
==== Front
ACS Omega
ACS Omega
ao
acsodf
ACS Omega
2470-1343
American Chemical Society

10.1021/acsomega.4c04261
Article
Extending the Carbon Chain Length of Carbohydrate-Derived 5-Substituted-2-furaldehydes by Condensing with Active Methylene Compounds under Organocatalytic Conditions
Prabhakar Poornachandra Shamanna †
https://orcid.org/0000-0003-4609-9256
Seikh Asiful H. ‡
Karim Mohammad Rezaul ‡
https://orcid.org/0000-0003-3310-348X
Dutta Saikat *†
† Department of Chemistry, National Institute of Technology Karnataka (NITK), Surathkal, Mangalore 575025, Karnataka, India
‡ Center of Excellence for Research in Engineering Materials (CEREM), Deanship of Scientific Research, College of Engineering, King Saud University, Riyadh 11421, Saudi Arabia
* Email: sdutta@nitk.edu.in.
06 09 2024
17 09 2024
9 37 3864838657
09 05 2024
27 08 2024
07 07 2024
© 2024 The Authors. Published by American Chemical Society
2024
The Authors
https://creativecommons.org/licenses/by-nc-nd/4.0/ Permits non-commercial access and re-use, provided that author attribution and integrity are maintained; but does not permit creation of adaptations or other derivative works (https://creativecommons.org/licenses/by-nc-nd/4.0/).

This work reports a high-yielding, organic solvent-free, gram-scale synthesis of novel Knoevenagel condensation products by reacting carbohydrate-derived 5-substituted-2-furaldehydes (SFLs) with active methylene compounds (AMCs) using various organic amines and inorganic bases as catalysts. Among the base catalysts examined, piperidine performed best, affording satisfactory selectivity and yield of the targeted Knoevenagel condensation products owing to the subtle balance between its nucleophilicity and basicity. The reaction was optimized on various reaction parameters, such as temperature, duration, solvent, catalyst loading, and molar ratio of the reactants. Even though the SFLs exhibited significantly different reactivity, a general synthetic protocol was developed successfully, affording good to excellent isolated yields (70–96%) of the novel Knoevenagel condensation products at ambient temperature. Moreover, the Knoevenagel products were purified by triturating with eco-friendly solvents (e.g., ethyl acetate and n-heptane) without chromatographic purification.

Science and Engineering Research Board 10.13039/501100001843 CRG/2021/001084 National Institute of Technology Karnataka, Surathkal 10.13039/501100008788 NA King Saud University 10.13039/501100002383 RSPD2024R956 Science and Engineering Research Board 10.13039/501100001843 CRG/2022/009346 document-id-old-9ao4c04261
document-id-new-14ao4c04261
ccc-price
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pmc1 Introduction

The valorization of biomass in a biorefinery setting promises to solve many economic, societal, and environmental complications ensuing from our overdependence on fossilized carbon-based resources.1 Over the past three decades, numerous journal publications and patents have been dedicated to producing furanic chemical platforms from biomass-derived carbohydrates and their synthetic value addition into organic chemicals of commercial significance.2 Two of the most crucial carbohydrate-derived furaldehydes are furfural (FUR, 1a) and 5-(hydroxymethyl)furfural (HMF, 1e) (Scheme 1A). FUR is typically produced by the acid-catalyzed dehydration of pentose sugars (e.g., xylose), whereas HMF is produced by the dehydration of hexose sugars (e.g., fructose, glucose). Both 1a and 1e can be produced directly from polymeric carbohydrates in the presence of appropriate acid catalysts and reaction media that promote depolymerization, hydrolysis, and dehydration reactions.3 The biorenewable 5-substituted-2-furaldehydes (SFLs) 1a and 1e have derivative chemistry that encompasses virtually all major classes of organic chemicals of industrial significance, including fuels, fuel additives, solvents, fragrances, monomers, plasticizers, dyes, surfactants, agrochemicals, and pharmaceuticals.4 The hydroxymethyl group in 1e can be synthetically modified selectively to produce a series of SFLs. 5-(Chloromethyl)furfural (CMF, 1f) can be produced by reacting 1e with a chlorinating reagent or directly from carbohydrates using hydrochloric acid.5,6 5-Methylfurfural (MF, 1b) can be produced by dehydrating hexose sugars like l-rhamnose or by partially reducing 1e and 1f.7,8 5-(Ethoxymethyl)furfural (EMF, 1c), a promising biofuel candidate, can be produced by etherification of 1e or by acid-catalyzed ethanolysis of hexose sugars and polymeric carbohydrates.9 5-(Acetoxymethyl)furfural (AcMF, 1d) can be produced from isolated 1e and 1f or directly from sugars by Fischer esterification or nucleophilic substitution reaction.10 Although 1b–1f are congeners, they differ noticeably in physicochemical properties (e.g., solubility, hydrolytic stability) and reactivity.11

