Organic Azides and Azide Sources

Since the preparation of the first organic azide, phenyl azide by Peter Griess in 1864, this energy-rich and versatile class of compounds has gained considerable interest. More recently, new perspectives have emerged, notably the use of organic azides for peptide synthesis, combinatorial synthesis, heterocycle synthesis, and the ligation or modification of biopolymers.¹ The most prominent fields of application are Huisgen 1,3-dipolar cycloadditions, and different variants of the Staudinger ligation.

The azido group can also be regarded as a protecting group for coordinating primary amines, especially in sensitive substrates like complex carbohydrates or peptidonucleic acids (PNA).² For example, it is stable to alkene metathesis conditions.³

An elegant way to produce organic azides from unactivated olefins was reported by Carreira and co-workers. A catalyst, that is easily prepared from Co(BF₄)₂ · 6H₂O and a Schiff base allows hydroazidation with p-toluenesulfonyl azide (TsN₃) to yield alkyl azides. Mono-, di-, and trisubstituted olefins are tolerated in this reaction, and complete Markovnikov selectivity is observed (Scheme 1).⁴

Scheme 1. Organic Azides and Azide Sources

References

1. Bräse S, Gil C, Knepper K, Zimmermann V. 2005. Organic Azides: An Exploding Diversity of a Unique Class of Compounds. Angew. Chem. Int. Ed.. 44(33):5188-5240. https://doi.org/10.1002/anie.200400657

2. Debaene F, Winssinger N. 2003. Azidopeptide Nucleic Acid. An Alternative Strategy for Solid-Phase Peptide Nucleic Acid (PNA) Synthesis. Org. Lett.. 5(23):4445-4447. https://doi.org/10.1021/ol0358408

3. Kanemitsu T, Seeberger PH. 2003. Use of Olefin Cross-Metathesis to Release Azide-Containing Sugars from Solid Support. Org. Lett.. 5(24):4541-4544. https://doi.org/10.1021/ol035463z

4. Waser J, Nambu H, Carreira EM. 2005. Cobalt-Catalyzed Hydroazidation of Olefins: Convenient Access to Alkyl Azides. J. Am. Chem. Soc.. 127(23):8294-8295. https://doi.org/10.1021/ja052164r