2-(2,6-Diisopropylphenyl)-1-methylimidazo[1,5-a]quinolin-2-ium Tetrafluoroborate

Abstract

A new heterocyclic compound, 2-(2,6-diisopropylphenyl)-1-methylimidazo[1,5-a]quinolin-2-ium tetrafluoroborate 1 was obtained from its precursor, N-(2,6-diisopropylphenyl)-N-(quinolin-2-ylmethyl)acetamide 2, by POCl₃-mediated cyclization. For the first time, tertiary acetamide 2, the precursor of 1, was synthesized by using commercially available starting materials. The structure of 1 was unquestionably confirmed by ¹H, ¹³C, 2D-NMR, and IR spectroscopies and mass spectrometry. Its optical properties were also studied.

1. Introduction

In recent years, the interest in new imidazolium salts has been growing rapidly. This is mostly as a result of the fact that they are precursors for the synthesis of N-heterocyclic carbenes [1]. The free N-heterocyclic carbene is generated after deprotonation of the imidazolium salt with a proper base. The formed carbene can serve as an organocatalyst [2] or as a transition metal ligand [3,4,5,6,7]. Such NHC-based metal complexes are used as homogeneous catalysts [4,5,6,7], for instance the PEPPSI catalyst [8]. When the carbon atom located between the two nitrogen atoms is substituted, deprotonation occurs at a different position on the imidazolium ring and thus abnormal N-heterocyclic carbenes are generated [9]. Their respective metal complexes are also reported [10,11].

On the other hand, imidazolium salts bearing suitable substituents and counterions are also useful ionic liquids [12,13]. They are mainly used as green recyclable solvents due to their stability, low vapor pressure, and low toxicity.

There are two main routes for the synthesis of imidazolium salts: (a) building an imidazole ring [14] and (b) alkylating an imidazole ring [14]. The first approach is applicable when the phenyl-substituted imidazolium salt is desired. The second approach is preferred when an imidazolium salt with two alkyl substituents is needed.

Imidazolium salts with an imidazole ring, condensed with an aromatic system, are also reported in the literature [15,16,17,18,19]. However, imidazoquinolinium salts are relatively rare [20,21,22,23,24,25]. Their synthesis can also follow the mentioned methods for the preparation of imidazolium salts. Representatives of this class of imidazolium salts have been prepared by cyclization of tertiary formamides [20,21], cyclization of aldimines [22,23,24,25], and alkylation of imidazoquinolines [24,25].

Despite the reported imidazoquinolinium salts, salts bearing a substituent at the carbon atom located between the two nitrogen atoms are not described in the literature.

Herein, we report for the first time a synthetic procedure for obtaining such a type of substituted imidazoquinolinium salt, which emits in the UV region of the light spectrum. This compound could later serve as a precursor for an abnormal N-heterocyclic carbene.

On the other hand, the new compound possesses a methyl group next to a positively charged quaternary nitrogen atom. It is known that such type of heterocycles can participate in aldol-type condensation, making this methyl-substituted imidazoquinoinium salt an attractive building block for cationic hemicyanine and styryl dyes [26,27].

2. Results and Discussion

2.1. Synthesis of 2-(2,6-Diisopropylphenyl)-1-methylimidazo[1,5-a]quinolin-2-ium Tetrafluoroborate 1

The synthesis of the title compound, 2-(2,6-diisopropylphenyl)-1-methylimidazo[1,5-a]quinolin-2-ium tetrafluoroborate 1, was achieved in several steps, using the adapted and previously reported [20,21] procedure (Scheme 1 and Scheme 2).

N-(2,6-Diisopropylphenyl)-N-(quinolin-2-ylmethyl)acetamide 2 was prepared by acylation of the respective aniline 3 with acetic anhydride at room temperature (Scheme 1). The amide 4 was isolated with a good yield. It is interesting to note that our first attempt for acylation, which included boiling 2,6-diisopropylaniline 3 for 8 h with a large excess of acetic acid, was unsuccessful because of the sterically hindered NH₂ group.

The second step of the procedure included alkylation of the nitrogen atom of the resulting primary amide 4 by 2-(chloromethyl)quinoline [28] in the presence of NaH under anhydrous conditions (Scheme 1). The product, N-(2,6-diisopropylphenyl)-N-(quinolin-2-ylmethyl)acetamide 2, was found to be unstable on silica. Fortunately, it was successfully purified by recrystallization. This tertiary amide 2 was applied as a substrate in a POCl₃-mediated cyclization to the desired 2-(2,6-diisopropylphenyl)-1-methylimidazo[1,5-a]quinolin-2-ium salt 1 (Scheme 2). In order to increase its solubility in organic solvents, the product of the cyclization was treated with an aqueous solution of NH₄BF₄.

