"On Water" Direct C-3 Arylation of 2H-Pyrazolo[3,4-b]pyridines

Article abstract of DOI:10.1021/acs.joc.7b02136

An "on water" palladium-catalyzed direct (hetero)arylation of 2H-pyrazolo[3,4-b]pyridines has been developed. The reactions proceeds smoothly with at low catalytic loading at low temperature providing the C3 (hetero)arylated products in good to excellent isolated yields. Free NH 3-arylated 7-azaindazoles were also prepared by simple cleavage of the N-protected groups.

Full text of DOI:10.1021/acs.joc.7b02136

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Article
“On Water” Direct C-3 Arylation of 2H-Pyrazolo[3,4-b]pyridines
Soukaina Faarasse, Saïd El Kazzouli, Mohammed Naas,
Jabrane Jouha, Franck Suzenet, and Gérald Guillaumet
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02136 • Publication Date (Web): 01 Nov 2017
Downloaded from http://pubs.acs.org on November 1, 2017
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“On Water” Direct Cꢀ3 Arylation of 2HꢀPyrazolo[3,4ꢀb]pyridines
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Soukaina Faarasse±,‡, Saïd El Kazzouli±*, Mohammed Naas‡, Jabrane Jouha‡, Franck
Suzenet‡* and Gérald Guillaumet‡*
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±
Euromed Faculty of Engineering, Euromed University of Fes (UEMF), Route de Meknès,
30000 Fès, Morocco.
‡
Institut de Chimie Organique et Analytique (ICOA), Université d'Orléans, UMR CNRS,
7311, BP 6759, 45067 Orléans Cedex 2, France
.
* Corresponding authors: s.elkazzouli@ueuromed.org; franck.suzenet@univꢀorleans.fr;
gerald.guillaumet@univꢀorleans.fr.
ABSTRACT. An “on water” palladium catalyzed direct (hetero)arylation of 2Hꢀ
pyrazolo[3,4ꢀb]pyridines has been developed. The reactions proceeds smoothly with at low
catalytic loading at low temperature providing the C3 (hetero)arylated products in good to
excellent isolated yields. NH Free 3ꢀarylated 7ꢀazaindazoles were also prepared by simple
cleavage of the Nꢀprotected groups.
INTRODUCTION
Direct arylation is considered nowadays as one of the most important achievements in
organic chemistry1ꢀ10. This method, in contrast to classical crossꢀcoupling reactions
(for example SuzukiꢀMiyaura and Stille), avoids the use of stoichiometric
organometallics, which are often expensive, need timeꢀconsuming preparation and may
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produce toxic byꢀproducts. Although the advances made in direct arylation, this
method still suffers from some drawbacks such as the use of drastic reaction conditions
including high temperatures, organic solvents, and high metal catalyst loading.
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2HꢀPyrazolo[3,4ꢀb]pyridines (2Hꢀ7ꢀazaindazoles) are quite rare in nature. 7ꢀAzaindazole
analogues have been reported with a broad range of biological activities. In recent examples,
they have shown activities such as potent and selective FGFR kinase inhibitors11, cꢀMet
inhibitors12,
anticancer
agents13ꢀ15
,
inhibitors
of
human
nicotinamide
phosphoribosyltransferase (NAMPT)16, dual orexin receptor antagonists (DORAs)17.
Moreover, 3ꢀarylated 7ꢀazaindazoles are present in drugs such as BAY 41ꢀ227218, BAY 63ꢀ
252119 (Riociguat, Adempas®) and BAY 41ꢀ854320 known as stimulators of soluble
guanylate cyclase (sGC) through a NOꢀindependent mechanism. This Bay drugs family
inhibit platelet aggregation, induce vasorelaxation and are used for the treatment of chronic
thromboembolic pulmonary hypertension and pulmonary arterial hypertension (Figure 1).
Fig. 1. Representative examples of drugs containing 3ꢀarylated 7ꢀazaindazoles.
