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

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 alpha-azido secondary acetamides (alpha-AzSAs) as minimal and unhindered azide structures. The NH-azide interaction in the alpha-AzSAs, supposed by DFT calculations, allowed selective conjugation in the presence of other azido moieties, even without steric hindrance. With Staudinger-Bertozzi ligation, alpha-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 alpha-AzSAs. We also demonstrated site-selective integration of the functional components onto the diazide modular hubs.

Automated summary

Organic azides, particularly alpha-azido secondary acetamides (alpha-AzSAs), have been shown to exhibit unique reactivities with selective conjugation in the presence of other azido moieties. These minimal and unhindered azide structures were found to undergo conjugation prior to other primary alkyl azides in Staudinger-Bertozzi ligation, but were slower than other alkyl azides in propargyl cation-mediated triazole synthesis. The study also demonstrated site-selective integration of functional components onto diazide modular hubs.