Synthesis of 3,6-diaryl-1: H -pyrazolo[3,4- b] pyridines via one-pot sequential Suzuki-Miyaura coupling

Article abstract of DOI:10.1039/c8ra07104g

A practical synthesis of diarylpyrazolo[3,4-b]pyridine derivatives by a combination of chemoselective Suzuki-Miyaura cross-coupling reactions was developed. The sequential arylation strategy can be performed in a one-pot manner without much loss of efficiency when compared to the corresponding stepwise synthesis. These conditions are applicable to the coupling of a wide variety of aryl and heteroaryl-boronic acids with pyrazolo[3,4-b]pyridines with high selectivity of the C3 over the C6 position, thus enabling the rapid construction of a diverse array of medicinally important diarylpyrazolo[3,4-b]pyridines.

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Synthesis of 3,6-diaryl-1H-pyrazolo[3,4-b]pyridines
via one-pot sequential Suzuki–Miyaura coupling†
Cite this: RSC Adv., 2018, 8, 34883
b
c
a
Urvashi,a Vibha Tandon,
Parthasarathi Das
*
*
and S. Kukreti
A practical synthesis of diarylpyrazolo[3,4-b]pyridine derivatives by a combination of chemoselective
Suzuki–Miyaura cross-coupling reactions was developed. The sequential arylation strategy can be
performed in a one-pot manner without much loss of efficiency when compared to the corresponding
stepwise synthesis. These conditions are applicable to the coupling of a wide variety of aryl and
heteroaryl-boronic acids with pyrazolo[3,4-b]pyridines with high selectivity of the C3 over the C6
position, thus enabling the rapid construction of a diverse array of medicinally important diarylpyrazolo
[3,4-b]pyridines.
Received 25th August 2018
Accepted 13th September 2018
DOI: 10.1039/c8ra07104g
rsc.li/rsc-advances
for the treatment of bladder cancer,8 as a Raf inhibitor to inhibit
1. Introduction
B-RafV600E
,
as metabotropic glutamate receptor 5 (mGluR5)
9
positive allosteric modulators (PAM's)10 and as a neuroprotector
in MPP+-induced neurodegeneration (Fig. 1).11
The transition-metal-catalysed cross-coupling reaction has been
well-established as a powerful synthetic tool in C–C bond
formation. In particular, the Suzuki–Miyaura cross-coupling
reaction has shown widespread applications in natural
product synthesis, the synthesis of medicinally important
pharmacophores and organic materials.1 To explore further
synthetic applications of transition-metal-catalyzed cross-
coupling reactions, organocatalytic reactions and arylation of
heteroaromatics have attracted attention in recent years.2 In the
last decade a selective arylation strategy in a sequential manner
has emerged as a valuable tool for cross-coupling technique-
s.3a–d In pursuit of this, selective and/or sequential arylation
were studied on a few pharmaceutically important heterocycles
e.g. indazoles,3e,f azaindoles,3g,h and imidazopyrazines.3i This
strategy, which explores the different reactivities of electrophilic
and nucleophilic cross-coupling partners, allows for multiple C-
aryl bond formations in a “controlled” manner to rapidly
construct functional molecules with complex structures appli-
cable to pharmaceutical and material science.4,5
A number of methods have been developed to functionalize
this fused heterocyclic system.12 Recently, Guillaumet reported
the direct heteroarylation of 2H-pyrazolo[3,4-b]pyridines using
“on water” conditions13a whereas, Popowycz has reported Pd-
catalyzed late-stage C-3 functionalization of pyrazolo[3,4-b]pyr-
idines.13b Despite many advances in the synthesis of C-arylated
pyrazolopyridines, a selective and high-yielding method from
accessible starting materials remains a goal within the synthetic
community. Herein, we report an efficient synthesis of 3,6-dia-
rylpyrazolo[3,4-b]pyridine via site selective sequential Suzuki–
Miyaura coupling (SMC).14 The salient features of this protocol
are its high chemoselectivity, easy removal of the protecting
group and tolerance towards functional groups. The designed
3,6-diarylpyrazolo[3,4-b]pyridines can be synthesized sequen-
tially in a one-pot reaction.
2. Results and discussion
Pyrazolo[3,4-b]pyridine, a privileged heterocyclic core, has
been actively pursued in medicinal research due to its wide
spectrum of biological activities; viz: glycogen synthase kinase-3
(GSK-3) inhibitors6 and A1 adenosine receptors7 (Fig. 1).
Recently, arylated pyrazolo[3,4-b]pyridine has been outlined as
a broblast growth factor inhibitor (FGF-R and FGFR3) specic
The synthesis of the 6-chloro-3-iodo-1-(4-methoxybenzyl)-1H-
pyrazolo[3,4-b]pyridine (1) core was accomplished through
cyclisation of 2-chloro-3-cyanopyridine and hydrazine followed
by in situ diazotization and iodination at the C3 position of the
ring.12a C6-chlorination was undertaken on its N-oxide product
and, lastly, removal of the N-protection.15 We commenced the
optimization of arylation by coupling 6-chloro-3-iodo-1-(4-
methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine (1) with phenyl-
boronic acid (2) using Pd(OAc)2 as a catalyst (5 mol%) and dppf
as a ligand (5 mol%) in the presence of Cs2CO3 at 60 ꢀC in THF,
giving 68% yield (Table 1, entry 1). Whereas other solvents, e.g.
acetonitrile and 1,4-dioxane, failed to provide higher yields
(Table 1, entries 2 and 3). However, in combination with 1,4-
aDepartment of Chemistry, University of Delhi, Delhi-110007, India
bSpecial Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi-
110067, India. E-mail: vtandon@mail.jnu.ac.in
cDepartment of Applied Chemistry, Indian Institute of Technology (Indian School of
Mines), Dhanbad-826004, Jharkhand, India. E-mail: partha@iitism.ac.in
† Electronic supplementary information (ESI) available: Spectroscopic data for all
compounds. CCDC 1828970 and 1817412. For ESI and crystallographic data in CIF
or other electronic format see DOI: 10.1039/c8ra07104g
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Fig. 1 Medicinal interest in arylated 1H-pyrazolo[3,4-b]pyridines.
Table 1 Optimization of reaction conditions for the C3-arylpyrazolo
[3,4-b]pyridinesa
screened but no fruitful results were obtained (Table 1, entries
6–8). Moderate yields (63–75%) were recorded with other bases;
viz: K2CO3 and Na2CO3 (Table 1, entries 9 and 10). Increasing
the water content in the reaction solvent did not lead to
a satisfactory result (Table 1, entry 11), suggesting that dioxa-
ne : water in a ratio of 3 : 1 is the best solvent combination. The
reaction yield decreased to 77% (Table 1, entry 12) using one
equivalent base and in the absence of a base the reaction did
not work (Table 1, entry 14). The reaction did not proceed at rt
(Table 1, entry 15). Thus, we identied Pd(OAc)2 (5 mol%)/dppf
(5 mol%)/Cs2CO3 (2 equiv.)/1,4-dioxane : water (3 : 1)/60 ꢀC as
the standard conditions for the coupling reaction (Table 1, entry
4). This reaction is selective for C3-arylation and in no case was
any C6-arylation product detected.
With the optimized protocol in hand, we evaluated the scope
of the substrate for coupling reactions (Scheme 1). Interestingly,
our standard conditions proved to be efficient for both electron-
rich (–Me, –OMe), and electron-decient (–Br, –F, –CF3, –NO2)
boronic acids, leading to the desired product within a range of
62–98% yield with different N-protected pyrazolo[3,4-b]pyridine
molecules (Me, PMB, THP) in 1 h. First, we examined coupling
of the 3-iodo derivative of N-Me-pyrazolo[3,4-b]pyridine with
electronically diverse boronic acids and observed a yield in the
range of 75–98% (3a–3g), except for 2,4-diuorophenylboronic
acid (3f, 46% yield). Implementation of standard reaction
conditions on 6-chloro-3-iodopyrazolopyridines led to the
desired product (3h–3k) in excellent yields and to our delight
the reaction was chemoselective. A reaction between N-PMB-
pyrazolo[3,4-b]pyridines and electron-rich boronic acids gave
good yields of 3m-3n, while 3o-3p were obtained in slightly
lower yields with electron-decient partners. The diuoro and
bis-(triuoromethyl)-containing boronic acids proved to be
Entry Catalyst
Ligand Base
Solvent
Yieldb
1
2
3
4
5
6
7
8
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2(PPh3)4 dppf
Pd(PPh3)4
PdCl2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
dppf
dppf
dppf
dppf
PPh3
Cs2CO3 THF
Cs2CO3 CH3CN
Cs2CO3 Dioxane
68
45
62
Cs2CO3 Dioxane : water (3 : 1) 93
Cs2CO3 Dioxane : water (3 : 1) 69
Cs2CO3 Dioxane : water (3 : 1) 73
Cs2CO3 Dioxane : water (3 : 1) 80
Cs2CO3 Dioxane : water (3 : 1) 78
K2CO3 Dioxane : water (3 : 1) 75
Na2CO3 Dioxane : water (3 : 1) 63
Cs2CO3 Dioxane : water (1 : 1) 82
Cs2CO3 Dioxane : water (3 : 1) 77
Cs2CO3 Dioxane : water (3 : 1) 86
dppf
dppf
dppf
dppf
dppf
dppf
dppf
dppf
dppf
9
10
11
12c
13d
14
15e
—
Dioxane : water (3 : 1) n.r.
Cs2CO3 Dioxane : water (3 : 1) n.r.
a
Reaction conditions: 6-chloro-3-iodo-1-(4-methoxybenzyl)-1H-pyrazolo
[3,4-b]pyridine (1.0 equiv.), arylboronic acid (1.0 equiv.), catalyst
(5 mol%), dppf (5 mol%), base (2.0 equiv.), 1,4-dioxane : water (3 : 1)
b
c
(5 mL), 60 ꢀC, 1 h, air. Isolated yields. 1.0 equiv. base used.
Reaction performed for 4 h. e At room temperature; n.r. ¼ no reaction.
d
dioxane : water (3 : 1), the desired product was isolated in 93%
yield. On substituting dppf with a PPh3 ligand we observed an
inferior result (Table 1, entry 5). Different Pd-catalysts were
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Scheme 1 Synthesis of C3-arylpyrazolo[3,4-b]pyridines and their derivatives.a,b aReaction conditions: 6-chloro-3-iodo-1-(4-methoxybenzyl)-
1H-pyrazolo[3,4-b]pyridine (1.0 equiv.), arylboronic acid (1.0 equiv.), catalyst (5 mol%), dppf (5 mol%), base (2.0 equiv.), 1,4 dioxane : water (3 : 1)
(5 mL), 60 ꢀC, 1 h, air; bisolated yields.
effective in giving 92% and 93% yields for 3q & 3r respectively. coupling with electron-donating 4-methoxyphenylboronic acid
High yields (89–93%, 3s–3v) were obtained in the case of 3-iodo- resulted in 81% yield (4b & 4c, Scheme 2). The formyl group
6-chloro-N-PMB-pyrazolo[3,4-b]pyridine and a similar pattern functionalized compound, 4e can be utilized for benecial
was observed with the single halogenated N-THP-pyrazolo[3,4-b] organic transformations. The reaction of electron-withdrawing
pyridines (3w–3ac). The thiophene, 3ad–3ae, 63–86% and 6-
membered heteroyclic (pyridyl, 3ai-3aj, 73–76%) boronic acids
gave desired products in signicantly good yields. We were also
successful in introducing naphthyl (3ag-3ah) and benzo[d][1,3]
dioxole groups (3af) onto the pyrazolo[3,4-b]pyridine core
moiety in excellent yields. The crystal structure of 3g was
conrmed by X-ray crystallography.
