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

Abstract

A Pd-catalyzed C−O cross-coupling of O-acyl hydroxylamines and tertiary or secondary alkyl electrophiles was reported without the cleavage of the rather fragile N−O bond. The described strategy provides direct access to congested N,N,Otrisubstituted hydroxylamines bearing an α-quaternary carbon center under mild conditions in high yields and features exclusively chemoselective C−O bond formation, a broad substrate scope, and excellent functional group tolerance. The synthetic potential of the cross-coupling was established via pharmaceuticals derivatizations and a series of postcatalytic modifications.

Recent Advances in the Synthesis of Di- and Trisubstituted Hydroxylamines

“…In 2022, Shao, Xiao, and Deng reported a synthesis of sterically encumbered O-tert -alkyl- N , N -disubstituted hydroxylamines by tandem in situ deacetylation of O -benzoyl- N , N -disubstituted hydroxylamines and coupling with -amido or -keto tertiary alkyl chlorides ( Scheme 8 ) [ 58 ]. The reaction proceeds under palladium catalysis with Xantphos as a ligand in up to 85% yield and exhibits good functional group tolerance.…”

Recent Advances in N-O Bond Cleavage of Oximes and Hydroxylamines to Construct N-Heterocycle

“…Hydroxylamine is a stable, easily prepared, and versatile amination reagent, which could not only act as a nucleophile, but also converts the hydroxyl group into a good leaving group and acts as an electrophile. Changing the substituents on the two electronegative atoms of hydroxylamine allows more diverse modifications and the introduction of functional groups [ 24 , 25 , 26 , 27 , 28 ]. It can also modulate the ability of both the electrophilic and nucleophilic properties, thereby regulating the activity of the reaction.…”

Site-Selective Radical Trifluoromethylaminoxylation of Olefins for the Modular Synthesis of Diverse β-Trifluoromethyl Trisubstituted Hydroxylamines and Beyond

“…11 Very recently, our group disclosed an efficient method for the synthesis of congested trisubstituted hydroxylamines via a Pdcatalyzed C−O cross-coupling of tertiary alkyl halides. 12 Inspired by the strategy of oxytrifluoromethylation and our ongoing research on the sustainable chemical process, we herein describe the transition-metal-free regioselective trifluoromethylaminoxylation of alkenes at room temperature (Scheme 1, c). Using a commercially available hypervalent iodine−CF 3 reagent (Togni reagent) and OH hydroxylamines in near-equal stoichiometric ratios to olefins (1.2:1.2:1.0), not only diverse β-trifluoromethyl trisubstituted hydroxylamines but also tertiary alcohols, isoxazolines, isoxazolidines, and valuable amino alcohols could be modularly accessed.…”

“…In 2020, Crich and co-workers developed a direct route toward a series of N , N , O -trisubstituted hydroxylamines by N–O bond formation via magnesium dialkylamides reacting with alcohol-derived peroxides (Scheme , b) . Very recently, our group disclosed an efficient method for the synthesis of congested trisubstituted hydroxylamines via a Pd-catalyzed C–O cross-coupling of tertiary alkyl halides …”

“…Inspired by our previous studies that showed N , N -disubstituted hydroxylamine could be in situ generated by a transesterification reaction between benzoyl hydroxylamine and tert -butoxide base, we therefore chose the facilely accessible benzoyl hydroxylamines 2′ as aminoxyl radical precursors for the exploration of other hydroxylamines. A wide range of cyclic and acyclic aliphatic hydroxylamines were appropriate coupling partners for this protocol and delivered the anticipated products 3aj – 3ay in 51–81% yields (for a detailed scope of benzoyl hydroxylamines, see Scheme S1 in the SI).…”