A mild method for the synthesis of bis-pyrazolo[3,4-b:4′,3′-e]pyridine derivatives

Article abstract of DOI:10.1016/j.tetlet.2018.09.033

A mild and efficient method for the synthesis of bispyrazolo[3,4-b:4′,3′-e]pyridines from 5-aminopyrazoles and aromatic aldehydes using an inexpensive FeCl₃ catalyst is reported. The reaction temperature was reduced from 220–250 °C to 130 °C compared to conventional methods. A large proportion of the products precipitated directly from the mixture at room temperature. Aliphatic and α,β-unsaturated aldehydes selectively resulted in formation of the corresponding 1H-pyrazolo[3,4-b]pyridine derivatives. A possible domino reaction mechanism was also proposed. Several aryl alkynyl groups were introduced to these tricyclic molecules via the Sonogashira coupling reaction.

Full text of DOI:10.1016/j.tetlet.2018.09.033

Accepted Manuscript
A mild method for the synthesis of bis-pyrazolo[3,4-b:4',3'-e]pyridine deriva-
tives
Rui Qiu, Shujia Qiao, Boyu Peng, Jiajia Long, Guodong Yin
PII:
S0040-4039(18)31123-7
https://doi.org/10.1016/j.tetlet.2018.09.033
TETL 50272
DOI:
Reference:
Tetrahedron Letters
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Revised Date:
Accepted Date:
6 August 2018
7 September 2018
12 September 2018
Please cite this article as: Qiu, R., Qiao, S., Peng, B., Long, J., Yin, G., A mild method for the synthesis of bis-
pyrazolo[3,4-b:4',3'-e]pyridine derivatives, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.
2018.09.033
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Tetrahedron Letters
A mild method for the synthesis of bis-pyrazolo[3,4-b:4',3'-e]pyridine derivatives
Rui Qiu, Shujia Qiao, Boyu Peng, Jiajia Long and Guodong Yin*
Hubei Collaborative Innovation Center for Rare Metal Chemistry, Hubei Key Laboratory of Pollutant Analysis and Reuse Technology, Hubei Normal University,
Huangshi 435002, China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A mild and efficient method for the synthesis of bispyrazolo[3,4-b:4',3'-e]pyridines from 5-
aminopyrazoles and aromatic aldehydes using an inexpensive FeCl3 catalyst is reported. The
reaction temperature was reduced from 220–250 oC to 130 oC compared to conventional
methods. A large proportion of the products precipitated directly from the mixture at room
temperature. Aliphatic and α,β-unsaturated aldehydes selectively resulted in formation of the
corresponding 1H-pyrazolo[3,4-b]pyridine derivatives. A possible domino reaction mechanism
was also proposed. Several aryl alkynyl groups were introduced to these tricyclic molecules via
the Sonogashira coupling reaction.
Available online
Keywords:
Bis-pyrazolo[3,4-b:4',3'-e]pyridine
1H-Pyrazolo[3,4-b]pyridine
Domino reaction
Strong fluorescence
Sonogashira coupling
2015 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and Discussion
Bis-pyrazolo[3,4-b:4',3'-e]pyridine (BPP) is an important
tricyclic skeleton,1 which exhibits strong fluorescence, and their
derivatives are widely employed as light-emitting materials in
electroluminescent devices.2 The most frequently-used route to
bis-pyrazolo[3,4-b:4',3'-e]pyridine derivatives is the three-
component reaction of 5-aminopyrazoles and aromatic
aldehydes. Nevertheless, the reported methods are performed at
In our preliminary study, the model reaction of 5-amino-3-
methyl-1-phenylpyrazole (1a, 1.0 mmol) and benzaldehyde (2a,
0.5 mmol) was examined in the presence of ZrCl4 (15 mol%)8 in
o
DMSO at 130 C for 24 h, and the expected strongly fluorescent
solid was isolated in 62% yield, which was identified as 3,5-
dimethyl-1,4,7-triphenyl-1,7-dihydrodipyrazolo[3,4-b:4',3'-e]
pyridine (3a) (Table 1, entry 1). After screening several Lewis
acids (I2, In(OTf)3, FeCl3) and Brønsted acids (L-proline), it was
found that FeCl3 gave the best result (Table 1, entries 2–5).
Notably, when the reaction was cooled to room temperature, a
large proportion of the yellow product precipitated directly from
the mixture. No reaction occurred in the absence of catalyst
(Table 1, entry 6). Prolonging the reaction time did not improve
the yield of 3a, but shortening the time, decreasing the
temperature or reducing the catalyst loading led to lower yields
(Table 1, entries 7–12). Only trace amounts of the product was
observed in low-boiling point solvents (Table 1, entries 13–15).
o
high temperatures (220–250 C) with low to moderate yields.3,4
Quiroga and co-workers found that the reactions could be carried
out under microwave irradiation and solvent-free conditions at
220–250 oC.5 Recently, Shi and co-workers reported that the ionic
liquid [bmim]Br could be used as a promoting medium for the
synthesis of bis-pyrazolo[3,4-b:4',3'-e]pyridines.6 In continuation
of our efforts to obtain functionalized nitrogen-containing
heterocycles,7 herein we report an efficient FeCl3-catalyzed
synthesis of 4-aryl substituted bis-pyrazolo[3,4-b:4',3'-
e]pyridines from 5-aminopyrazoles and aromatic aldehydes in
o
DMSO at 130 C. It was also found that the reactions of 5-
aminopyrazoles with aliphatic and α,β-unsaturated aldehydes
selectively gave the corresponding 1H-pyrazolo[3,4-b]pyridines.
———
*Corresponding author. Tel./fax: +86 0714 6515602; e-mail address: gdyin@hbnu.edu.cn (G.D. Yin)

