Latent enamine functionality of 5-methyl-2,3-dihydropyrazines.
Tautomerization of methyl-substituted dihydropyrazine (DHP) derivatives to their latent enamine form was investigated theoretically and empirically. Among two types of hydrogen transfer model simulated by means of density functional theory calculation, a simple intramolecular hydrogen shift mechanism for 5,6-dimethyl-2,3-dihydropyrazine (1) and 5-methyl-6-phenyl-2,3-dihydropyrazine (3) required high activation energies for tautomerism, while a water-assisted intermolecular hydrogen transfer mechanism gave smaller activation energies (about 160 kJ/mol). Examination of the deuterium exchange reaction of 3 in 50% (v/v) D(2)O/dimethyl sulfoxide-d(6) solution revealed temperature-dependent and stepwise deuterium exchange of the 5-methyl group. Reaction of compound 3 with phenyl isocyanate in acetonitrile afforded a mono adduct (7) at the 5-methyl group, and a cyclic adduct (8). These results represent evidence of tautomerism of 5-methyl-2,3-dihydropyrazines (imine forms) to the latent enamine tautomers, and suggest that DHPs may behave as enamines to a significant degree under physiological conditions.
Ito
Shigeru
S
Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Tokyo, Japan. ito.chem@tmd.ac.jp
Hirano
Tomoya
T
Sugimoto
Akiko
A
Kagechika
Hiroyuki
H
Takechi
Shinji
S
Yamaguchi
Tadatoshi
T
D003903:Deuterium / Q000737:chemistry; D041961:Deuterium Exchange Measurement; D007536:Isomerism; D009682:Magnetic Resonance Spectroscopy; D011719:Pyrazines / Q000737:chemistry*; D013696:Temperature; D013816:Thermodynamics; D014867:Water / Q000737:chemistry
D011719:Pyrazines; D014867:Water; D003903:Deuterium