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

Abstract

A novel N‐heterocyclic carbene (NHC)‐promoted regiodivergent protocol for exo (2‐OH) and endo (5‐OH) isosorbide (IS) imidates synthesis is described. The disclosed strategy allows the straightforward synthesis of monoimidate‐isosorbides (MIIs) endowed with the biologically relevant benzothiazole (BTA) moiety under mild oxidative conditions, starting from easy‐accessible aldimines. Process optimization encompassed the use of stoichiometric diquinone as well as atmospheric oxygen as oxidant species, focusing on reaction dichotomy between oxidative and oxygenative pathways. The reaction scope was investigated on a representative selection of BTA‐containing aldimines and further extended to congeners bearing different biologically pivotal N‐heterocyclic rings (benzoxazole, thiazole and isoxazole), observing good levels of yield (up to 87 %) and regioselectivity (exo/endo up to 10.0; endo/exo up to 7.0). Furthermore, the employment of an immobilized‐NHC under heterogeneous conditions was assessed, showing satisfactory selectivity towards exo‐MIIs (exo/endo=3.8). Overall, the methodology presented provided an unprecedented collection of high value‐added products with potential applications in different fields.

Aerobic Oxidative N‐Heterocyclic Carbene Catalysis

“…The oxidative pathway can also be accessed by the addition of an high molecular weight oxidant such as the Kharasch oxidant, [91] or using a system of ETM in combination with air. [92] The bifurcated reaction pattern of the aza-Breslow intermediate was nicely illustrated by Huang and co-workers (2017) who utilized NHC, air as oxidant and LiCl as a cooperative Lewis acid to synthesize amides 163 from aldimines 162 containing the benzothiazole (BTA) scaffold. (Scheme 39A).…”

“…The synthesis of monoimidate-isosorbides 200 and 201 (MIIs) starting from BTA containing aldimines 162 and isosorbides 200 (IS) performs well and the products (exo-201, endo-202) can be isolated with good regioselectivity and yields (up to 77 %). [92] The best results were obtained when air was used as the oxygen source in the combination with a system of ETMs. The regioselectivity of the reaction i. e., substitution on the exo (2-OH) or endo (5-OH) of the isosorbides, is dependent on solvent and additive effects.…”

Organocatalytic Upgrading of Biomass Derived Building Blocks

“…Oxidative NHC‐catalysis strategy was applied also to achieve the regiodivergent synthesis of exo (2‐OH) and endo (5‐OH) isosorbide imidates incorporating biologically important N‐heterocycles such as benzothiazole, benzoxazole, thiazole and isoxazole (Scheme 37). [75] Monoimidates isosorbides 66 can be accessed starting from aldimines in good yields (up to 87 %) and good regioselectivities (exo/endo 10–3.7; endo/exo 7–1.8). In analogy to the previous work, the possibility of using a heterogeneous immobilized NHC was investigated to allow catalyst recovery and recycling.…”

Oxidative N‐Heterocyclic Carbene Catalysis

“…In continuation of the work on the DQ-promoted NHCcatalyzed synthesis of MAIs, [20] the regiodivergent synthesis of endo-and exo-monoimidate-isosorbides (MIIs) equipped of biologically important N-heterocycles (benzothiazole, benzoxazole, thiazole, isoxazole) was recently studied by Bortolini group. [42] This strategy relied on oxidative NHC-catalyzed reactions of IS with (hetero)aromatic aldimines derived from 2-aminobenzothiazole and congeners (Scheme 23). Most performing conditions for the production of endo-MIIs (12-80 % yield, endo/exo selectivity: 1.8-7.0) involved the use of N-pentafluorophenyl pyrrolidine-based triazolium salt (10 mol%), DBU (25 mol%) and stoichiometric DQ in N-methyl-2-pyrrolidone (NMP) solvent, its strong HBA character helping preferential reaction of the more nucleophilic 5-OH of IS (dominant electronic factors).…”

“…In continuation of the work on the DQ ‐promoted NHC‐catalyzed synthesis of MAIs, [20] the regiodivergent synthesis of endo ‐ and exo ‐ monoimidate‐isosorbides (MIIs) equipped of biologically important N ‐heterocycles (benzothiazole, benzoxazole, thiazole, isoxazole) was recently studied by Bortolini group. [42] …”