Synthesis of Nitrogen Heterocycles via Pd-Catalyzed 1,3-Dipolar Cycloaddition Reactions

Synthesis of Nitrogen Heterocycles via Pd-Catalyzed 1,3-Dipolar Cycloaddition Reactions 

Although the use of 1,3-dipolar cycloaddition reactions that form carbon-heteroatom bonds is fairly common using traditional synthetic methods [2], palladium-catalyzed dipolar cydoaddition reactions of this type are rather rare. However, a few reports have described an interesting and synthetically useful approach to the synthesis of pyrrolidines via Pd-catalyzed [3 + 2] cydoaddition reactions oftrimethylenemethane vdth imines [91]. In very recent studies, Trost has developed an asymmetric variant of these reactions that provides access to enantioenridied pyrrolidine derivatives [92]. For example, treatment of trimethylenemethane precursor 131 with imine 132 proceeds to afford 133 in 84% yield and 91% ee when a catalyst composed of Pd (dba)2 and ligand 134 is used (Eq. (1.53)). 

Although many Pd-catalyzed [3 + 2] cydoaddition reactions employ 131 as a trimethylenemethane precursor, readily available 2-methylenepropane-l,3-diols and their corresponding benzyl ethers have also been used as sources of trimethylene-methane [93]. This approach allows construction of more highly substituted pyrrolidine derivatives than can be generated from 131. For example, treatment of 135 with 136 in the presence of diethylzinc and a palladium catalyst afforded pyrrolidine 137 in 92% yield as a single diastereomer (Eq. (1.54)). 

An unusual class of Pd-catalyzed [3 + 2] cycloaddition reactions between activated aziridines and heterocumulenes such as isocyanates and carbodiimides has been extensively examined by Alper and coworkers [94]. These transformations led to the preparation of ureas, carbamates, and other heterocydes in good yields. For example, treatment of 138 with phenylisocyanate afforded urea 139 in 72% yield (Eq. (1.55)) [94aj. The mechanism of these reactions presumably involves oxidative addition of the aziridine to Pd , followed by insertion of the isocyanate into the Pd—N bond and C—C bond-forming reductive elimination (similar to the reactions of vinylaziridines described in the section above, although allylpalladium intermediates are obviously not involved). 

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