Ethyl 2-(5-amino-2-bromo-4-fluorophenyl)acetate

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

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

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of Example C5 (3 g, 10.9 mmol) in DMF (50 mL) was treated with ZnCN2 (1.7 g, 16.4 mmol) and Pd(PPh3)4 (1.26 g, 1.09 mmol), sparged with N2 and heated at 100° C. for 12 h. The mixture was cooled to RT, treated with water and extracted with EtOAc (3×). The combined organics were washed with brine (3×), dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (EtOAc/pet ether) to afford ethyl 2-(5-amino-2-cyano-4-fluorophenyl)acetate (600 mg, 25% yield). 1H NMR (400 MHz, CDCl3): δ 7.19 (d, J=2.4 Hz, 1H), 6.67 (d, J=8.4 Hz, 1H), 4.13-4.11 (q, J=6.8 Hz, 2H), 3.66 (s, 2H), 1.23-1.19 (t, J=6.8 Hz, 3H). sparged with N2 The mixture was cooled to RT treated with water extracted with EtOAc (3×) The combined organics were washed with brine (3×) dried over Na2SO4 concentrated to dryness purified via silica gel chromatography (EtOAc/pet ether)

Conditions: temp:55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of ethyl 2-(2-bromo-4-fluoro-5-nitrophenyl)acetate (2.127 g, 6.95 mmol) in EtOH (70 mL) was treated with iron powder (3.88 g, 69.5 mmol) and satd ammonium chloride (14.48 mL, 69.5 mmol) and heated to 55° C. for 1 h. The mixture was cooled to RT, filtered through a pad of diatomaceous earth, rinsed well with EtOH and the organics concentrated under reduced pressure. The resulting aqueous residue was treated with satd. NaHCO3, extracted with EtOAc (2×) and the combined organics were washed with water, dried (MgSO4), and concentrated to afford ethyl 2-(5-amino-2-bromo-4-fluorophenyl)acetate (1.792 g, 93% yield) as an amber oil. 1H NMR (400 MHz, DMSO-d6): δ 7.25 (d, 1H), 6.76 (d, 1H), 5.35 (s, 2H), 4.08 (q, 2H), 3.61 (s, 2H), 1.18 (t, 3H); MS (ESI) m/z: 278.0 [M+H]+. The mixture was cooled to RT filtered through a pad of diatomaceous earth rinsed well with EtOH the organics concentrated under reduced pressure The resulting aqueous residue was treated with satd NaHCO3, extracted with EtOAc (2×) the combined organics were washed with water dried (MgSO4) concentrated

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of Example C5 (3 g, 10.9 mmol) in DMF (50 mL) was treated with ZnCN2 (1.7 g, 16.4 mmol) and Pd(PPh3)4 (1.26 g, 1.09 mmol), sparged with N2 and heated at 100° C. for 12 h. The mixture was cooled to RT, treated with water and extracted with EtOAc (3×). The combined organics were washed with brine (3×), dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (EtOAc/pet ether) to afford ethyl 2-(5-amino-2-cyano-4-fluorophenyl)acetate (600 mg, 25% yield). 1H NMR (400 MHz, CDCl3): δ 7.19 (d, J=2.4 Hz, 1H), 6.67 (d, J=8.4 Hz, 1H), 4.13-4.11 (q, J=6.8 Hz, 2H), 3.66 (s, 2H), 1.23-1.19 (t, J=6.8 Hz, 3H). sparged with N2 The mixture was cooled to RT treated with water extracted with EtOAc (3×) The combined organics were washed with brine (3×) dried over Na2SO4 concentrated to dryness purified via silica gel chromatography (EtOAc/pet ether)

Conditions: temp:55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of ethyl 2-(2-bromo-4-fluoro-5-nitrophenyl)acetate (2.127 g, 6.95 mmol) in EtOH (70 mL) was treated with iron powder (3.88 g, 69.5 mmol) and satd ammonium chloride (14.48 mL, 69.5 mmol) and heated to 55° C. for 1 h. The mixture was cooled to RT, filtered through a pad of diatomaceous earth, rinsed well with EtOH and the organics concentrated under reduced pressure. The resulting aqueous residue was treated with satd. NaHCO3, extracted with EtOAc (2×) and the combined organics were washed with water, dried (MgSO4), and concentrated to afford ethyl 2-(5-amino-2-bromo-4-fluorophenyl)acetate (1.792 g, 93% yield) as an amber oil. 1H NMR (400 MHz, DMSO-d6): δ 7.25 (d, 1H), 6.76 (d, 1H), 5.35 (s, 2H), 4.08 (q, 2H), 3.61 (s, 2H), 1.18 (t, 3H); MS (ESI) m/z: 278.0 [M+H]+. The mixture was cooled to RT filtered through a pad of diatomaceous earth rinsed well with EtOH the organics concentrated under reduced pressure The resulting aqueous residue was treated with satd NaHCO3, extracted with EtOAc (2×) the combined organics were washed with water dried (MgSO4) concentrated

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