Synthesis of 7H-indolo[2,3-c]quinolines: study of the Pd-catalyzed intramolecular arylation of 3-(2-bromophenylamino)quinolines under microwave irradiation

Article abstract of DOI:10.1016/j.tet.2005.12.062

D-ring substituted 5-methyl-5H-indolo[2,3-c]quinolines (4) have been synthesized in three steps starting from commercially available 3-bromoquinoline (5) and 2-bromoanilines (6). The methodology consists of two consecutive palladium-catalyzed reactions: a

Full text of DOI:10.1016/j.tet.2005.12.062

Tetrahedron 62 (2006) 4676–4684
Synthesis of 7H-indolo[2,3-c]quinolines: study of the Pd-catalyzed
intramolecular arylation of 3-(2-bromophenylamino)quinolines
under microwave irradiation
*
Steven Hostyn, Bert U. W. Maes, Gitte Van Baelen, Anna Gulevskaya,
Caroline Meyers and Koen Smits
Organic Synthesis, Department of Chemistry, University of Antwerp, Groenenborgerlaan 171, B-2020 Antwerp, Belgium
Received 1 November 2005; revised 23 December 2005; accepted 23 December 2005
Available online 31 March 2006
Abstract—D-ring substituted 5-methyl-5H-indolo[2,3-c]quinolines (4) have been synthesized in three steps starting from commercially
available 3-bromoquinoline (5) and 2-bromoanilines (6). The methodology consists of two consecutive palladium-catalyzed reactions: a
selective Buchwald–Hartwig amination followed by a regioselective intramolecular Heck-type reaction. The latter step has been investiga-
ꢀ
ted under microwave irradiation. Heating at 180 C allows to seriously reduce the catalyst loading and get a full conversion to reaction product
in 10 min. In addition, the former simplifies the purification.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
dial activity. Interestingly, the ‘missing’ benzo-b-carboline
isomer (5-methyl-5H-indolo[2,3-c]quinoline, for which we
have adopted the name isoneocryptolepine (4a) (Fig. 1) has
hitherto never been found in nature. Recently, we developed
an efficient synthetic route for 5-methyl-5H-indolo[2,3-
c]quinoline (4a) and its 7H-indolo[2,3-c]quinoline skeleton.3
The methodology is based on the combination of a selective
Buchwald–Hartwig amination with a regioselective Pd-
catalyzed intramolecular arylation reaction starting from
commercially available 3-bromoquinoline (5) and 2-bro-
moaniline (6a) (Scheme 1).3,4 Although 4a is about two times
less active (K1 strain of P. falciparum, resistant to chloro-
quine and pyrimethamine) than 1, the most active compound
of the quartet isomeric indoloquinolines, it is four times
less cytotoxic (L6 cells).5 Therefore, 4a has a much better
selectivity index (cytotoxicity/antiplasmodial activity ratio)
than 1, which makes it a better lead compound for further val-
idation of the indoloquinolines as a potential antiplasmodial
drugs (Table 1). The mechanism of action of 4a is similar to
that of chloroquine inhibition of the haeme detoxification
process.6 The choice to study first the D-ring substitution
of 4a is based on the fact that the quinoline part in chloro-
quine and analogues is very important in the haeme complex-
ation and only limited substitutions are tolerated. The
commercial availability of several substituted 2-bromo-
anilines makes the ‘selective Buchwald–Hartwig amina-
tion—regioselective Pd-catalyzed intramolecular arylation
reaction’ approach a preferred tool to easily get access to
these D-ring functionalized 7H-indolo[2,3-c]quinolines and
isoneocryptolepines.
Every year between 300 and 500 million people worldwide
are infected by the malaria parasite (Plasmodium). One to
two million of them die as a direct consequence of this dis-
ease.1 Besides the available synthetic drugs nature also has
shown to be an interesting source for antiplasmodial com-
pounds. For instance, in traditional medicine in West and
Central Africa a decoction of the root of the plant Cryptole-
pis sanguinolenta is used to treat fevers caused by malaria.
Cryptolepine(5-methyl-5H-indolo[3,2-b]quinoline)(1), neo-
cryptolepine (cryptotackieine, 5-methyl-5H-indolo[2,3-b]
quinoline) (2) and isocryptolepine (cryptosanguinolentine,
5-methyl-5H-indolo[3,2-c]quinoline) (3) are three of the
thirteen characterized alkaloids of the root (Fig. 1).2 These
isomeric indoloquinolines show an interesting antiplasmo-
D
N
D
C
C
N
D
N
C
A
A
B
A
B
C
A
B
B
N
D
N
N
N
N
CH3
CH3
CH3
CH3
4a
1
2
3
Figure 1. Cryptolepine (1), neocryptolepine (2), isocryptolepine (3) and
isoneocryptolepine (4a).
Keywords: Palladium; Amination; Heck-type reaction; Microwave; Malaria.
* Corresponding author. Tel.: +32 3 265 32 05; fax: +32 3 265 32 33; e-mail:
bert.maes@ua.ac.be
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.12.062

S. Hostyn et al. / Tetrahedron 62 (2006) 4676–4684
4677
Br
Br
NH
Br
Pd2(dba)3/XANTPHOS
NH2
6a
N
N
Cs2CO3
dioxane
reflux
5
7a
83%
NH
N
8a
N
N
H
I
NH3 in water
(28-30%)
MeI
H
PdCl2(PPh3)2
NaOAc.3H2O
DMA
130°C
45% (8a)
4% (9a)
N
N
toluene
N
reflux
88%
CH3
CH3
N
9a
4a
4a.HI
Scheme 1. Synthesis of isoneocryptolepine (4) based on a ‘selective Buchwald–Hartwig amination—regioselective Pd-catalyzed intramolecular arylation
reaction’ approach.
