Ester homoenolate

In practice, the original method had its limitations since one equivalent of TiCl4 had to be used and usually led to the cyclic derivatives. Nonetheless, more recently it has been found that "homoenolate esters" actually exist if the appropriate metal, ZnCl2 for example, is used [16], which reacts with carbonyl derivatives in the presence of one equivalent of Me SiCl to give 1,4-D systems by means of a "homo-... 

The aryl- and heteroarylfluorosilanes 541 can be used for the preparation of the unsymmetrical ketones 542[400], Carbonylation of aryl triflate with the siloxycyclopropane 543 affords the 7-keto ester 545. In this reaction, transme-tallation of the siloxycyclopropane 543 with acylpalladium and ring opening generate Pd homoenolate as an intermediate 544 without undergoing elimination of/3-hydrogen[401],... 

Homoenolate Protonation The p-protonation of homoenolates has been observed by Scheidt and co-workers, resulting in a redox transformation of enals to afford saturated esters 48. This process is catalysed by the NHC derived from imidazolium salt 46 and utilises phenol as a proton source [14]. A range of primary and secondary alcohols, and phenol itself, are competent nucleophiles with which to trap the acylazolium intermediate 47 generated by protonation (Scheme 12.8). 

This homoenolate methodology has been extended to the use of nitrones 170 as electrophiles [72]. Scheldt and co-workers have shown that enantiomerically enriched y-amino esters 172 can be prepared with excellent levels of stereocontrol from an enal 27 and a nitrone 170 using the NHC derived from triazolium salt 164 (Scheme 12.37). The oxazinone product 171, formally a result of a [3-1-3] cycloaddition, is cleaved to afford the y-amino ester product 172. The reaction shows broad substrate scope, as a range of substituted aryl nitrones containing electron donating and withdrawing substituents are tolerated, while the enal component is tolerant of both alkyl and aryl substituents. 

An alternative formation of titanated alkoxyallenes could be achieved by reaction of 3-alkoxy-2-propyn-l-yl carbonates 78 with (r/2-propene)titanium diisopropoxylate (79). Successive addition of 80 to benzaldehyde afforded the corresponding addition products 81 in high yield (Scheme 8.22) [70]. The results demonstrate that titanium species 75 and 80 can serve as easily available ester homoenolate equivalents. Notably, conversion of lithiated alkoxyallenes to the magnesium species by treatment with MgBr2 followed by addition to chiral carbonyl compounds resulted in a mixture of a- and y-products [71]. 

From the point of view of the synthesis of dissonant systems the most important finding reported by Reissig [19c] is the opening of cyclopropanes by fluoride ion-induced desilylation to give carboxylic ester stabilised "homoenolate" anions, from which a series of 4-oxoalkanoic esters (21a ). with a 1,4-D relationship, were prepared (Table 5.6) ... 

TABLE 5.6. Synthesis of 4-oxoalkanoic esters 21a via homoenolate (with NEtj. 2HF)... 

Vicinally donor-acceptor-substituted cyclopropanol carboxylic esters have been proven to be versatile synthetic building blocks in organic synthesis [11]. They readily undergo a retroaldol reaction, thus creating a stable enolate that at the same time can be considered as a homoenolate in relation to the newly formed carbonyl function. Shimada et al. applied this strategy to the preparation of y-substituted lactones starting from cyclopropane 21 (Scheme 3) [12]. 

In 1977, an article from the authors laboratories [9] reported an TiCV mediated coupling reaction of 1-alkoxy-l-siloxy-cyclopropane with aldehydes (Scheme 1), in which the intermediate formation of a titanium homoenolate (path b) was postulated instead of a then-more-likely Friedel-Crafts-like mechanism (path a). This finding some years later led to the isolation of the first stable metal homoenolate [10] that exhibits considerable nucleophilic reactivity toward (external) electrophiles. Although the metal-carbon bond in this titanium complex is essentially covalent, such titanium species underwent ready nucleophilic addition onto carbonyl compounds to give 4-hydroxy esters in good yield. Since then a number of characterizable metal homoenolates have been prepared from siloxycyclopropanes [11], The repertoire of metal homoenolate reactions now covers most of the standard reaction types ranging from simple... 

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)-... 

