Phenyl sulfoxide

Submitted by Carl R Johnson and Jeffrey E Reiser 1 Checked by Wayland E Noland, Leonard J Czuha, and William E Parham 

In a 500 ml round-bottomed flask equipped with a magnetic stirrer are placed 22 5 g (0 105 mole) of powdered sodium metaperiodate and 210 ml of water The mixture is stirred and cooled m an ice bath (Note 1), and 12 4 g (0 100 mole) of thio-anisole (Note 2) is added The reaction mixture is stirred for 15 hours at ice-bath temperature and is then filtered through a Buchner funnel The filter cake of sodium iodate is washed with three 30-ml portions of methylene chloride The wrater methylene chloride filtrate is transferred to a separatory funnel, the lower methylene chloride layer is removed, and the water layer is extracted with three 100-ml portions of methylene chloride The combined methylene chloride extracts are treated with activated carbon (Note 3) and dried over anhydrous sodium sulfate (Note 4) The solvent is removed at reduced pressure to yield 13 6-13 9 g of a slightly yellow oil (Note 5) which crystallizes on cooling The crude sulfoxide is transferred to a 25 ml distillation flask with the aid of a small amount of methylene chloride After removal of the solvent, a pinch of activated carbon is added to the distillation flask (Note 6) Simple vacuum distillation (Note 7) of the crude product through a short path still affords 12.7-12 8 g (91%) of pure methyl phenyl sulfoxide, b p 78-79° (0 1 mm ), m p. 33-34° (Notes 8 and 9) 

1 An insulated ice bucket such as the Nicer available from B F Goodrich Company is a convenient reservoir for maintaining 

2 Thioanisole (methyl phenyl sulfide) supplied by Aldrich Chemical Company, Milwaukee, Wisconsin, was used without further purification 

5 Gas-phase chromatography shows this crude material to be sulfide-free sulfoxide containing a small amount of methylene chloride 

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Tosylhydra2one and 7-phenyl sulfoxide groups have also been introduced into cholesterol and eliminated to prepare the 5,7-diene (45,46). The method of choice is the aHyUc brornination—dehydrobrornination procedures, and the commercial yields ia converting cholesterol to 7-dehydrocholesterol are ia the range of 35—50%. 

Replacement of the methyl ketone moiety in 78 by a phenyl sulfoxide, interestingly, leads to a relatively potent uricosuric agent with diminished antiinflammatory action. This effect in lowering serum levels or uric acid leads to the use of this drug in the treatment of gout. Alkylation of diethyl malonate with the chlorosulfide, 79, gives the intermediate, 80. The pyrazolodione (81) is prepared in the usual way by condensation with hydrazobenzene. Careful oxidation of the sulfide with one equiv-... 

Methyl phenyl sulfide Methyl phenyl sulfoxide Methyl phenyl sulfone... 

Methyl phenyl sulfide, see Thioanisole Methyl phenyl sulfoxide, 46, 78 from methylsulfinyl chloride and benzene with anhydrous alumi num chloride, 46, 80 Methyl vinyl ketone, reaction with 1-morpholino 1 cyclohexene, 45,... 

Thioamsole, oxidation, by dinitrogen tetroxidc, 46, 80 by hydrogen peroxide, 46, 80 by lead tetraacetate, 46, 80 reaction with sodium metaperiodate to form methvl phenyl sulfoxide, 46,75... 

Addition of BuLi to a 0.3 M solution of chloromethyl phenyl sulfoxide in THF at — 78 "C yields an immediate bright-yellow solution containing the lithio derivative which is stable for at least 2 h at —78 rC. Decomposition occurs rapidly above —20 C with the solution becoming turbid and the color changing to dark brown. Reaction of the lithiated solution of chloromethyl phenyl sulfoxide with cyclohexanone, acetone, or ben/ophenone for 10 min at —78 °C followed by 30 min at —20 rC yields one diastereomeT in 79, 75 and 68 % yields, respectively, after hydrolysis of the corresponding adducts. 

Methyl m-tolyl (8), ethyl m-tolyl, methyl n-butyl and methyl n-propyl sulfoxides were obtained in 100% e.e. This method was less successful when applied to methyl phenyl sulfoxide (5% e.e.) or to methyl isobutyl and methyl ethyl sulfoxides (25% e.e.). No complexes were formed between methyl o-tolyl, methyl p-tolyl, methyl 2-butyl and methyl isopropyl sulfoxides so these compounds could not be resolved using 7. A crystal structure of the 1 1 complex formed between 7 and 8 revealed that the partners were linked by OH—OS hydrogen bonds in endless zig-zag chains23. More recently, 2-chloroethyl m-tolyl sulfoxide (9) has been resolved using 724. 

