HETEROCYCLES

Paper | Regular issue | Vol. 83, No. 4, 2011, pp. 815-826
Received, 20th January, 2011, Accepted, 15th February, 2011, Published online, 23rd February, 2011.
DOI: 10.3987/COM-11-12144

■ Facile Synthesis of Pyrano[3,2-e]indoles via the Base-Promoted Pictet-Spengler Reaction of Nb-Benzylserotonin

Koji Yamada, Sayaka Yamaguchi, Noriyuki Hatae, Takumi Abe, Tatsunori Iwamura, and Minoru Ishikura*

Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Hokkaido 061-0293, Japan

Abstract

A novel and simple protocol for the synthesis of 1-(2-aminoethyl)pyrano[3,2-e]indole derivatives has been developed using the Pictet-Spengler reaction of Nb-benzylserotonin with α,β–unsaturated aldehydes in the presence of Et3N in 2-propanol or MeOH.

INTRODUCTION
Serotonin (5-hydroxytryptamine: 5-HT) (1a) exhibits various physiological effects on the peripheral nervous system, such as vasoconstriction and regulation of gastric secretion and intestinal peristalsis. Current studies have focused on the multifunctional role of 1a as a neurotransmitter in the central nervous system. Most notably, in an effort to understand the role of 1a and serotonin receptors, the development of 5-HT receptor specific ligands has been an area of intensive investigation.1 Recently, several reported serotonin analogues have displayed selectivity for 5-HT receptors. For example, 5-methoxy- N,N-dimethyltryptamine (2) exhibited improved selectivity for the 5-HT1 receptor. In contrast, 1-(2-aminoethyl)pyrano[3,2-e]indoles 3, which are potent full agonists, displayed selectivity for the 5-HT2 receptor, with markedly lower 5-HT1 affinity.2 To date, only a few synthetic methods for the pyrano[3,2-e]indoles have been reported. A Claisen rearrangement/olefin hydroxylation/intramolecular Mitsunobu reaction sequence was used to prepare pyrano[3,2-e]indole 3c from 5-allyloxytryptamine for the first time.3 In another report, pyrano[3,2-e]indoles 3 were prepared from 3-methyl-4-nitrophenol in several steps via a Claisen rearrangement/Batcho-Leimgruber reaction sequence.4 Additionally, a recent modification of the method involving a Claisen rearrangement/cyclization of 5-propargyloxytryptamine was used for the construction of 3.5

We previously reported that Nb-benzylserotonin (1b), when reacted with a variety of aldehydes in the presence of a base (e.g., Et3N, DABCO), gave azepino[5,4,3-cd]indoles regioselectively.6 This finding led to the development of a concise synthesis of (±)-aurantioclavine (6) in 3 steps from 1b and 3-methylbut-2-enal (4a) (Scheme 1).7 In the purification of azepinoindole 5 from the reaction mixture, a small amount of 1-(2-aminoethyl)pyranoindole 8a was obtained. The generation of 8a was possibly explained by sequences of ring-opening (5 to 7) and ring-closing (7 to 8a). Considering the lack of precedent for the concise preparation of pyrano[3,2-e]indoles, we became interested in developing a straightforward method for the preparation of pyrano[3,2-e]indoles using the base-promoted Pictet-Spengler reaction of 1b with an α,β–unsaturated aldehyde. Herein, we report a novel and facile protocol for the formation of 1-(2-aminoethyl)pyrano[3,2-e]indoles.

