408 JOURNAL OF CHEMICAL RESEARCH 2015
TLC was performed on F254 precoated silica gel plates. Column
chromatography was performed on silica gel (200-300 mesh). The
starting compound I (4-amino-3-methylbenzoic acid) was purchased
from Alfa Aesar Company, and all the reagents and solvents were
obtained commercially and were used without further purification.
4-Acetamido-3-methylbenzoic acid II: Et3N (25.09 mL, 180 mmol)
was added dropwise to 4-amino-3-methylbenzoic acid I (9 g, 60 mmol)
dissolved in CH2Cl2 (100 mL) in a 250 mL flask. After 0.5 h, Ac2O was
injected slowly. The reaction mixture was vigorously stirred at room
temperature for 3 days. The mixture was evaporated to remove the
solvent, and the residues were redissolved in 1 M hydrochloric acid (50
mL) and water (100 mL). Overnight, light-pink long crystals grew and
were filtered off (10.7 mg, 93%); m.p. 237–239 ℃ (lit.11 114–116 °C);
IR (KBr cm-1): 3270, 1662, 1522, 1422, 1279; 1H NMR (DMSO-d6): δ
12.79 (s, 1H), 9.40 (s, 1H), 7.78 (s, 1H), 7.73 (s, 2H), 2.27 (s, 3H), 2.11
(s, 3H); ESI: m/z = 386.7 [M+H]+ (double).
Ethyl 4-acetamido-3-methylbenzoate III: 4-Acetamido-3-methyl-
benzoic acid II (10 g, 56 mmol) dissolved in absolute ethanol (100 mL)
in a 250 mL flask was cooled to 0 oC, then sulfoxide chloride (8.2 mL,
112 mmol) was added dropwise. The reaction was complete at 50 °C
after 3h, monitored by TLC (ethyl acetate: petroleum ether 1:5, v/v).
The mixture was evaporated to remove the solvent, and the residues
were washed with ethyl acetate and saturated sodium bicarbonate
solution three times. The organic phase was dried with Na2SO4 and
concentrated. The crude solid was purified by recrystallisation in
ethanol and gave the colourless blocks (9.4 g, 95%); m.p. 139–140
°C (lit.12 133–135 °C); IR (KBr cm-1): 3277, 1710, 1646, 1521, 1367;
1H NMR (DMSO-d6) δ 9.41 (s, 1H), 7.80 (s, 1H), 7.75 (s, 2H), 4.28 (q,
J = 7.1 Hz, 2H), 2.28 (s, 3H), 2.11 (s, 3H), 1.31 (t, J = 7.1 Hz, 3H); ESI:
m/z = 442.7 [M+H]+ (double).
filtrate and washings were concentratedto give a dark red solid, without
any purification for the next step.
Ethyl 2-methoxy-4-methyl-1H-benzimidazole-6-carboxylate (1):
Ethyl 3,4-diamino-5-methylbenzoate VI (971.2 mg,
5 mmol),
tetramethoxymethane (10 mL) and acetic acid (286 μL, 5 mmol) in a
25 mL flask were stirred at 80 °C for 3h. Then tetramethoxymethane
was recycled by vacuum distillation. The red residue was purified by
recrystallisation from ethanol and gave red transparent crystals (761.3
mg, 77.5%); m.p. 155–156 °C; IR (KBr cm-1): 3235, 1682, 1628 1558,
1324, 1209 cm-1; 1H NMR (CDCl3-d) δ 7.91 (s, 1H), 7.61 (s, 1H), 4.33
(h, J = 6.3 Hz, 2H), 4.21–4.14 (m, 3H), 3.21 (s, 1H), 2.50 (s, 3H), 1.38
(t, J = 6.9 Hz, 3H); 13C NMR (CDCl3-d) δ 172.1, 165.1, 128.1, 128.0,
127.6, 65.2, 61.6, 21.6, 19.2; ESI: m/z = 235.1[M+H]+; HRMS: calcd for
C12 H15 N2 O3 (MH+) 235.1077, found 235.1077.
