3-bromo-4-hydroxybenzonitrile

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:0.00; pressure:0.00; stir:

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

Procedure: Bromocyclobutane (2.7 g, 20.2 mmol), 3-bromo-4-hydroxybenzonitrile (2.0 g, 10.1 mmol), and K2CO3 (2.8 g, 20.2 mmol) were mixed in 5 mL of dimethylformamide and reacted at 60° C. for 72 hours. The mixture was diluted with ethyl acetate, washed with water, brine, dried with MgSO4, filtered, and the solvent removed under reduced pressure. The residue was chromatographed (SiO2) using a gradient from hexane to 30% ethyl acetate in hexane over 500 mL to afford the title compound. (2.2 g, 8.7 mmol, 86% yield). 1H NMR (300 MHz, CDCl3) δ ppm 1.69-1.82 (m, 1H), 1.87-2.00 (m, 1H), 2.21-2.35 (m, 2H), 2.45-2.57 (m, 2H), 4.69-4.79 (m, 1H), 6.76 (d, J=8.48 Hz, 1H), 7.53 (dd, J=8.48, 2.03 Hz, 1H), 7.82 (d, J=2.03 Hz, 1H). MS (DCI/NH3) m/z 251.9 (M+H)+. reacted at 60° C. for 72 hours washed with water, brine dried with MgSO4 filtered the solvent removed under reduced pressure The residue was chromatographed (SiO2)

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-Bromo-4-hydroxybenzonitrile (2.0 g, 10.1 mmol), bromocyclobutane (2.7 g, 20.2 mmol), and K2CO3 (2.8 g, 20.2 mmol) were mixed in 5 mL of DMF and heated at 60° C. for 72 hours. The reaction was diluted with EtOAc washed with water, brine dried with MgSO4 and the solvent was removed. The product was purified by flash chromatography using a gradient from 0 to 30% EtOAc in hexane to provide the title compound. 1H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.69-1.82 (m, 1H) 1.87-2.00 (m, 1H) 2.21-2.35 (m, 2H) 2.45-2.57 (m, 2H) 4.69-4.79 (m, 1H) 6.76 (d, J=8.48 Hz, 1H) 7.53 (dd, J=8.48, 2.03 Hz, 1H) 7.82 (d, J=2.03 Hz, 1H). MS (DCI/NH3) m/z 251.9 (M+H)+. washed with water, brine dried with MgSO4 the solvent was removed The product was purified by flash chromatography

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-Bromo-4-hydroxybenzonitrile (2.0 g, 10.1 mmol), bromocyclobutane (2.7 g, 20.2 mmol), and K2CO3 (2.8 g, 20.2 mmol) were mixed in 5 mL of DMF and heated at 60° C. for 72 hours. The reaction was diluted with EtOAc washed with water, brine dried with MgSO4 and the solvent was removed. The product was purified by flash chromatography using a gradient from 0 to 30% EtOAc in hexane to provide the title compound. 1H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.69-1.82 (m, 1H) 1.87-2.00 (m, 1H) 2.21-2.35 (m, 2H) 2.45-2.57 (m, 2H) 4.69-4.79 (m, 1H) 6.76 (d, J=8.48 Hz, 1H) 7.53 (dd, J=8.48, 2.03 Hz, 1H) 7.82 (d, J=2.03 Hz, 1H). MS (DCI/NH3) m/z 251.9 (M+H)+. washed with water, brine dried with MgSO4 the solvent was removed The product was purified by flash chromatography

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-Bromo-4-hydroxy benzonitrile (10.0 g, 50.5 mmol) was dissolved in acetone and successively treated with 1-bromo-3-propanol (19.0 g, 138 mmol) and K2CO3 (20.9 g, 151 mmol) at ambient temperature. The resulting suspension was warmed to 50° C. and maintained 3 d. After cooling to ambient temperature, the solids were removed by filtration, exhaustively was with acetone and the filtrate concentrated. Purification by chromatography on SiO2 (A: hexanes; B: EtOAc; 0-100% B over 35.4 min; 200 mL/min; 330 g column) afforded a solid. Further purification by recrystallization from hot MTBE (131 mL) and pentane (130 mL), with cooling at −20° C. (12 h) to induce precipitation, afforded a solid (7.2 g, 58%). 1H NMR (300 MHz, CDCl3) δ 7.78 (s, 1H), 7.56 (d, J=9 Hz, 1H), 6.94 (d, J=6 Hz, 1H), 4.23 (t, J=6 Hz, 2H), 3.88 (t, J=6 Hz, 2H), 2.08 (m, J=6 Hz, 2H). maintained 3 d After cooling to ambient temperature the solids were removed by filtration the filtrate concentrated Purification by chromatography on SiO2 (A: hexanes 330 g column) afforded a solid Further purification by recrystallization from hot MTBE (131 mL) and pentane (130 mL) with cooling at −20° C. (12 h) precipitation

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-Bromo-4-hydroxy benzonitrile (10.0 g, 50.5 mmol) was dissolved in acetone and successively treated with 1-bromo-3-propanol (19.0 g, 138 mmol) and K2CO3 (20.9 g, 151 mmol) at ambient temperature. The resulting suspension was warmed to 50° C. and maintained 3 d. After cooling to ambient temperature, the solids were removed by filtration, exhaustively was with acetone and the filtrate concentrated. Purification by chromatography on SiO2 (A: hexanes; B: EtOAc; 0-100% B over 35.4 min; 200 mL/min; 330 g column) afforded a solid. Further purification by recrystallization from hot MTBE (131 mL) and pentane (130 mL), with cooling at −20° C. (12 h) to induce precipitation, afforded a solid (7.2 g, 58%). 1H NMR (300 MHz, CDCl3) δ 7.78 (s, 1H), 7.56 (d, J=9 Hz, 1H), 6.94 (d, J=6 Hz, 1H), 4.23 (t, J=6 Hz, 2H), 3.88 (t, J=6 Hz, 2H), 2.08 (m, J=6 Hz, 2H). maintained 3 d After cooling to ambient temperature the solids were removed by filtration the filtrate concentrated Purification by chromatography on SiO2 (A: hexanes 330 g column) afforded a solid Further purification by recrystallization from hot MTBE (131 mL) and pentane (130 mL) with cooling at −20° C. (12 h) precipitation