A new synthesis of 4-oxygenated β-carboline derivatives by Fischer indolization

Article abstract of DOI:10.1016/j.tetlet.2005.03.177

A new and short synthetic route to the 4-methoxy-β-carboline skeleton is described. The route involves Fischer indolization of enehydrazine of 1-tosylpiperidine-3,5-dione and successive acetalization-elimination for aromatization of 1,2,3,4-tetrahydro-2-tosyl-9H-β-carbolin-4-one. This method is efficiently applicable to synthesis of the benzene-part substituted 4-oxygenated β-carboline derivatives.

Full text of DOI:10.1016/j.tetlet.2005.03.177

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 3831–3834
A new synthesis of 4-oxygenated b-carboline derivatives
by Fischer indolizationq
Hideharu Suzuki,* Yoshiyuki Tsukakoshi, Takuya Tachikawa, Yuusuke Miura,
Makoto Adachi and Yasuoki Murakamiꢀ
Faculty of Pharmaceutical Sciences, Toho University, 2-2-1 Miyama, Funabashi, Chiba 274-8510, Japan
Received 3 December 2004; revised 26 March 2005; accepted 29 March 2005
Available online 14 April 2005
Abstract—A new and short synthetic route to the 4-methoxy-b-carboline skeleton is described. The route involves Fischer
indolization of enehydrazine of 1-tosylpiperidine-3,5-dione and successive acetalization–elimination for aromatization of 1,2,3,4-tet-
rahydro-2-tosyl-9H-b-carbolin-4-one. This method is efficiently applicable to synthesis of the benzene-part substituted 4-oxygenated
b-carboline derivatives.
Ó 2005 Elsevier Ltd. All rights reserved.
Recently, many 4-methoxy-b-carboline alkaloids (1)
have been isolated3 and some of them have been found
to be biologically active4 (cytotoxicity,4a anti-HIV,4b
anti-malaria,4c suppression of iNOS,4d antimicrobial
activity4e). We have developed5–8 a general synthetic
method of 1, starting from ethyl indole-2-carboxylates
(2) as shown in Scheme 1. On the other hand, synthesis
of 4-oxygenated b-carboline from a 3-substituted indole
derivative via Pictet–Spengler and Bischler–Napieralski
reactions has so far been unsuccessful.5
CO2Et
NCHO
3
2
N
H
2
CO2Et
N
H
3
R1
R1
R1=H or TsO-
O
OMe
NCHO
N
N
N
H
1
H
R2
R1
R1
4
Now, we are interested in a variety of benzene-part
substituted 4-methoxy-b-carbolines (10) (Table 3) from
the viewpoint of their biological activities. Therefore, a
new convenient synthetic method for the benzene-part
substituted 4-methoxy-b-carbolines is required. To this
end, we envisaged that the Fischer indolization starting
from a variety of substituted phenylhydrazines (5) was
feasible. On the other hand, Chen et al. reported9 the
synthesis of 1,2,3,4-tetrahydro-b-carbolin-4-ones from
1-benzylpiperidine-3,5-dione (6a)10 with aniline deriva-
tives via Pd-mediated C–C bond formation under
stoichiometric conditions,9a followed by a catalytic
reaction.9b We believe that our method is a more conve-
R1=H, OH, OCH3
R2=H, Et, CH=CH2,
CO2Me, COMe,
Scheme 1.
nient and general synthetic method for benzene-part
substituted 4-methoxy-b-carbolines (10).
First, we tried to prepare the phenylhydrazone of 1-benz-
ylpiperidine-3,5-dione (6a), but the reaction gave only
tarry products, probably owing to the basic property
of 6a (Table 1). A tosyl group was chosen as an
N-protecting group for the substrate (6b)10 because the
sulfonyl group stabilizes the amino group with a
stronger electron-withdrawing property. Thus, the hydro-
chlorides of phenylhydrazines (5a–e) were reacted with
1-tosylpiperidine-3,5-dione (6b, 1 mol equiv) in the
presence of sodium acetate (2 mol equiv) in acetic acid.
Keywords: Fischer indolization; b-carboline; Indole; Acetalization;
Aromatization.
q See Ref. 1.
*
Corresponding author. Tel.: +81 47472 1183; fax: +81 47472 1595;
e-mail: suzuki@phar.toho-u.ac.jp
ꢀ See Ref. 2.
