A one-pot, four-component synthesis of α-carboline derivatives

Article abstract of DOI:10.1016/j.tetlet.2009.10.077

A one-pot method for the efficient and simple synthesis of novel 1H-indolo[2,3-b]pyrazolo[4,3-e]pyridines via a four-component condensation reaction of indolin-2-one, 3-oxo-3-phenylpropanenitrile, and various hydrazines and aldehydes in the ionic liquid 1

Full text of DOI:10.1016/j.tetlet.2009.10.077

Tetrahedron Letters 50 (2009) 7379–7381
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A one-pot, four-component synthesis of
a-carboline derivatives
Ramin Ghahremanzadeh a,b, Somayeh Ahadi a, Ayoob Bazgir a,
*
a Department of Chemistry, Shahid Beheshti University, G.C., PO Box 19396-4716, Tehran, Iran
b Nanobiotechnology Research Center, Avicenna Research Institute, ACECR, Tehran, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
A one-pot method for the efficient and simple synthesis of novel 1H-indolo[2,3-b]pyrazolo[4,3-e]pyri-
dines via a four-component condensation reaction of indolin-2-one, 3-oxo-3-phenylpropanenitrile, and
various hydrazines and aldehydes in the ionic liquid 1-butyl-3-methylimidazolium bromide ([bmim]Br)
is reported.
Received 27 May 2009
Revised 6 October 2009
Accepted 16 October 2009
Available online 22 October 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Indolin-2-one
Aldehyde
Pyrazole
Indolopyrazolopyridine
Carboline
Pyrido[2,3-b]indoles (
a
-carbolines) display a number of inter-
according to current synthetic requirements, environmentally be-
nign multi-component procedures are particularly welcome.
As part of our continuing efforts on the development of new
routes for the synthesis of biologically active heterocyclic com-
esting biological properties.1 For example, natural products con-
taining this unit such as grossularine-1 and grossularine-2,
marine alkaloids isolated from Dendrodoa grossularia in 1989
(Fig. 1), have attracted considerable interest due to their antiprolif-
erative activity.2 Similarly, mescengricin, isolated from Streptomy-
ces griseoflavus, was found to protect neuronal cells by suppressing
pounds,22 herein we report an efficient synthesis of new
a-carbo-
line derivatives via a simple procedure under green conditions.
To achieve suitable conditions for the above transformation, we
investigated the reaction of indolin-2-one (1), 3-oxo-3-phenylpro-
panenitrile (2), phenylhydrazine (3a) and benzaldehyde (4a) under
various conditions (Scheme 1). We found that the best result was
obtained in the presence of p-toluenesulfonic acid (p-TSA) at
140 °C in [bmim]Br (Table 1, entry 1). The result was good in terms
of yield and product purity; without p-TSA, only a trace of product
was obtained even after 12 h (Table 1, entry 2).
After optimizing the reaction conditions, the scope of this meth-
od, particularly in regard to library construction, was evaluated
using hydrazines 3a–c, and aromatic aldehydes 4a–k. The corre-
sponding 1H-indolo[2,3-b]pyrazolo[4,3-e]pyridines 5a–q were ob-
tained in moderate to excellent yields (Table 2). To the best of our
knowledge, this procedure represents the first example of an effi-
cient, four-component method for the synthesis of 1H-indolo[2,3-
b]pyrazolo[4,3-e]pyridines.
the excitotoxicity induced by
eral synthetic -carboline derivatives are anxiolytic or neuropro-
L
-glutamate (Fig. 1).3 Moreover, sev-
a
tectant agents.4 Also, several synthetic
a-carbolines have been
found to exhibit antiviral and antitumor activity,5–7 and many have
been patented.8
Much effort has been devoted to the synthesis of
Surprisingly, direct functionalization of the -carboline skeleton
has been studied only briefly.9 In most cases, the substitution is
incorporated prior to formation of the -carboline ring system
a-carbolines.
a
a
resulting in lengthy synthetic routes, or in limitations in the avail-
ability of substituted starting materials.10,11 These approaches are
based on substituted indole,12,11,13 an arylalkyne,14 or arylalkene,15
oxoindole,4a,16 azaindole,17 or pyridine18,19 starting materials.
