Atropisomeric Properties of N-Alkyl/Aryl 5H-Dibenz[b,f]azepines

Abstract

The atropisomeric properties of N-alkyl and N-aryl 4-substituted 5H-dibenz[b,f]azepines were investigated. The N-alkylation and N-arylation of 4-Cl or 4-Me substituted compounds was performed; however, none of the atropisomers produced were separated by chiral HPLC. Notably, we observed that the rotation of the four axes (ax. 1–4) in the 4-substituted 5H-dibenz[b,f]azepine structure is so rapid that N-alkylation or N-arylation is not sufficient to freeze it at room temperature. Additionally, the X-ray crystal structures of N-aryl compounds 13b and 14a indicated that the N atom in the triphenyl amine moiety in their structures shows sp²-like property.

Introduction

The analogs of 5H-dibenz[b,f]azepine (Fig. 1), a pharmaceutically important structure, is present in many antidepressant drugs such as carbamazepine (1), which is used for the treatment of epilepsy, bipolar disorder, trigeminal neuralgia, and other neurological disorders.^1–6) In the course of our research on the atropisomerism of benzo-fused seven-membered-ring nitrogen-heterocycles,^7–21) we were particularly interested in the conformation of carbamazepine (1). Moreover, in our previous study, the atropisomers of N-acyl and N-thiocarbamoyl 5H-dibenz[b,f]azepine derivatives were isolated with high stereochemical stability.^22–24) The scaffold of nevirapine (2), a non-nucleoside reverse transcriptase inhibitor with an N-cyclopropyl moiety, is similar to that of 1; however, 2 is not atropisomeric at room temperature.²⁵⁾ Additionally, it was reported that N-aryl 5H-dibenz[b,f]azepine derivatives, sulphonamides (3) and (4), showed antimicrobial and antioxidant properties.²⁶⁾ However, the conformational properties of the triarylamine group in this scaffold have never been investigated. These observations prompted us to investigate the conformation of N-alkyl and N-aryl 5H-dibenz[b,f]azepine derivatives precisely. This study deals with the conformational properties of N-alkyl and N-aryl 5H-dibenz[b,f]azepine derivatives based on chiral HPLC and X-ray crystallography.

Fig. 1. Analogs of Pharmacologically Active 5H-Dibenz[b,f]azepine

Results and Discussion

Preparation of N-Alkyl 5H-Dibenz[b,f]azepines

First, N-alkyl compounds were prepared as shown in Chart 1. Because 5H-dibenz[b,f]azepine (5) is symmetric, we introduced Cl or Me substituents at the C4-position to restrict the concerted rotation of the four sp²–sp² axes (ax. 1–4). We employed the Pd-catalyzed condensation of 2-bromostyrene and 2-chloroaniline derivatives²⁷⁾ to produce 5H-dibenz[b,f]azepines 9 and 10. Using conventional methods,^21,28) the N-alkylation of 9 and 10 under basic conditions afforded various N-alkyl 5H-dibenz[b,f]azepines (11a–d, 12a–d). Why the yield of 11d was very low is unknown.

Chart 1. Synthesis of N-Alkyl 5H-Dibenz[b,f]azepines 11a–d and 12a–d

Preparation of N-Aryl 5H-Dibenz[b,f]azepines

The N-arylation of 5H-dibenz[b,f]azepine derivatives is shown in Chart 2. The palladium-catalyzed N-arylation²⁹⁾ of 9 and 10 produced compounds 13a–d and 14a–c, respectively.

Chart 2. Synthesis of N-Aryl 5H-Dibenz[b,f]azepines 13a–d and 14a–c

HPLC Analysis of N-Alkyl/N-Aryl 5H-Dibenz[b,f]azepines

Considering previous results,^22–25) the conformations of atropisomers can be represented in the forms of conformer A or B. These conformations result from the butterfly motion that is derived from the concerted rotation of axes 1–4 (Fig. 2).

