Synthesis of pyridocarbazoles and related intermediates

5.2.1.1 3,4-dibromofuran-2,5-dione (36)

1H-pyrrole-2,5-dione (40.0 g, 408 mmol), and aluminium trichloride (832 mg, 6.3 mmol) were suspended in bromine (42.0 mL, 810 mmol) and refluxed at 130 °C for 18 h. The resulting solid crude material was recrystallised from a mixture of toluene : ethylacetate (70 mL, 6:1). The pre-cipitate was washed with hexane and dried in vacuo. The product 36 was obtained as beige solid (27.74 g, 108 mmol, 27%). After concentration of the filtrate and a second recrystallisation procedure under same con-ditions, additional product was obtained (20.72 g, 81 mmol, 20%). ¹³C-NMR (75 MHz, CDCl₃): δ(ppm) 157.9 (2xCO), 131.1 (2xCBr). IR (film): v (cm^-1) 3081, 3000, 2649, 2520, 1699, 1584, 1417, 1389, 1268, 1224, 1181, 1136, 1056, 944, 906, 809, 761, 688.

5.2.1.2 1-benzyl-3,4-dibromo-1H-pyrrole-2,5-dione (37)

36 (17.0 g, 66.3 mmol) and benzyl amine (10.7 g, 99.5 mmol) were dissolved in acetic acid (150 mL) and heated to 130 °C for 16 h. The solvent was removed under reduced pressure and residual acetic acid

was coevaporated using toluene (3 x 40 mL). The dark crude material was subjected to column chromatography using hexane : ethylacetate (10:1) and dried in vacuo. The product 37 was obtained as beige solid (17.84 g, 51.7 mmol, 78%).

R_f = 0.33 (hexane : ethylacetate 10:1).

1H-NMR (300 MHz, CDCl3): δ(ppm) 7.40–

7.29 (m, 5H, H_ar), 4.75 (s, 2H, H_benzyl).

13C-NMR (75 MHz, CDCl₃): δ(ppm) 163.76 (2xCO), 135.37 (C_ar), 129.66 (2xCBr), 129.02 (2xC_ar), 128.93 (2xC_ar), 128.48 (C_ar), 43.41 (C_benzyl). IR (film): v (cm^-1) 1781, 1709, 1592, 1519, 1491, 1432, 1388, 1336, 1233, 1158, 1100, 1060, 906, 851, 812, 752, 722, 695, 626, 583.

5.2.1.3 3,4-dibromo-1-methyl-1H-pyrrole-2,5-dione (38)

36 (5.0 g, 19.5 mmol) and methyl ammonium chloride (2.02 g, 29.9 mmol) were dissolved in acetic acid (50 mL) and heated to 130 °C for 16 h. The solvent was removed under reduced pressure and resid-ual acetic acid was coevaporated using tol-uene (3 x 30 mL). The dark crude material was subjected to column chromatography using hexane : ethylacetate (3:1) and dried in vacuo. The product 38 was obtained as beige solid (2.85 g, 10.6 mmol, 55%).

R_f = 0.46 (CHCl₃). ¹H-NMR (300 MHz, CDCl₃): δ(ppm) 3.13 (t, J = 2.1 Hz, 3H, CH₃).¹³C-NMR (75 MHz, CDCl₃): δ(ppm) 164.1 (2xCO), 129.5 (2xCBr), 25.6 (CH3). IR (film): v (cm^-1) 2951, 2853, 1772, 1705, 1599, 1465, 1304, 1258, 1164, 1066, 1026, 848, 819, 790, 744, 706, 678.

5.2.1.4 3,4-dibromo-1H-pyrrole-2,5-dione (39)

36 (20.0 g, 78.2 mmol) and ammoni-um acetate (9.04 g, 117.2 mmol) were dis-solved in acetic acid (250 mL) and heated to 130 °C for 16 h. The solvent was removed under reduced pressure and residual acetic acid was coevaporated using toluene (3 x 50 mL). The dark crude material was subjected to column chromatography using hexane : ethylacetate (5:1  2:1) and dried in vacuo. The product 39 was obtained as beige solid (10.81 g, 42.4 mmol, 54%).

R_f = 0.16 (hexane : ethylacetate 8:1).

1H-NMR (300 MHz, (CD₃)₂SO): δ(ppm) 11.7 (bs, 1H, NH). ¹³C-NMR (75 MHz, (CD₃)₂SO):

δ(ppm) 165.15 (2xCO), 129.72 (2xCBr). IR (film): v (cm^-1) 3231, 3071, 1776, 1704, 1576, 1408, 1323, 1271, 1197, 1170, 1129, 1026, 994, 910, 872, 826, 788, 725.

5.2.1.5 tert-butyl(1-methoxyvinyloxy) di-methylsilane (41)

Diisopropylamine (22.4 mL, 159.6 mmol) were dissolved in THF (134 mL) and cooled to 0 °C. n-butyl lithium (58.5 mL, 146 mmol, 2.5 M in hexane) was added over a period of 30 min at -78 °C fol-lowed by the drop wise sequential addition of methylacetate (10.58 mL, 133 mmol), DMPU (24.1 mL, 199 mmol) over a period of 40 min. Tert-buytldimethylsilylchloride (20 g, 133 mmol) was dissolved in THF (32 mL) and added to the reaction mixture. The

reac-tion was continued for 1 h at -78 °C. The solvent was evaporated under reduced pressure and the crude material was solved in pentane (400 mL). The organic layer was washed with water (3 x 50 mL), saturated cupper sulfate solution (3 x 50 mL) and sat-urated sodium carbonate solution (3 x 50 mL). The combined aqueous layer was extracted with pentane (4 x 50 mL). The combined organic layer was dried over so-dium sulfate. The solvent was removed un-der reduced pressure and the crude material was subjected to bulb to bulb distillation (50 °C, 8 mbar). The product 41 was ob-tained as colourless oil (15 g, 68.7 mmol, 51%). R_f = 0.48 (hexane : ethylacetate 8:1).

1H-NMR (300 MHz, CDCl₃): δ(ppm) 3.53 (s, 3H, OCH₃), 3.23 (d, J = 2.6 Hz, 1H, C_vinylHH), 3.10 (d, J = 2.6 Hz, 1H, C_vinylHH), 0.93 (s, 9H, Cq(CH3)3), 0.17 (s, 6H, Si(CH₃)₂). ¹³C-NMR (75 MHz, CDCl₃):

δ(ppm) 162.49 (C_carbonyl), 60.26 (C_vinylH₂), 55.15 (OCH₃), 25.75 (3xC_q(CH₃)₃), 18.26 (C_q(CH₃)₃), -4.57 (Si(CH₃)₂).

5.2.1.6 3,4-dibromo-1-(tert-butyldimethyl-silyl)-1H-pyrrole-2,5-dione (42)

39 (10.7 g, 42 mmol) were dissolved in acetonitrile (100 mL) and stirred at ambi-ent temperature. 41 (10 mL, 46 mmol) were added dropwise and the reaction was then refluxed for 5 h. The reaction mixture was cooled down to ambient temperature over a period of 8 h. The solvent was evaporated under reduced pressure and the crude ma-terial was subjected to column chromatog-raphy using hexane : ethyl acetate (9:1  3:1). The product was 42 was obtained as white solid (8.38 g, 22.65 mmol, 54%).

R_f = 0.67 (hexane : ethylacetate 8:1).

1H-NMR (300 MHz, CDCl₃): δ(ppm) 0.94 (s, 9H, C_q(CH₃)₃), 0.46 (s, 6H, Si(CH₃)₂).

