Facile Synthesis and Antioxidant Evaluation of 4-Arylmethylideneisoxazol-5(4H)-ones

Full text of DOI:10.1080/00304948.2019.1677993

Organic Preparations and Procedures International
The New Journal for Organic Synthesis
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Facile Synthesis and Antioxidant Evaluation of 4-
Arylmethylideneisoxazol-5(4H)-ones
Rima Laroum, Raouf Boulcina, Chawki Bensouici & Abdelmadjid Debache
To cite this article: Rima Laroum, Raouf Boulcina, Chawki Bensouici & Abdelmadjid Debache
(2019): Facile Synthesis and Antioxidant Evaluation of 4-Arylmethylideneisoxazol-5(4H)-ones,
Organic Preparations and Procedures International, DOI: 10.1080/00304948.2019.1677993
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Organic Preparations and Procedures International, 0:1–6, 2019
# 2019 Taylor & Francis Group, LLC
ISSN: 0030-4948 print / 1945-5453 online
DOI: 10.1080/00304948.2019.1677993
OPPI BRIEF
Facile Synthesis and Antioxidant Evaluation of 4-
Arylmethylideneisoxazol-5(4H)-ones
Rima Laroum,1 Raouf Boulcina,1 Chawki Bensouici,2 and
Abdelmadjid Debache1
1
ꢀ
ꢁ
ꢁ ^ ꢁ
Laboratoire de Synthese de Molecules d’Interets Biologiques, Universite
ꢀ
Freres Mentouri de Constantine, Algeria
2Centre de Recherche en Biotechnologie, Constantine, Algeria
Isoxazolone derivatives show significant biological and medicinal properties.1–7 They con-
stitute excellent intermediates for the synthesis of numerous heterocycles and undergo sev-
eral chemical transformations.8–10 A literature review shows that the best method for the
synthesis of these molecules is a three-component reaction among aromatic aldehydes, ethyl
acetoacetate and hydroxylamine hydrochloride under different catalysts and conditions.11
In continuing our research on new simple and environmentally friendly procedures
for the preparation of heterocycles by multi-component reactions,12–14 we now report
the synthesis of 4-arylmethylideneisoxazol-5(4H)-ones by the reaction among aromatic
aldehydes, ethyl acetoacetate and hydroxylamine hydrochloride catalyzed by K2CO3.
This commonly available base is very inexpensive, well-tolerated in organic agriculture,
and safe; it has found wide use in numerous chemical transformations.15–19 Scheme 1
below shows the approach taken.
We chose as our model system an equimolar mixture of 4-hydroxybenzaldehyde,
ethyl acetoacetate and hydroxylamine chloride in a reaction catalyzed by different
amounts of K2CO3. The selected model was subjected to different solvent and tempera-
ture conditions, as shown in Table 1. The best result was observed in Entry 8, with
5 mol% catalyst in water at reflux for an hour (see Experimental Section).
The optimum reaction conditions were applied to a number of aromatic and hetero-
aromatic aldehydes bearing different substituents. The results are summarized in Table 2.
Reaction times were determined by thin layer chromatography in each case. Whatever the
position of the substituent, yields were generally good to very good (between 64% and 85%
and an average of 69%). Compounds 4k-4m are novel and reported here for the first time.
Antioxidant Activity
The antioxidant activity of some of the compounds (4i-4m) was determined using four
complementary methods: The 1,1-diphenyl-2-pycrilhydrazil (DPPH) free radical
Received August 20, 2018; in final form June 14, 2019.
Address correspondence to Abdelmadjid Debache, Laboratoire de Synthese de Molecules d’Interets
ꢀ
ꢁ
ꢁ ^
ꢁ
ꢀ
Biologiques, Universite Freres Mentouri de Constantine, Algeria. E-mail: a_debache@yahoo.fr
1

2
Debache et al.
Ar
H3C
H
H3C
O
K2CO3
O
.
NH2OH HCl
+
+
H2O/Reflux
Ar
N
O
CO2Et
O
4
1
2
3
Scheme 1. K2CO3-catalyzed synthesis of 3-methyl-4-arylmethylidene-isoxazol-5(4H)-ones.
scavenging assay, the cupric reducing antioxidant capacity assay, the b-carotene-linoleic
acid assay and the 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid (ABTS) scav-
enging assay. The results are summarized in Table 3.
