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

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-502 205, Medak District, Telangana. E-mail: 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

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 = 77.00 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 50-100 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

(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 1.5-3 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

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 1.5-3 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

X-ray crystal structure data for Dimethyl 4-(benzylamino)quinoline-2,3-dicarboxylate (5a) CCDC 1059037 Identification code exp_2959_216 Empirical formula C 20 H 18 N 2 O 4 Formula weight 350.36 Temperature/K 298 Crystal system monoclinic Space group C2/c a/å 19.3579(11) b/å 10.6509(6) c/å 16.8297(14) α/ 90.00 β/ 94.958(7) γ/ 90.00 Volume/Å 3 3456.9(4) Z 8 ρ calc mg/mm 3 1.350 m/mm -1 0.780 F(000) 1472.0 Crystal size/mm 3 0.06 0.05 0.05 2Θ range for data collection 9.18 to 141.34 Index ranges -23 h 20, -9 k 12, -20 l 20 Reflections collected 6934 Independent reflections 3258[R(int) = 0.0336] Data/restraints/parameters 3258/0/237 S5

Goodness-of-fit on F 2 0.934 Final R indexes [I>=2σ (I)] R 1 = 0.0564, wr 2 = 0.1409 Final R indexes [all data] R 1 = 0.0888, wr 2 = 0.1702 Largest diff. peak/hole / e Å -3 0.15/-0.27 X-ray crystal structure data for Dimethyl 4-((2-bromophenyl)amino)quinoline-2,3-dicarboxylate (5f) CCDC 1059035 Identification code exp_4184 Empirical formula C 19 H 16 BrN 2 O 4 Formula weight 416.25 Temperature/K 293(2) Crystal system triclinic Space group P-1 a/å 8.4200(12) b/å 10.1497(7) c/å 11.2030(17) α/ 66.531(11) β/ 88.054(12) γ/ 88.057(10) Volume/Å 3 877.5(2) Z 2 ρ calc mg/mm 3 1.575 m/mm -1 2.370 F(000) 422.0 Crystal size/mm 3 0.24 0.20 0.18 2Θ range for data collection 6.19 to 57.948 Index ranges -11 h 11, -13 k 13, -14 l 14 Reflections collected 6815 S6

Independent reflections 3972[R(int) = 0.0323] Data/restraints/parameters 3972/0/237 Goodness-of-fit on F 2 1.032 Final R indexes [I>=2σ (I)] R 1 = 0.0453, wr 2 = 0.1068 Final R indexes [all data] R 1 = 0.0717, wr 2 = 0.1224 Largest diff. peak/hole / e Å -3 0.29/-0.48 Spectral data of all compounds (3i & 3j) and (5a-5x) S7

5-Bromo-2-(3-methoxybenzyl)-2H-indazole (3i): Pale yellow solid (80%), Mp 49-51 o C. IR (MIR-ATR, 4000 600 cm -1 ): ʋ max = 3059, 2938, 2834.8, 1600, 1586, 1491, 1338.9, 1260.4, 1138, 1038.5, 914.7, 862.6, 778.6, 670, 575.5. 1 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), 7.28-7.24 (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, 113.7. HR-MS (ESI+) m/z calculated for [C 15 H 14 BrN 2 O] + = [M+H] + : 317.0284; found: 317.0281. 5-Bromo-2-(3,4-dimethoxybenzyl)-2H-indazole (3j): Pale yellow solid (85%), Mp 51-52 o C. IR (MIR-ATR, 4000 600 cm -1 ): ʋ max = 3062, 2934.4, 2834.1, 1606.7, 1593, 1513.5, 1461.5, 1340.9, 1259, 1236, 1136.7, 1024.5, 803.3, 752.6, 670.9, 552.4. 1 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, 147.24, 129.5, 127.7, 123.2, 122.4, 122.1, 120.9, 119.3, 115.1, 111.3, 111.2, 57.5, 55.9. HR-MS (ESI+) m/z calculated for [C 16 H 16 BrN 2 O 2 ] + = [M+H] + : 347.0390; found: 347.0387. S8

Dimethyl 4-(benzylamino)quinoline-2,3-dicarboxylate (5a): Light yellow solid (68%), Mp 80-82 o C. IR (MIR-ATR, 4000 600 cm -1 ): ʋ max = 2950, 1737, 1681, 1614, 1583, 1565, 1518, 1454, 1438, 1325, 1245, 1227, 1164, 1128, 1041, 986, 765, 698. 1 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), 7.72-7.68 (m, 1H), 7.42-7.26 (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, 52.4. HR-MS (ESI+) m/z calculated for [C 20 H 19 N 2 O 4 ] + = [M+H] + : 351.1339; found: 351.1326. Dimethyl 4-((2-chlorobenzyl)amino)quinoline-2,3-dicarboxylate (5b): Light yellow solid (72%), Mp 95-97 o C. IR (MIR-ATR, 4000 600 cm -1 ): ʋ max = 2951, 1733, 1683, 1614, 1583, 1565, 1517, 1437, 1325, 1224, 1163, 1129, 1039, 985, 98, 755, 731, 700. 1 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), 7.45-7.38 (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, 50.7. HR-MS (ESI+) m/z calculated for [C 20 H 18 ClN 2 O 4 ] + = [M+H] + : 385.0950; found: 385.0950. S9

