Esters, conjugated, reaction with cuprates

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. ... 

Besides simple enones and enals, less reactive Michael acceptors like /3,/3-disubstituted enones, as well as a,/3-unsaturated esters, thioesters, and nitriles, can also be transformed into the 1,4-addition products by this procedure.44,44a,46,46a The conjugate addition of a-aminoalkylcuprates to allenic or acetylenic Michael acceptors has been utilized extensively in the synthesis of heterocyclic products.46-49 For instance, addition of the cuprate, formed from cyclic carbamate 53 by deprotonation and transmetallation, to alkyl-substituted allenic esters proceeded with high stereoselectivity to afford the adducts 54 with good yield (Scheme 12).46,46a 47 Treatment with phenol and chlorotrimethylsilane effected a smooth Boc deprotection and lactam formation. In contrast, the corresponding reaction with acetylenic esters46,46a or ketones48 invariably produced an E Z-mixture of addition products 56. This poor stereoselectivity could be circumvented by the use of (E)- or (Z)-3-iodo-2-enoates instead of acetylenic esters,49 but turned out to be irrelevant for the subsequent deprotection/cyclization to the pyrroles 57 since this step took place with concomitant E/Z-isomerization. 

Related a,p-Unsaturated Esters. Similar a,p-unsaturated esters bearing a heterocyclic chiral auxiliary of a-amino acid origin at the p-position are known and have been utilized in asymmetric synthesis. Effective asymmetric conjugate additions of cuprates to (2), (3), and (5)J epoxidations of (3), and dipolar cycloadditions of (2) have been reported. Although oxazoli-dine (4) is only obtained as an 86 14 equilibrating mixture of stereoisomers, reactions with the lithium (Z)-enolate of methyl N-benzylideneglycinate (see Ethyl N-Benzylideneglycinate) are exclusively diastereoselective. 

Conjugate additions. Cuprate addition to ynoate esters and trapping with aldehydes (in the presence of EtjAlCl) provide special analogs of Baylis-Hillman reaction products. Trapping with phosphonoacetatic esters is another synthetically valuable variation. Silyl ketene acetals derived from 1,6-addition to allyl alk-4-yn-2-enoates undergo Claisen... 

Reaction with conjugated aHenic ketones and esters. Lithium dimethyl cuprate adds 1,4- to these unsaturated systems, and the intermediate lithium enolate a can be alkylated, as in related reactions (equation I). This reaction thus permits... 

Another route to this cyclohexyl derivative involves the preparation of 6.183 via an olefmation reaction with a substituted phenylalinal derivative followed by reduction of the phenyl ring. The alcohol moiety in 6.183 was converted to the N-phthal-oyl derivative (6.184) by a Mitsunobu inversion.m Conjugate addition with a higher order silyl cuprate gave 6.185. The silyl moiety was converted to an alcohol (6.186) by treatment with tetrafluoroboric acid and then KF/m-chloroperoxy-benzoic acid. Removal of the phthalimidoyl group with hydrazine led to an amino-ester, which cyclized to lactam 5.757.11 Hydrolysis gave 4-amino-5-cyclohexyl-3-hydroxypentanoic acid (6.188) in 60% yield. 

Reactions via Copper Reagents and Cuprates. The conjugate addition reactions of the copper-derived reagents prepared from PhMe2SiLi, their addition reactions with alkynes and al-lenes, and their use in displacements of aUyl halides and esters are covered in the relevant sections. 

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... 

The conjugate addition of lithium bis(phenyldimethylsilyl)cuprates to tt./t-unsaUi rated esters forms enolates, which readily react with aldehydes to give 2-substituted 3-silyl esters (equation 129)509. The products are useful as intermediates in the synthesis of allylsilanes and natural products. Yields of this reaction may be significantly increased by... 

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