A new route for the synthesis of highly substituted 4- aminoquinoline drug like molecules via aza hetero-diels-alder reaction

Transcription

1 Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry. This journal is The Royal Society of Chemistry 2015 Organic & Biomolecular Chemistry Electronic Supplementary Information (ESI) A new route for the synthesis of highly substituted 4- aminoquinoline drug like molecules via aza hetero-diels-alder reaction Shinde Vidyacharan, A. Sagar and Duddu S. Sharada* Department of Chemistry, Indian Institute of Technology (IIT) Hyderabad, Ordnance Factory Estate Campus, Yeddumailaram , Medak District, Telangana. sharada@iith.ac.in Table of Contents Experimental section (S2) General procedure for 2-azidoaldehyde preparation. (S3) General procedure for the synthesis of 2H-indazole (3a-3m). (S3) General procedure for the synthesis of 4-aminoquinoline (5a-w) (S4) General procedure for the synthesis of 4-aminoquinoline starting from 2-azidobenzaldehyde in one-pot fashion...(s5) X-ray crystal structure data for (5a & 5f)... (S5-S7) Spectral data of all compounds (3i & 3j) and (5a-5s, 5w & 5x)......(S7-S18) Copies of 1 H, 13 C NMR Spectra of all Compounds 3i & 3j) and (5a-5s, 5w & 5x).(S19-S41) References. (S42) S1

2 Experimental Section General: IR spectra were recorded on a Bruker Tensor 37 (FTIR) spectrophotometer. 1 H NMR spectra were recorded on Bruker Avance 400 (400 MHz) spectrometer at 295 K in CDCl 3 ; chemical shifts (δ in ppm) and coupling constants (J in Hz) are reported in standard fashion with reference to either internal standard tetramethylsilane (TMS) (δ H = 0.00 ppm) or CHCl 3 (δ H = 7.25 ppm). 13 C NMR spectra were recorded on Bruker Avance 400 (100 MHz) spectrometer at RT in CDCl 3 ; chemical shifts (δ in ppm) are reported relative to CHCl 3 (δ C = ppm). In the 1 H-NMR, the following abbreviations are used throughout: s = singlet, d = doublet, t = triplet, q = quartet, qui = quintet, m = multiplet and br s = broad singlet, sept = septet. The assignment of signals were confirmed by 1 H and 13 C spectral data. High-resolution mass spectra (HR-MS) were recorded on an Agilent 6538 UHD Q-TOF using multimode source. Microwave experiments were carried out with CEM Discover Labmate TM instrument in 10 ml vial, closed vessel, Power: 250W, Temperature: 60 C-100 o C for minutes. Melting points were determined using melting point apparatus manufactured by GUNA enterprises, India and are uncorrected. All small scale reactions were carried out using standard syringe-septum technique. Reactions were monitored by TLC on silica gel using a combination of hexane and ethyl acetate as eluents. Solvents were distilled prior to use. We gave all spectral data for known and unknown compounds. S2

3 (A) General procedure for 2-azidoaldehyde preparation: 1 B) General procedure for the synthesis of 2H-indazole (3a-3m): 2-Azidobenzaldehyde1 (1 mmol), amine 2 (1 mmol) were taken in a 10 ml schlenck tube and it was closed with stopper and placed in external heating oil bath at 120 o C for h (oil bath temperature). After completion, the mixture was cooled to room temperature. The reaction mixture was diluted with EtOH and slight amount of charcoal was added, filtered, dried in vacuo and recrystallized using ethanol and few of them were purified on a silica gel column chromatography (hexane/ethylacetate 90:10 to 85:15). All the compounds were confirmed by FTIR, 1 H NMR, 13 CNMR and HR-MS Spectral analyses. All are known compounds (see ref. 1-3) except 3i and 3j. S3

4 General procedure for the synthesis of 4-aminoquinoline (5a-w): 2H-indazole 3a-m (1 mmol), dienophiles 4a-e (3 mmol) were taken in a 10 ml screw cap vial. It was then placed in external heating oil bath at 100 o C for 30 h. After completion, the reaction mixture was cooled to room temperature and the solvent evaporated under vaccuo and was purified on a silica gel column chromatography (hexane/ethylacetate 80:20) which furnished the respective solids (5a-w). All the compounds were confirmed by FT-IR, 1 H NMR, 13 C NMR and HR-MS spectral analyses. General procedure for the synthesis of 4-aminoquinoline starting from 2- azidobenzaldehyde in one-pot fashion: 2-Azidobenzaldehyde 1 (1 mmol), amine 2 (1 mmol) were taken in a 10 ml screw cap vial. It was then placed in to external heating oil bath at 120 o C for h. Once indazole formation was confirmed by TLC, DMAD and toluene were added and the reaction mixture was heated in external oil bath at 100 o C for 30 h. After completion of the reaction, reaction vial was cooled to room temperature and solvent evaporated under vaccuo and was purified on a silica gel column chromatography (hexane/ethylacetate 80:20) which furnished the respective solids. All the compounds were confirmed by FTIR, 1 H NMR, 13 C NMR and HR-MS spectral analyses. S4