We observe that all the studied molecules had at least some activity, however the
best results were obtained with 4i and 4k for the DPPH assay (IC50 ¼ 35.91 2.23 and
64.00 0.48) and with 4i and 4m in the CUPRAC assay (A0.50 ¼ 10.86 0.49
and 11.18 1.59).
In this report, we describe a three-component reaction among aromatic aldehydes,
ethyl acetoacetate and hydroxylamine hydrochloride for the synthesis of 3-methyl-4-
arylmethylidene-isoxazol-5(4H)-ones in good to very good yields. The process is catalyzed
by potassium carbonate, a universally available and inexpensive reagent that is easy to han-
dle and comparatively green. The chief merits of our method are its simplicity, convenience
and low cost. We examined the antioxidant activity of some of the new derivatives and
found significant activity. We hope that our results will stimulate further exploration in this
interesting area.
Experimental Section
Chemistry
1
The solvents and reagents were used as received from commercial sources. H and 13C
NMR spectra were recorded on a BRUKER AVANCE DPX spectrometer at 250.13
and 62.5 MHz respectively, using TMS as an internal reference. Chemical shifts are
expressed in parts per million (ppm) and the coupling constants (J) in Hertz (Hz). IR
spectra were obtained as potassium bromide (KBr) pellets with a Shimadzu FT IR-
8201 PC spectrometer. The reaction monitoring was accomplished by layer chromatog-
raphy (TLC) which was carried out using 0.2 mm Kieselgel F254 silica plates (Merck)
with hexane/ethyl acetate (8/2) as eluting solvent. Mass spectrometry was performed on
Brucker MaXis 4G using ESI technique. Because of their low volatility, it was not pos-
sible to obtain elemental analyses for the new boron compounds, their HRMS
are given.
General Procedure for 3-methyl-4-arylmethylidene-isoxazol-5(4H)-one Synthesis
(4a-m)
One mmol of the aldehyde, 1 mmol of hydroxylamine hydrochloride, 1 mmol of ethyl
acetoacetate and 5 mol% of K2CO3 are mixed in a 25 ml flask equipped with a magnetic
stirrer. The mixture is refluxed in 5 ml of water for the time required (see Table 2), fol-
lowed by TLC. When the reaction is judged to be finished, the mixture is gradually
poured into ice-cold water. The stirring is maintained for a few minutes and the

4-Arylmethylideneisoxazol-5(4H)-ones
3
Table 1
Optimization of Reaction Conditions
Catalyst
(mol%)
Yield
(%)
Entry
Solvent
Time (h)
Temperature (ꢁC)
1
2
3
4
5
6
7
8
H2O
H2O
EtOH
10
10
10
10
10
10
10
5
24
1
1
1
1
1
1
1
1
1
1
ambient
reflux
reflux
reflux
reflux
reflux
80
reflux
reflux
reflux
reflux
78
83
44
traces
traces
–
EtOH/H2O (1/1)
CH2Cl2
CH3CN
–
42
83
79
78
H2O
H2O
H2O
H2O
9
10
11
15
20
30
76
Table 2
K2CO3-catalyzed Synthesis of Compounds (4a-m)
Time Yielda
ꢁ
ꢁ
Entry
Ar
Product
(h)
%
Mp C
Mp C (Lit.)
1
2
3
4
5
6
7
8
C6H5-
4-ClC6H4-
4-MeC6H4-
4-MeOC6H4-
2-MeOC6H4-
4-HOC6H4-
4-(Me)2NC6H4-
2-Thienyl
4a
4b
4c
4d
4e
4f
4g
4h
4i
3
4
3
1
2
2.5
2
3
3
4
70
76
72
83
85
80
73
72
77
41
40
68
66
142–144
128–130
130–132
175–177
151–152
222–224
208–210
144–146
130–132
100–102
>260
140–14224
128–13025
129–13224
175–17724
159–16027
214–21624
206–20924
146–14725
130–13226
99–10128
9
3-MeOC6H4-
2-MeC6H4-
2-(HO)2BC6H4-
4-(HO)2BC6H4-
3-(HO)2B-2-MeOC6H4-
10
11
12
13
4j
4k
4l
3
4
4
This work
This work
This work
>260
>260
4n
aIsolated yield.
obtained solid is filtered and purified by crystallization from ethanol. Spectrometric
data for selected compounds are provided below.
