Efficient synthesis of pyrazolopyridines containing a chromane backbone through domino reaction

Article abstract of DOI:10.3762/bjoc.15.85

An efficient approach for the synthesis of pyrazolopyridines containing the aminochromane motif through a base-catalyzed cyclization reaction is reported. The synthesis was carried out through a three-component reaction of (arylhydrazono)methyl-4H-chromen-4-one, malononitrile, primary amines in the presence of Et₃N at room temperature. However, carrying out the reaction under the same conditions without base led to a fused chromanyl-cyanopyridine. High selectivity, high atom economy, and good to high yields in addition to mild reaction conditions are the advantages of this approach.

Full text of DOI:10.3762/bjoc.15.85

Efficient synthesis of pyrazolopyridines containing a
chromane backbone through domino reaction
Razieh Navari1, Saeed Balalaie*1,2, Saber Mehrparvar1, Fatemeh Darvish1,
Frank Rominger3, Fatima Hamdan1 and Sattar Mirzaie1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2019, 15, 874–880.
1Peptide Chemistry Research Center, K. N. Toosi University of
Technology, P. O. Box 15875-4416, Tehran, Iran, Tel:
+98-21-23064226, Fax: +98-21-22889403, 2Medical Biology
Research Center, Kermanshah University of Medical Sciences,
Kermanshah, Iran and 3Organisch-Chemisches Institut der
Universitaet Heidelberg, Im Neuenheimer Feld 270, D-69120
Heidelberg, Germany
doi:10.3762/bjoc.15.85
Received: 07 February 2019
Accepted: 29 March 2019
Published: 11 April 2019
Associate Editor: T. J. J. Müller
Email:
© 2019 Navari et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Saeed Balalaie* - balalaie@kntu.ac.ir
* Corresponding author
Keywords:
chromane; domino reaction; fused heterocyclic skeletons;
pyrazolopyridines
Abstract
An efficient approach for the synthesis of pyrazolopyridines containing the aminochromane motif through a base-catalyzed cycliza-
tion reaction is reported. The synthesis was carried out through a three-component reaction of (arylhydrazono)methyl-4H-chromen-
4-one, malononitrile, primary amines in the presence of Et3N at room temperature. However, carrying out the reaction under the
same conditions without base led to a fused chromanyl-cyanopyridine. High selectivity, high atom economy, and good to high
yields in addition to mild reaction conditions are the advantages of this approach.
Introduction
The synthesis of new fused heterocyclic backbones has always Chromone derivatives have been found to exhibit a broad range
been a major challenge in the field of organic synthesis [1-3]. of biological activities [11-13]. 3-Formylchromone was used as
Multicomponent reactions (MCRs) and domino reactions are a suitable starting material for the construction of various
known as efficient synthetic approaches for the synthesis of heterocyclic skeletons [14-17].
complex molecules [4-6]. Domino reactions have been defined
by Tietze and were applied for the synthesis of complicated Pyrazolopyridines are a promising class of heterocyclic com-
scaffolds [7-9]. The selection of a suitable starting material and pounds which inhibits cyclin-dependent protein kinase-2 (cdk-
designing a post-transformational reaction is a key point for the 2), cyclin-dependent protein kinase-5 (cdk-5), and phos-
synthesis of complex molecules through the designing of phatidylinositol 3-kinase (PI3-K) [18-21]. Thus, these com-
domino reactions [10].
pounds have a high potential for the treatment of several neuro-
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Beilstein J. Org. Chem. 2019, 15, 874–880.
logical diseases. Some examples of pyrazolopyridine deriva- challenge in organic synthesis. In continuation of our research
tives are anxiolytic drugs such as tracazolate, cartazolate, and work to construct fused heterocyclic skeletons [37-40], we
etazolate [22]. Other pyrazolopyridine-containing bioactive describe the synthesis of pyrazolopyridines 4a–m containing a
compounds include a GSK-3 inhibitor [23] and BAY 41-2272, chromone moiety (Scheme 1). The synthetic approach was
[24,25] and could be used as cardiovascular therapeutic agents based on a domino reaction of (arylhydrazono)methyl-4H-
(Figure 1). Moreover, pyrazolopyridine derivatives also have chromen-4-one 1a–g, primary amines 2a–c, and malononitrile
industrial importance as fluorophores and luminophores in (3) in the presence of triethylamine in ethanol at room tempera-
organic light emitting diodes [26,27].
ture.
The synthesis of pyrazolopyridines has been reported in several Results and Discussion
different multistep manners [28-36]. However, some of the re- In the beginning, 3-formylchromone was prepared based on a
ported methods have several limitations such as long reaction known method [41]. Then, we focused our initial study on the
time, low yields, boring workup procedures, and several side preparation of the (arylhydrazono)methyl-4H-chromen-4-one
reactions with less selectivity of the process. Due to the extend- via the reaction of 3-formylchromone and phenylhydrazine
ed biological activities of pyrazolopyridines, finding a suitable [42,43]. Subjecting (arylhydrazono)methyl-4H-chromen-4-one
approach for the synthesis of these compounds is a synthetic (1a), benzylamine (2a), and malononitrile (3) in the presence of
Figure 1: Selected examples of bioactive molecules based on the pyrazolopyridine framework.
Scheme 1: Synthesis of pyrazolopyridines containing chromone 4a–m through a multicomponent reaction.
875

