10.1002/cmdc.201800587
ChemMedChem
FULL PAPER
reaction was heated to reflux overnight (16-20h). The solution was cooled
to -20°C and the precipitate that formed was collected. The crude product
was recrystallized with ethanol to yield 136mg (66%, Purity: 96.1%) of 3a
Ethyl 2-(4-(3-chloropropyl)piperazin-1-yl)acetate (2ha)- 1-bromo-3-
chloropropane (1.1mL, 1.72g, 11mmol; 1.5eq) of 1-bromo-3-
chloropropane and amine component (1.16g, 1eq) were dissolved in
acetonitrile (40mL) at room temperature while stirring. triethylamine
(3.1mL, 2.2g, 2eq) was then added dropwise, the reaction mixture was
stirred at room temperature for 24h and purified as above to yield a yellow
oil (yield: 654mg, 36%). LC-MS m/z: calculated for C11H21ClN2O2+H+,
248.1 [M+H]+, found 248.2 [M+H]+.
1
as a yellow solid. H NMR (500 MHz, DMSO-d6) δ 9.98 (s, 1H), 7.56 (s,
1H), 6.93 (d, J = 7.8 Hz, 1H), 6.88 (s, 1H), 6.75 (d, J = 1.7 Hz, 1H), 6.66
(dd, J = 7.9, 1.6 Hz, 1H), 6.06 (d, J = 1.9 Hz, 2H), 4.78 (s, 2H), 4.42 (s,
2H), 3.88 (s, 3H), 3.59 (s, 3H). ESI-MS (ESI+) m/z: calculated for
C21H18N2O6+H+, 395.1237 [M+H]+, found 395.1240 [M+H]+.
Hydrazone synthesis: General Procedure. 3a (50mg, 0.126mmol, 1eq)
and the select aromatic aldehyde (1.2eq) were dissolved in methanol
(10mL). The reaction was heated to reflux overnight (16-20h). The reaction
was then cooled to room temperature and concentrated under reduced
pressure. The residual solution was then cooled to -20°C to precipitate the
crude product from solution. The crude precipitate was collected and
recrystallized with ethanol to yield the final product.
2-(4-(3-chloropropyl)piperazin-1-yl)ethan-1-ol
(2ia)-
1-bromo-3-
chloropropane (1.1mL, 1.72g, 11mmol; 1.5eq) of 1-bromo-3-
chloropropane and amine component (0.952g, 1eq) were dissolved in
acetonitrile (40mL) at room temperature while stirring. triethylamine
(3.1mL, 2.2g, 2eq) was then added dropwise, the reaction mixture was
stirred at room temperature for 24h and purified as above to yield a yellow
oil (yield: 551mg, 36%). LC-MS m/z: calculated for C9H19ClN2O+H+, 207.1
[M+H]+, found 207.1 [M+H]+.
(E)-9-(benzo[d][1,3]dioxol-5-yl)-2-(benzylideneamino)-4-hydroxy-6,7-
dimethoxy-2,3-dihydro-1H-benzo[f]isoindol-1-one (3b)- 3a (50mg,
0.126mmol, 1eq) and benzaldehyde (15µl 16mg, 1.2eq) were dissolved in
methanol (10mL). The reaction was heated to reflux overnight, and the
final product was purified as above to give a yellow solid (yield: 52mg, 85%,
Purity: 96.2%). 1H NMR (500 MHz, DMSO-d6) δ 10.22 (s, 1H), 8.65 – 8.61
(m, 2H), 8.10 (s, 1H), 7.64 (d, J = 5.2 Hz, 4H), 6.98 (d, J = 8.0 Hz, 1H),
6.92 (s, 1H), 6.83 (s, 1H), 6.72 (d, J = 8.0 Hz, 1H), 6.09 (s, 2H), 4.84 (s,
2H), 3.90 (s, 3H), 3.61 (s, 3H). ESI-MS (ESI+) m/z: calculated for
C28H22N2O6 +H+, 483.1551 [M+H]+, found 483.1547 [M+H]+.
