Iron-catalyzed reactions alkylation

Recently, Fu and coworkers have shown that secondary alkyl halides do not react under palladium catalysis since the oxidative addition is too slow. They have demonstrated that this lack of reactivity is mainly due to steric effects. Under iron catalysis, the coupling reaction is clearly less sensitive to such steric influences since cyclic and acyclic secondary alkyl bromides were used successfully. Such a difference could be explained by the mechanism proposed by Cahiez and coworkers (Figure 2). Contrary to Pd°, which reacts with alkyl halides according to a concerted oxidative addition mechanism, the iron-catalyzed reaction could involve a two-step monoelectronic transfer. 

Furstner and Leitner " have recently described the synthesis of (f )-(-t-)-muscopyridine. This elegant strategy is based on two regioselective iron-catalyzed heteroaryl-alkyl coupling reactions (Scheme 65). 

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... 

E. Catalysis of Alkyl Disproportionation by Iron. Alkyl disproportionation is the sole reaction observed during the iron-catalyzed reaction of ethylmagnesium bromide and ethyl bromide.(47) The catalyst is a reduced iron species formed in situ by the reaction of iron(lI,III) with Grignard reagent, and ective... 

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. 

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...

The direct reductive amination (DRA) is a useful method for the synthesis of amino derivatives from carbonyl compounds, amines, and H2. Precious-metal (Ru [130-132], Rh [133-137], Ir [138-142], Pd [143]) catalyzed reactions are well known to date. The first Fe-catalyzed DRA reaction was reported by Bhanage and coworkers in 2008 (Scheme 42) [144]. Although the reaction conditions are not mild (high temperature, moderate H2 pressure), the hydrogenation of imines and/or enam-ines, which are generated by reaction of organic carbonyl compounds with amines, produces various substituted aryl and/or alkyl amines. A dihydrogen or dihydride iron complex was proposed as a reactive intermediate within the catalytic cycle. 

Phosphine ligands based on the ferrocene backbone are very efficient in many palladium-catalyzed reactions, e.g., cross-coupling reactions,248 Heck reaction,249 amination reaction,250 and enantioselective synthesis.251 A particularly interesting example of an unusual coordination mode of the l,l -bis(diphenylphosphino)ferrocene (dppf) ligand has been reported. Dicationic palladium(II) complexes, such as [(dppf)Pd(PPh3)]2+[BF4 ]2, were shown to contain a palladium-iron bond.252,253 Palladium-iron bonds occur also in monocationic methyl and acylpalladium(II) complexes.254 A palladium-iron interaction is favored by bulky alkyl substituents on phosphorus and a lower electron density at palladium. 

Recent notable improvements by Knochel and co-workers include iron-catalyzed cross-coupling reactions of various acid chlorides 148 with dialkylzinc reagents (Equation (24))324 as well as the iron-catalyzed arylation of aroyl cyanides 149 with Grignard reagents (Equation (25)).3 5 In the first case Knochel s reaction conditions tolerate ester groups on the organozinc compounds, while in the latter case ester, aryl alkyl ether, cyano, and chloro functionalities on the aromatic moieties are compatibles with the reaction conditions. 

In the course of a study on creation of a library of a great number of hetaryl ketones and related derivatives, Szewczyk et al. <2001AGE216> elaborated a ruthenium-catalyzed transformation of heterocycles with activated C-H bond by reaction with olefins and carbon monoxide. Thus, 253 gave 254, albeit in very poor yield. Synthetically, the more straightforward iron-catalyzed transformation was described by Fiirstner et al. <2002JA13856>. These authors reacted 255 with a Grignard reagent in the presence of Fe(acac)3 to afford the 7-alkyl-substituted derivative 256 in reasonable yield (acac = acetylacetonate). 

Although alkynes are highly reactive toward a wide range of transition metals, few instances of metal-catalyzed reactions of carbanions with alkynes are known. The most extensively developed system involves cationic iron complexes of internal alkynes. These complexes underwent alkylation by a range of carbanions to produce stable [Pg.582]

Although mechanistically different, a successful kinetic resolution of cyclic allyl ethers has recently been achieved by zirconium catalysis [2201. Other metals such as cobalt [221], ruthenium [222], and iron [2231 have been shown to catalyze allylic alkylation reactions via metal-allyl complexes. However, their catalytic systems have not been thoroughly investigated, and the corresponding asymmetric catalytic processes have not been forthcoming. Nevertheless, increasing interest in the use of alternative metals for asymmetric alkylation will undoubtedly promote further research in this area. 

An even more attractive version of Friedel-Crafts alkylations is the utilization of alkenes as electrophiles. These reactions profit on the one hand from the versatility and the availability of the starting materials and on the other from the high atom economy [57]. In this respect, in 2006 we presented a convenient iron-catalyzed protocol for the hydroarylation of styrenes (Scheme 6.14) [58]. 

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... 

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