A concise one-pot approach to the synthesis of 4-(1 H-indol-3-yl)quinolines

Article abstract of DOI:10.1055/s-0031-1289589

An operationally simple procedure, involving conjugate addition of NaI to β-(2-aminophenyl)-α,β-ynones/cyclization/Pd-catalyzed reaction with 2-alkynyl-trifluoroacetanilides, afforded 4-(1H-indol-3-yl)quinolines. The whole process was carried out in the same flask, without any intermediate work-up and using ethanol as solvent. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1289589

4084
PAPER
A Concise One-Pot Approach to the Synthesis of 4-(1H-Indol-3-yl)quinolines
O
ne-PotSynthesis
n
of 4-(1
H
-Ind
t
ol-3-y
o
l)quinolinesnio Arcadi,a Marco Chiarini,b Fabio Marinelli,*a Silvia Picchinia
a
Dipartimento di Chimica, Ingegneria Chimica e Materiali, Università dell’Aquila, via Vetoio, 67100 L’Aquila, Italy
Fax +39(862)433753; E-mail: fabio.marinelli@univaq.it
Dipartimento di Scienze degli Alimenti, Università degli Studi di Teramo, Via Carlo Lerici 1, Mosciano Sant’Angelo, 64023 Teramo,
Italy
b
Received 24 August 2011; revised 12 October 2011
annulation reactions leading to quinolines and fused poly-
cyclic quinolines.15
Abstract: An operationally simple procedure, involving conjugate
addition of NaI to b-(2-aminophenyl)-a,b-ynones/cyclization/Pd-
catalyzed reaction with 2-alkynyl-trifluoroacetanilides, afforded 4-
(1H-indol-3-yl)quinolines. The whole process was carried out in the
same flask, without any intermediate work-up and using ethanol as
solvent.
On the other hand, Pd-catalyzed reaction of 2-alkynyltri-
fluoroacetanilides 2 with organic electrophiles constitutes
an efficient tool for the synthesis of 3-substituted indoles
through an aminopalladation/reductive elimination se-
quence. This procedure allows the use of a wide range of
organic electrophiles, such as aryl/heteroaryl,16 alkyl17
and alkynyl halides,18 arenediazonium tetrafluorobo-
rates,19 a-iodoenones,20 aryl16b or vinyl16c triflates and al-
lyl esters.21
Key words: annulation, palladium, quinolines, indoles, heterocy-
cles, one-pot reaction
The quinoline nucleus1 is present in many biologically ac-
tive compounds as well as in naturally occurring products.
Quinoline-containing molecules are widely studied as an-
timalarial drugs2 and new quinoline derivatives are cur-
rently being investigated for their pharmacological
properties.3 Such compounds are active, for example, as
antidepressants,4 NK3 receptor antagonists,5 antifungals,6
antimicrobials,7 antioxidants,8 kinase inhibitors,9 and liver
X receptor agonists.10 In particular, quinolines bearing an
indolyl substituent, namely 4-(1H-indol-3-yl)quinolines
4, show potent and selective pharmacological activity as
antagonists of D2 prostaglandin receptor CRTh2, and are
thus potentially useful in treatments of asthma and other
allergic disorders.11
Our aim was therefore to explore a combination of these
two methodologies, leading to quinolines and indoles re-
spectively, and to develop a new, one-pot approach to 4-
(1H-indol-3-yl)quinolines 4. Herein, we report the results
of this investigation.
We previously reported that the conjugate addition of NaI
to 1 in acetic acid as solvent, followed by cyclization/
dehydration in situ, affords 4-iodoquinolines 3 that (after
an extractive work-up of the reaction mixture) can be used
in subsequent Pd-catalyzed functionalization reactions
(Scheme 1).15f However, the use of 3 as an organic elec-
trophile in an aminopalladation/reductive elimination pro-
cess leading to indoles has not been investigated.
Compounds 4 are generally obtained by reaction of 3-un-
substituted indoles with 4-chloroquinolines at 100–
140 °C.11 A related reaction between indole and 4-chloro-
2,8-bis(trifluoromethyl)quinoline in the presence of AlCl3
has been reported more recently.12 Moreover, Pd-cata-
lyzed coupling of 1-tosyl-3-tributylstannyl-indole with
2,8-bis(trifluoromethyl)quinolin-4-yl triflate13 and 3-in-
dolylboronic acid with 4-bromo-6-methoxyquinoline
were also described.14
O
I
Ar
NaI (2 equiv)
AcOH, 60 °C
16 h, 67%
NH2
N
Ar
3a
HN
1a Ar = 4-MeOC6H4
Ph
All these procedures rely on the coupling of a suitable in-
dole with a functionalized quinoline ring; direct assembly
of 4 from acyclic precursors has not been accomplished.
Therefore, it seemed desirable to develop a general and ef-
fective route to heterocycles 4 starting from alkynes 1 and
2.
