A concise synthesis of indoloquinoline skeletons applying two consecutive Pd-catalyzed reactions

Article abstract of DOI:10.1016/j.tet.2013.08.019

The indoloquinoline alkaloids cryptolepine (1), neocryptolepine (2), isocryptolepine (3), and isoneocryptolepine (4) are important tools in traditional medicine. Now, their precursors 1a-4a were synthesized in two steps starting from the corresponding bromo-iodoquinolines. Our strategy is based on palladium-catalyzed reactions, applying regioselective Buchwald-Hartwig amination on 2,3- and 3,4-dihaloquinolines followed by an intramolecular Heck-type reaction. Both steps were carried out under microwave irradiation.

Full text of DOI:10.1016/j.tet.2013.08.019

Tetrahedron 69 (2013) 9512e9519
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A concise synthesis of indoloquinoline skeletons applying two
consecutive Pd-catalyzed reactions
a
,
b
,
a,
*
*
ꢀ
ꢀ
ꢀ ꢀ
Borbala Boganyi
, Judit Kaman
ꢀ
a
ꢀ
BioBlocks Magyarorszag Kft., Berlini ut 47-49, Budapest 1045, Hungary
b
€
€
ꢀ
Institute of Chemistry, Eotvos Lorand University, Budapest, Hungary
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 24 April 2013
Received in revised form 31 July 2013
Accepted 12 August 2013
Available online 3 September 2013
The indoloquinoline alkaloids cryptolepine (1), neocryptolepine (2), isocryptolepine (3), and iso-
neocryptolepine (4) are important tools in traditional medicine. Now, their precursors 1ae4a were
synthesized in two steps starting from the corresponding bromo-iodoquinolines. Our strategy is based
on palladium-catalyzed reactions, applying regioselective BuchwaldeHartwig amination on 2,3- and 3,4-
dihaloquinolines followed by an intramolecular Heck-type reaction. Both steps were carried out under
microwave irradiation.
Keywords:
Crown Copyright Ó 2013 Published by Elsevier Ltd. All rights reserved.
Indoloquinoline
Dihaloquinoline
BuchwaldeHartwig amination
Heck-type reaction
Regioselectivity
Microwave
1. Introduction
indolo[2,3-c]quinoline) (4), has never been found in nature; how-
ever, two research groups have described its synthesis and bi-
Quinolines and related heterocyclic skeletons are important
target molecules in pharmaceutical chemistry since they occur in
numerous biologically active natural products.1 During the last few
decades the family of indoloquinoline alkaloids has attracted con-
siderable attention due to their broad spectrum of biological ac-
tivities.2 Cryptolepine (5-methyl-5H-indolo[3,2-b]quinoline) (1),
neocryptolepine (cryptotackieine, 5-methyl-5H-indolo[2,3-b]quin-
oline) (2) and isocryptolepine (cryptosanguinolentine, 5-methyl-
5H-indolo[3,2-c]quinoline) (3) have been isolated from Cryptolepis
sanguinolenta; the decoction of this plant has been used in tradi-
tional medicine against malaria, jaundice, hypertension, hepatitis,
and inflammation in West and Central Africa.3 The wide range of
interesting pharmacological properties is continually growing as
these compounds exhibit strong antiplasmodial activity and behave
as DNA intercalating agents, thereby inhibiting DNA replication,
transcription, and topoisomerase activities.4 Therefore these mol-
ecules are promising anticancer agents in modern health care, as
well. The fourth isomer, i.e., isoneocryptolepine (5-methyl-5H-
ological importance.5e7
Since properties of indoloquinolines represent an extensively
investigated topic in organic chemistry, several routes have been
developed for their synthesis.8e14 In recent years organometallic
catalysis has become a common tool to synthesize the target pre-
cursors 1ae4a mentioned above; however, regioselectivity
remained one of the main problems to be solved.5e7,15,16 Mohan et al.
has published a two-step route for the preparation of the four
scaffolds 1ae4a, however in the case of the reaction of
3-bromoquinoline with aniline, the resulting intermediate using
‘heteroatom directed photoannulation technique’ gave both linear
and angular products, i.e.,1a and 4a, respectively.7 Ablordeppey et al.
also reported on a palladium-catalyzed intramolecular arylation re-
action starting from 3-aminoquinoline, which afforded the mixture
of 1a and 4a.15 Maes et al. described a ‘Suzuki-intramolecular nitrene
insertion’ four-step approach starting from 4-chloroquinoline and
a ‘BuchwaldeHartwig amination-intramolecular Heck-type reaction’
approach from 3-bromoquinoline in two steps; in both cases a small
amount of the undesired regioisomer was also detected after the ring
closure.5,6 Ila et al. also published a palladium-catalyzed Buch-
waldeHartwig aryl-amination methodology, where not only the
targeted benzo[4,5]imidazo[1,2-a]quinoline but also a significant
amount of 2a was formed as a by-product during the intramolecular
cyclization step16 (Fig. 1).
* Corresponding authors. Tel.: þ36 1 231 2039; fax: þ36 1 231 0655; e-mail
ꢀ
addresses: borcsiboganyi@gmail.com (B. Boganyi), juditkaman@bioblocks.hu
ꢀ
ꢀ
(J. Kaman).
0040-4020/$ e see front matter Crown Copyright Ó 2013 Published by Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.08.019

ꢀ
ꢀ ꢀ
B. Boganyi, J. Kaman / Tetrahedron 69 (2013) 9512e9519
9513
9
10
11
10
9
9
8
10
1
4
11
N10
1
11
11N
8
2
3
8
1
4
2
3
9
1
4
7
N7
2
3
7
2
3
N 5
8
N6
N5
6
4
6
N5
6
CH3
7
N5
CH3
CH3
CH3
4
1
2
3
9
10
11
10
9
1
11
10
9
11
HN
8
H
N10
1
11
2
8
8
9
1
2
1
3
7
NH
2
7
8
N5
7
2
3
3
4
N
N5
3
6
6
4
7
H6
6
N5
4
N5
4a
4
1a
2a
3a
Fig. 1.
2. Results and discussion
carbonate afforded 3-bromo-1H-quinolin-2-one (15).23 Sub-
sequently, chlorination and Cl/I displacement as mentioned above
for the sequence 10e11e12 generated the desired 3-bromo-2-
iodoquinoline (17) with excellent yield (97%).
Our work focused on the synthetic challenge to identify
regioselective pathway towards the synthesis of benzo-
a
a
,
b
,
g
,
d
-carbolines 1ae4a involving Pd-catalyzed reactions.
The synthesis of 2-bromo-3-iodoquinoline (21) started with
a halogen-exchange reaction to give 3-iodoquinoline (18) from
3-bromoquinoline (13).24 The N-oxide derivative of 18 and its
rearrangement were both carried out similarly to the preparation of
15, with the difference that 3-chloroperoxybenzoic acid was used
instead of Oxone in the oxidation step. Finally, bromination of the
obtained 20 was performed by application of the same method as
in the case of 8, 9. The desired compound 21 was obtained in good
yield (74%) (Scheme 2).
To achieve our aim we synthesized the requisite dihaloquinolines,
i.e., bromoiodoquinolines 9, 12, 17, 21. To our best knowledge, only
the preparation of 3-bromo-2-iodoquinoline (17) is known in the
literature17 but the syntheses of the other three regioisomers have
never been described. On the route to 9 and 12 first the key in-
termediate 1H-quinolin-4-one (7) was prepared by condensation of
aniline (5) with Meldrum’s acid in the presence of trimethyl ortho-
formate, followed by thermolysis in diphenyl ether18 (Scheme 1).
O
Br
N
I
I
d
(87%)
O
O
N
H
O
NH2
O
c
O
8
9
a
b
(91%)
(92%)
(77%)
HN
e
O
Cl
N
I
N
H
Br
Br
Br
f
g
(99%)
(93%)
(55%)
5
6
7
N
H
N
10
11
12
(a) Meldrum's acid, trimethyl ortoformate, reflux; (b) diphenyl ether, 250 oC; (c) NIS, DMF, RT;
(d) POBr3, DMF, 70 oC; (e) Br2, AcOH, reflux; (f) POCl3, MeCN, reflux; (g) NaI, MeCN, reflux
Scheme 1.
The direct halogenation of 7 with N-iodosuccinimide19 and with
bromine,20 respectively, resulted in 3-iodo-1H-quinolin-4-one (8)
and 3-bromo-1H-quinolin-4-one (10). Treatment of 8 with phos-
phorus oxybromide gave the desired isomer 9 in high yield. The
synthesis of 12 was carried out in two steps: the 3-bromoquinolin-4-
one 10 was converted to 3-bromo-4-chloroquinoline (11), and finally
Cl/I displacement afforded the desired compound 1221,22 (Scheme 1).