RESULTS AND DISCUSSION
Previously, it was observed that treatment of 1b with excess cinnamaldehyde (4d) (3 equiv) in the presence of Et3N under forcing conditions (in refluxing MeOH for 24 h) resulted in a second Pictet-Spengler reaction, producing pyrano[3,2-e]pyrido[3,4-b]indole in 80% yield.7
We thus examined the reaction using a smaller amount of α,β–unsaturated aldehydes 4 (1.1 equiv) in the presence of Et3N. The results in Table 1 clearly indicate that 4 reacted well with 1b in refluxing 2-propanol, enabling a one-pot assembly of pyrano[3,2-e]indoles 8 in moderate to good yields. The treatment of 4a with 1b in 2-propanol and MeOH afforded 8a in 82% and 65% yields, respectively. The reaction using aldehyde 4b in 2-propanol gave 8b in 63% yield, whereas that in MeOH gave only azepinoindole 9 in 22% yield. Subjecting aldehyde 4c to the reaction in 2-propanol enabled the formation of spiropyranoindole 8c in 80% yield. Cinnamaldehyde (4d) reacted with 1b in 2-propanol afforded pyranoindole 8d in 79% yield, while the reaction in MeOH provided 8d in 68% yield. Treatment of 3-arylpropenals 4e and 4f with 1b in 2-propanol produced pyranoindoles 8e and 8f in 87% and 26% yields, respectively (Table 1).
On the other hand, the one-pot treatment of 4-nitrocinnamaldehyde 4g (1.1 equiv) with 1b in the presence of Et3N in refluxing 2-propanol for 8 h gave a complex mixture of products. Alternatively, pyranoindoles 8f and 8g were prepared in a stepwise manner: azepinoindole 10a was obtained in 85% yield by treatment of 1b with 4f (3 equiv) in the presence of Et3N in MeOH at room temperature for 12 h. The reaction of 4g (3 equiv) with 1b in the presence of Et3N proceeded smoothly to completion within 1 h, producing azepinoindole 10b in 85% yield, while for a longer reaction time of 8 h, the reaction using 4g (1.1 equiv) was found to afford 10b in 83% yield. In turn, 10b was heated in MeOH under reflux for 6 h to give 8g in only 19% yield. After several attempts, 10a and 10b could be transformed to 8f and 8g in 75% and 85% yields, respectively, by heating in 2,2,2-trifluoroethanol (TFE) under reflux. We do not have any definite explanation for the suitability of TFE (Scheme 2).

Next, we turned our attention to directly accessing pyranoindole 11. The treatment of 1b with acrolein (3 equiv) in the presence of Et3N in MeOH furnished only azepinoindole 12 with the addition of MeOH in 55% yield,7 whereas the reaction in refluxing 2-propanol for 4 h resulted in the formation of a mixture of several products. Alternatively, trimethylsilylpropenal 13 was used for the reaction. The reaction with 1b in the presence of Et3N in refluxing 2-propanol for 12 h was initially carried out using 3 equivalents of 13, giving 14 in only 26% yield. Next, stepwise generation of 14 was performed. Aldehyde 13 (3 equiv) was treated with 1b in MeOH at room temperature for 6 h to provide azepinoindole 15 in 79% yield. Heating 15 in TFE for 30 min furnished 14 in 76% yield, and subsequent removal of the TMS group in 14 with TBAF provided 11 in 74% yield. Catalytic hydrogenation of 11 using 10% Pd-C in MeOH for 18 h afforded 3a2a in 71% yield (Scheme 3).

The reactions using α,β–disubstituted aldehydes 16 and 20 (3 equiv) in the presence of Et3N in 2-propanol were extremely sluggish: after heating for 5 and 3 days, azepinoindole 17 and 21 were isolated in 53% and 47% yields along with 18 in yields of 10% and 12%, respectively. Subsequent heating of 17 and 21 in TFE afforded 19 and 22 in yields of 78% and 76%, respectively. Catalytic hydrogenation of 22 gave 23 in 79% yield. The stereochemistry of 23 was determined to be the cis-configuration based on NOE experiments (Scheme 4).
A plausible explanation for the generation of 18 is that severe steric repulsion between the methyl group of the styrene side chain (in 17) or the cyclopentene ring (in 21) and the N-Bn group triggers the elimination of the vinyl groups to relieve strain (Scheme 5).

CONCLUSION
In summary, we have developed a novel method for the concise assembly of 1-(2-aminoethyl)-pyrano[3,2-e]indoles through the base-promoted Pictet-Spengler reaction of 1b with α,β–unsaturated aldehydes. This method provides greater flexibility for the incorporation of various functionalities in the fused-pyran ring. Further application of these results in the preparation of serotonin analogues is currently being explored and investigations of the 5-HT receptor binding properties of the pyranoindole analogues are in progress. Recently, pyrano[3,2-e]indol-7(3H)-ones were evaluated in the growth inhibition of human tumor cell lines, but all of the compounds exhibited only weak cytotoxicity in all tumor cell lines.8 More notably, pyranoindoles 8 were evaluated for antiproliferative activity in human colon tumor cell lines, namely, HCT-116 cells.9 Compounds 8c, 8d and 8e exhibited potent antitumor activity against these tumor cells and their corresponding IC50 values were less than 10 μM, whereas compounds 8a, 8b and 8f exhibited lower activity.

