Highly efficient one-pot synthesis of D-ring chloro-substituted neocryptolepines via a condensation - Pd-catalyzed intramolecular direct arylation strategy

Article abstract of DOI:10.1016/j.tet.2010.10.077

D-ring chloro-substituted neocryptolepines have been synthesized in excellent yield starting from 3-bromo-2-chloro-1-methylquinolinium triflate via a one-pot condensation - Pd-catalyzed intramolecular direct arylation strategy involving chloroanilines. Th

Full text of DOI:10.1016/j.tet.2010.10.077

Tetrahedron 67 (2011) 655e659
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Tetrahedron
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Highly efficient one-pot synthesis of D-ring chloro-substituted neocryptolepines
via a condensationdPd-catalyzed intramolecular direct arylation strategy
*
ꢀ
Steven Hostyn, Kourosch Abbaspour Tehrani, Filip Lemiere, Veerle Smout, Bert U.W. Maes
Department of Chemistry, University of Antwerp, Groenenborgerlaan 171, B-2020 Antwerp, Belgium
a r t i c l e i n f o
a b s t r a c t
Article history:
D-ring chloro-substituted neocryptolepines have been synthesized in excellent yield starting from 3-
bromo-2-chloro-1-methylquinolinium triflate via a one-pot condensationdPd-catalyzed intramolecular
direct arylation strategy involving chloroanilines. The 3-bromo-2-chloro-1-methylquinolinium triflate
was obtained via methylation of commercial 3-bromo-2-chloroquinoline with methyl triflate.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 27 September 2010
Received in revised form 23 October 2010
Accepted 26 October 2010
Available online 12 November 2010
Keywords:
CeH Activation
Intramolecular direct arylation
Malaria
One-pot
1. Introduction
the required D-ring chloro-substituted neocryptolepine precursors
(3) (Fig.1) suffers from a low overall yield (8-chloroneocryptolepine
Within the framework of our research toward the synthesis of
new antiplasmodial indoloquinolines, we recently reported the
synthesis and antiplasmodial activity of a set of aminoalkylamino-
substituted derivatives of the natural product neocryptolepine
(5-methyl-5H-indolo[2,3-b]quinoline) (1) (Fig. 1).1 The most se-
lective compound identified, the D-ring substituted N1,N1-diethyl-
N4-(5-methyl-5H-indolo[2,3-b]quinolin-8-yl)pentane-1,4-diamine
(2) (Fig. 1), showed an IC50 of 10 nM against the chloroquine-sen-
sitive P. falciparum Ghana strain and a selectivity index of 1800,
which is a 1500-fold increase in comparison to the natural product
itself.1 Although these aminoalkylamino-substituted neo-
cryptolepines appear to be promising compounds, the synthesis of
(3b): 15.7%, 9-chloroneocryptolepine (3a): 7.9%) due to the in-
efficient GraebeeUllmann reaction used for their preparation.1 In
order to be able to synthesize a broader set of aminoalkylamino-
substituted neocryptolepines via Pd-catalyzed amination on 3,
a more efficient methodology to obtain these D-ring chloro-
substituted neocryptolepines is desirable. When looking at litera-
ture procedures for the synthesis of neocryptolepine and its basic
skeleton, generally three distinct strategies have been followed. The
first strategy is based on the construction of the indoloquinoline
skeleton via two consecutive cyclization steps in which both the
indole and quinoline moieties are formed.2e4 The second strategy
starts from an indole compound and builds up the quinoline
moiety.5e8 Reversely, the third strategy starts from a quinoline
compound and builds up the indole moiety.9e11 As a large variety of
substituted anilines is readily available, the third strategy that relies
on anilines to construct the indole moiety has a clear advantage
over the other strategies when D-ring substitution is aimed. We
herein report a new and highly efficient synthesis of D-ring chloro-
substituted neocryptolepines (3aed) based on the third strategy.
2. Results and discussion
Fig. 1. Neocryptolepine(1),D-ringchloro-substitutedneocryptolepines(3),N1,N1-diethyl-
N4-(5-methyl-5H-indolo[2,3-b]quinolin-8-yl)pentane-1,4-diamine (2), and substituted
1-methyl-1H-a-carbolines (4).
