Episulfonium ions, formation

Phenylthio-3-trimethylsilylalkanols lose the element of trimethylsilanol on treatment with an acid [208]. Ionization of the hydroxyl group is participated by the sulfur atom and the episulfonium intermediates then undergo desilylation. The Si-C-C-S segment is conjoint and its fragmentation proceeds upon activation by episulfonium ion formation. 

Structural variations that hinder episulfonium ion formation or sulfur nucleophilicity reduce activity. Thus, S(C(0)CH2C1)2 is reported to show little vesicant behavior (Sartori, 1939). 

Molecules with more extensive separation between sulfur and leaving groups, such as chlorine (e.g., C1(CH2)6S(CH2)6C1), behave like simple aliphatic halides (or sulfides) since three-membered ring (episulfonium ion) formation is no longer possible. One convenient method for verifying the formation of an episulfonium ion intermediate involves isotopic carbon labeling. Since this ion is symmetric, it would ultimately lead to a nearly 1 1 distribution of an appropriately placed label, something not observed in a direct displacement. 

Sulfides, including HD, undergo oxidation at sulfur. Initial oxidation produces a sulfoxide, whereas further oxidation produces a sulfone (below). Oxidants include hydrogen peroxide, perox-yacids, nitric acid, permanganate ion, ozone, dinitrogen tetroxide, and dichromate ion. Oxides of mustard are not as volatile as mustard. This may help to explain why British air raid shelters were sometimes painted using the oxidant calcium hypochlorite (Ca(OCl)2). Episulfonium ion formation is less likely in the sulfoxide of HD than in HD itself. 

Two examples of desulfurization reactions of sugar dithioacetals, in which episulfonium ion formation is postulated, are pertinent here. Treatment of the 3-amino-3,6-dideoxy-D-mannose derivative (324) with Raney nickel gave some of the 1,2,6-trideoxy alditol (326), along with the... 

Scheme 6 depicts a typical penicillin sulfoxide rearrangement (69JA1401). The mechanism probably involves an initial thermal formation of a sulfenic acid which is trapped by the acetic anhydride as the mixed sulfenic-acetic anhydride. Nucleophilic attack by the double bond on the sulfur leads to an episulfonium ion which, depending on the site of acetate attack, can afford either the penam (19) or the cepham (20). Product ratios are dependent on reaction conditions. For example, in another related study acetic anhydride gave predominantly the penam product, while chloroacetic anhydride gave the cepham product (7lJCS(O3540). The rearrangement can also be effected by acid in this case the principal products are the cepham (21) and the cephem (22 Scheme 7). Since these early studies a wide variety of reagents have been found to catalyze the conversion of a penicillin sulfoxide to the cepham/cephem ring system (e.g. 77JOC2887).

In 2008, Toste and coworkers reported the desymmetrization of me o-episulfonium ions 131 generated in situ from ring closure of sulfides 132 featuring a P-trichloro-acetimidate leaving group [76], Chiral BINOL-derived phosphoric acid (5)-3o (15 mol%, R = triggered the formation of the intermediate mera-epi-... 

An intramolecular regioselective sulfenocyclization of unsaturated ureas 447 resulted in formation of 5,6-dihydro-4//-l,3-oxazine derivatives 449 (Scheme 86). The procedure employed phenylsulfenyl chloride and ethyldiisopro-pylamine to generate an episulfonium ion intermediate 448, from which the cyclic products 449 were formed by internal nucleophilic displacement <1995M609>. 

Although in many cases the formation of the GSH conjugate protects cellular proteins from electrophilic attack, not all GSH conjugations with xenobiotics lead to detoxification. For example, in the case of haloalkanes, GST-catalyzed conjugation with GSH can lead to the formation of the highly electrophilic episulfonium ion [35], which can covalently bind DNA and cause mutations. 

Pearson, PG, Soderlund, E.J., Dybing, E. Nelson, S.D. (1990b) Metabolic activation of 1,2-dibromo-3-chloropropane evidence for the formation of reactive episulfonium ion intermediates. Biochemistry, 29, 4971-4981... 

