Nitriles acidic hydrolysis

Indole (I) condenses with formaldehyde and dimethylamine in the presence of acetie acid (Mannich reaction see Section VI,20) largely in the 3-position to give 3 dimethylaminomethylindole or gramine (II). The latter reaets in hot aqueous ethanol with sodium cyanide to give the nitrile (III) upon boiling the reaction mixture, the nitrile undergoes hydrolysis to yield 3-indoleaeet-amide (IV), part of which is further hydrolysed to 3-indoleacetic acid (V, as sodium salt). The product is a readily separable mixture of 20 per cent, of (IV) and 80 per cent, of (V). 

Nitriles are classified as carboxylic acid derivafives because fhey are convened fo car boxylic acids on hydrolysis The condifions required are similar fo fhose for fhe hydrol ysis of amides namely healing m aqueous acid or base for several hours Like fhe hydrolysis of amides nilrile hydrolysis is irreversible m fhe presence of acids or bases Acid hydrolysis yields ammonium ion and a carboxylic acid... 

Nitrile Group. Hydrolysis of the nitrile group proceeds through the amide to the corresponding carboxyUc acid. Because cyanohydrins are unstable at high pH, this hydrolysis must be cataly2ed by acids. In cases where amide hydrolysis is slower than nitrile hydrolysis, the amide may be isolated. 

Cyanides are dangerously toxic materials that can cause instantaneous death. They occur in a number of industrial situations but are commonly associated with plating operations, and sludges and baths from such sources. Cyanide is extremely soluble and many cyanide compounds, when mixed with acid, release deadly hydrogen cyanide gas. Cyanide is sometimes formed during the combustion of various nitrile, cyanohydrin, and methacrylate compounds. Cyanides (CN ) are commonly treated by chlorine oxidation to the less toxic cyanate (CNO ) form, then acid hydrolyzed to COj and N. Obviously, care should be taken that the cyanide oxidation is complete prior to acid hydrolysis of the cyanate. 

Nitriles are classified as carboxylic acid derivatives because they are converted to carboxylic acids on hydrolysis. The conditions required are similar- to those for the hydrolysis of amides, namely, heating in aqueous acid or base for several hours. Like the hydrolysis of amides, nitrile hydrolysis is ineversible in the presence of acids or bases. Acid hydrolysis yields fflnmonium ion and a carboxylic acid. 

In a departure from the prototype molecule, the benzylpiperi-done is first converted to the corresponding aminonitrile (a derivative closely akin to a cyanohydrin) by treatment with aniline hydrochloride and potassium cyanide (126). Acid hydrolysis of the nitrile affords the corresponding amide (127). Treatment with formamide followed by reduction affords the spiro oxazinone... 

Solvents influence the hydrogenation of oximes in much the same way as they do hydrogenation of nitriles. Acidic solvents prevent the formation of secondary amines through salt formation with the initially formed primary amine. A variety of acids have been used for this purpose (66 ), but acids cannot always be used interchangeably (43). Primary amines can be trapped also as amides by use of an anhydride solvent (2,/5,57). Ammonia prevents secondary amine formation through competition of ammonia with the primary amine in reaction with the intermediate imine. Unless the ammonia is anhydrous hydrolysis reactions may also occur. 

Among the most useful reactions of nitriles are hydrolysis to yield first an amide and then a carboxylic acid plus ammonia, reduction to yield an amine, and Grignard reaction to yield a ketone (Figure 20.3). 

HHTs derived from AMPA diethyl ester 56 also reacted with acetyl chloride to generate glyphosate nitriles 58 following cyanide displacement with the resulting iV-acetyl-Af-chloro-methyl-AMPA diethyl ester 57. Subsequent acidic hydrolysis of 58 gave GLYH3 (58). 

This method has been made more general by use of modern reagents low temperatures and the strong hindered base i-Pr NLi allow the deprotonation of many nitriles and their capture by a variety of epoxides. Acid hydrolysis gives lactones,... 

Hydrolysis may be effected with 10-20 per cent, sodium hydroxide solution (see TolunitrUe and Benzonitrile in Section IV,66) or with 10 per cent, methyl alcoholic sodium hydroxide. For difficult cases, e.g., OL-Naphthonitrile (Section IV.163), a mixture of 50 per cent, sulphuric acid and glacial acetic acid may be used. In alkaline hydrolysis the boiling is continued until no more ammonia is evolved. In acid hydrolysis 2-3 hours boiling is usually sufficient the reaction product is poured into water, and the organic acid is separated from any unchanged nitrile or from amide by means of sodium carbonate solution. The resulting acid is identified as detailed in Section IV,175. 

Moser et al. (1968) (one of the co-authors was Clifford Matthews) reported a peptide synthesis using the HCN trimer aminomalonitrile, after pre-treatment in the form of a mild hydrolysis. IR spectra showed the typical nitrile bands (2,200 cm ) and imino-keto bands (1,650 cm ). Acid hydrolysis gave only glycine, while alkaline cleavage of the polymer afforded other amino acids, such as arginine, aspartic acid, threonine etc. The formation of the polymer could have occurred according to the scheme shown in Fig. 4.9. 

Mild acidic hydrolysis of amino nitrile 369 gave m-4,9a-/7-rra r-9-7/-9-benzyloxy-4-phenyl-3,4,9,9a-tetrahydro-17/,67/-pyrido[2,l-d[l,4]oxazin-l-one <1996TL4001>. (2A)-2-Cyano-l-[(lR)-2-hydroxy-l-phenylethyl]piperidin-6-one, on standing for 20 days in ethanol saturated with HC1 gas, afforded (4/ ,9aA)-4-phenylperhydropyrido[l,2-4[l,4]oxazine-l,6-dione, which was sometimes accompanied by the unstable (26 )-l-[(l/ )-2-hydroxy-l-phenylethyl]-... 

