Synthesis of new Benzo[f]isoindole-4,9-diones as anticancer compounds

Article abstract of DOI:10.1007/s00706-009-0219-2

The design and synthesis of monosubstituted and disubstituted azanaphthoquinone annelated pyrroles with anticancer activity are described. N-alkylation with various side chains at the pyrrole ring led to a series of monosubstituted products. For preparation of disubstituted isoindole derivatives, appropriately substituted tosyl methyl isocyanides were used. The biological activity of all the compounds was evaluated against a number of cancer cell lines.

Full text of DOI:10.1007/s00706-009-0219-2

Monatsh Chem (2010) 141:53–62
DOI 10.1007/s00706-009-0219-2
ORIGINAL PAPER
Synthesis of new Benzo[f]isoindole-4,9-diones as anticancer
compounds
•
Nipawan Pongprom Hans Bachitsch Arnulf Bauchinger Hamid Ettefagh Tanja Haider
•
•
•
•
•
•
•
•
Manuela Hofer Heike Knafl Rita Slanz Markus Waismeyer Friedrich Wieser Helmut Spreitzer
•
Received: 17 August 2009 / Accepted: 23 October 2009 / Published online: 2 December 2009
Ó Springer-Verlag 2009
Abstract The design and synthesis of monosubstituted
and disubstituted azanaphthoquinone annelated pyrroles
with anticancer activity are described. N-alkylation with
various side chains at the pyrrole ring led to a series of
monosubstituted products. For preparation of disubstituted
isoindole derivatives, appropriately substituted tosyl
methyl isocyanides were used. The biological activity of all
the compounds was evaluated against a number of cancer
cell lines.
found by synthesis of BBR 2778 (pixantrone), which is
currently in phase III clinical trials in patients with non-
Hodgkin’s lymphoma. This compound has a better thera-
peutic index and lower cardiotoxicity than mitoxantrone
[4]. It seems that these advantages are based predominantly
on the substitution of the 5,8-dihydroxybenzene moiety in
mitoxantrone by a pyridine ring (Fig. 1) [5].
The rationale for the reported syntheses is the question
whether substitution of the bis-amino-substituted benzene
ring in BBR 2778 by a pyrrole ring would also lead to
compounds with suitable cytotoxic properties. This seems
reasonable, because the p-electron surplus aromatic system
of the pyrrole ring would substitute a phenyl ring con-
nected to two amino groups with distinct electron donating
effects. In this paper we report the synthesis of derivatives
with a [c]-annelated pyrrole moiety, thus furnishing a series
of naphthoquinone annelated isoindole structures. More-
over it should be emphasized that the isoindole core
annelated with a naphthoquinone moiety is found in natural
products such as azamonosporascone and bhimamycin C or
D, which have distinct biological activity including activity
against different cancer cell lines [6–8].
Keywords Anticancer agent ꢀ N-Heterocycles ꢀ
Isoindoles ꢀ Alkylating agents
Introduction
Mitoxantrone, an anticancer agent used in the therapy of
breast cancer, non-Hodgkin’s lymphoma, acute myeloid
leukaemia, and hormone refractory prostate cancer, and in
various combination regimes, has probably become the
most widely used synthetic DNA intercalating agent [1, 2].
The efficacy of this intercalating drug molecule is ham-
pered by the onset of cardiotoxicity, however [3]. Maybe a
solution for this severe cardiotoxicity problem has been
In face of the fact that the main core of the synthesized
compounds is a tricyclic system it should allow intercalation,
in the same way as mitoxantrone and pixantrone. Intercala-
tion (insertion of the chromophore between base pairs) is
driven primarily by stacking and electrostatic interactions
[9]. Because intercalation is a reversible binding process to
the DNA the side chains attached to the isoindole nucleus
were predominantly provided with alkylating groups
(oxiranyl, aziridinyl, mesylate) and/or amino groups. As a
consequence, alkylation should lead to irreversible connec-
tion of drug and DNA. In addition, side chains with amino
groups can enhance binding to double-helical DNA by
interaction with the phosphate ‘‘back-bone’’ of the DNA.
N. Pongprom (&) ꢀ H. Bachitsch ꢀ A. Bauchinger ꢀ
H. Ettefagh ꢀ T. Haider ꢀ M. Hofer ꢀ H. Knafl ꢀ R. Slanz ꢀ
M. Waismeyer ꢀ F. Wieser ꢀ H. Spreitzer (&)
Department of Drug and Natural Product Synthesis,
University of Vienna, Althanstrasse 14,
1090 Vienna, Austria
e-mail: scnipapo@ubu.ac.th
H. Spreitzer
e-mail: helmut.spreitzer@univie.ac.at
123

54
N. Pongprom et al.
Fig. 1 Structures of
H
N
NH2
NH2
NH2
mitoxantrone, BBR 2778, and
melphalan, monosubstituted (1)
and disubstituted (2)
azanaphthoquinone [c]-
annelated pyrroles
O
O
HN
HN
OH
OH
O
O
HN
HN
OH
OH
COOH
N
N
H
N
Cl
Cl
Mitoxantrone
BBR 2778
Melphalan
R2
N R1
O
O
N R
N
N
O
O
2
1
Moreover, to obtain the first information about structure–
activity relationships, the side chains contain linkers of dif-
ferent length.
for preparation of 3 [10]. To achieve the intended substi-
tution pattern, first the appropriately substituted TosMIC
derivative 13 had to be synthesized according to Ref. [13].
Ring closure to isoindole 14 occurred smoothly and was
followed by N-alkylation with N,N-dimethylaminopropyl
chloride yielding 15. Cleavage of the ketal function (with
PPTS) and deprotection of the THPO-protected alcohol
(with p-TsOH) led to 16. Subsequently the HO group was
converted via mesylate 17 to aziridine and amine-substi-
tuted derivatives 18a–18c.
Results and discussion
Synthesis of monosubstituted isoindoles
The synthesis of monosubstituted products was performed
as outlined in Scheme 1. Starting from isoindole 3 [10] the
epoxy substituted derivatives 4a–4c were prepared by N-
alkylation with oxiranyl halides. In addition, reaction with
aziridine gave access to the hydroxy-substituted aziridine
derivatives 5a–5c. The mesylated products 7a–7c were
synthesized by a three-step reaction sequence including N-
alkylation with silyloxyalkyl halides, deprotection with
tetrabutylammonium fluoride (TBAF), and subsequent
mesylation with methanesulfonyl chloride. Finally nucle-
ophilic substitution of mesylates 7a–7c with aziridine
furnished derivatives 8a–8c.
The biological activity of all synthesized target com-
pounds (4a–5c, 7a–8c, 10, 11a–11 b, 16, 17, 18a–18c) was
tested in vitro at Zentaris, Germany. The cytotoxicity was
evaluated on five different cell lines, cervix cancer (KB),
ovarian carcinoma (SK-OV-3), brain cancer (SF-268), non-
small-cell lung cancer (NCl-H460), and adenocarcinoma
colon cancer (RKOP-27) [14, 15]. The first screening was
carried out at a predefined concentration of 3.16 lg cm-3
.
If the compound led to more than 50% inhibition at this
concentration it was evaluated for EC50 mean values (lM)
from at least two experiments on those five different cell
lines.
