Studies On Models For The Tetrahydrofolic Acid. IV. Reactions Of Amines With Formamidinium Tetrahydroquinoxaline Analogs

The condensation of amines with formamidinium model compounds for 5,10-methenyltetrahydrofolic acid leads to N-formimidoyl products. The reaction involves decomposition of a presumed orthoamide intermediate to yield the formamidine product of kinetic control; the latter then isomerizes to the thermodynamically more stable N-formimidoyl derivative. In the absence of intramolecular effects, efficient transfer of the one-carbon unit to yield the N-formyl amine generally requires the pK_a of the condensing amine to be less than the pK_a of the formamidine nitrogens owing to the need for amine protonation prior to expulsion. The implications of kinetic vs. thermodynamic control for the mechanisms of folate catalyzed transfer reactions are discussed.