Iron (III)-catalyzed and air-mediated tandem reaction of aldehydes, alkynes and amines: An efficient approach to substituted quinolines

Article abstract of DOI:10.1002/chem.200900875

An economic method for the construction of quinolines by the FeCl₃-catalyzed three-component coupling/hydroarylation/dehydrogenation of aldehydes, alkynes, and amines was reported. Iron was used as catalyst for this reactions due to its low price, non-toxicity, and environmentally friendly characters. It was observed that during the synthesis of propargylamines by the FeCl₃-catalyzed three-component coupling of aldehydes, alkynes, and amines, when aniline was used to replace the secondary amine, 2, 4- diphenyl-substituted quinoline, the propargylamine product was formed in 56% yield with 70% conversion after 48 hours under argon. Phenylacetylene and aniline were used as model substrates for exploring the aldehyde substrate scope. It was concluded that when the aromatic aldehyde carried an electron-donating group or an electron withdrawing group, the reactions proceeded to produce the corresponding quinolines.

Full text of DOI:10.1002/chem.200900875

DOI: 10.1002/chem.200900875
IronACHTUNGTRENNUNG(III)-Catalyzed and Air-Mediated Tandem Reaction of Aldehydes,
Alkynes and Amines: An Efficient Approach to Substituted Quinolines
Ke Cao, Fu-Min Zhang, Yong-Qiang Tu,* Xiao-Tao Zhuo, and Chun-An Fan[a]
Quinolines and their derivatives occur in a large number
of biologically active natural products, and they are also im-
portant starting materials for the chemical and pharmaceuti-
cal industry.[1] Since Skraup reported the synthesis of quino-
line in 1880 for the first time,[2] there have been great ach-
ievements in this area, and many synthetic methods based
on the use of transition-metal catalysts have been devel-
oped.[3] However, the limited availability of starting materi-
als is the main drawback of many of these methods. For ex-
ample, the Friedlꢀnder reaction, one of the most useful
methods for synthesizing quinolines, is based on the Aldol
condensation of unstable 2-aminobenzaldehydes, which are
generated in situ by reduction of 2-nitrobenzaldehyde deriv-
atives, which themselves are not readily availible.[4] Consid-
ering their importance in pharmacology and functional ma-
terial chemistry, the development of more facile and eco-
nomic synthetic approaches is still desirable.
Recently, iron has emerged as a very promising catalyst
for cross-coupling reactions, and therefore it has been at-
tracting increasing research interest from chemists due to its
low price, non-toxicity, and environmentally friendly charac-
ter.[5] In the course of our research on synthesizing propar-
gylamines by the FeCl3-catalyzed three-component coupling
of aldehydes, alkynes, and amines [Eq. (1)],[6] we found that
when aniline was used to replace the secondary amine, 2, 4-
diphenyl-substituted quinoline [Eq. (2)] instead of the ex-
pected propargylamine product was formed in 56% yield
with 70% conversion after 48 h under argon, and the struc-
ture was confirmed by the X-ray crystallographic analysis.[7]
Inspired by this result, we next further investigated this
reaction in detail. Gratifyingly, when we decreased the load-
ing of aniline from 1.3 equiv to 1.05 equiv and increased the
concentration of catalyst from 0.025 mmolmLÀ1 to
0.1 mmolmLÀ1 in toluene at 1108C under an air atmosphere,
the desired quinoline was afforded in 70% yield. Following
these general conditions, we then examined the scope of this
reaction, and the results are summarized in Table 1.
Phenylacetylene and aniline were initially used as model
substrates for exploring the aldehyde substrate scope. From
Table 1 (see below), it can be seen that when the aromatic
aldehyde carried an electron-donating group or an electron-
withdrawing group, the reactions proceeded smoothly to
give the corresponding quinolines in moderate to good
yields (entries 2–5). However, when a bulky 1-naphthalde-
hyde was used, the desired quinoline was obtained in a
lower yield of 56% (entry 6). Additionally, a heteroaromatic
aldehyde is also compatible with this transformation and the
expected product was afforded in 83% yield (entry 7). How-
ever, when an aliphatic aldehyde (cyclohexanecarboxalde-
hyde) was subjected to the reaction, the desired product was
obtained only in 30%yield.
Then, we elucidated the scope of amine substrates that
were applicable for this reaction; both p-toluidine and p-me-
thoxyaniline were good substrates for this transformation
and the corressponding products were afforded in 95% and
65% yields (entries 8 and 9), respectively. The halogen-con-
taining anilines were also subjected to the reaction condi-
tions, and the desired quinolines were obtained in moderate
to excellent yields (entries 10–12).
[a] K. Cao, Prof. F.-M. Zhang, Prof. Y.-Q. Tu, X.-T. Zhuo,
Prof. C.-A. Fan
State Key Laboratory of Applied Organic Chemistry and
Department of Chemistry
Lanzhou University, Lanzhou 730000 (China)
Fax : (+86)931-8915557
Subsequently, the scope of alkynes in this reaction was
further investigated, and it was found that substituted phe-
nylacetylenes, heteroaromatic alkynes, and aliphatic alkynes
E-mail: tuyq@lzu.edu.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200900875.
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Chem. Eur. J. 2009, 15, 6332 – 6334

