HETEROCYCLES

Paper | Regular issue | Vol. 83, No. 11, 2011, pp. 2547-2562
Received, 22nd August, 2011, Accepted, 29th September, 2011, Published online, 4th October, 2011.
DOI: 10.3987/COM-11-12345

■ A Novel Synthesis of 3,4,5,6-Tetrahydro-7-hydroxy-1H-azepino[5,4,3-cd]indole Derivatives from Serotonin

Koji Yamada, Sakiko Teranishi, Ayako Miyashita, Minoru Ishikura, and Masanori Somei*

Faculty of Pharmaceutical Scicences, Graduate School of Natural Science and Technology, Kanazawa University, Kakuma, Kanazawa, Ishikawa 920-1192,

Abstract

Utilizing novel Nb-substituted serotonins, 5- and/or 6-substituted 3,4,5,6-tetrahydro-7-hydroxy-1H-azepino[5,4,3-cd]indole derivatives are produced simply by treating serotonins with aldehydes under basic conditions. Synthesis of 2,2a,3,4,5,6-hexahydro-7-hydroxy-1H-azepino[5,4,3-cd]indole-2-one derivatives is also reported.

In our synthetic project for discovering new biologically active compounds, we have thus far succeeded in the creation of efficient synthetic methods3a-d with high originality rate,4a,c-e intellectual property factor,4a,b and application potential factor4a,b culminating in the production of novel leads for an α2-blocker,3d,5 an inhibitor of platelet aggregation,3c,6 an anti-osteoporosis agent,3d,7 and potent root growth promotor.3a,b,8 These results are based on our hypothesis8,9 that any metabolite of tryptophan has each own function in vivo, and the combination of each structure is a promising method for designing a new possible drug.9

Tryptamine10 (1a), serotonin11 (1b), aurantioclavine12 (2a), and clavicipitic acid12 (2b) are well known natural products metabolized from tryptophan (Figure 1). Tryptamine (1a) is a minor amine in our body and its function has not been established yet.10 We created Nb-acyltryptamines (1c) and found them having potent activity as an α2-blocker.3c,d,5 Recently, we have also disclosed that 1c is an inhibitor for osteoblast differentiation13 and apoptosis,14 and even a stimulator of mineralization in osteoblasts.14 Serotonin (1b) is an important chemical transmitter in the central nervous system.11 Aurantioclavine (2a), and clavicipitic acid (2b) are members of ergot alkaloid.12
According to our hypothesis,8,9 when we unite the skeleton of 1b with that of 1c, 2a, and 2b, we get novel chimera compounds such as Nb-substituted serotonin derivatives (3) and 3,4,5,6-tetrahydro-7-hydroxy-1H-azepino[5,4,3-cd]indole derivatives (4). In addition, we can expect that compounds (1c) would be metabolized in our body to the corresponding 5-hydroxy compounds (3). The multimodal bioactivity of 1c might be originated from the function of 3 themselves. Therefore, we could expect 3 and 4 to become useful candidates for new biologically active substances.

On the other hand, in our preliminary study15 aiming at the synthesis of both compounds, 3 and 4, we reported an interesting finding that under basic conditions the reaction of 1b with acetaldehyde and benzaldehyde generated 6-substituted 3,4,5,6-tetrahydro-7-hydroxy-1H-azepino[5,4,3-cd]indoles (5), despite under acidic conditions the well known Pictet-Spengler16 reaction took place resulting in the formation of 1-substituted 6-hydroxy-β-carbolines (6, Scheme 1).
With an attempt to enlarge the scope of our above findings and to find new biologically active compounds, we now wish to describe the preparation of novel Nb-substituted serotonins (3) and 5- and/or 6-substituted 3,4,5,6-tetrahydro-7-hydroxy-1H-azepino[5,4,3-cd]indole derivatives (4).
I. Synthesis of Novel Nb-Substituted Serotonins
To meet our end, we needed various Nb-substituted serotonin derivatives. They are obtained by acylation of serotonin, followed by reduction of the resultant Nb-acylated serotonins (Scheme 2). Thus, serotonin hydrochloride (1b·HCl) was reacted with pentanoic acid by mixed anhydride method using methyl chloroformate in DMF–CHCl3 in the presence of Et3N at room temperature to give Nb-pentanoylserotonin (7a) in 92% yield. Similar reactions of 1b·HCl with nonanoic acid, hexadecanoic acid, cyclohexanecarboxylic acid, and benzoic acid afforded Nb-nonanoyl- (7b), Nb-hexadecanoyl- (7c), Nb-cyclohexylcarbonyl- (7d), and Nb-benzoylserotonins (7e) in 96, 88, 97, and 90% yields, respectively.
The compounds, 7b, 7c, and 7d, were similarly converted to Nb-nonyl- (8b), Nb-hexadecyl- (8c), and Nb-cyclohexylmethylserotonins (8d) in 81, 89, and 74% yields, respectively. It is interesting to note that the reduction of 7e under the same reduction conditions produced the desired Nb-benzylserotonin (8e) in only 47% yield together with 21% yield of unwanted 1b and 13% yield of the unreacted starting material. Addition of excess amount of LiAlH4 and longer refluxing time did not improve the yield effectively. As an alternative method, the reductive benzylation utilizing benzaldehyde and sodium cyanoborohydride was employed to 1b·HCl, but the yield of 8e was almost the same 56%.
Since various types of Nb-substituted serotonins are known as biologically active alkaloids,17 it would be safe to expect that the compounds, 7 and 8, have biological activities as well.
II. Synthesis of Novel 5- and 6-Substituted 3,4,5,6-Tetrahydro-7-hydroxy-1H-azepino[5,4,3-cd]indole Derivatives
Employing our basic conditions15 to the reaction of the above-mentioned Nb-substituted serotonins (8a–e) with aldehydes, selective preparation of various 5- and 6-substituted 3,4,5,6-tetrahydro-7-hydroxy-1H-azepino[5,4,3-cd]indole derivatives was successfully realized.
Thus, the reaction of 8a with acetaldehyde in Et3N-MeOH at room temperature for 2.5 h afforded 3,4,5,6-tetrahydro-7-hydroxy-6-methyl-5-pentyl-1H-azepino[5,4,3-cd]indole (10a) in 90% yield without the formation of the corresponding β-carboline (9a). Under similar reaction conditions, 8b, 8c, 8d, and 8e reacted with acetaldehyde to give 10b, 10c, 10d, and 10e in 97, 91, 80, and 89% yields, respectively. When decanal was employed instead of acetaldehyde in the reaction of 8a, 8b, and 8c, the corresponding 11a, 11b, and 11c were obtained in 76, 81, and 76% yields, respectively. In all of the above reactions, formation of the corresponding β-carbolines as by-products was not detected at all.
The 5-unsubstituted 3,4,5,6-tetrahydro-7-hydroxy-6-methyl-1H-azepino[5,4,3-cd]indole (12a) was obtained in 91% yield by the reductive debenzylation of 10e with 10% Pd/C at 1 atm hydrogen. The compound (12a) would be a useful starting material for the preparations of various 5-substituted derivatives. Treatment of 10e with Ac2O and Boc2O afforded 12b and 12c in 95 and 52% yields, respectively.
We next examined whether we can prepare 3,4,5,6-tetrahydro-7-hydroxy-1H-azepino[5,4,3-cd]indoles having a bulky substituent at the 5- and 6-positions employing 8a as a serotonin component. At room temperature the reaction of 8a with benzaldehyde (13a) in Et3N-MeOH did not take place, but the reflux temperature and longer reaction time (15 h) made it possible to form 3,4,5,6-tetrahydro-7-hydroxy-5-pentyl-6-phenyl-1H-azepino[5,4,3-cd]indole (14a) in 86% yield. Under the same conditions, slow reaction took place upon the reaction of 8a with more crowded 2-methylpropanal (13b). The desired product, 3,4,5,6-tetrahydro-7-hydroxy-6-isopropyl-5-pentyl-1H-azepino[5,4,3-cd]indole (14b), was obtained in 49% yield in addition to 11% yield of unwanted 10a and 23% yield of unreacted starting material. In the reaction of 8a with bulky 2,2-dimethylpropanal (13c) at reflux temperature for 15 h, the formation of the desired product (14c) was not detected at all, while 10a and unreacted starting material were obtained in 15 and 66% yields, respectively. The severe steric hindrance between 5 and 6 positions clearly precluded the formation of the seven-membered ring.
The isolation of 10a in the above two reactions proved the presence of the competing reaction of 8a with acetaldehyde, formed in situ from Et3N. The mechanism of the formation of acetaldehyde from Et3N in the reaction system is explained in detail in our previous paper.15

