Facile and efficient synthesis of a new class of bis(3′-indolyl)pyridine derivatives via one-pot multicomponent reactions

Article abstract of DOI:10.1016/j.tetlet.2008.01.054

A series of 4-aryl-3,5-dicyano-2,6-di(3′-indolyl)pyridine derivatives were synthesized via a one-pot multicomponent reaction of aromatic aldehydes, 3-cyanoacetyl indoles, and ammonium acetate under microwave irradiation. Particularly valuable features of

Full text of DOI:10.1016/j.tetlet.2008.01.054

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 1777–1781
Facile and efficient synthesis of a new class of bis(30-indolyl)pyridine
derivatives via one-pot multicomponent reactions
a,
a
a
a
Song-Lei Zhu a,b, Shun-Jun Ji , Xiao-Ming Su , Chang Sun , Yu Liu
*
a Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry and Chemical Engineering, Suzhou(Soochow) University,
Suzhou 215123, People’s Republic of China
b Department of Chemistry, Xuzhou Medical College, Xuzhou 221002, People’s Republic of China
Received 17 October 2007; revised 10 January 2008; accepted 11 January 2008
Available online 15 January 2008
Abstract
A series of 4-aryl-3,5-dicyano-2,6-di(30-indolyl)pyridine derivatives were synthesized via a one-pot multicomponent reaction of
aromatic aldehydes, 3-cyanoacetyl indoles, and ammonium acetate under microwave irradiation. Particularly valuable features of this
method include high yields of products, broad substrate scope, short reaction time, and straightforward procedure.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Bisindole; 3,5-Dicyanopyridine; Multicomponent reactions; Microwave irradiation
1. Introduction
non-small cell lung cancer, ovarian cancer, colon cancer,
renal cancer, and breast cancer (Fig. 1).
Indole moiety has been found in a wide variety of phar-
macologically and biologically active compounds.1 Many
bisindole alkaloids are recognized as one of the rapidly
growing groups of sponge metabolites because of their
broad spectrum of biological properties.2–5 For example,
Nortopsentins A–C, having 2,4-bis(30-indolyl)-imidazole
moieties, exhibit in vitro cytotoxicity against P388 cells;6
Hamacanthin B, having a characteristic 3,5-bis(30-indol-
yl)pyrazinone skeleton, exhibits cytotoxic activities against
a wide range of human tumor cell lines with GI50 values at
micromolar concentration.7 Moreover, a very interesting
group of these bisindole derivatives incorporated a five-
or six-membered heterocyclic ring between the two indole
rings, such as 2,5-bis(30-indolyl)pyrazine,8 2,4-bis(30-indol-
yl)thiazole,9 2,4-bis(30-indolyl)pyrimidine,10 and 2,5-bis(30-
indolyl)thiophene,11 demonstrate strong inhibitory effects
against a variety of tumor cell lines, including leukemia,
Although these classes of alkaloids are interesting from
both the structural and biological points of view, only very
small amounts of the biologically active substances have
been isolated from the natural materials. And the methods
for the synthesis of these important compounds often suffer
from tedious synthetic routes, long reaction time, drastic
reaction conditions, as well as narrow scope of substrates.
H
N
O
N
N
N
H
N
Br
R
N
N
R
Br
N
H
H
H
H
Hamacanthin B
3,5-bis((6'-bromo-3 -indolyl)pyrazinone
Nortopsentins A-C
2,4-bis(3 -indolyl)imidazole
R'
N
N
S
N
N
N
N
R
R
R
R
H
H
H
H
2,5-bis(3 -indolyl)thiophenes
2,4-bis(3-indolyl)pyrimidines
*
Corresponding author. Fax: +86 512 65880307.
Fig. 1. Representatives of bisindole heterocyclic compounds.
E-mail address: chemjsj@suda.edu.cn (S.-J. Ji).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.01.054

1778
S.-L. Zhu et al. / Tetrahedron Letters 49 (2008) 1777–1781
Table 1
In addition, to the best of our knowledge, there have been
few reports about the synthesis of bisindole derivatives
incorporated pyridine moieties.
