J.-C. G. Bꢁnzli et al.
(CBenzquat), 152.93 (CPyquat), 168.26 (CPy-Oquat), 168.47 ppm (C=O); ESI-MS:
m/z calcd: 975.40 [M+H]+, 488.20 [M+2H]+/2; found: 975.39 (high reso-
NCH3), 5.07 (s, 2H; CH2), 7.65 (s, H, HIsoqu), 7.66 (d, 4J=2.2 Hz, 2H;
H
Py), 7.95 (d, 4J=2.2 Hz, 2H; HPy), 8.13 (d, 3J=5.7 Hz, 2H; HIsoqu), 8.65
lution),
488.38;
elemental
analysis
calcd
(%)
for
(d, 3J=5.7 Hz, 2H; HIsoqu), 10.12 ppm (s, 2H; HIsoqu); 13C NMR
(600 MHz, [D6]DMSO): d=36.72 (NCH3), 40.03 (CH2), 58.06 (OCH3),
68.16 (OCH2), 68.53 (OCH2), 69.64 (OCH2), 69.81 (OCH2), 70.04
(OCH2), 71.29 (OCH2), 112.28 (CHPy), 112.57 (CHPy), 118.61 (CHIsoqu),
118,74 (CIsoququat), 124.77 (CIsoququat), 129.55 (CIsoququat), 130.70 (CHIsoqu),
133.08 (CIsoququat), 139.95 (CHIsoqu), 142.74 (CIsoququat), 145.76 (CBenzquat),
148.54 (CPyquat), 149.41 (CPyquat), 151.43 (CHIsoqu), 165.83 (CPy-Oquat),
166.11 ppm (C=O); ESI-MS: m/z calcd: 945.38 [M+H]+, 473.19
[M+2H]+/2; found: 945.38 (high resolution), 473.20; elemental analysis
calcd (%) for C49H52N8O12·0.6NH4OH·1.5NaCl: C 55.89, H 5.26, N 11.43;
found: C 55.94, H 5.25, N 11.30.
C49H54N10O12·0.25NH4OH·1.5H2O: C 58.22, H 5.80, N 14.20; found: C
58.19, H 5.59, N 14.25.
Diethyl
6,6’-{methylenebis[(7-nitro-5,8-isoquinolinediyl)(methylcarba-
moyl)]}bis(4-{2-[2-(2-methoxyethoxy)ethoxy]ethoxy}-2-pyridine carboxyl-
ate) (IC5b): A mixture of 1 (700 mg, 1.96 mmol), freshly distilled SOCl2
(2.33 g, 19.6 mmol), and dry DMF (20 mL, 0.250 mmol) were heated
under reflux for 120 min in dry CH2Cl2 (25 mL) under inert atmosphere.
After evaporation and pumping for 2 h, the pale yellow oil formed was
redissolved in dry CH2Cl2 (50 mL) and NEt3 (3 mL). Then, IC5a (300 mg,
0.717 mmol) was added in small portions over a period of 1 h. The solu-
tion was heated under reflux under an inert atmosphere for 24 h. and
evaporated. The brown residue was redissolved in CH2Cl2 (100 mL) and
washed with half-saturated NH4Cl (2ꢆ100 mL). The combined organic
phase were dried over anhydrous Na2SO4, evaporated, and the resulting
crude solid was purified by column chromatography (silica gel, CH2Cl2!
CH2Cl2/MeOH 98:2!95:5) to give the disubstituted product IC5b as
brown orange oil (364 mg, 47% yield). This product was directly convert-
ed into IC5c without further purification. ESI-MS: m/z calcd: 1097.41
[M+H]+, 549.71 [M+2H]+/2; found: 1097.39, 549.37.
Diethyl 6,6’-{methylanediylbis[(5-methoxy-2-nitrobenzene-4,1-diyl)(me-
thylcarbamoyl)]}bis(4-{2-[2-(2-methoxyethoxy)ethoxy]ethoxy}-2-pyridine
carboxylate) (IC6b): A mixture of 1 (730 mg, 2.04 mmol), freshly distilled
SOCl2 (2.43 g, 20.4 mmol), and dry DMF (20 mL, 0.250 mmol) were
heated under reflux for 2 h in dry CH2Cl2 (25 mL) under an inert atmos-
phere. Upon evaporation and pumping for 2 h, the pale yellow oil
formed was redissolved in dry CH2Cl2 (50 mL) and NEt3 (3 mL). Then,
IC6a (300 mg, 0.717 mmol) was added in small portions over a period of
one hour. The solution was heated under reflux under an inert atmos-
phere for 16 h and evaporated. The brown residue was redissolved in
CH2Cl2 (100 mL) and washed with half-saturated NH4Cl (2ꢆ100 mL).
