A convenient one-pot synthesis of 3,5-diarylisoxazoles via oxidative cyclisation using catalytic CuBr2 and oxone

Article abstract of DOI:10.1016/j.tetlet.2019.03.044

A facile one-pot synthesis of 3,5-diarylisoxazoles from α,β-unsaturated ketones and hydroxylamine hydrochloride is reported. The reaction is efficiently promoted by catalytic CuBr₂ and Oxone to afford the desired products mostly in high yields

Full text of DOI:10.1016/j.tetlet.2019.03.044

Accepted Manuscript
A Convenient one-pot synthesis of 3,5-diarylisoxazoles via oxidative cyclisa-
tion using catalytic CuBr2 and Oxone
Ashish Bhatt, Rajesh K. Singh, Ravi Kant
PII:
S0040-4039(19)30261-8
https://doi.org/10.1016/j.tetlet.2019.03.044
TETL 50685
DOI:
Reference:
Tetrahedron Letters
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Received Date:
Revised Date:
Accepted Date:
4 February 2019
15 March 2019
17 March 2019
Please cite this article as: Bhatt, A., Singh, R.K., Kant, R., A Convenient one-pot synthesis of 3,5-diarylisoxazoles
via oxidative cyclisation using catalytic CuBr2 and Oxone, Tetrahedron Letters (2019), doi: https://doi.org/10.1016/
j.tetlet.2019.03.044
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A Convenient one-pot synthesis of 3,5-
diarylisoxazoles via oxidative cyclisation
using catalytic CuBr2 and Oxone
Leave this area blank for abstract info.
Ashish Bhatta, Rajesh K. Singhb, Ravi Kanta
R1
NH2OH. HCl,
R2
5 mol% CuBr2
Oxone, EtOH
80 °C
R2
R1
N
O
O
2
1
R1 = H, 4-Me, 4-OMe, 4-OC2H5, 2,4-Me2, 4-Cl, 2-Cl, 4-Br, 3,4-Cl2, 4-NO2, R2 = H
R1 = H, R2 = 4-Me, 3-Me, 3-OMe, 4-Cl, 3-Cl, 2-Cl, 4-Br, 3-Br, 2-NO2

1
Tetrahedron Letters
journal homepage: www.elsevier.com
A Convenient one-pot synthesis of 3,5-diarylisoxazoles via oxidative cyclisation
using catalytic CuBr2 and Oxone
Ashish Bhatta,, Rajesh K. Singhb and Ravi Kanta
a Department of Chemistry, Mewar university, Chittorgarh, (Rajasthan),312901, India
b Department of Pharmacy, Mewar university, Chittorgarh, (Rajasthan),312901, India
———
ARTICLE INFO
ABSTRACT
 Ashish Bhatt. Tel.: +91-774-284-5501; e-mail: itsbhatt2007@yahoo.co.in
Article history:
Received
Received in revised form
Accepted
A facile one-pot synthesis of 3,5-diarylisoxazoles from α,β-unsaturated ketones and
hydroxylamine hydrochloride is reported. The reaction is efficiently promoted by catalytic
CuBr2 and Oxone to afford the desired products mostly in high yields and in relatively short
time. The mild nature of the synthesis and short reaction time are notable advantages of the
developed protocol. This protocol is effective toward various substrates having different
functionalities.
Available online
Keywords:
Chalcone
Isoxazoles
Oxone
2009 Elsevier Ltd. All rights reserved.
Ethanol
Introduction
(TPCD) [27], KOH-dioxane [28], N-bromosuccinimide [29],
NOBF4 30 and hypervalent iodine reagents, such as
Isoxazole derivatives represent a privileged class of five
membered nitrogen heterocycles and are extensively found in
numerous biologically active molecules with anticancer,
antidepressant, antibiotic, and analgesic activities [1–4].
Moreover, they are used as key building blocks in materials
science and as various complex synthetic intermediate in organic
PhI(OCOCH3)2 [31,32], PhI(OCOCF3)2 [33] are widely
employed to initiate the intramolecular oxidative cyclization.
Microwave-assisted synthesis of isoxazoles has also been
reported [34,35]. There are few reports of one-pot synthesis of
isoxazole [36–38]. However, the mentioned methods involve the
use of expensive catalyst, tedious synthetic procedures, time
taking reactions and unsatisfactory yields. Hence, the
development of milder and more general procedures to access
isoxazole derivatives with high yields in short reaction time
remains desirable.
synthesis [5,6]. By capitalizing on the presence of
a
comparatively weak N-O bond, for example, isoxazoles can be
transformed into such useful structures as those found in α-
hydroxy-β-diketones and other β-dicarbonyl compounds [7-10].
Owing to their good reactivity and synthetic utility, the
development of more efficient synthetic methods for isoxazoles
is of great importance to organic chemists [11–15].
Oxone is a versatile reagent and is becoming increasingly
popular because of its commercial availability at low cost and
lesser corrosiveness. The combination of CuBr2/Oxone has been
used for the several oxidative transformations. Our continued
interest in the development of useful synthetic methodologies
prompted us to explore the feasibility of CuBr2/Oxone for the
one-pot synthesis of isoxazole derivatives with high yields.
However, it has not been investigated as a catalyst in the
synthesis of isoxazole until now.
Isoxazoles are often synthesized through a [3+2] cycloaddition
of nitrile oxides with alkynes or alkenes followed by oxidation
[16-18]. As van Delft has noted, the thermal [3+2] cycloaddition
method can suffer from low yields, side-reactions and poor
regioselectivity [19]. While transition metal mediated
preparations of 3,5-disubstituted and 3,4-disubstituted isoxazoles
have been reported to provide satisfactory yields [20,21].
Result and Discussion
The reaction of hydroxylamine with 1,3-dicarbonyl or α,β-
unsaturated carbonyl compounds, followed by an intramolecular
oxidative cyclization provides another approach to isoxazoles
[22-23]. Since the oximes can be conveniently generated in high
yield, the oxidative cyclization of α,β-unsaturated oximes or β-
keto oximes constitutes the essential step for the successful
construction of the isoxazole framework.Various oxidants such
as 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) [24], MnO2
[25], I2/KI in NaHCO3 [26], tetrakis(pyridine)cobalt dichromate
Herein, we describe a convenient one-pot synthesis of 3,5-
diaryl isoxazoles from α,β -unsaturated ketones. The parent
chalcone 1a was prepared by Claisen–Schmidt condensation as
per the reported literature procedure [39-40]. Our preliminary
investigation began with the reaction of Chalcone 1a and
hydroxylamine hydrochloride in the presence of Oxone (1 equiv.)
and a catalytic amount of CuBr2 (2 mol%) in methanol at 80 °C.
We were delighted to observe the formation of the desired

