Cu(OTf)2: A reusable catalyst for high-yield synthesis of 3,4-dihydropyrimidin-2(1H)-ones

Article abstract of DOI:10.1016/S0040-4039(03)00619-1

Copper(II) triflate catalyzes efficiently the three-component condensation reaction of an aldehyde, β-ketoester and urea in acetonitrile to afford the corresponding 3,4-dihydropyrimidin-2(1H)-ones in high yields. The catalyst exhibited remarkable reusable activity.

Full text of DOI:10.1016/S0040-4039(03)00619-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 3305–3308
Cu(OTf)2: a reusable catalyst for high-yield synthesis of
3,4-dihydropyrimidin-2(1H)-ones
A. S. Paraskar, G. K. Dewkar and A. Sudalai*
Process Development Division, National Chemical Laboratory, Pashan Road, Pune 411008, India
Received 4 February 2003; revised 21 February 2003; accepted 28 February 2003
Abstract—Copper(II) triflate catalyzes efficiently the three-component condensation reaction of an aldehyde, b-ketoester and urea
in acetonitrile to afford the corresponding 3,4-dihydropyrimidin-2(1H)-ones in high yields. The catalyst exhibited remarkable
reusable activity. © 2003 Elsevier Science Ltd. All rights reserved.
Biginelli reactions are simple one-pot but low-yielding
condensations of b-dicarbonyl compounds with alde-
hydes and urea or thiourea in the presence of catalytic
amount of acid to produce 3,4-dihydropyrimidin-2-
(1H)-ones.1 In recent years, interest in this reaction
has increased rapidly and several modified procedures
aimed at improving the efficiency of the Biginelli dihy-
dropyrimidine synthesis have been reported. For
example, modifications and improvements using Lewis
acids such as BF3·OEt2, FeCl3, LaCl3, La(OTf)3,
Yb(OTf)3, InX3 (X=Cl, Br), ZrCl4, BiCl3, Mn(OAc)3,
LiClO4, clays, etc have been reported.2 However, some
of these procedures involve difficulties such as the use
of stoichiometric amounts of catalysts, high tempera-
tures, the use of metal halides as catalysts, the separa-
tion of the product from the catalyst, etc. Moreover,
the recovery and reuse of catalysts in any such process
offers advantages in terms of a clean and environmen-
tally benign process. We wish to report here a simple
but effective procedure for Biginelli’s three-component
cyclocondensation producing high yields of 3,4-dihy-
The results of optimization experiments for the three-
component Biginelli condensation involving benzalde-
hyde, urea and ethyl acetoacetate with copper salts as
catalysts are presented in Table 1. It is remarkable to
note that the condensation proceeded with a low cata-
lyst concentration [0.5 mol% of Cu(OTf)2] at ambient
conditions and gave 3,4-dihydropyrimidin-2(1H)-one
2a in high yields. Solvents such as CH3CN, THF and
EtOH proved to be effective. After the reaction was
complete as monitored by TLC, the product 2a was
isolated by simple filtration. When the filtered solution
containing the Cu(OTf)2 was further treated with the
reactants, only a slight decrease in the yield (from 95
to 80% after the fifth time) of the 3,4-dihydropyrim-
idin-2(1H)-one 2a was observed (Table 1). In another
experiment, when the filtered solution containing the
catalyst was used after 6 months of storage, it was
observed that the catalyst was quite active (no appre-
ciable change in the yield of the product), demonstrat-
ing that Cu(OTf)2 is stable and does not undergo any
deterioration. This study demonstrates that Cu(OTf)2
can be effectively used as a reusable catalyst for
Biginelli-type condensations. Also the reaction can be
3
dropyrimidin-2(1H)-ones 2 by employing Cu(OTf)2 as
a reusable catalyst (Scheme 1).
Scheme 1. Reagents and conditions: (i) Cu(OTf)2 (0.5 mol), CH3CN, 25°C, 12 h.
Keywords: aldehydes; Biginelli reactions; catalysts; 3,4-dihydropyrimidin-2(1H)-ones; copper and compounds.
* Corresponding author. Fax: +91-20-5893359; e-mail: sudalai@dalton.ncl.res.in
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00619-1

