Facile aromatization of 3,4-dihydropyrimidin-2(1H)-ones (DHPMs) by iodine

Article abstract of DOI:10.1016/j.cclet.2012.10.015

A facile aromatization of 3,4-dihydropyrimidin-2(1H)-ones using iodine in dimethyl sulfoxide under microwave irradiation was carried out which is more efficient and gives high yield in less time; presently it is the most important catalyst for dehydrogena

Full text of DOI:10.1016/j.cclet.2012.10.015

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Chinese Chemical Letters 23 (2012) 1339–1342
www.elsevier.com/locate/cclet
Facile aromatization of 3,4-dihydropyrimidin-2(1H)-ones (DHPMs)
by iodine
a
b
Manisha M. Kodape a, , Anand S. Aswar , Nandkishor D. Gawhale ,
*
Vivek T. Humne c, Bilal Ahmad Mir a
a Department of Chemistry, SGB Amravati University, Amravati 444602, MS, India
b Department of Chemistry, B.P. Science College, Digras 444520, MS, India
c Department of Chemistry, University of Pune, Pune 411007, MS, India
Received 16 July 2012
Available online 1 December 2012
Abstract
A facile aromatization of 3,4-dihydropyrimidin-2(1H)-ones using iodine in dimethyl sulfoxide under microwave irradiation was
carried out which is more efficient and gives high yield in less time; presently it is the most important catalyst for dehydrogenation.
# 2012 Manisha M. Kodape. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Dihydropyrimidiones; Iodine; Oxidation; Aromatization
The one-pot three-component Biginelli reaction has been known for more than a century [1], these nonplanar
heterocyclic compounds have received considerable attention from the pharmaceutical industry because of their
interesting multifaceted pharmacological profiles. These 1,4-dihydropyridines (DHPs) are a class of compounds of
NADH coenzyme [2], which have been extensively studied in view of the biological importance of these compounds to
the NADH redox process [3]. These compounds have therapeutic functions for treatment of a variety of diseases [4],
such as cardiovascular disorders [4a], cancer [4b] and AIDS [4c]. The oxidation of DHPs to the corresponding pyridine
derivatives constitutes the principal metabolic route in biological systems, as well as a facile access to the
corresponding pyridine derivatives, which show antihypoxic and antiischemic activities [5], from the easily available
DHPs [6]. Therefore, oxidative aromatization of DHPs has attracted continuing interests of organic and medicinal
chemists and a plethora of protocols has been developed [7].
Until now the aromatization can be carried out by different ways such as HNO3, KMnO4 and CAN, PhI(OAc)2 and
t-BuOOH. Recently, attention has been paid to more efficient and environmentally benign methods, such as
electrochemical oxidation [8] and catalytic aerobic oxidation using RuCl3 [9], Pd/C [10], activated carbon [11,12] or
Fe(ClO4)3 [13] as the catalyst. By going through the literature, we made our way to the iodine catalyzed aromatization
in microwave, as it is easy, efficient and 5–7 min reaction time. Moreover molecular iodine has environmentally
benign characteristics [14]; it is inexpensive, non-toxic, insensitive to air and moisture and can be easily removed from
* Corresponding author.
E-mail address: mmkodape@gmail.com (M.M. Kodape).
1001-8417/$ – see front matter # 2012 Manisha M. Kodape. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
http://dx.doi.org/10.1016/j.cclet.2012.10.015

