Trifluoromethyltrimethylsilane

Me3SiCF3

[81290-20-2]  · C4H9F3Si  · Trifluoromethyltrimethylsilane  · (MW 142.22)

(nucleophilic trifluoromethylating agent;1,2 difluorocarbene precursor1)

Physical Data: bp 54-55 °C; d20 0.963 g cm-3.

Solubility: sol THF, ether, CH2Cl2.

Form Supplied in: colorless liquid; commercially available.

Preparative Methods: is prepared2,6 based on the original procedure of Ruppert,7 by the reaction of Chlorotrimethylsilane with the complex of trifluoromethyl bromide and hexaethylphosphorous triamide in benzonitrile (eq 1). Other less convenient procedures for its preparation are also reported.8,9

Handling, Storage, and Precautions: is an acid-, base-, and moisture-sensitive compound and should be stored under anhydrous conditions in a refrigerator. Use in a fume hood.

Introduction.

TMSCF3 is a valuable reagent for trifluoromethylation of electrophilic substrates under nucleophilic catalysis or initiation.1,2 Homologous trifluoromethyltrialkylsilanes have also been used for the same purpose.3-5

TMSCF3 reacts as a trifluoromethide equivalent with a wide variety of electrophilic substrates such as carbonyls, sulfonyl fluorides, sulfoxides, deactivated aromatics, sulfur dioxide, and alkenes, etc.

Reactions with Carbonyl Compounds.

TMSCF3 reacts with aldehydes in the presence of a catalytic amount of Tetra-n-butylammonium Fluoride (TBAF) in THF to form the corresponding trifluoromethylated carbinols in good to excellent yields following aqueous hydrolysis of the silyl ethers (eq 2).2,3,6,10 The reaction also works very well for ketones under the same conditions, with the exception of extremely hindered ones such as 1,7,7-trimethylbicyclo[2.2.1]heptan-2-one, di-1-adamantyl ketone, and fenchone. The reaction has been characterized as a fluoride-induced autocatalytic reaction.3,10 Other initiators such as Tris(dimethylamino)sulfonium Difluorotrimethylsilicate (TASF), Potassium Fluoride, Ph3SnF2-, and RO- can also be used for these reactions. For the reactions of TMSCF3 and perfluorinated ketones and pentafluorobenzaldehyde, excess of KF is needed.16,17

TMSCF3 has been used in the preparation of polycyclic aromatic carcinogens, the key step being the addition of TMSCF3 to the carbonyl group (eq 3).11

A series of tripeptides containing the trifluoromethyl group has been prepared as potent inhibitors of human leukocyte elastase (HLE) by using TMSCF3.12 TMSCF3 has also been used to prepare trifluoromethyl analogs of L-fucose and 6-deoxy-D-ribose.13 Gassman et al. have prepared 1-trifluoromethylindene starting from 1-indanone.14

1,2-Diketones such as benzil give only the monoadduct. On the other hand, the highly enolizable cyclohexane-1,3-dione did not give the addition product with TMSCF3.15

A series of a,b-conjugated enones and ynones react with TMSCF3 to give predominant 1,2-addition products (eq 4).3,15

Simple unactivated esters do not react with TMSCF3.3 However, activated esters such as trifluoroacetic acid esters do react.3 Cyclic esters, i.e. lactones, react with TMSCF3 to give the corresponding adducts.3 An efficient and simple synthesis of trifluoropyruvic acid monohydrate has been developed starting from di-t-butyl oxalate.18

Direct trifluoromethylation of a-keto esters give Mosher's acid derivatives (eq 5).19

Acyl halides such as benzoyl chloride react with TMSCF3 to give a mixture of the trifluoroacetophenone and hexafluorocumyl alcohol in the presence of equimolar TBAF.3 Cyclic anhydrides react readily with TMSCF3; however, a stochiometric amount of TBAF is required. Acyclic anhydrides react less cleanly.3

Simple amides, such as benzamide and acetamide, do not react with TMSCF3 even with molar quantities of TBAF.3 However, an activated amide carbonyl such as in N-trifluoroacetylpiperidine reacts to give an adduct which upon subsequent hydrolysis gives hexafluoroacetone trihydrate.15 Imidazolidinetriones react with TMSCF3 to give 5-trifluoromethyl-5-hydroxyimidazolidine-2,4-diones upon aqueous acid workup.20 Imides such as N-methylsuccinimide react smoothly to afford the hemiaminal adducts (eq 6).15

Sulfur Derivatives.

Kirchmer and Patel have reported17 the preparation of trifluoromethylsulfinyl fluorides, sulfonyl fluorides, sulfoxides, and sulfuranes using TMSCF3 in the presence of a catalytic amount of KF.

