Montmorillonite clay Cu(II) catalyzed domino one-pot multicomponent synthesis of 3,5-disubstituted isoxazoles

Article abstract of DOI:10.1016/j.tetlet.2013.04.102

A simple and efficient one-pot multicomponent approach for the synthesis of 3,5-disubstituted isoxazoles directly from corresponding aldehydes and terminal alkynes using recyclable montmorillonite clay supported Cu(II)/NaN₃ catalytic system under aqueous conditions have been developed. The 'domino' one-pot MCR approach involves hydroxyamination of aldehydes followed by chlorination and then generation of reactive 'nitrile oxide' which undergoes 1,3-dipolar cycloaddition with alkynes to produce 3,5-disubstituted isoxazoles. The method is operationally simple, regioselective, economical, and possesses excellent functional group compatibility to synthesize structurally diverse isoxazoles in good yields.

Full text of DOI:10.1016/j.tetlet.2013.04.102

Accepted Manuscript
Montmorillonite clay Cu(II) catalyzed domino one-pot multicomponent syn‐
thesis of 3,5-disubstituted isoxazoles
Sandip B. Bharate, Anil K. Padala, Bashir A. Dar, Rammohan R. Yadav, Baldev
Singh, Ram A. Vishwakarma
PII:
S0040-4039(13)00708-9
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.04.102
TETL 42870
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
24 March 2013
24 April 2013
27 April 2013
Please cite this article as: Bharate, S.B., Padala, A.K., Dar, B.A., Yadav, R.R., Singh, B., Vishwakarma, R.A.,
Montmorillonite clay Cu(II) catalyzed domino one-pot multicomponent synthesis of 3,5-disubstituted isoxazoles,
Tetrahedron Letters (2013), doi: http://dx.doi.org/10.1016/j.tetlet.2013.04.102
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Montmorillonite clay Cu(II) catalyzed domino one-pot
multicomponent synthesis of 3,5-disubstituted
isoxazoles
Leave this area blank for abstract info.
Sandip B. Bharate,* Anil K. Padala, Bashir A. Dar, Rammohan R. Yadav, Baldev Singh,* Ram A.
Vishwakarma*
O
2
N
1
O
15 mol% Clay-Cu(II)
7.5 mol% NaN3
O
+ NH2OH. HCl
+
R2
3
R1
H
Cl
N
+
R2
R1
5
rt, water: ACN (1: 3)
4
2
5
O
1
1

2
Tetrahedron Letters
journal homepage: www.elsevier.com
Montmorillonite clay Cu(II) catalyzed domino one-pot multicomponent synthesis of
3,5-disubstituted isoxazoles
Sandip B. Bharate,a,c* Anil K. Padala,a,c Bashir A. Dar,b Rammohan R. Yadav,a,c Baldev Singhb,c and Ram
A. Vishwakarmaa,c*
a Medicinal Chemistry Division, Indian Institute of Integrative Medicine (CSIR), Canal Road, Jammu-180001, India
b Natural Products Chemistry Division, Indian Institute of Integrative Medicine (CSIR), Canal Road, Jammu-180001, India
c Academy of Scientific and Innovative Research (AcSIR), CSIR, Anusandhan Bhawan, 2 Rafi Marg, New Delhi – 110001, India
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A simple and efficient one-pot multicomponent approach for the synthesis of 3,5-disubstituted
isoxazoles directly from corresponding aldehydes and terminal alkynes using recyclable
montmorillonite clay supported Cu(II)/ NaN3 catalytic system under aqueous conditions have
been developed. The ‘domino’ one-pot MCR approach involves hydroxyamination of aldehydes
followed by chlorination and then generation of reactive ‘nitrile oxide’ which undergoes 1,3-
dipolar cycloaddition with alkynes to produce 3,5-disubstituted isoxazoles. The method is
operationally simple, regioselective, economical and possesses excellent functional group
compatibility to synthesize structurally diverse isoxazoles in good yields.