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M.M. Kodape et al. / Chinese Chemical Letters 23 (2012) 1339–1342
the reaction mixture. We have exposed the aromatization of 3,4-dihydropyrimidin-2(1H)-ones by iodine in DMSO
under microwave irradiation.
1. Experimental
The acid-catalyzed cyclo condensation reaction of benzaldehyde (1 mol), ethyl acetoacetate (1 mol) and urea
(1 mol) was carried out by refluxing with a catalytic amount of HCl on water bath for 1 h. The completion of reaction
was monitored by TLC (ethylacetate:hexane = 60:40). The reaction mixture was poured into crushed ice. The
separated solid product was filtered and dried.
Compound (1a): White color; IR (KBr, cmÀ1): 3649.44, 2977.23, 1897.54, 1602.90, 1222.43, 1H NMR (400 MHz,
DMSO-d6): d 8.1 (S, 1H), 5.7 (S, 1H), 5.2 (S, 1H), 7.2 (m, 5H) 4.1 (q, 2H), 1.2 (t, 3H), 2.3 (S, 3H).
3,4-Dihydropyrimidin-2(1H)-ones and iodine (1:1 mol) were taken in DMSO, and irradiated in microwave reactor
at 120 8C for 5 min. The completion of reaction was monitored by TLC (ethylacetate:hexane = 50:50). The brown-red
colored reaction mixture was poured into saturated solution of sodium thiosulfate. The separated solid product was
filtered, dried and recrystallized from methanol.
Compound (3a): Brown color; IR (KBr, cmÀ1): 3587.72, 3162.40, 1539.73, 1696.93, 1122.67, 1H NMR (400 MHz,
DMSO-d6): d 8.5 (S, 1H, exchangeable with D2O), 7.2–7.9 (m, 5H), 4.3 (q, 2H), 1.4 (t, 3H), 2.1 (S, 3H).
2. Result and discussion
The original Biginelli protocol for the preparation of the DHMPs (1a–e, 2a–e) was followed; i.e. the acid-catalyzed
cyclo condensation reaction of benzaldehyde, ethyl acetoacetate and urea in presence of catalytic amount of HCl
which is depicted in Table 1.
Oxidants such as PCC, KMnO4/clay, DDQ, Chloranil, CAN and NaNO2 are inefficient for the conversion of
DHPMs to pyrimidines [15]. There is a report in the literature which describes that the oxidizing properties of iodine.
Therefore, we decided to use iodine reagents. A clean and efficient oxidative dehydrogenation of 3,4-
dihydropyrimidin-2(1H)-ones to 1,2-dihydropyrimidines has been achieved using iodine and DMSO (see Scheme 1).
Table 1
Synthesis of 3,4-dihydropyrimidin-2(1H)-ones.
Entry
Product
R
X
Time (min)
Yield %
m.p. (8C)
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
1a
1b
1c
1d
1e
2a
2b
2c
2d
2e
H
O
O
O
O
O
S
45
60
65
50
85
50
65
65
50
80
90
80
72
86
67
70
71
74
69
62
217–221
212–215
225–227
238–240
249–251
258–261
261–263
260–263
252–254
272–275
4-O-CH3
2,5-O-CH3
4-OH
4-Cl
H
4-O-CH3
2,5-O-CH3
4-OH
S
S
S
4-Cl
S
R
R
O
O
O
N
(a)
O
NH
I2
N
H
X
N
H
X
(3a-e, 4a-e)
(1a-e, 2a-e)
Scheme 1. Reagent and condition: (a) I2 (1:1), DMSO, MW, 120 8C.

M.M. Kodape et al. / Chinese Chemical Letters 23 (2012) 1339–1342
1341
Table 2
Aromatization of various 3,4-dihydropyrimidin-2(1H)-ones.
Entry
Product
R
X
Time (min)
Yield %
m.p. (8C)
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
3a
3b
3c
3d
3e
4a
4b
4c
4d
4e
H
O
O
O
O
O
S
5
5
6
5
7
5
5
6
6
7
94
76
82
90
68
80
67
84
76
69
215–217
228–230
191–193
235–237
254–256
239–241
220–223
247–251
256–259
269–271
4-O-CH3
2,5-O-CH3
4-OH
4-Cl
H
4-O-CH3
2,5-O-CH3
4-OH
S
S
S
4-Cl
S
H
+
HI
I
Me2SO
I2
Me2SO
O
Ar
O
Ar
O
Ar
N
H
N
I
I
-HI
EtO
EtO
NH
EtO
N
H
X
N
H
X
-H
N
H
X
Scheme 2. The propose mechanism of the reaction.
Oxidations of several DHPMs with aryl and alkyl substituents at C-4 were carried out. All the reactions were
completed in between 5 and 7 min; high yields of the products were obtained. The structures of all the products were
established from IR, NMR, and mass spectral analysis. Mild reaction conditions, short reaction times, and easy
isolation of the desired product make the present method convenient. The results are summarized in Table 2.
The proposed mechanism (Scheme 2) for the reaction shows the formation of iodonium ion [16] which will catalyze
the reaction at 120 8C. The color of the reaction persist till end indicates the regeneration of iodine. The reaction was
quenched in dilute HCl.
Acknowledgments
M.M.K. thanks to CIF, SGBAU, Amravati for IR facility and (SAIF) Panjab University, Chandigarh 160 014 for
providing NMR.
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