Facile synthesis of 4-substituted-2-quinolinone-3-carboxylic acid ethyl esters

Article abstract of DOI:10.1002/jhet.967

An efficient route for the synthesis of 4-substituted-2-quinolinone-3- carboxylic acid ethyl esters has been developed through Suzuki or Sonogashira reactions. The advantages of the method include high yields, operational simplicity, and suitability for m

Full text of DOI:10.1002/jhet.967

1254
Facile Synthesis of 4‐Substituted‐2‐quinolinone‐3‐carboxylic Acid
Vol 49
Ethyl Esters
Lijuan Zhang,a Yu Luo,a Shanbao Yu,a and Wei Lua,b
*
aDepartment of Chemistry, East China Normal University, Shanghai 200062, China
bInstitute of Drug Discovery and Development, iAIR, East China Normal University,
Shanghai 200062, China
*
E-mail: wlu@chem.ecnu.edu.cn
Received February 22, 2011
DOI 10.1002/jhet.967
Published online 26 October 2012 in Wiley Online Library (wileyonlinelibrary.com).
An efficient route for the synthesis of 4‐substituted‐2‐quinolinone‐3‐carboxylic acid ethyl esters has
been developed through Suzuki or Sonogashira reactions. The advantages of the method include high
yields, operational simplicity, and suitability for medicinal modification of 4‐substituted quinolinones
and their derivatives.
J. Heterocyclic Chem., 49, 1254 (2012).
INTRODUCTION
RESULTS AND DISCUSSION
Quinolinones are an important class of heteroaromatic
compounds. Because of their wide spectrum of phar-
macological applications, much more attention is focused
on development of new members [1]. Among them,
4‐substituted‐2‐quinolinone is one of the scaffolds that
exhibit various biological activities (Scheme 1). For
instance, quinolin‐2(1H)‐one derivatives 1 were found
as potent inducible nitric oxide synthase inhibitors [2],
4‐aryl‐3‐(3‐aryl‐1‐oxo‐2‐propenyl)‐2(1H)‐quinolinones 2 were
apoptosis inducers in human cancer cells [3], and 3,4,6‐
substituted‐2‐quinolones 3 were considered as FMS kinase
inhibitors [4].
Several methods have been reported in the literature
for the synthesis of 4‐substituted‐2‐quinolinones [4,5]
(Scheme 2). Among them, the general method was that
the 4‐position substituent on the quinolinone ring was
introduced first before the formation of quinolinone ring.
However, this method limited the diversity of the 4‐position
substituent of quinolinone, because the processes were
always repeated.
As shown in Scheme 3, the starting material 11 was
initially reacted with ethyl malonyl chloride in the presence
of triethylamine to give the intermediate amide. Without
purification of the amide, the quinoline ring was formed
to generate compound 12 by sodium hydride [6]. Then
compound 12 was reacted with phosphoryl chloride to
yield the dichloroquinoline 13. Finally, compound 13
was dechlorinated in the presence of sodium acetate and
acetic acid to provide the precursor compound 14 [7].
Because of the strong electron deficiency of 4‐substituted
quinolinones, compound 14 was considered as the substrate
to perform Suzuki and Sonogashira reactions (Scheme 4).
Several boric acids containing either electron‐donating
groups or electron‐withdrawing groups, such as phenyl boric
acid 15a, 4‐methoxy‐phenyl boric acid 15b, 3‐cyano‐phenyl
boric acid 15c and 2‐allyl‐4,4,5,5‐tetramethyl‐[1,3,2]
dioxaborolane 15d were selected to react with compound
14 in the presence of base under nitrogen for several
hours. The reactions proceeded smoothly to produce the
corresponding compounds 16a–d in 77, 93, 71, 79% yield,
respectively. Obviously, 4‐methoxy‐phenyl boric acid 15b
gave the highest yield (93%) compared with phenyl boric
acid 15a (77%) and 3‐cyano‐phenyl boric acid 15c (71%),
suggesting that the electron‐donating group of phenyl
ring had positive influence on the Suzuki reaction.
Phenylacetylene 15e and trimethylsilylacetylene 15f were
successfully introduced to 4‐position of quinolinone ring
by Sonogashira reaction in 88 and 56% yield, respectively.
From the medicinal chemistry point of view, an
efficient method to fast synthesize diverse 4‐substituted‐
2‐quinolinones is still needed. Herein, we described an
efficient method to synthesize 4‐substituted‐2‐quinolinone‐
3‐carboxylic acid ethyl esters in good yields. The key
step of our approach involves substitution at 4‐position
of the quinolinone core using Suzuki and Sonogashira
reactions.
© 2012 HeteroCorporation

