Coupling of Grignard reagents

Copper-catalyzed cross-couplings between unactivated alkyl halides and organomagne-sium compounds have been known since the late 1960s and probably are the most studied alkyl-alkyl coupling reactions. The main drawback of this protocol was the need of stoichiometric amounts of copper salts for the formation of the organocuprate, and consequently this led to loss of 1 equiv. of the non-transferred alkyl group. 

After Kumada and Tamao and Corriu independently reported the nickel(II) salts-and complexes-catalyzed cross-coupling reaction of Grignard reagents with aryl and alkenyl halides, the Pd-catalyzed reaction of Grignard reagents was first reported by Murahashi.  

It is reported recently that unactivated aryl chlorides can be used as a substrate in the Kumada coupling. For example, when 4-chlorotoluene (5.34) is reacted with phenyl-magnesium bromide (5.35) in the presence of Pd2(dba)3 and IPr-HCl [l,3-bis(2,6-diisopropylphenyl)imidazolium chloride] in dioxane-THF (tetrahydrofuran), the product 4-phenyltoluene (5.36) is isolated in 99% yield °. 

Ni- and Pd-catalyzed cross-coupling reactions of halopurines with Grignard reagents can be used to introduce an aryl or alkyl group into 6- or 8-position. 

The best results were obtained when aromatic Grignard reagents were employed in the presence of NiCliCdppf). For example, neopentyl iodide (5.37) reacts with 5.35 to give 86% 5.38 in the presence of NiCl2(dppf). 

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Metals as Leaving Groups 14-31 Coupling of Grignard Reagents... 

Nickel(II) salts are able to catalyze the coupling of Grignard reagents with alkenyl and aryl halides. A soluble 6 -phosphine complex, Ni(dppe)2Cl2, is a particularly effective catalyst.266 The main distinction between this reaction and Pd-catalyzed cross... 

Ni(n)- or Co(II)-catalysed cross-coupling of Grignard reagents with organic tellurides... 

Coupling of Grignard reagents with primary halides and tosylates can by catalyzed by Li2CuCl4.29 This method, for example, was used to synthesize the long-chain carboxylic acid 1 in >90% yield. 

The direct coupling of Grignard reagents with carboxylic acids Is not generally useful for ketone synthesis because of the accompanying formation of tertiary alcohols. An exception is the recently-published method using a nickel catalyst. In order to accomplish such a chemoselective ketone... 

Hayashi et al.74 described a process of kinetic resolution in the coupling of Grignard reagents R Mgx (having a chiral center at the point of attachment to the metal) with various alkenyl halides under the influence of chiral phosphine-nickel complexes. Chiral amino acid derivatives (35) were used as ligands. 

TABLE 4. Iron-catalyzed coupling of Grignard reagents with alkenyl bromides... 

Cross-Coupling of Grignard Reagents with Various Aryl and Alkenyl Halides in the Presf.ncf of [Ni(dppp)Cl2] as a Catalyst"... 

Photochemical arylation 4-24 Reduction of diazonium salts 4-29 Dimerization of diazonium salts 4-30 Methylation of diazonium salts 4-33 Coupling of Grignard reagents 4-34 Coupling of arylboranes 4-35 Coupling of other organometallic compounds... 

Coupling with silyl enol ethers. Alkenes can be prepared by coupling of Grignard reagents with silyl enol elbers. Nickel aectylacetonate is the most active... 

An important advancement for the synthesis of well-defined PPPs was the site-controlled nickel-catalyzed coupling of Grignard reagents, derived from dihalobenzenes, to yield linear PPP as shown in Scheme 19 [63,64]. The PPPs obtained by Yamamoto chemistry range from yellow to brown infusible solids of low molecular weights typically with degrees of polymerization ranging from 10-12. 

The application of transition metal catalysis provided new opportunities to introduce diverse functionality to the diazepine ring system. Iron-catalyzed cross-coupling of Grignard reagents with the imidoyl chloride 40 provided a convenient and efficient method for substituting the heterocyclic ring (Scheme 9) <20060L1771>. 

The coupling of Grignard reagents with alkyl, vinyl or aryl halides under Ni-catalysis provides an economic transformation, but the reaction is limited to halide partners that do not react with organomagnesium compounds. One example is in the industrial-scale production of styrene derivatives, and the Kumada Coupling is the method of choice for the low-cost synthesis of unsymmetrical biaryls. 

Holzer, B. Hoffmann, R. W. Kumada-Corriu coupling of Grignard reagents, probed with a chiral Grignard reagent Chem. Commun. 

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