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HETEROCYCLES
An International Journal for Reviews and Communications in Heterocyclic ChemistryWeb Edition ISSN: 1881-0942
Published online by The Japan Institute of Heterocyclic Chemistry
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Received, 31st July, 2009, Accepted, 15th September, 2009, Published online, 17th September, 2009.
DOI: 10.3987/COM-09-11806
■ Heteroarylamination and Heteroarylsulfidation of 2-Chloro-1-azaazulenes
Eiko Yoshioka, Kazuya Koizumi, Shinya Yamazaki, Hiroyuki Fujii, and Noritaka Abe*
Graduate School of Medicine, Yamaguchi University, 1677-1 Yoshida, Yamaguchi 753-8512, Japan
Abstract
Heteroarylamination and heteroarylsulfidation of 2-chloro-1-azaazulenes (1) were investigated. Palladium catalyzed coupling of 2-amino-1-azaazulenes (2) with 1 underwent to give bis(1-azaazulen-2-yl)amine derivatives in good yields, but the reaction of 2-mercapto-1-azaazulenes (4) with 1 did not give good results in the same conditions. The reaction of 4 with 1 under basic conditions gave bis(1-azaazulen-2-yl) sulfide derivatives in good yields. Heteroarylamino-substitution was proceeded on the reaction of 4-amino-3-mercapto-4H-1,2,4-triazoles (6) with 1 in BuOH under reflux, whereas heteroarylsulfido-substitution was proceeded on the reaction of 6 with 1 in the presence of NaH in dioxane.The chemistry of azaazulenes1 is of interest for their physiological properties2,3 as well as physical and chemical properties. Aryl amines have a potential functionality in pharmaceutical drug candidates,4-8 therefore Pd-catalyzed amination of aryl halides has attracted attention.9 Recently, we reported that heteroarylaminatition of ethyl 2-chloro-1-azaazulene-3-carboxylate proceeded well by Pd-catalyzed amination.10 In the extension of the chemistry, we examined the reaction of 2-chloro-1-azaazulenes with 2-amino-1-azaazulenes, mercapto-1-azaazulenes, and 4-amino-3-mercapto-4H-1,2,4-triazoles.
Treatment of 2-chloro-1-azaazulene (1a) with 2-amino-1-azaazulene (2a) in the presence of Pd2(dba)3, Xantphos, and Cs2CO3 in dioxane under reflux for 4 h gave bis(1-azaazulen-2-yl)amine (3aa) in 39% yield. The 1H NMR spectrum of 3aa was symmetrical and the 13C NMR spectrum showed 9 signals; this showed that heteroarylamination occurred at amino group at C-2, and not at N-1 of 1-azaazulene nuclei. Similar treatment of 1b, 1c, and 1d with 2a and 2b gave 3ba (70%), 3ca (63%), and 3db (43%), respectively. Although the yields were slightly low as the case, the usefulness of Pd-catalyzed heteroarylamination was certified for the synthesis of bis(1-azaazulen-2-yl)amine derivatives.
Next, we investigated the reaction of 2-chloro-1-azaazulenes with 2-mercapto-1-azaazulenes. Treatment of 1b with 4a in the presence of Pd2(dba)3, Xantphos, and Cs2CO3 in dry 1,4-dioxane for 24 h under reflux gave 5ba in 50% yield. In a similar manner, the reaction of 1c with 4a gave 5ca (38%). Although the coupling products were obtained, the yields were not so well, and it is considered that the occurrence of SNAr reaction was within the bounds of possibility, because it is known that SNAr reaction occurs in the reaction of 2-chloro-1-azaazulenes with good nucleophile, such as alkoxide and sulfoxide.1 In addition, the possibility of poisoning of Pd-catalyst by S-atom would be considered. Therefore, we performed the reaction of 1a with 4a in the presence of NaH in dry 1,4-dioxane for 4 h under reflux, and 5aa was obtained in 88% yield. In a similar manner, the reaction of 1b and 1c with 4a and 4b gave 5ba (71%), 5ca (80%), and 5cb (85%), respectively. Thus, the reaction of 2-mercapto-1-azaazulenes in the presence of base was preferred to undergo the SNAr reaction on S-atom and gave bis(1-azaazulen-2-yl) sulfides, and heteroarylamination on N-1 atom of 4 did not proceed.
