Knoevenagel condensation of aldehydes with cyclic active methylene compounds in water

Article abstract of DOI:10.1081/SCC-120004844

A new route of Knoevenagel condensation of aromatic aldehydes with Meldrum's acid, barbituric acid and dimedone in the presence of cetyltrimethyl ammonium bromide at room temperature in water is described.

Full text of DOI:10.1081/SCC-120004844

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KNOEVENAGEL CONDENSATION OF ALDEHYDES WITH
CYCLIC ACTIVE METHYLENE COMPOUNDS IN WATER
a
a
a
a
Zhongjiao Ren , Weiguo Cao , Weiqi Tong & Xiuping Jing
a
Department of Chemistry, Shanghai University, Shanghai, 200436, P.R. China
Available online: 16 Aug 2006
To cite this article: Zhongjiao Ren, Weiguo Cao, Weiqi Tong & Xiuping Jing (2002): KNOEVENAGEL CONDENSATION OF
ALDEHYDES WITH CYCLIC ACTIVE METHYLENE COMPOUNDS IN WATER, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 32:13, 1947-1952
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SYNTHETIC COMMUNICATIONS, 32(13), 1947–1952 (2002)
KNOEVENAGEL CONDENSATION OF
ALDEHYDES WITH CYCLIC ACTIVE
METHYLENE COMPOUNDS IN WATER
Zhongjiao Ren,* Weiguo Cao, Weiqi Tong,
and Xiuping Jing
Department of Chemistry, Shanghai University,
Shanghai, 200436, P.R. China
ABSTRACT
A new route of Knoevenagel condensation of aromatic alde-
hydes with Meldrum’s acid, barbituric acid and dimedone in
the presence of cetyltrimethyl ammonium bromide at room
temperature in water is described.
The increased attention of the public is a driving force of searching
environmentally friendly chemical processes. In the last decade, there was
increased recognition that organic reactions carried out in aqueous media
[
1]
may offer advantages over those occurring in organic solvents. We concen-
trate our attention on using water instead of organic solvent in chemical
processes. The Knoevenagel reaction is a common synthetic method for
forming carbon–carbon bonds. It had been found that the Knoevenagel con-
densation reaction of aromatic aldehydes with malononitrile or ethyl cyano-
[
2]
acetate occurred in water. Our purpose is to broaden the scope of the
*
Corresponding author.
1
947
Copyright & 2002 by Marcel Dekker, Inc.
www.dekker.com

1
948
REN ET AL.
Knoevenagel reaction performed in water. The products of Knoevenagel
condensation reaction of aldehydes with cyclic active methylene compounds
[3]
are very useful reagents. Here we now report the Knoevenagel reaction of
aromatic aldehydes 1 with Meldrum’s acid, 2 barbituric acid 4 and dimedone
6 in the presence of cetyltrimethyl ammonium bromide (CTMAB) at room
temperature in water (Scheme 1).
Scheme 1.
Surfactants play an important role in the Knoevenagel condensation
reaction in water. The relationship between the structure of the surfactant
and efficiency of the reaction is investigated. As a model reaction we
examined a stirred mixture of benzaldehyde (5 mmol), Meldrum’s acid
(5 mmol), the surfactant (0.5 mmol), and water (30 mL) at room tempera-
ture. The results are listed in Table 1.
A plausible explanation of the role of the surfactants is that the sur-
factants form micelles in water. Molecules of starting material aggregate to
the hydrocarbon chain of the micelle and the reaction is facilitated by the
hydrophobic environment. CTMAB is the most efficient agent among the

