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

Abstract

Covalent modifiers of proteins are of importance in chemical proteomics, an emerging chemical technology used to assign protein function. In this study, high-field (1)H 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.

Optimisation of Conoidin A, a Peroxiredoxin Inhibitor

“…Compound 2 was prepared by conversion of butane-2,3-dione (3) to the brominated diketone 4. [8,9] Subsequent condensation of 4 with 1,2-phenylenediamine gave high yields of the mono-bromo quinoxaline 5 that was oxidised (mCPBA, 2 equiv) to give 2. The use of limited amounts of mCPBA led to a mixture of the two mono-Noxides 6 and 7, [10] as it was thought that pure samples of these two analogues would enable the role of the N-oxide functional groups to be explored.…”

Synthesis and chemical characterisation of target identification reagents based on an inhibitor of human cell invasion by the parasite Toxoplasma gondii

“…In the course of our efforts to develop novel chemical tools to help study this important biological process, we recently reported on the mechanism of reaction of 2,3-bis(bromomethyl)quinoxaline 1,4-dioxide (1) with primary and secondary amines (Scheme 1). 2 These studies provided the first experimental evidence in support of a mechanism that involves conversion of 1 via 2 to the disubstituted intermediate 3. Computational studies were used to support our hypothesis that the reaction outcome stems from an electrostatic repulsion between the N-oxide functional group and the bromide leaving group which raises the energy of the transition state such that the expected cyclisation reaction of 2 does not occur.…”

Halogen Bonding in New Dichloride-Cobalt(II) Complex with Iodo Substituted Chalcone Ligands

“…The O•••I halogen bond formed by co-crystallized molecule of Et 2 O was thoroughly studied by modern theoretical calculations, because reports on O•••I halogen bonding involving Et 2 O [35] or similar alkoxy compounds [36][37][38][39][40][41] are rare. Similarly, the crystal structures with short O•••Cl (e.g., [42,43]) and O•••Br (e.g., [44,45]) non-covalent interactions formed between halogen atoms and Et 2 O molecules can be found in the Cambridge Structural Database (CSD version 2.0.4, [46]), but to the best of our knowledge, reports applying advanced theoretical calculations for better understanding the nature of this certain type of halogen bond are missing.…”

“…Here, we report on the first results obtained using the above-mentioned approach. We used ligand 4I-L ( [42,43]) and O•••Br (e.g., [44,45]) non-covalent interactions formed between halogen atoms and Et2O molecules can be found in the Cambridge Structural Database (CSD version 2.0.4, [46]), but to the best of our knowledge, reports applying advanced theoretical calculations for better understanding the nature of this certain type of halogen bond are missing.…”