Tetrahedron Letters 58 (2017) 3256–3261

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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet

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 ⇑
Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Mumbai 400019, India

a r t i c l e i n f o a b s t r a c t

Article history: A rapid and highly efficient methodology for the synthesis of 3-methyl-4-(hetero)arylmethylene isoxa-
Received 14 June 2017 zole-5(4H)-ones has been developed using sulfated polyborate as a catalyst. The multicomponent reac-
Revised 24 June 2017 tion of an aromatic/heterocyclic aldehyde, hydroxylamine hydrochloride, and ethyl acetoacetate under
Accepted 3 July 2017
a solvent free condition at 80 °C is described. This protocol has promising features for the reaction
Available online 4 July 2017
response such as shorter reaction time, 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%)
Keywords:
and convenient reaction time (15–30 min). The method is operationally simple and eco-friendly.
Sulfated polyborate
Isoxazole
Ó 2017 Elsevier Ltd. All rights reserved.
Aldehyde
Ethyl acetoacetate
Hydroxylamine hydrochloride

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 photo-
graphic 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, anti-
fungal,9 anticancer,10 antitumor,11 and hypoglycemic activity.12,13
The isoxazole backbone is also a structural component of a
variety of natural products and drugs such as muscimol,14 cycloser-
ine,15 ibotenic acid, and isoxazole-4-carboxylic acid,16 Among
isoxazoles, 3,4-disubstituted isoxazole-5(4H)-ones are active agro-
chemical compounds, used as fungicides, and insecticides,17,18 and
selective inhibitors of protein kinase C,19 antiandrogen agents,20,21
antidiabetic agents,6 and enzyme inhibitors (Fig. 1).22
Thus, synthesis of isoxazole-containing compounds is of consid-
erable interest. There are various methods for synthesis of substi-
tuted isoxazole-5(4H)-ones, including cyclization of O-propionyl
oximes,23 reaction of ethyl acetoacetate and hydroxylamine
hydrochloride followed by Knoevenagel condensation with
aromatic aldehydes in two steps,24 condensation of substituted
⇑ Corresponding author.
E-mail address: gu.chaturbhuj@gmail.com (G.U. Chaturbhuj).
benzaldoximes and 1,3-dicarbonyl compounds,25 and reaction of
b-ketoesters with hydroxylamine and sodium hydroxide with sub-
sequent addition of aqueous HCl followed by heating.26
A number of catalysts have been used in one-pot three-compo-
nent reactions toward synthesis of isoxazole-5(4H)-one scaffolds
including sodium silicate,27 sodium benzoate,28 pyridine,29 sodium
citrate,30 sodium azide,31 sodium saccharin,32 1,4-diazabicyclo
[2.2.2]octane (DABCO),33 Ag/SiO2,34 phthalimide-N-oxyl salts,35
sodium tetraborate,36 sodium sulphide,37 boric acid,38 potassium
phthalimide,39 glycine,40 N-bromosuccinimide (NBS),41 2-hydroxy-
5-sulfobenzoic acid (2-HSBA),42 potassium hydrogen phthalate
(KHP),43 Dowex 50WX4,44 and tartaric acid.45 Furthermore, tech-
niques such as visible light in presence of sodium acetate in aqueous
EtOH,46 solid-state heating or grinding,47 ultrasonic irradiation,48,49
and microwave heating50 have also been reported for the prepara-
tion of isoxazole-5(4H)-ones.
Many of these methods have some limitations and drawbacks,
such as the use of toxic reagents, strongly acidic or basic condi-
tions, costly reagents and catalysts, stringent reaction conditions,
tedious steps, and low product yields and/or long reaction time,
which restrict their scope in practical applications. Therefore, a
novel protocol with good and inexpensive catalyst demanding
short reaction time 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-

http://dx.doi.org/10.1016/j.tetlet.2017.07.019
0040-4039/Ó 2017 Elsevier Ltd. All rights reserved.
 M.S. Patil et al. / Tetrahedron Letters 58 (2017) 3256–3261 3257

CF3

N
O
O N
O N
N O
N O O
O
F3CO
anti-androgen/ nonlinerar optical
anti-dibetic agent Fungicide agent (NLO)agent
O
O O
N O N
O O
N H3CO O
N
H
merocyanine dye fungicide agents

Fig. 1. Representative examples of interesting isoxazol-5(4H)-one containing heterocycles.

O
Dehydration
O O Cl-SO3 H HO S O O O
HO OH 200 oC HO B B
B B B O
OH O OH O
OH
n n
Sulfated Polyborate

Scheme 1. Preparation of the sulfated polyborate.

H O
O O sulfated polyborate
N
+ NH2 OH.HCl + O O
solvent free, 80°C O

Scheme 2. Synthesis of various 3-methyl 4-phenylmethylene isoxazol-5(4H)-one catalyzed by sulfated polyborate.

