Novel synthesis of tetrahydro-β-carbolines and tetrahydroisoquinolines via three-component reaction using hexagonally ordered mesoporous AlSBA-15 catalysts

Article abstract of DOI:10.1016/j.tetlet.2009.11.111

Tryptamine, aryl aldehyde, and benzyl chloride undergo smooth coupling using well-ordered mesoporous AlSBA-15 catalyst with hexagonal porous structure in acetonitrile at 80 °C to furnish tetrahydrocarbolines in good yields with a high selectivity. This reaction also proceeds with homoveratrylamine to give the corresponding tetrahydroisoquinolines. A variety of aryl and heteroaryl aldehydes have also been used for producing tetrahydrocarbolines in high yields. This AlSBA-15-promoted Pictet-Spengler reaction provides a mild alternative to the traditional Bro?nsted or Lewis acids typically employed for the preparation of tetrahydrocarbolines and tetrahydroisoquinolines. Crown Copyright

Full text of DOI:10.1016/j.tetlet.2009.11.111

Tetrahedron Letters 51 (2010) 702–706
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Novel synthesis of tetrahydro-b-carbolines and tetrahydroisoquinolines
via three-component reaction using hexagonally ordered mesoporous
AlSBA-15 catalysts
a
Ajayan Vinu a, , Pranjal Kalita , Leila Samie a,c, Murugulla Adharvana Chari a, Ravindra Pal a,
*
B. V. Subba Reddy a,b,
*
a International Center for Materials Nanoarchitectonics, World Premier International (WPI) Research Initiative, National Institute for Materials Science, Tsukuba,
Ibaraki 305-0044, Japan
b Discovery Laboratory, Indian Institute of Chemical Technology, Hyderabad 500 007, India
c Research Institute of Petroleum Industries, Tehran 14665-137, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
Tryptamine, aryl aldehyde, and benzyl chloride undergo smooth coupling using well-ordered mesopor-
ous AlSBA-15 catalyst with hexagonal porous structure in acetonitrile at 80 °C to furnish tetrahydrocarb-
olines in good yields with a high selectivity. This reaction also proceeds with homoveratrylamine to give
the corresponding tetrahydroisoquinolines. A variety of aryl and heteroaryl aldehydes have also been
used for producing tetrahydrocarbolines in high yields. This AlSBA-15-promoted Pictet–Spengler reaction
provides a mild alternative to the traditional Brönsted or Lewis acids typically employed for the prepa-
ration of tetrahydrocarbolines and tetrahydroisoquinolines.
Received 3 October 2009
Revised 21 November 2009
Accepted 26 November 2009
Available online 29 November 2009
Keywords:
Pictet–Spengler reaction
2-Arylethyl amine
AlSBA-15
Crown Copyright Ó 2009 Published by Elsevier Ltd. All rights reserved.
Carbolines
1. Introduction
friendly, and recyclable. Recently, mesoporous molecular sieves
have attracted significant attention in the field of adsorption, catal-
The tetrahydro-b-carboline ring is frequently found in various
natural products and synthetic pharmaceuticals displaying a wide
range of biological activities.1 The Pictet–Spengler reaction is one
of the powerful synthetic routes for the preparation of tetrahydro-
isoquinolines and b-carbolines.2 Typically, strong Brønsted acids
have been utilized to accomplish this reaction.3 Lewis acid-cata-
lyzed Pictet–Spengler reactions have also been reported in the lit-
erature.4 Generally, activated substrates containing a catechol
functionality undergo Pictet–Spengler reactions under mildly
acidic conditions whereas less activated substrates such as trypt-
amine and tryptophan provide low conversions (vide infra).5
Homogeneous catalysts such as chiral thiourea, (S)-BINOL phos-
phoric acid, molecular iodine, and TFA/H2O have recently been
used for this conversion.6,7 Unfortunately, the use of the above cat-
alysts in the industry triggers a lot of environment-related issues
as they are highly corrosive in nature and cannot be regenerated
for further use. In addition, tedious work-setup is required for
treating the large quantities of metal salt wastes. To avoid the
above environmental-related problems, it is desirable to develop
a catalyst process which is heterogeneous, stable, environmentally
ysis, and separation as they exhibit excellent textural characteris-
tics such as a high surface area, a large pore volume, and a
narrow pore size distribution. In addition, they are highly efficient,
sustainable, recyclable, and eco-friendly. SBA-15 mesoporous
material has been synthesized under acidic condition using a tri-
block copolymer as a structure-directing agent. This novel meso-
porous material has opened a new window in the field of
catalysis and material science owing to its significant properties
such as thick pore walls and tunable pores. Moreover, the wall
thickness and pore diameter of the SBA-15 are larger than those
of the MCM-41 which is synthesized by highly expensive cationic
surfactant in a highly basic medium.8 These superior properties
of SBA-15 make them more suitable to deal with the reaction be-
tween the bulky molecules or multi-component reactions.9 How-
ever, pure mesoporous silica is neutral in charge and offers only
mild acidity which limits its application in catalysis. Thus, the
incorporation of Al and other trivalent metals into the amorphous
silica walls is mandatory for the formation of catalytically active
sites.10,11 The incorporation of aluminum into SBA-15 by post-syn-
thetic and direct methods has been established.12 Recently, we
have reported the successful direct synthesis of aluminum substi-
tuted SBA-15 (AlSBA-15) materials with a high aluminum content
and tunable pore diameters by simply adjusting the molar water to
* Corresponding authors.
E-mail address: vinu.ajayan@nims.go.jp (A. Vinu).
0040-4039/$ - see front matter Crown Copyright Ó 2009 Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.11.111