Alkylation of isoindole 3 with N,N-dimethylaminoalkyl
chlorides led to 11a–11b (Scheme 2). In addition, the
bis(2-chloroethyl)aminophenyl moiety was attached to the
pyrrole ring via intermediate 9 to furnish product 10 as an
analog of the well known and widely used anticancer drug
melphalan [11]. This nitrogen mustard derivative is con-
sidered to act predominantly by DNA crosslinking via
intermediately built aziridinium cations [12].
The results showed that only five monosubstituted
compounds (4a, 5b, 5c, 8b, 8c) and one disubstituted
compound 18c exhibited moderate activity, as summa-
rized in Table 1. It seems evident that the substitution
of the bis-amino substituted benzene ring by a pyrrole
ring led to compounds with a poor biological activity.
Attachment of side chains with neither basic amino groups
nor alkylating groups led to satisfactory activity with EC50
values in the nM range. Moreover no structure–activity
relationships are noticeable. Further studies will give a
clear answer to the question about the effects on cytotoxic
impact of different kinds of annelation ([c] and [b]-ann-
elation) of the pyrrole ring to the azanaphthoquinone
nucleus.
Synthesis of disubstituted isoindoles
The synthesis of disubstituted products was performed as
outlined in Scheme 3. Starting from a,b-unsaturated ketone
12 [10] the cyclisation reaction for building up the pyrrole
ring was realized in a way similar to that already exploited
123

Synthesis of new Benzo[f]isoindole-4,9-diones as anticancer compounds
55
Scheme 1
O
O
O
NaH, DMF, rt
OSiPh -Bu
N ( )n
OSiPh -Bu
NH
N
N
2t
X
2t
n
O
6a: n = 2 (10%)
6b: n = 4 (90%)
6c: n = 7 (57%)
3
NaH, DMF, rt
X
O
n
1) TBAF,THF, rt
2) ClSO2CH3, CH2Cl2
O
O
N ( )n
N
N ( )n
O SO2CH3
O
O
N
4a: n = 1 (56%)
4b: n = 3 (99%)
4c: n = 6 (78%)
O
7a: n = 2 (4%)
7b: n = 4 (48%)
7c: n = 7 (26%)
Aziridine,
EtOH, rt
Aziridine
TEA/MeCN, rt
O
O
N ( )n
HO
N
N
N ( )n
N
O
N
5a:n = 1 (25%)
5b:n = 3 (38%)
5c:n = 6 (49%)
O
8a: n = 2 (60%)
8b: n = 4 (50%)
8c: n = 7 (53%)
Scheme 2
O
O
NaH, DMF
rt
NH
N
( )
N
N
3
OSiPh -Bu
2t
O
N
O
9
(46%)
3
NaH, DMF, 60oC
N CH3
1) TBAF, THF, rt
OSiPh -Bu
2t
2) ClSO2CH3, CH2Cl2, 0oC
3) LiCl, DMF, 100oC
X
n
CH3
O
O
N
n
N
N CH3
N
( )
3
H3C
N
O
Cl
O
N
11a: n = 2 (59%)
11b:n = 3 (23%)
10 (72%)
Cl
123

56
N. Pongprom et al.
Scheme 3
OTHP
MeO OMe
MeO
( )
3
OMe
Tos
OTHP
( )3
NC
-BuOK
t
+
NH
N
THF, rt
N
O
12
O
13
14 (81%)
OH
O
OTHP
( )3
MeO OMe ( )3
N
1) PPTS
NaH, DMF, 60oC
N ( )3
N CH3
H3C
2) -TsOH, rt
p
( )3
N CH3
H3C
N
N
Cl(CH2)3N(CH3 2
)
O
O
15 (87%)
16 (81%)
OSO2CH3
O
( )3
N
O
O
R
( )3
ClSO2CH3
CH2Cl2, 0oC
N
EtOH, rt
( )3
( )3
N CH3
H3C
N
NH2CH3
N
N CH
3 or NH(CH3)2
or Aziridine
H3C
O
17
(78%)
18a: R = -NHCH3 (32%)
18b
: R = -N(CH3)2 (77%)
18c: R = 1-Aziridinyl (77%)
General procedure I: N-alkylation reactions
Table 1 Cytotoxic activity of test compounds toward five cancer cell
lines
NaH (60% suspension in oil) was washed three times with
hexane before dissolution in DMF under Ar. The solution
was cooled to 0 °C, then starting material was added
dropwise. The reaction mixture was stirred for additional
0.5 h at 0 °C. Afterwards the appropriate alkyl halide
(dissolved in DMF) was added and the reaction mixture
was stirred at room temperature or at 60 °C until comple-
tion of the reaction. Afterwards water was added and the
mixture was extracted with EtOAc. The combined extracts
were dried (MgSO4), filtered, and concentrated and purified
by column chromatography.
Compound
EC50 (lM)
KB
SKOV3
SF268
NClH460
RKOP27
4a
5b
5c
3.269 [12
2.192 [12
2.841 [12
2.081 [12
2.833 [12
3.727 [12
2.082
7.166
8.426
1.446
1.437
[12
[12
4.622
10.410
2.143
[12
–
6.852
2.604
4.270
1.401
1.583
0.808
8b
8c
18c
Experimental
2-(Oxiran-2-ylmethyl)-2H-pyrrolo[3,4-g]isoquinoline-
4,9-dione (4a, C14H10N2O3)
1H NMR spectra were recorded on a Bruker DPX200
spectrometer (1H 200 MHz, 13C 50 MHz). Chemical
shifts are reported in ppm using TMS as internal standard.
IR spectra were recorded on a Perkin–Elmer 298 or a
Perkin–Elmer Spectrum 1000 FT-IR spectrometer. Mass
spectra were recorded on Hewlett–Packard GC–MS
equipment (GC 5890, MS 5970). Melting points were
determined on a Kofler-type Leica Galen III micro hot-
stage microscope. Thin-layer chromatography (TLC) was
performed on silica gel 60 PF254 plates or aluminum
oxide plates from Merck. Column chromatography was
performed on silica gel 60 from Merck (70–230 mesh
ASTM) or on alumina B (aluminum oxide), activity III
from ICN. Unless otherwise noted chemicals were pur-
chased from commercial suppliers and used without
further purification.
Following general procedure I, NaH (0.083 g, 2.06 mmol)
in DMF (4 cm3), 3 (0.408 g, 2.06 mmol) in DMF (4 cm3),
and epichlorohydrin (0.24 cm3, 3.09 mmol) were used.
The reaction mixture was stirred at room temperature for
24 h. The crude product was purified by column chroma-
tography (aluminum oxide; EtOAc/light petroleum, 1/1) to
1
obtain 0.295 g (56%) 4a as an oil. H NMR (200 MHz,
DMSO-d6): d = 2.62 (dd, J = 4.8, 2.5 Hz, 1H), 2.84 (dd,
J = 4.5, 4.5 Hz, 1H), 3.41 (m, 1H), 4.15 (dd, J = 14.3,
6.1 Hz, 1H), 4.46 (dd, J = 14.3, 3.5 Hz, 1H), 7.76 (d,
J = 1.8 Hz, 1H), 7.80 (d, J = 1.8 Hz, 1H), 7.87 (d,
J = 5.0 Hz, 1H), 8.99 (d, J = 5.0 Hz, 1H), 9.19 (s, 1H)
ppm; 13C NMR (50 MHz, DMSO-d6): d = 45.1, 50.3,
51.7, 118.8, 121.4, 121.4, 126.4, 126.8, 127.6, 140.3,
148.2, 154.8, 178.1, 178.7 ppm; IR (KBr): vꢀ ¼ 1; 659;
123

Synthesis of new Benzo[f]isoindole-4,9-diones as anticancer compounds
57
1,583, 1,537, 1,240 cm-1; HRMS: calcd. 254.0691, found
254.0687 5 ppm.
under reflux until completion of the reaction. Afterwards,
the solvent was removed and the residue was purified by
column chromatography (aluminum oxide; EtOAc/MeOH,
9/1).
