Synthesis of 6-methyl-6H-indolo[3,2-c]isoquinoline and 6-methyl-6H-indolo[2,3-c]isoquinoline: two new unnatural isoquinoline isomers of the cryptolepine series

Article abstract of DOI:10.1016/j.tet.2008.08.116

11H-indolo[3,2-c]isoquinoline has been synthesized in two steps starting from 4-bromoisoquinoline and 2-bromoaniline via a selective Buchwald-Hartwig reaction followed by a Pd-catalyzed intramolecular direct arylation involving C(sp²)-H activation. The synthesis of 7H-indolo[2,3-c]isoquinoline was achieved by a combination of a Suzuki reaction with an intramolecular nitrene insertion reaction starting from 4-bromoisoquinoline and {2-[(2,2-dimethylpropanoyl)amino]phenyl}boronic acid. Selective methylation of the tetracyclic skeletons yielded the title compounds 6-methyl-6H-indolo[3,2-c]isoquinoline and 6-methyl-6H-indolo[2,3-c]isoquinoline, which have never been described in the literature before.

Full text of DOI:10.1016/j.tet.2008.08.116

Tetrahedron 64 (2008) 11802–11809
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of 6-methyl-6H-indolo[3,2-c]isoquinoline and 6-methyl-6H-indolo
[2,3-c]isoquinoline: two new unnatural isoquinoline isomers
of the cryptolepine series
a
a
a
a
a
`
Gitte Van Baelen , Caroline Meyers , Guy L.F. Lemiere , Steven Hostyn , Roger Dommisse ,
Louis Maes b, Koen Augustyns c, Achiel Haemers c, Luc Pieters c, Bert U.W. Maes a
,
*
a Department of Chemistry, University of Antwerp, Groenenborgerlaan 171, B-2020 Antwerp, Belgium
b Department of Biomedical Sciences, University of Antwerp, Groenenborgerlaan 171, B-2020 Antwerp, Belgium
c Department of Pharmaceutical Sciences, Universiteitsplein 1, B-2610 Wilrijk, Belgium
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 1 July 2008
Received in revised form 8 August 2008
Accepted 26 August 2008
Available online 4 October 2008
11H-indolo[3,2-c]isoquinoline has been synthesized in two steps starting from 4-bromoisoquinoline and
2-bromoaniline via a selective Buchwald–Hartwig reaction followed by a Pd-catalyzed intramolecular
direct arylation involving C(sp2)–H activation. The synthesis of 7H-indolo[2,3-c]isoquinoline was ach-
ieved by a combination of a Suzuki reaction with an intramolecular nitrene insertion reaction starting
from 4-bromoisoquinoline and {2-[(2,2-dimethylpropanoyl)amino]phenyl}boronic acid. Selective
methylation of the tetracyclic skeletons yielded the title compounds 6-methyl-6H-indolo[3,2-c]iso-
quinoline and 6-methyl-6H-indolo[2,3-c]isoquinoline, which have never been described in the literature
before.
Keywords:
Malaria
Plasmodium falciparum
Cryptolepines
Ó 2008 Elsevier Ltd. All rights reserved.
Palladium
Buchwald–Hartwig reaction
C(sp2)–H activation
Suzuki reaction
Nitrene insertion
1. Introduction
most potent is quinine, isolated from the Cinchona bark and arte-
misinin, isolated from the leafy portions of Artemisia annua.2,3 The
Malaria is an infectious disease caused by protozoa of the genus
Plasmodium and transmitted by the Anopheles mosquito. Among
the four pathogenic species, Plasmodium falciparum is the most
dangerous one. Each year, at least 300 million acute cases of malaria
are estimated to occur globally. Although malaria can be prevented
and treated, it still kills more than one million people each year.1 A
major problem is the increasing resistance of the parasite against
the currently available drugs, hence the continuous need for new
and more efficient antiplasmodial drugs.
above mentioned synthetic drugs are currently used in combina-
tion with the artemisinin derivatives artesunate and artemether.
In Central and West African traditional folk medicine,
a
decoction of the root of the plant Cryptolepis sanguinolenta is
used to treat fevers, including those caused by malaria. Several
alkaloids have been isolated, such as cryptolepine4a (5-methyl-5H-
indolo[3,2-b]quinoline) (1), neocryptolepine4b,c (cryptotackieine,
5-methyl-5H-indolo [2,3-b]quinoline) (2) and isocryptolepine4d,e
(cryptosanguinolentine, 5-methyl-5H-indolo[3,2-c]quinoline) (3)
Although the synthetic drugs (e.g., chloroquine, halofantrine
and mefloquine) still prove their usefulness in prevention and/or
therapy, the World Health Organization (WHO) now strongly rec-
ommends to switch to combination therapy to avoid build up of
resistance and clinical failure. Besides synthetic drugs, several
natural products have shown antiplasmodial activity. Among the
(Fig. 1). The benzo-b-carboline (5-methyl-5H-indolo[2,3-c]quino-
line), for which we have adopted the name isoneocryptolepine) (4),
surprisingly has not yet been found in nature. Recently, we de-
veloped an efficient synthetic strategy for this ‘missing’ isomer and
for its 7H-indolo[2,3-c]quinoline core. The methodology used for
the synthesis of 7H-indolo[2,3-c]quinoline is based on the combi-
nation of a selective Buchwald–Hartwig reaction with a selective
Pd-catalyzed intramolecular direct arylation reaction.5,6
Molecules 1–4 are isomeric indoloquinolines which possess
an interesting antiplasmodial activity. The ‘missing’ isomer
* Corresponding author. Tel.: þ32 3 265 32 05; fax: þ32 3 265 32 33.
E-mail address: bert.maes@ua.ac.be (B.U.W. Maes).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.08.116

G. Van Baelen et al. / Tetrahedron 64 (2008) 11802–11809
11803
N
N
N
N
N
N
N
N
CH3
CH3
CH3
CH3
1
2
3
4
Figure 1. Cryptolepine (1), neocryptolepine (2), isocryptolepine (3) and isoneocryptolepine (4).
Table 1
isoneocryptolepine (4) is approximately two times less active (K1
strain of P. falciparum, resistant to chloroquine and pyrimethamine)
than cryptolepine (1) (the most active compound of the quartet),
but it is also four times less cytotoxic (L6 cells), resulting in the best
selectivity index (cytotoxicity/antiplasmodial activity ratio) of the
four indoloquinolines (Table 4).7
Selective Buchwald–Hartwig reaction of 4-bromoisoquinoline (8) with 2-bromo-
aniline (9)
Br
NH2
HN
Br
Br
The selectivity index of 4 stimulated us to synthesize new
unnatural indoloquinoline isomers. Here we describe the synthesis
of two indoloisoquinoline isomers; 6-methyl-6H-indolo[3,2-c]-
isoquinoline (5) and 6-methyl-6H-indolo[2,3-c]isoquinoline (6),
which are the isoquinoline analogues of, respectively, 3 and 4
(Fig. 2).