EXPERIMENTAL
Melting points were recorded with a Yamato MP21 and are uncorrected. High-resolution MS spectra were recorded with a Micromass AutoSpec 3100 and a JEOL JMS-T100LP mass spectrometers. IR spectra were measured with a Shimadzu IRAffinity-1 spectrometer. The NMR experiments were performed with a JEOL JNM-ECA500 (500 MHz) spectrometer, and chemical shifts are expressed in ppm (δ) with TMS as an internal reference. Flash column chromatography was performed on silica gel (Silica Gel 60N, Kanto Chemical Co., Ltd.).
One-pot preparation of pyrano[3,2-e]indoles 8: A mixture of 1b (1 mmol) and aldehydes 4 (1.1 mmol) in Et3N (8 mL) and 2-propanol or MeOH (8 mL) was heated under reflux. After cooling, the mixture was concentrated under reduced pressure. Purification of the residue by flash column chromatography with CHCl3/MeOH/28%NH4OH (46:3:0.3) provided 8a,7 8b, 8c, 8d, 8e, 8f and 97(Table 1).
N-Benzyl-2-(7-methyl-3,7-dihydropyrano[3,2-e]indol-1-yl)ethanamine (8b): A pale-yellow foam. IR (CHCl3): 3488 cm-1. 1H-NMR (CDCl3) δ: 1.47 (d, 3H, J = 6.2 Hz), 1.69 (br. s, 1H), 2.97 (t, 2H, J = 6.8 Hz), 3.05 (t, 2H, J = 6.8 Hz), 3.82 (s, 2H), 4.89 (qd, 1H, J = 6.2, 3.4 Hz), 5.67 (dd, 1H, J = 9.6, 3.4 Hz), 6.74 (d, 1H, J = 8.5 Hz), 6.96 (d, 1H, J = 1.7 Hz), 6.98 (d, 1H, J = 9.6 Hz), 7.08 (d, 1H, J = 8.5 Hz), 7.22-7.24 (m, 1H), 7.28-7.30 (m, 4H), 7.90 (br s, 1H). 13C-NMR (CDCl3) δ: 20.6, 27.8, 49.7, 54.0, 70.7, 111.4, 112.4, 114.0, 114.1, 122.2, 123.0, 123.8, 125.8, 127.0, 128.2, 128.5, 132.7, 140.3, 147.8. HR-MS (ESI) m/z: Calcd for C21H23N2O( [M+H]+): 319.1761. Found: 319.1810.
N-Benzyl-2-(1-benzyl-3’H-spiro[piperidine-4,7’-pyrano[3,2-e]indol]-1’-yl)ethanamine (8c): A pale- yellow foam. IR (CHCl3): 3480 cm-1. 1H NMR (CDCl3) δ: 1.62 (br s, 1H), 1.72-1.78 (m, 2H), 2.07 (d, 2H, J = 13.6 Hz), 2.53-2.64 (m, 4H), 2.97 (t, 2H, J = 6.8 Hz), 3.06 (t, 2H, J = 6.8 Hz), 3.57 (s, 2H), 3.82 (s, 2H), 5.59 (d, 1H, J = 9.6 Hz), 6.78 (d, 1H, J = 8.5 Hz), 6.95 (d, 1H, J = 9.6 Hz), 6.96 (s, 1H), 7.09 (d, 1H, J = 8.5 Hz), 7.21-7.36 (m, 10H), 7.87 (br s, 1H). 13C-NMR (CDCl3) δ: 22.7, 34.6, 49.1, 49.7, 54.0, 63.5, 73.5, 111.4, 112.9, 113.7, 113.8, 121.3, 122.9, 124.0, 127.1, 127.2, 128.3, 128.4, 128.6, 128.7, 129.4, 132.7, 138.5, 140.2, 146.2. HR-MS (ESI) m/z: Calcd for C31H34N3O ([M+H]+): 464.2702. Found: 464.2677.
N-Benzyl-2-(7-phenyl-3,7-dihydropyrano[3,2-e]indol-1-yl)ethanamine (8d): A pale-yellow foam. IR (CHCl3): 3480 cm-1. 1H-NMR (CDCl3) δ: 1.63 (br s, 1H), 2.99 (t, 2H, J = 6.9 Hz), 3.09 (t, 2H, J = 6.9 Hz), 3.83 (s, 2H), 5.82-5.85 (m, 2H), 6.76 (d, 1H, J = 8.6 Hz), 6.96 (d, 1H, J = 1.7 Hz), 7.08 (d, 1H, J = 8.6 Hz), 7.15 (d, 1H, J = 8.6 Hz), 7.21-7.25 (m, 1H), 7.28-7.32 (m, 5H), 7.36 (t, 2H, J = 7.4 Hz), 7.51 (d, 2H, J = 7.4 Hz), 7.90 (br s, 1H). 13C-NMR (CDCl3) δ: 27.8, 49.7, 54.0, 76.3, 111.6, 112.4, 113.6, 114.0, 122.5, 122.9, 123.7, 123.8, 126.9, 127.1, 128.1, 128.1, 128.4, 128.5, 132.7, 140.3, 141.0, 147.3. HR-MS (ESI) m/z: Calcd for C26H25N2O ([M+H] +): 381.1967. Found: 381.1931.
