90 ◦C. Reaction progress was monitored by TLC. The reaction
mixture was diluted with water and extracted by ethylacetate;
organic layer was washed by water and brine, dried (anhyd.
Na2SO4) and evaporated under reduced pressure to yield crude
product, which was chromatographed on silica gel (petroleum
ether 60–90 ◦C : ethyl acetate = 20 : 1) to afford the products 5
(71–90%) as yellow oil. See ESI file for characterization data.†
119.69, 110.58, 81.73, 50.48, 32.50. HRMS (ESI-TOF) m/z Calcd
for C12H12ClN2O [M+H]+ 235.0638, found 235.0588.
Compound 7d. Yield 36%. Yellow oil. IR (KBr) 3120, 2924,
2852, 1708, 1601, 1475, 1303, 1234, 1168, 1017, 809, 678 cm-1. 1H-
NMR (300 MHz, CDCl3) d: 7.36 (1H, s), 7.06–7.01 (2H, m), 6.65
(1H, d, J = 8.4 Hz), 4.97–4.90 (1H, m), 3.99 (2H, d, J = 5.7 Hz), 3.25
(1H, dd, J = 15.9, 9.2 Hz), 2.84 (1H, dd, J = 16.0, 7.0 Hz), 2.11 (6H,
s). 13C-NMR (75 MHz, CDCl3) d: 157.36, 135.42, 133.83, 128.30,
127.42, 125.70, 125.16, 122.22, 110.57, 81.76, 48.30, 32.67, 12.72,
8.58. HRMS (ESI-TOF) m/z Calcd for C14H15ClN2O [M+H]+
263.0951, found 263.0946.
Synthesis of compounds 6a–6d. Pd/C (10 wt% Pd on car-
bon; 15 mol%) was added to a solution of 2-(azidomethyl)-
dihydrobenzofuran derivatives 5 (1 mmol) in ethanol (50 ml)
and the reaction mixture was stirred at room temperature under
hydrogen atmosphere for 5–12 h. Reaction progress was monitored
by TLC. The catalyst was filtered off and the solvent was
evaporated to give a residue, which was purified by short silica
gel column (ethyl acetate : methanol : Et3N = 10 : 1 : 0.1) to afford
the products 6 (73–99%) as a colorless oil. See ESI file for
characterization data.†
Compound 7e. Yield 45%. Yellow oil. IR (KBr) 3050, 2923,
1
2852, 1675, 1601, 1500, 1445, 1289, 1227, 1027, 833 cm-1. H-
NMR (300 MHz, CDCl3) d: 7.54 (1H, s), 7.05 (1H, s), 7.02 (1H,
s), 6.50 (1H, s), 6.46 (1H, s), 5.02–4.92 (1H, m), 4.16 (2H, d, J =
5.4 Hz), 3.16 (1H, dd, J = 15.5, 9.3 Hz), 2.72 (1H, dd, J = 15.6,
7.2 Hz), 2.29 (3H, s), 2.25 (3H, s). 13C-NMR (75 MHz, CDCl3)
d: 158.65, 138.57, 137.70, 134.47, 129.54, 122.79, 121.42, 119.70,
107.72, 81.13, 50.79, 31.44, 21.39, 18.82. HRMS (ESI-TOF) m/z
Calcd for C14H17N2O [M+H]+ 229.1341, found 229.1301.
Synthesis of compounds 7a–7d. To a magnetically stirred
solution of the 30% aq. glyoxal or 2,3-butanedione (1.2 mmol) and
37% aq. formaldehyde (1.2 mmol) in methanol (30 mL) at 70 ◦C,
2-(aminomethyl)-dihydrobenzofurans 6 (1.0 mmol) and 25% aq.
ammonia (1.2 mmol) was added and reaction mixture was stirred
for 4 h at the same temperature. Reaction progress was monitored
by TLC. After removed the solvent, the dark residue was poured
into ice water (20 mL) and extracted by ethylacetate; organic
layer was washed by water and brine, dried (anhyd. Na2SO4). The
solvent was evaporated under reduced pressure and the residue was
chromatographed on silica gel (ethyl acetate : methanol : Et3N =
20 : 1 : 0.1) to afford the products 7 (36–60%) as yellow oil or
powder.
Synthesis of compounds 8–37.
dihydrobenzofuran-substituted imidazoles
A
mixture of 1-
(1 mmol) and
7
phenacyl bromides or alkyl bromides (1.2 mmol) was stirred in
dioxane (10 mL) at reflux for 8–16 h. An insoluble substance was
formed. After completion of the reaction as indicated by TLC, the
precipitate was filtered through a small pad of Celite, and washed
with toluene (3 ¥ 10 mL), then dried to afford imidazolium salts
8–37 in 65–96% yields. See ESI file for characterization data.†
Cytotoxicity assay. The assay was in five kinds of cell lines
(HL-60, SMMC-7721, A549, MCF-7 and SW480). Cells were
cultured at 37 ◦C under a humidified atmosphere of 5% CO2
in RPMI 1640 medium supplemented with 10% fetal serum
and dispersed in replicate 96-well plates. Compounds were
then added. After 48 h exposure to the compounds, cells
viability were determined by the [3-(4,5-dimethylthiazol-2-yl)-
2,5-diphenyltetrazolium bromide] (MTT) cytotoxicity assay by
measuring the absorbance at 570 nm with a microplate spectropho-
tometer. Each test was performed in triplicate.