Fig. 2. Structures of Conformers A and B

At first, the separation of N-alkyl 5H-dibenz[b,f]azepines 11a–d and 12a–d into enantiomers was attempted using chiral HPLC. Unfortunately, all compounds were not separated into enantiomers by chiral chromatography. Figure 3 shows the circular dichroism (CD) chromatograms and UV-HPLC profiles of 11a–d and 12a–d.

Fig. 3. CD Chromatograms and UV-HPLC Profiles of 11a–d and 12a–d Obtained Using Chiral Columns

In the CD spectra, which were collected at the same time as the UV spectra, both positive and negative bands were simultaneously observed as unseparated peaks. Our efforts to isolate these enantiomers by using preparative chiral HPLC resulted in failure. That is, the two peaks collected were immediately analyzed by chiral HPLC and found to comprise mixtures of the original unseparated peaks. This suggests that the interconversion of the enantiomeric conformations of 11a–d and 12a–d (Fig. 2) should have occurred at room temperature. Moreover, we found that the steric effects of the 4-Cl and 4-Me substituents are ineffective in restricting the concerted rotation of four sp²–sp² axes (ax. 1–4). Similarly, the high bulkiness of the N-alkyl group (Me < Et < i-Pr) in 11a–c and 12a–c adversely affected the stability of the enantiomers. To elucidate the stereochemical stability of compounds 11b and 11c, we performed VT-NMR at higher temperatures (details in the Supplementary Materials). Unfortunately, none of their diastereotopic protons coalesced until a temperature of 120 °C was achieved. That is, the N-alkylation in these cases works to raise the ground state energy more than that of the transition state for rotation. We therefore assumed that the rotational energy barrier around the inner sp²–sp² axes (ax. 1–4) was lower than initially expected in these compounds, and the separable enantiomers of N-alkyl 5H-dibenz[b,f]azepines did not exist at room temperature.

Next, we attempted to separate N-aryl 5H-dibenz[b,f]azepines into aropisomers. The chiral resolution of 13a–d and 14a–c by HPLC was investigated. The isolation of the enantiomers of 13a and 14a was impossible because they interconverted into each other at room temperature. Other compounds, 13b–d and 14b–c, were not separated into enantiomers at all. The CD chromatograms and UV-HPLC profiles of 13a–d and 14a–c are shown in Fig. 4. Moreover, the substituents at the 2′-position in 13b–c and 14b–c were ineffective in reducing the interconversion of enantiomers. In particular, in 13d, the bulky naphthyl group did not increase the energy barrier for the interconversion of enantiomers.

Fig. 4. CD Chromatograms and UV-HPLC Profiles of 13a–d and 14a–c Obtained Using Chiral Columns

Conformation of N-Aryl 5H-Dibenz[b,f]azepines

Fortunately, we succeeded in obtaining the single crystals of N-aryl 5H-dibenz[b,f]azepines 13b and 14a, and their X-ray structures³⁰⁾ yielded important information about their stereochemistry. In the crystal state, each enantiomer exists as expected; however, interconversion occurs in solution (Fig. 5). The X-ray structures revealed a butterfly-like shape, in which the planar benzene rings were bent from the puckered central azepine. Notably, the angle around the N atom in 13b is 350.44° and that in 14a is 354.98°. This result indicates that the N atom of the triphenyl amine group exhibits sp²-like property. Considering that the rapid inversion of the sp³ N of the tertiary amine group triggers the flipping of the tricyclic system,^22–24) an increase in the sp²-like property of N in N-aryl 5H-dibenz[b,f]azepines may provide a clue for the separation of atropisomers at room temperature. Moreover, the crystal structure of 13b showed a crowded conformation, in which the 2′-Cl substituent of the pendant phenyl group was located close to 4-Cl on the tricyclic system.

Fig. 5. X-Ray Crystal Structures of 13b and 14a

The structure of only one enantiomer (conformer A) extracted from the CIF data of the racemate is depicted.