Ph
Pd(PPh3)4
K2CO3
3a
+
MeCN, 80 °C
5 h, 75%
N
Ar
NHCOCF3
2a
4a
Scheme 1
We have previously investigated the use of b-(2-amino-
phenyl)-a,b-ynones 1 in a variety of sequential addition/
We started our study by reacting iodoquinoline 3a (ob-
tained by the methodology mentioned above) with 2-phe-
nylethynyltrifluoroacetanilide 2a in the presence of
K2CO3 and [Pd(PPh3)4]; 4-(1H-indol-3-yl)quinoline de-
rivative 4a was isolated in satisfactory yield in this exper-
iment (Scheme 1). With this result in hand, we tried to
SYNTHESIS 2011, No. 24, pp 4084–4090
x
x.
x
x
.
2
0
1
1
Advanced online publication: 03.11.2011
DOI: 10.1055/s-0031-1289589; Art ID: Z83711SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
One-Pot Synthesis of 4-(1H-Indol-3-yl)quinolines
4085
R5
develop a more convenient one-pot procedure for the syn-
thesis of target derivatives 4. According to our previous
results, the conjugate addition reaction of an iodide anion
to a,b-ynones 1 occurs under acidic conditions (no reac-
tion was observed by reacting 1a with NaI in neat MeCN
or EtOH at 80 °C), whereas the subsequent Pd-catalyzed
process requires a basic reaction medium, i.e., the pres-
ence of a carbonate base was required to generate an an-
ionic nitrogen nucleophile.22
R7
NHCOCF3
O
R6
2a–f
R4
NaI, TsOH, 1.5 h;
R1
R2
then: Pd(PPh3)4, K2CO3
EtOH, 80 °C
NH2
1a–f
one-pot, 50–72% overall yield
R3
Taking into account this difference, we attempted to carry
out a two-step, one-pot protocol by adding 2a, the base,
and the catalyst to the reaction mixture just after the con-
version of 1a into 3a. This approach clearly requires a re-
duction in the amount of acid used in the first step in order
to limit the excess of base needed for subsequent indole
formation. The reaction between 1a and NaI (2 equiv) was
then tested in acetonitrile at 80 °C in the presence of 1.1
equivalents of acetic acid, but GC-MS analysis of the re-
action mixture showed the formation of only negligible
amounts of 3a after 20 hours. In contrast, when the reac-
tion was carried out in the presence of 1 equivalent of p-
toluene sulfonic acid in ethanol at 80 °C, complete con-
version into 3a was observed in 1.5 hours; subsequent ad-
dition of 2a (1.2 equiv), K2CO3 (4 equiv) and [Pd(PPh3)4]
(0.03 equiv) to the reaction mixture, gave 4a, which was
isolated in 70% overall yield after 4.5 hours.
R6
HN
R7
R5
R1
R2
N
R4
R3
4
R1 R2 R3
R4
R5
R6 R7
1
2
H
H
H
H
H
H
H
H
H
H
1a
1b
1c
1d
1e
1f
Ph
H
H
H
H
2a
2b
2c
2d
2e
2f
4-MeOC6H4
3-MeC6H4
4-EtOCOC6H4
4-MeCOC6H4
2-MeOC6H4
4-NCC6H4
2-thienyl
3-MeOCOC
4-NCC6H4
4-MeCOC6H4
cycloocten-1-yl
H
H
F
H
H
F
H
H
F
H
H
F
6H4
H
H
H
H
Scheme 2
When the whole process was carried out in acetonitrile,
similar results were achieved (71% overall yield); howev-
er, the more environmentally benign solvent, ethanol, was
chosen as the reaction medium in further experiments.
The reaction was then extended to include a range of
a,b-ynones 1a–f and alkynyl-trifluoroacetanilides 2a–f
(Scheme 2).
ed in both the quinoline and indole moieties of 4. More-
over, substituents could also be introduced in the benzenic
rings of both indole (entry 7) and quinoline (entries 10–
12) systems. When 2c was reacted with 1e in ethanol, the
product 4ec was isolated as the ethyl ester, likely through
transesterification in situ (entry 11). According to this hy-
pothesis, the reaction of 2c with 1a in acetonitrile afforded
the expected methyl ester 4ac (entry 3).
As reported in Table 1, this two-step, one-pot reaction af-
forded the target indoloquinolines in moderate to good
overall yields, and various functional groups were tolerat-
Table 1 Synthesis of Indoloquinolines 4 from a,b-Ynones 1 and Alkynyltrifluoroacetanilides 2a
Entry
1, 2
4-(1H-Indol-3-yl)quinoline 4
Time (h)b
Yield (%)c
HN
Ph
1a
2a
1
4aa
4.5
70
N
OMe
HN
S
1a
2b
2
4ab
4
51
N
OMe
Synthesis 2011, No. 24, 4084–4090 © Thieme Stuttgart · New York

