title: Chemoselective amide formation using O-(4-nitrophenyl)hydroxylamines and pyruvic acid derivatives.
abstract: A series of O-(4-nitrophenyl)hydroxylamines were synthesized from their respective oximes using a pulsed addition of excess NaBH(3)CN at pH 3 in 65-75% yield. Steric hindrance near the oxime functional group played a key role in both the ease by which the oxime could be reduced and the subsequent reactivity of the respective hydroxylamine. Reaction of the respective hydroxylamines with pyruvic acid derivatives generated the desired amides in good yields. A comparison of phenethylamine systems bearing different leaving groups revealed significant differences in the rates of these systems and suggested that the leaving group ability of the N-OR substituent plays an important role in determining their reactivity with pyruvic acid. Competition experiments (in 68% DMSO/phosphate buffered saline) using 1 equiv of N-phenethyl-O-(4-nitrophenyl)hydroxylamine and 2 equiv of pyruvic acid in the presence of other nucleophiles such as glycine, cysteine, phenol, hexanoic acid, and lysine demonstrated that significant chemoselectivity is present in this reaction. The results suggest that this chemoselective reaction can occur in the presence of excess α-amino acids, phenols, acids, thiols, and amines.
authors.affiliation: Department of Medical Education, College of Medicine, University of Central Florida, 6850 Lake Nona Boulevard, Orlando, Florida 32827, USA.
authors.forename: Sonali
authors.initials: S
authors.lastname: Kumar
authors.forename: Rashi
authors.initials: R
authors.lastname: Sharma
authors.forename: Megan
authors.initials: M
authors.lastname: Garcia
authors.forename: Joseph
authors.initials: J
authors.lastname: Kamel
authors.forename: Caroline
authors.initials: C
authors.lastname: McCarthy
authors.forename: Aaron
authors.initials: A
authors.lastname: Muth
authors.forename: Otto
authors.initials: O
authors.lastname: Phanstiel
mesh_terms: D000577:Amides / Q000737:chemistry*; D000588:Amines / Q000737:chemistry; D000596:Amino Acids / Q000737:chemistry; D006898:Hydroxylamines / Q000138:chemical synthesis* / Q000737:chemistry; D015394:Molecular Structure; D009596:Nitrophenols / Q000138:chemical synthesis* / Q000737:chemistry; D010636:Phenols / Q000737:chemistry; D019289:Pyruvic Acid / Q000737:chemistry*
chemical_list: D000577:Amides; D000588:Amines; D000596:Amino Acids; D006898:Hydroxylamines; D009596:Nitrophenols; D010636:Phenols; C024719:4-nitrophenyl; D019289:Pyruvic Acid