4-Benzylidene-3-methylisoxazol-5(4H)-one (4a)
1H NMR (DMSO-d6): 2.4 (s, 3H, CH3), 7.42–7.66 (m, 5H), 8.2 (s, 1H, CH ¼ C). 13C
NMR (DMSO-d6): 11.18 (CH3), 118.82, 119.34, 128.46, 131.91, 133.38, 133.52,
150.41 (CH ¼ C), 161.11 (C ¼ N), 167.46 (C ¼ O). IR (cmꢀ1): ꢀmax ¼ 756, 1181, 1523,
1624, 1739, 2858.

4
Debache et al.
Table 3
Antioxidant Activity of Compounds (4i-4m)
Antioxidant activitya
b-Carotene-linoleic
DPPH. assay
ABTS.1 assay
acid assay
CUPRAC assay
Product
IC50 (mg/ml)
IC50 (mg/ml)
IC50 (mg/ml)
A0.50 (mg/ml)
4i
4j
4l
4l
4m
BHTb
BHAb
35.91 2.23
77.67 0.62
64.00 0.48
75.53 3.02
134.03 3.63
22.32 1.19
5.73 0.41
10.00 0.10
90.51 0.59
14.33 0.68
16.68 0.15
19.38 1.14
1.29 0.30
1.81 0.10
>200
>200
175.80 1.20
73.84 1.09
>200
10.86 0.49
16.34 0.47
11.79 1.11
18.13 2.88
11.18 1.59
9.62 0.87
3.64 0.19
1.05 0.01
0.90 0.02
aValues expressed are means S.D. of three parallel measurements. (p < 0.05).
bReference compounds.
BHA: Butylhydroxyanisole, BHT: Butylhydroxytoluene.
4-(4-Methoxybenzylidene)-3-methylisoxazol-5(4H)-one (4d)
1H NMR (DMSO-d6): 2.35 (s, 3H, CH3), 3.95(s, 3H, OCH3), 7.01 (d, 2H, J ¼ 7.5),
7.38 (s, 1H, CH ¼ C), 8.44 (d, 2H, J ¼ 7.5). 13C NMR (DMSO-d6): 11.72 (CH3), 55.79
(OCH3), 114.72, 125.87, 137.06, 137.21, 149.56, 163.78 (C ¼ N), 164.69 (C ¼ O). IR
(cmꢀ1): ꢀmax ¼ 813, 1218, 1550, 1593, 1720, 2935.
4-(2-Methoxybenzylidene)-3-methylisoxazol-5(4H)-one (4e)
1H NMR (DMSO-d6): 3.11 (s, 3H, CH3), 3.93(s, 3H, OCH3), 7.08 (t, 1H, J ¼ 7.33),
7.19 (d, 1H, J ¼ 8.28), 7.6 (t, 1H, J ¼ 7.41), 8.05 (s, 1H), 8.6 (d, 1H, J ¼7.71). 13C
NMR (DMSO-d6): 11.30 (CH3), 56.32 (O-CH3), 111.86, 117.96, 119.94, 120.56,
120.38, 132.44, 136.64, 144.86 (CH ¼ C), 162.14 (C ¼ N), 168.05 (C ¼ O). IR (cmꢀ1):
ꢀmax ¼ 860, 1373, 1550, 1593, 1728.
4-(4-Hydroxybenzylidene)-3-methylisoxazol-5(4H)-one (4f)
1H NMR (DMSO-d6): 3.2 (s, 3H, CH3), 6.85 (d, 2H, J ¼ 8.2), 7.35 (s, 1H, CH ¼ C),
8.25 (d, 2H, J ¼ 8.2), 10.5 (s, 1H, OH). 13C NMR (DMSO-d6): 11.23 (CH3), 113.95,
116.06, 124.26, 134.41, 137.21, 150.20, 163.78 (C ¼ N), 168.69 (C ¼ O). IR (cmꢀ1):
ꢀmax ¼ 813, 1172, 1550, 1593, 1728, 2935, 3741.
