Benzenesulfenyl Chloride1

[931-59-9]  · C6H5ClS  · Benzenesulfenyl Chloride  · (MW 144.62)

(useful reagent in regio- and stereoselective syntheses,2 directed alkylation,3 carbonyl transposition,4 functionalization of unsaturated groups,5 sulfenylation of silyl enolates,6 cycloaddition7)

Alternate Name: phenylsulfenyl chloride.

Physical Data: bp 88 °C/17 mmHg; 55 °C/3 mmHg; d 1.252 g cm-3; nD20 1.6120.

Solubility: sol pentane, benzene, acetone, CHCl3, CH2Cl2, CCl4.

Form Supplied in: oily, dark red liquid; fumes in air.

Preparative Methods: easily obtained in high yields (90-100%) from Thiophenol or Diphenyl Diselenide by chlorination at -5 to 0 °C with chlorine gas8 or Sulfuryl Chloride.9 Arenesulfenyl chlorides, including PhSCl, are conveniently prepared from arenethiols and N-Chlorosuccinimide in dichloromethane solution in quantitative yields and used without isolation in addition reactions to alkenes.10

Handling, Storage, and Precautions: extremely hygroscopic and must be carefully protected from moisture. It may be stored for months under dry inert gas in a refrigerator. However, there are two reports on the spontaneous explosion of PhSCl on storage, even in a refrigerator. It is recommended that PhSCl be prepared fresh as needed. Use in a fume hood.

Sulfenylation of Allylic Alcohols.

Sulfenyl (as well as sulfoxide and sulfonyl) groups favor formation of a stabilized carbanion at the neighboring carbon atom by metalation with strong bases, and thus direct sequential alkylation with alkyl halides to the a-position. However, directed g-alkylation of allylic alcohols can be realized by application of a reversible sulfenate-sulfoxide [2,3]-sigmatropic rearrangement of their benzenesulfenate esters (eq 1).3,11

Sequential treatment of an allylic alcohol with n-Butyllithium and benzenesulfenyl chloride forms the sulfenate ester which spontaneously rearranges to the sulfoxide. The latter is metalated with Lithium Diisopropylamide (LDA) (n-BuLi affords 5-10% of byproducts) and treated with an alkyl iodide to give predominantly an a-alkylated (relative to the sulfoxide group) product. Finally, the alkylated sulfoxide on treatment with Trimethyl Phosphite and methanol rearranges back to the sulfenate ester and liberates the g-alkylated allylic alcohol.

Formation of the trans isomer is favored, the trans:cis ratio being 2.7-30.0. Along with the a-alkylation of the sulfoxide, some of the g-isomer usually forms, the a:g ratio being 1.1 to >>10 depending on the structure of the sulfoxide. Cyclic allylic alcohols can be alkylated in the same way. The stereochemistry of [2,3]-sigmatropic rearrangements is discussed in Hoffmann's review.12 The alkylative sulfenate-sulfoxide rearrangement is widely used in stereoselective syntheses of natural products, e.g. to form the side chains of coenzyme ubiquinone-10 and the growth-promoting steroid brassinolide,13,14 for epimerization of 17-hydroxy-17-vinyl steroids.15 A transformation of a prostaglandin with 13-cis-15b-hydroxy configuration to the inverted natural 13-trans-15a-hydroxy configuration (PGE1) has been achieved employing this rearrangement and p-toluenesulfenyl chloride.16

The sulfenate-sulfoxide rearrangement can be used for alkylative carbonyl 1,3-transposition in vinyl carbonyl compounds, both acyclic and cyclic. In the case of saturated aldehydes or ketones they are treated at first with Vinylmagnesium Bromide (or Vinyllithium) to form the allylic alcohol and then sulfenylated as shown in eq 2.4

The sulfoxide formed is lithiated with LDA and sulfenylated with diphenyl disulfide to undergo simultaneous rearrangement and elimination of PhSSPh to yield the enol sulfide. The latter, after hydrolysis with Mercury(II) Chloride, gives the a,b-unsaturated aldehyde. Another example, for a cyclic alkenone, is shown in eq 3.

