Synthetic Procedures and Physical Characterization Data in Details for The

Synthetic Procedures and Physical Characterization Data in Details for the

Synthesis of the Compounds (2-11c)

Methyl 2-(3-methoxybenzylidene)-3-oxobutanoate (2, scheme 1): A solution of m-anisaldehyde (1.36 g, 10 mmol), methylacetoacetate (1.39 g, 12 mmol) and piperidinium acetate (catalytic amount) in toluene (40 mL) was refluxed in a Dean-Stark trap for 7 h and then concentrated. Chromatography of the residue eluting with ethyl acetate/hexane (1:4) gave (10) as yellow viscous mass (1.17 g, 50%) as a mixture of geometric isomers (0.9:1.0). FTIR (CHCl3, ν, cm-1): 3020 ( C-H stretch, Ar), 2982 and 2919 (C-H stretch of –CH3, antisymmetric and symmetric), 1734 (C=O stretch, ester), 1625 (C=O stretch, ketone), 1255 (C-O stretch, ester), 1215 (C-O stretch, aralkyl ether) 756 (C-C out of plane bending, phenyl ring 1,3-disubstituted); lH NMR (CDCl3, δ, ppm): 2.34 and 2.42 (two singlets, 3H each, -COCH3), 3.79 and 3.80 (two singlets, 3H each, -OCH3), 3.83 and 3.84 (two singlets, 3H each, -COOCH3), 6.91-6.98 (m, 2H, Ar), 7.01-7.03 (m, 1H, Ar), 7.26-7.32 (m, 1H, Ar), 7.66 and 7.54 (two singlets, 1H each, benzylidene) respectively for the minor and the major geometrical isomers; 13C NMR (CDCl3, δ, ppm): 194.71 (C=O of COCH3), 168.25 (C=O of COOCH3), 159.80, 141.51, 134.11, 129.98, 122.01, 116.86, 114.25, 113.13, 52.57 (COOCH3), 26.47 (-COCH3); GCMS m/z (%): 234 [M]+, 219, 203; Anal. % Calcd. for C13H14O4: C, 66.66; H, 6.02. Found: C, 66.91; H, 6.35.

Methyl-2-(3-hydroxybenzylidene)-3-oxobutanoate (3, scheme1): To a solution of 2 (3 g, 0.0128 mol) in DCM at 0°C was added BBr3 in DCM (13 ml, 1M solution) dropwise while stirring and stirring continued of 2 h at 0°C and then at room temperature for 16 h. The contents treated with ice cold water and the organic layers separated, washed with brine, dried over sodium sulphate, filtered and solvent evaporated and the residue purified by column chromatography EtOAc/Hexane (1:4) to yield 3a as pale yellow solid (1.04gm, 37%). mp: 135-138 °C. FTIR (KBr, ν, cm-1): 3350 (O-H stretch, H-bonded), 3059 (C-H stretch, aromatic), 2940 and 2890 (C-H stretch of –CH3, antisymmetric and symmetric), 1732 (C=O stretch, ester), 1646 (C=O stretch, ketone), 1598 (C=C stretch, Ar), 1573 (C=C stretch, Ar), 1510 (C=C stretch, Ar), 1483 (C-H bending, Methyl), 679 (C-C out of plane bending, phenyl ring 1,3-disubstituted); 1H NMR (CDCl3) δ, ppm: 2.42 (s, 3H, -COCH3), 3.83 (s, 3H, -COOCH3), 5.56 (s, 1H, -OH), 6.90 (m, 2H, Ar), 6.99 (m, 1H, Ar), 7.27 (m, 1H, Ar), 7.51 (s, 1H, benzylidene); 13C NMR (CDCl3, δ, ppm):208.45 and 198.38 (C=O of COCH3), 169.13 and 165.18 (C=O of COOCH3), 158.91, 158.54, 141.17, 141.04, 131.97, 131.89, 131.36, 130.69, 125.09, 124.90, 116.13, 116.11, 62.03 and 61.59 (COOCH3), 37.08 and 31.78 (-COCH3); GCMS (m/z): 220 (M.+), 205, 189, 160; Anal. % Calcd. for C12H12O4: C, 65.45; H, 5.49; Found: C, 65.27; H, 5.33.

