Microwave-assisted one-pot preparation of tetrahydro-β-carboline hydrochlorides under solvent-free conditions

Article abstract of DOI:10.1080/00397910701572555

An efficient and environmentally friendly synthesis of tetrahydro-β- carboline hydrochlorides via Pictet-Spengler reaction was described. Tryptamine hydrochlorides were used as the reactant and no additional acid catalyst was needed. This reaction was com

Full text of DOI:10.1080/00397910701572555

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Microwave‐Assisted One‐Pot Preparation of
Tetrahydro‐β‐carboline Hydrochlorides under
Solvent‐Free Conditions
a
a
Fei Liu & Qi‐Dong You
a
Department of Medicinal Chemistry, China Pharmaceutical University,
Nanjing, China
Version of record first published: 19 Nov 2007
To cite this article: Fei Liu & Qi‐Dong You (2007): Microwave‐Assisted One‐Pot Preparation of
Tetrahydro‐β‐carboline Hydrochlorides under Solvent‐Free Conditions, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 37:22, 3933-3938
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Synthetic Communications , 37: 3933–3938, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701572555
Microwave-Assisted One-Pot Preparation
of Tetrahydro-b-carboline Hydrochlorides
under Solvent-Free Conditions
Fei Liu and Qi-Dong You
Department of Medicinal Chemistry, China Pharmaceutical University,
Nanjing, China
Abstract: An efficient and environmentally friendly synthesis of tetrahydro-b-
carboline hydrochlorides via Pictet–Spengler reaction was described. Tryptamine
hydrochlorides were used as the reactant and no additional acid catalyst was needed.
This reaction was completed within 2.5–9 min in good yield.
Keywords: green chemistry, microwave reaction, Pictet–Spengler reaction, tetrahy-
dro-b-carboline hydrochlorides
The tetrahydro-b-carbolines constitute an important part of indole alkaloids.
Their broad spectrum of biological and pharmacological activity leads to con-
siderable interest in the synthesis of tetrahydro-b-carboline analogs. One of
the most powerful methods to synthesize the tetrahydro-b-carboline ring
[
1,2]
system is the Pictet–Spengler cyclization,
Scheme 1): a condensation reaction between tryptamine and aldehydes to
generate the corresponding imines and an intramocular cyclization
which involves two processes
(
[
3–5]
catalyzed by Brønsted acids or Lewis acids.
that this reaction could be carried out in one step in aprotic solvent and in
It has also been reported
[6,7]
protic solvent with the aid of zeolite catalysts.
Received in the USA March 28, 2007
Address correspondence to Qi-Dong You, Department of Medicinal Chemistry,
China Pharmaceutical University, P. O. BOX 51, 24 Tongjiaxiang, Nanjing 210009,
China. E-mail: youqidong@gmail.com
3
933

3
934
F. Liu and Q.-D. You
Scheme 1.
In recent years, microwave irradiation has been widely used in organic
[8]
synthesis because of its reduction in reaction time and its good yields.
Several researchers have reported the application of microwave irradiation in
the Pictet–Spengler cyclization for the preparation of tetrahydro-b-carbo-
[
9–12]
lines.
However, in most of these studies, this reaction was carried out in
protic solvent with catalysis of acids (acetic acid or trifluoroacetic acid
usually). One important symbol of green chemistry is the reduction of the use
of organic solvents and catalysts because of the economical and environmental
concerns associated with them. Therefore, the development of solvent-free or
catalyst-free synthetic methods is of fundamental importance. Recently, in the
study of Bikash et al., the Pictet–Spengler reaction was performed on silica
[11]
gel in the domestic microwave oven under solvent-free conditions.
In that
case, a large amount of glacial acetic acid was needed, and the yield was not
good. In this article, we describe a more environmentally friendly and facile
method for the synthesis of tetrahydro-b-carboline hydrochlorides under
solvent-free conditions by the direct reaction of tryptamine hydrochlorides
and aldehydes with the aid of microwave irradiation.
In our research, we used commercially available tryptamine hydrochlo-
rides as the original reactant (Scheme 2). 4-Nitrobenzalaldhyde was
selected as a representative aldehyde to optimize the reaction condition.
First, we compared the reaction result between conventional heating and
microwave. As shown in Table 1, there was a dramatic reduction in the
reaction time under microwave irradiation. Second, in the reactions
employing microwave, the reaction time had an important effect on the
yield. After the tryptamine hydrochloride and 4-nitrobenzalaldehyde had
been heated under microwave irradiation at 100 W for 2 min, a visible fall
of the reactant’s temperature occurred from 90 to 758C; this phenomenon
lasted for 0.5 min. Then the reaction was stopped. This change of temperature
was due to the difference of microwave irradiation’s absorbability between
reactants and products. Any more reaction time would lead to a lower yield
and bring by-products as well. The residue was recrystallized from ethanol
(
95%) to afford pure tetrahydro-b-carboline hydrochloride 3c in good yield.
Scheme 2.

