Straightforward and Clean Ultrasound-Promoted Synthesis of 2-(4,5-Dihydro‑1H‑pyrazol-1-yl)pyrimidines

Abstract

A series of twelve novel 2-(pyrazol-1-yl)pyrimidine derivatives was easily obtained under ultrasonic conditions by the cyclocondensation reaction of 1-carboxamidino-pyrazoles with 4-methoxyvinyl-trifluoromethyl ketones using ethanol as an environment-friendly solvent in the presence of potassium hydroxide. Comparison of the ultrasound-promoted reaction with classical methodology shows that the former is faster and gives better yield. The products were isolated in excellent purity grades without purification by chromatography or recrystalization.

Keywords
2-(4,5-dihydro-1H-pyrazol-1-yl)pyrimidines; pyrazolylpyrimidines; sonochemistry; pyrimidines; pyrazoles

Introduction

In the past years, significant efforts have been made in preparing 2-(pyrazol-1-yl)pyrimidines derivatives and several studies have pointed such compounds as promising bioactive molecules. In this direction, epirizole has been therapeutically applied as a nonsteroidal anti-inflammatory and analgesic agent in Japan.¹ Additionally, 2-(pyrazol-1-yl)pyrimidine derivatives have shown ulcerogenicity and protective activity against lesions induced by acidic anti-inflammatory agents in the rat stomach,² as well as fungicidal,³ herbicidal,⁴ and cardiotonic activities.⁵ Recently, several 2-(pyrazol-1-yl)pyrimidines were prepared and they showed efficacy as A_2A adenosine receptor antagonists for the treatment of Parkinson’s disease.^6,7 Moreover, structurally related 4-(pyrazol-4-yl)pyrimidines were recently identified as potent c-Jun N-terminal kinase (JNK)⁸ and cyclin-dependent kinase (CDK)⁹ protein inhibitors with potential application in the treatment of type 2 diabetes and human neoplasia, respectively. In the field of material chemistry, pyrazolylpyrimidines have attracted attention due to potential application as ligands for the synthesis of transition metal complexes¹⁰ which manifest luminescence¹¹ and catalytic activity.¹²

2-(Pyrazol-1-yl)pyrimidines are generally synthesized by the cyclocondensation of 1,3-dieletrophiles and 1-carboxamidino-pyrazoles^13,14 or 2-hidrazinopyrimidines¹⁵ in [3+3] or [3+2] processes, respectively. One-pot cyclocondensation of aminoguanidine bicarbonate with two equivalents of 4-alkoxyvinyl-trifluoromethyl ketones afforded trifluoromethyl-substituted 2-(pyrazol-1-yl)pyrimidines in moderate to good yields in long reaction times (4-8 h) in ethanol under reflux.¹⁶ Similarly, tetraaryl-substituted 2-(pyrazol-1-yl)pyrimidines were obtained in moderate yields when chalcones were used as the 1,3-dielectrophile in the cyclocondensation reaction with aminoguanidine bicarbonate under essentially the same conditions.¹⁷ The disadvantage of using such one-pot reaction is that both pyrazole and pyrimidine rings substituents are the same.

In the last years, our synthetic efforts have focused on the preparation of a variety of heterocyclic compounds^18-21 and in sonochemically promoted reactions in environmentally benign solvents,^22-25 as well as in the biological activity evaluation of the novel molecules.^26-29 The use of ultrasound to accelerate reactions has proven to be a particularly important tool for reaching the green chemistry goals of minimization of waste and reduction of energy requirements.³⁰ In concern, several studies clearly showed the importance of taking advantage of the unique features of ultrasound-assisted reactions in the synthesis of heterocyclic compounds.^31,32

In this context, we report here a clean and straightforward procedure to prepare a series of novel 2-(4,5-dihydro-1H-pyrazol-1-yl)pyrimidines under ultrasonic irradiation using ethanol as a green solvent in short reaction times and dispensing the use of complicated work-up.

Results and Discussion

The building blocks 1-carboxamidino-4,5-dihydro-1H-pyrazoles 1a-k and 4-alkoxyvinyl-trifluoromethyl ketones 2 and 3 were prepared according to previously reported procedures.^22,33 The novel products 4a-k and 5a were obtained in good yields by the ultrasound-promoted cyclocondensation reaction between compounds 1a-k and α,β-unsaturated ketones 2 or 3 in a molar ratio of 1:1 in the presence of 0.5 eq of KOH (Table 1). The reaction time was determined by monitoring the consumption of the starting materials by thin layer chromatography (TLC). The isolation of the pure products was achieved after keeping the crude reaction mixtures in a refrigerator followed by filtration of the white solid precipitates formed. The scope of the methodology is illustrated by the preparation of a series of twelve compounds.

