Cross alkyl halides, iron-catalyzed

Our group has recently developed an alternative method for alkyl-(hetero)aryl- as well as aryl-heteroaryl cross coupling reactions catalyzed by iron salts.3 4 This methodology was inspired by early reports of Kochi et al.5>6 on iron-catalyzed cross coupling of vinyl halides and is distinguished by several notable advantages. 

Scheme 29 Iron-catalyzed cross coupling reaction of aryl Grignard reagents with alkyl halides...

Transition metal-catalyzed cross-coupling reactions between vinyl organometallic compounds and unactivated alkyl halides that can be usually performed with palladium, nickel and cobalt are of particular synthetic interest [37-39]. Recently, the groups of Cahiez [48] and Cossy [49] concurrently reported the first iron-catalyzed reaction of alkenyl Grignard compounds with primary and secondary alkyl halides (X=Br, I) (Scheme 5.15). The two protocols basically differ in the iron source... 

The most prominent reactions catalyzed by low-valent iron species involving radical intermediates are cross-coupling reactions of alkyl halides (recent reviews [32-35]) and atom transfer radical reactions. In cross-coupling reactions the oxidation state of the catalytically active species can vary significantly depending on the reaction conditions very often it is not known exactly. To facilitate a summary, all iron-catalyzed cross-coupling reactions are treated together and involved oxidation states, where known, are mentioned at the example. In contrast, iron-catalyzed Kharasch reactions will be treated at the oxidation state of the iron precursors. 

Iron-Catalyzed Cross-Coupling Reactions of Alkyl Halides with Organometallic Reagents... 

Fig. 1 Iron-catalyzed cross-coupling of alkyl halides with organometallic compounds...

Fig. 3 Catalytic manifolds in iron-catalyzed cross-coupling reactions of alkyl halides 1 with organometallic species 2...

Cross coii ing of Grignard reagents with 1-alkenyl halides, in marked contrast to alkyl halides, occurs readily with the reduced iron catalyst, as described above. The iron-catalyzed reaction of Grignard reagents with 1-alkenyl halides can, however, be differentiated from the reaction with alkyl halides. Thus, a mixture of propenyl bromide and ethyl bromide on reaction with methylmagnesium bromide afforded butene-2 but no cross-over products such as pentene-2 or propylene. The latter certainly would have resulted if a propenyliron species per se were involved in the catalytic process. Cross coupling under tEese circumstances clearly merits further study. 

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]. 

A wide range of ligands, including monodentate or bidentate phosphines, phosphites, arsines and NHCs, have been examined by Bedford in iron-catalyzed cross-couphngs between alkyl halides and aryl Grignard reagents. Notably, various of these Hgands exerted a beneficial effect on selectivity and chemical yield (Equation 5.31) [38]. 

It has been established that Fe(II) complexes such as 74 and 75 are active catalysts in iron-catalyzed cross-couplings of alkyl halides (Figure 1.3) [347, 348]. The couplings probably involve a Fe(I)-Fe(III) cycle, in which radical intermediates in the coupling step can be excluded, although they might be involved in the oxidative addition step [349, 350]. 

Figure 1.3 Active catalysis in iron-catalyzed cross-couplings of alkyl halides.

Scheme 4-231. Example of a cross-coupling reaction of alkyl halides with aryl Grignard reagents catalyzed by iron(III).

In addition to the cross-coupling reactions of alkyl halides or sulfonates with organometallic nucleophiles, the former can also directly undergo C-C bond formation with nonactivated C-H bonds of alkenes or arenes in a Heck-type reaction. Iron-catalyzed intramolecular dehydrohalogenation of 2-iodoethanal alkenyl acetals with phenyl-magnesium bromide in the presence of a catalytic amount of iron(II) chloride provides tetrahydrofliran derivatives in moderate yields (Scheme 4-240). Allyl 2-halophenyl ethers provide dihydrobenzofiiran derivatives under these conditions. ... 

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