Highly efficient synthesis of polysubstituted 1,2-dihydroquinolines via tandem reaction of α-ketoesters and arylamines catalyzed by fluorous hydrazine-1,2-bis(carbothioate) and NCS

Article abstract of DOI:10.1016/j.tetlet.2012.11.143

A simple and convenient tandem reaction of α-ketoesters with primary or secondary aromatic amines for the synthesis of polysubstituted 1,2-dihydroquinolines has been developed. The catalytic system (fluorous hydrazine-1,2-bis(carbothioate)/NCS) of the reaction has the advantages of operational simplicity, high efficiency, as well as easy recyclability.

Full text of DOI:10.1016/j.tetlet.2012.11.143

Tetrahedron Letters 54 (2013) 638–641
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Tetrahedron Letters
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Highly efficient synthesis of polysubstituted 1,2-dihydroquinolines via
tandem reaction of a-ketoesters and arylamines catalyzed by fluorous
hydrazine-1,2-bis(carbothioate) and NCS
⇑
Yi-Wei Zhu, Jin-Long Qian, Wen-Bin Yi , Chun Cai
School of Chemical Engineering, Nanjing University of Science and Technology, 200 Xiao Ling Wei Street, Nanjing 210094, People’s Republic of China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 18 July 2012
Revised 22 November 2012
Accepted 30 November 2012
Available online 6 December 2012
A simple and convenient tandem reaction of a-ketoesters with primary or secondary aromatic amines for
the synthesis of polysubstituted 1,2-dihydroquinolines has been developed. The catalytic system (fluor-
ous hydrazine-1,2-bis(carbothioate)/NCS) of the reaction has the advantages of operational simplicity,
high efficiency, as well as easy recyclability.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Tandem reaction
Organocatalysis
Fluorine
Recovery
Green chemistry
1,2-Dihydroquinolines and their derivatives are ubiquitous in
nature, and can serve as important subunits to design tremendous
synthetic drug candidates due to their significant pharmacological
properties.1,2 They have attracted lots of attention because of their
wide spectrum of biological activities and potential pharmacolog-
ical applications.3–8 Various synthetic methods have been devel-
oped for the preparation of dihydroquinolines.9–26 In general,
traditional procedures are laborious, low yielding, and require spe-
cial synthetic precursors.15 Recently, efficient strategies toward the
synthesis of dihydroquinolines have been focused on a catalytic
version. For example, transition metals such as palladium,16 ruthe-
nium,17,18 silver,19 and gold20 catalyzed reactions of anilines with
alkynes; scandium triflate,21 silicotungstic acid,22 and zeolite23 cat-
alyzed reactions of anilines with ketones; indium mediated allyla-
tion of quinolines. Currently, there is much interest in
organocatalysts due to their low toxicity, operational simplicity,
efficiency, and good stereoselectivity compared to traditional me-
tal-based catalysts. To the best of our knowledge, there is a very
rare report about the synthesis of polysubstituted 1,2-dihydro-
construction of polysubstituted dihydroquinolines from various
ketoesters and arylamines.31,32 We found that the one-pot tandem
reaction catalyzed by fluorous hydrazine-1,2-bis(carbothioate)/
NCS co-catalyst demonstrated superior catalytic activity and effi-
ciency. Moreover, the fluorous catalyst C1 could be easily recov-
ered by fluorous solid-phase extraction (F-SPE).
The fluorous organocatalysts C1 and C2 were synthesized using
di(1H-imidazol-1-yl)methanethione or di(1H-imidazol-1-yl)meth-
anone I and 3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctan-1-ol II as
starting material (Scheme 1). C1 and C2 were obtained as white
solids in 72% and 56% yields, respectively. These compounds could
be easily purified by fluorous-solid phase extraction (F-SPE) with a
cartridge charged with fluorous silica gels.28,33 The catalysts are
S
S
(CF2)5CF3
(CF2)5CF3
N
H
N
H
O
O
O
O
F3C(F2C)5
quinoline from
a-ketoesters with primary or secondary aromatic
C1
amines catalyzed by organic catalysts (organocatalyst). In continu-
ation of our studies of organocatalytic reactions,27–30 we aimed to
explore the novel fluorous hydrazine-1,2-bis(carbothioate) C1 and
hydrazine-1,2-dicarboxylate C2 (Fig. 1) with NCS for the
O
O
N
H
N
H
F3C(F2C)5
C2
⇑
Corresponding author. Tel.: +86 25 84315514; fax: +86 25 84315030.
E-mail address: yiwenbin@mail.njust.edu.cn (W.-B. Yi).
Figure 1. Fluorous hydrazine-1,2-bis(carbothioate) C1 and hydrazine-1,2-dicar-
boxylate C2.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.11.143