13C-NMR (75 MHz, CDCl3): δ(ppm) 168.87 (2xCO), 131.72 (2xCBr), 26.24 (3xC_q(CH₃)₃), 19.02 (C_q(CH₃)₃), -4.44 (Si(CH₃)₂).

5.2.1.7 (E)-2-(1-(2-phenylhydrazono) ethyl)pyridine (45)

2-Methyl-pyridylketone (3.70 mL, 33.0 mmol) and phenylhydrazine (3.35 mL, 34.1 mmol) were dissolved in ethanol (10 mL, abs.) under nitrogen atmosphere.

The reaction mixture was heated up slowly to 80 °C over a period of 15 min and re-fluxed for another 45 min until a yellow pre-cipitate was formed. The reaction mixture was cooled down to 0 °C and filtrated. The yellow precipitate was washed with cooled ethanol (150 mL, abs.) and dried in vacuo.

The residual filtrate was concentrated and cooled to 0 °C to precipitate additional crude material which was filtrated and washed with cooled ethanol (100 mL, abs.) and dried in vacuo as the first product fraction. The com-bined product fractions led to the product 45 as a yellow solid (6.84 g, 32.4 mmol, 98%).

R_f = 0.55 (methylene chloride : methanol 15:1). ¹H-NMR (300 MHz, CDCl3): δ(ppm) 8.58 (d, J = 4.7 Hz, 1H, H_ar), 8.19-8.15 (m, 1H, H_ar), 7.73-7.68 (m, 1H, H_ar), 7.33-7.18 (m, 5H, H_ar), 6.93-6.88 (m, 1H, H_ar), 2.41 (s, 3H, CH₃). ¹³C-NMR (75 MHz, CDCl₃):

δ(ppm) 148.0, 144.7, 136.5, 129.4, 122.4, 120.9, 120.2, 113.6, 10.1 (CH3). IR (film): v (cm^-1) 3204, 3171, 3019, 2939, 1596, 1564, 1470, 1427, 1289, 1246, 1149, 1110, 1077, 1048, 993, 967, 892, 781, 748, 695, 652, 636, 549, 508, 411. HRMS calculated for C₁₃H₁₃N₃H (M + H⁺) 212.1188 found (M + H⁺) 212.1183.

5.2.1.8 2-(pyridin-2-yl)-1H-indole (46)

Polyphosphoric acid (34.0 g, 1.1 g per mmol of educt) were heated to 95 °C and firm stirring. 45 (6.50 g, 30.8 mmol) was added sequentially in small portions to the clear viscose reaction mixture. After 4 h the reaction mixture was cooled down to ambi-ent temperature and sodium hydroxide solu-tion (20%) was added until pH 9 was set. A crude material precipitated as yellow solid.

The reaction mixture was extracted with methylene chloride (3 x 150 mL). The com-bined organic layer was washed with BRINE (4 x 25 mL) dried over sodium sulfate, fil-trated and dried in vacuo. The product 46 was obtained as yellow solid (5.63 g, 29.0 mmol, 94%). R_f = 0.71 (hex-ane : ethylacetate 10:1). ¹H-NMR (300 MHz, CDCl₃): δ(ppm) 9.76 (s, 1H, NH), 8.57(dt, J

= 5.0 Hz, J = 1.1 Hz, 1H, CH_ar), 7.83 (dt, J = 8.0 Hz, J = 1.0 Hz, 1H, CH_ar), 7.75 (td, J = 7.7 Hz, J = 1.4 Hz, 1H, CH_ar), 7.66 (d, J = 7.9 Hz, 1H, CH_ar-10), 7.44 (dd, J = 8.1 Hz, J

= 0.7 Hz, 1H, CH_ar), 7.24-7.17 (m, 2H, CH_ar), 7.14-7.09 (m, 1H, CH_ar), 7.05 (dd, J = 2.1 Hz, J = 0.7 Hz, 1H, CH_ar). IR (film): v (cm^-1) 3114, 2968, 1591, 1557, 1439, 1408, 1337, 1299, 1255, 1143, 994, 776, 741, 616, 602, 563, 520, 493, 427, 400. HRMS calculated for C₁₃H₁₀N₂Na (M + Na⁺) 217.0742 found (M + Na⁺) 217.0740.

5.2.1.9 5-(tert-butyldimethylsilyloxy)-1H-indole (48)

5-(benzyloxy)-1H-indole (5.00 g, 22.39 mmol) were dissolved in 200 mL ethylacetate in a 1 L reaction flask. Pd/C (3.95 g, 3.81 mmol, 10% v/w) were sus-pended and the nitrogen atmosphere was completely substituted by hydrogen in three turns. The mixture was reacted at ambient temperature for 16 h under intensive stirring.

The suspension was filtrated over CELITE

and the filtrate was dried in vacuo. The resi-due was dissolved in 80 mL DMF and cooled to 4 °C. Over a period of 10 min di-isopropylethylamine (19.4 mL, 111.95 mmol) were added drop wise. Then, tert-butyl-dimethylsilyltriflate (6.1 mL, 22.39 mmol) was added drop wise over 16 h and the re-action mixture was warmed up to ambient temperature simultaneously. The orange coloured reaction mixture was quenched with ammonium acetate (200 mL, 1 M) and then diluted with of water (100 mL). The mixture was then extracted with ethylacetate (4 x 200 mL), the organic layer was sepa-rated, washed with BRINE (3 x 50 mL), and dried over sodium sulfate. The crude mate-rial was dried in vacuo and subjected to sili-ca gel chromatography hexane : ethyl-acetate (9:1). The product 48 was obtained as pale oil (3.78 g, 15.28 mmol, 68% over two steps). R_f = 0.57 (hexane : ethylacetate 3:1). ¹H-NMR (300 MHz, CDCl₃): δ(ppm) 8.03 (s, 1H, NH), 7.23 (d, J = 8.7 Hz, 1H, CH_ar-7), 7.18-7.15 (m, 1H, CH_ar-2), 7.07 (d, J = 2.3 Hz, 1H, CH_ar-4), 6.76 (dd, J = 8.7, 2.3, 1H, CH_ar-6), 6.44 (m, 1H, CH_ar-3), 1.01 (s, 9H, C_q(CH₃)₃), 0.20 (s, 6H, Si(CH₃)₂).

13C-NMR (75 MHz, CDCl3): δ(ppm) 149.53 (Car-5), 131.59 (Car-7a), 128.71 (Car-3a), 124.95 (C_ar-2), 116.48 (C_ar-6), 111.33 (C_ar

-7), 110.23 (C_ar-4), 102.42 (C_ar-3), 25.97 (3xCq(CH₃)₃), 18.39 (Cq(CH₃)₃), -4.26 (Si(CH3)2), -4.45 (Si(CH3)2). HRMS calculat-ed for C₁₄H₂₁NOSiNa (M + Na⁺) 270.1285, found (M + Na⁺) 270.1285.

5.2.1.10 tert-butyl 1H-indole-1-carboxylate (51)

Indole (10.0 g, 85.4 mmol) was dis-solved in THF (25 mL) and cooled to 4 °C.

Di-tert-butyl-dicarbonate (18.6 g, 85.4 mmol) was presolved in THF (25 mL) and added to the reaction mixture. Dimethylaminopyridine (DMAP, 15.7 g, 128 mmol) was added slow-ly. The reaction mixture was stirred for 16 h and warmed up to ambient temperature.

The reaction mixture was cooled to 4 °C and hydrochloric acid (60 mL, 1 M) was added followed by 15 min of stirring. The organic layer was separated. The aqueous layer was extracted with ethylacetate (5 x 50 mL).

