High efficient iron-catalyzed transfer hydrogenation of quinolines with Hantzsch ester as hydrogen source under mild conditions

Article abstract of DOI:10.1016/j.tetlet.2017.07.101

A highly efficient transfer hydrogenation of quinolines with Hantzsch ester as hydrogen source in the presence of 1 mol% Fe(OTf)₂ under mild conditions has been developed. A series of substituted 1,2,3,4-tetrahydroquinoline derivatives were afforded in excellent yields with good functional group tolerance.

Full text of DOI:10.1016/j.tetlet.2017.07.101

Accepted Manuscript
High efficient iron-catalyzed transfer hydrogenation of quinolines with
Hantzsch ester as hydrogen source under mild conditions
Renke He, Peng Cui, Danwei Pi, Yan Sun, Haifeng Zhou
PII:
S0040-4039(17)30970-X
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.07.101
TETL 49183
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
10 July 2017
25 July 2017
29 July 2017
Please cite this article as: He, R., Cui, P., Pi, D., Sun, Y., Zhou, H., High efficient iron-catalyzed transfer
hydrogenation of quinolines with Hantzsch ester as hydrogen source under mild conditions, Tetrahedron Letters
(
2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.07.101
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Tetrahedron Letters
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High efficient iron-catalyzed transfer hydrogenation of quinolines with Hantzsch ester as hydrogen
source under mild conditions
*
Renke He, Peng Cui, Danwei Pi, Yan Sun, and Haifeng Zhou
Hubei Key Laboratory of Natural Products Research and Development, College of Biological and Pharmaceutical Sciences, China Three Gorges University,
Yichang 443002, China.
ARTICLE INFO
ABSTRACT
Article history:
Received
A highly efficient transfer hydrogenation of quinolines with Hantzsch ester as hydrogen source
2
in the presence of 1 mol% Fe(OTf) under mild conditions has been developed. A series of
Received in revised form
Accepted
substituted 1,2,3,4-tetrahydroquinoline derivatives were afforded in excellent yields with good
functional group tolerance.
Available online
2017 Elsevier Ltd. All rights reserved.
Keywords:
Iron catalysis
Transfer hydrogenation
Quinolines
Hantzsch ester
Results and discussion
Introduction
1,2,3,4-Tetrahydroquinoline-based frameworks are widely
existed in fine chemicals, pharmaceuticals, agrochemicals, dyes,
We initiated our investigation with the reduction of quinoline
1a in chloroform at 40 C for 4 h using Hantzsch ester A as
o
1
fragrances, as well as hydrogen-storage materials. Traditionally,
hydrogen source. As shown in Table 1, some iron salts including
FeCl , FeCl , FeS, Cp Fe, Fe(OAc) , Fe(acac) , Fe(ClO ) , and
the quinoline derivatives were reduced by stoichiometric metal
hydrides or reactive metals as reductants. The catalytic
2
3
2
2
3
4 2
2
Fe(OTf) were screened first. The results revealed that Fe(OTf)
2
2
2
hydrogenation and transfer hydrogenation under homogenous or
heterogeneous conditions have been developed in the past
and Fe(ClO ) performed better than the others, and Fe(OTf)
4
2
afforded 1,2,3,4-terahydroquinoline 2a with 96% yield (Table 1,
entries 1-8). Considering the high catalytic activity of Fe(OTf)2,
the reaction was attempted within shorter time. It was found that
the yield remained unchanged for 2 h, but reduced by half for 1 h
(entries 8-10). A survey of solvents showed that chloroform
3
-5
decades. Among which, Reuping et al. reported a pioneering
biomimetic transfer hydrogenation of quinolines using diphenyl
phosphate as the catalyst and Hantzsch ester as the hydrogen
5
a
source. After that, various BrØnsted acid-catalyzed transfer7
hydrogenations of azaarenes including quinolines, quinoxalines,
6
is the best option comparing to acetonitrile (CH CN),
3
tetrahydrofuran (THF), 1,4-dioxane, methanol, toluene, and N,N-
8
9
indoles, and pyridines with Hantzsch ester as the hydrogen
source have been achieved. By contrast, the combination of metal
catalyst and Hantzsch ester promoted transfer hydrogenation was
dimethylformamide (DMF) (entries 9, 11-16). And then, other
hydrogen sources like NADH analogues B and C, as well as
popularly used i-PrOH, HCOOH, and HCOOH/Et N (5:2) were
1
0
very limited.
3
With the merits of environment benign, readily accessibility
and cost-benefit, iron seems to be promising catalyst in organic
synthesis. A number of iron-catalyzed organic transformations
also evaluated. Among which, the Hantzsch ester A afforded the
highest yield (entries 9, 17-21). Furthermore, the amount of
Hantzsch ester A was reduced to 1.0 equiv, but the product 2a
was obtained in only 58% yield even if prolonging the reaction
time to 4 h (entry 22). To verify the necessity of iron catalyst,
control experiments were also performed. No reaction occurred
in the absence of iron catalyst (entry 23). When 10 mol% of
11
have been realized in recent years. To continue our research
1
2
interest in iron-catalyzed reactions. Herein, we report an iron-
catalyzed efficient chemoselective hydrogenation of quinolines
employing Hantzsch ester as hydrogen source under mild
conditions.
TfOH was used instead of Fe(OTf) , the desired product 2a was
2
detected with 43% yield (entry 24). It means that the strong acid
———
Corresponding author; e-mail: zhouhf@ctgu.edu.cn
http://dx.doi.org/
*
2