Conclusion

N-Alkyl/aryl 4-substituted 5H-dibenz[b,f]azepines were prepared, and their atropisomeric properties were examined by HPLC and X-ray crystallography. Unfortunately, the enantiomers of all the derivatives were not isolated by chiral HPLC, which indicates the rapid rotation of axes 1–4 at room temperature. Bulky N-alkyl groups or 2′-substituted N-aryl groups adversely affect the stability of the enantiomers. The X-ray crystal structures of 13b and 14a indicated the sp²-like property of N in N-aryl 5H-dibenz[b,f]azepines. These results will help us establish a strategy for producing stable atropisomers, which will be reported in due course.

Experimental

General Information

All reagents were purchased from commercial suppliers and used as received. Materials including starting materials 6,³¹⁾ 7,²⁷⁾ and 8³²⁾ were obtained from commercial suppliers and used without further purification. Reaction mixtures were stirred magnetically, and the reactions were monitored by TLC on precoated silica gel plates. Column chromatography was performed using silica gel (45−60 µm). Extracted solutions were dried over anhydrous MgSO₄ or Na₂SO₄. Solvents were evaporated under reduced pressure. NMR spectra were recorded on a spectrometer at 400 or 600 MHz for ¹H-NMR and 100 or 150 MHz for ¹³C-NMR at 296 K unless otherwise stated. Chemical shifts are given in parts per million (ppm) downfield from tetramethylsilane, which was used as an internal standard. Coupling constants (J) are reported in Hertz (Hz). Splitting patterns are abbreviated as follows: singlet (s), doublet (d), triplet (t), quartet (q), multiplet (m), and broad (br). High-resolution mass spectra (HRMS) were recorded using an electrospray ionization/time-of-flight (ESI/TOF) or atmospheric pressure chemical ionization (APCI)/TOF mass spectrometer. Melting points were recorded on a melting point apparatus and are uncorrected. The CD spectra of the HPLC-separated compounds, except 14a, were detected at a wavelength of 254 nm; the CD spectrum of 14a was detected at a wavelength of 300 nm.

N-Alkyl 5H-Dibenz[b,f]azepine 11a–d, 12a–d

4-Chloro-5-methyl-5H-dibenz[b,f]azepine (11a); Standard Procedure

To a solution of 9 (145.3 mg, 0.64 mmol) in N,N-dimethylformamide (DMF) (2.2 mL, 0.3 M), sodium hydride (60%) in oil (51.1 mg, 1.28 mmol) was added before cooling in an ice bath. After the mixture was stirred at 80 °C for 2 h, iodomethane (0.08 mL, 1.28 mmol) was added. The reaction was stirred at 80 °C for 4 h; subsequently, the reaction mixture was poured into ice water. The reaction mixture was then extracted using EtOAc. The organic extract was washed with water and brine, dried over Na₂SO₄, and concentrated under reduced pressure. The mixture was purified by column chromatography on silica gel using hexane to afford 11a (143.0 mg, 92%); yellow oil; Rf = 0.37 (hexane); ¹H-NMR (600 MHz, dimethyl sulfoxide (DMSO)-d₆) δ: 3.14 (3H, s), 6.81 (1H, d, J = 11.4 Hz), 6.83 (1H, d, J = 11.4 Hz), 7.12–7.16 (2H, m), 7.18 (1H, dd, J = 1.2, 7.8 Hz), 7.23 (1H, dd, J = 1.2, 7.8 Hz), 7.26 (1H, d, J = 8.4 Hz), 7.35 (1H, td, J = 1.2, 7.8 Hz), 7.45 (1H, dd, J = 1.8, 7.8 Hz); ¹³C-NMR (150 MHz, DMSO-d₆) δ: 41.1, 125.0, 125.8, 126.4, 128.3, 129.7, 129.9, 130.2, 130.4, 131.3, 132.3, 134.2, 138.6, 144.4, 150.4; HRMS (ESI-TOF) m/z (M + H)⁺: 242.0730 (Calcd for C₁₃H₁₂NCl: 242.0731).