Tetrahydro-b-carboline Hydrochlorides
3935
Table 1. Reaction time optimization in the synthesis under microwave irradiation and
conventional conditions
Reaction
time (min)
Temperature
(8C)
a
Conditions
Yield (%)
80
Solvent
CH COOH
Conventional
heating
90
90
3
100
100
Conventional
heating
72
—
Microwave
Microwave
Microwave
2
60
95
86
—
—
—
,100
,100
,100
2.5
3
a
Isolated yields.
This methodology was also applicable for the reactions between trypta-
mine hydrochlorides and other aromatic aldehydes or aliphatic aldehydes in
good yields within 2.5–9 min (Table 2). When this methodology was
applied to 2-furancabox-aldehyde and tryptamine hydrochlorides, most of
Table 2. Synthesis of tetrahydro-b-carboline hydrochlorides under catalyst-free and
additional solvent-free conditions with the aid of microwave
Reaction
time (min)
a
Entry
R
1
R
2
Products
Yield (%)
1
2
3
4
5
2-Cl-C
3-Cl-C
6
H
H
4
H
H
H
H
H
3a
3b
3c
3d
3e
3
92
92
95
94
91
6
4
3
4-NO
3-CH -C H
2
-C
6
H
4
2.5
3
3
6
4
2-CH
3
O-
3.5
6 4
C H
6
4-CH O-
3
H
3f
3.5
92
C
C
6
H
H
4
7
8
9
6
5
H
H
3g
3h
3i
3
94
91
94
92
87
91
90
85
82
81
76
79
4-F-C H
6
2.5
3
4
C
C
6
H
5
H
5
5
5-Cl
5-CH
5-CH O
1
1
1
1
1
1
1
1
1
0
1
2
3
4
5
6
7
8
6
3
3j
3
C H
6
3k
3l
3
3
2-Cl-C H
6
5-Cl
5-CH
H
2.5
3
4
3-CH
3
-C
-CH
C H -CH
6
H
4
3
3m
3n
3o
3p
3q
3r
C
6
H
5
2
2
9
5-Cl
H
9
6
5
2-Thienyl
2-Thienyl
CH CH
5
5-Cl
H
6
6
3
2
a
Isolated yields.