Solvent optimization for the synthesis of 3a under MWa
Entry
Solvent
Time (min)
Yieldb (%)
1
2
3
4
5
6
7
8
a
EtOHc
HOAc
DMF
Glycol
HOAc/glycol(1:1)
HOAc/glycol(1:2)
HOAc/glycol(1:3)
HOAc/glycol(2:1)
20
18
18
18
16
15
15
16
Trace
67
50
65
73
78
70
71
Recently, multicomponent reactions (MCRs) are of
increasing importance in organic and medicinal chemis-
try.12 The strategies of MCRs offer significant advantages
over conventional linear-type syntheses for their high
degree of atom economy, convergence, ease of execution,
and broad applications characters. MCRs are particularly
useful to generate diverse chemical libraries of ‘druglike’
molecules for biological screening.13
In our previous researches, we had synthesized a series
of bis(indolyl)methanes (BIAs), which have shown some
potential biological activities under different conditions.14
As our continuous interest in the synthesis of indole deriv-
atives,15 guided by the observation that the presence of two
or more different heterocyclic moieties in a single molecule
often remarkably enhances the biocidal profile, we investi-
gated a simple and efficient protocol for the synthesis of a
series of bisindoles derivatives containing 3,5-dicyanopyr-
idine units, which have also attracted great interest in
medicinal and optical fields.16
The reaction was carried out under MW at 100 °C and 200 W.
Isolated yields.
The temperature was set at 80 °C.
b
c
conditions. All the reactions were carried out at a power
of 200 W. The results are summarized in Table 1.
As shown in Table 1, the reaction in the mixed HOAc/
glycol (the preferred volume ratio: 1:2) gave the best result
(Table 1, entry 6).
We also carried out the reaction at different tempera-
tures ranging from 100 to 160 °C, as well as different
MW powers from 100 to 300 W, respectively. The yield
of product 3a was increased and the reaction time was
shortened when the temperature and power were increased.
Microwave irradiation at 140 °C and 250 W gave the highest
yield.
Under these optimized conditions (140 °C, 250 W, and
HOAc/glycol (V/V: 1:2) as solvent), a series of 4-aryl-3,5-
dicyano-2,6-di(1H-indol-3-yl)-pyridine derivatives 3 were
synthesized (Scheme 3). The results are summarized in
Table 2.
To examine the efficiency of this new multicomponent
reaction, a series of different aldehydes and indoles were
employed. As shown in Table 2, this protocol can be
applied not only to aromatic aldehydes with either elec-
tron-withdrawing groups (such as nitro or halide groups)
or electron-donating groups (such as hydroxyl or alkoxyl
group), but also to heterocyclic aldehydes. Furthermore,
a series of different substituted 3-cyanoacetyl indoles were
used in this reaction, all of which gave excellent results.
However, when aliphatic aldehydes were used in the reac-
tions, we failed to get the expected products.
2. Results and discussion
Compounds such as 3-cyanoacetyl indoles 1 were previ-
ously prepared by Kreher and Wagner17 and recently by
Bergman18 via a new facile approach starting from indoles
and cyanoacetic acid (Scheme 1).
The target compounds 4-aryl-3,5-dicyano-2,6-di(1H-
indol-3-yl)-pyridine were synthesized by one-pot reactions
of aldehydes, 3-cyanoacetyl indoles, and ammonium acetate
under microwave irradiation conditions (Scheme 2).
Choosing an appropriate solvent is of crucial impor-
tance for the successful microwave-assisted synthesis. In
our initial studies, different organic solvents, such as ethanol,
glycol, acetic acid, DMF, and mixed HOAc/glycol
were tested in the synthesis of 3a under MW irradiation
O
CN
cyanoactic acid, Ac2O
60 - 70 oC, 5 min
N
N
H
In addition, the same temperature was applied to the
synthesis of 3f in HOAc/glycol under classical heating con-
ditions. After refluxing for 12 h, the desired product 3f was
obtained in 47% yield, accompanied by the non-aromatized
R
R
H
1
Scheme 1.
Cl
O
Cl
CN
NH4OAc
MW
2
NC
CN
+
N
H
N
CHO
N
N
H
H
1
2a
3a
Scheme 2.

S.-L. Zhu et al. / Tetrahedron Letters 49 (2008) 1777–1781
1779
Ar
O
CN
NC
CN
NH4 OAc
2
N
ArCHO
+
N
H
HOAc/glycol(1:2)
MW, 140 o
R
N
N
R
C
R
H
H
2
1
3
Scheme 3.