2-[3-(Oxiran-2-yl)propyl]-2H-pyrrolo[3,4-g]isoquinoline-
4,9-dione (4b, C16H14N2O3)
Following general procedure I, NaH (0.200 g, 5 mmol) in
DMF (5 cm3), 3 (0.800 g, 4 mmol) in DMF (6 cm3), and 2-
(3-bromopropyl)oxirane (0.729 g, 4.4 mmol) in DMF
(8 cm3) were used. The reaction mixture was stirred at
room temperature for 48 h. The crude product was purified
by column chromatography (aluminum oxide; EtOAc/light
petroleum, 1/1) to obtain 1.140 g (99%) 4b. M.p.: 162–
2-[3-(Aziridin-1-yl)-2-hydroxypropyl]-2H-pyrrolo-
3,4-g]isoquinoline-4,9-dione (5a, C16H15N3O3)
Following general procedure II, the reaction mixture 4a
(0.142 g, 0.6 mmol) and aziridine (0.19 cm3, 3.7 mmol) in
EtOH (6 cm3) was stirred at room temperature for 24 h and
worked up as described to give 0.035 g (25%) 5a. M.p.:
134–136 °C; 1H NMR (200 MHz, DMSO-d6): d = 1.14
(dd, J = 2.7, 1.5 Hz, 2H), 1.61 (dd, J = 2.7, 1.5 Hz, 2H)
2.03 (dd, J = 12.0, 5.7 Hz, 1H), 2.31 (dd, J = 12.0,
5.7 Hz, 1H), 4.08 (dd, J = 13.3, 7.9 Hz, 2H), 4.31 (dd,
J = 13.3, 2.7 Hz, 1H), 5.21 (d, J = 5.0 Hz, 1H), 7.76 (d,
J = 1.7 Hz, 1H), 7.79 (d, J = 1.7 Hz, 1H), 7.92 (d,
J = 5.0 Hz, 1H), 9.02 (d, J = 5.0 Hz, 1H), 9.24 (s, 1H)
ppm; 13C NMR (50 MHz, DMSO-d6): d = 26.5, 26.7,
54.4, 64.3, 69.5, 118.9, 121.0, 121.0, 126.9, 127.4, 127.7,
140.5, 148.3, 154.9, 178.1, 178.7; IR (KBr): vꢀ ¼ 3;241;
1
168 °C; H NMR (200 MHz, DMSO-d6): d = 1.30–1.65
(m, 2H), 1.80–2.05 (m, 2H), 2.43 (dd, J = 4.7, 2.7 Hz,
1H), 2.65 (dd, J = 4.7, 4.7 Hz, 1H), 2.80–3.00 (m, 1H),
4.13 (t, J = 7.0 Hz, 2H), 7.84 (s, 1H), 7.86 (s, 1H), 7.88 (d,
J = 5.0 Hz, 1H), 8.99 (d, J = 5.0 Hz, 1H), 9.20 (s, 1H)
ppm; 13C NMR (50 MHz, DMSO-d6): d = 26.9, 28.7,
46.0, 49.7, 50.9, 118.8, 121.3, 121.4, 126.1, 126.5, 127.7,
140.4, 148.2, 154.8, 178.1, 178.6 ppm; IR (KBr): vꢀ ¼
3;113; 1,656, 1,582, 1,538, 1,238, 1,226 cm-1; MS: m/z
(%) = 282 (M?, 25), 251 (35), 211 (49), 199 (48), 183
(33), 55 (100).
3,120, 1,665, 1,585, 1,447, 1,402, 1,239 cm-1
.
2-[5-(Aziridin-1-yl)-4-hydroxypentyl]-2H-pyrrolo-
[3,4-g]isoquinoline-4,9-dione (5b, C18H19N3O3)
2-[6-(Oxiran-2-yl)hexyl]-2H-pyrrolo[3,4-g]isoquinoline-
4,9-dione (4c, C19H20N2O3)
Following general procedure II, the reaction mixture 4b
(0.700 g, 2.5 mmol) and aziridine (0.87 cm3, 16.9 mmol)
in EtOH (26.8 cm3) was stirred and heated under reflux for
2 h and worked up as described to give 0.310 g (38%) 5b.
M.p.: 150–156 °C; 1H NMR (200 MHz, DMSO-d6):
d = 0.90–1.10 (m, 2H), 1.10–1.35 (m, 2H), 1.40–1.60
(m, 2H), 1.70–2.00 (m, 2H), 2.00 (dd, J = 11.8, 6.0 Hz,
1H), 2.13 (dd, J = 11.8, 6.0 Hz, 1H), 3.55 (Sbr, 1H), 4.11
(t, J = 6.9 Hz, 2H), 4.55 (d, J = 3.5 Hz, 1H), 7.84 (d,
J = 1.7 Hz, 1H), 7.88 (d, J = 1.7 Hz, 1H), 7.89 (d,
J = 5.0 Hz, 1H), 9.00 (d, J = 5.0 Hz, 1H), 9.22 (s, 1H)
ppm; 13C NMR (50 MHz, DMSO-d6): d = 26.3, 26.6,
26.8, 31.7, 50.2, 67.4, 69.3, 118.9, 121.3, 121.3, 126.2,
126.6, 127.7, 140.4, 148.2, 154.8, 178.1, 178.7 ppm; IR
Following general procedure I, NaH (0.067 g, 1.7 mmol)
in DMF (3 cm3), 3 (0.300 g, 1.5 mmol) in DMF (4 cm3),
and 2-(6-bromohexyl)oxirane (0.350 g, 1.7 mmol) in DMF
(4 cm3) were used. The reaction mixture was stirred at
room temperature for 18 h. The crude product was purified
by column chromatography (aluminum oxide; EtOAc/
MeOH, 9/1) to give 0.400 g (78%) 4c. M.p.: 155–156 °C;
1H NMR (200 MHz, DMSO-d6): d = 1.25–1.37 (m, 8H),
1.70–1.85 (m, 2H), 2.34 (dd, J = 5.0, 2.6 Hz, 1H), 2.59
(dd, J = 4.0, 4.0 Hz, 1H), 2.76–2.86 (m, 1H), 4.05 (t,
J = 7.0 Hz, 2H), 7.82 (d, J = 1.7 Hz, 1H), 7.86 (d,
J = 1.7 Hz, 1H), 7.89 (d, J = 5.0 Hz, 1H), 8.98 (d,
J = 5.0 Hz, 1H), 9.20 (s, 1H) ppm; 13C NMR (50 MHz,
DMSO-d6): d = 25.3, 25.6, 28.2, 30.0, 31.8, 46.0, 49.9,
51.5, 118.8, 121.3, 121.3, 126.1, 126.6, 127.7, 140.4,
148.2, 154.8, 178.1, 178.7 ppm; IR (KBr): vꢀ ¼ 3;108;
1,654, 1,583, 1,539, 1,417, 1,402, 1,239 cm-1; MS: m/z
(%) = 324 (M?, 19.9), 293 (38), 212 (100), 183 (50).
