Conjugate 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. 

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. 

Where possible, it may be most economical to effect a chiral transformation on a pre-formed, pro-chiral ring. Ben Feringa of the University of Groningen prepared (Chem Commun. 2005, 1711) the enone 2 from 4-methoxypyridine 1. Cu -catalyzed conjugate addition of dialkyl zincs to 2 proceeded in up 96% . Pd-mediated allylation of the intermediate zinc enolate led to 3, with the two alkyl subsituents exclusively trans to each other. 

The copper-catalysed asymmetric conjugate addition of dialkylzinc leads to homo-chiral zinc enolates.28 These intermediates have been trapped in situ with activated allylic electrophiles, without the need for additional palladium catalysis (Scheme 3). 

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). 

Transmetallation of 12 with a catalytic amount of the higher order cyanocuprate Me2Cu(CN)Li2, in the presence of Me3ZnLi and with slow addition of enone 7 led first to the initial conjugate addition product 14, then to zinc enolate 15 after Cu-to-Zn transmetallation. The third component, the electrophile, either an aide-... 

The Reformatsky reagents, i.e. zinc enolates of esters, undergo Ni catalysed cross-coupling with aryl halides.53 The Ni catalysed reaction of arylzincs with a-bromoacetates also permits a-arylation of esters54 (Scheme 11.13). However, a-alkenylation of enolates of ketones, aldehydes, and esters has been less satisfactory. Its further development is clearly desirable. Alternatively, a-alkenylation of a-iodoenones in conjunction with conjugate reduction discussed earlier should be considered. 

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... 

Another intermediate for which Die Is-Alder trapping provided convincing evidence is the oxy-allyl cation. This compound can be made from a,oc -dibromoketones on treatment with zinc metal. The first step is the formation of a zinc enolate (compare the Reformatsky reaction), which can be drawn in terms of the attack of zinc on oxygen or bromine. Now the other bromine can leave as an anion. It could not do so before because it was next to an electron-withdrawing carbonyl group. Now it is next to an electron-rich enolate so the cation is stabilized by conjugation. 

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. ... 

The preparation of silyl enol ethers from carbonyl compounds represents one of the major uses of TMSOTf. Recently, the stereochemistry and regiospeciflcity of such transformation has been addressed for aldehydes and Q -(lV-alkoxycarbonylamino) ketones, respectively. On the other hand, enantiopure silyl enol ethers can be formed by addition of TMSOTf to zinc enolates, which are obtained from the copper-catalyzed enantioselective conjugate addition of dialkyIzinc reagents to cyclic (eq 36) and acyclic enones. ... 

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... 

On a similar note, conjugate addition of Et2Zn to chalcones (266), catalysed by a complex of (TfO)2Cu and (269), generates zinc enolate (267), which can be captured by nitrostyrenes (259) to produce y-nitro ketones (268) with >20 1 dr and <95% ee " ... 

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. 

For instance, it is reported that a chiral copper catalyst (R,R)-L promotes asymmetric conjugate addition of dialkyl zinc to a,p-unsaturated ketone 19 to form homochiral zinc enolate 20. This intermediate is then trapped in situ with NPP as electrophile, without the need of additional palladium catalysis. Good yield, high trans/cis (95/5) ratio, and excellent enantioselectivity (99%) are obtained. Moreover, the multi-functionalized nature of 21 makes it a versatile intermediate for further elaboration. 

A derivatization of zinc enolates like 418, formed in a copper-catalyzed conjugate addition, by trapping as silyl enol ethers 419 was reported by Alexakis group [209]. The addition occurred in very high enantioselectivity when mediated by phosphoramidite 417 or related ligands. Remarkably, the selectivity was distinctly lower when chlorotrimethylsilane was present from the beginning. Therefore,... 

Scheme 5.107 Formation of zinc enolate 418 by enantioselective conjugate addition,...

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