2H-Benzimidazole 1,3-Dioxides
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 11 3221
(CH2), 43.59 (CH2), 110.01 (Ar), 111.72 (Ar), 119.57 (Ar), 133.50
(Ar), 140.47 (Ar), 145.05 (Ar), 154.51 (Ar). m/z (%): 233 (M+•,
38), 217 (100), 204 (11), 187 (36). Anal. (C11H11N3O3) C, H, N.
2,4-Dihydro-7-nitro-1H-[1,4]oxazino[4,3-a]benzimidazole 5-Ox-
ide (16). Reaction time: 22 h; yellow solid; mp 166.7 °C (dec).
1H NMR (acetone-d6) δH: 4.33 (m, 2H), 4.44 (m, 2H), 5.11 (s,
2H), 7.87 (d, 1H, J ) 9.0 Hz), 8.30 (dd, 1H, J1 ) 9.0 Hz, J2 ) 2.0
Hz), 8.59 (d, 1H, J ) 2.0 Hz). 13C NMR (acetone-d6) δC: 42.97
(CH2), 61.43 (CH2), 63.84 (CH2), 110.04 (Ar), 112.14 (Ar), 120.17
(Ar), 132.01 (Ar), 14.03 (Ar), 145.10 (Ar), 149.89 (Ar). m/z (%):
236 (M+• + H, 100), 220 (4), 206 (17). Anal. (C10H9N3O4) C, H,
N.
2,4-Dihydro-7-nitro-1H-[1,4]thiazino[4,3-a]benzimidazole 5-Ox-
ide (17). Reaction time: 36 h; yellow solid. 1H NMR (acetone-d6)
δH: 3.63 (m, 4H), 4.03 (m, 2H), 7.50 (d, 1H, J ) 9.0 Hz), 8.33
(dd, 1H, J1 ) 9.0 Hz, J2 ) 3.0 Hz), 8.64 (d, 1H, J ) 3.0 Hz). m/z
(%): 252 (M+• + H, 100), 236 (5), 222 (37). Anal. (C10H9N3O3S)
C, H, N, S.
General Procedure for the Preparation of 1-Hydroxybenz-
imidazole 3-Oxide Derivatives 20-23. The corresponding ben-
zofuroxan (Ia-f, 50 mg), nitroethane (1 equiv), piperidine (1 equiv),
and THF (5.0 mL) were stirred for 12 h at room temperature. The
product was filtered and crystallized from methanol.
1-Hydroxy-5(6)-methoxy-2-methyl-1H-benzimidazole 3-Oxide
(20). As mixture of positional isomers (50:50); white solid; mp
198.6-199.8 °C (dec).1H NMR (CD3OD) δH: 2.67 (s, 3H), 3.90
(two s, 3H), 7.08 (dd, 1H, J1 ) 9.0 Hz, J2 ) 2.0 Hz), 7.17 (d, 1H,
J ) 2.0 Hz), 7.62 (d, 1H, J ) 9.0 Hz). 13C NMR (CD3OD) δC:
9.07 (CH3), 55.46 (CH3), 92.77 (Ar), 112.11 (Ar), 115.57 (Ar),
122.50 (Ar), 128.86 (Ar), 137.50 (Ar), 158.86 (Ar). m/z (%): 194
(M+•, 17), 193 (25), 178 (100), 162 (83). Anal. (C9H10N2O3) C, H,
N.
(CH3), 62.23 (two carbons, CH2), 74.25 (two carbons, CH2), 108.32
(Ar), 108.59 (Ar), 119.63 (Ar), 119.91 (Ar), 124.44 (Ar), 124.63
(Ar), 128.80 (Ar), 130.86 (Ar), 132.66 (Ar), 133.36 (Ar), 136.73
(Ar), 138.97 (Ar), 147.90 (Ar), 148.35 (Ar), 167.07 (CO). m/z
(%): 264 (M+•, 3), 248 (5), 219 (7). Anal. (C13H16N2O4) C, H, N.
(E)-1-(Ethyloxycarbonylmethyloxy)-2-methyl-5(6)-(2-phen-
ylethenyl)-1H-benzimidazole 3-Oxide (26). As mixture of posi-
1
tional isomers; oil. H NMR (CDCl3) δH: 1.33 (m, 3H), 2.71 (s,
3H), 4.33 (m, 2H), 4.88 (s, 2H), 7.09-7.22 (m, 1.5H), 7.38 (m,
2H),, 7.50 (m, 1H), 7.54 (m, 3H), 7.61 (s, 1H), 7.71-7.72 (m,
1.5H). 13C NMR (CDCl3) δC: 13.33 (CH3), 14.47 (CH3), 62.34
(CH2), 74.42 (CH2), 106.56 (CH)), 109.01 (CH)), 118.05 (Ar),
120.18 (Ar), 123.20 (Ar), 126.79 (Ar), 127.95 (Ar), 128.70 (Ar),
131.24 (Ar), 132-138 (four carbons, Ar), 168.02 (CO). m/ z (%):
352 (M+•, 6), 336 (1), 307 (12). Anal. (C20H20N2O4) C, H, N.
