Iron-catalyzed three-component tandem process: A novel and convenient synthetic route to quinoline-2,4-dicarboxylates from arylamines, glyoxylic esters, and α-ketoesters

Article abstract of DOI:10.1016/j.tet.2013.10.025

A new and convenient iron-catalyzed three-component tandem reaction of aromatic amines, glyoxylic esters, and α-ketoesters has been developed for the synthesis of quinoline-2,4-dicarboxylates under mild conditions. The present protocol, which utilizes che

Full text of DOI:10.1016/j.tet.2013.10.025

Tetrahedron 69 (2013) 10747e10751
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Iron-catalyzed three-component tandem process: a novel and
convenient synthetic route to quinoline-2,4-dicarboxylates from
arylamines, glyoxylic esters, and
a-ketoesters
,
,
,
,
,b,c,
*
Wei Wei a b, Jiangwei Wen a b, Daoshan Yang a b, Xuejun Sun a b, Jinmao You a
,
Yourui Suo c, Hua Wang a
,b,
*
a The Key Laboratory of Life-Organic Analysis, Qufu Normal University, Qufu 273165, Shandong, China
b Key Laboratory of Pharmaceutical Intermediates and Analysis of Natural Medicine, Qufu Normal University, Qufu 273165, Shandong, China
c Key Laboratory of Evolution and Adaptation of Plateau Biota, Northwest Institute of Plateau Biology, Chinese Academy of Sciences, Xining 810001,
China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 7 July 2013
Received in revised form 24 September 2013
Accepted 10 October 2013
Available online 17 October 2013
A new and convenient iron-catalyzed three-component tandem reaction of aromatic amines, glyoxylic
esters, and a-ketoesters has been developed for the synthesis of quinoline-2,4-dicarboxylates under mild
conditions. The present protocol, which utilizes cheap catalysts, readily-available starting materials and
mild reaction conditions, provides an attractive approach to a series of functionalized quinoline de-
rivatives with promising unique pharmaceutical, biological, and fluorescence-labeling applications.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Iron catalysis
Tandem reaction
Arylamines
a
-Ketoesters
Glyoxylic esters
Quinoline-2,4-dicarboxylates
1. Introduction
condensation of dimethyl ketoglutaconate (DKG) with substituted
anilines.2e4 Alternatively, the selective conjugate reaction of the
Quinolines and their derivatives are ubiquitous in various nat-
ural products, and many of them have been widely recognized as
important structural motifs to design tremendous synthetic drug
candidates since they possess a broad spectrum of biological
properties of antimalarials, antibacterial, antipsychotic activity,
antiinflammatory, anticancer, anti-HIV, and antituberculosis, etc.1
In particular, quinoline-2,4-dicarboxylate derivatives are of great
importance as pharmaceutical and synthetic materials, because
their carboxyl groups could additionally play a pivotal role in
endowing the unique bioactivities of quinolines.2 For example,
quinoline 2,4-dicarboxylic acids (QDCs) I and II can be used as in-
hibitors against the vesicular glutamate transport (VGLUT) protein
(Fig. 1).2a,b Compounds III were discovered to be promising moie-
ties of new fluorescent tags for monitoring of biomolecules (Fig.1).3
Generally, quinoline-2,4-dicarboxylates were synthesized by
preformed N-arylphosphazenes to a,b-unsaturated carbonyl com-
pounds has also been developed.5 However, both methods suffer
from some disadvantages, such as the need of extra steps to prepare
active starting materials, a large amount of promoters, the low
yield. Therefore, the development of simple, convenient, efficient
and, especially, environmentally friendly synthetic methodologies
for the construction of quinoline-2,4-dicarboxylates still remains
highly desirable.
a
modified Doebnerevon Miller pathway prepared by the
* Corresponding authors. Tel./fax: þ86 537 4458317; e-mail addresses:
Fig. 1. Structures of some biologically important quinoline-2,4-dicarboxylate
derivatives.
jmyou6304@163.com (J. You), huawang_qfnu@126.com (H. Wang).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.10.025

10748
W. Wei et al. / Tetrahedron 69 (2013) 10747e10751
Table 1 (continued)
Recently, iron salts as an alternative and promising transition-
metal catalysts, have drawn much attention for various organic
transformations and synthesis of heterocyclic compounds due to
their cost-effectiveness, ready availability, sustainability, and en-
vironmentally friendly properties.6,7 Over the past few years, sev-
eral examples of iron-catalyzed coupling reactions for the
construction of quinoline compounds have been reported.8e11 For
example, Fan et al. described an iron-catalyzed A3-reaction of al-
dehydes, amines, and alkynes via a tandem process for preparing
2,4-disubstituted quinolines.9 Li et al. reported an iron-catalyzed
cascade reaction of ynone with o-aminoaryl compounds leading
to 3-carbonyl quinolines.10 Wang et al. presented the iron-
promoted (25 mol %) tandem reaction of anilines with styrene
oxides for the synthesis of 3-substituted quinolines.11 However,
quinoline-2,4-dicarboxylates could not be afforded by the reported
iron-catalyzed procedures. Herein, we wish to report a new and
convenient iron-catalyzed three-component tandem reaction of
Entry
Catalyst (mol %)
Solvent
Yield (%)b
11
12
13
14
15
16
17
18
19
20
21
22
FeCl3 (5)
FeCl3 (2)
FeCl3 (1)
FeCl3 (5)
FeCl3 (5)
FeCl3 (5)
FeCl3 (5)
FeCl3 (5)
FeCl3 (5)
FeCl3 (5)
FeCl3 (5)
FeCl3 (5)
CH3CN
CH3CN
CH3CN
Toluene
1,4-Dioxane
DME
DMSO
CH2Cl2
EtOAc
88
79
76
60
62
64
40
65
45
60
40
72c
THF
CH3OH
CH3CN
a
Reaction conditions: 1a (0.5 mmol), 2a (0.55 mmol), 3a (0.75 mmol), catalyst
(1e10 mol %), CH3CN (3 mL), room temperature, under air, 30 h.
