One-pot three-component synthesis of 3-methyl-4-arylmethylene-isoxazol- 5(4H)-ones catalyzed by sodium sulfide

Article abstract of DOI:10.1080/10426507.2011.621003

3-Methyl-4-arylmethylene-isoxazol-5(4H)-ones were synthesized by the convenient three-component reaction of ethyl acetoacetate, hydroxylamine hydrochloride, and aromatic aldehydes catalyzed by sodium sulfide in the presence of ethanol at room temperature.

Full text of DOI:10.1080/10426507.2011.621003

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Phosphorus, Sulfur, and Silicon and the
Related Elements
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One-Pot Three-Component Synthesis
of 3-Methyl-4-Arylmethylene-
Isoxazol-5(4H)- Ones Catalyzed by
Sodium Sulfide
Qing Liu a & Xianming Hou a
a Department of Chemistry and Environmental Science , Taishan
University , Tai’an , China
Published online: 31 Jan 2012.
To cite this article: Qing Liu & Xianming Hou (2012) One-Pot Three-Component Synthesis of 3-
Methyl-4-Arylmethylene- Isoxazol-5(4H)- Ones Catalyzed by Sodium Sulfide, Phosphorus, Sulfur, and
Silicon and the Related Elements, 187:4, 448-453, DOI: 10.1080/10426507.2011.621003
To link to this article: http://dx.doi.org/10.1080/10426507.2011.621003
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Phosphorus, Sulfur, and Silicon, 187:448–453, 2012
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2011.621003
ONE-POT THREE-COMPONENT SYNTHESIS
OF 3-METHYL-4-ARYLMETHYLENE-ISOXAZOL-5(4H)-
ONES CATALYZED BY SODIUM SULFIDE
Qing Liu and Xianming Hou
Department of Chemistry and Environmental Science, Taishan University, Tai’an,
China
GRAPHICAL ABSTRACT
O
O
O
O
Ar
Na2S 9H2O
Ethanol, r.t.
+
O
+
NH2OH HCl
Ar
H
OC2H5
N
CH3
Abstract 3-Methyl-4-arylmethylene-isoxazol-5(4H)-ones were synthesized by the convenient
three-component reaction of ethyl acetoacetate, hydroxylamine hydrochloride, and aromatic
aldehydes catalyzed by sodium sulfide in the presence of ethanol at room temperature. The
advantages of this procedure were mild reaction conditions, high yields, short reaction time,
and operational simplicity.
Keywords Sodium sulfide; 3-methyl-4-arylmethylene-isoxazol-5(4H)-ones; one-pot synthesis
INTRODUCTION
Multicomponent reactions (MCRs) are of increasing importance in organic and
medicinal chemistry because these reactions increase the efficiency by combining sev-
eral operational steps without the isolation of intermediates or change in the conditions.1
MCRs have recently emerged as valuable tools in the preparation of structurally diverse
chemical libraries of drug-like heterocyclic compounds.2 The search and discovery for
new MCRs on one hand and the full exploitation of the already known multicomponent
reactions on the other hand are therefore of considerable current interest.3 One such MCR
that belongs to the latter category is the synthesis of isoxazol-5(4H)-ones derivatives.
Isoxazol-5(4H)-ones compounds have attracted increasing interest due to their sig-
nificant pharmaceutical and therapeutic properties, such as hypoglycemic, immunosup-
pressive, anti-inflammatory, and anti-bacterial activities.4 In addition, isoxazole derivatives
have served as a versatile building block in organic synthesis.5 The traditional synthesis of
Received 13 July 2011; accepted 29 August 2011.
We gratefully thank Taishan University for the financial support.
Address correspondence to Qing Liu, Department of Chemistry & Environmental Science, Taishan Univer-
sity, Tai’an, 271021, China. E-mail: sdsslq@163.com
448