KNOEVENAGEL CONDENSATION OF ALDEHYDES
1949
Table 1. Effect of Surfactant on the Knoevenagel
Reaction of Benzaldehyde with Meldrum’s Acid to
give Arylidene Meldrum’s Acid 3a
Reaction
Time (h)
Yield (%)
3a
Surfactant
(
C
C
4
H
9
)
4
NBr
2 5 3
CH N(C H ) Cl
2
2
2
2
69
71
76
65
6
H
5
2
C H N(CH ) Br
3 3
1
6
33
C
12
H
4
26NaO S
surfactants which shows that the presence of short-chain alkyl groups
attached to the nitrogen seem to decrease the efficiency of adsorption of
the organic molecules. The dominant factor will always be the length of the
primary hydrophobic chain. The results also exhibits that cationic surfac-
þ
À
tants (R N X ) are more efficient than anionic surfactant (RSO Na) for the
4
4
Knoevenagel condensation reaction in water.
At first we hope to get arylidene dimedone from the reaction of
p-nitrobenzaldehyde (b) (5 mmol) with dimedone (6) (5 mmol) in the presence
of CTMAB in water, but only the 1.8-xanthenedione (7b), in 38% yield, was
obtained. The yield of compound 7b was 92% when two equivalents of dime-
done (6) was used. It is interesting that the condensation reaction of p-nitro-
benzaldehyde (b) with dimedone (6) occurs in water only, whereas the
reaction with other aromatic aldehydes does not occur. However, when
NH Cl is added to water containing surfactant, the condensation reaction
2
of aromatic aldehydes with dimedone gives 1.8-xanthenediones (7) easily. We
also examine the reaction of benzaldehyde (a) with two equivalents of
Meldrum’s acid (2) or barbituric acid (4) in water, in which the products
still were arylidene Meldrum’s acid (3a) or arylidene barbituric acid (5a), in
9
2% or 89% yield respectively. The experiment shows that Michael adducts,
excess (2) or (4) attacking at the initial Knoevenagel products, are not formed.
The different results of the reaction of aromatic aldehydes with Meldrum’s
acid (2), barbituric acid (4) and dimedone (6) may be related to the electron-
withdrawing effect of the ester and amide group weaker than that of carbonyl
group, so that arylidene Meldrum’s acid (3a–g) or arylidene barbituric acid
(5a,d,h) are not reactive enough to carry out Michael addition.
The experiments show that the order of reactivity of cyclic active methy-
lene compounds for the Knoevenagel reaction in water is barbituric acid (4)>
Meldrum’s acid (2)> dimedone (6). The difference of reaction rate of dime-
done (6) with barbituric acid (4) and Meldrum’s acid (2) may ascribe to
dimedone very easily transforming into the enol form strongly solvated by

1
950
REN ET AL.
water. The hydrophilicity of solvated dimedone increases, therefore the very
low concentration of dimedone adsorbed on the micelle slows the reaction
with the aldehydes collected on micelle by hydrophobic effect.
EXPERIMENTAL
Melting points are uncorrected. Melting points were determined on
WRS-1 digital melting point apparatus made by Shanghai physical instru-
ment factory (SPOIF), China. IR spectra were measured in KBr on
1
PE-580B spectrometer. H NMR spectra were recorded at Bruker AC-100SC,
using CDCl as solvent and TMS as internal reference.
3
General Procedure
A: Preparation of Arylidene Meldrum’s Acid (3a–g) or Arylidene
Barbituric Acid (5a,d,h)
The mixture of aromatic aldehydes (1) (5 mmol), Meldrum’s acid (2)
5 mmol) or barbituric acid (4) (5 mmol) and cetyltrimethyl ammonium
(
bromide 0.18 g (0.5 mmol) in 30 mL distilled water is stirred at room
temperature for 2 h or 0.5 h (see Table 2). The precipitate is allowed to
Table 2. Knoevenagel Condensation of Aromatic Aldehydes (1) with Cyclic Active
Methylene Compounds (2,4,6) in the Presence of CTMAB in Water
Cyclic Active
Methylene Compound
Reaction
Time (h)
Yield
(%)
Product
Ar
3
3
3
3
3
3
3
5
5
5
7
7
7
a
b
c
d
e
f
g
a
d
h
b
c
h
C
4-NO
4-CH
6
H
5
Meldrum’s acid (2)
Meldrum’s acid (2)
Meldrum’s acid (2)
Meldrum’s acid (2)
Meldrum’s acid (2)
Meldrum’s acid (2)
Meldrum’s acid (2)
Barbituric acid (4)
Barbituric acid (4)
Barbituric acid (4)
Dimedone (6)
2
2
2
2
2
76
85
78
69
98
72
83
76
79
82
92
51
78
2 6 4
C H
3
OC
6
H
4
4-(CH ) NC H
6
3
2
4
4-HOC
4-HO–3CH
6
H
4
3
OC
6
H
3
2
2
3,4-O–CH –OC H
2
6
3
C
6
H
5
0.5
0.5
0.5
24
24
24
4-(CH
4-ClC H4
4-NO
4-CH
4-ClC H4
3
)
2 6 4
NC H
6
2 6 4
C H
3
OC
6
H
4
Dimedone (6)
Dimedone (6)
6