b
Isolated yields based on 1a.
60 ꢀC, 12 h.
c
of catalyst (Table 1, entry 1). The screening of a range of solvents
using FeCl3 as catalyst demonstrated that CH3CN was the optimal
reaction medium while others, such as toluene, 1,4-dioxane, DME,
DMSO, CH2Cl2, EtOAc, THF, and CH3OH gave lower yields of the
quinolines (entries 14e21). Moreover, the reaction was accelerated
when the model reaction was carried out under 60 ꢀC, but the yield
was not improved as expected (Table 1, entry 22).
aromatic amines, glyoxylic esters, and
a-ketoesters for the con-
struction of a serial of quinoline-2,4-dicarboxylates under mild
conditions (Scheme 1). The present protocol provides an attractive
and environmentally friendly approach to a variety of functional-
ized quinoline-2,4-dicarboxylates in
procedure.
a simple and one-pot
Under the optimized conditions, the scope and generality of this
process were tested with respect to various aromatic amines, and
a series of substituted quinoline-2,4-dicarboxylates were obtained
in moderate to good yields (Table 2). Both electron-rich and
electron-withdrawing aromatic amines were suitable for this pro-
tocol. In general, aromatic amines containing electron-rich groups
showed the better activities than those bearing electron-
withdrawing groups (4ael). Long chain alkyl substituted aromatic
amine, such as 4-butylaniline and cycloalkyl substituted aromatic
amine, such as 4-cyclohexylaniline could be transformed into the
desired products in 72% and 71% yields, respectively, (4e and f). It is
noteworthy that a wide range of functionalities, such as halogen,
hydroxyl, cyano, and carbonyl groups were compatible with this
reaction leading to the products 4gel, which could be used for
further transformations. Furthermore, (2S, 5R)-2-isopropyl-5-
methylcyclohexyl 2-oxoacetate was also compatible with this re-
Scheme 1. Iron-catalyzed three-component reaction for the synthesis of quinoline-
2,4-dicarboxylates.
2. Results and discussion
Initially, the reaction for the synthesis of quinoline-2,4-
dicarboxylate 4a from p-anisidine 1a, ethyl glyoxylate 2a, and
methyl pyruvate 3a was conducted to examine the catalytic activity
of various simple metal complexes, such as Cu, Ag, Bi, Pd, Zn, Fe, and
In salts (10 mol %) in CH3CN at room temperature. As shown in
Table 1, among various metal salts screened, FeCl3 was found to be
the most effective catalyst that afforded the desired product 4a in
88% yield (Table 1, entry 8). Further optimization showed that FeCl3
could still maintain high activity even when the catalyst loading
was reduced to 5 mol % (Table 1, entry 11). A relatively lower yield
was obtained with the further reduction of the catalyst loading
(Table 1, entries 12 and 13). No product was observed in the absence
action, affording the desired product 4n in 62% yield. In addition, a-
alkyl substituted ketoester, such as methyl 2-oxo-4-
phenylbutanoate was tolerated in this process, but a relatively
low yield was obtained presumably because of the steric effect (4o).
To examine the feasibility of a large-scale reaction, the reaction
of p-anisidine 1a, ethyl glyoxylate 2a, and methyl pyruvate 3a was
investigated. The reaction could afford 2.36 g of 4a in 82% yield
without any significant loss of its efficiency (Scheme 2). Therefore,
this protocol could be used as a practical method to synthesize the
precursors of some important bioactive molecules, such as quino-
line 2,4-dicarboxylic acid (QDC), which can be employed as in-
hibitor against the vesicular glutamate transport (VGLUT).2a,b
Table 1
Reaction of p-anisidine 1a, ethyl glyoxylate 2a, and methyl pyruvate 3a under var-
ious reaction conditionsa
Entry
Catalyst (mol %)
Solvent
Yield (%)b
1
2
3
4
5
6
7
8
9
None
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
0
61
62
66
0
58
68
88
80
89
Cu(OTf)2 (10)
AgOTf (10)
Bi(OTf)3(10)
Pd(OAc)2 (10)
Zn(OTf)2 (10)
CuBr2 (10)
FeCl3 (10)
InCl3(10)
Scheme 2. The large-scale reaction for the construction of quinoline-2,4-
dicarboxylates.
