An efficient synthesis of substituted quinolines via indium(III) chloride catalyzed reaction of imines with alkynes

Article abstract of DOI:10.5012/bkcs.2012.33.1.43

An efficient synthetic method for the preparation of quinolines through indium(III) chloride-catalyzed tandem addition-cyclization-oxidation reactions of imines with alkynes was developed. The processes can provide a diverse range of quinoline derivatives

Full text of DOI:10.5012/bkcs.2012.33.1.43

An Efficient Synthesis of Substituted Quinolines via Indium(III)
Bull. Korean Chem. Soc. 2012, Vol. 33, No. 1 43
http://dx.doi.org/10.5012/bkcs.2012.33.1.43
An Efficient Synthesis of Substituted Quinolines via Indium(III) Chloride
Catalyzed Reaction of Imines with Alkynes
†
Mei Zhu, Weijun Fu, Chen Xun, and Guanglong Zou
†,*
†
‡
†
College of Chemistry and Chemical Engineering, Luoyang Normal University, Luoyang 471022, P.R. China
*
E-mail: wjfu@lynu.edu.cn
‡
School of Chemistry and Environmental Science, Guizhou University for Nationalities, Guiyang 550025, P.R. China
Received October 11, 2011, Accepted October 26, 2011
An efficient synthetic method for the preparation of quinolines through indium(III) chloride-catalyzed tandem
addition-cyclization-oxidation reactions of imines with alkynes was developed. The processes can provide a
diverse range of quinoline derivatives in good yields from simple imines and alkynes.
Key Words : Indium(III), Quinoline, Imine, Alkyne
18
Introduction
the synthesis of heterocycles, herein we present our recent
results on the InCl3-catalyzed tandem addition-cyclization-
oxidation reactions of imines with alkynes to afford quino-
line derivatives (Scheme 1).
Quinolines represent an important class of heterocyclic
compounds as they are pivotal skeletons in many biologi-
cally active natural products as well as numerous pharma-
1
cologically interesting compounds. A variety of compounds
Results and Discussion
with quinoline units have been used as anesthetic, tumor-
cidal, angina pectoris, antihypertensive, and antibacterial
We focused our initial efforts on establishing optimal
conditions for the tandem addition-cyclization-oxidation
reactions between benzaldimine 1a and phenylacetylene 2a,
which were selected as the first substrates for screening of
the catalytic activity of a variety of indium salts, and the
results are summarized in Table 1. The reaction of 1a with
2
activities and also act as insecticidal agents. Moreover,
quinolines also found wide utility as synthetic intermediates
or synthons for formation of conjugated molecules and poly-
mers or ligands for the preparation of OLED phosphorescent
3
complexes. As a consequence, much attention has been
o
2a in toluene at 120 C in the absence of any catalyst did not
paid to synthesize and functionalize them since the late
1800s. In addition to classical methods (e.g., the Conrad-
yield any desired product (Table 1, entry 1). As anticipated,
when 20 mol % of InCl3 was used as catalyst, the tandem
addition-cyclization-oxidation reactions proceeded smoothly
and generated the desired product 3a in 90% yield. Other
indium salts such as InBr3, InI3, In(CF3SO3)3, and In(CH3
COO)3 were also active and the corresponding quinolines
were obtained in 76, 78, 86, and 72% yields, respectively
(Table 1, entries 3-6). With respect to the catalyst loading, 20
mol % of InCl3 was found to be optimal. When a lower
loading of InCl3 (10 mol %), the reaction also proceeded but
sluggishly (Table 1, entry 7). However, no significant improve-
ment was observed with 30 mol % of InCl3 (Table 1, entry 8).
On using other solvent such as 1,4-dioxane, 1,2-dichloro-
ethane, CH3NO2 the desired product 3a could be isolated in
slightly lower yield (Table 1, entries 9-11).
