Synthesis of the benzo-β-carboline isoneocryptolepine: The missing indoloquinoline isomer in the alkaloid series cryptolepine, neocryptolepine and isocryptolepine

Article abstract of DOI:10.1016/j.tet.2004.11.073

7H-Indolo[2,3-c]quinoline has been synthesized in two steps via a new approach starting from commercially available 3-bromoquinoline and 2-bromoaniline. The new methodology consists of two consecutive palladium-catalyzed reactions: a selective Buchwald/Ha

Full text of DOI:10.1016/j.tet.2004.11.073

Tetrahedron 61 (2005) 1571–1577
Synthesis of the benzo-b-carboline isoneocryptolepine: the
missing indoloquinoline isomer in the alkaloid series cryptolepine,
neocryptolepine and isocryptolepine
b
a
c
Steven Hostyn,a Bert U. W. Maes,a, Luc Pieters, Guy L. F. Lemiere, Peter Matyus,
*
`
´
´
d
Gyorgy Hajos and Roger A. Dommisse
a
´
¨
aDepartment of Chemistry, University of Antwerp, Groenenborgerlaan 171, B-2020 Antwerp, Belgium
bDepartment of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium
c
˝
Department of Organic Chemistry, Semmelweis University, Hogyes E. u. 7, H-1092 Budapest, Hungary
dChemical Research Center, Institute of Chemistry, Hungarian Academy of Sciences, H-1525 Budapest, P.O. Box 17, Hungary
Received 5 August 2004; revised 15 November 2004; accepted 18 November 2004
Available online 15 December 2004
´ ´
Cordially dedicated to Professor Kalman Hideg on the occasion of his 70th birthday
Abstract—7H-Indolo[2,3-c]quinoline has been synthesized in two steps via a new approach starting from commercially available 3-
bromoquinoline and 2-bromoaniline. The new methodology consists of two consecutive palladium-catalyzed reactions: a selective
Buchwald/Hartwig amination followed by an intramolecular Heck-type reaction. Alternatively, the same skeleton has also been prepared via
the combination of a Suzuki arylation with an intramolecular nitrene insertion starting from 4-chloroquinoline and {2-[(2,2-
dimethylpropanoyl)amino]phenyl}boronic acid. Selective methylation of 7H-indolo[2,3-c]quinoline yielded 5-methyl-5H-indolo[2,3-
c]quinoline (Isoneocryptolepine) which is an interesting new lead compound in the search for new antiplasmodial drugs.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
Artemisia annua, respectively.2,3 In the last decade our
laboratories have been active in the field of antimalarial
natural products. In the Department of Pharmaceutical
Sciences of the University of Antwerp several alkaloids
have been isolated from the root of the West African plant
Cryptolepis sanguinolenta.4 In traditional folk medicine, a
decoction of the root of this plant is used to treat
fevers (including fever caused by malaria). Cryptolepine
(5-methyl-5H-indolo[3,2-b]quinoline) (1), neocryptolepine
(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 13 characterized
alkaloids (Fig. 1).4a,5 Chemically, these compounds are
isomeric indoloquinolines, but more importantly the two
linearly (1,2) as well as the angularly fused isomers (3)
possess an interesting antiplasmodial activity.4b,6 In
Antwerp and Budapest efficient synthetic strategies have
been developed for all three benzocarbolines based on
palladium-catalyzed reactions (Suzuki, Heck, Buchwald–
Hartwig).7–9 Interestingly, the benzo-b-carboline
(5-methyl-5H-indolo[2,3-c]quinoline, for which we have
adopted the name isoneocryptolepine) (4) (Fig. 1) has
hitherto never been found in nature. In order to be able to
study the antiplasmodial activity and cytotoxicity of this
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
disease. These shocking figures are estimations of the World
Health Organization (WHO) and put malaria besides
tuberculosis and AIDS on the top list of infection diseases
in the world.1 Although several drugs are available to treat
malaria, the increasing resistance of the parasite becomes
really problematic. Consequently, the development of new
and efficient drugs to treat and prevent malaria is of great
importance in order to stop the proliferation of Plasmodia.
Besides available synthetic drugs (e.g. chloroquine, halo-
fantrine and mefloquine) also nature has shown to be an
interesting source of antiplasmodial compounds. The best
known examples are of course quinine and artemisinine
isolated from Cinchona bark and the leafy portions of
Keywords: Palladium; Amination; Heck-type reaction; Suzuki; Nitrene
insertion; Malaria.
* Corresponding author. Tel.: C32 3 265 32 05; fax: C32 3 265 32 33;
e-mail: bert.maes@ua.ac.be
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.11.073

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S. Hostyn et al. / Tetrahedron 61 (2005) 1571–1577
Figure 1. Cryptolepine (1), neocryptolepine (2), isocryptolepine (3) and isoneocryptolepine (4).
isomer and to compare it with the three naturally occurring
ones we decided to develop an efficient synthetic route for
the 7H-indolo[2,3-c]quinoline skeleton of 5-methyl-5H-
indolo[2,3-c]quinoline.
