Alkyl iodides cross-coupling with Grignard reagents

The introduction of a polyfluorinated chain is not so easy as that of an alkyl chain. Transition metal catalyzed cross-coupling of Grignard reagents and organozinc compounds are inefficient in the synthesis of polyfluorinated 3-alkylthiophene. The copper-catalyzed perfluoroalkylation results in the formation of 2-and 3-substituted thiophenes, which are difficult to separate from each other. The reaction of fluorinated alkylmagnesium iodide with 3-formylthiophene, follwed by reduction with lithium aluminum hydride, gave (22) in an overall yield of 40% [27]. 

While alkynyllithiums react with primary alkyl halides in the presence of diamines or HMPA to afford the coupled products [35], this reaction proceeds slowly in the absence of these additives, even at elevated temperature. Luh has described a Pd/PPh3 catalyst that facilitates the cross-coupling of alkynyllithiums and alkynyl Grignard reagents with primary alkyl bromides and iodides (e.g.,Eq.l5) [37]. 

In sharp contrast to the palladium- and nickel-catalyzed cross-couplings described above, iron catalysts show a high catalytic activity towards secondary alkyl halides, as reported by Nakamura and coworkers. Thus, cyclohexyl chloride, bromide or iodide can be arylated by a phenyl Grignard reagent in almost quantitative yield in the presence of FeCh as catalyst, along with an excess amount of a diamine additive N,N,N, N -tetramethylethylenediamine (TMEDA). Primary alkyl halides, such as octyl chloride, bromide and iodide, can also be arylated by the action of the same iron catalyst. However, the yields are somehow decreased, especially when primary alkyl chlorides are used as electrophiles (Equations 5.24 and 5.25) [33]. 

Cuprous chloride coordinated with A,A,A, A -tetramethylethylenediamine is a good catalyst for the cross-coupling of aryl Grignard reagents and alkyl iodides (Onuma and Hashimoto, 1972). 

Primary, secondary, and tertiary Grignard reagents react with primary alkyl bromides, iodides, and tosylates in a CuCl-catalysed cross-coupling 5 2 reaction. Yields range from 73 to 94%. The reaction tolerates a wide variety of substituents on the alkyl halide and alkyl or aryl groups can be used in the Grignard reagent. 

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