4-{1-[2-(Benzylamino)ethyl]-3,7-dihydropyrano[3,2-e]indol-7-yl}-N,N-dimethylaniline (8e): A dark- yellow foam. IR (CHCl3): 3480 cm-1. 1H-NMR (CDCl3) δ: 1.84 (br s, 1H), 2.94 (s, 6H), 3.02 (t, 2H, J = 6.8 Hz), 3.12 (t, 2H, J = 6.8 Hz), 3.86 (s, 2H), 5.75 (dd, 1H, J = 3.7, 1.7 Hz), 5.85 (dd, 1H, J = 9.9, 3.7 Hz), 6.71 (d, 2H, J = 8.5 Hz), 6.72 (d, 1H, J = 9.1 Hz), 6.94 (d, 1H, J = 1.7 Hz), 7.04 (d, 1H, J = 9.1 Hz), 7.16 (dd, 1H, J = 9.9, 1.7 Hz), 7.23-7.25 (m, 1H), 7.30-7.34 (m, 4H), 7.39 (d, 2H, J = 8.5 Hz), 7.94 (br s, 1H). 13C-NMR (CDCl3) δ: 27.9, 40.7, 49.8, 54.0, 76.5, 111.6, 112.5, 112.7, 113.7, 113.9, 122.4, 122.9, 123.9, 124.2, 127.1, 128.3, 128.4, 128.5, 128.8, 132.7, 140.2, 147.5, 150.8. HR-MS (ESI) m/z: Calcd for C28H30N3O ([M+H]+): 424.2389. Found: 424.2369.
N-Benzyl-2-(7-pyridin-3-yl-3,7-dihydropyrano[3,2-e]indol-1-yl)ethanamine (8f): A dark-yellow foam. IR (CHCl3): 3478 cm-1. 1H-NMR (CDCl3) δ: 1.59 (br s, 1H), 3.00 (t, 2H, J = 7.2 Hz), 3.10 (t, 2H, J = 7.2 Hz), 3.85 (s, 2H), 5.84 (dd, 1H, J = 9.2, 4.2 Hz), 5.86 (d, 1H, J = 4.2 Hz), 6.74 (d, 1H, J = 8.6 Hz), 7.01 (s, 1H), 7.11 (d, 1H, J = 8.6 Hz), 7.21 (d, 1H, J = 9.2 Hz), 7.23-7.31 (m, 6H), 7.83 (dt, 1H, J = 8.0, 2.0 Hz), 7.89 (br s, 1H), 8.55 (dd, 1H, J = 4.9, 2.0 Hz), 8.73 (d, 1H, J = 2.0 Hz). 13C-NMR (CDCl3) δ: 27.9, 49.7, 54.0, 74.0, 112.0, 112.5, 113.6, 114.1, 122.4, 123.1, 123.4, 123.5, 124.0, 127.0, 128.2, 128.5, 132.9, 134.9, 136.3, 140.4, 146.9, 148.9, 149.6. HR-MS (ESI) m/z: Calcd for C25H24N3O ([M+H]+): 382.1919. Found: 382.1888.
Stepwise preparation of 8f: A mixture of 1b (282 mg, 1 mmol), 4f (399 mg, 3 mmol) and Et3N (8 mL) in MeOH (8 mL) was stirred at room temperature for 12 h, and the mixture was concentrated under reduced pressure. Purification of the residue by flash column chromatography on silica gel with CHCl3/MeOH/28%NH4OH (46:1:0.1) afforded 10a (324 mg, 85%) as a pale-yellow foam. Azepinoindole 10a (190 mg, 0.5 mmol) was heated in 2,2,2-trifluoroethanol (TFE) (5 mL) under reflux for 1 h. After the solvent was removed, the residue was purified by flash column chromatography on silica gel with CHCl3/MeOH/28%NH4OH (46:1:0.1) to give 8f (143 mg, 75%).
