Reaction with vinyl azides

Aryl and vinyl nitriles have been prepared very efficiently from the corresponding bromides by palladium-catalyzed reactions under microwaves. This energy source has been employed for the conversion of these nitriles into aryl and vinyl tetrazoles by cycloaddition reactions with sodium azide (Scheme 9.66). The direct transformation of aryl halides to the aryl tetrazoles in a one pot procedure could be accomplished both in solution and on a solid support [115], The reactions were complete in a few minutes, a reaction time considerably shorter than those previously reported for the thermal reactions. The cydoadditions were performed with sodium azide and ammonium chloride in DMF and, although no explosion occurred in the development of this work, the authors point out the necessity of taking adequate precautions against this eventuality. 

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. 

Reaction of vinyl azides with nitrosyl tetrafluoroborate gives furazans in good yield, particularly when the alkene is 1,2-dialkyl-substituted. For example, 1-azidocyclooctene and 2-azidobut-2-enes yield (19 n = 6) and (1, R1 = R2 = Me), respectively 1,2,4-oxadiazoles may also be formed as by-products. 

Hassner and Belinka118 generated primary enamines in situ by reaction of vinyl azides 67 with alkyl lithium derivatives and converted them to ketones (equation 45). 

Perfluorinated olefins have been found to give both vinyl azides and the saturated fluoroazides on reaction with triethylammonium azide apparently the intermediate carbanion tends to abstract a proton in this case. Reaction of hexafluoropropene (28) with sodium azide in DMF leads stereospecifically to the trans azide 29. 

The simplest member of the class of vinyl azides, H2C=CH-N3, has been known for about 100 years. However, it was not until the late 1960s that vinyl azides became an important and synthetically useful class of organic compound. The most interesting and important reaction of vinyl azides is the formation of azirines produced upon photolysis and thermolysis of vinyl azides. Smolinsky and Pryde first observed azirine formation, together with a small amount of keteneimine, by gas-phase pyrolysis of a-aryl-substituted vinyl azides. 

A solid-supported carbonate reagent was used to initiate the formation of 2H-l,4-benzoxazin-2-ones 303 from P-nitroacrylate 301 and 2-aminophenol 302 (Scheme 7.72) [154]. This hetero-Michael addition/intramolecular transesteri-fication/elimination of HN03/[l,3]-proton shift domino reaction proceeded in moderate to excellent yields. In another study, a series of various functionalized pyrrolo[l,2-r]pyrazines 305 were made synthetically available through the reaction of vinyl azides 304 and lH-2-pyrrolecarbaldehyde (Scheme 7.73). The deprotonated pyrrole initially reacts in a Michael manner with the vinyl azides, with nitrogen as... 

Aryl and vinyl azides can also be accessed in one step from the corresponding halides or triflates via a copper-catalyzed reaction with sodium azide in the presence of a catalytic amount of L-proline (Scheme 7.5C) [104]. In this fashion, a range of 1,4-disubstituted 1,2,3-triazoles can be prepared in excellent yields [105-107]. Anilines can also be converted to aryl azides by the reaction with tert-butyl nitrite and azidotrimethylsilane [108]. The resulting azides can be submitted to the CuAAC conditions without isolation, furnishing triazole products in excellent yields. Microwave heating further improves both reactions, significantly reducing reaction time [56, 62]. 

Fig. 4 Metabolic DNA labeling using alkyne- or alkene-modified nucleosides. A 5-Ethynyl-2 -deoxyuridine (EdU) [153], (2 S)-2 -deoxy-2 -fluoro-5-ethynyluridine (F-ara-EdU) [160] and 5-vinyl-2 -deoxyuridine (VdU) [167], B Labeling strategy cells are incubated with the alkyne-modified nucleoside EdU, which is incorporated into the cellular genome in proliferating cells. Subsequently, the cells are fixed, permeabilized and components for the Cu -mediated azide alkyne cUck reaction with flumescent azides are added. Detection can be carried out by flow cytometry or fluorescence microscopy...

In 2009, Chiba s group reported a manganese-mediated synthesis of pyridines from cyclopropanols with vinyl azides [70]. In the presence of 1.7 equivalents of Mn(AcAc)3, a variety of pyridine derivatives have been prepared in good yields at room temperature. In their further studies, they realized this transformation in a catalytic manner [71]. In their mechanistic studies, they found the reactions were initiated by a radical addition of /3-carbonyl radicals, generated by the one-electron oxidation of cyclopropanols with Mn(III), to vinyl azides to give imi-nyl radicals, which cyclized with the intramolecular carbonyl groups. Additionally, the application of this newly developed methodology in the synthesis of quaternary indole alkaloid, melinonine-E, was accomplished as well (Scheme 3.33). 

An investigation of the reactions of vinyl azides with enamines has been published, in which the results are given extensive discussion with consideration... 