+
N
N
Pd2(dba)3
XANTPHOS
base
10
8
9
dioxane
reflux
Entry
Pd2(dba)3
(mol %)
XANTPHOS
(mol %)
Base
Time
Recovered 8
Yielda 10
(%)
(h)
(%)
2. Results and discussion
1
2
3
4
2.5
2.5
5.0
5.0
5.5
5.5
11.0
11.0
Cs2CO3
K3PO4
Cs2CO3
Cs2CO3
27
27
27
48
20
25
7
61
64
74
72
Previously, our laboratory synthesized isocryptolepine (3) and
isoneocryptolepine (4) via the combination of a selective Buch-
8
a
wald–Hartwig reaction with
a Pd-catalyzed direct arylation
x mol % Pd2(dba)3, y mol % XANTPHOS, 3 mmol 8, 3.6 mmol 9, 9 mmol base,
reaction.5,6,8 Therefore, we attempted to prepare 11H-indolo[3,2-
c]isoquinoline (7) via a similar reaction sequence starting from
commercially available 4-bromoisoquinoline (8) and 2-bromoani-
line (9) (Tables 1 and 2). The selective amination of 8 with 9 (Table
1) was first executed under the reaction conditions previously used
for the amination of 3-bromoquinoline with 9 [2.5 mol % Pd2(dba)3/
5.5 mol % XANTPHOS (9,9-dimethyl-4,5-bis(diphenylphosphino)-
9H-xanthene) catalyst, 1.2 equiv amine, 3 equiv Cs2CO3, dioxane,
reflux]. In the rest of the article these reaction conditions will be
mentioned as ‘standard conditions’.5,6 After 27 h of reflux, complete
conversion of 8 was still not obtained (Table 1, entry 1). The use of a
stronger base such as K3PO4 did not provide a better result (Table 1,
entry 2). Doubling the catalyst loading allowed an almost complete
conversion in 27 h (Table 1, entry 3). An additional increase of the
reaction time to 48 h gave essentially the same isolated yield (Table
1, entry 4).
12 mL dioxane, reflux.
Table 2
Pd-catalyzed intramolecular direct arylation of 10 under conventional and micro-
wave heating
HN
NH
HN
Br
+
N
N
N
PdCl2(PPh3)2
NaOAc.3H2O
DMA, heat
10
7
11
Not observed
Entry
PdCl2(PPh3)2
Temperature
(ꢀC)
Time
Yield 7
(%)
(mol %)
Applying the Pd-catalyzed intramolecular direct arylation
reaction conditions developed earlier for the ring closure of
N-(2-bromophenyl)quinolin-3-amine on N-(2-bromophenyl)iso-
quinolin-4-amine (10) led to the formation of 11H-indolo[3,2-
c]isoquinoline (7) (Table 2).5 A catalyst loading of 10 mol % was not
sufficient to drive the reaction to completion within 16 h. A double
loading (20 mol %) gave full conversion in the same reaction time
and the indoloisoquinoline 7 could be isolated in 78% (Table 2,
entries 1 and 2). More, recently we reported on the high tem-
perature Pd-catalyzed intramolecular direct arylation using mi-
crowave irradiation. Among several other brominated substrates,
1
2
3
4
10.0
20.0
1.0
130
130
180
200
88 h
16 h
10 min
10 min
65a
78a
71b
79b
1.0
a
x mol % PdCl2(PPh3)2, 0.6 mmol 10,1.47 mmol NaOAc$3H2O,10 mL DMA, oil bath.
x mol % PdCl2(PPh3)2, 0.6 mmol 10, 1.47 mmol NaOAc$3H2O, 1 mL DMA, mW.
b
N-(2-bromophenyl)quinolin-3-amines could be smoothly cyclized
in only 10–30 min using a low catalyst loading (1 mol %) at a high
reaction temperature (180–200 ꢀC).6,9 The standard protocol uses
1 mol % PdCl2(PPh3)2, 0.6 mmol substrate, 1.47 mmol NaOAc$3H2O
and 1 mL DMA at 180 ꢀC (
mW) for 10 min. Applying these con-
ditions on 10 gave 71% of 7 and a recovery of 8% of starting
material (Table 2, entry 3). Increasing the reaction temperature to
200 ꢀC did drive the reaction to completion in 10 min and an
isolated yield of 79% was obtained (Table 2, entry 4). Besides 7,
theoretically isomeric 7H-pyrido[3,4,5-gh]phenanthridine (11) can
also be formed but we have never observed it. Compound 7 has
N
N
N
N
CH3
CH3
5
6
´
already been synthesized by Hajos and co-workers using
Figure 2. Target indoloisoquinolines: 6-methyl-6H-indolo[3,2-c]isoquinoline (5) and
6-methyl-6H-indolo[2,3-c]isoquinoline (6).
a Suzuki–nitrene insertion approach.10 They started from the

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G. Van Baelen et al. / Tetrahedron 64 (2008) 11802–11809
Table 3
Br
Buchwald–Hartwig reaction of isoquinolin-3-amine (14) with 1,2-dibromobenzene
(15)
Br
18
NH2
NH2
NBS
Br
Br
H
N
N
N
Pd2(dba)3
XANTPHOS
Cs2CO3
dioxane
reflux, 24 h
61%
NH2
+
Br
MeOH
RT, 1 h
65%
14
17
N
N
Pd2(dba)3
XANTPHOS
Cs2CO3
dioxane
reflux
16
14
15
24 h
Br
H
NH
Entry
Pd2(dba)3
(mol %)
XANTPHOS
(mol %)
Yield 16
(%)
N
N
N
PdCl2(PPh3)2
NaOAc.3H2O
DMA
1
2
2.5
2.5
5.5
5.5
56a
62b
19
12
a
130 °C
x mol % Pd2(dba)3, y mol % XANTPHOS, 1 mmol 15, 1.2 mmol 14, 3 mmol Cs2CO3,
10 mL dioxane, reflux, 24 h.
Scheme 2. Approach no. 2: synthesis of 7H-indolo[2,3-c]isoquinoline (12) via a Pd-
catalyzed intramolecular direct arylation of 19.
b
1.2 mmol 15 and 1 mmol 14 were used.
N-oxide of N-(2-isoquinolin-3-ylphenyl)-2,2-dimethylpropana-
mide. Our approach is shorter with respect to the number of
steps and the overall yield is higher (78% vs 43%).
alternative strategy we tried ring closure by oxidative cyclization
(Scheme 3).12 The required substrate 20 could easily be obtained in
a good yield (87%) via a Buchwald–Hartwig reaction of 14 with 18
under standard conditions. The aimed cyclization reaction was
unfortunately again not successful.
Secondly, the synthesis of 7H-indolo[2,3-c]isoquinoline (12) via
a selective Buchwald–Hartwig reaction followed by a Pd-catalyzed
intramolecular direct arylation reaction starting from commercially
available isoquinolin-3-amine (14) and 1,2-dibromobenzene (15)
was attempted. The amination reaction occurred fairly well under
standard conditions yielding 56% of 16 after 24 h of reflux (Table 3,
entry 1). TLC analysis showed that there was only a small fraction of
unconverted 15 left.
Before further optimizing the Buchwald–Hartwig reaction, the
intramolecular Pd-catalyzed direct arylation reaction of 16 was
tested. No reaction product 12 could be observed after 48 h of reflux
under conventional heating using a 20 mol % catalyst loading
(Scheme 1). Only substrate as well as dehalogenated starting ma-
terial was found.