2.2. NMR Studies

One-dimensional (¹H, ¹³C, and DEPT-135) and two-dimensional (COSY, HSQC, and HMBC) NMR techniques were used to confirm the structure of all compounds. See Supplementary Materials for copies of the NMR spectra. N-(2,6-diisopropylphenyl)-N-(quinolin-2-ylmethyl)acetamide 4 was studied in two deuterated solvents—chloroform and dimethyl sulfoxide (Figures S1–S6). In the ¹H-NMR spectrum in chloroform, we observed two sets of signals, assigned as major and minor forms, in a ratio of 1:0.57. This behavior in solution has been particularly discussed previously [29]. In dimethyl sulfoxide, the compound exists in only one form. This is the reason why 2D NMR studies were carried out in this solvent. Using these 2D NMR experiments, each signal was assigned to the respective atom. In contrast to the secondary amide, tertiary amide N-(2,6-diisopropylphenyl)-N-(quinolin-2-ylmethyl)acetamide 2 demonstrates only one form in solution (Figures S6–S17). In its ¹H spectrum, signals corresponding to the quinoline and 2,6-diisopropylphenyl systems, bonded by the CH₂ group, could be seen clearly. In the HMBC spectrum of the compound, interactions between methylene protons (4.98 ppm) and carbon atoms from both systems were observed.

All the spectra of 2-(2,6-diisopropylphenyl)-1-methylimidazo[1,5-a]quinolin-2-ium tetrafluoroborate 1 were recorded in deuterated dimethyl sulfoxide and methanol in order to avoid signal overlap (Figures S19–S42). Unfortunately, this could not be avoided completely: in the proton spectra, recorded in DMSO-d₆, three aromatic protons were overlapped. When methanol was used as a solvent, signals for only two protons were overlapped; however, the signal for one carbon atom could not be detected. Thus, deuterated DMSO was preferred. In the ¹H-spectrum, the singlet, corresponding to the imidazolium CH₃ group is shifted downfield (3.03 ppm) in comparison with the signal in the tertiary amide spectrum. Instead of a singlet for the protons of the CH₂ group at 4.98 ppm, the proton spectrum of compound 1 showed a signal for one proton (H3 from the imidazole ring) at 8.51 ppm. The signal of the carbon atom from the C=O group in the spectrum of N-(2,6-diisopropylphenyl)-N-(quinolin-2-ylmethyl)acetamide 2 in the spectrum of the imidazolium tetrafluoroborate 1 is shifted upfield.

2.3. Optical Properties

The photophysical properties of 2-(2,6-diisopropylphenyl)-1-methylimidazo[1,5-a]quinolin-2-ium tetrafluoroborate 1 were determined by UV-VIS and fluorescent spectroscopies. The absorption and fluorescence spectra were recorded in methanol (MeOH) and acetonitrile (MeCN), Figure 1 and

Table 1. Summary of the photophysical data of 2-(2,6-diisopropylphenyl)-1-methylimidazo[1,5-a]quinolin-2-ium tetrafluoroborate.

Solvent	ε, M−1·cm−1	λabs, nm 1	λem, nm 2	Stokes Shift, cm−1
MeOH	10,443	325	348; 358	2034; 2863
MeCN	10,106	325	348; 358	2034; 2863

¹ The longest wavelength maximum. ² Excitation at 325 nm.

. In the UV spectrum in MeOH, we observed maxima at 246, 256, 264, 300, 311, and 325 nm corresponding to the typical absorptions of benzene and quinoline π-π* electronic transitions (see Figure S43 for the whole spectrum). The same applies to the spectrum in MeCN. The molar absorptivities are almost identical—10 443 M⁻¹.cm⁻¹ (y = 10,443x − 0.0366; R² = 0.9990) and 10 106 M⁻¹.cm⁻¹ (y = 10,106x + 0.0013; R² = 0.9998) in MeOH and MeCN, respectively (Table 1 and Figure S45). The emission spectra are also very similar as a band with two maxima at 348 nm and 358 nm is observed in both solvents. The only difference is the ratio of the maxima; in MeOH, the maximum at 358 nm is slightly less intensive compared to that at 348 nm, while in the case of MeCN, they have equal intensity. Since 2-(2,6-diisopropylphenyl)-1-methylimidazo[1,5-a]quinolin-2-ium tetrafluoroborate emits at shorter wavelengths than visible light, it does not possess fluorescent properties.

