Preparation of Thiols

Thiols bound irreversibly to supports have mainly been used as linkers for carboxylic acids (Sections 3.1.2 and 3.3.3), for pyrimidines and triazines (Section 3.8), or for other thiols (Section 3.12). When working with these resins, special care must be taken to prevent atmospheric oxidation of the thiols to the corresponding disulfides. 

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). 

This reaction occurs only when the hydroxyl groups are on adjacent carbons. 

PROBLEM 15.13 Predict the products formed on oxidation of each of the foi-iowing with periodic acid  

SAMPLE SOLUTION (a) The carbon-carbon bond of 1,2-ethanedioi is cieaved by periodic acid to give two moiecuies of formaidehyde  

Cyclic diols give dicarbonyl compounds. The reactions are faster when the hydroxyl groups are cis than when they are trans, but both stereoisomers are oxidized by periodic acid. 

Periodic acid cleavage of vicinal diols is often used for analytical purposes as an aid in structure determination. By identifying the carbonyl compounds produced, the constitution of the starting diol may be deduced. This technique finds its widest application with carbohydrates and will be discussed more fully in Chapter 25. 

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Preparation Of Thiol Acids, Thiol Esters And Amides By Reactions Of Carbonyl Sulfides With Grignard Reagents," Katritzky. A.R. Moutou, J.-L. Yang, Z. Org. Prep. Proceed. Int., 1995, 27, 361... 

The preparation of thiols by nucleophilic displacement reactions using aqueous potassium or sodium hydrogen sulphide under catalytic conditions is not particularly effective. A limited number of simple alkane thiols have been obtained under mild and neutral conditions in moderate yield (70-80%) from the reaction of bis(n-butyltin) sulphide with bromoalkanes in the presence of a ca. twofold amount of tetra-n-butylammonium fluoride [1], but there has been no exploitation of this procedure. 

Chlorides of sulfonic acids can be reduced either partially to sulfinic acids, or completely to thiols. Both reductions are accomplished in high yields with lithium aluminum hydride. An inverse addition technique at a temperature of —20° is used for the preparation of sulfinic acids, while the preparation of thiols is carried out at the boiling point of ether [69S]. 

The preparation of thiols by S ,2 attack of nucleophilic HS on an alkyl halide gives poor yields because the mercaptan loses a proton to form an anion, RS, which reacts with a second molecule of alkyl halide to form a thioether. 

Gruber, H. J. Kada, G. Pragl, B. Riener, C. Hahn, C. D. Harms, G. S. Ahrer, W. Dax, T. G. Hohenthanner, K. Knaus, H. G. Preparation of thiol-reactive Cy5 derivatives from commercial Cy5 succinimidyl ester. Bioconjug. Chem. 11(2), 161-166. Gudgin Dickinson, E. F. Poliak, A. Diamandis, E. P. Time-resolved detection of lanthanide luminescence for ultrasensitive bioanalytical assays. J. Photochem. Photobiol. B Biol. 1995,27, 3-19. 

Thiol esters RC(0)SR are stronger acylating agents than simple alkyl esters, and have been prepared on solid phase mainly as synthetic intermediates. The preparation of thiol esters as intermediates for the synthesis of support-bound thiols is discussed in Section 8.1. Further examples of the preparation of thiol esters on insoluble supports include the aldol addition of ketene thioacetals to polystyrene-bound aldehydes... 

In addition, dextran tosylates may be used for the preparation of thiol-containing derivatives usable for self-assembly structures (Fig. 55) [368]. 

Methods available before 1971 for the preparation of thiol esters are briefly summarized in a review article.4 Since then, several newer techniques have been developed, to meet a certain set of criteria required for recent synthetic operations. This development may be summarized as follows. Whenever an acid chloride is available, the reaction of the T1(I) salt of a thiolate of virtually any kind, including alkane-, benzene-, 2-benzothiazoline-, and 2-pyridinethiol, proceeds efficiently and near-quan-titatively. However, if selective thiol ester formation in the presence of hydroxy or other functional groups in the same molecule is required, three main procedures are available. First, reaction of an acid (1), with... 

Preparation of Thiol Esters The 2-Methylpropane-2-Thiol Esters... 

Three different types of thiocarboxylic esters (and also thiolactones) exist the thiol, thioxo- and dithioesters which, according to the lUPAC rules, are named S-alkyl (S-aryl) carbothioates (1), 0-alkyl (0-aryl) carbothioates (2) or alkyl (aryl) carbodithioates (3). Acylation-type reactions were used for the first preparations of thiol carboxylic esters (1) by Tjuttschew (1863), Saytzeff and Lukaschewicz (1868) and Michler (1875). Thioxocarboxylic esters (2) were first obtained via an acylation route by Matsui (1908). On the other hand, alkyl dithiobenzoates (3 R = Ph), which were first mentioned in a patent by Bioch and H6hn (1908), and alkyl alkanedithioates (3 R = Me, Et, PhCH2), first described by Houben and Schultze (1910), were prepared by alkylation of the corresponding metal carbodithioates. 

Condensing agents that are well known for peptide synthesis are also very suitable for the preparation of thiol carboxylic esters. 

Table 2 Phosphorus Compounds R R P(0)X used as Activators for the Preparation of Thiol Carboxylic Esters (1)...

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