One-pot three-component synthesis of isoxazole using ZSM-5 as a heterogeneous catalyst

Article abstract of DOI:10.1080/00397911.2020.1815786

A mild and convenient route for the synthesis of isoxazole derivatives has been developed using ZSM-5 as a heterogeneous catalyst. The reaction was carried out under a solvent-free condition to afford the desired products in good yields. A variety of func

Full text of DOI:10.1080/00397911.2020.1815786

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
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One-pot three-component synthesis of isoxazole
using ZSM-5 as a heterogeneous catalyst
Navnath T. Hatvate & Shrikant M. Ghodse
To cite this article: Navnath T. Hatvate & Shrikant M. Ghodse (2020): One-pot three-component
synthesis of isoxazole using ZSM-5 as a heterogeneous catalyst, Synthetic Communications, DOI:
10.1080/00397911.2020.1815786
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https://doi.org/10.1080/00397911.2020.1815786
One-pot three-component synthesis of isoxazole using
ZSM-5 as a heterogeneous catalyst
Navnath T. Hatvatea
and Shrikant M. Ghodseb
aDepartment of Pharmaceutical Chemistry, St John Institute of Pharmacy and Research, Palghar, India;
bDepartment of Pharmaceutical Chemistry, Prin. K. M. Kundnani College of Pharmacy, Mumbai, India
ABSTRACT
ARTICLE HISTORY
Received 30 June 2020
A mild and convenient route for the synthesis of isoxazole deriva-
tives has been developed using ZSM-5 as a heterogeneous catalyst.
The reaction was carried out under a solvent-free condition to afford
the desired products in good yields. A variety of functional groups
was tolerated under the reaction conditions employed. Moreover,
the heterogeneous catalyst (ZSM-5) was recovered and reused sev-
eral times without significant loss of its catalytic activity.
KEYWORDS
Aldehydes; one pot;
isoxazole; ZSM-5; ethyl
acetoacetate
GRAPHICAL ABSTRACT
O
O
NH2OHHCl
OEt
O
ZSM-5
R
R
H
N
100 OC
O
Solvent Free,
O
14 examples
85-96 % Yield
Introduction
Isoxazole is an oxygen and nitrogen-containing heterocyclic scaffold consistently
regarded as privileged structural moiety owing to its extensive biological as well as
pharmacological importance. Several derivatives of isoxazole showed diverse biological
activities, such as antibacterial, anticancer, analgesic, anti-inflammatory, antifungal, anti-
tumor, anti-androgen (Figure 1) and antilipidemic activities.[1–7] Apart from that, isoxa-
zoles are widely used in the liquid crystalline material,[8] molecular devices,[9] organic
synthesis,[10] filter dyes,[11] and optical storage and optical research.[12] It is also a struc-
tural backbone for various phytochemicals and drugs, such as muscimol, ibotenic acid,
cycloserine, and isoxazole-4-carboxylic acid (Figure 1).[13–15] The present structural
CONTACT Navnath T. Hatvate
navnath711@gmail.com
Department of Pharmaceutical Chemistry, St John
Institute of Pharmacy and Research, Palghar, Maharashtra, India.
ß 2020 Taylor & Francis Group, LLC

