4-chloro-3-iodoquinoline as a synthon in the development of new syntheses of 1,2-disubstituted 1H-pyrrolo[3,2- c ]quinolines

Article abstract of DOI:10.1055/s-0031-1289909

New syntheses of novel 1,2-pyrrolo[3,2-c]quinolines were established using 4-chloro-3-iodoquinoline as a synthon. The approach involved a palladium-catalyzed Sonogashira reaction of 4-chloro-3-iodoquinoline with appropriate arylacetylenes, followed by nuc

Full text of DOI:10.1055/s-0031-1289909

LETTER
2955
4-Chloro-3-iodoquinoline as a Synthon in the Development of New Syntheses
of 1,2-Disubstituted 1H-Pyrrolo[3,2-c]quinolines
1
, 2-Disubstituted 1
n
H
-Pyrrolo[
3
d
,2-
c
]quinolin
r
e
s
eia I. S. Almeida, Artur M. S. Silva,* José A. S. Cavaleiro
Department of Chemistry & QOPNA, University of Aveiro, 3810-193 Aveiro, Portugal
Fax +351(234)370084; E-mail: artur.silva@ua.pt
Received 26 September 2011
in the presence of [Pd(PPh3)4] as catalyst and CuI as co-
Abstract: New syntheses of novel 1,2-pyrrolo[3,2-c]quinolines
were established using 4-chloro-3-iodoquinoline as a synthon. The
approach involved a palladium-catalyzed Sonogashira reaction of
4-chloro-3-iodoquinoline with appropriate arylacetylenes, followed
catalyst.20 Under these conditions 4-chloro-3-(phenyl-
ethynyl)quinoline (4a) was obtained in very good yield
(85%). We then extended the reaction to include arylace-
by nucleophilic displacement of chlorine and cyclization. Studies tylenes 3b and 3c and found that the expected Sonoga-
shira products 4b and 4c21 were also obtained in good
on the reaction of 4-chloroquinoline derivatives with sodium azide
led to the unexpected 4-aminoquinolines.
yields (57–75%),20 with some starting dihaloquinoline 2
Key words: pyrrolo[3,2-c]quinoline, Sonogashira reaction, nucleo-
philic substitution reaction, dihaloquinolines, 4-aminoquinolines
(10–18%) being recovered (Scheme 1).
We then considered the reactivity of 4a with an excess of
a high boiling point (196 °C) aliphatic amine, 2-phenyl-
ethylamine (PEA; 5), at 140 °C for 1 hour. Under these
conditions, 4-[(2-phenylethyl)amino]-3-(phenylethynyl)-
quinoline22 (6a) was obtained in moderate yield (51%),
together with a large amount of degradation products. In
order to circumvent the degradation problem, the reaction
was carried out at 60 °C for a longer reaction time
(24 h),23 with 6a being obtained in a better yield (67%).
These optimal conditions were applied to other deriva-
tives (4b and 4c) and it was found that the corresponding
3-(arylethynyl)-4-[(2-phenylethyl)amino]quinolines (6b
and 4c) were obtained in good yields (60–65%;
Scheme 1).
Pyrroloquinolines have awakened the interest of several
research groups, especially since martinelline and marti-
nellic acid, which are two pyrrolo[3,2-c]quinoline alka-
loids, were isolated from the root of Martinella
iquitosensis.1 These polynuclear heterocycles are known
for their wide range of pharmacological applications.2–4 In
fact, certain pyrrolo[3,2-c]quinoline derivatives present
antitumor activity,5 cytotoxicity against leukemia cells,6
and inhibit enzymes viewed as important therapy targets
for peptic ulcers7,8 and Parkinson’s disease.9 All these
properties highlight these compounds as interesting tar-
gets of research.
The intramolecular cyclization of compounds 6a–c to
yield 1H-pyrrolo[3,2-c]quinolines 7a–c was achieved by
treating 6a–c with CuI (5% mol) in anhydrous toluene at
reflux.24 Pyrrolo[3,2-c]quinolines 7a and 7b25 were ob-
tained in good yields (60–85%) after 20–24 hours reaction
time. However, 7c was only obtained in poor yield (18%),
and even after 36 hours reaction time, 39% of the starting
material 6c was still recovered. Changing the solvent to
anhydrous 1,2,4-trichlorobenzene (TCB) to allow the re-
action temperature to be increased 160 °C, led to the for-
mation of 7c in better yield (40%) after 6 hours reaction
time (Scheme 1).