September 2012
Facile Synthesis of 4‐Substituted‐2‐quinolinone‐3‐carboxylic Acid Ethyl Esters
1255
Scheme 1
Scheme 2. The previous methods.
Scheme 3. Reagents and conditions: (a) monoethyl malonate, EDAC; NaH, ethanol. (b) POCl3, reflux. (c) sodium acetate, acetic acid.
Scheme 4
In conclusion, we successfully synthesized several
4‐substituted quinolinones by Suzuki or Sonogashira
reactions. The advantages of the method include high
yields, operational simplicity, and suitability for med-
icinal chemistry of 4‐substituted quinolinones and
their derivatives.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1256
L. Zhang, Y. Luo, S. Yu, and W. Lu
Vol 49
128.64, 129.96, 132.01, 132.06, 132.49, 138.19, 160.64, 165.20.
HRMS (EI): m/z Calcd. For C20H15NO3: 317.1052. Found: 317.1052.
2‐Oxo‐4‐trimethylsilanylethynyl‐1,2‐dihydroquinoline‐3‐
carboxylic Acid Ethyl Ester 16f. A 25 mL sealed steel
reactor was charged with a mixture of 4‐chloro quinolinone 14
(200 mg, 0.8 mmol), K2CO3 (164 mg, 0.6 mmol), Pd(OAc)2
(36 mg, 0.16 mmol), PPh3 (170 mg, 0.64 mmol), CuI (30 mg,
0.16 mmol), trimethylsilylacetylene 15f (23 mg, 2.4 mmol) in
25 mL toluene. The system was heated at 100 °C under nitrogen
for 20 h, monitored by TLC, the solvent was evaporated in vacuo
and the crude product was purified by column chromatography
(ethyl acetate/petroleum ether = 1:3).
1HNMR (CDCl3): δ 0.32 (s, 3H), 1.45 (t, J = 5 Hz, 3H), 4.48
(m, 2H), 7.28 (t, J = 10 Hz, 1H), 7.37 (t, J = 7 Hz, 1H), 7.57
(m, 1H), 7.99 (d, J = 5 Hz, 1H), 11.97 (s, 1H). 13CNMR (100
MHz, CDCl3): δ 0.00, 14.60, 62.28, 97.10, 111.48, 117.07,
119.06, 123.78, 127.57, 129.91, 130.10, 132.37, 138.55, 161.05,
165.40. HRMS (ESI): m/z Calcd. For C17H19NNaO3Si [M + Na]+:
336.1026, Found: 336.1053.
EXPERIMENTAL
1HNMR spectra were recorded on a Bruker DRX‐500 (500 MHz).
13CNMR spectra were obtained on a JNM‐EX400 (100 MHz) and a
Bruker DRX‐500 (125 MHz). All reagents were used directly as
obtained commercially, unless otherwise noted.
Typical procedure for 16a–d. A mixture of 4‐chloro
quinolinone 14 (100 mg, 0.4 mmol), K2CO3 (82 mg, 0.6 mmol), Pd
(PPh3)4 (43 mg, 0.04 mmol), and the corresponding boric acid or
boric acid ester 15a–d (0.6 mmol) in 10 mL toluene and 1 mL water
was refluxed at the atmosphere of nitrogen for 3–7 h, monitored by
TLC, the solvents were evaporated in vacuo and the crude product
was purified by column chromatography (ethyl acetate/petroleum
ether = 1:1).
2‐Oxo‐4‐phenyl‐1,2‐dihydroquinoline‐3‐carboxylic Acid Ethyl
Ester 16a. 1HNMR (CDCl3): δ 0.96 (t, J = 6 Hz, 3H), 4.11 (m, 2H),
7.14 (t, J = 8 Hz, 1H), 7.29 (d, J = 8 Hz, 1H), 7.39 (m, 3H), 7.48
(m, 3H), 7.54 (t, J = 8 Hz, 1H), 11.44 (s, 1H). 13CNMR (125 MHz,
CDCl3): δ 13.68, 61.32, 116.80, 119.49, 122.91, 126.14, 127.59,
128.33, 128.78, 128.84, 131.53, 134.64, 138.41, 150.62, 161.09,