3. Materials and Methods

Melting points were determined on an SRS MPA120 EZ-Melt apparatus. The IR spectra were recorded with a Shimadzu FTIR-8400S spectrophotometer. ¹H and ¹³C NMR spectra were recorded on a Bruker AVNEO 400 spectrometer (at 400 MHz for ¹H and 100.6 MHz for ¹³C, respectively). Chemical shifts are given in ppm. By “⁴C” in the ¹³C-NMR are assigned carbon atoms which are quaternary and non-bonded to a hydrogen atom. The NMR spectra of all synthesized compounds can be found in the Supplementary Materials. Liquid chromatography mass spectrometry analysis (LC-HRAM) was carried out on Q Exactive^® hybrid quadrupole-Orbitrap^® mass spectrometer (ThermoScientific Co., Waltham, MA, USA) equipped with an HESI^® (heated electrospray ionization) module, TurboFlow^® Ultra High-Performance Liquid Chromatography (UHPLC) system (ThermoScientific Co., Waltham, MA, USA) and HTC PAL^® autosampler (CTC Analytics, Zwingen, Switzerland). The chromatographic separations of the analyzed compounds were achieved on a Nucleoshell C18 (100 × 2.1 mm, 2.7 µm) analytical column (Macherey-Nagel, Düren, Germany). Full-scan mass spectra over the m/z range 100–600 were acquired in positive ion mode at resolution settings of 140,000. The used mass spectrometer operating parameters were spray voltage—4.0 kV; capillary temperature—320 °C; probe heater temperature—300 °C; sheath gas flow rate 40 units; auxiliary gas flow rate 12 units; sweep gas rate 2 units (units refer to arbitrary values set by the Q Exactive Tune software); and S-Lens RF level of 50.00. Nitrogen was used for sample nebulization and collision gas in the HCD cell. All derivatives were quantified using 5 ppm mass tolerance filters to their theoretically calculated m/z values. Data acquisition and processing were carried out with XCalibur^® version 2.4 software package (ThermoScientific Co., Waltham, MA, USA). UV-Vis spectra were carried out on a Shimadzu UV-1800 spectrophotometer. Fluorescence spectra were recorded at room temperature on a PerkinElmer LS45. Reactions were monitored by TLC on silica gel 60 F₂₅₄.

Trichloroisocyanuric acid and 2,6-diisopropylaniline were purchased from Acros Organics. 2-Methylquinoline and toluene were purchased from Honeywell. All the other solvents and reagents were purchased from local suppliers. Toluene was dried by refluxing with sodium and benzophenone under argon atmosphere and distilled. N,N-Dimethylformamide (DMF) was dried by storing for one week over CaH₂ and used without distillation.

3.1. Synthesis of N-(2,6-Diisopropylphenyl)acetamide 4

2,6-Diisopropylaniline 3 (1.078 g, 6.08 mmol) was dissolved in 10 mL of dichloromethane by stirring at room temperature. Acetic anhydride (1.24 g, 12.16 mmol) was added to the solution in one portion. The mixture was stirred at room temperature for 8 h. Dichloromethane was removed under reduced pressure, and the crystalline residue was dried under a vacuum (water aspirator) at room temperature for 3 h. The light pink crystalline residue was dissolved in dichloromethane and transferred in a separatory funnel. Concentrated aqueous solution of Na₂CO₃ was added, and the funnel was shaken vigorously. The water layer was extracted with dichloromethane, and the combined organic layers were dried with anhydrous Na₂SO₄. After removal of the solvent (rotary evaporator), the product (1.3 g, 98%) was additionally purified by recrystallization from toluene to afford snow white crystals, m.p. = 189.0–189.5 °C.