Table 1
Reaction conditions, melting points and yields of synthesized compounds 4a-k and 5a

^aYield of the isolated product; ^bthis reaction was carried out using methanol as solvent.

A mixture of two products was detected by gas chromatography (GC) when 1-carboxamidino-4,5-dihydro-1H-pyrazole 1a and 4-alkoxyvinyl-trifluoromethyl ketone 3 were allowed to react using ethanol as solvent. The mass spectra of these products showed that they correspond to the desired methyl ester derivative and the ethyl ester derivative formed as coproduct due to a partial parallel transesterification reaction. In order to circumvent this mixture formation, methanol was used as solvent for the preparation of the pyrazolylpyrimidine 5a, exclusively.

All the synthesized compounds were fully characterized by ¹H and ¹³C nuclear magnetic resonance (NMR), infrared (IR) spectroscopy and high-resolution mass spectrometry (HRMS) or elemental analysis. The IR, ¹H and ¹³C NMR spectra of products showed sets of signals corresponding to the proposed structures and in agreement with data reported in the literature for analogous molecules.¹⁴ The structures were confirmed by elemental analysis or HRMS.

In order to show the beneficial effect of the ultrasonic irradiation in our sonochemical synthesis, we performed two control experiments in the absence of ultrasonic irradiation: first, the starting materials 1a and 2 were allowed to react for 60 min in 2:2:1 molar ratio with KOH under room temperature in ethanol; then, the reaction was carried out under reflux for 24 h. Under the former silent condition the formation of product 4a was not observed. The reaction conducted under reflux furnished a mixture of 1a and 4a in approximately 1:1 molar ratio, as determined by ¹H NMR.

Although the mechanism of the ultrasound-promoted cyclocondensation reaction was not yet experimentally established, a possible explanation is proposed in Scheme 1. Initially, the reaction involves the attack from 1-carboxamidino-4,5-dihydro-1H-pyrazoles 1 to the β-position of 4-alkoxyvinyl-trifluoromethyl ketones 2, 3, leading to intermediates I which are in equilibrium with II. In the next step, intermediates II eliminate MeOH to give intermediates III. Then an intramolecular nucleophilic attack of imino nitrogen to the carbonyl leads to intermediates IV, which are in equilibrium with V. Finally, the elimination of water from V occurs to give the compounds 4, 5.

Scheme 1
Proposed mechanism for the ultrasound-promoted cyclocondensation reaction.

Conclusions

In summary, we developed an efficient, clean and facile method for the preparation of a series of 2-(4,5-dihydro-1H-pyrazol-1-yl)pyrimidines. Our sonochemical method offers several advantages over existing methods, including improved yields, cleaner reactions, simple work-up and very short reaction times, which makes it an useful and environmentally attractive strategy for the synthesis of pyrazolylpyrimidines derivatives, compounds with promising bioactivity.

Experimental

General methods

The sonicated reactions were carried out with a microtip probe connected to a 500 W Sonics Vibracell ultrasonic processor operating at 20 kHz at 20% of the maximum power output. The progress of reactions was monitored by TLC. Melting points were recorded in open capillary on an Instrutherm DF-3600 II apparatus and are uncorrected. Infrared spectra were acquired on a JASCO-4100 spectrometer as KBr pellets. Low-resolution mass spectra were obtained on a Varian 210 MS connected to a Varian 431 GC. The GC was equipped with a split-splitless injector, cross-linked to a Varian Factor Four™ capillary column (30 m × 0.25 mm), and helium was used as the carrier gas. ¹H and ¹³C NMR spectra were acquired on a Bruker DPX400 spectrometer (400.13 MHz for ¹H and 100.62 MHz for ¹³C) in 5 mm sample tubes at 298 K in CDCl₃ using tetramethylsilane (TMS) as internal standard. The elemental analyses (CHN) were obtained from a PerkimElmer CHN 2400 analyzer. For the high resolution mass analyses, compounds were dissolved in a solution of 50% (v/v) chromatographic grade acetonitrile, 50% (v/v) deionized water and 0.1% formic acid. The solutions were infused directly individually into the electrospray ionization (ESI) source by means of a syringe pump (Harvard Apparatus) at a flow rate of 10 μL min⁻¹. ESI(+)-MS were acquired using a hybrid high-resolution and high accuracy (5 μL L⁻¹) microTof quadrupole time-of-flight (Q-TOF) mass spectrometer (Bruker Scientific) under the following conditions: capillary and cone voltages were set to +3500 and +40 V, respectively, with a de-solvation temperature of 100 °C. The data were collected in the m/z range of 70-700 at the speed of two scans per second, providing the resolution of 50,000 (full width at half maximum (FWHM)) at m/z 200. All reagents and solvents were used as obtained commercially. 1-Carboxamidino-pyrazoles and 4-alkoxyvinyl-trifluoromethyl ketones were prepared by us following reported procedures.^22,33