Although there are several methods for the synthesis of
pyrrolo[3,2-c]quinolines, synthetic routes for fully arom-
atized derivatives are not very abundant.7,10–13 In the last
decade, 1,2,3-10 and 1,2,4-trisubstituted,13 and 2,4-
disubstituted11 pyrrolo[3,2-c]quinolines were prepared by
palladium-catalyzed reactions of 3-iodoquinoline deriva-
tives. Following our interest in quinoline, 4-quinolone and
its halo-derivatives, and in palladium-catalyzed cross-
coupling reactions,14 we decided to study the use of 4-
chloro-3-iodoquinoline (2) as a synthon to establish new
synthetic routes for novel 1,2-disubstituted pyrrolo[3,2-
c]quinolines.
In order to eliminate one step of the described synthetic
route of pyrroloquinolines 7a–c from 4-chloro-3-(phenyl-
ethynyl)quinolines 4a–c, compound 4a was treated with
amine 5, in the presence of CuI (10% mol) and potassium
tert-butoxide in anhydrous toluene at reflux for 24 hours.
Under these conditions, large amounts of degradation
products were observed in the reaction mixture, and 7a
was obtained in poor yield (7%). Trying to circumvent
this degradation problem, the reaction of 4a with amine 5
was performed in the presence of only CuI at 70 °C for
30 hours. Under these conditions, only the nucleophilic
displacement of chlorine occurred. Pyrroloquinoline 7a
was obtained in low yield (35%) when the reaction was
One of the most efficient ways to form C(sp2)–C(sp)
bonds is the cross-coupling Sonogashira reaction,15 which
involves the reaction of terminal alkynes with heteroaryl
or aryl halides in the presence of palladium catalysts and
a copper(I) salt as co-catalyst.16 Our study started with a
Sonogashira reaction of 4-chloro-3-iodoquinoline (2),17
obtained by chlorination of 3-iodoquinolin-4(1H)-one
(1)18 with POCl3,19 with an excess of phenylacetylene (3a)
SYNLETT 2011, No. 20, pp 2955–2958
x
x
.x
x
.2
0
1
1
Advanced online publication: 28.11.2011
DOI: 10.1055/s-0031-1289909; Art ID: D30611ST
© Georg Thieme Verlag Stuttgart · New York

2956
A. I. S. Almeida et al.
LETTER
performed at 140 °C for 6.5 hours. Attempts to improve The next step of our study considered the reactivity of 4a
the yield by changing the solvent to anhydrous N,N-di- towards aromatic amines bearing an electron-donating
methylformamide (DMF) or anhydrous toluene, and by group (p-anisidine; 11a) and an electron-withdrawing
decreasing the amount of amine 5 and reducing the tem- group (p-nitroaniline; 11b; Scheme 1). The reaction of 4-
perature (to 100 °C) were unsuccessful (Scheme 1). The chloro-3-(phenylethynyl)quinoline (4a) with p-anisidine
optimal conditions were applied to the other derivatives in anhydrous DMF at 140 °C, for 2 hours, led to the for-
4b and 4c, but only pyrroloquinoline 7b was obtained mation of 1-(4-methoxyphenyl)-2-phenyl-1H-pyrrolo-
(40%). Compound 7c was finally obtained (32%) when 4c [3,2-c]quinoline (12a)26 in moderate yield (40%). To im-
was treated with CuI (10 mol%) in hot (160 °C) anhy- prove the reaction yield, a larger excess of amine 11a was
drous 1,2,4-triclorobenzene for 16 hours.
used under solvent-free conditions at 100 °C, however,
the results were not improved and large amounts of deg-
radation products were obtained. The reaction of 4a with
p-nitroaniline 11b in anhydrous DMF at 140 °C, afforded
pyrroloquinoline 12b in low yield (32%) over a longer re-
action time (21 h), due to the influence of the electron-
withdrawing character of the aromatic amine 11b.
