Nitrile, alkylative hydration

The alkylative hydration of nitriles is a quite different matter. The role of DMSO is that of a hard base for neutralizing a very hard nitrilium carbon. The synthesis of AT-tritylamides (140) is representative. 

For those nitriles which yield water-insoluble amides e.g., the higher alkyl cyanides), hydrolysis to the amide often leads to a satisfactory derivative. The hydration is eflfected by warming a solution of the nitrile in concentrated sulphuric acid for a few minutes, cooling and pouring... 

A disubstituted butyramide, disopyramide, distantly related to some acyclic narcotics interestingly shows good antiarrhythmic activity. Alkylation of the anion from phenylacetonitrile with 2-bromopyridine yields 99. Alkylation of the anion from the latter with N,N-diisopropyl-2-chloroethyl-amine leads to the amine 100. Hydration of the nitrile in sulfuric acid affords disopi/ramide (101). 

Crystalline derivatives of aliphatic nitriles may be prepared by an application of the Hoesch reaction. Equimolecular proportions of phloroglucinol and the nitrile react in dry ethereal solution in the presence of anhydrous zinc chloride and hydrogen chloride to give an imine hydrochloride, which is converted into a solid alkyl trihydroxyphenyl ketone by hydrolysis. The alkyl 2,4,6-trihydroxy-phenyl ketones are usually highly crystalline solids of sharp melting point and are purified by recrystallisation from hot water. Many contain water of crystallisation which can be removed by drying in vacuo at about 100 °C the melting points of both the hydrated and anhydrous compound should be determined. 

Abb. 7.16. Ritter reaction part I (cf. Fig. 7.17) SN1 reaction between a tertiary alcohol and a nucleophile containing C=N, with hydrogen cyanide acting as the nucleophile. Under reaction conditions the C=N group is tert-alkylated at the N atom and hydrated at the nitrile nitrogen leading to the formation of an W-tert-alkyl-formamide (B). 

When the nitriles were replaced by /V-(ethoxycarbonyl)cyanamide and the products reduced with ethanolic hydrazine hydrate, 2-(iV-ethoxycarbonylureido)-l-alkyl phenyl tellurium compounds were obtained1,2. 

Hydrolysis with powdered potassium hydroxide or potassium fluoride on alumina in r-butyl alcohol converts nitriles to amides without further hydrolysis to carboxlic acids. Under similar conditions, addition of alkyl halides gives iV-alkylcarboxyamides. Less drastic acidic or basic hydrolysis conditions involve disproportionation of alkaline hydrogen peroxide with concomitant hydration of the nitrile (equation 21). 

Dimethylsulfoxide was found to increase the rate of hydrolysis in esters which were resistant to saponification. Treatment of alkyl toluenesulfonates with sodium naphthalene anion radical in tetrahydrofuran constituted an almost ideal procedure for regenerating the corresponding alcohols. The hydration of nitriles to amides in the presence of nickel catalysts shows an increase in yield with the addition of pyridine. ... 

Hydrogenation of aromatic nitro compounds to aromatic amines Hydrogenation of aldehydes and ketortes to alcohols Hydrogenation of atomic olehnic groups Hydrogenation of unsaturatcd nitriles to unsaturated amines Hydrogenation of diolefins artd alkynes to monoolehns Hydration of ethylene oxide alkylation of aromatics with olehns oxidation of alcohols to aldehydes Oxidation of ethylene to ethylene oxide Synthesis of HCN from NH, and CH4 Oxidation of CH3OH to HCHO... 

An enzymatic acrylonitrile hydration was first patented in 1981 8nitrile hydratases of different origin have been shown to be able to convert acrylonitrile into acrylamide. However, a major problem associated with biocatalysis for production of acrylonitrile is the short half-life of the enzyme due to substrate and product inhibition. Acrylonitrile is a strong alkylating agent which reacts by Michael addition with the sulfhydryl groups of proteins f 8, 69L... 

C-19 methyl functionality in the tetracyclic ketone 164, the Nt-H group was alkylated with the optically active i .-tosylate 224 (which was in turn obtained from the R propargylic alcohol via a two-step sequence) in aceto-nitrile/K2C03, followed by treatment with tetrabutylammonium fluoride hydrate to obtain the acetylenic ketone 225 in 96% yield. The terminal alkyne in 225 was converted into the iodoolefm functionality by treating with dicyclohexyhodoborane [I-B(Cy)2], followed by protonolysis. The iodo-olefin 226 was obtained in 74% yield. It was subjected to a Pd-catalyzed a-vinylation to obtain the key C-19 methyl-substituted pentacy-clic system 227. This was followed by a Wittig/hydrolysis/epimerization... 

Amides without any A-alkyl groups (RCONH2) can also be prepared by partial hydration of a nitrile (RC N). Addition of one equivalent of water across the nitrile triple bond results in an enol-like intermediate that tautomer-izes to give a carbonyl. This mechanism is analogous to the hydration of an alkyne to give a ketone product. Since amides can also be hydrolyzed to give carboxylic acids, the nitrile partial hydrolysis reaction conditions are kept relatively mild when the amide product is desired. 

In 2014, Li and co-workers reported a direct synthesis of IV-alkylated amides via tandem hydration/7V-alkylation of nitriles and aldoximes with alcohols catalyzed by [Cp IrCl2]2 with a low catalyst loading (1 mol%) (Eq. 16) [91]. Control experiments revealed that nitriles were initially hydrated by aldoximes to give amides, which then reacted with alcohols to give IV-alkylated amide products. 

Wang N, Zou X, Li F et al (2014) The direct synthesis of A -alkylated amides via a tandem hydration/A/-alkylation reaction from nitriles, aldoximes and alcohols. Chem Commun 50(61) 8303 305... 

---