recrystallized from dichloromethane–pentane; mp 175–178 ◦C;
(Found: C, 57.6; H, 6.4; N, 20.4. C10H13N3O2 requires C, 58.0;
H, 6.3; N, 20.3%); (Found: M+, 207.1014. C10H13N3O2 requires
207.1008); mmax (KBr)/cm−1 3458, 3350, 3108, 2931, 2835, 1617,
1510, 1483, 1341, 1272, 1195, 1176, 1068, 1033; dH (300 MHz;
CDCl3) 6.89 (1 H, d, J 8.6, ArH), 6.57 (1 H, d, J 8.6, ArH), 4.82
(2 H, s, CH2), 4.50 (2 H, br, NH2), 3.87 (3 H, s, NMe), 3.72 (3 H, s,
OMe); dC (100 MHz; CDCl3) 152.7 (C), 141.5 (C), 131.9 (C), 130.6
(C), 127.8 (C), 110.1 (CH), 96.8 (CH), 57.6 (Me), 56.5 (CH2), 29.8
(Me); m/z (EI) 207 (M+, 9%), 190 (9), 175 (40), 155 (10), 149 (20),
97 (28), 85 (50), 71 (70), 57 (100).
reflux for 4 h. The reaction mixture was concentrated in vacuo,
washed with CuSO4 solution, extracted into dichloromethane (2 ×
100 ml), dried (MgSO4), filtered and the solvent removed in vacuo.
The crude product obtained was purified by chromatography,
gradient elution with methanol–dichloromethane (1–5%), to give
the title compound (5.24 g, 87%) as a beige crystalline solid;
◦
mp 113–115 C (from ethyl acetate); (Found: MH+, 235.1078.
C12H14N2O3 + H requires 235.1082); mmax (KBr)/cm−1 3012,
2996, 2970, 2935, 1737, 1619, 1481, 1250, 1224, 1214, 1019; dH
(300 MHz; CDCl3) 7.65 (1 H, d, J 8.8, 4-H), 6.93 (1 H, dd, J 8.8,
2.2, 5-H), 6.79 (1 H, d, J 2.2, 7-H), 5.35 (2 H, s, CH2OH), 3.89
(3 H, s, OMe), 3.78 (3 H, s, NMe), 2.14 (3 H, s, Me); dC (75 MHz;
CDCl3) 170.8 (C), 157.6 (C), 147.9 (C), 137.1 (C), 137.1 (C), 121.2
(CH), 112.4 (CH), 93.2 (CH), 58.7 (CH2), 56.3 (Me), 30.5 (Me),
21.1 (Me); m/z (CI) 235 (MH+, 100%), 175 (77).
2-Hydroxymethyl-5-methoxy-1-methylbenzimidazole-4,7-dione 11
To a solution of 4-amino-5-methoxy-1-methylbenzimidazole-2-
methanol 10 (60 mg, 0.29 mmol) in acetone (18 ml) was added
a solution of potassium nitrosodisulfonate (317 mg, 1.16 mmol) in
sodium dihydrogen phosphate buffer (0.3 M; 15 ml). The mixture
was stirred at room temperature for 1 h, and then evaporated. The
residue was extracted with dichloromethane and the combined
organic layers dried over MgSO4, filtered and evaporated under
reduced pressure to yield the title compound (39 mg, 66%) as a
yellow crystalline solid; mp 210–212 ◦C; (Found: MH+, 223.0724.
C10H10N2O4 + H requires 223.0719); kmax (acetonitrile)/nm 272
(log e 3.98), 290 (3.96), 401 (2.80); mmax (KBr)/cm−1 3319, 2924,
2852, 1695, 1654, 1588, 1526, 1316, 1244, 1116, 1091; dH (300 MHz;
CDCl3) 5.74 (1 H, s, 6-H), 4.82 (2 H, s, CH2), 4.01 (3 H, s, NMe),
3.86 (3 H, s, OMe); dC (100 MHz; CDCl3) 179.3 (C), 179.0 (C),
174.0 (C), 160.0 (C), 150.9 (C), 140.9 (C), 108.1 (CH), 62.6 (CH2),
57.0 (2 × Me); m/z (CI) 223 (MH+, 100%), 207 (35), 193 (10).
