An efficient one-step synthesis of heterobiaryl pyrazolo[3,4-u] pyridines via indole ring opening

Article abstract of DOI:10.1021/ol902147u

A mild one-step synthetic method to access privileged heterobiaryl pyrazolo[3,4-b]pyridines from indole-3-carboxaldehyde derivatives and a variety of aminopyrazoles has been developed. This novel method constructs heterobiaryls with the wide scope of substrate generality and excellent regioselectivity via indole ring opening.

Full text of DOI:10.1021/ol902147u

ORGANIC
LETTERS
2009
Vol. 11, No. 22
5214-5217
An Efficient One-Step Synthesis of
Heterobiaryl Pyrazolo[3,4-b]pyridines via
Indole Ring Opening
Sanghee Lee† and Seung Bum Park*,†,‡
Department of Chemistry and Department of Biophysics and Chemical Biology, Seoul
National UniVersity, Seoul 151-747, Korea
sbpark@snu.ac.kr
Received September 17, 2009
ABSTRACT
A mild one-step synthetic method to access privileged heterobiaryl pyrazolo[3,4-b]pyridines from indole-3-carboxaldehyde derivatives and a
variety of aminopyrazoles has been developed. This novel method constructs heterobiaryls with the wide scope of substrate generality and
excellent regioselectivity via indole ring opening.
Biaryls and heterobiaryls have attracted significant attention
from the scientific community because of their relevance to
various biological activities. Heterobiaryls frequently can be
observed in numerous bioactive small molecules, and in
particular, heterobiaryls fused with various heterocycles, such
as pyrazole, pyridine, and pyrimidine, have been used as key
pharmacophores.1 As shown in Figure 1, a blockbuster drug,
sildenafil citrate (Viagra),2 and a potent anticancer agent,
WYE-354,3 contain heterobiaryls fused with privileged
heterocycles as core skeletons. In addition, 1H-pyrazolo[3,4-
b]pyridine is recognized as a privileged substructural motif
of drug-like molecules and potential drugs. BAY 41-2272,
which contains the heterobiaryl pyrazolopyridine substruc-
ture, stimulates soluble guanylate cyclase (sGC) via a nitric
oxide independent regulatory site and induces vasodilation.4
6-Aryl pyrazolo[3,4-b]pyridines are also reported as potent
inhibitors of glycogen synthase kinase-3 (GSK-3).5 These
examples emphasize the importance of pyrazol-fused het-
erobiaryls, as well as pyrazolopyridines, as key pharma-
cophores in bioactive small molecules.
The general synthetic method for the construction of biaryl
and heterobiaryl compounds is via cross-coupling reactions
catalyzed by transition metals. Although cross-coupling
reactions offer several advantages such as broad reaction
scope, high efficiency, and functional group compatibility,
they have been reported to have some limitations: low
efficiency with bulky substrates; environmental toxicity and
safety of transition metals; laborious screening for proper
catalysts, ligands, or additives; and high cost of transition
metal catalysts.6,7 Furthermore, the existing synthetic method
requires multistep synthetic transformations to access im-
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bowsky, K.; Feurer, A.; Gerzer, R.; Minuth, T.; Perzborn, E.; Pleiss, U.;
Schroder, H.; Schroeder, W.; Stahl, E.; Steinke, W.; Straub, A.; Schramm,
M. Nature 2001, 410, 212.
† Department of Chemistry.
‡ Department of Biophysics and Chemical Biology.
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Kim, J.; Verheijen, J.; Curran, K.; Malwitz, D. J.; Cole, D. C.; Ellingboe,
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10.1021/ol902147u CCC: $40.75
Published on Web 10/16/2009
 2009 American Chemical Society