The syntheses of 3-bromo-2-iodoquinoline (17) and 2-bromo-3-
iodoquinolne (21) started from the readily available
3-bromoquinoline (13) (Scheme 2). In the first step towards the
formation of 3-bromo-2-iodoquinoline (17) 3-bromoquinoline (13)
was transformed into its N-oxide derivative with Oxone. Rear-
rangement of 14 in the presence of benzoyl chloride and potassium
Next, the targeted benzocarbolines 1ae4a were prepared from
the above dihaloquinolines 9, 12, 17, 21 by following a two-step
strategy based on a BuchwaldeHartwig amination as a first step
followed by an intramolecular Heck-type reaction to execute the
ring closure. By using the above bromo-iodoquinolines high
regioselectivity was achieved that was one of the main goals of our
work.
Based upon our earlier investigations on BuchwaldeHartwig
reactions on 3,4-dihaloquinolines with aminoheteroarenes,25 here
anilines were used as amine reactants. 4-Bromo-3-iodoquinoline
(9) was chosen as a representative substrate for the amination
step. As a first approach we applied an established protocol
(Pd(OAc)2, Xantphos, Cs2CO3 in toluene at reflux) with the

ꢀ
ꢀ ꢀ
9514
B. Boganyi, J. Kaman / Tetrahedron 69 (2013) 9512e9519
Br
Br
Br
Cl
Br
I
b
c
d
89%
N+
O -
71%
97%
N
H
O
a
N
N
Br
96%
e
14
15
16
17
N
99%
I
13
I
I
I
f
g
h
N+
O -
75%
74%
89%
N
H
O
N
N
Br
18
19
20
21
(a) MeOH, Oxone, H2O, 50 oC; (b) CH2Cl2, benzoyl chloride, K2CO3-solution, RT; (c) POCl3, MeCN, reflux;
(d) NaI, MeCN, reflux; (e) N,N-dimethylethylene diamine, CuI, NaI, 1,4-dioxane, 100 oC; (f) m-CPBA,
CH2Cl2, RT; (g) CH2Cl2, benzoyl chloride, K2CO3-solution, RT; (h) POBr3, toluene, reflux
Scheme 2.
modification employing microwave irradiation was employed with
shorter reaction time instead of conventional heating.25 In some
preliminary optimization studies the effects of solvents (toluene,
1,4-dioxane, and 1,2-dimethoxyethane), ligands (Xantphos, Binap),
and temperatures (100 ꢀC, 120 ꢀC) were investigated. Then, the four
available dihaloquinolines 9, 12, 17, 21 were coupled with aniline
according to the optimized protocol (toluene, Pd(OAc)2, Xantphos,
and Cs2CO3, microwave irradiation at 120 ꢀC for 90 min) to yield the
key intermediates 22e25 required for the preparation of the de-
sired indoloquinoline skeletons 1ae4a (Schemes 3 and 4). The
yields, along with those of the subsequent cyclizations, are sum-
marized in Table 2.
instead of Na2CO3 the desired indoloquinoline became the main
component of the reaction mixture (entry 5). The best results were
obtained with the system PdCl2(PPh3)2/NaOAc in DMA at 150 ꢀC5,6
where conversion became complete (entry 6).
The indoloquinoline precursors 1ae4a were then synthesized
under the above optimal conditions, with good yields received
(58e64%) (Table 2).
The efficacy of the microwave irradiation under the optimized
conditions was compared to that of the traditional oil bath heating
on the representative substrates
9 and 22 in the Buch-
waldeHartwig amination and Heck-type reaction, as well. Micro-
wave irradiation was found to result in higher conversion in both
Br
b
NH
NH
58%
N
x1
N
N
22
a
4a
x2
70%
c
HN
95%
9 X1=Br, X2=I
12 X1=I, X2=Br
HN
d
Br
64%
N
N
23
3a
(a) aniline, Pd(OAc)2, Xantphos, Cs2CO3, toluene, 120 oC, Mw; (b) PdCl2(PPh3)2, NaOAc, DMA, 150 oC, Mw;
(c) aniline, Pd(OAc)2, Xantphos, Cs2CO3, toluene, 120 oC, Mw; (d) PdCl2(PPh3)2, NaOAc, DMA, 150 oC, Mw,
Scheme 3.
Next, cyclization to the indoloquinoline skeletons 1ae4a was
reactions (100% vs 80% in the amination while 100% vs 30% in the
cyclization).
In view of these results we extended our study to substituted
performed in an intramolecular Heck-type reaction under micro-
wave irradiation. The influence of various parameters, such as
solvent (acetonitrile, 1,4-dioxane, DMF, DMA), base (sodium car-
bonate, sodium acetate), catalyst (Pd(OAc)2, PdCl2(PPh3)2), and
temperature was studied by starting from 4-bromo-(3-
phenylamino)quinoline (22) as a representative substrate. The
anilines, too (Scheme 5). It was found that anilines with electron
withdrawing substituents (4-nitroaniline (26a), 4-fluoroaniline
(26b)) needed longer reaction times to achieve good yields both in
the BuchwaldeHartwig amination and Heck-type reaction (Table 3,
entries 1, 2). Faster conversion was detected in the amination
reaction with an aniline bearing an electron donating substituent
(4-methoxyaniline (26c)) (Table 3, entry 3) compared to the reaction
with aniline (Table 2, entry 1). However, for the subsequent ring
closure the same reaction time was needed (Table 2, entry 1).
26
use of Pd(OAc)2 with Na2CO3 in DMF, 1,4-dioxane or acetonitrile
at 100e150 ꢀC (Table 1, entries 1, 2, 3) resulted in low conversions
and at 100 ꢀC a small amount of a debrominated anilinoquinoline
was also detected in the reaction mixture. The same system in DMA
worked better (entry 4) and upon using the weaker base NaOAc

ꢀ
ꢀ ꢀ
B. Boganyi, J. Kaman / Tetrahedron 69 (2013) 9512e9519
9515
Br
b
a
60%
N
N
N
H
N
H
x1
x2
N
N
78%
c
24
2a
N
H
N
H
N
70%
17 X1=Br, X2=I
21 X1=I, X2=Br
d
61%
Br
25
1a
(a) aniline, Pd(OAc)2, Xantphos, Cs2CO3, toluene, 120 oC, Mw; (b) PdCl2(PPh3)2, NaOAc, DMA, 150 oC, Mw;
(c) aniline, Pd(OAc)2, Xantphos, Cs2CO3, toluene, 120 oC, Mw; (d) PdCl2(PPh3)2, NaOAc, DMA, 150 oC, Mw
Scheme 4.
Table 1
Reaction conditions and yields in the Heck-type reaction on 4-bromo-(3-
phenylamino)quinoline (22) under microwave irradiation
Entry
Catalyst
Base
Solvent
T (ꢀC)
22:4aa
3. Conclusion
1
2
3
4
5
6
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2(PPh3)2
Na2CO3
Na2CO3
Na2CO3
Na2CO3
NaOAc
NaOAc
DMF
150
100
150
150
150
150
6:1
1,4-Dioxane
Acetonitrile
DMA
DMA
DMA
90:1
15:1
4:1
2:3
0:1
The synthesis of three hitherto unknown bromo-iodoquinoline
regioisomers 9, 12, 21, has been described. A regioselective two-
step strategy based on palladium chemistry was developed
for the preparation of the four indoloquinoline precursors
1ae4a of cryptolepine, neocryptolepine, isocryptolepine, and iso-
a
Ratio was determined by LCMS analysis.
neocryptolepine. The first step is
a
regioselective Buch-
waldeHartwig amination starting from 2,3- and 3,4-substituted
dihaloquinolines, followed by an intramolecular Heck-type reaction
to produce the ring-closed indoloquinoline scaffolds. The palla-
dium-catalyzed reactions were carried out under microwave irra-
diation ensuring both higher reaction rates and product yields
compared to oil-bath heating in the case of compound 9 and 22
(Table 2 entry 1). In summary, a concise and regioselective pro-
Table 2
Reaction conditions and yields in the regioselective BuchwaldeHartwig amination
on dihaloquinolines (9, 12, 17, 21) and subsequent Heck-type reaction on the ob-
tained phenylaminoquinolines (22e25) under microwave irradiation
Entry Dihaloquinolinea Yield (%) Phenylamino
intermediateb
Yield (%) Indolo-
quinoline
1
2
3
4
9
12
17
21
70
95
78
70
22
23
24
25
58
64
60
61
4a
3a
2a
1a
cedure was elaborated for the synthesis of benzo-a,b,g,d-carbolines
1ae4a.
a
BuchwaldeHartwig amination: t¼90 min, T¼120 ꢀC.