The combined organic layer was washed with BRINE (3 x 50 mL), and dried over sodi-um sulfate. The solvent was evaporated under reduced pressure and the crude ma-terial was subjected to column chromatog-raphy using hexane : ethylacetate (8:1). The product 51 was obtained as colourless oil (18.34 g, 84.5 mmol, quant.). R_f = 0.37 (hex-ane : ethylacetate 8:1). ¹H-NMR (300 MHz, CDCl₃): δ(ppm) 8.11 (d, J = 8.1 Hz, 1H, CH_ar-7), 7.55 (d, J = 3.7 Hz, 1H, CH_ar-2), 7.51 (ddd, J = 7.6, 1.3, 0.8 Hz, 1H, CH_ar-4), 7.26 (ddd, J = 8.4, 7.3, 1.4 Hz, 1H, CH_ar-6), 7.21–7.14 (m, 1H, CH_ar-5), 6.51 (dd, J = 3.7, 0.7 Hz, 1H, CH_ar-3), 1.62 (s, 9H, OC_q(CH₃)₃). ¹³C-NMR (75 MHz, CDCl₃):

δ(ppm) 149.92 (Ccarbonyl), 135.35 (Car-7a), 130.71 (Car-3a), 125.98, 124.29, 122.74, 121.03, 115.28, 107.38, 83.70 (C_q(CH₃)₃), 28.31 (C_q(CH₃)₃). IR (film): v (cm^-1) 2978,

2933, 1728, 1604, 1535, 1450, 1375, 1333, 1248, 1208, 1152, 1114, 1076, 1018, 935, 881, 850.

5.2.1.11 tert-butyl 5-(tert-butyldimethylsilyl-oxy)-1H-indole-1-carboxylate (52)

48 (3.78 g, 15.28 mmol) was dis-solved in THF (12 mL) and cooled to 4 °C.

Di-tert-butyl-dicarbonate (4.20 g, 19.32 mmol) was presolved in THF (3 mL) and added to the reaction mixture. Dime-thylaminopyridine (DMAP, 2.35 g, 19.22 mmol) was added slowly. The reac-tion mixture was stirred for 16 h and turned from orange to green while warming to am-bient temperature. The reaction mixture was cooled to 4 °C and hydrochloric acid (11 mL, 1 M) was added followed by 5 min of stirring.

The organic layer was separated. The aqueous layer was extracted with ethylacetate (4 x 50 mL). The combined organic layer was washed with BRINE (3 x 50 mL), and dried over sodium sulfate.

The solvent was removed in vacuo and the crude material subjected to column chroma-tography hexane : ethylacetate (20:1). The product 52 was obtained as colourless oil (4.95 g, 14.24 mmol, 93%). R_f = 0.63 (hex-ane : ethylacetate 10:1). ¹H-NMR (300 MHz, CDCl₃): δ(ppm) 7.96 (d, J = 8.6 Hz, 1H, CH_ar-7), 7.55 (d, J = 3.6, 1H, CH_ar-2), 6.99 (d, J = 2.4 Hz, 1H, CH_ar-4), 6.84 (dd, J = 8.9, 2.4, 1H, CHar-6), 6.46 (d, J = 3.7, 1H, CHar -3), 1.66 (s, 9H, OC_q(CH₃)₃), 1.00 (s, 9H, SiC_q(CH₃)₃), 0.20 (s, 6H, Si(CH₃)₂). ¹³C-NMR (75 MHz, CDCl₃): δ(ppm) 151.53 (C_carbonyl), 131.66 (C_ar-7a), 130.54 (C_ar-3a), 126.61, 117.74, 115.70, 111.12, 107.16, 83.55 (OC_q(CH₃)₃), 28.39 (OC_q(CH₃)₃), 25.92 (SiC_q(CH₃)₃), 18.40 (SiC_q(CH₃)₃), -4.27

(Si(CH₃)₂). IR (film): v (cm^-1) 2956, 2932, 2892, 2858, 1731, 1614, 1580, 1462, 1372, 1274, 1218, 1149, 1118, 1081, 1022, 966, 878, 840, 811, 770. HRMS calculated for C₁₉H₂₉NO₃SiNa (M + Na⁺) 370.1809, found (M + Na⁺) 370.1811.

5.2.1.12 tert-butyl 5-(benzyloxy)-1H-indole-1-carboxylate (53)

5-(benzyloxy)-1H-indole (49) (3.8 g, 17.1 mmol) was dissolved in THF (12.5 mL) and cooled to 4 °C. Di-tert-butyl-dicarbonate (3.9 g, 17.9 mmol) was presolved in THF (3 mL) and added to the reaction mixture.

Dimethylaminopyridine (DMAP, 3.2 g, 25.6 mmol) was added slowly. The reaction mixture became solid and was fluidised by heating to 50 °C for 5 min. The reaction mix-ture was then stirred for 16 h at ambient temperature. The reaction mixture was cooled to 4 °C and hydrochloric acid (12 mL, 1 M) was added followed by 10 min of stir-ring. The organic layer was separated. The aqueous layer was extracted with ethylacetate (3 x 20 mL). The combined organic layer was washed with BRINE (3 x 50 mL), and dried over sodium sulfate.

The solvent was evaporated under reduced pressure and the crude material was sub-jected to column chromatography using hexane : ethylacetate (15:1). The product 53 was obtained as colourless oil (5.08 g, 145.71 mmol, 92%). R_f = 0.59 (hex-ane : ethylacetate 8:1). ¹H-NMR (300 MHz, (CD₃)₂SO): δ(ppm) 7.93 (d, J = 9.1 Hz, 1H, CH_ar-7), 7.63 (d, J = 3.7 Hz, 1H, CH_ar-2), 7.48 (d, J = 1.7 Hz, 1H, CHar-o), 7.45 (d, J = 1.2 Hz, 1H, CH_ar-o), 7.43–7.29 (m, 3H, CH_ar-p, CH_ar-m), 7.23 (d, J = 2.5 Hz, 1H, CH_ar-4), 7.01 (dd, J = 9.0, 2.5 Hz, 1H,

CH_ar-6), 6.62 (d, J = 4.3 Hz, 1H, CH_ar-3), 5.13 (s, 2H, CH_2benzyl), 1.61 (s, 9H, OCq(CH3)3).

5.2.1.13 tert-butyl 5-methoxy-1H-indole-1-carboxylate (54)

5-methoxy-1H-indole (50) (5.0 g, 33.9 mmol) was dissolved in THF (15 mL) and cooled to 4 °C. Di-tert-butyl-dicarbonate (7.5 g, 34 mmol) was presolved in THF (3 mL) and added to the reaction mixture.

Dimethylaminopyridine (DMAP, 6.11 g, 50 mmol) was added slowly. The reaction mixture became solid and was fluidised by heating to 50 °C for 5 min. The reaction mix-ture was then stirred for 16 h at ambient temperature. The reaction mixture was cooled to 4 °C and hydrochloric acid (30 mL, 1 M) was added followed by 15 min of stir-ring. The organic layer was separated. The aqueous layer was extracted with ethylacetate (4 x 50 mL). The combined organic layer was washed with BRINE (3 x 50 mL), and dried over sodium sulfate.

