Efficient, green, solvent-free synthesis of 3,4-dihydropyrimidin-2(1H)-ones via biginelli reaction catalyzed by Cu(NO3)2?3H 2O

Article abstract of DOI:10.1080/00397910903043009

The synthesis of 3,4-dihydropyrimidin-2-(1H)-ones derivatives via a three-component Biginelli reaction using copper nitrate as a catalyst under solventless conditions is reported, providing a green, rapid, efficient, and convenient method for the preparat

Full text of DOI:10.1080/00397910903043009

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Efficient, Green, Solvent-Free Synthesis
of 3,4-Dihydropyrimidin-2(1H)-ones
via Biginelli Reaction Catalyzed by
Cu(NO3)2·3H2O
Dong-Chao Wang a , Hai-Ming Guo a & Gui-Rong Qu a
a College of Chemistry and Environmental Science, Henan Normal
University, Xinxiang, Henan, China
Version of record first published: 12 Mar 2010.
To cite this article: Dong-Chao Wang , Hai-Ming Guo & Gui-Rong Qu (2010): Efficient, Green, Solvent-
Free Synthesis of 3,4-Dihydropyrimidin-2(1H)-ones via Biginelli Reaction Catalyzed by Cu(NO3)2·3H2O,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 40:8, 1115-1122
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Synthetic Communications1, 40: 1115–1122, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903043009
EFFICIENT, GREEN, SOLVENT-FREE SYNTHESIS OF
3,4-DIHYDROPYRIMIDIN-2(1H)-ONES VIA BIGINELLI
REACTION CATALYZED BY Cu(NO3)2 ꢀ 3H2O
Dong-Chao Wang, Hai-Ming Guo, and Gui-Rong Qu
College of Chemistry and Environmental Science, Henan Normal University,
Xinxiang, Henan, China
The synthesis of 3,4-dihydropyrimidin-2-(1H)-ones derivatives via a three-component
Biginelli reaction using copper nitrate as a catalyst under solventless conditions is reported,
providing a green, rapid, efficient, and convenient method for the preparation of Biginelli
compounds in good yields.
Keywords: Biginelli reaction; copper nitrate; 3,4-dihydropyrimidin-2(1H)-ones
INTRODUCTION
3,4-Dihydropyrimidin-2-(1H)-ones (DHPMs) have attracted considerable
interest in recent years because of their important pharmacological properties and
use as calcium channel blockers (1),[1a] antihypertensive agents (2),[1a] a1a-
antagonists,[1b] mitotic kinesin Eg5 inhibitors (3),[1c] melanin concentrating hormone
receptor antagonists (4),[1d] and neuropeptide antagonists (Fig. 1). Moreover, some
alkaloids containing the dihydropyrimidine core unit, isolated from marine sources,
also show interesting biological properties. Most noteworthy among these are the
batzelladine alkaloids (5) (Fig. 1), known to be potent HIV gp-120-CD4 inhibitors.[2]
The Biginelli reaction,[3] one of the most useful multicomponent reactions, is a
one-pot cyclocondensation reaction of b-ketone ester with aldehydes and urea in the
presence of acid, and it provides the most simple and straightforward route to
DHPMs. One major drawback of this Biginelli reaction is the poor to moderate
yields (20–50%). Recently, because of the simplicity of the synthesis of DHPMs,
the Biginelli reaction has received renewed interest. To enhance the efficiency of
the Biginelli reaction, various catalysts and reaction conditions have been studied,
and many improved procedures catalyzed by different Lewis and protic acids such
as CeCl3,[4] Cu(OTf)2,[5a] Cu(BF4)2,[5b] Mg(ClO4)2,[6a] heteropoly acids,[6b]
Y(NO3)3,[6c] Ziegler–Natta,[6d] PhB(OH)2,[7a] propane phosphonic acid anhydride,[7b]
Received March 1, 2009.
Address correspondence to Hai-Ming Guo and Gui-Rong Qu, College of Chemistry and
Environmental Science, Henan Normal University, Xinxiang 453007, Henan, China. E-mail: ghm@
henannu.edu.cn; quguir@sina.com
1115

