Microwave-assisted simple synthesis of substituted 4-quinolone derivatives

Article abstract of DOI:10.1080/00397910902906503

A simple and efficient method was developed for the synthesis of 4-quinolone-3-carboxylic esters and 4-quinolone-3-carbonitriles under microwave (MW) activation using anilines and acrylates as materials. All reactions demonstrated the benefits of microwave reactions: convenient operation, short reaction time, and good yields.

Full text of DOI:10.1080/00397910902906503

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Microwave-Assisted Simple
Synthesis of Substituted 4-
Quinolone Derivatives
Xin Cao a b , Qi-Dong You a , Zhi-Yu Li a , Yan Yang a
& Xiao-Jian Wang a
a Jiangsu Key Laboratory of Carcinogenesis
and Intervention and Department of Medicinal
Chemistry , China Pharmaceutical University ,
Nanjing, China
b State Key Laboratory of Bio-organic and Natural
Products Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences , Shanghai,
China
Published online: 12 Nov 2009.
To cite this article: Xin Cao , Qi-Dong You , Zhi-Yu Li , Yan Yang & Xiao-Jian Wang
(2009) Microwave-Assisted Simple Synthesis of Substituted 4-Quinolone Derivatives,
Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 39:24, 4375-4383, DOI: 10.1080/00397910902906503
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Synthetic Communications1, 39: 4375–4383, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910902906503
Microwave-Assisted Simple Synthesis of
Substituted 4-Quinolone Derivatives
Xin Cao,1,2 Qi-Dong You,1 Zhi-Yu Li,1 Yan Yang,1 and
Xiao-Jian Wang1
1Jiangsu Key Laboratory of Carcinogenesis and Intervention and
Department of Medicinal Chemistry, China Pharmaceutical University,
Nanjing, China
2State Key Laboratory of Bio-organic and Natural Products Chemistry,
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
Shanghai, China
Abstract: A simple and efficient method was developed for the synthesis of
4-quinolone-3-carboxylic esters and 4-quinolone-3-carbonitriles under microwave
(MW) activation using anilines and acrylates as materials. All reactions demon-
strated the benefits of microwave reactions: convenient operation, short reaction
time, and good yields.
Keywords: Microwave, 4-quinolone, synthesis
INTRODUCTION
The synthesis of substituted 4-quinolones has been of considerable
interest to organic and medicinal chemists for many years as a large
number of natural products[1,2] and drugs[3,4] contain these heterocyclic
cores. Many compounds that possess a 4-quinolone-3-carboxylic acid
fragment have been synthesized and evaluated as potential antibacterial
agents during the past thirty years,[5,6] and many different substi-
tuted quinoline-3-carbonitriles have also been synthesized as the key
Received October 6, 2008.
Address correspondence to Qi-Dong You, Jiangsu Key Laboratory of
Carcinogenesis and Intervention, China Pharmaceutical University, Tongjiaxiang
Road No. 24, Nanjing 210009, China. E-mail: youqidong@gmail.com
4375

4376
X. Cao et al.
Figure 1. Some quinoline core drugs and drug candidates.
intermediates of protein tyrosine kinase inhibitors, anticancer drugs, in
recent years (Fig. 1).[7]
As already described,[8] the 4-quinolone ring construction was
generally synthesized by a Gould–Jacobs reaction. This method
involved thermal cyclization of aniline derivatives to 4-quinolones
under extremely harsh conditions. Reactions were typically carried
out in mineral oil, dowtherm, or diphenyl ether at 250ꢀC or greater.
The severe reaction conditions made the preparation of the 4-quino-
lone products difficult. Thus, many different methods have been devel-
oped for the synthesis of 4-quinolones.[9–14] However, most of these
methods are not satisfactory in terms of yields, reaction conditions,
and operational simplicity. For this reason, a simple, general, and
efficient procedure for the synthesis of these important heterocyclic
compounds is urgently needed.[8–14]
RESULTS AND DISCUSSION
Nowadays, there is an increasing environment need for clean and efficient
organic synthesis to replace the traditional synthetic methods. The micro-
wave (MW)–catalyzed reactions have many advantages, and so we report
here a convenient procedure under MW irradiation conditions for the
synthesis of substituted 4-quinolones. All reactions were carried out using
a CEM monomode MW synthesizer with a CEM Discover System
workstation.