III. Synthesis of 2,2a,3,4,5,6-Hexahydro-7-hydroxy-1H-azepino[5,4,3-cd]indole-2-one Derivatives
Treatment of 5-benzyl-3,4,5,6-tetrahydro-7-hydroxy-6-methyl-1H-azepino[5,4,3-cd]indole (10e) with bromine in AcOH produced 5-benzyl-2,2a,3,4,5,6-hexahydro-7-hydroxy-6-methyl-1H-azepino[5,4,3-cd]indole-2-one (15a) and its 8-bromo derivative (16a) in 16 and 83% yields, respectively (Scheme 3). The formation of 2,2a,3,4,5,6-hexahydro-7-hydroxy-1H-azepino[5,4,3-cd]indole-2-one skeleton can be explained by the initial generation of 2-bromo-3,4,5,6-tetrahydro-7-hydroxy-1H-azepino[5,4,3-cd]indole, followed by hydrolysis of the labile 2-bromo substituent. Similarly, 5-cyclohexylmethyl derivatives, 15b and 16e, were prepared from 10d in 17 and 52% yields, respectively.
Further treatment of 16a with diazomethane afforded 16b in 95% yield. The reactions of 10d and 16a with Ac2O in pyridine gave 17 and 16c in 86 and 88% yields, respectively, while the reaction of 16a with Boc2O in the presence of DMAP provided 16d in 46% yield. Similar reactions of 16e with Ac2O and Boc2O afforded the corresponding 16f and 16g in 83 and 71% yields, respectively. Since the C–Br bond of these compounds can be manipulated to various functional groups, these compounds would be useful for the preparation of 8-substituted 2,2a,3,4,5,6-hexahydro-7-hydroxy-1H-azepino[5,4,3-cd]indole-2-ones.

In conclusion, we established that our reaction of serotonins with aldehydes under basic conditions is a general and convenient synthetic method for creating novel 7-hydroxy-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indoles. We also succeeded in the synthesis of novel 2,2a,3,4,5,6-hexahydro-7-hydroxy-1H-azepino[5,4,3-cd]indole-2-ones. Biological evaluation of the compounds reported in this paper is now in progress.