4086
A. Arcadi et al.
PAPER
Table 1 Synthesis of Indoloquinolines 4 from a,b-Ynones 1 and Alkynyltrifluoroacetanilides 2a (continued)
Entry
1, 2
4-(1H-Indol-3-yl)quinoline 4
Time (h)b
Yield (%)c
O
MeO
HN
1a
2c
3
4ac
5
72d
N
OMe
HN
Ph
1b
2a
4
4ba
4bb
3
70
N
HN
S
1b
2b
5
2.5
70
N
HN
Ph
1c
2a
6
4ca
2.5
50e
N
COOEt
F
HN
F
1c
2e
MeOC
7
4ce
7
55
N
COOEt
HN
Ph
1d
2a
8
4da
6.5
51
N
COMe
HN
NC
1c
2d
9
4dd
6
60
N
COMe
Synthesis 2011, No. 24, 4084–4090 © Thieme Stuttgart · New York

PAPER
One-Pot Synthesis of 4-(1H-Indol-3-yl)quinolines
4087
Table 1 Synthesis of Indoloquinolines 4 from a,b-Ynones 1 and Alkynyltrifluoroacetanilides 2a (continued)
Entry
10
1, 2
4-(1H-Indol-3-yl)quinoline 4
Time (h)b
Yield (%)c
HN
Ph
1e
2a
4ea
5
69
F
OMe
N
F
O
EtO
HN
1e
2c
11
4ec
6
50
F
OMe
N
F
HN
1e
2f
12
4ef
6
56
F
OMe
N
F
HN
Ph
1f
2a
13
4fa
2.5
51e
N
CN
a Unless otherwise stated, reactions were carried out in EtOH at 80 °C using the following molar ratios: 1/NaI/TsOH = 1:2:1; then after 1.5 h:
2/K2CO3/[Pd(PPh3)4] = 1.2:4:0.03 (under N2).
b Reaction times refer to the second step.
c Overall yield of pure isolated products based on 1.
d Reaction carried out in MeCN.
e [Pd2(dba)3] (0.02 equiv) and P(Cy)3 (0.04 equiv) were used as catalyst.
gan LCQ Deca XP Plus. IR spectra were recorded in KBr pellets
with a Perkin-Elmer 683 or a Varian 100 FT-IR spectrometer.
4 through a two-step, one-pot double cyclization, without b-(2-Aminophenyl)-a,b-ynones 1a/1b,15f 1c15a and 1e/1f15b are
In conclusion, we have developed a straightforward meth-
odology for the synthesis of 4-(1H-indol-3-yl)quinolines
known compounds. Compound 1d was obtained in 75% yield by us-
ing the procedure reported previously.15b 2-Alkynyltrifluoroaceta-
nilides 2a/2b/2f23 and 2c/2e20 are known compounds; 2d was
obtained in 67% yield by using the procedure reported previously.20
any intermediate work-up. The results obtained widen
significantly the scope of both previously reported method-
ologies, leading to indoles from 2-alkynyltrifluoroacet-
anilides 2 and to quinolines from b-(2-aminophenyl)-a,b-
ynones 1. Moreover, while Pd-catalyzed aminopallada-
tion and reductive elimination procedures reported so far
were carried out in acetonitrile or tetrahydrofuran, envi-
ronmentally benign ethanol was used as reaction medium
in the present work.
1-(4-Acetylphenyl)-3-(2-aminophenyl)prop-2-yn-1-one (1d)
Yield: 75%; mp 138–140 °C.
IR (KBr): 3437, 2180, 1684, 1637, 1567, 1385 cm–1.
1H NMR (CDCl3): d = 2.68 (s, 3 H, CH3), 4.52 (br s, 2 H, NH2),
7.78–7.74 (m, 2 H), 7.32–7.24 (m, 1 H), 7.50 (dd, J = 8.0, 1.5 Hz,
1 H), 8.10–8.08 (m, 2 H), 8.31–8.28 (m, 2 H).
Melting points are uncorrected. 1H NMR (300 MHz) and 13C NMR
(75.49 MHz) spectra were recorded with a Varian Mercury 300
spectrometer. ESI mass spectra were recorded with a ThermoFinni-
13C NMR (CDCl3): d = 26.7 (CH3), 92.6 and 93.3 (C≡C), 103.3 (C),
114.8 (CH), 117.9 (CH), 128.3 (2 CH), 129.4 (2 CH), 132.9 (CH),
133.7 (CH), 140.0 (C), 140.7 (C), 150.7 (CNH2), 176.7 (C≡C CO),
197.2 (MeCO).
Synthesis 2011, No. 24, 4084–4090 © Thieme Stuttgart · New York

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PAPER
N-{2-[(4-Cyanophenyl)ethynyl]phenyl}-2,2,2-trifluoroacet-
amide (2d)
Yield: 67%; mp 137–139 °C.
IR (KBr): 3294, 2222, 1709, 1600, 1580, 1547 cm–1.