General procedure for the ultrasound-promoted synthesis of 2-(3,5-diaryl-4,5-dihydro-1H-pyrazol-1-yl)-6-(trifluoromethyl)pyrimidines 4a-k

To a 50 mL vial were added the 1-carboxamidino-4,5-dihydro-1H-pyrazoles 1a-k (0.5 mmol), the 4-alkoxyvinyl-trifluoromethyl ketone 2 (0.5 mmol), ethanol (10 mL) and KOH (0.25 mmol). The reaction mixture was sonicated for 60 min at room temperature (25 °C). The crude products were allowed to cool in a refrigerator. The precipitates obtained were filtered through a Büchner funnel under vacuum, washed with distilled water and dried in a desiccator to give the pure 2-(3,5-diaryl-4,5-dihydro-1H-pyrazol-1-yl)-6-(trifluoromethyl)pyrimidine derivatives 4a-k without further purification.

Procedure for the ultrasound-promoted synthesis of methyl 3-(2-(3,5-diphenyl-4,5-dihydro-1H-pyrazol-1-yl)-6-(trifluoromethyl)pyrimidin-4-yl)propanoate (5a)

To a 50 mL vial were added the 1-carboxamidino-4,5-dihydro-1H-pyrazole 1a (0.5 mmol), the 4-alkoxyvinyl-trifluoromethyl ketone 3 (0.5 mmol), methanol (10 mL) and KOH (0.25 mmol). The reaction mixture was sonicated for 60 min at room temperature (25 °C). The crude products were allowed to cool in a refrigerator. The precipitates obtained were filtered through a Büchner funnel under vacuum, washed with distilled water and dried in a desiccator to give the pure methyl 3-(2-(3,5-diphenyl-4,5-dihydro-1H-pyrazol-1-yl)-6-(trifluoromethyl)pyrimidin-4-yl)propanoate (5a) without further purification.

Characterization data for compounds 4a-k and 5a

2-(3,5-Diphenyl-4,5-dihydro-1H-pyrazol-1-yl)-4-methyl-6-(trifluoromethyl)pyrimidine (4a)

_max / cm^-1 3039, 2918, 1587-1482, 1394, 835-691; ¹H NMR (400 MHz, CDCl₃) δ 2.47 (s, 3H, CH₃), 3.32 (dd, 1H, J5.0, 17.5 Hz, H_A), 3.85 (dd, 1H, J12.0, 17.5 Hz, H_B), 5.74 (dd, 1H, J5.0, 12.0 Hz, H_C), 6.74 (s, 1H, H5), 7.18-7.43 (m, 8H, Ar), 7.84-7.87 (m, 2H, Ar); ¹³C NMR (100 MHz, CDCl₃) δ 24.7, 42.2, 62.2, 106.9 (q, J2.6 Hz, C5), 120.6 (q, J275.2 Hz, CF₃), 126.9, 127.5, 128.5, 130.0, 131.5, 142.2, 153.7, 155.8 (q, J35.5 Hz, C6), 158.2, 171.2; anal. calcd. for C₂₁H₁₇F₃N₄: C, 65.96; H, 4.48; N, 14.65; found: C, 66.06; H, 4.47; N, 14.60. Whitish solid; m.p. 173‑174 °C; IR (KBr) ν

4-Methyl-2-(3-phenyl-5-(p‑tolyl)-4,5-dihydro-1H-pyrazol-1-yl)-6-(trifluoromethyl)pyrimidine (4b)