yield was obtained (80%). The mechanism of this reaction
presumably occurs via the formation of a nitrene from the
azide which formally inserts into the C3–H bond.15,16
Interestingly, the intramolecular nitrene insertion is C-3
regioselective and only a trace amount of the C-5 ring
closed product (7H-pyrido[2,3,4-kl]acridine, 10)17 could be
observed in a chromatographic fraction during purification
of 9. This selectivity can be explained by taking into account
the kinetic preference for 5- versus 6-membered rings.18
2. Discussion
As a first approach towards the synthesis of the 7H-
indolo[2,3-c]quinoline skeleton we investigated the combi-
nation of a Suzuki arylation reaction with an intramolecular
nitrene insertion (Scheme 1). A similar approach has
already been used in our laboratories for the synthesis of
other indolo fused ring systems (11H-indolo[3,2-c]quino-
line,7a,7c 2,5-dihydro-1H-pyridazino(4,5-b(indol-1-one7c,10
and indolo[3,2-c]isoquinoline7c,11). Suzuki reaction of
commercially available 4-chloroquinoline12 (5) with {2-
[(2,2-dimethylpropanoyl)-amino]phenyl}boronic acid13
under Gronowitz conditions14 yielded 2,2-dimethyl-N-(2-
quinolin-4-ylphenyl)propanamide (6) in 96%. Acid
hydrolysis of the pivalamide in 20% aq H2SO4 gave
2-quinolin-4-ylaniline (7) in a moderate yield only (51%).
The reaction could be further optimized to 89% by using
40% aq H2SO4 in combination with ethanol as a co-solvent.
Subsequent diazotization of the amine 7 followed by
introduction of the azido group via an ArSN1 type reaction
on the diazonium salt gave 4-(2-azidophenyl)quinoline (8).
Finally, thermal decomposition of the azide in boiling
o-dichlorobenzene yielded the target indoloquinoline
skeleton 9 in 88%. When the lower boiling o-xylene was
used as solvent for the thermolysis of 8 a longer reaction
time (48 h instead of 3 h) was required and a slightly lower
Next, we investigated the synthesis of 7H-indolo[2,3-
c]quinoline via an alternative approach (Scheme 2) since
the ‘Suzuki—intramolecular nitrene insertion’ strategy is a
quite lengthy route (four steps) which does not allow an easy
introduction of substituents on the A and D ring. Recently,
our laboratories published two examples (11H-indolo[3,2-
c]quinoline7d and 2,5-dihydro-1H-pyridazino(4,5-b(indol-
1-one19) where indolo fused ring systems were prepared via
the combination of a selective Buchwald–Hartwig
amination with an intramolecular Heck-type reaction.
Commercially available 3-bromoquinoline and 2-bromo-
aniline seemed to be ideal starting materials for such a route
since 3-bromoquinolines substituted in the benzene ring are
easily accessible via regioselective C-3 bromination20 and
several substituted 2-bromoanilines can be obtained from
commercial sources. In this way easy A and D ring
functionalization can be obtained, respectively. First, we
investigated the Pd-catalyzed amination of 3-bromoquino-
line (11) with 2-bromoaniline using a Pd(0)/XANTPHOS
(9,9-dimethyl-4,5-bis(diphenylphosphino)-9H-xanthene)
catalyst.21 Interestingly, regioselective amination was
observed although each coupling partner contains an
Scheme 1. Synthesis of 7H-indolo[2,3-c]quinoline via a ‘Suzuki—intramolecular nitrene insertion’ approach.

S. Hostyn et al. / Tetrahedron 61 (2005) 1571–1577
1573
was obtained from the corresponding 3-aminoquinoline.
Dehydrogenation of the reaction product of the Fischer
indole synthesis (8,9,10,11-tetrahydro-7H-indolo[2,3-c]-
quinoline) also gave access to the 7H-indolo[2,3-c]quino-
line skeleton. Unfortunately, no experimental details and
yields have been reported for the latter route mentioned by
Clemo and Felton. More recently, Fan and Ablordeppey
reported a short route also based on 3-aminoquinoline.30
Phenylation of 3-aminoquinoline with triphenylbismuth
diacetate in the presence of metallic copper yielded
N-phenylquinolin-3-amine in 94% yield. Subsequent
oxidative cyclization with an excess of Pd(OAc)2 in
trifluoroacetic acid gave a mixture of quindoline (13)
(10H-indolo[3,2-b]quinoline) (23%) and 9 (50%). These
two indoloquinoline isomers result from a non-selective
palladation at C-2 and C-4 of the quinoline nucleus.
Interestingly, Fan and Ablordeppey were only interested
in the development of a new strategy for quindoline and the
major compound formed in the oxidative cyclization was
only an undesired side product. Unwittingly, they obtained a
concise synthesis for the indoloquinoline 9 with an overall
yield of 47%. Recently, Kannadasan and Srinivasan
published a new five step route towards 3,4-benzo-b-
carboline (9) starting from 2-methylindole. The obtained
overall yield of 9 is only 20%. The method used to build up
the tetracyclic skeleton is based on a radical cyclization of
N-(3-bromo-1-phenylsulfonylindol-2-ylmethyl)aniline.31
Scheme 2. Synthesis of 7H-indolo[2,3-c]quinoline via a ‘Buchwald–
Hartwig amination–intramolecular Heck type reaction’ approach.
unactivated C–Br bond. Clearly, the C–Br bond of
3-bromoquinoline is more reactive than the C–Br bond of
2-bromoaniline due to the amino substituent of the latter
which sterically and electronically deactivates the C2–Br
bond for oxidative addition. Subsequent Heck-type cycliza-
tion of N-(2-bromophenyl)quinolin-3-amine (12) gave
predominantly 7H-indolo[2,3-c]quinoline (9) and only a
small amount of the undesired regioisomer quindoline (13).