Table 1. Antiplasmodial activity (IC50, mM), cytotoxicity (IC50, mM) and
selectivity index of compounds 1–4
Table 2. Selective Buchwald–Hartwig amination of 3-bromoquinoline (5)
with 2-bromoanilines (6)
NH2
Br
Compound
Plasmodium falciparum
K1 IC50 (mM)
Cytotoxicity Selectivity
index
H
Br
Br
N
(L6 cells)
IC50 (mM)
R
+
Pd2(dba)3
XANTPHOS
base
dioxane
reflux
N
5
N
7a-d
R
1
2
3
4a
0.12ꢁ0.02
2.61ꢁ0.67
0.78ꢁ0.30
0.23ꢁ0.04
1.12ꢁ0.07
3.24ꢁ0.04
1.19ꢁ0.26
4.32ꢁ0.04
9.3
1.2
1.5
18.8
6a-d
a: R = H
b: R = 4-Me
c: R = 4-Cl
d: R = 5-CF3
Entry
6
Pd2(dba)3
loading
(mol %)
XANTPHOS Base
loading
(mol %)
Time Yielda
2. Discussion
(h)
(%)
First, we focussed on the amination of 3-bromoquinoline (5)
with 2-bromoanilines (6) and decided to restudy the selec-
tive coupling of 5 with 2-bromoaniline (6a) (Scheme 1), un-
der the same reaction conditions as previously reported by
us [standard conditions: 2.5 mol % Pd2(dba)3/5.5 mol %
XANTPHOS(9,9-dimethyl-4,5-bis(diphenylphosphino)-9H-
xanthene) catalyst, 1.2 equiv 6a, 3 equiv Cs2CO3, 12 mL di-
oxane and reflux], in order to determine whether there is
a ‘base effect’ for this C–N bond forming reaction.7 There-
fore, we carefully followed the reaction of 5 with 6a by
TLC and MS and found that the reaction is already completed
after 16 h.8 An isolated yield of 3-(2-bromophenylamino)-
quinoline (7a) of 85% was obtained (Table 2, entry 1), which
is essentially the same as we reported previously for a 30 h
reflux (Scheme 1). When the same experiment was per-
formed using only 2 equiv of caesium carbonate (instead of
3 equiv as used in the standard experiment) an incomplete
conversion of starting material was observed in 16 h. Work
up of the mixture yielded only 62% of 7a and a recovery
of 26% of substrate 5 (Table 2, entry 2). These data clearly
indicate a rate-limiting deprotonation of the Pd(II)-amine
complex intermediate formed in the catalytic cycle.7 Gratify-
ingly, selectiveamination of 5 with 2-bromo-4-methylaniline
(6b) using the optimized reaction conditions gave 85% of
3-(2-bromo-4-methylphenylamino)quinoline (7b) (Table 2,
entry 3). Unfortunately, amination of 5 with 4-chloro-2-
bromoaniline (6c) and 2-bromo-5-trifluoromethylaniline
(6d) gave incomplete conversions and an isolated yield of
3-arylaminoquinoline of 63% (7c) and 59% (7d) respectively
1
2
3
4
5
6
7
8
6a 2.5
6a 2.5
6b 2.5
6c 2.5
6d 2.5
6c 2.5
6c 2.5
6c 2.5
6c 2.5
6c 2.5
6c 5.0
5.5
5.5
5.5
5.5
5.5
5.5
10.0
5.5
Cs2CO3 16
Cs2CO3 16
Cs2CO3 16
Cs2CO3 16
Cs2CO3 16
Cs2CO3 24
Cs2CO3 24
Cs2CO3 24
85
62b
85
63
59
55c
62
61d
51e
37b
83
9
10
11
5.5
5.5
11.0
K3PO4
24
Cs2CO3 24
Cs2CO3 24
a
Pd2(dba)3 (5 mol %), 5.5 mol % XANTPHOS, 3 mmol 5, 3.6 mmol 6,
9 mmol Cs2CO3, 12 mL dioxane, reflux.
Cs2CO3 (6 mmol) was used.
5.4 mmol 6c was used.
6 mL dioxane was used.
9 mmol K3PO4 was used.
b
c
d
e
(Table 2, entries 4 and 5). We decided to study the coupling of
5 with 6c in more detail. Altering the excess of 6c from 1.2 to
1.8 equiv (Table 2, entry 6), changing the palladium/ligand
ratio from 1/1.1 to 1/2 (Table 2, entry 7) as well as doubling
the concentration of the reaction (Table 2, entry 8) all gave
similar isolated yield of 7c and an incomplete conversion
of starting material in a fixed reaction time of 24 h. Also
the use of K3PO4 as base did not provideuswith abetter result
(Table 2, entry 9). Interestingly, a test experiment with
2 equiv of Cs2CO3 gave only 37% 7c and a recovery of 37%
5 (Table 2, entry 10), which also supports that the deprotona-
tion of the Pd(II)-amine complex intermediate occurs in the

4678
S. Hostyn et al. / Tetrahedron 62 (2006) 4676–4684
Table 3. Pd-catalyzed intramolecular arylation of 7a under conventional
heating
rate-limiting step for the studied type of amination reactions.
Interestingly, when we doubled the catalyst loading for the
coupling of 5 and 6c within 24 h under otherwise standard
conditions an almost complete conversion was observed
with an isolated yield of 83% 7c (Table 2, entry 11). The
selective coupling reactions of 5 with 6a–d (via chemoselec-
tive oxidative addition) can be explained by taking into
account that the C–Br bond of 5 is more reactive than the
C–Br bond of 6a–d due to the amino substituent of the latter,
which sterically and electronically deactivates the C2–Br
bond for oxidative addition. Interestingly, the introduction
of a chlorine atom or a trifluoromethyl group (electron with-
drawing) on 2-bromoaniline does not seem to influence
the selectivity (chemoselective oxidative addition) of the
Buchwald–Hartwig amination reaction. Particularly, the suc-
cessful useof 6c is interestingsince the C4–Cl of6c is a poten-
tial third position for oxidative addition in the reaction of 5
with 6c.
Br
H
H
NH
N
N
+
PdCl2(PPh3)2
NaOAc.3H2O
DMA, heat
N
7a
N
8a
N
9a
Time (min)
Conversion (%)a
8ab,c (%)
Ad
1
2
3
4
5
6
10
20
30
60
120
360
48
61
66
71
74
75
85
84
81
80
81
79
Bd
1
2
3
4
5
6
10
20
30
60
120
360
26
32
34
36
37
39
87
87
85
87
86
86
Secondly, we turned our attention to the cyclodehydrobromi-
nation of 7a–d via a regioselective intramolecular Heck-type
reaction that involves C–H bond activation of an aryl group.9
The already previously reported cyclization of 7a required
a very high loading of catalyst (23 mol %) and a long reac-
tion time (48 h) to achieve a reasonable result (Scheme 1).3
Therefore, we decided to study the Pd-catalyzed cyclodehy-
drobromination of 7a in more detail with an HPLC–UV sys-
tem under the same reaction conditions [standard conditions:
23 mol % PdCl2(PPh3)2 catalyst, 2.45 equiv NaOAc$3H2O,
Cd
1
2
3
4
5
6
10
20
30
60
120
360
71
82
86
90
92
94
85
84
85
84
84
83
a
Conversion based on HPLC–UV: (8a+9a)/(7a+8a+9a)ꢂ100.