Despite these important biological properties, only one example on the direct arylation of 1Hꢀ
pyrazolo[3,4ꢀb]pyridine emerged from the elegant study reported by Yu et al.21 In this case,
the crossꢀcoupling reaction was achieved via palladium direct arylation using 10 mol% of
Pd(OAc)2 in organic solvent at high temperature (toluene at 160 °C, Scheme 1).
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Water, a nonꢀtoxic liquid, is the solvent of choice for green chemistry. However,
working with water is still challenging because of its limited chemical compatibility as
well as the low aqueous solubility of large number of reactants.
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Herein we wish to report the direct (hetero)arylation of 2Hꢀ7ꢀazaindazoles under “on water”
conditions at low temperature (70 °C) using a low amount of palladium catalyst (Scheme 1).
It is noteworthy that the use of “on water” conditions in direct CꢀH arylation is still
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challenging 22ꢀ33
.
Scheme 1. Reported method on 1Hꢀ7ꢀazaindazole versus our procedure on the 2Hꢀ7ꢀ
azaindazole series.
Results and discussion
We started our investigation using 2Hꢀ7ꢀazaindazole 1a and benzene iodide as model
substrates. In an initial attempt, 1a was treated by benzene iodide (2 equiv.) in the presence of
10 mol% of Pd(OAc)2 as catalyst, 20 mol% of PPh3 and 1 equiv. of Ag2CO3 as base in H2O at
60 °C. This sequence did not give the expected product but only the starting 2Hꢀ7ꢀazaindazole
1a which was quantitatively recovered (entry 1, Table 1). The same result was observed when
PdCl2 was used instead of Pd(OAc)2 (entry 2, Table 1). However, the use of Pd(PPh3)2Cl2 as
catalyst led to the desired product in very good yield (entry 3, Table 1). When the reaction
mixture was heated at 70 °C the yield was slightly enhanced without any traces of starting
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material (entry 4, Table 1). Then, the amount of both the catalyst and the ligand were reduced
to 10 mol% without any decrease in the reaction yield (entry 5, Table 1). More interestingly,
the amount of catalyst could be reduced to 5 mol% and the desired product was isolated in
92% yield (entry 6, Table 1). Further attempts to reduce the amount of both the catalyst and
the ligand did not induce coupling (entries 7 and 8, Table 1). We also tested the effect of the
ligand by carrying out the reaction without Ph3P. Although the desired product was obtained
in 50% isolated yield, a large amount of starting material was also recovered (entry 9, Table
1). When Pd(dppf)Cl2.DCM was used instead of Pd(PPh3)2Cl2 under the optimised reaction
conditions, the expected product was obtained in a 87/13 ratio with the starting material
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1
(based on H NMR, entry 10, Table 1). We also found that bromobenzene was less reactive
than benzene iodide. The mixture needed to be heated to 110 °C to achieve a good reaction
yield, and nevertheless, 15% of starting material 1a was recovered (entry 11, Table 1). The
replacement of Ag2CO3 by either K3PO4, Cs2CO3 or K2CO3 bases led to a total loss of the
reactivity. Thus, only starting material was recovered in the cases of K3PO4 and K2CO3
(entries 12 and 13, Table 1), while, a very low yield of desired product 2a was obtained with
Cs2CO3 (entry 14, Table 1).
