Cu(I) catalyzed microwave assisted telescopic synthesis of 3,5-disubstituted isoxazoles in green media

Article abstract of DOI:10.1016/j.tetlet.2016.10.109

A facile and efficient microwave assisted telescopic synthesis of diverse isoxazoles was reported in green reaction medium. Initially, N-hydroxyl imidoyl chlorides were reacted with substituted alkynes in aqueous medium using 2 mol% of [Cu(phen)(PPh₃

Full text of DOI:10.1016/j.tetlet.2016.10.109

Accepted Manuscript
Cu(I) catalyzed microwave assisted telescopic synthesis of 3,5-disubstituted
isoxazoles in green media
D.R. Meena, Barnali Maiti, Kaushik Chanda
PII:
S0040-4039(16)31442-3
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.10.109
TETL 48279
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
14 September 2016
19 October 2016
28 October 2016
Please cite this article as: Meena, D.R., Maiti, B., Chanda, K., Cu(I) catalyzed microwave assisted telescopic
synthesis of 3,5-disubstituted isoxazoles in green media, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/
j.tetlet.2016.10.109
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Cu(I) catalyzed microwave assisted telescopic
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synthesis of 3,5-disubstituted isoxazoles in green media
Meena DR, Barnali Maiti,* Kaushik Chanda*

1
Tetrahedron Letters
Cu(I) catalyzed microwave assisted telescopic synthesis of 3,5-disubstituted
isoxazoles in green media
Meena DR, Barnali Maiti and Kaushik Chanda
Department of Chemistry, School of Advanced Sciences, VIT University, Vellore-632014, India
ARTICLE INFO
ABSTRACT
Article history:
Received
A facile and efficient microwave assisted telescopic synthesis of diverse isoxazoles was reported in
green reaction medium. Initially, N-hydroxyl imidoyl chlorides were reacted with substituted
Received in revised form
Accepted
Available online
3 2 3
alkynes in aqueous medium using 2 mol% of [Cu(phen)(PPh ) ]NO as catalyst to yield the 3,5-
disubstituted isoxazoles. To improve the efficiency of the synthetic route for the regioselective
synthesis of isoxazoles, commercially available aromatic aldehydes were converted to N-hydroxyl
imidoyl chlorides followed by reaction with substituted alkynes in aqueous medium using Cu(I) as
catalyst in telescopic manner. This telescopic new synthetic strategy facilitates the rapid generation
of molecular frameworks in three-dimensional fashion leading to 3,5-disubstituted isoxazoles. This
approach is visualized as an environmentally benign process and a simple operation to the
privileged scaffolds. The present one-pot synthetic sequence allows the introduction of two points
of structural diversity to expand chemical space with excellent purity and yields.
Keywords:
Isoxazole
Telescopic Synthesis
(3+2) cycloaddition
Microwave
Green Media
2
009 Elsevier Ltd. All rights reserved.
1
. Introduction
(HADC) probes (A) antidepressant-like activity (B), β-lactamase-
resistant antibiotics, (C), powerful neurotoxin as a brain-
lesioning agent (D) along with synthetic androgenic steroid
Danazol (E) to suppresses the production of gonadotrophins
Synthesis of highly functionalized heterocyclic small molecules
are important in drug discovery programme due to their selective
binding ability to the biological targets with respect to their
chemical diversity. With respect to that, diversity oriented
synthesis (DOS) is proven a successful tool to swiftly synthesize
novel bioactive compounds with skeletal diversity from simple
7
1
(Figure 1). Moreover, isoxazole derivatives are useful as
primary precursors for the synthesis of different organic
8
compounds.
2
starting materials. Over the past two decades, multicomponent
reactions (MCRs) have gained prominent importance as starting
points for diversity oriented synthesis (DOS) owing to providing
3
direct admittance to small molecule libraries. MCRs provide
high degree of chemical and structural diversity. In comparison
to conventional multistep synthesis, MCRs has attracted special
attention to organic chemists owing to its cost-effectiveness,
time-efficiency and ecofriendly nature. Coupling of microwave
irradiation with multicomponent reactions has become
increasingly significant for both industry and academia on small
scale to synthesize the chemical libraries with high degree of
4
structural diversity. Moreover, pharmaceutical industry supports
Figure 1. Biologicallly active isoxazole derivatives
the use of water as a solvent, rather than toxic organic solvents
for the synthesis of drug entity. As a result, much effort has been
directed towards using water as a solvent for organic reactions in
Several synthetic methodologies are currently available for the
synthesis of isoxazole skeleton. In 2005, Fokin et al synthesized
the few isoxazole derivatives from N-hydroxyl imidoyl chlorides
5
recent years.
4 2
and alkynes using Cu(I) catalyst derived from CuSO .5H O
Isoxazoles are well established as privileged scaffolds which
are commonly encountered in many biologically active
molecules. Derivatives of isoxazoles were found to exhibit a
9
reduced by Na-ascorbate. In particular the conventional approach
towords the synthesis of isoxazole skeletons without metal catalyst
can be summarized as the reaction of 2-alkyn-1-one o-methyl
6
wide variety of biological activities such as histone deacetylase
—
——