1H NMR (CDCl3): d = 7.25 (td, J = 7.7, 1.1 Hz, 1 H), 7.46 (td, J =
8.0, 1.5 Hz, 1 H), 7.59 (ddd, J = 7.7, 1.5, 0.4 Hz, 1 H), 7.61–7.59
(m, 2 H), 7.69–7.66 (m, 2 H), 8.32 (dd, J = 8.0, 0.6 Hz, 1 H), 8.76
(br s, 1 H, NH)
13C NMR (CDCl3): d = 87.1 and 95.7 (C≡C), 112.6 (CCN), 113.0
(C), 115.8 (q, J = 289.2 Hz, CF3), 117.9 (CN), 120.3 (CH), 125.7
(CH), 126.5 (C), 130.6 (CH), 131.8 (2 CH), 132.0 (CH), 132.2 (2
CH), 136.25 (C), 154.3 (q, J = 37.5 Hz, CO).
1H NMR (DMSO-d6): d = 3.83 (s, 3 H, OCH3), 7.11–6.95 (m, 3 H),
7.28–7.18 (m, 2 H), 7.42–7.38 (m, 2 H), 7.56 (d, J = 8.1 Hz, 1 H),
7.65 (d, J = 8.0 Hz, 1 H), 7.76 (t, J = 7.5 Hz, 1 H), 8.10 (d, J =
8.2 Hz, 2 H), 8.22 (d, J = 8.2 Hz, 2 H), 8.43 (d, J = 8.0 Hz, 2 H),
12.00 (s, 1 H, NH).
13C NMR (DMSO-d6): d = 55.2 (OCH3), 109.0 (C), 111.3 (CH),
114.2 (2CH), 118.6 (CH), 120.0 (CH), 120.8 (CH), 122.5 (CH),
125.4 (CH), 125.7 (CH), 125.9 (CH), 126.4 (C), 126.6 (CH), 127.2
(CH), 128.6 (2CH), 129.4 (CH), 129.7 (CH), 130.1 (C), 131.0 (C),
133.6 (C), 136.0 (C), 142.4 (C), 148.3 (C), 155.5 (C), 160.6 (C),
163.2 (C).
MS (ESI): m/z (%) = 433 (100) [M + H]+.
Methyl 3-{3-[2-(4-Methoxyphenyl)quinolin-4-yl]-1H-indol-2-
yl}benzoate (4ac)
Yield: 50%; mp 165–166 °C.
4-(1H-Indol-3-yl)quinolines 4: Typical Procedure
To a solution of 3-(2-amino-3,5-difluorophenyl)-1-(2-methoxyphe-
nyl)prop-2-yn-1-one (1e; 0.194 g, 0.68 mmol) in EtOH (5 mL) were
added NaI (0.202 g, 1.35 mmol) and p-toluenesulfonic acid (0.117
g, 0.68 mmol). The mixture was stirred at 80 °C for 1.5 h and briefly
cooled for 5 min. Then, 2-(phenylethynyl)trifluoroacetanilide (2a;
0.234 g, 0.81 mmol), K2CO3 (0.376 g, 2.72 mmol) and [Pd(PPh3)4]
(0.023 g, 0.02 mmol) were added. The resulting mixture was stirred
under N2 at 80 °C for 5 h, then extracted with 0.5 M NH4Cl (100
mL) and EtOAc (3 × 50 mL). The organic layer was dried (Na2SO4)
and evaporated. Column chromatographic purification on silica gel
(hexane–EtOAc, 90:10 v/v) afforded 6,8-difluoro-2-(2-methoxy-
phenyl)-4-(2-phenyl-1H-indol-3-yl)quinoline (4ea).
IR (KBr): 3367, 3055, 2969, 1712, 1598, 1587, 1505, 1272, 1236
cm–1.
1H NMR (CDCl3): d = 3.85 (s, 3 H, OCH3), 3.87 (s, 3 H, COOCH3),
6.98–6.93 (m, 2 H), 7.14–7.06 (m, 2 H), 7.34–7.23 (m, 4 H), 7.48
(d, J = 7.1 Hz, 1 H), 7.64 (td, J = 7.0, 1.4 Hz, 1 H), 7.72 (d, J =
8.2 Hz, 1 H), 7.84–7.81 (m, 2 H), 8.07–8.02 (m, 2 H), 8.23–8.19
(m, 2 H), 9.51 (s, 1 H, NH).
13C NMR (CDCl3): d = 52.3 (OCH3), 55.4 (COOCH3), 111.3 (CH),
111.5 (C), 114.1 (2CH), 119.9 (CH), 120.8 (CH), 121.0 (CH), 123.3
(CH), 125.8 (CH), 126.3 (CH), 126.5 (C), 127.9 (CH), 128.70 (CH),
128.74 (CH), 128.9 (2CH), 129.5 (C), 129.6 (CH), 129.7 (CH),
130.9 (C), 132.0 (CH), 132.19 (C), 132.24 (C), 134.6 (C), 136.2 (C),
142.9 (C), 149.0 (C), 156.8 (C), 160.7 (C), 166.2 (CO).
