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A new insight into the Pfitzinger reaction. A facile synthesis of 6-sulfamoylquinoline-4-carboxylic acids
Tetrahedron Letters Tetrahedron Letters 45 (2004) 5473–5476
A new insight into the Pfitzinger reaction. A facile synthesis of 6-sulfamoylquinoline-4-carboxylic acids Alexandre V. Ivachtchenko,* Alexander V. Khvat, Vladimir V. Kobak, Volodymir M. Kysil and Caroline T. Williams Chemical Diversity Labs, Inc., 11558 Sorrento Valley Rd., Suite 5, San Diego, CA 92121, USA Received 7 April 2004; revised 3 May 2004; accepted 7 May 2004
Abstract—The unusual formation of 6-sulfamoylquinoline-4-carboxylic acids from 5-sulfamoylisatins under the conditions of Pfitzinger reaction is described. Key step in the suggested mechanism is the reaction of in situ generated acetaldehyde with the hydrolytically cleaved isatin ring. The suggested mechanism has been confirmed by dynamic LCMS measurements and by reactions with isotopically labeled reactants. 2004 Published by Elsevier Ltd.
1. Introduction The Pfitzinger reaction1 of isatins with a-methylene carbonyl compounds is widely used for the synthesis of physiologically active derivatives of substituted quinoline-4-carboxylic acids.2 For example, the interaction of various substituted derivatives of isatin with diethyl malonate under the Pfitzinger reaction conditions leads to the formation of the corresponding 2-oxo-1,2-dihydroquinoline-4-carboxylic acids.3 Recently we described the Pfitzinger reaction of 5-sulfamoylisatins with acetone, methyl aryl ketones, methyl heteroaryl ketones, cyclohexanone, and acetoacetic acid esters.4 We have shown that the reaction proceeds in the traditional way; the corresponding 2-substituted 6-sulfamoylquinoline-4carboxylic acids, such as 7-(4-methylpiperidinosulfonyl)-1,2,3,4-tetrahydro-9-acridinecarboxylic acid and 2-methyl-6-(4-methylpiperidinosulfonyl)-3,4-quinolinedicarboxylic acid, were isolated as the main products of this reaction. Recently, we discovered an unusual behavior of a 5-sulfamoylisatin in its interaction with diethyl malonate under the normal conditions of Pfitzinger reaction.5 We have observed that 6-sulfamoylquinoline-4-carboxylic
Keywords: Pfitzinger reaction; 5-Sulfamoylisatins; Quinoline-4-carboxylic acids; Ethanol; Acetaldehyde. * Corresponding author. Tel.: +858-794-4860; fax: +858-794-4931; e-mail: [email protected] 0040-4039/$ - see front matter 2004 Published by Elsevier Ltd. doi:10.1016/j.tetlet.2004.05.028
acid was isolated as the major product instead of the anticipated 2-oxo-1,2-dihydroquinoline-4-carboxylic acid. The structure of the reaction product was established by NMR studies, including HMBC and HMQC correlations. To investigate the observed phenomenon, we reacted two 5-sulfamoylisatins 1a,b with diethyl malonate under (a) thermal (classical Pfitzinger reaction), and (b) microwave conditions. The reactions proceeded in ethanol–water media, in the presence of KOH. In both cases, we observed formation of the corresponding 6-sulfamoylquinoline-4-carboxylic acids 3a,b,6 as the major reaction products, in moderate yields (35–42%) (Scheme 1). We can suggest the following mechanism for the observed transformations (Scheme 2). In the first step, 5-sulfamoylisatines 1a,b undergo alkali-mediated hydrolysis leading to their ring-opened forms 4a,b. The products of hydrolysis react with ethanol under strong basic conditions yielding hemi-acetals 5a,b. The intermolecular conversions within the hemi-acetal lead to acetaldehyde and anions 6a,b and 7a,b; the latters are further converted into 3-hydroxyindolones 8a,b upon the acidic work-up of the reaction mixture. Acetaldehyde reacts in situ with the open-chain hydrolyzed forms of isatin 4a,b to afford 4-carboxyquinolines 3a,b. This condensation proceeds more rapidly than the competitive classical Pfitzinger reaction, and, therefore, the products of condensation of 4a,b with malonate,
5474
A. V. Ivachtchenko et al. / Tetrahedron Letters 45 (2004) 5473–5476 OH
O O
R
S
O R
O
O
S
O
O
O
+
N H
O
EtO
(a) or (b)
2a,b
O
N H
OEt OH
O O
R
S
1a: R = NEt 2 O
1b: R = N
N 3a,b
Scheme 1. Reagents and conditions: (a) KOH, 1:1 EtOH/H2 O, reflux, 8–12 h, yield 40% (3a), 42% (3b); (b) KOH, 1:1 EtOH/H2 O, microwave irradiation (150–180 C), 5–30 min, yield 35% (3a), 38% (3b).