_max / cm^-1 3059, 3022, 2948, 2921, 1587-1491, 1391, 817-692; ¹H NMR (400 MHz, CDCl₃) δ 2.20 (s, 3H, CH₃), 2.40 (s, 3H, CH₃), 3.22 (dd, 1H, J4.8, 17.5 Hz, H_A), 3.75 (dd, 1H, J11.9, 17.5 Hz, H_B), 5.64 (dd, 1H, J4.8, 11.9 Hz, H_C), 6.67 (s, 1H, H5), 6.99 (d, 2H, J7.8 Hz, Ar), 7.14 (d, 2H, J7.9 Hz, Ar), 7.32-7.34 (m, 3H, Ar), 7.77-7.80 (m, 2H, Ar); ¹³C NMR (100 MHz, CDCl₃) δ 21.0, 24.7, 42.3, 62.0, 106.8 (q, 1H, J2.6 Hz, C5), 120.7 (q, J275.3 Hz, CF₃), 126.5, 127.0, 128.5, 129.2, 129.9, 131.8, 137.2, 139.3, 153.8, 156.0 (q, J34.8 Hz, C6), 158.3, 171.1; HRMS [MH]⁺ calcd. for C₂₂H₂₀F₃N₄: 379.0232; found 379.0247. Whitish solid; m.p. 170‑171 °C; IR (KBr) ν

2-(5-(2-Methoxyphenyl)-3-phenyl-4,5-dihydro-1H-pyrazol-1-yl)-4-methyl-6-(trifluoromethyl)pyrimidine (4c)

_max / cm^-1 3064, 3024, 2967, 2841, 1583-1487, 1387, 1242, 1031, 754‑687; ¹H NMR (400 MHz, CDCl₃) δ2.39 (s, 3H, CH₃), 3.14 (dd, 1H, J5.1, 17.4 Hz, H_A), 3.71 (dd, 1H, J12.1, 17.4 Hz, H_B), 3.77 (s, 3H, OCH₃), 5.95 (dd, 1H, J5.1, 12.1 Hz, H_C), 6.65 (s, 1H, H5), 6.70-6.74 (m, 1H, Ar), 6.79‑6.80 (m, 1H, Ar), 7.04-7.12 (m, 2H, Ar), 7.28-7.33 (m, 3H, Ar), 7.75-7.78 (m, 2H, Ar); ¹³C NMR (100 MHz, CDCl₃) δ 24.7, 41.2, 55.6, 57.7, 106.6 (q, J2.7 Hz, C5), 110.9, 120.6, 120.7 (q, J275.4 Hz, CF₃), 126.9, 127.1, 128.4, 128.4, 129.7, 130.0, 132.0, 154.4, 156.0 (q, J35.4 Hz, C6), 156.7, 158.5, 171.0; HRMS [MH]⁺ calcd. for C₂₂H₂₁F₃N₄O: 413.1589; found: 413.1609. Yellowish solid; m.p. 189-192 °C; IR (KBr) ν

2-(5-(4-Methoxyphenyl)-3-phenyl-4,5-dihydro-1H-pyrazol-1-yl)-4-methyl-6-(trifluoromethyl)pyrimidine (4d)

_max / cm^-1 3065, 3033, 2994, 2832, 1586-1489, 1387, 1244, 1039, 827-691; ¹H NMR (400 MHz, CDCl₃) δ 2.40 (s, 3H, CH₃), 3.24 (dd, 1H, J4.7, 17.6 Hz, H_A), 3.66 (s, 3H, OCH₃), 3.75 (dd, 1H, J12.0, 17.6 Hz, H_B), 5.62 (dd, 1H, J4.7, 11.9 Hz, H_C), 6.67 (s, 1H, H5), 6.71 (d, 2H, J8.7 Hz, Ar), 7.18 (d, 2H, J8.8 Hz, Ar), 7.32-7.33 (m, 3H, Ar), 7.77-7.80 (m, 2H, Ar); ¹³C NMR (100 MHz, CDCl₃) δ 24.7, 42.1, 55.1, 61.6, 106.8 (q, 1H, J2.7 Hz, C5), 120.6 (q, J275.3 Hz, CF₃), 113.8, 124.7, 126.9, 127.9, 128.5, 129.9, 131.6, 134.3, 153.7, 155.8 (q, J35.7 Hz, C6), 158.2, 158.9, 171.1; HRMS [MH]⁺ calcd. for C₂₂H₂₀F₃N₄O: 413.1589; found: 413.1592. Yellowish solid; m.p. 161-163 °C; IR (KBr) ν