Table 2 Optimization studies for C6-arylation of 3-arylpyrazolo[3,4-
b]pyridinesa
We extended the above ndings to C6-arylation on 6-chloro-
1-(4-methoxybenzyl)-3-phenyl-1H-pyrazolo[3,4-b]pyridine (3s)
with phenylboronic acid to yield 1-(4-methoxybenzyl)-3,6-
diphenyl-1H-pyrazolo[3,4-b]pyridine, 4a (Table 2). Only 54% of
the diarylated product was formed on applying the earlier
optimized conditions (Table 2, entry 1). Changing the ligand to
PPh3 decreased the yield of coupled product to 48% (Table 2,
entry 2). Incomplete conversion was observed on using a milder
base, such as K2CO3 and Na2CO3 (Table 2, entries 3 and 4). The
reaction yield was enhanced to 95% on increasing the temper-
ature to 100 ꢀC. No new spot was formed at rt (Table 2, entry 7).
Experimentation showed that the combination of Pd(OAc)2
(5 mol%) and dppf (5 mol%) with 2.0 equiv. of Cs2CO3 in 1,4-
dioxane and water (3 : 1) at 100 ꢀC for 2 h afforded the C6-
arylated product in the best yield (Table 2, entry 6).
Entry
Ligand [5mol%]
Base
T (ꢀC)
Yieldb (%)
1
2
dppf
PPh3
dppf
dppf
dppf
dppf
dppf
Cs2CO3
Cs2CO3
K2CO3
Na2CO3
Cs2CO3
Cs2CO3
Cs2CO3
60
60
60
60
80
100
rt
54
48
62
55
78
95
n.r.
3c
4d
5
6
7
a
Reaction
conditions:
6-chloro-1-(4-methoxybenzyl)-3-phenyl-1H-
pyrazolo[3,4-b]pyridine 3 (1.0 equiv.), arylboronic acid 2 (1.0 equiv.),
Pd(OAc)2 (5 mol%), ligand (5 mol%), base (2.0 equiv.), 1,4-
dioxane : water (3 : 1) (5 mL), 2 h. Isolated yields. 15% of starting
b
c
For substrate scope, coupling with 4-uorophenylboronic
acid facilitates excellent reaction yield (97%), when compared to
d
material recovered; n.r. ¼ no reaction. 25% of starting material
recovered; n.r. ¼ no reaction.
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Scheme 2 Pd-catalyzed C6-arylation of 3-arylpyrazolo[3,4-b]pyridines.a,b aReaction conditions: 6-chloro-1-(4-methoxybenzyl)-3-phenyl-1H-
pyrazolo[3,4-b]pyridine 3 (1.0 equiv.), arylboronic acid 2 (1.0 equiv.), Pd(OAc)2 (5 mol%), dppf (5 mol%), Cs2CO3 (2.0 equiv.), 1,4-dioxane : water
(3 : 1) (5 mL), 100 ꢀC, 2 h; bisolated yields.
(–CN, –NO2) boronic acid also proceeded smoothly with the same Pd (OAc)2/dppf (15 mol%) catalyst, at 100 ꢀC without
present starting moiety, giving 72% and 53% of desired prod- purication of the intermediate. The one-pot coupling reaction
ucts (4f & 4h). The diuorophenyl group containing pyr- afforded diaryl-1H-pyrazolo[3,4-b]pyridines (4a-b; 4f-g; 4i-j) in
azolopyridine coupled with 3-methoxyphenylboronic acid moderate to good yields (43–72%). In a one-pot reaction
produced 4g in 63% yield. The present strategy is efficient diphenyl-1H-pyrazolo[3,4-b]pyridine (4a) was isolated in 72%
enough to couple with heteroaromatic boronic acids producing yield. Insertion of 4-methoxyphenylboronic acid as a second
diarylated product (4i-j) in 62–68% yield. In addition, we arylating agent was successful, as 4b was isolated in 60% yield
successfully arylated the pyrazolo[3,4-b]pyridine with benzo[d] in 4h. The combination of 4-methylphenylboronic acid as the
[1,3]dioxol-5-ylboronic acid, giving 57% of 4k. The 3-hydrox- rst arylating agent and 4-cyanophenylboronic acid as the
yphenylboronic acid was quite stable under these conditions, as second proved to be successful, with an isolated yield of 60%
the coupled product (4l) was isolated in 52% yield.
Aer successful stepwise sequential diarylation, we turned raphy. Further, when 3-methoxyphenylboronic acid reacted
our focus to the one-pot arylation reaction to synthesize 3,6- with 6-chloro-3-(2,4-diuorophenyl)-1-(4-methoxybenzyl)-1H-
(4f). The structure of 4f was determined by X-ray crystallog-
diarylated pyrazolopyridines (Scheme 3). The combinations of pyrazolo[3,4-b]pyridine, the product (4g) was isolated in 48%
boronic acids that showed the best overall yield in our previous yield in 6 h. The combinations of 5/5 or 5/6 member heterocyclic
stepwise synthesis of diarylated pyrazolo[3,4-b]pyridines boronic acids were screened and afforded moderate yields of
(Scheme 2) were selected for one-pot sequential arylation of 6- 53% (4i) and 43% (4j) respectively. The study suggested that the
chloro-3-iodo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine
overall yield of biarylated product in the one pot method is
(1). The Suzuki cross-coupling was rst performed with comparable to the stepwise sequential method. We have
Pd(OAc)2/dppf as the catalyst in the presence of Cs2CO3 as base observed that C3 arylation was preferred over C6 arylation, in
and Ar1B(OH)2 at 60 ꢀC. Upon completion of the coupling, our reaction conditions. But, we cannot neglect the role of I vs.
a second arylation was accomplished with Ar2B(OH)2 and the Cl as one of the governing factors. Thus the one-pot method can
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Scheme 3 Sequential one-pot synthesis of 3,6-diarylpyrazolo[3,4-b]pyridines.a,b,c aReaction conditions: 6-chloro-3-iodo-1-(4-methox-
ybenzyl)-1H-pyrazolo[3,4-b]pyridine 1 (1.0 equiv.), arylboronic acid 2 (1.0 equiv.), Pd(OAc)2 (5 mol%), dppf (5 mol%), Cs2CO3 (2.0 equiv.), 1,4-
dioxane : water (3 : 1) (5 mL), 60 ꢀC for 1 h; after consumption of pyrazolopyridine 1, addition of Pd(OAc)2 (15 mol%), dppf (15 mol%), arylboronic
acid 2 (1.2 equiv.), 100 ꢀC, 2–4 h; bisolated yields; cformal average yields of the two steps shown in parentheses; d10% of starting material
f
recovered; e6 h for second arylation and 15% of starting material recovered; 6–8 h for second arylation.
be used as a time and cost-effective method for the diarylation can be de-protected to produce 5a–5d, in excellent yields
of pyrazolopyridines (Scheme 3).
(Scheme 4). The electron-withdrawing and electron-donating
The p-methoxybenzyl protecting group (PMB) was easily groups do not greatly inuence the yield of nal compounds.
cleaved by the action of triuoroacetic acid (TFA) at 70 ꢀC within It is important to mention here that the di-heteroarylated
0.25 h.16a We performed a THP de-protection reaction of 3w with product, e.g. a combination of thiophene and furan, remained
methanolic HCl, giving 97% yield of the required product.16b
rapid screening showed that diarylated pyrazolo[3,4-b]pyridines
A
intact under de-protection conditions to give 5d in 99% yield.
Scheme 4 De-protection of the PMB group.a,b aReaction conditions: 3,6-diaryl-1H-pyrazolo[3,4-b]pyridine 4 (1 equiv.), TFA (5 mL), 70 ꢀC,
0.25 h; bisolated yields.
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126.9, 116.8, 113.4, 33.9. HRMS (ESI): m/z calcd. for C13H11N3[M
+ H]+: 210.1031; found: 210.1015.
3. Conclusion
1-Methyl-3-(p-tolyl)-1H-pyrazolo[3,4-b]pyridine (3b). Light
In conclusion, we have developed catalytic systems for the
stepwise sequential arylation of pyrazolo[3,4-b]pyridines at the
C3 and C6 positions via Suzuki–Miyaura reactions. The che-
moselective sequential arylation strategy was also performed in
one pot without a loss of efficiency when compared to the cor-
responding stepwise synthesis. This route offers signicant
exibility to access heteroaromatic frameworks with chal-
lenging substitution patterns. We hope that this new method-
ology will open access to synthesizing new chemotypes and to
discovering functionalized pyrazolo[3,4-b]pyridines with thera-
peutic potential.
1
ꢀ
brown solid; 85% yield (94.4 mg) mp 52–53 C; H NMR (400
MHz, CDCl3) d 8.49 (dd, J ¼ 4.6, 1.4 Hz, 1H), 8.25–8.22 (m, 1H),
7.78 (d, J ¼ 8.2 Hz, 2H), 7.25 (d, J ¼ 8.2 Hz, 2H), 7.07 (dd, J ¼ 8.2,
4.6, 1H), 4.14 (s, 3H), 2.36 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 151.2, 148.4, 142.4, 138.0, 130.3, 130.2, 129.5, 126.7, 116.6,
113.8, 33.8, 21.2. HRMS (ESI): m/z calcd. for C14H13N3[M + H]+:
224.1187; found: 224.1182.
3-(3-Methoxyphenyl)-1-methyl-1H-pyrazolo[3,4-b]pyridine (3c).
1
ꢀ
Dusky white solid; 81% yield (96.5 mg); mp 85–86 C; H NMR
(400 MHz, CDCl3) d 8.63–8.61 (m, 1H), 8.40–8.38 (m, 1H), 7.59–
7.55 (m, 2H), 7.49–7.45 (m, 1H), 7.24–7.20 (m, 1H), 7.03–7.00
(m, 1H), 4.27 (s, 3H), 3.96 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 160.0, 151.3, 148.6, 142.3, 134.4, 130.4, 129.9, 119.4, 116.8,
114.1, 113.4, 112.0, 55.3, 33.9. HRMS (ESI): m/z calcd. for
4. Experimental
General information
C
14H13N3O[M + H]+: 240.1136; found: 240.1138.
Unless otherwise noted, all reagents were purchased from
3-(4-Methoxyphenyl)-1-methyl-1H-pyrazolo[3,4-b]pyridine (3d).
commercial suppliers and used without purication. All Dusky white solid, 97% yield (115.5 mg), mp 76–77 ꢀC; 1H NMR
Suzuki–Miyaura reactions were performed in a round bottom (400 MHz, CDCl3) d 8.55 (dd, J ¼ 4.6, 0.9 Hz, 1H), 8.29 (dd, J ¼
ask and monitored through thin layer chromatography (TLC 8.2, 0.9 Hz, 1H), 7.88–7.86 (m, 2H), 7.16–7.13 (m, 1H), 7.04 (d, J
silica gel F254, glass plates) and analysed using 254 nm UV light ¼ 8.2, 2H), 4.19 (s, 3H), 3.87 (s, 3H); 13C NMR (100 MHz, CDCl3)
and iodine, ninhydrin stains. Melting points were recorded on d 159.7, 151.3, 148.5, 142.3, 130.4, 128.1, 125.8, 116.5, 114.3,
a Buchi Melting Point B-545 instrument and are uncorrected. 113.3, 55.3, 33.8. HRMS (ESI): m/z calcd. for C14H13N3O[M + H]+:
¨
1H NMR and 13C NMR spectra were recorded with a 400 MHz 240.1136; found: 240.1141.
(1H ¼ 400 and 13C ¼ 100 MHz) or 500 MHz (1H ¼ 500 and 13C ¼
3-(4-Bromophenyl)-1-methyl-1H-pyrazolo[3,4-b]pyridine
(3e).
125 MHz) spectrometer. Chemical shi values of 1H NMR were White solid; 75% yield (107.1 mg); mp 104–105 ꢀC; 1H NMR (400
recorded in parts per million (ppm, d) relative to tetrame- MHz, CDCl3) d 8.61 (dd, J ¼ 4.6, 0.92 Hz, 1H), 8.32 (dd, J ¼ 8.6,
thylsilane (TMS, 0.00 ppm). Multiplicities are indicated as 1.36 Hz, 1H), 7.87–7.85 (m, 2H), 7.67–7.65 (m, 2H), 7.24–7.20
s(singlet), d(doublet), t(triplet), q(quartet), m(multiplet), (m, 1H), 4.24 (s, 3H); 13C NMR (100 MHz, CDCl3) d 151.3, 148.7,
coupling constants (J) were reported in Hertz (Hz) and inte- 141.2, 132.1, 132.0, 130.0, 128.3, 122.2, 117.0, 113.2, 33.9. HRMS
gration value. Chemical shi values of 13C NMR were recorded (ESI): m/z calcd. for C13H10BrN3[M + H]+: 288.0136; found:
in parts per million (ppm, d) and calibrated to the residual peak 288.0129.
as an internal standard (CDCl3: d ¼ 77.0 ppm and DMSO: d ¼
3-(2,4-Diuorophenyl)-1-methyl-1H-pyrazolo[3,4-b]pyridine (3f).
