Azide-alkene cycloaddition

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. 

Hassner et al. (8) reported a novel synthesis of 2,5-dihydroxyoxazoles (32) using an intramolecular azide-alkene cycloaddition. The ratio of reagents (aldehyde/allyl alcohol/hydrazoic acid, 1 3 9) was critical for the preparation of azide 30 (Scheme 9.8). 

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. 

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. 

Schkeryantz and Pearson (59) reported a total synthesis of ( )-crinane (298) using an intramolecular azide-alkene cycloaddition (Scheme 9.59). The allylic acetate 294 was first subjected to an Ireland-Claisen rearrangement followed by reduction to give alcohol 295, which was then converted into the azide 296 using Mitsunobu conditions. Intramolecular cycloaddition of the azide 296 in refluxing toluene followed by extrusion of nitrogen gave the imine 297 in quantitative yield. On reduction with sodium cyanoborohydride and subsequent reaction with... 

Pearson et al. (64) developed an approach to the fused bicyclic 3-pyrrolines 328 based on an intramolecular azide-alkene cycloaddition (Scheme 9.64). Azides (327) were heated at various temperamres between 70 and 110°C to afford the... 

The intramolecular azide alkene cycloaddition was exploited in a completely diastereoselective synthesis of mitomycin C intermediates 12128-130. 

Logothetis studied the thermal intramolecular azide-alkene cycloaddition (IAAC) of 5-azido-5-methyl-1-hexene and observed the formation of a mixture of imines and aziridines <65JA749>. The first case of utilization of silica gel in the selective decomposition of triazoline (35) to pyridines and aziridines (X = CH2—CH2, (CH2)3) was reported by Murthy and Hassner (Equation (17)) <87TL97>. The role of silica gel in the chemoselective reaction is still obscure, but it is likely that acidic surface... 

Ciufolini and co-workers demonstrated the use of 1,3-dipolar azide-olefin cycloaddition reactions in the total synthesis of ( )-FR66979 (52) [25], an antitiunor agent which is structurally related to the mitomycins [26]. Thus, the triazoline 50 was obtained as a single diastereomer by smooth cycloaddition of the activated double bond and the dipole in 49 by heating in toluene. Brief photolysis of 50 provided aziridine 51, which fragmented to 52 (Scheme 8B). Other intramolecular azide-alkene cycloaddition in natural product synthesis is illustrated by a munber of examples [27-32]. 

Hassner and co-workers have shown that the intramolecular azide-alkene cycloaddition reactions of azido vinyl j8-lactams primarily lead to cis fused triazolines. The triazoline 61, fused to a 6-membered ring, was formed exclusively as the cis-fused isomer and decomposed on treatment with silica gel to imine 66. On the other hand, the 8-membered ring fused triazoline 63 which was isolated as a cis trans mixture, on exposme to sUica, produced only aziri-... 

FIGURE 14.11 Intramolecular azide-alkene cycloaddition and nitrogen extrusion from 17. 

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