May-Jun 2008
Syntheses of Substituted 2-Methyl-5-nitroimidazoles
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run on a Finnigan mat TSQ-70 mass spectrometer in EI mode at
70 eV. Thin layer chromatography (tlc) was performed on plates
of silica gel 60 F254 plates. Silica gel 60, 0.040-0.063 mm (230-
400 mesh) was used for flash column chromatography. All
solvents used were reagent grade. Most of the solvents and
reagents were purchased from Merck, Aldrich and Fluka and
used as such without purification.
solvent was partially evaporated and the residue was neutralized
with aq. NaOH solution. The mixture was extracted with ethyl
acetate (200 mL), dried (Na2SO4) and evaporated under reduced
pressure. To the residue, petroleum ether was added to give a
white precipitate. Recrystallization from chloroform and
petroleum ether (1:9) gave compound 8 (21 g, 80%), mp 60-61
°C; ir (KBr): 1746 (C=O), 1531, 1365 (NO2); 1H nmr (CDCl3): δ
7.96 (s, 1H, imidazole), 5.03 (s, 2H, N-CH2), 4.21 (t, J=6.4 Hz,
2H, O-CH2), 2.46 (s, 3H, Me-imidazole), 1.57-1.23 (m, 4H,
CH2-CH2 butyl), 0.95 (t, J=6.2 Hz, 3H, CH3 butyl); ms: m/z (%)
241 (M+, 40), 195 (45), 185 (50), 138 (97), 108 (75), 79 (100),
54 (95). Anal. Calcd. for C10H15N3O4: C, 49.79; H, 6.27; N,
17.42. Found: C, 49.96; H, 5.97; N, 17.72.
Ethyl 2-(2-methyl-4-nitro-1H-imidazole-1-yl)acetate (2)
and ethyl 2-(2-methyl-5-nitro-1H-imidazol-1-yl)acetate (3).
To a suspension of 2-methyl-4(5)-nitroimidazole (1) [22] (2.11
g, 0.01 mol) in ethyl α-chloroacetate (14.20 mL, 0.1 mol),
propionic acid (6.66 mL) was added and refluxed for 16 h. The
mixture was filtered and concentrated under reduced pressure.
The residue was purified by column chromatography (silica gel,
ethyl acetate/petroleum ether, 1:1). The fast moving fraction was
compound 2 (150 mg, 7%), mp 110-111 °C (literature [23] mp
2-(2-Methyl-5-nitro-1H-imidazol-1-yl)acetohydrazide (9).
To a stirring solution of hydrazine hydrate (6.5 mL) in an ice
bath, a solution of 8 (9 g, 0.03 mol) in methanol (40 mL) was
added slowly (10 min). The stirring was continued for 4.5 h at 0
°C under argon atmosphere. The white precipitate which formed
in -10 °C was filtered and recrystallized from chloroform to give
compound 9 (3.5 g, 60%), mp 172-174 °C; ir (KBr): 3292
1
111-112 °C); H nmr (CDCl3): δ 7.75 (s, 1H, H-5 imidazole),
4.70 (s, 2H, N-CH2), 4.27 (q, J= 7.2 Hz, 2H, -CH2-CH3), 2.39 (s,
3H, Me-imidazole), 1.30 (t, J=7.2 Hz, 3H, CH3). The slower
moving fraction was compound 3 (171 mg, 8%), mp 71-72 °C
(literature [23] mp 71-72 °C); 1H nmr (CDCl3): δ 7.95 (s, 1H, H-
4 imidazole), 5.02 (s, 2H, N-CH2), 4.27 (q, J=7.2 Hz, 2H, -CH2-
CH3), 2.45 (s, 3H, Me-imidazole), 1.30 (t, J=7.2 Hz, 3H, CH3).
2-(2-Methyl-5-nitro-1H-imidazol-1-yl)acetic acid (5). To a
stirring suspension of metronidazole (4, 85.5 g, 0.5 mol) in 200
mL H2O at room temperature was added a solution of 142.5 g of
sodium dichromate in 690 mL H2O followed by drop wise
addition of 285 mL sulfuric acid 50%. The mixture was stirred
overnight. The reaction mixture was carefully neutralized with
250 mL of 4N NaOH solution. It was extracted with ethyl
acetate/THF (1:1, 4×300 mL). The combined organic layer was
washed with brine (1000 mL), dried (Na2SO4) and evaporated
under reduced pressure. The crude residue was recrystallized
from CH2Cl2 to give 56.5 g (61%) of compound 5, mp 176-178
°C (literature [19] mp 176-178 °C); ir (KBr): 3441 (OH), 1721
1
(NH), 1644 (C=O), 1529, 1362 (NO2); H nmr (DMSO-d6): δ
8.01 (s, 1H, imidazole) 4.94 (s, 2H, N-CH2), 2.37 (s, 3H, Me-
imidazole); ms: m/z (%) 200 (M++1, 50), 153 (100), 125 (30),
96 (25), 84 (42), 80 (65), 53 (90). Anal. Calcd. for C6H9N5O3: C,
36.18; H, 4.55; N, 35.16. Found: C, 35.93; H, 4.37; N, 35.44.
