Synthesis of 6-(2-furyl) and 6-(2-thienyl)-4-trifluoromethylpyrimidinones and pyrimidines from 4-(2-heteroaryl)-4-methoxy-1,1,1-trifluoro-3-buten-2-ones

Abstracts

The synthesis of biheterocyclic systems 6-(2-furyl)-pyrimidines and 6-(2-thienyl)pyrimidines in reasonable yields (50-67%), two 6-(2-heteroaryl)-4-trifluoromethyl-2-(1H)pyrimidinones (2a,b) and a series of ten 6-(2-heteroaryl)-4-trifluoromethylpyrimidines (3a,b 7a,b) from the cyclocondensation of 1,1,1-trifluoro-4-(2-heteroaryl)-4-methoxy-3-buten-2-ones with urea and amidines is reported. Structures of all compounds have been elucidated by elemental analysis, mass spectrometry and ¹H, 13C NMR measurements. The ¹H and 13C NMR data are systematically reported. The X-ray diffraction data for monocrystal from 2-amino-4trifluoromethyl-6-(thien-2-yl)-pyrimidine (5b) are reported.

4-trifluoromethylpyrimidines; 1,1,1-trifluoro-4-methoxy-3-buten-2-ones; [3 + 3] cyclocondensation

Neste trabalho é apresentada a síntese, em rendimentos razoáveis (50-67%), de novos sistemas biheterocíclicos, duas 6-(2-heteroaril)-4-trifluormetil-2-(1H)-pirimidinonas (2a,b) e uma série de dez 6-(2-heteroaril)-4-trifluormetilpirimidinas (3a,b -7a,b) a partir da ciclocondensação de 1,1,1-trifluor-4-(2-heteroaril)-4-metoxi-3-buten-2-onas com uréia e amidinas. As estruturas de todos os compostos foram atribuídas pelos dados de análise elementar, espectrometria de massas e dados de RMN ¹H e 13C. Os dados de RMN ¹H e 13C são mostrados de maneira sistemática. Também apresentamos os dados de difração de raios-X de um monocristal da 2-amino-6-(tien-2-il)-4-trifluormetilpirimidina (5b).

ARTICLE

Synthesis of 6-(2-furyl) and 6-(2-thienyl)-4-trifluoromethylpyrimidinones and pyrimidines from 4-(2-heteroaryl)-4-methoxy-1,1,1-trifluoro-3-buten-2-ones

Alex F. C. Flores^*; Lucas Pizzuti; Sergio Brondani; Marcelo Rossato; Nilo Zanatta; Marcos A. P. Martins

Departamento de Química, Universidade Federal de Santa Maria, 97105-900 Santa Maria-RS, Brazil

ABSTRACT

The synthesis of biheterocyclic systems 6-(2-furyl)-pyrimidines and 6-(2-thienyl)pyrimidines in reasonable yields (50-67%), two 6-(2-heteroaryl)-4-trifluoromethyl-2-(1H)pyrimidinones (2a,b) and a series of ten 6-(2-heteroaryl)-4-trifluoromethylpyrimidines (3a,b 7a,b) from the cyclocondensation of 1,1,1-trifluoro-4-(2-heteroaryl)-4-methoxy-3-buten-2-ones with urea and amidines is reported. Structures of all compounds have been elucidated by elemental analysis, mass spectrometry and ¹H, ¹³C NMR measurements. The ¹H and ¹³C NMR data are systematically reported. The X-ray diffraction data for monocrystal from 2-amino-4trifluoromethyl-6-(thien-2-yl)-pyrimidine (5b) are reported.

Keywords: 4-trifluoromethylpyrimidines, 1,1,1-trifluoro-4-methoxy-3-buten-2-ones, [3 + 3] cyclocondensation

RESUMO

Neste trabalho é apresentada a síntese, em rendimentos razoáveis (50-67%), de novos sistemas biheterocíclicos, duas 6-(2-heteroaril)-4-trifluormetil-2-(1H)-pirimidinonas (2a,b) e uma série de dez 6-(2-heteroaril)-4-trifluormetilpirimidinas (3a,b -7a,b) a partir da ciclocondensação de 1,1,1-trifluor-4-(2-heteroaril)-4-metoxi-3-buten-2-onas com uréia e amidinas. As estruturas de todos os compostos foram atribuídas pelos dados de análise elementar, espectrometria de massas e dados de RMN ¹H e ¹³C. Os dados de RMN ¹H e ¹³C são mostrados de maneira sistemática. Também apresentamos os dados de difração de raios-X de um monocristal da 2-amino-6-(tien-2-il)-4-trifluormetilpirimidina (5b).