EXPERIMENTAL
Melting points were determined on a Yanagimoto micro melting point apparatus and are uncorrected. IR spectra were determined with Horiba FT-720 spectrophotometer and 1H-NMR spectra with JEOL GSX 500 spectrometer with tetramethylsilane as an internal standard. MS were recorded on JEOL JMS-SX 102A spectrometer. Preparative thin-layer chromatography (p-TLC) was performed on Merck Kiesel-gel GF245 (Type 60) (SiO2). Column chromatography was performed on silica gel (SiO2, 100–200 mesh, from Kanto Chemical Co., Inc.) throughout the present study.
Nb-Pentanoylserotonin (7a) from Serotonin·HCl (1b·HCl) — General procedure: a solution of ClCO2Me (254.0 mg, 2.7 mmol) in anhydrous CHCl3 (5.0 mL) was added to a solution of pentanoic acid (275.0 mg, 2.7 mmol) and Et3N (545.1 mg, 5.4 mmol) in anhydrous CHCl3 (5.0 mL) under ice cooling and the mixture was stirred at rt for 20 min. The resulting mixture was added to a solution of 1b·HCl (520.3 mg, 2.5 mmol) in anhydrous DMF (5.0 mL) and the mixture was stirred at rt for 30 min. After addition of H2O, the whole was extracted with CHCl3–MeOH (95:5, v/v). The extract was washed with brine, dried over Na2SO4, and evaporated under reduced pressure to leave a residue, which was column- chromatographed on SiO2 with CHCl3–MeOH (99:1, v/v) to give 7a (583.2 mg, 92%). 7a: colorless viscous oil. IR (film): 3309, 1628, 1541, 1458, 1188 cm-1. 1H-NMR (CDCl3) δ: 0.88 (3H, t, J = 7.4 Hz), 1.30 (2H, sex, J = 7.4 Hz), 1.52 (2H, quint, J = 7.4 Hz), 2.12 (2H, t, J = 7.4 Hz), 2.90 (2H, t, J = 6.8 Hz), 3.57 (2H, q, J = 6.8 Hz, collapsed to t, J = 6.8 Hz on addition of D2O), 5.57 (2H, br s, disappeared on addition of D2O), 6.80 (1H, dd, J = 8.5, 2.2 Hz), 6.99 (1H, d, J = 1.7 Hz, collapsed to s on addition of D2O), 7.03 (1H, d, J = 2.2 Hz), 7.22 (1H, d, J = 8.5 Hz), 7.95 (1H, br s, disappeared on addition of D2O). HR-MS m/z: Calcd for C15H20N2O2: 260.1525. Found: 260.1520.
Nb-Nonanoylserotonin (7b) from 1b·HCl — In the general procedure, ClCO2Me (252.9 mg, 2.7 mmol), anhydrous CHCl3 (5.0 mL), nonanoic acid (426.1 mg, 2.7 mmol), Et3N (544.4 mg, 5.4 mmol), anhydrous CHCl3 (5.0 mL), 1b·HCl (520.0 mg, 2.5 mmol), and anhydrous DMF (5.0 mL) were used. After column chromatography, 7b (739.0 mg, 96%) was obtained. 7b: colorless viscous oil. IR (film): 3307, 2925, 2854, 1628, 1541, 1458 cm-1. 1H-NMR (CDCl3) δ: 0.87 (3H, t, J = 7.0 Hz), 1.20–1.30 (10H, m), 1.58 (2H, quint, J = 7.0 Hz), 2.11 (2H, t, J = 7.0 Hz), 2.90 (2H, t, J = 6.8 Hz), 3.58 (2H, q, J = 6.8 Hz, collapsed to t, J = 6.8 Hz on addition of D2O), 5.35 (1H, br s, disappeared on addition of D2O), 5.50 (1H, br t, J = 6.8 Hz, disappeared on addition of D2O), 6.80 (1H, dd, J = 8.5, 2.2 Hz), 6.99 (1H, d, J = 2.0 Hz, collapsed to s on addition of D2O), 7.02 (1H, d, J = 2.2 Hz), 7.22 (1H, d, J = 8.5 Hz), 7.93 (1H, br s, disappeared on addition of D2O). HR-MS m/z: Calcd for C19H28N2O2: 316.2151. Found: 316.2146.
Nb-Hexadecanoylserotonin (7c) from 1b·HCl — In the general procedure, ClCO2Me (252.5 mg, 2.7 mmol), anhydrous CHCl3 (5.0 mL), hexadecanoic acid (690.3 mg, 2.7 mmol), Et3N (544.3 mg, 5.4 mmol), anhydrous CHCl3 (5.0 mL), 1b·HCl (520.0 mg, 2.5 mmol), and anhydrous DMF (5.0 mL) were used. After column chromatography, 7c (887.4 mg, 88%) was obtained. 7c: mp 121–122 °C (colorless powder, recrystallized from CHCl3–MeOH). IR (KBr): 3415, 3307, 2918, 2848, 1635, 1541 cm-1. 1H-NMR (CDCl3) δ: 0.88 (3H, t, J = 7.0 Hz), 1.21–1.28 (24H, m), 1.57 (2H, quint, J = 7.0 Hz), 2.11 (2H, t, J = 7.0 Hz), 2.90 (2H, t, J = 6.8 Hz), 3.58 (2H, q, J = 6 .8 Hz, collapsed to t, J = 6.8 Hz on addition of D2O), 4.93 (1H, br s, disappeared on addition of D2O), 5.51 (1H, br t, J = 6.8 Hz, disappeared on addition of D2O), 6.79 (1H, dd, J = 8.5, 2.2 Hz), 7.01 (1H, d, J = 2.0 Hz, collapsed to s on addition of D2O), 7.03 (1H, d, J = 2.2 Hz), 7.23 (1H, d, J = 8.5 Hz), 7.89 (1H, br s, disappeared on addition of D2O). MS m/z: 414 (M+). Anal. C26H42N2O2: C, 75.32; H, 10.21; N, 6.76. Found: C, 75.05; H, 10.38; N, 6.72.
Nb-Cyclohexylcarbonylserotonin (7d) from 1b·HCl — In the general procedure, ClCO2Me (486.9 mg, 5.2 mmol), anhydrous CHCl3 (10 mL), cyclohexanecarboxylic acid (655.3 mg, 5.2 mmol), Et3N (1.07 g, 10.3 mmol), anhydrous CHCl3 (10 mL), 1b·HCl (995.7 mg, 4.7 mmol), and anhydrous DMF (10 mL) were used. After column chromatography, 7d (1.30 g, 97%) was obtained. 7d: colorless foam. IR (KBr): 3317, 2929, 1631, 1531 cm-1. 1H-NMR (DMSO-d6) δ: 1.10–1.25 (3H, m), 1.33 (2H, q, J = 10.3 Hz), 1.60 (1H, br d, J = 10.3 Hz), 1.65–1.71 (4H, m, J = 9.3 Hz), 2.07 (1H, tt, J = 11.3, 3.0 Hz), 2.70 (2H, t, J = 7.4 Hz), 3.24–3.28 (2H, m, collapsed to t, J = 7.4 Hz on addition of D2O), 6.58 (1H, dd, J = 8.8, 2.2 Hz), 6.82 (1H, d, J = 2.2 Hz), 6.99 (1H, d, J = 2.0 Hz), 7.11 (1H, d, J = 8.8 Hz), 7.69 (1H, br t, J = 5.5Hz, disappeared on addition of D2O), 8.55 (1H, br s, disappeared on addition of D2O), 10.41 (1H, br s, disappeared on addition of D2O). HR-MS m/z: Calcd for C17H22N2O2: 286.1681. Found: 286.1682.