1116
D.-C. WANG, H.-M. GUO, AND G.-R. QU
Figure 1. Dihydropyrimidine antagonists.
triphenylphosphine,[7c] hydrazine,[7d] SiCl4,[8] ionic liquid,[9] graphite–LaCl3,[10] and
polyethylene glycol (PEG)[11] have been reported.
However, some of these procedures involve drawbacks, such as the need for
strong acids, anhydrous conditions, toxic organic solvents, costly catalysts, high tem-
peratures, and complex operation and create environmental disposal problems.
Therefore, the search for a milder and environmentally acceptable catalytic method
for performing the Biginelli reaction has attracted much attention. Here, we report a
general and practical route for the Biginelli cyclocondensation reaction using copper
nitrate as a catalyst under solventless conditions at 70 ꢁC. As far as we know, there
was no report for the synthesis of DHPMs catalyzed by Cu(NO3)2 ꢀ 3H2O (Scheme 1).
RESULTS AND DISCUSSION
To evaluate the effect of the catalyst under different reaction conditions,
the reaction of benzaldehyde, ethyl acetoacetate, and urea was selected as a model
Scheme 1. Biginelli reaction catalyzed by Cu(NO3)2 ꢀ 3H2O.

GREEN SYNTHESIS OF 3,4-DIHYDROPYRIMIDINONES
1117
reaction, and the results are summarized in Table 1. Initially, the effects of different
catalysts on the reaction system were studied without solvents, and the results
showed that Cu(NO3)2 ꢀ 3H2O among all metal nitrates examined was the optimal
catalyst for this condensation (entries 1–8). Second, we examined different reaction
conditions in traditional organic solvents, water, and solvent-free conditions at
70 ꢁC. Excellent yields of the product 9a were observed with EtOH (yield 97%), tetra-
hydrofuran (THF; 96%), CH3CN (95%), no solvent (95%), and H2O (88%) (entries 8,
12–15), and lower yield was observed in CH2Cl2 (60%) (entry 16). At the same time,
we found that the temperature had little impact on the catalytic capacity of copper
nitrate; the excellent yields of the product 9a were observed in THF (93%) (entry 17)
at room temperature. Considering the efficiency and environment, the solvent-free
condition was selected for the reaction at 70 ꢁC. Third, the effect of catalyst loading
on the reaction efficiency was evaluated (entries 8–11). A similar result was obtained
for the reaction catalyzed by 10 mol% of Cu(NO3)2 ꢀ 3H2O as the reaction catalyzed
by 5 mol% of Cu(NO3)2 ꢀ 3H2O. The yield of product 9a was 91% even using 1 mol%
Cu(NO3)2 ꢀ 3H2O (entry 11). Finally, after completion of the reaction, 10 mL of
water were added to the mixture and stirred for 10 min. The product 9a was obtained
by filtration and washed with water without recrystallization.
Table 1. Reaction of benzaldehyde, ethyl acetoacetate, and urea under different reaction conditionsa
Entry
Solvent
Catalyst (mol%)
Time
Yield (%)b
1
2
None
None
None
None
None
None
None
None
None
None
None
EtOH
THF
Ce(NO3)2 ꢀ 6H2O (10)
Fe(NO3)2 ꢀ 9H2O (10)
Ba(NO3)2 (10)
30 min
30 min
30 min
30 min
30 min
30 min
30 min
30 min
40 min
4 h
79
75
25
60
67
46
72
95
93
91
91
97
96
95
88
60
93c
3
4
Mg(NO3)2 ꢀ 6H2O (10)
Al(NO3)2 ꢀ 9H2O (10)
Ca(NO3)2 ꢀ 4H2O (10)
La(NO3)2 ꢀ 6H2O (10)
Cu(NO3)2 ꢀ 3H2O (10)
Cu(NO3)2 ꢀ 3H2O (5)
Cu(NO3)2 ꢀ 3H2O (2)
Cu(NO3)2 ꢀ 3H2O (1)
Cu(NO3)2 ꢀ 3H2O (10)
Cu(NO3)2 ꢀ 3H2O (10)
Cu(NO3)2 ꢀ 3H2O (10)
Cu(NO3)2 ꢀ 3H2O (10)
Cu(NO3)2 ꢀ 3H2O (10)
Cu(NO3)2 ꢀ 3H2O (10)
5
6
7
8
9
10
11
12
13
14
15
16
17
4 h
6 h
6 h
6 h
CH3CN
H2O
8 h
6 h
CH2Cl2
THF
24 h
aReaction conditions: benzaldehyde (3 mmol), ethyl acetoacetate (4.5 mmol), urea (6 mmol), and cata-
lyst stirring in solvent (2 mL, entries 12–16) at 70 ꢁC.
bIsolated yield.
cRoom temperature.