Introduction

Interest in perfluoroalkylated heterocyclic compounds is largely due to the fact that they have enhanced biological activity and can be used as medicinal or agricultural chemicals.1-8 Among them, fluorinated pyrimidines have been shown to possess high biological activities as bactericides, fungicides, analgesics, antipyretics and antiinflammatories.^9-15

Perfluoroalkylated N-containing heterocycles can be obtained by various methods, including the widely used reactions of 1,3-dicarbonyl compounds with binucleophiles. For example, the cyclization of N-C-N blocks (urea, guanidines and amidines) with perfluoroalkyl containing 1,3-bielectrophiles (1,3-diketones, 1,3- ketoesters, 1,3-ketoamides, a,ß-enones) is considered the main procedure for the synthesis of perfluoroalkyl substituted pyrimidine derivatives.^15-18

Derivatives 2-substituted of the 6-(2-furyl)-4-trifluoromethylpyrimidines and 6-(2-thienyl)-4-trifluoromethylpyrimidines were early synthesized by cyclocondensation respectively of 1-(2-furyl)-4,4,4-trifluorobutane-1,3-dione or 1-(2-thienyl)-4-trifluorobutane-1,3-dione with amidines NH₂C(NH)X [ X = OR, NH₂, SMe], however only few analytical data were reported.^19-23 The patent reports show only melting point as accessible analytical data for these compounds.

The 6-furyl and 6-thienyl derivatives of 2-amino-4- trifluoromethylpyrimidine and 2-hydroxy (or 2-mercapto)- 4-trifluoromethylpyrimidine obtained from cyclocondensation of 1-(2-heteroaryl)-4,4,4-trifluorobutane-1,3-dione and guanidine or urea were applied in effective treatment of cardiorenal disease and in edema.¹⁹ Moreover had demonstrated eficient inhibitory activity in mevalonic acid incorporation during biosynthesis of cholesterol.²⁰

Recently we have reported the synthesis of 4-(2-heteroaryl)- 4-methoxy-1,1,1-trifluoro-3-buten-2-ones as building blocks to construct promising trifluoromethyl containing biheterocyclic systems.^9,24,25 The present work aimed to report efficient procedures for the systematic cyclocondensation of 4-(2-furyl)-4-methoxy-1,1,1-trifluoro-3-buten-2-one (1a) and 4-methoxy-4-(2-thienyl)-1,1,1-trifluoro-3-buten-2-one (1b) with urea, acetamidine, benzamidine, guanidine, 2-methyl-2- pseudothiourea and 1H-pyrazole-1-carboxyamidine for synthesis of the series of biheterocyclic 6-(2-heteroaryl)-4- trifluoromethylpyrimidinones 2 and 6-(2-heteroaryl)-4- trifluoromethylpyrimidines 3-5, 7 and new three ring system 2-(pyrazol-1-yl)-4-trifluoromethyl-6-(2-heteroaryl)pyrimidines 6.

Results and Discussion

The 4-(2-heteroaryl)-4-methoxy-1,1,1-trifluoromethyl- 3-buten-2-ones 1a and 1b were prepared using the previously reported procedure.²⁵ The 6-(2-furyl)-4- trifluoromethyl-1H-pyrimidin-2-one 2a and the 6-(2- thienyl)-4-trifluoromethyl-1H-pyrimidin-2-one 2b were prepared in very low yields (< 10%) from the reaction of 1a or 1b with urea in reflux EtOH or, even i-PrOH (Scheme 1).¹² Several attempts to improve the yields by refluxing 1a or 1b with urea for long periods (2 days) without catalysis were unsuccessful. However, polymeric material was obtained in reactions in MeOH with Brönsted HCl catalysis at room temperature or with Lewis acid BF₃ ·OEt2 or Ti(OiPr) ₄ catalysis at reflux temperature (>65 ºC) for long periods.¹⁵ Our experiments have demostrated that the best medium was anhydrous i-PrOH with drops of BF₃ ·OEt₂ at 50 ºC during 20 h, furnishing reasonable yields (50%) for 2a and 2b.¹² The 1H NMR spectra have show a single set of signals (see, Experimental) indicating that compounds 2a and 2b exist as one of the possible tautomers. The 2(1H)pyrimidin-2-one structure was confirmed by characteristic signal from N-H at 12.93-12.95 ppm.

