Arene thiols nucleophiles

Both methodologies described in this chapter impressively illustrate the versatility of Bi(OTf)3 as a mild Lewis acid catalyst. Most notably, in addition to arenes, other nucleophiles such as amines, amides, alcohols and thiols could as well be used in this transformation. 

Sulfur nucleophiles such as thiolate anion generally appear near the top of the nucleophi-licity scale and thus readily attack oxepins (Scheme 20). While adduct formation between oxepin (7) and thiols occurs spontaneously upon mixing (74JA6929), a similar reaction between the naturally occurring tripeptide thiol, glutathione, and oxepin-arene oxide intermediates formed during mammalian metabolism is catalyzed by a glutathione epoxide transferase. 

Soft and polarizable nucleophiles, e.g., azide, thiol anions, and phenoxides, add readily to arene oxides, whereas harder anions like carbanions and... 

Aryl-A3-iodanes bearing an electron-deficient alkyl ligand such as aryl(sul-fonylmethyl)-A3-iodanes (Section 3.2.7) and aryl(perfluoroalkyl)-A3-iodanes are relatively stable. A series of (perfluoroalkyl)phenyl-A3-iodanes 96 were synthesized in good yields by treating bis(trifluoroacetoxy)-A3-iodanes with benzene in the presence of triflic acid [47]. The AModanes 96 transfer the perfluoroalkyl groups to a variety of nucleophiles with reductive elimination of iodobenzene. The nucleophiles involve Grignard reagents, alkyllithiums, enolate anions, alkenes, alkynes, trimethylsilyl enol ethers, arenes, phenols, and thiols. In these reactions, the AModane 96 serves as a source of the perfluoroalkyl cation and, in... 

Trityl resins are particularly suitable for immobilization of nucleophilic substrates such as acids, alcohols, thiols, and amines. They are quite acid-sensitive and are cleavable even with acetic acid this is useful when acid-labile protecting groups are used. The stability of trityl resin can be tailored by use of substituted arene rings, as shown by chlorotrityl resin, which furnishes a more stable linker than the trityl resin itself. Steric hindrance also prohibits formation of diketopiperazines during the synthesis of peptides. Orthogonality toward allyl-based protective groups was demonstrated in the reverse solid-phase peptide synthesis of oligopeptides [30] (Scheme 6.1.4). 

Nucleophilic acyl substitution reactions take place in living organisms just as they take place in the chemical laboratory. The same principles apply in both cases. Nature, however, often uses a thiol ester, RCOSR, as the add derivative because it is intermediate in reactivity between an acid anhydride and an ester. Thiol esters aren t as reactive as anhydrides, yet they re more reactive than typical esters toward nucleophilic attack. 

The key to many of these degradation processes is oxidative metabolism by the cytochrome P450 enzyme family [10]. Cytochrome P450 oxidation is most easy for electron-rich -electron systems, for example aromatic moieties or olefinic substructures, from which epoxides are generated. These epoxides are often potent electrophiles, intercalating into DNA and reacting with all kinds of nucleophile, for example nucleobases, amines, or thiols. Metabolic processes like this are the reason for the mutagenicity of many polycyclic arenes. 

A number of catalysts have been used to promote ring opening of A-tosyl-aziridines, such as phospho-molybdic acid and silica gel, for azide, cyanide and alcohols " and tri-n-butylphosphine for thiols and amines. Opening with iodide occurs at room temperature with iodine and thiophenol in the presence of air. In the nucleophilic ring opening of A-tosyl-aziridines, silver ion catalysis facilitates reactions with electron-rich arenes or hetarenes. ... 

Phenol and (thiophenol)FeCp complexes were prepared by substitution for Cl by OH- and SH- nucleophiles. Alcohols are initially converted to alkoxides using a base such as KOt-Bu or NaH and then give smooth substitution [63,64]. Both aryl and alkyl thiols react smoothly using K2CO3 as a base [65]. Substitution with selenium nucleophiles is also known [66]. Primary and secondary amines are sufficiently reactive without added base if used in excess, although a base (e.g., Et3N, pyridine or K2CO3) can be used to drive the reaction [67-69]. Mild reaction conditions allow arylation of amino acids with (PhF)FeCp (Eq. 17) [69]. The process is of limited value, however, since decomplexation of the arene led to decomposition. 

Fig. 2. Reactions of arene oxides. Spontaneous aromatization into phenols and nucleophilic addition reactions by amines and thiols...

Reactions at acid centers to create 5 -2-(trimethylsilyl) ethanethiolesters are also common. Carboxylic 5-thiolesters are formed in high yield by the DCC/DMAP mediated coupling of 2-(trimethylsilyl)ethanethiol and carboxylic acids or by thiol substitution on a carboxylic acid chloride. 5 -2-(Tiimethylsilyl) ethyl p-toluenethiolsulfonate is formed by treating 2-(trimethyl-silyl)ethanethiol with tosyl bromide (eq 4). The product is a useful electrophile for carbon nucleophiles, allowing the introduction of the 2-(trimethylsilyl)ethylthio unit by an alternative mechanism. Independent of the thiol, aryl and alkyl 2-trimethylsilylethyl thioethers may be prepared by the radical addition of the appropriate arene- or aikanethiol to vinyl trimethyl-silane in a reaction comparable to that of eq l7 ... 

Progress has recently been made in cascade reactions. Use of aluminum reagents leads to the formation of nitriUum species, which add nucleophiles such as hydride [385], thiol [386] or cyanide [387]. Finally, cascade Friedel-Craft/Beckmann amidation reactions of electron-rich arenes have been developed. They involve reactions of carboxylic acids and hydroxylamine in the presence of polyphosphoric acid [388]. 

Thi< as Nudeo rtiiles.— Aryl-oxirans yield mixtures of 1- and 2-aryl-2-phenylthioethanols with PhSNa, proportions being determined by substituents on the oxiran." Glutathione is not more nucleophilic than simple thiols towards benzene oxide, thus disposing of a theory that this tripeptide has a special detoxification function for arene oxide intermediates... 

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