A direct synthesis of β-carbolines via a three-step one-pot domino approach with a bifunctional Pd/C/K-10 catalyst

Article abstract of DOI:10.1016/j.tetlet.2009.01.143

A rapid, microwave-assisted synthesis of β-carbolines via a successive condensation/cyclization/dehydrogenation approach is described. This methodology involves the coupling of various tryptamines with aromatic aldehydes/glyoxals. The product imine underg

Full text of DOI:10.1016/j.tetlet.2009.01.143

Tetrahedron Letters 50 (2009) 1791–1794
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A direct synthesis of b-carbolines via a three-step one-pot domino
approach with a bifunctional Pd/C/K-10 catalyst
a,
Aditya Kulkarni b, , Mohammed Abid a, , Béla Török b, , Xudong Huang
*
*
a Conjugate and Medicinal Chemistry Laboratory, Department of Radiology, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA
b Department of Chemistry, University of Massachusetts Boston, 100 Morrissey Blvd. Boston, MA 02125, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A rapid, microwave-assisted synthesis of b-carbolines via a successive condensation/cyclization/dehydro-
genation approach is described. This methodology involves the coupling of various tryptamines with aro-
matic aldehydes/glyoxals. The product imine undergoes a Pictet–Spengler cyclization followed by a final
dehydrogenation to yield b-carbolines in a three-step domino reaction. The use of the bifunctional cata-
lyst Pd/C/K-10 combined with microwave irradiation enabled the synthesis of b-carbolines in short reac-
tion times and in good to excellent yields.
Received 22 July 2008
Revised 28 January 2009
Accepted 28 January 2009
Available online 1 February 2009
Keywords:
b-Carbolines
Ó 2009 Elsevier Ltd. All rights reserved.
Microwave irradiation
Montmorillonite K-10
Solid acid/metal bifunctional catalysis
Aromatization
Pictet–Spengler cyclization
b-Carboline scaffolds are present in a wide range of biologically
active compounds of both natural and synthetic origin.1 b-Carbo-
line alkaloids isolated from different sources have been used for
the treatment of various diseases. Examples include (À)-isocyclo-
capitelline (1) that shows anti-cancer activity,2 sempervirine (2)
that is cyctostatic and anti-HIV active,3 3,10-dibromofascaplysin
(3), a marine alkaloid that exhibits antifungal, antiviral, and anti-
cancer activity,4 and tribulusterine (4), isolated from a famous tra-
ditional Chinese herbal medicine, Tribulus terrestris, that is used for
liver ailments (Fig. 1).5 Recently reported alkaloids isolated from
Korean Tunicate were found to have antibacterial activity.6 Due to
the broad biological activity, the synthesis of b-carbolines has re-
ceived considerable attention.7 Over the years, many synthetic
methods have been developed for these heterocycles; however,
most of the reported methods involve multiple steps.8 In particu-
lar, these methods involve cyclization and oxidation as separate
steps, with the latter requiring a stoichiometric amount of oxidant
and long reaction times.
synthesis of pyrazoles or pyridines in a two-step one-pot condition
by using a bifunctional noble metal/solid acid catalyst.10
Continuing our efforts in developing new methods for the syn-
thesis of important heterocycles, herein, we report the first direct,
one-pot synthesis of the b-carboline core. This approach is based
on a new pathway, namely, solid acid-catalyzed coupling and cycli-
zation followed by a catalytic oxidation (dehydrogenation). The
first step is the coupling between aldehyde and amine to form an
N
CH3
N
N
H
N
O
H
HO
Sempervirine (2)
(-)-Isocyclocapitelline (1)
Our earlier investigations proved that the solid acid-catalyzed
cyclization processes are very effective for the construction of var-
ious heterocycles such as pyrroles, indoles, and carbazoles.9 Our re-
cent studies also revealed that the combination of cyclization and
catalytic oxidation reactions can be effectively employed for the
N
N
H
Br
N
Br
Br
O
N
H
O
HO
Tribulusterine (4)
* Corresponding authors. Tel.: +1 617 582 4711; fax: +1 617 582 0004 (X.H.).
E-mail addresses: bela.torok@umb.edu (B. Török), xhuang3@partners.org (X.
Huang).
3,10-Dibromofascaplysin (3)
Equal contributions.
Figure 1. Representative b-carboline-based natural products.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.01.143

1792
A. Kulkarni et al. / Tetrahedron Letters 50 (2009) 1791–1794
imine that readily undergoes Pictet–Spengler cyclization under
acidic conditions to form tetrahydro-b-carboline followed by oxi-
dative aromatization to form b-carboline in a three-step one-pot
process using a special bifunctional noble metal/solid acid catalyst.