3
936
F. Liu and Q.-D. You
2-furancabox-aldehyde was decomposed, and a only little product was
obtained after 2 min of irradiation with microwaves. The ends of these
reactions were also determined by the changes in temperature respectively.
In summary, an efficient microwave-assisted Pictet–Spengler cyclization
of tryptamine hydrochlorides with aldehydes under additional catalyst-free
and solvent-free conditions was developed with high yields for the first
time. And there are several advantages to this methodology: environmentally
friendliness, high yields, and short reaction times.
EXPERIMENTAL
1
The H NMR spectra were recorded on a Bruker AV 500 spectrometer using
DMSO-d as the solvent and TMS as the internal standard. Chemical shifts are
6
reported in parts per million (ppm). The EI-MS were obtained on Shimadzu
GCMS-QP2010. Elemental analyses were performed on a Carlo Erba 1106
instrument. Melting points (uncorrected) were obtained on a Thomas
Hoover apparatus.
General Procedure of the Pictet–Spengler Reaction between
Tryptamine Hydrochloride and Aldehydes
All of the experiments were carried out in the Discover microwave synthesizer
from CEM Corp. The maximum temperature was set to 1008C. To control the
temperature, the melting point of all of the aldehydes should be less than
1008C. A mixture of 1 mmol of tryptamine hydrochloride and 1.2 mmol of
aldehyde was heated in the microwave synthesizer at 100 W for 2–9 min.
The residue was recrystallized from ethanol (95%) to yield pure products.
The structures of products 3a–r were confirmed from the spectroscopic
data and elemental analysis. The spectroscopic data were all consistent with
[13]
the data that reported in the literature.
Analytical and Spectroscopic Data for Some Representative
Compounds and New Compounds
1
Compound 3a: White solid, mp 267–2688C. H NMR (500 MHz, DMSO-d ):
6
d 3.03 (m, 1H), d 3.17 (m, 1H), d 3.36 (m, 2H), d 6.18 (s, 1H), d 7.05 (t, 1H), d
7.15 (m, 2H), d 7.29 (d, 1H), d 7.38 (m, 1H), d 7.53 (m, 2H), d 7.68 (m, 1H), d
9.8 (s, 2H), d 10.94 (s, 1H). Anal. calcd. for C H Cl N : C, 63.96; H, 5.05;
N, 8.78. Found: C, 63.78; H, 5.02; N, 8.60.
1
7
16
2 2
1
Compound 3c: Light yellow solid, mp 236–2388C. H NMR (500 MHz,
DMSO-d ): 3.07 (m, 1H), d 3.3.15 (m, 1H), d 3.47 (m, 2H), d 6.18 (s, 1H),
6

Tetrahydro-b-carboline Hydrochlorides
3937
d 7.08 (m, 2H), d 7.30 (d, 1H), d 7.56 (d, 1H), d 7.82 (m, 2H), d 8.35 (d, 2H), d
1
0.0 (s, 2H), d 10.92 (s, 1H). Anal. calcd. for C H ClN O : C, 61.92; H,
17 16 3 2
4
.89; N, 12.74. Found: C, 61.57; H, 5.10; N, 12.45.
1
Compound 3e: White solid, mp 263–2648C. H NMR (500 MHz, DMSO-d ):
6
3.06 (m, 2H), d 3.23 (m, 1H), d 3.44 (m, 1H), d 3.93 (s, 3H), d 6.04 (s, 1H), d
6.87 (m, 1H), d 6.96 (m, 1H), d 7.05 (m, 1H), d 7.12 (m, 1H), d 7.21 (d, 1H), d
7.30 (d, 1H), d 7.47 (m, 1H), d 7.53 (d, 1H), d 9.50 (s, 2H), d 10.91 (s, 1H).
Anal. calcd. for C H ClN O: C, 68.67; H, 6.08; N, 8.90. Found: C, 68.68;
2
1
8
19
H, 6.19; N, 8.55.
1
Compound 3j: White solid, mp 242–2468C. H NMR (500 MHz, DMSO-d ):
6
2
.35 (s, 3H), 3.16 (m, 2H), d 3.58 (m, 2H), d 6.14 (s, 1H), d 6.87 (m, 1H), d
.98 (m, 1H), d 7.10 (m, 2H), d 7.18 (m, 1H), d 7.35 (m, 2H), d 7.40 (m, 1H), d
.30 (s, 2H), d 10.10 (s, 1H). Anal. calcd. for C H ClN : C, 72.35; H, 6.41;
6
9
1
8
19
2
N, 9.37. Found: C, 72.24; H, 6.28; N, 9.50.
1
Compound 3m: White solid, mp 238–2408C. H NMR (500 MHz, DMSO-
d6): 2.36 (m, 6H), 3.16 (m, 2H), d 3.55 (m, 2H), d 6.14 (s, 1H), d 6.85
(
m, 2H), d 6.97 (m, 1H), d 7.03 (m, 2H), d 7.09 (m, 1H), d 7.23 (m, 1H), d
.15 (s, 2H), d 10.21 (s, 1H). Anal. calcd. for C H ClN : C, 72.95; H,
19 21 2
9
6
.77; N, 8.95. Found: C, 72.83; H, 6.69; N, 9.02.
ACKNOWLEDGMENTS
The present work was supported by Specialized Research Fund for the
Doctoral Program of Higher Education P.R.C. (No. 20060316006) and “The
Six Top Talents” of Jiangsu Province (No. 06-C-23).
REFERENCES
1
. Pictet, A.; Spengler, T. Uber die Bildung von Isochinohin-Derivaten durch Einwir-
kung von methylal auf phenylathylamimi. Berichte 1911, 44, 2030–2036.
. Cox, E. D.; Cook, J. M. The Pictet–Spengler condensation: A new direction for an
old reaction. Chem. Rev. 1995, 95, 1797–1842.
2
3
4
. Stuart, K.; Woo-Ming, R. b-Carboline alkaloids. Heterocycles 1975, 3, 223–264.
. Kawate, T.; Yamada, H.; Matsumizu, M.; Nishida, A.; Yamaguchi, K.;
Nakagawa, M. Enantioselective Pictet–Spengler reaction of nitrones derived
from N -hydroxytryptamine with aldehydes catalyzed by chiral Brønsted acid–
b
assisted Lewis acids. Synlett 1997, 7, 761–762.
5
. Waldmann, H.; Schmidt, G.; Henke, H.; Burkard, M. Asymmetric Pictet–Spengler
reactions employing N,N-phthaloyl amino acids as chiral auxiliary groups. Angew.
Chem., Int. Ed. Engl. 1995, 34, 2402–2403.

