Monoperoxyphthalic Acid1

[2311-91-3]  · C8H6O5  · Monoperoxyphthalic Acid  · (MW 182.14) (Mg salt.6H2O)

[84665-66-7]  · C16H22MgO16  · Magnesium Monoperoxyphthalate Hexahydrate  · (MW 494.69)

(mild peroxycarboxylic acids for effecting epoxidation of p-bonds, Baeyer-Villiger reactions, and the oxidation of diverse heteroatoms including nitrogen, sulfur, and selenium)

Alternate Name: MPP.

Physical Data: monoperoxyphthalic acid: mp 110-112 °C (dec).2

Solubility: monoperoxyphthalic acid: sol ether; magnesium monoperoxyphthalate: sol water, low molecular weight alcohols; very low sol organic solvents such as dichloromethane.

Form Supplied in: magnesium monoperoxyphthalate: white crystalline powder; commercially available as the hexahydrate.

Preparative Methods: monoperoxyphthalic acid is prepared as required by the addition of phthalic anhydride to 30% aqueous Hydrogen Peroxide,3a in the presence of Sodium Hydroxide3b or Sodium Carbonate.3c Magnesium monoperoxyphthalate is prepared by the addition of phthalic anhydride and Magnesium Oxide to aqueous hydrogen peroxide.3d Drying: magnesium monoperoxyphthalate should be dried over calcium chloride in a desiccator.

Handling, Storage, and Precautions: magnesium monoperoxyphthalate may be stored at room temperature. All work should be carried in an efficient fume hood behind a polycarbonate safety screen.

Monoperoxyphthalic Acid.

Before the introduction of m-Chloroperbenzoic Acid (m-CPBA), one of the most frequently used peroxy acids was monoperoxyphthalic acid (MPP). Although MPP is a weaker acid than m-CPBA, the fact that phthalic acid is essentially insoluble in ether is an advantage with MPP. A disadvantage of the reagent is that MPP has to be made each time that it is used, whereas m-CPBA (60%) is commercially available admixed with m-chlorobenzoic acid and water. The epoxidation of a number of alkenes can be achieved in reasonable yields using MPP. Cyclohexene, limonene, and a-pinene were converted into the respective epoxides in 64, 71, and 48% yields, respectively.3a The oxidation of bicyclo[2.2.1]heptadiene gave, in addition to a low yield of the expected epoxide, bicyclo[2.2.1]hex-2-ene-5-carbaldehyde.4 The epoxidation of a number of acid-sensitive alkenes, such as a-keto enol ethers, has been achieved in good yields in the presence of disodium phthalate as a buffer and is exemplified in eq 1.5 It is of interest to note that the yields in these reactions were halved in the absence of the buffer.

The oxidation of indole derivatives gives rise to a number of products, including those where ring fragmentation has occurred. Thus 2-t-butylindole affords N-pivaloylanthranilic acid.6 Monoperoxyphthalic acid has also been used to prepare N-oxides; for example, quinoline derivatives have been converted into their N-oxides.7 Although MPP is now not used as frequently as formerly, some useful examples have been published recently. The epoxidation reactions shown in eqs 2 and 3 and the Baeyer-Villiger type rearrangement (eq 4) are illustrative.8-10

Magnesium Monoperoxyphthalate.

The production of magnesium monoperoxyphthalate (MMPP) in commercial quantities has led to its use in a number of different types of oxidation reactions since its introduction.11 The use of MMPP has been reviewed in detail to early 1993.1c The different reaction types are outlined and exemplified in the following sections.

Epoxidation Reactions.

The majority of the successful examples of epoxidation reactions using MMPP have been carried out using water or a low molecular weight alcohol as a solvent. Where the substrate to be epoxidized is insoluble in such a solvent, water has been used together with a phase-transfer agent to take the monoperoxyphthalate ion into an organic phase, for example chloroform or dichloromethane. The formation of the monoepoxide from [2H6]buta-1,3-diene has been reported in a reaction where one atmosphere of the gas was kept over an aqueous solution of MMPP.12 There have also been cases reported where attempted epoxidation reactions have failed in the presence of MMPP.13 Typically these involve terminal alkenes where electron density in the double bond is relatively low. Epoxidation may then be successful using Kishi's high-temperature method in which the radical inhibitor 4,4-thiobis(6-t-butyl-3-methylphenol) is employed together with m-CPBA.14 An efficient alternative method for the epoxidation of terminal alkenes involves the use of Trifluoroperacetic Acid (TFPAA) generated by the interaction of urea-hydrogen peroxide (UHP) with trifluoroacetic anhydride (see Hydrogen Peroxide-Urea).15 It is of interest to note that the epoxidation of cholesterol proceeds efficiently in dichloromethane in the absence of a phase-transfer catalyst. Presumably in this case the hydroxyl group that is present in cholesterol acts as a crystal disrupting agent. This explanation may also apply to the observation that the MMPP epoxidation of cis-but-2-ene-1,4-diol proceeds efficiently, whereas a reaction of the diacetate does not.16 As with all peroxycarboxylic acid epoxidations of cholesterol, a reaction using MMPP results in the formation of a mixture of products in which the a:b ratio is about 4:1. It appears that the larger the peroxycarboxylic acid, the larger the amount of the a-epoxide formed. A direct comparison with m-CPBA can be made in the case of the epoxidation of 1,2-dimethylcyclohexa-1,4-diene,17,18 and also in the reactions with Ethyl Vinyl Ether.19 The oxidation shown in eq 5 gave about a 4:1 mixture of diastereomers in very good yield when carried out in a water-isopropanol mixture.20 Hydrogen bonding between the peroxy acid and the hydroxyl group is presumed to be responsible for the preferred formation of the a-epoxide. The failure of m-CPBA to effect epoxidation of the diene ester shown in eq 6 is surprising. However, MMPP and TFPAA both gave the a-epoxide exclusively. On the other hand, a reaction using 3,5-dinitroperbenzoic acid gave a 3:1 mixture of the a- and b-epoxides.21 As with epoxidation reactions carried out using m-CPBA, the reactions of MMPP with dienes (for example limonene) involve initial reaction at the more electron-rich double bond.