4-Chloro-5-ethyl-5H-dibenz[b,f]azepine (11b)

Compound 11b was prepared from 9 (141.1 mg) and iodoethane as per the standard procedure used for 11a. Subsequently, 11b was purified by column chromatography on silica gel using hexane; yield: 149.7 mg (94%); yellow oil; Rf = 0.50 (hexane); ¹H-NMR (600 MHz, CDCl₃) δ: 1.01 (3H, t, J = 7.2 Hz), 3.45–3.50 (1H, m), 3.54–3.59 (1H, m), 6.72 (1H, d, J = 11.4 Hz), 6.76 (1H, d, J = 11.4 Hz), 7.02–7.05 (2H, m), 7.10–7.13 (1H, m), 7.17 (1H, d, J = 8.4 Hz), 7.35 (2H, d, J = 3.0 Hz), 7.37 (1H, dd, J = 2.4, 6.6 Hz); ¹³C-NMR (150 MHz, CDCl₃) δ: 14.7, 48.2, 125.0, 125.7, 127.8, 128.1, 129.4, 129.6, 130.0, 130.5, 132.3, 133.5, 135.9, 139.5, 144.3, 149.1; HRMS (ESI-TOF) m/z (M + H)⁺: 256.0887 (Calcd for C₁₆H₁₅NCl: 256.0888).

4-Chloro-5-isopropyl-5H-dibenz[b,f]azepine (11c)

Compound 11c was prepared from 9 (146.7 mg) and 2-iodopropane as per the standard procedure for 11a except for 3 d stirring and purified by column chromatography on silica gel using hexane; yield: 101.2 mg (70%); yellow oil; Rf = 0.52 (hexane); ¹H-NMR (600 MHz, CDCl₃) δ: 0.87 (3H, d, J = 6.0 Hz), 0.88 (3H, d, J = 6.0 Hz), 3.61–3.67 (1H, m), 6.84 (1H, d, J = 10.8 Hz), 6.90 (1H, d, J = 10.8 Hz), 7.08 (1H, t, J = 7.8 Hz), 7.15 (1H, dd, J = 1.2, 7.8 Hz), 7.20 (1H, td, J = 1.2, 7.2 Hz), 7.27 (1H, dd, J = 2.4, 7.2 Hz), 7.35 (1H, td, J = 1.2, 7.2 Hz), 7.42–7.45 (2H, m); ¹³C-NMR (150 MHz, CDCl₃) δ: 22.0, 22.6, 49.8, 125.8, 126.0, 127.8, 129.1, 129.3, 129.6, 130.0, 131.5, 131.7, 136.1, 136.6, 139.2, 143.3, 146.3; HRMS (ESI-TOF) m/z (M + H)⁺: 270.1046 (Calcd for C₁₇H₁₇NCl: 270.1044).

4-Chloro-5-cyclopropyl-5H-dibenz[b,f]azepine (11d)

Compound 11d was prepared from 9 (94.3 mg) and bromocyclopropane as per the standard procedure for 11a except for 66 h stirring and purified by column chromatography on silica gel using hexane; yield: 4.2 mg (0.4%); yellow oil; Rf = 0.26 (hexane); ¹H-NMR (400 MHz, CDCl₃) δ: 0.39–0.58 (4H, m), 3.46–3.51 (1H, m), 6.70 (1H, d, J = 11.4 Hz), 6.74 (1H, d, J = 11.4 Hz), 7.00–7.06 (2H, m), 7.09–7.17 (2H, m), 7.31–7.39 (3H, m); ¹³C-NMR (100 MHz, CDCl₃) δ: 8.42, 8.70, 33.4, 124.9, 125.7, 126.8, 127.5, 129.3, 130.1, 130.4, 132.2, 132.7, 134.7, 138.9, 143.8, 149.8; HRMS (ESI-TOF) m/z (M + H)⁺: 268.0888 (Calcd for C₁₇H₁₅NCl: 268.0888).

