Polyguanidine as a highly efficient and reusable catalyst for knoevenagel condensation reactions in water

Article abstract of DOI:10.1071/CH12507

Polyguanidine is used as a novel and highly efficient catalyst in the Knoevenagel reaction of aldehydes with active methylene compounds in water to afford substituted electrophilic alkenes. This method is applicable for a wide range of aldehydes including

Full text of DOI:10.1071/CH12507

CSIRO PUBLISHING
Aust. J. Chem. 2013, 66, 500–504
Full Paper
http://dx.doi.org/10.1071/CH12507
Polyguanidine as a Highly Efficient and Reusable Catalyst
for Knoevenagel Condensation Reactions in Water
A
,
C
B
,
C
A
A
Xian-Liang Zhao,
Ke-Fang Yang,
Xuan-Gan Liu, Chun-Lin Ye,
B
B
Li-Wen Xu, and Guo-Qiao Lai
A
School of Biological and Chemical Engineering, Zhejiang University of Science and
Technology, Hangzhou 310023, China.
B
Key Laboratory of Organosilicon Chemistry and Material Technology of Ministry of
Education, Hangzhou Normal University, Hangzhou 310012, China.
C
Corresponding authors. Email: xlzhao@iccas.ac.cn; kfyang@iccas.ac.cn
Polyguanidine is used as a novel and highly efficient catalyst in the Knoevenagel reaction of aldehydes with active
methylene compounds in water to afford substituted electrophilic alkenes. This method is applicable for a wide range of
aldehydes including aromatic and heterocyclic substrates. The polyguanidine catalyst can be recovered by simple filtration
and reused many times for the aqueous Knoevenagel reaction without loss of activity.
Manuscript received: 15 November 2012.
Manuscript accepted: 12 December 2012.
Published online: 24 January 2013.
Introduction
[13]
chemistry is to perform reactions in water.
In comparison
The Knoevenagel condensation is a powerful tool for the con-
struction of carbon-carbon bonds and has been widely applied
for the production of fine chemicals such as cosmetics and
drugs. The Knoevenagel condensation is generally carried out
in organic solvents with catalytic bases such as primary or
with organic solvents, water is not only cheap and safe, but also
shows unique properties in promoting reactions and enhancing
selectivities.
In this paper we report on the use of polyguanidine-type
catalysts for the reactions of malononitrile with various alde-
hydes in water to give the Knoevenagel condensation products
in excellent yields. It is notable that water can greatly accelerate
this reaction, even though the reactions were carried out in a
heterogeneous system. The polyguanidine catalyst can be
recovered and still retains high catalytic activity.
[
14]
[
1]
[
1b,1c]
[2]
secondary amines and their salts,
Lewis acids can also be used as catalysts in the Knoevenagel
or amino acids. Several
[
3,4]
reaction.
such as aluminium oxide, alkali-containing MCM-41, and
Recently, a wide range of heterogeneous catalysts
[
5]
[6]
[
zeolites have been used in this reaction, as have ionic liquids
7]
[
8]
and functional ionic liquids. On the other hand, there have
been several reports describing the use of amines immobilised
on polymers to catalyse the Knoevenagel reaction. Sotelo has
reportedthatpolystyrene-supported 1,1,3,3-tetramethylguanidine
was used as a catalyst for the Knoevenagel reaction in aceto-
Results and Discussion
The polyguanidine-type catalysts (PG-1–3) were synthesised
[
according to literature procedures (Scheme 1).
15]
PG-1–3
[
9]
nitrile and tetrahydrofuran. Tamami reported the use of the
amino group immobilised on polyacrylamide as a catalyst for
the Knoevenagel reaction in water or solvent-free conditions,
contain different degrees of cross-linking. They are insoluble in
common laboratory solvents. We further investigated the
catalytic activity of PG-1–3 with the results shown in Table 1
(Scheme 2). PG-2 was found to be the best catalyst for the
reaction of benzaldehyde 1a with malononitrile 2a in water. The
amount of 1,6-hexanediamine (C) used as the cross-linking
agent in PG-2 was 10 mol-%. With an increase in the proportion
of hexanediamine, the catalytic activity of the PG decreased.
