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

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).

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.

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) λ_max, nm (log ε) 298 (4.49); FL (CHCl₃) λ_max em/ex, nm: 490/400.

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) ų, Z = 4, C₁₅H₄F₄N₂O, D_c = 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 (R_int. = 0.020), θ_max = 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.