Delft University of Technology Direct Diels-Alder reactions of furfural derivatives with maleimides Cioc, Rǎzvan C.; Lutz, Martin; Pidko, Evgeny A.; Crockatt, Marc; Van Der Waal, Jan C.; Bruijnincx, Pieter C.A. DOI 10.1039/d0gc03558k Publication date 2021 Document Version Final published version Published in Green Chemistry Citation (APA) Cioc, R. C., Lutz, M., Pidko, E. A., Crockatt, M., Van Der Waal, J. C., & Bruijnincx, P. C. A. (2021). Direct Diels-Alder reactions of furfural derivatives with maleimides. Green Chemistry, 23(1), 367-373. https://doi.org/10.1039/d0gc03558k Important note To cite this publication, please use the final published version (if applicable). Please check the document version above. Copyright Other than for strictly personal use, it is not permitted to download, forward or distribute the text or part of it, without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license such as Creative Commons. Takedown policy Please contact us and provide details if you believe this document breaches copyrights. We will remove access to the work immediately and investigate your claim. This work is downloaded from Delft University of Technology. For technical reasons the number of authors shown on this cover page is limited to a maximum of 10. Green Chemistry View Article Online PAPER View Journal | View Issue Direct Diels–Alder reactions of furfural derivatives with maleimides† Cite this: Green Chem., 2021, 23, 367 Răzvan C. Cioc,a Martin Lutz,b Evgeny A. Pidko, c Marc Crockatt,d Jan C. van der Waald and Pieter C. A. Bruijnincx *a The Diels–Alder (DA) reaction of furans is a versatile tool in synthetic organic chemistry and in the pro- duction of sustainable building blocks and smart materials. Numerous experimental and theoretical investigations suggest that the diene scope is effectively limited to electron-rich furans, which excludes the most abundant and readily accessible renewable derivatives: furfural and its 5-hydroxymethyl homol- ogue. Herein we show for the first time that electron-poor 2-formylfurans can also directly engage in Diels–Alder couplings. The key to success is the use of aqueous medium, which supplies an additional Received 21st October 2020, thermodynamic driving force by coupling the unfavorable DA equilibrium to the exergonic hydration of Accepted 24th November 2020 the carbonyl functionality in the adducts to form geminal diols. This finding enables the direct access to Creative Commons Attribution-NonCommercial 3.0 Unported Licence. DOI: 10.1039/d0gc03558k various novel DA adducts derived from renewable furfurals and maleimides, via a mild, simple and envir- rsc.li/greenchem onmentally-friendly synthetic protocol. Introduction furans bearing electron-donating groups (e.g. H, Me, OMe, CH2OH, etc.) display good kinetics, while electron-poor furans The Diels–Alder (DA) reaction of furan dienes towards 7-oxa- (e.g. with CHvO or COOR) are too sluggish, inactive substrates.2 norbornenes is an old yet powerful tool in organic chemistry, Predicting the thermodynamics of such furan DA cycloaddi- with applications ranging from natural product synthesis and tions is much less straightforward. Being typically moderately This article is licensed under a renewable chemical commodities production to drug discovery exothermic and entropically disfavored, the Gibbs free energy and materials science.1 The reaction generally proceeds che- of these reactions is generally in the order of only a few kJ − moselectively under mild conditions, often without the need mol 1. Thus, small changes in operating parameters (pressure, for a catalyst. Depending on the furan/dienophile combi- temperature, concentration, solvent) have a profound impact Open Access Article. Published on 24 November 2020. Downloaded 2/1/2021 12:24:02 PM. nation, yields may be low, however, as reactions may be kineti- on the position of the DA equilibrium. Various strategies have cally slow or suffer from thermodynamic equilibrium limit- been employed to overcome unfavorable thermodynamics ations; moreover, the DA adduct is often quite labile, leading (neat conditions, excess reactants, selective crystallization, to facile cyclo-reversion back to the addends. elevated pressures, coupling with secondary reactions, etc.). Asfaraskineticsisconcerned,itiswellknownthatthesub- The solutions offered are generally quite case-specific, stitution pattern of the furan diene strongly modulates reactivity. however, and small changes made in operating conditions to In line with the general Frontier Molecular Orbital (FMO) theory improve thermodynamics can adversely affect kinetics, and of [4 + 2] cycloadditions, numerous studies have shown that vice versa. For instance, in case of sluggish