ꢀ
b
10 mL dimethylacetamide and 130 C (oil bath tempera-
X mol % PdCl2(PPh3)2, 0.6 mmol 7a, 1.47 mmol NaOAc$3H2O, 10 mL
DMA.
ture)]. Surprisingly, we found that most of the conversion
of starting material occurs in the first hour and subsequently
an extremely slow further transformation to reaction product
8a follows (Table 3, A).10 Also with 5 mol % loading of
PdCl2(PPh3)2 a similar behaviour could be observed (Table
3, B). For both experiments complete conversion of substrate
7a can not be achieved and the reaction mixture obtained
a dark colour within the first hour of reaction. Importantly,
c
Percentage of 8a based on HPLC–UV: 8a/(8a+9a)ꢂ100.
A: 23 mol % PdCl2(PPh3)2 catalyst at 130 ꢀC, B: 5 mol % PdCl2(PPh3)2
catalyst at 130 ꢀC and C: 23 mol % PdCl2(PPh3)2 catalyst at 160 ꢀC.
d
a large amount of triphenylphoshine and triphenylphosphine
oxide, which makes the work up very difficult involving a lot
of purification steps with reaction product loss as an obvious
consequence. An attempt to further reduce the catalyst load-
ing to 0.1 mol % was unsuccessful since starting material 7a
remained and only 30% of 8a could be obtained in a reaction
ꢀ
increasing the oil bath temperature to 160 C for the former
experiment gave an almost complete reaction within 1 h
(Table 3, C). This observation inspired us to study the cyclo-
dehydrobromination of 7a under microwave irradiation in
a single-mode microwave unit (Discover, CEM).11 We
decided to perform the reactions on a same scale as the oil
bath experiments but increased the concentration of the
microwave reactions by a factor of ten (use of 1 mL instead
of 10 mL DMA) since the standard disposable microwave
ꢀ
time of 10 min at 180 C. We decided to study the Pd-
catalyzed cyclodehydrobromination of 7b–d with a higher
catalyst loading (1 mol %) than 0.2 mol % in order to have
Table 4. Pd-catalyzed intramolecular arylation of 7a–d under microwave
irradiation10
R
ꢀ
vials (with crimp cap) have a volume of 10 mL. At 180 C
using a loading of 23 mol % a complete conversion of 7a
was observed within 10 min of irradiation. Astonishingly,
a systematic reduction of the catalyst loading revealed that
0.2 mol % still gave a complete transformation of 7a in
10 min heating under microwave irradiation. This is a reduc-
tion in reaction time by a factor of 288 and a 115-fold
decrease of the catalyst loading. Working up the reaction
mixture gave an isolated yield of 7H-indolo[2,3-c]quinoline
(8a) of 66% (Table 4, entry 1). This is 21% higher than
the previously reported yield under standard conditions
(Scheme 1) and most probably a combination of two main
Br
H
NH
N
R
PdCl2(PPh3)2
NaOAc.3H2O
DMA, 180°C (µW)
10 min
N
N
a: R = H
8a-d
7a-d
b: R = 4-Me
c: R = 4-Cl
d: R = 5-CF3
Entry
7
PdCl2(PPh3)2
loading (mol %)
Yielda (%)
1
2
3
4
7a
0.2
1
66
58
69
76
7b
7c
7d
factors.12 First of all, in an oil bath at 130 C using
ꢀ
1
1
23 mol % of catalyst the reaction can never be brought to
complete conversion (even after 48 h of heating) (Table 3,
A) and secondly the very high loading of catalyst generates
a
X mol % PdCl2(PPh3)2, 0.6 mmol 7a–d, 1.47 mmol NaOAc$3H2O, 1 mL
DMA and 180 ꢀC (microwave).

S. Hostyn et al. / Tetrahedron 62 (2006) 4676–4684
4679
a general applicable protocol for the synthesis of the in-
doloquinoline skeleton of the substituted 5-methyl-5H-
indolo[2,3-c]quinolines. Upon the use of a 1 mol % catalyst
loading, 7b–d could be smoothly transformed to 8b–d in
only 10 min (Table 4, entries 2, 3 and 4). Complete conver-
sion of the substrates (7b–d) as well as the good isolated
yields of 8b–d support the generality of the developed
protocol. Interestingly, to the best of our knowledge
microwave-assisted Pd-catalyzed intramolecular arylation
reactions using dedicated microwave equipment are unprec-
edented in the literature.13 The studied intramolecular Heck-
type reactions on 7a–d are regioselective since only a small
fraction of quindolines 9a–d could be isolated during col-
umn chromatography.14 When one accepts the mechanism
of the Pd-catalyzed cyclodehydrohalogenation of 7a–d to
occur via the intramolecular electrophilic attack of the oxi-
dative addition complex on a p system,9,15 the preferential
C4–H activation of 7a–d can be explained by taking into ac-
count that in this case three resonance contributors, which do
not break the aromatic character of the benzene ring in the
carbocationic intermediate, can be drawn versus only one
in the case of C2–H activation. In addition, the electron den-
sity is larger on C-4 than on C-2.
reactions, we searched for a method which allows to mimic
the heating profile of an oil bath experiment with that of a
microwave reaction. This setup choice is inspired by the
fact that it should be easier to control microwave heating by
altering the power output of the machine (programming of
stages with a different set power) than controlling the heat-
ing gradient of an oil bath. Comparisons between oil bath
and microwave experiments can be best executed with the
same vessel and therefore, we constructed a homemade
‘attenuator’ which allows sealing of the 10 mL microwave
vessel, with internal fiber optic temperature measurement,
without placing it in the microwave cavity (Figs. 2 and 3).
Our system can be easily used to perform on-line pressure
and temperature monitoring of the oil bath experiment by
programming a hypothetical experiment with a set power
of 0 W and a set temperature higher than the desired value.
The heating profile we obtained by performing an intra-
molecular Heck-type reaction on 7a with 5 mol % of
ꢀ
PdCl2(PPh3)2 in a preheated oil bath at 155 C is shown in
Figure 4. An oil bath temperature of 155 C gave an internal
ꢀ
temperature of 150 C. This figure also shows the mimicked
ꢀ
profile of exactly the same experiment performed under
microwave heating. As can be seen in the figure the two heat-
ing profiles are not exactly the same but very similar. Differ-
ences are due to the software of the microwave system. A
power moderation algorithm is used which automatically
To investigate a possible existence of non-thermal micro-
wave effects11b in the Pd-catalyzed intramolecular arylation
F
A
E
C
B
D
Figure 2. Pressure sensor (A), 10 mL microwave vial (B), thermowell (C), homemade ‘attenuator’ (D), locking cover assembly (E) and fiber optic temperature
sensor (F).

4680
S. Hostyn et al. / Tetrahedron 62 (2006) 4676–4684
Figure 3. Experimental setup for the determination of a heating profile (via the microwave software) of an experiment executed in an oil bath.
alters the power to a lower value, even though it has not
been programmed by the user. This algorithm has been in-
corporated as a safety feature to prevent explosions due to
too rapid heating of a reaction mixture. Although a reason-
ably good comparison has been obtained between oil bath
and microwave heating profile, this algorithm prevented us
to exactly mimic the profiles. The two reactions shown in
Figure 4 have been analyzed by an HPLC–UV system.