KNOEVENAGEL CONDENSATION OF ALDEHYDES
1951
stand overnight, collected by suction filtration, washed with petroleum ether
and water, and finally dried at room temperature. The crude product is
recrystallized by 95% EtOH or 75% EtOH.
B: Preparation of 1.8-Xanthenedione (7b,c,h)
The mixture of aromatic aldehydes (1) (5 mmol), dimedone (6)
10 mmol), NH Cl 0.54 g (10 mmol) and CTMAB 0.18 g (0.5 mmol) in
4
(
3
0 mL distilled water is stirred at room temperature for 24 h. The precipitate
is allowed to stand overnight, collected by suction filtration, washed with
Petroleum ether and water, finally dried at room temperature. The crude
product is purified by recrystallization from 95% EtOH.
ꢀ
ꢀ
3
a: m.p. 84.5–85.0 C, (lit. (4) 85.0 C). IR: (KBr) 1776, 1738, 1605,
385, 1233, 818.
b: m.p. 213.5–214.5 C, (lit. (4) 217.0 C). IR: (KBr) 1758, 1728,
600, 1367, 1231, 831.
c: m.p. 122.0–123.0 C, (lit. (4) 126.0 C). IR: (KBr) 1747, 1714,
574, 1389, 1234, 836.
d: m.p. 174.0–175.0 C, (lit. (4) 175.0 C). IR: (KBr) 1730, 1698,
611, 1399, 1262, 819.
e: m.p. 200.0–201.0 C, (lit. (4) 195.0 C). IR: (KBr) 3280, 1750,
1
1
1
1
1
1
1
1
1
1
1
7
ꢀ
ꢀ
3
ꢀ
ꢀ
3
ꢀ
ꢀ
3
ꢀ
ꢀ
3
695, 1585, 1450, 1270, 840.
ꢀ
ꢀ
3
f: m.p. 135.5–136.5 C, (lit. (4) 136.0–138.0 C). IR: (KBr) 3343,
740, 1700, 1586, 1469, 1244, 811.
ꢀ
ꢀ
3
710, 1561, 1382, 1248, 814.
g: m.p. 172.0–173.0 C, (lit. (5) 167.0–169.0 C). IR: (KBr) 1740,
ꢀ
ꢀ
5
a: m.p. 248.5–249.5 C, (lit. (6) 256.0 C). IR: (KBr) 3211, 1700,
624.
ꢀ
ꢀ
5
d: m.p. 266.0–267.0 C, (lit. (7) 264.0 C). IR: (KBr) 3180, 3064,
732, 1660, 1614.
h: m.p. 271.0–272.0 C, (lit. (8) 271.0 C). IR: (KBr) 3211, 3084,
753, 1702, 1674.
b: m.p. 187.5–188.5 C, (lit. (9) 183.0 C). IR: (KBr) 3318, 1721,
634, 1302, 1186.
ꢀ
ꢀ
5
ꢀ
ꢀ
7
1
H NMR: d 1.1 (s, 6H), 1.2 (s, 6H), 2.3 (s, 4H), 2.4 (s, 4H), 5.5 (s, 1H),
.0 (d, 2H, J ¼ 8.7 Hz), 8.1 (d, 2H, J ¼ 8.7 Hz), 11.9 (s, 1.3H).
ꢀ
7
c: m.p. 125.5–126.5 C, IR: (KBr) 3424, 1790, 1590, 1303, 1165.
1
H NMR: d 1.1 (s, 12H), 2.5 (s, 8H), 3.8 (s, 3H), 5.3 (s, 1H), 6.8 (d, 2H,
J ¼ 9.0 Hz), 7.0 (d, 2H, J ¼ 9.0 Hz), 11.8 (s, 1.1H).
ꢀ
ꢀ
7h: m.p. 145.5–146.5 C, (lit. (9) 140.0–142.0 C). IR: (KBr) 3431,
720, 1592, 1302, 1121.
1

1
952
REN ET AL.
1
H NMR: d 1.0 (s, 6H), 1.2 (s, 6H), 2.3 (s, 4H), 2.4 (s, 4H), 5.5 (s, 1H),
6
.8 (d, 2H, J ¼ 8.5 Hz), 7.4 (d, 2H, J ¼ 8.5 Hz), 11.9 (s, 2H).
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Received in the USA June 23, 2001