Sulfenylation

By analogy with halogenation, thiiranium ions can be intermediates in electrophilic sulfenylation. However, the corresponding tetravalent sulfur compounds, which are called sulfuranes, may also lie on the reaction path.  

The sulfur atom is a stereogenic center in both the sulfurane and the thiiranium ion, and this may influence the stereochemistry of the reactions of stereoisomeric aikenes. Thiiranium ions can be prepared in various ways, and several have been characterized, such as the examples below. 

Similar results have been observed for other sulfenylating reagents. The somewhat more electrophilic trifluoroethylsulfenyl group shows a shift toward Markovnikov regioselectivity but retains anti stereospecificity, indicating a bridged intermediate.  

G2 computations have been used to model the reaction of sulfenyl electrophiles with alkenes. The reactions were modeled by HS-X+, where X= FH, OH2, NH3, and CIH. The additions showed no gas phase barrier and the electrophile approaches the midpoint of the tt bond. This is similar to halogenation. The overall exothermicity calculated for the reactions correlated with the leaving-group ability of HX. 

The reaction of arylsulfenyl halides with proteins at pH 3.5 is limited to the cysteinyl and tryptophanyl residues (Fontana and Scoffone 1972), as illustrated below for 2-nitrophenylsulfenyl chloride (NPS-Cl). 

In proteins devoid of — SH groups, or those in which these groups have been alkylated or otherwise modified ( 3.8), the reaction is restricted to tryptophanyl side-chains. 

The protein (10 mg/ml) is dissolved in either water or 5 % acetic acid. NBS-Cl (4 moles per mole of tryptophan) dissolved in glacial acetic acid is added, with vigorous stirring, to give a final acetic acid concentration of 25 %. After 6 hr in the dark at room temperature the reaction 

Site-specific sulfenylation of tryptophan residues in egg-white lysozyme has been attained by either limiting the amount of reagent, or modifying the reaction conditions. Thus, Trp-108 is the major site of modification upon addition of one equivalent of 2-thio-(2-nitro-4-carboxyphenyljsulfenyl chloride to lysozyme in 25% acetic acid (Veronese et al. 1972). Specific modification of Trp-62 was attained in approximately 8 hr by the addition of 5 consecutive portions of solid NPS-Cl (10 /imole for each ml of reaction mixture) to a solution of lysozyme (0.5 /imole/ml) in 0.1 M sodium acetate at pH 3.5 (Shechter et al. 1972). In both cases, the protein derivative was separated from other products, and unreacted enzyme by ion-exchange chromatography. 

It may be noted, parenthetically, that a novel reaction of NPS-Cl with the thioether bonds linking the heme to cytochrome c leads to quantitative release of the heme (Fontana et al. 1973). 

Selenocyanation has been used only in the reaction with indole (63ACS268). 

Excellent yields and enantioselectivites have been reported for variety of substituted indanones and oxindoles. Natural quinidine showed remarkable performance in 0.05 M dichloromethane at 75 to 80  

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Sulfenylation of indoles can be carried out with sulfenyl halides[7], disulfides[7-9] or with A -methylthiomorpholine[10]. With disulfides the indoles are converted to lithium[8] or zinc[9] salts prior to sulfenylation. Thiophenols and iodine convert indoles to 3-(arylthio)indoles[l 1]. 

Organosulfur Halides. When sulfur is directly linked only to an organic radical and to a halogen atom, the radical name is attached to the word sulfur and the name(s) and number of the halide(s) are stated as a separate word. Alternatively, the name can be formed from R—SOH, a sulfenic acid whose radical prefix is sulfenyl-. For example, CH3CH2—S — Br would be named either ethylsulfur monobromide or ethanesulfenyl bromide. When another principal group is present, a composite prefix is formed from the number and substitutive name(s) of the halogen atoms in front of the syllable thio. For example, BrS—COOH is (bromothio)formic acid. 

Tetrachloropyridine-4-thiol [10357-06-1] (41) reacts with chlorine in carbon tetrachloride to give a sulfenyl chloride (42), which is fairly stable. The sulfenyl chloride may be converted into a number of derivatives (39). 

With a few olefins, the addition can yield sulfenyl chlorides, eg, 2-dichloroethane sulfenyl chloride [2441 -27-2] ... 

Oxidation. Disulfides are prepared commercially by two types of reactions. The first is an oxidation reaction uti1i2ing the thiol and a suitable oxidant as in equation 18 for 2,2,5,5-tetramethyl-3,4-dithiahexane. The most common oxidants are chlorine, oxygen (29), elemental sulfur, or hydrogen peroxide. Carbon tetrachloride (30) has also been used. This type of reaction is extremely exothermic. Some thiols, notably tertiary thiols and long-chain thiols, are resistant to oxidation, primarily because of steric hindrance or poor solubiUty of the oxidant in the thiol. This type of process is used in the preparation of symmetric disulfides, RSSR. The second type of reaction is the reaction of a sulfenyl haUde with a thiol (eq. 19). This process is used to prepare unsymmetric disulfides, RSSR such as 4,4-dimethyl-2,3-dithiahexane. Other methods may be found in the Hterature (28). 