Next, for comparison of the reactivity of SH and NH2 groups in the reaction, we adopted 4-amino-3-mercapto-4H-1,2,4-triazoles (6) as reagents, which have SH and NH2 groups in a molecule. In addition, the mercapto group in 6 could have thione-form, therefore it is considered that the mercapto group of 6 would be a poor nucleophile. Thus, we treated 1b with 6a in the presence of Pd2(dba)3, Xantphos, and Cs2CO3 in dioxane at 120 ºC for 24 h, but the reaction showed complex feature and no distinct product was isolated. Then we treated 1b with 6a in BuOH under reflux for 30 min. Interestingly, the SNAr reaction by the NH2 group occurred and 7a was obtained in 92% yield. In the 1H NMR spectrum of 7a, two singlet signals owing to NH and SH appeared at δ 10.58 and 13.99. In the IR spectrum of 7a, an NH signal appeared at 3292 cm-1. From the results, we assigned the structure. In a similar manner, the reaction of 1b with 6b and 6c gave 7b (98%) and 7c (43%), respectively.
On the contrary, when 1b was treated with 6a in the presence of NaH in dry 1,4-dioxane for 10 h under reflux, the SNAr reaction by the sulfido group occurred and 8a was obtained in 91% yield. In the 1H NMR spectrum of 8a, a 2H singlet signal owing to NH2 appeared at δ 5.45, and in its IR spectrum, signals owing to NH2 appeared at 3251 and 3156 cm-1. From the results, we assigned the structure. Similar reaction of 1b with 6b gave 8b in 85% yield, but the reaction of 1b with 6c gave no good result.
It is observed that 6c decomposed by the treatment with NaH, therefore use of more weak base would be required. So we examined the reaction of 1b with 6c in the presence of K2CO3 and 18-crown-6 in dry dioxane under refluxed for 1 h, and obtained 8c in 92% yield. In a similar manner, the reaction of 1b with 6a and 6b gave 8b (92%) and 8c (86%), respectively.
Thus, each heteroarylamination and heteroarylsulfidation of 2-chloro-1-azaazulenes was achieved in the reaction of 1b with 6.
EXPERIMENTAL
Mps were measured using a Yanagimoto micro-melting apparatus and uncorrected. 1H NMR spectra (including HH-COSY and CH-COSY NMR) were recorded on a Bruker AVANCE 400S (400 MHz) and 13C NMR spectra were recorded on a Bruker AVANCE 400S (100.6 MHz) using CDCl3 as a solvent with tetramethylsilane as an internal standard unless otherwise stated; J values are recorded in Hz. IR spectra were recorded for KBr pellets on a Nicolet FT-IR AVATAR 370DTGS unless otherwise stated. Electronic spectra were recorded with JASCO V-570 spectrophotometer. Elemental analyses were taken with a Perkin Elmer 2400II. Kieselgel 60 was used for column chromatography.
Reaction of 2-chloro-1-azaazulenes with 2-amino-1-azaazulenes
Typical procedure: Under argon atmosphere, a mixture of 1a (0.046 g, 0.28 mmol), 2a (0.030 g, 0.20 mmol), Xantphos (0.008 g, 0.014 mmol), Pd2(dba)3 (0.011 g, 0.012 mmol), Cs2CO3 (0.081 g, 0.240 mmol) in dry 1,4-dioxane (6 mL) was refluxed for 4 h, then water (20 mL) was added. The mixture was extracted with CHCl3. The extract was dried over Na2SO4, and evaporated. Chromatography of the residue with CHCl3-AcOEt (1 : 1) gave 3aa (0.022 g, 39%).
