1-Benzyl isoquinolines: Studies in their synthesis, cyclisation and migration.

  • Anthony William Charles White

Student thesis: Doctoral ThesisPhD


Chapter 1 of this thesis contains a brief review of the structure-activity relationships in bronchodilator drugs, and describes the syntheses of 5-hydroxy and 7-hydroxy-6-hydroxymethyl-1(3,4,5-trimethoxybenzyl)-1,2,3,4-tetrahydroisoquinolines as potentially active compounds. The preliminary pharmacology of these saligenins are also included. The synthesis involves a Pomeranz-Fritsch type of cyclisation which occurs in an abnormally high yield with the additional anomaly of a high ortho/para ratio. Introduction of the 1-benzyl substituent was achieved by use of the Reissert reaction, and involves a novel, high yield method for decomposition of the 1-benzyl-2-benzoylisoquinaldonitrile to the 1-benzyl aromatic isoquinoline. An interesting tetracyclic compound is described which arises from acid treatment of the isoquinaldonitrile, and prompted the investigation of isopavine alkaloids discussed in Chapter 2. The two possible isomeric structures for the alkaloid reframoline are synthesised by a novel route involving aminonitrile intermediates. Professor J. Slavik showed that only one of the prepared isopavines was identical by thin layer chromatographic properties and infrared spectrum with the naturally occurring alkaloid reframoline. A significant difference was observed in the U.V. spectra in alkaline solution, of the two methine bases prepared by Hofmann degradations. From the same isopavine syratheses the two related pavines were prepared, one of which confirmed the structure of the alkaloid caryachine as 2,3-niethylenedioxy-8-hydroxy-9-methoxypavinane. Nor-caryachine was also prepared and identified with caryachine by N-demethylation and N-methylation reactions. Apart from pavine itself, nor-caxyachine is the only N-H pavine known. Among some interesting side reactions observed in the above work was an exanple of the known C1 - C3, benzyl migration via the 1-benzyl-1,2-dihydroisoquinoline intermediate. This reaction is believed to be a concerted bimolecular exchange reaction, and work described in Chapter 3 confirms this by crossed migration reactions of 1,2-dihydroisoquinolines, both chiral at C1 and racemic. Two possible transition states for the reaction have been advanced prior to this work, one of which involves two molecules of the same configuration at C1 and the other, two molecules of opposite configuration. The distribution of products of various migration reactions, as shown by T.L.C. and mass spectrometry, can only be explained by the involvement of both transition states.
Date of Award1975
Original languageEnglish
Awarding Institution
  • University of Bath

Cite this