Heck-type reaction: t¼60 min, T¼150 ꢀC.
b
R
R
Br
I
a
b
Br
NH
a: 84%
b: 70%
c: 53%
a: 76%
b: 60%
c: 65%
NH
N
N
N
27a-c
9
28a-c
a: R=NO2
b: R=F
c: R=OCH3
(a) 26a-c, Pd(OAc)2, Xantphos, Cs2CO3, toluene, 120 oC, Mw;
(b) PdCl2(PPh3)2, NaOAc, DMA, 150 oC, Mw
Scheme 5.
Table 3
Reaction conditions and yields in the regioselective BuchwaldeHartwig amination on 4-bromo-3-iodoquinoline (9) with substituted anilines 26aec and Heck-type reaction on
the obtained phenylaminoquinolines 27aec under microwave irradiation
Entry
ReC6H4NH2
t (min)
T (ꢀC)
Yield (%)
Phenylamino intermediate
t (min)
T (ꢀC)
Yield (%)
Indolo-quinoline
1
2
3
26a
26b
26c
180
180
60
130
130
120
76
60
65
27a
27b
27c
120
120
60
150
150
150
84
70
53
28a
28b
28c

ꢀ
ꢀ ꢀ
9516
B. Boganyi, J. Kaman / Tetrahedron 69 (2013) 9512e9519
4. Experimental section
(100 mL). The precipitate was filtered off, washed with water, and
dried in vacuo. The title compound was obtained as a beige solid
4.1. General
(16.92 g, 91%), mp 296e298 ꢀC (lit.,29 mp 296e299 ꢀC); 1H NMR
(DMSO-d6, 400 MHz)
d
12.18 (br s, 1H), 8.50 (d, 1H, J¼6.4), 8.11 (d,
€
All melting points were measured on a Buchi-540 apparatus and
are uncorrected. 1H NMR and 13C NMR spectra were recorded on
a Bruker Avance II 400 MHz instrument using CDCl3 or DMSO-d6 as
the solvent and TMS as the internal standard. Chemical shift values
1H, J¼8.0 Hz), 7.72e7.65 (m, 1H), 7.59 (d, 1H, J¼8.0 Hz), 7.42e7.35
(m, 1H); 13C NMR (DMSO-d6, 400 MHz)
d 172.9, 144.5, 139.3, 131.8,
125.3, 124.0, 122.3, 118.3, 80.5; C9H6INO (271.06); LCMS (ESIþ) m/z
272 [MþH]þ. Anal. Calcd for C9H6INO (271.06) C, 39.88; H, 2.23; N,
5.17. Found: C, 39.73; H, 2.22; N, 5.18.
are reported in d (parts per million), all coupling constants (J values)
are given in Hertz. Multiplicity is indicated using the following
abbreviations: br for broad, d for doublet, t for triplet, m for mul-
tiplet, s for singlet. LCMS analyses were performed on an in-
strument consisting of an Agilent 1200 liquid chromatograph and
an Agilent 6140 Simple Quadrupole mass spectrometer using
electrospray ionization (ESI) technique. Elemental analyses were
carried out on a VARIO EL III instrument. Reactions were monitored
by LCMS and/or TLC on silica gel plates (Type 60 F254, Merck) and
the spots were detected by exposure to a UV-lamp at 254/366 nm
for a few seconds. Column chromatography was performed on silica
gel (230e400 mesh). Certain reactions were carried out in a Biotage
Initiator EXP EU microwave oven. All materials were purchased
from Aldrich except 3-bromoquinoline, which was ordered from
Alfa Aesar. All the solvents were of the highest analytical grade.
4.3.2. 4-Bromo-3-iodoquinoline (9). To a stirred solution of 3-iodo-
1H-quinolin-4-one (8) (8.00 g, 29.51 mmol) in DMF (80 mL)
phosphorus oxybromide (10.15 g, 35.42 mmol) was added por-
tionwise at 0e10 ꢀC. The reaction mixture was stirred at 70 ꢀC for
3 h. After completion of the reaction the mixture was poured on
crushed ice (200 mL) and the pH was adjusted to 9 with potassium
carbonate solution (10%, 50 mL). The resulting precipitate was fil-
tered off, washed with water, and dried in vacuo. The title com-
pound was obtained as a brown solid (8.62 g, 87%), mp 109e111 ꢀC;
1H NMR (CDCl3, 400 MHz)
d
9.08 (s, 1H), 8.26 (dd, 1H, J¼0.8, 8.4 Hz),
8.07 (d, 1H, J¼8.4 Hz), 7.80e7.73 (m, 1H), 7.65e7.59 (m, 1H); 13C
NMR (CDCl3, 400 MHz)
d 156.3, 147.0, 140.4, 130.5, 129.9, 129.5,
128.9, 128.2, 99.3; C9H5BrIN (333.96); LCMS (ESIþ) m/z 334, 336
[MþH]þ. Anal. Calcd for C9H5BrIN (333.96) C, 32.37; H, 1.51; N, 4.19.
Found: C, 32.25; H, 1.51; N, 4.20.
4.2. 1H-Quinolin-4-one (7)
4.2.1. 5-Anilinomethylene-2,2-dimethyl-1,3-dioxane-4,6-dione (6). A
stirred mixture of Meldrum’s acid (51.07 g, 0.35 mol) and trimethyl
orthoformate (150.69 g, 1.42 mol) was refluxed for 30 min. Then
aniline (30.00 g, 0.32 mol) was added dropwise at the same tem-
perature, and the solution was stirred for 40 min. After cooling to
room temperature the resulting precipitate was filtered off, washed
with n-hexane, and dried in vacuo. The title compound was ob-
tained as an orange solid (61.71 g, 77%), mp 155e157 ꢀC (lit.,27 mp
4.4. 3-Bromo-4-iodoquinoline (12)
4.4.1. 3-Bromo-1H-quinolin-4-one (10). The stirred solution of 1H-
quinolin-4-one (7) (15.00 g, 0.10 mol) in acetic acid (90 mL) was
refluxed for 10 min and bromine (16.51 g, 0.10 mol) was added
dropwise at the same temperature. The reaction mixture was stir-
red for 2 h, then it was allowed to cool to room temperature. The
resulting suspension was poured on crushed ice (340 mL) and di-
luted further with sodium thiosulfate solution (1 N, 50 mL). The
resulting precipitate was filtered off, washed with water and dried
in vacuo. The title compound was obtained as a beige solid (22.94 g,
99%), mp 199e201 ꢀC (lit.,30 mp 278e279 ꢀC); 1H NMR (DMSO-d6,
156e157 ꢀC); 1H NMR (DMSO-d6, 400 MHz)
d
11.25 (d, 1H, J¼14 Hz),
8.58 (d, 1H, J¼14.4 Hz), 7.56 (d, 2H, J¼7.6 Hz), 7.47e7.40 (m, 2H),
7.27 (t, 1H, J¼7.2 Hz), 1.68 (s, 6H); 13C NMR (DMSO-d6, 400 MHz)
d
163.8, 162.6, 153.1, 138.4, 129.5, 126.2, 118.9, 104.0, 86.5, 26.4;
C13H13NO4 (247.25); LCMS (ESIþ) m/z 246 [MꢁH]ꢁ. Anal. Calcd for
C13H13NO4 (247.25) C, 63.15; H, 5.30; N, 5.66. Found: C, 62.93; H,
5.28; N, 5.70.
400 MHz)
d
12.27 (br s, 1H), 8.47 (d, 1H, J¼6.4 Hz), 8.14 (dd, 1H,
J¼0.8, 8.0 Hz), 7.72e7.66 (m, 1H), 7.60 (d, 1H, J¼8.0 Hz), 7.42e7.36
(m, 1H); 13C NMR (DMSO-d6, 400 MHz)
d 171.2, 140.0, 139.1, 131.8,
125.1, 124.1, 123.9, 118.4, 104.0; C9H6BrNO (224.06); LCMS (ESIþ) m/
z 224, 226 [MþH]þ. Anal. Calcd for C9H6BrNO (224.06) C, 48.25; H,
2.70; N, 6.25. Found: C, 48.08; H, 2.69; N, 6.27.