Available online
Keywords:
Montmorillonite clay
Cuo nanoparticles
Isoxazoles
Multicomponent
Heterogeneous
2013 Elsevier Ltd. All rights reserved.
Isoxazoles are commonly encountered in variety of natural
products and drugs and are known to exhibit diverse range of
pharmacological activities.1 Because of their medicinal
importance, synthetically this scaffold has been extensively
investigated.2,3 The cycloaddition approach has been extensively
used for the preparation of isoxazoles3 and structurally related
triazoles.4 To access 3,5-disubstituted isoxazoles,3 the 1,3-dipolar
cycloaddition of nitrile oxides with alkynes is most direct and
frequently used approach.5 This method involves in situ
generation of Cu(I) from Cu(II) using reducing agent like sodium
ascorbate because Cu(I) is unstable; moreover in reported
protocols excess base was employed for the generation of nitrile
oxide. In general, the nitrile oxides react with terminal alkynes
without catalyst, but this leads to formation of both isoxazole
regioisomers. The significant formation of byproducts has been
the major concern (particularly with reactive nitrile oxides)
leading to poor yields and difficulty in product isolations.
Furthermore, currently available protocols mostly involve the use
of homogeneous catalytic systems. With the advent of green
chemistry protocols, in recent years heterogeneous catalysts are
becoming overwhelmingly important. Since isoxazole class of
compounds are medicinally important, development of simple,
efficient and economical protocol for their synthesis using
recyclable catalyst will be of great use.
continuation to our recent work on synthesis of 1,2,3-triazoles,7
herein we report one-pot multicomponent approach for the
synthesis of 3,5-disubstituted isoxazoles
1 directly from
aldehydes 2 and acetylenes 5 via cycloaddition reaction between
in situ generated nitrile oxide and acetylenes (Figure 1).
O
+
NH2OH. HCl
R1
H
O
2
N
1
O
15 mol% Clay-Cu(II)
7.5 mol% NaN3
2
3
R2
R1
Water: MeCN (1: 3)
rt, 5-8 h
5
4
+
R2
1
Cl
N
+
68-88%
5
O
Figure 1. Clay-Cu(II)-catalyzed one-pot synthesis of 3,5-disubstituted
isoxazoles
The hydroximyl chlorides 4 are the key precursors which are
essential for in situ generation of reactive nitrile oxides which
takes part in 1,3-dipolar cycloaddition reaction for the synthesis
of 3,5-disubstituted isoxazoles. The precursor 4a was synthesized
from corresponding aldehyde 2a using a two-step procedure as
shown in Scheme 1.
As a part of our work on development of tandem protocols6,7 for
the preparation of medicinally important scaffolds and in
----
*Corresponding author. Tel. +91-191-2569111; Fax: 91-191-2569333
E-mail: sbharate@iiim.ac.in (SBB), ram@iiim.ac.in (RAV)
IIIM Communication number. IIIM/xxxx/2013

OH
Cl
OH
H
done viz. 2a + NH2OH.HCl, stirred for 30 min; NCS was added
and stirred for 3 h; clay-Cu/NaN3 solution and 5a were added,
stirred for 3 h. With this protocol, desired isoxazole 1a was
formed in >70% yield (Table 2, entries 6-8). Further, solvent
optimization studies indicated that water: acetonitrile (1: 3) as
best solvent for this one-pot multicomponent protocol (entry 8 of
Table 2).
