Phenylacetonitriles

This procedure is called chloromethylation and will not only turn 1,3-benzodioxole into a methyl chloride but will work equally well in converting plain old benzene into benzyl chloride. Both are important stepping stones towards the production of X and meth. For example, benzyl chloride is a schedule I controlled substance because it will beget benzaldehyde and phenylacetonitrile (a precursor for phenylacetic acid). 

Bromination of 2-brOmothia2ole leads to 2,5-dibromothiazole (5). 2-Bromothiazole can be used as a substrate in a malonic synthesis (72) starting from phenylacetonitrile the a phenyl-(2-thiazoiyl)-acetonitrile is obtained in high yields (84%) (Scheme 11). 

All lation of Garbanions. Concentrated N a OH—hen syl triethyl amm onium chloride is the base/catalyst system normally used for this type of process (20). Classes of compounds alkylated in this way include phenylacetonitriles, ben2ylketones, simple aUphatic ketones, certain aldehydes, aryl sulfones, P-ketosulfones, P-ketoesters, malonic esters and nitriles, phenylacetic esters, indene, and fluorene (see Alkylation). 

Reactions of the Side Chain. Benzyl chloride is hydrolyzed slowly by boiling water and more rapidly at elevated temperature and pressure in the presence of alkaHes (11). Reaction with aqueous sodium cyanide, preferably in the presence of a quaternary ammonium chloride, produces phenylacetonitrile [140-29-4] in high yield (12). The presence of a lower molecular-weight alcohol gives faster rates and higher yields. In the presence of suitable catalysts benzyl chloride reacts with carbon monoxide to produce phenylacetic acid [103-82-2] (13—15). With different catalyst systems in the presence of calcium hydroxide, double carbonylation to phenylpymvic acid [156-06-9] occurs (16). Benzyl esters are formed by heating benzyl chloride with the sodium salts of acids benzyl ethers by reaction with sodium alkoxides. The ease of ether formation is improved by the use of phase-transfer catalysts (17) (see Catalysis, phase-thansfer). 

Oxeladin [468-61-1] (54), an antitussive developed in the UK, is stmcturaHy related to carbetapentane in that the cyclopentane ring has been broken at the 3,4-bond. It is also similar pharmacologically. Extensive clinical studies using cough drops and symp containing oxeladin are described (73). The compound can be synthesized from phenylacetonitrile (74). 

Isoxazolin-5-imines were produced by nitrile oxide addition to cyanoacetates (62HC(17)l,p.7), by the reaction of nitrones with phenylacetonitrile (74CB13), and by base addition of nitrosobenzene to nitriles (Scheme 148) (72LA(762)154). 

Phenylacetonitrile reacts with diethyl sulfite to give 3-hydroxy-4,5-diphenylisothia2ole, together with other products (75SST(3)541). Phenylketene reacts with compound (199) to give a mixture of the isothiazolidinone (200) and the pyrrole (201 Scheme 33) (77SST(4)339, 79SST(5)345). 

A number of less-hazardous reagents that can be substituted for tert-hutyl azidoformate in tert-butoxycarbonylation reactions are available including 2-(te/t-butoxycarbonyloxyimino)-2-phenylacetonitrile (Aldrich Chemical Company), 0-teri-hutyl N-phenyl thiocarbonate (Eastman Organic Chemicals), di-butyl dicarbonate and tert-butyl phenyl carbonate. ... 

This method is an adaptation of that of Dengel. -Methoxy-phenylacetonitrile can also be prepared by the metathetical reaction of anisyl chloride with alkali cyanides in a variety of aqueous solvent mixtures by the nitration of phenylaceto-nitrile, followed by reduction, diazotization, hydrolysis, and methylation 1 by the reduction of ct-benzoxy- -methoxy-phenylacetonitrile (prepared from anisaldehyde, sodium cyanide, and benzoyl chloride) and by the reaction of acetic anhydride with the oxime of -methoxyphenylpyruvic acid. ... 

This procedure is an adaption of one described by Hauser and Chambers. Previous preparations include the benzylation of diethyl phenylmalonate followed by hydrolysis, the benzylation of phenylacetonitrile followed by hydrolysis, the benzylation of phenylacetic acid through the Ivanov reagent, and the reduction of oi-phenylcinnamic acid using sodium amalgam. ... 

Essentially the present procedure converted 1-methylgramine to l-methyl-S-indoleacetonitrile," but it failed to convert benzyl-dimethylphenylammonium chloride to phenylacetonitrile. ... 

