Cyclopentadiene-based Br?nsted acid as a new generation of organocatalyst for transfer hydrogenation of 2-substituted quinoline derivatives

Article abstract of DOI:10.1016/j.tetlet.2017.04.038

A simple and readily available cyclopentadiene-based Br?nsted acid was employed to catalyze the transfer hydrogenation of 2-substituted quinolines using Hantzsch ester as the hydrogen source. This conceptually new designed organocatalyst demonstrates remarkably high efficiency for this transformation and a variety of substituted 1,2,3,4-tetrahydroquinoline derivatives were afforded in excellent yields under mild reaction conditions.

Full text of DOI:10.1016/j.tetlet.2017.04.038

Accepted Manuscript
Cyclopentadiene-based Brønsted acid as a new generation of organocatalyst for
transfer hydrogenation of 2-substituted quinoline derivatives
Xiang Qiao, Mahmoud El-Shahat, Bakhtar Ullah, Zongbi Bao, Huabin Xing, Li
Xiao, Qilong Ren, Zhiguo Zhang
PII:
S0040-4039(17)30468-9
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.04.038
TETL 48830
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
8 March 2017
7 April 2017
10 April 2017
Please cite this article as: Qiao, X., El-Shahat, M., Ullah, B., Bao, Z., Xing, H., Xiao, L., Ren, Q., Zhang, Z.,
Cyclopentadiene-based Brønsted acid as a new generation of organocatalyst for transfer hydrogenation of 2-
substituted quinoline derivatives, Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.04.038
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Graphical Abstract
Cyclopentadiene-based Brønsted acid as a
new generation of organocatalyst for
transfer hydrogenation of 2-substituted
quinoline derivatives
Leave this area blank for abstract info.
Xiang Qiaoa, Mahmoud El-Shahata, b, Bakhtar Ullaha, Zongbi Baoa, Huabin Xinga, Li Xiaoc, Qilong Rena and
Zhiguo Zhanga, ∗

1
Tetrahedron Letters
journal homepage: www.els evier.com
Cyclopentadiene-based Brønsted acid as a new generation of organocatalyst for
transfer hydrogenation of 2-substituted quinoline derivatives
Xiang Qiaoa, Mahmoud El-Shahata, b, Bakhtar Ullaha, Zongbi Baoa, Huabin Xinga, Li Xiaoc, Qilong Rena
and Zhiguo Zhanga, ∗
a Key Laboratory of Biomass Chemical Engineering of Ministry of Education, College of Chemical and Biological Engineering, Zhejiang University, Zheda
Road 38, Hangzhou 310027, China.
b Photochemistry Department, Chemical Industries Research Division, National Research Centre, 33 EL-Bohouth St., Dokki, 12622, Giza, Egypt.
c College of Life Sciences, Huzhou University, Xueshi Road 1, Huzhou 313000, China
ARTICLE INFO
ABSTRACT
Article history:
Received
A simple and readily available cyclopentadiene-based Brønsted acid was employed to catalyze
the transfer hydrogenation of 2-substituted quinolines using Hantzsch ester as the hydrogen
Received in revised form
Accepted
source. This conceptually new designed organocatalyst demonstrates remarkably high efficiency
for this transformation and a variety of substituted 1,2,3,4-tetrahydroquinoline derivatives were
afforded in excellent yields under mild reaction conditions.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Cyclopentadiene-based Brønsted acid
Hantzsch ester
Organocatalysis
Quinoline derivatives
Transfer hydrogenation
1,2,3,4-Tetrahydroquinoline-based frameworks are widely
existed in biologically active natural products and
using diphenyl phosphate as the catalyst and Hantzsch ester as
the hydrogen source (eq. a of Scheme 1).6
pharmaceutics.1 The regioselective reduction of quinoline
derivatives for the synthesis of tetrahydroquinolines represents
one of the most prevalent approaches, upon which a number of
transition metal catalysts have been developed for this
transformation in conjunction with hydrogen as the reducing
agent.2 Although most of these transition metals catalyzed
processes showed high reactivity and selectivity, it is not free of
problems, such as pollution and toxicity of transition metals as
well as risk in handling high pressure of hydrogen gas. With
increased consciousness of the environmental impact on current
chemical processes, the development of sustainable synthetic
methodologies has attracted much interest.3 In this regard, nature
has been regarded to be an uncompetitive master in mediating
diverse redox transformations in biological systems with enzyme
and organic hydride reduction cofactors, such as nicotinamide
adenine dinucleotide (NAD(P)H) and flavin adenine dinucleotide
(FADH2).4 Inspired by the mode of action that nature performs
reductions, chemists have developed a plethora of biomimetic
protocols for the reduction of quinolines employing Hantzsch
ester (HEH) as NADH analogue in the presence of catalytic
amount of organic molecules.5
Scheme 1. Organocatalytic transfer hydrogenation of quinolines
with Hantzsch ester.
Later on, this strategy was extended to the asymmetric transfer
hydrogenation of quinolines catalyzed with chiral BINOL based
(BINOL = [1,1’-binaphthalene]-2,2’-diol) phosphoric acids.7 In
continuation of our interest in the development of non-covalent
organocatalytic transformations, we reported an example of
transfer hydrogenation of quinolines promoted by an electron-
Rueping and co-workers were among the first to report that
Brønsted acids catalyze transfer hydrogenation of quinolines
———
∗ Corresponding author. Tel: +86-571-87951224; Fax: +86-571-87952375; E-mail: zhiguo.zhang@zju.edu.cn.