Yield: 0.214 g (69%); mp 237–238 °C.
IR (KBr): 3300, 3050, 2981, 2910, 2809, 1628, 1550, 1492, 1481,
1435, 1418, 1247, 1227, 1100 cm–1.
1H NMR (CDCl3): d = 3.63 (s, 3 H, OCH3), 6.93 (d, J = 8.3 Hz,
1 H), 7.19–7.10 (m, 3 H), 7.28–7.21 (m, 4 H), 7.40–7.30 (m, 5 H),
7.51 (d, J = 8.0 Hz, 1 H), 7.98 (dd, J = 7.5, 1.6 Hz, 1 H), 8.06 (s,
1 H), 8.70 (br s, NH, 1 H).
MS (ESI): m/z (%) = 485 (100) [M + H]+.
2-(3-Methylphenyl)-4-(2-phenyl-1H-indol-3-yl)quinoline (4ba)
Yield: 70%; mp 198–200 °C.
13C NMR (CDCl3): d = 55.4 (OCH3), 104.7 (dd, J = 29.6, 22.9 Hz,
CH), 105.7 (dd, J = 22.7, 4.7 Hz, CH), 111.2 (CH), 111.4 (CH),
119.8 (CH), 120.6 (C), 120.9 (CH), 121.3 (CH), 123.2 (CH), 127.4
(C), 127.6 (2CH), 127.9 (CH), 128.2 (CH), 128.4 (C), 128.9 (2CH),
129.3 (C), 130.6 (CH), 131.9 (C), 136.0 (C), 140.1 (C), 140.2 (C),
156.2 (C), 157.4 (C), 158.1 (dd, J = 247.6, 11.3 Hz, CF), 158.8 (dd,
J = 259.1, 12.9 Hz, CF).
IR (KBr): 3413, 3100, 2960, 1750, 1615, 1600, 1470 cm–1.
1H NMR (DMSO-d6): d = 3.37 (s, 3 H, CH3), 7.02 (t, J = 7.2 Hz,
1 H), 7.40–7.13 (m, 11 H), 7.57 (d, J = 8.1 Hz, 1 H), 7.70–7.62 (m,
2 H), 7.98–7.90 (m, 2 H), 8.14 (d, J = 8.2 Hz, 1 H), 11.99 (s, 1 H,
NH).
13C NMR (DMSO-d6): d = 21.0 (CH3), 109.1 (C), 111.7 (CH), 118.7
(CH), 120.1 (CH), 120.9 (CH), 122.4 (CH), 124.4 (CH), 126.0
(CH), 126.2 (CH), 126.4 (C), 127.5 (2 CH), 127.8 (CH), 128.6 (2
CH), 128.7 (CH), 128.9 (C), 129.7 (CH), 129.8 (CH), 130.2 (CH),
131.2 (C), 132.1 (CH), 135.8 (C), 136.3 (C), 138.0 (C), 138.9 (C),
143.5 (C), 148.4 (C), 156.1 (C).
MS (ESI): m/z (%) = 463 (100) [M + H]+.
2-(4-Methoxyphenyl)-4-(2-phenyl-1H-indol-3-yl)quinoline
(4aa)
Yield: 70%; mp 138–139 °C.
IR (KBr): 3410, 1620, 1597, 1520, 1258 cm–1.
MS (ESI): m/z (%) = 411 (100) [M + H]+.
1H NMR (DMSO-d6): d = 3.78 (s, 3 H, OCH3), 7.04–6.97 (m, 3 H),
7.31–7.40 (m, 6 H), 7.43 (d, J = 6.9 Hz, 2 H), 7.68–7.58 (m, 3 H),
7.99 (s, 1 H), 8.10 (d, J = 8.3 Hz, 1 H), 8.17 (d, J = 8.7 Hz, 2 H),
12.01 (s, 1 H, NH).
13C NMR (DMSO-d6): d = 55.2 (OCH3), 109.22 (C), 111.7 (CH),
114.2 (2 CH), 118.8 (CH), 120.0 (CH), 120.2 (CH), 122.4 (CH),
125.7 (CH), 126.0 (CH), 126.1 (C), 127.5 (2 CH), 127.7 (CH),
128.6 (4 CH), 128.9 (C), 129.5 (CH), 129.6 (CH), 131.1 (C), 131.9
(C), 135.8 (C), 136.3 (C), 143.3 (C), 148.4 (C), 155.6 (C), 160.6
(C).
2-(3-Methylphenyl)-4-[2-(2-thienyl)-1H-indol-3-yl]quinoline
(4bb)
Yield: 70%; mp 205–206 °C.
IR (KBr): 3421, 3100, 3061, 3030, 2919, 2850, 1722, 1651, 1616,
1588, 1450, 1424, 1341, 1188, 1159 cm–1.
