Highly efficient synthesis of polysubstituted 1,2-dihydroquinolines via cascade reaction of α-ketoesters with arylamines mediated by iodine

Article abstract of DOI:10.1016/j.tet.2014.01.061

An efficient strategy enabling the construction of polysubstituted 1,2-dihydroquinoline derivatives mediated by the commercially available, economical, and environmentally benign iodine (3 mol %) under mild conditions was developed. Various arylamines and

Full text of DOI:10.1016/j.tet.2014.01.061

Accepted Manuscript
Highly Efficient Synthesis of Polysubstituted 1,2-Dihydroquinolines via Cascade
Reaction of α-Ketoesters with Arylamines Mediated by Iodine
Bao-Qiang Zhang, Yuan Luo, Yan-Hong He, Zhi Guan
PII:
S0040-4020(14)00116-1
10.1016/j.tet.2014.01.061
TET 25235
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 5 January 2014
Accepted Date: 27 January 2014
Please cite this article as: Zhang B-Q, Luo Y, He Y-H, Guan Z, Highly Efficient Synthesis of
Polysubstituted 1,2-Dihydroquinolines via Cascade Reaction of α-Ketoesters with Arylamines Mediated
by Iodine, Tetrahedron (2014), doi: 10.1016/j.tet.2014.01.061.
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ACCEPTED MANUSCRIPT
Highly Efficient Synthesis of Polysubstituted 1,2-Dihydroquinolines via Cascade
Reaction of α-Ketoesters with Arylamines Mediated by Iodine
Bao-Qiang Zhang,Yuan Luo, Yan-Hong He*, and Zhi Guan*
School of Chemistry and Chemical Engineering, Southwest University, Chongqing, 400715, P. R. China
Fax: +86-23-68254091; e-mail: heyh@swu.edu.cn for Y-H He; guanzhi@swu.edu.cn for Z. Guan
Abstract An efficient strategy enabling the construction of polysubstituted
1,2-dihydroquinoline derivatives mediated by the commercially available, economical, and
environmentally benign iodine (3 mol %) under mild conditions was developed. Various
arylamines and α-ketoesters could participate in this cascade reaction, and the desired products
were obtained in excellent yields up to 98%.
Keywords Polysubstituted 1,2-dihydroquinoline; α-Ketoester; Arylamine; Iodine; Cascade
reaction
1. Introduction
1-3
Dihydroquinolines and their derivatives are ubiquitous skeletons in pharmaceuticals,
4
5-7
synthetic
intermediates,
and
natural
products.
Among
these,
2,4-multisubstituted-1,2-dihydroquinoline derivative frameworks are important heterocycles
2,8,9
found in a wide range of bioactive and pharmacological compounds (Scheme 1).
As a
result, considerable efforts were directed toward the development of efficient methods for
their synthesis. Many high-efficiency catalytic methods were revealed, such as the cascade
1

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reaction of anilines with alkynes catalyzed by transition metals, 10-13 the condensation reaction
14,15
of anilines with ketones catalyzed by scandium triflate, silicotungstic acid,
of quinolines mediated by indium and 16 etc.
the allylation
Scheme 1 Representative bioactive or pharmacological multisubstituted dihydroquinolines.
Recently, a novel domino reaction of pyruvate with arylamine has been proposed to
construct 2,4-multisubstituted-1,2-dihydroquinoline derivatives. Kumar et al. first used the
domino reaction of α-ketoesters and arylamines in the formation of
2,4-multisubstituted-1,2-dihydroquinolines via variants of the Mannich and aryl C(sp2)-H
bond functionalization procedures employing AuCl3 and AgSbF6 in the presence of
17
acetonitrile and ethanol.
Subsequently, Ji et al. presented the same tandem reaction
catalyzed by indium triflate and HNO3 respectively. 18,19 The cascade reaction of pyruvates
with arylamines was also reported by Yi and coworkers using a complex catalytic system of
20
fluorous hydrazine-1,2-bis(carbothioate) and N-chlorosuccinimide.
Among the reported
approaches, some used expensive metal catalysts, strong corrosive acid, or multiple step
synthesized catalysts. These drawbacks limited their wide application in industry and
academia. Therefore, development of a highly efficient, environmentally friendly,
commercially available and cheap catalyst to realize this important transformation is still
desirable. Herein, we report another Mannich and aryl C(sp2)-H bond functionalization
2

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conversion for efficient synthesis of 2,4-multisubstituted-1,2-dihydroquinoline derivatives
using iodine as an easily available, economical, and environmentally benign catalyst.
2. Results and discussion
The cascade reaction was carried out using p-chloroaniline and ethyl pyruvate as a model
reaction. In initial investigation, various catalysts such as pyrrolidine, proline, [BMIm]HSO4,
[BMIm]Ac, and I2 were screened in MeCN at 30 oC. As can be seen from the summarized results
in Table 1, only iodine could promote the model reaction, giving the desired product in a
moderate yield of 62% (Table 1, entry 5). Therefore, we chose iodine as the catalyst for the
cascade reaction. Then solvent screening was performed to identify the optimal conditions (Table
1, entries 5-13). The reaction media played an important role in the model reaction. Among the
o
tested organic solvents, the highest yield of 62% was obtained in MeCN at 30 C (Table 1, entry
5). When the reaction was performed in EtOH, ethyl acetate, MTBE, or solvent-free respectively,
the yields were slightly inferior to the results in MeCN. The reaction in MeOH and THF only gave
product in low yields of 10% and 20% respectively (Table 1, entries 9 and 11). We did not get the
desired product in water (Table 1, entry 7), and only a low yield of 20% was obtained in
water/EtOH (1:1) (Table 1, entry 8). Thus, MeCN was chosen as the solvent for the further
investigation.
Table 1
The screening of catalysts and solventsa
3