Nb-Benzoylserotonin (7e) from 1b·HCl — In the general procedure, ClCO2Me (103.4 mg, 1.1 mmol), anhydrous CHCl3 (2.0 mL), benzoic acid (127.0 mg, 1.0 mmol), Et3N (212.5 mg, 2.1 mmol), anhydrous CHCl3 (2.0 mL), 1b·HCl (202.7 mg, 1.0 mmol), and anhydrous DMF (2.0 mL) were used. After column chromatography, 7e (240.5 mg, 90%) was obtained. 7e: mp 208–209 °C (colorless prisms, recrystallized from MeOH). IR (KBr): 3425, 1645, 1537, 1377, 1186, 939, 850, 795, 710, 625 cm-1. 1H-NMR (DMSO-d6) δ: 2.86 (2H, t, J = 7.6 Hz), 3.51 (2H, td, J = 7.6, 6.1 Hz), 6.59 (1H, dd, J = 8.5, 2.2 Hz), 6.89 (1H, d, J = 2.2 Hz), 7.06 (1H, d, J = 2.2 Hz), 7.12 (1H, d, J = 8.5 Hz), 7.46 (2H, t, J = 7.8 Hz), 7.52 (1H, tt, J = 7.8, 1.5 Hz), 7.85 (2H, dd, J = 7.8, 1.5 Hz), 8.56 (1H, t, J = 6.1 Hz), 8.57 (1H, s, disappeared on addition of D2O), 10.46 (1H, br s). MS m/z: 280 (M+). Anal. Calcd for C17H16N2O2: C, 72.84; H, 5.75; N, 9.99. Found: C, 72.73; H, 5.72; N, 9.86.
Nb-Pentylserotonin (8a) from 7a — General Procedure: LiAlH4 (765.0 mg, 20.1 mmol) was added to a solution of 7a (522.4 mg, 2.0 mmol) in anhydrous THF (20.0 mL) under ice cooling and the mixture was refluxed for 10 h with stirring. After addition of MeOH and 10% Rochelle salt under ice cooling, the whole was extracted with CHCl3. The extract was washed with brine, dried over Na2SO4, and evaporated under reduced pressure to leave a residue, which was column-chromatographed on SiO2 with CHCl3–MeOH–28% NH4OH (46:3:0.3, v/v) to give 8a (417.9 mg, 85%). 8a: pale yellow viscous oil. IR (film): 2929, 2856, 1468, 1213 cm-1. 1H-NMR (CDCl3) δ: 0.86 (3H, t, J = 7.0 Hz), 1.21–1.32 (4H, m), 1.51 (2H, quint, J = 7.0 Hz), 2.65 (2H, t, J = 7.0 Hz), 2.92–3.00 (4H, m), 6.78 (1H, dd, J = 8.5, 2.2 Hz), 6.95 (1H, d, J = 2.2 Hz), 6.99 (1H, br s), 7.20 (1H, d, J = 8.5 Hz), 7.97 (1H, br s, disappeared on addition of D2O). HR-MS m/z: Calcd for C15H22N2O: 246.1732. Found: 246.1737.
Nb-Nonylserotonin (8b) from 7b — In the general procedure, LiAlH4 (889.8 mg, 18.7 mmol), 7b (739.0 mg, 2.3 mmol), and anhydrous THF (20.0 mL) were used. After column chromatography, 8b (572.5 mg, 81%) was obtained. 8b: yellow viscous oil. IR (film): 2925, 2854, 1468, 1458, 1213 cm-1. 1H-NMR (CDCl3) δ: 0.87 (3H, t, J = 7.0 Hz), 1.19–1.29 (12H, m), 1.49 (2H, br quint, J = 7.0 Hz), 2.65 (2H, t, J = 7.0 Hz), 2.91–2.99 (4H, m), 6.77 (1H, dd, J = 8.5, 2.2 Hz), 6.95 (1H, d, J = 2.2 Hz), 6.99 (1H, br s), 7.20 (1H, d, J = 8.5 Hz), 7.95 (1H, br s, disappeared on addition of D2O). HR-MS m/z: Calcd for C19H30N2O: 302.2358. Found: 302.2359.
Nb-Hexadecylserotonin (8c) from 7c — In the general procedure, LiAlH4 (741.9 mg, 19.5 mmol), 7c (808.0 mg, 2.0 mmol), and anhydrous THF (20.0 mL) were used. After column chromatography, 8c (696.4 mg, 89%) was obtained. 8c: pale brown viscous oil. IR (film): 2924, 2852, 1468, 1458, 1215 cm-1. 1H-NMR (CDCl3) δ: 0.88 (3H, t, J = 6.8 Hz), 1.20–1.31 (26H, m), 1.49 (2H, br quint, J = 6.8 Hz), 2.64 (2H, t, J = 6.8 Hz), 2.91–2.99 (4H, m), 6.77 (1H, dd, J = 8.5, 2.2 Hz), 6.95 (1H, d, J = 2.2 Hz), 7.00 (1H, br s), 7.20 (1H, d, J = 8.5 Hz), 7.94 (1H, br s, disappeared on addition of D2O). HR-MS m/z: Calcd for C26H44N2O: 400.3453. Found: 400.3460.
Nb-Cyclohexylmethylserotonin (8d) from 7d — In the general procedure, LiAlH4 (712.5 mg, 15.0 mmol), 7d (537.1 mg, 1.9 mmol), and anhydrous THF (20.0 mL) were used. After column chromatography, 8d (376.9 mg, 74%) was obtained. 8d: yellow foam. IR (KBr): 3292, 2922, 2850, 1456 cm-1. 1H-NMR (CDCl3) δ: 0.83–0.91 (2H, m), 1.08–1.25 (3H, m), 1.44–1.53 (1H, m), 1.61–1.71 (5H, m), 2.50 (2H, d, J = 6.8 Hz), 2.90–2.97 (4H, m), 6.76 (1H, dd, J = 8.8, 2.3 Hz), 6.94 (1H, d, J = 2.3 Hz), 6.98 (1H, d, J = 2.0 Hz, collapsed to s on addition of D2O), 7.19 (1H, d, J = 8.8 Hz), 7.93 (1H, br s, disappeared on addition of D2O). HR-MS m/z: Calcd for C17H24N2O: 272.1889. Found: 272.1885.
Nb-Benzylserotonin (8e) from 7e — In the general procedure, LiAlH4 (72.5 mg, 1.9 mmol), 7e (51.8 mg, 0.2 mmol), and anhydrous THF (5.0 mL) were used. After column chromatography, unreacted 7e (6.5 mg, 13%), 8e (23.0 mg, 47%), and serotonin (1b, 6.9 mg, 21%) were obtained. 8e: colorless oil. IR (film): 3410, 3286, 1454, 1215, 750 cm-1. 1H-NMR (CDCl3) δ: 2.90–2.92 (2H, m), 2.95–2.98 (2H, m), 3.60 (2H, br s, disappeared on addition of D2O), 3.81 (2H, s), 6.75 (1H, dd, J = 8.7, 2.2 Hz), 6.87 (1H, d, J = 2.2 Hz), 6.92 (1H, d, J = 1.7 Hz, collapsed to s on addition of D2O), 7.16 (1H, d, J = 8.7 Hz), 7.20–7.29 (5H, m), 7.97 (1H, br s, disappeared on addition of D2O). HR-MS m/z: Calcd for C17H18N2O: 266.1420. Found: 266.1418.

