Grignard reagents, addition reactions nitriles

Ni-Catalyzed Reactions The nickel-catalyzed cross-coupling of alkenyl Grignard reagents with aryl nitrile derivatives has been exploited by Miller and coworkers [4]. The conditions are similar to those described in Scheme 22.2. In general, alkenyl Grignards were /Zmixtures and therefore provided styrene derivatives as a mixture of E and Z isomers in modest to good yields (43-80%). Milder conditions were later developed in the Ni-catalyzed arylcyanation of alkynes, in which the insertion of alkynes into an aromatic C-CN bond took place (Scheme 22.12a) [5, 21a, b]. The intramolecular version of the reaction was likewise reported, and cyclization in a 5-exo-dig fashion occurred (Scheme 22.12b) [21c]. The addition of Lewis acids, such as AlMe Cl, AlMe, and... 

The carbon-nitrogen triple bond of nitriles is much less reactive toward nucleophilic addition than is the car bon-oxygen double bond of aldehydes and ketones. Strongly basic nucleophiles such as Grignard reagents, however, do react with nitriles in a reaction that is of synthetic value ... 

The conversion of a nitrile R —CN into a ketone R —CO—R demonstrates that polarized multiple bonds other than C=0 also react with Grignard reagents, and that such reactions are synthetically useful. Esters 22 and acid chlorides can react subsequently with two equivalents of RMgX the initially formed tetravalent product from the first addition reaction can decompose to a ketone that is still reactive, and reacts with a second RMgX. The final product 23 then contains two substituents R, coming from the Grignard reagent ... 

Reaction of Nitriles with Organometallic Reagents Grignard reagents add to a nitrile to give an intermediate imine anion that is hydrolyzed by addition of water to yield a ketone. 

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). 

The above system failed entirely when nonstabilized carbanions such as ketone or ester enolates or Grignard reagents were used as carbon nucleophiles, leading to reductive coupling of the anions rather than alkylation of the alkene. However, the fortuitous observation that the addition of HMPA to the reaction mixture prior to addition of the carbanion prevented this side reaction1 extended the range of useful carbanions substantially to include ketone and ester enolates, oxazoline anions, protected cyanohydrin anions, nitrile-stabilized anions3 and even phenyllithium (Scheme 3).s... 

A more reactive equivalent for ketone synthesis is a nitrile 28. Addition of a Grignard reagent gives an intermediate 29, stable under the reaction conditions, rather like 21. Hydrolysis in acid solution releases the ketone 2. The exactly analogous reagent to DMF would be a tertiary amide... 

Two of the methods for converting alkyl halides to carboxylic acids are covered in Sections 20-8B and 20-8C. One is formation of a Grignard reagent followed by addition of carbon dioxide and then dilute acid. The other is substitution by cyanide ion, followed by hydrolysis of the resulting nitrile. For each of the following conversions, decide whether either or both of these methods would work, and explain why. Show the reactions you would use. 

The addition of vinyl and aryl Grignard reagents to propargyl alcohols followed by reaction with a nitrile provides access to furans and butenolides in a one-pot procedure. These reactions are believed to involve a magnesium-chelate intermediate. Highly substituted furans can be prepared with control over the substitution pattern by the judicious choice of substrates and reagents (Scheme 26) <2000TL17>. 

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