Thioacetic acid, addition

The addition of aromatic and aUphatic thiols, RSH and ArSH, and a thioacetic acid to isoprene yields mainly the trans-l,4-adduct (56). The aromatic thiyl radicals, ArS , add almost entirely to the first carbon atom however, aUphatic thiyl radicals, RS, also add to the fourth C atom in significant amounts. 

Another example of resort to heteroatoms to obtain both oral potency and a split between androgenic and anabolic activities Ls tiomestrone (99). Trienone, 98, prepared in much the same way as 23, undergoes sequential 1,6 and 1,4 conjugate addition of thioacetic acid under either irradiation or free radical catalysis to afford the compound containing two sulfur atoms. 

The chloroacetylurea derivative (A = C1CH2) obtained from the above addition (Eq. 1), on treatment first with thioacetic acid and Et3N and then with cysteamine, afforded the corresponding thiol (A = HSCH2) (Eq. 3)l5). 

A recent total synthesis of tubulysin U and V makes use of a one-pot, three-component reaction to form 2-acyloxymethylthiazoles <06AG(E)7235>. Treatment of isonitrile 25, Boc-protected Z-homovaline aldehyde 26, and thioacetic acid with boron trifluoride etherate gives a 3 1 mixture of two diastereomers 30. The reaction pathway involves transacylation of the initial adduct 27 to give thioamide 28. This amide is in equilibrium with its mercaptoimine tautomer 29, which undergoes intramolecular Michael addition followed by elimination of dimethylamine to afford thiazole 30. The major diastereomer serves as an intermediate in the synthesis of tubulysin U and V. 

The conjugate additions of thiols to a,p-unsaturated electrophiles was extended by Wang [96]. Catalyst 166 promoted the addition of thioacetic acid to a variety of enones, including aliphatic, aromatic and heteroaromatic substituents (Scheme 42). Wang expanded the scope of the reaction to include asymmetric additions of thioacetic acid to nitro-olefms (Scheme 43) [97]. Thiourea catalyst 166 promoted the addition reactions in high yields and high enantiomeric ratios for a variety of P-substituted nitro-olefms. 

The same group utilized thiourea 12 (10mol% loading) for the catalysis of the enantioselective Michael addition of thioacetic acid to various chalcones [214]. At room temperature and otherwise unchanged conditions, in comparison to the... 

Scheme 6.64 Michael adducts provided from the 12-catalyzed asymmetric addition of thioacetic acid to various chalcones.

Scheme 6.65 Mechanistic proposals for the biflinctional mode of action of catalyst 12 in the Michael addition of thioacetic acid to nitroalkenes (A) and to chalcones (B).

The first syntheses of 1,2-cfs-thioglycoses (a-D-gluco- and )3-D-manno- derivatives) have been achieved by the reaction in acetone of alkyl or benzyl xanthate or potassium thioacetate with the corresponding l,2-tra s-glycosyl halides [13]. More recently, tetra-O-acetyl-l-S-acetyl-l-thio-a-D-glucopyranose (10a) (Scheme 3) has been obtained i) by reaction of -acetochloroglucose (9 a) with either potassium thioacetate in HMPA or the tetrabutylammonium salt of thio-acetic acid in toluene [14] ii) by peroxide-induced addition of thioacetic acid to the pseudo-glucal (11) [15]. 

To further exploit the potential usefiilness of this new family of clusters, monoadduct 54 was saponified into 55 (0.05 M NaOH, quant) and condensed to L-lysine methyl ester using 2-ethoxy-l-ethoxycarbonyl-l,2-dihydroquinoline (EEDQ) to give extended dimer 56 in 50 % yield together with monoadduct in 15 % yield [75]. Additionally, tert-butyl thioethers 52 could be transformed into thiols by a two step process involving 2-nitrobenzenesulfenyl chloride (2-N02-PhSCl, HOAc, r.t, 3h, 84%) followed by disulfide reduction with 2-mercaptoethanol (60%). Curiously, attempts to directly obtain these thiolated telomers by reaction with thioacetic acid f ed. These telomers were slightly better ligands then lactose in inhibition of binding of peanut lectin to a polymeric lactoside [76]. 

The search for compounds that had improved oral activity led initially to the 7a-thioacetyl derivative (51-2) [48]. Dehydrogenation of the enone function in (50-5) using the now-familiar quinone, chloranU, leads to the dienone (51-1). This undergoes 1,6 conjugate addition on treatment with the sodium salt from thioacetic acid to give the la derivative (51-2) this compound, under the name spironolactone, was the first clinical aldosterone antagonist. Studies on the metabolic disposition of... 