(KBr): vꢀ ¼ 3;392; 3,113, 1,657, 1,585, 1,541, 1,238 cm-1
;
MS: m/z (%) = 325 (M?, 0.3), 282 (1.7), 269 (6.4), 126
(2.2), 56 (100).
2-[8-(Aziridin-1-yl)-7-hydroxyoctyl]-2H-pyrrolo-
[3,4-g]isoquinoline-4,9-dione (5c, C21H25N3O3)
Following general procedure II, the reaction mixture 4c
(0.304 g, 0.9 mmol) and aziridine (0.33 cm3, 6.3 mmol)
in EtOH (10 cm3) was stirred and heated under reflux for
2 h and worked up as described to give 0.190 g (49%)
5c. M.p.: 137-138 °C; 1H NMR (200 MHz, CDCl3):
d = 1.00–1.55 (m, 11H), 1.65–2.08 (m, 5H), 2.35–2.50
(m, 1H), 3.55–3.70 (m, 1H), 4.01 (t, J = 7.0 Hz, 2H), 7.43
(s, 2H), 7.97 (d, J = 5.0 Hz, 1H), 8.97 (d, J = 5.0 Hz,
1H), 9.43 (s, 1H) ppm; 13C NMR (50 MHz, CDCl3):
General procedure II: reaction with aziridine
and amines
The appropriate starting material (4a–4c) was dissolved in
absolute EtOH in the presence of 1% triethylamine or
acetonitrile/triethylamine (1/1) under Ar. The correspond-
ing amines were added dropwise at room temperature. The
reaction mixture was stirred at room temperature or heated
123

58
N. Pongprom et al.
d = 25.3, 26.3, 26.8, 27.4, 28.9, 30.6, 34.5, 51.1, 67.4,
70.5, 119.1, 122.3, 122.4, 124.6, 124.9, 128.0, 140.8,
149.2, 154.6, 178.8, 179.4 ppm; IR (KBr): vꢀ ¼ 3;109;
1,655, 1,583, 1,539, 1,239 cm-1; MS: m/z (%) = 367 (M?,
1.6), 311 (6.8), 211 (1.4), 56 (100).
General procedure III: deprotection of silyl ethers
The starting material was dissolved in absolute THF. Then
1 M tetrabutylammonium fluoride (TBAF) in THF was
added and the reaction mixture was stirred at room tem-
perature for an additional 1.5–5 h. Afterwards, water was
added and the mixture was extracted with EtOAc. The
combined organic layers were dried (MgSO4), the solvents
were removed by distillation, and the residue was purified
by column chromatography.
2-[2-(tert-Butyldiphenylsilyloxy)ethyl]-2H-pyrrolo-
[3,4-g]isoquinoline-4,9-dione (6a, C29H28N2O3Si)
Following general procedure I, the reaction mixture NaH
(0.133 g, 5.6 mmol) in DMF (6.8 cm3), 3 (0.684 g,
3.4 mmol) in DMF (6.8 cm3), and 2-bromoethoxy(tert-
butyl)diphenylsilane (1.881 g, 5.2 mmol) in DMF
(10.3 cm3) was stirred at room temperature for 20 h. The
crude product was purified by column chromatography
(aluminum oxide; DCM) to give 0.157 g (10%) 6a as an
oil. 1H NMR (300 MHz, CDCl3): d = 1.02 (s, 9H), 3.94 (t,
J = 5.1 Hz, 2H), 4.13 (t, J = 5.1 Hz, 2H), 7.27–7.52 (m,
12H), 8.03 (d, J = 5.0 Hz, 1H), 9.02 (d, J = 5.0 Hz, 1H),
9.50 (s, 1H) ppm; MS: m/z (%) = 423 (M?-57, 100), 345
(35), 197 (17), 105 (23).
General procedure IV: reaction with methanesulfonyl
chloride
The alcohol obtained was dissolved in DCM in the pres-
ence of a small amount (2–3 drops) of triethylamine under
Ar. Afterwards the mixture was cooled to 0 to -10 °C.
Then methanesulfonyl chloride was added dropwise and
the reaction mixture was stirred at this temperature for an
additional 0.25–2 h. Afterwards the solvent was removed
at room temperature under reduced pressure. The crude
product obtained was purified by column chromatography
(aluminum oxide; EtOAc/MeOH, 98/2) to give the mesy-
lated products.
2-[4-(tert-Butyldiphenylsilyloxy)butyl]-2H-pyrrolo-
[3,4-g]isoquinoline-4,9-dione (6b, C31H32N2O3Si)
Following general procedure I, the reaction mixture NaH
(0.080 g, 3.4 mmol) in DMF (5 cm3), 3 (0.600 g,
3.1 mmol) in DMF (5 cm3), and 4-chlorobutoxy(tert-
butyl)diphenylsilane (1.160 g, 3.4 mmol) in DMF
(8 cm3) was stirred and heated under reflux for 4 h. The
crude product was purified by column chromatography
(aluminum oxide; DCM) to give 1.419 g (90%) 6b. M.p.:
2-(4,9-Dihydro-4,9-dioxo-2H-pyrrolo[3,4-g]isoquinolin-2-
yl)ethyl methanesulfonate (7a, C14H12N2O5S)
Mesylate 7a was prepared in a two-step reaction (according
to general procedures III and IV).
1. The reaction mixture 6a (2.085 g, 4.3 mmol) and 1 M
TBAF (8.8 cm3, 8.8 mmol) in THF (29 cm3) was stirred at
room temperature for 5 h. After purification by column
chromatography (aluminum oxide; EtOAc) 0.137 g (13%)
of the corresponding alcohol was obtained. M.p.: 221–
222 °C; 1H NMR (300 MHz, DMSO-d6): d = 3.81 (d,
J = 4.7 Hz, 2H), 4.21 (d, J = 4.7 Hz, 2H), 5.05 (s, 1H),
7.86 (s, 1H), 7.89 (s, 1H), 7.98 (d, J = 5.1 Hz, 1H), 9.08
(d, J = 5.1 Hz, 1H), 9.30 (s, 1H) ppm; MS: m/z (%) = 242
(M?, 83), 211 (60), 198 (86), 115 (34), 43 (100).
1
173–174 °C; H NMR (200 MHz, CDCl3): d = 1.05 (s,
9H), 1.45–1.70 (m, 2H), 1.85–2.10 (m, 2H), 3.69 (t,
J = 6.0 Hz, 2H), 4.02 (t, J = 7.1 Hz, 2H), 7.28–7.50 (m,
8H), 7.55–7.75 (m, 4H), 8.00 (d, J = 5.0 Hz, 1H), 8.99
(d, J = 5.0 Hz, 1H), 9.47 (s, 1H) ppm; MS: m/z
(%) = 508 (M?, 0.07) 493 (0.3), 451 (100), 183 (16),
105 (5).
