Synthesis of substituted quinolines by iron-catalyzed oxidative coupling reactions

Article abstract of DOI:10.1016/j.tetlet.2012.09.090

A simple and efficient method has been developed for the synthesis of quinoline derivatives from N-alkyl anilines and alkynes or alkenes by iron-catalyzed oxidative coupling reactions. A variety of substituted quinolines are prepared in good to excellent yields.

Full text of DOI:10.1016/j.tetlet.2012.09.090

Tetrahedron Letters 53 (2012) 6654–6656
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of substituted quinolines by iron-catalyzed oxidative
coupling reactions
⇑
Peng Liu , Yuxi Li, Haiyu Wang, Zhiming Wang, Xianming Hu
State Key Laboratory of Virology, Ministry of Education Key Laboratory of Combinatorial Biosynthesis and Drug Discovery,
Wuhan University School of Pharmaceutical Sciences, Wuhan 430071, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 July 2012
Revised 11 September 2012
Accepted 21 September 2012
Available online 28 September 2012
A simple and efficient method has been developed for the synthesis of quinoline derivatives from N-alkyl
anilines and alkynes or alkenes by iron-catalyzed oxidative coupling reactions. A variety of substituted
quinolines are prepared in good to excellent yields.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Quinoline
Oxidative coupling
Iron
Quinolines and their derivatives occur in numerous natural
products, and display a wide variety of biological activities.1 The
quinoline skeleton is a valuable synthetic intermediate of many
synthetic compounds with pharmacological properties. In addition,
these compounds are well-known ligands for the preparation of
OLED phosphorescent complexes.2 In view of these points, a great
deal of effort has been done to develop new and efficient synthetic
methods for quinoline derivatives in both synthetic organic and
medicinal chemistry. Up to now, many methods have been devel-
oped for the synthesis of these compounds, such as Skraup, Doeb-
ner-von Miller, Friedländer, Combes methods, and so on.3 Among
these methods, The most simple and straightforward method is
the Friedländer synthesis based on acid- or base-catalyzed Aldol
condensation of unstable 2-aminobenzaldehyde or ketone with a
carbonyl compound containing a reactive methylene group.3g–l
However, this method is not satisfactory with regard to relatively
low yield, low regioselectivity, and drastic reaction conditions
due to the occurrence of several side reactions. Recently, transition
metal-catalyzed coupling reactions have emerged as a powerful
tool for the synthesis of heterocyclic compounds. These reactions
provide an effective route to the synthesis of quinoline deriva-
tives.4 Uneyama et al. reported that Rh(I) complexes could catalyze
the coupling cyclization of N-aryl trifluoroacetylimidoyl chloride
with alkynes to give 2-trifluoromethylated quinolines in good
yields.4c Fujiwara found an efficient synthesis of quinolin-
2(1H)-ones by using Pd(II) via the activation of aromatic C–H
bonds for addition to C–C multiple bonds.4d Takai and Kuninobu
developed an efficient synthesis of 2,4-disubstituted quinoline
derivatives from N-aryl-2-propynylamines with Au(I) and Cu(I)
used as catalysts.4e Also, an efficient synthesis of quinoline deriva-
tives through a three-component reaction of aldehydes, amines,
and alkynes has been reported using AuCl3/CuBr as catalyst.4f
Recently, Tu and co-workers reported FeCl3-catalyzed three-
component coupling of aldehydes, amines, and alkynes to give
quinoline derivatives for the first time.4g Although these methods
provide efficient access to quinoline derivatives, the development
of more facile and economic synthetic approaches is still desirable.
Recently, our group reported the iron-catalyzed direct cross-
dehydrogenative coupling reactions of glycine derivatives and
alkynes or ketones.5 Following the work, we have developed an
efficient process wherein oxidative coupling is carried out between
N-alkyl anilines and alkynes or alkenes; the iron salts in a tandem
process subsequently catalyze in situ cyclization and dehydrogena-
tion to form interesting quinoline derivatives. Three processes are
involved as shown in Figure 1: (i) the formation of an iminium ion
intermediate, (ii) the oxidative coupling reaction and cyclization in
the presence of an alkyne or alkene as nucleophile and (iii) the final
oxidative aromatization step of the hydroquinoline intermediate to
form the quinoline unit.