Ligand exchange provided a simple and effective solution to these problems. Addition of 0.5 eq. of Ti(0 Pr)4 to the trichlorotitanium homoenolate produces an alkoxytitanium species 19 which is more reactive than the original homoenolate, Eq. (30). This allows the addition to proceed under nearly neutral conditions. Preparation of 4-hydroxy esters by this method is summarized in Table 5. The structure of 19 has been studied by H NMR spectroscopy [19]. 

Table 9. Unsaturated esters by -allylation of zinc homoenolate of esters (Ref. [29])...

Two groups independently reported the formation of titanium homoenolates by the transmetalation reaction of 3-stannyl-propionate esters with TiCl, Eq. (48) [45, 46]. Amide homoenolates become available along this route [47], The trichlorotitanium species thus obtained have been shown ( H NMR) to be similar to that generated along the siloxycyclopropane route and indeed exhibit very similar reactivities. This method does provide a conventient alternative to the siloxycyclopropane route. 

Polladium(II) chloride or its phosphine complex smoothly reacts with siloxy-cyclopropane 1 to produce acrylic ester and a palladium mirror. This reaction probably involves the formation of a chloropalladium homoenolate followed by elimination of palladium hydridochloride (Eq. (56) [56]. 

Kleinman and co-workers 20 synthesized a lactone precursor to the (2/ ,46, 56 )- -hydroxy-ethylene dipeptide stereoselectively in four steps using the lithium salt of ethyl propiolate as a homoenolate equivalent. As summarized in Scheme 11, addition of ethyl lithiopropiolate to a protected a-amino aldehyde affords hydroxy acetylenic esters as a mixture of dia-stereomers. Reduction of the acetylene group and subsequent lactonization gives a readily separable (4S)-lactone-enriched mixture. Direct alkylation with alkyl halide and lithium hexamethyldisilanazide yields the tram-lactone as the major stereoisomer. 

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. 

Marino has reported that the fluoride-induced ring cleavage of l-silyloxy-2-carboalkoxycyclopropanes affords -y-oxo-a-ester enolates, modified homoenolates, which add to Michael acceptors to afford cyclopentanes and cyclopentenes, e.g. (258—>259) 196 alternatively, a carboannulation procedure affords octalin-l-ones (260—>261 Scheme 87) (note the intramolecular enolate addition to the a, -unsaturated sulfone). 

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... 

The unsaturated ester 10 would be made by dehydration of the tertiary alcohol 11. But this has an unhelpful 1,4-diCO relationship that leads to a homoenolate 13 that we should rather avoid. 

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. 

Recently, Bode et al. were able to demonstrate that the products formed after generation of the homoenolate equivalents 67 are determined by the catalytic base [64]. Strong bases such as KOt-Bu led to carbon-carbon bond-formation (y-butyrolactones), while weaker bases such as diisopropylethylamine (DIPEA) allowed for protonation of the homoenolate and the subsequent generation of activated carboxylates. The combination of triazolium catalyst 72 and DIPEA in THF as solvent required no additional additives and enabled milder reaction conditions (60 °C), accompanied by still high conversions in the formation of saturated esters out of unsaturated aldehydes (Scheme 9.21). Aliphatic and aromatic enals 62, as well as primary alcohols, secondary alcohols and phenols, are suitable substrates. a-Substituted unsaturated aldehydes did not yield the desired products 73. 

Movassaghi M, Schmidt MA (2005) N- Ielcrocyclic carbene-catalyzed amida-tion of unactivated esters with amino alcohols. Org Lett 7 2453-2456 Nair V, Vellalath S, Poonoth M, Mohan R, Suresh E (2006a) N- Ielcrocyclic carbene catalyzed reaction of enals and 1,2-dicarbonyl compounds stereoselective synthesis of spiro y-butyrolactones. Org Lett 8 507-509 Nair V, Vellalath S, Poonoth M, Suresh E (2006b) V-Heterocyclic carbene-catalyzed reaction of chalcones and enals via homoenolate an efficient synthesis of 1,3,4-trisubstituted cyclopentenes. J Am Chem Soc 128 8736-8737... 

This homoenolate anion also acylates acid chlorides readily to give y-keto esters (equation I), but does not react with aldehydes or epoxides. 

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