Dimethyl 4-((4-methoxybenzyl)amino)quinoline-2,3-dicarboxylate (5c): Light yellow solid (70%), Mp 84-86 o C. IR (MIR-ATR, 4000 600 cm -1 ): ʋ max = 2955, 1736, 1658, 1629, 1514, 1436, 1404, 1327, 1247, 1197, 1176, 1151, 1068, 1020, 814, 759, 631. 1 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), 7.29-7.24 (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, 51.4. HR-MS (ESI+) m/z calculated for [C 21 H 21 N 2 O 5 ] + = [M+H] + : 381.1445; found: 381.1441. Dimethyl 4-(4-chlorobenzylamino)quinolone-2,3-dicarboxylate (5d): Pale yellow solid (62%), Mp 129-133 o C. IR (MIR-ATR, 4000 600 cm -1 ): ʋ max = 3055, 2952, 1736, 1698, 1626, 1488, 1437, 1357, 1263, 1163, 1095, 1015, 730,702. 1 H NMR (CDCl 3, 400 MHz): δ H = 8.78 (br s, 1H), 8.09-8.02 (m, 2H), 7.73-7.70 (m, 1H), 7.43-7.33 (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, 52.1. HR-MS (ESI+) m/z calculated for [C 20 H 18 ClN 2 O 4 ] + = [M+H] + : 385.0950; found: 385.0958. Dimethyl 4-(phenylamino)quinoline-2,3-dicarboxylate (5e): Light yellow solid (60 %), Mp 110-112 o C. S10

IR (MIR-ATR, 4000 600 cm -1 ): ʋ max = 2920, 2849, 1732, 1693, 1577, 1563, 1495, 1437, 1417, 1328, 1240, 1220, 1168, 1105, 1034, 763, 732, 697. 1 H NMR (CDCl 3, 400 MHz): δ H = 9.73 (s, 1H), 8.07-8.05 (m, 1H), 7.68-7.65 (m, 2H), 7.30-7.25 (m, 3H), 7.15-7.11 (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, 52.7. HR-MS (ESI+) m/z calculated for [C 19 H 17 N 2 O 4 ] + = [M+H] + : 337.1183; found: 337.1183. Dimethyl 4-((2-bromophenyl)amino)quinoline-2,3-dicarboxylate (5f): Light yellow solid (64%), Mp 148-150 o C. IR (MIR-ATR, 4000 600 cm -1 ): ʋ max = 2950, 1763, 1694, 1614, 1583, 1563, 1503, 1438, 1416, 1362, 1328, 1241, 1225, 1101, 1028, 764, 662. 1 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), 7.66-7.61 (m, 2H), 7.34-7.30 (m, 1H), 7.10-7.06 (m, 1H), 6.98-6.93 (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, 52.9. HR-MS (ESI+) m/z calculated for [C 19 H 16 BrN 2 O 4 ] + = [M+H] + : 415.0288; found: 415.0285. Dimethyl -4-(2-aminophenylamino) quinolone-2,3-dicarboxylate (5g): Pale yellow solid (58%), Mp 75-77 o C. IR (MIR-ATR, 4000 600 cm -1 ): ʋ max = 3004, 2985, 1726, 1595, 1442, 1324, 1274, 1234, 1201, 1169, 1138, 1057, 967, 797. S11

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), 7.90-7.86 (m, 3H), 7.71-7.67 (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, 52.9. HR-MS (ESI+) m/z calculated for [C 19 H 18 N 3 O 4 ] + = [M+H] + : 352.1292; found: 352.1295. Dimethyl 4-((2,3-dimethylphenyl)amino)quinoline-2,3-dicarboxylate (5h): Light yellow solid (72 %), Mp 98-100 o C. IR (MIR-ATR, 4000 600 cm -1 ): ʋ max = 3235, 2922, 2853, 1732, 1685, 1610, 1568, 1506, 1436, 1354, 1324, 1216, 1163, 1116, 1060, 1028, 988, 800, 766, 732. 1 H NMR (CDCl 3, 400 MHz): δ H = 9.89 (s, 1H), 8.01 (d, 1H, J = 8.3 Hz), 7.64-7.59 (m, 1H), 7.47 (d, 1H, J = 8.3 Hz), 7.16-7.12 (m, 1H), 7.03-7.02 (m, 1H), 6.97-6.93 (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, 14.1. HR-MS (ESI+) m/z calculated for [C 23 H 24 N 2 O 4 ] + = [M+H] + : 365.1496; found: 365.1498. Dimethyl 6-bromo-4-(3-methoxybenzylamino) quinolone-2,3-dicarboxylate (5i): Pale yellow solid (63%), Mp 152-154 o C. IR (MIR-ATR, 4000 600 cm -1 ): ʋ max = 3055, 2952, 1735, 1698, 1622, 1483, 1436, 1365, 1262, 1210, 1165, 1081, 1030, 731, 701. S12