5 X-ray crystal structure data for Dimethyl 4-(benzylamino)quinoline-2,3-dicarboxylate (5a) CCDC Identification code exp_2959_216 Empirical formula C 20 H 18 N 2 O 4 Formula weight Temperature/K 298 Crystal system monoclinic Space group C2/c a/å (11) b/å (6) c/å (14) α/ β/ (7) γ/ Volume/Å (4) Z 8 ρ calc mg/mm m/mm F(000) Crystal size/mm Θ range for data collection 9.18 to Index ranges -23 h 20, -9 k 12, -20 l 20 Reflections collected 6934 Independent reflections 3258[R(int) = ] Data/restraints/parameters 3258/0/237 S5

6 Goodness-of-fit on F Final R indexes [I>=2σ (I)] R 1 = , wr 2 = Final R indexes [all data] R 1 = , wr 2 = Largest diff. peak/hole / e Å /-0.27 X-ray crystal structure data for Dimethyl 4-((2-bromophenyl)amino)quinoline-2,3-dicarboxylate (5f) CCDC Identification code exp_4184 Empirical formula C 19 H 16 BrN 2 O 4 Formula weight Temperature/K 293(2) Crystal system triclinic Space group P-1 a/å (12) b/å (7) c/å (17) α/ (11) β/ (12) γ/ (10) Volume/Å (2) Z 2 ρ calc mg/mm m/mm F(000) Crystal size/mm Θ range for data collection 6.19 to Index ranges -11 h 11, -13 k 13, -14 l 14 Reflections collected 6815 S6

7 Independent reflections 3972[R(int) = ] Data/restraints/parameters 3972/0/237 Goodness-of-fit on F Final R indexes [I>=2σ (I)] R 1 = , wr 2 = Final R indexes [all data] R 1 = , wr 2 = Largest diff. peak/hole / e Å /-0.48 Spectral data of all compounds (3i & 3j) and (5a-5x) S7

8 5-Bromo-2-(3-methoxybenzyl)-2H-indazole (3i): Pale yellow solid (80%), Mp o C. IR (MIR-ATR, cm -1 ): ʋ max = 3059, 2938, , 1600, 1586, 1491, , , 1138, , 914.7, 862.6, 778.6, 670, H NMR (CDCl 3, 400 MHz): δ H = 7.81 (s, 1H), 7.75 (s, 1H), 7.59 (d, 1H, J = 9.3 Hz), 7.31 (dd, 1H, J a = 9.3 and J b = 1.5 Hz), (d, 1H, J = 15.6 Hz), 6.85 (m, 2H), 6.79 (s,1h), 6.51 (s,2h), 3.74 (s, 3H). 13 C NMR (CDCl 3, 100 MHz): δ C = 160, 147.3, 136.9, 130, 129.6, 123.3, 122.5, 122.3, 120.3, 119.3, 115.2, 113.9, HR-MS (ESI+) m/z calculated for [C 15 H 14 BrN 2 O] + = [M+H] + : ; found: Bromo-2-(3,4-dimethoxybenzyl)-2H-indazole (3j): Pale yellow solid (85%), Mp o C. IR (MIR-ATR, cm -1 ): ʋ max = 3062, , , , 1593, , , , 1259, 1236, , , 803.3, 752.6, 670.9, H NMR (CDCl 3, 400 MHz): δ H = 7.78 (s, 1H), 7.73 (d, 1H, J = 1.5 Hz), 7.59 (d, 1H, J = 9.3 Hz), 7.3 (dd, 1H, J a = 9 and J b = 1.7 Hz), 6.87 (m, 1H), 6.82 (m, 2H), 5.47 (s,2h), 3.85 (s, 3H), 3.81 (s, 3H). 13 C NMR (CDCl 3, 100 MHz): δ C = 149.3, , 129.5, 127.7, 123.2, 122.4, 122.1, 120.9, 119.3, 115.1, 111.3, 111.2, 57.5, HR-MS (ESI+) m/z calculated for [C 16 H 16 BrN 2 O 2 ] + = [M+H] + : ; found: S8

