Alkylation phenylacetonitrile

No systematic study is available on other parameters in triphase alkylation of phenylacetonitrile, but the following isolated observations may be significant. Both dilution of the organic phase with benzene or cyclohexane and use of 10% NaOH in place of 50% NaOH greatly reduced the rate 101). The benzyltrimethylammonium ion is attacked by hydroxide ion under the conditions of phenylacetonitrile alkylation. Repeated use of either Dowex ion exchange resins101) or 2 % CL, 16-50 % RS resins 103) gave reduced activity. 

Active site structure, separation of active site from the backbone, organic solvent, and molecular size of the reactant have not been studied in phenylacetonitrile alkylations with polystyrene-supported onium ion catalyst. In conventional phase transfer catalyzed ethylation of phenylacetonitrile with tetra-n-butylammonium bromide, Chiellini found a formal rate dependence of [NaOH]5 3 which was attributed to much higher activity of hydroxide ion in... 

Uvarov, V.M., Schael, F and Reschetilowski, W. (2009) Experimental investigation and modeling approach of the phenylacetonitrile alkylation process in a microreactor. Chem. Eng. Technol., 6 (32), 919-925. 

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). 

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... 

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. 

Sulphoxides can be used as phase transfer catalysts, for example, a-phosphoryl sulphoxides (Scheme 24) have been used as phase transfer catalysts in the two-phase alkylation of phenylacetonitrile or phenylacetone with alkyl halides and aqueous sodium hydroxide. However, they are considered to be inefficient catalysts for simple displacement reactions226. 

Recently, it has been reported that methyl 2-pyridyl sulphoxides (10) and related pyridyl derivatives (11) (see Schepie 25) are good phase transfer catalysts for SN2 reactions of various primary or secondary alkyl halides in a two-phase reaction system and for the alkylation of phenylacetonitrile or phenylacetone with alkyl halides in liquid-liquid two-... 

In the mid-1960s a series of papers by Makosza and Serafinowa (1965, 1966) appeared under the common title Reactions of Organic Anions , in which the catalytic alkylation of phenylacetonitrile and its derivatives carried out in the presence of concentrated NaOH and the catalyst triethylbenzylammonium chloride (TEBA) was described. This was the beginning of phase-transfer catalysis (PTC), and since then thousands of papers haven been published on the subject. 

Lindblom and Blander (1980) have given a number of examples of relevance in the pharmaceutical industry. These include C-alkylations, 0-alkylations, and A-alkylations. The C-alkylation of phenylacetonitrile, (mono- and di-) alkylation of benzylpenicillin with a-chlorodiethyl carbonate (where the acid part and the halide part in the esterification would have degraded quickly under normal conditions adopted for the reaction), A-alkylation of purines and adenine, etc. are discussed at some length and the supremacy of PTC is clearly shown. 

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... 

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]. 

Tab. 5.14 Alkylation of phenylacetonitrile under MW + PTC conditions (NaOH 6 equiv.,TEBA 15%).

The interfacial mechanism provides an acceptable explanation for the effect of the more lipophilic quaternary ammonium salts, such as tetra-n-butylammonium salts, Aliquat 336 and Adogen 464, on the majority of base-initiated nucleophilic substitution reactions which require the initial deprotonation of the substrate. Subsequent to the interfacial deprotonation of the methylene system, for example the soft quaternary ammonium cation preferentially forms a stable ion-pair with the soft carbanion, rather than with the hard hydroxide anion (Scheme 1.8). Strong evidence for the competing interface mechanism comes from the observation that, even in the absence of a catalyst, phenylacetonitrile is alkylated under two-phase conditions using concentrated sodium hydroxide [51],... 

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). 

A variety of other carbon nucleophiles have been alkylated with alcohols including malonate esters, nitroaUcanes, ketonitriles [119, 120], barbituric acid [121], cyanoesters [122], arylacetonitriles [123], 4-hydroxycoumarins [124], oxi-ndoles [125], methylpyrimidines [126], indoles [127], and esters [128]. Selected examples are given in Scheme 35. Thus, benzyl alcohol 15 could be alkylated with nitroethane 147, 1,3-dimethylbarbituric acid 148, phenylacetonitrile 149, methyl-pyrimidine 150, and even f-butyl acetate 151 to give the corresponding alkylated products 152-156. 

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). ... 

The utility of SCFs for PTC was demonstrated for several model organic reactions - the nucleophilic displacement of benzyl chloride with bromide ion (26) and cyanide ion (27), which were chosen as model reversible and irreversible Sn2 reactions. The next two reactions reported were the alkylation and cycloalkylation of phenylacetonitrile (28,29). Catalyst solubility in the SCF was very limited, yet the rate of reaction increased linearly with the amount of catalyst present. Figure 5 shows data for the cyanide displacement of benzyl bromide, and the data followed pseudo-first order, irreversible kinetics. The catalyst amounts ranged from 0.06 (solubility limit) to 10% of the limiting reactant, benzyl chloride. 

Active methylene compounds have more than one activating group such as carbonyl, cyano, sulfonyl, or aryl bound to a methylene carbon. Bases such as hydroxide ion easily remove a proton to form a reactive carbanion. The most widely studied example is the alkylation of phenylacetonitrile (Scheme 1). The abstraction of the proton is generally the rate limiting step. 

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