1H NMR (CDCl3): d = 2.46 (s, 3 H, CH3), 6.71 (dd, J = 3.6, 0.8 Hz,
1 H), 7.01 (dd, J = 5.0, 3.6 Hz, 1 H), 7.12–7.05 (m, 3 H), 7.17 (td,
J = 7.6, 1.2 Hz, 1 H), 7.26–7.24 (m, 3 H), 7.39–7.41 (m, 3 H), 7.62–
7.57 (m, 2 H), 7.76–7.72 (m, 1 H), 8.10 (d, J = 8.2 Hz, 1 H), 8.3 (br
s, 1 H, NH)
13C NMR (CDCl3): d = 21.5 (CH3), 110.3 (C), 110.8 (CH), 119.9
(CH), 120.4 (CH), 120.5 (CH), 121.2 (CH), 122.5 (CH), 122.9
(CH), 124.5 (CH), 125.4 (CH), 126.3 (C), 126.8 (CH), 127.9 (CH),
128.4 (2CH), 128.9 (2CH), 130.5 (CH), 130.8 (C), 132.3 (C), 134.8
(C), 135.7 (C), 136.6 (C), 141.8 (C),145.4 (C), 148.5 (C), 157.1 (C).
MS (ESI): m/z (%) = 427 (100) [M + H]+.
2-(4-Methoxyphenyl)-4-[2-(2-thienyl)-1H-indol-3-yl]quinoline
(4ab)
Yield: 51%; mp 218–219 °C.
IR (KBr): 3322, 3015, 1654, 1583, 1532, 1443, 1348, 1255 cm–1.
MS (ESI): m/z (%) = 417 (100) [M + H]+.
Synthesis 2011, No. 24, 4084–4090 © Thieme Stuttgart · New York

PAPER
One-Pot Synthesis of 4-(1H-Indol-3-yl)quinolines
4089
Ethyl 4-[4-(2-Phenyl-1H-indol-3-yl)quinolin-2-yl]benzoate
(4ca)
Yield: 50%; mp 193–194 °C.
1H NMR (DMSO-d6): d = 2.60 (s, 3 H, CH3), 7.02 (t, J = 7.5 Hz,
1 H), 7.18 (d, J = 7.8 Hz, 1 H), 7.27 (t, J = 7.6 Hz, 1 H), 7.37 (t, J =
7.6 Hz, 1 H), 7.64–7.55 (m, 4 H), 7.76–7.67 (m, 3 H), 8.07 (d, J =
8.4 Hz, 2 H), 8.15 (s, 1 H), 8.19 (d, J = 8.4 Hz, 1 H), 8.37 (d, J =
8.2 Hz, 2 H), 12.15 (s, 1 H, NH).
IR (KBr): 3369, 3059, 2925, 2853, 1719, 1604, 1594, 1579, 1542,
1447, 1273, 1100 cm–1.
13C NMR (DMSO-d6): d = 26.6 (CH3), 109.7 (C), 111.0 (C), 111.8
(CH), 118.4 (CN), 119.0 (CH), 120.3 (CH), 120.8 (CH), 123.2
(CH), 125.6 (CH), 126.3 (C), 126.7 (CH), 127.3 (2CH), 127.7
(2CH), 128.5 (2CH), 128.7 (C), 129.8 (CH), 129.9 (CH), 132.3
(2CH), 133.6 (C), 136.2 (C), 136.6 (C), 137.2 (C), 142.5 (C), 143.0
(C), 148.3 (C), 154.7 (C), 197.3 (CO).
1H NMR (DMSO-d6): d = 1.42 (t, J = 7.0 Hz, 3 H, COOCH2CH3),
4.40 (q, J = 7.0 Hz, 2 H, COOCH2CH3), 7.11–7.03 (m, 1 H), 7.30–
7.24 (m, 5 H), 7.40 (d, J = 7.4 Hz, 1 H), 7.51–7.46 (m, 2 H), 7.66
(d, J = 8.3 Hz, 1 H), 7.79–7.75 (m, 2 H), 8.17–8.13 (m, 3 H), 8.18
(d, J = 8.8 Hz, 1 H), 8.33 (d, J = 8.1 Hz, 2 H), 12.05 (s, 1 H, NH).
13C NMR (DMSO-d6):
d
= 14.1 (COOCH2CH3), 60.7
MS (ESI): m/z (%) = 464 (50) [M + H]+.
(COOCH2CH3), 109.0 (C), 111.7 (CH), 118.7 (CH), 1120.0 (CH),
120.8 (CH), 122.3 (CH), 126.1 (CH), 126.4 (CH), 126.7 (C), 127.3
(2CH), 127.51 (2CH), 127.53 (CH), 128.5 (2CH), 128.9 (C), 129.5
(2CH), 129.8 (2CH), 130.5 (C), 131.9 (C), 136.0 (C), 136.3 (C),
143.0 (C), 143.9 (C), 148.5 (C), 154.7 (C), 165.4 (CO).