2
Tetrahedron
product 2a, albeit in a low yield of 55% (Table 1, entry 1).
Based on our experimental data and previous report, [41–42] a
plausible reaction mechanism for the formation of 3,5-
disubstituted isoxazole 2 is proposed (Scheme 1). According to
this route, chalcone on treatment with hydroxyl amine
hydrochloride first provides 3,5-diaryl isoxazoline and form
Cu(II) complex of isoxazoline with CuBr2 which finally oxidizes
to isoxazole via the formation of isoxazolinium radical cation
through a single electron transfer to Cu2+. Finally, the nucleophile
bromide ion (Br-) abstract proton form isoxazolinium cation to
give the product. CuBr formed in reaction oxidizes by Oxone to
regenerate the CuBr2.
Next, we optimized the reaction conditions in order to increase
the yield. Thus, different solvents were screened and the results
are summarized in Table 1. It was found that ethanol was the
most superior solvent in terms of the reaction time and yield of
the product (Table 1, entry 2). Once we had established a suitable
solvent for the synthesis of isoxazole, we then focused on the
quantity of Oxone and CuBr2. An increase in the amount of
Oxone (from 1 equiv. to 2 equiv.) and CuBr2 (from 2 mol% to 5
mol%) not only decreased the reaction time from 1.5 h to 30
min., but also increased the product yield from 55% to 85%
(Table 1, entry 8). Further increasing the quantity of Oxone to 3
equiv. and CuBr2 (10 mol%) led to a decrease in the yield to 65%
(Table 1, entry 9). Therefore, we decided to perform the
subsequent reactions of the various chalcones with
hydroxylamine hydrochloride in the presence of Oxone (2 equiv.)
and CuBr2 (5 mol%) as the catalyst in ethanol at 80 °C. The
effect of temperature on the reaction rate as well as on the yields
of the products were also investigated. Faster reactions occurred
on increasing the temperature but the product yields were not
satisfactory. The progress of the reactions was monitored by TLC
analysis (using EtOAc–hexane as the eluent).
OH
Ph
O
Ph'
NH2OH.HCl
Ph
Ph'
N O
-H2O
Ph
Ph'
HN
H
1
O
H
O
O
Cu2+
2+Cu
O
Ph'
Ph'
2+Cu
Cu2+
-Cu+
N
Ph'
N
N
H
Ph
Ph
H
Ph
Table-1 Optimization of the Reaction Conditions
2+Cu
O
Ph'
N
Br
O
H
O
Ph'
N
2+Cu
H
Ph'
N
2+Cu
-HBr
NH2OH. HCl,
Ph
Cu2+
H
Ph
H
Ph
Oxone/CuBr2
N
- Cu+
Solvent, 80°C
O
O
2a
1a
H
Ph'
2+Cu
Dissociation
step
O
O
2+Cu
O
Br
- HBr
Ph'
N
Ph'
N
N
Entry
Solvent
Oxone
(eq.)
1
CuBr2
(mol%)
2
Time
Yield
(%)
55
-Cu2+
Ph
H
Ph
Ph
1
2
3
4
5
7
8
9
MeOH
EtOH
IPA
1.5 h
1h
2
1
1
2
2
65
40
40
45
70
85
65
2.5 h
2KHSO5.KHSO4.K2SO4 + 2CuBr
+ 2HBr
K2S2O8.KHSO4.K2SO4 + 2CuBr2
+ 2H2O
Toluene
AcOH
EtOH
EtOH
EtOH
1
2
3 h
1
2
1.5 h
1.5
2
5
45 min.
30 min.
15 min.
Scheme 1. Plausible mechanism for oxidative cyclisation of
Chalcone with hydroxyl amine hydrochloride
5
3
10
Conclusion
With the optimized reaction conditions established, the scope
of this protocol was investigated as listed in Tables 2 and 3. A
variety of substituents on the chalcone (R1) were explored firstly.
As shown in Table 2, either electron-donating groups such as
methoxy, ethoxy and methyl or electron-withdrawing groups
such as chloro, bromo and nitro on the aryl rings were well
tolerated, affording the corresponding 3,5-diarylisoxazole
products in good yields (Table 2, 2a–2j). The reaction is
insensitive to steric hindrance, for substrate with ortho-
substituent resulted in similar yield with the para-substituted one
(2f vs 2g). High efficiency was performed for the reaction of
chalcone with strong electron deficient nitro group (2j). Notably,
the tolerance of halide substituents such as Cl and Br, provides
possibilities for further functionalizations (Table 2, 2f–2i).
In conclusion, we have developed a short and efficient
synthesis of 3,5-diarylisoxazoles using
a
mild and
straightforward one-pot oxidative cyclization method using the
combination of CuBr2/Oxone, which is a low cost commercially
available reagent. A variety of substituents are tolerated allowing
the synthesis of diverse products in good to excellent yields. The
main advantage of this procedure is to access 3,5-
diarylisoxazoles with high yields and short reaction time. The
newly developed synthetic route is believed to be valuable for the
construction of building blocks but also for medicinal chemistry
studies comprising isoxazole moiety.
Next, various substituents on the chalcone (R2) were tested.
Substrates with electron donating or withdrawing group all
reacted smoothly to generate the desired 3,5 diarylisoxazoles in
good yields (Table-3).
Table-2 Synthesis of Various 3,5-diarylisoxazoles with the
scope of substituents (R1) on the chalcone
Mechanism

