Sulfated polyborate catalyzed expeditious and efficient three-component synthesis of 3-methyl-4-(hetero)arylmethylene isoxazole-5(4H)-ones

Article abstract of DOI:10.1016/j.tetlet.2017.07.019

A rapid and highly efficient methodology for the synthesis of 3-methyl-4-(hetero)arylmethylene isoxazole-5(4H)-ones has been developed using sulfated polyborate as a catalyst. The multicomponent reaction of an aromatic/heterocyclic aldehyde, hydroxylamine

Full text of DOI:10.1016/j.tetlet.2017.07.019

Accepted Manuscript
Sulfated polyborate catalyzed expeditious and efficient three-component syn-
thesis of 3-methyl-4-(hetero)arylmethylene isoxazole-5(4H)-ones
Manisha S. Patil, Chirag Mudaliar, Ganesh U. Chaturbhuj
PII:
S0040-4039(17)30858-4
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.07.019
TETL 49101
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
14 June 2017
24 June 2017
3 July 2017
Please cite this article as: Patil, M.S., Mudaliar, C., Chaturbhuj, G.U., Sulfated polyborate catalyzed expeditious
and efficient three-component synthesis of 3-methyl-4-(hetero)arylmethylene isoxazole-5(4H)-ones, Tetrahedron
Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.07.019
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Graphical Abstract
Sulfated polyborate catalyzed expeditious and
efficient three-component synthesis of
3-methyl-4-(hetero)arylmethylene isoxazole-5(4H)-ones
Manisha S. Patil, Chirag Mudaliar, Ganesh U. Chaturbhuj*

1
Tetrahedron Letters
journal homepage: www.els evier.com
Sulfated polyborate catalyzed expeditious and efficient three-component synthesis of
3-methyl-4-(hetero)arylmethylene isoxazole-5(4H)-ones
Manisha S. Patil, Chirag Mudaliar and Ganesh U. Chaturbhuj∗
Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Mumbai- 400019 India.
ARTICLE INFO
ABSTRACT
Article history:
Received
A rapid and highly efficient methodology for the synthesis of 3-methyl-4-
(hetero)arylmethylene isoxazole-5(4H)-ones has been developed using sulfated
polyborate as a catalyst. The multicomponent reaction of an aromatic/heterocyclic
aldehyde, hydroxylamine hydrochloride, and ethyl acetoacetate under a solvent free
condition at 80 °C is described. This protocol has promising features for the reaction
response such as shorter reaction times, easy work-up, ease of separation of pure
product with high yields and simplicity in the experimental procedure. The products
have been obtained in high yields (80–90 %) and convenient reaction times (15-30
min). The method is operationally simple and eco-friendly.
Received in revised form
Accepted
Available online
Keywords:
Sulfated polyborate
Isoxazole
Aldehyde
Ethyl acetoacetate
Hydroxylamine hydrochloride