The effects of the molar ratio of PG-2 on the Knoevenagel
reaction were also investigated. It was found that the product 3a
was formed in high yields with catalyst loadings of between
5 and 15 mol-%, however longer reaction times were needed
when using less catalyst (entries 2–4).
[
10]
although the reaction was slower in water.
However, there
still exist some disadvantages with these catalysts, such as dif-
ficulties with recovery and reuse, longer reaction times, and
complex reaction conditions.
Organosuperbases have attracted much attention due to the
ease with which their structures can be modified, the easy reuse
of recovered materials, and simple operation based on the acid–
[
11]
base concept.
reactions because of their stronger affinity to protons or other
nucleophiles.
They have been widely used for organic
[
12]
In addition, they can be anchored on a solid
support, solving the problem of recovery and recycling and
simplifying the procedure for product isolation and purification.
With increasing concern over environmental issues, one of
the fundamental changes and ultimate goals for organic
To examine solvent effects, various solvents were employed
in the reaction of 1a with 2a in the presence of catalyst PG-2
(20 mol-%) at room temperature (Table 2). It was found that this
reaction proceeded smoothly in organic solvents, but that
Journal compilation Ó CSIRO 2013
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Polyguanidine for Knoevenagel Condensation
501
NHCN
NCHN
H
N
H
N
H
N
H
N
A
ϩ
NH
N
N
a
NH HBr
BrHH N
2
2
6
B
ϩ
H
N
HN
NH
PG-1–3
NH
N
H
NH2
c
H N
2
b
C
Scheme 1. Synthesis of polyguanidine-type catalysts PG-1–3.
A
Table 1. Effects of catalysts PG on the reaction of 1a with 2a
A
Table 2. Solvent effects on the reaction of 1a with 2a
Entry
PG
A : B : C
Cat. loading
B
Time
[min]
Yield of 3a
C
[%]
B
Entry
Solvent
Reaction time [min]
Yield of 3a [%]
[
mol-%]
1
2
3
4
5
6
7
CH
2
Cl
2
90
90
90
10
15
6 h
10
86
88
91
90
92
93
94
1
2
3
4
5
6
PG-2
PG-2
PG-2
PG-2
PG-1
PG-3
1 : 0.8 : 0.2
20
15
10
5
10
94
95
93
92
88
89
THF
30
CH
CH
3
CN
OH
4 h
10 h
15
3
DMF
–
1 : 0.6 : 0.4
1 : 0.5 : 0.5
20
20
30
2
H O
A
Reaction conditions: 1a (1 mmol), 2a (1 mmol), catalyst, H
2
O (3 mL),
A
Reaction conditions: 1a (1 mmol), 2a (1 mmol), PG-2 (20 mol-%), solvent
room temperature.
B
The catalyst loading is calculated by molecular weight of one guanidine
(
B
3 mL), room temperature.
Isolated yield.
unit.
C
Isolated yield.
E
O
Ar
O
PG-2
H O, rt
PG-cat.
CN
ϩ
NC
E
CN
3a–t
ϩ
Ph
Ar
H
NC
CN
2
Ph
H
Solvent
CN
1a–j
2a, b
E: CN, CO
1
a
2a
3a
2
Me
Scheme 2. The reaction of 1a with 2a in water catalysed by PG.
Scheme 3.
reaction times over 60 min were required, except with CH OH
3
Compared with malononitrile, the reactions of ethyl cyanoa-
and DMF (entries 4 and 5). In addition, the reaction time was
prolonged to 6 h under solvent-free conditions (entry 6). It is
interesting to note that this reaction was completed in only
cetate with the same aromatic aldehydes needed more time
(entries 11–20, Table 3). Because the electron-withdrawing
ability of the CN group is stronger than that of the carbonyl or
carboxylic group, the methylene group of malononitrile is more
activated than ethyl cyanoacetate in its reaction with aromatic
aldehydes.
Furthermore, this method failed to give the desired olefinic
products from aldehydes and diethyl malonate. No further
improvement was observed in the reaction of benzaldehyde
(1a) with diethyl malonate either by increasing the amount of
PG-2 (stoichiometric ratio) or by raising the reaction
temperature.