In a similar manner, reaction of 1b, 1c, and 1d with 2a and 2b gave 3ba (70%), 3ca (63%), and 3db (43%), respectively.
3aa: Red powders (from CH2Cl2-hexane), mp 197-199 ºC; 1H NMR (DMSO-d6) δ 7.54 (2H, like t, J 9.2, H-7,7’), 7.58 (2H, like t, J 9.1, H-5,5’), 7.64 (2H, s, H-3,3’), 7.66 (2H, like t, J 10.2, H-6,6’), 8.19 (2H, d, J 9.6, H-4,4’), 8.32 (2H, dm, J 10.7, H-8,8’), and 11.6 (1H, s, NH); 13C NMR (DMSO-d6) δ 103.1, 129.0, 129.5, 130.2, 130.3, 132.5, 147.2, 157.3, and 163.3; νmax / cm-1 3366 (NH); λmax (CH2Cl2) nm (log ε) 260 (4.43), 282 (4.50), 339 (4.32), 411(4.34), 468 (4.11, sh), 485 (4.15), 514 (4.02, sh), and 570 (3.32, sh). Anal. Calcd for C18H13N3: C, 79.68; H, 4.83; N, 15.49. Found: C, 79.77; H, 4.82; N, 15.35.
3ba: Orange needles (from CH2Cl2-hexane), mp 189-193 ºC; 1H NMR δ 1.55 (3H, t, J 7.1, Me), 4.57 (q, J 7.1, OCH2), 7.54 (1H, ddd, J 10.4, 9.5, and 1.2, H-5’), 7.60 (1H, ddd, J 10.0, 9.7, and 1.2, H-7’), 7.66 (1H, ddd, J 10.4, 9.7, and 0.9, H-6’), 7.69 (1H, td, J 10.0, and 0.8, H-7), 7.79 (1H, ddd, J 10.0, 9.8, and 0.3, H-6), 7.83 (1H, ddd, J 9.9, 9.8, and 0.9, H-5), 8.33 (1H, dd, J 9.5 and 0.9, H-4’), 8.36 (1H, d, J 10.0, H-8’), 8.37 (1H, s, H-3’), 8.51 (1H, dd, J 10.0 and 0.8, H-8), 9.15 (1H, d, J 9.9, H-4), and 10.71 (1H, s, NH); 13C NMR δ 14.7, 60.6, 100.2, 103.9, 129.2, 130.0, 130.6, 131.5, 132.1, 132.8, 133.2, 133.3, 133.5, 134.4, 147.2, 148.4, 156.7, 160.6, 161.6, 163.5, and 165.4; νmax / cm-1 3280 (NH) and 1660 (C=O); λmax (CH2Cl2) nm (log ε) 276 (4.58, sh), 288 (4.66), 315 (4.50, sh), 335 (4.47), 420 (4.58), 464 (3.97), and 484 (4.20). Anal. Calcd for C21H17N3O2: C, 73.45; H, 4.99; N, 12.24. Found: C, 73.55; H, 5.10; N, 12.03.
3ca: Orange powders (from AcOEt), mp 193-195 ºC; 1H NMR δ 7.63 (1H, dd, J 10.4 and 9.9, H-5’), 7.71 (1H, dd, J 10.6 and 10.4, H-7’), 7.74 (1H, dd, J 10.6 and 9.9, H-6’), 7.91 (1H, dd, J 10.3 and 9.9, H-5), 8.03 (1H, dd, J 9.9 and 9.8, H-7), 8.04 (1H, t, J 9.9, H-6), 8.44 (1H, d, J 10.4, H-4’), 8.45 (1H, d, J 9.8, H-8), 9.47 (1H, d, J 10.3, H-4), and 11.02 (1H, br s, NH); 13C NMR δ 104.4, 119.8, 129.5, 130.3, 132.3, 132.6, 132.8, 134.6, 135.8, 136.5, 136.7, 137.0, 141.3, 148.3, 156.3, 157.5, 159.6, and 160.0; νmax / cm-1 3330 (NH), 1534 and 1324 (NO2); λmax (CH2Cl2) nm (log ε) 270 (4.28), 298 (4.25), 329 (4.50), 348 (4.32, sh), 422 (4.31), 464 (4.11), and 492 (3.97, sh). Anal. Calcd for C18H12N4O2·1/3AcOEt: C, 67.16; H, 4.28; N, 16.21. Found: C, 67.24; H, 4.26; N, 15.93.