TMSCF3 reacts with Dimethyl Sulfoxide in the presence of catalytic amount of TBAF to give Me2CF3SOTMS.17 Arylsulfonyl fluorides react with TMSCF3 to give the corresponding trifluoromethyl sulfones.1,21

Sulfur Dioxide reacts with TMSCF3 in the presence of TMSONa to give the sodium trifluoromethyl sulfinate. The sulfinate has been further oxidized to trifluoromethanesulfonic acid in 30% overall yield.1

Nitroso Group.

Nitrosobenzene reacts with TMSCF3 to afford the O-silylated trifluoromethylated hydroxylamine quantitatively.1

Aromatic Compounds.

Nucleophilic trifluoromethylation of aromatic compounds containing nitro, fluoro, and trifluoromethyl groups as substituents using TMSCF3 has been investigated.22,15 Yagupolskii et al. have reported that TMSCF3-TASF (1:1) reacts with 1,2,4,5-tetrakis(trifluoromethyl)benzene at -30 °C to give the stable carbanion salt (eq 7).23

Phosphorus Compounds.

Treatment of (BuO)2P(O)F with TMSCF3 and a catalytic amount of KF gave (BuO)2P(O)CF3 in 93% isolated yield.1

Generation of Difluorocarbene.

Treatment of TMSCF3 with an anhydrous fluoride source such as TASF in THF results in the generation of singlet difluorocarbene. In the presence of an acceptor such as tetramethylethylene, the corresponding adduct can be isolated.1

Related Reagents.

Trifluoromethylcopper(I).


1. Prakash, G. K. S. In Synthetic Fluorine Chemistry; Olah, G. A.; Chambers, R. D.; Prakash, G. K. S., Eds.; Wiley: Chichester, 1992, Chapter 10.
2. Bosmans, J. P. Janssen Chim. Acta 1992, 10, 22 (CA 1992, 117, 7213q).
3. Krishnamurti, R.; Bellew, D. R.; Prakash, G. K. S. JOC 1991, 56, 984.
4. Stahly, G. P.; Bell, D. R. JOC 1989, 54, 2873.
5. Urata, H.; Fuchikami, T. TL 1991, 32, 91.
6. Ramaiah, P.; Krishnamurti, R.; Prakash, G. K. S. OS 1995, 72, 232.
7. Ruppert, I.; Schlich, K.; Volbach, W. TL 1984, 25, 2195.
8. Pawelke, G. JFC 1989, 42, 429.
9. Eaborn, C.; Griffiths, R. W.; Pidcock, A. JOM 1982, 225, 331.
10. Prakash, G. K. S.; Krishnamurti, R.; Olah, G. A. JACS 1989, 111, 393.
11. Coombs, M. M.; Zepik, H. H. CC 1992, 1376.
12. Skiles, J. W.; Fuchs, V.; Miao, C.; Sorcek, R.; Grozinger, K. G.; Mauldin, S. C.; Vitous, J.; Mui, P. W.; Jacober, S.; Chow, G.; Matteo, M.; Skoog, M.; Weldon, S. M.; Possanza, G.; Keirns, J.; Letts, G.; Rosenthal, A. S. JMC 1992, 35, 641.
13. Bansal, R. C.; Dean, B.; Hakomori, S-I.; Toyokuni, T. CC 1991, 796.
14. Gassman, P. G.; Ray, J. A.; Wenthold, P. G.; Mickelson, J. W. JOC 1991, 56, 5143.
15. Kantamneni, S. Ph.D Dissertation, University of Southern California, July 1993.
16. Kotun, S. P.; Anderson, J. D. O.; DesMarteau, D. D. JOC 1992, 57, 1124.
17. Patel, N. R.; Kirchmeier, R. L. IC 1992, 31, 2537.
18. Broicher, V.; Geffken, D. TL 1989, 30, 5243.
19. Ramaiah, P.; Prakash, G. K. S. SL 1991, 643.
20. Broicher, V.; Geffken, D. AP 1990, 323, 929.
21. Kolomeitsev, A. A.; Movchun, V. N.; Kondratenko, N. V.; Yagupolskii, Yu. L. S 1990, 1151.
22. Bardin, V. V.; Kolomeitsev, A. A.; Furin, G. G.; Yagupolskii, Yu. L. IZV 1990, 1693 (CA 1991, 115, 279 503c).
23. Kolomeitsev, A. A.; Movchun, V. N.; Yagupolskii, Yu. L. TL 1992, 33, 6191.

George. A. Olah, G. K. Surya Prakash, Qi Wang & Xing-Ya Li

University of Southern California, Los Angeles, CA, USA



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