2
Table 1. Optimization of the reaction conditions.a
Catalyst
Solvent
(mL)
Temp.
(oC)
130
130
130
130
130
130
130
130
110
90
130
130
80
100
110
Time
(h)
24
24
24
24
24
24
36
12
24
24
24
24
24
24
24
Yieldc 3a
(%)
62
Entry
(mol%)b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
ZrCl4 (15)
I2 (15)
L-proline (15)
In(OTf)3 (15)
FeCl3 (15)
None
FeCl3 (15)
FeCl3 (15)
FeCl3 (15)
FeCl3 (15)
FeCl3 (10)
FeCl3 (5)
FeCl3 (15)
FeCl3 (15)
FeCl3 (15)
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
EtOH
60
10
25
78
0
78
55
45
30
67
48
trace
<10
<5
n-PrOH
AcOH
aReagents and conditions: 5-amino-3-methyl-1-phenylpyrazole (1a, 1.0
b
mmol), benzaldehyde (2a, 0.5 mmol), solvent (3 mL). Calculated based on
2a. cIsolated yield.
With the optimized conditions in hand (Table 1, entry 5),
the substrate scope was examined (Table 2). Aromatic aldehydes
t
bearing electron-rich (Me, OMe, Bu, NMe2, NPh2) and electron-
deficient (F, Cl, Br, NO2) substituents on the phenyl ring gave the
expected products 3b–n in moderate to good yields. It should be
noted that triarylamine-substituted bis-pyrazolopyridines 3f and
3g could potentially be utilized as light-emitting materials in
electroluminescent devices, and are usually prepared via a two-
step palladium-catalyzed synthetic strategy.9 Using our present
method, the desired products were easily obtained from
commercial materials via
a
one-step approach. This
aReagents and conditions: 5-aminopyrazoles (1a–c, 1.0 mmol), aromatic
aldehydes (2a–t, 0.5 mmol), FeCl3 (0.075 mmol), DMSO (3 mL), 130 oC, 24
h. bIsolated yield.
transformation was also suitable for pyridine, thiophene and
naphthalene substrates, delivering the corresponding products
3o–q in 62–65% yield. To our delight, the reactions of 1,3-
diphenyl-1H-pyrazol-5-amine (2b) and 1,3-dimethyl-1H-pyrazol-
5-amine (2c) with aromatic aldehydes also furnished products
3r–t in satisfactory yields.
When a mixture of n-butyl aldehyde (4) and 1a was
heated under the optimised conditions, none of the expected
bis-pyrazolo[3,4-b:4',3'-e]pyridine was observed, and the
isomers of substituted 1H-pyrazolo[3,4-b]pyridines10 (5, 5’)
were isolated as the main products along with recovery of the
unreacted starting material 1a (Scheme 1). In addition, the
reaction of α,β-unsaturated aldehyde (6) with 1a selectively
gave 3-methyl-1,4-diphenyl-1H-pyrazolo[3,4-b]pyridine (7)
in 75% yield (Scheme 2).
Scheme 1. Synthesis of compounds 5 and 5’.
Table 2. Substrate scope.a,b
Scheme 2. Synthesis of compound 7.
In order to provide insight into the reaction mechanism, the
following control experiments were examined. When the reaction
o
of 3-bromobenzaldehyde (2k) with 1a was performed at 90 C
for 20 min, it was observed that acyclic product 8 and 3k were
generated simultaneously. To determine the exact structure of 8,