portant heterobiaryls, such as heterobiaryl pyrazolopyridines.5
Therefore, synthetic organic chemists and medicinal chemists
have been interested in the development of a novel synthetic
pathway to access these molecular frameworks.
of indole derivatives to construct privileged heterobiaryl
pyrazolopyridines. In fact, aminopyrazoles usually serve as
N′/N-1 dinucleophiles to yield pyrazolo[1,5-a]pyrimidine, as
has been reported in many cases.12 However, in our system,
aminopyrazole selectively attacked indole derivatives as N′/
C-4 dinucleophiles to yield pyrazolo[3,4-b]pyridines with
excellent regioselectivity, confirmed by X-ray crystallography
(see Scheme 1). Moreover, we could readily access hetero-
biaryl pyrazolopyridines without the involvement of toxic
transition metal catalysts or additives. Most importantly, our
synthetic method allows the construction of sterically
demanding 2,6-disubstituted biaryl pyrazolopyridines, which
are difficult to obtain by transition-metal-catalyzed cross-
coupling reactions.
Scheme 1. Synthetic Scheme of Heterobiaryl Pyrazolopyridines
and Their X-ray Crystal Structures (3a and 3c)
Figure 1. (a) Sildenafil, a potent and selective inhibitor of cGMP
phosphodiesterase type 5 (PDE5), for the treatment of erectile
dysfunction and pulmonary arterial hypertension (PAH). (b) WYE-
354, ATP-competitive and selective inhibitors of the mammalian
target of rapamycin (mTOR). (c) BAY 41-2272, stimulator of
soluble guanylate cyclase (sGC). (d) Nonnucleoside glycogen
synthase kinase-3 (GSK-3) inhibitor.
Here, we report a new synthetic method to access
heterobiaryl pyrazolopyridines via an efficient one-step
cyclization of aminopyrazoles with indole derivatives, as a
part of our continuing efforts on the development of
complexity-generating reactions (see Scheme 1).8 An indole
moiety is generally considered as a nucleophile in organic
chemistry.9 However, we induced indole to act as a dielec-
trophile by introducing an aldehyde moiety at the C-3
position and reacting it with dinucleophiles such as ami-
nopyrazoles and hydrazines. The formation of imines fol-
lowed by a second nucleophilic attack at the C-2 position of
indoles leads to the formation of heterobiaryl pyrazolo[3,4-
b]pyridines via indole ring opening. A similar indole ring
opening approach was used by the Colotta group to construct
2-arylpyrazolo[3,4-c]quinoline derivatives using 3-ethox-
alylindoles with hydrazines.10 The Kolotaev group also
observed that 2-substituted 3-acetylindoles can undergo
indole ring opening by the treatment of hydrazine as an
undesired side reaction.11 In this study, we utilized ami-
nopyrazoles as dinucleophiles for the one-step cyclization
After we identified that one-step cyclization of indole-3-
carboxaldehyde 1a with 3-amino-5-phenylpyrazole 2a yields
heterobiaryl pyrazolo[3,4-b]pyridine 3a via the indole ring
opening, we attempted to optimize this transformation (see
Table 1). First, we confirmed whether an acid catalyst could
significantly enhance formation of the imine and was
essential for this transformation (entry 1). Although various
Brønsted-Lowry acids and Lewis acids can catalyze the
formation of 3a in moderate yield, AlCl3 provides 3a in better
yield with cleaner reaction patterns (entries 2-10). By
screening various solvents and quantities of the acid catalyst,
we noted that polar protic solvents such as MeOH or EtOH
were the better solvent systems, and 10 mol % AlCl3 in
MeOH was sufficient for achieving this transformation
(entries 7, 11-17). When the reaction was conducted at room
temperature, complete conversion of the starting materials
was not achieved even after 24 h (entry 18).
(8) (a) Ko, S. K.; Jang, H. J.; Kim, E.; Park, S. B. Chem. Commun.
2006, 28, 2962. (b) Lee, S. C.; Park, S. B. J. Comb. Chem. 2006, 8, 50. (c)
Lee, S. C.; Park, S. B. Chem. Commun. 2007, 3714. (d) Kim, Y.; Kim, J.;
Park, S. B. Org. Lett. 2009, 11, 17. (e) Park, S. O.; Kim, J.; Koh, M.; Park,
S. B. J. Comb. Chem. 2009, 11, 315.
After the reaction optimization, we investigated the
reaction scope using 5-substituted aminopyrazoles (see Table
2). We successfully synthesized a series of desired products
with aryl (3a), unsubstituted (3b), alkyl (3c), and hydroxy
substituents (3d) in moderate to good yield. Aminopyrazoles
(9) (a) Bergman, J.; Venemalm, L. J. Org. Chem. 1992, 57, 2495. (b)
Lakhdar, S.; Westermaier, M.; Terrier, F.; Goumont, R.; Boubaker, T.; Ofial,
A. R.; Mayr, H. J. Org. Chem. 2006, 71, 9088. (c) Tsuchimoto, T.;
Matsubayashi, H.; Kaneko, M.; Nagase, Y.; Miyamura, T.; Shirakawa, E.
J. Am. Chem. Soc. 2008, 130, 15823.
(10) Colotta, V.; Catarzi, D.; Varano, F.; Capelli, F.; Lenzi, O.;
Filacchioni, G.; Martini, C.; Trincavelli, L.; Ciampi, O.; Pugliese, A. M.;
Pedata, F.; Schiesaro, A.; Morizzo, E.; Moro, S. J. Med. Chem. 2007, 50,
4061.
(12) (a) Quiroga, J.; Portilla, J.; Abonia, R.; Insuasty, B.; Nogueras,
M.; Cobo, J. Tetrahedron Lett. 2008, 49, 6254. (b) Ghotekar, B. K.; Jachak,
M. N.; Toche, R. B. J. Heterocycl. Chem. 2009, 46, 708.
(11) Kolotaev, A. V.; Belen’kii, L. I.; Kononikhin, A. S.; Krayushkin,
M. M. Russ. Chem. Bull., Int. Ed. 2006, 55, 892.
Org. Lett., Vol. 11, No. 22, 2009
5215

