Iodine-catalyzed versatile synthesis of 4,6-diarylpyrimidin-2(1H)-ones (DAPMs) via one-pot, multicomponent reaction

Article abstract of DOI:10.1080/00397911.2010.493263

An efficient, solvent-free, one-pot, three-component cyclocondensation reaction between aldehyde, ketone, and urea to give 4,6-diarylpyrimidin-2(1H)- ones (DAPMs) using iodine as catalyst is described. This new protocol provides a simple and environmental

Full text of DOI:10.1080/00397911.2010.493263

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Iodine-Catalyzed Versatile Synthesis of
4,6-Diarylpyrimidin-2(1H)-ones (DAPMs)
via One-Pot, Multicomponent Reaction
M. B. Madhusudana Reddy a & M. A. Pasha a
a Department of Studies in Chemistry, Central College Campus,
Bangalore University, Bengaluru, India
Version of record first published: 02 May 2011
To cite this article: M. B. Madhusudana Reddy & M. A. Pasha (2011): Iodine-Catalyzed Versatile
Synthesis of 4,6-Diarylpyrimidin-2(1H)-ones (DAPMs) via One-Pot, Multicomponent Reaction, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
41:13, 1875-1880
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Synthetic Communications1, 41: 1875–1880, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.493263
IODINE-CATALYZED VERSATILE SYNTHESIS OF
4,6-DIARYLPYRIMIDIN-2(1H)-ONES (DAPMs) VIA
ONE-POT, MULTICOMPONENT REACTION
M. B. Madhusudana Reddy and M. A. Pasha
Department of Studies in Chemistry, Central College Campus,
Bangalore University, Bengaluru, India
GRAPHICAL ABSTRACT
Abstract An efficient, solvent-free, one-pot, three-component cyclocondensation reaction
between aldehyde, ketone, and urea to give 4,6-diarylpyrimidin-2(1H)-ones (DAPMs)
using iodine as catalyst is described. This new protocol provides a simple and environmen-
tally benign route along with the associated advantages of good to excellent yield of the
products (90–96%) and short reaction times (5–15 min) at 80 ꢀC.
Keywords Aldehyde; 4,6-diarylpyrimidin-2(1h)-one; iodine; ketone; solvent-free
reaction; urea
INTRODUCTION
A practical synthesis of pyrimidinone would be very helpful for chemists
because pyrimidinone is found in many bioactive natural products and exhibits a
wide range of biological properties.[1] Some of the pyrimidinones have emerged as
integral backbones of several calcium-channel blockers and antihypertensive, anti-
bacterial, and anti-inflammatory agents.[2] The batzelladine alkaloids containing
3,4-dihydropyrimidine-2(1H)-one (DHPM) isolated from marine sources were found
to inhibit the binding of HIV envelope protein gp-120 to human CD4 cells.[3]
The most common route to DHPMs involves the cyclocondensation of
aromatic aldehydes, acetoacetate, and urea in the presence of HCl as catalyst. This
is one of the most representative Multicomponent reactions (MCRs), which is well
known as the Biginelli reaction.[4]
Received February 9, 2010.
Address correspondence to M. A. Pasha, Department of Studies in Chemistry, Central College
Campus, Bangalore University, Bengaluru 560 001, India. E-mail: m_af_pasha@ymail.com
1875

