Preparing Alcohols via Grignard Reactions

We can convert this ketone into our product (the desired alcohol) using either LAH followed by water, or NaBH4 together with methanol  

PROBLEMS Identify the starting ketone or aldehyde you would use to prepare each of the following alcohols through reduction reactions  

In the previous section, we saw that ketones and aldehydes can be attacked by a suitable source of H . In a similar way, ketones and aldehydes can also be attacked by a suitable source of R . Compare these two reactions  

Both H and R can attack a ketone or aldehyde to give an alcohol. The main difference is the effect on the carbon skeleton. With H, the carbon skeleton does not change at all. But with R, the carbon skeleton gets larger. We are forming a C—C bond. We will soon see that this is very important for synthesis problems. For now, let s focus on how we can make R in the first place. After all, a negative charge on a carbon atom is not very stable (and therefore not trivial to make). 

There are many ways to get a negative charge on a carbon atom. Later in this course, you will spend a lot of time learning about special C compounds. For now, we will just learn about one such compound, called a Grignard reagent  

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This Grignard reagent cannot be formed, as it will simply attack itself to produce an alkoxide. In the next section, we will learn how to circumvent this problem. But first, let s get some practice preparing alcohols via Grignard reactions. 

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. 

Answer B being an olefin can be prepared by procedures f I-I and II-2. Since we have already decided that carbon atoms are going to be added via a Grignard reaction which will yield an alcohol as the product, let us use procedure ] 1-2, the dehydration or an alcohol, to prepare B. The structure of the alcohols which will yield B as the principle product arc labelled C ami D below. 

Answer A can be prepared via procedure 11-1 or 11-2. Keeping in mind Hint we have to add carbon atoms and that the Grignard reaction is an cxccitcn way to accomplish this, let us use procedure II-2, the dehydration of an alcohol, which would be the product of the aforementioned Grignard read ion. 

The silicon linker 1.17 (74), prepared by Grignard reaction of a 4-bromoarylsilane with commercial formyl PS resin, was used to support acids, alcohols, and amines either as such via its acyl imidazole derivative cleavage with TBAF (tert-butylam-monium fluoride) in DMF for 3 h at 60 °C, or with CsF in DMF for 18-24 h at 90 °C validated the release of the three different functionalities. 

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]. 

Nichols group (25) successfully applied an acid-catalyzed intramolecular aminoalkylation reaction between an amine and alcohol to form the azepino ring system, the characteristic structure of this indolic amino acid in the route, via a functional equivalent of 10-hydroxylated DMAT 15. This hypothetical biochemical precursor of the alkaloid, which was not prepared previously, was the key intermediate for their efficient synthesis to clavicipitic acid. Nichols group first prepared the requisite alcohol 12 by the Grignard reaction of N-tosylated indole-4-carboxaldehyde 11 with 2-methyl-1-propenylmagnesium... 

Another atypical Lepidopteran sex pheromone is the Z unsaturated ketone (580, Scheme 98) produced by the Douglas-fir tussock moth (Orgyia pseudotsugata). The acetylenic ketone (577), produced via a dithiane intermediate, was used by Smith et al. (255, 25(5) to prepare both the Z- and f-isomers (580 and 582, respectively) (Scheme 98). Kocienski and Cernigliaro (257) and Mori et al. (194) used an Eschen-moser cleavage of an alkyl substituted a,P-epoxy ketone to obtain straight chain acetylenic ketones that were transformed into (580) (Schemes 99 and 100, respectively). Acetylenic alcohol (578) has also been prepared by Grignard reactions (258, 259). 

The tertiary alcohol above can be prepared via a Grignard reaction between butyl Grignard (prepared from A) and ketone B. 

In order to use this approach, we must first convert the starting material into llie necessary aldehyde. This can be achieved via benzylic bromination, followed by substitution, followed by oxidation with PCC (as shown in the following figure). Once the aldehyde is prepared, the Grignard reaction can be performed. And finally, the product of the Grignard reaction (an alcohol) can be treated with concentrated sulfuric acid to give an elimination reaction, affording the desired product ... 

Oppolzer and Battig have prepared the marine sesquiterpene via ingenious application of iterative intramolecular magnesium-ene reactions . Aldehyde 672 was converted to the allylic chloride 673, the Grignard of which was heated at 60 °C for 23 hours and subsequently treated with acrolein to furnish alcohol 674 (Scheme LXX). An analogous sequence transformed 675 to 676 and set the stage for final transformations which were patterned after earlier work. 

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>. 

Answer A can be prepared via procedures 11 1 and JJ-2. Keeping in mind that since we must add carbon atoms during some stage or the synthesis and that tile Grignard reagent reaction will allow one to add carbons and yield an alcohol as tiic product, let us use procedure II-2. 

Answer Since A is a primary alcohol, it can be prepared by reaction of the Grignard agent B and formaldehyde via procedure V -4a. 

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