Dithioacetals from aldehydes

Less is known concerning the partial, acid hydrolysis of alditol polyacetals derived from ketones, compared to those derived from aldehydes. The acid hydrolysis of 1,2 3,4 5,6-tri-O-isopropylidene-D-mannitol to 3,4-O-isopropylidene-D-mannitol55,56 and of l,2 3,4-di-0-isopropylidene-L-rhamnitol to 3,4-O-isopropylidene-L-rhamnitol57 indicates an order of isopropylidene acetal stability of a-threo > a, and this order is supported by the partial hydrolysis of 2,3 4,5-di-O-isopro-pylidene derivatives of dialkyl dithioacetals of D-arabinose58 and D-xylose59 to 2,3-acetals. 

Acid hydrolysis of 2,4 3,5-di-0-isopropylidene-D-xylose diethyl dithioacetal to give63 the 2,4-acetal afforded a rare opportunity to establish that, in isopropylidene acetals, as with acetals derived from aldehydes, f3-erythro rings are more stable than /3 rings. 

Dithioacetals of aldehydes are sources of carbanions and hence may be used to form new C-C bonds in reactions in which the formerly electron-deficient character of the aldehydic carbon has been reversed. The 1,3-dithianes derived from formaldehyde or a higher aldehyde may be metallated and then alkylated (Scheme 2.27). Hydrolysis of the dithioac-etal is usually carried out in the presence of a thiophilic (sulfur seeking) metal salt such as a mercury salt. The insoluble sulfides cause the equilibrium to move in favour of the parent carbonyl compound. 

The reaction of aldehydes or ketones with thiols, usually with a Lewis acid catalyst, leads to dithioacetals or dithioketals. The most common catalyst used is probably boron trifluoride etherate (BF3 OEt2). Similarly reactions that use 1,2-ethanedithiol or 1,3-propanedithiolleadto 1,3-dithiolanes, such as 18 or l,3-dithianes. " Dithioa-cetals can also be prepared from aldehydes or ketones by treatment with thiols in the presence of TiCU, SiCU, LiBp4, AKOTfls, with a disulfide RSSR (R = alkyl or aryl), or with methylthiotrimethylsilane (MeSSiMe3). " ... 

Synthesis of Dithiocarboxylic Acids and their Derivatives.—The preparation of thioterephthalic acid from l,4-di(chloromethyl)benzene, sulphur, and sodium methoxide (see Vol. 5, p. 179) has beeil reported by another group. In a similar reaction, the addition of chloroacetonitrile to sulphur and triethylamine in DMF, followed by alkylation, gave methyl and ethyl cyanodithioformates. These were not isolated, but they condensed when water was added, giving EfZ mixtures of l,2-di(alkylmercapto)-l,2-dicyanoethylenes. Ethylene dithioacetals from aromatic aldehydes are decomposed by sodium hydride in DMF containing HMPA, with elimination of ethylene and the liberation of an aryIdithiocarboxylate anion this may be alkylated to give the dithioester (Scheme 8). ... 

A novel synthesis of cr-diketones from aldehydes proceeds by the formation of the anion of the ethylene dithioacetal of the aldehyde, reaction with Fe(CO)j, alkylation, and hydrolysis. 

The aldehyde function at C-85 in 25 is unmasked by oxidative hydrolysis of the thioacetal group (I2, NaHCOs) (98 % yield), and the resulting aldehyde 26 is coupled to Z-iodoolefin 10 by a NiCh/CrCH-mediated process to afford a ca. 3 2 mixture of diaste-reoisomeric allylic alcohols 27, epimeric at C-85 (90 % yield). The low stereoselectivity of this coupling reaction is, of course, inconsequential, since the next operation involves oxidation [pyridinium dichromate (PDC)] to the corresponding enone and. olefination with methylene triphenylphosphorane to furnish the desired diene system (70-75% overall yield from dithioacetal 9). Deprotection of the C-77 primary hydroxyl group by mild acid hydrolysis (PPTS, MeOH-ClHhCh), followed by Swem oxidation, then leads to the C77-C115 aldehyde 28 in excellent overall yield. 

Treatment of selenoacetals 24 with butyllithium at 78 °C leads to the chiral a-seleno lithium compounds 25. Selenoacetals are stable compounds and can be readily prepared by selenoacetal-ization of the corresponding aldehydes25,26. In contrast to the corresponding dithioacetals, no competing deprotonation occurs on treatment with butyllithium, even with selenoacetals derived from aromatic aldehydes. 

The reaction of methylenesulphones with allyl halides in the presence of quaternary ammonium salts produces the 1-allyl derivatives [52], unlike the corresponding reaction in the absence of the catalyst in which the SN- product is formed (Scheme 6.5). In contrast, alkylation of resonance stabilized anions derived from allyl sulphones produces complex mixtures [51] (Scheme 6.6). Encumbered allyl sulphones (e.g. 2-methylprop-2-enyl sulphones) tend to give the normal monoalkyl-ated products. Methylene groups, which are activated by two benzenesulphonyl substituents, are readily monoalkylated hydride reduction leads to the dithioacetal and subsequent hydrolysis affords the aldehyde [61]. 

