encyclopedia of reagents for organic synthesis || dimethyldioxirane

DIMETHYLDIOXIRANE 1

Dimethyldioxirane1

O

O

[74087-85-7] C3H6O2 (MW 74.09)InChI = 1/C3H6O2/c1-3(2)4-5-3/h1-2H3InChIKey = FFHWGQQFANVOHV-UHFFFAOYSA-N

(selective, reactive oxidizing agent capable of epoxidation ofalkenes and arenes,11 oxyfunctionalization of alkanes,19 and ox-idation 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: soluble in acetone and CH2Cl2; soluble in 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 reactionwith an excess of an organosulfide and determination of theamount of sulfoxide formed by NMR or gas chromatography.

Preparative Methods: the discovery of a convenient method forthe preparation of dimethyldioxirane has stimulated importantadvances in oxidation technology.1 The observation2 that ke-tones enhance the decomposition of the monoperoxysulfate an-ion prompted mechanistic studies that implicated dioxiranes asintermediates.3 Ultimately, these investigations led to the iso-lation of dilute solutions of several dioxiranes.4 DDO is byfar the most convenient of the dioxiranes to prepare and use(eq 1). Several experimental set-ups for the preparation of DDOhave been described,4–6 but reproducible generation of highconcentration solutions of DDO (ca 0.1M) is aided by a well-formulated protocol.6 The procedure involves the portionwiseaddition of solid Oxone (Potassium Monoperoxysulfate) to avigorously stirred solution of NaHCO3 in a mixture of reagentgrade Acetone and distilled water at 5–10 ◦C. The appearanceof a yellow color signals the formation of DDO, at which pointthe cooling bath is removed and the DDO–acetone solution isdistilled into a cooled (−78 ◦C) receiving flask under reducedpressure (80–100 Torr). After preliminary drying over reagentgrade anhydrous MgSO4 in the cold, solutions of DDO arestored over molecular sieves in the freezer of a refrigerator at−10 to −20 ◦C. In instances where the concentration of DDOis crucial, analysis is typically based on reaction with an excessof an organosulfide monitored by NMR.4,7,8

OO

OOxone

H2O, NaHCO3(1)

5–10 °C

Concentrated solutions of DDO in chlorinated solvents may beobtained by a simple extraction technique.

A fresh solution (50 mL) of isolated DDO (0.06–0.08 M inacetone), prepared as reported, is diluted with an equal volumeof cold water (0–5 ◦C) and extracted in a chilled separatory fun-nel with four 10 mL portions of cold CH2Cl2, CHCl3, or CCl4to yield a total volume of ca. 35 mL of extract (pale yellow DDO

solution). In order to concentrate this DDO solution, the com-bined extracts in chlorinated solvent are washed three times ina separatory funnel at 0–5 ◦C with an equal volume of cold 0.01M phosphate buffer (pH 7). The resulting solution is 0.19–0.36M in DDO. Its concentration can be estimated by iodometry;the recovery of dioxirane from the initial acetone solution is35–45% in most cases. 1H NMR spectroscopy analysis revealsthat initial solvent acetone is not completely eliminated.

Handling, Storage, and Precaution: solutions of the reagent canbe kept in the freezer of a refrigerator (−10 to −20 ◦C) foras long as a week. The concentration of the reagent decreasesrelatively slowly, provided solutions are kept from light andtraces of heavy metals. These dilute solutions are not knownto decompose violently, but the usual precautions for handlingperoxides should be applied, including the use of a shield. Allreactions should be performed in a fume hood to avoid exposureto the volatile oxidant.

Introduction. Reactions with DDO are typically performedby adding the cold reagent solution to a cold solution of a re-actant in acetone or some other solvent. CH2Cl2 is a convenientsolvent which facilitates reaction in a number of cases. After thereactant has been consumed, as monitored by TLC, etc., the sol-vent and excess reagent are simply removed to provide a nearlypure product. An excess of DDO is often used to facilitate con-version, provided further oxidation is not a problem. Where theproduct is especially sensitive to acid, the reaction can be run inthe presence of solid Potassium Carbonate as an acid scavengerand drying agent. When it is important to minimize water content,the use of powdered molecular sieves in the reaction mixture isrecommended. Reactions can be run from ambient temperaturesdown to −78 ◦C.

