1.3- Dipolar cycloadditions diene double bonds

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. 

In the Diels-Alder reaction, the dienes had to have an s-cis conformation about the central single bond so that they were already in the shape of the product. Many useful 1,3-dipoles are actually linear and their 1,3-dipolar cycloadditions look very awkward. We shall start with the nitrile oxides, which have a triple bond where the nitrone had a double bond. 

Kobayashi et al. found that lanthanide triflates were excellent catalysts for activation of C-N double bonds —activation by other Lewis acids required more than stoichiometric amounts of the acids. Examples were aza Diels-Alder reactions, the Man-nich-type reaction of A-(a-aminoalkyl)benzotriazoles with silyl enol ethers, the 1,3-dipolar cycloaddition of nitrones to alkenes, the 1,2-cycloaddition of diazoesters to imines, and the nucleophilic addition reactions to imines [24], These reactions are efficiently catalyzed by Yb(OTf)3. The arylimines reacted with Danishefsky s diene to give the dihydropyridones (Eq. 14) [25,26], The arylimines acted as the azadienes when reacted with cyclopentadiene, vinyl ethers or vinyl thioethers, providing the tet-rahydroquinolines (Eq. 15). Silyl enol ethers derived from esters, ketones, and thio-esters reacted with N-(a-aminoalkyl)benzotriazoles to give the /5-amino carbonyl compounds (Eq. 16) [27]. The diastereoselectivity was independent of the geometry of the silyl enol ethers, and favored the anti products. Nitrones, prepared in situ from aldehydes and N-substituted hydroxylamines, added to alkenes to afford isoxazoli-dines (Eq. 17) [28]. Addition of diazoesters to imines afforded CK-aziridines as the major products (Eq. 18) [29]. In all the reactions the imines could be generated in situ and the three-component coupling reactions proceeded smoothly in one pot. 

Methylenecyclopropanes undergo a variety of [2 + 3] cycloadditions (1,3-dipolar cycloadditions) across the double bond. Examples of the addition of diradicals are some of the dimerization reactions of methylenecyclopropane vide infra). Small quantities (< 5%) of an addition product of a 1,3-diradical to methylenecyclopropane with preservation of the three-membered ring were isolated from the thermal reaction of dispiro[2.2.2.2]deca-4,9-diene with methylenecyclopropane. ... 

Cycloaddition. 4-Methylene-4,5-dihydroisoxazoles (174) are good dipolarophiles towards a variety of 1,3-dipoles (e.g., arylnitrile oxide (177)) to form a spiral compound (178), which is not easily accessible by other routes. The resulted 1,3-dipolar cycloaddition product (178) is regio- and stereoselective <95SL1208>. The exocyclic double bond of (174) is sluggish towards the diene systems, but with the activated diene, 2,5-dimethyl-3,4-diphenyl-2,4-cyclopoentadienone (179) yielded the Diels-Alder product (180) (Scheme 27) <95SL1208>. 

The heterocyclic double bond in simple indoles will take part in cycloaddition reactions with dipolar 4n components,and with electron-deficient dienes (i.e. inverse electron demand), in most reported cases, held close nsing a tetherf° a comparable effect is seen in the intermolecular cycloaddition of 2,3-cycloalkyl-indoles to ortfto-quinone generating a l,4-dioxane. ° The introduction of electron-withdrawing substituents enhances the tendency for cycloaddition to electron-rich dienes 3-acetyl-1-phenylsulfonylin-dole, for example, undergoes aluminium-chloride-catalysed cycloaddition with isoprene, " and 3-nitro-l-phenylsulfonylindole reacts with l-acylamino-buta-l,3-dienes without the need for a catalyst. Both 3- and 2-nitro-l-phenylsulfonyl-indoles undergo dipolar cycloadditions with azomethine ylides. ... 

Intramolecular 1,3-dipolar cycloadditions of azides have also been investigated as a route to the pyrrolizidine ring system. For example, ethyl 8-azidoocta-2,4-dienoate (56) was converted in high yield into the labile vinylaziildine 57 when it was heated under reflux in toluene. In other experiments it was demonstrated that activation of one of the double bonds of the diene was essential in order to achieve efficient intramolecular cycloaddition. The vinylaziridine 57 was then converted into the pyrrolizidine 58 by flash pyrolysis followed by catalytic hydrogenation of the product (Scheme 6.26). 

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