Azide alkyne Huisgen cycloaddition

Fused triazoles were synthesized in a similar manner through the Huisgen azide-alkyne cycloaddition, which was carried out by simple heating the Ugi adducts at 100°C. Five different fused triazole scaffolds 160-164 were obtained by placing the additional functions in different components or changing the distance between them and the Ugi-reacting group [131]. 

The reaction chosen to connect the tethers in situ was the Huisgen azide-alkyne cycloaddition (Scheme 10.5). The Huisgen cycloaddition forms 1,2,3-triazoles as a nearly 1 1 mixture of regioisomers (10.28 and 10.29). The reaction is slow at room temperature. However, if the azide and alkyne are positioned ideally, such as when bound in close proximity by AChE, then the reaction occurs at room temperature. 

E. Lallana, R. Riguera, E. Fernandez-Megia, Reliable and Efficient Procedures for the Conjugation of Biomolecules through Huisgen Azide-Alkyne Cycloadditions. Angew. Chem. Int. Ed., 50 (38) 8794-8804, 2011. 

Lallana E, Riguera R, Eemandez-Megia E (2011) Reliable and efficient procedures for the conjugation of biomolecules through Huisgen azide-alkyne cycloadditions. Angew Chem Int Ed 50 8794-8804... 

S. Dedola, S. A. Nepogodiev, and R. A. Field, Recent applications of the Cul-catalysed Huisgen azide-alkyne 1,3-dipolar cycloaddition reaction in carbohydrate chemistry, Org. Biomol. Chem.., 5 (2007) 1006-1017. 

The second step is the copper(l)-catalyzed azide-alkyne cycloaddition (CuAAC). CuAAC produces only 1,4-disubstituted-1,2,3-triazoles at room temperature in excellent yields. Formally, it is not a 1,3-dipolar cycloaddition and thus should not be termed a Huisgen cycloaddition. 

Recent studies on the reaction mechanism provided the experimental evidence for a dinuclear Cu intermediate complex involved within the reaction steps [28]. Although the Huisgen s original reaction mechanism is considered to be concerted, where the old bonds break at the same time as the new bonds form, the Cu-catalyzed azide-alkyne cycloaddition (CuAAC) is a stepwise process. Ever since the initial report, this reaction has found extensive applications in biotechnology [29-31], material sciences [32-34] and drug discovery [35, 36]. 

The Huisgen 1,3-dipolar cycloaddition to triazoles can be performed under copper-catalysis and is then known as Copper-Catalyzed Azide-Alkyne Cycloaddition... 

Amblard P, Cho JFl, Schinazi RF (2009) Cu(I)-catalyzed Huisgen azide-alkyne 1,3-dipolar cycloaddition reaction in nucleoside, nucleotide, and oligonucleotide chemistry. Chem Rev... 

The Huisgen azide-alkyne 1,3-dipolar cycloaddition (AAC) [75] and later developed Cu-catalyzed azide-alkyne cycloadditions (CuAAC) [76-80], which are the most commonly utilized methods for the synthesis of N-substituted 1,2,3-triazoles, will not covered here. Very recently, Bi and co-workers [81] developed an elegant silver-catalyzed tandem hydroazidation/alkyne-azide cycloaddition of diynes with TMSN3 providing an easy access to 1,5-fused 1,2,3-triazole frameworks [82, 83]. 

The orthogonal modification of a-alkyne, m-azido heterotelechelic polystyrene via sequential nitrile oxide-alkyne and azide-alkyne Huisgen cycloadditions was reported by the group of Lutz [36]. Alternatively, Su et al. reported a sequential triple chck modification of polyhedral oligomeric silsesquioxanes (POSS), involving strain-promoted azide-alkyne cycloaddition (SPAAC), copper-catalyzed azide-alkyne cycloaddition (CuAAC), and thiol-ene click coupling (TECC) [37]. 

Copper catalyzed azide-alkyne cycloaddition (CuAAC reaction) is the well-known Huisgen [3+2] cycloaddition reaction of an azide with a terminal alkyne. The CuAAC gives a mild efficient reaction, which requires no protection groups, and no purification in many cases. Appukuttan et al. (2004) reported a one pot, three-component synthesis of various 1,4-substituted-l,2,3-triazoles using the corresponding... 

Modifications of Nucleosides, Nucleotides, and Nucleic Acids using Huisgen s [3+2] Azide-Alkyne Cycloaddition ... 

The Huisgen [3+2] cycloaddition between azides and alkynes is another bioorthognal ligation reaction for incorporation of probes into protein and peptide scaffolds. Two variants of this reaction have been developed using either copper(I) [218] or strained cyclooctyne molecules [219] to promote the reaction. As with the Staudinger ligation this method has found extensive use in protein and peptide labeling studies. 

Click chemistry has also been applied in carbohydrate chemistry. Thus, Huisgen cyclization involving a sugar azide or alkyne has been extensively used for the preparation of a wide range of carbohydrates bearing a triazole moiety in different positions. In this volume, Santoyo Gonzalez and Herndndez-Mateo present a contribution concerning azide-alkyne 1,3-dipolar cycloadditions, mostly devoted to non-anomeric positions. 

The first application we found was the Huisgen [3+2]-cycloaddition, between a terminal alkyne and an azide, to date the most practical and useful click reaction, regioselectively affording 1,4-disubstituted 1,2,3-triazoles (Schane 5.14). 

The azide-alkyne Huisgen cycloaddition is a popular approach to access... 

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