¹H NMR (500 MHz, DMSO-d₆) δ 9.19 (s, 1H, NHCO), 7.24 (t, J = 7.8 Hz, 1H, H4), 7.14 (d, J = 7.7 Hz, 2H, H3, H5), 3.05 (hept, J = 6.9 Hz, 2H, CH-isopropyl), 2.05 (s, 3H, CH₃CO), 1.13 (s, 12H, CH₃-isopropyl). ¹H NMR (500 MHz, CDCl₃), major form: δ 7.31 (d, J = 7.7 Hz, 1H, H4), 7.19 (d, J = 7.7 Hz, 2H, H3, H5), 6.86 (s, 1H, NHCO), 3.10 (d, J = 6.9 Hz, 2H, CH-isopropyl), 2.23 (s, J = 3.6 Hz, 3H, CH₃CO), 1.22 (d, J = 6.9 Hz, 12H, CH₃-isopropyl). Minor form: δ 7.36 (t, J = 7.7 Hz, 1H), 7.22 (d, J = 7.7 Hz, 2H, H3, H5), 7.04 (s, 1H, H4), 3.22 (d, J = 6.9 Hz, 2H, CH-isopropyl), 1.76 (s, J = 3.2 Hz, 3H, CH₃CO), 1.27 (d, J = 6.9 Hz, 6H, CH₃-isopropyl), 1.18 (d, J = 6.8 Hz, 6H, CH₃-isopropyl). Major to minor form ratio = 1:0.57. ¹³C NMR (126 MHz, DMSO-d₆) δ 169.47 (CH₃CO), 146.40 (C2, C6), 133.22 (⁴C1), 127.81 (C4), 123.23 (C3, C5), 28.46 (CH-isopropyl), 24.18 (CH₃-isopropyl), 23.66 (CH₃-isopropyl), 22.97 (CH₃CO). HRMS (ESI) m/z calculated for [M+H]⁺ 220.16993, found 220.16959 (ppm: 1.54).

3.2. Synthesis of N-(2,6-Diisopropylphenyl)-N-(quinolin-2-ylmethyl)acetamide 2

N-(2,6-diisopropylphenyl)acetamide 4 (0.329 g, 1.5 mmol) was dissolved in 5 mL of dry DMF. The system was purged with argon and cooled in an ice bath for 15 min. To the transparent colorless solution, NaH (0.108 g, 2.2 mmol, and 50% in mineral oil) was added. Moderate effervescence was observed. The resulting white suspension was stirred for one hour in an ice bath. After that, 2-(chloromethyl)quinoline (0.266 g, 1.5 mmol) was added and the reaction mixture was stirred at room temperature for 12 h. DMF was removed under reduced pressure, and 5 mL of water was added to the crude residue. Ethyl acetate was added to the suspension, and the aqueous layer was extracted with the same solvent. The combined organic layers were dried with Na₂SO₄, and the volatiles were removed under reduced pressure (rotary evaporator), leaving yellow crystals (0.540 g, quantitative yield). The recrystallization from cyclohexane gave 0.250 g (46%) of yellow crystals, m.p. = 124.0–125.0 °C.

¹H NMR (500 MHz, CDCl₃) δ 8.07 (d, J = 8.5 Hz, 1H, H4), 7.86 (d, J = 8.5 Hz, 1H, H8), 7.81 (d, J = 8.5 Hz, 1H, H3), 7.72 (d, J = 8.0 Hz, 1H, H5), 7.57 (t, J = 7.1 Hz, 1H, H7), 7.43 (t, J = 7.5 Hz, 1H, H6), 7.24 (t, J = 7.7 Hz, 1H, H4-2,6-diisopropylphenyl), 7.07 (d, J = 7.7 Hz, 2H, H3, H5-2,6-diisopropylphenyl), 4.98 (s, 2H, CH₂N), 2.85 (hept, J = 6.8 Hz, 2H, CH-isopropyl), 1.80 (s, 3H, CH₃CO), 1.06 (d, J = 6.9 Hz, 6H, CH₃-isopropyl), 0.72 (d, J = 6.8 Hz, 6H, CH₃-isopropyl). ¹³C NMR (126 MHz, CDCl₃) δ 172.50 (CH₃CO), 158.05 (⁴C2), 147.32 (⁴C8a), 146.29 (⁴C2, ⁴C6-2,6-diisopropylphenyl), 138.80 (⁴C1-2,6-diisopropylphenyl), 136.48 (C4), 129.33 (C7), 129.09 (C4-2,6-diisopropylphenyl), 129.04 (C8), 127.45 (C5), 127.42 (⁴C4a),126.32 (C6), 124.86 (C3, C5-2,6-diisopropylphenyl), 122.25 (C3), 57.30 (CH₂N), 28.32 (CH-isopropyl), 24.36 (CH₃-isopropyl), 24.19 (CH₃-isopropyl), 22.28 (CH₃CO). HRMS (ESI) m/z calculated for [M+H]⁺ 361.22806, found 361.22744 (ppm: 1.72).

