Synthesis of a Human Urate Transporter-1 Inhibitor, an Arginine Vasopressin Antagonist, and a 17β-Hydroxysteroid Dehydrogenase Type-3 Inhibitor, Using Ring-Expansion of Cyclic Ketoximes with DIBALH

Abstract

Synthesis of three clinical candidates for medicines, a human urate transporter-1 inhibitor, an arginine vasopressin antagonist, and a 17β-hydroxysteroid dehydrogenase type-3 inhibitor, is described. These compounds were synthesized via construction of their 3,4-dihydro-2H-benzo[b][1,4]oxazine, dibenzodiazepine, and dibenzazocine skeletons, respectively, using the reductive ring-expansion reaction of the corresponding bicyclic or tricyclic oximes with diisobutylaluminum hydride.

Aromatic ring-fused nitrogen heterocycles are often found in biologically active compounds and functional molecules. The synthesis of this class of heterocycles is an important research topic from the viewpoint of both synthetic and medicinal chemistry. Recently, we devised a reductive ring-expansion reaction of aromatic ring-fused cyclic oximes or their hydroxylamine derivatives to the corresponding cyclic secondary amines using aluminum hydrides such as diisobutylaluminum hydride (DIBALH)^1–4) and AlHCl₂.⁵⁾ The most notable feature of this rearrangement reaction is that reaction of an E/Z mixture of ketoxime provides the corresponding ring-expanded aromatic secondary amine as the sole compound, which is in sharp contrast to the geometry-dependent migration of activated oximes in a typical Beckmann rearrangement reaction.

To demonstrate the synthetic utility of the DIBALH-mediated ring-expansion reaction, we selected three clinical candidates for medicines: a human urate transporter-1 (URAT-1) inhibitor 1,⁶⁾ an arginine vasopressin (AVP) antagonist 2,^7–9) and a 17β-hydroxysteroid dehydrogenase type-3 (17β-HSD3) inhibitor 3 (Fig. 1). We conducted synthetic studies on these molecules.^10,11) Herein, the synthesis of compounds 1, 2, and 3 via construction of their basic skeletons 4, 5, and 6 using the reductive ring-expansion reaction of the corresponding bicyclic and tricyclic oximes 7, 8, and 9, respectively, is reported (Chart 1).

Fig. 1. Clinical Candidates: URAT-1 Inhibitor, AVP Antagonist, and 17β-HSD3 Inhibitor

Chart 1. Rearrangement of Bicyclic Oximes 7 and Tricyclic Symmetrical and Pseudo-Symmetrical Oximes 8 and 9

Results and Discussion

Synthesis of URAT-1 Inhibitor 1

Synthesis of URAT-1 inhibitor 1, 2,6-dichloro-4-(2,3-dihydro-1,4-benzoxazin-4-ylcarbonyl)phenol, for the remedy of hyperuricemia and gout, was reported by Hirata et al.⁶⁾ They synthesized 1 in several steps through 3,4-dihydro-2H-benzo[b][1,4]oxazine 4 (X=O),¹²⁾ which was obtained by reduction of 2H-1,4-benzoxazin-3(4H)-one 10 with lithium aluminum hydride in tetrahydrofuran (THF) at reflux. Alternatively, we prepared 3,4-dihydro-2H-benzo[b][1,4]oxazine 4 in 80% yield by reduction of coumaran-3-one oxime 7 with DIBALH.³⁾ Successively, acylation of the resulting compound 4 with 3,5-dichloro-4-hydroxybenzoyl chloride afforded the URAT-1 inhibitor 1 (Chart 2).

Chart 2. Synthesis of URAT-1 Inhibitor 1 Using 4 Obtained by DIBALH Rearrangement of 7 and LiAlH₄ Reduction⁶⁾ of 10

Reagents and conditions: (a) DIBALH, CH₂Cl₂, 0°C to rt (80%)³⁾ (b) LiAlH₄, THF, reflux⁶⁾ (c) 3,5-dichloro-4-hydroxybenzoyl chloride, EtOAc, rt (29%)

Synthesis of Arginine Vasopressin Antagonist 2

AVP antagonists are useful in the treatment of syndrome of inappropriate secretion of antidiuretic hormone (SIADH).⁷⁾ We planned to construct the dibenzodiazepine ring in the AVP antagonist 2 by reductive ring-expansion reaction of symmetric tricyclic oxime 8 (D=W=H, X=NH) with DIBALH (Chart 1).

Synthesis of 2 commenced with preparation of tricyclic oxime 8 by the condensation reaction of 9(10H)-acridone 11 with hydroxylamine hydrochloride in pyridine (Chart 3). However, this conventional reaction did not proceed possibly due to the low electrophilicity of the carbonyl group. Therefore, we developed a new protocol for the preparation of oximes by nitrosation of the benzylic anion and tautomerization to the oxime form.¹³⁾ Reduction of 9(10H)-acridone 11 with BH₃·THF in THF afforded compound 12, which was protected with a Boc group to give 13 in 80% yield (two steps). A nitroso group was introduced by treating 13 with potassium hexamethyldisilazide (KHMDS) in THF in the presence of 1.2 eq of t-BuONO at 0°C for 0.5 h to provide oxime 14 in 93% yield.¹³⁾ Finally, the Boc group was deprotected to provide the desired 9(10H)-acridone oxime 8.

On treatment with 6 eq of DIBALH, oxime 8 underwent a smooth reductive ring-expansion reaction to yield expected diazepine derivative 5, which was directly converted to stable 15 by acylation with p-nitrobenzoyl chloride and Et₃N (80% overall yield). The o-methylbenzanilide moiety of compound 2 was then introduced by hydrogenation of the nitro group in 15, and subsequent acylation of the resultant aniline 16 with o-methylbenzoyl chloride and Et₃N provided the desired AVP antagonist 2 (85% overall yield).

Chart 3. Rearrangement of 9(10H)-Acridone Oxime 8 and Transformation to Arginine Vasopressin Antagonist 2

Reagents and conditions: (a) BH₃·THF, THF, reflux, 4 h; (b) Boc₂O, DMAP, CH₃CN, 0°C to rt, 11 h, 80% (two steps); (c) t-BuONO, KHMDS, THF, 0°C, 0.5 h, 93%; (d) TFA, CH₂Cl₂, 0°C to rt, 0.5 h; (e) DIBALH (6 eq), CH₂Cl₂, 0°C to rt, 2 h; (f) p-nitrobenzoyl chloride, Et₃N, CH₂Cl₂, 0°C to rt, 1 h, 80% (three steps); (g) H₂, cat. Pd/C, EtOAc, rt, 2 h; (h) 2-methyl-benzoyl chloride, Et₃N, CH₂Cl₂, 0°C to rt, 1 h, 85% (two steps).

Synthesis of 17β-Hydroxysteroid Dehydrogenase Type-3 Inhibitor 3

17β-HSD3 inhibitor 3, which has a dibenzazocine ring, exhibits inhibitory activity against 17β-HSD3 in cell-free enzymatic assays from picomolar to low nanomolar levels, as well as in cell-based transcriptional reporter assays. Therefore, this compound is considered to be useful for the treatment of prostate cancer.^10,11)

The synthetic strategy for 17β-HSD3 inhibitor 3 is shown in Chart 4. The biphenyl moiety would be formed by a transition metal-catalyzed cross-coupling reaction at one of the benzene rings with a halogen substituent such as a bromine atom. The dibenzazocine skeleton would be constructed by the reductive ring-expansion reaction of pseudo-symmetrical dibenzosuberone oxime 9 with DIBALH and acetylation of the resultant secondary amine 6. A key issue here was the regiochemistry of migration during the reductive ring-expansion reaction of pseudo-symmetrical dibenzosuberone oxime 9. We observed that the more electron-rich aromatic ring preferentially migrates when the reaction was examined by using 4,4′-disubstituted pseudo-symmetrical benzophenone oximes.³⁾ Therefore, we predicted that the regiochemistry could be controlled by the differentiation of electron densities between the two benzene rings by introduction of suitable substituents. We expected that the bromine atom would decrease the electron density of the right-hand benzene ring to control regiochemistry (9a: D=H, W=Br in Chart 4). Furthermore, introduction of a methylthio group, which is easily removed by Raney Ni, should enhance desired regioselectivity by increasing electron density of other benzene ring (9b: D=SMe, W=Br).