To gain further insights into this reaction, several control ex-
periments were conducted (Schemes 3e6). When the reaction of
ethyl glyoxylate 2a with methyl pyruvate 3a was performed in the
standard conditions, only a trace amount of 10 was detected
(Scheme 3), suggesting that this reaction mechanism might be
10
FeCl3 (15)

W. Wei et al. / Tetrahedron 69 (2013) 10747e10751
10749
Table 2
desired product 4a was not detected when the reaction of 5a with
methyl pyruvate 3a was conducted in absence of catalyst (Scheme
6). The above results indicated that imine complex might be the key
intermediate and FeCl3 played an important role in the formation of
quinoline-2,4-dicarboxylates.Based on the above experimental re-
sults and previous studies,9,12,13 a postulated reaction pathway was
proposed as shown in Scheme 7. Firstly, aromatic amine 1 reacted
with ethyl glyoxylate 2 to generate the imine intermediate 5, which
was followed by addition of the enolate 6 that quickly formed from
the tautomerization of ketoester in the presence of iron salts, and
produced intermediate 7.12 Subsequently, the nucleophilic attack of
phenyl ring to keto group led to the formation of intermediate 8.
Next, water elimination and following proton shift with help of
chloride ion would produce the 1,2-dihydroquinolines in-
termediate 9.12b,13 Finally, the dihydroquinoline intermediate 9 was
oxidized by air oxygen to give the desired quinoline 4.13
Iron-catalyzed three-component tandem reaction of aromatic amines, glyoxylic
esters, and a
-ketoestersa
Scheme 3. The reaction of 2a with 3a in the standard conditions.
Scheme 4. The reaction of 1a with 2a in the absence of catalyst.
Scheme 5. The reaction of imine 5a with 3a in the presence of FeCl3 (5 mol %).
Scheme 6. The reaction of imine 5a with 3a in the absence of catalyst.
different from the modified Doebnerevon Miller reaction.2 On the
other hand, imine 5a could be isolated in 92% yield when p-
methoxyaniline 1a reacted with ethyl glyoxylate 2a in the absence
of catalyst (Scheme 4). Furthermore, treatment of 5a with methyl
pyruvate 3a under the standard procedure led to the formation of
the desired product 4a in 86% yield (Scheme 5). Nevertheless, the
Scheme 7. Postulated reaction pathway.

10750
W. Wei et al. / Tetrahedron 69 (2013) 10747e10751
3. Conclusions
purified by flash chromatography on silica gel (petroleum ether/
ethyl acetate, 7:1) to give the desired product 4a in 86% yield.
In summary, a simple and convenient method has been de-
veloped for the preparation of substituted quinoline-2,4-
dicarboxylates via a new one-pot three-component tandem pro-
4.2.4. Reaction of imine 5a and 3a in the absence of catalyst. The
reaction mixture of imine 5a (0.5 mmol), methyl pyruvate 3a
(0.75 mmol), and CH3CN (3 mL) was stirred at room temperature
for 30 h. The solution was concentrated in vacuum, no desired
product was detected.
cess of aromatic amines, glyoxylic esters, and
a-ketoesters by
employing cheap iron salts as the catalysts. The present protocol,
which possesses some advantages of cheap catalysts, readily-
available starting materials, and mild reaction conditions over the
common methods, paves a new way towards the synthesis of ver-
satile quinoline building blocks potentially for constructing a vari-
ety of drug candidates, biofunctional molecules and fluorescent
tags. The detailed scope, mechanism, and synthetic application of
this reaction are under investigation.
Compound 4a was obtained in 88% yield according to the gen-
eral procedure (rt, 30 h). TLC (n-hexane/EtOAc, 3:1 v/v): Rf¼0.36; 1H
NMR (600 MHz, CDCl3):
d
¼1.48 (t, J¼7.1 Hz, 3H), 3.98 (s, 3H), 4.04 (s,
3H), 4.55 (q, J¼7.1 Hz, 2H), 7.45 (dd, J¼2.7, 9.3 Hz, 1H), 8.22 (d,
J¼9.2 Hz, 1H), 8.26 (d, J¼2.7 Hz, 1H), 8.68 (s, 1H); 13C NMR
(150 MHz, CDCl3):
d
¼14.4, 52.7, 55.7, 62.3, 103.0, 123.1, 123.8, 128.3,
132.8, 133.1, 145.0, 145.2, 161.0, 165.0, 166.3; HRMS calcd for
C
15H15NO5Na (MþNa)þ, 312.0842; found, 312.0837.
4. Experimental section
4.1. General
Compound 4b was obtained in 80% yield according to the gen-
eral procedure (rt, 30 h). TLC (n-hexane/EtOAc, 3:1 v/v): Rf¼0.39; 1H
NMR (600 MHz, CDCl3):
d
¼1.48 (t, J¼7.1 Hz, 3H), 2.59 (s, 3H), 4.05 (s,
3H), 4.56 (q, J¼7.1 Hz, 2H), 7.65 (d, J¼1.5, 8.6 Hz, 1H), 8.23 (d,
All commercially available reagent grade chemicals were pur-
chased from Aldrich, Acros and Alfa Aesar Chemical Company and
used as received without further purification unless otherwise
stated. All solvents were dried according to standard procedures.
