4 h. K2CO3 (ca. 1 g) was slowly added to the reaction mixture
until the evolution of CO2 ceased. The mixture was then filtered
and the solid was washed subsequently with CH2Cl2
(15 mL × 2) and water (15 mL × 2). The aqueous layer of the
filtrate was separated and extracted with ethyl acetate (15
mL × 3). The organic phases were combined and dried over
MgSO4. Evaporation of the solvents gave compound 9 as a
ated on a rotary evaporator. Ether (400 mL) was added to the
residue, and the mixture was washed with brine (40 mL × 2).
The organic layer was separated and dried over MgSO4. After
removal of the solvents, the residue was subjected to column
chromatography on silica gel (eluent: ethyl acetate–hexane =
15:85 v/v) to give 13 as an oil (9.54 g, 95%). 1H NMR (CDCl3)
δ 7.40 (dd, J = 8.1, 1.5 Hz, 1H), 7.29 (td, J = 8.1, 1.5 Hz, 1H),
6.95–6.89 (m, 2H), 4.93 (d, J = 17.4 Hz, 1H), 4.18–4.06 (m, 2H),
3.80 (s, 3H), 3.59 (d, J = 17.4 Hz, 1H), 1.81 (s, 3H), 1.21 (t,
J = 7.2 Hz, 3H). 13C NMR (CDCl3) δ 171.48, 169.53, 154.64,
131.27, 130.26, 129.62, 120.88, 111.68, 60.95, 55.42, 49.66,
1
white solid (0.79 g, 73%). Mp 98–100 ЊC. H NMR (CDCl3)
δ 7.77 (d, J = 1.2 Hz, 1H), 7.66 (d, J = 1.2 Hz, 1H), 7.24 (td,
J = 8.0, 1.4 Hz, 1H), 7.08 (dd, J = 8.0, 1.4 Hz, 1H), 6.84 (dd,
J = 8.0, 1.4 Hz, 1H), 6.80 (td, J = 8.0, 1.4 Hz, 1H), 3.89 (s, 3H),
3.66 (br s, 2H). 13C NMR (CDCl3) δ 163.06, 141.66, 138.48,
130.45, 126.90, 126.12, 122.16, 121.71, 118.70, 116.70, 51.80.
IR (KBr) 3440, 3378, 3017, 1725, 1092, 740 cmϪ1. EIMS (m/z)
217 (Mϩ), 186, 158 (100), 132, 119, 92, 77, 65. HRMS: calcd
for C11H11N3O2 (Mϩ): 217.0851; found: 217.0850.
21.45, 14.07. IR (neat) 3010, 2980, 1742, 1650, 1175, 750 cmϪ1
.
EIMS (m/z) 251 (Mϩ), 209, 136 (100), 120, 77. HRMS: calcd for
C13H17NO4 (Mϩ): 251.1158; found: 251.1153.
Ethyl 2-mercapto-1-(o-methoxyphenyl)imidazole-5-carboxylate
(14)
Methyl 1-phenylimidazole-4-carboxylate (10)
In a dry Schlenk flask was placed a mixture of 13 (5.02 g,
20.0 mmol), ethyl formate (5.0 g, 67 mmol) and benzene (5 mL).
The flask was cooled in an ice-bath and, with constant stirring,
potassium ethoxide (1.77 g, 21.0 mmol) was added in small
portions over 15 min. The reaction mixture was maintained
below 15 ЊC, and stirred for another hour after all of the potas-
sium ethoxide had been added. The mixture was then placed in
a refrigerator to stand overnight, and then extracted with water.