In the search for the optimum cyclocondensations condition for 1a, 1b and amidines acetamidine hydrochloride was used as a model amidine. The cyclocondensations in MeOH or iPrOH under Brönsted HC_l or Lewis BF₃ ·OEt₂ catalysis were unsuccessful, the reactants were recovered. In contrast to the synthesis of 4-polyfluoroalkylpyrimidines by condensation in refluxing iPrOH under Lewis BF₃ ·OEt₂ catalysis for 4 to 26 h,¹² we have obtained products 6-(2- heteroaryl)-2-methyl-4-trifluoromethyl-pyrimidines 3a and 3b in good yields using alkaline medium, reacting acetamidine hydrochloride with a 1 mol L^-1 KOH aqueous solution and adding to MeOH solution of 1a or 1b at room temperature. TLC analyses during reaction period have revealed that the 1,3-dielectrophiles were consumed after 1 hour, furnishing good yields of the pyrimidines 3. The 6-(2- heteroaryl)-2-phenyl-4-trifluoromethyl-pyrimidines 4a, 4b, 2-amino-6-(2-heteroaryl)-4-trifluormethyl-pyrimidines 5a, 5b, 6-(2-heteroaryl)-2-(1H-pyrazol-1-yl)-4-trifluoromethylpyrimidines 6a, 6b and the 6-(2-heteroaryl)-2- thiomethyl-4-trifluoromethyl-pyrimidines 7a, 7b were obtained in similar alkaline medium with the procedure described above. The structure of all compounds was determined from ¹H, ¹³C and mass spectrometry. Based on our previous reports on the chemistry of 6-aryl-4- trifluoromethyl-1H-pyrimidin-2-ones and 6-aryl-4- trifluoromethyl-pyrimidines derived from 4-aryl-4-methoxy- 1,1,1-trifluoro-3-buten-2-ones, the assignment of each signal in the ¹³C NMR spectra of compounds 2-7 was accurately established.^15,16

The ¹H and ¹³C spectra of products showed set of signals attributed to aromatic pyrimidines 3a, 3b to 7a, 7b. The structure of compound 2-amino-6-(2-thienyl)-4trifluoromethyl-pyrimidine 5b was established by X-ray diffraction analysis. The overall view of the molecule is shown in Figure 1. The 6-(2-thienyl)-pyrimidine system is virtually coplanar (the mean deviation of the atoms from the plane is 0.008 Å). The thienyl ring suffers a rotational disorder, atoms S1 and C7 were modeled as exchanged with a minor occupancy fraction refined to 19.6%. The trifluoromethyl group presents a rotational disorder; the three F atoms were refined in a position rotated approximately 45º from their original positions at 5.3% occupancy. Crystal data for 5b are shown in Table 1.

Conclusions

In conclusion, the biheterocyclic systems 6-(2-furyl)and 6-(2-thienyl)-pyrimidinones and 6-(2-furyl)- and 6-(2-thienyl)-pyrimidines were efficiently obtained by reacting 4-(2-heteroaryl)-4-methoxy-1,1,1-trifluoro-3buten-2-ones with N-C-N binucleophiles, in reasonable to good yields (50-67%). The best reactional medium for urea cyclocondensation was under BF₃·OEt₂ Lewis acid catalysis. However the cyclocondensations with hydrochoride amidines occurred only in alkaline media with NaOH, pH >15, furnishing good yields of 6-(2heteroaryl)-pyrimidines.The tricyclic systems 6-(2-furyl)and 6-(2-thienyl)-2-(1-pyrazolyl)-pyrimidines are new.