4,5-Dimethyl-5H-dibenz[b,f]azepine (12a)

Compound 12a was prepared from 10 (148.2 mg) and iodomethane as per the standard procedure used for 11a and purified by column chromatography on silica gel using hexane; yield: 140.1 mg (88%); yellow oil; Rf = 0.33 (hexane); ¹H-NMR (600 MHz, DMSO-d₆) δ: 2.42 (3H, s), 2.93 (3H, s), 6.78 (1H, d, J = 11.7 Hz), 6.81 (1H, d, J = 11.7 Hz), 7.04–7.08 (2H, m), 7.14 (1H, td, J = 1.8, 7.2 Hz), 7.23–7.26 (2H, m), 7.29 (1H, d, J = 7.8 Hz), 7.33 (1H, td, J = 1.2, 7.8 Hz); ¹³C-NMR (150 MHz, DMSO-d₆) δ: 18.5, 40.8, 125.1, 125.2, 127.1, 127.4 129.4, 129.7, 130.5, 131.2, 131.4, 135.2, 136.0, 136.1, 147.2, 150.5; HRMS (ESI-TOF) m/z (M + H)⁺: 222.1278 (Calcd for C₁₆H₁₆N: 222.1277).

5-Ethyl-4-methyl-5H-dibenz[b,f]azepine (12b)

Compound 12b was prepared from 10 (140.9 mg) and iodoethane as per the procedure used for 11a and purified by column chromatography on silica gel using hexane; yield: 144.8 mg (90%); yellow oil; Rf = 0.51 (hexane); ¹H-NMR (600 MHz, CDCl₃) δ: 0.94 (3H, t, J = 7.2 Hz), 2.50 (3H, s), 3.17–3.26 (2H, m), 6.76 (1H, d, J = 11.1 Hz), 6.80 (1H, d, J = 11.1 Hz), 7.04–7.07 (2H, m), 7.14–7.16 (1H, m), 7.22–7.24 (2H, m), 7.29–7.30 (2H, m); ¹³C-NMR (100 MHz, CDCl₃) δ: 14.7, 18.8, 47.3, 125.2, 125.3, 127.5, 128.9, 129.7, 129.7, 130.4, 131.2, 131.4, 136.7, 137.0, 137.7, 146.8, 148.6; HRMS (ESI-TOF) m/z (M + H)⁺: 236.1435 (Calcd for C₁₇H₁₈N: 236.1434).

5-Isopropyl-4-methyl-5H-dibenz[b,f]azepine (12c)

Compound 12c was prepared from 10 (144.7 mg) and 2-iodopropane as per the standard procedure used for 11a except for 3 d stirring and purified by column chromatography on silica gel using hexane; yield: 60.7 mg (34%); yellow oil; Rf = 0.53 (hexane); ¹H-NMR (600 MHz, CDCl₃) δ: 0.75 (3H, d, J = 6.0 Hz), 0.79 (3H, d, J = 6.0 Hz), 2.57 (3H, s), 3.45–3.51 (1H, m), 6.86 (1H, d, J = 11.4 Hz), 6.91 (1H, d, J = 11.4 Hz), 7.08 (1H, t, J = 7.8 Hz), 7.14 (1H, dd, J = 1.2, 7.2 Hz), 7.20 (1H, td, J = 1.2, 7.2 Hz), 7.27 (1H, dd, J = 1.2, 7.2 Hz), 7.28–7.33 (2H, m), 7.37 (1H, dd, J = 1.2, 7.8 Hz); ¹³C-NMR (150 MHz, CDCl₃) δ: 19.0, 21.9, 23.0, 48.4, 125.2, 125.7, 127.2, 128.6, 129.3, 129.9, 130.8, 131.1, 131.9, 136.8, 136.9, 139.3, 145.4, 146.9; HRMS (ESI-TOF) m/z (M + H)⁺: 250.1590 (Calcd for C₁₈H₂₀N: 250.1590).

5-Cyclohexyl-4-methyl-5H-dibenz[b,f]azepine (12d)