5-Benzyl-6-[(E)-2-(pyridin-3-yl)ethenyl]-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-7-ol (10a): IR (CHCl3): 3480 cm-1. 1H-NMR (CDCl3) δ: 2.87 (ddd, 1H, J = 15.9, 3.2, 2.3 Hz), 3.14 (ddd, 1H, J = 14.1, 4.0, 2.3 Hz), 3.24 (ddd, 1H, J = 15.9, 14.1, 4.0 Hz), 3.56 (td, 1H, J = 14.1, 3.2 Hz), 3.95 (d, 1H, J = 13.6 Hz), 4.09 (d, 1H, J = 14.2 Hz), 5.29 (dd, 1H, J = 5.1, 1.7 Hz), 5.51 (br s, 1H), 6.03 (dd, 1H, J = 16.4, 1.7 Hz), 6.65 (dd, 1H, J = 16.4, 5.1 Hz), 6.78 (d, 1H, J = 8.5 Hz), 6.99 (s, 1H), 7.17 (dd, 1H, J = 7.6, 4.8 Hz), 7.19 (d, 1H, J = 8.5 Hz), 7.25 (t, 1H, J = 7.4 Hz), 7.33 (t, 2H, J = 7.4 Hz), 7.41 (d, 2H, J = 7.4 Hz), 7.68 (d, 1H, J = 7.6 Hz), 8.01 (s, 1H), 8.37 (dd, 1H, J = 4.8, 1.7 Hz), 8.40 (d, 1H, J = 1.7 Hz). 13C-NMR (CDCl3) δ: 26.1, 46.4, 56.1, 63.0, 110.4, 112.8, 115.4, 119.4, 122.1, 123.5, 126.8, 127.0, 127.3, 128.4, 128.9, 132.3, 133.0, 133.1, 134.3, 140.0, 146.8, 148.1, 148.3. HR-MS (ESI) m/z: Calcd for C25H24N3O ([M+H]+) 382.1919. Found: 382.1885.
Stepwise preparation of 8g: A mixture of 1b (282 mg, 1 mmol), aldehyde 4g (195 mg, 1.1 mmol) and Et3N (8 mL) in MeOH (8 mL) was stirred at room temperature for 8 h, and the mixture was concentrated under reduced pressure. Purification of the residue by flash column chromatography with hexane/AcOEt (3:1) afforded 10b7 (352 mg, 83%). Azepinoindole 10b (213 mg, 0.5 mmol) was heated in 2,2,2-trifluoroethanol (TFE) (5 mL) under reflux for 0.5 h. After the solvent was removed, the residue was purified by flash column chromatography with CHCl3/MeOH/28%NH4OH (46:3:0.3) to give 8g7 (181 mg, 85%).
5-Benzyl-6-[(E)-2-(trimethylsilyl)ethenyl]-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-7-ol (15): A mixture of 1b (282 mg, 1 mmol), 13 (384 mg, 3 mmol) and Et3N (8 mL) in MeOH (8 mL) was stirred at room temperature for 6 h. The mixture was concentrated under reduced pressure, and the residue was then separated by flash column chromatography with hexane/AcOEt (3:1) to give 15 (310 mg, 79%) as a pale-yellow foam. IR (CHCl3): 3480 cm-1. 1H-NMR (CDCl3) δ: 0.03 (s, 9H), 1.50 (br s, 1H), 2.83 (dt, 1H, J = 16.4, 2.8 Hz), 3.06 (dq, 1H, J = 13.7, 2.8 Hz), 3.18 (ddd, 1H, J = 16.4, 13.7, 3.6 Hz), 3.46 (td, 1H, J = 13.7, 3.6 Hz), 3.87 (d, 1H, J = 13.6 Hz), 4.04 (d, 1H, J = 13.6 Hz), 4.94 (d, 1H, J = 4.5 Hz), 5.55 (dd, 1H, J = 19.0, 1.7 Hz, 1H), 6.34 (dd, J = 19.0, 4.5 Hz, 1H), 6.79 (d, J = 8.7 Hz, 1H), 6.94 (s, 1H), 7.15 (d, J = 8.7 Hz), 7.23 (t, 1H, J = 7.4 Hz), 7.29 (t, 2H, J = 7.4 Hz), 7.36 (d, 2H, J = 7.4 Hz), 7.95 (s, 1H). 13C-NMR (CDCl3) δ: -0.9, 26.5, 46.3, 56.7, 66.0, 110.3, 113.2, 115.4, 120.0, 121.9, 128.4, 128.9, 132.4, 140.0, 145.8, 146.5. HR-MS (ESI) m/z: Calcd for C23H29N2OSi ([M+H] +): 377.2049. Found: 377.2031.