Chart 4. Synthetic Strategy for 17β-HSD3 Inhibitor Based on Regiocontrolled Migration of Aryl Moiety

With these considerations, we prepared dibenzosuberone oximes 9a and 9b to examine the regiochemistry during the ring-expansion reaction (Chart 5). Sonogashira coupling of methyl 3-bromo-6-iodobenzoate 17 and trimethylsilylacetylene followed by basic removal of the trimethylsilyl (TMS) group gave arylacetylene 18. The second Sonogashira coupling with iodobenzene or 3-iodo-1-methylthiobenzene^14,15) provided 1,2-diarylacetylenes 19. While hydrogenation of 19a smoothly gave ester 20a with catalytic platinum oxide under atmospheric pressure, reduction of 19b required high-pressure (70 atm) conditions for the high-yielding process. Hydrolysis of 20 and subsequent Friedel–Crafts-type acylation of 21 using P₂O₅–MsOH (PPMA) afforded dibenzosuberones 22,^16,17) which was converted to the corresponding oximes 9a and 9b by treatment with NH₂OH·HCl in pyridine.

Chart 5. Preparation of Oximes 9

Reagents and conditions: (a) trimethylsilyl acetylene, PdCl₂(PPh₃)₂ (1 mol%), CuI (2 mol%), Et₃N, DMF, rt, 30 h; (b) K₂CO₃, MeOH, 0°C, 10 min, 75% (two steps); (c) iodobenzene or 3-iodo-1-methylthiobenzene, PdCl₂(PPh₃)₂ (1 mol%), CuI (2 mol%), Et₃N, DMF, rt, 3–7 h, 19a: 54%, 19b: 92%; (d) H₂ (1 atm), PtO₂ (10 mol%), EtOAc–EtOH–AcOH, rt, 1.5 h, 20a: 89%; (e) H₂ (70 atm), PtO₂ (5 mol%), THF, rt, 14 h; (f) 2 M NaOH aq, THF–MeOH, 0°C to rt, 9–11 h; (g) PPMA (P₂O₅/methanesulfonic acid), 80°C, 0.5 h, 22a: 68% (two steps), 22b: 71% (three steps); (h) NH₂OH·HCl, pyridine, reflux, 34–48 h, 9a: 90%, 9b: 66%.

The pseudo-symmetrical oximes 9a and 9b were then used to examine the regiochemistry of the reductive ring-expansion reaction during the construction of a dibenzazocine ring (Table 1). Reaction of oxime 9a using 6 eq of DIBALH at 0°C was incomplete even after increasing the reaction temperature to room temperature, giving a mixture of azocines 23a and 24a (23a : 24a=3.3 : 1.0) in 46% yield with recovery of 28% of the oxime 23a (Entry 1). When the reaction was carried out at 80°C in 1,2-dichloroethane, oxime 9a was completely consumed to afford a mixture of azocines (23a : 24a=2.0 : 1.0) in 73% yield (Entry 2). This low regiochemistry prompted us to test the reactions of 9b, which has an SMe group instead of H. To this end, treatment of 9b with DIBALH at 0°C gave a mixture of azocines with substantially improved regioselectivity (23b : 24b=8.5 : 1.0), albeit yield (42%) was modest (Entry 3). Finally, we established satisfactory conditions using 6 eq of DIBALH at room temperature to give azocines 23b and 24b in 67% yield (23b : 24b=6.0 : 1.0) (Entry 4).

Table 1. DIBALH-Mediated Ring-Expansion Reaction^a)

Entry	X	Temp. (°C)	Time (h)	Yield (%)b)	23 : 24c)
1	H	0 to rt	12	46d)	3.3 : 1.0
2e)	H	80	16	73	2.0 : 1.0
3	SMe	0 to rt	12	42f)	8.5 : 1.0
4	SMe	rt	12	67	6.0 : 1.0

a) Reaction conditions: DIBALH (6 eq) was added to the mixture of 9 in CH₂Cl₂ (0.1 M). b) Isolated yields as a mixture of 23 and 24. c) Determined by ¹H-NMR. d) Starting material 9a (28%) was recovered. e) Instead of CH₂Cl₂, 1,2-dichloroethane was used as a solvent. f) Starting material 9b (36%) was recovered.

Having succeeded in using a regioselective ring-expansion reaction to form a dibenzoazocine ring, we then proceeded to complete the synthesis of 17β-HSD3 inhibitor 3 (Chart 6). As the mixture of 23b and 24b was not easily separable, the mixture was subjected to acetylation conditions using Ac₂O and 4-(dimethylamino)pyridine (DMAP)–Et₃N. After flash column chromatography on silica gel, 25a and 27a were obtained in 66% and 19% isolated yields, respectively. The structure of compound 25a was confirmed by X-ray crystallographic analysis¹⁸⁾ (Fig. 2). Suzuki–Miyaura cross coupling of 25b with phenylboronic acid furnished 26 in 78% yield. Finally, desulfurization of 26 under hydrogen atmosphere in the presence of Raney Ni afforded 5-acetyl-5,6,11,12-tetrahydro-8-phenyldibenz[b,f]azocine 3 in 69% yield.

Chart 6. Regioselective Rearrangement of Asymmetric Oxime and Transformation to 17β-HSD3 Inhibitor 3

Reagents and conditions: (a) Ac₂O, DMAP, Et₃N, CH₂Cl₂, rt, 0.5–1 h, 25a: 66%, 27a: 19%, 25b: 70%, 27b: 11%; (b) PhB(OH)₂, Pd(PPh₃)₄ (10 mol%), K₂CO₃, THF–H₂O, reflux, 6–22 h, 3: 70%, 26: 78%; (c) H₂ (1 atm), Raney Ni, EtOH, reflux, 3 h, 69%.

Fig. 2. ORTEP Drawing of the Molecular Structure of Compound 25a with Thermal Ellipsoids at 50% Probability Levels

Hydrogen atoms are omitted for clarity.

Conclusion

Synthesis of three clinical candidates for medicines, the human urate transporter-1 (URAT-1) inhibitor 1, the arginine vasopressin (AVP) antagonist 2, and the 17β-hydroxysteroid dehydrogenase type-3 (17β-HSD3) inhibitor 3, was accomplished via efficient construction of their 3,4-dihydro-2H-benzo[b][1,4]oxazine 4, dibenzodiazepine 5, and dibenzazocine 6 skeletons using the reductive ring-expansion reaction of the corresponding bicyclic or tricyclic oximes 7, 8, and 9, respectively. As oximes are a readily available intermediate, this ring-expansion strategy should be a powerful tool to construct a broad range of 6-, 7-, and 8-membered benzo-fused nitrogen heterocyclic rings and should find widespread use in synthetic and medicinal chemistry in the near future.

