Diphenyl Disulfide1

[882-33-7]  · C12H10S2  · Diphenyl Disulfide  · (MW 218.36)

(source of phenylthio functionality, reactive with wide variety of organic nucleophiles,2-12 radicals;13-18 source of phenylthio radicals;19-27 incorporates phenylthio functionality with deoxygenation when used in conjunction with Bu3P28-30)

Alternate Name: phenyl disulfide.

Physical Data: mp 61-62 °C.

Solubility: sol EtOH, ether, THF, benzene, CS2; insol water.

Form Supplied in: white crystals; widely available in high purity.

Handling, Storage, and Precautions: air-stable; usually used as supplied. The odor of PhSSPh, while disagreeable, is not nearly as objectionable as that of the corresponding SH compound, thiophenol. Use in a fume hood. It has been reported that repeated skin contact with disulfides may cause irritation.31

Introduction.

Diphenyl disulfide is most frequently used as a reagent for incorporation of a phenylthio functionality into molecules. The phenylthio group is a useful functionality because of the variety of reactions in which it can be subsequently used. For example, phenyl sulfides undergo oxidative elimination, generating alkenes under relatively mild, neutral conditions.2,32 Certain allylic phenyl sulfides undergo [2,3]-sigmatropic shifts upon oxidation to sulfoxides, leading to allylic alcohols.33 Phenyl sulfides can also serve as a source of carbon-centered radicals in radical reactions, although they are usually not as reactive as alkyl halides and organoselenides in this regard.34 Other valuable synthetic uses of phenyl sulfides include reductive lithiation35 and a-deprotonation.36

Reactions of Diphenyl Disulfide with Carbon Nucleophiles.

The most common use of PhSSPh in organic synthesis is as an electrophilic source of the phenylthio functionality. Other related, and somewhat more reactive sulfenylating agents derived from PhSSPh include Benzenesulfenyl Chloride (PhSCl) and Phenyl Benzenethiosulfonate (PhSO2SPh).37 Phenyl benzenethiosulfonate is prepared from PhSSPh by a wide variety of oxidizing agents.38 While PhSCl is much more electrophilic than PhSSPh, it must be generated in situ from PhSSPh, and is therefore less convenient.

Ketone2,3 (eq 1) and ester2 (eq 2) enolates react readily with PhSSPh to generate the corresponding a-phenylthio carbonyl compound. Lactone4 enolates also react with PhSSPh, leading to synthetic intermediates which have been carried on to form a-methylene lactones (eq 3). Ketoester dianions have been successfully sulfenylated to generate a-phenylthio ketones (eq 4).5

Aldehydes have been converted to a-phenylthio aldehydes by sulfenylation of an N-cyclohexyl imine (eq 5).6 Modest enantiomeric excesses have been obtained when the imine generated from R-(+)-a-phenylethylamine is employed.7

Reaction of spirocyclobutanones with an excess of PhSSPh in the presence of Sodium Methoxide leads initially to a-bis(phenylthio) ketones, which can undergo in situ ring opening arising from nucleophilic attack of methoxide at the cyclobutanone carbonyl, to form g-bis(phenylthio) esters (eq 6).8

Cyclohexanones undergo dehydrogenative sulfenylation upon reaction with PhSSPh in methanolic NaOMe to give o-phenylthio phenols (eq 7).9 This reaction is interesting, in that the PhSSPh appears to behave both as a source of electrophilic phenylthio functionality and as an oxidizing agent in the course of the transformation.

The reaction of strongly nucleophilic organometallic reagents such as Grignard and organolithium species with PhSSPh, leading to the corresponding phenyl sulfide, is quite general. This type of reaction has seen extensive use in the chemistry of heterocycles as a method for incorporating the phenylthio functionality. Several illustrations of this mode of reaction are shown here.

A phenylthio group can be introduced at the 5-position of 2-alkylfurans (eq 8).10 This serves to block subsequent additions at C-5 and activate C-4 towards electrophilic attack. 3-Phenylthioindoles have been synthesized by metalation of indoles, with subsequent anion quenching by PhSSPh (eq 9).11 Lithiation of pyridyl phenyl sulfoxides with Lithium Diisopropylamide, followed by quenching with PhSSPh yields the corresponding phenylthio derivatives (eq 10).12

Reactions of Diphenyl Disulfide with Alkenes.

Diphenyl disulfide adds cleanly to many alkenes and dienes upon catalysis by BF3.OMe2.39 The trifluoroacetoxysulfenylation of unsaturated esters, carboxylic acids, nitriles, and amides has recently been described (eq 11).40 In this versatile addition reaction, the PhSSPh is oxidized to the phenylthio cation by Manganese(III) Acetate. The electrophilic sulfur species is believed to add to the alkene, activating it towards nucleophilic attack by Trifluoroacetic Acid. Mild aqueous hydrolysis leads to b-hydroxyalkyl phenyl sulfides in good yield and high regioselectivity.

