Efficient synthesis of new biheterocyclic 5-[(5-Trifluoromethyl-5-hydroxy-4,5-dihydro-1H-pyrazol-1-yl)-1-propan-1-one-3-yl]-2-methyl-7-trifluoromethylpyrazolo[1,5-a]pyrimidines

Flores, Alex F. C.; Rosales, Pauline F.; Malavolta, Juliana L.; Flores, Darlene C.

doi:10.5935/0103-5053.20140126

Abstracts

Twelve new 5-[(5-trifluoromethyl-5-hydroxy-4,5-dihydro-1H-pyrazol-1-yl)-1-propan-1-one-3-yl]-2-methyl-7-trifluoromethylpyrazolo[1,5-a]pyrimidines were prepared by cyclocondensation between 2-methyl-7-trifluoromethylpyrazolo[1,5-a]pyrimidine-5-propanoyl hydrazide derived from 2-methyl-5-(methylpropanoate-3-yl)-7-trifluoromethylpyrazolo[1,5-a]pyrimidine and a series of versatile 1,1,1-trifluoro-4-alkoxy-3-alken-2-ones [F3CC(O)C(R²)=C(R¹)OMe where R¹ = H, Me, (CH2)2CHCMe2, (CH2)2Ph, (CH2)2CO2Me, Ph, 4-MeC6H4, 4-MeOC6H4, EtO and R² = H; R¹, R² = -(CH2)4-, -(CH2)5-; R¹ = Ph and R² = Me]. The structures of new propionyl-spaced biheterocycles were derived from ¹H, 13C, and 19F nuclear magnetic resonance (NMR) spectroscopy and mass spectrometric (MS) data.

heterocycles; pyrazolo[1,5-a]pyrimidines; pyrazoles; levulinic acid

Neste trabalho relatamos a ciclocondensação entre a 2-metil-7-trifluorometilpirazolo[1,5-a]pirimidino-5-propanoil hidrazida derivada da 2-metil-5-(metilpropanoato-3-il)-7-trifluorometilpirazolo[1,5-a]pyrimidina e doze versáteis 1,1,1-trifluoro-4-alcóxi-3-alquen-2-onas [F3CC(O)C(R²)=C(R¹)OMe onde R¹ = H, Me, (CH2)2CHCMe2, (CH2)2Ph, (CH2)2CO2Me, Ph, 4-MeC6H4, 4-MeOC6H4, EtO e R² = H; R¹, R² = -(CH2)4-, -(CH2)5-; R¹ = Ph e R² = Me]. A estrutura molecular dos produtos 5-[(5-trifluorometil-5-hidroxi-4,5-diidro-1H-pirazol-1-il)-1-propan-1-ona-3-il]-2-metil-7-trifluorometilpirazolo[1,5-a]pirimidinas, novos bihetererociclos contendo o espaçador propionil, foram atribuídas com base nos dados de ressonância magnética nuclear (NMR) de ¹H, 13C e 19F, e espectrometria de massas (MS).

ARTICLE

Efficient synthesis of new biheterocyclic 5-[(5-Trifluoromethyl-5-hydroxy-4,5-dihydro-1H-pyrazol-1-yl)-1-propan-1-one-3-yl]-2-methyl-7-trifluoromethylpyrazolo[1,5-a]pyrimidines

Alex F. C. FloresI,^* * e-mail: alex.fcf@ufsm.br ; Pauline F. Rosales^II; Juliana L. Malavolta^II; Darlene C. Flores^I

^IEscola de Química e Alimentos, Universidade Federal do Rio Grande, 96203-900 Rio Grande-RS, Brazil

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

ABSTRACT

Twelve new 5-[(5-trifluoromethyl-5-hydroxy-4,5-dihydro-1H-pyrazol-1-yl)-1-propan-1-one-3-yl]-2-methyl-7-trifluoromethylpyrazolo[1,5-a]pyrimidines were prepared by cyclocondensation between 2-methyl-7-trifluoromethylpyrazolo[1,5-a]pyrimidine-5-propanoyl hydrazide derived from 2-methyl-5-(methylpropanoate-3-yl)-7-trifluoromethylpyrazolo[1,5-a]pyrimidine and a series of versatile 1,1,1-trifluoro-4-alkoxy-3-alken-2-ones [F₃CC(O)C(R²)=C(R¹)OMe where R¹ = H, Me, (CH₂)₂CHCMe₂, (CH₂)₂Ph, (CH₂)₂CO₂Me, Ph, 4-MeC₆H₄, 4-MeOC₆H₄, EtO and R² = H; R¹, R² = -(CH₂)₄-, -(CH₂)₅-; R¹ = Ph and R² = Me]. The structures of new propionyl-spaced biheterocycles were derived from ¹H, ¹³C, and ¹⁹F nuclear magnetic resonance (NMR) spectroscopy and mass spectrometric (MS) data.

Keywords: heterocycles, pyrazolo[1,5-a]pyrimidines, pyrazoles, levulinic acid

RESUMO

Neste trabalho relatamos a ciclocondensação entre a 2-metil-7-trifluorometilpirazolo[1,5-a]pirimidino-5-propanoil hidrazida derivada da 2-metil-5-(metilpropanoato-3-il)-7-trifluorometilpirazolo[1,5-a]pyrimidina e doze versáteis 1,1,1-trifluoro-4-alcóxi-3-alquen-2-onas [F₃CC(O)C(R²)=C(R¹)OMe onde R¹= H, Me, (CH₂)₂CHCMe₂, (CH₂)₂Ph, (CH₂)₂CO₂Me, Ph, 4-MeC₆H₄, 4-MeOC₆H₄, EtO e R² = H; R¹, R² = -(CH₂)₄-, -(CH₂)₅-; R¹ = Ph e R² = Me]. A estrutura molecular dos produtos 5-[(5-trifluorometil-5-hidroxi-4,5-diidro-1H-pirazol-1-il)-1-propan-1-ona-3-il]-2-metil-7-trifluorometilpirazolo[1,5-a]pirimidinas, novos bihetererociclos contendo o espaçador propionil, foram atribuídas com base nos dados de ressonância magnética nuclear (NMR) de ¹H, ¹³C e ¹⁹F, e espectrometria de massas (MS).

