Efficient green procedure for the Knoevenagel condensation under solvent-free conditions

Article abstract of DOI:10.1080/00397910600640289

Knoevenagel condensation of aromatic aldehydes with active methylene compounds under solvent-free conditions to synthesize arylidene compounds by grinding in the presence of TEBA at room temperature has been described. This method is simple, efficient, an

Full text of DOI:10.1080/00397910600640289

This article was downloaded by: [University of Memphis]
On: 06 July 2012, At: 14:13
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office:
Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An International
Journal for Rapid Communication of
Synthetic Organic Chemistry
Publication details, including instructions for authors and subscription
information:
http://www.tandfonline.com/loi/lsyc20
Efficient Green Procedure for the
Knoevenagel Condensation under
Solvent‐Free Conditions
Liangce Rong a b , Xiaoyue Li a , Haiying Wang a , Daqing Shi a b , Shujiang Tu
a b & Qiya Zhuang a b
a Department of Chemisty, Xuzhou Normal University, Xuzhou, Jiangsu,
China
b Key Laboratory of Biotechnology for Medicinal Plant, Xuzhou, Jiangsu,
China
Version of record first published: 22 Sep 2006
To cite this article: Liangce Rong, Xiaoyue Li, Haiying Wang, Daqing Shi, Shujiang Tu & Qiya Zhuang (2006):
Efficient Green Procedure for the Knoevenagel Condensation under Solvent‐Free Conditions, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 36:16,
2407-2412
To link to this article: http://dx.doi.org/10.1080/00397910600640289
PLEASE SCROLL DOWN FOR ARTICLE
Full terms and conditions of use: http://www.tandfonline.com/page/terms-and-conditions
This article may be used for research, teaching, and private study purposes. Any substantial
or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or
distribution in any form to anyone is expressly forbidden.
The publisher does not give any warranty express or implied or make any representation that the
contents will be complete or accurate or up to date. The accuracy of any instructions, formulae,
and drug doses should be independently verified with primary sources. The publisher shall not
be liable for any loss, actions, claims, proceedings, demand, or costs or damages whatsoever or
howsoever caused arising directly or indirectly in connection with or arising out of the use of this
material.

Synthetic Communicationsw, 36: 2407–2412, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910600640289
Efficient Green Procedure
for the Knoevenagel Condensation
under Solvent-Free Conditions
Liangce Rong
Department of Chemisty, Xuzhou Normal University, Xuzhou,
Jiangsu, China and Key Laboratory of Biotechnology for Medicinal Plant,
Xuzhou, Jiangsu, China
Xiaoyue Li and Haiying Wang
Department of Chemisty, Xuzhou Normal University, Xuzhou,
Jiangsu, China
Daqing Shi, Shujiang Tu, and Qiya Zhuang
Department of Chemisty, Xuzhou Normal University, Xuzhou,
Jiangsu, China and Key Laboratory of Biotechnology for Medicinal Plant,
Xuzhou, Jiangsu, China
Abstract: Knoevenagel condensation of aromatic aldehydes with active methylene
compounds under solvent-free conditions to synthesize arylidene compounds by
grinding in the presence of TEBA at room temperature has been described. This
method is simple, efficient, and environmentally friendly.
Keywords: Aromatic aldehydes, Knoevenagel condensation, methylene compounds,
TEBA
Developing green chemical methods is one of the most important purposes of
organic synthesis at present. Organic synthesis in the absence of solvent is a
powerful tool for the generation of structurally diverse molecules. Because
of their special selectivity, the ease of setup, and workup, they are arousing
Received in R.O.C. January 19, 2006
Address correspondence to Liangce Rong, Key Laboratory of Biotechnology for
Medicinal Plant, Xuzhou, Jiangsu 221116, China. E-mail: lcrong2005@yahoo.com
2407