1876
M. B. M. REDDY AND M. A. PASHA
In the Biginelli reaction, 1,3-diketones are the most commonly employed coun-
terparts, and use of acetophenone derivatives in this type of process is rare. Thus, an
isolated example published by Wang et al. in 2004 remarkably broadened the appli-
cation of Biginelli reaction, wherein a one-pot cyclocondensation of ketones (instead
of 1,3-diketone) with aldehydes and urea is reported to give substituted DHPMs.
The reaction is performed in MeCN medium employing FeCl3 ꢁ 6H2O=TMSCl as
catalyst[5] but requires a long time for completion.
Recently, Heravi et al. reported the synthesis of 4,6-diarylpyrimidin-2(1H)-ones
(DAPMs) using TMSCl and sulfamic acid as a green and reusable catalyst,[6]
Khosropour et al. used Bi(TFA)3 immobilized on [nbpy]FeCl4,[7] and concentrated
HCl in ionic liquid [BMIM][BF4] was used by Cai-hui to promote this reaction.[8] Other
reported methods for the synthesisof DAPMs from urea and 1,3-diphenyl-propenone or
1,3-diphenyl-propynone or 1,3-diphenyl-propane-1,3-dione require NaOEt=Et3N or
cyanourictrichloride=CF3SO3Zn as catalysts.[9–12] These reported methods suffer from
one or more drawbacks suchasuse of stoichiometric amounts of catalysts, use of expens-
ive reagents like TMSCl, and prolonged reaction time.
In recent years, MCRs have become modern synthetic protocols for the
one-pot syntheses of a wide variety of organic molecules,[13] because of ease of
execution, lack of isolation of intermediates, short reaction times, and quantitative
yields of products. In addition, carrying out the reaction in the presence of readily
available and inexpensive catalysts under a solvent-free, resource-effective, and
environmentally acceptable process could be an ideal synthesis.[14]
In continuing effort in our laboratory to develop new methods using molecular
iodine as catalyst for expeditious syntheses of various biologically important
molecules such as N,N0-disubstituted urea=thiourea,[15] azines,[16] b-acetamido-b-
aryl-propiophenones,[17] and aryl-14H-dibenzo[a,j]xanthenes,[18] we are reporting a
solvent-free protocol for the synthesis of 4,6-diarylpyrimidin-2(1H)-ones via cyclo-
condensation of urea and methylketones with various substituted aldehydes using
iodine as catalyst. Excellent yield of 4,6-diarylpyrimidin-2(1H)-ones (up to 96%)
was achieved within 5–15 min.
RESULTS AND DISCUSSION
We started our investigation with acetophenone (1a, R1 ¼ H), anisaldehyde
(2b, R2 ¼ OCH3), and urea (3) as a model substrates to screen the experimental
conditions. Selected results are summarized in Table 1.
First, the reaction was carried out by treating 2 equiv each of acetophenone
(1a) and anisaldehyde (2b) and 3 equiv of urea (3) at reflux in acetonitrile in the pres-
ence of iodine (10 mol%) to get the expected product 4b after 2 h in 65% yield. In an
attempt to improve the yields and owing to the benefits of solvent-free conditions,
the same reaction was performed in the absence of any solvent and in the absence
of catalyst but gave no product at 80 ꢀC even after 30 min. On addition of 10 mol%
of iodine to this mixture, rapidly induced cyclocondensation produced 4b in excellent
yield (80%, Table 1, entry 4) within 10 min. It was observed that the mixture, which
was initially in a partial liquid state, turned into a liquid and suddenly solidified dur-
ing the course of heating to a light yellow solid mass [thin-layer chromatography
(TLC) indicated the complete conversion]. The solid mass was washed with cold

4,6-DIARYLPYRIMIDIN-2(1H)-ONES
1877
Table 1. Optimization of the reaction conditions for the synthesis of 4-(p-methoxyphenyl)-6-
(phenyl)-pyrimidin-2-(1H)-one (4b)a
Entry
Solvent
Iodine (mol%)
Temp (ꢀC)
Time
Yield (%)b
1
2
3
4
5
6
7
CH3CN
10
—
10
5
80
100
100
100
80
2 h
65
15
78
80
96
66
57
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Solvent-free
30 min
10 min
5 min
5 min
5 min
5 min
5
1
80
70
5
ap-Methoxybenzaldehyde (2 mmol), acetophenone (2 mmol), and urea (3 mmol).
bYields are isolated products.
water to remove any unreacted urea, then washed with diethyl ether to remove
unreacted organic substrates or impurities, dried, and recrystallized from ethanol
to get 4-(p-methoxyphenyl)-6-(phenyl)-pyrimidin-2-(1H)-one (4b).
The effect of the reaction temperature on the yield of the products was evalu-
ated (70 ꢀC to 100 ꢀC). The yield of 4b reached a maximum of 96% at 80 ꢀC after
5 min, indicating that ketone reacts rapidly with aldehyde and urea to form diaryl-
pyridinones when the reaction is carried out with 5 mol% of the catalyst. Less than
5 mol% of iodine (1 mol%) led to poorer yields (66%) after longer reaction times, and
more than 2 to 4 mol% could not improve the yield. In view of the current interest in
environmentally benign catalytic processes, a protocol involving a lesser amount of
iodine would be more appreciable.
These results encouraged us to further investigate the formation of DAPMs
from a variety of ketones and aldehydes (Table 2, entries a–j) with urea (Scheme 1,
Table 2. Iodine-catalyzed three-component cyclocondensation of aldehyde and urea with acetophenonea
Entry
Ketone (1, R1)
Aldehyde (2, R2)
Productb
Time (min)
Yield (%)c
a
b
c
d
e
f
H
H
H
4-OCH3
4-CH3
4-Cl
4a
4b
4c
4d
4e
4f
6
5
95
96
90
92
90
91
93
90
92
94
H
10
9
H
H
4-OH
12
8
H
2,4-(OCH3)2
4-Cl
4-Cl
g
h
i
4-NO2
4-OCH3
4-OCH3
4-Cl
4g
4h
4i
15
10
14
8
N,N-(CH3)2
H
j
4j
aReaction condition: A mixture of aldehyde (2 mmol), methylketone (2 mmol), urea (2 mmol), and iod-
ine (5 mol%) was heated at 80 ꢀC until the reactions went to completion [5–15 min, TLC].
bAll the products are known and were characterized by comparison of the physical data with the sam-
ples prepared by the reported methods[6]and by IR spectral analysis: Compound 4b was characterized by
1H NMR and LC–mass spectral analysis.
cYields refer to pure isolated products.

