Nitrile group activation

A thioamide of isonicotinic acid has also shown tuberculostatic activity in the clinic. The additional substitution on the pyridine ring precludes its preparation from simple starting materials. Reaction of ethyl methyl ketone with ethyl oxalate leads to the ester-diketone, 12 (shown as its enol). Condensation of this with cyanoacetamide gives the substituted pyridone, 13, which contains both the ethyl and carboxyl groups in the desired position. The nitrile group is then excised by means of decarboxylative hydrolysis. Treatment of the pyridone (14) with phosphorus oxychloride converts that compound (after exposure to ethanol to take the acid chloride to the ester) to the chloro-pyridine, 15. The halogen is then removed by catalytic reduction (16). The ester at the 4 position is converted to the desired functionality by successive conversion to the amide (17), dehydration to the nitrile (18), and finally addition of hydrogen sulfide. There is thus obtained ethionamide (19)... 

The methyl groups adjacent to the pyridine nitrogens can also be modified without changing calcium channel blocking activity. The most significant change involves replacement of methyl by a nitrile group. Hantsch type condensation of the nitrobenzaldehyde 43 with methyl acetoacetate and the vinyl amine 44 from isopropyl 3-cyano-3-ketopropionate leads directly to nilvadipine (45) [13]. 

This, naturally, results in an increased electrophilicity of the nitrile group and also creates favourable conditions for the nucleophilic attack of the mercapto anion and an easy addition of hydrogen sulfide in accordance with the above scheme. The activation energy of the thioamidation of the model compounds is much higher (for glutarodinitrile — 11,8 [49,4] and for trinitrile - 7,97 kcal/mol [33,4 kJ/mol]) than in PAN (6,18 kcal/mol [25,9 kJ/mol]). 

The highest value of activation energy is observed in acetonitrile (17,52 kcal/mol [73,35 kJ/mol]), in which the mutual effect of the nitrile groups is absent. 

The biocatalytic differentiation of enantiotopic nitrile groups in prochiral or meso substrates has been studied by several research groups. For instance, the nitrilase-catalyzed desymmetrization of 3-hydroxyglutaronitrile [92,93] followed by an esterification provided ethyl-(Jl)-4-cyano-3-hydroxybutyrate, a useful intermediate in the synthesis of cholesterol-lowering dmg statins (Figure 6.32) [94,95]. The hydrolysis of prochiral a,a-disubstituted malononitriles by a Rhodococcus strain expressing nitrile hydratase/amidase activity resulted in the formation of (R)-a,a-disubstituted malo-namic acids (Figure 6.33) [96]. 

There are two pathways for the degradation of nitriles (a) direct formation of carboxylic acids by the activity of a nitrilase, for example, in Bacillus sp. strain OxB-1 and P. syringae B728a (b) hydration to amides followed by hydrolysis, for example, in P. chlororaphis (Oinuma et al. 2003). The monomer acrylonitrile occurs in wastewater from the production of polyacrylonitrile (PAN), and is hydrolyzed by bacteria to acrylate by the combined activity of a nitrilase (hydratase) and an amidase. Acrylate is then degraded by hydration to either lactate or P-hydroxypropionate. The nitrilase or amidase is also capable of hydrolyzing the nitrile group in a number of other nitriles (Robertson et al. 2004) including PAN (Tauber et al. 2000). 

Incompatibility of the nitrile group with the oxidative work-up of the L-Selectride reduction using basic hydrogen peroxide Significant hydrolysis to the primary amide with concomitant exothermic activity and loss of product... 

The 1,3-dipolar cycloaddition of azido-l,2,5-oxadiazoles (azidofurazans) to dicarbonyl compounds has been studied and a new procedure for the synthesis of (l,2,3-triazol-l-yl)-l,2,5-oxadiazoles was proposed <2002MC159>. The cycloaddition of 4-amino-3-azido-l,2,5-oxadiazole 168 to nitriles with activated methylene groups has been studied, and 3-amino-4-(5-amino-l/7-l,2,3-triazol-l-yl)-l,2,5-oxadiazoles 169 and the products of their Dimroth rearrangement 170 have been synthesized <2004MC76>. 

RCu(CN)ZnI.u These new copper reagents are prepared by reaction of primary or secondary iodides with zinc that has been activated with 1,2-dibromoethane and chlorotrimethylsilane. The resulting organozinc compounds are then allowed to react with the THF-soluble CuCN-2LiCl (equation I). Because of the mild conditions, these new reagents can be prepared from iodides containing keto, ester, and nitrile groups. 

Reduction of vinyloxiranes The substrates are reduced rapidly by Sml2 to (E)-allylic alcohols without effect on keto, ester, or nitrile groups. Chiral substrates are reduced to optically active alcohols with complete retention of stereochemistry. 

B Liberek. The nitrile group in peptide chemistry. V. Racemization during peptide synthesis. 4. Racemization of active esters of phthaloyl-P-cyano-L-alanine in the presence of trie thy lamine. Acad Pol Sci Ser Sci Chim 11, 677, 1963. 

Typical liquickliquid alkylation of methylene groups activated by a carbonyl or nitrile group... 

Addition of HCN to acetone to form the cyanohydrin is still the main route to methyl methacrylate. Hydrocyanins can be converted to amino acids as well. The nitrile group can be easily converted to amines, carboxylic acids, amides, etc. Addition to aldehydes and activated alkenes can be done with simple base, but addition to unactivated alkenes requires a transition metal catalyst. The methods of HCN addition have been discussed by Brown [2],... 

Hexamethylbiguanide (CLXIX) reacts additively in acetonitrile with a,P Unsaturated compounds activated by an electron-withdrawing group (e.g. with vinyl cyanide) to yield saturated adducts (CLXX). By a suitable choice of reagents, adducts bearing substituents other than the nitrile group (e.g. carbamoyl, carbalkoxy) are accessible 213) ... 

The nitrile group, similarly to a carbonyl, can serve as an activator for ketones in the syntheses of aminopyrans. Reaction of benzoylacetonitrile 39 with UNs 30 and 31 illustrates Method 1 (83LA1468,86M247) (Scheme 9). 

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