2408
L. Rong et al.
great interest.[1–3] Moreover, solvent-free reactions sometimes are faster,
taking just a few minutes rather than hours to complete, because the
reactants are in close contact with each other. This aspect, coupled with the
lower overall costs of running a reaction without solvent, including no
special equipment, could become a decisive factor in industry.
Knoevenagel condensations are one of the most useful and widely
employed reactions for carbon–carbon formation in organic synthesis.[4]
A
number of methods have been developed for this reaction.[5–13] However,
most of them were carried out in organic solvent and created much waste.
As environmental consciousness in chemical research and industry has
increased, efficient, economic, and clean procedures have received
increased attention in recent years. For example, many kinds of heterogeneous
basic catalysts were used in Knoevenagel condensations under solvent-free
conditions.[14–23]
a,b-Unsaturated nitriles and their derivatives are important precursors of
potentially bioactive pyrimidine derivatives[24] and also are versatile tools for
the construction of a variety of novel complex heterocycles.[25] They can be
prepared via Knoevenagel condensation between malononnitrile or methyl
(ethyl) cyanoacetate and various aromatic aldehydes. The reaction is
usually catalyzed by various amines or their corresponding ammonium
salts.[5–13] In recent years, a grinding method under solvent-free conditions
used in Knoevenagel condensation has rapidly increased. Many catalysts
have been used in the synthetic procedure, for example, K2O-Al2O3,[26]
CaO,[27] ZnCl2,[28] and NH4OAC.[29] Herein, and we report a convenient prep-
aration of some arylidene derivatives by Knoevenagel condensation using
aromatic aldehydes with malononnitrile or ethyl cyanoacetate under
solvent-free conditions, including phase-transfer catalysis of triethylbenzy-
lammonium chloride (TEBA) (Scheme 1).
Encouraged by the literature, recently we have studied the reaction of
Knoevenagel condensation under solvent-free conditions. We tried to use
various catalysts in this reaction. Surprisingly, when we chose and used
phase-transfer catalysis in the reaction of aromatic aldehydes with active
methylene compounds at room temperature under solvent-free condition
using a grinding method, we found the reaction was very efficient and gave
high yields.
As an extension of this study, first we decided to investigate the use of
different phase-transfer catalysts, such as hexadecyl trimethyl ammonium
bromide (HTMAB), 4-dodecylbenzenesulfonic acid (DBSA), and
Scheme 1.

Green Procedure for Knoevenagel Condensation
2409
Table 1. Catalytic activity of phase-transfer catalysis in solvent-free conditions
Amount of
catalyst (mmol)
Yield (%)
of 3a
Entry
Catalyst
Time (min)
1
2
3
4
5
HTMAB
DBSA
TEBA
TEBA
TEBA
4
4
4
2
2
15
15
15
6
70
55
90
89
90
10
triethylbenzylammonium chloride (TEBA). We found they all had catalytic
activity but triethylbenzylammonium chloride (TEBA) displayed the best
catalytic effect. The result is shown in Table 1.
We have examined the reaction by various aromatic aldehydes containing
electron-withdrawing or electron-donating groups as reactants. They all gave
the expected results with good to excellent yields for almost all the tested sub-
stracts. The results are listed in Table 2. From Table 2, we not only could see
that all the reactions were completed within a few minutes, but we could also
see that the condensation of aldehydes with electron-withdrawing groups such
as –Cl and –NO2 in the aromatic ring, with active methylene compounds,
Table 2. Reaction time, yields, and melting points of products 3
Mp (8C)
Time
(min)
Yield
(%)
Entry
Ar
Y
Found
Lit.
3a
3b
3c
3d
3e
3f
C6H5
CN
CN
10
15
5
90
95
97
93
97
85
95
96
82
87
90
92
89
78
86
89
92
90
81–83
82–84[13d]
4-CH3C6H4
4-ClC6H4
2-ClC6H4
132–134 133–135[12]
160–162 159–161[12]
CN
CN
5
96–98
95–96[12]
4-BrC6H4
CN
CN
5
153–154 153–155[13c]
100–102 101–103[13c]
144–146 145–147[13c]
134–136 137–138[13c]
182–183 180–182[12]
2,3-(CH3O)2C6H3
3,4-Cl2C6H3
2-NO2C6H4
4-N(CH3)2C6H4
C6H5
15
5
3 g
3 h
3i
CN
CN
5
CN
15
10
5
3j
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
50–52
86–88
167–168 168–169[27]
154–156 155–157[27]
170–172 170–171[27]
121–123 122–123[27]
49–50[27]
86–87[27]
3 k
3l
4-ClC6H4
4-NO2C6H4
3,4-(CH3O)2C6H3
4-OHC6H4
5
3 m
3n
3o
3p
3q
3r
15
15
15
15
5
4-N(CH3)2C6H4
4-CH3OC6H4
3-ClC6H4
83–85
102–103 102–103[27]
98–99
97–98[27]
80–84[13b]
4-OH-3-CH3OC6H3 CO2Et
15

