Knoevenagel condensation catalyzed by 1,1,3,3-tetramethylguanidium lactate

Article abstract of DOI:10.1080/00397910600941190

Knoevenagel condensation between malononitrile or ethyl cyanoacetate and carbonyl compounds could be effectively promoted by 1,1,3,3-tetramethylguanidium lactate, a basic ionic liquid, under mild conditions. Good to high isolated yields could be obtained.

Full text of DOI:10.1080/00397910600941190

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Knoevenagel Condensation Catalyzed by
1,1,3,3‐Tetramethylguanidium Lactate
Jicheng Zhang a , Tao Jiang a , Buxing Han a , Anlian Zhu a & Xiumin Ma a
a Beijing National Laboratory for Molecular Sciences (BNLMS), Center for
Molecular Sciences , Institute of Chemistry, Chinese Academy of Sciences ,
Beijing, China
Published online: 23 Nov 2006.
To cite this article: Jicheng Zhang , Tao Jiang , Buxing Han , Anlian Zhu & Xiumin Ma (2006) Knoevenagel
Condensation Catalyzed by 1,1,3,3‐Tetramethylguanidium Lactate, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 36:22, 3305-3317, DOI:
10.1080/00397910600941190
To link to this article: http://dx.doi.org/10.1080/00397910600941190
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Synthetic Communicationsw, 36: 3305–3317, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910600941190
Knoevenagel Condensation Catalyzed by
1,1,3,3-Tetramethylguanidium Lactate
Jicheng Zhang, Tao Jiang, Buxing Han, Anlian Zhu, and
Xiumin Ma
Beijing National Laboratory for Molecular Sciences (BNLMS), Center
for Molecular Sciences, Institute of Chemistry, Chinese Academy of
Sciences, Beijing, China
Abstract: Knoevenagel condensation between malononitrile or ethyl cyanoacetate and
carbonyl compounds could be effectively promoted by 1,1,3,3-tetramethylguanidium
lactate, a basic ionic liquid, under mild conditions. Good to high isolated yields
could be obtained. The ionic liquid can enhance the reaction rates significantly even
though it was used in catalytic amount. The ionic liquid could be prepared simply
and reused efficiently.
Keywords: Carbonyl compounds, condensation, ethyl cyanoacetate, ionic liquids,
Knoevenagel, malononitrile
The Knoevenagel condensation reaction is an effective C55C formation
reaction between carbonyl or heterocarbonyl compounds and any com-
pounds having an active methylene group.[1] This reaction was widely used
in the preparation of natural products,[2] functional polymers,[3] fine
chemicals,[4] and so forth. Generally, the reaction is performed in the
presence of bases, such as piperidine, pyridine, or their according salts.[1] Up
to now, a wide variety of new catalysts, such as Lewis acids,[5] inorganic
solids with special structure,[6] and amines immobilized on polymers,[7] have
been developed for this reaction. At the same time, grinding without
Received in Japan December 24, 2005
Address correspondence to Tao Jiang or Buxing Han, Beijing National Laboratory
for Molecular Sciences (BNLMS), Center for Molecular Sciences, Institute of
Chemistry, Chinese Academy of Sciences, Beijing 100080, China. E-mail: jiangt@
iccas.ac.cn; hanbx@iccas.ac.cn
3305

