Preparation of Alcohols via Grignard Reagents

In this section, we wiU discuss formation of alcohols using Grignard reagents. A Grignard reagent is formed by the reaction between an alkyl hahde and magnesium. 

These reagents are named after the French chemist Victor Grignard, who demonstrated their utility in preparing alcohols. For his achievements, he was awarded the 1912 Nobel Prize in Chemistry. Below are a couple of specific examples of Grignard reagents. 

Grignard reagents are carbon nucleophiles capable of attacking a wide range of electrophiles, including the carbonyl group of ketones or aldehydes (Mechanism 13.4). 

MECHANISM 13.4 THE REACTION BETWEEN A GRIGNARD REAGENT AND A KETONE OR ALDEHYDE 

The product is an alcohol, and the mechanism is similar to the mechanism of reduction via hydride reagents (LAH or NaBH4). In fact, the reaction here is also a reduction, but it involves introduction of an R group. 

---

Preparation of Alcohols via Reduction Preparation of Diols Preparation of Alcohols via Grignard Reagents... 

An interesting appetite suppressant very distantly related to hexahydroamphetamines is somanta-dine (24). The reported synthesis starts with conversion of 1-adamantanecarboxylic acid (20) via the usual steps to the ester, reduction to the alcohol, transformation to the bromide (21), conversion of the latter to a Grignard reagent with magnesium metal, and transformation to tertiary alcohol 22 by reaction with acetone. Displacement to the fomiamide (23) and hydrolysis to the tertiary amine (24) completes the preparation of somantadine [6]. 

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. 

Brown and co-workers developed a novel homoallenyl boronate reagent 169 based on diisopropyl tartrate for the stereoselective homoallenylation of aldehydes 170. The reagent 169 was prepared via homologation of the corresponding allenyl boronate or the alkylation of halomethyl boronate with allenyl Grignard similar to those reported in Scheme 26. The allyl boronate 169 upon reaction with aldehydes furnished the dienyl alcohols 172 with high ee (Scheme 28) <1996JOC100>. 

Reduction of an alkyl halide, either via the Grignard reagent or directly with metal and acid, involves simply the replacement of a halogen atom by a hydrogen atom the carbon skeleton remains intact. This method has about the same applicability as the previous method, since, like alkenes, alkyl halides are generally prepared from alcohols. Where either method could be used, the hydrogenation of alkenes would probably be preferred because of its simplicity and higher yield. 

Relatively straightforward benzene analogue reactivity is found with thenyl halides, alcohols (conveniently preparable by reducing aldehydes) and amines, from, for example, reduction of oximes. One exception is that 2-thenyl Grignard reagents usually react to give 3-substituted derivatives, presumably via a non-aromatic intermediate. ... 

Phosphorinanones have been utilized as substrates for the preparation of alkenes/ amines,indoles, - and in the synthesis of a series of secondary and tertiary alcohols via reduction,and by reaction with Grignard and Refor-matsky - reagents. Phosphorinanones have also been used as precursors to a series of 1,4-disubstituted phosphor ins. The use of 4-amino-l,2,5,6-tetrahydro-l-phenylphosphorin-3-carbonitrile for the direct formation of phosphorino-[4,3-< ] pyrimidines has been reported. ... 

Knorr 1932, The application of Gilman and McGlumphy s method for the preparation of allylic Grignard reagents does not look very attractive for industrial use only two years after its publication, the first patent for the preparation of homoallylic alcohols via the one-step Barbier reaction was applied for [42]. 

---