Interestingly, both gave exactly the same conversion to reac-
tion products (8a and 9a) in a reaction time of 10 min
[microwave: % reaction products ¼ 41.8 (this percentage
consists of 85% 8a), oil bath: % reaction products ¼ 41.4
(this percentage consists of 86% 8a)] and therefore, non-
thermal effects can be excluded. The studied microwave-
assisted reactions are governed only by thermal effects
(Arrhenius). Nevertheless, from a practical point of view,
160
140
120
100
Oil bath
Stage
Power
1
40
0
52
100
200
on
off
2
35
0
35
125
200
on
off
3
30
0
27
135
200
on
off
4
10
0
87
145
200
on
off
5
7
0
399
149
200
on
off
Microwave
80
Ramp Time
Hold Time
Temperature
Pressure
Stirring
60
40
20
0
Cooling
0
100
200
300
Time (sec)
400
500
600
Figure 4. Attempt to mimic the heating profile of an oil bath experiment with that of a microwave experiment.

S. Hostyn et al. / Tetrahedron 62 (2006) 4676–4684
4681
the microwave-assisted procedure is still more convenient
than classical heating since it is easier to reach high tem-
peratures.
3. Experimental
3.1. General
For the selective N-5 methylation of the 7H-indolo[2,3-
c]quinolines (8b–d) we first tried to use the conditions
(CH3I, toluene, reflux, 2 h; then 28–30% NH3 in H2O) we
previously reported for the selective methylation of 7H-
indolo[2,3-c]quinoline (8a).3 The use of toluene allowed
selective methylation of 8a since the formed isoneocrypto-
lepinium hydroiodide (4a$HI) immediately precipitated
and the formation of 7-methylisoneocryptolepinium iodide
could therefore be avoided. For 10-methyl-7H-indolo[2,3-c]
quinoline (8b) this procedure worked smoothly giving ac-
cess to the desired 5,10-dimethyl-5H-indolo[2,3-c]quinoline
(4b) in 95% yield (Table 5). However, under these reaction
conditions methylation of 10-chloro-7H-indolo[2,3-c]quino-
line (8c) and 9-trifluoromethyl-7H-indolo[2,3-c]quinoline
(8d) yielded the respective 5-methyl-5H-indolo[2,3-c]quino-
lines 4c and 4d in lower yields (75 and 60%). Interestingly,
based on a report for the selective methylation of quindoline,
we found that methylation of 8c and 8d with MeI in re-
fluxing tetrahydrofuran gave superior results (Table 5).16
Also in this case a precipitate (4c$HI and 4d$HI) forms
during the reaction.
All melting points were determined on a Buchi apparatus and
¨
are uncorrected. The 1H and 13C NMR spectra were recorded
on a Brucker spectrometer Avance 400 in the solvent indi-
¨
cated with TMS (7 and 8) or CD3COOD (4) as an internal
standard. All coupling constants are given in Hertz and
chemical shifts are given in parts per million. The assignment
of the 1H NMR signals of 4 is based on 2D NMR techniques
(NOESY and COSY). The chemical shifts of the signals in
1
the H NMR spectra of 4 are concentration dependant. For
mass spectrometric analysis, samples were dissolved in
CH3OH containing 0.1% formic acid and diluted to a con-
centration of approximately 10ꢃ5 mol/L. Injections (1 mL)
were directed to the mass spectrometer at a flow rate of
5 mL/min (CH3OH and 0.1% formic acid), using a CapLC
HPLC system. Accurate mass data were acquired on a
Qq-TOF 2 (Micromass) mass spectrometer equipped with
a standard electrospray ionisation (ESI) interface. Cone volt-
age (approx. 35 V) and capillary voltage (approx. 3.3 kV)
were optimized on one compound and used for all others.
For the determination of the accurate mass of the molecular
ion [M+H]+, a solution of polyethylene glycol 300 in
CH3OH/H2O with 1 mmol ammonium acetate, was added
just before the mass spectrometer (at a rate of 1 mL/min) to
the mobile phase. The calculated masses of PEG [M+H]+
and [M+NH4]+ ions were used as lock mass. For the product
ion experiments (MS) the mass of the [M+H]+ was used as
lock mass for the fragments. Fragmentation was induced
by low energy collisional activation using different collision
energies between 20 and 30 eV. All signals with a signal to
noise ratio ꢄ5/1 were reported. 3-Bromoquinoline (Acros),
2-bromanilines (Acros and Aldrich), XANTPHOS (Al-
drich), PdCl2(PPh3)2 (Aldrich) and Pd2(dba)3 (Acros) were
obtained from commercial sources and used as such. For
the Buchwald–Hartwig amination Cs2CO3 (99%) (Aldrich)
and freshly distilled dioxane (dried over sodium benzophe-
none) were used. Flash column chromatography was per-
formed on Kieselgel 60 (ROCC, 0.040–0.063 mm).
In conclusion, we smoothly synthesized D-ring substituted
5-methyl-5H-indolo[2,3-c]quinolines (4b–d) via our earlier
developed three-step approach for the construction of unsub-
stituted isoneocryptolepine. The procedure consists of the
combination of a selective Buchwald–Hartwig amination
and a regioselective intramolecular Heck-type reaction.
The latter step [Pd-catalyzed intramolecular arylation of
3-(2-bromophenylamino)quinolines] was studied under
microwave irradiation. Superior reaction conditions have
clearly been identified since the catalyst loading and reaction
time can be seriously reduced by performing the ring closure
reaction at a higher temperature. In addition the new condi-
tions allow an easier work up. The biological evaluation
(antiplasmodial activity and cytotoxicity) of 4b–d is cur-
rently in progress and the screening results will be reported
in due course.
3.2. Pd-catalyzed amination of 3-bromoquinoline (5)
with 2-bromoanilines (6)
3.2.1. 3-(2-Bromo-4-methylphenylamino)quinoline (7b).