Many other reactions of ethylene oxide are only of laboratory significance. These iaclude nucleophilic additions of amides, alkaU metal organic compounds, and pyridinyl alcohols (93), and electrophilic reactions with orthoformates, acetals, titanium tetrachloride, sulfenyl chlorides, halo-silanes, and dinitrogen tetroxide (94). 

The 2-thienylthiourea (245) on oxidation with bromine in acetic acid gave the thieno[3,2-djthiazole (247). It has been suggested that the intermediate electrophilic sulfenyl bromide adds to the 2,3-bond of the thiophene ring to form (246) when then loses HBr to give (247) (71AJC1229, 78JHC81). Pyrazolo(3,4- /]thiazoles are formed in a similar fashion (76GEP2429195). 

MO calculations for the gas phase indicate that sulfurane intermediate (17) is more stable than the ion (18) by about 380 kJ moP, which suggests that sulfuranes may be important in the reaction of sulfenyl halides with alkenes in non-polar solvents (77JCS(P2)1019). 

Chlorination of thiiranes in hydroxylic solvents gives /3-chloroethylsulfonyl chlorides due to further oxidation of the intermediate sulfenyl chloride by chlorine or hypochlorous acid (Scheme 40). Polymer is usually obtained also unless the reaction is done in concentrated hydrochloric acid, which causes rapid ring cleavage to 2-chloroethylthiols which are subsequently oxidized to the sulfonyl chlorides. An 85% yield of (37) is obtained in concentrated hydrochloric acid-HCl(g) whereas only a 15% yield is obtained in CCI4-H2O. 

Chloroethyldisulfides are obtained by electrophilic attack on the sulfur atom of thiiranes by sulfenyl halides (Scheme 39). Sulfur dichloride and disulfur dichloride react similarly to give more sulfur-rich derivatives di- and tri-sulfenyl halides, and tri- and tetra-sulfides (Scheme 42). A 1 1 ratio of sulfur halide to thiirane gives the di- or tri-sulfenyl halide a 2 1 ratio the tri- or tetra-sulfide. Thiirane 1-oxides are cleaved by sulfenyl halides to thiolsulfinates (Scheme 43) (74JAP7440461). 

Fluoride ion attacks the sulfur atom in 2,3-diphenylthiirene 1,1-dioxide to give ck-1,2-diphenylethylenesulfonyl fluoride (23%) and diphenylacetylene (35%). Bromide or iodide ion does not react (80JOC2604). Treatment of S-alkylthiirenium salts with chloride ion gives products of carbon attack, but the possibility of sulfur attack followed by addition of the sulfenyl chloride so produced to the alkyne has not been excluded (79MI50600). In fact the methanesulfenyl chloride formed from l-methyl-2,3-di- -butylthiirenium tetrafluoroborate has been trapped by reaction with 2-butyne. A sulfurane intermediate may be indicated by NMR experiments in liquid sulfur dioxide. 

Thiirane is more bactericidal than oxirane, and derivatives of 2-mei captomethylthiirane inhibit tuberculosis. The following pharmacological uses have been reported for compounds derived from thiirane derivatives gold complexes of the adducts of diethylphosphine and thiirane (antiarthritic), adducts of thiiranes and malononitrile (antibacterial, blood vessel dilators, muscle relaxants, sedatives), thermolysis products of thiirane 1-oxides and adducts of thiirane 1-oxides with sulfenyl chlorides (antibacterial), adducts of 2,3-diarylthiirene 1,1-dioxides with ynamines (antibacterial, parasiticidal), adducts of 2,3-diarylthiirene 1,1-dioxides with enamines (antifertility), adducts of p-aminophenylacetic esters with thiirane (immunosuppressants), adducts of amines and thiiranes (radioprotective drugs). 

NO2C6H4SCI NaBH4- Treatment of the thioether with the sulfenyl chloride initially produces a disulfide which is then reduced to afford the free thiol. 

The 5-(A -methyl-N -phenylcarbamoyl)sulfenyl group (Snm group) produced under these conditions is stable to HF or CF3SO3H. Since there are few acid-stable — SH protective groups, the Snm group should prove to be useful where strong acids are encountered in synthesis. 

CH30C(0)SC1, 0-5°, 1.5 h r-BuSH, MeOH, 5 days, 97% crude, 46% pure. The reaction proceeds through an 5-sulfenyl thiocarbonate. 

Three substituted 5-phenyl unsymmetrical disulfides have been prepared, i, ii, and iii —compounds i and ii by reaction of a thiol with a sulfenyl halide, compound iii from a thiol and an aiyl thiosulfonate (ArS02SAr). The disulfides are cleaved by reduction (NaBH4) or by treatment with excess thiol (HSCH2CH2OH). 

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