Oxidation to sulfone

The conversion of cyclic sulfides to sulfones is accompbshed by more energetic oxidations. Perhalogenated thiolanes [106] and 1,3-dithietanes [107] are oxidized to sulfones and disulfones, respectively, by a mixture of chromium trioxide and nitric acid (equation 98) The same reagent converts 2,4-dichloro-2,4-bis(tnfluoromethyl)-l,3-dif/u cto cs to disulfone derivatives [107], whereas trifluoromethaneperoxysulfonic acid converts the starting compound to a sul-fone-sulfoxide derivative [2(equation 99). 

The enzymatic oxygenation process is of particular value as there is a significant difference in the formation rates of sulfoxides and sulfones. The initial conversion of sulfide to the optically active sulfoxide by an MO is usually very fast compared to the subsequent oxidation step to sulfone, upon which chirality is lost (Scheme 9.26). In many cases, over-oxidation to sulfone is not observed at all when employing MOs. 

The oxidation of sulfides to sulfoxides are occasionally found to be unsatisfactory, since the resulting sulfoxides are easily oxidized to sulfones. In order to avoid the further oxidation of sulfoxides into sulfones, several oxidizing agents have been selected. Recently, we found that BTMA Bt3 is the most effective and satisfactory oxidizing agent for this purpose. That is, the reaction of sulfides with a calculated amount of BTMA Br3 and aq. sodium hydroxide in dichloromethane at room temperature, or in 1,2-dichloroethane under reflux, gave sulfoxides in good yields (Fig. 28) (ref. 36). 

Insulin, a small protein of molecular mass 6000 daltons, is composed of two chains designated A and B. There are no reduced cysteine residues in insulin, but it contains three essential disulfide bonds two that crosslink the A and B chains, and one internal to the A chain to stabilize the overall tertiary stmcture. These disulfide bonds are cleaved in the presence of excess AuX4, leaving A and B chains that have cysteine residues that have become oxidized to sulfonic adds [119]. With smaller amounts of AuX4, a single disulfide bond will be attacked to form sulfinic acid [119]. The reaction is second order for AuCU while AuBr4 reacts too quickly for accurate monitoring. 

According to Marshall [23] and Beech [26], the oxidation of the thiophenol linker would increase the reaction rate. To study this effect, the linker in resin (35) was oxidized to sulfone/sulfoxide using mCPBA. Cleavage reaction of resin (35) -OX with n-butylamine went to completion in less than 4 min (Fig. 12.20), compared with 24 h needed for this resin under the same conditions without oxidation. The rate constant was determined to be 0.0179, which was a 580-fold increase compared with the unoxidized form. This result indicated that a linker oxidation was preferred for high yield when the products will not be affected by oxidation conditions. 

Uemura and coworkers utilized (R)-binaphthol 85 as chiral ligand in place of DET in association with Ti(IV)/TBHP, which not only mediated the oxidation of sulfides to (R)-configurated sulfoxides, but also promoted the kinetic resolution of sulfoxides (equation 50). In this latter process the two enantiomers of the sulfoxide are oxidized to sulfone by the chiral reagent at different rates, with decrease of the chemical yield, but increase of the ee values. Interestingly, the presence of ortho-nilro groups on the binaphthol ligand lead to the reversal of enantioselectivity with formation of the (5 )-configurated sulfoxide. Non-racemic amino triols and simple 1,2-diols have been successfully used as chiral mediators. 

Sulfides in the electrophilic positions are often oxidized to sulfones to facilitate nucleophilic displacement reactions. The sulfoxide is initially formed, and can sometimes be isolated, but normally the oxidation is allowed to proceed fully to give the sulfone. Peroxyacids are commonly used as the oxidant, although other reagents such as oxone (potassium peroxymonosulfate) can also be employed <20030L1011, 2006ARK(vii)452>. 

