Degree Name

Doctor of Philosophy


Department of Chemistry


Reactions of the isoquinoline alkaloids, aporphine, papaverine, pavine, and berberine have been studied . The main aim of the work was to explore a potential route to the new strained aza(l,9)phenanthrenophane derivatives 23a, 23b, and 24 using the readily-available aporphine alkaloid, boldine as a starting material.

A ring construction approach to the aza(1,9)phenanthrenophane derivative 23a via a photochemical reaction of phenanthrene chloroacetamide derivatives 28b or 28c was pursued (Chapter 2). Photolysis of 28b gave rise to the reduced aza(1,9)phenanthrenophane analogue 47 in low yield. In addition, a range of other novel heterocyclic products were obtained from the photolysis of 28b and 28c including the phenanthroazepinone derivatives 44a or 44b, the spiro compounds 45a or 45b, and the fused medium size ring derivatives 46a, 46b, 48a, and 48b. Mechanistic pathways for the products were also indicated. All compounds prepared from these photolyses are representative of a new heterocyclic system.

A ring destruction approach to the aza(1,9)phenanthrenophane derivatives 23b and 24 through ring expansion of the quinoline 21 and 22a by a cyanogen bromide reaction was also investigated (Chapter 3). The closest result which has been achieved in the approach to compound 23b is the preparation of the intermediate 59. Two more steps are still required to afford the final compound 23b. The first is the selective reduction of the double bond to give the quinoline 21 and the second is the cyanogen bromide ring destruction with elimination. Unfortunately, the reduction of the phenanthrene system in 23b could not be achieved.

The cyanogen bromide reaction of 22a in ethanol-free chloroform, in the presence of potassium carbonate produced two compounds 76 and the reduced (1,9)phenanthrenophane derivative 77 respectively. The reaction of 22b with cyanogen bromide under the same conditions as for 22a gave 79, 80, and 81 respectively.

Further work described in this thesis was directed towards the preparation of new nitrogen-containing heterocyclic systems for later pharmacological and chemical evaluation. A photochemical reaction of chloroacetamide derivatives was employed to approach the isoquino[l,2-b][3]benzazepine ring systems in 25a-c (Chapter 4). This new synthetic approach is efficient and potentially generalisable to a range of other 1,2,3,4-tetrahydroisoquinoline precursor derivatives, including chiral forms. It also offers scope for the introduction of further functionality into the [3]benzazepine moiety.

Further reactions based on papaverine were also undertaken to prepare new systems including 2,3,5,6-tetrahydro-6-(α-hydroxy-3,4-dimethoxy)benzyl-8,9- dimethoxy-3-methyl-3-benzazocin-4(1H)-one 27, the isoquino[2,1-d][ 1,4]benzodiazocinone 101, 5,6-dihydro-8,9,13,14-tetramethoxy-1H-isoquino[ 2,1-d][1,4]benzodiazocine-2,3-dione 118, and 1,10-dihydro-7,8,12,13- tetramethoxy-2H-indolo[2,3-e][3]benzazonin-4(3H)-one 119 (Chapter 5).

In continuation of the work on the transformations of alkaloids, reactions based on pavine 11 and berberine 12 (Chapter 6), including the preparation of 13- acetyl-5,6,11,12-tetrahydro-12-hydroxy-2,3,8,9-tetramethoxydibenzo[ a,e]cyclooctene-5,11-imine 120 from a photochemical reaction on a chloroacetamide derivative of 11, were investigated. The preparation of the chlorinated homoprotoberberine 126 and protopine 132 derivatives from berberine was also achieved.

New isoquino[2,1-c][1,3]benzodiazepine derivatives were produced in moderate to high yields by reaction of 1,2,3,4-tetrahydro-6,7-dimethoxy-1-[(3,4- dimethoxy-2-aminophenyl)methyl]isoquinoline 133 with carbon disulfide or triphosgene and by hydrogenation of the nitro substituted isoquinolines 138a or 138b derived from dihydropapaverine (Chapter 7). This new synthetic approach is very efficient and potentially generalisable to a range of other tetrahydroisoquinoline precursor derivatives. It also offers scope for the introduction of further functionality into the [1,3]benzodiazepine moiety.