Transition Metal‐Free TEMPO‐Catalyzed Oxidative Cross‐ Coupling of Nitrones with Alkynyl‐Grignard Reagents

Abstract

An efficient mild one-pot protocol for the cross-coupling of nitrones and alkynyl-magnesium compounds using a catalytic amount of 2,2,6,6-tetramethylpiperidine-N-oxyl radical (TEMPO) as an environmentally benign organic oxidant and dioxygen as terminal oxidant is described. These coupling reactions can be performed without adding any transition metal on various N-tert-butylnitrones and alkynyl-Grignard reagents. Moreover, the alkynylated nitrone products are readily transformed to regioisomerically pure 3,5-disubstituted isoxazoles.

Progress and developments in the turbo Grignard reagent i-PrMgCl·LiCl: a ten-year journey

“…26 In 2011, Studer and co-workers 26 described that a series of α-alkynylated nitrones were efficiently and conveniently synthesized via an one-pot consecutive nucleophilic addition of alkynyl Grignard reagents to aliphatic nitrones, followed by TEMPO/O 2 catalyzed oxidation (Scheme 9). In this study, the authors found that the addition of water was beneficial, and this result could be rationalized considering that the formation of nitroxide with hydroxylamine by H-transfer was faster than direct electron-transfer from the metallized hydroxylamine.…”

Dehydrogenative TEMPO‐Mediated Formation of Unstable Nitrones: Easy Access to N‐Carbamoyl Isoxazolines

“…An umber of oxidants were tested under neat conditions or in dichloromethane as the solvent at room temperature to minimize the possible decomposition of the generated Ncarbamoyl nitrone. Whereast he typical reagents for dehydro-genative cross-coupling (CDC) reactions [14] such as organic peroxides, 2, , or TEMPO oxoammonium salts did not lead to the desired product ( Table 1, entries 1-3), the use of aT EMPO radical [15][16] provided isoxazoline 3a in ap romising 25 %y ield (entry 4). A complete conversion of the hydroxylamine 1a was observed with all the oxidants explored.…”

“…First, ah ydrogen atom abstraction from the hydroxylamine 1 occurs. This hydrogencan be abstracted directly by TEMPO [15] or by the carbon-centered radical 9 obtained upon reversible radicala ddition of TEMPO to 2a.T he nitroxide 10 is then formed together with 4 or TEMPOH,w hich can also react with 2a in ac onjugate addition way to form the same byproduct. Next, two molecules of nitroxide 10 disproportion- :hydroxyamine 1a.…”

TEMPO Derivatives as Alternative Mild Oxidants in Carbon-Carbon Coupling Reactions

“…16 This transformation implies the in situ oxidation of a propargyl N-hydroxylamine magnesium salt intermediate 16, obtained after a first addition of the Grignard reagent to the nitrone. Thus, synthetically valuable propargylic nitrones 15 were easily prepared in good yields by an efficient two-step one-pot approach.…”

“…Interest-2,6-lutidine (1.0 equiv) NaClO 4 (0. 16 ingly, the complete reduction of the TEMPO salt occurs, leading to the formation of 2,2,6,6-tetramethylpiperidine and permitting maximizing the oxidative properties of the N-O bond. A related three-component oxidative synthesis of quinolines from anilines, ethyl glyoxalate, and olefins has lately been successfully achieved.…”