A round-bottomed flask was charged with Pd2(dba)3
(0.069 g, 0.075 mmol, 2.5 mol %) and XANTPHOS [9,9-di-
methyl-4,5-bis(diphenylphosphino)-9H-xanthene] (0.096 g,
0.165 mmol, 5.5 mol %) followed by dry dioxane (12 mL)
(freshly distilled). The mixture was flushed with N2 for
10 min. Meanwhile, in another round-bottomed flask 3-
bromoquinoline (5) (0.624 g, 3 mmol), 2-bromo-4-methyla-
niline (6b) (0.670 g, 3.6 mmol) and caesium carbonate
(2.932 g, 9 mmol) (Aldrich, 99%) were weighed. To this
mixture, the Pd-catalyst was added and the flask was flushed
with N2 for 5 min. The resulting mixture was heated at reflux
Table 5. Methylation of 8a–d
R
R
NH
N
1) MeI 2) 28 -30%
solvent NH3 in H2O
reflux
a: R = H
b: R = 10-Me
N
N
8a-d c: R = 10-Cl
4a-d CH3
d: R = 9-CF3
Entry
8
Solvent
Yield (%)
1
2
3
4
8a
8b
8c
8d
Toluene
Toluene
THF
88a
95a
94b
95b
ꢀ
(oil bath temperature: 110 C) for 16 h under magnetic stir-
ring. After cooling down to room temperature dichlorome-
thane (25 mL) was added and the suspension was filtered
over a path of Celite and rinsed with dichloromethane
(125 mL). The solvent was removed under reduced pressure
and the residue was purified by column chromatography on
THF
a
0.5 mmol 8a–b, 3 mL MeI, 7.5 mL toluene, reflux, 2 h and then 28–30%
NH3 in H2O.
0.5 mmol 8c–d, 0.25 mL MeI, 2.5 mL THF, reflux, overnight and then
28–30% NH3 in H2O.
b

4682
S. Hostyn et al. / Tetrahedron 62 (2006) 4676–4684
silica gel using dichloromethane as the eluent yielding the
title compound in 85%.
on column mixed with silica) using dichloromethane/
methanol (98/2) as the eluent yielding the title compound
in 66%.3
ꢀ
White solid; mp 107 C; dH (CDCl3): 8.74 (d, J¼2.7 Hz, 1H,
H-2), 8.03 (dd, J¼8.4, 0.9 Hz, 1H, H-8), 7.67 (d, J¼2.7 Hz,
1H, H-4), 7.63 (dd, J¼8.1, 1.4 Hz, 1H, H-5), 7.53 (ddd,
J¼8.4, 6.9, 1.4 Hz, 1H, H-7), 7.46 (ddd, J¼8.1, 6.9,
0.9 Hz, 1H, H-6), 7.42 (d, J¼1.5 Hz, 1H, H-30), 7.26 (d,
J¼8.3 Hz, 1H, H-60), 7.05 (dd, J¼8.3, 1.5 Hz, 1H, H-50),
6.15 (br s, 1H, NH), 2.30 (s, 3H, CH3); MS (ESI): 313,
233, 218, 184; HRMS (ESI) for C16H14N2Br [M+H]+: calcd
313.0340, found 313.0352.
3.3.2. 10-Methyl-7H-indolo[2,3-c]quinoline (8b). 3-(2-
Bromo-4-methylphenylamino)quinoline (7b) (0.188 g,
0.6 mmol) and 1 mL of stock solution of catalyst
(1 mol %); eluent: dichloromethane/methanol (98/2); yield:
ꢀ
58%; beige solid; mp >270 C (decomp.); dH (DMSO-d6):
12.06 (br s, 1H, NH), 9.28 (s, 1H, H-6), 8.81 (dd, J¼8.2,
1.2 Hz, 1H, H-4), 8.49 (s, 1H, H-11), 8.19 (dd, J¼8.3,
1.2 Hz, 1H, H-1), 7.76 (ddd, J¼8.2, 6.9, 1.2 Hz, 1H, H-3),
7.66 (ddd, J¼8.3, 6.9, 1.2 Hz, 1H, H-2), 7.66 (d,
J¼8.4 Hz, 1H, H-8), 7.43 (d, J¼8.4 Hz, 1H, H-9), 2.59 (s,
3H, CH3); MS (ESI): 233, 218; HRMS (ESI) for C16H13N2
[M+H]+: calcd 233.1079, found 233.1069.
3.2.2. 3-(2-Bromo-4-chlorophenylamino)quinoline (7c).
2-Bromo-4-choroaniline (0.743 g, 3.6 mmol); eluent:
CH2Cl2/heptane (9/1); yield: 63%; white solid; mp
ꢀ
139 C; dH (CDCl3): 8.76 (d, J¼2.7 Hz, 1H, H-2), 8.06
(dd, J¼8.4, 0.9 Hz, 1H, H-8), 7.76 (d, J¼2.7 Hz, 1H, H-4),
7.68 (dd, J¼8.1, 1.5 Hz, 1H, H-5), 7.60 (ddd, J¼8.4, 6.9,
1.5 Hz, 1H, H-7), 7.58 (dd, J¼1.8, 0.9 Hz, 1H, H-30), 7.51
(ddd, J¼8.1, 6.9, 0.9 Hz, 1H, H-6), 7.20 (m, 2H, H-50 and
H-60), 6.25 (br s, 1H, NH); MS (ESI): 333, 253, 218, 204;
HRMS (ESI) for C15H11N2ClBr [M+H]+: calcd 332.9794,
found 332.9809.
3.3.3. 10-Chloro-7H-indolo[2,3-c]quinoline (8c). 3-(2-
Bromo-4-chlorophenylamino)quinoline (7c) (0.200 g,
0.6 mmol) and 1 mL of stock solution of catalyst
(1 mol %); eluent: dichloromethane/methanol (98/2); yield:
ꢀ
69%; light yellow solid; mp >250 C (decomp.); dH
(DMSO-d6): 12.38 (br s, 1H, NH), 9.33 (s, 1H, H-6), 8.82
(dd, J¼8.1, 1.1 Hz, 1H, H-4), 8.74 (d, J¼1.9 Hz, 1H,
H-11), 8.21 (dd, J¼8.3, 1.1 Hz, 1H, H-1), 7.81 (d, J¼
8.8 Hz, 1H, H-8), 7.78 (ddd, J¼8.1, 6.9, 1.1 Hz, 1H, H-3),
7.70 (ddd, J¼8.3, 6.9, 1.1 Hz, 1H, H-2), 7.62 (dd, J¼8.8,
1.9 Hz, 1H, H-9); MS (ESI): 253, 218, 190; HRMS (ESI)
for C15H10N2Cl [M+H]+: calcd 253.0533, found 253.0534.
3.2.3. 3-(2-Bromo-5-trifluoromethylphenylamino)quino-
line (7d). 2-Bromo-5-trifluoromethylaniline (0.864 g,
3.6 mmol); eluꢀent: CH2Cl2/heptane (9/1); yield: 59%; white
solid; mp 109 C; dH (CDCl3): 8.83 (d, J¼2.6 Hz, 1H, H-2),
8.10 (dd, J¼8.5, 1.1 Hz, 1H, H-8), 7.88 (d, J¼2.6 Hz, 1H,
H-4), 7.75 (dd, J¼8.1, 1.5 Hz, 1H, H-5), 7.70 (br dq,
3.3.4. 9-Trifluoromethyl-7H-indolo[2,3-c]quinoline (8d).
