Synthesis of new diversely linked biquinoline derivatives by multicomponent Imino-Diels-Alder cycloaddition and intramolecular friedel-crafts cyclization

Article abstract of DOI:10.1055/s-0029-1218613

New and efficient routes for diversely linked 2,6-, 2,7-, 2,2-, or 2,8-biquinoline derivatives are reported. These routes are based on the powerful methodologies of imino-Diels-Alder cycloaddition reactions and intramolecular Friedel-Crafts cyclization re

Full text of DOI:10.1055/s-0029-1218613

PAPER
593
Synthesis of New Diversely Linked Biquinoline Derivatives by
Multicomponent Imino-Diels–Alder Cycloaddition and Intramolecular
Friedel–Crafts Cyclization
S
ynthesis of
Lin
u
ked Biquino
i
line De
s
r
ivatives Astudillo Saavedra,*a Gabriel Vallejos C.,a Vladimir V. Kouznetsov,*b Margarita Gutierrez C.,a
Carlos Mario Meléndez Gómez,b Leonor Y. Vargas Méndez,c John Hervin Bermúdez Jaimesb
a
Laboratorio de Síntesis Orgánica, Instituto de Química de Recursos Naturales, Universidad de Talca, Casilla 747, Talca, Chile
Fax +56(71)200448; E-mail: lastudi@utalca.cl
Laboratorio de Química Orgánica y Biomolecular, Escuela de Química, Universidad Industrial de Santander,
b
A.A. 678, Bucaramanga, Colombia
Fax +57(76)349069; E-mail: kouznet@uis.edu.co
Laboratorio Química Orgánica Ambiental, Universidad Santo Tomas, A.A. 1076, Bucaramanga, Colombia
c
Received 28 September 2009; revised 21 October 2009
different quinoline nuclei, whose synthesis could be ac-
complished by cycloaddition and/or cyclization reactions.
Abstract: New and efficient routes for diversely linked 2,6¢-, 2,7¢-,
2,2¢-, or 2,8¢-biquinoline derivatives are reported. These routes are
based on the powerful methodologies of imino-Diels–Alder cy-
cloaddition reactions and intramolecular Friedel–Crafts cyclization
reactions.
Therefore, the proposed routes for these systems were
elaborated by retrosynthetic analysis for four different
biquinoline structures. The synthesis of 2,6¢- and 2,7¢-
biquinoline derivatives is based mainly on acid-catalyzed
three-component imino-Diels–Alder reactions of simple
anilines, benzaldehydes, and N-vinylpyrrolidin-2-one
(Scheme 1). Construction of the 2,2¢- and 2,8¢-biquinoline
derivatives is based on cationic intramolecular Friedel–
Key words: biquinoline derivatives, imino-Diels–Alder reactions,
cycloadditions, intramolecular Friedel–Crafts reaction, cyclizations
Quinoline and tetrahydroquinoline structures are essential
features of many natural products. These heterocycles
play a key role in organic and medicinal chemistry. Their
synthesis by various methodologies has been published
extensively.1–4 Compared to these systems, general syn-
thetic methods for the preparation of diversely linked
biquinolines are less developed.5–8 Among the biquino-
lines, the 2,2¢-biquinoline framework is the best known,
because of its excellent ability as ligand in coordination
chemistry.9–13
Crafts
cyclization
of
N-aryl-N-(quinolylbut-3-
enyl)amines (‘homoallylamines’) (Scheme 2). Both syn-
thetic approaches utilize simple anilines and aldehydes,
whose reactions could lead to the formation of N-aryl ald-
imines, important participants in these synthetic transfor-
mations.
In this paper, we disclose a new design for the construc-
tion of diversely linked 2,6¢- and 2,7¢-biquinoline deriva-
tives. Additionally, we wish to report a simple and
efficient two-step synthesis of 2,2¢- and 2,8¢-biquinoline
derivatives by 6-exo-trig reactions of the N-aryl-N-
(quinolylbut-3-enyl)amines derived from the respective
aldimines. The key (tetrahydro)quinoline compounds 4–
13 (Scheme 3) in our synthetic plan for novel 2,6¢- and
2,7¢-biquinoline derivatives were prepared on the basis of
In addition, these compounds also represent interesting
models for drug development, especially as anticancer
agents. As part of our research programme on N-
arylimines towards the synthesis of bioactive substituted
tetrahydroquinolines and quinolines, we are investigating
the synthesis of small drug-like molecules containing two
R2
EDG
2,6´-
R2
R2
EDG =
O
N
+
N
R1
N
NH2
O
N
NH2
NO2
EDG
2,7´- R2
R2
R2
+
N
NH2
NO2
NH2
O
N
N
R1
Scheme 1 Retrosynthetic analysis for 2,6¢- and 2,7¢-biquinolines by imino-Diels–Alder methodology
SYNTHESIS 2010, No. 4, pp 0593–0600
x
x
.
x
x
.2
0
1
0
Advanced online publication: 16.12.2009
DOI: 10.1055/s-0029-1218613; Art ID: M05309SS
© Georg Thieme Verlag Stuttgart · New York

594
L. Astudillo Saavedra et al.
PAPER
2,2´-
R2
R2
R2
R2
H
H
N
N
N
N
N
N
N
N
+
R1
R1
R1
O
H2N
R1
R2
2,8´-
R2
R2
R2
N
N
N
R1
+
H2N
R1
R1
R1
HN
O
N
HN
Scheme 2 Retrosynthetic analysis for 2,2¢- and 2,8¢-biquinolines by intramolecular Friedel–Crafts methodology
Table 1 (Tetrahydro)quinoline Compounds 4–13
Table 2 New Biquinoline Derivatives 19–24
Compound R1
R2
H
R3
H
2-Aryl group
m-O2NC6H4
m-O2NC6H4
m-O2NC6H4
p-O2NC6H4
p-O2NC6H4
m-H2NC6H4
m-H2NC6H4
m-H2NC6H4
p-H2NC6H4
p-H2NC6H4
Yield (%)
Compound R1
R2
R3
H
2-Aryl group
Yield (%)
4
5
H
93
70
81
95
98
95
92
98
54
94
14
15
16
17
18
19
20
21
22
23
24
H
H
m-H2NC6H4
70
85
80
89
73
58
60
65
70
33
40
H
Me
H
H
H
Me
OMe
Me
H
H
m-H2NC6H4
6
H
OMe
H
H
H
m-H2NC6H4
7
H
Me
H
H
H
p-H2NC6H4
8
Me
H
Me
H
Me
H
Me
H
p-H2NC6H4
9
H
H
–
–
–
–
–
–
10
11
12
13
H
Me
H
H
H
Me
OMe
H
H
H
OMe
H
H
H
H
Me
H
Me
H
Me
H
Me
Me
Me
H
Me
Me
our experience in the construction of diverse heterocycles
containing nitrogen, by means of a multicomponent
Povarov reaction.14–16
tives 9–13, which were obtained as stable solids with
well-defined cis stereochemistry (Scheme 3, Table 1).
