Model Studies for the Mechanism of Inactivation of Monoamine Oxidase by 5-(Aminomethyl)-3-ary1-2-oxazolidinones

3-[4-[(3-Chlorophenyl)methoxylphenyl]-5-[(methylamino)methyl]-2-oxazolidinone (MD 780236) has been reported to be an irreversible inactivator of monoamine oxidase (MAO), but the mechanism of inactivation is not known. A mechanism is now proposed that involves one-electron transfer to give the corresponding amine radical cation, removal of an a-proton, and decomposition of the oxazolidinone ring with loss of CO₂to another radical which attaches to an enzyme active site radical. Chemical model studies for the proposed inactivation mechanisms are reported. Treatment of 3-(4-methoxyphenyl)-5-(chloromethyl)-2-oxazolidinone with tributylstannane and AIBN at 190 °C gave N-allylanisidine (6%) and CO₂in addition to the hydrogen atom rebound product 3-(4-methoxypheny1)-5-methyl-2-oxazolidinone. A high yield of N-allylanisidine was obtained by treatment of the corresponding bromo analogue with zinc, magnesium, or n-butyllithium. These studies support a radical inactivation mechanism that may proceed through additional carbon radical or carbanion intermediates. MD 780236 labeled with ¹⁴C at the carbonyl of the oxazolidinone ring inactivates MAO with loss of ¹⁴CO₂, consistent with the model study results.