New organometallic catalysts for process-friendly redox neutral alkylations

Borrowing hydrogen chemistry is a convenient method of carrying out alkylation reactions, by forming carbonyl compounds from alcohols in situ, creating more reactive intermediates. These aldehydes or ketones react and the resulting product is reduced by return of the hydrogen abstracted from the alcohol starting material. Previous work within the Marsden group led to the development of a new family of catalysts for N-alkylation borrowing hydrogen reactions, featuring a Cp* ligand functionalised with an amine tether. The possibility for expanding the scope of these catalysts to polyfunctionalised compounds was investigated, including protected and unprotected diamines and diols, and the synthesis of pharmaceutically relevant compounds. Optimisation studies were carried out to reach the highest turnover number for our catalyst, reaching a maximum turnover number of 2250 for our model reaction of the alkylation of piperidine with benzyl alcohol. After a brief investigation into the synthesis of new catalysts bearing modified tethers was unsuccessful, methodology was developed for the synthesis of our original catalyst under conditions more viable for scale-up. Experiments were carried out to determine the catalyst’s potential for carrying out C-alkylation reactions. In particular, carbonyl alkylations via an aldol pathway were successful, and were shown to be viable for a series of substituted acetophenones and benzyl alcohols, as well as various heteroaromatic compounds. A one-pot procedure for alkylation and subsequent reduction to the respective alcohol compound was developed and utilised to synthesise a series of compounds based on the taccabulin natural products, which were tested for anti-cancer activity. Finally, the possibility of these reactions being carried out to a lower yield in the absence of catalyst was investigated. The scope of these uncatalyzed reactions was determined to include only aromatic ketones, while our catalyst was shown to be able to carry out alkylations onto alkyl ketones with either aromatic or alkyl alcohols.