The NMR data were collected in CDCl3 with TMS as internal stan-
dard on a Bruker Avance 600 spectrometer (600 MHz 1H, 150 MHz
13C) at room temperature. The following abbreviations were used to
express the multiplicities: s¼singlet; d¼doublet; t¼triplet;
q¼quartet; quint¼quintet; m¼multiplet; br¼broad, and the
J¼8.7 Hz, 1H), 8.57 (s, 1H), 8.61 (s, 1H); 13C NMR (150 MHz, CDCl3):
d
¼14.4, 22.3, 52.8, 62.4, 122.3, 124.2, 126.3, 131.0, 132.8, 135.1, 141.0,
146.9, 147.4, 164.9, 166.3; HRMS calcd for C15H15NO4Na (MþNa)þ,
296.0893; found, 296.0901.
Compound 4c was obtained in 86% yield according to the gen-
eral procedure (rt, 30 h). TLC (n-hexane/EtOAc, 3:1 v/v): Rf¼0.36; 1H
NMR (600 MHz, CDCl3):
d
¼1.47e1.51 (m, 6H), 4.03 (s, 3H), 4.22 (q,
J¼7.0 Hz, 2H), 4.55 (q, J¼7.2 Hz, 2H), 7.44 (d, J¼2.8, 9.2 Hz, 1H), 8.21
(d, J¼9.2 Hz, 1H), 8.24 (d, J¼2.7 Hz, 1H), 8.66 (s, 1H); 13C NMR
chemical shifts (
d) were described in parts per million and J values
(150 MHz, CDCl3):
d
¼14.4, 14.6, 52.7, 62.2, 64.1, 103.6, 123.0, 124.0,
were given in Hertz. High-resolution mass spectra was obtained in
a Bruker Daltonics Data Analysis 3.2. All reactions were carried out
in oven-dried glasswares with magnetic stirring and monitored by
thin-layer chromatography on TLC plates. The products were pu-
rified by flash column chromatography on silica gel (200e300
mesh).
128.4, 132.8, 133.1, 144.8, 145.1, 160.4, 165.0, 166.3; HRMS calcd for
C
16H17NO5Na (MþNa)þ, 326.0999; found, 326.0993.
Compound 4d was obtained in 60% yield according to the gen-
eral procedure (rt, 30 h). TLC (n-hexane/EtOAc, 3:1 v/v): Rf¼0.31; 1H
NMR (600 MHz, CDCl3):
d
¼1.51 (t, J¼10.6 Hz, 3H), 4.07 (s, 6H), 4.11
(s, 3H), 4.58 (q, J¼10.6 Hz, 2H), 7.68 (s, 1H), 8.36 (s, 1H), 8.64 (s, 1H);
13C NMR (150 MHz, CDCl3):
d
¼14.4, 52.7, 56.3, 56.3, 62.3, 103.0,
109.3, 121.1, 123.5, 132.5, 145.2, 146.6, 153.0, 165.1, 166.5; HRMS
calcd for C16H17NO6 Na (MþNa)þ, 342.0954; found, 342.0958.
Compound 4e was obtained in 72% yield according to the gen-
eral procedure (rt, 30 h). TLC (n-hexane/EtOAc, 3:1 v/v): Rf¼0.40; 1H
4.2. Experimental procedures
4.2.1. General procedures for preparation of quinoline-2,4-
dicarboxylates 4. The reaction mixture of arylamine 1 (0.5 mmol),
NMR (600 MHz, CDCl3)
d
¼0.95 (t, J¼1.4 Hz, 3H), 1.38e1.44 (m, 2H),
ethyl glyoxylate 2 (0.55 mmol),
a-ketoesters 3 (0.75 mmol), FeCl3
1.49 (t, J¼7.1 Hz, 3H), 1.68e1.75 (m, 2H), 2.85 (t, J¼7.7 Hz, 2H), 4.06
(s, 3H), 4.57 (q, J¼7.1 Hz, 2H), 7.68 (dd, J¼1.7, 8.7 Hz, 1H), 8.27 (d,
J¼8.6 Hz, 1H), 8.60 (s, 1H), 8.63 (s, 1H); 13C NMR (150 MHz, CDCl3)
(5 mol %) and CH3CN (3 mL) was stirred at room temperature or
60 ꢀC for the indicated time until complete consumption of the
starting material, which was monitored by TLC analysis (30e36 h).
Then the solvents were removed by rotary evaporation to provide
crude products. The residue was purified by flash chromatography
on silica gel to give the desired product 4.
d
¼13.9, 14.4, 22.4, 33.2, 36.3, 52.8, 62.4, 122.3, 123.7, 126.4, 131.1,
132.1, 135.1, 145.8, 146.9, 147.6, 165.0, 166.3; HRMS calcd for
C
18H21NO4Na (MþNa)þ, 338.1363; found, 338.1373.
