Synthesis of 3-methyl-4-arylmethylene isoxazole-5(4H)-ones by visible light in aqueous ethanol

Article abstract of DOI:10.1016/j.tetlet.2013.06.086

A highly efficient methodology for the synthesis of 3-methyl-4- arylmethylene-isoxazole-5(4H)-ones has been developed by visible light induced multicomponent reaction of aromatic aldehydes, ethyl acetoacetate, hydroxylamine hydrochloride, and sodium aceta

Full text of DOI:10.1016/j.tetlet.2013.06.086

Accepted Manuscript
Synthesis of 3-methyl-4-arylmethylene isoxazole-5(4H)-ones by visible light in
aqueous ethanol
Forid Saikh, Jhantu Das, Somnath Ghosh
PII:
S0040-4039(13)01062-9
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.06.086
TETL 43139
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
18 April 2013
15 June 2013
18 June 2013
Please cite this article as: Saikh, F., Das, J., Ghosh, S., Synthesis of 3-methyl-4-arylmethylene isoxazole-5(4H)-
ones by visible light in aqueous ethanol, Tetrahedron Letters (2013), doi: http://dx.doi.org/10.1016/j.tetlet.
2013.06.086
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Graphical Abstract
Synthesis of 3-methyl-4-arylmethylene isoxazole-5(4H)-ones by visible light in
aqueous ethanol
Forid Saikh, Jhantu Das and Somnath Ghosh*
Ar
CH3
hν
COCH3
CH3COONa / aq.C2H5OH /
5-10 min
Ar
Cl
CHO
NH3OH
N
CO2C2H5
O
O

Synthesis of 3-methyl-4-arylmethylene isoxazole-5(4H)-ones by visible light in
aqueous ethanol
Forid Saikh, Jhantu Das and Somnath Ghosh*
Department of Chemistry
Jadavpur University
Kolkata 700032, India
Telephone: +91 033 2414 6223
Fax: +91 033 2414 6223
E-mail: ghoshsn@yahoo.com
ABSTRACT
A highly efficient methodology for the synthesis of 3-methyl-4-arylmethylene-isoxazole-5(4H)-
ones has been developed by visible light induced multicomponent reaction of aromatic
aldehydes, ethyl acetoacetate, hydroxylamine hydrochloride and sodium acetate in aqueous
ethanol sans any phase transfer catalyst or promoter.
Keywords:
Multicomponent reaction
3-Methyl-4-arylmethylene-isoxazole-5(4H)-ones
Visible light
Aqueous ethanol
Isoxazole scaffolds, bearing both oxygen and nitrogen atoms, are important heterocyclic
compounds and possess various pharmacological activities. These heterocycles can act as anti-
bacterial, immunosuppressive, anti-inflammatory compounds, and show hypoglycemic activity.1
In addition, several isoxazole derivatives have been employed as versatile building blocks in
organic synthesis.2 Hence, these molecules are attractive target for the synthesis.3
The traditional procedure for the synthesis of the title compound consists of two
consecutive steps4 viz. a) formation of an oxime by the reaction of ethyl acetoacetate and
hydroxylamine hydrochloride followed by ring closure affords 3-methyl-isoxazole-5(4H)-ones;
b) a Knoevenagel condensation reaction between 3-methyl-isoxazole-5(4H)-ones and aromatic
aldehydes, which finally gives 3-methyl-4-arylmethylene-isoxazole-5(4H)-ones. More recently,
several other methodologies involving solid state heating or solid state grinding,5
multicomponent reaction,6 ultrasonic irradiation7 and stirring in water8 or ethanol at room

