Malononitrile hydrolysis

Maleonitrile, l,2-dicyanoethylene-l,2-dithio-metal complexes, 147 Malic acid metal complexes geochemistry, 867 Malononitrile hydrolysis metal catalysis, 450 Mammals iron... 

Malonic acid has been made by the hydrolysis of malononitrile with concentrated hydrochloric acid,2 by the hydration of carbon suboxide,3 and by the hydrolysis of cyanoacetic acid4 and its esters5 with potash. A method for the preparation of calcium malonate from chloroacetic acid and potassium cyanide is described by Fischer.6 Conrad7 liberated malonic acid from calcium malonate, so prepared, with oxalic acid. v. Miller,8 Grimaux and Tscherniak, and Bourgoin10 prepared malonic acid from chloroacetic acid and potassium cyanide, Petriev11 from... 

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]. 

Scheme 2.7 Asymmetric hydrolysis of disubstituted malononitrile 14 using a nitrile hydratase.

To complete the section on the synthesis of 4,4 -bipyridines, we summarize the methods reported for the preparation of some substituted 4,4 -bi-pyridines and 4,4 -bipyridinones. These methods are closely analogous to syntheses already discussed for some of the isomeric bipyridines. Thus the Hantzsch reaction using pyridine-4-aldehyde, ethyl acetoacetate, and ammonia gives 3,5-di(ethoxycarbonyl)-1,4-dihydro-2,6-dimethyl-4,4 -bipyridine, which after oxidation, followed by hydrolysis and decarboxylation, afforded 2,6-dimethyl-4,4 -bipyridine. Several related condensations have been reported. Similarly, pyridine-4-aldehyde and excess acetophenone gave l,5-diphenyl-3-(4-pyridyl)pentane-l,5-dione, which with ammonium acetate afforded 2,6-diphenyl-4,4 -bipyridine. Alternatively, 1-phenyl-3-(4-pyridyl)prop-2-enone, A-phenacylpyridinium bromide, and ammonium acetate gave the same diphenyl-4,4 -bipyridine, and extensions of this synthesis have been discribed. Condensation of pyridine-4-aldehyde with malononitrile in the presence of an alcohol and alkaline catalyst produced compounds such as whereas condensations of... 

The 6//-l,3-thiazin-6-iminium hydroperchlorate salts 78-81 give interesting products when treated with nucleophiles <2003H(60)2273>. Hydrolysis of 6-imino-6//-l,3-thiazine hydroperchlorate 78 affords (2Z,4Z)-2-cyano-5-hydroxy-5-phenyM-azapenta-2,4-dienethioamide 82 in excellent yield, while treatment with morpholine gives 2-(morpholinomethylene)malononitrile 83 and thiobenzamide. The 5-(ethoxycarbonyl) -(methylthio)-2-aryl-6/7-l,3-thiazin-6-iminium salts 79 and 80 react with hydroxide or morpholine to afford ethyl 4-(methylthio)-2-aryl-6-thioxo-l,6-dihydropyrimidine-5-carboxylates 84 and 85. In the case of the 4-chloro analogue 80, the (Z)-ethyl 2-(5-(4-chlorophenyl)-37/-l,2,4-dithiazol-3-ylidene)-2-cyanoacetate 87 is also formed for the reaction with sodium hydroxide. The 1,2,4-dithiazoles 86 and 87 can be obtained as the sole product when 79 and 80 are treated with sodium acetate in DMSO. Benzoxazine 88 is isolated when the iminium salt 81 is treated with morpholine or triethylamine. Nitrile 89 is formed as a ( /Z)-mixture when 6-imino-67/-l,3-thiazine hydroperchlorate 79 is reacted with triethylamine and iodomethane in methanol <2003H(60)2273>. 