Introduction

There has been increasing interest in the chemistry of organic trifluoromethyl compounds, largely due to the fact that they show enhanced biological activity and can be used as medicinal or agricultural chemicals, in addition to their role in the development of new potential technological materials. The presence of trifluoromethyl groups in organic substances modifies the physicochemical profile, increasing lipophilicity and metabolic stability.^1-3 The synthesis of trifluoromethyl heterocycles using a readily available building block with a trifluoromethyl group has often been found to be superior to selective introduction of a trifluoromethyl group into heterocyclic compounds as well as conversion of a carboxylic group into a trifluoromethyl group.^4-8

Heterocycles are present in a wide variety of drugs, biomolecules and biologically active compounds, and they are often key structural units in pharmaceuticals and agrochemicals.⁹ Among them, pyrazolo[1,5-a]pyrimidine rings have been shown to possess anti-inflammatory activity,^10,11 inhibitory activity against monoamine oxidase, which is crucial in compounds used for the treatment of Parkinson's and Alzheimer's diseases,¹² anticonvulsant activity^13,14 and cytotoxicity against cancer cell lines.^15,16 In addition, some pyrazole derivatives are used as insecticides,^17,18 analytical reagents for the complexation of transition metal ions^19,20 and ultraviolet stabilizers in the dyeing industry. Owing to their versatile chemotherapeutic uses, a large amount of research has been focused on these nuclei.²¹

Recently, we reported the synthesis of methyl 1,1,1-trihalo-4-methoxy-6-oxo-4-heptenoates, derived from renewable levulinic acid, as building blocks for the production of promising trifluoromethyl containing heterocyclic systems.^22,23 In a continuation of our interest in the versatility of precursors 7,7,7-trihalo-4-methoxy-6-oxo-4-heptenoates, we herein report an efficient procedure for synthesizing new heterocyclic systems using a propionyl spacer between heterocyclic pyrazolo[1,5-a]pyrimidine and pyrazole nuclei, namely 5-[(5-trifluoromethyl-5-hydroxy-4,5-dihydro-1H-pyrazol-1-yl)-1-propan-1-one-3-yl]-2-methyl-7-trifluoromethylpyrazolo[1,5-a]pyrimidines. The behavior of 2-methyl-7-trifluoromethylpyrazolo[1,5-a]pyrimidine-5-propanoyl hydrazide (2) towards some 1,1,1-trifluoro-4-alkoxy-3-alken-2-ones as potential precursors for interesting biologically active biheterocyclic systems was investigated.

Results and Discussion

The 2-methyl-7-trifluoromethylpyrazolo[1,5-a]pyrimidine-5-propanoyl hydrazide (2) was obtained from 2-methyl-5-(methylpropanoate-3-yl)-7-trifluoromethyl pyrazolo[1,5-a]pyrimidine 1 as described previously (Scheme 1).²²

Various 1,1,1-trifluoro-4-methoxy-3-alken-2-ones (a-l) were obtained by reacting enol ether or acetal with trifluoroacetic anhydride.^23,24 The reaction between 3e and 3-amino-5-methyl-1H-pyrazole was performed under conditions described previously²² and there was exclusive formation of 2-methyl-5-(methylpropanoate-3-yl)-7-trifluoromethylpyrazolo[1,5-a]pyrimidine 1 (Scheme 1).²² The condensation of 3-heteroarylpropanoyl hydrazide 2 with 1,1,1-trifluoro-4-methoxy-3-penten-2-one (3b) was carried out in MeOH at 25 ºC for 24 h, and the reactants were not consumed (see Supplementary Information). When performing the reaction at 50 ºC, the reactants were completely consumed after 16 h, leading to biheterocyclic derivative 4b at a yield of 89%. At the refluxing temperature of MeOH, 65 ºC, the reaction led to the same product within the same reaction time with only a slight decrease in yield (85%). The reaction conducted in EtOH at 50 ºC also led to product 4b at 85% yield, although this is again slightly lower than the 89% yield achieved with MeOH; we chose to use EtOH for further cyclocondensations due its lower toxicity and greater eco-affinity. These conditions were extended for the entire series of 1,1,1-trifluoro-4-alkoxy-3-alken-2-ones for cyclocondensations with hydrazide 2 (Scheme 2), the 4,5-dihydro-1H-pyrazole derivatives 4a-l were the only products obtained in the [3 + 2] cyclocondensation reactions. We attempted to perform the aromatization of 1H-pyrazoles (4b, 4d, 4f, 4l) using 98% H₂SO₄, however, probably due to the hydrolysis of the carboxamide bond, we isolated 3-[(2-methyl-7-trifluoromethyl)pyrazolo[1,5-a]pyrimidin-5-yl]propanoic acid (5), but no amount of the corresponding aromatic 1-substituted 1H-pyrazoles.

After the cyclocondensation reactions, each product was isolated, purified by recrystallization or column chromatography, and identified by nuclear magnetic resonance (NMR) spectroscopy, liquid chromatography-electrospray ionization mass spectrometry (LC-ESI-MS) and elemental analysis.