Ethyl 1-methyl-1H-indole-2-carboxylate (5, scheme 2): To a stirred solution of sodium hydride (1.100g, 27.5mmol, 60% w/w) in dry DMF (100ml) was added (4) (4.160g, 22mmol) at 2-5°C, and the mixture was stirred for 30 min at room temperature. A solution of iodomethane (3.750g, 26.4mmol) in dry DMF (5ml) was added dropwise over 15 min at 2-5°C, and stirred for 28h at room temperature. The reaction mixture was quenched with water, and extracted with EtOAc (3×25ml). The combined organic extracts were washed with brine and water, dried, and concentrated. The product (5) was isolated by column chromatography (EtOAc/ hexane, 1:20) as a white solid (3.35g, 75%). mp: 68-70 °C. FTIR (KBr), ν, cm-1: 3048 (C-H stretch, Ar), 2982 and 2850 (C-H stretch N-CH3, antisymmetric and symmetric), 1703 (C=O stretch, ester), 1515 and 1469 (C=C stretch, Ar), 1465 (bending antisymmetric, CH2CH3), 1400 (bending symmetric, CH2CH3), 1378 (C-N stretch, Ar), 1251 (C-O stretch ester), 1087 (C-N stretch N-Me), 747 (C-C out of plane bending, phenyl ring 1,3-disubstituted); 1H NMR, (CDCl3), δ, ppm: 1.41 (t, 3H, -OCH2CH3), 4.08 (s, 3H, N-CH3), 4.37 (q, 2H, -OCH2CH3), 7.16-7.12 (m, 1H, Ar), 7.30 (s, 1H, Ar), 7.36-7.31 (m, 1H, Ar), 7.42-7.37 (m, 1H, Ar), 7.67 (d, 1H, Ar); 13C NMR (CDCl3, δ, ppm): 162.30 (C=O of ester), 139.66, 128.04, 125.04, 125.91, 124.93, 122.63, 120.59, 110.12, 60.56 (COOCH2CH3), 31.62 (N-CH3), 14.42 (COOCH2CH3); Anal. % Calcd. for C12H13NO2: C, 70.92; H, 6.45; N, 6.89. Found: C, 71.08; H, 6.57; N, 6.60.

(1-methyl-1H-indol-2-yl)methanol (6, scheme 2): To a stirred suspension of lithium aluminium hydride (7.600g, 200mmol) in THF (100ml) was added (5) (4.060g, 20mmol) in THF (5ml), and the mixture was stirred at room temperature (ca. 30°C) for 36h. The reaction mixture was quenched with ice water, acidified with 2N- HCl, and extracted with ethyl acetate (3×20ml). The combined organic extracts were dried over sodium sulfate and concentrated to a white solid which upon recrystallization from ethyl acetate gave (6) (3.06g, 95%) as a white solid. mp: 108-110 °C. FTIR (KBr), ν, cm-1: 3600-3400 (O-H stretch, alcohol), 3049 (C-H stretch, Ar), 2962 (C-H stretch N-CH3, antisymmetric and symmetric), 2929 and 2850 (C-H stretch CH2-OH, antisymmetric and symmetric), 1612 (C=C stretch, Ar), 1515 (C=C stretch, Ar), 1468 (C=C stretch, Ar); 1H NMR (CDCl3), δ, ppm: 3.80 (s, 3H, N-CH3), 4.80 (s, 2H, -CH2OH), 6.45 (s, 1H, Ar), 7.08-7.11 (m, 1H, Ar), 7.21-7.25 (m, 1H, Ar), 7.30-7.33 (m, 1H, Ar), 7.59-7.57 (m, 1H, Ar); 13C NMR (CDCl3, δ, ppm): 138.71, 138.12, 127.21, 122.00, 120.85, 119.61, 109.29, 101.29, 57.31 (-CH2O-), 29.73(N-CH3); Anal. % Calcd. for C10H11NO: C, 74.51; H, 6.88; N, 8.69. Found: C, 74.38; H, 6.59; N, 8.52.

