Transformations of 2-aryl-4-(2-oxopyrrolidinyl-1)-1,2,3,4- tetrahydroquinolines, cycloadducts of the BiCl3-catalyzed three-component Povarov reaction: Oxidation and reduction processes towards new potentially bioactive 2-arylquinoline derivativ

Article abstract of DOI:10.1002/jhet.441

(Chemical Equation Presented) Synthesis and spectral characterization of new series of 2-aryl-4-(2-oxopyrrolidinyl-1)-1,2,3,4-tetrahydroquinolines and their aromatic analogs, 2-arylquinolines are reported. It was found that substituted tetrahydroquinoline

Full text of DOI:10.1002/jhet.441

1148
Transformations of 2-Aryl-4-(2-oxopyrrolidinyl-1)-1,2,3,4-
tetrahydroquinolines, Cycloadducts of the BiCl3-Catalyzed Three-
Component Povarov Reaction: Oxidation and Reduction
Processes Towards New Potentially Bioactive
Vol 47
2-Arylquinoline Derivatives
´ ´
Vladimir V. Kouznetsov,* Carlos M. Melendez Gomez,
´
and John H. Bermudez Jaimes
´
´
´
Laboratorio de Quımica Organica y Biomolecular, Escuela de Quımica, Universidad Industrial de
Santander, A.A. 678, Bucaramanga, Colombia
*E-mail: kouznet@uis.edu.co
Received October 19, 2009
DOI 10.1002/jhet.441
Published online 26 July 2010 in Wiley Online Library (wileyonlinelibrary.com).
Synthesis and spectral characterization of new series of 2-aryl-4-(2-oxopyrrolidinyl-1)-1,2,3,4-tetrahy-
droquinolines and their aromatic analogs, 2-arylquinolines are reported. It was found that substituted tet-
rahydroquinoline precursors are easily prepared using BiCl3-catalyzed three-component Povarov
reaction between 4-nitrobenzaldehyde or 2-naphtylcarboxyaldehyde, anilines and N-vinylpyrrolidin-2-
one, and could be transformed via oxidation and reduction processes into potentially bioactive 2-arylqui-
noline derivatives, unsubstituted at the C-4 position. The all set of (tetrahydro)quinolines were charac-
1
terized by IR, H and 13C-NMR spectroscopy.
J. Heterocyclic Chem., 47, 1148 (2010).
INTRODUCTION
or both. Moreover, the number of these commercially
available reagents is exceedingly small that limits the
preparation of quinolines substituted on the quinoline
aryl moiety.
Quinoline and tetrahydroquinoline structures are
essential feature of many natural products. These hetero-
cycles play a key role in heterocyclic and medicinal
chemistry. Their syntheses by various methodologies
have been published extensively [1–4]. Polyfunctional-
ized tetrahydroquinolines (THQs) are molecules of great
interest in organic synthesis because many natural prod-
ucts present this system in their structure, and these
compounds exhibit diverse biological activities [5–9].
Apart from their marked bioactivities, THQs are also
important and reliable precursors in quinoline prepara-
tion, another group of heterocyclic molecules that has a
great number of pharmacological properties [10]. How-
ever, general syntheses of functionalized quinolines sub-
stituted at the C-2 position and unsubstituted at the C-3
and C-4 positions are less common [11], and often suf-
fer from harsh reaction conditions, expensive reagents,
For these reasons, the synthesis of new THQs is still
of great interest. An efficient route for the preparation
of THQs is the acid-catalyzed Povarov reaction that is
classified as imino Diels-Alder cycloaddition [11,12].
Moreover, this methodology that permits the condensa-
tion of anilines, aldehydes, and electron-rich alkenes
using acidic catalysts under mild conditions to afford
new tetrahydroquinolines, can overcome synthetic limi-
tations for the construction of functionalized quinolines
substituted at the C-2 position and unsubstituted at the
C-3 and C-4 positions and are useful tool for the genera-
tion of quinoline derivatives with several degrees of
structural diversity. Then, appropriate choice of alde-
hydes and alkenes in this cycloaddition reaction
C
V
2010 HeteroCorporation

September 2010 Transformations of 2-Aryl-4-(2-oxopyrrolidinyl-1)-1,2,3,4-tetrahydroquinolines,
Cycloadducts of the BiCl3-Catalyzed Three-Component Povarov Reaction
1149
Scheme 1
and COSY), it was found that the cis-diastereoisomer
was prevalent in all of the cases studied. For example,
from 1H-NMR spectrum of comp. 4, it could clearly
observed two doublets of doublets at 5.69 ppm (J3,4
¼
11.1 and 6.4 Hz) and 4.65 ppm (J2,3 ¼ 10.7 and 3.1 Hz)
that correspond to the THQ protons 4-H and 2-H,
respectively.
