Conjugate addition reactions zinc enolates

Scheme 2.23 provides some examples of conjugate addition reactions. Entry 1 illustrates the tendency for reaction to proceed through the more stable enolate. Entries 2 to 5 are typical examples of addition of doubly stabilized enolates to electrophilic alkenes. Entries 6 to 8 are cases of addition of nitroalkanes. Nitroalkanes are comparable in acidity to (i-ketocslcrs (see Table 1.1) and are often excellent nucleophiles for conjugate addition. Note that in Entry 8 fluoride ion is used as the base. Entry 9 is a case of adding a zinc enolate (Reformatsky reagent) to a nitroalkene. Entry 10 shows an enamine as the carbon nucleophile. All of these reactions were done under equilibrating conditions. 

Another example of a domino allylation reaction was published by Cook and Jarugumili [169]. Fe2(CO)g in combination with PPhj has been identified as a low-cost and environmentally benign catalyst system for the allylation of zinc enolates 158 generated in situ from copper-catalyzed asymmetric conjugate addition reactions. This catalyst system provides the allylated products 159 in modest to good yields at room temperature with unprecedented diastereoselectivity in cyclic enone systems (Scheme 12.74). 

The zinc enolate formed as an intermediate in these conjugate addition reactions can be trapped by an electrophile in situ to provide further functionalization of the substrate. This is demonstrated by the synthesis of the anticancer agent clavularin B (eq 103). Sequential conjugate addition to cycloheptenone of Me2Zn in the presence of catalytic CuOTf-chiral peptide ligand complex, and enolate alkylation with 4-iodo-1-butene provide the key compound with 97% ee. 

The allylic or benzylic alkylation of chiral zinc enolates, resulting from an asynunetric copper-catalysed conjugate addition reaction of dialkylzinc, has been performed with allylic or benzylic halides in reasonable yields and high diastereoselectivities (up to 20 1 dr). ... 

Asymmetric conjugate addition of dialkyl or diaryl zincs for the formation of all carbon quaternary chiral centres was demonstrated by the combination of the chiral 123 and Cu(OTf)2-C H (2.5 mol% each component). Yields of 94-98% and ee of up to 93% were observed in some cases. Interestingly, the reactions with dialkyl zincs proceed in the opposite enantioselective sense to the ones with diaryl zincs, which has been rationalised by coordination of the opposite enantiofaces of the prochiral enone in the alkyl- and aryl-cuprate intermediates, which precedes the C-C bond formation, and determines the configuration of the product. The copper enolate intermediates can also be trapped by TMS triflate or triflic anhydride giving directly the versatile chiral enolsilanes or enoltriflates that can be used in further transformations (Scheme 2.30) [110],... 

The conjugate addition of bis(iodozincio)methane to -unsaturated carbonyl compound gives y-zincio substituted enolate. As shown in equation 31, bis(iodozincio)methane reacts with. v-cis a,/3-unsaturated ketone in the presence of chlorotrimethylsilane to afford the silyl enol ether carrying a C—Zn bond. These zinc-substituted silyl enolates can be used for further coupling reactions (equation 32)54. 

Three approaches to zinc enolates are commonly adopted the process associated to the classical Reformatsky reaction is based on the insertion of Zn(0) into the carbon—halogen bond of an a-haloester. Two additional routes involve (i) transmetallation of a lithium enolate with a Zn(II) salt (Section V.A) and (ii) the transition-metal-catalysed conjugate addition of diethylzinc to Michael acceptors (Section V.B). 

Dialkylzinc derivatives are inert towards conjugated enones (e.g. 181) in hydrocarbon or ethereal solvents. The discovery that a conjugate addition can be promoted by Cu(I) salts in the presence of suitable ligands L (e.g. sulphonamide 182) opened a new route to zinc enolates (e.g. 183), and hence to the development of three-component protocols, such as the tandem 1,4-addition/aldol addition process outlined in equation 92186. If the addition of the aldehyde is carried out at —78 °C, the single adduct 184 is formed, among four possible diastereomeric products. The presence of sulphonamide is fundamental in terms of reaction kinetics its role is supposed to be in binding both Cu(I) and Zn(II) and forming a mixed metal cluster compound which acts as the true 1,4-addition catalyst. 

In another study Feringa et al. [20] reported a catalytic enantioselective three-component tandem conjugate addition-aldol reaction of dialkyl zincs. Here, zinc enolates were generated in situ via catalytic enantioselective Michael addition of dialkylzinc compounds to cydohexenone in the presence of a chiral Cu catalyst. Their diastereoselective reaction with an aldehyde then gave trans-2,3-disubstituted cyclohexanones in up to 92% yields and up to >99% ees (Scheme 9.11). 

The reaction has been further extended into a tandem conjugate addition/ enolate trapping sequence, whereby the in situ generated zinc enolate was trapped with benzaldehyde. This resulted in an approximately 3 7 mixture of trans-erythro trans-threo aldol adducts, isolated in 88% yield. Subsequent oxidation of these products gave a single isomer of the corresponding diketone with 95% ee. 

Once again, the zinc enolates generated in the conjugate addition can be trapped with various electrophiles besides protons. For example, reaction of the enolate 270 obtained by treating cyclohex-2-enone with dimethylzinc in the presence of Cu(OTf)2 and phosphoramidite 269 with trimethylsilyl triflate and diiodomethane provided the cyclopropanation product 271 with good diastereoselectivity and high enantiomeric excess and chemical yield... 

Disubstituted furans are available from a,/3-unsaturated enones in a two-step sequence. At first, conjugate addition of a cuprate generates an enolate, which undergoes an aldol reaction with (tetrahydropyranyloxy)acetalde-hyde under zinc chloride catalysis (Scheme 19) <20000 L4095>. Treatment of the reaction product with acid affords the disuhstituted furans in good yields. 

Recently, Shchepin and coworkers described Michael addition reactions with zinc ketone enolates (144) for the preparation of chroman-2-one derivatives 146. The enolates were generated in situ from a-bromo ketones 143 by addition of excess zinc (equation 40), and subsequent conjugate addition to a, S-unsaturated ketones (145) (equation 40 ) provided chroman-2-ones (146a, b) in yields up to 82% . 

Simple stereoselective aldol reactions (chapter 3) can also be controlled by tandem conjugate addition. Addition of Me2CuLi to the simple unsaturated ketone 27 gives the lithium enolate 28. It would be very difficult to produce this enolate from the parent ketone MhiCO.Me with regio- or stereoselectivity. The cyclic transition state 29 with zinc replacing lithium then shows the way to the anti-aldol7 30. 

Heterocycles. A route to 2,3-disubstituted furans takes advantage of the Cu-Zn-transmetallation (with ZnCl2) from enolates derived from conjugate organocuprate addition to enones, and aldol reaction of zinc enolates to an alkoxyacetaldehyde. ... 

Gonzalez-Gomez, Foubelo, and Yus showed that zinc enolates can also be useful nucleophiles in Mannich-type reactions (Scheme 11.13). A Cu complex of phosphoramidite 28 catalyzed conjugate additions of diethylzinc (6a) to cyclic... 

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