Scheme 1 (A) Carbohydrate-Derived 5-Substituted-2-furaldehydes, (B) Active Methylene Compounds, and the (C) Knoevenagel Condensation Products Reported in This Study

A major technical challenge for expanding the derivative chemistry of the furanic platform chemicals is to develop economically attractive and environmentally acceptable synthetic strategies. The chemical reactivity patterns of the biomass-derived furaldehydes must be understood well by synthesizing their derivatives using innocuous reagents.12,13 Even though the substitution is distant from the aldehyde moiety in the SFLs, the reactivity is markedly different in some organic transformations. Many of the FUR and HMF derivatives reported in the literature involve the aldehyde group selectively without involving the furan ring and substitution at the C-5 carbon atom. In this regard, Knoevenagel condensation is one of the most established and efficient carbon-carbon bond-forming reactions in the synthetic organic chemistry literature, affording products of academic importance and industrial significance.14 The Knoevenagel condensation reaction between aromatic aldehydes and active methylene compounds (AMCs) works under mild reaction conditions using an organic or inorganic base as the catalyst. The reaction has a high atom economy, low E-factor, and 100% carbon economy, producing water as an innocuous byproduct. The Knoevenagel condensation products often show promising bioactive properties (e.g., antiviral, antibacterial, anticancer).15 They also act as chemical intermediates in downstream value-addition pathways for synthesizing therapeutic drugs, natural products, functional polymers, fine chemicals, herbicides, and insecticides.16 Numerous publications have reported Knoevenagel condensation of alkyl or aryl aldehydes (and ketones) with a range of AMCs, and these works have been reviewed.17 The preparative strategies vary on the type of catalyst, reaction media, and process conditions employed. Numerous acid and base catalysts (homogeneous and heterogeneous) have been employed for the Knoevenagel condensation reaction. However, the search for superior catalysts in terms of high catalytic efficiency (activity, selectivity), easy availability, low cost, eco-friendly nature, and convenient recoverability continues.18 In this regard, organocatalysts have received significant interest in biorefinery research due to their eco-friendly characteristics.19 Organic amines (primary, secondary, tertiary) are frequently used as base catalysts and organocatalysts in various organic transformations since they are inexpensive, commercially available in pure form, chemically stable, and recyclable via distillation.20,21 Piperidine is an efficient organocatalyst in Knoevenagel condensation and Knoevenagel–Doebner reactions.22 The mechanistic insights of piperidine-catalyzed Knoevenagel condensation reaction between substituted benzaldehydes and AMCs have been demonstrated, and the roles of iminium and enolate ions have been examined.23 FUR 1a has long been used as a substrate in many Knoevenagel condensation processes to demonstrate the wide substrate scope but is rarely depicted from the perspective of the renewability of the substrate used.24,25 On the contrary, the recent publications on Knoevenagel condensation reaction using HMF 1e as the substrate emphasize its biorenewable nature.26,27 A systemic study has never been performed on the Knoevenagel condensation reaction between various biorenewable SFLs and AMCs. Such a study will not only furnish novel and biorenewable Knoevenagel condensation products with hitherto unknown physicochemical and biological properties but also help to widen the product portfolios of SFLs as chemical building units in a carbohydrate-centric biorefinery and improve its commercial feasibility. This work reports the Knoevenagel condensation between SFLs (1a–1g) with malononitrile (2a), ethyl cyanoacetate (2b), diethyl malonate (2c), ethyl acetoacetate (2d), and acetylacetone (2e) as the AMCs (Scheme 1B,C). Among the thirty-five Knoevenagel condensation products synthesized in this study, seventeen have never been reported in the literature.