2-[7-(tert-Butyldiphenylsilyloxy)heptyl]-2H-pyrrolo-
[3,4-g]isoquinoline-4,9-dione (6c, C34H38N2O3Si)
2. The alcohol obtained (0.185 g, 0.8 mmol), methanesul-
fonyl chloride (0.07 cm3), and triethylamine (0.16 cm3) in
Following general procedure I, the reaction mixture NaH
(0.330 g, 8.3 mmol) in DMF (12 cm3), 3 (1.500 g,
7.6 mmol) in DMF (15 cm3), and 7-chloroheptoxy(tert-
butyl)diphenylsilane (3.610 g, 8.3 mmol) in DMF
(20 cm3) was stirred at room temperature for 18 h. The
crude product was purified by column chromatography
(aluminum oxide; DCM) to give 2.360 g (57%) 6c. M.p.:
1
DCM (7 cm3) gave 0.120 g (29%) 7a as an oil. H NMR
(300 MHz, DMSO-d6): d = 3.15 (s, 3H), 4.55 (d,
J = 4.8 Hz, 2H), 4.67 (d, J = 4.8 Hz, 2H), 7.89–7.95 (m,
3H), 9.03 (br s, 1H), 9.26 (br s, 1H) ppm; 13C NMR (75 MHz,
DMSO-d6): d = 36.6, 49.2, 68.7, 119.1, 121.5, 121.5, 126.6,
127.0, 127.9, 140.7, 148.1, 154.6, 178.1, 178.6 ppm; IR
1
135–136 °C; H NMR (200 MHz, CDCl3): d = 1.03 (s,
(KBr): vꢀ ¼ 3;420; 1,669, 1,584, 1,540, 1,344, 1,242 cm-1
;
9H), 1.20–1.40 (m, 6H), 1.45–1.60 (m, 2H), 1.75–1.95 (m,
2H), 3.64 (t, J = 6.3 Hz, 2H), 4.00 (t, J = 7.1 Hz, 2H),
7.28–7.48 (m, 8H), 7.55–7.73 (m, 4H), 8.00 (d,
J = 5.0 Hz, 1H), 8.99 (d, J = 5.0 Hz, 1H), 9.47 (s, 1H)
ppm; MS: m/z (%) = 535 (M?-15, 0.5), 493 (M?-57, 100),
295 (4), 199 (16), 183 (7).
MS: m/z (%) = 320 (M?, 75.3), 224 (64), 211 (100), 183 (29).
4-(4,9-Dihydro-4,9-dioxo-2H-pyrrolo[3,4-g]isoquinolin-2-
yl)butyl methanesulfonate (7b, C16H16N2O5S)
Mesylate 7b was prepared in a two-step reaction (accord-
ing to general procedures III and IV).
123

Synthesis of new Benzo[f]isoindole-4,9-diones as anticancer compounds
59
1. The reaction mixture 6b (2.200 g, 4.3 mmol) and 1 M
TBAF (8.7 cm3, 8.7 mmol) in THF (29 cm3) was stirred at
room temperature for 5 h. After purification by column
chromatography (aluminum oxide; EtOAc/MeOH, 9/1)
0.704 g (60%) of the corresponding alcohol was obtained.
M.p.: 217–218 °C; 1H NMR (200 MHz, DMSO-d6):
d = 1.36 (quint, J = 6.7 Hz, 2H), 1.82 (quint, J = 6.7 Hz,
2H), 3.41 (t, J = 6.0 Hz, 2H), 4.10 (t, J = 7.0 Hz, 2H), 4.47
(t, J = 5.3 Hz, 1H), 7.78–7.92 (m, 3H), 8.98 (d, J = 5.0 Hz,
1H), 9.19 (s, 1H) ppm; MS: m/z (%) = 270 (M?, 100), 242
(22), 213 (69), 199 (44), 183 (27).
2-[2-(Aziridin-1-yl)ethyl]-2H-pyrrolo[3,4-g]isoquinoline-
4,9-dione (8a, C15H13N3O2)
Following general procedure II, treatment of 7a (0.060 g,
0.19 mmol) and aziridine (0.4 cm3, 7.2 mmol) in acetoni-
trile/triethylamine (0.8/1 cm3) at room temperature for
48 h and subsequent purification with column chromatog-
raphy (aluminum oxide; EtOAc) gave 0.030 g (60%) 8a.
M.p.: 194–196 °C; 1H NMR (200 MHz, CDCl3):
d = 1.07–1.08 (m, 2H), 1.75–1.76 (m, 2H), 2.62 (t,
J = 5.6 Hz, 2H), 4.21 (t, J = 5.6 Hz, 2H), 7.55 (s, 2H),
7.99 (d, J = 5.1 Hz, 1H), 8.99 (d, J = 5.1 Hz, 1H), 9.45 (s,
1H) ppm; 13C NMR (50 MHz, CDCl3): d = 27.2, 51.0,
61.1, 119.1, 122.5, 122.6, 125.2, 125.6, 128.1, 140.8,
149.3, 154.7, 178.9, 179.5 ppm; IR (KBr): vꢀ ¼ 3;100;
1,660, 1,584, 1,537, 1,239 cm-1; MS: m/z (%) = 267 (M?,
5), 78 (3), 57 (4), 56 (100).
2. The alcohol obtained (0.593 g, 2.8 mmol), methane-
sulfonyl chloride (0.26 cm3, 3.4 mmol), and triethylamine
(0.59 cm3) in DCM (26 cm3) gave 0.780 g (80%) 7b. M.p.:
1
135–136 °C; H NMR (200 MHz, DMSO-d6): d = 1.50–
1.72 (m, 2H), 1.80–2.00 (m, 2H), 3.16 (s, 3H), 4.05–4.35
(m, 4H), 7.75–8.00 (m, 3H), 9.00 (d, J = 4.8 Hz, 1H), 9.22
(s, 1H) ppm; 13C NMR (50 MHz, DMSO-d6): d = 25.5,
26.4, 36.5, 49.4, 69.7, 118.9, 121.4, 121.4, 126.1, 126.6,
127.7, 140.4, 148.2, 154.8, 178.1, 178.7 ppm; IR (KBr):
vꢀ ¼ 3;120; 1,667, 1,583, 1,537, 1,452, 1,353 cm-1; MS: m/
z (%) = 252 (M?-SO3Me, 70), 237 (32), 223 (13), 96 (57),
79 (100).
2-[4-(Aziridin-1-yl)butyl]-2H-pyrrolo[3,4-g]isoquinoline-
4,9-dione (8b, C17H17N3O2)
Following general procedure II, treatment of 7b (0.069 g,
0.24 mmol) and aziridine (0.5 cm3, 9.6 mmol) in aceto-
nitrile/triethylamine (1/1, 2 cm3) at room temperature for
48 h and subsequent purification by column chromatogra-
phy (aluminum oxide; EtOAc) gave 0.035 g (50%) 8b.
M.p.: 158–160 °C; 1H NMR (200 MHz, CDCl3): d = 1.03
(dd, J = 4.2, 2.3 Hz, 2H), 1.53 (quint, J = 7.0 Hz, 2H),
1.67 (dd, J = 4.2, 2.3 Hz, 2H), 1.98 (quint, J = 7.0 Hz,
2H), 2.18 (t, J = 6.6 Hz, 2H), 4.07 (t, J = 7.1 Hz, 2H),
7.44 (s, 2H), 7.95 (d, J = 5.0 Hz, 1H), 8.95 (d, J = 5.0 Hz,
1H), 9.40 (s, 1H) ppm; 13C NMR (50 MHz, CDCl3):
d = 26.5, 27.2, 27.2, 28.7, 51.0, 60.8, 119.0, 122.3, 122.4,
124.6, 124.9, 128.0, 140.7, 149.2, 154.5, 178.8, 179.3 ppm;
7-(4,9-Dihydro-4,9-dioxo-2H-pyrrolo[3,4-g]isoquinolin-2-
yl)heptyl methanesulfonate (7c, C19H22N2O5S)
Mesylate 7c was prepared in a two-step reaction (according
to general procedures III and IV).