5(4H)-ones catalyzed of sulfated polyborate under solvent-free during relatively short reaction time in good to high yields
conditions. (Scheme 2).
A literature search revealed that boric acid catalyzes many use- To initiate our study, we checked the three-component reaction
ful organic transformations above 100 °C.51,52 Boric acid dehy- of benzaldehyde, hydroxylamine hydrochloride, and ethyl acetoac-
drates above 100 °C and turns to its polymeric forms, which etate as a model reaction. The effects of the amounts of catalyst
could be the active species catalyzing the reaction.53 Dehydrative and temperature were investigated; the experimental results are
polymerization of boric acid liberates water molecules which summarized in (Table 1). Yields of the product were traces, 30,
may hamper the progress of the reaction.
This persuades us to develop a polymeric boric acid catalyst
Table 1
with mild Bronsted acidity. To accomplish this boric acid was
Effect of catalyst loading and temperature for the synthesis of 3-methyl-4-phenyl-
dehydrated at 200 °C to convert it into its polymeric Lewis acid methylene isoxazole-5(4H)-one.a
form and then sulfonated to introduce the mild Bronsted acid char-
Entry Catalyst (wt%) Temperature (°C) Time (min) Yieldb (%)
acter.54 Boron being an electron deficient element and electron
withdrawing effect of adjacent sulfate enhances its Lewis acidity; 1 – 80 60 traces
hence the sulfated catalyst is acting as a Lewis/Bronsted acid. 2 2.5 80 45 30
3 5 80 30 50
(Scheme 1.) 4 7.5 80 30 70
The development of the green, practical, and convenient catalytic 5 10 80 15 90
methods for the commercial process of current interest and organic 6 15 80 30 80
synthesis is valuable. Hence, the sulfated polyborate was prepared 7 10 r.t. 60 NRc
8 10 50 30 45
from readily available boric acid, as economic and non-toxic starting
material, characterized and effectively applied for various organic a
Reaction conditions: benzaldehyde (1 mmol), hydroxylamine hydrochloride
transformations.54–63 Herein we report its applicability in the (1 mmol), ethyl acetoacetate (1 mmol).
b
Isolated yield.
promotion of the synthesis of 3-methyl 4-(hetero)arylisoxazol-5 c
No Reaction.
(4H)-ones. All reactions are performed under mild conditions
3258 M.S. Patil et al. / Tetrahedron Letters 58 (2017) 3256–3261

Table 2 7–8). The temperature effect was examined at ambient, 50 and

The effect of the solvents on the synthesis of 3-methyl-4-phenylmethylene isoxazole- 80 °C under the solvent free condition with sulfated polyborate
5(4H)-one.a
as a catalyst. The reaction proceeds very slow at room temperature.
Entry Solvent Temperature (°C) Time (min) Yieldb (%) while increasing temperature to 80 °C resulted in increased pro-
1 Solvent free 100 15 90 duct yield in shorter reaction time (Table 1, entries 6, 7 and 8).
2 EtOH reflux 60 70 Therefore, this was the optimum temperature for performing the
3 MeCN reflux 60 50 reaction.
4 THF reflux 60 30
5 Water reflux 60 30
The effect of various solvents on time and yield of the reaction
6 Toluene reflux 60 NRc was ascertained (Table 2, entire 2–7). In ethanol, the reaction pro-
7 DMF 100 60 NRc ceeds smoothly with high yield (Table 2, entire 2). While in MeCN,
a THF, and water reaction proceed with lower yields (Table 2, entire
Reaction conditions: benzaldehyde (1 mmol), hydroxylamine hydrochloride
(1 mmol), ethyl acetoacetate (1 mmol) and sulfated polyborate 10 wt%. 3, 4, and 5). In DMF and toluene reaction does not proceed (Table 2,
b
Isolated yield. entire 6, 7). None of the solvents presented the advantage of time
c
No Reaction. and yield over solvent free condition. Hence, the solvent free con-
dition was regarded as best for the cost and environmental accept-
ability. In all the experiments, the products were isolated by
aqueous quenching followed by filtration and recrystallized from
50, 70 and 90% with 0, 2.5, 5, 7.5 and 10 wt% loading of sulfated methanol.
polyborate, respectively (Table 1, entries 1–5). To study the substrate scope, optimized reaction condition was
Based on reaction time (15 min) and yield (90%), 10 wt% of applied to various aromatic/heterocyclic aldehydes with hydroxy-
catalyst provided the best result and was thus selected as the opti- lamine hydrochloride and ethyl acetoacetate.64 All the substrate
mum quantity for the promotion of the reaction. Use of larger variants reacted well and afforded high yields of the corresponding
amounts of sulfated polyborate resulted decreased the product 3-methyl-4-(hetero)arylmethylene isoxazole-5(4H)-ones within
yield (Table 1, entries 6). shorter reaction time (Table 3) except 2- and 4-nitrobenzaldehydes
Temperature played an important role in the synthesis of (Table 3, entries 3 and 12). Several electron-releasing or electron-
3-methyl-4-phenyllmethylene isoxazole-5(4H)-one (Table 1, entry withdrawing substituents at ortho, meta and para positions of aro-

