under reduced pressure and the residue taken up in water (10
mL) and extracted with ethyl acetate. The organic layer was
dried, filtered and evaporated under reduced pressure to give a
yellow solid which was further purified by flash chromato-
graphy eluting with CH2Cl2–EtOH–NH3 (200:8:1) to give 26
mg (67%) of 22 as a yellow powder (Mp 142–143 ЊC); MS m/z
triturated with diethyl ether. The solid was recrystallised from
ethanol–ether and dried under vacuum to give 6.37 g (97%) of
10 as white crystals (Mp 177–180 ЊC) (Found C, 62.49; H, 5.60;
N, 6.37. C22H20N2O3ؒ1.0HClؒ1.44H2O requires C, 62.49; H,
1
5.45; N, 6.63%); MS m/z 361 (M ϩ 1)ϩ; H NMR δ 1.78 (2H,
m, CH2), 2.25 (1H, m, CH), 2.31 (1H, m, CH), 2.79 (2H, m,
CH2N), 3.39 (2H, m, CH2), 3.57 (2H, m, CH2), 3.95 (1H, s,
CH), 7.1 (4H, m, H2, H3, H5, H6), 7.48 (3H, m, 3 × ArH), 9.6
(3H, br s, NH3ϩ); Anal. (C22H20N2O3ؒ1.0HClؒ1.44 H2O) C, H,
N.
1
494 (Mϩ); H NMR δ 1.93 (6H, s, 2 × NCH3), 2.25 (2H, m,
CH2NMe2), 2.88 (2H, m, 5-CH2), 3.0 (2H, m, 3-CH2), 3.85 (2H,
t, CH2Phth, J 7.0 Hz), 5.0 (2H, d, CH2NHCO), 7.0 (1H, d, H6),
7.3 (2H, m, H7, H4), 7.5–7.6 (4H, m, 4 × ArH), 7.9–8.2 (4H, m,
3 × ArH, NH), 9.7 (1H, t, NH), 11.2 (1H, s, NH); Found Mϩ
494.23456. C30H30N4O3 requires Mϩ 494.23179.
Ethyl 5-(dimethylamino)-2-{4-[2-(1,3,4-trioxo-2,3,5,6,10,10a-
hexahydro-1H,4H-acenaptho[1,8a-c]pyrrolyl)ethyl]phenyl}-
hydrazin-2-ylidenepentanoate (25). Method 6: a stirring solution
of the amine 10 (2.0 g, 5.0 mmol) in concentrated hydrochloric
acid (1.05 mL, 9.5 mmol), ethanol (6.6 mL) and water (10.0
mL) was cooled to 0 ЊC. A solution of sodium nitrite (0.35 g,
5.0 mmol) in water (3.1 mL) was added dropwise keeping the
temperature at ~0 ЊC and the solution was stirred for 30 min.
Meanwhile, a solution of sodium acetate trihydrate (3.52 g, 25.9
mmol) in water (4.5 mL) was added to a solution of the
diketone 1528 (1.08 g, 5.0 mmol) in ethanol (4.5 mL). This solu-
tion was stirred for 30 min and then added at once to the diazo-
nium salt solution. The solution was left to stir for 30 min at
0–5 ЊC then allowed to stir at 10–15 ЊC overnight. The orange
suspension was basified with 2 M NaOH solution, extracted
with CHCl3, dried and concentrated to give 1.5 g of a crude
residue which was purified by column chromatography eluting
with CH2Cl2–EtOH–NH3 (150:8:1) to give 1.1 g (40%) of 25 as
an orange powder. MS m/z 545 (M ϩ 1)ϩ; 1H NMR δ 1.27 (3H,
t, CH2CH3, J 7.2 Hz), 1.64 (2H, t, CH2, J 6.3 Hz), 1.75 (2H, m,
CH2), 2.11 (6H, s, 2 × NCH3), 2.25 (2H, m, CH2), 2.52 (2H, m,
CH2), 2.69 (2H, m, CH2), 2.72 (1H, m, CH), 2.83 (1H, m, CH),
3.31 (2H, m, CH2), 3.53 (2H, m, CH2), 3.94 (1H, s, CH), 4.12
(2H, q, CH2CH3, J 7.3 Hz), 6.87 (2H, d, H2, H6, J 8.4 Hz), 6.95
(2H, d, H3, H5, J 8.1 Hz), 7.41–7.55 (3H, m, 3 × ArH), 10.55
(1H, s, NH); Found Mϩ 544.26844. C31H36N4O5 requires Mϩ
544.26857.
