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Oxidation of 2,2,2-trifluoro-1-(4-methoxyphenyl)ethanol; 2,2,2-trifluoro-1-(4-methoxyphenyl)ethanone

SyntheticPage 581
DOI: 10.1039/SP581
Submitted Dec 21, 2012, published Dec 28, 2012
Christopher Kelly (christopher.b.kelly@uconn.edu)
A contribution from Leadbeater Group


			Reaction Scheme: <IMG src="/images/empty.gif">Oxidation of <SPAN id=csm1357126920391 class="csm-chemical-name csm-not-validated" title=2,2,2-trifluoro-1-(4-methoxyphenyl)ethanol grpid="1">2,2,2-trifluoro-1-(4-methoxyphenyl)ethanol</SPAN><IMG src="/images/empty.gif">

Chemicals Used

2,2,2-trifluoro-1-(4-methoxyphenyl)ethanol (Prepared in House, see SyntheticPage 550
4-acetamido-2,2,6,6-tetramethylpiperidine-1-oxoammonium tetrafluoroborate (Prepared In-House, See Comment 1) 
2,6 Lutidine (Synquest Laboratories (98.0%, Synquest Laboratories)
Dichloromethane (≥99.5%, ACS Reagent Grade, Sigma-Aldrich)
Diethyl Ether (≥99.0%, ACS reagent, anhydrous, contains BHT as inhibitor, Sigma-Aldrich)
Hexanes, Mixture of Isomers (≥99% ,anhydrous, Sigma-Aldrich)
Ethyl Acetate (99.8%, anhydrous, Sigma-Aldrich)
Silica Gel (Dynamic Adsorbants Inc. Flash Silica Gel, 60Å porosity, 32-63 µm). 

Procedure

To a one-neck 50 mL round bottom flask equipped with stir bar was added 4-acetamido-2,2,6,6-tetramethylpiperidine-1-oxoammonium tetrafluoroborate1 (3.01 g, 10 mmol, 2.5 equiv.), 2,2,2-trifluoro-1-(4-methoxyphenyl)ethanol2 (0.825 g, 4 mmol, 1 equiv.) in dichloromethane (10 mL, 0.4M in the CF3 carbinol) and stirred for about 2 minutes. After this time, 2,6-lutidine (0.964 g, 9 mmol, 2.25 equiv) was added to the flask.3 The flask was sealed with a rubber septum and stirred at room temperature.  When the reaction judged complete4 (≈ 4 h), the solvent was removed in vacuo by rotary evaporation to afford a thick red residue. Anhydrous diethyl ether (≈ 30 mL) was added to the flask and allowed to stir for 10 min. This causes immediate precipitation of the spent oxidant (4-acetamido-2,2,6,6-tetramethylpiperidine 1-oxyl). Note: It is imperative that the sides of the flask be scraped with a spatula to ensure all the oxyl precipitates out and can release the product into solution.

After stirring, the solution was filtered through a coarse-porosity fritted funnel to remove the spent oxidant. The filtrate was then adhered to silica gel by mixing it with 1.5 weight equivalents silica gel (relative to the theoretical yield, in this case 1.23 g) and removing the solvent in vacuo by rotary evaporation. A plug of silica was then assembled (A diagram of this apperatus is in the Data Files). This was done by adding 3-4 weight equivalents of silica (again relative to the theoretical yield) to a 60 mL coarse-porosity fritted glass funnel. An appropriately sized piece of filter paper relative to the size of the funnel was used to the top of the dry silica gel layer and this layer was pre-wet with hexanes.  The dry packed material  was gentle added  evenly atop the filter paper. Another piece of appropriately sized filter paper was added atop this layer.  The plug was eluted with a 95:5 by volume mixture of Hex:EtOAc (3-4 column volumes). The solvent was removed in vacuo by rotary evaporation in a room temperature water bath affording the pure trifluoromethylketone (0.737 g, 90%) as a clear yellow oil.

Author's Comments

1. While this oxoammonium salt is available commercially, is far more cost-effective to prepare in-house than  to purchase it. A procedure for its preperation from inexpensive commercially available 4-amino-2,2,6,6-tetramethylpiperidine can be found in the lead refence and a Chemspider Synthetic Page for its preperation is forthcoming.

2. See SyntheticPage 550 for the preparation of this carbinol

3.  These reactions are very colormetric in nature. Prior to addition of the pyridyl base, the reaction will be bright yellow from the oxoammonium salt. After the base is added the reaction will transition from yellow to orange to finally deep blood red. This red color typically indicates reaction completion but some form of spectroscopy should be used to formally identify reaction completion.

4. We have found that GC/MS is the best tool to analyze reaction progress 
 
Additional Note: These conditions are broadly applicable to most alcohols (CF3 or otherwise). However, if the CF3 alcohol without an adjecent sp2/sp center is to be oxidized, a stronger base must be used. A protocol using DBN is outlined in the lead reference. 

Data

1H NMR (CDCl3, 400 MHz) δ ppm 3.90 (s, 3 H) 6.99 (apparent doublet, J = 9.05 Hz, 2 H) 8.04 (apparent doublet, J = 8.07 Hz, 2 H)

13C NMR (CDCl3, 101 MHz) δ ppm 55.9 (CH3) 112.9 – 121.6 (q, JC-F = 294.2 Hz, CF3) 114.7 (CH) 123.1 (C) 133.0 (q, JC-C-C-C-F =2.2 Hz, CH ) 165.7 (C) 179.2 (q, JC-C-F = 34.5 Hz, C)

19F NMR (CDCl3, 377 MHz, Internal Reference Fluorobenzene(–115.3 ppm) ) δ ppm -71.06

GC-MS
(EI) 204 (21%), 135 (100%), 107 (12%), 92 (24%), 77 (26%), 69 (4%), 64 (10%), 63 (10%).

HRMS
(ESI+), calcd for C9H7F3O[M + H]+ 205.0476, found: 205.0475


Lead Reference

Kelly, C. B; Mercadante, M. A.; Hamlin, T. A.; Fletcher, M. H.; Leadbeater, N. E. J. Org. Chem., 2012, 77, 8131

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.
Apperatus (Plug Apperatus.jpg)
1H NMR (1H NMR.jpg)
13C NMR (13C NMR.jpg)
19F NMR (19F NMR.jpg)

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Keywords: alcohols, aromatics/arenes, Green Chemistry, ketones, Organic Oxidants, Organofluorine, oxidation, Oxoammonium Salts

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