May 2006
709
1
5,6,7,8-tetrahydro-3H-cycloheptimidazol-4-one (3) and 2- 1670. H-NMR (CDCl3) d: 0.88 (3H, t, Jꢁ7.2 Hz), 1.33 (2H, m), 1.65 (2H,
m), 2.62 (2H, t, Jꢁ7.6 Hz), 5.55 (2H, s), 7.04 (2H, d, Jꢁ7.2 Hz), 7.25—7.35
propyl-3H-cycloheptimidazol-4-one (7) was examined. High
regioselectivities were observed under the reaction condi-
(3H, m), 9.75 (1H, s). MS m/z: 276 (Mꢄ), 234, 91 (B.P.).
1-Benzyl-2-butyl-5-chloro-1H-imidazole-4-carbaldehyde (12b): Colorless
tions using aq. NaOH/PTC/toluene. High regioselectivity
was observed in the use of a lower alkaline concentration for
2-propyl-5,6,7,8-tetrahydro-3H-cycloheptimidazol-4-one (5)
and a higher alkaline concentration for 2-propyl-3H-cyclo-
heptimidazol-4-one (8). Application of this alkylation under
similar conditions to non-fused 4-acylimidazole did not re-
sult in clear regioselectivity in the non-fused ketone com-
pounds. However, relatively high selectivity was observed in
the N3 alkylation to ester and aldehyde compounds.
oil. IR (neat) cmꢃ1: 3016, 1685. 1H-NMR (CDCl3) d: 0.86 (3H, t, Jꢁ
7.2 Hz), 1.34 (2H, m), 1.65 (2H, m), 2.62 (2H, t, Jꢁ7.6 Hz), 5.12 (2H, s),
7.03 (2H, d, Jꢁ7.2 Hz), 7.26—7.39 (3H, m), 9.92 (1H, s). MS m/z: 276
(Mꢄ), 234, 91 (B.P.).
3-Benzyl-5-methyl-3H-imidazole-4-carboxylic Acid Ethyl Ester (11d):
mp 60—61 °C (IPE, colorless powder). IR (KBr) cmꢃ1: 2974, 1689. 1H-
NMR (CDCl3) d: 1.30 (3H, t, Jꢁ6.8 Hz), 2.51 (3H, s), 4.24 (2H, q, Jꢁ
6.8 Hz), 5.47 (2H, s), 7.13 (2H, d, Jꢁ7.6 Hz), 7.26—7.39 (3H, m), 7.50 (1H,
s). MS m/z: 244 (Mꢄ), 198, 91 (B.P.).
1-Benzyl-5-methyl-1H-imidazole-4-carboxylic Acid Ethyl Ester (12d):
mp 64—65 °C (IPE, colorless powder). IR (KBr) cmꢃ1: 2962, 1692. 1H-
NMR (CDCl3) d: 1.40 (3H, t, Jꢁ6.8 Hz), 2.45 (3H, s), 4.37 (2H, q, Jꢁ
6.8 Hz), 5.09 (2H, s), 7.05 (2H, d, Jꢁ7.2 Hz), 7.26—7.39 (3H, m), 7.48 (1H,
s). MS m/z: 244 (Mꢄ), 198, 91 (B.P.).
Experimental
Melting points were determined on Yamato melting point apparatus and
are uncorrected. Infrared (IR) spectra were recorded on a Hitachi 270-30.
Proton nuclear magnetic resonance (1H-NMR) spectra were measured at
3-(4-Iodo-benzyl)-3H-imidazole-4-carboxylic Acid Ethyl Ester (11e): mp
400 MHz on a JEOL EX-400 Fourier-transform NMR spectrometer. Chemi- 69—70 °C (IPE, colorless powder). IR (KBr) cmꢃ1: 2974, 1704. 1H-NMR
cal shifts are quoted in part per million (ppm) with trimethylsilane as an in- (CDCl3) d: 1.32 (3H, t, Jꢁ6.8 Hz), 4.26 (2H, q, Jꢁ6.8 Hz), 5.45 (2H, s),
ternal standard. Coupling constants (J) are given in Hz. The following ab- 6.90 (2H, d, Jꢁ8.4 Hz), 7.62 (1H, s), 7.65 (2H, d, Jꢁ8.4 Hz), 7.77 (1H, s).
breviations are used: s, singlet; d, doublet; t, triplet; q, quartet; br s, broad MS m/z: 356 (Mꢄ), 217 (B.P. J), 90.
singlet; dd, doublet of doublet; m, multiplet. Mass spectra (MS) were taken
1-(4-Iodo-benzyl)-1H-imidazole-4-carboxylic Acid Ethyl Ester (12e): mp
on a Hitachi M-80B spectrometer. For column chromatography, silica gel 115—117 °C (IPE, colorless powder). IR (KBr) cmꢃ1: 2962, 1689. 1H-NMR
(Merck, Kieselgel 60, 70—230 mesh) were used.
