5-Substituted Imidazole-4-acetic Acid Analogues
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 17 4155
(m, 8H), 6.92 (d, J ) 13.2, 1H), 5.70 (d, J ) 12.9, 1H), 5.23 (s,
2H), 4.51 (s, 2H), 3.65 (s, 3H) ppm. Z-isomer, NMR (CDCl3): δH
7.83-7.76 (m, 2H), 7.61 (s, 1H), 7.38-7.18 (m, 8H), 6.18 (d, J )
6.6, 1H), 5.36 (d, J ) 6.6, 1H), 5.30 (s, 2H), 4.41 (s, 2H), 3.54 (s,
3H) ppm. Both isomers, NMR (CDCl3): δC 152.7, 149.6, 138.4,
137.2, 137.2, 136.4, 136.1, 135.0, 134.8, 131.8, 128.4, 128.3, 128.1,
128.0, 127.9, 127.8, 127.7, 127.7, 126.9, 126.4, 126.3, 126.1, 123.6,
121.8, 93.4, 91.9, 74.1, 73.0, 69.8, 69.6, 60.1, 56.6 ppm. MS (EI):
m/z 320 [M]+•.
E/Z-1-(Benzyloxy)methyl-5-(2-methoxyethenyl)-4-(2-meth-
ylphenyl)imidazole (11d). Preparation was done according to the
general procedure using 10 (3.3 g, 8.8 mmol) and 2-methylben-
zeneboronic acid to afford 11d (2.3 g, 77%) as an orange oil. The
two isomers were isolated in a 10:7 ratio (E:Z), Rf ) 0.48, 0.40/
EtOAc. E-isomer, NMR (CDCl3): δH 7.55 (s, 1H), 7.38-7.28 (m,
6H), 7.24-7.13 (m, 3H), 6.62 (d, J ) 13.0, 1H), 5.58 (d, J ) 13.0,
1H), 5.29 (s, 2H), 4.53 (s, 2H), 3.51 (s, 3H), 2.28 (s, 3H) ppm.
Z-isomer, NMR (CDCl3): δH 7.62 (s, 1H), 7.38-7.28 (m, 6H),
7.24-7.13 (m, 3H), 5.98 (d, J ) 6.8, 1H), 5.35 (s, 2H), 5.18 (d, J
) 6.8, 1H), 4.46 (s, 2H), 3.31 (s, 3H), 2.32 (s, 3H) ppm. Both
isomers, NMR (CDCl3): δC 151.2, 148.4, 140.3, 138.3, 137.0,
136.9, 136.7, 136.6, 136.3, 135.2, 134.6, 130.5, 130.2, 130.0, 129.7,
128.5, 128.4, 128.1, 128.0, 127.8, 127.4, 127.0, 126.9, 125.8, 125.4,
124.8, 124.6, 123.3, 93.0, 91.8, 74.2, 73.4, 69.8, 69.7, 59.6, 56.3,
20.1, 20.0 ppm. MS (APPI): m/z 335 [M + H]+.
E/Z-1-(Benzyloxy)methyl-5-(2-methoxyethenyl)-4-(3-meth-
ylphenyl)imidazole (11e). Preparation was done according to the
general procedure using 10 (3.6 g, 9.6 mmol) and 3-methylben-
zeneboronic acid to afford 11e (2.2 g, 70%) as an orange oil. The
two isomers were isolated in a 21:19 ratio (E:Z), Rf ) 0.53, 0.44/
EtOAc. E-isomer, NMR (CDCl3): δH 7.66 (br s, 1H), 7.58 (br d,
J ) 7.3, 1H), 7.55 (s, 1H), 7.36-7.22 (m, 6H), 7.04 (br d, J ) 7.7,
1H), 6.94 (d, J ) 13.0, 1H), 5.72 (d, J ) 13.2, 1H), 5.24 (s, 2H),
4.51 (s, 2H), 3.65 (s, 3H), 2.37 (s, 3H) ppm. Z-isomer, NMR
(CDCl3): δH 7.71 (br s, 1H), 7.62 (s, 1H), 7.61 (br d, J ) 8.4,
1H), 7.36-7.22 (m, 6H), 7.06 (br d, J ) 8.2, 1H), 6.19 (d, J )
6.8, 1H), 5.37 (d, J ) 6.8, 1H), 5.31 (s, 2H), 4.41 (s, 2H), 3.55 (s,
3H), 2.37 (s, 3H) ppm. Both isomers, NMR (CDCl3): δC 152.7,
149.6, 138.7, 138.6, 137.8, 137.4, 137.3, 137.2, 136.6, 136.3, 135.0,
134.8, 128.5, 128.5, 128.4, 128.0, 128.0, 127.9, 127.8, 127.7, 127.7,
127.2, 127.0, 125.5, 124.0, 123.6, 123.6, 121.8, 93.6, 92.1, 74.1,
73.1, 69.8, 69.6, 60.0, 56.5, 21.3 ppm. MS (APPI): m/z 335 [M +
H]+.
