Palladium-catalyzed sequential formation of C-C bonds: Efficient assembly of 2-substituted and 2,3-disubstituted quinolines

Article abstract of DOI:10.1002/anie.201202412

A series of substituted quinolines was prepared from arylamines, aldehydes, and terminal olefins (see scheme). The palladium-catalyzed sequential formation of C-C bonds proceeds smoothly with both electron-deficient and electron-rich olefins. When acrylic acid is used as terminal olefin, decarboxylation occurs to provide 2-substituted quinolines. Copyright

Full text of DOI:10.1002/anie.201202412

Angewandte
Chemie
DOI: 10.1002/anie.201202412
Quinolines
ꢀ
Palladium-Catalyzed Sequential Formation of C C Bonds: Efficient
Assembly of 2-Substituted and 2,3-Disubstituted Quinolines**
Xiaochen Ji, Huawen Huang, Yibiao Li, Huoji Chen, and Huanfeng Jiang*
Transition-metal-catalyzed transformations are attractive
methodologies for the synthesis of heterocyclic compounds,
and enable the direct formation of complicated molecules
from readily accessible starting materials under mild con-
ditions.[1] The outstanding potential of palladium-catalyzed
processes lies 1) in the diversity of available bond-forming
ꢀ
ꢀ
ꢀ
processes, such as C C, C O, and C N bond forming, 2) in
the excellent chemo-, regio-, and stereoselectivity that is
generally observed, and 3) in their great functional-group
tolerance.[2] Besides, palladium-catalyzed processes constitute
an efficient strategy to synthesize an increasingly wide range
of polyfunctionalized compounds.[3]
Quinoline is one of the ubiquitous structural motifs that
occur in natural products[4a] and pharmaceutically active
substances.[4] 2-Arylquinoline scaffolds, for example, are
associated with a wide range of biological properties, such
as P-selectin antagonism, antimalarial, and antitumor activ-
ities.[5] Wide applications trigger continued interest in quin-
oline chemistry, and a variety of advanced methods for the
synthesis of substituted quinolines have been developed over
the years.[6] Because the substituents on the quinoline rings
have a great influence on their properties, development of
novel and expeditious approaches for the preparation of
a diverse range of substituted quinolines, based on the idea of
high efficiency and atom-economy, remains an active research
area.
Scheme 1. Synthesis of substituted quinolines. EDG=electron-donat-
ing group.
between N-aryl aldimines and electron-deficient alkenes
have not been reported for the synthesis of 2,3-disubstituted
quinolines. Herein, we present a novel palladium-catalyzed
reaction of easily available arylamines, aldehydes, and olefins
in air[9] to synthesize 2-substituted and 2,3-disubstituted
quinolines.[10] In this transformation, reactions of electron-
deficient and electron-rich olefins proceed smoothly to give
the corresponding products, and gratifyingly, when R is
a carboxy group, decarboxylation[11] occurs to provide 2-
substituted quinolines (Scheme 1).
Because of the diverse pharmacological value of 2-
arylquinolines, many synthetic protocols have been reported
in recent years.[7] The most attractive strategy for the synthesis
of these compounds is the acid-promoted imino-Diels–Alder
(DA) reaction between N-aryl aldimines (electron-deficient
azadienes) and electron-rich alkenes, such as vinyl enol
ethers, enamines, etc., and subsequent oxidization, which has
been a topic of continued interest for 40 years since the
pioneering works of Povarov (Scheme 1).[8] However, elec-
tron-deficient olefins show much less reactivity in these
reactions,[8f] and thus examples of imino-DA reactions
At the outset of this investigation, we explored the Pd-
catalyzed reaction between benzaldehyde 1a, aniline 2a, and
acrylic acid 3a, followed by decarboxylation.[12] We found that
the palladium catalyst was indispensable for the reaction, and
that the addition of LiBr·H2O[13] could greatly improve the
yield of the product. Furthermore, the reaction could
efficiently proceed in air to give 3a in excellent yield. After
extensive screening of the reaction conditions (the palladium
catalyst, additives, solvent, and pressure of oxygen), it was
concluded that the optimized reaction conditions included the
use of PdCl2 as catalyst and LiBr·H2O as additive in
acetonitrile at 608C in air.
