One-pot microwave-assisted synthesis of 3,4-disubstituted 2-quinolinones

Article abstract of DOI:10.1080/00397911.2013.850095

An improved one-pot synthesis of 3,4-disubstituted 2-quinolinones is described. The condensation of substituted 2-aminobenzophenone (or 2-aminophenyl alkyl ketone) with acid chlorides was carried out in the presence of triethylamine (or NaH) under microwa

Full text of DOI:10.1080/00397911.2013.850095

This article was downloaded by: [UTSA Libraries]
On: 11 October 2014, At: 10:16
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered
office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An
International Journal for Rapid
Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and
subscription information:
http://www.tandfonline.com/loi/lsyc20
One-Pot Microwave-Assisted Synthesis of
3,4-Disubstituted 2-Quinolinones
Chinh T. Bui a
a Walter and Eliza Hall Institute of Medical Research , Bundoora ,
Victoria , Australiaand Department of Medical Biology, University of
Melbourne, Melbourne, Victoria, Australia
Accepted author version posted online: 08 Nov 2013.Published
online: 19 Mar 2014.
To cite this article: Chinh T. Bui (2014) One-Pot Microwave-Assisted Synthesis of 3,4-Disubstituted
2-Quinolinones, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 44:8, 1122-1127, DOI: 10.1080/00397911.2013.850095
To link to this article: http://dx.doi.org/10.1080/00397911.2013.850095
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the
“Content”) contained in the publications on our platform. However, Taylor & Francis,
our agents, and our licensors make no representations or warranties whatsoever as to
the accuracy, completeness, or suitability for any purpose of the Content. Any opinions
and views expressed in this publication are the opinions and views of the authors,
and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content
should not be relied upon and should be independently verified with primary sources
of information. Taylor and Francis shall not be liable for any losses, actions, claims,
proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or
howsoever caused arising directly or indirectly in connection with, in relation to or arising
out of the use of the Content.
This article may be used for research, teaching, and private study purposes. Any
substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing,
systematic supply, or distribution in any form to anyone is expressly forbidden. Terms &

Conditions of access and use can be found at http://www.tandfonline.com/page/terms-
and-conditions

Synthetic Communications®, 44: 1122–1127, 2014
Copyright © Crown Copyright
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397911.2013.850095
ONE-POT MICROWAVE-ASSISTED SYNTHESIS
OF 3,4-DISUBSTITUTED 2-QUINOLINONES
Chinh T. Bui
Walter and Eliza Hall Institute of Medical Research, Bundoora, Victoria,
Australia, and Department of Medical Biology, University of Melbourne,
Melbourne, Victoria, Australia
GRAPHICAL ABSTRACT
Abstract An improved one-pot synthesis of 3,4-disubstituted 2-quinolinones is described.
The condensation of substituted 2-aminobenzophenone (or 2-aminophenyl alkyl ketone)
with acid chlorides was carried out in the presence of triethylamine (or NaH) under micro-
wave reaction conditions (150oC, 200 psi). The reactions were completed within minutes to
produce 2-quinolinones in moderate to excellent yields and good purities.
[Supplementary materials are available for this article. Go to the publisher’s online
edition of Synthetic Communications® for the following free supplemental resource(s):
Full experimental and spectral details.]
Keywords 2-Aminobenzophenone; 3,4-disubstituted 2-quinolinone; microwave reaction;
synthesis of quinolone
INTRODUCTION
2-Quinolinones are embedded in natural products[1] and have been used as a scaf-
fold for the preparation of many pharmaceutical targets and drug like candidates.[2]
The synthesis of the 2-quinolinones has been achieved through different pathways.[3–5]
Among these, one simple and versatile method is the condensation of
2-aminobenzophenone with ethyl ester of malonic acid (or ethyl malonyl chloride),
which has been employed by some research groups (this strategy is outlined in
Scheme 1).[5–7] Although this method provides a facile and practical route, it has some
drawbacks: (i) There are not many commercially available analogs of 1. Therefore,
diversified point at R2 of the target 4 is limited and the process to derive 4-substitituted
Received September 16, 2013.
Address correspondence to Chinh T. Bui, 4 Research Avenue, Latrobe R&D Park, Bundoora,
Victoria 3086, Australia. E-mail: bui@wehi.edu.au
1122

