5-BROMO-2-ISOPROPOXY-BENZONITRILE

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 solution of 5-bromo-2-hydroxybenzonitrile (25 g) in acetonitrile (150 mL) was added 2-iodopropane (15.14 mL) and potassium carbonate (34.9 g). The reaction mixture was stirred at room temperature for two days. The solvent was removed in vacuo, the residue was dissolved in ethyl acetate (150 mL), washed with water (2*30 mL), the organic phase was dried over sodium sulphate and concentrated to afford 5-bromo-2-[(1-methylethyl)oxy]benzonitrile (D38) (29.8 g) as a white solid without further purification. δH (CDCl3, 400 MHz): 1.39 (6H, d), 4.61 (1H, m), 6.85 (1H, d), 7.58 (1H, dd), 7.64 (1H, d). MS (ES): C10H10BrNO requires 239. found 240.0 (M+H+). The solvent was removed in vacuo the residue was dissolved in ethyl acetate (150 mL) washed with water (2*30 mL) the organic phase was dried over sodium sulphate concentrated

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

Procedure: A microwave vial was charged with 5-bromo-2-isopropoxybenzonitrile (200 mg, 0.83 mmol), thiophen-2-ylboronic acid (106.5 mg, 0.83 mmol), potassium carbonate (345.3 mg, 2.49 mmol) and 3:1 mixture of dimethylethylene glycol/H2O (2 mL). The reaction mixture was degassed by bubbling N2 gas through the stirred solution for 10 min. Pd(PPh3)4 (20.4 mg, 0.02 mmol) was added and the solution degassed for additional 2 min. The vial was subjected to microwave irradiation at 100° C. for 30 min. The solvent was removed and the residue dissolved in EA (10 mL), washed with brine, and dried over MgSO4. The product was purified chromatography (EA/hexanes) to afford 165 mg (82%) of 2-isopropoxy-5-(thiophen-2-yl)benzonitrile TRIO INT-1 as colorless oil. LCMS-ESI (m/z) calculated for C14H13NOS: 243.1; found 266.0 [M+Na]+, tR=3.90 min. 1H NMR (400 MHz, CDCl3) δ 7.74 (d, J=2.3 Hz, 1H), 7.69 (dd, J=8.8, 2.4 Hz, 1H), 7.28-7.23 (m, 1H), 7.19 (dd, J=3.6, 1.1 Hz, 1H), 7.05 (dd, J=5.1, 3.6 Hz, 1H), 6.95 (d, J=8.8 Hz, 1H), 4.65 (dt, J=12.2, 6.1 Hz, 1H), 1.43-1.37 (m, 6H). The reaction mixture was degassed by bubbling N2 gas through the stirred solution for 10 min the solution degassed for additional 2 min irradiation at 100° C. for 30 min The solvent was removed the residue dissolved in EA (10 mL) washed with brine dried over MgSO4 The product was purified chromatography (EA/hexanes)

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

Procedure: A solution of 5-bromo-2-isopropoxybenzonitrile (1.0 g, 4.16 mmol) in tetrahydrofuran was treated with copper (I) iodide (0.158 g, 0.83 mmol) and then purged with Argon for 5 minutes. Trimethyl silyl acetylene (2.85 g, 29.16 mmol) was then added followed by dichlorobis-(triphenylphosphine)palladium(II) (0.291 g, 0.41 mmol). The resultant mixture was heated at 80° C. overnight in a sealed tube. The mixture was evaporated and purified by column chromatography to give 2-isopropoxy-5-((trimethylsilyl)ethynyl)benzonitrile which was taken to the next step. 2-isopropoxy-5-((trimethylsilyl)ethynyl)benzonitrile (1.0 g, 3.8 mmol) in methanol (20 mL) was treated with potassium carbonate (1.07 g, 7.7 mmol) at room temperature overnight. The reaction was filtered and the filtrate was evaporated to give the crude product. The crude product was purified on a column (MPLC) using hexane:ethyl acetate and afforded Intermediate 1. purged with Argon for 5 minutes The mixture was evaporated purified by column chromatography