Ethanedithiolate

AHylestrenol (37) is prepared from (32), an intermediate in the synthesis of norethindrone. Treatment of (32) with ethanedithiol and catalytic boron trifluoride provides a thioketal. Reduction with sodium in Hquid ammonia results in the desired reductive elimination of the thioketal along with reduction of the 17-keto group. Oxidation of this alcohol with chromic acid in acetone followed by addition of aHyl magnesium bromide, completes the synthesis... 

This type of chemistry also functions for hydroxyketones and aldehydes. The process using 1,2-ethanedithiol or 2-mercaptoethanol results in cycHc stmctures (eq. 25). The 1,3-ditholenes (X = S) and 1,3-thioxalanes (X = O) resulting from these reactions have been shown to be of interest commercially. 

Thiols iateract readily with many mbber-containing materials. For this reason, care should be taken ia the selection of gasket and hose materials. Teflon, Kel-F, Viton, or other suitable fluoroelastomers function as gasket materials. Viton is suitable for hoses. Carbon steel is useful for many thiols, although some thiols become very discolored when carbon steel is utilized. In these cases, the use of stainless steel is very desirable. Isolation from air and water also minimizes color formation. 2-Mercaptoethanol and 1,2-ethanedithiol should be stored ia stainless steel (61). 

BF3 Et20, EtSH, 25°, 40 min, 80-90% yield. Addition of sodium sulfate prevents hydrolysis of a dithioacetal group present in the compound replacement of ethanethiol with ethanedithiol prevents cleavage of a dithiolane group. 

At about the same time Pedersen s work was underway, Bradshaw and his coworkers had undertaken the systematic preparation of numerous mono- and polysulfur macrocycles The syntheses were carried out in a fashion similar to that shown in Eq. (6.3). The two principal sources of sulfur in the first paper from this groupwere sodium sulfide and 1,2-ethanedithiol. The latter was utilized in the presence of sodium hydroxide base. Ethanol was generally used as solvent and the reactions were conducted at high dilution. Products were purified either by vacuum distillation or recrystallization as appropriate. The yields were generally in the 5—30% range. 

Thioketals are prepared efficiently from dithiols, but not from monothiols. However, 6-ketones do not react with ethanedithiol/boron trifluoride in the presence of a diluent such as acetic acid. 

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... 

Androst-4-ene-3,l7-dione 3-Ethylene Thioketal A solution of androst-4-ene-3,17-dione (1.42 g, 5 mmoles) in acetic acid (20 ml) is treated with ethanedithiol (0.47 g, 5 mmoles) and a solution of 0.45 of p-toluenesulfonic acid monohydrate in acetic acid (5 ml). After 1 hr at room temperature, the pale yellow solution is poured into water and the resulting suspension is extracted with chloroform. The chloroform solution is washed with water, 5 % sodium hydroxide solution and water, dried (Na2S04) and evaporated. Chromatography of the resulting oil (1.93 g) over silica gel yields androst-4-ene-3,17-dione bisethylene thioketal, mp 173-175° [0.16 g, eluted with petroleum ether-benzene (1 2)] and androst-4-ene-3,17-dione 3-ethylene thioketal, mp 173-176° [1.38 g (76%), eluted with benzene-ethyl acetate (19 1)]. 

Cyclohexane-1,2-dione reacts with ethylene glycol (TsOH, benzene, 6 h) to form the diprotected compound. Monoprotected 1,3-oxathiolanes and 1,3-dithi-olanes are isolated on reaction under similar conditions with 2-mercaptoethanol and ethanedithiol, respectively. ... 

The cyclohexyl phosphate, used in the protection of phosphorylated serine derivatives, is introduced by the phosphoramidite method and cleaved with TFMSA/MTB/m-cresol/l,2-ethanedithiol/TFA, 4 h, 0° to rt. " ... 

Similar cyclization of 367 leading to low yields (20%) of benzodithiine 368 was observed with triethylamine in DMSO (Eq. 32) (76ZOR844). On the other hand, coumarin derivative 369 treated with 1,2-ethanedithiole in the presence of triethylamine provided relatively stable spiro compound 370 (Eq. 33) (89ZOR669). 

Spirapril (37) is a clinically active antihypertensive agent closely related structurally and mechanistically to enalapril. Various syntheses are reported with the synthesis of the substituted proline portion being the key to the methods. This is prepared fkim l-carbobenzyloxy-4-oxopro-line methyl ester (33) by reaction with ethanedithiol and catalytic tosic acid. The product (34) is deprotected with 20% HBr to methyl l,4-dithia-7-azospiro[4.4 nonane-8-carboxylate (35), Condensation of this with N-carbobenzyloxy-L-alanyl-N-hydroxysuccinate leads to the dipeptide ester which is deblocked to 36 by hydrolysis with NaOH and then treatment with 20% HBr. The conclusion of the synthesis of spirapril (37) follows with the standard reductive alkylation [11]. 

Lactones can be protected as dithiolane derivatives using a method that is analogous to ketone protection. The required reagent is readily prepared from trimethyl-aluminum and ethanedithiol. 

Carbonyl groups can be converted to methylene groups by desulfurization of thioketals. The cyclic thioketal from ethanedithiol is commonly used. Reaction with excess Raney nickel causes hydrogenolysis of both C—S bonds. 

The DBSA-system is also applicable for the dithioacetalization of aldehdyes and ketones with 1,2-ethanedithiol to give the corresponding dithioacetals (Scheme 5.4, d). Increasing the reaction temperature decreases the yield of the products. Interestingly, increases in the concentration of the surfactant also decrease the yield of products formed, while shortening the alkyl chain of the surfactant abolishes its catalytic activity. Optical microscopy shows the formation of micelles, which are proposed to form hydrophobic environments and decrease the effective concentration of water and facilitate the dehydrative condensation reactions. 

The second method also relies on site-specific chemical modification ofphosphoproteins (Oda et al., 2001). It involves the chemical replacement of phosphates on serine and threonine residues with a biotin affinity tag (Fig. 2.7B). The replacement reaction takes advantage of the fact that the phosphate moiety on phosphoserine and phosphothreonine undergoes -elimination under alkaline conditions to form a group that reacts with nucleophiles such as ethanedithiol. The resulting free sulfydryls can then be coupled to biotin to create the affinity tag (Oda et al., 2001). The biotin tag is used to purify the proteins subsequent to proteolytic digestion. The biotinylated peptides are isolated by an additional affinity purification step and are then analyzed by mass spectrometry (Oda et al., 2001). This method was also tested with phosphorylated (Teasein and shown to efficiently enrich phosphopeptides. In addition, the method was used on a crude protein lysate from yeast and phosphorylated ovalbumin was detected. Thus, as with the method of Zhou et al. (2001), additional fractionation steps will be required to detect low abundance phosphoproteins. 

Tetrathia[6.6.1]propellane 72 has been prepared 21. This is the parent of the dibenzo compound 7/just mentioned 20). The same tetrasubstituted cyclopropane 24 was used, this time simply with 1,2-ethanedithiol, under conditions of high dilution... 

Despite the latent reactivity of ketene thioacetals,3-4 some members of this class such as the title compound have been little studied, perhaps because of preparative inaccessibility. The only previously reported route to 2-methylene-1,3-dlthiolane involves monoacetylation of 1,2-ethanedithiol, cyclization to 2-methyl-1,3-dithiolan-2-yl perchlorate, and exposure of this salt to diisopropylethylamine in acetonitrile 5... 

Ethanedithiol was purchased from the Aldrich Chemical Company, Inc., and used without further purification. 

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