1.3- dipolar cycloaddition reactions with azides

Dipolar cycloaddition reactions with azides, imines, and nitrile oxides afford synthetic routes to nitrogen-containing heterocycles (25—30). 

The field of dipolar cycloaddition reactions with azides in peptide chemistry has developed rapidly since Tompe and Meldal first described the copper(l)-catalyzed cycloaddition between azides and peptide-linked terminal alkynes to exclusively form the... 

Azidofurazans and -furoxans undergo dipolar cycloaddition reactions with unsaturated compounds, in some cases regiospecifically. Thus, reaction of 3-amino-4-azidofurazan with l-morpholinyl-2-nitroethene (toluene, reflux, 70 hours) gives 4-nitro-l,2,3-triazole 204 in 87% yield (99MI1, 000KGS406). Cycloaddition of the same azide to alkynes was accomplished by formation of a mixture of position isomers 205 and 206. Regiospecific addition was observed only in singular cases... 

Benzocyclobutene, when generated by oxidation of its iron tricarbonyl complex, can function as the dipolarophile in 1,3-dipolar cycloaddition reactions with arylnitrile oxides (Scheme 113).177 Unfortunately the synthetic versatility of this type of process is limited because of the unreactivity of other 1,3-dipolar species such as phenyl azide, benzonitrile N-phenylimide, and a-(p-tolyl)benzylidenamine N-oxide.177... 

Since the discovery of triazole formation from phenyl azide and dimethyl acetylenedicarboxylate in 1893, synthetic applications of azides as 1,3-dipoles for the construction of heterocychc frameworks and core structures of natural products have progressed steadily. As the 1,3-dipolar cycloaddition of azides was comprehensively reviewed in the 1984 edition of this book (2), in this chapter we recount developments of 1,3-dipolar cycloaddition reactions of azides from 1984 to 2000, with an emphasis on the synthesis of not only heterocycles but also complex natural products, intermediates, and analogues. 

The intramolecular 1,3-dipolar cycloaddition reaction of azides has become an increasingly useful process for the construction of natural products and molecules of theoretical interest.192 193 For example, 2-substituted azido enone (238) was prepared from the corresponding bromide by treatment with sodium azide. Thermolysis of this material afforded aziridinyl ketone (240) presumably via a transient dipolar cycloadduct (239).193 Ketone (240) was subsequently converted to an intermediate previously used to prepare histrionicotoxin (241 Scheme 56). 

It is known that aryl azides undergo 1,3-dipolar cycloaddition reaction with bis(trifluoromethyl)thioketene 156 to form the yellow A3-l,2,3,4-thiatriazolines 159 in very low to fair yield supporting the mechanism of reaction of this thioketene with hydrazoic acid (Equation 14) <1978JOC2500>. 

The azide complexes [Au(N3)2] and [Au(N3)(PPh3)] are readily prepared, and NMR studies indicate the presence of covalent Au—bonds. The complex [Au(N3)(PPh3)3] is also known. Both [Au(N3)2] and Au(N3)(PPh3)] undergo 1,3-dipolar cycloaddition reactions with unsaturated reagents, as illustrated in Scheme 2, but CO reacts to give isocyanatogold(I) derivatives. ... 

The appHcation of mild methods for the chemical modification of components in or on living organisms under physiological conditions has gained much interest in the past few years [235-237]. With the discovery of the mild Cu(I)-catalyzed 1,3-dipolar cycloaddition reaction of azides and alkynes, another powerful tool was provided for chemically modifying live organisms and proteins [74,231]. 

Azides are very versatile and valuable synthetic intermediates, known for their wide variety of applications, and have been employed for the synthesis of a number of important heterocyclic compounds. Azides also represent a prominent class of 1,3-dipoles, and their cycloaddition to multiple tt-bonds is an old and widely used reaction (1988CR297). The dipolar cycloaddition of an azide to an alkene furnishes a triazoline derivative (2003MI623). Azide-alkene cycloadducts can extrude nitrogen at elevated temperatures to form aziridines or imines, depending upon the substrate and reaction conditions. The cycloaddition of azides with alkynes affords triazolidine derivatives which have been a focus in the area of chemical biology and have received much recent attention (2008AGE2596, 2008CR2952). In this section of our review, we recount some developments of the 1,3-dipolar cycloaddition reaction of azides that have been used for the synthesis of various alkaloids. 

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. 

Dipolar Cycloaddition. The principal use of p-bromobenzenesulfonyl azide is in 1,3-dipolar cycloaddition reactions with functionally substituted alkenes. The reagent has been used at ambient temperature and pressure to convert simple trimethylsilyl and methyl enol ethers of cyclic ketones to ring-contracted p-bromobenzenesulfonimidates, and thence to the corresponding amides, esters, or acids (eqs 1 and 2). 

