Novel, efficient, and green procedure for the Knoevenagel condensation catalyzed by diammonium hydrogen phosphate in water

Article abstract of DOI:10.1080/00397910600781471

Knoevenagel condensation of various aromatic and heteroaromatic aldehydes with active methylene compounds like methyl and ethyl cyanoacetate, malononitrile, and cyanoacetamide proceeds smoothly with stirring in water in the presence of 4 mol% of diammoniu

Full text of DOI:10.1080/00397910600781471

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Novel, Efficient, and Green Procedure for
the Knoevenagel Condensation Catalyzed by
Diammonium Hydrogen Phosphate in Water
Saeed Balalaie a , Morteza Bararjanian a , Shohreh Hekmat b & Peyman
Salehi c
a Department of Chemistry, K.N. Toosi University of Technology, Tehran, Iran
b Department of Chemistry, Islamic Azad University, North Tehran Branch,
Iran
c Department of Phytochemistry, Medicinal Plants and Drugs Research
Institute, Shahid Beheshti University, Evin, Tehran, Iran
Published online: 27 Oct 2006.
To cite this article: Saeed Balalaie , Morteza Bararjanian , Shohreh Hekmat & Peyman Salehi (2006): Novel,
Efficient, and Green Procedure for the Knoevenagel Condensation Catalyzed by Diammonium Hydrogen
Phosphate in Water, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 36:17, 2549-2557
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Synthetic Communicationsw, 36: 2549–2557, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910600781471
Novel, Efficient, and Green Procedure
for the Knoevenagel Condensation
Catalyzed by Diammonium Hydrogen
Phosphate in Water
Saeed Balalaie and Morteza Bararjanian
Department of Chemistry, K.N. Toosi University of Technology,
Tehran, Iran
Shohreh Hekmat
Department of Chemistry, Islamic Azad University, North Tehran
Branch, Iran
Peyman Salehi
Department of Phytochemistry, Medicinal Plants and Drugs Research
Institute, Shahid Beheshti University, Evin, Tehran, Iran
Abstract: Knoevenagel condensation of various aromatic and heteroaromatic
aldehydes with active methylene compounds like methyl and ethyl cyanoacetate,
malononitrile, and cyanoacetamide proceeds smoothly with stirring in water in the
presence of 4 mol% of diammonium hydrogen phosphate. The reactions were carried
out at room temperature in short periods with very simple workup procedure and
good to high yields.
Keywords: Alkene, diamamonium hydrogen phosphate, Knoevenagel condensation,
water
Received in Poland January 18, 2005
Address correspondence to Saeed Balalaie, Department of Chemistry, K.N. Toosi
University of Technology, P.O. Box 15875-4416, Tehran, Iran. E-mail: balalaie@
kntu.ac.ir
2549

2550
S. Balalaie et al.
INTRODUCTION
The Knoevenagel condensation of aldehydes with active methylene
compounds is an important and widely employed method for carbon–
carbon bond formation in organic synthesis.[1] The versatile Knoevenagel
reaction has numerous applications in the elegant synthesis of fine
chemicals,[2] hetero Diels–Alder reaction,[3] and in synthesis of carbocyclic
as well as heterocyclic compounds of biological significance.[4] The
reaction is usually catalyzed by bases such as amines or their ammonium
salts, ammonia, and sodium ethoxide in organic solvents.[5] Lewis acids,[6]
zeolites,[7] and heterogenous catalysts[8] have also been employed to
catalyze the reaction. Recently, the solvent-free Knoevenagel condensation
on solid support promoted by infrared,[9] ultrasound,[10] or microwave
irradiation[11] and also in support-free stoichiometric molten condition[12]
has been a matter of interest. However, most of the reported procedures
were carried out in organic solvents with notable amounts of waste.
It should be emphasized that most of solvent-free methods still require
organic solvents during workup, and this is so for the catalyst free Knoevena-
gel reaction in water.[13] Kaupp et al.[14] reported a green method for the Knoe-
venagel condensation by molten catalyst and in the absence of solvent.
However, high reaction temperature (150–1708C) and long reaction time
were required for a complete reaction. There are also some new catalysts such
as TPP (triphenylphosphane),[15] urea,[16] ionic liquids,[17] and TBAH (tetrabu-
tylammonium hydroxide)[18] that were used for the Knoevenagel condensation.
Today, in the development of new syntheses, ecological points of view
must also be taken into account. In this process, the solvents are especially
important, as they are generally used in large quantities. Many organic
solvents are ecologically harmful, and their use should therefore be
minimized as far as possible or even avoided altogether. One ideal alternative
under investigation as solvent for organic reactions is water;[19] many
biochemical processes occur in the presence of water, and the diversity of the
in vivo reactions has prompted chemists to rediscover the potential of water
as a solvent. Some efforts have been made to perform the Knoevenagel conden-
sation in an aqueous medium as well as in the absence of organic solvents.[20]
RESULTS AND DISCUSSION
Because of our continued interest in Knoevenagel condensation and its appli-
cations in the synthesis of bioactive molecules,[21] we hereby report a very
simple, genuine green, and highly efficient method for the condensation of
various aromatic and heteroaromatic aldehydes (1) with several active
methylene compounds (2) such as malononitrile, methyl- and ethyl cyanoace-
tate, and cyanoacetamide. The reactions were carried out in water at room
temperature in the presence of 4 mol% of diammonium hydrogen

