Lithium esters

The use of nonstabilized carbon nucleophiles in this reaction has been rare. Recently, however, it was shown that lithium ester enolates participate in Pd-cata-lyzed 1,4-additions to cyclic and acyclic vinyloxiranes, affording the corresponding 6-hydroxy-4-enoates in good yields and with complete regioselectivity [117, 118]. 

Lithium ester enolate addition to imines has been used for the construction of optically active p-lactams, e.g. 64 and the lithium enolates have been found to be superior to other metal derivatives for both yields and diastereoselectivity in some cases <00H(53)1479>. Immobilized lithium ester enolates have been utilized for the first time <00OL907> and soluble polymer supported imines were used to obtain N-unsubstituted azetidin-2-ones under mild conditions <00CEJ193>. Both lithium and titanium enolates have been employed to obtain cholesterol absorption inhibitors <99TA4841>. Lithium ynolates 65 add to imines to provide P-lactams in good to excellent yield <00TL5943>. 

P-Lactams. In the presence of (CH3)2A1C1, lithium ester enolates react with enolizable aldimines to afford p-lactams in 60-95% yield as a mixture of cis- and trans-isomers. ... 

Silylimines fi-lactams.1 This lithium amide converts aldehydes, even enol-izable ones, into silylimines. Thus acetaldehyde can be converted into the imine (2), which cannot be isolated but which reacts with lithium ester enolates to form... 

More recently, a study pertaining to the condensation of lithium ester enolates with substituted imines has appeared (eq. [66]) (79). Although monosubstituted enolates (Rj = H R2 = Ph, N=C(OLi)Ph] afforded moderate yields (35-45%) of trans-lactam 87, disubstituted enolates (Rj = OLi, CH3 R2 = Ph, CH3) afforded good yields (66-91%) of lactam products. The authors concluded from their study that the condensation step was probably reversible. 

Lithium ester enolate-imine condensation has been used for the preparation of / -lactam rings via addition at the imine moiety <1996H(43)1057>. But treatment of imino derivatives of the pyridazine 293 with the lithium enolate of ethyl a,a-dimethylacetate 294 in THE led to the formation of the pyrido[3,4-r/ pyridazine 295 and its oxidized form 296. Compound 295 was obtained by nucleophilic attack of the carbanion species at C-5 of the pyridazine ring followed by cyclization (Equation 24) <1996JHC1731>. 

An interesting variation of this methodology was developed whereby zinc enolates 127 were employed giving 2-ester-substituted pyrrolidines 128-13060c. The enolates 127 were obtained via transmetallation of lithium ester enolates 126 with ZnBr2 (equation 59). 

Dimethylalkenes.1 The readily available a-silyl esters, obtained by C-silylation of lithium ester enolates with 1, are useful precursors to trisubstituted alkenes, including 1,1-dimethylalkenes. 

Keywords lithium ester enolate, 3,3-dimethyl butanoate, aromatic aldehyde, Michael addition, /2-hydroxy ester... 

Chiral 2-sulfinylcyclohexanones react with lithium alkyl acetates (i.e. lithium ester enolates) to produce alcohols with four contiguous chiral centres.57 This stereoselective aldol reaction is proposed to depend upon tricoordination by lithium of the enolate, sulfinyl, and carbonyl oxygens of the substrates. 

Highly stereoselective aldol reactions of lithium ester enolates (LiCR1 R2CC>2R3) with (/0-2-(/ -tolylsulfiny I (cyclohexanone have been attributed to intermediacy of tricoordinate lithium species which involve the enolate and the sulfinyl and carbonyl oxygens of the substrates.43 The O-metallated /<-hydroxyalkanoatcs formed by aldol-type reaction of carbonyl compounds with enolates derived from esters of alkanoic acids undergo spontaneous intramolecular cyclization to /1-lactones if phenyl rather than alkyl esters are used the reaction has also been found to occur with other activated derivatives of carboxylic acids.44... 

Asymmetric formation of /i-lactams (38) in high ee has been achieved by reaction of achiral imines (36) with a ternary complex of achiral lithium ester enolate (35), achiral lithium amide, and a chiral ether ligand (37) (in either stoichiometric or catalytic amount) 45 the size and nature of the lithium amide have a considerable effect on the enantioselectivity of the ternary complex. 