Experimental

General Remarks

Materials were obtained from commercial suppliers and used without further purification unless otherwise mentioned. All reactions were carried out in oven-dried glassware under a slight positive pressure of argon unless otherwise noted. Anhydrous THF and CH₂Cl₂ were purchased from Kanto Chemical Co., Inc. Anhydrous toluene, DMF, and MeCN were purchased from Wako Pure Chemical Industries, Ltd. Anhydrous EtOAc, MeOH, 1,2-dichloroethane, and EtOH were dried and distilled according to the standard protocols. Column chromatography was performed on Silica Gel 60N (Kanto, spherical neutral, 63–210 µm) and flash column chromatography was performed on Silica Gel 60N (Kanto, spherical neutral, 40–50 µm) using the indicated eluent. Preparative TLC and analytical TLC were performed on Merck 60 F₂₅₄ glass plates precoated with a 0.25 mm thickness of silica gel. All melting points were determined on a Yanaco micro melting point apparatus and uncorrected. IR spectra were measured on a SHIMADZU FTIR-8300 spectrometer or a JASCO FT/IR-4100 spectrometer. NMR spectra were recorded on a JEOL-ECA600, a GX500 spectrometer and JNM-AL400 spectrometer with tetramethylsilane (0 ppm) or chloroform (7.26 ppm) as an internal standard. Mass spectra were recorded on a JEOL JMS-DX-303 spectrometer, a JMS-AX-500 spectrometer, a JMS-T100GC spectrometer, or a MS-50070BU spectrometer. Optical rotations were measured on a Horiba SEPA-300 high sensitive polarimeter. Elemental analyses were performed by a Yanaco CHN CORDER MT-5.

3,5-Dichloro-4-hydroxybenzoyl Chloride

A screw top test tube equipped with a magnetic stirring bar was charged with 3,5-dichloro-4-hydroxybenzoic acid (57.8 mg, 0.279 mmol) and anhydrous dichloromethane (0.56 mL). To the solution were added oxalyl chloride (36 µL, 0.42 mmol) and N,N-dimethylformamide (DMF) (2.0 µL, 0.026 mmol) at 0°C. After the reaction mixture was stirred at 0°C for 5 min, the mixture was allowed to warm to room temperature and the solution was stirred for 1.5 h. The mixture was concentrated under reduced pressure to afford 3,5-dichloro-4-hydroxybenzoyl chloride as a yellow solid, which was used to the next reaction without further purification.

2,6-Dichloro-4-(2,3-dihydro-1,4-benzoxazin-4-ylcarbonyl)phenol (1)

A screw top test tube equipped with a magnetic stirring bar was charged with benzoxazine 4 (18.8 mg, 0.139 mmol) and anhydrous EtOAc (0.30 mL). To the stirred solution was added the crude acid chloride (0.279 mmol) in anhydrous EtOAc (0.26 mL) at room temperature. Stirring was continued for 4 h and the reaction mixture was quenched with saturated aqueous NaHCO₃ and extracted with EtOAc three times. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to leave the residue, which was purified by preparative TLC (hexanes–EtOAc=3 : 1) to afford the URAT-1 inhibitor 1 (12.9 mg, 0.0398 mmol, 29%) as a colorless solid; Rf=0.21 (Silica gel, hexanes–EtOAc=3 : 1); IR (neat) cm⁻¹: 2927, 1618, 1597, 1489, 1399, 1240, 1179, 1059, 755; ¹H-NMR (400 MHz, acetone-d₆) δ: 7.55 (2H, s), 7.25–7.11 (1H, m), 7.00 (1H, ddd, J=8.4, 7.6, 1.6 Hz), 6.88 (1H, dd, J=8.4, 1.6 Hz), 6.73 (1H, ddd, J=8.4, 7.6, 1.6 Hz), 4.43–4.33 (2H, m), 4.02–3.91 (2H, m), 2.81 (1H, br s); ¹³C-NMR (100 MHz, acetone-d₆) δ: 166.5, 151.8, 147.3, 129.9, 129.6, 127.0, 126.1, 125.1, 122.4, 120.4, 117.9, 66.8, 44.2; high resolution (HR)-MS (electrospray ionization (ESI)) Calcd for C₁₅H₁₂Cl₂NO₃ (M+H⁺): 324.0189; Found: 324.0173.

tert-Butyl Acridine-10(9H)-carboxylate (13)

A two-necked 20-mL round-bottomed flask equipped with a magnetic stirring bar was charged with acridone 11 (195 mg, 1.00 mmol), and THF (2.5 mL). To the solution was added BH₃·THF (1.08 M in THF, 1.3 mL, 1.4 mmol) at room temperature. The reaction mixture was heated at reflux for 4 h. The reaction was quenched with brine and 2 M aqueous NaOH, and the mixture was extracted with ether three times. The combined organic extracts were washed with saturated aqueous NaHCO₃, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to afford the crude dihydroacridine 12 as a colorless solid, which was used to the next reaction without further purification. A 50-mL round-bottomed flask equipped with a magnetic stirring bar was charged with 12, Boc₂O (766 mg, 3.51 mmol), and MeCN (3.3 mL). To the solution was added DMAP (203 mg, 1.66 mmol) at 0°C and stirring was continued for 11 h at room temperature. The reaction was diluted with ether. The mixture was washed with saturated aqueous NH₄Cl and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to leave the residue, which was purified by silica gel column chromatography (hexanes–EtOAc=9 : 1) to afford 13 (226 mg, 0.803 mmol, 80%); mp 97.4–98.9°C, colorless crystals; Rf=0.47 (Silica gel, hexanes–EtOAc=9 : 1); IR (neat) cm⁻¹: 1706, 1476, 1328, 1269, 1253, 1151, 760; ¹H-NMR (400 MHz, CDCl₃) δ: 7.63 (d, 2H, J=8.0 Hz), 7.36–7.17 (m, 4H), 7.12 (d, 2H, J=7.2 Hz), 3.80 (s, 2H), 1.54 (s, 9H); ¹³C-NMR (125 MHz, CDCl₃) δ: 152.5, 138.8, 133.0, 126.9, 125.9, 125.04, 124.96, 33.8, 28.2, 27.9; HR-MS (ESI) Calcd for C₁₄H₁₂NO₂ [(M−t-Bu+2H)⁺] 226.0863, Found: 226.0878.

tert-Butyl 9-(Hydroxyimino)acridine-10(9H)-carboxylate (14)

A two-necked 30-mL round-bottomed flask equipped with a magnetic stirring bar was charged with tert-butyl acridine-10(9H)-carboxylate 13 (100.5 mg, 0.36 mmol) and anhydrous THF (3.6 mL). To the solution was added t-BuONO (51.0 µL, 0.43 mmol) at 0°C, followed by KHMDS (0.47 M in toluene, 0.91 mL, 0.43 mmol) dropwise at 0°C. After 0.5 h, the reaction was quenched with saturated aqueous NH₄Cl, and the aqueous layer was extracted three times with ether. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, and filtered. The organic solvents were removed under reduced pressure to leave the residue, which was purified by flash silica gel column chromatography (hexanes–EtOAc=4 : 1) to afford oxime 14 (103.6 mg, 0.33 mmol, 93%) as a colorless solid; Rf=0.35 (hexanes–EtOAc=4 : 1); IR (neat) cm⁻¹: 3071, 2974, 2928, 1716, 1598, 1463, 1322, 1251, 1159, 955, 923, 755; ¹H-NMR (400 MHz, CDCl₃) δ: 8.42 (dd, 1H, J=8.0, 1.2 Hz), 8.23 (br s, 1H), 7.79 (d, 1H, J=8.0 Hz), 7.78 (d, 1H, J=8.0 Hz), 7.72 (dd, 1H, J=8.0, 1.2 Hz), 7.41 (ddd, 1H, J=8.0, 8.0, 1.2 Hz), 7.39 (ddd, 1H, J=8.0, 8.0, 1.2 Hz), 7.27 (dd, 1H, J=8.0, 8.0 Hz), 7.24 (dd, 1H, J=8.0, 8.0 Hz), 1.53 (s, 9H); ¹³C-NMR (100 MHz, CDCl₃) δ: 152.0, 146.4, 138.5, 137.5, 129.2, 129.0, 128.3, 128.2, 125.47, 125.42, 124.7, 124.6, 124.3, 124.2, 82.9, 28.1; HR-MS (ESI) Calcd for C₁₈H₁₉N₂O₃ (M+H⁺) 311.1390, Found: 311.1386; Anal. Calcd for C₁₈H₁₈N₂O₃: C, 69.66; H, 5.85; N, 9.03; Found: C, 69.79; H, 5.81; N, 8.94.