temperature in the presence of catalyst9 have also been described. However, in most of the cases
either long reaction time or harsh reactive conditions are required.
Photochemical reactions particularly using visible light in organic synthesis in eco-
friendly solvents like water or aqueous-ethanol are extremely useful and are generally considered
as clean and green procedure. This type of photo-activation of substrates very often minimizes
the formation of byproducts and requires much lesser time compared to thermal methods; and for
this reason, photochemical reactions occupy an interesting position and some fascinating
reviews10, 11 on this subject are available in the literature.
In connection with our continued interest for the photochemical synthesis of biologically
active heterocyclic compounds employing ultraviolet radiation12 and visible light,13 we wish to
report here, for the first time, a new, expeditious and eco-friendly visible light induced multi-
component reaction in aqueous-ethanol for the synthesis of 3-methyl-4-arylmethylene-isoxazole-
5(4H)-ones (Scheme 1).
[Please insert Scheme 1 here]
The present procedure for the multicomponent synthesis of isoxazolone derivatives
consists of photo-irradiation of aromatic aldehydes, ethyl acetoacetate, hydroxylamine
hydrochloride and sodium acetate in aqueous-ethanol for ca. 5-10 min only on an average and
the products are obtained with an average yield of 56–89%. The utmost advantage of this
procedure is that the desired products are obtained in almost analytical grade crystalline form
from the reaction mixture either on cooling or by dilution with water and requires no further
chromatographic separation. The results of these experiments are given in Table 1. It was also
observed that aromatic aldehydes containing electron donating groups smoothly participate in the
reaction whereas, under the same reaction condition aromatic aldehydes containing electron
withdrawing group (nitro or chloro) failed to afford the desired product; and only the
corresponding oxime of the aldehydes were isolated from the reaction mixture. It is to be
mentioned here the aliphatic aldehydes such as formaldehyde or acetaldehyde did not participate
in the reaction.
[Please insert Table 1 here]

In order to check the efficacy of the photochemical reaction as compared to thermal
reaction, the multicomponent reaction was performed with 4-methoxybenzaldehyde, ethyl
acetoacetate, hydroxylamine hydrochloride and sodium acetate in aqueous-ethanol under
refluxing condition for 4 h. The reaction mixture became a sticky reddish oily material after
dilution with water and 3-methyl-4-(4-methoxyphenyl) methylene-isoxazole-5(4H)-one (4c) was
obtained by chromatography in only 18% yield. However, the same combination of substrates
under identical condition in the presence of light afforded 4c in much higher yield (82%) in a
significantly lesser time (10 min), in purely crystalline form after dilution of the reaction
mixture. Similar experiment with indole-3-aldehyde for 2 h afforded 4i in 51% yield, whereas
photochemical reaction using the same substrate for only 18 min yielded 56% of the product.
This clearly shows that the present photochemical method is much superior to the conventional
thermal one.
It has been reported9 by Liu and Hou that the formation of the title compound proceeds
through the intermediacy of a Knoevenagel adduct of the preformed oxime of ethyl acetoacetate
followed by ring closure in the presence of sodium sulphide. We, therefore, tried first to prepare
the Knoevenagel condensation product with ethyl acetoacetate and 4-methoxybenzaldehyde in
the presence of sodium acetate in refluxing aqueous ethanol. However, the condensation product
was not obtained. This, therefore, led us, in the present instance, to speculate that the reaction
may plausibly be initiated by an electron transfer from hydroxylamine in the presence of light to
the carbonyl group of ethyl acetoacetate to produce a radical anion (I) that subsequently
transforms to oxime (II). The intermediate (II) then undergoes a photo-lactonization by a SET
pathway through (III) to generate isoxazolone (IV) which on further reaction with aldehydes
affords 4 via a photo-Knoevenagel reaction13b as depicted in Scheme 2.
[Please insert Scheme 2 here]
The structure of 3-methyl-4-(4-methoxyphenyl) methylene-isoxazole-5(4H)-one (4c) was
confirmed by X-ray crystallography and the ORTEP view is presented in Figure 1. The crystal
structure has been deposited at the Cambridge Crystallographic Data Centre and allocated the
deposition number CCDC 924978.

[Please insert Figure 1 here]
Single crystals of suitable quality for X-ray diffraction study of compound, 3-methyl-4-
(4-methoxyphenyl) methylene-isoxazole-5(4H)-ones (4c), were grown by slow evaporation from
acetone hexane mixture (1:1 v/v). The X-ray intensity data were measured at 296 K on Bruker
AXS SMART APEX CCD diffractometer (Mo Kα, λ= 0.71073 Å). The detector was placed at a
distance 6.03 cm from the crystal. The data were reduced in SAINTPLUS14 and empirical
absorption correction was applied using the SADABS package.14 All the non hydrogen atoms
were located by Direct Methods. The structures were refined by full matrix least-square
procedure on F2. All non-hydrogen atoms were refined anisotropically. The hydrogen atoms
were added theoretically and riding on the concerned atoms. Calculations were performed using
the SHELXTL v.6.1415, 16 program package. Molecular structure plots were drawn using
ORTEP.17 Relevant crystal data are given in Table 2.
[Please insert Table 2 here]
In conclusion, we have developed an efficient, environment-friendly, high yielding and
one-pot three-component reaction for the synthesis of 3-methyl-4-arylmethylene-isoxazole-
5(4H)-ones in aqueous ethanol. This new method18 is devoid of any unwarranted side reactions
and may be considered as an excellent improvement over the existing methods.
Acknowledgments
The authors wish to thank Dr. K. Pramanik and Dr. K. Rajak, Department of Chemistry,
Jadavpur University for X-Ray Crystallographic data. This research was supported by the
Council of Scientific and Industrial Research and University Grants Commission, Government of
India to the author (F.S) and partly by the Centre for Advance Studies, and DST-PURSE
program of the Department of Chemistry, Jadavpur University.
References and notes