SYNTHESIS OF 3,4-DISUBSTITUTED 2-QUINOLINONES
1123
Scheme 1. Synthesis of 3,4-disubstituted 2-quinolinones, where the product 3 can be represented by
the structure 4 {R1 =H, NO2, Br; R2 =−C6H5, −CH2Cl, −CH2C10H7 (naphthylmethyl-); R3 =−COOC2H5,
−CH2COOC2H5, −CH2CH2COOC2H5, CH2C6H5, −SC6H5}.
2-quinolone is usually lengthy[7] (ii) Reaction kinetics for the synthesis of 2-quinolinone
relies on the activation of the α-methylene unit, adjacent to both carbonyl groups to
obtain a good yield. Hence, most literature-available methods are suitable for synthesis
of 2-quinolinone-3-carboxylic acids[3] and limited work has been done for diversifying
the R3 position of 2-quinolinone.[8] (iii) Condensation reactions with inactivated
α-methylene esters require under harsh conditions (high temperature and prolonged
reaction time). In fact, the reaction was reported to be incomplete and it resulted in the
formation of the intermediate 2 (N-acyl-o-aminobenzophenone, Scheme 1) and/or
other impurities. Park and Lee[5] proposed a method that incorporated methyl iodide
as well as a high concentration of bases in the reaction conditions to improve both the
yield and the purity of the N-methylated 2-quinolinones.[5] Herein, we have reported
our investigation of the cyclization of substituted 2-aminobenzophenones as well as
o-aryl alkyl ketones with various acid chlorides to obtain 3,4-disubstituted 2-quinolo-
nes in one-pot microwave-assisted reaction conditions.
RESULTS AND DISCUSSION
At first, our attempt to shorten the reaction time led us to the development of
two separate reaction conditions (A and B). For condition A, the reaction is carried out
at 60°C for 30min in the presence of triethylamine–dichloromethane (1:2 v/v) while
condition B is carried out in the presence of stronger bases such as sodium hydride
(or sodium trimethylsillyl amide) under microwave reaction conditions (150°C at 200
psi for 30min). It was found that condition A worked well with simple benzophenones
and with ethyl malonyl chloride (entries 1 and 2in Table 1), achieving high yield and
purities. However, the more complex structures such as 2-aminophenyl alkyl ketones
with various aliphatic acid chlorides (entries 3–9in Table 1) led to the formation of the

1124
C. T. BUI
Table 1. Synthesis of 3,4-disubstituted quinolinones and analytical data
MS data
[M+H]+
Starting
material[9]
Acid chloride/
reaction condition
Yield % (expected
Entry
Product 4
(purity)
value)[11]
95
(99)
294.5
(294.3)
1
Condition A
91
(95)
339.3
(339.1)
2
3
Condition A
Condition B
91
(97)
346.6
(346.3)
71
(95)
438.4
(438.2)
4
Condition B
85
(98)
308.3
(308.1)
5
6
Condition B
Condition B
50
(98)
323.2
(323.1)
(Continued)