Compound 4f was obtained in 71% yield according to the general
procedure (rt, 30 h). TLC (n-hexane/EtOAc, 3:1 v/v): Rf¼0.50; 1H
4.2.2. Reaction of 1a and 2a in the absence of catalyst. The reaction
mixture of p-methoxyaniline 1a (1 mmol), ethyl glyoxylate 2a
(1.1 mmol), and CH3CN (3 mL) was stirred at room temperature for
30 min. Then the solvents were removed by rotary evaporation to
provide crude products. The residue was purified by flash chro-
matography on silica gel (petroleum ether/ethyl acetate, 8:1) to
give the desired imine 5a as a yellow oil. 1H NMR (600 MHz, CDCl3):
NMR (600 MHz, CDCl3):
d
¼1.27e1.33 (m, 1H), 1.42e1.46 (m, 2H),
1.48 (t, J¼7.1 Hz, 3H), 1.51e1.58 (m, 2H), 1.78 (d, J¼12.8 Hz, 1H), 1.89
(d, J¼12.9 Hz, 2H),1.97 (d, J¼12.0 Hz, 2H), 2.74e2.78 (m,1H), 4.06 (s,
3H), 4.56 (q, J¼7.1 Hz, 2H), 7.72 (dd, J¼1.6, 8.8 Hz, 1H), 8.27 (d,
J¼8.8 Hz, 1H), 8.62 (s, 1H), 8.63 (s, 1H); 13C NMR (150 MHz, CDCl3):
d
¼14.4, 26.0, 26.7, 34.1, 45.1, 52.8, 62.4, 122.1, 122.3, 126.5, 130.8,
131.1, 135.2, 146.9, 147.8, 150.7, 165.0, 166.3; HRMS calcd for
C
d
¼1.40 (t, J¼7.1 Hz, 3H), 3.83 (s, 3H), 4.41 (q, J¼7.1 Hz, 2H), 6.92 (d,
20H23NO4Na (MþNa)þ, 364.1519; found, 364.1518.
J¼8.8 Hz, 2H), 7.35 (d, J¼8.9 Hz, 2H), 7.93 (s, 1H).
Compound 4g was obtained in 57% yield according to the gen-
eral procedure (60 ꢀC, 36 h). TLC (n-hexane/EtOAc, 2:1 v/v):
4.2.3. Reaction of imine 5a and 3a in the presence of catalyst. The
isolated 5a (0.5 mmol) was immediately added into a mixture of
methyl pyruvate 3a (0.75 mmol), FeCl3 (5 mol %), and CH3CN (3 mL).
The reaction mixture was stirred at room temperature for 30 h.
After the completion of the reaction, the solvents were removed by
rotary evaporation to provide crude products. Then the residue was
Rf¼0.33; 1H NMR (600 MHz, CDCl3):
¼1.36 (t, J¼7.1 Hz, 3H), 3.97 (s,
d
3H), 4.40 (q, J¼7.0 Hz, 2H), 7.47 (dd, J¼2.6, 9.1 Hz, 1H), 8.03 (s, 1H),
8.09 (d, J¼9.1 Hz, 1H), 8.41 (s, 1H), 10.79 (s, 1H); 13C NMR (150 MHz,
CDCl3):
d
¼14.7, 53.3, 62.0, 106.7, 122.5, 124.2, 128.0, 133.1, 133.2,
144.1, 144.2, 159.9,164.8, 166.2; HRMS calcd for C14H14NO5 (MþH)þ,
276.0866; found, 276.0869.

W. Wei et al. / Tetrahedron 69 (2013) 10747e10751
10751
Compound 4h was obtained in 71% yield according to the gen-
eral procedure (60 ꢀC, 36 h). TLC (n-hexane/EtOAc, 3:1 v/v):
(dd, J¼2.2, 9.1 Hz, 1H), 8.10 (d, J¼9.2 Hz, 1H); 13C NMR (150 MHz,
CDCl3):
d
¼13.9, 14.1, 35.5, 55.6, 62.1, 102.1, 123.1, 126.0, 126.3, 128.3,
Rf¼0.39; 1H NMR (600 MHz, CDCl3):
d
¼1.49 (t, J¼7.1 Hz, 3H), 4.06 (s,
128.8, 129.0, 131.6, 139.0, 139.7, 141.9, 148.6, 159.8, 166.3, 167.4;
3H), 4.57 (q, J¼7.0 Hz, 2H), 7.76 (d, J¼8.9 Hz, 1H), 8.28 (d, J¼9.0 Hz,
HRMS calcd for C23H24NO5 (MþH)þ, 394.1649; found, 394.1656.
1H), 8.68 (s, 1H), 8.90 (s, 1H); 13C NMR (150 MHz, CDCl3):
d¼14.3,
53.0, 62.6, 123.2, 124.7, 126.8, 131.6, 132.7, 134.8, 136.9, 147.1, 148.1,
164.5, 165.6; HRMS calcd for C14H12ClNO4Na (MþNa)þ, 316.0347;
found, 316.0349.
Acknowledgements
This work was supported by the Taishan Scholar Foundation of
Shandong Province, the National Natural Science Foundation of
China (No. 21375075, 21302109, and 21302110), the Excellent
Middle-Aged and Young Scientist Award Foundation of Shandong
Province (BS2013YY019), and the Scientific Research Foundation of
Qufu Normal University (BSQD 2012020).