2 Materials and Methods

2.1 Materials

Furfural (99%), ethyl acetoacetate (99%), ethyl cyanoacetate (98%), and silica gel (60–120 mesh) were purchased from Spectrochem Pvt., Ltd. Piperidine (98%), diethyl malonate (98%), acetylacetone (98%), and chloroform (99%) were purchased from Loba Chemicals Pvt., Ltd. Malononitrile (98%) was purchased from Sisco Research Laboratories Pvt., Ltd. Ethanol (99.8%) was purchased from Aqlivia Pvt., Ltd. 5-Methylfurfural (MF, 99%) was purchased from Sigma. Ethyl acetate (99%) was purchased from Finar Limited. n-Heptane (99%) was purchased from Molychem. 5-(Hydroxymethyl)furfural (HMF), 5-(chloromethyl)furfural (CMF), 5-(acetoxymethyl)furfural (AcMF), 5-(ethoxymethyl)furfural (EMF), and 2,5-diformylfuran (DFF) were synthesized and purified following literature procedures.10,28−30 Ethanol was dried over preactivated molecular sieves (4 Å) for 12 h before use. Furfural was distilled and refrigerated in an airtight, amber-colored glass container. All other chemicals were used as received.

2.2 Characterization Methods

The synthesized compounds were characterized using Fourier transform infrared (FTIR) spectra using a Bruker FTIR 4000 instrument equipped with a zinc selenide (ZnSe) ATR. The FTIR spectra were collected by performing 16 scans at a scanning rate of 4 scans/s in the range between 500 and 4000 cm–1. Nuclear magnetic resonance (NMR) spectra of the synthesized compounds were collected in a Bruker NanoBay NMR instrument. The 1H NMR spectra were collected at the operating frequency of 400 MHz, whereas the 13C NMR spectra were collected in the same instrument at a calculated frequency of 100 MHz. Elemental analyses of the synthesized novel compounds were collected using Elementar, Germany (Model: vario MICRO select). The melting point of the solid compounds was checked in a Stuart digital melting point apparatus (Model: SMP3).

2.3 Typical Procedure for Preparing the Knoevenagel Condensation Products

Furfural 1a (0.500 g, 5.20 mmol) was introduced in a 50 mL round-bottomed flask. Malononitrile 2a (0.343 g, 5.20 mmol), piperidine (0.042 g, 0.49 mmol), and ethanol (5 mL) were added. A magnetic stirring bead was introduced, and the reaction mixture was stirred continuously on a magnetic stirrer for 30 min at room temperature. The progress of the reaction was monitored by thin-layer chromatography till the disappearance of 1a. Upon completion, ethanol was removed in a rotary evaporator under reduced pressure. The residue was diluted with ethyl acetate (10 mL) and washed with deionized water (20 mL × 3) in a separatory funnel. The ethyl acetate layer was separated, dried over anhydrous Na2SO4, and evaporated in a rotary evaporator under reduced pressure to produce crude 2-(furan-2-ylmethylene)malononitrile (3) as a red solid. The product from the crude was triturated with 5 vol % ethyl acetate in n-heptane to remove colored impurities. Evaporation of the solvent in a rotary evaporator under reduced pressure afforded pure 2-(furan-2-ylmethylene)malononitrile (3) (0.645 g, 86%) as a yellow solid.

The optimized synthetic protocol was extended to SFLs and other AMCs. When 1d and 1f were used as reactants, cyclohexane (5 mL) was used as a solvent instead of ethanol to avoid the formation of 1e and 1c during the reaction, respectively, by ethanolysis reaction.

