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 polystyrenesupported 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 mmol cat −1 ), which is the key intermediate in the synthesis of a commercial active pharmaceutical ingredient, namely, the vasodilator isosorbide-5mononitrate.

Regiodivergent Synthesis of Benzothiazole‐Based Isosorbide Imidates by Oxidative N‐Heterocyclic Carbene Catalysis

“…A clear selectivity switch was observed moving from DCM to NMP for pre‐catalyst A (entry 3 vs entry 13) and B (entry 14 vs entry 12), confirming the strong influence of solvent hydrogen‐bond‐accepting (HBA) character on the regioselectivity. As reported in our previous contribution, [20e] it can be hypothesized that the reaction preferentially occurs at the less sterically hindered exo ‐2‐OH in solvents with poor HBA character because of the intrinsic bulkiness of the imidoyl azolium intermediates, while involvement of the more nucleophilic endo ‐5‐OH occurs when intermolecular hydrogen‐bonding interactions are activated by the presence of a suitable coordinating solvent and/or counterion (Scheme 3). At the same time, catalyst effect was less determining, but not negligible.…”

“…The regioselective synthesis of monoimidates 3 a and 4 a starting from isosorbide 2 and aldimine 1 a was selected as the benchmark, using diquinone 7 as stoichiometric oxidant and a suitable base for pre‐catalysts A‐C activation (Table 1). Our investigation started from reaction conditions which revealed to be effective for the exo ‐selective acylation of IS, [20e] using a three‐fold excess of IS to minimize the formation of diimidate byproduct 5 a . Reaction run in anhydrous THF, at room temperature, using triazolium salt A (20 mol%) in combination with 1,8‐diazabicyclo[5.4.0]undec‐7‐ene (DBU) led, after 3 hours, to partial aldimine conversion with low regioselectivity ( exo ‐MII 3 a , 41 %; endo ‐MII 4 a , 30 %.…”

“…Recently, we have demonstrated that oxidative NHC‐catalysis can be efficiently used as the organocatalytic platform for the regiodivergent monoacylation of IS with aldehydes at either the endo ‐ and exo ‐positions, using diquinone 7 as the oxidant [20e] . In continuation of this work and inspired by the studies of Fu and Huang (Scheme 2a), [16] we speculated that isosorbide could be utilized as a nucleophile in NHC‐catalyzed oxidative reactions with 2‐aminobenzothiazole‐derived aldimines (Scheme 2b).…”

Organocatalytic synthesis of poly(hydroxymethylfuroate) via ring-opening polymerization of 5-hydroxymethylfurfural-based cyclic oligoesters

“…At this stage of our study we were interested in the development of a more sustainable and straightforward route to valuable c (HMF) n starting from the platform chemical HMF . Based on our experience in the application of oxidative NHC catalysis as synthetic platform to access bio-based furan polyesters/polyamides 3 c ,25 and HMF upgraded products, 26 we commenced our investigation by considering the polycondensation of HMF (0.13 M, THF) promoted by the triazolium pre-catalyst A (10 mol%) in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU; 0.25 mol%) and a stoichiometric amount (1.0 equiv.) of the quinone oxidant 2 (Table 2, entry 1).…”

“…Heterogeneous high dilution conditions were also tested using the polystyrene-supported triazolium pre-catalyst B , which proved to be a highly active promoter of this type of catalysis in our previous investigations. 26 Disappointingly, application of both oxidation systems (stoichiometric 2 and aerial oxygen) with heterogeneous B led to good HMF conversions but low selectivities toward c (HMF) n (25% and 13% isolated yield, entries 4 and 5). Additionally, the best conditions of entry 2 were tested using the biomass-derived Me-THF as the solvent observing a comparable reaction outcome by the recovery of c (HMF) n in 74% yield (entry 6).…”