3306
J. Zhang et al.
solvent,[8] aqueous synthesis,[9] high pressure,[10] microwave,[11] and ultrasound[12]
as new methods have been used in this reaction.
We also notice that room-temperature ionic liquids (ILs), which are recog-
nized as important “green” solvents, have been applied widely in multifarious
reactions and often brought aboutunexpected results.[13] Of course, some research-
ers have already brought ILs into the Knoevenagel reaction. For example, Harjani
et al.[14] described their Knoevenagel condensation using Lewis acidic ILs contain-
ing AlCl3; Khan et al.[15a] reported they carried out their reaction in 1-butyl-3-
methylimidazolium hexafluorophosphate ([bmim]PF6) or 1-butyl-3-methylimida-
zolium tetrafluoroborate ([bmim]BF4) with or without catalyst. Their efforts
showed many merits of the ILs, such as accelerating the reaction, making the
workup easier, and the potential for recycling.
We had synthesized an IL, 1,1,3,3-tetramethylguanidium lactate, through
neutralizing 1,1,3,3-tetramethylguanidine with lactic acid.[16] It had already
been used in preparing the immobilized catalyst for heterogeneous hydro-
genation of olefins,[17] in desulfurization of simulated flue gas,[18] and particu-
larly in the reactions between aldehydes or acetones and the compounds with
active hydrogen, such as Henry reaction[19] and direct aldol reaction.[20] In our
continuous pursuit in this area, here we demonstrate the application of this IL
in the Knoevenagel condensation reaction. In contrast to the previous work in
which the ILs were used as solvents,[14,15,21] we observed that when this IL
was used in a catalytic amount, the Knoevenagel condensation between
ethyl cyanoacetate or malononitrile and carbonyl compounds (Scheme 1)
could be performed with high efficiency.
The reactions were conducted at room temperature. Only IL was added
into the reactants, provided the reactants could dissolve each other to form
a homogenous mixture. Ethyl acetate was added as the solvent to dissolve
the reactants, and IL was added if the reactants are inhomogeneous. Here,
the solvent was not optimized. The results are shown in Table 1.
We can see from Table 1 that the reactions using aromatic aldehydes with
various substituents, such as nitro, chloro, hydroxy, methoxy, and so on, could
be carried out smoothly (Entries 1–8, 12–17). Toward terephthalaldehyde,
both of the carbonyls could react with ethyl cyanoacetate to yield a bis-conden-
sation product (Entry 3). In addition, furfural (Entries 9, 18) and
E-cinnamaldehyde (Entries 10, 19), the a,b-unsaturated aldehydes, could also
react rapidly with both of the active methylene compounds. When
ethylcyanoacetate was used as the active methylene compound, only E isomers
were obtained because of steric effects, and this was confirmed by 1H NMR.[22]
Scheme 1.

Table 1. Knoevenagel condensation between ethyl cyanoacetate or malononitrile and carbonyl compounds catalyzed by 1,1,3,3-tetramethylguani-
dium lactatea
Entry
1
R1
R2
H
R3
Product
Reaction time
5 min
Isolated yield (%)
CO2Et
91
2b
H
H
CO2Et
CO2Et
10 min
5 min
90 (94, 4 h)e (93, 1 h)f
3c
94
4b
H
H
CO2Et
CO2Et
7 h
80 (91, 6 h)e (93, 1 h)f
88 (86, 8 h)e (95, 1 h)f
5
2.5 h
(continued)

Table 1. Continued
Entry
6
R1
R2
H
R3
Product
Reaction time
15 min
Isolated yield (%)
CO2Et
95
7
H
CO2Et
6 h
87 (86, 1 h)f
8
9
H
H
CO2Et
CO2Et
1 h
91
5 min
94 (91,92,91)d (84, 8 h)e
(96, 1 h)f
10
11
H
CO2Et
CO2Et
20 min
24 h
81 (87, 10 h)e
-(CH2)4-
66 (90, 6 h)f

12b
13b
H
H
CN
CN
10 min
20 min
83
80 (89, 5 h)e
14
H
H
H
H
H
CN
CN
CN
CN
CN
,5 min
,5 min
,5 min
7 h
95 (84, 8 h)e
15b
16
96
87 (83, 8 h)e (93, 1 h)f
17b
18
92
94
,5 min
(continued)

Table 1. Continued
Entry
19
R1
R2
H
R3
Product
Reaction time
5 min
Isolated yield (%)
81 (89, 8 h)e
CN
aReaction conditions: rt, solvent free (if not stated), 0.4 mmol of carbonyl compound, 0.4 mmol of active methylene compound, and 0.08 mmol of
IL (20% mol equivalent).
bWith 0.4 ml of ethyl acetate as solvent.
c0.4 mmol of terephthalaldehyde, 0.8 mmol of ethyl cyanoacetate, and 0.08 of mmol IL.
dThe data in parentheses were the isolated yields in runs 2–4 of the recycled IL, respectively.
eThe data in parentheses were quoted from literature;[21a] they were the isolated yields and the reaction time, respectively. Reaction conditions: rt,
2 mmol of aldehyde, 2 mmol of active methylene compound, and 2 ml of ethylammonium nitrate (EAN).
fThe data in parentheses were quoted from literature;[21c] they were the isolated yields and the reaction time, respectively. Reaction conditions: rt,
2 mmol of aldehyde, 2 mmol of active methylene compound, 20% mol of equivalent ethylenediammonium diacetate (EDDA) as catalyst, and 2 ml of
1-butyl-3-methylimidazolium tetrafluoroborate ([bmim]BF4) as the solvent.

