Organometallic reagents amination

Nitriles are similar in some respects to carboxylic acids and are prepared either by SN2 reaction of an alkyl halide with cyanide ion or by dehydration of an amide. Nitriles undergo nucleophilic addition to the polar C=N bond in the same way that carbonyl compounds do. The most important reactions of nitriles are their hydrolysis to carboxylic acids, reduction to primary amines, and reaction with organometallic reagents to yield ketones. 

The most common reactions of carboxylic acid derivatives are substitution by water (hydrolysis) to yield an acid, by an alcohol (alcoholysis) to yield an ester, by an amine (aminolysis) to yield an amide, by hydride ion to yield an alcohol (reduction), and by an organometallic reagent to yield an alcohol (Grignard reaction). 

In the case of the amide 11 (R = CI13) derived from 2-oxopropanoic amid and amine G the chelation-controlled product is predominantly formed with all organometallic reagents. No reversal of the stereochemistry is observed, presumably for the same steric reason as with the corresponding pyruvic amides derived from amines E and F. 

The addition of organometallic reagents to the C —N double bond of imines 1 provides an attractive route to amines 21 2. However, due to the poor electrophilici ty of imines, this method is often plagued by competitive reactions ... 

Addition of Grignard and organolithium reagents to imines 2. derived from enantiomerically pure (S)-valinol (1), provides a-substituted phenethylamines 3 in moderate to good yield and excellent diastereoselectivity (in each case only one diastereomer can be detected by NMR)15. By appropriate selection of imine and organometallic reagent both diastereomeric amines are accessible (see also refs 16 and 17). 

The synthesis of alkoxy amines 2 by addition of organometallic reagents to the C-N double bond of oxime ethers 1 is plagued by the propensity for proton abstraction a. to the C-N double bond, the lability of the N-O bond and the poor electrophilicity of the oxime ethers. Therefore, frequently no products, undesired products or complex mixtures are obtained. The result depends on the substrate, organometallic reagent, solvent, temperature and additives1 6. 

Aziridines have been opened by organometallic reagents to give amines. Although less reactive than epoxides, it is also possible to open aziridines with organometallic reagents. Isopropylmagnesium chloride reacts with A-tosyl 2-... 

Amines are nucleophilic and easily oxidized. Primary and secondary amino groups are also sufficiently acidic that they are deprotonated by many organometallic reagents. If these types of reactivity are problematic, the amino group must be protected. The... 

Organocerium reagents also show excellent reactivity toward nitriles and imines,205 and organocerium compounds were found to be the preferred organometallic reagent for addition to hydrazones in an enantioselective synthesis of amines.206... 

The ring strain inherent in species XV increases its propensity for polymerization. A substantial number of organo-halogenocyclophosphazenes have now been polymerized (7-17). After polymerization, the halogen atoms can be replaced by treatment with alkoxides, aryloxides, primary or secondary amines, or organometallic reagents. 

The action of chloroamine and bromoamine on organometallic reagents has been reviewed102 and a comprehensive review of electrophilic aminations of carbanions has appeared103. Alkyl, alkenyl and aryllithium compounds are converted into tertiary amines 84 by reaction with the mesityl compounds 83 (R2 = Me or Et Ar = 2,4, 6-MesCeHj)104. 

The present procedure provides a facile and versatile synthesis, on large scale, of a variety of pyrrole-2-carboxylic acid derivatives without necessitating the use of moisture-sensitive organometallic reagents. The use of alcohols other than ethanol in the alcoholysis reaction provides virtually any desired ester. Ammonia or aliphatic amines readily give amides in high yields, and aqueous base can be used to give the free acid. 

Alternative synthetic approaches include enantioselective addition of the organometallic reagent to quinoline in the first step of the synthesis [16], the resolution of the racemic amines resulting from simple protonation of anions 1 (Scheme 2.1.5.1, Method C) by diastereomeric salts formation [17] or by enzymatic kinetic resolution [18], and the iridium-catalyzed enantioselective hydrogenation of 2-substituted quinolines [19]. All these methodologies would avoid the need for diastereomer separation later on, and give direct access to enantio-enriched QUINAPHOS derivatives bearing achiral or tropoisomeric diols. Current work in our laboratories is directed to the evaluation of these methods. 

Although the diastereoselective addition of nucleophiles to imines offers an attractive route to chiral amine derivatives, most chiral nonracemic imines suffer from low reactivity (electrophilicity), resulting in no reaction or competitive reduction with organometallic reagents. Other problems include enolization of aliphatic imines, poor... 

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