1. The reaction mixture of 6c (2.300 g, 4.2 mmol) and
1 M TBAF (8.36 cm3, 8.3 mmol) in THF (28 cm3) was
stirred at room temperature for 3.5 h. After purification by
column chromatography (aluminum oxide; EtOAc/MeOH,
9/1) 1.070 g (82%) of the corresponding alcohol was
obtained. M.p.: 179–180 °C; 1H NMR (200 MHz, DMSO-
d6): d = 1.10–1.50 (m, 8H), 1.65–1.90 (m, 2H), 3.36 (t,
J = 6.4 Hz, 2H), 4.09 (t, J = 7.0 Hz, 2H), 4.30 (t,
J = 5.1 Hz, 1H), 7.87 (d, J = 1.7 Hz, 1H), 7.90 (d,
J = 1.7 Hz, 1H), 7.92 (d, J = 5.0 Hz, 1H), 9.02 (d,
J = 5.0 Hz, 1H), 9.25 (s, 1H) ppm; MS: m/z (%) = 312
(M?, 100), 253 (37), 212 (97), 199 (35), 183 (60).
2. The alcohol obtained (0.621 g, 2.0 mmol), methane-
sulfonyl chloride (0.19 cm3), and triethylamine (0.42 cm3)
in DCM (18.6 cm3) gave 0.720 g (93%) 7c. M.p.: 129–
IR (KBr): vꢀ ¼ 3;109; 1,654, 1,582, 1,539, 1,240 cm-1
;
MS: m/z (%) = 295 (M?, 3.4), 211 (7.8), 97 (56), 56 (100).
2-[7-(Aziridin-1-yl)heptyl]-2H-pyrrolo[3,4-g]isoquinoline-
4,9-dione (8c, C20H23N3O2)
Following general procedure II, treatment of 7c (0.300 g,
0.77 mmol) and aziridine (1.6 cm3, 30 mmol) in acetoni-
trile/triethylamine (1/1, 6 cm3) at room temperature for
48 h and subsequent purification by column chromatog-
raphy (aluminum oxide; EtOAc/MeOH, 98/2) gave
0.140 g (53%) 8c. M.p.: 142–146 °C; 1H NMR
(200 MHz, CDCl3): d = 0.99 (d, J = 4.3 Hz, 2H),
1.15–1.55 (m, 8H), 1.63 (d, J = 4.3 Hz, 2H), 1.70–1.90
(m, 2H), 2.09 (t, J = 6.8 Hz, 2H), 3.99 (t, J = 7.0 Hz,
2H), 7.41 (s, 2H), 7.94 (d, J = 5.0 Hz, 1H), 8.94 (d,
J = 5.0 Hz, 1H), 9.39 (s, 1H) ppm; 13C NMR (50 MHz,
CDCl3): d = 26.2, 27.1, 27.1, 28.9, 29.5, 30.6, 51.0, 61.7,
119.0, 122.3, 122.4, 124.5, 124.8, 127.9, 140.7, 149.2,
154.5, 178.7, 179.3 ppm; IR (KBr): vꢀ ¼ 3;109; 1,655,
1,582, 1,539, 1,239 cm-1; MS: m/z (%) = 337 (M?, 28),
253 (28), 84 (18), 56 (100).
1
130 °C; H NMR (200 MHz, DMSO-d6): d = 1.10–1.40
(m, 6H), 1.50–1.70 (m, 2H), 1.70–1.90 (m, 2H), 3.13 (s,
3H), 3.95–4.24 (m, 4H), 7.83 (d, J = 1.7 Hz, 1H), 7.86 (d,
J = 1.7 Hz, 1H), 7.89 (d, J = 5.0 Hz, 1H), 8.99 (d,
J = 5.0 Hz, 1H), 9.21 (s, 1H) ppm; 13C NMR (50 MHz,
DMSO-d6): d = 24.7, 25.6, 27.8, 28.3, 30.0, 36.5, 49.9,
70.3, 118.8, 121.3, 121.3, 126.1, 126.5, 127.7, 140.4,
148.2, 154.8, 178.1, 178.6 ppm; IR (KBr):vꢀ ¼ 3;113;
1,655, 1,544, 1,533, 1,338, 1,240 cm-1
(%) = 390 (M?, 4), 294 (5), 91 (100).
; MS: m/z
123

60
N. Pongprom et al.
2-[3-[4-[Bis(2-chloroethyl)amino]phenyl]propyl]-2H-pyr-
rolo[3,4-g]isoquinoline-4,9-dione (10, C24 H23Cl2N3O2)
1. Following general procedure I, NaH (0.125 g, 3.3 mmol) in
DMF (4.8 cm3), 3 (0.413 g, 2.0 mmol) in DMF (3.7 cm3),
and 4-(3-bromopropyl)-N,N-bis[2-[(tert-butyl)diphenylsilyl-
oxy]ethyl]benzenamine [14] (2.44 g, 3.1 mmol) in DMF
(5.2 cm3) were used. Column chromatography (silica gel;
EtOAc/light petroleum, 4/6) furnished 0.821 g 9 as the crude
product.
118.9, 122.1, 122.2, 125.0, 125.4, 127.9, 140.7, 149.1,
154.4, 178.8, 179.3 ppm; IR (KBr): vꢀ ¼ 3;111; 1,657,
1,539, 1,238 cm-1; MS: m/z (%) = 270 (M??1, 0.9), 225
(2.1), 211 (2.3), 58 (100).
2-[3-(Dimethylamino)propyl]-2H-pyrrolo[3,4-g]isoquino-
line-4,9-dione (11b, C16H17N3O2)
According to general procedure I the reaction mixture NaH
(0.106 g, 2.7 mmol) in DMF (2.2 cm3), 3 (0.200 g,
1.0 mmol) in DMF (1.8 cm3), and 3-chloro-N,N-dimethyl-
propylamine hydrochloride (0.240 g, 1.5 mmol) in DMF
(2.5 cm3) was stirred at 60 °C for 2 h. The crude product
was purified by column chromatography (aluminum oxide;
2. According to general procedure III, the reaction
mixture 9 (0.821 g, 0.9 mmol) and 1 M TBAF/THF
(3.66 cm3, 3.7 mmol) in THF (6.4 cm3) was stirred at
room temperature for 1.5 h. After purification by column
chromatography (silica gel; EtOAc) 0.322 g (83%) of the
corresponding alcohol was obtained.
1
EtOAc) to give 0.067 g (23%) 11b. M.p.: 125–126 °C; H
NMR (200 MHz, CDCl3): d = 1.97 (quint, J = 6.7 Hz,
2H), 2.21 (s, 6H), 2.10–2.35 (m, 2H), 4.13 (t, J = 6.7 Hz,
2H), 7.47 (s, 2H), 8.00 (d, J = 5.0 Hz, 1H), 8.99 (d,
J = 5.0 Hz, 1H), 9.46 (s, 1H) ppm; 13C NMR (50 MHz,
CDCl3): d = 28.6, 45.3, 48.5, 55.2, 119.1, 122.5, 122.5,
124.9, 125.3, 128.1, 140.9, 149.4, 154.6, 178.9, 179.5 ppm;
IR (KBr): vꢀ ¼ 1;662; 1,536, 1,230 cm-1; MS: m/z
(%) = 283 (M?, 59), 227 (11), 212 (41), 183 (13), 58
(100).
3. Following general procedure IV, the reaction mixture
of the obtained alcohol (0.150 g, 0.4 mmol), methanesul-
fonyl chloride (0.06 cm3, 0.8 mmol), and triethylamine
(1.1 cm3) in DCM (1.7 cm3) was stirred at 0 °C for 0.25 h.