3 Results and Discussion

The compounds 1a and 2a were chosen as model reactants to form 2-(furan-2-ylmethylene)malononitrile (3) by the Knoevenagel condensation reaction. The Knoevenagel condensation reaction was performed at room temperature using ethanol as the biorenewable solvent and anhydrous sodium carbonate as a heterogeneous base catalyst. The reaction completed within 15 min at RT and 3 was obtained in an 86% isolated yield using only 10 mol% (calculated based on the amount of 1a) Na2CO3 (entry 1, Table 1). A major concern in the process is the efficient recovery and recyclability of the catalyst. The Knoevenagel condensation reaction produces water as the byproduct, which dissolves the catalyst and makes its recovery by filtration less efficient. Moreover, using Na2CO3 as a catalyst led to significant decomposition of 1d and 1f during the reaction. When CaCO3 was used as a heterogeneous inorganic base, catalyst recovery was convenient even though the reaction took significantly longer to complete (entry 2). However, CaCO3 had negligible catalytic activity when other AMCs, such as 2c and 2d, were employed. This can be explained by the diminished acidity of the methylene protons in 2c and 2d when compared to 2a.31 Various secondary and tertiary amines effectively catalyzed the Knoevenagel condensation reaction and exhibited comparable catalytic activity. When diazabicyclo[2.2.2]octane (DABCO) was used as the catalyst for the reaction, the product yielded an 83% yield in 15 min. Triethylamine (TEA) afforded an 86% isolated yield of 3 after only 15 min at RT. Imidazole gave 82% yield in 30 min. When piperidine was used as the base and organocatalyst, the conversion of 1a was complete within 30 min at RT, and an 86% isolated yield of 3 was obtained. 1,8-Diazabicyclo(5.4.0)undec-7-ene (DBU) (entry 6) and pyrrolidine (entry 8) afforded noticeably lower yields of 3 due to partial decomposition of 1a. In the control reaction (without catalyst), only a trace 3 was formed after 120 min at RT (entry 9). Evidently, the yields of 3 for TEA, DABCO, diisopropylethylamine (DIPEA), and piperidine were comparable. However, TEA and DABCO were not chosen as catalysts since they react with some SFLs, such as 1f, by nucleophilic substitution. The central idea of this work was to develop a general synthetic strategy that works well for all commonly encountered carbohydrate-derived SFLs. Considering the above observations and results, piperidine was chosen as the most efficient base and organocatalyst to catalyze the Knoevenagel condensation reaction between SFLs and AMCs.

Table 1 Effect of Various Inorganic Bases and Organic Amines as Catalysts on the Yield of 2-(Furan-2-ylmethylene)malononitrile (3)a

entry	catalyst	duration (min)	yield (%)b	
1	Na2CO3	15	86	
2	CaCO3	120	84	
2	DABCO	15	83	
3	TEA	15	86	
4	imidazole	30	82	
5	piperidine	30	86	
6	DBU	30	71	
7	DIPEA	30	85	
8	pyrrolidine	30	50	
9	no catalyst	12	trace	
a Reaction conditions: furfural (5.2 mmol), malononitrile (5.2 mmol), catalyst (0.5 mmol), ethanol (5 mL), RT.

b Isolated yield.

The loading of the catalyst plays a crucial role in reaction kinetics, selectivity, and process economics. Generally, a minimum loading of a homogeneous catalyst is warranted for cost minimization, easy recycling, and keeping the reaction volume low for maximum product density without compromising the reaction kinetics and product selectivity. A 10 mol% loading of piperidine, with respect to the initial amount of 1a, allowed the reaction to complete within 30 min at RT and afforded an 83% isolated yield of 3. Increasing the catalyst loading to 20 mol% did not improve the reaction kinetics or the yield of 3 to any significant extent. When the loading of piperidine was reduced to 5 mol%, the reaction required 4 h to complete, and only a 78% yield of 3 was obtained (Figure 1). In Figures 1 and 2, the percentage yield of the product is shown after ensuring quantitative conversion of the starting material. Different catalyst loadings needed different durations for the complete conversion of 1a. The reaction between 1a and a highly active methylene compound 2a gave only a 10% yield of 3 after 30 min using 5 mol% piperidine. However, increasing the catalyst loading to 10 mol% significantly improved the reaction kinetics and provided an 86% isolated yield of 3 in 30 min.

