Homoenolate Reaction with electrophiles

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]. 

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. 

In accordance with this model one finds diastereoselectively anti products on reaction of aldehydes with ( )-allyl compounds, whereas allyl systems with the (Z)-configuration give mainly syn products and it is even possible to effect asymmetric induction. As the double bond of the product can be oxidatively cleaved to a CW3 group, the reaction can be regarded as a stereoselective aldol reaction, an aspect which explains the widespread interest in this type of reaction. With heterosubstituted allylic anions it is sometimes possible to effect predominantly y-attack with different electrophiles by the choice of the heteroatom.2 For instance it is well known that with sulfur substituents like —SR, —SOR or —SOjR the a-attack dominates, but doubly lithiated allenethiol possesses high y-reactivity and can be used as a homoenolate anion equivalent in reaction with electrophiles such as alkyl halides (Scheme 7). ... 

Heteroatom-substituted allylic anions can serve as homoenolate anion equivalents in reaction with electrophiles, when y-attack can be realized and the formed vinyl heterocompound can be hydrolyzed to an aldehyde (Scheme 76). ... 

Beak et al. reported that chiral homoenolate equivalents can be formed by di-lithiation of an amide and highly diastereoselective reaction with electrophiles to provide the benzylically substituted products [76]. Treatment of (S)-N-(T-phenylethyl)-3-phenylpropionamide 95 with 2.2 equivalents of sec-BuLi and TMEDA followed by addition of an electrophile affords the alkylated products 96 in 46-55% yield with 90 10-94 6 drs (Scheme 27). 

In order to separate structural effects from the electronic differences of these two catalyst classes. Bode synthesized chiral imidazolium salt 57 (Scheme 14.28). This allowed direct comparison of imidazolium versus triazolium precatalysts across a number of different reaction manifolds including those involving the catalytic generation of homoenolate equivalents, ester enolate equivalents, and acyl anions. These studies conclusively demonstrated that imidazolium-derived catalysts are superior for homoenolate reactions with less reactive electrophiles, while the triazolium-derived pre-catalysts are preferred for all other reactions. Interestingly, from the currently published body of the work, it does not appear to be any effects from the counterion of the azolium pre-catalysts in the presence of bases. 

Functionalized allyllithium compounds of type XIII are also homoenolate equivalents [122,130], but in their reaction with electrophiles sometimes it is not possible to control the regioselectivity. These compounds have been prepared mainly by either deprotonation or tin-lithium exchange. Deprotonation of (F)-cinnamyl-N,N-diisopropylcarbamate 155 with n-BuLi in the presence of (-[-sparteine in toluene gave a configurationally stable lithiated O-allyl carbamate (epi-156), which equilibrates at -50 °C to give the (R)-intermediate 156. Whereas the reaction of these compounds with Mel and MeOTs gave the /-attack, however acylation, silylation and stannylation took place at the a-position (Scheme 2.21) [131]. 

A formal [3h-2] cycloaddition reaction with homoenolates has also been realised with nitrogen-based electrophiles such as A-acyl-A -aryldiazenes 180. Pyrazolidi-nones 178 can be prepared from enals 27 and acyldiazenes 180, as demonstrated by Scheldt and Chan [75]. An example of the asymmetric variant demonstrates excellent levels of enantioselectivity in this reaction (90% ee) (Scheme 12.39). 

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. ... 

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... 

Martin, S. F. DuPriest, M. T. Reactions of allylpyrrolidine carbanions with electrophiles. A new homoenolate equivalent. Tetrahedron Lett. 1977, 3925-3928. 

Trimethylsiloxy cyanohydrins (9) derived from an a,3-unsaturatied aldehyde form ambident anions (9a) on deprotonation. The latter can react with electrophiles at the a-position as an acyl anion equivalent (at -78 C) or at the -y-position as a homoenolate equivalent (at 0 C). The lithium salt of (9) reacts exclusively at the a-position with aldehydes and ketones. The initial kinetic product (10) formed at -78 C undergoes an intramolecular 1,4-silyl rearrangement at higher temperature to give (11). Thus the initial kinetic product is trapped and only products resulting from a-attack are observed (see Scheme 11). The a-hydroxyenones (12), -y-lactones (13) and a-trimethylsiloxyenones (11) formed are useful precursors to cyclopentenones and the overall reaction sequence constitutes a three-carbon annelation procedure. 

There are two main synthetic applications where the reaction of an allyl system with electrophiles is accompanied by an allylic rearrangement. One consists of the use of heteroatom-substituted allylic anions as homoenolate anion equivalents and the other represents a synthetically valuable alternative to the aldol reaction by addition of allyl metal compounds to aldehydes. 

The potential of homoenolate anions on reaction with different electrophiles (Scheme 77) is evident and explains why a great deal of effort has been expended to get high y-selectivity in reactions of such allyl metal compounds. 

Substitution reactions of sp halides have been achieved with the aid of a palladium catalyst (Scheme 23). 14,19 variety of aryl bromides and iodides serve as electrophiles. Reactions with vinyl halides are stereospecific. Vinyl trifluoromethanesulfonates (triflates) also react rapidly with homoenolates. 

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. 

Eunctionalized organolithium compounds, having a protected carboxylic acid functionality, can also be considered as masked lithium tris-homoenolates and were prepared by DTBB-catalyzed (5%) Uthiation of the corresponding )-chlorinated materials. Eor instance, compound 227 in THE at —78°C leads to the expected organoUthium intermediate 228, which reacts with a series of electrophiles present in the reaction medium... 

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)-... 

In 2012, Ye, Jiao, and co-workers described the first application of iV-aryl isatin imines as the electrophiles in NHC-catalyzed homoenolate additions, providing a simple and efficient approach to spirocyclic y-lactam oxindoles. Utilizing the catalyst with free hydroxyl group first developed in the Ye group, an asymmetric variant of this reaction was demonstrated in a moderate enantioselective manner (80% yield, 6 1 dr, 74% ee) (Scheme 7.48). 

In 2008, the Scheldt group reported a direct electrophilic amination via homoenolates catalyzed by N-heterocyclic carbenes using l-acyl-2-aryldiazenes as the electrophilic acceptors, which further increased the versatility of the homoenolate chemistry. It is worthwhile to note that only electron-rich substituents on the aryl component of the diazene could result in product formation (up to 84% yield), while electron-poor aryl substituents gave a lowyield (25%). An example of an asymmetric version of this new ami-nation reaction was achieved with the utilization of the chiral triazolium salt developed in their own group, providing the pyrazolidinone product in good yield (61%) and excellent enantioselectivity (90% ee) (Scheme 7.51). 

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