9(10H)-Acridone Oxime (8)

A 20-mL round-bottomed flask equipped with a magnetic stirring bar was charged with carbamate 14 (32.6 mg, 0.105 mmol) and anhydrous dichloromethane (0.7 mL). To the solution was added trifluoroacetic acid (TFA) (0.35 mL, 4.7 mmol) at 0°C. After the reaction mixture was stirred at 0°C for 5 min, the mixture was allowed to warm to room temperature and the solution was stirred for 3 h. The reaction mixture was quenched with saturated aqueous NaHCO₃ at 0°C and was extracted with EtOAc three times. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to afford the crude acridone oxime 8, which was subjected to the next reaction without further purification.

(5H-Dibenzo[b,e][1,4]diazepin-10(11H)-yl)(4-nitrophenyl)methanone (15)

A 20-mL round-bottomed flask equipped with a magnetic stirring bar was charged with oxime 8 and anhydrous dichloromethane (1.0 mL). To the stirred solution was added DIBALH (1.03 M in hexane, 0.60 mL, 0.62 mmol) at 0°C. After the reaction mixture was stirred at 0°C for 5 min, the mixture was allowed to warm to room temperature and the solution was stirred for 2 h. The reaction was quenched with NaF (127 mg) and H₂O (40 µL) at 0°C, and the resulting mixture was stirred for 30 min at the same temperature. Then the mixture was filtered through a pad of Celite. The filter cake was washed with ether and dichloromethane, and the filtrate was concentrated under reduced pressure to afford the crude dibenzodiazepine 5 as yellow solids, which was subjected to the next reaction without further purification. A 20-mL round-bottomed flask equipped with a magnetic stirring bar was charged with 5, Et₃N (73 µL, 0.52 mmol), and anhydrous dichloromethane (1.0 mL). To the solution was added p-nitrobenzoyl chloride (39.3 mg, 0.212 mmol) at 0°C. After the reaction mixture was stirred at 0°C for 5 min, the mixture was allowed to warm to room temperature and the solution was stirred for 1 h. The reaction was quenched with saturated aqueous NH₄Cl, and the mixture was extracted with dichloromethane three times. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to leave the residue, which was purified by silica gel column chromatography (hexanes–EtOAc=3 : 1 to 3 : 2) to afford amide 15 (29.1 mg, 0.0843 mmol, 80% for 3 steps) as a yellow solid; Rf=0.63 (Silica gel, hexanes–EtOAc=1 : 1); IR (neat) cm⁻¹: 3337, 1634, 1595, 1520, 1504, 1495, 1344, 745, 731; ¹H-NMR (400 MHz, CDCl₃) δ: 8.00 (d, 2H, J=8.4 Hz), 7.41 (d, 2H, J=8.4 Hz), 7.29 (d, 1H, J=8.0 Hz), 7.19 (dd, 1H, J=8.0, 8.0 Hz), 7.13–7.00 (m, 1H), 6.95–6.80 (m, 3H), 6.62–6.50 (m, 2H), 6.43 (br s, 1H), 5.81 (br s, 1H), 4.27 (br s, 1H); ¹³C-NMR (100 MHz, CDCl₃) δ: 167.0, 148.1, 142.1, 140.9, 138.6, 130.6, 130.2, 129.2, 128.8, 128.7, 128.3, 123.5, 123.0, 119.9, 119.8, 118.5, 117.6, 51.9; HR-MS (EI) Calcd for C₂₀H₁₅N₃O₃ (M⁺) 345.1113, Found: 345.1087.

N-(4-(10,11-Dihydro-5H-dibenzo[b,e][1,4]diazepine-10-carbonyl)phenyl)-2-methylbenzamide (2)

A Schlenk tube equipped with a magnetic stirring bar was charged with amide 15 (13.1 mg, 0.038 mmol), 10% Pd/C (10.6 mg, 0.010 mmol) and EtOAc (0.38 mL). To the flask was charged with hydrogen gas (1 atm). The resulting suspension was vigorously stirred for 2 h. The reaction mixture was filtered through a pad of Celite. The filter cake was washed with EtOAc, and the filtrate was concentrated under reduced pressure to leave the crude amine 16 as yellow solids, which was subjected to the next reaction without further purification. A 20-mL round-bottomed flask equipped with a magnetic stirring bar was charged with 16, Et₃N (26 µL, 0.19 mmol), and anhydrous dichloromethane (0.76 mL). To the solution was added 2-methylbenzoyl chloride (7.5 µL, 0.057 mmol) at 0°C. After the reaction mixture was stirred at 0°C for 5 min, the mixture was allowed to warm to room temperature and the solution was stirred for 1 h. The reaction was quenched with saturated aqueous NH₄Cl, and the mixture was extracted with dichloromethane three times. The combined organic extracts were washed with saturated aqueous NaHCO₃ and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to leave the residue, which was purified by preparative TLC (hexanes–EtOAc=1 : 1) to afford amide 2 (14.0 mg, 0.0323 mmol, 85% for 2 steps) as a yellow solid; Rf=0.39 (Silica gel, hexanes–EtOAc=1 : 1); IR (neat) cm⁻¹: 3320, 3229, 3056, 3012, 1660, 1623, 1594, 1525, 1493, 1407, 1317, 752; ¹H-NMR (400 MHz, CDCl₃) δ: 7.92 (br s, 1H), 7.60–7.06 (m, 10H), 6.98 (dd, 1H, J=7.6, 7.6 Hz), 6.83 (d, 2H, J=8.0 Hz), 6.79 (dd, 1H, J=7.6, 7.6 Hz), 6.70 (br s, 1H), 6.63–6.45 (m, 2H), 5.80 (br s, 1H), 4.20 (br s, 1H), 2.36 (s, 3H); ¹³C-NMR (125 MHz, CDCl₃) δ: 168.4, 168.1, 141.4, 139.5, 138.5, 136.4, 136.0, 132.0, 131.2, 130.3, 130.1, 129.7, 128.9, 128.5, 127.7, 126.9, 126.6, 125.8, 125.7, 123.8, 119.7, 119.4, 118.4, 117.4, 20.0, 19.7; HR-MS (ESI) Calcd for C₂₈H₂₄N₃O₂ (M+H⁺) 434.1863, Found: 434.1870.