ONE-POT SYNTHESIS OF 3-METHYL-4-ARYLMETHYLENE-ISOXAZOL-5(4H)-ONES 449
3-methyl-4-arylmethylene-isoxazol-5(4H)-ones derivatives were carried out in two steps.6
In the first step, ethyl acetoacetate reacts with hydroxylamine hydrochloride to afford an
oxime, and further ring closure forms the product 3-methyl-isoxazol-5(4H)-one. And then,
the Knoevenagel reactions between 3-methyl-isoxazol-5(4H)-one and aromatic aldehydes
produce 3-methyl-4-arylmethylene-isoxazol-5(4H)-ones. In recent years, some new meth-
ods (such as solid-state grinding,7 solid-state heating,7 and MCR8,9) have been reported,
each affording variable yields of condensation compounds in solution or under solvent-free
conditions. Using the methods indicated above, there were still some limitations, such as
the long reaction time, low yields, and the strict reactive condition (grinding or high tem-
perature), and they needed other special conditions, such as ultrasound irradiation. Hence,
the introduction of efficient and new methods is still in demand.
Sodium sulfide is probably one of the oldest and most widely used industrial chemicals
and has been used as a catalyst in some reactions.10 In continuation of our interest in
catalysis,11 we wish to report one-pot synthesis of 3-methyl-4-arylmethylene-isoxazol-
5(4H)-ones through a three-component reaction catalyzed by sodium sulfide. In this study,
the procedure showed various advantages such as mild reaction conditions, high yields,
short reaction time, and operational simplicity.
RESULTS AND DISCUSSION
In order to explore the feasibility of some different catalysts, the reaction between
benzaldehyde, ethyl acetoacetate, and hydroxylamine hydrochloride in ethanol was selected
as model. As shown in Table 1, only sodium sulfide was effective in catalyzing the reaction,
and others did not work. The basicity of different catalysts itself sometimes plays an
important role in the high catalytic activity in base-catalyzed reactions. However, mention
must be made here that hydroxylamine hydrochloride was active and would react with
the base tempestuously (effervescently). Sodium sulfide was found to be the best since it
resulted in the highest yield of the desired product.
Table 1 Screening of different catalysts for the condensation reaction
O
O
O
O
Catalyst
H
+
NH2OH HCl
+
O
OC2H5
N
CH3
Entry
Catalysta
Yield (%)b
1
2
3
4
5
6
Na2S · 9H2O
NaOH
KOH
80
0
0
0
0
Na2CO3 · 10H2O
K2CO3
NaHCO3
0
aThe reaction was carried out in ethanol (5 mL) with catalysts (5 mol%) for 2.5 h.
bIsolated yield.

450
Q. LIU AND X. HOU
Table 2 Effect of solvents on the condensation catalyzed by sodium sulfide
Entry
Solventa
Yield (%)b
1
2
3
4
5
6
C2H5OH
Cyclohexane
1, 4-dioxane
Acetone
H2O
Solvent-free
80
70
37
Trace
Trace
42
aThe reaction was carried out in solvents (5 mL) with catalysts (5 mol%) for 2.5 h.
bIsolated yield.
To investigate the influence of the solvents, the model reaction was carried out in
various solvents and also under solvent-free condition. As shown in Table 2, the reac-
tion proceeded well in ethanol (Table 2, entry 1), and also proceeded well in cyclohex-
ane (Table 2, entry 2), whereas in the other solvents or under solvent-free conditions,
the reaction proceeded dissapointingly. When water was used, the reaction was unsuc-
cessful (Table 2, entry 5). The reason might be that the solution of sodium sulfide was
strong alkaline and would react with hydroxylamine hydrochloride, which was the same
with the base in Table 1. Consequently, the remainder of reactions were carried out in
ethanol.
MCR strategies offer significant advantages over conventional linear-type syntheses.
In such reactions, three or more reactants come together in a single reaction vessel to
form new products that contain portions of all the components. However, the sequence of
feed-in sometimes plays an important role in MCRs. In this reaction, there was no product
when ethyl acetoacetate, hydroxylamine hydrochloride, and aromatic aldehyde were added
simultaneously in the presence of the catalyst. When, ethyl acetoacetate, hydroxylamine
hydrochloride, and the catalyst were stirred for 10 min, followed by the addition of aromatic
aldehyde, the reaction proceeded smoothly to high yield.
After optimizing the reaction conditions, aromatic aldehydes were treated with ethyl
acetoacetate and hydroxylamine hydrochloride in the presence of sodium sulfide in ethanol.
All of the results are presented in Table 3. The yields varied greatly because of the difference
in the substitutional group of aromatic aldehydes. The aromatic aldehydes with electron-
donating group afforded the target products in high yield and purity in short time (Table 3,
entries 3–6), while aromatic aldehydes with an electron-withdrawing group failed to convert
to the target products (Table 3, entries 8 and 9). It is important to note that heterocyclic
aldehyde (Table 3, entry 2) and α, β-unsaturated aldehyde (Table 3, entry 7) underwent
smoothly with ethyl acetoacetate and hydroxylamine hydrochloride, giving moderate or
high yields of the corresponding products.
In Scheme 1, we proposed a feasible mechanism for the reaction. Ethyl acetoacetate
reacted with hydroxylamine hydrochloride to afford oxime, and it was difficult for oxime
to close the ring to achieve 3-methyl-isoxazol-5(4H)-one. When intermediate a lost one
hydrogen atom, the methylene would convert to be the carbon anion b. Then, aromatic
aldehydes attacked carbon anion and the Knoevenagel reactions occurred. After losing one
ethanol molecule, ring-closing brought the product 3-methyl-4-arylmethylene-isoxazol-
5(4H)-ones.