2-Methyl-1-pentyloxy-1H-benzimidazole 3-Oxide (27). Oil. 1H
NMR (CDCl3) δH: 0.88 (t, 3H, J ) 7.2 Hz), 1.34 (m, 2H), 1.44
(m, 2H), 1.77 (m, 2H), 2.59 (s, 3H), 4.20 (t, 2H, J ) 6.6 Hz), 7.19
(m, 2H), 7.32 (d, 1H, J ) 7.8 Hz), 7.57 (d, 1H, J ) 7.4 Hz). 13C
NMR (CDCl3) δC: 12.56 (CH3), 14.25 (CH3), 22.79 (CH2), 28.32
(two carbons, CH2), 79.61 (CH2), 108.86 (Ar), 119.18 (Ar), 123.39
(Ar), 123.66 (Ar), 130.48 (Ar), 136.91 (Ar), 148.08 (Ar). m/z (%):
234 (M+•, 2), 219 (11), 218 (55), 148 (56), 131 (22). Anal.
(C13H18N2O2) C, H, N.
General Procedure for the Preparation of Benzimidazole 1,3-
Dioxide Derivatives 28-35. The corresponding benzofuroxan (Ia-
d, If, Ii-k, 50 mg), 2-nitropropane (1.2 equiv), piperidine (1.2
equiv), and THF (5.0 mL) were stirred at room temperature until
the benzofuroxan was not present. The solvent was evaporated in
vacuo and the product purified by column chromatography (SiO2,
hexane:ethyl acetate (0-50%)).
2,2-Dimethyl-2H-benzimidazole 1,3-Dioxide (28). Red solid;
mp 122.6-123.4 °C. 1H NMR (CDCl3) δH: 1.72 (s, 6H), 6.90 (m,
2H), 7.22 (m, 2H). 13C NMR (CDCl3) δC: 24.59 (CH3), 97.40 (C-
2), 116.14 (Ar), 131.20 (Ar), 136.91 (Ar). m/z (%): 178 (M+•, 58),
163 (18), 147 (4). Anal. (C9H10N2O2) C, H, N.
5(6)-Bromo-1-hydroxy-2-methyl-1H-benzimidazole 3-Oxide
(21). White solid; mp 211.7-211.9 °C (dec). Due to solubility
problems it was not possible to obtain NMR data. m/z (%):243
(M+•, 6), 226 (100), 212 (39). Anal. (C8H7BrN2O2) C, H, N.
5(6)-Chloro-1-hydroxy-2-methyl-1H-benzimidazole 3-Oxide
2,2,5-Trimethyl-2H-benzimidazole 1,3-Dioxide (29). Red solid;
1
(22). White solid; mp 212.7 °C (dec). H NMR (DMSO-d6) δH:
1
mp 116.4-117.7 °C. H NMR (CDCl3) δH: 1.70 (s, 6H), 2.23 (s,
2.70 (s, 3H), 7.46 (dd, 1H, J1 ) 9.0 Hz, J2 ) 2.0 Hz), 7.72 (d, 1H,
J ) 9.0 Hz), 7.76 (d, 1H, J ) 2.0 Hz). m/z (%): 198 (M+•, 4), 197
(15), 182 (100), 165 (45). Anal. (C8H7ClN2O2) C, H, N.
3H), 6.74 (d, 1H, J ) 9.5 Hz), 7.00 (s, 1H), 7.15 (d, 1H, J ) 9.5
Hz). 13C NMR (CDCl3) δC: 22.39 (CH3), 24.54 (CH3), 97.52 (C-
2), 113.73 (Ar), 115.58 (Ar), 134.81 (Ar), 136.01 (two carbons,
Ar), 142.30 (Ar). m/z (%): 192 (M+•, 95), 176 (35%), 161 (23).
Anal. (C10H12N2O2) C, H, N.
(E)-1-Hydroxy-2-methyl-5(6)-(2-phenylethenyl)-1H-benzimi-
dazole 3-Oxide (23). White solid; mp 217.4 °C (dec). Due to
solubility problems it was not possible to obtain NMR data. m/z
(%): 266 (M+•, 4), 251 (15), 250 (77), 233 (100). Anal. (C16H14N2O2)
C, H, N.
General Procedure for the Alkylation of 1-Hydroxybenzimi-
dazole 3-Oxide Derivatives. Synthesis of Derivatives 24-27. The
corresponding benzimidazole (18, 19, or 23, 50 mg) and the
alkylating agent (ethyl 2-bromoacetate or pentyl iodide, 1.2 equiv)
were dissolved in dimethyl sulfoxide (3 mL). Piperidine (1.2 equiv)
was added, and the reaction mixture was stirred at room temperature
until the solution became clear. After addition of water the solution
was extracted with ethyl acetate. The organic layer was dried and
evaporated in vacuo. The product was purified by column chro-
matography (SiO2, hexane:ethyl acetate (0 to 30%)).