Methyl 5-Bromo-2-ethynylbenzoate (18)

A two-necked 200-mL round-bottomed flask equipped with a magnetic stirring bar was charged with aryl iodide 17 (1.733 g, 5.083 mmol), CuI (20.8 mg, 0.109 mmol), and DMF (25 mL). To the solution were added Et₃N (2.1 mL, 15.1 mmol), PdCl₂(PPh₃)₂ (36.1 mg, 0.0514 mmol), and trimethylsilylacetylene (1.1 mL, 7.8 mmol). The solution was stirred for 30 h. The reaction was quenched with water, and the mixture was extracted with EtOAc three times. The combined organic extracts were washed with water and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to leave the residue, which was purified by short silica gel column chromatography (hexanes–EtOAc=9 : 1) to afford TMS-acetylene (1.706 g, 5.49 mmol, quant.) as yellow solids; Rf=0.74 (Silica gel, hexanes–EtOAc=3 : 1). A 100-mL round-bottomed flask equipped with a magnetic stirring bar was charged with TMS-acetylene and MeOH (10 mL). To the solution was added K₂CO₃ (1.4 g, 10.1 mmol) at 0°C. The solution was stirred for 10 min. The solution was concentrated under reduced pressure. The reaction mixture was filtered through a pad of Celite. The filter cake was washed with ether, and the filtrate was concentrated under reduced pressure to leave the residue, which was purified by silica gel column chromatography (hexanes–ether=9 : 1) to afford aryl acetylene 18 (909 mg, 3.80 mmol, 75% for 2 steps) as a pale yellow solid; Rf=0.50 (Silica gel, hexanes–ether=3 : 1); IR (neat) cm⁻¹: 3256, 3099, 2950, 2103, 1730, 1430, 1291, 1243, 1073, 689; ¹H-NMR (400 MHz, CDCl₃) δ: 8.09 (d, 1H, J=2.0 Hz), 7.61 (dd, 1H, J=8.0, 2.0 Hz), 7.48 (d, 1H, J=8.0 Hz), 3.94 (s, 3H), 3.45 (s, 1H); ¹³C-NMR (100 MHz, CDCl₃) δ: 165.1, 136.2, 134.8, 133.9, 133.3, 122.6, 121.6, 83.4, 81.1, 52.5; HR-MS (ESI) Calcd for C₁₀H₈BrO₂ (M+H⁺) 238.9702, Found: 238.9697.

Procedure for the Sandmeyer Reaction to Give 3-Iodo-1-methylthiobenzene

A 300-mL round-bottomed flask equipped with a magnetic stirring bar was charged with m-(methylthio)aniline (4.00 mL, 32.5 mmol), crushed ice (24 g), and MeCN (24 mL). To the stirred solution was added concentrated H₂SO₄ (24 mL) at 0°C over 30 min. To the slurry was added aqueous NaNO₂ (4.04 g, 58.6 mmol) in cold H₂O (8 mL) at 0°C dropwise over 30 min to maintain the internal temperature below 5°C. After the mixture was stirred at 0°C for 30 min, the mixture was poured into a solution of KI (18.9 g, 114 mmol) in H₂O (24 mL) at 0°C. After the resulting mixture was stirred at 0°C for 5 min, the mixture was allowed to warm to room temperature and the solution was stirred for 1 h. The reaction was quenched with H₂O, and the mixture was extracted with CHCl₃ three times. The combined organic extracts were washed with saturated aqueous NaHCO₃, saturated aqueous Na₂S₂O₃, and brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to leave the residue, which was purified by silica gel column chromatography (hexanes) to afford 3-iodo-1-methylthiobenzene (7.71 g, 30.8 mmol, 95%) as a pale yellow oil. The spectral data of 3-iodo-1-methylthiobenzene was identical with those reported in ref. 14.

Methyl 5-Bromo-2-[(3-methylthiophenyl)ethynyl]benzoate (19b)

A two-necked 200-mL round-bottomed flask equipped with a magnetic stirring bar was charged with aryl acetylene 18 (718 mg, 3.00 mmol), 3-iodo-1-methylthiobenzene (906 mg, 3.62 mmol), and DMF (6.0 mL). To the solution were added PdCl₂(PPh₃)₂ (21.5 mg, 0.0306 mmol), CuI (11.4 mg, 0.0599 mmol), and Et₃N (1.3 mL, 9.3 mmol). The solution was stirred for 3 h. The reaction was quenched with water, and the mixture was extracted with EtOAc three times. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to leave the residue, which was purified by silica gel column chromatography (hexanes–EtOAc=19 : 1) to afford diaryl acetylene 19b (999 mg, 2.77 mmol, 92%) as a pale yellow solid; Rf=0.25 (Silica gel, hexanes–EtOAc=19 : 1); IR (neat) cm⁻¹: 2214, 1726, 1561, 1475, 1437, 1286, 1241, 1092, 1078, 964, 817, 780, 679; ¹H-NMR (400 MHz, CDCl₃) δ: 8.12 (d, 1H, J=2.0 Hz), 7.61 (dd, 1H, J=8.4, 2.0 Hz), 7.49 (d, 1H, J=8.4 Hz), 7.42 (br s, 1H), 7.33 (ddd, 1H, J=6.8, 1.6, 1.6 Hz), 7.26 (dd, 1H, J=8.0, 6.8 Hz), 7.23 (ddd, 1H, J=6.8, 1.6, 1.6 Hz), 3.96 (s, 3H), 2.50 (s, 3H); ¹³C-NMR (100 MHz, CDCl₃) δ: 165.2, 139.0, 135.2, 134.7, 133.5, 133.2, 129.1, 128.7, 128.3, 126.9, 123.6, 122.5, 121.9, 95.0, 87.6, 52.4, 15.6; HR-MS (ESI) Calcd for C₁₇H₁₄BrO₂S (M+H⁺) 360.9892, Found: 360.9890.

Methyl 5-Bromo-2-(Phenylethynyl)benzoate (19a)

A pale yellow solid; IR (neat) cm⁻¹: 1727, 1492, 1438, 1289, 1244, 1077, 968, 825, 758, 690; ¹H-NMR (400 MHz, CDCl₃) δ: 8.12 (d, 1H, J=2.4 Hz), 7.61 (dd, 1H, J=8.4, 2.4 Hz), 7.59–7.54 (m, 2H), 7.50 (d, 1H, J=8.4 Hz), 7.41–7.32 (m, 3H), 3.97 (s, 3H); ¹³C-NMR (100 MHz, CDCl₃) δ: 165.3, 135.2, 134.8, 133.5, 133.2, 131.7, 128.8, 128.4, 123.0, 122.7, 121.8, 95.5, 87.3, 52.4; HR-MS (ESI) Calcd for C₁₆H₁₂BrO₂ (M+H⁺) 315.0015, Found: 315.0014.

Methyl 5-Bromo-2-phenethylbenzoate (20a)

A two-necked 10-mL round-bottomed flask equipped with a magnetic stirring bar was charged with acetylene 19a (58.1 mg, 0.184 mmol), PtO₂ (3.9 mg, 0.017 mmol), EtOAc (0.7 mL), EtOH (0.7 mL), and AcOH (0.4 mL). To the flask was charged with hydrogen gas (1 atm). The resulting suspension was vigorously stirred for 1.5 h. After the reaction mixture was filtered through a pad of Celite, the filter cake was washed with EtOAc. The filtrate was concentrated under reduced pressure to leave the residue, which was purified by silica gel column chromatography (hexanes–EtOAc=19 : 1) to afford ester 20a (52.2 mg, 0.164 mmol, 89%) as a yellow solid; Rf=0.35 (Silica gel, hexanes–EtOAc=19 : 1); IR (neat) cm⁻¹: 1726, 1434, 1288, 1246, 1081, 967, 700; ¹H-NMR (400 MHz, CDCl₃) δ: 8.03 (d, 1H, J=2.4 Hz), 7.50 (dd, 1H, J=8.4 and 2.4 Hz), 7.33–7.24 (m, 2H), 7.24–7.16 (m, 3H), 7.05 (d, 1H, J=8.4 Hz), 3.90 (s, 3H), 3.28–3.16 (m, 2H), 2.93–2.83 (m, 2H); ¹³C-NMR (100 MHz, CDCl₃) δ: 166.6, 142.6, 141.5, 134.8, 133.5, 132.9, 131.1, 128.5, 128.3, 126.0, 119.5, 52.2, 37.8, 36.2; HR-MS (ESI) Calcd for C₁₅H₁₂BrO [(M−OMe)⁺] 287.0066, Found: 287.0063.