The study by Baechler and coworkers31, cited above, also provided data on the (1,3)-allylic rearrangement in /J-methylallyl phenyl sulfoxide. Using the same approach as was used in reinterpreting the sulfone data, the activation energy is estimated to be 151 kj mol- and AfH°(PhSO) = 45kJmol-1. 

In the reaction of 88 with /(-phenethyl bromide, l-phenethyl-3-phenylpropyl methyl sulfoxide and bis-3-phenylpropyl sulfoxide, besides 3-phenylpropyl methyl sulfoxide are obtained118. Sulfoxides, bearing a /1-hydrogen to the sulfmyl function, give olefins upon thermolysis. Utilizing this reaction, Trost and Bridges120 alkylated benzyl phenyl sulfoxide, 3,4-methylenedioxybenzyl phenyl sulfoxide, phenylthiomethyl phenyl sulfoxide, phenylsulfinylmethyl phenyl sulfoxide and cyanomethyl phenyl sulfoxide with alkyl, allyl and benzyl halides and subjected these sulfoxides to thermolysis, obtaining olefins in one-pot processes. 

Lithiochloromethyl phenyl sulfoxide 99 was found to react with aryl or alkyl halides in the presence of one equivalent of hexamethylphosphoramide to afford alkylated products 100 in high yields135. Thermal decomposition of these products in the presence of a catalytic amount of hydroquinone in xylene gave the corresponding vinyl compounds 101. 

Photochemical oxygen transfer reactions involving sulfoxides have also been documented. For example, a photochemical rearrangement of 2-nitrophenyl phenyl sulfoxide to 2-nitrosophenyl phenyl sulfone224, and the inverse photoconversion of o-methylbenzoic acid225 have been reported. Finally, photochemical epimerizations of the sulfoxide centers... 

Several alkyl aryl sulfides were electrochemically oxidized into the corresponding chiral sulfoxides using poly(amino acid)-coated electrodes448. Although the levels of enan-tioselection were quite variable, the best result involved t-butyl phenyl sulfoxide which was formed in 93% e.e. on a platinum electrode doubly coated with polypyrrole and poly(L-valine). Cyclodextrin-mediated m-chloroperbenzoic acid oxidation of sulfides proceeds with modest enantioselectivity44b. 

In the case of diaryl sulfoxides the formation of both the aryl radical and the hydroxycyclohexadienyl radical was observed optically. Veltwisch and coworkers45 studied also the reaction of OH radicals from radiolysis of aqueous solutions of mixed (alkyl phenyl) sulfoxides (PhSOR). They found the formation of both alkylsulfinic and phenylsulfinic acids. 

The branching of the adduct decomposition was studied by measuring the pKa of the mixtures. Thus for pulse radiolysis of N20-saturated methyl phenyl sulfoxide the results yield a p/Ca obs value of 1.50 while the values for methane sulfinic and benzene sulfinic acids are 2.28 and 1.29, respectively. The fraction of each branch can be calculated from the equation,... 

For methyl phenyl sulfoxide it was found that 25% of the adduct decomposes to give phenyl radical and methane sulfinic acid, while 75% of the adduct leads to methyl radical and benzene sulfinic acid. For heavier alkyl groups the formation of the benzene sulfinic acid is even more dominant, 96% for R = Et and 100% for R = C2H4C1 or i-Pr. 

E. Reduction of Halomethyl Phenyl Sulfones and Chloromethyl Phenyl Sulfoxide by Fluorenide Anions... 

Sulfoxides such as methyl phenyl sulfoxide 1898 are readily reduced by hexa-methyldisilthiane 601 to give sulfides such as methyl phenyl sulfide 1899 in 90% yield, sulfur, and HMDSO 7 [108-110]. Analogously, the S-oxide of diethylsulfide... 

Molecules having only a sulfoxide function and no other acidic or basic site have been resolved through the intermediacy of metal complex formation. In 1934 Backer and Keuning resolved the cobalt complex of sulfoxide 5 using d-camphorsulfonic acid. More recently Cope and Caress applied the same technique to the resolution of ethyl p-tolyl sulfoxide (6). Sulfoxide 6 and optically active 1-phenylethylamine were used to form diastereomeric complexes i.e., (-1-)- and ( —)-trans-dichloro(ethyl p-tolyl sulfoxide) (1-phenylethylamine) platinum(II). Both enantiomers of 6 were obtained in optically pure form. Diastereomeric platinum complexes formed from racemic methyl phenyl (and three para-substituted phenyl) sulfoxides and d-N, N-dimethyl phenylglycine have been separated chromatographically on an analytical column L A nonaromatic example, cyclohexyl methyl sulfoxide, did not resolve. 

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