HOMOENOLATE, ZINC

In view of the remarkable stability of metal homoenolates of esters, the existence of homoenolate species containing a 3-halo substituent, i.e. zinc carbenoid moiety connected to an ester group, appeared to be possible. Indeed, when a silyl ketene acetal is treated with a carbenoid generated from CHBrj and Et2Zn, two types of highly intriguing reactions ensue [58]. With a purely aliphatic substrate, Eq. (61), an alkyl cyclopropylcarboxylate due to intramolecular p-CH-insertion of the intermediate zinc carbenoid formed. When the substrate contained an olefmic double bond in the vicinity of the carbenoid function, Eq. (62), in particular an intermediate derived from an a,P-unsaturated ester, internal cyclo-propanation occurred to give bicyclic or tricyclic product (Table 15). 

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A few further general examples of zinc catalytic activity or reactivity include the following. Other zinc-containing systems include a zinc phenoxide/nickel(0) catalytic system that can be used to carry out the chemo- and regioselective cyclotrimerization of monoynes.934 Zinc homoenolates have been used as novel nucleophiles in acylation and addition reactions and shown to have general utility.935,936 Iron/zinc species have been used in the oxidation of hydrocarbons, and the selectivity and conditions examined.362 There are implications for the mechanism of metal-catalyzed iodosylbenzene reactions with olefins from the observation that zinc triflate and a dizinc complex catalyze these reactions.937... 

The zinc homoenolates from cyclopropanes 15. react in the presence of MejSiCl/HMPA with a,[3-unsaturated ketones to give good yields of 1,6-D systems, by a copper-mediated (CuBr-Me2S) Michael-type addition (Table 5.4). 

COPPER-CATALYZED CONJUGATE ADDITION OF A ZINC HOMOENOLATE ETHYL 3-[3-(TRIHETHYLSILYL0XY)CYCL0HEX-... 

The formation of activated iminium intermediates derived from nitrogen heterocycles has been reported by Comins . The activation of pyridine derivative such as 214 with phenyl chloroformate provides the pyridinium salt 215, which smoothly reacts with the zinc homoenolate 216 leading to the addition product 217 in 66% yield . The reaction... 

Various types of carbon-carbon bond forming reactions of metal homoenolates have been reported, some of which are highly synthetically useful. Scheme 3 illustrates reaction types of zinc homoenolates (8 or 9). In this section the reactions of stable homoenolates are presented according to the reaction types. Examples, in which siloxycyclopropanes generate transient, unstable homoenolates, are described in Sect. 5. 

Among isolable metal homoenolates only zinc homoenolates cyclize to cyclo-propanes under suitable conditions. Whereas acylation of zinc alkyls makes a straightforward ketone synthesis [32], that of a zinc homoenolate is more complex. Treatment of a purified zinc homoenolate in CDC13 with acid chloride at room temperature gives O-acylation product, instead of the expected 4-keto ester, as the single product (Eq. (22) [33]). The reaction probably proceeds by initial electrophilic attack of acyl cation on the carbonyl oxygen. A C-acylation leading to a 4-keto ester can, however, be accomplished in a polar solvent Eq. (44)-... 

Treatment of zinc homoenolates with Me3SiCl in a polar solvent also results in cyclopropane formation Eq. (23). This provides a very mild route to the siloxycyclopropanes [24]. 

In line the with the chemistry of dialkylzinc [36], the zinc homoenolate is inert to carbonyl compounds in a variety of solvents, Eq. (33). Slow addition accurs only in an HMPA/THF mixture. When the reaction is conducted in halomethane in the presence of Me3SiCl, however, a very rapid addition reaction occurs [33], Control experiments indicate that the acceleration is due to the activation of the carbonyl group by Me3SiCl. The activating effect of the chlorosilane disappears in ethereal solvents. 

Interestingly, the carbonyl addition of the zinc homoenolate, in the presence of acid chloride, affords 4-acyloxyesters Eq. (35) [27]. 