1118
D.-C. WANG, H.-M. GUO, AND G.-R. QU
To evaluate the generality of the procedure, a series of Biginelli compounds
were synthesized under the optimized conditions as shown in Table 2. The original
Biginelli products from ethyl acetoacetate were obtained in good yield under these
reaction conditions (entries 1–8), and the products from acetylacetone were also
obtained in good yield (entries 9–17). When thiourea was used as reactant, S-analogs
of DHPMs could be easily obtained in excellent yields (entries 7, 10, and 12). More
important, the different substituent groups of aromatic aldehydes, such as either
electron-donating or electron-withdrawing substituents, had little impact on the
yields of the products. Further, the reactivity of aliphatic aldehydes was examined.
The Biginelli reaction of cyclohexanecarboxaldehyde catalyzed by copper nitrate
without solvent at 70 ꢁC for 25 min afforded 9h (yield 78%) and 9q (77%) (entries
8 and 17). Compared to the traditional methods, it has an advantage in yield.
In summary, this report describes a green, simple, and efficient one-pot pro-
cedure for the synthesis of Biginelli DHPMs using Cu(NO3)2 ꢀ 3H2O as a catalyst
under solvent-free conditions. This method offers several advantages such as mild
reaction conditions, excellent yields, short reaction times, and ease of manipulation.
Table 2. Copper nitrate-catalyzed synthesis of different dihydropyrimidinones under solventless
conditionsa
Entry
Compound
R1
R2
X
Time
Yield (%)b
1
2
9a
9b
9c
9d
9e
9f
C6H5
EtO
EtO
EtO
EtO
EtO
EtO
EtO
EtO
Me
O
O
O
O
O
O
S
40 min
40 min
30 min
50 min
40 minc
40 min
8 hc
93
94
93
95
96
89
87
78
96
86
96
85
97
94
95
98
77
4-CH3O-C6H4
4-CH3-C6H4
4-Cl-C6H4
3
4
5
4-NO2-C6H4
3-NO2-C6H4
4-CH3O-C6H4
Cyclohexyl
C6H5
6
7
9g
9h
9i
8
O
O
S
25 min
25 min
2.5 hc
9
10
11
12
13
14
15
16
17
9j
C6H5
Me
Me
9k
9l
4-CH3O-C6H4
4-CH3O-C6H4
4-CH3-C6H4
4-Cl-C6H4
O
S
60 min
8 h
Me
Me
9m
9n
9o
9p
9q
O
O
O
O
O
30 min
30 min
30 minc
30 min
25 min
Me
Me
4-NO2-C6H4
3-NO2-C6H4
Cyclohexyl
Me
Me
aReaction conditions: aldehyde (3 mmol), ethyl acetoacetate or acetylacetone (4.5 mmol), urea or thio-
urea (6 mmol), and Cu(NO3)2 ꢀ 3H2O (5 mol%) stirring without a solvent at 70 ꢁC.
bIsolated yield.
c90 ꢁC.