Br
H
N
N
Bu3SnH
16
NH
Br
AIBN
toluene
reflux
24 h
H
N
N
12
N
19
Pd(OAc)2
CF3COOH
90 °C
Br
24 h
H
N
18
NH2
Br
H
NH
N
N
N
Pd2(dba)3
20
14
XANTPHOS
N
N
PdCl2(PPh3)2
NaOAc.3H2O
DMA
Cs2CO3
16
12
dioxane
reflux, 46 h
87%
130 °C
Scheme 1. Approach no. 1: synthesis of 7H-indolo[2,3-c]isoquinoline (12) via a Pd-
catalyzed intramolecular direct arylation of 16.
Scheme 3. Approach no. 3 and 4: synthesis of 7H-indolo[2,3-c]isoquinoline (12) via
a radical and oxidative cyclization of 16, 19 and 20, respectively.
The Stille–Kelly reaction, a Pd-catalyzed intramolecular biaryl
coupling of aryl halides or aryl triflates in the presence of dis-
tannanes, was the fifth protocol we tried in order to obtain 12
(Scheme 4).13 In contrast to the previous methodologies where
the presence of one bromine atom was sufficient, a system with
two bromine atoms in the same molecule was needed. The sub-
strate for this kind of cyclization (21) was synthesized via a se-
lective Pd-catalyzed amination reaction of 17 with 15 under
standard conditions, only changing the catalyst loading to 5 mol
% Pd2(dba)3. The resulting yield (39%) was not high, but we
decided to test the possibility to synthesize 12 via Stille–Kelly
cyclization on 21 before considering optimizing the Buchwald–
Hartwig reaction. Unfortunately, also in this case no reaction
product was formed in the Stille–Kelly reaction on 21. Based on
results of Iwaki and co-workers, the nitrogen atom of the
N-phenylisochinolin-3-amine entity of 21 was protected with
a mesyl-group but also this substrate (22) did not allow cycliza-
tion (Scheme 4).14
In order to achieve cyclization via Pd-catalysis we attempted to
move the bromine atom leaving group from the benzene ring to the
isoquinoline ring (Scheme 2). The required 4-bromoisoquinolin-3-
amine (17) could be obtained by bromination of 14 with NBS
followed by a selective Buchwald–Hartwig reaction of 17 with
bromobenzene (18) under standard conditions. An isolated yield of
61% of 4-bromo-N-phenylisoquinolin-3-amine (19) was obtained
after 24 h of reflux (Scheme 2). Unfortunately, also on this substrate
the subsequent Pd-catalyzed intramolecular direct arylation re-
action failed and the main product found was dehalogenated
starting material.
After two defeated attempts based on C–H activation, we
changed tack. To obtain our target molecule 12, a radical cyclization
reaction using tributyltinhydride (Scheme 3) was attempted.11
Compound 16 as well as 19 was subjected to a radical C–C bond
formation reaction using AIBN as initiator. Unfortunately, no cy-
clization reaction occurred. After 24 h of reflux only substrate and
dehalogenated starting material could be found. As a second

G. Van Baelen et al. / Tetrahedron 64 (2008) 11802–11809
11805
Br
Br
15
Br
Br
Br
H
N
NH
NH2
N
N
N
Pd2(dba)3
XANTPHOS
Cs2CO3
(Bu3Sn)2
PdCl2(PPh3)2
Et4NI
17
12
21
MsCl
NaH
THF
dioxane
Li2CO3
reflux, 48 h
39%
toluene
reflux
RT, 2 h
15%
Br Ms Br
N
N
Ms
(Bu3Sn)2
PdCl2(PPh3)2
Et4NI
N
N
22
23
Li2CO3
toluene
reflux
Scheme 4. Approach no. 5: synthesis of 7H-indolo[2,3-c]isoquinoline (12) via a Stille–Kelly reaction of 21 and 22.
NH2
NHPiv
Br
NHPiv
B(OH)2
+
N
N
N
Pd(PPh3)4
aq. Na2CO3
DME
aq. H2SO4
EtOH
reflux, 24 h
97%
24
25
26
8
reflux, 2 h
98%
HN
N3
NH
+
N
1) aq. NaNO2/HCl
0 °C
N
N
o-dichlorobenzene
180 °C, 3 h
77%
12
27
28
2) aq. NaN3/
NaOAc.3H2O
0 °C
Not observed
Scheme 5. Synthesis of 7H-indolo[2,3-c]isoquinoline (12) via intramolecular nitrene insertion of 27.
I
HN
N
HN
MeI
THF
NH3 in water
(28-30%)
76%
reflux, 22 h
N
N
N
CH3
CH3
5.HI
7
5
I
MeI
NH
NH
N
THF
reflux, 6 h
NH3 in water
(28-30%)
99%
N
N
N
CH3
CH3
6.HI
12
6
Scheme 6. Selective N-6 methylation of 7 and 12.
In a last attempt to obtain the indoloisoquinoline 12 we tried to
combine a Suzuki reaction with an intramolecular nitrene insertion
reaction (Scheme 5). This protocol has been used by us and others
to obtain other indolo-fused ring systems.5,10,15–17 Suzuki reaction
of 4-bromoisoquinoline (8) with {2-[(2,2-dimethylpropanoyl)-
amino]phenyl}boronic acid18 (24) under Gronowitz conditions19
yielded N-(2-isoquinolin-4-ylphenyl)-2,2-dimethylpropanamide
(25) in 98% yield. Acid hydrolysis of pivalamide 25 in 40% aq H2SO4/
ethanol gave 2-(isoquinolin-4-yl)aniline (26) in a very good yield
(97%). Subsequent diazotization of the amine 26 followed by

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G. Van Baelen et al. / Tetrahedron 64 (2008) 11802–11809
Table 4
Antiprotozoal activity (IC50
,
m
M), cytotoxicity (IC50
P. falciparum K1
IC50 M)
,
m
M) and selectivity index (cytotoxicity/antiplasmodial activity ratio) of compounds 1–47 and 5–6
Compound
T.b. rhodesiense
IC50 M)
T. cruzi
IC50 M)
L. donovani
IC50 M)
Cytotoxicity (L6 cells)
IC50 M)
Selectivity index SI
(m
(m
(
m
(
m
(m
1
2
3
4
5
6
0.12ꢂ0.02
2.61ꢂ0.67
0.78ꢂ0.30
0.23ꢂ0.04
0.04ꢂ0.01
0.68ꢂ0.13
0.24ꢂ0.04
0.60ꢂ0.07
2.23ꢂ0.82
0.52ꢂ0.11
6.48ꢂ0.76
3.33
0.22ꢂ0.07
2.01ꢂ1.30
1.27ꢂ0.78
21.0ꢂ0.2
20.66
2.68ꢂ0.89
49.5ꢂ3.7
39.1ꢂ11.5
75.4ꢂ2.4
4.78
1.12ꢂ0.07
3.24ꢂ0.04
1.19ꢂ0.26
4.32ꢂ0.04
1.31ꢂ0.85
1.48ꢂ0.72
9.3
1.2
1.5
18.8
32.8
2.1
0.72
1.66
15.54
Chloroquinea
Melarsoprola
Benznidazolea
Miltefosinea
Podophyllotoxina
0.010ꢂ0.003
1.25ꢂ0.28
0.26ꢂ0.08
0.010ꢂ0.002
a
Positive control.
introduction of the azido group via a SN1 reaction on the diazonium
salt gave 4-(2-azidophenyl)isoquinoline (27). Finally, thermal de-
composition of the azide 27 in boiling 1,2-dichlorobenzene yielded
the target indoloisoquinoline 12 in a good yield (77%). The mech-
anism of this reaction presumably occurs via the formation of
a nitrene (formed from the azide), which formally inserts into the
C3-H bond.20,21 Interestingly, the intramolecular nitrene insertion
is C-3 regioselective since no C-5 ring closed product (7H-pyr-
ido[3,4,5-kl]acridine (28)) was found.