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Entry
1
Catalyst
Solvent
MeCN
Yieldb (%)
pyrrolidine
--
--
2
proline
MeCN
3
[BMIm]HSO4
MeCN
--
4
[BMIm]Ac
MeCN
--
5
I2
I2
I2
I2
I2
I2
I2
I2
I2
MeCN
62
54
--
6
EtOH
7
H2O
8
EtOH/H2O (1:1)
MeOH
20
10
60
20
41
52
9
10
11
12
13
ethyl acetate
THF
MTBE
none
a The reaction was carried out using 1a (0.3 mmol), 2a (1.8 mmol) and catalyst (10 mol %) in solvent (0.5 mL)
at 30 oC for 2 d.
b Isolated yield after silica gel chromatography.
Next, the effects of temperature, molar ratio of substrates and catalyst loading on the model
cascade reaction were investigated (Table 2). As the reaction temperature increased from 30 oC to
o
o
50 C, the yields increased from 62% to 94% (Table 2, entries 1-3), thus 50 C was a desired
temperature for this reaction. Then, the molar ratio (1a:2a) was investigated. The yields were
improved by increasing 2a from 2 to 3 equivalents (Table 2, entries 6 and 7). Further increasing
the equivalents of 2a could not enhance the yields notably (Table 2, entries 8 and 9). Therefore,
the 1:3 molar ratio of p-chloroaniline to ethyl pyruvate was selected as the optimal conditions.
Moreover, the I2 loading was tested from 1 mol % to 10 mol % (Table 2, entries 10-14 and 7). The
satisfactory yield of 96% was obtained when only 3 mol % of I2 was applied (Table 2, entry 12).
Thus, the optimized catalyst loading was set as 3 mol % for further investigation.
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Table 2
Optimization of reaction parametersa
Entry
1
I2 loading
T (oC)
30
Molar ratio (1a:2a)
Yieldb (%)
62c
70
I2ꢀ10%ꢁ
I2ꢀ10%ꢁ
I2ꢀ10%ꢁ
I2ꢀ10%ꢁ
I2ꢀ10%ꢁ
I2ꢀ10%ꢁ
I2ꢀ10%ꢁ
I2ꢀ10%ꢁ
I2ꢀ10%ꢁ
I2ꢀ1%ꢁ
I2ꢀ2%ꢁ
I2ꢀ3%ꢁ
I2ꢀ4%ꢁ
I2ꢀ5%ꢁ
1:6
1:6
1:6
1:6
1:6
1:2
1:3
1:4
1:5
1:3
1:3
1:3
1:3
1:3
2
40
3
50
94
4
60
95
5
70
93
6
50
89
7
50
94
8
50
94
9
50
97
10
11
12
13
14
50
86
50
88
50
96
50
95
50
97
a Unless otherwise indicated, the reaction was carried out using 1a (0.3 mmol), 2a and I2 in MeCN (0.5 mL) for
16 h.
b Isolated yield after silica gel chromatography.
c The reaction time was 2 d.
In order to explore the scope and generality of this iodine-mediated cascade reaction, various
aromatic amines and ketoesters were tested under the optimized conditions (Table 3). A wide
range of substrates could effectively participate in the reaction. Aromatic amines bearing either
electron-donating or electron-withdrawing groups could react with ethyl pyruvate and methyl
pyruvate giving desired products. For example, good to excellent yields were obtained with
non-substituted aromatic amine and substituted aromatic amines containing -Cl, -Br, -OMe, -Me,
or -OH (Table 3, 3a-3g and 3k-3p). However, bearing a strong electro-withdrawing -NO2 group,
p-nitroaniline afforded the desired product 3h in 97% yield in the presence of 10 mol % of I2 at 80
5

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oC (Table 3, 3h). The substituent position of arylamine did not obviously affect the yields. For
instance, both m- and p- bromoaniline gave good to excellent yields with ethyl pyruvate and
methyl pyruvate (Table 3, 3b, 3c, 3l and 3m). It was remarkable that 1-aminonaphthalene and
indoline were successfully introduced to this reaction, and complex tricyclic dihydroquinolines
could be prepared in yields of 43-75% when reacting with ethyl pyruvate and methyl pyruvate
(Table 3, 3i, 3j, 3q and 3r). Besides pyruvates, ethyl 2-oxohexanoate and ethyl
2-oxo-4-phenylbutyrate also could be used as α-ketoesters to react with p-chloroaniline, and the
desired products were obtained in yields of 26% and 21% respectively, in the presence of 10
mol % of I2 at 80 oC (Table 3, 3s and 3t).
Table 3
Iodine-mediated cascade reaction of various aromatic amines and α-ketoesters a,b
6