TfOH generated in situ could promote the reaction with lower
catalytic activity. Finally, 1 mol% Fe(OTf) , 2.5 equiv of
, 40 °C, and 2 h were set as the
benzoquinolines 1n and 1o, the desired products 2m-2o were
obtained in 68-72% yields by prolonging the reaction time to 8 h.
The iron-catalyzed transfer hydrogenation was further applied to
2-methylquinoxaline, affording the reduced product 2p in 73%
yield. To demonstrate the practicality, the gram scale (10 mmol)
synthesis of 2a was also conducted with 94% yield.
2
Hantzsch ester A, 1 mL of CHCl
optimal reaction conditions.
3
Table 1. Screening of reaction conditions for the transfer
a
a
Scheme 1. Scope of the transfer hydrogenation of quinolines
hydrogenation of quinoline 1a
Time
Yield
b
Entry
[Fe]
H source
solvent
(
h)
4
4
4
4
4
4
4
4
2
1
2
2
2
2
2
2
2
2
2
2
2
4
2
2
(%)
58
64
30
15
21
8
1
2
3
4
5
6
7
8
9
FeCl
FeCl
FeS
2
3
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
CHCl
CHCl
CHCl
CHCl
CHCl
CHCl
CHCl
CHCl
CHCl
CHCl
3
3
3
3
3
3
3
3
3
3
Cp
Fe(OAc)
Fe(acac)
Fe(ClO
2
Fe
2
3
4
)
2
89
96
96
46
14
32
30
15
35
12
49
26
11
19
24
58
nd
43
Fe(OTf)
Fe(OTf)
Fe(OTf)
Fe(OTf)
Fe(OTf)
Fe(OTf)
Fe(OTf)
Fe(OTf)
Fe(OTf)
Fe(OTf)
Fe(OTf)
Fe(OTf)
Fe(OTf)
Fe(OTf)
Fe(OTf)
--
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
1
1
1
1
1
1
1
1
1
1
2
2
0
1
2
3
4
5
6
7
8
9
0
3
CH CN
THF
1,4-dioxane
MeOH
toluene
DMF
B
CHCl
CHCl
CHCl
CHCl
CHCl
CHCl
CHCl
CHCl
3
3
3
3
3
3
3
3
a
C
i-PrOH
HCOOH
HCOOH/TEA
A
A
A
Reaction conditions: quinoline (1; 0.5 mmol), Hantzsch ester A (2.5 equiv),
o
(1.0 mL), 40 C, 2-8 h, isolated yield.
CHCl
3
b
c
Gram scale reaction (1a; 10 mmol).
mol% Fe(OTf) was used.
c
1
2
2
d
2
2
2
2
3
e
f
4
TfOH
a
Scheme 2 Attempt to asymmetric transfer hydrogenation of 2-
methylquinoline with iron complexes
Reaction conditions: quinoline (1a; 0.5 mmol), 1 mol% catalyst, hydrogen
source (2.5 equiv), 1 mL solvent.
b
c
d
e
f
Determined by GC analysis with an internal standard (mesitylene).
HCOOH/TEA = 5:2 (mol ratio).
1
.0 equiv of Hantzsch ester A was used.
nd = not detected.
1
0 mol% TfOH was used.
Under the optimal reaction conditions, the scope of the iron-
catalyzed transfer hydrogenation of quinoline derivatives was
investigated. As shown in Scheme 1, the hydrogenation of
electron-rich quinolines 1b-1e bearing methyl group at different
positions and 6-methoxyquinoline 1f proceeded smoothly
affording the corresponding reductive products 2b-2f with 86-
9
5% yields. Similarly, the 2,6-dimethylquinoline 1g was
hydrogenated to give 2g in 96% yield. Next, the electron-
deficient 7-chloroquinoline 1h was also subjected to this reaction
and the reductive product 2h was isolated in 88% yield without
dechlorination. Interestingly, the chemoselective reduction of
electron-withdrawing nitro group substituted quinolines 1i-1l was
observed, and the corresponding products 2i-2l were obtained in
2
After identifying Fe(OTf) as a valuable alternative to the
6
10a,b
established BrØnsted acids and Lewis acids
hydrogenation of quinolines, a preliminary attempt to the
asymmetric variant utilizing the complexes of Fe(OTf) with
for transfer
2
chiral phosphine ligand L1 or bis-oxazoline ligand L2 was
carried out. Unfortunately, only racemic 2-methyl-1,2,3,4-
tetrahydroquinoline was observed (Scheme 2).
76-90% yields with nitro group intact. This transfer
hydrogenation was also applicable to 2-phenylquinoline 1m,
3

