2,2,2-Trifluoroethyl Trifluoroacetate

[407-38-5]  · C4H2F6O2  · 2,2,2-Trifluoroethyl Trifluoroacetate  · (MW 196.06)

(agent for the efficient trifluoroacetylation of ketone enolates; useful in the preparation of a-diazo ketones)

Alternate Name: TFEA.

Physical Data: bp 55 °C; d 1.464 g cm-3.

Solubility: sol most commonly used organic solvents.

Form Supplied in: colorless liquid, widely available.

Purification: distillation from calcium hydride at atmospheric pressure.

Handling, Storage, and Precautions: for most applications the reagent can be adequately dried by simple distillation and can be stored under argon over 4Å molecular sieves. It is a flammable liquid and is reported to be corrosive.

General Considerations.

2,2,2-Trifluoroethyl trifluoroacetate has been employed for the in situ activation of a variety of ketone substrates as a-trifluoroacetyl derivatives.1 In general, activation via trifluoracetylation is superior to older technology, such as Claisen formylation, since kinetically generated ketone enolates react essentially instantaneously with TFEA at -78 °C in high yield. Formylation of ketone substrates with ethyl formate is usually carried out using either Sodium Hydride or Sodium Ethoxide as the base and generally requires 12-48 h at room temperature for complete reaction.2 TFEA is superior to other trifluoroacetylating agents, such as CF3CO2Et and Trifluoroacetic Anhydride, in that the desired C-acylated products are rapidly formed in high yields.

Synthesis of a-Diazo Ketones via Detrifluoroacetylative Diazo Transfer.

Danheiser and co-workers have employed this strategy in an improved method for the synthesis of a-diazo ketones.3 The diazo group transfer reaction requires that a stabilized b-diketone enolate be formed in situ for subsequent reaction with a sulfonyl azide reagent. The efficiency of the diazo group transfer reaction is improved, in some cases dramatically, by substituting the trifluoroacetylation of kinetically generated ketone enolates with TFEA for the classic formylation step. The method is particularly advantageous for diazo transfer reactions involving base-sensitive substrates such as certain a,b-enones and heteroaryl ketones. For example, as shown in eq 1, the yield of 1-diazo-4-phenyl-3-buten-2-one is improved from 17% to 85% when trifluoroacetylation with TFEA is substituted for Claisen formylation with ethyl formate. A variety of a-diazo ketones, which are not synthetically accessible via the classic procedures, can be obtained in excellent yields when the kinetic trifluoroacetylation procedure is employed (e.g. eq 2). This method has also been used by Doyle to achieve diazo group transfer to a base-sensitive N-acyloxazolidone derivative (eq 3).4

A crucial requirement for the success of the trifluoroacetylation reaction is that TFEA be rapidly added (1-5 s) to a cooled (-78 °C) solution of the ketone enolate (a small amount of white smoke may be noted above the reaction solution). The reaction is allowed to stir for 10 min, and then is quenched by pouring directly into a solution of 5% aq H2SO4. If the reagent is added too slowly in a dropwise fashion, varying amounts of starting material are often recovered from the reaction.

1. For a review of C- and O-acylation, see: Black. T. H. OPP 1989, 21, 179.
2. For an example, see: Regitz, C. B. CB 1968, 101, 2622.
3. (a) Danheiser, R. L.; Miller, R. F.; Brisbois, R. G.; Park, S. Z. JOC 1990, 55, 1959. (b) Danheiser, R. L.; Miller, R. F.; Brisbois, R. G.; OS 1995, in press.
4. Doyle, M. P.; Dorrow, R. L.; Terpstra, J. W.; Rodenhouse, R. A. JOC 1985, 50, 1663.

Raymond F. Miller

Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, CT, USA

Copyright 1995-2000 by John Wiley & Sons, Ltd. All rights reserved.