Table 2
Synthesis of 3 under microwave irradiation at 140 °C and 250 W
cyclization, and elimination. First, the condensations
between 3-cyanoacetyl indoles 1 with aldehydes 2, and 3-
cyanoacetyl indoles 1 with ammonium acetate could form
intermediates 5 and 6, respectively. Michael addition
between 5 and 6 could give intermediate 7, which could
isomerize to intermediate 8. Intramolecular condensation
of 8 could afford the compound 4, which could be oxidized
to afford the fully aromatized product 3 (Scheme 5). This
type of de-hydrogenation is well precedented.19
Entry Product Ar
R
Time Yielda Mp
(min) (%)
(°C)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
a
3a
3b
3c
3d
3e
3f
4-ClC6H4
C6H5
2-ClC6H4
3-BrC6H4
4-CH3C6H4
4-CH3OC6H4
3-NO2C6H4
4-NO2C6H4
4-OHC6H4
3,4-OCH2OC6H3
4-OH–3-OCH3C6H3
2-Thienyl
H
H
H
H
H
H
H
H
H
H
H
H
12
14
15
12
15
13
15
15
12
15
13
16
15
85
81
83
86
76
80
78
82
83
77
79
71
80
78
75
86
>300
>300
>300
>300
>300
>300
299–300
>300
>300
3g
3h
3i
In this study, all the products were characterized by
melting point, IR, NMR, and HRMS spectral data.20
3j
>300
3k
3l
285–287
247–248
>300
>300
>300
O
CN
R
O
+
3m
3n
3o
3p
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
2-Ph
N
H
CN
4-CH3 15
5-CH3 15
7-CH3 15
N
H
R
CHO
2
1
5
H
NH
>300
O
CN
CN
NH4OAc
Isolated yields.
N
N
H
H
1
6
compound
4-(4-chlorophenyl)-3,5-dicyano-1,4-dihydro-
R
R
O
2,6-di(1H-indol-3-yl)pyridine (4, yield: 34%). However,
under microwave irradiation condition, the yield of 3f
was up to 80% (Table 2, entry 6), and only trace amount
of 4 was detected (Scheme 4). Therefore, microwave irradi-
ation exhibited several advantages over the conventional
heating by significantly reducing the reaction times and
improving the reaction yields, as well as the purity of prod-
ucts, owing to a specific non-thermal microwave effect.
Although the detailed mechanism of the above reaction
remains to be fully clarified, the formation of 2,6-di(indol-
3-yl)pyridine derivatives could be explained by a possible
reaction procedure presented in Scheme 5. Compounds 3
may be synthesized via sequential condensation, addition,
NC
CN
NC
CN
NH HO
NH2
N
N
N
N
H
H
H
H
8
7
R
R
-H2O
NC
CN
-2H
NC
CN
N
N
H
N
H
N
N
N
H
H
H
4
3
Scheme 5.
OCH3
OCH3
O
OCH3
CHO
CN
NH4OAc
NC
CN
NC
CN
2
HOAc/glycol(1:2)
+
+
N
H
140 o
C
N
H
N
N
N
N
N
H
H
H
H
3f
4
47%
34%
oil bath:
MW:
trace (not isolated)
80%
Scheme 4.

1780
S.-L. Zhu et al. / Tetrahedron Letters 49 (2008) 1777–1781
Science Foundation of China (Nos. 20472062, 20672079),
Nature Science Key Basic Research of Jiangsu Province
for Higher Education (Nos. 06KJA15007, 05KJB150116),
Jiangsu Provincial Key Laboratory of Fine Petrochemical
Technology (KF0402), and a Research Grant from the Inno-
vation Project for Graduate Student of Jiangsu Province.
References and notes
1. Houlihan, W. J.; Remers, W. A.; Brown, R. K. Indoles: Part I; Wiley:
New York, NY, 1992.
2. Sundberg, R. J. The Chemistry of Indoles; Academic Press: New York,
1996.
3. (a) Casapullo, A.; Bifulco, G.; Bruno, I.; Riccio, R. J. Nat. Prod.
2000, 63, 447; (b) Bao, B.; Sun, Q.; Yao, X.; Hong, J.; Lee, C. O.; Sim,
C. J.; Im, K. S.; Jung, J. H. J. Nat. Prod. 2005, 68, 711.
4. Skibo, E. B.; Xing, C.; Dorr, R. T. J. Med. Chem. 2001, 44, 3545.
5. (a) Gupta, L.; Talwar, A.; Palne, N. S.; Gupta, S.; Chauhan, P. M. S.