E/Z-1-(Benzyloxy)methyl-5-(2-methoxyethenyl)-4-(4-meth-
ylphenyl)imidazole (11f). Preparation was done according to the
general procedure using 10 (2.5 g, 6.6 mmol) and 4-methylben-
zeneboronic acid to give 11f (1.7 g, 74%) as an orange oil. The
two isomers were isolated in a 14:11 ratio (E:Z), Rf ) 0.50, 0.42/
EtOAc. E-isomer, NMR (CDCl3): δH 7.68 (d, J ) 8.0, 2H), 7.57
(s, 1H), 7.37-7.27 (m, 5H), 7.19 (d, J ) 8.5, 2H), 6.93 (d, J )
13.0, 1H), 5.71 (d, J ) 13.0, 1H), 5.26 (s, 2H), 4.53 (s, 2H), 3.66
(s, 3H), 2.36 (s, 3H) ppm. Z-isomer, NMR (CDCl3): δH 7.72 (d, J
) 8.0, 2H), 7.64 (s, 1H), 7.37-7.27 (m, 5H), 7.17 (d, J ) 8.5,
2H), 6.20 (d, J ) 6.6, 1H), 5.37 (d, J ) 6.6, 1H), 5.32 (s, 2H),
4.43 (s, 2H), 3.57 (s, 3H), 2.36 (s, 3H) ppm. Both isomers, NMR
(CDCl3): δC 152.8, 149.6, 138.8, 138.7, 137.3, 137.3, 136.6, 136.3,
136.2, 135.9, 132.3, 132.1, 129.0, 128.7, 128.6, 128.5, 128.2, 128.0,
127.9, 127.9, 127.0, 126.5, 124.8, 123.4, 121.5, 93.8, 92.2, 74.2,
73.2, 69.9, 69.7, 60.1, 56.6, 21.1 ppm. HRMS (EI): m/z 334.1670
(calcd C21H22N2O3, 334.1681).
1H), 5.32 (s, 2H), 4.45 (s, 2H), 3.56 (s, 3H) ppm. Both isomers,
NMR (CDCl3): δC 162.7, 162.6, 160.6, 153.2, 150.0, 138.0, 137.8,
137.4, 137.3, 136.5, 136.3, 131.5, 131.4, 131.1, 131.1, 128.7, 128.7,
128.6, 128.5, 128.2, 128.2, 128.1, 127.9, 127.9, 123.6, 121.7, 115.2,
115.1, 114.8, 114.6, 93.2, 91.8, 74.1, 73.2, 69.9, 69.8, 60.1, 56.7
ppm. δF 61.1, 60.7 ppm. HRMS (EI): m/z 338.1432 (calcd
C20H19N2O2F, 338.1431).
E/Z-1-(Benzyloxy)methyl-2-chloro-5-(2-methoxyethenyl)-4-
phenylimidazole (14h). A solution of 11c (1.7 g, 5.2 mmol, dried
azeotropically with toluene) in dry THF (75 mL) was cooled to
-78 °C followed by dropwise addition of n-BuLi (1.6 M in hexane,
5.46 mmol). After the mixture was stirred at -78 °C for 15 min,
a solution of C2Cl6 (1.7 g, 7.3 mmol) in dry THF (3 mL) was added
dropwise. The mixture was allowed to reach room temperature and
stirred for further 5 h. Saturated aqueous NH4Cl and H2O (1:1,
200 mL) were added, and the resulting mixture was extracted three
times with EtOAc. The combined organic phases were washed with
brine, dried (MgSO4), and evaporated. DCVC of the residue
afforded 14h (1.7 g, 91%) as a yellow oil. The product was isolated
as a mixture of the E- and Z-isomers in a 13:9 ratio (E:Z), Rf )
0.38, 0.32/(1:2 EtOAc/n-heptane), which were not separated.
E-isomer, NMR (CDCl3): δH 7.79-7.75 (m, 2H), 7.38-7.22 (m,
8H), 6.91 (d, J ) 13.2, 1H), 5.65 (d, J ) 13.0, 1H), 5.34 (s, 2H),
4.63 (s, 2H), 3.67 (s, 3H) ppm. Z-isomer, NMR (CDCl3): δH 7.79-
7.75 (m, 2H), 7.38-7.22 (m, 8H), 6.23 (d, J ) 6.6, 1H), 5.37 (s,
2H), 5.36 (d, J ) 6.3, 1H), 4.51 (s, 2H), 3.56 (s, 3H) ppm. Both
isomers, NMR (CDCl3): δC 153.9, 150.6, 137.6, 137.2, 136.8,
136.6, 134.3, 134.0, 132.5, 132.1, 128.5, 128.4, 128.3, 128.1, 129.0,
128.0, 127.7, 127.7, 127.1, 126.9, 126.7, 126.6, 125.7, 123.7, 93.3,
91.8, 73.3, 72.8, 70.5, 70.4, 60.2, 56.7 ppm. MS (APPI): m/z 355
[M + H]+. Anal. (C20H19N2O2Cl) C, H, N.