Figure 1 Effect of piperidine loading on yield of 3. Reaction conditions: 1a (5.20 mmol), 2a (5.20 mmol), ethanol (5 mL), RT.

Figure 2 Effect of piperidine loading on the yield of 5. Reaction conditions: 1a (5.20 mmol), 2c (5.20 mmol), ethanol (5 mL), RT.

The reactions were carried out using equimolar amounts of 1a and 2a. Using a slight excess of 2a had no noticeable impact on the duration of the reaction or the isolated yield of 3. The optimized reaction protocol was extended to do the reaction with other SFLs (1b–1g). The Knoevenagel condensation reaction between 1a and ethyl cyanoacetate 2b was completed within 15 min, and ethyl (E)-2-cyano-3-(furan-2-yl)acrylate (4) was isolated in a 96% yield. Other organic amines, such as TEA and DABCO, took longer (30–90 min) and afforded slightly lower yields (88–92%) of 4.

It is worth mentioning that mild bases like Na2CO3, CaCO3, DABCO, imidazole, and triethylamine could not effectively catalyze the Knoevenagel condensation between 1a and less active methylene compounds such as diethyl malonate 2c, ethyl acetoacetate 2d, and acetylacetone 2e. A 50 mol% loading of piperidine allowed the reaction between 1a and 2c to complete within 6 h at RT and afforded an 88% yield of diethyl 2-(furan-2-ylmethylene)malonate (5) (Figure 2). Further lowering the loading to 10 mol% led to a significant increase in the reaction duration (36 h), giving only a 78% yield of 5 due to competing side reactions. Similarly, for the reaction between FUR 1a and a less active methylene compound, diethyl malonate, a catalyst loading of 10 mol% gave only a trace yield (<10% yield) of 5 after 3 h. Increasing the catalyst loading to 50 and 100 mol% improved the isolated yield of 5 to 30 and 88%, respectively, after a reaction duration of 3 h. Lower yields of 5 using lower loadings of piperidine were due to incomplete conversion of 1a. At 50 mol% loading of piperidine, the reaction took 6 h for the quantitative conversion of 1a and afforded an 88% isolated yield of 5.

When the reaction temperature was increased to 60 °C, the reaction kinetics got significantly faster, and the reaction was completed in 10 h. However, the yield of 5 did not improve further.

The Knoevenagel condensation reaction between 1a and 2d was then investigated. With a 25 mol% loading of piperidine, the conversion of 1a was not complete even after 24 h reaction at RT. Hence, the amount of 2d was slightly increased to 1.25 equiv based on the initial amount of 1a. The reaction was completed in 4 h, providing a 78% isolated yield of ethyl 2-(furan-2-ylmethylene)-3-oxobutanoate (6). Furthermore, when the piperidine loading was increased to 50 mol% (i.e., 0.5 equiv of 1a), the reaction duration was shortened to 3 h, but no improvement in the yield of 6 was observed. The use of Na2CO3, DABCO, triethylamine, and imidazole as base catalysts did not show appreciable conversion of 1a even after 12 h. The reaction between 1a and 2e was then investigated using equimolar amounts and 100 mol% piperidine catalyst. The reaction required 90 min for complete conversion of 1a, giving a 70% yield of 7. Reducing the catalyst loading to 50 mol% of 1a slowed down the reaction to some extent, but it was completed in 120 min. However, when the catalyst loading was further decreased to 25 mol%, the conversion of 1a remained incomplete even after 24 h of reaction at RT. Hence, 50 mol% (0.5 equiv of starting 1a) loading of piperidine was considered the optimum catalyst loading, providing a 70% yield of 7. The optimized process was then extended to the Knoevenagel condensation between 2e and other SFLs (1b–1g). Table 2 lists the molecular structure and yield of novel Knoevenagel condensation products (3–37). Slightly lower yields were obtained for Knoevenagel condensation products of 1e (i.e., 23–27). The observation may be explained by the inherent hydrolytic instability of 1e. No apparent trend was observed in the case of a specific AMC, and the reactivity was mostly dependent on the reactivity of SFLs. In the case of derivatives of 2b and 2d, the formation of E and Z isomers was apparent from the 1H NMR and 13C NMR spectra, and the thermodynamically more stable E-isomer dominated (Supporting Information). Moreover, the synthesis of 3 was scaled up, starting with 10 g of 1a. The yield of 3 marginally increased to 88%. After the reaction was complete, ethanol was evaporated in a rotary evaporator under reduced pressure. Piperidine was conveniently recovered by vacuum distillation of the crude mixture. The first recycling gave a 79% isolated yield of 3 after 6 h due to slight contamination of water in recycled piperidine.