Compound 4i was obtained in 62% yield according to the general
procedure (60 ꢀC, 30 h). TLC (n-hexane/EtOAc, 3:1 v/v): Rf¼0.39; 1H
NMR (600 MHz, CDCl3):
d
¼1.49 (t, J¼7.1 Hz, 3H), 4.07 (s, 3H), 4.57
(q, J¼7.1 Hz, 2H), 7.89 (d, J¼2.0, 9.0 Hz, 1H), 8.20 (d, J¼9.0 Hz, 1H),
8.67 (s, 1H), 9.07 (d, J¼2.0 Hz, 1H); 13C NMR (150 MHz, CDCl3):
d
¼14.3, 53.0, 62.6,123.2,125.5,127.1,128.0,132.7, 134.2,134.8,147.3,
148.2, 164.5, 165.6; HRMS calcd for C14H12BrNO4Na (MþNa)þ,
References and notes
359.9842; found, 359.9839.
Compound 4j was obtained in 55% yield according to the general
procedure (60 ꢀC, 30 h). TLC (n-hexane/EtOAc, 3:1 v/v): Rf¼0.38; 1H
1. (a) Balasubramanian, M.; Keay, J. G. In Comprehensive Heterocyclic Chemistry II;
Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon: Oxford, UK,1996; Vol.
5, pp 245e266; (b) Roma, G.; Braccio, M. D.; Grossi, G.; Mattioli, F.; Ghia, M. Eur. J.
Med. Chem. 2000, 35, 1021e1035; (c) Vaitilingam, B.; Nayyar, A.; Palde, P. B.;
Monga, V.; Jain, R.; Kaur, S.; Singh, P. P. Bioorg. Med. Chem. 2004, 12, 4179e4188;
(d) Hazeldine, S.; Polin, L.; Kushner, J.; White, K.; Bouregeois, N. H.; Crantz, B.;
Palomino, E.; Corbett, T. H.; Horwitz, J. P. J. Med. Chem. 2002, 45, 3130e3137; (e)
Hazeldine, S. T.; Polin, L.; Kushner, J.; White, K.; Corbett, T. H.; Horwitz, J. P. Bioorg.
Med. Chem. 2006,14, 2462e2467; (f) Martirosyan, A. R.; Rahim-Bata, R.; Freeman,
A. B.; Clarke, C. D.; Howard, R. L.; Strobl, J. S. Biochem. Pharmacol. 2004, 68,
1729e1738; (g) Perzyna, A.; Klupsch, F.; Houssin, R.; Pommery, N.; Lemoine, A.;
Henichart, J. P. Bioorg. Med. Chem. Lett. 2004,14, 2363e2365; (h) Michael, J. P. Nat.
Prod. Rep. 2007, 24, 223e246; (i) Jain, M.; Khan, S. I.; Tekwani, B. L.; Jacob, M. R.;
Singh, S.; Singh, P. P.; Jain, R. Bioorg. Med. Chem. 2005, 13, 4458e4466; (j) Lil-
ienkampf, A.; Mao, J.; Wan, B.; Wang, Y.; Franzblau, S. G.; Kozikowski, A. P. J. Med.
Chem. 2009, 52, 2109e2118; (k) Chen, S.; Chen, R.; He, M.; Pang, R.; Tan, Z.; Yang,
M. Bioorg. Med. Chem. 2009,17,1948e1956; (l) Michael, J. P. Nat. Prod. Rep.1997,14,
605e608; (m) Bray, P. G.; Ward, S. A.; O’Neil, P. M. Curr. Top. Microbiol. Immunol.
2005, 295, 3e38.
2. (a) Carrigan, C. N.; Bartlett, R. D.; Esslinger, C. S.; Cybulski, K. A.; Tongchar-
oensirikul, P.; Bridges, R. J.; Thompson, C. M. J. Med. Chem. 2002, 45,
2260e2276; (b) Carrigan, C. N.; Esslinger, C. S.; Bartlett, R. D.; Bridges, R. J.;
Thompson, C. M. Bioorg. Med. Chem. 1999, 9, 2607e2612; (c) Corey, E. J.;
Tramontano, A. J. Am. Chem. Soc. 1981, 103, 5599e5600; (d) Suzuki, F.; Nakazato,
N.; Oomori, T.; Nakajima, H. Jpn. Kokai Tokkyo Koho 1993, JP 05310702.
3. Laras, Y.; Hugues, V.; Chandrasekaran, Y.; Blanchard-Desce, M.; Acher, F. C.;
Pietrancosta, N. J. Org. Chem. 2012, 77, 8294e8302.
