Intermolecular Cycloaddition Reactions of Azides

The preparation of 85, a structurally diverse analog of carbocyclic ribavarine (86), was reported using an intermolecular 1,3-dipolar cycloaddition reaction of cyclopentyl azide 84 with methyl propiolate [53]. 

Cycloaddition Reactions with Azides for the Synthesis of Tetrazoles 9.7.1 Intermolecular Approaches... 

The first examples of a direct 1,5-substituents tetrazole synthesis via an intermolecular [2 + 3]-cycloaddition reaction of organic azides (based on the results for a similar synthesis of triazoles) were developed by Sharpless et al. in 2002 using sulfonyl or acyl cyaiudes (Scheme 9.8). In both cases, the Click reaction involved simple heating of the organic azides (hindered, aliphatic or aryl azides) and the nitriles into a homogenous liquid at higher reaction temperature (80-100 °C), in which no further purification was necessary. 

Click chemistry has been particularly active in various fields this year. For example, ample applications of click chemistry have been seen in carbohydrate chemistry. Various /weiido-oligosacchardies and amino acid glycoconjugates were synthesized via an intermolecular 1,3-dipolar cycloaddition reaction using easily accessible carbohydrate and amino acid derived azides and alkynes as building blocks <06JOC364>. The iterative copper(I)-catalyzed... 

For intramolecular 1,3-dipolar cycloadditions, the application of nitrones and nitrile oxides is by far most common. However, in increasing frequency, cases intramolecular reactions of azomethine ylides (76,77,242-246) and azides (247-259) are being reported. The previously described intermolecular approach developed by Harwood and co-workers (76,77) has been extended to also include intramolecular reactions. The reaction of the chiral template 147 with the alkenyl aldehyde 148 led to the formation of the azomethine ylide 149, which underwent an intramolecular 1,3-dipolar cycloaddition to furnish 150 (Scheme 12.49). The reaction was found to proceed with high diastereoselectivity, as only one diaster-eomer of 150 was formed. By a reduction of 150, the proline derivative 151 was obtained. 

In the intermolecular reaction of the nitrene that is derived from tosyl azide with benzene, little of the A -tosylazepine (5) is obtained at normal pressures, but the yield is markedly increased when the reaction takes place under a high pressure of nitrogen for example, to 48% at ca 90 atm.In a similar reaction with dimethyl terephthalate, it is suggested that the reaction involves an initial [1,3] cycloaddition of the azide to the aromatic ring to give (6), rather than a nitrene reaction. 

Shea et al. investigated whether strain involved in alkenes affects reactivity and regiochemistry of the intermolecular 1,3-dipolar cycloaddition reaction [14]. Therefore, the addition of picryl azide (18) with a series of mono-and bicyclic olefins including frans-cycloalkenes and bridgehead alkenes was studied (Scheme 5). In the cases of czs-cyclooctene (16) and ci5-cyclononene (17), decomposition of the initially formed cycloadducts 19 and 20 followed... 

Hetero Diels-Alder - intermolecular case - donor and acceptor are in different molecules (but interact via two orbital subsets) Intermolecular delocalization is not limited to the earlier discussed alkyne/ azide cycloadditions. It has been reported to provide significant contribution to the observed electronic effects in other cycloadditions. For example, Boger and coworkers reported that the Diels-Alder reaction of... 

Recently, Chen and coworkers reported an efficient new method to construct a series of densely functionalized 4,5-dihydro-IH-azepine products 41 from the intermolecular reaction of alkyl azides with propargylic esters. In this approach, sequential reaction of vinyl-gold carbenoids 42 with allqrl azides and formation of vinyl imine intermediates 43 may be involved fScheme 4.14). Then a subsequent formal [4+3] cycloaddition with another molecule of vinyl-gold carbenoid 42 afford the desired azepine 41. 

Photogenerated nitrenes can undergo cycloaddition with alkenes intermolecular reaction leads to aziridine products (5.38), and intramolecular reaction in vinyl azides gives azirines (5.39). The bicyclic azirine from phenyl azide has not been isolated, but it is the intermediate that best accounts for the formation of a substituted azepine when this azide is irradiated in the presence of a secondary amine (5.401. 

Another attractive method for E ring formation featured an intramolecular [2+3]cycloaddition of an azide moiety, emanating from the indole 3-position via a two-carbon linker, to, now, an electron-rich version of the C15-C16 double bond.19 The cycloaddition precursor 10 was made via 9, in turn assembled by regioselective cocylization of protected methoxyacetylene (Scheme 5). In a puzzling turn of events, thermolysis of the azide product in toluene at moderate temperature (to minimize nitrene formation) and in low concentration (to suppress intermolecular reactions) produced the two oxidized pentacyclic products 11 and 12 in a 2 1 ratio. Performing the reaction in a more polar solvent (DMF, 80 °C, 7 d) altered the ratio to 5 1.20... 

The simultaneous presence of an azido and an alkyne group on a scaffold is a prerequisite for performing the 1,3-dipolar cycloaddition of such functions in its intramolecular version. In the case of carbohydrates, the sequential introduction of such functions is always feasible but lengthy and laborious synthetic strategies, normally based on protection and deprotection of the hydroxyl sugar groups, are required. For this reason, the intramolecular alkyne-azide of 1,3-dipolar cycloadditions have found more limited application than the intermolecular reaction between these functions. However, this approach is irreplaceable for the oriented preparation of molecular ar-... 

Apart from the utilization of aryl- and vinyl-diazoacetates that can achieve the moderate to high chemo-, regio-, and enantioselectivity in intermolecular asymmetric C—H bond insertion reactions, Af-sulfonyl-l,2,3-triazole 11 was found to be able to function as an alternative carbene precursor for diverse transformations (Scheme 1.4). One advantage for using the N-sulfonyl-1,2,3-triazole is that it could be easily prepared by the Cu -catalyzed azide-alkyne cycloaddition (CuAAC) reaction, and in some cases, delicately designed reactions can be conducted in a one-pot procedure starting from alkynes and sulfonyl azides. Moreover, since there exists an inherent equilibrium... 

As described in the next sections, the [2+3]-cycloaddition of nitriles and azides is a reliable method for intramolecular reactions (Scheme 59), but volatile azides create tremendous hazards in intermolecular reactions. For large-scale processes, tin azides [194,195] may be used, however this leads to the problem of recovering the metal salts. The utilization of zinc catalysts... 

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