Beilstein J. Org. Chem. 2019, 15, 874–880.
40% triethylamine was stirred at room temperature in ethanol. carrying out the reaction in EtOH was found the best choice due
Compound 4a was precipitated and filtered. After confirmation to the better yield (65%). Based on this data, the optimized
of the structure, we tried to find a suitable base and solvent for reaction conditions were achieved using 40% of Et3N in ethanol
the model reaction. The results are summarized in Table 1.
at room temperature. The use of a protic solvent seems to be
essential for the progress of the reaction and may related to the
dipole moment and also the hydrogen-bonding ability of protic
solvents.
Table 1: Optimization of solvent and base for the synthesis of 4a as a
model reaction.
Entry
Base
Solvent
Yielda (%)
The spectroscopic data confirmed the formation of 4a. The
X-ray crystallographic data of compound 4a confirmed the
structure of the product (Figure 2). Meanwhile, via hydrogen
bridges and the solvent molecules (water and ethanol) the mole-
cules build pairs with π–π stacking of the aromatic systems.
1
2
3
4
5
6
Et3N 40%
DBU 40%
DIPEA 40%
Et3N 40%
Et3N 40%
Et3N 40%
EtOH
EtOH
EtOH
DCM
65
61
60
12
35
63
MeCN
MeOH
To examine the scope and generality of our reaction, other
(arylhydrazono)methyl-4H-chromen-4-ones were synthesized
and their reaction with different primary amines and malononi-
trile were examined and compounds 4a–m were formed. The
results are summarized in Figure 3. In another experiment, the
aThe reported yields are the related amount of pure precipitate that did
not require any further purification.
The reactions were studied in the presence of 10, 20, 30% tri- model reaction of (arylhydrazono)methyl-4H-chromen-4-one
ethylamine as a base in ethanol and the yields were formed 25, (1a), phenylethylamine (2b), and malononitrile (3) were investi-
38, 58%, respectively (entries 1–3, Table 1). After changing the gated in ethanol at room temperature. The formed precipitate
ratio of triethylamine to 40%, the yield of pure product was in- was collected as the sole product and the spectroscopic data
creased to 65% in ethanol. The yield of the reaction in the pres- were investigated and showed that the product is identified as
ence of DBU and diisopropylethylamine (DIPEA) as a base the fused heterocyclic pyridinochromane 5a. This confirmed
were 61 and 60%, respectively. This means that the type of base that the final cyclization needs basic reaction conditions.
does not play an effective role in this reaction. The effect of dif-
ferent solvents (EtOH, MeOH, MeCN, and DCM) was investi- The synthesized (arylhydrazono)methyl-4H-chromen-4-ones
gated on the progress of the reaction. As shown in Table 1, 1a–g have several electron-deficient centers such as at C-2, C-4
Figure 2: ORTEP Structure of compound 4a and intermolecular hydrogen bonding; the ellipsoid probability level of each ORTEP diagram is 50%.
876