High diastereofacial selectivity can be anticipated where a neighboring functional group can be involved to control the stereochemical course of the reaction. Both of the diastereomers of the phosphine oxides shown in eq 7 are epoxidized with de values in excess of 95%.22 Very low selectivities were observed where the chirality only involved the phosphorus center. Evidently the stereoselectivity is dominated by the effect of the chiral carbon center. Control may be less satisfactory when two functional groups have opposite influences. The epoxidation reaction shown in eq 8 was used in a study involving an enantiospecific synthesis of the nonproteinogenic a-amino acid anticapsin.23 The desired product (1) was formed along with (2) in the ratio 5:2 using MMPP, whereas a 1:1 mixture was obtained using m-CPBA. Hydrogen bonding of the peroxy acid to the amide group evidently competes with the sterically demanding t-butyldiphenylsilyl residue in this reaction.

The synthesis of a number of naturally occurring fused 3-methylfuran derivatives was achieved using, as a key step, the epoxidation-aromatization shown in eq 9.24 The oxidation of a number of heteroaromatic compounds has also been studied using MMPP and some of the products clearly result from initial epoxidation. A number of furan derivatives that carry electron-releasing substituents in the 2- and 5-positions are oxidized to give acyclic dienones in reactions with either m-CPBA or MMPP.25 The oxidation shown in eq 10 was used in a synthesis of bromobeckerelide,26 and the oxidation of 1-benzenesulfonylindole using MMPP gives the indoxyl derivative shown in eq 11.27

Baeyer-Villiger and Related Reactions.

The ease with which Baeyer-Villiger oxidation reactions of ketones occur is related to the strength of the conjugate acid of the leaving group. Since phthalic acid is not a particularly strong acid, it is not surprising that monoperoxyphthalic acid and MMPP are not used as frequently as trifluoroperacetic acid in Baeyer-Villiger reactions. Cyclohexanone and 3,3-dimethylbutanone are converted into ε-caprolactone and t-butyl acetate, respectively, in good yields.11 The oxidative rearrangement reactions of the b-lactams shown in eq 12 have been reported to give higher yields when using MMPP than using m-CPBA.28 The conversion of an aromatic aldehyde into a phenol via the formate ester (the Dakin reaction) is evidently related to the Baeyer-Villiger reaction. These reactions proceed well when the aromatic aldehyde has an electron releasing substituent ortho or para to the formyl residue. A number of peroxy acids have been used, for example m-CPBA and Peracetic Acid, including cases where the peroxy acid was generated using UHP and Acetic Anhydride. A limited number of examples have been reported using MMPP; the example shown in eq 13 is illustrative.29

Oxidation of Sulfur and Selenium.

The oxidation of sulfides to sulfoxides and sulfones can be achieved with a wide range of oxidizing agents, including various peroxycarboxylic acids. The second oxidation step is normally slower than the first and so using a controlled amount of peroxy acid normally allows the formation and isolation of either product. Thus tetrahydrothiophene can be oxidized either to the sulfoxide or to the sulfone using MMPP.11 A number of cases have been reported where good yields of sulfoxides have been obtained,30-32 including the example shown in eq 14 which was used in a synthesis of artemisinin.32 The oxidation of the selenide that is involved in the sequence shown in eq 15 also proceeds in high yield.33

The use of an excess of MMPP has allowed a number of research groups to obtain sulfones from sulfides in good yields.34 -37 The oxidation of phosphothionate to phosphate has been studied using a wide variety of oxidants. It was shown that MMPP was better than m-CPBA in the oxidation of malathion to malaoxon.38 The example shown in eq 16 exemplifies the successful use of a phase-transfer catalyst.34

Oxidation of Nitrogen Functional Groups.

The oxidations of a number of pyridine derivatives,11 pyrimidines,39 and pyridothiophenes40 to the related N-oxides have been reported. The oxidation of quinoxaline (eq 17) to the di-N-oxide also proceeds efficiently.29 The oxidative cleavage of suitable bicyclic isoxazolidines has been studied in connection with the synthesis of indolizidine alkaloids.41 In the example shown in eq 18 the use of m-CPBA afforded a mixture of the products (3) and (4) in which (3) predominated. Regiochemical control was better when using MMPP and in that case the nitrone (4) was the only product.

A number of methods are available for the oxidative regeneration of ketones from hydrazones. Very good yields have been reported for the conversion of N,N-dimethyl- and SAMP-hydrazones into their precursor ketones using MMPP. In the latter case (eq 19), the stereochemical integrity of the chiral center a to the carbonyl group was maintained.42 The oxidation of N,N-dimethylhydrazones derived from aldehydes has also been studied using MMPP. Nitriles are obtained in high yields in these reactions and once again (eq 20) there is no racemization of a chiral center a to the original formyl group.43


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Harry Heaney

Loughborough University of Technology, UK



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