Corresponding author. Tel.: +91-416-2202321; fax: +91-416-2243092; e-mail: barnalimaiti.m@gmail.com

Corresponding author. Tel.: +91-416-2202321; fax: +91-416-2243092; e-mail: chandakaushik1@gmail.com

2
Tetrahedron
o
oximes with ICl,
I
2
,
Br
2
,
reaction of N-hydroxyl-4-
Increasing the reaction temperature to 65 C using EtOH as
solvent for 6 h slightly increase the yield upto 60% (Table 1,
entry 2). The yield of the 1,3-dipolar cycloaddition reaction
gradually increased upto 70% when the reaction was performed
using binary mixture of H O-tBuOH (1:1) as solvent (Table 1,
2
entry 3). In order to obtain the 3,5-diphenylisoxazole 4a in high
toluenesulfonamide with α,β-unsaturated carbonyl compounds,
cycloaddition between alkynyliodides and nitrile oxide,
dehydration of nitro alkanes with dipolarophiles in the presence
DABCO, and cascade reaction of α-azido acrylates and aromatic
oximes. However, the homogeneous metal catalyzed synthesis of
isoxazole derivatives involve the Pd catalyzed four-component
coupling of a terminal alkyne, hydrazine (hydroxylamine), carbon
monoxide and an aryl iodide, Pd catalysed Sonogashira coupling
of acid chlorides with terminal alkynes, followed by 1,3-dipolar
10
yield, and under green synthetic condition, the same set of
reaction was carried out in H
o
2
O as solvent at 65 C for 6 h to
obtain the product 4a (80%) yield (Table 1, entry 4). However,
the same cycloaddition reaction carried out under neat conditions
with slight excess of phenyl acetylene, the yield of the product 4a
(75%) was obtained (Table 1, entry 5). The reason behind the
decreased yield was probably due to the decomposition of the
reactants under the neat condition. However to enrich the
synthetic efficiency, the same set of reaction was performed
3
cycloaddition, AuCl -catalyzed cycloisomerization of α,β-
acetylenic oximes, sequential Fe and Pd catalyzed four-step
sequence from propargylic alcohols, and the reaction of terminal
alkynes with n-BuLi, followed by aldehydes,
I
2
and
hydroxylamine. In 2013, Huang group studied the facet
dependent properties of Cu O nanocrystals for the regioselective
synthesis of 3,5-disubstituted isoxazoles using EtOH as solvent for
11
2
2
under microwave irradiation for 5 min using H O as solvent to
obtain the desired product 4a in 95% yield (Table 1, entry 6). The
table 1 provides the complete optimization study for the 1,3-
dipolar cycloaddtion reaction to obtain the 3,5-diphenylisoxazole
4a.
12
2
h. Recently Ramón et al have synthesized 3,5-disubstituted
13
isoxazoles in deep eutectic solvents. However, all these reactions
suffered from drawbacks such as low yields, multistep synthetic
sequence, harsh reaction conditions, use of expensive Pd or Au
catalyst, use of toxic reagents, and difficult work up procedure.
We therefore wished to develop a convenient, microwave assisted
Cu(I) catalyzed telescopic method for the disubstituted isoxazoles
in green medium. Compared to earlier methods, the major
advantages associated with the present methodology for the
