2- phenylacetonitriles, synthesis

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). 

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. 

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

Trichloromethyl chloroformate has proven effective in the preparation of N-carboxy-a-amino acid anhydrides from amino acids, and various compounds having isocyanate, acid chloride, and chloroformate groups.For example, trichloromethyl chloroformate may be used instead of phosgene in the preparation of 2-tert-butoxycarbonyloxyimino-2-phenylacetonitrile. The use of this reagent is illustrated here by the synthesis of 3-isocyanato-propanoyl chloride from 3-aminopropanoic acid hydrochloride. 

The dehydration reaction of aldoxime to form nitriles using the resting cells of Rhodococcus sp. YH3-3 was optimized. We found that the enzyme was induced by aldoxime and catalyzed the stoichiometric synthesis of nitriles from aldoximes at pH 7.0 and 30°C. Phenylacetonitrile once synthesized from phenylacetaldoxime was hydrolyzed to phenylacetic acid, since the strain has nitrile degradation enzymes such as nitrile hydratase and amidase. We have been successful in synthesizing phenylacetonitrile and other nitriles stoichiometrically by a selective inactivation of nitrile hydratase by heating the cells at 40°C for 1 h. Various nitriles were synthesized under optimized conditions from aldoximes in good yields. 

Phenylacetonitrile (p DMSO = 21.9) is considerably more acidic than acetonitrile. Dialkylation has been used in the synthesis of meperidine, an analgesic substance.78... 

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]. 

In the reaction of the phenylacetonitrile carbanion with thiocyanates, a major side reaction leads to the formation of the dialkyl disulphides, as a result of the base-catalysed decomposition of the thiocyanate. This side reaction is reported to be insignificant in the reactions of the other carbanions. Phenylacetonitrile reacts with 1,2-ethanyl bisthiocyanate to produce 2-cyano-2-phenyl-1,3-thiolanes [52] under conditions analogous to those used for the synthesis of the thioethers (Scheme 4.12). 

Autoxidation of secondary acetonitriles under phase-transfer catalytic conditions [2] avoids the use of hazardous and/or expensive materials required for the classical conversion of the nitriles into ketones. In the course of C-alkylation of secondary acetonitriles (see Chapter 6), it had been noted that oxidative cleavage of the nitrile group frequently occurred (Scheme 10.7) [3]. In both cases, oxidation of the anionic intermediate presumably proceeds via the peroxy derivative with the extrusion of the cyanate ion [2], Advantage of the direct oxidation reaction has been made in the synthesis of aryl ketones [3], particularly of benzoylheteroarenes. The cyanomethylheteroarenes, obtained by a photochemically induced reaction of halo-heteroarenes with phenylacetonitrile, are oxidized by air under the basic conditions. Oxidative coupling of bromoacetonitriles under basic catalytic conditions has been also observed (see Chapter 6). 

If di(tcrt-butyl)nitroxide (a radical trap) is present, the reaction with phenylacetonitrile-potassium does not proceed entirely. Acetonitrile-potassium (which is in equilibrium with potassium amide) forms only aminopyridine in the presence of the trap (Moon et al. 1983). Consequently, amination is a classical nucleophile reaction, and the formation of pyridyl acetonitrile is a reaction of the typs- These two reactions are quite different. A stronger CH acid leads to a well-defined synthesis. 

One of the early syntheses of meperidine (75) starts with the double alkylation of phenylacetonitrile with the bischloro-ethyl amine, 72. The highly lachrimatory nature of this material led to the development of an alternate synthesis for the intermediate piperidine (73). Alkylation of phenylacetonitrile with two moles of 2-chloroethylvinyl ether leads to the intermediate (69). This is then hydrolyzed without prior isolation to the diol, 70. Treatment with thionyl chloride affords the corresponding dichloro compound (71). This last is then used to effect a bis alkylation on methylamine, in effect forming the piperidine (73) by cyclization at the opposite end from the original scheme. Saponification to the acid (74) followed by esterification with ethanol affords the widely used analgesic meperidine (75) substitution of isopropanol for ethanol in the esterification affords properidine (76). ... 

