FULL PAPER DOI: 10.1002/ejoc.201201111 Comparative Study of the Regioselectivity and Reaction Media for the Synthesis of 1-tert-Butyl-3(5)-trifluoromethyl-1H-pyrazoles Marcos A. P. Martins,* [a] Mara R. B. Marzari, [a] Clarissa P. Frizzo, [a] Marcileia Zanatta, [a] Lilian Buriol, [a] Valquiria P. Andrade, [a] Nilo Zanatta, [a] and Helio G. Bonacorso [a] Keywords: Synthetic methods / Nitrogen heterocycles / Fluorinated substituents / Ionic liquids / Enones / Regioselectivity A study is presented for the synthesis of a series of 1-tert- butyl-3(5)-(trifluoromethyl)-1H-pyrazoles from the reaction of 4-alkoxy-1,1,1-trifluoro-3-alken-2-ones [CF 3 C(O)CH=C- (R 1 )(OR), where R = Et and R 1 = H or R = Me and R 1 = Me, Ph, 4-Me-C 6 H 4 , 4-MeO-C 6 H 4 , 4-F-C 6 H 4 , 4-Cl-C 6 H 4 , 4-Br- C 6 H 4 , 4-I-C 6 H 4 , fur-2-yl, thien-2-yl, or naphth-2-yl] with tert- butylhydrazine hydrochloride. When [BMIM][BF 4 ] (1-butyl- 3-methylimidazolium tetrafluoroborate) and pyridine were Introduction The pyrazole nucleus has pronounced pharmacological applications for analgesic and anti-inflammatory drugs. [1] The incorporation of fluorine into a drug allows the simul- taneous modulation of electronic, lipophilic, and steric pa- rameters, all of which can critically influence both the phar- macodynamic and pharmacokinetic properties of drugs. [2–4] Celecoxib is the most recognized example of a drug that contains a trifluoromethylated pyrazole moiety. [5] The reaction between trifluoromethylated 1,3-dielectro- philic compounds and hydrazines constitutes the main syn- thetic approach to the trifluoromethylated pyrazole ring. The synthesis of 3(5)-trifluoromethyl-1H-pyrazole from a fluorinated 1,3-dicarbonyl compound has been extensively studied, including regioselectivity studies in neutral media with the addition of acid [6–10] and fluorinated solvents. [11] Kinetic investigations of these condensation reactions with the addition of acid showed that the regioselectivity in the synthesis of pyrazole is influenced by a combination of ste- ric effects, reactant ratio, and acidity. [10] In general, authors observed that the 1,5 regioisomer (CF 3 group at the 5-posi- tion) is formed by maintaining a pH  1.7, whereas more acidic conditions led to larger quantities of the 1,3 re- gioisomer. [6–11] Our research group has extensively studied the reactions of 1,3-dielectrophilic compounds such as 4-alkoxy-1,1,1-tri- [a] Núcleo de Química de Heterociclos (NUQUIMHE), Depart- ment of Chemistry, Federal University of Santa Maria, 97105-900, Santa Maria, RS, Brazil Fax: +55-55-3220-8756 E-mail: mmartins@base.ufsm.br Homepage: http://lattes.cnpq.br/6457412713967642 Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/ejoc.201201111. © 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Eur. J. Org. Chem. 2012, 7112–7119 7112 used as the reaction media, we obtained a mixture of 1-tert- butyl-3(5)-trifluoromethylpyrazoles. The formation of 5-tri- fluoromethyl-1-tert-butyl-1H-pyrazoles with high regioselec- tivity occurred when the reaction was carried out with NaOH in EtOH. The formation of 1-tert-butyl-3-trifluoro- methyl-1H-pyrazoles occurred, after hydrolysis of the 4-alk- oxy-1,1,1-trifluoro-3-alken-2-ones in H 2 O and H 2 SO 4 , fol- lowed by cyclization in [BMIM][BF 4 ] and pyridine. halo-3-alken-2-ones, β-enaminones, and β-enamino ketones with hydrazines. [12–18] In general, we have observed that the regioselectivity of the reaction depends somewhat on the hydrazine, but mainly on the reactivity of the 1,3-dielectro- philic compound. The reaction of 4-alkoxy-1,1,1-trihalo-3- alken-2-ones with methyl and phenyl hydrazines generally results in a mixture of isomers. [19–21] On the other hand, the reaction between tert-butylhydrazine hydrochloride and β- enamino ketones in ethanol is highly regioselective and fur- nishes 1-tert-butyl-4,5-disubstituted-1H-pyrazoles. [22] Simi- larly, the reaction between tert-butylhydrazine hydrochlo- ride and β-enaminones using an ionic liquid results in the exclusive formation of 1-tert-butyl-5-substituted-1H-pyr- azoles. [23] Thus, the problem of regioselectivity in the for- mation of pyrazoles is evident when 4-alkoxy-1,1,1-tri- fluoro-3-alken-2-ones are used as the 1,3-dielectrophile. These 1,3-dielectrophiles are important precursors to the tri- fluoromethylated pyrazoles, however, the availability of di- versely substituted 1,3-diketones is limited. In this context, we decided to study the regioselectivity in the formation of pyrazoles by studying the reaction of 4-alkoxy-1,1,1-tri- fluoro-3-alken-2-ones with tert-butylhydrazine hydrochlo- ride under neutral conditions and with basic and acidic ad- ditions to highlight the dependence of acidic or basic reac- tion media on the regioselectivity of this reaction. Results and Discussion To evaluate the reactivity of 4-alkoxy-1,1,1-trifluoro-3- alken-2-ones 1a–1c with tert-butylhydrazine hydrochloride 2, a series of experiments were performed. The 4-alkoxy- 1,1,1-trifluoro-3-alken-2-ones used in the optimization of