2-(5-(4-Chlorophenyl)-3-phenyl-4,5-dihydro-1H-pyrazol-1-yl)-4-methyl-6-(trifluoromethyl)pyrimidine (4e)

_max / cm^-1 3065, 2921, 1587-1491, 1390, 832‑691; ¹H NMR (400 MHz, CDCl₃) δ 2.42 (s, 3H, CH₃), 3.21 (dd, 1H, J4.9, 17.6 Hz, H_A), 3.78 (dd, 1H, J12.1, 17.6 Hz, H_B), 5.63 (dd, 1H, J4.9, 12.0 Hz, H_C), 6.70 (s, 1H, H5), 7.15-7.20 (m, 4H,Ar), 7.33-7.35 (m, 3H, Ar), 7.78-7.80 (m, 2H, Ar); ¹³C NMR (100 MHz, CDCl₃) δ 24.6, 42.2, 61.7, 107.1 (q, J2.6 Hz, C5), 120.6 (q, J275.3 Hz, CF₃), 127.0, 128.0, 128.6, 128.7, 130.1, 131.5, 133.4, 140.8, 153.7, 156.1 (q, J35.7 Hz, C6), 158.1, 171.3; anal. calcd. for C₂₁H₁₆ClF₃N₄: C, 60.51; H, 3.87; N, 13.44; found: C, 60.61; H, 3.89; N, 13.40. Yellowish solid; m.p. 226‑228 °C; IR (KBr) ν

2-(5-(2-Bromophenyl)-3-phenyl-4,5-dihydro-1H-pyrazol-1-yl)-4-methyl-6-(trifluoromethyl)pyrimidine (4f)

_max / cm^-1 3062, 2922, 1585-1490, 1388, 821-691; ¹H NMR (400 MHz, CDCl₃) δ 2.40 (s, 3H, CH₃), 3.10 (dd, 1H, J4.9, 17.8 Hz, H_A), 3.85 (dd, 1H, J12.2, 17.3 Hz, H_B), 6.03 (dd, 1H, J4.9, 12.1 Hz, H_C), 6.71 (s, 1H, H5), 6.98-7.08 (m, 3H, Ar), 7.31-7.32 (m, 3H, Ar), 7.47-7.51 (m, 1H, Ar), 7.76-7.77 (m, 2H, Ar); ¹³C NMR (100 MHz, CDCl₃) δ 24.7, 41.5, 62.0, 107.1 (q, J2.7 Hz, C5), 120.6 (q, J275.2 Hz, CF₃), 122.1, 126.9, 127.8, 128.5, 128.7, 130.0, 131.6, 132.9, 141.1, 153.7, 156.2 (q, J35.7 Hz, C6), 158.3, 171.3; HRMS [MH]⁺ calcd. for C₂₁H₁₇BrF₃N₄: 461.0589; found: 461.0600. Whitish solid; m.p. 215‑218 °C; IR (KBr) ν

2-(5-(3-Bromophenyl)-3-phenyl-4,5-dihydro-1H-pyrazol-1-yl)-4-methyl-6-(trifluoromethyl)pyrimidine (4g)

_max / cm^-1 3065-3008, 2926, 1585-1489, 1390, 831-689; ¹H NMR (400 MHz, CDCl₃) δ 2.46 (s, 3H, CH₃), 3.26 (dd, 1H, J5.1, 17.7 Hz, H_A), 3.81 (dd, 1H, J12.1, 17.7 Hz, H_B), 5.62 (dd, 1H, J5.1, 12.0 Hz, H_C), 6.73 (s, 1H, H5), 7.07 (t, 1H, J7.8 Hz, Ar), 7.19 (d, 1H, J7.8 Hz, Ar), 7.28 (d, 1H, J7.8 Hz, Ar), 7.34-7.37 (m, 3H, Ar), 7.43 (s, 1H, Ar), 7.80-7.82 (m, 2H, Ar); ¹³C NMR (100 MHz, CDCl₃) δ 24.6, 42.1, 61.7, 107.2 (q, J2.7 Hz, C5), 120.5 (q, J275.2 Hz, CF₃), 122.6, 125.2, 127.0, 128.6, 129.7, 130.1, 130.2, 130.7, 131.2, 144.3, 153.9, 156.1 (q, J35.3 Hz, C6), 157.8, 171.3; anal. calcd. for C₂₁H₁₆BrF₃N₄: C, 54.68; H, 3.50; N, 12.15; found: C, 54.86; H, 3.48; N, 12.15. Whitish solid; m.p. 200-201 °C; IR (KBr) ν

