Sulfide-sulfone oxidation

The architecturally novel macrolide (+)-zampanolide was synthesized in the laboratory of A.B. Smith. The C8-C9 ( )-olefin moiety was constructed using the Kocienski-modified Julia oleHnation. The required PT-sulfone was prepared from the corresponding primary alcohol via a two-step protocol employing sequential Mitsunobu reaction and sulfide-sulfone oxidation. The primary alcohol and two equivalents of 1-phenyl-1 H-tetrazolo-5-thiol was dissolved in anhydrous THF at 0 °C and treated sequentially with triphenylphosphine and DEAD. The desired tetrazolo sulfide was isolated in nearly quantitative yield. 

Nucleophilic reactivity of exocyclic sulfur appears in acidic medium. 2-AryI thiazolyl sulfones are obtained from the corresponding sulfides by oxidation with HjO- in HOAc at 100°C (272). The same oxidation takes place with alkyl sulfides (203. 214, 273-275) and dithiazolylsulfides (129). However, the same reaction with 2-benzylthio derivatives gives benzylal-cohol and the related A-4-thiazoline-2-thione (169). 

Sulfones and sulfoxides (145) are obtained usually from the corresponding sulfide by oxidation (Scheme 75) (341). though some of them were prepared from a halothiazole and metal sulfinate (342). 2-Amino-5-acetamidophenylsulfonylthiazole has been prepared by direct heterocycli-zation (343. 344). 

Numerous diamines and aromatic dianhydrides have been investigated. WhoUy aromatic Pis have been stmctiirally modified by incorporating various functional groups, such as ether, carbonyl, sulfide, sulfone, methylene, isopropjlidene, perfluoroisopropyUdene, bipyridyls, sdoxane, methyl phosphine oxide, or various combinations of these, into the polymer backbone to achieve improved properties. The chemistry and apphcations of Pis have been described in several review articles (4). 

The kinetics of formation and hydrolysis of /-C H OCl have been investigated (262). The chemistry of alkyl hypochlorites, /-C H OCl in particular, has been extensively explored (247). /-Butyl hypochlorite reacts with a variety of olefins via a photoinduced radical chain process to give good yields of aUyflc chlorides (263). Steroid alcohols can be oxidized and chlorinated with /-C H OCl to give good yields of ketosteroids and chlorosteroids (264) (see Steroids). /-Butyl hypochlorite is a more satisfactory reagent than HOCl for /V-chlorination of amines (265). Sulfides are oxidized in excellent yields to sulfoxides without concomitant formation of sulfones (266). 2-Amino-1, 4-quinones are rapidly chlorinated at room temperature chlorination occurs specifically at the position adjacent to the amino group (267). Anhydropenicillin is converted almost quantitatively to its 6-methoxy derivative by /-C H OCl in methanol (268). Reaction of unsaturated hydroperoxides with /-C H OCl provides monocyclic and bicycHc chloroalkyl 1,2-dioxolanes. 

A-Chlorosuccinimide 1 N NaOH." With this method, the sulfide is oxidized completely to the sulfone, which is cleaved with hydroxide more readily than the sulfoxide formed by periodate oxidation. It has been reported that oxidation of the sulfide leads to oxidation of adenine and gua-nine." However, see the discussion of the TPTE group below. 

The thiophene sulfur atom shows very few of the reactions expected of a sulfide. The oxidation to a sulfone is difficult to achieve, but is of special interest, as knowledge of its aromatic character or lack of it would give information about the ability of sulfur to expand its valence shell beyond eight electrons. 

Bordwell and Boutan (BB)81 carried out extensive work on the methylsulfmyl group in 1957. It must be emphasized that they found that the preparation of pure arylmethyl sulfoxides from arylmethyl sulfides by oxidation was not a trivial matter. The frequently recommended reagent, hydrogen peroxide in acetic acid, tended to give sulfoxides contaminated with appreciable quantities of sulfones, which could not be removed by fractional crystallization. Oxidation by nitric acid was found to be more satisfactory. 

Sulfur(II)-containing compounds possess the reducing activity and react with hydroperoxides and peroxyl radicals [1-5]. They are employed as components of antioxidant additives to lubricants and polymers [30-35]. Denison and Condit [36] were the first to show that dialkyl sulfides are oxidized by hydroperoxides to sulfoxides and then to sulfones... 

Buynak et al. [53] synthesized several 6-(mercaptomethyl) penicillanates (9r and 9s, Table 1) that include both C-6 stereoisomers as well as the sulfide and sulfone oxidation states of the penam thiazolidine sulfur. Selected mercaptomethyl penicillanates inactivated both metallo- and serine /5-lactamases, and displayed synergism with piperacillin against various //-lactamase-producing strains, including metallo-/5-lactamase-producing P. aeruginosa strain. Compound 9r would be capable of bidentate chelation of zinc subsequent to enzymatic hydrolysis of the /5-lactam (Scheme 3). 

