July 2010
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(70 mg) in acetonitrile (1 ml) was added to a stirring solution of 3 (86 mg) in
acetonitrile (1 ml), and the mixture was heated at 70 °C for 7 h. After re-
moval of solvent in reduced pressure, residue was purified by silica gel col-
umn chromatography (ethyl acetate) to give 8 (Rf 0.66) as colorless solid
(40 mg, 20%) and 7 (Rf 0.52) as yellow solid (40 mg, 28%).
Compound 7: Recrystallization from diethyl ether/n-hexane to afford yel-
1
low granules, mp 171.5—172 °C. H-NMR (CDCl3) d: 3.26 (2H, m), 3.86
(2H, t), 4.58 (1H, s), 7.02 (1H, t), 7.03 (1H, br s), 7.25 (2H, t), 7.36—7.43
(5H, m), 7.55 (2H, m), 9.11 (1H, s). 13C-NMR d: 36.1, 38.6, 90.2, 119.5,
123.4, 128.0, 128.7, 128.8, 129.6, 137.5, 138.5, 145.5, 165.2, 168.8. IR
(KBr, cmϪ1) 3314, 1644, 1583, 1310. EI-MS m/z 291 (Mϩ), 289, 199
(MϩϪPhNH), 170 (MϩϪPhNHCOH). Anal. Calcd for C18H17N3O: C,
74.20, H, 5.88, N, 14.42. Found: C, 74.29, H, 6.11, N, 14.34.
Chart 2
Compound 8: Recrystallization from methanol afforded colorless leaflet,
mp 236—236.5 °C. H-NMR (CDCl3) d: 2.23 (1H, t, Jϭ7.3 Hz), 2.67 (1H,
1
Preparation of 5-Methyl-6-phenyl-2,3-dihydropyrazine (3) A solu-
tion of ethylenediamine (5.5 mmol) in acetonitrile (4 ml) was added drop-
wise to a solution of phenylpropane-1,2-dione (5 mmol) in acetonitrile
(10 ml) at room temperature, and the mixture was stirred for 10 min. After
removal of solvent in reduced pressure, the residual gum was dissolved in
dichloromethane, and was washed with cold water for three times to remove
excess ethylenediamine. The organic layer was dried with anhydrous sodium
sulfate, and evaporated to afford the dihydropyrazine in almost pure state.
Recrystallization from n-hexane to give yellow granules in a 77% yield, mp
36—37 °C (38—39 °C,12) 34—37 °C13,14)).
1-Methyl-6-methylene-5-phenyl-1,2,3,6-tetrahydropyrazine (4) The
reaction according to mentioned above and (70 °C, 10 min) to afford 4
(181 mg, 97%) crude orange oil. Kugel Role distillation of the crude oil at
135—140 °C/0.7 Torr afforded of 4 as pale yellow oil. 1H-NMR (CDCl3) d:
2.78 (3H, s), 3.05 (2H, t, Jϭ5.6 Hz), 3.93 (2H, t, Jϭ5.6 Hz), 4.16 (1H, d,
Jϭ1.2 Hz), 4.36 (1H, d, Jϭ1.2 Hz), 7.34—7.37 (3H, m), 7.45—7.48 (2H,
m). 13C-NMR d: 39.6, 47.6, 49.6, 92.6, 127.6, 128.4, 128.6, 139.7, 144.4,
165.8. NOE was observed between H-6a and H-6b, H-6b and 1-CH3, 1-CH3
and H-2, H-2 and H-3. EI-MS m/z 186 (Mϩ), 185 (Bp), 143. Anal. Calcd for
C12H14N2: C, 77.38, H, 7.58, N, 15.04. Found: C, 77.11, H, 7.68, N, 14.92.
2-Methyl-3-phenylpyrazine A mixture of ethylenediamine (1 ml) and
phenylpropane-1,2-dione (1 mmol) was heated at 100 °C for 2.5 h. Excess
ethylenediamine was evaporated off in reduced pressure, and the residue was
poured into ice, extracted with dichloromethane for three times. The com-
bined organic layer was washed with cold water, and dried with anhydrous
sodium sulfate. After evaporation, the residue was purified by silica gel col-
umn chromatography (30% diethyl ether/n-hexane) to afford colorless oil.
Kugel Role distillation at 205 °C/2 Torr (158—160 °C/22 Torr,15) 140 °C/7
Torr16)) afforded 102 mg (65%) of 2-methyl-3-pheny1pyrazine as colorless
oil, which solidified in Ϫ20 °C freezer, mp 31—32 °C. 1H-NMR15,17)
m), 2.92—3.07 (2H, m), 3.16 (1H, m), 7.05 (1H, t, Jϭ13.2, 6.1 Hz), 7.09—
7.14 (3H, m), 7.16—7.24 (5H, m), 7.30 (2H, t), 7.36 (2H, m), 7.63 (2H, m),
8.30 (1H, d, Jϭ4.3 Hz), 10.09 (1H, s). 13C-NMR d: 37.4, 38.6, 77.9, 90.2,
111.7, 123.3, 126.4, 126.6, 127.7, 128.5, 128.6, 128.8, 129.1, 134.5, 135.5,
138.5, 164.0, 170.1, 171.0. IR(KBr, cmϪ1) 1673, 1628. EIϩ-HR-MS m/z
411.1829 (Calcd for C25H22N4O2: 411.1821). Anal. Calcd for C25H22N4O2:
C, 73.15, H, 5.40, N, 13.65. Found: C, 73.41, H, 5.68, N, 13.65.
