Pyrazole-3,5-diones

Pyrazole-3,4-dicarboxylic acid, 1-phenyl-dimethyl ester synthesis, 5, 150 Pyrazole-3,5-dione, 1-phenyl-alkylation, 5, 230 synthesis, 5, 290... 

Novel steroidal pyridazines are readily prepared from ADC compounds and steroidal A2,4-dienes,163 A14,1 -dienes,164 and A16,20-dienes.165 ADC compounds are also commonly used in the protection of the steroid 5,7-diene system (see Section V,A). These Diels-Alder adducts of steroidal dienes and azo dienophiles should not be confused with the so-called azasteroids, which are also prepared from ADC compounds. Cyclic ADC compounds such as the pyrazole-3,5-diones (7), and the diazaquinones 12 and 13 readily add to dienes to give bicyclic pyridazine derivatives,166168 and these reactions have been adapted to the synthesis of 5,10-diazasteroids (106).42 Similarly, the 13,14-diaza- (107) and 13,14,16-triazasteroid (108) ring systems have been prepared.169... 

Other dienophiles, e.g., l,3,4-thiadiazole-2,5-dione 2, 4,4-dialkyl-4//-pyrazole-3,5-diones 3, 3H-pyrazol-3-ones 4 and azoquinones 5 and 6 are prepared in situ by oxidation of the dihydro precursor with lead tetraacetate or fcrt-butyl hypochlorite (see Section 7.2.10.3.). 

Pyrazole-3,5-diones 352a-d and phenylmagnesium bromide yielded pyrazol-3-one 354a-d in 70-75% yield (73IJC219) (Scheme 81) probably by addition product 353 which undergoes dehydration. 

Several years later other workers used the same method to confirm that pyrazol-3,5-diones 51a,b/5-hydroxypyrazol-3-ones 52a,b exist as tautomeric mixtures in solution. The reactions with diazomethane took place in a mixture of diethyl ether and methanol and afforded a mixture of the respective pyrazol-3,5-diones 53a,b and 5-methoxypyrazol-3-ones 54a,b. The suitability of these structurally fixed methyl derivatives as model compounds in the study of the tautomeric structures by NMR spectroscopy was investigated (80CB3910) (Scheme 16). 

Cyclocondensation of pyrazole-dione 348 with thiosemicarbazide in the presence of potassium carbonate gave (84JPR994) pyrazolotriazine thione... 

The original azole approach to the synthesis of this system, as outlined in CHEC-I, has been continued. The pyrazole dione (124) condenses with a 2-substituted formamidine derivative and is cyclized with aqueous potassium carbonate <84JHC923,84JPR994) or heat <88JPR57> giving the derivatives (125) in poor yield (Equation (10)). An alternative approach is shown in Equation (11)... 

Three double bonds. The most fully oxidized pyrazoles, the typical non-aromatic representatives of which are the pyrazoline-4,5-diones (1) and the pyrazolidine-3,4,5-triones (2), should be included here. 

A Hammett relationship of the form ApK = 5.8am has been proposed for 4-substituted pyrazoles (74TL1609) in order to explain the effect of 4-nitro ApK = 4.5, am = 0.71) and 4-diazo groups (Apiifa = 10.0, am = 1.76). The acidity constants of a series of pyrazolidine-3,5-diones have been determined (75AJC1583) and the 4- -butyl-1,2-diphenyl derivative phenylbutazone has a pK of 4.33. 

Pyrazolo[3,4-c]pyrazole, tetrahydro-rearrangement, 5, 250 Pyrazolo[4,3-c]pyrazole, tetraaryl-electrophilic substitution, 6, 1035 oxidation, 6, 1034-1035 reduction, 6, 1035 vacuum pyrolysis, 6, 1035 Pyrazolo[ 1,2-n]pyrazole-1,5-diones synthesis, 6, 991 Pyrazolo[ 1,2-n]pyrazoles reactions, 6, 1038 ring opening, 6, 983... 

H,3H- Pyrrolo[l, 2-c]oxazole-l, 3-dione, 5,6,7,8-tetrahydro-IR spectra, 6, 978 [2.2](2,5)Pyrrolophane, N-aryl-rearrangements, 4, 209 Pyrrolophanes natural products, 7, 764 synthesis, 7, 771 Pyrrolophanes, N-aryl-synthesis, 7, 774 (2,4)Pyrrolophanes synthesis, 7, 771 Pyrrolo[3,4-c]pyran-4-ones synthesis, 4, 288 Pyrrolopyrans synthesis, 4, 525, 526 Pyrrolopyrazines synthesis, 4, 526 Pyrrolo[l, 2-a]pyrazines synthesis, 4, 516 Pyrrolo[2,3-6]pyrazines Mannich reaction, 4, 504 Vilsmeier reaction, 4, 505 Pyrrolo[3,4-c]pyrazole, 1,3a,6,6a-tetrahydro-structure, 6, 976 synthesis, 6, 1019 Pyrrolopyrazoles synthesis, 5, 164 Pyrrolo[l,2-6]pyrazoles synthesis, 6, 1002, 1006 Pyrrolo[3,4-c]pyrazoles reactions, 6, 1034 synthesis, 6, 989, 1043 Pyrrolo[3,4-c]pyrazolones synthesis, 6, 989 Pyrfolopyridazines synthesis, 4, 517 Pyrrolo[l, 2-6]pyridazines synthesis, 4, 297 6/7-Pyrrolo[2,3-d]pyridazines synthesis, 4, 291 2/f-Pyrrolo[3,4-d]pyridazines synthesis, 4, 291 6/7-Pyrrolo[3,4-d]pyridazines synthesis, 4, 291... 

