Alkylations, 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...

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). 

B. Iron-catalyzed Arylation and Heteroarylation of Alkyl Grignard Reagents 610... 

D. Iron-catalyzed Alkylation of Aryl Grignard Reagents. 615... 

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... 

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... 

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

Table 1 Iron catalyzed alkylations of organometallic reagents 2 by alkyl halides 1...

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