As weak bases, hydroxylamines are not protonated under typical physiological conditions and have a low barrier (approximately 15 kcalmol-1) for inversion at the pyramidal nitrogen that is not sufficient to prevent rapid inversion at room temperature. These characteristics led the Crich group to employ hydroxylamines as achiral surrogates for glycosidic bonds.1 Subsequently, recognizing that hydroxylamines are relatively under-represented in the pharmacopeia, yet have the desirable properties of low basicity and rapid nitrogen inversion that potentially give them unique advantages in medicinal chemistry, we have undertaken a broad program of hydroxylamine synthesis and evaluation. Here we report a novel method for the synthesis of N,N,O-trialkyl hydroxylamines from N,N-dialkyl hydroxylamines in three steps based on the partial reduction of O-acyl hydroxylamines and manipulation of the resulting mixed acetals (Scheme 1).

Novel method for the synthesis of highly substituted hydroxylamines

251st National Meeting (2016)

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