3.3. Synthesis of 2-(2,6-Diisopropylphenyl)-1-methylimidazo[1,5-a]quinolin-2-ium Tetrafluoroborate 1

N-(2,6-diisopropylphenyl)-N-(quinolin-2-ylmethyl)acetamide 2 (0.170 g, 0.47 mmol) was dissolved in 30 mL of dry toluene. The resulting solution was heated to 100 °C, and POCl₃ (0.2 mL, 0.328 g, 2.14 mmol) was added. The temperature was elevated to 105 °C, and the reaction mixture was heated for 48 h. Volatiles were distilled under reduced pressure, leaving a dark solid. The crude product was dissolved in a minimal amount of boiling water, and the solution was filtered. To the hot yellow filtrate, concentrated aqueous NH₄BF₄ (0.065 g, 6.2 mmol) was added, resulting in the formation of a white precipitate. After cooling to room temperature, the precipitate was filtered and air-dried. Yield: 0.180 g (89%) white solid, m.p. > 230 °C.

¹H NMR (500 MHz, DMSO-d₆) δ 8.57 (d, J = 8.5 Hz, 1H, H9), 8.51 (s, 1H, H3), 8.10 (dd, J = 7.7, 1.4 Hz, 1H, H6), 7.86 (t, J = 7.9 Hz, 1H, H8), 7.80 (t, J = 7.3 Hz, 1H, H7), 7.76–7.67 (m, 3H, H4, H5, H4-2,6-diisopropylphenyl), 7.56 (d, J = 7.9 Hz, 2H, H3,H5-2,6-diisopropylphenyl), 3.03 (s, 3H, CH₃-imidazole), 2.28 (hept, J = 6.8 Hz, 2H, CH-isopropyl), 1.13 (d, J = 6.8 Hz, 6H, CH₃-isopropyl), 1.11 (d, J = 6.9 Hz, 6H, CH₃-isopropyl). ¹H NMR (500 MHz, MeOD) δ 8.63 (d, J = 8.6 Hz, 1H, H9), 8.30 (s, 1H, H3), 8.05 (d, J = 7.7 Hz, 1H, H6), 7.89 (t, J = 7.7 Hz, 1H, H8), 7.80 (t, J = 7.5 Hz, 1H, H7), 7.77–7.69 (m, 2H, H5, H4-2,6-diisopropylphenyl), 7.66 (d, J = 9.6 Hz, 1H, H4), 7.57 (d, J = 7.8 Hz, 2H, H3, H5-2,6-diisopropylphenyl), 3.14 (s, 3H, CH₃-imidazole), 2.28 (d, J = 6.8 Hz, 2H, CH-isopropyl), 1.24 (d, J = 6.8 Hz, 6H, CH₃-isopropyl), 1.21 (d, J = 6.8 Hz, 6H, CH₃-isopropyl). ¹³C NMR (126 MHz, DMSO-d₆) δ 145.96 (⁴C2, ⁴C6-2,6-diisopropylphenyl), 140.86 (⁴C1-CH₃), 132.48 (C4-2,6-diisopropylphenyl), 132.04 (⁴C9a), 130.20 (⁴C1-2,6-diisopropylphenyl), 130.17 (C8), 130.06 (C6), 129.47 (⁴C3a), 128.77 (C7), 127.32 (C5), 126.22 (⁴C5a), 125.48 (C3, C5-2,6-diisopropylphenyl), 119.55 (C9), 116.38 (C3), 115.95 (C4), 28.08 (CH-isopropyl), 25.01 (CH₃-isopropyl), 23.57 (CH₃-isopropyl), 15.16 (CH₃-imidazole). HRMS (ESI) m/z calculated for [M-BF₄+H]⁺ 343.21739, found 343.21633 (ppm: 3.10). IR (nujol): ν = 3120, 1645, 1610, 1597, 1568, 1423, 1049, 1030 cm⁻¹ (see Figure S46).

4. Conclusions

A new methyl-substituted imidazoquinolinium salt was prepared and studied via ¹H, ¹³C, 2D-NMR, IR, UV, and fluorescence spectroscopies and mass spectrometry. Its optical properties in methanol and acetonitrile are very similar as in both solvents, the longest wavelength maxima in the UV spectrum is at 315 nm. Although the synthesized imidazoquinolinium salt possesses planar-conjugated fragments, it emits in the UV region at 358 nm, and thus it is non-fluorescent.