The cis configuration of the C2 and C4 substituents on the
tetrahydroquinoline ring was determined by measurement
of the corresponding H–H coupling constants in 1H NMR
spectra.17
First, the selected tetrahydroquinoline molecules 4–8
were easily synthesized by means of a bismuth(III) chlo-
ride catalyzed three-component imino-Diels–Alder cy-
cloaddition reaction between substituted anilines 1a–d,
nitrobenzaldehydes 2a,b, and N-vinylpyrrolidin-2-one (3;
NVP) (Scheme 3).17 These reactions proceeded smoothly
in acetonitrile at room temperature to give the final prod-
ucts, substances easy to purify and manipulate. Hydroge-
nation (H2/Pd/C, MeOH)18 of these compounds gave the
corresponding (aminophenyl)tetrahydroquinoline deriva-
With these suitable precursors 9–13 for the synthesis of
the desired 2,6¢- and 2,7¢-biquinoline derivatives in our
hands, we carried out an oxidation reaction with elemental
sulfur (rapid fusion), which was accompanied by the loss
of the pyrrolidinone fragment to afford 2-(m- or p-amino-
O
O
R1
N
R1
N
R1
O
N
BiCl3
R2
R3
R2
R3
R2
R3
(20 mol%)
H2, Pd/C
MeOH
3
O
MeCN, r.t.
+
NO2
N
H
N
H
NH2
NO2
NH2
4–8
9–13
2a,b
1a–d
a R1 = R2 = R3 = H
a 3-NO2
b 4-NO2
b R1 = R3 = H, R2 = Me
c R1 = R3 = H, R2 = MeO
d R1 = R3 = Me, R2 = H
Scheme 3 Preparation of key (tetrahydro)quinoline compounds 4–13
Synthesis 2010, No. 4, 593–600 © Thieme Stuttgart · New York

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Synthesis of Linked Biquinoline Derivatives
595
O
R1
R1
R1
N
OH
HO
OH
R2
R3
R2
R3
R2
R3
S8
Δ, 10 min
NH2
4
Δ
3
2
H2SO4
NaI
N
N
N
H
NH2
9–13
14–18
N
23, 24
BiCl3, MeCN
r.t.
+ 2b + 3
BiCl3, MeCN
r.t.
+ 2a + 3
R1
O
N
R1
R2
R3
R2
R3
O
4
3
2
N
N
4¢
3¢
N
H
N
2¢
22
19–21
4¢
3¢
N
H
O
HN
2¢
NO2
NO2
Scheme 4 Synthesis of new 2,6¢- and 2,7¢-biquinoline derivatives
phenyl)quinolines 14–18 in excellent yields (Scheme 4, ing 2-(2¢-quinolyl)- and 2-(8¢-quinolyl)-1,2,3,4-tetra-
Table 2). The final steps of our synthesis consisted of the hydroquinolines 27 and 28 in good yields. Rapid fusion of
use of the same tactics and reagents employed in the initial these tetrahydroquinolines with elemental sulfur (200 °C,
step (reiterative process), to furnish the new 7-(2¢- 10 min) furnished the corresponding 2,2¢-biquinoline 29
quinolyl)-1,2,3,4-tetrahydroquinolines 19–21 or 2,6¢- and 2,8¢-biquinoline 30 as stable yellow substances
bi(tetrahydroquinoline) 22, obtained in moderate to good (Scheme 5).
yields from nitrobenzaldehydes 2a or 2b and 3.
The structures of all the precursors as well as the final
On the other hand, when 2-(p-aminophenyl)quinolines 17 products were consistent with their IR and H- and 13C
1
and 18 were employed as amino components in the NMR spectra and supported by their MS data. 1H and 13C
Skraup reaction18 of glycerol in the presence of sulfuric NMR analysis of the tetrahydroquinoline products indi-
acid and sodium iodide, new 2,6¢-biquinolines 23 and 24 cated that the structure of the major diastereomers 4–8 and
were produced in moderate to good yields (Scheme 4, 9–13 was the cis-(2e,4e) form (as shown in Scheme 1).
Table 2).
The large vicinal coupling constants J2a,3a and J3a,4a = 9.9–
11.0 Hz for this form indicate an axial–axial (trans) rela-
tionship and the aryl groups on C2 and C4 are both pseudo-
equatorial and located in the cis configuration. Isolated
biquinoline products 19–21 display the same behavior,
showing a cis configuration of the two substituents at the
reduced ring. With regard to the spatial structure of bi(tet-
rahydroquinoline) ring 22, it appears to also have a ‘dou-
ble’ cis configuration.
Finally, other biquinoline systems could be synthesized;
for example, 2,2¢- and 2,8¢-biquinoline systems 29 and 30
were obtained by three synthetic steps from the corre-
sponding N-[1-(6-methyl-2-quinolyl)but-3-enyl]-N-(p-
tolyl)amine (25) and N-(p-methoxyphenyl)-N-[1-(8-
quinolyl)but-3-enyl]amine (26), which were readily pre-
pared from the corresponding quinolinecarboxaldehydes
and primary anilines (Scheme 5).19,20 Acid-mediated
(85% H2SO4) intramolecular cyclization of homoallyl- From GC-MS analysis, the (quinolyl)tetrahydroquinoline
amines 25 and 26 straightforwardly gave the correspond- 28 (Scheme 5) exists as a unique diastereomer [4e-Me/2e-
H
H
N
S8
N
N
N
85% H2SO4, CHCl3
60 °C, 3 h
N
N
Δ, 10 min
2
3
4
25
27
29
89%
74%
OMe
OMe
OMe
4
N
N
N
3
S8
Δ, 10 min
2
N
H
85% H2SO4, CHCl3
60 °C, 3 h
N
H
N
26
28
30
65%
91%
Scheme 5 Two-step procedure for the preparation of new 2,2¢- and 2,8¢-biquinoline derivatives
Synthesis 2010, No. 4, 593–600 © Thieme Stuttgart · New York

596
L. Astudillo Saavedra et al.
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Anal. Calcd for C21H23N3O3: C, 69.02; H, 6.34; N, 11.50. Found C,
68.93; H, 6.55; N, 11.35.
(8¢-Qu)] (tR = 44.92 min), whereas (quinolyl)tetrahydro-
quinoline 27 consists of a mixture of the two geometric
isomers [4-Me/2-(2¢-Qu)] in a ratio of 1:2 (tR = 42.06,
44.01 min). According to NMR analysis of compound 28,
the methyl group and the quinoline ring are in cis config-
uration, both placed equatorially at C4 (J4a,3a = 12.1,
J4a,3e = 6.0 Hz) and C2 (J2a,3a = 11.6, J2a,3e = 2.5 Hz), re-
N-[5,7-Dimethyl-2-(4-nitrophenyl)-1,2,3,4-tetrahydro-4-
quinolyl]pyrrolidin-2-one (8)
Yellow crystals; mp 239–240 °C.