1,1,3,3-Tetramethylguanidium Lactate
3311
To compare this work with recent research in which other ILs (ethylammonium
nitrate[21a] or 1-butyl-3-methylimidazolium tetrafluoroborate[21c]) were used
as the solvents, some literature data are shown in Table 1 (Entries 2, 4, 5, 7,
9–11, 13, 14, 16, 19). We can find that for most comparable reactions
(Entries 2, 5, 9, 10, 13, 14, 16, 19), in this work, although no other catalysts
were introduced and lower amounts of IL were used, similar yields could be
obtained within shorter time.
Unfortunately, when some aliphatic aldehydes (such as n-propanal,
n-butanal, or n-heptanal) or ketones (such as cyclopentanone in Entry 11,
acetone, or acetophenone) were used, a large amount of reactants remained
even after a long time. The decrease of their reactivities may result from
the electron-donating property of alkyl groups (for aliphatic aldehydes) or
the steric hindrance accompanied with electronic effects (for ketones).
Similar results were also reported by Cabello[6e] or Tamami.[7a]
In our experiments, almost all reactions cannot proceed smoothly without the
IL even after a long time under similar conditions. Furthermore, according to 1H
NMR data, all reactions produced only the Knoevenagel condensation products
and did not cause the formation of the Michael adduct for furfural and E-cinnamal-
dehyde or all other initial Knoevenagel products as electron-deficient alkenes.
As one of the noticeable properties, the recyclability of IL was also studied
in this work. From Table 1, we can find that the isolated yield after the fourth run
of the reaction between furfural and ethyl cyanoacetate (Entry 9) could be com-
parable to that in the first run. Therefore, this IL can be reused.
In conclusion, Knoevenagel condensation can be promoted by 1,1,3,3-
tetramethylguanidium lactate in a catalytic amount. Here, the aromatic
aldehydes with various substituents or a,b-unsaturated aldehydes could
react with ethyl cyanoacetate or malononitrile rapidly with high isolated
yields under mild conditions. The preparation of the IL was simple and its
recycling was easy without apparent decrease of catalytic activity. This IL
was an efficient and economical catalyst for the Knoevenagel reaction.
EXPERIMENTAL
The melting points of the products were measured on a digital electrothermal
1
melting-point apparatus and are uncorrected. H NMR spectra were deter-
mined in CDCl3 or DMSO-d6 on a Brucker 300-MHz or 400-MHz spec-
trometer at room temperature.
Typical Procedure
At room temperature, 0.4 mmol of carbonyl compound and 0.4 mmol of active
methylene compound were mixed in a 10-ml flask with or without solvent and
stirred magnetically untill all reagents were homogeneous. Then 0.08 mmol of