Dimethyldioxirane is a powerful oxidant, but shows substantialselectivity in its reactions. It has been particularly valuable for thepreparation of highly reactive products, since DDO can be em-ployed under neutral, nonnucleophilic conditions which facilitatethe isolation of such species. Whereas DDO performs the generalconversions of more classic reagents like m-ChloroperbenzoicAcid, it generates only an innocuous molecule of acetone as abyproduct. This is to be contrasted with peracids whose acidicside-products can induce rearrangements and nucleophilic attackon products. Although several other dioxiranes have been pre-pared, these usually offer no advantage over DDO. An importantexception is Methyl(trifluoromethyl)dioxirane, whose greater re-activity is advantageous in situations where DDO reacts slug-gishly, as in the oxyfunctionalization of alkanes.

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

Oxidation of Alkenes and Other Unsaturated Hydrocar-bons. The epoxidation of double bonds has been the majorarea for the application of DDO methodology and a wide rangeof alkenes are effectively converted to epoxides by solutions ofDDO.4,7 Epoxidation is stereospecific with retention of alkene

2 DIMETHYLDIOXIRANE

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 electrophilicin nature and that alkyl substitution on the double bond enhancesreactivity.7 Interestingly, cis-disubstituted alkenes react 7–9 timesfaster than the trans isomers, an observation that has been inter-preted in terms of a ‘spiro’ transition state.9

Ph Ph1.1 equiv DDO O (2)in acetone

>95%

From a preparative viewpoint, the use of DDO solutions, whileefficient and easy to perform, are generally not needed for simplealkenes that give stable epoxides. Rather, in situ methodology issuggested. However, the extraordinary value of isolated DDO hasbeen amply demonstrated for the generation of unstable epoxidesthat would not survive most epoxidation conditions.1 A good ex-ample of this sort of application is the epoxidation of precocenes,as exemplified in eq 3.10 A number of impressive epoxidationshave been reported for oxygen-substituted alkenes, including enolethers, silyl enol ethers, enol carboxylates, etc.1 Examples includea number of 1,2-anhydro derivatives of monosaccharides.11 Stericfeatures often result in significant stereoselection in the epoxida-tion, as illustrated in eq 4.11 Conversions of alkenes with twoalkoxy substituents have also been achieved (eq 5), even when theepoxides are not stable at rt.12

O OMe O OMe

1.2 equiv DDOin acetone

O

(3)MeCN, –40 °C

ca 100%


(4)O

TBSO

TBSO

TBSOO

TBSO

TBSO

TBSO

OCH2Cl2, 0 °C, 1 h96%

excess DDOin acetone

(5)

O

O

O

O

OCH2Cl2, –70 °C, 1 h

ca 100%

Although reactions are much slower with conjugated carbonylcompounds, DDO is still effective for the epoxidation of theseelectron-deficient double bonds (eq 6).13 Alkoxy-substitution onsuch conjugated alkenes can also be tolerated (eq 7).14

excess DDOin acetone

(6)CO2H CO2H

OCH2Cl2, 23 h

93%


(7)

O

OEt

O

OEt

OCH2Cl2, –20 °C, 26 h

98%

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

O

Ot-Bu

H

t-Bu•

4 equiv DDOin acetone

H

(8)10 min84%

Certain polycyclic aromatic hydrocarbons can be converted totheir epoxides, as typified by the reaction of phenanthrene withDDO (eq 9).4 Aromatic heterocycles like furans and benzofuransalso give epoxides, although these products are quite suscepti-ble to rearrangement, even at subambient temperatures (eq 10).16

The oxidation of heavily substituted phenols by DDO leads toquinones, as shown in eq 11, which illustrates the formation ofan orthoquinone.17 The corresponding hydroquinones are inter-mediates in these reactions, but undergo ready oxidation to thequinones.