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M. M.; López-Vázquez, M. L.; San Feliciano, A. J. Med. Chem. 1996, 39, 2865-2868; (c)
Kwon, T.; Heimann, A. S.; Oriaku, E. T.; Yoon, K. J. Med. Chem. 1995, 38, 1048-1051;
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Abbiati, G.; Beccalli, E. M.; Broggini, G.; Zoni, C. Tetrahedron 2003, 59, 9887-9893.
a) Bhosale, S.; Kurhade, S.; Prasad, U. V.; Palle V. P.; Bhuniya D. Tetrahedron Letters
2009,50, 3948–3951; b) Jawalekar, A. M.; Reubsaet, E.; Floris P. J. T. Rutjes ; van Delft,
F. L. Chem. Commun., 2011, 47, 3198–3200; c) Gasparrini, F.; Giovannoli, M.; Misit, D.;
Natile, G.; Palmieri, G.; Marescat L. J. Am. Chem. Soc. 1993, 115. 4401-4402; d)
Kantorowski, E. J.; J. K. Mark. J. Org. Chem. 1997, 62, 6797-6803; e) Barrett, A. G. M.;
Procopiou, P, A.; Voigtmann, U. Org. Lett. 2001, 3, 3165-3168; f) Waldo, J. P.; Larock,
R. C. Org. Lett. 2005, 7, 5203-5205.
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Cheng, Q.; Xingyou, X.; Wang, Q.; Liu, L.; Liu, W.; Lin, Q.; Yang, X. J. Chin. J. Org.
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Liu, Q.; Zhang, Y-N. Bull. Korean Chem. Soc. 2011, 32, 3559-3560.
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Hoffmann, N. Chem. Rev. 2008, 108, 1052-1103.
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12.
(a) Ghosh, S. N.; Das, T. K.; Datta, D. B.; Mehta, S. Tetrahedron Lett. 1987, 28, 4611–
4614; (b) Ghosh, S. N.; Datta, I.; Chakraborty, R.; Das, T. K.; Sengupta, J.; Sarkar, D. C.
Tetrahedron 1989, 45, 1441–1447; (c) Ghosh, S. N.; Datta, D. B.; Datta, I.; Das, T. K.
Tetrahedron 1989, 45, 3775–3786; (d) Datta, I.; Das, T. K.; Ghosh, S. N. Tetrahedron
Lett. 1989, 30, 4009–4012; (e) Datta, I.; Das, T. K.; Ghosh, S. N. Tetrahedron 1990, 46,
6821–6830; (f) Ghosh, S. N.; Nandi, B.; Saima, Y. Tetrahedron Lett. 1996, 37, 3169–
3170; (g) Ghosh, S. N.; Baul, S. Arkivoc 2003, 58–68.
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Tetrahedron Lett. 2011, 52, 7189–7194; (d) Ghosh, S.; Das, J.; Saikh, F. Tetrahedron
Lett. 2012, 53, 5883–5886; (e) Ghosh, S.; Baul, S. Synth. Commun. 2001, 31, 2783–2786;
(f) Ghosh, S.; Saikh, F., Das, J.; Pramanik, A. K. Tetrahedron Lett. 2013, 54, 58–62.
SMART, SAINT, SADABS, XPREP, SHELXTL; Bruker AXS Inc.: Madison, WI, 1998.
Sheldrick, G. M, SHELXS-97, Program for solution of crystal structures, University of
Gottingen, Germany, 1997.
14.
15.
16.
Sheldrick, G. M. SHELXL-97, Program for refinement of crystal structures, University of
Gottingen, Germany, 1997.
17.
18.
ORTEP-32 for Windows: Farrugia, L. J. J. Appl. Crystallogr., 1997, 30, 565.
Method: Equivalent amounts (10 mmol) of different aromatic aldehydes, ethyl
acetoacetate, hydroxylamine hydrochloride and sodium acetate were taken in aqueous-
ethanol mixture (20 mL, 1:1 v/v) and irradiated with a 150W tungsten lamp (Philips India
Ltd). The reaction time varied on an average from 5-10 min (monitored by TLC after 5
min. interval). Upon completion of the reaction, the reaction mixture was cooled and the
crystalline product so obtained was filtered, washed with water and dried in vacuo. The
desired compounds, 3-methyl-4-arylmethylene-isoxazole-5(4H)-ones (4) were isolated in
high yields in essentially pure form.
3-Methyl-4-(2, 4-dimethoxyphenyl) methylene-isoxazol-5-(4H)-one (4e): Yellow needle
shaped crystal. Yield: 87%; mp. 191oC. IR (KBr) ν 3447, 2947, 2366, 1746, 1730, 1590, 1472,
max
1
1424, 1382, 1305, 1281, 1217 cm-1; H NMR (300 MHz, CDCl3, 22oC) ꢀ 2.27 (s, 3H), 3.91 (s,
6H), 6.43 (d, J = 2.3Hz, 1H), 6.63 (dd, J = 9.0 Hz, 2.3 Hz, 1H), 7.97 (s, 1H), 9.22 (d, J = 9.0 Hz,

