Alkenes azide 1,3-dipolar cycloadditions

Azines have been prepared by initial condensation of diethoxyphosphinyIhydrazine anions with aldehydes or ketones (Scheme 9). Phosphoryl azides undergo 1,3-dipolar cycloaddition to 2-tetralone enamines to give triazolines, possibly en route to amidines. A full paper on the addition of diethyl dibromophosphoramidate to alkenes(leading to the synthesis of 2-bromoalkylamines) has appeared. ... 

Alkenic bonds undergo 1,3-dipolar cycloadditions with azides to give A -l,2,3-triazolines. Azides can add to a wide range of angle-strained, unstrained, and inactivated double bonds to electron-... 

In 1984, a facile synthesis of pyrrolo[3,4-/7]indole (5) as a stable indole-2,3-quinodimethane analogue using an intramolecular azide-alkene cycloaddition-cycloreversion strategy was reported (Scheme 9.2) (3). Treatment of bromo compound 3 with NaNs in aqueous tetrahydrofuran (THF) produced the triazoline 4 via an intramolecular 1,3-dipolar cycloaddition of an intermediate azide. Treatment of the triazoline 4 with p-toluenesulfonic acid (p-TSA) effected 1,3-dipolar cycloreversion of 4 to give pyrroloindole 5 in 82% yield along with diethyl diazomalonate. 

Keshava et al. (10) reported a facile synthesis of the fused tricyclic (3-lactams 44 and 45 via an intramolecular 1,3-dipolar cycloaddition of an azide with an alkene (Scheme 9.10). 1,3-Dipolar cycloaddition of the azides 43 in benzene at reflux gave a mixture of cis and trans tricyclic (3-lactams 44 and 45. As the ring size increased... 

Ogawa et al. (12) used an intramolecular azide-alkene cycloaddition strategy to synthesize the oxygen-bridged aza[15]annulene 52 and the aza[15]annulene dicar-boxylate 55 (Scheme 9.12). 1,3-Dipolar cycloaddition of vinyl azide to the acrylate moiety followed by extrusion of nitrogen gave the aziridine 51. Rearrangement of 51 afforded the aza[15]annulene 52. The same approach was used to synthesize the aza[15]annulene 55. 

Weinreb and co-workers (16) reported a high-pressure-induced 1,3-dipolar cycloaddition of alkyl and phenyl azides with electron-deficient alkenes at ambient temperature. As a representative example, phenyl azide underwent cycloaddition with methyl crotonate (69) at 12 kbar to give the triazoline 70 (43%) and the p-amino diazoester 71 (53%). The high-pressure conditions resulted in high yield and a shorter reaction time (Scheme 9.16). 

Conformational constraints induced by various ortho-substitutents in 1-aUyloxy-2-azidomethylbenzenes (97) were used to accelerate intramolecular cycloadditions of the azide group to alkenes (21) (Scheme 9.21). For the unsubstituted azide 96, high temperature was required for the cycloaddition and the yield of the cycloadduct 100 was low. The monosubstituted azide 97 underwent cycloaddition in refluxing benzene in 10 h to give the cycloadduct 101 in good yield. Disubstituted azides 98 and 99 underwent 1,3-dipolar cycloaddition in 5-7 h to give the triazolines 102 and 103. 

Vogel and Delavier (26) reported a synthesis of the 6-azabicyclo[3.2.2]nonane skeleton 130 using an intramolecular azide-alkene cycloaddition strategy (Scheme 9.26). When refluxed in xylene, the azide 126 underwent an intramolecular 1,3-dipolar cycloaddition with the internal alkene. Nitrogen extrusion and subsequent rearrangement led to a mixmre of compounds 128, 129, and 130. Reactions of azides with the double bond of dienes were also used in various total syntheses of alkaloids, and will be discussed later in Section 9.2.2. 

Pearson and Lin (52) developed an elegant approach to the synthesis of optically active ( )-swainsonine (247) from isopropylidene-D-erythrose (242) (Scheme 9.52). Wittig reaction of the acetonide 242 led to the (Z) alkene 252 in 86% yield. The chloro alcohol 252 was converted to the azide 253 in 76% yield, which subsequently underwent 1,3-dipolar cycloaddition, isomerization and hydroboration-oxidation to give the indolizidine 255 in 70% overall yield. Cleavage of the acetonide unit in 255 using 6 N HCl gave the target molecule 247 in 85% yield. 

Pearson and Schkeryantz (56) developed a novel approach for synthesis of (i)-lycorane (280) using an intramolecular cycloaddition of an azide with an co-chloro alkene (Scheme 9.56). The bromide 276 was smoothly converted into the required chloro azide 277 in several steps. 1,3-Dipolar cycloaddition of the azide 277 in benzene at 140 °C followed by extrusion of nitrogen gave the unstable... 

Molander and Hiersemann (60) reported the preparation of the spirocyclic keto aziridine intermediate 302 in an approach to the total synthesis of (zb)-cephalotax-ine (304) via an intramolecular 1,3-dipolar cycloaddition of an azide with an electron-deficient alkene (Scheme 9.60). The required azide 301 was prepared by coupling the vinyl iodide 299 and the aryl zinc chloride 300 using a Pd(0) catalyst in the presence of fni-2-furylphosphine. Intramolecular 1,3-dipolar cycloaddition of the azido enone 301 in boiling xylene afforded the desired keto aziridine 302 in 76% yield. Hydroxylation of 302 according to Davis s procedure followed by oxidation with Dess-Martin periodinane delivered the compound 303, which was converted to the target molecule (i)-cephalotaxine (304). 

Ciufolini et al. (61) reported a facile assembly of the benzazocenone 307 as a part of the total synthesis of the antitumor alkaloids mitomycin C (309) and FR 900482 (310) based on intramolecular 1,3-dipolar cycloadditions of aryl azides with electron-rich alkenes (Scheme 9.61). Azide 305 was heated in refluxing toluene with a catalytic amount of K2CO3 to give the triazoline 306 in 55% yield. Irradiation of a solution of the triazoline 306 in wet THF with a sun lamp gave an 84% yield of the required benzazocene 308, which was converted to the target molecules 309 and 310. 

The regioselectivity of the 1,3-dipolar cycloadditions of azides to alkenes is usually difficult to predict due to the similar energies for the transition states which involve either the HOMO (dipole) or the LUMO (dipole). The results of a study which utilized 5-alkoxy-3-pyrrolin-2-ones as dipolar-ophiles in reactions with a variety of aryl azides seemed to reflect this problem the results suggested that the low regioselectivity observed was due to the frontier molecular orbital interactions between dipole and dipolarophile, and not any steric hindrance offered by the 5-alkoxy function <84H(22)2363>. 

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