Table 1. Optimisation of the “on water” palladium catalysed direct (hetero)arylation of
2Hꢀpyrazolo[3,4ꢀb]pyridine 1a.
entry
X
I
I
I
I
Pd (mol %)
Pd(OAc)2 (10)
PPh3 (%) Base(2éq)
T (°C)
60
yield (%)
(100)a
(100)a
92b (traces)a
94b
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2
3
4
5
6
Ag2CO3
20
Ag2CO3
Pd(Cl)2 (10)
20
60
Ag2CO3
Pd(PPh3)2Cl2 (10)
Pd(PPh3)2Cl2 (10)
Pd(PPh3)2Cl2 (10)
Pd(PPh3)2Cl2 (5)
20
60
Ag2CO3
20
70
94b
I
I
Ag2CO3
10
70
92b
Ag2CO3
10
70
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I
I
I
Ag2CO3
Ag2CO3
Ag2CO3
Pd(PPh3)2Cl2 (5)
5
5
0
70
70
70
77c (23)a
63c (37)a
50b (42)d
Pd(PPh3)2Cl2 (2.5)
Pd(PPh3)2Cl2 (5)
10
I
Ag2CO3
Pd(dppf)Cl2.DCM (5)
10
70
87c (13)a
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12
13
14
Br
I
I
Ag2CO3
K3PO4
Pd(PPh3)2Cl2 (5)
Pd(PPh3)2Cl2 (5)
Pd(PPh3)2Cl2 (5)
Pd(PPh3)2Cl2 (5)
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10
10
10
110
70
80c (15)d
(100)a
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K2CO3
70
(100)a
I
Cs2CO3
70
10b (80)d
a % of recovered starting material 1a based on 1H NMR, b yield of isolated product 2a
,
c % of product 2a based on 1H NMR. d yield of recovered starting material 1a
The scope and limitation of the “on water” palladium catalysed direct (hetero)arylation
were investigated from the starting 2 ꢀ7ꢀazaindazole 1a and 1b with various aryl and
.
H
heteroaryl iodides (Table 2). It was found that the nature of the substituents (electronꢀ
donating or electronꢀwithdrawing groups) or steric hindrance (methoxy group at the 2ꢀ
position of the aromatic ring) on the iodoaryl ring did not affect the reaction yields
(compounds 2a-i and 2k-m). This procedure also showed a very high tolerance to
various substituents on the aryl rings (methoxy, chlorine, amide, ester, nitro, cyano and
ether groups). In only two cases were low yields obtained (compounds 2j and 2n). We
were also able to introduce heteroaryl groups such as pyridyl and pyrazyl groups in
good yields (compounds 2o and 2p).
Very recently, free (NH) 7ꢀazaindazoles were reported with very interesting biological
applications such as metabotropic glutamate receptor 5 positive allosteric modulators34,
CDK8 Inhibitors35, FGFR Kinase Inhibitors11, or analgesic and antiꢀinflammatory
activities36. In order to generate 3ꢀarylated free (NH) 7ꢀazaindazoles, we decided to use
either p
ꢀmethoxybenzyl (PMB) or trimethylsilyl ethoxymethyl chloride (SEM)37 as
protecting groups instead of Bn. This choice was mandatory because the cleavage of
the Bn protecting group led to various byꢀproducts.
The treatment of starting materials 1b containing PMB or 1c containing SEM (the
preparation of starting materials 1b and 1c is described in the supporting information)
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by either benzene iodide or 1ꢀiodoꢀ3,5ꢀdimethylbenzene as coupling partner under the
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optimised reaction conditions led to the expected 3ꢀarylated compounds 2q 2r
2t in good yields (Table 2).
, 2s and
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Table 2. Scope and limitation of the “on water” palladium catalysed direct
(hetero)arylation of 2
H
ꢀpyrazolo[3,4ꢀb]pyridines 1a-c
.
