Cu(ClO4)2.6H2O as an efficient catalyst for the synthesis of 3,4-dihydropyrimidin-2(1H)-ones under solvent-free conditions

Article abstract of DOI:10.1080/00397911.2010.517364

Cu(ClO₄)6H₂O efficiently catalyzes the three-component Biginelli reaction of aldehyde,-dicarbonyl compounds, and urea or thiourea under solvent-free conditions to afford the corresponding 3,4-dihydropyrimidin-2(1H)-ones in excellent

Full text of DOI:10.1080/00397911.2010.517364

Synthetic Communications1, 41: 3071–3077, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.517364
Cu(ClO4)2 ꢀ 6H2O AS AN EFFICIENT CATALYST FOR THE
SYNTHESIS OF 3,4-DIHYDROPYRIMIDIN-2(1H)-
ONES UNDER SOLVENT-FREE CONDITIONS
Min Lei,1 Lei Ma,1 and Lihong Hu1,2
1School of Pharmacy, East China University of Science and Technology,
Shanghai, China
2Shanghai Institute of Materia Medica, Chinese Academy of Sciences,
Shanghai, China
GRAPHICAL ABSTRACT
Abstract Cu(ClO4) ꢀ 6H2O efficiently catalyzes the three-component Biginelli reaction of
aldehyde, b-dicarbonyl compounds, and urea or thiourea under solvent-free conditions to
afford the corresponding 3,4-dihydropyrimidin-2(1H)-ones in excellent yields.
Keywords b-Amino carbonyl compounds; aldehydes; Biginelli reaction; Cu(ClO4) ꢀ 6H2O
INTRODUCTION
Dihydropyrimidinones and their derivatives are an important class of com-
pounds because of their therapeutic and pharmacological properties,[1] such as anti-
bacterial, antiviral, antitumor, and anti-inflammatory activities. In recent years,
many members of this family have served as integral backbones of several calcium
channel blockers, antihypertensive agents, a-1a-antagonists, and neuropeptide
Y(NPY) antagonists.[2] Furthermore, several isolated marine alkaloids[3] with interest-
ing biological activities have also been found to contain the dihydropyrimidinone-5-
carboxylate core. Among these, most notable are the batzelladine alkaloids, which
have been found to be potent HIV gp-120-CD4 inhibitors.[4] Therefore, the synthesis
of this heterocyclic nucleus has gained a great importance in organic synthesis.
The Biginelli reaction is a simple one-pot cyclocondensation of b-dicarbonyl
compounds with aldehydes and urea or thiourea in the presence of a catalytic
Received September 4, 2009.
Address correspondence to Lei Ma, School of Pharmacy, East China University of Science and
Technology, 130 Meilong Road, Shanghai 200237, China. E-mail: malei@ecust.edu.cn or Lihong Hu,
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. E-mail:
simmhulh@mail.shcnc.ac.cn
3071

3072
M. LEI, L. MA, AND L. HU
Scheme 1. Biginelli reaction catalyzed by Cu(ClO4)ꢀ6H2O.
amount of HCl.[1a] However, yields of 3,4-dihydropyrimidin-2(1H)-ones obtained by
the Biginelli reaction are poor in the case of substituted aromatic and aliphatic alde-
hydes.[1a] To improve the yields of the Biginelli reaction, the use of a number of
Lewis acid catalysts, such as BF3 ꢀ OEt2,[5] FeCl3,[6] ZrCl4,[7] BiCl3,[8] LaCl3,[9]
InCl3,[10] Cu(OTf)2,[11] Sc(OTf)2,[12] Bi(OTf)3,[13] CeCl3,[14] and ionic liquid,[15] have
been reported. Additionally, the Biginelli reaction can strongly be accelerated by
various procedures including heteropoly acid,[16] ultrasound irradiation,[17] and
microware irradiation.[18]
Although numerous modified methods have been reported, many of these
methods have drawbacks, such as harsh reaction conditions, poor yields, cumber-
some workup procedures, and long reaction time. Furthermore, many of these
procedures require strongly acidic conditions. With increasing environmental con-
sciousness in chemical research and industry, the challenge for a sustainable environ-
ment calls for clean procedures that avoid using harmful organic solvents or do not
need solvents at all. In this article, we report a mild, efficient, and solvent-free
procedure for the synthesis of 3,4-dihydropyrimidin-2(1H)-ones by the condensation
of b-dicarbonyl compounds with aldehydes and urea or thiourea in the presence of a
catalytic amount of Cu(ClO4)2 ꢀ 6H2O (1 mol%) under stirring at 60 ꢁC in solvent-free
conditions (Scheme 1).
RESULTS AND DISCUSSION
Initially, we have studied the Biginelli one-pot condensation reaction of benzal-
dehyde (2 mmol), ethyl acetoacetate (2 mmol), and urea (3 mmol) using 1 mol%
Cu(ClO4)2 ꢀ 6H2O in EtOH as solvent at 60 ꢁC for 240 min. After completion of
the condensation, thin-layer chromatography monitored by (TLC), the reaction mix-
ture was poured into cold water and stirred for 5 min, and the corresponding product
was obtained by simple filtration in good yield (91%).
To improve the product yield and to optimize the reaction conditions, a series
of reaction conditions using Cu(ClO4)2 ꢀ 6H2O as a catalyst were examined when the
substrates were benzaldehyde, ethyl acetoacetate, and urea. The results are summar-
ized in Table 1. To determine the most appropriate solvent, the reaction was exam-
ined using EtOH, MeOH, MeCN, tetrahydrofuran (THF), dichloromethane
(DCM), and H2O. EtOH and MeCN were effective. We also found that the Biginelli
reaction could be carried out under solvent-free condition in excellent yield (93%).
We subsequently changed the amount of Cu(ClO4)2 ꢀ 6H2O from 0 mol% to 5 mol%
under solvent-free conditions, and 1 mol% performed significantly better (93% yield).
The results indicated that 1 mol% of Cu(ClO4)2 ꢀ 6H2O is sufficient, and excessive
amounts of catalyst do not increase the yields significantly.