Based on previous research of our group for the synthesis of 1-
methyl-1H-a-carbolines starting from 2,3-dichloropyridine, there
are in principle two routes to prepare target compounds 3 (Fig. 2).9
The first one involves Pd-catalyzed amination on a 2,3-dihaloqui-
* Corresponding author. Tel.: þ32 3 265 3205; fax: þ32 3 265 3233; e-mail
address: bert.maes@ua.ac.be (B.U.W. Maes).
noline with a chloroaniline (A), followed by Pd-catalyzed
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.10.077

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S. Hostyn et al. / Tetrahedron 67 (2011) 655e659
Fig. 2. Two proposed synthetic routes toward D-ring chloro-substituted neocryptolepines: A: Pd-catalyzed amination, B: Pd-catalyzed intramolecular direct arylation,
C: (regioselective) methylation, D: condensation.
intramolecular direct arylation (B) and regioselective methylation
(C). The second route has the methylation in the first step (C) fol-
lowed by condensation of the methylquinolinium salt with
a chloroaniline (D) and Pd-catalyzed intramolecular direct aryla-
tion (B). We opted for the latter approach as milder reaction con-
ditions can be used. In addition no palladium is required for the
CeN bond formation. In order to obtain the required chemo-
selectivity in the intramolecular direct arylation step we selected 3-
bromo-2-chloroquinoline (9) instead of 2,3-dichloroquinoline as
starting material,9 since a carbonebromine bond is more reactive
for oxidative addition to a Pd-catalyst than a carbonechlorine bond.
Although this substrate is commercially available, it can be easily
prepared from 3-bromoquinoline according to a literature pro-
cedure.12,13 2,3-Dibromoquinoline would also be a suitable sub-
chloroaniline (8b) could be obtained in excellent yield, N-[3-bromo-1-
methylpyridin-2(1H)-ylidene]-2-chloroaniline (8c)wasobtainedinlow
yield only under the same reaction conditions. When a longer reaction
time was applied (48 h instead of 24 h), this compound could be isolated
in an acceptable yield (50%). By using a larger excess of 2-chloroaniline
(7c) (5 equiv instead of 3 equiv), the yield increased to 69%. For the Pd-
catalyzed intramolecular direct arylation step we first applied reaction
conditions, which we previously optimized for related brominated
substrates [PdCl2(PPh3)2, NaOAc$3H2O, DMA, 130 ꢀC].15 A catalyst
loading of 1 mol % and a reaction time of 17 h were found optimal for the
intramolecular direct arylation reaction of N-[3-bromo-1-methylpyr-
idin-2(1H)-ylidene]-4-chloroaniline (8a). When using only 0.5 mol %
PdCl2(PPh3)2, an incomplete reaction was observed. Under optimized
reaction conditions, 6-chloro-1-methyl-1H-pyrido[2,3-b]indole (4a), 7-
chloro-1-methyl-1H-pyrido[2,3-b]indole (4b), and 8-chloro-1-methyl-
1H-pyrido[2,3-b]indole (4c) could be obtained in excellent yield
(Scheme 1). When using N-[3-bromo-1-methylpyridin-2(1H)-ylidene]-
3-chloroaniline (8b) as substrate for arylation, a 100:3 regioselectivity in
favor of 7-chloro-1-methyl-1H-pyrido[2,3-b]indole (4b) over 5-chloro-
1-methyl-1H-pyrido[2,3-b]indole was observed by 1H NMR.
