Fluorinated pyrazoles

They are used in the syntheses of fluorinated pyrazoles, 5-hydroxy-A2-isoxazolines,... 

Pyrazoles are obtained by [3 + 2] condensation of /3-diketones with hydrazine and its derivatives (96M7). The same applies to the synthesis of fluorinated pyrazoles and... 

Other routes to fluoroimidazoles have been reported, some of which are confined to specific structural motifs. For example, methyl and fluorine substituents were used in a study of the phototranspositions of the 1-methylpyrazole ring. The nitrogen walk mechanism produced ring-fluorinated imidazoles from the ring-fluorinated pyrazoles (Fig. 3.55). ° ... 

Introduction of a pyrazole ring is a popular choice for molecular modification in designing medicinal and agrochemical agents, and the use of fluorinated pyrazoles in particular has received much recent attention. The development of celecoxib provides a notable example. Many procedures have been developed for the preparation of fluorinated pyrazoles, but a majority of early work was concentrated on perfluoroalkyl groups substituted on the ring. However, in the past several years, new routes to 3-, 4-, and 5-fluoropyrazoles have been reported. 

Synthesis of Ring-Fluorinated Pyrazoles Early procedures for accessing fluoropyrazoles included the photochemical Schiemann reaction that had been developed earlier for preparation of ring-fluorinated imidazoles, as discussed above. 3-Fluoro-, 4-fluoro-, and 5-fluoro-l-methylpyrazoles were obtained in low yields (Fig. 3.65). This procedure was also used to prepare 3,4-, 4,5-, and 3,5-difluoropyrazoles. An electrochemical procedure was reported that lacked generality. ... 

The fluorinated building blocks have been more often used in more general approaches to ring-fluorinated pyrazoles. For example, reaction of hydrazines with 2-fluoro-1,3-diketones leads to efficient formation of 4-fluoropyrazoles (Fig. 3.66). Observed regiochemistry of products formed from unsymmetrical diketones was ascribed to initial attack of the more nucleophilic p-nitrogen of the hydrazine at the more electrophilic carbonyl group. 

FIGURE 3.65 Preparation of fluorinated pyrazoles by the photochemical Schiemann reaction. 

FIGURE 3.74 Synthesis of a fluorinated pyrazole as an estrogen receptor agonist. 

Fluorinated 1,3-dicarbonyl reagents or their equivalents can be used as building blocks for the preparation of trifluoromethyl-substituted pyrazoles in a strategy similar to that used for the synthesis of ring-fluorinated pyrazoles. Trifluoroacetyl dihydrofuran and pyran (135 or 136), as well as trifluoro-4-ethoxy-3-butene-2-one... 

FIGURE 3.80 3-Alkoxyvinyl trifluoroketones as fluorinated pyrazole precursors. 

Ichikawa, J. Kobayashi, M. Noda, Y Yokata, N. Amano, K. Minami, T. Regiocon-trolled syntheses of 3- or 5-fluorinated pyrazoles from 2,2-difluorovinyl ketones. J. Org. Chem. 1996, 61, 2763-2769. 

Song, L.-p. Zhu, S.-z. Regioselective synthesis of fluorinated pyrazole derivatives from trifluormethyl-1,3-diketone. J. Fluorine Chem. 2001, 111, 201-205. 

Synthesis of diversely fluorinated pyrazoles as novel active agrochemical ingredients 13JFC(152)2. 

In the last decade, metal-catalyzed intramolecular nitrogen addition to alkynes has been introduced as a new methodology for the preparation of pyrazole derivatives. Liu, Xu and co-workers [29] have developed a mild and efficient protocol for the synthesis of 4-fluorinated pyrazoles via gold(l)-catalyzed tandem aminofluorination of alkynes 53 in the presence of Selectfluor (Scheme 16). In all cases (except for R-=H), mixtures of 4-fluorinated 54 and nonfluorinated pyrazoles 55 (54 55=2.1 1... 

The l-aryl-3-trifluorometylpyrazole-5-carboxamide group is present in many of the orally available blood coagulation factor Xa inhibitors. Pinto and co-workers found in their medicinal chemistry program that a fluorinated pyrazole was an optimal five-membered heterocyclic core. Thus, two members of the 3-trifluoromethylpyrazole-5-carboxamide series were advanced to preclinical development (Fig. 2a) [81]. An additional structural modification, the incorporation of an aminobenzisoxazole moiety at N1 instead of the benzylamine group, led to the discovery of razaxaban (Fig. 2b), a potent, selective, and orally bioavailable inhibitor of factor Xa with in vivo efficacy in antithrombotic models [82], The amide hydrolysis observed in vivo could be modulated by introducing bicyclic core variants at the carboxamide portion, such as l/f-pyrazolo[4,3-rf pyrimidin-7(6//)-oneor 1,4,5,6-tetrahydropyrazolo-[3,4-c]pyridine-7-one [83]. 

Surmont R, Vemiest G, De Kimpe N (2010) New synthesis of fluorinated pyrazoles. Oig Lett 12 4648-4651... 

Qian J, Liu Y, Zhu J, Jiang B, Xu Z (2011) A novel synthesis of fluorinated pyrazoles via gold(I)-catalyzed tanem aminofluorination of alkynes in the presence of selectfluor. Oig Lett 13 4220-4223... 

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