synthesis of isoxazoles are the use of microwave irradiation, which
reduces the reaction time to minutes for the faster delivery of
compounds, water as green and ecofriendly solvent and excellent
yields with high purity.
a
Table 1. Optimization of 1,3-dipolar cycloaddition reaction
c
Entry
Solvent
EtOH
Temperature
rt
Time
12 h
6 h
Yield %
1
2
3
4
5
6
50
o
EtOH
65 C
60
t
o
As part of our ongoing programme on the diversity oriented
EtOH- BuOH
65 C
6 h
70
1
4
synthesis of bioactive heterocycles, we report a novel Cu(I)
catalyzed telescopic synthesis of 3,5-disubstituted isoxazoles from
readily available aromatic aldehydes and substituted alkynes on
water under microwave irradiation. The synthetic strategy
commences with the synthesis of N-hydroxyl imidoyl chlorides
from aromatic aldehydes, hydroxylamine hydrochloride and N-
chloro succinimide followed by 1,3-dipolar cycloaddition of
substituted alkynes to obtain the 3,5-disubstituted isoxazoles in
one-pot manner.
o
H
2
O
65 C
6 h
80
o
Neat
65 C
3 h
75
b
o
2
H O
MW , 65 C
5 min
95
a
The reaction was performed using 2a (1 mmol), 3a (2 mmol),
b
catalyst (2 mol%). Microwave reactions were carried out in
Microwave Model No. CATA R (Catalyst systems, Pune). Yield
of the isolated product.
c
In multicomponent reaction, sequential addition of reagent,
one at a time without any post- synthetic work up is known as
2
. Results and Discussion
1
5
telescoped reaction approach. Advantage of telescoped reaction
approach involves the reduction of number of purification steps,
use of toxic solvents, operational simplicity which boosts the
reaction result. We performed our multicomponent reaction by a
telescoped approach. Condensation of benzaldehyde 1a with
Our exploration starts with the synthesis of N-hydroxyl
imidoyl chlorides 2 as the primary precursors. To obtain the
substituted N-hydroxyl imidoyl chlorides 2, we reacted various
aromatic aldehydes 1 with hydroxylamine hydrochloride using
NaOH as base and water as solvent followed by chlorination with
N-chlorosuccinimide at room temperature for 4 h (Scheme 1).
hydroxylamine hydrochloride under microwave heating in the
o
presence of NaOH using H
2
O as solvent at 65 C for 5 min
followed by subsequent addition of N-chloro succinimide for
further 2 min heating at the same temperature yielded N-
hydroxybenzimidoyl chloride 2a.
Scheme 1. Synthesis of substituted N-hydroxyl imidoyl
chlorides 2
The model study for the Cu(I) catalyzed 1,3-dipolar
cycloaddition was performed on N-hydroxy benzimidoyl
chlorides 2a with phenylacetylene 3a under room temperature
condition for 12 h using EtOH as solvent (Table 1, entry 1). The
Scheme 2. Telescoped approach to 3,5-diphenylisoxazole 4a
3 2 3
reaction using 2 mol% of the [Cu(phen)(PPh ) ]NO as catalyst
yielded the 3,5-diphenylisoxazole 4a in 50% yield. Analysis of
the reaction mixtures indicated the presence of starting materials.
The in-situ generated N-hydroxybenzimidoyl chloride 2a
underwent 1,3-dipolar cycloaddition reaction with phenyl