4.2.2. 1H-Quinolin-4-one (7). Diphenylether (140 mL) was heated
to 250 ꢀC and stirred vigorously under nitrogen atmosphere. 5-
Anilinomethylene-2,2-dimethyl-1,3-dioxane-4,6-dione
(6)
(26.30 g, 0.11 mol) was added portionwise at the same temperature,
and the reaction mixture was stirred for 30 min. The resulting so-
lution was allowed to cool to 70 ꢀC and diluted with n-hexane
(200 mL). The precipitate was filtered off, washed with n-hexane,
and dried in vacuo. The title compound was obtained as a brown
solid (14.26 g, 92%), mp 200e202 ꢀC (lit.,28 mp 199e203 ꢀC); 1H
4.4.2. 3-Bromo-4-chloroquinoline (11). To a stirred suspension of 3-
bromo-1H-quinolin-4-one (10) (22.44 g, 0.10 mol) in acetonitrile
(100 mL) phosphorus oxychloride (18.43 g, 0.12 mol) was added
dropwise at room temperature. The reaction mixture was refluxed
for 7 h. After cooling to room temperature it was poured on crushed
ice (400 mL) and the pH was adjusted to 9 with potassium car-
bonate solution (10%, 220 mL). The resulting precipitate was fil-
tered off, washed with water, and dried in vacuo. The title
compound was obtained as a brown solid (22.58 g, 93%), mp
182e188 ꢀC (lit.,31 mp 69e69,5 ꢀC); 1H NMR (DMSO-d6, 400 MHz)
NMR (DMSO-d6, 400 MHz)
d
11.72 (br s, 1H), 8.08 (dd, 1H, J¼0.8,
8.0 Hz), 7.88 (d, 1H, J¼7.2 Hz), 7.66e7.60 (m, 1H), 7.53 (d, 1H,
J¼8.4 Hz), 7.34e7.27 (m, 1H), 6.02 (d, 1H, J¼7.6 Hz); 13C NMR
(DMSO-d6, 400 MHz)
d 176.7, 139.8, 139.2, 131.5, 125.7, 124.8, 122.9,
118.1, 108.6; C9H7NO (145.16); LCMS (ESIþ) m/z 146 [MþH]þ. Anal.
Calcd for C9H7NO (145.16) C, 74.47; H, 4.86; N, 9.65. Found: C, 74.19;
H, 4.84; N, 9.68.
d
9.08 (s, 1H), 8.25 (dd, 1H, J¼0.8, 8.4 Hz), 8.12 (d, 1H, J¼8.0 Hz),
7.95e7.89 (m, 1H), 7.86e7.80 (m, 1H); 13C NMR (DMSO-d6,
400 MHz)
d 151.6, 146.5, 140.2, 130.9, 129.5, 129.2, 126.4, 124.0,
117.7; C9H5BrClN (242.50); LCMS (ESIþ) m/z 242, 244 [MþH]þ. Anal.
Calcd for C9H5BrClN (242.50) C, 44.58; H, 2.08; N, 5.78. Found: C,
44.43; H, 2.09; N, 5.79.
4.3. 4-Bromo-3-iodoquinoline (9)
4.3.1. 3-Iodo-1H-quinolin-4-one (8). To
a stirred solution of
1H-quinolin-4-one (7) (10.00 g, 68.89 mmol) in DMF (100 mL)
N-iodosuccinimide (16.74 g, 74.40 mmol) was added portionwise at
room temperature. The reaction mixture was stirred for 3 h. The
solvent was evaporated and the residue was boiled in water
4.4.3. 3-Bromo-4-iodoquinoline (12). To a stirred solution of
3-bromo-4-chloroquinoline (11) (10.00 g, 41.24 mmol) in
dichloromethane (50 mL) HCl/diethyl ether (1 M, 40 mL) was added
below 5 ꢀC and stirred for 60 min, while the reaction mixture was

ꢀ
ꢀ ꢀ
B. Boganyi, J. Kaman / Tetrahedron 69 (2013) 9512e9519
9517
allowed to warm to room temperature. The resulting white pre-
cipitate was filtered off, washed with diethyl ether and dried in
vacuo (10.18 g, 88%). The obtained HCl salt was used in crude form
without further purification.
8.03 (d, 1H, J¼8.0 Hz), 7.98 (d, 1H, J¼8.8 Hz), 7.90e7.84 (m, 1H),
7.74e7.69 (m, 1H); 13C NMR (DMSO-d6, 400 MHz)
148.1, 145.4,
142.1, 131.3, 128.1, 127.8, 127.6, 127.2, 115.6; C9H5BrClN (242.50);
LCMS (ESIþ) m/z 242, 244 [MþH]þ; Anal. Calcd for C9H5BrClN
(242.50) C, 44.58; H, 2.08; N, 5.78. Found: C, 44.46; H, 2.07; N, 5.79.
d
The stirred suspension of 3-bromo-4-chloroquinoline hydro-
chloride (10.18 g, 36.49 mmol) and sodium iodide (27.35 g,
182.44 mmol) in acetonitrile (130 mL) was refluxed for 5 h. The
solvent was evaporated off, the residue was dissolved in dichloro-
methane (200 mL), and the solution was washed with potassium
carbonate solution (10%, 100 mL) and water (100 mL). The organic
layer was dried over Na2SO4, filtered, and evaporated to dryness.
The crude product was purified by column chromatography using
dichloromethane/ethyl acetate (100/0.5) as eluent. The title com-
pound was obtained as an off-white solid (7.79 g, 55%), mp
4.5.4. 3-Bromo-2-iodoquinoline (17). To
a stirred solution of
3-bromo-2-chloroquinoline (16) (3.95 g, 16.29 mmol) in dichloro-
methane (20 mL) HCl/diethyl ether (15 mL) was added below 5 ꢀC
and stirred for 60 min, while the reaction mixture was allowed to
warm to room temperature. The resulting white precipitate was
filtered off, washed with diethyl ether and dried in vacuo (3.80 g,
83%). The obtained HCl salt was used in crude form without further
purification.
The stirred suspension of 3-bromo-2-chloroquinoline hydro-
chloride (3.80 g, 13.62 mmol) and sodium iodide (10.21 g,
68.10 mmol) in acetonitrile (50 mL) was refluxed for 5 h. The sol-
vent was evaporated off, the residue was dissolved in dichloro-
methane (80 mL) and the solution was washed with potassium
carbonate solution (10%, 40 mL) and water (40 mL). After concen-
tration the crude product was recrystallized from isopropyl alcohol.
The title compound was obtained as a white solid (4.24 g, 97%), mp
119e121 ꢀC (lit.,35 mp 120e122 ꢀC); 1H NMR (DMSO-d6, 400 MHz)
148e149 ꢀC; 1H NMR (CDCl3, 400 MHz)
J¼0.8, 8.4 Hz), 8.03 (d, 1H, J¼8.0 Hz), 7.77e7.71 (m, 1H), 7.65e7.59
d
8.84 (s, 1H), 8.12 (dd, 1H,
(m, 1H); 13C NMR (CDCl3, 400 MHz)
d 150.3, 145.5, 133.1, 132.4,
130.2, 130.0, 129.3, 127.6, 118.1; C9H5BrIN (333.96); LCMS (ESIþ) m/z
334, 336 [MþH]þ. Anal. Calcd for C9H5BrIN (333.96) C, 32.37; H,
1.51; N, 4.19. Found: C, 32.27; H, 1.51; N, 4.20.
4.5. 3-Bromo-2-iodoquinoline (17)
4.5.1. 3-Bromoquinoline-1-oxide (14). To
a
stirred solution of
d
8.75 (s, 1H), 7.98 (d, 2H, J¼8.4 Hz), 7.86e7.80 (m, 1H), 7.72e7.67
3-bromoquinoline (13) (8.50 g, 40.85 mmol) in methanol (100 mL)
was added a solution of Oxone (25.14 g, 4.81 mmol) in water
(250 mL). The reaction mixture was stirred at 50 ꢀC for 3 h. The
resulting suspension was filtered, the filter cake was washed with
methanol, and the filtrate was evaporated to dryness. The residue
was dissolved in dichloromethane (170 mL) and washed with water
(80 mL). The organic layer was dried over Na2SO4, filtered, and
evaporated to dryness. The title compound was obtained as an off-
white solid (8.81 g, 96%), mp 97e99 ꢀC (lit.,32 mp 95e97 ꢀC); 1H
(m, 1H); 13C NMR (DMSO-d6, 400 MHz)
d 146.6, 138.5, 130.9, 128.1,
127.8, 127.6, 127.4, 125.5, 124.3; C9H5BrIN (333.96); LCMS (ESIþ) m/z
334, 336 [MþH]þ. Anal. Calcd for C9H5BrIN (333.96) C, 32.37; H,
1.51; N, 4.19. Found: C, 32.29; H, 1.51; N, 4.18.