The mechanism of a Pd-catalyzed cyclodehydrohalogena-
tion involving C–H bond activation is often considered to
occur via the intramolecular electrophilic attack of the
oxidative addition complex on a p system.22 If one accepts
this model the preferential C4–H activation can be
explained by taking into account 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 density is larger
on C-4 than on C-2.23
Although our ‘Suzuki—intramolecular nitrene insertion’
consists of four steps, which is longer than the two step route
developed by Fan and Ablordeppey (overall yield: 47%) and
also longer than our ‘Buchwald–Hartwig—intramolecular
Heck-type reaction’ procedure (overall yield: 37%), it gives
access to the target skeleton in the highest overall yield
(75%) hitherto reported in the literature. Our ‘Buchwald–
Hartwig amination—intramolecular Heck type reaction’
strategy on the other hand has an equal number of steps and
a similar overall yield as the procedure of Fan and
Ablordeppey but uses substantially cheaper reagents.32 In
addition, in our Pd-catalyzed cyclodehydrohalogenation
23 mol% palladium is used whereas Fan and Ablordeppey’s
oxidative cyclization is not catalytic and requires 200 mol%
of palladium. Moreover, D ring substituted 7H-indolo[2,3-
c]quinolines will require substituted triphenylbismuth
diacetates which are not commercially available in contrast
to the 2-bromoanilines.
A literature search revealed that only a very limited number
of synthetic approaches for the 7H-indolo[2,3-c]quinoline
(9) ring system have been reported up to now. In 1928,
Kermack and Slater published a six step route with an
overall yield of less than 36%.24,25 In their route, the indole
ring was built up via a Fischer26 synthesis on 3-(2-
nitrophenyl)-2-(phenylhydrazono)propanoic acid. Sub-
sequent decarboxylation of the Fischer indole reaction
product 3-(2-nitrophenyl)-1H-indole-2-carboxylic acid fol-
lowed by reduction of the nitro group and formamide
formation, using formic acid, yielded 2-(1H-indol-3-yl)-
phenylformamide. Finally, the quinoline ring was obtained
via a Bischler–Napieralski27 type ring closure yielding the
desired 7H-indolo[2,3-c]quinoline. In 1951, Clemo and
Felton published a modified version of the method
developed by Kermack and Slater with an equal number
of synthetic steps but a better overall yield (!59%).28,29
Fischer synthesis was executed on ethyl 3-(2-nitrophenyl)-
2-(phenylhydrazono)propanoate instead of the free acid.
Reduction of the nitro group of ethyl 3-(2-nitrophenyl)-1H-
indole-2-carboxylate afforded a quinolin-2(1H)-one ring via
spontaneous lactamization. Subsequent chlorodehydroxyl-
ation and hydrodehalogenation gave 9. In the same paper,
another approach based on the Fischer synthesis on
cyclohexanone quinolin-3-ylhydrazone is also mentioned.
The required 3-hydrazinoquinoline for hydrazone synthesis
For the selective N-5 methylation of 7H-indolo[2,3-c]quino-
line (9) we first tried to use the conditions (CH3I, DMF,
80 8C; then aq Na2CO3) we previously reported for the
selective methylation of 6H-indolo[2,3-b]quinolines and
11H-indolo[3,2-c]quinoline.7d,33,34 However, under these
reaction conditions and after work-up with aqueous Na2CO3
and extraction with dichloromethane, MS-data of the
reaction mixture clearly revealed the formation of undesired
5,7-dimethyl-5H-indolo[3,2-b]quinolinium iodide. To
avoid this selectivity problem we decided to perform the
methylation in refluxing toluene (Scheme 3). In this way,
the formed isoneocryptolepinium hydroiodide immediately
precipitated and the formation of 7-methylisoneocrypto-
lepinium iodide (14) (Fig. 2) could be avoided. After
cooling down the reaction mixture to room temperature the
yellow precipitate was filtered off and subsequently it was

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S. Hostyn et al. / Tetrahedron 61 (2005) 1571–1577
Scheme 3. Selective N-5 methylation of 7H-indolo[2,3-c]quinoline.34
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 [MCH]C and [MCNH4]C
ions were used as lock mass for the measurement of the
accurate mass values of the samples. 4-Chloroquinoline
(Aldrich), 3-bromoquinoline (Acros), XANTPHOS
(Aldrich), Pd(PPh3)4 (Acros), PdCl2(PPh3)2 (Acros) 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 benzophenone) were used. Flash column
chromatography was performed on Kieselgel 60 (ROCC,
0.040–0.063 mm).
Figure 2. 7-Methylisoneocryptolepinium iodide (14).
purified by flash column chromatography on silicagel
yielding pure 4$HI in 88%. Finally, the desired free base
4 could be obtained via an acid–base reaction using
ammonia in water (28%–30%).35
3.1.1. 2,2-Dimethyl-N-(2-quinolin-4-ylphenyl)propana-
mide (6). 4-Chloroquinoline (5) (4.0 mmol, 0.654 g) was
dissolved in DME (24 mL). Pd(PPh3)4 (0.20 mmol, 0.24 g)
was added and the solution subsequently stirred for 10 min
under a N2 atmosphere. Next, {2-[(2,2-dimethylpropanoyl)-
amino]phenyl}boronic acid (5.0 mmol, 1.105 g) 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 8C) under an inert atmosphere (N2)
for 20 h. After cooling the reaction mixture to room
temperature, water (60 mL) was added and the reaction
mixture was extracted with dichloromethane (3!60 mL).