3
acetylene 3a using 2 mol % of [Cu(phen)(PPh
3
)
2
]NO
3
as catalyst
assisted multicomponent coupling procedure in green media.
under microwave heating for 5 min to obtain the 3,5-
Further studies on the Cu(I) catalyzed synthesis of bioactive
heterocycles for biological applications are current pursuing in
our laboratory.
16
diphenylisoxazole 4a in 95 % yield as depicted in (Scheme 2).
1
Upon completion of the reaction, the H NMR spectrum of the
synthesized compound indicated the formation of pure 3,5-
disubstituted isoxazoles without forming any 3,4-disubstituted
4
. Acknowledgements
1
isoxazoles. The H NMR spectrum of 3,5-disubstituted isoxazole
contains a singlet at 6.88 which corresponds to the diagnostic
chemical shift of the 4H proton as compared to the chemical shift
of the 5H-isoxazole congener between 8 and 9 ppm. Encouraged
with this observation, we further investigated this telescopic
transformation with substituted aldehydes and alkynes. The
results are summarized in (Table 2).
The authors thank the Chancellor and Vice Chancellor of VIT
University for providing opportunity to carry out this study.
Further the authors wish to thank the management of this
university for providing seed money as research grant. Barnali
Maiti thanks DST- Govt of India for funding through DST-
SERB-YSS/2015/00450. The authors thank the reviewers for for
giving constructing comments for the overall improvement of the
manuscript.
Table 2. One-pot telescoped synthesis of 3,5-disubstituted
a,b
isoxazoles.
5
. References and notes
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ꢏenisson, ꢐ.; Rodriguez, J.; Constantieux, T. Chem. Soc. Rev.
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016, 6, 58142.
ꢇ
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011, 15, 204.
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Brunsteiner, M.; Blond, S. Y.; Petukhov, P. A. J. Med. Chem.
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J.; Kozikowski, A. P. J. Med. Chem. 2012, 55, 812. (c) Miranda-
ꢊoꢅales, ꢏ.; Leańos-Miranda, B. E.; Vilchis-Pérez, M;
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7
a
2
Reaction conditions: aldehydes (1 mmol), NH OH.HCl (1
mmol), NaOH (1.5 mmol), NCS (1 mmol), alkyne (1 mmol),
Cu(I) catalyst (2 mol%). Isolated yield
2
b
The overall reaction time is typically 12-20 min. The
corresponding highly regioselective 3,5-disubstituted isoxazoles
were obtained with excellent yields after a simple work-up
involving filtration of the catalyst, washing, and solvent
evaporation. Finally the crude products were purified by column
chromatography followed by spectroscopic characterization using
25. (d) Becker, A.; Grecksch, G.; Bernstein, H.-ꢏ.; Hȍllt, ꢆ.;
Bogerts, B. Psychopharmacology, 1999, 144, 333. (e) Neumann,
C.; Potts, G. O.; Ryan, W. T.; Stonner, F. W. J. Med. Chem.,
1
13
1970, 13, 948.
HNMR, C NMR, and mass spectroscopy (MS). We have
8. Baraldi, P. G.; Barco, A.; Benetti, S.; Pollini, G. P.; Simoni, D.
observed the substituent effects of both aldehydes and alkynes.
Aromatic aldehydes containing electron-withdrawing groups
reacted efficiently to obtain the corresponding isoxazoles in
excellent yields as compared to the electron-donating
substituents. The aromatic terminal alkynes containing electron-
withdrawing groups or electron-donating substituents have no
effect on the outcome of the reaction followed by hydroxy-, silyl-
Synthesis, 1987, 857.
. (a) Himo, F.; Lovell, T.; Hilgraf, R.; Rostovtsev, V. V.;
9
Noodleman, L.; Sharpless, K. B.; Fokin, V. V. J. Am. Chem.
Soc., 2005, 127, 210. (b) Hansen, T. V.; Wu, P.; Fokin, V. V. J.
Org. Chem., 2005, 70, 7761.
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Cecchi, L.; De Sarlo, F.; Machetti, F. Eur. J. Org. Chem., 2006,
,
and ester-substituted alkynes to obtain the corresponding
4
2
2
852. (c) Tang, S.; He, J.; Sun, Y.; He, L.; She, X.; Org. Lett.,
009, 11, 3982. (d) Crossley, J. A.; Browne, D. L. J. Org. Chem.,
010, 75, 5351. (e) Hu, M.; He, X.; Niu, Z.; Yan, Z.; Zhou, F.;
isoxazoles as single regioisomers in good to high yields.
Shang, Y. Synthesis, 2014, 46, 510.
1. (a) Ahmed, M. S. M.; Kobayashi, K.; Mori, A. Org. Lett.,
3
. Conclusions
1
In summary, we have developed an efficient one-pot,
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Synthesis, 2008, 293. (c) Praveen, C.; Kalyanasundaram, A.;
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Lemouzy, S.; Vrancken, E.; Campagne, J.-M. Org. Lett., 2011,
13, 6418. (e) Harigae, R.; Moriyama, K.; Togo, H.; J. Org.
Chem., 2014, 79, 2049. (f) Jeong, Y.; Kim, B.-I.; Lee, J. K.; Ryu,
J.-S. J. Org. Chem., 2014, 79, 6444.
telescoped approach for the synthesis of biologically interesting
disubstituted isoxazoles. The synergistic effect of microwave
irradiation and water as green solvent effectively accelerates the
reaction to proceed in short reaction times with excellent yields.
To the best of our knowledge, this procedure is the first example
for the synthesis of 3,5-disubstituted isoxazoles via microwave

