Dimethyldioxirane1

[74087-85-7]  · C3H6O2  · Dimethyldioxirane  · (MW 74.09)

(selective, reactive oxidizing agent capable of epoxidation of alkenes and arenes,11 oxyfunctionalization of alkanes,19 and oxidation of alcohols,23 ethers,21 amines, imines,32 and sulfides35)

Alternate Name: DDO.

Physical Data: known only in the form of a dilute solution.

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

Form Supplied in: dilute solutions of the reagent in acetone are prepared from Oxone and acetone, as described below.

Analysis of Reagent Purity: the 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: the discovery of a convenient method for the preparation of dimethyldioxirane has stimulated important advances in oxidation technology.1 The observation2 that ketones enhance the decomposition of the monoperoxysulfate anion prompted mechanistic studies that implicated dioxiranes as intermediates.3 Ultimately, these investigations led to the isolation of dilute solutions of several dioxiranes.4 DDO is by far the most convenient of the dioxiranes to prepare and use (eq 1). Several experimental set-ups for the preparation of DDO have been described,4-6 but reproducible generation of high concentration solutions of DDO (ca 0.1M) is aided by a well-formulated protocol.6 The procedure involves the portionwise addition of solid Oxone (Potassium Monoperoxysulfate) to a vigorously stirred solution of NaHCO3 in a mixture of reagent grade Acetone and distilled water at 5-10 °C. The appearance of a yellow color signals the formation of DDO, at which point the cooling bath is removed and the DDO-acetone solution is distilled into a cooled (-78 °C) receiving flask under reduced pressure (80-100 Torr). After preliminary drying over reagent grade anhydrous MgSO4 in the cold, solutions of DDO are stored over molecular sieves in the freezer of a refrigerator at -10 to -20 °C. In instances where the concentration of DDO is crucial, analysis is typically based on reaction with an excess of an organosulfide monitored by NMR.4,7,8

Handling, Storage, and Precautions: solutions of the reagent can be kept in the freezer of a refrigerator (-10 to -20 °C) for as long as a week. The concentration of the reagent decreases relatively slowly, provided solutions are kept from light and traces of heavy metals. These dilute solutions are not known to decompose violently, but the usual precautions for handling peroxides should be applied, including the use of a shield. All reactions should be performed in a fume hood to avoid exposure to the volatile oxidant.

Introduction.

Reactions with DDO are typically performed by adding the cold reagent solution to a cold solution of a reactant in acetone or some other solvent. CH2Cl2 is a convenient solvent which facilitates reaction in a number of cases. After the reactant has been consumed, as monitored by TLC, etc., the solvent and excess reagent are simply removed to provide a nearly pure product. An excess of DDO is often used to facilitate conversion, provided further oxidation is not a problem. Where the product is especially sensitive to acid, the reaction can be run in the presence of solid Potassium Carbonate as an acid scavenger and drying agent. When it is important to minimize water content, the use of powdered molecular sieves in the reaction mixture is recommended. Reactions can be run from ambient temperatures down to -78 °C.

Dimethyldioxirane is a powerful oxidant, but shows substantial selectivity in its reactions. It has been particularly valuable for the preparation of highly reactive products, since DDO can be employed under neutral, nonnucleophilic conditions which facilitate the isolation of such species. Whereas DDO performs the general conversions of more classic reagents like m-Chloroperbenzoic Acid, it generates only an innocuous molecule of acetone as a byproduct. This is to be contrasted with peracids whose acidic side-products can induce rearrangements and nucleophilic attack on products. Although several other dioxiranes have been prepared, these usually offer no advantage over DDO. An important exception is Methyl(trifluoromethyl)dioxirane, whose greater reactivity is advantageous in situations where DDO reacts sluggishly, as in the oxyfunctionalization of alkanes.

The need to prepare DDO solutions beforehand, the low yield of the reagent based on Potassium Monoperoxysulfate (Oxone) (ca. 5%),6 and the inconvenience of making DDO for large-scale reactions are drawbacks that can be avoided when the product has good stability. In these instances, an in situ method for DDO oxidations is recommended.

Oxidation of Alkenes and Other Unsaturated Hydrocarbons.

The epoxidation of double bonds has been the major area for the application of DDO methodology and a wide range of alkenes are effectively converted to epoxides by solutions of DDO.4,7 Epoxidation is stereospecific with retention of alkene stereochemistry, as shown by the reactions of geometrical isomers; for example, (Z)-1-phenylpropene gives the cis-epoxide cleanly (eq 2), whereas the (E) isomer yields the corresponding trans-epoxide. Rate studies indicate that this reagent is electrophilic in nature and that alkyl substitution on the double bond enhances reactivity.7 Interestingly, cis-disubstituted alkenes react 7-9 times faster than the trans isomers, an observation that has been interpreted in terms of a spiro transition state.9

From a preparative viewpoint, the use of DDO solutions, while efficient and easy to perform, are generally not needed for simple alkenes that give stable epoxides. Rather, in situ methodology is suggested. However, the extraordinary value of isolated DDO has been amply demonstrated for the generation of unstable epoxides that would not survive most epoxidation conditions.1 A good example of this sort of application is the epoxidation of precocenes, as exemplified in eq 3.10 A number of impressive epoxidations have been reported for oxygen-substituted alkenes, including enol ethers, silyl enol ethers, enol carboxylates, etc.1 Examples include a number of 1,2-anhydro derivatives of monosaccharides.11 Steric features often result in significant stereoselection in the epoxidation, as illustrated in eq 4.11 Conversions of alkenes with two alkoxy substituents have also been achieved (eq 5), even when the epoxides are not stable at rt.12

Although reactions are much slower with conjugated carbonyl compounds, DDO is still effective for the epoxidation of these electron-deficient double bonds (eq 6).13 Alkoxy-substitution on such conjugated alkenes can also be tolerated (eq 7).14

Allenes react with DDO by sequential epoxidation of the two double bonds to give the previously inaccessible, highly reactive allene diepoxides.15 In the case of the t-butyl-substituted allene shown in eq 8, a single diastereomer of the diepoxide is generated, owing to steric control of the t-butyl group on reagent attack.