Diammonium Hydrogen Phosphate
2551
phosphate. It was exciting to observe that, except in few cases, all reactions
run rapidly and were completed in just few minutes, giving excellent yields
of the Knoevenagel product 3 (Scheme 1).
It was also shown that natural phosphate,[22] AlPO4-Al2O3,[23] natural
phosphate doped with potassium fluoride,[24] and phosphate complexes[25]
are efficient catalysts for the Knoevenagel condensation, but the entire
reported methods need extraction with organic solvents or advanced
preparation of the catalyst. Diammonium hydrogen phosphate is a very
cheap, nontoxic, and commercially available compound that can be used in
practice without any special precaution. To the best of our knowledge, there
is only one report on the application of diammonium hydrogen phosphate in
the synthesis of some classes of heterocyclic compounds.[26]
At first, the reaction of 4-chlorobenzaldeyde with malononirlie was
selected as a model to examine the effects of catalyst ranging from 0–10%
at room temperature. The best yield was obtained when the reaction was
carried out in the presence of 4 mol% of diammonium hydrogen phosphate
in aqueous media. No other by-product was formed during the course of the
reaction. Electron-deficient aldehydes gave relatively higher yields than
electron-rich counterparts (Table 1).
In conclusion, we have demonstrated that the Knoevenagel condensation
between aromatic and heteroaromatic aldehydes with active methylene
compounds can be effectively performed at room temperature in the
presence of a catalytic amount (4 mol%) of diammonium hydrogen
phosphate in aqueous media, which provides a simple route to the synthesis
of tri-substituted alkenes. The present method has many obvious advantages
compared to those reported in literature, including simplicity of the method-
ology, ease of product isolation (only simple filtration), good yields, short
reaction times, very cheap catalyst, and environmental friendliness.
EXPERIMENTAL
Melting points were recorded on an Electrothermal 9100 melting-point
apparatus and are not corrected. IR spectra were recorded on a FT-IR
Perkin-Elmer GX spectrophotometer using KBr disks. 1H NMR spectra
were recorded on Bruker DRX 500 (500 MHz) Avance spectrometer in
CDCl3 using TMS as the internal standard.
Scheme 1.