To a solution of 10 (108.0 mg, 0.52 mmol) in toluene (0.58 mL, 0.9 M), NaNH₂ (120.3 mg, 3.08 mmol) and iodocyclohexane (65 µL, 0.50 mmol) were added. The reaction mixture was stirred for 20 h at 90 °C. After cooling to room temperature, the reaction mixture was quenched with NH₄Cl (5.0 mL). The reaction mixture was then extracted with CH₂Cl₂. The organic extract was washed with water and brine, dried over Na₂SO₄, and concentrated under reduced pressure. The mixture was purified by column chromatography on silica gel using hexane to afford 12d (84.5 mg, 56.0%); yellow oil; Rf = 0.40 (hexane); ¹H-NMR (400 MHz, CD₂Cl₂) δ: 1.03–1.61 (11H, m), 2.61 (3H, s), 6.91 (1H, d, J = 11.9 Hz), 6.95 (1H, d, J = 11.9 Hz), 7.11–7.19 (2H, m), 7.24 (1H, td, J = 7.3, 1.8 Hz), 7.30–7.41 (4H, m); ¹³C-NMR (100 MHz, CD₂Cl₂) δ: 19.2, 25.3, 25.5, 26.5, 32.5, 33.6, 57.2, 125.6, 126.0, 127.5, 129.0, 129.7, 130.4, 131.2, 131.6, 132.1, 137.5, 137.6, 139.7, 145.3, 147.0; HRMS (ESI-TOF) m/z (M + H)⁺: 290.1903 (Calcd for C₂₁H₂₄N: 290.1903).

N-Aryl 5H-Dibenz[b,f]azepine 13a–d, 14a–c

4-Chloro-5-phenyl-5H-dibenz[b,f]azepine (13a); Standard Procedure

Lithium bis(trimethylsilyl)amide (LiHMDS) (178 mg, 1.06 mmol), 9 (122.8 mg, 0.539 mmol), RuPhos Pd G4 (6.6 mg, 7.5 µmol), and iodobenzene (120 µL, 1.08 mmol) in 1,4-dioxane (1.0 mL, 0.5 M) were stirred at 100 °C for 3 h. After cooling to room temperature, the mixture was diluted with CH₂Cl₂ (2.5 mL) and filtered through a short plug of silica gel to remove the insoluble solids. The mixture was purified by column chromatography on silica gel using 100% hexane and hexane/CH₂Cl₂ (9 : 1 v/v) to afford 13a (148.1 mg, 90%); yellow solid; mp 115–116 °C; Rf = 0.29 (hexane/CH₂Cl₂ 10 : 1); ¹H-NMR (400 MHz, CD₂Cl₂) δ: 6.14 (2H, d, J = 7.8 Hz), 6.66 (1H, t, J = 7.3 Hz), 6.82 (1H, d, J = 11.4 Hz), 6.88 (1H, d, J = 11.4 Hz), 6.94–6.99 (2H, m), 7.27–7.40 (3H, m), 7.45–7.60 (4H, m); ¹³C-NMR (100 MHz, CD₂Cl₂) δ: 111.5, 118.4, 127.6, 127.9, 128.6, 128.8, 129.8, 129.8, 130.1, 130.4, 130.8, 131.4, 135.3, 136.2, 138.8, 142.3, 146.9; HRMS (ESI-TOF) m/z (M + H)⁺: 304.0889 (Calcd for C₂₀H₁₅NCl: 304.0888).

4-Chloro-5-(2-chlorophenyl)-5H-dibenz[b,f]azepine (13b)

Compound 13b was prepared from 9 (116.6 mg) and 1, 2-dichlorobenzene as per the standard procedure used for 13a and purified by column chromatography on silica gel using hexane; yield: 152.4 mg (69%); yellow solid; mp 124–126 °C; Rf = 0.25 (hexane); ¹H-NMR (400 MHz, CD₂Cl₂) δ: 6.23 (1H, dd, J = 1.6, 8.5 Hz), 6.61–6.65 (1H, m), 6.83–6.88 (1H, m), 6.92 (1H, d, J = 11.4 Hz), 6.97 (1H, d, J = 11.4 Hz), 7.04 (1H, dd, J = 1.8, 7.8 Hz), 7.23 (1H, t, J = 7.8 Hz), 7.28 (1H, dd, J = 1.8, 7.8 Hz), 7.36 (1H, td, J = 1.2, 7.4 Hz), 7.44 (1H, dd, J = 1.8, 7.8 Hz), 7.50 (2H, td, J = 1.8, 7.3 Hz), 7.72 (1H, dd, J = 0.9, 7.8 Hz); ¹³C-NMR (100 MHz, CD₂Cl₂) δ: 117.2, 118.8, 120.4, 127.1, 127.8, 127.8, 129.8, 129.8, 130.2, 130.2, 130.5, 131.2, 132.7, 135.7, 136.6, 139.0, 140.0, 142.7, 143.0; HRMS (APCI-TOF) m/z (M + H)⁺: 338.0501 (Calcd for C₂₀H₁₄NCl₂: 338.0498).