Ethyl 2-ethoxy-4-methyl-1H-benzimidazole-6-carboxylate (2):
Red transparent crystals (65%); m.p. 177–178 °C (ethanol); IR (KBr
1
cm-1): 3243, 1678, 1622, 1559, 1314, 1210 cm-1; H NMR (CDCl3-d) δ
9.05 (d, J = 32.3 Hz, 1H), 7.97 (d, J = 157.6 Hz, 1H), 7.73 (d, J = 13.4
Hz, 1H), 4.63 (m, 2H), 4.39 (m, 2H), 2.52 (d, J = 71.3 Hz, 3H), 1.44
(dt, J = 31.2, 6.6 Hz, 6H); 13C NMR (CDCl3-d) δ 167.5, 158.7, 140.4,
135.2, 131.2, 124.1, 117.3, 109.0, 66.3, 60.7, 16.7, 14.6, 14.4; (ESI): m/z
= 249.0[M+H]+; HRMS: calcd for C13 H17 N2 O3 (MH+) 249.1234, found
249.1234.
Ethyl 2-mercapto-4-methyl-1H-benzimidazole-6-carboxylate (3):
Under the protection of nitrogen, ethyl 3,4-diamino-5-methylbenzoate
VI (4.86 g, 25 mmol), potassium hydroxide (1.431 g, 25 mmol),
carbon disulfide (1.54 mL, 25 mmol) and ethanol (40 mL) in a 100
mL flask were stirred and heated at reflux for 3h. Removal of the
solvent gave a blue residue which was purified by recrystallisation
from water:ethanol (1:10) to give a pale blue solid (4.14 g, 68%); m.p.
1
>400 °C; IR (KBr cm-1): 3085, 1705, 1617, 1531, 1194 cm-1; H NMR
Ethyl 4-acetamido-3-methyl-5-nitrobenzoate IV: Fuming nitric acid
(15 mL) was added to ethyl 4-acetamido-3-methylbenzoate III (11 g,
50 mmol) in a 25 mL two-necked flask with cooling. The mixture was
stirred at –15 °C for 3h. After the reaction had finished, the resulting
mixture was poured into ice and a yellow solid was filtered off. The
crude solid purified by water washing and recrystallisation in ethanol
gave the light yellow lamella crystals (11.6 g, 86%); m.p. 182–184 °C;
(CDCl3-d) δ 7.62 (d, J = 12.6 Hz, 2H), 4.37 (m, 2H), 3.45 (s, 1H), 2.50
(s, 3H), 1.42 (t, J = 7.1 Hz, 3H); 13C NMR (CDCl3-d) δ 175.1, 170.9,
140.3, 137.0, 129.0, 124.5, 113.2, 65.5, 21.4, 19.4; ESI: m/z = 237.0
[M+H]+; HRMS: calcd for C11 H13 N2 O2 S (MH+) 237.0692, found
237.0690.
Ethyl 2-methylthio-4-methyl-1H-benzimidazole-6-carboxylate (4):
Under the protection of nitrogen, compound 3 (2 g, 8.5 mmol),
potassium hydroxide (477 mg, 8.5 mmol) and ethanol (40 mL) were
added to a 100 mL flask, and methyl iodide (529 μL, 8.5 mmol) was
added dropwise slowly. Then the reaction mixture was refluxed for
6h. After completion of the reaction, the solvent was removed. The
residue was purified by recrystallisation from ethanol to give a white
solid (1.83 g, 86%); m.p. 170–171 °C; IR (KBr cm-1): 3259, 1737, 1708,
1
IR (KBr cm-1): 3445, 3280, 1716, 1670, 1520, 1355, 1292; H NMR:
(DMSO-d6) δ 10.16 (s, 1H), 8.19–8.13 (m, 2H), 4.35 (q, J = 7.1 Hz, 2H),
2.38 (s, 3H), 2.08 (d, J = 2.0 Hz, 3H), 1.33 (t, J = 7.1 Hz, 3H); ESI: m/z
= 267.7 [M+H]+.
