New eco-friendly procedure for the synthesis of 4-arylmethylene-isoxazol-5(4H)-ones catalyzed by pyridinium p-toluenesulfonate (PPTS) in aqueous medium

Article abstract of DOI:10.1080/00397911.2018.1473440

In this work we describe a new, highly efficient method for the synthesis of 3-methyl-4-arylmethylidene-isoxazol-5(4H)-one derivatives by a three-component reaction between aromatic aldehydes, ethyl acetoacetate, and hydroxylamine hydrochloride under the

Full text of DOI:10.1080/00397911.2018.1473440

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New eco-friendly procedure for the synthesis of
4-arylmethylene-isoxazol-5(4H)-ones catalyzed by
pyridinium p-toluenesulfonate (PPTS) in aqueous
medium
Rima Laroum & Abdelmadjid Debache
To cite this article: Rima Laroum & Abdelmadjid Debache (2018): New eco-friendly procedure for
the synthesis of 4-arylmethylene-isoxazol-5(4H)-ones catalyzed by pyridinium p-toluenesulfonate
(PPTS) in aqueous medium, Synthetic Communications, DOI: 10.1080/00397911.2018.1473440
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https://doi.org/10.1080/00397911.2018.1473440
New eco-friendly procedure for the synthesis of
4-arylmethylene-isoxazol-5(4H)-ones catalyzed by
pyridinium p-toluenesulfonate (PPTS) in aqueous medium
Rima Laroum and Abdelmadjid Debache
ꢀ
ꢁ
ꢁ ^
ꢁ
Laboratoire de Synthese de Molecules d’Interets Biologiques, Universite de Constantine 1,
Constantine, Algerie
ꢁ
ABSTRACT
ARTICLE HISTORY
Received 12 January 2018
In this work we describe a new, highly efficient method for the
synthesis of 3-methyl-4-arylmethylidene-isoxazol-5(4H)-one derivatives
by a three-component reaction between aromatic aldehydes, ethyl
acetoacetate, and hydroxylamine hydrochloride under the influence
by PPTS as a low-toxicity, inexpensive, commercially available and
easy to handle catalyst. The advantages of this procedure are good
yields, short reaction times, simplicity of implementation, and respect
of the environment.
KEYWORDS
Aqueous media;
eco-friendly method;
3-methyl-4-arylmethylene-
isoxazol-5(4H)-ones; PPTS;
three-component reaction
GRAPHICAL ABSTRACT
Ar
H3C
H
H3C
O
PPTS
O
+
H2O/Reflux
Ar
N
1
O
CO2Et
3
O
NH2OH.HCl
4
2
Introduction
The ixoxazolone derivatives possess very interesting biological and pharmacological
properties. They are anti-prostate tumor[1] and antimicrobial,[2] inhibitors of the
factorization of tumor necrosis alpha (TNF-a),[3] potent inhibitors of PTP1B,[4] and
hormone-sensitive lipase.[5] These compounds are used for the treatment of cerebro-
vascular disorders and as muscle relaxants.[6] They are also used in agriculture as
herbicides, plant growth regulators,[7] and fungicides.[8] Otherwise, the isoxazolone unit
has also been used as the basis for the design and construction of merocyanine dyes
with applications in optical recording and nonlinear optical research.[9]
On the other hand the 4-arylmethyleneisoxazol-5(4H)-ones are very useful synthesis
intermediates of various heterocycles such as pyridopyrimidines,[10] imidazoles,[11]
ꢀ
ꢁ
ꢁ ^
CONTACT Abdelmadjid Debache
Biologiques, Universite de Constantine 1, Constantine, Algerie.
a_debache@yahoo.fr
Laboratoire de Synthese de Molecules d’Interets
ꢁ
ꢁ
Supplemental data for this article can be accessed on the publisher’s website.
ß 2018 Taylor & Francis