ONE-POT SYNTHESIS OF 3-METHYL-4-ARYLMETHYLENE-ISOXAZOL-5(4H)-ONES 451
Table 3 Synthesis of 3-methyl-4-arylmethylene-isoxazol-5(4H)-ones in the presence of sodium sulfide
O
O
O
O
Ar
Na2S 9H2O
Ethanol, r.t.
+
O
+
NH2OH HCl
Ar
H
OC2H5
N
CH3
mp (◦C)
Compound
Ar
Time (h)
Yield (%)a
Found
Reported8
1
2
3
4
5
6
7
8
9
C6H5
2-Furyl
4-CH3OC6H4
2-OHC6H4
4-OHC6H4
Vanillin
2.5
2.0
1.5
1.5
1.0
1.5
2.5
6.5
6.5
80
72
88
91
87
89
88
NRb
NRb
141–143
238–241
174–176
198–200
214–216
212–215
171–173
—
142–144
240–242
178–179
198–202
215–218
212–214
173–178
—
C6H5CH = CH
2-ClC6H4
2, 4-Cl2C6H3
—
—
aIsolated yield.
bNo reaction.
In order to show the merit of sodium sulfide in comparison with other catalysts used
for the same reaction, we have tabulated some of the results in Table 4. As is evident from
the results, although some reactions took more than 12 h, the yield was the highest with a
shorter reaction time in the presence of sodium sulfide. Mention must be made here that
other procedures were strict and complicated.
Table 4 Condensation catalyzed by different catalysts
O
O
O
O
Catalyst
H
+
+
NH2OH HCl
H3CO
O
OC2H5
N
CH3
H3CO
Amount
(mol%)
Time
(h)
Yield
(%)a
Entry
Catalyst and conditions
Reference
1
2
3
4
5
Na2S/EtOH/r.t.
5
100
0
0
100
1.5
3
88
71
61
66
82
This work
Pyridine/EtOH/reflux
Catalyst free/grinding
Catalyst free/105–110 ◦C
Pyridine/H2O/ultrasound
Zhang et al. (2008)9
Zhang et al. (2008)7
Zhang et al. (2008)7
Cheng et al. (2009)8
0.8b
0.25b
1c
aIsolated yield.
bThe mixture was allowed to stand 12 h after the completion of the reaction.
cThe mixture was allowed to stand overnight after the completion of the reaction.

452
Q. LIU AND X. HOU
O
O
O
O
OC2H5
OC2H5
OH
HC
OC2H5
OH
NH2OH HCl
Na2S
CH3
CH3
N
CH3
N
b
a
O
O
OH
O
Ar
OC2H5
Na2SH
ArCHO
Ar
OC2H5
OH
OH
CH3
N
O
CH3
N
d
c
O
OC2H5
-H2O
Ar
Ar
OC2H5
OH
OH
N
CH3
N
CH3
f
e
C2H5
O
O
O
Ar
H
Ar
-C2H5OH
O
O
N
N
CH3
CH3
h
g
Scheme 1
CONCLUSION
We have provided a facile and efficient method for the synthesis of 3-methyl-4-
arylmethylene-isoxazol-5(4H)-ones in the presence of sodium sulfide. Owing to its oper-
ational simplicity, high yields, and short reaction time, this method is better than other
currently examined reactions.
EXPERIMENTAL
All reagents were purchased and used without further purification. Melting points
were determined using XT-4 micro melting point apparatus.
A mixture of 20 mmol ethyl acetoacetate, 20 mmol hydroxylamine hydrochloride,
and 1 mmol sodium sulfide in ethanol (5 mL) were stirred for 10 min, then 20 mmol
aromatic aldehyde was added, and the mixture was further stirred until the completion
of the reaction (monitored by TLC). The product was filtered off and washed with cold
5% aqueous ethanol (2 × 30 mL), and recrystallized from EtOH (95%) to afford the pure
product.

ONE-POT SYNTHESIS OF 3-METHYL-4-ARYLMETHYLENE-ISOXAZOL-5(4H)-ONES 453
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