Dowex-promoted general synthesis of N,N′-disubstituted-4-aryl-3,4-dihydropyrimidinones using a solvent-free Biginelli condensation protocol

Article abstract of DOI:10.1016/j.tetlet.2006.04.061

Dowex-50W ion exchange resin-promoted solvent-free heating of an intimate mixture of an aldehyde, an active methylene compound and N,N′-dimethylurea furnished the title compounds in moderate to good yields.

Full text of DOI:10.1016/j.tetlet.2006.04.061

Tetrahedron Letters 47 (2006) 4205–4207
Dowex-promoted general synthesis of
N,N -disubstituted-4-aryl-3,4-dihydropyrimidinones using
a solvent-free Biginelli condensation protocol
0
*
Kamaljit Singh, Divya Arora and Sukhdeep Singh
Department of Applied Chemical Sciences and Technology, Guru Nanak Dev University, Amritsar 143 005, India
Received 3 March 2006; revised 4 April 2006; accepted 10 April 2006
Abstract—Dowex-50W ion exchange resin-promoted solvent-free heating of an intimate mixture of an aldehyde, an active methyl-
0
ene compound and N,N -dimethylurea furnished the title compounds in moderate to good yields.
Ó 2006 Elsevier Ltd. All rights reserved.
The demand for structure diversification to prepare
compound libraries for screening in drug discovery is
the driving force behind the development of new meth-
odologies and structural motifs. 4-Aryl-3,4-dihydropyri-
midinones (Biginelli compounds, DHPMs) of the type 4
represent a heterocyclic system of remarkable pharma-
fails or provides a multitude of products with the desired
DHPMs only in trace amounts. Solvent-free heating
conditions without catalyst also failed to furnish these
6
compounds. Recently, a high-pressure synthesis has
7
been explored but is confined to only one such DHPM.
0
To date, the direct synthesis of N,N -disubstituted
1
cological profile. In the area of calcium channel modu-
DHPMs remains a challenge for synthetic chemists.
lators, appropriately functionalized DHPMs occupy a
place of prominence and more recently these have
emerged as potent antihypertensive agents, a -adrener-
In this letter, we report a novel and highly efficient meth-
od that allows the rapid synthesis of N,N -disubstituted
0
1
a
1
gic antagonists and mitotic kinesin inhibitors. A num-
DHPMs 4 and does not rely on the use of traditional
complex catalysts or reagents. Instead, our procedure
involves heating a solvent-free mixture of an aldehyde, an
ber of improved variants of the classical Biginelli
2
condensation employing new reagents, catalysts, meth-
3
0
odologies and techniques have been reported. In addi-
active methylene compound, N,N -dimethylurea and
tion, several combinatorial approaches towards
DHPMs have been advanced, using, for example, solid
Dowex-50W ion exchange resin (Scheme 1). Dowex-
50W is used here for the first time in DHPM condensa-
tions, and this catalyst has shown considerable advanta-
ges as it is heterogeneous and can be recovered at the
end of the reaction by simple filtration of the solvent di-
luted residue. Thus, an aldehyde, a b-ketoester and
phase or fluorous phase reaction conditions.4b N,N -
4
a
0
Disubstituted DHPMs are important on account of
0
the fact that N,N -disubstitution enhances lipophilicity
and facilitates chemoenzymatic synthesis of enantiopure
DHPMs in organic solvents. In our programme aimed
5
at the functionalization of DHPMs to synthesize
R3
a-n
‘
drug-like’ molecules, the title compounds were re-
O
R4
R3
quired. To access the title DHPMs, the straightforward
O
O
3
0
R4
X
three component condensation involving N,N -dimeth-
HN
HN
R1
Dowex-50W
R1
N
ylurea, alkyl acetoacetate and a carbonyl substrate often
X
o
130 C
R2
O
R2
N
R5
R5
Keywords: Biginelli compounds; Solvent-free synthesis; Dowex;
DHPMs; Calcium channel modulators.
1
2
4a-p X = O
4q-r X = S
*
Corresponding author. Tel.: +91 183 2258853; PABX: +91 183
258802/09x3508; fax: +91 183 2258819/20; e-mail: kamaljit19in@
0
2
Scheme 1. Dowex-50W catalyzed preparation of N,N -dimethyl-4-
yahoo.co.in
substituted DHPMs.
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.04.061