(Het)Ar
Pd(PPh3)2Cl2, PPh3
N
P
(Het)Ar-I
N
P
N
N
N
2a-t
Ag2CO3, H2O, 70 °C, 24h
N
1a, P = Bn
1b, P = PMB
1c, P = SEM
N
N
Bn
N
Bn
N Bn
N
Bn
N
N
N
N
N
N
N
2d (75%)
2a (92%)
2b (95%)
2c (85%)
O
O
O
N
Bn
N
N
Bn
N
Bn
N
N
Bn
N
N
N
N
N
N
2e (84%)
2f (89%)
2g (75%)
2h (80%)
O
O
NO2
Cl
O
NH2
N
Bn
N
N
Bn
N
N
Bn
N
N
2j (40%)
Bn
N
N
N
N
N
N
2k (80%)
N
2l (90%)
2i (90%)
O
O
N
N
N
Bn
N Bn
N
N
N
Bn
N
N
2n (40%)
Bn
N
N
N
N
N
2m (85%)
2o (60%)
2p (77%)
N
SEM
N
N
PMB
N
SEM
N
N
PMB
N
N
N
N
N
N
2s (80%)
2q (95%)
2t (83%)
2r (91%)
Then, to produce 3ꢀarylated free (NH) 7ꢀazaindazole derivatives, we treated compounds 2q and
2r with AlCl3 in anisole (Method A). This procedure furnished the expected 3ꢀarylated free
(
NH) 7ꢀazaindazoles 3a and 3b in 80 and 72% yield, respectively. In the case of 3ꢀarylated
indazoles containing a SEM protecting group (derivatives 2s and 2t), the expected 3ꢀarylated
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free (NH) 7ꢀazaindazoles 3a and 3b were obtained using two different methods B and C.
Following method B37, 2s and 2t were treated with TBAF in THF at 80°C for 5h leading to 3a
and 3b in 70 and 84% yield, respectively. Using method C38 (TBAF /ethylenediamine in DMF
at 50°C for 2h), the expected 3ꢀarylated free (NH) 7ꢀazaindazoles 3a and 3b were isolated in
85 and 88% yield, respectively (Scheme 2).
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Scheme 2. Preparation of 3ꢀarylated free NH 7ꢀazaindazoles 3a-b
.
To produce 3ꢀarylated free (NH) 7ꢀazaindazole derivatives with limiting timeꢀ
consuming purifications, we proposed an arylation/deprotection sequence directly from
staring materials 1b and 1c, without any gel chromatography of the intermediates 2q
and 2s. Thus, 1b was arylated under optimized “on water” reaction conditions, then,
after filtration, extraction and removal of solvent, crude product 2q was treated by
AlCl3 in anisole (Method A). This procedure furnished the expected 3ꢀarylated free
(NH) 7ꢀazaindazoles 3a in 88% yield, (two steps yield). In the case of starting material
1c, the treatment under similar arylation conditions led to intermediate 2s, then, the
expected 3ꢀarylated free (NH) 7ꢀazaindazoles 3a was achieved by treatment of crude
intermediate 2s by TBAF /ethylenediamine in DMF at 50°C for 2h38. The expected 3ꢀ
arylated free (NH) 7ꢀazaindazoles 3a was isolated in 90% yield (two steps yield)
(Scheme 3).
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Scheme 3. Arylation/deprotection route to 3ꢀarylated free NH 7ꢀazaindazole 3a
.
CONCLUSIONS
In conclusion, we have reported an original direct (hetero)arylation of 2Hꢀ
pyrazolo[3,4ꢀb]pyridines in good to excellent yields under “on water” conditions at 70
°C using only 5 mol% of palladium catalyst. This procedure tolerates a wide variety of
functional groups. Under mild reaction conditions, we have also shown the possibility
of generating free (NH) pyrazolo[3,4ꢀ
protecting groups. Improved
b
]pyridines by the cleavage of the PMB or SEM
yields were obtained using an
(hetero)arylation/deprotection sequence avoiding gel chromatography purification of
crude intermediates.