6
.
(a) Rueping, M.; Theissmann, T.; Stoeckel, M.; Antonchick,
A. P. Org. Biomol. Chem. 2011, 9, 6844; (b) Cai, X. F.; Guo,
R. N.; Feng, G. S.; Wu, B.; Zhou, Y. G. Org. Lett. 2014, 16,
Conclusion
In summary, we have developed an iron-catalyzed transfer
2
680; (c) Rueping, M.; Stoeckel, M.; Sugiono, E.;
Theissmann, T. Tetrahedron 2010, 66, 6565; (d) Qiao, X.;
El-Shahat, M.; Ullah, B.; Bao, Z.; Xing, H.; Xiao, L.; Ren,
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hydrogenation of quinolines with low catalyst loading. The high
catalytic activity of iron makes it to be an environment benign
alternative to BrØnsted acids and other Lewis acids for the
reduction of quinolines. Further studies focused on iron-catalyzed
asymmetric variant are ongoing in our laboratory.
7
.
(a) Rueping, M.; Tato, F.; Schoepke, F. R. Chem. Eur. J.
2
010, 16, 2688; (b) Shi, F.; Tan, W.; Zhang, H. H.; Li, M.;
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Acknowledgments
8
9
1
.
.
We are grateful for financial support from the National
Natural Science Foundation of China (21202092) and for a
Startup Foundation from the China Three Gorges University
Rueping, M.; Antonchick, A. P. Angew. Chem. Int. Ed.
2
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4
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396.
4
.
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5
.
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3

Highlights
ꢀ
ꢀ
Environment benign iron-catalyzed
transfer hydrogenation.
Highly catalytic activity of iron with 1
mol% catalyst loading.
Excellent functional group tolerance
ꢀ
ꢀ
o
Mild reaction condition (40 C).
3

Graphical Abstract
High efficient iron-catalyzed transfer
hydrogenation of quinolines with Hantzsch
ester as hydrogen source under mild
conditions
Leave this area blank for abstract info.
Renke He, Peng Cui, Danwei Pi, Yan Sun, and Haifeng Zhou*
3