Hemithioketals

Dimethyl ketals and enol ethers are stable to the conditions of oxime formation (hydroxylamine acetate or hydroxylamine hydrochloride-pyridine). Thioketals and hemithioketals are cleaved to the parent ketones by cadmium carbonate and mercuric chloride. Desulfurization of thioketals with Raney nickel leads to the corresponding methylene compounds, while thioenol ethers give the corresponding olefin. In contrast, desulfurization of hemithioketals regenerates the parent ketone. ... 

Ketals bearing the double bond at the 4,5-position are prepared by reaction with glycol in the presence of weak acids such as adipic acid. In this case ketal formation proceeds via the intermediate 2,4-dien-3-ol ether. Hemithioketals (71) of A -3-ketones are prepared by reaction with mer-... 

Hemithioketals can be prepared from 12,20-diketones [e.g., (81)] by reaction with mercaptoethanol, zinc chloride and sodium sulfate in dioxane. The 12-hemithioketal of triketocholanic acid is prepared by selective cleavage of the 3,7,12-trihemithioketal. " ... 

Ketals other than ethylene ketals are prepared by the orthoformate procedure with heating. Thioketals are obtained from dithiols, monothiols and hemithioketals by the boron trifluoride-catalysis method. Hemi-thioketals have also been prepared in high yield by the exchange proce-dure.""""... 

Unsubstituted 20-ketones undergo exchange dioxolanation nearly with the same ease as saturated 3-ketones although preferential ketalization at C-3 can be achieved under these conditions. " 20,20-Cycloethylenedioxy derivatives are readily prepared by acid-catalyzed reaction with ethylene glycol. The presence of a 12-ketone inhibits formation of 20-ketals. Selective removal of 20-ketals in the presence of a 3-ketal is effected with boron trifluoride at room temperature. Hemithioketals and thioketals " are obtained by conventional procedures. However, the 20-thioketal does not form under mild conditions (dilution technique). ... 

Whereas aldehydes such as benzaldehyde or ketones are converted by trimethyl-silylated alkyl- or aryl-mercaptans such as 575, in the presence of catalytic amounts of cyanide, to give high yields to O-trimethylsilyl-hemithioketals such as... 

When the indole 3-position is already substituted, electrophilic reagents attack the 2-position instead often through a 3,3-spiro intermediate. For example, when 2-(3-indolyl)ethylmercaptan (27) reacts with methyl acetoacetate, the thia-p-carboline analogue 31 results. It seems plausible that the reaction involves initial hemithioketal formation (28), followed by electron release by the indole nitrogen and hydroxide... 

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. ... 

Figure 1.16 Left Schematic presentation of the 1,3-diaminopropanone core moiety as cysteine protease-directed and active site-spanning inhibitor principle (top). Upon reaction with the enzyme nucleophile, the ketone is reversibly converted to a hemithioketal (bottom). Right Peptidomimetic cysteine protease inhibitors of subsequent generations are depicted together with their inhibitory activity and primary targets.

The intermediacy of hemithioketals was indicated by the isolation of the analogous species 137, which could be converted to the thiazoline 138. 

The influence of thiols results from a rapid addition of this product to the protonated benzophenone Ar2C+ - OH (A) to form an hemithioketal which immediately reacts to give a new electrophilic species (B) ... 

Stereoselective hydrogen transfer reactions on oxacyclic radical intermediates are useful as shown in the synthesis of lauthisan (32) [126]. A key step in the total synthesis of brevetoxin B by Nicolaou [127] (Scheme 65) features conversion of the hydroxy dithioketal 189 into the oxoeene system 190 via cyclic hemithioketal formation and stereoselective radical-mediated desulfurization. More recently, Tachi-bana employed the same reaction sequence in the partial synthesis of ciguatoxin ]128]. 

Hydrolysis of hemithioacetals, hemithioketals, and thio- and thia-glycosides Two factors dominate the title process - the low basicity of dicovalent sulphur, which makes protonation and hydrogen bonding more difficult, and the lower ability of sulphur to stabilise an adjacent carbonium ion centre. This is conventionally attributed to poor overlap between the 3p orbital containing the sulphur lone pair and the vacant 2p orbital on carbon (Fig. 12), and is manifested in carbohydrate... 

Thioketalization. Contrary to the earlier report cited in 6, 399, the reaction of aldehydes and ketones with this reagent is initiated by traces of Lewis acids. The most satisfactory conditions use diethyl ether as solvent and zinc iodide as catalyst. The initial reaction results in O-trimethylsilyl hemithioketals, which in the presence of a second equivalent of the reagent are converted into dimethyl thioketals ... 

While chloro-mesylates 331 served as 2-hydrocarbylpenem precursors, the 2-alkylthio-, 2-oxy-, and 2-aminopenems were prepared from 4-chloroazetidin-ones 348a c, bearing at nitrogen a ketene dithioketal, hemithioketal, or aminothioketal moiety. Owing to the instability of the free SH form, S-protected precursors had to be used, whose deprotection could be accompanied by cyclization. Thioesters (e.g. 360,364) or thiolactones (351) were convenient forms of protection. 

A soln. of p-toluenesulfonic acid in acetic anhydride added to a stirred soln. of cholestanone 3-a-0-y -S-ethylene hemithioketal in methylene chloride, after 45 min. cooled to 0°, treated with more acetic anhydride and pyridine 2-(2 -cholesten-3 -yl)-3-( -acetylthioethoxy)-2-cholestene. Y 85%. F. e., also from ketals and enol-ethers, s. G. Karmas, J. Org. Chem. 33, 2436 (1968). 

Alkyl- and aryl-thiosilanes react with aldehydes or ketones to form either thio-ketals or O-silylated hemithioketals. With a/3-unsaturated ketones exclusive 1,4-addition can be achieved (Scheme 80). The procedures constitute an exceptionally mild method for carbonyl group protection. ... 

An acetal is named as a dialkoxy derivative, and a thioacetal is named as a dialkylthio derivative. The name of 65 is l,l-di(ethylthio)butane. Just as ketones react with alcohols to form ketals, they also react with thiols to form the sulfur analog. The mechanism is identical, and the reaction is illustrated by the reaction of cyclohexanone (23) with propanethiol to give 66. This is a dithioketal named l,l-di(propylthio)cyclohexane. The key intermediate in this latter reaction is a hemithioketal. 

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