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

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