For the selective N-6 methylation of 7 and 12 the conditions we
previously reported for the selective methylation of 10-chloro-7H-
indolo[2,3-c]quinoline and 9-trifluoromethyl-7H-indolo[2,3-c]-
quinoline were used (CH3I, THF, reflux; then 28–30% NH3 in H2O)
(Scheme 6).6,22 In previous selective methylation reactions toluene
was used.5,6 The use of THF instead of toluene facilitated the work-
up and also allowed the selective methylation of 7 and 12 since the
formed hydroiodide salts 5$HI and 6$HI immediately precipitated,
hereby avoiding dimethylation. A reaction time of 22 h was nec-
essary to obtain full conversion of 7 to 5$HI and a reaction time of
6 h to obtain 6$HI. The free bases 5 and 6 could be obtained from
5$HI and 6$HI in, respectively, 76% and 99% yield after an acid–base
extraction using ammonia in water (28–30%).
Antiprotozoal activity and cytotoxicity data of the new indoloi-
soquinolines 5 and 6 are outlined in Table 4. Although 5 is almost six
times more active against P. falciparum than isoneocryptolepine (4),
5 as well as 6 are around three times more cytotoxic than 4. These
data result in a selectivity index (SI) for 5 which is almost two times
better than the one for lead compound 4 and a SI for 6 which is nine
times worse. Because of the poor selectivity against any of the par-
asites, the relatively high cytotoxicity (which also may explain at
least in part the higher activity of 5) and the rather moderate or low
selectivity index of 5 and 6, respectively, both compounds cannot be
considered as promising new leads for further exploration.
substrates did not work and an alternative synthesis strategy was
searched. Neither a radical cyclization, nor an oxidative cyclization,
nor a Stille–Kelly reaction was successful. Finally, 7H-indolo[2,3-
c]isoquinoline (12) could be synthesized using a combination of
a Suzuki reaction with an intramolecular nitrene insertion reaction
in a 73% overall yield. Selective N-6 methylation gave the second
target compound 6-methyl-6H-indolo[2,3-c]isoquinoline (6). Bi-
ological evaluation of the indoloisoquinolines 5 and 6 revealed that
these compounds possess antiplasmodial activity, but are relatively
high in cytotoxicity and possess a moderate (compound 5) or low
(compound 6) selectivity.
4. Experimental
4.1. General
All melting points were determined on a Bu¨chi apparatus and
are uncorrected. The 1H and 13C NMR spectra were recorded on
a Bruker spectrometer Avance 400 in the solvent indicated with
TMS as an internal standard. All coupling constants are given in
hertz and chemical shifts are given in parts per million. The as-
signment of the 1H NMR signals of all products is based on 2D NMR
techniques (COSY, NOESY, HMQC and HMBC). In compounds 10, 16,
19, 20, 21, 22, 25 and 26 the aryl substituent is numbered with
primes and the isoquinoline core without. For mass spectrometric
analysis, samples were dissolved in CH3OH containing 0.1% formic
acid and diluted to a concentration of approximately 10ꢁ5 mol/L.
Injections (1 mL) were directed to the mass spectrometer at a flow
rate of 0.7 mL/min (CH3OH and 0.1% formic acid), using a Kontron
HPLC system. Mass spectrometric data were acquired on an AQA
Navigator mass spectrometer (ThermoQuest, Finigan) equipped
with an ApCI ionisation interface. The AQAMax voltage was set to
20 V, the corona voltage to 3.5 kV and the probe temperature to
250 ꢀC. Nitrogen gas was used for nebulation. Mass spectra were
acquired by summing the spectra in the elution plug. In positive ion
mode, the protonated molecule [MþH]þ was recorded. Accurate
mass data were acquired on a Q-TOF 2 (Micromass) mass spec-
trometer equipped with a Nanomate (Advion, Ithaca, NY) nano-
electrospray source in LC-mode. Cone voltage (approx. 35 V) and
ESI voltage (approx. 1.7 kV) were optimized on one compound and
used for all others. For the determination of the accurate mass of
the molecular ion [MþH]þ, a solution of polyethylene glycol 300 in
CH3OH/H2O with 1 mmol ammonium acetate, was added just be-
fore the mass spectrometer (at a rate of 1 mL/min) to the mobile
phase. The calculated masses of PEG ions ([MþH]þ and [MþNH4]þ)
were used as lock mass. 4-Bromoisoquinoline, XANTPHOS,
PdCl2(PPh3)2, Cs2CO3 (99%) and NaH (assay 55–65%) were obtained
from Sigma–Aldrich and used as such. Isoquinolin-3-amine,
3. Conclusions
In conclusion, we synthesized two new unnatural isoquinoline
isomers of the cryptolepine series: 6-methyl-6H-indolo[3,2-c]iso-
quinoline (5) and 6-methyl-6H-indolo[2,3-c]isoquinoline (6). To
the best of our knowledge these compounds have never been
synthesized before. 11H-Indolo[3,2-c]isoquinoline (7) was obtained
in 57% overall yield via a selective Buchwald–Hartwig – Pd-cata-
lyzed intramolecular direct arylation reaction starting from 4-bro-
moisoquinoline and 2-bromoaniline. Selective N-6 methylation of
11H-indolo[3,2-c]isoquinoline (7), gave indoloisoquinoline 5. The
synthesis of 6-methyl-6H-indolo[2,3-c]isoquinoline (6) was not so
straightforward. The selective Buchwald–Hartwig – Pd-catalyzed
intramolecular direct arylation reaction starting from two different

G. Van Baelen et al. / Tetrahedron 64 (2008) 11802–11809
11807
2-bromoaniline, 1,2-dibromobenzene, bromobenzene, NBS, MsCl,
THF (99.85%, water <50 ppm, extra dry over molecular sieve), DME,
DMA, 1,2-dichlorobenzene, MeI, Pd(OAc)2 and Pd2(dba)3 were
obtained from Acros and used as such. For the Buchwald–Hartwig
reaction freshly distilled dioxane (dried over sodium benzophe-
none) was used. Flash column chromatography was performed on
Kieselgel 60 (ROCC, 0.040–0.063 mm).
4.2.4. N-Phenylisoquinolin-3-amine (20)
Pd2(dba)3 (0.092 g, 0.10 mmol, 5 mol %), XANTPHOS (0.127 g,
0.22 mmol, 11 mol %), isoquinolin-3-amine (14) (0.288 g,
2.0 mmol), bromobenzene (18) (0.377 g, 2.4 mmol), Cs2CO3
(1.955 g, 6.0 mmol) and dry dioxane (12 mL) (freshly distilled).