2016 Elsevier Ltd. All rights reserved.
Isoxazole and its derivatives are an important class of
interesting nitrogen and oxygen-containing heterocyclic
compounds with a wide variety of applications in liquid
crystalline materials,1 organic synthesis,2 light-conversion
molecular devices,3 filter dyes in photographic films,4 and optical
storage and nonlinear optical research (fig.1).5 Several substituted
isoxazoles have been shown to have a broad range of biological
properties, e.g. anti-obesity,6 analgesic,7 anti-inflammatory,8 and
immunosuppressive, antibacterial, antifungal,9 anticancer,10
antitumor,11 and show hypoglycemic activity.12,13
The isoxazole backbone is also a structural component of a
variety of natural products and drugs such as muscimol,14
cycloserine,15 ibotenic acid, and isoxazole-4-carboxylic acid,16
Among isoxazoles, 3,4-disubstituted isoxazole-5(4H)-ones are
active agrochemical compounds, used as fungicides, and
insecticides,17-18 and selective inhibitors of protein kinase C,19
antiandrogen agents,20,21 antidiabetic agents,22 and enzyme
inhibitors (fig.1).23
Fig.1. Representative examples of interesting isoxazol-5(4H)-one containing
heterocycles
and sodium hydroxide with subsequent addition of aqueous HCl
followed by heating.27
Thus, synthesis of isoxazole-containing compounds is of
considerable interest. There are various methods for synthesis of
substituted isoxazole-5(4H)-ones, including cyclization of O-
propionyl oximes,24 reaction of ethyl acetoacetate and
hydroxylamine hydrochloride followed by Knoevenagel
condensation with aromatic aldehydes in two steps,25
condensation of substituted benzaldoximes and 1,3-dicarbonyl
compounds,26 and reaction of β-ketoesters with hydroxylamine
A number of catalysts have been used in one-pot three-
component reactions toward synthesis of isoxazole-5(4H)-one
scaffolds including sodium silicate,28 sodium benzoate,29
pyridine,30 sodium citrate,31 sodium azide,32 sodium saccharin,33
1,4- diazabicyclo[2.2.2]octane (DABCO),34
Ag/SiO2,35
phthalimide-N-oxyl salts,36 sodium tetraborate,37 sodium
sulphide,38 boric acid,39 potassium phthalimide,40 glycine,41 N-
bromosuccinimide (NBS),42 2-hydroxy-5-sulfobenzoic acid (2-
HSBA),43 potassium hydrogen phthalate (KHP),44 Dowex
50WX4,45 and tartaric acid.46 Furthermore, techniques such as
visible light in presence of sodium acetate in aqueous EtOH,47
solid-state heating or grinding,48 ultrasonic irradiation,49,50 and
microwave heating51 have also been reported for the preparation
Scheme 1. Preparation of the sulfated polyborate
———
∗ Corresponding author. Tel.: +91-223-361-2212; fax: +91-222-414-5614; e-mail: gu.chaturbhuj@gmail.com