strate but
condensation step. As a model system, efforts were made to first
synthesize the corresponding chloro-substituted 1-methyl-1H-
a chlorine atom at C-2 is more reactive in the
a
-
carbolines (4aec) from commercially available 2,3-dibromopyr-
idine (5) (Scheme 1) as 3-bromo-2-chloropyridine was not yet
commercially available at the start of this research.14
We implemented this methodology to the synthesis of neo-
cryptolepine (1) and subsequently to the synthesis of our target com-
pounds. Methylation of 3-bromo-2-chloroquinoline (9) with methyl
trifluoromethanesulfonate in toluene at room temperature afforded
3-bromo-2-chloro-1-methylquinolinium trifluoromethanesulfonate
(10) in 90% after a reaction time of 48 h (Scheme 2). Subsequent
reaction with aniline (11) under the same reaction conditions as used
for the synthesis of the N-[3-bromo-1-methylpyridin-2(1H)-ylidene]
chloroanilines (8aec) proceeded very smoothly. However, the purifi-
cation of N-[3-bromo-1-methylquinolin-2(1H)-ylidene]aniline (12)
was very tricky since hydrolysis to 3-bromo-1-methylquinolin-2(1H)-
one (13) during work-up occurred easily. Moreover, due to the exo-
thermic condensation reaction a side product was formed, which is
probably 1-methyl-N-phenyl-2-(phenylimino)-1,2-dihydroquinolin-
3-amine (14) as indicated by mass spectrometry. This side product
could not be separated via column chromatography. Its formation was
inhibited by slow addition of 3-bromo-2-chloro-1-methylquinolinium
trifluoromethanesulfonate (10) to aniline at ꢁ10 ꢀC and subsequent
addition of cold anhydrous THF. In a reaction time of 6 h, the reaction
mixture was allowed to reach room temperature. DBU was then added
to deprotonate the N-[3-bromo-1-methylquinolin-2(1H)-ylidene]ani-
linium salt, which is necessary to avoid hydrolysis of this compound in
the next step. To the resulting mixture, PdCl2(PPh3)2, NaOAc$3H2O, and
DMA were added and after 17 h heating at 130 ꢀC, neocryptolepine (1)
couldbe obtained. Acatalystloadingof2.5mol %wasrequired to obtain
complete conversion of starting material in this timeframe. After op-
timization of the work-up procedure, neocryptolepine (1) could be
isolated in 98% yield (Scheme 1). A careful literature investigation
Scheme 1. Synthesis of chloro-substituted 1-methyl-1H-a-carbolines (4aec) via con-
secutive condensation and Pd-catalyzed intramolecular direct arylation of 8aec.
Thus, 2,3-dibromo-1-methylpyridinium trifluoromethanesulfo-
nate (6) was prepared in nearly quantitative yield via methylation of
2,3-dibromopyridine (5) with methyl trifluoromethanesulfonate in
toluene (Scheme 1). Reaction of this substrate with 4-chloro- (7a),
3-chloro- (7b), and 2-chloroaniline (7c)inTHFfurnishedtherespective
N-[3-bromo-1-methylpyridin-2(1H)-ylidene]anilines 8aec (Scheme
1). While N-[3-bromo-1-methylpyridin-2(1H)-ylidene]-4-chloroani-
line (8a) and N-[3-bromo-1-methylpyridin-2(1H)-ylidene]-3-

S. Hostyn et al. / Tetrahedron 67 (2011) 655e659
657
Scheme 2. Synthesis of neocryptolepine (1) via a one-pot condensation – Pd-catalyzed intramolecular direct arylation.
shows that this three-reactions-two-step synthesis of neocryptolepine
(1) is the most efficient route hitherto reported in terms of overall yield
(88%). Our previously reported procedure in which the methyl group is
introduced in the last step rather than in the first step, requiring three
work-ups instead of two, gave 1 in 77% overall yield.
Finally, we successfully applied our optimized reaction condi-
tions to the synthesis of 7-, 8-, 9- ,and 10-chloroneocryptolepine
(3aed) from 3-bromo-2-chloro-1-methylquinolinium trifluoro-
methanesulfonate (10) and 4-chloro- (7a), 3-chloro- (7b), and
2-chloroaniline (7c) (Table 1). For the solid 4-chloroaniline (7a),
a concentrated solution in THF was used for the addition of 3-
bromo-2-chloro-1-methylquinolinium trifluoromethanesulfonate
(10). The Pd-catalyzed intramolecular direct arylation reaction step
required, in the three cases, a catalyst loading of only 1 mol %
PdCl2(PPh3)2. 7-Chloro- (3c) and 9-chloroneocryptolepine (3a) could
be obtained in excellent yield (Table 1). With 3-chloroaniline (7b) as
starting material,
a mixture of 8-chloro (3b) and 10-chlor-
oneocryptolepine (10d) was obtainedin excellent yield in an 85:15 ratio
in favor of the 8-chloro isomer as confirmed by 1H NMR. These isomers
could be separated using an automated chromatography system.