The multicomponent reaction (MCR) strategy offers significant
advantages over conventional linear-type synthesis due to its flex-
ible, convergent, and atom-efficient nature.20 In recent years, the
combinatorial synthesis of small-molecule heterocyclic libraries
has emerged as a valuable tool in the search for novel lead struc-
tures.21 The success of combinatorial chemistry in drug discovery
benefits from advances in heterocyclic MCR methodology and,
The nature of these compounds as 1:1:1:1 adducts was appar-
ent from their mass spectra, which displayed, in each case, a
molecular ion peak at the appropriate m/z value. Compounds 5a–
q are stable solids whose structures were established by IR, 1H,
and 13C NMR spectroscopy and by elemental analysis.
When this reaction was carried out with an aliphatic aldehyde
such as butanal or pentanal, the TLC and 1H NMR spectra of the
crude reaction mixture showed the presence of a combination of
* Corresponding author. Fax: +98 21 22431661.
E-mail address: a_bazgir@sbu.ac.ir (A. Bazgir).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.10.077

7380
R. Ghahremanzadeh et al. / Tetrahedron Letters 50 (2009) 7379–7381
OH
Me
N
Me
N
HO
Me
Me
N
N
O
HN
HN
O
O
O
O
O
Me
N
N
N
N
N
N
NH
HO
N
N
HO
H
H
H
H
OH
grossularine-1
α-carboline
Figure 1.
grossularine-2
mescengricin
-carboline-containing natural products.
Ar
a
-Carboline and examples of
a
Ph
O
[bmim]Br
X
NH2
N
CN
O
+
Ar-CHO
+
N
H
+
Ph
N
H
N
p-TSA/140 ºC
N
N
H
8 h
X
1
2
4a-k
5a-q
3a X= C6H5
3b X= 4-O2N-C6H4
3c
X= H
Scheme 1.
From a mechanistic view point, it is notable that when indolin-
Table 1
Optimization of the reaction conditionsa
2-one (1), 3-oxo-3-phenylpropanenitrile (2), phenylhydrazine (3a),
and benzaldehyde (4a) were reacted for 2 h, intermediates were
formed which could be isolated. Reaction of these intermediates
in the presence of p-TSA under the same reaction conditions affor-
ded product 5a in 70% yield (Scheme 2).
According to these results, the formation of products 5 can be
rationalized by initial formation of arylideneindolin-2-one 6 via
condensation of 1 and 4. Subsequent Michael-type addition of 7
(formed in situ by reaction of hydrazine 3 with nitrile 2), to the
intermediate 6 followed by cyclization afforded 8. The final prod-
uct 5 was then formed by oxidation of intermediate 8 (Scheme 3).
In summary, we have developed a facile, one-pot, four-compo-
nent procedure for the preparation of 1H-indolo[2,3-b]pyrazol-
o[4,3-e]pyridines of potential synthetic and biological interest.
Prominent among the advantages of this new method are novelty,
good yields, and easy work-up.
O
Ph
Ph
N
N
Ph
CN
Ph
Solvent
catalyst/Temp
2
O
+
PhCHO
4a
+
N
H
1
N
H
N
Ph
NH2
N
H
3a
5a
Entry
Conditions
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
9
[bmim]Br/140 °C/p-TSA
[bmim]Br/140 °C
8
12
12
24
24
15
15
15
15
15
85
Trace
75
Trace
37
Trace
Trace
Trace
Trace
35
[bmim]Br/120 °C/p-TSA
[bmim]Br/140 °C/Et3N
[bmim]BF4/120 °C/p-TSA
EtOH (reflux)/p-TSA
CH3CN (reflux)/p-TSA
DMF/120 °C/p-TSA
HOAc (reflux)/p-TSA
Solvent-free/120 °C/p-TSA
10
a
Indolin-2-one (1 mmol), benzaldehyde (1 mmol), 3-oxo-3-phenyl propaneni-
trile (1 mmol), phenylhydrazine (1 mmol), catalyst (0.1 g).