39.0 ppm). High-resolution mass spectra (HRMS) were obtained White solid; 46% yield (56.1 mg); mp 92–93 C; H NMR (400
1
ꢀ
using the ESI-TOF method.
MHz, CDCl3) d 8.63 (dd, J ¼ 4.6, 1.5 Hz, 1H), 8.25–8.22 (m, 1H),
General procedure for the synthesis of monoarylpyrazolo 7.95–7.87 (m, 1H), 7.24–7.20 (m, 1H), 7.10–7.01 (m, 2H), 4.28 (s,
[3,4-b]pyridines and their derivatives. To a round bottom ask, 3H); 13C NMR (100 MHz, CDCl3) d 163.0 (dd, J ¼ 247.9, 10.9 Hz,
were added 3-iodo-1-methyl-1H-pyrazolo[3,4-b]pyridine 1 (0.5 1C), 159.9 (dd, J ¼ 249.8, 11.4 Hz, 1C), 151.0, 148.9, 137.4, 131.3
mmol) dissolved in 5 mL of dioxane : water (3 : 1), catalyst and (dd, J ¼ 9.5, 5.7 Hz, 1C), 131.1, 131.0, 116.9, 114.1, 112.0 (dd, J ¼
ligand 5 mol% each. Arylboronic acid 2 (0.5 mmol, 1.0 equiv.) 20.9, 2.86 Hz, 1C), 104.4 (t, J ¼ 25.7 Hz, 1C), 34.0. HRMS (ESI):
and base (2 equiv.), were added to the above aer 5 min of m/z calcd. for C13H9F2N3[M + H]+: 246.0842; found: 246.0858.
ꢀ
stirring and started heating at 60 C. When the TLC indicated
3-(3,5-Bis(triuoromethyl)phenyl)-1-methyl-1H-pyrazolo[3,4-b]
the total consumption of starting material, the reaction mixture pyridine (3g). Off white solid; 79% yield (135.7 mg); mp 118–
1
ꢀ
was allowed to cool at ambient temperature. The reaction 119 C; H NMR (400 MHz, CDCl3) d 8.63 (dd, J ¼ 4.5, 1.5 Hz,
mixture was extracted with ethyl acetate and organic layer was 1H), 8.41 (s, 2H), 8.32 (d, J ¼ 8.4 Hz, 1H), 7.89 (s, 1H), 7.26 (dd, J
washed with brine. The combined organic layers were dried ¼ 8.4, 4.6, 1H), 4.25 (s, 3H); 13C NMR (100 MHz, CDCl3) d 151.4,
over Na2SO4 and concentrated under reduced pressure. The 149.2, 139.2, 135.4, 132.2 (q, J ¼ 34.3 Hz, 1C), 129.5, 126.4,
resulting residue was puried by column chromatography 124.6, 121.9, 121.49–121.42 (m, 1C), 117.8, 113.0, 34.2. HRMS
(silica gel, hexane/EtOAc) to give the desired products (3a–3ak). (ESI): m/z calcd. for C15H9F6N3[M + H]+: 346.0778; found:
1-Methyl-3-phenyl-1H-pyrazolo[3,4-b]pyridineꢀ (3a).
Light 346.0771.
6-Chloro-1-methyl-3-phenyl-1H-pyrazolo[3,4-b]pyridine
1
yellow solid; 98% yield (102 mg); mp 86–87 C; H NMR (400
(3h).
MHz, CDCl3) d 8.62 (dd, J ¼ 4.5, 1.5 Hz, 1H), 8.38 (dd, J ¼ 7.6, Creamy white solid; 67% yield (81.1 mg); mp 75–76 ꢀC; 1H NMR
1.5 Hz, 1H), 8.01–7.90 (m, 2H), 7.56 (t, J ¼ 7.6 Hz, 2H), 7.48–7.45 (400 MHz, CDCl3) d 8.21–8.19 (m, 1H), 7.87 (d, J ¼ 7.8 Hz, 2H),
(m, 1H), 7.22 (dd, J ¼ 8.4, 4.6, 1H), 4.27 (s, 3H); 13C NMR (100 7.50–7.46 (m, 2H), 7.41–7.39 (m, 1H), 7.14–7.12 (m, 1H), 4.13 (s,
MHz, CDCl3) d 151.3, 148.6, 142.4, 133.1, 130.4, 128.9, 128.2, 3H); 13C NMR (100 MHz, CDCl3) d 150.6, 150.4, 142.9, 132.5,
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132.5, 128.9, 128.5, 126.8, 117.3, 112.0, 34.1; HRMS (ESI): m/z 7.32 (m, 2H), 7.15 (d, J ¼ 8.2, 4.6 Hz, 1H), 6.82–6.80 (m, 2H), 5.68
calcd. for C13H10ClN3[M + H]+: 244.0641; found: 244.0621.
(s, 2H), 3.73 (s, 3H); 13C NMR (100 MHz, CDCl3) d 159.1, 151.1,
6-Chloro-1-methyl-3-(p-tolyl)-1H-pyrazolo[3,4-b]pyridine
(3i). 148.8, 141.6, 132.1, 131.9, 130.0, 129.3, 129.0, 128.4, 122.2,
White solid; 99% yield (126.8 mg); mp 141–142 ꢀC; 1H NMR (400 117.2, 113.8, 113.4, 55.1, 50.3. HRMS (ESI): m/z calcd. for
MHz, CDCl3) d 8.22–8.20 (m, 1H), 7.78 (d, J ¼ 8.2 Hz, 2H), 7.30
C
20H16BrN3O[M + H]+: 394.0554; found: 394.0546.
(d, J ¼ 7.8 Hz, 2H), 7.14 (dd, J ¼ 8.7, 1.3 Hz, 1H), 4.15 (s, 3H),
4-(1-(4-Methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)benzonitrile
2.42 (s, 3H); 13C NMR (100 MHz, CDCl3) d 150.6, 150.3, 143.0, (3p). Light yellow solid; 68% yield (115.3 mg); mp 175–176 C;
138.5, 132.5, 129.7, 129.6, 126.7, 117.2, 112.0, 34.0, 21.3; HRMS 1H NMR (400 MHz, CDCl3) d 8.62 (dd, J ¼ 4.5, 1.8 Hz, 1H), 8.33
(ESI): m/z calcd. for C14H12ClN3[M + H]+: 258.0797; found: (dd, J ¼ 8.2, 1.3 Hz, 1H), 8.09 (dd, J ¼ 6.88, 1.8 Hz, 2H), 7.76 (dd,
ꢀ
258.0796.
6-Chloro-3-(4-methoxyphenyl)-1-methyl-1H-pyrazolo[3,4-b]pyri-
J ¼ 6.8, 1.8 Hz, 2H), 7.40–7.38 (m, 2H), 7.23 (dd, J ¼ 8.2, 4.6 Hz,
1H), 6.83 (dd, J ¼ 6.88, 2.2 Hz, 2H), 5.72 (s, 2H), 3.75 (s, 3H); 13
C
dine (3j). White solid; 78% yield (106.1 mg); mp 137–138 ꢀC; 1H NMR (125 MHz, CDCl3) d 159.3, 151.2, 149.1, 140.6, 137.7, 132.6,
NMR (400 MHz, CDCl3) d 8.20 (d, J ¼ 8.2 Hz, 1H), 7.83 (d, J ¼ 129.9, 129.5, 128.8, 127.2, 118.8, 117.8, 114.0, 113.5, 111.4, 55.2,
8.2 Hz, 2H), 7.15–7.13 (m, 1H), 7.03 (d, J ¼ 8.2 Hz, 2H), 4.14 (s, 50.5. HRMS (ESI): m/z calcd. for C21H16N4O[M + H]+: 341.1402;
3H), 3.87 (s, 3H); 13C NMR (100 MHz, CDCl3) d 159.9, 150.6, found: 341.1391.
150.3, 142.8, 132.5, 128.1, 125.2, 117.1, 114.4, 111.9, 55.3, 34.0;
3-(2,4-Diuorophenyl)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]
HRMS (ESI): m/z calcd. for C14H12ClN3O[M + H]+: 274.0746; pyridine (3q). Pale yellow solid; 92% yield (161.0 mg); mp 60–
found: 274.0745.
6-Chloro-3-(4-uorophenyl)-1-methyl-1H-pyrazolo[3,4-b]pyridine
61 ꢀC; 1H NMR (400 MHz, CDCl3) d 8.65 (dd, J ¼ 4.6, 1.5 Hz, 1H),
8.25–8.22 (m, 1H), 7.93 (q, J ¼ 8.4 Hz, 1H), 7.48–7.45 (m, 2H),
(3k). White solid; 83% yield (107.9 mg); mp 149–150 ꢀC; 1H NMR 7.21 (dd, J ¼ 8.4, 4.6 Hz, 1H), 7.09–7.02 (m, 2H), 6.92–6.89 (m,
(400 MHz, CDCl3) d 8.19–8.17 (m, 1H), 7.89–7.85 (m, 2H), 7.26– 2H), 5.80 (s, 2H), 3.81 (s, 3H); 13C NMR (100 MHz, CDCl3). 13C
7.15 (m, 3H), 4.15 (s, 3H); 13C NMR (100 MHz, CDCl3) d 162.9 (d, NMR showed one less carbon, it might be due to one carbon
J ¼ 246.9 Hz, 1C), 150.6, 142.0, 132.2, 128.8, 128.5 (d, J ¼ 7.6 Hz, peak got merged at 129.3 ppm. d 162.9 (dd, J ¼ 248.8, 11.4 Hz,
1C), 117.5, 116.1, 115.9, 111.8, 34.1; HRMS (ESI): m/z calcd. for 1C), 159.3 (dd, J ¼ 250.7, 12.4 Hz, 1C), 159.0, 150.7, 148.9, 137.7,
C
13H9ClFN3[M + H]+: 262.0541; found: 262.0545.
131.5 (dd, J ¼ 9.5, 5.7 Hz, 1C), 130.9 (d, J ¼ 10.4, 1C), 129.3 (b,
1-(4-Methoxybenzyl)-3-phenyl-1H-pyrazolo[3,4-b]pyridine (3l). 1C), 129.0, 117.0, 114.2, 113.8, 111.9 (d, J ¼ 20.9 Hz, 1C), 104.6–
Dusky brown solid; 62% yield (97.4 mg); mp 115–116 ꢀC; 1H 104.0 (m, 1C), 55.2–54.9 (m, 1C), 50.2. HRMS (ESI): m/z calcd. for
NMR (400 MHz, CDCl3) d 8.64 (dd, J ¼ 4.6, 1.5 Hz, 1H), 8.39–8.37
C
20H15F2N3O[M + H]+: 352.1261; found: 352.1264.
3-(3,5-Bis(triuoromethyl)phenyl)-1-(4-methoxybenzyl)-1H-pyr-
(m, 1H), 8.01 (d, J ¼ 7.6 Hz, 2H), 7.55 (t, J ¼ 7.6 Hz, 2H), 7.48–
7.44 (m, 3H), 7.24–7.20 (m, 1H), 6.88 (dd, J ¼ 6.8, 2.2 Hz, 2H), azolo[3,4-b]pyridine (3r). White solid; 93% yield (209.1 mg); mp
5.78 (s, 2H), 3.80 (s, 3H); 13C NMR (100 MHz, CDCl3) d 59.0, 127–128 ꢀC; 1H NMR (400 MHz, CDCl3) d 8.63 (dd, J ¼ 4.5,
151.1, 148.7, 142.8, 133.2, 130.3, 129.3, 129.2, 128.8, 128.2, 1.5 Hz, 1H), 8.40 (s, 2H), 8.31–8.29 (m, 1H), 7.87 (s, 1H), 7.40 (d, J
127.0, 117.0, 113.8, 113.6, 55.1, 50.2. HRMS (ESI): m/z calcd. for ¼ 8.4 Hz, 2H), 7.28–7.26 (m, 1H), 6.84 (dd, J ¼ 6.84, 2.2 Hz, 2H),
C
20H1N3O[M + H]+: 316.1449; found: 316.1468.
