Convenient synthesis of 1,2,3,4-tetrahydroquinolines via direct intramolecular reductive ring closure

Article abstract of DOI:10.1016/j.tetlet.2006.07.144

A simple and convenient procedure for the synthesis of 3-aryl-1,2,3,4-tetrahydroquinolines is reported. 3-Aryl-1,2,3,4-tetrahydroquinolines are directly obtained by reductive ring closure of 2-phenyl-3-(2-nitrophenyl)-propionitrile derivatives in moderate to high yields.

Full text of DOI:10.1016/j.tetlet.2006.07.144

Tetrahedron Letters 47 (2006) 7191–7193
Convenient synthesis of 1,2,3,4-tetrahydroquinolines via
direct intramolecular reductive ring closure
Wuhong Chen, Bo Liu, Chunhao Yang* and Yuyuan Xie
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institute for
Biological Sciences, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China
Received 28 June 2006; revised 27 July 2006; accepted 28 July 2006
Available online 17 August 2006
Abstract—A simple and convenient procedure for the synthesis of 3-aryl-1,2,3,4-tetrahydroquinolines is reported. 3-Aryl-1,2,3,4-tetra-
hydroquinolines are directly obtained by reductive ring closure of 2-phenyl-3-(2-nitrophenyl)-propionitrile derivatives in moderate
to high yields.
Ó 2006 Elsevier Ltd. All rights reserved.
Tetrahydroquinolines (THQs) are important hetero-
cycles possessing diverse biological activities1 and multiple
applications.2 They are widely used as antimalarial,3
antibacterial,4 antiviral agents,5 and as key intermedi-
ates for the synthesis of photographic couplers.6
using a direct intramolecular reductive ring closure
strategy.
We first attempted to prepare 7-methoxy-3-(4-methoxy-
phenyl)-1,2,3,4-tetrahydroquinoline by reductive ring
closure of 2-phenyl-3-(2-nitrophenyl)-propionitrile deriv-
ative (Scheme 1), which is easily obtained by conden-
sation of 4-methoxy-2-nitro-benzaldehyde with (4-meth-
oxy-phenyl)-acetonitrile followed by reduction with
NaBH4. The reaction was carried out in THF and
MeOH at ambient temperature. It was found that
3-(2-amino-4-methoxy-phenyl)-2-(4-methoxy-phenyl)-
propionitrile (4c) was formed as the only product in
95% yield but ring closure did not occur with PtO2
(10 wt %) as the catalyst. The same result was observed
when Pd/C (10 wt %) was used as the catalyst for 10 h.
Extension of the reaction time to 48 h yielded the desired
ring closure product 7-methoxy-3-(4-methoxy-phenyl)-
1,2,3,4-tetrahydroquinoline (3c), but the yield was
fairly low (26%), accompanied by trace amount of
A number of methods have been reported for the con-
struction of THQ core.7 However, the application of
these methods is limited due to the inadequate diversity
of the substrates and/or products. In addition, the 3-
monosubstituted THQs have not been well studied and
only a few papers described their synthesis,8a,b and
reduction of 3-substituted quinoline is an ordinary alter-
native for 3-substituted THQ.8c,d The 3-aryl-substituted
THQs are aza analogs of isoflavans and isoflavans dis-
play promising biological activities.9 During the course
of our drug research we required certain 3-aryl-substi-
tuted THQs as intermediates. This prompted us to
devise a simple and efficient way to prepare them.
Herein, we wish to report our synthesis of THQs by
OMe
H2
OMe
OMe
OMe
+
+
CN
NO2
Pd/C
CN
NH2
MeO
MeO
N
H
MeO
N
MeO
2c
3c
5c
4c
Scheme 1. Catalytic hydrogenation of 3-(4-methoxy-2-nitrophenyl)-2-(4-methoxy-phenyl)-propionitrile.
Keywords: Tetrahydroquinolines; Synthesis; Reductive ring closure.
*
Corresponding author. Tel./fax: +86 21 50806770; e-mail: chyang@mail.shcnc.ac.cn
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.07.144

