Nucleophilic additions Grignard reagents

Methiodide derivatives of 2-alkyl-l-benzyl-2-imidazolines are central to a synthetic route to a-branched ketones (Scheme 3). The addition to the imi-dazolinium salt is sensitive to the nature of the nucleophile, only Grignard reagents prepared from primary alkyl halides giving useful yields. Attempts to reduce the salts, to afford a method for synthesis of aldehydes, virere not successful. 

This Michael-type addition is catalyzed by lanthanum(3+) [16096-89-2] (80). Ethylene glycol [107-21-1] reacts with maleate under similar conditions (81). A wide range of nucleophilic reagents add to the maleate and fumarate frameworks including alcohols, ammonia, amines, sulfinic acids, thioureas, Grignard reagents, Michael reagents, and alkali cyanides (25). 

The reaction involves nucleophilic substitution of for OR and addition of R MgX to the carbonyl group. With 1,4-dimagnesium compounds, esters are converted to cyclopentanols (40). Lactones react with Grignard reagents and give diols as products. 

Addition of Grignard reagents and organolithium compounds to the pyridazine ring proceeds as a nucleophilic attack at one of the electron-deficient positions to give initially... 

Additions of other nucleophiles to pyridopyrazines have been described in a number of cases for instance, Grignard reagents give 2,3-dialkyl compounds (398) (or 6-alkyl analogues with 2,3-diaryl compounds) (76BSF251), and other workers have also observed 6-addition <71CR(C)(273)1529). 

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. 

Grignard reagents do react with epoxides 24 by an SN2-mechanism, resulting in a ring-opening reaction. An epoxide carbon bearing no additional substituent—i.e. a methylene group—is more reactive towards nucleophilic attack than a substituted one ... 

As with the reduction of carbonyl compounds discussed in the previous section, we ll defer a detailed treatment of the mechanism of Grignard reactions until Chapter 19. For the moment, it s sufficient to note that Grignard reagents act as nucleophilic carbon anions, or carbanions ( R ), and that the addition of a Grignard reagent to a carbonyl compound is analogous to the addition of hydride ion. The intermediate is an alkoxide ion, which is protonated by addition of F O"1 in a second step. 

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. 

Acid halides are among the most reactive of carboxylic acid derivatives and can be converted into many other kinds of compounds by nucleophilic acyl substitution mechanisms. The halogen can be replaced by -OH to yield an acid, by —OCOR to yield an anhydride, by -OR to yield an ester, or by -NH2 to yield an amide. In addition, the reduction of an acid halide yields a primary alcohol, and reaction with a Grignard reagent yields a tertiary alcohol. Although the reactions we ll be discussing in this section are illustrated only for acid chlorides, similar processes take place with other acid halides. 

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