5.73 (s, 2H), 3.75 (s, 3H); 13C NMR (100 MHz, CDCl3) d 159.3,
1-(4-Methoxybenzyl)-3-(p-tolyl)-1H-pyrazolo[3,4-b]pyridine (3m). 151.2, 149.3, 139.6, 135.5, 132.2 (q, J ¼ 32.3 Hz, 1C), 129.5,
Light brown solid; 87% yield (142.7 mg); mp 76–77 ꢀC; 1H NMR 128.7, 126.6, 124.6, 121.9, 121.4 (b, 1C), 117.9, 114.0, 113.2, 55.2,
(400 MHz, CDCl3) d 8.52 (d, J ¼ 4.5, 1H), 8.23 (d, J ¼ 7.6 Hz, 1H), 50.6. HRMS (ESI): m/z calcd. for C22H15F6N3O[M + H]+: 452.1197;
7.84 (d, J ¼ 7.6 Hz, 2H), 7.39 (d, J ¼ 8.4 Hz, 2H), 7.29–7.26 (m, found: 452.1191.
2H), 7.09–7.06 (m, 1H), 6.85–6.80 (m, 2H), 5.70 (s, 2H), 3.69 (s,
6-Chloro-1-(4-methoxybenzyl)-3-phenyl-1H-pyrazolo[3,4-b]pyri-
3H), 2.39 (s, 3H); 13C NMR (100 MHz, CDCl3) d 158.9, 150.9, dine (3s). White solid; 93% yield (162 mg); mp 85–86 ꢀC; 1H
148.4, 142.7, 137.9, 130.2, 129.4, 129.2, 128.3, 126.8, 116.7, NMR (400 MHz, CDCl3) d 8.22–8.19 (m, 1H), 7.90–7.88 (m, 2H),
113.7, 113.6, 113.4, 54.9, 50.0, 21.1. HRMS (ESI): m/z calcd. for 7.49–7.45 (m, 2H), 7.41–7.38 (m, 3H), 7.16–7.13 (m, 1H), 6.83
C
21H19N3O[M + H]+: 330.1606; found: 330.1607.
(dd, J ¼ 3.6, 1.4 Hz, 2H), 5.63 (s, 2H), 3.74 (s, 3H); 13C NMR (100
1-(4-Methoxybenzyl)-3-(4-methoxyphenyl)-1H-pyrazolo[3,4-b]pyri- MHz, CDCl3) d 159.1, 150.5, 150.3, 143.2, 132.7, 132.4, 129.5,
dine (3n). White solid; 79% yield (135.9 mg); mp 125–126 ꢀC; 1H 128.8, 128.7, 128.5, 127.0, 117.6, 113.8, 112.2, 55.1, 50.3; HRMS
NMR (400 MHz, CDCl3) d 8.63 (d, J ¼ 4.6, 1H), 8.36 (dd, J ¼ 8.4, (ESI): m/z calcd. for C20H16ClN3O[M + H]+: 350.1059; found:
1.5 Hz, 1H), 7.96 (d, J ¼ 9.1 Hz, 2H), 7.45 (d, J ¼ 8.4 Hz, 2H), 350.1041.
7.24–7.20 (m, 1H), 7.10 (d, J ¼ 9.1 Hz, 2H), 6.90 (d, J ¼ 9.1 Hz,
6-Chloro-1-(4-methoxybenzyl)-3-(3-nitophenyl)-1H-pyrazolo[3,4-
2H), 5.78 (s, 2H), 3.99 (s, 3H), 3.82 (s, 3H); 13C NMR (100 MHz, b]pyridine (3t). Light yellow solid; 93% yield (182.7 mg); mp 155–
1
ꢀ
CDCl3) d 159.6, 159.0, 151.0, 148.6, 142.7, 130.3, 129.3, 129.2, 156 C; H NMR (400 MHz, CDCl3) d 8.76–8.75 (m, 1H), 8.27–
128.3, 125.9, 116.7, 114.2, 113.8, 113.5, 55.3, 55.1, 50.1. HRMS 8.22 (m, 3H), 7.65 (t, J ¼ 7.7 Hz, 1H), 7.42–7.40 (m, 2H), 7.26–
(ESI): m/z calcd. for C21H19N3O[M + H]+: 346.1555; found: 7.23 (m, 1H), 6.85 (dd, J ¼ 6.8, 1.8 Hz, 2H), 5.65 (s, 2H), 3.76 (s,
346.1555.
3H); 13C NMR (100 MHz, CDCl3) d 159.3, 151.0, 150.3, 148.6,
3-(4-Bromophenyl)-1-(4-methoxyphenyl)-1H-pyrazolo[3,4-b]pyri- 140.6, 134.5, 132.5, 131.8, 129.9, 129.7, 128.2, 122.9, 121.5,
dine (3o). Off white solid; 62% yield (121.4 mg); mp 75–76 ꢀC; 1H 118.4, 114.0, 111.8, 55.2, 50.6; HRMS (ESI): m/z calcd. for
NMR (400 MHz, CDCl3) d 8.56 (dd, J ¼ 4.1, 0.9 Hz, 1H), 8.23 (dd,
C
20H15ClN4O[M + H]+: 395.0910; found: it decompose during
J ¼ 8.2, 1.4 Hz, 1H), 7.81–7.79 (m, 2H), 7.60–7.58 (m, 2H), 7.37– mass analysis.
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6-Chloro-3-(2,4-diuorophenyl)-1-(4-methoxybenzyl)-1H-pyrazolo
3-(4-Bromophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-
[3,4-b]pyridine (3u). White solid; 89% yield (170.9 mg); mp 87– b]pyridine (3z). Creamy white solid; 67% yield (119.1 mg); mp
88 ꢀC; 1H NMR (500 MHz, CDCl3) d 8.12 (dd, J ¼ 8.4, 3.2 Hz, 1H), 112–113 ꢀC; 1H NMR (400 MHz, CDCl3) d 8.59 (dd, J ¼ 4.6,
7.87 (q, J ¼ 8.3 Hz, 1H), 7.42 (d, J ¼ 8.5 Hz, 2H), 7.19 (d, J ¼ 1.8 Hz, 1H), 8.28 (dd, J ¼ 8.2, 1.8 Hz, 1H), 7.88–7.85 (m, 2H),
8.4 Hz, 1H), 7.04–6.97 (m, 2H), 6.87 (d, J ¼ 8.5 Hz, 2H), 5.68 (s, 7.63–7.60 (m, 2H), 7.22 (q, J ¼ 4.6 Hz, 1H), 6.20 (dd, J ¼ 10.5,
2H), 3.79 (s, 3H); 13C NMR (125 MHz, CDCl3) d 163.1 (dd, J ¼ 2.3 Hz, 1H), 4.18–4.14 (m, 1H), 3.89–3.83 (m, 1H), 2.81–2.72 (m,
249.2, 32.7 Hz, 1C), 159.9 (dd, J ¼ 249.7, 11.7 Hz, 1C), 159.3, 1H), 2.19–2.16 (m, 1H), 2.03–2.00 (m, 1H), 1.86–1.79 (m, 2H),
150.8, 150.1, 138.2, 133.3 (d, J ¼ 10.8 Hz, 1C), 131.5 (dd, J ¼ 9.7, 1.65–1.63 (m, 1H); 13C NMR (100 MHz, CDCl3). 13C NMR showed
5.6 Hz, 1C), 129.6, 128.6, 117.8, 116.7 (dd, J ¼ 14.8, 2.5 Hz, 1C), one less carbon, it might be due to one carbon peak got merged
114.0, 112.9, 112.1 (d, J ¼ 20.8 Hz, 1C), 104.4 (t, J ¼ 25.8 Hz, 1C), at 131.9 ppm. d 151.3, 148.8, 142.7, 131.9, 130.2, 128.7, 122.5,
55.2, 50.5; HRMS (ESI): m/z calcd. for C20H14ClF2N3O[M + H]+: 117.8, 113.9, 82.3, 68.3, 29.9, 24.9, 23.0; HRMS (ESI): m/z calcd.
386.0871; found: 386.0859.
for C18H16BrN3O[M + H]+: 358.0554; found: 358.0547.
6-Chloro-1-(4-methoxybenzyl)-3-(p-tolyl)-1H-pyrazolo[3,4-b]pyri-
3-(4-Fluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-
dine (3v). White solid; 90% yield (162.9 mg); mp 110–111 ꢀC; 1H b]pyridine (3aa). White solid; 97% yield (143.6 mg); mp 92–93 ꢀC;
NMR (500 MHz, CDCl3) d 8.23 (d, J ¼ 8.2 Hz, 1H), 7.81 (d, J ¼ 1H NMR (400 MHz, CDCl3) d 8.59 (dd, J ¼ 4.6, 1.4 Hz, 1H), 8.28
7.2 Hz, 2H), 7.42 (d, J ¼ 7.6 Hz, 2H), 7.33–7.28 (m, 2H), 7.17 (d, J (dd, J ¼ 8.2, 1.4 Hz, 1H), 7.97–7.93 (m, 2H), 7.23–7.16 (m, 3H),
¼ 8.3 Hz, 1H), 6.86 (d, J ¼ 7.5 Hz, 2H), 5.66 (s, 2H), 3.78 (s, 3H), 6.20 (dd, J ¼ 10.5, 2.7 Hz, 1H), 4.18–4.11 (m, 1H), 3.89–3.83 (m,
2.44 (s, 3H); 13C NMR (125 MHz, CDCl3) d 159.2, 150.5, 150.4, 1H), 2.82–2.72 (m, 1H), 2.19–2.16 (m, 1H), 2.04–2.01 (m, 1H),
143.4, 138.5, 132.5, 129.9, 129.6, 129.6, 128.9, 126.9, 117.5, 1.89–1.79 (m, 2H), 1.68–1.63 (m, 1H); 13C NMR (100 MHz,
113.9, 112.2, 55.2, 50.3, 21.3; HRMS (ESI): m/z calcd. for CDCl3) d 162.9 (d, J ¼ 246.9 Hz, 1C), 151.4, 148.8 (d, J ¼ 3.8 Hz,
C
21H18ClN3O[M + H]+: 364.1216; found: 364.1201.
3-Phenyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyri-
1C), 143.0, 130.2 (d, J ¼ 3.82 Hz, 1C), 129.1 (d, J ¼ 2.86 Hz, 1C),
129.0 (d, J ¼ 8.58 Hz, 1C), 117.7 (d, J ¼ 5.72 Hz, 1C), 115.6 (dd, J
dine (3w). Light brown solid; 97% yield (135 mg); mp 74–75 ꢀC; ¼ 20.2, 5.7 Hz, 1C), 114.0, 82.3 (d, J ¼ 9.5 Hz, 1C), 68.4, 29.5,
1H NMR (400 MHz, CDCl3) d 8.42 (d, J ¼ 4.6 Hz, 1H), 8.13 (d, J ¼ 25.0, 23.1; HRMS (ESI): m/z calcd. for C17H16FN3O[M + H]+:
7.6 Hz, 1H), 7.86 (d, J ¼ 7.6 Hz, 2H), 7.35 (t, J ¼ 7.6 Hz, 2H), 7.27– 298.1355; found: 298.1324.
7.24 (m, 1H), 7.01–6.98 (m, 1H), 6.09 (dd, J ¼ 10.7, 2.3 Hz, 1H),
3-(2,4-Diuorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo
4.04–4.01 (m, 1H), 3.74–3.69 (m, 1H), 2.73–2.64 (m, 1H), 2.03 (b, [3,4-b]pyridine (3ab). Light brown liquid; 88% yield (138.1 mg);
1H), 1.91–1.88 (m, 1H), 1.70–1.60 (m, 2H), 1.48–1.46 (m, 1H); liquid; 1H NMR (400 MHz, CDCl3) d 8.59–8.58 (m, 1H), 8.19–8.17
13C NMR (100 MHz, CDCl3) d 151.0, 148.3, 143.3, 132.6, 130.0, (m, 1H), 7.96–7.90 (m, 1H), 7.21–7.18 (m, 1H), 7.04–6.95 (m,
128.4, 128.0, 126.8, 117.3, 113.7, 82.0, 67.8, 29.0, 24.6, 22.7. 2H), 6.22 (dd, J ¼ 10.5, 2.2 Hz, 1H), 4.18–4.11 (m, 1H), 3.89–3.84
HRMS (ESI): m/z calcd. for C17H17N3O[M + H]+: 280.1449; found: (m, 1H), 2.79–2.71 (m, 1H), 2.18 (b, 1H), 2.05–2.01 (m, 1H), 1.85–
280.1442.