O

(9)MeCN, 25 °C, 45 min

83%

O O

1.7 equiv DDOin acetone O

(10)CH2Cl2, –40 °C, 12 h

ca 100%

(11)t-Bu

t-Bu

OH

t-Bu

t-Bu

O

O1.7 equiv DDOin acetone

53%

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

OLi

Ph

O

Ph

addn to1.7 equiv DDO

in acetoneOH (12)

THF, pentane–78 °C, 30 min

77%

Oxidation of Saturated Hydrocarbons, Ethers, and Alco-hols. Surely the most striking reaction of dioxiranes is their abil-ity to functionalize unactivated C–H bonds by the insertion of anoxygen atom into this σ-bond. This has opened up an importantnew area of oxidation chemistry.1 While DDO has been used ina number of useful transformations outlined below, the more re-active Methyl(trifluoromethyl)dioxirane is often a better reagentfor this type of conversion, despite its greater cost and difficultyof preparation.

The discrimination of DDO for tertiary > secondary > pri-mary C–H bonds of alkanes is more pronounced than that of thet-butoxide radical.19 Good yields of tertiary alcohols can be se-cured in favorable cases, as in the DDO oxidation of adamantaneto 1-adamantanol, which occurs with only minor reaction at C-2(eq 13). Of major significance is the observation that these reac-tions are stereospecific with high retention of configuration, asillustrated by the oxidation of cis-dimethylcyclohexane shown ineq 14; the trans isomer gives exclusively the diastereomeric al-cohol. This and other data have been interpreted in terms of an‘oxenoid’ mechanism for the insertion into the C–H bond. Sev-eral interesting applications in the steroid field involve significant

DIMETHYLDIOXIRANE 3

site selectivity as well.20 The slower reactions of DDO with hy-drocarbons without tertiary hydrogens are less useful and lead toketones owing to a rapid further oxidation of the initially formedsecondary alcohol. For example, cyclododecane is converted tocyclododecanone.


(13)OH22 °C, 18 h

87%

DDO in acetone(14)OH22 °C, 18 h

ca 100%

Ethers and acetals are slowly converted by DDO to carbonylcompounds. This serves as a nontraditional method for depro-tection of these derivatives, an example of which is shown ineq 15.21,22 Hemiacetals are presumed intermediates in these trans-formations.


(15)

MeO Ort, 36 h

87%

While DDO has been little used for the oxidation of simple alco-hols, it has found application in useful conversions of vicinal diols.The oxidation of tertiary–secondary diols to α-hydroxy ketonesoccurs without the usual problem of oxidative cleavage betweenthe two functions (eq 16).23 DDO has also been used to convert ap-propriate optically active diols selectively into α-hydroxy ketonesof high optical purity; for example, see eq 17.24


(16)OH

OHO

OH

0 °C, 4 h98%


(17)

OH

O

OH

OH>98% ee >98% ee

CH2Cl2, 0 °C, 4 h96%

Finally, the Si–H bond of silanes suffers analogous oxidation tosilanols upon reaction with DDO. This reaction takes place withretention of configuration and is, as expected, more facile thanC–H oxidations.25

Oxidation of Nitrogen Functional Groups. Selective oxi-dations of nitrogen compounds are often difficult to achieve, butDDO methodology has been shown to be very useful in a num-ber of instances. For example, one of the first applications of thisreagent was in the conversion of primary amines to the correspond-ing nitro compounds (eq 18).26 This process probably proceeds bysuccessive oxidation steps via hydroxylamine and nitroso inter-mediates. Complications arise with unhindered primary aliphaticamines, owing to dimerization of the intermediate nitrosoalka-nes and their tautomerization to oximes.27 In oxidations of aminosugar and amino acid derivatives, it is possible to isolate the ini-tially formed hydroxylamines (eq 19).28


(18)

CO2H

NO2

CO2H

NH2

22 °C, 30 min95%


(19)

OHONHBzO

BzOOMe

OH2NBzO

BzOOMe –45 °C, 15 min

75%

The oxidation of secondary amines to hydroxylamines is read-ily achieved with 1 equiv of DDO (eq 20).29 The use of 2 equiv ofDDO results in further oxidation, the nature of which depends onthe structure of the amine. Thus cyclic secondary amines whichdo not possess α-hydrogens are converted to nitroxides,30 as illus-trated in eq 21. Secondary benzylamines give nitrones (eq 22).31


