Of dithianes

To create a setting favorable for the formation of the E-ring of ginkgolide B, it is first necessary to modify the reactivity potential of ring F in 23. Exposure of a solution of 23 in methylene chloride to 1,3-propanedithiol and titanium(iv) chloride at 0°C results in the formation of dithiane 24 in quantitative yield. Oxidation of the primary alcohol with PDC in the presence of acetic acid gives aldehyde 25 in a yield of 75 %. 

For further use of dithiane chemistry in the synthesis of spongistatin, see also a)... 

Alkylation and hydrolysis of imines alkylation of aldehydes 10-107 Alkylation and hydrolysis of dithianes 10-108 Alkylation and hydrolysis of oxazines and similar compounds 10-109 Reaction of diazo aldehydes with boranes... 

Alkylation and hydrolysis of dithianes and similar compounds 10-108 Alkylation and hydrolysis of oxazines... 

The preparation of dithianes from enamines by reaction with trimethylene dithiotosylate (propane-1,3-dithiol di-p-toluenesulfonate) has been applied with enamines derived from oholostan 3 one, aceto-acetic ester, and phenylacetone.6 7 Reactions of trimethylene dithiotosylate with hydroxymethylene derivatives of ketones also give rise to dithianes thus the hydroxymethylene derivative of cholest-4-en-3-one can be converted to 2,2-(trimethylenedithio)cholest-4-en-3-one. 1,3-Dithiolanes are obtained in a similar manner by reaction of ethylene dithiotosylate1 with the appropriately activated substrate.5,7... 

It has been known for many years that hydrogens adjacent to a heteroatom are more acidic when the heteroatom is sulfur than when oxygen359. A striking example of this phenomenon is the behavior of dithiane, A, compared to its oxygen analog,... 

Attempts to prepare 2 2 - difluorodiethyl sulphide by the action of sodium sulphide on chlorofluoroethane resulted in the production of dithian together with other polymeric substances. Aniline either did not react at all or, under drastic conditions, gave AiV -diphenylpiperazine and NN -diphenylethylenediamine. 

The oxidation of dithianes (Scheme 13) leads to a dicationic species that reacts with water affording aldehydes or ketones and 1,2-dithiolane, which undergoes further oxidation to the sulfoxide (20-74% yields) [18]. 

As previously illustrated in Scheme 13, the anodic oxidation of dithianes involves a ring contraction affording 1,2-dithiolane [18]. 

Assembling a five-component coupling product in a single operation further extended this methodology. Following alkylation of dithiane 78 with epoxide (—)79 (2.6 equivalent each) to generate the unrearranged alkoxy dithiane 80, sequential addition of HMPA and (—)-epichlorohydrin 81 (1 equivalent) furnished the bis(silyloxy dithiane) carbinols (- -)82 in 66% yield (equation 29) . ... 

The enantioselective lithiation of anisolechromium tricarbonyl was used by Schmalz and Schellhaas in a route towards the natural product (+)-ptilocaulin . In situ hthi-ation and silylation of 410 with ent-h M gave ewf-411 in an optimized 91% ee (reaction carried ont at — 100°C over 10 min, see Scheme 169). A second, substrate-directed lithiation with BuLi alone, formation of the copper derivative and a quench with crotyl bromide gave 420. The planar chirality and reactivity of the chromium complex was then exploited in a nucleophilic addition of dithiane, which generated ptilocaulin precnrsor 421 (Scheme 172). The stereochemistry of componnd 421 has also been used to direct dearomatizing additions, yielding other classes of enones. ... 

To the best of our knowledge, the allylation of dithianes has not been previously reported in the literature. A range of dithianes underwent smooth allylation to give the desired thioester products in good yield however, a slightly increased catalyst loading (2-10 mol%) was needed (Table 8). 

The same group has also reported the use of dithiane functionalized olefinic aldehydes in an intramolecular process. Treatment of 289 with the secondary amine 290 led to the formation of the intermediate ylide 291, which delivered a range of tricyclic products (292) in high material yield as essentially a single stereoisomer after in situ cycloaddition (Scheme 3.95). 

A one-pot procedure for the transformation of 6-thiopurine nucleosides to 6-aminopurines was developed using DMDO as the oxidant in the presence of a stoichiometric amount of various amines <1996T6759>. For example, 6-thio-9-(2, 3, 5 -tri-0-acetyl-/3-D-ribosyl)purine was readily converted to the 6-alkylamino derivatives (6-amino, 75% yield 6-methylamino, 55% yield). Similarly, A -6-acetyl-8-thio-9-(2, 3, 5 -tri-0-acetyl-/3-D-ribosyl)adenosine was converted to A -6-acetyl-8-methylamino-9-(2, 3, 5 -tri-0-acetyl-/3-D-ribosyl)adenosine (DMDO, methylamine, CH2CI2, 25 °C, 83% yield). Less nucleophilic 2-mercaptopurine derivatives did not undergo the displacement reaction, however, and only the products of dithiane formation and desulfurization were isolated. 

Finally, the synthesis of both attenols was accomplished by employing both electrophiles 106 and 112 as shown in Scheme 1.2.24. The alkylation of dithiane 113 with 106 proceeded cleanly in 96% yield. The second alkylation using 112 had to be carried out in the presence of HMPA and yielded 115 in 84% yield. Copper-mediated hydrolysis of the dithiane and p-toluenesulfonic acid catalyzed ketal formation finally gave a mixture of the title compounds 100 (57%) and 101 (9%), each over two steps. This synthesis is so far the shortest and most efficient one [60]. 

The combined filtrates are returned to the reaction vessel, and distillation with stirring is continued until virtually all the ethanol has been removed. The distillation is stopped when crystals of / -dithiane appear in the condenser or when dilution of the distillate with water causes a milky appearance or the formation of a small quantity of crystals. One liter of water is added to the residue, and the stirred mixture is distilled, using the apparatus... 

The most important use of 1,3-dithianes (792) stems from their ability to function as acyl anion equivalents (794 Scheme 184). Metallation of this heterocycle followed by alkylation of the anion and cleavage of the dithiane group produces a carbonyl compound. Since such aspects of dithiane chemistry have been extensively documented (69S17 75JOC231), only a few of the more current applications of these heterocycles are highlighted. We again note here that the application of heterocycles to the synthesis of carbonyl compounds has been the sole subject of an extensive review (77H(6)73l). 

Dithiane. Condensation of dithiane or substituted analogues [30J on ketosugars has been described by several groups [1], Further deprotection of dithiane gave formyl derivatives. Acetyl or 2-hydroxyacetyl groups can also be obtained using suitably substituted dithiane derivatives. Extensive work by Paulsen et al. has been reported and typical procedures have been published [31]. 

A photosensitized cleavage of dithianes and dithiolanes by visible light [53,54] deserves to be mentioned. 

To a cooled solution of dithiane (1) (2.00 g, 16.7 mmol) in methanol (125 ml) was added an aqueous solution (35 ml) of sodium periodate (3.68 g, 17.5 mmol) at such a rate (approximately 30 min) to maintain the temperature at 20°C. Stirring and cooling were continued for an additional 30 min. The reaction mixture was then filtered to remove sodium iodate, and the resulting solution taken to near dryness on a rotary evaporator. Extraction of the solids with chloroform produced a solution which was dried over sodium sulfate, and filtered. Evaporation left the crystalline sulfoxide (2) (2.13g, 94%), m.p. 86-87°C. 

The dithioacetal (0.01 mol) was stirred for a few hours at room temperature with clayfen (4) (10.4 g, 11 mmol of ferric nitrate) or with claycop (12.1 g, 20 mmol of copper nitrate) in toluene, n-pentane or, preferably, dichloromethane (120ml). Evolution of nitrogen oxides occurred rapidly. Stirring was maintained until gas evolution ceased. The clay was then filtered off and washed twice with portions (50 ml) of the solvent. The resulting pale-yellow or slightly green solution was filtered through a small quantity of neutral aluminium oxide and the solvent was evaporated under vacuum. In the case of dithiane and dithiolane derivatives, this afforded the pure carbonyl compound in excellent yield. 

A large number of workers have examined the effects of temperature, solvent and reaction times on the ratio of the products of 1,4-addition versus 1,2-addition of dithiane and other a-thioalkyl carb-anions.34 Their results show that in general 1,2-addition is kinetically favored and therefore predominates at low temperatures and in less polar solvents,34 34 5 whereas 1,4-addition is thermodynamically favored... 

The l,X-naphthyridines react with phenyllithium to afford the corresponding 2-phenyl derivatives.32 When 1,8-naphthyridine is treated with butyl-lithium, the 2-butyl derivative is obtained, whereas reaction of dithiane with butyl lithium followed by addition of 1,8-naphthyridine generates bisnaph-thyridine 49. An interesting application of the dimethyl sulfoxide-sodium... 

As is often found in asymmetric synthesis, temperature is an experimental parameter that can increase enantioselectivity. Here, however, a decrease in the reaction temperature does not always increase the enantioselectivity. An optimum temperature was found to be -20°C to -25°C for the oxidation of methyl p-tolyl sulfide [17], and this temperature range was retained for the standard oxidations. In the case of the monooxidation of dithianes, the maximum enantioselectivity was obtained at ca. —40°C [29] (Scheme 6C.1). 

One hydrolytic method that is useful for the preparation of ketones is the hydrolysis of dithianes. 1.3-Dithiane can be alkylated by treatment with butyl lithium followed by an alkylating agent. The two sulfurs flanking the acetal carbon acidify the protons on that carbon such that butyl lithium can remove one giving a sulfur-stabilized anion. This anion reacts with alkyl halides or sulfonates to give alkylated products. This sequence can be repeated to give a bis-alkylated product. Hydrolysis then yields a ketone. Ditliioacetals are much more resistant to hydrolysis than acetals and thus Hg2+ is often used to promote efficient hydrolysis. 

Stereoselective intramolecular conjugate addition reactions (Scheme 4) of dithiane anions tethered to an a,/ -unsaturated nitrile have been developed to advantage for the synthesis of axially substituted indolizidines and quinolizidines.81 The control of axial nitrile orientation by a peg-in-a-pocket template effect has been discussed. 

The acidity difference of hydrogen atoms adjacent to divalent sulfur compared to oxygen stems from the greater polarizability of sulfur and the longer C-S-bond length d-orbitals are not involved. In most cases treatment of dithianes with w-BuLi at temperatures of -30 °C is sufficient for the preparation of the lithio-derivatives. With pKA values of approximately 30, lithiated dithianes can react with aldehydes or ketones, epoxides and acid derivatives, but also with alkyl halides without competing elimination reactions. 

Sunay, U. Fraser-Reid, B. Synthetic studies relating to the C1-C9 eastern" half of rosara-micin. Tetrahedron Lett. 1986, 27, 5335-5338. Smith, A. B. Pitram, S. M. Boldi, A. M. Gaunt, M. J. Sfouggatakis, C. Moser, W. H. Multicomponent linchpin couplings. Reaction of dithiane anions with terminal epoxides, epichlorohydrin, and vinyl epoxides efficient, rapid, and stereocontrolled assembly of advanced fragments for complex molecule synthesis./. Am. Chem. Soc. 2003, 125, 14435— 14445. 

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