Synthesis of potentially neuroactive heterocycles using early transition metal chemistry

Abstract

The work presented in this thesis illustrates the synthetic utility of organozirconium chemistry through the synthesis of three distinct pharmacophores. A number of 3,4- and 4,5-disubstituted azepines have been synthesised from 3- and 4-aza-1, 8-dienes, enynes and diynes through zirconium induced cocyclisation reactions. The exocyclic dienes formed from the 1,8-diynes could be elaborated by Diels-Alder reactions, including examples where subsequent aromatisation afforded benzazepines. The zirconacyclopentadienes derived from 3- or 4-aza-1,8-diynes could also be elaborated directly to benzo[c]- or benzo[d]-azepines by copper induced addition to an alkyne. Some of the azepines and benzazepines have undergone biological testing at Eli Lilly (UK).

A novel synthesis of the 4-phenylpiperidine pharmacophore by zirconocene induced co-cyclisation of 3-arylbutenylallylamines have been developed. The aryl ring could be incorporated by a modified Suzuki coupling of an aryl boronate with 3-bromobutenylamines. The synthesis of a variety of other aryl substituted piperidines was attempted, but the yields were generally poor. An exception was co-cyclisation of diynes to give piperidines incorporating exocyclic dienes.

The cyclisation of 3-phenyl, 3-benzyl, and 3-benzylidiene pyrrolidines by zirconium induced co-cyclisation of 4-aza-1, 6-dienes -enynes and -diynes was generally high yielding.

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