The combination of heterogeneous catalysis and microwave irradi-
ation, a highly eco-friendly approach, results in excellent yields
and reduced reaction times.
First, we focused on finding a suitable catalyst that could pro-
vide high yields and desired selectivities. Optimization studies
were carried out using tryptamine and benzaldehyde as starting
materials. Based on our previous findings, we chose montmorillon-
ite K-10 as a solid acid catalyst, while we evaluated Pt and Pd as
metals for dehydrogenation. The reactions were carried out in a
CEM Discover microwave reactor and in a pressure vessel under
conventional heating. The results are shown in Table 1.
First, we tried several acid catalysts such as Al2O3, AcOH, and
K-10. The data show that the reaction is strongly catalyst dependent;
catalysts with moderate acidity provided comparatively low yields
(Table 1, entries 10 and 13). Under conventional heating conditions,
K-10 provided only cyclized saturated product (4) (Table 1, entry 2),
however, under microwave conditions it gave a substantial amount
of aromatic compound (5) (Table 1, entry 3). It appears that K-10 it-
self is capable of carrying out oxidation at a higher temperature;
however, it would require long reaction times and higher tempera-
tures for complete conversion to aromatic product. This results in
low product yields due to possible product decomposition. As an
alternative, the combination of a metal and K-10 provided excellent
results. Although Pd gave higher selectivities toward the aromatic
compound (5) (Table 1, entry 7), both Pt and Pd were effective in
dehydrogenation. Pd content was crucial: 5% Pd/C/K-10 provided
38% of (5) (Table 1, entry 12), while 10% Pd/C/K-10 provided 100%
selectivity for the aromatic product (Table 1, entries 5, 6 and 7). Also,
the reaction was optimized as a function of time and temperature.
Apparently at 130 °C, we obtained the best yield and selectivity.
Based on the above results (Table 1), we concluded that the best
combination was 10% Pd/C/K-10 catalyst at 130 °C. Based on our
previous investigations, the 1:1.2 equiv of tryptamine to benzalde-
hyde ratio was selected. After determining these optimized param-
eters, we decided to broaden the scope of this approach and
illustrate the applicability of our methodology by using various
substituted tryptamines and aromatic aldehydes. Table 2 summa-
rizes the results. The data show that reactions occurred efficiently
in short reaction times (20–55 min.), providing high selectivities
and isolated yields (68–91%). In addition, the reactions proceeded
without any byproduct formation, and even after extended time
of irradiation, the products did not undergo secondary reactions.
The substituents on tryptamine rings did not show any remarkable
effect. Tryptophan, however, provided the corresponding b-carbo-
line by undergoing decarboxylation under similar reaction condi-
tions (Table 2, entries 13–16).11
Encouraged by the above results, we further extended the
scope of our methodology with a variety of substituted aromatic
glyoxals. Table 3 summarizes the results. These data indicate the
usefulness of our method. Various tryptamines readily under-
went cyclization/dehydrogenation with glyoxals to form the cor-
responding b-carboline derivatives. As indicated in Table 3,
glyoxals showed higher reactivity as compared to aldehydes;
the reaction rates were much faster, and we achieved excellent
yields in 2–12 min of irradiation.
The proposed mechanism involved contribution from both
the K-10 and Pd. The first step is a coupling between primary
amino group and aldehyde to form an imine. This imine under-
went cyclization by the traditional Pictet–Spengler pathway
(Scheme 1).12 K-10 helps to activate the carbonyl group and
facilitate the imine formation as well as cyclization. K-10 is a
well known and widely used solid acid catalyst in organic
transformations.13 It offers several advantages over classical li-
quid acids; solid, non-corrosive, inexpensive, and easily reus-
able. Also, its high surface area (220–270 m2/g) ensures
excellent reaction rates. The Hammett acidity (Ho) value for
K-10 is ꢀÀ8, indicating strong acidity. It is also an excellent
catalyst for microwave-assisted organic synthesis.14 Finally, the
metal component carried out the catalytic oxidative aromatiza-
tion via dehydrogenation.
