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

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: Sodium hydride (60% dispersion in mineral oil, 2.40 g, 60.0 mmol) was cooled to 0° C., and anhydrous methyl sulfoxide (75.0 mL, 1.06 mol) was added. The mixture was stirred at 0° C. for 15 minutes before a solution of ethyl 3-formyl-1H-indole-2-carboxylate (10.9 g, 50.2 mmol, Lit. J. Heterocyclic Chem. 1997, 34, 1431.) in 75 mL of methyl sulfoxide was added over a 20 minute period. The resulting solution was warmed to room temperature and stirred for 1 hour. 3-Methoxybenzylbromide (9.8 mL, 70.0 mmol) was added, and the solution was heated at 60° C. for 16 hours. The solution was cooled and poured into water (500 mL). The aqueous solution was extracted with ethyl acetate (3×), and the combined organic extracts were washed with 1 N hydrochloric acid (2×), water, and brine. The solution was dried over anhydrous magnesium sulfate and concentrated in vacuo. Trituration of the residue with 33% hexane/Et2O provided the title compound as a solid (13.8 g, 81%). The product had: 1H NMR (300 MHz, acetone-d6) δ 10.61 (s, 1 H), 8.43 (d, 1 H), 7.61 (d, 1 H), 7.30-7.45 (m, 2 H), 7.19 (dd, 1 H), 6.80 (dd, 1 H), 6.63-6.74 (m, 2 H), 5.88 (s, 2 H), 4.48 (dq, 2 H), 3.70 (s, 3 H), 1.37 (t, 3 H); mass spectroscopy gave MH+=338.1 (calc'd exact mass for C20H19NO4=337.13). was added over a 20 minute period the solution was heated at 60° C. for 16 hours The solution was cooled The aqueous solution was extracted with ethyl acetate (3×) the combined organic extracts were washed with 1 N hydrochloric acid (2×), water, and brine The solution was dried over anhydrous magnesium sulfate concentrated in vacuo

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

Procedure: Using the procedure of Example 121 but replacing the resultant compound of Example 98 with the resultant compound of Example 97 and replacing the resultant compound of Example 120 with benzyltriphenylphosphonium bromide gave the desired compound in 73% yield after silica gel chromatography using 4:1 hexane/ethyl acetate. 1H NMR (CDCl3) δ 1.49 (t,J=7 Hz,3H), 4.48 (q,J=7 Hz,2H), 7.2-7.3 (m,2H), 7.35-7.45 (m,5H), 7.60 (br d,J=8 Hz,1H), 8.07 (d,J=16 Hz,1H), 8.16 (d,J=8 Hz,1H), 8.88 (br,1H). Mass spectrum: (M+H)+ =292.

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of 11.95 g (34.9 mmol) of methoxymethyltriphenylphosphonium chloride in 200 ml of anhydrous tetrahydrofuran was cooled to 0° C. under N2 atmosphere and treated dropwise with 14.3 ml (35.8 mmol) of n-butyllithium. The resulting solution was stirred for 15 min, treated with 3.70 g (17 mmol) of the resultant compound of Example 97, and stirred at ambient temperature for 3 h. After concentration of the solvent in vacuo, and the residue was taken up in ethyl acetate, washed sequentially with water and saturated brine, dried over MgSO4, and concentrated. The crude mixture of vinyl ethers was partially purified by silica gel chromatography using 6:1 hexane:ethyl acetate. The mixture (2.98 g, 71%) was subsequently treated with 20 ml of 1M HCl and 40 ml of tetrahydrofuran and heated at reflux for 6 h. After cooling, the solution was partitioned between ether and saturated aqueous NaHCO3, dried over MgSO4, and concentrated. Purification by silica gel chromatography using 4:1 hexane:ethyl acetate gave 1.35 g (48%) of the desired compound which was recrystallized from ethyl acetate/hexane. 1H NMR (CDCl3) δ 1.42 (t,J=7 Hz,3H), 4.17 (d,J=2 Hz,2H), 4.42 (q,J=7 Hz,2H), 7.19 (ddd,J=8,7,1 Hz,1H), 7.37 (ddd,J=8,7,1 Hz), 7.43 (br d,J=8 Hz,1H), 7.61 (br d,J=8 Hz,1H), 8.94 (br s,1H), 9.73 (t,J=2 Hz,1H). Mass spectrum: (M+H)+ =232. stirred at ambient temperature for 3 h washed sequentially with water and saturated brine dried over MgSO4 concentrated The crude mixture of vinyl ethers was partially purified by silica gel chromatography The mixture (2.98 g, 71%) was subsequently treated with 20 ml of 1M HCl and 40 ml of tetrahydrofuran heated at reflux for 6 h After cooling the solution was partitioned between ether and saturated aqueous NaHCO3 dried over MgSO4 concentrated Purification by silica gel chromatography

