Trichloroisocyanuric acid mediated one-pot synthesis of 3,5-diarylisoxazoles from α,β-unsaturated ketones

Article abstract of DOI:10.1080/00397911.2019.1590848

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 trichloroisocyanuric acid (TCCA) to afford the desired products, mostly in high yields and

Full text of DOI:10.1080/00397911.2019.1590848

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
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ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
Trichloroisocyanuric acid mediated one-pot
synthesis of 3,5-diarylisoxazoles from α,β-
unsaturated ketones
Ashish Bhatt, Rajesh K. Singh & Ravi Kant
To cite this article: Ashish Bhatt, Rajesh K. Singh & Ravi Kant (2019): Trichloroisocyanuric
acid mediated one-pot synthesis of 3,5-diarylisoxazoles from α,β-unsaturated ketones, Synthetic
Communications
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https://doi.org/10.1080/00397911.2019.1590848
Trichloroisocyanuric acid mediated one-pot synthesis of
3,5-diarylisoxazoles from a,b-unsaturated ketones
Ashish Bhatta , Rajesh K. Singhb, and Ravi Kanta
b
aDepartment of Chemistry, Mewar university, Chittorgarh, Rajasthan, India; Department of Pharmacy,
Mewar university, Chittorgarh, Rajasthan, India
ABSTRACT
ARTICLE HISTORY
Received 24 February 2019
A
facile one-pot synthesis of 3,5-diarylisoxazoles from
a,b-unsaturated ketones and hydroxylamine hydrochloride is
reported. The reaction is efficiently promoted by trichloroisocyanuric
acid (TCCA) 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 towards various substrates having different
functionalities.
KEYWORDS
Chalcone; ethanol;
isoxazoles; oxidative
cyclization; trichloroisocya-
nuric acid
GRAPHICAL ABSTRACT
R1
NH2OH.HCl
R2
R2
R1
TCCA
Ethanol, r.t
N
O
O
1
2a - j & 3a - i
R1 = H, 2-Me, 4-OMe, 4-OC2H5, 2,4-Me, 4-Cl, 2-Cl, 4-Br, 3,4-Cl, 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
Introduction
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 material science and as a various complex synthetic intermediate in
organic 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 a-hydroxy-b-diketones and other b-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]
CONTACT Ashish Bhatt
itsbhatt2007@yahoo.co.in
Department of Chemistry, Mewar University, Chittorgarh,
Rajasthan, 312901, India.
Supplemental data for this article is available online at on the publisher’s website.
ß 2019 Taylor & Francis Group, LLC

2
A. BHATT ET AL.
Isoxazoles are often synthesized through a [3 þ 2] cycloaddition of nitrile oxides with
alkynes or alkenes followed by oxidation.[16–18] As van Delft has noted, the thermal
[3 þ 2] cycloaddition method can suffer from low yields, side-reactions, and poor regio-
selectivity.[19] While transition metal mediated preparations of 3,5-disubstituted and 3,4-
disubstituted isoxazoles have been reported to provide satisfactory yields.[20,21]
The reaction of hydroxylamine with 1,3-dicarbonyl or a,b-unsaturated carbonyl com-
pounds, 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 a,b-unsaturated oximes or b-keto oximes constitute 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 (TPCD),[27]
[30]
2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO),[28] N-bromosuccinimide,[29] NOBF4,
[33]
and hypervalent iodine reagents, such as PhI(OCOCH3)2,[31,32], PhI(OCOCF3)2
are
widely employed to initiate the intramolecular oxidative cyclization. Microwave-
assisted synthesis of isoxazoles has also been reported.[34,35] There are a few reports
of one-pot synthesis of isoxazole.[36–38] However, the mentioned methods involve the
use of an 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.
Trichloroisocyanuric acid (TCCA) is a versatile reagent and is becoming increasingly
popular because of its commercial availability at low cost and lesser corrosiveness. Our
continued interest in the development of useful synthetic methodologies prompted us to
explore the feasibility of TCCA for the one-pot synthesis of isoxazole derivatives with
high yields. However, it has not been investigated as a reagent in the synthesis of isoxa-
zole until now.
Result and discussion
Herein, we describe a convenient one-pot synthesis of 3,5- diarylisoxazoles from a,b
-unsaturated ketones. The parent chalcone 1a was prepared by Claisen–Schmidt con-
densation 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 TCCA (0.3 eq.) in methanol at ambient temperature. We were delighted
to observe the formation of the desired product 2a, albeit in a low yield of 55%
(Table 1, entry 1). 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 an isoxazole, we then focused on the quantity of
TCCA. An increase in the amount of TCCA (from 0.3 eq to 1 eq) not only
decreased the reaction time from 1.5 h to 30 minutes, but also increased the product
yield from 55 to 85% (Table 1, entry 8). Further increasing the quantity of TCCA
(from 1 eq to 2 eq.) led to a decrease in the yield to 65% (Table 1, entry 9).

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3
Table 1. Optimization of the reaction conditions.
NH2OH.HCl
TCCA
Solvent, r.t
N
O
O
2a
1a
Solvent
MeOH
Entry
TCCA (eq.)
Time
Yield (%)
1
2
3
4
5
7
8
9
0.3
0.3
0.3
0.3
0.3
0.5
1
1.5 h
1 h
2.5 h
3 h
1.5 h
45 min.
30 min.
15 min.
55
65
40
40
45
70
85
65
EtOH
Isopropanol
Toluene
AcOH
EtOH
EtOH
EtOH
2
OH
O
Ph
NH2OH.HCl
Ph'
Ph
Ph'
Cl
Ph
Ph'
N
N
-H2O
O
O
HN
O
H
1
H
O
Cl
Cl
N
N
N
O
N
O
O
N
O
Ph'
H
O
O
O
Cl
Cl
Ph'
Ph'
Cl
N
N
Cl
N
H
H
OH
O
Ph
Ph
Ph
Cl
Cl
N
N
_
_
N
N
O
N
O
O
N
O
Cl
Cl
OH
Cl
N
N
O
N
O
Cl
OH
O
Cl
Ph'
N
Ph
N
N
Cl2
+
+
O
N
OH
2
Scheme 1. Plausible mechanism for oxidative cyclization of chalcone with hydroxylamine
hydrochloride.
Therefore, we decided to perform the subsequent reactions of the various chalcones
with hydroxylamine hydrochloride in the presence of TCCA (1 eq.) in ethanol at
ambient temperature. The progress of the reactions was monitored by TLC analysis
(using EtOAc–hexane as the eluent).