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.03.177

3832
H. Suzuki et al. / Tetrahedron Letters 46 (2005) 3831–3834
Table 3. Synthesis of 4-methoxy-b-carboline (10)
Table 1. Synthesis of enehydrazine (7)
O
(MeO)2CMe2
O
OMe
N
BF3·OEt2
X
X
AcONa
X
+
(20 mol equiv)
8a-d
N-Ts
N-Y
in AcOH
rt
N
H
N
H
O
NHNH2
·HCl
in (CHCl2)2
120 °C
N
H
10a-d
(1.0 eq)
5a-e
7a-e
6a Y:Bn
6b Y:Ts
X
Time (h)
Yield of 10 (%)
X
Y
Yield of 7 (%)
5aa
5aa
H
H
6a Bn
6b Ts
6b Ts
6b Ts
6b Ts
6b Ts
Many spots
8a H
0.2
0.7
0.3
0.8
92
84
86
94
8b Me
8c Cl
8d OMe
72
70
69
73
61
5b Me
5c Cl
5d OMe
5e NO2
a TsOH salt of 5a was used.
The reactions of these enehydrazines (7a–c) gave the tar-
get 1,2,3,4-tetrahydro-b-carbolin-4-ones (8a–c) in good
yields with the second intermediate11 (9) of the Fischer
indolization as a by-product. For the methoxy deriva-
tive 7d, yield of the target product (8d) was only 28%
and a de-methylated compound (8, X@OH) was
obtained in 11% yield as well. However, the thermal
Fischer indolization condition12 of 7d gave a reasonable
43% yield of 8d. The nitro derivative (7e) was not
cyclized under any examined conditions, due to the inac-
tiveness of the aromatic ring by the electron-withdraw-
ing effect of the nitro group.
O
X
N-Ts
N
N
7'
H
The reaction proceeded at room temperature to give the
product in good yields as shown in Table 1.23,27 The
structures of the product were found to be the enehydr-
azines 7a–e, tautomers of the corresponding phenylhyd-
razone (70). The enehydrazine structure was known to be
the first intermediate in the Fischer indolization of
phenylhydrazones.11
As compound (9) should be the second intermediate in
the Fischer indole synthesis, compound (9a) was treated
under the same conditions as the Fischer indolization.
The target 1,2,3,4-tetrahydro-b-carbolin-4-one (8a) was
obtained in 50% yield (Scheme 2). Compound (8) thus
obtained was treated with dimethoxypropane and excess
of BF3ÆOEt2 in 1,1,2,2-tetrachloroethane to give 4-meth-
oxy- b-carboline (10) directly with unexpected removal
of the N-tosyl group in good yield as shown in Table
3.25,29 In this reaction, we obtained p-toluenesulfinic
acid from the reaction mixture and identified it as the
methyl ester in the NMR spectrum.
The Fischer indolization of the enehydrazines 7a–e was
carried out under various conditions. The classical con-
ditions for Fischer indolization (HCl–MeOH, TsOH in
benzene, etc.) gave poor results, whereas the reaction
with excess of BF3ÆOEt2 in 1,1,2,2-tetrachloroethane at
120 °C gave a better result as shown in Table 2.24,28
Table 2. Fischer indolization of enehydrazine (7)
The mechanism of this successive acetalization and elimi-
nation for aromatization of 8 is proposed in Scheme 3.
The key step should be the reductive b-elimination
of the tosyl group as p-toluenesulfinic acid with the
intramolecular oxidative–reductive aromatization under
acidic condition.
O
BF3·OEt2
in (CHCl2)2
X
7a-e
N-Ts
120 °C
N
H
8a-d
There are some reports13,14 for aromatization toward
the pyridine ring by b-elimination of the tosyl group
under basic conditions. However, the reductive elimina-
tion of the tosyl group to sulfinic acid is not described in
their papers. We previously reported6 that the aromati-
X
BF3ÆOEt2
(mol equiv)
Time (h)
Yield (%)
8
9
7a H
27
20
20
20
1.5
0.3
2
84
64
66
19
32
12
—
7b Me
7c Cl
7d OMe
0.3
28 (X@OMe)
11 (X@OH)
43
7d OMe
7e NO2
Nonea
20
0.4
—
HO
O
.
BF3 OEt2 (27 eq.)
Decomp.
in (CHCl2)2
a Reflux in (CHCl2)2.
N Ts
X
HO
120 C / 3 h
50%
N-Ts
N
H
NH2 HN
N Ts
9a
8a
NH2 HN
9
Scheme 2.

H. Suzuki et al. / Tetrahedron Letters 46 (2005) 3831–3834
3833
+
10
Ar SO2H
OBn
N
8
a
8a
H+
OMe
N
H
MeO
b
H
OMe
N
13 (66%)
H
H+
O
OH
NTs
c
N
H
N
H
S
NTs
H
N
H
Ar
N
H
14
N
H
-
O
12
11
Nu
15 (90% from 8a)
Scheme 3.