3
its solution was heated in AcOH at reflux, resulting in N,N-
diacylated product 9, which was further identified by single
crystal X-ray diffraction (Fig. 1).11 In addition, 8 could not be
converted into 3k without a catalyst. Nevertheless, in the
presence of FeCl3, 3k was obtained in 98% yield from 8 within 1
h, which indicated that the catalyst was required during the
cyclization process. Notably, 8 was also converted into 3k in
excellent yield under argon in degassed DMSO, indicating the
role of DMSO as the oxidant (Scheme 3).12
catalyzed Sonogashira coupling reaction;15 the expected
products 11 were obtained in 80–95% yield (Scheme 5).
Scheme 3. Control experiments.
Scheme 4. Proposed reaction mechanism.
Figure 1. X-ray structure of compound 9.
On the basis of the current study and previous reports,13
a
possible reaction mechanism was proposed (Scheme 4). First, in
the presence of FeCl3, the nucleophilic addition reaction of 1a
with aromatic aldehyde 2k gives intermediate A, which is
converted into intermediate B after loss of water. This
subsequently reacts with another molecule of 1a via a Michael
addition reaction to give intermediate 8. Then the cyclization of
isomer C gives intermediate D. The latter gives E after releasing
ammonia, which could be further oxidized to the target product
3k in the presence of air and DMSO.6,12 When the reaction
occurred between 1a and aliphatic aldehyde 4, intermediate F
was obtained by the nucleophilic addition reaction between the
C-4 atom of the pyrazole ring and the carbonyl group of 4 in a
similar way, to give intermediate G after loss of water, which
was subsequently condensed with another molecule of 4 to give
H.14 Finally, product 5 was formed via a domino intramolecular
cyclization and aromatization. Similarly, intermediate H could be
isomerized to J, and the latter gives product 5’.
Scheme 5. Introduction of the alkynyl group to 3j–l.
Next, the UV–vis absorption spectra of 11a–d were
measured in a 1.0×10-5 mol·L-1 CHCl3 solution (Fig. 2) and their
spectral data are summarized in Table 3. These conjugated bis-
pyrazolo[3,4-b:4’,3’-e]pyridine derivatives displayed strong
absorption bands with maxima in the range of 278–298 nm. Then,
their photoluminescence spectra were also measured in CHCl3
solution and their quantum efficiencies (Φu) determined relative
Generally, the introduction of an alkynyl group to the
conjugated fused-ring increases its fluorescence intensity.
Accordingly, arylacetylenes (10) were reacted with bromo-
substituted bis-pyrazolo[3,4-b:4',3'-e]pyridine 3j–l via the Pd/Cu

