Melamine as a green and reusable catalyst for knoevenagel condensation at room temperature under solvent-free conditions

Article abstract of DOI:10.1080/00397911.2010.523858

A rapid, efficient, and ecofriendly protocol has been developed for the Knoevenagel condensation of active methylene compounds such as malononitrile or ethyl cyanoacetate with aldehydes in the presence of melamine with good to excellent yields at room tem

Full text of DOI:10.1080/00397911.2010.523858

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Melamine as a Green and Reusable
Catalyst for Knoevenagel Condensation
at Room Temperature Under Solvent-
Free Conditions
Xian-Cao Yang a , Hong Jiang a & Wen Ye a
a College of Science, Huazhong Agricultural University, Wuhan,
Hubei, China
Accepted author version posted online: 18 Jul 2011.Version of
record first published: 06 Oct 2011.
To cite this article: Xian-Cao Yang, Hong Jiang & Wen Ye (2012): Melamine as a Green and Reusable
Catalyst for Knoevenagel Condensation at Room Temperature Under Solvent-Free Conditions,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 42:3, 309-312
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Synthetic Communications1, 42: 309–312, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.523858
MELAMINE AS A GREEN AND REUSABLE CATALYST
FOR KNOEVENAGEL CONDENSATION AT ROOM
TEMPERATURE UNDER SOLVENT-FREE CONDITIONS
Xian-Cao Yang, Hong Jiang, and Wen Ye
College of Science, Huazhong Agricultural University, Wuhan, Hubei, China
GRAPHICAL ABSTRACT
Abstract A rapid, efficient, and ecofriendly protocol has been developed for the Knoevenagel
condensation of active methylene compounds such as malononitrile or ethyl cyanoacetate
with aldehydes in the presence of melamine with good to excellent yields at room temperature
without solvent.
Keywords Active methylene compounds; aldehydes; Knoevenagel condensation; melamine
INTRODUCTION
Since its discovery, there has been accumulating attention to the Knoevenagel
reaction in organic synthesis to produce a lot of important and useful chemicals in
the cosmetic, perfume, and pharmaceutical industry.[1,2] Moreover, as an important
precursor of potentially bioactive pyrimidine derivatives, arylmethylenemalononi-
trile can also be produced by Knoevenagel reaction.[3] Conventionally, Knoevenagel
condensation can be carried out in the presence of a base, such as piperidine, pyri-
dine, or their corresponding salts.[4] More recently, some catalysts such as amines
immobilized on polymers,[5] inorganic solids,[6] and Lewis acids[7] performed the
reaction smoothly. In recent years, the development of environmentally benign
solvent-free reactions for the production of fine chemicals is becoming an area of
growing interest.[8,9] Solvent-free Knoevenagel condensations at room temperature
are gaining popularity for their ecofriendly and easy workup. Several solvent-free
protocols such as 2-hydroxyethylammonium acetate ionic liquid,[10] high-surface-
area magnesium oxide,[11] and N-methylpiperazine[12] have been tested for this
reaction recently.
Received April 21, 2010.
Address correspondence to Hong Jiang, College of Science, Huazhong Agricultural University,
Wuhan, Hubei 430070, China. E-mail: jianghong0066@126.com
309

