Elsevier

Catalysis Communications

Volume 64, 5 April 2015, Pages 101-104
Catalysis Communications

Short communication
Knoevenagel condensation of aromatic aldehydes with active methylene compounds catalyzed by lipoprotein lipase

https://doi.org/10.1016/j.catcom.2015.02.007Get rights and content

Highlights

  • A green and efficient enzymatic method for Knoevenagel condensation was developed.

  • Products were obtained in good to excellent yields in short reaction times.

  • Only Z-isomers were obtained under our reaction conditions.

Abstract

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, enzyme 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.

Introduction

Knoevenagel condensation is one of the most important carbon–carbon double-forming reactions in organic synthesis, which is reacted between carbonyl compounds and active methylene compounds and widely used in the synthesis of chemically, biologically, and pharmaceutically significant compounds. Knoevenagel reaction was classically catalyzed by organic base, Lewis acid, ionic liquids, microwave, ultrasound, etc. [1], [2], [3]. However, many of these catalytic systems suffer from disadvantages such as excess starting materials needed, not being environmentally 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 attention due to their high selectivity and mild conditions [4], [5]. Biocatalytic promiscuity provides new and green tools for organic synthesis, and thus largely extends the application of enzymes [6], [7], [8], [9]. But only limited 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 condensation 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 challenged by Bornscheuer and Evitt [11]. It was reported that papain could catalyze the Knoevenagel condensation of aromatic aldehydes with 1, 3-carbonyl compounds in DMSO/H2O, while long reaction time (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 synthesis [14], [15], [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 efficiently catalyze the Knoevenagel condensation of aromatic aldehydes with various active methylene compounds in good to excellent yields with Z configuration exclusively.

Section snippets

Materials

Porcine pancreas lipase (PPL, 100–400 U/mg), Candida rugosa lipase (CRL, 1223 U/mg) and Bovine serum albumin (BSA) were purchased 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) were kindly donated by Amano Pharmaceuticals; Lipase lipoprotein from Aspergillus niger (LPL, 223 U/mg), was purchased from Ningxia Sunson group corporation. Other reagents were

Catalytic activities of different lipases for Knoevenagel condensation

In initial research, the reaction of 4-nitrobenzaldehyde 1a and the less active methylene compounds acetylacetone 2a were used as the model reaction (Scheme 1). Five lipases from different sources were screened to catalyze this Knoevenagel condensation and the results were shown in Table 1. Lipase lipoprotein (LPL) (Table 1, entry 6) was identified to be the most efficient catalyst for this Knoevenagel condensation, and no detectable products were obtained (Table 1, entry 1) in the absence of

Conclusions

In conclusion, we have developed an enzymatic method for Knoevenagel condensation between aromatic aldehydes and a wide range of active methylene compounds. LPL, with a mild, cheap, commercially available and environmentally benign quality, could catalyze the Knoevenagel condensation effectively with good to excellent yields and Z selectivity in short reaction times without the need of additive and excess substrates. This case of biocatalyst not only expanded the application of lipases to new

Acknowledgments

This research was financially supported by the Hi-Tech Research and Development Program of China (Grant No. 2011AA02A209), the National Basic Research Program of China (Grant No. 2011CB710800) and the National Science Foundation for Distinguished Young Scholars of China (Grant No. 21225626).

References (33)

  • W. Hu et al.

    Biochimie

    (2012)
  • W.M. Liu et al.

    Biochem. Eng. J.

    (2014)
  • Y. Hu et al.

    Chin. J. Catal.

    (2013)
  • W.M. Liu et al.

    Process Biochem.

    (2012)
  • R.J. Kazlauskas

    Curr. Opin. Chem. Biol.

    (2005)
  • J.S. Dordick

    Enzyme Microb. Technol.

    (1989)
  • N. Doukyu et al.

    Biochem. Eng. J.

    (2010)
  • Z. Wang et al.

    Chin. Chem. Lett.

    (2014)
  • Z.Q. Duan et al.

    Process Biochem.

    (2010)
  • M.M. Heravi et al.

    Curr. Org. Synth.

    (2014)
  • Y.J. Bian et al.

    Chin. J. Org. Chem.

    (2006)
  • R.V. Hangarge et al.

    Green Chem.

    (2002)
  • K.M. Koeller et al.

    Nature

    (2001)
  • T. Hudlicky et al.

    Chem. Soc. Rev.

    (2009)
  • H.R. Wang et al.

    Rsc Adv.

    (2014)
  • F.J. Yang et al.

    Rsc Adv.

    (2014)
  • Cited by (54)

    View all citing articles on Scopus
    View full text