Nu
Nu
HO
zation of the N-formyl derivative (4) to 4-methoxy-b-
carboline (10a), required chloranil as an oxidative agent.
In the present route, the intermediate (12) was inevitably
aromatized with reductive elimination of sulfonic acid
without an oxidative agent or air oxidation under acidic
condition.15
NTs
N
N
N
H
17
SO2R
16
Scheme 5. Reagents and conditions: (a) (BnO)2CMe2, BF3ÆOEt2
(20 mol equiv) in (CHCl2)2, 120 °C; (b) NaBH4 in CHCl3–MeOH, rt,
16 h; (c) HCl in MeOH, rt, 1 h.
The condition for this acetalization–elimination reaction
was similar to the Fischer indolization condition. Thus,
the one-pot reaction of 7a to 10a was carried out.
Dimethoxypropane was added to the reaction mixture
after the Fischer indolization of the enehydrazine (7a)
was conducted, and then the mixture was heated at
120 °C for 1 h (Scheme 4).26
nucleophilic addition, leading to the synthesis of
4-substituted b-carbolines such as 4-amino (17, Nu =
NHR),15a,17,18 4-aralkyl (17, Nu = alkyl or aryl),19–22
and 4-thio (17, Nu = SR) derivatives. These synthetic
applications and a precise study of the desulfination
mechanism of the N-tosyl group of this reaction are
now in progress.
The reaction gave the target 4-methoxy-b-carboline
(10a) in good yield (77%) as the two separate operations.
The conversion of 4-methoxy-b-carboline (10a) to the
natural products (1) was already reported6 by us.
References and notes
Cook and co-workers15c reported the synthesis of 4-benz-
yloxy-b-carboline (13), but their yield was 36% starting
from 2-benzoyl-4-oxo-1,2,3,4-tetrahydro-b-carboline (cor-
responding to 8a). By applying this acetalization–elimi-
nation reaction to compound 8a, we succeeded in the
synthesis of compound 13 in good yield (66%) using di-
benzyloxypropane15c instead of dimethoxypropane.
This compound (13) should be an important synthetic
intermediate to 4-hydroxy-b-carboline alkaloids.16 Fur-
thermore, the Fischer product (8a) was converted to
unsubstituted b-carboline (15) in 90% yield by the
reduction of the C4-carbonyl group using NaBH4,
followed by reductive elimination on treatment with
HCl/MeOH at room temperature for 1 h (Scheme 5).
1. This paper is ‘‘Synthetic Studies on Indoles and Related
Compounds 54’’: Part 53: ‘‘A Total Synthesis of 1-
Methoxycanthin-6-one: An Efficient One-Pot Synthesis
of the Canthin-6-one Skeleton from b-Carboline-1-carb-
aldehyde’’ Suzuki, H.; Adachi, M.; Ebihara, Y.; Gyou-
toku, H.; Furuya, H.; Murakami, Y.; Okuno, H. Synthesis
2005, 28–32.
2. Current address: Faculty of Pharmaceutical Sciences,
Chiba Institute of Science, 3 Shiomi-cho, Choshi, Chiba
288-0025, Japan.
3. (a) Johns, S. R.; Lamberton, J. A.; Sioumis, A. A. Aust. J.
Chem. 1970, 23, 629–630; (b) Kitagawa, I.; Mahmud, T.;
Simanjuntak, P.; Hori, K.; Uji, T.; Shibuya, H. Chem.
Pharm. Bull. 1994, 42, 1416–1421; (c) Ouyang, Y.;
Mitsunaga, K.; Koike, K.; Ohmoto, T. Phytochemistry
1995, 39, 911–913. Further references are cited in Ref. 5.
4. (a) Murakami, C.; Fukamiya, N.; Tamura, S.; Okano, M.;
Bastow, K. F.; Tokuda, H.; Mukainaka, T.; Nishino, H.;
Lee, K. H. Bioorg. Med. Chem. 2004, 4963–4968; (b) Xu,
Z.; Chang, F.-R.; Wang, H. K.; Kashiwada, Y.; McPhail,
A. T.; Bastow, K. F.; Tachibana, Y.; Cosentino, M.; Lee,
K. H. J. Nat. Prod. 2000, 63, 1712–1715; (c) Takasu, K.;
Shimogama, T.; Saiin, C.; Kim, H. S.; Wataya, Y.; Ihara,
M. Bioorg. Med. Chem. Lett. 2004, 1689–1692; (d) Lee, B.
G.; Kim, S. H.; Zee, O. P.; Lee, K. R.; Lee, H. Y.; Han,
J. W.; Lee, H. W. Eur. J. Pharmacol. 2000, 406, 301–309;
(e) Ajayeoba, E. O.; Adeniyi, B. A.; Okogun, J. I.
