Reaction of Nβ-benzylserotonin with α,β- unsaturated and aryl aldehydes in the presence of a base

Article abstract of DOI:10.3987/COM-08-S(F)98

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

Full text of DOI:10.3987/COM-08-S(F)98

HETEROCYCLES, Vol. 77, No. 2, 2009
825
HETEROCYCLES, Vol. 77, No. 2, 2009, pp. 825 - 828. © The Japan Institute of Heterocyclic Chemistry
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; e-mail:ishikura@hoku-iryo-u.ac.jp
Abstract – 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
Bn
N
Me
N
Bn
Me
NH
+
R'
R'
Me
H
+
N
HO
Me
O2
Et3N
HO
HO
HO
HO
aldehyde
NH
R
N
H
base
MeOH
MeOH
reflux
N
H
N
H
N
H
N
H
1
A
3
B
2
(R = Bn)
a
b
(R = Me)
: R=Me
: R=Bn
Scheme 1
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).
This paper is dedicated to Professor Emeritus Keiichiro Fukumoto on the occasion of his 75th birthday.

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HETEROCYCLES, Vol. 77, No. 2, 2009
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).
Table 1. Reaction of 1b with α,β–unsaturated aldehydes 4a
run
aldehyde 4
conditions
yield (%) of 3b
41 (3a)
1
rt / 24 h
CHO
4a
4a
(R’=CH2CH2OMe)
2
reflux / 3 h
rt / 24 h
55 (3a)
75 (3b)c
CHO
3
4b
(R’=CH2CHMeOMe)
Ph
Me
4
rt / 6 h
84 (3c)
10 (3d)c, d
CHO
4c
4d
4e
5
rt / 7 d
CHO
(R’=CHMeCH2OMe)
6
7
rt / 24 h
---e
4e
reflux / 5 d
50 (3e)
aTreatment of 1b with aldehyde (3 equiv.) in Et3N:MeOH (1:1). bIsolated yield based
d
c
on 1b. Two diastereoisomers in a 1:1 ratio. Isolation of 3f (R’=Et) in 16% yield.6
eNo reaction.
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.
MeO
HO
MeOH
MeO
HO
O
Bn
N
O
1b
Bn
N
+
H
4a
H
MeO
1b
N
H
N
H
3a
MeO
Bn
N
Bn
Me
+
MeO
MeO
HO
N
Bn
N
Bn
N
MeOH
HO
HO
Me
HO
N
H
N
H
5
N
H
N
H
3d
3b
Scheme 2
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

HETEROCYCLES, Vol. 77, No. 2, 2009
827
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.
Table 2. Reaction of 1b with aryl aldehydes 6a
run
1
aldehyde 6
PhCHO
conditions
Et3N / 24 h
yield (%) of 3b
86 (3g)
6a
6a
2
PhCHO
DABCO / 3 h
85 (3g)
CHO
3
4
5
DABCO / 12 h
DABCO / 3.5 h
DABCO / 3 h
74 (3h)
55 (3i)c
83 (3j)
Me2N
6b
CHO
NC
6c
CHO
N
6d
CHO
6
7
DABCO / 3 h
DABCO / 3 h
86 (3k)
84 (3l)
N
Boc
6e
6f
CHO
O
aTreatment of 1b with aldehyde (3 equiv.) in the presence of Et3N (large
b
excess) or DABCO (3 equiv.) in MeOH under reflux. Isolated yield based on
1b. cβ-Carboline 7 in 9% yield.
HO
N
Bn
N
H
7
CN
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.
ACKNOWLEDGEMENTS
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.

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REFERENCES AND NOTES
1. W. M. Whaley and T. R. Govindachari, Org. React., 1951, 6, 151; T. Hino and M. Nakagawa,
Heterocycles, 1998, 49, 499; J. Royer, M. Bonin, and L. Micouin, Chem. Rev., 2004, 104, 2311.
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T. Yamano, R. Miura, M. Kanashiro, and T. Uemura, Bioorg. Chem., 1988, 16, 189; Y. Maki, H.
Kimoto, S. Fujii, M. Nishida, and L. A. Cohen, J. Fluorine Chem., 1989, 43, 189; P. D. Bailey and K.
M. Morgan, J. Chem. Soc., Perkin Trans. 1, 2000, 3578; R. V. Connors, A. J. Zhang, and S. J.
Shuttleworth, Tetrahedron Lett., 2002, 43, 6661; M. Somei and M. Seto, Heterocycles, 2003, 60,
519; R. Tsuji, M. Nakagawa, and A. Nishida, Tetrahedron: Asymmetry, 2003, 14, 177.
3. M. Somei, S. Teranishi, K. Yamada, and F. Yamada, Chem. Pharm. Bull., 2001, 49, 1159.
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.
Me
OH
NBn2
HO
HO
MeCHO
NBn2
Et3N
MeOH
N
H
N
H
8
9
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),
13
7.41 (d, 2H, J = 7.4 Hz), 7.96 (s, 1H). C-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.
Me Bn
N
H2CO
Me
Me
Me
HO
1b
H2O
O
O
O
H
H
H
O
H
4d
N
H
3f