The ¹H NMR spectra for biheterocyclic derivatives 4a-l showed a general feature, namely displaying signals related to two methylenes from the propionyl chain and the diastereotopic H-4 from the 1H-pyrazole ring overlapping at about d 2.9 to 3.5 ppm.²⁵ The signal related to methylenes from the propionyl chain consisted of two triplets (multiplets) or an enlarged singlet. The signal for H-6 from the pyrimidine ring was at d 7.1 to 7.4 ppm. The ¹³C NMR spectra showed the characteristic signals for each derivative series. Two quartet signals related to the CF₃ group were found at about d 120 ppm with ³J_CF 275 Hz, the one related to C6 from the pyrimidine ring was at about d 155 ppm with J_CF 36 Hz, and the one related to C5 from the pyrazole ring was at about d 90 to 92 ppm with ³J_CF 35 Hz. The signals related to propionyl methylenes appeared at 31 to 32 ppm, and the carbonyl carbon signal appeared at about 174 ppm (see Supplementary Information).

Conclusions

In conclusion, we present a novel method for synthesizing biheterocyclic products, demonstrating the versatility of precursors methyl 7,7,7-trifluoro-4-methoxy-oxohept-6-enoate in cyclocondensations [3 + 3] and [3 + 2]. The dielectrophilic moiety in precursors 3a-l regioselectively reacts with both the 3-amino-5-methyl-1H-pyrazole as well as hydrazide dinucleophiles. This is an efficient protocol for the preparation of diverse 5-[(5-trifluoromethyl-5-hydroxy-4,5-dihydro-1H-pyrazol-1-yl)-1-propan-1-one-3-yl]-2-methyl-7-trifluoromethylpyrazolo[1,5-a]pyrimidine derivatives at good yields. These compounds are interesting structural analogues to central nervous system chemical mediators, making them good subjects for studies of biological activity. To the best of our knowledge, no biheterocyclic 5-[(5-trifluoromethyl-5-hydroxy-4,5-dihydro-1H-pyrazol-1-yl)-1-propan-1-one-3-yl]-2-methyl-7-trifluoromethylpyrazolo[1,5-a]pyrimidines have been previously described.

Experimental

¹H and ¹³C NMR spectra were collected at 300 K using a Bruker 5 mm dual probe on a Bruker DPX 400 spectrometer (¹H at 400.13 MHz, ¹⁹F at 376.4 MHz and ¹³C at 100.62 MHz). Chemical shifts (d) are quoted in ppm from tetramethylsilane (TMS) and coupling constants (J) are given in Hz. The chemical shifts in the ¹⁹F NMR spectrum are quoted in ppm from fluorobenzene at 113.15 ppm which was referenced from CFCl₃ at 0 ppm. Melting points were determined using open capillaries on an Electrothermal Mel-Temp 3.0 apparatus. The electrospray ionization (ESI) mass spectra were performed on an Agilent 6460 Triple Quadrupole connected to a 1200 series LC and equipped with a solvent degasser, binary pump, column oven, auto-sampler, and an ESI source. The Agilent QQQ 6460 tandem mass spectrometer was operated in the positive jet stream ESI mode. Nitrogen was used as a nebulizer, turbo (heater) gas, curtain gas, and collision activated dissociation gas. The capillary voltage was set at +3500 V and the nozzle voltage was at +500 V. The ion source gas temperature was 300 ºC with a flow rate of 5 L min^-1. The jet stream sheath gas temperature was 250 ºC with a flow rate of 11 L min^-1. All samples were infused into the ESI source at a flow rate of 5 µL min^-1. Data were acquired in positive MS total ion scan mode (mass scan range m/z 50-650) and in positive MS/MS product ion scan mode. The mass spectra recorded were evaluated by the Qualitative Analysis software from Agilent Technologies. CHN elemental analyses were performed on a Perkin-Elmer 2400 CHN elemental analyzer (University of São Paulo (USP), Brazil).

Synthesis of 2-methyl-7-trifluoromethylpyrazolo[1,5-a]pyrimidine-5-propanehydrazine 2: general procedure

A solution of 5 mmol 2-methyl-5-(methylpropanoate-3-yl)-7-trifluoromethylpyrazolo[1,5-a]pyrimidine (1) and 12.5 mmol hydrazine monohydrate in 15 mL anhydrous methanol was heated under reflux for 5 h. MeOH was evaporated under reduced pressure. Then, the solid was washed with distilled water. Product 2 was obtained (80%) as a white solid; m.p. (H₂O) 180-181 ºC; ¹H NMR (CDCl₃, 400 MHz) d 2.54 (s, 3H, CH₃), 2.73 (t, 2H, J_HH 6.93 Hz, CH₂), 3.01 (s, 2H, NH₂), 3.24 (t, 2H, J_HH 6.93 Hz, CH₂), 6.50 (s, 1H, H3), 6.98 (s, 1H, H6), 7.14 (s, 1H, NH); ¹³C{¹H} NMR (CDCl₃, 100 MHz) d 14.6 (CH₃), 31.4 (CH₂), 32.7 (CH₂), 96.8 (C-3), 105.7 (q, J_CF 4.15 Hz, C-6), 119.5 (q, J_CF 274.4 Hz, CF₃), 133.4 (q, J_CF 37.3 Hz, C-7), 150.0 (C-2), 156.5 (C-3a), 159.3 (C-5), 172.9 (CO); ¹⁹F{¹H} (CDCl₃, 376.4 MHz) d 61.86 (s, CF₃); ESI-MS (M + H + Na)⁺m/z: 311.2.

General procedure for the synthesis of 5-[(5-trifluoromethyl-5-hydroxy-(3-substituted)-4,5-dihydro-1H-pyrazol-1-yl)-1-propan-1-one-3-yl]-2-methyl-7-trifluoromethyl)pyrazolo[1,5-a]pyrimidines (4)

A solution of 2-methyl-7-trifluoromethylpyrazolo[1,5-a]pyrimidine-5-propanoyl hydrazide (2) (3 mmol) and 1,1,1-trifluoro-4-alkoxy-3-alken-2-one (3a-l, 3 mmol) in 10 mL ethanol were stirred at 50 ºC until complete dissolution, and the resulting solution was stirred for 16 h. EtOH was removed and residue was dissolved in CH₂Cl₂ (30 mL); the organic layer was washed with water (3 × 30 mL) and dried with Na₂SO₄. The solvent was evaporated, resulting in products 4a-l. The crystalline compounds were purified by column chromatography on a silica gel (SilicaFlashR G60, 70-230 mesh) with hexane/CH₂Cl₂ (3:1) as an eluent.