2-(5-(4-Bromophenyl)-3-phenyl-4,5-dihydro-1H-pyrazol-1-yl)-4-methyl-6-(trifluoromethyl)pyrimidine (4h)

_max / cm^-1 3063, 3021, 2948, 2918, 1587-1490, 1390, 831-692; ¹H NMR (400 MHz, CDCl₃) δ 2.40 (s, 3H, CH₃), 3.19 (dd, 1H, J5.0, 17.6 Hz, H_A), 3.77 (dd, 1H, J12.0, 17.6 Hz, H_B), 5.61 (dd, 1H, J5.0, 12.0 Hz, H_C), 6.69 (s, 1H, H5), 7.11-7.13 (m, 2H, Ar), 7.30-7.34 (m, 5H, Ar), 7.75-7.78 (m, 2H, Ar); ¹³C NMR (100 MHz, CDCl₃) δ 24.7, 42.1, 61.8, 107.1 (q, J2.5 Hz, C5), 120.6 (q, J275.3 Hz, CF₃); 121.4, 126.9, 128.3, 128.6, 130.1, 131.4, 131.7, 141.3, 153.6, 156.0 (q, J35.5 Hz, C6), 158.2, 171.3; anal. calcd. for C₂₁H₁₆BrF₃N₄: C, 54.68; H, 3.50; N, 12.15; found: C, 54.85; H, 3.51; N, 12.11. Yellowish solid; m.p. 235-238 °C; IR (KBr) ν

2-(5-(2,4-Dichlorophenyl)-3-phenyl-4,5-dihydro-1H-pyrazol-1-yl)-4-methyl-6-(trifluoromethyl)pyrimidine (4i)

_max / cm^-1 3013, 2922, 1587-1490, 1387, 832-689; ¹H NMR (400 MHz, CDCl₃) δ 2.44 (s, 3H, CH₃), 3.11 (dd, 1H, J5.5, 17.6 Hz, H_A), 3.84 (dd, 1H, J12.1, 17.6 Hz, H_B), 6.00 (dd, 1H, J5.5, 12.1 Hz, H_C), 6.74 (s, 1H, H5), 7.02-7.03 (m, 2H, Ar), 7.33-7.35 (m, 4H, Ar), 7.77-7.80 (m, 2H, Ar); ¹³C NMR (100 MHz, CDCl₃) δ 24.7, 41.3, 59.5, 107.3 (q, J2.7 Hz, C5), 120.5 (q, J275.6 Hz, CF₃), 127.0, 127.6, 127.7, 128.6, 129.5, 130.2, 131.5, 133.0, 133.7, 138.3, 153.8, 156.3, 158.3, 171.4; HRMS [MH]⁺ calcd. for C₂₁H₁₆Cl₂F₃N₄: 451.0704; found: 451.0693. Yellowish solid; m.p. 214‑215 °C; IR (KBr) ν

2-(5-(3,4-Dimethoxyphenyl)-3-phenyl-4,5-dihydro-1H-pyrazol-1-yl)-4-methyl-6-(trifluoromethyl)pyrimidine (4j)

_max / cm^-1 3082, 2952‑2832, 1585-1489, 1389, 1238, 1026, 831-691; ¹H NMR (400 MHz, CDCl₃) δ 2.42 (s, 3H, CH₃), 3.73 (s, 3H, OCH₃), 3.74 (s, 3H, OCH₃), 3.27 (dd, 1H, J4.9, 17.6 Hz, H_A), 3.76 (dd, 1H, J12.1, 17.8 Hz, H_B), 5.61 (dd, 1H, J4.9, 12.0 Hz, H_C), 6.68-6.69 (m, 1H, Ar), 6.69 (s, 1H, H5), 6.80-6.82 (m, 2H, Ar), 7.33-7.34 (m, 3H, Ar), 7.79-7.81 (m, 2H, Ar); ¹³C NMR (100 MHz, CDCl₃) δ 24.7, 42.3, 55.9, 62.0, 106.8 (q, J2.6 Hz, C5), 110.4, 111.5, 118.8, 120.7 (q, J275.2 Hz, CF₃), 126.9, 128.5, 129.9, 131.7, 135.1, 148.6, 149.1, 153.7, 155.9 (q, J35.4 Hz, C6), 158.4, 171.1; HRMS [MH]⁺ calcd. for C₂₃H₂₂F₃N₄O₂: 443.1695; found: 443.1710. Yellowish solid; m.p. 140-142 °C; IR (KBr) ν