7192
W. Chen et al. / Tetrahedron Letters 47 (2006) 7191–7193
3-(2-aminophenyl)-2-phenylpropionitrile, as well as
the dehydrogenated product 7-methoxy-3-(4-methoxy-
phenyl)-quinoline (5c).
sponding 1,2,3,4-tetrahydroquinolines in good yields
(Table 2, entries 2–10, 14, 15), while reactions of
propionitrile derivatives bearing electron-withdrawing
groups (CF3 and CN) gave low to moderate yields
(Table 2, entries 16 and 17). The reaction mixture
was especially complicated and the yield was remark-
ably low in the case of cyano-bearing compound (entry
17). A low yield of 21% was also observed with bulky
naphthalenyl substituted substrate (entry 19). When
the C-3 substituent was thiophenyl, the reaction did
not happen, possibly due to poisoning of the palladium
catalyst by sulfur.
We next systematically investigated the effect of the
amount of catalyst, temperature, and pressure on the
yield of the desired product. When the amount of cata-
lyst was increased to 30 wt %, a significant increase of
yield was observed (60%, Table 1, entry 3). Higher yield
(74%, Table 1, entry 4) was obtained when the reaction
temperature was raised to 40 °C. Changing the pressure
was found to have no effect on the reaction. On the basis
of these findings, an optimum reaction condition can be
reached: 30 wt % of catalyst, 40 °C, and normal
pressure.
When 3-(2-aminophenyl) propionitrile was used as start-
ing material, we also got the desired ring closure prod-
uct. The reaction may proceed as Sajiki et al.11
described.
We then performed this reaction on a series of propio-
nitriles with the optimum reaction conditions (Scheme
2).10 The results are summarized in Table 2. Reactions
of substrates bearing electron-donating (Me and OMe)
substituents proceeded smoothly to give the corre-
To explore the possible mechanism for the formation of
1,2,3,4-tetrahydroquinolines, we attempted to apply this
procedure to 2-(2-nitrobenzyl)-2-phenyl-butanenitrile.
2-Amino-3-ethyl-3-phenyl-3,4-dihydroquinoline N-oxide
was obtained as the major product, instead of the
expected product, 3-ethyl-3-phenyl-1,2,3,4-tetrahydro-
quinoline. This result confirmed the early report on
the reactions of substrates with variant R-substituents.12
This could not be explained by Sajiki’s postulation.
Table 1. Effect of the reaction condition on the reductive ring closure
of 3-(4-methoxy-2-nitrophenyl)-2-(4-methoxy-phenyl)-propionitrile
Entry
Pd/C (wt %)
Temp (°C)
3c Yield (%)
1
2
3
4
10
20
30
30
rt
rt
rt
40
26
53
60
74
To rationalize these results, we postulate a mechanism
as follows (Scheme 3): first, the nitro group is reduced
to the corresponding hydroxylamine. On the one hand,
R1
R4
R1
R1
R1
R2
R3
CHO
+
R2
R3
Ar
R2
Ar
R2
R3
Ar
iii
i
ii
Ar CH2CN
CN
NO2
CN
NO2
NO2
N
R3
H
R4
R4
R4
1a-1t
2a-2t
3a-3t
Scheme 2. Synthesis of 3a–3t. Reagents and conditions: (i) Na, C2H5OH, 5 h; (ii) NaBH4, THF, CH3OH; (iii) H2, Pd/C, THF, CH3OH.
Table 2. Yields of 3a–3t
Entry
R1
R2
R3
R4
Ar
3 Yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
H
H
H
H
H
H
OMe
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
OMe
H
H
OMe
OMe
H
H
H
H
H
H
H
H
H
H
H
H
OMe
H
H
Me
H
H
H
H
Phenyl
3a (57)
3b (73)
3c (74)
3d (64)
3e (57)
3f (62)
3g (64)
3h (63)
3i (65)
3j (72)
3k (47)
3l (45)
3m (50)
3n (63)
3o (60)
3p (48)
3q (7)
4-Methoxyphenyl
4-Methoxyphenyl
4-Methoxyphenyl
4-Fluorophenyl
OMe
OMe
OMe
OMe
OMe
OMe
3-Amino-4-methoxyphenyl
4-Methoxyphenyl
3,4-Methylenedioxyphenyl
3,4-Dimethoxyphenyl
4-Methoxyphenyl
4-Methoxyphenyl
4-Methoxyphenyl
3-Fluoro-4-methoxyphenyl
4-Methoxyphenyl
4-Methylphenyl
3-Trifluoromethylphenyl
2-Cyanophenyl
Biphenyl
Naphthalen-1-yl
Pyridin-2-yl
3,4-Methylenedioxyphenyl
OMe
H
F
H
Me
H
H
H
H
H
H
H
OMe
H
H
H
H
H
3r (57)
3s (21)
3t (54)
H
H
H
H
H
H