In another attempt to remove a step of the synthesis of
pyrroloquinolines 7a–c we examined the Sonogashira
reaction of 3-iodo-4-[(2-phenylethyl)amino]quinoline
[obtained by treating 4-chloro-3-iodoquinoline (2) with
amine 5, at 80 °C for 20 h] with phenylacetylene (3a) un-
der the conditions described above, but increasing the
amount of CuI to 10% mol. However, only the Sonoga- To perform further derivatization of 4-chloro-3-(phenyl-
shira reaction occurred and the cyclized compound 7a was ethynyl)quinoline (4a), a 1,3-dipolar cycloaddition reac-
not obtained.
tion with sodium azide (5 equiv) was attempted. On
treatment of 4a with an excess of sodium azide (NaN3) in
anhydrous DMF at 120 °C for 1.3 hours,27 unexpectedly,
4-amino-3-(phenylethynyl)quinoline (13)28 was obtained
in good yield (60%). A longer reaction time (6 h) and a
larger amount of sodium azide (two additions of 5 equiv)
led to the formation of 13 in lower yield (35%; Scheme 2).
To explore the scope of this reaction, 2 was reacted with
NaN3 under similar reaction conditions (Scheme 2), with
4-amino-3-iodoquinoline (14) being obtained in good
yield (73%). The formation of products 13 and 14 can be
rationalized by a nucleophilic 4-chlorine displacement by
azide ion, followed by nitrogen loss and nitrene forma-
tion, and reaction of the latter with water.29
We then decided to extend our study to include pentyl-
amine 8, which is a lower-boiling-point (104 °C) aliphatic
amine. The reaction of 4-chloro-3-(phenylethynyl)quino-
line (4a) with an excess of amine 8, at 60 °C for 21 hours,
led to the formation of the expected 4-(pentylamino)-3-
(phenylethynyl)quinoline (9) in good yield (62%). Fur-
thermore, the intramolecular cyclization of 9 under the
conditions described above gave a new pyrroloquinoline
derivative 10 in good yield (70%; Scheme 1). Attempts to
obtain pyrroloquinoline 10 in a one-pot reaction from 4-
chloro-3-(phenylethynyl)quinoline (4a) and an excess of
amine 8, in the presence of CuI (10 mol%), under solvent-
free conditions either at 70 °C or in refluxing toluene,
were unsuccessful, with only compound 9 being obtained. All novel compounds synthesized here have been charac-
terized by NMR spectroscopy and by high-resolution
NH2
R
R1
H
N
8
5
N
N1
N
11a,b
(i)
8a
4a
3a–c
2
3
7
6
(viii)
(ii)
1'
I
I
4
2''
1''
Cl
3''
4''
O
2
N
1''
Cl
2'
1
6''
8
4a–c
1'
2'
6''
5''
R
2''
NH2
5''
6'
3'
H2N
(vi)
8
6
(iii)
N 5
(v)
N1
4''
(CH2)2
3''
8a
4a
4'
5a
9a
1''
R1
5'
(vii)
4
2
NH2
7
8
7
6
12a,b
5
3
3a
(CH2)2
1'
2''
N
3
4
5
9b
9
8
5
N1
1''
8a
3''
4''
5
2'
NH
N
7
6
2
2
1'''
1
1'
2'
3
6''
(iv)
1'
9
2'''
4a
4
2''
6'
5''
3'
2''
3''
3'''
N
1''
3''
1''
1'
2'
4'
2'
NH
5'
4'''
1'''
4''
4''
2''
R
5'''
3'
6''
2'''
6'
5'
6''''
1'''
R
6a–c
2'''
5''
5''
5''''
4''''
4'
3'''
1''''
2''''
10
6'''
R
4'''
7a–c
5'''
3''''
Scheme 1 Reagents and conditions: (i) POCl3, anhyd DMF, 80 °C, 1.5 h; (ii) [Pd(PPh3)4] (5% mol), CuI (4% mol), MeCN–Et3N (2:1), r.t.,
4–20 h; (iii) 60 °C, 24 h; (iv) CuI (5% mol); reflux, anhyd toluene (20–24 h for 7a/7b) or anhyd TCB (6 h at 160 °C for 7c); (v) CuI (10% mol),
140 °C (6.5 h for 7a/7b) or hot (160 °C) anhyd TCB (16 h for 7c); (vi) 60 °C, 21 h; (vii) CuI (5% mol), reflux, anhyd toluene, 1.25 h; (viii)
anhyd DMF, 140 °C, 2–21 h; (for a, R = H or R1 = OMe; b, R = OMe or R1 = NO2; c, R = NO2).
Synlett 2011, No. 20, 2955–2958 © Thieme Stuttgart · New York

LETTER
1,2-Disubstituted 1H-Pyrrolo[3,2-c]quinolines
2957
(5) Marquez, V. E.; Cranston, J. W.; Ruddon, R. W.; Kier, L. B.;
Burckhalter, J. H. J. Med. Chem. 1972, 15, 36.