NMR (600 MHz, CDCl3):
d
¼1.49 (t, J¼7.1 Hz, 3H), 4.06 (s, 3H), 4.57
(q, J¼7.1 Hz, 2H), 7.61 (dd, J¼2.8, 7.9 Hz, 1H), 8.36 (dd, J¼5.6, 9.2 Hz,
1H), 8.57 (dd, J¼2.8, 10.6 Hz, 1H), 8.71 (s, 1H); 13C NMR (150 MHz,
CDCl3):
d
¼14.3, 52.9, 62.5, 109.6, 109.7, 121.0, 121.2, 123.2, 127.5,
127.6, 133.9, 134.0, 135.0, 146.0, 147.3, 162.1, 163.8, 164.6, 165.7;
HRMS calcd for
300.0654.
C
14H12FNO4Na (MþNa)þ, 300.0643; found,
Compound 4k was obtained in 31% yield according to the gen-
eral procedure (60 ꢀC, 36 h). TLC (n-hexane/EtOAc, 2:1 v/v):
Rf¼0.52; 1H NMR (600 MHz, CDCl3):
¼1.51 (t, J¼7.1 Hz, 3H), 4.11 (s,
d
3H), 4.60 (q, J¼7.1 Hz, 2H), 7.96 (dd, J¼1.6, 8.7 Hz, 1H), 8.45 (d,
J¼8.8 Hz,1H), 8.77 (s,1H), 9.36 (d, J¼1.3 Hz,1H); 13C NMR (150 MHz,
CDCl3):
d
¼14.3, 53.3, 63.0, 113.9, 118.2, 123.8, 125.5, 131.0, 132.2,
132.6,136.2,149.3,150.7,164.1,165.1; HRMS calcd for C15H12N2O4Na
(MþNa)þ, 307.0689; found, 307.0691.
Compound 4l was obtained in 40% yield according to the general
procedure (60 ꢀC, 30 h). TLC (n-hexane/EtOAc, 2:1 v/v): Rf¼0.50; 1H
NMR (600 MHz, CDCl3):
d
¼1.51 (t, J¼7.1 Hz, 3H), 2.78 (s, 3H), 4.11 (s,
3H), 4.59 (q, J¼7.1 Hz, 2H), 8.37 (dd, J¼1.7, 8.8 Hz, 1H), 8.41 (d,
J¼8.8 Hz,1H), 8.73 (s,1H), 9.53 (d, J¼1.4 Hz,1H); 13C NMR (150 MHz,
4. (a) Itoh, S.; Fukui, Y.; Haranou, S.; Ogino, M.; Komatsu, M.; Ohshiro, Y. J. Org.
Chem. 1992, 57, 4452e4457; (b) Carling, R. W.; Leeson, P. D.; Moseley, A. M.;
Baker, R.; Foster, A. C.; Grimwood, S.; Kemp, J. A.; Marshall, G. R. J. Med. Chem.
1992, 35, 1942e1953; (c) Itoh, S.; Kato, J.; Inoue, T.; Kitamura, Y.; Komatsu, M.;
Ohshiro, Y. Synthesis 1987, 1067e1071.
CDCl3):
d¼14.3, 26.8, 53.1, 62.8, 111.8, 123.1, 127.5, 128.4,130.8,131.8,
137.6, 150.0, 150.3, 164.5, 165.6, 197.5; HRMS calcd for C16H15NO5Na
(MþNa)þ, 324.0842; found, 324.0846.
5. Palacios, F.; Vicario, J.; de los Santos, J. M.; Aparicio, D. Heterocycles 2006, 70,
261e270.
Compound 4m was obtained in 52% yield according to the
general procedure (rt, 30 h). TLC (n-hexane/EtOAc, 3:1 v/v):
6. Selected reviews, see: (a) Enthaler, S.; Junge, K.; Beller, M. Angew. Chem., Int. Ed.
2008, 47, 3317e3321; (b) Correa, A.; GarcíaMancheno, O.; Bolm, C. Chem. Soc.
Rf¼0.34; 1H NMR (600 MHz, CDCl3):
¼1.49 (t, J¼7.1 Hz, 3H), 3.96 (s,
d
€
Rev. 2008, 37, 1108e1117; (c) Sherry, B. D.; Furstner, A. Acc. Chem. Res. 2008, 41,
3H), 4.56 (q, J¼7.1 Hz, 2H), 7.14 (dd, J¼0.9, 8.5 Hz, 2H), 7.23 (t,
J¼7.4 Hz, 3H), 7.42e7.45 (m, 2H), 7.57 (dd, J¼2.7, 9.2 Hz,1H), 8.29 (d,
J¼2.6 Hz, 1H), 8.32 (d, J¼9.2 Hz, 1H), 8.66 (s, 1H); 13C NMR
1500e1511; (d) Sun, C.-L.; Li, B.-J.; Shi, Z.-J. Chem. Rev. 2011, 111, 1293e1314; (e)
Bolm, C.; Legros, J.; Le Paih, J.; Zani, L. Chem. Rev. 2004, 104, 6217e6254.
€
7. Selected examples, see: (a) Furstner, A.; Majima, K.; Martin, R.; Krause, H.;
Kattnig, E.; Goddard, R.; Christian, W. L. J. Am. Chem. Soc. 2008, 130, 1992e2004;
(150 MHz, CDCl3):
d¼14.4, 52.7, 62.4, 110.3, 120.0,120.2, 123.1, 123.7,
€
(b) Chen, M. S.; White, M. C. Science 2007, 318, 783e787; (c) Furstner, A. Angew.