Experimental

The synthesis of 4-(2-heteroaryl)-4-methoxy-1,1,1trifluoro-3-buten-2-one, 1 has been reported elsewhere.²⁰ Urea, amidines and BF₃·OEt₂ were used as obtained from commercial suppliers. MeOH and i-PrOH were purified before using. 1 mol L^-1 solution of NaOH was prepared by the dissolution of 0.40 g of NaOH in 100 mL of distilled water. Yields listed in Table 2 are of isolated compounds. All melting points were determined on a Reichert Thermovar apparatus and are uncorrected. The ¹H and ¹³C spectra were recorded at 298 K on a Bruker DPX 400 spectrometer (¹H at 400.13 MHz, ¹³C at 100.63 MHz) with digital resolution of ± 0.01 ppm. All the chemical shifts are expressed in ppm, ¹H and ¹³C are reported with respect to internal TMS. 0.1 mol L^-1 CDCl₃ solutions were used except with compounds 2, 0.1 mol L^-1 in DMSO-d₆. H-H and C-F coupling constants are in Hz. Mass spectra were registered in a HP 5973 MSD connected to a HP 6890 GC and interfaced by a Pentium PC. The GC was equipped with a split-splitless injector, auto-sampler, cross-linked HP-5 capillary column (30 m, 0.32 mm of internal diameter), and helium was used as the carrier. Elemental analyses were performed on a Perkin-Elmer 2400 CHN elemental analyzer (São Paulo University-São Paulo, Brazil). The crystal and molecular structure of 5b was determined by a single crystal X-ray diffraction study. Data were recorded on a Bruker Kappa Apex II CCD area detector with graphite monochromatized Mo Ka radiation (l 0.71073 Å). The data were processed with SAINT and SADABS. The structure was solved by direct methods (SHELXS-97)²⁶ and additional atoms were located in the difference Fourier map and refined on F² using the SHELXTL and Wingx packages.²⁷

6-(2-Furyl)[(2-thienyl)]-4-trifluoromethylpyrimidin-2-one (2a, b). General Procedure

Compounds 1a (3 mmol, 0.67 g) or 1b (3 mmol, 0.71 g) and urea (3.3 mmol, 0.21 g) were dissolved in 3 mL of anhydrous i-PrOH. Then, 3 drops of BF₃·Et₂O were added and the mixture was stirred at 50 ºC for 20 h. The solvent was partially evaporated and the product crystallized by cooling. The solid was filtered, washed with cold water and recrystallized from MeOH to give 2a and 2b, respectively.

6-(2-Furyl)-4-trifluoromethyl-1H-pyrimidin-2-one, 2a

Yield 48 %; mp 282-284 ºC; ¹H NMR (400 MHz, DMSO-d₆): d 6.82 (dd, 1H, J 3.5, J 1.66, H4'), 7.48 (s, 1H, H5), 7.67 (d, 1H, J 3.5, H3'), 8.07 (d, 1H, J 1.66, H5'), 12.93 (s, 1H, NH); ¹³C NMR (100 MHz, DMSOd₆): d 163.1, 157.9 (²J_CF 35), 157.0, 148.5, 147.6, 120.2 (J_CF 277), 115.8, 112.9, 100.6; MS (70 eV) m/z 230 (M⁺, 100), 118 (16), 90 (11), 63 (18). Anal. Calc. for C-₉H₅F₃N₂O₂: C, 46.97; H, 2.19; N, 12.17. Found: C, 46.87; H, 2.18; N, 12.05.

6-(2-Thienyl)-4-trifluoromethyl-1H-pyrimidin-2-one, 2b

Yield 52 %; mp 266-268 ºC; ¹H NMR (400 MHz, DMSO-d₆): 7.24 (dd, 1H, J 4.8, J 3.4, H4'); 7.89 (d, 1H, J 4.8, H3'); 7.95 (s, 1H, H5); 8.24 (d, 1H, J 3.4, H5'); 12.95 (s, 1H, NH); ¹³C NMR (100 MHz, DMSO-d6): d 165.1, 163.5, 156.6 (²J_CF 35), 140.4, 132.6, 130.9, 128.7, 120.2 (J_CF 274), 103.5; MS (70 eV) m/z 246 (M⁺, 100), 227 (10), 134 (30), 69 (17). Anal. Calc. for C-₉H₅F₃N₂SO: C, 43.91; H, 2.05; N, 11.38. Found: C, 43.59; H, 2.02; N, 11.23.