conversions, heating may improve kinetics but will negatively impact thermodynamics, since ΔS° < 0. In addition, small changes in aOrganic Chemistry and Catalysis, Debye Institute for Nanomaterials Science, the addends structure often impact the DA equilibrium in an Faculty of Science, Utrecht University, Universiteitsweg 99, 3584 CG, Utrecht, the intricate manner as well. For example, furan reacts faster with Netherlands. E-mail: [email protected] maleic anhydride than with maleimide, but the reaction with bCrystal and Structural Chemistry, Bijvoet Centre for Biomolecular Research, Faculty the latter is more exergonic.3 Similarly, methylated furans of Science, Utrecht University, Padualaan 8, 3584 CH Utrecht, the Netherlands cInorganic Systems Engineering, Department of Chemical Engineering, Faculty of react more readily with itaconic anhydride than furan itself, 4 Applied Sciences, Delft University of Technology, Van der Maasweg 9, 2629 HZ Delft, but the equilibrium conversion is highest with the latter. the Netherlands Thus, the interplay between kinetics and thermodynamics in d Department of Sustainable Process and Energy Systems, TNO, Leeghwaterstraat 44, furan DA reactions is often rather subtle, making it challen- 2628 CA Delft, the Netherlands ging to understand, control and optimize them. †Electronic supplementary information (ESI) available. CCDC 2023757. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/ Currently, synthetic applications of furan DA chemistry are d0gc03558k dominated by electron-rich dienes such as furan itself, furfuryl This journal is © The Royal Society of Chemistry 2021 Green Chem.,2021,23,367–373 | 367 View Article Online Paper Green Chemistry alcohol and 2,5-dimethyl furan. To the best of our knowledge, sively present in the geminal diol form. This peculiar struc- no examples of direct DA reactions involving furfural (2-furan tural feature proved highly advantageous in downstream pro- carboxaldehyde) or its homologue 5-hydroxymethylfurfural cessing, as unreacted starting materials could be easily washed (5-HMF) have yet been reported; moreover, indirect strategies away with organic solvents leaving the DA adduct in the relying on redox-neutral chemical activation (acetalization,5 aqueous phase in essentially pure form (Fig. 1). Subsequent hydrazone formation6) are also scarce. That these substrates are optimization experiments (see ESI for details†) showed that not part of the current furan DA toolbox is unfortunate, as these the highest yields (60–65%) could be obtained in concentrated are in fact the most readily accessible furans (and precursors to aqueous solution (2 M), at 60 °C, and in the absence of cata- most other derivatives).7 Furthermore, having a reactive formyl lysts or additives. 5-HMF (1b) could also be cleanly reacted to handle on the DA product offers many opportunities for further its DA adducts, again giving only the geminal diol product and synthetic upgrading. The current mismatch between furan allowing product purification by simple extraction. diene availability, synthetic potential and reactivity in DA reac- The typical kinetic profiles of a reversible DA reaction were tions is particularly pressing in the context of the production of obtained, with stereoselectivity for the thermodynamically-pre- biobased chemicals, e.g. high-value oxygenates such as phthalic ferred exo-isomer gradually increasing in time (Fig. 2).12 anhydride and terephthalic acid.8 This field would greatly Conversion of 1a reached equilibrium within 60 h, at which point benefit from expansion of the furan diene scope beyond the ubi- the exo-3a : endo-3a ratiowasapprox.5:1.Thenearlyidentical quitous methylated derivatives that give high yields for the DA profiles of total adduct yield and furfural conversion highlight the reaction itself, but nevertheless show a low atom-, step- and reaction’s high chemoselectivity. For dienophile 2a,hydrolysisto redox-economy and thus poor sustainability for the overall maleic acid occurred to a very limited extent (typically 1–2% in process starting from the biomass resource (Scheme 1).9 16 h). The chemoselectivity for 5-HMF 1b was similarly high, but Acknowledging this major limitation in scope, we decided the endo isomer was still the major product after 60 h.13,14 to take a closer look at the feasibility of employing furfural as Creative Commons Attribution-NonCommercial 3.0 Unported Licence. diene. Using prototypical, reactive maleimide dienophiles, we Reaction scope chose to study the DA reaction in water as reaction medium, as water is well-known to improve both the kinetics and thermo- With the optimal conditions in hand, the substrate scope was dynamics of other DA reactions10 via the hydrophobic effect.11 further