O
R1
HO
O
S
R1
OH -
O
S
O
O
O N H
NH2 4a,b
1a,b H R1
O
O
H
H O
O
H COOH
S
O
O
O
H
O
R1
S
COOH
-H2O
NH2 5a,b
4a,b H O
O C
S
O
O
O
NH2
R1
H
O
COOH
O H
O
R1
S
H+
+
COOH
O
NH2
-H2O
7a,b HO R1 O
O
R1
NH2 4a,b
O
S
O
-2H2O
N 3a,b HO R1
CH2(COOEt)2
O N H
O
HO
O O
OH
8a,b
O S
O S
O
O
NH2
6a,b
R1
O
O S
O N H 2a,b
O
Scheme 2. Mechanism of conversion of 5-sulfamoylisatins into 6-sulfamoylquinoline-4-carboxylic acids.
2-oxo-1,2-dihydroquinoline-4-carboxylic acids 2a,b, are not formed.
subsequent reactions are kinetically controlled and are favorable over the classical Pfitzinger pathway.
The unanticipated behavior of isatin in these transformations can be explained by introduction of sulfonamide substituents into position 5 of isatin moiety. This electron-withdrawing group increases the susceptibility of isatin carbonyl group to the nucleophilic attack and, thus, facilitates the formation of hemi-acetal 5. The
In order to experimentally confirm the suggested mechanism, we performed reaction of 5-(diethylaminosulfonyl)isatin 1a with isotopically labeled reactants. In full accordance with our hypothesis, upon the reaction of 1a with 13 C-ethanol under the described conditions we observed the formation of 13 C-labeled
A. V. Ivachtchenko et al. / Tetrahedron Letters 45 (2004) 5473–5476 H H C H3C OH 13
N
O
O
KOH/H 2O
S
O
N
O
13
N H
N
1a
Scheme 3. Reaction of 1a with
C
9 13
ent CHCl3 –CH3 OH, 19:1 v/v) or by recrystallization from ethyl acetate. Yield: 40% (3a), 42% (3b).
S
O
O
OH
O
5475
C-labeled ethanol.
product 9 (Scheme 3).7 We also studied the reaction of 1a with 13 CH2 (CO2 Et)2 in the presence of unlabeled ethanol. Based on results of NMR spectroscopy, no 13 C atoms were incorporated into the structure of the final product. Dynamic LCMS analysis of the reaction mixture also supports the suggested mechanism. Thus, we observed successive appearance and disappearance of the molecular ions corresponding to initial 1a, its ring-opened form 4a, a-hydroxy acid 7a and 3-hydroxyindolone 8a. Structure of 8a was confirmed by direct reduction of the 3-oxo group of the initial isatin 1a with sodium hydrogen sulfite in water. Identical analytical spectral data8 suggest the identical structures for compounds synthesized using these alternative routes. In summary, we have investigated the Pfitzinger reaction of two different 5-sulfamoylisatins with diethyl malonate in ethanol–water media and found that it affords quinoline-4-carboxylic acids instead of the anticipated 2-oxo1,2-dihydroquinoline-4-carboxylic acids. Based on the dynamic LCMS analysis of the reaction mixture and on analysis of reactions with isotopically labeled reagents, we hypothesize a possible mechanism for the observed transformations. According to this scheme, the co-solvent, ethanol, is oxidized in situ to acetaldehyde, which is then incorporated in the structure of the quinoline-4carboxylic acid. The described observations provide interesting insights into the mechanism of Pfitzinger reaction and into the chemistry of sulfamoylisatins representing an important class of synthetic targets with promising biological activity.
