Synthesis of New Indeno[1,2-c]isoquinolines
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 20 3695
(m, 2 H), 7.42 (t, J ) 9 Hz, 1 H), 6.77 (d, J ) 9 Hz, 1 H), 6.56
(d, J ) 3 Hz, 1 H), 6.49 (dd, J ) 3 and 9 Hz, 1 H), 5.06 (d, J
) 6 Hz, 1 H), 4.78 (d, J ) 6 Hz, 1 H), 3.90 (qn, J ) 6.1 Hz, 1
H), 3.66 (s, 3 H), 3.80-3.55 (m, 2 H), 3.51 (s, 3 H), 3.01 (qn, J
) 6 Hz, 1 H), 2.07-1.90 (m, 2 H). Anal. Calcd for C21H22NO5-
Cl‚0.3H2O: C, H, N.
cis-N-(3-Ch lor o-1-p r op yl)-4-ca r b oxy-3,4-d ih yd r o-6,7-
d im eth oxy-3-(3,4-m eth ylen ed ioxyp h en yl)-1(2H)-isoqu i-
n olon e (14c). The isoquinolone 14c was isolated in 89%
yield: mp > 350 °C; IR (KBr) 3091, 2919, 1736, 1622, 1594
cm-1; 1H NMR (DMSO-d6, 500 MHz) δ 7.51 (s, 1 H), 7.12 (s, 1
H), 6.77 (d, J ) 7.5 Hz, 1 H), 6.55 (dd, J ) 2 and 8.5 Hz, 1 H),
6.45 (d, J ) 2 Hz, 1 H), 5.94 (s, 2 H), 5.00 (d, J ) 6 Hz, 1 H),
4.66 (d, J ) 6 Hz, 1 H), 3.90-3.82 (m, 1 H), 3.81 (s, 3 H), 3.74
(s, 3 H), 3.70-3.58 (m, 2 H), 2.95-2.85 (m, 1 H), 2.05-1.85
(m, 2 H). Anal. Calcd for C22H22NO7Cl: C, H, N.
cis-N-(3-Br om o-1-p r op yl)-4-ca r b oxy-3,4-d ih yd r o-6,7-
d im eth oxy-3-(3,4-m eth ylen ed ioxyp h en yl)-1(2H)-isoqu i-
n olon e (14d ). The isoquinolone 14d was isolated in 78%
yield: mp > 350 °C; IR (KBr) 3093, 2916, 1739, 1622, 1594
cm-1; 1H NMR (DMSO-d6) δ 12.98 (bs, 1 H), 7.51 (s, 1 H), 7.11
(s, 1 H), 6.78 (d, J ) 8.0 Hz, 1 H), 6.55 (d, J ) 8.1 Hz, 1 H),
6.45 (s, 1 H), 5.94 (s, 2 H), 5.01 (d, J ) 6.3 Hz, 1 H), 4.85-4.75
(m, 1 H), 4.68 (d, J ) 6.3 Hz, 1 H), 3.86 (s, 3 H), 3.74 (s, 3 H),
3.60-3.45 (m, 2 H), 2.98-2.88 (m, 1 H), 2.20-1.88 (m, 2 H).
cis-N-(3-Br om o-1-p r op yl)-4-ca r b oxy-3,4-d ih yd r o-6,7-
d im et h oxy-3-(3,4-d im et h oxyp h en yl)-1(2H )-isoq u in olo-
n e (14e). The isoquinolone 14e was isolated in 51% yield: mp
209-210 °C; 1H NMR (DMSO-d6) δ 7.25 (s, 1 H), 7.15 (s, 1 H),
6.78 (d, J ) 8.4 Hz, 1 H), 6.63 (d, J ) 1.9 Hz, 1 H), 6.52 (dd,
J ) 1.9 and 8.4 Hz, 1 H), 5.03 (d, J ) 6.1 Hz, 1 H), 4.66 (d, J
) 6.1 Hz, 1 H), 3.89 (m, 1 H), 3.81 (s, 3H), 3.74 (s, 3H), 3.66
(s, 3H), 3.56 (s, 3H), 3.52 (m, 2 H), 2.98 (m, 1 H), 2.11 (m, 1
H), 1.99 (m, 1 H). Anal. Calcd for C23H26NO7Br‚0.6H2O: C, H,
N.
Gen er a l P r oced u r e for th e Syn th esis of In d en oiso-
qu in olin es 15. Thionyl chloride (30 mL) was added to the
isoquinolones 14 (2 mmol) and the mixture was stirred at room
temperature for 5 h. Benzene was added to the red solution
and it was concentrated under reduced pressure. Chloroform
was added to the residue and the solution passed through a
short column of silica gel. The resulting product was crystal-
lized from chloroform-ethyl acetate to obtain pure indenoiso-
quinolines 15 in 20-72% yields.
yield after crystallization from chloroform-ethyl acetate (3:
1) as a dark purple solid: mp 273-276 °C; IR (KBr) 2916,
1694, 1645, 1554, 1486 cm-1; 1H NMR (CDCl3) δ 8.19 (s, 1 H),
7.81 (s, 1 H), 7.46 (s, 1 H), 7.44 (s, 1 H), 6.28 (s, 2 H), 4.76 (t,
J ) 7.6 Hz, 2 H), 4.23 (s, 3 H), 4.17 (s, 3 H), 3.83 (t, J ) 6.2
Hz, 2 H), 2.68-2.55 (m, 2 H). Anal. Calcd for C22H18NO6Br:
C, H, N.
