Oxidation to Sulfoxides or Sulfones

Several peroxyacids or related oxidants have been used to convert alkylthio- into alkylsulfinyl- or alkylsulfonylpyrazines the choice of reagent appears to be unimportant but the amount of reagent determines whether the major (or only) product is a sulfoxide or a sulfone. The following examples illustrate typical oxidation procedures  

3 -Phenylthio-2-pyrazinecarbonitrile gave 3 -phenylsulfonyl-2-pyrazinecarboni-trile (49) (ot-C1C6H4C03, CHC13, 10 - 20°C, 3 h 91%) 1507 and 5-bromo-3-methylthio- gave 5-bromo-3-methylsulfonyl-2-pyrazinamine (50) (likewise, 4 days 70%).1012 Also other examples.1551 

Using Hydrogen Peroxide-Maleic Anhydride (Peroxymaleic Acid) 

2-Cyanomethylthio-3,6-diethylpyrazine (51, R = Et) gave 2-cyanomethyl-sulflnyl-3,6-diethylpyrazine (52, R = Et) (maleic anhydride, 90% H202, CHC13, 20°C, 12 h then reflux, 2 h 81%) 297 the 3,6-diisopropyl (52, R = Pr ) (78%) and other homologues were made similarly.297 

2-Cyclohexylthiopyrazine gave 2-cyclohexylsulfinylpyrazine (53, R = C6Hn) (as preceding examples 66%) 318 2-phenylsulfinylpyrazine (53, R = Ph) (75%),318 and many other analogues were made similarly.302 308 318,319 

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Note The only reported reaction of these thioethers appears to be their oxidation to sulfoxides or sulfones, as illustrated here. 

Imidazole- and benzimidazole-2-thiols usually exist largely as the thione tautomers. The thiol (thione) group is susceptible to alkylation (especially in alkaline media), and can be oxidized to sulfide, disulfide and sulfonic acid. This oxidation can often be carried out quite selectively by careful choice of oxidizing agent. The sulfur function can be removed with nitric acid, iron(III) chloride, hydrogen peroxide or, most commonly, Raney nickel. Alkyl- and arylthio groups can be oxidized to sulfoxide or sulfone. 

The sulfur atom of thiazole has been reported to be resistant to oxidation to sulfoxide or sulfone <1996CHEC-II(3)373>. Desulfurization with Raney-nickel has been reviewed <1984CHEC(6)235>. 

Both 2- and 7-methylthiopyrido[2,3- f]pyrimidines have been oxidized to sulfoxides and sulfones with hydrogen peroxide or MCPBA, as have 2-arylthio derivatives in the... 

Hydroxy and mercapto substituents at the 3- and 5-positions can also exist in tautomeric forms (see Section 4.01.5.2) and can be alkylated at either the substituent or the ring nitrogen atom. 3-Methoxy groups are not replaced by nucleophiles, but both 3- and 5-alkylthio groups react readily, as does 3-methoxy-l,2-benzisothiazole. Alkylthio compounds can be oxidized to sulfoxides and sulfones, and the latter readily undergo nucleophilic replacement. All the hydroxy compounds react with phosphorus pentachloride to give the chloro derivatives. 

Data presentations should include the parent compound and all toxic transformation products. This is particularly important for oxidation of sulfide linkages to sulfoxides or sulfones. These products are often equally toxic to the parent with increased availability. Attention should also be given to oxidative desulfuration of phosphorothionate esters. 

Mercapto-l,2,4-thiadiazoles exist as an equilibrium of tautomers with the equilibrium favoring the thione tautomer. They are acidic with a pA a of around 5. A variety of methylating agents (e.g., diazomethane, dimethyl sulfate and methyl iodide) give S-methylated products and no N-methylation has been observed. They are readily oxidized to sulfoxides and sulfones with either z-chloroperbenzoic acid or hydrogen peroxide in acetic acid <1996CHEC-II(4)307>. There have been no new publications on S-linked substituents since the publication of CHEC-II(1996). 

No examples of direct oxidation of the 1,3,4-thiadiazole ring sulfur to sulfoxide or sulfone have been reported. A3-l,3,4-Thiadiazoline 1-oxide and 1,1-dioxide, however, can be obtained by indirect methods that are reviewed in CHEC(1984) <1984CHEC(6)545>. 