Benzyl or n-propyl)-5-methyl-3W-pyrazole-3,4-dione 4-oximes 31a,b were prepared by two routes. Thus, efliyl 3-oxobutanoate 27 was eiflier heated wifli... 

When pyrazole-4,5-diones 279a,b,d,e were heated with methanol, the 4-hy-droxy-4-methoxypyrazol-3-ones 278a,b,d,e were obtained in good yields. In an... 

Hydroxy group of 8-hyd oxy-2-cycloalkyl-2,3,4,6,ll,lla-hexahydro-l//-pyrazino[l,2-i]isoquinoline-l,4-diones was alkylated with allyl bromide, 2-(bromodifluoromethyl)pyridines, l-(bromodifluoromethyl)- and l-(bro-momethyl)benzenes, halomethyl derivatives of different heterocycles (pyridine, pyrazine, pyrazole, pyrrole, thiazole, thiophene) in the presence of CS2CO3 or K2CO3 (98MIP7). Hydroxy group of 8-hydroxy-2-cyclopentyl-... 

Aminothiocarbonylphenyl)methoxy] derivative 384 was obtained from 8-[(4-cyanophenyl)methoxy]-2-cyclohexy 1-2,3,4,6,11,11 a-hexahydro-l/7-pyrazino[l,2-i]isoquinoline-l,4-dione by treatment with (EtO)2P(S)SH and one drop of H2O at room temperature for 17 h, then followed by addition of more H2O (98MIP7). Reaction of 8-[(4-aminothiocarbonylphe-nyl)methoxy] derivative 384 and MeCOCH2Cl yielded 8- [4-(4-methylthia-zol-2-yl)phenyl]methoxy derivative 385. 7-Bromomethyl derivative was prepared from the 8-hydroxymethyl-8-[(4-cyanophenyl)methoxy]-2-cyclo-pentyl-2,3,4,6,11,1 la-hexahydro-177-pyrazino[l, 2-i]isoquinoline-1,4-dione with PBr3 in CH2CI2 at room temperature. 7-[(l-Pyrazolyl)methyl] derivative was obtained from 7-bromomethyl derivative by treatment with pyrazole in the presence of NaH in DMF at 50 °C. 

Aziridine 269 (Scheme 3.98), on treatment with pyrazole (270) and subsequent TFA deprotection, gave P-pyrazolylalanine 271, first isolated from Citrullus vulgaris (a water melon) and isosteric with histidine [148]. Treatment of 269 with 1,2,4-ox-adiazolidine-3,5-dione 272 gave (S)-quisqualic acid (273), an active ingredient of the ancient Chinese drug Shihchuntze, an anthelmintic made from the seeds of Quisqualis indica [148]. 

Dihydrazinoquinoxaline (234) and 5-methyl-2-phenyl-47/-pyrazole-3,4(2//)-dione (235) (2 equiv) gave 2,3-bis(3-methyl-5-oxo-l-phenyl-l,5-dihydro-... 

Compounds 39 and 40, in which a pyrazole ring is fused to a pyrido[2,3-2,]pyrazinc, are produced as a 3 2 mixture by reaction of pyridine-2,3-diamine with 3-methyl-l-phenylpyrazoline-4,5-dione (Equation 9) <1999T8475>, and the synthesis of compound 41 (Scheme 11) exemplifies a different approach to the same ring system <1997JCM318, 1997JRM2026>. 

The 3f/-pyrazole-3,5(4//)-diones (7), prepared by lead tetraacetate,29,30 or tert-butyl hypochlorite31,32 oxidation of malonic acid cyclic hydrazides, are generally less stable than the triazoles 5, and are not isolable. The monocarbonyl derivatives (8-10) have been reported.33-36 The unstable 1,3,4-thiadiazole-2,5-dione (11) has been generated and reacted in situ.31,3 ... 

A diastereoselective synthesis of bis(3,5)pyrazolophanes was accomplished by sequential inter- and intramolecular cycloadditions of homochiral nitrilimine intermediates . A-Alkyl pyrazolidine-3,5-diones were synthesized in a three-step sequence from dialkyl malonates <00JHC1209>. Methyl acetoacetate was employed as the initial substrate to 3-carboxamido-4-pyrazolecatboxylic acid derivatives <00JHC175>. Vilsmeier type reagent 33 reacted with imines 34 to afford enaminoimine hydrochlorides 35, which were transformed to pyrazoles 36 upon addition of hydrazine <0OJHC13O9>. 

Thus, derivatives of structure 84 were treated with iV-methylmaleinide to give the cycloadducts 85 in high yields. In accordance with the concerted nature of this process, the pyrazoles and pyrrolidine-dione had a rxr-fusion. Similar cycloaddition was also experienced with dimethyl acetylenedicarboxylate (DMAD) to afford 86 containing the partially unsaturated pyrazole ring. 

In Scheme 7, ring-opening reactions of some fused pyrazoles are shown. Thus, Baraldi et al. <1999S453> described that the pyrazolo[l,5-<7][l,2,4]triazine-dione derivative 72 is sensitive toward nucleophiles its reaction with benzylamine at room temperature gives rise to the acyl semicarbazide 73 in high yield (78%). 

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