Pyrazole oxidation

Extensive reviews have been pubUshed, covering the Hterature to about 1967 (1 3). Pyrazoles and the benzopyrazoles have been well reviewed in References 4 and 5. More up-to-date reviews, though much narrower in scope, have been pubUshed on pyrazole oxides (6), dihydropyrazoles as insecticides (7), the anticancer dmgs anthrapyrazoles (8,9), and pyrazole sulfonylureas as herbicides (10). 

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. 

The 4-hydroxypyrazoles are the metabolites of pyrazole oxidation (see Section 3.01.5.4.11). Costero <93ahc(58)171> reported the oxidation of 3,5-diphenyl-4-hydroxypyrazole into 2,5-diphenyl-... 

The pyrazole ring is resistant to oxidation and reduction. Only ozonolysis, electrolytic oxidations, or strong base can cause ring fission. On photolysis, pyrazoles undergo an unusual rearrangement to yield imidazoles via cleavage of the N —N2 bond, followed by cyclization of the radical iatermediate to azirine (27). 

Unsaturated ketones react with phenyUiydrazines to form hydrazones, which under acidic conditions cyclize to pyrazolines (35). Oxidation, instead of acid treatment, of the hydrazone with thianthrene radical cation (TH " ) perchlorate yields pyrazoles this oxidative cyclization does not proceed via the pyrazoline (eq. 4). 

Hydrazino groups are also converted into H-compounds with mercury(II) oxide (74CR(C)-(278)427) in other reactions they have given hydrazones, or have been converted into pyrazoles and fused heterocyclic rings (77JAP(K)7785194), e.g. (72) -> (73). 

N-Unsubstituted pyrazoles and imidazoles add to unsaturated compounds in Michael reactions, for example acetylenecarboxylic esters and acrylonitrile readily form the expected addition products. Styrene oxide gives rise, for example, to 1-styrylimidazoles (76JCS(P1)545). Benzimidazole reacts with formaldehyde and secondary amines in the Mannich reaction to give 1-aminomethyl products. 

Pyrazoles can undergo nitration at several positions 4-bromo-l-methylpyrazole yields the 3,5-dinitro product. 1-Methylpyrazole 2-oxide yields the 5-nitro derivative. 

The pyrazole ring is generally stable to oxidation and side chains are oxidized to carbonyl groups (66AHC(6)347). l-Aryl-3-methylpyrazoles (134) react with ozone to yield 1,3,4-oxadiazolinones (135) (66AHC(7)183). 

A -Pyrazolines are converted into pyrazoles by oxidation with bromine or Pb(OAc)4 and... 

Azole 7V-oxide groups are readily removed by reduction with Zn/HOAc, HI or PCI3, e.g. in the pyrazole series. 1,2,3-Thiadiazole 3-oxides isomerize on irradiation to the corresponding 2-oxides. 

The isoxazoles (585) were formed regioselectively from the (dioxoalkyl)phosphonium salts (584) with hydroxylamine hydrochloride, the direction of cyclization being different from that of the nonphosphorus-containing 1,3-dioxo compound (see Chapter 4.16). Aqueous sodium hydroxide converted (585) into the isoxazole (586) and triphenylphosphine oxide. Treatment of (585) with n-butyllithium and an aldehyde gave the alkene (587). With hydrazine or phenylhydrazine analogous pyrazoles were formed (80CB2852). 

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 new type of rearrangement has been reported for certain l-(o-nitrophenyl)pyrazoles (169), giving cis- and trans-benzotriazole 1-oxides (170 Scheme 12) (73TL891). The reaction was rationalized in terms of an intermediate azo compound (171 formed in turn either from the diradical species (172) or from the intramolecular 1,4-adduct (173). Subsequently... 

Surprisingly, there are very few examples of successful fV-oxidation of pyrazoles. Simple fV-alkylpyrazoles generally do not react with peracids (B-76MI40402,77JCS(P1)672). The only two positive results are the peracetic acid (hydrogen peroxide in acetic acid) transformation of 1-methylpyrazoIe into 1-methylpyrazole 2-oxide (268) in moderate yield and the peroxy-trifluoroacetic acid (90% hydrogen peroxide in trifluoroacetic acid) transformation of 5-amino-l-methylpyrazoIe into l-methyl-5-nitropyrazoIe 2-oxide (269). 

Pyrazole is very stable in acid media and even under more vigorous nitration conditions neither ring opening nor ring oxidation was observed (for oxidation to pyrazolones with a mixture of bromine and nitric acid see Section 4.04.2.1.4(v)). 

Bromine in chloroform and bromine in acetic acid are the reagents used most often to brominate pyrazole. When nitric acid is used as a solvent, both bromine and chlorine transform pyrazoles into pyrazolones (Scheme 24). Thus 3-methyl-l-(2,4-dinitrophe-nyOpyrazole is brominated at the 4-position (309). The product reacts with chlorine and nitric acid to give the pyrazolone (310). The same product results from the action of bromine and nitric acid on (311). The electrophilic attack of halogen at C-4 is followed by the nucleophilic attack of water at C-5 and subsequent oxidation by nitric acid. 

A-Oxidation with peracids (Section 4.04.2.1.3) and the transformation of pyrazoles into 4,4-dihalogeno-2-pyrazolin-5-ones (Section 4.04.2.1.4(v)) have already been discussed. Transformation of non-aromatic 2-pyrazolin-5-ones into the 4-oxo derivatives will be examined in Section 4.04.2.2.l(ii). 

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). 

Pyrazolidines are cyclic hydrazones and their reactivities are comparable, the main difference being found in the oxidation of pyrazolidines to pyrazolines and pyrazoles. 

We have already noted (Section 4.04.2.1.4(xi)) that alkyl groups on pyrazoles are oxidized with permanganate to carboxylic acids. Silver nitrate and ammonium persulfate transform 4-ethyl-1-methylpyrazole (436) into the ketone (437) (72JHC1373). The best yield was obtained starting with the alcohol (438) and using an acid dichromate solution as oxidizing agent. 

The iV-hydroxypyrazoles (523 R = H) and the pyrazole iV-oxides (268 Section 4.04.2.1.3 (xiii)) have been reduced to pyrazoles by means of zinc in acetic acid and catalytic hydrogenation, respectively (75MI40402). 

The creation of the N—N bond as the last step of the ring synthesis is common in indazoles and very rare in pyrazoles. In indazoles this method is well known (type B synthesis (67HC(22)l), for example, the dehydration of oximes (570) with acetic anhydride yields 1-acetylindazoles (571), and in basic medium the indazole 1-oxides (573) are formed from the nitro derivatives (572). 

Monosubstituted hydrazones react with alkenes and alkynic compounds to yield pyrazolidines and pyrazolines, respectively (71LA(743)50, 79JOC218). Oxidation often occurs during the reaction and pyrazoles are isolated as the end product. 

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). 

As regards toxicity, pyrazole itself induced hyperplasia of the thyroid, hepatomegaly, atrophy of the testis, anemia and bone marrow depression in rats and mice (72E1198). The 4-methyl derivative is well tolerated and may be more useful than pyrazole for pharmacological and metabolic studies of inhibition of ethanol metabolism. It has been shown (79MI40404) that administration of pyrazole or ethanol to rats had only moderate effects on the liver, but combined treatment resulted in severe hepatotoxic effects with liver necrosis. The fact that pyrazole strongly intensified the toxic effects of ethanol is due to inhibition of the enzymes involved in alcohol oxidation (Section 4.04.4.1.1). 

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