2
R. LAROUM AND A. DEBACHE
Ar
H3C
H
H3C
O
PPTS
O
+
H2O/Reflux
Ar
N
1
O
CO2Et
3
O
NH2OH.HCl
4
2
Scheme 1. PPTS-catalyzed 3-methyl-4-arylmethylene-isoxazol-5(4H)-ones synthesis.
1,3-oxazin-6-ones,[12] and quinolines.[13] They also undergo various chemical transforma-
tions[14] such as N-methylation, alkylation, epoxidation, reduction, reduction/bromination,
reduction/hydroxylation, Reformatsky reaction, and addition of organomagnesiens. Some
cycloaddition reactions are also described and provide access to several poly-
cycles types.[15]
Therefore, 4-arylmethylene-isoxazol-5(4H)-ones have interested the organic chemists
and the review of the literature shows two main methods for the synthesis of these
heterocycles. Carried out in two successive stages, the conventional process consists
firstly of a reaction between ethyl acetoacetate and hydroxylamine hydrochloride to
give the 3-methyl-isoxazole-5(4H)-one followed, in a second step, by a Knoevenagel
condensation type with aromatic aldehydes.[16] The recent method is a one-pot three-
component reaction between aromatic aldehydes, ethyl acetoacetate and hydroxylamine
hydrochloride. Catalyzed by the pyridine at reflux of ethanol, it has been reported
for the first time in 2008 by Zhang et al.,[17] and now in the literature, we note the
successful use of several catalysts and techniques[18] such as sodium silicate,[19] boric
R
acid,[20] DOWEXV50WX4/H2O,[21] sodium benzoate,[22] NaH2PO4,[23] sulfuric acid-
modified Mesolite,[24] sodium acetate under visible light,[25] imidazole under ultrasonic
irradiation[26] and Fe2O3, Clinoptilolite and H3PW12O40 under microwave irradiation.[27]
Some environmentally friendly catalysts such as tartaric acid,[28] sodium tetraborate,[29]
sodium ascorbate,[30] citric acid[31] and sodium saccharin[32] were reported. The same
reaction without catalyst in aqueous medium was also successfully performed.[33]
With a melting point of 120 ꢀC, PPTS is an ionic complex which can be assimilated
to an ionic liquid. It has been used as a catalyst in various chemical transformations
such as Fisher’s esterification,[34] the acetalization of a,b-unsaturated aldehydes,[35] and
as a mild and efficient catalyst for the regioselective tetrahydropyranylation of indazole
derivatives.[36]
For our part we have previously used PPTS as an efficient catalyst in the synthesis of
2-amino-4H-pyrans,[37] 1,4-benzoxazine derivatives,[38] 3,4-dihydropyrimidinones, and
tetrahydroquinazoline-2,5-diones.[39]
Here, we report its use in the synthesis of 4-arylmethylene-isoxazol-5(4H)-ones by the
reaction between aromatic aldehydes, ethyl acetoacetate and hydroxylamine hydrochloride,
in an aqueous medium (Scheme 1). This is an environmentally friendly method.
Results and discussion
The selected model, an equimolar mixture of 4-hydroxybenzaldehyde, ethyl acetoacetate,
hydroxylamine chloride, and PPTS (10 mol%), was subjected to various solvents and
temperatures such as H2O at room temperature and reflux, EtOH, EtOH/H2O (1/1),

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SYNTHETIC COMMUNICATIONSV
3
CH2Cl2, and CH3CN at reflux. The results are summarized in Table 1 (Entries 1–7). We
note that the best result has been obtained in refluxing H2O. The reaction in water
without catalyst was found more effective than the reaction without solvent and in the
presence of the catalyst (Table 1, entries 8 and 1). This is probably due to a better
solvation of the different reagents and a larger contact area. In addition, the water is a
polar solvent and the temperature is higher for the entry 8 and these conditions
facilitate this procedure. The combination of the effect of H2O and the catalyst makes
the method more efficient (Table 1, entry 9).
In a second step, and in order to determine the optimum amount of catalyst, we
worked with increasing amounts of 0, 5, 15, 20, 30, and 50 mol% in refluxing H2O
(Table 1, entries 8–13). The best yield of 80% was observed with 5 and 10 mol%.
Therefore, the optimum conditions of the PPTS catalyzed 3-substituted-4-4-arylmethyli-
deneisoxazol-5(4H)–ones synthesis are 5 mol% of catalyst in refluxing H2O.
The optimum conditions are applied to a variety of differently substituted aldehydes.
The results obtained are summarized in Table 2. We notice that whatever the nature of
the substituent and its position yields remain moderate to very good and vary between
50 and 80% (Table 2, entries 1–8): The best result is obtained with 4-hydroxybenzalde-
hyde (80%) while the worst with 3-metoxybenzaldehyde (50%). Moreover, it is observed
that the heteroaromatic aldehyde (Table 2, entry 9) leads to a good yield of 63%.
In Scheme 2, we suggest a plausible mechanism for the formation of 4-arylmethylene-
isoxazol-5(4H)-ones (4). The first step is a condensation reaction between the
Table 1. Optimization of reaction conditions.
Entry
Solvent
Catalyst (mol%)
Time (h)
Temp. (ꢀC)
Yield (%)
1
2
3
4
5
6
7
8
–
H2O
H2O
EtOH
EtOH/H2O
CH2Cl2
CH3CN
H2O
H2O
H2O
H2O
H2O
10
10
10
10
10
10
10
0
1
24
1
3
4
1
1
1
1
1
1
1
1
80 ꢀC
r.t
42
79
80
Traces
40
–
Traces
63
80
69
76
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
9
5
10
11
12
13
15
20
30
50
76
73
H2O
Table 2. PPTS-catalyzed 3-methyl-4-arylmethylene-isoxazol-5(4H)-ones synthesis (4a-i).
Entry
Ar
Producta
Time (h)
Yieldb
1
2
3
4
5
6
7
8
9
C6H5
4-MeC6H4
4-ClC6H4
4-MeOC6H4
4-HOC6H4
2-MeOC6H4
(Me)2NC6H4
3-MeOC6H4
2-Thienyl
4a
4b
4c
4d
4e
4f
4g
4h
4i
3
2
3
1
0.5
1
0.5
3
1
64
62
60
65
80
72
70
50
63
aConditions: 1 mmol of the aldehyde, 1 mmol of hydroxylamine hydrochloride, 1 mmol of ethyl acetoacetate and
5 mol% of PPTS in 5 ml of water at reflux. bIsolated yields of pure products.

