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.
Highlights
In recent years, biomass waste utilization has become a main focus of research activities in industry and academia for the production of bio-based platform chemicals by fractionalization or manipulation of lignocellulosic sources.[1]
The regioselective benzoylation of IS 2 with benzaldehyde 1a was selected as the benchmark using the quinone 5 as the stoichiometric oxidant and a suitable base (25 mol %) for the precatalyst A−E activation (Table 1)
We have presented a novel strategy for the regiodivergent monoesterification of IS based on oxidative N-heterocyclic carbene (NHC)
Summary
Biomass waste utilization has become a main focus of research activities in industry and academia for the production of bio-based platform chemicals by fractionalization or manipulation of lignocellulosic sources.[1]. The regioselective functionalization of the 2- and 5-hydroxyl groups is often the key for a successful strategy toward valuable IS-based products, the endo and exo derivatives being typically endowed with different chemical, biological, and physical properties. The commercial vasodilator isosorbide-5-mononitrate (IS-5MN) is preferred in the clinic over isosorbide-2-mononitrate and isosorbide-dinitrate because of its advantageous pharmacokinetics (Figure 1).[23] in the polymer field, different physical behaviors of polymethacrylates prepared from regioisomeric ISbased vinyl monomers have been reported (Figure 1).[24,25] the definition of efficient regioselective protocols for the monofunctionalization of IS is of great interest in the biorefinery context. The selective acylation leading to the monoesters of IS is an attractive process, which is currently used in a number of multistep syntheses based on protection/
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