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Reaction mixtures of naturally abundant aldoses and CH nucleophiles allow for the formation of functionalized furan precursors using low temperatures and metal-free catalysis in aqueous solutions of dilute base catalysts. We employ in situ NMR assays to clarify the mechanism and kinetics of the conversion. Catalysis serves a double role in ring-opening stable aldoses such as glucose and xylose and facilitating the subsequent reactions with CH acids such as malononitrile or cyanoacetamide. Resultant acyclic products are shown to convert quickly to a monocyclic product prior to the slower formation of a more stable bicyclic intermediate and dehydration to tri-functionalized furan. Especially the reversible 5-exo-dig ring closure entailing oxygen attack onto a nitrile carbon is surprisingly fast with an equilibrium vastly towards the cyclic state, sequestering reactive groups and allowing the selective conversion to tri-functionalized furan. The reaction hinges on the fast formation of intermediates without CH acidity and competes with the oligomerization of CH nucleophiles. Insight derived from in situ NMR analysis shows the prowess of high-resolution in situ spectroscopy in clarifying the interplay between catalysts and reactants. Such insight will be vital for the optimization of reactions that upgrade biorenewables under benign conditions.

Chain elongation of unprotected carbohydrates in water under mild conditions remains a challenge both in chemical and biochemical synthesis. The Knoevenagel addition or condensation enables transformations to bioactive scaffolds for pharmaceutical and agrochemical compounds. Unfortunately, the catalysts in use for these transformations often reduce the green metrics of the transformations. Here, we use in situ NMR visualizations to explore the prospective use of natural catalysts for the synthesis of triple- and quadruple-functionalized furan- or dihydrofuran-derivatives from glucose and malononitrile. The dihydrofuran derivatives are formed as kinetic, major intermediates in the pathway to furan derivatives when using naturally abundant MgO or bio-sourced chitosan and N-Methyl-D-glucamine (meglumine) as the catalysts in water. Both catalyst loading, solvent composition and pH can be adapted to populate dihydrofurans with four substituents by slowing down their further reactions. Higher temperatures and higher pH values favor the formation of triple-functionalized furans over quadruple-substituted dihydrofurans, which may be bicyclic or monocyclic. Compared to more traditional catalysts, nature-sourced options offer more sustainable options that emulate natural processes. Visualization with in situ NMR contributes to streamlining the development of cheap and environmentally benign procedures for carbohydrate chain elongation.