The development of sulfone linkers, the exploration of sulfone based chemical transformations and cleavage strategies are an important objective in soHd-phase organic synthesis. This kind of Hnker (Tab. 3.7) has been used with thioethers [108], sulfoxides [109], sulfones [110], sulfonic acids and their corresponding derivatives [111]. Because carbon-sulfur bonds can be cleaved under very mild conditions, some Hnkers have been based on this effect. They can be cleaved under reductive conditions ]112, 113], photolytic conditions [114, 115] or with strong bases [116]. Various safety catch Hnkers have been developed based on the fact that thiols can be oxidized to sulfoxides and sulfones [112, 113]. 

Abstract This chapter principally concerns oxidations of organic substrates containing N, O, S, P, As and Sb. Oxidations of amines are covered first, including primary amines to nitriles or amides secondary amines to imines or other products tertiary amines to N-oxides or other prodncts (Section 5.1) and the oxidation of amides (5.2). Oxidation of ethers to esters or lactones follows (5.3), then of sulfides to sulfoxides or sulfones (5.4) and of phosphines, arsine and stibines to their oxides (5.5). A final section (5.6) concerns such miscellaneous oxidations not covered by other sections in the book. 

Table 5.2 Oxidation of ethers to esters or lactones and suMdes to sulfoxides or sulfones... 

The sulfur atom of methionine residues may be modified by formation of sulfonium salts or by oxidation to sulfoxides or the sulfone. The cyanosulfonium salt is not particularly useful for chemical modification studies because of the tendency for cyclization and chain cleavage (129). This fact, of course, makes it very useful in sequence work. Normally, the methionine residues of RNase can only be modified after denaturation of the protein, i.e., in acid pH, urea, detergents, etc. On treatment with iodoacetate or hydrogen peroxide, derivatives with more than one sulfonium or sulfoxide group did not form active enzymes on removal of the denaturing agent (130) [see, however, Jori et al. (131)]. There was an indication of some active monosubstituted derivatives (130, 132). 

Oxidation with hydrogen peroxide is very popular in pharmaceutical development as a test for oxidative conditions55 (42). The most common reactions with organic compounds are electrophilic attack on amines and sulfides to give N-oxides and sulfoxides or sulfones, respectively, and the slower attack on carbon-carbon double bonds to give epoxides. These reaction are ionic and do not involve radicals ... 

Sulfides are much more reactive than ethers. In a sulfide, sulfur valence is not necessarily filled Sulfur can form additional bonds with other atoms. Sulfur forms particularly strong bonds with oxygen, and sulfides are easily oxidized to sulfoxides and sulfones. Sulfoxides and sulfones are drawn using either hypervalent double-bonded structures or formally charged single-bonded structures as shown here. 

Sulfides are easy to oxidize and, depending on the type and quantity of oxidizing agent used, they can be cleanly oxidized either to sulfoxides or sulfones. 

In most instances, double and triple bonds remain unaffected by the oxidation of sulfides to sulfoxides or sulfones, even when hydrogen peroxide and peroxy acids are used [163, 264, 322, 324, 506, 521], Evidently, the affinity of sulfur to oxygen is higher than that of the carbon-carbon multiple bonds (equations 574 and 575). 

N-dealkylation in the N10 side-chain N-oxidation in the N10 side-chain Oxidation of the heterocyclic S atom to sulfoxide or sulfone... 

The -oxidation of thiazoles to sulfoxides or sulfones has not been reported. Under base conditions both thiazoles and benzothiazoles are resistant to the action of PhI(OAc)2 <88IJC(B)929>. Raney Nickel promotes desulfuration of thiazoles, probably through an initial coordination of the sulfur at nickel, affording carbonyl compounds <84CHEC-I(4)240>. 

The oxidation of sulfides to sulfoxides or sulfones depend on the reaction conditions used. Hydrogen peroxide and ferf-butyl hydroperoxide have both been used as also has a variety of peroxycarboxylic acids. Since all of the peroxycarboxylic acids are stronger oxidants than hydrogen peroxide, reagents such as MCPBA have been used to oxidise sulfides to sulfoxides under very mild conditions. In the example shown in Eq. (38) the diastereomeric sulfoxides were obtained in good yield [46]. 

The oxidation of sulfides to sulfoxides or sulfones, as well as the reverse reduction strategy, is a well-known method for the design of a safety-catch protocol. As nucleophilic displacement is facilitated if electron-withdrawing groups are placed... 

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