9 Dimethyl 4-(benzylamino)quinoline-2,3-dicarboxylate (5a): Light yellow solid (68%), Mp o C. IR (MIR-ATR, cm -1 ): ʋ max = 2950, 1737, 1681, 1614, 1583, 1565, 1518, 1454, 1438, 1325, 1245, 1227, 1164, 1128, 1041, 986, 765, H NMR (CDCl 3, 400 MHz): δ H = 8.76 (br s, 1H), 8.15 (d, 1H, J = 8.8 Hz), 8.03 (d, 1H, J = 8.3 Hz), (m, 1H), (m, 6H), 4.92 (d, 2H, J = 5.4 Hz), 3.98 (s, 3H), 3.83 (s, 3H). 13 C NMR (CDCl 3, 100 MHz): 168.2, 168.0, 156.4, 152.7, 149.0, 138.0, 131.7, 130.4, 129.1, 128.8, 127.3, 125.7, 125.3, 119.4, 102.4, 52.9, 52.8, HR-MS (ESI+) m/z calculated for [C 20 H 19 N 2 O 4 ] + = [M+H] + : ; found: Dimethyl 4-((2-chlorobenzyl)amino)quinoline-2,3-dicarboxylate (5b): Light yellow solid (72%), Mp o C. IR (MIR-ATR, cm -1 ): ʋ max = 2951, 1733, 1683, 1614, 1583, 1565, 1517, 1437, 1325, 1224, 1163, 1129, 1039, 985, 98, 755, 731, H NMR (CDCl 3, 400 MHz): δ H = 8.70 (br s, 1H), 8.03 (t, 2H, J = 7.1 Hz), 7.71 (t, 1H, J = 7.6 Hz), 7.51 (dd, 1H, J a = 5.4 and J b = 3.9 Hz), (m, 2H), 7.33 (dd, 2H, J a = 5.9 and J b = 3.4 Hz), 4.97 (d, 2H, J = 5.9 Hz), 3.98 (s, 3H), 3.85 (s, 3H). 13 C NMR (CDCl 3, 100 MHz): 168.1, 168.0, 156.7, 152.2, 149.0, 135.6, 133.2, 131.7, 130.5, 129.9, 129.1, 127.4, 125.9, 119.6, 103.3, 52.9, 52.4, HR-MS (ESI+) m/z calculated for [C 20 H 18 ClN 2 O 4 ] + = [M+H] + : ; found: S9

10 Dimethyl 4-((4-methoxybenzyl)amino)quinoline-2,3-dicarboxylate (5c): Light yellow solid (70%), Mp o C. IR (MIR-ATR, cm -1 ): ʋ max = 2955, 1736, 1658, 1629, 1514, 1436, 1404, 1327, 1247, 1197, 1176, 1151, 1068, 1020, 814, 759, H NMR (CDCl 3, 400 MHz): δ H = 7.86 (s, 1H), 7.71 (d, 1H, J = 8.8 Hz), 7.60 (d, 1H, J = 8.3 Hz), (m, 3H), 7.05 (t, 1H, J = 7.3 Hz), 6.88 (d, 2H, J = 8.3 Hz), 5.52 (s, 2H), 3.78 (s, 3H), 3.73 (s, 3H), 3.62 (s, 3H). 13 C NMR (CDCl 3, 100 MHz): 172.6, 169.7, 168.4, 167.2, 148.9, 129.6, 127.8, 125.8, 122.7, 122.0, 121.6, 120.2, 117.4, 114.3, 91.8, 56.9, 55.2, 52.4, HR-MS (ESI+) m/z calculated for [C 21 H 21 N 2 O 5 ] + = [M+H] + : ; found: Dimethyl 4-(4-chlorobenzylamino)quinolone-2,3-dicarboxylate (5d): Pale yellow solid (62%), Mp o C. IR (MIR-ATR, cm -1 ): ʋ max = 3055, 2952, 1736, 1698, 1626, 1488, 1437, 1357, 1263, 1163, 1095, 1015, 730, H NMR (CDCl 3, 400 MHz): δ H = 8.78 (br s, 1H), (m, 2H), (m, 1H), (m, 5H), 4.90 (d, 2H, J = 5.9 Hz), 3.90 (s, 3H), 3.80 (s, 3H). 13 C NMR (CDCl 3, 100 MHz): δ C = 168.1, 168.0, 156.4, 152.3, 149.0, 136.5, 133.9, 131.7, 130.5, 129.3, 125.9, 125.1, 119.4, 102.6, 52.9, 52.4, HR-MS (ESI+) m/z calculated for [C 20 H 18 ClN 2 O 4 ] + = [M+H] + : ; found: Dimethyl 4-(phenylamino)quinoline-2,3-dicarboxylate (5e): Light yellow solid (60 %), Mp o C. S10