(6) Helissey, P.; Parrot-Lopez, H.; Renault, J.; Cros, S.; Pauletti,
C. Eur. J. Med. Chem. 1987, 22, 277.
(7) Brown, T. H.; Ife, R. J.; Keeling, D. J.; Laing, S. M.; Leach,
C. A.; Parsons, M. E.; Price, C. A.; Reavill, D. R.; Wiggall,
K. J. J. Med. Chem. 1990, 33, 527.
(8) (a) Leach, C. A.; Brown, T. H.; Ife, R. J.; Keeling, D. J.;
Laing, S. M.; Parsons, M. E.; Price, C. A.; Wiggall, K. J.
J. Med. Chem. 1992, 35, 1845. (b) Abass, M. Heterocycles
2005, 65, 901; and references cited therein.
mass spectrometry. The most noticeable features in their
1H NMR spectra are a singlet at d = 5.33–6.74 ppm due
proton resonance of the NH group of all 4-aminoquino-
lines 6a–c and 9, a singlet at d = 6.65–7.09 ppm assigned
to the H-3 resonance of pyrroloquinolines 7a–c, 10, 12a
and 12b, a resonance due to the aliphatic protons H-1¢¢ and
H-2¢¢ (two triplets at d = 4.75–4.76 and 3.07–3.10 ppm, re-
spectively) of 7a–c, and the aliphatic proton resonances of
pyrroloquinoline 10.
(9) Heidempergher, F.; Pevarello, P.; Pillan, A.; Pinciroli, V.;
Della Torre, A.; Speciale, C.; Marconi, M.; Cini, M.; Toma,
S.; Greco, F.; Varasi, M. Farmaco 1999, 54, 152.
(10) Kang, S. K.; Park, S. S.; Kim, S. S.; Choi, J.-K.; Yum, E. K.
Tetrahedron Lett. 1999, 40, 4379.
N
N
(i)
NH2
Cl
(11) Koradin, C.; Dohle, W.; Rodriguez, A. L.; Schmid, B.;
Knochel, P. Tetrahedron 2003, 59, 1571.
13
4a
(12) (a) Nyerges, M. Heterocycles 2004, 63, 1685. (b) Colacino,
E.; Benakki, H.; Gunoum, F.; Martinez, J.; Lamaty, F. Synth.
Commun. 2009, 39, 1571.
(13) Mphahlele, M. J.; Lesenyeho, L. G.; Makelane, H. R.
Tetrahedron 2010, 66, 6040.
(14) (a) Almeida, A. I. S.; Silva, V. L. M.; Silva, A. M. S.; Pinto,
D. C. G. A.; Cavaleiro, J. A. S. Synlett 2008, 2593.
(b) Almeida, A. I. S.; Silva, A. M. S.; Cavaleiro, J. A. S.
Synlett 2010, 462. (c) Seixas, R. S. G. R.; Silva, A. M. S.;
Cavaleiro, J. A. S. Synlett 2010, 2257. (d) Silva, V. L. M.;
Silva, A. M. S.; Cavaleiro, J. A. S. Synlett 2010, 2565.
(15) Sonogashira, K. J. Organomet. Chem. 2002, 653, 46.
(16) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett.
1975, 4467.
N
N
(ii)
I
I
Cl
NH2
14
2
Scheme 2 Reagents and conditions: (i) NaN3, anhyd DMF, 120 °C,
1.3 h; (ii) NaN3, anhyd DMF, 120 °C, 22 h.
In conclusion, several novel 1,2-disubstituted pyrro-
lo[3,2-c]quinolines (7a–c, 10, 12a, 12b) and 4-(alkyl-
amino)-3-(arylethynyl)quinolines (6a–c and 9) were syn-
thesized in very good yields using the synthon 4-chloro-3-
iodoquinoline (2). The reaction of 3-(arylethynyl)-4-chlo-
roquinolines 4a–c with aromatic and aliphatic amines led
directly to pyrrolo[3,2-c]quinolines 7a–c, 12a and 12b al-
beit in lower yields. Better yields were obtained with ali-
phatic amines under conditions that led sequentially to
halogen nucleophilic displacement followed by intramo-
lecular pyrrole ring formation. 4-Aminoquinoline deriva-
tives 13 and 14 were obtained from the reaction of 4-
chloro-3-iodoquinoline (2) and 4-chloro-3-(phenylethy-
nyl)quinoline (4a) with sodium azide.