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N. T. HATVATE AND S. M. GHODSE
Figure 1. Biologically active isoxazole.
moiety is also used as an intermediate in the synthesis of pyrazolo[4,3-d]isoxazoles and
pyrido[2,3-d]pyrimidine-4,7-dione.[16] Thus, the development of new methodologies to
isoxazole synthesis is very crucial in pharmaceutical chemistry, especially in
drug discovery.
Several methods have been reported for the synthesis of isoxazoles including the cyc-
lization of O-propioloyl oxime via intermolecular arylidene group transfer using gold
catalyst,[17] condensation of 3-Phenylisoxazol-5-one within aryl halide in the presence of
KF/alumina via a two-step reaction,[18] reaction of 1,3-dicarbonyl compounds with ben-
zaldoximes derivatives,[19] cycloaddition of ethyl 2-nitroacetate or benzoylnitromethane
with terminal alkynes or alkenes,[20] and condensation of hydroxylamine with b-ketoest-
ers in the presence of sodium hydroxide.[21] The most common method for the synthe-
sis of isoxazoles involves one-pot three-component reactions of ethyl acetoacetate,
hydroxylamine hydrochlorides and aryl aldehydes using various catalysts such as 2-
hydroxy-5-sulfobenzoic acid, sodium tetraborate, sodium saccharin, boric acid, sodium
silicate, sodium benzoate, sodium azide, DABCO, potassium phthalimide, tartaric acid
N-bromosuccinimide (NBS), zinc chloride, citric acid, starch solution and potassium
hydrogen phthalate.[22] Recently, there are several reports published which have milder
reaction conditions by using either the use of heterogeneous catalysis or the use of
advanced techniques such as microwave heating, ultrasonic irradiation, solid-state heat-
ing or grinding, and in the presence of visible light using NaOAc.[23]
The main drawbacks of the above literature methods are: it requires longer reaction
time, harsh reaction conditions and also use of the toxic solvents, moisture sensitive,
unstable and hazardous reagents in the reaction.[22d,22i]
ZSM-5, a pentasil aluminosilicate zeolite, is most widely used for hydrocarbon crack-
ing in the petrochemical industry but it might be unfamiliar to the many organic chem-
ists. Recently, ZSM-5 is used in organic chemistry in many chemical transformations
due to its high surface area and provides supports to the metal catalyst.[24]
Considering the significance of isoxazole derivatives and our continuous interests in
the synthesis of biologically active heterocycle or its intermediates,[25] we have devel-
oped a mild and convenient one-pot synthesis of 3-methyl-4-(hetero)arylmethylene iso-
xazole-5(4H)-ones derivatives from easily available aldehydes, under solvent-free
reaction condition in the presence of ZSM-5.

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3
Table 1. Optimization of reaction conditionsa,b
.
Entry
Catalyst
ZSM-5
Solvent
Temperature (ꢀC)
Time (min)
Yield (%)
1
2
3
4
5
6
7
8
MeCN
EtOH
THF
Reflux
Reflux
Reflux
Reflux
Reflux
100
30
30
30
30
30
30
30
15
15
15
15
40
70
30
25
40
50
97
96
96c
85d
96
ZSM-5
ZSM-5
ZSM-5
ZSM-5
ZSM-5
ZSM-5
ZSM-5
ZSM-5
ZSM-5
ZSM-5
Toluene
Water
DMF
Solvent free
Solvent free
Solvent free
Solvent free
Solvent free
100
100
100
100
9
10
11
110
aReaction conditions: 1 (0.5 mmol), 2 (0.5 mmol) and 3 (0.5 mmol) and solvent (5 mL).
bIsolated yield.
c20 Wt% ZSM-5 was used as catalyst.
d5 Wt% ZSM-5 was used as catalyst.
Results and discussion
We initiated the present study with benzaldehyde (1) and hydroxylamine hydrochloride
(2) and ethyl acetoacetate (3) as a model substrate using a ZSM-5 as catalyst and aceto-
nitrile as a solvent at reflux temperature. To our surprise, 30% yield of the product was
obtained (Table 1, entry 1). The effort was to hike the yield of the desired product using
different solvents such as EtOH, THF, Toluene, water, and DMF (Table 1, entries 2–6).
Later, we found that out of those solvents, reaction gives the excellent yield in the solv-
ent-free reaction condition at 100 ꢀC (entry 7 and 8). However, for our further study,
solvent-free reaction condition was chosen because the “best solvent is no solvent.”
Next, we studied the different wt % ratios of ZSM-5, the use of 5 Wt% of catalyst
decreases the yield whereas 20 Wt% did not affect the yield of the final product (entry 9
and 10). Hike in the temperature of more than the 100 ꢀC does not affect the chemical
yield of the desired final product (entry 11).
With these optimized reaction conditions, various aldehydes have been treated with
hydroxylamine hydrochloride and ethyl acetoacetate in presence of ZSM-5 as a catalyst
to explore the scope and universality of this reaction and results are summarized in
Table 2.
Almost all of the aromatic and heteroaromatic aldehyde resulted in satisfactory chem-
ical yields of the products considering their reaction scale (Table 2 entries 4a–4n).
Interesting to know that, aromatic aldehydes with electron-donating functional groups,
for example, 4-methyl benzaldehyde and 4-hydroxybenzaldehyde (entries 4b and 4c) as
well as electron-withdrawing groups such as p-nitrobenzaldehyde (entry 4f) are well tol-
erated and gives good to excellent yield of the desired product. Halo substitution, i.e.,
4-chlorobenzaldehyde also gives an excellent yield of the desired product (entry 4d).
The substitution of the methoxy group at meta and para does not affect the yield of the