Reaction time¼46 h. Eluent: CH2Cl2 (100%); yield 87%; greenish/
yellow powder; mp 102–103 ꢀC; dH (CDCl3): 8.93 (s, 1H, H-1), 7.82
(dd, 1H, J¼8.3, 0.9 Hz, H-8), 7.58–7.51 (m, J¼8.4, 8.3, 6.1, 1.6, 1.2 Hz,
2H, H-5 and H-6), 7.41–7.28 (m, J¼8.3, 6.1, 1.8 Hz, 5H, H-20, H-30 and
H-7), 7.20 (s, 1H, H-4), 7.09 (tt, J¼7.0, 1.5 Hz, 1H, H-40), 6.94 (br s, 1H,
NH); dC (CDCl3): 152.0, 151.9, 141.0, 138.7, 130.6, 129.4, 127.7, 125.2,
124.5, 123.6, 122.7, 120.1, 99.1; HRMS (ESI) for C15H13N2 [MþH]þ:
calcd 221.1079, found 221.1076.
4.2. General procedure for Buchwald–Hartwig reaction
4.2.1. N-(2-Bromophenyl)isoquinolin-4-amine (10)
A round-bottomed flask was charged with Pd2(dba)3 (0.137 g,
0.150 mmol, 5 mol %) and XANTPHOS [9,9-dimethyl-4,5-bis(di-
phenylphosphino)-9H-xanthene] (0.191 g, 0.330 mmol, 11 mol %)
followed by dry dioxane (12 mL) (freshly distilled). The mixture
was flushed with N2 for 10 min. Meanwhile, in another round-
bottomed flask 4-bromoisoquinoline (8) (0.624 g, 3.0 mmol), 2-
bromoaniline (9) (0.619 g, 3.6 mmol) and Cs2CO3 (2.932 g,
9.0 mmol) (Aldrich, 99%) were weighed. To this mixture, the Pd-
catalyst solution was added and the flask was subsequently flushed
with N2 for 5 min. The resulting mixture was heated at reflux (oil
bath temperature: 110 ꢀC) for 27 h under magnetic stirring. After
cooling down to room temperature dichloromethane (25 mL) was
added and the suspension was filtered over a pad of CeliteÒ and
rinsed with dichloromethane (125 mL). The solvent was removed
under reduced pressure and the residue was purified by flash col-
umn chromatography on silica gel using CH2Cl2/EtOAc (95:5) as the
eluent yielding 10 in 74%.
Red/brown crystals; mp 94–96 ꢀC; dH (CDCl3): 9.11 (s, 1H, H-1),
8.54 (s, 1H, H-3), 8.04 (dd, J¼7.9, 1.1 Hz, 1H, H-8), 7.96 (dd, J¼8.4,
0.9 Hz, 1H, H-5), 7.71 (ddd, J¼8.2, 6.9, 1.2 Hz, 1H, H-6), 7.65 (ddd,
J¼8.1, 6.9, 1.2 Hz, 1H, H-7), 7.57 (dd, J¼7.9, 1.5 Hz, 1H, H-30), 7.09
(ddd, J¼8.2, 7.3, 1.5 Hz, 1H, H-50), 6.80 (dd, J¼8.2, 1.5 Hz, 1H, H-60),
6.75 (ddd, J¼7.9, 7.3,1.5 Hz,1H, H-40), 6.28 (br s,1H, NH); dC (CDCl3):
149.1, 142.6, 137.5, 132.9, 132.2, 131.8, 130.5, 129.3, 128.3, 128.1, 127.7,
121.6, 121.0, 115.6, 111.5; HRMS (ESI) for C15H12N2Br [MþH]þ: calcd
299.0184, found 299.0184.
4.2.5. 4-Bromo-N-(2-bromophenyl)isoquinolin-3-amine (21)
Pd2(dba)3 (0.046 g, 0.05 mmol, 5 mol %), XANTPHOS (0.064 g,
0.11 mmol, 11 mol %), 4-bromoisoquinolin-3-amine (17) (0.2231 g,
1.0 mmol), 1,2-dibromobenzene (15) (0.283 g, 1.2 mmol), Cs2CO3
(0.978 g, 3.0 mmol) and dry dioxane (12 mL) (freshly distilled). Re-
action time¼48 h. Eluent: Heptane/CH2Cl2 (70:30); yield 39%;
greenish/yellow powder; mp 108–109 ꢀC; dH (CDCl3): 8.94 (s, 1H, H-
1), 8.42 (dd,1H, J¼8.3,1.5 Hz, H-30), 8.01 (ddd, J¼8.6,1.7, 0.8 Hz,1H, H-
5), 7.86 (br d, J¼8.1 Hz, 1H, H-8), 7.77 (br s, 1H, NH), 7.70 (ddd, J¼8.6,
6.8,1.3 Hz,1H, H-6), 7.59 (dd, J¼8.0,1.5 Hz,1H, H-60), 7.41 (ddd, J¼8.2,
6.8, 1.1 Hz, 1H, H-7), 7.34 (ddd, J¼8.3, 7.4, 1.5 Hz, 1H, H-40), 6.90 (ddd,
J¼8.0, 7.3,1.6 Hz,1H, H-50); dC (CDCl3): 149.8,148.1,138.5,136.9,132.5,
131.9,128.0,128.0,125.6,124.7,124.5,122.8,120.1,113.8,101.8; HRMS
(ESI) for C15H11N2Br2 [MþH]þ: calcd 376.9289, found 376.9278.
4.3. General procedure for the Pd-catalyzed intramolecular
direct arylation reaction
4.3.1. Conventional heating
4.3.1.1. 11H-Indolo[3,2-c]isoquinoline (7). A round-bottomed flask
was charged with Pd(PPh3)2Cl2 (0.084 g, 0.12 mmol, 20 mol %), N-
(2-bromophenyl)isoquinolin-4-amine (10) (0.180 g, 0.6 mmol) and
NaOAc$3H2O (0.200 g, 1.47 mmol) followed by DMA (10 mL). The
mixture was flushed with Ar for 5 min and then stirred at 130 ꢀC
under Ar atmosphere for 16 h. Subsequently, the mixture was
evaporated to dryness in vacuo. The crude product was purified via
flash column chromatography on silica gel (the residue was
brought on column mixed with silica) using CH2Cl2/EtOAc (97:3) as
the eluent yielding 7 in 78%.
Yellow/orange powder; mp >300 ꢀC; dH (DMSO-d6): 12.33 (br s,
1H, NH), 9.13 (s, 1H, H-5), 8.52 (dd, J¼8.2, 0.9 Hz, 1H, H-1), 8.28 (d,
J¼8.2 Hz, 1H, H-4), 8.25 (d, J¼7.8 Hz, 1H, H-7), 7.91 (ddd, J¼8.2, 6.9,
1.2 Hz, 1H, H-2), 7.71 (ddd, J¼8.2, 7.0, 1.1 Hz, 1H, H-3), 7.70 (dd,
J¼8.1, 0.9 Hz, 1H, H-10), 7.50 (ddd, J¼8.2, 7.1, 1.2 Hz, 1H, H-9), 7.32
(ddd, J¼7.8, 7.1, 0.9 Hz, 1H, H-8); dC (DMSO-d6): 144.5, 138.5, 133.5,
129.8, 128.5, 127.2, 126.4, 126.1, 125.4, 123.4, 122.6, 121.0, 119.7,
119.2, 111.8; HRMS (ESI) for C15H11N2 [MþH]þ: calcd 219.0922,
found 299.0922.