To initiate our study, the reaction of N-alkyl aniline 1a (1.0
equiv) with phenylacetylene (2a, 1.2 equiv) catalyzed by various
iron salts (10 mol %) with di-tert-butyl peroxide (2.0 equiv) as the
oxidant in 1,2-dichloroethane (DCE) at 80 °C was carried out in a
Schlenk reaction tube. Friedel–Crafts reaction and the followed
oxidation to provide final product 3a are assumed to occur after
the coupling reaction. As seen from Table 1, FeCl3 (entry 1, Table 1)
was found to be the best catalyst using di-tert-butylperoxide as the
⇑
Corresponding author. Tel.: +86 27 6875 9100; fax: +86 27 6875 9850.
E-mail address: liupenghk@gmail.com (P. Liu).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.09.090

P. Liu et al. / Tetrahedron Letters 53 (2012) 6654–6656
6655
Table 2
R3
Synthesis of quinolines from alkynesa
H
[Fe]
H
R3
R3
R3
N
R1
R1
+
H
N
oxidant
R2
or
(tBuO)2, FeCl3
N
R2
N
H
R2
R1
R3
R1
+
DCE, 12 h
R2
[O]
2
[O]
1
3
R3
Entry
R1, R2
R3
Product
Yieldb (%)
[Fe]
R3
R1
1
2
3
4
5
6
7
8
Ph, Ph (1a)
Ph, Ph (1a)
Ph, Ph (1a)
Ph, Ph (1a)
Ph, Ph (1a)
Ph, Ph (1a)
Ph, Ph (1a)
Ph, Ph (1a)
o-ClPh, Ph (1b)
m-ClPh, Ph (1c)
p-ClPh, Ph (1d)
Ph, p-MePh (1e)
Ph, p-MePh (1e)
Ph, p-MePh (1e)
Ph, p-ClPh (1f)
Ph, Me (1g)
Ph (2a)
3a
3b
3c
3d
3e
3f
81
72
78
83
R1
N
H
R2
p-FPh (2b)
p-MePh (2c)
p-OMePh (2d)
p-t-BuPh (2e)
o-MePh (2f)
Cyclopropyl (2g)
COOMe (2h)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
p-FPh (2b)
p-MePh (2c)
p-MePh (2c)
Ph (2a)
N
R2
or
R3
86
Figure 1. Synthesis of quinolines in a one-pot reaction.
74
N.R.c
73
3g
3h
3i, 3j
3k
3l
3m
3n
3o
9
86
32, 51
76
72
67
Table 1
10
11
12
13
14
15
16
17
Optimization of reaction conditionsa
Ph
oxidant
12h
+
69
N
H
Ph
74
N
3a
Ph
N.R.c
75
1a
2a
Ph, PhCO (1h)
Ph (2a)
3p
Yieldb (%)
a
b
c
Entry
Cat.
Solvent
T (°C)
Oxidant
Reaction conditions: 1:2:oxidant:cat. = 1:1.2:2:0.1, 12 h.
Isolated yield.
N.R.: no quinoline product detected.
1
2
3
4
5
6
7
8
FeCl3
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
80
80
80
80
80
80
80
80
80
60
40
80
80
60
60
50
(tBuO)2
(tBuO)2
(tBuO)2
(tBuO)2
(tBuO)2
(tBuO)2
TBHP
81
28
69
72
N.R.c
21
50
8
40
46
31
56
45
43
12
23
FeCl2Á4H2O
FeCl3Á6H2O
Fe(ClO4)3
—
Fe(DMF)6(ClO4)3
FeCl3
FeCl3
CF3SO3H
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
Table 3
Synthesis of quinolines from alkenesa
R3
H2O2
H
N
R2
9
DCE
(tBuO)2
(tBuO)2
(tBuO)2
(tBuO)2
(tBuO)2
(tBuO)2
(tBuO)2
(tBuO)2
(tBuO)2, FeCl3
R1
R3
R1
10
11
12
13
14
15
16
CHCl3
CH2Cl2
CH3CN
Toluene
THF
+
DCE, 12 h
N
R2
4
1
3
Entry
R1, R2
R3
Product
Yieldb (%)
FeCl3
FeCl3
MeOH
acetone
1
2
3
4
5
6
7
8
Ph, Ph (1a)
Ph, Ph (1a)
Ph, Ph (1a)
Ph, Ph (1a)
p-ClPh, Ph (1d)
Ph, p-MePh (1e)
Ph, p-ClPh (1f)
Ph, PhCO (1h)
Ph (4a)
3a
3q
3d
3f
3k
3l
64
68
71
65
75
69
78
73
p-ClPh (4b)
p-OMePh (4c)
o-MePh (4d)
Ph (4a)
Ph (4a)
Ph (4a)
a
b
c
Reaction conditions: 1a:2a:oxidant:cat. = 1:1.2:2:0.1, 12 h.