(17) 4-Chloro-3-iodoquinoline (2): Mp 91–92 °C. 1H NMR
(300 MHz, CDCl3): d = 7.63 (ddd, J = 8.0, 7.0, 1.0 Hz, 1 H,
H-6), 7.79 (ddd, J = 8.0, 7.0, 1.1 Hz, 1 H, H-7), 8.10 (d, J =
8.0 Hz, 1 H, H-8), 8.27 (dd, J = 8.0, 1.1 Hz, 1 H, H-5), 9.16
(s, 1 H, H-2); 13C NMR (75 MHz, CDCl3): d = 95.0 (C-3),
124.9 (C-5), 127.6 (C-4a), 128.5 (C-6), 129.8 (C-8), 130.6
(C-7), 146.0 (C-4), 147.6 (C-8a), 156.5 (C-2). MS (ESI+):
m/z (%) = 289 (100) [M + H]+. HRMS (ESI+): m/z calcd for
[C9H5ClIN + H]+: 289.9233; found: 289.9235
(18) For the preparation of 3-iodoquinolin-4 (1H)-one (1), see:
Almeida, A. I. S.; Silva, A. M. S.; Cavaleiro, J. A. S. Synlett
2010, 462.
(19) Optimized procedure for the synthesis of 4-chloro-3-
iodoquinoline (2): POCl3 (2.04 mL, 22.08 mmol) was added
to a solution of 3-iodoquinolin-4 (1H)-one (1; 200 mg, 0.74
mmol) in anhyd DMF (4 mL), in an ice bath. After the
addition, the reaction mixture was stirred at 80 °C, under an
N2 atmosphere for 1.5 h. Then the reaction mixture was
poured into H2O (50 mL) and ice (20 g) and neutralized with
NaHCO3. The obtained solid was filtered, taken in EtOAc
(50 mL) and washed with H2O (3 × 50 mL). The organic
layer was dried with anhyd Na2SO4 and evaporated to
dryness. The residue was recrystallized (CH2Cl2–light
petroleum) to give 4-chloro-3-iodoquinoline (2; 137.1 mg,
67%) as a pale-yellow solid.
(20) Optimized procedure for the synthesis of 3-
(arylethynyl)-4-chloroquinolines 4a–c: [Pd(PPh3)4]
(21.2 mg, 0.018 mmol), CuI (3.3 mg, 0.014 mmol) and the
appropriate alkyne 3a–c (0.67 mmol) were added to a
solution of 4-chloro-3-iodoquinoline (2; 106 mg, 0.366
mmol) in a MeCN–Et3N (2:1) mixture. The reaction mixture
was stirred at r.t. for 4 h (to obtain 4a) or 20 h (to obtain 4b/
4c), under an N2 atmosphere. After that period, the mixture
was poured into H2O (25 mL), neutralized with dilute
aqueous solution of HCl, and the organic layer was extracted
Acknowledgment
Thanks are due to the University of Aveiro, FCT and FEDER for
funding the Organic Chemistry Research Unit and the Portuguese
National NMR Network (RNRMN). A.I.S.A. also thanks the FCT
for her PhD Grant (SFRH/BD/40632/2007).
References and Notes
(1) Witherup, K. M.; Ransom, R. W.; Graham, A. C.; Bernard,
A. M.; Salvatore, M. J.; Lumma, W. C.; Anderson, P. S.;
Pitzenberger, S. M.; Varga, S. L. J. Am. Chem. Soc. 1995,
117, 6682.
(2) Okanya, P. W.; Mohr, K. I.; Gerth, K.; Jansen, R.; Müller, R.
J. Nat. Prod. 2011, 74, 603.
(3) Ferlin, M. G.; Marzano, C.; Via, L. D.; Chilin, A.; Zagotto,
G.; Guiotto, A.; Moro, S. Bioorg. Med. Chem. 2005, 13,
4733.
(4) Metobo, S.; Mish, M.; Jin, H.; Jabri, S.; Lansdown, R.; Chen,
X.; Tsiang, M.; Wright, M.; Kim, C. U. Bioorg. Med. Chem.
Lett. 2009, 19, 1187.