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a Unless otherwise indicated, the reaction was carried out using arylamine (0.3 mmol), pyruvate (0.9 mmol) and
I2 (3 mol %) in MeCN (0.5 mL) at 50 oC.
b Isolated yield after silica gel chromatography.
c I2 (10 mol %); 80 oC.
d I2 (10 mol %); MeCN (2.0 mL); 60 oC.
e MeCN (1.0 mL); 80 oC.
It is well known that acid can catalyze the cascade reaction of α-ketoesters with arylamines.
18,21
Regarding the role of iodine in the reaction, it is possible that trace amount of HI was
generated during the reaction, which might be the actual catalyst for this tandem process. Thus,
7

ACCEPTED MANUSCRIPT
some controlled experiments were performed by using different amounts of HI (Table 4). It can be
seen that even 0.1 mol % of HI was sufficient to catalyze the model reaction of p-chloroaniline
and ethyl pyruvate giving the product in a good yield of 86% at 50 oC after 12 h (Table 4, entry 2).
Therefore, we speculated that the trace amount of HI generated from I2 during the reaction may be
responsible for the cascade reaction.
Table 4
Control experiments using hydrogen iodide as a catalyst a
Entry
HI loading (mol %)
Yieldb (%)
1
2
3
4
5
6
0
0.1
0.5
1
0
86
95
95
97
96
2
3
a The reaction was carried out using 1a (0.3 mmol), 2a (0.9 mmol) in MeCN (0.5 mL) at 50 oC for 12 h.
b Isolated yield after silica gel chromatography.
Finally, based on the previous reports18-21 and some control experiments, we inferred that the
cascade reaction may be catalyzed by trace amount of HI generated from I2 during the reaction,
and this tandem process followed a reaction pathway similar to Brønsted acid-catalyzed cascade
reaction of α-ketoesters with arylamines proposed by Ji et al. 18 The process includes the formation
of intermediate imine, the Mannich reaction between α-ketoester and the imine, the intramolecular
aryl C(sp2)-H bond functionalization, and the elimination of water. The formation of intermediate
imine could be confirmed by isolating the imine 4d from control experiment in which 1d reacted
8

ACCEPTED MANUSCRIPT
with 2a in the absence of catalyst (Scheme 2). And the reaction pathway through intermediate
imine could be further verified by the control experiment in which imine 4d instead of same
equivalent of arylamine 1d and pyruvate 2a was used to react directly with another pyruvate 2a
giving the desired product 3d (Scheme 2). Moreover, the formation of un-dehydrated intermediate
was proved by isolating 6h from the reaction of 1h with 2a under the optimized conditions
(Scheme 2).
Scheme 2 Control experiments.
Yields refer to isolated products after silica gel chromatography.
3. Conclusion
An economical and environmentally benign iodine-mediated cascade reaction between
α-ketoesters and aromatic amines to prepare polysubstituted 1,2-dihydroquinolines was developed
under mild conditions. A series of substituted dihydroquinolines including complex tricyclic
dihydroquinolines could be conveniently obtained from simple and readily available starting
9

