Assessment of the regioselectivity in the condensation reaction of unsymmetrical o-phthaldialdehydes with alanine

Agathe C. A. D'Hollander, Nicholas J. Westwood

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Abstract

One approach for the synthesis of isoindolinones, a privileged bioactive heterocyclic core structure, involves a condensation reaction of o-phthaldialdehydes with a suitable nitrogen-containing nucleophile. This fascinating reaction is revisited here in the context of the use of o-phthaldialdehydes that contain additional substituents in the aromatic ring leading to a detailed analysis of the regioselectivity of the reaction. Eleven monosubstituted o-phthaldialdehydes were synthesised and reacted with alanine. The regioselectivity observed across the eleven substrates led to the design of a disubstituted substrate that reacted with very high control. A gram-scale reaction followed by esterification gave one major regioisomer in high yield. In addition, the regioselectivity observed on reaction of two novel monodeuterated substrates led to an increased mechanistic understanding.
Original languageEnglish
Pages (from-to)224-239
JournalTetrahedron
Volume74
Issue number2
Early online date16 Nov 2017
DOIs
Publication statusPublished - 11 Jan 2018

Keywords

  • o-phthaldialdehyde
  • Condensation reaction
  • Regioselectivity
  • Mechanistic understanding

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