A. Vinu et al. / Tetrahedron Letters 51 (2010) 702–706
703
hydrochloric acid ratio (nH2O/nHCl)13 and found better perfor-
mances in the tert-butylation of phenol as compared with that of
AlMCM-41, sulfated zirconia, and FeAl–MCM-41.14 Although AlS-
BA-15 possesses a large pore diameter, unfortunately, only the
reaction involving the transformation of small molecules inside
the pore channels of AlSBA-15 has been conducted so far.
furnish hydroxyl-substituted tetrahydroisoquinolines in good
yields. In the absence of benzyl chloride, the reaction was sluggish
as has been observed by Cook and co-workers.15 This may be attrib-
uted to the low electrophilicity of the imine which might be en-
hanced by activation with benzyl chloride. Similarly, in the
absence of catalyst, the resulting iminium ion (formed in situ from
imine and benzyl chloride) failed to undergo Friedal–Crafts-type
cyclization to give the desired product. The presence of both the
catalyst and benzyl chloride is essential to accomplish the reaction.
Mechanistically, the reaction proceeds via the formation of imine
from amine and aldehyde followed by iminium ion resulting from
benzyl chloride and imine. This iminium ion may undergo Frie-
dal–Crafts-type cyclization to provide the desired carboline
(Scheme 3).15
2. Results and discussion
Herein we demonstrate for the first time the Pictet–Spengler
reactions of tryptamine with aryl aldehydes in the presence of ben-
zyl chloride using highly ordered mesoporous AlSBA-15 with hex-
agonal pore structure as a catalyst (Scheme 1).
The reaction was carried out in a single-step operation. Initially,
the effect of the solvents including acetonitrile, ethanol, 1,4-diox-
ane, 1,2-dichloroethane, toluene, and THF on the reaction has been
studied over AlSBA-15 catalyst. Among the solvents studied, aceto-
nitrile was found to be the best solvent for the catalytic reaction.
The reactions proceeded smoothly at 80 °C and the desired prod-
ucts were obtained in good yields after 4–8 h. The results pre-
sented in Table 1 clearly show that all the studied aldehydes
participated in Pictet–Spengler reactions with tryptamine in short
reaction times affording good yields of products. The optimized
conditions were subsequently applied to several other aldehydes
(Table 1). When compared to other methods for the synthesis of
tetrahydro-b-carbolines, the solid acid-induced reaction tolerates
the sensitive indole unit well. Another interesting feature of this
method is that aryl aldehydes bearing either electron-withdrawing
or electron-donating groups successfully underwent the Pictet–
Spengler reaction with equal ease. Tryptamine was reacted with
various aldehydes in the presence of a catalytic amount of AlSBA
in acetonitrile to produce tetrahydro-b-carbolines in short reaction
times. Encouraged by the results obtained with tryptamine, we ex-
tended our protocol to veratrylamine, which is known to be a less
reactive substrate than tryptamine, toward Pictet–Spengler reac-
tion using our highly active AlSBA-15 catalyst. Interestingly, verat-
rylamine also participated effectively in Pictet–Spengler reaction
to furnish the tetrahydroisoquinoline 4l in good yield (Table 1,
entry l, Scheme 2).
Finally, we have examined the efficiency of solid acid catalysts
with different structure and aluminum contents in different sol-
vents in the preparation of product 4c. Among them, AlSBA-15
(6.6) where the number in the parenthesis denotes the Si/Al ratio
was found to be the best in terms of conversion. As solvent, aceto-
nitrile appears to give high conversions and the results are pre-
sented in Table 2. The higher activity of the AlSBA-15(6.6) could
be due to its high acidity, well-ordered pore structure, and excel-
lent textural characteristics.13,14
The advantage of the use of AlSBA-15 is that it can be easily
recovered and recycled in subsequent runs. After complete disap-
pearance of aldehyde as indicated by TLC, the reaction mixture
was centrifuged to separate the catalyst. Thus recovered catalyst
was further washed with ether, dried at 120 °C under reduced
pressure, and reused in three to four successive runs with only a
minimal decrease in activity and the results are presented in Table
3. The small decrease in the activity after the repeated reaction cy-
cles could be due to either the blockage of the active sites by the
product molecules or the slight deterioration of the structural or-
der of the materials.
In summary, we have developed a novel, convenient, and sim-
ple one-pot procedure for the synthesis of tetrahydro-b-carbolines
and tetrahydroisoquinolines using AlSBA-15. This method provides
a mild alternative to the typical conditions requiring strong
Brønsted acids.
It should be mentioned that the yield of the products is in the
range of 50–70% though the aldehyde molecules are converted
completely in the reaction. This could be mainly due to the fact
that the reaction of benzyl chloride with amine may produce HCl
as a by-product, which subsequently reacts with carboline result-
ing in the formation of carbolinehydrochloride. Therefore, the
product might have lost in work-up due to its high solubility in
water. Another reason is that carbolines might be binding with sil-
ica while purification. Therefore, we can expect some product loss
on silica gel column. Noteworthy, we have not observed any
byproduct formation by TLC under present reaction conditions.
Next, we have attempted the Pictet–Spengler cyclization be-
tween m-tyramine (3-hydroxyphenethyl amine) and aldehydes un-
der similar conditions. Interestingly, both electron-rich and
electron-deficient aldehydes participated well in this reaction to
3. Experimental section
Melting points were recorded on a Buchi R-535 apparatus and
are uncorrected. 1H NMR and 13C spectra were recorded on JEOL
AL-300/BZ spectrometer in CDCl3 using TMS as internal standard.
Mass spectra (MS) were measured by using AXIMA-CFR, Shima-
dzu/Kratos TOF Mass spectrometer. Column chromatography was
performed using E. Merck 60–120 mesh, silica gel.
3.1. General procedure
A mixture of aldehyde (1 mmol), tryptamine (1 mmol), benzyl
chloride (1 mmol), and AlSBA-15 (20 mg) in acetonitrile (2 mL)
was stirred at 80 °C for the specified amount of time (Table 1).
CHO
Cl
AlSBA-15
NH2
N
N
N
H
CH3CN, 80 ºC
H
NO2
2
1
3
4a
NO2
Scheme 1. Synthesis of tetrahydrocarboline 4a using AlSBA-15.