2. General procedure for the synthesis of 6-sulfamoylquinoline-4-carboxylic acids 2.1. Method A: using conventional heating 5-Sulfamoylisatin 1a,b (5.0 mmol) was added to a solution of 5.64 g (100.7 mmol) of KOH in 32 mL of ethanol–water (1:1). The reaction mixture was heated at reflux for 8 h, then cooled to room temperature and acidified with 1 N HCl until pH 1. The resulting mixture was extracted with ethyl acetate (3 · 50 mL), the organic extracts were combined and dried over anhydrous MgSO4 . The solvent was removed in vacuo, and the residue was purified by silica gel chromatography (elu-
2.2. Method B: using microwave heating 5-Sulfamoylisatin 1a,b (0.15 mmol) was added to 3 mL of a 2.5 N solution of KOH in ethanol–water (1:1) in a 5 mL microwave vial. The vial was sealed and irradiated with microwaves at 180 C for 15 min. The reaction mixture was diluted with water (5 mL) and acidified with 1 N HCl until pH 3. The resulting mixture was extracted with ethyl acetate (3 · 20 mL), the combined organic extracts were washed with water (3 · 10 mL) and brine (1 · 10 mL), and dried over anhydrous MgSO4 . The solvent was removed in vacuo, and the residue was purified by preparative HPLC (C18 column (10 · 25 mm; 10 lm); 95:5–5:95 v/v water–acetonitrile gradient; flow rate 5 mL/min; analysis cycle time 15 min). Yield: 35% (3a), 38% (3b).
References and notes 1. Pfitzinger, W. J. Prakt. Chem. 1886, 33, 100. 2. For example: (a) Eastland, G., Jr.; Prous, J.; Castacer, J. Drugs Future 1988, 13, 13; (b) Dejmek, L. Drugs Future 1990, 15, 126; (c) Giardina, G. A.; Raveglia, L. F.; Grugni, M.; Sarau, H. M.; Farina, C.; Medhurst, A. D.; Graziani, D.; Schmidt, D. B.; Rigolio, R.; Luttmann, M.; Cavagnera, S.; Foley, J. J.; Vecchietti, V.; Hay, D. W. J. Med. Chem. 1999, 42, 1053–1065; (d) Suzuki, F.; Nakasato, Y.; Tsumuki, H.; Ohmori, K.; Nakajima, H.; Tamura, T.; Sato, S. U.S. Patent 5,371,225, 1993; Chem. Abstr. 1994, 120, 217318; (e) Deady, L. W.; Desneves, J.; Kaye, A. J.; Finlay, G. J.; Baguley, B. C.; Denny, W. A. Bioorg. Med. Chem. 2000, 8, 977–984. 3. For example: (a) Scipchandler, M. T.; Mattingly, P. G. Heterocycles 1990, 31, 555–561; (b) Radul, O. M.; Bukhanyuk, S. M.; Rekhter, M. A.; Zhungietu, G. I.; Ivanova, I. P. Khim. Geterotsikl. Soedin. 1982, 18, 1427–1430; (c) Morales-Rios, M. S.; Martinez-Galero, M. L.-C.; JosephNathan, P. J. Org. Chem. 1995, 60, 6194–6197; (d) Chen, S. F.; Papp, L. M.; Ardecky, R. J.; Rao, G. V.; Hesson, D. P.; Forbes, M.; Dexter, D. L. Biochem. Pharmacol. 1990, 40, 709–714; (e) Lackey, K.; Sternbach, D. D. Synthesis 1993, 10, 993–997. 4. Ivachtchenko, A. V.; Kobak, V. V.; Ilyin, A. P.; Trifilenkov, A. S.; Busel, A. A. J. Comb. Chem. 2003, 5, 645– 652. 