Studies in 8-amino-6,7-benzomorphans.

  • Shabir Hirani

Student thesis: Doctoral ThesisPhD


This project involved the chemical modification of the 6,7-benzomorphan nucleus by introducing a second nitrogen pharmacophore at the benzylic position to give a series of 8-aminobenzomorphans with potential analgesic activity. Concise reviews of 6,7-benzomorphan, morphine and related analgesics, pertinent to this project together with background material are given in Part One of the thesis.;The introduction of oxygen at the benzylic carbon of the 6,7-benzomorphan in improved yields was achieved using dilute solution of chromium trioxide in acetic acid at room temperature. Various other oxidising agents which are known to attack benzylic methylene groups were also investigated and are reported in Chapter Two.;The stereoselective synthesis of the 8-amino-6,7-benzomorphan by reduction of the oxime is described. Catalytic hydrogenation of the oxime yielded 8alpha-aminobenzomorphan whereas LAH reduction gave the beta-isomer. These reductions together with the various factors which influence the stereochemical course of reduction are discussed in Chapter Three. The relative configuration of 8-aminobenzomorphan was assigned on the basis of 1H NMR studies. The stereochemistry of the 8beta-aminobenzomorphan was confirmed by its successful cyclization via 8beta-chloroacetamido-6,7-benzomorphan to the 2,8-bridged benzomorphan derivative. All attempts to cyclize the 8alpha-chloroacetamide under similar conditions proved to be impossible as anticipated on steric grounds.;The 8alpha-cyanobenzomorphan obtained from 8-oxo-benzomorphan and tosylmethyl isocyanide was catalytically reduced to 8-aminomethy1-6,7-benzomorphan. Introduction of an aminomethyl group at the 8 position creates a second phenylethylamine moiety in the benzomorphan nucleus.;The stereochemistry of 8alpha-cyanobenzomorphan was determined from the 1H NMR chemical shifts and coupling constant between C1 and C8 protons. Attempts to prepare the 8beta-cyano compound by base-catalysed racemisation of the alpha-isomer surprisingly gave 8-oxobenzomorphan. A possible mechanism for this transformation is discussed in Chapter Five.;The availability of the nitrogen non-bonding electrons in the aminobenzomorphans was modified by acylation and alkylation. An unusual acylation reaction was observed for the 8beta-amine and cyclo-propanecarbonyl chloride in that it gave 8beta-dicyclo-propionamidobenzomorphan instead of the expected monoacylated derivative. A possible mechanism for this reaction is discussed in Chapter Three. Approach to the synthesis of 8-alkylaminobenzomorphan via reductive amination of 8-oxobenzomorphan was investigated and shown to be unsatisfactory.;1H and 13C NMR data for a series of 6,7-benzomorphan derivatives prepared in this work is presented and discussed in Chapter Six. These data are not only of importance for identification and differentiation but also valuable in the evidence they provide of the configuration and conformation of the various derivatives. The experimental details of the syntheses of the aminobenzomorphans and their derivatives are given in Chapter Seven.
Date of Award1983
Original languageEnglish
Awarding Institution
  • University of Bath

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