The large vicinal coupling confirmed strongly axial–
axial dispositions of the THQ protons 4-H and 2-H and,
consequently, the substituents at C-4 and C-2 should
have an equatorial disposition that indicates at a cis con-
figuration of the THQ ring.
provides a facile entry to heterocyclic systems which is
an essential moiety in many active pharmaceuticals.
As a part of our research program on the N-aryl
imines towards the synthesis of bioactive substituted tet-
rahydroquinolines and quinolines, we are pursuing
investigations on the synthesis of small drug-like (tetra-
hydro)quinoline molecules containing C-2 aryl fragment,
those synthesis could be accomplished via cycloaddition
reactions. We now want to report simple preparation of
new 2-aryl-4-(2-oxopyrrolidinyl-1)-1,2,3,4-tetrahydroqui-
nolines using BiCl3-catalyzed three component Povarov
reaction between 4-nitrobenzaldehyde or 2-naphtylcar-
boxyaldehyde, anilines and N-vinylpyrrolidin-2-one
(NVP), and their transformations into potentially bioac-
tive 2-arylquinoline derivatives, unsubstituted at the C-4
position.
Having stable solid THQ derivatives in our hands, we
realized some simple chemical transformations, which
resulted in the efficient preparation of quinoline mole-
cules 10–14 (Scheme 2). First, to obtain new 2-(4-ami-
nophenyl)-THQs 8,9, we analysed reduction process of
nitro derivatives 4,5 under different reaction conditions.
The conventional hydrogenation process [H2/Pd-C
(10%)/MeOH] always gave in moderate yields the
desired products, contaminated with side-products. The
change of solvent nature (MeOH ! MeOH/CH2Cl2) in
H2/Pd-C hydrogenation reaction (method A) did not
improve this situation. Thus, we addressed to another
reduction reaction that uses NaBH4 and NiCl2 in
MeOH/CH2Cl2 (method B) that resulted an efficient and
selective system, which satisfied to our plans. Under
these reaction conditions, it was possible to prepare
desired cis-2-(4-aminophenyl)-THQs 8,9 in good yields.
However, it should be noted that among different
attempts to find ideal conditions for hydrogenation pro-
cess of comp. 4 we tested also a H2/Pd-C/MeCN-MeOH
system (method C) that allowed obtaining an unex-
pected quinoline product 10. This formation could be
assumed as a result of subsequent three processes: (1)
RESULTS AND DISCUSSION
Planning synthesis of new 2-arylquinoline derivatives,
we paid attention the following considerations: (i) N-
vinylpyrrolidin-2-one (NVP) is very active electron-rich
alkene in this reaction [13–16] and it is an available,
stable, and cheap reagent. Moreover, 2-oxopyrrolidinyl
moiety on the tetrahydroquinoline ring could be easily
removed; (ii) 4-nitrobenzaldehyde could provide 4-ami-
nophenyl fragment, those synthetic utilization to con-
struct N-heterocycles is well recognized; (iii) 2-naphtyl-
carboxyaldehyde was chosen for the preparation of new
2-naphtylquinolines, aromatic planar molecules, and
interesting models in biological tests (anticancer
activity).
Table 1
Tetrahydroquinolines 4–9 and quinolines 10–14 prepared by imino
Diels-Alder reaction.
Comp. R1
R2
R3
Ar
Mp (ꢁC) Yield (%)
4
5
6
7
8
9
10
11
12
13
14
H
Me
H
Me
H
Me
H
H 4-NO2Ph
Me 4-NO2Ph
222–223
239–240
95
98
72
90
So, using BiCl3-catalyzed (20 mol %) three compo-
nent Povarov reaction between anilines 1a,b, aldehydes
2a,b and NVP 3 in MeCN, a new series of the function-
alised THQs 4–7 was easily prepared in excellent yields
(Scheme 1).
Me
H
H
2-Naphtyl 214–215
Me 2-Naphtyl 182–183
4-NH2Ph
Me 4-NH2Ph
Me
H
Me
Me
H
H
233–234 95a (54)b
Me
H
183–185
4-NHEtPh 149–151
97a
47c
89a
73a
87
H
H
H
Me
H
4-NH2Ph
178–179
115–116
2-Naphtyl 160–161
Structural elucidation of obtained solid substances
(Table 1) was started with IR analysis that indicated at
the presence of characteristic intensive bands in zone
3394, 3271, and 1666 cmꢀ1 (NH and C¼¼O for all
comp. 4–7), and also 1512 and 1342 cmꢀ1 (NO2 for
comp. 4,5). From their spectral analyses (1H-, 13C-NMR
Me 4-NH2Ph
Me
H
H
Me
Me 2-Naphtyl 86–87
73
a Obtained by method B.
b Obtained by method A.
c Obtained by method C.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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V. V. Kouznetsov, C. M. Melendez Gomez, and J. H. Bermudez Jaimes
1150
Vol 47
Scheme 2
KBr. H, 13C-NMR spectra were recorded on Bruker AM-400
spectrometer. Chemical shifts are reported in ppm (d) relative
to the solvent peak (CHCl3 in CDCl3 at 7.24 ppm for protons).
