Regiodivergent Isosorbide Acylation by Oxidative N-Heterocyclic Carbene Catalysis in Batch and Continuous Flow

Abstract

A new N-heterocyclic carbene (NHC)-catalyzed strategy for the regioselective monoesterification of isosorbide (IS) at either the endo (5-OH) or exo (2-OH) position is described. Site-selective acylation proceeds under oxidative conditions in the presence of a quinone oxidant using aldehydes as mild acylating agents. Experimental evidences suggest a role of the stereoelectronic features of the acyl azolium salt intermediate in determining the selectivity of the acylation process. The solvent effect was also investigated, considering conventional and sustainable solvents. Aromatic aldehydes, including bio-based furfural and 5-hydroxymethyl furfural, together with α,β-unsaturated aldehydes proved to be effective reaction partners affording monoacyl-isosorbides with satisfactory levels of regioselectivity (exo/endo: 5.3-3.5; endo/exo: 5.3-3.3). Additionally, the exo-selective triazolium salt promoter was successfully transferred into the heterogeneous phase and applied to continuous-flow catalysis. In particular, the polystyrene-supported version of the selected NHC showed a catalytic activity comparable to that of the homogeneous counterpart in terms of both conversion efficiency (turnover number = 108) and regioselectivity (exo/endo up to 5.3). Also, the corresponding packed-bed mesoreactor was operated with long-term stability (ca. 110 h on stream) to produce 2-benzoyl-IS (1.32 mmol h-1 mmolcat-1), which is the key intermediate in the synthesis of a commercial active pharmaceutical ingredient, namely, the vasodilator isosorbide-5-mononitrate.