Nb-Benzylserotonin (8e) from 1b·HCl — A solution of benzaldehyde (504.5 mg, 4.8 mmol) in MeOH (5.0 mL) was added to a solution of 1b·HCl (336.3 mg, 1.6 mmol) and NaCNBH3 (95%, 315.0 mg, 4.8 mmol) in MeOH (20.0 mL) and the mixture was stirred at rt for 30 min. After addition of H2O, the whole was made alkaline (pH=9) with 8% NaOH and extracted with AcOEt. The extract was washed with brine, dried over Na2SO4, and evaporated under reduced pressure to leave a residue, which was column-chromatographed on SiO2 with CHCl3–MeOH–28% NH4OH (46:3:0.3, v/v) to give 8e (237.5 mg, 56%).
3,4,5,6-Tetrahydro-7-hydroxy-6-methyl-5-pentyl-1H-azepino[5,4,3-cd]indole (10a) from 8a — General Procedure: a solution of acetaldehyde (15.8 mg, 0.4 mmol) in MeOH (3.0 mL) was added to a solution of 8a (29.5 mg, 0.1 mmol) in Et3N (3.0 mL) under ice cooling and the mixture was stirred at rt for 2.5 h. The resulting mixture was evaporated under reduced pressure to leave a residue, which was column-chromatographed on SiO2 with CHCl3–MeOH–28% NH4OH (46:1:0.1, v/v) to give 10a (29.3 mg, 90%). 10a: colorless foam. IR (KBr): 3400, 2929, 1581, 1435, 1375 cm-1. 1H-NMR (CDCl3) δ: 0.86 (3H, t, J = 7.1 Hz), 1.20–1.35 (4H, m), 1.47 (3H, d, J = 6.8 Hz), 1.55–1.63 (2H, m), 2.64–2.70 (1H, m), 2.75–2.81 (1H, m), 2.90 (1H, br d, J = 16.1 Hz), 3.09 (1H, br d, J = 14.5 Hz), 3.20 (1H, ddd, J = 16.1, 12.9, 4.0 Hz), 3.58 (1H, br t, J = 14.5 Hz), 4.33 (1H, br s, disappeared on addition of D2O), 4.73 (1H, br s), 6.64 (1H, d, J = 8.5 Hz), 6.94 (1H, s), 7.04 (1H, d, J =8 .5 Hz), 7.86 (1H, br s, disappeared on addition of D2O). HR-MS m/z: Calcd for C17H24N2O: 272.1889. Found: 272.1888.
3,4,5,6-Tetrahydro-7-hydroxy-6-methyl-5-nonyl-1H-azepino[5,4,3-cd]indole (10b) from 8b — In the general procedure, acetaldehyde (15.3 mg, 0.4 mmol), MeOH (3.0 mL), 8b (35.0 mg, 0.1 mmol), and Et3N (3.0 mL) were used. After column chromatography, 10b (37.0 mg, 97%) was obtained. 10b: colorless foam. IR (KBr): 3400, 2927, 2852, 1581, 1435, 1375 cm-1. 1H-NMR (CDCl3) δ: 0.86 (3H, t, J = 6.8 Hz), 1.19–1.31 (12H, m), 1.48 (3H, d, J = 6.6 Hz), 1.53–1.69 (2H, m), 2.63–2.72 (1H, m), 2.75–2.84 (1H, m), 2.91 (1H, br d, J = 18.1 Hz), 3.09 (1H, br d, J = 13.9 Hz), 3.21 (1H, ddd, J = 16.1, 13.0, 4.0 Hz), 3.59 (1H, br t, J = 13.0 Hz), 4.40 (1H, br s, disappeared on addition of D2O), 4.72 (1H, br s), 6.65 (1H, d, J = 8.5 Hz), 6.94 (1H, s), 7.04 (1H, d, J = 8.5 Hz), 7.86 (1H, br s, disappeared on addition of D2O). HR-MS m/z: Calcd for C21H32N2O: 328.2514. Found: 328.2505.
5-Hexadecyl-3,4,5,6-tetrahydro-7-hydroxy-6-methyl-1H-azepino[5,4,3-cd]indole (10c) from 8c — In the general procedure, acetaldehyde (15.5 mg, 0.4 mmol), MeOH (3.0 mL), 8c (47.2 mg, 0.1 mmol), and Et3N (3.0 mL) were used. After column chromatography, 10c (45.7 mg, 91%) was obtained. 10c: colorless solid. IR (KBr): 3400, 2922, 2852, 1579, 1466, 1435, 1378 cm-1. 1H-NMR (CDCl3) δ: 0.88 (3H, t, J = 6.8 Hz), 1.20–1.30 (26H, m), 1.47 (3H, d, J = 6.6 Hz), 1.50–1.61 (2H, m), 2.63–2.69 (1H, m), 2.75–2.81 (1H, m), 2.90 (1H, br d, J = 12.9 Hz), 3.08 (1H, br d, J = 14.0 Hz), 3.20 (1H, ddd, J = 15.9, 12.5, 5.3 Hz), 3.58 (1H, br t, J = 12.5 Hz), 4.30 (1H, br s, disappeared on addition of D2O), 4.71 (1H, br q, J = 6.6 Hz), 6.63 (1H, d, J = 8.5 Hz), 6.93 (1H, s), 7.04 (1H, d, J = 8.5 Hz), 7.85 (1H, br s, disappeared on addition of D2O). HR-MS m/z: Calcd for C28H46N2O: 426.3610. Found: 426.3613.
5-Cyclohexylmethyl-3,4,5,6-tetrahydro-7-hydroxy-6-methyl-1H-azepino[5,4,3-cd]-
indole (10d) from 8d — In the general procedure, acetaldehyde (14.5 mg, 0.3 mmol), MeOH (2.5 mL), 8d (30.0 mg, 0.1 mmol), and Et3N (3.0 mL) were used. After column chromatography, 10d (26.4 mg, 80%) was obtained. 10d: yellow foam. IR (KBr): 3402, 2922, 1579, 1435, 1367 cm-1. 1H-NMR (CDCl3) δ: 0.80–0.89 (2H, m), 1.10–1.28 (3H, m), 1.46 (3H, d, J = 6.7 Hz), 1.59 (1H, br s), 1.62–1.71 (3H, m), 1.80 (2H, br t, J = 16.8 Hz), 2.48 (1H, br dd, J = 12.2, 6.7 Hz), 2.64 (1H, dd, J = 12.2, 6.7 Hz), 2.87 (1H, d, J = 15.9 Hz), 3.01 (1H, br d, J = 14.0 Hz), 3.22 (1H, ddd, J = 16.5, 12.8, 3.7 Hz), 3.59 (1H, br t, J = 12.8 Hz), 4.62 (1H, br s), 6.64 (1H, d, J = 8.2 Hz), 6.92 (1H, s), 7.03 (1H, d, J = 8.2 Hz), 7.82 (1H, s, disappeared on addition of D2O). HR-MS m/z: Calcd for C19H26N2O: 298.2046. Found: 298.2051.
5-Benzyl-3,4,5,6-tetrahydro-7-hydroxy-6-methyl-1H-azepino[5,4,3-cd]indole (10e) from 8e — In the general procedure, acetaldehyde (138.6 mg, 3.2 mmol), MeOH (10.0 mL), 8e (270.6 mg, 1.0 mmol), and Et3N (10.0 mL) were used. After column chromatography, 10e (264 mg, 89%) was obtained. 10e: colorless foam. IR (KBr): 3400, 1579, 1435, 1371, 1296, 1240 cm-1. 1H-NMR (CDCl3) δ: 1.48 (3H, t, J = 7.1 Hz), 2.86 (1H, br dt, J = 16.2, 2.7 Hz), 3.07 (1H, dq, J = 14.5, 2.3 Hz), 3.21 (1H, ddd, J = 13.3, 4.8, 1.6 Hz), 3.63 (1H, td, J = 13.8, 3.2 Hz), 3.86 (1H, d, J = 13.7 Hz), 4.00 (1H, d, J = 13.7 Hz), 4.24 (1H, br s), 4.65 (1H, q, J = 7.1 Hz), 6.65 (1H, d, J = 8.5 Hz), 6.94 (1H, s), 7.06 (1H, d, J = 8.5 Hz), 7.23 (1H, t, J = 7.3 Hz), 7.30 (2H, t, J = 7.3 Hz), 7.37 (2H, d, J = 7.3 Hz), 7.88 (1H, br s). MS m/z: 292 (M+). HR-MS m/z: Calcd for C19H20N2O: 292.1576. Found: 292.1573.
3,4,5,6-Tetrahydro-7-hydroxy-6-nonyl-5-pentyl-1H-azepino[5,4,3-cd]indole (11a) from 8a — General Procedure: A solution of decanal (57.1 mg, 0.4 mmol) in MeOH (3.0 mL) was added to a solution of 8a (30.0 mg, 0.1 mmol) in Et3N (3.0 mL) under ice cooling, and the mixture was stirred at rt for 3.5 h. The resulting mixture was evaporated under reduced pressure to leave a residue, which was column-chromatographed on SiO2 with CHCl3–MeOH–28% NH4OH (46:1:0.1, v/v) to give 11a (35.7 mg, 76%). 11a: colorless viscous oil. IR (film): 3408, 2925, 2854, 1579, 1466, 1437, 1375, 1369 cm-1. 1H-NMR (CDCl3) δ: 0.86 (3H, t, J = 7.1 Hz), 0.87 (3H, t, J = 7.1 Hz), 1.21–1.35 (18H, m), 1.39–1.60 (2H, m), 1.63–1.70 (1H, m), 1.78–1.86 (1H, m), 2.58–2.64 (1H, m), 2.80 (1H, ddd, J = 12.7, 8.3, 5.6 Hz), 2.86 (1H, br d, J = 16.1 Hz), 3.10 (1H, br d, J = 16.1 Hz), 3.24 (1H, ddd, J = 16.1, 12.7, 4.3 Hz), 3.49 (1H, br t, J = 12.7 Hz), 4.48 (2H, br s), 6.64 (1H, d, J = 8.3 Hz), 6.91 (1H, s), 7.01 (1H, d, J = 8.3 Hz), 7.84 (1H, br s, disappeared on addition of D2O). HR-MS m/z: Calcd for C25H40N2O: 384.3140. Found: 384.3130.
3,4,5,6-Tetrahydro-7-hydroxy-5,6-dinonyl-1H-azepino[5,4,3-cd]indole (11b) from 8b — In the general procedure, decanal (57.7 mg, 0.4 mmol), MeOH (3.0 mL), 8b (37.2 mg, 0.1 mmol), and Et3N (3.0 mL) were used. After column chromatography, 11b (43.8 mg, 81%) was obtained. 11b: colorless viscous oil. IR (film): 3402, 2924, 2852, 1577, 1466, 1435, 1369 cm-1. 1H-NMR (CDCl3) δ: 0.87 (3H, t, J = 7.1 Hz), 0.87 (3H, t, J = 7.1 Hz), 1.21–1.34 (26H, m), 1.40–1.60 (2H, m), 1.63–1.70 (1H, m), 1.77–1.85 (1H, m), 2.58–2.64 (1H, m), 2.80 (1H, ddd, J = 12.5, 8.1, 6.1 Hz), 2.86 (1H, br d, J = 15.9 Hz), 3.10 (1H, br d, J = 15.9Hz), 3.24 (1H, ddd, J = 15.9, 12.5, 3.7 Hz), 3.48 (1H, br t, J = 12.5 Hz), 4.28 (1H, br s, disappeared on addition of D2O), 4.47 (1H, br dd, J = 10.0, 4.5 Hz), 6.64 (1H, d, J = 8.3 Hz), 6.91 (1H, brs), 7.02 (1H, d, J = 8.3 Hz), 7.83 (1H, br s, disappeared on addition of D2O). HR-MS m/z: Calcd for C29H48N2O: 440.3766. Found: 440.3761.
5-Hexadecyl-3,4,5,6-tetrahydro-7-hydroxy-6-nonyl-1H-azepino[5,4,3-cd]indole (11c) from 8c — In the general procedure, decanal (56.7 mg, 0.4 mmol), MeOH (3.0 mL), 8c (48.5 mg, 0.1 mmol), and Et3N (3.0 mL) were used. After column chromatography, 11c (49.9 mg, 76%) was obtained. 11c: colorless viscous oil. IR (film): 3402, 2924, 2852, 1577, 1466, 1435, 1369 cm-1. 1H-NMR (CDCl3) δ: 0.87 (3H, t, J = 6.8 Hz), 0.88 (3H, t, J = 6.8 Hz), 1.23–1.33 (40H, m), 1.49–1.57 (2H, m), 1.63–1.69 (1H, m), 1.76–1.84 (1H, m), 2.57–2.62 (1H, m), 2.77–2.87 (2H, m), 3.09 (1H, br d, J = 14.5 Hz), 3.24 (1H, ddd, J = 14.5, 12.5, 4.3 Hz), 3.48 (1H, ddd, J = 14.5, 10.5, 3.3 Hz), 4.23 (1H, br s, disappeared on addition of D2O), 4.46 (1H, dd, J = 10.5, 4.4 Hz), 6.64 (1H, d, J = 8.3 Hz), 6.91 (1H, s), 7.02 (1H, d, J = 8.3 Hz), 7.82 (1H, br s, disappeared on addition of D2O). HR-MS m/z: Calcd for C36H62N2O: 538.4862. Found: 538.4876.