A majority of reaction sequences rely on the use of nucleophilic (metalated) variants of 1. However, the electrophilic character of the sterically congested methine carbon has been successfully exploited via displacement reactions with sodium azide.Ogata and Shimizu have also reported that 1 undergoes nucleophilic attack by 1,2,4-tiiazole in the presence of potassium carbonate to provide l-[bis(trimethylsilyl)methyl]-1,2,4-triazole (3) (eq 2). Subsequent introduction of TBAF results in desilylation of 3 to afford an a-sUyl carbanion intermediate that provides 1-vinyl-1,2,4-triazole products upon condensations with aldehydes or ketones (eq 3). While high yields of the alkene products are generally obtained, mixtures of 7Z-isomers are observed in all cases. 

MA copolymerization, 292, 294 nitrone adducts, 226 nitropropane addition, 64 radical copolymerization, 264, 314, 333, 335, 337, 365, 375, 379 reaction with carbamyl azides, 223 terpolymers, with vinyl acetate and ethylene, 295... 

As indicated in Table 6.1 some 2/f-aziiines are isolated from one-pot reactions in which the vinyl azide precursors are produced in situ. For example, 3-dialkylamino-2//-azirines 4 have been prepared from tertiary amides 3 the vinyl azide intermediates are generated by successive chlorination and reaction with sodium azide (Scheme 6.2). The conversion of these vinyl azides into azirines takes place at room temperature and it is clear that the nature of the substituents on the double bond of vinyl azides influences their temperature of decomposition. Fluoro substituted vinyl azides also decompose at room temperature. ... 

In addition, the Chiba group reported that the reaction of vinyl azides 72 and internal alkynes 73 in the presence of a catalytic amount of [Cp RhCl2]2 and Cu(OAc)2 with AcOH in dimethylformmide (DMF) could provide isoquinolines 74 in moderate to good yields (Scheme 16.33) [54]. It was speculated that the reaction could be initiated by the formation of N—H imines B from vinyl azides 72 via the Cu-mediated reductive ring opening of highly strained three-membered cyclic imines, 2//-azirines... 

Just like the aryl azides 2, the vinyl azides 11 are more reactive in their cycloadditions with active methylene compounds than are alkyl azides. In 1970, Alfred Hassner et al. developed a general synthetic approach to 1-vinyl-1,2,3-triazoles 12 and 14, (Scheme 4.4) [6] by the cycloaddition of active methylene compounds 10 or 13 with vinyl azides 11 (or their precursors, the P-haloalkyl azides), in the presence of 1 equiv. of an alkoxide (NaOMe). Decarboxylation of the l- dnyl-5-substituted l,2,3-triazole-4-carboxylic acids 14 synthesized from the reaction of ethyl acetoacetate or ethyl benzoylacetate with vinyl and P-haloalkyl azides led to 1-vinyl-5-substituted 1,2,3-triazoles in almost quantitative yield [6]. 

A novel method for preparing amino heterocycles is illustrated by the preparation of 2-amino-5-methylthiophene (159). In this approach vinyl azides act as NH2 equivalents in reaction with aromatic or heteroaromatic lithium derivatives (82TL699). A further variant for the preparation of amino heterocycles is by azide reduction the latter compounds are obtained by reaction of lithio derivatives with p- toluenesulfonyl azide and decomposition of the resulting lithium salt with tetrasodium pyrophosphate (Scheme 66) (82JOC3177). 

The aziridine aldehyde 56 undergoes a facile Baylis-Hillman reaction with methyl or ethyl acrylate, acrylonitrile, methyl vinyl ketone, and vinyl sulfone [60]. The adducts 57 were obtained as mixtures of syn- and anfz-diastereomers. The synthetic utility of the Baylis-Hillman adducts was also investigated. With acetic anhydride in pyridine an SN2 -type substitution of the initially formed allylic acetate by an acetoxy group takes place to give product 58. Nucleophilic reactions of this product with, e. g., morpholine, thiol/Et3N, or sodium azide in DMSO resulted in an apparent displacement of the acetoxy group. Tentatively, this result may be explained by invoking the initial formation of an ionic intermediate 59, which is then followed by the reaction with the nucleophile as shown in Scheme 43. 

Another important click reaction is the cycloaddition of azides. The addition of sodium azide to nitriles to give l//-tetrazoles is shown to proceed readily in water with zinc salts as catalysts (Eq. 11.71).122 The scope of the reaction is quite broad a variety of aromatic nitriles, activated and nonactivated alkyl nitriles, substituted vinyl nitriles, thiocyanates, and cyanamides have all been shown to be viable substrates for this reaction. The reaction of an arylacetylene with an azide in hot water gave 1,4-disubstituted 1,2,3-triazoles in high yields,123 while a similar reaction between a terminal aliphatic alkyne and an azide (except 111 - nitroazidobenzcnc) afforded a mixture of regioisomers with... 

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