IR (KBr): 3271, 2972, 2916, 2854, 1666 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.21 (d, J = 8.7 Hz, 2 H, 3(5)-
HAr), 7.62 (d, J = 8.6 Hz, 2 H, 2(6)-HAr), 6.47 (s, 1 H, 6-HTHQ), 6.37
(s, 1 H, 8-HTHQ), 5.57 (t, J = 8.5 Hz, 1 H, 4-HTHQ), 4.48 (dd,
J = 10.6, 2.5 Hz, 2 H, 2-HTHQ), 3.97 (br s, 1 H, 1-HTHQ), 3.08 (ddd,
J = 9.7, 8.7, 5.4 Hz, 1 H, 5-He), 2.82 (ddd, J = 9.9, 8.4, 6.0 Hz, 1 H,
5-Ha), 2.43–2.27 (m, 3 H, 3-H and 3-HTHQ), 2.23 (s, 3 H, 5-CH3),
2.10 (t, 1 H, J = 12.0, 3-HTHQ), 2.06 (s, 3 H, 7-CH3), 1.94–1.72 (m,
2 H, 4-H).
spectively. On the basis of the 1H NMR data (J4a,3a, J2a,3a
)
and comparison with previous data for analogous tetrahy-
droquinolines,21,22 we assumed that the major isomer (tR =
44.01 min) of mixture 27 also has the cis configuration.
In conclusion, we have described new and efficient routes
for diversely linked biquinoline derivatives, which repre-
sent interesting biological models in drug development;
some of them are also potential ligands in coordination
chemistry.
13C NMR (CDCl3): d = 174.5, 150.5, 147.5, 146.8, 138.3, 138.2,
127.2, 127.2, 123.9, 123.9, 122.9, 115.1, 114.3, 55.5, 46.5, 42.5,
36.3, 31.1, 20.91, 19.3, 17.9.
GC-MS: tR = 49.65 min, m/z (%) = 365 (8) [M+], 279 (100).
Melting points were determined on a Fisher-Johns melting point ap-
paratus and are uncorrected. IR spectra of samples prepared as KBr
pellets were obtained on a Lumex Infralum FT-02 or Nicolet Avatar
Anal. Calcd for C21H23N3O3: C, 69.02; H, 6.34; N, 11.50. Found: C,
69.12; H, 6.20; N, 11.37.
1
360-FTIR spectrometer. H (400 MHz) and 13C (100 MHz) NMR
N-[2-(Aminophenyl)-1,2,3,4-tetrahydro-4-quinolyl]pyrrolidin-
2-ones 9–13; General Procedure
spectra were measured on a Bruker AM-400 spectrometer; CDCl3
was used as the solvent. A Hewlett-Packard (HP) 5890 A series II
gas chromatograph interfaced to an HP 5972 mass-selective detec-
tor with an HP MS ChemStation data system was used for MS at 70
eV {60 m capillary column, coated with HP-5 [5% phenylpoly(di-
methylsiloxane)]; oven temperature 100 °C (3 min) to 200 °C (5
min) at 10 °C/min, then 280 °C (40 min) at 15 °C/min; ionization
chamber and transfer line temperatures 230 and 285 °C, respective-
ly}. The reaction progress was monitored by TLC (Merck Kieselgel
60, 230–240 mesh). Final purification of all products for elemental
analyses was by recrystallization.
A mixture of one of compounds 4–8 (1.5 mmol), wet 10% Pd/C
(cat.), and MeOH (100 mL) was stirred under H2 (1 atm) at r.t. for
14–16 h. The reaction mixture was filtered; the filtrate was concen-
trated in vacuo and extracted with EtOAc (3 × 15 mL). The organic
layer was separated and dried (Na2SO4) and concentrated in vacuo,
and the resulting product was purified by column chromatography
(silica gel, PE–EtOAc); this afforded the corresponding pure prod-
uct. The data of 9–11 have been published previously.17
N-[2-(4-Aminophenyl)-6-methyl-1,2,3,4-tetrahydro-4-
quinolyl]pyrrolidin-2-one (12)
Yellow crystals; mp 238–240 °C.
IR (KBr): 3456, 3425, 3317, 2947, 1666 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.28 (d, J = 8.4 Hz, 1 H, 2-HAr),
8.18 (d, J = 8.3 Hz, 1 H, 6-HAr), 7.70 (dd, J = 11.5, 8.7 Hz, 2 H,
3(5)-HAr), 6.90 (bt, J = 5.5 Hz, 1 H, 7-HTHQ), 6.69 (s, 1 H, 5-HTHQ),
6.55 (t, J = 6.9 Hz, 1 H, 8-HTHQ), 5.71 (dd, J = 10.2, 6.9 Hz, 1 H, 4-
N-[2-(Nitrophenyl)-1,2,3,4-tetrahydro-4-quinolyl]pyrrolidin-2-
ones 4–8; General Procedure
A mixture of the arylamine 1 (16.5 mmol) and aldehyde 2 (19.8
mmol) in anhyd MeCN (15 mL) was stirred at r.t. for 30 min. BiCl3
(20 mol%) was added. Over a period of 20 min, a soln NVP (3;
24.75 mmol) in MeCN (10 mL) was added dropwise. The resulting
mixture was stirred for 10–14 h. After completion of the reaction as
indicated by TLC, the reaction mixture was diluted with H2O (30
mL) and extracted with EtOAc (3 × 15 mL). The organic layer was
separated, dried (Na2SO4), and concentrated in vacuo, and the re-
sulting product was purified by column chromatography (silica gel,
PE–EtOAc); this afforded the pure tetrahydroquinolines. The data
of tetrahydroquinolines 4–6 have been published previously.17
HTHQ), 4.62 (ddd, J = 12.0, 10.6, 3.4 Hz, 1 H, 2-HTHQ), 3.96 (s, 1 H,
1-HTHQ), 3.20 (bd, J = 5.9 Hz, 2 H, 5-H), 2.59–2.43 (m, 2 H, 3-H),
2.23 (s, 3 H, 6-CH3), 2.12–1.01 (m, 4 H, 3-H and 4-H).
13C NMR (100 MHz, CDCl3): d = 175.8, 150.6, 143.0, 129.6, 129.1,
128.2, 128.1, 127.3, 127.1, 123.9, 119.0, 115.5, 56.2, 48.3, 42.3,
35.4, 31.3, 20.8, 20.5, 18.2.
GC-MS: tR = 25.34 min, m/z (%) = 321 (1) [M+], 234 (100).
N-[6-Methyl-2-(4-nitrophenyl)-1,2,3,4-tetrahydro-4-
quinolyl]pyrrolidin-2-one (7)
Yellow crystals; mp 222–223 °C.
IR (KBr): 3394, 2947, 2916, 1666, 1620 cm–1.
Anal. Calcd for C20H23N3O: C, 74.74; H, 7.21; N, 13.07. Found: C,
75.66; H, 7.39; N, 13.15.
1H NMR (400 MHz, CDCl3): d = 8.20 (d, J = 8.7 Hz, 2 H, 3(5)-
HAr), 7.61 (d, J = 8.7 Hz, 2 H, 2(6)-HAr), 6.90 (dd, J = 8.0, 1.7 Hz,
1 H, 7-HTHQ), 6.68 (s, 1 H, 5-HTHQ), 6.57 (d, J = 8.1 Hz, 1 H, 8-
N-[2-(4-Aminophenyl)-5,7-dimethyl-1,2,3,4-tetrahydro-4-
quinolyl]pyrrolidin-2-one (13)
Yellow crystals; mp 185–186 °C.
IR (KBr): 3440, 2916, 1666, 1620, 1589 cm–1.
HTHQ), 5.69 (dd, J = 11.1, 6.4 Hz, 1 H, 4-HTHQ), 4.65 (dd, J = 10.7,
3.1 Hz, 1 H, 2-HTHQ), 4.03 (br s, 1 H, 1-HTHQ), 3.21 (t, J = 6.9 Hz, 2
H, 5-H), 2.59–2.41 (m, 2 H, 3-H), 2.23 (s, 3 H, 6-CH3), 2.13–1.99
(m, 4 H, 3-HTHQ and 4-H).