11 IR (MIR-ATR, cm -1 ): ʋ max = 2920, 2849, 1732, 1693, 1577, 1563, 1495, 1437, 1417, 1328, 1240, 1220, 1168, 1105, 1034, 763, 732, H NMR (CDCl 3, 400 MHz): δ H = 9.73 (s, 1H), (m, 1H), (m, 2H), (m, 3H), (m, 1H), 7.0 (d, 2H, J = 7.8 Hz), 4.02 (s, 3H), 3.9 (s, 3H). 13 C NMR (CDCl 3, 100 MHz): 167.9, 167.7, 151.8, 151.6, 148.8, 142.7, 131.7, 130.4, 129.4, 126.4, 126.0, 124.5, 121.8, 120.0, 107.2, 53.0, HR-MS (ESI+) m/z calculated for [C 19 H 17 N 2 O 4 ] + = [M+H] + : ; found: Dimethyl 4-((2-bromophenyl)amino)quinoline-2,3-dicarboxylate (5f): Light yellow solid (64%), Mp o C. IR (MIR-ATR, cm -1 ): ʋ max = 2950, 1763, 1694, 1614, 1583, 1563, 1503, 1438, 1416, 1362, 1328, 1241, 1225, 1101, 1028, 764, H NMR (CDCl 3, 400 MHz): δ H = 9.35 (s, 1H), 8.12 (d, 1H, J = 8.3 Hz), 7.72 (td, 1H, J a = 7.7 and J b = 1.2 Hz), (m, 2H), (m, 1H), (m, 1H), (m, 1H), 6.68 (d, 1H, J = 7.8 Hz), 4.03 (s, 3H), 3.93 (s, 3H). 13 C NMR (CDCl 3, 100 MHz): 168.4, 167.2, 151.3, 149.8, 141.0, 133.3, 131.9, 130.6, 127.8, 126.7, 125.9, 124.8, 121.0, 115.9, 109.9, 84.7, 53.1, HR-MS (ESI+) m/z calculated for [C 19 H 16 BrN 2 O 4 ] + = [M+H] + : ; found: Dimethyl -4-(2-aminophenylamino) quinolone-2,3-dicarboxylate (5g): Pale yellow solid (58%), Mp o C. IR (MIR-ATR, cm -1 ): ʋ max = 3004, 2985, 1726, 1595, 1442, 1324, 1274, 1234, 1201, 1169, 1138, 1057, 967, 797. S11

12 1 H NMR (CDCl 3, 400 MHz): δ H = 8.79 (s, 1H), 8.27 (m, 1H), 8.22 (d, 3H, J = 8.3 Hz), (m, 3H), (m, 1H), 4.1 (s, 2H), 4.07 (s, 3H), 3.99 (s, 3H). 13 C NMR (CDCl 3, 100 MHz): δ C = 167.2, 165.6, 165.2, 150.4, 148.1, 143.8, 141.4, 139.6, 132.7, 132.5, 130, 129.9, 128.8, 128.7, 127, 124.2, 122.3, 53.6, HR-MS (ESI+) m/z calculated for [C 19 H 18 N 3 O 4 ] + = [M+H] + : ; found: Dimethyl 4-((2,3-dimethylphenyl)amino)quinoline-2,3-dicarboxylate (5h): Light yellow solid (72 %), Mp o C. IR (MIR-ATR, cm -1 ): ʋ max = 3235, 2922, 2853, 1732, 1685, 1610, 1568, 1506, 1436, 1354, 1324, 1216, 1163, 1116, 1060, 1028, 988, 800, 766, H NMR (CDCl 3, 400 MHz): δ H = 9.89 (s, 1H), 8.01 (d, 1H, J = 8.3 Hz), (m, 1H), 7.47 (d, 1H, J = 8.3 Hz), (m, 1H), (m, 1H), (m, 1H), 6.68 (d, 1H, J = 7.8 Hz), 4.01 (s, 3H), 3.89 (s, 3H), 2.37 (s, 3H), 2.32 (s, 3H). 13 C NMR (CDCl 3, 100 MHz): 168.2, 168.0, 153.1, 152.2, 148.8, 140.9, 138.4, 131.6, 130.4, 130.3, 127.3, 126.1, 126.0, 125.7, 121.3, 119.6, 53.0, 52.6, 20.6, HR-MS (ESI+) m/z calculated for [C 23 H 24 N 2 O 4 ] + = [M+H] + : ; found: Dimethyl 6-bromo-4-(3-methoxybenzylamino) quinolone-2,3-dicarboxylate (5i): Pale yellow solid (63%), Mp o C. IR (MIR-ATR, cm -1 ): ʋ max = 3055, 2952, 1735, 1698, 1622, 1483, 1436, 1365, 1262, 1210, 1165, 1081, 1030, 731, 701. S12