2410
L. Rong et al.
could be carried out in relatively shorter times and higher yields than
electron-donating groups such as –N(CH3)2 and –OCH3. The product was
1
identified by comparison of physical data and H NMR and IR spectra with
those described in the literature.
In summary, we have developed an environmentally friendly Knoevena-
gel condensation between various aldehydes and active methylene compounds
in the presence of phase-transfer catalyst TEBA in the absence of solvent at
room temperature using a grinding method. To our knowledge, TEBA is
first used in the Knoevenagel condensation reaction. Compared with the
classical heating reactions, the main advantages of the procedure are milder
reaction condition, better yield, shorter reaction time, and easier workup.
EXPERIMENTAL
All the reagents and aromatic aldehydes were obtained from suppliers and
were not purified. Melting points were determined on XT-5 microscopic
melting-point spectrometer and are uncorrected.
General Procedure
A mixture of aromatic aldehydes 1 (1 mmol), active methylene compounds 2
(1 mmol), and TEBA (2 mmol) were ground at room temperature with a glass
mortar and pestle. The reactions were monitored by TLC. The crude mixture
was treated with water. The product was filtered, dried, recrystallized from
ethanol, and dried at room temperature.
REFERENCES
1. Tannaka, K.; Toda, F. Solvent-free organic synthesis. Chem. Rev. 2000, 100, 1025.
2. Villemin, D.; Martin, B. Dry condensation of creatinine with aldehydes under
focused microwave irradiation. Synth. Commun. 1995, 25, 3135.
3. Lonpy, A.; Song, S. J.; Sohn, S. M.; Lee, Y. M.; Kwon, T. W. Solvent-free
bentonite-catalyzed condensation of malonic acid aromatic aldehydes under
microwave irradiation. J. Chem. Soc., Perkin Trans 1 2001, 1220.
4. Jones, G. Organic Reactions; Wiley: New York, 1967; Vol. 15, p. 204.
5. Angeletti, E.; Canepa, C.; Martinetti, G.; Venturello, P. Silica gel functionalized
with amino groups as a new catalyst for Knoevenagel condensation under hetero-
geneous catalysis conditions. Tetrahedron Lett. 1988, 29, 2261.
6. Prajapati, D.; Sandhu, J. S. Cadmium iodine as a new catalyst for Knoevenagel
condensations. J. Chem. Soc., Perkin Trans 1 1993, 739.
7. Lehnert, W. Knoevenagel condensation with titanium (IV) chloride-base catalyst
V: 3-Alkylidene and 3-aralkylidene-2,4-pentanedione from aldehydes and acetyl-
acetones. Synthesis 1974, 667.