3-((3-Methyl-5-oxoisoxazol-4(5H)-ylidene)methyl)phenylboronic acid (4k)
1H NMR (DMSO-d6): 2.55(s, 3H, CH3), 7.56 (t, 1H, J ¼ 7.2), 7.97 (s, 1HAr), 8,03
(dd,1HAr, J ¼ (7.2, 2.2), 8.2 (s, 2H, 2OH) 8.52 (s, 1H, CH ¼ C), 8.66 (dd, 1HAr, J ¼
(7.2, 2.2). 13C NMR (DMSO-d6): 11.73 (CH3), 118.91, 128.39, 132.11, 134.46, 139.83,
141.17, 152.76, 162 .71 (C-CH3), 168.2 (C ¼ O). IR (cmꢀ1): ꢀmax ¼ 686, 1161, 1566,

4-Arylmethylideneisoxazol-5(4H)-ones
5
1608, 1751, 2931, 3363. HRMS (MS-ESI, m/z): [M þ Na]þ calculated for
(C11H10BNO4Naþ) 254.06006, found 254.0607.
4-((3-Methyl-5-oxoisoxazol-4(5H)-ylidene)methyl)phenylboronic acid (4l)
1H NMR (DMSO-d6): 2.3 (s, 3H, CH3), 7.8-8.05 (m, 3H, 2OH, CH ¼ C), 8.24–8.47 (m,
4HAr). 13C NMR (DMSO-d6): 11.33 (CH3), 119.14, 126.82, 128.34, 132.31, 133.60,
134.23, 134.58, 151.63 (CH ¼ C). IR (cmꢀ1): ꢀmax ¼ 773, 1006, 1335, 1612, 1719,
2360, 3309. HRMS (MS-ESI, m/z): [M þ Na]þ calculated for (C11H10BNO4Naþ)
254.06006, found 254.0607.
4-Methoxy-3-((3-methyl-5-oxoisoxazol-4(5H)-ylidene)methyl)phenylboronic acid (4m)
1H NMR (DMSO-d6): 2.5 (s, 3H, CH3), 3.9 (s, 3H, O-CH3) 7.15 (d, 1H, J ¼ 7.6), 8.01
(s, 2H, 2OH), 8,03 (d, 1HAr, J ¼ 7.6), 8.13 (s, 1HAr), 8.55 (s, 1H, CH ¼ C). 13C NMR
(DMSO-d6): 11.20 (CH3), 56.20 (O-CH3), 110.90, 117.70, 120.00, 138.20, 141.10,
142.00, 147.00, 158.70, 161.90 (C-CH3), 167.60 (C ¼ O). IR (cmꢀ1): ꢀmax ¼ 879,
1122, 1577, 1608, 1728, 2947, 3502. MS-ESI, m/z: [M þ Na]þ calculated for
(C12H12BNO2Naþ) 236.08588, found 236.0859.
Antioxidant Activity
Bioactivity measurements were carried out on a 96-well microplate reader, namely, a
Perkin Elmer Multimode Plate Reader En Spire, at the Center for Biotechnology
Research. 1,1-Diphenyl-2-picrylhydrazyl (DPPH), butyldhydroxylanisole (BHA), butyl-
hydroxyltoluene (BHT), b-carotene, linoleic acid, polyoxyethylene sorbitan monopalmi-
tate (Tween-40), Neocuproine, and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic
acid) (ABTS), were obtained from Sigma-Aldrich GmbH, Sternheim, Germany; copper
(II) chloride, potassium persulfate, and ammonium acetate were obtained from Biochem
Chemopharma.
The DPPH free radical-scavenging activity was evaluated by a slight modification
of the well-documented method of Blois.20 The ABTS free cation-radical scavenging
activity was obtained by spectrophotometric analysis according to a slight modification
of the method proposed by Re et al.21 The b-carotene bleaching activity was determined
by the b-carotene-linoleic acid system described by Miller22 and the cupric-reducing
antioxidant capacity (CUPRAC) was evaluated according to the method of Apak
et al.,23 with slight modifications.
Acknowledgments
We gratefully acknowledge the Algerian Ministry of Higher Education and Scientific
Research for financial support.
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