Nitrile-stabilized anions addition reactions

Nitrile-stabilized anions, generated for example by lithiation of benzyl cyanide and propionitrile, have been added diastereoselectively to aromatic aldimines.50 Acid workup gives /5-cyano amines. Alternatively, addition of RX gives /3-R-substituted-/3-cyanoamines. The factors determining des in both reaction versions have been investigated. 

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... 

One potential problem in the reactions of stabilized allylic or propargylic carb-anions is the dimerization of the starting material if the carbanions are not formed stoichiometrically. Alkenes substituted with electron-withdrawing groups are good Michael acceptors, to which nucleophiles will undergo conjugate addition. For instance, the Baylis-Hillman reaction of allyl cyanide with benzaldehyde requires careful optimization of the reaction conditions to avoid dimerization of the nitrile (Scheme 5.12). This problem is related to a common side reaction of Michael additions reaction of the product with the Michael acceptor (Scheme 10.21). 

The term Michael addition has been used to describe 1,4- (conjugate) additions of a variety of nucleophiles including organometallics, heteroatom nucleophiles such as sulfides and amines, enolates, and allylic organometals to so-called Michael acceptors such as a,p-unsaturated aldehydes, ketones, esters, nitriles, sulfoxides, and nitro compounds. Here, the term is restricted to the classical Michael reaction, which employs resonance-stabilized anions such as enolates and azaenolates, but a few examples of enamines are also included because of the close mechanistic similarities. 

Reversibility, even at low temperatures, has been shown to be fast for stabilized carbanions (e.g., nitrile stabilized carbanions, ester enolates) whereas (most) sulfur stabilized carbanions and simple organo lithium compounds add irreversibly. Nevertheless protonation is more rapid than anion dissociation even for the first category of anions mentioned and nucleophile addition/proto-nation reactions allows efficient conversion to a dearomatized product. 

Reaction of the anionic cyclohexadienyl CrfCOlj, obtained by addition of a nitrile stabilized carbanion to [CrfbenzeneffCOlj], with Mel, regenerates the starting complex. However, treatment of the same intermediate with a strong acid at low temperature affords a mixture of isomeric cyclohexadienes. With time, the reaction tends to converge to the most stable diene (Scheme 2) [ 15-18]. It has also been reported that protonation under a CO atmosphere allows recycling of Cr(CO)g [19]. 

Reaction of the stabilized anions derived from )3-dicarbonyl compounds and related analogs (Table 23-1) with a,)3-unsaturated carbonyl compounds leads to 1,4-additions. This transformation, an example of Michael addition (Section 18-11), is base catalyzed and works with a,j8-unsaturated ketones, aldehydes, nitriles, and carboxylic acid derivatives, all of which are termed Michael acceptors. 

Because of resonance stabilization of the anion, a tet-nazolyl moiety is often employed successfully as a bioisosteric replacement for a carboxy group. An example in this subclass is provided by azosemide (27). Benzonitrile analogue is prepared by phosphorus oxychloride dehydration of the corresponding benzamide. Next, a nucleophilic aromatic displacement reaction of the fluorine atom leads to The synthesis concludes with the 1,3-dipolar addition of azide to the nitrile liinction to produce the diuretic azosemi de (27). ... 

Reduction Conversion of Nitriles into Amines Reduction of a nitrile with LiAIH4 gives a primary amine, RNH . The reaction occurs by nucleophilic addition of hydride ion to the polar C=N bond, yielding an imine anion, which still contains a C=N bond and therefore undergoes a second nucleophilic addition of hydride to give a dianion. Both monoanion and dianion intermediates are undoubtedly stabilized by Lewis acid-base complexafion to an aluminum species, facilitating the second addition that would otherwise be difficult Protonation of the dianion by addition of water in a subsequent step gives the amine. 

The formation of amide chlorides from nitriles and hydrogen halides under anhydrous conditions is a well-known reaction of wide scope7- There has been some confusion on the nature of the reaction products, but it has turned out that the isolable species are amide chlorides. The thermal stability of the addition products strongly depends on the acidity of the hydrogen halide used. Iodides are more stable than bromides, which in turn are more stable than the chlorides. As a consequence, thermally stable HQ adducts (38 equation 22) can be prepared if Lewis acids ate present, which incorporate the chlorine anion to give a less basic anion (39). 

Side reactions can occur in formation of hydrazone anions and limit the thermal stability of these anions. Most commonly these side reactions involve addition at the carbonyl carbon or elimination of a dialkylamide anion and nitrile formation. Normant has described both problems and has suggested that nitrile formation also occurs slowly in cases where HMPA has been added to azaallyllithium reagents derived from /V,N-dimethylhydrazones. These problems are exacerbated in the case of aldehyde hydrazones when there is branching at the carbon a or p to the carbonyl carbon. 

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