310
X.-C. YANG, H. JIANG, AND W. YE
Scheme 1. Knoevenagel condensation between aromatic aldehydes and active methylenes.
In this communication, we investigated the application of melamine as catalyst
for Knoevenagel condensation (Scheme 1) for the first time. Melamine (2,4,6-
triamino-s-triazine) is a chemical intermediate originally used to manufacture amino
resins and plastics. The Knoevenagel reactions between active methylene compounds
such as malononitrile and ethylacetoacetate with aromatic aldehydes in the presence
of melamine as catalyst without solvent were reported. The results are listed in
Table 1. This process was performed smoothly within a short time at room tempera-
ture in good to excellent yields. In addition, the workup procedure is simple. Another
Table 1. Melamine-catalyzed Knoevenagel condensation at room temperature under solvent-free
conditionsa
Mp (ꢀC)
Time
(min)
Yield
(%)b
Entry
Products
R
X
Observed
Reported
1
2
3a
3b
3c
3d
3e
3f
3-NO4C6H4
4-NO4C6H4
2-ClC6H4
CN
CN
1
1
98
98
97
97
97
90
89
90
96
95
95
90
84
83
85
85
85
85
84
84
102–103
159–160
91–92
104–105[13]
160[14]
3
CN
CN
1
95–96[13]
4
4-ClC6H4
C6H5
2-Furyl
1
158–160
78–79
70–71
159–161[14]
82–83[13]
70–72[15]
5
CN
CN
2
6
15
20
25
10
10
15
15
40
40
50
50
50
50
50
50
7
3g
3h
3i
4-(CH3)2NC6H4
4-CH3OC6H4
3-NO4C6H4
4-NO4C6H4
2-ClC6H4
CN
CN
180–182
115–116
131–132
166–168
53–55
179–180[14]
114–115[13]
134–135[16]
167–169[16]
50–52[17]
8
9
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
10
11
12
13
14
15
16
17c
18d
19e
20f
3j
3k
3l
4-ClC6H4
C6H5
2-Furyl
86–87
51–53
89–90[16]
3m
3n
3o
3p
3p
3p
3p
3p
47–48[18]
91–93
119–120
80–82
91–93[16]
4-(CH3)2NC6H4
4-CH3OC6H4
4-CH3OC6H4
4-CH3OC6H4
4-CH3OC6H4
4-CH3OC6H4
124–126[18]
79–80[17]
aThe reaction was carried out using melamine (0.4 mmol), aldehyde (5 mmol), and active methylene
compound (5 mmol). All the products are known compounds and were identified by comparison of their
melting points and spectral data with those reported.
bIsolated yield.
cThe second run.
dThe third run.
eThe fourth run.
fThe fifth run.

MELAMINE CATALYST FOR KNOEVENAGEL CONDENSATION
311
Scheme 2. Postulated catalytic mechanism.
attractive feature of this methodology is the easy recyclability of melamine, thus
decreasing both the cost and the amount of waste produced. Aromatic aldehydes
bearing electron-withdrawing substituents could react very well with malononitrile
in a very short period of time, while the less-active ethylcyanoacetate takes a longer
time for the corresponding aldehydes.
The reuse of melamine was investigated, in which 4-methoxylbenzaldehyde and
ethyl cyanoacetate were chosen as the substrates. It was shown that melamine still
can catalyze this reaction without loss of activity even after five runs. Furthermore,
melamine is insoluble in most organic solvents such as ethyl acetate, ether, and
benzene, so it is easy to separate the products after reaction by simple extraction.
In the meantime, as the condensate product of urea, melamine is a very cheap,
commercially available mass industrial product.
We reasoned that the catalyst may have efficiency for this reaction for two
reasons. The melamine should be basic, leading to efficient deprotonation of the
active methylene compound, and once deprotonated, the methylene anion should
be able to covalently interact with the carbonyl group of the aldehyde, which can
form a hydrogen bond with the amino group of melamine, bringing them into close
proximity and thereby increasing the reactivity of the reaction (Scheme 2).
In summary, we have developed an environmentally friendly Knoevenagel
condensation between various aldehydes and active methylene compounds in the
presence of catalytic melamine.
EXPERIMENTAL
Melting points were determined on RY-2 melting-point apparatus. Infrared
(IR) spectra were recorded on Avatar 330 IR spectrophotometer using KBr disks.
1HNMR were obtained on a Bruker AV 600-MHz instrument using CDCl3 as the
solvent. Mass spectra (MS) were measured on a Varian CP-3800 mass spectrometer
operating at an ionization potential of 70 eV.
Melamine (0.4 mmol) was added to a mixture of aldehyde 1 (5 mmol) and
active methylene compound 2 (5 mmol), and the resultant mixture was vigorously
ground using a mortar and pestle at room temperature for the specified time until
thin-layer chromatography (TLC) showed complete disappearance of the starting
material (Table 1). Then 20 mL ethyl acetate were added to extract the product.
Melamine was recollected by simple filtration. After removal of ethyl acetate by
evaporation, the product 3 was produced in excellent yield. The catalyst can be
reused in the next run.

312
X.-C. YANG, H. JIANG, AND W. YE
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