Preparation of enantiomerically enriched heterocycles via dynamic kinetic resolution: Exploration of new paths to benzocyclobutenones and benzocyclobutenols.

Abstract

The preparation of enantiomerically enriched bi- and tricyclic heterocycles via a dynamic kinetic resolution protocol is discussed. This methodology was applied to the reaction of o-bromo-alpha-iodo alkyl [R]-pantolactone esters with a number of bifunctional nucleophiles such as, 1,2-phenylenediamine, which resulted in the formation of bicyclic piperazines. Several other nucleophiles such as 2-aminophenols, also formed the expected heterocycles, but aliphatic 1,2-diamines tended to give elimination rather than displacement products, with the above dihalo esters. The preparation of these heterocycles in a simple three step sequence, starting from commercially available o-bromo alkyl acids is detailed. Attempts were made to prepare benzocyclobutenones and benzocyclobutenols via halogen-metal exchange and subsequent cyclization in o-halobenzyl cyanide. Finally, the reaction of amide, ester and ketone enolates with a benzyne species generated via reaction of halobenzenes with lithium 2,2,6,6-tetramethylpiperidide at room temperature or below is also discussed. The reaction of amide and ester enolates with benzynes has not been previously discussed in the literature. Surprisingly, reaction of ester or amide enolates with benzyne in the presence of excess iodobenzene afforded substituted iodobenzenes as the major reaction product. These products were obtained by reaction of the enolates with benzynes followed by transfer of iodine from iodobenzene. The results represent the first example in which iodobenzene acts as a positive source of halogen.