5-[(5-Trifluoromethyl-5-hydroxy-4,5-dihydro-1H-pyrazol-1-yl)-1-propan-1-one-3-yl]-2-methyl-7-trifluoromethylpyrazolo[1,5-a]pyrimidine (4a): 87% yield as a yellowish white solid; m.p. 81-83 ºC; ¹H NMR (CDCl₃, 400 MHz) d 2.54 (s, 3H, CH₃), 3.18-3.37 (m, 4H, CH₂CH₂), 6.48 (s, 1H, H3), 6.99 (s, 1H, H6), pyrazole: 3.18-3.37 (m, 2H, H4'a/ H4'b), 6.96 (m, 1H, H3'); ¹³C NMR (CDCl₃, 100 MHz) d 14.7 (CH₃), 31.9 (CH₂), 32.1 (CH₂), 96.9 (C-3), 105.6 (q, J_C-F 4.23 Hz, C-6), 119.7 (q, J_CF 274.4 Hz, CF₃), 133.2 (q, J_CF 37.0 Hz, C-7), 150.1 (C-2), 156.4 (C-3a), 159.1 (C-5), 174.2 (CO), pyrazole: 44.7 (C-4'), 90.1(q, J_CF 34.5 Hz, C-5'), 123.1 (q, J_CF 287.8 Hz, CF₃), 144.8 (C-3'); ESI-MS (M + H)⁺m/z: 410.2; anal. calcd. for C₁₅H₁₃F₆N₅O₂ 409.1 g mol^-1: C, 44.02; H, 3.20; N, 17.11; found: C, 44.3; H, 3.25; N, 17.4.

5-[(5-Trifluoromethyl-5-hydroxy-3-methyl-4,5-dihydro-1H-pyrazol-1-yl)-1-propan-1-one-3-yl]-2-methyl-7-trifluoromethylpyrazolo[1,5-a]pyrimidine (4b): 80% yield as yellow orange solid, m.p. 79-81 ºC; ¹H NMR (CDCl₃, 400 MHz) d 2.04 (s, 3H, CH₃), 2.55 (s, 3H, CH₃), 3.14-3.30 (m, 6H, -CH₂-, H-4 pyr), 6.49 (s, 1H, H-3), 7.0 (s, 1H, H-6); ¹³C NMR (CDCl₃, 100 MHz) d 14.7 (CH₃), 15.6 (CH₃), 32.1 (-CH₂-), 32.3 (-CH₂-), 46.7 (C-4, pyr), 91.5 (q, ²J_CF 34.7 Hz, C-5 pyr), 96.9 (C-3 pym), 105.7 (q, ³J_CF 4.1 Hz, C-6 pym), 121.3 (q, J_CF 274.5 Hz, CF₃), 123.9 (q, J_CF 287.8 Hz, CF₃), 133.2 (q, ²J_CF 37.3 Hz, C-7 pym), 150.1 (C-2 pym), 154.7 (C-3 pyr), 156.4 (C-3a pym), 159.1 (C-5 pym), 172.9 (C=O); ¹⁹F NMR (CDCl₃, 376.4 MHz) d 68.9 (pym), 81.8 (pyr); ESI-MS (M + H)⁺m/z: 424.2; anal. calcd. for C₁₅H₁₃F₆N₅O₂ 423.11 g mol^-1: C, 45.4; H, 3.57; N, 16.54; found: C, 45.1; H, 3.6; N, 16.8.

5-[(5-Trifluoromethyl-5-hydroxy-3-(2-methylpent-3-enyl)-4,5-dihydro-1H-pyrazol-1-yl)-1-pro pan-1-one-3-yl]-2-methyl-7-trifluoromethylpyrazolo[1,5-a]pyrimidine (4c): 68% yield as white solid, m.p. 86-87 ºC; ¹H NMR 400 MHz, CDCl₃ d ppm: 1.62 (s, 3H, CH₃), 1.69 (s, 3H, CH₃), 2.28 (m, 2H, -CH₂-), 2.37 (m, 2H, -CH₂-), 2.54 (s, 3H, CH₃), 2.68 (t, 2H, -CH₂-), 2.91 (t, 2H, -CH₂-), 3.06 (d, 1H, ²J_HH 10 Hz, H-4 pyr), 3.19-3.3 (m, 5H, -CH₂-, H-4 pyr), 5.08 (t, 1H, ³J_HH 6.6 Hz, =CH), 6.49 (s, 1H, H-3), 7.0 (s, 1H, H-6); ¹³C NMR (CDCl₃, 100 MHz) d 14.7 (CH₃), 17.7 (CH₃), 24.8 (-CH₂-), 25.6 (CH₃), 29.9 (-CH₂-), 32.1 (-CH₂-), 32.4 (-CH₂-), 32.4 (-CH₂-), 45.6 (C-4, pyr), 91.3 (q, ²J_CF 34.2 Hz, C-5 pyr), 96.8 (C-3 pym), 105.7 (q, ³J_CF 4.1 Hz, C-6 pym), 119.8 (q, J_CF 274.5 Hz, CF₃), 121.9 (=CH), 123.7 (q, J_CF 287.4 Hz, CF₃), 133.6 (C=), 133.1 (q, ²J_CF 37.0 Hz, C-7 pym), 150.1 (C-2 pym), 156.4 (C-3a pym), 158.2 (C-3 pyr), 159.4 (C-5 pym), 173.7 (C=O); ¹⁹F NMR (CDCl₃, 376.4 MHz) d 68.9 (pym), 81.8 (pyr); ESI-MS (M + H)⁺m/z: 492.3; anal. calcd. for C₂₁H₂₃F₆N₅O₂ 491.18 g mol^-1: C, 51.32; H, 4.72; N, 14.25; found: C, 51.5; H, 4.8; N, 14.2.

