Derivatives pyrazole

There are only a few derivatives of the indazole-6,7-dione 178 and 4,5-dione all other indazolequinones belong to the 4,7-dione system 179. 

Unsubstituted 178 and some 4-substituted derivatives were prepared by conventional oxidation of the 7-amino-6-hydroxy- or 6,7-dihydroxy- or chlorohydroxyindazoles (12LA318 14LA81 26JA1097). 

Only a few derivatives of 179 were prepared similarly with MnO (77C49, 77ZN(B)1072) or periodic acid (82LA420). A mixture of the 4,7-dione (88%) and the 4,5-dione 180 (11%) was obtained when the 5,7-dibromo-4-hydroxy precursor was oxidized in the same manner (82LA420). 

4-Benzoquinone reacts readily with either diazomethane or diazoethane to give a bis adduct (189), which can be further N-alkylated (72CB3915 75CB693). Instead of diazoalkanes, mesoionic heterocycles may be used. 

X-Ray analysis of a 2-phenyl derivative of 179 revealed that the bond lengths and bond angles of the pyrazole part are similar to those reported for an unsubstituted pyrazole ring and that the carbon-carbon and carbon-oxygen bonds in the quinone part are clearly double bonds (87JHC971). 

5-dione all other indazolequinones belong to the 4,7-dione system 179. 

3-Dichloro-l,4-benzoquinone reacts similarly (75CB693 83JMC876). Facile nucleophilic substitution of a chlorine atom is possible and chlorine at position 5 is replaced preferentially (83JMC876). Some substituted indazole- 

5-diones were reported to be active against the growth of certain rodent tumors (74IJC129 83JMC876). 

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The application described here shows how a classified data set of reactions producing pyrazole derivatives can be used to predict the correct regioisomer in a pyrazole synthesis before it is carried out practically in the laboratory. 

Fig. 2. Pyrazole-derived pharmaceuticals (a) butaglyon [2603-23-8] an antidiabetic (b) dazopride [70181 -03-2] an antiemetic (c) feclobuzo [23111-34 ] an antiinflammatory (d) kebuzone [833-34-9], an antirheumatic (e) muzolimin [55294-15-0], a diuretic (f) phenazobz [20610-63-3], an antiasthmatic (g) selenofob [39102-63-1], an antibiotic (h) sulfamazo [65761-24-2], an antiseptic and (i) sulfinpyrazone [57-96-5], an antigout preparation (50).

Hydroxy-6-methyl-2-phenylpyridazin-3(2Fr)-one and 4-hydroxy-5-nitropyridazin-3(2FT)-one rearrange in acidic medium to 3-methyl-l-phenylpyrazole-5-carboxylic acid and 4-nitropyrazole-5-carboxylic acid. 4-Hydroxypyridazin-3(2FT)-ones with a hydroxy group or other group at positions 5 or 6, which is easily replaced in alkaline medium, are transformed into 5-(or 3-)pyrazolones with hot alkali. An interesting example is ring contraction of 5-chloro-4-(methylthio)-l-phenylpyridazin-6(lFT)-one which gives, besides pyrazole derivative (127), 4-hydroxy-5-methylthio-l-phenylpyridazin-6(lFf)-one (128 Scheme 41). 

AK(30)26l). 2-Acetoxyfuran-3(2i/)-ones react with hydrazine to give 3,6-disubstituted-4-ethoxycarbonylpyridazin-4(li/)-ones (184) as the main product, but with mono-substituted hydrazines in addition to these pyridazines anhydro-5-hydroxypyridazinium hydroxide (185) derivatives and some pyrazole derivatives are also formed (Scheme 102) (79JOC3053). The... 

Pyridazines are formed from pyrones or their thioxo analogs or from appropriate pyridones. Pyrones or pyridones react with diazonium salts to give the corresponding hydrazones (187) and (188) which are rearranged under the influence of acid or base into pyridazinones as shown in Scheme 107. On the other hand, kojic acid is transformed with hydrazine into a 1,4-dihydropyridazine and a pyrazole derivative. 4H-Pyran-4-thiones... 

Bielectrophiles have found appreciable applications in the synthesis of ring-fused systems, especially those involving [5,6] fused systems. The following serve to illustrate these applications. Reaction of pyrazole with (chlorocarbonyl)phenyl ketene (214) (Type 1, Scheme 6) readily formed the zwitterionic pyrazolo[l,2-a]pyrazole derivative (215) (80JA3971). With l-methylimidazole-2-thione (216), anhydro-2-hydroxy-8-methyl-4-oxo-3-phenyl-4//-imidazo[2,l-6][l,3]thiazinium hydroxide (217) was obtained (80JOC2474). 

