Trifluoromethylation of p-Anisaldehyde; 2,2,2-Trifluoro-1-(4-methoxyphenyl)ethanol
Submitted Mar 29, 2012, published Apr 06, 2012
p-Anisaldehyde (98%, Sigma-Aldrich)
Trifluoromethyltrimethylsilane (98%, Synquest Labs)
Tetrabutylammonium Fluoride ( 1M in THF, 98%, Synquest Labs)
Tetrahydrofuran (inhibitor-free, CHROMASOLV® Plus, for HPLC, ≥99.9% Sigma-Aldrich)
To a 100 mL round bottom flask equipped with a stirbar was added the aldehyde (2.723 g, 0.020 mol, 1 equiv.), THF (24 mL, 0.85 M in the aldehyde), and trifluoromethyltrimethylsilane (3.12 g, 0.022 mol, 1.3 equiv.). The flask was sealed with a rubber septum and placed under a N2 atmosphere via an inlet needle. The reaction mixture was cooled to 0 oC in an ice-water bath and stirred via a magnetic stir plate. After approximately 10 minutes1, TBAF ( 0.2 mL, 0.0002 mol, 0.01 equiv.) was added dropwise via a syringe.2a
After 10 minutes, the ice-bath was removed and the solution was allowed to stir for approximately 6 hour at room temperature.2b To cleave the silyl ether formed by the reaction, the reaction mixture was cooled to 0 oC in an ice bath.3 After 10 minutes, H2O (2 mL, 0.110 mol, 5.5 equiv.) was added via a syringe. TBAF (1 M in THF, 2 mL, 0.002 mol, 0.1 equiv.) was then added slowly. After 10 minutes the ice bath was removed and the reaction mixture was allowed to stir at room temperature. When the cleavage was judged complete4 , the contents of the flask were transferred to a separatory funnel. Deionized water (≈100 mL) and Et2O (≈150 mL) were added and the layers were partitioned. The aqueous layer was back-extracted (3X, ≈50 mL each) with Et2O. The combine ether layers were washed once with brine (≈100 mL) dried with Na2SO4 and the solvent was removed in vacuo via rotary evaporation to afford crude CF3 carbinol which was further purified by vacuum distillation (b.p. 87-90 oC @ 1 mmHg) giving the pure 2,2,2-trifluoro-1-(4-methoxyphenyl)ethanol (3.284 g, 80%).5
1H NMR (CDCl3, 400 MHz) d ppm 3.24 - 3.37 (m, 1 H) 3.80 (s, 3 H) 4.91 (q, J=6.85 Hz, 1 H) 6.92 (d, J=8.80 Hz, 2 H) 7.37 (d, J=8.80 Hz, 2 H) 13C NMR (CDCl3, 101 MHz) d ppm 55.51 (CH3) 72.60 (q, JC-C-F = 31.50 Hz, CH) 114.28 (CH) 120.44 – 128.84 (q, JC-F = 281.70 Hz, CF3) 126.54 (d, JC-C-C-F = 1.47 Hz, CH) 129.07 (C) 160.60 (C) 19F NMR (CDCl3, 377 MHz) d ppm -78.61 (d, J = 6.81 Hz) GC-MS (EI) 206 ([M]+, 37%), 137 (100%), 109 (27%), 94 (28%), 77 (25%), 69 (4%).
Kelly, C. B.; Colthart, A. M.; Constant, B.D.; Corning, S.R.; Dubois, L. N. E.; Genovese, J. T.; Radziewicz, J. L.; Sletten, E. M.; Whitaker, K. R.; Tilley, J. J. Org. Lett. 2011, 13, 1646.
Krishnamurti, R.; Bellew, D. R.; Prakash, G. K. S. J. Org. Chem. 1991, 56, 984.
1H NMR (p-methoxy oh hnmr.pdf)
13C NMR (p ome oh c13nmr.pdf)
19F NMR (p-methoxy oh f19.pdf)
e.g. Actual NMR spectra (as images or jdx files for interactive spectra), photographs of apparatus, TLC’s or crystals or videos. Please contact the ChemSpider team (ChemSpider-at-rsc.org) for help with this.
Keywords: addition, alcohols, aldehydes, C-C bond formation, ketones, nucleophilic, organofluorine, Ruppert-Prakash reagent, trifluoromethylation