5-[(2-Methyl-5-nitro-1H-imidazol-1-yl)methyl]-1,3,4-oxadi-
azole-2(3H)-thione (10). Compound 9 (4 g, 20.2 mmol) was
suspended in 30 mL of methanol at 0 °C, potassium hydroxide
(1.31 g, 20.2 mmol) and carbon disulfide (20 mL) was added.
The mixture was stirred at 0 °C for 2 h, at 25 °C for another 2 h
and then the mixture was refluxed for 4 h. The volatiles were
evaporated under reduced pressure. Water (20 mL) was added to
the residue, and the mixture was filtered. The filtrate was poured
into ice and dilute HCl, and the product was collected by
filtration, washed with water and recrystallized from acetic acid
to give compound 10 (3.1 g, 64%), mp 205-206 °C; ir (KBr):
3452 (NH), 1536, 1378 (NO2), 1265 (C=S); 1H nmr (DMSO-d6):
δ 8.09 (s, 1H, imidazole), 5.70 (s, 2H, N-CH2), 2.50 (s, 3H, Me-
imidazole); ms: m/z (%) 241 (M+, 15), 193 (100), 136 (20), 80
(20), 53 (30). Anal. Calcd. for C7H7N5O3S: C, 34.85; H, 2.92; N,
29.03. Found: C, 34.59; H, 3.15; N, 29.27.
Methyl 2-(5-[(2-methyl-5-nitro-1H-imidazol-1-yl)methyl]-
1,3,4-oxadiazol-2-ylthio)acetate (11a). A mixture of 10 (1.4 g,
5.8 mmol) and methyl α-chloroacetate (0.62 g, 5.8 mmol) in 25
mL of dioxane was treated with 0.8 g (5.8 mmol) potassium
carbonate and stirred at room temperature for 6 h. The solvent
was removed under reduced pressure, water was added, and the
solution was neutralized with dilute HCl and extracted with
ethyl acetate (3×25 mL). The combined organic layer was
washed with brine (50 mL), dried (Na2SO4) and evaporated to
obtain an oily residue which on purification by Silica gel flash
chromatography (ethyl acetate/chloroform 1:3) afforded 0.8 g
(48%) pure yellow crystals of 11a, mp 76-77 °C; ir (KBr): 1741
(C=O), 1526, 1362 (NO2); 1H nmr (CDCl3): δ 7.97 (s, 1H,
imidazole), 5.75 (s, 2H, N-CH2), 4.03 (s, 3H, O-Me), 3.78 (s,
2H, S-CH2), 2.57 (s, 3H, Me-imidazole); ms: m/z (%) 314
(M++1, 20), 296 (100), 267 (92), 202 (65), 187 (40), 106 (95),
73 (97), 46 (95). Anal. Calcd. for C10H11N5O5S: C, 38.34; H,
3.54; N, 22.35. Found: C, 38.12; H, 3.85; N, 22.54.
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(C=O), 1547, 1357 (NO2); H nmr (DMSO-d6): δ 8.10 (s, 1H,
imidazole), 5.15 (s, 2H, N-CH2), 2.42 (s, 3H, Me-imidazole);
ms: m/z (%) 185 (M+, 40), 139 (60), 109 (23), 83 (25), 80 (50),
54 (80), 52 (100).
Methyl 2-(2-methyl-5-nitro-1H-imidazol-1-yl)acetate (7). A
solution of 5 (2.5 g, 0.01 mol) in thionyl chloride (15 mL) was
refluxed for 1 h. Solvent was evaporated under reduced pressure
to give crude acyl chloride 6 which without further purification
was dissolved in 15 mL dry methanol and refluxed for 15 min.
The reaction mixture was evaporated to dryness. To the residue
water (20 mL) was added followed by addition of sodium
bicarbonate solution to obtain neutral pH. The mixture was
extracted with CH2Cl2 (2×20 mL). The combined organic layer
was washed with brine (50 mL), dried (Na2SO4) and evaporated
under reduced pressure. The crude residue was recrystallized
from water to give 0.7 g (40%) of 7, mp 139-140 °C (literature
1
[19] mp 140 °C); ir (KBr): 1746 (C=O), 1536, 1372 (NO2); H
nmr (CDCl3): δ 7.94 (s, 1H, imidazole), 5.04 (s, 2H, N-CH2),
3.80 (s, 3H, O-Me), 2.44 (s, 3H, Me-imidazole).
Ethyl ester of carboxylic acid 5 (compound 3, Scheme 1) was
prepared similarly from the reaction of ethanol (instead of
methanol) with acyl chloride 6 in 27% yield.
Butyl 2-(2-methyl-5-nitro-1H-imidazol-1-yl)acetate (8).
2-(2-methyl-5-nitro-1H-imidazol-1-yl)acetic acid (5, 20 g, 0.1
mol) was suspended in 1-butanol (80 mL) and treated with 200
mL benzene and 7 mL sulfuric acid. The reaction mixture was
refluxed in a Dean-Starck condenser for 4 h. The reaction
Ethyl 2-(5-[(2-methyl-5-nitro-1H-imidazol-1-yl)methyl]-
1,3,4-oxadiazol-2-ylthio)acetate (11b). This compound was
prepared similar to 11a using ethyl α-bromoacetate as an oil in