To the aqueous solution were added KSCN (2.04 g, 21.0 mmol)
and 12 M HCl (3.8 mL). The mixture was heated with an oil
bath at 50–70 ЊC for 2 h, and then allowed to stand overnight at
room temperature. The mixture was extracted with ethyl acetate
(15 mL × 3) and the combined organic layer was dried over
MgSO4. After evaporation of the solvents, the residue was
subjected to column chromatography on silica gel (eluent: ethyl
acetate–hexane = 20:80 v/v) to give 14 (2.50 g, 45%). Mp
The diazotization reaction of 9 followed a literature procedure.3
The reduction product, methyl 1-phenylimidazole-4-carboxyl-
1
ate (10) was obtained in 50% yield. Mp 89–90 ЊC. H NMR
(CD3OD) δ 8.17 (d, J = 1.4 Hz, 1H), 8.12 (d, J = 1.4 Hz, 1H),
7.53 (d, J = 7.6 Hz, 2H), 7.46 (t, J = 7.6 Hz, 2H), 7.36 (t, J = 7.6
Hz, 1H), 3.76 (s, 3H). IR (KBr) 3005, 1720, 1125, 764 cmϪ1
.
EIMS (m/z) 202 (Mϩ), 171 (100), 144, 116, 104, 89, 77. HRMS:
calcd for C11H10N2O2 (Mϩ): 202.0742; found: 202.0750.
Methyl 1-(o-methoxyphenyl)imidazole-4-carboxylate (11)
A dry 100 mL Schlenk flask equipped with a reflux condenser
was charged with 2-iodoanisole (1.40 g, 6.0 mmol), methyl
imidazole-4-carboxylate (7) (0.63 g, 5.0 mmol), Cs2CO3 (1.48 g,
5.0 mmol), 4 Å molecular sieves (1 g) and anhydrous DMF (20
mL). The system was degassed by evacuation and refilling with
N2 several times. CuOTf (53 mg, 0.25 mmol) was then added to
the mixture against a slow N2 flow. The resulting mixture was
heated to 100 ЊC and stirred for 8 h. After cooling to room
temperature, the reaction mixture was filtered. The filtrate
was concentrated in vacuo while controlling the temperature at
40–50 ЊC. The residue was subjected to preparative TLC on
silica gel (eluent: CH2Cl2–hexane = 30:70 v/v saturated with
1
196 ЊC (decomp.). H NMR (CDCl3) δ 12.45 (br s, 1H), 7.46
(s, 1H), 7.44 (td, J = 7.4, 1.5 Hz, 1H), 7.30 (dd, J = 7.4, 1.5 Hz,
1H), 7.08 (t, J = 7.4 Hz, 1H), 7.03 (d, J = 7.4 Hz, 1H), 4.15–4.05
(m, 2H), 3.76 (s, 3H), 1.12 (t, J = 7.2 Hz, 3H). 13C NMR
(CDCl3) δ 157.66, 154.87, 130.77, 129.43, 125.23, 122.52,
123.17, 121.72, 120.59, 111.97, 60.85, 55.82, 13.92. IR (KBr)
3015, 2065, 1722, 1250, 1124, 1040, 750 cmϪ1. EIMS (m/z) 278
(Mϩ, 100), 245, 219, 189, 175, 77. HRMS: calcd for C13H14N2-
O3S (Mϩ): 278.0725; found: 278.0730.
1
ammonia) to give 11 (0.46 g, 40%). Mp 86–87 ЊC. H NMR
(CDCl3) δ 7.88 (d, J = 1.4 Hz, 1H), 7.74 (d, J = 1.4 Hz, 1H), 7.39
(td, J = 7.6, 1.6 Hz, 1H), 7.27 (dd, J = 7.6, 1.6 Hz, 1H), 7.08–
7.02 (m, 2H), 3.91 (s, 3H), 3.84 (s, 3H). 13C NMR (CDCl3)
δ 163.31, 152.42, 138.41, 133.33, 129.83, 126.43, 125.37, 121.05,
115.04, 112.35, 55.82, 51.67. IR (KBr) 3010, 1722, 1245, 1110,
745 cmϪ1. EIMS (m/z) 232 (Mϩ), 201, 174 (100), 147, 134, 77.