1-(Tetrahydro-2H-pyran-2-yl)-3-(p-tolyl)-1H-pyrazolo[3,4-b]pyri-
1.80 (m, 2H), 1.65–1.63 (m, 1H); 13C NMR (100 MHz, CDCl3)
d 163.1 (dd, J ¼ 249.8, 11.4 Hz, 1C), 160.0 (dd, J ¼ 250.7, 12.3 Hz,
1
ꢀ
dine (3x). Brown solid; 88% yield (128.5 mg); mp 76–77 C; H 1C), 150.9, 148.9, 138.9, 131.7 (q, J ¼ 4.7 Hz, 1C), 131.1 (d, J ¼
NMR (400 MHz, CDCl3) d 8.56 (dd, J ¼ 4.6, 1.3 Hz, 1H), 8.32 (dd, 10.4 Hz, 1C), 117.6, 116.8 (dd, J ¼ 14.3, 3.8 Hz, 1C), 114.8, 111.9
J ¼ 8.2, 1.8 Hz, 1H), 7.88 (d, J ¼ 7.7 Hz, 2H), 7.31–7.29 (m, 2H), (dd, J ¼ 20.9, 2.8 Hz, 1C), 104.2 (t, J ¼ 25.7 Hz, 1C), 82.3, 68.3,
7.21–7.18 (m, 1H), 6.19 (dd, J ¼ 10.5, 2.3 Hz, 1H), 4.18–4.15 (m, 29.4, 24.9, 23.0; HRMS (ESI): m/z calcd. for C17H15F2N3O[M +
1H), 3.89–3.86 (m, 1H), 2.83–2.74 (m, 1H), 2.43–2.42 (m, 3H), H]+: 316.1261; found: 316.1259.
2.18–2.17 (m, 1H), 2.04–2.01 (m, 1H), 1.84–1.83 (m, 2H), 1.65 (b,
3-(3,5-Bis(triuoromethyl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-
1H); 13C NMR (100 MHz, CDCl3) d 151.4, 148.6 (d, J ¼ 2.8 Hz, 1H-pyrazolo[3,4-b]pyridine (3ac). Creamy white solid; 90% yield
1C), 143.9, 138.3, 130.5 (d, J ¼ 2.8 Hz, 1C), 130.1, 129.4 (d, J ¼ (186.2 mg); mp 160–161 ꢀC; 1H NMR (400 MHz, CDCl3) d 8.65 (d,
4.7 Hz, 1C), 127.2, 117.5 (d, J ¼ 6.67 Hz, 1C), 114.2, 82.3 (d, J ¼ J ¼ 4.5 Hz, 1H), 8.46 (s, 2H), 8.33 (dd, J ¼ 7.3, 0.92 Hz, 1H), 7.91
9.5 Hz, 1C), 68.3, 29.5, 25.0, 23.1, 21.3 (d, J ¼ 3.8 Hz, 1C). HRMS (s, 1H), 7.33–7.31 (m, 1H), 6.25 (dd, J ¼ 10.5, 2.3 Hz, 1H), 4.20–
(ESI): m/z calcd. for C18H19N3O[M + H]+: 294.1606; found: 4.17 (m, 1H), 3.91–3.85 (m, 1H), 2.84–2.75 (m, 1H), 2.22–2.18
294.1605.
3-(3-Methoxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo
(m, 1H), 2.05–2.02 (m, 1H), 1.87–1.82 (m, 2H), 1.68–1.66 (m,
1H); 13C NMR (100 MHz, CDCl3) d 151.4, 149.4, 140.7, 135.2,
[3,4-b]pyridine (3y). Yellow liquid; 96% yield (147.9 mg); liquid; 132.2 (q, J ¼ 32.4 Hz, 1C), 129.7, 126.9, 124.6, 121.9–121.7 (m,
1H NMR (400 MHz, CDCl3) d 8.60 (dd, J ¼ 4.6, 1.4 Hz, 1H), 8.35 1C), 118.5, 113.6, 82.5, 68.6, 29.5, 24.9, 23.0; HRMS (ESI): m/z
(dd, J ¼ 8.2, 1.3 Hz, 1H), 7.59–7.57 (m, 2H), 7.43 (t, J ¼ 8.0 Hz, 1H), calcd. for C19H15F6N3O[M + H]+: 416.1197; found: 416.1183.
7.21 (d, J ¼ 8.2, 4.6 Hz, 1H), 7.00–6.97 (m, 1H), 6.23 (dd, J ¼ 10.5,
1-(4-Methoxybenzyl)-3-(thiophen-3-yl)-1H-pyrazolo[3,4-b]pyriꢀ-
2.2 Hz, 1H), 4.21–4.11 (m, 1H), 3.91 (s, 3H), 3.89–3.85 (m, 1H), dine (3ad). Brown solid; 63% yield (100.8 mg); mp 108–109 C;
2.88–2.78 (m, 1H), 2.21–2.18 (m, 1H), 2.06–2.03 (m, 1H), 1.86– 1H NMR (400 MHz, CDCl3) d 8.56 (dd, J ¼ 4.6, 1.3 Hz, 1H), 8.26
1.82 (m, 2H), 1.67–1.65 (m, 1H); 13C NMR (100 MHz, CDCl3) (dd, J ¼ 7.8, 1.4 Hz, 1H), 7.76 (dd, J ¼ 3.2, 1.4 Hz, 1H), 7.68 (dd, J
d 159.8, 151.3, 148.6, 143.6, 134.1, 130.4, 129.6, 119.7, 117.6, ¼ 5.0, 1.4 Hz, 1H), 7.43 (dd, J ¼ 5.0, 3.2 Hz, 1H), 7.36–7.34 (m,
114.2, 114.1, 112.4, 82.3, 68.2, 55.2, 29.53, 24.9, 23.0; HRMS (ESI): 2H), 7.15 (dd, J ¼ 7.8, 4.6 Hz, 1H), 6.81 (dd, J ¼ 6.8, 2.2 Hz, 2H),
m/z calcd. for C18H19N3O2[M + H]+: 310.1555; found: 310.1538.
5,68 (s, 2H), 3.74 (s, 3H); 13C NMR (100 MHz, CDCl3). 13C NMR
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showed one less carbon, it might be due to one carbon peak got 149–150 ꢀC; 1H NMR (400 MHz, CDCl3) d 8.70 (d, J ¼ 5.5 Hz, 2H),
merged at 129.2 ppm. d 159.0, 150.8, 148.8, 139.2, 134.3, 130.0, 8.26–8.24 (m, 1H), 7.81 (d, J ¼ 5.0 Hz, 2H), 7.40 (d, J ¼ 8.6 Hz,
129.2, 126.4, 126.1, 121.8, 116.9, 113.8, 113.5, 55.1, 50.1; HRMS 2H), 7.24–7.22 (m, 1H), 6.84 (d, J ¼ 8.2 Hz, 2H), 5.65 (s, 2H), 3.76
(ESI): m/z calcd. for C18H15N3OS[M + H]+: 322.1013; found: (s, 3H); 13C NMR (100 MHz, CDCl3). 13C NMR showed one less
322.1001.
6-Chloro-1-(4-methoxybenzyl)-3-(thiophen-3-yl)-1H-pyrazolo[3,4-
carbon, it might be due to one carbon peak got merged. d 159.3,
150.9, 150.3, 140.2, 140.0, 131.9, 129.7, 128.2, 120.9, 118.5,
b]pyridine (3ae). Orange solid; 86% yield (152.2 mg); mp 130– 113.9, 112.1, 55.2, 50.6; HRMS (ESI): m/z calcd. for C19H15ClN4O
1
131 C; H NMR (500 MHz, CDCl3) d 8.17 (d, J ¼ 8.3 Hz, 1H), [M + H]+: 351.1012; found: 351.1003.
ꢀ
7.74–7.74 (m, 1H), 7.65 (d, J ¼ 5.0 Hz, 1H), 7.45–7.44 (m, 1H),
1-Methyl-3-(pyridin-4-yl)-1H-pyrazolo[3,4-b]pyridine
(3ak).
1
ꢀ
7.38 (d, J ¼ 8.5 Hz, 2H), 7.17 (d, J ¼ 8.3 Hz, 1H), 6.84 (d, J ¼ Brown solid; 78% yield (81.6 mg); mp 70–71 C; H NMR (400
8.6 Hz, 2H), 5.62 (s, 2H), 3.76 (s, 3H); 13C NMR (125 MHz, MHz, CDCl3) d 8.71 (d, J ¼ 4.1 Hz, 2H), 8.59 (dd, J ¼ 4.1, 1.3 Hz,
CDCl3). 13C NMR showed one less carbon, it might be due to one 1H), 8.34 (dd, J ¼ 8.2, 1.3 Hz, 1H), 7.86–7.85 (m, 2H), 7.23–7.20
carbon peak got merged at 126.3 ppm. d 159.2, 150.6, 150.1, (m, 1H), 4.21 (s, 3H); 13C NMR (100 MHz, CDCl3) d 151.4, 150.2,
139.6, 133.9, 132.1, 129.5, 128.8, 126.3 (b, 1C), 122.2, 117.6, 148.9, 140.6, 139.3, 129.8, 120.8, 117.6, 113.4, 34.1; HRMS (ESI):
113.9, 112.1, 55.2, 50.2; HRMS (ESI): m/z calcd. for C18H14
-
m/z calcd. for C12H10N4[M + H]+: 211.0983; found: 211.0981.
General procedure for the synthesis of monoarylpyrazolo
[3,4-b]pyridines and their derivatives (4a–4l). To a round bottom
ask, were added 6-chloro-1-(4-methoxybenzyl)-3-phenyl-1H-
ClN3OS[M + H]+: 356.0624; found: it decomposes during mass
analysis.
3-(Benzo[d][1,3]dioxo-5-yl)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-
b]pyridine (3af). White solid; 77% yield (137.8 mg); mp 97–98 ꢀC; pyrazolo[3,4-b]pyridine 3 (0.5 mmol) dissolved in 5 mL of
1H NMR (500 MHz, CDCl3) d 8.50 (s, 1H), 8.20 (s, 1H), 7.37–7.31 dioxane : water (3 : 1), catalyst and ligand 5 mol% each. Aryl-
(m, 4H), 7.09 (s, 1H), 6.87–6.76 (m, 3H), 5.95 (s, 2H), 5.62 (s, 2H), boronic acid 2 (0.5 mmol, 1.0 equiv.) and base (2 equiv.) were
3.69 (s, 3H); 13C NMR (125 MHz, CDCl3) d 159.1, 151.2, 148.7, added to the above aer 5 min of stirring and started heating at
148.2, 147.8, 142.6, 130.2, 129.4, 127.5, 120.9, 116.9, 113.9, 100 ꢀC. When the TLC indicated the total consumption of
113.5, 108.6, 107.6, 101.2, 55.2, 50.2; HRMS (ESI): m/z calcd. for starting material, the reaction mixture was allowed to cool at
C
21H17N3O3[M + H]+: 360.1347; found: 360.1225.
