Compound 4r

View in PubChem | HPLC | 1H NMR | 13C NMR | 19F NMR | MDL Molfile | ChemDraw

Synthetic procedure: See article for the definitive version of this procedure and for full experimental details.

In a N₂ filled glove box, aminophenol 1d (6.7 mg, 0.017 mmol), Zn(OMe)₂(8.5 mg, 0.067 mmol) and toluene (1.0 mL) were added to an oven-dried two-dram vial equipped with a stir bar. Methanol (33 µL, 0.82 mmol) was subsequently added to the vial to make a stock solution. A separate oven-dried two-dram vial equipped with a stir bar was charged with 0.3 mL of the stock solution containing 1d (2.0 mg, 0.005 mmol, 2.5 mol %), Zn(OMe)₂(2.5 mg, 0.02 mmol, 10 mol %) and methanol (10 µL, 0.26 mmol, 1.3 equiv.). Pentane (0.45 mL), allylboronic acid pinacol ester (42 µL, 0.22 mmol, 1.1 equiv.) and 3’,5’-dichloro-2,2,2-trifluoroacetophenone 3r (32 µL, 0.20 mmol, 1.0 equiv.) were subsequently added by syringe. This vial was sealed with a cap and electrical tape and removed from the glove box. The reaction mixture was allowed to stir at 22 ºC for 6 h after which the cap was removed and α,α,α-trifluorotoluene (24.4 µL, 0.199 mmol) was added as an internal standard. Following ¹⁹F NMR analysis of the unpurified mixture, it was passed through a short plug of silica gel (eluted with Et₂O) and concentrated in vacuo. The resulting clear colorless oil was purified by silica gel chromatography (10 mm diameter column slurry packed with 2.5 g of silica gel in hexanes and eluted with 40:1 hexanes:Et₂O) to afford desired product 4r (55.3 mg, 0.194 mmol, 97% yield) as colorless oil. IR (neat): 3379 (w, br), 2981 (w), 1590 (m), 1568 (m), 1439 (m), 1373 (m), 1271 (m), 1231 (m), 1163 (s), 1142 (s), 1024 (w), 1009 (m), 924 (m), 860 (m), 800 (s), 729 (m), 679 (m) 578 (w) cm^–1; ¹H NMR (600 MHz, CDCl₃): δ 7.50–7.43 (2H, m), 7.41–7.35 (1H, m), 5.55 (1H, ddt, J = 17.4, 10.3, 7.5 Hz), 5.35–5.17 (2H, m), 2.90–2.82 (2H, m), 2.64 (1H, s); ¹³C NMR (100 MHz, CDCl₃): δ140.6, 135.3, 129.6, 129.0, 125.5, 125.0 (q, J = 284.3 Hz), 122.8, 75.5 (q, J = 28.8 Hz), 40.4; ¹⁹F NMR (376 MHz, CDCl₃): δ 74.08 (3F, s); HRMS Calcd for C₁₁H₈Cl₂F₃ [M+H–H₂O]⁺: 266.9955; Found: 266.9949. [α]^21.7_D = –64.75 (c = 1.10, CHCl₃) for a 95:5 er sample. The enantiomeric purity of this compound was determined by HPLC analysis in comparison with authentic racemic material (Chiralpak AS-H, 98:2 hexanes:i-PrOH, 0.5 mL/min, 220 nm): t_R: 12 min (major) and 12.5 min (minor).