Selective α‐Oxyamination and Hydroxylation of Aliphatic Amides

Abstract

Compared to the α-functionalization of aldehydes, ketones, even esters, the direct α-modification of amides is still a challenge because of the low acidity of α-CH groups. The α-functionalization of N-H (primary and secondary) amides, containing both an unactived α-C-H bond and a competitively active N-H bond, remains elusive. Shown herein is the general and efficient oxidative α-oxyamination and hydroxylation of aliphatic amides including secondary N-H amides. This transition-metal-free chemistry with high chemoselectivity provides an efficient approach to α-hydroxy amides. This oxidative protocol significantly enables the selective functionalization of inert α-C-H bonds with the complete preservation of active N-H bond.

Differentiation between enamines and tautomerizable imines in the oxidation reaction with TEMPO

“…Recently, a series of α -aminoxylation reactions of carbonyl compounds 14 , 15 , 23 – 30 using 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) as oxidant has been established, some of which involved metal-promoted oxidation of the enamine intermediates generated in-situ from the condensation of aldehydes with secondary amines 14 , 15 , 23 – 28 . These elegant studies provided a good starting point for our investigation of the structure-reactivity relationship of enamine and tautomerizable imine.…”

Chemoselective Catalytic α-Oxidation of Carboxylic Acids: Iron/Alkali Metal Cooperative Redox Active Catalysis

“…We focused on TEMPO, a commercially available free radical compound, as an oxidation reagent. Lithium amide mediated α-oxidation of carboxylic acid using TEMPO was previously reported. − Undesired dimerization of carboxylic acid was inevitably observed, however, resulting in a low chemical yield . Because it is quite difficult to deprotonate a less acidic α-proton (RC H 2 COOH) over the highly acidic proton of carboxylic acid (RCH 2 COO H ), we began our investigation with the addition of greater than stoichiometric amounts of carbonate salt as a Brønsted base and molecular sieves as a desiccant (Details described in Supporting Information).…”

Synthesis of γ-substituted carbonyl compounds from DMSO-mediated oxidation of enynamides: mechanistic insights and carbon- and hetero-functionalizations

“…Intermolecular Umpolung reaction leading to α-hetero-functionalization has been studied with various nucleophiles, including (thio)phenols,19 a oxyacids,19b,c halogen,19 d thiocyanate,19 d azides,19d,e amines,4f,19f,g and TEMPO 19h–j. Although unmodified phenols/thiols19 a and amines19f,g could be used as nucleophiles, use of oxidizable aliphatic (primary and secondary) alcohols/thiols is surprisingly rare 19…”