1.3- Dithianes Michael addition

RSSiMe3 [R = Me, Et, (-CH2-)3], Zn, Et20, 0-25°, 70-95% yield. This method is satisfactory for a variety of aldehydes and ketones and is also suitable for the preparation of 1,3-dithianes. Methacrolein gives the product of Michael addition rather than the thioacetal. The less hindered of two ketones is readily protected using this methodology. ... 

Methoxytrimethylsilane, 123 Methyl acetoacetate, 92 Methyl bromoacetate, 107 Methyl 11-hydroxyundecanoate, 58 Methyl lithium, 27,28 Methyl 10-undecenoate, 58 2-Methyl-l, 3-dithiane, 81 (fl/ ,5 )-Methyl-3-phenyldiniethyl-silyl-3-phenylpropionic acid, 53-4 2-Methyl-3-Phenylprop-2-cnal, 111 2-Methyl 2-lrimethylsilyl-1,3-dithiane, 81 2-Methyl-l-(trimcthylsilyloxy)cyclo-hex-l-ene, 100,109 2-Melhyl-l-lrimethylsilyloxy)cyclo-hcx-6-enc, 100 2-Methyl-2-trimethylsilyloxy-pentan-3-one, 132 2-Methylacetophenone, 42-3 2-Methylbutyraldehyde, 85 2-Methylcyclohexanone, 99,100 2-Methylcyclohexanone, 131 4-Methyldec-4-ene, 67-8 Methylenation, 63 2-Methylpropen-l-ol, 131 Methyltriphenylphosphonium bromide, 27 Michael addition, 85 Monohydridosilanes, 128 Monohydroalumination, 29... 

The stereospecific base-cleavage of the trimethylsilyl group in 1,3-dithiane 1-oxides 499 enables to obtain the specifically deuteriated products 500 (equation 303), A nitro group in y-nitroalkyl sulphoxides 501 (obtained by the Michael addition of nitroalkanes to a, j8-unsaturated sulphoxides) is replaced by hydrogen by means of tributyltin hydride (equation 304). This reagent does not affect the sulphinyl function. The overall procedure provides an efficient method for the conjugate addition of alkyl groups to a, -unsaturated sulphoxides . ... 

It has been shown that Lewis acid catalyzed isomerization of thionolactones provides access to thiolactones. For example, exposure of the substrate 22 to catalytic amounts of BF3 OEt2 led to efficient conversion to the thiolactone 23. Such transformations were also found to give minor amounts of lactone or dithiolactone side products <06TL6067>. Substituted tetrahydrothiophene derivatives have also been obtained from 1,4-dithiane-2,5-diol and 2-nitroethyl acetate derivatives by a base induced sequence featuring a Michael addition and a Henry reaction <06TL8087>. 

Alkynones are suitable substrates for the preparation of 2-substituted-l,3-dithianes by Michael addition. Either 1,3-propanedithiol <20030BC15> or the diamide of thiomalonic acid <2002RJ01205> gave the 1,3-dithianes in reasonable to excellent yields (Scheme 107). The reaction is in the first case base and in the latter case acid-induced. 

Michael addition of a dithiane anion 20, generated from the dithiane 19 with butyllithium, to the butenolide 21 creates the enolate 22 which has been efficiently alkylated in situ by 3,4,5-trimethoxybenzyl chloride to give 24 (mp 146-146.5 °C) in 65% overall yield. Protona-tion of 22 furnished the Michael adduct 23, which again can be deprotonated16 with LDA at — 78 °C to give 22 and alkylated (trimethoxybenzyl chloride, THF, HMPA, 3 h at — 78 °C, 18 h at 20 °C) to yield 24. Both variants are equally completely diastereoselective giving rise to the trans- product. 

Spirocyclization with 2-silyt- 1,3-dithianes. Treatment of the trimcthylsilyl-alkanal 1 with fluoride ion liberates an anion that undergoes cyclization to the aldehyde group to yield 2. Various Lewis acids do not promote this cyclization. Similar desilylation of 3 is followed by an intramolecular Michael addition to give 4 in 64% yield. 

A total synthesis of ( )-aromatin has utilized the lithium anion of the dithiane of (E)-2-methyl-2-butenal as a functional equivalent of the thermodynamic enolate of methyl ethyl ketone in an aprotic Michael addition (Scheme 189) (81JOC825). Reaction of the lithium anion (805) with 2-methyl-2-cyclopentenone followed by alkylation of the ketone enolate as its copper salt with allyl bromide delivered (807). Ozonolysis afforded a tricarbonyl which cyclized with alkali to the aldol product (808). Additional steps utilizing conventional chemistry converted (808) into ( )-aromatin (809). 

In the case of the enone 142, an intermediate in the synthesis of the anticancer natural product OSW-1, the Michael addition of bis(phenylsulfanyl)methyllithium 126 took place in the presence of HMPA, whereas 2-lithio-l,3-dithiane gave the 1,2-addition product (Scheme 39)150. Unfortunately, this strategy was abandoned because compound 143 could not be further alkylated. 

Michael addition. ° The synthesis of the naturally occurring benz[a]anthraquinones, X-14881 (64 R = Me) and ochrotnycinone (R H) utilizes 2-phenyldithiane anion (Scheme 38), while 11-deoxydauno-mycinone was prepared using 2-methyldithiane. The formation of bicyclo[3.3.0]oct-l(5)-ene-2,6-dione utilizes 2-(2,2-diethoxyethyl)-l,3-dithiane anion. Conjugate addition of the highly stabilized anion (65) occurs readily with enamide (66), whereas the related acyclic anion (67) appears to be less reactive than the cyclic analog (Scheme 39). Conjugate addition of lithiated a-alkylthio monosulfoxide provides a new route for the synthesis of dihydrojasmone. ... 

Unlike the carbanions from 1,3-dithians (see Chapter 3, p. 31 and Chapter 6, p. 90), the sulfinyl carbanions have the ability to undergo Michael additions (conjugate or 1,4-additions) with a,p-unsaturated carbonyl compounds. For instance, the secondary carbanion (44) from the ethyl ethylthiomethyl sulfoxide (45) may be sucessively reacted with ethyl iodide and 3-butene-2-one to give heptan-2,5-dione (46) via the tertiary carbanion (47), as shown in Scheme 23. The carbanion (47) may also be condensed with propyl bromide, and hydrolysis of the product yields ethyl propyl ketone (48) (Scheme 23). 

Winterfeldf s synthesis of brefeldin A (Scheme 1.36) also entailed use of a Michael addition in an anti fashion to a 4-substituted cyclopentenone. Dithiane anion 217 was added in a 1,4 sense to enone 216 to give, after elimination of acetic acid, cyclopentenone 218. Addition of cuprate 219 to 218 in the expected anti manner cleanly afforded the trans cyclopentane 220. Hydride reduction gave the unnatural P-alcohol, which was inverted by a Mitsunobu reaction and the resulting ester cleaved to the desired a-alcohol 221. Protection of the alcohol... 

Double Michael addition. In the presence of MgO alky ny 1 ketones and 1,3-propane-dithiol react to afford 2-acylmethyl-l,3-dithianes. ... 

This methodology furnished also an efficient access into the furofuran skeleton, Scheme (19). A tandem Michael addition-aldol reaction was used to provide lactone 107 in 62% yield as a mixture of diastereomers in a ratio of 60 40. Dithiane 107 was converted into ketone 108 using HgO in combination with BF3 Et20. Subsequent reduction using an excess of LiAlH4 afforded tetraol 109 in 67% yield. The synthesis of (-)-eudesmin (110) was completed in 16% overall yield by dehydratation of 109 with BF3 Et20. 

A number of branched chain nitro-cyclitols have been prepared by Michael addition of lithium dithiane to unsaturated nitrosugars followed by cyclization (Scheme 4) conformational effects in the 6-nitro-a/de/iydo-sugar on the stereo-... 

The use of unsaturated nitriles as Michael acceptors represents a facet of the synthetic utility of cyano-compounds that nicely complements the reactivity discussed above. Michael addition of 2-lithio-1,3-dithianes to a,B-unsaturated nitrile derivatives appears to be of use in the preparation of protected cyanoketones, although the method may be limited by the fact that reactions of substrates unable to stabilise the negative charge of the adduct before workup were difficult to achieve satisfactorily. 

Michael additions. In this sense, the preferred formation of the (S)-diastereomers of the Michael adducts 17 generated from the enolate 15 of the diacetone-glucose dithiane-2-carboxylic acid ester with arylidene malonic acid esters 16 can be explained by assuming that the electrophile attacks from the lithium site in a way, which minimizes the steric repulsion between the dithiane ring and the aryl group ( formula A) ... 

Various versions of the acyl anion equivalent (32) are described by Stork etal. (use of Et2NCH2CN), Krief and co-workers (1,3-dithianes in regioselective Michael addition), Gokel et al. (use of sulphur heterocycles with thermal deblocking), Cohen and Weisenfeld" (conversion of acids into vinyl sulphides), Meyers and Campbell " (acetals derived from aryl aldehydes), and Hunig and co-workers (cyanohydrin derivatives of aryl aldehydes). 

Finally, Seebach has used the cyclic urea (69), DMPU, as a co-solvent in double lithiations, oxirane ring-opening, Wittig reactions, Michael additions of lithiated dithianes to cycloalkenones, and the selective generation of enolates." The interesting point here is that DMPU exhibits the same solvent effect as the carcinogen HMPA and might therefore be a safe substitute. 

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