No abstract

The controlled construction of defined oxidation patterns is one of the key aspects in the synthesis of natural products and bioactive molecules. Towards this goal, we herein report a novel protocol for the Pd-catalyzed direct β-C­(sp3)–H acetoxylation of aliphatic carboxylic acids. The protocol enables the use of free carboxylic acids in one step and without the need of introducing specialized strong directing groups. In our studies, we found that the use of a “traceless base” was crucial for the development of a synthetically useful transformation. Furthermore, the synthetic utility of the products obtained was demonstrated by their use in subsequent transformations.

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Amino diphenylphosphinates, which are commercially available or easily prepared from hydroxylamine, undergo ring expansion of cyclobutanones toward γ-lactams under mild conditions. A reaction pathway profoundly different from the common Beckmann reaction is achieved through the ambivalent character of the aminating agent. Thus, rearrangement occurs from a Criegee-like intermediate prior to the formation of the oxime species, which is corroborated by mechanistic experiments. Based on this observation, the migrating aptitude of the adjacent groups is analyzed and found to be in line with the parent Baeyer−Villiger reaction rendering a regioselective (up to >99:1 rr), stereospecific (>99% enantiospecificity), and chemoselective (>99%) insertion process possible. The method thus qualifies for late-stage skeletal editing as showcased by the synthesis of Rolipram and its N-alkylated analogs.