Synthesis of Different Heterocyclic Compounds of Pharmaceutical Relevance

This thesis describes the synthesis of different cyclic imines and the exploration of their reactivity with cyclopropenones and 1,3-dipoles,as well as an investigation of the chemistry of the products. The synthesis of biologically and pharmaceutically important heterocyclic natural product analogues, such as the pyrroloazepines, indolizidines and pyrrolizidines has been achieved using a cycloaddition reaction between cyclic imidates and cyclopropenones.

A new route to pyridines has been developed using the generation of a proposed 3-azacyclopentadienone as the key step. The 3-azacyclopentadienones are generated by using boiling toluene to induce a [2+2]-cycloreversion in a series of azabicyclo[3.2.0]hept-2-en-4- ones. Regiospecific Diels-Alder reaction of the intermediate 3-azacyclopentadienone with a styrene is followed by chelotropic extrusion of carbon monoxide and loss of hydrogen to give the pyridine.

The process is similar to the well-known process by which benzenes are accessed from cyclopentadienones. The azabicyclo[3.2.0]hept-2 en-4-ones were available from the reaction of cyclopropenones with 1-azetines, where cyclopropenones behave as an all carbon 1,3- dipole equivalents. Using the same methodology 1,3-dipolar cycloaddition of nitrile oxides to 4-aryl-2-alkylthio-1-azetines afforded a series of oxadiazabicyclo[3.2.0]heptenes as single diastereoisomers. Heating these cycloadducts in toluene resulted in an overall [2+2]- cycloreversion to give 5-alkylthio-3-aryl-1,2,4 oxadiazoles.

Cycloaddition reactions of a series of benzodiazepines were also studied. The benzodiazepines were formed using literature methods and converted to cyclic imines with the help of Meerwein’s reagent. Reactions between such cyclic imines and cyclopropenones and 1,3 dipoles were attempted to produce tricyclic and tetracyclic benzodiazepine analogues.

Finally, some multicomponent reactions of aryl aldehydes with cyanides and 1,3-dicarbonyl compounds were investigated to produce fully substituted heterocyclic compounds like dihydropyridines and pyrans with substituents suitable for intramolecular cyclization and imine formation. The main substituent of interest was the azide group as this had been used in section 2.3.3.1.2 & 2.3.3.1.3 in this thesis.