Ph
Ph
Ph
N
Ph
N
[bmim]Br
O
+
N
NH2
N
Ph
N
Table 2
p-TSA/140 ºC
N
H
N
Synthesis of indolopyrazolopyridines 5
H
Ph
Yielda (%)
70%
5a
6
7
Product
Ar
X
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
5q
C6H5
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
85
92
88
88
81
80
75
76
81
72
80
68
71
70
68
63
61
Scheme 2.
4-O2N–C6H4
3-O2N–C6H4
2-O2N–C6H4
4-Br–C6H4
3-Br–C6H4
4-Cl–C6H4
3-Cl–C6H4
4-F–C6H4
4-Me–C6H4
4-HO–C6H4
C6H5
4-O2N–C6H4
3-O2N–C6H4
4-Cl–C6H4
4-O2N–C6H4
3-O2N–C6H4
Ar
O
O
ArCHO
+
N
N
H
Ph
Ph
Ph
Ar
H
Ph
1
4
6
N
N
X
HN
4-O2N–C6H4
4-O2N–C6H4
4-O2N–C6H4
4-O2N–C6H4
H
O
Ph
N
O
H2N
H
N
CN
+
H2N
X
Ph
NH2
N
X
-H2O
2
3
7
Ar
H
Ph
a
Yield of isolated product.
N
-2H
5
N
H
N
N
H
X
8
starting materials and numerous by-products, the yield of the ex-
pected product being very poor.
Scheme 3.

R. Ghahremanzadeh et al. / Tetrahedron Letters 50 (2009) 7379–7381
7381
9. (a) Saxena, J. P. Indian J. Chem. 1966, 4, 148; (b) Stephenson, L.; Warburton, W.
K. J. Chem. Soc. 1970, 1355; (c) Wieczorek, J.; Peczynska-Czoch, W.;
Typical procedure for the preparation of 1,3,4-triphenyl-1H-indo-
lo[2,3-b]pyrazolo[4,3-e]pyridine (5a): A mixture of indolin-2-one
(1 mmol), benzaldehyde (1 mmol), 3-oxo-3-phenylpropanenitrile
(1 mmol), phenylhydrazine (1 mmol), p-TSA (0.3 mmol), and
[bmim]Br (0.30 g) was heated at 140 °C for 8 h (TLC). After cooling,
the reaction mixture was washed with water (15 mL) and the res-
idue crystallized from EtOH to afford pure 5a as a cream powder
C
Mordarski, M.; Kaczmarek, L.; Nantka-Namirski, P. Arch. Immunol. Ther. Exp.
1986, 34, 315; (d) Dininno, F. P.; Guthikonda, R. N.; Meurer, L. C. U.S. Patent
5,532,261, 1996; Chem. Abstr. 1996, 125, 167688.
10. (a) Das, S.; Brown, J. W.; Dong, Q.; Gong, X.; Kaldor, S. W.; Liu, Y.; Paraselli, B. R.;
Scorah, N.; Stafford, J. A.; Wallace, M. B. Appl. Int. WO 2007/044779; Chem.
Abstr. 2007, 146, 441771.; (b) Sennhenn, P.; Mantoulidis, A.; Treu, M.; Tontsch-
Grunt, U.; Spevak, W.; McConnell, D.; Schoop, A.; Brueckner, R.; Jacobi, A.;
Guertler, U.; Schnapp, G.; Klein, C.; Himmelsbach, F.; Pautsch, A.; Betzemeier,
B.; Herfurth, L.; Mack, J.; Wiedenmayer, D.; Bader, G.; Reiser, U. Appl. Int. WO
2006/131552; Chem. Abstr. 2006, 146, 62695.; (c) Brown, J. W.; Dong, Q.;
Paraselli, B. R.; Stafford, J. A.; Wallace, M. B.; Wijesekera, H. Appl. Int. WO 2008/
054956; Chem. Abstr. 2008, 148, 495928.