1-(Ethyloxycarbonylmethyloxy)-2-methyl-1H-benzimida-
zole 3-Oxide (24). Oil. 1H NMR (CDCl3) δH: 1.32 (t, 3H, J ) 7.0
Hz), 2.91 (s, 3H), 4.30 (q, 2H, J ) 7.0 Hz), 4.95 (s, 2H), 7.38-
7.42 (m, 2H), 7.60 (d, 1H, J ) 7.0 Hz), 7.83 (d, 1H, J ) 8.0 Hz).
13C NMR (CDCl3) δC: 12.26 (CH3), 14.42 (CH3), 62.64 (CH2),
74.47 (CH2), 109.59 (Ar), 118.41 (Ar), 125.08 (two carbons, Ar),
129.04 (Ar), 134.50 (Ar), 149.00 (Ar), 167.01 (CO). m/z (%): 250
(M+•, 2), 234 (1), 205 (10). Anal. (C12H14N2O4) C, H, N.
1-(Ethyloxycarbonylmethyloxy)-2,5(6)-dimethyl-1H-benzimi-
dazole 3-Oxide (25). As mixture of positional isomers (57:43). Oil.
1H NMR (CDCl3) δH: 1.24-1.32 (m, 3H), 2.46 (s, 1.3H), 2.49 (s,
1.7H), 2.66 (s, 3H), 4.26-4.31 (m, 2H), 4.81-4.82 (two s, 2H),
7.05-7.10 (m, 1H), 7.26 (s, 0.57H), 7.36 (d, 0.43H, J ) 8.0 Hz),
7.43 (s, 0.43H), 7.52 (d, 0.57H, J ) 8.0 Hz). 13C NMR (CDCl3)
δC: 13.00 (CH3), 14.45 (two carbons, CH3), 21.83 (CH3), 22.07
5-Methoxy-2,2-dimethyl-2H-benzimidazole 1,3-Dioxide (30).
1
Deep red solid; mp 142.4-143.2 °C. H NMR (CDCl3) δH: 1.73
(s, 6H), 3.85 (s, 3H), 6.41 (s, 1H), 6.65 (d, 1H, J ) 10.0 Hz), 7.19
(d, 1H, J ) 10.0 Hz). 13C NMR (CDCl3) δC: 24.47 (CH3), 56.62
(CH3), 90.68 (Ar), 97.90 (C-2), 116.99 (Ar), 129.10 (Ar), 132.52
(two carbons, Ar), 162.52 (Ar). m/z (%): 208 (M+•, 100), 192 (90),
177 (63). Anal. (C10H12N2O3) C, H, N.
5-Bromo-2,2-dimethyl-2H-benzimidazole 1,3-Dioxide (31).
1
Red solid; mp 134.5-135.3 °C. H NMR (CDCl3) δH: 1.71 (s,
6H), 6.96 (d, 1H, J ) 9.0 Hz), 7.12 (d, 1H, J ) 10.0 Hz), 7.50 (s,
1H). 13C NMR (CDCl3) δC: 24.61 (CH3), 98.25 (C-2), 117.11 (Ar),
118.35 (Ar), 126.34 (Ar), 135.11 (Ar), 136.30 (two carbons, Ar).
m/z (%): 258 (M+• + 2, 6), 256 (M+•, 8), 242 (26), 240 (38). Anal.
(C9H9N2O2) C, H, N.
(E/Z)-2,2-Dimethyl-5-(2-phenylethenyl)-2H-benzimidazole 1,3-
Dioxide (32). As mixture of geometric isomers E/Z (2:8); red solid;
1
mp 117.8-118.9 °C. H NMR (CDCl3) δH: 1.72 (bs, 6H), 6.41-
7.51 (m, 10H). 13C NMR (CDCl3) δC: 24.58 (CH3), 97.76 (C-2),
97.92 (C-2), 112.57-140.84 (CHd and Ar-carbons). m/z (%): 280
(M+•, 88), 264 (100), 249 (51). Anal. (C17H16N2O2) C, H, N.
2,2-Dimethyl-5-(hydroxyimino)methyl-2H-benzimidazole 1,3-
Dioxide (33). Red solid; mp 177.5-177.6 °C (dec). 1H NMR (CD3-
OD) δH: 1.70 (s, 6H), 4.51 (s, 1H, OH), 7.25 (m, 2H), 7.55 (d,
1H, J ) 10.0 Hz), 8.03 (s, 1H). 13C NMR (CD3OD) δC: 23.36
(CH3), 96.27 (C-2), 113.90 (Ar), 115.54 (Ar), 129.62 (Ar), 137.5
(two carbons, Ar), 138.0 (Ar), 146.97 (CHd). m/z (%): 221 (M+•,
100), 205 (16), 190 (8). Anal. (C10H11N3O3) C, H, N.