The unactivated aziridine-2-carboxylic acid methyl ester was found to react with two molecules of aromatic thiol47 Initial ring opening is followed by a faster reaction (since little mono substitution product is found), probably involving formation of an episulfonium ion which is then ring opened by the second ArSH. The same result... 

Figure 13.8. GST may enhance the toxicity of xenobiotics. Ethylene dibromide is a substrate of GST (theta and others) to be converted to l-bromo-2-.S -glutathionyl ethane, which facilitates spontaneous formation of the episulfonium ion. The episulfonium ion attacks the N7 position of guanine and causes DNA adduct formation. GST pi Ilel05 to Val polymorphism, causing increased GSTpi activity, appears to correlate with higher testicular and bladder cancer. This may also be involved in GSTpi-mediated activation of unidentified xenobiotics. (Adapted from Henderson et al. Proc. Natl. Acad. Sci. USA 95, 5275-5280,1998.)...

The reaction of a-fluoro-/f-hydroxy-a-phenylsulfanyl esters 4, which can be readily synthesized from aldehydes and ethyl bromofluoroacetate, with diethylaminosulfur triduoride leads to the formation of a,o -difluoro-/I-phenylsulfanyl esters Instead of the expected substitution of the j8-hydroxy group by fluorine, a rearrangement via an episulfonium ion and addition of a fluoride ion % to the ester function gives the a,a-difluorinated product 5. The reaction proceeds under mild conditions with moderate to good yields. In the case of ethyl 2-fluoro-3-hydroxy-3-phenyl-2-(phcnylsulfanyl)propanoate only the nonrearranged product ethyl 2.3-di-fluoro-3-phenyl-2-(phenylsulfanyr)propanoate was isolated. 

There are several related reactions involving probable formation of episulfonium ions from aikenes, with subsequent addition of various nitrogen nucleophiles giving products of net rraru-1,2-(N + S) addition (ref. 197 and references cited therein). In a recent example ( heme 64) the sulfur reagent also provides the nitrogen nucleophile yields were best with styrene. Related cyclizations are known in the 3-lactam area, e.g. Scheme 65 compounds (43) and (44) are also available by related but base-catalyzed cyclizations. ... 

When suitably constructed unsaturated compounds, such as olefinic alcohols or unsaturated carboxylic acids 1, react with phenylsulfenyl chloride the formation of the corresponding bicyclic /j-phenylthio derivatives 3 takes place31. This presumably proceeds via the intermediacy of an episulfonium ion 2 which is captured intramolecularly by the hydroxy group leading to the final sulfenylation product 3 in high yield. 

When this reaction was carried out in the presence of DMAD in carbon disulfide, thiophene 253 was obtained in 51% yield (Equation 39). A tentative mechanism of formation of a-dithiones is shown in Scheme 72. First, episulfonium ions 254 are formed and then sulfur ylides 255 are obtained. From the ylides the a-dithiones 256 are formed, while the episulfonium ions 254, by reaction with DMAD to produce 257, finally lead to the formation of 253. 

At low temperatures, the three-membered-ring episulfonium ion, 4-56, which resembles a bromonium ion, reacts with bromide only at the primary carbon. The product of this 8 2 reaction is determined by the reaction rate, which is faster at the primary carbon than at the secondary carbon. This is a reaction in which product formation is rate-controlled. 

The formation of cyclic compound 381, formed in 50% by reaction of 377 with thiol (1 equiv) in a 1/1 mixture of acetonitrile and sodium phosphate buffer, was explained as a result of attachment by water on the episulfonium ion 380, which is stmcturally related to the intermediate 376. 

Trost and Martin have used the dimethylsulfoxonium ion to provide a leaving group. Thus, a cis addition of DMTSF to alkenes flrst led to adducts of the type (15), which then reacted with lithium alkynides in the presence of diethylaluminum chloride to give the trans adduct (Scheme 28). The reaction is presum to involve the episulfonium ion, which then ensures the observed stereospecificity. The reaction is also regiospecific, the anti-Markovnikov addition being illustrated by the second example in Scheme 28. The adducts can be converted to alkanes with Raney nickel and to alkenes by sulfoxide formation and elimination. 

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