2552
S. Balalaie et al.
Table 1. Synthesis of alkenes catalyzed by diammonium hydrogen phosphate in
aqueous media
Mp (8C)
Yielda
(%)
Product
Ar
R
Found
161
179
Reported
3a
3b
3c
3d
3e
3f
4-Cl-C6H4
4-Me2N-C6H4
4-NO2-C6H4
C6H5
CN
CN
70
80
85
90
75
90
87
92
92
90
90
85
80
82
83
95
90
80
90
70
162[27]
179–180[23]
160[18,27]
89[5a,21a]
CN
160
89
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CONH2
CONH2
4-Cl-C6H4
2,4-Cl2-C6H3
3-OH-C6H4
4-Me2N-C6H4
3-NO2-C6H4
4-NO2-C6H4
PhCH ¼ CH-
2-Furyl
122
78
79–80
3g
3h
3i
145
146
146[18]
135[18]
178[18]
145[21a]
95[15,21a]
135
178
3j
3k
3l
144
94
3m
3n
3o
3p
3q
3r
3s
2-Thienyl
113–114
91–92
125
4-Cl-C6H4
4-Me2N-C6H4
3-NO2-C6H4
2-Furyl
91[23]
125[18]
139
91–93
106
139[18]
91–93[16]
105–108[18]
2-Thienyl
3-NO2-C6H4
4-NO2-C6H4
156–159
235–236
3t
237–238[16]
aIn all cases, the yields are related to pure isolated compounds.
General Procedure for the Preparation of Alkenes at Room
Temperature
To a stirred solution of malononitrile (2.2 mmol, 145 mg) in water (10 ml),
diammonium hydrogen phosphate (7 mg, 0.04 mmol) and benzaldehyde
(212 mg, 2 mmol) were added. Progress of the reaction was monitored by
TLC (eluent, petroleum ether–EtOAc, 3 : 1). After 1 min, the produced
solid material was isolated by simple filtration. Further purification for
some samples was made by recrystallization from EtOH.
Selected Data for Compounds 3a–t
3a: 2-(4-Chlorophenylmethylene)malononitrile: mp 1618C [lit. 1628C][27]; IR
(KBr, cm21): 3038, 2227, 1583,1486; 1H NMR (d,CDCl3) 7.56 (d, 2H,
J ¼ 8.4 Hz,H-Ar), 7.77 (s,1H,H-C55C), 7.89 (d, 2H, J ¼ 8.4 Hz,H-Ar).
3b: 2-(4-N,N-Dimethylphenylmethylene)malononitrile: mp 1798C [lit. 179–
180][18,23]; IR (KBr, cm21): 3010, 2208, 15609.

