3H, methanesulfonyl) 2.56 (s, 3H, 2-methyl); APCI+: calcd for
C19H22N5O7S 464.1240, found 464.1218.
(n-butanol–acetic acid–water [5 : 2 : 3]) Rf = 0.41; FTIR 3310,
2982, 2918, 2758, 1655, 1516, 1334, 1205, 1047, 829, 557 cm−1; 1H
NMR (DMSO-d6) d 7.11 (1 s, 1H, C(10)), 6.98 (broad s, 1H, N-
H), 4.38 and 3.63 (2t, J = 5.1 Hz, 4H, ethylene bridgehead), 3.73
(multiplet, 1H, methylene), 2.71 and 2.69 (2 s, 6H, methyls), 0.79
and 0.62 (2 multiplet, 4H, ethylene); APCI+: calcd for C15H18N5
268.1562, found 268.1576.
1-(2-Methanesulfonoxyethyl)-2-methyl-5,7-dinitro-6-(cyclopro-
pylamino)-1H-benzimidazole (7c). 320 mg (86% yield); Mp 185–
188 ◦C; TLC (dichloromethane–methanol [95 : 5]) Rf = 0.46; FTIR
3398, 3029, 3028, 2933, 1629, 1579, 1512, 1460, 1356, 1269 cm−1;
1H NMR (CDCl3) d 8.64 (1 s, 1H, C(4)), 8.39 (broad s, 1H, N-H),
4.40 (multiplet, 4H, ethylene), 2.98 (s, 3H, methanesulfonyl), 2.59
(multiplet, 1H, methylene), 2.66 (s, 3H, 2-methyl), 0.79 and 0.62
(2 doublet of triplets, J = 5.4 and 2.1, 4H, ethylene); APCI+: calcd
for C14H18N5O7S 400.0927, found 400.0920.
5,6-Dihydro-2,8-dimethyl-7-(2-methoxyethyl)-diimidazo[1,5,4-
de, 1,5,4-h]-quinoxaline (9d). 65mg (71% yield); Mp dec >
◦
295 C; TLC (n-butanol–acetic acid–water [5 : 2 : 3]) Rf = 0.36;
FTIR 3396, 3306, 2931, 2814, 1655, 1577, 1633, 1516, 1431, 1342,
1194, 1039, 785, 559 cm−1; too unstable for an 1H-NMR; APCI+:
calcd for C15H20N5O 286.1668, found 286.1645.
1-(2-Methanesulfonoxyethyl)-2-methyl-6-(2-methoxyethylamino)-
5,7-dinitro-1H-benzimidazole(7d). 324 mg 88% yield); Mp
160–164 ◦C; TLC (dichloromethane–methanol [97 : 3]) Rf =
0.36; FTIR 3304, 3078, 2980, 2933, 2891, 2814, 1633, 1579, 1520,
1437, 1361, 1248, 1180, 1047 cm−1; 1H NMR (CDCl3) d 8.55 (1 s,
1H, C(4)), 4.29 (multiplet, 4H, N(1) ethylene), 3.57 and 3.15 (2t,
J = 4.8 Hz, 4H, C(6) ethylene), 3.30 (s, 3H, methanesulfonyl),
2.84 (s, 3H, methoxy), 2.59 (s, 3H, 2-methyl); APCI+: calcd for
C14H20N5O8S 418.1032.
General procedure for the synthesis of 1a–d
A solution of 20–100 mg of 9a–d in 20 ml of 0.2 M pH 7.0
phosphate buffer was combined with (excess) 250 mg of Fremy
salt. This mixture was stirred for 5 min at room temperature and
then the aqueous solution was extracted with 3 × 15 mL portions
of chloroform. The organic layer was dried over Na2SO4 and then
concentrated to a solid under reduced pressure. The final product
was crystallized from ethyl acetate–hexane.
General procedure for the synthesis of 9a–d
A solution of 100 mg of 7a–d in 60 mL of methanol was purged
with N2 and then combined with 100 mg of 5% Pd on carbon.
This mixture was then shaken in a hydrogenation apparatus under
50 psi of H2 for 24 h. After the reduction, the catalyst was filtered
through a bed of Celite and the solution concentrated to an oil (8a–
d) under reduced pressure. To this oil were added 5 mL of acetic
anhydride and the mixture refluxed for 1 h. After completion of
the reflux, the mixture was allowed to cool to room temperature
and then concentrated under reduced pressure to an oil. For the
synthesis of 9a–c, 2 mL of 48% HBr were added to facilitate closure
of the imidazo ring. For the synthesis of 9d, 37% HCl was used
to protect the side chain methoxy group. For 9a–d, the respective
acid mixtures were refluxed for 1 h. Afterwards, the mixture was
allowed to cool to room temperature and concentrated under
reduced pressure. The resulting dark oil was then crystallized using
ethanol–ethyl acetate, yielding a hydrohalide salt.
4,5-Dihydro-2,7,8-trimethyldiimidazo[1,5,4-de, 1,5,4-h]quinoxa-
lin-10-one (1a). 5.0 mg (50% yield); Mp dec ≥ 280 ◦C; TLC
(dichloromethane–methanol [90 : 10]) Rf = 0.27; FTIR 3493,
3041, 2982, 2947, 2850, 1685, 1655, 1606, 1541, 1249, 1103, 1028,
1
885 cm−1; H NMR (CDCl3) d 4.35 and 4.08 (2t, J = 7.2 Hz,
4H, ethylene bridge), 4.11 (s, 3H, N(7) methyl), 2.79 (s, 3H, C(2)
methyl), 2.78 (s, 3H, 2-methyl); MALDI: calcd for C13H14N5O
(M + 1) 256.120, found 256.115.