2
Tetrahedron Letters
poor H-bond donor catalyst, i.e., N,N’-Bis[3,5-
but giving 1,2,3,4-tetrahydroquinoline in different yields at the
same time interval (2 h) (Table 1). The reaction performed in
nonpolar solvents such as chloroform, dichloromethane, and
toluene shows superior rate and isolated yields (Table 1, entries
6–8), and chloroform appeared to be the best solvent for this
transformation. The reaction in ethyl acetate, in agreement with
Mukaiyama-Mannich reaction, also gives the product in high
yield (Table 1, entry 2). Performing the reaction in other polar
solvents results in inferior reactivity, probably due to the effect of
competitive intermolecular hydrogen bonding interaction
between polar solvents and PCCP (Table 1, entries 1, 3−5).
bis(trifluoromethyl)phenyl]thiourea (Schreiner’s thiourea) via
hydrogen bonding activation with Hantzsch ester as the hydrogen
source (eq. b of Scheme 1).8
Scheme 2. Lambert’s catalyst design.
Recently, a fundamentally new strategy on the design of
Brønsted acid catalyst has been introduced by Lambert and co-
workers.9 The new catalyst class is based on 1,2,3,4,5-
pentacarboxycyclopentadiene (PCCP), which preferably exists in
the enol form and its deprotonation leads to the stable aromatic
cyclopentadienyl anion and comparable acidity to mineral acids
(Scheme 2). Further modification of the structure with chiral
alcohols and amines give rise to a new type of chiral acid
catalyst, which demonstrated high reactivity and selectivity for
the enantioselective Mukaiyama-Mannich reaction.
Table 2
Assessment of catalyst loading in PCCP-catalyzed transfer
hydrogenation of 2-phenylquinoline.
PCCP (mol
Entrya
t (h)
Yieldb (%)
%)
In line with previous work and our observations, we reasoned
that this new generation of Brønsted acid would also serve as an
efficient organocatalyst for transfer hydrogenation of quinolines
through activation of the substrate by protonation and subsequent
hydride transfer from Hantzsch ester (eq. c of Scheme 1). This
present work would not only be the first example of
cyclopentadiene-based Brønsted acid catalyzed transfer
hydrogenations, but also provide some preliminary guidance for
the utilization of its chiral derivatives in asymmetric catalysis.
1
5
2
96
2
4
2
96
3
3
2
96
4
2
2
97
5
1
2
97
6
0.1
0.1
0.01
0.01
0.001
0.001
0
24
48
24
63
24
74
48
trace
92
Table 1
7c
Influence of the solvent on the PCCP catalyzed transfer
hydrogenation of 2-phenylquinoline.
8
trace
86
9c
10
11c
12c
trace
77
0
Entrya
Solvent
MeOH
EtOAc
DMF
Yieldb (%)
a All reactions were performed using 2-phenylquinoline (0.1 mmol) and HEH
(3.0 equiv.) in 2 mL of CHCl3 at room temperature.
1
2
3
4
5
6
7
8
33
86
48
75
73
96
92
90
b Yield of isolated product after column chromatography.
c The reaction was performed at 60 oC.
THF
Having established chloroform as the best solvent for transfer
hydrogenation of 2-phenylquinoline 1a, we next examined the
catalyst loading (Table 2). Starting from 5 mol % of PCCP, the
catalyst loading can be reduced to 1 mol % without obvious
compromise of reactivity (Table 2, entry 5). When the catalyst
loading was continued to decrease to the range of 0.1–0.001 mol
%, only trace amount of product was obtained. However, after
heating the reaction to 60 ºC, the corresponding product 2a can
be isolated in good to excellent yield even with 0.001 mol % of
catalyst loading (Table 2, entries 6−11). No reaction takes place
without PCCP catalyst (Table 2, entry 12), indicating the crucial
role of PCCP in promoting this transformation. For comparison,
a control experiment with diphenyl phosphate (1 mol%) was also
performed under identical reaction conditions, giving the product
in 61% yield, which suggests that PCCP is somewhat superior
over diphenyl phosphate for this title transformation.
MeCN
CHCl3
CH2Cl2
PhMe
a All reactions were performed using 2-phenylquinoline 1a (0.1 mmol) and
HEH (3.0 equiv.) in 2 mL of solvent with PCCP (10 mol%) at room
temperature for 2 h.
b Yield of isolated product after column chromatography.
We initiated our investigation by the synthesis of 1,2,3,4,5-
pentacarboxycyclopentadiene (PCCP) according to the procedure
reported.10 Our initial study concentrated on solvent employed
using 2-phenyquinoline as a model substrate. In the presence of
10 mol % of PCCP and 3 equiv. of HEH, we found that the
reaction could proceed in all solvents tested at room temperature,
Table 3