4 5
Limpach-Knorr synthesis, the Skraup synthesis, and the
6
Friedländer synthesis ), numerous transition-metal-catalyzed
heteroannulation reactions have been developed with remark-
able improvements in terms of efficiency and wide scope of
7
application. These include rhodium-catalyzed cyclization of
8
trifluoroacetimidoyl chloride with alkynes, Zn(II), indium
(III) or gold(I)-catalyzed cyclization of 2-aminoaryl ketones
9
with alkynes. Nevertheless, the development of new and
efficient methodologies for the synthesis of substituted
quinolines from simple, readily available starting materials
remains an important research theme in organic chemistry
10
despite many strategies already existed.
Indium salts as effective, alternative, and promising
transition-metal catalysts have received much more attention
in recent years because of their intriguing chemical prop-
After having established the optimized conditions for the
present reaction, various imine derivatives 1a-m and terminal
11
erties of reactivity, selectivity, and low toxicity. Over the
past decade, many efficient indium-mediated organic reac-
12 13
tions such as the Diels-Alder, Friedel-Crafts, Mukaiyama
14 15
aldol, Sakurai-Hosomi allylation reactions and other spe-
16
cific reactions have been intensively investigated. Recently,
the design of indium-catalyzed hydroarylation of alkynes
has attracted attention because of the application to efficient
17
construction of molecular structures. As a continuation of
our interest in the design and discovery of new reactions for
Scheme 1. InCl3-catalyzed reactions of imines with alkynes.

44 Bull. Korean Chem. Soc. 2012, Vol. 33, No. 1
Mei Zhu et al.
a
a
Table 1. Optimization of the reaction conditions
Table 2. Synthesis of substituted quinolines
b
1
R , R
2
3
R
b
Entry
Catalyst
Solvent
Time (h) Yield (%)
Entry
Yield (%)
1
2
3
4
5
6
No catalyst
InCl3
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
1,4-dioxane
DCE
24
24
24
24
24
24
36
24
30
36
30
NR
90
76
78
86
72
88
90
62
68
75
1
2
Ph, H
4-MeC6H4, H
4-MeOC6H4, H
4-ClC6H4, H
4-BrC6H4, H
4-FC6H4, H
2-BrC6H4, H
3-ClC6H4, H
Ph, 4-Me
Ph, 4-MeO
Ph, 4-Cl
Ph
3a, 90
3b, 92
3c, 89
3d, 85
3e, 88
3f, 83
3g, 80
3h, 82
3i, 85
Ph
InBr3
3
Ph
InI3
4
Ph
In(OTf)3
In(OAc)3
InCl3
5
Ph
Ph
6
c
7
7
Ph
d
8
InCl3
8
Ph
9
InCl3
9
Ph
10
11
InCl3
10
11
12
13
14
15
16
17
18
Ph
3j, 87
3k, 89
3l, 81
InCl3
CH3NO2
Ph
a
Ph, 2-Cl
Ph
Reaction conditions: 1a (1 equiv), 2a (1.5 equiv), catalyst (20 mol %),
b
solvent (3.0 mL), unless otherwise noted. Isolated yield. In the present
c
Ph, 2-Me
Ph, H
Ph
3m, 83
3n, 88
3o, 90
3p, 85
3q, 87
3r, 75
d
of InCl3 (10 mol %). In the present of InCl3 (30 mol %).
4-MeC6H4
4-MeOC6H4
4-ClC6H4
4-FC6H4
n-Bu
Ph, H
Ph, H
alkynes 1n-q were subjected to the above conditions, and the
results are summarized in Table 2. As indicated, the
addition-cyclization-oxidation reactions proceeded smooth-
ly to provide the corresponding products 3a-q in moderate to
good yields. The reaction could tolerate various substituents
on the aromatic groups. For imines 1 having electron-
withdrawing group including chloro, fluoro and electron-
donating group such as methoxy on the benzene ring, the
reaction proceeded well to give the products 3. In addition,
the reaction was no sensitive to steric effects. For imines 1
with aryl groups including o-bromo, m-chloro, o-chloro and
o-methyl, the desired products were also obtained in 80, 82,
81 and 83% yields, respectively (Table 2, entries 7-8 and 12-
13). Subsequently, the scope of alkynes in this reaction was
further investigated, and it was found that substituted
phenylacetylenes with electron-donating or electron-with-
drawing groups were perfectly suitable substrates for this
transformation, and the expected products were obtained in
moderate to excellent yields (Table 2, entries 14-17). Inter-
estingly, aliphatic alkyne like 1-hexyne with benzaldimine
1a also reacted smoothly to give 4-butyl-2-phenylquinoline
3r in 75% yield (Table 2, entry 18).