GREEN SYNTHESIS OF 3,4-DIHYDROPYRIMIDINONES
1119
Apart from water, no solvents were used in the procedure. It is noteworthy synthetic
methodology for the preparation of DHPMs.
EXPERIMENTAL
General Procedure for Synthesis of DHPMs
A mixture of aldehyde (3 mmol), ethyl acetoacetate or acetylacetone
(4.5 mmol), urea or thiourea (6 mmol), and Cu(NO3)2 ꢀ 3H2O (0.15 mmol) was heated
at 70 ꢁC under stirring for the appropriate time (Table 2). Then water was added,
and the mixture was stirred for 10 min. The solid was filtered and washed with cold
water but not recrystallized to afford the pure product (9).
1H NMR Spectral and Melting-Point Data for All the Products
Compound 9a. Mp 202–203 ꢁC. 1H NMR (DMSO-d6): d ¼ 9.18 (s, 1H), 7.73
(s, 1H), 7.27 (m, 5H), 5.14 (d, J ¼ 3.2 Hz, 1H), 3.98 (q, J ¼ 7 Hz, 2H), 2.25 (s, 3H),
1.09 (t, J ¼ 7 Hz, 3H).
1
Compound 9b. Mp 199–201 ꢁC. H NMR (CDCl3): d ¼ 8.39 (s, 1H), 5.92 (s,
1H), 7.24 (d, J ¼ 8.4 Hz, 2H), 6.84 (d, J ¼ 8.4 Hz, 2H), 5.36 (s, 1H), 3.95 (q,
J ¼ 6.8 Hz, 2H), 3.79 (s, 3H), 2.34 (s, 3H), 1.18 (t, J ¼ 6.8 Hz, 3H).
Compound 9c. Mp 214–216 ꢁC. 1H NMR (CDCl3): d ¼ 7.39 (s, 1H), 7.22 (d,
J ¼ 7.6 Hz, 2H), 7.13 (d, J ¼ 7.6 Hz, 2H), 5.47 (s, 1H), 5.38 (s, 1H), 4.09 (q,
J ¼ 7.0 Hz, 2H), 2.34 (s, 6H), 1.19 (t, J ¼ 7.0 Hz, 3H).
Compound 9d. Mp 213–215 ꢁC. 1H NMR (CDCl3): d ¼ 7.84 (s, 1H), 7.28 (m,
4H), 5.73 (s, 1H), 5.40 (s, 1H), 4.10 (q, J ¼ 6.8 Hz, 2H), 2.36 (s, 3H), 1.19 (t,
J ¼ 6.8 Hz, 3H).
Compound 9e. Mp 206–208 ꢁC. 1H NMR (DMSO-d6): d ¼ 9.37 (s, 1H), 8.23
(d, J ¼ 8 Hz, 2H), 7.91 (s, 1H), 7.52 (d, J ¼ 8 Hz, 2H), 5.29 (s, 1H), 4.00 (q, J ¼ 6.8 Hz,
2H), 2.28 (s, 3H), 1.11 (t, J ¼ 6.8 Hz, 3H).
Compound 9f. Mp 230–231 ꢁC. 1H NMR (DMSO-d6): d ¼ 9.36 (s, 1H),
8.07–8.14 (m, 2H), 7.89 (s, 1H), 7.68 (m, 2H), 5.29 (d, J ¼ 2 Hz, 1H), 4.00 (q,
J ¼ 6.8 Hz, 2H), 2.27 (s, 3H), 1.09 (t, J ¼ 6.8 Hz, 3H).
1
Compound 9g. Mp 153–154 ꢁC. H NMR (DMSO-d6): d ¼ 10.27 (s, 1H),
9.58 (s, 1H), 7.12 (d, J ¼ 7.2 Hz, 2H), 6.90 (d, J ¼ 7.2 Hz, 2H), 5.11 (s, 1H), 4.01
(q, J ¼ 6.8 Hz, 2H), 3.72 (s, 3H), 2.28 (s, 3H), 1.10 (t, J ¼ 6.8 Hz, 3H).
Compound 9h. Mp 232–234 ꢁC. 1H NMR (DMSO-d6): d ¼ 8.88 (s, 1H), 7.29
(s, 1H), 4.05 (q, J ¼ 7.2 Hz, 2H), 3.92 (t, J ¼ 3.6 Hz, 1H), 2.16 (s, 3H), 1.68 (m, 2H),
1.58 (m, 2H), 1.39–1.27 (m, 3H), 1.18 (t, J ¼ 7.2 Hz, 3H), 1.13–1.05 (m, 4H).
1
Compound 9i. Mp 236–238 ꢁC. HNMR (DMSO-d6): d ¼ 9.17 (s, 1H), 7.81
(s, 1H), 7.22–7.34 (m, 5H), 5.26 (d, J ¼ 3.6 Hz, 1H), 2.29 (s, 3H), 2.10 (s, 3H).
1
Compound 9j. Mp 186–188 ꢁC. HNMR (DMSO-d6): d ¼ 10.28 (s, 1H), 9.75
(s 1H), 7.22–7.34 (m, 5H), 5.30 (d, J ¼ 4 Hz, 1H), 2.33 (s, 3H), 2.15 (s, 3H).

