D. V. LaBarbera, E. B. Skibo / Bioorg. Med. Chem. 13 (2005) 387–395
393
afforded the dihydrochloride salt of 1: 335mg yield
(ꢀ99%); mp dec > 320ꢁC; TLC (butanol, acetic acid,
water [5:2:3]) Rf = 0.29; FTIR 3410, 2964, 2511, 1718,
nium hydroxide was then added drop wise until the
pH was equal to 8 resulting in crystallization of a white
solid. These crystals were then filtered and dried under
high vacuum: 2.4g (96%) yield; mp 131–133ꢁC, TLC
(chloroform/methanol [95:5]), Rf = 0.13; FTIR 3420,
3146, 2920, 2843, 1670, 1512, 1404, 1357, 1074,
1606, 1543, 1346, 1255, 1049, 846cmÀ1 1H NMR d
;
11.0, 9.6, and 8.9 (3s, 3H, NH protons), 5.70 (s, 1H, 7-
H), 4.3 and 3.4 (2t, J = 7Hz, 4H, ethylene bridge),
2.41 (s, 3H, 2-methyl). Mass Spectrum (EI mode) m/z
202 (M+). Anal. (C10H10N4OÆ2HCl) C, H, N.
1
856cmÀ1; H NMR (CDCl3), d 7.26 (1H, s, aromatic
proton), 7.06 and 6.93 (2H, 2d, J = 8.7Hz, aromatic
protons), 4.19 and 4.05 (4H, 2t, J = 4.2Hz, methylenes),
2.51 (3H, s, methyl), 2.32 (3H, s, methyl); MS (EI mode)
m/z 190 (M+). Anal. (C11H14N2OÆ0.2NH3Æ0.6H2O) C, H,
N.
3.7. 4-(2-Hydroxyethylamino)-3-nitrotoluene (11)
A solution of 4mL (5.2g, 0.03mol) of 4-chloro-3-nitro-
toluene in 4mL (4.08g, 0.07mol) of ethanolamine was
refluxed for 2h. The reaction was then cooled to room
temperature and diluted with dichloromethane and
water. The organic phase was dried with sodium sulfate,
filtered, and concentrated giving red oil. Triturating the
oil with hexane yielded a red solid. The solid was filtered
off and then washed with hexane and dried. The crude
product was recrystallized from dichloromethane:
4.44g (75% yield); mp 80–81ꢁC; TLC (chloroform/meth-
anol [90:10]) Rf = 0.44; FTIR 3445, 3346, 2957, 2926,
2872, 1637, 1568, 1523, 1433, 1406, 1356, 1311, 1219,
3.10. 6-Acetamido-1-(2-acetoxyethyl)-2,5-dimethylbenz-
imidazole (14)
To 3mL of 90% nitric acid, cooled in an ice-salt bath
(0ꢁC), was added 100mg (0.53mmol) of 13 in small por-
tions while keeping the temperature below 10ꢁC. After
the addition, the reaction was allowed to stir at 0ꢁC
for 10min, poured over ice, and neutralized with sodium
bicarbonate solution (pH = 8). The mixture is then ex-
tracted with chloroform and dried with sodium sulfate.
