Phenylacetonitrile carboxylation

The recombinantly expressed nitrilase from Pseudomonas fluorescens EBC 191 (PFNLase) was applied in a study aimed at understanding the selectivity for amide versus acid formation from a series of substituted 2-phenylacetonitriles, including a-methyl, a-chloro, a-hydroxy and a-acetoxy derivatives. Amide formation increased when the a-substituent was electron deficient and was also affected by chirality of the a- stereogenic center for example, 2-chloro-2-phenylacetonitrile afforded 89% amide while mandelonitrile afforded 11% amide from the (R)-enantiomer but 55% amide was formed from the (5)-enantiomer. Relative amounts of amide and carboxylic acid was also subject to pH and temperature effects [87,88]. 

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. 

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. 

Fig. 7.9. Partial hydrolysis of phenylacetonitrile (A) under basic conditions to give the primary carboxylic acid amide B, and the possibility of hydrolyzing the latter to yield phenylacetic acid (C).

This ring closure takes place readily whenever the carbonyl and amino groups occur in the relative positions shown above. Reduction of o-nitro-phenylacetonitrile by stannous chloride produces indole rather than the corresponding amino aldehyde. The synthesis is most useful for the preparation of indole-2-carboxylic acid by reduction of o-nitrophenyl-pyruvic acid with ferrous sulfate and ammonia or with sodium hydrosulfite. The ethyl ester is obtained by a similar reduction with zinc and acetic acid or by catalytic hydrogenation of ethyl o-nitrophenyl-pyruvate over platinum oxide catalyst. ... 

Carboxylation reaction of active methylene compounds with lanthanoid system was first attained by using a lanthanoid complex obtained from the reaction between lanthanum isopropoxide (LalO Prlj) and 2 equiv of phenyl isocyanate (Ph-N=C=0). Under CO2 at atmospheric pressure, phenylacetonitrile, an active methylene compound (equimolar with respect to LalCyPrlj), was effectively... 

In addition to phenylacetonitrile and fluorene, various active methylene compounds such as indene, propiophenone, phenyl propionate, benzyl phenylacetate afforded the corresponding carboxylated products by the carboxylation reaction with La(0 Pr)3-Ph-N=C=0-C02 system. Of fundamental and practical importance is that S-benzyl thiopropionate was effectively carboxylated into a thioester of 2-methylmalonate in a good yield, since this reaction is related to the biological carboxylation of propionyl coenzyme A with a biotin enzyme. Other thioesters were also carboxylated similarly, where successful examples were thioesters of phenylacetic, acetic, and isovaleric acids carrying active methylene and methyne groups, respectively. 

Pyrido[2,3-(7]pyrimidincs 23, unsubstituted in the 2,4-positions, have been synthesized by condensation of ethyl 4-aminopyrimidine-5-carboxylate with several esters, phenylacetonitrile, phenylacetamide, or malonic ester chloride.173 In the first step, the 4-amino group reacts with the ester, nitrile, or acid chloride function of the cyclization partner, ring closure then being effected by a Dieckmann-type cyclization. 

Other reactions which form nitrile oxides or their cycloadducts from furoxans are known, but in the majority of these cases their course is not clear. 4-Phenylfuroxan with mild base rearranges to the isomeric a-oximino-phenylacetonitrile oxide (see Section VI). The distillation of 3-ethoxy-carbonylfuroxan-4-carboxylic acid (70) appears to generate the nitrile oxide 72, since one of the products isolated is diethyl furoxandicarboxylate (71).335,336 The diester (71) with anethole is reported to form ethyl 4-anisyI-5-methylisoxazole-3-carboxylate (73),337 but it is not established that the reaction involves the generation of 72 by dissociation of 71, as the authors suggested (see Section V,C,1). See also Section X. 

NaOH), leading to the formation of significant amounts of diethylated product. Under solid-supercritical fluid PTC, only traces of this by-product were detected. Moreover, the use of a weak solid base presents evident advantages in view of an industrial application of the method. It should be noted that the use of SCCO2 as a bulk solvent led to the formation of an undesired cyanoester as the main product (Fig. 13), because the carbanion formed by deprotonation of phenylacetonitrile quickly reacts with CO2, forming a carboxylate anion that is then alkylated by ethyl bromide. 

During an investigation of approaches to the total synthesis of anthracyclinone antibiotics, it has been found that carbanions derived from phenylacetonitrile add to ethyl cyclohex-2-en-l-carboxylate in a Michael fashion to give, after oxidative decyanation, the y-keto-ester (155) in good yield. 

Other substances possessing an addic methylene group have been incorporated in aldol-type reactions. These materials include ethyl cyanoacetate and ethyl acetoacetate, as well as phenylacetonitrile, benzyl ketones, and aliphatic nitro compounds. The reaction is often run in benzene or toluene solvent, so that the water formed can be continuously removed. Other cocatalysts, besides carboxylic adds, are various ammonium salts, such as ammonium... 

Nitrile enolates can also react with carbonyl derivatives such as oxalate, which serves as a carboxyl surrogate. Reaction of 2-phenylacetonitrile and diethyl oxalate, in the presence of sodium amide, gave 4.99. " Catalytic hydrogenation of the cyano group and hydrolysis led to ethyl 2-phenyl-3-aminopropanoate, 4.100. In this case also, the nitrile moiety was an amine surrogate. Other a-aryl acetonitrile derivatives... 

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