Mild hydrolysis or alcoholysis of amides. Ti(IV) catalyzed conversion of primary carboxamides to carboxylic acids or esters

Authors:
  • LFLawrence E. Fisher
    Lawrence E. Fisher
  • JCJoan M. Caroon
    Joan M. Caroon
  • SSS. Russell Stabler
    S. Russell Stabler
  • SLScott Lundberg
    Scott Lundberg
  • SZShahid Zaidi
    Shahid Zaidi
  • CSCarole M. Sorensen
    Carole M. Sorensen
  • MSMark L. Sparacino
    Mark L. Sparacino
  • JMJoseph M. Muchowski
    Joseph M. Muchowski
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Abstract
Reaction of primary amides (e.g., 1a or 6–13) or O-methylhydroxamates (1b and 1c) with a catalytic amount of TiCl4 and one equivalent of aqueous HCl converts these compounds in good yields to carboxylic esters (when an alcohol is used as solvent) or to carboxylic acids (when 9:1 dioxane:H2O is used as solvent). These conversions are chemoselective for primary amides: mono- and dialkyl amides are not affected by the reaction conditions. The hydrolysis conditions described do not compromise the stereochemical integrity of an adjacent chiral center. This is exemplified by the hydrolysis of naproxen amide (34) to naproxen (33) without detectable racemization as determined by chiral HPLC.