Transformation of both the ester and nitrile derivatives 726 or 727 into pyrano[2,3-t7 pyridazines 728 or 729, respectively, by treatment with dilute HCl at room temperature involved nucleophilic displacement of the morpholine group by the hydroxyl group with an acidic hydrolysis followed by intramolecular iminolactonization and then hydrolysis of the formed imino group to a carbonyl group. Compounds 726 and 727 were prepared by Vilsmeier-Haack formylation of 2-methyl-5-morpholino-3(2/7)-pyridazinone 724 followed by condensation of the resulting product 725 with either ethyl a-cyanoacetate or malononitrile in EtOH (Scheme 34) <1994H(37)171>. 

Excellent results were also obtained using activated hydrotalcite as a solid base catalyst in the Knoevenagel condensation of benzaldehyde with ethylcya-noacetate [110], ethylacetoacetate [111] or malononitrile [112] (see Fig. 2.34). Similarly, citronitrile, a perfumery compound with a citrus-like odor, was synthesized by hydrotalcite-catalyzed condensation of benzylacetone with ethyl-cyanoacetate, followed by hydrolysis and decarboxylation (Fig. 2.34) [113]. 

The general approach can be enlarged and conditions for condensation made milder by the use of further-activated esters, thus condensation with methyl nitroacetate produces 3-nitro-coumarins, condensations with Wittig ylides " allow orffto-hydroxyaryl ketones to be used ° and the use of diethyl malonate (or malonic acid ) (a 3-ester can be removed by hydrolysis and decarboxylation ), malononitrile, ethyl trifluo-roacetoacetate, or substituted acetonitriles in a Knoevenagel condensation, produces coumarins with a 3-ester, 3-trifluoroacetyl, " 3-cyano, or 3-alkyl or -aryl substituent. Condensation with IV-acetylglycine generates 3-acetylamino-coumarins. ... 

Acetonitrile (130) and malononitrile (131) both react with salt (1) to yield products of disubstitution (Scheme 10). llie monosubstituted intermediates (132) and (133) react at carbon and nitrogen, giving, after hydrolysis, products (134) and (135), respectively. Salt (135) affords the heterocycle (136) when treated with ammonia. - ... 

Malononitrile (in THE at 20-25 °C overnight) and cyanoacetamide (in water at 20-25 °C for 5 days) react with pteridines, e.g. I, to give pyrido[2,3-6]pyrazines, e.g. 2, by addition across the 3,4-bond followed by scission of that bond and a nitrogen-eliminating recyclization. The intermediate of the reaction with cyanoacetamide can be isolated by addition of aqueous sodium hydroxide. Because the product from malononitrile can be generated under anhydrous conditions, it can be concluded that the reaction takes place by a concerted cyclization of the amidine intermediate with elimination of hydrogen cyanide, rather than via a pyridazinamine which could arise by hydrolysis of this amidine (cf. similar reactions in other fused pyrimidine series).56,64-66... 

Note CS = o-chlorobenzylidene malononitrile CR = dibenz-(b,f)-l 4 oxazepine CN = chloroace-tophenone OC = oleoresin capsicum DM = adamsite CA = bromobenzylcyanide PS = chloropicrin. Vapor pressure at 20°C (68°F) (mmHg). Volatility, mg/mVC for other than 20°C. Solubility, I = limited in water, O = soluble in organics, C = soluble in chlorinated organics. Hydrolysis (rate of hydrolysis). (—) Denotes no value. 

Dimethoxy-2-pyrrolidinopropene (196) has been shown to be a useful synthon for the synthesis of formylpterins and related compounds. Thus treatment of (196) with nitrosyl chloride, followed by hydrolysis, yields 1,1-dimethoxy-3-oximino-2-propanone (197), which on treatment with amino-malononitrile gives a pyrazine (198) that is suitable for elaboration to a formylpterin (Scheme 89). Two nine-step syntheses, from pyrazine intermediates, of deoxyurothione (199) have been announced. A practical synthesis of the urinary thienopterin urothione (200) still remains a synthetic challenge. ... 

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