The pharmacokinetics and metabolism of tazarotene (2) is especially worth noting. Topical gel application provides the direct delivery of tazarotene into the skin. Ten hours after a topical application of 0.1% tazarotene gel to the skin, approximately 4-6% of the dose resides in the stratum comeum and 2% of the dose is distributed to the viable epidermis and dermis. As depicted in Scheme 3, both tazarotene (2) and tazarotenic acid (11) undergo further metabolism to their corresponding sulfoxides 12 and 13, respectively. Sulfoxides 12 and 13, in turn, are even further oxidized to sulfones 14 and 15, respectively. These very polar metabolites do not accumulate in adipose tissue, but are rapidly eliminated via both urinary and fecal pathways with a terminal half-life of approximately 18 h. A lesson learned here is that installation of a sulfide moiety promotes clearance because it is oxidized to polar metabolites that are rapidly cleared. As the consequence, the systemic exposure is minimized. Percutaneous absorption of tazarotene (2) led to a plasma concentration below 1 gg/L. The systemic... 

Thiols, sulfoxides, sulfones, disulfides,407 and other sulfur compounds can be oxidized to sulfonic acids with many oxidizing agents, though for synthetic purposes the reaction is most important for thiols.408 Among oxidizing agents used are boiling nitric acid and barium... 

For a general review of Ihe oxidation of thiols, see Capozzi Modena, in Patai The Chemistry of the Thiol Group. pt. 2 Wiley New York, 1974, pp. 785-839. For a review specifically on the oxidation to sulfonic acids, sec Gilbert Sulfonation and Related Reactions Wiley New York. 1965, pp. 217-239. 

Sulfonation of benzo[6 ]thiophene with concentrated sulfuric acid in acetic anhydride at 20 °C gives a mixture which is chiefly the 3-sulfonic acid, with some 2-isomer and 3-acetylbenzo[6 Jthiophene (70AHC(i)l77). Chlorosulfonation of 2- or 3-methyl-benzo[6 Jthiophene gives the corresponding 3- or 2-sulfonyl chloride in satisfactory yield. The various available 4-, 5-, 6- and 7-mercaptobenzothiophenes or sulfides (Section 3.15.9.5.2) can be oxidized to sulfonic acids or sulfones by conventional means. 

Sulfoxides are easily obtained by oxidation of sulfides. They can be further oxidized to sulfones. Many reagents have been used, and the possibility to synthesize selectively sulfoxides and sulfones, often in the presence of other sensitive functionalities, is an important feature for synthetic applications. The reaction is well documented [75], and only a few notable aspects are mentioned here. 

For studies of sulfoxide complexes of simple cations, perchlorate has been used in almost every case to provide an uncompetitive anion. There are many cautionary notes about explosive properties and it must be concluded that the latent potential for being oxidized to sulfones renders the combination of sulfoxides and perchlorates hazardous and unpredictable. 

The H0F-CH3CN complex readily oxidizes sulfides to sulfones.120 The electrophilic nature was confirmed by an X o value (see Peroxides and Peracids for a discussion of Xgo) of 0.45. Examples include electron-deficient sulfides that cannot be oxidized to sulfone by any other method. 

Mechanisms have been suggested for the N-bromosuccinimide (NBS) oxidation of cyclopentanol and cyclohexanol, catalysed by iridium(III) chloride,120 of ethanolamine, diethanolamine, and triethanolamine in alkaline medium,121 and for ruthenium(III)-catalysed and uncatalysed oxidation of ethylamine and benzylamine.122 A suitable mechanism has been suggested to explain the break in the Hammett plot observed in the oxidation of substituted acetophenone oximes by NBS in acidic solution.123 Oxidation of substituted benhydrols with NBS showed a C-H/C-D primary kinetic isotope effect and a linear correlation with er+ values with p = —0.69. A cyclic transition state in the absence of mineral acid and a non-cyclic transition state in the presence of the acid are proposed.124 Sulfides are selectively oxidized to sulfoxides with NBS, catalysed by ft-cyclodextrin, in water. This reaction proceeds without over-oxidation to sulfones under mild conditions.125... 

Analytical procedures for the isolation of the sulfide and thiophene classes of compounds from petroleum are described. The methods are based on the selective oxidation of first the sulfides to sulfoxides, followed by silica gel separation of the sulfoxides and their reduction back to sulfides. The thiophenes are then separated from the sulfide-free oil by selective oxidation to sulfones, followed by silica gel separation of the sulfones from the oil and their reduction back to thiophenes. 

Aliphatic sulfides are oxidized to sulfones in SSE s containing water (see 8,1). 

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