Hydrazones pyrazoles, 5-amino

Reaction of 4-amino-l-azabutadienes (45) with various hydrazine salts at 60°C leads to the expected pyrazoles (46) without isolation of the hydrazone intermediate (eq. 8) (39). 

While cycloaddition approaches have been discussed extensively in this chapter, there are certain substitution patterns that are not amendable to such approaches. In these cases, the more traditional annelative approaches are necessary. For example, the 5,6-dihydropyrrolo[3,4-rf]imidazol-4(3//)-one (286) is obtained from the diamine (285) and triethyl orthoformate. If formamide is used in excess, 6-(formamidomethylene)-5,6-dihydropyrrolo[3,4-d]imidazol-4(3//)-one (287) is obtained (Scheme 53) <70JPS1732>. A variant of the Thorpe cyclization was employed in the preparation of 3-amino-4//-pyrrolo[3,4-c]isoxazoles (289) from a-cyanooximes (288) (Equation (66)) <68JMC453>. 3-Acyltetramic acid (290 X = NR2) and 3-acyltetronic acid (292 X = O) hydrazones undergo ready cyclization in refluxing xylene with catalytic p-toluenesulfonic acid to afford 4-oxo-l,4-dihydro-6/f-pyrrolo[3,4-c]pyrazoles (291) and 4-oxo-l,4-dihydro-6//-furo[3,4-c]pyrazoles (293), respectively (Equation (67)) <82SC43l>. The novel synthesis of 5-amino-6a-hydroxydihydro-6//-pyrrolo[2,3-j]isoxazole (296) from 3,4-disubstituted 4-(amino)isoxazol-(4//)-ones (294) is hypothesized to occur by the cyclization of the ketene aminal intermediates (295) (Scheme 54) <91S127>. 

Pyrazol 3-Amino-5-oxo-l-(2,4,6-trichlor-phenyl)-4,5-dihydro-E16a, 670 (Hydrazon-Bild./red.-Cyclis.)... 

Pyrazol 3-Amino-l-(2-brom-4,6-dimethyl-phenyl)-5-oxo-4,5-dihydro- E16a, 669 (Hydrazon-Bild./Red.-Cyclis.)... 

Generally speaking, unsymmetrical 1,3-dicarbonyl components produce mixtures of 1,2-azole products/ Sometimes this difficulty can be circumvented by the use of acetylenic-aldehydes or -ketones, for here a hydrazone or oxime can be formed first by reaction at the carbonyl group and this can then be cyclised in a separate, second step/ Pyrazole itself can be formed by the reaction of hydrazine with propargyl aldehyde/ Using /3-chloro-, / -alkoxy- or /3-amino- -enones as 1,3-dicarbonyl synthons is another way to influence the regiochemistry of reaction, and in favourable situations this can be effective. ... 

Pyrazoles.—Formation. 3-Amino-4-ethylthio-5-methylpyrazole (311) is formed by the action of hydrazine on the nitrile MeBrC=C(SEt)CN. Acetylenic hydrazones R C=C-C(R )=NNHTos (R = H, Pr, or Ph R = H or Me) cyclize in the presence of potassium carbonate to the pyrazoles (312) via the iV-tosyl derivatives. Treatment of the (p-chlorophenyl)hydrazone (313) of ethyl 2-furylpyruvate with sulphuric acid affords only 10% of the expected ethyl 3-(2-furyl)indole-2-carboxyIate the main product is the pyrazole (314), formed presumably by way of the spiro-intermediate shown. ... 

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. 

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