5-Methyl-1-phenyl-3-(thieno[2,3-d]pyrimidin-4-yl)chromeno[4,3-d]pyrazolo[3,4-b]pyridin-6(3H)-one

Abstract

A chromeno[4,3-d]pyrazolo[3,4-b]pyridinone derivative 3 bearing thieno[2,3-d]pyrimidine moiety, 5-methyl-1-phenyl-3-(thieno[2,3-d]pyrimidin-4-yl)chromeno[4,3-d]pyrazolo[3,4-b]pyridin-6(3H)-one, was efficiently prepared in 75% yield by the reaction of 3-phenyl-1-(thieno[2,3-d]pyrimidin-4-yl)-1H-pyrazol-5-amine 1 with 3-acetyl-2H-chromen-2-one 2 in the presence of FeCl₃-SiO₂ as a catalyst in refluxing ethanol for 6 h. The structure of the new synthesized compound was characterized by ¹H-, ¹³C- NMR, IR spectroscopy, mass-spectrometry, and elemental analysis.

1. Introduction

Many coumarin-based derivatives have been synthesized and explored due to considerable attention to their biological properties and therapeutic potentials. They displayed diverse biological and pharmacological activities, such as antimicrobial [1], anticonvulsant [2], anticancer [3], and antiviral [4] activities. Coumarin derivatives with intramolecular charge transfer character have also been investigated and applied in fluorescence sensors [5,6]. Pyrazolo[3,4-b]pyridine and its derivatives are known to have a wide range of biological activities such as anticancer [7], anti-inflammatory [8], and neuroactive agent [9]. Fused pyrazolo[3,4-b]pyridines showed photochemical properties of high fluorescence [10]. On the other hand, thieno[2,3-d]pyrimidine derivatives [11] continue to attract considerable interest in medicinal chemistry because of remarkable biological properties such as antibacterial [12], anticancer [13], antimalarial [14], and anti-inflammatory [15,16] activities. However, there are only a few reports on the synthesis of fused coumarin-pyrazolo[3,4-b]pyridine derivatives [17,18]. We report herein the synthesis of a hybrid compound 3 associated with these two pharmacophores, bearing thieno[2,3-d]pyrimidine moiety.

2. Results

The target compound 3 was prepared as shown in Scheme 1. The starting material 1, 3-phenyl-1-(thieno[2,3-d]pyrimidin-4-yl)-1H-pyrazol-5-amine, was obtained according to the previously reported procedure [19]. When 1 was allowed to react with 3-acetyl-2H-chromen-2-one 2 in refluxing ethanol for 6 h in the presence of FeCl₃ adsorbed on silica gel [20] as a catalyst, a fused tetracyclic compound 3, 5-methyl-1-phenyl-3-(thieno[2,3-d]pyrimidin-4-yl)chromeno[4,3-d]pyrazolo[3,4-b]pyridin-6(3H)-one, was formed in 75% yield. The use of the heterogeneous catalyst, FeCl₃-SiO₂, for this reaction has the advantages of low cost, easy work-up, and enhanced yield compared to FeCl₃ alone (69% yield) or other catalysts [18]. The ¹H-NMR spectrum of 3 showed exhibited the expected pattern with a sharp singlet δ 9.24 ppm attributed to a pyrimidine proton and two doublets δ 7.94 and 7.63 (J = 5.7 Hz, respectively) ppm for thiophene protons in thieno[2,3-d]pyrimidine ring (Supplementary Materials). Two multiplet signals from the protons of phenyl bonded to the pyrazole ring were observed at δ 7.60—7.58 and 7.48—7.44 ppm, respectively. It is noteworthy that one of the aromatic protons of the coumarin ring appeared at δ 6.73 (t, 1H, J = 7.4 Hz) in a higher field, whereas others were found at δ 7.52 (m, 1H), 7.38 (d, 1H, J = 7.3 Hz) and 7.34 (d, 1H, J = 7.4 Hz), respectively. This may be attributed to the through-space anisotropic effect of the phenyl group attached to the pyrazole ring on this proton of the coumarin ring. It presented a sharp signal at δ 3.25 ppm attributed to methyl proton in the pyridine ring of 3. In the ¹³C-NMR spectrum, compound 3 showed a peak δ 28.5 ppm for a methyl carbon, including six carbons for thienopyrimidine ring and tetracyclic carbons having a phenyl group shown at δ 171.8–108.1 ppm. The IR spectrum revealed a characteristic CO absorption at 1722 cm⁻¹. The mass spectrum showed m/z = 461 (M⁺) corresponding to the molecular formula, C₂₆H₁₅N₅O₂S. The elemental analysis also provided satisfactory results.

