Sulfoxides, alkyl phenyl

Cyclodextrins, toroidal molecules composed of 6, 7 and 8 D-glucose units, are now commercially available at reasonable cost. They form inclusion compounds with a variety of molecules and often differentially include sulfoxide enantiomers29,30. This property has been used to partially resolve some benzyl alkyl, phenyl alkyl and p-tolyl alkyl sulfoxides. The enantiomeric purities after one inclusion process ranged from 1.1 % for t-butyl p-tolyl sulfoxide to 14.5% for benzyl r-butyl sulfoxide. Repeating the process on methyl p-tolyl sulfoxide (10) increased its enantiomeric purity from 8.1% to 11.4% four recrystallizations raised the value to 71.5%. The use of cyclodextrins in asymmetric oxidations is discussed in Section II.C.l and in the resolution of sulfmate esters in Section II.B.l. 

A major problem with the sulfoxide synthesis using menthyl sulfmates is its failure to produce optically pure dialkyl sulfoxides. The prerequisite menthyl alkanesulfinates are oils which have resisted separation into the individual epimers. The menthyl phenyl methanesulfmates are an exception the R epimer is crystalline . One solution to this problem, at least for preparing methyl alkyl sulfoxides, was achieved using cholesteryl methanesulfmates (27) . Both epimers were crystalline and could be separated by fractional crystallization, although in poor yield. Treatment of the epimers with n-propyl, n-butyl, isobutyl, p-tolyl and benzyl magnesium halides yielded the respective methyl alkyl sulfoxides (28) in greater than 95% e.e. and in 32 to 53% yields. 

A different approach to the resolution of sulfoxides was recently reported by MikcJajczyk and Drabowicz (35). It takes advantage of the fact that sulfoxides as well as other sulfinyl compounds ry easily form inclusion complexes with 3-cyclodextrin. Since -cycl dextrin (the host) is chiral, its inclusion complexes with racemic guest substances are mixtures of diastereomeis that can be formed in unequal amounts. In this way a series of alkyl phenyl, alkyl p-tolyl, and alkyl benzyl sulfoxides has been resolved. However, the optical... 

Holland s group40 has shown that the most versatile biotransformation using whole cell biocatalyst is the one using the fungus species NRRL 4671. From analysis of the sulfoxidation of a large number of substrates (> 90), they recently proposed a predictive model for chiral sulfoxidation by the fungus. The model (Fig. 2), developed from energy-minimized (MM+) structures of substrates produced by Hyperchem, is able to explain the stereochemical inversion seen for sulfoxidation of some phenyl alkyl sulfides, such as phenyl vinyl and phenyl hexyl sulfide. 

The reaction of phenyl vinyl sulfoxide 234 with isobutene, in the presence of trifluoroacetic anhydride, yielded the to-alkylated product 238 (Scheme 59).128 It was suggested that this reaction proceeded by a different mechanism than the usual additive Pummerer mechanism. The alkene reacts with the electrophilic sulfur atom of intermediate 235, giving, after loss of a trifluoroacetate ion and a proton, the sulfonium ion 236. Thio-Claisen rearrangement of the ion then gives the thonium ion 237 which reacts with a further molecule of isobutene to give the product 238. 

In the mid-1960s Mislow started a research program on the mechanism of the thermal racemization of sulfoxides [97-99]. In the course of these efforts he recognized an enormous racemization rate acceleration for (R)-allyl-p-tolyl sulfoxide ((R)-151) as compared to benzyl or, even more pronounced, to alkyl sulfoxides (Scheme 42). For this compound, prepared by Andersen synthesis [100,101], he found a racemization rate exceeding that of the phenyl-substituted sulfoxide by a factor of 560 000. Based on kinetic measurements Mislow et al. determined the activation parameters to be AH = 22 kcal mor ... 

Tanikaga and coworkers have reported the addition of nitroalkane anions to a-halo-a,P-unsaturated sulfoxides [72]. Further development of this work led to the use of nitroalkanes as alkyl group equivalents in conjugate addition to a,P-unsaturated sulfoxides [73-75]. Primary or secondary nitroalkanes such as 2-nitropropane (77), with DBU as a non-nucleophilic base, add to a,P-unsaturated sulfoxides including phenyl vinyl sulfoxide (26) to give products such as (78), which can be denitrated to yield (79) (Scheme 5.25). The Michael addition of nitroalkanes, and of diethyl N-acetylaminomalonate, to racemic phenyl vinyl sulfoxide using solid-liquid phase-transfer catalysis in the absence of solvent has also been accomplished [76]. 