Certain polycyclic aromatic hydrocarbons can be converted to their epoxides, as typified by the reaction of phenanthrene with DDO (eq 9).4 Aromatic heterocycles like furans and benzofurans also give epoxides, although these products are quite susceptible to rearrangement, even at subambient temperatures (eq 10).16 The oxidation of heavily substituted phenols by DDO leads to quinones, as shown in eq 11, which illustrates the formation of an orthoquinone.17 The corresponding hydroquinones are intermediates in these reactions, but undergo ready oxidation to the quinones.

Finally, preformed lithium enolates are converted to a-hydroxy ketones by addition to a cold solution of DDO (eq 12).18

Oxidation of Saturated Hydrocarbons, Ethers, and Alcohols.

Surely the most striking reaction of dioxiranes is their ability to functionalize unactivated C-H bonds by the insertion of an oxygen atom into this s-bond. This has opened up an important new area of oxidation chemistry.1 While DDO has been used in a number of useful transformations outlined below, the more reactive Methyl(trifluoromethyl)dioxirane is often a better reagent for this type of conversion, despite its greater cost and difficulty of preparation.

The discrimination of DDO for tertiary > secondary > primary C-H bonds of alkanes is more pronounced than that of the t-butoxide radical.19 Good yields of tertiary alcohols can be secured in favorable cases, as in the DDO oxidation of adamantane to 1-adamantanol, which occurs with only minor reaction at C-2 (eq 13). Of major significance is the observation that these reactions are stereospecific with high retention of configuration, as illustrated by the oxidation of cis-dimethylcyclohexane shown in eq 14; the trans isomer gives exclusively the diastereomeric alcohol. This and other data have been interpreted in terms of an oxenoid mechanism for the insertion into the C-H bond. Several interesting applications in the steroid field involve significant site selectivity as well.20 The slower reactions of DDO with hydrocarbons without tertiary hydrogens are less useful and lead to ketones owing to a rapid further oxidation of the initially formed secondary alcohol. For example, cyclododecane is converted to cyclododecanone.

Ethers and acetals are slowly converted by DDO to carbonyl compounds. This serves as a nontraditional method for deprotection of these derivatives, an example of which is shown in eq 15.21,22 Hemiacetals are presumed intermediates in these transformations.

While DDO has been little used for the oxidation of simple alcohols, it has found application in useful conversions of vicinal diols. The oxidation of tertiary-secondary diols to a-hydroxy ketones occurs without the usual problem of oxidative cleavage between the two functions (eq 16).23 DDO has also been used to convert appropriate optically active diols selectively into a-hydroxy ketones of high optical purity; for example, see eq 17.24

Finally, the Si-H bond of silanes suffers analogous oxidation to silanols upon reaction with DDO. This reaction takes place with retention of configuration and is, as expected, more facile than C-H oxidations.25

Oxidation of Nitrogen Functional Groups.

Selective oxidations of nitrogen compounds are often difficult to achieve, but DDO methodology has been shown to be very useful in a number of instances. For example, one of the first applications of this reagent was in the conversion of primary amines to the corresponding nitro compounds (eq 18).26 This process probably proceeds by successive oxidation steps via hydroxylamine and nitroso intermediates. Complications arise with unhindered primary aliphatic amines, owing to dimerization of the intermediate nitrosoalkanes and their tautomerization to oximes.27 In oxidations of amino sugar and amino acid derivatives, it is possible to isolate the initially formed hydroxylamines (eq 19).28

The oxidation of secondary amines to hydroxylamines is readily achieved with 1 equiv of DDO (eq 20).29 The use of 2 equiv of DDO results in further oxidation, the nature of which depends on the structure of the amine. Thus cyclic secondary amines which do not possess a-hydrogens are converted to nitroxides,30 as illustrated in eq 21. Secondary benzylamines give nitrones (eq 22).31

A related transformation is the oxidation of imines to nitrones by DDO (eq 23).32 It is interesting that the isomeric oxaziridines are not produced here, given that peracids favor these heterocycles.

Reaction of a-diazo ketones with DDO leads to a-keto aldehyde hydrates (eq 24).33 Oximes are converted to the free ketones by DDO.34

Oxidation of Sulfur Functional Groups.

Dimethyldioxirane rapidly oxidizes sulfides to sulfoxides and converts sulfoxides to sulfones (eq 25).4,35 The partial oxidation of sulfides to sulfoxides can be controlled by limiting the quantity of DDO. Since Oxone is one of the many reagents that can perform these reactions, the extra effort involved in preparing DDO solutions is often not warranted. An exception involves the transformation of thiophenes to the corresponding sulfones (eq 26).36 A similar procedure gives a-oxo sulfones by DDO oxidation of thiol esters (eq 27).37

Alkanethiols are selectively oxidized to alkanesulfinic acids by DDO (eq 28).38 Air oxidation of an intermediate species appears to be important in this transformation.


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Jack K. Crandall

Indiana University, Bloomington, IN, USA



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