In conclusion, a hybrid compound 3, fused coumarin-pyrazolo[3,4-b]pyridine derivative bearing thieno[2,3-d]pyrimidine moiety, was synthesized efficiently by the reaction of 3-phenyl-1-(thieno[2,3-d]pyrimidin-4-yl)-1H-pyrazol-5-amine 1 with 3-acetyl-2H-chromen-2-one 2 in the presence of FeCl₃-SiO₂ in refluxing ethanol. This compound could be useful as a potential material having biological activities or photochemical properties of fluorescence.

3. Materials and Methods

3.1. General Information

All chemicals and reagents were purchased from Sigma-Aldrich (St. Louis, MO, USA) and TCI (Tokyo, Japan). The solvents used were purified using standard techniques. Melting point was determined on Kofler apparatus. Thin-layer chromatography (TLC) was used to monitor reactions and performed using aluminum sheets precoated with silica gel 60 (HF₂₅₄, Merck, Waltham, MA, USA) and visualized with UV radiation (Fisher Scientific, Waltham, MA, USA). The ¹H- and ¹³C- NMR spectra were recorded in deuterated chloroform with TMS as the standard on a Bruker Avancell 500 FT-NMR. The IR spectrum was recorded on Bruker Invenio FT-IR (Billerica, MA, USA). The mass spectrum was obtained with Agilent 6890 Mstation instrument (Santa Clara, CA, USA).

3.2. Synthesis of 5-Methyl-1-phenyl-3-(thieno[2,3-d]pyrimidin-4-yl)chromeno[4,3-d]pyrazolo-[3,4-b]pyridin-6(3H)-one (3)

A solution of 3-phenyl-1-(thieno[2,3-d]pyrimidin-4-yl)-1H-pyrazol-5-amine 1 (293 mg, 1.0 mmol), 3-acetyl-2H-chromen-2-one 2 (188 mg, 1.0 mmol), and FeCl₃-SiO₂ (176 mg, 0.01 mmol FeCl₃) in ethanol (20 mL) was refluxed at 80 °C with stirring. After completion of the reaction (6 h, monitored by TLC), the mixture was cooled, filtered, and washed with ethanol. The filtrate was evaporated in vacuo, and the collected solid was recrystallized from chloroform to give light yellow solid of 3 in 75% yield (345 mg). Mp 294–295 °C; TLC Rf = 0.42 (fluorescent blue spot, dichloromethane:MeOH = 40:1). ¹H-NMR (500 MHz, CDCl₃) (ppm) δ 9.24 (s, 1H), 7.94 (d, J = 5.7 Hz, 1H), 7.63 (d, J = 5.7 Hz, 1H), 7.60–7.58 (m, 2H), 7.52 (m, 1H), 7.48–7.44 (m, 3H), 7.38 (d, 1H, J = 7.3 Hz), 7.34 (d, 1H, J = 7.4 Hz), 6.73 (t, 1H, J = 7.4 Hz), 3.25 (s, H). ¹³C-NMR (125 MHz, CDCl₃) (ppm) δ 171.8, 165.5, 159.6, 153.5, 153.1, 152.8, 151.6, 149.9, 142.5, 133.6, 133.1, 131.6, 129.8, 129.6, 127.4, 123.1, 123.0, 122.2, 117.0, 115.4, 112.6, 108.1, 28.5. IR (KBr) 1722, 1429 cm⁻¹. MS (EI) m/z = 461 (M⁺, 100%). Anal. calc. for C₂₆H₁₅N₅O₂S, %: C, 67.67; H, 3.28; N, 15.18. Found, %: C, 67.78; H, 3.11; N, 15.29.

Author Contributions

Conceptualization, Y.-H.S.; methodology, X.Y. and Y.-H.S.; investigation, X.Y.; writing—original draft preparation, Y.-H.S.; writing—review and editing, Y.-H.S. All authors have read and agreed to the published version of the manuscript.

Data Availability Statement

Not applicable.

Acknowledgments

This work was supported by Mokwon University.

Conflicts of Interest

The authors declare no conflict of interest.

Sample Availability

Samples of the compounds are available from the authors.

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Scheme

Scheme 1. Synthesis of the target compound 3.

Supplementary Materials

The following supporting information can be downloaded online. ¹H-NMR, ¹³C-NMR, Mass, and IR spectra of compound 3.

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