Aminoisobutyric acid (AIB) is an important building block widely incorporated by medicinal chemists in molecular design. Owing to the steric challenge, elaborating AIB's carboxylic acid using conventional amidation protocols is often problematic. We discovered that an amidation protocol utilizing methyl Boc-aminoisobutyrate and magnesium amidates of various reactivities produces the corresponding amide derivatives in good to excellent yields.

4,4-Dimethyloxazolones derived from N-protected aminoisobutyric acid (AIB) are particularly known as poor electrophiles due to the steric hindrance around the carbonyl and not employed as useful intermediates for amidation whereas numerous examples have been reported to support the utility of other oxazolones in amidation. AIB is an important and strategical synthon in medicinal chemistry but the peptide bond formation of the N-protected urethane derivatives of AIB is known to be often unproductive due to the rapid formation of the stable 4,4-dimethyloxazolone via an intramolecular cyclization. We discovered that the 4,4-dimethyloxazolone of an AIB urethane is in fact an excellent electrophile that enables efficient amidation even with weakly reactive nucleophiles. The 4,4-dimethyloxazolone can be stored in a pure form and used as a reagent offering an efficient and convenient synthetic tool for generating AIB-peptide analogs.