E/Z-1-(Benzyloxy)methyl-5-(2-methoxyethenyl)-2-methyl-4-
phenylimidazole (14i). A solution of 11c (2.0 g, 6.1 mmol, dried
azeotropically with toluene) in dry THF (75 mL) was cooled to
-78 °C followed by dropwise addition of n-BuLi (1.6 M in hexane,
6.4 mmol). After the mixture was stirred at -78 °C for 15 min,
CH3I (1.2 g, 8.5 mmol) was added dropwise. The mixture was
allowed to reach room temperature and stirred for further 18 h.
Saturated aqueous NH4Cl and H2O (1:1, 200 mL) were added, and
the resulting mixture was extracted three times with EtOAc. The
combined organic phases were washed with brine, dried (MgSO4),
and evaporated in vacuo. DCVC of the residue afforded 14i (1.6
g, 80%) as an orange oil. The product was isolated as a mixture of
the E- and Z-isomers in a 6:5 ratio (E:Z), Rf ) 0.55, 0.47/EtOAc,
which were not separated. E-isomer, NMR (CDCl3): δH 7.81-
7.77 (m, 2H), 7.38-7.18 (m, 8H), 6.75 (d, J ) 13.0, 1H), 5.61 (d,
J ) 13.2, 1H), 5.22 (s, 2H), 4.54 (s, 2H), 3.63 (s, 3H), 2.46 (s, 3H)
ppm. Z-isomer, NMR (CDCl3): δH 7.81-7.77 (m, 2H), 7.38-7.18
(m, 8H), 6.17 (d, J ) 6.6, 1H), 5.34 (d, J ) 6.8, 1H), 5.29 (s, 2H),
4.42 (s, 2H), 3.55 (s, 3H), 2.49 (s, 3H) ppm. Both isomers, NMR
(CDCl3): δC 153.1, 149.6, 145.6, 145.1, 137.0, 136.7, 136.3, 135.3,
135.1, 128.6, 128.5, 128.4, 128.2, 128.1, 127.9, 127.9, 127.7, 127.6,
127.1, 126.6, 126.2, 126.1, 124.7, 123.5, 122.0, 94.3, 92.3, 72.9,
72.1, 69.8, 60.1, 56.6, 13.6, 13.5 ppm. HRMS (EI): m/z 334.1669
(calcd C21H22N2O2, 334.1681).
General Procedure for Hydrolysis of the Enol Ethers 10,
11c-i, and 14h,i. The enol ether was dissolved in 1,4-dioxane,
and 6 M HCl (aq) (50 equiv) was added. The reaction mixture was
heated to 70 °C for 20 min, cooled to room temperature, and poured
into saturated aqueous NaHCO3 (pH 8) followed by three extrac-
tions with EtOAc. The combined organic phases were washed with
brine, dried (MgSO4), and evaporated in vacuo. DCVC furnished
the aldehyde.
1-(Benzyloxy)methyl-5-(formylmethyl)-4-iodoimidazole (12b).
Preparation was done according to the general procedure from 10
(1.0 g, 2.8 mmol) to give 12b (0.79 g, 78%) as colorless crystals:
mp 105-107 °C, Rf ) 0.58/EtOAc. NMR (CDCl3): δH 9.62 (s,
1H), 7.53 (s, 1H), 7.41-7.33 (m, 3H), 7.27-7.24 (m, 2H), 5.24
(s, 2H), 4.40 (s, 2H), 3.81 (s, 2H) ppm. δC 195.8, 139.7, 135.3,
128.6, 128.4, 127.9, 126.1, 88.2, 74.1, 70.0, 39.8 ppm. MS
(APPI): m/z 357 [M + H]+. Anal. (C13H13N2O2I) C, H, N.
E/Z-1-(Benzyloxy)methyl-4-(4-fluorophenyl)-5-(2-methoxy-
ethenyl)imidazole (11g). Preparation was done according to the
general procedure using 10 (2.6 g, 6.9 mmol) and 4-fluoroben-
zeneboronic acid to give 11g (1.7 g, 71%) as an orange oil. The
two isomers were isolated in a 10:8 ratio (E:Z), Rf ) 0.48, 0.40/
EtOAc. E-isomer, NMR (CDCl3): δH 7.77 (dd, J ) 12.9, J ) 8.9,
2H), 7.57 (s, 1H), 7.39-7.28 (m, 5H), 7.07 (dd, J ) 8.9, J ) 2.0,
2H), 6.90 (d, J ) 12.9, 1H), 5.67 (d, J ) 12.9, 1H), 5.27 (s, 2H),
4.54 (s, 2H), 3.67 (s, 3H) ppm. Z-isomer, NMR (CDCl3): δH 7.76
(dd, J ) 12.7, J ) 8.9, 2H), 7.63 (s, 1H), 7.39-7.28 (m, 5H), 7.03
(dd, J ) 8.9, J ) 2.1, 2H), 6.21 (d, J ) 6.6, 1H), 5.34 (d, J ) 6.6,