Nitriles hydrolytic amidation

Platinum-catalyzed hydrolytic amidation of unactivated nitriles was reported by Cobley and coauthors. The platinum(ii) complex, [(Me2PO- H- PMe2)PtH (PMe2OH)], efficiently catalyzes the direct conversion of unactivated nitriles into N-substituted amides with both primary and secondary amines. Possible mechanisms for this reaction are discussed and evidence for initial amidine formation is reported. Isolated yields vary from 51 to 89% [25]. 

Cobley, C.J., den Heuvel, M., Abbadi, A. and deVries, J.G. (2000) Platinum catalysed hydrolytic amidation of unactivated nitriles. Tetrahedron Lett., 41, 2467-2470. 

As shown in Scheme 1, NHase catalyzes the conversion of nitriles to amides 4), The active site contains either a non-corrin cobalt(III) or non-heme iron(III). Amino acid sequence comparisons have shown that the primary coordination sphere is conserved regardless of the identity of the metal center and consists of a -C-S-L-C-S-C- motif (5). EPR studies on Fe-NHase revealed the iron center maintains a low-spin Fe(III) state throughout the catalytic cycle, and that the iron center has a variable coordination site for substrate interaction (6). These findings are consistent with the hypothesis that the enzyme functions solely as a hydrolytic (i.e., redox-inactive) catalyst. Incubation of the enzyme with nitric oxide in the dark inactivates the enzyme. Exposure to light was found to reinstate activity with concomitant loss of NO, thus revealing a novel photo-regulatory mechanism (7-70). 

Keywords Amide-bond formation Dehydrogenative amidation Hydrolytic amidation Nitrile hydration Rearrangements Ruthenium catalysts... 

Ruthenium-Catalyzed Hydrolytic Amidation of Nitriles with Amines. 93... 

Mechanistic studies by Duchateau and co-workers, employing the [RuH2(PPh3)4]-catalyzed hydrolytic amidation of pentanenitrile with n-hexylamine as model reaction, pointed out that the process proceeds through the initial hydration of the nitrile to form an intermediate primary amide, which subsequently reacts with the amine to give the final A-substituted amide product (path (a) in Scheme 14) [79]. This reaction pathway contrasts with that commonly proposed for other... 

Scheme 10 The hydrolytic amidation of nitriles with amines...

The dehydration which leads to the formation of nitriles and the action of hypohalides on amides are dealt with in the following preparations. The amino-group of the amides, as distinguished from that of the amines, is more or less easily removed by hydrolytic agents, acids being re-formed. For the cause of this difference in behaviour compare the explanation given on p. 128. 

The formation of a very electrophilic intermediate 258 from 256 and 257 is proposed (equation 78). The hydroxyl group of the oxime adds to 259, giving a reactive cationic species 260 that rearranges and affords the nitrile 261 (in the case of aldoxime, equation 79), or the amide 262 upon hydrolytic workup (equation 80). The conversion of 260 to the nitrilium ion should occur through a concerted [1,2]-intramolecular shift. This procedure can be applied in the conversion of aldoximes to nitriles. It was observed that the stereochemistry of the ketoximes has little effect on the reaction, this fact being explained by the E-Z isomerization of the oxime isomers under the reaction conditions. 

Furazan- and furoxan-carboxylic acids are thermally and hydrolytically unstable decomposing to a-(hydroxyimino)nitriles, but their amide, ester, halide, and nitrile derivatives are readily accessible and all undergo the expected functional group interconversions. Dicyanofuroxan reacts with hydroxylamine to give the fused oxazino compound (63) and the pyridazino analogue (64) is similarly formed with hydrazine <82H(19)1063>. 

Amides, azides and nitriles are reduced to amines by catalytic hydrogenation (H2/Pd—C or H2/Pt—C) as well as metal hydride reduction (LiAlH4). They are less reactive towards the metal hydride reduction, and cannot be reduced by NaBITj. Unlike the LiAlIU reduction of all other carboxylic acid derivatives, which affords 1° alcohols, the LiAlIU reduction of amides, azides and nitriles yields amines. Acid is not used in the work-up step, since amines are basic. Thus, hydrolytic work-up is employed to afford amines. When the nitrile group is reduced, an NH2 and an extra CH2 are introduced into the molecule. 

Other examples of catalysis by metal ions refer to hydrolytic reactions. In phenanthro line-1-nitrile, the hydration of the nitrile group (to form the amide group) is catalyzed by metal ions (Cu2+, Ni2+, Zn2+) which form complexes with the substrate [270]. The rate equation is... 

The N-alkylation of amides followed by hydrolysis furnishes a good route for making secondary amines. The formyl, acetyl, and aryl-sulfonyl " derivatives of amines are best suited for alkylation (method 358). Hydrolysis is accomplished by refluxing concentrated hydrochloric acid alone or in acetic acid. N-Alkyl-formamides prepared by the addition of olefins to nitriles (method 355) are hydrolyzed with aqueous alkali. Similar hydrolytic procedures... 

The enzymatic hydrolysis of nitriles to yield either the corresponding amides or carboxylic adds has been studied in some detail over the last 10 yr (70,71). The enzymatic hydrolytic cleavage of nitriles can be achieved by two types of hydrolase nitrile hydratase or nitrilase (Fig. 23). Nitrile hydratase has been commerdally exploited for the production of various amides, the most notable being acrylamide (10-12,71,72). 

Another biocatalytic option is the hydrolysis of p-aminonitriles, compounds that are relatively easily synthesized. There are two hydrolytic routes for the enzymatic conversion of nitriles to the corresponding carboxylic acids. These transformations can be achieved either through a two-step cascade reaction involving a nitrile hydratase followed by an amidase that hydrolyzes the intermediate amide, or through use of a nitrilase, an enzyme able to perform the two sequential transformations (Scheme 14.4). The focus of this chapter is on nitrile hydrolysis enzymes. 

Amides and nitriles may be readily hydrolyzed to produce the corresponding acids together with ammonia or, in the ease of certain amides, substituted ammonia. To he sure, the amides and nitriles may also be reduced to amines, ospticially with sodium in alcoholic solution with acidic reagents the hydrolytic reaction is, however, the prominent one and the one adaptable for analytical purposes. 

Several recent review articles provide excellent summaries of the stoichiometric and catalytic reactivity of synthetic metal aqua and hydroxide complexes with carbon-centered electrophiles (esters, amides, peptides, CO2, nitriles) [8, 10-13, 82-90] and phosphate derivatives (activated phosphate esters, DNA, RNA) [6, 11-13, 17-20, 82, 83, 85, 91-99]. In particular, these reviews provide insight into how various metal/ligand assemblies influence catalytic hydrolytic reactions. 

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