SYNTHESIS OF 3,4-DISUBSTITUTED 2-QUINOLINONES
1125
Table 1. Continued
MS Data
[M+H]+
Starting
material[9]
Acid chloride/
reaction condition
Yield % (expected
Entry
Product 4
(purity)
value)[11]
91
(99)
312.2
(312.0)
7
Condition B
Condition B
Condition B
92
(99)
330.3
(330.1)
8
55
(99)
335.2
(335.3)
9
anilide (intermediate 2) instead of the final cyclized product 3, regardless of the time
taken for reaction to occur.
Surprisingly the microwave conditions accelerated the reaction to completion
and the desired products were usually obtained within 30min. In fact, the condition B
was applied to several substrates (entries 3–9in Table 1), which generated the desired
products, in all cases, with moderate to good yields and purities. This is a signifi-
cantly reduced reaction time when compared to the conventional heating vessels used
in the past that require approximately 2−20 h.[4] In addition, the microwave conditions
improved our product’s purities. Workup procedures only required filtering the reac-
tion mixture through a plug of silica using 5% methanol in dichloromethane (DCM)
as an eluent to obtain the salt-free products. In some cases, preparative chromatogra-
phy was required (SiO2/5% methanol in DCM) to achieve a high rate of more than
95% purity.
Our results are tabulated in Table 1 and they show that the reaction
worked very well with various acid chlorides to give variable 3-substituted posi-
tions, including malonyl chloride, as well as aliphatic acids such as ethyl
4-chloro-4-oxobutyrate chloride, glutaric acid chlorides, hydrocinamoyl chloride,
and (phenylthio)-acetyl chloride. It is also reconfirmed that when malonyl chloride

1126
C. T. BUI
was used, the formation of 2-quinolinone occurred under mild condition (A) due
to activation of the α-methylene ester induced by two adjacent carbonyl groups.
When malonyl chloride was replaced with unreactive α-methylene esters or ali-
phatic acid chlorides, the reactions required stronger basic conditions (condition B)
for the cyclization reaction to occur. Our results are comparable, in some aspects,
with the recent studies,[6] which replaced ethyl malonyl chloride by substituted ace-
tic acids such as isoxazole-5-acetic acids or imidazole-acetic acids at the 3-position
of quinolone templates. This method had its own merit even though the pathway
was lengthy (three steps).[6]
Our described condition could be employed in a rigid and tricyclic structure,
such as 2, 3-diaminoanthracines (entry 9, Table 1), to obtain the tetracyclic product in
moderate yield and good purity.
In summary, we have demonstrated that 3,4-disubstituted quinolinones can be effec-
tively prepared from various substituted benzophenones or ketones and acid chlorides in
one-pot microwave reactions, compared to current methods, which all require high con-
centration of bases, refluxing at high temperatures, and long reaction times. Because a
wide range of acid chlorides are commercially available, synthesis of benzyl-aryl ketones
are feasible and a large number of 3,4-disubstituted-2-quinolinones can be easily obtained
within minutes using the microwave-assisted conditions.
EXPERIMENTAL
Solvents and fine chemicals were purchased from Aldrich chemical company
(Castle Hill, Australia) and used as supplied.
LC-MS Analysis
Liquid Chromatographic (LC) analysis was conducted with a Phenomenex
C18 (20×4.00mm) column, using isocratic mobile phase containing 10% acetonitrile,
89.9% water, and 0.1% of formic acid solution. Detection was measured at 214nm
and a flow rate was constant at 0.5ml/min. Mass Spectral (MS) analysis was con-
ducted with a Finnigan LCQ Avantage Max system. Proton (1H) and Carbon (13 C)
NMR spectra were recorded with a Bruker-300 spectrometer operating at 300 MHz
for proton. All spectra were recorded in CDCl3 or MeOD-d4 at 25°C.
Typical Reaction Condition A Compound 1 (Entry 1, Product)
Triethyl amine (1ml) was added to a mixture of ethyl malonyl chloride (180.6mg,
1.2mmol) and benzophenone (197mg, 1mmol) in dichloromethane (2ml). The result-
ant mixture was stirred at 60°C for 30min. After the reaction, the mixture was filtered
through a plug of silica and eluded by 10ml of 5% methanol in dichloromethane. The
filtrate was collected and concentrated under reduced pressure to afford the cyclized
product 1 (entry 1, 280mg, 95%).