5-[(5-Trifluoromethyl-5-hydroxy-3-(2-phenylethyl)-4,5-dihydro-1H-pyrazol-1-yl)-1-propan-1-one-3-yl]-2-methyl-7-trifluoromethylpyrazolo[1,5-a]pyrimidine (4d): 60% yield as pale brown solid, m.p. 135-136 ºC; ¹H NMR (CDCl₃, 400 MHz) d 2.54 (s, 3H, CH₃), 2.68 (t, 2H, -CH₂-), 2.91 (t, 2H, -CH₂-), 3.03 (d, 1H, ²J_HH 10 Hz, H-4 pyr), 3.14-3.25 (m, 5H, -CH₂-, H-4 pyr), 6.49 (s, 1H, H-3), 6.9 (s, 1H, H-6), 7.18-7.31 (m, 5H, Ph); ¹³C NMR (CDCl₃, 100 MHz) d 14.8 (CH₃), 31.5 (-CH₂-), 32.1 (-CH₂-), 32.2 (-CH₂-), 32.4 (-CH₂-), 45.8 (C-4, pyr), 91.3 (q, ²J_CF 34.3 Hz, C-5 pyr), 96.9 (C-3 pym), 105.7 (q, ³J_CF 4.2 Hz, C-6 pym), 119.8 (q, J_CF 275.5 Hz, CF₃), 122.1 (q, J_CF 287.5 Hz, CF₃), 126.5, 128.2, 128.6 (Ph), 133.2 (q, ²J_CF 37.1 Hz, C-7 pym), 139.9 (Ph), 150.1 (C-2 pym), 156.5 (C-3a pym), 157.5 (C-3 pyr), 159.4 (C-5 pym), 173.8 (C=O); ¹⁹F NMR (CDCl₃, 376.4 MHz) d 68.9 (pym), 81.7 (pyr); ESI-MS (M + H)⁺m/z: 514.3; anal. calcd. for C₂₃H₂₁F₆N₅O₂ 513.16 g mol^-1: C, 53.8; H, 4.12; N, 13.64; found: C, 54.0; H, 4.15; N, 13.5.

Methyl 3-(5-hydroxy-1-(3-(2-methyl-7-trifluoromethylpyrazolo[1,5-a]pyrimidin-5-yl)propa noyl)-5-trifluoromethyl-4,5-dihydro-1H-pyrazol-3-yl)propanoate (4e): 89% yield as white solid, m.p. 92-94 ºC; ¹H NMR (CDCl₃, 400 MHz) d 2.48 (s, 3H, CH₃), 2.61 (m, 4H, -CH₂-), 3.01- 3.18 (m, 6H, -CH₂-, H-4 pyr), 3.63 (s, 3H, OCH₃), 6.42 (s, 1H, H-3), 6.9 (s, 1H, H-6); ¹³C NMR (CDCl₃, 100 MHz) d 14.7 (CH₃), 25.1 (-CH₂-), 29.9 (-CH₂-), 32.0 (-CH₂-), 32.2 (-CH₂-), 46.0 (C-4, pyr), 51.9 (OMe), 91.4 (q, ²J_CF 33.0 Hz, C-5 pyr), 96.8 (C-3 pym), 105.6 (q, ³J_CF 4.1 Hz, C-6 pym), 119.9 (q, J_CF 277.7 Hz, CF₃), 123.1 (q, J_CF 283.4 Hz, CF₃), 133.2 (q, ²J_CF 42.0 Hz, C-7 pym), 150.1 (C-2 pym), 156.4 (C-3a pym), 156.6 (C-3 pyr), 159.3 (C-5 pym), 172.3 (C=O), 173.7 (C=O); ESI-MS (M + H)⁺m/z: 496.3; anal. calcd. for C₁₉H₁₉F₆N₅O₄ 495.13 g mol^-1: C, 46.07; H, 3.87; N, 14.14; found: C, 46.2; H, 3.9; N, 14.35.

5-[(5-Trifluoromethyl-5-hydroxy-3-phenyl-4,5-dihydro-1H-pyrazol-1-yl)-1-propan-1-one-3-yl]-2-methyl-7-trifluoromethylpyrazolo[1,5-a]pyrimidine (4f): 68% yield as orange solid, m.p. 94.8-96 ºC; ¹H NMR (CDCl₃, 400 MHz) d 2.52 (s, 3H, CH₃), 3.1-3.42 (m, 4H, -CH₂-), 3.51 (d, 1H, ²J_HH 18.6 Hz, H-4 pyr), 3.67 (d, 1H, ²J_HH 18.6 Hz, H-4 pyr), 6.47 (s, 1H, H-3), 7.0 (s, 1H, H-6), 7.44 (m, 3H, Ph), 7.67 (m, 2H, Ph); ¹³C NMR (CDCl₃, 100 MHz) d 14.6 (CH₃), 32.2 (-CH₂-), 32.5 (-CH₂-), 43.4 (C-4, pyr), 92.0 (q, ²J_CF 33.0 Hz, C-5 pyr), 96.9 (C-3 pym), 105.6 (q, ³J_CF 5.0 Hz, C-6 pym), 119.6 (q, J_CF 274.5 Hz, CF₃), 122.8 (q, J_CF 287.5 Hz, CF₃), 126.2, 126.6, 129.5, 131.2 (Ph), 133.3 (q, ²J_CF 36.0 Hz, C-7 pym), 150.1 (C-2 pym), 153.3 (C-3 pyr), 156.4 (C-3a pym), 159.3 (C-5 pym), 174.0 (C=O); ¹⁹F NMR (CDCl₃, 376.4 MHz) d 68.9 (pym), 81.3 (pyr); ESI-MS (M + H)⁺m/z: 486.2; anal. calcd. for C₂₁H₁₇F₆N₅O₂ 485.13 g mol^-1: C, 51.96; H, 3.53; N, 14.43; found: C, 52.1; H, 3.5; N, 14.5.

