• 10.1081/scc-200050350
  • Synthetic Communications
  • Volume 35
  • March 2005
  • pp 657-662

A Practical Synthesis of 3,3‐Difluorocyclobutane Carboxylic Acid

Steven P. Cummings, Post-Doc


This communication was outstanding in providing a vast improvement to a very dangerous and potentially synthetically challenging method in obtaining 3,3-difluorocyclobutane carboxylic acid.  Ultimately the synthesis provided greater yields, easier workups, and a less dangerous method compared to the initial report (J. Org. Chem. 1987, 52, 1872). The purpose behind the authors work was to avoid using the toxic reagent acrylonitrile and limited availability of 1,1-dichloro-2,2-difluroethene.  The purpose behind the reviewers work was to use 3,3-difluorocyclobutane carboxylic acid as an intermediate in the synthesis of 3-bromo-2,2-difluoro-cyclobutene.  The initial procedure was performed as described in the paper with slightly lower yields than described in the paper (ca. 5-10% less, likely due to the scale being performed on less than 250 mg compared to 284 g starting).  A second synthesis was repeated, this time using Xtal-Fluor with TEA:3HF as the fluorinating agent rather than DAST (primarily due to product availability) with successful results (J. Org. Chem. 2010, 75, 3401).  This second synthesis was performed on a 1 g scale and equivalent yields to the reporters were obtained.

The experimental section was adequately detailed in procedure and results describing necessary NMR and IR data were given.  Melting points, MS and elemental analysis were provided for the final product as expected.  No substantial differences were recorded during the analysis of the intermediates and final product.

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