Nucleophilic substitution with thiolates

Some strategies used for the preparation of support-bound thiols are listed in Table 8.1. Oxidative thiolation of lithiated polystyrene has been used to prepare polymeric thiophenol (Entry 1, Table 8.1). Polystyrene functionalized with 2-mercaptoethyl groups has been prepared by radical addition of thioacetic acid to cross-linked vinyl-polystyrene followed by hydrolysis of the intermediate thiol ester (Entry 2, Table 8.1). A more controllable introduction of thiol groups, suitable also for the selective transformation of support-bound substrates, is based on nucleophilic substitution with thiourea or potassium thioacetate. The resulting isothiouronium salts and thiol acetates can be saponified, preferably under reductive conditions, to yield thiols (Table 8.1). Thiol acetates have been saponified on insoluble supports with mercaptoethanol [1], propylamine [2], lithium aluminum hydride [3], sodium or lithium borohydride, alcoholates, or hydrochloric acid (Table 8.1). 

Aromatic nucleophilic substitution with a thiolate anion can be represented as... 

Thioetherification of PECH is feasibly performed in DA-solvents as already described in the patent (20J. For example, the highest substitution was obtained by the reaction of P(ECH-EO)(1 1 copolymer of epichloro-hydrin and ethylene oxide) and equimolar thiophenoxide in HMPA at 100°C for 10 h as DS 83% for sodium and 93% for potassium salts. The DS in our nucleophilic substitution was estimated by the elemental analysis as well as the titration of liberated chloride ion with mercuric nitrate (21). In the latter method, reacted medium was pretreated with hydrogen peroxide when the reductive nucleophiles which can react with mercuric ion were used. As described before for PVC, thiolation was also achieved conveniently with iso-thiuronium salt followed by alkaline hydrolysis without the direct use of ill-smelling thiolate. The thiolated PECH obtained are rubbery solids, soluble in toluene, methylene chloride, ethyl methyl ketone and DMF and insoluble in water, acetone, dioxane and methanol. 

Thiolate anions RS- are excellent nucleophiles. The substrate, a 1° alkyl halide, is a good substrate for nucleophilic substitutions under basic conditions. The product is PhSCH2CHMe2. Ethanol acts merely as a solvent in this case. It is not nearly as nucleophilic as the thiolate, nor is it acidic enough to be deprotonated by the thiolate, so it s unlikely to react with the alkyl halide. 

In an extension of the procedure, thiols react with gem-dihaloalkanes (Table 4.4) to produce thioacetals [ 10,20-23] and the reaction can be employed in the Corey-Seebach synthesis of aldehydes and ketones (see ref. 24 and references cited therein), gem-Dichlorocyclopiopanes having an electron-withdrawing group at the 2-position react with thiols to produce the thioacetals [25]. In the corresponding reaction of the thiols with biomochloromethane exclusive nucleophilic substitution of the bromo group by the thiolate anion occurs to yield the chloromethyl thioethers [13, 14] (Table 4.5). 

An S Ar (nucleophilic substitution at aromatic carbon atom) mechanism has been proposed for these reactions. Both nonenzymatic and enzymatic reactions that proceed via this mechanism typically exhibit inverse solvent kinetic isotope effects. This observation is in agreement with the example above since the thiolate form of glutathione plays the role of the nucleophile role in dehalogenation reactions. Thus values of solvent kinetic isotope effects obtained for the C13S mutant, which catalyzes only the initial steps of these reactions, do not agree with this mechanism. Rather, the observed normal solvent isotope effect supports a mechanism in which step(s) that have either no solvent kinetic isotope effect at all, or an inverse effect, and which occur after the elimination step, are kinetically significant and diminish the observed solvent kinetic isotope effect. 

