1.5- Dimethylpyrazole 1,3 -Dimethylpyrazoles

Dimethylpyrazole (III) may be prepared from acetylacetone (I) and hydrazine (II) (produced from hydrazine sulphate and aqueous alkali). The reaction may be represented as ... 

Another example is a claim of possible industrial appHcation for preparing l-cyclohexyl-3,5-dimethylpyrazole [79580-49-7] (75) and similar compounds from 1,2,6-thiadiazine-l,1-dioxide (74) by extmsion of SO2 (eq. 20) (48). This process has the added advantage of not requiring hydrazine derivatives as reactants. 

Under alkaline conditions, alkyl nitrites nitrosate imidazoles which possess a free NH group in the 4-position (70AHC(12)103). Nitrosation of 3,5-dimethylpyrazole gives the 4-diazonium salt by further reaction of the nitroso compound with more NO". 5-Pyrazolinones are often nitrosated readily at the 4-position. 3-Alkyl-5-acetamidoisothiazoles undergo 4-nitrosation. 

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. 

Although the thermodynamic aspects of acylotropy are well documented, there have been few kinetic studies of the process. The activation barrier is much higher than for prototropy and only Castells et al. (72CC709) have succeeded in observing a coalescence phenomenon in H NMR spectra. At 215 °C in 1-chloronaphthalene the methyl groups of N-phenyl-3,5-dimethylpyrazole-l-carboxamide coalesce. The mechanism of dissociation-combination explains the reversible evolution of the spectra (Scheme 9). 

In a mixture of ether and tetrahydrofuran.In HMPT the same barrier is obtained for the 3,5-dimethylpyrazole. Tn DMSO. Pr TPP = tetrakis(p-isopropylphenyl)porphinate dianion. 

Niai) Dimethylbis(3,5 -dimethylpyrazol-1 -yl)gallate [GaMe2(DMPz)2] Complicated structure 80CJC1091 s... 

Cuai) l-Carboxamido-3,5-dimethylpyrazole (CDMPz) Cu(CDMPz)2 (220) 79JCS(D)1867 ... 

Mo(II) Methylbis(3,5-dimethylpyrazol-l-yl)hydroxygallate [GaMe(OH)(DMPz)2] Mo(CO)2(r) AC4H7) [GaMe(OH)(DMPz)2] 79CJC139 ... 

Mo(V) Hydrotris(3,5-dimethylpyrazol-l-yl)borate [BH(DMPz)3] MoOCl2-C6H5Cl[BH(DMPz)3] 82JCR(S)6 ... 

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). 

With an activated C—C triple bond two successive additions can occur if the intermediate alkene is reactive enough. DMAD and 3,5-dimethylpyrazole give an initiaj fumarate (255) which reacts further at the other end to form regioselectively the succinates (256). On the other hand, methyl ethynyl ketone reacts twice at the same carbon atom with pyrazole to form 1,1-pyrazolylbutanone (258) (68ZC458). The probable intermediate, a pyrazolide vinylogue (257), can be prepared from methyl chlorovinyl ketone and pyrazole, in a reaction which is similar to acetylation (Section 4.04.2.1.3(x)). 

Phosphorus derivatives of different structures have been prepared including pyrazol-1-ylphosphines PPzs, PhPPz2 and Ph2PPz (Pz for pyrazolate anion (72CRV497,80MI40402)). By transamination with tris(dimethylamino)phosphine, pyrazoles and indazole are converted into (291) and (292), respectively (67CR(C)(265)1507). 3,5-Dimethylpyrazole reacts with amidodichlorophosphates to yield triamides (293) whereas 1-substituted pyrazolones yield amidophosphates (294) (71LA(750)39). 

Dimethylpyrazole (L) reacts with mercury(II) chloride to give complexes of the structure L2(HgCl2)3. In connection with metallotropy (Section 4.04.1.5.1) the behaviour of compounds (295) has been described. These phenylmercury derivatives were synthesized by the action of phenylmercury hydroxide on the appropriate pyrazole (71MI40400). 

Dimethylpyrazole 1.4- Dimethyl-3-nitropyrazole The attack at the 3- and 5-positions occurs on the free base. Standard rates 1,4-dimethylpyrazole (attack at the 3-position), log /co = 3.55, l,4-dimethyl-3-nitropyrazole (attack at the 5-position), log /c = -4.73 (deactivating effect of the nitro group) 75JCS(P2)1632... 

In man, the metabolic pathways of mepirizole were distinct from those in experimental animals, since hydroxylation on each of the aromatic rings did not occur in man. Compound (752) was obtained by oxidation of the 3-methyl group to the carboxylic acid (a similar process occurs with 5-methylpyrazole-3-carboxylic acid, an active metabolite of 3,5-dimethylpyrazole). However, the carboxylic acid metabolite of mepirizole had no analgesic activity and did not decrease blood glucose. 

Acetophenone (6) 3 5 Dimethylpyrazole (580 mg, 6 mmol) was added to a suspension of Cr03 (600 mg 6 mrrx ) in CH2CI2 (20 mL) and the mixture was stirred at 20° under Ar for 15 min To this red solution ol 4 1 phenyiethanol 5 (263 mg 2 2 mmol) in CH2CI2 (2 mL) was added in one portion and the mixture was stirred for 30 min at 20° (GC imnitoring on Carbowax 20M) Evaporation, extraction with EI2O and evaporalion left a residue which was dissolved in pentane and filtered through silica Evaporation gave 280 mg of 6 (98%)... 

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