Huisgen 1,3-dipolar cycloaddition

The NHCs have been used as ligands of different metal catalysts (i.e. copper, nickel, gold, cobalt, palladium, rhodium) in a wide range of cycloaddition reactions such as [4-1-2] (see Section 5.6), [3h-2], [2h-2h-2] and others. These NHC-metal catalysts have allowed reactions to occur at lower temperature and pressure. Furthermore, some NHC-TM catalysts even promote previously unknown reactions. One of the most popular reactions to generate 1,2,3-triazoles is the 1,3-dipolar Huisgen cycloaddition (reaction between azides and alkynes) [8]. Lately, this [3h-2] cycloaddition reaction has been aided by different [Cu(NHC)JX complexes [9]. The reactions between electron-rich, electron-poor and/or hindered alkynes 16 and azides 17 in the presence of low NHC-copper 18-20 loadings (in some cases even ppm amounts were used) afforded the 1,2,3-triazoles 21 regioselectively (Scheme 5.5 Table 5.2). 

Like the 1,3-dipolar Huisgen cycloaddition reaction between azides and acetylenes, thiol-ene chemistry is more than a century old, with the first thiol-alkene addition reaction having been reported by Posner in 1905 [19]. The first thiol-ene... 

F-Click labeling of peptides via Cu(l)-catalyzed 1,3-dipolar Huisgen cycloaddition... 

The 1,3-dipolar eyeloaddition, also known as the Huisgen cycloaddition, is a elassie reaetion in organic chemistry consisting in the reaetion of a dipolar-ophile with a 1,3-dipolar compound that allows the produetion of various five-membered heteroeyeles. This reaction represents one of the most productive fields of modern synthetic organic chemistry. Most dipolarophiles are alkenes, alkynes, and molecules possessing related heteroatom functional... 

The Huisgen Cycloaddition (or 1,3-Dipolar Cycloaddition) is the reaction of a dipolarophile with a 1,3-dipolar compound that leads to 5-membered (hetero)cycles. Examples of dipolarophiles are alkenes and alkynes and molecules that possess related heteroatom... 

Cycloaddition reactions between azides and alkynes—exemplified by the Huisgen 1,3-dipolar cycloaddition—have tremendous potential for the development of biomolecules and have been employed for conjugation of sugars to peptides [184]. Drawbacks of the Huisgen cycloadditions, however, are poor regioselectivity and incompatibility with physiological conditions. These limitations, which hinder MOE applications in living cells, were first overcome by cop-... 

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. 

P. Salehi, M. Dabiri, M. Koohshari, S. K. Movahed, M. Baraijanian, Mol. Divers. 2011, 15, 833-837. One-pot synthesis of 1,2,3-triazole linked dihydropyrimidinones via Huisgen 1,3-dipolar/Biginelli cycloaddition. 

The synthesis of 1,2,3-triazoles has been routinely achieved using click chemistry approach. The main advantages of this methodology include high specificity, efficiency, simple reaction workup procedures, and good product yields. The reaction involves copper(I) catalyzed 1,3-dipolar cycloaddition (Huisgen cycloaddition) between an... 

Cycloaddition reactions of 1,3-dipoles with two-atom dipolarophiles are known as Huisgen cycloadditions [99]. When the 1,3 dipole is formed in situ, for example, by condensation of an a-aminocarbonyl compound and an amine, a three-component reaction can be performed in a domino imine formation/cycloaddition fashion. Organocatalytic domino 1,3-dipolar [3-1-2] cycloadditions were first described by the Gong group. They showed that (aromatic) aldehydes 191 and a-amino-substituted malonates 190 selectively form the corresponding imine dipole that reacts further with electron-deficient olefin dipolarophiles 192 (Scheme 42.44) [100]. 

The synthesis of triazoles by 1,3-dipolar cycloaddition between azides and alkynes has been extensively studied recently with numerous synthetic applications in the field of click chemistry. However, the Huisgen cycloaddition between azides 39 and alkenes 40 (Scheme 41.9) although less studied offers interesting opportunities for the stereoselective formation of C N bonds in the context of natural products synthesis. The triazolines 41 thus formed are in fact good precursors of aziridines via ring contraction and expulsion of N2. 

The classical thermal 1,3-dipolar cycloaddition that involves azides and alkynes (either terminal or internal) derivatives is known as the Huisgen cycloaddition and gives access to 1,2,3-triazoles as a mixture of 1,4- and 1,5-regioisomers (Scheme 3.1) [3]. Regiospecific couplings to furnish the 1,4-disubstituted 1,2,3-triazoles are promoted by copper(I) salts as faster procedures (more than 100 times faster). 

In general, reaction of diazomethane with a, -unsaturated carbonyl compounds affords pyrazolines in which the nucleophilic methylene group is attached to the carbon atom of the carbonyl compound. According to Huisgen, the reactions belong to the general class of 1,3-dipolar cycloadditions. 

Dipolar cycloaddUions. Interest in 1,3-dipolar cycloadditions increased dramatically during the past 20 years, largely because of the pioneering studies of Huisgen [7, 2] The versatility of this class of pericychc reactions in the synthesis of five-membered-ring heterocyclic compounds is comparable with that of the Diels-Alder reaction in the synthesis of six-membered-ring carbocyclic systems (equation 1)... 

This type of reaction is represented by 1,3-dipolar cycloadditions, corresponding to one of the Huisgen categories (69MI1). The 1,3-dipolar cycloaddition corresponds to the interaction between a 1,3-dipole and a multiple system five-membered ring closure (Scheme 1). 

Huisgen, R., 1,3-Dipolar Cycloadditions - Introduction, Survey, Mechanism, in... 

Huisgen has reported in 1963 about a systematic treatment of the 1,3-dipolar cycloaddition reaction as a general principle for the construction of five-membered heterocycles. This reaction is the addition of a 1,3-dipolar species 1 to a multiple bond, e. g. a double bond 2 the resulting product is a heterocyclic compound 3. The 1,3-dipolar species can consist of carbon, nitrogen and oxygen atoms (seldom sulfur) in various combinations, and has four non-dienic r-electrons. The 1,3-dipolar cycloaddition is thus An +2n cycloaddition reaction, as is the Diels-Alder reaction. 

The class of 1,3-dipolar cycloadditions embraces a variety of reactions that can accomplish the synthesis of a diverse array of polyfunctional and stereochemically complex five-membered rings.3 The first report of a 1,3-dipolar cycloaddition of a nitrone (a 1,3-dipole) to phenyl isocyanate (a dipolarophile) came from Beckmann s laboratory in 1890,4 and a full 70 years elapsed before several investigators simultaneously reported examples of nitrone-olefin [3+2] cycloadditions.5 The pioneering and brilliant investigations of Huisgen and his coworkers6 have deepened our under-... 

Huisgen, R. In 1,3-Dipolar Cycloaddition Chemistry, Padwa, A., Ed., John Wiley Sons New York, 1984, pp. 1-176. 

The azomethine imine 6.39 reacts readily to give various 1,3-dipolar cycloaddition products (Huisgen and Eckell, 1977 for the naming of cycloadditions see Huisgen 1968). 

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