Formation of Dithioacetals

Water-soluble and low-melting dithioacetals (for example, derivatives of D-xylose) were virtually inaccessible to Fischer, as his technique of isolation relied on spontaneous separation of a crystalline product after dilution of the reaction mixture with water. Alternative isolative methods that were subsequently developed to deal with such problems of solubility include the use of lead carbonate,16 barium carbonate,17 or an anion-exchange resin18 to remove the acid catalyst, with subsequent removal of all or part of the diluent by evaporation, and the use of chloroform19 or ether20 to remove the excess of thiol from the water layer and induce crystallization of the product. 

Although the original paper reported1 isolation of diethyl dithioacetals of only one pentose, four hexoses, and a heptose, this reaction has subsequently been generalized, with examples ranging from trioses21 to octoses.22,23 

Mercaptalation of simple, organic, carbonyl compounds is considered24 to proceed by way of electrophilic addition of one thiol molecule, followed, for favorable examples, by bimolecular displacement of water from the protonated monothiohemiacetal intermediate, and, finally, deprotonation of the dithioacetal thus formed each step is presumed to be reversible, and Bethell and Ferrier25 demonstrated an example in which a diethyl dithioacetal reacted with ben-zenethiol in the presence of acid to form, in 80% yield, a diaster-eoisomeric mixture of ethyl phenyl dithioacetals. It is also known 

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The differing nucleophilicity of acetate and trifluoroacetate anion determined the manner in which naphtho[l,8-/yt]-l,5-dithiocinc sulfoxide 127 rearranged on treatment with acetic and trifluoroacetic anhydrides. In both cases, the reaction proceeded through formation of a disulfonium dication 128, but the final products were different. When acetic anhydride was used, the reaction afforded the corresponding a-acetylsulfide 130, a normal product of the Pummerer rearrangement, while trifluoroacetic anhydride caused isomerization with formation of dithioacetal 132 (see Scheme 16) <1995HAC559>. 

This reaction was first reported by MacDonald and Fischer in 1952. It is the degradation of hexoses into pentoses involving the steps of formation of dithioacetal, oxidation to unsaturated disulfone by means of perphthalic acid, hydrazine treatment, and benzalde-hyde splitting of the corresponding hydrazone. Therefore, the whole process is known as the MacDonald-Fischer degradation. In addition, when the unsaturated disulfone is dissolved in aqueous ammonia or methanol saturated with ammonia, 2-deoxy-2-amino sugar is resolved. This reaction in combination with mass spectroscopy was used to study the structure and stereochemistry of carbohydrates. ... 

Although the formation of dithioacetals generally is a simple reaction, side reactions become prevalent when a reasonable leaving group is in the a-position to the carbonyl or to a conjugated double bond. In the reaction of 2-bromo-2-phenylacetophenone with ethanedithiol, 2,3-diphenyl-5,6 dihydro-l,4-dithiin (equation 8) was obtained . Similarly, the dihydro-dithiin (1) was obtained from 6-j3-acetoxy 4-cholesten-3-one (equation 9 f, Additional examples exist for the formation of dihydro-1,4-dithiins via halides , epoxides and even amides . 

Normally the reaction of thiols with carbonyls, saturated or unsaturated, leads to the formation of dithioacetals when acid catalysts such as zinc chloride or p-toluene-sulphonic acid are present (see section II.A. 1). Occasionally, under special reaction conditions thioenol ethers have been formed using these same catalysts but never in the presence of acid-sensitive substituents. Pyridine hydrochloride as the catalyst has been successfully used to give excellent yields of the thioenol ethers of A -3-ketosteroids even in the presence of sensitive groups . Thus, desoxy-corticosterone acetate (92) was converted to its 3-benzylthioenol ether... 

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. 

Another route involves a palladium-copper-catalyzed tandem carbon-carbon formation/cycloaddition sequence (Equation 12) <2005TL8531>. Notably, cycloadditions of azide to the internal alkynes failed under click chemistry reaction conditions <2003DDT1128>. Cyclization under oxidative conditions has been reported from dithioacetal 163 (Equation 13) <1996TL3925>. The formation of 164 as a single diastereoisomer has been explained by stereoelectronic effects. 

