Keggin heteropolyacid catalyzed synthesis of isoxazolo- [5,4-d]pyrimidine-4,6(5H,7H)-diones at room temperature

Article abstract of DOI:10.1002/cjoc.201090180

Isoxazolo[5,4-d]pyrimidine-4,6(5H,7H)diones 2a-2f have been synthesized from the reaction of ethyl 5-amino-3-methyl-4-isoxazole carboxylate (1) with aryl isocyanates in the presence of Keggin heteropolyacid H₃[PW₁₂O₄₀] as

Full text of DOI:10.1002/cjoc.201090180

FULL PAPER
Keggin Heteropolyacid Catalyzed Synthesis of Isoxazolo-
[5,4-d]pyrimidine-4,6(5H,7H)-diones at Room Temperature
Bamoharram, Fatemeh F.*,a
Mahdavi, Masoumeh a
Roshani, Minaa
Heravi, Majid M.b
Javid, Alia Emampour, Jalal Sh.c
a Department of Chemistry, Islamic Azad University-Mashhad Branch, Mashhad, Iran
b Department of Chemistry, Azzahra University, Vanak, Tehran, Iran
c Ferdowsi University of Mashhad, Mashhad, Iran
Isoxazolo[5,4-d]pyrimidine-4,6(5H,7H)diones 2a— 2f have been synthesized from the reaction of ethyl
5-amino-3-methyl-4-isoxazole carboxylate (1) with aryl isocyanates in the presence of Keggin heteropolyacid
H3[PW12O40] as a green solid acid catalyst at room temperature in a one-pot process in good yields.
Keywords isoxazolopyrimidine, cyclization, heteropolyacid, Keggin, catalyst
Introduction
homogeneous and heterogeneous acid catalysis reac-
tions for the synthetic reactions.14
The purine base has been utilized to obtain biologi-
cally active compounds. The idea of modifying purine
bases by replacing the imidazole ring with isoxazole to
obtain the corresponding structure of isoxazolo-
pyrimidine has been the subject of numerous studies.
Derivatives of isoxazolopyrimidine have significant
biological activity and display analgesic,1-3 anti-
inflammatory,4 bactericidal,5-7 circulatory,8 and anxio-
lytic activities.9 Of the four structural isomers of isoxa-
zolopyrimidines, only the isomer [5,4-d] has not been
thoroughly investigated. To date, there have been only a
few reports concerning the synthesis of derivatives of
this isomer.10-13 However, this synthesis has been usu-
ally carried out in polar organic solvents and with
multi-step processes, without use of catalyst, in long
reaction time. Therefore, improvements in such synthe-
sis methods have been sought continuously. One of the
important factors that can be improved besides the time
and conditions of reaction, is catalyst, and along this
line introduction of inexpensive and green catalysts with
high acidity and excellent reusability is in much demand.
Among various solid acids, heteropolyacids (HPA) have
unique physical-chemical properties. Their acidity is
significantly higher than those of traditional mineral
acids. They have very strong Brønsted acidity ap-
proaching the superacid region and this acid-base prop-
erty can be varied over a wide range by changing the
chemical composition. Furthermore, they are capable of
protonating and activating the substrate; and in some
cases, they are more effective than usual inorganic acid
and the traditional acid catalysts and can improve and
reduce reaction time. Therefore, they are widely used as
solid acid catalysts as green and eco-friendly catalysts in
Due to our interest in developing and improving
green catalysts such as HPA,15 and in continuation of
our work with application of HPA to heterocyclization
reactions,16 in this article we wish to describe the syn-
thesis of new derivatives of isoxazolo[5,4-d]pyrimidine
2a— 2f by use of heteropolyacid as solid acid catalyst.
The novelty of this work lies in shorter time than earlier
work, along with reusability new derivatives and
greenness of the used catalyst.
Results and discussion
Recently, we described synthesis of new derivatives
of heterocycles by HPA instead of mineral acids like
HCl or H2SO4 as eco-friendly catalysts.16 Therefore, it
was a great interest to continue our investigations on
other reactions. We selected 1 and aryl isocyanates as
starting materials and Keggin HPA as catalyst which is
low in toxicity, highly stable towards humidity, air sta-
ble and is very well documented in green chemistry.
When a mixture of 1 and aryl isocyanates in acetic
acid was stirred at room temperature in the presence of a
catalytic amount of H3[PW12O40], during 1.5— 2 h, cy-
clization occurred and compounds 2a— 2f were ob-
tained [Eq. (1)]. The results are shown in Table1. The
synthesis of 2a— 2f was investigated, using various sol-
vents, such as hexane, chloroform, xylene, dioxane,
toluene and acetic acid at room temperature and reflux
conditions. We found out that acetic acid was the most
effective solvent for making the reaction faster and giv-
ing the best yields. It is also noteworthy to mention that
mixing of the reactants in acetic acid without any cata-
lyst did not give any good yields even in prolonged re-
*
E-mail: abamoharram@yahoo.com, fbamoharram@mshdiau.ac.ir; Tel.: 0098-511-8435000; Fax: 0098-511-6226605
Received March 24, 2009; revised October 11, 2009; accepted January 24, 2009.
974
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Chin. J. Chem. 2010, 28, 974— 976