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, 34.8. HR-MS (ESI+) m/z calculated for [C 22 H 22 BrN 2 O 6 ] + = [M+H] + : 489.0656; found: 489.0663. Dimethyl 6-bromo-4-(phenylamino) quinolone-2,3-dicarboxylate (5j): Pale yellow solid (55%), Mp 142-144 o C. IR (MIR-ATR, 4000 600 cm -1 ): ʋ max = 2953, 2925, 1794, 1730, 1596, 1509, 1435, 1367, 1251, 1105, 1021, 803, 782, 759, 733, 688. 1 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), 7.38-7.32 (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, 53.4. HR-MS (ESI+) m/z calculated for [C 19 H 16 BrN 2 O 4 ] + = [M+H] + : 415.0288; found: 415.0305. Diethyl 4-(benzylamino)quinoline-2,3-dicarboxylate (5k): Light yellow solid (74%), Mp 78-80 o C. IR (MIR-ATR, 4000 600 cm -1 ): ʋ max = 2982, 2903, 1730, 1677, 1614, 1582, 1565, 1517, 1454, 1373, 1306, 1242, 1222, 1170, 1127, 1024, 763, 698. 1 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), 7.71-7.69 (m, 1H), 7.41-7.29 (m, 6H), 4.93 (d, 2H, J = 4.9 Hz), 4.45 (q, 2H, J = 7 Hz), 4.3 S13

(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, 13.9. HR-MS (ESI+) m/z calculated for [C 22 H 23 N 2 O 4 ] + = [M+H] + : 379.1652; found: 379.1641. Diethyl 4-((2-chlorobenzyl)amino)quinoline-2,3-dicarboxylate (5l): Light yellow solid (75%), Mp 78-80 o C. IR (MIR-ATR, 4000 600 cm -1 ): ʋ max = 2981, 1729, 1679, 1614, 1582, 1564, 1516, 1444, 1373, 1320, 1305, 1241, 1220, 1169, 1130, 1022, 861, 758, 701. 1 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), 7.43-7.36 (m, 2H), 7.30-7.26 (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, 14.0. HR-MS (ESI+) m/z calculated for [C 22 H 22 ClN 2 O 4 ] + = [M+H] + : 413.1263; found: 413.1264. Diethyl 4-(4-chlorobenzylamino)quinolone-2,3-dicarboxylate (5m): Pale yellow solid (70%), Mp 139-141 o C. IR (MIR-ATR, 4000 600 cm -1 ): ʋ max = 3326, 2982, 1727, 1678, 1567, 1513, 1459, 1403, 1375, 1308, 1220, 1167, 1127, 1091, 1017, 856, 808, 764. S14

1 H NMR (CDCl 3, 400 MHz): δ H = 8.89 (t, 1H, J = 5.4 Hz), 8.09-8.02 (dd, 2H, J a = 18.8 and J b = 8.8 Hz), 7.72-7.68 (t, 1H, J = 7.8 Hz), 7.42-7.30 (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, 13.5. HR-MS (ESI+) m/z calculated for [C 22 H 21 ClN 2 O 4 ] + = [M+H] + : 413.1263; found: 413.1263. Diethyl 4-((2-bromophenyl)amino)quinoline-2,3-dicarboxylate (5n): Light yellow solid (65%), Mp 98-100 o C. IR (MIR-ATR, 4000 600 cm -1 ): ʋ max =2937, 1729, 1689, 1614, 1581, 1562, 1499, 1439, 1415, 1372, 1324, 1308, 1239, 1219, 1098, 1023,862, 808, 762, 656. 1 H NMR (CDCl 3, 400 MHz): δ H = 9.42 (s, 1H), 8.12 (d, 1H, J = 8.3 Hz), 7.72-7.59 (m, 3H), 7.32-7.28 (m, 1H), 7.08-7.04 (m, 1H), 6.96-6.92 (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, 14.0. HR-MS (ESI+) m/z calculated for [C 21 H 20 BrN 2 O 4 ] + = [M+H] + : 443.0601; found: 443.0601. Diethyl 4-(2-bromo-4-methylbenzylamino) quinolone-2,3-dicarboxylate (5o): Pale yellow solid (68%), Mp 107-109 o C. IR (MIR-ATR, 4000 600 cm -1 ): ʋ max = 2980, 2924, 2852, 1734, 1611, 1582, 1564, 1503, 1463, 1372, 1324, 1242, 1221, 1195, 1101, 1021, 865. S15