Other pyrazole derivatives have not been the subject of systematic studies. Owing to the variety of structures involved, figures instead of tables are used to describe chemical shift... 

Table 21 Some References to UV Studies of Pyrazole Derivatives...

Figure 19 Barriers to internal rotation (in kJ tnol ) for pyrazole derivatives...

Another possibility is that both nitrogen atoms react with a double alkylating agent. In this way fused pyrazole derivatives (pyrazolo[l,2-a]pyrazoles) like (237) can be obtained by reaction of 3,5-dimethylpyrazole with 1,3-dichloropropane or l-chloro-3-propanol (69BSF2064). More surprising is the reaction with a-chlorocarbonylphenylketene which yields the paraionic compound (238) (80JA3971) which can also be obtained from 3,5-dihydroxy-4-phenylpyrazole and /3-dicarbonyl compounds (82JOC295). 

Many reagents are able to chlorinate aromatic pyrazole derivatives chlorine-water, chlorine in carbon tetrachloride, hypochlorous acid, chlorine in acetic acid (one of the best experimental procedures), hydrochloric acid and hydrogen peroxide in acetic acid, sulfuryl chloride (another useful procedure), etc. iV-Unsubstituted pyrazoles are often used as silver salts. When methyl groups are present they are sometimes chlorinated yielding CCI3 groups. Formation of dimers and trimers (308 R = C1) has also been observed. 

A -Pyrazolines such as (410) are oxidized by iodine, mercury(II) acetate and trityl chloride to pyrazolium salts (411), and compound (410) even reduces silver nitrate to Ag° (69JOU1480). Electrochemical oxidation of l,3,5-triaryl-2-pyrazolines has been studied in detail (74BSF768, 79CHE115). They Undergo oxidative dimerization and subsequent transformation into the pyrazole derivative (412). 

Acid chlorides are useful reagents, but when the pyrazole is N- unsubstituted a dimerization occurs and the diketopiperazine (254) is isolated (Section 4.04.2.3.3(x)). However, (254) reacts with many compounds as an acid chloride would, for example with amines to yield amides (67HC(22)l). The difunctional pyrazole derivative (441) affords polymers by reaction with diphenols (69RRC763). Cyanopyrazoles can be hydrolyzed to the corresponding carboxylic acids (68CB829). 

Another example of the analogy between pyrazole and chlorine is provided by the alkaline cleavage of l-(2,4-dinitrophenyl)pyrazoles. As occurs with l-chloro-2,4-dinitrobenzene, the phenyl substituent bond is broken with concomitant formation of 2,4-dinitrophenol and chlorine or pyrazole anions, respectively (66AHC(6)347). Heterocyclization of iV-arylpyrazoles involving a nitrene has already been discussed (Section 4.04.2.1.8(i)). Another example, related to the Pschorr reaction, is the photochemical cyclization of (515) to (516) (80CJC1880). An unusual transfer of chlorine to the side-chain of a pyrazole derivative was observed when the amine (517 X = H, Y = NH2) was diazotized in hydrochloric acid and subsequently treated with copper powder (72TL3637). The product (517 X = Cl, Y = H) was isolated. 

Fused ring systems containing a pyrazole unit can be prepared either from the heterocyclic moiety by formation of a pyrazole ring or from the reaction between a pyrazole derivative and a suitably functionalized reagent. The ring systems thus obtained are discussed in detail in other chapters (Chapters 4.05, 4.35, 4.36) but it is of interest to discuss here those methods which start from a pyrazole derivative as the reactions involved can be considered as examples of the reactivity of pyrazoles. The most widely studied fused ring systems are the [5.6] systems and the examples described in this section will be chosen from this group and, occasionally, from [5.5] and [5.7] systems. 

Pyrazoles can be prepared by ring opening reactions of fused systems already containing the pyrazole nucleus. Thus several [5.5], [5.6] and [5.7] fused heterocycles have been opened to substituted pyrazoles, usually in basic medium. In general, the method has little preparative interest since another pyrazole derivative has usually been used to build the ring-fused system. However, due to the unexpected structures obtained, two publications are worthy of notice. 6//-Cyclopropa[5a,6a]pyrazolo[l,5-a]pyrimidine (638) was readily obtained from the corresponding pyrazolopyrimidine by the action of diazomethane at room temperature (Scheme 59) (81H(15)265). When (638) was treated with potassium hydroxide, the pyrazole (640) was formed, probably via the diazepine (639). 