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of 11.95 g (34.9 mmol) of methoxymethyltriphenylphosphonium chloride in 200 ml of anhydrous tetrahydrofuran was cooled to 0° C. under N2 atmosphere and treated dropwise with 14.3 ml (35.8 mmol) of n-butyllithium. The resulting solution was stirred for 15 min, treated with 3.70 g (17 mmol) of the resultant compound of Example 97, and stirred at ambient temperature for 3 h. After concentration of the solvent in vacuo, and the residue was taken up in ethyl acetate, washed sequentially with water and saturated brine, dried over MgSO4, and concentrated. The crude mixture of vinyl ethers was partially purified by silica gel chromatography using 6:1 hexane:ethyl acetate. The mixture (2.98 g, 71%) was subsequently treated with 20 ml of 1M HCl and 40 ml of tetrahydrofuran and heated at reflux for 6 h. After cooling, the solution was partitioned between ether and saturated aqueous NaHCO3, dried over MgSO4, and concentrated. Purification by silica gel chromatography using 4:1 hexane:ethyl acetate gave 1.35 g (48%) of the desired compound which was recrystallized from ethyl acetate/hexane. 1H NMR (CDCl3) δ 1.42 (t,J=7 Hz,3H), 4.17 (d,J=2 Hz,2H), 4.42 (q,J=7 Hz,2H), 7.19 (ddd,J=8,7,1 Hz,1H), 7.37 (ddd,J=8,7,1 Hz), 7.43 (br d,J=8 Hz,1H), 7.61 (br d,J=8 Hz,1H), 8.94 (br s,1H), 9.73 (t,J=2 Hz,1H). Mass spectrum: (M+H)+ =232. stirred at ambient temperature for 3 h washed sequentially with water and saturated brine dried over MgSO4 concentrated The crude mixture of vinyl ethers was partially purified by silica gel chromatography The mixture (2.98 g, 71%) was subsequently treated with 20 ml of 1M HCl and 40 ml of tetrahydrofuran heated at reflux for 6 h After cooling the solution was partitioned between ether and saturated aqueous NaHCO3 dried over MgSO4 concentrated Purification by silica gel chromatography

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

Procedure: Sodium borohydride (0.23 g) was added to a stirred solution of ethyl 3-formylindole-2-carboxylate (0.2 g) and 10% palladium on carbon (0.11 g) in isopropanol (45 ml). The solution was heated at reflux for 4 hours, cooled and filtered through Celite. The solution was partitioned between ethyl acetate and water. Combined organic extracts were dried (MgSO4) and concentrated in vacuo and the residue purified by column chromatography using isohexane-10% ethyl acetate as eluent to give the desired end product as a white solid (0.05 g, 25%); NMR δ (CD3SOCD3) 1.3 (d, 6H), 2.5 (s, 3H), 5.2 (m, 1H), 7.0 (m, 1H), 7.2 (m, 1H), 7.4 (m, 1H), 7.6 (d, 1H), 11.3 (bs, 1H). The solution was heated at reflux for 4 hours cooled filtered through Celite The solution was partitioned between ethyl acetate and water Combined organic extracts were dried (MgSO4) concentrated in vacuo the residue purified by column chromatography