13C NMR (100 MHz, CDCl3): d = 175.8, 150.6, 147.4, 142.9, 129.0,
128.1, 127.3 (2 C), 126.9, 123.9 (2 C), 118.8, 115.4, 56.0, 48.1,
42.2, 35.3, 31.3, 20.5, 18.1.
1H NMR (400 MHz, CDCl3): d = 8.29 (d, J = 8.2 Hz, 1 H, 2-HAr),
8.18 (d, J = 8.1 Hz, 1 H, 6-HAr), 7.55 (dd, J = 11.6, 8.9 Hz, 2 H,
3(5)-HAr), 6.45 (d, J = 5.9 Hz, 1 H, 6-HTHQ), 6.36 (d, J = 4.3 Hz, 1
H, 8-HTHQ), 5.58 (t, J = 8.5 Hz, 1 H, 4-HTHQ), 4.42 (t, J = 12.1 Hz,
1 H, 2-HTHQ), 3.97 (s, 1 H, 1-HTHQ), 3.11 (dd, J = 14.1, 8.5 Hz, 1 H,
5-He), 2.82 (dd, J = 15.3, 7.8 Hz, 1 H, 5-Ha), 2.41 - 2.31 (m, 3 H, 3-
H and 3-HTHQ), 2.22 (s, 3 H, 5-CH3), 2.11 (t, J = 12.0 Hz, 1 H, 3-
HTHQ), 2.07 (s, 3 H, 7-CH3), 1.85 (dd, J = 13.8, 6.0 Hz, 2 H, 4-H).
GC-MS: tR = 44.57 min, m/z (%) = 351 (8) [M+], 265 (100).
Synthesis 2010, No. 4, 593–600 © Thieme Stuttgart · New York

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Synthesis of Linked Biquinoline Derivatives
597
13C NMR (100 MHz, CDCl3): d = 174.3, 147.9, 145.9, 138.2, 137.7,
132.8, 127.4, 122.1, 115.2, 115.1, 114.3, 113.9, 55.5, 46.5, 42.5,
36.3, 31.1, 20.9, 19.3, 17.9.
2-(4-Aminophenyl)-6-methylquinoline (17)
Yellow crystals; mp 178–179 °C.
IR (KBr): 3386, 3301, 3193, 3055, 3023 cm–1.
GC-MS: tR = 26.62 min, m/z (%) = 335 (1) [M+], 248 (100).
1H NMR (400 MHz, CDCl3): d = 8.03 (d, J = 8.7 Hz, 1 H, 3-HQu),
8.01 (m, 3 H, 2(6)-HAr and 8-HQu), 7.76 (d, J = 8.6 Hz, 1 H, 4-HQu),
7.53 (s, 1 H, 5-HQu), 7.52 (dd, J = 8.8, 1.3 Hz, 1 H, 7-HQu), 6.80 (dt,
J = 8.6, 2.0 Hz, 2 H, 3(5)-HAr), 3.85 (br s, 2 H, H2NAr), 2.53 (s, 3 H,
6-CH3).
13C NMR (100 MHz, CDCl3): d = 156.4, 147.6, 146.9, 135.8, 135.3,
131.6, 130.1, 129.1, 128.6 (2 C), 126.8, 126.3, 118.3, 115.1 (2 C),
21.5.
Anal. Calcd for C21H25N3O: C, 75.19; H, 7.51; N, 12.53. Found: C,
75.25; H, 7.68; N, 12.39.
2-(Aminophenyl)quinolines 14–18; General Procedure
A mixture of one of tetrahydroquinoline precursors 9–13 (0.5
mmol) and homogenated elemental sulfur (1.5 mmol) was heated at
260–280 °C for 10–15 min. The reaction mixture was purified by
column chromatography (silica gel, PE–EtOAc) to afford the pure
product, one of 14–18.
GC-MS: tR = 25.13 min, m/z (%) = 234 (100) [M+].
Anal. Calcd for C16H14N2: C, 82.02; H, 6.02; N, 11.96. Found: C,
81.88; H, 6.15; N, 12.17.
2-(3-Aminophenyl)quinoline (14)
Yellow crystals; mp 111–112 °C.
IR (KBr): 3428, 3310, 3207, 2917, 2849 cm–1.
2-(4-Aminophenyl)-5,7-dimethylquinoline (18)
Yellow crystals; mp 115–116 °C.
IR (KBr): 3433, 3317, 3201, 3032, 2962 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.20 (dd, J = 8.3, 3.0 Hz, 1 H, 8-
HQu), 8.18 (d, J = 8.6 Hz, 1 H, 4-HQu), 7.81 (d, J = 8.6 Hz, 1 H, 3-
1H NMR (400 MHz, CDCl3): d = 8.23 (d, J = 8.9 Hz, 1 H, 3-HQu),
8.01 (d, J = 8.5 Hz, 2 H, 2(6)-HAr), 7.75 (s, 1 H, 8-HQu), 7.73 (d,
J = 8.9 Hz, 1 H, 4-HQu), 7.13 (s, 1 H, 6-HQu), 6.79 (d, J = 8.5 Hz, 2
H, 3(5)-HAr), 3.85 (br s, 2 H, H2NAr), 2.63 (s, 3 H, 7-CH3), 2.50 (s,
3 H, 5-CH3).
13C NMR (100 MHz, CDCl3): d = 156.6, 148.8, 147.6, 139.2, 133.8,
132.6, 130.0, 128.6 (2 C), 128.5, 126.7, 124.1, 117.0, 115.1 (2 C),
21.8, 18.4.
HQu), 7.80 (d, J = 7.3 Hz, 1 H, 5-HQu), 7.72 (t, J = 8.1 Hz, 1 H, 7-
Qu), 7.57 (br s, 1 H, 2-HAr), 7.51 (t, J = 7.8 Hz, 1 H, 6-HQu), 7.47
(d, J = 7.8 Hz, 1 H, 5-HAr), 7.29 (t, J = 7.8 Hz, 1 H, 4-HAr), 6.78 (dd,
J = 7.8 Hz, 1 H, 1.5 Hz, 3-HAr), 3.57 (br s, 2 H, H2NAr).
13C NMR (100 MHz, CDCl3): d = 157.4, 147.9, 146.9, 140.5, 136.8,
129.8, 129.7, 129.5, 127.4, 127.2, 126.2, 119.2, 117.9, 116.3, 114.2.
H
MS (EI, 70 eV): m/z (%) = 220 (100) [M+].
Anal. Calcd for C15H12N2: C, 81.79; H, 5.49; N, 12.72. Found: C,
81.50; H, 5.30; N, 12.65.
GC-MS: tR = 26.94 min, m/z (%) = 248 (100) [M+].
Anal. Calcd for C17H16N2: C, 82.22; H, 6.49; N, 11.28. Found: C,
82.07; H, 6.67; N, 11.19.
2-(3-Aminophenyl)-6-methylquinoline (15)
Yellow crystals; mp 100–101 °C.
IR (KBr): 3403, 3297, 3207, 3059, 2914 cm–1.