W. Chen et al. / Tetrahedron Letters 47 (2006) 7191–7193
7193
R1
R1
R
R
C
R2
R3
Ar
N
R2
R3
Ar
Pd
Pd
R=alkyl
aryl
C
NH2
R1
R4
R1
R4
NH
HO
N
O
R
R
R2
R3
Ar
R2
R3
Ar
R4
R1
R4
R1
CN
NO2
CN
NHOH
R2
R3
Ar
N
R2
R3
Ar
R=H
C
C
NH
NH2
N
H
R4
R1
R4
H2
R1
R1
R2
R3
Ar
R2
R3
Ar
-NH3
R2
R3
Ar
NH2
N
N
N
H
R4
R4
H
R4
Scheme 3. Possible mechanism for the formation of 1,2,3,4-tetrahydroquinolines.
2. Katritzky, A. R.; Rachwal, S.; Rachwal, B. Tetrahedron
1996, 52, 15031–15070, and references cited therein.
3. Theeraladanon, C.; Arisawa, M.; Nakagawa, M.; Nishida,
A. Tetrahedron: Asymmetry 2005, 16, 827–831.
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Lett. 2002, 12, 129–132.
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1991, 114, 122075w.
7. (a) Talukdar, S.; Chen, C. T.; Fang, J. M. J. Org. Chem.
2000, 65, 3148–3153; (b) Gallou-Dagommer, I.; Gastaud,
P.; RajanBabu, T. V. Org. Lett. 2001, 3, 2053–2056; (c)
Fujita, K.; Yamamoto, K.; Yamaguchi, R. Org. Lett.
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Chem. 1995, 60, 2588–2596; (b) Katritzky, A. R.; Rach-
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the produced hydroxylamine could be further reduced to
primary amine and then subjected to the expected ring
closure, and on the other hand, the hydroxylamine
could directly attack the cyano group and yield the N-
oxide product. The distance between the hydroxylamine
and cyano group may play a determinant role. In fact we
detected neither N-oxide product nor any hydroxyl-
amine intermediate during the whole procedure when
R is hydrogen. The mechanism of the reaction is valu-
able so as to be investigated further.
In summary, we have developed a simple route for con-
struction of the 3-aryl-substituted 1,2,3,4-tetrahydro-
quinolines (THQs). Further investigations on the scope
of the substrates for construction of other heterocyclic
systems are underway.
Acknowledgments
This work was financially supported in part by the Na-
tional Natural Science Foundation of China (20302009
and 20502028), and by Shanghai Municipality Science
and Technology Development Fund (05ZR14141).
10. General procedure for preparation of 1,2,3,4-tetrahydro-
quinoline derivatives (Table 2).
Supplementary data
After several vacuum/H2 cycles to remove air from the
reaction flask, the stirred mixture of the various propio-
nitriles (200 mg), 10% Pd/C (60 mg, 30 wt % of the
propionitrile) in THF (10 mL) and MeOH (2 mL) was
hydrogenated at ordinary pressure and at temperature (ca.
40 °C) for 48 h. The reaction mixture was filtrated using a
membrane filter and the filtrate was concentrated under
reduced pressure. The crude mixture was purified by flash
silica gel column chromatography, using petroleum ether/
ethyl acetate with different volume proportions as eluent,
thus obtaining the desired compounds.
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2006.07.144.
References and notes
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