N-(4-Aminobenzyl)-3-[2-(dimethylamino)ethyl]-5-[2-(phthal-
imido)ethyl]-1H-indole-2-carboxamide (23). Method 3 (using
4-aminobenzylamine): yellow solid, 40 mg (63%) (Found
C, 66.81; H, 5.83; N, 12.54. C30H31N5O3ؒ1.0HCl requires C,
1
65.99; H, 5.86; N, 12.83%); MS m/z 510 (M ϩ 1)ϩ; H NMR
δ 1.89 (6H, s, 2 × NCH3), 2.23 (2H, m, CH2NMe2), 2.86 (2H, t,
5-CH2, J 6.8 Hz), 2.98 (2H, t, 3-CH3, J 7.2 Hz), 3.82 (2H, m,
CH2Hyd), 4.3 (2H, d, CH2NHCO, J 5.4 Hz), 4.9 (2H, s, NH2),
6.5 (2H, d, H2Ј, H6Ј, J 8.4 Hz), 6.97 (2H, d, H3Ј, H5Ј, J 8.4 Hz),
7.0 (1H, d, H6, J 8.4 Hz), 7.23 (2H, m, H7, H4), 7.8 (4H, s,
4 × Phth-H), 9.51 (1H, t, NH, J 5.7 Hz), 9.5 (1H, s, NH), 11.15
(1H, s, NH); Found Mϩ 509.23919. C30H31N5O3 requires Mϩ
509.24269; Anal. (C30H31N5O3ؒ1.0HCl) C, H, N. RT = 15.77
min.
N-(2-Aminobenzyl)-3-[2-(dimethylamino)ethyl]-5-[2-(phthal-
imido)ethyl]-1H-indole-2-carboxamide (24). Method 3 (using
2-aminobenzylamine): yellow lyophilate, 45 mg (72%) (Found
C, 56.74; H, 5.77; N, 10.58. C30H31N5O3ؒ2.0HClؒ3.0H2O
requires C, 56.63; H, 6.13; N, 11.01%); MS m/z 510 (M ϩ 1)ϩ;
1H NMR δ 1.92 (6H, s, 2 × NCH3), 2.22 (2H, m, CH2NMe2,
J 6.0 Hz), 2.88 (2H, m, 5-CH2), 2.97 (2H, t, 3-CH2, J 6.6 Hz),
3.82 (2H, t, CH2Hyd, J 6.6 Hz), 4.34 (2H, d, CH2NHCO, J 5.4
Hz), 5.12 (2H, s, NH2), 6.51 (1H, m, ArH, J 8.1 Hz), 6.61 (1H,
d, ArH, J 7.2 Hz), 7.0 (3H, m, 2 × ArH, H6), 7.23 (2H, m, H7,
H4), 7.79 (4H, s, 4 × PhthH), 9.65 (1H, t, NH, J 5.7 Hz), 11.2
(1H, s, NH); Found Mϩ 509.23919. C30H31N5O3ؒ1.0HCl
requires Mϩ 509.24269; Anal. (C30H31N5O3ؒ2.0HClؒ3.0H2O) C,
H, N. RT = 17.52 min.
Ethyl
5-[2-(1,3,4-trioxo-2,3,5,6,10,10a-hexahydro-1H,4H-
acenaptho[1,8a-c]pyrrolyl)ethyl]-3-[2-(dimethylamino)ethyl]-
1H-indole-2-carboxylate (26). Method 7: to a solution of the
ethyl ester hydrazone 25 (1.1 g, 2.0 mmol) in ethanol (100 mL)
was added dropwise concentrated hydrochloric acid (2.35 mL).
