The cyclisation of benzylaminoacetonitriles: Evidence of exclusive participation of a spirocyclic intermediate.

  • Fazal Hussain

Student thesis: Doctoral ThesisPhD


A survey has been made of isoquinoline preparation via Pomeranz-Fritsch and benzylaminoacetonitrile syntheses. Over the past fifteen years considerable effort has been made to establish the mechanism by which cyclisations of 3,4-dialkoxybenzylaminonitriles proceeds. Initially a dual mechanism was postulated, one mode involving an electrophilic attack para to the C3-substituent and the second involving attack para to the C4-substituent. Recent evidence from the cyclisations of the isomeric ethoxymethoxybenzylaminoacetonitriles suggested that only the second mechanism may be operating, giving a spiro-intermediate which undergoes rearrangement to an iminium ion, followed by a Pictet-Spengler cyclisation. However, since no attempt has been made to fully characterise the composition of the crude reaction products (dialkoxy and phenolic isoquinolinones), the classical cyclisation could not be precluded. The work described in this thesis involves preparation and cyclisation of a series of aminonitriles at three different temperatures, -10°, room temperature and 50° followed by chromatographic analysis (t.l.c.) and separation of the crude products. All results obtained indicate that cyclisation proceeds exclusively via the spiro-intermediate. No products arising from classical cyclisation were obtained. The yield of the products obtained from all cycli-sations depended upon the temperature of the reactions. For example, at -10° and room temperature the major products are dialkoxyisoquinolinones, whereas at 50° O-dealkylation readily occurs to give phenolic products. Orientation of substitution was unequivocally established by means of 1H n.m.r. (NaOD shift), ultra-violet spectroscopy and by preparing 4-benzyl-4-hydroxy-1,2,3,4-tetrahydroisoquinoline derivatives. A minor part of this work involves a reinvestigation of the cyclisation of 3,4-dimethoxybenzyIglycine esters to establish whether the above mechanism ws involved. However, unlike the nitriles, the glycine esters failed to cyclise readily in sulphuric acid.
Date of Award1985
Original languageEnglish
Awarding Institution
  • University of Bath

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