N
N
O
NH2OH.HCl
NCS/ DMF
rt, 3 h, 80%
H
NaOH/ H2O
rt, 1h, 85%
2a
3a
4a
Scheme 1. Synthesis of hydroximyl chloride 4a from aldehyde 2a
After the synthesis of hydroximyl chloride 4a, we explored the
utility of clay-Cu(II)/NaN3 catalytic system for in situ formation
of reactive intermediate nitrile oxide from 4a followed by its 1,3-
dipolar cycloaddition reaction with alkyne 5a. The optimization
results of catalyst and sodium azide loading are shown in Table
1. In this study, a mixture of clay-Cu(II) catalyst and sodium
azide in water was stirred at room temperature for 4 h, after
which the reaction mixture color changed from brown to black
indicating conversion of Cu(II) to Cu(I) state.7 The treatment of
hydroximyl chloride 4a with alkyne 5a in presence of this active
catalytic system furnished desired 3,5-disubstituted isoxazole 1a
as depicted in Table 1 (entries 2-4). Catalyst loading studies
indicated that 15 mol% of clay-Cu(II) catalyst and 7.5 mol% of
NaN3 was optimum, producing good yields of desired product 1a
(Table 1, entry 4). We also performed a control experiment with
normal CuSO4 instead of clay-Cu(II) catalyst. When 10 mol% of
CuSO4 and 7.5 mol% of NaN3 were used, desired isoxazole 1a
was produced in 83% yield (entry 6). This result indicated that
both Cu(II) sources are efficient, however clay-Cu(II) catalyst
have recyclability advantage.
Table 2. Optimization of reaction conditions for synthesis of 3,5-
disubstituted isoxazole 1a using one-pot MCR strategy
OH
N
OH
H
O
OH
N3
N
N
Cl
H
NH2OH. HCl
+
Clay-Cu(II)/ NaN3
room temp.
2a
3a
4a
6a
O
O
N
+
+
Cl
N
1a
O
5a
Entry Method Solvent
Yield (%)
3a
80
22
25
0
0
0
0
0
4a
0
0
0
55
60
0
0
0
6a
0
58
62
0
0
0
0
0
1a
0
0
0
18
20
70
82
84
50
1
2
3
4
5
6
7
8
9
A
A
A
B
B
C
C
C
C
Water
Water: EtOH (1: 3)
Water: MeCN (1: 3)
Water: EtOH (1: 3)
Water: MeCN (1: 3)
Water
Water: EtOH (1: 3)
Water: MeCN (1: 3)
Water: t-BuOH (1: 1)
0
0
0
Method A: A mixture of aldehyde 2a (1 mmol), NH2OH.HCl (1.2 mmol),
NCS (1.3 mmol), phenylacetylene 5a (1.3 mmol), clay-Cu(II) (15 mol%) and
NaN3 (7.5 mol%) in water stirred at rt for 6 h; Method B: Aqueous solution of
clay-Cu(II) and NaN3 (7.5 mol%) was stirred until the color changes from
brown to black. To this mixture was added aldehyde 2a (1 mmol),
NH2OH.HCl (1.2 mmol), NCS (1.3 mmol), phenyl acetylene 5a (1.3 mmol).
Resulting mixture stirred for 6 h; Method C: A mixture of aldehyde 2a (1
mmol), NH2OH.HCl (1.2 mmol) in water stirred at rt for 30 min. NCS (1.3
mmol) was added and stirred for 3 h. To this mixture was added aqueous
solution of clay-Cu(II)/NaN3 (prepared as per method B) followed by
addition of phenylacetylene 5a (1.3 mmol) and reaction mixture stirred for 3
h.8
Table 1. Optimization of catalyst loading for synthesis of 3,5-disubstituted
isoxazole 1aa
O
OH
Cl
N
N
O
N
5a
Cu(II)/NaN3
H2O
1a
4a
Entry
Cu(II) catalyst
(mol%)
None
Clay-Cu(II) (5)
Clay-Cu(II) (10)
Clay-Cu(II) (15)
Clay-Cu(II) (15)
CuSO4 (10)
NaN3
Reaction
conditions c
rt, 4.5 h
rt, 4.5 h
rt, 4.5 h
rt, 4.5 h
rt, 4.5 h
rt, 4.5 h
Yieldb
(mol%)
None
2.5
5
7.5
1
2
3
4
5
6
0
Next we sought to explore the scope of this multicomponent
protocol. The wide range of aromatic aldehydes/ nitrile oxides
and acetylenes were investigated. Both aromatic (e.g. 1a-1e, 1g-
1n and 1p) and heteroaromatic aldehydes (1f and 1o) participated
well in this reaction. The aromatic nitrile oxides substituted with
strong electron-withdrawing (e.g. –NO2 substituted 1f and 1o),
moderately electron-withdrawing (e.g. Cl, F substituted 1b-1e
and 1g-1n) as well as electron-donating groups (e.g. –OMe
substituted 1e, 1j and 1p) produced corresponding isoxazoles in