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A. S. Paraskar et al. / Tetrahedron Letters 44 (2003) 3305–3308
Table 1. Cu-catalyzed condensation of benzaldehyde, ethyl acetoacetate and ureaa
No.
Catalyst
Catalyst (mol%)
Solvent
Yield of 2a (%)b
TONc
1
2
None
–
0.5
1
1
1
1
1
5
10
5
CH3CN
CH3CN
–
CH3CN
THF
00
85
90
–
170
90
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
CuCl
95, 90, 88, 85, 80d
95, 90, 88, 85, 80
62
83
05
95
94
20
30
05
00
62
83
05
19
9.4
04
06
01
00
EtOH
H2O
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
3
4
5
6
CuCN
Cu(OAc)2·H2O
CuSO4·5H2O
5
5
5
a Reaction conditions:4 benzaldehyde (2 mmol), urea (2 mmol), ethyl acetoacetate (2 mmol), 25°C.
b Isolated yield after recrystallization.
c TON=turn-over number (defined as: mmol of product/mmol of catalyst).
d Catalyst was reused at least five times.
In order to gauge the scope of these conditions, several
aromatic and aliphatic aldehydes were examined under
the optimized conditions using 1 mol% of Cu(OTf)2.
conducted under ‘solvent free’ conditions. Among the
copper salts screened, Cu(OTf)2 showed excellent activ-
ity in terms of yield in producing the required product.
Table 2. Cu(OTf)2-catalyzed synthesis of 3,4-dihydropyrimidin-2(1H)-onesa
No.
R
Temp. (°C)
Time (h)
Product 2a–x
Mp (°C)
TONc
Yieldb (%)
a
b
c
d
e
Ph
2-Cl-C6H4
3-Cl-C6H4
4-Cl-C6H4
4-OMe-C6H4
2-OH-C6H4
4-OH-C6H4
3-O2N-C6H4
4-NO2-C6H4
25
50
60
50
40
50
40
60
50
70
60
50
50
50
50
50
50
70
70
60
50
70
70
70
6
9
9
4
5
6
5
9
6
12
9
6
6
6
6
6
6
9
95
70
80
85
90
80
90
75
80
60
65
85
85
85
85
85
80
65
80
70
85
70
60
60
200–202
216–218
190–193
212–213
200–201
200–202
199–200
226–225
207–209
219–222
230–232
204–205
185–187
175–177
180–182
188–189
185–188
240–243
195–196
218–219
246–248
203–205
236–237
122–124
95
70
80
85
90
80
90
75
80
60
65
85
85
85
85
85
80
65
80
70
85
70
60
60
f
g
h
i
j
k
l
m
n
o5
p
q5
r
s
t
u
v
w
x
4-NC-C6H4
4-Me2N-C6H4
3-OMe-4-OH-C6H3
3-OH-4-OMe-C6H3
3,4-(OMe)2-C6H3
3,4,5-(OMe)3-C6H2
3,4-(O-CH2-O)-C6H3
3-(Cyclopentyloxy)-4-OMe-C6H3
2-OH-4-Cl-C6H3
2-OH-4-Br-C6H3
3-NO2-4-Me-C6H3
1-Naphthyl
9
9
6
6
12
12
2-Furyl
c-C6H11
n-C9H19
a Reaction conditions:4 aldehyde (2 mmol), urea (2 mmol), ethyl acetoacetate (2 mmol), Cu(OTf)2 (1 mol%), 25°C.
b Isolated yield after recrystallization.
c TON=turn over number (defined as: mmol of product/mmol of catalyst).

