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28 April 2025

6,7,8,9-Tetrafluoro-11H-indeno[1,2-b]quinoxalin-11-one

,
,
and
1
Kizhner Research Center, National Research Tomsk Polytechnic University, 634050 Tomsk, Russia
2
Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia
*
Author to whom correspondence should be addressed.
Molbank2025, 2025(2), M2001;https://doi.org/10.3390/M2001
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Abstract

Fluorinated aza-heterocycles are important in organic and medicinal chemistry. Currently, a quarter of the drugs on the global market contain fluorine. We report the synthesis of the title compound and its single-crystal XRD structure.

1. Introduction

Fluorine is massively involved in chemistry and biomedicine with special emphasis on drug design. Replacing hydrogen atoms in organic compounds with fluorine atoms often produces positive pharmacological and physicochemical effects, particularly by increasing compounds’ metabolic stability, membrane permeability, and binding affinity towards biological targets. At present, a quarter of the drugs on the global market contain fluorine. Of these, heterocyclics are essentially important [1,2,3,4,5,6,7,8,9,10].
Similarly to many other aza-heterocyclics, quinoxalines are promising for the design and synthesis of new bioactive substances [11]. They exhibit a wide range of pharmacological activities encompassing, for example, anti-HIV [12], anti-inflammatory, anti-tumor [13] and anti-depressant [14] effects. Indenoquinoxalines are currently of interest as antioxidants and anticancer agents [15]. Low-fluorinated indenoquinoxalines, e.g., compound A, display exciting antitumor properties and c-Jun N-terminal kinase (JNK) inhibitory activity [16] (note that JNK plays a key role in the pathogenesis of serious diseases such as Alzheimer’s, Parkinson’s, cardiovascular diseases, and ischemic damage). Re(I) complexes that contain fluorinated indenoquinoxaline ligand B are effective against MCF-7 cancer cells [17]. Compound C is able to effectively intercalate with DNA [18], whereas compound D is a hepatocellular carcinoma (HCC) drug targeting the tyrosine kinase [19] (for A–D, see Scheme 1).
Scheme 1. Selected bioactive fluorinated indenoquinoxalines.
Alongside this, there is an emerging interest in highly fluorinated chemotypes [20,21,22], which include still-unknown highly fluorinated indenoquinoxalinones. Here, we report on synthesis of 6,7,8,9-tetrafluoro-11H-indeno[1,2-b]quinoxalin-11-one and elucidate its structure by means of single-crystal XRD.

2. Results and Discussion

Synthesis and Molecular and Crystal Structure

The target indenoquinoxalinone (compound 3, Scheme 2) was synthesized by the Körner–Hinsberg-type condensation of 1,2-diamino-3,4,5,6-tetrafluorobenzene [23] with ninhydrin (compounds 1 and 2, respectively; Scheme 2) in THF. The structure of 3 was confirmed by single-crystal XRD (Figure 1), multinuclear NMR, LC-MS, and elemental analysis. The compound is a fluorophore emitting at 490 nm in CHCl3 solution.
Scheme 2. Synthesis of indenoquinoxalinone 3.
Figure 1. XRD molecular structure of 3 (CCDC 2433446; thermal ellipsoids at 50% probability). The molecule is perfectly planar; the standard deviations from the mean plane are 0.055 Å. The bond distances and bond angles correspond to the statistical means [24]. Color code: C, gray; H, light gray; F, green; N, blue; O, red.
In its crystal form, 3 exhibits infinite π-stacks with an interplanar separation of ~3.36 Å; the sums of the van der Waals (VdW) radii of the C and E atoms are ~3.54 and 3.43 Å for E = C and N, respectively [25]. The stacks are connected by C–H···O hydrogen bonds featuring a H···O distance of ~2.32 Å (the sum of the VdW radii is ~2.70 Å [25]) and a C–H···O angle of 168°. The F atoms reveal F···π orientations; however, the atom-to-plane F···π distances of ~3.21–3.63 Å are close to or exceed the sum of the VdW radii of the C and F atoms, which are equal to 3.23 Å [25] (see CCDC 2433446 for 3D visualization and details). Such secondary bonding interactions in the crystalline state are typical of fluoroorganics [26].

3. Materials and Methods

3.1. General

XRD was carried out with a Bruker Kappa Apex CCD diffractometer. The 1H (400 MHz), 13C (100 MHz), and 19F (376 MHz) NMR spectra were collected using a Bruker AVANCE III HD spectrometer. The chemical shifts, δ, were measured with respect to TMS (1H, 13C) and C6F6 (δ = −162.9 ppm with respect to CFCl3). LC-MS analysis was performed with a DFS Thermo Electron Corporation instrument. Electronic absorption (UV-Vis) and emission (FL) spectra were measured on Varian Cary 5000 and Varian Cary Eclipse spectrophotometers, respectively. The elemental analysis for C, H, N, and F was performed with a Carlo Erba Model 1106 instrument. The melting point of 3 was measured using a Melting Point Apparatus SMP30 at a heating rate of 2.5 °C min−1.