Phenyl sulfoxides, formed by reaction of 3-trimethylsilylallylic alcohols with PhSCl, have been used for the synthesis of unsaturated aldehydes (eq 4).17 The a-silyl sulfoxide undergoes a sila-Pummerer rearrangement.

4-Trimethylsilyl-1-buten-3-ol by alkylation of the phenyl sulfoxide produced by reaction with PhSCl, and subsequent desulfonylation and desilylation by Tetra-n-butylammonium Fluoride, affords (E)-1,3-alkadienes in yields >90%.18

Sulfenylation of Propargylic Alcohols.

Benzenesulfenates of propargylic alcohols form allene sulfoxides by [2,3]-sigmatropic rearrangement. These can be easily transformed to useful derivatives2d,e or cyclized.2f,h The starting propargylic alcohols are readily accessible from the reaction of aldehydes or ketones with metal acetylides. Thus b-cyclocitral treated with propynyllithium, followed by PhSCl, after rearrangement affords the triene sulfoxide. Reduction with t-Butyllithium and methanol (as an internal proton source) yields 72% of the desulfurized hydrocarbon with retention of the double bond configuration (eq 5).19

A steroid 17-methylallene sulfoxide has been desulfurized under similar conditions with Methyllithium to give 72% of the b-methylallene derivative.20 Trienyl and allenyl phenyl sulfoxides can therefore be desulfurized stereospecifically with retention of configuration using t-BuLi or MeLi.

The allene sulfoxide obtained when androst-4-ene-3,17-dione is treated with Dipotassium Acetylide and PhSCl, is functionalized as shown in eq 6 (only the D-ring of the steroid is shown) to form the corticosteroid structure.21

Phenyl sulfoxides with the cis-allenyldiene structure, obtained from corresponding propargylic alcohols, undergo spontaneous electrocyclic ring closure (eq 7).22 As shown by detailed studies,22b the chiral center in the starting propynyl alcohol is stereospecifically transferred to the bridgehead carbon in the cyclized product drimatriene sulfoxide. This type of rearrangement has been used for an enantioselective synthesis of the sesquiterpene (+)-sterpurene.2h,23

A tandem [2,3]-sigmatropic rearrangement/Michael addition sequence occurs when the hydroxyphenylpropynol is sulfenylated with PhSCl (eq 8).24 Other substituted benzofurans are obtained in this way.

Ketones from Arylacetonitriles.2a

Secondary aryl, alkyl, or diaryl acetonitriles, on sulfenylation with PhSCl and subsequent oxidative decyanation by N-Bromosuccinimide and NaOH, afford aryl, alkyl, or diaryl ketones in good yields (eq 9).25 Four other oxidative decyanation methods were tested;25b the one shown is the best.

Reaction with a-Diazo Ketones.2d

The mild displacement of diazo nitrogen in a-diazo ketones by PhSCl represents a convenient and regiospecific method for functionalization of both cyclic and acyclic ketones at the a-position with halogen and phenylthio substituents (eqs 10-12).26 These functionalized ketones are useful for a variety of syntheses, particularly phenylthiocyclopentenone for the synthesis of natural products based on 2,3-disubstituted cyclopentanone.27

Addition to Alkenic and Alkynic Compounds.

The most commonly used reaction of PhSCl is the addition to double and triple bonds. The regioselectivity of this reaction is not high and is determined mainly by the steric bulk of neighboring groups. Mixtures of regioisomers are usually formed with anti-Markovnikov adducts predominating, which on standing or refluxing in MeCN undergo conversion to Markovnikov products. Addition to cycloalkenes and alkynes is stereoselective and trans isomers form almost exclusively. This fact is consistent with an episulfonium ion intermediate.

Combined chlorosulfenylation-dehydrochlorination reactions have great synthetic utility for the conversion of alkenes to cyclic and acyclic vinyl, allyl, or dienyl phenyl sulfides (eqs 13 and 14).10 The addition reaction is achieved by simply adding the alkene to a cooled (-50 to -78 °C) solution of PhSCl in CH2Cl2 and allowing the mixture to warm to rt. The dechlorination is carried out by briefly heating the b-chloroalkyl sulfides with the amidine base 1,8-Diazabicyclo[5.4.0]undec-7-ene. Higher yields on dechlorination are achieved with sulfones quantitatively formed by oxidation of the b-chlorosulfides with peroxy acids.