3. Conclusion
In conclusion, we succeeded in developing a simple but efficient
protocol that is suitable for the synthesis of D-ring chloro-
substituted neocryptolepines (3). This protocol consists of a meth-
ylation and a one-pot condensationdPd-catalyzed intramolecular
direct arylation reaction. For the latter step, a catalyst loading of
only 1 mol % Pd was sufficient. The new protocol has clear advan-
tages in terms of efficiency over the GraebeeUllmann method for
the synthesis of chloroneocryptolepines 3.
Table 1
Synthesis of D-ring chloro-substituted neocryptolepines (3aed) via one-pot con-
densation and Pd-catalyzed intramolecular direct arylation
Br
i, ii
+
Cl
Cl
4. Experimental
4.1. General
N
Cl
H2N
N
N
3a d
-
10
CH3 TfO
7a-c
CH3
Entry
Product
Yielda
€
All melting points were determined on a Buchi apparatus and
Cl
are uncorrected. The 1H and 13C NMR spectra were recorded on
a Bruker spectrometer Avance II 400 in the solvent indicated with
TMS as the internal standard. All coupling constants are given in
hertz and chemical shifts are given in parts per million. For mass
spectrometric analysis, samples were dissolved in CH3OH con-
taining 0.1% formic acid and diluted to a concentration of approx-
1
2
3a
98%
N
CH3
N
Cl
N
CH3
N
3b, 3d
98%
87%
imately 10ꢁ5 mol/L. Injections (1
spectrometer at a flow rate of 5
m
L) were directed to the mass
L/min (CH3OH and 0.1% formic
8-chloro : 10-chloro
m
85:15
acid) using a CapLC HPLC system (Waters-Micromass). Accurate
mass data were acquired on a Q-TOF 2 mass spectrometer (Waters-
Micromass) equipped with a standard electrospray ionisation (ESI)
interface. Cone voltage (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
4
3c
N
CH3
N
Cl
a
Reaction conditions: (i) 1. 10, 5 equiv 7aec, THF, ꢁ10 ꢀC to rt 2. 2 equiv DBU. (ii)
1 mol % PdCl2(PPh3)2, NaOAc$3H2O, DMA, 130 ꢀC, 17 h.

658
S. Hostyn et al. / Tetrahedron 67 (2011) 655e659
[MþH]þ, a solution of polyethylene glycol 300 in CH3OH/H2O with
mp 92 ꢀC; dH (CDCl3): 7.34 (dd, J¼7.1, 1.7 Hz, 1H, H-60), 7.18 (dd,
J¼6.8, 1.7 Hz, 1H, H-40), 7.08 (dd, J¼7.9, 7.9 Hz, 1H, H-5), 6.85
(ddd, J¼7.9, 2.1, 1.0 Hz, 1H, H-4), 6.75 (dd, J¼2.1, 2.0 Hz, 1H, H-
2), 6.64 (ddd, J¼7.9, 2.0, 1.0 Hz, 1H, H-6), 5.75 (dd, J¼7.1, 6.8 Hz,
1H, H-50), 3.49 (s, 3H, NeCH3); dC (CDCl3): 151.6, 145.6, 142.1,
138.8, 133.5, 128.7, 121.6, 120.5, 119.9, 109.2, 103.1, 41.8;
HRMS (ESI) for C12H11BrClN2 [MþH]þ: calcd: 296.9789, found:
296.9782.
1 mmol ammonium acetate was added just before the mass spec-
trometer (at a rate of 1 mL/min) to the mobile phase. The calculated
masses of PEG [MþH]þ and [MþNH4]þ ions were used as internal
calibrant (lock mass). PdCl2(PPh3)2 (Aldrich), 2,3-dibromopyridine
(ABCR), NaOAc$3H2O (Acros), anhydrous THF (Acros), DMA (Acros),
toluene (Acros), DBU (Aldrich), methyl trifluoromethanesulfonate
(Aldrich) as well as the anilines (Acros) were obtained from com-
mercial sources and used without further purification. Flash col-
umn chromatography was performed on Kieselgel 60 (ROCC SI
4.3.3. N-[3-Bromo-1-methylpyridin-2(1H)-ylidene]-2-chloroaniline
(8c). Reagent: 2-chloroaniline (7c) (1.276 g, 10 mmol); reaction
time: 48 h; yield: 69%; yellow solid; mp 77 ꢀC; dH (CDCl3): 7.32 (dd,
J¼7.1, 1.7 Hz, 1H, H-60), 7.25 (ddd, J¼7.9, 1.5, 0.3 Hz, 1H, H-3), 7.19
(dd, J¼6.8, 1.7 Hz, 1H, H-40), 7.08 (ddd, J¼8.0, 7.3, 1.5 Hz, 1H, H-5),
6.84 (ddd, J¼8.0, 1.5, 0.3 Hz, 1H, H-6), 6.81 (ddd, J¼7.9, 7.3, 1.5 Hz,
1H, H-4), 5.75 (dd, J¼7.1, 6.8 Hz, 1H, H-50), 3.55 (s, 3H, NeCH3); dC
(CDCl3): 147.5, 145.9, 141.4, 138.5, 128.5, 126.3, 126.2, 123.3, 121.3,
109.5, 103.0, 41.9; HRMS (ESI) for C12H11BrClN2 [MþH]þ: calcd:
296.9789, found: 296.9790.
