Grignard reagents with carboxylic esters

Reduction of carboxylic acids to aldehydes Replacement of the Rosenmund reaction (conversion of carboxylic acids to acid chlorides followed by catalytic hydrogenation) or the reaction of Grignard reagents with formic esters by molecular hydrogen and heterogeneous catalysts (Ru3Sn7 alloy). 

The methyl ester has also been obtained by esterification of cyclopentanecarboxylic acid.8 The acid, in turn, has been prepared by the Favorskii rearrangement,6 7 9-11 by the reaction of cyclopentyl Grignard reagent with carbon dioxide,12 by the carbonylation of cyclopentyl alcohol with nickel carbonyl13 or with formic acid in the presence of sulfuric acid,14 and by the hydrogenation of cyclopentene-1-carboxylic acid prepared from ethyl cyclopentanone-2-carboxylate 15 or from cyclopentanone cyanohydrin.16... 

The reactions of Grignard reagents with aldehydes and ketones give alcohols, reaction with acid chlorides and esters give tertiary alcohols, reaction with carbon dioxide to give carboxylic acids, reaction with nitriles give ketones, and reaction with epoxides give alcohols. 

Reactions of either Grignard or organolithium reagents with most aldehydes, ketones, or esters produce alcohols. Reactions of organolithium reagents with carboxylic acids, or of Grignard reagents with nitriles, produce ketones. 

The procedure has also been applied to halobenzoic acids.3 Thus p-bromo-benzoic acid (6) was converted into the corresponding 2-oxazoline (7) as usual, and then into the Grignard derivative (8). This is, in effect, an aryl Grignard reagent with a protected carboxyl function. Reaction with an electrophile, for example benzonitrile, gives (9). The final step is hydrolysis. If carried out in 5-7% ethanolic sulfuric acid, the ester (10b) is obtained if carried out in an aqueous medium, the free acid (10a) is obtained. 

Pyrazinyl ketones have been prepared by treatment of pyrazinecarboxylic esters with an organo-metallic (alkyllithium or Grignard) reagent <84MI 603-01 >. Homolytic acylation of pyrazines and quinoxalines with a-keto acids is an important method for preparation of the acyl compounds (Section 6.03.5.6.1), but the procedure for monosubstitution needs care because the electron-withdrawing effect of the first-formed monoacyl compounds facilitates further substitution. An additional synthesis of pyrazinyl ketones is the lithiation of halogenopyrazines followed by treatment with carboxylic esters or carboxamides (Equation (8) and Scheme 24). Reaction of 2-chloropyrazine... 

The reactions of Grignard reagents with different types of carbonyl groups yield a number of important functional groups. For example, reaction with formaldehyde yields 1° alcohols with higher aldehydes, 2° alcohols with ketones, 3° alcohols with esters, 3° alcohols with acyl halides, ketones with N,N-dialkylformamides, aldehydes and with carbon dioxide, carboxylic acids. 

For the preparation of prostacyclin derivative ([3- " C]nonyl)SM-10902 1821. halo-decarboxylation of (35)-3-methylheptanoic acid 1781 gave key intermediate 79. Grignard reagent preparation, carboxylation with " COj, esterification and subsequent reaction of the resulting ethyl ester with lithiated dimethyl methylphosphonate afforded ketophos-phonate SI in 70% overall radiochemical yield. Homer—Wadsworth—Emmons reaction with the corresponding aldehyde derivative and reduction of the resulting a,/3-unsaturated ketone converted 81 into 82". ... 

We ve seen how Grignard reagents add to the carbonyl group of aldehydes ketones and esters Grignard reagents react m much the same way with carbon dioxide to yield mag nesium salts of carboxylic acids Acidification converts these magnesium salts to the desired carboxylic acids... 

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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