3db: Dark red powders (from CHCl3-AcOEt), mp 255-256 ºC; 1H NMR (DMSO-d6) δ 7.29 (2H, like t, J 9.1, H-6,6’), 7.32 (2H, t, J 7.6, H-p-Ph), 7.34 (2H, like t, J 9.3, H-5,5’), 7.47 (4H, dd, J 7.6 and 7.3, H-m-Ph), 7.49 (2H, like t, J 10.0, H-7, 7’), 7.78 (4H, d, J 7.3, H-o-Ph), 8.04 (2H, dm, J 10.0, H-8, 8’), and 8.05 (1H, dm, J 9.3, H-4,4’) (NH was not observed); 13C NMR (DMSO-d6) δ 120.3, 122.6, 126.8, 128.1, 128.6, 130.2, 131.1, 131.8, 131.9, 133.2, 140.1, 151.6, and 163.0; νmax / cm-1 3440 (NH); λmax (CH2Cl2) nm (log ε) 289 (4.64), 369 (4.29), 404 (4.08, sh), 468 (4.09, sh), 498 (4.19), 568 (4.40), 603 (4.41), and 650 (4.06, sh). Anal. Calcd for C30H21N3: C, 85.08; H, 5.00; N, 9.92. Found: C, 85.12; H, 5.13; N, 9.74.
Reaction of 2-chloro-1-azaazulenes with 2-mercapto-1-azaazulenes
Typical procedure A: Under argon atmosphere, a mixture of 1b (0.055 g, 0.233 mmol), 4a (0.036 g, 0.223 mmol), Xantphos (0.0088 g, 0.015 mmol), Pd2(dba)3 (0.0146 g, 0.016 mmol), Cs2CO3 (0.101 g, 0.310 mmol) in dry 1,4-dioxane (6 mL) was refluxed for 24 h under stirring, then water (80 mL) was added. The mixture was extracted with CHCl3. The extract was dried over Na2SO4, and evaporated. Chromatography of the residue with AcOEt gave 5ba (0.040 g, 50%).
In a similar manner, reaction of 1c with 4a gave 5ca (38%).
5ba: Reddish brown micro needles (from CH2Cl2-hexane), mp 119 °C (decomp.); 1H NMR δ 1.54 (3H, t, J 7.1, CH3), 4.53 (2H, q, J 7.1, OCH2), 7.62 (1H, like t, J 9.7, H-7’), 7.72 (1H, like t, J 10.2, H-5’), 7.79 (1H, like t, J 10.0, H-6’), 7.83-7.90 (3H, m, H-5,6,7), 8.48 (1H, d, J 10.0, H-8’), 8.57 (1H, dm, J 10.6, H-8), 8.59-8.64 (1H, m, H-4’), and 9.40-9.49 (1H, m, H-4); 13C NMR δ 14.5, 60.7, 113.1, 116.5, 129.1, 129.7, 132.7, 132.9, 133.9, 134.3, 134.8, 135.4, 136.7, 137.9, 146.6, 147.2, 157.0, 159.1, 164.0, and 167.3; νmax / cm-1 1685 (C=O). Anal. Calcd for C21H16N2O2S: C, 69.98; H, 4.47; N, 7.77. Found: C, 70.07; H, 4.32; N, 7.83.