The solvent was evaporated under reduced pressure and the crude material was sub-jected to column chromatography using hexane : ethylacetate (10:1). The product 54 was obtained as white solid (8.2 g, 33.2 mmol, 98%). R_f = 0.54 (hex-ane : ethylacetate 8:1). ¹H-NMR (300 MHz, CDCl₃): δ(ppm) 8.01 (d, J = 8.0 Hz, 1H, CH_ar-7), 7.56 (d, J = 3.5 Hz, 1H, CH_ar-2), 7.03 (d, J = 2.5 Hz, 1H, CH_ar-4), 6.92 (dd, J

= 9.0, 2.5 Hz, 1H, CH_ar-6), 6.50 (d, J = 3.7 Hz, 1H, CH_ar-3), 3.85 (s, 3H, OCH₃), 1.66 (s, 9H, OC_q(CH₃)₃). ¹³C-NMR (75 MHz, CDCl₃):

δ(ppm) 155.98 (Car-5), 149.83 (Ccarbonyl), 131.49 (C_ar-7a), 130.08 (C_ar-3a) 126.58, 115.91, 113.07, 107.21, 103.66, 83.53

(OC_q(CH₃)₃), 55.74 (OCH₃), 28.28 (OC_q(CH₃)₃). IR (film): v (cm^-1) 2978, 2937, 1726, 1614, 1585, 1471, 1443, 1373, 1342, 1260, 1152, 1117, 1081, 1019, 937, 842, 805, 761, 720, 627.

5.2.1.14 1-(tert-butoxycarbonyl)-1H-indol-2-ylboronic acid (55)

Diisopropylamine (19 mL, 135 mmol) was dissolved in THF (50 mL) and cooled to -78 °C. n-Butyllithium (54 mL, 135 mmol, 2.5 M in hexane) was added drop wise. The reaction mixture was warmed up to 0 °C and stirred for 30 min. 51 (19.7 g, 90 mmol) was predried in vacuo, and dissolved in a second flask with THF (100 mL). Triisopropyl borate (32 mL, 139 mmol) was added drop wise while cooling the reaction mixture to 0 °C.

The lithium diisopropylamide solution was added over a period of 1.5 h. After 16 h of stirring hydrochloric acid (150 mL, 2 M)was added to quench the reaction over 15 min at ambient temperature. The organic layer was separated and the aqueous layer was ex-tracted with ethylacetate (4 x 50 mL). The combined organic layer was washed with BRINE (3 x 50 mL), dried over sodium sul-fate and concentrated in vacuo to dryness.

The dark orange oil (23.5 g, 90 mmol, quant.) was processed directly to the cou-pling reaction without further characterisa-tion due to the instability of the boronic acid intermediate.

5.2.1.15 1-(tert-butoxycarbonyl)-5-(tert-butyl- dimethylsilyloxy)-1H-indol-2-ylboro-nic acid (56)

Diisopropylamine (1.21 mL, 8.64 mmol) was dissolved in THF (0.865 mL) and cooled to -78 °C. n-Butyllithium (3.46 mL, 8.64 mmol, 2 M in hexane) was added drop wise. The reaction mixture was warmed up to 0 °C and stirred for 30 min. 52 (1.95 g, 5.61 mmol) was predried in vacuo, and dissolved in a second flask with THF (15 mL). Triisopropyl borate (2.0 mL, 8.64 mmol) was added drop wise while cooling the reaction mixture to 0 °C.

The lithium diisopropylamide solution was added over a period of 1.5 h. The colour of the reaction mixture turned from pallid to yellow. After 2 h of stirring hydrochloric acid (15 mL, 2 M)was added to quench the reac-tion over 15 min at ambient temperature.

The organic layer was separated and the aqueous layer was extracted with ethyl-acetate (4 x 25 mL). the combined organic layer was washed with BRINE (3 x 50 mL), dried over sodium sulfate and concentrated in vacuo to dryness. The dark brown oil (2.1 g, 5.5 mmol, 98%) was processed di-rectly to the coupling reaction without further characterisation due to the instability of the boronic acid intermediate.

5.2.1.16 5-(benzyloxy)-1-(tert-butoxycarbo-nyl)-1H-indol-2-ylboronic acid (57)

53 (2.98 g, 9.2 mmol) was predried in vacuo, and dissolved in a second flask with THF (15 mL). Triisopropyl borate (3.2 mL, 14.2 mmol) was added drop wise while cooling the reaction mixture to 0 °C.

Lithium diisopropylamide solution (6.96 mL, 13.8 mmol, 2 M in hexane) was added over a period of 1 h. The colour of the reaction mixture turned from pallid to yellow. After 2 h of stirring hydrochloric acid (22 mL, 2 M) was added to quench the reaction over 15 min at ambient temperature. The organic layer was separated and the aqueous layer was extracted with ethylacetate (5 x 25 mL).

The combined organic layer was washed with BRINE (3 x 50 mL), dried over sodium sulfate and concentrated in vacuo to dry-ness. The dark brown oil (3.3 g, 9 mmol, 98%) was processed directly to the coupling reaction without further characterisation due to the instability of the boronic acid interme-diate.

5.2.1.17 1-(tert-butoxycarbonyl)-5-methoxy-1H-indol-2-ylboronic acid (58)

54 (4 g, 16.2 mmol) was predried in vacuo, and dissolved in THF (18.8 mL).

Triisopropyl borate (5.7 mL, 24.9 mmol) was added drop wise while cooling the reaction mixture to 0 °C. Lithium diisopropylamide solution (13.5 mL, 24.3 mmol, 1.8 M in hex-ane) was added over a period of 1 h. After 2 h of stirring hydrochloric acid (40 mL, 2 M) was added to quench the reaction over 15 min at 0 °C. The organic layer was sepa-rated and the aqueous layer was extracted with ethylacetate (5 x 25 mL). The combined organic layer was washed with BRINE (3 x 50 mL), dried over sodium sulfate and concentrated in vacuo to dryness. The dark orange oil (4.6 g, 15.8 mmol, 98%) was pro-cessed directly to the coupling reaction without further characterisation due to the instability of the boronic acid intermediate.

5.2.1.18 tert-butyl 2-(5-(trifluoromethyl) pyri-din-2-yl)-1H-indole-1-carboxylate (65)

Sodium carbonate (4.7 g, 45.0 mmol), and tetrakis(triphenylphos-phine)palladium (1.04 g, 0.90 mmol) were reacted with the boronic acid 55 (4.7 g, 18 mmol) dissolved in dimethoxy-ethane : water (95 mL, 4:1). 2-bromo-5-(tri-fluoromethyl)pyridine (3.7 g, 16.4 mmol) was

added and the entire reaction mixture re-fluxed for 16 h. The dark red suspension was cooled to ambient temperature and di-luted with water (65 mL). The organic layer was separated. The aqueous layer was ex-tracted with ethylacetate (3 x 50 mL), the combined organic layer was washed with BRINE (3 x 50 mL), dried over sodium sul-fate. The crude material was concentrated in vacuo and subjected to column chromatog-raphy using hexane : ethylacetate (20:1  5:1). The product 65 was obtained as a white solid (3.71 g, 10.2 mmol, 61.6%).

R_f = 0.54 (hexane : ethylacetate 8:1).

1H-NMR (300 MHz, CDCl₃): δ(ppm) 8.80 (dd, J = 1.4, 0.9 Hz, 1H, CH_ar-6´), 8.05 (dd, J

= 8.4, 0.8 Hz, 1H, CH_ar-7), 7.83 (ddd, J = 8.2, 2.3, 0.6 Hz, 1H, CH_ar), 7.52 – 7.43 (m, 2H, CH_ar-4, CH_ar), 7.26 (ddd, J = 8.6, 7.2, 1.3 Hz, 1H, CHar-6), 7.18 – 7.10 (m, 1H, CH_ar-5), 6.73 (d, J = 0.6 Hz, 1H, CH_ar-3), 1.25 (s, 9H, OC_q(CH₃)₃). ¹³C-NMR (75 MHz, CDCl₃): δ(ppm) 156.62 (C_ar-2´), 149.93 (C

car-bonyl), 145.98 (q, J = 4.0 Hz), 138.18, 138.08, 133.25 (q, J = 3.4 Hz), 128.80, 125.76, 125.22, 124.78, 123.31, 122.85, 121.45, 115.25, 112.67, 84.08 (OC_q(CH₃)₃), 27.74 (OC_q(CH₃)₃). IR (film): v (cm^-1) 2983, 1726, 1601, 1557, 1479, 1449, 1398, 1367, 1316, 1227, 1153, 1114, 1076, 1036, 1008, 938, 852, 822, 770, 743.

