Studies on inorganic solid supports under microwave irradiation using synthesis of pyrano[2,3-d]pyrimidines

Article abstract of DOI:10.1081/SCC-120005424

Difference in activity of inorganic solid supports under microwave irradiation, for the synthesis of pyrano[2,3-d]pyrimidines is reported.

Full text of DOI:10.1081/SCC-120005424

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STUDIES ON INORGANIC SOLID SUPPORTS UNDER
MICROWAVE IRRADIATION USING SYNTHESIS OF
PYRANO[2,3-d]PYRIMIDINES
M. Kidwai a , R. Venkataramanan a & B. Dave a
a Department of Chemistry, University of Delhi, Delhi, 110 007, India
Version of record first published: 18 Oct 2011.
To cite this article: M. Kidwai , R. Venkataramanan & B. Dave (2002): STUDIES ON INORGANIC SOLID SUPPORTS UNDER
MICROWAVE IRRADIATION USING SYNTHESIS OF PYRANO[2,3-d]PYRIMIDINES, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 32:14, 2161-2168
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SYNTHETIC COMMUNICATIONS
Vol. 32, No. 14, pp. 2161–2168, 2002
STUDIES ON INORGANIC SOLID
SUPPORTS UNDER MICROWAVE
IRRADIATION USING SYNTHESIS OF
PYRANO[2,3-d ]PYRIMIDINES
*
M. Kidwai, R. Venkataramanan, and B. Dave
Department of Chemistry, University of Delhi,
Delhi-110 007, India
ABSTRACT
Difference in activity of inorganic solid supports under micro-
wave irradiation, for the synthesis of pyrano[2,3-d ]pyrimi-
dines is reported.
Key Words: Inorganic solid supports; Microwave irradia-
tion; Pyranopyrimidines; Thiobarbituric acids; Chalcone
Pyranopyrimidines have proved to be interesting due to their associ-
ated diverse biological activities.[1–3] Further their application in organic
chemistry, especially as oxidising agents,[4] has stimulated the interest of
chemists all over the world. Though various methods for their synthesis
are known,[4–6] the majority are multistep with poor yield and often involves
environmentally unacceptable reagents.
*Corresponding author. E-mail: mkidwai@mantraonline.com
2161
DOI: 10.1081/SCC-120005424
Copyright & 2002 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

2162
KIDWAI, VENKATARAMANAN, AND DAVE
Enhanced reactivity, selectivity and associated ease of manipulation has
made solid phase reactions very attractive in organic synthesis. Moreover, the
advantages of coupling solid phase synthesis with microwaves are now well
established.[7] During the course of investigation,[8] of organic reactions under
microwave irradiation, we have observed that such procedures lead to faster
reactions with improved yield. Further, the reactions in dry media condition
are specially appealing as they provide an opportunity to work with open
vessels, thus avoiding the risk of high pressure development, and offer the
possibility of carrying out reactions upto a manufacturing scale.
In the present work, we have made an attempt to provide a milder
synthesis of pyranopyrimidines and to study the differential activity of solid
supports under microwave irradiation.
Pyrano[2,3-d ]pyrimidines are known to be prepared by various routes.
The most common methodology involves building the pyrano ring on to the
pyrimidine ring using the active methylene side. One of the literature pro-
cedure[6] reporting a general approach of its synthesis, involves condensa-
tion of ꢀ,ꢁ-unsaturated carbonyl compounds with thiobarbituric acids using
the noxious P2O5 as condensing agent and glacial acetic acid as solvent. The
mechanism involves Michael addition of the carbonyl group to the active
methylene of thiobarbituric acid and subsequent cyclization of the Michael
adduct so formed, or the concerted addition of mesomeric cations of the
ꢀ,ꢁ-unsaturated carbonyl compounds.
Synthesis of the adduct (3a–f ) (Figure A) is generally achieved by
refluxing the reactants in methanol in the presence of triethylamine and
on further refluxing in glacial acetic acid this is cyclized to give the required
product. Single step synthesis have also been achieved by refluxing the
reactants in presence of P2O5 and glacial acetic acid. The above method-
ology is environmentally unacceptable and demands a modification.
Michael addition of chalcone (2) to thiobarbituric acids (1a–f )
was attempted on inorganic solid supports under microwave irradiation.
Figure A.

INORGANIC SOLID SUPPORTS
2163
Figure B.
The best results (Table 1) were seen, when the reactants were adsorbed over
basic alumina.[9a] In 2–3 min the adduct (3a–f ) was obtained. On neutral
alumina,[9b] the reactions do not go to completion and only about 40–60%
of the Michael adduct was obtained even after 5 min of irradiation. On the
other hand, reaction on acidic alumina[9c] resulted in multiple spots along
with the reactants, as followed by TLC examination. With Silica Gel[9d] also,
results similar to acidic alumina were observed. The Michael addition of
chalcone to active methylene group of thiobarbituric acid requires basic
condition for the abstraction of proton, in line with the preferential forma-
tion of the adduct on basic alumina.
Cyclization of the Michael adduct (3a–f ) to the required product
(4a–f ) (Figure B) was achieved on both acidic alumina and montmoril-
lonite,[9e] in approximately same irradiation time (Table 1), though the
yields were marginally better in montmorillonite as compared to acidic
alumina. The above observation is consistent with requirement of acidic
condition for the cyclization of these compound.
When adsorbed over montmorillonite the reactants gave the required
product (4a–f ) (Figure C) directly without detection of intermediate adduct.
This can be explained by the fact that clay behaves like a ditopic catalyst[10]
containing both acidic and basic sites. Moreover unlike the two step
mechanism involving Michael adduct and its cyclization, its mechanism
may involve the formation of mesomeric cation as reported by Ahluwalia
et al.[6] On the other hand, single step reaction is not observed with other
inorganic solid supports. Acidic alumina and silica gel resulted in multiple
spots on TLC examination, which corresponded to both the intermediate
adduct and final product in addition to uncharacterized byproducts. On
basic alumina, the reaction lead to the intermediate adduct (3a–f ) only.
Even on prolonged irradiation, the cyclization of the adduct to the required
product (4a–f ) was not observed. These further supports the original