3-[(1-methyl-1H-indol-2-yl)methoxy]benzaldehyde (7, scheme 2): A solution of diethyl azodicarboxylate (1.6 g, 9 mmol) and triphenylphosphine (2.33 g, 9 mmol) in THF (40 ml) at 0 °C was added dropwise to a stirred mixture of (6) (0.805 gm, 5 mmol) and 3-hydroxybenzaldehyde (0.700 gm, 6 mmol) taken in THF (10 ml) at 0 °C. The reaction mixture was stirred at 0 °C for an hour and then at room temperature for 16 h and solvent removed under reduced pressure. The residue was taken up in 30 ml of EtOAc/ water (2:1). The organic layer was separated, dried over anhydrous sodium sulphate, filtered and solvent evaporated in vaccuo and the residue upon preparative chromatography using EtOAc: n-hexane (15:85) gave the desired title compound (7) (0.600 g, 45.5%). mp: 102-105 °C. FTIR (CHCl3, ν, cm-1): 3065 (C-H stretch, Ar), 2963 and 2923 (C-H stretch N-CH3, antisymmetric and symmetric), 2850 and 2729 (C-H stretch, aldehyde), 1697 (C=O stretch, aldehyde), 1594 (C=C stretch, Ar), 1484 (C=C stretch, Ar), 1469 (C=C stretch, Ar), 755 (C-C out of plane bending, phenyl ring 1,3-disubstituted); 1H NMR (CDCl3, δ, ppm): 3.80 (s, 3H, N-CH3), 5.26 (s, 2H, -CH2O-), 7.10-7.13 (m, 1H, Ar), 7.25 (m, 2H, Ar), 7.35 (m, 1H, Ar), 7.46 (m, 2H, Ar), 7.55 (m, 1H, Ar), 7.61 (m, 1H, Ar), 9.99 (s, 1H, -CHO); 13C NMR (CDCl3, δ, ppm): 193.55 , 157.07, 138.32, 130.35, 127.26, 123.09, 119.70, 114.93, 109.43, 101.60, 57.13, 29.64; LCMS (m/z): 266 [M+1]+; Anal. % Calcd for C17H15NO2: C, 76.96; H, 5.70; N, 5.28. Found: C, 76.58; H, 5.55; N, 5.60.

5-{3-[(1-methyl-1H-indol-2-yl)methoxy]benzylidene}-1,3-thiazolidine-2,4-dione (7a, scheme 2): A mixture of (7) (0.265 gm; 1 mmol), thiazolidine-2,4-dione (0.117 gm; 1 mmol), and piperidinium acetate (0.1ml) in toluene (25 ml) was refluxed for 7 h with continuous removal of water using a Dean-Stark trap. The reaction mixture was cooled to room temperature and evaporated to dryness under reduced pressure. The crude product was purified by column chromatography using a mixture of ethyl acetate/hexane (1:4) as eluent to obtain the title compound (7a) (0.26 g, 72%) as yellow solid. mp: 168-172 oC. FTIR (CHCl3, ν, cm-1): 3361 (N-H stretch), 2923 and 2852 (C-H stretch N-CH3, antisymmetric and symmetric), 1728 (C=O stretch), 1706 (C=O stretch), 1614 (C=C stretch, Ar), 1500 (C=C stretch, Ar), 1452 (C=C stretch, Ar), 1445 (C=C stretch, Ar), 760 (C-C out of plane bending, phenyl ring 1,3-disubstituted); lH NMR (CDCl3, δ, ppm): 3.81 (s, 3H, N-CH3), 5.22 (s, 2H, -CH2O-), 6.59 (s, 1H, Ar), 6.94 (m, 2H, Ar), 7.11 (m, 1H, Ar), 7.30 (m, 3H, Ar), 7.49 (m, 1H, Ar), 7.60 (m, 1H, Ar), 7.86 (s, 1H, benzylidene); 13C NMR (CDCl3, δ, ppm): 138.66, 136.36, 127.49, 122.33, 120.84, 120.80, 119.59, 119.38, 119.24, 118.95, 117.29, 109.26, 108.96, 108.82, 107.03, 101.39, 57.48 (-CH2O-), 29.76 (N-CH3); LCMS (m/z): 364 [M+1]+; Anal. % calcd. for C20H16N2O3S: C, 65.92; H, 4.43; N, 7.69; S, 8.80. Found: C, 66.11; H, 4.28; N, 7.35, S, 8.88.