3,4-DIHYDROPYRIMIDIN-2(1H)-ONES
3073
Table 1. Cu(ClO4)2 ꢀ 6H2O-catalyzed condensation of benzaldehyde, ethyl acetoacetate, and ureaa
Entry
Catalyst (mol%)
Solvent
Time (min)
Yield of 4a (%)b
1
2
1
1
EtOH
MeOH
MeCN
THF
240
240
240
240
240
360
240
40
91
88
91
84
85
20
0
3
1
4
1
5
1
DCM
H2O
6
1
7
0
None
None
None
None
None
8
0.5
1
80
93
93
94
9
30
20
10
11
3
5
20
aThe reactions were carried out in the presence of benzaldehyde (2 mmol), ethyl acetoacetate (2 mmol),
and urea (3 mmol) at 60 ꢁC.
bIsolated yield after recrystallization.
We selected the optimized reaction conditions to examine the application of
the catalyst. A series of aldehydes were selected to undergo the condensation in
the presence of a catalytic amount of Cu(ClO4)2 ꢀ 6H2O (1 mol%) at 60 ꢁC under
solvent-free conditions (Table 2). We found that this one-step procedure worked well
Table 2. Cu(ClO4)2 ꢀ 6H2O-catalyzed dihydropyrimidinones under solvent-free conditionsa
Time
(min)
Yield of
4 (%)b
Mp (ꢁC)
found
Mp (ꢁC)
reported
Entry
R1
R2
X
4a
4b
4c
4d
4e
4f
C6H5
Et
Et
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
S
30
30
93
93
95
90
88
87
91
83
92
88
86
90
95
93
93
87
89
84
86
85
86
205–208
204–205
199–201
254–256
237–239
233–234
252–254
208–210
233–234
180–182
155–157
196–198
214–216
200–202
194–195
222–224
271–274
205–207
212–214
153–155
207–209
206–208[12]
205–206[12]
200–201[11]
253–254[12]
237–238[12]
230–232[12]
251–253[19]
208–210[12]
231–232[18c]
179–181[20]
154–157[21]
195–196[22]
212–213[12]
200–203[23]
190–192[21]
226–228[21]
273–275[12]
207–208[12]
214–215[12]
150–152[20]
206–207[12]
4-CH3C6H4
4-CH3OC6H4
4-(CH3)2NC6H4
4-OHC6H4
3-NO2C6H4
2,4-Cl2C6H3
2-Furyl
Et
Et
30
60
Et
Et
30
40
4g
4h
4i
Et
Et
60
45
=
PhCH CH
Et
Et
30
60
4j
CH3CH2
CH3CH2CH2
(CH3)2CH
C6H5
4k
4l
Et
Et
20
10
4m
4n
4o
4p
4q
4r
4s
4t
Me
Me
Me
Me
Me
Et
30
40
4-CH3C6H4
4-CH3OC6H4
4-OHC6H4
3-NO2C6H4
C6H5
40
30
30
120
120
120
120
4-CH3C6H4
4-CH3OC6H4
3-NO2C6H4
Et
Et
S
S
4u
Et
S
aThe reactions were carried out in the presence of aldehyde (2 mmol), b-diketoeaster (2 mmol), and urea
or thiourea (3 mmol) at 60 ꢁC.
bIsolated yield after recrystallization.