good yields. It was observed that electron-deficient nitrile oxides
were preferred over electron-rich nitrile oxides in this
multicomponent reaction. Amongst electron-rich benzonitrile
oxides, 4-methoxy benzonitrile reacted with phenyl acetylene to
produce desired isoxazole in 55% yield (example 1p). However,
other electron-rich benzonitrile oxides such as 4-hydroxy
benzonitrile oxide and p-N,N’-dimethylamino benzonitrile oxide
did not participate in this reaction. Similarly aliphatic nitrile
oxides such as n-butyryl, acetyl, tert-butyryl nitrile oxides have
not participated in this reaction. In these substrates, the formation
of hydroximyl chloride was observed (as indicated by MS
spectra), however the cycloaddition reaction was found to be the
limiting step. In case of acetylene component, both aromatic (e.g.
1a-1g and 1p) as well as aliphatic (e.g. 1h-1o) acetylenes
participated well in this reaction. The chemical structures and
yields of isoxazoles synthesized using optimized protocol
(method C) are shown in Figure 2.
52
65
95
0
0
7.5
83
a A mixture of Clay-Cu(II) and NaN3 in water was stirred for 4 h. Hydroximyl
chloride 4a and alkyne 5a were added. Reaction further stirred for 30 min;
b Isolated yields after silica gel column chromatography;
c The combined reaction time is mentioned which includes time required to
prepare Cu(I) from Cu(II) plus actual reaction time.
Next we investigated the protocol for one-pot multicomponent
synthesis of 3,5-disubstituted isozaxole 1a directly from aldehyde
2a and alkyne 5a. In order to optimize reaction conditions for
one-pot multicomponent protocol, we investigated effect of
variation in sequence of addition of substrates and reagents on
formation of desired isoxazole 1a. During this study, we
investigated three methods A-C as mentioned in the Table 2.
Method A involved mixing together all substrates and reagents at
one time, which mainly produced intermediate oxime 3a (entry
1) and an azido linked oxime 6a (entries 2-3) as a major side
product when reaction was performed in a mixture of water and
organic solvent. In method B, the clay-Cu(II) and NaN3 were pre-
mixed in water and stirred for 4 h until the solution color changed
from brown to black. The treatment of all substrates 2a, 5a and
reagents (NH2OH.HCl and NCS) together with this prepared
active clay-Cu/NaN3 catalytic system led to the formation of
desired isoxazole 1a, but only in 20% yield (Table 2, entries 4-5).
In method C, a stepwise addition of substrates and reagents was
3

4
Tetrahedron Letters
The clay-supported Cu(II) catalyst was characterized using
benzaldehyde
(2a),
hydroxylamine
hydrochloride,
N-
XRD, SEM, TPR experiment and XPS analysis (see ESI).7 The
catalyst characterization results suggested that catalyst exists in
the form of highly dispersed CuO nanoparticles supported on
montmorillonite KSF (MKSF). The Cu content and total surface
area of the catalyst were found to be 8.83% and 96.4551 m2/g
respectively. Analysis of catalyst-sodium azide mixtures by XPS
evidenced the conversion of Cu(II) supported on clay to Cu(I)
state by treatment with sodium azide.7 This Cu(I) reacts with
acetylene to form copper(I) acetylide which undergoes stepwise
addition to in situ generated nitrile oxide furnishing 3,5-
disubstituted isoxazoles. The proposed mechanism for this
domino one-pot multicomponent protocol is depicted in Figure 3.
chlorosuccinamide, sodium azide and phenylacetylene (5a) in the
presence of clay-Cu(II)/NaN3 catalytic system led to formation of
isoxazole 1a in 84, 82, 82 and 80% over four cycles respectively.