Diethyl 2-{3-[(1-methyl-1H-indol-2-yl)methoxy]benzylidene}propanedioate (7b, scheme 2): A mixture of (7) (0.265 gm, 1 mmol), diethylmalonate (0.160 gm, 1 mmol), and piperidinium acetate (0.1ml) in toluene (25 ml) was refluxed for 14 h with continuous removal of water using a Dean-Stark trap. After cooling to room temperature, the solution was concentrated to crude reaction mixture, which was purified by column chromatography using a mixture of ethyl acetate/hexane (1:4) as eluent to obtain the title compound (7b) (0.205 g, 50%) as white solid. mp: 156-159 oC. FTIR (CHCl3, ν, cm-1): 3057 (C-H stretch, Ar), 2924 and 2851 (C-H stretch N-CH3, antisymmetric and symmetric), 1728 (C=O stretch, ester), 1700 (C=O stretch, ester), 1629 (C=C stretch, Ar), 1597 (C=C stretch, Ar), 1578 (C=C stretch, Ar), 1469 (C=C stretch, Ar), 1447, 1225 (C-O-C asymmetric stretch, aralkyl), 1094, 1064, 786, 751; lH NMR (CDCl3, δ, ppm): 1.27 (t, 3H, -OCH2CH3), 1.33 (t, 3H, -OCH2CH3), 3.79 (s, 3H, N-CH3), 4.31 (two overlapping quartets, 2H each, -OCH2CH3), 5.18 (s, 2H, -CH2O-), 6.60 (s, 1H, Ar), 7.18 (m, 4H, Ar), 7.30 (m, 3H, Ar), 7.61 (d, 1H, Ar), 7.70 (s, 1H, benzylidene); 13C NMR (CDCl3, δ, ppm): 169.14 (2 C=O of ester), 139.22, 138.55, 138.13, 136.33, 136.03, 129.73, 127.16, 122.34, 120.87, 119.99, 119.38, 117.30, 115.85, 114.01, 109.50, 101.45, 61.70 (-CH2O), 57.40 (COOCH2CH3), 34.54 (N-CH3), 14.02 (COOCH2CH3); LCMS (m/z): 408 [M+1]+; Anal. % calcd. for C24H25NO5: C, 70.74; H, 6.18; N, 3.44; Found: C, 70.33; H, 5.99; N, 3.55.

Methyl 2-{3-[(1-methyl-1H-indol-2-yl)methoxy]benzylidene}-3-oxobutanoate (8, scheme 2): A solution of diethyl azodicarboxylate (0.157 g, 0.9 mmol) and triphenylphosphine (0.236 g, 0.9 mmol) in THF (5 ml) at 0 °C was added dropwise to a stirred mixture of (6) (0.97 g, 0.6 mmol) and (3) (0.159 g, 0.72 mmol) in THF (10 ml) at 0 °C. The reaction mixture was stirred at 0 °C for an hour and then at room temperature for 16 h and solvent removed under reduced pressure. The residue was taken up in 30 ml of EtOAc/water (2:1). The organic layer was separated, dried over anhydrous sodium sulphate, filtered and solvent evaporated under vacuum and the residue upon preparative chromatographyusinf EtOAc:n-hexane (15:85) gave the coupled targeted compound (8) (0.055 g, 15.3%). mp: 153-156 °C. FTIR (CHCl3, ν, cm-1): 3020 (C-H stretch, Ar), 2924 and 2874 (C-H stretch N-CH3, antisymmetric and symmetric), 1720 (C=O stretch, ester), 1699 (C=O stretch, ketone), 1520 (C=C stretch, Ar), 1450 (C=C stretch, Ar), 1113, 1056, 752 (C-C out of plane bending, phenyl ring 1,3-disubstituted); 1H NMR (CDCl3), mixture of E and Z isomers, δ, ppm: 2.32 (s, 3H, -COCH3), 2.42 (s, 3H, -COCH3), 3.79 (s, 3H, -OCH3), 3.80 (s, 3H, -OCH3), 3.83 (s, 3H, -NCH3), 3.84 (s, 3H, -NCH3), 5.16 (s, 2H, -CH2O-), 5.19 (s, 2H, -CH2O-), 6.58 (s, 1H, Ar), 6.61 (s, 1H, Ar), 6.94 (m, 1H, Ar), 6.99 (m, 4H, Ar), 7.09 (m, 2H, Ar), 7.23 (m, 2H, Ar), 7.28 (m, 2H, Ar), 7.33 (m, 3H, Ar), 7.54 (s, 1H, benzylidene), 7.61 (two overlapping doublets, J = 7.8 Hz, 1H each, Ar), 7.65 (s, 1H, benzylidene); 13C NMR (CDCl3, mixture of E and Z isomers, δ, ppm): 208.16 and 198.13 (C=O of COCH3), 169.05 and165.16 (C=O of COOCH3), 158.96 and 158.61, 141.03 and 140.83, 138.49 and 138.12, 136.32 and 136.03, 131.98 and 131.90, 131.34 and 130.74, 127.48 and 127.15, 125.06 and 124.87, 122.36 and 122.04, 120.84 and 120.79, 119.98 and 119.60, 119.39 and 119.25, 118.94 and 117.29, 116.07 and110.30, 109.27 and 108.97, 108.84 and 107.02, 61.95 and 61.54 (-CH2O-), 57.43 and 54.39 (-COOCH3), 29.82 and 29.74 (N-CH3), 22.47 and 20.47 (-COCH3); LCMS (m/z): 386 (M.++23), 363 (M.+); Anal. % Calcd for C22H21NO4: C, 72.71; H, 5.82; N, 3.85. Found: C, 72.63; H, 5.57; N, 3.68.

