ethyl 2-(2-iodophenoxy)acetate

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:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of ethyl 2-(2-iodophenoxy)acetate (900 mg, 2.94 mmol) in EtOH (3 mL) was added 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (677 mg, 3.24 mmol). The reaction mixture was heated under microwave conditions at 80° C. for 3 h, cooled and concentrated. The crude product was used in the next step without further purification. (1.3 g, yield 95%) MS (ESI+) e/z: 467.1 [M+1]+. 1H NMR (MeOD, 400 MHz), δ ppm: 7.80 (dd, J=1.0, 7.8 Hz, 1H), 7.41-7.30 (m, 1H), 7.15-7.05 (m, 3H), 7.05-6.99 (m, 1H), 6.96 (d, J=8.0 Hz, 1H), 6.87-6.76 (m, 1H), 4.66-4.53 (m, 2H), 4.06 (quin, J=5.9 Hz, 1H), 3.77-3.63 (m, 2H), 3.58 (dd, J=4.5, 13.6 Hz, 1H), 3.38 (dd, J=6.4, 13.7 Hz, 1H), 2.98-2.86 (m, 2H), 2.86-2.76 (m, 2H), 2.66-2.57 (m, 2H). cooled concentrated The crude product was used in the next step without further purification

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of ethyl 2-(2-iodophenoxy)acetate (900 mg, 2.94 mmol) in EtOH (3 mL) was added 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (677 mg, 3.24 mmol). The reaction mixture was heated under microwave conditions at 80° C. for 3 h, cooled and concentrated. The crude product was used in the next step without further purification. (1.3 g, yield 95%) MS (ESI+) e/z: 467.1 [M+1]+. 1H NMR (MeOD, 400 MHz), δ ppm: 7.80 (dd, J=1.0, 7.8 Hz, 1H), 7.41-7.30 (m, 1H), 7.15-7.05 (m, 3H), 7.05-6.99 (m, 1H), 6.96 (d, J=8.0 Hz, 1H), 6.87-6.76 (m, 1H), 4.66-4.53 (m, 2H), 4.06 (quin, J=5.9 Hz, 1H), 3.77-3.63 (m, 2H), 3.58 (dd, J=4.5, 13.6 Hz, 1H), 3.38 (dd, J=6.4, 13.7 Hz, 1H), 2.98-2.86 (m, 2H), 2.86-2.76 (m, 2H), 2.66-2.57 (m, 2H). cooled concentrated The crude product was used in the next step without further purification

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

Procedure: To a solution of 2-iodophenol (1 g, 4.55 mmol) in CH3CN (20 mL) was added K2CO3 (0.93 g, 6.83 mmol) and ethyl 2-bromoacetate (0.835 g, 5.0 mmol). The reaction mixture was stirred at reflux for 2 h, cooled to room temperature, extracted with EtOAc, washed with brine, dried over sodium sulfate and concentrated. The crude product was used in the next step without further purification. (1.1 g, yield 79%) MS (ESI+) e/z: 307.1 [M+1]+. at reflux for 2 h extracted with EtOAc washed with brine dried over sodium sulfate concentrated The crude product was used in the next step without further purification

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

Procedure: A three neck reaction flask was successively charged with 12.65 g (41.3 mmol) of the above prepared (2-iodo-phenoxy)-acetic acid ethyl ester, 128 ml of acetonitrile, 5.793 g (2 eq.) of 3-methoxy-1-propyne, 17.28 ml (3 eq.) of NEt3, 1.45 g (0.05 eq.) of (PPh3)2PdCl2, and 0.394 g (0.05 eq.) of CuI. After stirring for 4 h the bulk of the solvent was removed i. V. and the residue distributed between HCl and EtOAc. Washing of the organic layer with cold water and brine, drying over magnesium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, hexane/EtOAc=8/2), yielded 9.54 g of the title compound as light brown oil, MS: 248.2 (M)+. A three neck reaction flask was successively charged with 12.65 g (41.3 mmol) of the was removed i Washing of the organic layer with cold water and brine drying over magnesium sulfate, and evaporation of the solvents

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

Procedure: 9.10 g (41.4 mmol) of o-iodophenol was dissolved in 102 ml of acetone and treated subsequently at 0° C. with 14.8 g (1.1 eq.) of cesium carbonate and 4.57 ml (1.0 eq.) of ethyl bromoacetate. After vigorous stirring for 1 h at ambient temperature and filtration, the bulk of solvent was evaporated and the residue redissolved in EtOAc. Washing with water, drying over magnesium sulfate, and evaporation of the solvents finally produced 12.66 g of pure title compound as colorless oil, MS: 306.0 (M)+. filtration the bulk of solvent was evaporated the residue redissolved in EtOAc Washing with water drying over magnesium sulfate, and evaporation of the solvents finally produced 12.66 g of pure title compound as colorless oil, MS

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

Procedure: A three neck reaction flask was successively charged with 12.65 g (41.3 mmol) of the above prepared (2-iodo-phenoxy)-acetic acid ethyl ester, 128 ml of acetonitrile, 5.793 g (2 eq.) of 3-methoxy-1-propyne, 17.28 ml (3 eq.) of NEt3, 1.45 g (0.05 eq.) of (PPh3)2PdCl2, and 0.394 g (0.05 eq.) of CuI. After stirring for 4 h the bulk of the solvent was removed i. V. and the residue distributed between HCl and AcOEt. Washing of the organic layer with cold water and brine, drying over magnesium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, hexane/AcOEt=8/2), yielded 9.54 g of the title compound as light brown oil. A three neck reaction flask was successively charged with 12.65 g (41.3 mmol) of the was removed i Washing of the organic layer with cold water and brine drying over magnesium sulfate, and evaporation of the solvents

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

Procedure: 9.10 g (41.4 mmol) of o-iodophenol was dissolved in 102 ml of acetone and treated subsequently at 0° C. with 14.8 g (1.1 eq.) of cesium carbonate and 4.57 ml (1.0 eq.) of ethyl bromoacetate. After vigorous stirring for 1 h at ambient temperature and filtration, the bulk of solvent was evaporated and the residue redissolved in AcOEt. Washing with water, drying over magnesium sulfate, and evaporation of the solvents finally produced 12.66 g of pure title compound as colorless oil. filtration the bulk of solvent was evaporated the residue redissolved in AcOEt Washing with water drying over magnesium sulfate, and evaporation of the solvents finally produced 12.66 g of pure title compound as colorless oil