Ketones zinc enolates from

Fig. 17.49. Reductions of a-heterosubstituted ketones to a-unsubstituted ketones (see Figures 15.34 and 17.59 for the preparation of compounds A and B, respectively). Here, a ketyl is formed as a radical anion intermediate (for more details about ketyls see Section 17.4.2). The ketyl obtained from A releases a chloride ion, the ketyl resulting from B releases a hydroxide ion. In each case, an enol radical is formed thereby which picks up an electron. This leads to the formation of a zinc enolate from which the final product is generated by protonation.

There is no danger of self-condensation with zinc enolates as they do not react with esters. But they do react cleanly with aldehydes and ketones to give aldols on work-up. You will appreciate that the use of zinc enolates is therefore special to esters you cannot make a zinc enolate from a 2-bro-moaldehyde or an a-bromoketone as then you would get self-condensation. 

Zinc ester enolates may also be obtained by the addition of ZnX2 to lithium or sodium enolates as first described by Hauser and Puterbaugh (equation 6)P This approach has so far received little attention but similar reactions have been used to obtain zinc ketone enolates. In this regard, it should be noted that Heathcock and coworkers have shown that deprotonation reactions of ketones with zinc dialkylamide bases reach equilibrium at only about 50% conversion (equation 7). This result implies that attempts to prepare zinc enolates from solutions of amide-generated lithium enolates will be successful only when the lithium enolate is made amine-free. 

Enantioselective allylations of prostereogenic enolates have been attempted using catalytic amounts of a palladium complex incorporating (5,5)-Diop as the chiral ligand. The reactions of ketone zinc enolate 2 with allyl chloride 17 and of the sodium enolate derived from aldehyde 5 with phenyl ether 423 yield 3 and 6 of low enantiomeric excess, respectively. 

The addition of carbonyl compounds towards lithiated 1-siloxy-substituted allenes does not proceed in the manner described above for alkoxyallenes. Tius and co-work-ers found that treatment of 1-siloxy-substituted allene 67 with tert-butyllithium and subsequent addition of aldehydes or ketones led to the formation of ,/i-unsaturated acyl silanes 70 (Scheme 8.19) [66]. This simple and convenient method starts with the usual lithiation of allene 67 at C-l but is followed by a migration of the silyl group from oxygen to C-l, thus forming the lithium enolate 69, which finally adds to the carbonyl species. Transmetalation of the lithiated intermediate 69 to the corresponding zinc enolate provided better access to acylsilanes derived from enolizable aldehydes. For reactions of 69 with ketones, transmetalation to a magnesium species seems to afford optimal results. 

Zinc enolates obviously give a better induction than the corresponding lithium enolates. This condensation also occurs with good yields with various enolates generated from ketones, esters and lactones, however, the enantiomeric excesses are poor27. 

Aldol condensation of the zinc enolate of resin-bound alkyl ester 29 with aromatic aldehyde or ketone forms a P-hydroxy ester, which upon treatment with DIBAL-H leads to simultaneous reduction and cleavage of the ester moiety from the resin to give a soluble 1,3-diol 31 [31], Parallel synthesis utilizing three ester and nine carbonyl building blocks afforded a library of 27 analogs which was screened for antioxidative efficiency using a ferric thiocyanate assay. 

An alternative method for the preparation of a kinetic zinc ketone enolate (123) from an arene thiol ester 121 and bis(iodozincio)methane (122) in the presence of a palladium(O) catalyst was developed by Matsubara and coworkers (equation 36) . The modest reactivity of the zinc reagent 122 makes this transformation highly chemo- and regioselective neither isomerization of the kinetic enolate 123 nor a palladium-catalyzed coupling with the thiol ester 121 could be observed. Thus, treatment of zinc enolate 123 with various aldehydes or ketones led regioselectively to one aldol product 124. The method provides access to reactive functionalized zinc enolates which are otherwise hard to obtain. 

A feature distinguishing Reformatsky enolates from base-generated enolates is that zinc enolates add to highly hindered as well as to easily enolizable ketones, such as cyclopentanones, thus avoiding formation of condensation products. Moreover, there is no danger of a Claisen-type self-condensation since zinc-enolates do not react with esters but react readily with aldehydes and ketones to furnish aldol-type products. 

Spectroscopic and crystallographic studies of Reformatsky reagents derived from a-halo esters showed that the enoiate is present in the C-enolate form and in ether solvents they form dimers. Enolates derived from a-halo ketones prefer the O-metal enoiate form. It is assumed, based on theoretical calculation, that the zinc enoiate dimers are dissociated by the action of the carbonyl compound and converted to the corresponding O-zinc enolates. Subsequently, the reaction goes through six-membered chairlike transition state. 

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. 