N-[2¢-(3-Nitrophenyl)-1¢,2¢,3¢,4¢-tetrahydro-2,7¢-biquinolin-4¢-
yl]pyrrolidin-2-ones 19–21; General Procedure
1H NMR (400 MHz, CDCl3): d = 8.11 (d, J = 8.6 Hz, 1 H, 8-HQu),
7.97 (d, J = 8.6 Hz, 1 H, 3-HQu), 7.70 (d, J = 8.6 Hz, 1 H, 4-HQu),
7.55 (br s, 1 H, 5-HQu), 7.51 (dd, J = 8.6, 2.0 Hz, 1 H, 7-HQu), 7.48
(br s, 1 H, 2-HAr), 7.47 (ddd, J = 7.8, 2.2, 0.8 Hz, 1 H, 6-HAr), 7.30
(t, J = 7.8 Hz, 1 H, 5-HAr), 6.77 (ddd, 1 H, J = 7.8, 2.2, 0.8, 4-HAr),
3.82 (br s, 2 H, H2NAr), 2.50 (s, 3 H, 6-CH3).
13C NMR (100 MHz, CDCl3): d = 156.7, 146.9, 146.8, 140.9, 136.1,
135.9, 131.9, 129.7, 129.3, 127.3, 126.4, 119.2, 117.9, 116.1, 114.1,
21.6.
A mixture of one of anilines 14–18 (0.5 mmol) and aldehyde 2a
(0.55 mmol) in anhyd MeCN (15 mL) was stirred at r.t. for 30 min.
BiCl3 (20 mol%) was added. Over a period of 20 min, a soln NVP
(3; 0.56 mmol) in MeCN (10 mL) was added dropwise. The result-
ing mixture was stirred for 10–14 h. After completion of the reac-
tion as indicated by TLC, the reaction mixture was diluted with H2O
(30 mL) and extracted with EtOAc (3 × 15 mL). The organic layer
was separated, dried (Na2SO4), and concentrated in vacuo, and the
resulting product was purified by column chromatography (silica
gel, PE–EtOAc); this afforded the pure product.
MS (EI, 70 eV): m/z (%) = 234 (100) [M+].
Anal. Calcd for C16H14N2: C, 82.02; H, 6.02; N, 11.96. Found: C,
82.13; H, 6.19; N, 11.65.
N-[2¢-(3-Nitrophenyl)-1¢,2¢,3¢,4¢-tetrahydro-2,7¢-biquinolin-4¢-
yl]pyrrolidin-2-one (19)
Yellow crystals; mp 134–136 °C.
IR (KBr): 3427, 3261, 2917, 1660, 1513 cm–1.
2-(3-Aminophenyl)-6-methoxyquinoline (16)
Yellow crystals; mp 102–103 °C.
1H NMR (400 MHz, CDCl3): d = 8.34 (br s, 1 H, 2-HAr), 8.16 (d,
J = 8.0 Hz, 1 H, 6¢-HTHQ), 8.14 (d, J = 8.0 Hz, 1 H, 8-HQu), 8.12 (dd,
J = 8.3, 2.0 Hz, 1 H, 4-HAr), 7.79 (d, J = 8.0 Hz, 1 H, 4-HQu), 7.71
(d, J = 8.0 Hz, 1 H, 3-HQu), 7.70 (t, J = 8.0 Hz, 1 H, 7-HQu), 7.70 (t,
J = 8.0 Hz, 1 H, 5-HAr), 7.50 (br s, 1 H, 8¢-HTHQ), 7.49 (d, J = 8.3
Hz, 1 H, 6-HAr), 7.22 (t, J = 8.0 Hz, 1 H, 6-HQu), 6.90 (d, J = 8.0 Hz,
5-HQu), 6.75 (d, J = 8.0 Hz, 1 H, 5¢-HTHQ), 6.0 (dd, J = 12.0, 8.0 Hz,
1 H, 2¢-HTHQ), 4.66 (dd, J = 12.0, 4.0 Hz, 1 H, 4¢-HTHQ), 4.29 (br s,
1 H, 1¢-HTHQ), 2.97–2.90 (m, 2 H, 5-H), 2.17–2.15 (m, 2 H, 3-H),
1.98–1.61 (m, 2 H, 3¢-HTHQ), 1.15–1.12 (m, 2 H, 4-H).
13C NMR (100 MHz, CDCl3): d = 173.3, 159.3, 148.3, 147.7, 146.7,
144.9, 141.5, 135.8, 132.8, 129.7, 129.6, 129.2, 128.7, 127.5, 126.8,
126.3, 122.8, 121.5, 121.3, 121.2, 116.6, 116.4, 55.0, 47.0, 42.1,
35.3, 30.0, 16.7.
IR (KBr): 3376, 3305, 3183, 3065, 3013 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.05 (d, J = 9.1 Hz, 1 H, 4-HQu),
8.04 (d, J = 9.1 Hz, 1 H, 3-HQu), 7.78 (d, J = 8.3 Hz, 1 H, 8-HQu),
7.52 (br s, 1 H, 5-HQu), 7.44 (d, J = 8.3 Hz, 1 H, 7-HQu), 7.39 (dd,
J = 8.0, 2.0 Hz, 1 H, 6-HAr), 7.28 (t, J = 7.8 Hz, 1 H, 5-HAr), 7.05 (br
s, 1 H, 2-HAr), 6.75 (d, J = 7.8 Hz, 1 H, 4-HAr), 3.92 (s, 3 H, 6-
CH3O), 3.79 (br s, 2 H, H2NAr).
13C NMR (100 MHz, CDCl3): d = 157.3, 154.8, 146.6, 143.9, 140.5,
134.9, 130.8, 129.3, 127.8, 121.8, 119.0, 117.3, 115.5, 113.5, 104.7,
55.2.
MS (EI, 70 eV): m/z (%) = 250 (70) [M+].
Anal. Calcd for C16H14N2O: C, 76.78; H, 5.64; N, 11.19. Found: C,
76.61; H, 5.79; N, 11.32.
MS (EI, 70 eV): m/z (%) = 464 (70) [M+].
Synthesis 2010, No. 4, 593–600 © Thieme Stuttgart · New York

598
L. Astudillo Saavedra et al.
PAPER
Anal. Calcd for C28H24N4O3: C, 72.40; H, 5.21; N, 12.06. Found: C,
72.30; H, 5.15; N, 12.10.
IR (KBr): 3264, 2967, 1660, 1513, 1351 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.19 (d, J = 8.0 Hz, 2 H, 3(5)-
HAr), 7.60 (d, J = 8.0 Hz, 2 H, 2(6)-HAr), 7.12 (dd, J = 8.0, 4.0 Hz,
1 H, 7¢-HTHQ), 6.81 (br s, 1 H, 5-HTHQ); 6.65 (d, J = 8.0 Hz, 1 H, 8¢-
HTHQ), 6.39 (br s, 1 H, 7-HTHQ), 6.27 (d, J = 4.0 Hz, 1 H, 5¢-HTHQ),
5.67 (dd, J = 12.0, 8.0 Hz, 1 H, 4-HTHQ), 5.53 (dd, J = 12.0, 8.0 Hz,
1 H, 4¢-HTHQ), 4.68 (dd, J = 12.0, 4.0 Hz, 1 H, 2-HTHQ), 4.31 (br s,
1 H, 1¢-HTHQ), 4.17 (dd, J = 12.0, 4.0 Hz, 1 H, 2¢-HTHQ), 3.80 (br s,
1 H, 1-HTHQ), 3.22–3.00 (m, 4 H, 5-H), 2.90–2.50 (m, 4 H, 3(3¢)-
HTHQ), 2.19 (s, 3 H, 5-CH3), 2.15–2.05 (m, 4 H, 3-H), 2.02 (s, 3 H,
7-CH3), 1.98–1.85 (m, 4 H, 4-H).
