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D. E. Beck et al. / Bioorg. Med. Chem. 24 (2016) 1469–1479
5.1.7. 3-Fluoro-6-(3-(1H-imidazol-1-yl)propyl)-8,9-methylene-
dioxy-5,11-dioxo-11H-indeno[1,2-c]isoquinoline (25)
product was dried under high vacuum to provide the free base
(15 mg, 33%) as a dark purple solid. The trifluoroacetate salt was
prepared by treating the free base with neat TFA (5 mL) for 5 min
at room temperature with stirring and then evaporating the TFA.
Chemical characterization data pertain to the free base: mp 290–
294 °C. 1H NMR (300 MHz, CDCl3) d 8.56 (d, J = 8.7 Hz, 1H), 8.26
(d, J = 2.3 Hz, 1H), 7.62 (dd, J = 8.7, 2.3 Hz, 1H), 7.50 (s, 1H), 7.13
(s, 1H), 6.12 (s, 2H), 4.59–4.46 (m, 2H), 3.76 (t, J = 4.7 Hz, 4H),
2.62–2.44 (m, 6H), 2.08–1.93 (m, 2H); ESIMS m/z (rel intensity)
453/455 (MH+, 100/29); HRESIMS calcd for C24H22ClN2O5
(MH+) 453.1217, found 453.1211; HPLC purity, 95.04% (MeOH,
100%).
Lactone 13 (53 mg, 0.17 mmol) was dissolved in CHCl3 (20 mL)
with stirring and 3-imidazolylpropylamine (18, 43 mg, 0.34 mmol)
was added. The mixture was heated at reflux for 16 h, cooled, and
concentrated to ꢂ5 mL. Hexanes (1 mL) were added and the sus-
pension was filtered. The product was washed with hexanes
(5 mL) and MeOH (5 mL) and dried under high vacuum with heat-
ing to 125 °C to furnish 25 (54 mg, 76%) as a purple solid: mp
235 °C (dec). IR (film) 1667, 1503, 1377, 1310, 1027 cmꢀ1 1H
;
NMR (300 MHz, DMSO-d6) d 8.50 (dd, J = 8.9, 5.4 Hz, 1H), 7.83
(dd, J = 9.5, 2.8 Hz, 1H), 7.78–7.64 (m, 2H), 7.26 (s, 1H), 7.15 (s,
1H), 7.10 (s, 1H), 6.91 (s, 1H), 6.20 (s, 2H), 4.41 (t, J = 7.4 Hz, 2H),
4.18 (t, J = 6.8 Hz, 2H), 2.32–2.09 (m, 2H); EIMS m/z (rel intensity)
417 (M+, 100); HRESIMS calcd for C23H17FN3O4 418.1203 (MH+),
found 418.1208; HPLC purity, 100% (MeOH, 100%).
5.1.11. 3-Fluoro-5,6-dihydro-6-(3-(2-hydroxyethyl)amino)-8,9-
methylenedioxy-5,11-dioxo-11H-indeno[1,2-c]isoquinoline
(29)
Lactone 13 (69 mg, 0.22 mmol) was dissolved in CHCl3 (15 mL)
with stirring and a solution of 3-(2-hydroxyethyl)propylamine (20,
36 mg, 0.30 mmol) in CHCl3 (1 mL) was added. The mixture was
heated at reflux with stirring under an argon atmosphere for
3.5 h and concentrated in vacuo until ꢂ1 mL of solvent remained.
Hexanes (1 mL) were added and the suspension was filtered. The
product was dried under high vacuum to provide 29 (69 mg,
76%) as a dull purple solid: mp 170 °C. 1H NMR (500 MHz,
DMSO-d6) d 8.45 (dd, J = 9.0, 5.4 Hz, 1H), 7.77 (dd, J = 9.5, 2.8 Hz,
1H), 7.71–7.53 (m, 2H), 7.10 (s, 1H), 6.17 (s, 2H), 4.56–4.27 (m,
3H), 3.43 (d, J = 6.3 Hz, 2H), 2.73–2.51 (m, 2H), 1.92–1.65 (m,
2H); ESIMS m/z (rel intensity) 411 (MH+, 100); HRESIMS calcd for
5.1.8. 3-Chloro-6-(3-(1H-imidazol-1-yl)propyl)-8,9-methylene-
dioxy-5,11-dioxo-11H-indeno[1,2-c]isoquinoline (26)
Lactone 14 (77 mg, 0.24 mmol) was dissolved in CHCl3 (20 mL)
with stirring and a solution of 3-imidazolylpropylamine (18,
59 mg, 0.47 mmol) in CHCl3 (1 mL) was added. The mixture was
heated at reflux with stirring under an argon atmosphere for
14.5 h, cooled to room temperature, and filtered. The product
was washed with hexanes (2 mL) and dried under high vacuum
at 60 °C to provide 26 (81 mg, 79%) as a dark purple solid: mp
286–287 °C. IR (film) 1668, 1537, 1482, 1304, 826 cmꢀ1 1H NMR
;
(300 MHz, DMSO-d6) d 8.46 (d, J = 8.8 Hz, 1H), 8.31 (s, 1H), 8.09
(d, J = 2.3 Hz, 1H), 7.82 (dd, J = 8.6, 2.3 Hz, 1H), 7.69 (s, 1H), 7.24
(d, J = 1.1 Hz, 1H), 7.18 (s, 1H), 7.13 (s, 1H), 6.89 (d, J = 1.4 Hz,
1H), 6.21 (s, 2H), 4.41 (t, J = 7.3 Hz, 2H), 4.17 (t, J = 6.9 Hz, 2H),
2.33–2.09 (m, 2H); MALDI m/z (rel intensity) 434/436 (MH+,
100/83); HRESIMS calcd for C23H17ClN3O4 434.0908 (MH+), found
434.0887; HPLC purity, 100% (MeOH, 100%).
