4- -pyrazol-3-ones, reaction with hydrazones

Diazotization of 4-[(4-aminophenyl)sulfonamido]-2,6-dimethyl pyrimidine 10, followed by coupling of the diazonium salt with ethyl 3-oxobutanoate 11a or l,3-diphenyl-l,3-propanedione lib, afforded hydrazones 12a,b. Reaction of hydrazone 12a with aminoguanidine nitrate in refluxing acetic acid yielded the pyrazol-3-one 13a in 55% yield (00JIC42) (Scheme 4). 

Hydrazones and malononitrile can attack the imine carbon of 4-(arylimino)-pyrazol-3-ones resulting in an overall addition-elimination product. Heinisch (88JPR57) (Scheme 121) described the use of several hydrazone derivatives 395a-d,f in their reaction with (Z/ )-4-(arylimino)pyrazol-3-ones 394a-j in concentrated... 

A-Arylhydrazones are useful agricultural materials. Moreover, they can be cleaved to form A-arylhydrazines for pyrazole synthesis, and the hydrazine portion can be transferred to ketones to serve as substrates for the Fischer indole synthesis.t The reactions of benzophenone hydrazone with aryl halides have been reported, and to date these reactions are best conducted with chelating phosphine ligands such as DPPF and BINAP, as shown in Eq. 22. These catalyst systans have been the only ones reported for hydra-zone arylation. The chemistry of hydrazonato complexes is similar to that of aniUdes and diarylamides.f Thus, the reactions of aryl chlorides with hydrazones should be accessible in the future using alkylphosphine ligands. 

Katritzky and co-workers studied the mechanism of this reaction in detail. His work involved a NMR study of 16 reactions of methyl-, phenyl-, 1,2-dimethyl-, and l-methyl-2-phenylhydrazine with /3-keto esters. In many cases starting materials, intermediates, and products were detected simultaneously. Most reactions proceed by nucleophilic addition of the less hindered hydrazine nitrogen atom to the keto carbon of the keto ester. For example, the pathway given in Scheme 3 for the reaction of methyl 3-oxobutanoate 9 with methyl- or phenyUiydrazine 2 (R = Me or Ph) was found to be dominant. The initially formed addition product 10 dehydrates to hydrazone 11, which then isomerizes to hydrazone 12. Intermediate 12 then cyclizes to pyrazol-3-one 13, which tautomerizes to the kinetically more stable pyrazol-3-otie 14 [87JCS(P2)969]. 

The reaction of ethyl 3-oxobutanoate with 4-aryltetrahydropyridazine-3,6-di(Mie 3-hydrazones 60a-d afforded the corresponding hydrazonobutanoates 61a-d. When heated with ethanolic sodium ethoxide, compounds 618-d cyclized to the sodium derivatives 62a-d which, upon acidification, gave the respective pyrazol-3-one derivatives 63a-d (97JHC389) (Scheme 19). 

In an altogether different type of approach, the hydrazone is formed in situ as a lithium salt. Wilson et al. (80JHC389) described this approach in the one-pot synthesis of 5-aryl-2-phenylpyrazol-3-ones 72a-f from the corresponding hydrazones 65a-f (Scheme 20). The latter were obtained by condensing ketones 64a-f with phenylhydrazine. Treatment of hydrazones 65a-f with n-butyllithium in dry THF, followed by the addition of half a molar equivalent of diethyl carbonate 67 and then quenching the reaction mixture with hydrochloric acid, produced pyrazol-3-ones 72a-f, along with products 71. The yields of the products 72 are in the range 22-97%. Four intermediates—66a-f, 68a-f, 69a-f, and 70a-f— were proposed for this reaction. 

An analogous series of reactions is used to produce depyrimidinated DNA fragments. Hydrazine is used in these reactions, since both cytosine and thymine react with hydrazine. The bases are cleaved to yield urea and a pyrazole ring. The deoxyribose moiety is left as a hydrazone. Piperidine, which reacts with the hydrazone, is used to cleave the nucleotide chain. Cytosines react specifically with hydrazine in 5 mol/ L NaCl, but no specific reaction exists for thymines. Consequently, one aliquot yields labeled oligonu-cleotides 3 -terminated at cytosines, whereas a second aliquot contains nucleotides cleaved in the absence of NaCI at both cytosine and thymine residues. 

Hydrazones are also useful substrates in the preparation of pyrazoles. Reaction of N-monosubstituted hydrazones with nitroolefins led to a regioselective synthesis of substituted pyrazoles <060L3505>. lf/-3-Ferrocenyl-l-phenylpyrazole-4-carboxaldehyde was achieved by condensation of acetylferrocene with phenylhydrazine followed by intramolecular cyclization of the hydrazone obtained under Vilsmeier-Haack conditions <06SL2581>. A one-pot synthesis of oxime derivatives of l-phenyl-3-arylpyrazole-4-carboxaldehydes has been accomplished by the Vilsmeier-Haack reaction of acetophenone phenylhydrazones <06SC3479>. 