Compound 7a. Yield 60%. Yellow oil. IR (KBr) 3105, 2929,
2852, 1597, 1475, 1230, 1020, 865, 750 cm-1. 1H-NMR (300 MHz,
CDCl3) d: 7.50 (1H, s), 7.08 (2H, t, J = 7.8 Hz), 7.01 (1H, s),
6.98 (1H, s), 6.84–6.74 (2H, m), 4.97–4.88 (1H, m), 4.16–4.05
(2H, m), 3.24 (H, dd, J = 15.7, 9.3 Hz), 2.82 (1H, dd, J = 15.7,
7.1 Hz). 13C-NMR (75 MHz, CDCl3) d: 158.58, 137.60, 129.38,
128.30, 125.38, 124.96, 120.93, 119.63, 109.57, 80.97, 50.53, 32.53.
HRMS (ESI-TOF) m/z Calcd for C12H13N2O [M+H]+ 201.1028,
found 201.1020.
Acknowledgements
Compound 7b. Yield 55%. Yellow powder, mp 66–67 ◦C. IR
(KBr) 3104, 2989, 2944, 2839, 1604, 1493, 1438, 1240, 1195, 1024,
844, 802 cm-1. 1H-NMR (300 MHz, CDCl3) d: 7.53 (1H, s), 7.04
(1H, s), 7.01 (1H, s), 6.71–6.63 (3H, m), 4.99–4.96 (1H, m), 4.16
(2H, d, J = 5.3 Hz), 3.72 (3H, s), 3.27 (1H, dd, J = 15.4, 9.2 Hz),
2.84 (1H, dd, J = 15.8, 7.2 Hz). 13C-NMR (75 MHz, CDCl3)
d: 154.53, 152.76, 137.68, 129.54, 126.42, 119.70, 113.34, 111.33,
109.61, 81.23, 56.00, 50.63, 33.12. HRMS (ESI-TOF) m/z Calcd
for C13H15N2O2 [M+H]+ 231.1134, found 231.1133.
This work was supported by grants (30960460, 20925205 and
20832005) from National Natural Science Foundation of China
and a grant (2009CB522300) from National Basic Research
Program of China (973 Program).
Notes and references
1 (a) M. Getlik, C. Gru¨tter, J. R. Simard, S. Klu¨ter, M. Rabiller, H. B.
Rode, A. Robubi and D. Rauh, J. Med. Chem., 2009, 52, 3915; (b) R.
Morphy, C. Kay and Z. Rankovic, Drug Discovery Today, 2004, 9,
641; (c) A. Natarajan, Y. Guo, F. Harbinski, Y. H. Fan, H. Chen, L.
Luus, J. Dierck, H. Aktas, M. Chorey and J. A. Halperin, J. Med.
Chem., 2004, 47, 4979; (d) R. Romagnoli, P. G. Baraldi, J. B. Tabrizi,
F. Estec´vez, M. Borgatti and R. Gambari, J. Med. Chem., 2005, 48,
7906; (e) P. G. Baraldi, R. Romagnoli, A. E. Guadix, M. J. P. de Ias
Infantas, M. A. Gallo, A. Espinosa, A. Martinez, J. P. Bingham and
J. A. Hartley, J. Med. Chem., 2002, 45, 3630; (f) A. R. Shrestha, T.
Shindo, N. Ashida and T. Nagamatsu, Bioorg. Med. Chem., 2008, 16,
Compound 7c. Yield 47%. Yellow powder, mp 92–93 ◦C. IR
(KBr) 3113, 2938, 2848, 1597, 1475, 1429, 1293, 1234, 1165, 1071,
1
1007, 811, 747, 667 cm-1. H-NMR (300 MHz, CDCl3) d: 7.52
(1H, s), 7.07–7.04 (3H, m), 7.00 (1H, s), 6.69 (1H, d, J = 8.4 Hz),
5.06–4.98 (1H, m), 4.25–4.16 (2H, m), 3.28 (1H, dd, J = 15.9,
9.3 Hz), 2.86 (1H, dd, J = 15.9, 7.2 Hz). 13C-NMR (75 MHz,
CDCl3) d: 157.37, 137.69, 129.69, 128.33, 127.40, 125.74, 125.13,
4254 | Org. Biomol. Chem., 2011, 9, 4250–4255
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