Table 1
Synthesis of b-carboline core under various experimental conditions from tryptamine and benzaldehyde
NH2
N
Ph
NH
Ph
N
N
H
O
N
H
N
H
N
H
Ph
H
Tetrahydro-β-carboline
-Carboline
β
(4)
(5)
Entry
Catalyst
Temperature (°C)
Conditionsa
Time (min)
Conversionb (%)
Selectivityb (%) 4/5
1c
2c
3
4
5
6
7
8
9
10
11c
12
13c
—
K-10
K-10
160
160
160
160
160
150
130
120
130
130
130
130
130
Conventional heating
Conventional heating
MW
MW
MW
MW
MW
MW
120
120
60
60
60
45
45
45
45
0
37
70
85
88
93
93
85
78
47
75
90
15
0/0
100/0
65/35
21/79
0/100
0/100
0/100
8/92
20/80
8/92
18/82
62/38
9/91
10% Pt/C/K-10
10% Pd/C/K-10
10% Pd/C/K-10
10% Pd/C/K-10
10% Pd/C/K-10
5% Pt/Al2O3
5% Pd/C/Al2O3
10% Pd/C/K-10
5% Pd/C/K-10
10 Pd/AcOH
MW
MW
45
720
45
Conventional heating
MW
Conventional heating
120
a
1:1.2 equiv tryptamine/benzaldehyde ratio used.
Determined by GC, based on residual tryptamine.
Reactions were carried out in a pressure vessel.
b
c

A. Kulkarni et al. / Tetrahedron Letters 50 (2009) 1791–1794
1793
Table 2
Table 3
Synthesis of b-carbolines from tryptamines in the presence of Pd/C/K-10 catalyst
Synthesis of b-carbolines from tryptamines in the presence of Pd/C/K-10 catalyst
R1
R1
NH2
O
NH2
OHC
Pd/C/K-10
MW, 130 oC
Pd/C/K-10
MW, 130 o
OHC
R2
R2
R2
N
N
H
C
H
R3
R4
6
7
R
1 = COOH
R1 = COOH
R2 = H, 5-F, 5-OCH3
R3 = H, 4-CH3, 4-F
R2 = H, 5-F, 5-OCH3
R4 = H, 4-CF3, 4-F
5-OCH3
R2
N
N
N
H
N
H
O
R3
R4
Entry Tryptamines
7
Time
(min)
Yielda
(%)
Entry Tryptamines
6
Time (min) Yielda (%)
1
2
3
4
PhCHO
4-CH3–C6H4CHO
4-F–C6H4CHO
45
35
30
89
78
90
82
1
2
3
4
PhCOCHO
4-CF3C6H4COCHO
4-FC6H4COCHO
6-OCH3-Naphth-2-yl-
COCHO
5
2
10
5
94
96
91
80
NH2
NH2
N
H
Naphth-2-yl-CHO 30
N
H
5
6
7
8
PhCHO
4-CH3–C6H4CHO
4-F–C6H4CHO
35
30
25
85
91
90
80
H3CO
5
6
7
8
PhCOCHO
2
6
7
5
93
90
94
92
H3CO
4-CF3C6H4COCHO
4-FC6H4COCHO
6-OCH3-Naphth-2-yl-
COCHO
NH2
Naphth-2-yl-CHO 40
NH2
N
H
N
H
9
10
11
12
PhCHO
4-CH3–C6H4CHO
4-F–C6H4CHO
50
45
40
75
81
88
70
H
3C
9
10
11
12
PhCOCHO
4
8
5
9
95
93
89
90
H3C
4-CF3C6H4COCHO
4-FC6H4COCHO
6-OCH3-Naphth-2-yl-
COCHO
NH2
Naphth-2-yl-CHO 55
NH2
N
H
N
H
13
14
15
16
PhCHO
4-CH3–C6H4CHO
4-F–C6H4CHO
25
35
20
68
71
88
83
COOH
NH2
13
14
15
16
PhCOCHO
5
10
12
7
85
81
83
79
COOH
NH2
4-CF3C6H4COCHO
4-FC6H4COCHO
6-OCH3-Naphth-2-yl-
COCHO
Naphth-2-yl-CHO 45
N
H
N
H
a
Isolated yields after flash chromatography.
a
Isolated yields after flash chromatography.
filtered. The filtrate was concentrated, and the residue was sub-
jected to column chromatography.
In summary, we have developed an effective and direct micro-
wave-assisted, three-step one-pot method for the synthesis of
b-carbolines from tryptamines and aromatic aldehydes or glyoxals.
We have also proved the usefulness of a bifunctional catalyst
(Pd/C/K-10) for the one-pot cyclization/dehydrogenation reaction.
