Chiral hypernucleophilic acylation catalysts and synthesis of bipyridyls via palladium-catalysed reductive homocoupling of chloropyridines

Abstract

Chapter 1 of this thesis discusses the explosion of interest in the non-enzymatic kinetic resolution of secondary alcohols catalysed by chiral derivatives of the hypemucleophilic acylation catalyst, 4-dimethylaminopyridine. Particular attention is drawn to the work of Gregory Fu and Craig Ruble of the Massachusetts Institute of Technology, Kaoru Fuji of Kyoto University and Edwin Vedejs of the University of Wisconsin who have been pioneers in this type of work during the last five years, and who collectively represent the benchmark in terms of non-enzymatic kinetic resolution via enantioselective acylation. Also reviewed is the work of other more recent entrants into the field such as Alan Spivey of Sheffield University and Tarek Sammakia of the University of Colorado. Finally, our own tentative steps into this area are discussed as is the structure of the present work, the majority of which has been carried out during the last three years. Chapter 2 discusses in detail several efficient procedures for the synthesis of 2-halo and 2,6-dihalo-4-dialkylaminopyridines, precursors to the more elaborate compounds discussed in Chapter 3. Also there is a substantial discussion on other synthetic routes to 2-halo-4-dialkylaminopyridines which did not have the desired outcome, particularly the failed conversion of 4-(1'-pyrrolidinyl)-2-pyridone into 2-chloro-4- (1'-pyrrolidinyl)pyridine, and the failure to synthesise 2-amino-4- dimethylaminopyridine in acceptable quantities via the generation of a heteroaryne from 3 -bromo-4-dimethylaminopyridine. Chapter 3 describes the synthesis of novel chiral 4-dialkylaminopyridines incorporating the terpene alcohols (-)-menthol and (-)-borneol from 2-bromo-4- dimethylaminopyridine. Thus, (-)-2-bomyloxy-4-dimethylaminopyridine and (-)-2- menthyloxy-4-dimethylaminopyridine proved to be efficient catalysts in the acylation of 1-phenylethyl alcohol but showed no enantioselectivity. Also researched was the ability of heterocyclic N-oxides to act as catalysts for the acylation of 1-phenylethyl alcohol in the presence of acetic anhydride. Of particular significance was the fact that 2-dimethylaminopyridine N-oxide is an efficient acylation catalyst whereas the free base is inactive. This implied that potential catalysts may not require a 4-dimethylamino substituent to achieve an acceptable rate of reaction. A number of homochiral N-oxides were synthesised and indeed they did act as efficient acylation catalysts but showed no enantioselectivity. A detailed kinetic investigation into the acylation of 1 phenylethyl alcohol in deuteriochloroform was undertaken for all compounds showing catalytic activity. It was shown that 4-dimethylaminopyridine was only 1.2 times better than 4-dimethylaminopyridine N-oxide as an acylation catalyst. 2-Dimethylaminopyridine N-oxide was shown to be almost twice as effective as pyridine under similar conditions.Chapter 4 deals with an efficient palladium-catalysed synthesis of bipyridines, which is believed to occur via a reductive homocoupling reaction. The regeneration of palladium(O) was believed to occur via a Wacker reaction involving the alkene present in the reaction mixture although this has not been conclusively demonstrated. Also discussed are initial attempts to synthesise the novel ligand 4,4’-dimethylamino-2,2’-bipyridine from the 2-bromo-4-dimethylaminopyridine synthesised in Chapter 2.