5. Ivachtchenko, A. V.; Kobak, V. V.; Khvat, A. V.; Williams, C. T. Presented at the 19th International Congress of Heterocyclic Chemistry, Fort Collins, CO, Aug 10–15, 2003; Abstract: 12-PO-105, 205. 6. Satisfactory analytical data (IR, 1 H NMR, 13 C NMR, mass spectra, elementary analysis) were obtained for compounds 3a and 3b. Spectroscopic data of 3a: IR (KBr) 1705 cm1 (mC@O ); 1 H NMR (DMSO-d6 300 MHz (Varian), ppm) d 1.05 (t, 6H, NCH2 CH3 ), 3.22 (q, 4H, NCH2 CH3 ), 8.11 (d, 1H, Ar), 8.13 (dd, 1H, Ar), 8.30 (d, 1H, Ar), 9.21 (d, 1H, Ar), 9.30 (d, 1H, Ar), 14.2 (br s, 1H, OH); 13 C NMR (DMSO-d6 75 MHz (Varian), ppm) d 14.48, 42.26, 124.7, 126.02, 126.65, 131.73, 136.87, 139.21, 149.62, 163.63, 167.12; m=z 309.0901 [M+H]. Anal. Calcd. for C14 H16 N2 O4 S: C, 54.53; H, 5.23; N, 9.08; S, 10.40. Found: C, 54.67; H, 5.46; N, 9.21; S, 10.51. Spectroscopic data of
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A. V. Ivachtchenko et al. / Tetrahedron Letters 45 (2004) 5473–5476
3b: IR (KBr) 1705 cm1 (mC@O ); 1 H NMR (DMSO-d6 500 MHz, (Varian), ppm) d 0.83 (d, 3H), 1.14 (m, 2H), 1.26 (m, 1H), 1.61 (d, 2H), 2.30 (t, 2H), 3.66 (d, 2H), 8.05 (d, 1H), 8.12 (d, 1H), 8.30 (d, 1H), 9.21 (d, 1H), 9.24 (s, 1H), 14.1 (br s, 1H, OH); 13 C NMR (DMSO-d6 125 MHz (Varian), ppm) d 21, 29, 32, 46, 123, 126.5, 126.7, 131, 134, 136, 149, 153, 166; HMQC NMR correlations (13 Cd:1 Hd) (21:0.8), (29:1.26), (32:1.61,1.14), (46:3.66,2.30), (123:8.12), (126.5:9.24), (126.7:8.05), (131:8.30), (153:9.21); HMBC NMR correlations (13 Cd:1 Hd) (29:3.66,1.14,0.83), (32:3.66, 2.30,1.61,0.83), (46:1.14,3.66), (123:9.21,8.30,8.12), (126.5:8.05), (126.7:9.24), (134:8.30), (136:9.24,9.21), (149:9.24,9.21,8.05), (166:8.12); m=z 335.4 [M+H]. Anal. Calcd. for C16 H18 N2 O4 S: C, 57.47; H, 5.43; N, 8.38; S, 9.59. Found: C, 57.75; H, 5.84; N, 8.55; S, 10.05.
7. 6-(Diethylaminosulfonyl)quinoline-4-carboxylic acid-213 C: yield 35% (method B, ethanol-1-13 C was used); mp > 300 C (dec); 1 H NMR (Varian, 300 MHz, DMSOd6 ) d 1.07 (t, 6H, NCH2 CH3 ), 3.24 (q, 4H, NCH2 CH3 ) 8.11 (d, 1H, Ar), 8.13 (dd, 1H, Ar), 8.30 (d,1H, Ar), 9.21 (dd, 1H, Ar, JC–H ¼ 184 Hz), 9.30 (d, 1H, Ar), 14.18 (br s, 1H, OH); 13 C NMR (Varian, 75 MHz, DMSO-d6 ) d 153.44 (dd, J ¼ 184 Hz, J ¼ 4 Hz); HRMS calcd [M+H] for C13 13 CH17 N2 O4 S: 310.0944, found m=z 310.0944 [M+H]. 8. Spectroscopic data of 8a: 1 H NMR (DMSO-d6 300 MHz (Varian), ppm) d 1.05 (t, 6H, NCH2 CH3 ), 3.10 (q, 4H, NCH2 CH3 ), 4.95 (d, 1H, CH–O), 6.36 (d, 1H, exchangeable in D2 O, OH), 6.95 (d, 1H, Ar), 7.61 (s, 1H, Ar), 7.66 (d, 1H, Ar), 10.69 (s, 1H, NH); m=z 285 [M+H].