Phytotherapy Res. 1995, 9, 69–71. Further references are
cited in Ref. 5.
From these experiments, it is expected that the Fischer
product (8) becomes the key intermediate for the general
synthesis of various 4-substituted b-carbolines. The 4-
carbonyl group of 8 must be modified variously by
OMe
BF3·OEt2
(MeO)2CMe2
7a
[ 8a ]
N
in (CHCl2)2
120 °C, 2 h
in (CHCl2)2
120 °C, 1 h
N
H
10a
one-pot (77%)
5. Murakami, Y.; Yokoyama, Y.; Aoki, C.; Suzuki, H.;
Sakurai, K.; Shinohara, T.; Miyagi, C.; Kimura, Y.;
Scheme 4.

3834
H. Suzuki et al. / Tetrahedron Letters 46 (2005) 3831–3834
Takahashi, T.; Watanabe, T.; Ohmoto, T. Chem. Pharm.
Bull. 1991, 39, 2189–2195.
6. Suzuki, H.; Iwata, C.; Sakurai, K.; Tokumoto, K.;
Takahashi, H.; Hanada, M.; Yokoyama, Y.; Murakami,
Y. Tetrahedron 1997, 53, 1593–1606.
under reduced pressure. The residual solid was purified by
column chromatography on silica gel using CH2Cl2–
EtOAc (1:1) as a solvent system to afford the product (7)
shown in Table 1.
24. General procedure for preparation of 8 from 7: To a
stirred solution of phenylhydrazone (7) (0.20 mmol) in
1,1,2,2-tetrachloroethane (4.0 mL), borontrifluoride ether-
ate (4.0 mmol) was added at 0 °C under argon atmo-
sphere, and then the reaction mixture was heated to
120 °C for 0.2–3 h. The reaction mixture was poured into
saturated aqueous NaHCO3, and extracted with EtOAc.
The organic layer was washed with brine, dried over
anhydrous MgSO4, and evaporated under reduced pres-
sure. The residual solid was purified by column-chroma-
tography on silica gel using CH2Cl2–EtOAc (1:1) as a
solvent system to afford the product (8) shown in Table 2.
25. General procedure for preparation of 10 from 8: To a
stirred solution of 1,2,3,4-tetrahydro-b-carbolin-4-one (8)
(0.050 mmol) in 1,1,2,2-tetrachloroethane (1.0 mL),
dimethoxypropane (0.40 mmol), and borontrifluoride eth-
erate (1.0 mmol) were added at 0 °C under argon atmo-
sphere, and then the reaction mixture was heated to
120 °C for 0.2–0.8 h. The reaction mixture was poured
into saturated aqueous NaHCO3, and extracted with
EtOAc. The organic layer was washed with brine, dried
over anhydrous MgSO4, and evaporated under reduced
pressure. The residual solid was purified by column-
chromatography on silica gel using CH2Cl2–MeOH (10:1)
as a solvent system to afford the product (10) shown in
Table 3.
7. Suzuki, H.; Ebihara, Y.; Yokoyama, Y.; Murakami, Y.
Heterocycles 1997, 46, 57–60.
8. Suzuki, H.; Unemoto, M.; Hagiwara, M.; Ohyama, T.;
Yokoyama, Y.; Murakami, Y. J. Chem. Soc. Perkin Trans
1 1999, 1717–1723.
9. (a) Chen, L. C.; Yang, S. C. Heterocycles 1990, 31, 911–
916; (b) Chen, L. C.; Yang, S. C.; Wang, H. M. Synthesis
1995, 385–386.
10. Tamura, Y.; Chen, L. C.; Fujita, M.; Kiyokawa, H.; Kita,
Y. J. Heterocycl. Chem. 1980, 17, 1–4.
11. Robinson, B. In The Fischer Indole Synthesis; John Wiley
and Sons: New York, 1982, pp 70–71.
12. Miyata, O.; Kimura, Y.; Muroya, K.; Hiramatsu, H.;
Naito, T. Tetrahedron Lett. 1999, 40, 3601–3604.
13. Love, B. E.; Raje, P. S. J. Org. Chem. 1994, 59, 3219–3222.
14. Tokuyama, H.; Sato, M.; Ueda, T.; Fukuyama, T.
Heterocycles 2001, 54, 105–108.