1878
M. B. M. REDDY AND M. A. PASHA
Scheme 1. Cyclocondensation of ketone and aldehyde with urea.
Table 2). In this study, the araldehydes containing both electron-withdrawing and
electron-donating substituents were found to be active toward cyclocondensation as
their reactions were completed in a short time. Methylketones with electron-donating
and araldehydes substituted with electron-withdrawing groups (Table 2, entry h) were
also found to react smoothly to afford excellent yield of the desired products. The
yields of all the products are good to excellent (Table 2).
EXPERIMENTAL
The chemicals used were commercial reagents. Melting points were determined
using a Buchii apparatus. Reactions were monitored on TLC by comparison with the
¨
authentic samples. Nuclear magnetic resonance (NMR) spectra were obtained on a
400 MHz Bruker AMX spectrometer in dimethylsulfoxide (DMSO-d6) using tetra-
methylsilane (TMS) as standard. Liquid chromatography–mass spectrometry
(LC-MS) spectra were obtained using an Agilent Technologies 1200 series instru-
ment. Infrared (IR) spectra were recorded using a Shimadzu Fourier transform
(FT)–IR-8400 s spectrophotometer as KBr pellets for solids.
Typical Experimental Procedure for the Synthesis of 4b
A mixture 4-methoxybenzaldehyde (0.272 g, 2.0 mmol), acetophenone (0.24 g,
2.0 mmol), urea (0.18 g, 3.0 mmol), and iodine (0.1360 g, 5 mol%) was mixed well
and heated on a preheated hot plate for 5 min at 80 ꢀC. (At the end of the reaction,
the liquefied reaction mixture suddenly becomes solid.) Water (5 ml) was added into
the flask, stirred for several minutes, and then filtered through a sintered funnel to
afford the crude product, which was purified by recrystallization from absolute
ethanol to get 4b.
4-(p-Methoxy-phenyl)-6-phenyl-Pyrimidin-2(1H)-one (4b)
Mp 257 ꢀC; IR (KBr) nmax ¼ 3439, 3096, 2930, 1608, 1514, 1458 cmꢂ1; 1H NMR
(DMSO, 400 MHz): dH ¼ 3.9 (s, 3H, CH3), 7.2–8.2 (m, 10H, H-5 and H-Ar) ppm.

4,6-DIARYLPYRIMIDIN-2(1H)-ONES
1879
CONCLUSION
We have developed an efficient, one-pot, three-component cyclocondensation
of an aldehyde, a methylketone, and urea under solvent-free conditions to get
4,6-diarylpyrimidin-2(1H)-ones using iodine as catalyst. This new protocol has
advantages such as (i) use of a small amount (5.0 mol%) of inexpensive, easy-to-
handle, and commercially available catalyst; (ii) short reaction times (10–15 min);
and (iii) excellent yields of the products (90–96%). With increasing environmental
concerns, the present methodology is environmentally friendly and may be useful
for the large-scale production of the products.
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