Aldol condensations of zinc enolates under conditions of thermodynamic control are reasonably discussed in terms of the relative stability of the two chelated aldolates (19), which leads to the syn aldol, and (20), which leads to the anti aldol. If R is larger than R, the anti chelate, with R and R trans in a six-atom ring, is expected to be the more stable form. Heathcock has noted that the most common mechanism for equilibration of aldolate stereochemistry is reverse aldolization (reversal of equation 29). Aldolates obtained by reaction of an enolate with ketone substrates are expected to undergo reverse aldolization at a faster rate than those obtained with aldehyde substrates, in part for steric reasons. Similarly, aldolates derived from ketone enolates are expected to undergo reverse aldolization at a faster rate than those derived from the more basic ester or amide enolates. 

Trifluoromethylation. Zinc enolates generated from enol silyl ethers on treatment with Et2Zn react with CF3I in the presence of (Ph3P)3RhCl to provide a-trifluoromethylated ketones. ... 

The asymmetric Michael addition of nonstabilised ketone enolates has proved difficult, with most success achieved using 1,3-dicarbonyls as donors. However, Shibasaki and coworkers have achieved high ees in the addition of a-hydroxyketones with both aromatic Michael acceptors such as (11.32) and also cyclic enones and alkyl vinyl ketones, using bifiinctional zinc catalysts prepared from linked BINOL (11.33). These catalysts are also effective in the asymmetric aldol reaction (see Section 7.1) and incorporate two zinc atoms, one of which activates the acceptor carbonyl group and the other forms a zinc enolate with the donor. In addition, catalysts of this type have been used to good effect in the addition of P-ketoesters to cyclic enones. 

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. ... 

Allenic esters readily react with dialkylzinc reagents in the presence of DIFLUORPHOS-complexed copper (from Cu(OAc)2) in THF at -20 While this initial adduct bears no new central chirality, the intermediate nonracemic copper/zinc enolate can then add in a stereocontrolled 1,2-fashion to unsymmetrical ketones. Ring closure to the resulting S-lactone completes the sequence. Both 4 A molecular sieves and 20 mol% Lewis basic Ph2S=0 (or DMSO, hexamethylphosphoramide [HMPA]) are required to direct attack at the y-position rather than the otherwise reversible aldol event at the a-site, thereby facilitating conversion to cyclic products. 

The role of stoichiometric amount of zinc compounds in the aldol reaction was studied 30 years ago (107). The first study of asymmetric zinc-catalyzed aldol reaction was carried out by Mukaiyama and co-workers the chiral zinc catalyst was prepared from diethylzinc and chiral sulfonamides and was effective in the reaction of ketene silyl ethers with aldehydes (108). Among the subsequent studies on zinc-catalyzed aldol reactions, Trost s group gave important contribution to zinc/prophenol ligand complexes (109,110). The chiral dinuclear zinc catalyst promotes the direct aldol reaction of ketones, including a-hydroxyketones, and aldehydes with excellent enantioselectivity (Scheme 17). It is proposed that one zinc metal coordinated different substrates to form zinc enolate, and another zinc metal center provided the bridge between the interaction of donor and acceptor. 

Ester enolates, much more sensitive and capricious than ketone and amide enolates, seemed to be unsuitable for palladium-catalyzed allylic alkylations. Thus, Hegedus and coworkers [24] reported on low yields and predominant side reactions in the allylation of the lithium enolate of methyl cyclohexanecarboxylate. It seems that so far the only reliable and efficient version of a Tsuji-Trost reaction with ester enolates is based on the chelated zinc enolates 41 derived from N-protected glycinates 40 - a procedure that was developed by Kazmaier s group. 

In the approaches toward a direct asymmetric Mannich reaction by enolate formation with the metal of the catalyst also, the well-proved systems of the analogous aldol reactions were widely applied. Here, it is referred to some of these protocols wherein a metal enolate is involved, as least as assumed and plausible intermediate [183]. Shibasaki and coworkers used a dinuclear zinc complex derived from linked BINOL ligand 371 for catalyst in direct Mannich reactions of a-hydroxy ketones 370 with Af-diphenylphosphinoyl imines 369 to give ti-configured a-hydroxy-P-amino ketones 372 in high yield, diastereoselectivity, and enantioselectivity (Scheme 5.97) [184]. The authors postulate the metal to form a chelated zinc enolate by double deprotonation of the a-hydroxy ketone. This enolate approaches with its Si-face to the Si-face of the imine, as illustrated by the transition state model 373, in agreement with the observed stereochemical outcome. It is remarkable that opposite simple diastereoselectivity arises from the Mannich reaction (anti-selective) and the previously reported syn-selective aldol reaction [185], although the zinc enolates... 

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