3,4,5,6-Tetrahydro-7-hydroxy-6-methyl-1H-azepino[5,4,3-cd]indole (12a) from 10e — A suspension of 10e (25.2 mg, 0.01 mmol) and 10% Pd/C (5.4 mg) in MeOH (3.0 mL) was stirred at rt for 3 h under hydrogen atmosphere. The resulting mixture was filtered and the filtrate was evaporated under reduced pressure to leave a residue, which was column-chromatographed on SiO2 with CHCl3–MeOH–28% NH4OH (46:10:1, v/v) to give 12a (15.8 mg, 91%). 12a: pale brown oil. IR (film): 3399, 3299, 1579, 1417, 794 cm-1. 1H-NMR (CD3OD) δ: 1.49 (3H, d, J = 6.8 Hz), 2.93–3.01 (1H, m), 3.10–3.15 (2H, m), 3.35–3.41 (1H, m), 4.91 (1H, q, J = 6.8 Hz), 6.63 (1H, d, J = 8.6 Hz), 6.95 (1H, s), 7.03 (1H, d, J = 8.6 Hz). HR-MS m/z: Calcd for C12H14N2O: 202.1107. Found: 202.1110.
7-Acetoxy-5-acetyl-3,4,5,6-tetrahydro-6-methyl-1H-azepino[5,4,3-cd]indole (12b) from 12a — Acetic anhydride (1 mL) was added to a solution of 12a (46.7 mg, 0.2 mmol) in pyridine (2.0 mL) at rt and the mixture was stirred at rt for 2 h. The resulting mixture was evaporated under reduced pressure to leave a residue, which was column-chromatographed on SiO2 with CHCl3–MeOH (98:2, v/v) to give 12b (63.1 mg, 95%). 12b: pale brown foam. IR (KBr): 1755, 1628, 1616, 1425 cm-1. 1H-NMR (CDCl3, rotamer ratio, 5:2. On heating, 12b decomposed) δ: 1.42 (6/7H, d, J = 7.3 Hz), 1.55 (15/7H, d, J = 7.3 Hz), 2.14 (15/7H, s), 2.22 (6/7H, s), 2.37 (6/7H, s), 2.39 (15/7H, s), 2.98 (5/7H, dt, J = 15.9, 2.4 Hz), 3.09–3.17 (4/7H, m), 3.34 (5/7H, m), 3.45 (5/7H, td, J = 13.3, 2.6 Hz), 3.82–3.93 (4/7H, m), 4.43 (5/7H, dt, J = 13.3, 3.4 Hz), 5.43 (5/7H, q, J = 7.3 Hz), 6.58 (2/7H, q, J = 7.3 Hz), 6.83 (5/7H, d, J = 8.5 Hz), 6.87 (2/7H, d, J = 8.5 Hz), 7.00 (2/7H, br s), 7.01 (5/7H, br s), 7.17 (2/7H, d, J = 8.5 Hz), 7.23 (5/7H, d, J = 8.5 Hz), 8.20 (2/7H, br s, disappeared on addition of D2O), 8.23 (5/7H, br s, disappeared on addition of D2O). MS m/z: 286 (M+). HR-MS m/z: Calcd for C16H18N2O3: 286.1318. Found: 286.1313.
5-tert-Butoxycarbonyl-7-tert-butoxycarbonyloxy-3,4,5,6-tetrahydro-6-methyl-1H-azepino[5,4,3-cd]indole (12c) from 12a — A solution of di-tert-butyl dicarbonate (45.6 mg, 0.2 mmol) in anhydrous CHCl3 (2.0 mL) was added to a solution of 12a (13.3 mg, 0.07 mmol), DMAP (16.5 mg, 0.1 mmol) in anhydrous CHCl3 (1.0 mL) at rt and the mixture was stirred at rt for 1 h. After addition of H2O, the whole was extracted with CHCl3–MeOH (95:5, v/v). The extract was washed with brine, dried over Na2SO4, and evaporated under reduced pressure to leave a residue, which was column-chromatographed on SiO2 with CHCl3–MeOH (98:2, v/v) to give 12c (13.7 mg, 52%). 12c: colorless viscous oil. IR (film): 3386, 2979, 1757, 1691, 1668 cm-1. 1H-NMR (CDCl3, rotamer ratio, 1:1. On heating, 12c decomposed) δ: 1.40 (9/2H, s), 1.45 (3/2H, d, J = 7.1 Hz), 1.47 (9/2H, s), 1.49 (3/2H, d, J = 7.1 Hz), 1.56 (9/2H, s), 1.59 (9/2H, s), 2.97 (1H, dd, J = 14.3, 12.3 Hz), 3.18 (1/2H, t, J = 14.3 Hz), 3.29 (1/2H, t, J = 14.3 Hz), 3.50 (1H, m), 3.97 (1/2H, d, J = 14.3 Hz), 4.12 (1/2H, d, J=14.3 Hz), 5.91 (1/2H, q, J = 7.1 Hz), 6.19 (1/2H, q, J = 7.1 Hz), 6.89–6.93 (1H, m), 6.97 (1H, br s), 7.13–7.18 (1H, m), 8.08–8.13 (1H, m, disappeared on addition of D2O). HR-MS m/z: Calcd for C22H30N2O5: 402.2155. Found: 402.2152.
3,4,5,6-Tetrahydro-7-hydroxy-5-pentyl-6-phenyl-1H-azepino[5,4,3-cd]indole (14a) from 8a — A solution of benzaldehyde (13a, 39.4 mg, 0.4 mmol) in MeOH (3.0 mL) was added to a solution of 8a (30.0 mg, 0.1 mmol) in Et3N (3.0 mL) under ice cooling, and the mixture was refluxed for 15 h with stirring. The resulting mixture was evaporated under reduced pressure to leave a residue, which was column-chromatographed on SiO2 with CHCl3–MeOH–28% NH4OH (46:1:0.1, v/v) to give 14a (35.8 mg, 86%). 14a: mp 166–168 °C (colorless powder, recrystallized from CHCl3–hexane). IR (KBr): 3448, 3273, 2952, 2931, 1583, 1491, 1435, 1378 cm-1. 1H-NMR (CDCl3) δ: 0.91 (3H, t, J = 7.1 Hz), 1.32–1.42 (4H, m), 1.65 (2H, quint, J = 7.1 Hz), 2.78–2.86 (3H, m), 2.94 (1H, dt, J =1 2.5, 7.1 Hz), 3.13 (1H, td, J = 14.4, 2.9 Hz), 3.21–3.28 (1H, m), 3.98 (1H, br s, disappeared on addition of D2O), 5.72 (1H, s), 6.71 (1H, d, J = 8.5 Hz), 6.96 (1H, s), 7.14 (2H, d, J = 7.6 Hz), 7.15 (1H, d, J = 8.5 Hz), 7.19 (1H, t, J = 7.6 Hz), 7.24 (2H, t, J = 7.6 Hz), 7.91 (1H, br s, disappeared on addition of D2O). MS m/z: 334 (M+). Anal. Calcd for C22H26N2O: C, 79.00; H, 7.84; N, 8.38. Found: C, 78.98; H, 7.91; N, 8.38.
3,4,5,6-Tetrahydro-7-hydroxy-6-isopropyl-5-pentyl-1H-azepino[5,4,3-cd]indole (14b) from 8a — A solution of 2-methylpropanal (13b, 27.2 mg, 0.4 mmol) in MeOH (3.0 mL) was added to a solution of 8a (30.0 mg, 0.1 mmol) in Et3N (3.0 mL) under ice cooling, and the mixture was refluxed for 15 h with stirring. The resulting mixture was evaporated under reduced pressure to leave a residue, which was column-chromatographed on SiO2 with CHCl3–MeOH–28% NH4OH (46:1:0.1, 46:3:0.3, v/v) to give 14b (18.5 mg, 49%), 10a (3.6 mg, 11%), and unreacted 8a (4.6 mg, 23%) in the order of elution. 14b: colorless viscous oil. IR (film): 3410, 2956, 2929, 2870, 1577, 1466, 1435, 1363 cm-1. 1H-NMR (CDCl3) δ: 0.79 (3H, d, J = 6.6 Hz), 0.87 (3H, t, J = 6.9 Hz), 1.15 (3H, d, J = 6.6 Hz), 1.23–1.34 (4H, m), 1.46–1.58 (2H, m), 2.04–2.11 (1H, m), 2.56 (1H, dq, J = 6.4, 6.2 Hz), 2.65 (1H, dq, J = 6.4, 6.2 Hz), 2.94 (1H, dt, J = 15.5, 4.2 Hz), 3.01 (1H, dt, J = 14.2, 4.6 Hz), 3.08 (1H, ddd, J = 17.3, 10.3, 3.7 Hz), 3.51 (1H, ddd, J = 17.3, 10.3, 3.7 Hz), 4.07 (1H, d, J = 9.5 Hz), 4.20 (1H, br s, disappeared on addition of D2O), 6.64 (1H, d, J = 8.5 Hz), 6.89 (1H, br s), 7.03 (1H, d, J = 8.5 Hz), 7.77 (1H, br s, disappeared on addition of D2O). HR-MS m/z: Calcd for C19H28N2O: 300.2202. Found: 300.2203.
5-Benzyl-8-bromo- (16a) and 5-Benzyl-2,2a,3,4,5,6-hexahydro-7-hydroxy-6-methyl-1H-azepino[5,4,3-cd]indol-2-one (15a) from 10e — A solution (1.5 mL, 0.6 mmol) of Br2 in AcOH [prepared with Br2 (287.9 mg, 1.8 mmol) and NaOAc (24.5 mg, 0.3 mmol) in AcOH (5.0 mL)] was added to a solution of 10e (54.1 mg, 0.2 mmol) in AcOH (5.0 mL), and the mixture was stirred at rt for 2 h. After addition of 10% Na2S2O3 (ca. 0.5 mL), the whole was evaporated under reduced pressure to leave a residue, which was column-chromatographed on SiO2 with CHCl3–MeOH (97:3, 95:5, v/v) to give 16a (59.3 mg, 83%) and 15a (9.2 mg, 16%) in the order of elution. 16a: mp 100–105 °C (colorless fine needles, recrystallized from CHCl3–hexane). IR (KBr): 1705, 1620, 1599, 1450, 1313 cm-1. 1H-NMR (pyridine-d5) δ: 1.60 (3H, d, J = 7.1 Hz), 1.99–2.12 (2H, m), 3.13 (1H, dt, J = 14.6, 2.4 Hz), 3.59 (1H, br t, J = 12.8 Hz), 3.78 (2H, s), 3.91 (1H, dd, J = 12.8, 4.3 Hz), 5.12 (1H, q, J=7.1 Hz), 7.24 (1H, s), 7.24 (1H, t, J = 7.3 Hz), 7.31 (2H, t, J = 7.3 Hz), 7.45 (2H, d, J = 7.3 Hz), 11.61 (1H, br s, disappeared on addition of D2O). HR-MS m/z: Calcd for C19H19BrN2O2: 388.0610, 386.0630. Found: 388.0598, 386.0625. Anal. Calcd for C19H19BrN2O2: C, 58.93; H, 4.95; N, 7.23. Found: C, 58.68; H, 4.97; N, 7.30. 15a: colorless solid. IR (KBr): 3201, 1699, 1618, 1469 cm-1. 1H-NMR (pyridine-d5, 60 °C) δ: 1.64 (3H, d, J = 7.3 Hz), 2.00–2.16 (2H, m), 3.18 (1H, br d, J = 14.6 Hz), 3.63 (1H, br t, J = 14.0 Hz), 3.82 (1H, d, J = 14.0 Hz), 3.87 (1H, d, J = 14.0 Hz), 3.90 (1H, dd, J = 12.8, 4.3 Hz), 5.09 (1H, q, J = 7.3 Hz), 6.76 (1H, d, J=8.1 Hz), 6.97 (1H, d, J = 8.1 Hz), 7.21 (1H, t, J = 7.3 Hz), 7.29 (2H, t, J = 7.3 Hz), 7.48 (2H, d, J = 7.3 Hz), 10.88 (1H, br s, disappeared on addition of D2O). HR-MS m/z: Calcd for C19H20N2O2: 308.1525. Found: 308.1506.