4.6. 2-Bromo-3-iodoquinoline (21)
4.6.1. 3-Iodoquinoline (18). 3-Bromoquinoline (13) (8.50 g,
40.85 mmol), N,N-dimethylethylenediamine (720 mg, 8.17 mmol),
copper(I) iodide (389 mg, 2.04 mmol), and sodium iodide (12.25 g,
81.71 mmol) in 1,4-dioxane (30 mL) were stirred under argon at
100 ꢀC for 8 h. The reaction mixture was allowed to cool to room
temperature, diluted with dichloromethane (40 mL), and washed
with ammonia solution (25 mL) and water (25 mL). The organic
layer was dried over Na2SO4, filtered, and evaporated to dryness.
The title compound was obtained as a yellow solid (10.30 g, 99%),
mp 56e58 ꢀC (lit.,36 mp 58e59 ꢀC); 1H NMR (CDCl3, 400 MHz)
NMR (CDCl3, 400 MHz)
d
8.67 (d, 1H, J¼8.8 Hz), 8.62 (s, 1H), 7.89 (s,
1H), 7.82e7.71 (m, 2H), 7.70e7.63 (m, 1H); 13C NMR (CDCl3,
400 MHz) d 140.6, 137.1, 130.4, 130.3, 129.8, 127.5, 127.3, 119.9, 114.4;
C9H6BrNO (224.06); LCMS (ESIþ) m/z 224, 226 [MþH]þ. Anal.
Calcd for C9H6BrNO (224.06) C, 47.82; H, 3.57; N, 6.20. Found: C,
47.98; H, 3.56; N, 6.18.
4.5.2. 3-Bromo-1H-quinolin-2-one (15). To a stirred solution of
3-bromoquinoline-1-oxide (14) (6.69 g, 29.88 mmol) in dichloro-
methane (80 mL), benzoyl chloride (5.04 g, 35.86 mmol), and po-
tassium carbonate solution (10%, 80 mL) were added at 0e10 ꢀC.
The resulting two phase system was stirred vigorously at room
temperature for 3 h. After completion of the reaction the resulting
precipitate was filtered off and washed with dichloromethane. The
title compound was obtained as an off-white solid (4.76 g, 71%), mp
261e264 ꢀC (lit.,33 mp 265e269 ꢀC); 1H NMR (DMSO-d6, 400 MHz)
d
9.04 (br s, 1H), 8.54 (d, 1H, J¼1.6 Hz) 8.06 (d, 1H, J¼8.4 Hz),
7.77e7.69 (m, 2H), 7.59e7.54 (m, 1H); 13C NMR (CDCl3, 400 MHz)
d
155.6, 146.4, 143.7, 130.0, 129.9, 129.5, 127.4, 126.8, 89.8; C9H6IN
(255.06); LCMS (ESIþ) m/z 256 [MþH]þ. Anal. Calcd for C9H6IN
(255.06) C, 42.38; H, 2.37; N, 5.49. Found: C, 42.25; H, 2.36; N, 5.51.
4.6.2. 3-Iodoquinoline-1-oxide (19). To
a stirred solution of
3-iodoquinoline (18) (5.87 g, 23.01 mmol) in dichloromethane
(100 mL) 3-chloroperoxybenzoic acid (10.32 g, 46.03 mmol) was
added portionwise at room temperature. The reaction mixture was
stirred at the same temperature overnight. The resulting suspen-
sion was filtered, the filtrate was washed with sodium bicarbonate
solution (10%, 30 mL) and water (30 mL). The organic layer was
dried over Na2SO4, filtered, and evaporated to dryness. The residue
was purified by column chromatography using dichloromethane/
ethyl acetate (9/1) as eluent. The title compound was obtained as an
off-white solid (4.67 g, 75%), mp 137e140 ꢀC; 1H NMR (CDCl3,
d
12.24 (br s, 1H), 8.50 (s, 1H), 7.67 (dd, 1H, J¼0.8, 8.0 Hz), 7.58e7.50
(m, 1H), 7.33 (d, 1H, J¼8.4 Hz), 7.26e7.18 (m, 1H); 13C NMR (DMSO-
d6, 400 MHz)
d 157.5, 141.6, 138.0, 130.6, 127.2, 122.2, 119.3, 116.9,
115.1; C9H6BrNO (224.06); LCMS (ESIþ) m/z 224, 226 [MþH]þ. Anal.
Calcd for C9H6BrNO (224.06) C, 48.25; H, 2.70; N, 6.25. Found: C,
48.09; H, 2.69; N, 6.26.
4.5.3. 3-Bromo-2-chloroquinoline (16). To a stirred suspension of
3-bromo-1H-quinolin-2-one (15) (4.16 g, 18.57 mmol) in acetoni-
trile (30 mL) phosphorus oxychloride (3.42 g, 22.28 mmol) was
added dropwise at room temperature. The reaction mixture was
refluxed for 3 h. After cooling to room temperature it was poured
on crushed ice (70 mL) and the pH was adjusted to 9 with potas-
sium carbonate solution (10%, 40 mL). The resulting precipitate was
filtered off, washed with water and dried in vacuo. The title com-
pound was obtained as a white solid (4.00 g, 89%), mp 101e103 ꢀC
400 MHz)
d
8.76 (d, 1H, J¼1.2 Hz), 8.67 (d, 1H, J¼8.8 Hz), 8.10 (s, 1H),
7.80e7.72 (m, 2H), 7.68e7.62 (m, 1H); 13C NMR (CDCl3, 400 MHz)
d
141.2, 140.8, 134.1, 131.0, 130.7, 129.6, 127.0, 119.9, 84.1; C9H6INO
(271.06); LCMS (ESIþ) m/z 272 [MþH]þ. Anal. Calcd for C9H6INO
(271.06) C, 39.59; H, 2.95; N, 5.13. Found: C, 39.72; H, 2.96; N, 5.15.
4.6.3. 3-Iodo-1H-quinolin-2-one (20). To
3-iodoquinoline-1-oxide (19) (4.56 g, 16.82 mmol) in
a stirred solution of
(lit.,34 mp 96e98 ꢀC); 1H NMR (DMSO-d6, 400 MHz)
d 8.95 (s, 1H),

ꢀ
ꢀ ꢀ
9518
B. Boganyi, J. Kaman / Tetrahedron 69 (2013) 9512e9519
dichloromethane (50 mL) benzoyl chloride (2.84 g, 20.18 mmol)
and potassium carbonate solution (10%, 50 mL) were added at
0e10 ꢀC. The resulting two phase system was stirred vigorously at
room temperature overnight. The resulting precipitate was filtered
off and washed with dichloromethane. The title compound was
obtained as an off-white solid (2.03 g, 89%), mp 256e258 ꢀC; 1H
NMR (DMSO-d6, 400 MHz)
J¼7.6 Hz), 7.77 (d, 1H, J¼8.0 Hz), 7.67e7.59 (m, 2H), 7.39e7.32 (m,
3H), 7.09e7.03 (m, 1H); 13C NMR (DMSO-d6, 400 MHz)
149.5,
145.2, 140.1, 139.9, 130.0, 128.2, 126.7, 126.0, 124.6, 123.5, 122.4,
120.6, 107.7; C15H11BrN2 (299.17); LCMS (ESIþ) m/z 299, 301
[MþH]þ. Anal. Calcd for C15H11BrN2 (299.17) C, 60.22; H, 3.71; N,
9.36. Found: C, 60.13; H, 3.70; N, 9.38.
d 8.59 (s, 1H), 8.36 (br s, 1H), 7.91 (d, 2H,
d
NMR (DMSO-d6, 400 MHz)
d 12.09 (br s,1H), 8.70 (s,1H), 7.64 (d,1H,
J¼7.6 Hz), 7.56e7.50 (m, 1H), 7.31 (d, 1H, J¼8.4 Hz), 7.22e7.16 (m,
1H); 13C NMR (DMSO-d6, 400 MHz)
d
158.7, 148.7, 138.7, 130.7,
4.7.4. 2-Bromo-(3-phenylamino)quinoline (25). Prepared from 21.