The transformations between pyrazole derivatives of different oxidation levels, i.e. between pyrazolones and pyrazolines, will not be discussed here since they have been examined in the reactivity sections (Section 4.04.2). 

Table 38 Some Selected Pyrazole Derivatives with Biological Activity...

Tricyclic pyrazole derivatives (698) are described by Hashem et al. as inhibitors of the growth of Bacillus subtilis, Pseudomonas fluorescens, Staphylococcus aureus and KB cells at moderate concentrations (76JMC229). 

Other pyrazole derivatives (737) suitable as coupling components for diazotype printing have been prepared by Pett et al. (79M140406). 

The influenee of pyrazole derivatives on Prebiotie Condensation Reaetions of a-Amino Aeids indueed by polyphosphates in aqueous solution has been studied in eomparison with other azoles (81C59). In the ease of triglyeine formation the presenee of pyrazole did not inerease the yield signifieantly. 

Knorr reported the first pyrazole derivative in 1883. The reaction of phenyl hydrazine and ethylacetoacetate resulted in a novel stmcture identified in 1887 as l-phenyl-3-methy 1-5-pyrazolone 9. His interest in antipyretic compounds led him to test these derivatives for antipyretic activity which led to the discovery of antipyrine 10. He introduced the name pyrazole for these compounds to denote that the nucleus was derived from the pyrrole by replacement of a carbon with a nitrogen. He subsequnently prepared many pyrazole analogs, particularly compounds derived from the readily available phenyl hydrazine. The unsubstituted pyrazole wasn t prepared until 1889 by decarboxylation of liT-pyrazole-3,4,5-tricarboxylic acid. ... 

Derivatives of imidazole 41 also exhibit fast degenerate rearrangement, whieh, unlike those of pyrazole derivatives, are exelusively intermoleeular and also very sensitive to the influenee of traees of water (Seheme 23) [74JOM(70)347 76IC3054 77JOM(132)69]. 

Numerous data on kinetics of annular tautomerism have been obtaifled for the degenerate rearrangements of pyrazole derivatives. Since all these rearrangements were found to be intramolecular, we can compare kinetic measurements carried out in different media. The following order of increase in migration ability of various groups is established ... 

In other cases, attempts to cyclize the hydrazone proved more difficult and resulted in mixtures of compounds. The products obtained along with pyrazol-3-ones were ring-opened compounds or other pyrazole derivatives. Pilgram, who obtained hydrazones 56a,b by standard methodology, reported one such example. 

Compound [PtCl( Bu2PCMe2CH2)2l reacts with pyrazole or 3,5-dimethyl-pyrazole in the presence of sodium hydroxide to form 242 (R = H, Me) [84ICA (82)L9]. The chelate ring is not planar in this case, and the trans strucmre of the pyrazolate derivative was demonstrated. Tlie four-coordinated platinum atoms are characterized by a distorted square-planar coordination. 

Dipolar additions of diazomethane to acetylenes under mild conditions are restricted to monosubstituted acetylenes thus the formation of pyrazole derivatives 1 (1,3-dipolar addition, C=C isomerization, then methylation) confirms the existence of a terminal acetylene in caryoynencins (87TL3981) (Scheme 5). 

While Kakisawa et al. (87TL3981) reported formation of Wmethylpyrazole 1, Yamaguchi et al. obtained the NH derivative 2 by reaction of caryoynencins with diazomethane in ethyl acetate at 0°C (94BSJ1717 95JMC5015). The 1,3-dipolar addition was quite sensitive to the solvent employed, and a very low yield of pyrazole derivative 2 was obtained in ether or methanol (Scheme 5). 

The triple bond in pyrazole derivatives gives, as do other acetylene derivatives, typical addition reactions. 

The attempted oxidation of pyrazole derivatives with eleetron-withdrawing substituents (R = Me R R = COOCH3 R" = CHO Seheme 91) failed (2001UP4). For the same reason the oxidation of the triple bond in 4-ehloro-5-(2-ehloro-5-nitrophenylethynyl)- ,3-dimethyl-1//-pyrazole was also unsueeessful. 

Ethynylpyrazole was obtained under similar conditions in 46% yield (88M253). There are other examples of the trimethylsilyl cleavage with aqueous solution of potassium hydroxide for l-(hetaryl)-4-(trimethylsilylethynyl)pyrazole derivatives (96EUP703234). 

It has already been mentioned that 5-methylisoxazole is converted into a pyrazole derivative by phenylhydrazine. All 4-nitroisoxazoles undergo this same reaction (136— 137)/° 5,5 -Dimethyl-4,4 -dinitro-3,3 -diisoxazolyI reacts similarly... 

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