Synthesis of O-tert-Butyl-N,N-disubstituted Hydroxylamines by N–O Bond Formation

Abstract

The reaction of magnesium amides with tert-butyl 2,6-dimethyl perbenzoate in tetrahydrofuran at 0 °C provides a method for the synthesis O-tert-butyl-N,N-disubstituted hydroxylamines by direct N–O bond formation with a broad functional group tolerance. Less sterically hindered magnesium amides require ortho,ortho-disubstitution on the perester electrophile component, whereas sterically encumbered magnesium amides perform comparably with either tert-butyl perbenzoate or tert-butyl 2,6-dimethyl perbenzoate. A reaction mechanism is presented to account for the observed reactivity.

The N,N,O-Trisubstituted Hydroxylamine Isostere and Its Influence on Lipophilicity and Related Parameters

“…20 Additionally, and in contrast to the common perception that hydroxylamines are inherently toxic, 10-aza-9-oxakalkitoxin (2) was found not to be genotoxic in the Samonella typhimurium test strain TA98 with and without metabolic activation by the PB/β-naphthoflavone-induced rat liver metabolic activation system. 20,22−24 Motivated by these results, we developed 25,26 synthetic methods to access the trisubstituted hydroxylamine moiety by N−O bond formation from 1°, 2°, and 3°alcohols and 2°a mines, thereby providing concise, convergent approaches to this isostere. 27 We now report a matched molecular pair (MMP) 28,29 analysis of the effect of N,N,O-trisubstituted hydroxylamine incorporation on lipophilicity using scaffolds present in small molecules, ranging from the pre-clinical to FDA-approved status, and reveal that in most cases the N,N,O-trisubstituted hydroxylamine moiety decreases lipophilicity in carbon−carbon bond replacements to a degree similar to that obtained by tertiary amine incorporation.…”

“…For ether (28) we selected Rychnovsky's methodology. 41 Accordingly, 2-tetralone (21) was reduced in 74% yield to the alcohol (25) and coupled with valeric acid in 75% yield to give ester (26). Partial reduction and in situ acetylation afforded a 60% yield of the α-acetoxyacetal (27), which gave the desired ether (28) in 79% yield on reduction with BF 3 •OEt 2 and Et 3 SiH.…”

“…Motivated by these results, we developed , synthetic methods to access the trisubstituted hydroxyl­amine moiety by N–O bond formation from 1°, 2°, and 3° alcohols and 2° amines, thereby providing concise, convergent approaches to this isostere . We now report a matched molecular pair (MMP) , analysis of the effect of N,N,O -trisubstituted hydroxyl­amine incorporation on lipophilicity using scaffolds present in small molecules, ranging from the pre-clinical to FDA-approved status, and reveal that in most cases the N,N,O -trisubstituted hydroxyl­amine moiety decreases lipophilicity in carbon–carbon bond replacements to a degree similar to that obtained by tertiary amine incorporation.…”

Synthesis of 10-Aza-9-oxakalkitoxin by N–O Bond Formation

“…With this in mind, subsequently we developed general methods for the convergent construction of N , N , O -trisubstituted hydroxylamines involving reaction of secondary-amine-derived magnesium amides with (i) methyltetrahydropyranyl (MTHP) derivatives of primary and secondary alkyl hydroperoxides and (ii) tert -butyl perbenzoates. , We now demonstrate that the application of the first of these methods coupled with Mukaiyama Markovnikov hydroperoxidation of a terminal alkene prepared by chiral-auxiliary-directed diastereoselective synthesis affords a convenient entry into the key acid 9 and thereby a considerably shortened formal synthesis of hydroxalog 1 .…”

Pd-Catalyzed C–O Bond Formation Enabling the Synthesis of Congested N,N,O-Trisubstituted Hydroxylamines

“…However, with these two methods, the preparation of N , N , O -trisubstituted alkyl hydroxylamines still requires several steps and low temperature. Recently, a direct route toward a broad scope of N , N , O -trisubstituted hydroxylamines was developed by Crich and co-workers by N–O bond formation via the reaction of magnesium dialkylamides with alcohol-derived peroxides . This methodology is highlighted by compatibility with a wide range of primary and secondary alcohol-derived peroxides, with even a tert -butyl group as a coupling partner, and emphasizes the significance of hydroxylamines in medicinal chemistry.…”