Next, the substrate scope of the synthesis of substituted 2-
arylquinolines was investigated under the optimized condi-
tions (Scheme 2). The reaction worked well, regardless of the
electron-donating or electron-withdrawing nature of the
substituents on the benzaldehyde, and heteroaryl aldehydes,
such as furan-2-carbaldehyde and thiophene-2-carbaldehyde,
were also compatible with the reaction conditions, though
thiophene-2-carbaldehyde furnished 4g in relatively low
yield. Both electron-deficient and electron-rich aniline com-
ponents delivered the corresponding products in good to
excellent yields. The reaction of 3,4-dimethylaniline gave two
regioisomers, with almost exclusive formation of quinoline 4l
[*] X. Ji, H. Huang, Y. Li, H. Chen, Prof. Dr. H. Jiang
School of Chemistry and Chemical Engineering
South China University of Technology
Guangzhou 510640 (China)
E-mail: jianghf@scut.edu.cn
[**] This work was supported by the National Natural Science
Foundation of China (20932002 and 21172076), the National Basic
Research Program of China (973 Program) (2011CB808600), the
Guangdong Natural Science Foundation (10351064101000000),
and the Fundamental Research Funds for the Central Universities
(2010ZP0003).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201202412.
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Scheme 2. Synthesis of substituted 2-phenylquinolines. Reaction con-
ditions: aldehyde 1 (0.5 mmol), arylamine 2 (0.5 mmol), acrylic acid
3a (1 mmol), PdCl2 (0.025 mol, 5 mol%), LiBr·H2O (0.5 mmol,
1 equiv), in acetonitrile (2 mL) at 608C in air for 8 h. Yields of isolated
products are reported.
Scheme 3. Synthesis of a variety of substituted quinolines. Reaction
conditions: aldehyde 1 (0.5 mmol), arylamine 2 (0.5 mmol), terminal
olefin 3 (1 mmol), PdCl2 (0.025 mol, 5 mol%), LiBr·H2O (0.5 mmol,
1 equiv), in acetonitrile (2 mL) at 608C in air for 8 h. Yields of isolated
products are reported.
(24:1 d.r.). In the case of 3-fluoroaniline, two regioisomeric
quinoline products were formed, and, intriguingly, 5-substi-
tuted regioisomer 4n (12:1 d.r.) was obtained as the main
product, that is, the more acidic hydrogen atom was prefer-
entially activated in these reactions. Whereas good selectivity
were observed with a fluoro-substituted aniline, 3-chloro-
phenylamine led to the formation of two quinoline regioiso-
mers with decreased selectivity, and the 7-substituted regio-
isomer was the major product (4p–4r). Evidently, both the
electronic character and steric demand of the substituents
increase the selectivity in this transformation. The substrate
3,4-dichloroaniline led to poorly selective formation of two
regioisomeric products 4m and 4m’ (5:4 d.r.). Furthermore,
many useful substituents, such as halogen atoms, a trifluoro-
methyl group, and heterocycles (furyl and thienyl groups),
were successfully introduced into the product.
excellent yields; decarboxylation did not occur. In accordance
with the results of reactions with acrylic acid, 3,4-dimethylani-
line reacted well with benzaldehyde 1a and methyl acrylate,
and 5e was formed as the major regioisomeric product (22:1
d.r.). When 3-fluoroaniline was used as the substrate,
quinoline 5 f was obtained as the main regioisomer (23:1
d.r.), which was in good agreement with the result obtained
when the corresponding reaction was performed with acrylic
acid instead of methyl acrylate. 3,4-Dichloroaniline gave two
regioisomeric products 5g and 5g’ with poor selectivity (5:3
d.r.). It is noteworthy that the reaction of 3-methoxyaniline
proceeded exclusively at the sterically less-hindered aromatic
carbon atom of the aniline to afford the major products in
good selectivity (5k–5m and 5o). The reaction of cyclo-
hexanecarbaldehyde also proceeded smoothly to afford
product 5j in excellent yield. Furthermore, other alkenes
with electron-withdrawing groups, including acrylonitrile and
acrylamide, gave the corresponding 2,3-disubstituted quino-
lines 5o–5r in good to excellent yields. Remarkably, allylcy-
After the successful conversion of acrylic acid to sub-
stituted 2-phenylquinoline, we were interested in extending
the method to other terminal olefins to prepare a variety of
substituted quinolines (Scheme 3). To our delight, reactions
of aldehydes, arylamines, and methyl acrylate proceeded
smoothly to give 2,3-disubstituted quinolines in good to
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clohexane as aliphatic olefin was also converted successfully
to the desired product 5s, albeit in moderate yield. The
structure of 5m was further characterized by X-ray crystal
diffraction measurement.[12]
To extend the applicability of our reaction, we next turned
our attention to styrene derivatives as alkene substrates.