In this recyclability study, catalyst was recovered by filtration
after each experiment. The SEM image of the used catalyst
showed similar morphology and the structural integrity after 4th
run, which clearly indicated that the Clay-Cu(II) catalyst is
robust, recyclable and was not affected under the reaction
conditions of this MCR protocol.
In summary, we have developed a simple and efficient one-pot
multicomponent protocol for regioselective synthesis of 3,5-
disubstituted isoxazoles directly from aldehydes in good yields.
As nitrile oxides are obtained directly from oximes, the isolation
and handling of potentially harmful and unstable hydroximoyl
chlorides is avoided. The clay-Cu(II) catalyst is ligand-free,
leaching-free, easy to prepare, easy to handle, environmentally
friendly and can be recycled several times without significant
loss of catalytic activity; thus it will be highly useful for
economical synthesis of 3,5-disubstituted isoxazoles.
O
N
O
O
N
N
Cl
Br
1a, 6 h, 84%
1b, 6 h, 76%
1c, 6 h, 72%
O
N
O
N
O
N
O
N
F
O2N
H3CO
F
1e, 6 h, 75%
1f, 7h, 68%
1d, 5h, 70%
F
O
N
O
O
N
F
Cl
Acknowledgements
AKP, BAD and RRY are thankful to CSIR for award of Research
Fellowships. Authors thank analytical department, IIIM for NMR
and MS analysis of our compounds.
Cl
Cl
F
1i, 6 h, 78%
1h, 6 h, 72%
1g, 5 h, 88%
O
N
O
Cl
N
O
N
Supplementary material
F
Cl
Br
O
1l, 6 h, 70%
1j, 6 h, 80%
Spectra of catalyst and all new compounds. Supplementary data
associated with this article can be found, in the online version at
http://www.sciencedirect.com
1k 6 h, 82%
F
O
N
O
N
O
O
N
Cl
N
O
H3CO
O2N
F
References and notes
Cl
Br
1n, 6 h, 68%
1p,10 h, 55%
1o, 8 h, 70%
1m, 6 h, 82%
1. For various pharmacological activities of isoxazoles, see: (a)
Musad, E. A.; Mohamed, R.; Saeed, B. A.; Vishwanath, B. S.;
Rai, K. M. L. Bioorg. Med. Chem. Lett. 2011, 21, 3536-3540; (b)
Kumar, A.; Maurya, R. A.; Sharma, S.; Ahmad, P.; Singh, A. B.;
Tamrakar, A. K.; Srivastava, A. K. Bioorg. Med. Chem. 2009, 17
5285–5292; (c) Haddad, T.; Gershman, R.; Dilis, R.; Labaree,
D.; Hochberg, R. B.; Hanson, R. N. Bioorg. Med. Chem. Lett.
2012, 22, 5999-6003.
Figure 2. Isoxazoles synthesized using optimized protocol (reaction time and
yields are mentioned).
O
N
1a
2. For references on synthesis of various isoxazoles, see: (a)
Ueda, M.; Sato, A.; Ikeda, Y.; Miyoshi, T.; Naito, T.; Miyata, O.
Org. Lett. 2010, 12, 2594-2597; (b) Minakata, S.; Okumura, S.;
Nagamachi, T.; Takeda, Y. Org. Lett. 2011, 13, 2966–2969; (c)
Praveen, C.; Kalyanasundaram, A.; Perumal, P. T. Synlett 2010,
777-781; (d) Tang, S.; He, J.; Sun, Y.; He, L.; She, X. Org. Lett.