An elegant method for the formation of glycosidic bonds from acyclic dithioacetal monosulfoxides and glycosyl acceptors with triflic anhydride has been developed. This method takes advantage of the sulfenyl triflate generated from the reaction of... 

Extended irradiation of the diethyl dithioacetal 44 increases the yield of L-fucitol (46) at the expense of 1-S-ethyl-l-thio-D-galactitol (45) also galactitol (52) was isolated from the photolysis mixture.109 The intermediacy of 45 in the formation of 46, a possibility that was suggested by the extended photolysis of 44, is supported by the observation that irradiation of 45 in methanol produces L-fucitol (46) in 44% yield.109 (Compounds 47 and 52 also are formed during irradiation of 45, but in low yield.) The mechanism for sulfide photoreaction parallels that109 for the alkyl dithioacetals (see Scheme 18). 

The formation of 2,3,4-tri-0-acetyl-5-5-ethyl-5-thio-L-arabinose diethyl dithioacetal (67) when a-L-arabinopyranose tetraacetate (57) was treated o) th ethanethiol in the presence of either zinc chloride or boron trichloride was rationalised by the sequence of reactions shown subsequent work (see below) suggests that an orthoester may be inter-... 

Dithioacetals derived from heteropine 177 smoothly react with methylene iodide in the presence of a zinc-copper couple in refluxing ether to give the corresponding fused thiophenes 178. The suggested mechanism involves formation of an ylide which undergoes intramolecular aldol-type condensation assisted by coordination of zinc with a carbonyl followed by demethylation of the S-methylthiophenium species (Scheme 35 (1989TL3093)). 

Acidic compounds of type R—XH, which are able to protonate thiocarbonyl ylides, also undergo 1,3-addition leading to products of S,S-, S,0-, or 5,A-acetal type (Scheme 5.20). Thiophenols and thiols add smoothly to thiocarbonyl ylides generated from 2,5-dihydro-l,3,4-thiadiazoles (36,38,86,98,99). Thiocamphor, which exists in solution in equilibrium with its enethiol form, undergoes a similar reaction with adamantanethione (5)-methylide (52) to give dithioacetal 53 (40) (Scheme 5.21). Formation of analogous products was observed with some thiocarbonyl functionalized NH-heterocycles (100). 

Ketene dithioacetal 82 reacts with aromatic methyl ketones to generate thiopyranones. Further reaction with ethyl mercaptoacetate leads to the formation of thieno[3,2-f]pyranones in good yields (Scheme 18) <1997BML3101>. 

Cyanogen Iodide (ICN) has been used extensively for the cyanation of alkenes and aromatic compounds [12], iodination of aromatic compounds [13], formation of disulfide bonds in peptides [14], conversion of dithioacetals to cyanothioacetals [15], formation of trans-olefins from dialkylvinylboranes [16], lactonization of alkene esters [17], formation of guanidines [18], lactamization [19], formation of a-thioethter nitriles [20], iodocyanation of alkenes [21], conversion of alkynes to alkyl-iodo alkenes [22], cyanation/iodination of P-diketones [23], and formation of alkynyl iodides [24]. The products obtained from the reaction of ICN with MFA in refluxing chloroform were rrans-16-iodo-17-cyanomarcfortine A (14)... 

Aldose dithioacetals, which are devoid of leaving groups, notably oxygen-bonded functions at C-2, on treatment with strong bases, afford stable C-l carbanions that allow the formation of cyclohexane derivatives when suitable leaving groups are present at C-6. 

Oxidation of a thioacetal at one of the sulfur atoms offers some useful features. After formation of the carbaniun and addition to an electrophilic partner, the hydrolysis is easier than for dithioacetals and can be made with dilute sulfuric or perchloric acid. Moreover, the addition of a lithiated carbanion derived from these species to enones occurs in a 1,4 rather than a 1,2 manner (the usual way for less stabilized more reactive thiocarbanions). The chemistry of these thioacetal monoxides was developed in the 1970s mainly by Ogura and Tsuchihashi [287-290] and by Schlessinger and co-workers [291-293], Two examples of application are given. 

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