Microwave-Assisted Synthesis of 4-Quinolone
4377
Scheme 1. Convenient MW-assisted synthesis of 4-quinolones derivatives.
This procedure included two continuous reactions (Scheme 1). The
first reaction led to a condensation intermediate I in short time under
MW irradiation using the readily available aniline and acrylate as raw
=
=
materials. Most anilines and acrylates (X CO2C2H5, EMME; X CN,
2-cyano-3-ethoxyacrylic acetate) used were liquid at room temperature or
had low melting points, and the reaction could be carried out in a
solvent-free environment without using poisonous condensation solvents
such as benzene or toluene. The power of the CEM MW synthesizer was
30–50 W, the reaction temperature was 120ꢀC, and the pressure within
the reaction tube was less than 30 bar. This reaction had a good yield,
generally greater than 95%.
This condensation was followed by a cyclization reaction also
under MW irradiation in diphenyl ether.[15] The handling of this reac-
tion was convenient, and the brown solid product could be easily
recovered by filtration from diphenyl ether and washing with petro-
leum ether and ethyl acetate twice. Ten different 4-quinolone deriva-
tives (compounds 1–10) were synthesized by this method, and most
examples got good yields. The reaction conditions and results are
listed in Table 1.
A further one-pot, solvent-free procedure including both reaction
steps was also evaluated in the MW irradiation environment, but the
transformation rate was not as high. The raw materials disappeared,
and the 4-quinolones partly formed, but some products charred even
though the reactions were under an N2 atmosphere. Perhaps because of
the high melting points of all 4-quinolone compounds, they would
precipitate from the melting condensation intermediates at the reaction
temperature and adhere to the surface of reaction tubes when generated.
As the solid product increased, the nonhomogeneous phase turned
complex and was partly carbonized.

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X. Cao et al.
Table 1. Results of MW-assisted cyclization reactions of 4-quinolone derivatives
Traditional
Yield cyclization
Compounds
(II)
T
t
R
X
(ꢀC) (min) (%)a
yields (%)b
1
2
H
4-Me
3-MeO-4-Me
3-iPrO-4-Me
3-iPrO-4-MeO
3-Cl-4-F
2,3,4-Trifluoro
H
3-Cl-4-F
CN
CN
CN
CN
CN
CN
CN
175
235
210
230
225
210
200
15
8
58.2
56.6
55.1
76.5
94.3
75.6
74.2
82.8
81.3
85.7
44.5
46.3
38.5
42.0
40.5
46.0
48.2
75.0
72.5
74
3
30
30
30
20
20
25
25
25
4
5
6
7
8
CO2C2H5 190
CO2C2H5 190
9
10
2,3,4-Trifluoro CO2C2H5 190
aAll microwave-catalyzed reactions were performed with a CEM microwave
synthesizer, and the power used in the reactions was 280 W.
bThe conventional yields were obtained after thermal cyclization reactions at
250–280ꢀC over 4–10 h.
CONCLUSION
In conclusion, this work demonstrates an easy and convenient method
for synthesizing 4-quinolone-3-carboxylic esters and 4-quinolone-3-
carbonitriles under MW irradiation. The solvent-free method for the
condensation step proved to be more efficient and friendlier to the envir-
onment than the classical procedures because it avoids using organic
solvents during the reactions. The MW-assisted cyclization reactions take
place at relatively low temperatures and with in short times compared to
the classical methods. This method also simplifies the handling of the
reactions and gets good yields of 4-quinolone derivatives.
EXPERIMENTAL
All purchased starting materials and reagents were used without further
purification unless noted. 1H NMR spectra were recorded on an
ACF-300 or an ACF-500 Bruker instrument. Chemical shifts are
expressed in parts per million (ppm, d units). Coupling constants are in
units of hertz (Hz). Splitting patterns describe apparent multiplicities
and are designated as s (singlet), d (doublet), t (triplet), q (quartet), m
(multiplet), or br s (broad singlet). Mass spectra (MS) were recorded