2164
KIDWAI, VENKATARAMANAN, AND DAVE
Figure C.
mechanism of the reaction involving base catalyzed Michael addition fol-
lowed by acid catalyzed cyclization.
For comparison, these solid supported reactions were carried out by
conventional heating in oil bath, under similar reaction conditions of tem-
perature. Heating on basic alumina for about 4 h gave the adduct with
60–70% yields and on monomorillonite the required product was obtained
in 5–6 h of heating with only 50% yield.
In conclusion, the experiment clearly showed the versatility of the
inorganic solid supports under microwave irradiation, for preparation of
bioactive compounds, avoiding the noxious reagents originally used.
EXPERIMENTAL SECTION
The microwave reactor is a multimode, domestic oven (Padmini
Essentia, Model Brownie, 2450 MHz). For TLC analysis, silica gel coated
Al plates (Merck) were employed. Melting points were determined by means
of a Thomas-Hoover melting point apparatus and are uncorrected. IR spec-
tra (KBr pellets) were recorded on a Perkin-Elmer spectrophotometer model
1
599. H NMR spectra were recorded on a Perkin-Elmer R-32 (90 MHz)
instrument using TMS as internal standard. Elemental analysis were per-
formed by means of a Heraeus CHN rapid analyser; their results agreed
satisfactorily with the calculated values. The melting point and the spectral
data of the known compounds (3–4a,b,c,e,f) were in close agreement with
those reported.[6]
The approximate bulk temperature (approx. 90–120ꢀC, 750 W) of the
reaction was monitored by inserting the thermometer into the reaction
vessel, immediately after taking out from microwave oven.

INORGANIC SOLID SUPPORTS
2165

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KIDWAI, VENKATARAMANAN, AND DAVE
General Procedure for the Synthesis of Pyrano[2,3-d ]pyrimidines
Method A
Synthesis of Michael adduct: Equimolar (0.01 mole) amount of thio-
barbituric acid (1a–f ) and chalcone (2) dissolved in methanol were taken
in a beaker and adsorbed over the basic alumina (20 g). The reaction
mixture was air dried, kept in an alumina bath and irradiated in the
microwave oven. On completion of reaction as monitored by TLC ex-
amination (after every 30 s), the product was eluted using methanol
(4 ꢁ 5 mL). Removal of the solvent gave the adduct, which was recrystal-
lized using methanol.
Cyclization of the adduct: The Michael adduct dissolved in methanol
was absorbed over acidic alumina (20 g) or montmorillonite (15 g), air dried
and irradiated in an alumina bath. On completion of reaction, the product
was eluted in methanol. Evaporating the solvent gave the required product
which was recrystallized from chloroform : methanol mixture.
Method B
Equimolar (0.01 mole) amount of thiobarbituric acids (1a–f ) and
chalcone (2) in methanol (5 mL), were adsorbed over the montmorillonite
(15 g), and air dried at room temperature. The adsorbed reactants taken in a
beaker were kept in an alumina bath and irradiated in the microwave oven.
On completion of reaction as monitored by TLC examination (after
every 30 s), product was eluted using methanol (4 ꢁ 5 mL). Product obtained
on removal of solvent was recrystallized using chloroform : methanol
mixture.
3a: M.p. 298–300ꢀC (300–301ꢀC).[6] 3b: m.p. 230–232ꢀC
(230–231ꢀC).[6] 3c: m.p. 190–191ꢀC (190–191ꢀC).[6] 3d: m.p. 198–200ꢀC;
1H-NMR (CDCl3, 90 MHz) ꢂ: 3.50 (m, 1H, H-10), 3.85 (s, 6H, 2 ꢁ OCH3),
4.20–4.75 (m, 3H, CH2-20 and H-5), 6.90–8.10 (m, 18H, Ar-H). Anal. Calcd.
for C33H28N2O5S: C, 70.21; H, 4.96; N, 4.96. Found: C, 70.18; H, 4.93; N,
4.94. 3e: m.p. 191–193ꢀC (191–191ꢀC).[6] 3f: m.p. 240–242ꢀC (240–241ꢀC).[6]
4a: M.p. 290–292ꢀC (290–291ꢀC).[6] 4b: m.p. 209–211ꢀC
(210–211ꢀC).[6] 4c: m.p. 221–222ꢀC (220–221ꢀC).[6] 4d: m.p. 230–232ꢀC;
1H-NMR (CDCl3, 90 MHz) ꢂ: 4.10 (s, 6H, 2 ꢁ OCH3), 4.90 (d, J ¼ 5 Hz,
1H, H-5), 6.12 (d, J ¼ 5 Hz, 1H, H-6), 7.10–8.00 (m, 18H, Ar-H). Anal.
Calcd. for C33H26N2O4S: C, 72.53; H, 4.76; N, 5.13. Found: C, 72.50; H,
4.74; N, 5.10. 4e: m.p. 198–200ꢀC (198–199ꢀC).[6] 4f: m.p. 179–181ꢀC
(180–181ꢀC).[6]

INORGANIC SOLID SUPPORTS
ACKNOWLEDGMENT
2167
One of the authors (R.V.) is thankful to the Council of Scientific and
Industrial Research, New Delhi, for financial assistance.
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KIDWAI, VENKATARAMANAN, AND DAVE
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Received in Japan May 1, 2001