Diversified upgrading of HMF via acetylation, aldol condensation, carboxymethylation, vinylation and reductive amination reactions
Graphical abstract
Introduction
5-Hydroxymethyl-2-furfural (HMF) is among the most promising platform chemicals derived from the acid-catalyzed hydrolysis of lignocellulose. [1] As illustrated by several comprehensive reviews, [2,3,4] the multiple functionalization of HMF makes it a suitable substrate for a range of reactions, including oxidations, hydrogenations, etherifications, couplings, condensations, and others. [5,6] Carbon-carbon and carbon-heteroatom bond forming processes are an exemplificative large family of transformations where the reactivity of the HMF carbonyl with a variety of nucleophiles has been investigated for the construction of bio-based organic frameworks. [7,8,9,10] A model case is the aldol condensation, particularly with acetone as a donor, which has been explored to produce renewable polymers and pigments. [11,12,13,14] Another relevant route is the reductive amination of HMF for the synthesis of nitrogen functionalized compounds of interest in the pharmaceutical and surfactants sectors. [15,16] Less studied but not less noteworthy is also the conversion of HMF to the corresponding olefins via Wittig-type reactions: an example is the vinylated homologue 5-hydroxymethyl-2-vinylfuran (HMFV) which undergoes free radical polymerization to yield renewable glues. [17] On the other hand, remarkable strategies for the upgrading of HMF have been designed by taking advantage of its benzyl alcohol-like reactivity. Among them, one of most investigated reactions was the (trans)esterification, particularly the acetylation to 5-formylfuran-2-yl)methyl acetate (HMF-acetate or AMF) which thanks to its lower hydrophilicity and improved stability has been proposed as an alternative platform to HMF. [18] Several acetyl donors including acetic anhydride, acetic acid and even simple esters, and catalysts (pyridine, sodium acetate, I2, etc., [19,20,21]) or biocatalysts (e.g. Lipase Cal-B, [22,23]) proved effective for the synthesis of AMF. Intriguingly, albeit similar to the transesterification reaction, the transcarbonation of HMF with organic carbonates is a largely unexplored field. To the best of our knowledge, notwithstanding HMF-derived carbonates are expected to display attractive properties as intermediates and monomers for polycarbonate materials, only one paper has reported a bio-catalyzed carboxymethylation of HMF with dimethyl carbonate for the synthesis of (5-formylfuran-2-yl) methyl carbonate (HMFC) in 91% yield. [22] Reduction of 5-hydroxymethylfurfural is also a key reaction towards a variety of chemicals and biofuels such as, 2,5-bis(hydroxymethyl)furan, 2,5-dimethylfuran, and linear derivatives such as HHD (1-hydroxyhexane-2,5‑dione) and polyols, just to name a few. [24]
Most if not all of these strategies, however, have issues. These include: i) the limited thermal and chemical stability of HMF which easily undergoes undesired polymerization or degradation to humins and char; [25,26,27] ii) the challenging control of the selectivity between mono- and bis-substituted products in aldol-type reactions; [28] iii) the explosive potential and corrosivity of acetic anhydride, and its legal restrictions for large-scale manufacturing in many countries; [29,30] iv) the use of tailored solvents, e.g. deep-eutectics (DES), to cope with the separation of equilibrium mixtures obtained in (trans)esterification reactions; [22] v) the poor atom economy, the use of harmful solvents and organohalogens, and the formation of stoichiometric salts to dispose of in Wittig-type reactions; [31] vi) severe catalysts poisoning by heavy byproducts during hydrogenation and hydrogenolysis of HMF. [24] Not to mention that even storage of HMF must be controlled (at T below 4 °C) to avoid aging of the substrate and spontaneous formation of dimers and oligomers. [2] This scenario clearly highlights that the design of innovative protocols for the upgrading of HMF still remains a highly desirable target.
In light of these considerations, as a part of our longstanding interest in the development of greener protocols for the conversion of biomass derived platform chemicals, [32,33,34] we conceived the functionalization of HMF and its derivatives in a logic as much as possible integrated in the green chemistry principles. [35] The five transformations described above, namely acetylation, transcarbonation, aldol condensation, reductive amination, and Wittig vinylation were approached by favoring the use of safe reagents and solvents, and catalytic processes. Scheme 1 summarizes the selection of experimental conditions used in this work and the major results achieved.
Nontoxic isopropenyl acetate (iPAc) and dimethyl carbonate (DMC) were selected as acetylating and carboxymethylating agents (reactions A and B) to replace harmful and corrosive compounds (Ac2O, acetyl halides, haloformates), and poorly active reactants (AcOH). Both iPAc and DMC served also as solvents. The use of alkaline heterogenous catalysts such as calcined hydrotalcites and alkali metal carbonates (C-HT-30 and M2CO3; M = K, Cs) was optimized to facilitate work-up, product separation and catalyst recycle. The same catalysts were used in combination with acetone for the aldol condensation (C). Renewable aminated glycerol derivatives 3-amino- (3-APD) and 2-amino-propanediol (2-APD) were investigated for the reductive amination reaction in the presence of water as a solvent (D). Simpler model substrates as ethanolamine (EA) and propanolamine (PA) were also used.
Finally, the latent ylide reactivity of the Wittig vinylation reagent developed in our laboratories, [36] methyltriphenylphosphonium methylcarbonate ( [MePPh3] [MeOCO2]) was exploited for the vinylation of the carbonyl (E). Contrarily to conventional ylides used for Wittig olefinations, the Wittig vinylation reagent is synthesized simply by heating Ph3P and dimethyl carbonate without added bases or co-product salts to dispose of. [31]
All the designed strategies proved not only efficient, but also scalable routes that afford gram-scale quantities of 12 HMF derivatives (85–98% yields), 7 of which novel.
Section snippets
General
Reagents and solvents were commercially available compounds and were used as received unless otherwise stated. HMF, isopropenyl acetate, acetone, dimethyl carbonate, ethanolamine, propanolamine, 2-aminopropanediol, 3-aminopropanediol, Na2CO3, K2CO3, Cs2CO3, d6-acetone, Pd/C (5 wt%), D2O, CDCl3 were sourced from Sigma Aldrich (now Merck). Hydrotalcites HT-30 and HT-63 were a generous gift of Sasol Italy SpA. Ionic liquids [MePPh3] [MeOCO2] and [MeNPh3] [MeOCO2] were synthesized according to a
General
All reactions were run in duplicate to ensure reproducibility: unless otherwise specified, the conversions, GC and NMR yields and isolated yields differed by less than 5% from one another. Catalysts used in this work were selected from the current literature among most active systems for esterifications, transcarbonations, aldol condensations, and reductive amination reactions.
The acetylation of HMF
Isopropenyl acetate (iPAc) is a privileged reagent for the catalytic transesterification with alcohols not only because
Conclusions
The present work described diversified, robust, and greener protocols for the chemical upgrading of HMF. A variety of reactions have been described based on new or improved procedures by which a total of 12 different HMF derivatives were synthesized, isolated, and fully characterized, 7 of which new. The design of the transformations has been inspired by the green chemistry principles regarding the choice of catalytic protocols, the safety and/or renewability of reagents and solvents. Reagents
CRediT authorship contribution statement
Davide Rigo: Conceptualization, Investigation, Methodology, Writing – review & editing. Daniele Polidoro: Investigation, Methodology, Writing – original draft. Alvise Perosa: Writing – review & editing, Funding acquisition. Maurizio Selva: Conceptualization, Supervision, Writing – review & editing, Funding acquisition.
Declaration of Competing Interest
The authors report no declarations of interest.
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