13 1 H NMR (CDCl 3, 400 MHz): δ H = 8.14 (s, 1H), 7.44 (dd, 1H, J a = 8.8 and J b = 2 Hz), 7.31 (d, 1H, J = 2 Hz), 7.12 (m, 1H), 7.05 (d, 1H, J = 8.8 Hz), 6.97 (m, 2H), 6.73 (dd, 1H and J a = 8.1, J b = 1.7 Hz), 3.98 (s, 2H), 3.68 (s, 3H), 3.57 (s, 3H), 3.06 (s, 3H). 13 C NMR (CDCl 3, 100 MHz): δ C = 170.9, 163.8, 163.3, 154.6, 148.9, 147.7, 140.9, 136.1, 135.3, 131.5, 122.1, 119.2, 116.3, 112.8, 107.3, 87.7, 65.6, 55.3, 53.6, 52.1, 51.5, HR-MS (ESI+) m/z calculated for [C 22 H 22 BrN 2 O 6 ] + = [M+H] + : ; found: Dimethyl 6-bromo-4-(phenylamino) quinolone-2,3-dicarboxylate (5j): Pale yellow solid (55%), Mp o C. IR (MIR-ATR, cm -1 ): ʋ max = 2953, 2925, 1794, 1730, 1596, 1509, 1435, 1367, 1251, 1105, 1021, 803, 782, 759, 733, H NMR (CDCl 3, 400 MHz): δ H = 8.31 (s, 1H), 7.82 (m, 3H), 7.61 (d, 1H, J = 8.8 Hz), 7.47 (t, 2H, J = 7.8 Hz), (m, 2H), 3.79 (s, 6H). 13 C NMR (CDCl 3, 100 MHz): δ C = 152.1, 148, 140, 130.4, 129.6, 128.2, 123.9, 122.5, 120.9, 119.9, 119.7, 74.6, HR-MS (ESI+) m/z calculated for [C 19 H 16 BrN 2 O 4 ] + = [M+H] + : ; found: Diethyl 4-(benzylamino)quinoline-2,3-dicarboxylate (5k): Light yellow solid (74%), Mp o C. IR (MIR-ATR, cm -1 ): ʋ max = 2982, 2903, 1730, 1677, 1614, 1582, 1565, 1517, 1454, 1373, 1306, 1242, 1222, 1170, 1127, 1024, 763, H NMR (CDCl 3, 400 MHz): δ H = 8.89 (br s, 1H), 8.19 (d, 1H, J = 8.8 Hz), 8.03 (d, 1H, J = 8.3 Hz), (m, 1H), (m, 6H), 4.93 (d, 2H, J = 4.9 Hz), 4.45 (q, 2H, J = 7 Hz), 4.3 S13

14 (q, 2H, J = 7 Hz), 1.43 (t, J = 7.3 Hz), 1.32 (t, J = 7.3 Hz). 13 C NMR (CDCl 3, 100 MHz): 167.9, 167.7, 156.7, 152.8, 149.1, 138.1, 131.6, 130.3, 129.1, 128.0, 127.3, 125.5, 119.5, 102.5, 61.9, 61.6, 52.9, 14.1, HR-MS (ESI+) m/z calculated for [C 22 H 23 N 2 O 4 ] + = [M+H] + : ; found: Diethyl 4-((2-chlorobenzyl)amino)quinoline-2,3-dicarboxylate (5l): Light yellow solid (75%), Mp o C. IR (MIR-ATR, cm -1 ): ʋ max = 2981, 1729, 1679, 1614, 1582, 1564, 1516, 1444, 1373, 1320, 1305, 1241, 1220, 1169, 1130, 1022, 861, 758, H NMR (CDCl 3, 400 MHz): δ H = 8.81 (br s, 1H), 8.03 (t, 2H, J = 8.3 Hz), 7.69 (t, 1H, J = 7.6 Hz), 7.5 (dd, 1H, J a = 5.4 and J b = 3.9 Hz), (m, 2H), (m, 2H), 4.96 (d, 2H, J = 5.9 Hz), 4.44 (q, 2H, J = 6.8 Hz), 4.30 (q, 2H, J = 7.3 Hz), 1.42 (t, 3H, J = 7.1 Hz), 1.32 (m, 3H). 13 C NMR (CDCl 3, 100 MHz): 167.8, 167.7, 156.9, 152.6, 149.0, 135.7, 133.2, 131.6, 130.4, 129.9, 129.4, 129.1, 127.4, 125.8, 126.1, 119.6, 103.4, 62.0, 61.6, 50.8, 14.1, HR-MS (ESI+) m/z calculated for [C 22 H 22 ClN 2 O 4 ] + = [M+H] + : ; found: Diethyl 4-(4-chlorobenzylamino)quinolone-2,3-dicarboxylate (5m): Pale yellow solid (70%), Mp o C. IR (MIR-ATR, cm -1 ): ʋ max = 3326, 2982, 1727, 1678, 1567, 1513, 1459, 1403, 1375, 1308, 1220, 1167, 1127, 1091, 1017, 856, 808, 764. S14