6-(3-Br om o-1-pr opyl)-5,6-dih ydr o-2,3,8,9-tetr am eth oxy-
5,11-d ioxo-11H-in d en o[1,2-c]isoqu in olin e (15e). The in-
denoisoquinoline 15e was isolated in 55% yield as a purple
1
solid: mp 216-217 °C; H NMR (DMSO-d6) δ 7.71 (s, 1 H),
7.36 (s, 1 H), 6.99 (s, 1 H), 6.96 (s, 1 H), 4.45 (m, 1 H), 3.88 (s,
3 H), 3.86 (s, 3 H), 3.82 (s, 6 H), 3.72 (m, 2 H), 2.32 (m, 2 H),
2.03 (m, 1 H). Anal. Calcd for C23H22NO6Br‚0.3H2O: C, H, N.
Gen er a l P r oced u r e for th e Syn th esis of Azid es 16. The
halide 15 (2 mmol) was dissolved in anhydrous DMF (10 mL)
and sodium azide (0.153 g, 2.5 mmol) was added. The reaction
mixture was heated at reflux for 1-2 h. After the complete
disappearance of the starting material (TLC), ice-cold water
(100 mL) was added to the reaction mixture and the precipi-
tated solid was filtered off and dried. The product on column
purification on silica gel using chloroform as an eluent
provided the pure azides 16 in 79-98% yields.
6-(3-Az i d o -1-p r o p y l)-5,6-d i h y d r o -5,11-d i o x o -8,9-
d im eth oxy-11H-in d en o[1,2-c]isoqu in olin e (16a ). The chlo-
ride 15b was converted to the azide 16a in 79% yield: mp
230-232 °C; IR 2943, 2092, 1695, 1648, 1573, 1547, 1492 cm-1
;
1H NMR (CDCl3) δ 8.57 (d, J ) 8.1 Hz, 1 H), 8.23 (d, J ) 8.1
Hz, 1 H), 7.66 (t, J ) 8.0 Hz, 1 H), 7.38 (t, J ) 5.62 Hz, 1 H),
7.25 (d, J ) 5.9 Hz, 1 H), 7.16 (s, 1 H), 4.50 (t, J ) 8.0 Hz, 2
H), 4.00 (s, 3 H), 3.95 (s, 3 H), 3.68 (t, J ) 5.8 Hz, 2 H), 2.20-
2.01 (m, 2 H). Anal. Calcd for C21H18N4O4: C, H, N.
6-(3-Azid o -1-p r o p y l)-5,6-d ih y d r o -5,11-d ik e t o -2,3-
dim eth oxy-8,9-m eth ylen edioxy-11H-in den o[1,2-c]isoqu in -
olin e (16b). The azide 16b was prepared from the bromide
15d and the product was isolated as dark purple solid in 98%
yield after crystallization from ethyl acetate-chloroform: mp
180-184 °C; IR (KBr) 2932, 2912, 2098, 1697, 1646, 1609, 1552
and 1482 cm-1; 1H NMR (CDCl3) δ 8.00 (s, 1 H), 7.61 (s, 1 H),
7.21 (s, 1 H), 7.04 (s, 1 H), 6.08 (s, 2 H), 4.50 (t, J ) 7.6 Hz, 2
H), 4.02 (s, 3 H), 3.96 (s, 3 H), 3.62 (t, J ) 6.2 Hz, 2 H), 2.18-
2.02 (m, 2 H). Anal. Calcd for C22H18N4O6‚0.3H2O: C, H, N.
6-(3-Azid o-1-p r op yl)-5,6-d ih yd r o-2,3,8,9-tetr a m eth oxy-
5,11-d ioxo-11H-in d en o[1,2-c]isoqu in olin e (16c). The azide
16c was synthesized from the bromide 15e in 88% yield as a
6-(3-Ch lor o-1-p r op yl)-5,6-d ih yd r o-5,11-d ioxo-8,9-m eth -
ylen ed ioxy-11H-in d en o[1,2-c]isoqu in olin e (15a ). The in-
denoisoquinoline 15a was isolated in 25% yield: mp 222-224
1
purple solid: mp 203-204 °C; H NMR (CDCl3) δ 7.99 (s, 1
H), 7.59 (s, 1 H), 7.24 (s, 1 H), 7.13 (s, 1 H), 4.51 (t, J ) 6.5
Hz, 2 H), 4.06 (s, 3 H), 4.03 (s, 3 H), 3.98 (s, 3 H), 3.96 (s, 3 H),
3.71 (t, J ) 6.0 Hz, 2 H), 2.12 (t, J ) 6.0 Hz, 2 H); LRCIMS
m/z 450 (MH+). Anal. Calcd for C23H22N4O6: C, H, N.