The combined organic phase was dried over MgSO4, filtered
and subsequently evaporated to dryness. Finally, the residue
was purified via column chromatography on silicagel using
dichloromethane/ethyl acetate (95/5) and dichloromethane/
ethyl acetate (9/1) as the eluent yielding the title compound
in 96%.
In conclusion, we have developed two new synthetic
strategies for the 7H-indolo[2,3-c]quinoline (9) skeleton.
Upon selective methylation of 9 the desired 5-methyl-5H-
indolo[2,3-c]quinoline (4) was obtained. Preliminary in
vitro screening results indicate that the selectivity index
(ratio antiplasmodial activity/cytotoxicity) of isoneocrypto-
lepine is superior to the reported indices of the three
naturally occurring isomeric methylated indoloquinolines
(1–3). Consequently, 4 can be regarded as an important new
lead compound for future research. A detailed description of
the antiplasmodial activity and cytotoxicity of 4 will be
published in a pharmaceutical journal in due course.
3. Experimental
3.1. General
All melting points were determined on a Bu¨chi apparatus
1
and are uncorrected The H- and 13C NMR spectra were
Yellow solid; mp 115 8C; dH (CDCl3): 9.02 (d, JZ4.4 Hz,
1H, H-200), 8.34 00(d, JZ8.4 Hz, 1H, H-60), 8.22 (d, JZ
8.4 Hz, 1H, H-8 ), 7.77 (ddd, JZ8.4, 6.7, 1.6 Hz, 1H,
H-700), 7.57 (dd, JZ8.6, 1.6 Hz, 1H, H-500), 7.52 (ddd, JZ
8.4,007.3, 1.7 Hz, 1H, H-50), 7.51 (dd, JZ8.6, 6.7 Hz, 1H,
H-6 ), 7.37 (d, 0 JZ4.4 Hz, 1H, H-300), 7.32 (dd, JZ8.0,
1.7 Hz, 1H, H-3 ), 7.28 (dd, JZ8.0, 7.3 Hz, 1H, H-40), 6.87
(brs, 1H, NH), 0.76 (s, 9H, CH3); dc (CDCl3): 176.3, 150.4,
148.6, 144.7, 135.5, 130.3, 130.0, 129.8, 129.7, 128.3,
127.5, 126.5, 125.6, 124.5, 122.2, 122.0, 39.5, 27.0; HRMS
(ESI) for C20H21N2O [MCH]C: calcd: 305.1654, found:
305.1650.
recorded on a Varian Unity 400 spectrometer in the solvent
indicated with TMS as the internal standard. All coupling
constants are given in Hertz and chemical shifts are given in
ppm. For mass-spectrometric analysis, samples were
dissolved in CH3OH containing 0.1% formic acid and
diluted to a concentration of approximately 10K5 mol/L.
1 mL injections were directed to the mass spectrometer at a
flow rate of 5 mL/min CH3OH (0.1% formic acid), using a
CapLC HPLC system (Waters, Millford). Accurate mass
data were acquired on a quadrupole-time-of-flight mass
spectrometer (Q-Tof-II, Micromass, Manchester, UK)
equipped with a standard electrospray ionisation (ESI)
interface. Cone voltage (approx. 35 V) and capillary voltage
(approx. 3.3 kV) were optimised on one compound and used
for all others. For the determination of the high-resolution
m/z-values of the molecular ion [MCH]C, a solution of
3.1.2. 2-Quinolin-4-ylaniline (7). 2,2-Dimethyl-N-(2-
quinolin-4-ylphenyl)propanamide (6) (2.0 mmol, 0.609 g)
was dissolved in ethanol (150 mL). Next, aq H2SO4 (40%,
150 mL) was added dropwise. The obtained mixture was

S. Hostyn et al. / Tetrahedron 61 (2005) 1571–1577
1575
stirred and refluxed in an oil bath (oil bath temperature:
130 8C) 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 chloroform (3!100 mL). The organic phase
was dried over MgSO4, filtered and evaporated to dryness.
Finally, the residue was purified via column chromato-
graphy on silicagel using dichloromethane/ethyl acetate
(1/1) as the eluent yielding the title compound in 89%.
keeping the temperature below 3 8C. Next, the mixture
was stirred for another 1 h at 0 8C. The reaction mixture was
neutralized with saturated aq Na2CO3 while keeping the
temperature below 3 8C and subsequently extracted with
EtOAc (5!100 mL). The combined organic phases were
dried over MgSO4, filtered and the solvent removed under
reduced pressure. The residue was dissolved in 150 mL
o-dichlorobenzene and flushed with Ar. The mixture was
stirred and heated in an oil bath at 180 8C for 3 h under Ar
atmosphere. After cooling down to room temperature, the
solvent was removed under reduced pressure. Finally, the
obtained residue was purified via column chromatography
on silicagel using ethyl acetate/methanol (95/5) as the eluent
yielding the title compound 9 in 88%.