1721, 40e60 mm) or using an automated chromatography system
with Silica Flash Cartridges.
4.2. Methylation of 2,3-dibromopyridine (5) and 3-bromo-2-
chloroquinoline (9)
A flame dried round-bottomed flask was charged with the re-
spective dihalo compound (10 mmol), methyl trifluoromethane-
sulfonate (1.2 mL,10.6 mmol) (CAUTION: Causes burns byall exposure
routes.) and dry toluene (15 mL). The resulting solution was stirred
under Ar atmosphere for the time indicated at room temperature. A
white precipitate was formed, which was collected on a fritted filter,
rinsed well with dry toluene (50 mL), and dried under reduced
pressure.
4.4. Synthesis of chloro-substituted 1-methyl-1H-
a-
carbolines (4aec)
A
round-bottomed flask was charged with PdCl2(PPh3)2
According to this procedure, the following compounds were
prepared:
(0.0070 g, 0.01 mmol, 1 mol %), N-[3-bromo-1-methylpyridin-2
(1H)-ylidene]chloroaniline (8aec) (0.298 g, 1 mmol), NaOAc$3H2O
(0.204 g, 1.5 mmol) followed by dimethylacetamide (DMA)
(10 mL). The mixture was flushed with Ar for 2 min and then
stirred at 130 ꢀC under Ar atmosphere for 17 h. After cooling
down, the mixture was evaporated to dryness under reduced
pressure. Finally, the crude product was purified via column
chromatography on silica gel (the residue was brought on column
mixed with silica).
4.2.1. 2,3-Dibromo-1-methylpyridiniumtrifluoromethanesulfonate (6).
2,3-Dibromopyridine (2.369 g, 10 mmol); Reaction time: 2 h; yield:
96%. As this compound is very hydrolysis sensitive it was immediately
used in subsequent condensation reactions.
4.2.2. 3-Bromo-2-chloro-1-methylquinolinium trifluoromethanesulfo-
nate (10). 3-Bromo-2-chloroquinoline (2.425 g, 10 mmol); Reaction
time: 48 h; yield: 90%. As this compound is very hydrolysis sensitive
it was immediately used in subsequent condensation reactions.
According to this procedure, the following compounds were
synthesized:
4.4.1. 6-Chloro-1-methyl-1H-pyrido[2,3-b]indole (4a). Substrate: N-
[3-bromo-1-methylpyridin-2(1H)-ylidene]-4-chloroaniline (8a);
eluent: dichloromethane/(7 N) ammonia in methanol (98:2); yield:
96%; yellow solid; mp 151 ꢀC; dH (DMSO-d6): 8.67 (dd, J¼7.2, 1.0 Hz,
1H, H-4), 8.28 (dd, J¼6.4,1.0 Hz,1H, H-2), 8.24 (d, J¼2.2 Hz,1H, H-5),
7.63 (d, J¼8.6 Hz,1H, H-8), 7.43 (dd, J¼8.6, 2.2 Hz,1H, H-7), 6.99 (dd,
J¼7.2, 6.4 Hz, 1H, H-3), 4.23 (s, 3H, NeCH3); dC (DMSO-d6): 153.7,
152.0, 136.9, 131.7, 127.3, 124.7, 124.5, 122.6, 121.2, 119.3, 107.7, 40.1;
HRMS (ESI) for C12H10ClN2 [MþH]þ: calcd: 217.0527, found:
217.0527.
