CDCl3, Me4Si) 1.80 (4H, m, CH2 × 2), 2.54 (4H, m, CH2N × 2),
2.54 (2H, t, J 7 Hz, CH2CO), 2.76 (2 H, t, J 7 Hz, CH2N),
3.68 (3H, s, CH3); dC (125 MHz, CDCl3, Me4Si) 23.8 (CH3),
4 hours. The reaction mixture was then evaporated to dryness to
give a thick yellow oil that was purified by column chromatography
using 10% ethyl acetate in petroleum ether on neutralised silica gel.
The title compound 4 was obtained as a pale yellow oil (536 mg,
61%). mmax (film)/cm−1 2940, 2880, 2828, 1688, 1600, 1468 and
1159; dH (300 MHz, CDCl3, Me4Si) 2.36 (2H, quintet, J 6 Hz,
2ꢀ-H2), 3.62 (2H, t, J 6 Hz, 3ꢀ-H2), 4.20 (2H, t, J 6 Hz, 1ꢀ-H2), 7.02
(2H, d, J 8.5 Hz, 3-H and 5-H), 7.69 (2H, d, J 8.5 Hz, 2-H and
6-H), 9.89 (1H, s, CHO); dC (125 MHz, CDCl3, Me4Si) 25.7 (C-
2ꢀ), 29.9 (C-3ꢀ), 66.0 (C-1ꢀ), 115.2 (C-3 and C-5), 130.6 (C-1), 132.4
(C-2 and C-6), 164.1 (C-1), 191.2 (CHO); m/z (EI) 241.9940 (M+,
C10H11O2Br requires 241.9942), 244 (40%), 242 (41), 138 (40), 122
(47), 121 (100), 77 (23), 65 (33).
34.3 (CH2 × 2), 51.8 (CH2CO), 51.9 (CH2N), 54.4 (CH2N), 173.3
+
=
(C O); m/z (CI) 158 (MH , 100%), 130 (47), 84 (30), 70 (15).
3-Pyrrolidin-1ꢀ-yl propan-1-ol. A suspension of lithium alu-
minium hydride (525 mg, 13.84 mmol) in dry diethyl ether
◦
(10 mL) at 0 C was treated dropwise with a solution of methyl-
3-pyrrolidin-1ꢀ-yl propanoate (2.12 g, 13.84 mmol) in diethyl
ether (10 mL). The reaction mixture was left to stir for 1 hour.
Water (525 lL) was then added slowly, followed by a solution of
sodium hydroxide (15%, 525 lL), and finally water (1.58 mL). A
white precipitate formed. Dichloromethane (15 mL) was added to
solubilise the alcohol, the suspension was filtered and the filtrate
was concentrated in vacuo to give the title product as a colourless
oil (1.52 g, 85%). mmax (film)/cm−1 3367, 2944, 2877, 2803, 1457,
1134, 1065; dH (300 MHz, CDCl3, Me4Si) 1.56–1.78 (6H, m, 2-H2
and CH2 × 2), 2.56 (4H, CH2N × 2), 2.73 (2 H, t, J 6 Hz, 3-H2),
3.81 (2H, t, J 6 Hz, 1-H2), 5.50 (1H, s, OH); dC (125 MHz, CDCl3,
Me4Si) 23.7 (CH2 × 2), 29.5 (C-2), 54.6 (CH2N × 2), 56.8 (C-3),
65.1 (C-1); m/z (CI) 130 (MH+, 100%), 84 (22), 58 (100).
2,2-Bis[4ꢀ-(3ꢀꢀ-pyrrolidinopropoxy)phenyl]-5,5-bi-1H-benzimida-
zole 6c. A solution of 3,3ꢀ-diaminobenzidine tetrahydrochloride
dehydrate (200 mg, 541 mmol), in N,N-dimethylformamide
(15 mL) was treated with sodium hydroxide (80 mg) in water
(1 mL), followed by a solution of aldehyde 8 (252 mg, 1.082 mmol)
R
in DMF (14 mL), and finally Oxoneꢀ (432 mg, 0.703 mmol).
The reaction mixture was left stirring for 18 hours. A solution of
potassium carbonate in water (1 M, 2 mL) was added, followed
by water (30 mL). The solid that precipitated was then filtered
under vacuum, and washed with water. It was then left to dry in
the air. The title compound was obtained as a tan-coloured solid
4-(3ꢀ-Pyrrolidin-1ꢀꢀ-ylpropoxy)benzaldehyde 8. A solution of
3-pyrrolidin-1ꢀ-yl propan-1-ol (250 mg, 1.93 mmol) in
dichloromethane was cooled to 0 ◦C, then treated dropwise with
thionyl chloride (3 mL, 41 mmol). The reaction mixture was stirred
in the cold for 2.5 h. The solvent and excess reagent were then
removed in vacuo and the solid residue was then dried under high
vacuum to give the desired chloride 7 as a white solid that was
used fresh and without further purification in the next step.