11. Tanaka, K.; Kitamura, M.; Narasaka, K. Bull. Chem. Soc. Jpn. 2005, 78, 1659.
12. (a) Levacher, V.; Boussad, N.; Dupas, G.; Bourguignon, J.; Queguiner, G.
Tetrahedron 1992, 48, 831; (b) Molina, P.; Fresneda, P. M.; Sanz, M. A.
Tetrahedron Lett. 1997, 38, 6909; (c) Molina, P.; Fresneda, P. M.; Sanz, M. A.;
Foces-Foces, C.; Ramirez de Arellano, M. C. Tetrahedron 1998, 54, 9623.
13. (a) Molina, P.; Fresneda, P. Synthesis 1989, 878; (b) Bonini, C.; Funicello, M.;
Spagnolo, P. Synlett 2006, 1574.
(85%); mp 249 °C (dec). IR (KBr): 3214, 3147, 1596 cmÀ1 1H NMR
.
(300 MHz, DMSO-d6): d 6.92–8.43 (19H, m, H-Ar), 12.19 (1H, s,
NH). 13C NMR (75 MHz, DMSO-d6): d 110.0, 111.5, 112.3, 120.0,
121.1, 121.2, 121.9, 126.0, 127.0, 127.6, 128.6, 128.9, 129.3,
129.3, 129.4, 129.5, 133.1, 135.6, 139.9, 140.3, 140.7, 146.9,
153.4. MS (EI, 70 eV) m/z: 436 (M+). Anal. Calcd for C30H20N4: C,
82.55; H, 4.62; N, 12.84. Found: C, 82.39; H, 4.58; N, 12.78.
Acknowledgment
14. (a) Tahri, A.; Buysens, K. J.; Van Der Eycken, E. V.; Vandenberghe, D. M.;
Hoornaert, G. J. Tetrahedron 1998, 54, 13211; (b) Zhang, Q.; Shi, C.; Zhang, H. R.;
Wang, K. K. J. Org. Chem. 2000, 65, 7977; (c) Schmittel, M.; Rodriguez, D.;
Steffen, J.-P. Molecules 2000, 5, 1372.
We gratefully acknowledge financial support from the Research
Council of Shahid Beheshti University.
15. (a) Saito, T.; Ohmori, H.; Furuno, E.; Motoki, S. J. Chem. Soc., Chem. Commun.
1992, 22; (b) Molina, P.; Alajarin, M.; Vidal, A.; Sanchez-Andrada, P. J. Org.
Chem. 1992, 57, 929.
Supplementary data
16. Beccalli, E. M.; Clerici, F.; Marchesini, A. Tetrahedron 2001, 57, 4787.
17. Joseph, B.; Da Costa, H.; Mérour, J.-Y.; Léonce, S. Tetrahedron 2000, 56, 3189.
18. (a) Rocca, P.; Marsais, F.; Godard, A.; Queguiner, G. Tetrahedron 1993, 49, 49; (b)
Achab, S.; Guyot, M.; Potier, P. Tetrahedron Lett. 1993, 34, 2127.
19. Iwaki, T.; Yasuhara, A.; Sakamoto, T. J. Chem. Soc., Perkin Trans. 1 1999, 1505.
20. (a) Weber, L. Drug Discovery Today 2002, 7, 143; (b) Dömling, A. Curr. Opin.
Chem. Biol. 2002, 6, 306.
Supplementary data (experimental procedures and spectral
data of the products) associated with this Letter can be found, in
the online version, at doi:10.1016/j.tetlet.2009.10.077.
