Catalysis Communications
Short communication
Knoevenagel condensation of aromatic aldehydes with active methylene
compounds catalyzed by lipoprotein lipase
a,b,
Yan Ding a, Xiao Ni b, Mengjie Gu a, Shuang Li a,b, He Huang a,b, , Yi Hu
⁎
⁎
a
College of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University, Nanjing 210009, PR China
State Key Laboratory of Materials-Oriented Chemical Engineering, Nanjing Tech University, Nanjing 210009, PR China
b
a r t i c l e i n f o
a b s t r a c t
Article history:
A screening of using different lipases to catalyze the Knoevenagel reaction was realized, and lipase lipoprotein
(LPL) from Aspergillus niger showed the best catalytic performance. The reaction conditions including solvent, en-
zyme loading, and temperature were screened to improve the reaction efficiency. Various kinds of substrates
were investigated, and almost all the target products were obtained in good to excellent yields (76–98%) with
Z configuration exclusively. This procedure provides a novel, green and efficient method for the Knoevenagel
condensation of aromatic aldehydes with active methylene compounds.
Received 26 November 2014
Received in revised form 22 January 2015
Accepted 4 February 2015
Available online 7 February 2015
Keywords:
Lipases
© 2015 Elsevier B.V. All rights reserved.
Knoevenagel condensation
Aromatic aldehydes
Active methylene compounds
1. Introduction
could catalyze the Knoevenagel condensation of aromatic aldehydes
with 1, 3-carbonyl compounds in DMSO/H2O, while long reaction time
Knoevenagel condensation is one of the most important carbon–car-
bon double-forming reactions in organic synthesis, which is reacted be-
tween carbonyl compounds and active methylene compounds and
widely used in the synthesis of chemically, biologically, and pharmaceu-
tically significant compounds. Knoevenagel reaction was classically cat-
alyzed by organic base, Lewis acid, ionic liquids, microwave, ultrasound,
etc. [1–3]. However, many of these catalytic systems suffer from disad-
vantages such as excess starting materials needed, not being environ-
mentally friendly, inevitable byproducts formed, narrow substrates
scope, and sometimes only moderate yields and Z/E selectivity
obtained.
In recent years, enzymes as biocatalysts have attracted significant at-
tention due to their high selectivity and mild conditions [4,5]. Biocata-
lytic promiscuity provides new and green tools for organic synthesis,
and thus largely extends the application of enzymes [6–9]. But only lim-
ited examples of enzyme-catalyzed Knoevenagel condensation have
been reported. In 2009, Yu et al. first reported that lipase from Candida
antarctica (CAL-B) could catalyze decarboxylative Knoevenagel conden-
sation in CH3CN/H2O, while a primary amine was necessarily used as an
additive to form a schiff base in the course of the reaction and the active
methylene compounds was limited to β-ketoesters [10]. Moreover, the
mechanism of CAL-B catalyzed Knoevenagel condensation was chal-
lenged by Bornscheuer and Evitt [11]. It was reported that papain
(60 °C, 120 h) and excess substrates (1.2 equivalent) was used, and
for some substrates only low to moderate yields were achieved with
combined Z/E products [12]. Recently, esterase BioH showed the ability
to catalyze the Knoevenagel reaction in the DMF/H2O, nevertheless long
reaction time (168–200 h), large amount of excess 1,3-dicarbonyl
compounds (15 equivalent) was used, and low yields (35.1–54.7%)
were obtained [13]. Therefore, in the field of enzymatic Knoevenagel
condensation, there are still some drawbacks needed to be overcome,
such as narrow substrates scope, long reaction time, excess amount of
active methylene compounds, with additives, and expensive enzymes.
In continuation of our interest in the enzyme-catalyzed organic synthe-
sis [14–16], herein, we found that several lipases displayed observable
activities for Knoevenagel condensation, especially the commercially
cheap available lipase lipoprotein (LPL), from Aspergillus niger, could ef-
ficiently catalyze the Knoevenagel condensation of aromatic aldehydes
with various active methylene compounds in good to excellent yields
with Z configuration exclusively.
2. Experimental
2.1. Materials
Porcine pancreas lipase (PPL, 100–400 U/mg), Candida rugosa li-
pase (CRL, 1223 U/mg) and Bovine serum albumin (BSA) were pur-
chased from Sigma; Novozym 435 (lipase B from Candida antarctica,
immobilized on a macroporous acrylic resin) was purchased from
Novo Nordisk; Lipase PS (Pseudomonas cepacia lipase, ≥30 U/mg)
⁎
Corresponding authors at: State Key Laboratory of Materials-Oriented Chemical
Engineering, Nanjing Tech University, Nanjing 210009, PR China.
1566-7367/© 2015 Elsevier B.V. All rights reserved.