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13C NMR (100 MHz, D2O): d=179.3, 140.2, 134.3, 134.1, 130.23,
130.06, 128.1, 117.7, 48.7, 39.5 ppm; Anal. calcd
(C12H12N2O2·0.2H2O): C 65.56, H 5.69, N 12.74, found: C 65.46, H
5.36, N 12.52.
CD3OD): d=8.85 (1H, d, J=1.3 Hz), 7.44 (1H, s), 3.89 (2H, s),
3.75 ppm (3H, s). Under a nitrogen atmosphere, the crude methyl
2-(1H-imidazol-4-yl)acetate was dissolved in anhydrous DMF
(75 mL) and added Et3N (14.7 mL, 105 mmol) and trityl chloride
(10.05 g, 36.0 mmol). The mixture was stirred overnight before
EtOAc (650 mL) was added. The organic phase was washed with
saturated aqueous NaHCO3 (300 mL), H2O (700 mL), brine (300 mL),
dried over anhydrous MgSO4, filtered, and evaporated in vacuo. Pu-
rification by FC (EtOAc/petroleum ether 40–658C, 1:1) afforded 10
(12.14 g, 97% over two steps) as yellow crystals: mp 1388C (lit.[21]
2-(5-Methyl-1H-imidazol-4-yl)propanoic acid (7): The mixture of
regioisomers 15a and 15b (121 mg, 0.4 mmol) was dissolved in
aqueous HBr (48%, 10 mL) and heated at 1108C for 2 h. The mix-
ture was cooled to RT and evaporated in vacuo. Purification by
preparative HPLC (gradient 0!25% B (0.1% HCOOH) over 10 min)
afforded 7 as a white solid (40 mg, 63%): mp 2478C (decomp).
1H NMR (600 MHz, D2O): d=8.47 (1H, s), 3.80 (1H, q, J=7.5 Hz),
2.28 (3H, s), 1.50 ppm (3H, d, J=7.5 Hz); 13C NMR (150 MHz, D2O):
d=179.7, 130.9, 129.2, 125.0, 38.0, 16.6, 8.1 ppm; Anal. calcd
(C7H10N2O2·0.31HCOOH): C 52.20, H 6.36, N 16.68, found: C 52.31, H
6.03, N 16.84.
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140–1428C). H NMR (400 MHz, CDCl3): d=7.37 (1H, d, J=1.4 Hz),
7.34–7.30 (9H, m), 7.16–7.12 (6H, m), 6.79–6.77 (1H, m), 3.69 (3H,
s), 3.62 ppm (2H, d, J=0.3 Hz); 13C NMR (100 MHz, CDCl3): d=
171.8, 142.5, 138.7, 134.0, 129.9, 128.1, 119.8, 75.4, 52.0, 34.5 ppm.
(ꢁ)-Methyl 2-(1-trityl-1H-imidazol-4-yl)propanoate (11a) and
methyl 2-methyl-2-(1-trityl-1H-imidazol-4-yl)propanoate (11b):
Under a nitrogen atmosphere, a solution of 10 (4.92 g, 13.0 mmol)
in anhydrous THF (50 mL) was cooled to ꢀ788C and added
LiHMDS (1m in THF, 14.1 mL, 14.1 mmol) and DMPU (1.7 mL,
14.1 mmol) dropwise. The mixture was stirred for 1 h at ꢀ788C
before methyl iodide (0.8 mL, 13 mmol) was added in one portion.
