Malononitrile hydrazine

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). 

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>. 

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). 

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... 

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. 

The preparation of amide hydrazones is quite simple, by mixing corresponding nitriles (or dinitriles) and hydrazine (1 1.5 molar ratio) in ethanol at room temperature and then allowing the mixture to stand overnight. This is called the direct method. The yield by this method is normally good (>90%). If this method does not work, the so-called indirect method can be used, in which a nitrile, e.g., malononitrile, is converted into its imidate then reacted with hydrazine. In early references (e.g., Case, 1965150), anhydrous or 95% hydrazine was employed. We have found that 85% hydrazine hydrate still works without any difference in yield. Common recrystallization solvents are benzene or toluene. The amide hydrazones are stable to moisture, and so some amide hydrazones can be recrystallized from water, but they are sensitive to light and heat. As an example, we observed that picolinamide hydrazone (white crystals) partially turns into an orange compound, which has been identified as 3,6-picolin-(2H)-tetrazine. 

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

This presumably goes by dimerization of the malononitrile to give a substituted /3-amino-crotononitrile. This dimer also reacts with hydrazines to give 5-imino-2-pyrazolin-4-carbonitriles. These can be hydrolyzed to amides. 

The nitroethylidene-hydrazine sodium salt 198 was refluxed with the arylidene-malononitrile 179 in acetonitrile to yield the pyrazolidine 199. Since they are useful as pharmaceuticals and drugs, cyanopyrazoles are of special preparative interest. Additions... 

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. 

The four-component reaction of ethyl acetoacetate, hydrazine hydrate, malononitrile and various aldehydes using L-Pro (10 mol%) as catalyst affords a series of 2,4-dihydropyrano-[2,3-c]-p5Tazoles (Scheme 2.12). Polysubstituted tetrahydropyridines were eoneisely synthesised in a one-pot multicomponent reaction between aromatie allgmones, aliphatic amines, active methylene compounds and formaldehyde (Scheme 2.12). ... 

A multi-component one-potreaction of ethyl acetoacetate (57), aromatic aldehydes (58), hydrazine (31), and malononitrile (50) in water afforded dihydropyrano[2,3-c] pyrazoles (59) in good yields (79%-95%) under ultrasonic irradiation in relatively short reaction times (15-40 min). In the absence of nltrasound, the products were obtained in comparatively lower yields (70%-86%) and longer reaction times (60-300 min) (Zou et al. 2011). Darandale et al. (2012) reported a simple and practical ultrasound-promoted synthetic protocol for the synthesis of dihydropyrano[2,3-c] pyrazoles (59) nsing sodium bisulfite (NaHSOj) as a green catalyst in solvent-free conditions. The latter method provides the advantage of a shorter reaction time (30 s) and excellent yields (97%-99%) (Scheme 8.19). 

One-pot four-component reactions of carbonyl compounds, hydrazines, malononitrile, and P-ketoesters mediated by meglumine (13T9931), cetyltri-methylammonium chloride in aqueous medium (13SC1721), or in the absence of catalyst under ultrasound irradiation in water (13JHC1174) are versatile routes for the synthesis of pyrazole-fused 2-amino-3-carbonitrile-4f/-pyrans. Quinohnone-fiised 3-nitro-4H-pyrans result from the ZnCl2-cat-alyzed three-component reaction of 4-hydroxy-l-methylquinolin-2(lH)-one, nitroketene N,S-dimethyl acetal, and various aromatic aldehydes, in excellent yields (Scheme 14) (13TL3248). 

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