Next, we validated the generality and efficiency of our
synthetic methodology using a wide range of indole-3-
carboxaldehyde derivatives, 4a-4q. Most of the indole-3-
carboxaldehyde derivatives were commercially available or
couldbeeasilypreparedfromindolesviatheVilsmeier-Haack
reaction. As shown in Table 3, indole-3-carboxaldehyde
derivatives were transformed to the corresponding hetero-
biaryl pyrazolopyridines (5a-5n) in reasonable to good yield.
It is worth mentioning that our one-step indole cyclization
could successfully yield 2,6-substituted heterobiaryl com-
pounds (5a-5f), especially sterically congested 5f with six
consecutive quaternary carbons, which would be difficult to
achieve by cross-coupling reactions because of the steric
hindrance.13
Table 1. Reaction Optimization for the Synthesis of
Heterobiaryl Pyrazolo[3,4-b]pyridinesa
entry
acid
solvent
conditions
yield (%)b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
AcOH
EtOH
ACN
THF
toluene
DCE
DMF
MeOH
MeOH
7
46
60
58
30
19
74
0
AcOH
formic acid
TFA
HCl
HCl
5:95 v/v
5:95 v/v
5:95 v/v
5:95 v/v
10 mol %
10 mol %
10 mol %
10 mol %
AlCl3
AgOAc
Cu(OAc)2
AcOH
AlCl3
AlCl3
AlCl3
AlCl3
AlCl3
AlCl3
AlCl3
Table 3. Synthesis of Heterobiaryl Pyrazolopyridines Using
Indole-3-carboxaldehyde Derivatives 4a-4qa
0
41
63
17
21
29
60
44
51
22c
10 mol %
10 mol %
10 mol %
10 mol %
10 mol %
10 mol %
30 mol %
10 mol %
AlCl3
a All reactions employed indole-3-carboxadehyde 1a (0.1 mmol) and
1.0 equiv of aminopyrazole 2a in each solvent (50 mM) at 70 °C for 4 h.
b Yield was determined by HPLC analysis using anthracene as an internal
standard. c Reaction was performed at rt for 24 h.
with an electron-donating group (EDG) (2e) demonstrated
slightly better yields than those with an electron-withdrawing
group (EWG) (2f), because an EDG on pyrazole can increase
the nucleophilicity of pyrazole at the C-4 position. The
generality of this synthetic method was adequate to utilize
heterocycle-substituted aminopyrazoles with furyl and thienyl
groups (3g, 3h).
Table 2. Synthesis of Heterobiaryl Pyrazolopyridines with
Various Aminopyrazole Derivativesa
product
R1
yield(%)b
3a
3b
3c
3d
3e
3f
phenyl
H
methyl
58
71
79
62
78
69
72
65
a For detailed experimental procedures, see Supporting Information.
b Isolated yields.
hydroxy
4-methoxyphenyl
4-fluorophenyl
2-furyl
3g
3h
The electronic characters of the substituents on indole-3-
carboxaldehydes contribute to this transformation: EWGs on
2-thienyl
a For the reaction condition and a detailed experimental operation, see
Supporting Information. b Isolated yields.
(13) Wallace, T. W. Org. Biomol. Chem. 2006, 4, 3197.
Org. Lett., Vol. 11, No. 22, 2009
5216