The combination of solid acid-catalysis, heterogeneous catalytic
oxidative aromatization, and microwave irradiation provided
excellent selectivities and yields in short reaction times. In addi-
tion to efficiency and effective catalysis, the very limited energy
consumption and its waste-free nature make the process very
attractive as an environmentally benign synthesis of these impor-
tant heterocycles.
NH
C-3 attack
NH
R
N
H
N
H
R
C-2 attack
-H+
General experimental procedure: Tryptamine (100 mg, 0.62
mmol) and benzaldehyde (76 lL, 0.75 mmol) were dissolved in
NH
NH
N
H
N
H
3 mL CH2Cl2 in a round bottomed flask. Catalyst was prepared by
mixing 21 mg 10%Pd/C and 500 mg of K-10. The catalyst was
mixed with the above reaction mixture, and a few drops of MeOH
were added to dissolve the tryptamine. After 5 min of stirring the
solvent was removed. The dry mixture was transferred to a reac-
tion vial and irradiated in the CEM Discover Benchmate microwave
reactor for the specified time. After the reaction was complete,
CH2Cl2 was added to the reaction mixture and the catalyst was
R
R
-4H
N
N
H
R
Scheme 1. Proposed mechanism for the Pd/C/K-10-catalyzed synthesis of b-
carbolines via cyclization–dehydrogenation domino sequence.

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A. Kulkarni et al. / Tetrahedron Letters 50 (2009) 1791–1794
6. Wang, W.; Nam, S.-J.; Lee, B.-C.; Kang, H. J. Nat. Prod. 2008, 71, 163.
Acknowledgments
7. (a) Cain, M.; Mantei, R.; Cook, J. M. J. Org. Chem. 1982, 47, 4933; (b) Trudell,
M. L.; Fukada, N.; Cook, J. M. J. Org. Chem. 1987, 52, 4293; (c) Hudlicky, T.;
Rinner, U.; Finn, K. J.; Ghiviriga, I. J. Org. Chem. 2005, 70, 3490; (d) Busacca,
C. A.; Eriksson, M. C.; Dong, Y.; Prokopowicz, A. S.; Salvagno, A. M.; Tschantz,
M. A. J. Org. Chem. 1999, 4, 4564; (e) Wu, T. Y. H.; Schultz, P. G. Org. Lett.
2002, 4, 4033.
8. (a) Zhang, H.; Larock, R. C. Org. Lett. 2001, 3, 3083; (b) Bonnet, D.; Ganesan, A. J.
Comb. Chem. 2002, 4, 546; (c) Yeh, W.-P.; Chang, W.-J.; Sun, M.-L.; Sun, C. M.
Tetrahedron 2007, 63, 11809; (d) Lee, S.-C.; Choi, S. Y.; Chung, Y. K.; Park, S. B.
Tetrahedron Lett. 2006, 47, 6843; (e) Ivanov, I.; Nikolova, S.; Statkova-Abeghe, S.
Heterocycles 2005, 65, 2483; (f) Garcia, M. D.; Wilson, A. J.; Emmerson, D. P. G.;
Jenkins, P. R. Chem. Commun. 2006, 2586; (g) Kusurkar, R. S.; Goswami, S. K.
Tetrahedron 2004, 60, 5315.
9. (a) Abid, M.; Spaeth, A.; Török, B. Adv. Synth. Catal. 2006, 348, 2191; (b) Abid,
M.; Landge, S. M.; Török, B. Org. Prep. Proced. Int. 2006, 35, 495; (c) Abid, M.; De
Paolis, O.; Török, B. Synlett 2008, 410; (d) Landge, S. M.; Berryman, M.; Török, B.
Tetrahedron Lett. 2008, 49, 4505.
10. Landge, S. M.; Schmidt, A.; Outerbridge, V.; Török, B. Synlett 2007, 1600.
11. (a) Rönner, B.; Lerche, H.; Bergmüller, W.; Freilinger, C.; Severin, T.;
Pischetsrieder, M. J. Agric. Food. Chem. 2000, 48, 2111; (b) Maki, Y.; Kimoto,
H.; Fujii, S.; Nishida, M.; Cohen, L. A. J. Fluorine. Chem. 1989, 43, 189; (c) Song,
Y.; Wang, J.; Teng, S. F.; Kesuma, D.; Deng, Y.; Duan, J.; Wang, J. H.; Qi, R. Z.; Sim,
M. M. Bioorg. Med. Chem. Lett. 2002, 12, 1129.
Financial support provided by the Alzheimer’s Association and
NIH/NIA (XH) and the ACS-PRF (BT) is highly acknowledged. The
authors thank Ms. Kimberly Lawson at the Radiology Department
of Brigham and Women’s Hospital, for her manuscript editing.