5-Benzyl-8-bromo-2,2a,3,4,5,6-hexahydro-7-methoxy-6-methyl-1H-azepino[5,4,3-cd]-
indol-2-one (16b) from 16a — Excess amount of CH2N2 in Et2O was added to a solution of 16a (40.9 mg, 0.1 mmol) in MeOH (5.0 mL) at rt and the mixture was refluxed for 15 min with stirring. The resulting mixture was evaporated under reduced pressure to leave a residue, which was column-chromatographed on SiO2 with CHCl3–MeOH (99:1, v/v) to give 16b (40.3 mg, 95%). 16b: mp 168–169 °C (colorless prisms, recrystallized from CHCl3–hexane). IR (KBr): 1701, 1604, 1452 cm-1. 1H-NMR (pyridine-d5) δ: 1.57 (3H, d, J = 7.3 Hz), 1.94 (1H, dq, J = 2.0, 12.5 Hz), 2.01–2.06 (1H, m), 3.04 (1H, dt, J = 15.1, 2.9 Hz), 3.52 (1H, br ddd, J = 14.4, 12.2, 2.0 Hz), 3.63 (3H, s), 3.68–3.74 (2H, m), 3.87 (1H, dd, J = 12.7, 3.9 Hz), 4.64 (1H, q, J = 7.3 Hz), 7.17 (1H, s), 7.27 (1H, t, J = 7.3 Hz), 7.36 (2H, t, J = 7.3 Hz), 7.43 (2H, d, J = 7.3 Hz), 11.77 (1H, s, disappeared on addition of D2O). MS m/z: 402 (M+), 400 (M+). Anal. Calcd for C20H21BrN2O2·1/2H2O: C, 58.55; H, 5.40; N, 6.83. Found: C, 58.75; H, 5.29; N, 6.83.
7-Acetoxy-5-benzyl-8-bromo-2,2a,3,4,5,6-hexahydro-6-methyl-1H-azepino[5,4,3-cd]-
indol-2-one (16c) from 16a — Acetic anhydride (1.0 mL) was added to a solution of 16a (34.0 mg, 0.09 mmol) in pyridine (2.0 mL) and the mixture was stirred at rt for 1 h. The resulting mixture was evaporated under reduced pressure to leave a residue, which was column-chromatographed on SiO2 with CHCl3–MeOH (98:2, v/v) to give 16c (33.0 mg, 88%). 16c: mp 242–244 °C (decomp., colorless powder, recrystallized from CHCl3–hexane). IR (KBr): 1772, 1722, 1614 cm-1. 1H-NMR (pyridine-d5, 60 °C) δ: 1.55 (3H, t, J = 7.3 Hz), 1.94 (1H, qd, J = 12.2, 2.4 Hz), 2.02–2.07 (1H, m), 2.13 (3H, s), 3.09 (1H, dt, J = 15.1, 3.2 Hz), 3.57 (1H, br t, J=12.5 Hz), 3.67–3.75 (2H, m), 3.87 (1H, dd, J = 12.5, 4.0 Hz), 4.33 (1H, q, J = 7.3 Hz), 7.13 (1H, s), 7.26 (1H, t, J = 7.4 Hz), 7.34 (2H, t, J = 7.4 Hz), 7.38 (2H, d, J = 7.4 Hz), 11.54 (1H, br s, disappeared on addition of D2O). HR-MS m/z: Calcd for C21H21BrN2O3: 430.0715, 428.0736. Found: 430.0736, 428.0748. Anal. Calcd for C21H21BrN2O3·1/2H2O: C, 57.54; H, 5.06; N, 6.39. Found: C, 57.73; H, 4.88; N, 6.35.
5-Benzyl-8-bromo-1-tert-butoxycarbonyl-7-tert-butoxycarbonyloxy-2,2a,3,4,5,6-hexahydro-6-methyl-1H-azepino[5,4,3-cd]indol-2-one (16d) from 16a — A solution of di-tert-butyl dicarbonate (63.2 mg, 0.3 mmol) in anhydrous CHCl3 (1.0 mL) was added to a solution of 16a (22.6 mg, 0.06 mmol), DMAP (4.0 mg, 0.03 mmol), and Et3N (29.2 mg, 0.3 mmol) in anhydrous CHCl3 (3.0 mL) at rt, and the mixture was stirred at rt for 30 min. The resulting mixture was evaporated under reduced pressure to leave a residue, which was purified by p-TLC on SiO2 developed with CHCl3. Extraction of the band having an Rf value of 0.23–0.13 with CHCl3–MeOH (95:5, v/v) gave 16d (15.7 mg, 46%). 16d: colorless viscous oil. IR (film): 2981, 1799, 1766, 1732, 1593, 1456 cm-1. 1H-NMR (pyridine-d5) δ: 1.49 (9H, s), 1.63 (3H, d, J = 7.1 Hz), 1.64 (9H, s), 1.90–2.02 (2H, m), 2.98 (1H, d, J = 9.3 Hz), 3.46 (1H, t, J = 13.2 Hz), 3.75 (2H, s), 4.06 (1H, dd, J = 12.3, 4.0 Hz), 4.65 (1H, q, J = 7.1 Hz), 7.29 (1H, t, J=7.4 Hz), 7.37 (2H, t, J = 7.4 Hz), 7.43 (2H, d, J = 7.4 Hz), 8.22 (1H, s). HR-MS m/z: Calcd for C29H35BrN2O6: 588.1658, 586.1678. Found: 588.1628, 586.1696.
8-Bromo- (16e) and 5-Cyclohexylmethyl-2,2a,3,4,5,6-hexahydro-7-hydroxy-6-methyl-1H-azepino[5,4,3-cd]indol-2-one (15b) from 10d — A solution (1.0 mL, 0.3 mmol) of Br2 in AcOH [prepared with Br2 (252.2 mg, 1.6 mmol) and NaOAc (25.1 mg, 0.3 mmol) in AcOH (5.0 mL)] was added to a solution of 10d (31.0 mg, 0.1 mmol) in AcOH (3.0 mL), and the mixture was stirred at rt for 2 h. After addition of 10% Na2S2O3 (0.2 mL), the whole was evaporated under reduced pressure to leave a residue, which was column-chromatographed on SiO2 with CHCl3–MeOH–28% NH4OH (46:2:0.2, v/v) to give 16e (21.4 mg, 52%) and 15b (5.6 mg, 17%) in the order of elution. 16e: yellow oil. IR (film): 3236, 2924, 1701, 1618, 1448, 1315 cm-1. 