Ethyl 3-{3-[6,8-Difluoro-2-(2-methoxyphenyl) quinolin-4-yl]-
1H-indol-2-yl}benzoate (4ec)
Yield: 50%; mp 188–190 °C.
IR (KBr): 3320, 3038, 2905, 2830, 1715, 1587, 1572, 1260, 1085
cm–1.
MS (ESI): m/z (%) = 469 (100) [M + H]+.
Ethyl 4-{4-[2-(4-Acetylphenyl)-5,7-difluoro-1H-indol-3-
yl]quinolin-2-yl}benzoate (4ce)
Yield: 55%; mp 270 °C (dec.).
1H NMR (DMSO-d6): d = 1.21 (t, J = 7.0 Hz, 3 H, CH2CH3), 3.70
(s, 3 H, OCH3), 4.22 (q, J = 7.0 Hz, 2 H, CH2CH3), 7.21–7.09 (m,
5 H), 7.33 (t, J = 7.4 Hz, 2 H), 7.48 (t, J = 7.6 Hz, 2 H), 7.76–7.63
(m, 2 H), 7.87 (d, J = 7.5 Hz, 1 H), 7.94 (dd, J = 7.5, 1.7 Hz, 1 H),
8.06 (d, J = 9.1 Hz, 2 H), 12.28 (s, 1 H, NH).
IR (KBr): 3437, 3295, 3070, 2990, 2964, 2925, 1714, 1684, 1648,
1607, 1595 cm–1.
13C NMR (DMSO-d6): d = 13.8 (CH2CH3), 55.5 (OCH3), 60.7
(CH2CH3), 105.1 (m, 2CH), 109.1 (C), 112.0 (2CH), 118.6 (CH),
120.4 (CH), 120.8 (CH), 122.9 (CH), 127.1 (CH), 127.3 (C), 127.9
(C), 128.21 (CH), 128.26 (C), 128.32 (CH), 129.2 (CH), 130.2
(CH), 131.0 (2CH), 131.9 (C), 132.0 (C), 134.8 (C), 136.2 (t,
J = 7 Hz, C), 136.5 (C), 140.8 (t, J = 3 Hz, C), 155.7 (C), 157.1 (C),
157.1 (dd, J = 245.3, 10.3 Hz, CF), 158.9 (dd, J = 260.2, 11.7 Hz,
CF), 165.1 (CO).
1H NMR (DMSO-d6): d = 1.32 (t, J = 6.94 Hz, 3 H, OCH2CH3),
2.43 (s, 3 H, CH3), 4.32 (q, J = 6.94 Hz, 2 H, OCH2CH3), 6.78 (d, J
= 6.78 Hz, 1 H), 7.15 (t, J = 9.83 Hz, 1 H), 7.38 (t, J = 7.37 Hz,
1 H), 7.57–7.52 (m, 3 H), 7.79–7.70 (m, 3 H), 8.03 (d, J = 8.1 Hz,
2 H, A part of AB system), 8.17–8.14 (m, 2 H), 8.36 (d, J = 8.1 Hz,
2 H, B part of AB system), 12.64 (s, 1 H, NH).
13C NMR (DMSO-d6): d = 14.2 (OCH2CH3), 26.6 (CH3CO), 60.9
(OCH2CH3), 98.2 (t, J = 20 Hz, CH), 99.9 (d, J = 20 Hz, CH), 111.4
(C), 121.0 (CH), 121.5 (d, J = 14 Hz, C), 125.5 (CH), 126.3
(C),127.1 (CH), 127.5 (2 CH), 127.9 (2 CH), 128.4 (2 CH), 129.6
(2 CH), 129.9 (CH), 130.2 (CH), 130.5 (C), 131.2 (dd, J = 11, 7 Hz,
C), 135.3 (C), 135.9 (C), 137.6 (C), 142.3 (C), 142.6 (C), 148.3 (C),
148.4 (dd, J = 248, 14 Hz, CF), 154.8 (C), 156.5 (dd, J = 237, 10 Hz,
CF), 165.5 (COOEt), 197.2 (CH3CO).
MS (ESI): m/z (%) = 535 (100) [M + H]+.
4-(2-Cyclooct-1-en-1-yl-1H-indol-3-yl)-6,8-difluoro-2-(2-meth-
oxyphenyl)quinoline (4ef)
Yield: 56%; mp 217–218 °C.
IR (KBr): 3450, 2940, 2900, 2820, 1628, 1595, 1550, 1485, 1249
cm–1.
1H NMR (CDCl3): d = 1.38–1.33 (m, CH2, 8 H), 2.27–2.15 (m,
4 H), 3.82 (s, CH2, 3 H), 6.01 (t, J = 8.3 Hz, 1 H), 7.32–7.00 (m,
7 H), 7.45–7.37 (m, 2 H), 7.99 (dd, J = 7.5, 1.7 Hz, 1 H), 8.10 (s,
1 H), 8.46 (br s, NH, 1 H).
MS (ESI): m/z (%) = 547 (100) [M + H]+.