Ph, H
Ph, H
a
Reaction conditions: 1 (0.5 mmoL), 2 (1.5 equiv), catalyst (20 mol %),
b
toluene (3.0 mL) at reflux for 24 h. Isolated yield.
Scheme 2. InCl3-catalyzed cyclization of propargyl amine 4.
To understand the reaction mechanism for the formation
of quinolines, we conducted the reaction of the proparg-
o
ylamine 4 with InCl3 (20 mol %) in toluene at 120 C. As a
consequence, the desired product 3a was obtained in 85%
yield after 24 h. This indicates that propargylamines are the
most probable intermediates (Scheme 2).
On the basis of the above observations, a plausible mech-
anisms is proposed for this InCl3-catalyzed transformation
(Scheme 3). Initially, The catalyst InCl3 would be first
III
reacted with terminal alkyne to form a stable In alkynyl ate
Scheme 3. Possible mechanisms of the InCl3-catalyzed transform-
19
complex A, which then underwent nucleophilic addition to
ation.

An Efficient Synthesis of Substituted Quinolines via Indium(III)
Bull. Korean Chem. Soc. 2012, Vol. 33, No. 1 45
imine affording propargylamine B. InCl3 as Lewis acid
coordinates to the triple bond to enhance the electrophilicity
of the alkyne. The subsequent intramolecular nucleophilic
attack by the N-substituted aromatic ring to give inter-
mediate C. Protonolysis of the resulting intermediate C gives
dihydroquinoline D and regenerates the In(III) catalyst. In
the presence of air oxygen, the generated dihydroquinoline
could be oxidized by O2 to afford the corresponding quino-
line product 3.
8.4 Hz, 2H), 7.92 (d, J = 8.4 Hz, 1H), 7.80-7.73 (m, 2H),
13
7.55-7.46 (m, 8H); C NMR (100 MHz, CDCl3): δ 155.4,
149.4, 148.6, 138.1, 137.9, 135.5, 129.9,129.7, 129.5, 129.0,
128.9, 128.7, 128.6, 126.5, 125.8, 125.7, 118.8.
7g
1
2-(4-Bromophenyl)-4-Phenylquinoline (3e) . H NMR
(400 MHz, CDCl3): δ 8.25 (d, J = 8.4 Hz, 1H), 8.10 (d, J =
8.4 Hz, 2H), 7.85-7.79 (m, 1H), 7.76 (s, 1H), 7.74-7.68 (m,
13
1H), 7.62-7.58 (m, 2H), 7.52-7.41 (m, 6H); C NMR (100
MHz, CDCl3): δ 155.4, 149.3, 148.7, 138.3, 138.1, 131.9,
129.9, 129.6, 129.5, 129.0, 128.6, 128.4, 126.5, 125.8,
125.6, 123.9, 118.7.
Conclusion
19
1
2-(4-Fluorophenyl)-4-Phenylquinoline (3f) . H NMR
(400 MHz, CDCl3): δ 8.23-8.17 (m, 3H), 7.90-7.88 (m, 1H),
7.77-7.73 (m, 2H), 7.54-7.47 (m, 6H), 7.25-7.18 (m, 2H);
In conclusion, we have developed a InCl3-catalyzed
tandem addition-cyclization-oxidation reactions and applied
the reaction for divergent syntheses of quinolines from
readily available imines with alkynes. The method has
advantages of broad substrate scope, simple operation, mild
reaction conditions, and high effectiveness. Further studies,
including the reaction mechanism and synthetic application
of this methodology, are in progress.