3-(2-Bromo-5-trifluoromethylphenylamino)quinoline (7d)
(0.220 g, 0.6 mmol) and 1 mL of stock solution of catalyst
(1 mol %); eluent: dichloromethane/methanol (98/2); yield:
5
J¼8.3 Hz, JH–F¼0.8 Hz, 1H, H-30), 7.66 (ddd, J¼8.5, 6.9,
1.5 Hz, 1H, H-7), 7.56 (ddd, J¼8.1, 6.9, 1.1 Hz, 1H, H-6),
7.44 (br d, J¼1.9 Hz, 1H, H-60), 7.06 (br ddq, J¼8.3,
4
1.9 Hz, JH–F¼0.6 Hz, 1H, H-40), 6.44 (br s, 1H, NH); MS
76%; light yellow solid; mp 240 C; dH (DMSO-d6): 12.52
ꢀ
(ESI): 367, 287; HRMS (ESI) for C16H11N2BrF3 [M+H]+:
calcd 367.0058, found 367.0069.
(br s, 1H, NH), 9.41 (s, 1H, H-6), 8.89 (d, J¼8.6 Hz, 1H,
H-11), 8.82 (dd, J¼8.2, 1.2 Hz, 1H, H-4), 8.24 (dd, J¼8.3,
1.1 Hz, 1H, H-1), 8.13 (s, 1H, H-8), 7.81 (ddd, J¼8.2, 7.0,
1.1 Hz, 1H, H-3), 7.73 (ddd, J¼8.3, 7.0, 1.2 Hz, 1H, H-2),
7.67 (d, J¼8.6 Hz, 1H, H-10); MS (ESI): 287, 267, 233,
218; HRMS (ESI) for C16H10N2F3 [M+H]+: calcd
287.0796, found 287.0791.
3.3. Microwave-assisted intramolecular arylation of
3-(2-bromophenylamino)quinolines (7)
3.3.1. 7H-Indolo[2,3-c]quinoline (8a). A microwave vial of
10 mL was charged with 3-(2-bromophenylamino)quinoline
(7a) (0.180 g, 0.6 mmol) and NaOAc$3H2O (0.200 g,
1.47 mmol). Subsequently, the vial was flushed with Ar for
1 min. Then, 0.2 mL of a stock solutiony of the catalyst in
DMA (0.2 mol %) and DMA (0.8 mL) was added via a
syringe and the resulting mixture was stirred and flushed
with Ar for an additional 2 min. Next, the vial was sealꢀed
with an Al crimp cap with a septum and heated at 180 C
in a CEM Discover microwave apparatus. The set power
was 100 W and the total heating time was 10 min. After
the reaction vial was cooled down to room temperature using
a propelled air flow, it was opened and poured in a round-
bottomed flask. The vial was rinsed with methanol
(50 mL) and the combined organic phase was evaporated
to dryness. Finally, the crude product was purified via col-
umn chromatography on silica gel (the residue was brought
3.4. Methylation of 7H-indolo[2,3-c]quinolines (8)
3.4.1. 5,10-Dimethyl-5H-indolo[2,3-c]quinoline (4b). In
a round-bottomed flask 10-methyl-7H-indolo[2,3-c]quino-
line (8b) (0.116 g, 0.5 mmol), toluene (7.5 mL) and CH3I
(3 mL) were heated aꢀt reflux under N2 atmosphere (oil
bath temperature: 120 C) for 2 h under magnetic stirring.
Then the precipitated material was filtered off and rinsed
well with toluene (100 mL). The residue was dissolved in
methanol (300 mL) to remove it from the filter and the solu-
tion was subsequently evaporated to dryness under reduced
pressure. The crude product was purified via column chro-
matography on silica gel [eluent: dichloromethane/methanol
(8/2)]. The residue was brought on column mixed with silica
giving 10-methylisoneocryptolepine hydroiodide (4b$HI) as
a yellow solid. To obtain the free base, 4b$HI was brought in
a mixture of dichloromethane (100 mL) and 28–30% ammo-
nia in water (100 mL). The organic phase was separated and
the aqueous phase was subsequently extracted with dichloro-
methane (2ꢂ100 mL). The combined organic phase was
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.

S. Hostyn et al. / Tetrahedron 62 (2006) 4676–4684
4683
ꢀ
dried over MgSO4, filtered and evaporated to dryness to
quantitatively yield 4b as a red solid in 75%.
then stirred at 130 or 160 C under Ar atmosphere in a pre-
heated oil bath. At 10, 20, 30, 60, 120 and 360 min 50 mL
of fluid was taken from the flask via a septum and diluted
with MeOH to a concentration of 1.5ꢂ10ꢃ3 M. The obtained
solutions were filtered (0.2 mm; Nylon) and diluted with
MeOH to a concentration of 1.5ꢂ10ꢃ4 M. Subsequently,
the samples were analyzed with LC–UV–MS. The conver-
sion is determined by dividing the sum of the UV peak areas
of 7H-indolo[2,3-c]quinoline (8a) and 10H-indolo[3,2-
b]quinoline (9a) by the sum of the peak areas of the starting
material (7a), 7H-indolo[2,3-c]quinoline (8a) and 10H-
indolo[3,2-b]quinoline (9a) after a correction factor on the
peak areas, based on the difference in extinction coefficient
of the starting material and reaction products at the used
wavelength (260 nm), has been taken into account.
Red solid; mp >180 C (decomp.); dH (CD3COOD):17 9.48
ꢀ
(s, 1H, H-6), 8.62 (d, J¼7.2 Hz, 1H, H-1), 8.24 (d, J¼8.7 Hz,
1H, H-4), 8.03 (s, 1H, H-11), 7.94 (m, 2H, H-2 and H-3),
7.60 (d, J¼8.5 Hz, 1H, H-8), 7.48 (d, J¼8.5 Hz, 1H, H-9),
4.60 (s, 3H, NCH3), 2.50 (s, 3H, CCH3); dC (CD3COOD):
143.0, 137.7, 134.2, 133.8, 133.4, 130.8, 130.6, 130.3,
127.0, 126.0, 125.0, 123.6, 120.9, 119.6, 114.1, 46.3, 21.6;
MS (ESI): 247, 232; HRMS (ESI) for C17H15N2 [M+H]+:
calcd 247.1235, found 247.1239.