The reaction mixture was stirred for 3 h at ꢀ788C before quench-
ing with saturated aqueous NH4Cl (100 mL) and allowed to reach
RT. H2O (150 mL) was added and the phases were separated. The
aqueous phase was extracted with CH2Cl2 (3ꢄ100 mL). The com-
bined organic phase was dried over anhydrous MgSO4, filtered,
and evaporated in vacuo. Purification by FC (EtOAc/petroleum
ether 40–658C, 3:7, 4:6, and 1:1) afforded compounds 11 a and
11 b as a white solid and a clear oil, respectively. 11 a (3.08 g, 60%):
mp 130–1318C; Rf =0.46 (EtOAc/petroleum ether 40–658C, 2:3);
1H NMR (400 MHz, CDCl3): d=7.35 (1H, d, J=1.4 Hz), 7.34–7.31
(9H, m), 7.15–7.11 (6H, m), 6.70 (1H, dd, J=0.7, 1.4 Hz), 3.77 (1H,
dq, J=0.4, 7.2, Hz), 3.68 (3H, s), 1.47 ppm (3H, d, J=7.2 Hz);
13C NMR (100 MHz, CDCl3): d=175.0, 142.6, 140.5, 138.6, 130.0,
128.17, 128.15, 118.3, 75.5, 52.1, 39.8, 17.2 ppm. 11 b (163 mg, 7%):
4,5,6,7-Tetrahydro-1H-benzo[d]imidazole-4-carboxylic acid (9a):
Under a nitrogen atmosphere, ethyl 2-oxocyclohexanecarboxylate
(5.0 mL, 31.3 mmol) was dissolved in Et2O (10 mL) and cooled to
08C. Br2 (1.61 mL, 31.3 mmol) was added dropwise over a period of
5 min, and the reaction mixture was allowed to warm to RT over
a period of 2 h. The reaction mixture was added dropwise to an
ice-cooled saturated aqueous Na2CO3 solution and extracted with
EtOAc (2ꢄ50 mL). The combined organic phase was dried over an-
hydrous MgSO4, filtered, and evaporated in vacuo to give ethyl 3-
bromo-2-oxocyclohexane-1-carboxylate as mixture of diastereo-
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mers (7.55 g, 97%) as a pale-yellow oil. H NMR (400 MHz, CD3OD):
d=4.75–4.73 (1H, m), 4.28–4.20 (2H, m), 2.49–2.41 (1H, m), 2.32–
2.24 (1H, m), 2.20–2.05 (3H, m), 1.98–1.87 (1H, m), 1.79–1.72 (1H,
m), 1.32–1.29 ppm (3H, m); 13C NMR (101 MHz, CD3OD): d=173.6,
168.0, 100.7, 62.0, 46.9, 33.3, 23.4, 18.9, 14.5 ppm. A solution of 3-
bromo-2-oxocyclohexane-1-carboxylate (1.00 g, 4.0 mmol) in neat
formamide (2.07 mL, 52.2 mmol) was heated at 1508C for 2 h.
Upon cooling, the reaction mixture was diluted with H2O (50 mL)
and washed with Et2O (2ꢄ50 mL). The aqueous phase was adjust-
ed to pH 8–9 with saturated aqueous Na2CO3 and extracted with
CHCl3 (3ꢄ50 mL). The combined organic phase was dried over an-
hydrous MgSO4, filtered, and evaporated in vacuo to give ethyl
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Rf =0.62 (EtOAc/petroleum ether 40–658C, 2:3); H NMR (400 MHz,
CDCl3): d=7.34 (1H, d, J=1.5 Hz), 7.34–7.30 (9H, m), 7.15–7.10
(6H, m), 6.66 (1H, d, J=1.5 Hz), 3.65 (3H, s), 1.52 ppm (6H, s);
13C NMR (100 MHz, CDCl3): d=176.8, 145.3, 142.5, 138.3, 129.8,
128.03, 127.98, 117.4, 75.3, 52.1, 43.2, 25.5 ppm.
4,5,6,7-tetrahydro-1H-benzo[d]imidazole-4-carboxylate as
a pale-
yellow oil (0.73 g, 93%) which was used without purification.