124.8, 127.7, 130.1, 133.3, 134.3, 145.6, 146.1, 155.5, 159.2, 164.8,
166.0; HRMS calcd for C20H17NO5Na (MþNa)þ, 374.0999; found,
374.1004.
Chem., Int. Ed. 2009, 48, 1364e1367; (d) Buchwald, S. L.; Bolm, C. Angew. Chem.,
Int. Ed. 2009, 48, 5586e5587; (e) Fan, J.; Gao, L.; Wang, Z. Chem. Commun. 2009,
5021e5023; (f) Fan, J.; Wang, Z. Chem. Commun. 2008, 5381e5383; (g) Mai, S.;
Biswas, S.; Jana, U. J. Org. Chem. 2010, 75, 1674e1683.
Compound 4n was obtained in 62% yield according to the gen-
8. (a) Kumar, S.; Saini, A.; Sandhu, J. S. Synth. Commun. 2007, 37, 4071e4078; (b)
Liu, P.; Wang, Z. M.; Lin, J.; Hu, X. M. Eur. J. Org. Chem. 2012, 8, 1583e1589; (c)
Patil, S. S.; Patil, S. V.; Bobade, V. D. Synlett 2011, 2379e2383; (d) Richter, H.;
eral procedure (rt, 30 h). TLC (n-hexane/EtOAc, 3:1 v/v): Rf¼0.44; 1H
NMR (600 MHz, CDCl3):
d
¼0.83 (d, J¼6.9 Hz, 3H), 0.93 (t, J¼5.3 Hz,
~
Mancheno, O. G. Org. Lett. 2011, 13, 6066e6069.
6H), 1.14e1.30 (m, 3H), 1.59e1.60 (m, 1H), 1.66e1.76 (m, 3H),
1.99e2.03 (m, 1H), 2.21 (d, J¼11.8 Hz, 1H), 3.97 (s, 3H), 4.04 (s, 3H),
5.07e5.14 (m, 1H), 7.43 (d, J¼9.3 Hz, 1H), 8.22 (s, 1H), 8.23 (d,
9. (a) Cao, K.; Zhang, F.-M.; Tu, Y.-Q.; Zhou, X.-T.; Fan, C.-A. Chem.dEur. J. 2009, 15,
6332e6334; (b) Zhang, Y.; Li, P.; Wang, L. J. Heterocycl. Chem. 2011, 48, 153e157;
(c) Yao, C. S.; Qin, B. B.; Zhang, H. H.; Lu, J.; Wang, D. L.; Tu, S. J. RSC Adv. 2012, 2,
3759e3764.
10. Li, H.-F.; Xu, X.-L.; Yang, J.-Y.; Xie, X.; Huang, H.; Li, Y.-Z. Tetrahedron Lett. 2011,
52, 530e533.
11. Zhang, Y. C.; Wang, C. M.; Li, P. H.; Wang, L. Org. Lett. 2012, 14, 2206e2209.
12. (a) Waldmann, H.; Karunakar, G. V.; Kumar, K. Org. Lett. 2008, 10, 2159e2162;
(b) Nakajima, T.; Inada, T.; Igarashi, T.; Sekioka, T.; Shimizu, I. Bull. Chem. Soc.
Jpn. 2006, 79, 1941e1949.
13. (a) Xiao, F.; Chen, Y.; Liu, Y.; Wang, J. B. Tetrahedron 2008, 64, 2755e2763; (b)
Huang, H.; Jiang, H.; Chen, K.; Liu, H. J. Org. Chem. 2009, 74, 5476e5480; (c)
Guchhait, S.; Jadeja, K.; Madaan, C. Tetrahedron Lett. 2009, 50, 6861e6865; (d)
Li, X. J.; Mao, Z. J.; Wang, Y. G.; Chen, W. X.; Lin, X. F. Tetrahedron 2011, 67,
3858e3862.
J¼8.9 Hz, 1H), 8.62 (s, 1H); 13C NMR (150 MHz, CDCl3):
¼16.5, 20.7,
d
22.0, 23.6, 26.5, 31.5, 34.3, 40.8, 47.0, 52.7, 55.7, 76.2, 102.9, 122.9,
123.6, 128.2, 132.9, 133.1, 145.2, 145.3, 160.9, 164.4, 166.4; HRMS
calcd for C23H29NO5Na (MþNa)þ, 422.1943; found, 422.1946.
Compound 4o was obtained in 33% yield according to the general
procedure (60 ꢀC, 36 h). TLC (n-hexane/EtOAc, 3:1 v/v): Rf¼0.40; 1H
NMR (600 MHz, CDCl3):
d
¼1.17 (t, J¼7.1 Hz, 3H),1.31 (t, J¼7.1 Hz, 3H),
3.92 (s, 3H), 4.27 (q, J¼7.1 Hz, 2H), 4.41e4.44 (m, 4H), 7.00 (s, 1H),
7.09 (d, J¼7.4 Hz, 2H), 7.15 (t, J¼7.1 Hz,1H), 7.21 (t, J¼7.3 Hz, 2H), 7.41