Degree Name

Doctor of Philosophy


Department of Chemistry


The general aim of the work was to explore the design and synthesis of new ligands which could have potential to mimic the action of neurotransmitters at the dopaminergic or serotonergic receptor sites.

The first part of the project involved studies on the design and development of medium-ring cyclophane-based potential prodrugs which could be ultimately converted to an endogenous ligand, dopamine. A photochemical route to the m-cyclophane lactams was improved and extended. New chloroacetamides and derivatives were prepared for photochemical investigation. Photolysis of (40) gave rise to a new m-cyclophane analogue (64) in good yield whose structure was confirmed by X-ray crystallography. In addition, a range of other m-cyclophanes (65), (66) and (67) were obtained from the photolysis of chloroacetamides (42), (44) and (46) respectively. Photolysis of other new chloroacetamide derivatives (52), (53), (54), (57), (58), (59), (60), (61) and (63), however, did not result in the formation of m-cyclophane lactams. Benzazepinone analogues or nonheterocyclic products were obtained instead. Mechanistic pathways for the products were indicated.

The usefulness of the photochemical approach to medium ring heterocycles was further extended. Photolysis of N-chloroacetamide derivatives, 3-chloroacetyl-7,8-dimethoxy-4,5-dihydro-lH-3-bezazepin-2 (3H)-one (86) in aqueous acetonitrile gave 11a-hydroxy-8,9-dimethoxy- 5,6,11,lla-tetrahydrooxazolo[2,3-b][3]benzazepin-2-(2H)-one (87) in good yield. This representative of a new heterocyclic system could be converted into the 11a-ethoxy derivative (88) by recrystallization from ethanol. The structure of (88) was confirmed by X-ray crystallography.

Work was also conducted to develop methods to modify the bridging chain of the m-cyclophane derivatives as part of the potential prodrug studies. Further to this effort, some new chemistry associated with approaches to fused indole systems from the m-cyclophane precursors was uncovered. Reaction of cyclophane lactams (8) and (64) with N-bromosuccinimide in the presence of a catalytic amount of azobisisobutyronitrile led to new seven membered ring fused indolic derivatives (104-112) via C-N intramolecular cyclisation. The reaction, however, did not proceed with N-protected lactam functionality in the bridging ring. Alternative C-C cyclisation in (8) by using boron tribromide gave the previously reported imine (102) which, in turn, was used to prepare the new tricyclic chloroacetamide derivatives (119), (120) and (121) for photochemical investigation. Ultraviolet irradiation of the silylated eneamide (121) afforded a benzopyran chloroacetamide derivative (122) in low yield.

The second part of this project was involved with the design and development of non-natural ligands for serotonergic sites and was carried out under a scientific exchange program at the Universite of Orleans (France). A new series of 3,4-dihydro-3-amino-2H-benzopyran derivatives with various C5-substituents, (146), (143), (145), (137), (158), (159), (160), (141) and (178) were successfully prepared. The substituents were introduced via palladium-mediated cross-coupling reactions. The effect of these different groups in the 5-position on the interactions with 5HT1A-and 5HT7-subtype receptors was evaluated. In vitro studies, carried out by the pharmaceutical company SERVIER indicated that these derivatives are very active agonists while the ketones (145) and (160) are more potent than the lead compounds at the serotonergic receptor sites. In an extension of this work,an azido derivative, (69) was also synthesised for future photo-affinity labelling of the above receptors.



Unless otherwise indicated, the views expressed in this thesis are those of the author and do not necessarily represent the views of the University of Wollongong.