Cleavage of hindered α-methylbenzylamides, intermediates in the resolution of carboxylic acids

✍ Scribed by Francis X Webster; Jocelyn G Millar; Robert M Silverstein

• Publisher: Elsevier Science
• Year: 1986
• Tongue: French
• Weight: 188 KB
• Volume: 27
• Category: Article
• ISSN: 0040-4039
• DOI: 10.1016/s0040-4039(00)85102-3

✦ Synopsis

a-Methylbenzylamides, useful intermediates in the resolution of carboxylic acids, are cleaved with a two step procedure; enolizable amides are not racemized. The usefulness of diastereomericct-methylbenzylamides in the resolution of racemic carboxylit acids has been amply dem0nstrated.l We have found, for example, that diastereomers 3 and 4 2 prepared from racemic acid chloride 1 and the commercially available (S)-(-)-a-methylbenzylamine 2 are readily separated by preparative flash liquid chromatography on a multigram scale. Unfortunately, these amides proved remarkably difficult to cleave. Since racemization at the carbon atom next to the carboxyl group in 3 or 4 is impossible, standard hydrolytic methods were tried. -_ Potassium hydroxide in refluxing ethanol or refluxing ethylene glycol yielded starting material. Potassium hydroxide in ethylene glycol at 2OO'C in a sealed stainless steel bomb for 24 hours completely cleaved the amide, but, under these extreme conditions the ketal moiety underwent partial conversion to a hydroxyl group.' Furthermore, nucleophilic attack did not occur at the hindered carbonyl center; rather, the compound apparently underwent nucleophilic displacement at the benzylic carbon atom, resulting in the isolation of l-phenylethanol instead of the expected 1-phenylethylamine (Scheme 1). Other basic hydrolytic methods that were ineffective included