Signals are designated as follows: s, singlet; d, doublet; dd,
doublet of doublets; ddd, doublet of doublets of doublets; t, tri-
plet; td, triplet of doublets; q, quartet; sp, septet; m, multiplet;
b, broad. A Hewlett Packard 5890a series II Gas Chromato-
graph interfaced to an HP 5972 Mass Selective Detector
(MSD) with an HP MS Chemstation Data system was used for
ms identification at 70 EV using a 60 m capillary column
coated with HP-5 [5%-phenyl-poly(dimethyl-siloxane)]. Ele-
mental analyses were performed on a Perkin–Elmer 2400 Se-
ries II analyzer and were within 60.4 of theoretical values.
The reaction progress was monitored using thin layer chroma-
tography on a silufol UV254 TLC aluminium sheet.
General procedure for the imino Diels-Alder reaction of
anilines, aldehydes and NVP. To a solution of the appropri-
ate aniline (1.00 mmol) and aldehyde (1 mmol) in anhydrous
CH3CN (20 mL) under N2 atmosphere, was added 20 mol %
BiCl3 (0.57 mmol) and N-vinylpyrrolidone (1.2 mmol). The
reaction mixture was stirred at room temperature for 4 h and
then quenched with a solution of Na2CO3. The organic layer
was separated, and dried with Na2SO4. The organic solvent
was removed in vacuo and the product purified with chroma-
tography column (hexane/ethyl acetate).
1
ring aromatization reaction with pyrrolidine fragment
elimination, (2) nitro group reduction into amine func-
tion, (3) N-ethylation of amine group to give N-ethyla-
mino derivative 10 (Scheme 2). Its quinoline structure
was strongly confirmed by 1H-, 13C-NMR spectra and
2D NMR spectroscopy.
Other quinoline derivatives 11–14 were easily pre-
pared from the respective tetrahydroquinolines by use of
their rapid fusion with elemental sulfur following our
developed protocol [17]. These quinoline molecules are
stable, yellowish substances that were purified by means
of a short chromatographic column (Table 1).
Finally, the obtained THQs 6–9 were subjected into
oxidation process using our rapid fusion-sulfur protocol
to prepare new corresponding2-(4-aminophenyl)quino-
lines 11,12 and 2-(2-naphtyl)quinolines 13,14. This aro-
matization reaction was achieved by its fusion with ele-
mental sulfur at 220–240ꢁC in 5–10 min. All new com-
pounds were directly isolated without previous extrac-
tion using flash column chromatographic and were com-
pletely identified using NMR spectroscopy.
In conclusion, we reported the efficient synthesis of
new series of 2-aryl-4-(2-oxopyrrolidinyl-1)-1,2,3,4-tet-
rahydroquinolines and their aromatic analogs, 2-arylqui-
nolines, unsubstituted at the C-4 position. These poten-
tially bioactive 2-(aryl)quinoline derivatives could be
important models in antioxidant, antiparasitic or/and
anticancer studies [18].
1-[6-Methyl-2-(4-nitrophenyl)-1,2,3,4-tetrahydroquinolin-4-
yl]pyrrolidin-2-one (4). The compound 4 was obtained in 95%
yield, yellow solid, m.p. 222–223ꢁC. IR (potassium bromide):
1
m 3394, 2947, 2916, 1666, 1620 cmꢀ1. H-NMR (CDCl3, 400
MHz): d 8.20 (2H, d, J ¼ 8.7 Hz, 3-HAr and 5-HAr), 7.61 (2H,
d, J ¼ 8.7 Hz, 2-HAr and 6-HAr), 6.90 (1H, dd, J ¼ 8.0, 1.7
Hz, 7-HTHQ), 6.68 (1H, s, 5-HTHQ), 6.57 (1H, d, J ¼ 8.1 Hz,
8-HTHQ), 5.69 (1H, dd, J ¼ 11.1, 6.4 Hz, 4-HaTHQ), 4.65 (1H,
dd, J ¼ 10.7, 3.1 Hz, 2-HaTHQ), 4.03 (1H, br.s, NAH), 3.21
(2H, t, J ¼ 6.9 Hz, 5-HPyrr), 2.59–2.41 (2H, m, 3-HPyrr), 2.23
(3H, s, 6-MeTHQ), 2.13–1.99 (4H, m, 4-HPyrr and 3-HTHQ).
