Synthesis of 1,2,5-Trisubstituted 1H-Imidazoles
J . Org. Chem., Vol. 62, No. 24, 1997 8453
(CDCl3) δ 1.41 (d, 6H, J ) 6.3 Hz), 4.48 (septet, 1H, J )
6.3 Hz), 7.67 (s, 1H), 9.09 (s, 1H); 13C NMR (CDCl3) δ
22.4, 80.9, 105.2, 166.7, 184.3.
46.0, 52.2, 126.7 (2), 129.8, 130.3 (2), 141.9, 166.6, 171.0;
HRMS calcd for C14H21N2O2 (M + H)+, 249.1603, found
249.1596.
Meth yl 4-[(2-Bu tyl-5-for m yl-1H-im id a zol-1-yl)m -
eth yl]ben zoa te (6a ) a n d Its Regioisom er Meth yl
4-[(2-Bu t yl-4-for m yl-1H -im id a zol-1-yl)m et h yl]b en -
zoa te (7a ) via th e Alk yla tion of 2-Bu tyl-1H-im id a -
zole-4-ca r boxa ld eh yd e (4). A solution of 2-butyl-1H-
imidazole-4-carboxaldehyde (4)3 (30.4 g, 200 mmol) in
DMF (90 mL) was treated with a 40% aqueous solution
of tetraethylammonium hydroxide (76.7 g, 220 mmol).
After being stirred for 1 h, the reaction was cooled to 0
°C and treated dropwise with a solution of methyl
4-(bromomethyl)benzoate (50.5 g, 220 mmol) in DMF (60
mL) so that the internal temperature did not exceed 10
°C. Stirring was continued for 1 h at 0 °C and 2 h at
ambient temperature. The reaction mixture was quenched
into 5% aqueous sodium chloride solution (150 mL) and
extracted with ethyl acetate (2 × 150 mL). The combined
ethyl acetate layers were washed with water (150 mL).
Isomers 6a and 7a were separated by forming their
bisulfite salts in ethyl acetate. The less soluble bisulfite
adduct of 7a crystallized from the reaction medium
first. It was converted back to 7a in 54% overall yield
with saturated sodium carbonate solution. Imidazole
7a was converted to its carboxylic acid derivative 7k for
characterization: mp 197-198 °C; IR (KBr) 3430, 3100-
3000, 3000-2800, 2789, 1702, 1680, 1612, 1546, 1517,
Gen er a l P r oced u r e for th e P r ep a r a tion of 1,2-
Disu bstitu ted 5-F or m yl-1H-im id a zoles 6a -j. A solu-
tion of amidine 12a -j (30.0 mmol) and 14 (8.69 g, 45.0
mmol) in chloroform (60 mL) and water (7.5 mL) was
treated with solid potassium carbonate (6.22 g, 45.0
mmol) and stirred at ambient temperature for 18 h. The
reaction mixture was partitioned between methylene
chloride and water. The organic phase was washed with
water and brine and dried (MgSO4). The product was
isolated by flash chromatography on silica with 5% (v/v)
acetonitrile/methylene chloride as eluant.
Meth yl 4-[(2-bu tyl-5-for m yl-1H-im id a zol-1-yl)m -
eth yl]ben zoa te (6a ) was obtained as a white solid in
52% yield after recrystallization from tert-butyl methyl
ether: mp 72-74 °C; IR (KBr) 3400, 3100-3000, 3000-
2800, 2750, 1715, 1663, 1614, 1527, 1465, 1286, 1161,
1107, 804, 749, 717 cm-1; 1H NMR (CDCl3) δ 0.88 (t, 3H,
J ) 7.4 Hz), 1.30-1.39 (m, 2H), 1.65-1.73 (m, 2H), 2.64
(t, 2H, J ) 7.8 Hz), 3.90 (s, 3H), 5.63 (s, 2H), 7.07 (d, 2H,
J ) 8.3 Hz), 7.82 (s, 1H), 7.99 (d, 2H, J ) 8.3 Hz), 9.67
(s, 1H); 13C NMR (CDCl3) δ 13.7, 22.4, 26.5, 29.3, 47.9,
52.2, 126.2 (2), 129.8, 130.2 (2), 131.3, 141.2, 143.7, 156.7,
166.6, 178.8. Anal. Calcd for C17H20N2O3: C, 67.98; H,
6.71; N, 9.33. Found: C, 67.90; H, 6.77; N, 9.17.