1120
D.-C. WANG, H.-M. GUO, AND G.-R. QU
1
Compound 9k. Mp 172–174 ꢁC. HNMR (DMSO-d6): d ¼ 9.13 (s, 1H), 7.75
(s 1H), 7.15 (d, J ¼ 8.4 Hz, 2H), 6.87 (d, J ¼ 8.4 Hz, 2H), 5.19 (d, J ¼ 3.2 Hz, 1H),
3.72 (s, 3H), 2.27 (s, 3H), 2.07 (s, 3H).
Compound 9l. Mp 186 ꢁC. 1H NMR (CDCl3): d ¼ 7.56 (s, 1H), 7.19 (d,
J ¼ 8.8 Hz, 2H), 7.10 (d, J ¼ 1.6 Hz, 1H), 6.86 (d, J ¼ 8.8 Hz, 2H), 5.40 (d, J ¼ 1.6 Hz,
1H), 3.79 (s, 3H), 2.35 (s, 3H), 2.12 (s, 3H).
Compound 9m. Mp 208–210 ꢁC. 1H NMR (DMSO-d6): d ¼ 9.16 (s, 1H), 7.79
(s, 1H), 7.13 (s, 4H), 5.21 (d, J ¼ 3.2 Hz, 2H), 2.28 (s, 3H), 2.26 (s, 3H), 2.08 (s, 3H).
Compound 9n. Mp 210–212 ꢁC. 1H NMR (DMSO-d6): d ¼ 9.24 (s, 1H), 7.87
(s, 1H), 7.40 (d, J ¼ 8.4 Hz, 2H), 7.25 (d, J ¼ 8.4 Hz, 2H), 5.25 (d, J ¼ 3.2 Hz, 1H),
2.29 (s, 3H), 2.13 (s, 3H).
1
Compound 9o. Mp 268–270 ꢁC. HNMR (DMSO-d6): d ¼ 9.33 (s, 1H), 8.20
(d, J ¼ 8.8 Hz, 2H), 7.98 (s, 1H), 7.50 (d, J ¼ 8.8 Hz, 2H), 5.39 (d, J ¼ 3.6 Hz, 1H),
2.31 (s, 3H), 2.18 (s, 3H).
Compound 9p. Mp 278–280 ꢁC. 1HNMR (DMSO-d6): d ¼ 9.37 (s, 1H),
8.10–8.13 (m, 2H), 8.02 (s, 1H), 7.61–7.68 (m, 2H), 5.40 (d, J ¼ 3.2 Hz, 1H), 2.32
(s, 3H), 2.19 (s, 3H).
Compound 9q. Mp 189–191 ꢁC. 1H NMR (DMSO-d6): d ¼ 8.85 (s, 1H), 7.32
(s, 1H), 4.00 (t, J ¼ 3.6 Hz, 1H), 2.20 (s, 3H), 2.17 (s, 3H), 1.66–1.70 (m, 4H),
1.56–1.60 (m, 3H), 1.05–1.14 (m, 4H).
ACKNOWLEDGMENT
We are grateful for financial support from the National Nature Science
Foundation of China (Grants 20772024 and 20802016).
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