N-Benzyl-2-[7-(trimethylsilyl)-3,7-dihydropyrano[3,2-e]indol-1-yl]ethanamine (14): A solution of 15 (392 mg, 1 mmol) in TFE (5 mL) was heated under reflux for 0.5 h. Then, the mixture was concentrated under reduced pressure, and the residue was separated by flash column chromatography with CHCl3/MeOH/28%NH4OH (46:3:0.3) to give 14 (298 mg, 76%) as a dark-yellow foam. IR (CHCl3): 3480 cm-1. 1H-NMR (CDCl3) δ: 0.10 (s, 9H), 1.56 (br s, 1H), 2.96 (t, 2H, J = 6.8 Hz), 3.04 (t, 2H, J = 6.8 Hz), 3.82 (s, 2H), 4.52 (dd, 1H, J = 4.2, 2.3 Hz), 5.79 (dd, 1H, J = 9.9, 4.2 Hz), 6.63 (d, 1H, J = 8.5 Hz), 6.88 (dd, 1H, J = 9.9, 2.3 Hz), 6.93 (d, 1H, J = 2.3 Hz), 7.01 (d, 1H, J = 8.5 Hz), 7.21-7.24 (m, 1H), 7.28-7.30 (m, 4H), 7.73 (br s, 1H). 13C-NMR (CDCl3) δ: -3.7, 27.9, 49.9, 54.1, 71.2, 110.8, 112.2, 114.0, 115.4, 120.8, 122.9, 123.7, 124.3, 127.0, 128.2, 128.5, 132.8, 140.5, 149.2. HR-MS (ESI) m/z: Calcd for C23H29N2OSi ([M+H]+): 377.2049. Found: 377.2000.
N-Benzyl-2-(3,7-dihydropyrano[3,2-e]indol-1-yl)ethanamine (11): To a solution of 14 (376 mg, 1 mmol) in THF (10 mL), TBAF (1.0 M solution in THF, 1.2 mL, 1.2 mmol) was added. After stirring at room temperature for 3 h, the mixture was diluted with AcOEt, washed with brine and dried over MgSO4. The solvent was removed, and the residue was separated by flash column chromatography with CHCl3/MeOH/28%NH4OH (46:3:0.3) to give 11 (225 mg, 74%) as a pale-yellow foam. IR (CHCl3): 3480 cm-1. 1H-NMR (CDCl3) δ: 1.54 (br s, 1H), 2.93 (t, 2H, J = 6.9 Hz), 3.07 (t, 2H, J = 6.9 Hz), 3.82-3.83 (m, 2H), 3.83 (s, 2H), 4.93 (dt, 1H, J = 6.9, 3.5 Hz), 6.51 (d, 1H, J = 6.9 Hz), 6.54 (d, 1H, J = 9.2 Hz), 6.78 (s, 1H), 6.90 (d, 1H, J = 9.2 Hz), 7.10-7.14 (m, 5H), 7.69 (s, 1H). 13C-NMR (CDCl3) δ: 22.1, 27.3, 51.0, 54.0, 99.3, 110.2, 111.1, 112.8, 115.0, 123.3, 125.1, 127.1, 128.3, 128.5, 133.1, 140.1, 140.7, 144.9. HR-MS (ESI) m/z: Calcd for C20H21N2O1 ([M+H]+): 305.1654. Found: 305.1613.
2-(3,7,8,9-Tetrahydropyrano[3,2-e]indol-1-yl)ethanamine (3a)2a: Catalytic hydrogenation of 11 (152 mg, 0.5 mmol) was carried out using 10% Pd-C (10 mg) in MeOH (10 mL) at room temperature for 18 h. After the catalyst and the solvent were removed, the residue was separated by flash column chromatography with CHCl3/MeOH/28%NH4OH (46:3:0.3) to give 3a (77 mg, 71%). IR (CHCl3): 3480 cm-1. 1H NMR (CDCl3) δ: 1.50 (br s, 2H), 2.09 (tt, 2H, J = 6.5, 5.1 Hz,), 3.01 (s, 4H), 3.21 (t, 2H, J = 6.5 Hz), 4.19 (t, 2H, J = 5.1 Hz), 6.70 (d, 1H, J = 8.5 Hz), 6.93 (s, 1H), 7.06 (d, 1H, J = 8.5 Hz), 8.11 (br s, 1H). 13C-NMR (CDCl3) δ: 22.7, 23.0, 31.2, 43.6, 66.0, 110.1, 113.3, 113.5, 114.2, 123.1, 125.8, 131.6, 148.7. HR-MS (ESI) m/z: Calcd for C13H17N2O ([M+H]+): 217.1341. Found: 217.1301.
