Pyrazoles 3 -methylpyrazole

Rhodium(I) complexes of pyrazole, such as (81) have been studied by H and C NMR the boat conformation of the metallocycle was thus established <84JCPB25l>. Ruthenium(II) complexes of pyrazole, 3-methylpyrazole, 3,5-dimethylpyrazole, and indazole were described (x-ray crystallography and a careful H and C NMR study) in <90JCS(D)1463>. 

Methylpyrazole has been investigated as a possible treatment for alcoholism. The stmcture—activity relationship (SAR) associated with a series of pyrazoles has been examined ia a 1992 study (51). These compounds were designed as nonprostanoid prostacyclin mimetics to inhibit human platelet aggregation. In this study, 3,4,5-triphenylpyrazole was linked to a number of alkanoic acids, esters, and amides. From the many compounds synthesized, triphenyl-IJT-pyrazole-l-nonanoic acid (80) was found to be the most efficacious candidate (IC g = 0.4 //M). 

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). 

The reactivities of 1-methylpyrazole (33) and pyrazole (29) are similar and so are the corresponding charges. The competition between C-4 and C-4 in 1-phenylpyrazole depends on the electrophile and on the experimental conditions (Section 4.04.2.3.10(i)). Thus in an acidic medium the reaction takes place on the conjugate acid (34) and considering the calculated charge densities the attack on C-4 would always be favoured. 

Free valences and localization energies have been calculated for a series of pyrazoles (neutral molecules and conjugate acids) for homolytic substitution. In all the compounds the site with the lowest localization energy has the Wghest free valence index. This parallel between the two indices of reactivity is maintained in pyrazole, 1-methylpyrazole and their conjugate acids, but not in 1-phenylpyrazole and its conjugate acid. For the three compounds examined experimentally, (32), (33) and (35) (Section 4.04.2.1.8(ii)), only the predictions for (33) are in agreement with the experimental results. 

Pyrazole and its C-methyl derivatives acting as 2-monohaptopyrazoles in a neutral or slightly acidic medium give M(HPz) X, complexes where M is a transition metal, X is the counterion and m is the valence of the transition metal, usually 2. The number of pyrazole molecules, n, for a given metal depends on the nature of X and on the steric effects of the pyrazole substituents, especially those at position 3. Complexes of 3(5)-methylpyrazole with salts of a number of divalent metals involve the less hindered tautomer, the 5-methylpyrazole (209). With pyrazole and 4- or 5-monosubstituted pyrazoles M(HPz)6X2... 

With iodine in carbon tetrachloride, 4-methylpyrazole affords a deep-red oil for which the structure (266) has been proposed. Nitric acid, silver nitrate and iodine together convert pyrazole into 1,3,4-triiodopyrazole (267 = R" = I, = H). The fV-iodopyrazoles are... 

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). 

Better results were obtained when a mixture of chloroform and either pyrazole or C-methylpyrazoles was heated at 555 °C in a continuous-flow vapour phase reactor (79JCS(P1)2786). 2-Chloropyrimidines were obtained in high yields (51-89%). Indazole similarly gave only 2-chloroquinazoline (68%). 

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. 

In addition to (461), Dorn has described the imine (463) isolated from 5-amino-l-methylpyrazole and arenesulfonyl chloride (80CHE1). Upon heating, or in the presence of triethylamine, it undergoes rearrangement to the more stable 5-bis(arylsul-fonamido)pyrazoles (464). 5-Iminopyrazolines (461) react with acyl chlorides at the exocyclic nitrogen atom to afford amidopyrazolium salts (B-76MI40402). 

AH, AS, AGt2i3 = 11-7 kcal mol (CD2CI2), AHt and d5. Larina et al. (98MRC110) used DNMR to determine the activation barrier of 4-trimethylsilylpyrazole (65) (dGtc = H-9 kcal mol ) and DNMR to determine the activation barrier of 3(5)-methylpyrazole (66) (54% 66a -46% 66b, AGtc = 10 kcal mol ) [similar barriers have been reported for other pyrazoles (93CJC1443)]. In the case of 3(5)-trimethylsilylpyrazole only the 3-substituted tautomer is present, preventing the determination of the barrier. 

ICA 97)19]. Compound 163 (R = Br) and perchloric acid yield 164, where the monodentate pyrazolate ligand is protonated. Potassium hydroxide regenerates 163 (R = Br). Dicationic complexes of the type 164 can alternatively be produced from [Rh2(r/ -Cp )2(/x-0H)3]Cl04 and perchloric acid in the presence of excess pyrazole, 4-bromopyrazole, 3-methylpyrazole, or 3,5-dimethylpyrazole. 

Complex (NBu4)2[Pd(QCl5)2(/x.-OH)]2 behaves differently in the presence of an alkali with respect to pyrazole and 3-methylpyrazole, on the one hand, and... 

The above method can also be used to simultaneously transform two acetyl groups into acetylenic ones in positions 3 and 5 of the pyrazole ring. This is demonstrated by the synthesis of 3,5-diethynyl- 1-methylpyrazole (yield 62%) from 3,5-diacetyl-1-methylpyrazole (Scheme 30). 

The high stability of terminal aeetylenes of the pyrazole series allows the preparation of polyethynyl derivatives like 3,4-diethynyl-, 4,5-diethynyl-, and even 3,4,5-tiiethynyl-l-methylpyrazole in 64%, 78%, and 41% yields, respeetively, in these strong eonditions (71IZV1764) (Sehemes 93 and 94). 

Such an easy isomerization of acetylenylbenzoic acid amides implies the formation of a five-membered nonaromatic ring condensed with the pyrazole ring. However, the pyrazole analog of o-iodobenzamide (amide of 4-iodo-l-methylpyrazole-3-carboxylic acid) formed under heating with CuC=CPh in pyridine for 9 h only the disubstituted acetylene in 71 % yield is identical in all respects to the compound obtained from the corresponding acid by successive action of SOCI2 and NH3 (90IZV2089) (Scheme 126). 

The acidity of 4-ethynyl- 1-methylpyrazole is lower than that of phenylacetylene (pK =29.1) [75IZV2351 79JCS(P2)726 84IZV923]. The ethynyl group in other positions of pyrazoles has smaller values i.e., 4-pyrazolyl radicals have a weaker electron-acceptor characteristic than the phenyl ring. 

Synthesis of l-guanyl-3-methylpyrazole (29) (86% yield) from pyrazole 13 and aqueous cyanamide has been claimed (94GEP4237687). 

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