4.3. Synthesis of N-[3-bromo-1-methylpyridin-2(1H)-ylidene]
chloroanilines (8aec)
A flame dried round-bottomed flask was charged with 2,3-
dibromo-1-methylpyridinium
trifluoromethanesulfonate
(6)
(0.802 g, 2.0 mmol), chloroaniline (7) (0.765 g, 6 mmol), and an-
hydrous THF (5 mL). The resulting suspension was stirred for 24 h at
30 ꢀC. After cooling down, the solvent was removed under reduced
pressure. Next, the residue was extracted with 28e30% NH4OH
(30 mL) and dichloromethane (3ꢂ30 mL). The combined organic
phase was dried using MgSO4, filtered, and evaporated to dryness.
The crude product was purified via flash column chromatography
on silica gel using a dichloromethane/(7 N) ammonia in methanol
gradient (from dichloromethane to dichloromethane/(7 N) NH3 in
MeOH 98:2).
4.4.2. 7-Chloro-1-methyl-1H-pyrido[2,3-b]indole (4b). Substrate:
N-[3-bromo-1-methylpyridin-2(1H)-ylidene]-3-chloroaniline (8b);
eluent: dichloromethane/(7 N) ammonia in methanol (99:1); yield:
93%; yellow solid; mp 146 ꢀC; dH (DMSO-d6): 8.64 (dd, J¼7.2, 1.2 Hz,
1H, H-4), 8.27 (dd, J¼6.4, 1.2 Hz, 1H, H-2), 8.15 (dd, J¼8.2, 0.5 Hz, 1H,
H-5), 7.63 (dd, J¼1.9, 0.5 Hz, 1H, H-8), 7.14 (dd, J¼8.2, 1.9 Hz, 1H, H-
6), 7.02 (dd, J¼7.2, 6.4 Hz, 1H, H-3), 4.22 (s, 3H, NeCH3); dC (DMSO-
d6): 154.4, 154.2, 136.5, 131.9, 131.1, 124.8, 122.9, 122.1, 118.6, 117.3,
108.1, 40.1; HRMS (ESI) for C12H10ClN2 [MþH]þ: calcd: 217.0527,
found: 217.0526.
According to this procedure, the following compounds were
prepared:
4.3.1. N-[3-Bromo-1-methylpyridin-2(1H)-ylidene]-4-chloroaniline
(8a). Reagent: 4-chloroaniline (7a); yield: 95%; yellow solid; mp
97 ꢀC; dH (CDCl3): 7.32 (dd, J¼7.1, 1.7 Hz, 1H, H-40), 7.17 (dd, J¼6.8,
1.7 Hz, 1H, H-60), 7.12 (d, J¼8.8 Hz, 2H, H-3, and H-5), 6.68 (d,
J¼8.8 Hz, 2H, H-2, and H-6), 5.73 (dd, J¼7.1, 6.8 Hz,1H, H-50), 3.49 (s,
3H, NeCH3); dC (CDCl3): 148.9, 145.4, 142.0, 138.8, 127.8, 125.5,
122.7, 109.1, 102.8, 41.7; HRMS (ESI) for C12H11BrClN2 [MþH]þ:
calcd: 296.9789, found: 296.9788.
4.4.3. 8-Chloro-1-methyl-1H-pyrido[2,3-b]indole (4c). Substrate: N-
[3-bromo-1-methylpyridin-2(1H)-ylidene]-2-chloroaniline (8c);
eluent: dichloromethane/(7 N) ammonia in methanol (99:1); yield:
98%; yellow solid; mp 210 ꢀC; dH (DMSO-d6): 8.69 (dd, J¼7.2, 0.9 Hz,
1H, H-4), 8.33 (dd, J¼6.3, 0.9 Hz, 1H, H-2), 8.12 (dd, J¼7.7, 0.9 Hz, 1H,
H-5), 7.51 (dd, J¼7.6, 0.9 Hz, 1H, H-7), 7.12 (dd, J¼7.7, 7.6 Hz, 1H, H-
6), 7.04 (dd, J¼7.2, 6.3 Hz, 1H, H-3), 4.28 (s, 3H, NeCH3); dC (DMSO-
d6): 153.4, 149.8, 137.0, 132.0, 127.0, 125.5, 125.1, 121.9, 120.5, 119.2,
4.3.2. N-[3-Bromo-1-methylpyridin-2(1H)-ylidene]-3-chloroaniline
(8b). Reagent: 3-chloroaniline (7b); yield: 94%; yellow solid;

S. Hostyn et al. / Tetrahedron 67 (2011) 655e659
659
108.3, 40.3; HRMS (ESI) for C12H10ClN2 [MþH]þ: calcd: 217.0527,
acetate gradient (from heptane to heptane/ethyl acetate (1:1) in
35 min, 35 mL/min).
found: 217.0543.