3.2. Synthesis

A stirring solution of 786 mg (4.4 mmol) of 1 and 776 mg (4.4 mmol) of 2 in 50 mL of dried THF was refluxed for 5 h. The solvent was distilled off under reduced pressure, and a dark red solid was chromatographed on a silica column with chloroform. The bright yellow zone collected was evaporated, and the residue was recrystallized using acetone. Compound 3 was obtained in the form of yellow plates (907 mg, 69%), m. p. 276–279 °C (from ethanol). Single crystals suitable for XRD were obtained by recrystallization using chloroform. The following ratios were found/calculated for C15H4F4N2O, in %: C 58.91/59.23, H 1.07/1.33, F 25.80/24.98, N 9.08/9.21. NMR (CDCl3; ESI, Figures S1–S3), δ, ppm (J, Hz): 1H (for atom numbering, see Figure 2)—7.68 (dt, J = 7.6, J = 1, 1H, H-16), 7.82 (dt, J = 7.5, J = 1, 1H, H-17), 7.95 (d, J = 7.6, 1H, H-15), 8.17 (d, J = 7.6, 1H, H-14). 13C—187.7, 157.3, 150.3, 143.4, 142.9, 142.4, 141.1, 140.4, 137.3, 136.9, 133.7, 129.9, 129.4, 125.2, 123.4. 19F—13.9, 13.5, 10.9, 9.8; ESI LC-MS: M+, m/z: measured 304.0256 [C15H4F4N2O + H]+, calculated 304.0254. UV-Vis (CHCl3) λmax, nm (log ε) 298 (4.49); FL (CHCl3) λmax em/ex, nm: 490/400.
Figure 2. Atom numbering to assign 1H NMR spectrum of 3.

3.3. X-Ray Diffraction

XRD data for 3 (CCDC 2433446) were obtained at 296 K with a Bruker Kappa Apex II CCD diffractometer using φ and ω scans of narrow (0.5°) frames with Mo Kα radiation (λ = 0.71073 Å) and a graphite monochromator. The structure was solved by direct methods using the SHELXT 2014/5 programs set [27] and refined by the full-matrix least-squares method against all F2 in anisotropic approximation using the SHELXL-2018/3 programs set [27]. The H atoms’ positions were calculated with the riding model. Absorption corrections were applied empirically using SADABS programs [28]. Compound 3 crystallizes in an orthorhombic system with the space group P212121, a = 5.5581(3), b = 6.2028(4), c = 34.309(2) Å, V = 1182.8(1) Å3, Z = 4, C15H4F4N2O, Dc = 1.708 g cm−3, μ = 0.153 mm−1, F(000) = 608, crystal size 0.90 × 0.50 × 0.10 mm3, 2252 independent reflections (Rint. = 0.020), θmax = 27.5°, wR2 = 0.0845, and S = 1.03 for all reflections (R = 0.0332 for 1996 F > 4σ). The obtained crystal structures were analyzed for shortened contacts between non-bonded atoms using the PLATON program [29].

4. Conclusions

The new highly fluorinated title compound 3 was synthesized and unambiguously structurally characterized for further biomed studies.

Supplementary Materials

Figures S1–S3 (1H, 13C, and 19F NMR spectra of 3).

Author Contributions

Conceptualization was conducted by A.R.K., A.V.Z. and A.I.K.; experiments were carried out by A.R.K. and I.Y.B.; data analysis and the writing of the initial manuscript were performed by A.R.K., I.Y.B. and A.I.K.; editing of the final version of the manuscript was performed by A.R.K., A.I.K., A.V.Z. and I.Y.B.; project administration and supervision were conducted by A.I.K. All authors have read and agreed to the published version of the manuscript.

Funding

This research was supported by the Russian Science Foundation (project no. 24-73-00202).

Data Availability Statement

Experimental data associated with this research are available from the authors. Crystallographic data for compound 3 were deposited at the Cambridge Crystallographic Data Centre, CCDC 2433446. Copies of the data can be obtained free of charge from the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK (Fax: +44-1223-336-033; e-mail: deposit@ccdc.cam.ac.uk).

Acknowledgments

The authors are grateful to Arkady G. Makarov for his participation in preliminary experiments and his helpful discussions.

Conflicts of Interest

The authors declare no conflicts of interest.

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