Preparation of Tertiary Alcohols from Esters and Grignard Reagents

10 PREPARATION OF TERTIARY ALCOHOLS FROM ESTERS AND GRIGNARD REAGENTS 

Tertiary alcohols can be prepared by a variation of the Grignard synthesis that employs an ester as the carbonyl component. Methyl and ethyl esters are readily available and are the types most often used. Two moles of a Grignard reagent are required per mole of ester the first mole reacts with the ester, converting it to a ketone. 

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Preparation of Tertiary Alcohols from Esters and Grignard Reagents... 

The addition of Grignard reagents to aldehydes, ketones, and esters is the basis for the synthesis of a wide variety of alcohols, and several examples are given in Scheme 7.3. Primary alcohols can be made from formaldehyde (Entry 1) or, with addition of two carbons, from ethylene oxide (Entry 2). Secondary alcohols are obtained from aldehydes (Entries 3 to 6) or formate esters (Entry 7). Tertiary alcohols can be made from esters (Entries 8 and 9) or ketones (Entry 10). Lactones give diols (Entry 11). Aldehydes can be prepared from trialkyl orthoformate esters (Entries 12 and 13). Ketones can be made from nitriles (Entries 14 and 15), pyridine-2-thiol esters (Entry 16), N-methoxy-A-methyl carboxamides (Entries 17 and 18), or anhydrides (Entry 19). Carboxylic acids are available by reaction with C02 (Entries 20 to 22). Amines can be prepared from imines (Entry 23). Two-step procedures that involve formation and dehydration of alcohols provide routes to certain alkenes (Entries 24 and 25). 

Apart from the common heteroatom-derived nucleophiles described, cleavage with other nucleophiles is also possible. For example, reductive cleavage with hydride sources is possible. For ester-linked substrates, Kurth et al. reported an example in which substituted propane-1,3-diols were prepared (Table 1.2, Entry 11). In related work, Chandrasekhar et al. prepared tertiary alcohols by treating an ester-linked substrate with excess Grignard reagent (Table 1.2, Entry 12). If, however, it is desirable to prepare the carbonyl derivative (and not reduce all the way to the corresponding alcohol), then Weinreb-type linker units can be used (Table 1.2, Entries 13 and 14). Treatment of substrates attached via such linkers... 

Solution to 8a A tertiary alcohol prepared by the reaction of an ester with two equivalents of a Grignard reagent must have at least two identical substituents bonded to the carbon to which the OH is attached because two of the three substituents come from the Grignard reagent. Alcohols 3 and 5 do not have two identical substituents, so they cannot be prepared in this way. 

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