ethyl 2,3-dihydro-1H-indene-2-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:; See reaction.notes.procedure_details.

Procedure: Dissolve 2-(carboethoxy)indan (6.49 g, 34.1 mmol) in ethanol (95%, 150 mL) and water (75 mL). Add potassium hydroxide (9.5 g, 0.17 mol) and stir at room temperature for 1 hour. Partition between water (150 mL) and ethyl ether (2×150 mL). Acidify the aqueous phase with hydrochloric acid to pH 1. Extract with methylene chloride (2×150 mL), dry (Na2SO4) and evaporate the solvent in vacuo to give 2-indancarboxylic acid as a tan solid (3.82 g, 69%). Partition between water (150 mL) and ethyl ether (2×150 mL) Extract with methylene chloride (2×150 mL) dry (Na2SO4) evaporate the solvent in vacuo

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

Procedure: Dissolve 2-(carboethoxy)indan (6.49 g, 34.1 mmol) in ethanol (95%, 150 mL) and water (75 mL). Add potassium hydroxide (9.5 g, 0.17mol) and stir at room temperature for 1 hour. Partition between water (150 mL) and ethyl ether (2×150 mL). Acidify the aqueous phase with hydrochloric acid to pH 1. Extract with methylene chloride (2×150 mL), dry (Na2SO4) and evaporate the solvent in vacuo to give 2-indancarboxylic acid as a tan solid (3.82 g, 69%). Partition between water (150 mL) and ethyl ether (2×150 mL) Extract with methylene chloride (2×150 mL) dry (Na2SO4) evaporate the solvent in vacuo

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

Procedure: Dissolve 2-(carboethoxy)indan (6.49 g, 34.1 mmol) in ethanol (95%, 150 mL) and water (75 mL). Add potassium hydroxide (9.5 g, 0.17mol) and stir at room temperature for 1 hour. Partition between water (150 mL) and ethyl ether (2×150 mL). Acidify the aqueous phase with hydrochloric acid to pH 1. Extract with methylene chloride (2×150 mL), dry (Na2SO4) and evaporate the solvent in vacuo to give 2-indancarboxylic acid as a tan solid (3.82 g, 69%). Partition between water (150 mL) and ethyl ether (2×150 mL) Extract with methylene chloride (2×150 mL) dry (Na2SO4) evaporate the solvent in vacuo

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

Procedure: To a solution of ethyl indane-2-carboxylate (Schaaf et al., J. Med. Chem. 1983, 26, 328-334) (2.00 g, 10.5 mmol) in THF at −78° C. was added sodium bis(trimethylsilyl)amide (15.8 mL of a 1.0 M solution in THF, 15.8 mmol) dropwise, over 10 min. The mixture was stirred for 15 min, then tert-butyl bromoacetate (3.08 g, 15.8 mmol) was added dropwise, over 30 min. The resulting mixture was stirred for 30 min at −78° C., then poured into brine (20 mL) and extracted with EtOAc (50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 90:10, to give the title compound. MS: m/z=368 (M+Na+CH3CN). The resulting mixture was stirred for 30 min at −78° C. extracted with EtOAc (50 mL) The organic layer was dried over Na2SO4 filtered concentrated in vacuo The crude product was purified by silica gel chromatography eluting with a gradient of hexane

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

Procedure: To a solution of ethyl indane-2-carboxylate [Schaaf et al., J. Med. Chem. 1983, 26, 328-334] (6.87 g, 36.1 mmol) in THF (100 mL) at −78° C. was added sodium bis(trimethylsilyl)amide (1.0 M in THF, 39.7 mL, 39.7 mmol) dropwise over 20 min. The resulting yellow solution was stirred for 1 h, and then allyl bromide (3.75 mL, 43.3 mmol) was added over 5 min. Stirring was continued for 1.5 h at −78° C., and then the reaction was quenched by the addition of saturated NH4Cl and warmed to ambient temperature. The reaction mixture was partitioned between saturated NH4Cl (100 mL) and EtOAc (100 mL). The aqueous phase was further extracted with EtOAc (2×50 mL), and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 75:25, to give the title compound. MS: m/z=231 (M+1). Stirring was continued for 1.5 h at −78° C. the reaction was quenched by the addition of saturated NH4Cl The reaction mixture was partitioned between saturated NH4Cl (100 mL) and EtOAc (100 mL) The aqueous phase was further extracted with EtOAc (2×50 mL) the combined organic layers were dried over Na2SO4 filtered concentrated under reduced pressure The crude product was purified by silica gel chromatography eluting with a gradient of hexane

