Carboxylic acids with alkyl Grignard reagents

Titanocene dichloride catalyzes the reduction of alkyl, aryl, and vinyl bromides, aryl chlorides, alkoxy- and halosilanes ketones, esters, and carboxylic acids with alkyl Grignard reagents. This Cp2TiCl2/RMgX system can also be used for the hydromagnesation of alkynes, dienes, and alkenes (Section 3.2.5). Kambe et al. have reported a new type of titanocene-catalyzed transformation with vinyl Grignard reagents and chlorosilanes to furnish l,4-disilyl-2-butenes, as shown in Scheme 3.43 [31]. 

The reaction of tert-alkyl Grignard reagents with carboxylic acid chlorides in the presence of a copper catalyst provides ieri-alkyl ketones in substantially lower yields than those reported here.4,14 The simplicity and mildness of experimental conditions and isolation procedure, the diversity of substrate structural type, and the functional group selectivity of these mixed organocuprate reagents render them very useful for conversion of carboxylic acid chlorides to the corresponding secondary and tertiary alkyl ketones.15... 

The same disconnection 41 can be used for carboxylic acids with CO2 as the electrophile for a Grignard reagent 40. Dry ice (solid CO2) is particularly convenient for these reactions. Switching polarity by FGI to the nitrile 42, the same disconnection now uses cyanide ion as the nucleophile but the same alkyl halide 39 that was used to make the Grignard reagent. Mechanistic considerations should decide between these alternatives. 

The a.a-dimethyl derivative 23 was used in the formation of amides 30 with carboxylic acids and thus applied to the enantioselective a-alkylation of carbanions (Section D.1.1.1.3.1.). The amides are obtained either by Ar-acylation of 2-(l-hydroxy-l-methylethyl)pyrrolidine or by first acylating an ester of proline and subsequent treatment with a Grignard reagent which reacts selectively with the ester group, leaving the amide intact. 

Methods of synthesis for carboxylic acids include (1) oxidation of alkyl-benzenes, (2) oxidative cleavage of alkenes, (3) oxidation of primary alcohols or aldehydes, (4) hydrolysis of nitriles, and (5) reaction of Grignard reagents with CO2 (carboxylation). General reactions of carboxylic acids include (1) loss of the acidic proton, (2) nucleophilic acyl substitution at the carbonyl group, (3) substitution on the a carbon, and (4) reduction. 

In the Grignard reagent, the alkyl radical acts like a carbanion as shown by its reactions with C02 leading to the formation of carboxylic acids... 

Alkylation or acylation of ketones, sulfides, and amines. This reagent generally reacts with alcohols or carboxylic acids to form 2,2,2-trifluoroethyl ethers or esters in satisfactory yields, except in the case of alcohols prone to dehydration. The reaction of these ethers provides a simple synthesis of unsymmctrical sulfides (equation I). A similar reaction can be used for preparation of secondary amines or amides (equation II). Enolatc anions (generated from silyl cnol ethers with KF) can be alkylated or acylated with a or b (equation III). Use of Grignard reagents in this type of coupling results in mediocre yields. 

---