5.2.1.19 tert-butyl 2-(5-hydroxypyridin-2-yl)-1H-indole-1-carboxylate (66)

Sodium carbonate (4.7 g, 45 mmol), and tetrakis(triphenylphosphine)palladium (1.04 g, 0.9 mmol) were reacted with the boronic acid 55 (4.7 g, 18 mmol) dissolved in dimethoxyethane : water (95 mL, 4:1).

6-bromopyridin-3-ol (2.85 g, 16.4 mmol) was added and the entire reaction mixture re-fluxed for 16 h. The dark brown suspension was cooled to ambient temperature and di-luted with water (65 mL). The organic layer was separated. The aqueous layer was ex-tracted with ethylacetate (3 x 50 mL), the combined organic layer was washed with BRINE (3 x 50 mL), dried over sodium sul-fate. The crude material was concentrated in vacuo and subjected to column chromatog-raphy using methylene chloride : methanol (35:1  10:1). The product 66 was obtained as brown oil (2.40 g, 7.7 mmol, 47%).

R_f = 0.51 (hexane : ethylacetate 8:1). The product could only be obtained as mixture of tert-butyloxycarbonyl protected and unpro-tected form and was therefore processed without further characterisation.

5.2.1.20 tert-butyl 2-(5-nitropyridin-2-yl)-1H-indole-1-carboxylate (67)

Sodium carbonate (4.7 g, 45.0 mmol), and tetrakis(triphenylphos-phine)palladium (1.04 g, 0.90 mmol) were reacted with the boronic acid 55 (4.7 g, 18 mmol) dissolved in dimethoxy-ethane : water (95 mL, 4:1). 2-bromo-5-nitropyridine (3.3 g, 16.4 mmol) was added and the entire reaction mixture refluxed for 16 h. The dark red suspension was cooled to ambient temperature and diluted with wa-ter (65 mL). The organic layer was separat-ed. The aqueous layer was extracted with ethylacetate (3 x 50 mL), the combined or-ganic layer was washed with BRINE (3 x 50 mL), dried over sodium sulfate. The crude material was concentrated in vacuo and subjected to column chromatography using hexane : ethylacetate (20:1  5:1).

The product 67 was obtained as a yellow solid (3.58 g, 10.5 mmol, 64%). R_f = 0.27 (hexane : ethylacetate 8:1). ¹H-NMR (300 MHz, CDCl₃): δ(ppm) 9.48 (dd, J = 2.6, 0.5 Hz, 1H, CH_ar-6´), 8.55 (dd, J = 8.7, 2.6 Hz, 1H, CHar-4´), 8.14 (d, J = 9.2 Hz, 1H, CH_ar-7), 7.72 (dd, J = 8.7, 0.6 Hz, 1H, CH_ar-3´), 7.64 (d, J = 7.8 Hz, 1H, CH_ar-4), 7.43 (ddd, J = 8.5, 7.2, 1.3 Hz, 1H, CH_ar-6), 7.35–7.28 (m, 1H, CH_ar-5), 7.02 (d, J = 0.6 Hz, 1H, CH_ar-3), 1.46 (s, 9H, OC_q(CH₃)₃). IR (film): v (cm^-1) 3048, 2974, 2929, 1731, 1595, 1566, 1513, 1474, 1445, 1399, 1342, 1314, 1266, 1223, 1189, 1142, 1110, 944, 848, 830, 768.

5.2.1.21 tert-butyl 2-(5-aminopyridin-2-yl)-1H-indole-1-carboxylate (68)

Sodium carbonate (4.7 g, 45 mmol), and tetrakis(triphenylphosphine)palladium (1.04 g, 0.9 mmol) were reacted with the boronic acid 55 (4.7 g, 18 mmol) dissolved in dimethoxyethane : water (95 mL, 4:1).

6-bromopyridin-3-amine (2.8 g, 16.4 mmol) was added and the entire reaction mixture refluxed for 16 h. The dark brown suspen-sion was cooled to ambient temperature and diluted with water (65 mL). The organic layer was separated. The aqueous layer was ex-tracted with ethylacetate (3 x 50 mL), the combined organic layer was washed with BRINE (3 x 50 mL), dried over sodium sul-fate. The crude material was concentrated in vacuo and subjected to column chro-matography using methylene chlo-ride : methanol (35:1  10:1). The product 68 was obtained as a brown oil (2.40 g, 14 mmol, 77%). R_f = 0.56 (hexane : ethyl-acetate 8:1). The product could only be ob-tained as mixture of tert-butyloxycarbonyl protected and unprotected form and was therefore processed without further charac-terisation.

5.2.1.22 tert-butyl 2-(5-cyanopyridin-2-yl)-1H-indole-1-carboxylate (69)

Sodium carbonate (4.7 g, 45.0 mmol), and tetrakis(triphenylphos-phine)palladium (1.04 g, 0.90 mmol) were reacted with the boronic acid 55 (4.7 g, 18 mmol) dissolved in dimethoxye-thane : water (95 mL, 4:1). 6-bromo-nicotinonitrile (2.9 g, 16.4 mmol) was added and the entire reaction mixture refluxed for 16 h. The dark red suspension was cooled to ambient temperature and diluted with wa-ter (65 mL). The organic layer was separat-ed. The aqueous layer was extracted with ethylacetate (3 x 50 mL), the combined or-ganic layer was washed with BRINE (3 x 50 mL), dried over sodium sulfate. The crude material was concentrated in vacuo and subjected to column chromatography using hexane : ethylacetate (15:1  3:1).

The product 69 was obtained as a brown oil (3.9 g, 12.2 mmol, 68%). R_f = 0.62 (methyl-ene chloride : methanol 35:1). ¹H-NMR (300 MHz, CDCl₃): δ(ppm) 8.76 (dd, J = 2.1, 0.8 Hz, 1H, CH_ar-6´), 8.00 (dd, J = 8.4, 0.8 Hz, 1H, CHar-7), 7.82 (dd, J = 8.2, 2.2 Hz, 1H, CH_ar-4´), 7.49–7.42 (m, 2H, CH_ar-4, CH_ar-3´), 7.26 (ddd, J = 8.3, 7.3, 1.3 Hz, 1H, CH_ar-6), 7.18–7.09 (m, 1H, CH_ar-5), 6.77 (d, J = 0.4 Hz, 1H, CH_ar-3), 1.28 (s, 9H, OC_q(CH₃)₃). ¹³C-NMR (75 MHz, CDCl₃):

δ(ppm) 156.26 (C_ar-2´), 151.74 (C_carbonyl), 139.09, 128.65, 126.10, 124.78, 123.40, 122.79, 121.87, 121.62, 120.87, 119.28, 116.89, 115.18, 113.52, 84.35 (OC_q(CH₃)₃), 27.81 (OC_q(CH₃)₃). IR (film): v (cm^-1) 2227, 1731, 1587, 1552, 1470, 1445, 1391, 1363, 1316, 1227, 1139, 1023, 945, 849, 824, 794, 772, 743, 686, 660. HRMS calculated for

C₁₉H₁₈N₃O₂ (M + H⁺) 320.1394 found (M + H⁺) 320.1395.