Datafor3b:yellow-orangesolid;mp187ꢀC;dH (CDCl3): 8.35 (s,1H,
H-11), 7.90 (d, J¼7.8 Hz,1H, H-1), 7.82 (d, J¼8.1 Hz,1H, H-10), 7.74 (dd,
J¼8.5, 7.1 Hz,1H, H-3), 7.67 (d, J¼8.5 Hz,1H, H-4), 7.64 (d, J¼1.7 Hz,1H,
H-7), 7.42 (dd, J¼7.8, 7.1 Hz, 1H, H-2), 7.13 (dd, J¼8.1, 1.7 Hz, 1H, H-9),
4.26 (s, 3H, NeCH3); dC (CDCl3): 156.8, 156.4, 136.8, 134.7, 130.6, 130.0,
128.3, 127.1, 122.4, 122.2, 121.5, 120.8, 119.9, 117.8, 114.2, 33.0; HRMS
(ESI) for C16H12ClN2 [MþH]þ: calcd: 267.0684, found: 267.0681.
Data for 3d: yellow solid; mp 178 ꢀC; dH (CDCl3): 8.92 (s, 1H, H-
11), 7.99 (dd, J¼8.0, 1.1 Hz, 1H, H-1), 7.79e7.69 (m, 2H, H-3, and H-
4), 7.62 (dd, J¼7.9, 0.5 Hz, 1H, H-7), 7.46e7.41 (m, 2H, H-2, and H-8),
7.17 (dd, J¼7.9, 0.5 Hz, 1H, H-9), 4.33 (s, 3H, NeCH3); dC (CDCl3):
156.4, 156.0, 136.8, 131.7, 130.9, 130.5, 129.4, 129.0, 126.7, 122.1,
121.4, 121.0, 120.4, 116.1, 114.1, 33.1; HRMS (ESI) for C16H12ClN2
[MþH]þ: calcd: 267.0684, found: 267.0681.
4.5. Synthesis of 5-methyl-5H-indolo[2,3-b]quinolines (1 and
3aec)
A flame dried round-bottomed flask was charged with cold
aniline (11 or 7aec) (5.0 mmol) under Ar atmosphere. The flask
was placed in an acetone/ice bath at ꢁ10 ꢀC and magnetically
stirred for 15 min. Then, 3-bromo-2-chloro-1-methylquinolinium
trifluoromethanesulfonate (10) (1.0 mmol, 0.407 g) was added in
small portions (an exothermic reaction occurred and an orange-
red precipitate was formed) to the vigorously stirred aniline. When
addition was completed, cold anhydrous THF (2.5 mL) was added,
the acetone/ice bath was removed and the resulting mixture was
stirred for 6 h at room temperature under Ar atmosphere. Sub-
sequently, DBU (2 mmol, 0.3 mL) was added and the reaction
mixture was stirred for another 30 min. In another round-bot-
tomed flask, PdCl2(PPh3)2 (0.0175 g, 2.5 mol % or 0.0070 g, 1 mol %)
and NaOAc$3H2O (0.204 g, 1.5 mmol) were weighed. Then, DMA
(5 mL) was added and the mixture was stirred for 5 min under Ar
atmosphere. The catalyst solution was added to the amidine so-
lution and the flask was rinsed with DMA (5 mL). The resulting
mixture was magnetically stirred at 130 ꢀC for 17 h under Ar at-
mosphere. After cooling down, the solvent was removed under
reduced pressure and the residue was dried under vacuum. Sub-
sequently, the crude reaction mixture was extracted with 28e30%
NH4OH (30 mL) and dichloromethane (3ꢂ30 mL). The combined
organic phase was dried over MgSO4 and evaporated to dryness.
The crude product was further purified via flash column chroma-
tography on silica gel.
