A facile synthesis of 1,1-disubstituted 1,2,3,4-tetrahydro-β-carbolines via trifluoroacetic acid catalyzed Pictet-Spengler reaction using titanium(IV) isopropoxide as an imination reagent

Article abstract of DOI:10.3987/COM-02-S79

A synthesis of 1,1-disubstitued 1,2,3,4-tetrahydro-β-carbolines (13) was achieved in a highly effective manner via the trifluoroacetic acid catalyzed Pictet-Spengler reaction of the keto imines (9) prepared from tryptamine (8) with acyclic and cyclic keto

Full text of DOI:10.3987/COM-02-S79

HETEROCYCLES, Vol. 59, No. 2, 2003, pp. 691 - 705, Received, 29th October, 2002
A FACILE SYNTHSIS OF 1,1-DISUBSTITUTED 1,2,3,4-TETRAHYDRO-
β-CARBOLINES VIA TRIFLUOROACETIC ACID CATALYZED
PICTET-SPENGLER
REACTION
USING
TITANIUM(IV)
ISOPROPOXIDE AS AN IMINATION REAGENT
Yoshie Horiguchi,* Masayoshi Nakamura, Akiko Kida, Hirokazu Kodama,
Toshiaki Saitoh, and Takehiro Sano
Showa Pharmaceutical University, 3-3165 Higashi-tamagawagakuen, Machida,
Tokyo 194-8543, Japan
Abstract - A synthesis of 1,1-disubstitued 1,2,3,4-tetrahydro-β-carbolines (13)
was achieved in a highly effective manner via the trifluoroacetic acid catalyzed
Pictet-Spengler reaction of the keto imines (9) prepared from tryptamine (8)
with acyclic and cyclic ketones using titanium(IV) isopropoxide as the
imination reagent under one pot procedure. This reaction provides a convenient
and general method for preparing various 1,2,3,4-tetrahydro-β-carbolines
derivatives.
Recently, we have developed
a
convenient method of preparing 1,1-disubstituted
1,2,3,4-tetrahydroisoquinolines via Pictet-Spengler reaction1 of arylethylamines with ketones using
titanium(IV) isopropoxide which overcame the difficulty of imination reaction. 2 The cyclization of the
imines to the isoquinoline ring system catalyzing with trifluoroacetic acid (TFA) proceeded in a highly

effective manner via the formyliminium ion in situ formed with acetic-formic anhydride. For example, the
reaction of 2-(3,4-dimethoxyphenyl)ethylamine (1) with acetophenone (2a) produced the corresponding
N-formyl-1,2,3,4-tetrahydroisoquinoline (3) in 99% yield. We also found that the Pictet-Spengler reaction
of arylethylamines with ketones does not proceed via the iminium ion (6) generated from the imine (4) by
protonation (Scheme 1). In this paper we describe the Pictet-Spengler reaction of tryptamine with ketones
using titanium (IV) isopropoxide, which would provide a method of preparing 1,1-substituted
1,2,3,4-tetrahydro-β-carbolines.3
O
MeO
MeO
MeO
MeO
HCOOH-
Ac2O
MeO
MeO
MeO
MeO
Me
Ph
CF3COOH
+
2a
N CHO
N
NH2
N
Me Ph
3
CHO
Ti(O-iPr)4
Me
Ph
Me
Ph
1
5
4
CF3COOH
MeO
MeO
MeO
MeO
+
N H
N
H
Me Ph
Me
Ph
7
6
Scheme 1
Results and Discussions
The mixture of tryptamine (8) (1.2 mol eq.), acetophenone (2a) (1 mol eq.) and titanium(IV) isopropoxide
(1.5 mol eq.) was heated at 80°C for 3 h and then to this mixture a large excess amount of acetic-formic
anhydride (prepared from formic acid 100 mol eq.: acetic anhydride 100 mol eq.) was added, and the
solution was heated at 70°C for 3 h. This mixture was further treated with TFA (200 mol eq) under
heating at 70°C for 3 h. Thus, the reaction yielded two products, N-formyl-1-methyl-1-phenyl-
1,2,3,4-tetrhydro-β-carboline (11a) in 73% and the other is 6-acetyl derivative (12a) in 27% yield (Table
1, Run 1). This result demonstrated that the reaction, although it induced the cyclization leading to the
carboline ring system in a quantitative manner, causes the acetylation of the initially formed β-carboline
(11a)
at
C6.
The
similar
reaction
of
8
with
acetone
(2b)
produced

N-formyl-1,1-dimethyl-1,2,3,4-tetrahydro-β-carboline (11b) in 39% yield (Table 1, Run 2). Prolonged
reaction gave 6-acetyl derivative (12b)4 as a sole product in 83 % yield instead of 11b (Table 1, Run 3).
O
R1
R2
HCOOH-Ac2O
NH2
+
N CHO
N
2
N
N
N
H
H
H
R1
R2
R1
R2
Ti(O-iPr)4
8
9
10
CH3OC
+
N
R2
N
N
CHO
N
2 CHO
1
H R1
H
R
R
11
12
Scheme 2
Table 1. Synthesis of N-Formyl-1,1-disubstituted Tetrahydro-β-carbolines (11)
Reagent (mol eq.)
Conditions
Temp.
Products yields (%)
R2
Ph
Ac2O
100
R1
Me
Time (h)
(%)
(%)
CF3COOH
HCOOH
12
Run
Ketones
11
100
200
70
3
11a 73
12a 27
1
2
3
2a
2b
2b
2a
--
Me
Me
Me
Me
Me
Ph
100
100
100
100
200
200
70
70
3
11b
39
--
18
12b 83
4
5
11a 53
11b 49
100
300
300
70
70
18
18
2b
Me
Me
Et
100
100
Me
Me
300
300
70
70
18
18
11c 61
11d 51
6
7
2c
2d
CH2SPh 100
8
9
Ph
Ph
100
100
300
300
70
70
18
18
2e
2f
11e 27
52
9
11f
11g
2g
10
100
100
300
300
70
70
18
18
11
2h
11h 24
Next, we investigated the reaction under the relatively weak acidic condition using formic acid instead of
TFA, which may avoid the undesired acetylation reaction at the indole ring, and found that the
formyliminium ion (10), when treated with formic acid, caused the expected cyclization without
accompanying the undesired reaction. Thus, the treatment of formyliminium ion (10a) in situ prepared
from 8 and acetophenone (2a) with formic acid (200 mol eq.) under heating at 70 °C for 18 h afforded
11a as a sole product, although the yield was relatively low (53%) (Table 1, Run 4). Several attempts of