4
Tetrahedron
1
2. Chanda, K.; Rej, S.; Huang, M. H. Nanoscale, 2013, 5,
immediately added to the reaction mixture. Subsequently, the
1
1
3
1
2494.
reaction mixture was irradiated under microwave for 5 min. The
reaction progress was monitored by TLC. After completion, the
reaction mixture was cooled to room temperature and extracted
with ethyl acetate (10 mL, twice). The combined organic layer
3. Pérez, J. M; Ramón, D. J. ACS Sustainable Chem. Eng. 2015,
, 2343.
4. (a) Maiti, B.; Chanda, K. RSC. Adv. 2016, 6, 50384. (b)
Rajasekhar, S.; Maiti, B.; Balamurali, M. M.; Chanda, K. Curr.
4
was dried over anhydrous MgSO . The combined filtrate was
Org. Syn., 2016, 13, 0000. (Article in Press).
subjected to evaporation to obtain the crude compound, which
was purified over silica gel column (60–120 mesh) using 1%
ethyl acetate in hexane as eluent to obtain the corresponding 3,5-
diphenylisoxazoles 4a as the product.
15. (a) Ishikawa, H.; Suzuki, T.; Hayashi, Y. Angew. Chem., Int.
Ed. 2009, 48, 1304. (b) Cuthbertson, J. D.; Taylor, R. J. K.
Angew. Chem., Int. Ed. 2013, 52, 1490.
16. General Procedure for the one-pot multistep synthesis of
3,5-diphenyl isoxazoles (4a). In a round bottomed flask, a
Supplementary Material
mixture of benzaldehyde 1a (0.027 g, 0.25 mmol, 1.0 equiv) and
NaOH (0.020 g, 0.50 mmol, 2.0 equiv) was added to a solution of
hydroxylamine hydrochloride (0.0177 g, 0.25 mmol, 1.0 equiv)
Experimental procedures, compound characterization data and
copies of NMR spectra for all products are included in
Supplementary data. Supplementary data associated with this
article can be found in the online version.
2
containing 5 mL of H O. The reaction mixture was irradiated
under microwave heating at 210 watt for 5 min at 65 ºC. The
progress of the reaction was monitored by TLC. After
completion, N-chlorosuccinimide (0.034 g, 0.25 mmol, 1.0
equiv) was added in small proportions for over 2 min, followed
by microwave irradiation at same power for 2 min. After
completion, phenylacetylene 3a (0.0255 g, 0.25 mmol, 1.0 equiv)
Click here to remove instruction text...
3 2 3
and [Cu(phen)(PPh ) ]NO catalysts (0.0042 g, 2 mol% ) was

5
Highlights




Microwave assisted one-pot telescopic synthesis of
isoxazoles in green media
Readily accessible starting materials and short
reaction times.
Using [Cu(phen)(PPh
in green media.
3 2 3
) ]NO as an efficient catalyst
Broad substrate scope and good functional group
tolerance