(20)(PhCH2)2NH (PhCH2)2NOH0 °C, 15 min

98%

NH

CONH2

N

CONH22 equiv DDOin acetone

O•

(21)0 °C, 30 min

98%


(22)PhCH=N(O)-t-BuPhCH2NH-t-Bu0 °C, 10 min

96%

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


(23)C6Me5CH=NMe C6Me5CH=N(O)MeCH2Cl2, 0 °C, 2 h

71%

Reaction of α-diazo ketones with DDO leads to α-keto aldehydehydrates (eq 24).33 Oximes are converted to the free ketones byDDO.34


(24)

N

COCH(OH)2

N

COCHN2

100%

Oxidation of Sulfur Functional Groups. Dimethyldioxiranerapidly oxidizes sulfides to sulfoxides and converts sulfoxides tosulfones (eq 25).4,35 The partial oxidation of sulfides to sulfoxidescan be controlled by limiting the quantity of DDO. Since Oxone isone of the many reagents that can perform these reactions, the extraeffort involved in preparing DDO solutions is often not warranted.An exception involves the transformation of thiophenes to thecorresponding sulfones (eq 26).36 A similar procedure gives α-oxo sulfones by DDO oxidation of thiol esters (eq 27).37

(25)PhSMeDDO

PhSOMeDDO

PhSO2Me

S SO O

>2 equiv DDOin acetone

(26)CH2Cl2

93%

4 DIMETHYLDIOXIRANE

O

ArS Ar

O

S Ar

Ar

OO

>2 equiv DDOin acetone

(27)CH2Cl2, –30 °C, 2–4 h

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

(28)

DDOin acetone

Me(CH2)4SHO2

Me(CH2)4SO2H

Related Reagents. Potassium monoperoxosulfate (Oxone);potassium monoperoxosulfate (Oxone)/acetone (DDO in situ);methyl(trifluoromethyl)dioxirane.

1. (a) Adam, W.; Hadjiarapoglou, L. P.; Curci, R.; Mello, R. In OrganicPeroxides; Ando, W., Ed.; Wiley: New York, 1992; Chapter 4, p 195.(b) Murray, R. W., Chem. Rev. 1989, 89, 1187. (c) Curci, R. In Advancesin Oxygenated Processes; Baumstark, A., Ed; JAI: Greenwich, CT, 1990;Vol. 2, Chapter 1, p 1. (d) Adam, W.; Edwards, J. O.; Curci, R., Acc.Chem. Res. 1989, 22, 205. (e) Adam, W.; Hadjiarapoglou, L., Top. Curr.Chem. 1993, 164, 45.

