U542563.pdf (4.62 MB)
Download file

Homotropanes - synthetic approaches to the 9-azabicyclo [4.2.1] nonane/ene ring system.

Download (4.62 MB)
posted on 19.11.2015, 08:47 by Craig. Smith
Homotropanes and homotrop-7-enes have been synthesised in reasonable yields by the method of intramolecular cyclisation of cis-1,4-aminocyclooctanols. The strategy of nitroso-cycloaddition to 1,3-cyclooctadiene provided the required cis-stereochemistry, and the choice of nitroso-compound determined the nitrogen protecting group of the resulting homotropane or homotrop-7-ene. A modification of the scheme led to the construction of the 1-methylhomotropane skeleton via intramolecular cyclisation of nitrogen onto an sp2 carbon of an exocyclic methylene group. A similar method was utilised to create the unsaturated 1-methylhomotrop-7-ene skeleton. 4-Hydroxycyclooctanone and 4-hydroxycyclooct-2-enone have been shown to exist in equilibrium with their respective bicyclic tautomers, as indicated by 1H and 13C NMR spectroscopy. The incorporation of a double bond into the hydroxy-ketone system results in a greater preference for the bicyclic form. The corresponding 4-aminocyclooctanones and 4-amino- cyclooct-2-enones have been synthesised and these amino-ketones show similar behaviour, but the equilibrium in these cases is much more evenly balanced. The position of equilibrium has also been found to vary with temperature and substitution. The unsaturated bicyclic amines synthesised in this project were successfully N-demethylated and N-debenzylated using ?-chloroethylchloroformate. This N-dealkylation to nor- homotrop-7-ene should allow future work to investigate epoxidation of the double bond by protection of the nitrogen of the free amine as a urethane. Attempts to measure nitrogen inversion barriers of the N-chloroamines derived from the bicyclic secondary amines using variable temperature 1H and 13C NMR spectroscopy were unsuccessful. However, 15N NMR spectra of various homotropanes synthesised were obtained, and these exhibit 15N chemical shifts typical of normal secondary and tertiary amines. The nitrogen atoms in these homotropanes do not experience the deshielding associated with 7-azabicyclo [2.2.1] heptyl systems in which the "bicyclic effect" is thought to operate.


Date of award


Author affiliation


Awarding institution

University of Leicester

Qualification level


Qualification name




Usage metrics