2009, 11, 3982-3985; (e) Gayon, E.; Quinonero, O. e.; Lemouzy,
S.; Vrancken, E.; Campagne, J.-M. Org. Lett. 2011, 13, 6418–
6421; (f) Willy, B.; Rominger, F.; Müller, T. J. J. Synthesis 2008,
293-303; (g) Jackowski, O.; Lecourt, T.; Micouin, L. Org. Lett.
2011, 13, 5664-5667; (h) Waldo, J. P.; Larock, R. C. J. Org.
Chem. 2007, 72, 9643-9647; (i) Crossley, J. A.; Browne, D. L. J.
Org. Chem. 2010, 75, 5351-5354; (j) Sheng, S.-R.; Liu, X.-L.;
Xu, Q.; Song, C.-S. Synthesis 2003, 2763-2764; (k) Cecchi, L.;
Sarlo, F. D.; Machetti, F. Eur. J. Org. Chem. 2006, 4852-4860;
(l) Ahmed, M. S. M.; Kobayashi, K.; Mori, A. Org. Lett. 2005, 7,
4487-4489; (m) Bourbeau, M. P.; Rider, J. T. Org. Lett. 2006, 8,
3679-3680; (n) Chen, C.-Y.; Andreani, T.; Li, H. Org. Lett.
2011, 13, 6300-6303; (o) Stokes, B. J.; Vogel, C. V.; Urnezis, L.
K.; Pan, M.; Driver, T. G. Org. Lett. 2010, 12, 2884-2887.
NaN3
Clay Cu(II)
H
Clay Cu(I)
Clay Cu
5a
C
C
C
O
N
Clay Cu
C
C
C
Clay Cu
C
O
O
N
C
C
N
C
C
O
Clay Cu
C
N
OH
N
O
N
Cl
4a
3. For references on synthesis of 3,5-disubstituted isoxazoles,
see: (a) Himo, F.; Lovell, T.; Hilgraf, R.; Rostovtsev, V. V.;
Noodleman, L.; Sharpless, K. B.; Fokin, V. V. J. Am. Chem. Soc.
2005, 127, 210-216; (b) Xu, J.; Hamme, A. T. Synlett 2008, 919-
923; (c) Hansen, T. V.; Wu, P.; Fokin, V. V. J. Org. Chem. 2005,
Figure 3. Plausible mechanism of one-pot multicomponent protocol for
synthesis of 3,5-disubstituted isoxazole 1a using clay-Cu(II)/NaN3 catalyst
The clay-Cu(II) catalyst was reused repeatedly to prove its
heterogeneous nature and its recyclability. The MCR between

70, 7761-7764; (d) Waldo, J. P.; Larock, R. C. Org. Lett. 2005,
7, 5203-5205.
4. (a) Beckmann, H. S. G.; Wittmann, V. Org. Lett. 2006, 9, 1-4;
(b) Bénéteau, V.; Olmos, A.; Boningari, T.; Sommer, J.; Pale, P.
Tetrahedron Lett. 2010, 51, 3673-3677; (v) Sharghi, H.;
Khalifeh, R.; Doroodmand, M. M. Adv. Synth. Catal. 2009, 351,
207–218; (d) Sreedhar, B.; Reddy, P. S.; Kumar, N. S.
Tetrahedron Lett. 2006, 47, 3055-3058; (e) Tao, C.-Z.; Cui, X.;
Li, J.; Liu, A.-X.; Liu, L.; Guo, Q.-X. Tetrahedron Lett. 2007,
48, 3525–3529.
5. (a) Dadiboyena, S.; J., X.; Hamme, A. T. Tetrahedron Lett. 2007,
48, 1295-1298; (b) Sanders, B. C.; Friscourt, F.; Ledin, P. A.;
Mbua, N. E.; Arumugam, S.; Guo, J.; Boltje, T. J.; Popik, V. V.;
Boons, G.-J. J. Am. Chem. Soc. 2011, 133, 949–957; (c)
Jawalekar, A. M.; Reubsaet, E.; Rutjes, F. P. J. T.; Delft, F. L. v.
