Studies on Models for Tetrahydrofolic Acid. 7. Reactions and Mechanisms of Tetrahydroquinoxaline Derivatives at the Formaldehyde Level of Oxidation

T. H. Barrows, P. R. Farina, R. L. Chrzanowski, Patricia Ann Benkovic, Stephen Benkovic

Research output: Contribution to journalArticlepeer-review

35 Scopus citations


Trapping of the formaldehyde condensation product, ethyl p-(3,4,4a,5-tetrahydroimidazo[1,5-a]quinoxalin-2(1H)-yl)benzoate (2a) in aqueous solution (pH 1-8) by sodium cyanoborohydride yields a single N-methyl product (at N-1 of the tetrahydroquinoxaline ring) which was identified by comparison with the two possible N-methyl isomers. The N-1 methyl compound reacts with formaldehyde at the N-4 and N-10 positions to give a benzotriazocine adduct (hexahydropyrimidine) whose chair conformation and stability were elucidated by high resolution NMR and kinetic studies, respectively. Below pH 2, 2a undergoes an irreversible rearrangement through the N-l iminium cation to yield 2-carbethoxy-5,6,7,8-tetrahydro-14H-quinoxo[2,1 -c] [1,4]benzodiazepine. Crossover experiments indicate that the methylene bridge of 2a is completely exchanged with added formaldehyde before yielding the benzodiazepine. The above results were interlocked with further investigations of the kinetics for condensation of formaldehyde with various para-substituted tetrahydroquinoxaline derivatives under conditions both first and zero order in formaldehyde concentration. It was demonstrated that benzotriazocine formation competes with synthesis of the imidazolidine adducts across the series. Structure-reactivity correlations were obtained that demonstrate: (1) the interconversion of benzotriazocine and imidazolidine is through formaldehyde and not an intramolecular rearrangement; (2) the exocyclic nitrogen (N-10) catalyzes the condensation of formaldehyde at the N-1 tetrahydroquinoxaline nitrogen; and (3) ring opening of the imidazolidine adduct is directed to the more stable iminium cation under kinetic and thermodynamic control. The overall mechanism then involves a reaction cascade ultimately under thermodynamic control: parent amine → benzotriazocine → imidazolidine → benzodiazepine. The initial kinetic control is imposed by differences in the condensa tion-cyclization rates at the tetrahydroquinoxaline nucleus but the overall sequence proceeds through intermolecular reactions mediated by free formaldehyde. The implications of these results to the mechanism of action of the natural cofactor.

Original languageEnglish (US)
Pages (from-to)3678-3689
Number of pages12
JournalJournal of the American Chemical Society
Issue number12
StatePublished - Jun 1 1976

All Science Journal Classification (ASJC) codes

  • Catalysis
  • General Chemistry
  • Biochemistry
  • Colloid and Surface Chemistry


Dive into the research topics of 'Studies on Models for Tetrahydrofolic Acid. 7. Reactions and Mechanisms of Tetrahydroquinoxaline Derivatives at the Formaldehyde Level of Oxidation'. Together they form a unique fingerprint.

Cite this