Azide Click Chemistry

A "Click" Away from Discovery

The traditional process of drug discovery based on natural secondary metabolites has often been slow, costly, and labor-intensive. Even with the advent of combinatorial chemistry and high-throughput screening in the past two decades, the generation of leads is dependent on the reliability of the individual reactions to construct the new molecular framework.

Click Chemistry Mechanism

Click chemistry is a newer approach to the synthesis of drug-like molecules that can accelerate the drug discovery process by utilizing a few practical and reliable reactions. Sharpless and coworkers defined what makes a click reaction as one that is wide in scope and easy to perform, uses only readily available reagents, and is insensitive to oxygen and water. In fact, in several instances water is the ideal reaction solvent, providing the best yields and highest rates. Reaction work-up and purification uses benign solvents and avoids chromatography.1

Click Chemistry Reaction Processes

  • Simple to perform
  • Modular
  • Wide in scope
  • High yielding
  • Stereospecific
  • Adhere to the

12 Principles of Green Chemistry by generating only harmless byproducts that can be removed by nonchromatographic methods

Click Chemistry Reaction Characteristics1

  • Simple reaction conditions
  • Readily and easily available starting materials and reagents
  • Use of no solvent, a benign solvent (such as water), or one that is easily removed
  • Simple product isolation
  • Product should be stable under physiological conditions

Click chemistry involves the use of a modular approach and has important applications in the field of drug discovery, combinatorial chemistry, target-templated in situ chemistry, and DNA research.1

Of the reactions comprising the click universe, the “perfect” example is the Huisgen 1,3-dipolar cycloaddition of alkynes to azides to form 1,4-disubsituted-1,2,3-triazoles (Scheme 1). The copper(I)-catalyzed reaction is mild and very efficient, requiring no protecting groups, and requiring no purification in many cases.2The azide and alkyne functional groups are largely inert towards biological molecules and aqueous environments, which allows the use of the Huisgen 1,3-dipolar cycloaddition in target guided synthesis3 and activity-based protein profiling.4 The triazole has similarities to the ubiquitous amide moiety found in nature, but unlike amides, is not susceptible to cleavage. Additionally, they are nearly impossible to oxidize or reduce.

Huisgen 1,3-dipolar cycloaddition of alkynes to azides to form 1,4-disubsituted-1,2,3-triazoles

Scheme 1

Using Cu(II) salts with ascorbate has been the method of choice for preparative synthesis of 1,2,3-triazoles, but is problematic in biocojugation applications. However, tris[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amine, TBTA (Figure 1), has been shown to effectively enhance the copper-catalyzed cycloaddition without damaging biological scaffolds.5

tris[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amine, TBTA

Figure 1

Sharpless and coworkers reported the ruthenium-catalyzed cycloaddition of azides to alkynes to form the complementary 1,5-disubstituted triazoles.6 Several ruthenium complexes were employed, but the pentamethylcyclopentadienyl (Cp*) analogues gave the best results, with Cp*RuCl(PPh3)2 being employed in most cases. Whereas the Cu(I)-catalyzed reaction is limited to terminal alkynes, the Ru(II)-catalyzed reaction is active with internal alkynes as well (Scheme 2).

Ru(II)-catalyzed reaction

Scheme 2

Of course many aliphatic azides are not commercially available. Carreira and coworkers recently reported the hydroazidation of unactivated olefins to yield alkyl azides in the presence of a cobalt catalyst prepared in situ from a Schiff base ligand and Co(BF4)2·6H2O (Scheme 3).7 Additionally, the reaction can be coupled to the Sharpless cycloaddition to yield the 1,4-triazole in a one-pot process.

hydroazidation of unactivated olefins to yield alkyl azides

Scheme 3

We are pleased to offer our click chemistry reagents and substrates for your research requirements.

For more specific information on each product line follow the appropriate link, or browse the Materials List below.

  • Functionalized Alkynes
  • Fluorophore Alkynes/Azides
  • Nucleoside Azides/Alkynes
  • Carbohydrate Azides
  • Organic Azides
  • PEG Azides
  • Azide Sources
  • Amino Acid Azides/Alkynes
  • Click Chemistry: Catalysts, Ligands and Reagents
Materials
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References

1.
Kolb HC, Sharpless K. 2003. The growing impact of click chemistry on drug discovery. Drug Discovery Today. 8(24):1128-1137. http://dx.doi.org/10.1016/s1359-6446(03)02933-7
2.
Kolb H. 2001. Angew. Chem. Int. 402004.
3.
Rostovtsev V. 2002. Angew. Chem. 412596.
4.
Tornøe CW, Christensen C, Meldal M. 2002. Peptidotriazoles on Solid Phase:  [1,2,3]-Triazoles by Regiospecific Copper(I)-Catalyzed 1,3-Dipolar Cycloadditions of Terminal Alkynes to Azides. J. Org. Chem.. 67(9):3057-3064. http://dx.doi.org/10.1021/jo011148j
5.
Manetsch R, Krasi?ski A, Radi? Z, Raushel J, Taylor P, Sharpless KB, Kolb HC. 2004. In Situ Click Chemistry:  Enzyme Inhibitors Made to Their Own Specifications. J. Am. Chem. Soc.. 126(40):12809-12818. http://dx.doi.org/10.1021/ja046382g
6.
Lewis W. 2002. Angew. Chem. Int. . 411053.
7.
Speers AE, Adam GC, Cravatt BF. 2003. Activity-Based Protein Profiling in Vivo Using a Copper(I)-Catalyzed Azide-Alkyne [3 + 2] Cycloaddition. J. Am. Chem. Soc.. 125(16):4686-4687. http://dx.doi.org/10.1021/ja034490h
8.
Chan TR, Hilgraf R, Sharpless KB, Fokin VV. 2004. Polytriazoles as Copper(I)-Stabilizing Ligands in Catalysis. Org. Lett.. 6(17):2853-2855. http://dx.doi.org/10.1021/ol0493094
9.
Zhang L, Chen X, Xue P, Sun HHY, Williams ID, Sharpless KB, Fokin VV, Jia G. 2005. Ruthenium-Catalyzed Cycloaddition of Alkynes and Organic Azides. J. Am. Chem. Soc.. 127(46):15998-15999. http://dx.doi.org/10.1021/ja054114s

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