Base‐Promoted [3+2]‐Annulation of Oxime Esters and Aldehydes for Rapid Isoxazoline Formation

Abstract

A base‐promoted [3+2]‐annulation of ketoxime esters and aldehydes is disclosed for the facile and rapid synthesis of 3,5‐disubstituted and 3,4,5‐trisubstituted isoxazolines. The key to our success is the pivalate leaving group of the oxime substrates, combined with cesium carbonate as promoter. This chemistry allows the assembly of a vast array of isoxazoline derivatives under simple base conditions in a method complementary to the classic isoxazoline formation via [3+2]‐dipolar cycloaddition of nitrile oxides and olefins. It also represents a new reaction pattern involving electrophilic amination/N–O bond substitution.magnified image

Copper-Catalyzed Cascade Annulation of Malonate-Tethered O-Acyl Oximes with Cyclic 1,3-Dicarbonyl Compounds for the Synthesis of Spiro-Pentacyclic Derivatives

“…Transition metal-catalyzed intermolecular [4+2] annulation of ketoximes via directing C–H activation has proven to be an efficient method for the synthesis of pyridines, isoquinolines, and isoquinolinones . The O -acyl ketoxime bearing an α-C­(sp 3 )–H can also act as an N–C–C synthon in [3+ n ] reactions with a different coupling partner to give various five-, six-, and seven-membered heterocycles, including pyrroles, pyrrolines, oxazoles, isoxazolines, thiazoles, imidazoles, pyrazoles, pyrazolines, triazoles, pyrrolinones, pyridines, , pyridones, quinolines, and tetrahydroazepines …”

Crystal structure of 5-(4-tert-butoxyphenyl)-3-(4-n-octyloxyphenyl)-4,5-dihydroisoxazole

“…Nitrogen-and oxygen-containing heterocycles known as Á 2isoxazolines constitute an important class of five-membered heterocycles which have significant synthetic and biological applications (Pirrung et al, 2002;Choe et al, 2016;Huang et al, 2017;Stosic-Grujicic et al, 2007). Isoxazolines display diverse biological and pharmacological properties.…”

Stereoselective Synthesis of 4,5‐Dihydroisoxazole Derivatives from 1,1‐Dicyanocyclopropanes and Hydroxylamine Hydrochloride

“…Accordingly, not surprisingly, numerous synthetic approaches leading to an isoxazoline nucleus have been developed, principally consisting of the cycloaddition from 1,3‐dicarbonyl intermediates and hydroxylamine or from modified three‐carbon 1,3‐electrophilic intermediates of 1,3‐dicarbonyl compounds, including β‐alkylthioenones, enamino ketones, ynones, and α,β‐unsaturated ketones [41–46] . Another most efficient strategy based on the 1,3‐dipolar cyclic addition reactions of alkenes or alkynes and nitrile oxides, formed readily from aldoximes or nitroalkanes, also was burgeoned [47–61] . Furthermore, other powerful protocols involving oximes [62,63] and hydroxylamines [64–66] have also been described employing intramolecular cyclization.…”