3- pyrazoles, reactions with hydrazine

There are two methods for the introduction of a hydroxyalkyl group at position 5 of the pyrazol-3-one ring. Schmidt and Zimmer converted furanediones 258a-k into arylmethylenepyrazol-3-reaction with hydrazine hydrate or methylhydrazine (83Jmechanism proposed for the reaction involves nucleophilic attack of the hydrazine on the ketone carbonyl, followed by attack on the ester carbonyl and ring opening of the... 

Since l-heterobut-l-en-3-ynes are readily alkylated and functionalized at the terminal acetylenic carbon atom, their reaction with hydrazines makes it possible to introduce diverse (including functional) substituents into the pyrazole ring. For instance, from benzylated methoxybutenyne 112, isomeric 2-phenylethylpyrazoles 113 were obtained in 74% yield (81H146). 

The resin-bound reagents thus obtained were reacted with a variety of nucleophiles to give different heterocycles (Scheme 13). So, reaction with hydrazine or hydroxylamine gave respectively pyrazoles and isoxazoles in excellent yields (94-99%, 34 examples) and excellent purities (> 95%). Reaction with guanidines afforded 2-aminopyrimidines. 

It is known that certain coumarins are transformed into 5-(2-hydroxy-phenyl)-3H-pyrazol-3-ones by reaction with hydrazines [10]. Upon appUca-tion of this method, the expected pyrazolones 25 were synthesized starting from 3-nitrocoumarins [11] as known in (Scheme 6). 

The synthetically versatile 6-amino-7-cyano-l,4-dihydro-3-methyl-l-phenyl-4-thioxothiopyrano[4,3-c]pyrazole 107 has been used for the synthesis of several bicyclic and tricyclic systems. For example, reaction with hydrazine gives 108, which can be used to generate tricycles 109-111 (Scheme 8) <2002H(57)1121>. 

Stanozol Stanozol, 17a-methyl-5a-androstano[3,2-c]pyrazol-17j3-ol (29.3.13), is made by reducing the double bond at C4-C5 in methyltestosterone, which has independent interest as an anabolic drug of mestanolone (29.3.11). Mestanolone undergoes formylation with ethylformate in the presence of sodium ethoxide, forming a 2-formyl (oxymethylene) derivative (29.3.12), which upon reaction with hydrazine easily cyclizes to the desired stanazole (29.3.13), which is a pyrazol-condensed steroid system [33,34]. 

The reaction between 1,3-dicarbonyl compounds 1 and hydrazines is the most general method for preparing l//-pyrazoles 2 (Scheme 2).2-4,5 If a 2,2-disubstituted 1,3-diketone is employed (1 R3, R4 H), reaction with hydrazine hydrate gives instead a 4//-pyrazole 3, as was first reported by Knorr.Sa Generally, the reactants are heated under reflux in a solvent such as methanol, ethanol, benzene, or carbon tetrachloride yields range from 50% to quantitative. 

In the majority of cases alkyl hydrazines give single pyrazoles.160, 328, 336,337 In 1958 Bertrand established that allenic ketones give pyrazoles quantitatively with hydrazine.338 The reaction may be formulated as follows, the second stage being stabilization by aromatization. Acetylenic nitriles give aminopyrazoles with hydrazine.339... 

One-pot synthesis of pyrazole (112) bearing a perfluoroalkyl group is performed by the treatment of a-chlorostyrene (111), perfluoroalkyl iodide, and Bu3SnSnBu3, followed by reaction with hydrazine (eq. 4.38d). 

In the second, the use of diazopropane is avoided the alcohol (250) is converted to the pyrazole (251) by a two step sequence of reaction with hydrazine in acetic acid and then oxidation with manganese dioxide. Photolysis then leads cleanly to the cyclopropene, without any interference by cyclisation of an intermediate carbene to the alcohol group the product is hydrogenated directly, the conversion of (251) to (252) occurring in 94% yield. Elimination of the elements of water leads to m-chrysanthemic acid in good overall yield 175) ... 

Dimethylpyrazole has been prepared from acetylacetone and hydrazine hydrate in ethanol3 or hydrazine sulfate in aqueous alkali.4 6 The latter method is preferred, because the reaction with hydrazine hydrate is sometimes violent.3 4 3,5-Dimethyl-pyrazole has also been prepared by hydrolysis and decarboxylation of the 1-carbamido- or 1-carboxamidine derivatives, obtained by reaction of semicarbazide 7 or aminoguanidine 8 with acetylacetone. 

A modified procedure for the preparation of pyrazoles includes the solventless condensation of diketones and hydrazines in the presence of a catalytic amount of sulfuric acid at ambient temperature <2004GC90>. 1,3-Diketones can be synthesized directly from ketones and acid chlorides and then converted in situ into pyrazoles by the addition of hydrazine <2006OL2675>. The possible modifications to the 1,3-dioxo component in the reaction with hydrazines include the use of -ketoesters, -ketonitriles, -halocarbonyl compounds, -hydroxyketones, -sulfonylketones, and 1,3-dihaloalkanes . 

Various groups substituted between the two carbonyl groups of 1,3-ketones give highly substituted pyrazoles on reaction with hydrazine. Eor example, 4-alkoxypyrazoles 519 were synthesized from 3,5-heptadiones 518 with... 

