The Synthesis and Structure-Activity Relations of some Benzomorphan Analogues

  • J. O'Sullivan

Student thesis: Doctoral ThesisDoctor of Philosophy


A brief review of the history of analgesics leading to the
introduction of the 6,7-benzomorphans is presented

In the hope of obtaining compounds of biological interest,
some 6-cycloalkylamino derivatives of -nethylS-azebicyclo[3.3.1]
nonan-9-one have been synthesised and submitted for pharmacological
testing. The route adopted consisted of the addition of acrolein to
the various cycloalkylamino enamines of N-methyl-piperidone, to
give in each case, a mixture of two stereoisomeric ketones. A
Successful separation of these pairs of ketones was not achieved.
However, after reduction of each pair of ketones to the corresponding
tertiary alcohols, a successful route has been established to the
isolation of three of the four possible stereoisomeric alcohols. The stereochemistry of each of the amino-alcohols has been defined by
a study of their chemical properties, pKa values, NMR, infrared, and
mass spectra. Of special interest, is the discovery of a new band in
the infrared spectra of certain amino-alcohol salts which confirms
their stereochemistry. In addition, each series of alcohols contains
at least one compound containing the piperidine ring in a boat form.
Further proof of the boat form is at present being sought by X-ray

A further series of compounds have also been prepared by the
reaction between cinnamaldehyde and the pyrrolidine enamine of N-methyl-l,-piperidone, to yield, S-nethy1-3-azabicyelo [3.3.1] nonenee
derivatives substituted at the 6- and 8- positions. In order to
facilitate the interpretation of the NMR spectra of the 6- and
6,8-disubstituted compounds obtained, a number of model compounds of
known stereochemistry were prepared. The reaction between the morpholine
enamine of cyclohexanone and acrolein yielded 6-substituted bicyclo
[5.3.4] nonenes, and the reaction with cinnamaldehyde yielded 6,8-
disubstituted bicyclo [3.3.1] nonanes of known stereochemistry.

The infrared spectra of all, and the NWR spectra of a number
of the new compounds have been recorded.

A brief consideration of the mass spectra of the 6-substituted
and 6,8-disubstituted S-nethyl-3-azabicyolo[3.3-1] nonananes and
bicycle [5.3.1] nonanes has been recorded, and possible fragmentation
pathways for these compounds have been suggested. A correlation between
the stereochemistry of the amino-alcohols and their fragmentation
pathways has been discovered.

Selected compounds were tested for pharmacological activity,
but a variety of differing results have been obtained.

Date of Award1973
Original languageEnglish


  • pharmacy
  • synthesis
  • benzomorphan analogues

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