Ethyl 3-bromo-1H-indole-2-carboxylate (9, scheme 3): To a solution of (4) (0.378 gm, 2 mmol) in dry DMF (10 ml) was added NBS (0.355 gm, 2 mmol). The resulting mixture was stirred at room temperature under nitrogen for 12 h. Crushed ice was then added into the reaction mixture and the white precipitate thus separated was filtered, washed with cold water recrystallized from EtOAc to get the title compound (9) (0.42 g, 78 %). mp: 146-148 oC. FTIR (KBr, ν, cm-1): 3378 (N-H stretch), 3297 (C-H stretch, Ar), 2953 and 2899 (C-H stretch N-CH3, antisymmetric and symmetric), 1688 (C=O stretch, ester), 1574 (C=C stretch, Ar), 1516 (C=C stretch, Ar), 1473 (C=C stretch, Ar), 742 (C-C out of plane bending, phenyl ring), 643 (C-Br stretch); 13C NMR (CDCl3, δ, ppm): 160.15 (C=O of ester), 135.76, 126.84, 125.59, 123.85, 120.81, 120.01, 112.88, 95.94, 60.58 (COOCH2CH3), 14.12 (COOCH2CH3); GCMS (m/z): 270 [M+2]+, 269 [M+1]+, 268 [M]+, 267 [M-1]+; Anal. % calcd. for C11H10BrNO2: C, 49.28; H, 3.76; N, 5.22. Found: C, 49.71; H, 3.98; N, 5.31.

Ethyl 3-bromo-1-methyl-1H-indole-2-carboxylate (10, scheme 3): To a solution of (9) (0.268 gm, 1 mmol) and potassium carbonate (0.414 gm, 3mmol) in dry DMF (10 ml) was added CH3I (0.169 gm, 1.2 mmol). The resulting mixture was stirred at room temperature under nitrogen for 24 h. Crushed ice was then added and the white precipitate thus separated was filtered, washed with cold water, and dried to get the title compound (10) (0.24 g, 85%) as white solid. mp: 128-130 oC. FTIR (KBr, ν, cm-1): 3052 (C-H stretch, Ar), 2981 and 2923 (C-H stretch N-CH3, antisymmetric and symmetric), 1704 (C=O stretch, ester), 1500, 1465, 1398, 1380, 771 (C-C out of plane bending, phenyl ring), 600 (C-Br stretch); lH NMR (CDCl3, δ, ppm): 1.47 (t, 3H, -OCH2CH3), 4.03 (s, 3H, N-CH3), 4.45 (q, 2H, -OCH2CH3), 7.22 (m, 1H, Ar), 7.38 (m, 2H, Ar), 7.67 (m, 1H, Ar); 13C NMR (CDCl3, δ, ppm): 161.46 (C=O of ester), 138.11, 126.68, 126.08, 125.56, 121.47, 121.24, 110.32, 98.60, 61.21 (COOCH2CH3), 32.65 (N-CH3), 14.32 (COOCH2CH3); GCMS (m/z): 284 [M+2]+, 283 [M+1]+, 282 [M]+, 281 [M-1]+; Anal. % calcd. for C12H12BrNO2: C, 51.09; H, 4.29; N, 4.96. Found: C, 51.66; H, 3.85; N, 4.38.