4
N. T. HATVATE AND S. M. GHODSE
Table 2. Synthesis of various 3-methyl-4-(hetero)arylmethylene isoxazole-5-(4H)-ones deriva-
tives using ZSM-5a,b
.
aReaction conditions: aldehydes (0.5 mmol), Hydroxylamine hydrochloride (0.5 mmol) and ethyl acetoacetate
(0.5 mmol), 10 wt % ZSM-5. Reaction time: 15 min.
bIsolated yield.
final product (entry 4e and 4i). The double bond of unsaturated aldehyde, i.e., cinna-
maldehyde is stable in the present reaction condition and gives an excellent yield of the
desired product (entry 4k). Not only bulkier naphthaldehyde (entry 4l) but also hetero-
aryl furan-2-carboxyaldehyde and thiophene-2-carboxyaldehyde (entries 4m and 4n) led

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SYNTHETIC COMMUNICATIONSV
5
101
81
61
41
21
1
1
2
3
4
5
Figure 2. Recycle study of catalyst ZSM-5.
Scheme 1. Plausible reaction mechanism.
to excellent chemical yield of the desired product. There was no significant effect of
substitution on ortho, meta, and para position observed on product yields and reaction
time (entries 4e, 4h, 4i, and 4j).
Recyclability and reusability is an important attributes for the every heterogeneous
catalyst. Therefore, the recycling and reusability study of ZSM-5 catalyst was carried out
using benzaldehyde as a substrate. Surprisingly it was observed that ZSM-5 was active
even after 5 recycles (Figure 2).
According to the literature, the proposed reaction mechanism is illustrated in Scheme
1.[26] The first step might be the Lewis-acid sites (Al3þ) of ZSM-5 activate carbonyl oxy-
gen of ethyl acetoacetate (3). Oximation of activated ethyl acetoacetate produce

