1-(4-Fluorobenzoyl)-9H-carbazole

Abstract

1-(4-Fluorobenzoyl)-9H-carbazole (1) was synthesized, starting from 9H-carbazole and 4-fluorobenzonitrile, by Friedel–Crafts acylation, using boron trichloride to direct the substitution in 1-position. Single-crystal X-ray diffraction analysis unambiguously revealed the molecular structure of 1.

1. Introduction

9H-Carbazole, an aromatic three-membered heterocycle, is a structural motif that is present in several bioactive natural compounds [1]. Thus, methods for the synthesis and functionalization of this heterocycle are important.

In general, access to 1-aroyl-substituted carbazoles was reported, using lithiation as a key step [2], a Suzuki–Miyaura type coupling reaction starting from 1-(9H-carbazole)-boronic acid [3], and ruthenium-catalyzed [4,5] or photochemical [6] rearrangements. The Friedel–Crafts reaction between carbazole and benzoyl chloride was utilized, but resulted in a mix of four benzoylated products with 3,6-di-benzoyl-9H-carbazole as the main product [7]. Recently, intramolecular cyclization using metal-free CH-bond activation [8] or palladium-catalyzed oxidative acylations [9], leading to N-pyridinyl-protected carbazoles, was reported, offering access to 1-aroyl-substituted carbazoles after deprotection.

Based on our interest in the development of ¹⁸F-labeled COX-2 inhibitors [10,11,12], we were interested in using 1-(4-fluorobenzoyl)-9H-carbazole (1) as a building block to design a new class of cyclooxygenase-2 inhibitors. We decided to utilize BCl₃-mediated Friedel–Crafts acylation for the synthesis of 1, because the use of BCl₃ allows for the selective ortho-benzoylation of primary and secondary aromatic amines and has been successfully used in the synthesis of 1-cyano- and 1-alkylthiocarbonyl-substituted 9H-carbazoles [13]. Herein, we report the synthesis and structural characterization of 1.

2. Results and Discussion

In analogy to a procedure described by Lo et al. [14], 1 was successfully synthesized by BCl₃-mediated Friedel–Crafts acylation, starting from 9H-carbazole and 4-fluorobenzonitrile (Scheme 1). The reaction mechanism is suggested to follow the mechanism known in the literature, which involves (1) the formation of 9-(dichloroboryl)-9H-carbazole and, subsequently, a six-membered complex with the nitrile group of 4-fluorobenzonitrile; (2) the Friedel–Crafts reaction, which leads to 1-aroylation due to the spatial proximity; (3) hydrolysis of the ketimine with HCl [15]. This gave 1 as a crude product, which was purified by column chromatography and finally isolated with a 38% yield. Crystals suitable for single-crystal X-ray diffraction experiments were isolated and analyzed.

The molecular structure of 1 is shown in Figure 1. A moderate intramolecular N1−H···O1 hydrogen bonds with a donor-acceptor distance of 3.055(1) Å causes the orientation of the carbonyl moiety to almost occur in a plane with the carbazole moiety. The fluoro-substituted phenyl ring is twisted out of the plane of the carbazole moiety with a dihedral angle of 54.9°.

In the plane (0,0,1), the molecules are packed in chains along the a-axis, which are oriented anti-parallel, in the direction [0,0,1]. This is due to the intermolecular N1−H∙∙∙O1 hydrogen bonds between the carbonyl and amine groups with D∙∙∙A = 3.056(1) Å) and π∙∙∙π-interactions. Further weak hydrogen bonds between fluorine and the C5−H group of the neighboring phenyl ring at a D∙∙∙A distance of 3.397(1) Å cause binding along the b-axis. The weak interactions are shown in Figure 2 as dashed lines.

3. Materials and Methods

3.1. General

All commercial reagents and solvents were used without further purification. NMR spectra were recorded on a Varian Inova-400 and referenced to the residual solvent shifts for ¹H and ¹³C, and to CFCl₃ for ¹⁹F spectra as internal standard. J-Values are given in Hz. Carbazole and phenyl are abbreviated as Ca and Ph, respectively. UPLC-MS was performed using the following system: column Aquity UPLC^® BEH C18 column (Waters, 100 × 2.1 mm, 1.7 µm, 130 Å), UPLC I-Class (Waters, Milford, MA, USA): binary gradient pump BSM, autosampler FTN, column manager CM, and diode array detector PDAeλ coupled to Waters Xevo TQ-S, flow rate 0.4 mL/min, eluent: (A): 0.1% acetic acid in MeCN/MeOH 1/1/ (B): 0.1% acetic acid in H₂O; gradient: t_{0 min} 45/55-t₀._{5 min} 45/55-t_{5.5 min} 95/5-t_{7.0 min} 95/5-t_{8.0 min} 45/55-t_{8.5 min} 45/55). The crystallographic data were collected with a Bruker-Nonius APEX-II CCD diffractometer with Mo-Kα radiation (λ = 0.71073 Å). The structures were solved using SHELXS-14 and refined against F² for all data by full-matrix least squares with SHELXL-14 [16,17]. All non-hydrogen atoms were refined anisotropically; all hydrogen atoms bonded to carbon atoms were placed on geometrically calculated positions and refined using a riding model. CCDC-2178615 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via http://www.ccdc.cam.ac.uk/conts/retrieving.html (accessed on 23 July 2022 or from the CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; E-mail: [email protected]).