Isolated yield.
N.R.: no quinoline product detected.
3r
3p
Ph (4a)
oxidant. As seen from entries 2-4, FeCl2Á4H2O, FeCl3Á6H2O, and
Fe(ClO4)3 are less effective as catalysts. Clearly a catalyst is
necessary as seen from entry 5. Iron complex Fe(DMF)6(ClO4)3
was disappointing as a catalyst (entry 6). The effect of varying
the oxidant was examined. Both TBHP and H2O2 were found to lead
to lower or no yields (entries 7, 8). Brønsted acid CF3SO3H was
relatively ineffective as the catalyst (entry 9). Different solvents
were also screened and 1,2-dichloroethane was found to be the
best for this reaction (entries 10–16).
The scope of this synthesis method for quinoline derivatives
using oxidative coupling reactions was explored and the results
are summarized in Table 2. Various N-alkyl anilines and a range
of substituted acetylenes examined under the standard reaction
condition provided moderate to excellent yields. 1a readily reacted
with various substituted alkynes, including electron-donating or
electron-withdrawing substituents on the aryl ring of the alkynes,
which proceeded well (entries 2–6). Notably, a bulky substituent at
the para-position 2e does not affect the reaction process at all in
terms of steric effect (entry 5). However, the catalytic process
was unsatisfactory with simple aliphatic substrates 2g, and no
quinoline product was detected (entry 7). But 73% yield was
obtained, when electron-deficient aliphatic alkyne 2h was used
(entry 8). We also found that substituents on N-alkyl aniline
a
Reaction conditions: 1:4:oxidant:cat. = 1:1.2:2:0.1, 12 h.
Isolated yield.
b
(1b–1f) have no significant effect on the reaction (entries 9-15).
When meta-substitution on aniline part 1c was employed, the
products of C–H bond activated at ortho- and para-positions of Cl
were obtained in 32 and 51% yields, respectively (entry 10). Unfor-
tunately, no reaction was detected when N-alkyl aniline 1g reacted
with 2a under the standard reaction condition (entry 16). The
phenyl group on N-alkyl aniline was then changed to electron
withdrawing group such as ketone 1h, providing the correspond-
ing quinolines in good yields (entry 17).
We continued to explore the scope of the oxidative coupling
reactions by changing alkynes to alkenes, quinoline derivatives
being prepared in good yield under the optimized condition
(Table 3). Quinoline derivative 3a was prepared in 64% yield, when
1a reacted with styrene 4a (entry 1). The scope of substituted sty-
renes was studied first. Both electron withdrawing (entry 2) and
electron donating groups (entry 3) were compatible, providing
the corresponding quinolines 3q and 3d in good yields (68 and
71%). Ortho substituent was also tolerated to give 65% yield (entry

6656
P. Liu et al. / Tetrahedron Letters 53 (2012) 6654–6656
vol. 5, p 245; (b) Michael, J. P. Nat. Prod. Rep. 1997, 14, 605; (c) Eicher, T.;
Hauptmann, S. The Chemistry of Heterocycles, 2nd ed.; Wiley-VCH: Weinheim,
2003. p 316; (d) Musiol, R.; Serda, M.; Hensel-Bielowka, S.; Polanski, J. Curr. Med.
Chem. 1960, 2010, 17.
4). The substitution at the N-alkyl aniline was then explored
(entries 5–8), similar to the reaction with alkynes, providing the
corresponding quinolines in good yields.
2. (a) Thompson, M. E.; Ma, B.; Djurovich, P. U.S. Patent 20050164031A1, 2005.; (b)
Kim, J. L.; Shin, I. S.; Kim, H. J. Am. Chem. Soc. 2005, 127, 1614.