13C NMR (100 MHz, CDCl3): d = 175.9, 174.4, 150.3, 147.9, 147.5,
138.2, 137.7, 135.1, 133.2, 127.2 (2 C), 126.3, 124.9, 123.9 (2 C),
122.3, 118.7 (2 C), 115.6, 114.2, 55.8, 55.3, 48.2, 48.1, 42.3 (2 C),
36.7, 35.1, 31.2 (2 C), 20.9, 19.4, 18.2 (2 C).
N-[6-Methyl-2¢-(3-nitrophenyl)-1¢,2¢,3¢,4¢-tetrahydro-2,7¢-
biquinolin-4¢-yl]pyrrolidin-2-one (20)
Yellow crystals; mp 138–140 °C.
IR (KBr): 3405, 3325, 3208, 1667, 1527 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.31 (br s, 1 H, 2-HAr), 8.12 (dd,
J = 8.0, 1.5 Hz, 1 H, 4-HAr), 8.07 (d, J = 8.6 Hz, 1 H, 4-HQu), 7.99
(d, J = 8.3, Hz, 1 H, 7¢-HTHQ), 7.75 (d, J = 8.6 Hz, 1 H, 3-HQu), 7.67
(d, J = 7.6 Hz, 1 H, 8-HQu), 7.54 (br s, 1 H, 5-HQu), 7.52 (dd, 1 H,
J = 7.6, 1.0, 7-HQu), 7.47 (t, J = 8.0 Hz, 1 H, 4-HAr), 7.42 (dd,
J = 8.0, 1.5 Hz, 1 H, 5-HAr), 7.02 (d, J = 8.3 Hz, 1 H, 8¢-HTHQ), 5.75
(dd, J = 11.0, 4.0 Hz, 1 H, 2¢-HTHQ), 4.67 (dd, J = 11.0, 3.0 Hz, 1 H,
4¢-HTHQ), 4.46 (br s, 1 H, 1¢-HTHQ), 3.26 (t, 2 H, J = 7.0, 5-H), 2.57–
2.46 (m, 2 H, 3¢-HTHQ), 2.13–2.10 (m, 2 H, 3-H), 2.07–2.02 (m, 2 H,
4-H).
13C NMR (100 MHz, CDCl3): d = 175.9, 156.0, 148.6, 146.6, 145.9,
145.1, 140.0, 136.2, 136.1, 132.8, 132.0, 129.6, 129.2, 127.4, 127.3,
126.3, 122.9, 121.4, 120.1, 118.8, 117.9, 114.4, 55.8, 48.2, 42.3,
35.3, 31.3, 21.5, 18.3.
MS (EI, 70 eV): m/z (%) = 579 (90) [M+].
Anal. Calcd for C34H37N5O4: C, 70.45; H, 6.43; N, 12.08. Found: C,
70.15; H, 6.10; N, 12.05.
2,6¢-Biquinolines 23 and 24; General Procedure
A mixture of the appropriate 2-(aminophenyl)quinoline (0.4 mmol),
concd H2SO4 (5 mL), and NaI (0.1 mmol) was stirred at 120 °C for
10 min. Then glycerol (0.05 g, 0.5 mmol) was added and the mix-
ture was stirred at 150 °C for 3 h. After completion of the reaction
as indicated by TLC, the reaction mixture was treated with 30% aq
NaOH (10 mL) and extracted with EtOAc (3 × 15 mL). The organic
layer was separated, dried (Na2SO4), and concentrated in vacuo, and
the resulting product was purified by column chromatography (sili-
ca gel, PE–EtOAc, 4:1).
MS (EI, 70 eV): m/z (%) = 478 (80) [M+].
Anal. Calcd for C29H26N4O3: C, 72.79; H, 5.48; N, 11.71. Found: C,
72.50; H, 5.25; N, 11.10.
N-[6-Methoxy-2¢-(3-nitrophenyl)-1¢,2¢,3¢,4¢-tetrahydro-2,7¢-
biquinolin-4¢-yl]pyrrolidin-2-one (21)
Yellow crystals; mp 156–158 °C.
IR (KBr): 3407, 3322, 3205, 1669, 1522 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.27 (br s, 1 H, 2-HAr), 8.14 (dd,
J = 8.0, 1.5 Hz, 1 H, 4-HAr), 8.08 (d, J = 8.0 Hz, 1 H, 7¢-HTHQ), 8.07
(d, J = 8.0, Hz, 1 H, 4-HQu), 7.94 (d, J = 8.0 Hz, 1 H, 3-HQu), 7.73
(d, J = 8.0 Hz, 1 H, 8-HQu), 7.51 (t, J = 8.0 Hz, 1 H, 5-HAr), 7.49 (d,
J = 8.0 Hz, 1 H, 7-HQu), 7.40 (d, J = 8.0 Hz, 1 H, 6-HAr), 7.36 (br s,
1 H, 5-HQu), 7.33 (br s, 1 H, 5¢-HTHQ), 7.26 (d, J = 8.0 Hz, 8¢-HTHQ),
5.37 (dd, J = 12.0, 4.0 Hz, 1 H, 2¢-HTHQ), 4.53 (dd, J = 12.0, 4.0 Hz,
1 H, 4¢-HTHQ), 4.39 (br s, 1 H, 1¢-HTHQ), 3.42–3.23 (m, 2 H, 5-H),
2.40–2.35 (m, 2 H, 3¢-HTHQ), 2.17–2.03 (m, 2 H, 3-H), 2.00–1.82
(m, 2 H, 4-H).
13C NMR (100 MHz, CDCl3): d = 175.9, 157.7, 156.9, 148.7, 146.7,
145.2, 143.9, 135.5, 134.7, 134.6, 133.0, 129.5, 127.8, 127.4, 123.0,
122.6, 122.4, 121.7, 120.9, 119.1, 117.8, 105.1, 55.6, 55.2, 48.2,
42.4, 35.5, 31.4, 18.3.
6-Methyl-2,6¢-biquinoline (23)
Yellow crystals; mp 152–153 °C.
IR (KBr): 3039, 2916, 1589, 1481, 1365, 1311 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.95 (d, J = 4.2 Hz, 1 H, 2¢-H),
8.58 (s, 1 H, 5¢-H), 8.56(m, 1 H, 7¢-H), 8.28 (d, J = 8.2 Hz, 1 H, 4¢-
H), 8.24 (d, J = 8.1 Hz, 1 H, 8¢-H), 8.17 (d, J = 8.6 Hz, 1 H, 3-H),
8.10 (d, J = 8.4 Hz, 1 H, 8-H), 7.97 (d, J = 8.6 Hz, 1 H, 4-H), 7.60
(s, 1 H, 5-H), 7.60 (m, 1 H, 7-H), 7.44 (dd, J = 8.2, 4.2 Hz, 1 H, 3¢-
H), 2.56 (s, 3 H, 6-CH3).