2. Montgomery, R. E., J. Am. Chem. Soc. 1974, 96, 7820.

3. Edwards, J. O.; Pater, R. H.; Curci, P. R.; Di Furia, F., Photochem.Photobiol. 1979, 30, 63.

4. Murray, R. W.; Jeyaraman, R., J. Org. Chem. 1985, 50, 2847.

5. Eaton, P. E.; Wicks, G. E., J. Org. Chem. 1988, 53, 5353.

6. Adam, W.; Bialas, J.; Hadjiarapoglou, L., Chem. Ber. 1991, 124, 2377.

7. Baumstark, A. L.; Vasquez, P. C., J. Org. Chem. 1988, 53, 3437.

8. Murray, R. W.; Shiang, D. L., J. Chem. Soc., Perkin Trans. 2 1990, 2,349.

9. Baumstark, A. L.; McCloskey, C. J., Tetrahedron Lett. 1987, 28, 3311.

10. Bujons, J.; Camps, F.; Messeguer, A., Tetrahedron Lett. 1990, 31, 5235.

11. Halcomb, R. L.; Danishefsky, S. J., J. Am. Chem. Soc. 1989, 111, 6661.

12. Adam, W.; Hadjiarapoglou, L.; Wang, X., Tetrahedron Lett. 1991, 32,1295.

13. Adam, W.; Hadjiarapoglou, L.; Nestler, B., Tetrahedron Lett. 1990, 31,331.

14. Adam, W.; Hadjiarapoglou, L., Chem. Ber. 1990, 123, 2077.

15. (a) Crandall, J. K.; Batal, D. J.; Sebesta, D. P.; Lin, F., J. Org. Chem.1991, 56, 1153. (b) Crandall, J. K.; Batal, D. J.; Lin, F.; Reix, T.; Nadol,G. S.; Ng, R. A., Tetrahedron 1992, 48, 1427.

16. (a) Adger, B. M.; Barrett, C.; Brennan, J.; McGuigan, P.; McKervey, M.A.; Tarbit, B., J. Chem. Soc., Chem. Commun. 1993, 1220. (b) Adger,B. M.; Barrett, C.; Brennan, J.; McKervey, M. A.; Murray, R. W., J.Chem. Soc., Chem. Commun. 1991, 1553. (c) Adam, W.; Bialas, J.;Hadjiarapoglou, L.; Sauter, M., Chem. Ber. 1992, 125, 231.

17. (a) Crandall, J. K.; Zucco, M.; Kirsch, R. S.; Coppert, D. M., TetrahedronLett. 1991, 32, 5441. (b) Altamura, A.; Fusco, C.; D’Accolti, L.; Mello,R.; Prencipe, T.; Curci, R., Tetrahedron Lett. 1991, 32, 5445. (c) Adam,W.; Schönberger, A., Tetrahedron Lett. 1992, 33, 53.

18. Guertin, K. R.; Chan, T. H., Tetrahedron Lett. 1991, 32, 715.

19. Murray, R. W.; Jeyaraman, R.; Mohan, L., J. Am. Chem. Soc. 1986, 108,2470.

20. (a) Bovicelli, P.; Lupattelli, P.; Mincione, E.; Prencipe, T.; Curci, R., J.Org. Chem. 1992, 57, 2182. (b) Bovicelli, P.; Lupattelli, P.; Mincione,E.; Prencipe, T.; Curci, R., J. Org. Chem. 1992, 57, 5052.

21. Curci, R.; D’Accolti, L.; Fiorentino, M.; Fusco, C.; Adam, W.; González-Nuñez, M. E.; Mello, R., Tetrahedron Lett. 1992, 33, 4225.

22. van Heerden, F. R.; Dixon, J. T.; Holzapfel, C. W., Tetrahedron Lett.1992, 33, 7399.

23. Curci, R.; D’Accolti, L.; Detomaso, A.; Fusco, C.; Takeuchi, K.; Ohga,Y.; Eaton, P. E.; Yip, Y. C., Tetrahedron Lett. 1993, 34, 4559.

24. D’Accolti, L.; Detomaso, A.; Fusco, C.; Rosa, A.; Curci, R., J. Org.Chem. 1993, 58, 3600.

25. Adam, W.; Mello, R.; Curci, R., Angew. Chem., Int. Ed. Engl. 1990, 102,890.

26. Murray, R. W.; Rajadhyaksha, S. N.; Mohan, L., J. Org. Chem. 1989,54, 5783.

27. Crandall, J. K.; Reix, T., J. Org. Chem. 1992, 57, 6759.

28. Wittman, M. D.; Halcomb, R. L.; Danishefsky, S. J., J. Org. Chem. 1990,55, 1981.

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30. Murray, R. W.; Singh, M., Tetrahedron Lett. 1988, 29, 4677.

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34. Olah, G. A.; Liao, Q.; Lee, C.-S.; Prakash, G. K. S., Synlett 1993, 427.

35. Murray, R. W.; Jeyaraman, R.; Pillay, M. K., J. Org. Chem. 1987, 52,746.

36. Miyahara, Y.; Inazu, T., Tetrahedron Lett. 1990, 31, 5955.

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Jack K. CrandallIndiana University, Bloomington, IN, USA

encyclopedia of reagents for organic synthesis || dimethyldioxirane

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