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Latent enamine functionality of 5-methyl-2,3-dihydropyrazines
Shigeru Ito1, Tomoya Hirano, Akiko Sugimoto
1Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Tokyo, Japan. ito.chem@tmd.ac.jp
Chemical & Pharmaceutical Bulletin
|July 8, 2010
Summary
Methyl-substituted dihydropyrazines (DHPs) tautomerize to enamine forms. Water-assisted hydrogen transfer lowers activation energy, suggesting DHPs act as enamines under physiological conditions.
Area of Science:
- Organic Chemistry
- Theoretical Chemistry
- Physical Chemistry
Background:
- Dihydropyrazine (DHP) derivatives exhibit tautomerism.
- Understanding tautomeric equilibria is crucial for predicting chemical reactivity.
Purpose of the Study:
- Investigate the tautomerization of methyl-substituted dihydropyrazines (DHPs) to their enamine forms.
- Determine the mechanisms and energetics of DHP tautomerization.
- Assess the potential for DHPs to act as enamines under physiological conditions.
Main Methods:
- Density functional theory (DFT) calculations to simulate hydrogen transfer mechanisms.
- Empirical investigation using deuterium exchange reactions.
- Reactions with phenyl isocyanate to identify adducts.
Main Results:
- A water-assisted intermolecular hydrogen transfer mechanism showed significantly lower activation energies (~160 kJ/mol) compared to intramolecular hydrogen shifts.
- Deuterium exchange experiments confirmed temperature-dependent, stepwise deuterium incorporation in the 5-methyl group of compound 3.
- Reactions with phenyl isocyanate yielded mono and cyclic adducts, supporting the enamine character.
Conclusions:
- Methyl-substituted DHPs tautomerize to latent enamine forms.
- Water significantly facilitates DHP tautomerization by lowering activation barriers.
- DHPs likely exhibit significant enamine character under physiological conditions, impacting their reactivity and biological roles.
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