Other Reactions of (Formally) Electrophilic Diphenyl Disulfide.

While PhSSPh is not electrophilic enough to react with alkynyltrimethylsilanes, a more reactive phenylthio electrophile is generated upon addition of Copper(I) Trifluoromethanesulfonate and Calcium Carbonate to the mixture. This reagent combination effects the conversion of alkynyltrimethylsilanes to alkynyl phenyl sulfides (eq 12).41

The coupling of 5-(chloromercurio)-2-deoxyuridine with PhSSPh, as well as with other diaryl and dialkyl disulfides, has been observed, leading to the corresponding phenylthio derivative (eq 13).42

Diphenyl Disulfide as a Source of Thiiyl Radicals.

Thiiyl radicals can be generated from PhSSPh upon photolysis, or thermolysis, or in the presence of radical initiators. The radicals thus generated add reversibly to alkenes19 and alkynes,20 generating b-phenylthio alkyl and vinyl radicals, respectively. Diphenyl disulfide adds to alkynes irreversibly to generate bis(phenylthio)alkenes only under forcing conditions (eq 14).21 The aniline and n-pentyl nitrite used in this example serve to generate phenyl radicals which initiate the radical chain process. The major product obtained is a substituted benzothiophene upon reaction with phenyl and t-butyl alkynes.21,22

The reversible addition of PhSSPh to alkenes under photolytic conditions has been used extensively for the isomerization of alkenes23 as illustrated in the synthesis of humulene (eq 15).23b

The reversible addition of a thiiyl radical arising from catalytic PhSSPh has been recently used in more complex radical processes. In eq 16,24 the addition of a thiiyl radical initiates a cascade of radical processes leading to carbocyclization via an epoxide fragmentation, which terminates with expulsion of the initially added radical. Thiiyl radical-induced ring opening of a vinylcyclopropane, followed by intermolecular addition to an acrylate ester and subsequent cyclopentane formation, is illustrated in eq 17.25 This transformation can also be accomplished upon addition of Trimethylaluminum. A mechanistically analogous process involving addition of O2 to vinylcyclopropanes, leading to formation of five-membered endoperoxides, has also been described.26

Thiiyl radicals have been incorporated into molecules via radical addition-elimination processes. Diphenyl disulfide reacts with b-tributylstannylacrylates upon photolysis to generate the corresponding b-phenylthioacrylate (eq 18).27

Diphenyl Disulfide as a Radical Trapping Agent.

Diphenyl disulfide is an effective radical trapping reagent, leading to formation of phenyl sulfides. Reactions of this type may proceed through an SH2 mechanism, or possibly through the intermediacy of a trivalent sulfuranyl radical species.13 Photolysis of 5-hexenylmercury(II) chloride in the presence of varying concentrations of PhSSPh leads to mixtures of uncyclized 5-hexenyl phenyl sulfide and cyclized product (eq 19). Upon analysis of these product ratios, a rate constant of 7.6 × 104 sec-1 was obtained for the reaction of the hexenyl radical with PhSSPh.14 Radicals generated from benzoylmethylmercury(II) chlorides add to alkenes prior to termination by attack at PhSSPh, leading to more synthetically interesting products (eq 20).15

The carbon-centered radicals generated upon heating thiohydroxamate esters can react with PhSSPh to generate the corresponding phenyl sulfide (eq 21).16 Diphenyl disulfide has also been used to trap radicals generated upon homolyses of organocobalt species.17 The alkyl radicals generated from trialkylboranes upon photolysis or exposure to O2 have also been trapped by PhSSPh in synthetically useful yields.18

Diphenyl Disulfide/Tributylphosphine.

The mixture of PhSSPh and Tri-n-butylphosphine has proven to be of use for a variety of transformations. Aldehydes can be readily converted to diphenyl thioacetals upon treatment with these reagents (eq 22), while ketones are converted to diphenyl thioacetals only in poor yield.28 The thioacetals thus formed are of synthetic interest due to their potential use as acyl anion synthons. Similar conditions convert oxiranes to vicinal diphenyl thioethers (eq 23).28 The PhSSPh/Bu3P reagent is also useful for the conversion of carboxylic acids to phenyl thioesters29 and the related conversion of alcohols to phenyl thioethers (eq 24).30

The reduction of nitro43 and oxime44 functionality to imines has been accomplished by this reagent system. The PhSSPh used in this reaction is also reduced to thiophenol. In several examples, the imine thus formed has been trapped intramolecularly to generate a pyrrole (eq 25). In each of these examples the phosphine serves as a deoxygenating agent through its conversion to Bu3PO.

Related Reagents.

Dimethyl Disulfide; Diphenyl Disulfide; 2,2-Dipyridyl Disulfide.


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Jeffrey H. Byers

Middlebury College, VT, USA



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