165.55. HRMS (EI): m/z Calcd. For C18H15NO3: 293.1052, Found:
293.1054.
4‐(4‐Methoxyphenyl)‐2‐oxo‐1,2‐dihydroquinoline‐3‐carboxylic
Acid Ethyl Ester 16b. 1HNMR (CDCl3): δ 1.04 (t, J = 6 Hz, 3H), 3.88
(s, 3H), 4.16 (m, 2H), 7.01 (d, J = 10 Hz, 2H), 7.14 (t, J = 7 Hz, 1H),
7.34 (m, 3H), 7.40 (d, J = 8 Hz, 1H), 7.53 (t, J = 7 Hz, 1H), 11.63
(s, 1H). 13CNMR (125 MHz, CDCl3): δ 13.85, 55.34, 61.31, 113.80,
116.66, 119.78, 122.81, 126.76, 127.63, 130.18, 131.40, 138.36,
160.05, 161.01, 165.77. HRMS (EI): m/z Calcd. For C19H17NO4:
323.1158, Found: 323.1157.
Acknowledgments. The authos gratefully acknowledge the
financial support for Shanghai Municipal Natural Science
Foundation (10ZR1409600) and the Fundamental Research
Funds for the Central Universities. The authos also thank Lab of
Organic Functional Molecules, the Sino‐French Institute of
ECNU for supports.
REFERENCES AND NOTES
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4‐(3‐Cyanophenyl)‐2‐oxo‐1,2‐dihydroquinoline‐3‐carboxylic
Acid Ethyl Ester 16c. 1HNMR (CDCl3): δ 1.05 (t, J = 7 Hz, 3H),
4.16 (m, 2H), 7.12 (d, J = 7 Hz, 1H), 7.18 (t, J = 7 Hz, 1H), 7.50
(d, J = 8 Hz, 1H), 7.57 (t, J = 7 Hz, 1H), 7.64 (m, 2H), 7.71(s,
1H), 7.81 (m, 1H), 12.43 (s, 1H). 13CNMR (125 MHz, CDCl3): δ
13.81, 61.62, 112.86, 117.04, 117.95, 118.69, 123.35, 126.64,
126.85, 129.43, 132.05, 132.24, 132.50, 133.22, 135.96, 138.47,
147.84, 160.73, 164.90. HRMS (EI): m/z Calcd. For C19H14N2O3:
318.1004. Found: 318.1001.
4‐Allyl‐2‐oxo‐1,2‐dihydroquinoline‐3‐carboxylic Acid Ethyl
Ester 16d. HNMR (CDCl3): δ 1.43 (m, 3H), 3.64 (d, J = 7 Hz,
1
2H), 4.46 (m, 2H), 5.17 (t, J = 10 Hz, 2H), 5.97 (m, 1H), 7.24
(d, J = 9 Hz, 1H), 7.28 (s, 1H), 7.53 (t, J = 7 Hz, 1H), 7.76 (d,
J = 9 Hz, 1H), 10.63 (d, J = 5 Hz, 1H). 13CNMR (125 MHz,
CDCl3): δ 14.23, 34.19, 61.70, 117.14, 117.96, 118.68, 122.88,
125.41, 126.52, 131.27, 133.63, 138.35, 147.36, 161.30, 166.35.
HRMS (EI): m/z Calcd. For C15H15NO3: 257.1052. Found: 257.1054.
2‐Oxo‐4‐phenylethynyl‐1,2‐dihydroquinoline‐3‐carboxylic
Acid Ethyl Ester 16e. A mixture of 4‐chloro quinolinone 14
(100 mg, 0.4 mmol), K2CO3 (82 mg, 0.6 mmol), Pd(OAc)2 (10 mg,
0.04 mmol), PPh3 (42 mg, 0.16 mmol), CuI (8 mg, 0.04 mmol) and
phenylacetylene 15e (61 mg, 0.6 mmol) in 10 mL acetonitrile was
refluxed under nitrogen for 4 h, monitored by TLC, the solvent was
evaporated in vacuo and the crude product was purified by column
chromatography (ethyl acetate/petroleum ether = 1:1).
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1HNMR (CDCl3): δ 1.44 (t, J = 7 Hz, 3H), 4.52 (m, 2H), 7.34
(m, 2H), 7.44 (t, J = 7 Hz, 3H), 7.61 (m, 3H), 8.11 (d, J = 9 Hz,
1H), 11.39 (s, 1H). 13CNMR (100 MHz, CDCl3): δ 14.33, 61.92,
82.14, 103.84, 111.89, 116.67, 118.72, 121.57, 123.33, 127.17,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet