ethyl 3-phenyl-1H-indole-2-carboxylate

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of 3-phenyl-1H-indole-2-carboxylic acid ethyl ester (3.99 g, 15.0 mmol) in DMF (25 mL) cooled to 0° C. and under a nitrogen atmosphere was added NaH (60% in mineral oil, 720 mg, 18.0 mmol). After stirring for 10 min at RT, the reaction mixture was cooled to 0° C. and 4-methylbenzenesulfonyl chloride (3.44 g, 18.0 mmol) in DMF (15 mL) added. Stirring was continued for 16 h at RT then the mixture was poured into 1.0M HCl and extracted with EtOAc (×2). The combined organic fractions were washed with water, dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 30-100% DCM in pentane) affording the title compound as a colourless oil (3.25 g, 52%). 1H NMR (CDCl3, 400 MHz): δ 8.08 (1H, d, J=8.43 Hz), 7.92 (2H, d, J=8.37 Hz), 7.53-7.36 (7H, m), 7.28-7.21 (3H, m), 4.35 (2H, q, J=7.15 Hz), 2.36 (3H, s), 1.25 (3H, t, J=7.14 Hz) the reaction mixture was cooled to 0° C. Stirring was continued for 16 h at RT extracted with EtOAc (×2) The combined organic fractions were washed with water dried (Na2SO4) concentrated in vacuo The resulting residue was purified by column chromatography (Si—PCC, gradient 30-100% DCM in pentane)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of 3-phenyl-1H-indole-2-carboxylic acid ethyl ester (3.99 g, 15.0 mmol) in DMF (25 mL) cooled to 0° C. and under a nitrogen atmosphere was added NaH (60% in mineral oil, 720 mg, 18.0 mmol). After stirring for 10 min at RT, the reaction mixture was cooled to 0° C. and 4-methylbenzenesulfonyl chloride (3.44 g, 18.0 mmol) in DMF (15 mL) was added. Stirring was continued for 16 h at RT then the mixture was poured into 1.0M HCl and extracted with EtOAc (×2). The combined organic layers were washed with water, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 30-100% DCM in pentane) affording 3-Phenyl-1-(toluene-4-sulfonyl)-1H-indole-2-carboxylic acid ethyl ester as a colourless oil (3.25 g, 52%). 1H NMR (CDCl3, 400 MHz): δ 8.08 (1H, d, J=8.43 Hz), 7.92 (2H, d, J=8.37 Hz), 7.53-7.36 (7H, m), 7.28-7.21 (3H, m), 4.35 (2H, q, J=7.15 Hz), 2.36 (3H, s), 1.25 (3H, t, J=7.14 Hz). the reaction mixture was cooled to 0° C. Stirring was continued for 16 h at RT extracted with EtOAc (×2) The combined organic layers were washed with water dried (Na2SO4) concentrated in vacuo The resulting residue was purified by column chromatography (Si—PCC, gradient 30-100% DCM in pentane)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of 3-phenyl-1H-indole-2-carboxylic acid ethyl ester (3.99 g, 15.0 mmol) in DMF (25 mL) cooled to 0° C. and under a nitrogen atmosphere was added NaH (60% in mineral oil, 720 mg, 18.0 mmol). After stirring for 10 min at RT, the reaction mixture was cooled to 0° C. and 4-methylbenzenesulfonyl chloride (3.44 g, 18.0 mmol) in DMF (15 mL) was added. Stirring was continued for 16 h at RT then the mixture was poured into 1.0M HCl and extracted with EtOAc (×2). The combined organic layers were washed with water, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 30-100% DCM in pentane) affording 3-Phenyl-1-(toluene-4-sulfonyl)-1H-indole-2-carboxylic acid ethyl ester as a colourless oil (3.25 g, 52%). 1H NMR (CDCl3, 400 MHz): δ 8.08 (1H, d, J=8.43 Hz), 7.92 (2H, d, J=8.37 Hz), 7.53-7.36 (7H, m), 7.28-7.21 (3H, m), 4.35 (2H, q, J=7.15 Hz), 2.36 (3H, s), 1.25 (3H, t, J=7.14 Hz). the reaction mixture was cooled to 0° C. Stirring was continued for 16 h at RT extracted with EtOAc (×2) The combined organic layers were washed with water dried (Na2SO4) concentrated in vacuo The resulting residue was purified by column chromatography (Si—PCC, gradient 30-100% DCM in pentane)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1-(4-Nitro-benzyl)-3-phenyl-1H-indolecarboxylic acid ethyl ester was prepared from of 3-phenyl-1H-indolecarboxylic acid ethyl ester and 4-nitrobenzyl bromide followed the procedure of Example 3 Step 1 as a yellow powder: 1H NMR (DMSO-d6) δ 1H NMR (DMSO-d6) δ 0.91 (t, J=7.2 Hz, 3H), 4.05 (q, J=7.2 Hz, 2H), 5.97 (s, 2H), 7.17-7.23 (m, 1H), 7.32 (d, J=8.8 Hz, 2H), 7.36-7.42 (m, 1H), 7.38-7.42 (m, 1H), 7.45-7.48 (m, 4H), 7.52 (d, J=8.2 Hz, 1H), 7.62 (d, J=8.2 Hz, 1H), 8.19 (d, J=8.8 Hz, 2H); MS (ESI) m/z 401 (MH+); 399 ([M−H]−); HRMS calcd for C24H21N2O4: 401.1490; found (ESI+): 401.1494; Anal. calcd for C24H20N2O4.0.05 TFA C, 71.99; H, 5.03; N, 7.00 Found: C, 71.27; H, 4.98; N, 6.90.

Conditions: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3-bromo-1H-indolecarboxylic acid ethyl ester (0.50 g, 1.87 mmol), phenylboronic acid (0.27 g, 2.25 mmol), 2 M aqueous sodium carbonate (8 mL), tetrakis(triphenylphosphine)palladium (0) (0.20 g, 0.17 mmol) in ethanol (16 mL) and toluene (30 ml) was heated at 65° C. for 16 h and then cooled. The reaction mixture was diluted with 1 N hydrochloric acid and then extracted with ethyl acetate. The organic extracts were washed with water, dried over magnesium sulfate and concentrated. Flash silica gel chromatography using ethyl acetate/hexane as elutant gave 0.34 g (68%) of 3-phenyl-1H-indolecarboxylic acid ethyl ester as a pink solid: 1H NMR (DMSO-d4) δ 1.18 (t, J=7.2 Hz, 3H), 4.22 (q, J=7.2 Hz, 2H), 7.07-7.11 (m, 1H), 7.29-7.33 (m, 1H) 7.45 (dd, J=8.3, 0.8 Hz, 1H), 7.48-7.50 (m, 5H), 7.50 (dd, J=8.3, 0.8 Hz, 1H), 11.90 (br s, 1H); MS (ESI) m/z 266 (MH+); 264 ([M−H]−). cooled extracted with ethyl acetate The organic extracts were washed with water dried over magnesium sulfate concentrated

Conditions: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3-bromo-1H-indolecarboxylic acid ethyl ester (0.50 g, 1.87 mmol), phenylboronic acid (0.27 g, 2.25 mmol), 2 M aqueous sodium carbonate (8 mL), tetrakis(triphenylphosphine)palladium (0) (0.20 g, 0.17 mmol) in ethanol (16 mL) and toluene (30 ml) was heated at 65° C. for 16 h and then cooled. The reaction mixture was diluted with 1 N hydrochloric acid and then extracted with ethyl acetate. The organic extracts were washed with water, dried over magnesium sulfate and concentrated. Flash silica gel chromatography using ethyl acetate/hexane as elutant gave 0.34 g (68%) of 3-phenyl-1H-indolecarboxylic acid ethyl ester as a pink solid: 1H NMR (DMSO-d4) δ 1.18 (t, J=7.2 Hz, 3H), 4.22 (q, J=7.2 Hz, 2H), 7.07-7.11 (m, 1H), 7.29-7.33 (m, 1H) 7.45 (dd, J=8.3, 0.8 Hz, 1H), 7.48-7.50 (m, 5H), 7.50 (dd, J=8.3, 0.8 Hz, 1H), 11.90 (br s, 1H); MS (ESI) m/z 266 (MH+); 264 ([M−H]−). cooled extracted with ethyl acetate The organic extracts were washed with water dried over magnesium sulfate concentrated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of Example 1B (2.65 g, 10 mmol) in ethanol (20 mL) was treated with hydrazine hydrate (3.12 mL, 100 mmol), heated to reflux for 18 hours, cooled to room temperature, and filtered. The resulting solid was washed with ethanol and dried under vacuum to provide 1.86 g (74%) of the desired product of sufficient purity for subsequent use. heated to reflux for 18 hours filtered The resulting solid was washed with ethanol dried under vacuum

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of Example 1A (7.81 g, 40.7 mmol) and phenylhydrazine (4.00 mL, 40.7 mmol) was treated with concentrated sulfuric acid (4 drops), heated to 120° C. for 15 minutes, cooled to room temperature, treated with ethanol (50 mL), treated with bubbling HCl gas for 2 minutes, and heated to reflux for 1 hour. The mixture was poured into water (100 mL) and extracted with diethyl ether. The combined extracts were washed with water and brine, dried (Na2SO4), filtered, and concentrated. The concentrate was recrystallized from ethanol to provide 3.43 g (32%) of the desired product. cooled to room temperature heated to reflux for 1 hour extracted with diethyl ether The combined extracts were washed with water and brine dried (Na2SO4) filtered concentrated The concentrate was recrystallized from ethanol

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of Example 1A (7.81 g, 40.7 mmol) and phenylhydrazine (4.00 mL, 40.7 mmol) was treated with concentrated sulfuric acid (4 drops), heated to 120° C. for 15 minutes, cooled to room temperature, treated with ethanol (50 mL), treated with bubbling HCl gas for 2 minutes, and heated to reflux for 1 hour. The mixture was poured into water (100 mL) and extracted with diethyl ether. The combined extracts were washed with water and brine, dried (Na2SO4), filtered, and concentrated. The concentrate was recrystallized from ethanol to provide 3.43 g (32%) of the desired product. cooled to room temperature heated to reflux for 1 hour extracted with diethyl ether The combined extracts were washed with water and brine dried (Na2SO4) filtered concentrated The concentrate was recrystallized from ethanol

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of 3-phenyl-1H-indole-2-carboxylic acid ethyl ester (3.99 g, 15.0 mmol) in DMF (25 mL) cooled to 0° C. and under a nitrogen atmosphere was added NaH (60% in mineral oil, 720 mg, 18.0 mmol). After stirring for 10 min at RT, the reaction mixture was cooled to 0° C. and 4-methylbenzenesulfonyl chloride (3.44 g, 18.0 mmol) in DMF (15 mL) added. Stirring was continued for 16 h at RT then the mixture was poured into 1.0M HCl and extracted with EtOAc (×2). The combined organic fractions were washed with water, dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 30-100% DCM in pentane) affording the title compound as a colourless oil (3.25 g, 52%). 1H NMR (CDCl3, 400 MHz): δ 8.08 (1H, d, J=8.43 Hz), 7.92 (2H, d, J=8.37 Hz), 7.53-7.36 (7H, m), 7.28-7.21 (3H, m), 4.35 (2H, q, J=7.15 Hz), 2.36 (3H, s), 1.25 (3H, t, J=7.14 Hz) the reaction mixture was cooled to 0° C. Stirring was continued for 16 h at RT extracted with EtOAc (×2) The combined organic fractions were washed with water dried (Na2SO4) concentrated in vacuo The resulting residue was purified by column chromatography (Si—PCC, gradient 30-100% DCM in pentane)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of 3-phenyl-1H-indole-2-carboxylic acid ethyl ester (3.99 g, 15.0 mmol) in DMF (25 mL) cooled to 0° C. and under a nitrogen atmosphere was added NaH (60% in mineral oil, 720 mg, 18.0 mmol). After stirring for 10 min at RT, the reaction mixture was cooled to 0° C. and 4-methylbenzenesulfonyl chloride (3.44 g, 18.0 mmol) in DMF (15 mL) was added. Stirring was continued for 16 h at RT then the mixture was poured into 1.0M HCl and extracted with EtOAc (×2). The combined organic layers were washed with water, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 30-100% DCM in pentane) affording 3-Phenyl-1-(toluene-4-sulfonyl)-1H-indole-2-carboxylic acid ethyl ester as a colourless oil (3.25 g, 52%). 1H NMR (CDCl3, 400 MHz): δ 8.08 (1H, d, J=8.43 Hz), 7.92 (2H, d, J=8.37 Hz), 7.53-7.36 (7H, m), 7.28-7.21 (3H, m), 4.35 (2H, q, J=7.15 Hz), 2.36 (3H, s), 1.25 (3H, t, J=7.14 Hz). the reaction mixture was cooled to 0° C. Stirring was continued for 16 h at RT extracted with EtOAc (×2) The combined organic layers were washed with water dried (Na2SO4) concentrated in vacuo The resulting residue was purified by column chromatography (Si—PCC, gradient 30-100% DCM in pentane)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1-(4-Nitro-benzyl)-3-phenyl-1H-indolecarboxylic acid ethyl ester was prepared from of 3-phenyl-1H-indolecarboxylic acid ethyl ester and 4-nitrobenzyl bromide followed the procedure of Example 3 Step 1 as a yellow powder: 1H NMR (DMSO-d6) δ 1H NMR (DMSO-d6) δ 0.91 (t, J=7.2 Hz, 3H), 4.05 (q, J=7.2 Hz, 2H), 5.97 (s, 2H), 7.17-7.23 (m, 1H), 7.32 (d, J=8.8 Hz, 2H), 7.36-7.42 (m, 1H), 7.38-7.42 (m, 1H), 7.45-7.48 (m, 4H), 7.52 (d, J=8.2 Hz, 1H), 7.62 (d, J=8.2 Hz, 1H), 8.19 (d, J=8.8 Hz, 2H); MS (ESI) m/z 401 (MH+); 399 ([M−H]−); HRMS calcd for C24H21N2O4: 401.1490; found (ESI+): 401.1494; Anal. calcd for C24H20N2O4.0.05 TFA C, 71.99; H, 5.03; N, 7.00 Found: C, 71.27; H, 4.98; N, 6.90.