General synthetic procedure for hydrophilic phenol ether derivatives:
2a (50mg, 0.131mmol, 1eq), the chloropropylamine precursor (2eq), and
potassium carbonate (91mg, 0.655mmol, 5eq) were dissolved in dimethyl
sulfoxide (6mL). The reaction was heated to reflux overnight (16-20h). The
reaction was then cooled to room temperature and 20mL of distilled water
was added to the flask. The mixture was added to a separatory funnel and
extracted with ethyl acetate (5x30mL). The organic layers were combined
and washed with brine (30mL) before concentrating the organic layers
under reduced pressure. The crude product was purified with normal
phase silica gel chromatography (DCM/MeOH 100/0 to 80/20) to yield the
pure solid.
(E)-9-(benzo[d][1,3]dioxol-5-yl)-4-hydroxy-6,7-dimethoxy-2-((pyridin-
3-ylmethylene)amino)-2,3-dihydro-1H-benzo[f]isoindol-1-one (3c)- 3a
(50mg, 0.126mmol, 1eq) and nicotinaldehyde (14µl, 16mg, 1.2eq) were
dissolved in methanol (10mL). The reaction was heated to reflux overnight,
and the final product was purified as above to give a yellow solid (yield:
45mg, 74%, Purity: 95.5%). 1H NMR (300 MHz, DMSO-d6) δ 10.24 (s, 1H),
8.90 (s, 1H), 8.60 (s, 1H), 8.23 (s, 1H), 8.13 (d, J = 8.1 Hz, 1H), 7.67 (s,
1H), 7.56 – 7.45 (m, 1H), 7.06 – 6.91 (m, 2H), 6.86 (d, J = 1.6 Hz, 1H),
6.75 (d, J = 8.1 Hz, 1H), 6.11 (s, 2H), 4.88 (s, 2H), 3.93 (s, 3H), 3.64 (s,
3H), 1.90 (s, 1H). 13C NMR (201 MHz, DMSO-d6) δ 164.0, 150.9, 150.5,
149.9, 149.2, 147.2, 146.8, 146.0, 140.7, 133.7, 131.2, 130.1, 129.7, 129.1,
124.5, 124.2, 123.2, 115.8, 111.7, 108.1, 106.0, 101.5, 101.4, 56.0, 55.5,
45.5, 21.5. ESI-MS (ESI+) m/z: calculated for C27H21N3O6 +H+, 483.1503
[M+H]+, found 483.1500 [M+H]+.
9-(benzo[d][1,3]dioxol-5-yl)-6,7-dimethoxy-4-(3-
morpholinopropoxy)naphtho[2,3-c]furan-1(3H)-one (2g)- 2a (50mg,
0.131mmol, 1eq), 2ga (22mg, 2eq), and potassium carbonate (80mg,
0.579mmol, 5eq) were dissolved in dimethyl sulfoxide (6mL). The reaction
was heated to reflux overnight and purified as above to give a yellow solid
1
(yield: 45mg, 67%, Purity: 95.2%). H NMR (500 MHz, DMSO-d6) δ 7.49
(s, 1H), 7.00 (d, J = 7.9 Hz, 1H), 6.93 (s, 1H), 6.85 (d, J = 1.6 Hz, 1H), 6.73
(dd, J = 7.9, 1.7 Hz, 1H), 6.09 (s, 2H), 5.58 (s, 2H), 4.27 (t, J = 6.1 Hz, 2H),
3.92 (s, 3H), 3.63 (s, 3H), 3.55 (t, J = 4.5 Hz, 4H), 2.53 (t, J = 7.3 Hz, 2H),
2.36 (s, 4H), 1.97 (p, J = 6.6 Hz, 2H). 13C NMR (201 MHz, DMSO-d6) δ
169.5, 151.7, 150.4, 147.4, 147.3, 146.9, 133.3, 130.0, 128.8, 126.0, 125.8,
124.1, 119.4, 111.3, 108.4, 106.0, 101.6, 101.0, 70.4, 67.1, 66.7, 56.0,
55.7, 55.4, 53.9, 27.3. ESI-MS (ESI+) m/z: calculated for C28H29NO8+H+,
508.1966 [M+H]+, found 508.1967 [M+H]+.