Synlett 2011, No. 20, 2955–2958 © Thieme Stuttgart · New York

2958
A. I. S. Almeida et al.
LETTER
silica gel column chromatography (light petroleum to
remove the TCB, then CH2Cl2–acetone, 5:1) to give purified
7c (21.7 mg, 40%) as a brown oil.
with EtOAc (3 × 50 mL), dried with anhyd Na2SO4, and
concentrated. The crude product was purified by preparative
thin layer chromatography (light petroleum–EtOAc, 56:4).
3-(Arylethynyl)-4-chloroquinolines 4a–c were obtained
without recrystallization (4a: 82.0 mg, 85%; 4b: 80.6 mg,
75%; 4c: 64.4 mg, 57%) as yellow solids. In addition, 10 and
18% of starting material were recovered for derivatives 3b
and 3c, respectively.
(25) Physical data of 1-(2-phenylethyl)-2-(4-methoxyphenyl)-
1H-pyrrolo[3,2-c]quinoline (7b). Mp 143–144 °C. 1H
NMR (300 MHz, CDCl3): d = 3.10 (t, J = 7.4 Hz, 2 H, H-2¢¢),
3.90 (s, 3 H, 4¢-OCH3), 4.76 (t, J = 7.4 Hz, 2 H, H-1¢¢), 6.65
(s, 1 H, H-3), 6.82–6.86 (m, 2 H, H-2¢¢¢,6¢¢¢), 6.97 (d,
J = 8.8 Hz, 2 H, H-3¢,5¢), 7.17–7.23 (m, 3 H, H-3¢¢¢,4¢¢¢,5¢¢¢),
7.19 (d, J = 8.8 Hz, 2 H, H-2¢,6¢), 7.64–7.69 (m, 2 H, H-7,
H-8), 8.29–8.33 (m, 1 H, H-6), 8.43–8.46 (m, 1 H, H-9),
9.19 (s, 1 H, H-4); 13C NMR (75 MHz, CDCl3): d = 36.3 (C-
2¢¢), 47.7 (C-1¢¢), 55.4 (4¢-OCH3), 103.0 (C-3), 113.8 (C-
3¢,5¢), 118.8 (C-9a), 120.5 (C-9), 121.7 (C-3a), 124.4 (C-1¢),
125.9 (C-7 and C-8), 126.8 (C-4¢¢¢), 128.6 (C-2¢¢¢,6¢¢¢ and C-
3¢¢¢,5¢¢¢), 130.9 (C-6), 131.4 (C-2¢,6¢), 133.7 (C-9b), 137.3
(C-1¢¢¢), 141.8 (C-2), 144.7 (C-5a), 146.3 (C-4), 159.8 (C-
4¢). MS (ESI+): m/z (%) = 379 (100) [M + H]+. HRMS
(ESI+): m/z calcd for [C26H22N2O + H]+: 379.1810; found:
379.1806.
(26) Physical data of 1-(4-methoxyphenyl)-2-phenyl-1H-
pyrrolo[3,2-c]quinoline (12a). Mp 171–171 °C. 1H NMR
(300 MHz, CD3OD): d = 3.92 (s, 3 H, 4¢¢-OCH3), 7.09 (s,
1 H, H-3), 7.12 (d, J = 8.9 Hz, 2 H, H-3¢¢, 5¢¢), 7.25–7.31 (m,
5 H, H-8, H-9, H-4¢, H-2¢¢,6¢¢), 7.35–7.39 (m, 4 H, H-
2¢,3¢,5¢,6¢), 7.54–7.59 (m, 1 H, H-7), 8.10 (d, J = 8.4 Hz, 1 H,
H-6), 9.15 (s, 1 H, H-4); 13C NMR (75 MHz, CD3OD): d =
46.6 (4¢¢-OCH3), 95.0 (C-3), 106.5 (C-3¢¢, 5¢¢), 110.1 (C-9a),
112.5 (C-9), 112.9 (C-3a), 117.2 (C-8), 118.1 (C-7), 119.5
(C-4¢), 119.7 (C-2¢¢, 6¢¢), 120.3 (C-6), 121.3 (C-3¢, 5¢), 122.3
(C-2¢, 6¢), 123.6 (C-1¢ or C-1¢¢), 123.7 (C-1¢ or C-1¢¢), 127.9
(C-9b), 134.5 (C-2), 135.7 (C-5a), 137.3 (C-4), 152.4 (C-
4¢¢). MS (ESI+): m/z (%) = 251 (100) [M + H]+. HRMS
(ESI+): m/z calcd for [C24H18N2O + H]+: 251.1497; found:
251.1498.