Green Procedure for Knoevenagel Condensation
2411
8. Li, Y. Q. Potassium phosphate as a catalyst for Knoevenagel condensation.
J. Chem. Res., Synop. 2000, 524.
9. Zhou, L. H.; Gao, Y.; Shi, D. Q.; Dai, G. Y. Condensation reaction of o-nitro-
aromatic aldehyde with active methylene compound catalyzed by potassium
fluoride on alumina. Chin. Chem. Reagents 1998, 20, 135.
10. Wang, Q. L.; Ma, Y. D.; Zuo, B. J. Knoevenagel condensation catalyzed by Usy
zeolite. Synth. Commun. 1997, 27, 4107.
11. Chalais, S.; Laszle, P.; Mathy, A. Catalysis of the Knoevenagel condensations.
Tetrahedron Lett. 1985, 26, 4453.
12. Jin, T. S.; Zhang, J. S.; Wang, A. Q.; Li, T. S. An efficient and environment
friendly procedure for the synthesis of arylmethylenemalononitrile catalyzed by
strong base anion-exchange resin in water. Synth. Commun. 2004, 34, 2611.
13. (a) Rao, P. S.; Venkataratnanm, R. V. Zinc chloride as a new catalyst for Knoeve-
nagel condensation. Tetrahedron Lett. 1991, 32, 5821; (b) Cabello, J.A.;
Campelo, J.M.; Garcia, A.; Luna, D.; Marinas, J.M. Knoevenagel condensation
in the heterogeneous phase using AlPO4-Al2O3 as a new catalyst. J. Org. Chem.
1984, 49, 5195; (c) Wang, X. S.; Zeng, Z. S.; Li, Y. L.; Shi, D. Q.; Tu, S. J.;
Wei, X. Y.; Zong, Z. M. Simple procedure for the synthesis of arylmethylenema-
lononitrile without catalyst. Synth. Commun. 2005, 35, 1915.
14. Kaupp, G.; Naimi-Jamal, M. R. Schmeyers, J Solvent-free Knoevenagel conden-
sations and Michael additions in the solid state and in the melt with quantitative
yield. Tetrahedron 2003, 59, 3753.
15. Wada, S.; Suzuki, H. Calcite and fluorite as catalyst for the Knoevenagel conden-
sation of malononitrile and methyl cyanoacetate under solvent-free conditions.
Tetrahedron Lett. 2003, 44, 399.
16. Franca, B.; Luca, C.; Raimondo, M.; Giovanni, S. Montmorillonite KSF as an
inorganic, water stable, and reusable catalyst for the Knoevenagel synthesis of
coumarin-3-carboxylic acids. J. Org. Chem. 1999, 64, 1033.
17. Prajapati, D.; Sandhu, J. S. Bismuth (III) chloride as a new catalyst for Knoevena-
gel condensation in the absence of solvent. Chem. Lett. 1992, 1945.
18. Cao, Y. Q.; Dai, Z.; Zhang, R.; Chen, B. H. A practical Knoevenagel condensation
catalyzed by PEG400 and anhydrous K2CO3 without solvent. Synth. Commun.
2004, 34, 2965.
19. Mongilaiah, K.; Prashanthi, G. Microwave assisted Knoevenagel condensation
using sodium fluoride and lithium chloride as a catalyst under solvent-free con-
ditions. Synth. Commun. 2003, 33, 2309.
20. Bogdal, D. Fast synthesis by Knoevenagel condensation under microwave
irradiation. J. Chem. Res., Synop. 1998, 468.
21. Harjarni, J. R.; Nara, S. J.; Salunkhe, M. M. Lewis acidic ionic liquids for the
synthesis of electrophilic alkenes via the Knoevenagel condensation. Tetrahedron
Lett. 2002, 43, 1127.
22. Su, C.; Chen, Z. C.; Zheng, Q. G. Organic reactions in ionic liquids:
Knoevenagel condensation catalyzed by ethylenediammonium diacetate.
Synthesis 2003, 4, 555.
23. Ren, Z. J.; Cao, W. G.; Tong, W. Q. The Knoevenagel condensation reaction of
aromatic aldehydes with malononitrile by grinding in the absence of solvent and
catalyst. Synth. Commun. 2002, 32, 3475.
24. Quiroga, J.; Alvarado, M.; Insuatry, B.; Moreno, R. Reaction of 5- aminopyrazoles
with b-dimethylaminopropiophenones synthesis of new pyrazole[3,4-b]pyridimes.
J. Heterocycl. Chem. 1999, 36, 1311.

2412
L. Rong et al.
25. (a) Freeman, F. Properties and reactions of ylidenemalononitriles. Chem. Rev.
1980, 80, 329; (b) Freemn, F. Reactions of malononitrile derivatives. Synthesis.
1981, 925; (c) Sasaki, T.; Minamato, K.; Suzuki, T.; Yamashita, S. Search for a
simple synthetic model system for intramolecular 1,3-dipolar cycloaddition to
the 5,6-double bond of pyrimidine nucleoside. Tetrahedron 1980, 36, 865.
26. Wang, S. X.; Li, J. T.; Yang, W. Z.; Yin, Y. H.; Xie, Z. H. Solvent-free synthesis of
ethyl a-cyanocinnamates catalyzed by K2O-Al2O3 using grinding method. Synth.
Commun. 2004, 34, 829.
27. Lu, Y. Y.; Ren, Z. J.; Cao, W. G.; Tong, W. Q.; Gao, M. F. Solvent-free synthesis
of ethyl a-cyanocinnamate in the presence of CaO. Synth. Commun. 2004, 34,
2047.
28. Geng, L. J.; Wang, S. X.; Li, J. T.; Liu, C. H. preparation of derivatives of
5-arylidene babituric acid by grinding method. Chin. J. Org. Chem. 2002, 22,
1047.
29. Tu, S. J.; Rong, L. C.; Gao, Y.; Guo, S. M.; Lu, S. H.; Yang, X. J. Solid phase
synthesis of arylmethylenemalononitrile and arylmethylenecyanoacetamide.
Chin. J. Org. Chem. 2002, 22, 364.