Alkylation of phenylacetonitrile

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. 

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... 

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. 

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%).

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). ... 

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. 

Only limited information is available on the effect of active site structure on activity of polymer-supported quaternary ammonium ion catalysts for alkylation of phenylacetonitrile (Eq. (7)). Dou and co-workers 10l) reported approximately the same activity for six different type 1 (2) and type 2 (14) Dowex105) ion exchange resins. Conversions of 5(1-70% were obtained in 10 h at 70 °C using 0.1 mol each of phenylacetonitrile and 1-bromobutane, 40 ml of 50% NaOH and 1 4 g (3.5-18 mequiv) of resin. The triphase mixtures were vigorously stirred by a method not reported. The similar results from resins of widely different cross-linking and porosity, both macro-... 

Effects of polymer structure on reaction of phenylacetonitrile with excess 1-bromo-butane and 50% NaOH have been studied under conditions of constant particle size and 500 rpm stirring to prevent mass transfer limitations I03). All experiments used benzyltrimethylammonium ion catalysts 2 and addition of phenylacetonitrile before addition of 1-bromobutane as described earlier. With 16-17% RS the rate constant with a 10 % CL polymer was 0.033 times that with a 2 % CL polymer. Comparisons of 2 % CL catalysts with different % RS and Amberlyst macroporous ion exchange resins are in Table 6. The catalysts with at least 40% RS were more active that with 16 % RS, opposite to the relative activities in most nucleophilic displacement reactions. If the macroporous ion exchange resins were available in small particle sizes, they might be the most active catalysts available for alkylation of phenylacetonitrile. 

Table 6. Effect of % Ring Substitution on Activity for Alkylation of Phenylacetonitrile 103)...

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. 

Makosza and Goetzen82 have described the preparation of a four-membered ether by a method similar to that used for the alkylation of phenylacetonitrile and its derivatives. 

The 2-substituted-2-cyano-arylethyltriazoles were prepared by sequential alkylation of substituted phenylacetonitriles (4) as shown in Figure 2. The alkylation of phenylacetonitriles were performed under a variety of basic... 

Alkylation of phenylacetonitrile usingNaOH, instead of expensive sodium ethoxide. 

Makosza, M., andE. Bialecka, Reactions of Organic Ions LXXIIL Alkylation of Phenylacetonitrile at the Interface with Aqueous Sodium Hydroxide, Tetr.Lett., 2, 1983 (1977). 

Ragaini, V., G. Colombo, P. Barzhagi, E. Chiellini, and S. D Antone, Phase Transfer Alkylation of Phenylacetonitrile in Prototype Reactors Under Magnetic or Ultrasound Mixing Conditions 2. Kinetic Modeling, Eng. Chem. Res., 29, 924 (1990). 

Double alkylation of phenylacetonitrile with 1, 5-dibromopentane yields the eorresponding cyclohexane, with the elimination of two moles of hydrogen bromide. The resulting product on saponification gives the corresponding aeid, which on first treatment with N, N-diethylethanolamine hydrochloride and secondly with catalytic reduction yields the desired official compound. 

In the case of methylenic carbanions there is an important problem of selectivity of mono- versus di-alkylation, exemplified by the alkylation of phenylacetonitrile ... 

It should be stressed that, on the other hand, the catalytic process proceeds efficiently with alkyl bromides whereas PT-catalyzed alkylation with alkyl iodides is inhibited by the iodide ions produced during the reaction. The interfacial alkylation of phenylacetonitrile with alkyl iodides is limited by the rate of transfer of iodide anions from the interface to the aqueous phase. 

In order to exemplify the benefits and advantages of the PTC methodology over traditional techniques direct comparison is made of the alkylation of phenylacetonitrile, the first industrial application of this technique. 

One should stress that the first industrial application of this green technology for alkylation of phenylacetonitrile was in a Polish pharmaceutical factory in the early 1960s it was subsequently used in many other companies. 

Fig. 13 Alkylation of phenylacetonitrile in supercritical fluids Adapted from Ref [61].

Alkylation of Phenylacetonitrile. Phenylacetonitrile is very selectively monomethylated with DMC into 2-phenylpropionitrile over alkali ion-exchanged zeolites, as mentioned before, [reaction (13)] (58). Phenylacetonitrile is also methylated with methanol over alkali ion-exchanged zeolites (58). 

The way of operation of PTC is best explained using typical examples of reactions of inorganic anions and carbanions cyanation of an alkyl halide and alkylation of phenylacetonitrile. 

Alkylation of phenylacetonitrile proceeds via reaction of its carbanion, generated usually by action on the nitrile of such strong bases as NaNH2, NaH, R2NLi etc., with an appropriate alkyl halide (eq. 3). 

In the PT-catalyzed alkylation, concentrated aqueous NaOH solution is used instead of these bases. No reaction proceeds when a two-phase system, phenylacetonitrile with an alkyl halide and concentrated aqueous NaOH solution, is vigorously stirred. Addition of small quantities of a TAA salt results in exothermic process of alkylation of phenylacetonitrile proceeding according to equations 4a and 4b. 

The problem of recovering the heterogeneous catalyst after the sonication reaction in a slurry reactor (SR) is an important one on the industrial scale. In fact the breaking of the catalytic particles, due to ultrasound action, can produce a very fine powder recoverable only with difficulty by filtration, and therefore easily contaminating the reaction products. The authors of the present chapter have faced this problem for the phase transfer (PT) alkylation of phenylacetonitrile with butyl bromide (Eq. 11) using a PT catalyst supported on insoluble polystyrene cross-linked with divinylbenzene. ... 

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