Methyl(trifluoromethyl)dioxirane1

[115464-59-0]  · C3H3F3O2  · Methyl(trifluoromethyl)dioxirane  · (MW 128.06)

(selective, reactive oxidizing agent capable of epoxidation of unreactive alkenes5 and arenes,7 oxyfunctionalization of alkanes,3 oxidation of alcohols16 and ethers19)

Alternate Name: TFDO.

Physical Data: known only as a dilute solution.

Solubility: sol acetone and CH2Cl2; sol most other organic solvents, but reacts slowly with many of these.

Form Supplied in: dilute solutions of the reagent in 1,1,1-trifluoro-2-propanone are prepared from Oxone (Potassium Monoperoxysulfate) and this ketone as described below. Drying: initial drying of reagent solutions is accomplished with reagent grade anhyd MgSO4 in the cold. After filtration, solutions are typically stored over molecular sieves.

Analysis of Reagent Purity: concentrations of the reagent can be determined by classical iodometric titration or by reaction with an excess of an organosulfide and determination of the amount of sulfoxide formed by NMR or gas chromatography.

Preparative Methods: TFDO solutions are prepared by mixing 1,1,1-trifluoro-2-propanone (TFP) and aqueous buffered Oxone in the cold and collecting the volatile TFDO-TFP mixture by transfer into a cold trap in a stream of inert gas under reduced pressure (eq 1).3

Handling, Storage, and Precautions: solutions of the reagent can be kept in the freezer of a refrigerator at -20 °C for as long as a week. The concentration of the reagent decreases relatively slowly (ca. 6-8% in 48 h), provided solutions are properly stored. It is particularly important that solutions be kept from light and traces of heavy metals, since the reagent is particularly susceptible to their influence. These dilute solutions are not known to decompose explosively, but the usual precautions for handling peroxides should be applied, including the use of a shield. All reactions should be performed in a hood to avoid exposure to the powerful, volatile oxidant.

Introduction.

Methyl(trifluoromethyl)dioxirane is a fluorinated derivative of the extremely useful oxidant Dimethyldioxirane (DDO), over which it has several advantages as a reagent. However, it is more expensive and difficult to prepare, since it is obtained from the volatile (bp 22 °C) ketone TFP.2 Nonetheless, the much greater reactivity of TFDO can be of major advantage for less reactive substrates. Furthermore, the concentration of TFDO (ca. 0.8 M) normally obtained is several times greater than that of DDO. Solutions of TFDO in halocarbon solvents free of starting ketone can be obtained by extraction of the TFP into water, owing to the water solubility of the ketone hydrate.4 Oxidations with TFDO are performed by adding the reagent to the reactant, often in CH2Cl2 solution, and then simply removing the volatile solvents when reaction is complete (usually minutes).

Alkenes and Arenes.

Like DDO, TFDO performs rapid epoxidations of alkenes with retention of alkene stereochemistry.1,2 Since DDO is adequately reactive towards most double bonds, there is ordinarily no reason to employ TFDO in reactions of this type. One important exception is the epoxidation of trifluoromethyl-substituted alkenes, which are resistant to classic epoxidizing reagents and which require a large excess of DDO during two weeks to complete epoxidation.5 TFDO rapidly converts such alkenes to epoxides (eq 2). Another example of the beneficial effect of TFDO is in the preparation of the sensitive epoxides of enol ethers, where the short reaction times and facile product isolation are crucial.6

Polycyclic aromatic hydrocarbons like phenanthrene are converted to epoxides by TFDO.7 This reactive reagent even permits the epoxidation of naphthalene, which undergoes fast sequential diepoxidation as shown in eq 3. Interestingly, the second epoxidation shows high anti stereoselectivity. Catechol is oxidatively cleaved by TFDO into (Z,Z)-muconic acid in good yield (eq 4).8 This reagent also oxidizes 2,6-di-t-butylphenol to the corresponding quinone and a hydroxyquinone derivative (eq 5).8

Alkynes are oxidized by TFDO to give a variety of different products, depending on the nature of the alkynic substituents.9 Reaction is thought to proceed via an oxirene intermediate. This highly unstable, anti-aromatic heterocycle quickly rearranges to the isomeric a-ketocarbene, which then leads to the observed products by typical carbenoid transformations. For example, cyclodecyne gives bicyclic ketones by transannular insertion processes common to this medium-ring system (eq 6).

Alkanes.

The most impressive applications of TFDO to date have involved the hydroxylation of unactivated C-H bonds.1,3 While dimethyldioxirane performs similar reactions, the much greater reactivity of TFDO permits higher conversions of alkanes with less oxidant and in minutes rather than hours. Despite its more reactive nature, TFDO displays selectivity for attack at tertiary > secondary > primary C-H bonds almost as advantageous as that for DDO.3 Examples include the exclusive formation of the tertiary alcohol from 2,3-dimethylbutane (eq 7) and the stereospecific oxidation of cis-1,2-dimethylcyclohexane (eq 8). Cyclohexane is oxidized to cyclohexanone by TFDO in a slower process that involves a fast second oxidation of the initially formed cyclohexanol. Heptane generates a 41:41:18 mixture of 2-, 3-, and 4-heptanone.

The stereospecificity of these C-H oxidations is illustrated in eq 9 by the benzylic oxidation of optically active (S)-(-)-2-phenylbutane, which gives only the tertiary alcohol with total retention of configuration.10 Interestingly, ketone-free TFDO in CH2Cl2 is three times more reactive than TFDO-TFP.