1
°C; H NMR (CDCl3) δ 8.56 (d, J ) 8.1 Hz, 1 H), 8.25 (d, J )
8.0 Hz, 1 H), 7.66 (t, J ) 7.7 Hz, 1 H), 7.38 (t, J ) 7.8 Hz, 1
H), 7.28 (s, 1 H), 7.06 (s, 1 H), 6.07 (s, 2 H), 4.57 (t, J ) 7.7
Hz, 2 H), 3.79 (t, J ) 6.0 Hz, 2 H), 2.39-2.20 (m, 2 H). Anal.
Calcd for C20H14NO4Cl: C, H, N.
Gen er a l P r oced u r e for th e Syn th esis of Am in e Hy-
d r och lor id es 17. The azides 16 (1 mmol) were heated at
reflux with triethyl phosphite (0.4 mL) in benzene (60 mL)
for 12 h, after which the TLC showed the complete disappear-
ance of the starting azide. The reaction mixture was cooled
and methanolic HCl (3 N, 3 mL) was added (an exothermic
reaction was observed) and the mixture was heated at reflux
for 2 h and cooled. The precipitated solid was filtered and
washed with cold methanol (5 mL) and dried under vacuum
to afford the hydrochloride salts 17 in 89-99% yields.
6-(3-C h lo r o -1-p r o p y l)-5,6-d ih y d r o -5,11-d io x o -8,9-
d im eth oxy-11H-in d en o[1,2-c]isoqu in olin e (15b). The in-
denoisoquinoline 15b was isolated in 20% yield: IR (KBr)
1
1693, 1656, 1612, 1575, 1548 cm-1; H NMR (CDCl3) δ 8.52
(d, J ) 8.1 Hz, 1 H), 8.20 (d, J ) 8.0 Hz, 1 H), 7.62 (dd, J )
1.6 and 8.2 Hz, 1 H), 7.35 (dd, J ) 1.1 and 7.5 Hz, 1 H), 7.15
(s, 1 H), 7.08 (s, 1 H), 4.56 (t, J ) 8.0 Hz, 2 H), 3.97 (s, 3 H),
3.92 (s, 3 H), 3.85 (t, J ) 9.4 Hz, 2 H), 2.38-2.29 (m, 2 H).
Anal. Calcd for C21H18NO4Cl: C, H, N.
6-(3-Am in o -1-p r o p y l)-5,6-d ih y d r o -5,11-d io x o -8,9-
d im et h oxy-11H -in d en o[1,2-c]isoq u in olin e H yd r och lo-
r id e (17a ). The azide 16a was converted to the hydrochloride
17a in 98% yield as a purple solid: mp 284-286 °C; IR 2745,
2596, 2049, 1699, 1648, 1610, 1589, 1574, 1545, 1508, 1492,
6-(3-C h lo r o -1-p r o p y l)-5,6-d ih y d r o -5,11-d io x o -2,3-
dim eth oxy-8,9-m eth ylen edioxy-11H-in den o[1,2-c]isoqu in -
olin e (15c). The indenoisoquinoline 15c was isolated in 72%
yield after crystallization in chloroform-ethyl acetate (3:1) as
a purple solid: mp 273-276 °C; IR (KBr) 2916, 1694, 1645,
1468, 1440, 1429 cm-1 1H NMR (CDCl3) δ 8.45 (d, J ) 8.1
;
1
1554, 1486 cm-1; H NMR (CDCl3, 500 MHz) δ 8.01 (s, 1 H),
Hz, 1 H), 8.10 (d, J ) 8.1 Hz, 1 H), 8.07 (bs, 1 H), 7.74 (t, J )
7.1 Hz, 1 H), 7.41 (t, J ) 7.2 Hz, 1 H), 7.15 (s, 1 H), 7.13 (s, 1
H), 4.51 (t, J ) 6.9 Hz, 2 H), 4.0 (s, 3 H), 3.85 (s, 3 H), 2.95 (m,
2 H), 2.20-2.05 (m, 2 H). Anal. Calcd for C21H21N2O4Cl: C,
H, N.
7.62 (s, 1 H), 7.26 (s, 1 H), 7.06 (s, 1 H), 6.07 (s, 2 H), 4.60 (t,
J ) 7.6 Hz, 2 H), 4.03 (s, 3 H), 3.96 (s, 3 H), 3.80 (t, J ) 6.2
Hz, 2 H), 2.40-2.30 (m, 2 H). Anal. Calcd for C22H18NO6Cl:
C, H, N.
6-(3-B r o m o -1-p r o p y l)-5,6-d ih y d r o -5,11-d io x o -2,3-
dim eth oxy-8,9-m eth ylen edioxy-11H-in den o[1,2-c]isoqu in -
olin e (15d ). The indenoisoquinoline 15d was isolated in 57%
6-(3-Am in o -1-p r o p y l)-5,6-d ih y d r o -5,11-d io x o -2,3-
dim eth oxy-8,9-m eth ylen edioxy-11H-in den o[1,2-c]isoqu in -
olin e Hyd r och lor id e (17b). The azide 16b was converted to