Grignard reagents, with acetals

Trimethylsilylacetone and related compounds have been prepared by the low-temperature reaction of trialkylsilylmethyl Grignard reagents with acetic anhydride at - 70° C, although the instability of the compounds has led to some difficulties in isolation at times (43, 63, 91-93). 

Aldehydes can be obtained by reaction of Grignard reagents with triethyl orthoformate. The addition step is preceded by elimination of one of the alkoxy groups to generate an electrophilic oxonium ion. The elimination is promoted by the magnesium ion acting as a Lewis acid.93 The acetals formed by the addition are stable to the reaction conditions, but are hydrolyzed to aldehydes by aqueous acid. 

Uncatalyzed addition reactions of Grignard reagents with nonconjugated alkenes and aUcynes are of limited use in synthesis. However, carbon-carbon double bonds substituted by a leaving group, such as an acetate, are susceptible to be displaced by organomagnesium compounds presumably by an addition-elimination pathway. A few examples have been reported (equation 64). 

Reaction of halides with oxide ion 0-68 Cleavage of oxonium salts 0-79 Reduction of acetals or ketals 0-92 Reaction between Grignard reagents and acetals or ketals dimerization of acetals... 

Metals other than palladium and molybdenum can be used for allylic substitution reactions. For example, nickel in the presence of the oxazolinylferrocenylphosphine 9 provides good asymmetric induction for the reaction of a Grignard reagent with allylic electrophilic systems such as acetates.151... 

Our first goal was to develop a scaleable route to the single enantiomer propargylic alcohol. The racemic alcohol was readily produced on a multi-kilogram scale by alkylation of the phenol with inexpensive bromoacetaldehyde diethyl acetal, hydrolysis to the aldehyde, and addition of the acetylenic Grignard reagent. With this material at hand we developed an efficient bioresolution process that esterified the alcohol in the presence of Chirazyme L9 (Scheme 30.7).26 At this point... 

Acetylenic ketones can be prepared in moderate yield by the reaction of acetylenic Grignard reagents with acid chlorides or anhydrides [Eq. (41) 75-78]. Alkynyl magnesium chloride reacts with acetic anhydride to give acetylenic ketones in good yield (see Table 4, entry 17). 

Chiral acetals can be used as auxiliaries in the diastereoselective reactions of Grignard reagents with acyclic as well as cyclic a-keto acetals. Nucleophilic addition to the monoprotected diketone (69 equation 18) occurs with excellent stereoselectivity to generate the corresponding tertiary alcohol (70) as the major product, usually with greater than 95 5 selectivity. Removal of the ketal yields a-hydroxy ketones of high optical purity. In most examples, enantiomeric excesses of 95% and higher are observed in the resultant keto alcohols. Table 17 represents the results of additions to cyclic and acyclic substrates. 

Coupling of Grignard reagents with allylic acetates (5, 226). This reaction has been extended to a l-acetoxy-2,4-diene for a synthesis of the sex pheromone of the codling moth (3)." ... 

Trisubstituted allenes. The reaction of aliphatic Grignard reagents with a 1,1-disubstituted propargylic acetate (1) in ether results in formation of a tri-alkylallene (2). Yields are satisfactory with Grignard reagents of primary halides, but less satisfactory when R - is an aryl group. ... 

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