4-Chloro-5-(o-tolyl)-5H-dibenz[b,f]azepine (13c)

Compound 13c was prepared from 9 (232.3 mg) and 2-bromotoluene as per the standard procedure used for 13a and purified by column chromatography on silica gel using hexane; yield: 223.8 mg (69%); yellow solid; mp 87–88 °C; Rf = 0.4 (hexane/CH₂Cl₂ 2 : 1); ¹H-NMR (400 MHz, CD₂Cl₂) δ: 1.57 (3H, s), 6.10 (1H, dd, J = 1.1, 8.5 Hz), 6.61 (1H, td, J = 1.4, 7.3 Hz), 6.76–6.82 (2H, m), 6.90 (1H, d, J = 11.2 Hz), 6.96 (1H, d, J = 11.2 Hz), 7.20–7.52 (7H, m), 7.72 (1H, d, J = 7.8); ¹³C-NMR (100 MHz, CD₂Cl₂) δ: 20.6, 115.4, 119.5, 123.7, 126.0, 127.1, 127.3, 127.7, 129.4, 129.7, 129.8, 130.5, 131.2, 133.2, 135.2, 136.8, 139.4, 144.1, 145.0; HRMS (APCI-TOF) m/z (M + H)⁺: 318.1043 (Calcd for C₂₁H₁₆NCl: 318.1044).

4-Chloro-5-(naphthalen-1-yl)-5H-dibenz[b,f]azepine (13d)

Compound 13d was prepared from 9 (168.2 mg) and 1-bromonaphthalene as per the standard procedure used for 13a and purified by column chromatography on silica gel using hexane; yield: 238.8 mg (91%); yellow solid; mp 163–165 °C; Rf = 0.30 (hexane/CH₂Cl₂ 4 : 1); ¹H-NMR (400 MHz, CD₂Cl₂) δ: 6.33–6.35 (1H, m), 6.88–6.99 (3H, m), 7.07 (1H, t, J = 7.8 Hz), 7.20–7.30 (4H, m), 7.33–7.37 (1H, m), 7.40 (1H, d, J = 6.6 Hz), 7.46 (1H, dd, J = 1.8, 7.8 Hz), 7.53–7.58 (2H, m), 7.65 (1H, dd, J = 1.4, 8.2 Hz), 7.86 (1H, d, J = 9.1 Hz); ¹³C-NMR (100 MHz, CD₂Cl₂) δ: 111.2, 120.6, 123.9, 124.5, 124.8, 125.3, 127.2, 127.4, 128.2, 128.6, 129.7, 129.8, 130.0, 130.1, 131.4, 134.5, 135.6, 136.5, 138.9, 141.3, 142.4, 144.3; HRMS (APCI-TOF) m/z (M + H)⁺: 354.1041 (Calcd for C₂₄H₁₆NCl: 354.1044).

4-Methyl-5-phenyl-5H-dibenz[b,f]azepine (14a)

Compound 14a was prepared from 10 (105.9 mg) and iodobenzene as per the standard procedure used for 13a and purified by column chromatography on silica gel using hexane and hexane/CH₂Cl₂ (5/1); yield: 77.5 mg (54%); white solid; mp 106–107 °C; Rf = 0.4 (hexane/CH₂Cl₂ 2 : 1); ¹H-NMR (400 MHz, CD₂Cl₂) δ: 2.49 (3H, s), 6.09–6.12 (2H, m), 6.63–6.67 (1H, m), 6.82 (1H, d, J = 11.9 Hz), 6.85 (1H, d, J = 11.9 Hz), 6.94–6.99 (2H, m), 7.26–7.30 (2H, m), 7.37–7.43 (2H, m), 7.48–7.54 (3H, m); ¹³C-NMR (100 MHz, CD₂Cl₂) δ: 18.1, 111.6, 118.1, 127.3, 127.6, 128.4, 128.9, 129.9, 130.2, 130.8, 130.9, 131.2, 131.3, 136.9, 137.0, 138.9, 141.7, 143.1, 148.0; HRMS (ESI-TOF) m/z (M + H)⁺: 284.1437 (Calcd for C₂₁H₁₈N: 284.1434).