A. S. Paraskar et al. / Tetrahedron Letters 44 (2003) 3305–3308
3307
Scheme 2. Cu2+-activation in three-component coupling for Biginelli reaction.
The results are shown in Table 2. In all cases studied,
the three-component reaction proceeded smoothly to
give the corresponding 3,4-dihydropyrimidin-2(1H)-
ones in high yields. Most importantly, aromatic alde-
R.; Reddy, V. V. N. Tetrahedron Lett. 2002, 43, 2657–
2659; (h) Ramalinga, K.; Vijayalaxmi, P.; Kaimal, T. N.
B. Synlett 2001, 863; (i) Kumar, A. K.; Kasthuraiah, M.;
Reddy, S. C.; Reddy, C. D. Tetrahedron Lett. 2001, 42,
7873–7875; (j) Yadav, J. S.; Reddy, B. V. S.; Srinivas, R.;
Venugopal, C.; Ramalingam, T. Synthesis 2001, 1341–
1345; (k) Bigi, F.; Carloni, S.; Frullanti, B.; Maggi, R.;
Sartori, G. Tetrahedron Lett. 1999, 40, 3465–3468; (l)
Kappe, C. O.; Falsone, S. F. Synlett 1998, 718–720; (m)
Peng, J.; Deng, Y. Tetrahedron Lett. 2001, 42, 5917–5919;
(n) Kidwai, M.; Saxena, S.; Mohan, R.; Venkataramanan,
R. J. Chem. Soc., Perkin Trans. 1 2002, 1845–1846; (o)
Xia, M.; Wang, Y. Tetrahedron Lett. 2002, 43, 7703–7705.
3. Sibi, M. P.; Cook, G. R. In Lewis Acids in Organic
Synthesis; Yamamoto, H., Ed.; Wiley-VCH, New York,
2000; Chapter 12, pp. 543–574.
hydes
carrying
either
electron-donating
or
electron-withdrawing substituents including hydroxy
groups reacted efficiently giving excellent yields. It was
established that the mechanism of this reaction
involves, at first, the formation of activated acylimine 3
so that addition of enolate 4 is facilitated to afford
intermediate 5 which then undergoes facile condensa-
tion to give 3,4-dihydropyrimidin-2(1H)-ones
2
(Scheme 2) [the formation of 3 and 5 was confirmed in
1
our studies by in situ H and 13C NMR experiments in
CD3OD at 25°C].
In conclusion, we describe a simple modification of the
Biginelli 3,4-dihydropyrimidin-2(1H)-one synthesis
using Cu(OTf)2 as a reusable catalyst. Excellent yields,
recycling of the catalyst with negligible loss of activity,
and the application to a variety of substituted/function-
alized aryl aldehydes are some of the salient features of
this reaction. It is noteworthy that many 3,4-dihydro-
pyrimidin-2(1H)-ones 2 and their derivatives are medic-
inally important as calcium channel blockers, antihy-
pertensive agents, a-1a-antagonists and anti-HIV
agents.6
4. General experimental procedure: A 25 ml RB flask was
charged with aldehyde 1a–x (2 mmol), urea (0.120 g, 2
mmol), ethyl acetoacetate (0.260 g, 2 mmol), Cu(OTf)2 ( 7
mg, 1 mol%) and acetonitrile (5 ml). The resulting reaction
mixture was stirred at given temperature in (see Table 2).
After the reaction was complete (monitored by TLC), the
reaction mixture was cooled to room temperature and
filtered through a sintered funnel. The crude product was
further purified by recrystallization (EtOH or iPrOH) to
afford pure 3,4-dihydropyrimidin-2(1H)-ones 2a–x.
5. All the compounds listed in Table 2 were thoroughly
1
characterized by H NMR, FT-IR and MS spectroscopy.
Spectral data for selected new compounds:
Acknowledgements
5-Ethoxycarbonyl-4-(3,4,5-trimethoxyphenyl)-6-methyl-
3,4-dihydropyrimidin-2(1H)-one (2o): mp 180–182°C
(recrystallized from EtOH); IR (THF) 3227, 3102, 2925,
A.S.P. and G.K.D. thank the CSIR, New Delhi, for the
award of Senior Research Fellowship (SRF). The
authors also thank Dr. S. Devotta, Head, Process
Development Division, for his constant encouragement.
2840, 1705, 1646, 1610, 1581, 1512 cm−1 1H NMR (200
;
MHz, DMSO-d6): l 1.13 (t, J=7.0 Hz, 3H), 2.25 (s, 3H),
3.72 (s, 9H), 4.02 (q, J=6.66 Hz, 2H), 5.13 (s, 1H), 6.53 (s,
2H), 7.75 (s, 1H), 9.23 (s, 1H); 13C NMR (200 MHz,
DMSO-d6): l 14.26, 17.87, 54.11, 56.09, 59.40, 60.17,
99.54, 104.03, 140.60, 148.54, 152.55, 152.99, 165.63; MS
m/z (% rel. int.): 350 (M+, 68), 335 (9), 321 (50), 304 (23),
277 (41), 261 (22), 238 (69), 222 (22), 195 (100), 183 (72),
168(23), 155 (45), 137 (75), 125 (52), 110 (40), 77 (32), 66
(41). Anal. calcd for C17H22N2O6: C, 58.27; H, 6.32; N,
7.99. Found: C, 58.32; H, 6.22; N, 8.01%.
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3308
A. S. Paraskar et al. / Tetrahedron Letters 44 (2003) 3305–3308
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