Methyl fluoro(diethoxyphosphono)dithioacetate (34) has been prepared from difluorinated precursors [56], Fluorophosphonothioacetamides (35) derived from this dithioester, have been successfully transformed into highly functionalized fluoroalkenes (36). Judicious selection of the aldehyde coupling partner can lead expeditiously to the preparation of fluoroolefin dipeptide isosteres following elaboration of the carboethoxy group and desulfurization (Scheme 11). 

The stoichiometric equivalents of halofluorides have been recently applied to transform alkylene dithioacetals into gcm-difluorides.70-71 Dithioacetals such as 1,3-dithiolanes and 1,3-dithianes arc readily obtained from the corresponding carbonyl compounds by the reaction with ethane-1,2-dithiol or propane-1,3-dithiol in the presence of the complexes boron trifluoride-bis(acetic acid) or boron trifluoride-diethyl ether. Using a two-step procedure, a range of aldehydes and ketones can be converted into gem-difluorides under mild conditions. 

Chiral a-methoxy aldehydes.2 The anion of 1 undergoes 1,2-addition to bcnzaldehyde in quantitative yield. The adduct can be methylated under phase-transfer conditions and then reduced3 to give the dithioacetal 2, from which the aldehyde 3 is liberated by reaction with I2 and NaIlC03.4 The optical yield of 3 is >70%. 

The orf/to-formylation of 2-aminopyridines can be effected via the rearrangement of the azasulfonium salt prepared from a 2-aminopyridine, 1,3-dithiane, f-butyl hypochlorite and sodium methoxide (74CC685). The crude sulfilimine (815) was refluxed in f-butanol containing potassium f-butoxide to yield the dithioacetal (816). Hydrolysis of (816) with mercury(II) oxide/boron trifluoride etherate gave the aldehyde (817 Scheme 191). This method should be applicable to the formylation of other heterocyclic amines. 

The syntheses of dithioacetals are generally straightforward [43]. Standard methods may be unselective for multifunctional molecules. Therefore, new procedures have been developed. It has thus been reported that 1,3-dithianes are readily synthesized by reaction of aldehydes, ketones or acetals with 2-stanna-l,3-dithianes under catalysis of organotin triflates [45]. These odourless reagents are prepared from dialkyldichlorotin and 1,3-propanedithiol. 

In a recent approach to the preparation of dihydro-3(2H)-furanones by chemists from Thailand it was shown that consecutive, one-pot conventional treatment of 1,3-dithiane in THF with equimolar n-butyllithium, an epoxide, n-butyllithium, an aldehyde or ketone and, finally, methanesulfonyl chloride gave a spirocyclic dithioacetal in good (ca. 70%) yield. Hydrolysis with HgO/HgCl2 gave the corresponding dihydrofuranone. 

Protection of 194 as a p-methoxybenzylether and subsequent epoxydation led to the trans-epoxide 195, which was transformed into the unsaturated aldehyde 196 by a three-reaction sequence, including regioselective oxirane opening with a 1,3-dithiane anion, hydrolysis of the dithioacetal formed, and dehydration. Chlorite promoted aldehyde oxidation, methyl ester formation, and removal of the hydroxyl protections delivered methyl (+)-shikimate 197 in a remarkable 12% yield from 193. 

Optically active dithioacetals can be prepared by use of the thiolacid prepared from (R)-( - )-a-methoxyphenylacetic acid by reaction with oxalyl chloride and then with NaSH. This thiolacid reacts with an aldehyde and a thiol to form the mixed thioacetals corresponding to 1 as a 1 1 mixture of diastereomers, separable by chromatography (—75% yield). These are convertible into optically active dithioacetals corresponding to 2 with no loss of diastereomeric purity. 

Lithiosilanes derived from cyclopropane dithiocetals add to aldehydes to give precursors for Peterson olefinations - one of the best ways of making alkylidene cyclopropanes. In the example below, the lithiated allyl sulfide 72 adds cleanly to a ketene dithioacetal to give cyclopropane 73. Successive reductive lithiations give silane 74 and then a mixture of... 

Dithianes are extremely important compounds in organic synthesis because going from ketone to thioacetal inverts the polarity at the functionalized carbon atom. Aldehydes, as you are well aware, are electrophiles at the C=0 carbon atom, but dithioacetals, through deprotonation to an anion, are nucleophilic at this same atom. 

The thiol combines with the aldehyde group of the open-chain form to give a stable dithioacetal. The dithioacetal is evidently more stable than the alternative hemiacetals or monothioacetals that could be formed from the pyranose or furanose forms. 

---