Table 8. Products of conjugate addition of zinc homoenolate in the presence of Cu(I) and Me3SiCl (Ref. [28, 29]...

Among the characterized metal homoenolates, only zinc homoenolate of alkyl propionate undergoes substitution reactions with electrophiles under suitable conditions. Two types of metal catalysts, copper(I) and metals of the nickel triad (e.g. Pd), have successfully been used to effect allylation, arylation, and vinylation reactions. 

Zinc homoenolate reacts with allylic halides and diene monoepoxides under copper catalysis [29]. Treatment of the zinc nomoenolate with a catalytic amount of Cu(II) in a polar solvent (e.g. hexamethylphosphoramide, HMPA, N,N-dimethylacetamide, DMA) generates a copper species which undergoes clean Sn2 allylation reactions Eq. (40). Polar solvents not only accelerate the reaction but greatly improve the SN2 selectivity. A variety of allylating reagents can be employed in this reaction (Table 9). The SN2 /SN2 ratio is particularly high (close to 100%) when the alkylated carbon bears no substituents. The reaction of... 

The allylation and the conjugate addition (vide supra) of zinc homoenolate proceed under essentially the same conditions except that the latter requires the presence of Me,SiCl as well. Due to this subtle difference, selective allyl substitution is possible even with an enone function is present in the same molecule (Table 9). 

Table 10. Arylated and vinylated propionates by palladium-catalyzed reaction of zinc homoenolate (Ref. [29,40])...

The reaction of zinc homoenolate 9 with acid chlorides in ethereal solvents containing 2 equiv of HMPA rapidly produces 4-ketoesters in high yield Eq. (44) [33]. A palladium catalyst [40] (or less effectively a copper catalist) [28] accelerates the reaction. This is in contrast to the cyclopropane formation in a nonpolar solvent see (Eq. 22 above). 

A very practical route to zinc homoenolate involves reduction of 3-iodoesters with zinc/copper couple in the presence of a polar solvent, e.g. DMF, DMA [49] Eq. (51). The nature of the species obtained in this approach is not well-defined, but appears to be essentially the same as the one obtained along the siloxycyclo-propane route. Acylation, arylation, and vinylation reactions have been reported. 

Homo-Reformatsky reaction.1 The reaction of 1-ethoxy-1-trimethylsilyloxy-cyclopropane (1) with an aldehyde in the presence of ZnCl2 results in y-silyloxy esters via a zinc homoenolate (a) of ethyl propionate (equation I). Znl2 is the preferred catalyst in the case of reactions with acetophenone and benzaldehyde dimethyl acetal and in reactions of l-isopropoxy-l-(t-butyldimethylsilyl-oxy)cyclopropane with aromatic aldehydes. 

The zinc homoenolate a reacts with acid chlorides in CH2C12 to form l-(acyl-oxy)cyclopropanes. 

One well defined compound in this series8 is the cyclopropane 64 made9 from chloro-propionate esters 63 and sodium in the presence of Me3SiCl. On treatment with ZnCl2, the ring is opened and a zinc homoenolate 65 with internal coordination is formed. This reacts with... 

Carboalkoxycyclopentenones.3 The zinc homoenolate 1, prepared as shown (13, 349-350), can undergo a formal [3 + 2]cycloaddition to acetylenic esters in the presence of CuBr-S(CH3)2, ClSi(CH3)3, and HMPA to give 2-carboalkoxycyclopen-tenones. The reaction probably involves conjugate addition to give an allenolate followed by intramolecular cyclization. 

A further example of the effectiveness of these reagents is demonstrated in the synthesis of the complex spiroventivane phytoalexin-lubiminol 3 (Scheme 1.2).4 Generation in situ of a zinc homoenolate, Et02C(CH2)2ZnCl,3 allows formation of the functionalized cyclopentenone intermediate, essential for the synthesis. 

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