5-[(5-Trifluoromethyl-5-hydroxy-3-(4-methylphenyl)-4,5-dihydro-1H-pyrazol-1-yl)-1-propan-1-one-3-yl]-2-methyl-7-trifluoromethylpyrazolo[1,5-a]pyrimidine (4g): 66% yield as yellow solid, m.p. 118.0-120 ºC; ¹H NMR (CDCl₃, 400 MHz) d 2.39 (s, 3H, CH₃), 2.52 (s, 3H, CH₃), 3.2-3.42 (m, 4H, -CH₂-), 3.49 (d, 1H, ²J_HH 18.6 Hz, H-4 pyr), 3.64 (d, 1H, ²J_HH 18.6 Hz, H-4 pyr), 6.47 (s, 1H, H-3), 7.0 (s, 1H, H-6), 7.22 (d, 2H, ³J_HH 8.0 Hz, Ph), 7.56 (d, 2H, ³J_HH 8.0 Hz, Ph); ¹³C NMR (CDCl₃, 100 MHz) d 14.6 (CH₃), 21.4 (CH₃), 32.2 (-CH₂-), 32.5 (-CH₂-), 43.4 (C-4, pyr), 91.9 (q, ²J_CF 35.0 Hz, C-5 pyr), 96.9 (C-3 pym), 105.6 (q, ³J_CF 5.0 Hz, C-6 pym), 119.6 (q, J_CF 270.0 Hz, CF₃), 121.9 (q, J_CF 277.5 Hz, CF₃), 126.6, 127.2, 129.6 (Ph), 133.3 (q, ²J_CF 34.0 Hz, C-7 pym), 141.7 (Ph), 150.2 (C-2 pym), 153.4 (C-3 pyr), 156.4 (C-3a pym), 159.3 (C-5 pym), 174.0 (C=O); ¹⁹F NMR (CDCl₃, 376.4 MHz) d 68.9 (pym), 81.4 (pyr); ESI-MS (M + H)⁺m/z: 500.2; anal. calcd. for C₂₂H₁₉F₆N₅O₂ 499.14 g mol^-1: C, 52.91; H, 3.83; N, 14.02; found: C, 53.1; H, 3.9; N, 14.2.

5-[(5-Trifluoromethyl-5-hydroxy-3-(methoxyphenyl)-4,5-dihydro-1H-pyrazol-1-yl)-1-propan-1-one-3-yl]-2-methyl-7-trifluoromethylpyrazolo[1,5-a]pyrimidine (4h): 95% yield as red solid, m.p. 77-79 ºC; ¹H NMR (CDCl₃, 400 MHz) d 2.53 (s, 3H, CH₃), 3.2-3.40 (m, 4H, -CH₂-), 3.48 (d, 1H, ²J_HH 18.5 Hz, H-4 pyr), 3.63 (d, 1H, ²J_HH 18.5 Hz, H-4 pyr), 3.86 (s, 3H, CH₃), 6.48 (s, 1H, H-3), 6.93 (d, 2H, ³J_HH 8.0 Hz, Ph), 7.0 (s, 1H, H-6), 7.62 (d, 2H, ³J_HH 8.0 Hz, Ph); ¹³C NMR (CDCl₃, 100 MHz) d 14.8 (CH₃), 32.2 (-CH₂-), 32.5 (-CH₂-), 43.4 (C-4, pyr), 55.5 (OMe), 91.8 (q, ²J_CF 34.0 Hz, C-5 pyr), 96.9 (C-3 pym), 105.7 (q, ³J_CF 4.0 Hz, C-6 pym), 114.3 (Ph), 119.6 (q, J_CF 270.0 Hz, CF₃), 121.9 (q, J_CF 277.5 Hz, CF₃), 126.6, 127.2, 129.6 (Ph), 133.3 (q, ²J_CF 34.0 Hz, C-7 pym), 141.7 (Ph), 150.2 (C-2 pym), 153.4 (C-3 pyr), 156.4 (C-3a pym), 159.3 (C-5 pym), 174.0 (C=O); ¹⁹F NMR (CDCl₃, 376.4 MHz) d 68.9 (pym), 81.3 (pyr); ESI-MS (M + H)⁺m/z: 516.2; anal. calcd. for C₂₂H₁₉F₆N₅O₃ 515.14 g mol^-1: C, 51.27; H, 3.72; N, 13.59; found: C, 51.4; H, 3.7; N, 13.8.