5ca: Red micro needles (from CH2Cl2-hexane), mp 216 °C (decomp.); 1H NMR δ 7.72 (1H, like t, J 9.7, H-5’), 7.82 (1H, like t, J 9.3, H-6’), 7.90 (like t, J 9.8, H-7’), 8.03-8.15 (3H, m, H-5,6,7), 8.60 (1H, d, J 9.8, H-4’), 8.68 (1H, dm, J 9.6, H-8’), 8.69 (1H, dm, J 9.8, H-8), and 9.65 (1H, dm, J 9.6, H-4); 13C NMR δ 117.5, 123.3, 129.3, 129.9, 134.7, 135.1, 135.2, 135.8, 135.9, 136.4, 137.8, 138.1, 139.8, 140.5, 145.0, 146.8, 157.2, and 163.5; νmax / cm-1 1481, 1394 (NO2). Anal. Calcd for C18H11N3O2S: C, 64.85; H, 3.33; N, 12.60. Found: C, 65.02; H, 3.32; N, 12.81.
Typical procedure B: A mixture of 4a (0.151 g, 0.936 mmol) and 60% NaH (0.047 g, 1.17 mmol) in dioxane (10 mL) was stirred for 30 min at rt. Then 1a (0.212 g, 1.23 mmol) was added to the mixture, and the mixture was refluxed for 4 h then water (20 mL) was added. The mixture was extracted with CHCl3. The extract was dried over Na2SO4, and evaporated. Chromatography on alumina of the residue with CHCl3-AcOEt (1 : 1) gave 5aa (0.240 g, 88%).
In a similar manner, reaction of 1b and 1c with 4a and 4b gave 5ba (71%), 5ca (80%), and 5cb (85%), respectively.
5aa : Red micro needles (from CH2Cl2-hexane), mp 217-219 ºC; 1H NMR (CDCl3) δ 7.78 (2H, s, H-3,3’), 7.63 (dd, 2H, ddd, J 10.2, 9.9, and 1.3, H-7,7’), 7.76 (2H, ddd, J 10.2, 9.9, and 1.0, H-6,6’), 7.81 (2H, ddd, J 10.2, 9.9, and 1.0, H-5,5’), 8.41 (2H, d, J 9.9, H-4,4’), and 8.58 (2H, dd, J 10.1 and 1.3, H-8,8’); 13C NMR δ 114.5, 129.4, 130.0, 133.4, 134.0, 136.6, 146.8, 157.8, and 164.4. Anal. Calcd for C18H12N2S: C, 74.97; H, 4.19; N, 9.71. Found: C, 74.75; H, 4.32; N, 9.84.
5cb : Yellow micro needles (from CH2Cl2-hexane), mp 203-204 ºC; 1H NMR δ 7.99-8.06 (1H, m, H-5), 8.08-8.13 (2H, m, H-5’,7’), 8.17-8.22 (3H, m, H-5), 8.63 (1H, d, J 9.5, H-8), 8.87-8.94 (2H, m, H-4’,8’), and 9.61-9.68 (1H, m, H-4); 13C NMR δ 134.1, 134.7, 134.8, 135.0, 135.3, 135.4, 135.7, 138.3, 139.1, 139.3, 140.4, 157.6, 163.1, and 164.1; νmax / cm-1 1485, 1304 (NO2); λmax nm (log ε) 253 (4.55), 286 (4.32), 335 (4.37), 351 (4.37), 387 (4.28), and 465 (2.89, sh). Anal. Calcd for C17H10N4O2S: C, 61.07; H, 3.01; N, 16.76. Found: C, 61.26; H, 3.07; N, 16.52.
Reaction of ethyl 2-chloro-1-azaazulene-3-carboxylate with 4-amino-3-mercapto-4H-1,2,4-triazoles
Typical procedure: A mixture of 1b (0.059 g, 0.25 mmol), 4-amino-3-mercapto-4H-1,2,4-triazole (6a) (0.059 g, 0.51 mmol) in BuOH (5 mL) was refluxed for 30 min. To the mixture hexane was added, and the trituration of the mixture gave yellow solid. The solid was collected by filtration and washed with Et2O to give 7a (0.073 g, 92%) as yellow powders.