(CDCl3) d: 1.37 (3H, t, Jꢁ6.8 Hz), 4.35 (2H, q, Jꢁ6.8 Hz), 5.08 (2H, s),
6.91 (2H, d, Jꢁ8.4 Hz), 7.54 (1H, s), 7.56 (1H, s), 7.71 (2H, d, Jꢁ8.4 Hz).
General Procedure for 3-[2ꢀ-(1-tert-Butyl-1H-tetrazol-5-yl)biphenyl-4-
ylmethyl]-2-propyl-5,6,7,8-tetrahydro-3H-cycloheptimidazol-4-one (5) MS m/z: 356 (Mꢄ), 217 (B.P.), 90.
and 3-[2ꢀ-(1-tert-Butyl-1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-2-propy-
5,6,7,8-tetrahydro-1H-cycloheptimidazol-4-one (6) To a mixture of 20%
aqueous NaOH (7 ml) and toluene (22 ml), 2-propyl-5,6,7,8-tetrahydro-3H-
cycloheptimidazol-4-one (1.02 g) and 5-(4ꢀ-bromomethyl-biphenyl-2-yl)-1- Jꢁ6.8 Hz), 5.40 (2H, s), 6.86 (2H, d, Jꢁ8.4 Hz), 7.52 (1H, s), 7.65 (2H, d,
tert-butyl-1H-tetrazole (2.20 g) was added tetra-n-butylammonium bromide
3-(4-Iodo-benzyl)-5-methyl-3H-imidazole-4-carboxylic Acid Ethyl Ester
(11f): mp 128—129 °C (EtOAc, colorless powder). IR (KBr) cmꢃ1: 2968,
1695. 1H-NMR (CDCl3) d: 1.31 (3H, t, Jꢁ6.8 Hz), 2.50 (3H, s), 4.25 (2H, q,
Jꢁ8.4 Hz). MS m/z: 370 (Mꢄ), 217 (B.P.), 90.
(0.68 g) and the mixture was stirred at room temperature for 2 h. The reac-
1-(4-Iodo-benzyl)-5-methyl-1H-imidazole-4-carboxylic Acid Ethyl Ester
tion mixture was treated with excess saturated aqueous ammonium chloride (12f): mp 146—148 °C (EtOAc, colorless powder). IR (KBr) cmꢃ1: 2968,
and extracts with toluene (3ꢂ50 ml). The combined extracts layers were 1680. 1H-NMR (CDCl3) d: 1.40 (3H, t, Jꢁ6.8 Hz), 2.43 (3H, s), 4.37 (2H, q,
washed with brine and dried over Na2SO4. The solvent was removed under Jꢁ6.8 Hz), 5.04 (2H, s), 6.79 (2H, d, Jꢁ8.4 Hz), 7.48 (1H, s), 7.68 (2H, d,
the reduced pressure. The residue was purified by silica gel column chro- Jꢁ8.4 Hz). MS m/z: 370 (Mꢄ), 217 (B.P.), 90.
matography (AcOEt/MeOHꢁ30/1, 10/1), affording pure 5 (2.14 g, 83.5%
3-Allyl-3H-imidazole-4-carboxylic Acid Ethyl Ester (11g): Oil. IR (neat)
yield) and pure 6 (0.28 g, 11.1% yield). 5: Recrystallization from iso-propyl cmꢃ1: 2971, 1685. 1H-NMR (CDCl3) d: 1.36 (3H, t, Jꢁ6.8 Hz), 4.31 (2H, q,
ether (IPE), gave colorless powder. mp 87—89 °C. IR (KBr) cmꢃ1: 2914, Jꢁ6.8 Hz), 4.94 (2H, d, Jꢁ4.4 Hz), 5.08 (1H, d, Jꢁ16.8 Hz). 5.23 (1H, d,
1620. 1H-NMR (CDCl3) d: 0.97 (3H, t, Jꢁ7.2 Hz), 1.55 (9H, s), 1.65—1.80 Jꢁ7.2 Hz), 5.94—6.05 (1H, m), 7.60 (1H, s), 7.75 (1H, s). MS m/z: 180
(2H, m), 1.80—1.95 (4H, m), 2.59 (2H, t, Jꢁ8.0 Hz), 2.60—2.70 (2H, m),
3.00 (2H, t, Jꢁ6.0 Hz), 5.56 (2H, s), 6.89 (2H, d, Jꢁ8.4 Hz), 7.10 (2H, d,
(Mꢄ), 135, 107 (B.P.).