EXPERIMENTAL SECTION
General Information: The reactions were monitored by thinꢀlayer chromatography (TLC)
using aluminum sheets coated with silica gel 60 F254. Flash column chromatography was
1
carried out using silica gel 60 Å (0.04−0.06 mm). H and 13C NMR spectra were recorded
with a 250 MHz (1H: 250 and 13C: 63 MHz) or 400 MHz (1H: 400 and 13C: 100.7 MHz)
1
Bruker spectrometer using CDCl3 as solvent. Chemical shifts of H NMR were recorded in
parts per million (ppm, δ) relative to tetramethylsilane (δ = 0.00 ppm) calibrated to the
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residual solvent peak as an internal standard (CDCl3: δ = 7.26 ppm). Data are reported as
follow: chemical shift in ppm (δ), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet,
m = multiplet), coupling constant (Hz), and integration. Chemical shifts of 13C NMR were
reported in ppm and calibrated to the residual solvent peak as an internal standard (CDCl3: δ =
77.0 ppm). Highꢀresolution mass spectra (HRMS) were recorded with a Maxis Bruker 4G
instrument and were performed in positive mode with an ESI source on a QꢀTOF mass
spectrometer with an accuracy tolerance of 2 ppm by the “Federation de Recherche”
ICOA/CBM (FR2708) platform.
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Materials: Unless otherwise noted, all reagentꢀgrade chemicals and solvents commercially
available were used without further purification. All aryl iodides, silver carbonate and
triphenylphosphine were stored in sealed, cool and dry conditions.
Synthesis of starting material 1H-pyrazolo [3,4-b] pyridine
Hydrazine hydrate (10 mL) was added to a mixture of 2ꢀchloroꢀ3ꢀformylpyridine (5.00 g, 35
mmol) and pꢀTsOH (3.50 g, 18 mmol). The reaction mixture was stirred for 3 h at 130 °C.
Upon cooling with cold water, the mixture was extracted with EtOAc. The combined organic
extracts were dried over anhydrous MgSO4. After filtration, the solvent was removed in
vacuum to give 1Hꢀpyrazolo [3,4ꢀb] pyridine (3.74 g, 90%) as a yellow solid.
1H-Pyrazolo [3,4-b]pyridine :
Yield: (3,8 g, 90%) White solid, mp 98ꢀ99 °C. (literature, 88ꢀ90°C39, 97ꢀ98°C40), IR (neat): ν˜
= 3450, 3089 , 2958, 1429 cm–1. 1H NMR (400 MHz, CDCl3): δ = δ13.65 (s, 1H), 8.66 (dd, J
= 4.6, 1.6 Hz, 1H), 8.13 (s, 1H), 8.12 (d, J = 1.6 Hz, 1H), 7.16 (dd, J = 8.0, 4.6 Hz, 1H) ppm.
13C NMR (101 MHz, CDCl3): δ = 151.8, 148.7, 133.7, 130.6, 117.0, 115.4 ppm. HRMS:
calcd. for C6H6N3[M+H]+: 120.0555, found 120.0556.
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N-Alkylation of 1H-pyrazolo [3,4-b] pyridine
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Potassium hydroxide (1.4 g, 25.21 mmol) was added to a solution of 1Hꢀpyrazolo [3,4ꢀb]
pyridine (1 g, 8.40 mmol) in acetone (10 mL), and the mixture was maintained for 60 min at
0 °C. Then, benzyl chloride (1.5 g, 12.6 mmol, 1.5 equiv) or 4ꢀmethoxybenzyl chloride (1.9 g,
12.6 mmol, 1.5 equiv) was added. The reaction mixture was warmed to room temperature and
maintained for 7 h. The reaction mixture was quenched with water and extracted with EtOAc.
The combined organic extracts were dried over anhydrous MgSO4. After filtration, the solvent
was removed in vacuum. The desired products were purified by column chromatography
(petroleum ether /AcOEt, 8:2) for the benzylated product 1a (50% yield) and (petroleum ether
/AcOEt, 1:1) for the paraꢀmethoxybenzylated product 1b (51% yield).
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2-Benzyl-2H-pyrazolo[3,4-b]pyridine 1a.