1-(4-Methoxybenzyl)-3(naphthalen-2-yl)-1H-pyrazolo[3,4-b]pyri-
ambient temperature. The reaction mixture was extracted with
ethyl acetate and organic layer was washed with brine and
dine (3ag). Creamy white solid, 88% yield (160.1 mg); mp 96– distilled water. The combined organic layers were dried over
97 ꢀC; 1H NMR (400 MHz, CDCl3) d 8.63 (dd, J ¼ 4.5, 1.8 Hz, 1H), Na2SO4 and concentrated under reduced pressure. The result-
8.46 (dd, J ¼ 8.2, 1.4 Hz, 1H), 8.42 (s, 1H), 8.17 (dd, J ¼ 8.72, ing residue was puried by column chromatography (silica gel,
1.8 Hz, 1H), 7.99–7.96 (m, 2H), 7.92–7.89 (m, 1H), 7.56–7.53 (m, hexane/EtOAc) to give the desired products (4a–4l).
2H), 7.48–7.46 (m, 2H), 7.22–7.20 (m, 1H), 6.89–6.87 (m, 2H),
1-(4-Methoxybenzyl)-3,6-diphenyl-1H-pyrazolo[3,4-b]pyridine
5.80 (s, 2H), 3.77 (s, 3H); 13C NMR (100 MHz, CDCl3) d 159.0, (4a). White solid; 95% yield (185.3 mg); mp 118–119 ꢀC; 1H
151.1, 148.7, 142.7, 133.4, 133.0, 130.6, 130.4, 129.3, 129.2, NMR (400 MHz, CDCl3) d 8.33 (d, J ¼ 8.2 Hz, 1H), 8.18–8.16 (m,
128.5, 128.1, 127.7, 126.3, 126.1, 125.8, 124.9, 117.0, 113.8, 2H), 7.96 (dd, J ¼ 8.7, 1.3 Hz, 2H), 7.64 (d, J ¼ 8.7 Hz, 1H), 7.52–
113.8, 55.1, 50.2; HRMS (ESI): m/z calcd. for C24H19N3O[M + H]+: 7.45 (m, 7H), 7.40–7.36 (m, 1H), 6.83 (dd, J ¼ 6.6, 0.9 Hz, 2H),
366.1606; found: 366.1592.
5.76 (s, 2H), 3.74 (s, 3H); 13C NMR (100 MHz, CDCl3) d 159.1,
6-Chloro-1-(4-methoxybenzyl)-3-(naphthalen-2-yl)-1H-pyrazolo
156.2, 151.5, 142.7, 139.2, 133.4, 130.7, 129.6, 126.5, 129.3,
[3,4-b]pyridine (3ah). White solid; 92% yield (183.1 mg); mp 143– 128.8, 128.7, 128.1, 127.4, 127.0, 114.6, 113.8, 112.3, 55.2, 50.2;
1
144 C; H NMR (500 MHz, CDCl3) d 8.38–8.36 (m, 2H), 8.11– HRMS (ESI): m/z calcd. for C26H21N3O[M + H]+: 392.1762; found:
ꢀ
8.07 (m, 1H), 8.02–7.89 (m, 3H), 7.57–7.54 (m, 2H), 7.49–7.45 392.1746.
(m, 2H), 7.23 (d, J ¼ 8.3 Hz, 1H), 6.83 (d, J ¼ 8.5 Hz, 2H), 5.71 (s,
1-(4-Methoxybenzyl)-6-(4-methoxyphenyl)-3-phenyl-1H-pyrazolo
2H), 3.79 (s, 3H); 13C NMR (125 MHz, CDCl3) d 159.2, 150.6, [3,4-b]pyridine (4b). White solid; 81% yield (170.1 mg); mp 123–
143.2, 133.4, 133.2, 132.6, 130.2, 129.8, 129.6, 128.8, 128.7, 124 ꢀC; 1H NMR (500 MHz, CDCl3) d 8.31 (d, J ¼ 8.5 Hz, 1H), 8.16
128.2, 127.8, 126.5, 126.4, 126.0, 124.8, 117.7, 114.0, 112.4, 55.2, (d, J ¼ 8.8 Hz, 2H), 7.97 (d, J ¼ 7.15 Hz, 2H), 7.60 (d, J ¼ 8.4 Hz,
50.4; HRMS (ESI): m/z calcd. for C24H18ClN3O[M + H]+: 400.1216; 1H), 7.52–7.47 (m, 4H), 7.40 (t, J ¼ 7.4, 1H), 7.05 (d, J ¼ 8.8 Hz,
found: 400.1202.
2H), 6.85 (d, J ¼ 8.6 Hz, 2H), 5.76 (s, 2H), 3.90 (s, 3H), 3.76 (s,
1-(4-Methoxybenzyl)-3-(pyridin-4-yl)-1H-pyrazolo[3,4-b]pyridine 3H); 13C NMR (125 MHz, CDCl3) d 160.8, 159.1, 156.0, 151.6,
(3ai). Brown solid; 73% yield (114.9 mg); mp 88–89 ꢀC; 1H NMR 142.8, 133.5, 131.8, 130.7, 129.6, 128.8 (d, J ¼ 2.7 Hz, 1C), 128.1,
(400 MHz, CDCl3) d 8.69 (dd, J ¼ 4.5, 1.3 Hz, 2H), 8.46 (dd, J ¼ 127.0, 116.0, 114.8, 114.2, 114.1, 113.9, 111.9, 55.4, 55.2, 50.2;
4.6, 1.3 Hz, 1H), 8.34 (dd, J ¼ 8.2, 1.3 Hz, 1H), 7.85 (dd, J ¼ 4.1, HRMS (ESI): m/z calcd. for C27H23N3O2[M + H]+: 422.1868;
1.3 Hz, 2H), 7.38 (d, J ¼ 8.2 Hz, 2H), 7.22 (m, 1H), 6.83–6.81 (m, found: 422.1857.
2H), 5,71 (s, 2H), 3.74 (s, 3H); 13C NMR (100 MHz, CDCl3)
6-(4-Fluorophenyl)-1-(4-methoxyphenyl)-3-phenyl-1H-pyrazolo
d 159.2, 151.1, 150.3, 149.0, 140.6, 139.8, 129.8, 129.5, 128.7, [3,4-b]pyridine (4c). White solid; 97% yield (197.9 mg); mp 136–
1
ꢀ
121.0, 117.7, 113.9, 113.6, 55.1, 50.5; HRMS (ESI): m/z calcd. for 137 C; H NMR (500 MHz, CDCl3) d 8.37–8.34 (m, 1H), 8.20–
C
19H16N4O[M + H]+: 317.1402; found: 317.1405.
6-Chloro-1-(4-methoxybenzyl)-3-(pyridin-4-yl)-1H-pyrazolo[3,4-
8.16 (m, 2H), 7.97 (d, J ¼ 7.2 Hz, 2H), 7.61 (d, J ¼ 8.4 Hz, 1H),
7.51 (t, J ¼ 7.5 Hz, 2H), 7.46 (d, J ¼ 8.6 Hz, 2H), 7.41 (t, J ¼ 7.4 Hz,
b]pyridine (3aj). Light brown solid; 76% yield (132.6 mg); mp 1H), 7.22 (t, J ¼ 8.6, 2H), 6.85 (d, J ¼ 8.6 Hz, 2H), 5.76 (s, 2H),
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3.76 (s, 3H); 13C NMR (125 MHz, CDCl3) d 163.8 (d, J ¼ 247.8 Hz, d 159.2, 153.2, 151.3, 148.8, 143.0, 140.9, 138.3, 133.1, 131.4,
1C), 159.1, 155.2, 151.5, 142.8, 135.3 (d, J ¼ 2.9 Hz, 1C), 133.3, 130.2, 129.7, 129.6, 129.2, 126.9, 123.8, 122.4, 114.1, 113.9,
130.9, 129.6, 129.5, 129.3 (d, J ¼ 8.3 Hz, 1C), 128.8, 128.2, 127.0, 113.2, 55.2, 50.5, 21.3; HRMS (ESI): m/z calcd. for C27H22N4O3[M
115.7 (d, J ¼ 21.4 Hz, 1C), 114.3, 113.9, 112.3, 55.2, 50.2; HRMS + H]+: 451.1769; found: 451.1775.
(ESI): m/z calcd. for C26H20FN3O[M + H]+: 410.1668; found:
6-(Furan-2-yl)-1-(4-methoxybenzyl)-3-(thiophen-3-yl)-1H-pyrazolo
410.1681.
[3,4-b]pyridine (4i). White solid; 68% yield (131.3 mg); mp 163–
1-(4-Methoxybenzyl)-6-(3-methoxyphenyl)-3-phenyl-1H-pyrazolo 164 ꢀC; 1H NMR (400 MHz, CDCl3) d 8.25 (d, J ¼ 8.4 Hz, 1H),7.77
[3,4-b]pyridine (4d). White solid; 68% yield (142.8 mg); mp 95.9– (d, J ¼ 1.5 Hz, 1H), 7.69 (d, J ¼ 4.9 Hz, 1H), 7.63–7.60 (m, 2H),
1
ꢀ
96.6 C; H NMR (400 MHz, CDCl3): 8.33 (d, J ¼ 8.2 Hz, 1H), 7.44–7.41 (m, 3H), 7.24 (d, J ¼ 3.1 Hz, 1H), 6.83 (d, J ¼ 8.4 Hz,
7.97–7.95 (m, 2H), 7.77–7.76 (m, 1H), 7.72–7.70 (m, 1H), 7.63 (d, 2H), 6.60 (s, 1H), 5.70 (s, 2H), 3.75 (s, 3H); 13C NMR (100 MHz,
J ¼ 8.2, 1H), 7.48–7.38 (m, 6H), 7.02–6.99 (m, 1H), 6.82 (d, J ¼ CDCl3). [We found less 1C.] d 159.1, 153.9, 151.0, 148.2, 143.8,
8.7 Hz, 2H), 5.75 (s, 2H), 3.92 (s, 3H), 3.73 (s, 3H); 13C NMR (100 139.3, 134.5, 130.3, 129.6, 129.5, 126.4, 126.1, 121.8, 113.9,
MHz, CDCl3): 160.0, 159.0, 157.0, 156.0, 151.4, 142.7, 140.6, 113.0, 112.3, 109.8, 55.2, 50.1. HRMS (ESI): m/z calcd. for
133.3, 130.7, 130.0, 129.7, 129.6, 129.4, 128.8, 128.1, 127.0,
119.9, 114.9, 114.8, 113.8, 113.0, 112.4, 55.1, 50.2; HRMS (ESI):
C
27H17N3O2S[M + H]+: 388.1119; found: 388.1103.
1-(4-Methoxybenzyl)-3-(pyridine-4-yl)-6-(thiophen-3-yl)-1H-pyr-
m/z calcd. for C27H23N3O2[M + H]+: 422.1868; found: 422.1841. azolo[3,4-b]pyridine (4j). White solid; 62% yield (123.1 mg); mp
3-(3-(4-Methoxyphenyl)-1-methyl-1H-pyrazolo[3,4-b]pyridin-6-
150–151 ꢀC; 1H NMR (500 MHz, CDCl3) d 8.71 (d, J ¼ 5.6 Hz, 2H),
yl)benzaldehyde (4e). Creamy white solid; 76% yield (129.9 mg); 8.31 (d, J ¼ 8.3 Hz, 1H), 8.06 (d, J ¼ 1.7 Hz, 1H), 7.88–7.86 (m,
mp 179–180 ꢀC; 1H NMR (500 MHz, CDCl3) d 10.17 (s, 1H), 8.67 3H), 7.59 (d, J ¼ 8.2 Hz, 1H), 7.47–7.45 (m, 3H), 6.85 (d, J ¼
(s, 1H), 8.46 (d, J ¼ 7.4 Hz, 1H), 8.38–0.36 (m, 1H), 7.98 (d, J ¼ 8.6 Hz, 2H), 5.74 (s, 2H), 3.76 (s, 3H); 13C NMR (125 MHz, CDCl3)
7.3 Hz, 1H), 7.92 (d, J ¼ 8.0 Hz, 2H), 7.71–7.67 (m, 2H), 7.07 (d, J d 159.2, 152.6, 151.4, 150.3, 142.0, 140.8, 139.8, 130.2, 129.7,
¼ 7.9 Hz, 2H), 4.26 (s, 3H), 3.90 (s, 3H); 13C NMR (125 MHz, 129.0, 126.7, 126.5, 124.9, 120.9, 115.4, 114.0, 112.1, 55.2, 50.5.