1-Allyl-1H-imidazole-4-carboxylic Acid Ethyl Ester (12g): Oil. IR (neat)
Jꢁ8.4 Hz), 7.39 (1H, dd, Jꢁ1.6, 7.6 Hz), 7.42—7.54 (2H, m), 7.88 (2H, dd, cmꢃ1: 2972, 1686. 1H-NMR (CDCl3) d: 1.39 (3H, t, Jꢁ6.8 Hz), 4.36 (2H, q,
Jꢁ1.6, 7.2 Hz). MS m/z: 482 (Mꢄ), 178 (B.P.), 57. 6: Colorless amorphous
Jꢁ6.8 Hz), 4.58 (2H, d, Jꢁ5.6 Hz), 5.23 (1H, d, Jꢁ18.0 Hz), 5.34 (1H, d,
substance. IR (KBr) cmꢃ1: 2926, 1653. 1H-NMR (CDCl3) d: 0.96 (3H, t, Jꢁ10.4 Hz), 5.90—6.03 (1H, m), 7.49 (1H, s), 7.60 (1H, s). MS m/z: 180
Jꢁ7.2 Hz), 1.59 (9H, s), 1.69—1.82 (2H, m), 1.83—1.97 (4H, m), 2.63 (2H, (Mꢄ), 135, 107 (B.P.).
t, Jꢁ8.0 Hz), 2.71 (2H, t, Jꢁ6.0 Hz), 2.77 (2H, t, Jꢁ6.0 Hz), 5.07 (2H, s),
3-Allyl-5-methyl-3H-imidazole-4-carboxylic Acid Ethyl Ester (11h): Oil.
6.84 (2H, d, Jꢁ8.4 Hz), 7.17 (2H, d, Jꢁ8.4 Hz), 7.41 (1H, dd, Jꢁ1.6, IR (neat) cmꢃ1: 2962, 1684. 1H-NMR (CDCl3) d: 1.37 (3H, t, Jꢁ6.8 Hz),
7.6 Hz), 7.45—7.54 (2H, m), 7.90 (2H, dd, Jꢁ1.6, 7.6 Hz). MS m/z: 482 2.49 (3H, s), 4.32 (2H, q, Jꢁ6.8 Hz), 4.88 (1H, d, Jꢁ5.2 Hz), 5.06 (1H, d,
(Mꢄ), 178 (B.P.), 57.
The following compounds 8, 9, 11a—j and 12a—j were prepared using a
procedure similar to that described 5 and 6 from the corresponding imida-
zole compounds and alkylhalides.
Jꢁ18.8 Hz), 5.20 (1H, d, Jꢁ11.2 Hz), 5.99 (1H, ddd, Jꢁ5.2, 11.2, 18.8 Hz),
7.47 (1H, s). MS m/z: 194 (Mꢄ, B.P.), 165, 149.
1-Allyl-5-methyl-1H-imidazole-4-carboxylic Acid Ethyl Ester (12h): Oil.
IR (neat) cmꢃ1: 2969, 1682. 1H-NMR (CDCl3) d: 1.40 (3H, t, Jꢁ7.2 Hz),
3-[2ꢀ-(1-tert-Butyl-1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-2-propyl-3H- 2.50 (3H, s), 4.35 (2H, q, Jꢁ7.2 Hz), 4.50 (1H, d, Jꢁ4.8 Hz), 4.99 (1H, d,
cycloheptimidazol-4-one (8): mp 117—119 °C (EtOAc, colorless powder). Jꢁ17.2 Hz), 5.27 (1H, d, Jꢁ10.8 Hz), 5.91 (1H, ddd, Jꢁ4.8, 10.8, 17.2 Hz),
1
IR (KBr) cmꢃ1: 2956, 1575. H-NMR (CDCl3) d: 1.02 (3H, t, Jꢁ7.2 Hz),
7.42 (1H, s). MS m/z: 194 (Mꢄ), 149 (B.P.), 122.