improving the yield were unsuccessful. As judged from reaction time the cyclization of 10 in formic acid
is relatively slow and seems to reach a plateau at 18 h. At longer reaction time (40 h) the yield of 11a was
decreased (45%). The reactions of 8 with acyclic ketones (2b-e) and cyclic ketones (2f-h) also gave the
corresponding N–formyl-β-carbolines (11b-h) as a sole product, in moderate to low yields (Table 1,
Rruns 5-11).
Finally, we found that the Pictet-Spengler cyclization of 8 with ketones occurs from the imine (9) to yield
β-carboline (13) directly. The solution of imine (9a) in situ prepared by condensation of 8 with
acetophenone (2a) in the presence of titanium(IV) isopropoxide was treated with excess amount of TFA
(100 mol eq.) under heating at 80 °C for 3 h to give 13a in 99% yield (Table 2, Run 1). The use of formic
acid instead of TFA and a longer reaction time (18 h) gave 13a in 70% yield (Table 2, Run 2). The fact
O
R1
R2
NaOH
CF3COOH
2
11
N
NH2
N
N
N
R2
H
H
N
H
R1
R2
Ti(O-iPr)4
1
H
R
8
9
13
Scheme 3
Table 2. Synthesis of 1,1-Disubstituted Tetrahydro-β-carbolines (13)
R1
R2
Ph
Temp. (°C) Time (h)
Yield (%)
Acid
Products
13a
Ketones
2a
Run
1
CF3COOH
HCOOH
CF3COOH
CF3COOH
70
70
70
3
18
3
99
70
91
Me
2
2a
13a
Me
Me
Ph
3
2b
13b
Me
70
70
3
3
4
5
6
2c
2d
2e
13c
13d
13e
13f
93
69
57
72
76
Me
Me
Et
CH2SPh
Ph
CF3COOH
CF3COOH
70
70
70
3
3
3
Ph
CF3COOH
CF3COOH
7
8
2f
2g
13g
70
3
CF3COOH
9
2h
13h
12

indicated that the increasing acidity of the reaction medium accelerated the Pictet-Spengler cyclization as
shown in the dication chemistry reported by Shudo et al.5
The reaction of 8 with acetone (2b), ethyl methyl ketone (2c), 1-phenylsulfanylproan-2-one (2d),
benzophenone (2e), cyclopentanone (2f), and cyclohexanone (2g) gave the corresponding
1,1-disubstituted tetrahydro-β-carbolines (13b-g) in excellent to good yields, although indanone gave the
β-carboline (13h) only in 14% yield (Table 2, Run 9). It is worthy to note that this reaction of 8 by using
titanium(IV) isopropoxide and TFA caused the Pictet-Spengler cyclization even in the cases of highly
sterically congested ketones such as diphenyl ketone and indanone.
Alkaline hydrolysis of the N-formate (11) with NaOH yielded 13 in good yields (see EXPERIMENTAL)
except that of the 1,1-diphenyl derivative (11e) which was resistant to this hydrolysis because of the steric
hindrance of the phenyl groups at C1.
Thus, the Pictet-Spengler reaction of tryptamine with ketones using titanium(IV) isopropoxide and TFA
provides a convenient and highly effective method of synthesizing various 1,1-disubstituted
1,2,3,4-tetrahydro-β-carbolines.
EXPERIMENTAL
Unless otherwise noted, the following procedures were adopted. Melting points were taken on a
Yanagimoto SP-M1 hot-stage melting point apparatus and are uncorrected. IR spectra were measured as
films for oils and gums, and KBr disks for solids with a HORIBA FT-710 spectrophotometer, and the values
are given in cm-1. NMR spectra were measured on a JEOL JNM-AL 300 (1H-NMR, 300 MHz; 13C-NMR,
75 MHz) NMR spectrometer in CDCl3 with tetramethylsilane as an internal standard and the chemical
shifts are given in δ values. LR-MS were taken on JMS-AM20, and high resolution MS (HR-MS) on a
JEOL JMS-D300 spectrometer at 70 eV (EI-MS) or at 270 eV [(CI-MS), reactant gas: iso-butane] using
direct or GC/MS inlet systems. FAB-MS spectra were recorded with JEOL-HX100A spectrometer using
glycerol as a matrix. Elemental analyses were recorded on a Yanaco-CHN-corder MT-3. TLC was