Microwave-Assisted Synthesis of 4-Quinolone
4379
on Shimadzu GC-MS 2010 (EI) or a Mariner Mass Spectrum (ESI)
instruments.
General Procedure for the Condensation Reaction
Both aniline (3 mmol) and acrylates (3 mmol) were put into a 10-ml CEM
reaction tube sealed by the rubber stopper. Then MW irradiation was
carried out for 5–15 min at 120ꢀC. After that, the tube cooled and a light
yellow solid formed in the reaction tube. The crude product was recrys-
tallized by dehydrated alcohol, and then the white solid was formed.
Data for Compounds 11–15
2-Cyano-3-(3-isopropoxy-4-methylphenylamino)-acrylic Acid
Ethyl Ester (11)
1
Mp 138ꢀC; MS m=z 288.1; H NMR (CDCl3, 500 MHz) d 1.30 (m, 9H),
2.08 (s, 3H), 4.21 (m, 2 H), 4.55 (m, 1H), 6.88 (m, 2H), 7.02 (s, 1H), 8.29
(d, J ¼ 14 Hz, 1H), 10.68 (bs, 1H).
2-Cyano-3-(3-isopropoxy-4-methoxyphenylamino)-acrylic Acid
Ethyl Ester (12)
1
Mp 122–124ꢀC; MS m=z 304.1; H NMR (CDCl3, 500 MHz) d 1.29 (s,
3H), 1.30 (s, 3H), 1.31 (s, 3H), 4.22–4.24 (m, 2H), 4.48–4.50 (m, 1H),
6.56–6.57 (m, 1H), 6.79–6.81 (d, J ¼ 7 Hz, 1H), 7.67–7.69 (d, J ¼ 13Hz,
1H), 10.58 (s, 1H).
2-Cyano-3-(2,3,4-trifluorophenylamino)-acrylic Acid Ethyl Ester (13)
1
Mp 118ꢀC; MS m=z 270.1; H NMR (CDCl3, 300 MHz) d 1.28–1.33 (t,
3H), 4.22–4.29 (q, 2H), 6.83–7.03 (m, 2H), 7.69–7.73 (d, J ¼ 13 Hz,
1H), 10.79 (b, 1H).
2-Cyano-3-(3-chloro-4-fluorophenylamino)-acrylic Acid Ethyl Ester (14)
1
Mp 114ꢀC; MS m=z 268.1; H NMR (CDCl3, 300 MHz) d 1.25–1.32 (t,
3H), 4.19–4.26 (q, 2H), 6.96–7.08 (m, 2H), 7.19–7.20 (m, 1H),
8.18–8.23 (d, J ¼ 14 Hz, 1H), 8.45 (bs, 1H).