6-(2-Furyl)[(2-thienyl)]-4-trifluoromethylpyrimidines (37a, b). General Procedure

Acetamidine hydrochloride (3 mmol) was added to an aqueous KOH 1 mol L^-1 solution (3 mL). The resulting solution was added to a MeOH solution of compounds 1a (3 mmol, 0.66 g) or 1b (3 mmol, 0.71 g). The resulting mixture was stirred at room temperature at 50 ºC for 1 h. Then MeOH was evaporated and the resulting material was diluted with CHCl₃ (50 mL) and washed with water (3 × 20 mL). The organic solution was dried over anhydrous MgSO₄ and the solvent was removed, the solid products were recrystallized from hexane, furnishing the pure crystalline products 3a, 3b, 5a, 5b, 6a and 6d. The compounds 7a and 7b were oils purified by chromatography column with hexane:chloroform (1:1) as eluent. When the precipitated product was formed, it was filtered, washed with water and dried over CaCl₂. The products 4a, 4b were obtained pure (GC-MS, ¹H NMR).

6-(2-Furyl)-2-methyl-4-trifluoromethylpyrimidine, 3a

Yield 48 % (71 %, ref. 28); mp 41-43 ºC; ¹H NMR (400 MHz, CDCl₃): 2.82 (s, 3H, Me); 6.62 (dd, 1H, J 3.52 Hz, J 1.76 Hz, H4'); 7.38 (d, 1H, J 3.52 Hz, H3'); 7.65 (d, 1H, J 1.76 Hz, H5'); 7.72 (s, H5); ¹³C NMR (100 MHz, CDCl₃): d 169.4, 157.4, 156.1 (²J_CF 35 Hz), 151.0, 145.8, 120.2 (J_CF 274), 113.9, 112.8, 107.5 (⁴J_CF 2.8 Hz), 25.9; (MS (70 eV) m/z 228 (M⁺, 95), 209 (27), 118 (100), 90 (48), 63 (78). Anal. Calc. for C₁₀H₇F₃N₂O: C, 52.64; H, 3.09; N, 12.28. Found: C, 52.82; H, 3.36; N, 12.38.

2-Methyl-6-(2-thienyl)-4-trifluoromethylpyrimidine, 3b

Yield 53 %; mp 47-49 ºC; ¹H NMR (400 MHz, CDCl₃): 2.81 (s, 3H, Me); 7.18 (dd, 1H, J 5.01, J 3.79 Hz, H4'); 7.59 (dd, 1H, J 5.01 Hz, J 1.04 Hz, H3'); 7.65 (s,1H, H5); 7.84 (dd, 1H, J 3.79 Hz, J 1.04 Hz, H5'); ¹³C NMR (100 MHz, CDCl₃): d 169.6, 161.1, 155.9 (²J_CF 35 Hz), 141.3, 131.5, 128.7, 128.6, 120.2 (J_CF 273 Hz), 107.8 (⁴J2.8 Hz), 25.9; MS (70 eV) m/z 244 (M⁺, 100), 225CF (13), 134 (72), 69 (21). Anal. Calc. for C₁₀H₇F₃N₂S: C, 49.18; H, 2.89; N, 11.47. Found: C, 48.78; H, 2.91; N, 11.41.

6-(2-Furyl)- 2-phenyl-4-trifluoromethylpyrimidine, 4a

Yield 61 % (69 %, ref. 29); mp 66-68 ºC; ¹H NMR (400 MHz, CDCl₃): 7.46-7.51 (m, 3H, Ph); 7.47 (d, 1H, J 3.3 Hz, H3'); 7.57 (dd, 1H, J 3.3 Hz, J 1.7 Hz, H4'); (d, 1H, J 1.7 Hz, H5'); 7.74 (s, 1H, H5); 8.52 (m, 2H, Ph); ¹³C NMR (100 MHz, CDCl₃): d 165.2, 157.6, 156.6 (²J_CF 36 Hz), 151.4, 145.8, 136.1, 131.5, 128.6, 128.5, 120.8 (J_CF 274 Hz), 113.8, 112.8, 107.9 (⁴J_CF 2.7 Hz); MS (70 eV) m/z 290 (M⁺, 96), 271 (16), 118 (100), 90 (52), 63 (75). Anal. Calc. for C₁₅H₉F₃N₂O: C, 62.07; H, 3.13; N, 9.65. Found: C, 61.54; H, 3.10; N, 9.38.

