Grignard reagents protect acidic groups

Alkyl-l,3-oxazolines are prepared to protect both the carbonyl and hydroxyl groups of an acid. They are stable to Grignard reagents and to lithium aluminum hydride (25°, 2 h). ... 

The heterocyclic derivative successfully protects the acid from attack by Grignard or hydride-transfer reagents. The carboxylic acid group can be regenerated by acidic hydrolysis or converted to an ester by acid-catalyzed reaction with the appropriate alcohol. 

The ketone 15 was eventually prepared by Grignard addition to Weinreb amide 21, as shown in Scheme 5.5. The Weinreb amide 21 was prepared from p-iodobenzoic acid (20). The phenol of readily available 3-hydroxybenzaldehyde (22) was first protected with a benzyl group, then the aldehyde was converted to chloride 24 via alcohol 23 under standard conditions. Preparation of the Grignard reagent 25 from chloride 24 was initially problematic. A large proportion of the homo-coupling side product 26 was observed in THF. The use of a 3 1 mixture of toluene THF as the reaction solvent suppressed this side reaction [7]. The iodoketone 15 was isolated as a crystalline solid and this sequence was scaled up to pilot plant scale to make around 50 kg of 15. 

With the alcohol protected, preparation of the Grignard reagent can proceed, and this can then react with the ketone carbonyl in a nucleophilic addition. The protecting group can then be removed by treatment with acid, to restore the hydroxyl function. This also involves a tertiary carbocation that is subsequently quenched with water. 

As mentioned already, the interest in 5,6-dihydro-4//-1,3-oxazines is considerably increased by their use in the synthesis of aldehydes, ketones, and carboxylic acids.2-4 They are also useful protecting groups for reactions involving Grignard reagents. 

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