Thioketals thiols

Thioketals are readily prepared by reaction of saturated 3-ketones with thiols or dithiols in the presence of boron trifluoride or hydrogen chloride catalysts. Selective protection of the 3-ketone in the presence of a 6-ketone is possible by carrying out the reaction in diluted medium. Similarly, 3-ketones react selectively with monothiols " " or with bulky dithiols in the presence of 6-, 7-, 11- and 12-ketones. 

Thioketals are readily prepared by treating the corresponding ketone with ethanedithiol and propane-1,3-dithiol. The 12-ketone fails to react with monothiols such as ethanethiol or thiophenol or with the bulkier 1-phenylethane-1,2-dithiol or tetralin-2,3-di thiol. The A Ei2-ketone... 

As a consequence, thiols are preferred to alcohols for the protection of aldehyde and ketone groups in synthetic procedures. Thioacetals and thioketals are... 

Theoretical studies have been done in order to understand this behavior difference. Semiempirical calculations (AMI, MNDO) of formation energy (of the hemithio-ketal-hemiketal interconversion) have shown that hemithioketals are less stable than the corresponding hemiketal (from 10 to 15 kcal/mol). This difference can be due to steric factors, connected to the respective sizes of sulfur and oxygen. Stereoelectronic factors can also be evoked stabilization that is brought about by the anomeric effect is a priori more important for a gem-dihydroxylated compound than for the hemi-thioketal. Moreover, at the kinetic level, displacement of the water molecule of the inhibitor (under aqueous conditions, the inhibitor is hydrated) by the thiol of the enzyme is a slow and disfavored reaction. In contrast, the same reaction is favored with the hydroxyl of a serine. Experimentally, equilibrium occurs very slowly with the enzyme as well as with model molecules. ... 

Secondary thiols.8 A new preparation involves dithiolane cleavage with n-butyllilhium to thiones, which are known to be reduced by the same reagent to sec-thiols by /8-hydride transfer. Yields are 78 90% from saturated thioketals. The mtthod is less useful for preparation of aryl substrates owing to competitive ItlflUltttion of the aromatic ring. 

Thioketals, unlike ordinary ketals, are formed readily from ketones and thiols (RSH) in the presence of acid catalysts. The desulfurization procedure usually goes well, but the product is rather difficult to separate by extraction from the large excess of Raney nickel required for optimum yields. 

Other means of improving sulfide yields in the reaction of halides with thiolates are (1) the use of thiols and platinum(II) complex catalysts287, (2) the generation of thiolate anions by electrochemical means288 and (3) the use of phase-transfer conditions237. The first method has been used for the synthesis of thioketals from geminal diiodides and the third has been used for the conversion of gem-dichlorocyclopropanes into cyclopropane thioketals, which are effectively masked cyclopropane moieties. 

The reactions of isatins360,159 and 1-alkylisatins361 with thiols yield substitution products at position C-3, such as isatin-3-thioketals and 3-alkylthiooxindoles362 (Scheme 86). 

Several different amino acid side chains can act as nucleophiles in enzyme catalysis. The most powerful nucleophile is the thiol side chain of cysteine, which can be deproto-nated to form the even more nucleophilic thiolate anion. One example in which cysteine is used as a nucleophile is the enzyme glyceraldehyde 3-phosphate dehydrogenase, which uses the redox coenzyme NAD+. As shown in Fig. 10, the aldehyde substrate is attacked by an active site cysteine, Cys-149, to form a hemi-thioketal intermediate, which transfers hydride to NAD+ to form an oxidized thioester intermediate (7). Attack of phosphate anion generates an energy-rich intermediate 3-phosphoglycerate. 

Veralinine, a minor alkaloid from Veratrum album subsp. lobelianum, also has the rearranged 22,26-epiminocholestane skeleton (74). From chemical and spectroscopic evidence this Veratrum base is regarded as (22S,25S)-22,26-epimino-17/3-methyl-18-Jior-cholesta-5,12-dien-3 iS-ol (118). This structure was confirmed by correlation with veralkamine. The ketone 115 prepared from veralkamine was treated with ethanedi-thiol. Desulfurization of the resultant thioketal 119 with Raney nickel yielded the C-16 deoxo compound 120, which is identical with (22S,25S)-22,26-acetyl-epimino-17 3-methyl-18-7ior-5a,13a-cholestan-3j8-ol, also prepared from veralinine (118) via catalytic hydrogenation... 

Aldehydes and ketones react with thiols to form thioacetals and thioketals. The mechanism for addition of a thiol is the same as that for addition of an alcohol. Recall that thiols are sulfur analogs of alcohols (Section 12.10). 

Reaction of an aldehyde or a ketone with a thiol forms a thioacetal or a thioketal (Section 18.9) ... 

Heteroaryl Sulphides.—Oxidation of thiols in the presence of pyrrole, using I2-KI, gives 2-pyrrolyl sulphides, via the sulphenyl iodide analogous 2-methylthio-indoles are obtained directly from the indole and MeSCl, while isatin (37) gives the thioketal (38) through the route shown, from... 

Further studies have been reported on the production of thiols and sulphides by deprotonation of thioketals (Scheme 43). ... 

Thiols are the sulfur analogs of alcohols (Section 15.11). The sulfur atom of a thiol is a better nucleophile than the oxygen atom of an alcohol. Thus, thiols react with aldehydes or ketones to form thioacetals or thioketals by a mechanism similar to that described for acetals and ketals. These sulfur derivatives form in high yield because the equdibrium constant for thioacetal formation is much greater than that for acetal formation. We use Lewis acids such as BFj or ZnCl2 rather than protic acids to catalyze the formation of the thioacetal. Both 1,2-ethanedithiol and 1,3-propanedithiol are used to form cyclic thioacetals and thioketals. 

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