A solution of 4-hydroxybenzaldehyde (207 mg, 1.70 mmol) in
dry DMF (15 mL) was treated with caesium carbonate (1.4 g,
4.3 mmol), followed after 5 minutes by sodium iodide (220 mg,
1.46 mmol) and the chloride 7 (270 mg, 1.46 mmol). The reaction
mixture was stirred vigorously and heated to 100 ◦C, in the dark,
for 10 hours. After cooling, the mixture was treated with a solution
of sodium hydroxide (2 M, 50 mL). Sodium chloride was added
to help the separation of the layers, and the aqueous mixture
was extracted with ethyl acetate (4 × 50 mL). The combined
organic layer was washed with brine (100 mL), and a solution
of sodium hydroxide (2 M, 100 mL). It was then dried over
magnesium sulfate, concentrated, and dried under high vacuum to
give the desired product as an orange oil. (253 mg, 74%). mmax (KBr
disc)/cm−1 2957, 2796, 1690, 1601, 1259 and 1159; dH (300 MHz,
CDCl3, Me4Si) 1.82 (4H, m, CH2 × 2), 2.04 (2H, quintet, J 6.5 Hz,
2-H2), 2.52 (4H, m, CH2N × 2), 2.63 (2H, t, J 7 Hz, 3-H2), 4.12 (2H,
t, J 6.5 Hz, 1-H2), 7.04 (2H, d, J 7 Hz, 2ꢀ-H and 6ꢀ-H), 7.82 (2H, d,
J 7 Hz, 3ꢀ-H and 5ꢀ-H), 9.87 (1H, s, CHO); dC (125 MHz, CDCl3,
Me4Si) 23.8 (C-3ꢀꢀ and C-4ꢀꢀ), 29.1 (C-2ꢀ), 53.3 (C-3ꢀ), 54.6 (C-2ꢀꢀ and
C-5ꢀꢀ), 67.2 (C-1ꢀ), 115.2 (C-3 and C-5), 130.2 (C-1), 132.36 (C-2
◦
(301 mg, 87%). Mp 192–194 C (decomp.); mmax (KBr disc)/cm−1
3400, 2959, 1612, 1254 and 1179; dH (500 MHz, DMSO-d6) 1.66
(8H, m, 3ꢀꢀꢀ-H2 and 4ꢀꢀꢀ-H2), 1.89 (4H, quintet, J 7 Hz, 2ꢀꢀ-H2),
2.48 (8H, m, 2ꢀꢀꢀ-H2 and 5ꢀꢀꢀ-H2), 2.52 (4H, t, J 7 Hz, 3ꢀꢀ-H2), 4.08
(4H, t, J 6.5 Hz, 1ꢀꢀ-H2), 7.10 (4H, d, J 8.5 Hz, 3ꢀ-H2 and 5ꢀ-H2),
7.50 (2H, d, J 8.5 Hz, 7-H), 7.61 (2H, d, J 8.5 Hz, 6-H), 7.78
(2H, s, 4-H), 8.12 (4H, d, J 8.5 Hz, 2ꢀ-H and 6ꢀ-H); dC (125 MHz,
DMSO-d6) 24.0, 29.1, 53.1, 54.4, 67.0, 115.7, 122.4, 123.5, 128.9,
136.4, 152.9, 160.9; m/z (ES) 641.6 (M, 17), 321.6 (100).
General procedure for the preparation of 2,2-bis[4ꢀ-(3ꢀꢀ-
piperidinylpropoxy)phenyl]-5,5-bi-1H-benzimidazole 6a and
2,2-bis[4ꢀ-(3ꢀꢀ-N-methylpiperazinylpropoxy)phenyl]-5,5-bi-1H-
benzimidazole 6b
A solution of 3,3ꢀ-diaminobenzidine tetrahydrochloride dehydrate
(1 equivalent), in N,N-dimethylformamide (29 mL) was treated
with sodium hydroxide (3 equivalents) in water (1 mL), followed
by a solution of 4-bromopropoxybenzaldehyde (2 equivalents) in
R
DMF, and Oxoneꢀ (1.3 equivalents). The reaction mixture was left
to stir for 18 hours, then excess methyl piperazine or piperidine
was added. The mixture was left to stir for an additional hour. A
solution of potassium carbonate in water (1 M, 1.5 mL/100 mg
starting tetraamine) was added, followed by water (30 mL/100 mg
starting tetraamine). The solid that precipitated was filtered under
vacuum, and washed with water. It was then left to dry in air.
+
+
=
and C-6), 164.5 (C-4), 191.2 (C O); m/z (CI ) 234.1489 (MH ,
Bis-benzimidazole derivative 6a. The reaction was carried
C14H20NO2 requires 234.1494), 234 (100%), 112 (12), 84 (43).
out following the procedure described above with tetraamine
R
4-(3ꢀ-Bromo-1ꢀꢀ-propoxy)benzaldehyde 4. A solution of bro-
mopropanol (500 mg, 3.6 mmol), triphenylphosphine (1.575 g,
5.4 mmol) and 4-hydroxybenzaldehyde (440 mg, 3.6 mmol) in
dry tetrahydrofuran (15 mL) at 0 ◦C was treated with diethyl
azodicarboxylate (DEAD) (0.62 mL, 5.4 mmol), dropwise. The
reaction mixture was left to stir and warm to room temperature for
3 (394 mg), aldehyde 4 (480 mg), Oxoneꢀ (782 mg), sodium
hydroxide (163 mg), DMF (29 mL), water (1 mL), and piperidine
(2.5 mL). The title compound◦was obtained as a tan-coloured solid
(541 mg, 82%). Mp 164–166 C (decomp.); mmax (KBr disc)/cm−1
3400, 3152, 2854, 2818, 1611, 1492, 1180, 1038 and 803; dH
(500 MHz, DMSO-d6) 1.37 (4H, m, 4ꢀꢀ-H2), 1.49 (8H, m, 3ꢀꢀ-H2
This journal is
The Royal Society of Chemistry 2006
Org. Biomol. Chem., 2006, 4, 1305–1312 | 1309
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