Carbonyl compound homoenolates

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). 

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]. 

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) . 

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. ... 

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. 

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... 

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. 

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. 

Aldol-iype Condensation. Dimetalation of (R)-(+)-3-(p-tolylsulfinyl)propionic acid with Lithium Diisopropylamide produces a chiral homoenolate dianion equivalent which reacts with carbonyl compounds to afford p-sulfinyl-y-hydroxy acids these spontaneously cyclize to give the corresponding p-sulfinyl 7-lactones (eq 2) ... 

The ring-opened dipolar intermediate suggests reactivity towards nucleophiles and electrophiles. The latter occurs in the TiCl4 promoted addition of methyl 2-siloxycyclo-propanecarboxylates to carbonyl compounds and to an iminium salt (equation 99). The products of both processes are very versatile intermediates allowing synthesis of different furan derivatives and other compounds Concerning the liberated carbonyl function, both reactions can be classified as homoenolate additions, thus putting further emphasis on the cyclopropane homoalkene equivalence. 

Yet another development which is worth mentioning in this context is the 5n substitution of acetals of unsaturated carbonyl compounds. The phenomenon that the reaction of an allylic acetal with a Grignard reagent in the presence of CuBr may occur as a vinylogous substitution with double bond shift has been long known.The reaction can be utilized in an efficient synthesis of 3-substituted propionaldehydes using the acrolein acetal as a homoenolate cation equivalent (Scheme 38). ... 

Unusual carbanions. Lithium homoenolates are formed from P-aryl-a,P-unsaturated ketones and esters. Their reaction with carbonyl compounds leads to y-lactols and lactones. Reductive dechlorination of a-chloroimines provides a-amino carbanions. Access to 1,2-amino alcohols is assured. 

Enolisation 1 involves the removal of the a-proton from a carbonyl compound to form an enolate ion 2. Homoenolisation involves the removal of a (i-proton 3 to form the homoenolate ion 4 or 5. Both the enolate and the homoenolate can be represented as carbanions, but whereas the enolate version 2b is merely a different way of representing a single delocalised structure, the homoenolate 5 is a different compound from the cyclopropane 4. No literal examples of homoenolates 5 are known so they have the status of synthons which may be represented in real life by reagents derived from cyclopropanols 4 among many other possibilities.1... 

Perhaps the only true homoenolates used in synthesis are derived by metallation of derivatives of 3-haloacids. The acids themselves 12 give lithium 3-halocarboxylates 13 and hence by metallation the homoenolate which probably exists as 15, an analogue of the dilithium enolates of carboxylic acids (chapter 2). Reaction 16 with aldehydes or ketones gives y-lactones 19, by a homoaldol reaction via y-hydroxyacids 18, common products from addition of acid homoenolates to carbonyl compounds.3... 

Palladium homoenolates readily undergo p-elimination to give a,P-unsaturated carbonyl compounds. Treatment of a mercurio ketone with a catalytic amount of palladium(II) in the presence of CuCh results in the formation of an enone via a 3-palladio ketone (Scheme 3). Treatment of a silyloxycyclopropane (8) with PdCh also generates in situ a palladium homoenolate which then undergoes -elimination (Scheme 3). Heating a mixture of a 3-trichlorostannyl ketone or aldehyde with DMSO results in the formation of an enone or an enal in excellent yield (Scheme 4). ... 

Addition of a homoenolate to a carbonyl compound, which may be called a homoaldol reaction , provides a straightforward route to 4-hydroxy esters and y-lactones. Only two classes of well-characterized homoenolates that undergo nucleophilic addition to carbonyl compounds are known, namely titanium and zinc homoenolates of esters. 

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