Directing activator-assisted regio- and oxidation state-selective aerobic oxidation of secondary C(sp³)–H bonds in aliphatic alcohols

Abstract

The regioselective conversion of an unactivated C(sp(3))-H bond of a methylene carbon (CH2) into a C-O single bond is an attractive reaction in organic synthesis. Herein, we present a strategy for a regio- and oxidation state-selective aerobic C-H oxidation based on an N-hydroxyamide-derived directing activator (DA), which is attached to a hydroxy group in alcohol substrates. The DA reacts with NOx species generated in situ from NaNO2, a Brønsted acid, and aerobic oxygen, and effectively generates an amidoxyl radical from the N-hydroxy moiety of the DA. Then, the amidoxyl radical promotes site-selective intramolecular C-H abstraction from methylenes with γ- (or δ-) selectivity. The thus-generated methylene radicals are trapped by molecular oxygen and NO. This process results in the predominant formation of nitrate esters as products, which suppresses undesired overoxidation. The products can be easily converted into alcohols after hydrogenolysis.

Catalytic Aerobic Oxidation of C(sp3)−H Bonds

“…Moreover,l ow conversions are typically observed. [111] This method provided predominantly the nitrate esters with significant amounts of ketone present. [110] Oxygenation of benzylic,p ropargylic,t ertiary and secondary CÀHb onds with good regioselectivity for the g and d position depending on the substrate was possible.…”

“…Co(OAc) 2 was used as acocatalyst either in combination with catalytic Mn(OAc) 3 •2 H 2 Oo r, in the case of tertiary CÀH bonds,stoichiometric Me 2 S, which acts as areductant for the initially formed hydroperoxides.I nafollow-up paper they proposed am etal-free alternative using superstoichiometric NaNO 2 in combination with an acid activator. [111] This method provided predominantly the nitrate esters with significant amounts of ketone present. Thed irecting activator can be removed by reduction with LiAlH 4 ,with concomitant reduction of the ketone,resulting in the formation of 1,3-diols.…”

Remote C–H Functionalization via Selective Hydrogen Atom Transfer

“…125 Also in 2016, the Oisaki and Kanai group showed that these radical precursor scaffolds can be combined with in situ generated NO x species to form γ-nitrated alcohols. 126…”

Katalytische, aerobe Oxidation von C(sp3)‐H‐Bindungen

“…In einer auf diesen Ergebnissen aufbauenden Arbeit schlugen die Autoren eine metallfreie Alternative vor, in der sie überstçchiometrische Mengen an NaNO 2 in Kombination mit einer Säure als Aktivator einsetzten. [111] Dabei wurden hauptsächlich die Nitratester und signifikante Mengen der Ketone erhalten. Der DA kann durch Reduktion mit LiAlH 4 abgespalten werden, wobei gleichzeitig das Keton reduziert wird und so 1,3-Diole erhalten werden.…”