A novel approach to furopyrimidinones using dry media

Article abstract of DOI:10.1246/bcsj.76.203

An environmentally benign approach to the synthesis of furopyrimidin-4(3H)-one under microwave irradiation (MWI) using an inorganic solid support for catalytic activity as well as an energy-transfer medium is described. The reaction time can be decreased

Full text of DOI:10.1246/bcsj.76.203

c. Jpn.
Bull. Chem. Soc. Jpn., 76, 203–204 (2003)
203
e Chemical
ciety of Ja-
n
Short Articles
e Chemical
ciety of Ja-
n
A Novel Approach to Furopyrimidi-
nones Using Dry Media
M. Kidwai et al.
Mazaahir Kidwai,* Shweta Rastogi, and
R. Venkataramanan
03
3
4
Department of Chemistry, University of Delhi,
Delhi-110007, India
SJA8
09-2673
2736
(Received July 1, 2002)
02
02
An environmentally benign approach to the synthesis of
furopyrimidin-4(3H)-one under microwave irradiation
(MWI) using an inorganic solid support for catalytic activity
as well as an energy-transfer medium is described. The reac-
tion time can be decreased from hours to minutes along with
a yield enhancement. In addition, the differential activity of
various solid supports was studied for a reaction which en-
ables one to accomplish the one-pot synthesis of the required
product via the 2-aminofuran-3-carbonitrile intermediate.
Scheme 1.
2-Amino-4,5-diphenylfuran-3-carbonitrile (3) upon a reac-
tion with different arenecarbonyl and alkanoyl chlorides (4a–f)
under MWI19 in dry media yielded 2-Alkyl/Aryl-5,6-diphenyl-
furo[2,3-d]pyrimidin-4-(3H)-one (5a–f) (Step A2) (Scheme 1).
Conventionally, a similar cyclization of 2-aminofuran-3-carbo-
nitrile with acyl chlorides to the fused pyrimidin-4-ones, as re-
ported byYamazaki et al.,20 is a two-step reaction requiring ab-
solute ethanol and dry HCl. In an attempt to greenify this
methodology, the reaction was tried on different solid supports.
The best result in terms of the yield and reaction time was ob-
tained with montmorillonite K-10 clay under microwaves,
which afforded the required furopyrimidin-4-one in one step
from the 2-aminofuran-3-carbonitrile (Table 1). This result
may be attributed to the ditopic21 nature of montmorillonite.
The reaction on acidic alumina did not go to completion, even
after 15 min of irradiation, indicating that acidic conditions are
not sufficient for the formation of furopyrimidin-4-ones (5a–f).
In the IR spectrum (Table 1), the disappearance of band at
2200 cm−1 due to CWN and the appearance of a band at 1600
cm−1 due to CwN and 1650 cm−1 due to CwO confirmed the
formation of the products (5a–f).
The increasing environmental consciousness throughout the
world has triggered a search for new products and processes
that are compatible with the environment. Strict legal restric-
tions on pollution exposure have enforced the application of
solvent-less conditions into practice. In this endeavor, inor-
ganic solid supports (alumina, bentonite, zeolite, montmorillo-
nite, etc.) have made a landmark, because reactions can be per-
formed in a “dry media” or under “solvent-free conditions.”1–4
The risk of high-pressure development associated with solu-
tion-phase reactions has been circumvented in dry media,5–6
thus allowing work to be conducted with open vessels. In
addition, the use of solid supports7–8 in conjunction with
microwaves9 leads to a higher yield, a remarkable reaction rate
enhancement, and high catalytic activity with the optimum
utilisation of energy. This solvent-less approach provides an
opportunity to conduct selective organic functional-group
transformations more efficiently and expeditiously, thereby
increasing the potential of such reactions to be upscaled.10
The furo[2,3-d]pyrimidine ring system, because of a formal
isoelectronic relationship with purine, is specially of biological
interest.11–13 It has numerous pharmacological and agrochemi-
cal applications viz. herbicides,14 antimalarials,15 antitumour,16
and antihypertensive17 drugs, as well as potential radiation pro-
tection agents.18
The classical Gewald22 method for the synthesis of the inter-
mediate, 2-aminofuran-3-carbonitrile (3), involving the reac-
tion of acyloins with CH- acidic nitriles under alkaline condi-
tions in DMF, is time consuming and gives a relatively low
yield. The synthesis was thus modified23 by using basic alumi-
na/montmorillonite under MWI (Step A1) (Scheme 1), giving
an improved yield with a large reduction of the reaction time.
Montmorillonite gave an 85% yield, but basic alumina gave a
relatively better yield (90%) for a shorter irradiation time. This
is attributed to the requirement of basic conditions for the ab-
straction of a proton by the active methylene group.
Further, the formation of both the precursor, 2-aminofuran-
3-carbonitrile, and the final cyclized product, furopyrimidin-
4(3H)-one, on montmorillonite prompted us to attempt a one-
pot synthesis of the final product from the reactants: benzoin
(1), malononitrile (2) and acyl chloride (4a–f) (Method B)24
(Scheme 1). This one-pot synthesis minimizes the yield loss,
and energy loss, and limits the necessity of hazardous sol-
vents.25
In view of the ecofriendly role of dry media using micro-
waves, the biopotential of furopyrimidines and our ongoing
endeavor towards green synthesis, we herein report a facile,
rapid, and an environmentally benign synthesis of furopyrimi-
din-4-ones. Moreover, we studied the behavior of different
solid supports under microwaves for the synthesis of the inter-
mediate, 2-aminofuran-3-carbonitrile, and a product, furopyri-
midin-4-one, and developed a one-pot synthesis of furopyrimi-
din-4-one.