A new insight into the Pfitzinger reaction. A facile synthesis of 6-sulfamoylquinoline-4-carboxylic acids Alexandre V. Ivachtchenko,* Alexander V. Khvat, Vladimir V. Kobak, Volodymir M. Kysil and Caroline T. Williams Chemical Diversity Labs, Inc., 11558 Sorrento Valley Rd., Suite 5, San Diego, CA 92121, USA Received 7 April 2004; revised 3 May 2004; accepted 7 May 2004
Abstract—The unusual formation of 6-sulfamoylquinoline-4-carboxylic acids from 5-sulfamoylisatins under the conditions of Pfitzinger reaction is described. Key step in the suggested mechanism is the reaction of in situ generated acetaldehyde with the hydrolytically cleaved isatin ring. The suggested mechanism has been confirmed by dynamic LCMS measurements and by reactions with isotopically labeled reactants. 2004 Published by Elsevier Ltd.
1. Introduction The Pfitzinger reaction1 of isatins with a-methylene carbonyl compounds is widely used for the synthesis of physiologically active derivatives of substituted quinoline-4-carboxylic acids.2 For example, the interaction of various substituted derivatives of isatin with diethyl malonate under the Pfitzinger reaction conditions leads to the formation of the corresponding 2-oxo-1,2-dihydroquinoline-4-carboxylic acids.3 Recently we described the Pfitzinger reaction of 5-sulfamoylisatins with acetone, methyl aryl ketones, methyl heteroaryl ketones, cyclohexanone, and acetoacetic acid esters.4 We have shown that the reaction proceeds in the traditional way; the corresponding 2-substituted 6-sulfamoylquinoline-4carboxylic acids, such as 7-(4-methylpiperidinosulfonyl)-1,2,3,4-tetrahydro-9-acridinecarboxylic acid and 2-methyl-6-(4-methylpiperidinosulfonyl)-3,4-quinolinedicarboxylic acid, were isolated as the main products of this reaction. Recently, we discovered an unusual behavior of a 5-sulfamoylisatin in its interaction with diethyl malonate under the normal conditions of Pfitzinger reaction.5 We have observed that 6-sulfamoylquinoline-4-carboxylic
Keywords: Pfitzinger reaction; 5-Sulfamoylisatins; Quinoline-4-carboxylic acids; Ethanol; Acetaldehyde. * Corresponding author. Tel.: +858-794-4860; fax: +858-794-4931; e-mail: [email protected] 0040-4039/$ - see front matter 2004 Published by Elsevier Ltd. doi:10.1016/j.tetlet.2004.05.028
acid was isolated as the major product instead of the anticipated 2-oxo-1,2-dihydroquinoline-4-carboxylic acid. The structure of the reaction product was established by NMR studies, including HMBC and HMQC correlations. To investigate the observed phenomenon, we reacted two 5-sulfamoylisatins 1a,b with diethyl malonate under (a) thermal (classical Pfitzinger reaction), and (b) microwave conditions. The reactions proceeded in ethanol–water media, in the presence of KOH. In both cases, we observed formation of the corresponding 6-sulfamoylquinoline-4-carboxylic acids 3a,b,6 as the major reaction products, in moderate yields (35–42%) (Scheme 1). We can suggest the following mechanism for the observed transformations (Scheme 2). In the first step, 5-sulfamoylisatines 1a,b undergo alkali-mediated hydrolysis leading to their ring-opened forms 4a,b. The products of hydrolysis react with ethanol under strong basic conditions yielding hemi-acetals 5a,b. The intermolecular conversions within the hemi-acetal lead to acetaldehyde and anions 6a,b and 7a,b; the latters are further converted into 3-hydroxyindolones 8a,b upon the acidic work-up of the reaction mixture. Acetaldehyde reacts in situ with the open-chain hydrolyzed forms of isatin 4a,b to afford 4-carboxyquinolines 3a,b. This condensation proceeds more rapidly than the competitive classical Pfitzinger reaction, and, therefore, the products of condensation of 4a,b with malonate,
5474
A. V. Ivachtchenko et al. / Tetrahedron Letters 45 (2004) 5473–5476 OH
O O
R
S
O R
O
O
S
O
O
O
+
N H
O
EtO
(a) or (b)
2a,b
O
N H
OEt OH
O O
R
S
1a: R = NEt 2 O
1b: R = N
N 3a,b
Scheme 1. Reagents and conditions: (a) KOH, 1:1 EtOH/H2 O, reflux, 8–12 h, yield 40% (3a), 42% (3b); (b) KOH, 1:1 EtOH/H2 O, microwave irradiation (150–180 C), 5–30 min, yield 35% (3a), 38% (3b).