performed on Merck precoated Silica gel 60 F254 plates (Merck). Column chromatography was carried out
with silica gel (Wakogel C-200) or aluminum oxide (aluminum oxide 90, Merck). The organic extract from
each reaction mixture was washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo to
dryness.
The Pictet-Spengler Reaction of Tryptamine (8) with Ketones (2) under Formylation Reaction
Condition Using Trifluoroacetic Acid.
Reaction with 2a (Table 1, Run 1): A mixture of 8 (1.00 g, 6 mmol), acetophenone (2a) (0.62 g, 5.2
mmol) and Ti(O-iPr)4 (2.22 g, 7.8 mmol) was heated at 80°C for 3 h under an argon atmosphere. To the
reaction mixture, a solution of acetic-formic anhydride [prepared from HCOOH (24 g, 0.52 mol) and
Ac2O (53 g, 0.52 mol)] was added at 0°C, then the mixture was heated at 70°C for 2 h. To this reaction
mixture CF3COOH (119 g, 1.04 mol) was added and heated at 70°C for 3 h. The reaction mixture was
diluted with MeOH (100 mL) and passed through a short SiO2 column (CHCl3-MeOH) to remove TiO2.
The eluent was concentrated in vacuo to ca. 50 mL and the residue was extracted with CHCl3. After
removal of the solvent of extract in vacuo, the residue was purified by chromatography over SiO2
(AcOEt-hexane (1:1)) to give 11a (1.10 g, 73%) and 12a (0.466 g, 27%).
2-Formyl-1-methyl-1-phenyl-1,2,3,4-tetrahydro-β-carboline (11a)
Colorless plates recrystallized from MeOH-hexane, mp: 206-209℃. IR: 1637, 1493. 1H-NMR: 2.10, 2.23
(3H, each s, CH3), 2.92-3.01 (2H, m, 4-H), 3.65-3.71, 4.21-4.28 (total 2H, each m, 3-H), 7.1-7.4 (8H, m,
13
PhH), 7.55 (1H, d, J= 8 Hz, 5-H), 8.12, 8.16 (total 1H, s, CHO). C-NMR: 20.8 (C4), 26.3 (CH3), 36.2
(C3), 61.0 (C1), 109.1 (C4a), 111.1 (C8), 118.4 (C7), 119.7 (C5), 122.2 (C6), 126.4 (C4b), 127.1
(Ph-CHx2), 128.1 (Ph-CH), 128.8 (Ph-CHx2), 136.4 (C8a and C9a), 142.7 (Ph-C), 162.1 (CHO).
LR-EIMS (m/z): 290 (M+), 57 (base peak). HR-EIMS m/z (M+): Calcd for C19H18N2O: 290.1416. Found:
290.1408. Anal. Calcd for C19H18N2O: C, 78.36; H, 6.33; N, 9.52. Found: C, 78.59; H, 6.25; N, 9.65.
6-Acetyl-2-formyl-1-methyl-1-phenyl-1,2,3,4-tetrahydro-β-carboline (12a)

Colorless prisms crystallized from AcOEt-hexane, mp: 250-253°C. IR: 1647. 1H-NMR: 2.13 (3H, s, CH3),
2.66 (3H, s, COCH3), 3.0-3.1 (2H, m, 4-H), 3.65-3.73, 4.3-4.4 (total 2H, m, 3-H), 7.24 (1H, d, J=8.5 Hz,
8-H), 7.3-7.4 (5H, m, Ph), 7.83 (1H, dd, J=8.5 Hz, 1.5 Hz, 7-H), 8.16 (1H, s, CHO), 8.21 (1H, d, J=1.5
Hz, 5-H), 8.29 (1H, br s, Ar-NH). 13C-NMR: 20.8 (C4), 26.2 (CH3), 26.6 (COCH3), 36.0 (C3), 61.0 (C1),
110.4 (C4a), 111.0 (C8), 120.6 (C7), 122.6 (C5), 126.0 (C4b), 127.0 (Ph-CHx2), 128.3(Ph-CH), 128.9
(Ph-CHx2), 130.0 (C6), 138.3 (C9a), 139.2 (C8a), 142.2 (Ph-C), 162.2 (CHO), 198.4 (COCH3).
EI-LRMS (m/z): 332 (M+), 58 (base peak). HR-EIMS m/z (M+): Calcd for C21H20N2O2: 332.1525. Found:
332.1558.
Reaction with 2b (Table 1, Run 2). The reaction of 8 (1.00 g, 6 mmol) with 2b (0.38 g, 5.2 mol) gave
11b (0.48g, 39%) under similar reaction condition.
2-Formyl-1,1-dimethyl-1,2,3,4-tetrahydro-β-carboline (11b)
Colorless plates recrystallized from AcOEt-hexane, mp: 188-190°C. IR: 1635. 1H-NMR: 1.79, 1.88, 2.00
(total 6H, each s, CH3x2), 2.7-2.9 (2H, m, 4-H), 3.62, 4.00 (total 2H, each t, J=6 Hz, 3-H), 7.1-7.2 (2H, m,
6-H and 7-H), 7.34 (1H, d, J=8 Hz, 5-H), 7.49 (1H, d, J=8 Hz, 8-H), 8.05 (1H, br s, Ar-NH), 8.63, 8.69
13
(total 1H, each s, -CHO). C-NMR: 21.0 (C4), 29.0(CH3x2), 35.9 (C3), 55.6 (C1), 108.6 (C4a), 110.9
(C8), 118.4 (C7), 119.8 (C5), 122.3 (C6), 126.6 (C4b), 136.0 (C9a), 136.9 (C8a), 160.6 (CHO). LR-EIMS
(m/z): 228 (M+), 213 (base peak). HR-EIMS m/z (M+): Calcd for C14H16N2O: 228.1263. Found: 228.1278.
Anal. Calcd for C14H16N2O: C, 73.46; H, 7.12; N, 12.08. Found: C, 73.66; H, 7.06; N, 12.27.
Reaction with 2b (Table 1, Run 3). The reaction of 8 (1.00 g, 6 mmol) with 2b (0.38 g, 5.2 mol) gave
12b (1.16g, 83%) under heating for 18 h.
6-Acetyl-2-formyl-1,1-dimethyl-1,2,3,4-tetrahydro-β-carboline (12b)
A Pale yellow gum. IR: 2360, 1647. 1H-NMR: 1.75, 1.83 (total 6H, each s, CH3x2), 2.67, 2.70 (total 3H,
each s, COCH3), 2.83 (2H, t, J=6 Hz, 4-H), 3.65, 4.01 (total 2H, each t, J=6 Hz, 3-H), 7.35, 7.52 (total 1H,
each d, J=8 Hz, 8-H), 7.7-7.9 (1H, m, 7-H), 8.09, 8.17 (total 1H, each d, J=1 Hz, 5-H), 8.31, 8.64 (total