13C-NMR (CDCl3, 100 MHz): d 175.8, 150.6, 147.4, 142.9,
129.0, 128.1, 127.3 (2C), 126.9, 123.9 (2C), 118.8, 115.4,
56.0, 48.1, 42.2, 35.3, 31.3, 20.5, 18.1. gc-ms tR: 44.57 min,
EXPERIMENTAL
The melting points (uncorrected) were determined on a
Fisher-Johns melting point apparatus. The IR spectra were
recorded on a Lumex Infralum FT-02 spectrophotometer in
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2010 Transformations of 2-Aryl-4-(2-oxopyrrolidinyl-1)-1,2,3,4-tetrahydroquinolines,
Cycloadducts of the BiCl3-Catalyzed Three-Component Povarov Reaction
1151
m/z: 351 (molecular ion). Anal. Calcd. for C20H21N3O3: C,
68.36; H, 6.02; N, 11.96. Found: C, 68.40; H, 5.99; N, 11.97.
1-[5,7-Dimethyl-2-(4-nitrophenyl)-1,2,3,4-tetrahydroquinolin-
4-yl]pyrrolidin-2-one (5). The compound 5 was obtained in
98% yield, yellow solid, m.p. 239–240ꢁC. IR (potassium bro-
removed in vacuo and the product was purified with chroma-
tography column (hexane/ethyl acetate).
1-[6-Methyl-2-(4-aminophenyl)-1,2,3,4-tetrahydroquinolin-
4-yl]pyrrolidin-2-one (8). The compound (8) was obtained in
54% yield, yellow solid, m.p. 233–234ꢁC. IR (potassium bro-
mide): m 3271, 2972, 2916, 2854, 1666 cmꢀ1
(CDCl3, 400 MHz): d 8.21 (2H, d, J ¼ 8.7 Hz, 3-HAr and 5-
Ar), 7.62 (2H, d, J ¼ 8.6 Hz, 2-HAr and 6-HAr), 6.47 (1H, s,
.
1H-NMR
1
mide): m 3440, 3379, 3356, 3240, 2947, 2916, 1666 cmꢀ1. H-
NMR (CDCl3, 400 MHz): d 8.28 (1H, d, J ¼ 8.4 Hz, 2-HAr),
8.18 (1H, d, J ¼ 8.3 Hz, 6-HAr), 7.70 (2H, dd, J ¼ 11.5, 8.7
Hz, 3-HAr and 5-HAr), 6.90 (1H, bt, J ¼ 5.5 Hz, 7-HTHQ), 6.69
(1H, s, 5-HTHQ), 6.55 (1H, t, J ¼ 6.9 Hz, 8-HTHQ), 5.71 (1H,
dd, J ¼ 10.2, 6.9 Hz, 4-HaTHQ), 4.62 (1H, ddd, J ¼ 12.0, 10.6,
3.4 Hz, 2-HaTHQ), 3.96 (1H, s, NH2), 3.20 (2H, d, J ¼ 5.9 Hz,
5-HPyrr), 2.59-2.43 (2H, m, 3-HPyrr), 2.23 (3H, s, 6-MeTHQ),
2.12-1.01 (4H, m, 3-HTHQ and 4-HPyrr) ppm. gc-ms tR: 25.34
min, m/z: 321 (molecular ion). Anal. Calcd. for C20H23N3O C,
74.74; H, 7.21; N, 13.07. Found: C, 74.75; H, 7.20; N, 13.05.
General procedure for reduction reaction with NiCl2/
NaBH4 (method B). To a mixture of nitro derivatives (4,5)
(2.85 mmol) and nickel chloride (II) (0.28 mmol) in
MeOH:CH2Cl2 (2:1), NaBH4 (8.55 mmol) was added in small
portions, keeping reaction system at 0ꢁC. The reaction was
stirred by 1 hour at room temperature and the organic layer
was filtered and washed (methanol and distilled water),
extracted with CH2Cl2 (3 ꢂ 10 mL) and dried under Na2SO4.
1-[6-Methyl-2-(4-aminophenyl)-1,2,3,4-tetrahydroquinolin-
4-yl]pyrrolidin-2-one (8). The compound (8) was obtained in
95% yield. Their physicochemical parameters were identical to
product (8) obtained by method A.