C
22H20FN2O5 411.1357 (MH+), found 411.1363; HPLC purity,
95.00% (0.1% TFA in MeOH, 100%).
5.1.12. 3-Chloro-5,6-dihydro-6-(3-((2-hydroxyethyl)amino)-
propyl)-8,9-methylenedioxy-5,11-dioxo-11H-indeno[1,2-c]
isoquinoline (30)
Lactone 14 (84 mg, 0.26 mmol) was dissolved in CHCl3 (15 mL)
with stirring and a solution of 3-(2-hydroxyethyl)propylamine (20,
35 mg, 0.30 mmol) in CHCl3 (1 mL) was added. The mixture was
heated at reflux with stirring under an argon atmosphere for
22 h and concentrated in vacuo until ꢂ1 mL of solvent remained.
Hexanes (1 mL) were added and the suspension was filtered and
dried under high vacuum to provide 30 (93 mg, 84%) as a purple
5.1.9. 3-Fluoro-5,6-dihydro-6-(3-morpholinopropyl)-8,9-
methylenedioxy-5,11-dioxo-11H-indeno[1,2-c]isoquinoline
trifluoroacetate (27)
Lactone 13 (29 mg, 0.093 mmol) was dissolved in CHCl3 (9 mL)
with stirring and a solution of 3-morpholinopropylamine (19,
14 mg, 0.096 mmol) in CHCl3 (1 mL) was added. The mixture was
heated at reflux with stirring under an argon atmosphere for
20 h and concentrated in vacuo until ꢂ1 mL of solvent remained.
Hexanes (1 mL) were added and the suspension was filtered to pro-
vide the free base (15 mg, 37%) as a red–violet solid. The trifluo-
roacetate salt was prepared by treating the free base with neat
TFA (5 mL) for 5 min at room temperature with stirring and then
evaporating the TFA. Chemical characterization data pertain to
the free base: mp 294–296 °C. 1H NMR (300 MHz, CDCl3) d 8.64
(dd, J = 9.0, 5.3 Hz, 1H), 7.94 (dd, J = 9.3, 2.9 Hz, 1H), 7.49 (s, 1H),
7.43 (td, J = 8.6, 2.8 Hz, 1H), 7.12 (s, 1H), 6.11 (s, 2H), 4.60–4.46
(m, 2H), 3.85–3.65 (m, 4H), 2.64–2.40 (m, 6H), 2.12–1.92 (m,
2H); ESIMS m/z (rel intensity) 437 (MH+, 100); HRESIMS calcd for
solid: mp 198 °C. 1H NMR (500 MHz, DMSO-d6)
d 8.38 (d,
J = 8.7 Hz, 1H), 8.02 (d, J = 2.4 Hz, 1H), 7.76 (dd, J = 8.7, 2.4 Hz,
1H), 7.63 (s, 1H), 7.10 (s, 1H), 6.18 (s, 2H), 4.59–4.27 (m, 3H),
3.44 (t, J = 5.7 Hz, 2H), 2.67 (t, J = 6.4 Hz, 2H), 2.58 (t, J = 5.8 Hz,
2H), 1.92–1.71 (m, 2H); ESIMS m/z (rel intensity) 427/429 (MH+,
100/31); HRESIMS calcd for C22H20ClN2O5 427.1061 (MH+), found
427.1067; HPLC purity, 98.60% (0.1% TFA in MeOH, 100%).
5.1.13. (2-Bromo-4,5-difluorophenyl)methanol (32)
Benzoic acid derivative 31 (5.05 g, 21.3 mmol) was dissolved
with stirring in THF (25 mL). A solution of BH3 in THF (1.0 M,
21.3 mL, 21.3 mmol) was added dropwise at room temperature
with frequent pausing to allow violent bubbling to subside. The
mixture was heated at reflux with stirring for 4 h. A solution of
aqueous KOH (2 M, 11 mL) was added and the mixture was cooled
to room temperature with stirring for 30 min. The mixture was
extracted with Et2O (6 ꢁ 25 mL). The combined organic layers
were washed with brine (1 ꢁ 25 mL) and dried over Na2SO4. The
organic solution was concentrated in vacuo to yield a yellow-tinted
liquid. Drying under high vacuum with heating to ca. 100 °C
afforded 32 (4.01 g, 84%) as an off-white solid: mp 59–66 °C. 1H
NMR (300 MHz, CDCl3) d 7.46–7.32 (m, 2H), 4.68 (d, J = 1.3 Hz,
2H), 2.12 (br s, 1H); EIMS m/z (rel intensity) 222/224 (M+, 70/70),
143 [(MꢀBr)+, 93], 115 [(MꢀBrꢀH2O)+, 100].
C
24H22FN2O5 437.1513 (MH+), found 437.1493; HPLC purity,
99.35% (MeOH, 100%).
5.1.10. 3-Chloro-5,6-dihydro-6-(3-morpholinopropyl)-8,9-
methylenedioxy-5,11-dioxo-11H-indeno[1,2-c]isoquinoline
trifluoroacetate (28)
Lactone 14 (34 mg, 0.10 mmol) was dissolved in CHCl3 (9 mL)
with stirring and a solution of 3-morpholinopropylamine (19,
15 mg, 0.11 mmol) in CHCl3 (1 mL) was added. The mixture was
heated at reflux with stirring under an argon atmosphere for
20 h and concentrated in vacuo until ꢂ1 mL solvent remained.
Hexanes (1 mL) were added and the suspension was filtered. The