3312
J. Zhang et al.
IL was added into the flask. The reactions were monitored by thin-layer
chromatography (TLC). After the reaction was finished, 5 ml of water was
added, and the mixture was extracted three times with ethyl acetate, each
time 5 ml of ethyl acetate was used. The IL could be recycled after vaporizing
water, and the purified product could be obtained by column chromatography
on silica gel (200–300 mesh) using a mixture of petroleum ether (with a
boiling-point range of 60–908C) and ethyl acetate as the eluent. The
recycled IL could be used repeatedly under the same reaction conditions.
Data of the Products
Ethyl (E)-2-cyano-3-(3-nitrophenyl)-2-propenoate: colorless solid, mp 130–
1
1318C (lit.[23a] 128–1328C); H NMR (300 MHz, CDCl3) (ppm): 1.42 (t, 3H,
J ¼ 7.1 Hz, CH3), 4.41 (q, 2H, J ¼ 7.1 Hz, CH2), 7.74 (t, 1H, J ¼ 7.9 Hz,
ArH), 8.31 (s, 1H, C55CH), 8.40–8.43 (m, 2H, ArH), 8.70 (s, 1H, ArH).
Ethyl (E)-2-cyano-3-(4-nitrophenyl)-2-propenoate: pale yellow solid, mp
1
168–1698C (lit.[11b] 170–1718C); H NMR (300 MHz, CDCl3) (ppm): 1.42
(t, 3H, J ¼ 7.1 Hz, CH3), 4.42 (q, 2H, J ¼ 7.2 Hz, CH2), 8.14 (d, 2H,
J ¼ 8.7 Hz, ArH), 8.30 (s, 1H, C55CH), 8.35 (d, 2H, J ¼ 8.7 Hz, ArH).
Ethyl (E)-2-cyano-3-f4-[(E)-2-cyano-2-ethoxycarbonyl-ethenyl]phenylg-2-
propenoate: pale green solid, mp 199–2008C (lit.[23b] 202.2–203.28C);
1H NMR (300 MHz, CDCl3) (ppm): 1.42 (d, 3H, J ¼ 7.1 Hz, CH3), 4.41
(q, 2H, J ¼ 7.1 Hz, CH2), 8.09 (s, 4H, ArH), 8.25 (s, 2H, C55CH).
Ethyl (E)-3-(4-chlorophenyl)-2-cyano-2-propenoate: colorless solid, mp
89–908C (lit.[11b] 89–908C); 1H NMR (300 MHz, CDCl3) (ppm): 1.40
(t, 3H, J ¼ 7.1 Hz, CH3), 4.38 (q, 2H, J ¼ 7.2 Hz, CH2), 7.48 (d, 2H,
J ¼ 8.4 Hz, ArH), 7.93 (d, 2H, J ¼ 8.4 Hz, ArH), 8.19 (s, 1H, C55CH).
Ethyl (E)-2-cyano-3-phenyl-2-propenoate: colorless solid, mp 46–478C
1
(lit.[23c] 488C); H NMR (300 MHz, CDCl3) (ppm): 1.41 (t, 3H, J ¼ 7.1 Hz,
CH3), 4.39 (q, 2H, J ¼ 7.2 Hz, CH2), 7.49–7.59 (m, 3H, ArH), 8.00 (d, 2H,
J ¼ 7.3 Hz, ArH), 8.26 (s, 1H, C55CH).
Ethyl (E)-2-cyano-3-(3,4-methylenedioxyphenyl)-2-propenoate: pale
1
yellow solid, mp 102–1038C (lit.[23d] 1068C); H NMR (300 MHz, CDCl3)
(ppm): 1.38 (t, 3H, J ¼ 7.1 Hz, CH3), 4.36 (q, 2H, J ¼ 7.1 Hz, CH2), 6.09
(s, 2H, OCH2O), 6.90 (d, 1H, J ¼ 8.1 Hz, ArH), 7.41 (d, 1H, J ¼ 8.1 Hz,
ArH), 7.70 (s, 1H, ArH), 8.11 (s, 1H, C55CH).
Ethyl (E)-2-cyano-3-(4-methoxyphenyl)-2-propenoate: pale yellow solid,
1
mp 80–818C (lit.[23e] 81–828C); H NMR (300 MHz, CDCl3) (ppm): 1.39

1,1,3,3-Tetramethylguanidium Lactate
3313
(t, 3H, J ¼ 7.0 Hz, CH3), 3.89 (s, 3H, OCH3), 4.36 (q, 2H, J ¼ 7.1 Hz, CH2),
7.05 (d, 2H, J ¼ 8.4 Hz, ArH), 8.00 (d, 2H, J ¼ 8.5 Hz, ArH), 8.17 (s, 1H,
C55CH).
Ethyl (E)-2-cyano-3-(4-hydroxyphenyl)-2-propenoate: pale yellow solid,
1
mp 168–1698C (lit.[11b] 169–1718C); H NMR (300 MHz, CDCl3) (ppm):
1.39 (t, 3H, J ¼ 7.0 Hz, CH3), 4.37 (q, 2H, J ¼ 7.0 Hz, CH2), 5.81 (s, 2H,
OH), 6.96 (d, 2H, J ¼ 8.3 Hz, ArH), 7.96 (d, 2H, J ¼ 8.2 Hz, ArH), 8.18
(s, 1H, C55CH).
Ethyl (E)-2-cyano-3-(2-furyl)-2-propenoate: colorless solid, mp 88–898C
(lit.[11b] 89–918C); 1H NMR (300 MHz, CDCl3) (ppm): 1.38 (t, 3H,
J ¼ 7.1 Hz, CH3), 4.36 (q, 2H, J ¼ 7.14 Hz, CH2), 6.65–6.67 (m, 1H,
furfuryl), 7.38–7.39 (m, 1H, furfuryl), 7.75 (s, 1H, furfuryl), 8.02 (s, 1H,
C55CH).
Ethyl (2E, 4E)-2-cyano-5-phenyl-2, 4-pentadienoate: yellow solid, mp
1
101–1028C (lit.[23f] 109–1108C); H NMR (400 MHz, DMSO-d6) (ppm):
7.23 (dd, 1H, J ¼ 11.6 Hz, 15.3 Hz, C55CH), 7.47–7.49 (m, 3H, ArH),
7.71–7.75 (m, 3H, ArH and C55CH), 8.19 (d, 1H, J ¼ 11.6 Hz, C55CH).
Ethyl 2-cyano-2-cyclopentylidene-acetate: colorless solid, mp 48–498C
(lit.[23g] 54–558C); 1H NMR (300 MHz, CDCl3) (ppm): 1.34 (t, 3H,
J ¼ 7.1 Hz, CH3), 1.79–1.88 (m, 4H, -CH2CH2-), 2.80 (t, 2H, J ¼ 6.8 Hz,
CH2C55C), 2.99 (t, 2H, J ¼ 6.7 Hz, CH2C55C), 4.26 (q, 2H, J ¼ 7.1 Hz,
CH2 in ethoxy).
2-(3-Nitrophenylmethylene)malononitrile: colorless solid, mp 100–1018C
(lit.[11a] 1008C); 1H NMR (300 MHz, CDCl3) (ppm): 7.79 (t, 1H,
J ¼ 8.1 Hz, ArH), 7.88 (s, 1H, C55CH), 8.32 (d, 1H, J ¼ 7.8 Hz, ArH),
8.47 (d, 1H, J ¼ 8.3 Hz, ArH), 8.66 (s, 1H, ArH).
2-(4-Chlorophenylmethylene)malononitrile: colorless solid, mp 159–
1
1608C (lit.[23] h 1608C); H NMR (300 MHz, CDCl3) (ppm): 7.53 (d, 2H,
J ¼ 8.3 Hz, ArH), 7.74 (s, 1H, C55CH), 7.86 (d, 2H, J ¼ 8.3 Hz, ArH).
2-(Phenylmethylene)malononitrile: colorless solid, mp 80–818C (lit.[23i]
81–828C); 1H NMR (300 MHz, CDCl3) (ppm): 7.54 (t, 2H, J ¼ 7.5 Hz,
ArH), 7.64 (t, 1H, J ¼ 7.5 Hz, ArH), 7.78 (s, 1H, C55CH), 7.91 (d, 2H,
J ¼ 7.6 Hz, ArH).
2-(3,4-Methylenedioxyphenylmethylene)malononitrile: yellow solid, mp
1
196–1978C (lit.[23j] 198–1998C); H NMR (300 MHz, CDCl3) (ppm): 6.12
(s, 2H, OCH2O), 6.92 (d, 1H, J ¼ 8.2 Hz, ArH), 7.32 (d, 1H, J ¼ 8.2 Hz,
ArH), 7.59 (s, 2H, C55CH and ArH).

3314
J. Zhang et al.
2-(4-Methoxyphenylmethylene)malononitrile: yellow solid, mp 110–1118C
(lit.[23f] 112–1148C); 1H NMR (300 MHz, CDCl3) (ppm): 3.91 (s, 3H, OCH3),
7.01 (d, 2H, J ¼ 8.6 Hz, ArH), 7.65 (s, 2H, C55CH), 7.91 (d, 2H, J ¼ 8.6 Hz,
ArH).
2-(4-Hydroxyphenylmethylene)malononitrile: yellow solid, mp 183–1848C
1
(lit.[23k] 183–1868C); H NMR (300 MHz, CDCl3) (ppm): 5.57 (s, 1H, OH),
6.97 (d, 2H, J ¼ 8.6 Hz, ArH), 7.66 (s, 1H, C55CH), 7.89 (d, 2H,
J ¼ 8.6 Hz, ArH).
2-(2-Furylmethylene)malononitrile: pale yellow solid, 68–698C (lit.[11b]
1
67–688C); H NMR (300 MHz, CDCl3) (ppm): 6.71–6.72 (m, 1H, furfuryl),
7.36–7.37 (m, 1H, furfuryl), 7.52 (s, 1H, C55CH), 7.81 (s, 1H, furfuryl).
2-[(E)-Cinnamylidene]malononitrile: yellow solid, mp 121–1228C (lit.[23l]
126–1288C); 1H NMR (400 MHz, DMSO-d6) (ppm): 7.28 (dd, 1H,
J ¼ 11.5 Hz, 15.2 Hz, C55CH), 7.47–7.51 (m, 3H, ArH), 7.62 (d, 1H,
J ¼ 15.2 Hz, C55CH), 7.77–7.79 (m, 2H, ArH), 8.31 (d, 1H, J ¼ 11.4 Hz,
C55CH).
ACKNOWLEDGMENTS
This work was supported by National Natural Science Foundation of China
(20332030, 20473105).
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