Alkylation reactions pyrazole

C-Alkylation of pyrazoles was a rather uneommon reaction until Grandberg and Kost found the experimental conditions necessary to obtain high yields of 4-benzylpyrazoles (66AHC(6)347). With A-unsubstituted pyrazoles a large excess of aluminum ehloride is neeessary to aeeomplish alkylation at C-4. 

Fused pyrazole compounds have been prepared from A-alkyl substituted pyrazoles. For example, a palladium-catalyzed/norbornene-mediated sequential coupling reaction involving an aromatic sp2 C-H functionalization as the key step has been described, in which an alkyl-aryl bond and an aryl-heteroaryl bond were formed in one pot <060L2043>. A variety of highly substituted six-membered annulated pyrazoles 59 were synthesized in a one-step process in moderate yields from IV-bromoalkyl pyrazoles 57 and aryl iodides 58. 

Despite the greater acidities of the diazoles and triazoles (pKa = 10-14), fairly vigorous reaction conditions are still required for the alkylation of the unsubstituted systems [26] (Table 5.32) and the effectiveness of the alkylation of pyrazoles and imidazoles is enhanced under solidiliquid conditions [27-30]. Under these conditions, quaternization is avoided if no solvent is added [27],... 

An unexpected aromatization that takes place during the A-alkylation reaction performed on several 3-(2-nitrobenzoyl)-4,5-dihydro-l //-pyrazolc-5-carboxylic acid methyl esters, giving rise to a mixture of l-alkyl-3-(2-nitrobenzoyl)-4,5-dihydro-1 II-pyrazole-5-carboxylic acid methyl esters and 1 -al kyl-3-(2-ni trobcnzoyl)-1 //-pyrazole-5-carboxylic acid methyl esters is reported. It is suggested that reaction involves both inter- and intra-molecular oxidation by the nitro group.107... 

This microwave-accelerated double alkylation reaction was applicable to a variety of aniline derivatives and dihalides, furnishing N-aryl azacycloalkanes in good to excellent yields [89]. The reaction was applicable to alkyl chlorides, bromides and iodides and was extended to include hydrazines [90]. This improved synthetic methodology provided a simple and straightforward one-pot approach to the synthesis of a variety of heterocycles such as substituted azetidines, pyrrolidines, piperidines, azepanes, N-substituted-2,3-dihydro-Iff-isoindoles, 4,5-dihydro-pyrazoles, pyrazolidines, and 1,2-dihydro-phthalazines [91]. The mild reaction conditions tolerated a variety of functional groups such as hydroxyls, carbonyls, and esters. 

Holzer and Plagens (97H309) (Scheme 24) studied the alkylation of pyrazol-3-ones 62 and of the tautomeric pyrazol-3-one 78a-d/pyrazol-5-ol 79a d mixtures by applying the Mitsunobu reaction [triphenylphosphine, diethyl azodicarboxylate (DEAD), alcohol, solvent]. The reactions were performed in various solvents. Using methanol as the alkylating agent the reaction of 62 in dichloromethane or THF,... 

Alkylation of pyrazol-3-one 70 with 4-[morpholin-4-yl-(4-nitrophenyl)methyl]-morpholine 84 was performed at room temperature since at higher temperatures polymerization occurred. However the reaction was extremely slow. It took... 

The third reaction studied was the alkylation of pyrazoles with alkyl halides. This reaction was not possible using the ionic liquid heating technique, because the aryl halide reacted with the ionic liquid at the elevated temperatures used in the reaction. This highlights one of the limitations of this method. 

Solid-phase scavenger methods are employed with increasing frequency as a prehminary reaction cleanup step in combinatorial chemistry, and have recently become commercially available (Argonaut, Calbiochem-Novabiochem, Varian, Alltech). lilly researchers first reported on this approach, employing sohd supported electrophiles and nucleophiles for reaction purification in acylation and alkylation reactions. Yield and purity values reported were 90-95% and 50-99%, respectively, for a library generated by reductive amination. Parke-Davis researchers achieved the removal of known reaction product impurities by the application of custom synthesized polymer supported reagents, specifically polystyrene-divinylbenzene supported derivatives of methylisocyanate and tm(2-aminomethyl)amine for cleanup of by-products resulting from urea, thiourea,sulfonamide,amide, and pyrazole libraries. 

Alkylation Reactions of Pyrazole Matos et al. proposed for the first time (Cs)Al-SBA-15 and DEAPTS/ MCM-41 mesoporous materials (where DEAPTS is diethylamino propyl) as efficient basic catalysts in the alkylation of pyrazole and diethyl iminodiacetate with various reactive alkyl bromides under conventional thermal activation (Scheme 21) [92]. The alkylation of pyrazole catalyzed by both (Cs)Al-SBA-15 and DEAPTS/MCM-41 catalysts in the presence of a solvent (acetonitrile or dimethylformamide (DMF)) afforded selectively N-alkylpyrazole 30 with high... 

The synthesis of N-alkylpyrazoles was also carried out over different pillared saponites impregnated with cesium [93]. The alkylation of pyrazole with different alkyl bromides was conducted using acetonitrile or DMF as solvents, at 338-353 K, achieving total conversion and selectivity after Ih of reaction time. The reactivity order found for the different alkyl bromides seemed to depend on the solvent used in the reaction and the different coordination properties of Cs+ on the catalysts. 

There are some recent examples of this type of synthesis of pyridazines, but this approach is more valuable for cinnolines. Alkyl and aryl ketazines can be transformed with lithium diisopropylamide into their dianions, which rearrange to tetrahydropyridazines, pyrroles or pyrazoles, depending on the nature of the ketazlne. It is postulated that the reaction course is mainly dependent on the electron density on the carbon termini bearing anionic charges (Scheme 65) (78JOC3370). 

Figure 22 represents the main consequences on pyrazole reactivity when a positive charge is present at the 2-position of the nucleus. A similar situation occurs in the indazolium salts, which thermally decompose into an alkylindazole and an alkyl halide, a reaction sequence described by von Auwers. 

Although A-alkylation is one of the most important and most studied reactions of pyrazoles, its quantitative (orientation ratios) and qualitative (mechanism) aspects are still unclear. All the classical results are reported in (67HC(22)l, B-76MI40402) and can be summarized as follows. 

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). 

To shed light on the reaction pathway, a cyclization with methylhydrazine was carried out (70ZOR439 73ZOR832), since pyrazoles with nonequivalent positions 3 and 5 are obtained in this case. From l-methoxybut-l-en-3-yne and methylhydrazine sulfate a 4 5 mixture of 1,3- (110) and 1,5-dimethylpyrazoles (111) was formed (GLC) (70ZOR439). In the reaction of methoxybutenyne homologs (R = Ft, -Pr) with methylhydrazine (72°C, H", H2O, 2 h), lengthening of the alkyl radical leads to an increase in the content of 1,5-isomer (111), with yields of 50-60%. Thus, when R = Ft, the ratio is 2 3 (73ZOR832). 

Since l-heterobut-l-en-3-ynes are readily alkylated and functionalized at the terminal acetylenic carbon atom, their reaction with hydrazines makes it possible to introduce diverse (including functional) substituents into the pyrazole ring. For instance, from benzylated methoxybutenyne 112, isomeric 2-phenylethylpyrazoles 113 were obtained in 74% yield (81H146). 

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