Grignard reagents, reactions copper-catalyzed

Acyclic allylic systems are sufficiently reactive that pivaloates can always be used without detectable carbonyl attack. With alkyl Grignard reagents, the CuCN-catalyzed reaction is highly regiospecific and gives either exclusively, or predominantly, the Sn2 products, whereas copper halides completely reversed the regioselectivity of the reaction in favor of the SN2-coupled product (see Table 10). 

The a,(3-unsaturated ester (8), aldehyde (9), and nitro (10) compounds participate as electrophiles in a number of useful conjugate addition reactions. Copper-catalyzed addition of Grignard reagents provides access to aryl butanoic acid derivatives substituted with an oxetane (equation 1 in scheme 13.7). The ester, aldehyde, and nitro electrophiles also undergo mild Rh-catalyzed additions of aryl and vinyl boronic acids (equation 2 through equation 4 in scheme 13.7). Interestingly, the unsaturated aldehyde participates readily in an amine conjugate addition to afford oxetane substituted 3-amino-acetaldehyde derivatives. 

Scheme 8.4. Copper-Catalyzed Reactions of Grignard Reagents...

In the 1952 paper mentioned above [3], Gilman reported on the formation of lithium dimethylcuprate from polymeric methylcopper and methyllithium. These so-called Gilman cuprates were later used for substitution reactions on both saturated [6] and unsaturated [7, 8, 9] substrates. The first example of a cuprate substitution on an allylic acetate (allylic ester) was reported in 1969 [8], while Schlosser reported the corresponding copper-catalyzed reaction between an allylic acetate and a Grignard reagent (Eq. 2) a few years later [10]. 

Kinetic experiments have been performed on a copper-catalyzed substitution reaction of an alkyl halide, and the reaction rate was found to be first order in the copper salt, the halide, and the Grignard reagent [121]. This was not the case for a silver-catalyzed substitution reaction with a primary bromide, in which the reaction was found to be zero order in Grignard reagents [122]. A radical mechanism might be operative in the case of the silver-catalyzed reaction, whereas a nucleophilic substitution mechanism is suggested in the copper-catalyzed reaction [122]. The same behavior was also observed in the stoichiometric conjugate addition (Sect. 10.2.1) [30]. 

Chiral butenolides are valuable synthons towards y-butyrolactone natural products [37] and have also been successfully applied to the synthesis of paraconic acids. The lactone 91, readily available from the hydroxyamide (rac)-90 by enzymatic resolution [38] followed by iodolactonization, proved to be an especially versatile key intermediate. Copper(I)-catalyzed cross coupling reactions with Grignard reagents allowed the direct introduction of alkyl side chains, as depicted in 92a and 92b (Scheme 13) [39, 40]. Further... 

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