O
R1
HO
O
S
R1
OH -
O
S
O
O
O N H
NH2 4a,b
1a,b H R1
O
O
H
H O
O
H COOH
S
O
O
O
H
O
R1
S
COOH
-H2O
NH2 5a,b
4a,b H O
O C
S
O
O
O
NH2
R1
H
O
COOH
O H
O
R1
S
H+
+
COOH
O
NH2
-H2O
7a,b HO R1 O
O
R1
NH2 4a,b
O
S
O
-2H2O
N 3a,b HO R1
CH2(COOEt)2
O N H
O
HO
O O
OH
8a,b
O S
O S
O
O
NH2
6a,b
R1
O
O S
O N H 2a,b
O
Scheme 2. Mechanism of conversion of 5-sulfamoylisatins into 6-sulfamoylquinoline-4-carboxylic acids.
2-oxo-1,2-dihydroquinoline-4-carboxylic acids 2a,b, are not formed.
subsequent reactions are kinetically controlled and are favorable over the classical Pfitzinger pathway.
The unanticipated behavior of isatin in these transformations can be explained by introduction of sulfonamide substituents into position 5 of isatin moiety. This electron-withdrawing group increases the susceptibility of isatin carbonyl group to the nucleophilic attack and, thus, facilitates the formation of hemi-acetal 5. The
In order to experimentally confirm the suggested mechanism, we performed reaction of 5-(diethylaminosulfonyl)isatin 1a with isotopically labeled reactants. In full accordance with our hypothesis, upon the reaction of 1a with 13 C-ethanol under the described conditions we observed the formation of 13 C-labeled
A. V. Ivachtchenko et al. / Tetrahedron Letters 45 (2004) 5473–5476 H H C H3C OH 13
N
O
O
KOH/H 2O
S
O
N
O
13
N H
N
1a
Scheme 3. Reaction of 1a with
C
9 13
ent CHCl3 –CH3 OH, 19:1 v/v) or by recrystallization from ethyl acetate. Yield: 40% (3a), 42% (3b).
S
O
O
OH
O
5475
C-labeled ethanol.
product 9 (Scheme 3).7 We also studied the reaction of 1a with 13 CH2 (CO2 Et)2 in the presence of unlabeled ethanol. Based on results of NMR spectroscopy, no 13 C atoms were incorporated into the structure of the final product. Dynamic LCMS analysis of the reaction mixture also supports the suggested mechanism. Thus, we observed successive appearance and disappearance of the molecular ions corresponding to initial 1a, its ring-opened form 4a, a-hydroxy acid 7a and 3-hydroxyindolone 8a. Structure of 8a was confirmed by direct reduction of the 3-oxo group of the initial isatin 1a with sodium hydrogen sulfite in water. Identical analytical spectral data8 suggest the identical structures for compounds synthesized using these alternative routes. In summary, we have investigated the Pfitzinger reaction of two different 5-sulfamoylisatins with diethyl malonate in ethanol–water media and found that it affords quinoline-4-carboxylic acids instead of the anticipated 2-oxo1,2-dihydroquinoline-4-carboxylic acids. Based on the dynamic LCMS analysis of the reaction mixture and on analysis of reactions with isotopically labeled reagents, we hypothesize a possible mechanism for the observed transformations. According to this scheme, the co-solvent, ethanol, is oxidized in situ to acetaldehyde, which is then incorporated in the structure of the quinoline-4carboxylic acid. The described observations provide interesting insights into the mechanism of Pfitzinger reaction and into the chemistry of sulfamoylisatins representing an important class of synthetic targets with promising biological activity.
