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Trifluoromethylation of p-Anisaldehyde; 2,2,2-Trifluoro-1-(4-methoxyphenyl)ethanol

SyntheticPage 550
DOI: 10.1039/SP550
Submitted Mar 29, 2012, published Apr 06, 2012
Christopher Kelly (christopher.b.kelly@uconn.edu)
A contribution from Leadbeater Group


			Reaction Scheme: <IMG src="/images/empty.gif">Trifluoromethylation of <SPAN id=csm1378730185970 class=csm-chemical-name title=p-Anisaldehyde grpid="1">p-Anisaldehyde</SPAN><IMG src="/images/empty.gif">

Chemicals Used

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)

Procedure

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 CFcarbinol 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  

Author's Comments

1. On small scales such as in this procedure, cooling for an extended period is not imperative to the reaction. However, on larger scales (>50 mmol), this time must be observed to sufficiently cool the solution. 
2. (a) CAUTION: Reaction is very exothermic, add TBAF slowly (b) Often a drastic change in color will be observed upon warm. colors range from red to a pale yellow to brown. 
3. See Note 1
4. It is recommended that this cleavage step be monitored by some form of spectroscopy (e.g. GC/MS or NMR). Some of the silyl ethers were very slow to cleave and required another addition of TBAF and H2O.
5. This procedure has been recently used for the undergraduate Advanced Organic Laboratory course at the University of Connecticut with great success. In the case of our students, vacuum distillation was not performed as most carbinols come out pure by NMR following workup.

 

Data

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%).


Lead Reference

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. 201113, 1646.

Other References

Krishnamurti, R.; Bellew, D. R.; Prakash, G. K. S.  J.  Org. Chem. 1991, 56, 984.

Supplementary Information

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.
1H NMR (p-methoxy oh hnmr.pdf)
13C NMR (p ome oh c13nmr.pdf)
19F NMR (p-methoxy oh f19.pdf)

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Keywords: addition, alcohols, aldehydes, C-C bond formation, ketones, nucleophilic, organofluorine, Ruppert-Prakash reagent, trifluoromethylation

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