1-{4-[4-(2-Phenyl-1H-indol-3-yl)quinolin-2-yl]phenyl}etha-
none (4da)
Yield: 51%; mp 219–220 °C.
IR (KBr): 3219, 3062, 3040, 2919, 1686, 1595, 1579, 1540, 1504,
1450, 1356 cm–1.
13C NMR (CDCl3): d = 25.9 (CH2), 26.6 (CH2), 27.0 (CH2), 27.9
(CH2), 29.1 (CH2), 29.6 (CH2), 55.6 (CH3), 104.7 (dd, J = 29.6,
23.0 Hz, CH), 105.8 (dd, J = 22.5, 4.7 Hz, CH), 109.2 (C), 110.7
(CH), 111.4 (CH), 119.2 (CH), 120.5 (CH), 121.3 (CH), 122.7
(CH), 123.9 (C), 127.1 (C), 127.5 (CH),130.6 (CH), 130.8 (C),
131.2 (C), 131.7 (CH), 131.9 (CH), 133.1 (C), 135.1 (C), 138.0 (C),
141.7 (C), 156.2 (C), 157.5 (C), 158.0 (dd, J = 247.5, 11.3 Hz, CF),
158.7 (dd, J = 259.0, 13.0 Hz, CF).
1H NMR (CDCl3): d = 2.59 (s, 3 H, CH3), 7.34–7.07 (m, 9 H), 7.49
(d, J = 8.1 Hz, 1 H), 7.67 (t, J = 7.5 Hz, 1 H), 7.81 (d, J = 8.2 Hz,
1 H), 7.87 (s, 1 H), 8.01 (d, J = 8.2 Hz, 2 H, A part of AB system),
8.16 (d, J = 8.2 Hz, 2 H, B part of AB system), 8.25 (d, J = 8.4 Hz,
1 H), 8.77 (br s, 1 H, NH).
13C NMR (CDCl3): d = 26.6 (CH3CO), 111.0 (C), 111.2 (CH), 119.9
(CH), 120.9 (CH), 121.4 (CH), 123.2 (CH), 126.4 (CH), 126.6
(CH), 127.3 (C), 127.6 (2 CH), 127.7 (2 CH), 128.1 (CH), 128.7 (2
CH), 128.8 (2 CH), 129.6 (C), 129.7 (CH), 130.2 (CH), 132.0 (C),
136.1 (C), 136.2 (C), 137.5 (C), 143.6 (C), 144.1 (C), 149.2 (C),
155.7 (C), 197.7 (CO).
MS (ESI): m/z (%) = 495 (100) [M + H]+.
4-[4-(2-Phenyl-1H-indol-3-yl)quinolin-2-yl]benzonitrile (4fa)
Yield: 51%; mp 275 °C (dec.).
IR (KBr): 3318, 3940, 2900, 2822, 2200, 1720, 1590, 1572, 1438,
1223 cm–1.
1H NMR (DMSO-d6): d = 7.01 (d, J = 7.5 Hz, 1 H), 7.22–7.16 (m,
5 H), 7.41–7.35 (m, 3 H), 7.57 (d, J = 8.0 Hz, 1 H), 7.71 (d, J =
8.0 Hz, 2 H), 7.91 (d, J = 8.3 Hz, 2 H), 8.09 (s, 1 H), 8.16 (d, J =
8.6 Hz, 1 H), 8.39 (d, J = 8.3 Hz, 2 H), 11.94 (s, 1 H, NH).
MS (ESI): m/z (%) = 439 (100) [M + H]+.
4-{3-[2-(4-Acetylphenyl)quinolin-4-yl]-1H-indol-2-yl}benzoni-
trile (4dd)
Yield: 60%; mp 290 °C (dec.).
IR (KBr): 3366, 3058, 2926, 2866, 2226, 1679, 1605, 1267, 1239
cm–1.
13C NMR (DMSO-d6): d = 108.6 (C), 111.6 (CH), 111.9 (C), 118.6
(C), 118.7 (CH), 120.0 (CH), 120.7 (CH), 122.2 (CH), 126.1 (CH),
Synthesis 2011, No. 24, 4084–4090 © Thieme Stuttgart · New York

4090
A. Arcadi et al.
PAPER
126.61 (CH), 126.63 (CH), 127.5 (2CH), 127.9 (2CH), 128.1 (C),
128.4 (2CH), 128.8 (C), 129.8 (2CH), 131.8 (C), 132.5 (2CH),
136.0 (C), 136.3 (C), 142.9 (C), 144.1 (C), 148.4 (C), 153.9 (CN).
MS (ESI): m/z (%) = 422 (100) [M + H]+.
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Acknowledgment
This work was financed by the Ministero dell’Università e della
Ricerca, Rome, and by the University of L’Aquila.
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Synthesis 2011, No. 24, 4084–4090 © Thieme Stuttgart · New York