Under the standard reaction conditions, the reactions of
various styrene derivatives proceeded well with benzaldehyde
1a and aniline 2a to afford the desired 2,3-diphenylquino-
lines, along with some 2,4-diphenylquinolines as side products
(Table 1).[14] In general, the selectivity toward 2,3-diphenyl-
Table 1: Reactions with styrene derivatives.[a]
Scheme 4. Kinetic isotope effect (KIE) experiment.
Ultimately, when we subjected methyl 3-(2-benzylidene-
amino phenyl)acrylate to the standard reaction conditions,
only a trace of the desired product 5a was detected, thus
indicating that intermediate D was not formed through 6p-
electrocyclic rearrangement[15] of the intermediate derived by
b-H elimination of C.[12] Actually, b-H elimination of C may
be unfavored by the addition of excess halide ions in this
reaction system.[13]
On the basis of the above-mentioned results, a possible
catalytic cycle is shown in Scheme 5. The palladium catalyst
reacts not only as a transition-metal catalyst, but also as
a Lewis acid in the reaction. The reaction is initiated by ortho
palladation of the palladium-catalyst-activated N-benzylide-
neaniline A, which is formed in situ from precursors 1a and
Entry
R3
6
7
Yield [%][b]
(6+7)
6:7
1
2
3
4
5
6
7
8
C6H5
4-FC6H4
6a
6b
6c
6d
6e
6 f
7a
7b
7c
7d
7e
7 f
83
79
87
73
77
89
82
81
3.5:1
1:1.3
19:1
15:1
14:1
1:32
1:1
1:3
4-ClC6H4
3-BrC6H4
4-CNC6H4
4-OMeC6H4
4-MeC6H4
4-tBuC6H4
6g
6h
7g
7h
[a] Reaction conditions: benzaldehyde 1a (0.5 mmol), aniline 2a
(0.5 mmol), styrene derivative 3 (1 mmol), PdCl2 (0.025 mmol, 5 mol%),
LiBr·H2O (0.5 mmol, 1 equiv), in acetonitrile (2 mL) at 608C in air for 8 h.
[b] Yields of isolated products.
quinolines from styrene substrates with electron-withdrawing
substituents was better than that with electron-donating
substituents. For example, while styrene gave regioisomers
6a and 7a in a ratio of 7:2, styrenes with electron-withdrawing
substituents (4-chloro, 3-bromo, and 4-cyano) afforded the
desired 2,3-diphenylquinolines (6c–6e) in good selectivity
(> 14:1). However, 4-fluoro and 4-methyl styrene gave two
regioisomeric products in poor selectivity with a ratio of
around 1:1. A mixture of two products, with 2,4-diphenylqui-
noline 7h as the major one, was obtained with 4-tert-butyl
styrene. 2,4-Diphenylquinoline 7 f was exclusively formed
from 4-methoxy styrene.
ꢀ
To probe the mechanism of the C H bond cleavage,
a mixture of substrates 2a and [D5]-2a (1:1) was subjected to
the standard reaction conditions to determine the intermo-
lecular isotope effect, and substrate [D1]-2a was used to probe
the intramolecular isotope effect (Scheme 4). Neither inter-
nor intramolecular kinetic isotope effects were observed [kH/
kD ꢁ 1:1, Eqs. (1) and (2) in Scheme 4], thus illustrating that
ꢀ
the rate-limiting step does not involve the C H cleavage of
the aniline. Interestingly, when a mixture of substrates 1a and
[D6]-1a (1:1) was used as the benzaldehyde reaction partner,
the isotope effect (kH/kD) was determined to be 2.1:1 [Eq. (3)
in Scheme 4]. These results indicate that the abstraction of the
hydrogen atom from N-benzylideneaniline contributed to the
rate-determining step during the process.