(E)-9-(benzo[d][1,3]dioxol-5-yl)-2-((4-chlorobenzylidene)amino)-4-
hydroxy-6,7-dimethoxy-2,3-dihydro-1H-benzo[f]isoindol-1-one (3d)-
3a (49mg, 0.124mmol, 1eq) and 4-chlorobenzaldehyde (21mg, 1.2eq)
were dissolved in methanol (10mL). The reaction was heated to reflux
overnight, and the final product was purified as above to give a yellow solid
(yield: 51mg, 77%, Purity: 99.2%). 1H NMR (500 MHz, DMSO-d6) δ 10.19
(s, 1H), 8.16 (s, 1H), 7.75 (d, J = 8.6 Hz, 2H), 7.64 (s, 1H), 7.55 – 7.48 (m,
2H), 6.98 (d, J = 7.9 Hz, 1H), 6.91 (s, 1H), 6.82 (d, J = 1.7 Hz, 1H), 6.72
(dd, J = 7.9, 1.7 Hz, 1H), 6.08 (s, 2H), 4.84 (s, 2H), 3.91 (s, 3H), 3.61 (s,
3H). ESI-MS (ESI+) m/z: calculated for C28H21ClN2O6 +H+, 517.1161
[M+H]+, found 517.1156 [M+H]+.
Ethyl 2-(4-(3-((9-(benzo[d][1,3]dioxol-5-yl)-6,7-dimethoxy-1-oxo-1,3-
dihydronaphtho[2,3-c]furan-4-yl)oxy)propyl)piperazin-1-yl)acetate
(2h)- 2a (51mg, 0.134mmol, 1eq), 2ha (33mg, 2eq), and potassium
carbonate (90mg, 0.655mmol, 5eq) were dissolved in dimethyl sulfoxide
(6mL). The reaction was heated to reflux overnight and purified as above
to give an off-white, amorphous solid (yield: 36mg, 46%, Purity: 97.1%).
1H NMR (500 MHz, DMSO-d6) δ 7.47 (s, 1H), 6.99 (d, J = 7.9 Hz, 1H), 6.92
(s, 1H), 6.84 (d, J = 1.6 Hz, 1H), 6.72 (dd, J = 8.0, 1.7 Hz, 1H), 6.09 (s,
2H), 5.56 (s, 2H), 4.24 (t, J = 6.1 Hz, 2H), 4.04 (q, J = 7.1 Hz, 2H), 3.91 (s,
3H), 3.62 (s, 3H), 3.15 (s, 2H), 2.59 – 2.53 (m, 2H), 2.50 (s, 8H), 1.96 (p,
J = 6.6 Hz, 2H), 1.14 (t, J = 7.1 Hz, 3H). 13C NMR (201 MHz, DMSO-d6) δ
170.2, 169.4, 151.5, 147.2, 147.1, 146.7, 133.2, 129.8, 128.7, 125.9, 125.7,
123.9, 119.3, 111.2, 108.2, 105.8, 101.4, 100.8, 70.3, 66.9, 60.1, 58.8,
55.9, 55.5, 53.1, 52.3, 40.7, 27.3, 14.5. ESI-MS (ESI+) m/z: calculated for
C32H36N2O9+H+, 593.2493 [M+H]+, found 593.2491 [M+H]+.
(E)-9-(benzo[d][1,3]dioxol-5-yl)-2-((4-bromobenzylidene)amino)-4-
hydroxy-6,7-dimethoxy-2,3-dihydro-1H-benzo[f]isoindol-1-one (3e)-
3a (50mg, 0.126mmol, 1eq) and 4-bromobenzaldehyde (28mg, 1.2eq)
were dissolved in methanol (10mL). The reaction was heated to reflux
overnight, and the final product was purified as above to give a yellow solid
(yield: 55mg, 76%, Purity: 97.9%). 1H NMR (300 MHz, DMSO-d6) δ 10.23
(s, 1H), 8.16 (s, 1H), 7.68 (dd, J = 5.8, 2.9 Hz, 5H), 7.05 – 6.89 (m, 2H),
6.88 – 6.69 (m, 2H), 6.11 (s, 2H), 4.86 (s, 2H), 3.93 (s, 3H), 3.63 (s, 3H).