126.9, 122.0, 120.2, 115.1, 95.7; C9H6INO (271.06); LCMS (ESIþ) m/z
272 [MþH]þ. Anal. Calcd for C9H6INO (271.06) C, 39.88; H, 2.23; N,
5.17. Found: C, 39.74; H, 2.24; N, 5.18.
Eluent: hexane/ethyl acetate (95/5). Yellow oil (126 mg, 70%), 1H
NMR (CDCl3, 400 MHz)
7.60e7.55 (m, 1H), 7.52e7.38 (m, 4H), 7.28 (s, 1H), 7.18e7.12 (m, 1H),
6.32 (br s, 1H); 13C NMR (CDCl3, 400 MHz)
142.8, 140.3, 136.3,
d
7.92 (d, 1H, J¼8.0 Hz), 7.69 (s, 1H),
d
4.6.4. 2-Bromo-3-iodoquinoline (21). To a stirred suspension of
3-iodo-1H-quinolin-2-one (20) (1.90 g, 6.99 mmol) in toluene
(20 mL) phosphorus oxybromide (2.01 g, 6.99 mmol) was added in
small portions at 0e10 ꢀC. The reaction mixture was refluxed for
3 h. After completion of the reaction the solvent was evaporated off,
the residue was dissolved in dichloromethane (40 mL) then washed
with potassium carbonate solution (10%, 20 mL) and water (20 mL).
The organic layer was dried over Na2SO4, filtered, and evaporated to
dryness. The crude product was recrystallized from isopropyl al-
cohol. The title compound was obtained as a beige solid (1.74 g,
136.2, 129.8, 128.7, 128.2, 127.5, 126.9, 126.0, 123.9, 121.2, 115.6;
C15H11BrN2 (299.17); LCMS (ESIþ) m/z 299, 301 [MþH]þ. Anal.
Calcd for C15H11BrN2 (299.17) C, 60.22; H, 3.71; N, 9.36. Found: C,
60.08; H, 3.70; N, 9.39.
4.7.5. 4-Bromo-3-(4-nitrophenylamino)quinoline (27a). Prepared
from 9 and 26a by irradiation at 130 ꢀC for 180 min. Eluent: hexane/
ethyl acetate (3/2). Yellow solid (156 mg, 76%), mp 189e190 ꢀC; 1H
NMR (CDCl3, 400 MHz)
d
8.94 (s, 1H), 8.19 (d, 2H, J¼8.8 Hz), 8.14 (d,
1H, J¼8.4 Hz), 8.10 (d, 1H, J¼8.0 Hz), 7.75e7.65 (m, 2H), 7.07 (d, 2H,
74%), mp 126e128 ꢀC; 1H NMR (DMSO-d6, 400 MHz)
d
9.02 (s, 1H),
J¼9.2 Hz), 6.54 (br s, 1H); 13C NMR (CDCl3, 400 MHz)
d 148.3, 145.7,
7.99e7.92 (m, 2H), 7.87e7.81 (m, 1H), 7.72e7.66 (m, 1H); 13C NMR
145.0, 141.6, 132.7, 129.8, 129.0, 128.7, 128.1, 126.2, 124.6, 115.2,
110.0; C15H10BrN3O2 (344.17); LCMS (ESIþ) m/z 344, 346 [MþH]þ.
Anal. Calcd for C15H10BrN3O2 (344.17) C, 52.35; H, 2.93; N, 12.21.
Found: C, 52.48; H, 2.92; N, 12.24.
(DMSO-d6, 400 MHz)
d 148.3, 146.3, 146.2, 131.2, 127.9, 127.8, 127.6,
127.1, 96.1; C9H5BrIN (333.96); LCMS (ESIþ) m/z 334, 336 [MþH]þ.
Anal. Calcd for C9H5BrIN (333.96) C, 32.37; H, 1.51; N, 4.19. Found: C,
32.25; H, 1.51; N, 4.20.
4.7.6. 4-Bromo-3-(4-fluorophenylamino)quinoline (27b). Prepared
from 9 and 26b by irradiation at 130 ꢀC 180 min. Eluent: hexane/
ethyl acetate (9/1). Yellow solid (114 mg, 60%), mp 120e122 ꢀC; 1H
4.7. General procedure for the BuchwaldeHartwig reactions
A microwave vial (2e5 mL) was charged with palladium acetate
(6.7 mg, 0.03 mmol), Xantphos (4,5-bis(diphenylphosphino)-9,9-
dimethylxanthene) (34.7 mg, 0.06 mmol), the requisite dihaloqui-
noline, i.e., 9, 12, 17 or 21 (200.0 mg, 0.60 mmol), cesium carbonate
(782.0 mg, 2.40 mmol) and aniline (59.0 mg, 0.63 mmol) followed
by toluene (3 mL) and flushed with argon. The reactions were run at
120 or 130 ꢀC for 60, 90 or 180 min (see Tables 2 and 3). After
completion of the reaction the solvent was evaporated and the
residue was purified by column chromatography.
NMR (DMSO-d6, 400 MHz)
1H, J¼1.2, 8.4 Hz), 7.99e7.93 (m, 1H), 7.72e7.60 (m, 2H), 7.19e7.10
(m, 4H); 13C NMR (DMSO-d6, 400 MHz)
158.7, 156.3, 144.2, 143.5,
138.8, 138.7, 136.5, 129.2, 128.5, 127.9, 127.2, 125.1, 120.6, 120.6,
118.4, 116.0, 115.8; C15H10BrFN2 (317.16); LCMS (ESIþ) m/z 317, 319
[MþH]þ. Anal. Calcd for C15H10BrFN2 (317.16) C, 56.81; H, 3.18; N,
8.83. Found: C, 56.65; H, 3.19; N, 8.80.
d 8.68 (s, 1H), 8.13 (br s, 1H), 8.04 (dd,
d
4. 7 . 7 . 4 - B ro m o- 3- ( 4 - m e t h o xy p h e nyla m i no ) qu i n ol i n e
(27c). Prepared from 9 and 26c by irradiation for 60 min. Eluent:
hexane/ethyl acetate (3/2) Yellow oil (129 mg, 65%), 1H NMR (CDCl3,
4.7.1. 4-Bromo-(3-phenylamino)quinoline (22). Prepared from 9.
Eluent: hexane/ethyl acetate (9/1). Green solid (126 mg, 70%), mp
400 MHz)
(d, 2H, J¼8.8 Hz), 6.93 (d, 2H, J¼8.8 Hz), 6.17 (br s, 1H), 3.83 (s, 3H);
13C NMR (CDCl3, 400 MHz)
157.0, 143.3, 141.2, 137.2, 133.4, 129.6,
128.2, 128.2, 126.3, 125.0, 124.4, 115.1, 55.6; C16H13BrN2O (329.20);
LCMS (ESIþ) m/z 329, 331 [MþH]þ. Anal. Calcd for C16H13BrN2O
(329.20) C, 58.38; H, 3.98; N, 8.51. Found: C, 58.21; H, 3.99; N, 8.49.
d 8.64 (s, 1H), 8.05e7.95 (m, 2H), 7.60e7.48 (m, 2H), 7.18
103e105 ꢀC; 1H NMR (DMSO-d6, 400 MHz)
d 8.76 (s, 1H), 8.17 (br s,
1H), 8.06 (dd, 1H, J¼8.4, 8.0 Hz), 8.00e7.96 (m, 1H), 7.72e7.63 (m,
d
2H), 7.29 (t, 2H, J¼8.0 Hz), 7.10 (d, 2H, J¼7.6 Hz), 6.98e6.93 (m, 1H);
13C NMR (DMSO-d6, 400 MHz)
d 145.0, 143.6, 142.5, 136.0, 129.2,
129.1, 128.4, 127.9, 127.3, 125.2, 121.2, 119.6, 117.9; for C15H11BrN2
(299.17); LCMS (ESIþ) m/z 299, 301 [MþH]þ. Anal. Calcd for
C15H11BrN2 (299.17) C, 60.22; H, 3.71; N, 9.36. Found: C, 60.05; H,
3.72; N, 9.33.
4.8. General procedure for the Heck-type reactions
A
microwave vial (2e5 mL) was charged with bis(-
4.7.2. 3-Bromo-(4-phenylamino)quinoline (23). Prepared from 12.
Eluent: dichloromethane (100%). Yellow solid (170 mg, 95%), mp
138e140 ꢀC (lit.,37 mp 136.5e137.5 ꢀC); 1H NMR (DMSO-d6,
triphenylphosphine)palladium(II) dichloride (23.2 mg, 0.03 mmol),
the corresponding phenylaminoquinoline: 22e25 (100 mg,
0.33 mmol) or 27aec (0.33 mmol) and sodium acetate (108.3 mg,
1.32 mmol) followed by N,N-dimethylacetamide (4.8 mL) and
flushed with argon. The reactions were run at 150 ꢀC for 60 or
120 min (see Tables 2 and 3). After completion of the reaction the
solvent was evaporated and the residue was purified by column
chromatography.
