Nitrile imines generation mechanisms

Of the general methods for the generation of transient nitrile imines for use in synthesis (19), perhaps the most convenient are the base-induced dehydrochlorination of hydrazonyl chlorides and the oxidation of hydrazones. Developments in both of these areas have either increased the convenience of the method or given a deeper insight into the reaction mechanism. 

The mechanism of the Strecker reaction has received considerable attention over its lifespan.4 The conversion of a carbonyl compound into an a-amino acid, by this method, requires a two-step process. The first step consists of the three-component condensation of cyanide and ammonia with the carbonyl compound 1 to produce an intermediate, a-aminonitrile 3. The second step involves the hydrolysis of the nitrile functional group to reveal the latent carboxylic acid 4. Whereas the second step is fairly straightforward and can be done under basic or acid conditions, the first step is more involved than one may expect. The widely accepted sequence for the first step is the nucleophilic addition of ammonia to the carbonyl carbon to produce the corresponding imine derivative 2. Once formed, this initial species is captured by the cyanide anion to generate the requisite a-aminonitrile 3. 

A few miscellaneous oxidations using oxoammonium salts generated from TEMPO or substituted TEMPO analogs have been reported in the literature. These include the electrochemical oxidation of thiols to disulfides by a TEMPO-modified felt electrode [66], the electrochemical oxidation of amines to imines or nitriles [67], the cleavage of benzyl ethers by a single electron transfer mechanism with an oxoammonium bromide salt [68], and the dibromination of propargyl acetates by catalytic oxoammonium tribromide generated from a nitroxide and bromine [69]. 

Amides such as A/ AT-dimethylcyclohexanecarboxamide (23 see Chapter 20, Section 20.7) are also carboxylic acid derivatives. Sodium borohydride does not reduce an amide. Lithium aluminum hydride reacts with 23, but the product is an amine rather than an alcohol—specifically, l-(iV, Ar-dimeth-ylaminomethyl)cyclohexane, 24. Amine 24 is isolated in 88% yield. Although the mechanism will not be discussed here in a formal manner, delivery of hydride to the acyl carbon of the C=0 is followed by formation of an imine (C=N) that is further reduced to the amine. Nitriles such as octanenitrile (25) also react with LiAlH4 in one experiment, reduction of 25 gave amine 26 (1-aminopentane) in 92% isolated yield. This reduction also proceeds by delivery of hydride to the carbon of the nitrile, generating an imine that is further reduced to the amine. In general, NaBH4 does not reduce amides or nitriles. 

The mechanism of this reaction was discussed by the authors (Scheme 4.40). Initially, aldehydes are formed by the PIDA mediated oxidative C-C bond cleavage of 1,2-diols, which are generated from the dihydroxylation of alkenes [142]. Upon the decomposition of ammonium bicarbonate, the aldehydes could be trapped by ammonia to give imines, which would be further oxidized to give nitriles. This reaction shows the efiftciency of the combination of metal-free oxidant and inexpensive nitrogenation agent for the synthesis of nitriles, which should be of great value in further studies. 

Intensive studies using NMR methods, kinetic experiments, and computational calculations were conducted to elucidate the catalytic mechanism and observed stereoinduction [22]. The data revealed that the hydrocyanation catalyzed by 33 presumably proceed over an initial amido-thiourea catalyzed proton transfer from hydrogen isocyanide to imine 32 to generate a catalyst-bound diastereomeric iminium/cyanide ion pair. Thereby, hydrogen isocyanide, as the tautomeric form of HCN, is stabilized by the thiourea moiety of 33. The stabilization degree of the formed iminium ion by the catalyst is seen as the basis for enantioselectivity. Subsequent collapse of the ion pair and bond formation between the electrophile and the cyanide ion forms the a-amino nitrile. It should be emphasized that the productive catalytic cycle with 33 does not involve a direct imine-urea binding, although this interaction was observed both kinetically and spectroscopically in the Strecker reaction catalyzed by 25 (see above) [19],... 

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