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] + : 459.0554; found: 459.055. Dimethyl 4-((2,3-dimethylphenyl)amino)quinoline-2,3-dicarboxylate (5p): Light yellow solid (60%), Mp 112-114 o C. IR (MIR-ATR, 4000 600 cm -1 ): ʋ max = 2982, 1734, 1680, 1613, 1579, 1563, 1508, 1472, 1419, 1395, 1371, 1322, 1241, 1219, 1173, 1114, 1065, 1022, 766, 567. 1 H NMR (CDCl 3, 400 MHz): δ H = 305: 10 (s, 1H), 8.02 (d, 1H, J = 8.3 Hz), 7.63-7.59 (m, 1H), 7.47 (d, 1H, J = 8.8 Hz), 7.15-7.11 (m, 1H), 7.03-7.01 (m, 1H), 6.96-6.92 (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, 14.0. HR-MS (ESI+) m/z calculated for [C 23 H 24 N 2 O 4 ] + = [M+H] + : 392.1736; found: 392.1736. Diethyl 4-((2-aminophenyl)amino)quinoline-2,3-dicarboxylate (5q): Light yellow solid (60 %), Mp 54-56 o C. IR (MIR-ATR, 4000 600 cm -1 ): ʋ max = 2982, 1721, 1618, 1518, 1466, 1445, 1368, 1322, 1270, 1230, 1181, 1137, 1113, 1056, 1018, 912, 860, 761, 700. S16

1 H NMR (CDCl 3, 400 MHz): δ H = 8.81 (s, 1H), 8.29-8.22 (m, 3H), 7.97-7.93 (m, 3H), 7.88-7.86 (m, 1H), 7.71-7.69 (m, 1H), 4.60-4.57 (m, 2H), 4.56-4.55 (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, 14.1. HR-MS (ESI+) m/z calculated for [C 21 H 22 N 3 O 4 ] + = [M+H] + : 380.1605; found: 380.1603. Diethyl 6-bromo-4-(3-methoxybenzylamino) quinolone-2,3-dicarboxylate (5r): Pale yellow solid (55%), Mp 107-109 o C. IR (MIR-ATR, 4000 600 cm -1 ): ʋ max = 2981, 2903, 1732, 1678, 1604, 1583, 1558, 1510, 1491, 1465, 1374, 1315, 1267, 1242, 1210, 1129, 1039, 831, 783, 693. 1 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), 6.97-6.87 (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, 13.9. HR-MS (ESI+) m/z calculated for [C 23 H 24 BrN 2 O 5 ] + = [M+H] + : 487.0859; found: 487.0863. Diethyl 6-bromo-4-(3-methoxybenzylamino) quinolone-2,3-dicarboxylate (5s): Pale yellow solid (68%), Mp 110-112 o C. IR (MIR-ATR, 4000 600 cm -1 ): ʋ max = 2983, 2920, 1815, 1723, 1580, 1507, 1462, 1444, 1369, 1263, 1234, 1202, 1143, 1057, 1033, 942, 860. S17

1 H NMR (CDCl 3, 400 MHz): δ H = 9.32 (s, 1H), 7.32 (s, 1H), 6.98-6.94 (m, 2H), 6.88-6.85 (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, 13.9. HR-MS (ESI+) m/z calculated for [C 22 H 20 FN 2 O 6 ] + = [M+H] + : 427.1300; found: 427.1295. Dimethyl 4-((5-(diethylamino)pentan-2-yl)amino)quinolone-2,3-dicarboxylate (5w): yellow viscous liquid (38%) IR (MIR-ATR, 4000 600 cm -1 ): ʋ max = 2933, 2857, 1730, 1680, 1657, 1602, 1501, 1451, 1366, 1274, 1247, 1180, 1150, 1095, 1054, 976, 833, 752, 695, 670, 576. 1 H NMR (CDCl 3, 400 MHz): δ H = 8.79 (s, 1H), 8.23 (d, 1H, J = 8.3 Hz), 7.96-7.86 (m, 2H), 7.71-7.68 (m, 1H), 4.61 (s, 1H), 4.07 (s, 3H), 3.99 (s, 3H), 3.95-3.91 (m, 6H), 3.65-3.63 (m, 4H), 3.22-3.15 (m, 6H), 1.21-1.13 (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, 12.7. HR-MS (ESI+) m/z calculated for [C 22 H 32 N 3 O 4 ] + = [M+H] + : 402.2387; found: 402.2382. Diethyl quinolone-2,3-dicarboxylate (5x): Light yellow liquid (26 %) IR (MIR-ATR, 4000 600 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, 700. 1 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), 7.87-7.83 (m, 1H), 7.68-7.64 (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, 14.1. HR-MS (ESI+) m/z calculated for [C 15 H 16 NO 4 ] + = [M+H] + : 274.1074; found: 274.1073. S18

