Malononitrile, reaction with hydrazines

Reaction of 2-amino-3-bromoprop-l-ene-l,l,3-tricarbonitrile 284, easily accessible from the bromination of the dimer of malononitrile, with hydrazine or phenyl hydrazine yielded 1,4-dihydropyridazines 285 and 286, respectively (Scheme 70) <2003HAC612>. 

A heated solution of 458 in dry EtOH containing hydrazine gives 459b <1995JHC69>. The thienopyrimidine-acetonitriles 459c-f were prepared from 458 through an initial reaction with malononitrile to form a thioureido intermediate, followed by treatment with alkyl halides <2001JHC419>. 

The 4-aminopyrimidines 367 and 368 were prepared by the reaction of the benzylidene malononitriles with thiourea or S-methylisothiourea, respectively. Nucleophilic substitution at the 2-position of 368 with hydrazine gave the 2-hydrazino derivative 369, whose treatment with carbon disulfide yielded the triazolopyrimidine 373 rather than its isomeric compound [83ZN(B)1686]. Heating 369 with benzoyl chloride in anhydrous dioxane,... 

Like / -keto esters, /3-keto nitriles react smoothly with hydrazine the latter give aminopyrazoles.78,310-321 Under the same conditions cyanoacetic ester and its derivatives give aminopyrazolones.322-325 The reaction of malononitrile is more complex, giving 1-substituted 3-cyanomethyl-4-cyano-5-aminopyrazole and products formed by further condensation.328... 

Imino-2-pyrazolin-4-carbonitriles and 4-carboxamides have been prepared by Taylor by reaction of hydrazines with malononitrile.1478... 

A new approach to the synthesis of the fused 1,2,3-thiadiazolo ring systems, for example (81) and (82), has been studied by Dehaen and coworkers. Displacement of 5-halo-l,2,3-thiadiazoles (77) with sodium salts of malononitrile has led to the formation of the intermediate (78) which upon treatment with alkali gave the pyrano fused system (81) via the intermediate carboxylate anion (79). Alternatively, reaction of (78) with methylamine or with hydrazine furnished the fused pyridinone (82) via the amide (80) <97JCR(S)396>. 

The reaction of diethyl 3,4-dimethylthieno[2,3-Z ]thiophene-2,5-dicarboxylate (117, R = Me, EWG = C02Et) with hydrazine hydrate afforded dihydrazide 231, which was subjected to various transformations. For example, the reactions with acetylacetone, ethyl acetoacetate or malononitrile (93BCJ2011) are accompanied by the closure of the exocyclic pyrazole ring to form the corresponding derivatives 232-234. The reaction of dihydrazide 231 with carbon disulfide in the presence of KOH followed by decomposition with dilute HCl or concentrated H2SO4 produces di(oxadiazole) (235) or di(thiadiazole) derivative (236). Condensation of di(oxadia-zolyl)thienothiophene 235 with hydrazine hydrate affords di(triazolyl)thienothio-phene 237. 

A 100 mL flask was charged with hydrazine (1 1 mmol), p-keto ester (2 1 mmol), isatin (3 1 mmol) and malononitrile/ethyl cyanoacetate (4 1 mmol) and piperdine (20 mol%, 0.2 mmol) in ethanol (15 mL). The mixture was sonicated in the water bath of an ultrasonic cleaner (power 250 W irradiation frequency 40 kHz) at room temperature (25 30 °C). After the completion of the reaction (monitored by TLC), the resulting precipitate was filtered and washed with ethanol to afford the pure product of spiro[indoline-3,4 -pyrano[2,3-c]pyrazole] 5 as solid in good to excellent yields. Each of the products was characterized by IR, NMR, C-NMR and HRMS studies. 

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). 

Thiazolyl)pyrimido[4,5-i/]pyridazines have been prepared by utilizing the reaction of the active methylene compound 46 with benzenediazonium chloride (Scheme 24) to give a hydrazone, which cyclizes spontaneously <1999JPR147>. A further approach described recently <2002HAC108> involves reaction of the malononitrile derivative 47 with a further equivalent of malononitrile, forming a pyrimidine with a suitably disposed hydrazine, which cyclizes on exposure to strong base (Scheme 25). 

With more vigorously reacting nucleophiles, such as malononitrile, hy-droxylamine, and hydrazines, the 1,2-addition reactions are often followed by ring opening, as described in Section III,C. 

To a stirred aqueous mixture of hydrazine hydrate 98% (1 0.107 g, 2 mmol) and ethyl acetoacetate (2 0.260 g, 2 mmol), 2-hydroxy benzaldehyde (3 2 mmol), malononitrile (4 0.132 g, 2 mmol) were added successively at ambient temperature (30 °C) tmder an open atmosphere with vigorous stirring for 5-10 min. On completion of the reaction (as monitored by TLC), a sohd precipitate was obtained. The precipitate was filtered, washed with water and then with 5 mL of ethyl acetate/hexane mixture (1 1) affording pure 2-amino-4-(5-hydroxy-3-methyl-l//-pyrazol-4-yl)-4//-chromene-3-carbonitrile (5), characterized by IR, NMR, C-NMR and mass spectral studies. 

Nucleophilic Reactions.—Nucleophilic substitution in the isothiazole nucleus, as well as a variety of nucleophilic ring fissions, continue to attract a good deal of attention. The methylsulphonyl group is particularly prone to nucleophilic replacement 3,5-bis(methylsulphonyl)isothiazole-4-carbo-nitrile, readily accessible from malononitrile and carbon disulphide, yields the 5-(substituted)amino-compounds on treatment with ammonia, amines, or hydrazine, and the 5-ethoxy-compound when treated with ethanol in the presence of sodium carbonate. The electron-attracting cyano-group appears to promote the nucleophilic displacement, since 3,5-bis(methyIsuIphonyl)-4-phenylisothiazole displays reduced reactivity. ... 

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