Intramolecular cycloadditions five-atom tether

An increase in the tether length requires substantially more severe reaction conditions. For tethers containing more than five atoms between the reacting fragments, intramolecular [3+ 2]-cycloaddition reactions remain unknown. 

Intramolecular cycloaddition of nitrile ylides to olefinic dipolarophiles linked to the dipole by a three-atom chain leads to pyrazoles fused to five-membered rings. Work on stereoselectivity in such reactions has been carried out using the reactant 266 in which the alkene moiety is linked to the C-terminus via a tether that incorporates an enantiomerically pure (R) stereogenic group (165). Both diastereo-isomers 267 and 268 were isolated and it was found that the reaction showed moderate stereoselectivity favoring 267. 

The two components of the [4 + 2] cycloaddition can be linked to react intramolecularly. The dienophile can be tethered to either a- or (3-carbon of the nitroalkene, which in turn creates bicyclic fused or bridged nitronates, depending upon the regioselectivity (Figure 16.4). To date, only cycloadditions of (3-tethered nitroalkenes are known. The reaction can be used to prepare five- and six-membered rings [58], which correspond to a three- or four-atom linker between the diene and dienophile. An attempted preparation of a seven-membered ring led to an intermolecular cycloaddition instead. 

Wender et al. demonstrated the rhodium-catalyzed intramolecular [6 + 2]-cycloaddition of 2-(l,6-dienyl)-cyclobutanones 158 (Scheme 55).130 The five-mem-bered heterocycles 159 were synthesized using substrates 158, which had a nitrogen or oxygen atom in a tether moiety. The reaction proceeds through formation of the five-membered metallacycle 160 and subsequent /Tcarbon elimination (de-carborhodation), leading to the nine-membered metallacycle 161, which produces 159 upon reductive elimination of Rh. 

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