Lithium ester enolates, condensation with

In the presence of a strong base, the ot carbon of a carboxylic ester can condense with the carbonyl carbon of an aldehyde or ketone to give a P-hydroxy ester, which may or may not be dehydrated to the a,P-unsaturated ester. This reaction is sometimes called the Claisen reaction,an unfortunate usage since that name is more firmly connected to 10-118. In a modem example of how the reaction is used, addition of tert-butyl acetate to LDA in hexane at -78°C gives the lithium salt of ferf-butyl acetate, " (12-21) an enolate anion. Subsequent reaction a ketone provides a simple rapid alternative to the Reformatsky reaction (16-31) as a means of preparing P-hydroxy erf-butyl esters. It is also possible for the a carbon of an aldehyde or ketone to add to the carbonyl carbon of a carboxylic ester, but this is a different reaction (10-119) involving nucleophilic substitution and not addition to a C=0 bond. It can, however, be a side reaction if the aldehyde or ketone has an a hydrogen. 

Enolates, lithium salts, aldol condensation with, 54, 49 Enol esters, preparation, 52,... 

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>. 

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. 

A comprehensive review article on 3-lactam formation via the ester enolate-imine condensation has been written by Hart and Ha. Achiwa and coworkers have published a full paper detailing their work on the synthesis of N-benzyloxy-3-lactams utilizing the reaction of N-benzyloxyimines with silylketene acetals in the presence of TMS-OTf, or with lithium ester enolates. ... 

Ester enolates are somewhat less stable than ketone enolates because of the potential for elimination of alkoxide. The sodium and potassium enolates are rather unstable, but Rathke and co-workers found that the lithium enolates can be generated at -78° C.69 Alkylations of simple esters require a strong base because relatively weak bases such as alkoxides promote condensation reactions (see Section 2.3.1). The successful formation of ester enolates typically involves an amide base, usually LDA or LiHDMS, at low temperature.70 The resulting enolates can be successfully alkylated with alkyl bromides or iodides. HMPA is sometimes added to accelerate the alkylation reaction. 

Ethyl 3-oxoalkanoates when not commercially available can be prepared by the acylation of tert-butyl ethyl malonate with an appropriate acid chloride by way of the magnesium enolate derivative. Hydrolysis and decarboxylation in acid solution yields the desired 3-oxo esters [59]. 3-Keto esters can also be prepared in excellent yields either from 2-alkanone by condensation with ethyl chloroformate by means of lithium diisopropylamide (LDA) [60] or from ethyl hydrogen malonate and alkanoyl chloride usingbutyllithium [61]. Alternatively P-keto esters have also been prepared by the alcoholysis of 5-acylated Mel-drum s acid (2,2-dimethyl-l,3-dioxane-4,6-dione). The latter are prepared in almost quantitative yield by the condensation of Meldrum s acid either with an appropriate fatty acid in the presence of DCCI and DMAP [62] or with an acid chloride in the presence of pyridine [62] (Scheme 7). 

The kinetic enolization of esters with amide bases such as lithium diisopropylamide (LDA) and the resultant aldol condensations with representative aldehydes have been investigated by several groups (2,32,33). The enolate stereochemical assignments were determined by silylation in direct analogy to studies reported by Ireland (34). The preponderance of (E )-enolate observed with LDA (THF) in these... 

Detailed investigations indicate that the enolization process (LDA, THF) affords enolates 37 and 38 with at/east 97% (Z)-stereoselection. Related observations have recently been reported on the stereoselective enolization of dialkylthioamides (38). In this latter study, the Ireland-Claisen strategy (34) was employed to assign enolate geometry. Table 10 summarizes the enolization stereo selection that has been observed for both esters and amides with LDA. Complementary kinetic enolization ratios for ketonic substrates are included in Table 7. Recent studies on the role of base structure and solvent are now beginning to appear in the literature (39,40), and the Ireland enolization model for lithium amide bases has been widely accepted, A tabular survey of the influence of the ester moiety (ORj) on a range of aldol condensations via the lithium enolates is provided in Table 11 (eq. [24]). Enolate ratios for some of the condensations illustrated may be found in Table 10. It is apparent from these data that ( )-enolates derived from alkyl propionates (Rj = CH3, t-C4H9) exhibit low aldol stereoselectivity. In contrast, the enolates derived from alkoxyalkyl esters (Rj = CHjOR ) exhibit 10 1 threo diastereo-... 

Extensive investigations have been directed toward the development of chiral ester enolates that might exhibit practical levels of aldol asymmetric induction. Much of the early work in this area has been reviewed (111). In general, metal enolates derived from chiral acetate and propionate esters exhibit low levels of aldol asymmetric induction that rarely exceed 50% enantiomeric excess. The added problems associated with the low levels of aldol diastereoselection found with most substituted ester enolates (cf. Table 11) further detract from their utility as effective chiral enolates for the aldol process. Recent studies have examined the potential applications of the chiral propionates 121 to 125 in the aldol condensation (eq. [94]), and the observed erythro-threo diastereoselection and diastere-oface selection for these enolates are summarized in Table 31. For the six lithium enolates the threo diastereoselection was found to be... 

The one-pot condensation of an ester enolate with an imine is a very powerful synthetic procedure toward azetidin-2-ones (Equation 183). Various types of esters and imines can be utilized. Although in the vast majority the reactions have been mediated by lithium, various other metals mediate the reaction as well. Some examples include zinc, aluminium, tin, boron, indium, and titanium <1996MI119>. Theoretical studies on these reactions have been reviewed <1998JCC1826>. 

For the synthesis of (69), the enol ether (71) from the indanone (70) was carboxylated with COa-n-butyl-Iithium in THF at —70 C to yield (72). The methyl ester (73) was converted into (75) via the maleic anhydride adduct (74), essentially as described in earlier work. Lithium aluminium hydride reduction followed by oxidation with dicyclohexylcarbodi-imide afforded the aldehyde (76). This was condensed with excess (77) to yield a mixture of the diastereomers (78). Oxidation with chromium trioxide-pyridine in methylene dichloride gave (79), which could be converted into the diketone (80) by treatment with excess benzenesulphonylazide. The diketo-lactam (81) was prepared from (80) as described for the synthesis of the analogous intermediate used in the synthesis of napelline. Reduction of (81) with lithium tri-t butoxyaluminohydride gave the desired dihydroxy-lactam (82). Methylation of (82) with methyl iodide-sodium hydride gave (83). Reduction of this lactam to the amine (84) with lithium aluminium hydride, followed by oxidation with potassium permanganate in acetic acid, gave (69). 

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