1.3- Oxathiane alkylation

Oxathiane 101 is readily deprotonated using s-BuLi, and the resulting anion reacts with alkyl halides, ketones, and benzonitrile (85JOC657). The majority of work in this area, however, is due to Eliel and coworkers and has involved chiral 1,3-oxathianes as asymmetric acyl anion equivalents. In the earliest work it was demonstrated that the oxathianes 102 and 103, obtained in enantiomeri-cally pure form by a sequence involving resolution, could be deprotonated with butyllithium and added to benzaldehyde. The products were formed with poor selectivity at the new stereocenter, however, and oxidation followed by addition... 

Moreover, the sulfur atom of 1,4-oxathianes can be alkylated. Thus, reaction of 3-aryl-l,4-oxathianes 84 with (trimethylsilyl)methyl trifluoromethanesulfonate gave a mixture of cis- and /ra t-isomers of 3-aryl-4-(trimethylsilyl)-methyl-l,4-oxathianium triflates 85 (Equation 12) <1997J(P1)715>. 

Carbon-13 shift values of parent heterocycloalkanes [408] collected in Table 4.61 are essentally determined by the heteroatom electronegativity, in analogy to the behavior of open-chain ethers, acetals, thioethers, thioacetals, secondary and tertiary amines. Similarly to cyclopropanes, three-membered heterocycloalkanes (oxirane, thiirane, and azirane derivatives) display outstandingly small carbon-13 shift values due to their particular bonding state. Empirical increment systems based on eq. (4.1) permit shift predictions of alkyl- and phenyl-substituted oxiranes [409] and of methyl-substituted tetrahydropyrans, tetrahydrothiapyrans, piperidines, 1,3-dithianes, and 1,3-oxathianes [408], respectively. Methyl increments of these heterocycloalkanes are closely related to those derived for cyclohexane (Table 4.7) due to common structural features of six-membered rings. 

The stereochemistry, physical and chemical properties and some transformations of 1,3-oxathianes, especially alkyl substituent effects on the preferred conformers, were reviewed (99MI73, 00MI17). Also 1,3-oxathiane and its 2-substituted homologs were theoretically calculated using the semiempirical AMI and PM3 methods (98MI14) the experimental parameters are adequately reproduced. In the case of 5-alkyl substituted... 

The lithiation of 1,3-oxathiane (296) takes place with s-BuLi at —78 °C to give 2-lithio-1,3-oxathiane (315), an analogue of 2-lithio-l,3-dithiane (161), but with lower stability487. This intermediate reacts with different electrophiles, such as alkyl halides, carbonyl compounds, benzonitrile, dimethyl disulfide, dimethyl diselenide, trimethylplumbyl acetate and trimethylsilyl, germyl and stannyl chlorides488,489. However, further deprotection of 2-substituted 1,3-oxathianes has not been reported yet. 

Trimethylsilyl)-l,3-oxathianyllithium 332 was obtained by deprotonation of compound 323 with s-BuLi at —78 °C and reacted with different electrophiles such as deuterium oxide, alkyl iodides, dimethyl disulfide and carbonyl compounds, providing the corresponding products 333 in moderate to good yields. However, the reaction with benzonitrile, followed by acid hydrolysis, gave 2-benzoyl-l,3-oxathiane 334 (X = H) (Scheme 87)503,504. When the last reaction was quenched with methyl iodide before... 

Several other acyl anions or potential acyl anion equivalents bearing at least one nonoxidized sulfur atom have since been proposed, and some of them have been alkylated successfully. This is effectively the case for the following metallated compounds (i) yV-methylthioformaldine (Scheme 73, entry c) (ii) 1,3-oxathianes, and a-trimethylsilylmethyl analogs (iii) a-methoxythioanisole (Scheme 74, entry a Scheme 75, entry the parent compound also allows the synthesis of acetals (on acid-... 

Lithio-l,3-oxathiane - has proved to be much less reactive than phenylthiomethyllithium (Scheme 74, entry a).- Although the latter reacts well with alkyl or benzyl bromides and with alkyl iodides without distinction, 2-lithio-l,3-oxathiane works well only with alkyl iodides. ... 

A single sulfonium ylide is beUeved to be formed as alkylation of oxathiane 3a gave the equatorial sulfonium salt exclusively [29]. Ylide conformation has been studied by X-ray, NMR, and computation [30]. All of these studies indicate that the preferred conformation of sulfur yUdes is one in which the filled orbital on the ylide carbon is orthogonal to the lone pair on sulfur. The barrier to rotation around the C-S bond of the semi-stabilized ylide, dimethylsulfonium fluorenide, has been found to be 42 1.0 kJmol [30]. This impHes that the ylide will adopt conformations 6a and 6b and that these will be in rapid equilibrium at room temperature. Of these two, conformation 6b will be favored as 6a suffers from... 

When deprotonation is effected in a 2-allyl-1,3-oxathiane with 5cc-butyllithium, the expected allylic anion is generated. Interestingly, reaction with alkyl halides leads to substitution at the a-terminus (52), whereas reaction with carbonyl compounds gives products of substitution at the y-terminus (53) (Scheme 18) <92TL250l>. In contrast, when the anion derived from 2-allyl-1,3-dithiane... 

Dimethyl-1,3-oxathiane 3,3-dioxide (60), obtained by oxidation of the parent compound with mcpba, also undergoes efficient deprotonation and alkylation at the 4-position, so acting as a y-hydroxylpropyl anion equivalent (Equation (29)) <92S852>. 

The reactivity of these heterocycles towards hydrogen atom abstraction at C-2 has been shown to increase in the expected order, from 1,3-dioxane, through 1,3-oxathiane, to 1,3-dithiane. Hydrogen atom abstraction from C-2 in 4-methyl-1,3-dioxane, 2,4-dimethyl-1,3-dioxane, and 2-ethyl-4-methyl-1,3-dioxane has also been investigated <77MI 608-01 >. The radical-mediated alkylation of 2-stannyl-l,3-dithianes (67) with alkenes and enol ethers has been observed (Equation (30)) <92CL1229>. 

We found that PhSCH2OCH3 can be lithiated completely within 45 min at temperatures between —40 and — 45 °C using n-BuLi in THF and hexane. Subsequent functionalizations gave high yields. When during the lithiation or derivatization reaction the temperature was allowed to rise above — 20 °C, however, reduced or low yields of impure products were obtained. Since reactions with most electrophiles can be completed within 1 to 2 hours at temperatures below — 40 °C, the lower stability of PhSCH(Li)OCH3 is not a serious drawback in syntheses performed on a small or moderate scale. Problems may arise if first an alkyl chain is introduced and the methyne proton in the product PhSCH(Alkyl)OCH3 is to be replaced by lithium. 1,3-Oxathiane has been incidentally used as a substrate for lithiation-functionalization reactions [4]. 

Whereas thioanisole, CH3SPh, is reported to give a mixture of ring-metallated and side-chain-metallated products upon interaction with butyllithium, the 0,S-acetal CH3OCH2SPh is lithiated only on the methylene carbon atom by BuLi in THF or sec-BuLi-TMEDA in THF [1-3]. Analogous metallations have been realized with 1,3-oxathiane [4]. The obtained lithium compounds have a limited thermal stability [5], so functionalizations with alkyl halides and epoxides, which are usually less fast than reactions with other electrophiles , give reduced yields. The 0,S-acetal PhSCH2OCH3 can be lithiated in a reasonable time with butyllithium in a THF-hexane mixture but the temperature has to be kept below — 40 °C to prevent decomposition of the lithiated intermediate into PhSLi and other (unidentified) products [5],... 

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