5,5-dimethylcyclopent-2-en-1-one

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

Procedure: A solution of 5,5-dimethylcyclopent-2-en-1-one (42.0 g, 343.15 mmol), 4-chloro-2-fluorophenylboronic acid (94.47 g, 514.72 mmol), sodium acetate (56.30 g, 686.30 mmol), acetic acid (1130 mL), Pd(OAc)2 (7.70 g, 34.31 mmol), and antimony trichloride (7.83 g, 34.31 mmol) are stirred at ambient temperature for 16 hours. The solvent is evaporated to low volume and the residual acetic acid is removed using toluene. MTBE (500 mL) is added and the resulting precipitate is filtered off and discarded. The MTBE solution is washed with water (500 mL), aq. NaHCO3 (2×300 mL), dried over MgSO4, filtered, and concentrated to dryness. The residue is purified by silica gel flash chromatography, eluting with hexane to hexane 10% MTBE to give the title compound (72 g, 87%). 1H NMR (300.16 MHz, CDCl3) δ 7.21-7.06 (m, 3H), 3.67-3.59 (m, 1H), 2.81-2.72 (m, 1H), 2.41-2.31 (m, 1H), 2.21 (ddd, J=12.6, 6.3, 2.2 Hz, 1H), 1.89 (t, J=12.3 Hz, 1H), 1.159 (s, 3H), 1.137 (s, 3H). The solvent is evaporated to low volume the residual acetic acid is removed MTBE (500 mL) is added the resulting precipitate is filtered off The MTBE solution is washed with water (500 mL), aq. NaHCO3 (2×300 mL) dried over MgSO4 filtered concentrated to dryness The residue is purified by silica gel flash chromatography eluting with hexane to hexane 10% MTBE

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

Procedure: Bis(1,5-cyclooctadienerhodium chloride) (1.09 g, 2.18 mmol), racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (3.05 g, 4.90 mmol) are added to tetrahydrofuran (72 mL) and the mixture is stirred under a nitrogen atmosphere for 30 minutes. This solution is added to a mixture of 4-cyanophenylboronic acid (80.04 g, 544.68 mmol), 5,5-dimethylcyclopent-2-en-1-one (24 g, 217.87 mmol), potassium carbonate (40.65 g, 294.13 mmol), tetrahydrofuran (144 mL), and isopropyl alcohol (16.7 mL) at 60° C. The mixture is stirred at 60° C. for 16 hours and then concentrated to dryness. The crude mixture is poured into water (500 mL) and is extracted with ethyl acetate (2×500 mL). The organic extracts are dried over MgSO4, filtered through silica gel, and concentrated to dryness. The residue is purified by silica gel flash chromatography, eluting with 6:1 hexane:ethyl acetate to give the title compound (41 g, 88%, 192.24 mmol). 1H NMR (300.13 MHz, CDCl3) δ 7.65-7.62 (m, 2H), 7.37 (d, J=8.1 Hz, 2H), 3.56-3.43 (m, 1H), 2.86-2.76 (m, 1H), 2.42-2.32 (m, 1H), 2.32-2.24 (m, 1H), 1.86 (t, J=12.4 Hz, 1H), 1.17 (s, 3H), 1.15 (s, 3H). The mixture is stirred at 60° C. for 16 hours concentrated to dryness The crude mixture is poured into water (500 mL) is extracted with ethyl acetate (2×500 mL) The organic extracts are dried over MgSO4 filtered through silica gel concentrated to dryness The residue is purified by silica gel flash chromatography eluting with 6:1 hexane