In addition, the recyclability of the catalyst PG-2 was
examined (Fig. 1). Once product 3a was removed from the
reaction mixture (it dissolved in hot ethanol), PG-2 was directly
used for another cycle. It was found, as seen in Fig. 1, that the
catalyst showed no substantial reduction in activity even after
the tenth run. All reactions were completed in 10 min and
afforded 3a in yields of 90–94 %.
In conclusion, polyguanidine was employed as a novel and
efficient catalyst for the Knoevenagel condensation of aromatic
aldehydes with active methylene compounds in water. Further-
more, the attractive features of this procedure are the green and
1
0 min in water, with the yield of 3a reaching 94 % (entry 7). It is
clear that the reaction rate is faster in water than in organic non-
polar solvents or solvent-free conditions. Since polyguanidine
swells considerably in polar solvents, the guanidine functional
group is better able to catalyse the condensation reactions in
water than in other non-polar solvents. Any highly polar or polar
protic organic solvent is just as good as water, however these
solvents have toxicity problems compared with water.
Based on these results, various aldehydes were allowed to
react with active methylene compounds in the presence of PG-2
(20 mol-%) in water (Scheme 3, Table 3). Both electron-rich and
electron-deficient aromatic aldehydes worked well, giving high
yields of the products. Electron-deficient aldehydes needed
shorter reaction times and gave somewhat higher yields than
their electron-rich counterparts (entries 1–6, Table 3).
Heterocyclic aldehydes, such as furfural and thiophene-2-
carboxaldehyde, also gave high yields (entries 9–10, Table 3).
However, aliphatic aldehydes afforded complex mixtures
including aldol products and Michael addition products (entries
7
–8, Table 3).

5
02
X.-L. Zhao et al.
A
Table 3. Reaction of aldehydes (1a]j) with 2a]b in water catalysed by PG-2
B
Entry
1
Aldehyde
CHO
2 (E)
Time [min]
10
Product
Yield [%]
CN
CN
1
a
3a
3b
2a CN
94
93
CHO
CN
CN
1
b
2
3
2a
2a
10
15
Cl
Cl
Cl
Cl
CHO
CHO
CN
CN
92
1
1
c
3c
CN
CN
d
3d
4
5
6
2a
2a
2a
8
20
15
90
93
94
O N
O N
2
2
CHO
CHO
CN
CN
3
e
1
e
MeO
MeO
CN
CN
1
f
3f
HO
HO
CN
CN
3
g
CHO
CHO
1
g
7
8
9
2a
2a
2a
2a
40
40
15
15
15
–
CN
CN
3h
1
h
–
CHO
CHO
CN
CN
1
i
3i
91
93
92
O
O
S
CN
CN
1
j
3j
1
1
0
1
S
CO Me
2
3
k
1a
2
2b CO Me
CN
CO Me
2
3
l
Cl
1
1
2
3
1b
1c
2b
15
20
92
90
CN
Cl
CO Me
2
2b
3
m
CN
CO Me
2
3
n
1
1
1
4
5
6
1d
1e
1f
2b
2b
2b
13
30
25
93
92
93
CN
O N
2
CO Me
2
3
OMe
o
CN
CO Me
2
3
p
HO
CN
(
Continued)

Polyguanidine for Knoevenagel Condensation
503
Table 3. (Continued)
B
Entry
Aldehyde
2 (E)
Time [min]
Product
Yield [%]
–
CO Me
2
3
q
17
18
19
20
1g
2b
60
60
15
60
CN
CO Me
–
2
1h
1i
2b
2b
2b
3r
CN
CO Me
2
3s
91
94
O
S
CN
CO Me
2
3
t
1j
CN
A
B
2
Reaction conditions: aldehyde (1 mmol), active methylene compound (1 mmol), PG-2 (20 mol-%) in H O (3 mL), room temperature.
Isolated yield.
100
General Procedure for the Knoevenagel Condensation
A 10 mL round bottomed flask was charged with the carbonyl
compound (1 mmol), active methylene compound (1 mmol),
PG-2 (14 mg, 20 mol-%), and water (3 mL). The reaction mix-
ture was stirred at room temperature for the time shown in
Table 3. Progress of the reaction was monitored by TLC, using
n-hexane–EtOAc (5 : 1) as eluent. After completion of the
reaction, the reaction mixture often solidified in the round bot-
tomed flask. The solids were dissolved in hot ethanol (30 mL).