4.2.2. N-(2-Bromophenyl)isoquinolin-3-amine (16)
Pd2(dba)3 (0.023 g, 0.025 mmol, 2.5 mol %), XANTPHOS (0.032 g,
0.055 mmol, 5.5 mol %), 1,2-dibromobenzene (15) (0.283 g,
1.2 mmol), isoquinolin-3-amine (14) (0.144 g, 1.0 mmol), Cs2CO3
(0.978 g, 3.0 mmol) and dry dioxane (10 mL) (freshly distilled).
Reaction time¼24 h. Eluent: CH2Cl2 (100%); yield 62%; green solid;
mp 103–104 ꢀC; dH (CDCl3): 9.00 (s, 1H, H-1), 7.85 (dd, J¼8.2, 0.9 Hz,
1H, H-8), 7.81 (dd, J¼8.2, 1.5 Hz, 1H, H-30), 7.63–7.59 (m, J¼8.4, 8.0,
1.5 Hz, 2H, H-5 and H-60), 7.56 (ddd, J¼8.4, 6.6, 1.2 Hz, 1H, H-6), 7.35
(ddd, J¼8.2, 6.6, 1.3 Hz, 1H, H-7), 7.31 (ddd, J¼8.1, 7.3, 1.5 Hz, 1H, H-
40), 7.21 (s, 1H, H-4), 6.93 (br s, 1H, NH), 6.89 (ddd, J¼8.0, 7.3, 1.5 Hz,
1H, H-50); dC (CDCl3): 152.0, 150.8, 139.2, 138.4, 133.1, 130.7, 128.2,
127.7, 125.4, 125.1, 124.3, 122.9, 119.2, 114.4, 101.3; HRMS (ESI) for
C15H12N2Br [MþH]þ: calcd 299.0184, found 299.0184.
4.2.3. 4-Bromo-N-phenylisoquinolin-3-amine (19)
Pd2(dba)3 (0.023 g, 0.025 mmol, 2.5 mol %), XANTPHOS (0.032 g,
0.055 mmol, 5.5 mol %), 4-bromoisoquinolin-3-amine (17) (0.223 g,
1.0 mmol), bromobenzene (18) (0.188 g, 1.2 mmol), Cs2CO3 (0.978 g,
3.0 mmol) and dry dioxane (4 mL) (freshly distilled). Reaction
time¼20 h. Eluent: CH2Cl2 (100%); yield 61%; shiny yellow powder;
mp 127 ꢀC; dH (CDCl3): 8.91 (d, J¼0.6 Hz, 1H, H-1),23 7.97 (ddd,
J¼8.7, 1.7, 0.9 Hz, 1H, H-5), 7.84 (d, J¼8.2 Hz, 1H, H-8), 7.67 (ddd,
J¼8.6, 6.8, 1.3 Hz, 1H, H-6), 7.56 (dd, J¼8.6, 1.1 Hz, 2H, H-20), 7.39–
7.33 (m, J¼8.6, 7.5, 1.0 Hz, 3H, H-30 and H-7), 7.14 (br s, 1H, NH), 7.07
(tt, J¼7.3, 1.2 Hz, 1H, H-40); dC (CDCl3): 150.0, 148.7, 140.5, 136.9,
131.8, 129.0, 128.1, 125.4, 124.4, 124.0, 122.7, 120.2, 100.3; HRMS
(ESI) for C15H12N2Br [MþH]þ: calcd 299.0184, found 299.0184.
4.3.2. Microwave irradiation
4.3.2.1. 11H-Indolo[3,2-c]isoquinoline (7). A microwave vial of
10 mL was charged with N-(2-bromophenylisoquinolin-4-amine)
(10) (0.180 g, 0.6 mmol) and NaOAc$3H2O (0.200 g, 1.47 mmol).
Subsequently, the vial was flushed with Ar for 1 min. Then, 1 mL of
a stock solutiony of catalyst (1 mol %) in DMA was added via
y
Preparation of the stock solution of catalyst: PdCl2(PPh3)2 (0.211 g, 0.03 mmol)
was dissolved in 5 mL of DMA. Next, the mixture was flushed with Ar for 5 min and
subsequently stirred until the catalyst was completely dissolved.

11808
G. Van Baelen et al. / Tetrahedron 64 (2008) 11802–11809
a syringe and the resulting mixture was stirred and flushed with Ar
for an additional 2 min. Next, the vial was sealed with an Al crimp
cap with a septum and heated at 200 ꢀC in a CEM Discover mi-
crowave apparatus. The set power was 100 W and the total heating
time was 10 min. After the reaction vial was cooled down to room
temperature using a propelled air flow, it was opened and the
content was poured into a round-bottomed flask. The vial was
rinsed with methanol (50 mL) and the combined organic phase was
evaporated to dryness. Finally, the crude product was purified via
flash column chromatography on silica gel (the residue was
brought on column mixed with silica) using CH2Cl2/EtOAc (97:3) as
the eluent yielding the pure compound in 79%. The characterization
data of it were identical to those described in Section 4.3.1.
solutionwas subsequentlystirred for10 min underaN2 atmosphere.
Next, {2-[(2,2-dimethylpropanoyl)amino]phenyl}boronic acid (24)
(1.105 g, 5.0 mmol) and aq Na2CO3 (10%, 4 mL) were added. The
mixture was magnetically stirred and heated at reflux in an oil bath
(oil bath temperature: 110 ꢀC) under an inert atmosphere (N2) for
2 h. After cooling the reaction mixture to room temperature, water
(60 mL) was added and the reaction mixture was extracted with
CH2Cl2 (3ꢃ60 mL). The combined organic phase was dried over
MgSO4, filtered and subsequently evaporated to dryness. Finally, the
residue was purified via flash column chromatography on silica gel
using CH2Cl2/EtOAc (90:10) as the eluent yielding 25 in 98%.
Off white to pale yellow powder; mp 148 ꢀC; dH (CDCl3): 9.40 (s,
1H, H-1), 8.51 (s, 1H, H-3), 8.27 (d, J¼8.3 Hz, 1H, H-60), 8.16 (dd,
J¼7.0, 2.0 Hz, 1H, H-8), 7.79–7.71 (m, 2H, H-6 and H-7), 7.62 (dd,
J¼7.0, 1.8 Hz, 1H, H-5), 7.54 (ddd, J¼8.1, 7.2, 2.0 Hz, 1H, H-50), 7.34
(dd, J¼7.6, 1.7 Hz, 1H, H-30), 7.30 (td, J¼7.4, 1.1 Hz, 1H, H-40), 6.97 (br
s, 1H, NH), 0.77 (s, 9H, CH3); dC (CDCl3): 176.2, 152.9, 143.5, 136.4,
134.3, 131.5, 130.7, 129.5, 129.2, 128.2, 128.1, 128.0, 126.9, 124.7,
124.4, 121.8, 39.4, 27.0; HRMS (ESI) for C20H21N2O1 [MþH]þ: calcd
305.1654, found 305.1655.
