Ketene thioacetals

The hetero Diels-Alder [4+2] cycloaddition (HDA reaction) is a very efficient methodology to perform pyrimidine-to-pyridine transformations. Normal (NHDA) and Inverse (IHDA) cycloaddition reactions, intramolecular as well as intermolecular, are reported, although the IHDA cycloadditions are more frequently observed. The NHDA reactions require an electron-rich heterocycle, which reacts with an electron-poor dienophile, while in the IHDA cycloadditions a n-electron-deficient heterocycle reacts with electron-rich dienophiles, such as 0,0- and 0,S-ketene acetals, S,S-ketene thioacetals, N,N-ketene acetals, enamines, enol ethers, ynamines, etc. 

Considerable efforts have been devoted to the stereoselective introduction of a /(-methyl function in intermediates for the synthesis of 1 jS-methylcarbapenems. While the trimethylsilyl trifluoromethanesulfonate catalyzed reaction of a 4-acetoxyazetidinone derivative with ketene acetals shows no selectivity, ketene thioacetals lead to stereoselective formation of the a-methyl isomer108. The zirconium enolate, however, shows high /(-methyl selectivity. 

Hermann and colleagues218,219 found that treatment of ketene thioacetal monoxides 172 and 173, with enamines, sodium malonates, /J-dicarbonyl compounds and lithio-... 

Ketene thioacetals 619 a-Ketoacylamides, synthesis of 615 a-Ketocarbothioates 635 a-Ketocycloalkyl sulphoxides, synthesis of 261... 

Scheme 2.2 illustrates several examples of the Mukaiyama aldol reaction. Entries 1 to 3 are cases of addition reactions with silyl enol ethers as the nucleophile and TiCl4 as the Lewis acid. Entry 2 demonstrates steric approach control with respect to the silyl enol ether, but in this case the relative configuration of the hydroxyl group was not assigned. Entry 4 shows a fully substituted silyl enol ether. The favored product places the larger C(2) substituent syn to the hydroxy group. Entry 5 uses a silyl ketene thioacetal. This reaction proceeds through an open TS and favors the anti product. 

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... 

Substituted derivatives 219 were prepared from 1,2,3,4-tetrahydroiso-quinoline-l,4-dione 217 and sulfonyl ketene thioacetals 218. The same products were also obtained from 220 and 221 (Scheme 52) (79YZ1234). 

The octalinyl ester 166 is produced in excellent yield when the butenylcyclohexenol 165 is treated with formic acid at room temperature (equation 80)89. The dimethyl analogue 167 reacts similarly to give 168 (equation 81)90. The trifluoroacetic acid-catalysed ring-closure of the ketene thioacetal 169 to give a 1 2 mixture of the cis- and trans-ketones 170 and 171 (equation 82) has been reported91. 

Carbon disulphide should not be used as the solvent for alkylation of fS-diketones, as the carbanion reacts preferentially with the solvent to generate the dithiocarboxyl-ate derivative, which undergoes mono- and dialkylation (Scheme 6.9) [95]. Ketene thioacetals have also been isolated from acetophenones (60-80%) and cyclopenta-diene (80%) using an ultrasound technique in carbon disulphide [96] and, in a similar manner, pyrazol-5-ones form pyrazole-4-dithiocarboxylic esters [97]. 

The phosphonate, e.g. (MeO)2POCH(SMe)2, (10 mmol) and the aryl aldehyde (10 mmol) in CH2C12 (5 ml) are added to aqueous NaOH (50%, 10 ml), TEBA-Cl (0.1 g, 0.43 mmol) in CH2C12 (5 ml) and the mixture is stirred for 30 min at room temperature. The organic phase is separated, washed well with aqueous NH4C1, dried (MgS04), and evaporated to yield the ketene thioacetal (>80%). 

A Mukaiyama-type aldol reaction of silyl ketene thioacetal (48) with an aldehyde with large and small a-substituents (e.g. Ph and Me), catalysed by boron trifluoride etherate, gives mainly the iyn-isomer (49), i.e. Cram selectivity. For the example given, changing R from SiBu Me2 to Si(Pr )3 raises the syn preference considerably, which the authors refer to as the triisopropylsilyl effect. Even when the and R groups are as similar as ethyl and methyl, a syn. anti ratio of 5.4 was achieved using the triisopropylsilyl ketene thioacetal. 

Ketene thioacetals can also be used as ketene equivalents in the preparation of cyclobutanones and cyclobutanes. Boron trifluoride catalyzes the [2 + 2] cycloaddition of 2-[(l-pyrro-lidinyl)mcthylene]-1,3-dithiane (39) with dimethyl maleate (40).17 Although the cycloadduct is obtained in good yield, stereochemical integrity is not maintained and the thermodynamically most stable isomer predominates. 

Reaction of the anion prepared by deprotonation of a ketene thioacetal (799) (LDA or s-butyllithium) with a carbonyl compound has been shown to afford generally the product of y-addition (800) (80JOC2236). Mercury ion-assisted hydrolysis of the 5-hydroxy ketene thioacetal provides access to a y-lactone (801 Scheme 187). The y-selectivity of carbonyl substrates is to be contrasted with the a-selectivity generally exhibited by alkyl halides in... 

Thiol esters RC(0)SR have been prepared by nucleophilic cleavage of polystyrene-bound /V-acylsulfonamides with mixtures of a thiol and sodium thiophenolate [377] or LiBr [378], or by treatment of Wang or PAM resin bound carboxylic esters with ethanethiol in the presence of a Lewis acid (AlMe2Cl or AlMe3, DCM, 20 °C, 3 h [379,380]). The latter method can also give rise to the formation of orthoesters RC(SEt)3 and ketene thioacetals, which can, however, be hydrolyzed to the desired thiol esters by treatment with TFA [379]. 

Thiol esters RC(0)SR are stronger acylating agents than simple alkyl esters, and have been prepared on solid phase mainly as synthetic intermediates. The preparation of thiol esters as intermediates for the synthesis of support-bound thiols is discussed in Section 8.1. Further examples of the preparation of thiol esters on insoluble supports include the aldol addition of ketene thioacetals to polystyrene-bound aldehydes... 

Aggarwal and co-workers have used Jackson s metal peroxide oxidants for the epoxidation of ketene thioacetals. This resulted in highly diastereoselective epoxide formation (>20 1 selectivity).136 Carmen Carreiio and colleagues showed that epoxidation of (S)-(2-p-tolylsulfonyl)-2-cyclohexan-1 -ol and its OAc and OMOM derivatives, with lithium tert-butyl hydroperoxide, proceeds with high stereoselectivity to give the syn epoxy alcohols.137... 

Ketene thioacetals. The enolate (1) of 2-carbomethoxy-1,3-dithiane does not normally react with aldehydes or ketones, but a 1 1 mixture of trimethylacetyl chloride and an aldehyde reacts in THF to form the pivaloxy ester 2. This product undergoes dccar-boalkoxylation (9, 283 11, 301) when heated in ilry DMF with excess Li I to form ketene thioacetals (3). 

Diethyoxymethyldiphenylphosphine oxide. KETENE THIOACETALS Lithium iodide. a-KETO aldehydes Nafion-H. a-KETO esters f-Butyl hydroperoxide. Cy-anotrimethylsilane. 1,2-Diethoxy-1,2-disi-lyloxyethane. Trimethylphosphonoglyco-late. 

Some of the useful applications of ketene thioacetals of this type are shown in Scheme (I) for some reactions of 2. For other examples, see lithium naphthalenide, this volume. 

Ketene Ikioacetals. The oxidation of a-hydroxy thioacetals with 1 equiv. of lead tetraacetate in some cases results in clean fragmentation to a ketene thioacetal. The reaction proceeds particularly well when the reacting center is part of a strained ring system, as in examples formulated in equations (I) and (II). The oxidation of one open-chain substrate also proceeded cleanly. In general, the reaction tends to be slow and capricious (7,186-187), but can be a useful approach to ketene acetals with an unprotected carbonyl group. 

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