In a similar manner, reaction of 1b with 6b and 6c gave 7b (98%) and 7c (43%), respectively.
7a: Yellow powders (from CH2Cl2-hexane), mp 169 ºC (decomp.); 1H NMR (DMSO-d6) δ 1.41 (3H, t, J 7.1, Me), 4.46 (2H, q, J 7.1, OCH2), 8.03-8.13 (3H, m, H-5,6,7), 8.32-8.40 (1H, m, H-8), 8.81 (1H, s, H-5’), 9.19 (1H, dm, J 9.9, H-4), 10.58 (1H, br s, NH), and 13.99 (1H, s, SH); νmax / cm-1 3292 (NH), 1673 (C=O); λmax (DMSO) nm (log ε) 290 (4.66), 361 (3.85), and 435 (3.65). Anal. Calcd for C14H13N5O2S·H2O: C, 50.44; H, 4.54; N, 21.01. Found: C, 50.15; H, 4.46; N, 21.30.
7b: Yellow powders (from CH2Cl2-hexane), mp 217 ºC (decomp.); 1H NMR (DMSO-d6) δ 1.43 (3H, t, J 7.1, Me), 2.43 (3H, s, Me), 4.47 (2H, q, J 7.1, OCH2), 8.05-8.12 (3H, m, H-5,6,7), 8.34-8.38 (1H, m, H-8), 9.19 (1H, dm, J 9.8, H-4), 10.48 (1H, br s, NH), and 14.86 (1H, s, SH); νmax / cm-1 3270 (NH), 1701 (C=O); λmax (EtOH) nm (log ε) 243 (4.32), 260 (4.27), 290 (4.58), 354 (3.85), and 427 (3.33). Anal. Calcd for C15H15N5O2S·2H2O: C, 49.31; H, 5.24; N, 19.17. Found: C, 49.29; H, 4.49; N, 19.43.
7c: Yellow powders (from CH2Cl2-hexane), mp 215 ºC (decomp.); 1H NMR δ 1.40 (3H, t, J 7.1, Me), 4.42 (2H, q, J 7.1, OCH2), 7.92-8.08 (3H, m, H-5,6,7), 8.25-8.30 (1H, m, H-8), 9.12 (1H, dm, J 10.2, H-4), 14.54 (1H, s, NH), and 14.86 (1H, s, SH); νmax / cm-1 3286 (NH), 1701 (C=O); λmax (DMSO) nm (log ε) 297 (4.66), 357 (3.94), and 430 (3.53). Anal. Calcd for C15H12N5O2F3S: C, 47.00; H, 3.16; N, 18.27. Found: C, 47.19; H, 3.29; N, 18.10.
Reaction of ethyl 2-chloro-1-azaazulene-3-carboxylate with 4-amino-3-mercapto-4H-1,2,4-triazoles in the presence of base
Typical procedure A: A mixture of 6a (0.1016 g, 0.875 mmol) and 60% NaH (0.07 g, 1.75 mmol) in dioxane (8 mL) was stirred for 30 min at rt. Then 1a (0.212 g, 1.23 mmol) was added to the mixture, and the mixture was refluxed for 10 h, then water (20 mL) was added. The mixture was extracted with CHCl3. The extract was dried over Na2SO4, and evaporated. The mixture was evaporated and the residue was chromatographed with AcOEt to give 1b (0.0051 g, 5%) and 8a (0.1307 g, 91%).
In a similar manner, reaction of 1b with 6b gave 8b (85%).
