Nitriles acid exchange

Aromatic thioamides can be prepared as described in the literature by different ways, either by S -> O exchange between the corresponding benzamides and phosphorus pentasulfide in pyridine solution in the presence of triethylamine (65, 646) as strong base, or by action of H2S on the appropriate nitrile with pyridine and triethylamine solvents using the method of Fairfull et al. (34, 374, 503). In this reaction, thioacetamide in acidic medium can also be used as a H2S generator with dimethylform-amide as the solvent (485). 

Even ia 1960 a catalytic route was considered the answer to the pollution problem and the by-product sulfate, but nearly ten years elapsed before a process was developed that could be used commercially. Some of the eadier attempts iacluded hydrolysis of acrylonitrile on a sulfonic acid ion-exchange resia (69). Manganese dioxide showed some catalytic activity (70), and copper ions present ia two different valence states were described as catalyticaHy active (71), but copper metal by itself was not active. A variety of catalysts, such as Umshibara or I Jllmann copper and nickel, were used for the hydrolysis of aromatic nitriles, but aUphatic nitriles did not react usiag these catalysts (72). Beginning ia 1971 a series of patents were issued to The Dow Chemical Company (73) describiag the use of copper metal catalysis. Full-scale production was achieved the same year. A solution of acrylonitrile ia water was passed over a fixed bed of copper catalyst at 85°C, which produced a solution of acrylamide ia water with very high conversions and selectivities to acrylamide. 

Tiazofurine (142) is an antimetabolite with antineoplastic activity. It preferentially affects leukemic lymphocytes over normal cells due to selective activation by formation of its adenine dinucleotide by transformed cells. Of the syntheses available, one starts by conversion of iniidate 138 to methyl 2,5-anhydroallonothioate (139). Next, condensation with ethyl 2-amino-2-cyanoac-etate leads to the thioamide which undergoes thiol addition to the nitrile function to produce the amminothiazolecarboxyester system of 140 directly. Sodium nitrite in aqueous hypophosphorus acid eliminates the superfluous amino group via the diazonium transformation to give 141. This synthesis of tiazofurine (142) concludes by ester amide exchange in methanolic ammonia [48]. 

Trimetrexate (88) Is an antineoplastic agent related to the well-established folic acid antimeta-bolite methotrexate. It can be synthesized by selective diazotization of the most basic amino group of 2,4,6-triamino-5-methylquinazoline (85) followed by a Sandmeyer displacement with CuCN to give nitrile 86. Careful reduction asing Raney nickel produces the aminomethyl intermediate 87 or, if the reaction is carried out in the presence of 3,4,5-triniethoxyaniline, trimetrexate (88) [24]. One presumes that that outcome is a consequence of amine exchange at the partially reduced imine stage and further reduction. 

Thus, almost no examples have been reported of a-alkylation of /3-halo or /3-alkoxy ketones, nitriles, sulfones, or propanoic acid derivatives under basic reaction conditions. 1,2-Dihalides are usually converted into alkenes when halogen-metal exchange is attempted, even if highly strained alkenes are thereby formed (Scheme 5.53). 

The synthesis is straightforward. The nitrile 53 is alkylated and treated directly with acidic ethanol to give the ester 54 so that the new ester 55 can be made by ester exchange. The reduction of the benzene ring is the last step.10... 

Carboxylic -acids, nitriles, aldehydes, ketones Steam - distillation, solvent extraction, ion exchange chromatography, GC [677]... 

The 4-position is the most benzenelike and a 4-halogen resists nucleophilic attack with the exception of the formation of nitriles with cuprous cyanide9,70,93,94,99 and one case of the formation of a lithium derivative (see Section III,B). Halogen exchange has been observed during the diazotization of a 5-amino-4-bromoisothiazole in the presence of concentrated hydrochloric acid.119... 

Methylene groups adjacent to coordinated nitrile carbon are acidic (e.g. for R = CH2CN, P= 5.7) and rapidly undergo base-catalyzed proton exchange (for R = Me this is faster than hydrolysis), and addition of electrophiles other than H+ to the resulting carbanion (35 Scheme 19). 

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