Grignard nucleophilic addition

Two examples of the preparation of dihydropyridinones from pyridines via Grignard nucleophilic addition to acyl pyridinium salts <07TL8536 07BMC1106> were published in the literature this year. 

The carbon-nitrogen triple bond of nitriles is much less reactive toward nucleophilic addition than is the car bon-oxygen double bond of aldehydes and ketones. Strongly basic nucleophiles such as Grignard reagents, however, do react with nitriles in a reaction that is of synthetic value ... 

The irnine formed by nucleophilic addition of the Grignard reagent to the nitrile is normally not isolated but is hydrolyzed directly to a ketone. The overall sequence is used as a means of preparing ketones. 

Heterocyclic structures analogous to the intermediate complex result from azinium derivatives and amines, hydroxide or alkoxides, or Grignard reagents from quinazoline and orgahometallics, cyanide, bisulfite, etc. from various heterocycles with amide ion, metal hydrides,or lithium alkyls from A-acylazinium compounds and cyanide ion (Reissert compounds) many other examples are known. Factors favorable to nucleophilic addition rather than substitution reactions have been discussed by Albert, who has studied examples of easy covalent hydration of heterocycles. 

Formation of C—Nu The second mode of nucleophilic addition, which often occurs with amine nucleophiles, involves elimination of oxygen and formation of a C=Nu bond. For example, aldehydes and ketones react with primary amines, RNH2, to form imines, R2C=NR. These reactions proceed through exactly the same kind of tetrahedral intermediate as that formed during hydride reduction and Grignard reaction, but the initially formed alkoxide ion is not isolated. Instead, it is protonated and then loses water to form an imine, as shown in Figure 3. 

Nucleophilic Addition of Grignard and Hydride Reagents Alcohol Formation... 

We saw in Section 17.5 that treatment of an aldehyde or ketone with a Grignard reagent, RMgX, yields an alcohol by nucleophilic addition of a carbon anion, or carbanion. A carbon-magnesium bond is strongly polarized, so a Grignard reagent reacts for all practical purposes as R - +MgX. 

A Grignard reaction begins with an acid-base complexation of Vfg2+ to the carbonyl oxygen atom of the aldehyde or ketone, thereby making the carbonyl group a better electrophile. Nucleophilic addition of R then produces a tetrahedral magnesium alkoxide intermediate, and protonation by addition of water... 

Mechanism of the Grignard reaction. Nucleophilic addition of a carbanion to an aldehyde or ketone, followed by protonation of the alkoxide intermediate, yields an alcohol. 

In contrast to the extraordinarily high preference for endo attack observed with camphor (1), nucleophilic additions of organolithium and Grignard reagents to norcamphor (3) proceed with exclusive attack of the nucleophile from the exo face of the carbonyl group. 

The nucleophilic addition of Grignard reagents to a-epoxy ketones 44 proceeds with remarkably high diastereoselectivity70. The chelation-controlled reaction products are obtained in ratios >99 1 when tetrahydrofuran or tetrahydrofuran/hexamethylphosphoric triamide is used as reaction solvent. The increased diastereoselectivity in the presence of hexamethylphos-phoric triamide is unusual as it is known from addition reactions to a-alkoxy aldehydes that co-solvents with chelating ability compete with the substrate for the nucleophile counterion, thus reducing the proportion of the chelation-controlled reaction product (vide infra). 

The high diastereoselectivity which is found in the nucleophilic addition of Grignard reagents to chiral 2-0x0 acetals can be explained by a chelation-controlled mechanism. Thus, coordination of the magnesium metal with the carbonyl oxygen and the acetal moiety leads to a rigid structure 3A in the transition state with preferred attack of the nucleophile occurring from the S/-side. 

The diastereoselectivity of the nucleophilic addition to nitrone 2 may be rationalized by assuming that magnesium bromide preferentially coordinates with the nitrone oxygen. The Grignard reagent is therefore forced to interact with the acetal oxygen in position 3. 

Bromo-2-(t-butylsulfonyl)propene (79) reacts with nucleophiles such as lithium benzenethiolate, lithium enolates and Grignard reagents to give a, /(-unsaturated sulfones, which undergo nucleophilic addition of lithium cuprates (equation 68)58. 

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