Table 2 Molecular Structure of 5-Substituted-2-furaldehydes, Active Methylene Compounds, and the Knoevenagel Condensation Products

a Isolated yield of spectroscopically pure compounds.

b E:Z ratio 3:1.

c E:Z ratio 7:3.

d E:Z ratio 4:1.

e E:Z ratio 9:1.

f E:Z ratio 7:3.

g E:Z ratio 4:1.

h (2E,2′E):(2Z,2′E):(2Z,2′Z) ratio 6.5:2.2:1.3.

# A scale-up of the reaction using 10 g of FUR 1a gave an 88% isolated yield of 3.

* Novel compounds.

A general reaction mechanism has been proposed for the piperidine-catalyzed Knoevenagel reaction between MF 1b and 2c, which agrees with a published work (Scheme 2).23 Initially, 1b condenses with piperidine to form an iminium ion, which then reacts with the deprotonated 2c. The adduct then undergoes a proton transfer process followed by elimination of the piperidine molecule, leading to the Knoevenagel condensation product 10. The 1H NMR spectrum of the incomplete reaction mixture showed the iminium proton around 8 ppm.

Scheme 2 Proposed Mechanism of Piperidine-Catalyzed Synthesis of Knoevenagel Condensation Products from 5-Methylfurfural and Diethyl Malonate (Adapted from Reference (23))

It must be noted that the reaction gets accelerated at elevated temperatures, allowing a significantly lesser amount of piperidine catalyst to be used. However, elevated temperature leads to side reactions when 1d, 1e, and 1f are used as substrates.

4 Conclusions

In conclusion, a piperidine-catalyzed general synthetic protocol was developed for preparing several novel Knoevenagel condensation products by reacting carbohydrate-derived 5-substituted-2-furaldehydes with active methylene compounds. The reaction was performed in the aqueous medium or under organic solvent-free conditions to improve the eco-friendly characteristics of the synthetic protocol. The gram-scale reaction afforded satisfactory yields of the targeted compounds at room temperature. The compounds were isolated and purified by solvent-solvent extraction and trituration using eco-friendly solvents, such as ethyl acetate and n-heptane. The biorenewable aldehydes as substrates, ambient temperature, a metal-free recyclable catalyst, convenient purification of products, and satisfactory yield of products, make this process an economically amenable and environmentally acceptable process of extending the carbon chain of 5-substituted-2-furaldehydes for downstream value addition pathways. All the synthesized compounds were characterized by FTIR, NMR (1H, 13C), and elemental analysis. Future studies will focus on the biological activities of these renewable compounds.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.4c04261.FTIR, 1H NMR, and 13C NMR, characterization data, spectra, elemental analysis data, and melting points of all synthesized Knoevenagel condensation products (PDF)

Supplementary Material

ao4c04261_si_001.pdf

Author Contributions

P.S.P. performed the experiments and analyzed the spectroscopic data. A.H.S. and M.R.K. acquired research funding and edited the manuscript. S.D. conceptualized the work, supervised the progress, and wrote the original manuscript.

The authors declare no competing financial interest.

Acknowledgments

The authors thank the Central Research Facility (CRF), NITK, Surathkal, and Raman Research Institute, Bangalore, for their assistance in collecting the NMR and Elemental Analysis data, respectively. The authors extend their appreciation to the Researchers Supporting Project number (RSPD2024R956), King Saud University, Riyadh, Saudi Arabia. S.D. thanks DST-SERB for the research project under the Core Research Grant (CRG) scheme (File nos. CRG/2021/001084 and CRG/2022/009346). P.S.P. thanks NITK, Surathkal, for scholarship support.
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