Bioorg. Med. Chem. Lett. 2007, 17, 4075; (b) Kaniwa, K.; Arai, M. A.;
Li, X.; Ishibashi, M. Bioorg. Med. Chem. Lett. 2007, 17, 4254.
6. (a) Sakemi, S.; Sun, H. H. J. Org. Chem. 1991, 56, 4304; (b)
Kawasaki, I.; Yamashita, M.; Ohta, S. Chem. Pharm. Bull. 1996, 44,
1831.
Fig. 2. The crystal structure of 3f.
7. (a) Kouko, T.; Matsumura, K.; Kawasaki, T. Tetrahedron 2005, 61,
2309; (b) Higuchi, K.; Takei, R.; Kouko, T.; Kawasaki, T. Synthesis
2007, 669.
8. Jiang, B.; Xiong, X.; Yang, C. Bioorg. Med. Chem. Lett. 2001, 11,
475.
9. (a) Jiang, B.; Gu, X. Bioorg. Med. Chem. Lett. 2000, 10, 363; (b) Gu,
X.; Wan, X.; Jiang, B. Bioorg. Med. Chem. Lett. 1999, 9, 569.
10. (a) Jiang, B.; Xiong, X.; Yang, C. Bioorg. Med. Chem. 2001, 9, 1149;
(b) Xiong, W.; Yang, C.; Jiang, B. Bioorg. Med. Chem. 2001, 9,
1773.
11. Diana, P.; Carbone, A.; Barraja, P.; Montalbano, L.; Martorana, A.;
Dattolo, G.; Gia, O.; Via, D. L.; Cirrincione, G. Bioorg. Med. Chem.
Lett. 2007, 17, 2342.
12. (a) Tietze, L. F. Chem. Rev. 1996, 96, 115; (b) Do¨mling, A.; Ugi, I.
Angew. Chem., Int. Ed. 2000, 39, 3169.
Fig. 3. The crystal structure of 4.
13. (a) Weber, L. Drug Discovery Today 2002, 7, 143; (b) Do¨mling, A.
Curr. Opin. Chem. Biol. 2002, 6, 306.
Furthermore, the structures of 3f and 4 were confirmed by
X-ray crystallographic analysis (Figs. 2 and 3).21
14. (a) Ji, S.-J.; Wang, S.-Y.; Zhang, Y.; Loh, T.-P. Tetrahedron 2004, 60,
2051; (b) Gu, D.-G.; Ji, S.-J.; Jiang, Z.-Q.; Zhou, M.-F.; Loh, T.-P.
Synlett 2005, 959; (c) Wang, S.-Y.; Ji, S.-J. Tetrahedron 2006, 62,
1527; (d) Zeng, X.-F.; Ji, S.-J. Lett. Org. Chem. 2006, 3, 374.
15. (a) Wang, S.-Y.; Ji, S.-J. Synlett 2007, 2222; (b) Zhu, S.-L.; Ji, S.-J.;
Zhang, Y. Tetrahedron 2007, 63, 9365.
3. Conclusion
In summary, we have demonstrated a simple and effi-
cient approach to bis(30-indolyl)pyridine derivatives by
multicomponent reactions of aldehydes, 3-cyanoacetyl
indoles, and ammonium acetate under microwave irradia-
tion conditions. This method incorporates both bisindole
and 3,5-dicyanopyridine moieties into a single molecule.
In view of those molecules having either functionality,
these novel compounds may potentially have enhanced
biological activity and optical property. Further work is
in progress in our laboratories.
16. Labaudiniere, R.; Dereu, N.; Cavy, F.; Guillet, M. C.; Marquis, O.;
Terlain, B. J. Med. Chem. 1992, 35, 4315.
17. Kreher, R.; Wagner, P. H. Chem. Ber. 1980, 113, 3675.
18. Slatt, J.; Romero, I.; Bergman, J. Synthesis 2004, 2760.
19. (a) Devi, I.; Kumarb, B. S. D.; Bhuyan, P. J. Tetrahedron Lett. 2003,
44, 8307; (b) Evdokimov, N. M.; Magedov, I. V.; Kireev, A. S.;
Kornienko, A. Org. Lett. 2006, 8, 899.