Ethyl 4-amino-3-methyl-5-nitrobenzoate V: Ethyl 4-acetamido-
3-methyl-5-nitrobenzoate IV (12 g, 45 mmol) and 3 M hydrochloric
acid (200 mL) were added to a 500 mL three-necked flask, and
concentrated hydrochloric acid (20 mL) was then added dropwise at
room temperature. Then the flask was equipped with a condenser and
stirred under reflux for 8h. The reaction system yielded a large amount
of bright yellow solid floating above the solvent. After cooling, the
yellow solid was filtered and dried to remove the moisture. The dry
solid and absolute ethanol (200 mL) were added to a 500 mL three-
necked flask and cooled, then sulfoxide chloride (6.5 mL) was added
dropwise. The reaction was completed at 50 °C with a condenser after
3h, monitored by TLC (ethyl acetate: petroleum ether = 1:5, v/v). The
mixture was evaporated to remove the solvent, and the residues were
washed with ethyl acetate (50 mL) and saturated sodium bicarbonate
solution (3x 20 mL). The organic phase was dried with Na2SO4 and
concentrated. The crude solid was purified by recrystallisation fom
ethanol and gave bright yellow needles (10 g, 87%); m.p. 136–138 ℃;
1
1614, 1313, 1232 cm-1; H NMR (CDCl3-d) δ 7.94 (s, 1H), 7.63 (s,
1H), 4.35 (m, 2H), 3.36 (m, 2H), 2.55 (s, 3H), 1.43 (s, 3H); 13C NMR
(CDCl3-d) δ 167.6, 153.8, 124.3, 124.2, 61.0, 16.9, 14.7, 14.4; ESI: m/z =
251.0 [M+H]+; HRMS: calcd for C12 H15 N2 O2 S (MH+) 251.0849, found
251.0849.
Ethyl 2-ethylthio-4-methyl-1H-benzimidazole-6-carboxylate (5):
White solid (85%); m.p. 176–177 °C (ethanol); IR (KBr cm-1): 3250,
1708, 1681, 1613, 1313, 1214 cm-1; 1H NMR (DMSO-d6) δ 7.94 (s, 1H),
7.63 (s, 1H), 4.35 (m, 2H), 3.36 (m, 2H), 2.55 (s, 3H), 1.43 (t, J = 7.3
Hz, 3H), 1.38 (t, J = 7.1 Hz, 3H); 13C NMR (CDCl3-d) δ 167.7, 153.2,
124.2, 61.0, 34.5, 23.0, 17.0, 14.4; ESI: m/z = 265.0 [M+H]+; HRMS:
calcd for C13 H17 N2 O2 S (MH+) 265.1005, found 265.1007.
Ethyl 2-n-propylthio-4-methyl-1H-benzimidazole-6-carboxylate (6):
White solid (91%); m.p. 135–136 °C (ethanol); IR (KBr cm-1): 3248,
1
IR (KBr cm-1): 3459, 3355, 1700, 1635, 1527, 1362, 1341; H NMR
1
1704, 1665, 1615, 1311, 1185 cm-1; H NMR (CDCl3-d) δ 11.32 (s,
(DMSO-d6) δ 8.48 (s, 1H), 7.81 (s, 1H), 7.70 (s, 2H), 4.32–4.22 (m,
2H), 2.25 (s, 3H), 1.30 (t, J = 7.2 Hz, 3H); ESI: m/z = 225.7 [M+H]+.
Ethyl 3,4-diamino-5-methylbenzoate VI: Ethyl 4-amino-3-methyl-
5-nitrobenzoate V (5.7 g, 25 mmol) and ethanol:water (160 mL, 10:1)
were added to a 250 mL three-necked flask and sodium dithionite
(10.5 g, 75 mmol) was added slowly. The mixture was stirred and
heated under reflux for 5h, after which the colour of the reaction
system turned from yellow to dark red. After cooling, the insoluble
solid was filtered off and washed with cold ethanol (50 mL×5). The
1H), 8.11 (s, 1H), 7.77 (s, 1H), 4.41 (m, 2H), 3.29 (t, J = 7.3 Hz, 2H),
2.55 (s, 3H), 1.77 (m, 2H), 1.41 (t, J = 7.2 Hz, 3H), 0.98 (t, J = 7.4 Hz,
3H); 13C NMR (CDCl3-d) δ 167.7, 153.2, 124.2, 67.0, 34.5, 23.0, 17.0,
14.4, 13.2; ESI: m/z = 279.1 [M+H]+; HRMS: calcd for C14 H19 N2 O2 S
(MH+) 279.1162, found 279.1161.
X-Ray crystallography
Compound 1 was recrystallised from petroleum/ethyl acetate to
give red single crystals. The structure was solved by direct methods