15 1 H NMR (CDCl 3, 400 MHz): δ H = 8.89 (t, 1H, J = 5.4 Hz), (dd, 2H, J a = 18.8 and J b = 8.8 Hz), (t, 1H, J = 7.8 Hz), (m, 5H), 4.89 (d, 2H, J = 5.9 Hz), 4.45 (q, 2H, J = 7.3 Hz), 4.31 (q, 2H, J = 7.3 Hz), 1.43 (t, 3H, J = 7.1 Hz), 1.34 (t, 3H, J = 7.1 Hz). 13 C NMR (CDCl 3, 100 MHz): δ C = 174.7, 165, 162, 161.5, 145.5, 139.7, 137.9, 133.4, 132, 127.2, 126.6, 124.4, 116.5, 114.6, 63.4, 62.3, 61.7, 14.0, HR-MS (ESI+) m/z calculated for [C 22 H 21 ClN 2 O 4 ] + = [M+H] + : ; found: Diethyl 4-((2-bromophenyl)amino)quinoline-2,3-dicarboxylate (5n): Light yellow solid (65%), Mp o C. IR (MIR-ATR, cm -1 ): ʋ max =2937, 1729, 1689, 1614, 1581, 1562, 1499, 1439, 1415, 1372, 1324, 1308, 1239, 1219, 1098, 1023,862, 808, 762, H NMR (CDCl 3, 400 MHz): δ H = 9.42 (s, 1H), 8.12 (d, 1H, J = 8.3 Hz), (m, 3H), (m, 1H), (m, 1H), (m, 1H), 6.65 (d, 1H, J = 7.8 Hz), 4.49 (q, 2H, J =7.3 Hz), 4.39 (q, 2H, J = 7.2 Hz), 1.45 (t, 3H, J = 7.1 Hz), 1.38 (t, 3H, J =7.1 Hz). 13 C NMR (CDCl 3, 100 MHz): 167.1, 166.8, 151.7, 149.9, 148.7, 141.1, 133.3, 131.8, 130.6, 127.8, 126.6, 125.8, 124.7, 121.0, 120.5, 115.6, 110.0, 62.2, 14.2, HR-MS (ESI+) m/z calculated for [C 21 H 20 BrN 2 O 4 ] + = [M+H] + : ; found: Diethyl 4-(2-bromo-4-methylbenzylamino) quinolone-2,3-dicarboxylate (5o): Pale yellow solid (68%), Mp o C. IR (MIR-ATR, cm -1 ): ʋ max = 2980, 2924, 2852, 1734, 1611, 1582, 1564, 1503, 1463, 1372, 1324, 1242, 1221, 1195, 1101, 1021, 865. S15

16 1 H NMR (CDCl 3, 400 MHz): δ H = 9.55 (s, 1H), 8.09 (d, 1H, J = 8.3 Hz), 7.69 (t, 1H, J = 7.8 Hz), 7.59 (d, 1H, J = 8.3 Hz), 7.48 (s, 1H), 7.3 (s, 1H), 6.89 (d, 1H, J = 8.3 Hz), 6.6 (d, 1H, J = 7.8 Hz), 4.49 (q, 2H, J = 7.2 Hz), 4.39 (q, 2H, J = 7 Hz), 2.32 (s, 3H), 1.45 (t, 3H, J = 7.1 Hz ), 1.38 (t, 3H, J = 7.1 Hz ). 13 C NMR (CDCl 3, 100 MHz): δ C = 167.4, 167, 150.7, 148.7, 138.6, 135.3, 133.6, 131.7, 130.5, 128.6, 126.2, 125.9, 121.7, 120.2, 116.1, 62.2, 62.1, 20.5, 14.2, 14. HR-MS (ESI+) m/z calculated for [C 22 H 19 BrN 2 O 5 ] + = [M+H] + : ; found: Dimethyl 4-((2,3-dimethylphenyl)amino)quinoline-2,3-dicarboxylate (5p): Light yellow solid (60%), Mp o C. IR (MIR-ATR, cm -1 ): ʋ max = 2982, 1734, 1680, 1613, 1579, 1563, 1508, 1472, 1419, 1395, 1371, 1322, 1241, 1219, 1173, 1114, 1065, 1022, 766, H NMR (CDCl 3, 400 MHz): δ H = 305: 10 (s, 1H), 8.02 (d, 1H, J = 8.3 Hz), (m, 1H), 7.47 (d, 1H, J = 8.8 Hz), (m, 1H), (m, 1H), (m, 1H), 6.66 (d, 1H, J = 7.8 Hz), 4.48 (q, 2H, J = 7.2 Hz), 4.36 (q, 2H, J = 7.2 Hz), 2.37 (s, 3H), 2.33 (s, 3H), 1.45 (t, 3H, J = 7.1 Hz), 1.38 (t, 3H, J = 7.1 Hz). 13 C NMR (CDCl 3, 100 MHz): 167.8, 167.7, 153.1, 152.6, 141.1, 138.4, 131.4, 130.3, 130.2, 127.1, 126.1, 126.0, 125.6, 121.2, 119.6, 104.7, 62.0, 61.8, 20.6, 14.2, 14.1, HR-MS (ESI+) m/z calculated for [C 23 H 24 N 2 O 4 ] + = [M+H] + : ; found: Diethyl 4-((2-aminophenyl)amino)quinoline-2,3-dicarboxylate (5q): Light yellow solid (60 %), Mp o C. IR (MIR-ATR, cm -1 ): ʋ max = 2982, 1721, 1618, 1518, 1466, 1445, 1368, 1322, 1270, 1230, 1181, 1137, 1113, 1056, 1018, 912, 860, 761, 700. S16

