- Email: [email protected]
Facile and efficient synthesis of quinoline-4-carboxylic acids under microwave irradiation
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 been described for the synthesis of 2-substituted quinoline-4-carboxylic acids, including Pfitzinger 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-4carboxylic 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: [email protected] (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
36
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 3 4 5 6 7 8 9 10
Water Water Water Water Water Water Water Water Ethanol Water
MW MW MW MW MW MW MW MW MW CHb
50 70 90 110 110 110 110 150 110 110
15 min 15 min 15 min 3 min 5 min 10 min 20 min 10 min 10 min 6h
68 78 82 77 85 92 89 82 86 45
a b
Isolated yield. 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 3 4 5 6 7 8 9 10 11
H H H H Br H H H H H F
H F Cl Br H H H OMe H OEt H
H H H H H H Br H H H H
H H H H H F H H OMe H H
a b c d e f g h i j k
10 10 10 10 10 10 10 15 15 15 15
92 93 91 92 89 94 95 85 84 82 87
a
All the products were characterized by 1H NMR.
13
C 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] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18]
J. Striga´c´ova´, D. Hudecova´, Folia Microbiol. 45 (2000) 305. B.S. Holla, K.N. Poojary, et al. Indian J. Chem. Sect. B 44 (2005) 2114. G. Stemp, T. Ashmeade, et al. J. Med. Chem. 43 (2000) 1878. P.W. Smith, L.A. Dawson, Drug Discov. 3 (2008) 1. N. Kaila, K. Janz, et al. J. Med. Chem. 50 (2007) 21. W.J. Pfitzinger, J. Prakt. Chem. 33 (1886) 100. L. Karen, D.D. Sternbach, Synthesis (1993) 993. M.G. Shvekhgeimer, N.N. Kondrashova, Dokl. Akad. Nauk. 383 (2002) 221. O. Doebner, Bericht 16 (1883) 2357. S.H. Park, Bull. Korean Chem. Soc. 24 (2003) 677. D. Duvelleroy, C. Perrio, et al. Org. Biomol. Chem. 3 (2005) 3794. S. Sakaguchi, A. Shibamoto, et al. Chem. Commun. (2002) 180. K.N. Campbell, J. Org. Chem. 11 (1946) 803. P. Phillips, J. Am. Chem. Soc. 68 (1946) 2568. S. Dumouchel, F. Mongin, et al. Tetrahedron Lett. 44 (2003) 2033. R.R. Renshaw, J. Am. Chem. Soc. 61 (1939) 3320. A.E. Senear, J.F. Mead, J. Am. Chem. Soc. 68 (1946) 2695. V.B. Brasyunas, A.T. Andreyanova, Chem. Heterocycl. Compd. 24 (1988) 670.
38 [19] [20] [21] [22]
H. Zhu et al. / Chinese Chemical Letters 21 (2010) 35–38
H.E. Ashry, E.S. Ramadan, Synth. Commun. 35 (2005) 2243. J.F. Silva, S.J. Garden, et al. J. Braz. Chem. Soc. 12 (2001) 273. M.G. Shvekhgeimer, Chem. Heterocycl. Compd. 40 (2004) 257. 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.
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 been described for the synthesis of 2-substituted quinoline-4-carboxylic acids, including Pfitzinger 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-4carboxylic 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: [email protected] (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
36
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 3 4 5 6 7 8 9 10
Water Water Water Water Water Water Water Water Ethanol Water
MW MW MW MW MW MW MW MW MW CHb
50 70 90 110 110 110 110 150 110 110
15 min 15 min 15 min 3 min 5 min 10 min 20 min 10 min 10 min 6h
68 78 82 77 85 92 89 82 86 45
a b
Isolated yield. 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 3 4 5 6 7 8 9 10 11
H H H H Br H H H H H F
H F Cl Br H H H OMe H OEt H
H H H H H H Br H H H H
H H H H H F H H OMe H H
a b c d e f g h i j k
10 10 10 10 10 10 10 15 15 15 15
92 93 91 92 89 94 95 85 84 82 87
a
All the products were characterized by 1H NMR.
13
C 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] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18]
J. Striga´c´ova´, D. Hudecova´, Folia Microbiol. 45 (2000) 305. B.S. Holla, K.N. Poojary, et al. Indian J. Chem. Sect. B 44 (2005) 2114. G. Stemp, T. Ashmeade, et al. J. Med. Chem. 43 (2000) 1878. P.W. Smith, L.A. Dawson, Drug Discov. 3 (2008) 1. N. Kaila, K. Janz, et al. J. Med. Chem. 50 (2007) 21. W.J. Pfitzinger, J. Prakt. Chem. 33 (1886) 100. L. Karen, D.D. Sternbach, Synthesis (1993) 993. M.G. Shvekhgeimer, N.N. Kondrashova, Dokl. Akad. Nauk. 383 (2002) 221. O. Doebner, Bericht 16 (1883) 2357. S.H. Park, Bull. Korean Chem. Soc. 24 (2003) 677. D. Duvelleroy, C. Perrio, et al. Org. Biomol. Chem. 3 (2005) 3794. S. Sakaguchi, A. Shibamoto, et al. Chem. Commun. (2002) 180. K.N. Campbell, J. Org. Chem. 11 (1946) 803. P. Phillips, J. Am. Chem. Soc. 68 (1946) 2568. S. Dumouchel, F. Mongin, et al. Tetrahedron Lett. 44 (2003) 2033. R.R. Renshaw, J. Am. Chem. Soc. 61 (1939) 3320. A.E. Senear, J.F. Mead, J. Am. Chem. Soc. 68 (1946) 2695. V.B. Brasyunas, A.T. Andreyanova, Chem. Heterocycl. Compd. 24 (1988) 670.
38 [19] [20] [21] [22]
H. Zhu et al. / Chinese Chemical Letters 21 (2010) 35–38
H.E. Ashry, E.S. Ramadan, Synth. Commun. 35 (2005) 2243. J.F. Silva, S.J. Garden, et al. J. Braz. Chem. Soc. 12 (2001) 273. M.G. Shvekhgeimer, Chem. Heterocycl. Compd. 40 (2004) 257. 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.