5.2.1.23 tert-butyl 5-(tert-butyldimethyl- silyloxy)-2-(5-fluoropyridin-2-yl)-1H-indole-1-carboxylate (70)

Sodium carbonate (1.53 g, 14.44 mmol), and tetrakis(triphenylphos-phine)palladium (350 mg, 0.303 mmol) were reacted with the boronic acid 56 (2.25 g, 5.76 mmol) dissolved in dimethoxy-ethane : water (30 mL, 4:1). 5-Fluoro-2-bromopyridine (0.95 g, 5.40 mmol) was added and the entire reaction mixture re-fluxed for 16 h. The dark red suspension was cooled to ambient temperature and di-luted with water (25 mL). The organic layer was separated. The aqueous layer was ex-tracted with ethylacetate (4 x 25 mL), the combined organic layer was washed with BRINE (3 x 50 mL), dried over sodium sul-fate. The crude material was concentrated in vacuo and subjected to column chromatog-raphy with hexane : ethylacetate (15:1). The product 70 was obtained as a colourless oil (1.52 g, 3.43 mmol, 60%). R_f = 0.53 (hex-ane : ethylacetate 15:1). ¹H-NMR (300 MHz, CDCl₃): δ(ppm) 8.52 (dd, J = 2.0, 1.0, 1H, CH_ar-6´), 8.01 (d, J = 8.9 Hz, 1H, CH_ar-7), 7.53 - 7.42 (m, 2H, CHar-3´,CHar-4´), 7.00 (d, J = 2.3 Hz, 1H, CH_ar-4), 6.89 (dd, J = 8.9, 2.4, 1H, CH_ar-6), 6.64 (s, 1H, CH_ar-3), 1.37 (s, 9H, OC_q(CH₃)₃), 1.00 (s, 9H, SiC_q(CH₃)₃), 0.20 (s, 6H, Si(CH₃)₂). ¹³C-NMR (75 MHz, CDCl3): δ(ppm) 158.72 (d, J = 256. Hz, C_ar-5´), 151.78 (C_carbonyl), 150.06 (C_ar-5), 149.71 (d, J = 3.9 Hz, C_ar-2´) , 138.78 (C_ar-2), 137.23 (d, J = 23.7 Hz, C_ar-6´), 132.98 (C_ar-7a), 129.79 (C_ar-3a), 124.47 (d, J = 4.4 Hz, C_ar-3´), 122.99 (d, J = 18.79 Hz,

C_ar-4´), 118.77 (C_ar-6), 115.91 (C_ar-7), 111.28 (C_ar-4), 110.99 (C_ar-3), 83.59 (OCq(CH3)3), 27.86 (OCq(CH3)3), 25.91 (SiC_q(CH₃)₃), 18.40 (SiC_q(CH₃)₃), -4.28 (Si(CH₃)₂). HRMS calculated for C₂₄H₃₁FN₂O₃SiNa (M + Na⁺) 465.1980 found (M + Na⁺) 465.1981.

5.2.1.24 2-(5-fluoropyridin-2-yl)-5-methoxy-1H-indole (71)

Sodium carbonate (4.5 g, 42.5 mmol), and tetrakis(triphenylphos-phine)palladium (1.9 g, 1.7 mmol) were re-acted with the boronic acid 58 (4.95 g, 17 mmol) dissolved in dimethoxye-thane : water (72 mL, 4:1). 2-Bromo-5-fluoropyridine (2.69 g, 15.4 mmol) was add-ed and the entire reaction mixture refluxadd-ed for 16 h. The dark yellow suspension was cooled to ambient temperature and diluted with water (50 mL). The organic layer was separated. The aqueous layer was extracted with ethylacetate (5 x 30 mL), the combined organic layer was washed with BRINE (3 x 50 mL), dried over sodium sulfate. The crude material was concentrated in vacuo and subjected to column chromatography using hexane : ethylacetate (10:1). The tert-butyloxycarbonyl protected intermediate was obtained as a brown oil (4.43 g, 12.9 mmol).

The intermediate was dissolved in methyl-ene chloride and subjected to silica gel (40 g). After complete removal of the solvent under reduced pressure, the soaked com-pound was heated to 80 °C in vacuo for 16 h. The silica gel was suspended in ethyl-acetate and filtrated over CELITE. The prod-uct was dried in vacuo to obtained 71 as a beige solid (3.24 g, 13.4 mmol, 79% over 2 steps). R_f = 0.26 (hexane : ethylacetate 8:1).

1H-NMR (300 MHz, CDCl₃): δ(ppm) 9.38 (bs, 1H, NH), 8.41 (d, J = 2.9 Hz, 1H, CH_ar

-6´), 7.75 (dd, J = 8.8, 4.3 Hz, 1H, CH_ar-3´), 7.47–7.40 (m, 1H, CH_ar-4´), 7.30 (d, J = 8.8 Hz, 1H, CHar-7), 7.09 (d, J = 2.4 Hz, 1H, CH_ar-4), 6.90 (dd, J = 8.9, 2.5 Hz, 1H, CH_ar-6), 6.88–6.86 (m, 1H, CH_ar-3), 3.87 (s, 3H, OCH₃). ¹³C-NMR (75 MHz, CDCl₃):

δ(ppm) 158.63 (d, J = 255.7 Hz, C_ar-5´), 154.72 (Car-5), 147.01 (d, J = 3.9 Hz, Car-2´), 137.17 (d, J = 24.4 Hz, C_ar-6´), 136.48 (C_ar -2), 132.11 (C_ar-7a), 129.68 (C_ar-3a), 124.01 (d, J = 19.1 Hz, C_ar-4´), 120.73 (d, J = 4.3 Hz, C_ar-3´), 114.13 (C_ar-6), 112.26 (C_ar-7), 102.66 (C_ar-4), 100.34 (C_ar-3), 55.98 (OCH₃).

IR (film): v (cm^-1) 3446, 1545, 1455, 1354, 1297, 1216, 1148, 1111, 1027, 942, 888, 825, 787, 738, 652, 616, 577, 516.

5.2.1.25 5-(tert-butyldimethylsilyloxy)-2-(5-fluoropyridin-2-yl)-1H-indole (72)

Pyridylindole 70 (1.44 g, 3.26 mmol) was dissolved in methylene chloride and subjected to silica gel (15 g). After complete removal of the solvent under reduced pres-sure, the soaked compound was heated to 80 °C in vacuo for 16 h. The silica gel was suspended in ethylacetate and filtrated over CELITE. The crude material was concen-trated in vacuo and subjected to column chromatography with hexane : ethylacetate (6:1). The product 72 was dried in vacuo and obtained as a white solid (1.04 g, 3.04 mmol, 93%). R_f = 0.40 (hexane : ethyl-acetate 6:1). ¹H-NMR (300 MHz, CDCl₃):

δ(ppm) 9.35 (s, 1H, NH), 8.41 (d, J = 2.8 Hz, 1H, CH_ar-6´), 7.76 (dd, J = 8.5, 4.3 Hz, 1H, CH_ar-3´), 7.45 (ddd, J = 8.7, 8.2, 2.9 Hz, 1H, CH_ar-4´), 7.25 (d, J = 8.7 Hz, 1H, CH_ar-7), 7.06 (d, J = 2.3 Hz, 1H, CH_ar-4), 6.84 (d, J = 1.4 Hz, 1H, CH_ar-3), 6.80 (dd, J = 8.7, 2.3 Hz, CH_ar-6), 1.01 (s, 9H, SiC_q(CH₃)₃), 0.21 (s, 6H, Si(CH₃)₂). ¹³C-NMR (75 MHz,

CDCl₃): δ(ppm) 158.59 (d, J = 255.7 Hz, C_ar-5´), 155.18 (C_ar-2´), 149.86 (C_ar-5), 136.99 (d, J = 24.55 Hz, Car-6´), 132.54 (C_ar-2), 132.53 (C_ar-7a), 129.85 (C_ar-3a), 124.18 (d, J = 18.98 Hz, C_ar-4´), 120.81 (d, J

= 4.46, C_ar-3´), 118.12 (C_ar-4), 111.86 (C_ar-6), 110.40 (C_ar-7), 100.30 (C_ar-3), 25.96 (SiCq(CH3)3), 18.40 (SiCq(CH3)3), -4.25 (Si(CH₃)₂). IR (film): v (cm^-1) 3457, 2957, 2858, 2251, 1625, 1549, 1459, 1385, 1288, 1229, 1152, 1118, 1010, 965, 903, 835, 784, 724, 650, 585, 527, 488, 440, 395. HRMS calculated for C₁₉H₂₃FN₂OSiH (M + H⁺) 343.1642 found (M + H⁺) 343.1636.