(21) 4-Chloro-3-[(4-methoxyphenyl)ethynyl]quinoline (4b).
Mp 110–111 °C. 1H NMR (500 MHz, CDCl3): d = 3.86 (s,
3 H, 4¢¢-OCH3), 6.93 (d, J = 8.9 Hz, 2 H, H-3¢¢,5¢¢), 7.59 (d,
J = 8.9 Hz, 2 H, H-2¢¢,6¢¢), 7.68 (ddd, J = 7.9, 7.1, 0.5 Hz,
1 H, H-6), 7.76 (ddd, J = 8.0, 7.1, 1.1 Hz, 1 H, H-7), 8.11 (d,
J = 8.0 Hz, 1 H, H-8), 8.27 (d, J = 7.9 Hz, 1 H, H-5), 8.95 (s,
1 H, H-2); 13C NMR (125 MHz, CDCl3): d = 55.4 (4¢¢-
OCH3), 83.2 (C-1¢), 98.1 (C-2¢), 114.4 (C-3¢¢,5¢¢), 114.7 (C-
1¢¢), 117.9 (C-3), 124.3 (C-5), 126.0 (C-8a), 128.2 (C-6),
129.8 (C-4a), 130.4 (C-7), 133.8 (C-2¢¢,6¢¢), 142.7 (C-4),
147.2 (C-9), 151.9 (C-2), 160.3 (C-4¢¢). MS (ESI+): m/z (%)
= 294 (100) [M + H]+. HRMS (ESI+): m/z calcd for
[C18H12ClNO + H]+: 294.0686; found: 294.0689.
(22) Physical data of 4-[(2-phenylethyl)amino]-3-[(4-
nitrophenyl)ethynyl]quinoline (6c). Mp (dp) 189–190 °C.
1H NMR (300 MHz, CDCl3): d = 3.10 (t, J = 6.7 Hz, 2 H, H-
2¢¢¢), 4.40 (dt, J = 6.7, 6.5 Hz, 2 H, H-1¢¢¢), 5.39 (br s, 1 H,
NH), 7.25–7.33 (m, 5 H, 2¢¢¢-Ph), 7.41–7.48 (m, 1 H, H-6),
7.49 (d, J = 8.8 Hz, 2 H, H-2¢¢,6¢¢), 7.63–7.69 (m, 1 H, H-7),
7.72 (d, J = 8.5 Hz, 1 H, H-5), 7.98 (d, J = 8.5 Hz, 1 H, H-8),
8.19 (d, J = 8.8 Hz, 2 H, H-3¢¢,5¢¢), 8.66 (s, 1 H, H-2); 13
C
NMR (75 MHz, CDCl3): d = 36.7 (C-2¢¢¢), 47.1 (C-1¢¢¢), 93.1
(C-1¢ or C-2¢), 93.3 (C-1¢ or C-2¢), 96.7 (C-3), 118.7 (C-4a),
120.5 (C-5), 123.7 (C-3¢¢,5¢¢), 125.7 (C-6), 127.0 (C-4¢¢¢¢),
128.8 (C-2¢¢¢¢,6¢¢¢¢ or C-3¢¢¢¢,5¢¢¢¢), 128.9 (C-2¢¢¢¢,6¢¢¢¢ or C-
3¢¢¢¢,5¢¢¢¢), 130.2 (C-8), 130.3 (C-7), 131.4 (C-2¢¢,6¢¢), 131.8
(C-1¢¢), 137.8 (C-1¢¢¢¢), 146.7 (C-4¢¢), 148.0 (C-8a), 151.1 (C-
4), 154.4 (C-2). MS (ESI+): m/z (%) = 394 (100) [M + H]+.
HRMS (ESI+): m/z calcd for [C25H19N3O2 + H]+: 394.1556;
found: 394.1540.