Reaction of 1b with 16 in the presence of Et3N in 2-propanol: A mixture of 1b (282 mg, 1 mmol), 16 (438 mg, 3 mmol) and Et3N (8 mL) in 2-propanol (8 mL) was heated under reflux for 5 days. The mixture was concentrated under reduced pressure, and the residue was separated by flash column chromatography with CHCl3/MeOH/28%NH4OH (46:3:0.3) to give 177 (209 mg, 53%) and 18 (27 mg, 10%) as a pale-yellow foam.
5-Benzyl-1,3,4,5-tetrahydro-7H-azepino[5,4,3-cd]indol-7-one (18): IR (CHCl3): 1618, 3474 cm-1. 1H-NMR (CDCl3) δ: 2.79 (t, 2H, J = 4.5 Hz), 3.57 (t, 2H, J = 4.5 Hz), 4.72 (s, 2H), 6.39 (d, 1H, J = 9.6 Hz), 6.72 (d, 1H, J = 2.3 Hz), 7.28-7.39 (m, 6H), 8.47 (br s, 1H), 8.55 (s, 1H). 13C-NMR (CDCl3) δ: 27.9, 52.4, 65.2, 108.2, 117.4, 119.5, 121.4, 123.7, 124.4, 127.5, 128.2, 128.7, 129.1, 134.5, 155.9, 182.7. HR-MS (ESI) m/z: Calcd for C18H17N2O ([M+H]+): 277.1341. Found: 277.13409.
N-Benzyl-2-(8-methyl-7-phenyl-3,7-dihydropyrano[3,2-e]indol-1-yl)ethanamine (19): A solution of 17 (197 mg, 0.5 mmol) in TFE (5 mL) was heated under reflux for 1 h. Then, the mixture was concentrated under reduced pressure, and the residue was separated by flash column chromatography with CHCl3/MeOH/28%NH4OH (46:3:0.3) to give 19 (153 mg, 78%) as a dark yellow foam. IR (CHCl3): 3482 cm-1. 1H-NMR (CDCl3) δ: 1.69 (br s, 1H), 1.79 (s, 3H), 3.03 (t, 2H, J = 6.2 Hz), 3.14 (t, 2H, J = 6.2 Hz), 3.85 (s, 2H), 5.61 (s, 1H), 6.64 (d, 1H, J = 8.5 Hz), 6.94 (d, 1H, J = 2.3 Hz), 6.98 (s, 1H), 6.98 (d, 1H, J = 8.5 Hz), 7.21-7.24 (m, 1H), 7.32-7.26 (m, 7H), 7.41 (dd, 2H, J = 7.1, 2.0 Hz),7.84 (br s, 1H). 13C-NMR (CDCl3) δ: 20.7, 28.0, 49.9, 54.2, 80.3, 110.8, 112.4, 113.7, 114.0, 118.1, 122.4, 123.8, 127.2, 127.9, 128.3, 128.6, 128.6, 128.7, 131.7, 132.9, 139.3, 140.3, 145.2. HR-MS (ESI) m/z: Calcd for C27H27N2O ([M+H]+): 395.2123. Found: 395.2084.
Reaction of 1b with 20 in the presence of Et3N in 2-propanol: A mixture of 1b (282 mg, 1 mmol), 20 (288 mg, 3 mmol) and Et3N (8 mL) in 2-propanol (8 mL) was heated under reflux for 3 days. The mixture was concentrated under reduced pressure, and the residue was separated by flash column chromatography with CHCl3/MeOH/28%NH4OH (46:3:0.3) to give 21 (162 mg, 47%) as a pale-yellow foam and 18 (33 mg, 12%).
5-Benzyl-6-cyclopent-1-en-1-yl-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-7-ol (21): IR (CHCl3): 3480 cm-1. 1H-NMR (CDCl3) δ: 1.91-1.98 (m, 2H), 2.23-2.28 (m, 2H), 2.41 (dt, 1H, J = 15.3, 7.5 Hz), 2.74 (dt, 1H, J = 15.3, 7.5 Hz), 2.82 (d, 1H, J = 15.9 Hz), 3.06 (d, 1H, J = 13.9 Hz), 3.24 (dd, 1H, J = 15.9, 13.6 Hz), 3.34 (t, 1H, J = 13.9 Hz), 3.86 (d, 1H, J = 13.6 Hz), 4.05 (d, 1H, J = 13.6 Hz), 4.27 (br s, 1H), 4.91 (s, 1H), 5.03 (dd, 1H, J = 3.7, 2.0 Hz), 6.78 (d, 1H, J = 8.7 Hz), 6.96 (s, 1H), 7.15 (d, 1H, J = 8.7 Hz), 7.22 (t, 1H, J = 7.4 Hz), 7.30 (t, 2H, J = 7.4 Hz), 7.36 (d, 2H, J = 7.4 Hz), 7.93 (br s, 1H). 13C-NMR (CDCl3) δ: 23.7, 25.3, 32.3, 34.5, 44.6, 54.9, 62.7, 109.9, 113.2, 115.2, 121.7, 121.9, 126.4, 126.8, 128.2, 128.6, 128.7, 132.4, 140.5, 146.0, 146.3. HR-MS (ESI) m/z: Calcd for C23H25N2O ([M+H]+): 345.1967. Found: 345.1930.