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materials. This protocol avoids the use of exorbitant metallic reagents, strong corrosive acids, and
complex catalysts prepared by multi-step synthesis. In the present method only 3 mol % of iodine
could promote the reaction effectively, and a wide range of arylamines could participate in this
cascade reaction with ethyl pyruvate or methyl pyruvate. Besides pyruvates, α-ketoesters ethyl
2-oxohexanoate and ethyl 2-oxo-4-phenylbutyrate also could be used in this reaction. These
advantages provide a potential possibility for application in industry and academia.
4. Experimental section
4.1 General
The NMR spectra were recorded with TMS as the internal standard in CDCl3 on a Bruker
300 MHz instrument at room temperature. All reactions were monitored by thin-layer
chromatography (TLC) with Haiyang GF254 silica gel plates. Flash column chromatography was
carried out using 200-300 mesh silica gel at increased pressure. All chemical reagents and solvents
were purchased from commercial vendors. They were used without any further purification.
4.2 Experiments
General procedure for the iodine-mediated cascade reaction of
α-ketoesters and arylamines:
A round-bottomed flask was charged with arylamine (0.3 mmol), pyruvate (0.9 mmol),
iodine (3 mol %) and MeCN (0.50 mL). The resultant mixture was stirred for a specified time at
50 °C. Upon completion of the reaction (monitored by TLC), the solvents were removed by rotary
evaporation and the mixture was purified by column chromatography, eluted with petroleum ether
and ethyl acetate to afford the desired product.
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4.3 Characterization Data
1
4.3.1 Diethyl 6-chloro-2-methyl-1,2-dihydroquinoline-2,4-dicarboxylate (3a). Yellow oil; H
NMR (300 MHz, CDCl3): δ = 1.27 (t, J = 7.1 Hz, 3H), 1.38 (t, J = 7.1 Hz, 3H), 1.55 (s, 3H),
4.11-4.26 (m, 2H), 4.30-4.37 (m, 2H), 4.53 (brs, 1H), 6.56 (d, J = 8.5 Hz, 1H), 6.74 (s, 1H), 7.02
13
(dd, J = 2.4, 8.5 Hz, 1H), 7.86 (d, J = 2.2 Hz, 1H); C NMR (75 MHz, CDCl3): δ = 14.1, 14.2,
27.2, 58.5, 61.2, 61.9, 115.2, 117.6, 123.2, 126.3, 127.4, 129.2, 133.9, 141.1, 165.2, 173.5. 18-20
4.3.2 Diethyl 6-bromo-2-methyl-1,2-dihydroquinoline-2,4-dicarboxylate (3b). Yellow oil; 1H
NMR (300 MHz, CDCl3): δ = 1.26 (t, J = 7.1 Hz, 3H), 1.38 (t, J = 7.1 Hz, 3H), 1.54 (s, 3H),
4.13-4.25 (m, 2H), 4.29-4.36 (m, 2H), 4.58 (brs, 1H), 6.52 (d, J = 8.5 Hz, 1H), 6.72 (s, 1H), 7.15
(dd, J = 2.0, 8.5 Hz, 1H), 7.99 (d, J = 1.9 Hz, 1H); 13C NMR (75 MHz, CDCl3): δ = 14.1, 14.2,
27.2, 58.5, 61.2, 61.9, 110.3, 115.6, 118.1, 127.2, 129.1, 132.0, 133.8, 141.6, 165.2, 173.4. 20
4.3.3 Diethyl 7-bromo-2-methyl-1,2-dihydroquinoline-2,4-dicarboxylate (3c). Yellow oil; 1H
NMR (300 MHz, CDCl3): δ = 1.26 (t, J = 7.1 Hz, 3H), 1.35 (t, J = 7.1 Hz, 3H), 1.53 (s, 3H),
4.13-4.26 (m, 2H), 4.27-4.34 (m, 2H), 4.63 (brs, 1H), 6.68 (d, J = 1.3 Hz, 1H), 6.77 (d, J = 1.8 Hz,
1H), 6.80 (dd, J = 1.9, 8.4 Hz, 1H), 7.68 (d, J = 8.4 Hz, 1H); 13C NMR (75 MHz, CDCl3): δ = 14.1,
14.2, 27.4, 58.6, 61.1, 62.0, 115.3, 116.7, 121.3, 123.2, 127.6, 127.9, 132.8, 143.8, 165.4, 173.4.
18,19
4.3.4 Diethyl 6-methoxy-2-methyl-1,2-dihydroquinoline-2,4-dicarboxylate (3d). Yellow oil; 1H
NMR (300 MHz, CDCl3): δ = 1.25 (t, J = 7.1 Hz, 3H), 1.38 (t, J = 7.1 Hz, 3H), 1.54 (s, 3H), 3.75
(s, 1H), 4.11-4.25 (m, 2H), 4.29-4.37 (m, 2H), 4.38 (brs, 1H), 6.60 (d, J = 8.6 Hz, 1H), 6.71 (dd, J
11

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= 2.7, 8.7 Hz, 1H), 6.75 (s, 1H), 7.49 (d, J = 2.6 Hz, 1H); 13C NMR (75 MHz, CDCl3): δ = 14.1,
14.2, 26.7, 55.6, 58.5, 61.0, 61.7, 111.4, 115.1, 116.2, 117.5, 128.1, 134.1, 136.7, 152.5, 165.7,
174.1. 18-20
4.3.5 Diethyl 2,6-dimethyl-1,2-dihydroquinoline-2,4-dicarboxylate (3e). Yellow oil; 1H NMR (300
MHz, CDCl3): δ = 1.26 (t, J = 7.1 Hz, 3H), 1.38 (t, J = 7.1 Hz, 3H), 1.53 (s, 3H), 2.23 (s, 3H),
4.11-4.24 (m, 2H), 4.29-4.36 (m, 2H), 4.43 (brs, 1H), 6.55 (d, J = 8.0 Hz, 1H), 6.65 (s, 1H), 6.90
(d, J = 7.7 Hz, 1H), 7.60 (s, 1H); 13C NMR (75 MHz, CDCl3): δ = 14.1, 14.2, 20.7, 27.0, 58.4,
60.9, 61.7, 114.2, 116.6, 126.7, 127.7, 128.4, 130.1, 132.7, 140.3, 165.9, 174.0. 19,20
4.3.6 Diethyl 2-methyl-1,2-dihydroquinoline-2,4-dicarboxylate (3f). Yellow oil; 1H NMR (300
MHz, CDCl3): δ = 1.19 (t, J = 7.1 Hz, 3H), 1.30 (t, J = 7.1 Hz, 3H), 1.47 (s, 3H), 4.05-4.18 (m,
2H), 4.22-4.29 (m, 2H), 4.46 (brs, 1H), 6.54 (d, J = 8.0 Hz, 1H), 6.59 (s, 1H), 6.65 (t, J = 7.5 Hz,
1H), 7.00 (t, J = 7.4 Hz, 1H), 7.70 (d, J = 7.8 Hz, 1H); 13C NMR (75 MHz, CDCl3): δ = 14.1, 14.2,
27.3, 58.4, 61.0, 61.8, 114.2, 116.5, 118.5, 126.4, 128.4, 129.5, 132.5, 142.6, 165.8, 173.9. 18-20
1
4.3.7 Diethyl 6-hydroxy-2-methyl-1,2-dihydroquinoline-2,4-dicarboxylate (3g). Yellow oil; H
NMR (300 MHz, CDCl3): δ = 1.25 (t, J = 7.1 Hz, 3H), 1.36 (t, J = 7.1 Hz, 3H), 1.54 (s, 3H),
4.11-4.24 (m, 2H), 4.27-4.33 (m, 2H), 5.67 (brs, 1H), 6.54 (d, J = 8.5 Hz, 1H), 6.63 (dd, J = 2.7,
13
8.5 Hz, 1H), 6.74 (s, 1H), 7.44 (d, J = 2.6 Hz, 1H); C NMR (75 MHz, CDCl3): δ = 14.0, 14.1,
26.6, 58.5, 61.2, 61.8, 113.2, 115.3, 116.8, 117.6, 127.9, 134.4, 136.4, 148.5, 165.8, 174.4. 18
1
4.3.8 Diethyl 2-methyl-6-nitro-1,2-dihydroquinoline-2,4-dicarboxylate (3h). Yellow solid; H
NMR (300 MHz, CDCl3): δ = 1.28 (t, J = 7.1 Hz, 3H), 1.39 (t, J = 7.1 Hz, 3H), 1.60 (s, 3H),
12