Y.-W. Zhu et al. / Tetrahedron Letters 54 (2013) 638–641
639
X
X
(CF2)5CF3
DCM
(CF2)5CF3
N
O
N
N
HO
N
N
N
I
II
III
X
X
NH2NH2
Et3N
HCl
(CF2)5CF3
N
H
N
O
O
F3C(F2C)5
H
C1 X= S
C2 X= O
Scheme 1. Preparation of fluorous hydrazine-1,2-bis(carbothioate) C1 and hydrazine-1,2-dicarboxylate C2.
Table 1
nation of the fluorous organocatalysts and NCS, in which C1 was
more efficiently structured compared to C2 (Table 1, entries 9
and 10). After screening the solvents (MeCN, THF, DMSO, DMF,
and toluene) and changing the reaction temperature from rt to
80 °C, we obtained the target compound in 80% yield with
5 mol % C1 and NCS as co-catalyst. Importantly, the use of the flu-
orous hydrazine could be recovered from the reaction mixture by
fluorous solid-phase extraction (F-SPE) with excellent purity for di-
rect reuse. For example, the yields of reaction from the first run to
the second run were almost same. By calculating weight and
detecting IR, 13C NMR, and 1H NMR, we found that the catalyst
was recovered in 93% yield and in 99% purity (Scheme 2).
Reaction of methyl pyruvate (1a) and p-chloroaniline (2a) under various reaction
conditionsa
CO2CH3
O
Cl
NH2
OCH3
cat.
solvent
2
CO2CH3
N
H
O
Cl
1a
2a
3aa
Entry
Catalyst (mol %)
Solvent
T (°C)
Yieldb (%)
1
2
3
4
5
6
7
8
None
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
THF
60
60
60
60
60
60
60
60
60
60
RT
60
80
Reflux
80
80
80
None
63
None
None
7
CF3COOH (10)
HCOOH (10)
CH3COOH (10)
H3BO3 (10)
NCS (10)
C1 (10)
The scope and generality of this reaction were tested with var-
ious combinations of aromatic amines and pyruvates (Table 2).
Electronic effect on the aromatic ring of amines had a significant
influence on the productivity. Those containing electron-donating
or neutral groups gave the desired products (3ab, 3ac, 3ae, 3ag,
and 3ah) in good to excellent yields. Amines bearing electron-
withdrawing groups gave the targets in comparatively lower yields
(3aa, 3ad, and 3ai). Substituent at the 2-position of arylamine re-
duced the yield significantly because of steric effect (3af). It was
noteworthy that when 1-aminonaphthalene was used, the ex-
pected compound 3aj was afforded in 71% yields, which provided
a convenient route for the construction of tricyclicdihydroquino-
lines. Ethyl pyruvate was also a good substrate for the reaction.
Attempts were made to obtain further insights into this cata-
lytic reaction. Imine 4ag could be isolated together with a trace
amount of enamine isomer in the reaction of methyl pyruvate
(1a) with p-methoxyaniline (2g) in the same ratio without catalyst.
The sequential treatment of 4ag with 1a under the standard condi-
tions of Table 2 led to the formation of desired product 3ag. The
above results indicated that imine or enamine complex might be
the critical intermediate in this tandem reaction (Scheme 3).
The precise role of NCS was not very clear in this method. One
explanation for this process was that NCS probably generated a
trace of HCl together with C1, which might be the actual catalyst
for the tandem reaction. The speculation was supported by the
pH experiments we did with a pH meter. The fluorous ponytail
played an important role in this reaction. We compared it in the
model reaction with its non-fluorous counterpart and found the
non-fluorous version afforded a lower yield (71% vs 80%). The flu-
orous ponytail probably helped to generate the HCl in the reaction
with its electron-withdrawing property.
59
None
None
85
65
13
80
82
77
16
C2 (10)
9
C1 (10) + NCS (10)
C2 (10) + NCS (10)
C1 (5) + NCS (5)
C1 (5) + NCS (5)
C1 (5) + NCS (5)
C1 (5) + NCS (5)
C1 (5) + NCS (5)
C1 (5) + NCS (5)
C1 (5) + NCS (5)
10
11
12
13
14
15
16
17
DMF
DMSO
Toluene
21
11
a
Reaction conditions: compound 1a (1.5 mmol), 2a (1 mmol), catalyst (5–
10 mol %) in solvent (1.5 mL) for 12 h.
b
Isolated yields based on 1a.
stable in air and soluble in solvents such as THF, CH3OH, and
CH3CN.
Firstly, the model reaction involving methyl pyruvate (1a) and
p-chloroaniline (2a) was used to optimize the reaction condition.
The results were illustrated in Table 1. Some organic acid catalysts
such as HCOOH, CH3COOH, CF3COOH, and H3BO3 gave the yields
ranging from 0% to 63% (Table 1, entries 2–5). Moderate yield
was obtained in the presence of NCS (N-Chlorosuccinimide) (Ta-
ble 1, entry 6). The fluorous catalysts C1 and C2 were found to have
poor catalytic activity for this tandem reaction (Table 1, entries 7
and 8). However, the results were improved greatly by the combi-
CO2CH3
O
In summary, we have developed a simple and efficient method-
ology for the construction of polysubstituted 1,2-dihydroquinoline
derivatives via a one-pot tandem reaction of a-ketoesters and aro-
matic amines catalyzed by fluorous hydrazine-1,2-bis(carbothio-
ate) and NCS. A series of substituted dihydroquinolines were
conveniently obtained from simple and readily available starting
materials. The fluorous catalyst could be easily recovered by F-
SPE. The role of the co-catalytic system is being studied in detail.
MeCN, 60 oC
NCS
Cl
NH2
OCH3
2
CO2CH3
N
H
fluorous catalyst C1
O
Cl
F-SPE recovery
1a
2a
3aa
recovery yield: 93%
purity: 99%
Scheme 2. Fluoruos catalyst recovery experiment.