The mechanism of hydrolysis of cysteine peptidases, in particular cysteine endopeptidases (EC 3.4.22), shows similarities and differences with that of serine peptidases [2] [3a] [55 - 59]. Cysteine peptidases also form a covalent, ac-ylated intermediate, but here the attacking nucleophile is the SH group of a cysteine residue, or, rather, the deprotonated thiolate group. Like in serine hydrolases, the imidazole ring of a histidine residue activates the nucleophile, but there is a major difference, since here proton abstraction does not appear to be concerted with nucleophilic substitution but with formation of the stable thiolate-imidazolium ion pair. Presumably as a result of this specific activation of the nucleophile, a H-bond acceptor group like Glu or Asp as found in serine hydrolases is seldom present to complete a catalytic triad. For this reason, cysteine endopeptidases are considered to possess a catalytic dyad (i.e., Cys-S plus H-His+). The active site also contains an oxyanion hole where the terminal NH2 group of a glutamine residue plays a major role. 

In order to clarify the different behavior of anion 2 and 3 (Scheme 4.10) toward DMC, various anions with different soft/hard character (aliphatic and aromatic amines, alcohoxydes, phenoxides, thiolates) were compared with regard to nucleophilic substitutions on DMC, using different reaction conditions. Results were in good agreement with the hard-soft acid-base (HSAB) theory. Accordingly, the high selectivity of monomethylation of CH2 acidic compounds and primary aromatic amines with DMC can be explained by two different subsequent reactions, which are due to the double electrophilic character of DMC. The first... 

It is not surprising that chloro esters 1, 2 readily add thiols, catalyzed by sodium thiolates or triethylamine, to give the corresponding 2-(r-organylthiocy-clopropyl)-2-chloroacetates 85,86 (Scheme 22) [15 b, 22b, 27]. This reaction with thiophenol has been used to quantify the Michael reactivity of 1-Me, 2-Me, 3-X in comparison to simple acrylates (see above). With an excess of PhSH, the nucleophilic substitution of the chlorine in 85 a (but not in 85h) proceeded to give the corresponding bis(phenylthio) derivative in 63% yield [15bj. Alkali thiolates (e.g. NaSMe, NaSBn) add smoothly onto 1-Me, 2c-Me and 2p-Me at - 78 °C, because at this temperature subsequent nucleophilic substitution of the chlorine is much slower [7l, 9]. The Michael additions of sodium phenylselenide and sodium arylsulfenates onto 1-Me and their synthetic utility have been discussed above (see Table 1). 

Thiodisaccharides in the GlcNAc series were recently synthesized. The substitution reaction of the triflate at C-4 of 2-acetamido- and 2-azido-o- galacto-sides (34 d) and (34 e) in DMF with thiolate nucleophiles (8i) or (8j) and (30b) afforded the expected disaccharides (aroimd 50 and 68%), from which the deprotected (41) and (42) were obtained [39a, 32] (Scheme 13). The coupling of the triflate (34 f) with the thiol (8j) in DMF in the presence of cysteamine gave a 63% yield of the expected thiocfrsaccharide which was converted into (41) in high yield [39b],... 

All nuclear nucleophilic substitutions on derivatives of compound 4 have involved the replacement of a substituent at position 7 (the equivalent of the y -position in pyridine). In the 7-chloro derivative 244, replacement is possible by methoxide ion,151 by ammonia (with some rearrangement)192 and by amines,151 and by thiourea to give the sulfide (245).151 Substituted 7-chloro derivatives undergo replacement by benzyl oxide ion to give a 7-benzyloxy derivative155,220 and by azide,153 hydrazine,216 hydrosulfide (to give the 7-thione166), and methyl thiolate.220 Some of these compounds carry D-ribofuranosyl benzoate substituents on N-2 or N-3, and methoxide ion... 

Aryl- and heteroaryl halides can undergo thermal or transition metal catalyzed substitution reactions with amines. These reactions proceed on insoluble supports under conditions similar to those used in solution. Not only halides, but also thiolates [76], nitro groups [76], sulfinates [77,78], and alcoholates [79] can serve as leaving groups for aromatic nucleophilic substitution. 

Successful substitutions at neopentyl-type substrates can be performed, but can be accompanied by rearrangements. The best results are obtained with small nucleophiles, for example halides, azide, or cyanide. Some representative examples are shown in Scheme 4.20, to illustrate the reaction conditions required. If electron-rich nucleophiles such as thiolates are used, substitutions at neopentyl derivatives can also occur via SET [95],... 

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