Substituted-3-aryl[l,6]naphthyridin-2-amines and 7-substituted-3-aryl[l,6]naphthyridin-2(l//)-ones have been prepared by diazotization of 3-aryl[l,6]naphthyridine-2,7-diamines, themselves obtained by the condensation cycli-zation of 4,6-diaminonicotinaldehyde and phenylacetonitrile <2000J(P1)1843>. Derivatives of cyanoacetic acid have rarely been used in the synthesis of naphthyridines, although a recent study has shown that they may be reacted with 4-piperidone derivatives to give [l,6]naphthyridines <2000CHE496>. 

Reaction of piperazine-2-carboxylic acid (22) with Z-OSu at pH 11 leads to the N4-(benzyloxycarbonyl) monoprotected derivative,12421 which is then converted with 2-(/er/-bu-toxycarbonyloxyimino)-2-phenylacetonitrile at pH 9.5 into the W-/ert-butoxycarbonyl-/V4-benzyloxycarbonyl bis-protected derivative. 242 For further steps in peptide synthesis standard protocols are applied. 

A useful synthesis of heteroaryl ketones uses the photostimulated a-cyanoalkylation reaction followed by oxidation (Scheme 4). The oxidation of products formed from phenylacetonitrile (R = Ph in Scheme 4) proceeded in over 90%.110... 

In a pyrrole synthesis, cyclopropene 85 and a twofold excess of phenylacetonitrile were treated with GaCl3 at 80 °G for 2h. The 1,3-diazepine 86 was formed in 10% yield as a by-product in this reaction (Equation 14)... 

In comparison, the l,3-dialkylimidazolium-2-carboxylate isolated by Tommasi et al. [27, 40] was revealed to be a more versatile catalyst that allowed the synthesis of benzoylacetic acid from benzophenone and C02 in good yield and under mild conditions (isolated yield 81%). The presence of tetrafluoroborate- or tetraphenyl-borate sodium salts in the reaction was essential, as this allowed the formation of the related 1,3-dialkylimidazolium tetrafluoroborate or tetraphenylborate and the concomitant quantitative trans-carboxylation to sodium benzoylacetate. Likewise, compounds such as acetone, cyclohexanone, and phenylacetonitrile could also be converted with this system to afford the corresponding carboxylate salts (methyl a-cyanophenylacetate) (Scheme 5.8). Following the same general procedure, acetone was carboxylated, being simultaneously the cosolvent and reagent. 

Schwartz, M. A. Zoda, M. Vishnuvajjala, B. Mami, I. A convenient synthesis of o- andp-hydroxy substituted phenylacetonitriles and phenethylamines./. Org. Chem. 1976, 43, 2502-2503. 

A one-pot quinoline synthesis starting with 2-aminobenzyl alcohol and a,/3-unsaturated ketones using ruthenium-grafted hydrotalcites as a heterogeneous catalyst has been reported (Scheme 64) <2004TL6029>. Molecular oxygen was used for the oxidation of ruthenium and the styryl quinoline 42 was produced in good yield. The use of other donors, for example, octanal and phenylacetonitrile, yielded 3-amylquinoline and 2-amino-3-phenylquinoline, respectively. 

A wide variety of methods have been described for the synthesis of variously substituted phenethylamines. Some frequently used procedures are presented in Scheme 1. Most of these have been discussed in previous reviews (305, 306). Condensation of an appropriately substituted benzaldehyde with nitromethane followed by reduction of the nitrostyrene (Method A) has proved to be a versatile method which has been employed by numerous workers (cf. 306, 358). Another common method (Method B) affords the amines by reduction of substituted phenylacetonitriles obtained via benzylchlorides (cf.. 306) or benzylamines (307). Reduction of phenylacetamides with lithium aluminum hydride (Method C) has also been applied successfully (308, 309). The substituted phenylacetamides were obtained either via diazoketones by an Amdt-Eistert synthesis (308) or by transformation of the corresponding acetophenones (310). 

Hydrogenation of nitriles under conditions favorable for the formation of secondary and tertiary amines can be applied to the synthesis of mixed secondary and tertiary amines. The iV-substituted phenethylamines were synthesized by hydrogenation of a phenylacetonitrile in the presence of an amine an example is shown in eq. 7.45,90... 

A synthesis of nitriles from the cyanohydrins of aromatic aldehydes via the reduction of the corresponding a-halo cyanides has been proposed. As an example, benzaldehyde cyanohydrin is converted by the action of thionyl chloride to phenylchloroacetonitrile (80%). This substance is reduced with zinc in acetic acid to phenylacetonitrile (70%). ... 

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