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.

Fig. 1

Proposed activation mode for direct β-arylation of carbonyls—an elusive transformation.

Fig. 2

Photoredox C–H β-arylation: Proposed mechanistic pathway (Me, methyl).

Fig. 3

Photoredox C–H β-arylation: aldehyde and arene scope. For each entry number (in boldface), data are reported as percent isolated yield. R = generic alkyl or aryl substituent; X = CH, C, or N; DMPU, 1,3-dimethyltetrahydropyrimidin-2(1H)-one; DABCO, 1,4-diazabicyclo[2.2.2]octane; Me, methyl; Bn, benzyl; t-Bu, tert-butyl; Boc, tert-butyl carbamoyl; Cbz, benzyl carbamoyl. *See supplementary materials for experimental details. †1.0 equiv of Na₂CO₃ added. ‡Product isolated as β-aryl alcohol. §Regiomeric ratio (r.r., determined by ¹H nuclear magnetic resonance analysis; see supplementary materials). Major isomer is shown; minor isomer is 3-methoxy-4-alkylbenzonitrile.

Fig. 4

(A) Direct β-arylation of ketones. For each entry number, data are reported as percent isolated yield; for entries 37 to 39, diastereomeric ratio (d.r.) was determined by ¹H nuclear magnetic resonance analysis. R = hydrogen or methyl; R’ = hydrogen, generic alkyl, or aryl substituent; X = CH or O. (B) Enantioselective β-arylation of cyclohexanone (ee, enantiomeric excess). *20 mol % piperidine used as the organocatalyst. †40 mol % azepane used as the organocatalyst.