The addition of PhSCl can be used for functionalization of unsaturated groups,2d especially the isopropylidene terminus of natural isoprenoids. The synthetic sequence, as shown for the model compound 2-methylbut-2-ene (eq 15), involves addition of PhSCl, dehydrochlorination of isomeric adducts with Et3N in DMF to methallyl sulfide, oxidation to the sulfoxide, and its rearrangement to the terminal trans-allylic alcohol.5,28a,c This procedure is used for the synthesis of the biologically important oxygenated terpenes nuciferal, ar-turmerone, ipsdienol, neotorreyol, 6-hydroxydendrolasin, 6-oxodendrolasin, and solanesol.28a,b

Complete cis-trans alkene isomerization can be achieved by PhSCl addition and dehydrochlorination with t-BuOK in DMSO, which causes trans elimination of HCl and formation of vinyl sulfide with inverted configuration.29

Selective functionalization of 1,3-dienes by PhSCl involves formation of 1,2-adducts (which convert on heating or storage to 1,4-adducts) and hydrolysis, alcoholysis, or acetolysis of the chlorine in these adducts. The allyl alcohol obtained from the 1,2-adduct may be converted to an epoxide and aldehyde as shown in eq 16.30

Adducts of PhSCl to alkenes and cycloalkenes undergo methylation with Me2Zn/TiCl4 at the chlorine position with complete retention of configuration (controlled by the episulfonium ion intermediate).2h,31 This one-pot process is termed carbosulfenylation.

Addition to O-Silylated Enols and Alkenols.2d,i

Silyl enol ethers react smoothly with PhSCl to give a-keto sulfides.32 The reaction proceeds by addition of PhSCl to the enol double bond and elimination of chlorosilane.33 O-Silylated dienolates (from unsaturated esters, ketones, and aldehydes) undergo g-sulfenylation with this reagent,34 with the exception of g-chloro-substituted dienolates, which give a-products.35 This type of reaction may be used for stereoselective synthesis of a-sulfenyl-b-hydroxy esters with the anti configuration (eq 17).6 The latter can be converted into either syn- or anti-epoxides.

1-Phenylthiocyclohexanecarbaldehyde, obtained via PhSCl addition to trimethylsiloxymethylenecyclohexane, has been used in stereocontrolled synthesis of allylic alcohols.36 Benzenesulfenyl chloride adducts of mono- and disubstituted alkenes and cycloalkenes, under Zinc Bromide catalysis, give stereospecific (anti) alkylation of O-silylated ester enolates.37

t-Butyldimethylsilyl ethers of 1-alkenylcycloalkanols, when treated with PhSCl, readily rearrange to the ring-expanded a-1-phenylthioalkylcycloalkanones via the episulfonium ion (eq 18).38


A range of benzenesulfenyl chloride addition reactions to unsaturated bonds proceeds with simultaneous cyclization to form important compounds, examples of which are depicted below. These reactions include cyclization of isoprenoid b-keto esters (eq 19),2f,39 homoconjugative cycloaddition to form tricyclenes (precursors of natural sesquiterpenes) (eq 20),2d,e,7 cyclization of aryloxyphenylalkynes (eq 21),40 lactonization (eq 22),2c,41,42 and sulfenocycloamination of unsaturated amides and amines to form lactams, and pyrrolidine and piperidine rings (eqs 23 and 24).2f,g,43

Related Reagents.

Benzeneselenenyl Bromide; Benzeneselenenyl Chloride; 2,4-Dinitrobenzenesulfenyl Chloride; Diphenyl Disulfide; o-Nitrobenzenesulfenyl Chloride; N-Phenylthiophthalimide; 2-Pyridinesulfenyl Bromide.

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Gunars Zel&cbreve;ans

Institute of Organic Synthesis, Riga, Latvia

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