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4.17-4.29 (m, 2H), 4.32-4.39 (m, 2H), 5.35 (brs, 1H), 6.58 (d, J = 8.9 Hz, 1H), 6.76 (s, 1H), 7.96
13
(dd, J = 2.3, 8.9 Hz, 1H), 8.82 (d, J = 2.0 Hz, 1H); C NMR (75 MHz, CDCl3): δ = 14.0, 14.1,
28.4, 59.2, 61.6, 62.4, 113.1, 114.4, 123.4, 126.0, 126.7, 133.3, 138.9, 147.9, 164.7, 172.4. 18
4.3.9 Diethyl 2-methyl-1,2-dihydrobenzo[h]quinoline-2,4-dicarboxylate (3i). Reddish brown oil;
1H NMR (300 MHz, CDCl3): δ = 1.28 (t, J = 7.1 Hz, 3H), 1.41 (t, J = 7.1 Hz, 3H), 1.62 (s, 3H),
4.16-4.28 (m, 2H), 4.34-4.41 (m, 2H), 5.36 (brs, 1H), 6.68 (d, J = 1.6 Hz, 1H), 7.23 (d, J = 8.7 Hz,
1H), 7.44-7.47 (m, 2H), 7.73-7.77 (m, 1H), 7.85-7.88 (m, 1H), 7.91 (d, J = 8.8 Hz, 1H); 13C NMR
(75 MHz, CDCl3): δ = 14.1, 14.2, 27.2, 58.6, 61.1, 61.9, 111.3, 117.7, 120.0, 122.2, 124.0, 125.1,
126.4, 128.5, 129.3, 130.1, 134.2, 137.9, 166.2, 173.9. 19,20
4.3.10 Diethyl 4-methyl-2,4-dihydro-1H-pyrrolo[3,2,1-ij]quinoline-4,6-dicarboxylate (3j). Yellow
1
oil; H NMR (300 MHz, CDCl3): δ = 1.15 (t, J = 7.1 Hz, 3H), 1.29 (t, J = 7.1 Hz, 3H), 1.56 (s,
3H), 2.88-3.09 (m, 2H), 3.43-3.52 (m, 2H), 4.06-4.13 (m, 2H), 4.20-4.28 (m, 2H), 6.35 (s, 1H),
13
6.50 (t, J = 7.6 Hz, 1H), 6.87 (d, J = 7.2 Hz, 1H), 7.51 (d, J = 7.9 Hz, 1H); C NMR (75 MHz,
CDCl3): δ = 14.1, 14.2, 22.6, 28.1, 47.4, 60.9, 61.4, 63.3, 112.7, 117.7, 123.5, 125.0, 126.3, 128.1,
133.3, 148.2, 165.5, 171.4. 19
1
4.3.11 Dimethyl 6-chloro-2-methyl-1,2-dihydroquinoline-2,4-dicarboxylate (3k). Yellow oil; H
NMR (300 MHz, CDCl3): δ = 1.55 (s, 3H), 3.74 (s, 3H), 3.86 (s, 3H), 4.58 (brs, 1H), 6.56 (d, J =
13
8.5 Hz, 1H), 6.74 (s, 1H), 7.02 (dd, J = 2.3, 8.5 Hz, 1H), 7.86 (d, J = 2.3 Hz, 1H); C NMR (75
MHz, CDCl3): δ = 27.3, 52.2, 52.9, 58.6, 115.2, 117.5, 123.3, 126.3, 127.1, 129.3, 134.0, 141.1,
165.5, 174.1. 18
13