References and notes
21. (a) Nefzi, A.; Ostresh, J. M.; Houghten, R. A. Chem. Rev. 1997, 97, 449; (b)
Thompson, L. A. Curr. Opin. Chem. Biol. 2000, 4, 324.
1. (a) Bolton, D.; Forbes, I. T.; Hayward, C. J.; Piper, D. C.; Thomas, D. R.; Thompson,
M.; Upton, N. Bioorg. Med. Chem. Lett. 1993, 3, 1941; (b) Love, B. E. Top.
Heterocycl. Chem. 2006, 2, 93.
2. Moquin-Pattey, C.; Guyot, M. Tetrahedron 1989, 45, 3445.
3. Kim, J.-S.; Shinya, K.; Furihata, K.; Hayakawa, Y.; Seto, H. Tetrahedron Lett. 1997,
38, 3431.
4. (a) Barun, O.; Patra, P. K.; Ila, H.; Junjappa, H. Tetrahedron Lett. 1999, 40, 3797;
(b) Stolc, S. Life Sci. 1999, 65, 1943.
5. Semenov, A. A.; Tolstikhina, V. V. Khim. Geterotsikl. Soedin. 1984, 4, 435–447.
6. Kaczmarek, L.; Nantka-Namirski, P. Pol. J. Pharmacol. Pharm. 1981, 33, 121–127.
7. Helbecqe, N.; Bemier, J. L.; Henichard, J. P.; Morel, E.; Moquin, C.; Guyot, M.
Cancer Biochem. Biophys. 1987, 9, 271–279.
22. (a) Bazgir, A.; Mohammadi Khanaposhtani, M.; Abolhasani Soorki, A. Bioorg.
Med. Chem. Lett. 2008, 18, 5800; (b) Bazgir, A.; Seyyedhamzeh, M.; Yasaei, Z.;
Mirzaei, P. Tetrahedron Lett. 2007, 48, 8790; (c) Sayyafi, M.; Seyyedhamzeh, M.;
Khavasi, H. R.; Bazgir, A. Tetrahedron 2008, 64, 2375; (d) Dabiri, M.; Arvin-
Nezhad, H.; Khavasi, H. R.; Bazgir, A. J. Heterocycl. Chem. 2007, 44, 1009; (e)
Dabiri, M.; Azimi, S. C.; Arvin-Nezhad, H.; Bazgir, A. Heterocycles 2008, 75, 87;
(f) Dabiri, M.; Delbari, A. S.; Bazgir, A. Synlett 2007, 821; (g) Dabiri, M.; Arvin-
Nezhad, H.; Khavasi, H. R.; Bazgir, A. Tetrahedron 2007, 63, 1770; (h) Dabiri, M.;
Delbari, A. S.; Bazgir, A. Heterocycles 2007, 71, 543; (i) Bazgir, A.; Noroozi
Tisseh, Z.; Mirzaei, P. Tetrahedron Lett. 2008, 49, 5165; (j) Ghahremanzadeh, R.;
Imani Shakibaei, G.; Bazgir, A. Synlett 2008, 1129; (k) Jadidi, K.;
Ghahremanzadeh, R.; Bazgir, A. Tetrahedron 2009, 65, 2005; (l) Dabiri, M.;
Azimi, S. C.; Khavasi, H. R.; Bazgir, A. Tetrahedron 2008, 64, 7307; (m) Jadidi, K.;
Ghahremanzadeh, R.; Bazgir, A. J. Comb. Chem. 2009, 11, 341.
8. (a) Elks, J.; Webb, G. B.; Gregory, G. I.; Cocker, J. D. German Patent 1,913,124,
1969; Chem. Abstr. 1970, 72, 473636r.; (b) Elks, J.; Webb, G. B.; Gregory, G. I.;
Cocker, J. D. British Patent 1,268,773, 1972; Chem. Abstr. 1972, 76, 140760s.