Arylacetonitrile

The hydrolysis of arylacetonitriles may be arrest at the arylacetamide stage by treatment with concentrated hydrochloric acid at about 40° thus benzyl cyanide yields phenylacetamlde ... 

Inclusion of additional alkyl groups on the aromatic ring leads to decongestants with longer duration of action. Thus, reaction of the arylacetonitrile, 109, obtainable from hydrocarbon, 107, by chloromethylation (108), followed by displacement of the halogen by means of cyanide ion with ethylenediamine, leads to xylometazoline (111). The analogous reaction of the oxygenated derivative, 110, affords oxymetazoline (112). ... 

Lithiated areneacetonitriles react with a,/i-unsaturated ketones at low temperatures using short reaction times to give both 1,2- and 1,4-adducts. The 1,2-addition is reversible and under thermodynamic control (higher temperatures and longer reaction times) only the 1,4-adducts, i.e., <5-oxonitriles, arc obtained. When lithiated arylacetonitrile is added to 2-substituted 2-cy-cloalkenones in THF or in THF/HMPA mixtures at — 70-0°C, followed by protonation or alkylation under kinetically controlled conditions, predominantly cis- or fnms-2,3-disubstitut-ed cycloalkanones respectively, are obtained. 

A diastereoselective route to d.v-2,3-disubstituted cyclohexanones is based on the kinetically controlled protonation of the enolate obtained via the addition of an arylacetonitrile to 2-sub-stituted 2-cycloalkenones in THF or in THF/HMPA mixtures at — 70-0 °C 299,30°, see also refs 301, 302 and 403. 

This reaction is illustrative of a general procedure for the alkylation of active methylene functions in the presence of concentrated aqueous alkali catalyzed by tetraalkylammonium salts. This catalytic method has been used to alkylate arylacetonitriles with monohaloalkanes,2 dihaloalkanes,3 a-chloroethers,4 chloronitriles,.5 haloacetic acid esters,6 and halonitro aromatic compounds.7 It has also been used to alkylate ketones,8 lf/ indene,9 9i/-fluorene,ll) and the Reissert compound.11 The reaction is inhibited by alcohols and by iodide ion.2... 

A somewhat different type of coupling is observed when salts of (i-keto esters, arylacetonitriles (ArCH2CN), and other compounds of the form ZCH2Z are treated with an oxidizing agent such as iodine," " or Cu(II) salts." Arylmethanesulfonyl chlorides (ArCH2S02Cl) couple to give ArCH=CHAr when treated with Et N." ... 

An unusual domino process was observed by Biehl and coworkers [69] in the reaction of 2-bromo-l-naphthol 4-196 with arylacetonitriles in the presence of LDA or LiTMP by employing 3-thienylacetonitrile 4-197, the tetracyclic compound 4-200 was obtained in 57% yield (Scheme 4.43). The reaction probably includes the formation of an aryne and a ketenimine which undergo [2+2] cycloaddition to give 4-198, followed by rearrangement and allylic addition to the intermediately formed aryl cyano compound 4-199. 

A systematic study of the substrate specificity profile of this nitrilase (Table 8.6) illustrated that arylacetonitriles, including phenylacetonitrile derivatives indole-3-acetonitrile and... 

Bando and coworkers99 published a study where water-gas shift was used in an applied manner, to assist in the methylation of arylacetonitrile with formaldehyde, using RhCl3 as the homogeneous catalyst. Conditions T = 200 °C Pco = 101 atm 20 mg RhCl3 3H20 20 mmol arylacetonitrile 60-200 mmol paraformaldehyde 5 ml w-methylmorpholine 1 ml H20 and 10 ml dioxane 5 hours of reaction time. Results of their findings are presented in Table 25, and their proposed mechanism is shown in Scheme 38. 

Table 25 Methylation of arylacetonitrile with formaldehyde under water-gas shift conditions"... 

Arylacetonitrile ch2o/ arylacetonitrile Conversion Selectivity of arylpropionitrile... 

In the nitrogen analogue of the aldol condensation, nitrosoarenes condense with arylacetonitriles to produce cyanoimines [39]. When two equivalents of the acetonitrile is used, further condensation occurs to form [J-cyanovinylamines (Scheme 5.29) [40],... 

The most interesting and best-studied reaction, particularly in view of its selectivity, is the mono-C-methylation of arylacetonitriles (Scheme 4.6). 

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. 

It has been shown that, in the presence of lithium diethylamide at —70 °C, bromoben-zoic acids form arynes which may react with arylacetonitriles to yield, predominantly, 2-cyanobenzoic acids. The reaction of alkyl and aryl isocyanides with benzyne may yield benzamide derivatives, showing their ability to act as charge-reversed equivalents to isocyanates. The generation and cyclization of a benzyne-tethered alkyllithium have been reported, and lead to a convenient synthetic route for 4-substituted indans. ... 

The carbon-bond-forming reactions based on hydrogen transfer catalyzed by Cp Ir complex have been extended to the alkylation of active methylene compounds. Grigg et al. reported the alkylation of arylacetonitriles catalyzed by the... 

A possible mechanism for the alkylation of arylacetonitriles is shown in Scheme 5.30. The reaction would proceed via successive hydrogen transfer and Knoevena-gel condensation as follows ... 

Table 5.13 Alkylation of arylacetonitriles with benzyl alcohols catalyzed by [Cp lrCl2]2 ( ) ...

The [Cp lrCl2]2-catalyzed alkylation of arylacetonitrile 96 with primary alcohols has also been reported (Equation 10.21) [43]. Here, KOH proved to be the most successful base and the reaction proceeded in the absence of any solvent. 

In a related reaction arylacetonitriles are nitrated to the corresponding a-nitronitriles, which on alkaline hydrolysis and subsequent acidification, yield arylnitromethanes. This method has been used to convert phenylacetonitrile to phenylnitromethane in 70 % overall yield without the need for intermediate purification. 

Nucleophilic aromatic substitution of the anion from arylacetonitrile 113 on the dichloroni-trobenzene 114 results in replacement of the para halogen and formation of 115. Reduction of the nitro group gives the corresponding aniline (116). Acylation of the amine with 3,5-diiodoacetylsa-licylic acid 117 by means of the mixed anhydride formed by use of ethyl chloroformate, gives, after alkaline hydroly.sis, the anthelmintic agent closantel (118) [28]. 

A recent literature report described a green procedure for the condensation of arylacetonitriles with cyclic ketones using phase-transfer catalysis. This process was applied to the synthesis of venlafaxine, which was realized in overall 30% yield in two steps from commercially available 14. The condensation step was run in aqueous sodium hydroxide in the presence of tetrabutylammonium sulfate, to provide quantitative yield of intermediate 15. Hydrogenation in a formalin-methanol mixture provided the final product venlafaxine (1) in 30% overall yield. This protocol did not necessitate intermediate purification steps, making it attractive from the commercial standpoint. 

Pyrrolo[3,4-< ]pyridine derivatives can be synthesized from arylacetonitriles and 5-bromonicotinamide upon reaction with lithium diisopropylamide (LDA). The reaction proceeds in moderate yields (36-54%) <1998T3391>. 

The present method is that of Wenner 21 and is applicable to other arylacetonitriles.4... 

This compound has not been described in the literature previously. The method of preparation follows the general method described by Bruson for the cyanoethylation of arylacetonitriles. 

Phase-transfer alkylation has been utilized in the preparation of 1-arylcyclobutanecarbonitriles starting from arylacetonitriles and 1,3-dihalopropanes.10... 

---