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Communication | Special issue | Vol. 77, No. 2, 2009, pp. 825-828
Received, 5th August, 2008, Accepted, 18th September, 2008, Published online, 22nd September, 2008.
DOI: 10.3987/COM-08-S(F)98
Reaction of Nβ-Benzylserotonin with α,β-Unsaturated and Aryl Aldehydes in the Presence of a Base

Koji Yamada, Yuichi Namerikawa, Takumi Abe, and Minoru Ishikura*

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

The reaction of Nβ-benzylserotonin with α,β-unsaturated and aryl aldehydes in the presence of a base produced 1H-azepino[5,4,3-cd]indoles.

Pictet-Spengler reaction is widely accepted as one of the most fundamental and versatile synthetic protocol in heterocyclic synthesis.1 Generally, tryptamine derivatives are known to react with aldehydes under acidic or neutral conditions through an initial iminium ion formation, followed by cyclization onto the 2-position of the indole ring, leading to β–carbolines.2 On the other hand, it has been previously proved that heating of Nβ-methylserotonin (1a) with large excess Et3N under O2 atmosphere in MeOH provided azepinoindole 2 in moderate yield, in which the intermediary formation of A from 1a and acetaldehyde equivalent generated in situ from Et3N and O2 was speculated.3 Therein, ready availability of 2 from treatment of 1a with acetaldehyde in the presence of Et3N in high yield was also shown.3 Therefore, we have become interested in the applicability of other aldehydes to the cyclization reaction from the standpoint of synthetic potential. In this report, we describe the reaction of Nβ-benzylserotonin 1b with α,β−unsaturated and aryl aldehydes in the presence of a base.4

The reaction was carried out simply by treating 1b with aldehydes 4 and 6 (3 equiv.) in the presence of a base in MeOH, and products were separated by flash chromatography.5 At first, the reaction of 1b with α,β-unsaturated aldehyde 4a was undertaken, leading to 3a in moderate yield (Table 1, runs 1 and 2).
Reactions of
4b and 4c produced 3b and 3c, respectively, in good yields. Since the reactions of 4d and 4e equipped with an α-Me group were subject to steric hindrance (runs 5-7). On treating 4d at room temperature for 7 days, only small amount of 3d was isolated along with 3f in 16% yield.6 Heating of 4e under reflux for 5 days gave 3e in 50% yield (run 7).

Scheme 2 depicts the outcome for the production of 3a involving the facile addition of MeOH to 4a and/or the addition of MeOH to iminium ion 5, which is also illustrative of the generation of 3b and 3d.

Next, aryl aldehydes 6 were subjected to the reaction with 1b (Table 2). While the reaction with 6a was completed in 24 h under reflux, substitution of large excess Et3N for DABCO (3 equiv.) was, to our delight, found to lead to a significant shortening of the reaction time in producing 3g in high yield (runs 1 and 2). Aldehyde 6b equipped with an electron donating group required elongation of the reaction time. In contrast, the reaction with 6c having an electron withdrawing group produced moderate amount of 3i accompanied by a small amount of β-carboline 7. The treatment of indole-3-carbaldehyde with 1b gave no identifiable products, whereas subjection of 6e bearing the N-Boc group to the reaction was far more successful producing 3k in high yield.

In summary, we have shown that the reaction of Nβ-benzylserotonin (1b) with α,β−unsaturated and aryl aldehydes proceeded smoothly with the aid of a base, successfully providing azepinoindoles 3. Further studies of the present cyclization reaction, including applications to natural product synthesis, are underway.

This work was supported in part by a Grant-in Aid for High Technology Research program from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and in part by a Grant-in Aid for Scientific Research (No. 18590011) from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

This paper is dedicated to Professor Emeritus Keiichiro Fukumoto on the occasion of his 75th birthday.


1. W. M. Whaley and T. R. Govindachari, Org. React., 1951, 6, 151; T. Hino and M. Nakagawa, Heterocycles, 1998, 49, 499; CrossRef J. Royer, M. Bonin, and L. Micouin, Chem. Rev., 2004, 104, 2311. CrossRef
2. T. Hudlicky, T. M. Kutchan, G. Shen, V. E. Sutliff, and C. J. Coscia, J. Org. Chem., 1981, 46, 1738; CrossRef T. Yamano, R. Miura, M. Kanashiro, and T. Uemura, Bioorg. Chem., 1988, 16, 189; CrossRef Y. Maki, H. Kimoto, S. Fujii, M. Nishida, and L. A. Cohen, J. Fluorine Chem., 1989, 43, 189; CrossRef P. D. Bailey and K. M. Morgan, J. Chem. Soc., Perkin Trans. 1, 2000, 3578; CrossRef R. V. Connors, A. J. Zhang, and S. J. Shuttleworth, Tetrahedron Lett., 2002, 43, 6661; CrossRef R. Tsuji, M. Nakagawa, and A. Nishida, Tetrahedron: Asymmetry, 2003, 14, 177. CrossRef
3. M. Somei, S. Teranishi, K. Yamada, and F. Yamada, Chem. Pharm. Bull., 2001, 49, 1159. CrossRef
4. Since we were unable to detect 9 on treating 8 with MeCHO, it seemed likely that the reaction proceeded through the formation of iminium ion B, followed by Pictet-Spengler type cyclization onto the 4-position of the indole ring.
5. Reaction of 1b with 4c: Typical procedure: A mixture of 1b (100 mg, 0.4 mmol), 4c (0.14 mL, 1.2 mmol), Et3N (5 mL) and MeOH (5 mL) was stirred at rt for 6 h. The mixture was concentrated, and the residue was separated by flash chromatography (SiO2/ hexane-AcOEt = 1:3) to give 3c in 84% yield. 1H-NMR (CDCl3) δ: 2.85 (dt, 1H, J = 16.6, 2.4 Hz), 3.07 (ddd, 1H, J = 13.7, 3.2, 2.4 Hz), 3.20 (ddd, 1H, J = 16.6, 13.7, 3.2 Hz), 3.59 (td, 1H, J = 13.7, 3.2 Hz), 3.94 (d, 1H, J = 13.7 Hz), 4.10 (d, 1H, J = 13.7 Hz), 5.18 (d, 1H, J = 5.7 Hz), 6.16 (d, 1H, J = 16.0 Hz), 6.58 (dd, 1H, J = 16.0, 5.2 Hz), 6.78 (d, 1H, J = 8.6 Hz), 6.98 (s, 1H), 7.19 (d, 1H, J = 8.6 Hz), 7.24-7.27 (m, 5H), 7.30-7.34 (m, 3H), 7.41 (d, 2H, J = 7.4 Hz), 7.96 (s, 1H). 13C-NMR (CDCl3) δ: 26.4, 46.2, 56.6, 63.3, 110.2, 113.0, 115.5, 119.9, 121.9, 126.6, 126.9, 127.4, 128.3, 128.4, 128.8, 130.5, 131.6, 132.4, 136.9, 140.0, 146.3. HR-MS m/z: Calcd for C26H24N2O: 380.1889. Found: 380.1890.
6. It seemed likely that 3f resulted from the reaction of 1b with propionaldehyde generated in situ through the addition of H2O to 4d and the subsequent retro-aldol step

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