400 MHz)
7.79e7.72 (m, 1H), 7.57e7.50 (m, 1H), 7.24e7.16 (m, 2H), 6.91e6.85
(m, 1H), 6.80e6.75 (m, 2H); 13C NMR (DMSO-d6, 400 MHz)
152.7,
d 8.89 (s, 1H), 8.66 (br s, 1H), 8.04e7.95 (m, 2H),
d
147.7, 144.0, 143.3, 129.6, 129.4, 128.7, 126.3, 124.7, 123.7, 120.5, 117.1,
110.7; C15H11BrN2 (299.17); LCMS (ESIþ) m/z 299, 301 [MþH]þ.
Anal. Calcd for C15H11BrN2 (299.17) C, 60.22; H, 3.71; N, 9.36. Found:
C, 60.11; H, 3.71; N, 9.39.
4.8.1. 7H-Indolo[2,3-c]quinoline (4a). Prepared from 22. Eluent:
dichloromethane/methanol (95/5). Yellow solid (42.5 mg, 58%),
mp 253e255 ꢀC (lit.,15 mp 242e244 ꢀC); 1H NMR (DMSO-d6,
4.7.3. 3-Bromo-(2-phenylamino)quinoline (24). Prepared from 17.
Eluent: hexane/ethyl acetate (9/1). Pale pink foam (140 mg, 78%), 1H
400 MHz)
d
12.150 (s, 1H), 9.29 (s, 1H), 8.79 (d, 1H, J¼7.6 Hz), 8.67

ꢀ
ꢀ ꢀ
B. Boganyi, J. Kaman / Tetrahedron 69 (2013) 9512e9519
9519
(d, 1H, J¼8.0 Hz), 8.19 (d, 1H, J¼8.0 Hz), 7.80e7.72 (m, 2H),
7.70e7.64 (m, 1H), 7.62e7.56 (m, 1H), 7.43e7.37 (m, 1H);13C NMR
(DMSO-d6, 400 MHz) 142.1, 139.3, 138.6, 132.6, 129.8, 126.9, 126.6,
125.1,124.1,123.1, 122.8, 121.1,120.2,119.3,112.6; C15H10N2 (218.26);
LCMS (ESIþ) m/z 219 [MþH]þ. Anal. Calcd for C15H10N2 (218.26) C,
82.55; H, 4.62; N, 12.83. Found: C, 82.76; H, 4.63; N, 12.88.
(DMSO-d6, 400 MHz)
d
12.0 (s, 1H), 9.24 (s, 1H), 8.79 (d, 1H,
J¼8.0 Hz), 8.16 (d, 1H, J¼8.0 Hz), 8.05 (d, 1H, J¼2.4 Hz), 7.78e7.72
d
(m, 1H), 7.70e7.62 (m, 2H), 7.25 (dd, 1H, J¼2.0, 9.2 Hz), 3.98 (s, 3H);
13C NMR (DMSO-d6, 400 MHz)
d 154.0, 141.8, 138.8, 134.3, 133.1,
129.7, 126.8, 124.9, 124.2, 123.2, 121.3, 118.9, 117.0, 113.4, 104.2, 55.7;
C16H12N2O (248.29); LCMS (ESIþ) m/z 249 [MþH]þ. Anal. Calcd for
C16H12N2O (248.29) C, 77.40; H, 4.87; N, 11.28. Found: C, 77.15; H,
4.89; N, 11.31.
4.8.2. 11H-Indolo[3,2-c]quinoline (3a). Prepared from 23. Eluent:
dichloromethane/methanol (95/5). Beige solid (46.5 mg, 64%), mp
316e318 ꢀC (lit.,38 mp 320 ꢀC); 1H NMR (DMSO-d6, 400 MHz)
d
12.70 (s, 1H), 9.60 (s, 1H), 8.53 (d, 1H, J¼7.2 Hz), 8.32 (d, 1H,
References and notes
J¼8.0 Hz), 8.14 (d, 1H, J¼8.0 Hz), 7.78e7.66 (m, 3H), 7.50 (t, 1H,
J¼7.6 Hz), 7.34 (t, 1H, J¼7.6 Hz); 13C NMR (DMSO-d6, 400 MHz)
1. (a) Michael, J. P. Nat. Prod. Rep. 2008, 25, 166e187; (b) Katritzky, A. R.; Rees, C.
W.; Scriven, E. F. V.; Eds.; Pergamon: Oxford, 1996; Vol. 5, pp 245e266.
2. Subbaraju, G. V.; Kavitha, J.; Rajasekhar, D.; Jimenez, J. I. J. Nat. Prod. 2004, 67,
461e462.
d
145.3, 144.7, 139.6, 138.6, 129.4, 127.8, 125.5, 125.4, 121.9, 121.7,
120.4, 119.9, 117.0, 114.2, 111.7; C15H10N2 (218.26); LCMS (ESIþ) m/z
219 [MþH]þ. Anal. Calcd for C15H10N2 (218.26) C, 82.55; H, 4.62; N,
12.83. Found: C, 82.69; H, 4.60; N, 12.86.
3. (a) Appiah, A. A. The Golden Roots of Cryptolepis sanguinolenta. African Natural
Plant Products: New Discoveries and Challenges in Chemistry and Quality;
American Chemical Society: December 20, 2009, Chapter 13, pp 231–239; (b)
Whittell, L. R.; Batty, K. T.; Wong, R. P. M.; Bolitho, E. M.; Fox, S. A.; Davis, T. M.
E.; Murray, P. E. Bioorg. Med. Chem. 2011, 19, 7519e7525; (c) Lavrado, J.; Cabal,
4.8.3. 6H-Indolo[2,3-b]quinoline (2a). Prepared from 24. Eluent:
dichloromethane/methanol (9/1). Yellow foam (25.2 mg, 60%), 1H
^
G. G.; Prudencio, M.; Mota, M. M.; Gut, J.; Rosenthal, P. J.; Díaz, C.; Guedes, R. C.;
dos Santos, D. J. V. A.; Bichenkova, E.; Douglas, K. T.; Moreira, R.; Paulo, A. J. Med.
Chem. 2011, 54, 734e750.
4. (a) Lu, Y. J.; Ou, T. M.; Tan, J. H.; Hou, J. Q.; Shao, W. Y.; Peng, D.; Sun, N.; Wang,
X. D.; Wu, W. B.; Bu, X. Z.; Huang, Z. S.; Ma, D. L.; Wong, K. Y.; Gu, L. G. J. Med.
Chem. 2008, 51, 6381e6392; (b) Sayed, I. E.; Van der Veken, P.; Steert, K.;
Dhooghe, L.; Hostyn, S.; Baelen, V. G.; Lemiere, G.; Maes, B. U. W.; Cos, P.; Maes,
L.; Joossens, J.; Haemers, A.; Pieters, L.; Augustyns, K. J. Med. Chem. 2009, 52,
2979e2988.
NMR (DMSO-d6, 400 MHz) d 11.74 (br s, 1H), 9.04 (s, 1H), 8.26 (d,1H,
J¼7.6 Hz), 8.11 (d,1H, J¼8.0 Hz), 7.97 (d, 1H, J¼8.4 Hz), 7.75e7.68 (m,
1H), 7.56e7.45 (m, 3H), 7.29e7.23 (m, 1H); 13C NMR (DMSO-d6,
400 MHz)
d 152.8, 146.2, 141.4, 128.5, 128.0, 127.4, 126.9, 123.6,
ꢁ
122.6, 121.7, 120.2, 119.5, 117.8, 110.8; C15H10N2 (218.26); LCMS
(ESIþ) m/z 219 [MþH]þ. Anal. Calcd for C15H10N2 (218.26) C, 82.55;
H, 4.62; N, 12.83. Found: C, 82.86; H, 4.63; N, 12.81.
ꢁ
ꢀ
ꢀ
5. Hostyn, S.; Maes, B. U. W.; Pieters, L.; Lemiere, G. L. F.; Matyus, P.; Hajos, G.;
Dommisse, R. A. Tetrahedron 2005, 61, 1571e1577.
6. Hostyn, S.; Maes, B. U. W.; Baelen, V. G.; Gulevskaya, A.; Meyers, C.; Sits, K.
Tetrahedron 2006, 62, 4676e4684.