5-[(3-Ethoxy-5-trifluoromethyl-5-hydroxy-4,5-dihydro-1H-pyrazol-1-yl)-1-propan-1-one-3-yl]-2-methyl-7-trifluoromethylpyrazolo[1,5-a]pyrimidine (4i): 75% yield as white solid, m.p. 97.3-99 ºC; ¹H NMR (CDCl₃, 400 MHz) d 1.35 (t, 3H, ³J_HH 6.5 Hz, CH₃), 2.54 (s, 3H, CH₃), 3.0-3.30 (m, 6H, -CH₂-, H-4 pyr), 4.23 (q, 2H, ³J_HH 6.5 Hz, -CH₂-), 6.49 (s, 1H, H-3), 7.0 (s, 1H, H-6); ¹³C NMR (CDCl₃, 100 MHz) d 14.0 (CH₃), 14.7 (CH₃), 32.1 (-CH₂-), 32.2 (-CH₂-), 40.7 (C-4, pyr), 66.2 (OMe), 91.8 (q, ²J_CF 34.4 Hz, C-5 pyr), 96.8 (C-3 pym), 105.7 (q, ³J_CF 4.1 Hz, C-6 pym), 119.5 (q, J_CF 274.4 Hz, CF₃), 124.1 (q, J_CF 287.8 Hz, CF₃), 133.2 (q, ²J_CF 37.0 Hz, C-7 pym), 150.1 (C-2 pym), 156.4 (C-3a pym), 159.6 (C-5 pym), 161.8 (C-3 pyr), 173.2 (C=O); ¹⁹F NMR (CDCl₃, 376.4 MHz) d 68.9 (pym), 82.6 (pyr); ESI-MS (M + H)⁺m/z: 454.3; anal. calcd. for C₁₇H₁₇F₆N₅O₃ 453.12 g mol^-1: C, 45.04; H, 3.78; N, 15.45; found: C, 44.8; H, 3.65; N, 15.8.

5-[1-(3-Hydroxy-3-trifluoromethyl-3,3a,4,5,6,7-hexahydroindazol-2-yl)-1-propan-1-one-3-yl]-2-methyl-7-trifluoromethylpyrazolo[1,5-a]pyrimidine (4j): 63% yield as yellow oil; ¹H NMR (CDCl₃, 400 MHz) d 1.26-1.63 (m, 8H, -(CH₂)₄-), 2.55 (s, 3H, CH₃), 3.04 (m, 1H, CH), 3.18-3.3 (m, 4H, -CH₂-), 6.49 (s, 1H, H-3), 7.0 (s, 1H, H-6); ¹³C NMR (CDCl₃, 100 MHz) d 14.7 (CH₃), 23.7, 25.9, 26.4, 27.7 (cyclo-CH₂-), 31.2 (-CH₂-), 32.5 (-CH₂-), 51.8 (C-4, pyr), 90.7 (q, ²J_CF 34.0 Hz, C-5 pyr), 96.9 (C-3 pym), 105.6 (q, ³J_CF 4.0 Hz, C-6 pym), 118.8 (q, J_CF 274.8 Hz, CF₃), 120.1 (q, J_CF 287.9 Hz, CF₃), 133.1 (q, ²J_CF 34.0 Hz, C-7 pym), 150.0 (C-2 pym), 156.4 (C-3a pym), 159.1 (C-5 pym), 161.0 (C-3 pyr), 174.1 (C=O); ESI-MS (M + H)⁺m/z: 464.3; anal. calcd. for C₁₉H₁₉F₆N₅O₂ 463.14 g mol^-1: C, 49.25; H, 4.13; N, 15.11; found: C, 49.4; H, 4.3; N, 15.2.

1-(3-Hydroxy-3-trifluoromethyl-3,3a,4,5,6,7,8,9-octahydrocycloocta[c]pyrazol-2-yl)-1-propan-1-one-3-yl]-2-methyl-7-trifluoromethylpyrazolo[1,5-a]pyrimidine (4k): 79% yield as yellow oil; ¹H NMR (CDCl₃, 400 MHz) d 1.67 (m, 3H, -CH₂-), 1.82 (m, 5H, -CH₂-), 2.53 (s, 3H, CH₃), 2.65 (m, 2H, -CH₂-), 2.73 (m, 2H, -CH₂-), 3.04 (m, 1H, CH), 3.22 (m, 4H, -CH₂-), 6.48 (s, 1H, H-3), 7.0 (s, 1H, H-6); ¹³C NMR (CDCl₃, 100 MHz) d 14.6 (CH₃), 23.7, 25.4, 26.7, 28.0, 29.5, 30.7 (cyclo-CH₂-), 31.6 (-CH₂-), 32.2 (-CH₂-), 54.6 (C-4, pyr), 91.5 (q, ²J_CF 34.0 Hz, C-5 pyr), 96.8 (C-3 pym), 105.6 (q, ³J_CF 4.0 Hz, C-6 pym), 122.5 (q, J_CF 275.0 Hz, CF₃), 123.7 (q, J_CF 287.5 Hz, CF₃), 133.1 (q, ²J_CF 35.0 Hz, C-7 pym), 150.1 (C-2 pym), 156.4 (C-3a pym), 159.4 (C-5 pym), 163.5 (C-3 pyr), 174.0 (C=O); ESI-MS (M + H)⁺m/z: 492.3; anal. calcd. for C₂₁H₂₃F₆N₅O₂ 491.18 g mol^-1: C, 51.32; H, 4.72; N, 14.25; found: C, 51.5; H, 4.72; N, 14.5.

1-(5-Trifluoromethyl-5-hydroxy-4-methyl-3-phenyl-4,5-dihydropyrazol-1-yl)-1-propan-1-one-3-yl]-2-methyl-7-trifluoromethylpyrazolo[1,5-a]pyrimidine (4l): 68% yield as pale brown solid; m.p. 99-101 ºC; ¹H NMR (CDCl₃, 400 MHz) d 1.26 (d, 3H, ³J_HH 8 Hz, Me), 2.42 (s, 3H, CH₃), 3.1-3.32 (m, 4H, -CH₂-), 3.71 (d, 1H, ³J_HH 8 Hz, H-4 pyr), 6.37 (s, 1H, H-3), 6.9 (s, 1H, H-6), 7.36 (m, 3H, Ph), 7.63 (m, 2H, Ph); ¹³C NMR (CDCl₃, 100 MHz) d 11.6 (Me),14.6 (Me), 32.0 (-CH₂-), 32.2 (-CH₂-), 46.0 (C-4, pyr), 92.3 (q, ²J_CF 35.0 Hz, C-5 pyr), 96.9 (C-3 pym), 105.6 (q, ³J_CF 5.0 Hz, C-6 pym), 120.1 (q, J_CF 274.5 Hz, CF₃), 123.8 (q, J_CF 287.5 Hz, CF₃), 127.2, 129.3, 129.5, 131.2 (Ph), 133.3 (q, ²J_CF 36.0 Hz, C-7 pym), 150.1 (C-2 pym), 153.3 (C-3 pyr), 156.4 (C-3a pym), 159.3 (C-5 pym), 174.2 (C=O); ESI-MS (M + H)⁺m/z: 500.2; anal. calcd. for C₂₂H₁₉F₆N₅O₂ 499.14 g mol^-1: C, 52.91; H, 3.83; N, 14.02; found: C, 53.0; H, 3.85; N, 14.1.

