3-(4-Fluorophenyl)-1-(1-(4-fluorophenyl)-3,3,3-trifluoroprop-1-en-1-yl)-5-fluoro-1H-pyrazole

Abstract

In this work, the title compound was synthesized via the visible-light-induced radical denitrogenative trifluoromethylation of the corresponding vinyl azide followed by Cs₂CO₃-mediated defluorinative cyclization of the resultant azine. The widely available sodium trifluoromethanesulfinate is used as a precursor of CF₃ radicals, while graphitic carbon nitride (g-C₃N₄) is employed as an environmentally friendly, cheap, and efficient heterogeneous photocatalyst. The structure of the synthesized compound was established by ¹H, ¹³C, ¹⁹F-NMR, IR spectroscopy, and mass-spectrometry.

1. Introduction

The development of new methods for the synthesis of organofluorine compounds is among the most urgent tasks of modern organic and medicinal chemistry [1,2]. Since the middle of the last century, organofluorine bioactive compounds have accounted for 5–15% of the annual number of new drugs approved on the world pharmaceutical market [3,4]. Fluorinated heterocyclic compounds [5,6], including pyrazoles [7], are often found among biorelevant structures. In this regard, the demand for the incorporation of fluorine atoms and fluorine-containing functional groups into organic molecules is constantly growing.

One of the most powerful and widely used tools in the chemistry of organofluorine compounds is radical fluoroalkylation [8,9] and, in particular, trifluoromethylation. It is known that the introduction of the CF₃ group into a molecule can enhance its ability to permeate through biological membranes, increase the strength of binding to target receptors, and improve metabolic stability [10]. Recently, significant advances were achieved in the field of photochemical radical fluoroalkylation [11,12]. Photoredox catalysis allows one to selectively introduce fluoroalkyl moiety under mild conditions with the use of available and stable precursors of fluorinated radicals [13]. Therefore, the search for new efficient photocatalytic systems is quite topical.

As an alternative to traditional homogeneous (molecular) photocatalysis, heterogeneous photocatalysis on semiconductors is gaining increasing attention [14]. Visible light-induced heterogeneous photocatalysis with semiconducting graphitic carbon nitride (g-C₃N₄) provided an excellent platform for the introduction of the CF₃ group into various classes of substrates, including heterocyclic compounds [15,16]. g-C₃N₄ is characterized by its stability, ease of production and separation, high efficiency under visible light irradiation, and powerful oxidizing and reduction abilities [17,18].

In this work, a one-pot synthetic radical transformation of vinyl azide 1 leading to the formation of fluorinated trisubstituted pyrazole 2 was implemented (Scheme 1).

2. Results and Discussion

At the first stage, the interaction between 1-(1-azidovinyl)-4-fluorobenzene 1 and sodium trifluoromethanesulfinate (Langlois reagent) under the g-C₃N₄-mediated heterogeneous photocatalytic conditions was performed (Scheme 2). The reaction proceeds under irradiation with a high-power blue (450 nm) LED lamp in an air atmosphere in DMSO. In this process, the photoexcited g-C₃N₄ acts as an electron acceptor due to its hole-electron semiconductor nature. Oxidation of the CF₃SO₂ anion leads to the formation of trifluoromethyl radicals with the extrusion of the SO₂ molecule. Then, the CF₃ radical is added to the terminal carbon atom of the C=C double bond of vinyl azide 1 [19]. This addition leads to the elimination of nitrogen molecule and the formation of N-centered iminyl radicals prone to dimerization with the formation of an N–N bond [20].

The resulting intermediate azine was used in the next step without isolation and purification. The cyclization reaction was carried out for 2 h at 100 °C in DMSO. Cesium carbonate was used as the base. Transformation proceeds with the elimination of two hydrogen fluoride molecules from the azine molecule [21]. The structure of compound 2 was confirmed by ¹H, ¹³C, and ¹⁹F NMR spectroscopy, high-resolution mass spectrometry, and FT-IR spectroscopy (Figures S1–S5, Supplementary Materials).