H
6-H), 6.37 (1H, s, 8-HTHQ), 5.57 (1H, t, J ¼ 8.5 Hz, 4-HaTHQ),
4.48 (2H, dd, J ¼ 10.6, 2.5 Hz, 2-HaTHQ), 3.97 (1H, br.s,
NAH), 3.08 (1H, ddd, J ¼ 9.7, 8.7, 5.4 Hz, 5-HePyrr), 2.82
(1H, ddd, J ¼ 9.9, 8.4, 6.0 Hz, 5-HaTHQ), 2.43-2.27 (3H, m, 3-
HPyrr and 3-HeTHQ), 2.23 (3H, s, 5-MeTHQ), 2.10 (1H, t, J ¼
12.0 Hz, 3-HaTHQ), 2.06 (3H, s, 7-MeTHQ), 1.94-1.72 (2H, m,
4-HPyrr). 13C-NMR (CDCl3, 100 MHz): d 174.5, 150.5, 147.3,
146.7, 138.3, 138.2, 127.2 (2C), 123.9 (2C), 122.8, 114.9,
114.3, 55.4, 46.5, 42.4, 36.3, 31.0, 21.0, 19.3, 17.8. gc-ms tR:
49.65 min, m/z: 365 (molecular ion). Anal. Calcd. for
C21H23N3O3: C, 69.02; H, 6.34; N, 11.50. Found: C, 69.01; H,
6.35; N, 11.48.
1-(6-Methyl-2-(2-naphtyl)-1,2,3,4-tetrahydroquinolin-4-yl)pyr-
rolidin-2-one (6). The compound 6 was obtained in 72% yield,
white solid, m.p. 214–215ꢁC. IR (potassium bromide): m 3332,
1
3055, 3024, 2954, 2916 cmꢀ1. H-NMR (CDCl3, 400 MHz): d
7.88 (1H, s, 1-HNapht), 7.85-7.82 (3H, m, 4-HNapht, 5-HNapht
and 8-HNapht), 7.52-7.50 (1H, m, 3-HNapht), 7.49-7.45 (2H, m,
6-HNapht and 7-HNapht), 6.89 (1H, d, J ¼ 7.9 Hz, 8-HTHQ),
6.70 (1H, s, 5-HTHQ), 6.55 (1H, d, J ¼ 8.0 Hz, 7-HTHQ), 5,74
(1H, t, J ¼ 8.9, 4-HaTHQ), 4.71 (1H, t, J ¼ 6.9 Hz, 2-HaTHQ),
3.99 (1H, br.s, NAH), 3.28-3.18 (2H, m, 5-HPyrr), 2.50-2.42
(2H, m, 3-HPyrr), 2.24 (3H, s, 6-MeTHQ), 2.18-2.14 (2H, m, 3-
1-[5,7-Dimethyl-2-(4-aminophenyl)-1,2,3,4-tetrahydroquino-
lin-4-yl]pyrrolidin-2-one (9). The compound (9) was obtained
in 97% yield, yellow solid, m.p. 255–258ꢁC. IR (potassium
.
bromide): m 3440, 2916, 1666, 1620, 1589 cmꢀ1 1H-NMR
H
THQ), 2.04-1.97 (2H, m, 4-HPyrr). 13C-NMR (CDCl3, 100
(CDCl3, 400 MHz): d 8.29 (1H, d, J ¼ 8.2 Hz, 2-HAr), 8.18
(1H, d, J ¼ 8.1 Hz, 6-HAr), 7.55 (2H, d, J ¼ 8.9 Hz, 3-HAr
and 5-HAr), 6.45 (1H, s, 6-HTHQ), 6.36 (1H, m, 8-HTHQ), 5.58
(1H, t, J ¼ 8.5 Hz, 4-HaTHQ), 4.42 (1H, t, J ¼ 12.1 Hz, 2-
MHz): d 175.8, 143.6, 140.6, 133.4, 133.1, 128.9, 128.5,
127.8, 127.7, 127.5, 127.1, 126.2, 125.9, 125.0, 124.6, 119.0,
115.2, 56.6, 48.5, 42.3, 35.4, 31.4, 20.6, 18.2. gc-ms tR: 55.83
min, m/z: 356 (molecular ion). Anal. Calcd. for C24H24N2O:
C, 80.87; H, 6.79; N, 7.86. Found: C, 80.84; H, 6.78; N, 7.84.
1-[5,7-Dimethyl-2-(2-naphtyl)-1,2,3,4-tetrahydroquinolin-4-
yl]pyrrolidin-2-one (7). The compound 7 was obtained in 90%
yield, white solid, m.p. 182–183ꢁC. IR (potassium bromide): m
H
aTHQ), 3.97 (2H, br.s, NH2), 3.11 (1H, dd, J ¼ 14.1, 8.5 Hz,
5-HePyrr), 2.82 (1H, dd, J ¼ 15.3, 7.8 Hz, 5-HaPyrr), 2.41-2.31
(3H, m, 3-HPyrr and 3-HeTHQ), 2.22 (3H, s, 5-MeTHQ), 2.11
(1H, t, J ¼ 12.0 Hz, 3-HaTHQ), 2.07 (3H, s, 7-MeTHQ), 1.85
(2H, dd, J ¼ 13.8, 6.0 Hz, 4-HPyrr) ppm. gc-ms tR: 26.62 min,
m/z: 335 (molecular ion). Anal. Calcd. for C21H25N3O C,
75.19; H, 7.51; N, 12.53. Found: C, 75.18; H, 7.50; N, 12.55.