15. (a) Cain, M.; Mantei, R.; Cook, J. M. J. Org. Chem. 1982,
47, 4933–4936; (b) Hagen, T. J.; Cook, J. M. Tetrahedron
Lett. 1988, 29, 2421–2424; (c) Hagen, T. J.; Narayanan,
K.; Names, J.; Cook, J. M. J. Org. Chem. 1989, 54, 2170–
2178.
16. (a) Matsumura, S.; Enomoto, H.; Aoyagi, Y.; Nomiyama,
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2062–2063; (c) Fukamiya, N.; Okano, M.; Aratani, T.;
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26. One-pot procedure for 10a from 7a: To a stirred solution
of compound (7a) (38.6 mg, 0.108 mmol) in 1,1,2,2-
tetrachloroethane (2.0 mL), borontrifluoride etherate
(0.36 mL, 2.9 mmol) was added at 0 °C under argon
atmosphere, and then the reaction mixture was heated to
120 °C for 2 h. To the reaction mixture, dimethoxypro-
pane (0.2 mL, 1.6 mmol) was added at 120 °C, and heated
at 120 °C for 1 h. The reaction mixture was worked up as
described above to afford the product (10a, 16.5 mg) in
77% yield.
17. Fukada, N.; Trudell, M. L.; Johnson, B.; Cook, J. M.
Tetrahedron Lett. 1985, 26, 2139–2142.
18. Batch, A.; Dodd, R. H. J. Org. Chem. 1998, 63, 872–877.
19. Choshi, T.; Matsuya, Y.; Okita, M.; Inada, K.; Sugino, E.;
Hibino, S. Tetrahedron Lett. 1998, 39, 2341–2344.
20. Busacca, C. A.; Eriksson, M. C.; Dong, Y.; Prokopowicz,
A. S.; Salvagno, A. M.; Tschantz, M. A. J. Org. Chem.
1999, 64, 4564–4568.
27. Data for selected compounds: 5-[(4-chloro-phenyl)-
hydrazono]-1-(p-toluenesulfonyl)-piperidin-3-one
(7c):
mp 190–191 °C. 1H NMR (DMSO-d6) d: 2.39 (3H, s),
3.62 (2H, s), 4.10 (2H, s), 4.83 (1H, s), 6.59 (2H, d,
J = 8.8), 7.17 (2H, d, J = 8.8), 7.45 (2H, d, J = 8.3), 7.62
(2H, d, J = 8.3), 8.04 (1H, br s), 9.14 (1H, br s). IR max
(KBr) cmꢀ1: 3345, 3255, 1595.
21. Agnusdei, M.; Bandini, M.; Melloni, A.; U-Ronchi, A. J.
Org. Chem. 2003, 68, 7126–7129.
22. Abbiati, G.; Beccalli, E. M.; Broggin, G.; Zoni, C. J. Org.
Chem. 2003, 68, 7625–7628.
28. 6-Chloro-1,2,3,4-tetrahydro-2-(p-toluenesulfonyl)-9H-b-
carbolin-4-one (8c): mp 248–250 °C. 1H NMR (DMSO-d6)
d: 2.15 (3H, s), 3.98 (2H, s), 4.78 (2H, s), 7.18 (2H, d,
J = 8.3), 7.22 (1H, dd, J = 8.8 and 2.0), 7.50 (1H, d,
J = 8.8), 7.54 (2H, d, J = 8.3), 7.66 (1H, d, J = 2.0), 12.16
(1H, br s). IR max (KBr) cmꢀ1: 3388, 1660.
29. 6-Chloro-4-methoxy-b-carboline (10c): mp 265–267 °C.
1H NMR (DMSO-d6) d: 4.17 (3H, s), 7.54 (1H, dd,
J = 8.8 and 2.0), 7.63 (1H, d, J = 8.8), 8.14 (1H, d,
J = 2.0), 8.14 (1H, br s), 8.63 (1H, br s), 11.86 (1H, br s).
IR max (KBr) cmꢀ1: 3447.
23. General procedure for preparation of 7 from 5: To a
suspended solution of 1-(p-toluenesulfonyl)-piperidine-
3,5-dione (6b) (4.0 mmol) and NaOAc (8.0 mmol) in
AcOH (10 mL) was added a solution of phenylhydrazine
hydrochloride (5) (2.0 mmol) in AcOH (10 mL) at 0 °C.
Then the mixture was stirred at rt for 0.3–2 h. The reaction
mixture was poured into saturated aqueous NaHCO3, and
then extracted with EtOAc. The organic layer was washed
with brine, dried over anhydrous Na2SO4, and evaporated