SYNTHESIS OF 3,4-DISUBSTITUTED 2-QUINOLINONES
1127
Compound 1 (Entry 1, Product)
1
Rt =5.13min. by LC; MS: m/z=294.5 [M+H]+; H NMR (300 MHz, CDCl3):
7.48–7.61 (m, 5 H), 7.39–7.45 (m, 2H), 7.31 (d, J=8.3Hz, 1H), 7.10–7.12 (m, 1H)
4.15 (q, J=7.3Hz, 2H), 0.99 (t, J=7.1Hz, 3H); 13 C NMR (75 MHz, CDCl3): 165.53,
150.66, 138.42, 134.67, 131.55, 128.86, 128.82, 128.35, 127.62, 122.94, 119.55, 116.82,
61.33,13.71.
Typical Reaction Condition B Compound 7 (Entry 7, Product)
Ethyl malonyl chloride (98.5mg, 0.5mmol) and hydrocinnamoyl chloride
(84mg, 0.5mmol) in 2ml of dichloromethane were dispensed in 10-ml microwave ves-
sel. Sodium hydride (38mg, 1mmol, 60% in mineral oil) was added slowly in small
portions to the mixture. The vessel was capped and placed in the microwave reac-
tor (Explorer-24, CEM) under 150°C, 200psi for 30min. After reaction, the reaction
mixture was subjected to chromatography (SiO2, 5% methanol in dichloromethane) to
afford the desired product (entry 7, 152mg, 92 % yield):
Compound 7 (Entry 7, Product)
1
Rt =7.95min. by LC; MS: m/z=312.2 [M+H]+; H NMR (300 MHz, CDCl3):
7.28–7.54 (m, 4H), 7.12–7.35 (m, 8H), 7.09 (d, J=4Hz, 2H), 3.97 (s, 2H); 13 C NMR
(75 MHz, CDCl3): 164.36, 150.03, 140.57, 137.56, 136.38, 130.19, 129.73, 128.98,
128.66, 128.56, 128.12, 128.04, 127.07, 125.72, 122.18, 121.19, 115.99, 33.59.
SUPPLEMENTAL MATERIAL
Supplemental date for this article can be accessed on the publisher’s Web site.
REFERENCES
1. Kobayashi, Y.; Harayama, T. Org. Letters 2009, 11, 1603–606.
2. Lee, K. Y.; Kim, N. Bull. Korean Chem. Soc. 2002, 23 (7), 939–940.
3. Jung, J.; Yung, Y.; Park, O. J. Heterocycl. Chem. 2001, 38 (61), 61–67.
4. Minville, J.; Poulin, J.; Dufresne, C.; Sturino, C. F., Tetrahedron Lett. 2008, 49, 3677–3681.
5. Park, K. K.; Lee, J. J. Tetrahedron 2004, 60, 2993–2999.
6. Wall, M. J.; Chen, J.; Meegalla, S.; Ballentine, S. K.; Wilson, K. J.; Desjarlais, R. L.; Schubert, C.;
Chaikin, M. K.; Crysler, C.; Petrourina, I. P.; Donatelli, R. R.; Yurkow, E. J.; Boczon, L.;
Mazzulla, M.; Player, M. R.; Patch, R. J.; Manthey, C. L.; Molloy, C.; Tomczuk, B.; Illig, C. R.
Bioorg. Med. Chem. Lett. 2008, 18, 2097–2102.
7. Jang, L.; Luo, Y.; Yu, S.; Lu, W. J. Heterocyl. Chem. 2012, 49, 1254–1256.
8. Wang, J.; Discodia, R. P.; Crispino, G. A.; Li, J.; Grosso, J. A.; Polniaszek, R.; Truc, V. C.
Tetrahedron Lett. 2003, 44, 4271–4273.
9. All starting materials (except for entries 3 and 4) are commercially available, purchased from
Aldrich chemical company (Castle Hill, Australia), and used as supplied. Starting materials
for entries 3 and 4 were prepared according to the literature procedures (Glennon, R. A.;
Schubert, E.; Jacyno, J. M. J. Med. Chem. 1980, 23, 1222–1226).