Chem. Commun. 2011, 47, 3198–3200.
6. (a) Mudududdla, R.; Jain, S. K.; Bharate, J. B.; Gupta, A. P.;
Singh, B.; Vishwakarma, R. A.; Bharate, S. B. J. Org. Chem.
2012, 77, 8821-8827; (b) Bharate, S. B.; Mudududdla, R.;
Bharate, J. B.; Battini, N.; Battula, S.; Yadav, R. R.; Singh, B.;
Vishwakarma, R. A. Org. Biomol. Chem. 2012, 10, 5143-5150.
7. Mohammed, S.; Padala, A. K.; Dar, B. A.; Singh, B.; Sreedhar,
B.; Vishwakarma, R. A.; Bharate, S. B. Tetrahedron 2012, 68,
8156-8162.
8. Typical procedure for one-pot synthesis of isoxazoles (method
C): The aqueous solution of hydroxylamine hydrochloride (1.2
mmol) and aldehyde
2 (1 mmol) were stirred at room
temperature for 30 min. After complete conversion of aldehyde
to oxime, N-chlorosuccinamide (1.3 mmol) was added to the
reaction mixture and was allowed to stir for 3 h. The clay-
Cu(II)/NaN3 mixture (prepared by stirring 15 mol% clay-Cu
catalyst and 7.5 mol% NaN3 in water until the color changes
from brown to black) and phenyl acetylene 5a (1.3 mmol) was
added and the reaction mixture was further stirred for another 3
h. After completion of reaction, the reaction mixture was filtered
through Whatman filter paper, residue was washed with EtOAc.
Organic layer was separated from filtrate and was dried over
anhydrous sodium sulfate. Combined organic layers were
concentrated in vacuo and crude reaction mixture was purified by
silica gel (#100-200) column chromatography using EtOAc:
hexane as eluting solvent to get corresponding 3,5-disubstituted
isoxazoles 1a-1o in 68-88% yield. Spectral data of all
compounds is provided in supplementary material. The spectral
data of representative two compounds is provided here. 1f: Yield:
o
68%; yellow solid; m.p. 190-193 C; Rf (5% EtOAc: n-hexane)
1
0.18; H NMR (CDCl3, 500 MHz): δ 7.82-7.84 (m, 2H). 7.49-
7.51 (m, 3H), 7.46 (d, J = 3.8 Hz, 1H), 7.24, (d, J = 3.8 Hz, 1H),
6.80 (s, 1H); 13C NMR (CDCl3, 125 MHz): δ 171.57, 153.84,
146.63, 130.97, 129.21, 126.46, 126.00, 113.09, 111.97, 97.20;
IR (neat): νmax 3435, 3118, 2923, 2851, 1616, 1570, 1514, 1363,
1025 cm-1; ESI-MS: m/z 257.013 [M+1]+; HRMS (ESI+): m/z
257.0554 calcd for C13H8N2O4+H+ (257.0557). 1h: Yield: 72%;
colorless liquid; Rf (5% EtOAc: n-hexane) 0.54; 1H NMR
(CDCl3, 500 MHz): δ 7.70 (d, J = 8.4 Hz, 2H), 7.45 (d, J = 8.4
Hz, 2H), 6.20 (s, 1H), 2.76 (t, J = 7.6 Hz, 2H), 1.80-1.70 (m,
2H), 1.48-1.38 (m, 2H), 0.85 (t, J = 7.3 Hz, 3H); 13C NMR
(CDCl3, 125 MHz,): δ 174.08, 160.79, 135.18, 128.55, 127.44,
127.36, 98.09, 29.01, 25.93, 21.63, 13.14; IR (neat): νmax 2959,
2931, 2872, 1604, 1569, 1509, 1456, 1427, 1092, 1015 cm-1;
ESI-MS: m/z 236.0373 [M+1]+; HRMS (ESI+): m/z 236.0832
calcd for C13H14ClNO + H+ (236.0837).
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