Synthetic routes to these derivatives - as also discussed earlier in CHEC-II(1996) <1996CHEG-II(8)445> - utilize the reaction of a 3-substituted pyrazole derivative bearing a carbonylhydrazine or hydrazone side chain with an appropriate reagent providing a one-carbon-atom stmctural unit. Scheme 60 summarizes the recent results. 

The fused pyrrole ring system (204) has been obtained by the reaction of 17/3-hydroxy-17-methylandrosta-l,4-dien-3-one with tosylmethyl isocyanide in the presence of sodium hydride in DMSO,92 and 17/3-hydroxy-17-methyl-7-oxa-5o -androstano-[3,2-c]- (205) or -[2,3-d]-isoxazoles (206 X = O) have been prepared by treating 7-oxa-2-(hydroxymethylene)-17/3 -hydroxy-17-methyl-5 a -androstan-3-one with hydroxylamine hydrochloride.93 In the presence of pyridine, the isox-azole (206 X = O) is formed, but when the reaction is catalysed by sodium acetate in acetic acid the isomeric steroid (205) results. Cycloaddition of hydrazine hydrate to the same 2-hydroxymethylene-7-oxa-steroid results in the [3,2-c]pyrazole (206 X = NH). A similar addition is encountered in the reactions between 3/3-hydroxy-16-(hydroxymethylene)-5a-androstan-17-one and the substituted hydrazines RNHNH2 (R = H, o-COC6H4NH2, or p-COQHUNH ,) when the corresponding [17,16-c]pyrazoles (207) are formed after cyclization of the intermediate hydrazones.94... 

Tautomeric lactose hydrazone 77/78 was obtained from 2,2,2-trifluoroethyl-3-oxobutanoate 76 with hydrazine tautomers 74/74 in a 1 3 ratio using acetonitrile and water to give, after lyophilization, a mixture of pyrazol-3-one 79 and l-lactosylpyrazol-3-one 80 (00CAR169) (Scheme 19). They were identified by HPLC-ESIMS, their stability being limited due to rapid atmospheric oxidation. Further reaction of this mixture with 4-methylbenzenediazonium chloride in aqueous sodium bicarbonate followed by addition of 2,4-pentadione gave, after purification by HPLC, stable 2-/)-D-lactosyl-4-[2-(methylphenyl)diazenyl]pyra-zol-3-one 81 in 15% yield. 

A completely different approach initially involves the addition of the carbanion of ethyl 2-cyanoacetate 142 in the presence of base to the imine group of 2-naphthylsulfonyl hydrazone 147 followed by cyclization and oxidation to pyrazol-3-one 150 (02NN469) (Scheme 34). The reaction requires heating in ethanol with triethylamine and it is suggested that intermediate 148 is first produced, and then undergoes an intramolecular acyl substitution resulting in the unstable pyrazol-3-one 149. The latter is prone to oxidation by molecular oxygen and is converted to stable pyrazol-3-one 150. 

Formation of Pyrazoles from Bis(hydrazones).—Mesoxaldehyde bis(phenylhydrazone) (193), obtained by periodate oxidation of saccharide osazones (192) is readily cyclized in the presence of acids to give l-phenyl-4-phenylazo-pyrazole (195).162 365 Hexulose phenylosazones (192) are also disproportionaled in the presence of acidic salts of carbonyl reagents, such as hydroxylamine hydrochloride, to give l-phenyl-4-phenylazo-pyrazolin-5-one (196). The reaction probably proceeds via mesoxalic acid 1,2-bis(phenylhydrazone) (194).365 The hydroxalkyl derivatives of 196 are produced from dehydroascorbic acid bis(phenylhydrazone) by treatment with base to open the lactone ring and permit the conversion of 197 to 199.351,366 Another type of pyrazole that is formed by dehydrating osazones with acetic anhydride is discussed later under anhydroosazones (see Schemes 45,53). 

Kidwai et al. have demonstrated that formic acid can be used to catalyze cydocon-densation of hydrazones to give new fungicidal pyrazoles, as shown in Scheme 10.17 [37]. The significance of their work, dearly exploiting nonthermal spedfic microwave effects, is noticeable when one considers that in the classical approach cyclocondensation of hydrazones requires 30-35 h with constant heating at 100-120 °C whereas the same reaction is complete in 4-7 min with improved yield when performed under the action of microwave irradiation. 

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