Three-Component Coupling Approach for the Synthesis of Diverse Heterocycles Utilizing Reactive Nitrilium Trapping

Abstract

The formation of an unexpected heterocyclic scaffold, a benzoxazole, in a three-component reaction between a ketone, isocyanide, and 2-aminophenol was encountered. This reaction involved a benzo[b][1,4]oxazine intermediate resulting from intramolecular attack of the aminophenol hydroxyl group on the nitrilium ion. Unlike previous literature examples, the trapped nitrilium benzo[b][1,4]oxazine could readily be subjected to ring opening with bis-nucleophiles. The reaction scope includes simple linear as well as complex cyclic ketones and substituted 2-aminophenols. A representative benzoxazole product could be further diversified to yield drug-like compounds.

Synthesis of Carfentanil Amide Opioids Using the Ugi Multicomponent Reaction

“…14 Recently, we have reported a novel MCR between 2-aminophenol, ketones and isocyanides to generate a diverse library of heterocyclic drug-like scaffolds. 15 In the present work, four-component Ugi reactions were carried out between N -alkylpiperidones, aniline, propionic acid and an array of aliphatic isocyanides. The reaction has previously been used to synthesize a carfentanil precursor 16 and bivalent ligands.…”

3,4-Dihydro-2H-1,3-benzoxazines and their oxo-derivatives - Chemistry and bioactivities

“…Interestingly, benzoxazin-4-onium perchlorate (15) reacts with dialdehyde methyl 3,5-diformyl-2,4-dihydroxybenzoate (16) in glacial acetic acid obtaining spiropyran of 1,3-benzoxazine series (5) through the formation of intermediate styryl salt (17). This intermediate has been isolated and then cyclized under the action of triethylamine in anhydrous diethyl ether to yield the compound (18) as shown in Scheme 22.…”

“…10,16 Furthermore, benzoxazine nucleus not only is present in many pharmacologically active molecules, medicinally significant derivatives and natural products but also they have been used as intermediates for the synthesis of other heterocyclic scaffold of bioactive compounds. 17 Also, several of 1,3-benzoxazines ( Figure 3) show interesting biological and pharmaceutical properties. 18,19 Moreover, these derivatives are very valuable in the chemistry of natural products due to the formation of acetal-glycosides in plant 20 which act as a plant's own resistance factor towards insects, pests, fungi and other microbial diseases.…”

Enantioselective Organocatalytic Intramolecular Aza‐Diels–Alder Reaction

“…These key products are highly functionalized heterocycles, which, in their enantiomerically enriched form, could be employed as new templates in postcondensation transformations to introduce additional molecular diversity (Scheme ). For example, the phenol close to the secondary amine was protected in a highly regioselective manner with 1,1‐carbonyldiimidazole (CDI), thus allowing differentiation between the C4 and C11 hydroxy groups of 6 a to give 8 in excellent yield . Pleasingly, the remaining C4 phenol was triflated with N ‐phenylbistriflimide in the presence of triethylamine and 4‐dimethylaminopyridine (DMAP) in quantitative yield and then underwent palladium‐catalyzed reduction to yield 9 without erosion of enantioselectivity .…”