Thioketal formation

An older method,which also retains the double bond in its original location, utilizes the fact that thioketal formation from A" -3-ketones does not induce bond migration. Subsequent desulfurization with Raney nickel gives the A" -olefin (see section XI-D). 

Thioketals are readily formed by acid-catalyzed reaction with ethane-dithiol. Selective thioketal formation is achieved at C-3 in the presence of a 6-ketone by carrying out the boron trifluoride catalyzed reaction in diluted medium. Selective protection of the 3-carbonyl group as a thioketal has been effected in high yield with A" -3,17-diketones, A" -3,20-diketones and A" -3,l 1,17-triones in acetic acid at room temperature in the presence of p-toluenesulfonic acid. In the case of thioketals the double bond remains in the 4,5-position. This result is attributed to the greater nucleophilicity of sulfur as compared to oxygen, which promotes closure of intermediate (66) to the protonated cyclic mercaptal (67) rather than elimination to the 3,5-diene [cf. ketal (70) via intermediates (68) and (69)]." " ... 

The electrophilic component in these co-cyclisation reactions can bear other functionality. For example, reaction of isobutenyl dichloride 10 with the appropriate linear dithiols gives good yields of polythiacycles such as 11, 12 and 13.11 A related reaction allows the direct introduction of a keto group into such poly-thia macrocycles. The electrophilic component in this case is 1,3-dichloropropanone, 14. The reaction conditions (Cs2C03, DMF, 60 °C), are insufficiently basic to induce a Favorskii reaction. Furthermore, under the aprotic, basic conditions, thioketal formation cannot take place, allowing successful co-cyclisation to be undertaken, such as in the formation of 15 (Scheme 3.4). Similar reactions allow the preparation of 16,17 and 18.11... 

Imidazole, TBDMSCl, DME, rt, 88-96% yield. This group was stable to NaBH4, MeMgCl, and thioketal formation with HSCH2CH2SH/BE3-Et20. 

For over a decade, hormonal activity of any consequence was thought to be limited to steroids containing a A4-3-keto group. A recent development of much interest, therefore, is the removal of the 3-ketone from VIII (R = X = H) via thioketal formation and reduction with sodium in liquid ammonia. Subsequent oxidation and ethinylation afforded the 3-deoxy derivatives of XIII and XV (20). The latter, lynestrenol, possesses marked progestational properties. High potency was also found when the ketone (XV, R = X = H) was reduced... 

Thioacetal (or thioketal) formation is a synthetically useful reaction because a thioacetal (or thioketal) is desulfurized when it reacts with H2 and Raney nickel. Desulfurization replaces the C — S bonds with C—H bonds. 

Thioketal formation followed by desulfurization provides us with a third method that can be used to convert the carbonyl group of a ketone into a methylene group. We have already seen the other two methods—the Clemmensen reduction and the Wolff-Kishner reduction (Sections 15.15 and 18.6). 

Dimethyl ketals and enol ethers are stable to the conditions of oxime formation (hydroxylamine acetate or hydroxylamine hydrochloride-pyridine). Thioketals and hemithioketals are cleaved to the parent ketones by cadmium carbonate and mercuric chloride. Desulfurization of thioketals with Raney nickel leads to the corresponding methylene compounds, while thioenol ethers give the corresponding olefin. In contrast, desulfurization of hemithioketals regenerates the parent ketone. ... 

Unsubstituted 20-ketones undergo exchange dioxolanation nearly with the same ease as saturated 3-ketones although preferential ketalization at C-3 can be achieved under these conditions. " 20,20-Cycloethylenedioxy derivatives are readily prepared by acid-catalyzed reaction with ethylene glycol. The presence of a 12-ketone inhibits formation of 20-ketals. Selective removal of 20-ketals in the presence of a 3-ketal is effected with boron trifluoride at room temperature. Hemithioketals and thioketals " are obtained by conventional procedures. However, the 20-thioketal does not form under mild conditions (dilution technique). ... 

Olefin formation by reduction of keto derivatives via tosylhydrazones, 354 Olefin formation by reduction of thioketals, 356... 

Addition of hydrogen sulfide results in formation of monomeric gem dithiols or trimeric thioketals (511,512). The initially reported thione formation (513-515), analogous to hydration of morpholinocyclohexene... 

Complications often arise in the use of 1,3-diketones under the above reaction conditions. This is primarily due to the lack of regioselectivity with regard to formation of the intermediate thioacetal. However, when benzoyl acetone derivatives are employed, the thioketal forms preferentially with the aromatic ketone. ... 

Acetalization or ketalization with silylated glycols or 1,3-propanediols and the formation of thioketals by use of silylated 1,2-ethylenedithiols and silylated 2-mer-captoethylamines have already been discussed in Sections 5.1.1 and 5.1.5. For cyclizations of ketones such as cyclohexanone or of benzaldehyde dimethyl acetal 121 with co-silyl oxyallyltrimethylsilanes 640 to form unsaturated spiro ethers 642 and substituted tetrahydrofurans such as 647, see also Section 5.1.4. (cf. also the reaction of 654 to give 655 in Section 5.2) Likewise, Sila-Pummerer cyclizations have been discussed in Chapter 8 (Schemes 8.17-8.20). 

Theoretical studies have been done in order to understand this behavior difference. Semiempirical calculations (AMI, MNDO) of formation energy (of the hemithio-ketal-hemiketal interconversion) have shown that hemithioketals are less stable than the corresponding hemiketal (from 10 to 15 kcal/mol). This difference can be due to steric factors, connected to the respective sizes of sulfur and oxygen. Stereoelectronic factors can also be evoked stabilization that is brought about by the anomeric effect is a priori more important for a gem-dihydroxylated compound than for the hemi-thioketal. Moreover, at the kinetic level, displacement of the water molecule of the inhibitor (under aqueous conditions, the inhibitor is hydrated) by the thiol of the enzyme is a slow and disfavored reaction. In contrast, the same reaction is favored with the hydroxyl of a serine. Experimentally, equilibrium occurs very slowly with the enzyme as well as with model molecules. ... 

Fischwick has detailed a rapid synthetic approach to the imidazole based y-lactam alkaloid, (+/—) cynometiine (67), isolated from the stem bark of Cynometra hankei, and which has been shown to be a potential analgesic (16). Cesium fluoride induced formation of the ylide, from precursor 68, followed by cycloaddition to alkene 69 furnished the required adduct 70 in 71% yield as a 4 1 diastereomeric mixture in favor of the desired isomer. Deprotection of the thioketal followed by NaBH4 reduction delivered the desired racemic product (Scheme 3.17). 

Hydantocidin, which bears a spiro skeleton, is a natural product and a herbicide. Eq. 3.113 shows the typical preparation method of spiro-diketone (277) from the reaction of a-diazoketone (276) with Rh2(OAc)4 via a carbenoide species. However, this spiro skeleton can be also constructed by radical reactions. Treatment of (3-keto ester (278) with Mn(OAc)3 in the presence of electron-rich olefin generates spiro-cyclic thioketal (279) through the formation of a (3-keto ester radical, intermolecular radical addition to... 

For the compounds that we overview here, an attractive conversion of thionoesters to ethers [191] has used the radical addition of an excess of triphenyltin hydride, instead of tri-n-butyltin hydride, which avoided the deoxygenation reaction. The process involves in a first step the very favourable formation of a sulfur-tin bond and the subsequent desulfurisation of the mixed thioketal. 

Many other examples of chemoselective enone reduction in the presence of other reducible functionalities have been reported. For instance, the C—S bonds of many sulfides and thioketals are readily cleaved by dissolving metals. " Yet, there are examples of conjugate reduction of enones in the presence of a thioalkyl ether group." " Selective enone reduction in the presence of a reducible nitrile group was illustrated with another steroidal enone. While carboxylic acids, because of salt formation, are not reduced by dissolving metals, esters" and amides are easily reduced to saturated alcohols and aldehydes or alcohols, respectively. However, metal-ammonia reduction of enones is faster than that of either esters or amides. This allows selective enone reduction in the presence of esters"" and amides - -" using short reaction times and limited amounts of lithium in ammonia. 

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