4206
K. Singh et al. / Tetrahedron Letters 47 (2006) 4205–4207
0
N,N -dimethylurea upon heating, in the presence of a
when the reaction was run at 130 °C for 90 min. An
increase in the reaction temperature and time did not
improve the yields significantly.
0
catalytic amount of Dowex-50W resin, gave N,N -
disubstituted DHPMs. The method also allowed the
8
preparation of N-1 methyl DHPMs, when N-methylurea
is condensed with a b-ketoester and an aldehyde.
To establish the scope and usefulness of this method-
ology, a number of reactions (Table 2) were conducted
and the products isolated. The yields given in Table 2
refer to the purified products from the reactions run
at 20 mmol scale. It was also found that in scaling-up
the reaction the amount of Dowex did not need to be
increased proportionally. Further, apart from the simp-
licity of the procedure, an important feature is the
ability to tolerate functional group variations in all three
building blocks. The aryl aldehyde 2, for example,
can be varied to include many pharmaceutically relevant
In order to be able to carry out such a Biginelli conden-
sation in a more efficient way minimizing the time, tem-
perature and amount of catalyst, a series of reactions
were run using p-nitrobenzaldehyde, ethyl acetoacetate
0
and N,N -dimethylurea in equimolar ratios. The amount
of Dowex resin does not appear to be critical, as we have
run successful experiments with 100–300 mg of Dowex
per mole of the aldehyde. However, for optimum con-
version, the amount of catalyst could be reduced to
1
00 mg for 20 mmol of aldehyde. The results are sum-
substitution patterns (NO , Br, OH) on the aryl ring.
2
marized in Table 1. The best conversion was obtained
Similarly, variation of the b-ketoester as well as the urea
was employed. Replacing substituted urea derivatives
0
with urea/thiourea furnish the corresponding N,N -
9
unsubstituted DHPMs 4o–r in near quantitative yields
Table 1. Dowex-50W catalyzed condensation of p-nitrobenzaldehyde,
ethyl acetoacetate and N,N -dimethylurea under different reaction
conditions
0
(Table 2). In view of the simplicity of the process and
the importance of parallel synthesis, we have carried
out the synthesis of a number of DHPM analogues
4 in a parallel fashion. At least 10 experiments were
run simultaneously by taking appropriate mixtures of
b-ketoesters, aldehydes and urea and Dowex-50W, and
after usual work-up the individual DHPMs were
Entry
Reaction
temperature (°C)
Reaction
time (min)
Conversion
to 4g (%)
a,b,c
1
2
3
4
5
6
7
95
120
130
130
130
130
130
90
90
90
10
30
45
60
38
74
81
30
52
64
66
1
0
obtained. In analogy with microwave aided synthesis,
this solvent-free protocol is applicable to the parallel
synthesis of DHPM libraries.
a
In conclusion, we have described a highly efficient Dow-
ex-50W catalyzed solvent-free method for obtaining a
category of DHPMs for which a general synthetic meth-
odology was not available. The method is environmen-
tally benign, amenable to parallel synthesis and offers
operational advantages, such as clean reaction profiles
and simple experimental/product isolation procedures,
Conversion was deduced from the relative intensity of the aldehydic-
H and C-4H signals of the reactants and products in the H NMR
spectra of crude reaction mixtures.
Aldehyde decomposes at temperatures above 130 °C.
Under traditional Biginelli condensation conditions (solvent, acid),
very little product formation is observed and only in some cases after
prolonged reflux.
1
b
c
Table 2. Scope of the Dowex-50W promoted solvent-free Biginelli condensation
Entry
a,b
Isolated yields (%)
4
Mp (°C)
1
2
3
4
5
R
R
R
R
R
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
a
b
c
d
e
f
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
Ph
OMe
OEt
OEt
OEt
OEt
OEt
OEt
Me
Me
Me
Me
Me
Me
Me
Me
Me
Ph
Me
Me
Me
Me
Me
Me
Me
Me
Ph
3,4,5-(MeO)
4-MeOC
4-BrC
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
54–56
93–95
84–86
65–67
59
48
56
42
62
58
65
38
27
55
50
62
69
63
92
95
90
93
3
C
6
H
2
6
H
4
6
H
4
2-NO
3-NO
4-NO
2
C
C
C
6
H
H
H
4
134–136
125–127
105–107
162–164
85–87
164–165
159–160
140–142
106–107
130–131
210–211
238–239
223–224
205–206
2
2
6
6
4
4
g
h
i
6 4
3-HOC H
4-Me NC H
2
6 4
j
4-NO
4-NO
4-NO
4-NO
3-NO
Ph
2
2
2
2
2
C
C
C
C
C
6
H
6
H
6
H
6
H
6
H
4
4
4
4
4
k
l
m
n
o
p
q
r
H
H
H
H
3-NO
Ph
2
C
C
6
H
H
4
H
H
H
3-NO
2
6
4
H
a
Use of HCl as a catalyst in place of Dowex-50W did not lead to any noticeable improvement in yields.
Yields based on recovered aldehyde (4a–n); 4o–r were compared with authentic samples.
b
9

K. Singh et al. / Tetrahedron Letters 47 (2006) 4205–4207
4207
which make it a useful and attractive strategy for the
preparation of DHPMs of synthetic importance.
3. (a) Kappe, C. O. Tetrahedron 1993, 49, 6937–6963; (b)
Kappe, C. O.; Stadler, A. Org. React. 2004, 63, 1–117.
4
. (a) Wipf, P.; Cunningham, A. Tetrahedron Lett. 1995, 36,
819–7822; (b) Studer, A.; Jeger, P.; Wipf, P.; Curran, D.
P. J. Org. Chem. 1997, 82, 2917–2924.
5. Singh, K.; Singh, S.; Mahajan, A. J. Org. Chem. 2005, 70,
114–6117.
6. Ranu, B. C.; Hajra, A.; Dey, S. S. Org. Process. Res. Dev.
002, 6, 817–818.
7
Acknowledgements
6
We thank CSIR (01(1960)/04/EMR-II) and UGC
2
(
F. No. 31-53/2005, S.R.), New Delhi, for funding.
7
8
. Jenner, G. Tetrahedron Lett. 2004, 45, 6195–6198.
. Typical procedure: A mixture of p-nitrobenzaldehyde
(
3.02 g, 20.0 mmol), ethyl acetoacetate (2.60 g, 20 mmol),
0
Supplementary data
N,N -dimethylurea (1.76 g, 20 mmol) and Dowex-50W
Aldrich Chemical Company) (100 mg) in a glass test tube
(
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
was heated for 3 h at 130 °C, in an oil bath. After cooling
to room temperature, the reaction was dissolved in ethyl
acetate and Dowex-50W was removed by filtration. The
filtrate was concentrated under reduced pressure. Recrys-
tallization from dichloromethane gave pure 4g. For
2
006.04.061.
5
0 mmol reactions, the quantity of Dowex-50W was
References and notes
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spectral and microanalytical data (kindly see Supplemen-
tary data).
1
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. Biginelli, P. Gazz. Chim. Ital. 1893, 23, 360–413.