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

Procedure: Sodium borohydride (0.23 g) was added to a stirred solution of ethyl 3-formylindole-2-carboxylate (0.2 g) and 10% palladium on carbon (0.11 g) in isopropanol (45 ml). The solution was heated at reflux for 4 hours, cooled and filtered through Celite. The solution was partitioned between ethyl acetate and water. Combined organic extracts were dried (MgSO4) and concentrated in vacuo and the residue purified by column chromatography using isohexane-10% ethyl acetate as eluent to give the desired end product as a white solid (0.05 g, 25%); NMR δ (CD3SOCD3) 1.3 (d, 6H), 2.5 (s, 3H), 5.2 (m, 1H), 7.0 (m, 1H), 7.2 (m, 1H), 7.4 (m, 1H), 7.6 (d, 1H), 11.3 (bs, 1H). The solution was heated at reflux for 4 hours cooled filtered through Celite The solution was partitioned between ethyl acetate and water Combined organic extracts were dried (MgSO4) concentrated in vacuo the residue purified by column chromatography

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

Procedure: Using general procedure B, 3-formyl-1H-indole-2-carboxylic acid ethyl ester was coupled with 3-bromomethyl-5-fluoro-benzo[b]thiophene (Lit. 18) to give 1-(5-fluoro-benzo[b]thiophen-3-ylmethyl)-3-formyl-1H-indole-2-carboxylic acid ethyl ester as white solid. MS: 382.3 ([M+H]+).

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

Procedure: Using general procedure B, 3-formyl-1H-indole-2-carboxylic acid ethyl ester was coupled with 3-bromomethyl-5-fluoro-benzo[b]thiophene (Lit. 18) to give 1-(5-fluoro-benzo[b]thiophen-3-ylmethyl)-3-formyl-1H-indole-2-carboxylic acid ethyl ester as white solid. MS: 382.3 ([M+H]+).

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

Procedure: Butyllithium (1.1 equiv.) was added to a suspension of (2-dimethylaminoethyl)triphenylphosphonium bromide in THF (0.2 M) at 0° C. After stirring for 30 minutes, lithium diethylamine (1.1 equiv.) was added dropwise followed by the cold suspension of 3-formyl-1H-indole-2-carboxylic acid ethyl ester (3.96 g, 18.2 mmol) in THF. The resulting orange suspension was stirred for 18 hours. The reaction was then quenched with saturated ammonium chloride and extracted with 10% MeOH in DCM. The organic layer was washed with saturated sodium bicarbonate, dried and concentrated to give 3-(3-dimethylaminopropenyl)-1H-indole-2-carboxylic acid ethyl ester as a brownish-red waxy solid. The resulting orange suspension was stirred for 18 hours The reaction was then quenched with saturated ammonium chloride extracted with 10% MeOH in DCM The organic layer was washed with saturated sodium bicarbonate dried concentrated

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

Procedure: Ethyl indole-2-carboxylate (10 g, 52.8 mmol) was formylated using POCl3 (1.3 equiv.) and DMF (1.3 equiv.) as above to give 3-formyl-1H-indole-2-carboxylic acid ethyl ester as a white solid.

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

Procedure: Butyllithium (1.1 equiv.) was added to a suspension of (2-dimethylaminoethyl)triphenylphosphonium bromide in THF (0.2 M) at 0° C. After stirring for 30 minutes, lithium diethylamine (1.1 equiv.) was added dropwise followed by the cold suspension of 3-formyl-1H-indole-2-carboxylic acid ethyl ester (3.96 g, 18.2 mmol) in THF. The resulting orange suspension was stirred for 18 hours. The reaction was then quenched with saturated ammonium chloride and extracted with 10% MeOH in DCM. The organic layer was washed with saturated sodium bicarbonate, dried and concentrated to give 3-(3-dimethylaminopropenyl)-1H-indole-2-carboxylic acid ethyl ester as a brownish-red waxy solid. The resulting orange suspension was stirred for 18 hours The reaction was then quenched with saturated ammonium chloride extracted with 10% MeOH in DCM The organic layer was washed with saturated sodium bicarbonate dried concentrated