Alkynyl ketones can be formed from addition of alkynyllithium or Grignard reagents to phthalimides and then the products converted into pyrazoles by reaction with hydrazines. For example, A -alkyl-substituted phthalimides 633 were easily transformed to mono-, di-, or trisubstituted pyrazoles 634 via a one-pot addition/decyclization/cyclocon-densation process (Equation 131) <2002J(P1)207>. A -Alkyl-substituted phthalimides 635 were easily converted into di-, tri-, and tetrasubstituted pyrazoles 636 via a one-pot addition-decyclization-cyclocondensation process (Equation 132) <2003H(60)2499>. 

Reaction with Hydrazines, Guanidine, and Amidines Synthesis of Pyrazoles and Pyrimidines... 

The reaction of mono(alkylsulfanyl)- or mono(arylsulfanyl)-substituted cyclopropenylium ions 20 with secondary amines in the presence of triethylamine afforded the substituted indenes 21 or pyrroles 22 depending on the substituents, whereas the reaction with hydrazines gave pyrazole derivatives 24. ... 

Transformation of (l,3-dioxolan-2-ylidene)methylphosphonates (or phosphinates) to 5-amino-A -substituted-3-(2-hydroxyethoxy)-4-phosphono (or phosphino)pyrazoles occurs by reaction with hydrazines, R —NH—NH2 (R = CH3, CsHj, OEt) <92HCA124>. Similarly, dioxolanes (259) are transformed into 5-hydroxypyrazoles (260) by reaction with hydrazine and into pyrazolium betaines (261) by reaction with 1,1-disubstituted hydrazines <92HCA1039>. 

The diazines are very susceptible to nucleophilic addition pyrimidine, for example, is decomposed when heated with aqueous alkali by a process which involves hydroxide addition as a first step, and it is converted into pyrazole by reaction with hydrazine. 

The synthesis of the 5a-cholestano[7,6-c]pyrazole (348) from 5a-cholestan-7-one (346) has been achieved by hydroxymethylation at C-6, giving (347), followed by reaction with hydrazine. Various other cholestan[7,6-c]pyrazoles have also been prepared. Attempts to obtain the isomeric pyrazoles from 5a-cholestan-6-ones were unsuccessful. 

Mercapto pyrimidines 82 were synthesized from acetoacetanilide, dihydroxybenzaldehyde, and thiourea, which were readily alkylated with benzyl chloride to afford 2-benzylthio derivatives 83 (Scheme 32). 83 when reacted with different amines in acetic acid furnished 2-amino derivatives 84 (R = Ar), whereas upon reaction with hydrazine hydrate 83 afforded 2-hydrazinyl derivative 84 (R = NH2), which with different aldehydes gave hydrazones 85 (R = 2-furyl, 2-thienyl). Arylidene thiazolidinone 86 was obtained from 84 with carbon disulfide, monochloroacetic acid, and aryl aldehydes, while 84 with ethyl acetoacetate and different aromatic aldehydes provided pyrazoles 87 (Scheme 32) (10MI9). Such tetrasubstituted pyrimidines act as cyclin-dependent kinase (CDK2) inhibitors. 

Condensation of syn- or anti-27 with hydrazine afforded new pyrazole derivatives 28 with a stereodefined and protected amino diol side chain [64]. The preparation of push-pull substituted unsaturated monosaccharide derivatives and their use in the synthesis of nucleoside analogs have been reviewed [65]. Thus, the 2-formyl pentose glycals were transformed to the corresponding acyclo-C-nucleosides 29 [66]. Similarly, the benzy-lated 2-formylglycals reacted with hydrazine derivatives to afford the substituted l,2,4-tri-0-benzyl-lC-(lH-pyrazol-4-yl)-D-tetritols the deprotection of which was achieved with Pd/H2 to yield the lC-( 1-methyl-lH-pyrazol-4-yl)-D-tetritols [67]. 3-0-Benzyl-6-deoxy-l,2-0-isopropylidene-o -D-xylo-hept-5-ulofuranurono-nitrile was reacted with f, N-dimethylformamide dimethyl-acetal in THF to furnish the (E)-3-0-benzyl-6-deoxy-6-dimethyl-aminometh-ylene-l,2-0-isopropylidene-Q -D-xylo-hept-5-ulofuranurono-nitrile as a major product, and on treatment with carbon disulfide and methyl iodide under basic conditions afforded 3-0-benzyl-6-deoxy-l,2-0-isopropylidene-6-[bis(methylsulfanyl)methylene]-a-D-xylo-hept-5-ulofuranurono-nitrile. Further reaction with hydrazines yielded the reversed pyrazole-C-nucleoside analogs [68]. 

Pyrazolo[3,4-d]pyridazines are readily obtained from pyrazoles having 4,5-dicarbonyl or carboxy substituents (19970PPI285, 2003T5869). This reaction has been used to elucidate the structure of products from 51 with 52 or 53. Thus, the produced 54 and 55 afforded pyrazolo[3,4-djpyridazines 56 and isoxazolo[3,4-d]pyridazines 57 on reaction with hydrazine (2004JHC647 Scheme 10). 

The cyclization of 1 -alkoxybut-1 -en-3-ynes with hydrazine was first achieved by Franke and Kraft (55AG395). By heating 1-methoxybut- l-en-3-yne with hydrazine sulfate in an aqueous alcohol medium they obtained 3(5)-methylpyrazole (13) in high yield. Winter (63HCA1754) used the cyclization of 1-methoxybut-l-en-3-yne with hydrazine hydrate and phenylhydrazine to estabhsh the stmcture of the initial enyne ether [in this case a mixture of l-phenyl-3(5)-propylpyrazoles was obtained]. The reaction with hydrazine sulfate gives only one product, 3(5)-propyl-pyrazole. 

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