3074
M. LEI, L. MA, AND L. HU
Scheme 2. A possible mechanism for Biginelli reaction catalyzed by Cu(ClO4)ꢀ6H2O.
for a variety of aldehydes. The results are shown in Table 2. Both aromatic and ali-
phatic aldehydes could react efficiently to give the corresponding 3,4-dihydropyrimi-
din-2(1H)-ones in good yields. Aromatic aldehydes carrying either electron-donating
or electron-withdrawing substituents afforded good yields. Similarly, the a,b-unsatu-
rated aldehyde also gave the product (entry 4i) in 92% yield. Furthermore, the use-
fulness of this methodology has also been extended successfully with thiourea in a
similar manner to provide the corresponding 3,4-dihydropyrimidin-2(1H)-thiones
in good yields.
We propose a mechanism of the Cu(II)-catalyzed reaction as shown in Scheme 2.
The aldehyde reacts with urea to form an acyl imine intermediate 5, which is activated
by Cu(II). Subsequent addition of the b-dicarbonyl compound, followed by cycliza-
tion and dehydration, afforded the dihydropyrimidin-2(1H)-ones 4.[9,11,12]
In conclusion, we have described a simple, efficient, and practical method for
the synthesis of 3,4-dihydropyrimidin-2(1H)-ones by using Cu(ClO4)2 ꢀ 6H2O under
solvent-free conditions. A simple workup procedure, mild reaction conditions, short
reaction times, environmentally friendly procedure, and very good yields make our
methodology a valid contribution to the existing processes in the field of
dihydropyrimidin-2(1H)-one derivative synthesis.
EXPERIMENTAL
All reagents were commercially available and used without further purification.
The melting points were recorded on Digital melting-point apparatus WRS-1B and
1
are uncorrected. H NMR spectra were recorded on Bruker WP-500SY (500 MHz)
instrument using tetramethylsilane (TMS) as an internal standard.
General Procedure for the Preparation of 3,4-Dihydropyrimidiones 4
A mixture of aldehyde (2 mmol), b-dicarbonyl compound (2 mmol), urea or
thiourea (3 mmol), and Cu(ClO4)2 ꢀ 6H2O (0.02 mmol, 1 mol%) was heated at 60 ꢁC

3,4-DIHYDROPYRIMIDIN-2(1H)-ONES
3075
under stirring for the appropriate time (Table 2). After completion of the reaction as
indicated by TLC, the reaction mixture was poured into cold water and stirred for
5 min. The solid was filtered, and recrystallized from EtOH or i-PrOH to afford
the pure product.
Selected 1H NMR Data
Compound 4a. 1H NMR (500 MHz, CDCl3) 7.74 (s, 1H, NH), 7.25–7.35
(m, 5H, ArH), 5.58 (s, 1H, NH), 5.41 [s, 1H, CH), 4.07–4.08 (m, 2H, CH2], 2.35
(s, 3H, CH3), 1.16 (t, 3H, J ¼ 6.98 Hz, CH3).
Compound 4c. 1H NMR (500 MHz, CDCl3) 7.63 (s, 1H, NH), 7.25 (d,
2H, J ¼ 8.65 Hz, ArH), 6.84 (d, 2H, J ¼ 8.65 Hz, ArH), 5.52 (s, 1H, NH), 5.35 (s,
1H, CH), 4.05–4.10 (m, 2H, CH2), 3.79 (s, 3H, CH3O), 2.34 (s, 3H, CH3), 1.16 (t,
3H, J ¼ 7.11 Hz, CH3).
Compound 4d. 1H NMR (500 MHz, CDCl3) 7.63 (s, 1H, NH), 7.18 (d, 2H,
J ¼ 8.67 Hz, ArH), 6.65 (d, 2H, J ¼ 8.67 Hz, ArH), 5.45 (s, 1H, NH), 5.31 (s, 1H,
CH), 4.07 (q, 2H, J ¼ 7.12 Hz, CH2), 2.92 [s, 6H, N(CH3)2], 2.33 (s, 3H, CH3),
1.19 (t, 3H, J ¼ 7.12 Hz, CH3).
ACKNOWLEDGMENTS
This work was supported by the Chinese National Science and Technology
Major Project ‘‘Key New Drug Creation and Manufacturing Program’’ (Grants
2009ZX09301-001 and 2009000ZX09102), the Chinese National High-Tech R&D
Program (Grant 2007AA02Z147), the National Natural Science Foundation of
China (Grants 90713046, 30772638, and 30925040), and the CAS Foundation
(Grant KSCX2-YW-R-179).
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