4380
X. Cao et al.
2-Cyano-3-(3-methoxy-4-methylphenylamino)-acrylic Acid Ethyl
Ester (15)
1
Mp 124ꢀC; MS m=z 260.1; H NMR (CDCl3, 300 MHz) d 1.25–1.32 (t,
3H), 2.11 (s, 3H), 3.78 (s, 3H), 4.19–4.26 (q, 2H), 6.43–6.44 (d, J ¼ 2 Hz,
1H), 6.51–6.54 (dd, 1H), 7.03–7.06 (d, J ¼ 8 Hz, 1H), 8.29–8.34 (d,
J ¼ 15 Hz, 1H), 10.67 (b, 1H).
General Procedure for the Cyclization Reaction
The intermediate I (1 mmol) and diphenyl ether (8 mL) were put into a
10-mL CEM reaction tube sealed by the rubber stopper. Then MW irra-
diation was carried out for 15–30 min at 175–225ꢀC. After that, the tube
cooled, and there was a brown solid on the inner wall of the tube. The
solid was collected by filtration and washed with petroleum ether and
ethyl acetate twice. The crude product was further purified by column
chromatography with ethyl acetate and methanol.
Data for Compounds 1–10
4-Quinolone-3-carbanitrile (1)
1
Mp > 280ꢀC, (lit.[15] mp 306–308ꢀC); MS m=z 170.1; H NMR (DMSO-
d6, 300 MHz) d 7.46–7.51 (dd, 1H), 7.62–7.65 (d, 1H), 7.76–7.81 (m,
1H), 8.12–8.15 (m, 1H), 8.73 (s, 1H), 12.81 (bs, 1H).
6-Methyl-4-quinolone-3-carbanitrile (2)
1
Mp > 280ꢀC; MS m=z 184.2; H NMR (DMSO-d6, 300 MHz) d 2.43 (s,
3H), 7.55–7.60 (d, J ¼ 13 Hz, 2H), 7.93 (s, 1H), 8.68 (s, 1H), 12.75 (bs,
1H).
7-Methoxy-6-methyl-4-quinolone-3-carbonitrile (3)
1
Mp > 280ꢀC; MS m=z 214; H NMR (DMSO-d6, 300 MHz) d 2.24 (s,
3H), 4.00 (s, 3H), 6.95 (s, 1H), 7.87 (s, 1H), 8.61 (s, 1H), 12.54 (bs,
1H).

Microwave-Assisted Synthesis of 4-Quinolone
4381
7-Isopropoxy-6-methyl-4-quinolone-3-carbonitrile (4)
Mp > 280ꢀC; MS m=z 242.1; 1H NMR (DMSO-d6, 300 MHz) d 1.35
(s, 3H), 1.37 (s, 3H), 2.21 (s, 3H), 4.66–4.68 (m, 1H), 7.00 (s, 1H), 7.87
(s, 1H), 8.60 (s, 1H), 12.46 (bs, 1H).
7-Isopropoxy-6-methoxy-4-quinolone-3-carbonitrile (5)
Mp > 280ꢀC; MS m=z 258.1; 1H NMR (DMSO-d6, 300 MHz) d 1.31
(s, 3H), 1.32 (s, 3H), 3.81 (s, 3H), 4.65–4.67 (m, 1H), 7.05 (s, 1H), 7.41
(s, 1H), 8.55 (s, 1H).
6-Fluoro-7-chloro-4-quinolone-3-carbonitrile (6)
Mp > 280ꢀC; MS m=z 222.1; 1H NMR (DMSO-d6, 300 MHz) d
7.84–7.86 (d, J ¼ 6 Hz, 1H), 7.96–7.99 (d, J ¼ 9 Hz, 1H), 8.80 (s, 1H),
12.95 (bs, 1H).
6,7,8-Trifluoro-4-quinolone-3-carbonitrile (7)
Mp > 280ꢀC; MS m=z 224.1; 1H NMR (DMSO-d6, 300 MHz) d 7.87–7.95
(dd, 1H), 8.73 (s, 1H).
4-Quinolone-3-carboxylic Acid Ethyl Ester (8)
Mp 273–275ꢀC, (lit.[6] mp 275–276ꢀC).
6-Fluoro-7-chloro-4-quinolone-3-carboxylic Acid Ethyl Ester (9)
1
Mp > 280ꢀC, (lit.[16] mp 290–291ꢀC); MS m=z 269.0; H NMR (DMSO-
d6, 300 MHz) d 1.56–1.58 (t, 3H), 4.71 (q, 2H), 8.35 (s, 1H), 8.37 (s,
1H), 9.36 (1H).
6,7,8-Trifluoro-4-quinolone-3-carboxylic Acid Ethyl Ester (10)
Mp 203–205ꢀC, (lit.[16] mp 205–206ꢀC); MS m=z 271.1; 1H NMR
(DMSO-d6, 300 MHz) d 1.58–1.59 (t, 3H), 4.74–4.76 (q, 2H), 7.98–8.01
(dd, 1H), 8.78 (s, 1H).

4382
X. Cao et al.
ACKNOWLEDGMENT
We are grateful to the National Natural Science Foundation of China
(NSFC Grant Nos. 30271543 and 30371676) for financial support.
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