An Efficient Knoevenagel Condensation Catalyzed by LaCl3.7H 2O in Heterogeneous Medium

Article abstract of DOI:10.1081/SCC-120025194

Knoevenagel condensation was carried out in absence of solvent with a mild Lewis acid Lanthanum(III) chloride, to prepare substituted alkenes. A systematic study of the reaction to establish the generality of the method has been undertaken with various aldehydes and active methylene compounds.

Full text of DOI:10.1081/SCC-120025194

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An Efficient Knoevenagel Condensation Catalyzed by
LaCl3.7H2O in Heterogeneous Medium#
A. Venkat Narsaiah a & Dr. K. Nagaiah a
a Organic Chemistry Division, Fine Chemicals Laboratory, Indian Institute of Chemical
Technology, Hyderabad, India
Version of record first published: 16 Aug 2006.
To cite this article: A. Venkat Narsaiah & Dr. K. Nagaiah (2003): An Efficient Knoevenagel Condensation Catalyzed by
LaCl3.7H2O in Heterogeneous Medium# , Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 33:21, 3825-3832
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 21, pp. 3825–3832, 2003
An Efficient Knoevenagel Condensation
Catalyzed by LaCl3.7H2O in
Heterogeneous Medium#
*
A. Venkat Narsaiah and K. Nagaiah
Organic Chemistry Division, Fine Chemicals
Laboratory, Indian Institute of Chemical Technology,
Hyderabad, India
ABSTRACT
Knoevenagel condensation was carried out in absence of solvent with
a mild Lewis acid Lanthanum(III) chloride, to prepare substituted
alkenes. A systematic study of the reaction to establish the generality
of the method has been undertaken with various aldehydes and
active methylene compounds.
Key Words: Lanthanum chloride; Knoevenagel condensation;
Active methylene compounds; Substituted alkenes; Trimethoprim.
*Correspondence: Dr. K. Nagaiah, Organic Chemistry Division, Fine Chemicals
Laboratory, Indian Institute of Chemical Technology, Tarnaka, Hyderabad-
500 007, India; Fax: þ91-40-27160512; E-mail: nagaiah@iict.ap.nic.in.
3825
DOI: 10.1081/SCC-120025194
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

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3826
Narsaiah and Nagaiah
INTRODUCTION
The reaction of active methylene carbon with carbonyl compounds is
a classical synthetic route to make carbon–carbon bond. Knoevenagel[1]
condensation is one of the most important preparating method for
substituted alkenes and it has numerous applications in the elegant
synthesis of fine chemicals which are valuable precursors to a wide variety
of target molecules in pharmaceutical industry. It may be carried out either
in homogeneous or heterogeneous phase. Ammonium[2] salts (primary,
secondary, and tertiary) generally catalyzed these reactions. There are
few reports with Lewis[3] acids (ZnCl2, TiCl4-Base). In recent years, the
use of inorganic solid[4] supports as catalyst (Al2O3 LiBr SiO2, AlPO4-
Al2O3, Clay-KSF, K10-ZnCl2, and xonolite, Silicagel functionalized
with amine group), is well known. Most of the organic reactions have
been studying in solvent medium. But there is a considerable interest in
developing solvent-free green processes. It may be conventional or non-
conventional where as in conventional, the reactants, reagents, and catalyst
were mixed and heated to a required temperature without any solvent.
In continuation of our ongoing research efforts to develop newer,
environmentally benign methods for chemical transformations, we
decided to investigate the effect of a milder Lewis acid i.e., Lanthanum(III)
chloride as a catalyst for Knoevenagel condensation. The earlier known
work in this area is permitted only to the reactions of acetalization,[5]
selective reductions in association with sodium borohydride[6] (NaBH4)
and lithium aluminum hydride (LAH).[7]
Herein, we wish to report the use of a new catalyst, Lanthanum(III)
chloride heptahydrate, for the preparation of substituted alkenes in
heterogeneous phase in the absence of solvent at 80–85ꢀC (Sch. 1). It
can perform, the reaction to produce the products in high purity and
excellent yields. The efficient Knoevenagel condensation between diethyl
malonate, dicyano malonate, ethyl cyano malonate, and different alde-
hydes, consequently a systematic and comparative study of this reaction
R
R1
CHO
.
R
R1
2
LaCl3 7H2O
+
80-85˚C
X
X
1
3
X = H, OH, Me, OMe, Cl, NO2
R1, R2 = CN, CO2Et
Scheme 1.

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Knoevenagel Condensation Catalyzed by LaCl3.7H2O
3827
CN
CN
CO Et
2
CO Et
CHO
OMe
2
CN
CO Et
2
OMe
OMe
OMe
MeO
MeO
MeO
H N
2
OMe
OMe
NH
H N
2
4
5
6
7
MeO
N
H2N
MeO
NH
2
OMe
8,Trimethoprim
Scheme 2.
to establish the generality of the method has been undertaken with var-
ious aromatic aldehydes, bearing a variety of functional groups such as
electron donating groups (hydroxy, methoxy, chloro, methyl) and
electron withdrawing group (nitro) and aliphatic aldehydes were also
studied. Aliphatic aldehydes did not give good results but aromatic
aldehydes reacts faster and in excellent yields. The reaction conditions
and the corresponding yields of these active methylene species suggest
their reactivity order is CN>CO2Et. The results obtained with various
aldehydes and different malonates were shown in Table 1.
In the reaction of 3,4,5-trimethoxybenzaldehyde and active
methylene compound of ethyl cyano acetate, the product obtained
compound 6 was treated with Pd/c to saturate the double bond. This
saturated product 7 on condensation with guanidine[8] by literature
procedure gives a product which is a well known antibacterial agent
called ‘‘Trimethoprim.’’ This is an easy and convenient method for the
preparation of Trimethoprim (Sch. 2).[9]
In conclusion, we have demonstrated the general utility of
Lanthanum(III) chloride heptahydrate in the Knoevenagel condensation.
The reaction of carbonyl substrates and active methylene compounds,
using LaCl3.7H2O in catalytic (0.01 equiv.) amount to produce the cor-
responding olefinic products in excellent yields, without using any solvent
and easy work-up procedures.
EXPERIMENTAL
General Procedure for the Synthesis of Substituted Alkenes
To a mixtures of the carbonyl compound (10 mmol) and active
methylene compound (10 mmol) was added Lanthanum(III) chloride

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3828
Narsaiah and Nagaiah
Table 1. Knoevenagel condensation catalyzed by Lanthanum(III) chloride.
Entry
1
R
R1
CN
R2
Producta
Time (h) Yieldb
CN
H
CO2Et
1.5
2.0
89
85
CO2Et
CN
2
4-CH3
CN
CO2Et
CN
CO2Et
H3C
CN
CN
3
4
2-Cl 4-Cl CN
1.0
2.5
90
86
Cl
Cl
CO2Et
4-OCH3
CO2Et CO2Et
CO2Et CO2Et
CO2Et
MeO
CO2Et
CO2Et
5
6
H
2.5
1.5
84
90
CN
CN
4-OCH3
CN
CN
CN
MeO
HO
CN
7
8
4-OH
CO2Et
2.5
2.5
85
87
CO2Et
CO2Et
4-NO2
CO2Et CO2Et
CO2Et
CN
O2N
9
2-Cl 4-Cl CN
CO2Et
CN
1.5
88
CO2Et
Cl
Cl
CN
CN
10
11
H
CN
1.0
3.0
95
80
CO2Et
CO2Et
4-OH
CO2Et CO2Et
HO
CN
CO2Et
12
4-OCH3
CN
CO2Et
2.0
88
MeO
aAll the products were characterized by comparison of their M.p, IR and
1H NMR spectra with those of authentic samples.[10]
bIsolated yields.
(1 mmol) heptahydrate at room temperature. After being stirred for few
minutes, the resulting mixture was heated at 80–85ꢀC in an oil bath for
required time (see in Table 1). Then it was cooled to room temperature,
the solidified material was dissolved in ethyl acetate and washed with
water. The organic layer was dried over Na2SO4 and concentrated to

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Knoevenagel Condensation Catalyzed by LaCl3.7H2O
3829
yield crude product, which was purified by column chromatography.
(Silicagel 60–120 mesh).
Preparation of Ethyl 3,4,5-Trimethoxy
Benzylidene Malononitrile (6)
To a mixture of 3,4,5-trimethoxy benzoldehyde (1.96 gm, 10 mmol)
and ethyl cyano acetic acid (1.13 gm, 10 mmol) was added Lanthanum(III)
chloride hyptahydrate (0.245 g, 1 mmol). The contents were heated to
80–85ꢀC for 1 h. Then cooled to room temperature and the solidified
mass was dissolved in ethyl acetate (25 mL) washed with water the
organic layer was dried over Na2SO4 and concentrated to yield crude
product, which was purified by column chromatography to yield a
1
white solid (2.62 g, 90%). H NMR (CDCl3): ꢀ 8.08 (s, 1H), 7.27 (s, 2H),
4.3 (q, 2H, OCH-CH3, J ¼ 6.5 Hz), 3.9 (two singlets, 9H), 1.35–1.45
(t, 3H, J ¼ 6 Hz). IR (CDCl3): 3100–2800, 2210, 1705, 1600 cmꢁ1
.
Preparation of Ethyl Ester 2-(3,4,5-Trimethoxy Benzyl)
Cyano Acetic Acid (7)
A mixture of alkene compound[6] (2.0 g), Ethyl acetate (20 mL) and
10% pd/c (150 mg) were stirred under hydrogen atmosphere (Balloon) for
5 h at room temperature. The reaction mixture was filtered and purified
by column chromatography to yield pure product, light brown solid. The
1
yield was quantitative (96%). H NMR (CDCl3): ꢀ 6.5 (s, 2H), 4.2–4.35
(q, 2H, J ¼ 8 Hz), 3.8–3.9 (two singlets, 9H), 3.6–3.7 (q, 1H, J ¼ 6 Hz),
3.1–3.2 (q, 2H), 1.25–1.35 (t, 3H, J ¼ 6 Hz).
In the similar manner, the Knoevenagel condensations of aldehydes
(Showed in Table 1) were performed to obtain the corresponding malano
esters. The spectral data of entry 1–12 are as follows:
Entry-1. IR (Neat). 3100–2800, 2210, 1710, 1600 cmꢁ1 1H NMR
.
(CDCl3): ꢀ 8.25 (s, 1H), 8.0 (d, d, 2H), 7.5 (m, 3H), 4.35–4.4.45 (q, 2H,
OCH2-CH3, J ¼ 7 Hz), 1.38–1.48 (t, 3H, OCH2-CH3, J ¼ 7 Hz).
Entry-2. IR (Neat): 3100–2860, 2215, 1715, 1610 cmꢁ1 1H NMR
.
(CDCl3): ꢀ 8.2 (s, 1H), 7.8 (d, 2H, J ¼ 8.0 Hz), 7.3 (d, 2H, J ¼ 7.5 Hz),
4.4 (q, 2H, OCH2-CH3 J ¼ 6.5 Hz), 2.4 (s, 3H, Ar-CH3), 1.4 (t, 3H,
OCH2-CH3, J ¼ 6.5 Hz).
Entry-3. IR (Neat): 3050–2800, 2220, 1710, 1600 cmꢁ1 1H NMR
.
(CDCl3): ꢀ 8.23 (s, 1H), 8.18 (s, 2H), 7.6 (d, 1H), 7.5 (d, d, 1H,
J ¼ 8 Hz).

