Heteroarylation aryl Grignard reagents

C. Iron-catalyzed Heteroarylation of Aryl Grignard Reagents. 614... 

The coupling procedure requires only 0.6 equivalent of 1,2-dihalogenoethane as an oxidant and can be applied to various simple aryl and heteroaryl Grignard reagents. It should be noted that in the case of hindered and functionalized aryl Grignard reagents, a dramatic improvement was observed by using 1,2-dibromo- or 1,2-diiodoethane instead of 1,2-dichloroethane (Table 9). 

A few palladium-catalyzed Kumada cross-couplings of heteroaryl chlorides have been reported [101]. Knochel has recently determined that certain 2-chloropyridine derivatives react with functionalized aryl Grignard reagents under mild conditions (Equation 2.61) [102]. 

Well-defined homobimetallic catalysts such as 86 prepared from palladium(II) salts and air-stable HASPOs of type 48 can catalyze the coupling of aryl Grignard reagents and aryl, heteroaryl, or alkenyl tosylates [57] (Scheme 5.15). Likewise, palladium complexes of bulky, electron-rich ligands of the JosiPhos family such as 92 catalyze the coupHng of aromatic tosylates at room temperature with both aryl and alkenyl Grignard reagents [58] (Scheme 5.15). 

The Stille reaction of 2-chloro-3,6-diisopropylpyrazine (7) and 2-chloro-3,6-diisopropylpyrazine 4-oxide (9) with tetra(p-methoxyphenyl)stannane (readily prepared in situ from the corresponding Grignard reagent and SnCU) led to the corresponding arylation products 8 and 10, respectively [9]. Additional Stille coupling reactions of chloropyrazines and their N-oxides have been carried out with tetraphenyltin [10] and aryl-, heteroaryl-, allyl- and alkylstannanes [11]. 

Remarkably, halogen-magnesium exchange can also be extended to aryl and heteroaryl bromides [24, 25], Thus, the functionalized aryl bromides 28 and 29 (Scheme 2.7) were converted, at 0 °C and at —30 °C, respectively, into the corresponding Grignard reagents. After treatment with CuCN, the copper derivative 30 and 31 were obtained. Subsequent treatment with typical electrophiles such as benzoyl bromide or allyl bromide furnished the products 32 and 33, in 70 and 80% yields. 

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

In 2002, Figad re and coworkers reported the mono-reduction of 2-aryl (or heteroaryl)-1,1-dibromo-l-alkenes (Scheme 23). The reaction is achieved with one equivalent of isopropylmagnesium chloride in the presence of iron(III) acetylacetonate. Pure ( )-alkenyl bromides are obtained. With two equivalents of alkyl Grignard reagent, the mono-substituted product is obtained in moderate yield. 

TABLE 6. Cross-coupling between alkyl Grignard reagents and aryl or heteroaryl chlorides, triflates, and tosylates... 

TABLE 9. Homocoupling of aryl and heteroaryl Grignard reagents... 

Although aryl chlorides are not usually reactive enough to couple efficiently with alkyl-coppers, heteroaryl chlorides often couple quite well. For example, the most efficient way of alkylating chlorinated phenanthrolines and quinolines, and both 2- and 3-substitued pyridines involves the use of Grignard reagents and copper salts (equation 51)73. 

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