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1
4.3.12 Dimethyl 6-bromo-2-methyl-1,2-dihydroquinoline-2,4-dicarboxylate (3l). Yellow solid; H
NMR (300 MHz, CDCl3): δ = 1.54 (s, 3H), 3.73 (s, 3H), 3.84 (s, 3H), 4.60 (brs, 1H), 6.50 (d, J =
13
8.5 Hz, 1H), 6.71 (s, 1H), 7.14 (dd, J = 2.1, 8.5 Hz, 1H), 7.97 (d, J = 2.1 Hz, 1H); C NMR (75
MHz, CDCl3): δ = 27.3, 52.2, 52.9, 58.5, 110.4, 115.6, 117.9, 127.0, 129.0, 132.2, 134.0, 141.5,
165.5, 174.0. 20
1
4.3.13 Dimethyl 7-bromo-2-methyl-1,2-dihydroquinoline-2,4-dicarboxylate (3m). Yellow oil; H
NMR (300 MHz, CDCl3): δ = 1.55 (s, 3H), 3.75 (s, 3H), 3.85 (s, 3H), 4.65 (brs, 1H), 6.70 (s, 1H),
13
6.78 (d, J = 1.8 Hz, 1H), 6.82 (dd, J = 1.9, 8.4 Hz, 1H), 7.69 (d, J = 8.4 Hz, 1H); C NMR (75
MHz, CDCl3): δ = 27.5, 52.1, 52.9, 58.6, 115.1, 116.7, 121.4, 123.3, 127.4, 127.9, 132.9, 143.7,
165.7, 174.0. 18,19
4.3.14 Dimethyl 6-methoxy-2-methyl-1,2-dihydroquinoline-2,4-dicarboxylate (3n). Yellow oil; 1H
NMR (300 MHz, CDCl3): δ = 1.55 (s, 3H), 3.73 (s, 3H), 3.75 (s, 3H), 3.86 (s, 3H), 4.36 (brs, 1H),
6.58 (d, J = 8.6 Hz, 1H), 6.72 (dd, J = 2.8, 8.7 Hz, 1H), 6.75 (s, 1H), 7.50 (d, J = 2.8 Hz, 1H); 13C
NMR (75 MHz, CDCl3): δ = 26.8, 52.0, 52.7, 55.7, 58.5, 111.5, 115.1, 116.2, 117.4, 127.8, 134.2,
136.6, 152.5, 166.0, 174.7. 18
1
4.3.15 Dimethyl 2,6-dimethyl-1,2-dihydroquinoline-2,4-dicarboxylate (3o). Yellow oil; H NMR
(300 MHz, CDCl3): δ = 1.54 (s, 3H), 2.23 (s, 3H), 3.72 (s, 3H), 3.85 (s, 3H), 4.44 (brs, 1H), 6.55
(d, J = 8.0 Hz, 1H), 6.66 (s, 1H), 6.90 (dd, J = 1.1, 8.0 Hz, 1H), 7.60 (s, 1H); 13C NMR (75 MHz,
CDCl3): δ = 20.7, 27.1, 52.0, 52.7, 58.4, 114.2, 116.4, 126.7, 127.8, 128.2, 130.3, 132.9, 140.2,
166.2, 174.6. 19,20
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4.3.16 Dimethyl 2-methyl-1,2-dihydroquinoline-2,4-dicarboxylate (3p). Yellow oil; 1H NMR (300
MHz, CDCl3): δ = 1.55 (s, 3H), 3.72 (s, 3H), 3.85 (s, 3H), 4.57 (brs, 1H), 6.62 (d, J = 8.0 Hz, 1H),
6.66 (s, 1H), 6.72 (t, J = 7.4Hz, 1H), 7.07 (t, J = 7.6 Hz, 1H), 7.79 (dd, J = 0.9, 7.9 Hz, 1H); 13C
NMR (75 MHz, CDCl3): δ = 27.4, 52.0, 52.7, 58.5, 114.2, 116.3, 118.6, 126.4, 128.2, 129.6, 132.7,
142.6, 166.1, 174.4. 18
4.3.17 Dimethyl 2-methyl-1,2-dihydrobenzo[h]quinoline-2,4-dicarboxylate (3q). Reddish brown
oil; 1H NMR (300 MHz, CDCl3): δ = 1.64 (s, 3H), 3.77 (s, 3H), 3.90 (s, 3H), 5.36 (brs, 1H), 6.70
(d, J = 1.5 Hz, 1H), 7.24 (d, J = 8.8 Hz, 1H), 7.44-7.47 (m, 2H), 7.74-7.78 (m, 1H), 7.85-7.89 (m,
1H), 7.90 (d, J = 8.8Hz, 1H); 13C NMR (75 MHz, CDCl3): δ = 27.3, 52.1, 52.9, 58.6, 111.1, 117.8,
120.0, 122.2, 124.0, 125.2, 126.4, 128.6, 129.0, 130.3, 134.2, 137.9, 166.5, 174.5. 19,10
4.18 Dimethyl 4-methyl-2,4-dihydro-1H-pyrrolo[3,2,1-ij]quinoline-4,6-dicarboxylate (3r). Yellow
oil; 1H NMR (300 MHz, CDCl3): δ = 1.64 (s, 3H), 2.98-3.14 (m, 2H), 3.50-3.62 (m, 2H), 3.71 (s,
3H), 3.84 (s, 3H), 6.42 (s, 1H), 6.57 (t, J = 7.6 Hz, 1H), 6.95 (d, J = 7.2 Hz, 1H), 7.60 (d, J = 7.7
13
Hz, 1H); C NMR (75 MHz, CDCl3): δ = 22.8, 28.1, 47.4, 51.9, 52.5, 63.3, 112.5, 117.8, 123.5,
125.2, 126.4, 127.8, 133.3, 148.0, 165.8, 171.8. 19
4.3.19 Diethyl 2-butyl-6-chloro-3-propyl-1,2-dihydroquinoline-2,4-dicarboxylate (3s). Yellow oil;
1H NMR (300 MHz, CDCl3): δ = 0.87-0.95 (m, 6H), 1.23-1.44 (m, 10H), 1.44-1.55 (m, 2H),
1.88-1.93 (m, 2H), 2.20-2.37 (m, 2H), 4.12-4.23 (m, 2H), 4.31-4.41 (m, 3H), 6.52 (d, J = 4.2 Hz,