Synthesis of Isoxazolo[5,4-d]pyrimidine-4,6(5H,7H)-diones
action time.
progress of reaction was monitored by TLC. After 3 h,
the reaction was completed. After cooling, the reaction
mixture was filtrated. The solid residue was then
washed with acetone and the solvent evaporated to give
the crude product (75%), m.p. 133—135 ℃. The solid
product was ethyl 5-amino-3-methyl-4-isoxazole car-
boxylate (1).
Isoxazolo[5,4-d]pyrimidine-4,6(5H,7H)-diones 2a— 2f
Table 1 Catalytic synthesis of isoxasolo[5,4-d]pyrimidine-
4,6(5H,7H)-diones
To a mixture of ethyl 5-amino-3-methyl-4-isoxazole
carboxylate (1 mmol) in acetic acid (5—7 mL) with
stirring and during 10 min at room temperature, were
added aryl isocyanat (1 mmol) and then H3[PW12O40]
(0.06 g, 0.02 mmol). The progress of the reaction was
monitored by TLC. Then the reaction mixture was fil-
tered to give the product. For further purification, it was
crystallized from n-hexane to afford the pure products
2a—2f.
Compd.
2a
Ar
Yield/%
65
m.p./℃
C6H5
210—212
202—204
205—206
250—252
272—274
176—178
2b
4-MeC6H4
3-MeC6H4
3-ClC6H4
3,4-Cl2C6H3
4-NO2C6H4
76
2c
70
2d
73
2e
46
2a: 1H NMR (DMSO-d6) δ: 8.55 (s, NH, 1H), 7.11—
7.65 (m, phenyl ring, 5H), 2.08 (s, CH3-isoxazol ring,
3H); 13C NMR (DMSO-d6) δ: 158.6 (amid carbonyl),
98.2—155.6 (isoxazole ring), 149.8 (urea carbonyl),
128.1—136.3 (phenyl ring), 12.5 (CH3-isoxazol ring);
MS m/z: 243 (M＋).
2f
46
Reusability of catalyst
An important advantage of this catalyst is the ease of
separating it from the reaction mixture, as well as the
fact that it could be recycled a number of times. In our
studies it has been found that the used catalyst catalyzed
the reaction without any degradation of structure. This
leads to the recovery and recycling of the catalyst,
which is very important in catalytic processes, espe-
cially, in industry. Recovery has decreased the catalytic
activity by only 2%—4%.
2b: 1H NMR (DMSO-d6) δ: 8.39 (s, NH, 1H) 7.04—
7.54 (dd, phenyl ring, 4H), 2.21 (s, CH3-isoxazol ring,
3H) 1.90 (s, CH3-phenyl ring, 3H); 13C NMR
(DMSO-d6) δ: 153.4 (amid carbonyl), 102.7—159.1
(isoxazole ring), 143.3 (urea carbonyl), 129.7—137.7
(phenyl ring), 22.6 (CH3-phenyl ring), 11.8
(CH3-isoxazol ring); MS m/z: 257 (M＋).
1
2c: H NMR (DMSO-d6) δ: 8.6 (s, 1H, NH), 7.08—
7.52 (m, 4H, phenyl ring), 2.15 (s, 3H, CH3-isoxazol
ring) 1.84 (s, 3H, CH3-phenyl ring); 13C NMR
(DMSO-d6) δ: 159.4 (amid carbonyl), 95.2 —147.6
(isoxazole ring), 150.7 (urea carbonyl), 126.3—139.5