N-Benzyl-2-(6a,7,8,9-tetrahydro-3H-cyclopenta[5,6]pyrano[3,2-e]indol-1yl)ethanamine (22): A solution of 21 (197 mg, 0.5 mmol) in TFE (5 mL) was heated under reflux for 30 min. Then, the mixture was concentrated under reduced pressure, and the residue was separated by flash chromatography on silica gel (CHCl3/MeOH/28%NH4OH, 46:3:0.3) to give 22 (149 mg, 76%) as a dark-yellow foam. IR (CHCl3): 3480 cm-1. 1H-NMR (CDCl3) δ: 1.70-1.77 (m, 1H), 1.91-2.00 (m, 2H), 2.31-2.37 (m, 1H), 2.47-2.53 (m, 1H), 2.57-2.65 (m, 1H), 2.98 (t, 2H, J = 7.1 Hz), 3.02-3.13 (m, 2H), 3.82 (s, 2H), 4.85 (t, 1H, J = 6.8 Hz), 6.78 (d, 1H, J = 8.5 Hz), 6.79 (s, 1H), 6.93 (d, 1H, J = 1.7 Hz), 7.02 (d, 1H, J = 8.5 Hz), 7.21-7.23 (m, 1H), 7.28-7.30 (m, 4H), 7.96 (br s, 1H). 13C-NMR (CDCl3) δ: 22.6, 27.8, 29.1, 32.5, 49.8, 54.0, 78.8, 110.1, 112.1, 114.3, 114.7, 116.5, 123.0, 123.5, 127.0, 128.2, 128.5, 133.0, 140.1, 140.4, 147.4. HR-MS (ESI) m/z: Calcd for C23H24N2O ([M+H]+): 345.1967. Found: 345.1940.
rel-2-[(6aS,9aS)-6a,7,8,9,9a,10-Hexahydro-3H-cyclopenta[5,6]pyrano[3,2-e]indol-1-yl]ethanamine (23): Catalytic hydrogenation of 22 (344 mg, 1 mmol) was carried out using 10% Pd-C (30 mg) in MeOH (10 mL) at room temperature for 6 h. After the catalyst and the solvent were removed, the residue was separated by flash chromatography with CHCl3/MeOH/28%NH4OH (46:3:0.3) to give 23 (202 mg, 79%) as a dark-yellow foam. IR (CHCl3): 3480 cm-1. 1H-NMR (CDCl3) δ: 1.51-1.60 (m, 1H), 1.62 (br s, 2H), 1.65-1.74 (m, 1H), 1.81-2.03 (m, 4H), 2.29-2.36 (m, 1H), 2.98-3.04 (m, 4H), 3.07 (dd, 1H, J = 17.0, 2.3 Hz), 3.38 (dd, 1H, J = 17.0, 7.4 Hz), 4.33 (dd, 1H, J = 3.7, 2.6 Hz), 6.73 (d, 1H, J = 8.5 Hz), 6.94 (s, 1H), 7.07 (d, 1H, J = 8.5 Hz), 8.12 (br s, 1H). 13C-NMR (CDCl3) δ: 22.1, 24.7, 29.3, 31.4, 33.2, 38.2, 43.6, 78.6, 109.8, 112.8, 113.7, 114.1, 123.1, 125.6, 132.0, 147.8. HR-MS (ESI) m/z: Calcd for C16H21N2O ([M+H]+): 257.1654. Found: 257.1644.

ACKNOWLEDGEMENTS
This research was partially supported by a Grant-in-Aid for Scientific Research (22590010), a Grant-in-Aid for High Technology Research program from the Ministry of Education, Culture, Sports, Science and Technology, and a Grant-in-Aid for the 2009-2010 Research Project of the Research Institute of Personalized Health Sciences from Health Sciences University of Hokkaido.

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