The solvent was removed under vacuum.
4. The crude product from the previous step was
dissolved in DMF (1.5 cm3). Then LiCl (0.377 g,
8.9 mmol) was added and the mixture was heated at
100 °C for 5 min. After addition of water the mixture was
extracted with EtOAc. The combined organic layers were
dried (MgSO4) and concentrated. The crude product was
recrystallized (EtOAc) to give 0.160 g (72%) 10. M.p.:
9,9-Dimethoxy-1-[3-(tetrahydro-2H-pyran-2-yloxy)-
propyl]-2H-pyrrolo[3,4-g]isoquinolin-
4(9H)-one (14, C21H26N2O5)
To a vigorously stirred mixture of ketone 12 (1.038 g,
5 mmol) and 13 (1.693 g, 5 mmol) in dry THF (10 cm3)
under Ar, tert-BuOK (0.720 g, 6.15 mmol) in absolute
THF (5 cm3) was added. The reaction mixture was stirred
at room temperature for 18 h. After dilution with water the
mixture was exhaustively extracted with EtOAc. The
combined organic layers were dried (MgSO4) and concen-
trated in vacuo. The crude product was purified by column
chromatography (silica gel; EtOAc) to give 1.567 g (81%)
1
150–151 °C; H NMR (200 MHz, CDCl3): d = 2.02–2.28
(m, 2H), 2.57 (t, J = 7.1 Hz, 2H), 3.50–3.75 (m, 8H), 4.20
(t, J = 7.0 Hz, 2H), 6.63 (d, J = 8.6 Hz, 2H), 7.03 (d,
J = 8.6 Hz, 2H), 7.43 (s, 2H), 7.99 (d, J = 5.0 Hz, 1H),
8.99 (d, J = 5.0 Hz, 1H), 9.46 (s, 1H) ppm; 13C NMR
(50 MHz, CDCl3): d = 31.1, 32.1, 40.4, 40.4, 50.2, 53.5,
53.5, 112.2, 119.1, 122.5, 122.6, 124.6, 124.9, 128.1,
128.4, 129.5, 140.8, 144.7, 149.3, 154.7, 178.9, 179.4 ppm;
IR (KBr): vꢀ ¼ 3;114; 1,657, 1,579, 1,236 cm-1; MS: m/z
(%) = 456 (M?, 3.7), 406 (100), 357 (48), 214 (77), 118
(80).
1
14 as an oil. H NMR (200 MHz, CDCl3): d = 1.40–1.62
(m, 4H), 1.68–2.10 (m, 4H), 2.86 (s, 3H), 2.89 (s, 3H), 3.03
(t, J = 7.6 Hz, 2H), 3.46–3.60 (m, 2H), 3.74–3.94 (m, 2H),
4.45–4.60 (m, 1H), 7.51 (d, J = 3.0 Hz, 1H), 7.67 (d,
J = 5.2 Hz, 1H), 8.81 (d, J = 5.2 Hz, 1H), 9.36 (s, 1H)
ppm; MS: m/z (%) = 387 (M??1, 0.4), 356 (2), 341 (53),
270 (34), 226 (70).
2-[2-(Dimethylamino)ethyl]-2H-pyrrolo[3,4-g]isoquino-
line-4,9-dione (11a, C15H15N3O2)
According to general procedure I the reaction mixture NaH
(0.525 g, 12.9 mmol) in DMF (10 cm3), 3 (0.972 g,
4.9 mmol) in DMF (15 cm3), and 2-chloro-N,N-dimethyl-
ethylamine hydrochloride (1.083 g, 7.4 mmol) in DMF
(15 cm3) was stirred at 60 °C for 4 h. The crude product
was purified by column chromatography (aluminum oxide;
EtOAc/light petroleum, 9/1) to give 0.774 g (59%) 11a.
M.p.: 180–181 °C; 1H NMR (200 MHz, CDCl3): d = 2.28
(s, 6H), 2.71 (t, J = 6.1 Hz, 2H), 4.09 (t, J = 6.1 Hz, 2H),
7.53 (d, J = 1.8 Hz, 1H), 7.55 (d, J = 1.8 Hz, 1H), 8.01
(d, J = 5.0 Hz, 1H), 9.00 (d, J = 5.0 Hz, 1H), 9.47 (s, 1H)
ppm; 13C NMR (50 MHz, CDCl3): d = 45.2, 48.7, 59.2,
2-[3-(Dimethylamino)propyl]-9,9-dimethoxy-1-[3-(tetrahy-
dro-2H-pyran-2-yloxy)propyl]-2H-pyrrolo[3,4-g]isoquino-
lin-4(9H)-one (15, C26H37N3O5)
According to general procedure I, the reaction mixture
NaH (0.390 g, 9.7 mmol), 14 (1.303 g, 3.38 mmol), and 3-
chloro-N,N-dimethylpropylamine hydrochloride (0.816 g,
5.07 mmol) in DMF (24 cm3) was heated for 18 h at 60 °C
to give 1.384 g (87%) 15 as the crude product. The
compound was submitted to the next reaction step with-
out further purification. 1H NMR (200 MHz, CDCl3):
123

Synthesis of new Benzo[f]isoindole-4,9-diones as anticancer compounds
61
d = 1.40–1.62 (m, 4H), 1.68–2.00 (m, 6H), 2.15 and 2.19
(s, 6H), 2.25 (t, J = 6.7 Hz, 2H), 2.89 (s, 6H), 2.80–3.00
(m, 2H), 3.40–3.58 (m, 2H), 3.75–3.92 (m, 2H), 4.04 (t,
J = 7.1 Hz, 2H), 4.59 (br s, 1H), 7.49 (s, 1H), 7.68 (d,
J = 5.2 Hz, 1H), 8.84 (d, J = 5.2 Hz, 1H), 9.39 (s, 1H)
ppm; MS: m/z (%) = 472 (M??1, 0.6), 315 (43), 285 (89),
226 (86).
EtOH (3.6 cm3) and DMF (1.5 cm3) was stirred at room
temperature under Ar for 22 h. The crude product was
purified by column chromatography (aluminum oxide;
EtOAc/MeOH, 8/2) to give 0.038 g (32%) 18a. M.p.: 97–
1
100 °C; H NMR (200 MHz, CDCl3): d = 1.72–2.00 (m,
4H), 2.10–2.38 (m, 2H), 2.19 (s, 6H), 2.43 (s, 3H), 2.65 (t,
J = 6.8 Hz, 2H), 3.14 (t, J = 7.7 Hz, 2H), 4.07 (t,
J = 6.9 Hz, 2H), 7.41 (s, 1H), 7.98 (d, J = 5.0 Hz, 1H),
8.96 (d, J = 5.0 Hz, 1H), 9.42 (s, 1H) ppm; 13C NMR
(50 MHz, CDCl3): d = 22.4, 28.4, 28.7, 36.1, 44.4, 44.9,
50.7, 55.1, 117.6, 118.7, 121.2, 123.9, 127.7, 141.2, 142.0,
148.8, 154.2, 178.7, 178.7 ppm; IR (KBr): vꢀ ¼ 3;425;
1,662, 1,539, 1,258, 1,066 cm-1; MS: m/z (%) = 354 (M?,
2.3), 297 (4.2), 252 (11.5), 240 (15.1), 226 (23.4), 58 (100).
