The synthesis of isoxazol(in)es via 1,3-dipolar cycloaddition, other heterocyclic systems, and developments in solid-phase organic synthesis

Isoxazoles as potential chelating ligands for the removal of metals from industrial wastewater have been developed. The synthesis focused on developing methods for the actualization of tetraheterocyclic systems containing three isoxazoles. In this case two were connected as a 3,3'-diisoxazole. All the isoxazoles were synthesized employing the 1,3-dipolar cycloaddition of nitrile oxides with alkynes. Nitrile oxides were generating in situ from nitroalkanes, aldoximes, and hydroximoyl chlorides.; Several isoxazoles, isoxazolines, and benzimidazolones were synthesized and tested as activators of the cystic fibrosis transmembrane conductance regulator protein (CFTR). The isoxazol(in)es were chosen based on initial hits that were synthesized. These initial hits came from compounds submitted as a random-based library. NS004 is a known activator of CFTR and thus similar benzimidazolones synthesized and tested were part of a lead-based library.; Our laboratory had also observed an interesting reaction between 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and 1,4-diphenyltetrazine. The syntheses of a few 1,4-disubstituted tetrazines were carried out according to known methods. The reaction of this electron-deficient heterocycle with DBU was examined. A novel fused tetraheterocyclic azepine was isolated and this ascertained that tetrazine was acting as both reactant and oxidant.; Solid-phase organic synthesis (SPOS) has become an important tool in organic, medicinal, agricultural, and combinatorial chemistry. Polystyrene resin supported benzyl acrylate, known as REM resin, has been employed previously for the synthesis of tertiary amines. Polymer-supported tertiary amines were obtained via Michael addition of secondary amines or Michael addition of primary amines followed by reductive amination of the intermediate secondary amine. Instead of quaternization of the resin-bound tertiary amine (which undergoes retro-Michael/Hoffmann elimination), the amine is oxidized to the amine-oxide. Cope elimination of the N-oxide proceeds concomitantly at room temperature to afford the cleaved hydroxylamine.; The Baylis-Hillman reaction or a step-wise MAC procedure (Michael addition, Aldol reaction, and Cope elimination) of methyl acrylate with various aldehydes (RCHO) affords allylic alcohols. 1,3-Dipolar cycloaddition of these alkenes with nitrile oxides (R'CNO) was followed by Swern oxidation of the secondary alcohol to provide the corresponding beta-ketoesters. Hydrazones of these beta-ketoesters were formed in situ with treatment of hydrazines (R″NHNH2) and cycloelimination ensued to provide the corresponding spiro-fused (C5)-isoxazolino-(C4)-pyrazolone.