In summary, we have developed a simple and efficient method
for the synthesis of quinoline derivatives from N-alkyl anilines and
alkynes or alkenes by iron-catalyzed oxidative coupling reactions.
This approach allows the direct reaction of simple N-alkyl anilines
with a variety of alkynes or alkenes to give quinoline derivatives in
good to excellent yield. Moreover, the iron catalyst is cheap, readily
available, and environmentally friendly.
3. (a) Jones, G. In Comprehensive Heterocyclic Chemistry II; Katritzky, A. R., Rees, C.
W., Scriven, E. F. V., McKillop, A., Eds.; Pergamon Press: Oxford, 1996; vol. 5, p
167; (b) Larsen, R. D. In Science of SynthesisThieme; Black, D. S., Ed.; Stuttgart,
2005; vol. 15, pp 389–551; (c) Madapa, S.; Tusi, Z.; Batra, S. Curr. Org. Chem.
2008, 12, 1116; (d) Marco-Contelles, J.; Pérez-Mayoral, E.; Samadi, A.; Carreiras,
M. D.; Soriano, E. Chem. Rev. 2009, 109, 2652; (e) Skraup, Z. H. Ber. 1880, 13,
2086; (f) McNaughton, B. R.; Miller, B. L. Org. Lett. 2003, 5, 4257; (g) Friedlander,
P. Chem. Ber. 1882, 15, 2572; (h) Cheng, C.-C.; Yan, S.-J. Org. React. 1982, 28, 37;
(i) Cho, C. S.; Kim, B. T.; Kim, T. J.; Shim, S. C. Chem. Commun. 2001, 2576; (j)
Hsiao, Y.; Rivera, N. R.; Yasuda, N.; Hughes, D. L.; Reider, R. J. Org. Lett. 2001, 3,
1101; (k) Dormer, P. G.; Eng, K. K.; Farr, R. N.; Humphrey, G. R.; McWilliams, J. C.;
Reider, P. J.; Sager, J. W.; Volante, R. P. J. Org. Chem. 2003, 68, 467; (l) Hu, Y.-Z.;
Zhang, G.; Thummel, R. P. Org. Lett. 2003, 5, 2251.
4. (a) Takahashi, T.; Li, Y.; Stepnicka, P.; Kitamura, M.; Liu, Y.; Nakajima, K.; Kotora,
M. J. Am. Chem. Soc. 2002, 124, 576; (b) Beller, M.; Thiel, O. R.; Trauthwein, H.;
Hartung, C. G. Chem. Eur. J. 2000, 6, 2513; (c) Amii, H.; Kishikawa, Y.; Uneyama,
K. Org. Lett. 2001, 3, 1109; (d) Jia, C. G.; Piao, D. G.; Oyamada, J. Z.; Lu, W. J.;
Kitamura, T.; Fujiwara, Y. Science 1992, 2000, 287; (e) Kuninobu, Y.; Inoue, Y.;
Takai, K. Chem. Lett. 2007, 36, 1422; (f) Xiao, F. P.; Chen, Y. L.; Liu, Y.; Wang, J. B.
Tetrahedron 2008, 64, 2755; (g) Cao, K.; Zhang, F.-M.; Tu, Y.-Q.; Zhuo, X.-T.; Fan,
C.-A. Chem. Eur. J. 2009, 15, 6332; (h) Sangu, K.; Fuchibe, K.; Akiyama, T. Org. Lett.
2004, 6, 353; (i) Huang, H.; Jiang, H.; Chen, K.; Liu, H. J. Org. Chem. 2009, 74,
5476; (j) Kulkarni, A.; Török, B. Green Chem. 2010, 12, 875; (k) Richter, H.;
Mancheño, O. G. Org. Lett. 2011, 13, 6066.
Acknowledgments
This investigation was supported by the National Mega Project
on Major Drug Development (2011ZX09401-302), the National
Natural Science Foundation of China (No. 21102107), and China
Postdoctoral Science Foundation (No. 20110491199).
A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.09.
090.
5. Liu, P.; Wang, Z. M.; Lin, J.; Hu, X. M. Eur. J. Org. Chem. 2012, 1583.
References and notes
1. (a) Balasubramanian, M.; Keay, J. G. In Comprehensive Heterocyclic Chemistry II;
Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon Press: Oxford, 1996;