640
Y.-W. Zhu et al. / Tetrahedron Letters 54 (2013) 638–641
Table 2
C1/NCS-catalyzed tandem reaction of various aromatic amines and pyruvatesa,b
Products (yield)
CO2CH3
CO2CH3
CO2CH3
Cl
CO2CH3
N
CO2CH3
CO2CH3
N
H
N
H
3aa (H80%)
3ac (92%)
3ab (89%)
CO2CH3
CO2CH3
CO2CH3
O2N
HO
nBu
Cl
CO2CH3
CO2CH3
CO2CH3
N
H
N
H
N
H
3ad (32%)
3ae (90%)
3af (64%)
CO2CH3
CO2CH3
CO2CH3
H3CO
Br
CO2CH3
CO2CH3
CO2CH3
N
H
N
H
N
H
3ai (81%)
3ag (92%)
3ah (94%)
CO2CH3
CO2CH2CH3
CO2CH3
CO2CH2CH3
N
H
N
H
3ba (74%)
3aj (71%)
a
Reaction conditions: C1 (5 mol %), NCS (5 mol %), a-ketoester (1.5 mmol), and arylamine (1 mmol) in CH3CN (1.5 mL) for 8–24 h.
Isolated yields based on a-ketoester.
b
OMe
OMe
OMe
O
MeCN
N
HN
OCH3
60 oC, 3h
OCH3
OCH3
O
NH2
O
O
trace
4ag
1a
2g
(41%)
(1 mmol)
(1 mmol)
OMe
CO2CH3
O
C1 (5 mmol%)
MeO
N
NCS (5 mmol%)
60 oC, MeCN
OCH3
CO2CH3
OCH3
N
H
O
O
4ag
1a
(0.5 mmol)
(0.5 mmol)
3ag
(92%)
Scheme 3. Control Experiments of 1a with 2g or 4ag.
Acknowledgments
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