7. Dhanabal, T.; Sangeetha, R.; Mohan, P. S. Tetrahedron 2006, 62, 6258e6263.
8. Hayashi, K.; Choshi, T.; Chikaraishi, K.; Oda, A.; Yoshinaga, R.; Hatae, N.; Ishi-
kura, M.; Hibino, S. Tetrahedron 2012, 68, 4274e4279.
4.8.4. 10H-Indolo[3,2-b]quinoline (1a). Prepared from 25. Eluent:
dichloromethane/ethyl acetate (95/5). Beige solid (44.3 mg, 61%),
mp 252e254 ꢀC (lit.,15 mp 249e251 ꢀC); 1H NMR (DMSO-d6,
400 MHz)
(d, 1H, J¼8.4 Hz), 8.10 (d, 1H, J¼8.0 Hz), 7.68e7.52 (m, 4H),
7.32e7.26 (m, 1H); 13C NMR (DMSO-d6, 400 MHz)
145.6, 143.9,
d
11.39 (br s, 1H), 8.36 (d, 1H, J¼8.0 Hz), 8.28 (s, 1H) 8.19
9. Zhang, X.; Yao, T.; Campo, M. A.; Larock, R. C. Tetrahedron 2010, 66, 1177e1187.
ꢁ
10. Hostyn, S.; Tehrani, K. A.; Lemiere, F.; Smout, V.; Maes, B. U. W. Tetrahedron
2011, 67, 655e659.
11. Timari, G.; Soos, T.; Hajos, G. Synlett 1997, 1067e1068.
d
ꢀ
ꢀ
ꢀ
143.3, 132.3, 129.6, 128.6, 127.4, 126.6, 125.9, 124.7, 121.2, 120.9,
119.2, 112.9, 111.4; C15H10N2 (218.26); LCMS (ESIþ) m/z 219 [MþH]þ.
Anal. Calcd for C15H10N2 (218.26) C, 82.55; H, 4.62; N, 12.83. Found:
C, 82.79; H, 4.63; N, 12.87.
ꢀ
ꢀ
ꢀ
12. Csanyi, D.; Timari, G.; Hajos, G. Synth. Commun. 1999, 29, 3959e3969.
13. Lettesier, J.; Detert, H. Synthesis 2012, 44, 290e296.
14. Fresneda, P. M.; Molina, P.; Delgado, S. Tetrahedron 2001, 57, 6197e6202.
15. Etukala, J. R.; Kumar, E. V. K. S.; Ablordeppey, S. Y. J. Heterocycl. Chem. 2008, 45,
507e511.
16. Venkatesh, C.; Sundaram, G. S. M.; Ila, H.; Junjappa, H. J. Org. Chem. 2006, 71,
1280e1283.
4.8.5. 10-Nitro-7H-indolo[2,3-c]quinoline (28a). Prepared from 27a.
Reaction time: 120 min. Eluent: dichloromethane/methanol (95/5).
Beige solid (73.0 mg, 84%), mp >340 ꢀC; 1H NMR (DMSO-d6,
17. Jeganmohan, M.; Knochel, P. Angew. Chem., Int. Ed. 2010, 49, 8520e8524.
18. Cassis, R.; Tapia, R.; Valderrama, J. A. Synth. Commun. 1985, 15, 125e133.
19. Nolt, M. B.; Zhao, Z.; Wolkenberg, S. E. Tetrahedron Lett. 2008, 49, 3137e3141.
20. Boudet, N.; Lachs, J. R.; Knochel, P. Org. Lett. 2007, 9, 5525e5528.
21. Margolis, B. J.; Long, K. A.; Laird, D. L. T.; Ruble, J. C.; Pulley, S. R. J. Org. Chem.
2007, 72, 2232e2235.
400 MHz)
d
9.43 (d,1H, J¼2.0 Hz), 9.35 (s,1H), 8.78 (d,1H, J¼8.0 Hz),
8.39 (dd, 1H, J¼2.0, 8.8 Hz), 8.20 (d, 1H, J¼8.0 Hz), 7.89 (d, 1H,
J¼9.2 Hz), 7.84e7.77 (m, 1H), 7.73e7.67 (m, 1H); 13C NMR (DMSO-
22. Wolf, C.; Tumambac, G. E.; Villalobos, C. N. Synlett 2003, 1801e1804.
23. Miura, Y.; Takaku, S.; Nawata, Y.; Hamana, M. Heterocycles 1991, 32, 1579e1586.
24. Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 14844e14845.
d6, 400 MHz)
d 143.6, 142.3, 140.4, 139.7, 135.7, 130.0, 127.5, 125.8,
123.6, 123.0, 121.1, 120.6, 120.2, 119.5, 113.6; C15H9N3O2 (263.26);
LCMS (ESIþ) m/z 264 [MþH]þ. Anal. Calcd for C15H9N3O2 (263.26) C,
68.44; H, 3.45; N, 15.96. Found: C, 68.66; H, 3.44; N, 15.93.
ꢀ
ꢀ ꢀ
25. Boganyi, B.; Kaman, J. J. Heterocycl. Chem. 2009, 46, 33e38.
26. Iwaki, T.; Yasuhara, A.; Sakamoto, T. J. Chem. Soc., Perkin Trans. 1 1999,
1505e1510.
27. Dotsenko, V. V.; Krivokolysko, S. G.; Chernega, A. N.; Litvinov, V. P. Russ. Chem.
Bull., Int. Ed. 2002, 51, 1556e1561.
28. Lange, J.; Bissember, A. C.; Banwell, M. G.; Cade, I. A. Aust. J. Chem. 2011, 64,
454e470.
4.8.6. 10-Fluoro-7H-indolo[2,3-c]quinoline (28b). Prepared from
27b. Reaction time: 120 min. Eluent: hexane/ethyl acetate (9/1).
Yellow solid (54.6 mg, 70%), mp >340 ꢀC; 1H NMR (DMSO-d6,
29. Hosseini, A.; Tajbakhsh, M.; Khalilzadeh, M. A.; Hosseinzadeh, M. Monatsh.
Chem. 2012, 143, 619e623.
30. Okamoto, T.; Kimura, E.; Iwasaki, S.; Yamamoto, K. Chem. Pharm. Bull. 1969, 17,
2083e2086.
31. Schofield, K.; Swain, T. J. Chem. Soc. 1950, 384e389.
32. Blank, B.; DiTullio, N. W.; Owings, F. F.; Deviney, L.; Miao, C. K.; Saunders, H. L. J.
Med. Chem. 1977, 20, 572e576.
400 MHz)
d
12.33 (br s, 1H), 9.30 (s, 1H), 8.77 (d, 1H, J¼8.0 Hz), 8.48
(dd, 1H, J¼2.0, 10.0 Hz), 8.18 (d, 1H, J¼8.4 Hz), 7.81e7.71 (m, 2H),
7.69e7.63 (m, 1H), 7.50e7.42 (m, 1H); 13C NMR (DMSO-d6,
400 MHz) d 158.3,156.0,141.9,139.0,135.9,133.7,129.9,127.2,125.3,
124.0, 123.2, 121.2, 121.1, 119.1, 119.1, 115.1, 114.9, 113.9, 113.8, 108.0,
107.7, C15H9FN2 (236.25), LCMS (ESIþ) m/z 237 [MþH]þ. Anal.
Calcd for C15H9FN2 (236.25) C, 76.26; H, 3.84; N, 11.86. Found: C,
76.01; H, 3.85; N, 11.89.
33. Payack, J. F.; Vazquez, E.; Matty, L.; Kress, M. H.; McNamara, J. J. Org. Chem.
2005, 70, 175e178.
34. Kaneko, C. Chem. Pharm. Bull. 1959, 7, 273e275.
35. Krasovskiy, A.; Krasovskaya, V.; Knochel, P. Angew. Chem., Int. Ed. 2006, 45,
2958e2961.
36. Furayama, T.; Yonehara, M.; Uchiyama, M.; Arimoto, S.; Matsumoto, Y.; Ko-
bayashi, M. Chem.dEur. J. 2008, 14, 10348e10356.
37. Surrey, A. R.; Cutler, R. A. J. Am. Chem. Soc. 1946, 68, 2570e2573.
38. Uchuskin, M. G.; Pilipenko, A. S.; Butin, A. V.; Serdyuk, O. V.; Trushkov, I. V. Org.
Biomol. Chem. 2012, 10, 7262e7265.
4.8.7. 10-Methoxy-7H-indolo[2,3-c]quinoline (28c). Prepared from
27c. Eluent: dichloromethane/methanol (95/5). Yellow solid,
(43.4 mg, 53%), mp 223e225 ꢀC (lit.,15 mp 142e144 ꢀC); 1H NMR