Scheme 5. Possible mechanism for palladium-catalyzed cyclization
reaction of aldehydes, amines, and alkenes.
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ꢀ
alkene into the C Pd bond is followed by abstraction of the
hydrogen atom of N-benzylideneaniline, which is the rate-
determining step of the reaction and leads to intermediate C.
Subsequent reductive elimination generates D and releases
Pd0, which could be oxidized by O2 to recover the PdII
catalyst. Oxidation of D by both O2 and N-benzylideneaniline
A, which is reduced to the side product N-benzylaniline,
afforded the product. Furthermore, when R is is a carboxy
group, decarboxylation occurs under the reaction conditions
to provide product 4a.[11]
In conclusion, we have established a novel protocol based
ꢀ
on the palladium-catalyzed sequential formation of two C C
bonds for the construction of a series of 2-substituted and 2,3-
disubstituted quinolines from arylamines, aldehydes, and
terminal olefins (electron-deficient and electron-rich olefins)
under mild conditions. Gratifyingly, when acrylic acid is used
in the transformation, decarboxylation occurs to provide 2-
substituted quinolines. This methodology thus provides a tool
for the synthesis of diversely substituted quinolines, apart
from Povarov reactions. The products are expected to be
useful intermediates for the preparation of pharmaceutically
and biologically active compounds as well as functional
materials. Moreover, the use of inexpensive starting materials
and environmentally benign oxidants makes this atom-
efficient method particularly attractive. Further investiga-
tions toward the scope of the reaction, a detailed mechanism,
and applications in organic synthesis are ongoing in our
laboratory.
Experimental Section
Typical procedure for the synthesis of 2-phenylquinoline 4: A 25 mL
Schlenk tube was charged with a solution of aldehyde 1 (0.5 mmol)
and arylamine 2 (0.5 mmol) in MeCN (2 mL). PdCl2 (0.025 mmol),
LiBr·H2O (0.5 mmol), and acrylic acid 3a were added and, under
magnetic stirring, the mixture was heated in air at 608C for 8 h. The
solvent was removed under reduced pressure, and the products were
isolated by column chromatography on silica gel (petroleum ether/
ethyl acetate = 30:1!20:1) to give 4, which was further recrystallized
from ethyl acetate/petroleum ether (3–6% ethyl acetate in petroleum
ether). The structures of the known products were confirmed by
comparison with reported spectroscopic data. Products 5, 6, and 7
were prepared using the same procedure as described for 4.
Received: March 28, 2012
Revised: May 16, 2012
Published online: && &&, &&&&
ꢀ
Keywords: C C bond formation · oxidation · palladium ·
quinolines
.
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133, 9250; e) X. Chen, K. M. Engle, D.-H. Wang, J.-Q. Yu,
Angew. Chem. 2009, 121, 5196; Angew. Chem. Int. Ed. 2009, 48,
5094; f) I. V. Seregin, V. Gevorgyan, Chem. Soc. Rev. 2007, 36,
1173.
[11] For selected PdII-catalyzed decarboxylation reactions of arenas,
see: a) P. Hu, M. Zhang, X. Jie, W. Su, Angew. Chem. 2012, 124,
231; Angew. Chem. Int. Ed. 2012, 51, 227; b) M. Zhang, J. Zhou,
J. Kan, M. Wang, W. Su, M. Hong, Chem. Commun. 2010, 46,
5455; c) K. Xie, Z. Yang, X. Zhou, X. Li, S. Wang, Z. Tan, X. An,
Angew. Chem. Int. Ed. 2012, 51, 1 – 6
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
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.
Angewandte
Communications
Communications
Quinolines
X. Ji, H. Huang, Y. Li, H. Chen,
H. Jiang*
&&&& — &&&&
Palladium-Catalyzed Sequential
ꢀ
Formation of C C Bonds: Efficient
Assembly of 2-Substituted and 2,3-
Disubstituted Quinolines
A series of substituted quinolines was
prepared from arylamines, aldehydes,
and terminal olefins (see scheme). The
palladium-catalyzed sequential formation
both electron-deficient and electron-rich
olefins. When acrylic acid is used as
terminal olefin, decarboxylation occurs to
provide 2-substituted quinolines.
ꢀ
of C C bonds proceeds smoothly with
6
www.angewandte.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 1 – 6
These are not the final page numbers!