Rapid monoalkylations are achieved in good yield compared with classical methods. Of particular interest is the synthesis of ot-amino acids by alkylation of aldimines with microwave activation. Subsequent acidic hydrolysis of the alkylated imine provides leucine, serine, or phenylalanine in preparatively useful yields within 1-5 min [50], Alkylation of phenylacetonitrile was performed by solid-liquid PTC in 1-3 min under microwave irradiation (Eq. 36 and Tab. 5.14). The nitriles obtained can subsequently be quickly hydrolyzed in a microwave oven to yield the corresponding amides or acids [56]. 

The 1,3-dipolar cycloaddition of a variety of aromatic and aliphatic nitrile oxides to 2.5-/ra//.v-2.5-diphenylpyrrolidine-derived acrylamide and cinnamamide 399, efficiently affords the corresponding 4,5-dihydroisoxazole-5-carboxamides 400 in highly regio- and stereoselectivity (Scheme 1.47). Acid hydrolysis of these products affords enantiopure 4,5-dihydroisoxazole-5-carboxylic acids 401 (443). 

The in i /V -generated CpeZ Bu Cl converts the arene into a zirconocene-benzyne complex which undergoes C-C bond formation with a nitrile to form an intermediary azazirconacycle (Equation (14)). The acidic hydrolysis of the latter species provides the corresponding 3-acyl-l-substituted benzene derivatives. 

A subsequent report outlined the synthesis of a diastereomer of tetrazole 58 that used similar methodology <1997TL4655>. Treatment of nitrile mesylate 60 with sodium azide affords D-talonotetrazole 62, presumably by intramolecular [1,3] dipolar cycloaddition of a 4-azido-4-deoxy-D-talonitrile intermediate 61. Acid hydrolysis affords the deprotected tetrazole 63 (Scheme 5). 

The chiral cyanohydrins also lead directly to a-hydroxy acids by hydrolysis (sequence B) [69] and to protected a-hydroxy aldehydes by first hydroxyl group protection, followed by reduction of the nitrile and hydrolysis of the intermediate imine (not shown) (sequence C) [114]... 

The nitrile produced in the above reaction can be converted into the corresponding carboxylic acid by acid hydrolysis, l.e. reaction with water catalysed by hydrogen ions from the acid. 

The above hydrochloride is treated with thionyl chloride in liquid sulfur dioxide, to produce an amorphous chloride hydro chloride, which is converted to the nitrile with sodium cyanide in liquid hydrogen cyanide, Methanolysis then gives the ester of the nitrile. Alkaline hydrolysis of this last compound, followed by catalytic dehydrogenation in water using a deactivated Raney Nickle catalyst (see JOC, 13, 455 1948) gives dl-lysergic acid. 

Fusion of an all cyclic ring onto the piperidine so as to form a perhydroisoquinoline is apparently consistent with analgesic activity. Synthesis of this agent, ciprefadol (68), starts with the Michael addition of the anion from cyclohexanone 56 onto acrylonitrile (57). Saponification of the nitrile to the corresponding acid (58) followed by Curtius rearrangement leads to isocyanate J9. Acid hydrolysis of the isocyanate leads directly to the indoline... 

The basic hydrolysis (reaction with water) of a nitrile (R-CN) followed by acidification yields a carboxylic acid. In general, an reaction (nucleophilic substitution) of an alkyl halide is used to generate the nitrile before hydrolysis. Figure 12-12 illustrates the formation of a carboxylic acid beginning with an alkyl halide. 

Doxapram Doxapram, l-ethyl-4-(2-morpholinoethyl)-3,3-diphenyl-2-pyrrolidinone (8.2.4), is synthesized in the following manner. Diphenylacetonitrile in the presence of sodium amide is alkylated with l-ethyl-3-chlorpyrrolidine, giving (l-ethyl-3-pyrrolidinyl) diphenylacetonitrile (8.2.1). Acidic hydrolysis of the nitrile group gives (l-ethyl-3 pyrrolidinyl)diphenylacetic acid (8.2.2). Reacting this with phosphorous tribromide... 

Removal of the acetyl and nitrile groups by acid hydrolysis was also achieved by Wohl, who isolated a pentosazone from the products from heating pentaacetyl-D-glucononitrile with 2 N hydrochloric acid. Fischer also isolated what is now known to have been a 5-desoxy-L-arabinosazone from the products obtained by treatment of tetraacetyl-L-rhamnononitrile with 5% hydrochloric acid. At the same time partial transformation of the nitrile into the aldonic acid takes place as shown by Maquenne, who obtained D-xylonic acid by treating tetraacetyl-D-xylononitrile with concentrated hydrochloric acid. 

The synthesis of valsartan (2) by Novartis/Ciba-Geigy chemists is highlighted in Scheme 9.5. Biphenylbenzyl bromide 18 is converted to biphenyl acetate 19 in the presence of sodium acetate in acetic acid. Hydrolysis of 19 followed by Swern oxidation delivered the biphenyl aldehyde 20, which underwent reductive amination with (L)-valine methyl ester (21) to give biphenyl amino acid 22. Acylation of 22 with penta-noyl chloride (23) afforded biphenyl nitrile 24, which is reacted with tributyltin azide to form the tetrazole followed by ester hydrolysis and acidihcation to provide valsartan (2). [See Biihlmayer et al. (1994, 1995).]... 

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