Carbonylation homoenolates

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],... 

The chiral siloxycyclopropane 106 undergoes carbonylative homocoupling to form the 4-ketopimelate derivative 108 via the palladium homoenolate 107 without racemization. The reaction is catalytic in CHCI3, but stoichiometric in benzene[93]. 

Allyl anion synthons A and C, bearing one or two electronegative hetero-substituents in the y-position are widely used for the combination of the homoenolate (or / -enolate) moiety B or D with carbonyl compounds by means of allylmetal reagents 1 or 4, since hydrolysis of the addition products 2 or 5 leads to 4-hydroxy-substituted aldehydes or ketones 3, or carboxylic acids, respectively. At present, 1-hetero-substituted allylmetal reagents of type 1, rather than 4, offer the widest opportunity for the variation of the substitution pattern and for the control of the different levels of stereoselectivity. The resulting aldehydes of type 3 (R1 = H) are easily oxidized to form carboxylic acids 6 (or their derivatives). 

CH2 groups are not acidic enough for this base (2) recovered 18 was racemized 20 is symmetrical and can be attacked equally well from either side (3) when the experiment was performed in deuterated solvent, the rate of deuterium uptake was equal to the rate of racemization and (4) recovered 18 contained up to three atoms of deuterium per molecule, though if 19 were the only ion, no more than two could be taken up. Ions of this type, in which a negatively charged carbon is stabilized by a carbonyl group two carbons away, are called homoenolate ions. 

Allyltitanium complexes derived from a chiral acetal have been reacted with carbonyl compounds and imines [63], While the chiral induction proved to be low with carbonyl compounds, high induction was observed with imines. This complex represents the first chiral homoenolate equivalent that reacts efficiently with imines. Finally, the reactions with electrophiles other than carbonyl compounds and imines, namely a proton source, NCS, and I2, furnished the corresponding alkene, chloro, and iodo derivatives in good yields [64]. 

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]. 

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-... 

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]. 

A completely different approach to lithium homoenolate synthons uses a carbon-oxygen bond cleavage. Lithiation of acrolein diethyl acetal 180 with lithium and a catalytic amount of DTBB (2.5%) in the presence of different carbonyl compounds in THF at 0°C gave, after final hydrolysis, the corresponding y-products 181 in different diastereomeric ratios (Z/ 3/1 to 20/1) (Scheme 63) . 

Lithium homoenolates derived from carboxylic acids were generated from the corresponding /3-chloro acids by means of an arene-catalyzed lithiation. Chloro acids 186 were deprotonated with n-butyllithium and lithiated in situ with lithium and a catalytic amount of DTBB (5%) in the presence of different carbonyl compounds to yield, after hydrolysis, the expected hydroxy acids (187). Since the purification of these products is difficult, they were cyclized without isolation upon treatment with p-toluenesulfonic acid (PTSA) under benzene reflux, into substituted y-lactones 188 (Scheme 64) . 

Lithinm homoenolates 560 were generated by lithiation of enones 559 with lithium and a catalytic amonnt of naphthalene (4%) in the presence of different carbonyl com-ponnds as electrophiles and a Lewis acid (LiCl, TiCLj, SnBu4, SnCLj, BF3) in THF at... 

If the mesomeric stabilization is provided by a double bond, the lithiated species is a homoenolate synthon, as shown in Scheme 44a. Reaction with an electrophile typically occurs at the y-position, yielding an enamine, which can then be hydrolyzed to a carbonyl compound. An important application of this approach is to incorporate a chiral auxiliary into the nitrogen substituents so as to effect an asymmetric synthesis. 2-AzaaUyl anions (Scheme 44b), which are generated by tin-lithium exchange, can be useful reagents for inter- and intramolecular cycloaddition reactions. ... 

Although these allylic stannanes are rather resistant to uncatalysed or Lewis acid-catalysed carbonyl addition , they are valuable, shelf-stable homoenolate reagents (see Section IV.C.5), which are activated by Lewis acids or lithiodestannylation. Titanium tetrachloride converts the allylstannanes stereospecifically with inversion into very reactive intermediates (equation 83) . Both isomers, (R,Z)- and (5, )-315, are transformed... 

Once regiocontrol was achieved, donor-substituted allyl metallics found two synthetically important applications. The hetero-substituted vinyl compounds, obtained by alkylation of a substituted allyl carbanion in the 3-position ( ), can be hydrolyzed to carbonyl compounds substituted on the /1-carbon atom. Thus, the substituted allyl carbanion was used as an equivalent of the homoenolate synthon18 19. 

Aminoallyl carbanions, obtained by deprotonation of enamines or allylamines, are well-known homoenolate equivalents, since electrophilic attack occurs, in most cases, highly regiose-lectively to give the 3-substituted enamines, hydrolysis of which leads to the corresponding carbonyl compounds15 24,25. 

Homologation reaction of lithium enolates with bis(iodomethyl)zinc (58) yields a homoenolate, namely the organozinc derivatives bearing a carbonyl group at the /3 position (Scheme 6)55. Treatment of the lithium enolate of cyclohexanone, generated from the silyl... 

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... 

Strongly Lewis acidic SbCl5 rapidly reacts with one equivalent of the cyclopropane 16 in chloroform to give monoalkylated antimony derivate 18 in 87% yield Eq. (20) [11]. The internal chelation is especially strong, as indicated by the carbonyl band in the IR spectrum at 1600 cm-1. In contrast to the common monoalkyltetrachloroantimony, the chelated homoenolate 18 is stable at room temperature for many hours. 

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)-... 

Next to the cyclopropane formation, elimination represents the simplest type of a carbon-carbon bond formation in the homoenolates. Transition metal homoenolates readily eliminate a metal hydride unit to give a,p-unsaturated carbonyl compounds. Treatment of a mercurio ketone with palladium (II) chloride results in the formation of the enone presumably via a 3-palladio ketone (Eq. (24), Table 3) [8], The reaction can be carried out with catalytic amounts of palladium (II) by using CuCl2 as an oxidant. Isomerization of the initial exomethylene derivative to the more stable endo-olefin can efficiently be retarded by addition of triethylamine to the reaction mixture. 

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]. 

Tetr 36 2531 (1980) (carbonyl homologation and masked homoenolate equivalents)... 

Another common umpolung synthon is a homoenolate. Normally the ft position of a carbonyl compound is an electrophilic center (by Michael addition to an 0, /3-unsaturated carbonyl derivative). To make it a nucleophilic center, an organometallic is needed since it is unactivated and nonconjugated. A common way to do this is to use a /3-bromo acetal. 

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