Metal azides, 1,3-dipolar cycloaddition

Complexes of the heteroaromatic compounds may be prepared by building up the heterocyclic ligand. The most effective method for the N (10, E = N) and C (11) derivatives is 1,3-dipolar cycloaddition from the metal azides. The N and C derivatives of triazole (67) and (68), tetrazole (69-72) and other azoles, e.g., 73, were prepared.The transformations leading to the complexes are summarized later. 

Reactions between 5-cyanotetrazole and transition metals, when performed in boiling acetone, lead to hydrolysis of the cyano group and formation of 5-carbamyl tetrazolate complexes (68). Complexes containing 1- or 5-substituted tetrazolate anions can also be obtained by 1,3-dipolar cycloaddition of organic isonitriles (RNC) (15) or nitriles (RCN) (61), respectively, to coordinated azide ligands [Eqs. (3) and (4)]. 

Other metal-mediated reactions of azide reagents to terminal alkynes have also been reported. Indium(ll) triflate catalyzed tandem azidation/l,3-dipolar cycloaddition of various (o,(o-dialkoxyalkynes 134 with trimethylsilyl azide yielded fused 1,2,3-triazoles 135 <05TL8639>. A new ruthenium-catalyzed process for the regioselective synthesis of 1,5-disubstituted-1,2,3-triazoles has been developed <05JA15998>. 

The Huisgen 1,3-dipolar cycloaddition of azides to alkynes or nitriles as dipolaro-philes, resulting in 1,2,3-triazoles or tetrazoles, is one of the most powerful click reactions . A limitation of this approach, however, is the absence of regiospecificity normally found in thermal 1,3-cycloaddition of nonsymmetrical alkynes this leads to mixtures of the different possible regioisomers. In other reports, classical 1,3-dipolar cycloadditions of azides to metal acetylides, alkynic Grignard reagents, phosphonium salts and acetylenic amides have been described. Extended reaction times and high temperatures are required in most of the reactions, but they can also be performed more effectively with the aid of microwave irradiation. The main results reported are reviewed in this section. 

In the mechanism of the CuAAC reaction described above, the metal catalyst activates terminal alkyne for reaction with a Cu-coordinated azide. This mode of reactivity operates with other dipolar reagents as well. In fact, the first example of a copper-catalzyed 1,3-dipolar cycloaddition reaction of alkynes was reported for nitriones by Kinugasa in 1972 [124]. An asymmetric version of the Kinugasa reaction was developed by Fu et al. in 2002 [125, 126]. 

The above-described method which employs copper powder to activate 1,3-dipolar cycloaddition reaction of azides and alkynes in ball mill is related to work by Mack et al. [11], Here, copper catalyst was replaced by Cu vial and Cu milling balls as a source of metal catalyst. The efficacy and simplicity of the method is clearly shown by reaction of phenylacetylene and benzylazide in Spex Certiprep 8000M mixer mill (Scheme 5.11). Minute amounts of copper peeled off the balls were sufficient to afford 1,2,3-triazole 38 in excellent yield, without the need for purification of product. The ICP-MS analysis determined very low level of copper metal present in product after isolation (4.61 mg/g of copper in the product). Multicomponent variant of this reaction includes the in situ preparation of... 

Dipolar cycloaddition reactions of alkynes to organic azides 13SL1899. Direct metalation of 1,2,3-triazoles and 1,2,4-triazoles 12THC(29)415. 

Ess DH, Jones GO, Houk KN (2008) Transition states of strain-promoted metal-free click chemistry 1,3-dipolar cycloadditions of phenyl azide and cyclooctynes. Org Lett 10 1633-1636... 

Though in case of the azide-alkyne 13-dipolar cycloaddition process, exclusively Cu(l) catalysts have been used (in 0.25-2 molcatalysts (Ru, Ni, Pd, and Pt salts) have also been employed. For Cu(l) catalysts, most methods directly use Cu(T) salts, while other methods generate Cu(I) by reduction of Cu(ll) salts with sodium ascorbate or metallic copper. The catalyzed cycloaddition reaction is experimentally simple, perfecdy rehable, quantitative, proceeds well in aqueous solutions under ambient conditions without protection from oxygen, requires only stoichiometric... 

Though tremendous success has been achieved with the development of Cu(I)-mediated Huisgen 1,3-dipolar cycloaddition reaction of azides and acetylenes as a robust and ef cient synthetic tool, it has several limitations which inclnde the need for a metal catalyst, an inability to photochemi-cally control the reaction or to conduct the reaction in the absence of solvent. In comparison, the century-old addition of thiols to alkene (the hydrothiolation of a C=C bond), which is currently called thiol-ene coupling (TEC), has many of the attributes of chck chemistry without, however, some of the aforesaid disadvantages of the CuAAC reaction. 

Wei J, Chen J, Xu J, Cao L, Deng H, Sheng W, Zhang H, Cao W (2012) Scope and regi-oselectivity of the 1,3-dipolar cycloaddition of azides with methyl 2-perfluoroalkynoates for an easy, metal-free route to perfluoroalkylated 1,2,3-triazoles. J Eluorine Chem 133 146-154... 

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. 

Until recently, azides were relatively rare precursors of interlocked molecules and most of the time they were meant to be linked to alkynes using 1,3-dipolar cycloaddition. In this review, we will restrict ourselves to their use in attachment of stoppers to pseudo-rotaxanes and present a selection of the most representative papers. They can be divided into purely organic molecular entanglements and into interlocked molecules prepared by transition metal templated approaches. 

Dipolar cycloaddition reactions constitute a powerful and convergent tool for the preparation of various heterocyclic compounds, which have been widely applied in the synthesis of numerous natural products, pharmaceuticals, and functional materials. The chemistry of 1,3-dipolar cycloaddtion reactions has been well documented in a number of reviews [3]. In this section the focus is on transition-metal-mediated 1,3-dipolar cycloaddition reactions with some important 1,3-dipoles, including azides, diazoalkanes, carbonyl ylides, and azomethine ylides, rather than a full review of the reactions of all types of 1,3-dipoles. 

The 1,3-dipolar cycloaddition of organic azides onto dipolarophiles is a versatile method of synthesizing 1,2,3-triazole derivatives [6]. The thermal cycloaddition without metal catalysts [Scheme 16.4, Eq. (a)] of organic azides 1 to alkynes 2 was utilized for triazole formation, but frequently with low regioselectivity. Recently, this reaction has been improved in terms of the reaction rate and regioselectivity by using copper(I) catalysts, which were reported independently by Sharpless et al. [7] and Meldal et al. [8] [Scheme 16.4, Eq. (b)]. 

Copper-containing metal-organic frameworks (MOFs) based on 5-(4-pyridyl)tetrazole building blocks, easily prepared in situ by 1,3-dipolar cycloaddition between 4-cyanopyridine and azide in the presence of copper(II)... 

Schweinfurth D, Hardcastle KI, Bunz UHF (2008) 1,3-Dipolar cycloaddition of alkynes to azides. Construction of operationally functional metal responsive fluorophores. Chem Commun 2203-2205... 

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