Thiocarboxylates, 0-alkyl

S-Alkylation of a thiocarboxylic acid with an a-halogenated carbonyl compound gives a thiol ester in which the two carbons to be connected... 

SYNTHESIS OF THIOLS, THIOETHERS, THIOACETALS AND S-ALKYL THIOCARBOXYLIC ESTERS... 

A procedure, which has been used successfully for the synthesis of dialkyl thioethers from thioacetamide has been extended to the preparation of a range of 5-alkyl thiocarboxylic esters [35] (Table 4.20). The intermediate 5-acyl ethaniminium salt (Scheme 4.14) is not stable and is converted directly into the 5-alkyl thioester. The choice of catalyst affects the yield of the thioesters. Thus, 5-n-octyl thiobenzoate... 

TABLE 4.20 S-Alkyl thiocarboxylic esters from thioacetamide ... 

The Pd-catalyzed allylic alkylation of thiocarboxylate ions was carried out with potassium thioacetate (KSAc) and potassium thiobenzoate (KSBz) and the racemic cyclic and acyclic carbonates rac-3aa, rac-3ba, rac-lda, rac-laa, rac-lba, and rac-lca, respectively (Scheme 2.1.4.21). The carbonates rac-3aa, rac-3ba, rac-lda, rac-laa, and rac-lba were treated with KSAc (1.4 equiv) or KSBz (2.0 equiv) in the presence of Pd(0)/L (2 mol%) and BPA (8 mol%) in CH2CI2/H2O. Under these conditions the acyclic carbonates rac-3aa and rac-3ba gave the thioesters 18aa, 18ab and 18ba, respectively (Table 2.1.4.14, entries 1-3), with high enantioselec-tivities in high yields [26]. 

The kinetic resolution of the racemic allylic acetates rac-3ab, rac-ldb, rac-lab, and rac-lbb with thiocarboxylate ions and BPA were investigated in more detail (Scheme 2.1.4.22). The acetates were selected instead of the corresponding carbonates in order to avoid the competing formation of the corresponding allylic alcohols (vide supra). All reactions were carried out in CH2CI2/H2O (9 1) using 2 mol% of Pd(0)/L and 8 mol% of BPA. Termination of the reaction of the pen-tenyl acetate rac-3ab with KSAc at 35% conversion showed the operation of highly selective kinetic resolution (entry 4). However, 50% conversion of the substrate could be achieved neither at room nor at reflux temperature. This is in contrast to the reactivity of carbonate roc-3aa (cf. Table 2.1.4.14, entry 1) and perhaps reflects the lower reactivity of allylic acetates in Pd-catalyzed alkylation. This... 

The Pd-catalyzed allylic alkylation of sulfinate ions, thiols, and thiocarboxylate ions with racemic cyclic and acyclic allylic esters in the presence of bisphosphane BPA generally provides for an efficient asymmetric synthesis of allylic sulfones, sulfides, and thioesters. The Pd-catalyzed rearrangements of allylic sulfinates and allylic O-thiocarbamates, both of which proceed very efficiently in the presence of BPA, are attractive alternative ways to the asymmetric synthesis of allylic sulfones and allyUc thioesters also starting from the corresponding racemic alcohols. 

Both Bu3SnH and (Me3Si)3SiH are able to reduce alkyl iodides or bromides but not alcohols. However, in the Barton-McCombie reaction, they reduce certain alcohol derivatives, namely, ones that contain a C=S double bond (e. g., thiocarboxylic esters or thiocarbonic esters). Figure 1.39 shows how the OH group of cholesterol can he removed by means of a Barton-McCombie reaction. The C=S-containing alcohol derivative used there is a xanthate. 

Nucleophilic attack of ammonia or of a primary or secondary amine on an O-alkyl thiocarboxylate (2) provides a formally straightforward approach to thioamides and a number of examples have been reported (equation l). - However, some limitations should be noted. Thus, there is a tendency of esters (2) to rearrange to their 5-alkyl isomers on heating (cf. Volume 6, Chapter 2.5) and these yield amides with amines rather than thioamides. Besides, excess primary amine will lead to amidine formation, or the tetrahedral intermediate of the substitution reaction may break down to an imidate rather than a thioamide (cf. Volume 6, Chapter 2.7). These unwanted side reactions are favoured in polar, protic solvents such as ethanol. In contrast, THF has proven to be particularly useful in the synthesis of tertiary thioamides according to equation (1). For improved reactivity in the preparation of V-aryl derivatives and milder reaction conditions, it is advantageous to employ the amine in the form of its Mg salt. ... 

Methyl thiocarboxylates are very suitable for the V-thioacylation of V-unprotected amino acids. Thus, shaking a heterogenous mixture of PhCSOMe in ether and the amino acid in aq. NaOH gives g(X)d yields of V-thiobenzoylated material. Using (9-alkyl thiocarboxylates of amino acids (2 R = R NHCHR ), the approach has been extended to synthesize endothiopeptides such as (5) formation of imidates may interfere with the desired process. The reaction has been carried out in water/THF using NazCOj or as shown in equation (3). ... 

Dithiocarboxylates, R CSSR give a faster reaction with amines than G-alkyl thiocarboxylates (2 cf. Section 2.4.2. ). As shown in equation (8), this pronounced reactivity may lead to an undesired in situ reaction with the liberated ammonia to give a primary thioamide, when the ester is generated by thiolysis of a thioimidate. ... 

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. 

Although acylation reactions rank among the best-known methods for the synthesis of thiocarboxylic 5-esters (1), there exist other important and convenient routes, - e.g. the alkylation of thiocarboxylate anions (equation 1) or radical addition of thiocarboxylic acids to carbon-carbon double bonds (equation 2). These methods are not dealt with here (qf. Volume 4, Chapter 1.5). 

Alternatives to the acylation-type reaction are even more important in the thioxo- and dithio-carbox-ylic ester series 4 >5,24-29 dithiocarboxylate salts are most conveniently obtained from a variety of precursors and can be not only alkylated but also arylated by arenediazonium hydrogen sulfates (equation 3). An advantage of the latter method is that no thiophenols are needed, which are necessary, but sometimes not easily obtained, educts in most other S-aryl thiocarboxylate preparations (c/. Chapter 1.5). 

Unlike carboxylic esters, open-chained S-alkyl thiocarboxylates cannot be obtained by direct proton-catalyzed esterification. Whereas thiocarboxylic acids react with alcohols to form esters as expected, thiol esters are formed on reaction of carboxylic acids with thiols, but the equilibrium is shifted towards the educts and the reaction is not useful for synthetic purposes. Therefore, activation is necessary and several methods have been developed to meet this requirement. 

DCC can be used to prepare 5-alkyl and 5-aryl thiocarboxylates (1) from carboxylic acids and thiols according to equation (5). This method has been successfully applied to the synAesis of thiol esters with sensitive substituents, e.g. 5-methyl thioacrylate, a natural product. In particular, N-protected amino acid and peptide 5-phenyl esters, which are useful building blocks in peptide synthesis, are obtained in excellent yields without racemization. N-Hydroxyphthalimide and DMAP have been used as cocatalysts to facilitate the reaction. The preparation of the Wittig reagent (5) by this route is shown in equation (6). 

The open-chained thioacetamide, on the other hand, yields iminium salts (34) on acylation. Reaction of (34) with alkyl halides and subsequent hydrolysis results in the formation of thiocarboxylic esters (1). This reaction is actually performed in one step under phase transfer catalysis (equation 21). No unpleasant smelling thiols or thiocarboxylic acids are required as educts, the yields are high and a large variety of substituents R and R are possible. ... 

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