Supplementary data
Experimental procedures and spectral data for all compounds
are provided. Supplementary data associated with this article can
be found, in the online version, at doi:10.1016/j.tetlet.2009.01.143.
References and notes
1. (a) Trujillo, J. I.; Meyers, M. J.; Anderson, D. R.; Hegde, S.; Mahoney, M. W.;
Vernier, W. F.; Buchler, I. P.; Wu, K. K.; Yang, S.; Hartmann, S. J.; Reitz, D. B. Bioorg.
Med. Chem. Lett. 2007, 17, 4657; (b) Winkler, J. D.; Londregan, A. T.; Ragains, J. R.;
Hamann, M. T. Org. Lett. 2006, 8, 3407; (c) Costa, E. V.; Pinheiro, M. L. B.; Xavier, C.
M.; Silva, J. R. A.; Amaral, A. C. F.; Souza, A. D. L.; Barison, A.; Campos, F. R.; Ferreira,
A. G.; Machado, G. M. C.; Leon, L. L. P. J. Nat. Prod. 2006, 69, 292.
2. (a) Phuong, N. M.; Van Sung, T.; Porzel, A.; Schmidt, J.; Merzweiler, K.; Adam, G.
Phytochemistry 1999, 52, 1725; (b) Hartung, J.; Drees, S.; Geiss, B.; Schmidt, P.
Synlett 2003, 223.
12. (a) Narayanan, K.; Schindler, L.; Cook, J. M. J. Org. Chem. 1991, 56, 359; (b)
Ungemach, F.; DiPierro, M.; Weber, R.; Cook, J. M. J. Org. Chem. 1981, 46, 164;
(c) Gremmen, C.; Willemse, B.; Wanner, M. J.; Koomen, G.-J. Org. Lett. 2000, 2,
1955.
13. (a) Szöllösi, G.; Török, B.; Baranyi, L.; Bartók, M. J. Catal. 1998, 179, 619; (b)
Kantam, M. L.; Choudary, B. M.; Reddy, C. V.; Rao, K. K.; Figueras, F. Chem.
Commun. 1998, 1033; (c) Török, B.; London, G.; Bartók, M. Synlett 2000, 631; (d)
Ebitani, K.; Ide, M.; Mitsudome, T.; Mizugaki, T.; Kaneda, K. Chem. Commun.
2002, 690; (e) Abid, M.; Török, B. Adv. Synth. Catal. 2005, 347, 1797.
14. (a) Balogh, M.; Laszlo, P. Organic Chemistry Using Clays; Springer: Berlin/
Heidelberg, 1993; (b) Varma, R. S.; Dahiya, R.; Kumar, S. Tetrahedron Lett.
1997, 38, 2039; (c) Kappe, C. O.; Stadler, A. Microwaves in Organic and
Medicinal Chemistry; Wiley-VCH, 2005; (d) Li, A.; Li, T.; Ding, T. Chem.
Commun. 1997, 1389; (e) Polshettiwar, V.; Varma, R. S. Acc. Chem. Res. 2008,
41, 629.
3. (a) Potts, K. T.; Mattingly, G. S. J. Org. Chem. 1968, 33, 3985; (b) Gribble, G. W.;
Barden, T. C.; Johnson, D. A. Tetrahedron 1988, 44, 3195; (c) Lipinska, T.
Tetrahedron Lett. 2002, 43, 9565.
4. (a) Segraves, N. L.; Robinson, S. J.; Garcia, D.; Said, S. A.; Fu, X.; Schmitz, F. J.;
Pietraszkiewicz, H.; Valeriote, F. A.; Crews, P. J. Nat. Prod. 2004, 67, 783; (b)
Zhidkov, M. E.; Baranova, O. V.; Balaneva, N. N.; Fedorov, S. N.; Radchenko, O. S.;
Dubovitskii, S. V. Tetrahedron Lett. 2007, 48, 7998.
5. (a) Wu, T.-S.; Shi, L.-S.; Kuo, S.-C. Phytochemistry 1999, 50, 1411; (b) Li, C.-Y.;
Lee, E.-J.; Wu, T.-S. J. Nat. Prod. 2004, 67, 473; (c) Bremner, J. B.; Sengpracha, W.;
Southwell, I.; Bourke, C.; Skelton, B. W.; White, A. H. Aust. J. Chem. 2004, 57, 273.