CDCl3) d 192.2, 159.8, 154.6, 151.7, 142.4, 140.2, 136.9, 133.2, HRMS (ESI): m/z calcd. for C23H18N4OS[M + H]+: 399.1279;
131.1, 130.3, 129.5, 128.6, 128.1, 125.8, 114.4, 114.0, 112.4, 55.3, found: 399.1269.
33.8; HRMS (ESI): m/z calcd. for C21H17N3O2[M + H]+: 344.1398;
found: 344.1371.
6-(Benzo[d][1,3]dioxol-5-yl)-1-(4-methoxybenzyl)-3-phenyl-1H-
pyrazolo[3,4-b]pyridine (4k). White solid; 57% yield (123.6 mg);
mp 143–144 ꢀC; 1H NMR (500 MHz, CDCl3) d 8.80 (d, J ¼ 2.6 Hz,
4-(1-(4-Methoxybenzyl)-3-(p-tolyl)-1H-pyrazolo[3,4-b]pyridin-6-
yl)benzonitrile (4f). Light yellow solid; 72% yield (154.5 mg); mp 1H), 8.43 (d, J ¼ 2.5 Hz, 1H), 7.99–7.96 (m, 2H), 7.63–7.61 (m,
186–187 ꢀC; 1H NMR (500 MHz, CDCl3) d 8.38 (d, J ¼ 8.4 Hz, 1H), 2H), 7.52–7.47 (m, 4H), 7.43–7.38 (m, 4H), 6.85–6.82 (m, 2H),
8.28 (d, J ¼ 8.2 Hz, 2H), 7.86 (d, J ¼ 8.0 Hz, 2H), 7.81 (d, J ¼ 5.73 (s, 2H), 3.75 (s, 3H); 13C NMR (125 MHz, CDCl3).13C NMR
8.2 Hz, 2H), 7.64 (t, J ¼ 8.4 Hz, 1H), 7.44 (d, J ¼ 8.6 Hz, 2H), 7.32 showed one less carbon, it might be due to one carbon peak got
(d, J ¼ 7.9 Hz, 2H), 6.85 (d, J ¼ 8.7 Hz, 2H), 5.76 (s, 2H), 3.76 (s, merged. d 159.3, 150.5, 150.4, 148.2, 148.0, 143.0, 132.4, 129.6,
3H), 2.44 (s, 3H); 13C NMR (125 MHz, CDCl3) d 159.2, 153.7, 129.5, 128.8, 127.0, 126.9, 121.7, 120.9, 117.5, 113.9, 112.0,
151.1, 143.4, 143.0, 138.3, 132.5, 131.3, 130.2, 129.6, 129.6, 108.7, 107.5, 101.3, 55.2, 50.3; HRMS (ESI): m/z calcd. for
129.3, 127.9, 126.9, 118.8, 114.5, 113.9, 113.1, 112.6, 55.2, 50.3,
21.3; HRMS (ESI): m/z calcd. for C28H22N4O[M + H]+: 431.1871;
found: 431.1888.
C
27H21N3O3[M + H]+: 436.1660; found: 436.1648.
3-(1-(4-Methoxybenzyl)-3-(naphthalen-2-yl)-1H-pyrazolo[3,4-b]
pyridin-6-yl)phenol (4l). White solid; 52% yield (118.5 mg); mp
179.6–180.4 C; H NMR (500 MHz, CDCl3): 8.45–8.41 (m, 2H),
1
ꢀ
3-(2,4-Diuorophenyl)-1-(4-methoxybenzyl)-6-(3-methoxyphenyl)-
1H-pyrazolo[3,4-b]pyridine (4g). White solid; 63% yield (143.6 8.15 (d, J ¼ 8.5 Hz, 1H), 7.98–7.95 (m, 2H), 7.89 (d, J ¼ 7.1 Hz,
mg); mp 100–101 ꢀC; 1H NMR (500 MHz, CDCl3) d 8.22 (dd, J ¼ 1H), 7.735–7.731 (b, 2H), 7.63 (d, J ¼ 8.4 Hz, 1H), 7.55–7.51 (m,
8.4, 3.4 Hz, 1H), 7.89 (q, J ¼ 6.8 Hz, 1H), 7.78 (s, 1H), 7.74 (d, J ¼ 2H), 7.47 (d, J ¼ 8.5 Hz, 2H), 7.40 (t, J ¼ 8.1 Hz, 1H), 6.96 (dd, J ¼
7.2 Hz, 1H), 7.65 (d, J ¼ 8.5 Hz, 1H), 7.49–7.43 (m, 3H), 7.04–6.97 7.9, 1.7 Hz, 1H), 6.83 (d, J ¼ 8.5 Hz, 2H), 5.91 (s, 1H), 5.79 (s, 2H),
(m, 3H), 6.85 (d, J ¼ 8.5, 2H), 5.78 (s, 2H), 3.94 (s, 3H), 3.77 (s, 3.74 (s, 3H); 13C NMR (125 MHz, CDCl3): 159.1, 156.2, 156.0,
3H); 13C NMR (125 MHz, CDCl3) d 163.05 (dd, J ¼ 248.9, 11.7 Hz, 151.5, 142.8, 140.6, 133.5, 133.1, 131.0, 130.7, 130.0, 129.6,
1C), 160.0, 159.9 (dd, J ¼ 249.8, 11.9 Hz, 1C), 159.2, 156.3, 151.1, 129.4, 128.6, 128.2, 127.8, 126.4, 126.2, 125.9, 125.0, 119.9,
140.7, 137.7, 131.5 (t, J ¼ 2.4 Hz, 1C), 131.5 (t, J ¼ 3.4 Hz, 1C), 116.6, 114.9, 114.4, 113.9, 112.7, 55.2, 50.2. HRMS (ESI): m/z
129.8, 129.7, 129.3, 120.0, 117.3 (dd, J ¼ 14.7, 3.7 Hz, 1C), 115.0, calcd. for C3H23N3O2[M + H]: 458.1868; found: 458.1846.
114.9, 113.9, 113.2, 113.1, 112.0 (dd, J ¼ 21.1, 3.3 Hz, 1C), 104.4
General procedure for sequential one-pot Suzuki–Miyaura
(t, J ¼ 25.6 Hz, 1C), 55.4, 55.2, 50.4; HRMS (ESI): m/z calcd. for cross-coupling reactions. To a round bottom ask were added 6-
C
27H21F2N3O2[M + H]+: 458.1679; found: 458.1664.
chloro-3-iodo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine 1
1-(4-Methoxybenzyl)-6-(3-nitrophenyl)-3-(p-tolyl)-1H-pyrazolo
(0.5 mmol) dissolved in 5 mL of dioxane : water (3 : 1), catalyst
[3,4-b]pyridine (4h). Yellow solid; 53% yield (118.9 mg); mp 160– and ligand 5 mol% each. Arylboronic acid 2 (0.5 mmol, 1.0
1
ꢀ
161 C; H NMR (500 MHz, CDCl3) d 9.03 (s, 1H), 8.49 (d, J ¼ equiv.) and base (2 equiv.) were added to the above aer 5 min
7.4 Hz, 1H), 8.38 (dd, J ¼ 8.3, 2.4 Hz, 1H), 8.30 (d, J ¼ 7.9 Hz, of stirring and started heating at 60 ꢀC. When the TLC indicated
1H), 7.86 (d, J ¼ 7.8 Hz, 2H), 7.70–7.66 (m, 2H), 7.48 (d, J ¼ the total consumption of starting material, the condenser tted
8.2 Hz, 2H), 7.32 (d, J ¼ 7.7 Hz, 2H), 6.87 (d, J ¼ 8.3 Hz, 2H), 5.77 to the RB, next 15 mol% of catalyst and 15 mol% of ligand were
(s, 2H), 3.76 (s, 3H), 2.43 (s, 3H); 13C NMR (125 MHz, CDCl3) added to the same pot. Arylboronic acid 2 (0.5 mmol, 1 equiv.)
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was ꢀadded aer 5 min of stirring and stirring continued at MHz, DMSO-d6) d 13.7 (s, 1H), 8.66 (d, J ¼ 8.3 Hz, 1H), 8.23 (s,
100 C. Aer the reaction was completed as monitored by TLC 1H), 7.93 (s, 1H), 7.74 (d, J ¼ 8.9 Hz, 2H), 7.67 (d, J ¼ 8.4 Hz, 1H),
the reaction mixture was allowed to cool at ambient tempera- 7.29 (s, 1H), 6.73 (s, 1H); 13C NMR (125 MHz, DMSO-d6) d 153.4,
ture. The reaction mixture was extracted with ethyl acetate and 152.9, 147.9, 145.3, 140.0, 134.6, 131.6, 127.4, 126.5, 122.8,
the organic layer was washed with brine and distilled water. The 113.2, 113.0, 111.2, 110.6; HRMS (ESI): m/z calcd. for C14H9N3OS
combined organic layers were dried over Na2SO4 and concen- [M + H]+: 268.0544; found: 268.0524.
trated under reduced pressure. The resulting residue was
puried by column chromatography (silica gel, hexane/EtOAc)
to give the desired products. The characterisation of 4a-4b, 4f-
Conflicts of interest
4g, 4i-4j is given above.
There are no conicts of interest.
General procedure for the de-protection of diarylpyrazolo
[3,4-b]pyridines and their derivatives. To a round bottom ask
equipped with a condensor was added appropriate the pyrazolo
Acknowledgements
[3,4-b]pyridine (0.1 mmol) and it was kept in ice water for the We gratefully acknowledge the University Grants Commission
addition of TFA. TFA (2–5 mL) was carefully added to the above (UGC) and DBT for nancially supporting this work, University
and heating started at 70 ꢀC. On completion, as indicated by of Delhi for the SC-XRD analysis; USIC-CIF University of Delhi,
TLC, the reaction mixture was quenched with the satd. NaHCO3 Delhi, India and AIRF, Jawaharlal Nehru University for NMR
solution and extracted with ethyl acetate. The combined organic data and Instrumentation facility, Mass analysis.
layers were dried over Na2SO4 and concentrated under reduced
pressure. The resulting residue was puried by column chro-
matography (silica gel, hexane/EtOAc) to give the desired
References
products (5a–5d).
1 For selected reviews on Suzuki-Miyaura see:(a) N. Miyaura
and A. Suzuki, Chem. Rev., 1995, 95, 2457; (b) S. Kotha,
K. Lahiri and D. Kashinath, Tetrahedron, 2002, 58, 9633; (c)
F.-S. Han, Chem. Soc. Rev., 2013, 42, 5270; (d) R. Martin
and S. L. Buchwald, Acc. Chem. Res., 2008, 41, 1461; (e)
I. Maluenda and O. Navarro, Molecules, 2015, 20, 7528; (f)
A. J. J. Lennox and G. C. Lioyd-Jones, Chem. Soc. Rev., 2014,
43, 412; (g) A. Chatterjee and T. R. Ward, Catal. Lett., 2016,
146, 820.
3,6-Diphenyl-1H-pyrazolo[3,4-b]pyridine (5a). White solid; 99%
yield (25.9 mg); mp 207.7–208.2 ꢀC; 1H NMR (500 MHz, DMSO-
d6) d 13.8 (s, 1H), 8.61 (d, J ¼ 8.4 Hz, 1H), 8.18 (d, J ¼ 7.4 Hz, 2H),
8.05 (d, J ¼ 7.5 Hz, 2H), 7.84 (d, J ¼ 8.5 Hz, 1H), 7.54–7.51 (m,
4H), 7.49–7.41 (m, 2H); 13C NMR (125 MHz, DMSO-d6) d 155.9,
153.7, 143.0, 139.0, 133.6, 131.7, 129.9, 129.4, 129.3, 128.6,
127.6, 126.9, 115.1, 111.5; HRMS (ESI): m/z calcd. for
C
18H13N3[M + H]+: 272.1187; found: 272.1167.
6-(4-Fluorophenyl)-3-phenyl-1H-pyrazolo[3,4-b]pyridine
(5b).