1H), 6.89-7.00 (m, 1H), 7.24-7.35 (m, 1H); 13C NMR (75 MHz, CDCl3): δ = 13.9, 14.0, 14.2, 14.6,
22.7, 23.3, 25.8, 32.9, 36.0, 61.2, 61.7, 64,8, 114.7, 119.2, 124.1, 122.9, 128.5, 129.0, 136.0, 140.1,
167.9, 172.8. 19
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4.3.20 Diethyl 3-benzyl-6-chloro-2-phenethyl-1,2-dihydroquinoline-2,4-dicarboxylate (3t). Yellow
1
oil; H NMR (300 MHz, CDCl3): δ =1.11 (t, J = 7.1 Hz, 3H), 1.19 (t, J = 7.1 Hz, 3H), 2.13-2.21
(m, 2H), 2.52-2.57 (m, 2H), 3.71-3.84 (m, 4H), 4.12-4.25 (m, 2H), 4.42 (brs, 1H), 6.48 (d, J = 4.2
Hz, 1H), 6.99-7.01 (m, 3H), 7.15-7.32 (m, 10H); 13C NMR (75 MHz, CDCl3): δ = 13.8, 13.9, 30.0,
36.2, 37.8, 61.4, 61.9, 64.9, 115.2, 118.9, 119.7, 121.9, 123.1, 124.5, 126.1, 126.4, 128.2, 128.2,
128.4, 128.7, 129.1, 131.1, 132.4, 137.8, 140.0, 140.8, 167.6, 171.8. 19
1
4.3.21 (Z)-ethyl 2-((4-methoxyphenyl)imino)propanoate (4d). Yellow oil; H NMR (300 MHz,
CDCl3): δ = 1.40 (t, J = 7.1 Hz, 3H), 2.14 (s, 3H), 3.81 (s, 3H), 4.36-4.43 (m, 2H), 6.80 (d, J =
28.6 Hz, 2H), 6.90 (d, J = 8.6 Hz, 2H); 13C NMR (75 MHz, CDCl3): δ = 14.0, 21.4, 62.0, 68.8,
105.7, 118.6, 128.2, 134.4, 154.5, 158.6, 167.7, 171.6. 19
4.3.22 Diethyl 4-hydroxy-2-methyl-6-nitro-1,2,3,4-tetrahydroquinoline-2,4-dicarboxylate (6h).
Yellow solid; 1H NMR (300 MHz, CDCl3): δ = 1.23 (t, J = 7.1 Hz, 3H), 1.29 (t, J = 7.1 Hz, 3H),
1.60 (s, 3H), 2.36 (d, J = 13.8 Hz, 1H), 2.74 (d, J = 15.2 Hz, 1H), 3.70 (brs, 1H), 4.12-4.19 (m,
2H), 4.30-4.37 (m, 2H), 5.36 (brs, 1H), 6.67 (d, J = 9.0 Hz, 1H), 7.87 (d, J = 2.3 Hz, 1H), 8.00 (dd,
J = 2.4, 9.0 Hz, 1H); 13C NMR (75 MHz, CDCl3): δ = 14.0, 27.1, 41.2, 55.6, 61.7, 63.0, 72.0,
114.6, 119.8, 124.2, 125.9, 138.4, 148.9, 174.2. 19
Acknowledgements
This work was financially supported by the National Natural Science Foundation of China (No.
21276211).
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References
1. Craig, J. C.; Pearson, D. E.; Potential antimalarials. J. Med. Chem. 1971, 14, 1221.
2. Dillard, R. D.; Pavey, D. E.; Benslay, D. N. J. Med. Chem. 1973, 16, 251.
3. Johnson, J. V.; Rauckman, B. S.; Baccanari, D. P.; Roth, B. J. Med. Chem. 1989, 32, 1942.
4. Theeraladanon, C.; Arisawa, M.; Nakagawa, M.; Nishida, A. Tetrahedron: Asymmetry. 2005, 16, 827.
5. Abe, F.; Yamauchi, T.; Shibuya, H.; Kitagawa, I.; Yamashita, M. Chem. Pharm. Bull. 1998, 46, 1235.
6. Balayer, A.; Sévenet, T.; Schaller, H.; Hadi, A. H. A.; Chiaroni, A.; Riche, C.; Païs, M. Nat. Prod. Lett. 1993, 2,
61.
7. Sangnoi, Y.; Sakulkeo, O.; Yuenyongsawad, S.; Kanjana-opas, A.; Ingkaninan, K.; Plubrukarn, A.;
Suwanborirux, K. Mar Drugs. 2008, 6, 578.
8. Söderholm, A. A.; Lehtovuori, P. T.; Nyrönen, T. H. J. Med. Chem. 2006, 49, 4261.
9. Fotie, J.; Kaiser, M.; Delfín, D. A.; Manley, J.; Reid, C. S.; Paris, J.-M.; Wenzler, T.; Maes, L.; Mahasenan, K. V.;
Li, C.; Werbovetz, K. A. J. Med. Chem. 2010, 53, 966.
10. Yi, C. S.; Yun, S. Y.; Guzei, I. A. J. Am. Chem. Soc. 2005, 127, 5782.
11. Yi, C. S.; Yun, S. Y. J. Am. Chem. Soc. 2005, 127, 17000.
12. Luo, Y.; Li, Z.; Li, C.-J. Org. Lett. 2005, 7, 2675.
13. Liu, X.-Y.; Ding, P.; Huang, J.-S.; Che, C.-M. Org. Lett. 2007, 9, 2645.
14. M.-E.; Robinson, L. A. Tetrahedron Lett. 2002, 43, 3907.
15. Kamakshi, R.; Reddy, B. S. R. Catal. Commun. 2007, 8, 825.
16. Lee, S. H.; Park, Y. S.; Nam, M. H.; Yoon, C. M. Org. Biomol. Chem. 2004, 2, 2170.
17. Waldmann, H.; Karunakar, G. V.; Kumar, K. Org. Lett. 2008, 10, 2159.