1H NMR (400 MHz, CDCl3): d=9.82 (1H, b s), 7.49 (1H, s), 4.22–4.14
(2H, m), 3.71–3.67 (1H, m), 2.66–2.54 (2H, m), 2.13–1.94 (3H, m),
1.83–1.73 (1H, m), 1.26 ppm (3H, t, J=7.6 Hz). Ethyl 4,5,6,7-tetrahy-
dro-1H-benzo[d]imidazole-4-carboxylate (697 mg, 3.6 mmol) was
dissolved in aqueous HBr (48%, 15 mL) and heated at 1108C for
2 h. The mixture was cooled to RT and evaporated in vacuo. Purifi-
cation by ion-exchange chromatography [Amberlite IR-120 (H+),
sample was loaded with H2O, rinsed with H2O (2ꢄ20 mL), 1,4-diox-
ane (2ꢄ10 mL), and H2O (2ꢄ10 mL), eluted with aqueous NH3 (2n,
3 mL), and evaporated in vacuo] afforded 9a as off-white crystals
(437 mg, 73%): mp 143–1458C. 1H NMR (400 MHz, D2O): d=8.32
(1H, s), 3.61 (1H, tt, J=6.3, 1.4 Hz), 2.67–2.63 (2H, m), 2.20–2.12
(1H, m), 2.05–1.96 (1H, m), 1.93–1.83 ppm (m, 2H); 13C NMR
(101 MHz, D2O): d=182.0, 133.3, 130.5, 128.6, 42.5, 28.7, 21.8,
21.7 ppm; Anal. calcd (C8H10N2O2·0.1NH3·0.3H2O): C 55.45, H 6.34, N
16.97, found: C 55.25, H 6.24, N 17.12.
Methyl 1-(1-trityl-1H-imidazol-4-yl)cyclopropane-1-carboxylate
(11c): Under nitrogen atmosphere, a stirred solution of 10 (1.0 g,
2.6 mmol) in anhydrous THF (30 mL) was cooled to 08C and added
LiHMDS (1m, 2.9 mL, 2.9 mmol). The mixture was stirred for 5 min
before 1,2-dibromoethane (0.43 mL, 2.9 mmol) was added in one
portion. The reaction mixture was allowed to reach RT and stirred
overnight before quenching with saturated aqueous NH4Cl
(20 mL). The phases were separated, and the aqueous phase was
extracted with EtOAc (3ꢄ50 mL) and Cl2CH2 (3ꢄ50 mL). The com-
bined organic phase was dried over anhydrous MgSO4, filtered,
and evaporated in vacuo. Purification by FC (EtOAc/heptane, 1:1)
resulted in 11 c (303 mg, 28%) as a white solid: mp 128–1298C.
1H NMR (400 MHz, CD3OD): d=7.41–7.36 (9H, m), 9.33 (1H, d, J=
1.5 Hz), 7.17–7.13 (6H, m), 6.99 (1H, d, J=1.5 Hz), 3.63 (s, 3H), 1.52
(2H, dd, J=3.9, 7.3 Hz), 1.27 ppm (2H, dd, J=3.9, 7.3 Hz); 13C NMR
(100 MHz, CD3OD): d=175.6, 143.6, 140.1, 138.9, 130.9, 129.4,
129.2, 122.1, 77.0, 52.6, 23.4, 18.1 ppm.
Methyl 2-(1-trityl-1H-imidazol-4-yl)acetate (10): Under a nitrogen
atmosphere, a suspension of IAA (5.31 g, 32.7 mmol) in anhydrous
MeOH (130 mL) was cooled to 08C and added AcCl (8.9 mL,
126 mmol) dropwise. Stirring was continued for 1 h at 08C and 3 h
at RT before the mixture was evaporated in vacuo to give the
crude methyl 2-(1H-imidazol-4-yl)acetate (6.4 g) as a yellow solid,
which was used without further purification. 1H NMR (300 MHz,
(ꢁ)-Methyl 2-(1-trityl-1H-imidazol-4-yl)butanoate (11d): Under
a nitrogen atmosphere, a solution of 10 (1.00 g, 3.9 mmol) in anhy-
drous THF (14 mL) was cooled to 08C and added LiHMDS (1m in
THF, 4.3 mL, 4.3 mmol). The mixture was stirred at 08C for 1 h
before ethyl bromide (0.20 mL, 2.6 mmol) was added in one por-
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ChemMedChem 2016, 11, 1 – 13
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