2 For selected reviews on arylation of heteroaromatics see:(a)
S. W. Cho, Ji Y. Kim, J. Kwak and S. Chang, Chem. Soc.
Rev., 2011, 40, 5068; (b) R. Rossi, F. Bellina, M. Lessi and
C. Manzini, Adv. Synth. Catal., 2014, 356, 17; (c) S. El-
Kazzouli, J. Koubachi, N. El-Brahmi and G. Guillaumet,
RSC Adv., 2015, 5, 15292; (d) S. Suzuki and J. Yamaguchi,
Chem. Commun., 2017, 53, 1568; (e) Y. Yang, J. Lan and
J. You, Chem. Rev., 2017, 117, 8787; (f) V. F. Slagt,
A. H. M. Vries, J. G. Vries and R. M. Kellogg, Org. Process
Res. Dev., 2010, 14, 30; (g) L. W. Qi, J. H. Mao, J. Zhang and
B. Tan, Nat. Chem., 2018, 10, 58; (h) H. H. Zhang,
C. S. Wang, C. Li, G. J. Mei, Y. Li and F. Shi, Angew. Chem.,
Int. Ed., 2017, 56, 116; (i) Y. Y. He, X. X. Sun, G. H. Li,
G. J. Mei and F. Shi, J. Org. Chem., 2017, 82, 2462.
White solid; 86% yield (24.7 mg); mp 250–251 ꢀC; 1H NMR (500
MHz, DMSO-d6) d 13.8 (s, 1H), 8.61 (d, J ¼ 8.0 Hz, 1H), 8.24–8.17
(m, 2H), 8.04 (d, J ¼ 7.3 Hz, 2H), 7.83 (d, J ¼ 8.0 Hz, 1H), 7.53 (t, J
¼ 7.2 Hz, 2H), 7.42 (t, J ¼ 7.1 Hz, 1H), 7.35 (t, J ¼ 8.4 Hz, 2H); 1H
NMR-deutrated (500 MHz, DMSO-d6) d 8.45 (d, J ¼ 8.4 Hz, 1H),
8.09–8.06 (m, 2H), 7.89 (d, J ¼ 7.6 Hz, 2H), 7.67 (d, J ¼ 8.4 Hz,
1H), 7.43 (t, J ¼ 7.4 Hz, 2H), 7.32 (t, J ¼ 7.2 Hz, 1H), 7.22 (t, J ¼
8.6 Hz, 2H); 13C NMR (125 MHz, DMSO-d6) d 163.5 (d, J ¼
245.7 Hz, 1C), 162.6, 154.8, 153.5, 143.1, 135.5, 133.6, 131.8,
129.8 (d, J ¼ 33.7 Hz, 1C), 129.4, 128.6, 126.9, 116.2 (d, J ¼
21.4 Hz, 1C), 114.9, 111.4; HRMS (ESI): m/z calcd. for
C
18H12FN3[M + H]+: 290.1093; found: 290.1075.
6-(4-Methoxyphenyl)-3-phenyl-1H-pyrazolo[3,4-b]pyridine (5c).
White solid; 85% yield (25.5 mg); mp 252–253 ꢀC; 1H NMR (500
MHz, DMSO-d6) d 13.6 (s, 1H), 8.46 (d, J ¼ 8.5 Hz, 1H), 8.07 (d, J
¼ 8.6 Hz, 2H), 7.96 (d, J ¼ 7.7 Hz, 2H), 7.71 (d, J ¼ 8.5 Hz, 1H),
7.45 (t, J ¼ 7.6 Hz, 2H), 7.34 (t, J ¼ 7.4 Hz, 1H), 6.99 (d, J ¼ 8.7 Hz,
2H), 3.74 (s, 3H); 1H NMR-deutrated (500 MHz, DMSO-d6) d 8.42
(d, J ¼ 8.2 Hz, 1H), 8.01 (d, J ¼ 8.4 Hz, 2H), 7.89 (d, J ¼ 7.9 Hz,
2H), 7.66 (d, J ¼ 8.4 Hz, 1H), 7.43 (t, J ¼ 7.5 Hz, 2H), 7.33 (t, J ¼
7.0 Hz, 1H), 6.97 (d, J ¼ 8.4 Hz, 2H), 3.70 (s, 3H); 13C NMR (125
MHz, DMSO-d6) d 161.0, 155.6, 153.7, 143.0, 133.7, 131.5, 131.4,
129.4, 129.0, 128.5, 126.8, 114.7, 114.5, 111.0, 55.7; HRMS (ESI):
m/z calcd. for C19H15N3O[M + H]+: 302.1293; found: 302.1273.
6-(Furan-2-yl)-3-(thiophen-3-yl)-1H-pyrazolo[3,4-b]pyridine (5d).
White solid; 99% yield (25.9 mg); mp 252–253 ꢀC; 1H NMR (500
3 (a) S. Yanagisawa, K. Ueda, H. Sekizawa and K. Itami, J. Am.
Chem. Soc., 2009, 131, 14622; (b) F. Shibahara, E. Yamaguchi
and T. Murai, J. Org. Chem., 2011, 76, 2680; (c) J. M. Joo,
B. B. Toure and D. Sames, J. Org. Chem., 2010, 75, 4911; (d)
F. Shibahara, T. Yamauchi, E. Yamaguchi and T. Murai, J.
Org. Chem., 2012, 77, 8815; (e) S. El. Kazzaouli,
L. Boussane, M. Khouili and G. Guillaumet, Tetrahedron
Lett., 2005, 46, 6163; (f) M. Ye, A. J. F. Edmunds,
J. A. Morris, D. Sale, Y. Zhanga and Yu. Jin-Quan, Chem.
Sci., 2013, 4, 2374; (g) P. Kannabodia, K. Anilkumar,
S. Aravida, R. A. Vishwakarma and P. Das, Org. Lett., 2013,
15, 5718; (h) M. P. Heutis and K. A. Fagnou, Org. Lett.,
2009, 11, 1357; (i) V. Gembus, J.-F. Bonfanti, O. Querolle,
This journal is © The Royal Society of Chemistry 2018
RSC Adv., 2018, 8, 34883–34894 | 34893

View Article Online
RSC Advances
Paper
P. Jubault, V. Levacher and C. Hoarau, Org. Lett., 2012, 14, 10 M. D. Hill, H. Fang, J. M. Brown, T. Molski, A. Easton,
6012.
X. Han, R. Miller, M. Hill-Drzewi, L. Gallagher,
M. Matchett, M. Gulianello, A. Balakrishnan,
R. L. Bertekap, K. S. Santone, V. J. Whiterock, X. Zhuo,
J. J. Bronson, J. E. Macor and A. P. Degnan, ACS Med.
Chem. Lett., 2016, 7, 1082.
4 (a) J. A. Thynne, D. C. Blakemore, D. C. Pryde and
A. C. Spivey, Chem. Sci., 2017, 8, 40; (b) K. Sato, Z. Omahdi,
K. Shibata, K. Sonoda, S. Yamasaki and H. Tanaka, Chem.–
Eur. J., 2017, 23, 16374.
5 (a) S. D. Roughley and A. M. Jordan, J. Med. Chem., 2011, 54, 11 J. Jouha, M. Loubidi, J. Bouali, S. Hamri, A. Had, F. Suzenet,
3451; (b) L. G. Mercier and M. Leclerc, Acc. Chem. Res., 2013,
41, 1597; (c) Y. Segawa, T. Maekawa and K. Itami, Angew.
Chem., Int. Ed., 2015, 54, 66.
6 (a) J. Witherington, V. Bordas, S. L. Garland, D. M. B. Hickey,
R. J. Ife, J. Liddle, M. Saunders, D. G. Smith and R. W. Ward,
Bioorg. Med. Chem. Lett., 2003, 13, 1577; (b) J. Witherington,
V. Bordas, A. Gaiba, N. S. Garton, A. Naylor, A. D. Rawlings,
B. P. Slingsby, D. G. Smith, A. K. Takle and R. W. Ward,
G. Guillaumet, T. Dagci, M. Khouili, F. Aydin, L. Saso and
G. Armagan, Eur. J. Med. Chem., 2017, 129, 41.
12 (a) G. Lavecchia, S. Berteina-Raboin and G. Guillaumet,
Tetrahedron Lett., 2004, 45, 2389; (b) S. T. Heller and
S. R. Natarajan, Org. Lett., 2007, 9, 4947; (c) S. Lee and
S. B. Park, Org. Lett., 2009, 11, 5214–5217; (d)
G. L. Beutner, J. T. Kuethe, M. M. Kim and N. Yasuda, J.
Org. Chem., 2009, 74, 789.
Bioorg. Med. Chem. Lett., 2003, 13, 3055; (c) S. Huang, 13 (a) S. Faarasse, S. El-Kazzouli, M. Naas, J. Jouha, F. Suznet
R. Lin, Y. Yu, Y. Lu, P. J. Connolly, G. Chiu, S. Li,
S. L. Emanuel and S. A. Middleton, Bioorg. Med. Chem.
and G. Guillaumet, J. Org. Chem., 2017, 82, 12300; (b)
H. Lavrard and F. Popowycz, Synthesis, 2018, 50, 998.
Lett., 2007, 17, 1243; (d) R. Lin, G. Chiu, Y. Yu, 14 (a) M. Hussain, R. A. Khera, N. T. Hunga and P. Langer, Org.
P. J. Connolly, S. Li, Y. Lu, M. Adams, A. R. Fuentes-
Pesquera, S. L. Emanuel and L. M. Greenberger, Bioorg.
Med. Chem. Lett., 2007, 17, 4557; (e) P. Czodrowski,
A. Mallinger, D. Wienke, C. Esdar, O. Poschke, M. Busch,
F. Rohdich, S. A. Eccles, M. Ortiz-Ruiz, R. Schneider,
P. A. Raynaud, D. Clarke, D. Musil, T. Schwarz, K. Dale,
K. Urbahns, J. Blagg and K. Schiemann, J. Med. Chem.,
2016, 59, 9337.
7 F. Manetti, S. Schenone, F. Bondavalli, C. Brullo, O. Bruno,
A. Ranise, L. Mosti, G. Menozzi, P. Fossa, M. L. Trincavelli,
C. Martini, A. Martenelli, C. Tintori and M. Botta, J. Med.
Chem., 2005, 48, 7172.
Biomol. Chem., 2011, 9, 370; (b) S. Reimann, P. Ehlers,
A. Petrosyan, S. Kohse, A. Spannenberg, A. E. Surkus,
T. V. Ghochikyan, A. S. Saghyan, S. Lochbrunner, O. Khn,
R. Ludwig and P. Langer, Adv. Synth. Catal., 2014, 356,
1987; (c) X. Dai, Y. Chen, S. Garrell, H. Liu, Li-K. Zhang,
A. Palani, G. Hughes and R. Nargund, J. Org. Chem., 2013,
78, 7758; (d) S. Reimann, S. Parpart, P. Ehlers, M. Sharif,
A. Spannenberg and P. Langer, Org. Biomol. Chem., 2015,
13, 6832; (e) D. Montoir, A. Tonnerre, M. Duos and
B. Marc-Antoine, Eur. J. Org. Chem., 2014, 7, 1487; (f)
Sanfoi and A. Chantal, Patent WO2014/198942, 2014, A1.
15 S. Minakata, M. Komatsu and Y. Ohshiro, Synthesis, 1992, 7,
661.
8 (a) B. Zhao, Y. Li, P. Xu, Y. Dai, C. Luo, Y. Sun, J. Ai, M. Geng
and W. Duan, ACS Med. Chem. Lett., 2016, 7, 629; (b) 16 (a) T. Chan, K. Guckian, T. Jenkins, J. Thomas, J. Vessels,
A. F. Abdel-Magid, ACS Med. Chem. Lett., 2015, 6, 369.
9 Y. Li, H. Cheng, Z. Zhang, X. Zhuang, J. Luo, H. Long,
Y. Zhou, Y. Xu, R. Taghipouran, D. Li, A. Patterson,
J. Smaill, Z. Tu, D. Wu, X. Ren and K. Ding, ACS Med.
Chem. Lett., 2015, 6, 543.
G. Kumaravel, R. Meissner, J. Lyssikatos, B. Lukas, I. Leaf
and J. Duffield, Patent WO 2016/011390 A1, 2016, 105; (b)
B. S. Furniss, A. J. Hannaford, P. W. G. Smith and
A. R. Tatchell, Vogel's Textbook of Practical Organic
Chemistry, John Wiley & Sons, Inc., New York, 5th edn, 1989.
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