Methyl 5-Bromo-2-(3-(Methylthio)phenethyl)benzoate (20b)

A Parr pressure bomb equipped with a magnetic stirring bar was charged with acetylene 19b (917 mg, 2.54 mmol), PtO₂ (28.9 mg, 0.127 mmol), and THF (12.7 mL). To the flask was charged with hydrogen gas (70 atm). The resulting suspension was vigorously stirred for 14 h. After the reaction mixture was filtered through a pad of Celite, the filter cake was washed with EtOAc. The filtrate was concentrated under reduced pressure to leave the residue, which was purified by silica gel column chromatography (hexanes–EtOAc=19 : 1) to afford ester 20b as a mixture of inseparable compounds (855 mg, <2.34 mmol, <92%) as a yellow solid; Rf=0.25 (Silica gel, hexanes–EtOAc=19 : 1); IR (neat) cm⁻¹: 2949, 2921, 1725, 1591, 1479, 1434, 1291, 1244, 1078, 967, 788; ¹H-NMR (400 MHz, CDCl₃) δ: 8.03 (d, 1H, J=2.4 Hz), 7.50 (dd, 1H, J=8.0, 2.4 Hz), 7.19 (dd, 1H, J=8.0, 8.0 Hz), 7.13–7.06 (m, 2H), 7.04 (d, 1H, J=8.0 Hz), 6.99–6.92 (m, 1H), 3.89 (s, 3H), 3.26–3.14 (m, 2H), 2.92–2.88 (m, 2H), 2.45 (s, 3H); ¹³C-NMR (100 MHz, CDCl₃) δ: 166.4, 142.4, 142.1, 138.2, 134.8, 133.5, 132.8, 131.1, 128.8, 126.9, 125.4, 124.3, 119.6, 52.2, 37.7, 35.9, 15.8; HR-MS (ESI) Calcd for C₁₆H₁₄BrOS [(M–OMe)⁺] 332.9943, Found: 332.9915.

3-Bromo-10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-one (22a)

A 10-mL round-bottomed flask equipped with a magnetic stirring bar was charged with ester 20a (38.0 mg, 0.119 mmol), THF (0.6 mL), and MeOH (0.6 mL). To the solution was added 2 M aqueous NaOH (1.2 mL) at 0°C. After the reaction mixture was stirred at 0°C for 5 min, the mixture was allowed to warm to room temperature and the solution was stirred for 11 h. The reaction was quenched with 2 M aqueous HCl at 0°C, and the mixture was extracted with EtOAc three times. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to afford the crude carboxylic acid 21a as a colorless solid, which was subjected to the next reaction without further purification. A screw top test tube equipped with a magnetic stirring bar was charged with carboxylic acid 21a. To the tube was added the PPMA solution, which was prepared from P₂O₅ (161 mg, 1.13 mmol) and MsOH (1.0 mL) at 80°C for 1 h. After the mixture was stirred for 0.5 h at 80°C, the reaction mixture was poured into ice-water and extracted with CHCl₃. The combined extracts were washed with brine and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to leave the residue, which was purified by preparative TLC (hexanes–EtOAc=17 : 3) to afford ketone 22a (23.3 mg, 0.0811 mmol, 68% for 2 steps) as a yellow oil; Rf=0.51 (Silica gel, hexanes–EtOAc=17 : 3); IR (neat) cm⁻¹: 3060, 2921, 2856, 1652, 1597, 1584, 1474, 1289, 841, 751; ¹H-NMR (400 MHz, CDCl₃) δ: 8.14 (d, 1H, J=2.4 Hz), 7.98 (dd, 1H, J=8.0, 2.4 Hz), 7.53 (dd, 1H, J=8.0, 1.6 Hz), 7.45 (ddd, 1H, J=8.0, 8.0, 1.6 Hz), 7.33 (ddd, 1H, J=8.0, 8.0, 1.2 Hz), 7.22 (dd, 1H, J=8.0, 1.2 Hz), 7.11 (d, 1H, J=8.0 Hz), 3.24–3.10 (m, 4H); ¹³C-NMR (100 MHz, CDCl₃) δ: 193.9, 141.8, 140.8, 140.1, 138.0, 135.0, 133.3, 132.7, 131.1, 130.7, 129.3, 126.8, 120.5, 34.7, 34.4; HR-MS (ESI) Calcd for C₁₅H₁₂BrO (M+H⁺), 287.0066; Found: 287.0059.

7-Bromo-2-(Methylthio)-10,11-dihydro-5H-dibenzo[a,d]-[7]annulen-5-one (22b)

Yellow solid; IR (neat) cm⁻¹: 2918, 1622, 1573, 1558, 1261, 1112, 774; ¹H-NMR (400 MHz, CDCl₃) δ: 8.15 (d, 1H, J=2.4 Hz), 8.03 (d, 1H, J=8.0 Hz), 7.52 (dd, 1H, J=8.0, 2.4 Hz), 7.16 (dd, 1H, J=8.0, 2.0 Hz), 7.10 (d, 1H, J=8.0 Hz), 7.03 (d, 1H, J=2.0 Hz), 3.19–3.09 (m, 4H), 2.52 (s, 3H); ¹³C-NMR (100 MHz, CDCl₃) δ: 192.1, 145.5, 142.8, 140.6, 140.2, 134.9, 133.8, 133.5, 131.8, 130.8, 125.7, 123.4, 120.6, 35.3, 34.3, 14.7; HR-MS (ESI) Calcd for C₁₆H₁₄BrOS (M+H⁺) 332.9943, Found: 332.9921.

3-Bromo-10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-one Oxime (9a)

A 20-mL round-bottomed flask equipped with a magnetic stirring bar was charged with ketone 22a (608 mg, 2.12 mmol) and pyridine (4.2 mL). To the solution was added hydroxylamine hydrochloride (1.8 g, 26 mmol). The solution was stirred at 130°C for 48 h. The reaction was quenched with water. The resulting mixture was extracted with EtOAc three times. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to leave the residue, which was purified by silica gel column chromatography (hexanes–EtOAc=17 : 3) to afford oxime 9a (577 mg, 1.91 mmol, 90%) as a pale yellow solid; Rf=0.53 (Silica gel, hexanes–EtOAc=3 : 1); IR (neat) cm⁻¹: 3172, 3059, 2916, 1426, 1311, 1006, 935, 819, 745; ¹H-NMR (400 MHz, CDCl₃) δ: 7.92 (br s, 0.55H), 7.82–7.70 (m, 0.9H), 7.62–7.57 (m, 0.55H), 7.57–7.51 (m, 0.55H), 7.48–7.09 (m, 5H), 7.05–6.97 (m, 0.45H), 3.24–2.96 (m, 4H); ¹³C-NMR (100 MHz, CDCl₃) δ: 157.6, 157.3, 138.5, 138.1, 137.8, 137.4, 136.1, 135.4, 133.8, 133.0, 132.2, 132.0, 132.0, 131.1, 131.0, 130.5, 130.0, 129.6, 129.5, 128.6, 128.4, 128.3, 126.4, 125.8, 119.6, 119.3, 33.3, 33.1, 31.8, 31.5; HR-MS (ESI) Calcd for C₁₅H₁₃BrNO (M+H⁺) 302.0175, Found: 302.0176.