(phenyl ring), 27.2 (CH3-phenyl ring), 14.5
(CH3-isoxazol ring); MS m/z: 257 (M＋).
Experimental
Chemicals and apparatus
All of the chemicals were obtained from commercial
sources and used as received. All yields were calculated
from crystallized products. IR spectra were obtained on
2d: 1H NMR (DMSO-d6) δ: 8.64 (s, 1H, NH),
7.12 — 7.58 (m, 4H, phenyl ring), 2.22 (s, 3H,
CH3-isoxazol ring); 13C NMR (DMSO-d6) δ: 161.2
(amid carbonyl), 106.2—151.9 (isoxazole ring), 144.1
(urea carbonyl), 122.1 — 138.3 (p＋henyl ring), 15.8
(CH3-isoxazol ring); MS m/z: 277 (M ), 279 (M＋＋2).
2e: 1H NMR (DMSO-d6) δ: 9.01 (s, 1H, NH), 7.23—
7.68 (m, 3H, phenyl ring), 2.13 (s, 3H, CH3-isoxazol
ring); 13C NMR (DMSO-d6) δ: 154.3 (amid carbonyl),
96.6—157.2 (isoxazole ring), 151.8 (urea carbonyl),
125.1—139.3 (phenyl ring), 12.5 (CH3-isoxazol ring);
MS m/z: 311 (M＋), 313 (M＋＋2), 315 (M＋＋4).
1
a Brucker 500 scientific spectrometer. H NMR spectra
were recorded on an FT NMR Bruker 100 MHz Aspect
3000 spectrometer. Mass spectra were recorded on an
MS5973 Network Mass Selective detector. Melting
points were obtained on an Electrothermal type 9100
apparatus.
Ethyl 5-amino-3-methyl-4-isoxazole carboxylate (1)
A mixture of ethyl cyanoacetate (7 mmol), and
triethyl orthoacetate (7.7 mmol) in acetic anhydride (5
mL) was refluxed with stirring for 3 h. After cooling,
the reaction mixture was filtrated. The solid product
(ethyl 2-cyano-3-ethoxy-2-butenoate) was collected,
dried and crystallized from MeOH. Yield 75%, m.p.
42—44 ℃. Then to a mixture of hydroxylamine hy-
drochloride (1 mmol) in solution of 10% NaOH (5 mL)
was added ethyl 2-cyano-3-ethoxy-2-butenoate (1 mmol)
and the resulting mixture was refluxed with stirring. The
2f: 1H NMR (DMSO-d6) δ: 8.83 (s, 1H, NH), 7.11—
7.95 (dd, 4H, phenyl ring), 2.23 (s, 3H, CH3-isoxazol
ring); 13C NMR (DMSO-d6) δ: 153.6 (amid carbonyl),
107.1—152.4 (isoxazole ring), 152.8 (urea carbonyl),
124.7—145.3 (phenyl ring), 17.7 (CH3-isoxazol ring);
MS m/z: 288 (M＋).
Chin. J. Chem. 2010, 28, 974— 976
© 2010 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
975

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FULL PAPER
Conclusion
A facile and green procedure for the syntheses of
2a— 2e is realized in the presence of H3[PW12O40] in
short time. This Keggin type catalyst is inexpensive,
eco-friendly and recyclable, which can be used for the
synthesis of other heterocyclic compounds.
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Chin. J. Chem. 2010, 28, 974— 976