HRMS: calcd for C12H12N2O3 (Mϩ): 232.0848; found 232.0855.
Ethyl 1-(o-methoxyphenyl)imidazole-5-carboxylate (15)
A solution of concentrated nitric acid (3.3 mL) and NaNO2 (20
mg) in water (9.5 mL) was cooled to 0 ЊC in an ice-bath. To the
solution was added 14 (2.36 g, 8.5 mmol) with continuous stir-
ring. After all material had been added, the solution was stirred
for another 10 min until the evolution of nitric oxide ceased. An
excess of solid K2CO3 was added carefully with stirring. The
mixture was extracted with ethyl acetate (15 mL × 3); the
extract was dried (MgSO4) and concentrated on a rotary evap-
orator. The residue was subjected to column chromatography
on silica gel (eluent: ethyl acetate–hexane = 10:90 v/v) to give
Methyl 1-(o-hydroxyphenyl)imidazole-4-carboxylate (2)
This compound was prepared from 11 using the same pro-
cedure as for 1. Yield 90%. Mp 211–213 ЊC. 1H NMR (CDCl3)
δ 7.85 (d, J = 1.3 Hz, 1H), 7.70 (d, J = 1.3 Hz, 1H), 7.20 (td,
J = 7.8, 1.5 Hz, 1H), 7.11 (dd, J = 7.8, 1.5 Hz, 1H), 6.98–6.92
(m, 2H), 3.84 (s, 3H). 13C NMR (CDCl3) δ 164.21, 150.91,
139.21, 135.34, 128.72, 127.67, 127.48, 121.85, 111.14, 110.50,
51.67. IR (KBr) 3550, 3010, 1718, 1195, 1110, 735 cmϪ1. EIMS
(m/z) 218 (Mϩ), 187, 165, 113, 92 (100), 77, 57. HRMS: calcd
for C11H10N2O3 (Mϩ): 218.0691; found: 218.0685.
1
15 (1.80 g, 86%). Mp 90–92 ЊC. H NMR (CDCl3) δ 7.82 (s,
1H), 7.61 (s, 1H), 7.42 (t, J = 8.0 Hz, 1H), 7.23 (d, J = 8.0 Hz,
1H), 7.05–6.88 (m, 2H), 4.16 (q, J = 7.2 Hz, 2H), 3.74 (s, 3H),
1.18 (t, J = 7.2 Hz, 3H). 13C NMR (CDCl3) δ 159.19, 150.98,
131.87, 130.03, 125.65, 124.27, 122.62, 121.76, 115.33, 110.56,
61.88, 55.44, 13.43. IR (KBr) 3015, 1724, 1245, 1110, 740 cmϪ1
.
EIMS (m/z) 246 (Mϩ), 245 (Mϩ Ϫ H), 193, 176, 150, 136, 85, 64
(100). HRMS: calcd for C13H14N2O3 (Mϩ): 246.100; found:
246.100.
N-Acetyl-N-(o-methoxyphenyl)glycine ethyl ester (13)
A solution of 2-acetamidoanisole (12) (6.60 g, 40.0 mmol) in
anhydrous THF (50 mL) was cooled to 0 ЊC with an ice–water
bath. To this solution was added slowly 60% NaH in mineral oil
(1.68 g, 42.0 mmol) with constant stirring. After addition of
NaH, the mixture was stirred for another 1 h at rt, and ethyl
bromoacetate (7.02 g, 42.0 mmol) was added. The resulting
mixture was stirred for 24 h at rt. Most of the THF was evapor-
Ethyl 1-(o-hydroxyphenyl)imidazole-5-carboxylate (3)
This compound was prepared from 15 using the same pro-
cedure as for 1 except that ethanol was used to quench the
1
reaction instead of methanol. Yield 90%. Mp 215–217 ЊC. H
1220
J. Chem. Soc., Perkin Trans. 1, 2000, 1217–1221