Conjugate addition of Grignard reagents

Kharasch has shown that the presence of a small amount of cuprous chloride favored the conjugate addition of Grignard reagents to a, -un-saturated ketones rather than 1,2-addition. 

Substantially high diastereoselectivity was accomplished by the conjugate addition of Grignard reagents to the amide 1 derived from 1-ephedrine32. The reagent attacked from the Re-face of the double bond, as shown in 2, via a chelated intermediate. Low asymmetric induction was observed when butyllithium was used instead of butylmagnesium bromide. 

The conjugate addition of Grignard reagents to 2-cyclohexenone was promoted by catalytic amounts (2-4 mol %) of alkylcopper(I) complexes of the lithium amide prepared from N- (R)-1 -phenylethyl]-2-[(/ )-l-phenylethyliminojcycloheptatrienamine, Li[CuR(CHIRAMT)]52,11. However, 3-substituted cyclohexanones were obtained in very low ee (4-14%). 

Catenated Organic Compounds of the Group IV Elements, 4,1 Conjugate Addition of Grignard Reagents to Aromatic Systems, 1, 221 Cyclobutadiene Metal Complexes, 4, 95 Cyclopentadienyl Metal Compounds, 2, 365 Diene-Iron Carbonyl Complexes, 1, 1... 

This reaction is extended to the intramolecular ring closure of the intermediate radical 224 with olefinic or trimethylsilylacetylenic side chains [121]. Cu(BF4)2 is also effective as an oxidant (Scheme 89) [122]. Conjugate addition of Grignard reagents to 2-eyclopenten-l-one followed by cyclopropanation of the resulting silyl enol ethers gives the substituted cyclopropyl silyl ethers, which are oxidized to 4-substituted-2-cyclohexen-l-ones according to the above-mentioned method [123]. (Scheme 88 and 89)... 

Conjugate Addition of Grignard Reagents to Aromatic Systems, 1, 221... 

Conjugate additions to enals and enones.1 ClSi(CH,)3/HMPT markedly accelerates the Cu(I)-catalyzed conjugate addition of Grignard reagents to enals, enones, and unsaturated esters. The conjugate addition of organocopper reagents is also facilitated. 

Seebach et al. (154) showed that a 0-isopropylidene-2,3-dihydroxy-l, 1,4,4-tetraphenyl-l,4-diol (TADDOL)-derived aminothiolate serves as a moderately effective ligand for the catalyzed conjugate addition of Grignard reagents to cyclic enones. The catalyst, synthesized from the lithiothiolate and CuCl, exhibits optimal selectivities under a slow addition protocol (2 h), Eq. 124. 

Condensation of p-acetylben-zenediazonium bromide with acrylic acid, 51, 1 Conduritol-D, 50, 27 Conjugate addition of Grignard reagents, 50, 41 CONTROLLED POTENTIAL ELECTROLYTIC REDUCTION 1,1-BIS (BROMOMETHYL)CYCLOPROPANE,... 

The introduction of asymmetry in conjugate additions can be promoted by chiral acceptors. The preparation of regio-defined magnesium enolates from copper(I)-mediated conjugate addition of Grignard reagents has been extensively used in many important... 

If thioamide enolates are prepared by conjugate addition of Grignard reagents to a,/3-unsaturated thioamides of secondary amines, the reaction of these enolates with aldehydes affords anti aldols. These results are rationalized by the formation of a boat-like, chelate transition state" Representative examples are provided in equation 112 and Table 16. 

V. APPLICATION OF THE CONJUGATE ADDITION OF GRIGNARD REAGENTS TO a,/9-UNSATURATED THIOESTERS IN THE... 

SCHEME 1. Asymmetric conjugate addition of Grignard reagents to substrates containing chiral auxiliaries... 

FIGURE 1. Selected catalysts developed for the conjugate addition of Grignard reagents to enones. Adapted with permission from Acc. Chem. Res., 40, 179-188 (2007). Copyright 2007 American Chemical Society... 

FIGURE 4. Chiral NHC ligands for the enantioselective copper-catalyzed conjugate addition of Grignard reagents... 

The conjugate addition of Grignard reagents to a, S-nnsatnrated acid derivatives, in partic-nlar to esters, is highly attractive. Despite the enormons synthetic potential of the resnlting... 

TABLE 6. CuI/Tol-BINAP-catalyzed conjugate addition of Grignard reagents O Cul (1 mol%) R O... 

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