1,3 Dipolar cycloaddition second approach

Muthusamy et al. (82) prepared a number of oxacyclic ether compounds from the tandem ylide formation-dipolar cycloaddition methodology. Their approach provides a synthetic tactic to compounds such as ambrosic acid, smitopsin, and linearol. Starting with either cyclopentane or cyclohexane templates, they prepared ylide sizes of five or six, which are trapped in an intermolecular cycloaddition reaction by the addition of DMAD. The products are isolated in good overall yield. In a second system, 2,5-disubstituted cyclohexenyl derivatives are utilized to generate the pendent ylide, then, A-phenylmaleimide is added in an intermolecular reaction, accessing highly substituted oxatricyclic derivatives such as 182 (Scheme 4.43). 

The addition of nitrogen across a double bond to form a fused-ring aziridine of type II generally takes one of two forms. The simplest is the dipolar cycloaddition of an azide across a double bond followed by loss of dinitrogen to provide an aziridine. A second and operationally more complex approach is the generation of a nitrene, which then adds to the olefin to directly provide the aziridine. 

A second approach involving a 1,3 dipolar cycloaddition is shown in Scheme... 

As nitriles are generally readily available this is the main route to simple tetrazoles. More complicated ones are made by alkylation of the product of a cycloaddition. The tetrazole substitute for indomethacin that we mentioned in Chapter 29 is made by this approach. First, the nitrile is prepared from the indole. The 1,3-dipolar cycloaddition works well by the azide route we have just discussed, even though this nitrile will form an enoT rather easily. Finally, the indole nitrogen atom must be acylated. The tetrazole is more acidic so it is necessary to form a dianion to get reaction at the right place. The usual rule is followed (see Chapter 23)— the second anion formed is less stable and so it reacts first. 

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