Supplementary Information

Supplementary information is available free of charge at http://jbcs.sbq.org.br as PDF file.

Acknowledgments

The authors are grateful for the financial support from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, Universal Grant 6577818477962764-01) and Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (FAPERGS, PqG Grant 1016236). The fellowships from CAPES (P. F. Rosales) and CNPq (J. L. Malavolta) are also acknowledged.

Submitted: April 4, 2014

Published online: May 30, 2014

Supplementary Information

The supplementary material is available in pdf: [Supplementary material]

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*

e-mail:

alex.fcf@ufsm.br

Publication Dates

Publication in this collection
04 Aug 2014
Date of issue
Aug 2014

History

Received
04 Apr 2014
Accepted
30 May 2014

This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

[1] 1. Quirmbach, M.; Steiner, H.; Chim. Oggi 2009, 27, 23.

[2] 2. Filler, R.; Saha, R. Future Med. Chem. 2009, 1, 777.

[3] 3. Gao, W.; Liu, R.; Li, Y.; Heterocycl. Commun. 2012, 18, 223.

[4] 4. Honey, M. A.; Pasceri, R.; Lewis, W.; Moody, C. J.; J. Org. Chem 2012, 77, 1396.

[5] 5. López, S. E.; Restrepo, J.; Salazar, J.; Curr. Org. Synth. 2010, 7, 414.

[6] 6. Nenajdenko, V. G.; Balenkova, E. S.; ARKIVOC 2011, (i), 246.

[7] 7. Kawai, H.; Sugita, Y.; Tokunaga, E.; Sato, H.; Shiro, M.; Shibata, N.; Chem. Commun. 2012, 48, 3836.

[8] 8. Ji, Y.; Brueckl, T.; Baxter, R. D.; Fujiwara, Y.; Seiple, I. B.; Su, S.; Blackmond, D.; Baran, P. S.; Proc. Natl. Acad. Sci. U. S. A. 2011, 108, 14411.

[9] 9. Dua, R.; Shrivastava, S.; Sonwane, S. K.; Srivastava, S. K.; Adv. Biol. Res. 2011, 5, 120.

[10] 10. Almansa, C.; Arriba, A. F.; Cavalcanti, F. L.; Gómez, L. A.; Miralles, A.; Merlos, M.; Gárcia-Rafanell, J.; Forn, J.; J. Med. Chem. 2001, 44, 350.

[11] 11. Shaaban, M. R.; Saleh, T. S.; Mayhoub, A. S.; Mansour, A.; Farag, A. M.; Bioorg. Med. Chem. 2008, 16, 6344.

[12] 12. Gillian, P. J.; Baldauf, C.; Cocuzza, A.; Chidester, D.; Zaczek, R.; Fitzgerald, L. W.; McElroy, J.; Smith, M. A.; Shen, H.-S. L.; Saye, J. A.; Christ, D.; Trainor, G.; Robertson, D. W.; Hartig, P.; Bioorg. Med. Chem. 2000, 8, 181.

[13] 13. Ivachtchenko, A. V.; Golovina, E. S.; Kadieva, M. G.; Kysil, V. M.; Mitkin, O. D.; Pharm. Chem. J. 2013, 46, 595.

[14] 14. Ivachtchenko, A. V.; Golovina, E. S.; Kadieva, M. G.; Kysil, V. M.; Mitkin, O. D.; Okun, I. M.; Pharm. Chem. J. 2012, 46, 406.

[15] 15. Ramaiah, M. J.; Pushpavalli, S. N. C. V. L.; Lavanya, L.; Bhadra, K.; Haritha, V.; Patel, N.; Tamboli, J. R.; Kamal, A.; Bhadra, U.; Pal-Bhadra, M.; Bioorg. Med. Chem. Lett. 2013, 23, 5699.

[16] 16. Kaliszczak, M.; Patel, H.; Kroll, S. H. B.; Carroll, L.; Smith, G.; Delaney, S.; Heathcote, D. A.; Bondke, A.; Fuchter, M. J.; Coombes, R. C.; Barrett, A. G. M.; Ali, S.; Aboagye, E. O.; Br. J. Cancer 2013, 109, 2356.

[17] 17. Song, H.; Liu, Y.; Xiong, L.; Li, Y.; Yang, N.; Wang, Q.; J. Agric. Food Chem. 2012, 60, 1470.

[18] 18. Ozoe, Y.; Yagi, K.; Nakamura, M.; Akamatsu, M.; Miyake, T.; Matsumura, F.; Pestic. Biochem. Physiol. 2000, 66, 92.

[19] 19. Malinkin, S. O.; Penkova, L.; Moroz, Y. S.; Haukka, M.; Maciag, A.; Gumienna-Kontecka, E.; Pavlenko, V. A.; Pavlova, S.; Nordlander, E.; Fritsky, I. O.; Eur. J. Org. Chem. 2012, 1639.

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Efficient synthesis of new biheterocyclic 5-[(5-Trifluoromethyl-5-hydroxy-4,5-dihydro-1H-pyrazol-1-yl)-1-propan-1-one-3-yl]-2-methyl-7-trifluoromethylpyrazolo[1,5-a]pyrimidines

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