2. General procedure for the synthesis of 6-sulfamoylquinoline-4-carboxylic acids 2.1. Method A: using conventional heating 5-Sulfamoylisatin 1a,b (5.0 mmol) was added to a solution of 5.64 g (100.7 mmol) of KOH in 32 mL of ethanol–water (1:1). The reaction mixture was heated at reflux for 8 h, then cooled to room temperature and acidified with 1 N HCl until pH 1. The resulting mixture was extracted with ethyl acetate (3 · 50 mL), the organic extracts were combined and dried over anhydrous MgSO4 . The solvent was removed in vacuo, and the residue was purified by silica gel chromatography (elu-
2.2. Method B: using microwave heating 5-Sulfamoylisatin 1a,b (0.15 mmol) was added to 3 mL of a 2.5 N solution of KOH in ethanol–water (1:1) in a 5 mL microwave vial. The vial was sealed and irradiated with microwaves at 180 C for 15 min. The reaction mixture was diluted with water (5 mL) and acidified with 1 N HCl until pH 3. The resulting mixture was extracted with ethyl acetate (3 · 20 mL), the combined organic extracts were washed with water (3 · 10 mL) and brine (1 · 10 mL), and dried over anhydrous MgSO4 . The solvent was removed in vacuo, and the residue was purified by preparative HPLC (C18 column (10 · 25 mm; 10 lm); 95:5–5:95 v/v water–acetonitrile gradient; flow rate 5 mL/min; analysis cycle time 15 min). Yield: 35% (3a), 38% (3b).
References and notes 1. Pfitzinger, W. J. Prakt. Chem. 1886, 33, 100. 2. For example: (a) Eastland, G., Jr.; Prous, J.; Castacer, J. Drugs Future 1988, 13, 13; (b) Dejmek, L. Drugs Future 1990, 15, 126; (c) Giardina, G. A.; Raveglia, L. F.; Grugni, M.; Sarau, H. M.; Farina, C.; Medhurst, A. D.; Graziani, D.; Schmidt, D. B.; Rigolio, R.; Luttmann, M.; Cavagnera, S.; Foley, J. J.; Vecchietti, V.; Hay, D. W. J. Med. Chem. 1999, 42, 1053–1065; (d) Suzuki, F.; Nakasato, Y.; Tsumuki, H.; Ohmori, K.; Nakajima, H.; Tamura, T.; Sato, S. U.S. Patent 5,371,225, 1993; Chem. Abstr. 1994, 120, 217318; (e) Deady, L. W.; Desneves, J.; Kaye, A. J.; Finlay, G. J.; Baguley, B. C.; Denny, W. A. Bioorg. Med. Chem. 2000, 8, 977–984. 3. For example: (a) Scipchandler, M. T.; Mattingly, P. G. Heterocycles 1990, 31, 555–561; (b) Radul, O. M.; Bukhanyuk, S. M.; Rekhter, M. A.; Zhungietu, G. I.; Ivanova, I. P. Khim. Geterotsikl. Soedin. 1982, 18, 1427–1430; (c) Morales-Rios, M. S.; Martinez-Galero, M. L.-C.; JosephNathan, P. J. Org. Chem. 1995, 60, 6194–6197; (d) Chen, S. F.; Papp, L. M.; Ardecky, R. J.; Rao, G. V.; Hesson, D. P.; Forbes, M.; Dexter, D. L. Biochem. Pharmacol. 1990, 40, 709–714; (e) Lackey, K.; Sternbach, D. D. Synthesis 1993, 10, 993–997. 