Table 3
Sulfated polyborate catalyzed synthesis of 3-methyl-4-(hetero)arylmethylene isoxazole-5(4H)-ones.a, 64

O O sulfated polyborate
H O R
+ NH2 OH.HCl + N
O solvent free, 80 °C
R O
O

Entry R Product Time (min) % Yieldb

1 C6H5 15 90

N
O
O
2 2-HO-C6H4 OH 20 85

N
O
O
3 2-O2N-C6H4 NO2 30 traces

N
O
O
4 3-Cl-C6H4 20 85
Cl
N
O
O
5 3-Br-C6H4 25 85
Br
N
O
O
6 3-O2N-C6H4 25 80
O2N
N
O
O
 M.S. Patil et al. / Tetrahedron Letters 58 (2017) 3256–3261 3259

Table 3 (continued)

Entry R Product Time (min) % Yieldb

7 4-Cl-C6H4 20 90

N
Cl O
O
8 4-Br-C6H4 30 80

N
Br O
O
9 4-CH3-C6H4 22 86

N
H3C O
O
10 4-CH3O-C6H4 15 85

N
H3CO O
O
11 4-HO-C6H4 30 85

N
HO O
O
12 4-O2N-C6H4 40 traces

N
O2 N O
O
13 2-Thienyl 20 90

N
S O
O
14 5-Methyl furan-2-yl 18 92

N
O O
O
15 Indol-3-yl 20 80

N
HN O
O
16 C6H5CH@CH 20 85

N
O
O
a
Reaction conditions: aldehyde (1 mmol), hydroxylamine hydrochloride (1 mmol), ethyl acetoacetate (1 mmol) and sulfated polyborate 10 wt%.
b
Isolated yield.

matic aldehydes showed no significant effect on product yield and 100

time. This protocol is also extendable to heteroaromatic and a/b
80
unsaturated aldehydes (Table 3, entries 13–16) which also reacted
very well and afforded good to high yields of the corresponding 60
% Yield

3-methyl-4-(hetero)arylmethylene isoxazole-5(4H)-ones. We have

also attempted applying the optimized reaction condition to the 40
aliphatic and alicyclic aldehyde with no success. 20
Recyclability of the catalyst is an important attribute for the
industrial suitability. Therefore, reusability of the catalyst in the 0
model reaction under optimized reaction condition was evaluated. 1 2 3 4 5
In this study, after completion of each reaction cycle, water was No. of cycles
added and the product was filtered off. The filtrate was evaporated
Fig. 2. Reusability of the catalyst.
in vacuum rotary evaporator to recover catalyst. Recovered cata-
lyst was recycled for four times with no significant loss in catalytic
activity (Fig. 2).
A plausible mechanism sulfated polyborate catalyzed the intermediate [F] via intermediate [E]. Further intramolecular
synthesis of 3-methyl-4-(hetero)arylmethylene isoxazole- cyclization of intermediate [F] to intermediate [G] and elimina-
5(4H)-ones is as suggested in Scheme 3. The mechanism might tion of ethanol to obtain target compound. The Bronsted acid
begin with the acid catalyzed oximation of ethyl acetoacetate to sites of the catalyst not only activates carbonyl of aldehyde
produce [C], followed by Knoevenagel condensation of the but also interacts with all other intermediates in the stated
activated aldehyde [2] with the tautomer [D] of [C] to produce mechanism.
3260 M.S. Patil et al. / Tetrahedron Letters 58 (2017) 3256–3261

H
HO
O O H O O NH2 OH N O

O O -H2O O
[A] [B] [C]

H O H O
H HO
H N OH

O
[D]
[1] [2]
Knoevenagel
condensation

HO
N O HO
N OH
O -H2O
O
H
OH
[F]
[E]
Interamolecular
cyclization

N -C2 H5OH N
N O O
O H
O OH [I] O
[H]
[G] O O

O
H = HO S O O O
B B
O
OH O
n

Scheme 3. A plausible mechanism for sulfated polyborate catalyzed synthesis of 3-methyl-4-phenylmethylene isoxazole-5(4H)-ones.

Conclusion
We have developed a rapid, simple, efficient, and environmen-
tally 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 proto-
col. The main advantages of this approach are a solvent free condi-
tion, cheap raw materials, easy workup, non-hazardous and
environment-friendly reaction conditions, recyclable catalyst,
excellent yields, and short reaction time.
Acknowledgements
Authors are thankful to Department of Science and Technology,
India for their financial support.
A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2017.07.
019.
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