1- Substituted pyrazoles, oxidation

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. 

A similar use of maleimide was seen in Yu s hetero-Diels-Alder reactions. The Ar-ethyl pyrazole reacted under aqueous conditions at room temperature, with air oxidation to furnish the fully aromatized product <2001TL8931>. Other 1,3-substituted pyrazoles required heating in acetic acid at 50°C for 24h, with product yields of 42-67%. 

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>. 

Another type of substituted pyrazole is obtained by refluxing osazones with acetic anhydride during the acetylation, two molecules of water per molecule are removed. The structure of the resulting 5-(D-g/ycero-diacetoxyethyl)-3-formyl-l-phenylpyrazole 2-acetyl-2-phenylhydrazone (71) was determined by deacetylation followed by oxidation with (a) periodate to a pyrazolaldehyde (72), and (b) permanganate to the known l-phenyl-pyrazole-3,5-dicarboxylic acid (73), as well as by a study of its n.m.r. spectrum, which confirmed the pres-... 

The aromatic 2-substituted pyrazole 1-oxides 74 are derived from pyrazoles 89 by appending an oxygen atom to the pyridine type ring nitrogen atom of the pyrazole nucleus. The second nitrogen atom of the pyrazole ring can be attached to an alkyl, aryl, hydroxy, or amino group. 

The first pyrazole 1-oxide 74 was isolated in 1957 during an investigation of the degradation of a pyrazole when treated with H202 in HOAc (1957JA3175). Until 2011, about 215 2-substituted pyrazole 1-oxides 74 with a variety of substituents at C3, C4, and C5 have been reported. A review appeared in 1989 (1989H1615). Examples of the use of pyrazole 1-oxides in synthesis have been discussed (1988BSB573). 

The resonance structures of the 2-substituted pyrazole 1-oxides 74 are discussed in Section 1.1.1. According to IUPAC nomenclature, structure 86 is a 1-substituted lH-pyrazole 2-oxide since the rules dictate that when R=H the indicated hydrogen position takes numbering precedence. Other names found in the literature are 1-substituted pyrazole 2-oxides or 1-substituted 2-oxo-1 H-pyrazoles. Frequently the numbering is switched to give the names 2-substituted 2H-pyrazole 1-oxide, 2-substituted pyrazole... 

The 2-alkyl- or aryl-substituted pyrazole 1-oxides are usually stable, crystalline, semipolar, and slightly hygroscopic compounds. 2-Substituted pyrazole 1-oxides are weak bases, being subject to protonation at the negatively charged oxygen atom. 2-Hyd roxypyrazole 1-oxides 74 (R = OH) are acids, no pf(a values seem to have been reported. 

Substituted pyrazole 1-oxides 74 can be prepared by N-oxidation of 1-substituted pyrazoles 89, by A/-alkylation of 1 -hydroxypyrazoles 90, or by cyclization of 1,3-oximimines, conjugated oximenamines, or conjugated 1,3-nitrosoimines. 

N-Alkylation of 1-hydroxypyrazoles 90 produces 2-substituted pyrazole 1-oxides 91 (Scheme 26). Competing O-alkylation of the... 

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). 

Reaction of 3-bromo-l,5-di-(4-tolyl)-l,5-diazapenta-l,3-diene 99 with hydroxyamine affords 2-substituted pyrazole 1-oxides 100 (1995JCS(P1)2773) (Scheme 29). 

N-AryloxosuIfonium ylides 101 react with nitriloxides to give 2-substituted pyrazole 1-oxides 94. Conjugated nitrosoimines 103 have been suggested as intermediates (1977JCS(P1)1196) (Scheme 30). 

Chlorination of 2-substituted pyrazole 1-oxides 86 using chlorine in tetrachloromethane (1992ACSA972) and sulfuryl chloride in dichloro-methane follows the same trend (1992ACSA972). 

The regioselectivity by electrophilic aromatic substitution is conserved when switching to acidic reaction conditions. Thus 2-substituted pyrazole 1-oxide 123 was nitrated regio and monoselectively at C3 by HN03-H2S04 to give 124 in quantitative yield (1992ACSA972). Further nitration takes place first at the benzyl 4-position, and then at the pyrazole 5-position (Scheme 39). 

Bromine at C3 and C5 of 2-substituted pyrazole 1-oxides is readily removed by treatment with aqueous-methanolic Na2S03 without removing the N-oxygen atom (1992ACSA972, 2002T7635). The debromination occurs stepwise but with moderate regioselectivity. Thus 2-benzyl 3,4,5-tribromopyrazole 1-oxide 127 produces a 5.2 1 mixture of the 4,5- and the 3,4-dibromo compounds 128 and 130, both of which are debrominated into the 4-bromo compound 129 (1992ACSA972) (Scheme 40). 

The lithiated and magnesiated 2-substituted pyrazole 1-oxides undergo metal-metal exchange by treatment with zinc chloride (2001JOC8654, 2002JOC3904) (see Scheme 43,49 and 50). 

Except for the brief statement that 2-methyl-3-nitropyrazole 1-oxide reacts with acetyl chloride to give l-methyl-5-chloro-4-nitropyrazole apparently no reports on the reaction between 2-substituted pyrazole 1-oxides 86 and acetylchloride or acetic anhydride exist (1977JCS(P1)672). 

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). 

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