4. Ivachtchenko, A. V.; Kobak, V. V.; Ilyin, A. P.; Trifilenkov, A. S.; Busel, A. A. J. Comb. Chem. 2003, 5, 645– 652. 5. Ivachtchenko, A. V.; Kobak, V. V.; Khvat, A. V.; Williams, C. T. Presented at the 19th International Congress of Heterocyclic Chemistry, Fort Collins, CO, Aug 10–15, 2003; Abstract: 12-PO-105, 205. 6. Satisfactory analytical data (IR, 1 H NMR, 13 C NMR, mass spectra, elementary analysis) were obtained for compounds 3a and 3b. Spectroscopic data of 3a: IR (KBr) 1705 cm1 (mC@O ); 1 H NMR (DMSO-d6 300 MHz (Varian), ppm) d 1.05 (t, 6H, NCH2 CH3 ), 3.22 (q, 4H, NCH2 CH3 ), 8.11 (d, 1H, Ar), 8.13 (dd, 1H, Ar), 8.30 (d, 1H, Ar), 9.21 (d, 1H, Ar), 9.30 (d, 1H, Ar), 14.2 (br s, 1H, OH); 13 C NMR (DMSO-d6 75 MHz (Varian), ppm) d 14.48, 42.26, 124.7, 126.02, 126.65, 131.73, 136.87, 139.21, 149.62, 163.63, 167.12; m=z 309.0901 [M+H]. Anal. Calcd. for C14 H16 N2 O4 S: C, 54.53; H, 5.23; N, 9.08; S, 10.40. Found: C, 54.67; H, 5.46; N, 9.21; S, 10.51. Spectroscopic data of
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3b: IR (KBr) 1705 cm1 (mC@O ); 1 H NMR (DMSO-d6 500 MHz, (Varian), ppm) d 0.83 (d, 3H), 1.14 (m, 2H), 1.26 (m, 1H), 1.61 (d, 2H), 2.30 (t, 2H), 3.66 (d, 2H), 8.05 (d, 1H), 8.12 (d, 1H), 8.30 (d, 1H), 9.21 (d, 1H), 9.24 (s, 1H), 14.1 (br s, 1H, OH); 13 C NMR (DMSO-d6 125 MHz (Varian), ppm) d 21, 29, 32, 46, 123, 126.5, 126.7, 131, 134, 136, 149, 153, 166; HMQC NMR correlations (13 Cd:1 Hd) (21:0.8), (29:1.26), (32:1.61,1.14), (46:3.66,2.30), (123:8.12), (126.5:9.24), (126.7:8.05), (131:8.30), (153:9.21); HMBC NMR correlations (13 Cd:1 Hd) (29:3.66,1.14,0.83), (32:3.66, 2.30,1.61,0.83), (46:1.14,3.66), (123:9.21,8.30,8.12), (126.5:8.05), (126.7:9.24), (134:8.30), (136:9.24,9.21), (149:9.24,9.21,8.05), (166:8.12); m=z 335.4 [M+H]. Anal. Calcd. for C16 H18 N2 O4 S: C, 57.47; H, 5.43; N, 8.38; S, 9.59. Found: C, 57.75; H, 5.84; N, 8.55; S, 10.05.
7. 6-(Diethylaminosulfonyl)quinoline-4-carboxylic acid-213 C: yield 35% (method B, ethanol-1-13 C was used); mp > 300 C (dec); 1 H NMR (Varian, 300 MHz, DMSOd6 ) d 1.07 (t, 6H, NCH2 CH3 ), 3.24 (q, 4H, NCH2 CH3 ) 8.11 (d, 1H, Ar), 8.13 (dd, 1H, Ar), 8.30 (d,1H, Ar), 9.21 (dd, 1H, Ar, JC–H ¼ 184 Hz), 9.30 (d, 1H, Ar), 14.18 (br s, 1H, OH); 13 C NMR (Varian, 75 MHz, DMSO-d6 ) d 153.44 (dd, J ¼ 184 Hz, J ¼ 4 Hz); HRMS calcd [M+H] for C13 13 CH17 N2 O4 S: 310.0944, found m=z 310.0944 [M+H]. 8. Spectroscopic data of 8a: 1 H NMR (DMSO-d6 300 MHz (Varian), ppm) d 1.05 (t, 6H, NCH2 CH3 ), 3.10 (q, 4H, NCH2 CH3 ), 4.95 (d, 1H, CH–O), 6.36 (d, 1H, exchangeable in D2 O, OH), 6.95 (d, 1H, Ar), 7.61 (s, 1H, Ar), 7.66 (d, 1H, Ar), 10.69 (s, 1H, NH); m=z 285 [M+H].