5.2.1.26 3-bromo-4-(5-(tert-butyldimethyl- silyloxy)-2-(5-fluoropyridin-2-yl)-1H- indol-3-yl)-1-methyl-1H-pyrrole-2,5-dione (73)

72 (921 mg, 2.69 mmol) was dis-solved in THF (8 mL) and cooled to -15 °C.

Lithium bis(trimethylsilyl)amide (8.1 mL, 8.07 mmol, 1 M in hexane) was added drop wise over a period of 90 min and the solu-tion turned from colourless to yellow. 38 (796 mg, 2.96 mmol) was dissolved in THF (5 mL) and added drop wise to the reaction mixture over a period of 20 min. An immedi-ate colour change from yellow to dark purple was observed. The reaction mixture was protected from light and stirred for 1 h at -15 °C followed by 16 h at ambient tem-perature. The reaction was finished by pour-ing the entire reaction mixture into ice cooled hydrochloric acid (63 mL). The or-ganic layer was separated and the aqueous layer was extracted with ethylacetate (4 x 50 mL). The combined organic layer was washed with BRINE (3 x 50 mL), and

dried over sodium sulfate. The crude mate-rial was concentrated in vacuo and subject-ed to column chromatography hex-ane : ethylacetate (6:1  1:1). The product 73 was dried in vacuo and obtained as a red solid (923 mg, 1.74 mmol, 65%). R_f = 0.26 (hexane : ethylacetate 3:1). Due to its light sensitivity the mono bromide intermediate was directly processed to the cyclisation reaction without further characterisation.

5.2.1.27 3-bromo-1-(tert-butyldimethylsilyl)- 4-(2-(5-fluoropyridin-2-yl)-5-meth- oxy-1H-indol-3-yl)-1H-pyrrole-2,5-dione (74)

71 (3.25 g, 13.4 mmol) was dis-solved in THF (40 mL) and cooled to -15 °C.

Lithium bis(trimethylsilyl)amide (40 mL, 40 mmol, 1 M in hexane) was added drop wise over a period of 90 min and the solu-tion turned from colourless to yellow. 42 (5.43 g, 14.74 mmol) was dissolved in THF (30 mL) and added drop wise to the reaction mixture over a period of 30 min. An immedi-ate colour change from yellow to dark purple was observed. The reaction mixture was protected from light and stirred for 1 h at -15 °C followed by 16 h at ambient tem-perature. The reaction was finished by pour-ing the entire reaction mixture into ice cooled hydrochloric acid (400 mL). The or-ganic layer was separated and the aqueous layer was extracted with ethylacetate (5 x 75 mL). The combined organic layer was washed with BRINE (3 x 50 mL), and dried over sodium sulfate. The crude mate-rial was concentrated in vacuo and subject-ed to column chromatography using

hex-ane : ethylacetate (8:1  1:1). The product 74 was dried in vacuo and obtained as a red solid (5.03 g, 9.46 mmol, 71%). Rf = 0.78 (hexane : ethylacetate 1:1). Due to its light sensitivity the mono bromide intermediate was directly proceeded to the cyclisation reaction without further characterisation.

5.2.1.28 3-bromo-1-(tert-butyldimethylsilyl)- 4-(2-(pyridin-2-yl)-1H-indol-3-yl)-1H-pyrrole-2,5-dione (75)

46 (875 g, 4.5 mmol) was dissolved in THF (15 mL) and cooled to -15 °C. Lithi-um bis(trimethylsilyl)amide (13.5 mL, 1 M in hexane) was added drop wise over a period of 45 min and the solution turned from col-ourless to yellow. 42 (1.85 g, 5.0 mmol) was dissolved in THF (20 mL) and added drop wise to the reaction mixture over a period of 20 min. An immediate colour change from yellow to dark purple was observed. The reaction mixture was protected from light and stirred for 1 h at -15 °C followed by 16 h at ambient temperature. The reaction mix-ture turned into a dark purple colour. The reaction was finished by pouring the entire reaction mixture into ice cooled hydrochloric acid (135 mL). The organic layer was sepa-rated and the aqueous layer was extracted with ethylacetate (5 x 50 mL). The combined organic layer was washed with BRINE (3 x 50 mL), and dried over sodium sulfate.

The crude material was concentrated in vacuo and subjected to column chroma-tography using hexane : ethylacetate (6:1  1:1). The product was dried in vacuo and obtained as a red solid (1.47 g, 3.1 mmol, 68%). Due to its light sensitivity the mono

bromide intermediate was directly pro-ceeded to the cyclisation reaction without further characterisation.

5.2.1.29 1-benzyl-3-bromo-4-(2-(pyridin-2- yl)-1H-indol-3-yl)-1H-pyrrole-2,5-dione (76)

46 (1.1 g, 5.68 mmol) was dissolved in THF (14.5 mL) and cooled to -15 °C. Lith-ium bis(trimethylsilyl)amide (25 mL, 1 M in hexane) was added drop wise over a period of 90 min and the solution turned from col-ourless to yellow. 37 (2.05 g, 5.95 mmol) was dissolved in THF (18 mL) and added drop wise to the reaction mixture over a pe-riod of 20 min. An immediate colour change from yellow to dark red was observed. The reaction mixture was protected from light and stirred for 1 h at -15 °C followed by 16 h at ambient temperature. The reaction mix-ture turned into a dark purple colour. The reaction was finished by pouring the entire reaction mixture into ice cooled hydrochloric acid (125 mL). The organic layer was sepa-rated and the aqueous layer was extracted with ethylacetate (4 x 50 mL). The combined organic layer was washed with BRINE (3 x 50 mL), and dried over sodium sulfate.

The crude material was concentrated in vacuo and subjected to column chroma-tography using hexane : ethylacetate (3:1  1:1). The product 76 was dried in vacuo and obtained as a orange solid (1.4 mg, 3.7 mmol, 54%). R_f = 0.51 (hexane : ethyl-acetate 3:1). Due to its light sensitivity the mono bromide intermediate was directly pro-ceeded to the cyclisation reaction without further characterisation.