Copies of 1 H, 13 C NMR Spectra of all Compounds (3a & 3j) and (5a-5s, 5w & 5x): 7.81 7.75 7.60 7.58 7.33 7.32 7.30 7.30 7.24 6.86 6.85 6.83 6.79 5.51 3.74 1.00 0.98 1.06 1.05 1.21 2.15 1.08 2.11 3.17 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 1 H NMR (400 MHz) spectrum of compound 3i in CDCl 3 160.05 147.31 136.86 130.11 129.62 123.30 122.46 122.37 120.25 119.35 115.25 113.91 113.74 77.45 77.13 76.82 57.62 55.30 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 13 C NMR (100 MHz) spectrum of compound 3i in CDCl 3 S19

7.78 7.73 7.73 7.60 7.58 7.32 7.31 7.29 6.86 6.86 6.83 6.83 6.82 5.47 3.85 3.81 1.00 0.99 1.04 1.18 1.15 2.16 2.14 3.09 3.07 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 1 H NMR (400 MHz) spectrum of compound 3j in CDCl 3 149.33 149.29 147.24 129.51 127.66 123.22 122.36 122.15 120.92 119.29 115.12 111.33 111.26 77.53 77.21 76.90 57.54 55.93 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 13 C NMR (100 MHz) spectrum of compound 3j in CDCl 3 S20

8.7463 8.1351 8.1144 8.0227 8.0019 7.6963 7.6792 7.3993 7.3822 7.3651 7.3443 7.3236 7.2600 4.9035 4.8913 3.9672 3.8206 3.8181 1.00 1.07 1.03 1.05 6.46 2.15 3.19 3.42 9 8 7 6 5 4 3 2 1 0 1 H NMR (400 MHz) spectrum of compound 5a in CDCl 3 168.2042 168.0729 156.3923 152.3602 149.0135 137.9818 131.6749 130.3843 129.0937 128.0730 127.2709 125.7179 125.2585 119.4328 102.4295 77.3767 77.0559 76.7424 52.9072 52.8051 52.3749 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 13 C NMR (100 MHz) spectrum of compound 5a in CDCl 3 S21

8.7010 8.0496 8.0312 8.0141 7.7061 7.5057 7.4274 7.4067 7.3113 7.3028 7.2967 7.2881 7.2600 4.9805 4.9658 3.9831 3.8474 1.6290-0.0039 0.91 1.95 0.99 1.02 2.05 1.98 2.00 2.79 2.81 9 8 7 6 5 4 3 2 1 0 1 H NMR (400 MHz) spectrum of compound 5b in CDCl 3 167.8056 167.7108 156.3947 151.9033 148.6587 135.2573 132.8876 131.3710 130.1680 129.5847 129.0962 128.7754 127.0692 125.5964 124.7360 119.2384 102.9861 77.0000 76.6865 76.3657 52.5742 52.0857 50.3868 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 13 C NMR (100 MHz) spectrum of compound 5b in CDCl 3 S22

7.8528 7.7147 7.6927 7.6096 7.5888 7.2930 7.2722 7.2600 7.2392 7.0632 7.0449 6.8811 6.8603 5.5146 5.1455 3.9489 3.7753 3.7301 3.6140 3.2326 1.07 0.981.04 2.94 1.00 2.01 2.11 3.55 2.87 4.29 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 1 H NMR (400 MHz) spectrum of compound 5c in CDCl 3 172.1439 169.3367 167.9149 166.6754 159.2092 148.4181 129.1472 127.3317 125.3849 122.1184 121.5862 121.1487 119.7050 116.9999 113.8137 91.3638 77.0000 76.6865 76.3657 56.5261 54.8126 51.9836 50.9264 48.1995 40.2082 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 13 C NMR (100 MHz) spectrum of compound 5c in CDCl 3 S23

8.78 8.10 8.08 8.05 8.03 7.72 7.43 7.42 7.39 7.37 7.33 7.31 7.27 4.91 4.89 3.99 3.85 1.00 2.14 1.02 5.39 2.07 3.11 3.06 9 8 7 6 5 4 3 2 1 0 1 H NMR (400 MHz) spectrum of compound 5d in CDCl 3 168.13 168.06 156.40 152.32 149.00 136.51 133.89 131.76 130.46 129.25 128.61 125.84 125.11 119.37 102.62 77.38 77.27 77.06 76.74 52.95 52.45 52.14 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 13 C NMR (100 MHz) spectrum of compound 5d in CDCl 3 S24

9.6960 8.0459 8.0276 8.0239 7.6560 7.6401 7.6340 7.6303 7.2600 7.2392 7.2356 7.1048 6.9838 6.9642 3.9941 3.8731 1.6498 1.2245-0.0296 1.00 1.01 2.07 3.39 1.05 2.07 3.19 3.18 10 9 8 7 6 5 4 3 2 1 0 1 H NMR (400 MHz) spectrum of compound 5e in CDCl 3 167.9125 167.7302 151.7769 151.5582 148.8094 142.6774 131.7259 130.4426 129.4437 126.4397 125.9877 124.5513 121.8098 120.0015 107.2053 77.3621 77.0486 76.7278 53.0749 52.7176 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 13 C NMR (100 MHz) spectrum of compound 5e in CDCl 3 S25