4,5-Dihydro-2,8-dimethyl-7-(2-phenethyl)-diimidazo[1,5,4-de, 1,
5,4-h]-quinoxalin-10-one (1b). 6.5 mg (17% yield); Mp dec ≥
264 ◦C; TLC (dichloromethane–methanol [96 : 4]) Rf = 0.29; FTIR
3431, 3149, 3028, 2930, 1655, 1560, 1438, 1174, 1111, 619 cm−1; 1H
NMR (CDCl3) d 7.14 (t, 3H, phenyl (C3ꢀ, C4ꢀ and C5ꢀ)), 6.94 (dd,
J = 1.8 Hz and 6.0 Hz, phenyl (C2ꢀ and C6ꢀ)), 4.40 and 3.96 (2t,
J = 7.2 Hz, ethylene bridgehead), 4.25 and 2.96 (2t, J = 7.2 Hz,
4H, ethylene sidechain), 2.70 (s, 8-methyl), 2.15 (s, 3H, 2-methyl);
MALDI: calcd for C20H20N5O (M + 1) 346.167, found 346.166.
5,6-Dihydro-2,7,8-trimethyl-7-diimidazo[1,5,4-de, 1,5,4-h]-qui-
noxaline (9a). 45 mg (46% yield); Mp ≥ 280 ◦C dec; TLC (n-
butanol–acetic acid–water [5 : 2 : 3]) Rf = 0.29; FTIR 3431,
3346, 2920, 2750, 1655, 1529, 1462, 1423, 1317, 1195, 1072, 798,
563 cm−1; 1H NMR (DMSO-d6) d 7.30 (broad s, 1H, amine), 7.25
(1 s, 1H, C(10)), 4.42 and 3.71 (2t, J = 5.4 Hz, 4H, ethylene bridge),
2.79 and 2.78 (2 s, 6H, methyls); APCI+: calcd for C13H16N5
242.1406, found 242.1386.
4,5-Dihydro-2,8-dimethyl-7-cyclopropyl-diimidazo[1,5,4-de, 1,5,
4-h]-quinoxalin-10-one (1c). 23 mg (33% yield); Mp dec ≥ 255 ◦C;
TLC (dichloromethane–methanol [90 : 10]) Rf = 0.27; FTIR 3427,
3082, 3009, 2960, 2926, 1658, 1496, 1437, 1357, 1265, 1072 cm−1;
1H NMR (CDCl3) d 4.38 and 4.05 (2t, J = 6.9 Hz, 4H, ethylene
bridge), 3.25 (sept, J = 3.3 Hz, 1H, methylene), 2.54 (s, 3H, 8-
methyl), 2.41 (s, 3H, 2-methyl), 1.32 and 1.85 (2 multiplet, 4H,
ethylene); MALDI: calcd for C15H16N5O (M + 1) 282.135, found
282.134.
5,6-Dihydro-2,8-dimethyl-7-(2-phenethyl)-diimidazo[1,5,4-de, 1,
◦
5,4-h]-quinoxaline (9b). 80 mg (75% yield); Mp ≥ 255 C; TLC
(n-butanol–acetic acid–water [5 : 2 : 3]) Rf = 0.51; FTIR 3188,
2920, 2741, 1653, 1512, 1421, 1340 cm−1; 1H NMR (DMSO-d6) d
7.17 (1 s, 1H, C(10)), 7.13 and 6.85 (2 multiplet, 5H, phenyl), 4.72
and 4.36 (2t, J = 6 Hz, 4H, N(7) ethylene), 3.63 and 3.04 (2t, J =
6.6 Hz, 4H, ethylene bridgehead), 2.70 and 2.15 (2 s, 6H, methyls);
APCI+: calcd for C20H22N5 332.1875, found 332.1885.
4,5-Dihydro-7-(2-methoxyethyl)-2,8-dimethyl-diimidazo[1,5,4-
de, 1,5,4-h]-quinoxalin-10-one (1d). 10.5 mg (28% yield); Mp
dec ≥ 180 ◦C; TLC (dichloromethane–methanol [95 : 5]) Rf =
0.32; FTIR 3365, 3261, 3163, 2924, 2852, 1656, 1514, 1460, 1377,
1
1118, 1070, 659 cm−1; H NMR (CDCl3) d 4.89 and 3.79 (2t,
7-Cyclopropyl-5,6-dihydro-2,8-dimethyl-diimidazo[1,5,4-de, 1,5,
4-h]-quinoxaline (9c). 85 mg (80% yield); Mp dec ≥ 235 ◦C; TLC
J = 5.4 Hz, 4H, ethylene bridgehead), 4.34 and 4.07 (2t, J =
6.6 Hz, 4H, ethylene sidechain), 3.28 (s, 3H, methoxy), 2.50 (s, 3H,
This journal is
The Royal Society of Chemistry 2008
Org. Biomol. Chem., 2008, 6, 3059–3064 | 3063
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