Yield: (875 mg, 50%) yellow solid, mp 142ꢀ143 °C (literature 142ꢀ144 C°40). IR (neat): ν˜ =
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3088, 2943, 1615, 1157, cm–1. H NMR (400 MHz, CDCl3): δ = 8.69 (dd, J = 4.2, 1.8 Hz,
1H), 7.98 (dd, J = 8.3, 1.8 Hz, 1H), 7.86 (s, 1H), 7.41 – 7.30 (m, 5H), 7.03 (dd, J = 8.3, 4.2
Hz, 1H), 5.63 (s, 2H) ppm. 13C NMR (101 MHz, CDCl3): δ = 158.5, 151.6, 135.2, 129.7,
129.1, 128.7, 128.5, 122.5, 117.9, 114.4, 58.2 ppm. HRMS: calcd. for C13H12N3[M+H]+:
210.1025, found 210.1025.
2-(4-Methoxybenzyl)-2H-pyrazolo[3,4-b]pyridine 1b.
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Yield: (1,02 g, 51%) red liquid. IR (neat): ν˜ = 3417, 2935, 1667, 1176, cm–1. H NMR (400
MHz, CDCl3): δ = 8.65 (d, J = 4.2 Hz, 1H), 7.95 (d, J = 8.3 Hz, 1H), 7.83 (s, 1H), 7.30 (d, J =
8.3 Hz, 2H), 6.98 (dd, J = 8.3, 4.2 Hz, 1H), 6.87 (d, J = 8.3 Hz, 2H), 5.52 (s, 2H), 3.77 (s, 3H)
ppm. 13C NMR (101 MHz, CDCl3) δ = 159.8, 158.3, 151.2, 130.0, 129.6, 127.0, 122.2, 117.6,
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114.2, 114.2, 57.5, 55.2 ppm. HRMS: calcd. for C14H14N3O[M+H]+: 240.1133, found
240.1131.
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Procedure of 1H-pyrazolo [3,4-b]pyridine protection by SEM6
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To a cold, stirred solution of 1Hꢀpyrazolo [3,4ꢀb]pyridine (150 mg, 1.26 mmol) in dry THF (5
mL), N,Nꢀdicyclohexylmethylamine (1.5 mmol) was added dropwise over a period of 15 min.
Then a solution of 2ꢀ(trimethylsilyl)ethoxymethyl chloride (1.26 mmol) in THF (1 mL) was
added over a period of 45 min. The reaction mixture was slowly warmed to room temperature
and stirred for 36 hours. The reaction was then diluted with pentane and the resulting
suspension was stirred at 20 °C for 30 min. The reaction mixture was filtered through a pad of
celite and the solid was washed with of pentane. The filtrate was concentrated under vacuum
and purified by column chromatography on silica gel (elution with DCM/AcOEt, 1:1) to yield
compound 1c in 60% as a white solid.
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2-((2-(Trimethylsilyl)ethoxy)methyl)-2H-pyrazolo[3,4-b]pyridine 1c.
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Yield: (188 mg, 60%) White solid, mp 75ꢀ77 °C. IR (neat): ν˜ = 3103, 2952, 1615, cm–1. H
NMR (250 MHz, CDCl3) δ = 8.66 (dd, J = 4.2, 1.7 Hz, 1H), 8.09 (s, 1H), 8.01 (dd, J = 8.4, 1.7
Hz, 1H), 7.00 (dd, J = 8.4, 4.2 Hz, 1H), 5.71 (s, 2H), 3.59 (t, J = 8.0 Hz, 2H), 0.87 (t, J = 8.0
Hz, 2H), ꢀ0.09 (s, 9H) ppm. 13C NMR (101 MHz, CDCl3) δ 158.2, 152.2, 130.1, 122.3, 118.3,
114.5, 82.5, 68.1, 18.0, ꢀ1.2. HRMS: calcd. for C12H20N3OSi[M+H]+: 250.1368, found
250.1370.