4.4. 4-Bromoisoquinolin-3-amine (17)
To a round-bottomed flask filled with isoquinolin-3-amine (14)
(0.144 g, 1.0 mmol) a solution of NBS (0.208 g, 1.17 mmol) in MeOH
(5 mL) was added dropwise. After the addition was complete, the
mixture was stirred at room temperature for 1 h. The solvent was
evaporated under reduced pressure and the crude reaction product
was dissolved in EtOAc (20 mL) and poured into a separating fun-
nel. An equal amount of water was added. The water layer was
extracted three more times (3ꢃ20 mL EtOAc) before the combined
organic layers were dried over MgSO4. The solvent was removed
under reduced pressure and the reaction product was purified by
recrystallization from water yielding 17 in 65%.
Paleyellowpowder;mp120–122 ꢀC;dH (CDCl3):8.78 (d, J¼0.6 Hz,
1H, H-1),23 7.91 (ddd, J¼8.6,1.7, 0.9 Hz,1H, H-5), 7.81 (d, J¼8.2 Hz,1H,
H-8), 7.67 (ddd, J¼8.6, 6.8, 1.3 Hz, 1H, H-6), 7.33 (ddd, J¼8.2, 6.8,
1.7 Hz, 1H, H-7), 5.18 (br s, 2H, NH2); dC (CDCl3): 151.7, 150.3, 137.1,
132.0, 128.1, 124.7, 123.8, 123.6, 97.7; HRMS (ESI) for C9H8N2Br
[MþH]þ: calcd 222.9871, found 222.9876.
4.7. 2-(Isoquinolin-4-yl)aniline (26)
2,2-Dimethyl-N-(2-isoquinolin-4-ylphenyl)propanamide (25)
(0.609 g, 2.0 mmol) was dissolved in ethanol (150 mL). Next, aq
H2SO4 (40%,150 mL) was added dropwise. The obtained mixturewas
stirred and refluxed in an oil bath (oil bath temperature: 130 ꢀC) for
24 h. Subsequently, the pH of the reaction mixture was adjusted to
8–9 with 28–30% NH4OH under cooling in an ice bath. Next, the
aqueous phase was extracted with CHCl3 (3ꢃ100 mL). The organic
phase was dried over MgSO4, filtered and evaporated to dryness.
Finally, theresiduewaspurifiedviaflashcolumnchromatographyon
silica gel using CH2Cl2/EtOAc(70:30) as the eluent yielding 26 in 97%.
Yellow/orange viscous oil: dH (CDCl3): 9.31 (s, 1H, H-1), 8.50 (s,
1H, H-3), 8.08 (dt, J¼7.9, 1.2 Hz, 1H, H-8), 7.72–7.64 (m, 3H, H-5 and
H-6 and H-7), 7.30 (ddd, J¼8.1, 7.4, 1.6 Hz, 1H, H-50), 7.15 (ddd, J¼7.6,
1.7, 0.3 Hz, 1H, H-30), 6.90 (td, J¼7.5, 1.1 Hz, 1H, H-40), 6.86 (ddd,
J¼8.0, 1.2, 0.3 Hz, 1H, H-60), 3.13 (br s, 2H, NH2); dC (CDCl3): 151.4,
144.6, 142.1, 135.0, 131.5, 131.4, 131.3, 129.7, 128.4, 128.3, 128.0,
125.4, 121.4, 118.6, 115.7; HRMS (ESI) for C15H13N2 [MþH]þ: calcd
221.1079, found 221.1076.
4.5. N-(4-Bromoisoquinolin-3-yl)-N-(2-bromo-
phenyl)methanesulfonamide (22)
A solution of 4-bromo-N-(2-bromophenyl)isoquinolin-3-amine
(21) (0.378 g, 1.0 mmol) in THF (5 mL) was added dropwise to
a suspension of NaH (assay 55–65%) (0.166 g) in THF (5 mL). The
mixture was stirred for 1 h at room temperature. Mesyl chloride
(0.16 mL, 2.0 mmol) was added in one aliquot to the mixture and
stirring at room temperature was continued for two more hours.
Then the solvent was evaporated under reduced pressure and the
crude reaction product was dissolved in EtOAc (100 mL) and
poured into a separating funnel. After this, 100 mL of water was
added. The organic layer was then washed with brine and dried
over MgSO4. The solvent was removed under reduced pressure and
the reaction product was purified by flash column chromatography
on silica gel using CH2Cl2/heptane (60:40) as the eluent yielding 22
in 15%.
Yellow powder; mp 197–198 ꢀC, decomp.; dH (CDCl3): 9.11 (d,
1H, J¼0.7 Hz, H-1),23 8.22 (ddd, 1H, J¼8.6, 1.7, 0.8 Hz, H-5), 8.12 (dd,
J¼8.2, 1.6 Hz, 1H, H-30), 7.98 (br d, J¼8.1 Hz, 1H, H-8), 7.78 (ddd,
J¼8.6, 6.9,1.3 Hz,1H, H-6), 7.66 (ddd, J¼8.1, 6.9, 1.1 Hz,1H, H-7), 7.57
(dd, J¼8.0, 1.5 Hz, 1H, H-60), 7.42 (ddd, J¼8.2, 7.4, 1.6 Hz, 1H, H-40),
7.21 (ddd, J¼8.0, 7.4, 1.7 Hz, 1H, H-50), 3.59 (s, 3H, CH3); dC (CDCl3):
149.5,147.1, 137.8, 137.5, 136.6, 134.3, 131.9, 129.9, 128.5, 128.3, 127.6,
127.4, 127.0, 123.0, 116.1, 42.6; HRMS (ESI) for C16H13N2O2Br2S
[MþH]þ: calcd 454.9064, found 454.9061.
4.8. 7H-Indolo[2,3-c]isoquinoline (12)
2-(Isoquinolin-4-yl)aniline (26) (0.419 g, 1.9 mmol) was dis-
solved in aq HCl (37%, 20 mL) and the mixture cooled to 0 ꢀC using an
ice bath. Subsequently, ice cooled aq NaNO2 (0.4 M, 11 mL) was
added dropwise keeping the temperature below 3 ꢀC. The mixture
was stirred for 1.5 h at 0 ꢀC. Ice cooled aq NaN3/NaOAc solution
(4.0 mmol NaN3 and 26.6 mmol NaOAc$3H2O in 10 mL water) was
added dropwise keeping the temperature below 3 ꢀC. Next, the
mixture was stirred for another hour at 0 ꢀC. The reaction mixture
was neutralized with saturated aq Na2CO3 while keeping the tem-
perature below 3 ꢀC and subsequently extracted with EtOAc
(5ꢃ100 mL). The combined organic phases were dried over MgSO4,
filtered and the solvent removed under reduced pressure. The res-
idue was dissolved in 35 mL of 1,2-dichlorobenzene and flushed
with Ar. The mixture was stirred and heated in an oil bath at 180 ꢀC
for 3 h under Ar atmosphere. After cooling down to room temper-
ature, the solvent was removed under reduced pressure. Finally, the
obtained residue was purified via flash column chromatography on
silica gel using CH2Cl2/EtOAc (90:10) as the eluent yielding 12 in 77%.