18. Hu, X.-Y.; Zhang, J.-C.; Wei, W.; Ji, J.-X. Tetrahedron Lett. 2011, 52, 2903.
19. Zhang, J.-C.; Ji, J.-X. ACS Catal. 2011, 1, 1360.
20. Zhu, Y.-W.; Qian, J.-L.; Yi, W.-B.; Cai, C. Tetrahedron Lett. 2013, 54, 638.
21. Tapia, I; Alcazar, V; Grande, M; Moran, J. R. Tetrahedron. 1988, 44, 5113.
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Graphical Abstract
Highly Efficient Synthesis of Polysubstituted 1,2-Dihydroquinolines via Cascade
Reaction of α-Ketoesters with Arylamines Mediated by Iodine
Bao-Qiang Zhang, Yuan Luo, Yan-Hong He*, and Zhi Guan*
School of Chemistry and Chemical Engineering, Southwest University, Chongqing, 400715, P. R. China
Fax: +86-23-68254091; e-mail: heyh@swu.edu.cn for Y-H He; guanzhi@swu.edu.cn for Z. Guan
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Supporting Information
Highly Efficient Synthesis of Polysubstituted
1,2-Dihydroquinolines via Cascade Reaction of α-Ketoesters
with Arylamines Mediated by Iodine
Bao-Qiang Zhang, Yuan Luo, Yan-Hong He*, and Zhi Guan*
School of Chemistry and Chemical Engineering, Southwest University, Chongqing, 400715, P. R. China
Fax: +86-23-68254091; e-mail: heyh@swu.edu.cn for Y-H He; guanzhi@swu.edu.cn for Z. Guan
Table of Contents
1. Experiments
2-3
2. The 1H, 13C NMR Spectra of the Products
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1. Experiments
1.1 The reaction of 1d and 2a in the absence of catalyst:
A round-bottomed flask was charged with p-methoxyaniline 1d (1.0 mmol), ethyl pyruvate
2a (1.5 mmol), and MeCN (1.5 mL). The resultant mixture was stirred at 50 °C for 0.5 h. Then the
solvents were removed by rotary evaporation to provide a crude product, which was purified by
flash chromatography on aluminium oxide (petroleum ether/ethyl acetate, 15:1) to give imine 4d
(109 mg, 49%) as yellow oil.
1.2 The reaction of imine 4d with 2a:
A round-bottomed flask was charged with imine 4d (0.3 mmol), ethyl pyruvate 2a (0.6 mmol),
iodine (3 mol %), and MeCN (0.5 mL). The reaction mixture was stirred at 50 °C for 19 h. After
completion of the reaction, the solvents were removed by rotary evaporation to provide a crude
product, which was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate,
9:1) to give the desired product 3d (92%) as yellow oil.
1.3 The reaction of p-nitroaniline 1h with ethyl pyruvate 2a:
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A round-bottomed flask was charged with p-nitroaniline 1h (0.3 mmol), ethyl pyruvate 2a (0.9
mmol), iodine (3 mol %) and MeCN (0.50 mL). The resultant mixture was stirred at 50 °C for 18 h.
The mixture was purified by column chromatography, eluted with petroleum ether and ethyl
acetate (5:1-3:1) to afford 6h (45 mg, 43%) and 3h (20 mg, 20%).
1.4 The time course of the iodine-mediated cascade reaction
The time course of the iodine-mediated cascade reaction was investigated (Figure S1). The
yield increased as the reaction time prolonged and reached its peak (95%) at 12 h.
Figure S1. Time course of the reaction.a
a
The reaction was carried out using p-chloroaniline (0.3 mmol), ethyl pyruvate (0.9 mmol) and I2 (3 mol %) in
MeCN (0.5 mL) at 50 oC. The yield refers to isolated product after silica gel chromatography.
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2. The 1H and 13C NMR Spectra of the Products
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