Esters reactions with cuprate reagents

There is also a correlation between the reduction potential of the carbonyl compound and the ease of reaction with cuprate reagents. The more easily reduced, the more reactive is the compound toward organocuprate reagents. Compounds such as a,/3-unsaturated esters and nitriles which are not as easily reduced as a,j3-unsaturated ketones do not react readily with simple alkyl cuprates even though they are good acceptors in conjugate addition reactions involving other types of nucleophiles (Michael reactions). 

All of the mixed organocopper reagents shown in Scheme 6.6 react with a,/3-unsaturated ketones. The efficiency of the reaction can be promoted by the addition of trialkylphosphines. a,/0-Unsaturated esters are borderline in terms of reactivity toward simple cuprates. Unsubstituted and monosubstituted acrylates generally are reactive but more extensively substituted acrylates are not. The R-Cu-BFs reagents are more reactive than simple cuprates toward a,j8-unsaturated esters and also react with a,/3-unsaturated nitriles. Boron trifluoride has been found to catalyze addition of dimethylcuprate to very hindered a,)0-unsaturated ketones.Conjugated acetylenic esters react readily with cuprate reagents, with syn addition being the kinetically preferred mode of addition. ... 

The optimum results were obtained with Grignard reagents in the presence of 10 mol % of Cu(I)CN. The stereochemical course of this MIRC reaction can be explained by adopting Yamamoto s model for conjugate addition of cyano-cuprates to y-alkoxy-a,)5-unsaturated esters (Fig. 2) [35]. In this model, it is proposed that the larger substituent (L), in our case the tosyl group, will adopt the... 

Cyclopentanones. Hewson et ah have used the related reagent, 1-methylthiovi-nyl(triphenyl)phosphonium chloride (1) for a synthesis of prostaglandin D, methyl ester (8). Thus reaction of the diketodithiane 2 with 1 in the presence of NaH gives 3, which is readily converted into the enone 4. Addition of the cuprate reagent 5 to 4 shows unexpected selectivity in favor of the natural (rani-arrangement of the side chains, perhaps because of the spiro dithiane unit. 

Even with these developments, the synthetic potential of acetoacetic ester was still not completely exhausted. Notice in the transformations that not all four of the carbon atoms of this reagent are used. In the concluding step of the synthesis, the COOEt or CH3CO group is usually removed as if it were simply an extraneous pendant. The strive to find a 100% utilization of the acetoacetic ester carbon skeleton was realized with the development of a method for substitution at vinylic positions with the use of cuprate reagents (Section 2.12). It turns out that a similar reaction can be carried out with the enol esters of 1,3-dicarbonyl compounds. 

This finding made it easy to carry out the following reaction sequence (i) alkylation at the y-carbon atom of a bis-anion of acetoacetic ester (ii) O-acetylation of the resulting product and (iii) reaction with a cuprate reagent to lead to the substitution of the OAc group by another alkyl group. This route now constitutes one of the most reliable methods to assemble stereoselectively... 

As a rule, stoichiometric cuprate reagents have provided the most consistently successful results in reactions with primary alkyl electrophiles. Diethyl ether is the solvent of choice for reactions of alkyl sulfonates, while reactions of alkyl halides appear to be facilitated by THF. The enhanced basicity of the cuprate reagent in THF may be problematic, however, when racemization of an adjacent chiral center or elimination is a competing side reaction. For example, reactions of serine-derived 3-halo esters must be performed in ether, since elimination by-products are the only products isolated when THF is employed as the solvent elimination is more problematic with sulfonate than with halide leaving groups. 

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