Esters zinc ester enolates

Scheme 2.44 Chelate-controlled Claisen rearrangement of zinc ester enolates 136. Cbz = benzyloxycarbonyl Boc = tert-butoxycarbonyl.

Aldol Condensation of Zinc Ester Enolates with Benzaldehyde Anil Solvent Effects (Scheme 16) (76)... 

The different carbosilane dendrimer supports (generation 0, 1 R=H, Me) were then used for the synthesis of the / -lactam (13). As shown in Scheme 7.2, the first step was again an immobilization of a carboxylic acid via ester bond formation. Treatment with LDA and ZnCl2 yielded in situ the corresponding zinc ester enolate (11) which reacts with N-(trimethylsilyl)phenylimine (12) to form the final four membered lactam ring (13). The last reaction step includes several intermediates. The last one is a supported /9-amino ester which undergoes spontaneous... 

The insight that zinc ester enolates can be prepared prior to the addition of the electrophile has largely expanded the scope of the Reformatsky reaction.1-3 Substrates such as azomethines that quaternize in the presence of a-halo-esters do react without incident under these two-step conditions.23 The same holds true for acyl halides which readily decompose on exposure to zinc dust, but react properly with preformed zinc ester enolates in the presence of catalytic amounts of Pd(0) complexes.24 Alkylations of Reformatsky reagents are usually difficult to achieve and proceed only with the most reactive agents such as methyl iodide or benzyl halides.25 However, zinc ester enolates can be cross-coupled with aryl- and alkenyl halides or -triflates, respectively, in the presence of transition metal catalysts in a Negishi-type reaction.26 Table 14.2 compiles a few selected examples of Reformatsky reactions with electrophiles other than aldehydes or ketones.27... 

Besides allylic alkylation reactions chelated zinc ester enolates 231 also give good results in various types of standard enolate reactions, including alkylations, aldol reactions" and Michael additions" . 

Reaction of zinc ester enolates with conjugated enones... 

The Reformatsky reaction is the reaction of an a-halo ester with an aldehyde or ketone in the presence of zinc metal as shown in Scheme 1. The usual product of the reaction is a -hydroxy ester, which may be dehydrated in subsequent steps to give an unsaturated ester. A zinc ester enolate (1), the so-called Reformatsky reagent, is an intermediate in the reaction and the sequence is thus classified as an aldol condensation. Compared to the usual base-promoted aldol procedures, the distinguishing features of the Reformatsky reaction are the use of a metal-halogen redox reaction rather than an acid-base reaction to form the enolate, and the fact that the counterion of the enolate is zinc. 

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. 

Reaction of zinc ester enolates with a conjugated enone can give either -hydroxy esters (12) from 1,2-addition, or 8-keto esters (13) from 1,4-addition, as shown in Scheme 8. Cyclization of the 1,4-pro-duct to the corresponding 8-lactone (14) is occasionally observed. 

The optimum approach to kinetic stereoselection in the Reformatsky reaction would appear to be the use of two-stage procedures, which allows the zinc aldolates to be formed at the lowest possible temperature. Gaudemar-Bardone and Gaudemar prepared a variety of zinc ester enolates in dimethoxymethane at 40 C which were then reacted at lower temperatures with benzaldehyde or with acetophenone (equation 38). Selected data from their study are shown in Table 5. If these data are the result of total kinetic control, as concluded by the authors, it is clear that the reactions exhibit only a modest kinetic stereoselectivity. 

Although zinc-carbon bonded structures have been established for zinc ester enolates, it is conceivable that the alternate zinc-oxygen bonded structure is the reactive form in aldol condensations. Two research groups have observed a modest degree of optical activity in the products from reaction of benzalde-... 

Van Koten and coworkers prepared zinc ester enolates of IV-protected a-amino esters from the corresponding lithium enolates and allowed them to react with imines at low temperature to obtain trans-3-amino-P-lactams, often with high stereoselectivity as shown in Scheme 19. Interestingly, the authors interpreted their results in terms of an internally chelated zinc-oxygen bonded enolate (37). 

The preference of zinc ester enolates for carbon-bonded structures and zinc ketone enolates for oxygen-bonded structures is reminiscent of the situation with silicon. A carbon-bonded structure (9) is the thermodynamically more stable form for the trimethylsilyl derivatives of esters, while the oxygen-bonded structure (10) is the more stable form for ketone derivatives. This has been attributed to the greater resonance stability of ester compared to ketone carbonyls.32... 

Zinc ester enolates react with (1) to give the corresponding A Boc a-amino carboxylic esters in moderate yield (eq 3). In contrast, diethyl a-cuprophosphonates give WBoc a-amino phos-phonic esters in acceptable yields (eq 4). ... 

General Considerations and Mechanism In 1977, Fauvarque/Jutand reported the first palladium- and nickel-catalyzed cross-coupling reaction of aiyl halides with a zinc ester enolate the Reformatsky reagent (Scheme 19.29) [26b, 32]. When PdCljCPPhj) and NiCljjPPhj) are used... 

SCHEME 19.29 Nickel- and Palladium-catalyzed arylation of zinc ester enolate (1977). 

Scheme 8.62 Palladium-catalyzed a-arylation of zinc ester enolates as described by Hartwig and coworkers [110].

A novel use of a wide range of nitriles as mediator has enabled the regioselective inter-molecular addition of unstabilized zinc ester enolates to 1-alkynes and l.S-enynes. " This reaction was made possible by a reversible addition of enolates to a nitrile (Blaise reaction), generating a zinc aza-enolate that, unlike zinc ester enolates, can add inter-molecularly to 1-alkynes and 1,3-enynes. Subsequent removal of the nitrile through a retro-Blaise reaction has generated the targeted addition product. 

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