Beilstein J. Org. Chem. 2019, 15, 874–880.
Figure 3: Structures of synthesized pyrazolopyridines 4a–m. Reaction conditions: 3-formylchromone derivatives (1 mmol), primary amine (1.2 mmol),
malononitile (1.2 mmol), Et3N (40 mmol %) in 3 mL ethanol at room temperature for 8–12 h.
and C=N and are susceptible to different intramolecular and gated system in intermediate A that allows malononitrile to
intermolecular ring formations.
attack through Michael addition and produces the intermediate
B (Scheme 2). Due to the presence of acidic hydrogen in inter-
It seems that a proposed mechanism could proceed initially mediate B, it is possible to form chromonyl-malononitrile
through (arylhydrazono)methyl-4H-chromen-4-one as a suit- conjugated system C and to eliminate the phenylhydrazine.
able Michael acceptor that can react with benzylamine or any Intermediate C is a highly potent Michael acceptor that may
primary amine to produce the intermediate A. There is a conju- allow the addition of hydrazine to the nitrile group resulting in
877

Beilstein J. Org. Chem. 2019, 15, 874–880.
intermediate D that after elimination of water led to intermedi- The chemical structures of the products 5a–d are shown in
ate E and this intermediate in the presence of a base can be con- Figure 4.
verted to the 4a–m after tautomerization. The compounds 5a–d
were formed through the same procedure without the base and Usually, to activate the nitrile group for cyclization reaction, the
after air oxidation. To confirm the mechanism, the reaction was existence of Lewis acid, the addition of organolithium reagents
done under inert atmosphere and the products 5a–d were not or metal hexamethylenedisalazane is necessary. However, in
formed. The reaction mechanism is shown in Scheme 2.
this approach, the nucleophilic addition on the nitrile group and
Figure 4: Structures of synthesized compounds 5a–d.
Scheme 2: The proposed mechanism for the synthesis of pyrazolopyridines derivatives 4a–m and 5a–d.
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Beilstein J. Org. Chem. 2019, 15, 874–880.
General procedure for the synthesis of com-
the cyclization was achieved without the addition of a catalyst
[44]. This reaction possesses a highly atom economical char- pounds 5a–d
acter and requires only triethylamine (40 mol %) as a base in In a 25 mL flask containing 3 ml ethanol, 1 mmol (arylhydra-
EtOH and provides fused heterocyclic backbones with high zono)methyl-4H-chromen-4-one derivatives (1a,b), 1.2 mmol
selectivity.
amine derivatives or 4-chloroaniline (2a–c), and 1.2 mmol
malononitrile (3) were added and the mixture was stirred at
room temperature for 3–4 hours. The progress of the reaction
Conclusion
In conclusion, we have successfully established an efficient was monitored by TLC (eluent ethyl acetate/n-hexane 1:2).
route toward the synthesis of a diverse array of fused hetero- After completion of the reaction, the yellow precipitate (5a–d)
cyclic skeletons through a domino reaction. We showed an was filtered and washed with water and ethanol. Yields:
interesting behavior of the base for the cyclization reaction and 20–40%.
provided access to fused heterocycles pyrazolopyridines con-
taining chromane. The same reaction without base led to the
Supporting Information
formation of pyridochromanes 5a–d. The presented procedure
provides several advantageous features including domino reac-
Supporting Information File 1
tion character, one-pot procedure, high selectivity, mild reac-
tion conditions, the simplicity of operation, high atom-
economy, and good to high yields.
Analytical and spectroscopic data.
[https://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-15-85-S1.pdf]
Experimental
General information
Acknowledgements
Reagents and solvents were purchased from various commer-
cial sources and were used directly without any further purifica-
tion unless otherwise stated. 1H and 13C NMR spectra were re-
corded at 300 and 75 MHz, respectively. Chemical shifts were
reported in parts per million (δ) using TMS, and coupling con-
stants were expressed in Hertz. Melting points were recorded
using an electrothermal capillary melting point apparatus and
were uncorrected. HRMS spectra were recorded using high-
resolution mass spectra and were recorded on Mass-ESI-
POS(FT-ICR-Qe) spectrometer.
Saeed Balalaie thanks the Alexander von Humboldt Foundation
for the research fellowship. We thank the Iran National Science
Foundation (INSF, Grant No 97020936) for financial support.
ORCID® iDs
Fatima Hamdan - https://orcid.org/0000-0003-3463-1591
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