13C NMR (100 MHz, CDCl3): d = 155.4, 150.9, 148.7, 146.9, 137.8,
136.8, 136.5 (2 C), 136.3, 132.2 130.0, 129.4, 128.7, 126.6, 126.4,
121.5, 118.9, 21.6.
GC-MS: tR = 27.51 min, m/z (%) = 270 (100) [M+].
MS (EI, 70 eV): m/z (%) = 494 (80) [M+].
Anal. Calcd for C19H14N2: C, 84.42; H, 5.22; N, 10.36. Found: C,
84.65; H, 5.01; N, 10.28.
Anal. Calcd for C29H26N4O4: C, 70.43; H, 5.30; N, 11.33. Found: C,
70.15; H, 5.25; N, 11.10.
5,7-Dimethyl-2,6¢-biquinoline (24)
Yellow crystals; mp 77–79 °C.
IR (KBr): 2954, 2924, 2854, 1666 cm–1.
5,7-Dimethyl-2¢-(4-nitrophenyl)-4,4¢-bis(2-oxopyrrolidin-1-yl)-
1,1¢,2,2¢,3,3¢,4,4¢-octahydro-2,6¢-biquinoline (22)
A mixture of aniline 13 (0.97 g, 2.9 mmol) and aldehyde 2b (0.54
g, 3.6 mmol) in anhyd MeCN (15 mL) was stirred at r.t. for 30 min.
BiCl3 (0.18 g, 20 mol%) was added. Over a period of 20 min, a soln
of NVP (3; 0.50 g, 4.5 mmol) in MeCN (10 mL) was added drop-
wise. The resulting mixture was stirred for 10–14 h. After comple-
tion of the reaction as indicated by TLC, the reaction mixture was
diluted with H2O (30 mL) and extracted with EtOAc (3 × 15 mL).
The organic layer was separated, dried (Na2SO4), and concentrated
in vacuo, and the resulting product was purified by column chroma-
tography (silica gel, PE–EtOAc, 4:1); this gave pure biquinoline 22.
1H NMR (400 MHz, CDCl3): d = 8.85 (d, J = 4.3 Hz, 1 H, 2¢-H),
8.70 (m, 1 H, 7¢-H), 8.44 (s, 1 H, 5¢-H), 8.37 (m, 1 H, 4¢-H), 8.23 (d,
J = 8.1 Hz, 1 H, 4-H), 8.09 (d, J = 8.6 Hz, 1 H, 8¢-H), 7.60 (s, 1 H,
6-H), 7.57 (m, 1 H, 3¢-H), 7.50 (s, 1 H, 8-H), 7.30 (m, 1 H, 3-H),
2.55 (s, 3 H, CH3), 2.33 (s, 3 H, CH3).
13C NMR (100 MHz, CDCl3): d = 153.0, 149.8, 147.2, 146.8, 142.6,
139.8, 138.9, 136.4–133.0 (3 C), 129.5–127.0 (4 C), 123.3, 121.6,
117.8, 21.5, 19.7.
GC-MS: tR = 29.70 min, m/z (%) = 284 (100) [M+].
Yield: 1.18 g (70%); white powder; mp 150–152 °C.
Anal. Calcd for C20H16N2: C, 84.48; H, 5.67; N, 9.85. Found: C,
84.23; H, 5.88; N, 9. 91.
Synthesis 2010, No. 4, 593–600 © Thieme Stuttgart · New York

PAPER
Synthesis of Linked Biquinoline Derivatives
599
Tetrahydrobiquinolines 27 and 28; General Procedure
13C NMR (150 MHz, CDCl3): d = 157.8–119.4 (C-Qu), 21.9 (6¢-
85% H2SO4 (2 mL) was added dropwise at 0 °C to the appropriate
homoallylamine 25 or 26 (3.7 mmol) in CHCl3 (3–5 mL), and the
resulting mixture was heated at 60 °C for 3 h. Upon completion of
the reaction (monitored by TLC), the mixture was cooled to r.t.,
concd NH4OH soln was added to adjust the pH to 10, and the result-
ing mixture was extracted with Et2O (3 × 50 mL). After removal of
the solvent from the combined extracts, the oily residue was puri-
fied by column chromatography (silica gel, heptane–EtOAc, 20:1);
this gave the corresponding tetrahydrobiquinoline 27 or 28.
CH3), 21.7 (6-CH3), 19.0 (4-CH3).
GC-MS: tR = 49.51 min, m/z (%) = 298 (100) [M+].
Anal. Calcd for C21H18N2: C, 84.56; H, 6.04; N, 9.40. Found: C,
84.85; H, 6.33; N, 9.05.
6-Methoxy-4-methyl-2,8¢-biquinoline (30)
Yield: 65%; yellow crystals; mp 208 °C.
1H NMR (600 MHz, CDCl3): d = 8.95–7.05 (m, 9 H, HQu), 3.80 (s,
3 H, OCH3), 2.84 (s, 3 H, 4-CH3).
13C NMR (150 MHz, CDCl3): d = 158.9–119.5 (C-Qu), 55.2 (6-
CH3O), 19.5 (4-CH3).
GC-MS: tR = 47.15 min, m/z (%) = 300 (100) [M+].
4,6,6¢-Trimethyl-1,2,3,4-tetrahydro-2,2¢-biquinoline (27)
Yield: 89%; yellow crystals; mp 201–202 °C.
IR (KBr): 3417, 1595 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.07 (d, 1 H, J = 8.1 Hz, 3-HQu),
7.99 (dd, J = 8.6 Hz, 1 H, 8-HQu), 7.70–7.40 (m, 2 H, 4(7)-HQu),
7.58 (s, 1 H, 5-HQu), 7.01 (d, J = 1.9 Hz, 1 H, 5-H), 6.86 (dd, J = 7.3,
1.9 Hz, 1 H, 7-H), 6.59 (d, J = 7.9 Hz, 1 H, 8-H), 4.75 (dd,
J = 11.6, = 3.1 Hz, 1 H, 2-H), 3.25 (sept, J = 11.2, 6.8, 5.3 Hz, 1 H,
4-H), 2.54 (s, 3 H, CH3Qu), 2.09–2.00 (m, 1 H, 3-Heq), 2.26 (s, 3 H,
6-CH3), 1.78 (q, 1 H, J = 11.6, 11.6 Hz; 3-Hax), 1.37 (d, 3 H, J = 6.8
Hz; 4-CH3).
Anal. Calcd for C20H16N2O: C, 79.98; H, 5.37; N, 9.33. Found: C,
79.81; H, 5.54; N, 9.23.
Acknowledgment
This work was supported by a grant of the PBCT Anillo ACT-38.
V.K. thanks DIEF-UIS (grant No. 5151) and COLCIENCIAS
(grant CENIVAM, contract No. 432-2004) for financial support.
C.M.M.G. also thanks COLCIENCIAS for his fellowship.
