Of ketene dithioacetals

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. 

An interesting pyrrolo[l,2-tf]pyrimidine was described as the product of the reaction of the heterocyclic ketene-aminals 236 that was synthesized by cyclocondensation of ketene dithioacetals 237 and 1,3-diamino propane. These compounds reacted with diethyl oxomalonate that behaves as an hetero-enophile, yielding the corresponding products 238 in acceptable to good yield (Scheme 31). A mechanism that involves an aza-ene reaction, via adduct 239 which isomerizes to ketene aminal 240 to produce the lactam ring of 238, has been proposed <1999J(P1)321>. 

A practical synthesis of ketene dithioacetals of sugars was discovered by Horton and Wander.281,182 This reaction does not need to be emphasized here, as it has been discussed in this Series (see Ref. 7, and references cited therein). We only recall as an example that the... 

Ketene dithioacetals. These useful synthetic intermediates can be prepared from Grignard reagents in a one-pot sequence (equation I). The method/ails with allylmagnesium bromide, and only low yields of ketene dithioacetals are obtained from cyclohexylmagnesium chloride and benzylmagnesium chloride (5 10%). 

A general method for the synthesis of 2-deoxyaldoses utilizes a reaction sequence involving the formation and subsequent reduction of ketene dithioacetal intermediates (Scheme 10). Reduction of ketene diethyl dithioacetal 12 with lithium aluminum hydride proceeds via the alkoxyaluminum hydride salt involving the 3-hydroxyl group. Several deoxy hexoses and pentoses were prepared by this method, and also their 2-deuterio analogues.45... 

Disulfides are good electrophiles for the introduction of an alkyl or arylsulfanyl group at the 2-position of 2-lithio-l,3-dithianes141,151,440. By treatment of the resulting orthoth-ioesters 265 with Lewis acids441, l,3-dithian-2-yl carbenium ions can be generated, as in the case of ketene dithioacetals with Bronsted acids439. 

In general, the reaction of ketene dithioacetals and amines serves well to prepare the conjugated 1,1-enediamines. 

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>. 

The high diastereoselectivity attending the spirocyclisation of ketene dithioacetals provides an effective means for controlling the stereochemistry of a methyl substituent at the a-position on a 6-lactone ring,244 The method was applied to the synthesis of the polyether antibiotic Salinomycin [Scheme 2.120].242 Condensation of the methyl ketone 120 1 with the lithiated l,3-dithian-2-yl-phospho-nic acid diethyl ester 120.2 gave the ketene dithioacetal 1203 in 76% yield. After hydrolysis of the two benzoate ester groups, cyclisation of diol 120.4 was... 

Acyl anion equivalents. Benzotriazol-l-ylmethyl methyl sulfide can undergo consecutive C-alkylations. The products are readily hydrolyzed with acidic aqueous methanol to give ketones. A related process involving alkylation and sulfenylation followed by treatment with a Grignard reagent to eliminate benzotriazole completes the synthesis of ketene dithioacetals. ... 

A general synthesis of keten dithioacetals, using (106), has been reported. The carbanion can be generated by using conventional bases of by using phase-transfer... 

Reaction of ketene dithioacetals 260 with thioamides gave 5-substituted 2-methyl(phenyl)-6-methylthio-4-thioxopyrimidine (262) (92H1573). The reaction mechanism involves the addition of the thioamide to the ketene dithioacetal 260 to afford 2-cyano-3-methylthio-3-thioamido-propenoni-trile or -propenoate intermediate, which cyclizes in situ by site-selective nucleophilic attack of the sulfur on the cyano group to give 6-imino-l,3-thiazine 261, which rearranged to 262 (Scheme 84). 

A different approach to a-methylenebutyrolactones is a further development of the chemistry of 2-silyloxycyclopropane carboxylates (393), which, when treated with the trifluoromethanesulphonate analogue of Eschenmoser s salt and a Lewis acid (TMSOTf), are converted into 8-amino-esters (394) and thence lactones (395) following borohydride reduction and elimination.33 Overall yields are reasonable for this multi-step approach. A carbanion based approach to monosubstituted lactones. (390) begins by metallation and regio-selective condensation of ketene dithioacetal (396) with an aldehyde. 

Careful acid-catalysed cyclisation of ketene dithioacetals (460) can take place with > 90% selectivity in favour of isomers (461)... 

TMSOTf also plays an important role in sugar chemistry. In fact it often mediates in the formation of the glycosidic bond, either alone or in conjunction with trimethylsilyl chloride, Af-bromosuccinimide (NBS), or iV-iodosuccinimide (NIS). In such reactions, different moieties have acted as leaving groups in the glycosyl donor and 0-, N-, or C-nucleophiles have been employed (eq 86). The addition of hydroxyl unprotected sugar units to the ero-anomeric double bond of ketene dithioacetals, which act as glycosyl donors, is also promoted by TMSOTf. 6... 

Nucleophilic additions to the carbon-carbon double bond of ketene dithioacetal monoxides have been reported [84-86]. These substrates are efficient Michael acceptors in the reaction with enamines, sodium enolates derived from P-dicarbonyl compounds, and lithium enolates from simple ester systems. Hydrolysis of the initiEil products then led to substituted 1,4-dicarbonyl systems [84]. Alternatively, the initial product carbanion could be quenched with electrophiles [85]. For example, the anion derived from dimethyl malonate (86) was added to the ketene dithioacetal monoxide (87). Regioselective electrophilic addition led to the product (88) in 97% overall yield (Scheme 5.28). The application of this methodology to the synthesis of rethrolones [87] and prostaglandin precursors [88] has been demonstrated. Recently, Walkup and Boatman noted the resistance of endocyclic ketene dithioacetals to nucleophilic attack [89]. 

Recent developments of ketene dithioacetal chemistry including their use in the synthesis of heterocycles 13CSR1251. 

Khalili B, Jajarmi P, Efiekhari-Sis B, Hashemi MH (2008) Novel one-pot, three-component synthesis of new 2-alkyl-5-aryl-(fH)-pyrrole-4-ol in water. J Org Chem 73 2090-2095 Murthy SN, Madhav B, Kumar AV, Rao KR, Nageswar YVD (2009) Multicomponent approach towards the synthesis of substituted pyrroles under supramolecular catalysis using P-cyclodextrin as a catalyst in water under neutral conditions. Helv Chim Acta 92 2118-2124 Pan L, Bi X, Liu Q (2013) Recent developments of ketene dithioacetal chemistry. Chem Soc Rev 42 1251-1286... 

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