Electrophilic sulfenic acid

In the previous examples, the sulfur atom acted as a nucleophile. Electron-deficient sulfur species such as sulfenyl ion and its equivalents (e.g. disulfide/Lewis acid complexes, sulfenic acids, sulfenyl halides, sulfonium ions, sulfines, etc.), can also serve as an electrophile. Oxidative ring closure of enethiols (a-thioketocarboxylic acid) (124), which proceeds via disulfides, produces thiophenes (125) in good yields (86EUP158380, 88JHC367). 

The first highly stereocontrolled total synthesis of a natural penicillin was reported 2 years later by Baldwin et al. <1976JA3045>. In this case, the methodology relies on the formation of the fi-lactam ring before the thiazolidine ring closure, via the sulfenic acid intermediate 97 (Rz = OH), which gives electrophilic attack on the double bond to produce a penam sulfoxide 98 (see Section 2.03.5.3) (Scheme 52). A similar route has been developed independently by Kishi for the total synthesis of 6cr-methoxy penicillin derivatives <1975JA5008>. 

Polar Processes. Kice (5) has presented extensive evidence that cleavage of the S-S bond can be catalyzed by electrophilic and nucleophilic assistance. Heterolytic cleavage would generate sulfenic acid as the active peroxide decomposing species. Traces of water and sulfur-containing compounds may be considered as potential nucleophiles. 

The chemistry of the PPIs dictates reaction with electrophilic groups in amino adds after add-catalyzed conversion of the prodrug. The reactive group is the free SH of cysteine, which can then form a disulfide bond with the sulfenic acid or sulfenamide derivative of the PPI. In principle, cysteine disulfides can also react, but reformation of the native disulfide would eliminate the bound drug. 

In studying both the electrophilic and nucleophilic nature of the sulfenic acid group, it was found that the sulfenic acid from 106 reacted with thiols (e.g., 2-methylpropane-1-thiol) to give a mixture of the disulfides 152 and 153 (Barton et al., 1970 1971a). The concomitant isomerization of the double bond appeared to be dependent upon both the side chain... 

Results which were obtained by electrochemistry thermospray mass spectrometry in the oxidation of 6-thioxanthine are summarized in Table 1 . The EC/TSP/MS/MS shows formation of xanthine at potentials where only the thio group can be oxidized. Xanthine has been identified by derivatization and GC/MS as the product of exhaustive oxidation at these potentials. In addition to xanthine, 2-hydroxypurine was identified as a product. Simultaneously with these products, the parent compound, 6-thioxanthine, was detected. The results support the pathway (Fig. 3) which has been proposed on the basis of the off-line methods . The two products, xanthine and 2-hydroxypurine, may form as a result of nucleophilic or electrophilic attack, respectively, on the initial oxidation product, sulfenic acid (Fig. 7). Control experiments confirmed that the two products form only during oxidation at these potentials. 

Normally, reactive derivatives of sulfonic acids serve to transfer electrophilic sulfonyl groups259. The most frequently applied compounds of this type are sulfonyl halides, though they show an ambiguous reaction behavior (cf. Section III.B). This ambiguity is additionally enhanced by the structure of sulfonyl halides and by the reaction conditions in the course of electrophilic sulfonyl transfers. On the one hand, sulfonyl halides can displace halides by an addition-elimination mechanism on the other hand, as a consequence of the possibility of the formation of a carbanion a to the sulfonyl halide function, sulfenes can arise after halide elimination and show electrophilic as well as dipolarophilic properties. 

The electrophilic reactivity of sulfenic esters strongly increases after addition of suitable Lewis acids and such binary systems effectively promote not only simple addition to a C—C double bond, but also induce cationic arene-alkene cyclization in a wide range of substrates29,30. 

Nucleophiles with two sites that could react with electrophiles are called ambident nucleophiles. The Hard and Soft Acids and Bases (HSAB) principle applies because a hard electrophile reacts at the harder nucleophilic site and a soft electrophile at the softer nucleophilic site. For instance, the sulfenate ion 70 is an ambident nucleophile, because it reacts (a) with methyl fluorosulfonate, a hard electrophile, at the oxygen atom, where most of the negative charge is concentrated, to give the sulfenate ester 71 and (b) with methyl iodide, a soft electrophile, to give the sulfoxide 72. Sulfur atom is the softer of the two nucleophilic sites available in the sulfenate ion and, furthermore, it is rendered more nucleophilic by the a-effect arising from the adjacent oxygen atom. 

Dehydrogenation of sulfenamides. The expedient transformation to sulfen- mines is applicable to the synthesis of an electrophilic glycine synthon appropriate for the elaboration of other amino acids. 

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