The catalyst was removed by filtration and washed with hot
ethanol. The solid product was obtained after solvents were
9
8
0
0
1
2
3
4
5
6
7
8
9
10
removed under vacuum. The product 3a was purified through
1
recrystallisation from ethanol. H NMR (CDCl , 400 MHz)
Run number
3
d ¼ 7.91 (d, J ¼ 7.8 Hz, 2H), 7.80 (s, 1H), 7.65 (t, J ¼ 7.3 Hz,
1
3
Fig. 1. Recycling of catalyst PG-2 in the aqueous reaction of 1a with 2a.
Reaction conditions: 1a (1 mmol), 2a (1 mmol), solvent (3 mL), PG-2
1
H), 7.56 (t, J ¼ 7.8 Hz, 2H). C NMR (CDCl , 100 MHz)
3
d ¼ 159.9, 134.6, 130.9, 130.7, 129.6, 113.7, 112.5, 82.9.
(20 mol-%), room temperature. The yield of 3a is the isolated yield.
Supplementary Material
mild reaction conditions, medium to short reaction times,
excellent yields, and operational simplicity. The catalysts can
be recycled more than ten times without obvious loss of catalytic
activity. Thus, we believe that this simple and green procedure
will be a practical method to cater for the needs of academia as
well as chemical industries. The scope and synthetic application
of the polyguanidine catalyst is under investigation.
Experimental procedures, characterisation data and copies of
1
13
H and C NMR spectra are available on the Journal’s website.
Acknowledgements
We thank the National Natural Science Foundation of China (grant no.
2
1242004) and Education Program of Zhejiang Province (Y200803767).
Experimental
References
Typical Procedure for Preparation of Catalyst PG-2
[
1] (a) E. Knoevenagel, Ber. Dtsch. Chem. Ges. 1898, 31, 2585.
doi:10.1002/CBER.18980310307
To a solution of hexamethylenediamine (2.32 g, 0.02 mol) in
isopropanol was added hexamethylenedicyanamide (16.60 g,
(b) G. Jones, Org. React. 1967, 15, 204.
0
0
.1 mol) and hexamethylenediamine dihydrobromide (22.08 g,
.08 mol). The mixture was heated at reflux for 6 h. After the
(c) L. F. Tietze, Chem. Rev. 1996, 96, 115. doi:10.1021/CR950027E
(d) L. F. Tietze, U. Beifuss, in Comprehensive Organic Synthesis (Eds
B. M. Trost, I. Fleming, C. H. Heathcock) 1991, Vol. 2, pp. 341–392
reaction, the isopropanol was removed by distillation under
reduced pressure, leaving a colourless, transparent, gel-like
mass. The crude product was solidified by being heated at 1308C
for 3 h, resulting in 41 g of a water-insoluble resinous product.
The product was then soaked in 100 g of an aqueous solution of
NaOH (10 %) at room temperature for 24 h, then the product was
filtered and repeatedly washed with hot water (608C) until pH
was neutral. The product was dried in a vacuum drying oven at
(
(
Pergamon Press: Oxford).
e) F. Bigi, L. Chesini, R. Maggi, G. Sartori, J. Org. Chem. 1999, 64,
1
033. doi:10.1021/JO981794R
f) N. Yu, J. M. Aramini, M. W. Germann, Z. Huang, Tetrahedron Lett.
000, 41, 6993. doi:10.1016/S0040-4039(00)01195-3
(
2
[
2] G. Cardillo, S. Fabbroni, L. Gentilucci, M. Gianotti, A. Tolomelli,
Synth. Commun. 2003, 33, 1587. doi:10.1081/SCC-120018782
[3] W. Lehnert, Tetrahedron Lett. 1970, 11, 4723. doi:10.1016/S0040-
6
08C for 24 h to give catalyst PG-2.
4039(00)89377-6

5
04
X.-L. Zhao et al.