3.4.2. 10-Chloro-5-methyl-5H-indolo[2,3-c]quinoline
(4c). A round-bottomed flask was charged with 10-chloro-
7H-indolo[2,3-c]quinoline (8c) (0.126 g, 0.5 mmol), dry
THF (2.5 mL) and MeI (0.25 mL).ꢀ After overnight heating
at reflux (oil bath temperature: 75 C) under Ar atmosphere
and magnetic stirring, the solvent was evaporated under re-
duced pressure. The crude product was purified via column
chromatography on silica gel [eluent: dichloromethane/
methanol (9/1)]. The residue was brought on column mixed
with silica giving 10-chloroisoneocryptolepine hydroiodide
(4c$HI) as a yellow solid. To obtain the free base, 4c$HI
was brought in a mixture of dichloromethane (100 mL)
and 28–30% ammonia in water (100 mL). The organic phase
was separated and the aqueous phase was subsequently ex-
tracted with dichloromethane (2ꢂ100 mL). The combined
organic phase was dried over MgSO4, filtered and evapo-
rated to dryness to yield 4c as a red solid in 94%.
3.6. Chromatographic conditions
The analytical column [XBridge C18 (4.6ꢂ50) mm,
dp¼2.5 mm] was purchased from Waters. The LC analysis
was executed with a gradient elution at 1 mL/min starting
at 70/30 (v/v) H2O/MeOH containing 0.1% formic acid.
The composition of the mobile phase was altered to 45/55
(v/v) H2O/MeOH containing 0.1% formic acid in 3 min
and subsequently to 20/80 (v/v) H2O/MeOH containing
0.1% formic acid in 7 min thus giving a total elution time
of 10 min. For peak detection a UV-detector (SP8450)
from Spectra-physics was used at a fixed wavelength
(260 nm). Peak identification was performed with an AQA
LC/MS (Quadrupole mass analyzer, APCI+ mode,
Vinj¼25 mL) apparatus from Thermo Finnigan.
Red solid; mp >200 C (decomp.); dH (CD3COOD):17 9.80
ꢀ
(s, 1H, H-6), 8.73 (dd, J¼7.2, 2.5 Hz, 1H, H-1), 8.37 (m, 2H,
H-4 and H-11), 8.02 (m, 2H, H-2 and H-3), 7.78 (d,
J¼8.9 Hz, 1H, H-8), 7.62 (dd, J¼8.9, 1.7 Hz, 1H, H-9),
4.73 (s, 3H, NCH3); dC (CD3COOD): 142.4, 138.6, 133.8,
132.0, 131.1, 131.0, 130.7, 128.6, 126.1, 125.6, 124.6,
123.2, 121.0, 119.8, 115.9, 46.5; MS (ESI): 267, 252, 232;
HRMS (ESI) for C16H12N2Cl [M+H]+: calcd 267.0689,
found 267.0685.
Acknowledgements
Steven Hostyn thanks the IWT-Flanders (The Institute for
the promotion of Innovation by Science and Technology in
Flanders), Gitte Van Baelen the University of Antwerp
(BOF IWT), Caroline Meyers the FWO-Flanders (Fund for
Scientific Research-Flanders) and Prof. Dr. A. Gulevskaya
at the University of Antwerp (BOF Visiting Postdoc
Researcher) for a scholarship. Prof. Dr. B. Maes is indebted
to the foundation ‘Rosa Blanckaert’ for a research grant.
The authors acknowledge the financial support of the
FWO-Flanders (Fund for Scientific Research-Flanders)
(project 1.5.088.04), the European Union, the University
of Antwerp (Concerted action of the Special Fund for
Research of the University of Antwerp) and the Flemish
Government (Impulsfinanciering van de Vlaamse Overheid
voor Strategisch Basisonderzoek PFEU 2003) as well as
the technical assistance of J. Aerts, G. Rombouts, W. Van
Dongen and J. Verreydt. We would like to thank Prof. Dr.
3.4.3. 9-Trifluoromethyl-5-methyl-5H-indolo[2,3-c]quino-
ꢀ
line (4d). Yield: 95%; orange solid; mp >250 C (decomp.);
dH (CD3COOD):17 9.90 (s, 1H, H-6), 8.80 (dd, J¼7.3, 2.3 Hz,
1H, H-1), 8.64 (d, J¼8.6 Hz, 1H, H-11), 8.40 (dd, J¼7.7,
2.2 Hz, 1H, H-4), 8.13 (s, 1H, H-8), 8.03 (m, 2H, H-2 and
H-3), 7.67 (dd, J¼8.6, 0.8 Hz, 1H, H-10), 4.75 (s, 3H,
NCH3); dC (CD3COOD): 143.4, 139.7, 134.3, 132.8 (q,
2JC–F¼32.4 Hz), 132.3, 131.3, 131.2, 126.9, 126.0, 125.9
1
(br d, JC–F¼2.8 Hz), 125.4, 125.2 (q, JC–F¼272.2 Hz),
122.9, 120.2, 119.3 (q, JC–F¼3.1 Hz), 112.5 (q, JC–F
¼
4.5 Hz), 46.9; MS (ESI): 301, 286, 281, 233, 183; HRMS
(ESI) for C17H12N2F3 [M+H]+: calcd 301.0953, found
301.0954.
`
E. Esmans and Prof. Dr. F. Lemiere for HRMS measure-
ments and Prof. Dr. R. Dommisse for NMR spectra.
3.5. General procedure for the kinetic experiments
References and notes
A two-necked round-bottom flask was charged with
PdCl2(PPh3)2 (0.097 g, 0.138 mmol, 23 mol % or 0.021 g,
0.030 mmol, 5 mol %), 3-(2-bromophenylamino)quino-
line (7a) (0.180 g, 0.6 mmol), NaOAc$3H2O (0.200 g,
1.47 mmol) followed by dimethylacetamide (DMA)
(10 mL). The mixture was flushed with Ar for 5 min and
1. (a) Website of the World Health Organization: http://
www.who.int/en/; (b) Egan, T. J. Drug. Des. Rev.—Online
2004, 1, 93–110.
2. (a) Cimanga, K.; De Bruyne, T.; Pieters, L.; Claeys, M.;
Vlietinck, A. Tetrahedron Lett. 1996, 37, 1703–1706; (b)

4684
S. Hostyn et al. / Tetrahedron 62 (2006) 4676–4684
Sharaf, M. H. M.; Schiff, P. L.; Tackie, A. N.; Phoebe, C. H.;
at the Speed of Light; CEM: Matthews, NC, 2002; (b) Micro-
waves in Organic Synthesis; Loupy, A., Ed.; Wiley-VCH:
Weinheim, 2002; (c) Hayes, B. L. Aldrichimica Acta 2004,
37, 66–77; (d) Microwave-Assisted Organic Synthesis;
Martin, G. E. J. Heterocycl. Chem. 1996, 33, 239–243; (c)
Pousset, J.-L.; Martin, M.-T.; Jossang, A.; Bodo, B. Phyto-
chemistry 1995, 39, 735–736.
