A new approach to the synthesis of 1,2,3,4-Tetrahydroisoquinoline derivatives using benzotriazole methodology

  • Cornelia Locher

    Student thesis: Doctor of Philosophy (PhD) - CDU


    Using benzotriazole as auxiliary gives convenient access to a range of 1,2,3,4-tetra-hydroisoquinolines with different aromatic substitution patterns. In the light of the well-known difficulties in the preparation of derivatives with electron-withdrawing aromatic substituents and the interesting pharmacological properties of these compounds, the simple procedures and conditions of the described reactions as well as the very high yields, which are frequently obtained, make this approach an important new route to the 1,2,3,4-tetrahydroisoquinoline skeleton.

    After a brief introduction to the multi-facetted field of benzotriazole chemistry and some background information to the class of simple isoquinolines, different multi-step preparations of various 1,2,3,4-tetrahydroisoquinolines are presented.

    The description of the synthesis of l-hydroxymethylbenzotriazole, used as starting material to introduce the benzotriazolyl moiety, is followed by the discussion of its reactions with 3-phenylethylamines which, depending on the chosen conditions, yield the corresponding N,N-bis(benzotriazol- 1-ylmethy1)-3-phenylethylaniines or N-benzotriazol- 1-ylmethyl-j3-phenylethylamines. The condensation reactions between 1-hydroxymethyl-benzotriazole and the secondary amines N-methyl-3-phenylethylamine and 1,2,3,4-tetra-hydroisoquinoline are also described.

    The obtained intermediates are subject to an aluminium chloride assisted Friedel-Crafts reaction. A successful intramolecular cyclisation of the N,N-bis(benzotriazol-l-ylmethyl)-3-phenylethylamines under these conditions, independent from the nature of any aromatic substituent, gives rise to N-benzotriazol-1-ylmethyl-1,2,3,4-tetrahydro-isoquinolines. These compounds are also accessible via a simple one-pot procedure involving 1-hydroxymethylbenzotriazole, the respective -phenylethylamines and aluminium chloride.

    As a possible alternative to the use of a Lewis acid to assist the intramolecular ring-closure of the intermediate benzotriazolyl amines, Brensted acids are also investigated. In 20% hydrochloric acid an intermolecular mechanism dominates and the corresponding azomethines are obtained, but using concentrated sulfuric acid the intramolecular cyclisation succeeds and yields bis(N-1,2,3,4-tetrahydroisoquinolinyl)-methanes which can be expected to posses very interesting pharmacological properties. Using N,N-bis(benzotriazol- 1-ylmethyl)-3-phenylethylamines with electron-withdrawing aromatic substituents as starting material in the sulfuric acid-catalysed reaction, a variation in temperature and ratio of catalyst to reactant results in the successful isolation of the corresponding deactivated N-benzotriazol- 1-ylmethyl- 1,2,3 ,4-tetrahydroiso- quinolines, a reaction which can be seen as complementary to the classic Pictet-Spengler method.

    The last step in the synthetic sequence is the replacement of the remaining benzotriazolyl moiety in the obtained N-benzotriazol-1-ylmethyl-1,2,3,4-tetrahydro-isoquinolines. A reaction with sodium borohydride yields the corresponding N-methyl-1,2,3 ,4-tetrahydroisoquinolines, its substitution with electron-rich aromatics and heteroaromatics, such as pyrrole, 1,3-dimethoxybenzene and 2-hydroxynaphthalene, is also described.

    The discussion of the results of the above outlined synthetic steps is followed by a detailed description of the employed methodology and a full characterisation of all obtained compounds, a brief conclusion and a list of references as well as copies of some publications resulting from this work.

    Note: Permission to digitised not granted.
    Date of AwardNov 2000
    Original languageEnglish

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