17 1 H NMR (CDCl 3, 400 MHz): δ H = 8.81 (s, 1H), (m, 3H), (m, 3H), (m, 1H), (m, 1H), (m, 2H), (m, 2H), 4.46 (q, 2H, J = 6.8 Hz), 1.5 (m, 3H), 1.47 (m, 3H). 13 C NMR (CDCl 3, 100 MHz): 166.9, 165.1, 164.8, 151.0, 148.1, 144.2, 141.8, 139.6, 132.5, 132.4, 129.9, 128.6, 127.0, 122.4, 119.8, 89.7, 62.9, 62.4, 14.2, HR-MS (ESI+) m/z calculated for [C 21 H 22 N 3 O 4 ] + = [M+H] + : ; found: Diethyl 6-bromo-4-(3-methoxybenzylamino) quinolone-2,3-dicarboxylate (5r): Pale yellow solid (55%), Mp o C. IR (MIR-ATR, cm -1 ): ʋ max = 2981, 2903, 1732, 1678, 1604, 1583, 1558, 1510, 1491, 1465, 1374, 1315, 1267, 1242, 1210, 1129, 1039, 831, 783, H NMR (CDCl 3, 400 MHz): δ H = 8.93 (br s, 1H), 8.3 (d, 1H, J = 1.5 Hz), 7.89 (d, 1H, J = 9.3 Hz), 7.75 (m, 1H), 7.32 (t, 1H, J = 7.8 Hz), (m, 3H), 4.86 (d, 2H, J = 5.9 Hz), 4.33 (q, 2H, J = 7.3 Hz), 4.31 (q, 2H, J = 7.2 Hz), 1.43 (t, 3H, J = 7.3 Hz ), 1.33 (t, 3H, J = 7.1 Hz ). 13 C NMR (CDCl 3, 100 MHz): δ C = 167.6, 167.5, 160.2, 155.6, 153, 147.8, 139.3, 134.8, 131.9, 130.2, 127.9, 120.7, 119.5, 119.2, 113.7, 112.7, 103.2, 62.1, 61.8, 55.3, 52.8, 14.1, HR-MS (ESI+) m/z calculated for [C 23 H 24 BrN 2 O 5 ] + = [M+H] + : ; found: Diethyl 6-bromo-4-(3-methoxybenzylamino) quinolone-2,3-dicarboxylate (5s): Pale yellow solid (68%), Mp o C. IR (MIR-ATR, cm -1 ): ʋ max = 2983, 2920, 1815, 1723, 1580, 1507, 1462, 1444, 1369, 1263, 1234, 1202, 1143, 1057, 1033, 942, 860. S17

18 1 H NMR (CDCl 3, 400 MHz): δ H = 9.32 (s, 1H), 7.32 (s, 1H), (m, 2H), (m, 3H), 6.06 (s, 2H), 4.46 (q, 2H, J = 7.2 Hz), 4.46 (q, 2H, J = 7.2 Hz), 1.44 (t, 3H, J = 7.1 Hz), 1.35 (t, 3H, J = 7.1 Hz). 13 C NMR (CDCl 3, 100 MHz): δ C = 167.4, 150.0, 147.7, 122.6, 122.5, 116.3, 107.0, 102.2, 102.0, 62.1, 62.0, 14.2, HR-MS (ESI+) m/z calculated for [C 22 H 20 FN 2 O 6 ] + = [M+H] + : ; found: Dimethyl 4-((5-(diethylamino)pentan-2-yl)amino)quinolone-2,3-dicarboxylate (5w): yellow viscous liquid (38%) IR (MIR-ATR, cm -1 ): ʋ max = 2933, 2857, 1730, 1680, 1657, 1602, 1501, 1451, 1366, 1274, 1247, 1180, 1150, 1095, 1054, 976, 833, 752, 695, 670, H NMR (CDCl 3, 400 MHz): δ H = 8.79 (s, 1H), 8.23 (d, 1H, J = 8.3 Hz), (m, 2H), (m, 1H), 4.61 (s, 1H), 4.07 (s, 3H), 3.99 (s, 3H), (m, 6H), (m, 4H), (m, 6H), (m, 9H). 13 C NMR (CDCl 3, 100 MHz): δ C = 168.4, 167.2, 166.2, 165.6, 153.8, 148.1, 139.6, 134.2, 132.5, 129.9, 129.6, 128.8, 128.7, 127.1, 122.3, 83.9, 82.8, 53.2, 53.1, 52.9, 52.8, 50.7, 44.9, 32.5, HR-MS (ESI+) m/z calculated for [C 22 H 32 N 3 O 4 ] + = [M+H] + : ; found: Diethyl quinolone-2,3-dicarboxylate (5x): Light yellow liquid (26 %) IR (MIR-ATR, cm -1 ): ʋ max = 2983, 2938, 2130, 1717, 1619, 1596, 1564, 1461, 1368, 1320, 1270, 1249, 1230, 1196, 1153, 1095, 1050, 1023, 860, 800, 733, H NMR (CDCl 3, 400 MHz): δ H = 8.78 (s, 1H), 8.21 (d, 1H, J = 8.3 Hz), 7.94 (d, 1H, J = 7.8 Hz), (m, 1H), (m, 1H), 4.53 (q, 2H, J = 7.3 Hz), 4.46 (q, 2H, J = 7.3 Hz), 1.46 (t, 3H, J = 7.1 Hz), 1.42 (t, 3H, J = 7.1 Hz). 13 C NMR (CDCl 3, 100 MHz): δ C = 166.9, 165.1, 151.1, 148.1, 139.6, 132.3, 129.8, 128.6, 128.6, 127.0, 125.3, 122.6, 122.4, 120.8, 111.9, 108.6, 62.4, 62.0, 60.9, 14.2, HR-MS (ESI+) m/z calculated for [C 15 H 16 NO 4 ] + = [M+H] + : ; found: S18