4-Methyl-2-(3-phenyl-5-(3,4,5-trimethoxyphenyl)-4,5-dihydro-1H-pyrazol-1-yl)-6-(trifluoromethyl)pyrimidine (4k)

_max / cm^-1 3076, 2959-2825, 1584-1487, 1385, 1245, 1010, 833-693; ¹H NMR (400 MHz, CDCl₃) δ 2.44 (s, 3H, CH₃), 3.28 (dd, 1H, J5.4, 17.7 Hz, H_A), 3.70 (s, 6H, OCH₃), 3.71 (s, 3H, OCH₃), 3.77 (dd, 1H, J12.1, 17.7 Hz, H_B), 5.57 (dd, 1H, J5.3, 12.0 Hz, H_C), 6.49 (s, 2H, Ar), 6.71 (s, 1H, H5), 7.32-7.35 (m, 3H, Ar), 7.78-7.80 (m, 2H, Ar); ¹³C NMR (100 MHz, CDCl₃) δ 24.6, 42.3, 56.1, 60.7, 103.9, 107.0 (q, J2.6 Hz, C5), 120.6 (q, J275.4 Hz, CF₃), 126.9, 128.5, 130.0, 131.5, 137.7, 138.0, 153.4, 153.9, 156.0 (q, J35.0 Hz, C6), 158.3, 171.1; anal. calcd. for C₂₄H₂₃F₃N₄O₃: C, 61.01; H, 4.91; N, 11.86; found: C, 61.17; H, 4.91; N, 11.84. Yellowish solid; m.p. 214‑217 °C; IR (KBr) ν

Methyl 3-(2-(3,5-diphenyl-4,5-dihydro-1H-pyrazol-1-yl)-6-(trifluoromethyl)pyrimidin-4-yl)propanoate (5a)

_max / cm^-1 3085, 3023, 2950-2917, 1735, 1584-1486, 864-700; ¹H NMR (400 MHz, CDCl₃) δ 2.58 (m, 2H, CH₂), 2.90 (m, 2H, CH₂), 3.21 (dd, 1H, J5.1, 17.5 Hz, H_A), 3.56 (s, 3H, CO₂CH₃), 3.76 (dd, 1H, J12.0, 17.5 Hz, H_B), 5.61 (dd, 1H, J5.1, 12.0 Hz, H_C), 6.70 (s, 1H, H5), 7.10-7.24 (m, 5H, Ar), 7.31-7.33 (m, 3H, Ar), 7.75-7.77 (m, 2H, Ar); ¹³C NMR (100 MHz, CDCl₃) δ 31.1, 32.4, 42.4, 51.6, 62.5, 106.4 (q, J2.7 Hz, C5), 120.6 (q, J75.4 Hz, CF₃), 126.2, 126.9, 127.4, 128.5, 128.6, 129.9, 137.7, 142.4, 153.7, 156.4 (q, J35.5 Hz, C6), 158.3, 172.1, 172.8; anal. calcd. for C₂₄H₂₁F₃N₄O₂: C, 63.43; H, 4.66; N, 12.33; found: C, 63.61; H, 4.69; N, 12.28. Yellowish solid; m.p. 157‑160 °C; IR (KBr) ν

• Supplementary Information
  Supplementary information (1H and 13C NMR spectra) is available free of charge at http://jbcs.sbq.org.br as PDF file.
• FAPESP has sponsored the publication of this article.
  FAPERGS has sponsored the publication of this article.

Acknowledgments

We acknowledge Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, 483021/2013-0) and Fundação de Apoio ao Desenvolvimento do Ensino, Ciência e Tecnologia do Estado de Mato Grosso do Sul (FUNDECT, 0180/12) for financial support. We are grateful to Prof Sidnei Moura (Universidade de Caxias do Sul) for the HRMS analysis.

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Data availability

https://minio.scielo.br/documentstore/1678-4790/nDrgD5QWxyZnJgjykDd4Fnv/76250d09e75eacd90389ca7475b4460eca7cf157.pdf

Publication Dates

• Publication in this collection
  June 2015

History

• Received
  07 Jan 2015
• Accepted
  31 Mar 2015