Facile and efficient synthesis of quinoline-4-carboxylic acids under microwave irradiation

Article abstract of DOI:10.1016/j.cclet.2009.09.012

A facile and efficient method for the preparation of 2-non-substituted quinoline-4-carboxylic acids is described via the Pfitzinger reaction of isatins with sodium pyruvate following consequent decarboxylation under microwave irradiation.

Full text of DOI:10.1016/j.cclet.2009.09.012

Available online at www.sciencedirect.com
Chinese Chemical Letters 21 (2010) 35–38
www.elsevier.com/locate/cclet
Facile and efficient synthesis of quinoline-4-carboxylic
acids under microwave irradiation
*
Hui Zhu , Ri Fang Yang, Liu Hong Yun, Jin Li
Beijing Institute of Pharmacology and Toxicology, Department of Medicinal Chemistry, Beijing 100850, China
Received 13 May 2009
Abstract
A facile and efficient method for the preparation of 2-non-substituted quinoline-4-carboxylic acids is described via the Pfitzinger
reaction of isatins with sodium pyruvate following consequent decarboxylation under microwave irradiation.
# 2009 Hui Zhu. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Quinoline-4-carboxylic acids; Pfitzinger reaction; Microwave irradiation
Quinoline-4-carboxylic acids are of great synthetic interest due to a wide variety of medicinal applications such as
antimicrobial, antitumor, and antiinflammatory agents, or as the key intermediates for synthesis of drugs [1–5]. Various
methods have beendescribed for the synthesis of 2-substituted quinoline-4-carboxylic acids, includingPfitzinger reaction
[6–8], Doebner-pyruvic acid synthesis and aza-Diels-Alder reaction [9–11]. By contrast, there are fewer approaches for
the preparation of 2-non-substituted compounds despite their potential importance. Current synthetic routes usually
employ 4-substituted quinoline (e.g. 4-methyl, 4-styryl, 4-formyl and 4-bromo quinoline) as starting material through
corresponding oxidation or bromine–magnesium exchange reactions to afford the target compounds [12–15]. Most of the
above protocols not only require hazardous reagents but also limit adequate diversities of target compounds.
Alternatively, quinoline-4-carboxylic acids could be obtained via the Pfitzinger reaction of isatin with pyruvic acid
following selective decarboxylation of quinoline-2,4-dicarboxylic acids (QDCs) [16–18]. However, it requires long
time to accomplish this two step reactions along with low production. Recently, Ashry and Ramadan performed the
Pfitzinger type reaction of isatin with some kinds of ketones to afford corresponding 2-substituted quinoline-4-
carboxylic acids under microwave irradiation (MW) [19]. Nevertheless, the use of sodium pyruvate in this reaction has
not yet been studied. In this article, we investigated the condensation reaction between isatins and sodium pyruvate and
further optimized the microwave conditions including reaction solvent, time and temperature. We also successfully
performed the subsequent decarboxylation reaction of QDCs in water instead of toxic nitrobenzene under MW. The
detail process was described in Scheme 1, which is based on Pfitzinger reactions of substituted isatins (1) with sodium
pyruvate to form sodium salts of QDCs (2) under basic condition, then acidification and decarboxylation to afford the
desired quinoline-4-carboxylic acids (3).
* Corresponding author.
E-mail address: zwhw797@gmail.com (H. Zhu).
1001-8417/$ – see front matter # 2009 Hui Zhu. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2009.09.012

