ethyl 6-hydroxy-1-benzofuran-3-carboxylate

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

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

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

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

Procedure: A −78° C. solution of 6-methoxy-benzofuran-3-carboxylic acid ethyl ester (1.50 g, 6.81 mmol) in dichloromethane (20 mL) is treated with boron tribromide (20 mL) dropwise. The mixture is stirred at 0° C. for 60 minutes. The reaction is quenched by adding MeOH (10 mL) dropwise over 10 minutes. The mixture is concentrated. The residue is purified via flash chromatography eluting with 25% EtOAc/hexanes to provide the title compound (0.95 g, 68%). ES/MS m/e 207.0 (M+1), 205.0 (M−1). The reaction is quenched by adding MeOH (10 mL) dropwise over 10 minutes The mixture is concentrated The residue is purified via flash chromatography eluting with 25% EtOAc/hexanes

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

Procedure: A −78° C. solution of 6-methoxy-benzofuran-3-carboxylic acid ethyl ester (1.50 g, 6.81 mmol) in dichloromethane (20 mL) is treated with boron tribromide (20 mL) dropwise. The mixture is stirred at 0° C. for 60 minutes. The reaction is quenched by adding MeOH (10 mL) dropwise over 10 minutes. The mixture is concentrated. The residue is purified via flash chromatography eluting with 25% EtOAc/hexanes to provide the title compound (0.95 g, 68%). ES/MS m/e 207.0 (M+1), 205.0 (M−1). The reaction is quenched by adding MeOH (10 mL) dropwise over 10 minutes The mixture is concentrated The residue is purified via flash chromatography eluting with 25% EtOAc/hexanes

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

Procedure: A −78° C. solution of 6-methoxy-benzofuran-3-carboxylic acid ethyl ester (1.50 g, 6.81 mmol) in dichloromethane (20 mL) is treated with boron tribromide (20 mL) dropwise. The mixture is stirred at 0° C. for 60 minutes. The reaction is quenched by adding MeOH (10 mL) dropwise over 10 minutes. The mixture is concentrated. The residue is purified via flash chromatography eluting with 25% EtOAc/hexanes to provide the title compound (0.95 g, 68%). ES/MS m/e 207.0 (M+1), 205.0 (M−1). The reaction is quenched by adding MeOH (10 mL) dropwise over 10 minutes The mixture is concentrated The residue is purified via flash chromatography eluting with 25% EtOAc/hexanes

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

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

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

Procedure: To a cooled (0° C.) solution of 6-hydroxy-benzofuran-3-carboxylic acid ethyl ester (5.85 g, 28.4 mmol) in THF (250 mL) was added DIBALH as a solution in THF (100 mL, 100 mmol) and the reaction mixture was allowed to warm (rt, 1 h). The reaction was cooled (−78° C.) and treated dropwise with Rochelles salt (120 mL). The resulting mixture was stirred (rt, o/n). The layers were separated and the aqueous layer was extracted with DCM (2×200 mL) and EtOAc (2×200 mL). The organic layers were combined, dried, filtered and concentrated in vacuo to provide the title compound as a white solid (4.72 g, 100%). 1H NMR (500 MHz, CD3OD): 7.53 (s, 1H), 7.45 (d, J=8.4, 1H), 6.85 (d, J=2.1, 1H), 6.76 (dd, J=8.4, 2.1, 1H), 4.70 (s, 2H). The reaction was cooled (−78° C.) The layers were separated the aqueous layer was extracted with DCM (2×200 mL) and EtOAc (2×200 mL) dried filtered concentrated in vacuo

Conditions: temp:10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a cooled (0° C.) solution of 6-methoxy-benzofuran-3-carboxylic acid ethyl ester (90.0 g, 408.67 mmol) in DCM (700 mL) was slowly added BBr3 (159.0 g, 634.67 mmol) in DCM (200 mL) maintaining a controlled temperature (<5° C.). The resulting mixture was stirred (10° C., 6 h). The reaction mixture was slowly poured into ice/water with vigorous stirring followed by stirring in a temperature gradient (0° C.−rt, 18 h). The solids were filtered off and the filtrate was extracted with EtOAc (2×250 mL). The solids were dissolved (required heat) with the combined organic phase. The organic phase was washed with saturated NaHCO3 (700 mL), H2O (700 mL), dried, filtered and concentrated in vacuo to provide a yellow solid. The crude solid was suspended in EtOAc:hexane (20%), stirred (24 h) and filtered to provide the title compound as a solid (75.6 g). The filtrate was concentrated in vacuo and the resulting residue was purified by flash column chromatography using EtOAc:hexanes (20%) to provide the title compound (2.4 g) as a white solid (93% combined yield). MS (ESI): mass calcd. for C11H10O4, 206.2; m/z found, 207.1 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.15 (s, 1H), 7.88 (d, J=8.5, 1H), 7.01 (s, 1H), 6.90 (dd, J=8.5, 2.3, 1H), 5.05 (s, 1H), 4.4 (q, J=7.1, 2H) 1.42 (t, J=7.2, 3H). maintaining a controlled temperature (<5° C.) with vigorous stirring by stirring in a temperature gradient (0° C.−rt, 18 h) The solids were filtered off the filtrate was extracted with EtOAc (2×250 mL) The solids were dissolved (required heat) with the combined organic phase The organic phase was washed with saturated NaHCO3 (700 mL), H2O (700 mL) dried filtered concentrated in vacuo to provide a yellow solid filtered

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

Procedure: 4-[6-(2-Ethoxy-ethoxy)-benzofuran-3-ylmethoxy]-1H-indole-2-carboxylic acid (30c) is synthesized analogous to 30a from 6-hydroxy-benzofuran-3-carboxylic acid ethyl ester (26) and 2-bromoethyl ethyl ether.

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

Procedure: 4-(6-cyclopropylmethoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (30b) is synthesized analogous to 30a from 6-Hydroxy-benzofuran-3-carboxylic acid ethyl ester (26) and bromomethyl cyclopropane.