13
C NMR (100 MHz, CDCl3): δ 165.5, 155.6, 149.3, 148.8,
138.3, 129.9, 129.7, 129.6, 129.4, 129.1, 129.0, 128.9,
128.5, 126.4, 125.6, 118.9, 117.7, 115.8, 115.5, 112.9.
19
1
2-(2-Bromophenyl)-4-Phenylquinoline (3g) . H NMR
(400 MHz, CDCl3): δ 8.26 (d, J = 8.4 Hz, 1H), 7.96 (d, J =
8.4 Hz, 1H), 7.78-7.69 (m, 4H), 7.55-7.44 (m, 7H), 7.31-
13
7.27 (m, 1H); C NMR (100 MHz, CDCl3): δ 158.5, 148.6,
Experimental Section. Chemicals used were obtained
from commercial suppliers and used without further purifi-
148.0, 141.4, 137.9, 133.1, 131.6, 130.0, 129.9, 129.8, 129.5,
128.6, 128.5, 127.7, 126.9, 125.6, 125.5, 122.8, 121.8.
1 13
cations. H NMR spectra and C NMR spectra were meas-
7f
1
ured in CDCl3 and recorded on Bruker Avance-400 spectro-
2-(3-Chlorophenyl)-4-Phenylquinoline (3h) . H NMR
(400 MHz, CDCl3): δ 8.25 (d, J = 8.4 Hz, 1H), 7.96-7.93 (m,
1H), 7.75-7.68 (m, 2H), 7.67 (s, 1H), 7.54-7.43 (m, 7H),
1 13
meter (400 MHz for H NMR, 100 MHz for C NMR) with
TMS as an internal standard.
13
7.41-7.30 (m, 2H); C NMR (100 MHz, CDCl3): δ 156.4,
Typical Procedure for Synthesis of Quinolines 3. The
mixture of imine 1 (0.5 mmoL), alkyne 2 (0.75 mmoL) and
148.5, 148.0, 139.4, 137.1, 132.3, 131.7, 130.0, 129.9, 129.8,
129.6, 129.5, 128.5, 128.3, 127.0, 126.7, 125.7, 125.5, 122.9.
o
InCl3 (20 mol %) in toluene (5 mL) was stirred at 120 C until
7c 1
6-Methyl-2,4-Diphenylquinoline (3i) . H NMR (400
the substrates were consumed completely in a 25 mL two-
necked round-bottom flask. The mixture was cooled to room
temperature and the solvent was evaporated, the residue was
purified by flash chromatography to give the corresponding
product 3.
MHz, CDCl3): δ 8.16-8.12 (m, 3H), 7.76 (s, 1H), 7.63 (s,
13
1H), 7.55-7.44 (m, 9H), 2.45 (s, 3H); C NMR (100 MHz,
CDCl3): δ 155.9, 148.3, 147.3, 139.7, 138.6, 136.3, 131.8,
129.8, 129.5, 129.1, 128.8, 128.5, 128.3, 127.4, 125.6, 124.3,
119.3, 21.8.
6e 1
2,4-Diphenylquinoline (3a) . H NMR (400 MHz, CDCl3):
20 1
6-Methoxyl-2,4-Diphenylquinoline(3j) . H NMR (400
δ 8.24 (d, J = 8.4 Hz, 1H), 8.16-8.14 (m, 2H), 7.82-7.84 (m,
13
1H), 7.74 (s, 1H), 7.62-7.65 (m, 1H), 7.36-7.45 (m, 9H); C
MHz, CDCl3): δ 8.16-8.14 (m, 3H), 7.77 (s, 1H), 7.58-7.35
13
(m, 9H), 7.19 (d, J = 2.4 Hz, 1H), 3.79 (s, 3H); C NMR
NMR (100 MHz, CDCl3): δ 156.6, 148.9, 148.70, 139.4,
138.2, 130.0, 129.4, 129.3, 129.2,128.6, 128.4, 128.2, 127.4,
126.1, 125.6, 125.4, 119.1.