3-Benzyl-3,5,6,7-tetrahydro-benzimidazol-4-one (11l): mp 66—67 °C
1.51 (9H, s), 1.84 (2H, m), 2.77 (2H, t, Jꢁ7.6 Hz), 6.03 (2H, s), 6.89—7.00
(1H, m), 6.95 (1H, d, Jꢁ8.0 Hz), 7.10 (1H, d, Jꢁ8.0 Hz), 7.10 (1H, Jꢁ (IPE, colorless powder). IR (KBr) cmꢃ1: 2932, 1662. H-NMR (CDCl3) d:
1
12.0 Hz), 7.19 (1H, dd, Jꢁ8.0, 12.0 Hz), 7.38 (1H, dd, Jꢁ1.6, 7.2 Hz),
2.14 (2H, m), 2.52 (2H, t, Jꢁ6.2 Hz), 2.86 (2H, t, Jꢁ6.2 Hz), 5.46 (2H, s),
7.43—7.54 (2H, m), 7.71 (1H, d, Jꢁ11.2 Hz), 7.88 (1H, dd, Jꢁ1.6, 8.8 Hz). 7.26 (2H, m), 7.34 (3H, m), 7.55 (1H, s). MS m/z: 226 (Mꢄ), 91 (B.P.), 65.
MS m/z: 478 (Mꢄ), 178 (B.P.), 57.
1-Benzyl-1,5,6,7-tetrahydro-benzimidazol-4-one (12l): Colorless oil. IR
3-[2ꢀ-(1-tert-Butyl-1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-2-propyl-1H- (neat) cmꢃ1: 2926, 1662. 1H-NMR (CDCl3) d: 2.14 (2H, m), 2.66 (2H, t, Jꢁ
cycloheptimidazol-4-one (9): mp 82—84 °C (EtOAc, colorless powder). IR 6.4 Hz), 2.86 (2H, t, Jꢁ6.4 Hz), 5.10 (2H, s), 7.26 (2H, m), 7.34 (3H, m),
(KBr) cmꢃ1: 2956, 1579. H-NMR (CDCl3) d: 1.02 (3H, t, Jꢁ7.2 Hz), 1.54
7.57 (1H, s). MS m/z: 226 (Mꢄ), 91 (B.P.), 65.
1-(3-Benzyl-3H-imidazol-4-yl)ethanone (11m): mp 103—104 °C (IPE,
1
(9H, s), 1.88 (2H, m), 2.87 (2H, t, Jꢁ8.0 Hz), 5.40 (2H, s), 6.80 (1H, dd, Jꢁ
8.8, 11.6 Hz), 6.90 (2H, d, Jꢁ8.0 Hz), 7.10 (1H, d, Jꢁ8.0 Hz), 7.10 (1H, d, colorless powder). IR (neat) cmꢃ1: 3088, 1656. 1H-NMR (CDCl3) d: 2.45
Jꢁ12.0 Hz), 7.31 (1H, d, Jꢁ12.0 Hz), 7.39 (1H, dd, Jꢁ1.6, 7.2 Hz), 7.43— (3H, s), 5.53 (2H, s), 7.17 (2H, d, Jꢁ8.0 Hz), 7.31 (3H, m), 7.63 (1H, s),
7.54 (2H, m), 7.90 (1H, dd, Jꢁ1.6, 8.8 Hz). MS m/z: 478 (Mꢄ), 178 (B.P.), 7.81 (1H, s). MS m/z: 200 (Mꢄ), 158, 91 (B.P.).
57.
3-Benzyl-2-butyl-5-chloro-3H-imidazole-4-carbaldehyde (11b): mp 93—
1-(1-Benzyl-1H-imidazol-4-yl)ethanone (12m): mp 62—63 °C (IPE, col-
orless powder). IR (neat) cmꢃ1: 3100, 1662. 1H-NMR (CDCl3) d: 2.55 (3H,
95 °C (i-PrOH, colorless powder, Lit. 94—96 °C). IR (KBr) cmꢃ1: 3009, s), 5.14 (2H, s), 7.19 (2H, d, Jꢁ8.0 Hz), 7.36 (3H, m), 7.54 (1H, s), 7.57