3.2. Synthesis of 1-(4-Fluorobenzoyl)-9H-carbazole (1)

The synthesis followed the procedure described by Lo et al. [14]. Under nitrogen atmosphere, in this order, carbazole (809.6 mg, purity 95%, 4.6 mmol) in 2.0 mL toluene, 4-fluorobenzonitrile (676 mg, 5.6 mmol) and anhydrous AlCl₃ (676 mg, 5.1 mmol) were added to a solution of 1 M BCl₃ in toluene (5.06 mL, 5.06 mmol). The mixture was heated to reflux for 18 h. After that, water (0.25 mL) and 10% HCl (5.1 mL) were added at a temperature of 0 °C and the mixture was heated to reflux for 2 h. The mixture was cooled to 0 °C and the resulting precipitate was filtered by vacuum filtration. The solid was suspended in 2.5% NaOH (11.5 mL) and stirred for 1 h at RT. Filtration and drying in vacuo gave the crude product, which was purified by Dry Column Vacuum Chromatography [18] (MERCK Silica Gel (mesh size 40–63 µm); 1. PE/ EtOAc 90:10→50:50; fractions containing impurities were purified with: 2. PE/ EtOAc 100:0→90:10). 1 was obtained as a pale-yellow solid (505 mg, 38%). mp (Galen III (Cambridge Instruments) melting points apparatus (Leica, Vienna, Austria); uncorrected) 151–153°C; R_f = 0.35 (Merck silica gel F-254 aluminum plates; PE/ EtOAc 85:15); ¹H-NMR (400 MHz, CDCl₃): δ = 7.22 (t, 2H, ³J_2,3 8.6, ³J_H,F 8.6, H_{Ph H3/H5}), 7.26* (t, 1H, ³J_2,3 7.8, ³J_3,4 7.6, H_{Ca H3}), 7.32 (t, 1H, ³J_5,6 7.9, ³J_6,7 7.0, ³J_6,8 1.0, H_{Ca H6}), 7.51 (t, 1H, ³J_7,8 8.1, ³J_6,7 7.1, ⁴J_5,7 1.0, H_{Ca H7}), 7.58 (d, 1H, ³J_7,8 8.1, H_{Ca H8}), 7.78 (d, 1H, ³J_5,6 7.7, ⁴J_4,6 1.0, H_{Ca H5}), 7.85 (dd, 2H, ³J_2,3 8.8, ⁴J_H,F 5.4, H_{Ph H2/H6}), 8.14 (d, 1H, ³J_2,3 7.8, H_{Ca H2}), 8.34 (d, 1H, ³J_3,4 7.6, H_{Ca H4}), 10.47 (br. s., 1 H, NH) ppm, *signal overlay with solvent signal; ¹³C-NMR (101 MHz, CDCl₃): δ = 111.5 (CH), 115.6 (d, ²J_C,F 22, CH_{Ph C3/C5}), 118.2 (CH), 118.5 (C), 120.4 (CH), 120.6 (CH), 122.4 (C), 125.3 (C), 126.2 (CH), 126.8 (CH), 130.6 (CH), 132.0 (d, ³J_C,F 9, CH_{Ph C2/C6}), 135.3 (d, ⁴J_C,F 3, C_{Ph C1}), 140.1 (C), 140.3 (C), 165.0 (d, ¹J_C,F 253, C_{Ph C4}), 196.6 (CO) ppm; ¹⁹F-NMR (376 MHz, CDCl₃): δ = −107.9 ppm; UPLC: t_R = 4.64 min (99%, monitored at 254 nm); MS (ESI⁺, M calculated for C₁₉H₁₂N₃FNO = 289.09) m/z (%): 290.25 (100) [M + H]⁺. Crystals suitable for X-ray analysis were obtained by slow evaporation of a solution of 1 in DCM layered with petroleum ether. For copies of ¹H-NMR, ¹³C-NMR and ¹⁹F-NMR spectra, HPLC chromatogram and MS spectrum see Supplementary Material.

4. Conclusions

The synthesis of 1-(4-fluorobenzoyl)-9H-carbazole (1) was achieved by BCl₃-mediated Friedel–Crafts acylation which represents a novel and site-specific entry to 1-aroyl-substituted carbazoles that lack the need to protect aromatic amine before synthesis.