1H, each s, CHO), 8.86, 9.14 (total 1H, each br s, Ar-NH). LR-EIMS: m/z 270 (M+), 255 (base peak).
HR-EIMS m/z (M+): Calcd for C16H18N2O2: 270.1380. Found: 270.1369.
Hydrolysis of 12b4
A solution of 12b (140 mg, 0.52 mmol) in 10% HCl-MeOH (5 mL) was stirred for 12 h at rt. The solution
was basified with 10% NaOH solution and the mixture was extracted with CHCl3. The residue was
purified by chromatography over Al2O3 (AcOEt-hexane (1:1)) to give 6-acetyl-1,1-dimethyl-1,2,3,4-
tetrahydro-β-carboline (35 mg, 28%) as pale yellow prisms recrystallized from AcOEt-hexane, mp
1
193-196°C. IR: 3214, 2962, 1652. H-NMR: 1.50, 1.52 (total 6H, each s, CH3x2), 2.63, 2.68 (total 3H,
each s, COCH3), 2.7-2.8 (2H, m, 4-H), 3.21-3.24 (2H, m, 3-H), 7.32, 7.49 (total 1H, each d, J=8 Hz, 9 Hz,
8-H), 7.73, (dd, J=1 Hz, 8 Hz), 7.82 (dd, J=2 Hz, 9 Hz): total 1H, 7-H, 8.02, (d, J=1 Hz), 8.15 (d, J=2
13
Hz): total 1H, 5-H, 8.14, 8.28 (total 1H, each br s, Ar-NH). C-NMR: 22.8 (C4), 26.7, 26.7 (COCH3),
28.8 (CH3x2), 50.5, 50.7(C1), 108.0, 109.0 (C4a), 110.5, 117.7 (C8), 111.8, 120.3 (C7), 120.0, 122.1 (C5),
127.1, 129.2 (C6), 130.7, 131.3 (C4b), 135.0, 138.5 (C9a), 142.2, 145.2 (C8a), 198.8(s, COCH3).
LR-EIMS (m/z): 242 (M+), 227 (base peak). HR-EIMS m/z (M+): Calcd for C15H18N2O: 242.1431. Found:
242.1420.
Synthesis of 2-Formyl-1,1-disubstitued 1,2,3,4-Tetrahydro-β-carbolines (11). Typical Procedure: A
mixture of 8 (1.00 g, 6 mmol), 2a (0.62 g, 5.2 mmol) and Ti(O-iPr)4 (2.22 g, 7.8 mmol) was heated at
80°C for 3 h under an argon atmosphere. To the reaction mixture, a solution of acetic-formic anhydride
[prepared from HCOOH (71.76 g, 1.56 mol) and Ac2O (53 g, 0.52 mol)] was added at 0°C, then the
mixture was heated at 70°C for 18 h. The reaction mixture was diluted with MeOH (100 mL) and passed
through a short SiO2 column (CHCl3-MeOH) to remove TiO2. The eluent was concentrated in vacuo to ca.
50 mL and the residue was extracted with CHCl3. After removal of the solvent of extract in vacuo, the
residue was purified by chromatography over SiO2 (AcOEt-hexane (1:1)) to give 11a (0.80 g, 53%).
1-Ethyl-2-formyl-1-methyl-1,2,3,4-tetrahydro-β-carboline (11c) (768 ｍｇ，61%) was obtained from 8

