Enabling Unfavorable Hydroamination Reactions Using a Chemoselective N-O Bond Reduction.

Despite major advances, intramolecular alkene hydroamination reactions often face limitations. Herein, a redox-enabled process featuring oxidation of an amine to a hydroxylamine, a concerted hydroamination step, followed by catalytic reduction of -oxide is shown to be broadly applicable. Catalyst screening and optimization showed that a KOsO(OH)-pinacol complex rapidly and chemoselectively reduces the -oxide cycloadduct in the presence of hydroxylamine and dimethyl sulfoxide.

Oxidative Syntheses of ,-Dialkylhydroxylamines.

Despite the wide utility of hydroxylamines in organic synthesis, relatively few are commercially available, and there is a need for direct, efficient, and selective methods for their synthesis. Herein, we report two complementary methods to accomplish direct oxidation of secondary amines using UHP as an oxidant. The first method uses 2,2,2-trifluoroethanol (TFE) and a large excess of amine.

Insights on Structure-Passive Permeability Relationship in Pyrrole and Furan-Containing Macrocycles.

Macrocycles have recognized therapeutic potential, but their limited cellular permeability can hinder their development as oral drugs. To better understand the structure-permeability relationship of heterocycle-containing, semipeptidic macrocycles, a library was synthesized. These compounds were created by developing two novel reactions described herein: the reduction of activated oximes by LiBH and the aqueous reductive mono--alkylation of aldehydes using catalytic SmI and stoichiometric Zn.

A redox-enabled strategy for intramolecular hydroamination.

Metal- or acid-catalyzed intramolecular hydroamination and Cope-type intramolecular hydroamination, a distinct concerted approach using hydroxylamines, typically suffer from significant synthetic limitations. Herein we report a process for intramolecular hydroamination that uses a redox-enabled strategy relying on efficient generation of hydroxylamines by oxidation, followed by Cope-type hydroamination, then reduction of the resulting pyrrolidine -oxide. The steps are performed sequentially in a single pot, no catalyst is required, the conditions are mild, the process is highly functional group tolerant, and no chromatography is generally required for isolation.