Controlling the Outcome of an N-Alkylation Reaction by Using N-Oxide Functional Groups

• Published in: Journal of organic chemistry 2005-06, Vol.70 (13), p.5055-5061
• Main Authors: Pearson, Russell J, Evans, Kathryn M, Slawin, Alexandra M. Z, Philp, Douglas, Westwood, Nicholas J
• Format: Article
• Language: English
• Subjects: Alkylation; Amines - chemistry; Chemistry; Crystallography, X-Ray; Cyclic N-Oxides - chemistry; Cyclization; Exact sciences and technology; Heterocyclic compounds; Heterocyclic compounds with several n hetero atoms in the same ring, in separated rings or in fused rings; Kinetics and mechanisms; Magnetic Resonance Spectroscopy; Models, Molecular; Molecular Conformation; Molecular Structure; Organic chemistry; Preparations and properties; Proteins - chemistry; Quinoxalines - chemistry; Reactivity and mechanisms
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo0503106

Covalent modifiers of proteins are of importance in chemical proteomics, an emerging chemical technology used to assign protein function. In this study, high-field 1H NMR techniques were used to analyze the reaction of the bioactive compound, 2,3-bis(bromomethyl)quinoxaline 1,4-dioxide, with amines (a model system for proteins containing nitrogen-based nucleophiles). Unexpectedly, the results show that a double nucleophilic substitution reaction involving 2 equiv of the amine is preferred to an intramolecular cyclization pathway. A direct comparison with the reaction carried out on a substrate lacking the N-oxide functional groups is also provided. X-ray crystal structures and computational studies are used to rationalize the observed differences in reactivity between the two systems.