(1.00 g, 6 mmol) and 2c (0.38, 5.2 mmol) as colorless needles recrystallized from MeOH-hexane,
mp:162-164℃. IR: 1631, 1491. 1H-NMR: 0.64, 0.79 (total 3H, each t, J=7 Hz, CH2CH3), 1.74, 1.80 (total
3H, each s, CH3), 2.06-2.18, 3.13-3.18 (total 2H, each m, -CH2CH3), 2.80-2.87, 3.52-3.60 (total 2H, each
m, H-4), 3.69-3.76, 3.89-4.02 (total 2H, each m, 3-H), 7.10-7.26 (2H, m, 6-H and 7-H), 7.35 (1H, d, J=8
Hz, 8-H), 7.50 (1H, d, J=8 Hz, 5-H), 8.15, 8.22 (total 1H, each br s, Ar-NH), 8.33, 8.53 (total 1H, each s,
13
CHO). C-NMR: 8.0 (CH2CH3), 20.7 (C4), 27.6 (CH3), 33.4 (CH2CH3), 36.3 (C3), 59.0 (C1), 109.4
(C4a), 110.9 (C8), 118.2 (C7), 119.5 (C5), 122.0 (C6), 126.4 (C4b), 135.9 (C9a), 136.2 (C8a), 161.3
(CHO). EI-LRMS (m/z): 242 (M+), 213 (base peak). HR-EIMS m/z (M+): Calcd for C15H18N2O: 242.1419.
Found: 242.1445. Anal. Calcd for C15H18N2O: C, 74.17; H, 7.62; N, 11.74. Found: C, 74.35; H, 7.49; N,
11.56.
2-Formyl-1-methyl-1-phenylsulfanyl-1,2,3,4-tetrahydro-β-carboline (11d) (891 mg ， 51%) was
obtained from 8 (1.00 g, 6 mmol) and 2d (0.86 g, 5.2 mmol) as pale yellow plates recrystallized from
1
MeOH-hexane, mp: 179-181℃. IR: 1639, 1510. H-NMR: 1.87, 1.90 (total 3H, each s, CH3), 2.74-2.90
(2H, m, 4-H), 2.94-3.06, 3.78-3.86, 4.41-4.57 (total 2H, each m, 3-H), 3.47, 3.56 (total 1H, each d, J=14
Hz, CH2S), 3.67, 4.38 (total 1H, each d, J=13 Hz, CH2S), 7.0-7.4 (8H, m, PhH), 7.49 (1H, d, J=8 Hz,
13
5-H), 8.07, 8.19 (total 1H, br s, Ar-NH), 8.23, 8.62 (total 1H, each s, CHO). C-NMR: 20.9 (C4), 24.8
(CH3), 35.8 (C3), 45.4 (CH2S), 58.9 (C1), 109.1 (C4a), 111.7 (C8), 118.4 (C7), 119.6 (C5), 122.3 (C6),
126.2 (C4b), 127.0 (Ph-CH), 129.0 (Ph-CHx2), 130.7 (Ph-CHx2), 135.2 (C9a), 135.5 (Ph-C), 136.2 (C8a),
161.1 (CHO). RL-EIMS (m/z): 336 (M+), 213 (base peak). HR-EIMS m/z (M+): Calcd for C20H20N2OS:
336.1293. Found: 336.1275. Anal. Calcd for C20H20N2OS: C, 71.16; H, 6.01; N, 8.19. Found: C, 71.40; H,
5.99; N, 8.33.
2-Formyl-1,1-diphenyl-1,2,3,4-tetrahydro-β-carboline (11e) (494 mg，27%) was obtained from 8 (1.00
g, 6 mmol) and 2e (0.96 g, 5.2 mmol) as colorless plates recrystallized from MeOH-hexane, mp:
266-268℃. IR:1658, 1583. 1H-NMR: 2.97-3.06 (total 2H, each t, J=6 Hz, 4-H), 3.62, 3.84 (total 2H, each

t, J=6 Hz, H-3), 7.1-7.4 (13H, m, PhH), 7.57 (1H, d, J=7 Hz, 5-H), 7.88 (1H, br s, Ar-NH), 8.17 (1H, s,
CHO). 13C-NMR: 20.9 (C4), 36.4 (C3), 69.1 (C1), 110.6 (C4a), 111.2 (C8), 118.7 (C7), 119.7 (C5), 122.5
(C6), 126.3 (C4b), 128.4 (Ph-CHx2), 28.7 (Ph-CHx4), 128.9 (Ph-CHx4), 135.1 (C9a), 136.4 (C8a), 140.5
(Ph-C), 162.4 (CHO). LR-EIMS (m/z): 352 (M+), 58 (base peak). HR-EIMS m/z (M+): Calcd for
C24H20N2O: 352.1576. Found: 352.1606. Anal. Calcd for C24H20N2O: C, 81.68; H, 5.89; N, 7.65. Found:
C, 81.79; H, 5.72; N, 7.95.
2-Formyl-1,2,3,4-tetrahydro-β-carboline-1-spirocyclopentane (11f) (611 ｍｇ，52 %) was obtained
from 8 (1.00 g, 6 mmol) and 2f (0.44g, 5.2 mmol) as colorless plates recrystallized from MeOH-hexane,
mp: 246-248℃ IR: 1631, 1585. 1H-NMR: 1.89-2.36 (8H, m, 2’-H, 3’-H, 4’-H and 5’-H), 2.82, 2.86 (total
2H, each t, J=6 Hz, 4-H), 3.66, 3.98 (total 2H, each t, J=6 Hz, 3-H), 7.09-7.21 (2H, m, 6-H and 7-H), 7.33
(1H, d, J=8 Hz, 8-H), 7.48 (1H, d, J=8 Hz, 5-H), 7.85 (1H, br s, Ar-NH), 8.26, 8.40 (total 1H, s, CHO).
13C-NMR: 21.0 (C4), 24.0 (C3’ and C4’), 36.8 (C3), 38.7 (C2’and C5’), 67.0 (C1), 109.9 (C4a), 111.1
(C8), 118.2 (C7), 119.8 (C5), 122.2 (C6), 126.7 (C4b), 135.5 (C9a), 136.0 (C8a), 160.4 (CHO). LR-EIMS
(m/z): 254 (M+), 184 (base peak). Anal. Calcd for C16H18N2O: C, 75.39; H, 7.15; N, 10.75. Found: C,
75.56; H, 7.13; N, 11.01.
2-Formyl-1,2,3,4-tetrahydro-β-carboline-1-spirocyclohexane (11g) (112 ｍｇ，9%) was obtained from
8 (1.00 g, 6 mmol) and 2g (0.54 g, 5.2 mmol) as colorless plates recrystallized from MeOH-hexane,
1
mp:280-281℃. IR: 1627, 1508. H-NMR: 1.40-1.99 (8H, m, 3’-H, 4’-H, 5’-H and 6’-H), 2.36 (2H, d,
J=15 Hz, 2’-H), 2.79-2.84 (2H, m, 4-H), 3.97-4.02 (2H, m, 3-H), 7.07-7.20 (2H, m, 6-H and 7-H), 7.33
(1H, d, J=8 Hz, 8-H), 7.47 (1H, d, J=8 Hz, 5-H), 7.85 (1H, br s, Ar-NH), 8.64 (total 1H, s, CHO).
13C-NMR: 19.7 (C3’ and C5’), 25.0 (C4), 27.4 (C4’), 37.8 (C2’ and C6’), 47.4 (C4), 57.7 (C1), 111.0 (C8),
112.8 (C4a), 119.6 (C7), 120.5 (C5), 121.7 (C6), 131.5 (C4b), 135.3 (C9a), 136.2 (C8a), 161.1 (CHO).
RL-EIMS (m/z): 268 (M+), 184 (base peak). Anal. Calcd for C17H20N2O: C, 75.79; H, 7.48; N, 10.14.
Found: C, 76.09; H, 7.51; N, 10.44.