Pale yellow needles; mp 259–260 ꢀC; dH (DMSO-d6): 12.21 (br
s, 1H, NH), 9.20 (s, 1H, H-5), 8.73 (br dd, 1H, J¼8.4, 0.8 Hz, H-1),
8.56 (d, J¼8.0 Hz, 1H, H-11), 8.27 (br d, J¼8.1 Hz, 1H, H-4), 7.93
(ddd, J¼8.4, 6.9, 1.3 Hz, 1H, H-2), 7.66 (dt, J¼8.1, 0.8 Hz, 1H, H-8),
4.6. N-(2-Isoquinolin-4-ylphenyl)-2,2-dimethyl-
propanamide (25)
4-Bromoisoquinoline (8) (0.832 g, 4.0 mmol) was dissolved in
DME (24 mL). Pd(PPh3)4 (0.231 g, 0.2 mmol) was added and the

G. Van Baelen et al. / Tetrahedron 64 (2008) 11802–11809
11809
7.59 (ddd, J¼8.2, 6.9, 1.0 Hz, 1H, H-3), 7.48 (ddd, J¼8.1, 7.2, 1.1 Hz,
cytotoxicity. Results are expressed as IC50 in
viation (SD) (n¼3).
mMꢂstandard de-
1H, H-9), 7.36 (ddd, J¼7.9, 7.2, 1.1 Hz, 1H, H-10); dC (DMSO-d6):
151.0, 148.3, 137.7, 132.4, 131.7, 129.9, 125.3, 124.6, 124.0, 122.8,
122.6, 121.6, 120.5, 112.3, 105.6; HRMS (ESI) for C15H11N2
[MþH]þ: calcd 219.0922, found 219.0923.
Acknowledgements
Gitte Van Baelen would like to thank the IWT-Flanders (The
Institute for the promotion of Innovation by Science and Technol-
ogy in Flanders) for a Ph.D. scholarship. The authors acknowledge
financial support from the University of Antwerp (GOA BOF UA, NOI
BOF UA) and the Flemish Government (Impulsfinanciering van de
Vlaamse Overheid voor Strategisch Basisonderzoek PFEU 2003) for
financial support. The authors would like to thank R. Brun of the
Swiss Tropical Institute for biological evaluation of the compounds.
C.M. thanks the FWO-Flanders for a Ph.D. scholarship.
4.9. General procedure for the selective methylation of
indoloisoquinolines 7 and 12
4.9.1. 6-Methyl-6H-indolo[3,2-c]isoquinoline (5)
In a round-bottomed flask 11H-indolo[3,2-c]isochinoline (7)
(0.109 g, 0.5 mmol), dry THF (7.5 mL) and CH3I (3 mL) were
heated at reflux under N2 atmosphere (oil bath temperature:
80 ꢀC) for 22 h with magnetic stirring. Then the solvent was
evaporated to dryness under reduced pressure and the crude
product was mixed with silica gel and purified via flash col-
umn chromatography on silica gel using CH2Cl2/MeOH (90:10)
as the eluent yielding 6-methyl-6H-indolo[3,2-c]isoquinoline
hydroiodide (5$HI) as a yellow powder. To obtain the free
base, 5$HI was brought in a mixture of CH2Cl2 (100 mL) and
28–30% ammonia in water (100 mL). The organic phase was
separated and the aqueous phase was subsequently extracted
with CH2Cl2 (6ꢃ50 mL). The combined organic phase was
dried over MgSO4, filtered and evaporated to dryness to yield
5 in 76%.
Bright red/orange powder; mp 208–210 ꢀC, decomp.; dH (DMSO-
d6): 9.05 (s, 1H, H-5), 8.82 (dd, J¼8.4, 1.1 Hz, 1H, H-1), 8.32–8.26 (m,
2H, H-4 and H-7), 7.97 (ddd, J¼8.4, 6.9, 1.2 Hz, 1H, H-2), 7.82 (dt,
J¼8.2, 0.9 Hz, 1H, H-10), 7.75 (ddd, J¼8.2, 6.8, 1.2 Hz, 1H, H-3), 7.41
(ddd, J¼8.4, 6.7, 1.2 Hz, 1H, H-9), 7.16 (ddd, J¼8.1, 6.9, 1.1 Hz, 1H, H-
8), 4.86 (d, J¼0.5 Hz, 3H, CH3); dC (DMSO-d6): 151.4, 142.3, 131.9,
131.5, 128.8, 128.6, 126.3, 124.4, 124.3, 123.5, 122.2, 120.5, 118.5,
117.2, 117.1, 45.7; HRMS (ESI) for C16H13N2 [MþH]þ: calcd 233.1079,
found 233.1076.
References and notes
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´
´
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7H-Indolo[2,3-c]isoquinoline (12) (0.109 g, 0.5 mmol), dry THF
(7.5 mL) and CH3I (3 mL). Reaction time¼6 h. Eluent: CH2Cl2/
MeOH (90:10); yield 99%; bright red powder; mp 91–92 ꢀC; dH
(DMSO-d6): 9.35 (s, 1H, H-5), 8.68 (d, J¼8.6 Hz, 1H, H-1), 8.54 (d,
J¼8.0 Hz, 1H, H-11), 8.19 (d, J¼8.3 Hz, 1H, H-4), 7.91 (ddd, J¼8.6,
6.7, 1.3 Hz, 1H, H-2), 7.79 (dt, J¼8.2, 0.9 Hz, 1H, H-8), 7.44 (ddd,
J¼8.2, 6.9, 1.1 Hz, 2H, H-3 and H-9), 7.24 (ddd, J¼7.9, 7.0, 1.0 Hz,
1H, H-10), 4.55 (s, 3H, CH3); dC (DMSO-d6): 151.2, 149.3, 140.2,
134.1, 134.0, 130.7, 125.0, 123.6, 122.8, 122.3, 122.2, 118.9, 118.6,
118.3, 113.4, 41.7; HRMS (ESI) for C16H13N2 [MþH]þ: calcd
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4.10. Antiprotozoal evaluation and cytotoxicity
Antiplasmodial activity was determined against the K1 strain of
P. falciparum (resistant to chloroquine and pyrimethamine), using
a modified [3H]-hypoxanthine incorporation assay as described
before.24 Chloroquine was used as positive control. Activity against
Trypanosoma brucei rhodesiense, Trypanosoma cruzi and Leishmania
donovani and cytotoxicity against rat skeletal myoblasts (L6 cells)
were evaluated as described before.24 Melarsoprol was used as
positive control against T.b. rhodesiense, benznidazole against
T. cruzi, miltefosine against L. donovani and podophyllotoxin for
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23. This doublet is due to the homoallylic 5J coupling (H-1 with H-5) Gu¨ nther, H.
NMR Spectroscopy: Basic Principles, Concepts and Applications in Chemistry, 2nd
ed.; John Wiley & Sons: New York, NY, 1995; p 126.
24. Mbwambo, Z. H.; Apers, S.; Moshi, M. J.; Kapingu, M. C.; Van Miert, S.;
Claeys, M.; Brun, R.; Cos, P.; Pieters, L.; Vlietinck, A. Planta Med. 2004, 70,
706–710.