Ketene dithioacetal derivative

Apart from the addition reaction to electrophilic olefins, the / -carbon atom of 1,1-enediamines can also substitute a,/ -unsaturated compounds carrying a leaving group. Schafer and Gewald129 have shown that 141 and 142 react with 143 to give product 144 in moderate to good yields (equation 54). Ketene dithioacetals derived from an alkyl cyanoacetate and malononitrile behave similarly to 143130. When imine 145 is employed, the reaction results in the formation of 146 (equation 55)129. Apparently displacement of ethoxy group and cyclocondensation by attack on the nitrile moiety are the key steps in the reaction. 

Ketene dithioacetal derivatives (2) are available from 2,3 4,5-di-0-isopropylidene-D>arabinose diethyl dithioacetal (1) by treatment with BuOK followed by an alkyl halide to cause in situ alkylation. On exposure to nucleophiles in the presence of a Lewis acid they undergo substitution at C-3 (rather than addition to the double bond) presumably via the carbocation (3) as shown in Scheme 1. This reaction has been used, with moderate success, to introduce a thio sugar residue and hence afford a sulphur-linked disaccharide derivative. ... 

Ketene Dithioacetal Formation. These versatile intermediates arise from 1,3-dithiane anions by elimination (eq 8) or vinylogous alkylation (eq 4), and by condensation of carboxylic acid derivatives with (1) (eq 13). Ketene dithioacetals derived from lactones can cyclize to give dithio orthoesters, which can be selectively deprotected (eq 16). ... 

The pivotal step in this sequence is an electrophilic substitution on indole. Although the use of l,3-dithian-2-yl carbanions is well documented, it has been shown only recently that 1,3-dithian-2-yl carbenium ions can be used in a Priedel-Crafts type reaction. This was accomplished initially using 2-methoxy-l,3-dithiane [1,3-Dithiane, 2-methoxy-] or 2-metlioxy-l,3-dithiolane [1,3-Dithiolane, 2-methoxy-] and titanium tetrachloride [Titanate(l —), tetrachloro-] as the Lewis acid catalyst.9 2-Substituted lysergic acid derivatives and 3-substituted indoles have been prepared under these conditions, but the method is limited in scope by the difficulties of preparing substituted 2-methoxy-1,3-dithianes. l,3-Dithian-2-yl carbenium ions have also been prepared by protonation of ketene dithioacetals with trifluoroacetic acid,10 but this reaction cannot be used to introduce 1,3-dithiane moieties into indole. 

The use of ethyl ethylthiomethyl sulphoxide in this reaction leads to the desired addition products in much better yields (95-97%). These products were then converted into ketene dithioacetal monoxide derivatives 430 by a sequence of reactions (equation 258)505. Reaction of 2-lithio-l,3-dithiane-l-oxide with benzophenone affords a mixture of the diastereoisomeric tertiary alcohols 431 in a ratio which is temperature dependent (cis trans changes from 3 1 at — 78 °C to 1 1 at room temperature)268. 

The Lewis acid catalyst 53 is now referred to as the Narasaka catalyst. This catalyst can be generated in situ from the reaction of dichlorodiisopropoxy-titanium and a diol chiral ligand derived from tartaric acid. This compound can also catalyze [2+2] cycloaddition reactions with high enantioselectivity. For example, as depicted in Scheme 5-20, in the reaction of alkenes bearing al-kylthio groups (ketene dithioacetals, alkenyl sulfides, and alkynyl sulfides) with electron-deficient olefins, the corresponding cyclobutane or methylenecyclobu-tene derivatives can be obtained in high enantiomeric excess.18... 

The ketene dithioacetal method group has proved useful for the synthesis of a number of biologically interesting molecules <2000BML703, 2004EJM969>, including 5-cyanopyrimidine derivatives which are orally active inhibitors... 

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... 

Cyclic ketene acetals can also react with amines to give 1,1-enediamines with elimination of ethylene glycol76. Treatment of 2-[(methoxycarbonyl)cyanomethylene]-1,3-dioxolane (38) with 1,3-diaminopropane or with 4,5-dimethyl-1,2-phenylenediamine gives the hexahydropyrimidine and the benzimidazoline derivatives 39 and 40, respectively (equation 11). Similarly to the reaction of ketene dithioacetals with amines, the reaction between ketene acetals and amines proceeds via monoamino-substituted intermediates and ketene 7V,Oacetals can be isolated when one molar amine is used72. 

It has been demonstrated that reactions of ketene dithioacetals with suitable glycine derivatives provides convenient access to a variety of densely substituted pyrroles, as illustrated for instance by conversion of the readily available substrate 412 into the product 413 (Equation 117) <2005SC693>. 

Oxidation of enethiolates derived from dithioesters 123 with A -sulfonyloxaziridine 117 gave the corresponding vinyl sulfenates 124. Subsequent alkylation with alkyl halides led to ketene dithioacetal A-oxides 125 in good to excellent yields (Equation 5) <2004JOC6916>. 

Pyridone derivatives, synthesis using ketene dithioacetals 89-YGK413. 

The chiral titanium reagent (6) also catalyzes the [2 + 2] cycloaddition reaction of 1,3-oxazolidin-2-one derivatives of a,(3-unsaturated carboxylic acids and ketene dithioacetals in the presence of MS 4A to give cyclobutanone dithioacetal derivatives with high optical purity (eq 10). Vinyl sulfides, alkynyl sulfides, and 1,2-propadienyl sulfides can also be employed in this reaction to give the corresponding cyclobutanes, cyclobutenes and methylenecyclobutane derivatives with high optical purity (eqs 11 and 12). ... 

Conjugate reduction. Ketene dithioacetals in which the C=C double bond is part of a conjugate system suffer reduction to give dithiane derivatives. The stereocontrol afforded by an Ar-complexed tricarbonylchromium moiety during reduction of a conjugated ester (also with transesterification) is a critical feature of a synthesis of mutisianthol. ... 

The most widely explored method is the formation of tri- and tetrasubstituted cyclopropanes by reaction of vinylsulfonium salts with methylene compounds activated by ester, ketone, nitrile, or sulfone substituents. A series of examples is collected in Table 25. A variant of this method, where cyclopropanedicarboxylates cis-1 were actually obtained by intramolecular cyclization of the sulfonium salt Cj building block is also shown.Alkylthiocyclopropane derivatives 8 were obtained by the reaction of a ketene dithioacetal monosulfonium salt with carbanions derived from doubly activated methylene compounds. ... 

Balczewski, P., and Mikolajczyk, M., Sulfenylation of tz-phosphoryl sulfides. Chemical evidence for intermediate formation of a-phosphoryl trithioorthoformate, Heteroatom Chem., 5, 487, 1994. Mikolajczyk, M., and Balczewski, P., Org anosulphur compounds. Part 71. Diverse reactivity of a-carhanions derived from a-phosphoryl dithioacetals and a-phosphoryl sulphides towards a.P-unsat-urated carhonyl compounds. A general synthesis of conjugated ketene dithioacetals. Tetrahedron. 48. 8697, 1992. 

It has also been found that the reaction of a-keto-ketene dithioacetals (8) with the carbanions derived from methyl ketones (9) gives unsaturated 1,5-dicarbonyl compounds (10). The latter compounds can be ring-closed to pyridines (11) by treatment with ammonium acetate. ... 

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