The product is concentrated by evaporation and crystal-
lized with chloroform/hexane: 111mg (89%) yield. These
crystals are a mixture of isomers that cannot be sepa-
rated. As a result the mixture was taken to the next step
where it was reduced and acetylated. A suspension of
500mg (2.23mmol) of the mixture in 100mL of metha-
nol and 100mg of 5% Pd on carbon and shaken under
50psi of H2 for 3h at room temperature. The catalyst
was removed by filtering through Celite and the filtrate
was concentrated to a residue. The residue was dissolved
in an excess solution of acetic acid/acetic anhydride (1:1)
and stirred at room temperature for 15h. The acetic
acid/acetic anhydride solution was evaporated by high
vacuum and the resulting solid was taken up in satu-
rated sodium bicarbonate solution and extracted with
chloroform. The organic phase was dried with sodium
sulfate, filtered, and concentrated to yield a mixture of
isomers that were separated by column chromatography
(5% methanol in chloroform) to give 200mg (33% yield)
of the desired isomer: mp 223–225ꢁC; TLC (chloroform/
methanol [90:10]) Rf = 0.58; FTIR 3281, 2924, 1745,
1
1178, 1151, 1039, 922, 812cmÀ1; H NMR (CDCl3) d
8.06 (1H, s, N-(4-amino), 7.98 (1H, s, C(2) aromatic pro-
ton), 7.29 and 6.83 (2H, 2d, J = 8.7Hz, C(5) and C(6)
aromatic protons), 3.95 and 3.53 (4H, 2t, J = 4.8Hz,
methylenes), 2.27 (3H, s, C(1) methyl); MS (EI mode)
m/z 196 (M+). Anal. (C9H12N2O3) C, H, N.
3.8. 3-Acetamido-4-(N-acetyl-2-acetoxyethylamino)tolu-
ene (12)
A suspension consisting of 11.8g (0.0602mol) of 11 dis-
solved in methanol and 2.36g of 5% Pd on carbon was
shaken under 50psi H2 for 3h. The reaction mixture
was then filtered through Celite. The methanol was re-
moved from the filtrate by evaporation and the residue
dissolved in an excess solution of acetic acid/acetic anhy-
dride (1:1) and refluxed for 1h. The reaction was cooled
to room temperature, made basic with saturated sodium
bicarbonate solution (pH = 8) and extracted with chlo-
roform. The chloroform extracts were dried with sodium
sulfate, filtered, and concentrated to yield a crude prod-
uct 15.3g (77% yield). An analytically pure sample was
obtained by recrystallization from chloroform and hex-
ane: mp 145–147ꢁC; TLC (chloroform/methanol [95:5])
Rf = 0.53; FTIR 3235, 1711, 1663, 1607, 1514,
1655, 1535, 1473, 1402, 1234, 1053, 868cmÀ1 1H
;
NMR (CDCl3) d 7.99 (1H, s, aromatic proton), 7.46
(1H, s, aromatic proton), 7.04 (1H, s, amide proton),
4.35 (4H, 2t, J = 2.7Hz, methylenes), 2.59 (3H, s,
methyl), 2.36 (3H, s, methyl), 2.24 (3H, s, methyl),
2.09 (3H, s, methyl); MS (EI mode) m/z 289 (M+). Anal.
(C15H19N3O3).
1468, 1395, 1337, 1231, 1038, 826cmÀ1 1H NMR
;
(DMSO-d6) d 9.24 (1H, s, amide proton), 7.61 (1H, s,
aromatic proton), 7.14 and 7.01 (2H, 2d, J = 8.1Hz,
aromatic protons), 4.11 and 3.99 (4H, 2t, J = 3.0Hz,
methylenes), 2.28, 2.04, 1.88, and 1.66 (12H, 4s, meth-
yls); MS (EI mode) m/z 292 (M+). Anal. (C15H20N2O4)
C, H, N.
3.11. 6-Acetamido-1-(2-acetoxyethyl)-2,5-dimethyl-7-
nitrobenzimidazole (15)
To 10mL of 90% nitric acid at room temperature was
added 900mg (3.11mmol) in small portions. After the
addition, the reaction was stirred at room temperature
for 1.5h. The reaction was then made basic with sodium
bicarbonate solution (pH = 8) and extracted with chlo-
roform, dried with sodium sulfate and concentrated.
The resulting pale yellow solid was recrystallized
from chloroform and hexane: 930mg (89%) yield; mp
3.9. 1-(2-Hydroxyethyl)-2,5-dimethylbenzimidazole (13)
To 100mL of 4N HCl was added 3.78g (0.0129mol) of
crude 12. This mixture was then heated under reflux for
3h. The reaction was cooled to room temperature fol-
lowed by cooling in an ice bath. Concentrated ammo-