Mixed aggregates of chiral lithium amide and lithium ester enolate have been employed in the enantioselective conjugate addition on a,/S-unsaturated esters.27 Michael adducts have been obtained in ees up to 76% combining a lithium enolate and a chiral 3-aminopyrrolidine lithium amide. The sense of the induction has been found to be determined by both the relative configuration of the stereogenic centres borne by the amide and the solvent. 

Addition of several lithium ester enolates to chiral 1-aminoalkyl choromethyl ketones gave the corresponding chlorohydrins which, when the solvent was completely evaporated to dryness at room temperature, underwent an intramolecular heterocyclization affording 3-hydroxyazetidinium salts 5 <02OL1299>. Azetidinium salts 5 were isolated in enantiomerically pure form, and with total or high diastereoselectivity. The degree of stereoselectivity was only moderately affected by the size of R1 in the a-amino-ketone and the substituents in the ester enolate. 

In Chapter 28 you will meet the reaction of an ester with its own enolate the Claisen condensation. This reaction can be an irritating side-reaction in the chemistry of lithium ester enolates when alkylation is desired, and again it can be avoided only if the ester is converted entirely to its enolate under conditions where the Claisen condensation is slow. A good way of stopping this happening is to add the ester to the solution of LDA (and not the LDA to the ester) so that there is never excess ester for the enolate to react with. 

An intramolecular tandem Michael aldol reaction was described for esters that have an enolizable aldehyde in the molecule. The lithium ester enolate generated through the Michael reaction undergoes an intramolecular aldol reaction. Thus, the reaction of unsaturated esters 153 with lithium benzylthiolate provided the expected cyclization products 156 and 157 via (w-formylenolate 154 in an excellent cis stereoselectivity (Scheme 49)no. 

SCHEME 51. Lithium coordination modes in acetaldehyde enolate and in lithium ester silenolate201... 

Lithium ester enolates are extremely important in polymer chemistry as initiators and active centers of the anionic polymerization of acrylic and methacrylic monomers in polar solvents. Thus, HF-SCF studies, comparable to those mentioned above, were undertaken on monomeric methyl isobutyrate (MIB) enolate210,211. The overall conclusions on the aggregation and solvation trends are exactly the same, the bent rj3-0,C mode being preferred over the rj1-O planar one by ca 3.3 kcalmol-1. While the dimeric MIB enolate solvated by four molecules of THF was found to be the enthalpically most stable aggregate, the prismatic S6 unsolvated MIB hexamer was computed as the preferred structure in non-polar solvents (Scheme 55)212. In the latter case, the supplementary oxygen of the ester acting as a side-chain ligand for the lithium seems to explain this remarkable stability. 

We complete this section with a study of the effect of TMEDA on the polymerization of methyl methacrylate lithium enolate in THF262. It was concluded that TMEDA hardly affects the kinetics of the polymerization and therefore the monomer-dimer equilibrium. From these figures, TMEDA does not seem to be a better ligand for lithium ester enolates than THF, in line with previous observations by Collum on other organolithium compounds263. 

The stereoselective chelation-controlled aldol reaction of unsubstituted lithium ester enolates with (7 s)-2-(p-tolylsulfinyl) cyclohexanone A (Figure 16) led to a high enantio-face differentiation (> 90 < 10), while the simple diastereoselection was rather low for prochiral enolates567. The role of the lithium cation acting as a template is here essential, since sodium, potassium, HMPA or even added ZnCl2 resulted in decreased yield and selectivity. 

SCHEME 134. Enantioselective condensation of a lithium ester enolate on an imine in the presence of a chiral diether618... 

OL-Alkyl-OL, -unsaturated esters. a-Silyl esters can be obtained in >80% yield by reaction of lithium ester cnolatcs with this silane (10, 91 11, 247). Aldehydes and ketones react with the cnolatcs of these a-silyl esters to give adducts that undergo a Peterson elimination to form a-alkyl-a.p-unsaturatcd esters in which the (Z)-isomer predominates. 