6-Methoxy-1-methyl-7-nitrobenzimidazole-2-methanol
A mixture of nitric acid and sulfuric acids (9 : 1; 47 ml) was
cooled in an ice bath and added slowly to 2-acetoxymethyl-6-
methoxy-1-methylbenzimidazole (4.2 g, 17.95 mmol) cooled in
an ice bath. This was stirred for 10 min at −5 ◦C and then at
room temperature for 18 h. The reaction mixture was basified
with a saturated aqueous solution of potassium carbonate to pH 9,
stirred for 30 min, and extracted into dichloromethane (4 × 50 ml),
dried (MgSO4), filtered and the solvent removed in vacuo. The
crude product, a 1 : 1.6 mixture of 5- and 7-nitro isomers, was
purified by chromatography, eluting with ethyl acetate, to give
the title compound (1.32 g, 31%) as a yellow crystalline solid; mp
◦
207.5–209.5 C (from ethyl acetate); (Found: C, 50.3; H, 4.4; N,
17.9. C10H11N3O4 requires C, 50.6; H, 4.7; N, 17.7%); (Found: M+,
237.0740. C10H11N3O4 requires 237.0750); mmax (KBr)/cm−1 3132,
1636, 1583, 1521, 1472, 1393, 1334, 1315, 1228, 1244, 1166, 1121,
1076; dH (300 MHz; DMSO-d) 7.83 (1 H, d, J 8.9, ArH), 7.20 (1 H,
d, J 8.9, ArH), 5.71 (1 H, t, J 5.8, CH2OH), 4.70 (2 H, d, J 5.8,
CH2OH), 3.93 (3 H, s, OMe), 3.63 (3 H, s, NMe); dC (75 MHz;
DMSO-d) 155.9 (C), 147.4 (C), 137.9 (C), 126.6 (C), 125.5 (C),
122.7 (CH), 107.5 (CH), 57.3 (Me), 56.1 (CH2), 30.8 (Me); m/z
(EI) 237 (M+, 100%), 161 (61), 160 (20), 131 (45), 104 (20).
6-Methoxy-1-methylbenzimidazole-2-methanol 13
To a solution of 2-amino-5-methoxy-N-methylaniline (4.98 g,
32.76 mmol) in hydrochloric acid (4 M; 40 ml) was added glycolic
acid (8.60 g, 113.82 mmol). The reaction mixture was heated under
reflux for 4 h. After cooling, the reaction mixture was basified with
a saturated aqueous solution of sodium hydrogen carbonate to
pH 6.5. The reaction mixture was extracted into dichloromethane
(3 × 50 ml), and the combined organic layers dried (MgSO4),
filtered and the solvent removed in vacuo. The crude product
obtained was purified by chromatography, gradient elution with
methanol–dichloromethane (1–5%), to give the title compound
(5.01 g, 80%) as an orange crystalline solid; mp 159–162 ◦C (from
chloroform–hexane); (Found: MH+, 193.0973. C10H12N2O2 + H
requires 193.0977); mmax (KBr)/cm−1 3370, 3145, 3001, 2935, 2848,
2059, 1885, 1634, 1593, 1491, 1475, 1460, 1429, 1342, 1209, 1040;
dH (300 MHz; CDCl3) 7.52 (1 H, d, J 8.8, 4-H), 6.85 (1 H, dd, J
8.8, 2.3, 5-H), 6.64 (1 H, d, J 2.3, 7-H), 4.83 (2 H, s, CH2OH), 3.85
(3 H, s, OMe), 3.76 (3 H, s, NMe); dC (75 MHz; CDCl3) 157.1 (C),
153.3 (C), 136.8 (C), 136.1 (C), 120.0 (CH), 112.0 (CH), 93.1 (CH),
57.4 (CH2), 56.2 (Me), 30.3 (Me); m/z (CI) 193 (MH+, 100%), 177
(38), 191 (22), 175 (16).
7-Amino-6-methoxy-1-methylbenzimidazole-2-methanol 14
To a solution of 6-methoxy-1-methyl-7-nitrobenzimidazole-2-
methanol (1.50 g, 6.33 mmol) in ethanol (95 ml) was added
palladium-on-carbon (10%; 270 mg). The mixture was stirred
under a hydrogen atmosphere for 18 h. The reaction mixture
was filtered through Celite and the solvent removed in vacuo to
give the title compound (1.08 g, 72%) as a colourless crystalline
◦
solid; mp 208.5–210.5 C (from methanol–pentane); (Found: C,
57.9; H, 6.5; N, 20.5. C10H13N3O2 requires C, 58.0; H, 6.3; N,
20.3%); (Found: M+, 207.1009. C10H13N3O2 requires 207.1008);
mmax (KBr)/cm−1 3402, 3309, 3221, 2930, 2839, 2719, 1623, 1508,
1487, 1476, 1451, 1400, 1231, 1217, 1195, 1029; dH (400 MHz;
DMSO-d) 6.87–6.81 (2 H, m, ArH), 5.48 (1 H, t, J 5.7, CH2OH),
4.61–4.58 (4 H, m, CH2OH + NH2), 4.03 (3 H, s, OMe), 3.78
(3 H, s, NMe); dC (100 MHz; DMSO-d) 153.3 (C), 142.4 (C), 138.3
(C), 126.0 (C), 123.0 (C), 108.6 (CH), 107.7 (CH), 57.2 (Me), 56.3
(CH2), 31.9 (Me); m/z (EI) 207 (M+, 40%), 192 (100), 162 (35).
2-Acetoxymethyl-6-methoxy-1-methylbenzimidazole
6-Methoxy-1-methylbenzimidazole-2-methanol 13 (4.91 g,
25.57 mmol), dry pyridine (3.1 ml), a catalytic amount of DMAP
(200 mg) and acetic anhydride (3.62 ml, 38.36 mmol) were
dissolved in dry dichloromethane and the mixture heated under
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The Royal Society of Chemistry 2007
Org. Biomol. Chem., 2007, 5, 3665–3673 | 3669
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