidene)-3-methylisoxazol-5
(400 MHz, CDCl3): δppm 8.38–8.35 (2H, m, Haromatic); 7.33
(1H, s, CH); 7.14–7.10 (2H, m, Haromatic); 2.23 (3H, s,
CH3) ppm, 13C NMR (400 MHz, CDCl3): δppm 168.04;
167.23; 164.65; 161.10; 148.37; 136.77 (d, J = 36 Hz);
128.87 (d, J = 12 Hz); 119.17 (d, J = 8 Hz); 116.58;
116.36; 11.60 ppm. IR (neat/cm−1): 1723.36; 1650.36;
1065.36.
(Z)-4-(2-Fluorobenzylidene)-3-methylisoxazol-5
(4H)-one (4i). Yield: 85%; m.p. 159–160 ꢀC; 1H
NMR (400 MHz, CDCl3): δppm 8.22–8.19 (1H, d,
J = 8.00 Hz, Haromatic); 7.92–7.90 (1H, d, J = 12 Hz,
Haromatic); 7.45–7.39 (1H, m, Haromatic); 7.32 (1H, s,
CH); 7.24–7.19 (1H, m, Haromatic); 2.24 (3H, s, CH3)
ppm. 13C NMR (400 MHz, CDCl3): δppm 167.50;
163.76; 161.30; 160.91; 148.11 (d, J = 12 Hz); 134.00
(d, J = 32 Hz); 130.54 (d, J = 32); 129.87 (d,
J = 12 Hz); 121.02 (d, J = 84 Hz); 119.72 (d,
J = 92 Hz); 11.59 ppm. IR (neat/cm−1): 1731.15;
1640.98.
(Z)-3-Methyl-4-((E)-3-phenylallylidene)isoxazol-
5(4H)-one (4j). Yield: 70%; m.p. 172–173 ꢀC; 1H
NMR (400 MHz, CDCl3): δppm 8.35–8.28 (dd,
J = 12 Hz, 1H, CH), 7.66–7.64 (2H, m, CH═CH),
7.44–7.43 (3H, m, Haromatic),; 7.32–8.26 (2H, m, Haro-
matic); 2.25 (s, 3H, CH3)ppm 13C NMR (400 MHz, CDCl3):
δppm 168.94; 159.78; 151.31; 147.45; 135.00; 131.53;
129.18; 128.93; 122.47; 117.99; 11.15 ppm. IR
(neat/cm−1): 1735.00; 1670.21.
1
ꢀ
(4H)-one (4c). Yield: 98%. m.p. 175–176 C H NMR
(400 MHz, CDCl3): δppm 8.38–8.36 (2H, d,
J = 8.00 Hz, Haromatic); 7.27 (1H, s, CH); 6.95–6.93
(2H, d, J = 8.00 Hz, Haromatic); 3.85 (3H, s, OCH3);
2.21 (3H, s, CH3) ppm. 13C NMR (400 MHz, CDCl3):
δppm 168.78;164.62; 161.29; 149.37; 136.97; 125.83;
116.33; 114.66; 55.71; 11.64 ppm. IR (neat/cm−1
1726.37; 1648.12; 1112.23.
)
(Z)-4-(2,4-Dihydroxybenzylidene)-3-methylisoxazol-
5(4H)-one (4d). Yield: 91%, m.p. 233–234 ꢀC; 1H NMR
(400 MHz, DMSO-d6): δppm 11.15 (2H, s, OH);
9.00–8.98 (1H, d, J = 8.00 Hz, Haromatic); 7.96 (1H, s,
CH), 6.45–6.40 (3H, t, Haromatic), 2.20 (3H, s, CH3) ppm.
13C NMR (400 MHz, DMSO-d6): δppm 169.90, 167.13,
163.61, 162.70, 144.42, 135.64, 113.52, 111.05, 109.52,
102.20, 11.66 ppm. IR (neat/cm−1): 1719.36; 1673.36;
1055.36.
(Z)-4-(2-Hydroxybenzylidene)-3-methylisoxazol-5
(4H)-one (4e). Yield: 90%, m.p. 203–204 ꢀC; 1H
NMR (400 MHz, DMSO-d6): δppm 11.00 (1H, s, OH);
8.75–8.73(1H, d, J = 8.00 Hz, Haromatic); 8.09 (1H, s,
CH), 7.47–7.51 (1H, t, Haromatic), 7.03–7.00 (1H, d,
J = 12 Hz, Haromatic), 6.95–6.91 (1H, t, Haromatic), 2.26
(3H, s, CH3) ppm, 13C NMR (400 MHz, DMSO-d6):
δppm 168.73, 162.59, 160.11, 145.45, 137.19, 132.78,
119.95, 119.56, 116.90, 116.60, 11.65 ppm. IR
(neat/cm−1): 1770.02; 1670.25; 1080.25.
4-(4-(Dimethylamino)benzylidene)-3-methylisoxazol-
1
ꢀ
5(4H)-one (4f). Yield: 85%; m.p. 225–226 C; H NMR
(400 MHz, CDCl3): δppm 2.23 (s, 3H, CH3); 3.15 (6H, s,
N(CH3)2); 6.71–6.73 (2H, d, J = 8 Hz, Haromatic); 7.21 (s,
CONCLUSIONS
In conclusion, we have developed a simple and
green process to access substituted isoxazol-5(4H)-ones
using lithium bromide as catalyst in water. A library of
aromatic aldehydes was constructed under those condi-
tions, which can be generalized for the synthesis of
other substituted isoxazol-5(4H)-ones. The process is
easy and can accommodate multi-gram scale syntheses,
thus making it attractive for industrial use. The evalua-
tion of the antibacterial activity of the various com-
pounds tested against three bacterial strains showed
good activity.
1H, CH), 8.39–8.41 (2H, d, J = 8 Hz, Haromatic) ppm; 13
C
NMR (400 MHz, CDCl3): δppm 170.25; 162.08; 154.71;
149.10; 127.02; 125.22; 124.71; 111.53; 40.05; 11.64 ppm;
IR (neat/cm−1): 1780.25, 1626.0.36; 1012.36.
(Z)-4-((3-Methyl-5-oxoisoxazol-4(5H)-ylidene)
methyl) benzonitrile (4g). Yield: 87%; m.p. 193–194
1
ꢀC, H NMR (400 MHz, DMSO-d6):): δppm 8.46–8.44
(2H, d, J = 8.00 Hz, Haromatic); 8.06–8.04 (3H, t,
CH + Haromatic); 2.31 (3H, s, CH3) ppm, 13C NMR
(400 MHz, DMSO-d6):): δppm 167.73; 162.53; 149.29;
136.56; 133.68; 132.92, 130.34, 122.35, 118.74,
115.09, 11.74 ppm. IR (neat/cm−1): 1720.70; 1675.30;
1055.50; 2265.25.
ACKNOWLEDGMENTS
The authors would like to thank the Algerian
DGRST-MESRS and the French PHC Tassili (grant
15MDU939) for financial support.
(Z)-4-(4-Fluorobenzylidene)-3-methylisoxazol-5(4H)-
one (4h). Yield: 86%; m.p. 139–140 ꢀC; 1H NMR
J. Chin. Chem. Soc. 2017
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Article
Ferouani et al.
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