5.2.1.30 9-(tert-butyldimethylsilyloxy)-3- fluoro-6-methylpyrido[2,3-a]pyr- rolo[3,4-c]carbazole-5,7(6H,12H)-dione (77)

Mono bromide 73 (860 mg, 1.62 mmol) was suspended in toluene (900 mL), continuously purged with nitrogen and subjected 2 h to an iron iodide endowed mercury UV lamp (700 W, _max = 350 nm) under intensive stirring and water cooling in a UV reactor. The crude material was con-centrated under reduced pressure and sub-jected to column chromatography using methylene chloride : methanol (100:0  20:1). The product 77 was dried in vacuo and obtained as an orange solid (388 mg, 0.86 mmol, 53%). Rf = 0.39 (methylene chlo-ride 100%). ¹H-NMR (300 MHz, CDCl₃/(CD₃)₂SO (4:1)): δ(ppm) 8.65 (dd, J = 6.3, 2.7 Hz, 2H, CH_ar-2, CH_ar-4), 8.24 (d, J = 2.3 Hz, 1H, CH_ar-8), 7.48 (d, J = 8.6 Hz, 1H, CH_ar-11), 6.99 (dd, J = 8.7, 2.4 Hz, 1H, CHar-10), 3.10 (s, 3H, NCH3), 0.97 (s, 9H, SiC_q(CH₃)₃), 0.23 (s, 6H, Si(CH₃)₂). ¹³C-NMR (75 MHz, CDCl₃/(CD₃)₂SO (4:1)): δ(ppm) 168.90 (C_ar-7), 168.04 (C_ar-5), 156.80 (d, J = 257.7 Hz, C_ar-3), 149.83 (C_ar-9), 140.20 (C_ar), 139.79 (d, J = 27.6 Hz, C_ar-2), 135.05 (Car), 134.11 (Car), 128.67 (Car), 121.46 (Car), 121.29 (C_ar), 121.20 (C_ar), 120.51 (C_ar), 116.02 (d, J = 19.0 Hz, C_ar-4), 113.22 (C_ar), 112.20 (C_ar), 25.29 (SiC_q(CH₃)₃), 23.13 (NCH₃), 17.70 (SiC_q(CH₃)₃), -4.88 (Si(CH₃)₂).

IR (film): v (cm^-1) 3322, 2931, 2892, 2857, 1753, 1689, 1620, 1566, 1527, 1468, 1442, 1415, 1373, 1331, 1279, 1250, 1219, 1167, 1125, 959, 891. HRMS calculated for C₂₄H₂₅FN₃O₃Si (M + H⁺) 450.1644 found (M + H⁺) 450.1664.

5.2.1.31 6-(tert-butyldimethylsilyl)-3-fluoro-9- methoxypyrido[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H,12H)-dione (78)

74 (2.2 g, 4.15 mmol) were dissolved in toluene (900 mL), continuously purged with nitrogen and subjected 5 h to an iron iodide endowed mercury UV lamp (700 W,

_max = 350 nm) under intensive stirring and water cooling in a UV reactor. The orange coloured crude material was concentrated under reduced pressure and subjected to column chromatography using methylene chloride : methanol (100:1  10:1). The product 78 was dried in vacuo and obtained as an orange solid (1.25 g, 2.7 mmol, 67%).

R_f = 0.42 (hexane : ethylacetate 3:1).

1H-NMR (300 MHz, CDCl₃): δ(ppm) 10.12 (bs, NH), 9.27 (dd, J = 9.1, 2.6 Hz, 1H, CH_ar-4), 8.89 (d, J = 2.7 Hz, 1H, CH_ar-2), 8.61 (d, J = 2.2 Hz, 1H, CH_ar-8), 7.63 (d, J = 8.9 Hz, 1H, CH_ar-11), 7.29 (m, 1H, CH_ar-10), 4.04 (s, 3H, OCH₃), 1.06 (s, 9H, SiC_q(CH₃)₃), 0.63 (s, 6H, Si(CH₃)₂). IR (film): v (cm^-1) 3443, 2929, 2855, 1744, 1687, 1627, 1557, 1528, 1473, 1412, 1363, 1337, 1305, 1252, 1213, 1179, 1153, 1035, 938, 904, 823, 804.

HRMS calculated for C₂₄H₂₅FN₃O₃Si (M + H⁺) 450.1644 found (M + H⁺) 450.1644.

5.2.1.32 6-(tert-butyldimethylsilyl)pyrido[2,3-

a]pyrrolo[3,4-c]carbazole-5,7(6H,12H)-dione (79)

Mono bromide 75 (1.00 g, 2.08 mmol) was suspended in toluene (900 mL), continuously purged with nitrogen and subjected 3 h to an iron iodide endowed mercury UV lamp (700 W, _max = 350 nm) under intensive stirring and water cooling in a UV reactor. The crude material was con-centrated under reduced pressure and sub-jected to column chromatography using methylene chloride : methanol (100:0  20:1). The product 79 was dried in vacuo and obtained as an orange solid (526 mg, 1.31 mmol, 63%). Rf = 0.71 (methylene chlo-ride : methanol 15:1). ¹H-NMR (300 MHz, CDCl₃): δ(ppm) 10.27 (bs, 1H, NH), 9.41 (dd, J = 8.6 Hz, J = 1.6 Hz, 1H, CH_ar), 9.09 (d, J = 7.9 Hz, 1H, CH_ar), 9.02 (dd, J = 4.2 Hz, J = 1.7 Hz, 1H, CH_ar), 7.65 (dd, J = 8.4 Hz, J = 4.3 Hz, 1H, CHar), 7.65-7.54 (m, 2H, CH_ar), 7.45–7.40 (m, 1H, CH_ar), 1.07 (s, 9H, SiC_q(CH₃)₃), 0.64 (s, 6H, Si(CH₃)₂). ¹³C-NMR (75 MHz, CDCl₃): δ(ppm) 175.5 (C_ar-7), 173.9 (C_ar-5), 150.4, 140.1, 139.7, 138.5, 134.5, 130.8, 127.3, 125.7, 122.8, 122.3, 121.7, 121.9, 120.9, 115.3, 111.6, 26.6 (SiC_q(CH₃)₃), 19.1 (SiC_q(CH₃)₃), −4.0 (Si(CH₃)₂). HRMS calculated for C₂₃H₂₄N₃O₂Si (M + H⁺) 402.1632 found (M + H⁺) 402.1632.

5.2.1.33 6-benzylpyrido[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H,12H)-dione (80)

76 (334 mg, 729 µmol) were dis-solved in toluene (900 mL), continuously purged with nitrogen and subjected 2.5 h to an iron iodide endowed mercury UV lamp (700 W, max = 350 nm) under intensive stir-ring and water cooling in a UV reactor. The orange coloured crude material was concen-trated under reduced pressure and subject-ed to column chromatography using meth-ylene chloride : methanol (100:1  10:1).

The product 80 was dried in vacuo and ob-tained as an orange solid (220 mg, 583 µmol, 80%). R_f = 0.28 (hexane : ethyl-acetate 1:1). ¹H-NMR (300 MHz, CDCl₃):

δ(ppm) 10.40 (s, 1H, NH), 9.28 (dd, J = 8.5, 1.6, Hz, 1H, CHar), 8.93 (d, J = 8.0 Hz, 1H, CH_ar), 8.89 (dd, J = 1.6, 4.3 Hz, 1H, CH_ar), 7.58-7.50 (m, 5H, CH_ar), 7.41-7.28 (m, 4H, CH_ar), 4.94 (s, 2H, CH_benzyl). IR (film): v (cm^-1) 3334, 2924, 2853, 2078, 1754, 1695, 1640, 1529, 1499, 1461, 1430, 1385, 1334, 1295, 1234, 1145, 1104, 1070, 976, 934, 796, 737, 694, 624, 498. HRMS calculated for C₂₄H₁₅N₃O₂Na (M + Na⁺) 400.1062 found (M + Na⁺) 400.1056.

5.2.2 Synthesis of ligands and related

Im Dokument Design and Synthesis of Enantiopure Organometallic Kinase Inhibitors as Potential Chemotherapeutics (Seite 122-138)