Cycloaddition Reactions with Azides An Overview

Christine Schilling, Nicole Jung and Stefan Brdse 

Institute of Organic Chemistry, Karlsruhe Institute of Technology (KIT), Fritz-Haber-Weg 6, Karlsruhe, D-76131, Germany 

The history of 1,3-dipoles began in the nineteenth century, when Curtius reported on the diazoacetic ester. A few years later, Buchner et al successfully performed the first 1,3-dipolar cycloaddition of the diazoacetic ester with a,j8-unsaturated esters. Despite the fact that, over the subsequent years, different 1,3-dipoles have been discovered, only a few have been generally effective in organic synthesis, e.g. the well-known Diels-Alder reaction.  

In 1963, Huisgen et al. published a systematic study on the concerted 1,3-dipolar cycloaddition, based on previous results from Smith and coworkers about the 1,3-addition of diazoalkanes, ozone and azides, as well as kinetic studies on the mechanism. The addition of a 1,3-dipole 1 (a-b-c), possessing ambivalent electrophilic as well as nucleophilic activity to a multiple bond system like the dipolarophile 2 (d-e), leads to a remarkably wide variety of five-membered heterocyclic compounds.  

Nowadays a broad range of different 1,3-dipoles, ozone, azides ° and diazoalkanes on the one hand as well as dipoles like nitrones, nitro compounds, carbonyl ylides, nitrile oxides, nitrile imines and ylides on the other hand, are well-established. The addition of these 1,3-dipoles to an alkene is one of the most frequently used cycloaddition reactions in organic synthesis.  

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Even though the CuAAC is a rather new reaction, more than 800 publications on Cu AAC chck chemistry has been pubhshed (May 2008), and it has been extensively reviewed. The focus of this chapter will be on azides in 1,3-dipolar cycloaddition reactions, mainly catalyzed by transition metals, in peptide chemistry. Protein ligation and protein modification by dipolar cycloaddition reactions has been reviewed and will not be included. Angell and Burgess published an excellent review on peptidomimetics generated by CuAAC in early 2007 with a thorough overview of the field and since then more than twenty new pubhcations describing dipolar cycloaddition reactions in peptide chemistry have appeared. 

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