Ethyl malononitrile

Hydrochlorides of. V-(2-cyanovinyI)benzene-l,2-diamine, prepared from benzenc-1,2-diamine and (ethoxymethylene)malononitrile or ethyl cyano(ethoxymethylene)acetate, cyclize to salts of 3//-l,5-benzodiazepin-2-amine 1 on heating.254a b... 

A variety of products has been obtained from benzopentathiepin and reactive methylene compounds in the presence of triethylamine or sodium ethoxide. Malononitrile and ethyl cy-anoacetate yield the benzodithiins 9, R = CN and C02Et, respectively, ethyl acetoacetate and acetylacetone give benzodithioles 10, R = C02Et and Ac, respectively, and ethyl 2-chloro-propanoate gives the benzotrithiin 11, accompanied by a small amount of the benzodithiole 12.410... 

Condensation of 165 with chloroacetamide derivatives afforded (89JIC246) carbamoylhydrazino derivatives 168. Some are active against S. aureus and Escherichia coli. Condensation of 165 with ethyl cyanoace-tate, malononitrile, ethyl acetoacetate, or acetylacetone gave (87AP1191, 87PHA664 89JHC769) 169 and 170, whose bactericidal activity has been reported. 

Amino-5-hydrazinopyrazole dihydrochloride 300 is a good source for the synthesis of this type of heterocyclic compound [78JCS(P1)885] and it was prepared by reaction of malononitrile with two equivalents of hydrazine. Reaction of 300 with ethyl pyruvate afforded 301. Unstable hydra-zone 302 formed when 300 was boiled with diacetyl rapidly cyclized to 303. Reaction of 300 with benzil gave 304 directly, which gave an acetyl derivative and resisted reductive deamination. On the other hand, a polymer was isolated from the reaction of 300 with glyoxal (Scheme 65). 

Chloroquinoxaline with diethyl malonate, ethyl cyanoacetate, or malononitrile gave 2-(diethoxycarbonylmethyl)- (57), 2-(a-cyano-a-ethoxycarbonylmethyl)-(58, R = COaEt), or 2-(dicyanomethyl)quinoxaline (58, R = CN) [KOH,... 

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]. 

Pyridopyridazine 413 when treated with benzylidenemalononitrile in a mixture of DMF/ethanol (1 1) and a catalytic amount of triethylamine gives compound 414 as the only isolated product and formation of the corresponding regioisomer is not reported. The same starting compound treated with malononitrile and ethyl cyanoacetate under similar conditions provides products 415 and 220, respectively (Scheme 65) <2005HC089>. Similar reactivity of phthalahydrazide 416 to malononitrile and ethyl cyanoacetate was also described <1996PHA714>. 

Lithiothiophene, arising from lithiation of thiophene with n-BuLi, was treated with iodine to give 2-iodothiophene, which was allowed to react with sodium malononitrile in the presence of catalytic PdCl2(Ph3P)2 to afford thienylmalononitrile 18. Interestingly, a-metalation of ethyl 3-... 

Uncharged styryl (methine) disperse dyes were originally introduced to provide greenish yellow colours on cellulose acetate fibres. One such dye still in use is Cl Disperse Yellow 31 (6.226), which is made by condensing 4-(N-butyl-N-chloroethylamino)benzaldehyde with ethyl cyanoacetate. Suitable compounds for polyester usually contain the electron-accepting dicyanovinyl group, introduced with the aid of malononitrile. An increased molecular size leads to improved fastness to sublimation, as in the case of Cl Disperse Yellow 99 (6.227). A novel polymethine-type structure of great interest is present in Cl Disperse Blue 354 (6.228), which is claimed to be the most brilliant blue disperse dye currently available [85]. 

The treatment of isopropylidene phenylaminomethylenemalonates (1319) with ethyl cyanoacetate or malononitrile in the presence of potassium hydroxide in DMF at 90°C afforded the potassium salts of derivatives of Meldrum s acid in 74% yields, which were converted without isolation to pyridones (1320) in 91% yield on the action of aqueous hydrochloric acid [78ZN(B)1550]. 

Finally, Nikishin and coworkers have reported that the mediated oxidations of doubly activated methylene compounds can be used to synthesize cyclopropane derivatives (Scheme 17) [30]. Reactions using dimethyl malonate, ethyl cyanoacetate, and malononitrile were studied. Metal halides were used as mediators. When the activated methylene compound was oxidized in the absence of a carbonyl compound, three of the substrate molecules were coupled together to form the hexasubstituted product. Interestingly, when the ethyl cyanoacetate substrate was used the product was formed in a stereoselective fashion (18b). In an analogous reaction, oxidation of the activated methylene compounds in the presence of ketones and aldehydes led to the formation of cyclopropane products that had incorporated the ketone or aldehyde (20). In the case of 19a, the reactions typically led to a mixture of stereoisomers. 

With ethyl cyanoacetate, the 9-oxo compound 79 X = O) is obtained. When the reaction is carried with malononitrile a similar rearrangement into the 9-imino compound 79 (X = N) takes place. 

Since the pyrido[2,3-pyrimidine ring system is found to exist in a number of biologically active compounds, these rearrangements were extensively studied. Reaction of compound 86 with malononitrile leads to 7-amino-6-cyano-l,3-dimethylpyrido[2,3-ethyl cyanoacetate, 7-amino-6-ethoxycarbonyl-l,3-... 

Knoevenagel adduct 239 of oxohomophthalimide 240 with malononitrile 27a in reactions with CH-acids behaves ambiguously (82CPB1215). Reactions of 239 with acetylacetone, ethyl esters of acetoacetic and ben-zoylacetic acids, as well as methyl pyruvate led to the formation of the desired spiropyrans 241. However, benzoylacetone, dibenzoylmethane, cyanacetamide, and oxindole always gave the same 242. Authors explain this feature in terms of a retro-cleavage of adducts of Michael product 239... 

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>. 

The condensation product of malononitrile and ethyl acetonedicarboxylate cyclizes in acid conditions to give the 2,7-naphthyridine (263), reaction of which with POCl3 gave the... 

Thiophenes can be synthesized from a sequence involving the reaction of activated methylene compounds with carbon disulfide in base. The resulting disulfide salts, without isolation, are reacted with phenacyl bromide to afford highly substituted thiophenes, 78. Compound 78 reacts with ethyl cyanoacetate, malononitrile, or acrylonitrile to afford thieno[3,2-/ ]pyridine derivatives <1995CCC1578>. 

Cyanopyrroles, formed from malononitrile and phenacyl halides, offer another route to the synthesis of pyrrolo[2,3-3]pyridines <2004MI15>. Treatment of the cyanopyrroles with ethyl acetoacetate leads to propenylamino-pyrroles which undergo further cyclization to form highly functionalized pyrtolo[2,3-3]pyridine derivatives. 

---