5-(2-Chlorophenyl)-4-methyl-5H-dibenz[b,f]azepine (14b)

Compound 14b was prepared from 10 (223.9 mg) and 1,2-dichlorobenzene as per the standard procedure used for 13a and purified by column chromatography on silica gel using hexane; yield: 131.0 mg (38%); yellow solid; mp 104–106 °C; Rf = 0.30 (hexane); ¹H-NMR (400 MHz, CD₂Cl₂) δ: 2.58 (3H, s), 6.13 (1H, dd, J = 1.6, 8.5 Hz), 6.59–6.63 (1H, m), 6.82–6.87 (1H, m), 6.90 (1H, d, J = 11.4 Hz), 6.94 (1H, d, J = 11.4 Hz), 7.05 (1H, dd, J = 1.8, 7.8 Hz), 7.21–7.26 (2H, m), 7.34–7.38 (2H, m), 7.44 (1H, dd, J = 1.4, 7.8 Hz), 7.48 (1H, td, J = 1.4, 7.5 Hz), 7.64 (1H, dd, J = 1.1, 8.0 Hz); ¹³C-NMR (100 MHz, CD₂Cl₂) δ: 18.4, 117.0, 118.4, 119.5, 126.7, 126.7, 126.9, 127.1, 129.3, 129.3, 129.6, 130.2, 130.8, 130.8, 132.4, 136.5, 136.8, 138.3, 142.2, 143.1, 143.3; HRMS (ESI-TOF) m/z (M + H)⁺: 318.1045 (Calcd for C₂₁H₁₇NCl: 318.1044).

4-Methyl-5-(o-tolyl)-5H-dibenz[b,f]azepine (14c)

Compound 14c was prepared from 10 (144.7 mg) and 2-bromotoluene as per the standard procedure used for 13a and purified by column chromatography on silica gel using hexane; yield: 100.0 mg (65%); white solid; mp 100–101 °C; Rf = 0.34 (hexane/CH₂Cl₂ 10 : 1); ¹H-NMR (400 MHz, CD₂Cl₂) δ: 1.50 (3H, s), 2.52 (3H, s), 6.05 (1H, dd, J = 0.9, 8.2 Hz), 6.56 (1H, td, J = 0.9, 7.3 Hz), 6.72–6.80 (2H, m), 6.87 (1H, d, J = 11.4 Hz), 6.91 (1H, d, J = 11.4 Hz), 7.17–7.24 (2H, m), 7.30–7.34 (2H, m), 7.39 (1H, dd, J = 1.6, 7.5 Hz), 7.45 (1H, td, J = 1.8, 7.5 Hz), 7.61 (1H, dd, J = 0.9, 7.8 Hz); ¹³C-NMR (100 MHz, CD₂Cl₂) δ: 18.3, 21.1, 115.1, 118.8, 123.4, 126.0, 126.4, 126.8, 127.0, 129.2, 129.3, 129.8, 130.5, 130.9, 130.9, 133.3, 137.2, 137.4, 137.9, 143.6, 144.6, 145.5; HRMS (APCI-TOF) m/z (M + H)⁺: 298.1589 (Calcd for C₂₂H₁₉N: 298.1590).

Acknowledgments

This work was supported in part by a Grant-in-Aid for Scientific Research (C) (19K06980) from the Japan Society for the Promotion of Science.

Conflict of Interest

The authors declare no conflict of interest.

Supplementary Materials

This article contains supplementary materials of ¹H-NMR and ¹³C-NMR of 11a–d, 12a–d, 13a–d and 14a–c and ¹H VT-NMR spectra of 11b and 11c.

References and Notes

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