Diammonium Hydrogen Phosphate
2553
3c: 2-(4-Nitrophenylmethylene)malononitrile: mp 1608C [lit. 160][18,27]
;
IR (KBr, cm21): 3038, 2227, 1582, 1519; 1H NMR (d, CDCl3) 7.88
(s,1H, H-C55C), 8.10 (d, 2H, J ¼ 7.20 Hz, H-Ar), 8.39 (d, 2H,
J ¼ 7.2 Hz,H-Ar).
3d: Methyl-(E)-2-cyano-3-phenyl-2-propenoate: mp 898C [lit. 89][5a,21a]; IR
(KBr, cm21): 3038, 2227, 1725, 1608, 1428; 1H NMR (d, CDCl3) 3.90
(s, 3H, OMe), 7.70–8.15 (m, 5H, Ar), 8.25 (s, 1H, H-C55C).
3e: Methyl-(E)-2-cyano-3-(4-chlorophenyl)-2-propenoate: mp 1228C; IR
1
(KBr, cm21): 3060, 2227, 1725, 1583; H NMR (d, CDCl3) 3.99 (s, 3H,
OMe), 7.53 (d, 2H, J ¼ 8.60 Hz, H-Ar), 7.98 (d, 2H, J ¼ 8.60 Hz, H-Ar),
8.25 (s, 1H, H-C55C).
3f: Methyl-(E)-2-cyano-3-(2,4-dichlorophenyl)-2-propenoate: mp 788C; IR
1
(KBr, cm21): 3050, 2250, 1731, 1577; H NMR (d, CDCl3) 4.00 (s, 3H,
OMe), 7.45 (dd, 1H, J ¼ 8.50, 1.70 Hz, H-Ar), 7.59 (d, 1H, J ¼ 1.70 Hz,
H-Ar) 8.25 (d, 1H, J ¼ 8.50, H-Ar), 8.65 (s, 1H, H-C55C).
3g: Methyl-(E)-2-cyano-3-(3-hydroxyphenyl)-2-propenoate: mp 1458C; IR
(KBr, cm21): 3412, 3032, 2227, 1725, 1596; 1H NMR (d, CDCl3) 3.98
(s, 3H, Me), 5.90 (brs, 1H, OH), 7.12 (m, 1H, Ar), 7.41 (t, 1H, J ¼ 7.80 Hz,
H-Ar), 7.47 (d, 1H, J ¼ 7.80 Hz, H-Ar), 8.25 (s, 1H, H-C55C).
3h: Methyl-(E)-2-cyano-3-(4-N,N-dimethylphenyl)-2-propenoate: mp 1468C
1
[lit. 146][18]; IR: (KBr): [cm21] 2907, 2215, 1715, 1610, 1575; H NMR:
(d, CDCl3) 3.10 (s, 6H, -NMe), 3.90 (s, 3H, OMe), 6.70 (d, 2H, J ¼ 9 Hz,
H-Ar), 7.90 (d, 2H, J ¼ 9 Hz, H-Ar), 8.20 (s, 1H, 55CH).
3i: Methyl-(E)-2-cyano-3-(3-nitrophenyl)-2-propenoate: mp 1358C [lit.
1358C][18]; IR (KBr, cm21) 3080, 2226, 1720, 1609, 1536, 1359.
3j:
Methyl-(E)-2-cyano-3-(4-nitrophenyl)-2-propenoate:
1788C
[lit.
1788C][18]; IR (KBr, cm21) 3119, 2847, 2225, 1731, 1613; H NMR (d,
CDCl3) 4.0 (s, 3H,OMe), 8.15 (d, 2H, J ¼ 9 Hz, Ar), 8.34 (s, 1H, H-C55C),
8.38 (d, 2H, J ¼ 9 Hz,Ar).
1
3k: Methyl-(E)-2-cyano-5-phenyl-2,4-pentadieneoate: 1458C [lit. 1458C][21a]
;
IR (KBr, cm21) 3031, 2220, 1611, 1583; H NMR (d, CDCl3) 3.94 (s, 3H,
OMe), 7.33 (m, 2H, HC55C), 7.42–7.48 (m, 3H, H-Ar), 7.63 (m, 2H,
H-Ar), 8.06 (dd, 1H, J ¼ 11, 2.9 Hz, HC55C).
1
3l: Methyl-(E)-2-cyano-3-(furyl)-2-propenoate: 948C [lit. 958C][15,21a]; IR
(KBr, cm21) 3135, 2961, 2221, 1725, 1538; 1H NMR (d, CDCl3) 3.95 (s, 3H,
OMe), 6.70; (dd, 1H, J ¼ 4.0, 1.9 Hz, H-Furyl), 7.45 (d, 1H, J ¼ 4.0 Hz,
H-Furyl), 7.78 (d, 1H, J ¼ 1.9 Hz, H-Furyl), 8.05 (s, 1H, H-C55C).
3m: Methyl-(E)-2-cyano-3-(thienyl)-2-propenoate: 1138C IR (KBr, cm21
)
3090, 2961, 2220, 1719, 1596; H NMR (d, CDCl3) 3.96 (s, 3H, OMe),
1