9.3476 8.1339 8.1131 7.7220 7.6670 7.6633 7.6462 7.6437 7.6327 7.6107 7.3260 7.2636 7.0815 6.9593 6.6855 6.6659 4.0332 3.9293 1.6070 1.2562 0.0009 1.00 1.03 1.07 2.13 1.05 1.05 1.08 1.06 3.39 3.43 9 8 7 6 5 4 3 2 1 0 1 H NMR (400 MHz) spectrum of compound 5f in CDCl 3 168.4302 167.1907 151.3030 149.9249 141.0223 133.3300 131.8936 130.6468 127.8469 126.7095 125.8200 124.8429 121.0952 120.5338 115.6924 109.8521 84.7846 77.3621 77.2455 77.0413 76.7205 53.1551 52.9218 25.1201 23.9535 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 13 C NMR (100 MHz) spectrum of compound 5f in CDCl 3 S26

8.79 8.28 8.27 8.26 8.23 8.21 7.96 7.96 7.95 7.94 7.88 7.69 4.10 4.07 3.99 0.96 1.16 1.00 2.21 1.04 1.01 3.59 2.95 3.02 9 8 7 6 5 4 3 2 1 0 1 H NMR (400 MHz) spectrum of compound 5g in CDCl 3 167.18 165.58 165.18 150.55 148.06 143.84 141.42 139.60 132.74 132.50 129.90 129.86 128.76 128.68 127.04 122.31 77.37 77.06 76.74 53.65 53.26 52.94 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 13 C NMR (100 MHz) spectrum of compound 5g in CDCl 3 S27

9.8903 8.0227 8.0019 7.6193 7.4825 7.4617 7.2600 7.1647 7.1463 7.0388 7.0204 6.9703 6.9508 6.6880 6.6684 4.0613 4.0149 3.9843 3.8939 2.3661 2.3184 1.7134-0.0063 1.01 0.99 1.08 1.03 1.04 1.04 1.05 1.08 2.94 3.10 3.10 3.01 10 9 8 7 6 5 4 3 2 1 0 1 H NMR (400 MHz) spectrum of compound 5h in CDCl 3 167.6452 152.7126 151.8668 148.4545 140.5799 138.0645 131.2252 129.9274 126.8869 125.6620 125.3630 120.9591 119.2311 104.3058 77.0000 76.6792 76.3584 52.6326 52.2242 20.2447 13.7628 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 13 C NMR (100 MHz) spectrum of compound 5h in CDCl 3 S28

8.14 7.45 7.45 7.43 7.42 7.31 7.31 7.26 7.06 7.04 6.95 6.74 6.74 3.98 3.68 3.57 3.06 1.01 1.02 1.02 1.00 1.09 1.95 1.04 2.29 3.17 3.04 3.02 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 1 H NMR (400 MHz) spectrum of compound 5i in CDCl 3 170.94 163.89 163.25 154.56 147.74 140.87 136.09 135.32 131.55 122.06 119.24 116.34 112.79 107.34 87.70 77.37 77.25 77.05 76.74 65.57 55.29 53.63 53.39 52.13 51.67 51.47 34.80 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 13 C NMR (100 MHz) spectrum of compound 5i in CDCl 3 S29

8.31 7.84 7.82 7.80 7.62 7.60 7.47 7.45 7.36 7.32 7.30 3.79 1.00 3.03 1.09 2.05 2.17 5.54 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 1 H NMR (400 MHz) spectrum of compound 5j in CDCl 3 152.13 148.03 140.15 130.38 129.61 128.20 123.88 122.54 120.86 119.88 119.68 115.82 77.47 77.15 76.84 74.58 53.43 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 13 C NMR (100 MHz) spectrum of compound 5j in CDCl 3 S30

8.9064 8.8929 8.8795 8.1523 8.1315 8.0374 8.0166 7.6902 7.4116 7.3944 7.3798 7.3614 7.3529 7.3321 7.2600 4.9316 4.9181 4.4537 4.4354 4.4170 4.3229 4.3046 4.2862 4.2691 1.4420 1.4237 1.4066 1.3333 1.3161 1.2978 1.2807 1.2501-0.0039 1.00 1.16 1.09 1.146.79 2.33 2.40 2.50 3.61 4.25 9 8 7 6 5 4 3 2 1 0 1 H NMR (400 MHz) spectrum of compound 5k in CDCl 3 167.8615 167.7156 156.6766 152.7612 149.0645 138.1276 131.5655 130.3333 129.0646 128.0219 127.2782 125.5429 125.3679 119.4838 102.5608 77.3621 77.0486 76.7278 61.9484 61.5546 52.9728 14.1322 13.9280 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 13 C NMR (100 MHz) spectrum of compound 5k in CDCl 3 S31