2-Phenyl-6-(2-thienyl)-4-trifluoromethylpyrimidine, 4b

Yield 67 % (67 %, ref. 28); mp 104-106 ºC; ¹H NMR (400 MHz, CDCl₃): 7.17 (dd, 1H, J 5.0, J 3.8 Hz, H4'); 7.48-7.51 (m, 3H, Ph); 7.57 (dd, 1H, J 5.0 Hz, J 1.05 Hz, H3'); 7.65 (s, 1H, H5); 7.85 (dd, 1H, J 3.8 Hz, J 1.05 Hz, H5'); 8.53 - 8.56 (m, 2H, Ph);¹³C NMR (100 MHz, CDCl₃): d 165.3, 161.2, 156.4 (²J_CF 36 Hz), 141.8, 136.1, 131.5, 131.4, 128.7, 128.6, 128.5, 120.8 (J_CF 274 Hz), 108.2 (⁴J_CF 2.8 Hz); MS (70 eV) m/z 306 (M⁺, 100), 287 (5), 134 (73), 69 (8). Anal. Calc. for C₁₅H₉F₃N₂S: C, 58.82; H, 2.96; N, 9.15. Found: C, 58.80; H, 3.12; N, 8.72.

2-Amino-6-(2-furyl)-4-trifluoromethylpyrimidine, 5a

Yield 50 %; mp 130-132 ºC; ¹H NMR (400 MHz, CDCl₃): 5.61 (s, 2H, NH₂); 6.58 (dd, 1H, J 3.52 Hz, J 1.73 Hz, H4'); 7.23 (dd, 1H, J 3.52 Hz, J 0.7 Hz, H3'); 7.24 (s, 1H, H5); 7.61 (dd, 1H, J 1.73 Hz, J 0.7 Hz, H5'); ¹³C NMR (100 MHz, CDCl₃): d 163.2, 158.7, 157.2 (²J_CF 35 Hz), 151.1, 145.6, 120.6 (J_CF 274 Hz), 113.8, 112.8, 101.2 (⁴J_CF 2.9 Hz); MS (70 eV) m/z 229 (M⁺, 100), 118 (35), 90 (24), 63 (37). Anal. Calc. for C₉H₆F₃N₃O: C, 47.17; H, 2.64; N, 18.34. Found: C, 48.00; H, 3.20; N, 18.38.

2-Amino-6-(2-thienyl)-4-trifluoromethylpyrimidine, 5b

Yield 51 %; mp 141-143 ºC; ¹H NMR (400 MHz, CDCl₃): 5.57 (s, 2H, NH₂); 7.15 (dd, 1H, J 5.0 Hz, J 3.8 Hz, H4'); 7.19 (s, 1H, H5); 7.54 (dd, 1H, J 5.0 Hz, J 1.04 Hz, H3'); 7.77 (dd, 1H, J 3.8 Hz, J 1.04 Hz, H5'); ¹³C NMR (100 MHz, CDCl₃): d 163.1, 162.4, 157.0 (²J_CF 35 Hz), 141.5, 130.9, 128.6, 128.4, 120.6 (J_CF 274 Hz), 101.4 (⁴J_CF 2.9 Hz); MS (70 eV) m/z 245 (M⁺, 100), 226 (10), 204 (45), 134 (59), 69 (28); Anal. Calc. for C₉H₆F₃N₃S: C, 44.08; H, 2.47; N, 17.14. Found: C, 44.70; H, 2.65; N, 16.59.

6-(2-Furyl)-2-(1H-pyrazol-1-yl)-4-trifluoromethylpyrimidine, 6a

Yield 54 %; mp 108-110 ºC; ¹H NMR (400 MHz, CDCl₃): 6.53 (dd, 1H, J 2.8 Hz, J 1.6 Hz, H4-pyr); 6.64 (dd, 1H, J 3.4 Hz, J 1.8 Hz, H4'); 7.57 (d, 1H, J 3.4 Hz, H3'); 7.69 (d, 1H, J 1.6 Hz, H5-pyr); 7.76 (s, 1H, H5); 7.89 (d, 1H, J 1.8 Hz, H5'); 8.65 (d, 1H, J 2.8 Hz, H3pyr); ¹³C NMR (100 MHz, CDCl₃): d 159.4, 157.2 (²J_CF 37 Hz), 156.3, 150.4, 146.7, 144.4, 129.8, 120.2 (J_CF 274 Hz), 115.6, 113.2, 109.8, 107.6; MS (70 eV) m/z 280 (M⁺, 100), 261 (8), 213 (75), 118 (8), 90 (8), 63 (14). Anal. Calc. for C₁₂H₇F₃N₄O: C, 51.44; H, 2.52; N, 19.99. Found: C, 50.84; H, 2.64; N, 20.09.