Failure to achieve the bicyclization of diallyl ether with nBu2ZrCp2 led to the unexpected discovery of the oxidative addition reaction,226 shown in Scheme 44. This reaction has been extensively used for developing synthetically useful reactions, also shown in Scheme 44 232 234>234a-234c Another breakthrough on this topic was made with alkenyl chloride,235 which led to more recent similar discoveries with alkenyl sulfides, sulfones, and ethers236,23611 237 (Scheme 45). 

The first oxidation product of a sulfide is a sulfoxide and this can be further oxidized to a sulfone (Fig. 4.91). A good example is sulindac, which is a sulfoxide. It can be reduced to a sulfide or oxidized to a sulfone (Fig. 4.91). The sulfide is more active as a nonsteroidal anti-inflammatory agent than the parent drug but the sulfone is inactive (160). 

The established mechanism of sulfide photo-oxidation in solution invokes the novel formation of two intermediates a persulfoxide. A, and a hydroperoxy sulfonium ylide, B, (Fig. 13A) [25], In this mechanism the sulfide substrate intercepts the second intermediate, k o, and does not competitively inhibit the predominant sulfone forming pathway, kso2. As a consequence, the sulfone/sulfoxide ratio is independent of sulfide concentration. In contrast, the results in the zeolite are inconsistent with this mechanism but are consistent with the trapping of a single intermediate with both sulfide and adventitious sulfoxide (Fig. 13B). 

Scheme 8 summarizes the introduction of the missing carbon atoms and the diastereoselective epoxidation of the C /C double bond using a Sharpless asymmetric epoxidation (SAE) of the allylic alcohol 64. The primary alcohol 62 was converted into the aldehyde 63 which served as the starting material for a Horner-Wadsworth-Emmons (HWE) reaction to afford an E-configured tri-substituted double bond. The next steps introduced the sulfone moiety via a Mukaiyama redox condensation and a subsequent sulfide to sulfone oxidation. The sequence toward the allylic alcohol 64 was com-... 

As already mentioned above, sulfides are oxidized to the corresponding sulfoxides with alkyl hydroperoxides in the presence of various metal catalysts like Mo, W, Ti and V. In the presence of excess hydroperoxide further oxidation to the sulfone occurs. Sulfides are generally oxidized much faster than alkenes, which is reflected in the selective oxidation of unsaturated sulfides exclusively at the sulfur atom. During the last years many asymmetric versions of this reaction have been developed and can be mainly divided... 

Oxidation of sulfides to sulfones.[ Sulfides are oxidized chemoselectively to sulfones by KHSOs (3 equivalents) in high yield. Peracids are usually used for this oxidation, but can also oxidize olefinic groups. Oxidation of sulfides to sulfoxides is also possible with 1 equivalent of reagent. 

The Orsay group found serendipitously that methyl p-tolyl sulfide was oxidized to methyl p-toly 1 sulfoxide with high enantiomeric purity (80-90% ee) when the Sharpless reagent was modified by addition of 1 mole equiv. of water [16,17]. The story of this discovery was described in a review [19], Sharpless conditions gave racemic sulfoxide and sulfone. Careful optimization of the stoichiometry of the titanium complex in the oxidation of p-tolyl sulfide led to the selection of Ti(0iPr)4/(7 ,7 )-DET/H20 (1 2 1) combination as the standard system [ 17]. In the beginning of their investigations, the standard conditions implied a stoichiometric amount of the chiral titanium complex with respect to the prochiral sulfide [16,17,20-23]. Later, proper conditions were found, which decreased the amount of the titanium complex without too much alteration of the enantioselectivity [24,25],... 

Oxidation of sulfur and phosphorus compounds. The peroxide has been used to oxidize the sulfide (2) to the corresponding sulfone in 83% yield without attack of the double bond. Geranyl phenyl sulfide is oxidized to the corresponding sulfone in Ninular yield.4 Trialkylphosphines and phosphites are oxidized to the corresponding oxides in high yield.5... 

Sulfur Compounds of Beef Flavor. Methional, which results from the degradation of methionine, is an important contributor to flavor in meat. Thiolanes, formed during the cooking of beef, have peculiar oniony flavors that also augment the quality of the meaty flavor. Thiophenes and thiofurans are also important to meaty flavors. Sulfides, such as methyl sulfide, are oxidized to methyl sulfoxide and methyl sulfone. Condensation reactions of Maillard browning products also result in thiazoles such as benzothiazole, an important component of meat flavor. 

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

Susceptibility to oxidation of disulfides built into proteins is strongly dependent on their location in the protein molecule (G3). Since the disulfides have a crucial role in maintaining protein tertiary structure, oxidation of certain —S—S— bridges may expose further disulfides and cause unfolding of the protein molcule. The final disulfide oxidation is a sulfone residue, which is stable and does not tend to reverse to sulfide. Therefore oxidative breakage of disulfides is irreversible. The spatial location of disulfides inside protein molecules influences their susceptibility to oxidation. The ribonuclease molecule has four —S—S— bonds, and at least three correctly located disulfide bonds are necessary to retain the ribonuclease enzyme properties. The compact ribonuclease molecule is relatively resistant to HOC1 oxidation (D18). 

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