4
to quinine sulfate (Φs = 0.55). These compounds have high
fluorescence quantum yields in the range of 0.62–0.89 (Fig. 3
and Table 3). The excitation spectra of these compounds were
dominated by a broad band (λex = 267, 265, 267 and 267 nm,
respectively), which were blue-shifted relative to their absorption
spectra. The photoluminescence spectra showed that these
compounds displayed blue emission at 443–458 nm in CHCl3
solution.
conjugated bromo-substituted tricyclic molecules via the Pd/Cu
catalyzed Sonogashira coupling reaction. Their photophysical
properties were also examined.
Acknowledgments
We gratefully acknowledge support from the National Natural
Science Foundation of China (21542009).
0.6
11a
11b
11c
Supplementary data
0.5
11d
Supplementary data related to this article can be found, in the
online version at:
0.4
0.3
0.2
0.1
0.0
References and notes
1. (a) C. Allais, J. M. Grassot, J. Rodriguez, T. Constantieux. Chem.
Rev. 114 (2014) 10829–10868; (b) J. Safaei-Ghomi, R.
Sadeghzadeh, H. Shahbazi-Alavi, RSC Adv. 6 (2016) 33676–
33685.
2. (a) C. W. Ko, Y. T. Tao, Appl. Phys. Lett. 79 (2001) 4234–4236;
(b) E. Balasubramaniam, Y. T. Tao, A. Danel, P. Tomasik,
Chem. Mater. 12 (2000) 2788–2793; (c) Z. He, G. H. W.
Milburn, A. Danel, A. Puchala, P. Tomasik, D. Rasala, J. Mater.
Chem. 7 (1997) 2323–2325.
250
300
350
400
450
Wavelength (nm)
Figure 2. UV-vis spectra for compounds 11a–d in CHCl3
solution (1.0×10-5 mol·L−1).
3. E. Gondek, J. Niziol, A. Danel, B. Jarosz, P. Gasiorski, A. V.
Kityk, Spectrochim. Acta Part A 95 (2012) 610–613.
4. A. Puchala, D. Rasala, E. Kolehmanien, M. Prokesová, Org. Prep.
Proced. Int. 29 (1997) 226–230.
5. J. Quiroga, J. Portilla, B. Insuasty, R. Abonia, M. Nogueras, M.
Sortino, S. Zacchino, J. Heterocyclic Chem. 42 (2005) 61–66.
6. D.-Q. Shi, F. Yang, J. Chin. Chem. Soc. 55 (2008) 755–760.
7. (a) L. Fan, M.-L. Liu, Y. Ye, G.-D. Yin, Org. Lett. 19 (2017)
186–189; (b) M.-L. Liu, M.-M. Shu, C.-C. Yao, G.-D. Yin, D.-J.
Wang, J.-K. Huang, Org. Lett. 18 (2016) 824–827.
8. (a) M.-L. Liu, S.-Z. Qiu, Y. Ye, G.-D. Yin, Tetrahedron Lett. 57
(2016) 5856–5858; (b) M.-L. Liu, C. Zhu, C.-C. Yao, G.-D. Yin,
J. Heterocyclic Chem. 53 (2016) 1617–1625.
700
11a
11b
11c
11d
600
500
400
300
200
100
0
9. Y. T. Tao, C. H. Chuen, C. W. Ko, J. W. Peng, Chem. Mater. 14
(2002) 4256–4261.
10. (a) R. Aggarwal, S. Kumar, Beilstein J. Org. Chem. 14 (2018)
203–242; (b) A. Charris-Molina, J.-C. Castillo, M. Macías, J.
Portilla, J. Org. Chem. 82 ( 2017) 12674–12681.
350
400
450
500
550
600
Wavelength (nm)
Figure 3. Photoluminescence spectra for compounds 11a–d in
CHCl3 solution (1.0×10-5 mol·L−1)
11. X-ray data (CCDC no.1859780) can be obtained free of charge
from the Cambridge Crystallographic Data Center.
Table 3. Photophysical data of compounds 11a–d in CHCl3
solution.
12. X.-F. Wu, K. Natte, Adv. Synth. Catal. 358 (2016) 336–352.
13. (a) B. Jiang, Q. Ye, W. Fan, S.-L. Wang, S.-J. Tu, G.-G. Li,
Chem. Commun. 50 (2014) 6108–6111; (b) W. Fan, Q. Ye, H.-
W. Xu, B. Jiang, S.-L. Wang, S.-J. Tu, Org. Lett. 15 (2013)
2258–2261; (c) Q.-H. Gao, S. He, X. Wu, J.-J. Zhang, S.-P. Bai,
Y.-D. Wu, A.-X. Wu, Org. Chem. Front. 5 (2018) 765–768; (d)
λmax
(nm) (nm)
286
278
284
298
λex
λem
(nm)
458
456
443
448
Stokes shift
(cm-1)
13131
14041
12638
Compounds
log εmax
Φu
11a
11b
11c
11d
267
265
267
267
4.53
4.54
4.71
4.54
0.77
0.64
0.62
0.89
A. Esteves-Souza, A. Echevarrıa, I. Vencato, M. L. Jimeno, J.
́
11236
Elguero, Tetrahedron 57 (2001) 6147–6153.
14. X. Zhang, K. Long, J.-Y. He, J.-L. Fu, F.-R. Zhang, C.-M. Li. J.
Heterocyclic Chem. 55 (2018) 729–735.
15. (a) M.-L. Liu, M.-Y. Ye, Y.-Y. Xue, G.-D. Yin, D.-J. Wang, J.-
K. Huang, Tetrahedron Lett. 57 (2016) 3137–3139; (b) S.-Z. Qiu,
C.-Y. Zhang, R. Qiu, G.-D. Yin, J.-K. Huang, Adv. Synth. Catal.
360 (2018) 313–321.
In summary, we have developed a mild method for the
synthesis of bis-pyrazolo[3,4-b:4',3'-e]pyridines from 5-
aminopyrazoles and aromatic aldehydes. The inexpensive FeCl3
catalyst permits the reaction temperature to be decreased from
o
220–250 oC to 130 C compared with conventional methods and
this route has the advantage of wide substrate scope. In addition,
it was found that a large proportion of the products precipitated
directly from the mixtures when the reactions were cooled to
room temperature. None of the expected bispyrazolo[3,4-b:4',3'-
e] pyridines were formed using aliphatic and α,β-unsaturated
aldehydes, selectively giving the corresponding 1H-pyrazolo[3,4-
b]pyridines. A possible domino reaction mechanism was also
proposed. Finally, several alkynyl groups were introduced to the
Research highlights
 This method allows the mild route for
functionalized bispyrazolo[3,4-b:4',3'-

5
e]pyridines.
room temperature.
 The reaction temperature decreased
from 220–250 oC to 130 oC compared to
conventional methods.
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 A large proportion of the products
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A mild method for the synthesis of bis-
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pyrazolo[3,4-b:4',3'-e]pyridine derivatives
Rui Qiu, Shujia Qiao, Boyu Peng, Jiajia Long, and Guodong Yin*
Hubei Collaborative Innovation Center for Rare Metal Chemistry, Hubei Key Laboratory of Pollutant Analysis
and Reuse Technology, Hubei Normal University, Huangshi 435002, China