4
A. BHATT ET AL.
Mechanism
Based on our experimental data and a previous report,[41,42] a plausible reaction mech-
anism for the formation of 3,5-disubstituted isoxazole 2 is proposed (Scheme 1).
According to this route, chalcone on treatment with hydroxylamine hydrochloride first
provides 3,5-diaryl isoxazoline which finally oxidizes to isoxazole with the help of
TCCA via the formation of N-chloro isoxazolinium cation and cyanurate anion as a
proton acceptor.
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-diaryli-
soxazole 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 substitu-
ents such as Cl and Br provides possibilities for further functionalization
(Table 2, 2f–2i).
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-diaryli-
soxazoles in good yields (Table 3). (For more information, see supporting informa-
tion files)
Conclusion
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 trichloroi-
socyanuric acid, which is a low cost commercially available reagent. A variety of sub-
stituents 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.
Experimental section
All solvents and reagents were purchased from commercial sources and used without
further purification. Melting points were determined on a Stuart SMP3 melting point
1
apparatus without corrections. H NMR and 13C NMR spectra were recorded on Bruker
Avance using the solvents indicated with 400 and 100 MHz, respectively. High-reso-
lution mass spectra (HRMS) were performed on a Thermo Finnigan MAT95XP micro-
spectrometer. Thin–layer chromatography was performed on silica gel 60 F254 (Merck)
TLC plates using hexane/EtOAc (5:1 v/v) as the mobile phase. Column chromatography
was carried out using Merck silica gel (200–300 mesh) and hexane/EtOAc (5:1 v/v) as
the eluent.

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5
Table 2. Synthesis of various 3,5-diarylisoxazoles with the scope of substituents (R1) on
the chalcone.
R1
NH2OH.HCl
R1
TCCA
Ethanol, r.t
N
O
2
O
1
Entry
1
R1
Product
Time Yield
(min)
(%)
Hydrogen
4-Me
30
85
N
O
2a
2b
2c
2
3
35
83
N
O
O
4-OMe
30
35
81
85
N
O
O
4
5
6
7
8
4-OC2H5
N
O
2d
2,4-Me
4-Cl
40
35
40
35
82
83
81
84
N
O
2e
2f
Cl
N
O
2-Cl
N
Cl
O
N
2g
2h
Br
4-Br
O
Cl
Cl
9
3,4-Cl
4-NO2
40
45
79
79
N
O
2i
2j
O2N
10
N
O

6
A. BHATT ET AL.
Table 3. Synthesis of various 3,5-diarylisoxazoles with the scope of substituents (R2) on
the chalcone.
NH2OH.HCl
R2
TCCA
Ethanol, r.t
R2
N
O
3
O
1
Entry
R2
Product
Time Yield
(min) (%)
1
2
4-Me
30
30
78
80
N
O
3a
3-Me
N
O
O
3b
O
3
4
5
3-OMe
4-Cl
35
35
30
77
83
81
N
3c
Cl
N
O
3d
Cl
3-Cl
N
O
O
3e
Cl
6
7
2-Cl
4-Br
40
40
80
78
N
O
3f
Br
N
3g
Br
8
9
3-Br
40
40
75
77
N
O
3h
3i
O2N
2-NO2
N
O
3 ,5-diarylisoxazole 2a-j and 3a-i; general procedure
To a stirred solution of chalcone 1 (1 mmol) and hydroxylamine hydrochloride
(76.43 mg, 1.1 mmol) in ethanol (10 mL) were added trichloroisocyanuric acid
(232.4 mg, 1 mmol). The mixture was stirred at ambient temperature until the starting

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SYNTHETIC COMMUNICATIONSV
7
material was completely consumed (monitored by TLC, 30 min.). The reaction mixture
was quenched with sat. NaHCO3 solution and extracted with ethyl acetate. The organic
layer was washed with water, dried over Na2SO4, and evaporated. The resulting crude
compound was purified by silica gel column chromatography (EtOAc/Hexane, 1:5 v/v),
affording the pure 3,5-diarylisoxazoles derivative 2a–j & 3a–i.
3 ,5-diphenylisoxazole (2a):[12]
1
White solid; Yield: 45.1 mg, (85%); Mp. 141–142 ꢀC; H NMR (400 MHz, CDCl3): d
7.91–7.81 (m, 4 H, ArH), 7.53–7.43 (m, 6 H, ArH), 6.84 (s, 1 H, isoxazole-H); 13C NMR
(100 MHz, CDCl3): d 170.3, 162.9, 130.1, 129.9, 129.0, 128.9, 128.8, 127.4, 126.7, 125.7,
97.4; HRMS-ESI (m/z): [M þ H]þ calcd. for C15H11NO: 222.0841; Found, 222.0835.
Acknowledgments
The authors are thankful to the Department of Chemistry, Mewar University, Chittorgarh,
Rajasthan for experimental and spectroscopic analysis of synthesized compounds.
ORCID
Ashish Bhatt
http://orcid.org/0000-0002-1362-8425
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