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H. Zhu et al. / Chinese Chemical Letters 21 (2010) 35–38
Scheme 1. Microwave-assisted synthesis of quinoline-4-carboxylic acids.
Table 1
Optimization of the condensation conditions in the reaction of isatin with sodium pyruvate.
Entry
Solvent
Heating
Temp (8C)
Time
Yielda (%)
1
2
Water
Water
Water
Water
Water
Water
Water
Water
Ethanol
Water
MW
MW
MW
MW
MW
MW
MW
MW
MW
CHb
50
70
15 min
15 min
15 min
3 min
68
78
82
77
85
92
89
82
86
45
3
90
4
110
110
110
110
150
110
110
5
5 min
6
10 min
20 min
10 min
10 min
6 h
7
8
9
10
a
Isolated yield.
b
Conventional heating.
The starting isatins for the Pfitzinger reaction were commercially available or prepared by the Sandmeyer reaction
of aniline derivatives with chloral hydrate and hydroxylamine hydrochloride [20]. Pfitzinger type condensation
reaction for the preparation of QDCs was carried out in a mono-mode microwave apparatus (Biotage InitiatorTM),
operating at a frequency of 2.45 GHz with continuous irradiation power from 0 to 400 W. An automatic heating
program is applied to adjust the irradiation power for the desired reaction temperature. To optimize the reaction
parameters, we performed the reaction using isatin and sodium pyruvate under several different conditions (Table 1).
The best result was obtained with 10 min hold time at 110 8C, giving QDC in 92% isolated yield (entry 6). According
to the literature, ethanol and water are both popular solvents used for Pfitzinger type condensation reactions under
conventional heating method. For comparison, we studied the reaction of isatin with sodium pyruvate in the presence
of MW in water and ethanol, and found that the yield of quinoline-4-carboxylic acid was lower when the reaction is
carried out in ethanol (entry 9). We also carried out the reaction under conventional conditions, using an external oil
bath for heating (entry 10). The experiment was carried out in a closed pressure tube at the same temperature. The 6-h
reaction time gave multiple byproducts and only 45% yield for the target compound. It clearly indicates that the
microwave initiated reaction conditions are more effective than the traditional set up.
To further demonstrate the simplicity and potential generality of this microwave-assisted reaction, a variety of
substituted isatins were subjected to the previous optimized reaction conditions, the yields were generally good. Some
trends in the QDCs synthesis were noted, that is, the yields were slightly affected by the substituents, electron
withdrawers (e.g. F, Cl, Br) facilitate the reaction, whereas strong electron donor groups (e.g. OMe, OEt) lower the
yields under the same MW condition. This observation is consistent with the proposed mechanism which involves a
base induced ring opening of isatins to render salts of the corresponding isatic acids and subsequent condensation with
sodium pyruvate [21]. In an effort to increase the yields, we further investigated the appropriate reaction time for each
reaction substrates. The results are summarized in Table 2.
Generally, QDCs were precipitated after acidification with hydrochloric acid, the precipitates were filtered with no
further purification, and directly subjected to decarboxylation. Usually, the decarboxylation of QDCs requires long
reaction time in boiling nitrobenzene free of air. In our modified method, the decarboxylation reactions were carried
out at 190–200 8C under MW using water as reaction media instead of toxic nitrobenzene, each QDCs completely
decarboxylated with high yields (ꢀ90%) in 5 min. As a reaction solvent, water offers many practical and economic
advantages including low cost, safe handling and environmental compatibility.

H. Zhu et al. / Chinese Chemical Letters 21 (2010) 35–38
37
Table 2
Synthesis of compounds 2a–k [22,23].
.
Entry
R1
R2
R3
R4
Product 2
Time (min)
Yielda (%)
1
2
H
H
H
H
Br
H
H
H
H
H
F
H
H
H
H
H
H
H
Br
H
H
H
H
H
a
b
c
d
e
f
10
10
10
10
10
10
10
15
15
15
15
92
93
91
92
89
94
95
85
84
82
87
F
H
3
Cl
Br
H
H
4
H
5
H
6
H
F
7
H
H
g
h
i
8
OMe
H
H
9
OMe
H
10
11
OEt
H
j
H
k
a
All the products were characterized by 1H NMR. 13C NMR and HRMS.
In summary, we have introduced a facile microwave-assisted process suitable for the preparation of a series of
quinoline-4-carboxylic acids. The described procedure, allowing the introduction of diverse substituents at the 5-, 6-,
7-, and/or 8-position, complements well the previously described direct synthesis of quinoline-4-carboxylic acids from
4-substituted quinolines, has the advantages of being environment-friendly, facile and convenient along with high
efficient.
Acknowledgment
We wish to thank the National Basic Research Program (No. 2003CB515400), administered by the Ministry of
Science and Technology of China.
References
´´
´
´
[1] J. Strigacova, D. Hudecova, Folia Microbiol. 45 (2000) 305.
[2] B.S. Holla, K.N. Poojary, et al. Indian J. Chem. Sect. B 44 (2005) 2114.
[3] G. Stemp, T. Ashmeade, et al. J. Med. Chem. 43 (2000) 1878.
[4] P.W. Smith, L.A. Dawson, Drug Discov. 3 (2008) 1.
[5] N. Kaila, K. Janz, et al. J. Med. Chem. 50 (2007) 21.
[6] W.J. Pfitzinger, J. Prakt. Chem. 33 (1886) 100.
[7] L. Karen, D.D. Sternbach, Synthesis (1993) 993.
[8] M.G. Shvekhgeimer, N.N. Kondrashova, Dokl. Akad. Nauk. 383 (2002) 221.
[9] O. Doebner, Bericht 16 (1883) 2357.
[10] S.H. Park, Bull. Korean Chem. Soc. 24 (2003) 677.
[11] D. Duvelleroy, C. Perrio, et al. Org. Biomol. Chem. 3 (2005) 3794.
[12] S. Sakaguchi, A. Shibamoto, et al. Chem. Commun. (2002) 180.
[13] K.N. Campbell, J. Org. Chem. 11 (1946) 803.
[14] P. Phillips, J. Am. Chem. Soc. 68 (1946) 2568.
[15] S. Dumouchel, F. Mongin, et al. Tetrahedron Lett. 44 (2003) 2033.
[16] R.R. Renshaw, J. Am. Chem. Soc. 61 (1939) 3320.
[17] A.E. Senear, J.F. Mead, J. Am. Chem. Soc. 68 (1946) 2695.
[18] V.B. Brasyunas, A.T. Andreyanova, Chem. Heterocycl. Compd. 24 (1988) 670.

