Benzylation, thiol groups

Deacetalization, the reverse of acetalization, was similarly promoted by TiCU. The example shown in Eq. (245) [561] illustrates the compatibility of functional groups. Neither demethylation of anisole nor elimination of the benzylic thiol group occurred. Equation (246) shows the regeneration of the diol moiety from an acetal [562]. 

In the presence of sulfide or sulfhydryl anions, the quinonemethide is attacked and a benzyl thiol formed. The P-aryl ether linkage to the next phenylpropane unit is broken down as a result of neighboring-group attack by the sulfur, eliminating the aryloxy group which becomes reactive phenolate ion (eq. 2). If sulfide is not present, a principal reaction is the formation of the stable aryl enol ether, ArCH=CHOAr. A smaller amount of this product also forms in the presence of sulfhydryl anion. 

Furakawa et al. (1978) have suggested that the reaction of benzyl a-toluenethiolsulfinate shown in (71) proceeds through a mechanism (72) where there is an initial cycloelimination, followed by a recombination of PhCHjSOH and PhCH=S to give an or-sulfinylthiol, and then subsequent acylation of the thiol group. 

A variant of this procedure is provided by the preparation of S-benzyl-l-cysteine (Expt 5.206). The required thiolate salt is prepared by the reductive cleavage with sodium in liquid ammonia of the disulphide linkage in the amino acid, (S)-cystine, and is alkylated in situ with benzyl chloride. The preparation of this S-benzyl derivative constitutes a method of protection of the thiol grouping in cysteine. 

Typically, substitution reactions occur by attack of a nucleophilic reagent on a benzyl carbon present in the form of a carbonium ion or a methine group in a quinonemethide structure. Several representative substitution reactions are illustrated in Fig. 1.5. At moderate temperatures ( 100°C) and under mildly alkaline conditions, benzylic hydroxyl groups in phenolic units are converted to thiols by reaction with bisulfide (Q, Fig. 1.5). At higher temperatures and alkalinities, e.g., under kraft pulping conditions, the mercaptide group undergoes a series of transformations in which the sulfur is ultimately eliminated. 

In the uncondensed imidazoles the standard method reacts an a-aminocarbonyl compound with a thiocyanate (see Section 4.1 and Table 4.1.1). If a 2-alkylthioimidazole is required directly, one can combine an N-alkyT or A -arylcarbonimidodithioate in refluxing acetic acid with the aminocarbonyl substrate (see Section 4.1 and Scheme 4.1.3). Alternatively, reaction between thiourea and a two-carbon synthon (ot-hydroxy-, a-halogeno-, a-dicarbonyl) leads to imidazoline-2-thiones (see Section 4.3). In sulfuric acid, 3-butynylthiourea cyclizes to 4,5-dimethylimidazolin-2-thione (see Section 2.2.1). 1-Substituted 2-methylthioimidazoles can be made, albeit in rather poor yields, from appropriately substituted 2-azabutadienes (see Section 3.2 and Scheme 3.2.3), and 2-arylthioimidazoles are available in moderate yields from benzyl isocyanides and arylsulfenyl chlorides (see Section 4.2 and Scheme 4.2.12). Ring transformations of 5-amino-2-alkylaminothiazoles and 2-acylamino-5-aminothiazoles may have occasional applications (see Section 6.1.2.7). The ease with which a thiol group or imidazole or benzimidazole can be alkylated, in comparison with the annular nitrogens, usually makes it more convenient to prepare alkylthioimidazoles from the thiols (or thiones). 

At this point it is interesting to note, that the method of reducing disulfides with sodium in liquid ammonia [16], benzylation of the thiol groups in situ and their debenzylation in the same solvent [17] had been elaborated by du Vigneaud many years earher (cf, p. 71) as if some intuition would have directed his efforts toward the chemistry of oxytocin. An account of this continued interest in sulfur containing natural products can be found in his book A Trail of Research [18]. 

The actual preparation of the tetrapeptide amide required several steps, among them acylation with di-benzyloxycarbonyl-L-cystine, activated in the form of acid chloride, removal of the benzyloxycarbonyl group by reduction with sodium in liquid ammonia, rebenzylation of the thiol group, conversion to benzyl ester and then to the amide. The tetrapeptide amide was secured in crystalline form. 

The addition of thioacetic acid to tra 5-chalcones furnished only moderate enantioselectivity (33-65% ee with Takemoto s catalyst 11) [33]. Better results were obtained by the Chen group, with various thiols employing quinine-derived squaramide 13 [34]. It is worth noting that, in this case, substituted benzyl thiols, furfuryl thiol, and aliphatic thiols were better donors than thiophenol (Scheme 14.6). 

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