Aryl Grignard reagents functionalized

In 2001, Cahiez, Knochel and coworkers reported an extension of this work to the coupling of functionalized aryhnagnesium compounds with alkenyl bromides or iodides (Scheme 20). It should be noted that with aryl Grignard reagents the use of NMP is not necessary. 

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). 

By means of an orfho-lithiation of suitably functionalized aromatics it is possible to obtain aryllithium compounds from halogen-free aromatics in a way and with a regioselectivity (Section 5.3.1) for which there is no analogy in the preparation of aryl Grignard reagents. 

In a parallel study, it was found that chelating chiral diamines 208 or 209 are well suited as ligands to promote Kumada-type couplings of primary and secondary alkyl halides 202 with aryl Grignard reagents 203 (entry 4) [281]. This reaction was applicable to alkyl bromides and alkyl iodides, while alkyl chlorides gave only low yields. Acetal and ester functions are tolerated. A notable feature is the stereoretentive arylation of fra s-a-bromo acetals with excellent diastereo-selectivity. The involvement of radicals is supported by the stereoconvergent formation of cxo-phenvI norbornane from both endo- or exo-bromonorbomane (cf. Part 1, Fig. 9) and radical 5-exo cyclizations (see below). 

NHCs are also efficient ligands for the palladium-catalyzed coupling of primary alkyl chlorides with aryl Grignard reagents [99]. Functionalization on both coupling partners is also tolerated in this case. This was due to the mild reaction conditions and fast reaction rates (1 hour of reaction at room temperature). 

The procedure has also been applied to halobenzoic acids.3 Thus p-bromo-benzoic acid (6) was converted into the corresponding 2-oxazoline (7) as usual, and then into the Grignard derivative (8). This is, in effect, an aryl Grignard reagent with a protected carboxyl function. Reaction with an electrophile, for example benzonitrile, gives (9). The final step is hydrolysis. If carried out in 5-7% ethanolic sulfuric acid, the ester (10b) is obtained if carried out in an aqueous medium, the free acid (10a) is obtained. 

In the presence of a Pd catalyst, CIPd[P(Cf,Hvinyl iodide couples with mctalatcd aromatics, particularly arylzinc chloride or arylboronic acids. Aryl Grignard reagents, however, couple in very low yield. The resulting C-aryl glucals can be converted to C-aryl glycosides by functionalization of the enol ether double bond.2... 

Relatively little is known of aryl Grignard reagents or aryllithium reagents, for example, produced from bromostyrene, but the former seems to have a tendency to polymerize during coupling [8]. On the other hand, the corresponding reagents prepared from vinylbenzyl chloride may in principle be used to couple a variety of functionalities to the styrene moiety. 

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