Deuterium Exchange Experiment All experiments were carried out in
20 mM concentration solutions of 3, 4 or 2-methyl-3-phenylpyrazine in 50%
(v/v) D2O/DMSO-d6 or 50% (v/v) D2O/pyridine-d5, and were prepared
under ice-water cooling. Each sample was kept in freezer (Ϫ4 °C), at room
temperature (23 °C), and HPLC column oven kept at 37 °C and 65 °C, re-
spectively. 1H- and 13C-NMR spectra of each sample were measured without
defining an interval. Change of integral value of the 5-methyl group and that
of the combined 2,3-ethylene part of DHPs in each sample was calibrated on
the basis of the integral value of the residual proton signal of DMSO-d6 in
the solutions, respectively.
Results and Discussion
Simulation of Tautomerism of DHP In this study we
focused on two DHP derivatives 1, and unsymmetrical 3.
First, we considered the intramolecular hydrogen shift model.
The relative energies based on the DHP form and the imagi-
nary frequencies of the TS are summarized in Table 1. The
fully optimized structures of the tautomers and the geome-
try of the TS for compound 3 at the DFT B3LYP/6-
(CDCl3) d: 2.65 (3H, s), 7.43—7.51 (3H, m), 7.57—7.60 (2H, dd, Jϭ8.5, 311ϩG**//B3LYP/6-311ϩG** basis set are illustrated in
1.9 Hz), 8.45 (1H, d, Jϭ2.5 Hz), 8.49 (1H, d, Jϭ2.5 Hz).
Reaction of 4 with Phenyl Isocyanate Phenyl isocyanate (60 mg) was
added to a solution of 4 (47 mg) in acetonitrile (1 ml) at room temperature,
and the reddish solution was stirred at room temperature for 1 h. After re-
Fig. 1. The geometry of the DHP skeleton in 1 and 3, the
enamine forms, and even the TSs are closely similar to each
other. Animation based on vibrational frequency analysis in-
dicated hyperconjugative transfer of the hydrogen atom be-
tween the 5-methyl group and nitrogen at the 4-position of 1
and 3. In each case, the global minimum energy of the imine
moval of solvent in reduced pressure, the residue was purified by silica gel
column chromatography (ethyl acetate, Rf 0.12) to give 5 as a colorless solid
(47 mg, 61%). Recrystallization from methanol afforded colorless powder,
mp 234—235 °C. 1H-NMR (CDCl3) d: 2.17 (1H, br s), 2.86 (3H, s), 2.89
(2H, m), 3.00 (1H, dt, Jϭ13.2, 6.1 Hz), 3.12 (1H, dt, Jϭ13.2, 6.1 Hz), 5.08
(1H, s), 7.01—7.19 (8H, m), 7.29—7.32 (2H, m). 13C-NMR d: 39.6, 39.7,
49.3, 79.3, 89.2, 126.0, 126.3, 127.8, 128.1, 128.2, 136.4, 137.4, 167.1,
171.9. IR (KBr, cmϪ1) 1673, 1628, 1329. Anal. Calcd for C19H19N3O: C,
74.73, H, 6.27, N, 13.76. Found: C, 75.01, H, 6.49, N, 13.76.
Table 1. Summary of Energy Profile of Intramolecular Hydrogen Shift
Model
Reaction of 5 with Phenyl Isocyanate A mixture of 5 (12 mg) and
phenyl isocyanate (60 mg) was stirred for 2 h at room temperature, and the
mixture was purified by silica gel column chromatographic (5% ethyl ac-
etate/dichloromethane, then ethyl acetate, Rf 0.5) to afford 6 as colorless
solid (16 mg, 96%). Recrystallization from acetone to afford 12 mg of color-
DETs-imine
kJ/mol
DEenamine-imine
kJ/mol
Imaginary frequency
1
less prisms of 6, mp 214—215.5 °C. H-NMR (DMSO-d6) d: 2.86 (3H, s),
at TS (cmϪ1
)
2.96 (1H, dt, Jϭ12.6, 5.4 Hz), 3.12 (1H, ddd, Jϭ12.6, 7.6, 6.0 Hz), 3.52
(1H, ddd, Jϭ14.2, 7.7, 5.3 Hz), 3.89 (1H, td, Jϭ14.2, 5.4 Hz), 5.16 (1H, s),
6.89 (2H, dd, Jϭ8.6, 1.2 Hz), 6.99 (1H, dt, Jϭ7.3, 1.0 Hz), 7.02 (1H, dt,
Jϭ7.3, 1.1 Hz), 7.12 (2H, dt, Jϭ7.7, 1.8 Hz), 7.20—7.28 (5H, m), 7.33 (2H,
dd, Jϭ8.5, 1.6 Hz), 7.42 (2H, dd, Jϭ8.7, 1.1 Hz), 9.49 (1H, s). 13C-NMR d:
39.6, 46.2, 48.0, 80.7, 90.1, 119.3, 123.0, 125.9, 126.3, 127.4 128.5, 128.7,
128.7, 129.2, 137.7, 138.9, 140.0, 157.2, 165.9, 171.3. IR (KBr, cmϪ1) 1685,
1673, 1630. EI-MS m/z 424 (Mϩ), 332, 305. Anal. Calcd for C26H24N4O2: C,
73.56, H, 5.70, N, 13.20. Found: C, 73.68, H, 5.91, N, 13.01.
1: RϭMe
3: RϭPh
271a)
285b)
293c)
264a)
276b)
281c)
14a)
27b)
35c)
15a)
28b)
34c)
Ϫ1955a)
Ϫ1969b)
Ϫ2002c)
Ϫ1953a)
Ϫ1966b)
Ϫ1999c)
a) B3LYP/6-311ϩG**//B3LYP/6-311ϩG**. b) B3LYP/6-31G*//B3LYP/6-31G*.
c) B3LYP/6-31G*//B3LYP/6-31G* with aqueous solvation effect by SM8.
Reaction of 3 with Phenyl Isocyanate A solution of phenyl isocyanate