Adamantane is an informative substrate for oxidation by TFDO; it not only shows very high bridgehead selectivity, but can be converted to mono-, di-, tri-, and even tetrahydroxylated adamantane (eq 10) in good yields by varying the ratio of oxidant to hydrocarbon.11

Several impressive oxyfunctionalization reactions on steroid substrates illustrate the enormous potential of this process. Not only is there a preference for tertiary C-H oxidation, but there is also significant site selectivity, presumably governed by steric features. For example, the cholestane derivative in eq 11 gives rapid, selective C-25 side-chain oxidation without appreciable reaction at other tertiary carbons.12 Coprostane13 and estrone14 derivatives undergo C-5 and C-10 hydroxylation, respectively.

The stability of TFDO to strong acid adds a further dimension to its chemistry, as illustrated by the reactions of amines in the form of their fluoroborate salts with ketone-free solutions of TFDO.15 The amino group is deactivated under these conditions and remote C-H hydroxylation takes place (eq 12).

Alcohols.

Secondary alcohols are smoothly oxidized to the corresponding ketones by TFDO, whereas primary alcohols are converted to acids in a slower process.16 In view of the many methods for alcohol oxidations, this reagent will be advantageous for such conversions only in special situations. However, TFDO does perform sensitive oxidations under favorable experimental conditions that may be useful with problem cases. Cyclobutanol is oxidized by TFDO without the ring cleavage that is often problematic (eq 13). Other reactive functions can be accommodated as shown for the epoxy alcohol in eq 14.

Vicinal diols are oxidized to a-hydroxy ketones by TFDO without cleavage between the two functional groups. Thus, tertiary-secondary vic-diols are usefully oxidized by TFDO (eq 15).17 Optically active secondary-secondary diols have been converted to a-hydroxy ketones without racemization.18

Ethers and Acetals.

TFDO selectively oxidizes adjacent to an oxygen atom in compounds of these types.19 The initially generated hemiacetals decompose to carbonyl compounds and alcohols, which may be subject to further oxidation. Ethylene glycol acetals are attacked at the dioxolane ring, leading to an interesting deprotection of the carbonyl unit under nonacid conditions (eq 16). Cyclic ethers like tetrahydropyran yield lactones by subsequent oxidation of a stable cyclic hemiacetal intermediate (eq 17). Even methyl t-butyl ether is oxidatively liberated to t-butanol upon reaction with TFDO.


1. (a) Adam, W.; Hadjiarapoglou, L. P.; Curci, R.; Mello, R. In Organic Peroxides; Ando W., Ed.; Wiley: New York, 1992; Chapter 4, pp 195-219. (b) Murray, R. W. CRV 1989, 89, 1187: (c) Curci, R. In Advances in Oxygenated Processes; Baumstark, A., Ed; JAI Press: Greenwich, CT, 1990; Vol. 2, Chapter 1, pp 1-59: (d) Adam, W.; Edwards, J. O.; Curci, R. ACR 1989, 22, 205. (e) Adam, W.; Hadjiarapoglou, L. Top. Curr. Chem. 1993, 164, 45.
2. Mello, R.; Fiorentino, M.; Sciacovelli, O.; Curci, R. JOC 1988, 53, 3890.
3. Mello, R.; Fiorentino, M.; Fusco, C.; Curci, R. JACS 1989, 111, 6749.
4. Adam, W.; Curci, R.; González-Núñez, M. E.; Mello, R. JACS 1991, 113, 7654.
5. Lluch, A.-M.; Sanchez-Baeza, F.; Messeguer, A.; Fusco, C.; Curci, R. T 1993, 49, 6299.
6. Troisi, L.; Cassidei, L.; Lopez, L.; Mello, R.; Curci, R. TL 1989, 30, 257.
7. Mello, R.; Ciminale, F.; Fiorentino, M.; Fusco, C.; Prencipe, T.; Curci, R. TL 1990, 31, 6097.
8. Altamura, A.; Fusco, C.; D'Accolti, L.; Mello, R.; Prencipe, T.; Curci, R. TL 1991, 32, 5445.
9. Curci, R.; Fiorentino, M.; Fusco, C.; Mello, R.; Ballistreri, F. P.; Failla, S.; Tomaselli, G. A. TL 1992, 33, 7929.
10. Adam, W.; Asensio, G.; Curci, R.; González-Núñez, M. E.; Mello, R. JOC 1992, 57, 953.
11. Mello, R.; Cassidei, L.; Fiorentino, M.; Fusco, C.; Curci, R. TL 1990, 31, 3067.
12. Bovicelli, P.; Lupattelli, P.; Mincione, E.; Prencipe, T.; Curci, R. JOC 1992, 57, 5052.
13. Bovicelli, P.; Gambacorta, A.; Lupattelli, P.; Mincione, E. TL 1992, 33, 7411.
14. Bovicelli, P.; Lupattelli, P.; Mincione, E.; Prencipe, T.; Curci, R. JOC 1992, 57, 2182.
15. Asensio, G.; González-Nuñez, M. E.; Bernardini, C. B.; Mello, R.; Adam, W. JACS 1993, 115, 7250.
16. Mello, R.; Cassidei, L.; Fiorentino, M.; Fusco, C.; Hümmer, W.; Jäger, V.; Curci, R. JACS 1991, 113, 2205.
17. Curci, R.; D'Accolti, L.; Detomaso, A.; Fusco, C.; Takeuchi, K.; Ohga, Y.; Eaton, P.; Yip, C. Y. TL 1993, 34, 4559.
18. D'Accolti, L.; Detomaso, A.; Fusco, C.; Rosa, A.; Curci, R. JOC 1993, 58, 3600.
19. Curci, R.; D'Accolti, L.; Fiorentino, M.; Fusco, C.; Adam, W.; González-Núñez, M. E.; Mello, R. TL 1992, 33, 4225.

Jack K. Crandall

Indiana University, Bloomington, IN, USA



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