7-Bromo-2-methylthio-10,11-dihydro-5H-dibenzo[a,d][7]-annulen-5-one Oxime (9b)

Pale yellow solid; IR (neat) cm⁻¹: 3214, 1588, 1427, 1002, 931, 812; ¹H-NMR (400 MHz, acetone-d₆) δ: 10.64 (br s, 0.5H), 10.60 (br s, 0.5H), 7.70 (d, 0.5H, J=2.4 Hz), 7.56 (d, 0.5H, J=1.6 Hz), 7.54–6.80 (m, 5H), 3.20–2.95 (m, 4H), 2.49 (s, 1.5H), 2.46 (s, 1.5H); ¹³C-NMR (100 MHz, acetone-d₆) δ: 140.7, 140.6, 140.0, 139.9, 138.84, 138.77, 138.2, 137.6, 133.3, 132.3, 132.14, 132.09, 132.06, 132.01, 131.95, 131.5, 131.3, 130.9, 130.3, 130.3, 128.3, 126.1, 124.4, 123.8, 119.6, 119.3, 34.1, 33.8, 32.4, 31.9, 15.1, 15.0; HR-MS (ESI) Calcd for C₁₆H₁₅BrNOS (M+H⁺) 348.0052, Found: 348.0037.

8-Bromo-5,6,11,12-tetrahydrodibenz[b,f]azocine (23a) and 3-Bromo-5,6,11,12-tetrahydrodibenz[b,f]azocine (24a)

A screw top test tube equipped with a magnetic stirring bar was charged with oxime 9a (15.6 mg, 0.0516 mmol) and anhydrous 1,2-dichloroethane (0.26 mL). To the solution was added DIBALH (1.03 M in hexane, 0.30 mL, 0.31 mmol) dropwise at 80°C for 0.5 h. The solution was stirred for 15 h. The reaction mixture was cooled to 0°C, and diluted with ether. The reaction was quenched with methanol and 2 M aqueous NaOH, and the mixture was extracted with ether three times. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to leave the residue, which was purified by preparative TLC (hexanes–EtOAc=17 : 3) to afford a mixture of 23a and 24a (10.8 mg, 0.0375 mmol, 73%) as a yellow solid.

8-Bromo-2-methylthio-5,6,11,12-tetrahydrodibenz[b,f]azocine (23b) and 3-Bromo-9-methylthio-5,6,11,12-tetrahydrodibenz[b,f]azocine (24b)

A two-necked 30-mL round-bottomed flask equipped with a magnetic stirring bar was charged with oxime 9b (175 mg, 0.503 mmol) and anhydrous dichloromethane (5.0 mL). To the stirred solution was added DIBALH (1.03 M in hexane, 3.0 mL, 3.09 mmol) dropwise at room temperature in water bath for 10 min. The solution was stirred for 12 h. The reaction mixture was cooled to 0°C and diluted with ether. The reaction was quenched with methanol and 2 M aqueous NaOH, and the mixture was extracted with diethyl ether three times. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to leave the residue, which was purified by silica gel column chromatography (hexanes–EtOAc=9 : 1) to afford an inseparable mixture of 23b and 24b (113 mg, 0.337 mmol, 67%) as a yellow solid; IR (neat) cm⁻¹: 3376 (br), 2919, 2891, 1592, 1484, 1258, 813, 756; ¹H-NMR (400 MHz, CDCl₃, isomeric mixture (6 : 1)). Major isomer: δ: 7.22–7.15 (m, 2H), 6.96 (d, 1H, J=2.0 Hz), 6.90 (dd, 1H, J=8.0, 2.0 Hz), 6.89 (d, 1H, J=7.6 Hz), 6.46 (d, 1H, J=8.0 Hz), 4.35 (s, 2H), 3.27–3.18 (m, 2H), 3.16–3.08 (m, 2H), 2.37 (s, 3H). Minor isomer: δ: 7.02–7.15 (m, 3H), 6.81 (d, 1H, J=8.0 Hz), 6.77 (dd, 1H, J=7.6, 2.0 Hz), 6.61 (d, 1H, J=2.0 Hz), 4.37 (s, 2H), 3.27–3.18 (m, 2H), 3.16–3.08 (m, 2H), 2.41 (s, 3H); ¹³C-NMR (100 MHz, CDCl₃) δ: 148.5, 145.3, 140.7, 139.3, 137.3, 133.7, 132.5, 132.2, 132.1, 131.9, 131.8, 131.2, 130.22, 130.19, 129.7, 128.3, 127.7, 127.6, 125.8, 124.6, 122.5, 121.2, 119.9, 119.8, 51.1, 50.8, 35.4, 34.8, 32.1, 31.6, 17.9, 15.6; HR-MS (ESI) Calcd for C₁₆H₁₇BrNS (M+H⁺), 334.0260; Found: 334.0249.

5-Acetyl-8-bromo-5,6,11,12-tetrahydrodibenz[b,f]azocine (25a)

A screw top test tube equipped with a magnetic stirring bar was charged with mixture of 23a and 24a, Et₃N (25 µL, 0.18 mmol) and anhydrous dichloromethane (0.36 mL). To the solution were added Ac₂O (7.0 µL, 0.074 mmol) and DMAP (2.2 mg, 0.018 mmol) at room temperature. The solution was stirred for 0.5 h. The reaction mixture was quenched with saturated aqueous NH₄Cl, and the mixture was extracted with dichloromethane three times. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to leave the residue, which was purified by preparative TLC (hexanes–EtOAc=3 : 1) to afford acetamide 25a (7.9 mg, 0.024 mmol, 66%) as colorless plates and acetamide 27a (2.3 mg, 0.0070 mmol, 19%) as colorless plates.

5-Acetyl-8-bromo-5,6,11,12-tetrahydrodibenz[b,f]azocine (25a)

mp 146.5–148.3°C, colorless crystals; IR (neat) cm⁻¹: 2944, 1651, 1496, 1386, 1282, 724; ¹H-NMR (400 MHz, CDCl₃) δ: 7.25–7.12 (m, 4H), 7.10–7.00 (m, 2H), 6.96–6.88 (m, 1H), 5.75 (d, 1H, J=14.8 Hz), 4.02 (d, 1H, J=14.8 Hz), 3.26–3.12 (m, 2H), 2.94–2.72 (m, 2H), 1.80 (s, 3H); ¹³C-NMR (100 MHz, CDCl₃) δ: 170.2, 140.5, 139.3, 139.0, 137.3, 132.7, 131.2, 131.1, 130.8, 128.7, 128.5, 128.0, 119.7, 52.0, 34.6, 30.9, 22.7; HR-MS (ESI) Calcd for C₁₇H₁₇BrNO (M+H⁺) 330.0488, Found: 330.0489.

5-Acetyl-3-bromo-5,6,11,12-tetrahydrodibenz[b,f]azocine (27a)

mp 140.7–142.2°C, colorless crystals; IR (neat) cm⁻¹: 3019, 2927, 1660, 1486, 1385, 1295, 761; ¹H-NMR (600 MHz, CDCl₃) δ: 7.31–7.19 (m, 2H), 7.16–7.01 (m, 4H), 6.91 (d, 1H, J=7.8 Hz), 5.76 (d, 1H, J=15.0 Hz), 4.07 (d, 1H, J=15.0 Hz), 3.30–3.18 (m, 1H), 3.16–3.07 (m, 1H), 2.93–2.77 (m, 2H), 1.82 (s, 3H); ¹³C-NMR (100 MHz, CDCl₃) δ: 169.8, 142.0, 139.9, 138.7, 134.5, 132.6, 131.6, 131.5, 130.2, 129.4, 128.0, 126.5, 120.2, 52.5, 34.4, 31.0, 22.9; HR-MS (ESI) Calcd for C₁₇H₁₇BrNO (M+H⁺) 330.0488, Found: 330.0484.

