Grignard reactions, copper catalysis

The related 6-trifluoromethyl-l,3-dioxin-4-ones underwent conjugate addition reactions with Gilman reagents, or with Grignards with copper(I) catalysis (Eq. 112). The 6-substituted compounds were also available, and were used to synthesise threonine and aZZo-threonine analogues [303]. Stark contrast between the behaviour of fluorinated and non-fluorinated compounds is revealed in Eq. (113). While benzylmagnesium chloride adds smoothly to the 6-methyl... 

Palladium-catalyzed allylation reactions proceed with net retention of configuration that is the result of two inversions.118-120 132-135 Grignard reactions with nickel or copper catalysis proceed with net inversion.128 136-138... 

Other authors have also described copper catalysis in the Grignard reaction. In the presence of copper salt, cyclohexene oxide reacts with phenylmagnesium chloride under mild conditions to give tra s-2-phenylcyclohexanol in good yield in the absence of the catalyst, the conversion is low. At the same time, benzylmagnesium chloride led to a yield of 90% even without the catalyst. The reactions between epoxynitriles and Grignard reagents have likewise been studied in detail. ... 

Fujisawa [63] reported the nucleophilic ring-opening reaction of five- and six-membered lactones with Grignard reagents by a copper catalysis [Eq. (50) and Table 12]. 

Although 1,2-addition of Grignard reagent to N-alkyl-N-silylformamide aflforded the same type of product, imines, in the presence or absence of a copper salt, N-phenyl-N-silylformamide afforded a doubly alkylated amine in the reaction of Grignard reagent under copper catalysis [Eq. (73) 152]. 

By derivatizing an a,p-unsaturated acid into the mono ester of chiral 1,1 -bi-8,8 -naphthol the reaction with lithium dialkylcuprates leads to saturated ketones containing chirality centers at the p-carbon atoms." Consecutive 1,4-addition and 1,2-addition account for this result. The alkyl transfer to enones from Grignard reagents under copper catalysis is subject to chiral modification, e.g., by the introduction of 56" or 57." ... 

Conventionally, organometallic chemistry and transition-metal catalysis are carried out under an inert gas atmosphere and the exclusion of moisture has been essential. In contrast, the catalytic actions of transition metals under ambient conditions of air and water have played a key role in various enzymatic reactions, which is in sharp contrast to most transition-metal-catalyzed reactions commonly used in the laboratory. Quasi-nature catalysis has now been developed using late transition metals in air and water, for instance copper-, palladium- and rhodium-catalyzed C-C bond formation, and ruthenium-catalyzed olefin isomerization, metathesis and C-H activation. Even a Grignard-type reaction could be realized in water using a bimetallic ruthenium-indium catalytic system [67]. 

Electrophiles also react at C-5 of 1,3-dioxin-4-ones. Two ways of activation have been reported (1) magnesiation of 5-iodo-l,3-dioxin-4-ones afforded the Grignard reagents which can be cross-coupled with allyl halides in the presence of copper cyanide <2001TL6847> or with iodoalkenes under Pd(0) catalysis <2002T4787> and (2) Sc(OTf)3-catalyzed reaction of a side-chain-hydroxylated l,3-dioxin-4-one with aldehydes provided the bicyclic dioxinone in 60-85% yield (Scheme 27) <20050L1113>. 

The vinyl Grignard reagent was used with Cu(I) catalysis and the reduction of both ester and ketone was achieved with UAIH4. The stereoselectivity was excellent and 75 could easily be separated from the minor equatorial alcohol. In the next chapter we shall revisit both the use of copper in getting regioselectivity and the stereoselectivity of such reactions. 

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