8.8074 8.0459 8.0251 8.0044 7.6890 7.5057 7.4226 7.4140 7.3859 7.3003 7.2906 7.2857 7.2771 4.9707 4.9560 4.4671 4.4500 4.4317 4.4146 4.3315 4.3131 4.2960 4.2777 1.4384 1.4200 1.4029 1.3394 1.3223 1.3039 1.2819 1.2465-0.0076 1.00 2.14 1.12 1.13 2.22 2.95 2.26 2.41 2.55 3.38 4.00 9 8 7 6 5 4 3 2 1 0 1 H NMR (400 MHz) spectrum of compound 5l in CDCl 3 167.8104 167.7156 156.9245 152.6227 149.0208 135.7288 133.2279 131.6019 130.4353 129.8958 129.3854 129.1375 127.3949 125.7835 125.1492 119.6078 103.4139 77.3767 77.2600 77.0559 76.7424 61.9630 61.6276 50.8219 14.1395 13.9207 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 13 C NMR (100 MHz) spectrum of compound 5l in CDCl 3 S32

8.91 8.89 8.88 8.10 8.08 8.05 8.03 7.71 7.42 7.40 7.38 7.36 7.33 7.30 7.27 4.90 4.89 4.48 4.46 4.44 4.42 4.33 4.32 4.30 4.28 1.45 1.43 1.41 1.35 1.34 1.32 1.01 2.19 1.03 5.43 2.08 2.41 2.14 3.21 3.22 9 8 7 6 5 4 3 2 1 0 1 H NMR (400 MHz) spectrum of compound 5m in CDCl 3 174.73 165.04 162.03 161.59 145.48 139.72 137.91 133.36 132.06 127.15 126.61 125.45 116.57 114.59 77.41 77.30 77.10 76.78 63.36 62.26 61.66 14.19 13.91 13.59 13.56 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 13 C NMR (100 MHz) spectrum of compound 5m in CDCl 3 S33

9.4197 8.1290 8.1082 7.7061 7.6548 7.6377 7.6181 7.5973 7.3260 7.3077 7.2600 7.0669 7.0485 6.9447 6.6599 6.6403 4.5172 4.4989 4.4818 4.4635 4.4182 4.4011 4.3828 4.3645 1.6523 1.4689 1.4518 1.4335 1.4017 1.3834 1.3663-0.0051 1.00 1.02 3.13 1.55 1.06 1.04 1.03 2.17 2.19 3.13 3.34 10 9 8 7 6 5 4 3 2 1 0 1 H NMR (400 MHz) spectrum of compound 5n in CDCl 3 167.4702 167.1129 152.0418 150.1607 148.9795 141.4403 133.5876 132.0418 130.9044 128.1046 126.8432 126.1140 124.9766 121.2945 120.8133 115.8698 110.2409 77.6343 77.5250 77.3208 77.0000 62.5341 14.4408 14.2440 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 13 C NMR (100 MHz) spectrum of compound 5n in CDCl 3 S34

9.55 8.10 8.08 7.70 7.69 7.67 7.60 7.58 7.48 7.30 7.28 7.27 7.26 6.90 6.88 6.61 6.59 4.51 4.50 4.48 4.46 4.42 4.40 4.38 4.37 2.31 1.58 1.47 1.45 1.43 1.41 1.39 1.37 TMS 0.98 1.05 1.10 1.03 1.00 0.90 1.05 1.04 2.19 2.16 3.24 3.05 3.38 9 8 7 6 5 4 3 2 1 1 H NMR (400 MHz) spectrum of compound 5o in CDCl 3 167.39 150.68 148.74 138.56 135.34 133.60 131.67 130.53 128.58 126.24 125.89 121.73 120.17 116.08 77.35 77.24 77.03 76.72 62.17 20.54 14.15 13.98 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 13 C NMR (100 MHz) spectrum of compound 5o in CDCl 3 S35

10.0003 8.0264 8.0056 7.6120 7.4825 7.4605 7.2600 7.1586 7.1378 7.0302 7.0119 6.9630 6.9434 6.6721 6.6525 4.5062 4.4891 4.4720 4.4537 4.3914 4.3742 4.3559 4.3376 2.3685 2.3294 1.4701 1.4530 1.4347 1.4017 1.3834 1.3663-0.0039 1.00 1.08 1.15 1.13 1.20 1.15 1.14 1.09 2.14 2.33 3.33 3.37 3.42 3.44 10 9 8 7 6 5 4 3 2 1 0 1 H NMR (400 MHz) spectrum of compound 5p in CDCl 3 167.7618 167.6670 153.0626 152.5449 148.8045 141.0685 138.3269 131.4002 130.2117 130.1680 127.0327 126.0338 125.9245 125.5234 121.1414 119.5738 104.7287 77.3135 77.1969 77.0000 76.6792 61.9800 61.7977 20.5655 14.1127 14.0690 13.9086 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 13 C NMR (100 MHz) spectrum of compound 5p in CDCl 3 S36