20. Typical experimental procedure: Preparation of compound 3a by
microwave irradiation.The reaction was performed in a monomodal
EmrysTM Creator from Personal Chemistry, Uppsala, Sweden. In a
10 mL EmrysTM reaction vial, 3-cyanoacetyl indole (2 mmol), 4-
chlorobenzaldehyde (1 mmol), ammonium acetate (5 mmol), and
acetic acid (0.5 mL), glycol (1.0 mL) were mixed and then capped.
The mixture was irradiated for the given time at a power of 250 W
and 140 °C. Upon completion, monitored by TLC, the reaction
mixture was allowed to cool to room temperature and then poured
into cold water (100 mL). The solid product was filtered and washed
with EtOH (95%). The product was purified by recrystallization from
EtOH–DMF (1:1) to afford (3a): 4-(4-chlorophenyl)-2,6-di(1H-indol-
3-yl)pyridine-3,5-dicarbonitrile: Yellow solid; mp: >300 °C; IR (KBr):
Acknowledgments
This work was partially supported by the Key Laboratory
of Organic Synthesis of Jiangsu Province at Suzhou Univer-
sity (No. S8109108), the Natural Science Foundation
of Jiangsu Province (No. BK2006048), and the National

S.-L. Zhu et al. / Tetrahedron Letters 49 (2008) 1777–1781
1781
m 3303, 3063, 2971, 2199, 1613, 1481, 1304, 1234, 1041, 740 cmꢀ1; H
NMR (400 MHz, DMSO-d6): d 12.16 (br s, 2H, NH), 8.52 (s, 2H,
Indolyl-H), 8.37 (d, J = 8.0 Hz, 2H, Indolyl-H), 7.83 (d, J = 8.0 Hz,
2H, Ar-H), 7.75 (d, J = 8.0 Hz, 2H, Ar-H), 7.58 (d, J = 8.0 Hz, 2H,
Indolyl-H), 7.26 (t, J = 7.6 Hz, 2H, Indolyl-H), 7.08 (t, J = 7.6 Hz,
2H, Indolyl-H); 13C NMR (75 MHz, DMF-d7): d 159.2, 158.7, 137.5,
132.3, 132.2, 131.2, 126.6, 123.3, 122.9, 121.4, 118.3, 116.3, 116.0,
113.6, 112.6, 100.3; HRMS [Found: m/z 469.1080 (M+), calcd for
C29H16N5Cl: M, 469.1094].
Preparation of compound 4 by conventional heating.A mixture
containing 3-cyanoacetyl indole (2 mmol), anisaldehyde (1 mmol),
ammonium acetate (5 mmol), and acetic acid (0.5 mL), glycol (1.0 mL)
was introduced into a 25 mL reaction vial and stirred at 140 °C (oil
bath temperature) for the given time. When the reaction was complete
(TLC), the reaction mixture was allowed to cool to room temperature.
The solid was filtered and washed with water and EtOH (95%). The
product was purified by column chromatography (silica gel, 200–
300 mesh, PE–acetone, 4:1) to give compounds 3f and 4.
1
4-(4-Methoxyphenyl)-1,4-dihydro-2,6-di(1H-indol-3-yl)pyridine-3,5-
dicarbonitrile (4): Light yellow solid; mp: >300 °C; IR (KBr): m 3310,
3249, 3056, 2932, 2215, 1606, 1512, 1435, 1258, 1034, 741 cmꢀ1 1H
;
NMR (400 MHz, DMSO-d6): d 11.80 (br s, 2H, NH), 9.82 (br s, 1H,
NH), 7.94 (s, 2H, Indolyl-H), 7.55–7.58 (m, 6H, ArH + Indolyl-H),
7.48 (d, J = 8.0 Hz, 2H, Ar-H), 7.18 (d, J = 8.4 Hz, 2H, Indolyl-H),
7.16 (d, J = 8.4 Hz, 2H, Indolyl-H), 4.55 (s, 1H, CH), 3.81 (s, 3H,
OCH3); 13C NMR (75 MHz, DMSO-d6): d 162.2, 158.7, 143.6, 137.3,
135.9, 129.9, 128.2, 124.9, 121.9, 120.7, 119.9, 114.3, 112.1, 107.4, 81.5,
55.1, 41.9; HRMS [found: m/z 467.1754 (M+), calcd for C30H21N5O:
M, 467.1746].
21. Crystallographic data for the structures of 3f and 4 reported in this
paper have been deposited at the Cambridge Crystallographic Data
Centre with No. CCDC 632750 and 632751, respectively.