The combined organic phases were dried over anhydrous Na2SO4, evapo-
rated, and the resulting crude solid was purified by column chromatogra-
phy (silica gel, CH2Cl2!CH2Cl2/MeOH 100:0!97:3) to give the disubsti-
tuted product IC6b as brown orange oil (654 mg, 79% yield), which was
directly converted into IC6c without further purification. ESI-MS: m/z
calcd: 1055.41 [M+H]+, 528.21 [M+2H]+/2; found: 1055.83, 528.34.
Diethyl
(6,6’-[methylenebis(1-methyl-1H-imidazoACTHNGUETRNNU[G 4,r5-h]isoquinoline-
5,2-diyl)]bis(4-{2-[2-(2-methoxyethoxy)ethoxy]ethoxy}-2-pyridine carbox-
ylate) (IC5c): Freshly activated iron powder (550 mg, 9.85 mmol) and HCl
solution (25%, 2.7 mL) were added to
a
solution of IC5b (460 mg,
0.408 mmol) in ethanol/water (66/18 mL). The mixture was heated under
reflux overnight under an inert atmosphere. The solution was cooled, the
excess of unreacted iron filtered and the solvent evaporated. The crude
product was redissolved in absolute EtOH (30 mL); H2SO4 (97%, 2 mL)
was added carefully and the solution was heated under reflux overnight.
It was cooled and the solvents were removed. Distilled water (100 mL)
was added and the pH was adjusted to 6 with a saturated solution of
aqueous NaHCO3; Na2EDTA (2.44 g, 6.57 mmol) was added to this solu-
tion. The colour turned to brown upon addition of H2O2 solution (30%,
1 mL). The pH was adjusted to 7 with a saturated solution of aqueous
NaHCO3 before extraction with CH2Cl2 (5ꢆ250 mL). The organic phases
were combined, and extracted again with a saturated solution of aqueous
NaHCO3 containing Na2EDTA (2.44 g), dried over anhydrous Na2SO4,
filtered and evaporated to dryness, which resulted in a brown crude solid
subsequently purified by column chromatography (silica gel; CH2Cl2!
CH2Cl2/MeOH 95:5) to give a pale orange solid (54 mg, 17% yield).
1H NMR (400 MHz, CDCl3): d=1.51 (t, 3J=7.1 Hz, 6H; OCH2CH3),
3.38 (s, 6H; OCH3), 3.54–3.56 (m, 4H; H6), 3.64–3.67 (m, 4H; H5), 3.67–
3.70 (m, 4H; H4), 3.73–3.76 (m, 4H; H3), 3.90–3.93 (m, 4H; H2), 4.33–
4.36 (m, 4H; H1), 4.53 (q, 3J=7.1 Hz, 4H; OCH2CH3), 4.98 (s, 6H;
NCH3), 5.00 (s, 2H; CH2), 7.76 (d, 4J=2.6 Hz, 2H; HPy), 7.77 (s, 2H;
Diethyl 6,6’-[methanediylbis(6-methoxy-1-methyl-1H-benzimidazole-5,2-
diyl)]bis(4-{2-[2-(2-methoxyethoxy)ethoxy]ethoxy}pyridine-2-carboxylate)
(IC6c): Freshly activated iron powder (1.04 g, 18.61 mmol) and HCl (25%,
5.2 mL) were added to a solution of IC6b (654 mg, 0.620 mmol) in ethanol/
water (128/35 mL). The mixture was heated under reflux overnight under
an inert atmosphere. The solution was cooled, the excess of unreacted
iron filtered and the solvents evaporated. The crude product was redis-
solved in absolute EtOH (30 mL); H2SO4 (97%, 2 mL) was added care-
fully and the solution was refluxed overnight. The solvents were removed
after cooling and distilled water (100 mL) was added; the pH was then
adjusted to 6 with a saturated solution of aqueous NaHCO3; Na2EDTA
(4.62 g, 12.41 mmol) was added to this solution. The colour turned to
brown upon addition of H2O2 solution (30%, 2 mL). The pH was then in-
creased to 7 with a saturated solution of aqueous NaHCO3 before extrac-
tion with CH2Cl2 (5ꢆ250 mL). The organic phases were combined, and
extracted again with a saturated solution of aqueous NaHCO3 containing
Na2EDTA (4.62 g), dried over anhydrous Na2SO4, filtered and evaporat-
ed to dryness, which resulted in a brown crude solid subsequently puri-
fied by column chromatography (silica gel; CH2Cl2!CH2Cl2/MeOH
3
4
H
Isoqu), 8.01 (d, J=5.4 Hz, 2H; HIsoqu), 8.02 (d, J=2.6 Hz, 2H; HPy), 8.66
(d, 3J=5.4 Hz, 2H; HIsoqu), 10.12 ppm (s, 2H; HIsoqu); 13C NMR
(400 MHz, CDCl3): d=17.41 (OCH2CH3), 39.19 (NCH3), 40.19 (CH2),
58.40 (OCH3), 62.06 (OCH2CH3), 68.60 (OCH2), 69.20 (OCH2), 70.52
(OCH2), 71.46 (OCH2), 71.96 (OCH2), 72.89 (OCH2), 116.11 (CHPy),
117.80 (CHPy), 121.45 (CHIsoqu), 123.03 (CIsoququat), 128.73 (CIsoququat),
130.34 (CIsoququat), 133.80 (CHIsoqu), 137.62 (CIsoququat), 144.32 (CHIsoqu),
145.70 (CIsoququat), 147.49 (CBenzquat), 148.18 (CPyquat), 149.95 (CPyquat),
153.05 (CHIsoqu), 168.50 (C=O), 170.29 ppm (CPy-Oquat); ESI-MS: m/z
calcd: 1001.44 [M+H]+, 501.22 [M+2H]+/2; found: 1001.35, 501.80.