8a: Yellow needles (from CH2Cl2-hexane), mp 173 ºC (decomp); 1H NMR δ 1.43 (3H, t, J 7.1, Me), 2.43 (3H, s, Me), 4.47 (2H, q, J 7.1, OCH2), 5.45 (2H, s, NH2), 7.92 (1H, ddd, J 10.1, 9.7, and 1.2, H-5), 7.96 (1H, ddd, J 10.1, 9.4, and 1.3, H-6), 8.01 (1H, ddd, J 9.8, 9.4, and 1.3, H-7), 8.47 (1H, d, J 9.8, H-8), 8.53 (1H, s, H-5’), and 9.47 (1H, dd, J 9.7 and 1.3, H-4); 13C NMR (DMSO-d6) δ 14.5, 61.1, 112.3, 133.3, 133.7, 135.8, 136.2, 139.1, 147.1, 147.3, 147.6, 158.9, 163.7, and 166.5; νmax / cm-1 3251, 3156 (NH), 1698 (C=O); λmax (CH2Cl2) nm (log ε) 250 (4.26), 298 (4.57), 355 (4.03), 450 (3.19). Anal. Calcd for C19H15N3O2S·H2O: C, 50.44; H, 4.54; N, 21.01. Found: C, 50.18; H, 4.49; N, 21.22.
8b: Yellow powders (from CH2Cl2-hexane), mp 225 ºC (decomp.); 1H NMR δ 1.54 (3H, t, J 7.1, Me), 2.62 (3H, s, Me), 4.54 (2H, q, J 7.1, OCH2), 5.29 (2H, br s, NH2), 7.91 (1H, ddd, J 10.2, 9.7, and 1.3, H-5), 7.95 (1H, ddd, J 10.2, 9.3, and 1.4, H-6), 8.01 (1H, ddd, J 9.8, 9.3, and 1.4, H-7), 8.47 (1H, d, J 9.8, H-8), and 9.46 (1H, dd, J 9.7 and 1.4, H-4); νmax / cm-1 3247, 3147 (NH), 1699 (C=O); λmax (CH2Cl2) nm (log ε) 251 (4.59), 299 (4.51), 312 (4.31, sh), 357 (4.00), and 453 (3.18). Anal. Calcd for C15H15N5O2S·2H2O: C, 49.17; H, 5.50; N, 19.11. Found: C, 49.41; H, 5.35; N, 19.03.
Typical procedure B: A mixture of 6a (0.060 g, 0.52 mmol), K2CO3 (0.059 g, 0.43 mmol), and 18-crown-6 (0.229 g, 0.87 mmol) in dioxane (5 mL) was stirred for 30 min at rt. Then 1b (0.061 g, 0.26 mmol) was added to the mixture, and the mixture was refluxed for 1 h. The mixture was evaporated and the residue was chromatographed with AcOEt to give 8a (0.074 mg, 92%) as yellow powders.
In a similar manner, reaction of 1b with 6b and 6c gave 8b (86%) and 8c (92%), respectively.
8c: Yellow needles (from CH2Cl2-hexane), mp 207-210 ºC; 1H NMR δ 1.54 (3H, t, J 7.1, Me), 4.55 (2H, q, J 7.1, OCH2), 5.58 (2H, s, NH2), 7.95 (1H, ddd, J 10.2, 9.6, and 1.2, H-5), 7.99 (1H, dddd, J 10.2, 9.9, 1.4, and 0.8, H-6), 8.04 (1H, ddd, J 9.9, 9.8, and 1.2, H-7), 8.49 (1H, dd, J 9.8, and 0.8, H-7), and 9.48 (1H, dd, J 9.6 and 1.4, H-4); 13C NMR δ 14.5, 61.2, 112.4, 117.8 (average of 114.6, 116.7, 118.9, and 121.0, q, J 270.9, CF3), 133.6, 133.9, 136.2, 136.6, 139.6, 147.0, 147.5 (average of 147.0, 147.3, 147.6, and 147.9, q, J 39.7, CCF3), 151.4, 158.8, 163.5, and 164.1; νmax / cm-1 3320, 3193 (NH), 1687 (C=O); λmax (CH2Cl2) nm (log ε) 246 (4.29), 296 (4.63), 352 (4.05), 451 (3.21), and 476 (3.01, sh). Anal. Calcd for C15H12N5O2F3S: C, 47.00; H, 3.16; N, 18.27. Found: C, 46.82; H, 3.21; N, 18.45.
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