General procedure for the hydrogenation with H2/Pd/C
(method C). To a solution of nitro derivative (4) (2.85 mmol)
in MeOH/MeCN (2:1) was added Pd/C (10% p/p). Molecular
hydrogen was injected to the system; the reaction mixture was
stirred at room temperature for 24 h. The organic layer was fil-
tered in a chromatographic column (silica gel), the solvent was
removed in vacuo and the product was purified with chroma-
tography column (hexane/ethyl acetate).
3332, 3047, 3016, 2978, 2924 cmꢀ1 1H-NMR (CDCl3, 400
.
MHz): d 7.87 (1H, s, 1-HNapht), 7.84-7.81 (3H, m, 4-HNapht, 5-
HNapht and 8-HNapht), 7.51-7.50 (1H, m, 3-HNapht), 7.48-7.45
(2H, m, 6-HNapht and 7-HNapht), 6.44 (1H, s, 6-HTHQ), 6.36
(1H, s, 8-HTHQ), 5.62 (1H, t, J ¼ 8.5 Hz, 4-HaTHQ), 4.50 (1H,
d, J ¼ 10.6 Hz, 2-HaTHQ), 4.01 (1H, br.s, NAH), 3.16-3.10
(1H, m, 5-HePyrr), 2.85-2.70 (1H, m, 5-HaPyrr), 2.46-2.26 (3H,
m, 3-HPyrr and, 3-HeTHQ), 2.23 (3H, s, 7-MeTHQ), 2.19-2.14
(1H, m, 3-HaTHQ), 2.08 (3H, s, 5-MeTHQ), 1.92-1.97 (2H, m,
4-HPyrr). 13C-NMR (CDCl3, 100 MHz): d 174.4, 147.5, 140.4,
138.3, 138.0, 133.4, 133.0, 128.4, 127.8, 127.6, 126.2, 125.9,
124.8, 124.6, 122.3, 115.1, 114.1, 55.9, 46.8, 42.4, 36.4, 31.1,
21.0, 19.4, 17.8. gc-ms tR: 54.14 min, m/z: 370 (molecular
ion). Anal. Calcd. for C25H26N2O: C, 81.05; H, 7.07; N, 7.56.
Found: C, 81.06; H, 7.03; N, 7.54.
2-(4-N-Ethylaminophenyl)-6-methylquinoline (10) The com-
pound (10) was obtained in 46% yield, yellow solid, m.p.
149–151ꢁC. IR (potassium bromide): m 3394, 2961, 2916,
1
2854, 1605 cmꢀ1. H-NMR (CDCl3, 400 MHz): d 8.02 (2H, d,
General procedure for the hydrogenation with H2/Pd/C
(method A). To a solution of nitro derivative (4) (2.85 mmol)
in MeOH:CH2Cl2 (2:1) was added Pd/C (10% p/p). Molecular
hydrogen was injected to the system; the reaction mixture was
stirred at room temperature for 24 h. The organic layer was fil-
tered in a chromatographic column (silica gel), the solvent was
J ¼ 8.6 Hz, 3-HAr and 5-HAr), 8.00 (1H, d, J ¼ 8.1 Hz, 8-
HQu), 7,99 (1H, d, J ¼ 8.6 Hz, 3-HQu), 7.74 (1H, d, J ¼ 8.7
Hz, 4-HQu), 7.50 (1H, s, 5-HQu), 7.49 (1H, d, J ¼ 8.5 Hz, 7-
HQu), 6.69 (2H, d, J ¼ 8.7 Hz, 2-HAr and 6-HAr), 3.79 (1H,
br.s, NAH), 3.21 (2H, q, J ¼ 7.1 Hz, ACH2MeAr), 2.50 (3H,
s, 6-MeQu), 1.26 (3H, t, J ¼ 7.1 Hz, ACH2MeAr) ppm. 13C-
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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V. V. Kouznetsov, C. M. Melendez Gomez, and J. H. Bermudez Jaimes
1152
Vol 47
NMR (CDCl3, 100 MHz): d 156.5, 149.4, 146.8, 135.6, 135.0,
131.5, 129.0, 128.5 (2C), 128.4, 126.6, 126.3, 118.2, 112.6
(2C), 38.2, 21.5, 14.7, ppm. gc-ms tR: 26,50 min, m/z: 262
(molecular ion). Anal. Calcd. for C18H18N2 C, 82.41; H, 6.92;
N, 10.68. Found: C, 82.40; H, 6.93; N, 10.69.
General procedure for the aromatization with sulfur.