95:5) to give
a
pale yellow solid (501 mg, 85% yield). 1H NMR
(400 MHz, CDCl3): d=1.44 (t, 3J=7.0 Hz, 6H; OCH2CH3), 3.35 (s, 6H;
OCH3), 3.52–3.54 (m, 4H; H6), 3.63–3.65 (m, 4H; H5), 3.66–3.68 (m, 4H;
H4), 3.72–3.74 (m, 4H; H3), 3.88–3.90 (m, 4H; H2), 3.93 (s, 6H; OCH3),
4.16 (brs, 2H; CH2), 4.30–4.33 (m, 4H; H1), 4.36 (s, 6H; NCH3), 4.45 (q,
3J=7.0 Hz, 4H; OCH2CH3), 6.81 (s, 2H; HBenz), 7.47 (s, 2H; HBenz), 7.65
(d, 4J=2.4 Hz, 2H; HPy), 8.00 ppm (d, 4J=2.4 Hz, 2H; HPy); 13C NMR
(800 MHz, CDCl3): d=14.60 (OCH2CH3), 31.45 (CH2), 33.31 (NCH3),
56.19 (OCH3), 59.35 (OCH3), 62.11 (OCH2CH3), 68.48 (OCH2), 69.53
(OCH2), 70.90 (OCH2), 70.95 (OCH2), 71.25 (OCH2), 72.23 (OCH2),
91.30 (CHBenz), 111.46 (CHPy), 113.46 (CHPy), 121.39 (CHBenz), 126.90
(CBenzquat), 136.61 (CBenzquat), 136.98 (CBenzquat), 148.05 (CBenzquat), 148.79
(CPyquat), 152.78 (CPyquat), 156.35 (CBenzquat), 165.31 (C=O), 166.58 ppm
(CPy-Oquat); ESI-MS: m/z calcd: 959.44 [M+H]+, 480.22 [M+2H]+/2;
found: 959.84, 480.38.
6,6’-[Methylenebis(1-methyl-1H-imidazoACHTNUGTRNEUNG[4,5-h]isoquinoline-5,2-diyl]-
bis(4-{2-[2-(2-methoxyethoxy)ethoxy]ethoxy}-2-pyridine carboxylic acid)
(H2LC5): An amount of IC5c (54 mg, 0.0540 mmol) was dissolved in abso-
lute EtOH/H2O (8/3 mL) containing NaOH (9.1 mg, 0.227 mmol). This
mixture was stirred at room temperature for 2 h. After completion of the
reaction, the solvents were removed under reduced pressure. The crude
product was subsequently purified by column chromatography (silica gel;
CH3CN/NH4OH 75:25) to give a pale yellow solid (49 mg, 94% yield).
1H NMR (400 MHz, [D6]DMSO): d=3.18 (s, 6H; OCH3), 3.35–3.38 (m,
4H; H6), 3.46–3.48 (m, 4H; H5), 3.49–3.51 (m, 4H; H4), 3.56–3.59 (m,
4H; H3), 3.76–3.78 (m, 4H; H2), 4.33–4.35 (m, 4H; H1), 4.91 (s, 6H;
6,6’-[Methanediylbis(6-methoxy-1-methyl-1H-benzimidazole-5,2-diyl)]-
bis(4-{2-[2-(2-methoxyethoxy)ethoxy]ethoxy}pyridine-2-carboxylic acid)
(H2LC6): Intermediate IC6c (501 mg, 0.523 mmol) was dissolved in absolute
EtOH/H2O (30 mL) containing NaOH (72 mg, 1.80 mmol). This mixture
898
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Chem. Eur. J. 2009, 15, 885 – 900