3
Substrate scope of the PCCP catalyzed transfer hydrogenation
of 2-substituted quinolines.
pentakis((1R,2S,5R)-2-isopropyl-5-methylcyclo hexyl) cyclo
penta-1,3-diene-1,2,3,4,5-pentacarboxylate as the catalyst. In the
presence of 1 mol% of chiral PCCP, 2-phenylquinoline and 2-
methylquinoline furnished the corresponding product with 34%
and 43% ee, respectively (Scheme 3). Further optimization of
reaction parameters such as solvent, temperature, and
concentrations did not show beneficial effect in the improvement
of enantioselectivities.
Yieldb
Entrya
R1
R2
(%)
Conclusions
1
H
4-Methylphenyl
2,4-Dimethylphenyl
4-Isopropylphenyl
4-Methoxyphenyl
1,1'-Biphenyl-4-yl
2-Fluorophenyl
4-Chlorophenyl
4-Bromophenyl
n-Butyl
77
In summary, we have successfully developed a highly
efficient cyclopentadiene-based Brønsted acid catalyzed transfer
hydrogenation of various 2-substituted quinolines with Hantzsch
ester as the hydrogen source. This novel and alternative Brønsted
acid catalytic reduction requires low catalyst loading and
tolerates both 2-alkyl and aryl-substituted quinolines, giving the
corresponding product in high to excellent yields. Furthermore,
we were able to extend this valuable methodology to
enantioselective reduction of 2-substituted quinolines. It should
be highlighted that this organocatalytic procedure was the first to
expand the application scope of cyclopentadiene-based Brønsted
acid catalyst after its advent. The mild reaction conditions as well
as the relatively low catalyst loading render this protocol an
attractive approach to the synthesis of 1,2,3,4-
2
H
92
97
93
96
84
87
89
96
91
89
98
94
3
H
4
H
5
H
6
H
7
H
8
H
9
H
10
11
12
13
H
Methyl
tetrahydroquinoline derivatives. Further investigation will be
directed toward the design of more efficient cyclopentadiene-
based chiral derivatives for enantioselective transfer
5-Me
6-F
6-Cl
Methyl
Methyl
hydrogenations.
Methyl
Acknowledgments
a All reactions were performed using quinolines (0.1 mmol), HEH (3.0 equiv.)
and PCCP (1 mol %) in 2 mL of CHCl3 at room temperature.
We are grateful for financial support from the MOST
(2016YFA0202900), the National Natural Science Foundation of
China (21376212, 21436010), the Foundation of Zhejiang
Educational Committee (Y201224067) and the Natural Science
Foundation of Zhejiang Province, China (LY13B060001).
b Yield of isolated product after column chromatography.
With the optimized conditions in hand we explored the scope
of PCCP catalyzed transfer hydrogenation of 2-substituted
quinolines (Table 3). In general, differently 2-substituted
quinolines bearing either with electron-donating or electron-
withdrawing groups are compatible with this protocol, giving
respective product in good to excellent yields (Table 3, entries 1–
8). Notably, quinolines with aliphatic substituents such as 2-n-
butyl and 2-methyl could also be reduced to afford the product in
excellent yields (Table 3, entries 9−10). In addition, 5- and 6-
substituted quinolines were also successfully reduced with this
Supplementary Material
Supplementary material associated with this article can be
found in...
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−13
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5
First expanding application of cyclopentadiene-
based Brønsted acid catalyst
Attractive approach with mild reaction conditions
and low catalyst loading
Enantioselective reduction of 2-substituted
quinolines