13
1H) ppm; C NMR (75 MHz, CDCl3, 22oC) ꢀ 169.3, 166.9, 162.2, 161.8, 143.0, 136.1, 115.5,
114.7, 105.9, 97.7, 55.9, 55.8, 11.6 ppm; HRMS (ESI) m/z [M.+ + H] 248.0334.
3-Methyl-4-(3, 4-dimethoxyphenyl) methylene-isoxazol-5-(4H)-one (4f): Yellow needle
shaped crystal. Yield: 83%; mp. 135oC. IR (KBr) ν 2938, 2836, 1729, 1587, 1554, 1519, 1439,
max
1
1376, 1336, 1279, 1213 cm-1; H NMR (300 MHz, CDCl3, 22oC) ꢀ 2.26 (s, 3H), 3.98 (s, 6H),
6.94 (d, J = 8.4 Hz, 1H), 7.31 (s, 1H), 7.58 (dd, J = 8.4 Hz, 1.8 Hz, 1H), 8.72 (s, 1H) ppm;
HRMS (ESI) m/z [M.+ + H] 248.2197.
3-Methyl-4-(3, 4-methylynedioxyphenyl) methylene-isoxazol-5(4H)-one (4g): Yellow needle
shaped crystal. Yield: 79%; mp. 204oC. IR (KBr) ν 3448, 3085, 2912, 2369, 1730, 1608,
max
1
15984 1498, 1452, 1278 cm-1; H NMR (300 MHz, CDCl3, 22°C) δ2.27 (s, 3H), 6.11 (s, 2H),
6.93 (d, J = 8.23 Hz, 1H), 7.29 (s, 1H), 7.68 (d, J = 9.6 Hz, 1H), 8.42 (d, J = 1.4 Hz, 1H) ppm;
13C NMR (75 MHZ, CDCl3, 22°C) δ 168.5, 161.1, 153.1, 149.2, 148.5, 132.8, 127.4, 116.8,
112.3, 108.7, 102.4, 11.5 ppm; HRMS (ESI) m/z [M.+ + H] 231.7979.
3-Methyl-4-(2-thiaphenyl) methylene-isoxazol-5(4H)-one (4h): Yellow needle shaped crystal.
Yield: 89%; mp. 147oC (lit.9c mp. 145-147oC). 1H NMR (300 MHz, CDCl3, 22°C) δ2.29 (s, 3H),
7.27 (dd, J = 4.9, 4.0 Hz, 1H), 7.61 (s, 1H), 7.93 (d, J = 5.0 Hz, 1H), 8.11 (d, J = 3.5 Hz, 1H)
ppm; 13C NMR (75 MHz, CDCl3, 22°C) δ168.6, 160.6, 141.4, 139.5, 139.1, 136.5, 128.9, 114.6,
11.4 ppm; HRMS (ESI) m/z [M.+ + H] 194.0270.
3-Methyl-4-(3-indolyl) methylene-isoxazol-5(4H)-one (4i): Orange needle shape crystal. Yield:
56%; mp. 240oC (lit.6b mp. 239-241 o C). 1H NMR (300 MHz, CDCl3, 22°C) δ1.99 (s, 3H), 6.97
(m, 2H), 7.19 (m, 1H), 7.52 (d, J = 5.3 Hz, 1H), 7.55 (s, 1H), 9.26 (d, J = 3.4 Hz, 1H) ppm; 13C
NMR (75 MHz, CDCl3, 22°C) δ175.6, 165.9, 143.9, 143.8, 141.1, 132.9, 128.7, 127.6, 122.86,
117.9 117.7, 114.1, 16.3 ppm; HRMS (ESI) m/z [M.+ + H] 227.0204.

