Arylation of thiols

Practically the same set of reaction conditions can be applied to 5-arylation of thiols, giving rise to aiyl sulfides. ... 

Aryl sulfides. Arylation of thiols is mediated by the title reagent mix/... 

The arylation of thiols has also been investigated. Starting from immobilized aryl iodides, smooth reaction occurs with various thiols using dppf as the preferred ligand (Schemes 17 and 18). ° ... 

Figure 2.9 A cross-section of results obtained by Hartwig and coworkers [48] on the arylation of thiols with a Pd-Josiphos catalyst.

In 2012, Xu et al. [117] reported the development of a Chan-Lam-type S -arylation of thiols using boronic acids at room temperature, and this has been a significant development over previous work that used stoichiometric Cu or high temperatures. The reaction could be performed using CuSO ... 

Scheme 4-263. Arylation of thiols catalyzed by iron(III) chloride.

Guy has explored copper-mediated S-arylation of thiols and aryl boronic acids [67]. Earlier studies revealed that the reactions were slow for S-arylation under the conditions developed previously for N- and O-arylation reactions because of a significant disulfide formation. However, it was shown later that the reaction of a wide range of electronically diverse aryl boronic acids with a range of thiolate substrates proceeded well when heated at 155 °C in DME affording cross-coupled products in good yields. Similarly cysteine phenyl sulfide 103 and an arylthio glycoside 104 were also prepared in 50-80% yields (Scheme 3.46). 

Thioethers (sulfides) can be prepared by treatment of alkyl halides with salts of thiols (thiolate ions). The R group may be alkyl or aryl and organolithium bases can be used to deprotonate the thiol. As in 10-37, RX cannot be a tertiary halide, and sulfuric and sulfonic esters can be used instead of halides. As in the Williamson... 

The coupling of thiols with aryl halides has been recently reported using Ni(NHC)2 complexes [171]. After screening different pre-catalysts, compound 28 showed the best behaviour in terms of activity and substrate scope, allowing the coupling of electron rich and poor aryl bromides with aryl or alkyl thiols (Scheme 6.52). 

Several palladium catalysts for formation of aryl sulfides from aryl halides have been investigated more recently. A combination of Pd2(dba)3 and DPEphos catalyzed the formation of a broad range of diaryl sulfides in the presence of 1 mol.% palladium and NaO-t-Bu base in toluene solvent.12,rThe highest yields of alkyl aryl sulfides were obtained from aryl triflates and n-butyl thiol catalyzed by a combination of palladium acetate and BINAP. However, these reactions contained 10 mol.% catalyst, were long, and required deactivated aryl triflates. A combination of Pd2(dba)3 and DPPF catalyzed the coupling of thiols with resin-bound aryl halides.121... 

Although not directly analogous to the coupling of thiols with aryl halides, the reaction of thiourea with an aryl halide in the presence of palladium catalyst, nevertheless, can be used to generate a thiophenol from an aryl halide after hydrolysis (Equation (39)).129 This process occurred in greater than 90% yield with a variety of simple aryl halides ... 

Aryl halide compounds such as fluorobenzene derivatives can be used to form covalent bonds with amine-containing molecules like proteins. The reactivity of aryl halides, however, is not totally specific for amines. Other nucleophiles such as thiol, imidazolyl, and phenolate groups of amino acid side chains also can react (Zahn and Meinhoffer, 1958). Conjugates formed with sulfhydryl groups are reversible by cleaving with an excess of thiol (Shaltiel, 1967). 

There now are available a number of alkyl azide compounds that may be used in click chemistry reactions and the Staudinger ligation processes. It is not recommended, however, to use aryl azide compounds, as these are light sensitive and photoreactive as well as highly susceptible to reduction in the presence of thiols. Unfortunately, at the time of this writing there are fewer choices in aryl phosphine compounds to participate in this reaction, as commercial sources of labeling reagents are limited. 

Peptides typically are prepared for this ligation process using a-alkyl thioesters, because they are simple to make at the time of peptide synthesis. However, due to the relatively slow reaction kinetics of alkyl thioesters, most native chemical ligation processes have been catalyzed through the use of thiol compound additives, such as benzyl mercaptan or thiophenol (Dawson et al., 1997). These compounds react with the initial a-alkyl thioester to form another intermediate, an aryl thioester, which is more reactive toward the N-terminal cysteine on the other peptide to be coupled. A study... 

With a low concentration of thiol, propargyl aryl ethers or amines show vicinal bis(stannation), and it is suggested that this results from stabilization of the initial radical by cyclization onto the aromatic ring (Equation (17)). 

A superior and relatively versatile procedure for the synthesis of unsymmetrical dialkyl thioethers, which avoids the unattractive direct use of thiols, utilizes the stable l-alkylthioethaniminium halides, which are readily obtained from thioacet-amidc [32] (Scheme 4.4). The reaction has also been used for the synthesis of alkyl aryl thioethers from activated aryl halides [33], but it cannot be used for the synthesis of cyclic thioethers, as polymeric sulphides are formed from a,co-dihaloalkanes. A similar sequence to that which leads to the thioethers has been used for the synthesis of S-alkyl thioesters [34] (see 4.1.26). 

