Grignard reagents benzylic carbon atoms

The reactions of Grignard reagents with acyclic sugar derivatives have also been investigated as potential routes for the synthesis of compounds containing asymmetric, benzylic carbon atoms.22 W. A. 

Unfortunately this route gives only a 40% yield IJ. Amer. Cham. Soc 1951, 73, 3237) in the Grignard reaction, largely because benzyl Grignard reagents easily give radicals which polymerise. In any case, it s poor tactics to chop off carbon atoms one at a time, and a better disconnection would be ... 

The sole method of synthesis that has been developed thus far involves the formation of a diGrignard or dilithio reagent from o,o -dibromobi-benzyl. The dibromo derivative is prepared by the coupling of o-bromobenzylbromide with phenyllithium (215). An alternative route that would utilize ring closure at the bridging carbon atoms (i.e., a site remote from the heteroatom) has not yet been explored. The dibenzazepin and dibenzoxepin derivatives have been prepared by this approach 35). The Grignard reactions are summarized in Eq. (97). 

Two reports have described the use of nickel-phosphine complexes as catalysts in the cross-coupling of Grignard reagents with aryl and vinyl halides. The reaction of benzal and other benzylic halides with lithium di-alkylcopper reagents has been explored as a potential route to quaternary carbon atoms preliminary results are not promising. ... 

One carbon atom in the form of a carboxyl group must be added to the side chain of the aromatic compound. We cannot use a Grignard reaction followed by carbonation because the acidic phenolic hydroxyl group would destroy the Grignard reagent (unless we protect it first). However, benzyl bromide is a primary haloalkane that readily reacts with cyanide ion in an Sj,j2 reaction to give a nitrile. Hydrolysis of the nitrile under acidic conditions gives the desired carboxylic acid. 

Now let s draw the forward scheme. Benzene is converted into isopropyl benzene upon treatment with 2-chloropropane and a Lewis acid (via a Friedel-Crafts alkylation). Benzylic bromination replaces the benzylic hydrogen atom with a bromine atom. Conversion to a Grignard reagent, followed by reaction with carbon dioxide and subsequent acidification, gives the desired carboxylic acid. 

---