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

Procedure: A 40 mL reaction vial which contains a stirring bar is charged with 3-n-propoxypicolinic acid (397 mg, 2.19 mmol) and dry DCM (6 mL). Stirring is initiated. After 2 min, the HTBU (831 mg, 2.195 mmol) is added. After 5 min, the 2-amino)-indane-2-carboxylic acid ethyl ester (450 mg, 2.19 mmol is added followed by DIPEA (0.96 mL, 5.48 mmol). The reaction is allowed to stir at ambient temperature. After 20 days, analysis by tlc of the reaction mixture (silica, 5% iPrOH/DCM) indicates complete consumption of the starting amine. The contents of the reaction flask are transferred to a separatory funnel and diluted with EtOAc (50 mL). This is washed consecutively with dilute aqueous HCl (3%, 25 mL), saturated aqueous NaHCO3 (25 mL) and brine (25 mL), and dried over MgSO4, filtered and evaporated in vacuo to give 1.23 g of light orange solid. This material is dissolved in 10 mL of DCM. This material is purified utilizing an ISCO Companion with a 40 g cartridge of silica. The gradient is 10% EtOAc in heptanes over 3 column volumes followed by a linear gradient to 60% EtOAc in heptanes over 10 column volumes. 17 mL fractions eluent are collected. Fractions 57 through 67 are combined and evaporated in vacuo by pumping to constant weight to give white solid (0.8 g, 99%). A 40 mL reaction vial which the HTBU (831 mg, 2.195 mmol) is added After 5 min to stir at ambient temperature After 20 days consumption of the starting amine The contents of the reaction flask are transferred to a separatory funnel diluted with EtOAc (50 mL) This is washed consecutively with dilute aqueous HCl (3%, 25 mL), saturated aqueous NaHCO3 (25 mL) and brine (25 mL) dried over MgSO4 filtered evaporated in vacuo to give 1.23 g of light orange solid This material is purified 17 mL fractions eluent are collected evaporated in vacuo

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

Procedure: A 40 mL reaction vial which contains a stirring bar is charged with 3-n-propoxypicolinic acid (397 mg, 2.19 mmol) and dry DCM (6 mL). Stirring is initiated. After 2 min, the HTBU (831 mg, 2.195 mmol) is added. After 5 min, the 2-amino)-indane-2-carboxylic acid ethyl ester (450 mg, 2.19 mmol is added followed by DIPEA (0.96 mL, 5.48 mmol). The reaction is allowed to stir at ambient temperature. After 20 days, analysis by tlc of the reaction mixture (silica, 5% iPrOH/DCM) indicates complete consumption of the starting amine. The contents of the reaction flask are transferred to a separatory funnel and diluted with EtOAc (50 mL). This is washed consecutively with dilute aqueous HCl (3%, 25 mL), saturated aqueous NaHCO3 (25 mL) and brine (25 mL), and dried over MgSO4, filtered and evaporated in vacuo to give 1.23 g of light orange solid. This material is dissolved in 10 mL of DCM. This material is purified utilizing an ISCO Companion with a 40 g cartridge of silica. The gradient is 10% EtOAc in heptanes over 3 column volumes followed by a linear gradient to 60% EtOAc in heptanes over 10 column volumes. 17 mL fractions eluent are collected. Fractions 57 through 67 are combined and evaporated in vacuo by pumping to constant weight to give white solid (0.8 g, 99%). A 40 mL reaction vial which the HTBU (831 mg, 2.195 mmol) is added After 5 min to stir at ambient temperature After 20 days consumption of the starting amine The contents of the reaction flask are transferred to a separatory funnel diluted with EtOAc (50 mL) This is washed consecutively with dilute aqueous HCl (3%, 25 mL), saturated aqueous NaHCO3 (25 mL) and brine (25 mL) dried over MgSO4 filtered evaporated in vacuo to give 1.23 g of light orange solid This material is purified 17 mL fractions eluent are collected evaporated in vacuo

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

Procedure: 11.7 g of 2,2-indandicarboxylic acid was heated at 200° C. for 30 minutes. After liberation of bubbles ceased, the reaction product was cooled and dissolved in 150 ml of ethanol. 4 ml of concentrated sulfuric acid was added to the solution and the mixture was heated under reflux for 4 hours. The reaction mixture was concentrated in vacuo and the residue was neutralized by addition of sodium carbonate. The mixture was extracted with chloroform. The extract was washed with water and dried and then concentrated in vacuo to give 9.4 g of ethyl 2-indancarboxylate as an oil. the reaction product was cooled the mixture was heated under reflux for 4 hours The reaction mixture was concentrated in vacuo the residue was neutralized by addition of sodium carbonate The mixture was extracted with chloroform The extract was washed with water dried concentrated in vacuo

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

Procedure: 11.7 g of 2,2-indandicarboxylic acid was heated at 200° C. for 30 minutes. After liberation of bubbles ceased, the reaction product was cooled and dissolved in 150 ml of ethanol. 4 ml of concentrated sulfuric acid was added to the solution and the mixture was heated under reflux for 4 hours. The reaction mixture was concentrated in vacuo and the residue was neutralized by addition of sodium carbonate. The mixture was extracted with chloroform. The extract was washed with water and dried and then concentrated in vacuo to give 9.4 g of ethyl 2-indancarboxylate as an oil. the reaction product was cooled the mixture was heated under reflux for 4 hours The reaction mixture was concentrated in vacuo the residue was neutralized by addition of sodium carbonate The mixture was extracted with chloroform The extract was washed with water dried concentrated in vacuo

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

Procedure: 11.7 g of 2,2-indandicarboxylic acid was heated at 200° C. for 30 minutes. After liberation of bubbles ceased, the reaction product was cooled and dissolved in 150 ml of ethanol. 4 ml of concentrated sulfuric acid was added to the solution and the mixture was heated under reflux for 4 hours. The reaction mixture was concentrated in vacuo and the residue was neutralized by addition of sodium carbonate. The mixture was extracted with chloroform. The extract was washed with water and dried and then concentrated in vacuo to give 9.4 g of ethyl 2-indancarboxylate as an oil. the reaction product was cooled the mixture was heated under reflux for 4 hours The reaction mixture was concentrated in vacuo the residue was neutralized by addition of sodium carbonate The mixture was extracted with chloroform The extract was washed with water dried concentrated in vacuo