(100 MHz, CDCl3): δ 157.7,154.6, 147.7, 144.8, 139.7, 138.6,
131.5, 129.3, 128.9, 128.7, 128.6, 128.3, 127.2,126.5, 121.8,
119.6, 103.5, 55.4.
7f
1
4-Phenyl-2-P-Tolylquinoline (3b) . H NMR (400 MHz,
CDCl3): δ 8.24 (d, J = 8.4 Hz, 1H), 8.05 (d, J = 7.8 Hz, 2H),
7.73 (d, J = 8.4 Hz, 1H), 7.70 (s, 1H), 7.68-7.64 (m, 1H),
7.50-7.44 (m, 5H), 7.43-7.40 (m, 1H), 7.28 (d, J = 7.8 Hz,
7c 1
6-Chloro-2,4-diphenylquinoline (3k) . H NMR (400
MHz, CDCl3): δ 8.18-8.15 (m, 3H), 7.86 (d, J = 2.4 Hz, 1H),
13
7.82 (s, 1H), 7.66-7.63 (m, 1H), 7.58-7.43 (m, 8H); C NMR
13
1H), 2.41 (s, 3H); C NMR (100 MHz, CDCl3): δ 156.7,
(100 MHz, CDCl3): δ 156.9, 148.4, 147.1, 139.1, 137.6, 132.1,
131.7, 130.4, 129.6, 129.4, 129.0, 128.9, 128.8, 128.7, 127.5,
126.4, 124.4, 119.9.
148.8, 148.7, 139.5, 138.3, 136.9, 130.0, 129.5, 129.3,
128.5, 128.3, 127.3, 126.2, 125.6, 125.5, 119.3, 21.2.
7h
1
7c 1
8-Chloro-2,4-Diphenylquinoline (3l) . H NMR (400
2-(4-Methoxyphenyl)-4-Phenylquinoline (3c) . H NMR
(400 MHz, CDCl3): δ 8.21 (d, J = 8.4 Hz, 1H), 8.16 (d, J =
8.8 Hz, 2H), 7.86 (d, J = 8.4 Hz, 1H), 7.74 (s, 1H), 7.73-7.68
(m, 1H), 7.51-7.45 (m, 5H), 7.44-7.39 (m, 1H), 7.05 (d, J
MHz, CDCl3): δ 8.31-8.29 (m, 2H), 7.87 (s, 1H), 7.81-7.76
13
(m, 2H), 7.52-7.33 (m, 9H); C NMR (100 MHz, CDCl3): δ
156.7, 149.7, 144.8, 138.9, 138.1, 134.3, 129.8, 129.6, 129.5,
128.8, 128.7, 128.5, 127.7, 127.1, 125.9, 124.7, 119.8.
13
= 8.8 Hz, 2H), 3.83 (s, 3H); C NMR (100 MHz, CDCl3): δ
7f 1
8-Methyl-2,4-Diphenylquinoline (3m) . H NMR (400
160.8, 156.3, 148.9, 148.7, 138.4, 132.1, 129.8, 129.5,
129.4, 128.8, 128.5, 128.3, 125.9, 125.6, 125.5, 118.8, 114.1,
55.3.
MHz, CDCl3): δ 8.29-8.26 (m, 2H), 7.82 (s, 1H), 7.73-7.69
13
(m, 1H), 7.52-7.31 (m, 10H), 2.96 (s, 3H); C NMR (100
7g 1
2-(4-Chlorophenyl)-4-Phenylquinoline (3d) . H NMR
MHz, CDCl3): δ 154.9, 149.2, 147.7, 139.8, 138.9, 137.90,
(400 MHz, CDCl3): δ 8.27 (d, J = 8.0 Hz, 1H), 8.17 (d, J =
129.6, 129.5, 129.2, 128.7, 128.3, 128.2, 127.4, 125.9, 125.6,

46 Bull. Korean Chem. Soc. 2012, Vol. 33, No. 1
Mei Zhu et al.
