Oxidative Cross-Coupling of α-Amino Ketones with Alcohols Enabled by I₂-Catalyzed C–H Hydroxylation

Abstract

An I 2 -catalyzed oxidative cross-coupling of α-amino ketones with a wide range of alcohols is described. Using a combination of air and dimethyl sulfoxide (DMSO) as oxidants, the protocol allows an efficient synthesis of α-carbonyl N,O-acetals with high functional group tolerance and enables the late-stage introduction of α-amino ketones into biorelevant alcohols. Moreover, the present method can be used in the coupling of αamino ketones with other kinds of nucleophiles, which demonstrates great generality for the functionalization of αamino ketones. A preliminary mechanistic investigation suggests that C−H hydroxylation of α-amino ketones has been recognized as the key step followed by subsequent dehydration coupling.

DMAP-promoted oxidative functionalization of α-amino ketones via oxygen delivery from water/alcohols

“…In our continuing efforts on developing useful transformations of α-amino ketones, 5 we are particularly interested in C–H oxidation of α-amino ketones to α-ketoamides that represent important structural motifs found in various natural products and pharmaceuticals, and have been recognized as versatile building blocks in organic synthesis and drug discovery. 6 Among various methods for the synthesis of α-ketoamides, 7 the C–H oxidation of α-amino ketones to tertiary α-ketoamides with O 2 as an oxygen source has proven to be a highly efficient and mild process, 8 but the construction of secondary α-ketoamides by this approach has not been reported.…”