Pale brown solid; mp 119 8C; dH (CDCl3): 8.98 (d, JZ
4.4 Hz, 1H, H-20), 8.18 (d, JZ8.3 Hz, 1H, H-80), 7.74 (ddd,
JZ8.3, 6.8, 1.4 Hz, 1H, H-70), 7.71 (dd, JZ8.5, 1.4 Hz, 1H,
H-50), 7.50 (dd, JZ8.5, 6.8 Hz, 1H, H-60), 7.39 (d, JZ
4.4 Hz, 1H, H-30), 7.30 (ddd, JZ8.1, 7.4, 1.6 Hz, 1H, H-5),
7.14 (dd, JZ6.8, 1.6 Hz, 1H, H-3), 6.90 (ddd, JZ7.4, 6.8,
1.1 Hz, 1H, H-4), 6.85 (dd, JZ8.1, 1.1 Hz, 1H, H-6), 3.50
(brs, 2H, NH2); dc (CDCl3): 150.5, 148.8, 146.1, 143.9,
130.6, 130.0, 129.7, 129.6, 127.0, 126.8, 126.1, 123.1,
122.2, 118.5, 115.7; HRMS (ESI) for C15H13N2 [MCH]C:
calcd: 221.1079, found: 221.1086.
Only a trace amount of the C-5 ring closed product (7H-
pyrido[2,3,4-kl]acridine, 10) could be observed in a
chromatographic fraction during purification of 9.
Compound 10. dH (400 MHz, DMSO-d6): 10.58 (brs, 1H,
NH), 8.49 (d, JZ5.0 Hz, 1H), 7.98 (dd, JZ7.8, 1.3 Hz, 1H),
7.44 (t, JZ8.2 Hz, 1H), 7.41 (d, JZ5.0 Hz, 1H), 7.40 (ddd,
JZ7.7, 7.0, 1.3 Hz, 1H), 7.09 (dd, JZ8.2, 0.9 Hz, 1H), 7.03
(dd, JZ8.2, 0.9 Hz, 1H), 6.98 (ddd, JZ7.8, 7.0, 1.0 Hz,
1H), 6.65 (dd, JZ7.7, 1 Hz, 1H).36
3.1.3. N-(2-Bromophenyl)quinolin-3-amine (12). A
round-bottomed flask was charged with Pd2(dba)3 (0.069 g,
0.075 mmol, 2.5 mol%) and XANTPHOS (9,9-dimethyl-
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 (11) (0.624 g, 3 mmol), 2-bromoaniline
(0.619 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 (oil
bath temperature: 110 8C) for 30 h under magnetic stirring.
After cooling down to room temperature dichloromethane
(25 mL) was added and the suspension filtered over a path
of celite and rinsed with dichloromethane (75 mL). The
solvent was removed under reduced pressure and the residue
purified by column chromatography on silicagel using
dichloromethane as the eluent yielding the title compound
in 83%.
Method B. A round-bottomed flask was charged with
Pd(PPh3)2Cl2 (0.097 g, 0.138 mmol, 23 mol%), N-(2-
bromophenyl)quinolin-3-amine (12) (0.180 g, 0.6 mmol),
NaOAc$3H2O (0.200 g, 1.47 mmol) followed by dimethyl
acetamide (DMA) (10 mL). The mixture was flushed with
Ar for 5 min and then stirred at 130 8C under Ar atmosphere
for 48 h. Subsequently, the mixture was evaporated to
dryness in vacuo and the residue was filtered over celite
using dichloromethane/methanol (95/5) (300 mL). The
filtrate was evaporated to dryness and the residue dissolved
in dichloromethane (100 mL). The organic phase was
extracted with 0.6 M HCl (10!50 mL) and the aqueous
phase was subsequently washed with toluene (3!100 mL).
Next, 10 M NaOH (30 mL) was added to the aqueous phase
until the colour changed from yellow to white. The water
phase was extracted with dichloromethane (3!100 mL).
The organic phase was dried over MgSO4, filtered and
evaporated to dryness. Finally, the residue was purified via
column chromatography on silicagel using dichloro-
methane/methanol (97/3) as the eluent yielding the title
compound (9) in 45%. The fractions with Rf value between
0.35 and 0.58 contained quindoline (13), starting material
(12) and N-phenylquinolin-3-amine (dehalogenated starting
material). Evaporation of these fractions, followed by a
second column on silicagel using dichloromethane/ethyl
acetate (95/5) as the eluent yielded a mixture of 12 (2%) and
13 (4%). Calculation of the yield of 13 was done based on
White solid; mp 109 8C; dH (CDCl3): 8.78 (d, JZ2.7 Hz,
1H, H-2), 8.05 (d, JZ8.4 Hz, 1H, H-8), 7.79 (d, JZ2.7 Hz,
1H, H-4), 7.68 (dd, JZ8.0, 1.2 Hz, 1H, H-30), 7.59 (dd, JZ
8.1, 1.5 Hz, 1H, H-5), 7.58 (ddd, JZ8.4, 6.9, 1.5 Hz, 1H,
H-7), 7.50 (dd, JZ8.1, 6.9 Hz, 1H, H-6), 7.32 (dd, JZ8.03,
1.6 Hz, 1H, H-60), 7.23 (ddd, JZ8.3, 7.0, 1.2 Hz, 1H, H-5 ),
6.85 (ddd, JZ8.0, 7.0, 1.6 Hz, 1H, H-40), 6.27 (brs, 1H,
NH); dc (CDCl3): 146.2, 144.6, 140.5, 135.6, 133.4, 129.3,
128.7, 128.4, 127.4, 127.3, 126.7, 122.4, 120.9, 116.7,
113.3; HRMS (ESI) for C15H12BrN2 [MCH]C: calcd:
299.0184, found: 299.0192.