2-Formyl-1,2,3,4-tetrahydro-β-carboline-1-spiro-1’-(2’,3’-dihydro-1H-indene) (11h) (282 ｍｇ，24%)
was obtained from 8 (1.00 g, 6 mmol) and 2h (0.69 g, 5.2 mmol) as colorless plates recrystallized from
1
MeOH-hexane, mp: 180-181℃. IR: 1653. H-NMR: 2.56, 2.61 (total 1H, each t, J=8 Hz, 3’-H), 2.62,
2.67 (total 1H, each t, J=8 Hz, 3’-H), 2.94, 2.96 (total 1H, each t, J=3 Hz, 4-H), 3.10, 3.70 (total 3H, each
dd, J=5, 12 Hz, 3-H and 4-H), 3.18, 3.24 (total 1H, each dd, J=3, 8 Hz, 2’-H), 4.90, 4.94 (total 1H, each q,
J=3 Hz, 2’-H), 7.0-7.6 (8H, m, Ph), 7.96, 8.10 (1H, s, CHO). 13C-NMR: 21.0 (C4), 29.8 (C3’), 37.0 (C2’),
40.9 (C3), 69.2 (C1), 110.7 (C4a), 111.0 (C8), 118.5 (C7), 119.8 (C5), 122.4 (C6), 125.4 (C5’), 125.9
(C6’), 126.5 (C4b), 128.0 (C4’), 129.9 (C7’), 135.6 (C3a’ or C7a’), 136.3 (C3a’ or C7a’), 141.0 (C9a),
145.5 (C8a), 161.2 (CHO). LR-EIMS (m/z): 302 (M+), 244 (base peak). HR-EIMS m/z (M+): Calcd for
C15H18N2: 302.1437. Found: 302.1431.
Synthesis of 1,1-Disubstituted 1,2,3,4-Tetrahydro-β-carbolines (13) Typical procedure: A mixture
of 8 (1.00 g, 6 mmol), 2a (0.62 g, 5.2 mmol) and Ti(O-iPr)4 (2.22 g, 7.8 mmol) was heated at 80°C for 3 h
under an argon atmosphere. To the reaction mixture was added a mixture of CF3COOH (59.3 g, 0.52 mol)
and trifluoroacetic anhydride (1.1 g, 5.2 mmol) at 0°C, then the mixture was heated at 70°C for 3 h. The
reaction mixture was diluted with MeOH (100 mL) and passed through a short SiO2 column
(CHCl3-MeOH) to remove TiO2. The eluent was concentrated in vacuo to ca. 50 mL and the residue was
extracted with CHCl3. After removal of the solvent of extract in vacuo, the residue was purified by
chromatography over Al2O3 (AcOEt-hexane (1:1)) to give 13a (1.35 g, 99%).
1-Methyl-1-phenyl-1,2,3,4-tetrahydro-β-carboline (13a) A pale brown solid. (HCl salt: colorless
prisms recrystallized from MeOH-Et2O, mp: 273-275°C (decomp), (lit., 6 mp: 267-269°C)). IR: 3397,
1
2929, 1490. H-NMR: 1.83 (3H, s, CH3), 2.2-3.2 (4H, m, 3-H and 4-H), 7.1-7.3 (9H, m, 5-H, 6-H, 7-H,
13
8-H and PhH), 7.78 (1H, br s, Ar-NH). C-NMR: 22.7 (C4), 28.2 (CH3), 39.7 (C3), 56.8 (C1), 109.7
(C4a), 110.8 (C8), 118.4 (C7), 119.4 (C5), 121.8 (C6), 126.8 (Ph-CHx2), 127.2 (Ph-CH), 127.3 (C4b),
128.2(Ph-CHx2), 135.7 (C9a), 138.1 (C8a), 146.2 (Ph-C). LR-EIMS (m/z): 262 (M+), 247(base peak).

