Grignard conjugated addition

The first example of a copper(I)-catalyzed Grignard conjugate addition was that described by Kha-rasch and Tawney 4 subsequently this protocol was the cornerstone for various natural products syntheses, but it lacked predictability and dependability.87 Experimental aspects that affect the efficiency... 

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. 

A new role of iron catalyst in the Grignard conjugate addition has been disclosed.97 It catalysed 1,6-addition of aryl Grignard reagents to 2,4-dienoates or -dienamines in a highly regio- and stereo-selective manner. 

To preform a strong enone sulfoxide-metal ion complex and thus possibly to increase the amount of asymmetric induction, several metal dibromides were added to eyelopentenone sulfoxide ( )-(+)-10. As shown in eq. 12, only zinc dibromide was highly effective in raising the extent of asymmetric induction during methyl Grignard conjugate addition. 

Conjugate addition of vinyllithium or a vinyl Grignard reagent to enones and subsequent oxidation afford the 1.4-diketone 16[25]. 4-Oxopentanals are synthesized from allylic alcohols by [3,3]sigmatropic rearrangement of their vinyl ethers and subsequent oxidation of the terminal double bond. Dihydrojasmone (18) was synthesized from allyl 2-octenyl ether (17) based on Claisen rearrangement and oxidation[25] (page 26). 

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. 

The stereochemistry of the 1,4-addition to A -octal-l-one and 1,1-di-methyl-A -octal-2-one has been investigated by House and Marshall, respectively. In summary, steric and stereoelectronic factors play a part in the mechanism of conjugate addition of Grignard compounds. With methylmagnesium iodide, the introduction of an axial methyl group into steroidal 5a-A -3-ketones (3) and 5 -A -3-ketones (6) is favored by stereo-electronic factors in the transition state. 

In contrast to these ring-opening reactions, it was observed by Horner and Schwahn that 4-arylidene-(isopropylidene and cyclo-hexylidene)-oxazolones react with alkyl Grignard reagents by conjugate addition to give saturated azlactones 29a as the only products [Eq. (18)]. 

Conjugate addition of an alkyl group to an c /S-unsaturated ketone (but not aldehyde) is one of the more useful 1,4-addition reactions, just as direct addition of a Grignard reagent is one of the more useful 1,2-additions. 

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%). 

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... 

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... 

A similar stereospecific conjugate addition to epoxysulfone 323 was also Observed S , with Grignard reagents in the presence of nickel ion or palladium catalysts Methyllithium and n-butyllithium did not add to 1-propenyl phenyl sulfone nor to phenyl -styryl sulfone but underwent lithiation at — 95 However methyllithium, n-... 

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