4- -pyrazol-3-ones, nucleophilic reactions

The reactions described in this section refer to addition of C4 of pyrazol-3-ones onto different types of electrophiles to form er-bonds. Addition to a,/f-unsaturated compounds may involve the elimination of small molecules from the electrophile. A rare case would involve a double nucleophilic reaction by the pyrazol-3-one to form a spiro compound. 

Nitrogen nucleophiles used to diplace the 3 -acetoxy group include substituted pyridines, quinolines, pyrimidines, triazoles, pyrazoles, azide, and even aniline and methylaniline if the pH is controlled at 7.5. Sulfur nucleophiles include aLkylthiols, thiosulfate, thio and dithio acids, carbamates and carbonates, thioureas, thioamides, and most importandy, from a biological viewpoint, heterocycHc thiols. The yields of the displacement reactions vary widely. Two general approaches for improving 3 -acetoxy displacement have been reported. One approach involves initial, or in situ conversion of the acetoxy moiety to a more facile leaving group. The other approach utilizes Lewis or Brmnsted acid activation (87). 

Scheme 4 shows in a general manner cyclocondensations considered to involve reaction mechanisms in which nucleophilic heteroatoms condense with electrophilic carbonyl groups in a 1,3-relationship to each other. The standard method of preparation of pyrazoles involves such condensations (see Chapter 4.04). With hydrazine itself the question of regiospecificity in the condensation does not occur. However, with a monosubstituted hydrazine such as methylhydrazine and 4,4-dimethoxybutan-2-one (105) two products were obtained the 1,3-dimethylpyrazole (106) and the 1,5-dimethylpyrazole (107). Although Scheme 4 represents this type of reaction as a relatively straightforward process, it is considerably more complex and an appreciable effort has been expended on its study (77BSF1163). Details of these reactions and the possible variations of the procedure may be found in Chapter 4.04. 

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]. 

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... 

A somewhat related approach was followed by Molteni and coworkers, who have described the three-component, one-pot synthesis of fused pyrazoles by reacting cyclic 1,3-diketones with DMFDMA and a suitable bidentate nucleophile, such as a hydrazine derivative (Scheme 6.195) [357]. Again, the reaction proceeds by initial formation of an enamino ketone as the key intermediate from the 1,3-diketone and DMFDMA precursors, followed by a tandem addition-elimination/cydodehydration step. The details of this reaction, carried out in superheated water as solvent, have been described in Section 4.3.3.1. 

The catalysed alkylation of l//,4//-pyrazol-5-ones is solvent dependent. In benzene, bis-alkylation occurs at the 4-position whereas, in a carbon disulphide benzene mixture, O-alkylation is observed, although the major product (4, Scheme 5.22) results from nucleophilic attack by the pyrazolone on the carbon disulphide, followed by alkylation of the dithiolate dianion [92]. The catalysed reaction of 2-thiono-3-aryl-thiazolidin-4-ones with alkylating agents under soliddiquid two-phase conditions results in alkylation at the 5-position (60-80%) [93]. The aldol condensation of the thiazolidinones with aryl aldehydes is also catalysed by quaternary ammonium salts. 

When only one heteroatom of the dinucleophile possesses a hydrogen substituent, the reactions lead instead to alkenyl complexes rather than carbene compounds. Effectively, treatment of diphenylallenylidenes 1 and 6 with pyrazoles yields the heterocyclic derivatives 61 (Scheme 2.25) [76]. Interestingly, the dissymmetric 3-methylpyrazole (R=H, R = Me) provides only one regioisomer, in which the methyl group points towards the metal. This process, which formally corresponds to the addition of two nitrogen nuclei at C and Cy and a hydrogen atom at Cp, is assumed to take place through an initial nucleophilic attack at the Ca position. 

Abstract Synthesis methods of various C- and /V-nitroderivativcs of five-membered azoles - pyrazoles, imidazoles, 1,2,3-triazoles, 1,2,4-triazoles, oxazoles, oxadiazoles, isoxazoles, thiazoles, thiadiazoles, isothiazoles, selenazoles and tetrazoles - are summarized and critically discussed. The special attention focuses on the nitration reaction of azoles with nitric acid or sulfuric-nitric acid mixture, one of the main synthetic routes to nitroazoles. The nitration reactions with such nitrating agents as acetylnitrate, nitric acid/trifluoroacetic anhydride, nitrogen dioxide, nitrogen tetrox-ide, nitronium tetrafluoroborate, V-nitropicolinium tetrafluoroborate are reported. General information on the theory of electrophilic nitration of aromatic compounds is included in the chapter covering synthetic methods. The kinetics and mechanisms of nitration of five-membered azoles are considered. The nitroazole preparation from different cyclic systems or from aminoazoles or based on heterocyclization is the subject of wide speculation. The particular section is devoted to the chemistry of extraordinary class of nitroazoles - polynitroazoles. Vicarious nucleophilic substitution (VNS) reaction in nitroazoles is reviewed in detail. 

Elnagdi and co-workers (84AP289) (Scheme 58) described both nucleophilic and electrophilic reactions of 3-(3-oxopyrazol-4-yl)-3-oxopropionitrile 215. Therefore, 215 was condensed with benzaldehyde or salicylaldehyde in refluxing ethanol containing triethylamine and with hydroxylamine, hydrazine hydrochloride or phenylhydrazine to give the corresponding pyrazol-3-one derivatives 216, 217, 218 and 219a,b in, 60%, 25%, 72% and 95% yield, respectively. 

The chloro group of 2-(2-chloro-5-nitrophenyl)pyrazol-3-one 303 was displaced by morpholine which was used both as solvent and nucleophile. The reaction was reported by Ainsworth and Suschitzky (67JCS(C)1003) (Scheme 81) and gave 2-(2-morpholin-4-yl-5-nitrophenyl)pyrazol-3-one 304. 

The keto group of pyrazol-4,5-diones is susceptible to nucleophilic addition that leads to pyrazol-3-ones. Thus, 3-methyl-l H-l-(4-nitrophe-nyl)pyrazole-4,5-dione 355 readily hydrated to 4,4-dihydroxypyrazol-3-one 356 (99T10447) (Scheme 82). The keto group of pyrazole-4,5-dione 357 undergoes a Wittig reaction as demonstrated by Tacconi et al. 

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