LC-MS m/z: calculated for C28H21BrN2O6+H+, 561.1 [M+H]+, found 561.4
[M+H]+.
9-(benzo[d][1,3]dioxol-5-yl)-4-(3-(4-(2-hydroxyethyl)piperazin-1-
yl)propoxy)-6,7-dimethoxynaphtho[2,3-c]furan-1(3H)-one (2i)- 2a
(51mg, 0.131mmol, 1eq), 2ia (27mg, 2eq), and potassium carbonate
(90mg, 0.655mmol, 5eq) were dissolved in dimethyl sulfoxide (6mL). The
reaction was heated to reflux overnight and purified as above to give a
yellow, amorphous solid (Yield: 32mg, 44%, Purity: 95.1%). 1H NMR (500
MHz, DMSO-d6) δ 7.48 (s, 1H), 7.00 (d, J = 7.9 Hz, 1H), 6.93 (s, 1H), 6.73
(dd, J = 7.9, 1.7 Hz, 1H), 6.09 (s, 2H), 5.57 (s, 2H), 4.42 (s, 1H), 4.26 (t, J
= 6.0 Hz, 2H), 3.92 (s, 3H), 3.62 (s, 3H), 3.46 (t, J = 6.3 Hz, 2H), 2.57 –
2.48 (m, 4H), 2.38 (s, 8H), 1.96 (p, J = 6.6 Hz, 2H). 13C NMR (126 MHz,
DMSO-d6) δ 169.4, 151.5, 150.2, 147.2, 147.1, 146.7, 133.2, 129.8, 128.7,
125.9, 125.7, 123.9, 119.3, 111.2, 108.3, 105.8, 101.4, 100.8, 70.3, 66.9,
60.5, 58.6, 55.9, 55.5, 54.8, 53.4, 53.0, 27.4. ESI-MS (ESI+) m/z:
calculated for C30H34N2O7+H+, 551.2388 [M+H]+, found 551.2383 [M+H]+.
(E)-9-(benzo[d][1,3]dioxol-5-yl)-4-hydroxy-6,7-dimethoxy-2-((4-
methylbenzylidene)amino)-2,3-dihydro-1H-benzo[f]isoindol-1-one
(3f)- 3a (49mg, 0.124mmol, 1eq) and 4-methylbenzaldehyde (18µl, 18mg,
1.2eq) were dissolved in methanol (10mL). The reaction was heated to
reflux overnight, and the final product was purified as above to give a
yellow solid (yield: 39mg, 62%, Purity: 97.3%). 1H NMR (500 MHz, DMSO-
d6) δ 10.17 (s, 1H), 8.10 (s, 1H), 7.61 (d, J = 6.9 Hz, 3H), 7.24 (d, J = 7.7
Hz, 2H), 6.98 (d, J = 7.9 Hz, 1H), 6.91 (s, 1H), 6.82 (s, 1H), 6.71 (d, J =
7.9 Hz, 1H), 6.08 (s, 2H), 4.80 (s, 2H), 3.90 (s, 3H), 3.60 (s, 3H), 2.30 (s,
3H). LC-MS m/z: calculated for C29H24N2O6+H+, 497.2 [M+H]+, found 497.3
[M+H]+.
2-amino-9-(benzo[d][1,3]dioxol-5-yl)-4-hydroxy-6,7-dimethoxy-2,3-
dihydro-1H-benzo[f]isoindol-1-one (3a)- 2a (200mg, 0.526mmol, 1eq)
and hydrazine hydrate (0.5mL) were dissolved in 50mL of methanol. The
(E)-4-(((9-(benzo[d][1,3]dioxol-5-yl)-4-hydroxy-6,7-dimethoxy-1-oxo-
1,3-dihydro-2H-benzo[f]isoindol-2-yl)imino)methyl)benzonitrile (3g)-
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