`
3. Hostyn, S.; Maes, B. U. W.; Pieters, L.; Lemiere, G. L. F.;
Matyus, P.; Hajos, G.; Dommisse, R. Tetrahedron 2005, 61,
Lindstrom, P., Tierney, J. P., Eds.; Blackwell: Oxford, 2004;
¨
´
´
(e) Kappe, C. O. Angew. Chem., Int. Ed. 2004, 43, 6250–6284.
12. The overall yield for the synthesis of 7H-indolo[2,3-c]quino-
line (8a) via the combination of a selective Buchwald–Hartwig
amination (yield 7a: 85%) with a regioselective Pd-catalyzed
intramolecular arylation reaction (yield 8a: 66%), starting
from commercially available 3-bromoquinoline (5) and 2-bro-
moaniline (6a), could be improved to 56%. This is 19% higher
than previously reported by us (see Ref. 3). Following our
optimized procedure a slightly higher overall yield can be ob-
tained than with the two-step procedure developed by Fan and
Ablordeppey (overall yield: 47%). Fan, P.; Ablordeppey, S. Y.
J. Heterocycl. Chem. 1997, 34, 1789–1794; For other reported
procedures to synthesize the 7H-indolo[2,3-c]quinoline skele-
ton see: (a) Kermack, W. O.; Slater, R. H. J. Chem. Soc. 1928,
32–45; (b) Clemo, G. R.; Felton, D. G. I. J. Chem. Soc. 1951,
671–677; (c) Kannadasan, S.; Srinivasan, P. C. Synth. Commun.
2004, 34, 1325–1335; (d) Banwell, M. G.; Lupton, D. W.;
Ma, X.; Renner, J.; Sydnes, M. O. Org. Lett. 2004, 6, 2741–
2744; (e) Zhang, X.; Campo, A.; Yao, T.; Larock, R. C. Org.
Lett. 2005, 7, 763–766.
1571–1577.
4. For synthetic procedures based on the combination of a selec-
tive Buchwald–Hartwig amination with an intramolecular
Heck or Heck-type reaction see: (a) Iwaki, T.; Yasuhara, A.;
Sakamoto, T. J. Chem. Soc., Perkin Trans. 1 1999, 1505–1510;
(b) Edmondson, S. D.; Mastracchio, A.; Parmee, E. R. Org.
Lett. 2000, 2, 1109–1112; (c) Bedford, R. B.; Cazin, C. S. J.
Chem. Commun. 2002, 2310–2311; (d) Jonckers, T. H. M.;
`
Maes, B. U. W.; Lemiere, G. L. F.; Rombouts, G.; Pieters,
L.; Haemers, A.; Dommisse, R. A. Synlett 2003, 615–618;
(e) Ferreira, I. C. F. R.; Queiroz, M.-J. R. P.; Kirsch, G. Tetra-
´
hedron 2003, 59, 3737–3743; (f) Dajka-Halasz, B.; Monsieurs,
K.; Elias, O.; Karolyhazy, L.; Tapolcsanyi, P.; Maes, B. U. W.;
´
´
´
´
´
´
`
Riedl, Z.; Hajos, G.; Dommisse, R. A.; Lemiere, G. L. F.;
Kosmrlj, J.; Matyus, P. Tetrahedron 2004, 60, 2283–2291; (g)
ˇ
´
´
Matyus, P.; Maes, B. U. W.; Riedl, Z.; Hajos, G.; Lemiere,
G. L. F.; Tapolcsanyi, P.; Monsieurs, K.; Elias, O.; Dommisse,
´
`
´
´
´
R. A.; Krajsovszky, G. Synlett 2004, 1123–1139.
5. Van Miert, S.; Hostyn, S.; Maes, B. U. W.; Cimanga, K.; Brun,
´
`
R.; Kaiser, M.; Matyus, P.; Dommisse, R.; Lemiere, G.;
Vlietinck, A.; Pieters, L. J. Nat. Prod. 2005, 68, 674–677.
6. The antiplasmodial activity of 1–4 is due to a combination of
at least two mechanisms of action; haeme detoxification
and DNA-intercalation. Haeme detoxification is a selective
whereas DNA-intercalation is a nonselective mechanism. The
latter process is responsible for the cytotoxicity of the com-
pounds (see Ref. 5).
13. Fluorenones have been synthesized via an intramolecular Pd-
catalyzed arylation in a kitchen microwave oven: (a) Qabaja,
G.; Jones, G. B. Tetrahedron Lett. 2000, 41, 5317–5320; (b)
Qabaja, G.; Jones, G. B. J. Org. Chem. 2000, 65, 7187–7194.
14. The column chromatography fractions that contained the quin-
dolines 9a–d were impure and contained hydrodebrominated
7a–d. No attempts were made to further purify the minor iso-
mers 9a–d.
´
´
15. Echavarren, A. M.; Gomez-Lor, B.; Gonzalez, J. J.; de Frutos,
7. For examples on the ‘base effect’ in Buchwald–Hartwig amina-
tions see: (a) Maes, B. U. W.; Loones, K. T. J.; Jonckers, T. H.
´
O. Synlett 2003, 585–597.
`
M.; Lemiere, G. L. F.; Dommisse, R. A.; Haemers, A. Synlett
2002, 1995–1998; (b) Meyers, C.; Maes, B. U. W.; Loones,
`
K. T. J.; Bal, G.; Lemiere, G. L. F.; Dommisse, R. A. J. Org.
Chem. 2004, 69, 6010–6017.
16. Ho, T. L.; Jou, D. G. Helv. Chim. Acta 2002, 85, 3823–3827.
17. Selective N-5 methylation of 8b–d could be determined by 2D-
NMR (NOESY experiment). Observation of a NOE enhance-
ment between the hydrogens of the methyl group and H-4
proved their neighbourhood. Moreover another NOE enhance-
ment, between H-1 and H-11, further supported that in the
intramolecular Heck-type reaction 7H-indolo[2,3-c]quinolines
(8b–d) were formed as the major isomers.
8. In the previously reported procedure we did not follow the
progress of the amination reaction (see Ref. 3). After a 30 h re-
flux, we checked the reaction by TLC and MS and found that all
3-bromoquinoline was converted and subsequently worked up
the crude reaction mixture.
9. For a recent review dealing with direct arylation via cleavage of
activated and unactivated C–H bonds see: Miura, M.; Nomura,
M. Top. Curr. Chem. 2002, 219, 211–241.
10. Hydrodebrominated 7a–d and homocoupled 7a–d are identi-
fied side products.
11. For recent reviews and books on microwave-assisted organic
synthesis: (a) Hayes, B. L. Microwave Synthesis: Chemistry
9
10
8
11
1
4
N
7
2
3
6
N
CH3
5