1
1463, 1416, 1313, 1270, 1159, 1092, 1016, 824 cm-1; H
4-[(2-Bu tyl-5-for m yl-1H-im id a zol-1-yl)m eth yl]ben -
zoic Acid (6k ). A solution of 12k (30.0 mmol) and 14
(8.69 g, 45.0 mmol) in chloroform (60 mL) and water (7.5
mL) was treated with solid potassium carbonate (6.22 g,
45.0 mmol) and refluxed under nitrogen for 8 h. As the
reaction proceeded, the initially heterogeneous reaction
mixture became homogeneous. After cooling, water (30
mL) was added. The aqueous phase was washed with
methylene chloride (2 × 30 mL). The pH of the aqueous
phase (typically 9.0-10.5) was adjusted to 5.0-5.3 by the
addition of 10% aqueous HCl and then extracted with
methylene chloride (3 × 30 mL). The combined organic
phases were washed with water (30 mL) and brine (30
mL) and dried (MgSO4). After concentration and recrys-
tallization from 2-butanone:ethyl acetate, the product
was obtained as a white solid in 83% yield: mp 147-
148 °C; IR (KBr) 3400, 3100-3000, 3000-2800, 2750,
2600, 1684, 1663, 1612, 1578, 1539, 1488, 1468, 1319-
NMR (acetone-d6) δ 0.84 (t, 3H, J ) 7.4 Hz), 1.22-1.31
(m, 2H), 1.47-1.57 (m, 2H), 2.63 (t, 2H, J ) 7.8 Hz), 4.81
(s, 1H), 5.34 (s, 2H), 7.25 (d, 2H, J ) 8.3 Hz), 7.92 (s,
1H), 8.00 (d, 2H, J ) 8.3 Hz), 9.68 (s, 1H); 13C NMR
(acetone-d6) δ 12.5, 21.9, 25.9, 29.3, 51.0, 126.7 (2), 129.6,
130.1 (2), 130.9, 139.8, 140.8, 152.0, 168.0, 184.2; MS (CI,
CH4) m/z 287 (M + H). Anal. Calcd for C16H18N2O3: C,
67.12; H, 6.34; N, 9.78. Found: C, 67.09; H, 6.41; N, 9.54.
A 40% yield of 6a was obtained as a white solid. Its
spectral data and mp are reported below.
Gen er a l P r oced u r e for th e P r ep a r a tion N-Mon o-
su bstitu ted Am id in es 12a -l). Under nitrogen, a solu-
tion of the imidate hydrochloride 2a or 2b (140 mmol) in
DMF (100 mL) at 0 °C was treated with triethylamine
(19.6 mL, 140 mmol). The resultant suspension was
stirred for 1 h at ambient temperature and then filtered.
The filter cake of triethylamine hydrochloride was washed
with DMF (10 mL). The combined filtrates were trans-
ferred to a clean vessel under nitrogen and treated with
the amine (100 mmol) and triethylamine (14.0 mL, 100
mmol). The reaction was heated at 60 °C for 16 h. After
cooling, the reaction mixture was partitioned between
ethyl acetate and water. The organic phase was washed
with water and brine and dried (MgSO4). Volatile
solvents were removed in vacuo. The resulting amidines
were generally used in the next step without further
purification. In the cases of 12k and 12l the reaction
mixture remained heterogeneous throughout. After cool-
ing to 20 °C, the amidine product was isolated by
filtration and dried.
1
1244, 1157, 805, 779, 754 cm-1; H NMR (DMSO-d6) δ
0.81 (t, 3H, J ) 7.4 Hz), 1.23-1.32 (m, 2H), 1.52-1.59
(m, 2H), 2.65 (t, H, J ) 7.6 Hz), 5.67 (s, 2H), 7.11 (d, 2H,
J ) 8.2 Hz), 7.91 (d, 2H, J ) 8.2 Hz), 7.96 (s, 1H), 9.67
(s, 1H); 13C NMR (DMSO-d6) δ 13.4, 21.5, 25.3, 28.7, 47.0,
126.1 (2), 129.6 (2), 129.8, 131.0, 141.7, 143.4, 156.0,
166.8, 179.3. Anal. Calcd for C16H18N2O3: C, 67.12; H,
6.34; N, 9.78. Found: C, 67.11; H, 6.45; N, 9.71.
Gen er a l P r oced u r e for th e P r ep a r a tion of 1,2-
Disu bstitu ted 5-Cya n o-1H-im id a zoles 16a -h . A so-
lution of amidine 12a -h (30.0 mmol) and 2-bromo-3-
methoxy-2-propenenitrile (18) (7.29 g, 45.0 mmol) in
chloroform (60 mL) and water (7.5 mL) was treated with
solid potassium carbonate (6.22 g, 45.0 mmol) and heated
to reflux for 18 h. After cooling, the reaction mixture
was partitioned between methylene chloride and water.
The organic phase was washed with water and brine and
dried (MgSO4). The product was isolated by flash chro-
matography on silica with 1:1 ether:petroleum ether as
eluant.
Meth yl 4-[[N-(1-im in op en tyl)a m in o]m eth yl]ben -
zoa te (12a ) was obtained as a colorless oil in 93% yield:
IR (neat) 3250, 3100-3000, 3000-2800, 1724, 1642,
1614, 1572, 1402, 1281, 1110, 756 cm-1; 1H NMR (CDCl3)
δ 0.89 (t, 3H, J ) 7.3 Hz), 1.29-1.38 (m, 2H), 1.54-1.61
(m, 2H), 2.28 (t, 2H, J ) 7.7 Hz), 3.88 (s, 3H), 4.43 (s,
2H), 6.07 (br, 2H), 7.35 (d, 2H, J ) 7.9 Hz), 7.94 (d, 2H,
J ) 7.9 Hz); 13C NMR (CDCl3) δ 13.5, 22.3, 28.1, 29.5,