Esters Grignard additions, copper catalyzed

Ethyl acrylate reacts efficiently under the copper-catalyzed Grignard addition protocol, in which the combination of low temperatures (-20 - -50 C) and catalytic copper(I) chloride (2.6%) was necessary to afford moderate to excellent yields of 1,4-addition products, while elaboration of complex a,(3-unsatu-rated esters is not predictable.91 a In contrast, addition to the a,(3-unsaturated ester (116) affords the... 

The a,(3-unsaturated ester (8), aldehyde (9), and nitro (10) compounds participate as electrophiles in a number of useful conjugate addition reactions. Copper-catalyzed addition of Grignard reagents provides access to aryl butanoic acid derivatives substituted with an oxetane (equation 1 in scheme 13.7). The ester, aldehyde, and nitro electrophiles also undergo mild Rh-catalyzed additions of aryl and vinyl boronic acids (equation 2 through equation 4 in scheme 13.7). Interestingly, the unsaturated aldehyde participates readily in an amine conjugate addition to afford oxetane substituted 3-amino-acetaldehyde derivatives. 

The ferrocene-derived ligand (R,S)-Josiphos is an efficient catalyst for the asymmetric copper-catalyzed 1,4-addition. These reactions proceed readily in the presence of 6 mol% of this ligand in t-BuOMe and afford the Michael-adducts with up to 98% ee. Unsaturated esters like 158 react also with Grignard reagents in the presence... 

The copper(I)-catalyzed addition of Grignard reagents to P-(alkylthio)-a,p-unsaturated esters is the preferred protocol for substitution of the alkylthio substituent, e.g. (310 - 311),21 while potassium enolates add to a-ketoketene dithioacetals, e.g. (312 — 313), without dialkylation (Scheme 96).218b,c Further, Hanessian reports an expedient synthesis of penam (315) via intramolecular cyclization of the (3-lactam nitroalkene (314), but loss of the methylthio moiety does not occur spontaneously (Scheme 97).219... 

The combinations of chlorotrimethylsilane-hexamethylphosphoramide (HMPA) or chlorotrimethylsi-lane-4-(dimethylamino)pyridine (DMAP) are also powerful accelerants for copper(I)-catalyzed Grignard conjugate additions,33 and stoichiometric organocopper and homocuprate additions (Scheme 21 ).36 However, these reactions must be performed in tetrahydrofuran instead of ether.37 These procedures are noted for their high yields with stoichiometric quantities of Grignard reagents, excellent chemoselectivity and efficiency with a,3-unsaturated amides and esters and enals.58 Typically, additions to enals proceed via the S-trans conformers to afford stereo-defined silyl enol ethers for example, enals (122) and (124) give the ( )-silyl enol ether (123) and (Z)-silyl enol ether (125), respectively. 

Sakai and co-workers [38] studied the additions to conjugate esters protected with a cyclic diol as a chiral auxiliary. The ester is protected with enantiomerically pure ( R2R) rrfl/js-cyclohexane diol (see Table 4, entry 7). Addition of phenyl Grignard reagent, catalyzed by Cul, produced a moderate yield (50%) of a mixture of the two diastereomers (prochiral carbon R/5 = 78% 22%) with a d.e. of 55%. In contrast, the authors also reported that addition of the phenyl lithium cuprate gave 94 6 ratio with the major product having the S-configuration for the prochiral carbon. Because of the differences in the structures of the complexes, attack from the lithium cuprate comes from the Re-face, whereas attack from the copper-Grignard comes from the Si-face. 

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