The 2-(aminophenyl) and 2-(nitroaryl) substituted tetrahydro-
quinolines (4-7) were heated quickly (10–15 min) in the pres-
ence of elemental sulfur (S8) to 220–230ꢁC. The reaction mix-
ture was adsorbed under silica gel and separated by chroma-
tography column to afford the 2-arylquinolines.
¼ 8.7, 1.5 Hz, 4-HNapht), 8.28 (1H, d, J ¼ 8.7 Hz, 3-HQu),
7.97-7.94 (1H, m, 8-HNapht), 7.95 (1H, d, J ¼ 8.5 Hz, 3-
HNapht), 7.91 (1H, d, J ¼ 8.7 Hz, 4-HQu), 7.88–7.85 (1H, m, 5-
HNapht), 7.85 (1H, s, 8-HQu), 7.50 (2H, dd, J ¼ 6.2, 3.2 Hz, 6-
HNapht and 7-HNapht), 7.17 (1H, s, 6-HQu), 2.63 (3H, s, 7-
MeQu), 2.52 (3H, s, 5-MeQu) ppm. 13C-NMR (CDCl3, 100
MHz): d 156.5, 148.9, 139.5, 137.0, 133.9, 133.8, 133.5,
132.9, 129.1, 128.8, 128.4, 127.7, 127.0, 126.9, 126.5, 126.2,
125.0, 124.6, 117.8, 21.8, 18.5 ppm. gc-ms tR: 29.02 min, m/z:
283 (molecular ion). Anal. Calcd. for C21H17N C, 89.01; H,
6.05; N, 4.94. Found: C, 89.02; H, 6.04; N, 4.93.
2-(4-Aminophenyl)-6-methylquinoline (11). The compound
(11) was obtained in 89% yield, yellow solid, m.p. 178–
179ꢁC. IR (potassium bromide): m 3386, 3301, 3193, 3055,
Acknowledgments. This work was supported by DIEF-UIS
(grant No. 5151) and the Instituto Colombiano Para el Desarrollo
1
3023 cmꢀ1. H-NMR (CDCl3, 400 MHz): d 8.03 (1H, d, J ¼
´
´
de La Ciencia y La Tecnologıa ‘‘Francisco Jose de Caldas’’
(COLCIENCIAS-CENIVAM, grant No. 432-2004). CMMG
thanks COLCIENCIAS for his fellowship.
8.7 Hz, 4-HQu), 8.01 (3H, dt, J ¼ 8.6, 2.0 Hz, 2-HAr and 6-
H
Ar), 7.92 (1H, dd, J ¼ 8.8, 1.3 Hz, 8-HQu)7.76 (1H, d, J ¼
8.6 Hz, 3-HQu), 7.53 (1H, s, 5-HQu), 7.52 (1H, dd, J ¼ 8.8,
1.3 Hz, 7-HQu), 6.80 (2H, dt, J ¼ 8.6, 2.0 Hz, 3-HAr and 5-
Ar), 3.85 (2H, br.s, NH2), 2.53 (3H, s, 6-MeQu) ppm. 13C-
REFERENCES AND NOTES
H
NMR (CDCl3, 100 MHz): d 156.4, 147.6, 146.9, 135.8, 135.3,
131.6, 130.1, 129.1, 128.6 (2C), 126.8, 126.3, 118.3, 115.1
(2C), 21.5 ppm. gc-ms tR: 25.13 min, m/z: 234 (molecular
ion). Anal. Calcd. for C16H14N2 C, 82.02; H, 6.02; N, 11.96.
Found: C, 82.00; H, 6.03; N, 11.97.
[1] Jones, G. In Pyridines and Their Benzo Derivatives;
Katritzky, A., Eds.; Pergamon Press: Oxford, 1984, Vol. 2, pp 395–
510.
[2] Katrizky, A. R.; Rachwal, S.; Rachwal, B. Tetrahedron
1996, 52, 15031.
2-(4-Aminophenyl)-5,7-dimethylquinoline (12). The com-
pound (12) was obtained in 73% yield, yellow solid, m.p.
115–116ꢁC. IR (potassium bromide): m 3433, 3317, 3201,
[3] Kouznetsov, V.; Palma, A.; Ewert, C.; Varlamov, A. J. Het-
erocycl Chem 1998, 35, 761.
´ ´
[4] Kouznetsov, V. V.; Vargas Mendez, L. Y.; Melendez
1
3032, 2962 cmꢀ1. H-NMR (CDCl3, 400 MHz): d 8.23 (1H, d,
´
Gomez, C. M. Curr Org Chem 2005, 9, 141.