2-[3-(Dimethylamino)propyl]-1-(3-hydroxypropyl)-2H-
pyrrolo[3,4-g]isoquinoline-4,9-dione (16, C19H23N3O3)
After dissolving compound 15 (1.381 g, 2.93 mmol) in
acetone/H2O (60/6 cm3/cm3) 0.677 g (2.64 mmol) pyridi-
nium p-toluenesulfonate (PPTS) and p-toluenesulfonic acid
monohydrate (0.230 g, 1.21 mmol) were added. The reac-
tion mixture was stirred at room temperature for 18 h.
Afterwards the solvents were removed in vacuo and the
crude product was dissolved in MeOH (20 cm3). p-Tolu-
enesulfonic acid monohydrate (0.915 g, 4.81 mmol) was
added and the reaction mixture was stirred at room temper-
ature for 4 h. Afterwards the solvent was removed in vacuo
and the crude product was purified by column chromatog-
raphy (aluminum oxide; EtOAc/MeOH, 8/2) to furnish
1,2-Bis[3-(dimethylamino)propyl]-2H-pyrrolo[3,4-g]iso-
quinoline-4,9-dione (18b, C21H28N4O2)
Following general procedure II, the reaction mixture 17
(0.143 g, 0.34 mmol) and 40% dimethylamine in H2O
(2.0 cm3, 2 mmol) in EtOH (5.5 cm3) was stirred at room
temperature for 18 h. The stirring was continued for a
further 48 h at 30–35 °C. The crude product was purified
by column chromatography (aluminum oxide; EtOAc/
MeOH, 95/5) to give 0.077 g (77%) 18b. M.p.: 100–
1
0.812 g (81%) 16 as an oil. H NMR (200 MHz, CDCl3):
d = 1.82–2.10 (m, 5H), 2.22 (s, 6H) 2.29 (t, J = 6.2 Hz,
2H), 3.26 (t, J = 7.0 Hz, 2H), 3.58 (t, J = 5.5 Hz, 2H), 4.11
(t, J = 7.0 Hz), 7.45 (s, 1H), 8.00 (d, J = 5.0 Hz, 1H), 8.99
(d, J = 5.0 Hz, 1H), 9.45 (s, 1H) ppm; MS: m/z (%) = 341
(M?, 2.4), 323 (1), 270 (15), 226 (70).
1
102 °C; H NMR (200 MHz, CDCl3): d = 1.75–2.05 (m,
4H), 2.22 (s, 6H), 2.24 (s, 6H), 2.24 (t, J = 7.0 Hz, 2H),
2.37 (t, J = 7.0 Hz, 2H), 3.11 (t, J = 7.0 Hz, 2H), 4.10 (t,
J = 7.0 Hz, 2H), 7.42 (s, 1H), 8.00 (d, J = 5.0 Hz, 1H),
8.98 (d, J = 5.0 Hz, 1H), 9.44 (s, 1H) ppm; 13C NMR
(50 MHz, CDCl3): d = 23.0, 26.9, 28.7, 44.8, 45.3, 45.4,
55.5, 58.8, 117.9, 119.1, 121.5, 124.2, 128.1, 141.6, 142.5,
149.2, 154.5, 178.9, 179.7 ppm; IR (KBr): vꢀ ¼ 1;663;
1,643, 1,539, 1,257, 1,038 cm-1; MS: m/z (%) = 368 (M?,
5.6), 297 (10.1), 252 (6.2), 240 (15.8), 226 (22.8), 58 (100).
3-[2-[3-(Dimethylamino)propyl]-4,9-dihydro-4,9-dioxo-
2H-pyrrolo[3,4-g]isoquinolin-1-yl]propyl
methanesulfonate (17, C20H25N3O5S)
Following general procedure IV, the reaction mixture 16
(0.150 g, 0.44 mmol), methanesulfonyl chloride (0.1 cm3,
1 mmol), and triethylamine (0.1 cm3) in DCM (5 cm3) was
stirred at 0 °C for 1 h. The crude product was purified by
column chromatography (aluminum oxide; EtOAc/MeOH,
95/5) to give 0.143 g (78%) 17. M.p.: 208–210 °C; 1H
NMR (200 MHz, CDCl3): d = 1.83–2.03 (m, 2H), 2.10–
2.32 (m, 4H), 2.22 (s, 6H), 3.06 (s, 3H), 3.24 (t,
J = 7.6 Hz, 2H), 4.09 (t, J = 7.0 Hz, 2H), 4.35 (t,
J = 5.9 Hz, 2H), 7.45 (s, 1H), 7.98 (d, J = 5.0 Hz, 1H),
9.00 (d, J = 5.0 Hz, 1H), 9.46 (s, 1H) ppm; 13C NMR
(50 MHz, CDCl3): d = 21.4, 28.5, 28.6, 37.5, 44.8, 45.2,
55.2, 69.2, 118.3, 119.0, 121.6, 124.4, 128.0, 140.3, 141.3,
149.3, 154.6, 179.1, 179.3 ppm; IR (KBr): vꢀ ¼ 1;663;
1,539, 1,243, 1,058 cm-1; MS: m/z (%) = 420 (M??1,
0.4), 225 (10.4), 211 (10.3), 58 (100).
1-[3-(1-Aziridinyl)propyl]-2-[3-(dimethylamino)propyl]-
2H-pyrrolo[3,4-g]isoquinoline-4,9-dione
(18c, C21H26N4O2)
Following general procedure II, a mixture of 17 (0.194 g,
0.46 mmol), aziridine (0.82 cm3, 11.56 mmol), and triethyl-
amine (2.2 cm3) in acetonitrile (2.2 cm3) was stirred at room
temperature for 52 h. The crude product was purified by
column chromatography (aluminum oxide; EtOAc) to give
0.130 g (77%) 18c. M.p.: 107–109 °C; 1H NMR (200 MHz,
CDCl3): d = 1.14 (dd, J = 4.2, 2.1 Hz, 2H), 1.75 (dd,
J = 4.2, 2.1 Hz, 2H), 1.80–2.05 (m, 4H), 2.17–2.38 (m,
4H), 2.22 (s, 6H), 3.21 (t, J = 7.8 Hz, 2H), 4.12 (t,
J = 7.0 Hz, 2H), 7.43 (s, 1H), 7.99 (d, J = 4.8 Hz, 1H),
8.98 (d, J = 4.8 Hz, 1H), 9.45 (s, 1H) ppm; 13C NMR
(50 MHz, CDCl3): d = 23.0, 27.2, 28.7, 29.0, 44.8, 45.3,
55.5, 60.9, 117.9, 119.0, 121.5, 124.2, 128.1, 141.6, 142.4,
149.2, 154.5, 179.0, 179.7 ppm; IR (KBr): vꢀ ¼ 1;657; 1,533,
1,225, 1,072 cm-1; MS: m/z (%) = 366 (M?, 7.5), 323 (8.8),
297 (9.0), 282 (8.1), 265 (8.9), 252 (18.2), 58 (100).
2-[3-(Dimethylamino)propyl]-1-[3-(methylamino)propyl]-
2H-pyrrolo[3,4-g]isoquinoline-4,9-dione
(18a, C20H26N4O2)
Following general procedure II, the reaction mixture 17
(0.143 g, 0.34 mmol) in 33% methylamine in absolute
123

62
N. Pongprom et al.
Acknowledgments N. Pongprom thanks ‘‘The Royal Thai Gov-
ernment Scholarship’’ for financial support throughout her Ph.D.
program.
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