3
938
F. Liu and Q.-D. You
6
. Soerens, D.; Sandrin, J.; Ungemach, F.; Mokry, P.; Wu, G. S.; Yamanaka, E.;
Hutchins, L.; DiPierro, M.; Cook, J. M. Study of the Pictet–Spengler reaction in
aprotic media: Synthesis of the b-galactosidase inhibitor, pyridindolol. J. Org.
Chem. 1979, 44, 535–545.
7
. Heged u¨ s, A.; Hell, Z. One-step preparation of 1-substituted tetrahydroisoquinolines
via the Pictet–Spengler reaction using zeolite catalysts. Tetrahedron Lett. 2004, 45,
8
553–8555.
8
9
. Kappe, C. O. Controlled microwave heating in modern organic synthesis. Angew.
Chem., Int. Ed. Engl. 2004, 43, 6250–6284.
. Srinivasan, N.; Ganesan, A. Highly efficient Lewis acid–catalysed Pictet–
Spengler reactions discovered by parallel screening. Chem. Commun. 2003, 7,
9
16–917.
1
1
0. Wu, C. Y.; Sun, C. M. Parallel synthesis of 1,2,3,4-tetrahydro-b-carbolines using
microwave irradiation. Synlett 2002, 10, 1709–1711.
1. Bikash, P.; Parasuraman, J.; Venkatachalam, S. Microwave assisted Pictet–
Spengler and Bischler–Napieralski reactions. Synth. Commun. 2003, 33,
2
339–2348.
1
2. Campiglia, P.; Gomez-Monterrey, I.; Lama, T.; Novellino, E.; Grieco, P. A new
efficient synthetic methodology for tetrahydroisoquinoline and tetrahydro-b-
carboline derivatives using the Pictet–Spengler reaction. Molecular Diversity
2
004, 8, 427–430.
1
3. (a) Skinner, W. A.; Parkhurst, R. M. Synthesis of 1-aryl substituted 9H-pyrido[3,4-
b]indoles. Can. J. Chem. 1965, 43, 2251–2253; (b) Agafonov, N. E.; Dudin, A. V.;
Preobrazhenskii, A. A.; Zhulin, V. M. Synthesis of 1-aryl-1,2,3,4-tetrahydro-9H-
pyrido[3,4-b]indoles(1,2,3,4-tetrahydro-b-carbolines) under high pressures. Russ.
Chem. Bull. 2001, 50, 560–562; (c) DeGraw, J. I.; Kennedy, J. G.;
Skinner, W. A. Substituted 1,2,3,4-tetrahydro-b-carbolines, II. J. Med. Chem.
1
967, 10, 127–128.