Lithium enolates elimination reactions

The lithium enolates of cyclopentanone and cyclohexanone undergo addition-elimination to the 2,2-dimethylpropanoic acid ester of ( )-2-nitro-2-hepten-l-ol to give 2-(l-butyl-2-nitro-2-propenyl)cycloalkanones with modest diastereoselection. An analogous reaction of the enolate ion of cyclohexanone with the 2,2-dimethylpropanoic acid ester of (Z)-2-nitro-3-phenyl-2-propenol to give 2-(2-nitro-l-phenyl-2-propenyl)cyclohexanones was also reported. The relative configuration of these products was not however determined6. 

Seven-membered carbocycles are also available from the reaction of alkenylcarbene complexes of chromium and lithium enolates derived from methyl vinyl ketones [79b] (Scheme 65). In this case, the reaction is initiated by the 1,2-addition of the enolate to the carbene complex. Cyclisation induced by a [1,2]-migration of the pentacarbonylchromium group and subsequent elimination of the metal fragment followed by hydrolysis leads to the final cyclo-heptenone derivatives (Scheme 65). 

The same elimination strategy was used for the synthesis of the natural product (i )-(-)-dysidazirine 15 as is shown in Scheme 10 [23]. The requisite aziri-dine ester was prepared by treatment of sulfimine 19 with the lithium enolate of methyl bromoacetate. This reaction is a Darzens-type condensation leading to czs-M-sulfinylaziridine ester 20. The elimination of sulfenate was accomplished in the same manner as mentioned above (see Scheme 9). The natural product 15 (see Fig. 1) was obtained in 42% yield. Attempts to prepare azirinomycin 14 in a similar fashion all failed [23]. 

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. 

The study of Fuji et al. shows that the addition of lithium enolate 75 to ni-troamine 74 is readily reversible quenching conditions are thus essential for getting a good yield of product 76. An equilibrium mixture of the adducts exists in the reaction mixture, and the elimination of either the prolinol or lactone moiety can take place depending on the workup condition (Scheme 2-34). A feature of this asymmetric synthesis is the direct one pot formation of the enantiomer with a high ee value. One application of this reaction is the asymmetric synthesis of a key intermediate for indole type Aspidosperma and Hun-teria alkaloids.68 Fuji69 has reviewed the asymmetric creation of quaternary carbon atoms. 

An unexpected result was obtained when DTBB-catalyzed lithiation was applied to the vinyl-oxetane 313 . After work-up, lactone 314 was isolated, the process being explained by an elimination reaction via a radical pathway more than by reduction of the benzyl radical into the anion. Thus, this hypothetical intennediate reacted with the lithium enolate of acetaldehyde, generated in situ by reductive decomposition of THF (Scheme 92). 

The zinc-enolate cyclizations are not restricted to a-aminoesters as /3-aminoesters have also been successfully involved in such reactions275. The preformed lithium enolate generated by treatment of the /J-arninoester 423 with LDA had to be added dropwise to an ethereal solution of ZnBr2 in order to avoid a competing /3-elimination reaction induced by the zinc enolate. this reverse addition protocol was respected, a smooth carbocyclization reaction occurred and provided, after hydrolysis, the substituted 3-carbomethoxypyrrolidine 424 as a 87/13 mixture of diastereomers (equation 183). 

The final step in a recent synthesis of cannabichromene (2) is the aromatization of the cyclohexenone ring of 1. Reagents used for this purpose also attack the double bond in the side chain, but the desired reaction was effected by treatment of the lithium enolate of 1 with benzeneselenenyl chloride followed by selenoxide elimination in the presence of 3,5-dimethoxyaniline.5... 

The further transformations of the enolate C start with a reductive elimination (additional examples of this type of reaction can be found in Chapter 13), which gives the enolate D. This compound is not a normal lithium enolate because it is associated with one equivalent of CuR. The CuR-containing enolate D remains inert until the aqueous workup. As you can see from Figure 8.35, 50% of the groups R contained in the Gilman cuprate are lost through formation of the stoichiometric by-product CuR. This disadvantage does not occur in the 1,4-additions of Normant and Knochel cuprates. 

The best alkylating agents for silyl enol ethers are tertiary alkyl halides they form stable carbocations in the presence of Lewis acids such as TiCLj or SnCLj. Most fortunately, this is just the type of compounds that is unsuitable for reaction with lithium enolates or enamines, as elimination results rather than alkylation a nice piece of complementary selectivity. 

The formation of the lithium enolate is straightforward but it might be expected to be unstable because of a simple elimination reaction. It is not possible to make open-chain lithium enolates with P oxygen substituents like this because they do undergo elimination. 

Aspects of the synthesis, structure and reactivity of lithium enolates 553 2. By elimination reactions... 

Few ester enolate crystal structures have been described. The lack of structural information is no doubt due to the fact that the ester enolates undergo a-elimination reactions at or below room temperature. A good discussion of the temperatures at which lithium ester enolates undergo this elimination is presented in the same paper with the crystal structures of the lithium enolates derived from r-butyl propionate (163), r-butyl isobutyrate (164) and methyl 3,3-dimethylbutanoate (165). It is significant Aat two of the lithium ester enolates derived from (163) and (165) are both obtained with alkene geometry such that the alkyl group is trans to the enolate oxygen. It is also noteworthy that the two TMEDA-solvated enolates from (163) and (164) are dimeric, while the THF-solvated enolate from (165) exists as a tetramer. 

You have already met LDA in Chapter 19 promoting elimination reactions, but no other use of this base compares in importance with what we are telling you now. By far the most important use of LDA is for making lithium enolates. 

Lithium enolates can be used directly in aldol reactions, even with enolisable aldehydes, a simple example6 being the synthesis of the enone 32. The ketone 15 forms mostly the less substituted lithium enolate which condenses 29 with butanal to give aldol 31 in reasonable yield. Elimination is usually carried out in acid solution. 

Sulfenylation of lithium enolates with PhS-SPh or of silyl enol ethers with PhS-Cl allows any a-PhS carbonyl compound to be made regioselectively, e.g. 149 and 152 from 147 (see chapter 5). Oxidation with sodium periodate gives the sulfoxide without over-oxidation to the sulfone, but elimination requires reasonably high temperatures (about 120 °C for MeSO but only about 50 °C for PhSO). Together with the unpleasant by-products, the results of disproportionation of unstable PhSOH, this has led to a preference for the selenium version of the reaction, though we must admit that the by-products are even more offensive.22... 

The selenium version of this reaction offers the advantages that over-oxidation is no problem and that the elimination of the selenoxides occurs at room temperature or below so that the oxidation and elimination normally occur as a single step.23 A simple example is the preparation of another starting material 158 for a dienone-phenol rearrangement.24 The lithium enolate of spirocyclic ketone 155 reacts with PhSeCl to give 156 and oxidation with H202 gives the dienone 158 directly, with the selenoxide 157 as an intermediate. The overall yield is 83%. 

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