1
the H NMR spectrum of the mixture of 12 and 13. The
obtained NMR data of 13 were identical with those reported
3.1.4. 7H-Indolo[2,3-c]quinoline (9). Method A. 2-Quino-
lin-4-ylaniline (7) (4.0 mmol, 0.881 g) was dissolved in aq
HCl (37%, 35 mL) and the mixture cooled to 0 8C using an
ice bath. Subsequently, ice cooled aq NaNO2 (0.4 M,
22 mL) was added dropwise keeping the temperature below
3 8C. The mixture was stirred for 1.5 h at 0 8C. Ice cooled aq
NaN3/NaOAc solution (8.46 mmol NaN3 and 56 mmol
NaOAc$3H2O in 20 mL water) was added dropwise
in the literature.7b,8
For the work-up of the reaction mixture an alternative
approach can be used yielding the title compound in
essentially the same yield.
The mixture was evaporated to dryness in vacuo. The
obtained residue was taken up in some dichloromethane/

1576
S. Hostyn et al. / Tetrahedron 61 (2005) 1571–1577
methanol (95/5) and filtered over celite (using the same
solvent combination (total volume: 300 mL)) and the filtrate
subsequently evaporated to dryness in vacuo. Amberlyst 15
(1.2 g resin washed with 30 mL dichloromethane) was
added to the residue (for the complete transfer 60 mL
dichloromethane was used to rinse). The resulting mixture
was stirred for 16 h. Next, the dichloromethane was
decanted. Subsequently, the amberlyst was washed with
dichloromethane (3!60 mL), toluene (3!60 mL) and
diethyl ether (60 mL). 7 N NH3 in MeOH (60 mL) was
added to the amberlyst and the mixture was stirred for 1 h.
The amberlyst was filtered over a glass filter and then rinsed
with 7 N NH3 in MeOH (1!60 mL) and MeOH (1!
60 mL). Next, the filtrate was concentrated to dryness in
vacuo. Finally, the residue was purified via column
chromatography on silicagel using dichloromethane/
methanol (97/3) as the eluent yielding the title compound
(9).
(C-8), 118.6 (C-4), 118.5 (C-10), 44.0 (CH3); HRMS (ESI)
for C16H13N2 [MCH]C: calcd: 233.1079, found: 233.1069.
Acknowledgements
Steven Hostyn thanks the IWT-Vlaanderen (‘Instituut voor
de Aanmoediging van Innovatie door Wetenschap en
Technologie in Vlaanderen’) for a scholarship. Professor
Dr. B. Maes is indebted to the foundation ‘Rosa Blanckaert’
for a research grant. The authors acknowledge the financial
support of the University of Antwerp (Concerted Action of
the Special Fund for Research of the University of Antwerp
and RAFO RUCA), ETT 121/2003, OTKA T047328, COST
B16 and QLK2-CT-2002-90436 (‘Center of Excellence in
Biomolecular Chemistry’ project funded by the European
Union) and the technical assistance of J. Aerts, G.
Rombouts, J. Schrooten, W. Van Dongen, W. Van Lierde
and J. Verreydt. We would like to thank Balazs Balogh for
the PM3 calculations and Professor Dr. E. Esmans and
Compound 9. White solid; mpO240 8C (decomp.); dH
(DMSO-d6): 12.15 (brs, 1H, NH), 9.29 (s, 1H, H-6), 8.80
(dd, JZ8.2, 1.3 Hz, 1H, H-4), 8.67 (d, JZ8.1 Hz, 1H,
H-11), 8.19 (dd, JZ8.2, 1.1 Hz, 1H, H-1), 7.70 (dd, JZ8.2
1.1 Hz, 1H, H-8), 7.76 (ddd, JZ8.2, 7.1, 1.1 Hz, 1H, H-3),
7.67 (ddd, JZ8.2, 7.1, 1.3 Hz, 1H, H-2), 7.60 (dd, JZ8.3,
7.1 Hz, 1H, H-9), 7.40 (ddd, JZ8.1, 7.1, 1.1 Hz, 1H, H-10);
dc (DMSO-d6): 142.1, 139.4, 138.7, 132.6, 129.9, 126.9,
126.6, 125.1, 124.2, 123.2, 122.8, 121.2, 120.2, 119.3,
112.6; HRMS (ESI) for C15H11N2 [MCH]C: calcd:
219.0922, found: 219.0929.
`
Professor Dr. F. Lemiere for HRMS measurements.
References and notes
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int/en/
2. Meshnick, S. R.; Taylor, T. E.; Kamchonwongpaisan, S.
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3.1.5. Isoneocryptolepine (5-methyl-5H-indolo[2,3-c]-
quinoline) (4). In a round-bottomed flask 7H-indolo[2,3-
c]quinoline (9) (0.109 g, 0.5 mmol), toluene (7.5 mL) and
CH3I (3 mL) were heated at reflux under N2 atmosphere (oil
bath temperature: 120 8C) 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
solvent subsequently evaporated to dryness under reduced
pressure. The crude product was purified via column
chromatography on silica gel (eluent: chloroform/methanol
(9/1)) (the residue was brought on column as a suspension in
a minimal amount of acetonitrile) giving isoneocryptolepine
hydroiodide (4$HI) as a yellow solid in 88% yield. To
obtain the free base, 4$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 subsequently extracted with dichloromethane (2!
100 mL). The combined organic phase was dried over
MgSO4, filtered and evaporated to dryness to quantitatively
yield 4 as a red solid.
