Nitrile 3-cyanopyridine

P-Cyanopyridine. Mix 25 g. of powdered nicotinamide with 30g. of phosphoric oxide in a 150 ml. distilling flask by shaking. Immerse the flask in an oil bath and arrange for distillation under a pressure of about 30 mm. Raise the temperature of the oil bath rapidly to 300°, then remove the oil bath and continue the heating with a free flame as long as a distillate is obtained. The nitrile crystallises on cooling to a snow-white solid. Redistil the solid at atmospheric pressure practically all of it passes over at 201° and crystallises completely on cooling. The yield of p-cyanopyridine, m.p. 49°, is 20 g. 

Cyanopyridines are usually manufactured from the corresponding picoline by catalytic, vapor-phase ammoxidation (eq. 7) in a fixed- or fluid-bed reactor (28). 3-Cyanopyridine (25) is the most important nitrile, as it undergoes partial or complete hydrolysis under basic conditions to give niacinamide... 

A process research investigation on p38 MAP kinase inhibitors examined the synthesis (on 7 mol scale) of a group of closely related pyrimidinones such as 37, by condensation of a number of arylacetic esters with 4-cyanopyridine and methyl isothiocyanate. Other nitriles were also examined but were much less successful than 4-cyanopyridine 3-cyanopyridine gave a much lower yield and both benzonitrile and 2-cyanopyridine failed completely <06T11714>. 

Surprisingly, aromatic nitriles were found not to yield 1-arylcyclopropylamines under these conditions. However, this deficit is compensated for by a complementary method developed by de Meijere et al. using diethylzinc in the presence of methyltitanium triiso-propoxide and lithium isopropoxide (Scheme 11.40). While aliphatic nitriles 152 gave primary cyclopropylamines 155 in only 12—16% yield with this reagent mixture, aromatic nitriles 156 and 158 furnished 1-arylcyclopropylamines 157 and 159 in moderate (28—40% for substituted benzonitriles 156) to good (70% for 3-cyanopyridine 158) yields (Scheme 11.40) [138],... 

Cyanides can react with 1-aminopyridinium salts to give 2-substituted triazolopyridines, possibly via the pyridinium ylide. With 1-aminopyridinium iodide and cyanide ion the intermediate 4-cyanopyridine reacts with the aminopyridinium salt to give 2-(4-pyridyl)triazolopyridine (45).51 When acetonitrile or benzonitrile are used, 2-methyl- and 2-phenyltriazolo-pyridines are obtained.58 60 The reaction is thought to involve a dipolar cycloaddition of the N- mi nopyridine with the nitrile, as shown in Eq. (4). 

In recent years there has been considerable interest in the reactions of nitriles in the coordination sphere of metal ions. Breslow et al.312 first reported that the hydrolysis of 2-cyano-l,10-phenanthro-line to the corresponding carboxamide is strongly promoted by metal ions such as copper(II), nickel(II) and zinc(II). Base hydrolysis of the 1 1 nickel complex is 107 times faster than that of the uncomplexed substrate. The entire rate acceleration arises from a more positive value of AS. Somewhat similar effects have been observed for base hydrolysis of 2-cyanopyridine to the corresponding carboxamide. In this case rate accelerations of 109 occurred with the nickel(II) complex.313... 

In basic chemicals, nitrile hydratase and nitrilases have been most successful. Acrylamide from acrylonitrile is now a 30 000 tpy process. In a product tree starting from the addition of HCN to butadiene, nicotinamide (from 3-cyanopyridine, for animal feed), 5-cyanovaleramide (from adiponitrile, for herbicide precursor), and 4-cyanopentanoic acid (from 2-methylglutaronitrile, for l,5-dimethyl-2-piperidone solvent) have been developed. Both the enantioselective addition of HCN to aldehydes with oxynitrilase and the dihydroxylation of substituted benzenes with toluene (or naphthalene) dioxygenase, which are far superior to chemical routes, open up pathways to amino and hydroxy acids, amino alcohols, and diamines in the first case and alkaloids, prostaglandins, and carbohydrate derivatives in the second case. 

Nitrile Hydratase Acrylamide from Acrylonitrile, Nicotinamide from 3-Cyanopyridine, and 5-Cyanovaleramide from Adiponitrile... 

Characteristic of this process are its extremely high concentration level and space-time-yield (Figure 7.2). Solid nitrile substrates render precipitating product up to a solid medium at high degrees of conversion liquid nitriles can be run as neat substrate. Figure 12.3 illustrates the connection between substrate concentration up to 15 m ( ) and achievable degree of conversion for the example of the transformation of 3-cyanopyridine to nicotinamide discussed in Chapter 7, Section 7.1.1.2. 

The nitrile group in cyanopyridine can participate in intramolecular reactions. The presence in chalcone 118 of an ortho-hydroxyl substituent can lead to its addition to a carbon-nitrogen triple bond, with the formation of the 2/7-pyran-2-iminic moiety (compound 119) [126, 127] (Scheme 3.36). 

The palladium-catalyzed, microwave-assisted conversion of 3-bromopyridine to 3-cyanopyridine using zinc cyanide in dimethylformamide (DMF) has been reported <2000JOC7984>. Substoichiometric quantities of copper or zinc species improve both conversion rate and efficiency of Pd-catalyzed cyanation reactions <1998JOC8224>. A modification of this procedure uses a heterogeneous catalyst prepared from a polymer-supported triphenylphosphine resin and Pd(OAc)2 the nitriles were obtained from halopyridines in high yields <2004TL8895>. The successful cyanation of 3-chloropyridine is observed with potassium cyanide in the presence of palladium catalysts and tetramethylethylenediamine (TMEDA) as a co-catalyst <2001TL6707>. 

Isoquinolines can be generated from benzocyclobutanol and 2-cyanopyridine <1994TL9191> (Equation 185). Zirconocene-copper-mediated coupling of benzocyclobutanes in the presence of nitriles gives the isoquinoline, albeit with only select examples of 3-substitution (Scheme 116) <20030L877>. 

The carbon-nitrogen triple bond in nitriles is reducible to an aminomethyl group in acidic media at lead or mercury electrodes 9 whereas in neutral or alkaline medium cleavage of the C-CN bond takes place 146 148). This duality of mechanism has been studied in great detail for 2- and 4-cyanopyridine 146 and it was demonstrated that both pH and electrode potential is of importance in determining the mechanism. 

Similarly, DuPont employs a nitrile hydratase (as whole cells of P. chlororaphis B23) to convert adiponitrile to 5-cyanovaleramide, a herbicide intermediate [122]. In the Lonza nitrotinamide (vitamin B6) process [123] the final step (Fig. 1.42) involves the nitrile hydratase (whole cells of Rh. rhodocrous) catalysed hydration of 3-cyanopyridine. Here again the very high product purity is a major advantage as conventional chemical hydrolysis affords a product contaminated with nicotinic acid, which requires expensive purification to meet the specifications of this vitamin. 

Alkylnitriles, arylnitriles, arylalkylnitriles, 3-cyanopyridine, Heterocyclic nitriles, arylalkylnitriles, (cyclo) alkylnitriles... 

Nagasawa, T., Mathew, C.D., Manger, 1., et al. 1988. Nitrile hydratase-catalysed prodnction of nicotinamide from 3-cyanopyridine in Rhodococcus rhodochrous 11. Applied and Environmental Microbiology, 54 1766-9. 

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