The reaction was gently refluxed under nitrogen for 24 h. The
solution was cooled, the solvent evaporated under reduced
pressure, water added (30 mL) and the pH adjusted to 9 with
potassium carbonate. The aqueous layer was extracted with
ethyl acetate, dried, filtered and the solvent evaporated under
reduced pressure to give an orange solid which was purified
by column chromatography eluting with CH2Cl2–EtOH–NH3
(80:8:1) to give 0.26 g (25%) of 26 as a white powder. MS m/z
528 (M ϩ 1)ϩ; 1H NMR δ 1.34 (3H, t, CH2CH3, J 7.2 Hz), 1.71
(2H, m, CH2), 2.19 (1H, m, CH), 2.21 (6H, s, 2 × NCH3), 2.25
(1H, m, CH), 2.39 (2H, m, CH2), 2.65 (3H, m, CH2, CH), 2.84
(3H, m, CH2, CH), 3.6 (2H, m, CH2), 3.9 (1H, s, CH), 4.33 (2H,
q, CH2CH3, J 7.3 Hz), 6.9 (1H, d, H7, J 8.4 Hz), 7.18 (1H, d,
H6, J 8.1 Hz), 7.23 (1H, s, H4), 7.37 (2H, m, 2 × ArH), 7.5 (1H,
m, ArH), 11.34 (1H, s, NH); Found Mϩ 527.24446. C32H33N3O5
requires Mϩ 527.24202.
2-(4-Nitrophenethyl)-2,3,5,6,10,10a-hexahydro-1H,4H-
acenaptho[1,8a-c]pyrrole-1,3,4-trione (5). Method 4: 4-nitro-
phenethyl alcohol (3.33 g, 20 mmol) was dissolved in DMF (50
mL) and the succinimide derivative 10 (4.8 g, 20 mmol) was
added. To the stirring solution was added triphenylphosphine
(5.2 g, 20 mmol) and the solution was cooled to 0 ЊC. A solution
of diisopropyl azodicarboxylate (4.02 g, 20 mmol) in DMF (20
mL) was added dropwise over 20 min and then the solution was
stirred up to room temperature overnight. The solution was
poured onto ice–water (250 mL) and stirring continued for 3 h
to form a yellow gum. The solvent was decanted off and the
yellow solid recrystallised from ethanol to give 6.06 g (78%) of
1
5 as yellow crystals (Mp 175–177 ЊC); MS m/z 390 (Mϩ); H
NMR δ 1.75 (2H, m, CH2), 2.23 (2H, m, CH2), 2.7 (1H, m,
CH), 2.94 (2H, m, CH2N), 3.11 (1H, m, CH), 3.64 (2H, m,
CH2), 3.92 (1H, s, CH), 7.23 (2H, d, H3, H5, J 8.5 Hz), 7.48
(3H, m, 3 × ArH), 7.93 (2H, d, H2, H6, J 8.0 Hz).
2-(4-Aminophenethyl)-2,3,5,6,10,10a-hexahydro-1H,4H-
acenaptho[1,8a-c]pyrrole-1,3,4-trione (10). Method 5: a suspen-
sion of the nitro intermediate 5 (5.9 g, 15 mmol) in a mixture
of ethanol (125 mL), water (96 mL) and 2 M HCl (7.6 mL) was
hydrogenated at room temperature and atmospheric pressure
over 10% palladium on carbon (0.45 g) overnight. The catalyst
was filtered through Celite, washed with ethanol (2 × 15 mL)
and the solvent removed under vacuum. The remaining residue
was azeotropically dried with absolute ethanol (50 mL) and
Benzyl 5-[2-(1,3,4-trioxo-2,3,5,6,10,10a-hexahydro-1H,4H-
acenaptho[1,8a-c]pyrrolyl)ethyl]-3-[2-(dimethylamino)ethyl]-
1H-indole-2-carboxylate (27). Method 1: yellow powder, 84 mg
(43%); MS m/z 590 (M ϩ 1)ϩ; 1H NMR δ 1.7 (2H, m, CH2), 2.1
(6H, s, 2 × NCH3), 2.4 (2H, m, CH2), 3.06 (4H, m, 2 × CH2),
3.2 (4H, m, 2 × CH2), 3.3 (2H, m, CH2, under water peak), 3.6
(2H, m, CH2NCO), 3.8 (1H, s, CH), 5.37 (2H, s, CH2O), 6.9–7.5
(11H, m, H7, H4, 8 × ArH), 11.47 (1H, s, NH); Found Mϩ
589.25654. C36H35N3O5 requires Mϩ 589.25767.
2706
J. Chem. Soc., Perkin Trans. 1, 1999, 2699–2711