COMMUNICATION
Table 1. Synthesis of quinolines by iron
ACHTUNGTRENN(UNG III)-catalyzed three-component cou-
pling/hydroarylation of aldehydes, alkynes, and amines.[a]
Entry Aldehyde
1
Amine
Alkyne
Product Yield
[%][b]
1aa
70
2
3
4
2a
2a
2a
3a
3a
3a
1bb
1cc
1dd
72
83
65
5
2a
3a
3a
1ee
1 ff
85
56
6
7
2a
2a
Scheme 1. Mechanism for iron-catalyzed tandem coupling/hydroarylation
of aldehyde, alkyne, and amine.
3a
3a
3a
1gg
2bb
2cc
83
92
65
8
9
1a
1a
the propargylamine intermediate B, which then undergoes
an intramolecular hydroarylation[9,10] of alkyne to give dihy-
droquinoline intermediate C.[11] In this course, we deem that
the forming of the propargylamine intermediate B and the
subsequent hydroarylation reaction experience a coopera-
tive process since we did not detect the propargylamine B in
the reaction mixture. A final oxidation of C by O2 in air af-
fords the quinoline product.[12] Comparing with the similar
AuCl3-mediated process, the stronger Lewis acidity of FeCl3
than AuCl3 appears to be the main reason for the higher ef-
ficiency of our catalytic system.[11]
10
11
12
1a
1a
1a
3a
3a
3a
2dd
2ee
2 ff
90
95
70
13
14
15
16
1a
1a
1a
1a
2a
2a
2a
2a
3bb
3cc
3dd
3ee
85
62
92
88
In summary, we have developed a facile and economic
method for the construction of quinolines by the FeCl3-cata-
lyzed three-component coupling/hydroarylation/dehydrogen-
ation of aldehydes, alkynes, and amines for the first time. A
series of 2, 4-disubstituted quinolines have been synthesized
from simple and readily available starting materials. Further
studies on the reaction mechanism and the synthetic appli-
cation are currently ongoing in our group.
[a] Reaction conditions: aldehyde (1.0 mmol), amine (1.05 mmol), alkyne
(1.5 mmol), FeCl3 (0.1 mmol), toluene (1 mL), 1108C, under an air atmos-
phere. [b] Isolated yield calculated on the basis of aldehyde.
Experimental Section
were perfectly suitable substrates for this transformation,
and the expected products were obtained in moderate to ex-
cellent yields (entries 13–16).
Based on the experimental results above and together
with our previous work,[6] a tentative mechanism was pro-
posed (Scheme 1). Intermediate A was initially formed by
coordination of imine, which was generated in situ, and
alkyne to FeIII,[8] and then addition of alkyne to imine forms
Typical procedure: To a 10 mL flask were sequentially added toluene
(1 mL), FeCl3 (16.2 mg, 0.1 mmol), benzaldehyde (0.104 mL, 1.0 mmol),
aniline (0.096 mL, 1.05 mmol), and phenylacetylene (0.168 mL, 1.5 mmol)
under an air atmosphere. The reaction mixture was then stirred at 1108C
until the substrate had been consumed completely (ca. 24 h), and then it
was cooled to room temperature and filtered through a short silica gel
column using CH2Cl2 as eluent. After evaporation of the solvent, the resi-
due was purified by flash chromatography (petroleum ether/AcOEt=
20:1) to afford 1aa (197 mg, 70% yield).
Chem. Eur. J. 2009, 15, 6332 – 6334
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www.chemeurj.org
6333

Y.-Q. Tu et al.
Junge, M. Beller, Angew. Chem. 2008, 120, 3363; Angew. Chem. Int.
Ed. 2008, 47, 3317; e) B. D. Sherry, A. Fꢄrstner, Acc. Chem. Res.
2008, 41, 1500.
Acknowledgements
This work was supported by the NSFC (Nos. 20621091, 20672048,
20732002) and the “111” program of Chinese Education Ministry.
[6] During the preparation of our manuscript, Wang and co-workers re-
ported a similar reaction, see: P. Li, Y. Zhang, L. Wang, Chem. Eur.
J. 2009, 15, 2045.
À
[7] CCDC-722236 contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
Keywords: C C bond formation · hydroarylation · iron ·
propargylamine · quinolines
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[10] A supporting experiment was performed by using the propargyl-
amine 4 under current standard conditions, and the desired 2,4-di-
phenyl-substituted quinoline 1aa was obtained in 60% yield after
72 h.
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Received: April 2, 2009
Published online: May 26, 2009
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