1H-NMR (pyridine-d5) δ: 0.72–0.84 (2H, m), 1.04–1.22 (3H, m), 1.51–1.65 (4H, m), 1.60 (3H, d, J = 7.2 Hz), 1.69 (1H, br d, J = 12.7 Hz), 1.80 (1H, br d, J = 12.7 Hz), 1.96 (1H, br qd, J = 13.9, 2.4 Hz), 2.12 (1H, br d, J = 13.9 Hz), 2.33–2.41 (2H, m), 3.07 (1H, br dt, J = 15.1, 2.9 Hz), 3.60 (1H, br t, J = 13.4 Hz), 3.89 (1H, dd, J = 12.8, 3.8 Hz), 5.05 (1H, q, J = 7.2 Hz), 7.18 (1H, s), 10.77 (1H, br s disappeared on addition of D2O), 11.58 (1H, s, disappeared on addition of D2O). HR-MS m/z: Calcd for C19H25BrN2O2: 394.1079, 392.1099. Found: 394.1080, 392.1093. 15b: yellow oil. IR (film): 3255, 2924, 1689, 1467 cm-1. 1H-NMR (pyridine-d5) δ: 0.77–0.89 (2H, m), 1.06–1.24 (3H, m), 1.55–1.70 (4H, m), 1.66 (3H, d, J = 7.3 Hz), 1.78 (1H, br d, J = 12.5 Hz), 1.84 (1H, br d, J = 12.5 Hz), 2.02 (1H, br qd, J = 12.7, 2.1 Hz), 2.18 (1H, br d, J=12.7 Hz), 2.39–2.52 (2H, m), 3.12 (1H, br dt, J = 14.6, 3.0 Hz), 3.64 (1H, br t, J = 13.1 Hz), 3.96 (1H, dd, J=12.7, 3.7 Hz), 5.05 (1H, q, J = 7.3 Hz), 6.78 (1H, d, J = 8.1 Hz), 7.01 (1H, d, J = 8.1 Hz), 10.92 (1H, br s, disappeared on addition of D2O), 11.31 (1H, s, disappeared on addition of D2O). HR-MS m/z: Calcd for C19H26N2O2: 314.1994. Found: 314.1989.
7-Acetoxy-8-bromo-5-cyclohexylmethyl-2,2a,3,4,5,6-hexahydro-6-methyl-1H-azepino-
[5,4,3-cd]indol-2-one (16f) from 16e — Acetic anhydride (1.0 mL) was added to a solution of 16e (22.5 mg, 0.06 mmol) in pyridine (2.0 mL) at rt, and the mixture was stirred at rt for 1.5 h. The resulting mixture was evaporated under reduced pressure to leave a residue, which was column-chromatographed on SiO2 with CHCl3–MeOH–28% NH4OH (46:2:0.2, v/v) to give 16f (20.8 mg, 83%). 16f: colorless solid. IR (KBr): 2924, 1768, 1716, 1612 cm-1. 1H-NMR (pyridine-d5) δ: 0.77–0.89 (2H, m), 1.11–1.29 (3H, m), 1.43–1.68 (7H, m), 1.75–1.83 (2H, m), 1.91 (1H, br q, J = 12.2 Hz), 2.07 (1H, br d, J = 14.0 Hz), 2.34 (2H, br s), 2.43 (3H, s), 3.03 (1H, br dt, J = 15.0, 2.9 Hz), 3.57 (1H, t, J = 13.4 Hz), 3.90 (1H, dd, J = 12.8, 3.7 Hz), 4.33 (1H, br s), 7.15 (1H, s), 11.88 (1H, s, disappeared on addition of D2O). HR-MS m/z: Calcd for C21H27BrN2O3: 436.1185, 434.1205. Found: 436.1186, 434.1197.
8-Bromo-1-tert-butoxycarbonyl-7-tert-butoxycarbonyloxy-5-cyclohexylmethyl-2,2a,3,4,5,6-hexahydro-6-methyl-1H-azepino[5,4,3-cd]indol-2-one (16g) from 16e — A solution of di-tert-butyl dicarbonate (41.8 mg, 0.2 mmol) in anhydrous CHCl3 (3.0 mL) was added to a solution of 16e (13.9 mg, 0.04 mmol), DMAP (9.5 mg, 0.08 mmol), and Et3N (22.3 mg, 0.2 mmol) in anhydrous CHCl3 (2.0 mL) at rt, and the mixture was stirred at rt for 1.5 h. The resulting mixture was evaporated under reduced pressure to leave a residue, which was purified by p-TLC on SiO2 developed with CHCl3–MeOH (99:1, v/v). Extraction of the band having an Rf value of 0.40–0.30 with CHCl3–MeOH (95:5, v/v) gave 16g (15.0 mg, 71%). 16g: colorless solid. IR (KBr): 2927, 1797, 1765, 1732, 1456, 1273, 1252, 1149 cm-1. 1H-NMR (pyridine-d5) δ: 0.77–0.87 (2H, m), 1.09–1.26 (3H, m), 1.46–1.69 (7H, m), 1.57 (9H, s), 1.64 (9H, s), 1.72–1.91 (3H, m), 1.99 (1H, br d, J = 13.2 Hz), 2.33 (2H, d, J = 6.6 Hz), 2.98 (1H, dt, J = 15.1, 2.8 Hz), 3.51 (1H, t, J = 13.3 Hz), 4.01 (1H, dd, J = 12.6, 3.8 Hz), 4.48 (1H, br d, J = 7.0 Hz), 8.18 (1H, s). HR-MS m/z: Calcd for C29H41BrN2O6: 594.2128, 592.2148. Found: 594.2127, 592.2136.
7-Acetoxy-5-cyclohexylmethyl-2,2a,3,4,5,6-hexahydro-6-methyl-1H-azepino-
[5,4,3-cd]indole (17) from 10d — Acetic anhydride (1.0 mL) was added to a solution of 10d (19.3 mg, 0.07 mmol) in pyridine (2.0 mL) at rt, and the mixture was stirred at rt for 3 h. The resulting mixture was evaporated under reduced pressure to leave a residue, which was column-chromatographed on SiO2 with CHCl3–MeOH–28% NH4OH (46:1:0.1, v/v) to give 17 (19.0 mg, 86%). 17: yellow oil. IR (film): 3400, 3246, 2924, 2850, 1751, 1435, 1369 cm-1. 1H-NMR (pyridine-d5) δ: 0.79–0.89 (2H, m), 1.10 (1H, tt, J = 12.5, 3.2 Hz), 1.18–1.27 (3H, m), 1.56–1.72 (6H, m), 1.85 (2H, br t, J = 12.9 Hz), 2.32 (3H, s), 2.61–2.65 (1H, m), 2.81 (1H, dd, J = 12.8, 6.7 Hz), 3.00 (1H, br d, J = 16.4 Hz), 3.15–3.22 (1H, m), 3.37 (1H, ddd, J = 16.4, 12.5, 4.3 Hz), 3.74 (1H, br t, J = 13.4 Hz), 4.82 (1H, br s), 7.07 (1H, d, J = 8.5 Hz), 7.30 (1H, s), 7.38 (1H, d, J = 8.5 Hz). HR-MS m/z: Calcd for C21H28N2O2: 340.2151. Found: 340.2145.

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