8.8111 8.2928 8.2843 8.2769 8.2684 7.9775 7.9616 7.9542 7.9457 7.9371 7.8858 7.6963 7.2881 4.6052 4.5881 4.5698 4.5625 4.5515 4.5441 4.4732 4.4549 1.7170 1.5117 1.4934 1.4750 1.4665 1.4567 1.4481 1.4164 1.2709 0.0157 1.00 3.05 2.80 1.17 1.16 2.51 2.23 2.14 3.50 3.04 9 8 7 6 5 4 3 2 1 0 1 H NMR (400 MHz) spectrum of compound 5q in CDCl 3 166.9136 164.8210 164.1429 151.0405 148.0802 144.2013 141.3868 139.6151 132.5134 132.3530 129.8958 129.8302 128.6490 128.5906 127.0230 122.4441 119.7682 89.7427 77.3694 77.0486 76.7278 62.9254 62.3931 62.0359 14.1832 14.1176 9.3053 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 13 C NMR (100 MHz) spectrum of compound 5q in CDCl 3 S37

8.93 8.30 8.30 7.90 7.87 7.76 7.76 7.74 7.74 7.32 7.27 6.97 6.95 6.90 6.89 6.87 4.87 4.85 4.47 4.45 4.43 4.42 4.34 4.32 4.30 4.28 3.82 1.63 1.44 1.43 1.41 1.34 1.33 1.31 0.00 1.00 1.02 1.00 0.99 1.14 3.11 2.03 2.19 2.11 3.08 3.25 3.21 9 8 7 6 5 4 3 2 1 0 1 H NMR (400 MHz) spectrum of compound 5r in CDCl 3 167.60 167.48 160.17 155.56 152.98 147.78 139.32 134.79 131.94 130.24 127.87 120.67 119.50 119.18 113.75 112.75 103.20 77.36 77.25 77.04 76.73 62.06 61.77 55.31 52.78 14.13 13.90 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 13 C NMR (100 MHz) spectrum of compound 5r in CDCl 3 S38

9.3158 7.3724 7.2600 6.9874 6.9654 6.9447 6.8884 6.8774 6.8664 6.8567 6.0573 4.4891 4.4720 4.4537 4.4354 4.3706 4.3535 4.3351 4.3168 1.5863 1.4579 1.4408 1.4225 1.3724 1.3540 1.3430 1.3369 1.2501-0.0039 1.00 1.37 2.81 3.46 2.35 2.72 4.07 3.87 4.78 9 8 7 6 5 4 3 2 1 0-1 1 H NMR (400 MHz) spectrum of compound 5s in CDCl 3 172.5376 167.7181 152.3408 150.6054 150.2992 147.9587 122.8986 122.8184 116.5771 116.3510 110.0003 108.5712 107.3098 102.4757 102.2643 77.6416 77.5250 77.3208 77.0000 62.4102 62.2935 14.4627 14.1784 180 160 140 120 100 80 60 40 20 0 13 C NMR (100 MHz) spectrum of compound 5s in CDCl 3 S39

8.7910 8.2373 8.2165 7.9684 7.9476 7.9073 7.8865 7.8682 7.7191 7.7166 7.6995 7.2668 4.6145 4.0682 3.9924 3.9435 3.9349 3.9141 3.8090 3.6526 3.6343 3.2065 3.1881 3.1698 3.1527 1.3633 1.3486 1.2851 1.2557 1.2130 1.1971 1.1799 1.1616 1.1396 0.8805 0.0005 1.00 1.06 2.14 1.08 1.18 3.28 3.49 5.67 4.74 5.67 8.89 9 8 7 6 5 4 3 2 1 0 1 H NMR (400 MHz) spectrum of compound 5w in CDCl 3 168.6732 167.4556 166.4494 165.8588 154.0834 150.8169 148.3379 139.8727 134.4844 132.7710 130.1315 129.9128 129.0378 128.9503 127.3244 122.5924 84.1746 83.1611 77.6343 77.5177 77.3208 77.0000 53.5148 53.3763 53.2086 53.1429 53.1065 50.9847 32.8440 29.9786 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 13 C NMR (100 MHz) spectrum of compound 5v in CDCl 3 S40

8.7829 8.2207 8.1999 7.9494 7.9298 7.8772 7.8565 7.8394 7.6878 7.6682 7.6499 7.2600 7.2246 4.5539 4.5356 4.5185 4.5001 4.4647 4.4464 4.4292 4.4109 1.4653 1.4481 1.4396 1.4298 1.4213 1.4041 1.2782 1.2465 1.2318-0.0088 0.99 1.00 1.03 1.09 1.26 2.09 2.44 3.13 3.45 9 8 7 6 5 4 3 2 1 0 1 H NMR (400 MHz) spectrum of compound 5x in CDCl 3 166.5442 164.7286 150.6929 147.7254 139.2310 131.9762 129.4753 128.2796 128.2139 126.6609 124.9693 122.2278 122.0893 120.4196 111.4950 108.2577 77.0000 76.6865 76.3657 62.0237 61.6592 60.6384 14.0471 13.8284 13.7336 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 13 C NMR (100 MHz) spectrum of compound 5x in CDCl 3 S41

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