19 Copies of 1 H, 13 C NMR Spectra of all Compounds (3a & 3j) and (5a-5s, 5w & 5x): H NMR (400 MHz) spectrum of compound 3i in CDCl C NMR (100 MHz) spectrum of compound 3i in CDCl 3 S19

20 H NMR (400 MHz) spectrum of compound 3j in CDCl C NMR (100 MHz) spectrum of compound 3j in CDCl 3 S20

21 H NMR (400 MHz) spectrum of compound 5a in CDCl C NMR (100 MHz) spectrum of compound 5a in CDCl 3 S21

22 H NMR (400 MHz) spectrum of compound 5b in CDCl C NMR (100 MHz) spectrum of compound 5b in CDCl 3 S22

23 H NMR (400 MHz) spectrum of compound 5c in CDCl C NMR (100 MHz) spectrum of compound 5c in CDCl 3 S23

24 H NMR (400 MHz) spectrum of compound 5d in CDCl C NMR (100 MHz) spectrum of compound 5d in CDCl 3 S24

25 H NMR (400 MHz) spectrum of compound 5e in CDCl C NMR (100 MHz) spectrum of compound 5e in CDCl 3 S25

26 H NMR (400 MHz) spectrum of compound 5f in CDCl C NMR (100 MHz) spectrum of compound 5f in CDCl 3 S26

27 H NMR (400 MHz) spectrum of compound 5g in CDCl C NMR (100 MHz) spectrum of compound 5g in CDCl 3 S27

28 H NMR (400 MHz) spectrum of compound 5h in CDCl C NMR (100 MHz) spectrum of compound 5h in CDCl 3 S28

29 H NMR (400 MHz) spectrum of compound 5i in CDCl C NMR (100 MHz) spectrum of compound 5i in CDCl 3 S29

30 H NMR (400 MHz) spectrum of compound 5j in CDCl C NMR (100 MHz) spectrum of compound 5j in CDCl 3 S30

31 H NMR (400 MHz) spectrum of compound 5k in CDCl C NMR (100 MHz) spectrum of compound 5k in CDCl 3 S31

32 H NMR (400 MHz) spectrum of compound 5l in CDCl C NMR (100 MHz) spectrum of compound 5l in CDCl 3 S32

33 H NMR (400 MHz) spectrum of compound 5m in CDCl C NMR (100 MHz) spectrum of compound 5m in CDCl 3 S33

34 H NMR (400 MHz) spectrum of compound 5n in CDCl C NMR (100 MHz) spectrum of compound 5n in CDCl 3 S34

35 TMS H NMR (400 MHz) spectrum of compound 5o in CDCl C NMR (100 MHz) spectrum of compound 5o in CDCl 3 S35

36 H NMR (400 MHz) spectrum of compound 5p in CDCl C NMR (100 MHz) spectrum of compound 5p in CDCl 3 S36

37 H NMR (400 MHz) spectrum of compound 5q in CDCl C NMR (100 MHz) spectrum of compound 5q in CDCl 3 S37

38 H NMR (400 MHz) spectrum of compound 5r in CDCl C NMR (100 MHz) spectrum of compound 5r in CDCl 3 S38

39 H NMR (400 MHz) spectrum of compound 5s in CDCl C NMR (100 MHz) spectrum of compound 5s in CDCl 3 S39

40 H NMR (400 MHz) spectrum of compound 5w in CDCl C NMR (100 MHz) spectrum of compound 5v in CDCl 3 S40

41 H NMR (400 MHz) spectrum of compound 5x in CDCl C NMR (100 MHz) spectrum of compound 5x in CDCl 3 S41

42 References: 1 (a) M. Shen and T. G. Driver, Org Lett, 2010, 12, 2884; (b) J. Hu, Y. Cheng, Y. Yang, and Y. Rao, Chem.Commun., 2011, 47, S. Vidyacharan, A. Sagar, N. C. Chaitra and D. S. Sharada, RSC Adv., 2014, 4, (a) M. R. Kumar, A. Park, N. Park, and S. Lee, Org. Lett., 2011, 13, 3542; (b) N. E. Genung, L. Wei, and G. E. Aspnes, Org. Lett. 2014, 16, S42