2-(1H-Pyrazol-1-yl)-6-(2-thienyl) 4-trifluoromethylpyrimidine, 6b

Yield 58 %; mp 116-118 ºC; ¹H NMR (400 MHz, CDCl₃): 6.53 (dd, 1H, J 2.8 Hz, J 1.58 Hz, H4-pyr); 7.21 (dd, 1H, J 4.99 Hz, J 3.83 Hz, H4'); 7.65 (dd, 1H, J 4.99 Hz, J 1.04 Hz, H3'); 7.68 (s, 1H, H5); 7.89 (d, 1H, J 1.58 Hz, H3-pyr); 7.95 (dd, 1H, J 3.83 Hz, J 1.04 Hz, H5'); 8.66 (d, 1H, J 2.7 Hz, H5-pyr); ¹³C NMR (100 MHz, CDCl₃): d 163.2, 157.7 (²J_CF 36 Hz), 156.2, 144.5, 140.3, 132.5, 129.9, 129.8, 128.8, 120.2 (J_CF 274 Hz), 109.1, 107.9; MS (70 eV) m/z 296 (M⁺, 100), 287 (8), 229 (82), 134 (15), 69 (9). Anal. Calc. for C₁₂H₇F₃N₄S: C, 48.65; H, 2.38; N, 18.91. Found: C, 48.76; H, 2.47; N, 18.90.

6-(2-Furyl)-2-tiomethyl-4-trifluoromethylpyrimidine, 7a

Yield 52 %, oil; ¹H NMR (400 MHz, CDCl₃): 2.61 (s, 3H, SMe); 6.59 (dd, 1H, J 3.52 Hz, J 1.71 Hz, H4'); 7.36 (dd, 1H, J 3.52 Hz, J 0.71 Hz, H3'); 7.51 (s, 1H, H5); 7.63 (dd, 1H, J 1.71 Hz, J 0.71 Hz, H5'); ¹³C NMR (100 MHz, CDCl₃): d 174.0, 157.1, 156.0 (²J_CF 36 Hz), 150.7, 146.1, 120.4 (J_CF 274 Hz), 114.2, 112.8, 105.3, 13.8; MS (70 eV) m/z 260 (M⁺, 100), 241 (12), 214 (38), 118 (18), 90 (13), 63 (28). Anal. Calc. for C₁₀H₇F₃N₂OS: C, 46.15; H, 2.71; N, 10.76. Found: C, 46.10; H, 2.80; N, 10.78.

6-(2-Thienyl)-2-tiomethyl-4-trifluoromethylpyrimidine, 7b

Yield 53 %, oil; ¹H NMR (400 MHz, CDCl₃): 2.61 (s, 3H, SMe); 7.15 (dd, 1H, J 5.0 Hz, J 3.9 Hz, H4'); 7.43 (s, 1H, H5); 7.56 (dd, 1H, J 5.0 Hz, J 1.1 Hz, H3'); 7.80 (dd, 1H, J 3.90 Hz, J 1.10 Hz, H5'); ¹³C NMR (100 MHz, CDCl₃): d 174.2, 162.7, 155.8 (²J_CF 36 Hz), 140.9, 131.7, 129.1, 128.6, 120.4 (J_CF 274 Hz), 105.7, 14.1; MS (70 eV) m/z 276 (M⁺, 100), 257 (14), 229 (60), 134 (45), 69 (16). Anal. Calc. for C₁₀H₇F₃N₂S₂: C, 43.47; H, 2.55; N, 10.14. Found: C, 43.55; H, 2.60; N, 10.20.

Acknowledgments

Financial support from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) and Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (FAPERGS) is acknowledged. The Bruker X-ray diffractometer was funded by infrastructure grant from the Financiadora de Estudos e Projetos (CT-INFRA/ FINEP). Both of us L.Pizzuti and M.Rossato thank CNPq for fellowships.

Supplementary Information

Supplementary data ¹H, ¹³C NMR and mass spectra are available free of charge at http://jbcs.sbq.org.br, as PDF file.

Received: February 6, 2007

Web Release Date: October 19, 2007

Supplementary information

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Publication Dates

• Publication in this collection
  08 Jan 2008
• Date of issue
  2007

History

• Received
  06 Feb 2007
• Accepted
  19 Oct 2007