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). 

Equilibrium data are also available for some Ag1 complexes with alkyl-, alkenyl- and phenyl-thioacetic acids. An important conclusion here is that the strength of the Ag—S bond is mainly determined by its o component.34 In addition, the fact that the cis isomer (1) isomerizes to the trans isomer (2) upon moderate heating suggests that there is no strong metal-to-sulfur -interaction.35 Affinity data for other systems have been compiled by Kuehn and Isied.4... 

Addition of bromine in dichloromethane or of thioacetic acid in ethanol onto the methylene group of 9-arylidene and 9-carboxymethylene moieties of 6,7,8,9-tetrahydro-4//-pyrido[l,2-a]pyrimidines 546 stereoselectively gave 9-substituted 6,7,8,9-tetrahydro derivatives 547 and 548, respectively, at ambient temperature (Scheme 34) (90JHC247). Addition was also stereoselective with respect to the C(9) and C(9)—C centers, giving the erythro diastereomers as the primary products, which may then undergo epimerization to the threo isomers. The structure and epimerization of the products were studied by H and l3C NMR spectroscopy and by molecular mechanics calculations. 

Cinchona alkaloids and their derivatives have been reported to catalyse the Michael addition of (V-heterocycles, such as benztriazole, to nitroalkenes in moderate to high enantioselectivities (<94% ee) 15 The thiourea derivative (149) catalysed Michael addition of thioacetic acid to a range of frafts-/f-nitrostyrenes to afford RCH(SAc)- CH2NO2 (<70% ee) 16 The thiourea derivative (149) and its congeners have been identified as efficient organocatalysts for the Michael addition of a-substituted cyano-acetates RCH(CN)C02Et to vinyl sulfones CH2=C(R)S02Ph (72-96% ee) 17 ... 

In contrast to the previous reaction, free-radical addition of thioacetic acid to 1-chlorocyclo-hexene is less diastereoselective and a much higher percentage of the frany-diastereomer trans-3 is formed1. 

Asymmetric induction also takes place in the cinchona catalyzed addition of thioacetic acid to a,/3-unsaturated dicarboxylic acid esters. Both the reaction rate and optical purity of the addition products are influenced by the nature of the alkoxy or thioalkoxy group in the unsaturated substrate. Generally, thioesters are more reactive towards thioacetic acid and better enantioselectivities are observed for unhindered esters11. 

The hydrolysis of thiol esters is achieved in either acidic or basic media. Alcoholic solutions of hydrogen chloride or potassium hydroxide are the most common reagents. Dithiols, hydroxy mercaptans/ and mercapto ethers, ketones, and acids have been prepared by this method. The corresponding thiol esters are obtained by the addition of thioacetic acid to oxides and olefinic acids or by the action of its potassium salt on halo ketones or sulfonic esters. ... 

Tetrahydropyridazines were shown to undergo radical addition of thioacetic acid to the 4,5-double-bond to yield the corresponding 4-thioacetoxy derivatives (80JHC1465). One electron oxidation of maleic... 

Deoxy-6-thio-D-a yfo-hexose forms a 1,6-anhydro compound analogous to 270. S-Acetyl-5-deoxy-l,2-0-isopropylidene-6-thio-a-D-xyZo-hexofuranose is obtained either by nucleophilic displacement on the corresponding 6-p-tolylsulfonyloxy compound with potassium thioacetate or by the photochemical addition of thioacetic acid to... 

Radical addition to peracetylated 2-hydroxyglucals proceeds efficiently using either photochemical initiation and thiols or f-butyl or cumene peroxides and thioacetic acid to give the l-thio-a-D- / co derivative (O Scheme 24) [97,98]. 

Sulfur ylides have been used to generate bicyclic macrolactams, as shown in Scheme 35. Argogel-bound thioacetic acid 130 was synthesized from thioacetic acid esters by alkylation with Argogel-Cl resin and subsequent basic hydrolysis of the ester (not shown in Scheme 35). Esterification with co-hydroxy vinyl ketone 131 gave intermediate 132. Alkylation with MeOTf activated the thioether and reaction of 133 with DBU in CH2CI2 at room temperature provided the macrocycle 134 containing an additional cyclopropyl unit in 52 % yield as the pure trans diastereoi-somer [51]. 

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