(27) Optimized procedure for the synthesis of 4-amino-3-
(phenylethynyl)quinoline (13). NaN3 (61.8 mg, 0.95
mmol) was added to a solution of 4-chloro-3-(phenyl-
ethynyl)quinoline (4a; 50 mg, 0.19 mmol) in anhyd DMF (2
mL) and the mixture was stirred at 120 °C, under an N2
atmosphere for 1.3 h. After that period, the mixture was
added into H2O (50 mL) and ice (20 g), neutralized with
dilute aqueous HCl solution, and the organic layer was
extracted with EtOAc (3 × 50 mL), dried with anhyd
Na2SO4, and concentrated. The residue was taken up in
acetone and purified by preparative thin layer
(23) Optimized procedure for the synthesis of 3-
(arylethynyl)-4-[(2-phenylethyl)amino]quinolines 6a–c:
A mixture of 3-(arylethynyl)-4-chloroquinolines 4a–c
(0.288 mmol) and 2-phenylethylamine (5; 2.9 mL, 2.88
mmol) was stirred at 60 °C for 24 h, under an N2
atmosphere. The mixture was poured into H2O (50 mL),
neutralized with a dilute aqueous solution of HCl, and the
organic layer was extracted with EtOAc (3 × 50 mL), dried
with anhyd Na2SO4, and concentrated. The residue was
purified by preparative thin layer chromatography (CH2Cl2–
acetone, 36:04). 3-(Arylethynyl)-4-[(2-phenylethyl)amino]-
quinolines 6a–c were obtained without recrystallization (6a:
67.0 mg, 67%; 6b: 70.8 mg, 65%; 6c: 73.7 mg, 60%) as
yellow solids.
chromatography using CH2Cl2 as solvent. 4-Amino-3-
(phenylethynyl)quinoline (13; 33.4 mg, 72%) was obtained
after recrystallization (CH2Cl2–light petroleum) as an off-
white solid.
(28) Physical data of 4-amino-3-(phenylethynyl)quinoline
(13). Mp 205–206 °C. 1H NMR (300 MHz, acetone-d6):
d = 6.74 (s, 2 H, NH2), 7.41–7.47 (m, 3 H, H-3¢¢,4¢¢,5¢¢), 7.51
(ddd, J = 8.0, 7.0, 1.1 Hz, 1 H, H-6), 7.64–7.72 (m, 3 H, H-
7, H-2¢¢,6¢¢), 7.91 (d, J = 8.7 Hz, 1 H, H-8), 8.26 (d,
J = 8.0 Hz, 1 H, H-5), 8.60 (s, 1 H, H-2); 13C NMR (75
MHz, acetone-d6): d = 85.2 (C-1¢), 97.2 (C-2¢), 98.1 (C-3),
118.2 (C-4a), 122.6 (C-5), 124.3 (C-1¢¢), 125.8 (C-6), 129.1
(C-4¢¢), 129.3 (C-3¢¢, 5¢¢), 130.4 (C-7), 130.5 (C-8), 132.2 (C-
2¢¢, 6¢¢), 148.9 (C-8a), 152.7 (C-4), 152.9 (C-2). MS (ESI+):
m/z (%) = 245 (100) [M + H]+. HRMS (ESI+): m/z calcd for
[C17H12N2 + H]+: 245.1079; found: 245.1064.
(24) Optimized procedure for the synthesis of 2-aryl-1-(2-
phenylethyl)-1H-pyrrolo[3,2-c]quinolines 7a–c:
A mixture of 3-(arylethynyl)-4-[(2-phenylethyl)amino]-
quinolines 6a–c (0.138 mmol) and CuI (5.23 mg, 0.0276
mmol) in anhyd toluene (4 mL) was stirred at 120 °C, under
an N2 atmosphere for 20 h (6a) or 24 h (6b). After that
period, the solvent was evaporated and the residue was taken
up in EtOAc and purified by preparative thin layer
chromatography (CH2Cl2–acetone, 36:4). Recrystallization
(light petroleum–CH2Cl2) gave 2-aryl-1-(2-phenylethyl)-
1H-pyrrolo[3,2-c]quinolines 7a/7b as yellow solids (7a:
40.8 mg, 85%, 7b: 31.3 mg, 60%). In the case of 7c, anhyd
1,2,4-trichlorobenzene (3 mL) was used at 160 °C for 6 h,
under an N2 atmosphere. The crude material was purified by
(29) (a) L’abbe, G. Chem. Rev. 1969, 69, 345. (b) Budyka, M.
F.; Kantor, M. M.; Pleshkova, A. P. Russ. Chem. Bull. 1990,
39, 605. (c) Arenas, J. F.; Marcos, J. I.; Otero, J. C.; Tocón,
I. L.; Soto, J. Int. J. Quantum Chem. 2001, 84, 241.
Synlett 2011, No. 20, 2955–2958 © Thieme Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not be copied or
emailed to multiple sites or posted to a listserv without the copyright holder's express written permission.
However, users may print, download, or email articles for individual use.