3
O
NH2OH. HCl,
3
3-OMe
35
77
R1
Oxone/CuBr2
EtOH, 80°C
N
O
3c
R1
N
O
O
2
1
Cl
4
5
6
4-Cl
3-Cl
2-Cl
N
35
30
40
83
81
80
O
Entry
R1
Product
Time Yield
3d
3e
Cl
(min)
(%)
N
N
O
O
1
2
Hydrogen
4-Me
30
35
85
83
N
O
2a
Cl
3f
N
O
2b
O
Br
7
4-Br
40
78
3
4
4-OMe
30
35
81
85
N
O
N
O
3g
2c
O
Br
4-OC2H5
N
O
N
N
40
40
75
77
2d
8
9
3-Br
O
O
3h
3i
O2N
5
6
2,4-Me2
4-Cl
40
35
82
83
2-NO2
N
O
2e
2f
Cl
Acknowledgments
N
O
The authors are thankful to department of chemistry, Mewar
University, Chittorgarh, Rajasthan for experimental and
spectroscopic analysis of synthesized compounds.
7
8
2-Cl
4-Br
40
35
40
45
81
84
79
79
N
Cl
O
N
2g
2h
Br
Appendix A. Supplementary data
O
Supplementary data to this article can be found online at
https://doi.org/xxxx/j.tetlet.xxxxxxxx.
Cl
Cl
9
3,4-Cl2
4-NO2
N
O
2i
2j
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Highlights
 CuBr2 catalysed one-pot synthesis of
3,5-diarylisoxazole from chalcone and
NH2OH.HCl
 Oxone is used as an oxidant to oxidise
CuBr (formed in the reaction) to CuBr2
 Various substituted chalcones tolerated
and gave 3,5-diarylisoxazole in good
yields.