704
A. Vinu et al. / Tetrahedron Letters 51 (2010) 702–706
Table 1
Synthesis of tetrahydrocarbolines using A1SBA-15 in 1,4-dioxane
Entry
Aldehyde
Amine
Time (h)
9.0
Product
Yield (%)
70
a
b
c
9.0
9.0
73
76
d
7.0
72
e
8.0
7.0
75
77
f
g
10.0
9.0
61
70
h
i
9.0
79
j
8.0
8.0
58
81
k

A. Vinu et al. / Tetrahedron Letters 51 (2010) 702–706
705
Table 1 (continued)
Entry
Aldehyde
Amine
Time (h)
12.0
Product
Yield (%)
l
55
78
m
12.0
n
o
12.0
12.0
79
75
Table 2
Synthesis of tetrahydro-b-carbolines using various catalysts and solvents
Entry
Catalyst
Solvent
Yield (%)
1
2
3
4
5
6
7
8
A1-KITS (3.3)
A1SBA-15 (6.6)
A1-KITS (3.3)
A1SBA-15 (6.6)
A1SBA-15 (6.6)
A1SBA-15 (6.6)
A1SBA-15 (6.6)
A1SBA-15 (6.6)
MeCN
MeCN
EtOH
EtOH
1,4-Dioxane
1,2-Dichloroethane
Toluene
THF
65
76
48
56
73
70
65
48
Scheme 2. Synthesis of tetrahydroisoquinoline 4l using AlSBA-15 catalyst.
After complete disappearance of aldehydes as indicated by TLC, the
reaction mixture was centrifuged to separate the catalyst. The
resulting supernatant liquid was concentrated under reduced pres-
sure and the crude product was purified by column chromatogra-
phy using silica gel (60–120 mesh, ethyl acetate–hexane, 1:3) to
give the desired product. The product thus obtained was character-
ized by NMR and MALDI mass spectroscopy. The spectral data of
the product were found to be consistent with those of the authen-
tic sample.3–7
Table 3
Reusability of the catalyst in the preparation of 4a
Entry
Number of cycles
Time (h)
Yield (%)
1
2
3
4
1st cycle
2nd cycle
3rd cycle
4th cycle
9.0
10.0
12.0
13.0
70
75
71
65
NH2
AlSBA-15
CH3CN, 80 ºC
Cl
N
H
+
CHO
+
Cl-
..
N
N
H
N
N
N
H
N
H
Scheme 3. Mechanism of the formation of tetrahydro-b-carbolines using AlSBA-15 catalyst.

706
A. Vinu et al. / Tetrahedron Letters 51 (2010) 702–706
Seayad, A. M.; List, B. J. Am. Chem. Soc. 2006, 128, 1086; (c) Taylor, M. S.;
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cation, Culture, Sports, Science, and Technology (MEXT) under the
Strategic Program for Building an Asian Science and Technology
Community Scheme and World Premier International Research
Center (WPI) Initiative on Materials Nanoarchitectonics, MEXT, Ja-
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nical support.
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