Sulfoxide, dimethyl conjugate additions

In the presence of suitable a,/5-unsaturated carbonyl compounds (3) the nucleophilic methylide (2) undergoes conjugate addition followed by expulsion of dimethyl sulfoxide to give cyclopropanes (5). 

This stabilized ylide reacts with aldehydes and ketones to furnish epoxides. The difference in reactivity between dimethylsulfonium methylide and dimethyloxosulfo-nium methylide is apparent when considering their reactions with a, 3-unsaturated ketones. Whereas the nonstabilized ylide yields the epoxide, the stabilized ylide affords a cyclopropane via conjugate addition followed by ring closure and loss of dimethyl sulfoxide. 

CONJUGATE ADDITION Alkylmethyl-magncsiocuprates. 2-Carboethoxyl-benzyl phenyl sulfoxide. Cyanodiethyl-aluminum chloride. 1-Cyclopropyl-l-tiimethylsilyloxyethylene. Lithium 1,3-butadiene-l-olate. Lithium dimethyl-cuprate. Magnesium ethyl malonate. Potassium carbonate. Tri-n-butyl-stannyllithium. Trimethylzinclithium. 

CONJUGATE ADDITION Diethyl acetylmethylmalonate. Dilithium trimethyl cuprate. N,N-Dimethylbenzeneselenenamide. Dimethyl sulfoxide. Lithium di-(2-vinylcyclo-propyl)cuprate. Lithium phenylthio(cyclopropyi)cuprate. Lithium phenylthio[(a-diethoxymethyl)vinyi]cuprate. 2-(2-Mcthoxy)-aIiylidene-l,3-dithiane. 2-Nitropropene. Tetra- -butylammonium fluoride. Titanium(IV) chloride -is(methyithio)methyl-lithium. 

Jones and colleagues have prepared 1,4-dicarbonyl compounds by conjugate additions of enolate and related anions to a,P-unsaturated sulfoxides [80,81]. For example, the lithium enolate of acetone dimethylhydrazone (83), in the presence of dimethyl sulfide-copper(I) bromide complex, underwent conjugate addition to 2-phenylsulfinyloct-l-ene (82). Quenching the reaction mixture with dimethyl disulfide gave the doubly protected 1,4-diketone derivative (84), which, on sequential hydrolysis with copper(II) acetate and trifluoroacetic acid gave the dodecane-2,5-dione (85) as the product in 54% yield from (82) (Scheme 5.27). Other examples of the addition of enolate-type species to a,p-unsaturated sulfoxides have also been reported [82.83]. 

During the initial studies on the chemistry of the suifenic acid functionality, Shelton and Davis (1967) observed that t-butylsulfenic acid (103) underwent conjugate addition to a propiolic ester to produce the vinyl sulfoxide (104). Similarly, the azetidinone suifenic acid (105), thermally generated from penicillin sulfoxide (106), was also found to undergo a conjugate addition with dimethyl acetylenedicarboxylate to yield a mixture of epimeric sulfoxides 107 and 108 (Barton et al., 1973 1974). This isomeric mixture could be reduced to the single sulfide (109). The double bond was isomerized to the a,p-unsaturated compound 110 which on progressive ozonolysis first produced the thiooxalate (111) and then the oxamide (112). 

The formation of the above anions ("enolate type) depend on equilibria between the carbon compounds, the base, and the solvent. To ensure a substantial concentration of the anionic synthons in solution the pA" of both the conjugated acid of the base and of the solvent must be higher than the pAT -value of the carbon compound. Alkali hydroxides in water (p/T, 16), alkoxides in the corresponding alcohols (pAT, 20), sodium amide in liquid ammonia (pATj 35), dimsyl sodium in dimethyl sulfoxide (pAT, = 35), sodium hydride, lithium amides, or lithium alkyls in ether or hydrocarbon solvents (pAT, > 40) are common combinations used in synthesis. Sometimes the bases (e.g. methoxides, amides, lithium alkyls) react as nucleophiles, in other words they do not abstract a proton, but their anion undergoes addition and substitution reactions with the carbon compound. If such is the case, sterically hindered bases are employed. A few examples are given below (H.O. House, 1972 I. Kuwajima, 1976). 

In view of the hydrogen bond conjugation effect reported by Lemieux and Pavia (17), the gradual addition of dimethyl sulfoxide to a solution of 4 in 1,2-dichloroethane should initially enrich the population... 

The sulfoxonium ylid 78 is more stable and is therefore liable to do conjugate rather than direct addition (chapter 21). The intermediate eliminates dimethyl sulfoxide 79 to give the cyclopropane 76. The intermediate is long lived and the single bond that was the alkene can rotate so the geometry of the alkene is lost. In this case we expect the more stable trans cyclopropane to be formed by choice. 

Proline was among the first compounds to be tested in asymmetric conjugated reactions, both as a chiral ligand [8] and also as an organic catalyst [3]. The earliest asymmetric intermolecular Michael-type addition, in which proline catalyzed the reaction (arguably via enamine formation) was reported by Barbas and colleagues [9, 10] and by List and co-workers [11]. The reaction, which proceeded in high chemical yield (85-97%) and diastereoselectivity, albeit afforded near-racemic products in dimethyl sulfoxide (DMSO) [11] (Scheme 2.37). The enantio-selectivity of the addition was later ameliorated by Enders, who demonstrated that a small amount of methanol rather than DMSO was beneficial to the enantiose-lectivity of the addition reaction [12]. 

When isomerization of the double bond of the intermediate cyclopropene into the exo methylene position is energetically unfavored, double elimination followed by double addition of base can occur. Thus, reaction of (cu/tra i )-l,l-dichloro-2-methyl-3-vinylcyclopropane (9) with potassium terf-butoxide plus methoxide in dimethyl sulfoxide gave a mixture of cis- and trans-, -dimethoxy-2-methyl-3-vinylcyclopropane (10). Both double bonds formed via elimination appear to be conjugated with the vinyl group and do not migrate to the exo position. The similar reaction of l,l-dichloro-2-[( )-propenyl]cyclopropane (11) gave a small amount of 1-/ert-butoxy-2-(prop-2-enylidene)cyclopropane (13) in addition to products of double addition. Without added methoxide, 13 was the only product isolated. ... 

Stronger bases, such as amide anion, methylsulfinylcarbanion (the conjugate base of dimethyl sulfoxide), and triphenylmethyl anion, are capable of effecting rapid and essentially complete conversion of a ketone to its enolate. Lithium diisopropylamide, generated by addition of Ai-butyllithium to diisopropylamine, is widely used for this purpose. It is a very strong base, yet is sufficiently bulky so as to be relatively nonnucleophilic—a feature that is important in reducing a number of side reactions. The lithium and sodium salts of hexamethyldisilazane [(CH3)3Si]2NH are easily prepared and handled compounds with properties similar... 

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