The base-catalysed addition of thiols to Jt-electron-deficient alkenes is an important aspect of synthetic organic chemistry. Particular use of Triton-B, in place of inorganic bases, has been made in the reaction of both aryl and alkyl thiols with 1-acyloxy-l-cyanoethene, which behaves as a formyl anion equivalent in the reaction [1], Tetra-n-butylammonium and benzyltriethylammonium fluoride also catalyse the Michael-type addition of thiols to a,P-unsaturated carbonyl compounds [2], The reaction is usually conducted under homogeneous conditions in telrahydrofuran, 1,2-dimethoxyethane, acetone, or acetonitrile, to produce the thioethers in almost quantitative yields (Table 4.22). Use has also been made of polymer-supported qua-... 

The oxidation of a series of alkyl and aryl thiols in aqueous alkaline solution has been studied in the presence of various metal ions. Quantitative amounts of disulfide were produced in all cases. The oxidation rate of thiols has been found to be affected by the geometric size and electron-directing properties of substituent groups in the organic chains of the thiols. The best three catalysts, when added as simple salts, have been found to be copper, cobalt, and nickel. The dependence of the rates of oxidation on the concentrations of reactants have been investigated in some detail. 

As a preliminary to the detailed investigation of the kinetics and mechanism of the oxidation of thiols in the presence of metal-containing catalysts (8), the present paper describes a survey of the rates and end products of oxidation of a series of alkyl and aryl thiols under comparable conditions. The reaction in the absence and presence of various metal-containing catalysts has been studied under conditions of minimal impurity concentrations. 

The Pd-catalyzed enantioselective allylic alkylation of thiols in the presence of BPA is limited to aryl and heteroaryl thiols [10]. However, allylic thioesters should... 

Thioethers (sulfides) can be prepared by treatment of alkyl halides with salts of thiols (thiolate ions).7S2 R may be alkyl or aryl. As in 0-35, RX cannot be a tertiary halide, and sulfuric and sulfonic esters can be used instead of halides. As in the Williamson reaction (0-12), yields are improved by phase-transfer catalysis.753 Instead of RS ions, thiols themselves can be used, if the reaction is run in benzene in the presence of DBU (p. 1023).754 Neopentyl bromide was converted to Me3CCH2SPh in good yield by treatment with PhS in liquid NH3 at -33°C under the influence of light.755 This probably takes place by an SrnI mechanism (see p. 648). Vinylic sulfides can be prepared by treating vinylic bromides with PhS in the presence of a nickel complex,756 and with R3SnPh in the presence of Pd(PPh3)4.757 R can be tertiary if an alcohol is the substrate, e.g,758... 

Methyl- and 2-aryl-substituted benzo[fc]thiophenes (26) can be synthesized starting from o-toluenethiol in three steps, which involves the intramolecular addition of thiols, produced by acid hydrolysis, to the carbonyl group followed by dehydration as the final step (Scheme 3) (91JHC173). 

Acceptor-substituted haloarenes have been successfully used to O-arylate phenols by aromatic nucleophilic substitution (Table 7.14). The most common arylating agents are 2-fluoro-l-nitroarenes, 2-halopyridines, 2-halopyrimidines, and 2-halotriazines. When sufficiently reactive haloarenes are used, the reaction proceeds smoothly with either the arylating agent or the phenol linked to the support. The thallium(III) nitrate catalyzed arylation of phenols with aryl iodides has been used for macrocycli-zations on solid phase [184], Burgess and co-workers have developed a solid-phase synthesis of 3-turri mimetics based on ring-closure by aromatic nucleophilic substitution (Entry 4, Table 7.14 see also Table 10.5). Phenols, alkylamines, and thiols have been successfully used as nucleophiles for this type of macrocyclization [185],... 

Isothioureas can be prepared on insoluble supports by S-alkylation or S-arylation of thioureas (Entry 7, Table 14.6). Further methods for the preparation of isothioureas on insoluble supports include the N-alkylation of polystyrene-bound, A/,/V -di(alkoxy-carbonyl)isothioureas with aliphatic alcohols by Mitsunobu reaction (Entry 7, Table 14.6) and the addition of thiols to resin-bound carbodiimides [7]. Resin-bound dithio-carbamates, which can easily be prepared from Merrifield resin, carbon disulfide, and amines [76], react with phosgene to yield chlorothioformamidines, which can be converted into isothioureas by treatment with amines (Entry 8, Table 14.6). The conversion of support-bound a-amino acids into thioureas can be accompanied by the release of thiohydantoins into solution (see Section 15.9). The rate of this cyclization depends, however, on the type of linker used and on the nucleophilicity of the intermediate thiourea. 

The reactions of vinyl sulfones with various nucleophiles are usually stereoselective. Substituted vinyl sulfones are less reactive toward nucleophiles than the analogous vinyl ketones or esters 10 and are quite inert toward thiols. Peptide vinyl sulfones do not react with thiols such as glutathione under enzyme assay conditions. The reaction of thiols with aryl vinyl sulfones has been reported, however, it is performed in the presence of base. 11 ... 

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