Alkyl halides and Grignard reagents

Synthesis of [a>-11 C]-labelled fatty acids using alkyl halides and Grignard reagents... 

Fig. 1-24. Pd-catalyzed cross-coupling of alkyl halide and Grignard reagent. (Solv = coordinating solvent P = monophosphine, PR3) (adapted from [264]).

Table 21 Stability of DCPH Toward Alkyl Halide and Grignard Reagent Reaction of Bromooctane with Magnesium in the Presence of DCPH...

In another development, it was shown that simple Ni(II) or Ni(0) precursors (e.g. NiCb, Ni(acac)2, Ni(COD)2, etc.) can catalyze the coupling of primary alkyl halides with Grignard reagents (Kumada-Corriu reaction). This otherwise challenging coupling of two sp -C centers is facilitated by the presence of various 1,3-butadienes this feature allows even the normally unreactive aUcyl chlorides to be coupled in very good yields and low catalyst loadings... 

Fairly bulky alkyl substituents such as neopentyl and (trimethylsilyl)methyl are also introduced by this method (equation 2) . Unsymmetrical compounds have also been prepared from the appropriate halide and Grignard reagents. For example the synthesis of and 2 has been reported (equations 3 and 4). 

Imido complexes can also be formed from metal-nitrido species by alkylation of the nitrogen (Equation 13.61). Electron-rich nitrido species undergo alkylation with organic electrophiles, such as alkyl halides and trimethyloxonium reagents. Electron-poor nitrido species undergo alkylation with carbon nucleophiles, and an example of the alkylation of a metal-nitride by a Grignard reagent is shown in Equation 13.62.257... 

Organocuprates are much less prone to 8-hydride elimination reaction and rapidly couple with alkyl halides. In this respect, they complement the palladium reagents. A disadvantage is their basicity and that their most common sources are the strongly basic and nucleophilic alkyl lithium and Grignard reagents, which require protection of sensitive functionalities. 

Reaction with Alkyl Halides. The Grignard reagent (1) can be alkylated by allyl halides to afford the homoallylsilane. The use of a nickel(II) catalyst facilitates coupling of the Grignard reagent (1) to vinyl halides and aryl halides, triflates and O-carbamates and provides a useful method for the preparation of allyl- andbenzylsilanes (eq 7). Palladium catalysis is also effective to couple (1) with vinyl halides. 

Pyrroles do not react with alkyl halides in a simple fashion polyalkylated products are obtained from reaction with methyl iodide at elevated temperatures and also from the more reactive allyl and benzyl halides under milder conditions in the presence of weak bases. Alkylation of pyrrole Grignard reagents gives mainly 2-alkylated pyrroles whereas N-alkylated pyrroles are obtained by alkylation of pyrrole alkali-metal salts in ionizing solvents. 

Oddo reported that the organomagnesium derivatives of p3Trole, indole, skatole, and carbazole could be prepared in a single operation by mixing the parent heterocyclic compound with an alkyl halide and magnesium in anhydrous ether.The product formed was reported to be the same as that obtained by the more conventional procedure. However, this approach to the synthesis of the indole Grignard reagents does not seem to have been exploited in subsequent work. 

This reaction can be used for the synthesis of hydrocarbons but it may also take place as a side-reaction during generation of a Grignard reagent from an alkyl halide and magnesium, then leading to formation of undesired side-products. 

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