Photoredox Activation for the Direct β-Arylation of Ketones and Aldehydes

Abstract

The direct β-activation of saturated aldehydes and ketones has long been an elusive transformation. We found that photoredox catalysis in combination with organocatalysis can lead to the transient generation of 5π-electron β-enaminyl radicals from ketones and aldehydes that rapidly couple with cyano-substituted aryl rings at the carbonyl β-position. This mode of activation is suitable for a broad range of carbonyl β-functionalization reactions and is amenable to enantioselective catalysis.

Functionalization of C(sp 3 )–H bonds using a transient directing group

“…While β-arylation of ketones via reaction pathways other than β-metal insertion has been limited to the substrates without α-substitution (24, 25), directed C(sp 3 )–H activation of ketones has only been studied through the intermediacy of preformed oximes (9, 26, 27). We were aware that direct arylation of ketones using a transient directing group would face several challenges: First, in situ formation of ketimines is generally less favored than that of aldimines.…”

O–H hydrogen bonding promotes H-atom transfer from α C–H bonds for C-alkylation of alcohols

“…By combining photoredox activation with organocatalysis (23, 24) and nickel catalysis (25), we have recently highlighted the potential of photoredox catalysis to achieve bond constructions that are not possible with more traditional methods.…”

Reactivity in the nucleophilic aromatic substitution reactions of pyridinium ions

“…19 We were surprised by these results, and considered the possibility that the cyano substrates react by a radical mechanism, e.g., the S RN 1 pathway, since the cyano group is well known to stabilize free radicals. 20,21 We examined the effect of two different radical scavengers, 2,2,6,6-tetramethylpiperidine oxide (TEMPO) and 2,6-di- t -butylphenol, on the rate of reaction of piperidine with all substrates, but found no inhibition at two or more scavenger concentrations. Hence, if radical intermediates are formed they are paired or otherwise inaccessible to the scavengers.…”