6
N. T. HATVATE AND S. M. GHODSE
intermediate (5) which can undergo Knoevenagel condensation with an activated alde-
hyde (1) leads the formation of intermediate (6). Dehydration of 6 and subsequent
intermolecular cyclization of 7 forms intermediate 8. Finally, the elimination of ethanol
leads to the formation of the desired final products 4.
Conclusion
In conclusion, we developed a mild, green and solvent-free protocol for the synthesis of
3-methyl-4-(hetero)arylmethylene isoxazole-5(4H)-ones derivatives using ZSM-5 is an
impressive heterogeneous catalyst. The products are obtained in good to excellent chem-
ical yield and also the catalyst was recovered and recycled without loss of noticeable
catalytic activity.
Experimental
General procedure for the synthesis of 3-methyl-4-(hetero)arylmethylene
isoxazole-5(4H)-ones
A mixture of aldehydes (0.5 mmol), ethyl acetoacetate (0.5 mmol) and hydroxylamine
hydrochloride (0.5 mmol) was stirred at 100 ꢀC in presence of ZSM-5 (10 wt %) in a
round bottom flask (RBF). The progress of the reaction was monitored by TLC using
hexane/EtOAc (2:1) as a mobile phase. After completion of the reaction, the reaction
mixture was filtered and washed with the hot EtOH to separate the product (as filtrate)
from the catalyst. 10 ml of cold water was added to the filtrate to precipitate the final
product and then the precipitate was filtered and washed with the mixture of cold water
and ethanol and then dried in the air.
4-Benzylidene-3-methylisoxazol-5(4H)-one (4a) m.p. 142–144 ꢀC (Lit: 140–142 ꢀC),[22a]
1H NMR: (400 MHz, DMSO-d6): d (ppm) ¼ 8.39–8.37 (d, J ¼ 8 Hz, 2H), 7.94 (s, 1H),
7.65–7.61 (t, J ¼ 8 Hz, 1H), 7.57-7.54 (t, J ¼ 8 Hz, 2H), 2.26 (s, 3H).
ORCID
Navnath T. Hatvate
http://orcid.org/0000-0002-3388-3247
References
[1] Kan, O. H.; Adachi, I.; Kido, R.; Hirose, K. J. Med. Chem. 1967, 10, 411–418. DOI: 10.
1021/jm00315a028.
[2] Karabasanagouda, T.; Adhikari, A. V.; Girisha, M. Indian J. Chem. 2009, 48B, 430–437.
[3] Santos, M. M. M.; Faria, N.; Iley, J.; Coles, S. J.; Hursthouse, M. B.; Martins, M. L.;
Moreira, R. . Bioorg. Med. Chem. Lett. 2010, 20, 193–195. DOI: 10.1016/j.bmcl.2009.10.
137.
[4] Kamal, A.; Bharathi, E. V.; Reddy, J. S.; Ramaiah, M. J.; Dastagiri, D.; Reddy, M. K.;
Viswanath, A.; Reddy, T. L.; Shaik, T. B.; Pushpavalli, S. N. C. V. L.; Bhadra, M. P. Eur. J.
Med. Chem. 2011, 46, 691–703. DOI: 10.1016/j.ejmech.2010.12.004.
[5] Diana, P.; Carbone, A.; Barraja, P.; Kelter, G.; Fiebig, H. H.; Cirrincione, G. Bioorg. Med.
Chem. 2010, 18, 4524–4529. DOI: 10.1016/j.bmc.2010.04.061.

