Taming the reactivity of alkyl azides by intramolecular hydrogen bonding: site-selective conjugation of unhindered diazides

Abstract

Organic azides are still in the center of click chemistry connecting two molecules. However, taming the conjugation selectivity of azides is difficult without the help of bulky groups. We report herein the unique reactivities of α-azido secondary acetamides (α-AzSAs) as minimal and unhindered azide structures. The NH–azide interaction in the α-AzSAs, supposed by DFT calculations, allowed selective conjugation in the presence of other azido moieties, even without steric hindrance. With Staudinger–Bertozzi ligation, α-AzSAs underwent conjugation prior to the other primary alkyl azides. On the other hand, in propargyl cation-mediated triazole synthesis, other alkyl azides, including tertiary alkyl azides, underwent the conjugation faster than α-AzSAs. We also demonstrated site-selective integration of the functional components onto the diazide modular hubs.