3. Kumar, A.; Katiyar, S. B.; Agarwal, A.; Chauhan, P. M. S.
Curr. Med. Chem. 2003, 10, 1137–1150.
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Cimanga, K.; de Bruyne, T.; Pieters, L.; Vlietinck, A.; Turger,
C. A. J. Nat. Prod. 1997, 60, 688–691.
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´ ´
´
7. (a) Timari, G.; Soos, T.; Hajos, G. Synlett 1997, 1067–1068.
´
For the synthesis of quindoline see: (b) Csanyi, D.; Timari, G.;
´
´
Hajos, G. Synth. Commun. 1999, 29, 3959–3969. (c) Hajos, G.;
´
´ ´ `
Riedl, Z.; Timari, G.; Matyus, P.; Maes, B. U. W.; Lemiere,
G. L. F. Molecules 2003, 8, 480–487. (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.
8. Quindoline can be selectively methylated at N-5 yielding
cryptolepine: Ho, T. L.; Jou, D. G. Helv. Chim. Acta 2002, 85,
3823–3827.
mpO220 8C (decomp.); dH (DMSO-d6): 9.55 (s, 1H, H-6),
8.91 (dd, JZ8.3, 1.3 Hz, 1H, H-1), 8.61 (brd, JZ8.4 Hz,
1H, H-11), 8.28 (dd, JZ8.6, 1.0 Hz, 1H, H-4), 7.85 (ddd,
JZ8.3, 7.0, 1.0 Hz, 1H, H-2), 7.81 (brd, JZ8.4 Hz, 1H,
H-8), 7.71 (ddd, JZ8.6, 7.0, 1.3 Hz, 1H, H-3), 7.45 (ddd,
JZ8.4, 6.6, 1.1 Hz, 1H, H-9), 7.18 (ddd, JZ8.4, 6.6,
1.0 Hz, 1H, H-10), 4.57 (s, 3 H, NCH3); dc (DMSO-d6):
156.7 (C-7a), 141.2 (C-6), 141.1 (C-6a), 130.2 (C-4a), 127.2
(C-2), 126.4 (C-9), 125.1 (C-3), 125.0 (C-11c), 124.2
(C-11b), 123.8 (C-1), 123.4 (C-11), 122.1 (C-11a), 120.2
9. The ‘Suzuki—intramolecular nitrene insertion’ and ‘Buchwald–
Hartwig—intramolecular Heck-type reaction’ are alternatives
´
for the ‘Suzuki—SNAr’ approach, reported by Queguiner and
co-workers, for the synthesis of carbolines: (a) Godard, A.;
´ ´ ´
Marsais, F.; Ple, N.; Trecourt, F.; Turck, A.; Queguiner, G.
Heterocycles 1995, 40, 1055–1091. (b) Rocca, P.; Marsais, F.;
´
Godard, A.; Queguiner, G. Tetrahedron 1993, 49, 49–64. (c)

S. Hostyn et al. / Tetrahedron 61 (2005) 1571–1577
1577
´
´
¨
Arzel, E.; Rocca, P.; Grellier, P.; Labaeıd, M.; Frappier, F.;
´ ´
Gueritte, F.; Gaspard, C.; Marsais, F.; Godard, A.; Queguiner,
211–241. (b) Echavarren, A. M.; Gomez-Lor, B.; Gonzalez,
´
J. J.; de Frutos, O. Synlett 2003, 585–597.
G. J. Med. Chem. 2001, 44, 949–960.
´ ´
10. (a) Krajsovszky, G.; Matyus, P.; Riedl, Z.; Csanyi, D.; Hajos,
23. Calculations at PM3 level on 12 indicated that C-4 has always
a larger electron density than C-2 independent of which low
energy conformer we used for calculations. When the dihedral
angle between C-4–C-3 (of the quinoline) and N (aniline)
–C-10 (phenyl) is 126.278 the most stable conformer is
obtained (EZ83.468 kcal/mol). In this case, the charge for
C-2 is 0.214 and for C-4 K0.121.
´
´
G. Heterocycles 2001, 55, 1105–1111. (b) Tapolcsanyi, P.;
´ ´ ´
Krajsovszky, G.; Ando, R.; Lipcsey, P.; Horvath, G.; Matyus,
´ `
P.; Riedl, Z.; Hajos, G.; Maes, B. U. W.; Lemiere, G. L. F.
Tetrahedron 2002, 58, 10137–10143.
´
11. Beres, M.; Timari, G.; Hajos, G. Tetrahedron Lett. 2002, 43,
´
´
6035–6038.
24. Kermack, W. O.; Slater, R. H. J. Chem. Soc. 1928, 32–45.
25. For two of the six reaction steps the obtained reaction product
was not completely pure. Therefore only a maximum overall
yield (36%) could be calculated using the reported maximum
yield for these steps (see Ref. 24).
12. To the best of our knowledge hitherto only one Suzuki
arylation on 4-chloroquinoline has been described in the
literature. For the Suzuki reaction of 4-chloroquinoline with
phenylboronic acid under standard reaction conditions
(Pd(PPh3)4, benzene/ethanol, 2 M Na2CO3) see: (a) Ali,
N. M.; McKillop, A.; Mitchell, M. B.; Rebelo, R. A.;
Wallbank, P. J. Tetrahedron 1992, 48, 8117–8126. For a
recent review which contains a chapter on Suzuki arylation
reactions on haloquinolines see: (b) Ahmad, N. M.; Li, J. J.