3. Materials and Methods

3.1. General

1-(1-azidovinyl)-4-fluorobenzene (1) [22] and g-C₃N₄ [23] were prepared according to the published methods. All commercially available reagents and solvents were used without purification. ¹H, ¹³C NMR, and ¹⁹F NMR spectra were taken with a Bruker AM-300 machine (Bruker AXS Handheld Inc., Kennewick, WA, USA) (at frequencies of 300, 75, and 282 MHz) in CDCl₃ using the residual solvent peak as a reference. J values are given in Hz. The high-resolution mass spectrum was measured on a Bruker microTOF II instrument using electrospray ionization (ESI). FT-IR spectra were recorded on a Bruker ALPHA FT-IR spectrometer. The TLC analysis was carried out on silica gel chromatography plates Macherey-Nagel Alugram UV254 (Macherey-Nagel GmbH & Co. KG, Düren, Germany). The melting points were determined on a Stuart SMP10 Kofler hot-stage apparatus (Stuart Scientific Co. Ltd., Staffordshire, UK). Chromatography of final product was performed on silica gel (0.060–0.200 mm, 60 Å, CAS 7631-86-9).

3.2. 3-(4-Fluorophenyl)-1-(1-(4-Fluorophenyl)-3,3,3-Trifluoroprop-1-en-1-yl)-5-Fluoro-1H-Pyrazole (2)

A 10 mL test tube was charged with vinyl azide (1) (82 mg, 0.5 mmol), sodium trifluoromethanesulfinate (156 mg, 1.0 mmol), g-C₃N₄ (30 mg), and DMSO (5 mL). Reaction mixture was stirred for 24 h at 28−30 °C under air atmosphere while irradiated with 36 W 450 nm LED. After that, Cs₂SO₃ (0.6 mmol, 196 mg) was added, and reaction mixture was stirred at 100 °C for 2 h. Upon completion, the reaction mixture was cooled to room temperature, diluted with water (100 mL), and extracted with DCM (3 × 20 mL). Combined organic phases were dried over anhydrous Na₂SO_4, and rotary evaporated. The crude product was purified by column chromatography (hexane/dichloromethane, 1:1, v/v) to afford 77 mg (42%) of target compound (2) as a light-yellow oil, Rf = 0.50 (hexane/dichloromethane, 1:1, v/v). ¹H NMR (CDCl₃, ppm): δ 7.75 (dd, J = 8.8, 5.4, 2H), 7.43 (dd, J = 8.8, 5.4, 2H), 7.20–7.05 (m, 4H), 6.46 (q, J = 7.9, 1H), and 6.13 (d, J = 5.1, 1H). ¹³C NMR (CDCl₃, ppm): δ 164.1 (d, J = 251.2), 163.6 (d, J = 248.8), 158.7 (d, J = 282.9), 151.1 (d, J = 10.4), 131.3 (dq, J = 9.1, 1.5), 129.0, 127.6 (d, J = 8.4), 127.1, 123.0 (q, J = 271.3), 116.0 (d, J = 21.8), 115.7 (d, J = 22.1), 110.2 (q, J = 35.7), and 87.0 (d, J = 14.2). ¹⁹F NMR (CDCl₃, ppm): δ −54.62 (d, J = 8.4), −109.34 (tt, J = 8.4, 5.1), −111.89 (tt, J = 8.4, 5.1), and −122.44 (d, J = 8.4). IR spectrum, ν, cm⁻¹: 2104, 1662, 1607, 1586, 1530, 1512, 1477, 1447, 1364, 1265, 1234, 1160, 1123, and 841. HRMS (ESI-TOF), m/z: calcd for C₁₈H₁₀F₆N₂ [M + H]⁺, 369.0821, found, 369.0821.

4. Conclusions

Previously unknown 3-(4-fluorophenyl)-1-(1-(4-fluorophenyl)-3,3,3-trifluoroprop-1-en-1-yl)-5-fluoro-1H-pyrazole (2) was obtained with a yield of 42% via a one-pot synthetic sequence, including g-C₃N₄-catalyzed heterogeneous photochemical trifluoromethylation of vinyl azide 1 with sodium trifluoromethanesulfinate as the CF₃-radical source under visible-light irradiation and defluorinative cyclization of intermediate azine under basic conditions. The structure of the compound was confirmed by NMR spectroscopy, mass spectrometry, and IR analysis.