indole-3-carboxaldehydes enhance the efficiency of this
transformation compared to EDGs (5 g, 5i-5k), but the
positional effects of substituents were marginal with ortho
and para substitutents showing slight preferences toward the
amine moiety (5j, 5l, 5n). We also confirmed that the
N-modification of indole-3-carboxaldehydes did not hinder
the acid-catalyzed one-step cyclization via the indole ring
opening (5o-5p, S-5a).
the desired product S-3a in moderate yield. However,
modification of the C-4 position of pyrazole (S-2b) did not
lead to the formation of the product under the identical
conditions. Interestingly, we did not observe any heterobiaryl
pyrazolo[1,5-a]pyrimidine formation in the case of S-2b with
1a, even after the extending the reaction time and elevating
the temperature (see Supporting Information). These results
support the notion that N′/C-4 dinucleophilic attack of
aminopyrazole leads to the regioselectivity of this one-step
cyclization. However, it is still unclear whether this one-
step cyclization achieves this regioselectivity via N′/C-4
dinucleophilic addition of aminopyrozole or via the pericyclic
rearrangement.
Scheme 2. Postulated Mechanism
The resulting collection of heterobiaryl pyrazolo[3,4-
b]pyridines was evaluated for their potential anticancer
activity against various human cancer cell lines [lung
carcinoma cell (A549) and cervical cancer cell (HeLa)] and
normal cell lines [human embryonic kidney cell (293T) and
muscle myoblast cell (C2C12)] (Table 2 in Supporting
Information). The in Vitro cell viability assay revealed that
some compounds have cancer-cell specific inhibitory activity.
Compound 5s exhibited an excellent cancer-cell selectivity
over normal cells as measured by mean % inhibition of cell
proliferation at 10 µM (90% in A549, 81% in HeLa, 1% in
293T, 12% in C2C12). Compound 5r also showed ap-
preciable antiproliferative activities (IC50) at 3.2 and 4.2 µM
in HeLa and A549 cell lines (see Supporting Information).
In Scheme 2, we postulate a mechanism for this one-step
cyclization of indole-3-carboxaldehyde 1 with 5-aminopy-
razole 2 to yield heterobiaryl pyrazolo[3,4-b]pyridine 3. The
first step is formation of the imine, as confirmed by TLC
analysis, followed by intramolecular cyclization either via a
pericyclic rearrangement of intermediate I or via C-4
nucleophilic addition of pyrazole to iminium electrophile (II)
to generate a tetracyclic adduct (III). Finally, the resulting
cyclic intermediate (IV) undergoes rearomatization, which
leads to the opening of the indole ring, thereby yielding the
desired heterobiaryl pyrazolo[3,4-b]pyridine 3. Thus far,
much previous literature has suggested that aminopyrazole
serves as an N′/N-1 dinucleophile to yield pyrazolo[1,5-
a]pyrimidine.12 However, we did not observe the formation
of pyrazolo[1,5-a]pyrimidines in our representative tested
cases, which was confirmed by LC/MS using regioisomers
of different masses (see Supporting Information). Therefore,
we conclude that aminopyrazoles only serve as N′/C-4
dinucleophiles in this transformation to yield heterobiaryl
pyrazolo[3,4-b]pyridines, which is supported by previous
reports.14 The regioisomer of heterobiaryl pyrazolo[3,4-
b]pyridines was confirmed by X-ray crystallography (see
Scheme 1) and 1H nuclear Overhauser enhancement (NOE)
NMR spectra (see Supporting Information). To confirm our
conclusion, we tried the one-step cyclization of indole-3-
carboxaldehyde 1a either with 5-amino-3-methyl-1-phenyl-
pyrazole S-2a or with 4-(4-fluorophenyl)-1H-pyrazol-5-amine
S-2b to block N-1 nucleophilic attack or C-4 nucleophilic
attack of pyrazoles, respectively. In fact, the modification
on the N-1 position of pyrazole (S-2a) did not affect the
one-step cyclization and C-4 nucleophilic addition producing
In conclusion, we have developed a new one-step cycliza-
tion method for the synthesis of privileged heterobiaryl
pyrazolo[3,4-b]pyridines from indole-3-carboxaldehyde de-
rivatives and 5-aminopyrazoles. This transformation can
efficiently generate heterobiaryl moieties without the limita-
tions associated with the steric hindrance of substrates and
we successfully demonstrated the wide scope of substrate
generality, which is compatible with various functional
groups, heteroaryl, and 2,6-substituted aryls with bulky
substituents. We also observed excellent regioselectivity with
5-aminopyrazoles as the N′/C-4 dinucleophile to provide
heterobiaryl pyrazolo[3,4-b]pyridines in moderate to good
yield. The detailed mechanism of this regioselectivity and
biological activities are currently being studied.
Acknowledgment. This work was supported by the
National Research Foundation of Korea (NRF) and the WCU
program through the NRF funded by the Korean Ministry
of Education, Science, and Technology (MEST). We thank
Dr. Ram Sagar for his scientific input and discussion. S.L.
is grateful for the fellowship award of the BK21 Program
and Seoul Science Fellowship award.
Supporting Information Available: Experimental details,
X-ray crystal structure, 1H and 13C NMR spectra of all new
compounds, and LC/MS data for the confirmation of regi-
oselectivity. This material is available free of charge via the
Internet at http://pubs.acs.org.
(14) (a) Quiroga, J.; Portilla, J.; Serrano, H.; Abonia, R.; Insuasty, B.;
Nogueras, M.; Cobo, J. Tetrahedron Lett. 2007, 48, 1987. (b) Singh, S. P.;
Naithani, R.; Aggarwal, R.; Prakash, O. Synth. Commun. 2004, 34, 4359.
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