HR-EIMS m/z (M+): Calcd for C18H18N2: 262.1469. Found: 262.1449.
1,1-Dimethyl-1,2,3,4-tetrahydro-β-carboline (13b) (0.95 g, 91%) was obtained from 8 (1.00 g, 6.3
mmol) and 2b (0.38 g, 5.2 mmol) as pale yellow plates crystallized from Et2O-hexane, mp: 110-113°C
1
(lit.,7 mp 140-141°C (recrystallized from cyclohexane)) . IR: 3399. H-NMR: 1.47 (6H, s, CH3x2), 2.72
(2H, t, J=6 Hz, 4-H), 3.21 (2H, t, J=6 Hz, 3-H), 7.1-7.2 (2H, m, 6-H and 7-H), 7.30 (1H, d, J=8 Hz, 5-H),
13
7.47 (1H, d, J=8 Hz, 8-H), 7.75 (1H, br s, Ar-NH). C-NMR: 22.8 (C4), 28.8 (CH3x2), 39.6 (C3), 50.4
(C1), 107.2 (C4a), 110.6 (C8), 118.1 (C7), 119.1 (C5), 121.3 (C6), 127.2 (C4b), 135.4 (C9a), 140.2 (C8a).
LR-EIMS (m/z): 200 (M+), 57 (base peak). HR-EIMS m/z (M+): Calcd for C13H16N2: 200.1314. Found:
200.1327.
1-Ethyl-1-methyl-1,2,3,4-tetrahydro-β-carboline (13c) (1.04 g, 91%) was obtained from 8 (1.00 g,
1
6.3 mmol) and 2c (0.38 g, 5.2 mmol)as a pale yellow gum. IR: 3199. H-NMR: 0.89 (3H, t, J=8 Hz,
CH2-CH3), 1.42 (3H, s, CH3), 1.7-1.9 (2H, m, CH2-CH3), 2.69-2.73 (2H, m, 4-H), 3.1-3.3 (2H, m, 3-H),
7.1-7.5 (4H, m, 5-H, 6-H, 7-H, 8-H), 7.69 (1H, br s, Ar-NH). 13C-NMR: 8.2 (CH2-CH3), 22.9 (C4), 26.7
(CH3), 33.8 (CH2-CH3), 39.6 (C3), 53.3 (C1), 108.4 (C4a), 110.6 (C8), 118.0 (C7), 119.1 (C5), 121.3
(C6), 127.3 (C4b), 135.5 (C9a), 140.0 (C8a). LR-EIMS (m/z): 214 (M+), 185 (base peak). HR-EIMS m/z
(M+): Calcd for C14H18N2: 214.1457. Found: 214.1467.
1-Methyl-1-phenylsulfanyl-1,2,3,4-tetrahydro-β-carboline (13d) (1.06 g, 69%) was obtained from 8
1
(1.00 g, 6.3 mmol) and 2d (0.86 g, 5.2 mmol) as a pale yellow gum. IR: 1581. H-NMR: 1.46 (3H, s,
CH3), 1.85 (brs s, 2-H), 2.67 (2H, t, J=6 Hz, 4-H), 3.08-3.12 (2H, m, 3-H), 3.23 (1H, d, J=13 Hz, CH2S),
3.40 (1H, d, J=13 Hz, CH2S), 7.0-7.3 (9H, m, 5-H, 6-H, 7-H, 8-H and PhH), 7.89 (1H, br s, Ar-NH).
13C-NMR: 22.8 (C4), 26.9 (CH3), 39.7 (CH2S), 46.2 (C3), 53.9 (C1), 109.2 (C4a), 110.9 (C8), 118.3 (C7),
119.4 (C5), 121.8 (C6), 126.4 (Ph-CH), 127.0 (C4b), 128.9 (Ph-CHx2), 129.9 (Ph-CHx2), 135.6 (C9a),
136.5 (Ph-C), 137.7 (C8a). CIMS (m/z): 309 (MH+), 89 (base peak).
1,1-Diphenyl-1,2,3,4-tetrahydro-β-carboline (13e) (0.95 g, 57%) was obtained from 8 (1.00 g, 6.2