R
SYNTHETIC COMMUNICATIONSV
7
[6] Ishioka, T.; Kubo, A.; Koiso, Y.; Nagasawa, K.; Itai, A.; Hashimoto, Y. Bioorg. Med. Chem.
2002, 10, 1555–1566. DOI: 10.1016/S0968-0896(01)00421-7.
[7] Kwon, T.; Heiman, A. S.; Oriaku, E. T.; Yoon, K.; Lee, H. J. Med. Chem. 1995, 38,
1048–1051. DOI: 10.1021/jm00006a026.
[8] Han, J.; Guo, H.; Wang, X. G.; Pang, M. L.; Meng, J. B. Chin. J. Chem. 2007, 25, 129–131.
DOI: 10.1002/cjoc.200790007.
[9] Pineiro, M.; Pinho, e.; Melo, T. M. Eur. J. Org. Chem. 2009, 2009, 5287–5307. DOI: 10.
1002/ejoc.200900644.
[10] Biju, S.; Reddy, M. L. P.; Freire, R. O. Inorg. Chem. Commun. 2007, 10, 393–396. DOI: 10.
1016/j.inoche.2006.12.008.
[11] Aret, E.; Meekes, H.; Vlieg, E.; Deroover, G. Dyes Pigments 2007, 72, 339–344. DOI: 10.
1016/j.dyepig.2005.09.018.
[12] Zhang, X. H.; Zhan, Y. H.; Chen, D.; Wang, F.; Wang, L. Y. Dyes Pigments 2012, 93,
1408–1415. DOI: 10.1016/j.dyepig.2011.10.003.
[13] Getal, J. Antibiotics 1975, 28, 91–94.
[14] Bowden, K.; Crank, G.; Ross, W. J. J. J. Chem. Soc. C 1968, 0, 172–185. DOI: 10.1039/
j39680000172.
[15] Stammer, C. H.; Wilson, A. N.; Spencer, C. F.; Bachelor, F. W.; Holly, F. W.; Folkers, K.
J. Am. Chem. Soc. 1957, 79, 3236–3240. DOI: 10.1021/ja01569a065.
[16] (a) Gomha, S. M.; Badrey, M. G.; Abdalla, M. M.; Arafa, R. K. Med. Chem. Comm. 2014,
5, 1685–1692. DOI: 10.1039/C4MD00282B. (b) Tu, S.; Zhang, J.; Jia, R.; Jiang, B.; Zhang,
Y.; Jiang, H. Org. Biomol. Chem. 2007, 5, 1450–1453. DOI: 10.1039/b617201f.
[17] Nakamura, I.; Okamoto, M.; Terada, M. Org. Lett. 2010, 12, 2453–2455. DOI: 10.1021/
ol100581m.
[18] Villemin, D.; Martin, B.; Garrigues, B. Synth. Commun. 1993, 23, 2251–2257. DOI: 10.
1080/00397919308013781.
[19] Donleavy, J. J.; Gilbert, E. E. J. Am. Chem. Soc. 1937, 59, 1072–1076. DOI: 10.1021/
ja01285a032.
[20] Gangadhara Chary, R.; Rajeshwar Reddy, G.; Ganesh, Y. S. S.; Vara Prasad, K.;
Raghunadh, A.; Krishna, T.; Mukherjee, S.; Pal, M. Adv. Synth. Catal. 2014, 356, 160–164.
DOI: 10.1002/adsc.201300712.
[21] Lowe, D. B.; Magnuson, S.; Qi, N.; Campbell, A.-M.; Cook, J.; Hong, Z.; Wang, M.;
Rodriguez, M.; Achebe, F.; Kluender, H.; et al. Bioorg. Med. Chem. Lett. 2004, 14,
3155–3159., DOI: 10.1016/j.bmcl.2004.04.015.
[22] (a) Kiyani, H.; Darbandi, H.; Mosallanezhad, A.; Ghorbani, F. Res. Chem. Intermed. 2015,
41, 7561–7579. DOI: 10.1007/s11164-014-1844-x. (b) Kiyani, H.; Ghorbani, F. Open. J.
Org. Chem. 2013, 1, 6–10. (c) Kiyani, H.; Ghorbani, F. Heterocycl. Lett. 2013, 3, 359–369.
(d) Liu, Q.; Wu, R. T. J. Chem. Res. (S) 2011, 35, 598–599. DOI: 10.3184/
174751911X13176501108975. (e) Kiyani, H.; Ghorbani, F. Res. Chem. Intermed. 2015, 41,
2653–2664. DOI: 10.1007/s11164-013-1411-x. (f) Liu, Q.; Zhang, Y. N. Bull. Korean Chem.
Soc. 2011, 32, 3559–3560. DOI: 10.5012/bkcs.2011.32.10.3559. (g) Kiyani, H.; Ghorbani, F.
Elixir Org. Chem. A 2013, 58, 14948–14950. (h) Mirzazadeh, M.; Mahdavinia, G. H. E-j
Chem. 2012, 9, 425–429. DOI: 10.1155/2012/562138. (i) Kiyani, H.; Ghorbani, F. J. Saudi
Chem. Soc .2017, 21, S112–S119. DOI: 10.1016/j.jscs.2013.11.002. (j) Khandebharad, A. U.;
Gill, C. H.; Agrawal, B. R. Res. J. Chem. Sci. 2015, 5, 27–32. (k) Kiyani, H.; Kanaani, A.;
Ajloo, D.; Ghorbani, F.; Vakili, M. Res. Chem. Intermed. 2015, 41, 7739–7773. DOI: 10.
1007/s11164-014-1857-5. (l) Kiyani, H.; Ghorbani, F. Res. Chem. Intermed. 2015, 41,
7847–7882. DOI: 10.1007/s11164-013-1411-x. (m) Ningaiah, S.; Vrushabendra, B.;
Chandra. Javarashetty, C.; Shridevi, D. J. Applicable Chem. 2018, 7, 1159–1582. (n) Rikani,
A. B.; Setamdideh, D. Orient. J. Chem. 2016, 32, 1433–1437. DOI: 10.13005/ojc/320317.
(o) Vekariya, R. H.; Patel, H. D. Indian J. Chem. 2017, 56B, 890–896.
[23] (a) Saikh, F.; Das, J.; Ghosh, S. . Tetrahedron Lett. 2013, 54, 4679–4682. DOI: 10.1016/j.
tetlet.2013.06.086. (b) Zhang, Y. Q.; Wang, C. Chin. J. Org. Chem. 2008, 28, 141–144. (c)
Ablajan, K.; Xiamuxi, H. Synth. Commun. 2012, 42, 1128–1136. DOI: 10.1080/00397911.

