Reaction with cyanoacetamides

An analogous scheme is used for the synthesis of the cardiotonic agent milrinone [28]. The key aminoformyl derivative (26-2) is obtained in this case by condensation of 4-pyridylacetone (26-1) with DMF acetal. Reaction with cyanoacetamide in the presence of a strong base proceeds exactly as above to give the pyridone (26-3) by a parallel set of transformations. Note that the nitrile is left as such in this drug. 

Cyanoacetamides yield a-cyanoacrylamides (124) stereoselectively upon reaction with aldehydes and nonselectively with ketones under standard Knoevenagel conditions. a-Cyanoacrylamides (124) are also obtained by partial hydrolysis of methylenemalonodinitriles. With 1,3-diketones, e.g. acetyl-acetone, pyridones like (125) are formed upon reaction with cyanoacetamides. Base-catalyzed dimerization of a-cyanoacrylamides (124) yields piperidones. ... 

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... 

Diphenyl-1,2-dithiolium perchlorate (12) has been employed as a 1,3-dicarbonyl equivalent for pyridine synthesis, as illustrated by its reaction with cyanoacetamide to give the cyanopyridone (13) (Scheme 1) ... 

The dicarbanion of acetoacetaldehyde is alkylated in the y-position to give salts and copper chelates of j3-ketoaldehydes (W-112 R = C6H5CH2, CH3, n-C Hg and n-CgHn), which are converted to 3-cyano-2-pyridones (XII-113 R = CH3, C6H5CH2, -C4H9) by reaction with cyanoacetamide. n-Butylation of the dianion of a-benzylacetoacetaldehyde followed by cyclization with aqueous cyanoacetamide gives 5-benzyl-3-carboxamido-6-n-pentyl-2-pyridone... 

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)... 

A novel synthesis of alkylsulfanylisothiazoles 230 starts with sodium a-cyanoketene dithiolates 227, obtained by the reaction of cyanoacetamides 226 with carbon disulfide in the presence of sodium ethoxide <06SC825>. Treatment of 227 with sulphur and piperidine acetate generates sodium isothiazole-3,5-dithiolates 229. The formation of 229 is assumed to arise from the addition of anionic sulphur to the nitrile group in 227 to give the intermediate 228, which cyclizes upon elimination of anionic sulphur to yield 229. Salts 229 are readily alkylated to furnish 3,5-bis(alkylthio)isothiazole derivatives 230. 

Azide 367 is prepared from 4-r -butyl-2-nitroaniline in 76% yield by its diazotization followed by treatment with sodium azide. In a 1,3-dipolar cycloaddition with cyanoacetamide, azide 367 is converted to triazole 368 that without separation is directly subjected to Dimroth rearrangement to give derivative 369 in 46% yield. Reduction of the nitro group provides ortfc-phenylenediamine 371 in 91% yield <2000EJM715>. Cyclocondensation of diamine 371 with phosgene furnishes benzimidazol-2-one 370 in 39% yield, whereas its reaction with sodium nitrite in 18% HC1 leads to benzotriazole derivative 372, which is isolated in 66% yield (Scheme 59). Products 370 and 372 exhibit potassium channel activating ability <2001FA841>. 

Likewise, suitable starting materials are iminoisoindolines, especially diimino-isoindoline (l-amino-3-iminoisoindolenine), which reacts with a cyanoacetamide NCCH2CONHR5 to afford a mono-condensation product 49. Further reaction with a compound containing an activated methylene group (such as cyanoacetamide derivatives, barbituric acid) yields the desired pigment 47 ... 

The reaction was found to fail with l-methyl-5-nitrouracil and 5-nitrouracil. This is because both uracils, containing dissociable protons, exist in the basic solution in the anionic forms, which inhibit the addition of the nucleophiles at the C-6 position. Attempts to bring about these pyrimidine-to-pyrimidine ring transformations with cyanoacetamide, ace-toacetamide, and phenylacetamide were not successful. A substituent at C-6 of 5-nitrouracil suppressed the reaction l,3,6-Trimethyl-5-nitrouracil was recovered almost quantitatively. 

Starting material for the synthesis is the enaminoaldehyde obtainable by some version of the Villsmeyer reaction on pi coline derivative 9. Condensation of that with cyanoacetamide in the presence of methoxide leads to pyridone J. The reaction can be rationalized by assuming that the initial step consists in Michael addition of the anion from acetamide to the acrolein elimination of dimethyl amine would afford the intermediate Conden-... 

Malononitrile and cyanoacetamide only give aminopyrans. However, in reaction with cyanoacetic ester 27b aminopyran 233 has been isolated from the mother liquor and also side product 234 from the cooled mixture. Mechanistic considerations have been proved by the isolation of a deace-tylated intermediate (95M615). Similar transformations occur in the synthesis of spiropyrans 235 from benzothiazole 236 (97G605) (Scheme 90). 

The condensation of the N- methylpiperidine (270) with cyanoacetamide gives the hexahydro-2,7-naphthyridine (271) (67AK(26)489), and the reaction between a-oxoketene S,S- acetals (272) and N- methylcyanoacetamide gives the 2,7-naphthyridine derivatives (273) <78JCS(P1)554>. 

Dicyanomethane or Malononitrile (called Malonsaure-dinitril, Malonitril or Methylen-cyanid in Ger), NC.CH2.CN mw 66.06, N 42.41% col crysts, mp 31.6-32.4°, bp 108-09° at 17mm press, cryst d 1.191 at 20°, liq d 1.0494 at 35°, nfi 1.4139 at 34.2° prepd by esterification of cyanoacecic acid, and treatment of the ester with NH3 which leads to cyanoacetamide which, on reaction with phosphorous oxychloride or pentachloride, gives Dicyanomethane (Ref 1)... 

Vinylogous ketone 12 reacts with cyanoacetamide (3) in a Michael reaction to give a diastereomeric mixture of chain and ring tautomers 13a and 13b... 

By reaction of ethyl acetoacetate with cyanoacetamides, pyridones are easily accessible. By selection of suitable substituents in the diazo components, shade and fastness properties and build up can be controlled (e.g., 39-42 and Disperse Yellow 211). 

The 1,3-dipolar cycloaddition of azidoalkylphosphonates to enamines afforded A2-1,2,3-triazoles which are further converted to the 1,2,3-triazoles [95H(40)543] fused triazoles are similarly obtained when a cyclic enamine was employed. Fused 1,2,3-triazole (88), a xanthine oxidase inhibitor, was prepared by the reaction of an alkyl azide with cyanoacetamide with further elaboration of intermediate (87) by treatment with HMDS in xylene [95FES257]. The fused 4H-l,2,3-triazolo[l,5- ][l,4]benzodiazepin-6(5H)-one (90) was obtained from propargylamide (89) via an intermediate azide [95S647]. 

Benzo-TAs 63 were obtained from 2-mercaptobenzoic acid and functionally substituted nitriles (malonodinitrile, cyanoacetamide, cyanoaceto-anilide, etc.). In this case, however, the formation of by-product 65 takes place. The ratio of yields of products 63 and 65 depends on the conditions. Thus, in pyridine only 1,3-benzo-TAs 63 are formed, while in acetic acid the ratio of mono and bis products 63 and 65 is 3 1. The authors suggest that the initial intermediate 62 may give 1,3-benzo-TAs 63, whose reaction with another molecule of 2-mercaptobenzoic acid leads to bis product 65,... 

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