5- Substituted pyrazol-3-ones

More recently, Tietze and Steinmetz (96SL667) used the patented polystyrene-resin methodology for for the solid-phase synthesis of a large number of diverse )3-keto esters 40a-h. These were reacted with phenylhydrazine in THF at room temperature to give hydrazones 41a-h that were then cychzed into 2-phenyl 5-substituted pyrazol-3-ones 42a-h by heating in toluene at 1(X)°C (Scheme 12). 

The ultraviolet spectra of compounds which may exist as either 1-substituted pyrazol-3-oncs (70, R — H) or 1-substituted 3-hydroxypy-razoles (71, R = H) do not allow distinction between the two possible forms, because their spectra and those of fixed derivatives of both types (70, R = Me and 71, R = Me) are too similar. The solid state infrared spectra of these compounds have been interpreted to support both the NH form (see reference 79a for a similar conclusion regarding indazoI-3-one) and the OH form. Basicity data have also been considered to indicate the predominance of the OH form. ... 

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>. 

A one-pot process to form 1,3,4-substituted pyrazoles 25 by Suzuki coupling of arylboronic acids to chromone 24, followed by condensation with hydrazine has been reported <06JCO286>. The synthesis of 3 or 5-o-hydroxyphenol-4-benzylpyrazoles has been accomplished by treatment of 3-benzylchromones, 3-benzylflavones and their 4-thiochromone analogs with hydrazine hydrate in hot pyridine <06EJO2825>. 

Fused pyrazole compounds have been prepared from A-alkyl substituted pyrazoles. For example, a palladium-catalyzed/norbornene-mediated sequential coupling reaction involving an aromatic sp2 C-H functionalization as the key step has been described, in which an alkyl-aryl bond and an aryl-heteroaryl bond were formed in one pot <060L2043>. A variety of highly substituted six-membered annulated pyrazoles 59 were synthesized in a one-step process in moderate yields from IV-bromoalkyl pyrazoles 57 and aryl iodides 58. 

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. 

Shen L, Cao S, Liu NJ, Wu JJ, Zhu LJ, Qian XH (2008) Ytterbium(III) perfluorooctanoate catalyzed one-pot, three-component synthesis of fully substituted pyrazoles under solvent-free conditions. Synlett 1341-1344... 

Studies on the potential of the electrochemical approach to pyrazolotriazoles 117 showed that under the conditions of bicycle synthesis from 3-amino-4-hydrazonopyrazoles the N-l-unsubstituted triazole ring of 117 was further oxidized in a one-electron peak, followed by proton removal to yield the bis-(l,l )-2-phenylpyrazolo[3,4-i/][l,2,3]triazoles 118. This observation is significant, since in spite of pronounced pharmaceutical applications of pyrazoles, the redox characteristics of substituted pyrazoles have received limited attention (Scheme 13) <2001MI1022>. 

Oxidation of N, -substituted pyrazoles to 2-substituted pyrazole-] -oxides using various peracids facilitates the introduction of halogen at C i, followed by selective nitration at C4. The halogen aiom at C3 or C5 is easily removed by sodium sulfite and acts as a protecting group. Formaldehyde was used to direct the selective introduction of electrophiles at C in a simple one-pot procedure. 

Kidwai, M., Kumar, P., Goel, Y. and Kumar, K., Microwave assisted synthesis of 5-methyl- 1,3,4-thiadiazol-2-ylthio/tetrazol-l-yl substituted pyrazoles, 2-azetidinones, 4-thiazolidinones, benzopyran-2-ones and 1,3,4-oxadiazoles, Indian. J. Chem., Sect. B, 1997, 36, 281. 

Alkyl- or aryl-substituted pyrazole 1-oxides 94 can be obtained in acceptable yields by oxidative cyclization of O-silylated 3-oximimines like 1 -tert-hutyldimethyIsilyloxy-4-methylamino-1 -azab nta-1,3-diene 93 using copper(II) sulfate as the oxidant and pyridine and acetonitrile as the solvent. The oximimines are prepared from 1,3-dicarbonyl compounds 92 in a one-pot process. The method also gives access to 2-alkyl and aryl-pyrazole 1-oxides R=H devoid of substituents at the ring carbon atoms (94 Ri = R2=H) (1995JCS(P1)2773) (Scheme 27). 

O-Silylation of 2-substituted pyrazole 1-oxides also activates lateral protons at the 3- and 5-positions. Thus the 5-methyl derivative 189 upon silylation furnishes the silyloxypyrazolium ion 190, which is deprotonated at the methyl group by PMP giving rise to a neutral species 191. Next, the iodide ion replaces the trimethylsilyloxy group of the intermediate 191 in an allylic type substitution to give iodomethyl-substituted pyrazole 192. The whole sequence 189 -> 192 takes place in one pot (1992JCS(P1)2555) (Scheme 54). 

After a paper devoted to GIAO/B3LYP calculations of 13 monosubstituted benzenes and 21 1-substituted pyrazoles [148] that allowed discussion of some structural problems (such as conformation, tautomerism, and structure of salts) we have continued to use this combination of experimental (in solution and in the solid state, CPMAS NMR) and calculated values as a very useful exploratory technique. For instance, we have used II, 13C, and 15NNMR spectroscopy to study compounds 149-154. In para-disubstituted derivatives 149,151,152,153, in the solid state (no free rotation) the signals of the ortho carbons are split (one is close to N2) and, thanks to the calculated values, they can be assigned [149],... 

When compounds such as pyrazoles are being made to develop new drugs, a number of related compounds can be prepared at once by diversity-oriented synthesis, that is, methods designed to be general for a wide range of compounds. An example where both components are aliphatic 13 and a tri-substituted example 15 make the point. In this work, the synthesis of 25 different di-or tri-substituted pyrazoles was attempted by the same method only one example failed. 

N. K. Kochetkov and A. N. Nesmeyanov showed that / -chlorovinyl ketones react with hydrazine in ethanolic solution to give high yields of 3-substituted pyrazoles.297 Unlike hydroxymethylene ketones, which by tautomerism give mixtures of isomeric pyrazoles, /3-chloro-vinyl ketones react with phenylhydrazine to give only one isomer, a point which was verified experimentally.340 This can only be explained... 

The H chemical shifts were assigned in C.I. Disperse Yellow 211,41 in sodium l-(2-,l-(3- and l-(4-trifluoromethylphenylazo)-2-hydroxy-5-benzene-sulfonate,42 in some o,o -dihydroxyazo dyes containing the sulfo group43 and l(4)-substituted pyrazol-5-one azoderivatives 8.44... 

N-Unsubstituted pyrazole is readily converted into 3(5)-substituted derivatives in a one-pot sequence, using formaldehyde both for N-protection and to mediate the lithiation at the 5-position the transient N-(hy droxymethy 1) unit is readily removed during work-up. Direct lithiation of 1-substituted pyrazoles provides an efficient entry to 1,5-disubstituted pyrazoles. 

Several d and / transition metals have been found to yield polymeric complexes with pyrazoles 14, 178). Reactions of these polymers with HFA produce monomeric species, HFA adding to the free nitrogen atom and the metal. Substitution of one carbon atom adjacent to nitrogen also results in degradation of the polymers. However, no reaction has been found when both a carbon atoms are sterically hindered 14). 

This latter formulation may give access to metal derivatives in which such a di(l-pyrazolyl)borate unit rves as a chiral ligand, i.e., by employing a C-substituted pyrazole as donor molecule. There exists only one report in the literature on forming poly(l-pyrazolyl)borate ions containing two different pyrazole groups, which were obtained in quite laborious manner... 

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