1
mmol) and 2e (0.96 g, 5.2 mmol) as a pale yellow gum. IR: 1617. H-NMR: 3.11 (2H, t, J=7 Hz, 4-H),
3.69 (2H, t, J=7 Hz, 3-H), 7.0-7.8 (14H, m, 5-H, 6-H, 7-H, 8-H and PhHx2), 7.94 (1H, br s, Ar-NH).
13C-NMR: 26.9 (C4), 54.5 (C3), 54.5 (C1), 110.9 (C8), 114.0 (C4a), 118.8 (C7), 121.9 (C5), 122.1 (C6),
127.5 (C4b), 127.6 (Ph-CHx2), 128.0 (Ph-CHx2), 128.1 (Ph-CH), 128.2 (Ph-CHx2), 128.3 (Ph-CHx2),
129.8 (Ph-CH), 136.0 (C9a), 136.6 (C8a), 139.8 (Ph-Cx2). LR-EIMS (m/z): 324 (M+), 130 (base peak).
HR-EIMS m/z (M+): Calcd for C23H20N2: 324.1585. Found: 324.1605
1,2,3,4-Tetrahydro-β-carboline-1-spirocyclopentane (13f) (0.84 g, 72%) was obtained from 8 (1.00 g,
6.2 mmol) and 2f (0.44 g, 5.2 mmol) as colorless plates recrystallized from AcOEt-hexane, mp:
1
112-115°C (lit.,8 mp 138-140°C). IR: 1560. H-NMR: 1.8-2.0 (8H, m, 2’-H, 3’-H, 4’-H and 5’-H), 2.72
(2H, t, J=6 Hz, 4-H), 3.17 (2H, t, J=6 Hz, 3-H), 7.1-7.5 (4H, m, 5-H, 6-H, 7-H and 8-H), 7.65 (1H, brs,
Ar-NH). 13C-NMR: 22.8 (C4), 24.7 (C3’ and C4’), 40.1 (C2’ and C5’), 40.5 (C3), 61.7 (C1), 108.5 (C4a),
110.5 (C8), 117.9 (C7), 119.1 (C5), 121.3 (C6), 127.3 (C4b), 135.5 (C9a), 139.2 (C8a). LR-EIMS (m/z):
226 (M+), 197 (base peak). HR-EIMS m/z (M+): Calcd for C15H18N2: 226.1467. Found: 226.1449.
1,2,3,4-Tetrahydro-β-carboline-1-spirocyclohexane (13g) (0.95 g, 76%) was obtained from 8 (1.00 g,
6.2 mmol) and 2g (0.54 g, 5.2 mmol) as a colorless plates recrystallized from AcOEt-hexane, mp:
128-130°C (lit.,8 mp 133-134°C). IR: 3394, 2927. 1H-NMR: 1.6-1.9 (10H, m, 2’-H, 3’-H, 4’-H, 5’-H and
6’-H), 2.69 (2H, t, J=6 Hz, 4-H), 3.12 (2H, t, J=6 Hz, 3-H), 7.1-7.5 (4H, m, 5-H, 6-H, 7-H and 8-H), 7.70
13
(1H, br s, Ar-NH). C-NMR: 20.6 (C3’ and C5’), 22.3 (C4), 25.0 (C4’), 35.8 (C2’ and C6’), 38.4 (C3),
51.6 (C1), 107.2 (C4a), 110.0 (C8), 117.4 (C7), 118.5 (C5), 120.6 (C6), 126.8 (C4b), 137.4 (C9a), 140.5
(C8a). LR-EIMS (m/z): 240 (M+), 209 (base peak). HR-EIMS m/z (M+): Calcd for C16H20N2: 240.1634.
Found: 240.1630.
1,2,3,4-Tetrahydro-β-caeboline-1-spiro-1’-(2’,3’-dihydro-1H-indene) (13h) (0.20 g, 14%) was
obtained from 8 (1.00 g, 6.2 mmol) and 2h (0.69 g, 5.2 mmol) as colorless plates recrystallized from
1
ether-hexane, mp: 167-169°C. IR: 3401, 2931. H-NMR: 1.2-1.3 (1H, m, 2’-H), 2.3-2.5 (2H, m, one of

2’-H and 3’-H), 2.8-3.3 (5H, m, 3’-H and 3-H, 4-H), 7.0-7.6 (8H, m, 5-H, 6-H, 7-H, 8-H and ArH), 7.69
(1H, br s, Ar-NH). 13C-NMR: 22.8 (C4), 30.0 (C3’), 40.1 (C2’), 40.9 (C3), 65.6 (C1), 110.3 (C4a), 110.8
(C8), 118.2 (C7), 119.3 (C5), 121.7 (C6), 124.1 (C5’), 125.2 (C6’), 126.8 (C4’), 127.3 (C4b), 128.5 (C7’),
135.9 (C9a), 137.5 (C8a), 144.4 (C3a’), 147.0 (C7a’). LR-EIMS (m/z): 274 (M+, base peak). HR-EIMS
m/z (M+): Calcd for C19H18N2: 274.1469. Found: 274.1454.
Hydrolysis of 11 . General Procedure: A solution of 11 (0.35 mmol) in EtOH (20 mL) and 20% NaOH
(20 mL) was refluxed for 18 h. The reaction mixture was concentrated in vacuo, and the residue was
extracted with CHCl3. After removal of the solvent in vacuo, the residue was purified by chromatography
over SiO2 (AcOEt-hexane (4:1)) to give 13. Yields were described as below.
13a (159 mg, 88%) was obtained from 11a (200 mg, 0.69 mmol). 13b (169 mg, 96%) was obtained from
11b (200 mg, 0.88 mmol). 13c (160 mg, 90%) was obtained from 11d (200 mg, 0.83 mmol). 13d (146 mg,
79%) was obtained from 11d (200 mg, 0.60 mmol). 13f (158 mg, 89%) was obtained from 11f (200 mg,
0.79 mmol). 13g (158 mg, 88%) was obtained from 11g (200 mg, 0.75 mmol). 13h (154 mg, 85%) was
obtained from 11d (200 mg, 0.66 mmol).
REFERENCES AND NOTES
1. A. Pictet and T. Spengler, Ber., 1911, 44, 2030.
2. Y. Horiguchi, H. Kodama, M. Nakamura, T. Yoshimura, K. Hanezi, H. Hamada, T. Saitoh, and T.
Sano, Chem. Pharm. Bull., 2002, 50, 253.
3. G. Bringmann, C. T. Ewers, and R.Walter, "Comprehensive Organic Synthesis," Vol. 6, ed. by B.
M. Trost and I. Fleming, Pergamon Press, Oxford, pp. 736-740, 1991 ; E. D. Cox and J. M.
Cook, Chem. Rev., 1995, 95, 1797.
4. The structure of 12b was determined from spectral analysis of 6-acetyl-1,1-dimethyl-1,2,3,4-
tetrahydro-β-carboline which was obtained by hydrolysis of 12b with HCl.

5. A. Yokoyama, T. Ohwada, and K. Shudo, J. Org. Chem., 1999, 64, 611.
6. M. Ohkubo, A. Kuno, K. Katsuta, Y. Ueda, K. Shirakawa, H. Nakanishi, T. Kinoshita, and H.
Takasugi, Chem. Pharm. Bull., 44, 1996, 778.
6. N. Carrasco, A. Urzua, and B. K. Cassels, J. Org. Chem., 1973, 38, 4342.
8. J. G. Rodriguez and P. Gil-Lopetegui, J. Heterocycl. Chem., 1993, 30, 373.