Ar
CH3
CH3COONa / aq.C2H5OH
COCH3
Ar
CHO
Cl
NH3OH
N
hν
CO2C2H5
O
O
1
3
2
4
Ar
=
HO
H CO
3
HO
H CO
3
OCH
3
OCH
d
3
e
a
b
c
S
H CO
3
N
H
O
OCH
f
3
O
g
h
i
Scheme 1. Photochemical synthesis of 3-methyl-4-arylmethylene-isoxazol-5(4H)-ones

O
EtOOC
EtOOC
EtOOC
NH2OH
H2O
OEt
NHOH
OH
NH2OH
hν
O
O
N-OH
I
II
O
O
OEt
O
Ar
Ar CHO
hν
EtOH
O
H
O
O
13b
N
photo-Knovenagel
N
N
4
III
IV
Scheme 2. Plausible mechanistic pathway for the photochemical synthesis of 3-methyl-4-
arylmethylene isoxazole-5(4H)-ones

Table 1
Results of visible light promoted synthesis of 3-methyl-4-arylmethylene-isoxazole-5(4H)-ones
Entry
1
Reactant
CHO
Producta
Mp.
Time
(min.)
Yieldb
(%)
1
139oC
CH3
15
61
(lit. 8 mp.
N
141-143oC)
O
1a
4a
O
CHO
CHO
196oC
HO
CH3
(lit. 8 mp.
2
3
10
10
66
82
HO
N
214-216oC)
O
1b
4b
O
176oC
H3CO
CH3
(lit. 8 mp.
H3CO
N
1c
O
175-177oC)
4c
O
CHO
H3CO
HO
212oC
4
CH3
10
68
(lit. 8 mp.
HO
211-214oC)
OCH3
N
4d
O
1d
O
CHO
OCH3
5
6
191oC
135oC
204oC
5
4
3
87
83
79
H3CO
CH3
H3CO
OCH3
N
4e
H3CO
1e
O
O
O
CHO
H3CO
CH3
H3CO
OCH3
N
1f
O
4f
CHO
O
O
7
CH3
O
O
1g
N
4g
O
O

CHO
CH3
8
9
S
147oC
7
89
56
S
N
O
1h
O
(lit. 9c mp.
145-147oC)
4h
CHO
240oC
18
CH3
N
HN
H
(lit. 6b mp.
239-241oC)
N
1i
O
O
4i
a: All products were characterized by their satisfactory spectral data and also by comparison with
b
literature data; : Yield refers to combined amounts of first and second crops of crystallized
products.

Table 2
Crystal data and structure refinement parameters for 3-methyl-4-(4-methoxyphenyl)
methylene-isoxazole-5(4H)-ones (4c)
3-Methyl-4-(4-methoxyphenyl)-methylene-isoxazole-5(4H)-ones (4c)
formula
FW
C12 H11NO3
217.22
crystal system
space group
a [Å]
Monoclinic
P21/c
12.8059(5)
6.9143(3)
12.7500(5)
90.00
b [Å]
c [ Å]
ꢀ [°]
111.890(2)
β [°]
90.00
γ [°]
V [Å3]
1047.54(7)
Z
4
Dcalcd [ mg m−3]
1.377
µ[mm−1]
0.100
1.71, 27.59
θ [°]
T [K]
296(2)
Unique Reflections/Rint
2027/0.0649
R1 a wR2b [I > 2σ(I)]
GOF on F2
0.0649, 0.1470
1.127
a R1 = Fo−Fc/ Fo. bwR2 = [ w (Fo2 −Fc2)2/ w (Fo2)2]1/2

Figure 1. ORTEP view of 3-Methyl-4-(4-methoxyphenyl) methylene-isoxazole-5(4H)-ones
(4c) is represented by 35% thermal probability ellipsoid.