GC-MS: tR = 42.06 and 44.01 min (ratio 1:2); tR (minor isomer) =
42.06 min, m/z (%) = 302 (95) [M+], 287 (99), 271 (5), 260 (5), 246
(1), 207 (4), 196 (2), 181 (2), 170 (14), 157 (78), 144 (100), 130
(24), 115 (28), 103 (4), 91 (12), 77 (8), 65 (7), 55 (4), 41 (7); tR (ma-
jor isomer) = 44.01 min, m/z (%) = 302 (99) [M+], 287 (20), 273 (6),
259 (5), 245 (1), 207 (2), 195 (0.5), 182 (1), 170 (7), 160 (100), 144
(95), 130 (22), 115 (23), 102 (3), 91 (10), 77 (6), 65 (4), 55 (3), 41
(5).
References
(1) Jones, G. Pyridines and Their Benzo Derivatives: Synthesis,
In Comprehensive Heterocyclic Chemistry, Vol. 2;
Katritzky, A. R., Ed.; Pergamon Press: Oxford, 1984, 395.
(2) Katritzky, A. R.; Rachwal, S.; Rachwal, B. Tetrahedron
1996, 52, 15031.
(3) Kouznetsov, V.; Palma, A.; Ewert, C.; Varlamov, A.
J. Heterocycl. Chem. 1998, 35, 761.
(4) Kouznetsov, V. V.; Vargas Méndez, L. Y.;
Meléndez Gómez, C. M. Curr. Org. Chem. 2005, 9, 141.
(5) Glushenko, T. P.; Goncharov, V. I.; Aksenov, A. V. Chem.
Heterocycl. Compd. 2008, 44, 973.
(6) Broch, S.; Anizon, F.; Moreau, P. Synthesis 2008, 2039.
(7) Chen, Y.-X.; Yang, L.-W.; Li, Y.-M.; Zhou, Z.-Y.; Lam, K.-
H.; Chan, A. S. C.; Kwong, H.-L. Chirality 2000, 12, 510.
(8) Ichikawa, J.; Mori, T.; Miyazaki, H.; Wada, Y. Synlett 2004,
1219.
Anal. Calcd for C21H22N2: C, 83.44; H, 7.28; N, 9.27. Found: C,
83.25; H, 7.63; N, 9.15.
6-Methoxy-4-methyl-1,2,3,4-tetrahydro-2,8¢-biquinoline (28)
Yield: 91%; yellow oil.
IR (neat): 3353, 1599 cm–1.
1H NMR (600 MHz, CDCl3): d = 8.06 (d, J = 8.5 Hz, 1 H, 2-HQu),
7.84 (dd, J = 7.1 Hz, 1 H, 5-HQu), 7.67 (d, J = 8.1 Hz, 1 H, 7-HQu),
7.45 (dd, J = 8.4, 7.1 Hz, 2 H, 4(6)-HQu), 6.89 (dd, J = 8.5, 8.4 Hz,
1 H, 3-HQu), 6.85 (d, J = 2.6 Hz, 1 H, 5-H), 6.66 (dd, J = 8.6, 2.6 Hz,
1 H, 7-H), 6.57 (d, J = 8.6 Hz, 1 H, 8-H), 5.67 (dd, 1 H, J = 11.3, 2.0
Hz; 2-H), 3.79 (s, 3 H, OCH3), 2.65 (sept, J = 12.0, 6.8, 5.5, Hz, 1
H, 4-H), 2.42 (ddd, J = 11.9, 5.5, 2.0 Hz, 1 H, 3-Heq), 1.88 (q,
J = 12.0, 11.9 Hz, 1 H, 3-Hax), 1.40 (d, J = 6.8 Hz, 3 H, 4-CH3).
(9) Morsali, A.; Mahjoub, A. R.; Ramazani, A. J. Coord. Chem.
2004, 57, 347.
(10) Trpkovska, M.; Šoptrajanov, B.; Pejov, L. J. Mol. Struct.
13C NMR (150 MHz, CDCl3): d = 155.1, 152.3, 145.9, 141.5, 139.9,
136.6, 132.4, 128.4, 127.1, 126.6, 126.1, 118.9, 115.9, 113.2, 112.4,
55.9, 50.6, 39.1, 31.6, 20.7.
2003, 654, 21.
(11) Youssef, A. O.; Khalil, M. M. H.; Ramadan, R. M.; Soliman,
A. A. Transition Met. Chem. 2003, 28, 331.
(12) Pazderski, L.; Tošuek, J.; Sitkowski, J.; Kozerski, L.; Szłyk,
E. Magn. Reson. Chem. 2007, 45, 1059.
(13) Guerrero, J.; Farías, L.; Lemus, L.; Quintanilla, A.; Mena,
A.; Cortez, L.; Baggio, R. F.; Garland, M. T. Polyhedron
2006, 25, 9.
(14) Kouznetsov, V. V. Tetrahedron 2009, 65, 2721.
(15) Kouznetsov, V. V.; Mora Cruz, U. Lett. Org. Chem. 2006, 3,
699.
(16) Kouznetsov, V. V.; Mora Cruz, U.; Zubkov, F. I.; Nikitina,
E. V. Synthesis 2007, 375.
GC-MS: tR = 44.92 min, m/z (%) = 304 (100) [M+], 143 (86).
Anal. Calcd for C20H20N2O: C, 78.95; H, 6.58; N, 9.21. Found: C,
78.85; H, 6.83; N, 9.11.
Biquinolines 29 and 30; General Procedure
A mixture of the appropriate tetrahydroquinoline 27 or 28 (0.5
mmol) and homogenated elemental sulfur (0.041 g, 1.3 mmol) was
heated at 200 °C for 5–10 min until the evolution of gas (H2S)
ceased. The solid residue was purified by column chromatography
(alumina, heptane–EtOAc, 50:1).
(17) Kouznetsov, V. V.; Bohórquez Romero, A. R.;
Astudillo Saavedra, L.; Fierro Medina, R. Mol. Diversity
2006, 10, 29.
4,6,6¢-Trimethyl-2,2¢-biquinoline (29)
Yield: 74%; yellow crystals; mp 203 °C.
1H NMR (600 MHz, CDCl3): d = 8.98–7.27 (m, 9 H, HQu), 2.79 (s,
3 H, 4-CH3), 2.58 (s, 3 H, 6¢-CH3), 2.55 (s, 3 H, 6-CH3).
(18) Denmark, S. E.; Venkatraman, S. J. Org. Chem. 2006, 71,
1668.
(19) Vargas, M. L. Y.; Castelli, M. V.; Kouznetsov, V. V.;
Urbina, G. J. M.; López, S. N.; Sortino, M.; Enriz, R. D.;
Synthesis 2010, No. 4, 593–600 © Thieme Stuttgart · New York

600
L. Astudillo Saavedra et al.
PAPER
(21) Vargas Méndez, L. Y.; Kouznetsov, V.; Poveda, J. C.;
Ribas, J. C.; Zacchino, S. A. Bioorg. Med. Chem. 2003, 11,
1531.
Yolaçan, Ç.; Öcal, N.; Aydogan, F. Heterocycl. Commun.
(20) Öcal, N.; Yolaçan, Ç.; Kaban, Ş.; Vargas Méndez, L. Y.;
Kouznetsov, V. J. Heterocycl. Chem. 2001, 38, 233.
2001, 7, 129.
(22) Kuznetsov, V. V.; Aliev, A. E.; Prostakov, N. S. Khim.
Geterotsikl. Soedin. 1993, 73; Chem. Abstr. 1994, 121,
300738.
Synthesis 2010, No. 4, 593–600 © Thieme Stuttgart · New York