204 Bull. Chem. Soc. Jpn., 76, No. 1 (2003)
© 2003 The Chemical Society of Japan
Table 1. Physical and Spectroscopic Data of Compounds (5a–f)
Method Aa)
time/yield
(min) (%)
Method Bb)
time/yield
(min) (%)
MP/°C
(Recrystalliza-
tion solvent)
Spectroscopic datac)
Compd
No.
IR (νmax/cm−1
)
1H NMR/δ(CDCl3,
DMSO-d6, 60 MHz)
R
NH CwN CwO
5a
5b
5c
5d
C6H5
CH3
4.5/78
4.0/70
10.0/75
6.5/72
9/82
94–96
(pet. ether)
342–34626
(DMF)
167–170
3385 1602 1663
7.4–7.9 and 8.2–8.0
(m, 16H, 3 × Ph and NH)
1.3 (s, 3H, CH3), 7.3–7.6
(m, 11H, 2 × Ph and NH)
3.8 (s, 2H, CH2), 7.3–8.0
(m, 11H, 2 × Ph and NH)
0.90 (t, 3H, CH3), 2.3–2.8 (m,
10H, CH2), 3.1–3.4 (t, 2H, CH2),
7.2–7.8 (m, 11H, 2 × Ph and NH)
0.88 (t, 3H, CH3), 2.2–2.7 (m,
16H, CH2), 3–3.3 (t, 2H, CH2),
7.5–8.3 (m, 11H, 2 × Ph and NH)
7.5–7.9 and 8.1–8.3 (m, 15H, 2
× Ph, NH and nicotinyl)
8/74
3318 1592 1616
3360 1611 1661
3343 1598 1650
CH2Cl
C7H15
14/80
11/73
(benzene–EtOH)
275–277
(hexane–benzene)
5e
5f
C11H23
8.0/80
7.5/82
12/81
80–83
(hexane)
3279 1591 1611
3393 1600 1654
3-C5H4N
13.0/85
248–250
(benzene–hexane)
a) (Step A2). b) Total time for one pot synthesis (4 + x) min, 4 min is the time required for the synthesis of the intermediate 3 over
montmorillonite. “x” is the additional time required for the synthesis of furopyrimidin-4(3H)-one, 5a–f from intermediate, 3.
c) All the compounds gave satisfactory CHN analysis.
Kimura, A. Kamya, and M. Kataoka, Jpn. Kokai Tokkyo Koho JP
05, 112, 559; Chem. Abstr., 119, 160315 (1993).
13 R. G. Edie, R. E. Hackler, and E. V. Krumkains, Eur Pat.
Appl. Ep. 49; Chem. Abstr., 116, 128957 (1992).
14 M. P. Roer, Eu. Pat., 164268; Chem. Abstr., 105, 242726
(1986).
15 D. S. Sanghavi, D. T. Chaudhari, and P. P. Gudadhe, Bull.
Falkine. Inst., 9, 51 (1981).
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19 Microwave irradiations were carried out in Kenstar micro-
wave oven, Model No. OM9925E (2450 MHz, 800 Watts).
20 Y. Tomioka, Yakihiko, K. Ohkubo, and M. Yamazaki,
Chem. Pharm. Bull., 33, 1360 (1985).
The above-mentioned solid supported reactions (basic alu-
mina/montmorillonite) were performed conventionally in an
oil bath under similar conditions. Heating in an oil bath (main-
tained at ~110–120 °C) for about 4 h gave the intermediate
with 30% and 35% yields on montmorillonite and basic alumi-
na, respectively. The final cyclized product was obtained with-
in 6 hours of heating with a 25% yield.
In conclusion, the proposed methodology provides an easi-
er, practically convenient and environmentally benign one-pot
synthesis of bioactive furopyrimidin-4-one under much milder
reaction conditions. The procedure clearly highlights the ver-
satility of solid supports, especially when coupled with micro-
waves.
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