4.5.4. 7-Chloro-5-methyl-5H-indolo[2,3-b]quinoline (3c). Reagent:
2-chloroaniline (7c) (0.53 mL, 5 mmol). 1 mol % PdCl2(PPh3)2 was
used. Eluent: dichloromethane/(7 N) ammonia in methanol (99:1);
yield: 87%; orange solid; mp 234 ꢀC; dH (CDCl3): 9.10 (s, 1H, H-11),
8.20 (d, J¼7.9 Hz, 1H, H-1), 8.13 (d, J¼7.5 Hz, 1H, H-10), 8.06 (d,
J¼8.6 Hz, 1H, H-4), 7.91 (dd, J¼8.6, 7.1 Hz, 1H, H-3), 7.58e7.53 (m,
2H, H-2, and H-8), 7.18 (dd, J¼7.8, 7.5 Hz, 1H, H-9), 4.38 (s, 3H,
NeCH3); dC (CDCl3): 156.2, 151.9, 137.1, 130.8, 130.1, 129.3, 128.9,
127.9, 125.6, 122.3, 122.2, 120.8, 120.2, 119.3, 114.4, 33.3; HRMS (ESI)
for C16H12ClN2 [MþH]þ: calcd: 267.0684, found: 267.0679.
Acknowledgements
This work was financially supported by the University of Antwerp
(BOF), the Fund for Scientific Research-Flanders (FWO-Flanders), and
the Hercules foundation. The authors would like to thank Philippe
Franck, Heidi Seykens and Norbert Hancke for technical assistance.
According to this procedure, the following compounds were
prepared:
4.5.1. 5-Methyl-5H-indolo[2,3-b]quinoline (1). Reagent: aniline (11)
(0.46 mL, 5 mmol). 2.5 mol % PdCl2(PPh3)2 was used. Eluent:
dichloromethane/(7 N) ammonia in methanol (98:2); yield: 98%;
orange solid; the characterization data are identical to those
reported in literature.4
Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2010.10.077.
4.5.2. 9-Chloro-5-methyl-5H-indolo[2,3-b]quinoline (3a). Reagent:
4-chloroaniline (7a) (0.638 g, 5 mmol); solid 4-chloroaniline was
dissolved in anhydrous THF (0.5 mL); additional THF (2 mL instead
of 2.5 mL) was added; 1 mol % PdCl2(PPh3)2 was used. Eluent:
dichloromethane/(7 N) ammonia in methanol (99:1); yield: 98%;
orange solid; mp 227 ꢀC; dH (CDCl3): 8.37 (s, 1H, H-11), 7.91 (dd,
J¼8.0, 1.5 Hz, 1H, H-1), 7.87 (d, J¼2.2 Hz, 1H, H-10), 7.75 (ddd, J¼8.6,
7.0, 1.5 Hz,1H, H-3), 7.67 (d, J¼8.6 Hz, 1H, H-4), 7.58 (d, J¼8.5 Hz,1H,
H-7), 7.42 (dd, J¼8.0, 7.0 Hz, 1H, H-2), 7.41 (dd, J¼8.5, 2.2 Hz, 1H, H-
8), 4.27 (s, 3H, NeCH3); dC (CDCl3): 156.0, 153.4, 137.0, 130.8, 130.1,
129.1, 129.0, 126.9, 124.9, 124.9, 122.1, 120.7, 120.6, 118.4, 114.1, 33.0;
HRMS (ESI) for C16H12ClN2 [MþH]þ: calcd: 267.0684, found:
267.0685.
References and notes
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4.5.3. 8-Chloro-5-methyl-5H-indolo[2,3-b]quinoline (3b) and 10-
chloro-5-methyl-5H-indolo[2,3-b]quinoline (3d). Reagent: 3-chlor-
oaniline (7b) (0.53 mL, 5 mmol). 1 mol % PdCl2(PPh3)2 was used.
Eluent: dichloromethane/(7 N) ammonia in methanol (99:1); yield:
98%. The isomers were separated with an automated chromatog-
raphy system using Silica Flash Cartridges applying a heptane/ethyl
14. 3-Bromo-2-chloropyridine should work equally well.
15. Hostyn, S.; Maes, B. U. W.; Pieters, L.; Lemiere, G. L. F.; Matyus, P.; Hajos, G.;
ꢀ
ꢁ
ꢁ
Dommisse, R. A. Tetrahedron 2005, 61, 1571.