2-(bromomethyl)-4-chlorobut-1-ene

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Step AAJ (1): NaHMDS 2.0 M in THF (10.2 mL, 20.4 mmol) was added to a solution of 2-(4-(trifluoromethoxy)phenyl)acetic acid (2.00 g, 9.08 mmol) in THF (18.2 mL) at 0° C. The resulting mixture was stirred for 20 min at 0° C., then neat 2-(bromomethyl)-4-chlorobut-1-ene (1.83 g, 9.99 mmol, from Step AAI (3)) was added. The mixture was quenched at 0° C. after 10 min with water (5 mL) and concentrated in vacuo. The mixture was diluted with EtOAc and the organic layer was extracted with 1N HCl, then brine, dried over sodium sulfate, and concentrated in vacuo to afford after purification by silica gel column chromatography (60-100% EtOAc/chloroform), 6-chloro-4-methylene-2-(4-(trifluoromethoxy)phenyl)hexanoic acid (2.21 g, 6.85 mmol, 75% yield) as a pale-yellow oil. LC-MS (M−H)− 321.1. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.35-7.44 (2 H, m), 7.20 (2 H, d, J=8.5 Hz), 4.89-4.97 (2 H, m), 3.81-3.93 (1 H, m), 3.55-3.66 (2 H, m), 2.86 (1 H, dd, J=15.3, 8.9 Hz), 2.39-2.57 (3 H, m). The mixture was quenched at 0° C. after 10 min with water (5 mL) concentrated in vacuo The mixture was diluted with EtOAc the organic layer was extracted with 1N HCl brine, dried over sodium sulfate concentrated in vacuo to afford

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Step AAI (4): NaHMDS 2.0 M in THF (11.0 mL, 21.9 mmol) was added to a solution of 2-(4-fluorophenyl)acetic acid (1.50 g, 9.73 mmol) in THF (19.5 mL) at 0° C. The resulting mixture was stirred for 20 min at 0° C., then neat 2-(bromomethyl)-4-chlorobut-1-ene (1.96 g, 10.7 mmol) was added. After 10 min, the mixture was quenched with a water (5 mL) and concentrated in vacuo. The mixture was diluted with EtOAc and the organic layer was washed with 1N HCl, then brine, dried over sodium sulfate, and concentrated in vacuo to afford 5-(chloromethyl)-2-(4-fluorophenyl)hex-5-enoic acid. The titled product was used for subsequent chemistry without further purification. LC-MS (M−H)− 255.1. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.24-7.41 (2 H, m), 6.96-7.11 (2 H, m), 4.91 (2 H, d, J=3.1 Hz), 3.82 (1 H, dd, J=8.7, 6.9 Hz), 3.60 (2 H, t, J=7.2 Hz), 2.84 (1 H, dd, J=15.0, 8.9 Hz), 2.39-2.55 (3 H, m). After 10 min the mixture was quenched with a water (5 mL) concentrated in vacuo The mixture was diluted with EtOAc the organic layer was washed with 1N HCl brine, dried over sodium sulfate concentrated in vacuo