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21
1
2-Phenyl-4-P-Tolylquinoline (3n) . H NMR (400 MHz,
CDCl3): δ 8.25 (d, J = 8.4 Hz, 1H), 8.19-8.17 (m, 2H), 7.96-
7.93 (m, 1H), 7.80 (s, 1H), 7.75-7.71 (m, 1H), 7.53-7.49 (m,
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13
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7e
1
4-(4-Methoxyphenyl)-2-Phenylquinoline (3o) . H NMR
(400 MHz, CDCl3): δ 8.31 (d, J = 8.4 Hz, 1H), 8.22 (d, J =
7.2 Hz, 2H), 7.98 (d, J = 8.4 Hz, 1H), 7.81 (s, 1H), 7.75-7.72
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21
1
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K.; Liu, H. J. Org. Chem. 2009, 74, 5476. (y) Zhao, Y.; Zhang, W.;
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8. Amii, H.; Kishikawa, Y.; Uneyama, K. Org. Lett. 2001, 3, 1109.
9. (a) Jiang, B.; Si, Y. G. J. Org. Chem. 2002, 67, 9449. (b) Liu, X. Y.;
Ding, P.; Huang, J. S.; Che, C. M. Org. Lett. 2007, 9, 2645. (c)
Lekhok, K. C.; Prajapati, D.; Boruah, R. C. Synlett 2008, 655.
10. (a) Sakai, N.; Annaka, K.; Konakahara, T. J. Org. Chem. 2006, 71,
3653. (b) Yanada, R.; Hashimoto, K.; Tokizane, T.; Miwa, Y.;
Minami, H.; Yanada, K.; Ishikura, M.; Takemoto, Y. J. Org. Chem.
2008, 73, 5135. (c) Sakai, N.; Annaka, K.; Fujita, A.; Sato, A.;
Konakahara, T. J. Org. Chem. 2008, 73, 4160.
13
7.43 (m, 8H); C NMR (100 MHz, CDCl3): δ 156.8, 148.7,
147.8, 139.4, 136.7, 134.5, 130.8, 130.1, 129.6, 129.4, 128.8,
128.7, 127.6, 126.5, 125.3, 125.2, 119.1.
7e
1
4-(4-Fluorophenyl)-2-Phenylquinoline (3q) . H NMR
(400 MHz, CDCl3): δ 8.26-8.22 (m, 1H), 8.17-8.15 (m, 2H),
7.84-7.81 (m, 1H), 7.75 (s, 1H), 7.75-7.70 (m, 1H), 7.55-
13
7.43 (m, 6H), 7.23-7.18 (m, 2H); C NMR (100 MHz, CDCl3):
δ 164.1, 161.6, 156.8, 148.7, 148.0, 139.4, 134.3, 134.2,
131.2, 131.1, 130.0, 129.5, 129.4, 128.8, 127.5, 126.4, 125.7,
125.2, 119.3, 115.8, 115.49
7c
1
4-Butyl-2-Phenylquinoline (3r) . H NMR (400 MHz,
CDCl3): δ 8.19 (d, J = 8.0 Hz, 1H), 8.14 (d, J = 8.8 Hz, 2H),
8.05 (d, J = 8.8 Hz, 1H), 7.71-7.67 (m, 2H), 7.57-7.46 (m,
4H), 3.16 (t, J = 8.0 Hz, 2H), 1.83-1.76 (m, 2H), 1.53-1.48
13
(m, 2H), 0.98 (t, J = 7.2 Hz, 3H); C NMR (100 MHz, CD
Cl3): δ 157.0, 149.5, 148.4, 140.0, 130.5, 129.3, 128.9, 128.6,
127.7, 126.6, 126.1, 123.5, 118.8, 32.4, 32.3, 22.7, 13.8.
Acknowledgments. We are grateful to the National
Natural Science Foundation of China (Project Nos. 20902042;
20902043) and Foundation of He’nan Educational Com-
mittee (No. 2010B150020).
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