2
Table 2
The effect of the solvents on the synthesis of 3-methyl-4-phenylmethylene
isoxazole-5(4H)-one a
Entry
Solvent
Temperature
(°C)
Time
(min)
Yieldb
(%)
Scheme2. Synthesis of various 3-methyl 4-(hetero)arylisoxazol-5(4H)-one
derivatives catalyzed by sulfated polyborate.
1
2
3
Solvent free
EtOH
100
15
60
60
90
70
50
reflux
reflux
of isoxazole-5(4H)-ones.
MeCN
Many of these methods have some limitations and
drawbacks, such as the use of toxic reagents, strongly acidic or
basic conditions, costly reagents and catalysts, stringent reaction
conditions, tedious steps, and low product yields and/or long
reaction times, which restrict their scope in practical applications.
Therefore, a novel protocol with good and inexpensive catalyst
demanding short reaction times and high yield is desirable.
Having the above points in mind, herein we report a rapid
and efficient synthesis of 3-methyl-4-(hetero)arylmethylene
isoxazole-5(4H)-ones catalyzed of sulfated polyborate under
solvent-free conditions.
A literature search revealed that boric acid catalyzes many
useful organic transformations above 100°C.52,53 Boric acid
dehydrates above 100 °C and turns to its polymeric forms, which
could be the active species catalyzing the reaction.54 Dehydrative
polymerization of boric acid liberates water molecules which
may hamper the progress of the reaction.
This persuades us to develop a polymeric boric acid catalyst
with mild Bronsted acidity. To accomplish this boric acid was
dehydrated at 200 °C to convert it into its polymeric Lewis acid
form and then sulfonated to introduce the mild Bronsted acid
character.55 Boron being an electron deficient element and
electron withdrawing effect of adjacent sulfate enhances its
Lewis acidity; hence the sulfated catalyst is acting as a
Lewis/Bronsted acid. (Scheme 1).
The development of the green, practical, and convenient
catalytic methods for the commercial process of current interest
and organic synthesis is valuable. Hence, the sulfated polyborate
was prepared from readily available boric acid, as economic and
non-toxic starting material, characterized and effectively applied
for various organic transformations.55-64 Herein we report its
applicability in the promotion of the synthesis of 3-methyl 4-
(hetero)arylisoxazol-5(4H)-ones. All reactions are performed
under mild conditions during relatively short reaction time in
good to high yields (Scheme 2).
4
5
6
7
THF
reflux
reflux
reflux
100
60
60
60
60
30
Water
Toluene
DMF
30
NRc
NRc
a Reaction conditions: benzaldehyde (1 mmol), hydroxylamine hydrochloride (1 mmol),
ethyl acetoacetate (1mmol)b Isolated yield. cNo Reaction
Based on reaction time (15 min) and yield (90 %), 10 wt% of
catalyst provided the best result and was thus selected as the
optimum quantity for the promotion of the reaction. Use of larger
amounts of sulfated polyborate resulted decreased the product
yield (Table 1, entries 6).
Temperature played an important role in the synthesis of 3-
methyl-4-phenyllmethylene isoxazole-5(4H)-one (Table 1, entry
7 - 8). The temperature effect was examined at ambient, 50 and
80 °C under the solvent free condition with sulfated polyborate as
a catalyst. The reaction proceeds very slow at room temperature.
while increasing temperature to 80 °C resulted in increased
product yield in shorter reaction time (Table 1, entries 6, 7 and
8). Therefore, this was the optimum temperature for performing
the reaction.
The effect of various solvents on time and yield of the
reaction was ascertained (Table 2, entire 2-7). In ethanol, the
reaction proceeds smoothly with high yield (Table 2, entire 2).
While in MeCN, THF, and water reaction proceed lower yields
(Table 2, entire 3,4, and 5). In DMF and toluene reaction does
not proceed (Table 2, entire 6,7). None of the solvents presented
the advantage of time and yield over solvent free condition.
Hence, the solvent free condition was regarded as best for the
cost and environmental acceptability. In all the experiments, the
products were isolated by aqueous quenching followed by
filtration and recrystallized from methanol.
Table 3
Sulfated polyborate catalyzed synthesis of 3-methyl-4-(hetero)arylmethylene
isoxazole-5(4H)-ones a 65
To initiate our study, we checked the three-component
reaction of benzaldehyde, hydroxylamine hydrochloride, and
ethyl acetoacetate as a model reaction. The effects of the amounts
of catalyst and temperature were investigated; the experimental
results are summarized in (Table 1). Yields of the product were
traces, 30, 50, 70 and 90 % with 0, 2.5, 5, 7.5 and 10 wt%
loading of sulfated polyborate, respectively (Table 1, entries 1-5).
Entry
1
R
Product
Time
(min)
%
Yield
15
90
Table 1
C6H5
N
O
Effect of catalyst loading and temperature for the synthesis of 3-methyl-4-
phenylmethylene isoxazole-5(4H)-one a
O
OH
Yieldb
(%)
2
3
4
20
85
Entry
Catalyst
(wt %)
Temperature
(°C)
Time
(min)
2-HO-C6H4
2- O2N-C6H4
3-Cl-C6H4
N
O
O
1
2
3
4
5
6
7
8
-
80
80
80
80
80
80
r.t.
50
60
45
30
30
15
30
60
30
traces
30
2.5
5
30
20
traces
85
50
7.5
10
15
10
10
70
90
80
NRc
45
a Reaction conditions: benzaldehyde (1 mmol), hydroxylamine hydrochloride (1 mmol),
ethyl acetoacetate (1mmol)b Isolated yield. cNo Reaction