2554
S. Balalaie et al.
7.27 (d, 1H, J ¼ 4.50 Hz, H-thienyl), 7.83 (d, 1H, J ¼ 4.50 Hz, H-thienyl),
7.89 (d, 1H, J ¼ 3.50 Hz, H-thienyl), 8.39 (s,1H, H-C55C).
3n: Ethyl-(E)-2-cyano-3-(4-chlorophenyl)-2-propenoate: 91–928C [lit.
918C][23]; IR (KBr, cm21) 3050, 2950, 2220, 1725, 1608;1H NMR (d, CDCl3)
1.45 (t, 3H, J ¼ 7.12Hz), 4.43 (q, 2H, J ¼ 7.12Hz, OCH2), 7.52 (d, 2H,
J ¼ 8.56Hz, H-Ar), 7.97 (d, 2H, J ¼ 8.56Hz, H-Ar), 8.23 (s, 1H, H-C55C).
3o: Ethyl-(E)-2-cyano-3-(4-N,N-dimethylphenyl)-2-propenoate: 1258C [lit.
1258C][18]; IR (KBr, cm21) 2944, 2212, 1713, 1611, 1575; 1H NMR
(d, CDCl3) 1.40 (t, 3H, J ¼ 8 Hz, CH3), 3.10 (s, 6H, 2NMe), 4.30 (q, 2H,
J ¼ 8 Hz, OCH2), 6.70 (d, 2H, J ¼ 9 Hz, H-Ar), 7.90 (d, 2H, J ¼ 9 Hz,
H-Ar), 8.10 (s, 1H, HC55C).
3p: Ethyl-(E)-2-cyano-3-(3-nitrophenyl)-2-propenoate: 1398C [lit. 1398C][18]
;
IR (KBr, cm21) 3036, 2226, 1727, 1609, 1537; 1H NMR (d, CDCl3) d ¼ 1.50
(t, 3H, J ¼ 7.2 Hz, CH3), 4.40 (q, 2H, J ¼ 7.2 Hz, OCH2), 7.6–8.80 (m, 4H,
Ar), 8.32 (s, 1H, 55CH).
3q: Ethyl-(E)-2-cyano-3-(furyl)-2-propenoate: 91–938C [lit. 91–938C][16]
;
IR (KBr, cm21) 3130, 3040, 2223, 1716, 1621; H NMR (d, CDCl3) 1.42
(t, 3H, J ¼ 7.2 Hz, Me), 4.40 (q, 2H, J ¼ 7.2 Hz, OCH2), 6.69 (dd, 1H,
J ¼ 3.6, 1.5 Hz, H-Furyl), 7.44 (d, 1H, J ¼ 3.6 Hz, H-Furyl), 7.75 (d, 1H,
J ¼ 1.5 Hz, H-Furyl), 8.05 (s, 1H, H-C55C).
1
3r: Ethyl-(E)-2-cyano-3-(thienyl)-2-propenoate: 1068C [lit. 105–
1088C][15,18]; IR (KBr, cm21) 3086, 2219, 1717, 1599; 1H NMR: (d,
CDCl3) 1.39 (t, 3H, J ¼ 7.1 Hz, CH3), 4.36 (q, 2H, J ¼ 7.1 Hz, CH2), 7.26
(t, J ¼ 4.79 Hz, 1H, H-Thienyl), 7.81 (d, J ¼ 4.90 Hz, 1H, H-Thienyl), 7.88
(d, J ¼ 3.70 Hz, 1H, H-Thienyl), 8.37 (s, 1H, H-C55C).
3s: 2-Cyano-3-(3-nitrophenyl)-2-propenamide: 156–1598C; IR (KBr, cm21
)
1
3418, 3129, 2227, 1706, 1608; H NMR (d, CDCl3) 5.80 (brs, 1H, NH),
6.30 (brs, 1H, NH), 7.77 (t, 1H, J ¼ 8 Hz, H-Ar), 8.32 (d, 1H, J ¼ 7.7 Hz,
H-Ar), 8.43 (d, 1H, J ¼ 7.7 Hz, H-Ar), 8.45 (s, 1H,H-C55C), 8.77 (d, 1H,
J ¼ 1.67 Hz, H-Ar).
3t: 2-Cyano-3-(4-nitrophenyl)-2-propenamide: 235–2388C [lit. 237–
1
2388C][16]; IR (KBr, cm21) 3438, 3347, 2227, 1688, 1596; H NMR (d,
CDCl3) 7.35 (brs, 1H, NH), 7.45 (brs, 1H, NH), 8.12 (d, 2H, J ¼ 8.7 Hz,
H-Ar), 8.39 (d, 2H, J ¼ 8.7 Hz, H-Ar), 8.44 (s, 1H, H-C55C).
ACKNOWLEDGMENTS
Saeed Balalaie is grateful to the Alexander von Humboldt foundation for the
research fellowship and equipment donation. Partial support of this work by
the K. N. Toosi University of Technology Research Council is gratefully
acknowledged.

Diammonium Hydrogen Phosphate
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