Phenyl vinyl sulfoxide can be polymerized and randomly oxidized to form sections of phenyl vinyl sulfone (VSO2) before elimination (vide supra) to control the conjugation length of the resulting PA (Scheme XVI) [74]. To a flask containing dry and distilled THF was added a few drops of alkyl lithium (1M solution) to remove any remaining impurities from the solvent. Next, more of the carbanion initiator (0.5 ml of a 1 M solution) was added, and the temperature was lowered to —78°C. The VSO monomer (5 ml) was then added, and the color of the solution turned to... 

A variety of methods for the reduction of sulfoxides to sulfides are available. PI3 rapidly reduces aryl alkyl and dialkyl sulfoxides and selenoxides, usually at —78 °C (eq 3). For example, treatment of ethyl phenyl sulfoxide with 1 equiv of PI3 (CH2CI2, -78 °C, 15 min) affords ethyl phenyl sulfide in 91% yield. Others have successfully employed this procedure. Dialkyl sulfoxides generally react in somewhat lower yield. A phenyl vinyl sulfoxide (eq 3, entry c) requires ambient temperatures to react. Selenoxides behave similarly, and P2I4 can usually be used in place of PI3. Treatment of decyl phenyl selenone with PI3 (CH2CI2, 0 °C, 30 min) affords a mixture of the reduced product, decyl phenyl se-lenide (69%), and the substitution product, n-decyl iodide. ... 

It is known that cydodextrins have a hydrophobic cavity (a binding site for aromatics) and a hydrophilic external surface. A template-directed asymmetric sulfoxidation has been attempted with various aryl alkyl sulfides. [91]. Oxidations were performed by using metachlo-roperbenzoic add in water in the presence of an excess of p-cyclodextrin. The best ee (33%) was attained for mem-(r-butyl)phenyl ethyl sulfoxide. The decrease in the amount of P-cyclodex-trin below 1 mol equiv. causes a sharp decrease in enantioselectivity because of competition with oxidation of free substrate by the oxidant. Similarly, Drabowicz and Mikolajczyk observed modest asymmetric induction (27% ee) in the oxidation of Ph-S-n-Bu with H2O2 in the presence of P-cyclodextrin [92]. 

Abbreviations aapy, 2-acetamidopyridine Aik, alkyl AN, acetoniuile Ar, aryl Bu, butyl cod, 1,5-cyclooctadiene COE, cyclooctene COT, cyclooctatetraene Cp, cyclopentadienyl Cp , penta-methylcyclopentadienyl Cy, cyclohexyl DME, 1,2-dimethoxyethane DME, dimethylformamide DMSO, dimethyl sulfoxide dmpe, dimethylphosphinoethane dppe, diphenylphosphinoethane dppm, diphenylphosphinomethane dppp, diphenylphosphinopropane Et, ethyl Ec, feirocenyl ind, inda-zolyl Me, methyl Mes, mesitylene nb, norbomene orbicyclo[2.2.1]heptene nbd, 2,5-norbomadiene OTf, uiflate Ph, phenyl PPN, bis(triphenylphosphoranylidene)ammonium Pi , propyl py, pyridine pz, pyrazolate pz, substituted pyi azolate pz , 3,5-dimethylpyrazolate quin, quinolin-8-olate solv, solvent tfb, teti afluorobenzobaiTelene THE, tetrahydrofuran THT, tetrahydrothiophene tmeda, teti amethylethylenediamine Tol, tolyl Tp, HB(C3H3N2)3 Tp , HB(3,5-Me2C3HN2)3 Tp, substituted hydrotiis(pyrazol-l-yl)borate Ts, tosyl tz, 1,2,4-triazolate Vin, vinyl. 

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-... 

Alkyl-3-ethoxy-4-[(mesyloxy)methyl]-l,4-dihydroisoquinolines 27 on treatment with potassium /Vrt-butoxide in dimethyl sulfoxide undergo ring expansion to 1/7-2-benzazepines.24 0 (For related ring expansions of acridines, see Section 3.2.1.4.1.5.) The 4-methyl and 4-methyl-l-phenyl derivatives 27a and 27b, respectively, yield mixtures of the 3-ethoxy-5-methyl- 28 and 3-ethoxy-4-methyl- 29 l//-2-benzazcpines cyclopropaquinolines are thought to be involved as intermediates (see Section 3.2.1.4.1.6.). In contrast, the 4-[l-(mesyloxy)ethyl] derivatives 27e and 27d yield only the 4,5-dimethyl-li/-2-benzazepines 29c and 29d. 

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