3
5
25
85
3-Br-C6H4
6
7
8
9
25
20
30
22
80
90
80
86
3-O2N-C6H4
4-Cl-C6H4
4-Br-C6H4
4-CH3-C6H4
Fig. 2. Reusability of the catalyst.
isoxazole-5(4H)-ones. We have also attempted applying the
optimized reaction condition to the aliphatic and alicyclic
aldehyde with no success.
Recyclability of the catalyst is an important attribute for the
industrial suitability. Therefore, reusability of the catalyst in the
model reaction under optimized reaction condition was
evaluated. In this study, after completion of each reaction cycle,
water was added and the product was filtered off. The filtrate was
evaporated in vacuum rotary evaporator to recover catalyst.
Recovered catalyst was recycled for four times with no
significant loss in catalytic activity (Fig. 2).
10
11
15
30
85
85
4-CH3O-C6H4
4-HO-C6H4
A plausible mechanism sulfated polyborate catalyzed the
synthesis of 3-methyl-4-(hetero)arylmethylene isoxazole-5(4H)-
ones is as suggested in Scheme 3. The mechanism might begin
with the acid catalyzed oximation of ethyl acetoacetate to
produce [C], followed by Knoevenagel condensation of the
activated aldehyde [2] with the tautomer [D] of [C] to produce
intermediate [F] via intermediate [E]. Further intramolecular
cyclization of intermediate [F] to intermediate [G] and
elimination of ethanol to obtain target compound. The Bronsted
acid sites of the catalyst not only activates carbonyl of aldehyde
but also interacts with all other intermediates in the stated
mechanism.
12
13
40
20
traces
4-O2N-C6H4
2-Thienyl
90
14
15
18
20
92
80
5-methyl
furan-2-yl
Conclusion
We have developed
a rapid, simple, efficient, and
environmentally benign one-pot three-component protocol for the
synthesis of 3-methyl-4-(hetero)arylmethylene isoxazole-5(4H)-
ones with good to excellent yields. The new homogeneous
catalyst, sulfated polyborate is simple, highly efficient and
recyclable in this protocol. The main advantages of this approach
are a solvent free condition, cheap raw materials, easy workup,
non-hazardous and environment-friendly reaction conditions,
recyclable catalyst, excellent yields, and short reaction time.
Indol-3-yl
16
20
85
C6H5CH=CH
a Reaction conditions: aldehyde (1 mmol), hydroxylamine hydrochloride (1 mmol), ethyl
acetoacetate (1mmol) and sulfated polyborate 10 wt%, b Isolated yield. cNo Reaction
Acknowledgements
To study the substrate scope, optimized reaction condition
was applied to various aromatic/heterocyclic aldehydes with
hydroxylamine hydrochloride and ethyl acetoacetate.65 All the
substrate variants reacted well and afforded high yields of the
corresponding 3-methyl-4-(hetero)arylmethylene isoxazole-
5(4H)-ones derivatives within shorter reaction time (Table 3)
except 2- and 4-nitrobenzaldehydes (Table 3, entries 3 and 12).
Several electron-releasing or electron-withdrawing substituents at
ortho, meta and para positions of aromatic aldehydes showed no
significant effect on product yield and time. This protocol is also
extendable to heteroaromatic α/β unsaturated (Table 3, entries
13-16) which also reacted very well and afforded good to high
yields of the corresponding 3-methyl-4-(hetero)arylmethylene
Authors are thankful to Department of Science and
Technology, India for their financial support.

4
Scheme 3. A plausible mechanism for sulfated polyborate catalyzed synthesis of 3-methyl-4-phenylmethylene isoxazole-5(4H)-ones.
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65. General
procedure
for
the
synthesis
of
3-methyl-4-
(hetero)arylmethylene isoxazole-5(4H)-ones. A mixture of equimolar
quantities of hydroxylamine hydrochloride (1 mmol) and ethyl
acetoacetate (1 mmol) and 10 wt% sulfated polyborate were stirred at
80 °C in an oil bath. Then, added aromatic/heterocyclic aldehyde (1
mmol) and the reaction mixture was stirred. The reaction was
monitored by TLC. After completion of the reaction, the mixture was
cooled to room temperature and quenched in water; solid precipitated
was filtered at the pump, washed with water (3 X 5 mL), dried under

6
Graphical Abstract

7
Highlights:
•
•
•
Sulfated polyborate catalyzed preparation of
substituted isoxazole-5(4H)-ones.
An accelerated procedure under solvent free
condition.
Key advantages are high yields, short
reaction time and simple work-up
procedure.
•
•
Catalyst is recyclable with no significant
loss in activity.
Method tolerates a variety of functionality
with multiple substrates extendibility.