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. 

A homogeneous Ag(I)-catalyst (65) has been developed for the 3 -I- 2-cycloaddition reaction of azides to terminal alkynes to form the corresponding 1,4-triazoles. A simple metal-free synthesis of pentafluoroalkylated 1,2,3-triazoles has been developed from the 1,3-dipolar cycloaddition reaction of azides with methyl 2-perfluoroalkynoates. Again, the intramolecular alkyne-azide Huisgen 3 -I- 2-cycloaddition reaction in water is an example of Click reaction in the absence of a metal catalyst. The Cu(I)-catalysed azide-alkyne 3-1-2-cycloaddition reaction yielded 1,4-disubstimted 1,2,3-triazoles in excellent yields in 2-25 min under solvent-free conditions. The use of 16-electron... 

Azides can partake in stereoselective dipolar cycloaddition reactions with olefins. The unstable resulting triazolines typically expel N2 under the conditions of the cycloaddition reaction, leading to the corresponding stable azir-idines. Cha has reported that heating of azide 32 leads directly to aziridine 33 as a single diastereomer (Scheme 18.8) [55]. The allylic stereocenter resident in 32 thus effectively controls the stereochemical outcome of the transformation. The product aziridine 33 was subsequently elaborated into 6,7-di-epi-castanospermine (34). 

Similarly, the regiospecific 1,3-dipolar cycloaddition reaction of 1-methyl-1,2-dihydropyridines 41 with cyanogen azide (50a) and selected organic azides 50c and 50g afforded 2-methyl-2,7-diazabicyclo[4.1.0]hept-4-enes 57, which can be elaborated to 1-methyl-l,2,5,6-tetrahydropyridylidene-2-cyanamide (58) and 1-methyl-2-piperidylidenes 59a-d (85CJC2362). 

The authors have also elaborated a microwave-enhanced one-pot procedure [90] for the Huisgen 1,3-dipolar cycloaddition reaction. In a typical procedure, a pyrazinone with a triple bond connected to the core via C - O linkage, was reacted with a suitable benzylic bromide and NaNs in presence of the Cu(I) catalyst in a t Bu0H/H20 system under microwave irradiation (Scheme 26). The cycloaddition was found to proceed cleanly and with full regioselectivity. As the azide is generated in situ, this procedure avoids the isolation and purification of hazardous azides, which is especially important when handling the ahphatic ones, which are known to be toxic and explosive in nature. 

The 1,3-dipolar cycloaddition reactions to unsaturated carbon-carbon bonds have been known for quite some time and have become an important part of strategies for organic synthesis of many compounds (Smith and March, 2007). The 1,3-dipolar compounds that participate in this reaction include many of those that can be drawn having charged resonance hybrid structures, such as azides, diazoalkanes, nitriles, azomethine ylides, and aziridines, among others. The heterocyclic ring structures formed as the result of this reaction typically are triazoline, triazole, or pyrrolidine derivatives. In all cases, the product is a 5-membered heterocycle that contains components of both reactants and occurs with a reduction in the total bond unsaturation. In addition, this type of cycloaddition reaction can be done using carbon-carbon double bonds or triple bonds (alkynes). 

PM3 calculations of the 2 + 3-cycloaddition of t-butylphosphaacetylene with 2,4,6-triazidopyridine are consistent with the dipole-LUMO-controlled reaction type. An FTIR spectroscopic study of the 1,3-dipolar cycloaddition of aryl azides with acetylenes shows that the rate of reaction increases logarithmically with pressure (below 1 GPa). The 3 -I- 2-cycloaddition between an azide (69) and a maleimide (70) has been greatly accelerated by utilizing molecular recognition between an amidopyridine and a carboxylic acid [see (71)] (Scheme 24). ... 

Scheme 7.1 Click chemistry synthesis of 1,4-disubstituted-l,2,3-triazoles by a 1,3-dipolar cycloaddition reaction of organic azides with terminal acetylenes.

The 1,3-dipolar cycloaddition of organic azides with nitriles could give rise to two regioisomers. Since organic azides are Type II 1,3-dipoles on the Sustmann classification (approximately equal HOMO-LUMO gaps between the interacting frontier orbital pairs) the reactions could be dipole HOMO or LUMO controled and the regioselectivity should be determined by the orbital coefficients for the dominant HOMO-LUMO interaction. Such systems show U-shaped kinetic curves in their... 

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