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Narsaiah and Nagaiah
1
Entry-4. IR (Neat): 3100–2800, 1730, 1605 cmꢁ1. H NMR (CDCl3):
ꢀ 7.6 (s, 1H), 7.35 (d, 2H, J ¼ 8.0 Hz), 6.8 (d, 2H, J ¼ 8.0 Hz), 4.4 (q, 2H,
J ¼ 7.0 Hz), 4.3 (q, 2H, J ¼ 7.0 Hz), 3.8 (s, 3H, OCH3), 1.4 (t, 3H,
J ¼ 7.0 Hz), 1.3 (t, 3H, J ¼ 7.0 Hz, OCH2-CH3).
1
Entry-5. IR (Neat): 3100–2800, 1730, 1630 cmꢁ1. H NMR (CDCl3):
ꢀ 7.8 (s, 1H), 7.5–7.3 (m, 5H, Ar-H), 4.4 (q, 2H, J ¼ 7.0 Hz, OCH2-CH3),
4.3 (q, 2H, J ¼ 7.0 Hz, OCH2-CH3), 1.32 (t, 3H, J ¼ 7.0 Hz, OCH2-CH3),
1.26 (t, 3H, J ¼ 7.0 Hz, OCH2-CH3).
Entry-6. IR (Neat): 3100–2800, 2230, 1700, 1620 cmꢁ1 1H NMR
.
(CDCl3): ꢀ 7.95 (d, 2H, J ¼ 8.5 Hz), 7.65 (s, 1H), 7.0 (d, 2H, J ¼ 8.5 Hz),
3.95 (s, 3H, OCH3).
Entry-7. IR (Neat): 3460–3180, 3080–2900, 2220, 1710, 1600 cmꢁ1
.
1H NMR (CDCl3): ꢀ 8.2 (s, 1H), 7.9 (d, 2H, J ¼ 8.0 Hz), 7.0 (d, 2H,
J ¼ 8.0 Hz), 4.4 (q, 2H, OCH2-CH3 J ¼ 7.0 Hz), 1.4 (t, 3H, OCH2-CH3,
J ¼ 7.0 Hz).
1
Entry-8. IR (Neat): 3100–2850, 1725, 1638 cmꢁ1. H NMR (CDCl3):
ꢀ 8.2–8.0 (d, 2H, J ¼ 10 Hz), 7.8 (s, 1H), 7.7–7.6 (d, 2H, J ¼ 10 Hz),
4.45–4.3 (m, 4H), 1.35–1.25 (t, 6H).
Entry-9. IR (Neat): 3100–2850, 2210, 1710, 1600 cmꢁ1 1H NMR
.
(CDCl3): ꢀ 8.6 (s, 1H), 8.3 (d, 1H, J ¼ 8.5 Hz), 7.6 (d, 1H), 7.45 (d, d,
1H, J ¼ 8.0 Hz), 4.4 (q, 2H, OCH2-CH3), 1.45 (t, 3H, OCH2-CH3).
1
Entry-10. IR (Neat): 3100–2800, 2230, 1700, 1620 cmꢁ1. H NMR
(CDCl3): ꢀ 7.9 (d, 2H, J ¼ 8.5 Hz), 7.8 (s, 1H), 7.5–7.7 (m, 3H).
1
Entry-11. IR (Neat): 3340, 3100–2900, 1730, 1630 cmꢁ1. H NMR
(CDCl3): ꢀ 7.7 (s, 1H), 7.4 (d, 2H, J ¼ 8.0 Hz), 6.9 (d, 2H, J ¼ 8.0 Hz),
6.75 (br, s, 1H, OH), 4.4 (q, 2H, OCH2-CH3 J ¼ 7.0 Hz), 4.3 (q, 2H,
J ¼ 7.0, OCH2-CH3), 1.3 (t, 6H, J ¼ 7.0 Hz, OCH2-CH3).
1
Entry-12. IR (Neat): 3100–2800, 2210, 1705, 1600 cmꢁ1. H NMR
(CDCl3): ꢀ 8.15 (s, 1H), 8.0 (d, 2H, J ¼ 7.0 Hz), 7.0 (d, 2H, J ¼ 7 Hz),
4.3–4.43 (q, 2H, OCH2-CH3, J ¼ 7 Hz), 3.9 (s, 3H, OCH3), 1.35–1.4
(t, 3H, OCH2-CH3, J ¼ 7 Hz).
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Knoevenagel Condensation Catalyzed by LaCl3.7H2O
3831
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Received in the UK May 17, 2003