The mixed Tishchenko reaction involves the reaction of the aldol prodnct 113 from one aldehyde with another aldehyde having no a-hydrogens to yield an ester The products were proposed to be formed through an aldol step (equation 33), followed by addition of another aldehyde (equation 34) and an intramolecular hydride transfer (equation 35). However, several aspects of this mechanism need to be clarified. As part of the continuing mechanistic studies carried out by Streitwieser and coworkers on reactions of alkali enolates ", it was found that the aldol-Tishchenko reaction between certain lithium eno-lates and benzaldehyde proceeded cleanly in thf at room temperature". Reaction of the lithium enolate of isobutyrophenone (Liibp) with 1 equiv of benzaldehyde in thf at — 65 °C affords a convenient route to the normal aldol product 113 (R = R" = Ph, R = Me). At room temperature, however, the only product observed after acid workup was the diol-monoester 116, apparently derived from the corresponding lithium ester alcoholate (115, R = R" = Ph, R = Me), which was quantitatively transformed into 116 after quenching. As found in other systems", only the anti diol-monoester diastereomer was formed. 

The reaction of a lithium ester enolate (146) with a nitrone (147) to yield a fi-hydroxylamino acid ester (149) has been recently investigated by Domingo, Merino and coworkers, using DFT (B3LYP/6-31G ) methods, to gain insight on the molecular mechanism. The proposed transition structure (148) shown in equation 42 derives from attack of the most nucleophilic center of enolate 146 on the most electrophilic center of... 

The formation of carbon-carbon bonds by conjugate addition of carbonucleophiles to a,/3-unsaturated systems has been studied intensively and reviewed over the past few years . Interestingly, applications with simple, unstabilized lithium enolates are relatively rare. Most reported examples are limited to the addition of stabilized enolates, such as those derived from malonates or acetoacetates. Nevertheless, some diastereo- and enantioselective versions of the conjugate addition, even with unstabilized lithium enolates, are well known. In 2004, Tomioka and coworkers studied the influence of a chiral diether (191) on the 1,4-addition of lithium ester enolates (189) to a,-unsaturated ketones (equation 51) . Their investigations showed that good enantioselectivities were obtained with cyclic enones, like 2-cyclopentenone (190) addition to a mixture of 189 and 191 gave the desired 1,4-adduct (R)-192 with 74% ee, but only 47% yield. Unfortunately, also the Peterson product 193 was formed in a yield of 22% by initial 1,2-addition of the enolate to the Michael acceptor. 

As far as the use of electrochemical oxidation of metal enolates in organic synthesis is concerned, more than 30 years ago the electrochemical oxidation of lithium ester enolates was used for the preparation of snccinate esters . An excellent review on the applications of anodic electrochemistry in organic synthesis has been published . 

Lithium ynolates from lithium ester enolates. 746... 

Asymmetric cycloadditions of the chiral non-racemic nitrones 101 and 103 afford the isoxazolidinones 102 and 104 respectively, with high diastereoselectivity. This process can lead to an efficient asymmetric synthesis of /3-amino acids (equations 42 and 43) . This is the first example of asymmetric reactions with ynolates. It is noteworthy that the ynolates show higher reactivity and stereoselectivity than the corresponding lithium ester enolates and demonstrate the high potential of lithium ynolates in asymmetric reactions. 

As a rule, the aggregation of lithium ester enolates is mainly governed by concentration, temperature and structure of the ester group. There is thus no reason for the polymerization of methyl methacrylate and f-butyl methacrylate to be influenced by the same experimental parameters. 

Zune and coworkers studied the structure of the species propagating the anionic polymerization of tBMA by NMR spectroscopy . The spectrum of the lithium ester enolate was perturbed by LiCl, as result of an equilibrium established between free lithium chloride and complexed active end-groups. The structure of the chain-end was not modified by a large excess of LiCl. 

The (E)I(Z) notation is adopted for the definition of the geometries of silylketene acetals as well as metal enolates. As a consequence, silylation of ( )-lithium ester enolates leads to (Z)-silylketene acetals. 

The efficiency of Me2AlCl in a new synthesis of /3-lactams from lithium ester eno-lates and enolizable aldimines was demonstrated by Akiba and co-workers [112]. In the absence of MeaAlCl no /3-lactam formation was observed, probably because of the proton removal from the enolizable aldimines with lithium ester enolate (Sch. 76). 

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