4
R. LAROUM AND A. DEBACHE
PPTS
H
O
OH
PPTS
OC2H5
O
O
O
-H2O
N
O
N
Cyclization
OC2H5
OC2H5
+
2
1
NH2OH
-C2H5OH
O
O
O
Ar
N
N
O
O
H
H
PPTS
-H2O
3
Ar
4
Scheme 2. Mechanism of formation of 3-methyl-4-arylmethylene-isoxazol-5(4H)-ones catalyzed
by PPTS.
hydroxylamine and the carbonyl function of ethyl acetoacetate leading to an oxime
(intermediate 1). The second step is an intramolecular cyclization (intermediate 2) fol-
lowed by the loss of an EtOH molecule to give 3-methyl-isoxazole-5(4H)-one (inter-
mediate 3). A Knoevenagel condensation type of intermediate 3 and aromatic aldehydes
leads to the final products (4). All the steeps were facilitated by the presence of PPTS.
Conclusions
We describe here a new, efficient process for the synthesis of 3-methyl-4-arylmethylene-
isoxazol-5(4H)-ones by a three-component reaction between aromatic aldehydes, ethyl
acetoacetate, and hydroxylamine hydrochloride catalyzed by PPTS as a benign catalyst,
commercially available, inexpensive, and easy to handle. The essential advantages of this
method are simplicity of use, good yields, short reaction times and the use of non-toxic
solvent. It is an environmentally friendly process.
Experimental
The chemicals and solvents of grade “for synthesis” have been purchased from Aldrich
(USA) and Alfa Aesar (Germany) and used without further purification. 1 H and 13 C
NMR spectra were recorded as solutions in DMSO-d6 on a BRUKER ADVANCE 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 on potassium bromide (KBr) pellets with a
Shimadzu FT IR-8201 PC spectrometer, mmax are given in cmꢁ1. The melting points
were determined in a Kofler apparatus and were not corrected.

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SYNTHETIC COMMUNICATIONSV
5
General procedure for 3-methyl-4-arylmethylene-isoxazol-5(4H)-ones
synthesis (4a-k)
1 mmol of the aldehyde, 1 mmol of hydroxylamine hydrochloride, 1 mmol of ethyl
acetoacetate and 5 mol% of PPTS 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 (Table 2), followed
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 obtained
solid is filtered and purified by crystallization from ethanol.
Spectral data for selected products
4-(4-Methylbenzylidene)-3-methylisoxazol-5(4H)-one 4b
M.p.: 148–150 ꢀC; lit.[14] 140–142 ꢀC;1 H NMR: 2.3 (s, 3H, CH3), 2.5 (s, 3H, CH3), 7.5 (s,
1H, CH¼C), 7.3 (d, 2H, J ¼ 8.2), 8.3 (d, 2H, J ¼ 8.2). 13C NMR: 11(CH3), 22 (CH3-Ar),
128, 130, 140, 150 (CH¼C), 162 (C¼N), 169 (C¼O). IR (cmꢁ1): mmax ¼ 771, 1122, 1512,
1631, 1735, 2923.
4-(4-Methoxybenzylidene)-3-methylisoxazol-5(4H)-one 4d
1
M.p.: 178–180 ꢀC; lit.[23] 175–177; H NMR: 2.35 (s, 3H, CH3), 3.95 (s, 3H, OCH3), 7.01
(d, 2H, J ¼ 7.5), 7.38 (s, 1H, CH¼C), 8.44 (d, 2H, J ¼ 7.5). 13C NMR: 11.72 (CH3), 55.79
(OCH3), 114.72, 125.87, 137.06, 137.21, 149.56, 163.78 (C¼N), 164.69 (C¼O).
IR (cmꢁ1): mmax ¼ 813, 1218, 1550, 1593, 1720, 2935.
4-(3-Methoxybenzylidene)-3-methylisoxazol-5(4H)-one 4i
M.p.: 130–132 ꢀC; 1H NMR: 3.11 (s, 3H, CH3), 3.80 (s, 3H, O-CH3), 7.10 (t, 1H,
J ¼ 6.25), 7.4 (t, 1H, J ¼ 6.25), 7.70 (d, 1H, J ¼ 5), 7.60 (s,1H, CH¼C),8.20 (s, 1H).
13C NMR:11 (CH3), 55 (CH3-O), 113.5, 120, 120.6, 150, 160.5 (C-OCH3), 163.2
(C-CH3), 169.2 (C¼O). IR (cmꢁ1): mmax ¼ 813, 1218, 1550, 1593, 1720, 2935. HRMS
(MS-ESI, m/z): [M þ H]þ calculated for (C12H12NO3) 218.08117, found 218.0812.
Funding
ꢀ
The study received financial support from the Algerian MESRS (Ministere de l’Enseignement
ꢁ
Superieur et de la Recherche Scientifique).
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