Girgensohnia spp. G. diptera Bge. contains N-methylpiperidine and dipterine, CHH14N2, m.p. 87-8°, [a]D 0° hydrochloride, m.p. 177-8°, picrate, m.p. 189-190°, and picrolonate, m.p. 242-3°, which was later shown to be N-methyltryptamine.i G. oppositiflora Pall, contains N-methylpiperidine and girgensonine, C13H13ON2, m.p. 147-8°, [aJjj 0°. The latter forms a hydrochloride, m.p. 145-8°, and a picrolonate, m.p. 192-4°, and on hydrolysis by alkali yields piperidine, hydrocyanic acid and p-hydroxybenzaldehyde, indicating that it is N-piperidyl-p-hydroxy-phenylacetonitrile, and this has been confirmed by comparison with a synthetic specimen. ( (1) Juraschevski and Stepanova, J. Gen. Chem. Russ., 1939, 9, 2203 Juraschevski, ibid., 1940, 10, 1781. (2) Juraschevski and Stepanova, ibid., 1946, 16, 141). 

CN/CC replacements were also observed when the pyrimidine ring is part of a bicyclic system. Reaction of quinazoline with active methylene compounds, containing the cyano group (malonitrile, ethyl cyanoacetate, phenylacetonitrile) gave 2-amino-3-R-quinoline (R = CN, C02Et, Ph) (72CPB1544) (Scheme 12). The reaction has to be carried out in the absence of a base. When base is used, no ring transformation was observed only dimer formation and SnH substitution at C-4 was found. 

Replacement of one of the phenyl groups by an alkyl group of similar bulk, on the other hand, alters the biologic activity in this series. Alkylation of phenylacetonitrile with isopropyl bromide affords the substituted nitrile, 136. Treatment of the anion prepared from 136 with strong base with 2-dimethylamino-l-chloropropane gives isoaminile (137). It is of note that alkylation of this halide, isomeric with that used in the early methadone synthesis, is apparently unaccompanied by isomer formation. Isoaminile is an agent with antitussive activity. 

In fact, esters of amino alcohols and 2,2-disubstituted plii iiylacetic acids show useful antitussive activity the mecha-lM iii of action may include bronchiodilation. Double alkylation III the anion of phenylacetonitrile with 1,4-dibromobutane gives llit i cyclopentane-substituted derivative (33). Saponification... 

Attachment of a basic amino group to the side chain leads to a compound with antiparkinsonian activity. Alkylation of the carbanion from phenylacetonitrile with 2-chlorotriethylamine affords the product, 36. Conjugate addition of the anion from this to acrylonitrile gives the glutarodinitrile (37). Partial hydrolysis of this in a mixture of sulfuric and acetic acid leads to phenglutarimide (38). ... 

The key intermediate, normeperidine (81), is obtained by a scheme closely akin to that used for the parent molecule, Thus, alkylation of phenylacetonitrile with the tosyl analog of the bischloroethyl amine (78) leads to the substituted piperidine... 

A phenylacetonitrile derivative, closantel (41), is an anthelmintic agent useful against sheep liver flukes. Its patented synthesis involves a Schotten-Baumann amidation... 

Phenylacetonitrile Diisopropylaminoethyl chloride Sulfuric acid Phosphoric acid... 

To a solution of 35.3 parts of phenylacetonitrile and 47.6 parts of 2-bromopyridine in 175 parts of dry toluene is added 53.4 parts of sodamide slowly with stirring over a period of 45 minutes. The resultant mixture is stirred at 100 C for 2 hours before it is cooled and the excess sodamide is decomposed by the addition of water. The toluene layer is separated and washed with water to remove excess alkali. The toluene solution is extracted with 6N hydrochloric acid and the acid extract is made alkaline and then extracted with toluene. The toluene solution is dried over sodium sulfate and the solvent is evaporated. Recrystal-lization of the residue from alcohol-hexane gives a-phenvl-2-pyridineacetonitrile melting at about 87°-88°C. 

As a starting material, phenylacetonitrile was reacted with N-(2-chloroethyl)dimethylamine. This then underwent the following reaction sequence. 

Preparation of Diethylphenylacetonitrile 25 grams of sodium was dissolved in 300 ml liquid ammonia containing 0.3 gram ferric chloride and 59 grams phenylacetonitrile was added slowly with stirring. After about 15 minutes a cooled solution of 80 grams of ethyl chloride in 200 ml dry ether was added and the mixture stirred for 1 hour. The ammonia was then allowed to evaporate, water added and the ether layer separated, dried, concentrated and the residual oil distilled in vacuo to yield diethylphenylacetonitrile as an oil,... 

Phenylacetonitrile Sec-Butyl bromide Thionyl chloride Dimethyl sulfate... 

Phenylacetonitrile is alkylated with secondary butyl bromide and the resultant nitrile is hydrolyzed to 3-methyl-2-phenylvaleric acid. The acid is converted to the acid chioride with thionyl chloride and the acid chloride is in turn reacted with 1-methyl-4-piperidinol. Finally dimethyl sulfate is reacted with the ester. 

The starting materials for the overall process are phenylacetonitrile with bis-chloroethyl toluene sulfonyl amide. These react to give a product which hydrolyzes to normeperidine (4-carboethoxy-4-phenylpiperidine). Condensation of that material with benzoylethylene gives the ketone /3-(4-carboethoxy-4-phenylpiperidino)propiophenone. 

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