PAPER 894 Regiospecific Cyclization of 4-Alkoxyvinyl Trifluoro[chloro]methyl Ketones with 6-Trifluoro[chloro]methyl-2-hydrazine Pyrimidines. A Convenient Me- thod to Obtain Trifluoro[chloro]methylated 2-(5-Hydroxy-5-trifluoro[chlo- ro]methyl-4,5-dihydro-1H-Pyrazol-l-yl]-pyrimidines Regiospecific Cyclization of 4-Alkoxyvinyl Trifluoro[chloro]methyl Ketones Nilo Zanatta,* Darlene C. Flores, Claudia C. Madruga, Débora Faoro, Alex F. C. Flores, Helio G. Bonacorso, Marcos A. P. Martins Núcleo de Química de Heterociclos (NUQUIMHE), Departamento de Química, Universidade Federal de Santa Maria, 97.105-900, Santa Maria, RS, Brazil Fax +55(55)2208031; E-mail: zanatta@base.ufsm.br Received 27 September 2002; revised 14 December 2002 Synthesis 2003, No. 6, Print: 29 04 2003. Art Id.1437-210X,E;2003,0,06,0894,0898,ftx,en;M04202S.pdf. © Georg Thieme Verlag Stuttgart · New York ISSN 0039-7881 Abstract: The regiospecific synthesis of a novel series of 4- trifluoro[chloro]-2-(5-hydroxy-5-trifluoro[chloro]methyl-4,5-dihy- dro-1H-pyrazol-1-yl]-pyrimidines from the reactions of 4-alkoxy- 1,1,1-trifluoro[chloro]-alk-3-en-2-ones with 6-trifluoro[chloro]me- thyl-2-hydrazine pyrimidines is presented. Key words: pyrazolylpyrimidines, pyrazoles, pyrimidines, haloge- nated heterocycles Pyrazolylpyrimidines have attracted much attention due to the important pharmacological properties that these molecules present. For example, mepirizole (4-methoxy- 6-methyl-2-[5-methoxy-3-methyl-(1H-pyrazol-1-yl)]-py- rimidine is a non-steroidal anti-inflammatory drug used in Japan and the analog 4-methoxy-6-methyl-2-(1H-pyra- zol-1-yl)-pyrimidine showed potent inhibition of the HCl–ethanol-induced and water immersion stress-in- duced ulcers in rats. 1 Also, 2- or 4-(1H-pyrazol-1-yl)-py- rimidine presented a potent cytoprotective effect on HCl– ethanol- and stress-induced gastric lesions in rats. 2 Fur- thermore, 2-(4,5-dimethyl-pyrazol-1-yl)-4-thioxo-6-me- thyl-4H-pyrimidine, 2-methylthio-pyrimidine-4-yl- hydroxyacet-(5-hydroxy-3,5-dimethyl)-1-5H-pyrazo- lide, and 2-methylthio-4-oxo-4H-pyrimidine-3-yl-acet- (5-hydroxy-3,5-dimethyl)-1-5H-pyrazolide showed car- diotonic activity with ED 50 values close to those of mil- rinone. 3 Recently, several new 1-(pyrimidin-2-yl)-3- pyrazolin-5-ones were described to present elevated anti- inflammatory, analgesic, hypothermic, and antipyretic ac- tivities. 4 In a previous publication of our group, a convenient one pot synthesis of a series of 4-trifluoromethyl-6-alkyl(ar- yl)-2-[3-alkyl(aryl)-5-hydroxy-5-trifluoromethyl-4,5-di- hydro-1 H -pyrazol-1-yl]-pyrimidines and 4-tri- fluoromethyl-6-alkyl(aryl)-2-[3-alkyl(aryl)-5-trifluoro- methyl-1H-pyrazol-1-yl]-pyrimidines from the reactions of 4-methoxy-4-alkyl[aryl]-1,1,1-trifluoro-3-buten-2- ones with aminoguanidine bicarbonate was reported. 5 This method, however, is restricted to the preparation of trifluorinated pyrazolylpyrimidines since the cyclizations performed using 1,1,1-trichloro-4-alkoxy-alk-3-en-2- ones with aminoguanidine bicarbonate furnished a com- plex mixture of compounds. This was probably due to the fact that the trichloromethyl group is considerably labile and often hydrolyzed to a carboxyl group or eliminated during the course of the ring closure. 6 Furthermore, the one pot method allows only a symmetric substitution pat- tern (same substituents in both pyrazol and pyrimidine rings) to be obtained due to the condensation of two mol- ecules of the vinyl ketone with one of the ami- noguanidines. In order to introduce trichloromethyl groups and an independent substituent pattern in the pyra- zol and in the pyrimidine moieties a different synthetic strategy for the cyclocondensation was required. This strategy relies on the cyclocondensation of 2-hydrazi- nopyrimidine which bears the trichloromethyl group with a proper trichlorinated 4-alkoxyvinyl ketone. Although the strategy adopted in this work is well known, 7 this method allows one to obtain trichloromethylated-2-pyra- zolylpyrimidines and it probably represents the only effi- cient method to obtain these compounds. The difficulties to obtain trichloromethylated-2-pyra- zolylpyrimidines due to the lability of the trichloromethyl group or the poor selectivity of the ring side chain chlori- nation and the potential of these compounds for biological activity, we were prompted to investigate the synthesis of a series of 6-trifluoro[chloro]-2-(5-hydroxy-5-trifluo- ro[chloro]methyl-4,5-dihydro-1H-pyrazol-1-yl]-pyrimid- ines from the reaction of 4-alkoxy-1,1,1-trifluoro[chloro]- alk-3-en-2-ones with 6-trifluoro[chloro]methyl-2-hy- drazinopyrimidines. The importance of -alkoxyvinyl tri- halomethyl ketones as potential building blocks for the synthesis of many heterocyclic systems such as isox- azoles, 8 pyrazoles, 9 pyrimidines, 10 pyridines, 11 pyrrolidi- nones, 12 and diazepines, 13 has been demonstrated in previous publications of our group and by other groups. 14 More recently, -alkoxyvinyl trihalomethyl ketones have been successfully used to obtain several series of bi-het- erocycles. 5,15 The syntheses of pyrazolylpyrimidines 9a–c, 10a–c, 11a– c, and 12a–c were accomplished from the cyclocondensa- tion reaction of 6-trifluoro[chloro]methyl-2-hydrazinopy- rimidines (5, 6) with 4-alkoxy-1,1,1-trifluoro[chloro]-alk- 3-en-2-ones (7a–c, 8a–c) in methanol or chloroform, as presented in Scheme 1. For the reactions of 5 and 6 with