8
N. T. HATVATE AND S. M. GHODSE
2010.535949. (d) Cheng, Q. F.; Liu, X. Y.; Wang, Q. F.; Liu, L. S.; Liu, W. J.; Lin, Q.;
Yang, X. J. Chin. J. Org. Chem. 2009, 29, 1267–1271. (e) Tu, S.; Zhang, J.; Jia, R.; Jiang,
B.; Zhang, Y.; Jiang, H. Org. Biomol. Chem. 2007, 5, 1450–1453. DOI: 10.1039/b617201f.
[24] (a) Bai, P.; Wu, P.; Xing, W.; Liu, D.; Zhao, L.; Wang, Y.; Xu, B.; Yan, Z.; Zhao, X. S.
J. Mater. Chem. A 2015, 3, 18586–18597. DOI: 10.1039/C5TA05350A. (b) Nayak, Y. N.;
Nayak, S.; Nadaf, Y. F.; Shetty, N. S.; Gaonkar, S. L. LOC 2020, 17, 491–506. DOI: 10.
2174/1570178616666190807101012.
[25] (a) Hatvate, N. T.; Ghodse, S. M.; Telvekar, V. N. Synth. Commun. 2018, 48, 285–290.
DOI: 10.1080/00397911.2017.1398330. (b) Hatvate, N. T.; Ghodse, S. M.; Telvekar, V. N.
Synth. Commun. 2019, 49, 3553–3559. DOI: 10.1080/00397911.2019.1679185. (c) Hatvate,
N. T.; Ghodse, S. M.; Takale, B. S.; Telvekar, V. N. Tetrahedron Lett. 2018, 59, 3892–3894.
DOI: 10.1016/j.tetlet.2018.09.034.
[26] (a) Kasar, S. B.; Thopate, S. R. COCAT 2019, 6, 231–237. DOI: 10.2174/
2213337206666190411115402. (b) Patil, M.; Mudaliar, S. C.; Chaturbhuj, G. U.
Tetrahedron Lett. 2017, 58, 3256–3261. DOI: 10.1016/j.tetlet.2017.07.019. (c) Setamdideh,
D. J. Mex. Chem. Soc. 2015, 59, 191–197. (d) Ghodse, S. M.; Takale, B. S.; Hatvate, N. T.;
Telvekar, V. N. ChemistrySelect 2018, 3, 4168–4172. DOI: 10.1002/slct.201800690.