Grignard reagents sterically hindered

For ketones and aldehydes in which adjacent substituents permit the possibility of chelation with a metal ion, the stereochemistry can often be interpreted in terms of the steric requirements of the chelated TS. In the case of a-alkoxyketones, for example, an assumption that both the alkoxy and carbonyl oxygens are coordinated with the metal ion and that addition occurs from the less hindered face of this chelate correctly predicts the stereochemistry of addition. The predicted product dominates by as much as 100 1 for several Grignard reagents.120 Further supporting the importance of chelation is the correlation between rate and stereoselectivity. Groups that facilitate chelation cause an increase in both rate and stereoselectivity.121 This indicates that chelation not only favors a specific TS geometry, but also lowers the reaction barrier by favoring metal ion complexation. 

The availability of oxepins that bear a side chain containing a Lewis basic oxygen atom (entry 2, Table 6.4) has further important implications in enantioselective synthesis. The derived alcohol, benzyl ether, or methoxyethoxymethyl (MEM) ethers, in which resident Lewis basic heteroatoms are less sterically hindered, readily undergo diastereoselective uncatalyzed alkylation reactions when treated with a variety of Grignard reagents [17]. The examples shown below (Scheme 6.7) demonstrate the excellent synthetic potential of these stereoselective alkylations. 

Treatment of phosphorus trichloride with an excess of the Grignard reagent (4) leads to the sterically hindered phosphine (5).4 A sample of 14C-labelled triethyl-phosphine has been synthesized from 14C-labelled ethylmagnesium iodide and phosphorus trichloride.5 The reaction of chlorodiphenylphosphine with the Grignard... 

The polarimetric method, in combination with the results of chemical correlation, made it possible to determine the optical purity of a range of chiral sulftnates (105-107), thiosulfinates (35,105), and sulfinamides (83) with the sulfur atom as a sole center of chirality. These compounds were converted by means of Grignard or alkyl-lithium reagents into sulfoxides of known specific rotations. This approach to the determination of optical purity of chiral sulfinyl compounds has at least two limitations. The first is that it cannot be applied to sterically hindered compounds [e.g., t-butyl /-butanethio-sulfinate 72 does not react with Grignard reagents]. Second, this... 

The second is that sterically hindered ketones bearing hydrogen atoms on their a-carbons, R2CH(CO)R (cf. 3b), tend to be converted to their enolates (6), where the Grignard reagent, R MgX, is lost as R —H in the process via 4b (Scheme 4). 

One of the simplest methods is the addition of Grignard reagent onto a sterically hindered enone . For example, the (Z)-magnesium enolate is formed from the reaction of benzalacetomesitylene and phenylmagnesium bromide (equation 31). 

The preparation of magnesium enolates by metallation competes with nucleophilic addition. Thus, until recently, this strategy was only valuable for sterically hindered or relatively acidic substrates, which were metallated by Grignard reagents or magnesium diaUtoxydes. 

No product was formed in this reaction in the absence of the soluble lanthanide salt or even in the presence of CeCL. Heteroaryl Grignard reagents react smoothly in the presence of LaCl3 2LiCl even with highly sterically hindered ketones like 211 (equation 137). 

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