[
4] F. Delgado, J. Tamariz, G. Zepeda, M. Landa, R. Miranda, J. Garcia,
[11] P. Anastas, J. C. Warner, Green Chemistry: Theory and Practice 1998
(Oxford University Press: Oxford).
Synth. Commun. 1995, 25, 753. doi:10.1080/00397919508011413
5] F. Texier-Boullet, A. Foucaud, Tetrahedron Lett. 1982, 23, 4927.
doi:10.1016/S0040-4039(00)85749-4
[
[
[
[12] Superbases for Organic Synthesis: Guanidines, Amidines and Phos-
phazenes and Related Organocatalysts (Ed. T. Ishikawa) 2009 (Wiley-
VCH: Weinheim).
6] Y. V. Subba Rao, D. E. De Vos, P. A. Jacobs, Angew. Chem. Int. Ed.
1977, 36, 2661.
[13] (a) C.-J. Li, L. Chen, Chem. Soc. Rev. 2006, 35, 68. doi:10.1039/
B507207G
7] (a) T. I. Reddy, R. S. Varma, Tetrahedron Lett. 1997, 38, 1721.
doi:10.1016/S0040-4039(97)00180-9
(b) D. Dallinger, C. O. Kappe, Chem. Rev. 2007, 107, 2563.
doi:10.1021/CR0509410
(
b) Q. L. Wang, Y. D. Ma, B. Zuo, Synth. Commun. 1997, 27, 4107.
doi:10.1080/00397919708005458
8] (a) C. Su, Z.-C. Chen, Q. G. Zheng, Synthesis 2003, 555.
(c) V. Polshettiwar, R. S. Varma, J. Org. Chem. 2007, 72, 7420.
doi:10.1021/JO701337J
[14] (a) C. J. Li, T. H. Chan, Organic Reactions in Aqueous Media 1997
[
(
b) J. R. Harjani, S. J. Nara, M. M. Salunkhe, Tetrahedron Lett. 2002,
3, 1127. doi:10.1016/S0040-4039(01)02341-3
c) D. W. Morrison, D. C. Forbes, J. H. Davis, Jr, Tetrahedron Lett.
001, 42, 6053. doi:10.1016/S0040-4039(01)01228-X
d) F. A. Khan, J. Dash, R. Satapathy, S. K. Upadhyay, Tetrahedron
Lett. 2004, 45, 3055. doi:10.1016/J.TETLET.2004.02.103
e) B. C. Ranu, R. Jana, Eur. J. Org. Chem. 2006, 3767. doi:10.1002/
EJOC.200600335
f) Y. O. Sharma, M. S. Degani, Green Chem. 2009, 11, 526.
doi:10.1039/B818540A
g) D. Z. Xu, Y. J. Liu, S. Shi, Y. M. Wang, Green Chem. 2010, 12, 514.
4
(John Wiley: New York, NY).
(
2
(b) Organic Synthesis in Water (Ed. P. A. Grieco) 1998 (Thomson
Science: Glasgow)
(
(c) U. M. Lindstrom, Chem. Rev. 2002, 102, 2751. doi:10.1021/
CR010122P
(d) C. J. Li, Chem. Rev. 2005, 105, 3095. doi:10.1021/CR030009U
(e) C. J. Li, Chem. Rev. 1993, 93, 2023. doi:10.1021/CR00022A004
(f) A. Chanda, V. V. Fokin, Chem. Rev. 2009, 109, 725. doi:10.1021/
CR800448Q
(
(
(
(g) R. N. Butler, A. G. Coyne, Chem. Rev. 2010, 110, 6302.
doi:10.1021/CR100162C
doi:10.1039/B918595J
9] A. Coelho, A. Crespo, F. Fernandez, P. Biagini, A. Stefanachi,
[
[15] K. Sugino, K. Shirai, R. Kitawaki, J. Org. Chem. 1961, 26, 4122.
doi:10.1021/JO01068A610
E. Sotelo, Comb. Chem. High T. Scr. 2008, 11, 843. doi:10.2174/
138620708786734253
[10] B. Tamami, A. Fadavi, Catal. Commun. 2005, 6, 747. doi:10.1016/
J.CATCOM.2005.07.012