Copper catalyzed Grignard reaction

In copper-catalyzed Grignard reactions of allylic carboxylates, high y regioselectivity is observed when copper(I) cyanide is used as catalyst16. 

One of these products (49) was used as a key intermediate for the synthesis of the Amaryllidaceae alkaloids a- and /-lycorane (Scheme 12)53. A copper-catalyzed Grignard reaction with 49 afforded 50 via a selective y-anti displacement of the chloride. Hydrogenation followed by Bischler-Napieralski cyclization gave 51. Interestingly, reversal of the latter two steps gave the isomer 52 where an epimerization at the benzylic carbon had occurred in the cyclization step (>99% selectivity). Subsequent reduction of the amide in each case afforded the target molecules a- and y-lycorane, respectively. The purity of the final product was very high with respect to the opposite stereoisomer. Thus <0.2% of /-lycorane was present in a-lycorane and vice versa. 

A synthesis of 4-alkyl-3-pyridinols (55) from 3-benzyloxypyridine (52) utilizes a copper-catalyzed Grignard reaction. The dihydropyridine intermediates 53 are aromatized to 4-alkyl-3-benzyloxypyridines (54), which on hydrogenolysis provide the pyridinols 55 (85JHC1419). Substitution at the 4-position of 3-pyridinecarboxaldehydes can be achieved via 1-acylpyri-dinium salt 56. The intermediate acetal 57 is hydrolyzed to give pyridine-carboxaldehyde 58 (84H339). 

Conjugate addition to an a,3-unsaturated carbonyl compound is achieved routinely by using a lithium organocopper reagent or a copper-catalyzed Grignard reaction. " It should be noted that in many of these examples, and in particular in the case of lithium diorganocuprates, the resultant enolate has... 

Etiolates formed by organocopper conjugate addition may be acylated cleanly by acid chlorides to give 3-diketones. Although 0- and C-acylation are both possible, the latter is favored by the use of acid chlorides rather than anhydrides and by the use of diethyl ether as solvent, rather than DME. Good yields of 3-diketones have been obtained by acylation of the anions derived from both acyclic and cyclic unsaturated ketones with cuprates, or in copper-catalyzed Grignard reactions. Some synthetic applications are given in Scheme 54. 

PS-TsCI was also used in an exploration of a solid-phase synthesis of a vitamin D hbrary (eq 10). The resin was shown to be compatible with oxidation reactions using either the Dess-Martin reagent or PDC. Simultaneous alkylation and cleavage of the sulfonate linker by a copper-catalyzed Grignard reaction proceeded in 52% isolated yield (eq 10). The PS-TsCI resin proved too sterically congested for the hbrary synthesis however, a sulfonate linker strategy was eventually pursued with a different solid support. ... 

Opening of this epoxide in a copper-catalyzed Grignard reaction led to this cis-diol 366, which was easily characterized and purified by an acetonide. 

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]. 

Organometallic Reagents. The major product of the Dilithium Tetrachlorocuprate(II)- or Copper(I) /odide-catalyzed Grignard reaction in THF or ether at low temperature arises from epoxide opening rather than from direct tosylate displacement (Table... 

Althou little studied, asymmetric copper-catalyzed substitution reactions of dialkylzinc [236] and Grignard reagents [237] vrith allylic substrates have been achieved vrith ferrocenylamidocopper and arenethiolatocopper catalysts, respec-tivdy. Good enantiosdectivity can be achieved vrith the zinc compounds (87% ee), but the method is limited to stericaUy hindered dialkylzinc reagents v/hile Grignard methodology gives only modest selectivities (18-50% ee). 

The mechanisms of most of these reactions are not well known. The 1,4 uncatalyzed Grignard reaction has been postulated to proceed by the cyclic mechanism shown, but there is evidence against it. The R2CuLi and copper-catalyzed Grignard additions may involve a number of mechanisms, since the actual attacking species and substrates are so diverse. A free-radical mechanism of some type... 

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