Stereoelectronic features of a complex ketene dimerization reaction

Robert D. Barrows, Mark J. Dresel, Thomas J. Emge, Paul R. Rablen, Spencer Knapp

Research output: Contribution to journalArticlepeer-review


The amidation reaction of a tetrahydroisoquinolin-1-one-4-carboxylic acid is a key step in the multi-kilogram-scale preparation of the antimalarial drug SJ733, now in phase 2 clinical trials. In the course of investigating THIQ carboxamidations, we found that propanephosphonic acid anhydride (T3P) is an effective reagent, although the yield and byproducts vary with the nature and quantity of the base. As a control, the T3P reaction of a 3-(2-thienyl) THIQ was performed in the absence of the amine, and the products were characterized: among them are three dimeric allenes and two dimeric lactones. A nucleophile-promoted ketene dimerization process subject to subtle steric and stereoelectronic effects accounts for their formation. Two novel monomeric products, a decarboxylated isoquinolone and a purple, fused aryl ketone, were also isolated, and mechanisms for their formation from the ketene intermediate are proposed.

Original languageEnglish (US)
Article number66
Issue number1
StatePublished - Jan 1 2022

All Science Journal Classification (ASJC) codes

  • Analytical Chemistry
  • Chemistry (miscellaneous)
  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery
  • Physical and Theoretical Chemistry
  • Organic Chemistry


  • Amidation
  • Arylketene
  • Carbene insertion
  • Decarbonylation
  • Decarboxylation
  • Friedel–Crafts
  • Malaria


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