Azidation Made Easy

Something as simple as an extra nitrogen atom can make a big difference when developing a drug. Take, for example, erythromycin: Tweaking the antibiotic’s structure to remove a ketone and add a tertiary amine produces azithromycin, an antibiotic that can be dosed less frequently and requires a shorter treatment time. Now, University of California, Berkeley, chemists John F. Hartwig and Ankit Sharma have developed a mild, iron-catalyzed azidation process for C–H bonds (Nature 2015, DOI: 10.1038/nature14127). The reaction uses an azide-containing hypervalent iodine reagent to selectively transform tertiary C–H bonds into C–N bonds. The resulting azides, Hartwig and Sharma note, can be further transformed into various nitrogen-based functional groups, such as amines and triazoles. In one example (shown), the researchers use the reaction on a derivative of the plant hormone gibberellic acid. The compound contains four tertiary C–H bonds, but only the most electron rich and least sterically hindered undergoes azidation. Hartwig and Sharma anticipate that the reaction will be useful for making analogs of natural products and drug candidates as well as for adding fluorescent tags or other handles directly onto complex molecular structures.