5-Acetyl-5,6,11,12-tetrahydro-8-phenyldibenz[b,f]azocine (3)

A screw top test tube equipped with a magnetic stirring bar was charged with aryl bromide 25a (10.8 mg, 0.0287 mmol), phenylboronic acid (6.7 mg, 0.055 mmol), K₂CO₃ (7.9 mg, 0.057 mmol), Pd(PPh₃)₄ (2.2 mg, 1.9 µmol), THF (0.15 mL), and H₂O (0.04 mL). The reaction mixture was heated to reflux for 6 h. The reaction mixture was diluted with EtOAc, washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to leave the residue, which was purified by preparative TLC (hexanes–acetone=3 : 1) to afford 3 (6.7 mg, 0.020 mmol, 70%) as a colorless oil; IR (neat) cm⁻¹: 3027, 2930, 1658, 1494, 1389, 765; ¹H-NMR (400 MHz, CDCl₃) δ: 7.49 (d, 2H, J=7.2 Hz), 7.45–7.27 (m, 5H), 7.21–7.00 (m, 5H), 5.83 (d, 1H, J=14.8 Hz), 4.16 (d, 1H, J=14.8 Hz), 3.38–3.15 (m, 2H), 3.00–2.81 (m, 2H), 1.82 (s, 3H); ¹³C-NMR (150 MHz, CDCl₃) δ: 170.3, 140.5, 139.43, 139.37, 139.1, 135.4, 131.2, 130.0, 128.8, 128.7, 128.6, 128.54, 128.46, 127.8, 127.1, 126.9, 126.3, 52.8, 34.8, 31.2, 22.8; HR-MS (ESI) Calcd for C₂₃H₂₂NO (M+H⁺) 328.1696, Found: 328.1699.

5-Acetyl-8-bromo-5,6,11,12-tetrahydro-2-methylthiodibenz[b,f]azocine (25b)

A screw top test tube equipped with a magnetic stirring bar was charged with mixture of 23b and 24b, Et₃N (33 µL, 0.24 mmol) and anhydrous dichloromethane (0.50 mL). To the solution were added Ac₂O (10 µL, 0.11 mmol) and DMAP (1.0 mg, 8.2 µmol) at room temperature. The solution was stirred for 1 h. The reaction was quenched with saturated aqueous NH₄Cl, and the mixture was extracted with dichloromethane three times. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to leave the residue, which was purified by preparative TLC (hexanes–EtOAc=3 : 1) to afford acetamide 25b (12.4 mg, 0.033 mmol, 70%) and acetamide 27b (2.0 mg, 0.0053 mmol, 11%).

5-Acetyl-8-bromo-5,6,11,12-tetrahydro-2-methylthiodibenz[b,f]azocine (25b)

A colorless oil; IR (neat) cm⁻¹: 3002, 2921, 1657, 1491, 1386, 1286, 754; ¹H-NMR (400 MHz, CDCl₃) δ: 7.26–7.20 (m, 2H), 7.03 (dd, 1H, J=8.0, 2.0 Hz), 6.97 (d, 1H, J=8.0 Hz), 6.91 (d, 1H, J=8.0 Hz), 6.89 (d, 1H, J=2.0 Hz), 5.73 (d, 1H, J=14.8 Hz), 3.99 (d, 1H, J=14.8 Hz), 3.24–3.10 (m, 2H), 2.88–2.70 (m, 2H), 2.42 (s, 3H), 1.80 (s, 3H); ¹³C-NMR (100 MHz, CDCl₃) δ: 170.3, 139.4, 139.3, 139.1, 137.3, 137.2, 132.7, 131.1, 130.8, 128.8, 128.4, 125.1, 119.8, 52.0, 34.7, 30.7, 22.7, 15.3; HR-MS (ESI) Calcd for C₁₈H₁₉BrNOS (M+H⁺) 376.0365, Found: 376.0381.

5-Acetyl-3-bromo-5,6,11,12-tetrahydro-9-methylthiodibenz[b,f]azocine (27b)

A colorless oil; IR (neat) cm⁻¹: 2292, 1660, 1587, 1487, 1382, 1295, 754; ¹H-NMR (600 MHz, CDCl₃) δ: 7.31–7.25 (m, 1H), 7.22 (d, 1H, J=1.8 Hz), 7.03 (d, 1H, J=7.2 Hz), 6.99–6.90 (m, 3H), 5.68 (d, 1H, J=15.0 Hz), 4.03 (d, 1H, J=15.0 Hz), 3.26–3.15 (m, 1H), 3.15–3.05 (m, 1H), 2.91–2.81 (m, 1H), 2.81–2.73 (m, 1H), 2.42 (s, 3H), 1.81 (s, 3H); ¹³C-NMR (100 MHz, CDCl₃) δ: 169.8, 142.1, 140.6, 138.5, 138.0, 132.6, 131.7, 131.5, 131.4, 130.8, 127.6, 124.2, 120.3, 52.1, 34.2, 31.3, 22.8, 15.7; HR-MS (ESI) Calcd for C₁₈H₁₉BrNOS (M+H⁺), 376.0365; Found: 376.0351.

5-Acetyl-5,6,11,12-tetrahydro-2-methylthio-8-phenyldibenz[b,f]azocine (26)

A screw top test tube equipped with a magnetic stirring bar was charged with aryl bromide 25b (35.2 mg, 0.0935 mmol), phenylboronic acid (23.2 mg, 0.190 mmol), K₂CO₃ (65.5 mg, 0.474 mmol), Pd(PPh₃)₄ (11 mg, 9.5 µmol), THF (0.4 mL), and H₂O (0.1 mL). The mixture was heated to reflux for 22 h. The reaction mixture was diluted with EtOAc, washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to leave the residue, which was purified by preparative TLC (hexanes–EtOAc=3 : 1) to afford 26 (27.1 mg, 0.0726 mmol, 78%) as a colorless oil; IR (neat) cm⁻¹: 3349, 2888, 1637, 1388, 1017, 762; ¹H-NMR (400 MHz, CDCl₃) δ: 7.51 (d, 2H, J=8.0 Hz), 7.43–7.26 (m, 5H), 7.11 (d, 1H, J=8.0 Hz), 7.04–6.96 (m, 2H), 6.91 (s, 1H), 5.82 (d, 1H, J=14.8 Hz), 4.13 (d, 1H, J=14.8 Hz), 3.35–3.12 (m, 2H), 2.94–2.80 (m, 2H), 2.40 (s, 3H), 1.81 (s, 3H); ¹³C-NMR (100 MHz, CDCl₃) δ: 170.3, 140.5, 139.8, 139.2, 139.1, 138.9, 137.7, 135.4, 130.0, 128.8, 128.7, 128.6, 128.5, 127.1, 126.9, 126.4, 125.0, 52.7, 34.9, 31.0, 22.8, 15.3; HR-MS (ESI) Calcd for C₂₄H₂₄NOS (M+H⁺) 374.1573, Found: 374.1576.

5-Acetyl-5,6,11,12-tetrahydro-8-phenyldibenz[b,f]azocine (3)

A Schlenk tube equipped with a magnetic stirring bar was charged with sulfide 26 (10.8 mg, 0.0289 mmol) and Raney nickel (W-2) in ethanol (0.5 mL). To the flask was charged with hydrogen gas (1 atm). The reaction mixture was heated to reflux for 3 h. The reaction mixture was filtered through a pad of Celite. The filter cake was washed with EtOAc, and the filtrate was concentrated under reduced pressure to leave the residue, which was purified by preparative TLC (hexanes–EtOAc=3 : 1) to afford 3 (6.6 mg, 0.020 mmol, 69%).

Acknowledgment

This work was supported by KAKENHI, a Grant-in-Aid for Scientific Research (C) (23590001), the Cabinet Office, Government of Japan through its “Funding Program for Next Generation World-Leading Researchers,” Platform for Drug Discovery, Informatics, and Structural Life Science from the Ministry of Education, Culture, Sports, Science and Technology of Japan, a JSPS predoctoral fellowship to Y.I., Japan Tobacco Inc. to H.C., and Banyu Life Science Foundation International.

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