J ¼ 8.9 Hz, 3-HQu), 8.01 (2H, d, J ¼ 8.5 Hz, 2-HAr and 6-
HAr), 7.75 (1H, s, 8-HQu), 7.73 (1H, d, J ¼ 8.9 Hz, 4-HQu),
7.13 (1H, s, 6-HQu), 6.79 (2H, d, J ¼ 8.5 Hz, 3-HAr and 5-
HAr), 3.85 (2H, br.s, NH2), 2.63 (3H, s, 7-MeQu), 2.50 (3H, s,
5-MeQu) ppm. 13C-NMR (CDCl3, 100 MHz): d 156.6, 148.8,
147.6, 139.2, 133.8, 132.6, 130.0, 128.6 (2C), 128.5, 126.7,
124.1, 117.0, 115.1 (2C), 21.8, 18.4 ppm. gc-ms tR: 26.94 min,
m/z: 248 (molecular ion). Anal. Calcd. for C17H16N2 C, 82.22;
H, 6.49; N, 11.28. Found: C, 82.23; H, 6.51; N, 11.30.
[5] Kouznetsov, V.; Vargas, L.; Leal, S.; Mora, U.; Coronado,
´
C.; Melendez, C.; Romero, A.; Escobar, P. Lett Drug Des Discov
2007, 4, 293.
´
[6] Melendez, C.; Kouznetsov, V.; Sortino, M.; Alvarez, S.;
´
Zacchino, S. Bioorg Med Chem 2008, 16, 7908.
´
[7] Vargas, L.; Castelli, M.; Kouznetsov, V.; Urbina, J.; Lopez,
S.; Sortino, M.; Enriz, R.; Ribas, J.; Zacchino, S. Bioorg Med Chem
2003, 11, 1531.
[8] Nandhakumar, R.; Suresh, T.; Calistus, A.; Rajesh, K.;
Mohan, P. Eur J Med Chem 2007, 42, 1.
6-Methyl-2-(2-napthyl)quinoline (13). The compound (13)
was obtained in 87% yield, white solid, m.p. 160–161ꢁC. IR
.
(KBr): m 3055, 3008, 2916, 2854, 1589 cmꢀ1 1H-NMR
[9] Bekhit, A.; El-Sayed, O.; Aboulmagd, E.; Park, J. Eur J
Med Chem 2004, 39, 249.
[10] Kariba, R.; Houghton, P.; Yenesew, A. J Nat Prod 2002,
65, 566.
(CDCl3, 400 MHz): d 8.58 (1H, s, 1-HNapht), 8.35 (1H, d, J ¼
8.5 Hz, 4-HNapht), 8.12-8.00 (2H, m, 3-HQu and 8-HQu), 7.99-
7.95 (3H, m, 4-H, 3-HNapht, 8-HNapht), 7.89-7.56 (1H, m, 5-
HNapht), 7.58 (1H, s, 5-HQu), 7.58-7.56 (1H, m, 7-HQu), 7.53-
7.49 (2H, m, 6-HQu and 7-HNapht), 2.54 (3H, s, 6-MeQu) ppm.
13C-NMR (CDCl3, 100 MHz): d156.2, 146.9, 137.0, 136.2,
136.1, 133.7, 133.5, 131.9, 129.4, 128.8, 128.5, 127.7, 127.2,
126.9, 126.5, 126.3, 126.2, 125.0, 119.1, 21.6 ppm. gc-ms tR:
27.02 min, m/z: 269 (molecular ion). Anal. Calcd. for C20H15N
C, 89.19; H, 5.61; N, 5.20. Found: C, 89.20; H, 5.62; N, 5.21.
5,7-Dimethyl-2-(2-napthyl)quinoline (14). The compound
(14) was obtained in 73% yield, white solid, m.p. 86–87ꢁC. IR
[11] Katrizky, A. R.; Rachwal, B.; Rachwal, S. J Org Chem
1995, 60, 3993.
[12] Kouznetsov, V. V. Tetrahedron 2009, 65, 2721.
[13] Povarov, L.S. Russ Chem Rev 1967, 36, 656.
[14] Zhang, W.; Guo, Y.; Liu, Z.; Jin, X.; Yang, L.; Liu, Z.-L.
Tetrahedron 2005, 61, 1325.
[15] Han, B.; Jia, X.-D.; Jin, X.-L.; Zhou, Y.-L.; Yang, L.; Liu,
Z.-L.; Yu, W. Tetrahedron Lett 2006, 47, 3545.
[16] Srinivasa, A.; Mahadevan, K. M.; Hulikal, V. Monatsh
Chem 2008, 139, 255.
[17] Kouznetsov, V.; Mora U. Lett Org Chem 2006, 3, 699.
[18] Antiparasitic and cytotoxic activities for this new series of
compounds will be published in due course.
(KBr): m 3055, 2970, 2900, 2854, 1620 cmꢀ1
.
1H-NMR
(CDCl3, 400 MHz): d 8.58 (1H, s, 1-HNapht), 8.34 (1H, dd, J
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet