Conjugate addition sulfones

Potassium or lithium derivatives of ethyl acetate, dimethyl acetamide, acetonitrile, acetophenone, pinacolone and (trimethylsilyl)acetylene are known to undergo conjugate addition to 3-(t-butyldimethylsiloxy)-1 -cyclohexenyl t-butyl sulfone 328. The resulting a-sulfonyl carbanions 329 can be trapped stereospecifically by electrophiles such as water and methyl iodide417. When the nucleophile was an sp3-hybridized primary anion (Nu = CH2Y), the resulting product was mainly 330, while in the reaction with (trimethylsilyl)acetylide anion the main product was 331. 

Thus, the dianion derived from a-amino acid substitutes the /1-chloride to give the ester of 2-(phenylsulfonyl)ethenyl amino acid and subsequent desulfonylation provides N-(benzoyl)vinylalanine methyl ester (62) (equation 61). The conjugate addition of enolates to methyl styryl sulfone (63) and subsequent intramolecular addition to the carbonyl moiety provide a synthetically valuable method for the construction of bicyclic and tricyclic skeletons52. Desulfonylation of the cyclization product 64 with sodium in ethanol-THF gives the diene 65 in good yield (equation 62). 

Cory and Renneboog53 have devised an efficient bicycloannulation for the synthesis of tricyclo[3.2.1.02,7]octane-6-one (66) as shown in equation 63. The method involves three steps (1) the enolate undergoes an initial conjugate addition to phenyl vinyl sulfone, (2) the resulting sulfone-stabilized carbanion undergoes an intramolecular Michael addition to the enone, and (3) the resulting enolate displaces phenylsulfinyl moiety from the tricyclooctanone. The amount of HMPA (3 mol equivalents) is critical for effective cyclization of the enolate. 

An example for synthesis of the chiral [l-keto ester 69 is illustrated in equation 64. It involves conjugate addition of the dipotassium / -keto ester 68 to vinyl sulfone 67 followed by in situ quenching with allyl bromide54. The method provides a new procedure to sevenring annulation product 70 that is a potential precursor for (l)-(-)-cytochalasin C. 

The stereoselective conjugate addition of lithium (Z)-dialkenylcuprates to vinyl sulfones gives (Z)-olefms in the range of 70-80% overall yield and no ( )-isomer is detected (equation 66)56. The degree of stereoselectivity is higher than 90%. 

Deprotonation of the vinylic proton is a serious side-reaction in the conjugate addition of organometallic reagents to y-siloxy-a, /J-unsaturated sulfones (89)63b. The use of the... 

The conjugate addition of tributylstannylmethyllithium to unsaturated sulfones 100, followed by trapping with an aldehyde, provides a route to the allyl alcohol 101 which may be transformed into 2(5H)-furanones (equation 81)67. 

The conjugate addition of 103 to phenyl vinyl sulfone (53) proceeds under phase-transfer conditions. The yield of cyclopropanes in the following cyclization is low for synthetic purposes (equation 84)69. 

Conjugate addition of chiral amines to allenic and acetylenic sulfones has been reported73. The reaction 112 with (—)-ephedrine gives only one of the two possible diastereomeric oxazolines in high yield (equation 89). 

Ethyleneimine reacts with (p-tolylsulfonyl)acetylene to give only the (Z)-product 115 via trans addition (equation 91), while primary and secondary aliphatic amines afford ( )-products76. With nonterminal acetylenes such as l-(ethylsulfonyl)-l-propyne, the reactions of ethyleneimine, n-propylamine and f-butylamine give mixtures of ( )- and (Z)-adducts. The double conjugate addition of sodium sulfide, selenide and telluride to bis(l-propynyl)sulfone (116) produces heterocycles (117) as illustrated in equation 9277. 

Giblin, G.M.P., Jones, C.D., Simpkins, N.S. (1997) A Concise Stereoselective Synthesis of Epi-batidine Employing Conjugate Addition to an Alkenyl Sulfone Intermediate as the Key Step. Syniett, 589-590. 

A similar stereospecific conjugate addition to epoxysulfone 323 was also Observed S , with Grignard reagents in the presence of nickel ion or palladium catalysts Methyllithium and n-butyllithium did not add to 1-propenyl phenyl sulfone nor to phenyl -styryl sulfone but underwent lithiation at — 95 However methyllithium, n-... 

TABLE 6. Conjugate addition of organometallic reagents to vinyl sulfones ... 

In contrast to a, -ethylenic ketones or even a, -ethylenic sulfones, a, ) -ethylenic sulfoxides generally are not sufficiently electrophilic to undergo successful nucleophilic j8-addition . a-Carbonyl-a, j8-ethylenic sulfoxides, however, are potent, doubly activated alkenes which undergo rapid and complete -addition of various types of nucleophiles even at — 78 °C. A brief account summarizing this area is available . The stereochemical outcome of such asymmetric conjugate additions to enantiomerically pure 2-sulfmyl 2-cycloalkenones and 2-sulfinyl-2-alkenolides has been rationalized in terms of a metal-chelated intermediate in which a metal ion locks the -carbonyl sulfoxide into a rigid conformation (36 cf. 33). In this fixed conformation, one diastereoface of the cyclic n... 

When conjugate addition is carried out under aprotic conditions with stoichiometric formation of the enolate, the adduct is present as an enolate until the reaction mixture is quenched with a proton source. It is therefore possible to effect a second reaction of the enolate by addition of an alkyl halide or sulfonate to the solution of the adduct enolate, which results in an alkylation. This reaction sequence permits the formation of two new C-C bonds. 

Vinyl ethers can also be generated by thermal elimination reactions. For example, base-catalyzed conjugate addition of allyl alcohols to phenyl vinyl sulfone generates 2-(phenylsulfinyl)ethyl ethers that can undergo elimination at 200° C.223 The sigmatropic... 

Among the olefination reactions, those of phosphonium ylides, phosphonate anions, silylmethyl anions, and sulfone anions are discussed. This chapter also includes a section on conjugate addition of carbon nucleophiles to a, (J-unsaturated carbonyl compounds. The reactions in this chapter are among the most important and general of the carbon-carbon bond-forming reactions. 

Alternatively, the enamine portion may be located in the Aralkyl chain. For instance, piperidines bearing a 7-chloro substituent yielded quinolizidines 263 through a conjugate addition of the nitrogen atom to acetylenic sulfones followed by an intramolecular alkylation (Scheme 55) <2000JOC4543>. Other cyclizations that are summarized below used as starting materials piperidine derivatives obtained by similar conjugate additions to vinyl sulfones (see Section 12.01.9.3.6). 

In one example of this type of cyclization aminoalcohol, 288, which was obtained by conjugate addition of racemic 2-(2-hydroxyethyl)piperidine to allyl phenyl sulfone, was converted into the corresponding chloride and cyclized in the presence of LDA to give 289 as a single diastereomer (Scheme 63) <2003JOC9389>. In a related approach, the primary alcohol group was activated for a similar cyclization by transformation into a mesylate <20010L2957>. 

Other interesting electron-deficient olefin substrates for the asymmetric conjugate addition include cr-acet-amidoacrylic ester SI,101 dimethyl itaconate S2,114 ct,/3-unsaturated sulfones S3,115 and alkenylphosphonate S4116 (Figure 8). 

Radical-induced addition of 4-MeC6H4S02-SePh to conjugated ynenyl sulfones occurs in a trans-fashion with high regioselectivity (Equation (70)).203... 

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