Adv. Heterocycl. Chem. 2003, 84, 1–30.
26. (a) Fischer, E.; Jourdan, F. Ber. 1883, 16, 2241. (b) Fischer, E.;
Hess, O. Ber. 1884, 17, 559.
27. Bischler, A.; Napieralski, B. Ber. 1893, 26, 1903.
28. (a) Clemo, G. R.; Felton, D. G. I. J. Chem. Soc. 1951, 671–677.
For the synthesis of ethyl 3-(2-nitrophenyl)-2-(phenyl-
hydrazono)propanoate see: (b) Wislicenus, W.; Thoma, E. J.
Liebigs Ann. Chem. 1924, 436, 42–69.
13. For the synthesis of {2-[(2,2-dimethylpropanoyl)amino]-
phenyl}boronic acid, see Ref. 9b.
29. For one of the six reaction steps the obtained yield was not
mentioned. Therefore only a maximum overall yield (59%)
could be calculated based on the 5 reported yields (see
Ref. 28).
14. (a) Gronowitz, S.; Bobosik, V.; Lawitz, K. Chem. Scr. 1984,
23, 120–122. (b) Martin, A. R.; Yang, Y. H. Acta Chem.
Scand. 1993, 47, 221–230.
15. Moody, C. J.; Whitham, G. H. Reactive Intermediates; Oxford
University Press: New York, 1992.
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1789–1794.
16. Lindley, J. M.; McRobbie, I. M.; Meth-Cohn, O.; Suschitzky,
H. J. Chem. Soc., Perkin Trans. 1 1977, 2194–2204.
17. For the synthesis of 7H-pyrido[2,3,4-kl]acridines starting from
31. Kannadasan, S.; Srinivasan, P. C. Synth. Commun. 2004, 34,
1325–1335.
32. Calculated on the basis of the price of the minimum amount of
product available at Aldrich 1 mol costs: 3-bromoquinoline:
V 456; 3-aminoquinoline: V 1459; 2-bromoaniline: V 248;
triphenylbismuth diacetate: V 15691.
33. Jonckers, T. H. M.; Van Miert, S.; Cimanga, K.; Bailly, C.;
`
Colson, P.; de Pauw, M.-C.; Lemiere, F.; Esmans, E. L.;
4-chloro-5-nitroquinolines via
a ‘Suzuki—intramolecular
nitrene insertion’ see: Ali, N. M.; Chattopadhyay, S. K.;
McKillop, A.; Perret-Gentil, R. M.; Ozturk, T.; Rebelo, R. A.
J. Chem. Soc., Chem. Commun. 1992, 1453–1454.
18. Ciufolini, M. A.; Byrne, N. E. J. Am. Chem. Soc. 1991, 113,
8016–8024.
`
Rozenski, J.; Quirijnen, L.; Maes, L.; Dommisse, R.; Lemiere,
G. L. F.; Vlietinck, A.; Pieters, L. J. Med. Chem. 2002, 45,
3497–3508.
´
19. (a) Dajka-Halasz, B.; Monsieurs, K.; Elias, O.; Karolyhazy, L.;
´
´ ´
Tapolcsanyi, P.; Maes, B. U. W.; Riedl, Z.; Hajos, G.;
´
´
´
` ˇ
Dommisse, R. A.; Lemiere, G. L. F.; Kosmrlj, J.; Matyus, P.
´
34. In 1928, the methylation of 7H-indolo[2,3-c]quinoline (9) with
methyl sulphate has been investigated by Kermack and Slater:
Kermack, W. O.; Slater, R. H. J. Chem. Soc. 1928, 789–797.
Elemental analysis on the reaction product indeed proved the
introduction of a methyl group in the reaction product but no
evidence for N-5 methylation of 9 could be given.
35. Selective N-5 methylation of 9 could be proven by the
observation of a 3J long range coupling in the HMBC-
spectrum between the hydrogens of the methyl group and C-4a
and C-6.
´
Tetrahedron 2004, 60, 2283–2291. (b) 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.
20. 3-Bromoquinolines substituted in the benzene ring can be
easily obtained via selective C-3 bromination of the corre-
´
sponding substituted quinolines: (a) Trecourt, F.; Mongin, F.;
´
Mallet, M.; Queguiner, G. Synth. Commun. 1995, 25,
4011–4024. (b) Butler, J. L.; Gordon, M. J. Heterocycl.
Chem. 1975, 12, 1015–1020. (c) Kress, T. J.; Costantino, S. M.
J. Heterocycl. Chem. 1973, 10, 409–410.
1
36. Based on this H NMR spectrum we can not conclude which
tautomer is obtained (3H-pyrido[2,3,4-kl]acridine or 7H-
pyrido[2,3,4-kl]acridine). We did not use any additional
NMR-techniques to try to find out which tautomer we prepared
since only one chromatographic fraction contained the
pyridoacridine skeleton mixed with 9. Based on PM3
calculations 7H-pyrido[2,3,4-kl]acridine is the most stable
tautomer.
21. For the amination of 2-chloroquinoline using
a
Pd(0)/XANTPHOS catalyst see: (a) Yin, J. J.; Zhao, M. M.;
Huffman, M. A.; McNamara, J. M. Org. Lett. 2002, 4,
3481–3484.(b) For the amination of 4-chloroquinoline using a
Pd(0)/XANTPHOS catalyst see: Ref. 7d.
22. (a) Miura, M.; Nomura, M. Top. Curr. Chem. 2002, 219,