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H. Zhu et al. / Chinese Chemical Letters 21 (2010) 35–38
[19] H.E. Ashry, E.S. Ramadan, Synth. Commun. 35 (2005) 2243.
[20] J.F. Silva, S.J. Garden, et al. J. Braz. Chem. Soc. 12 (2001) 273.
[21] M.G. Shvekhgeimer, Chem. Heterocycl. Compd. 40 (2004) 257.
[22] General procedure for the synthesis of 2a: A mixture of isatin 1a (1.0 mmol) and sodium pyruvate (1.2 mmol) were placed in a microwave test
tube (10 mL) containing a magnetic stirring bar, rubber cap, and 4 mL of 20% aqueous NaOH. The test tube was subjected to MW at 110 8C
(110 W) for 10–15 min. The internal pressure of the reaction vessel never surpassed 6 bar. After completion of the reaction, the tube was
removed, cooled to room temperature, The reaction solution was acidified to pH 2 with 1 mol/L aqueous hydrochloric acid. The precipitate was
collected by filtration, washed with water, and dried under vacuum. The crude product was purified by recrystallization from hot water. mp:
235–240 8C; 1H NMR (DMSO-d6): d 8.81 (d, 1H, J = 7.6 Hz), 8.48 (s, 1H,), 8.26 (d, 1H, J = 7.8 Hz), 7.95 (m, 1H), 7.86(m, 1H); 13C NMR
(DMSO-d6): d 167.4, 166.2, 148.9, 148.3, 137.6, 131.2, 131.0, 130.5, 126.0, 125.9, 122.0; HRMS (ESI) m/z calcd. for C11H7NO4 (M+H)
218.0375, found 218.0363.
[23] General procedure for the synthesis of 3a: A suspension of QDCs 2a (1.0 mmol) were placed in a microwave test tube (10 mL) containing a
magnetic stirring bar, rubber cap, and 4 mL of water. The test tube was subjected to MW at 190–200 8C for 5 min. The internal pressure of the
reaction vessel rised to 16–18 bar. After completion of the reaction, the tube was removed, cooled to room temperature. The precipitate was
collected by filtration, washed with water, and dried under vacuum. The crude product was purified by recrystallization from hot water. mp:
255–258 8C; 1HNMR (DMSO-d6): d 9.06 (d, 1H, J = 4.5 Hz), 8.72 (d, 1H, J = 8.7 Hz), 8.14 (d, 1H, J = 8.4 Hz), 7.95 (d, 1H, J = 4.2 Hz), 7.85(t,
1H, J = 7.0 Hz), 7.74(t, 1H, J = 7.0 Hz); 13C NMR (DMSO-d6): d 169.0, 151.2, 147.0, 136.1, 132.3, 130.6, 129.9, 125.1, 124.7, 121.0; HRMS
(ESI) m/z calcd. for C10H7NO2 (M+H) 174.0477, found 174.0471.