Procedure for on water direct arylation of 2-benzyl-2H-pyrazolo [3,4-b]pyridine with
benzene iodide :
A sealed tube was charged with 2ꢀbenzylꢀ2Hꢀpyrazolo[3,4ꢀb]pyridine (50 mg, 0.23 mmol,
1equiv), benzene iodide (93.84 mg, 0.46 mmol, 2 equiv), Pd(PPh3)2Cl2 (8.39 mg, 0.011 mmol,
5 mol%), Ag2CO3 (63.42 mg, 0,23 mmol, 1 equiv) and PPh3 (6.03 mg, 0,023 mmol, 10
mol%). A magnetic stirrer bar was added and the mixture of solids was gently shaken for a
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few seconds to ensure all solids were well mixed. Distilled water (3 mL) was added and the
tube was covered with a cap. The tube and its contents were then heated and stirred in a
preheated oil bath at 70 °C for 24 h. After this time the reaction mixture was cooled down to
room temperature. CH2Cl2 (5 mL) was added and the contents of the tube were filtered
through a short pad of celite. The tube was rinsed once with an additional 2 mL of CH2Cl2.
The organic layer was separated, and the aqueous phase extracted once with CH2Cl2. The
organic layers were combined and concentrated in vacuo. The residue was purified by flash
chromatography (silica; petroleum ether /ethyl acetate, 1:1) to provide the title compound as a
white solid in 92% yield.
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2-Benzyl-3-phenyl-2H-pyrazolo [3,4-b] pyridine 2a.
Yield: (60 mg, 92%) White solid, mp 135ꢀ136 °C. IR (neat): ν˜ = 3048, 3033, 1614, 1336,
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cm–1. H NMR (400 MHz, CDCl3): δ = 8.73 (dd, J = 4.2, 1.7 Hz, 1H), 7.93 (dd, J = 8.3, 1.7
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Hz, 1H), 7.59 – 7.16 (m, 10H), 7.04 (dd, J = 8.3, 4.2 Hz, 1H), 5.66 (s, 2H) ppm. C NMR
(101 MHz, CDCl3): δ = 157.9, 152.0, 136.4, 136.4, 129.9, 129.7, 129.46, 129.2, 129.0, 128.7,
128.0, 127.4, 118.0, 113.8, 54.9 ppm. HRMS: calcd. for C19H16N3 [M+H]+: 286.1337, found
286.1338.
2-Benzyl-3-p-tolyl-2H-pyrazolo [3,4-b] pyridine 2b.
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Yield: (65 mg, 95%) yellow liquid. IR (neat): ν˜ = 3031, 1609, 1337 cm–1. H NMR (400
MHz, CDCl3): δ = 8.73 (dd, J = 4.1, 1.8 Hz, 1H), 7.92 (dd, J = 8.3, 1.8 Hz, 1H), 7.41 – 7.12
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(m, 9H), 7.03 (dd, J = 8.3, 4.1 Hz, 1H), 5.65 (s, 2H), 2.45 (s, 3H) ppm. C NMR (101 MHz,
CDCl3): δ = 158.0, 152.0, 139.6, 136.6, 130.1, 130.0, 129.9, 129.7, 128.8, 128.0, 127.5,
126.0, 117.9, 113.8, 54.8, 21.5 ppm. HRMS: calcd. for C20H18N3 [M+H]+: 300.1495, found
300.1496.
2-Benzyl-3-m-tolyl-2H-pyrazolo[3,4-b]pyridine 2c.
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Yield: (58 mg, 85%) yellow solid, mp 110ꢀ111 °C. IR (neat): ν˜ = 3051, 1615, 1337, cm–1. 1H
NMR (400 MHz, CDCl3): δ = 8.72 (d, J = 4.0 Hz, 1H), 7.92 (d, J = 8.3 Hz, 1H), 7.39 (t, J =
7.5 Hz, 1H), 7.34 – 7.14 (m, 8H), 7.02 (dd, J = 8.3, 4.0 Hz, 1H), 5.64 (s, 2H), 2.39 (s, 3H). 13C
NMR (101 MHz, CDCl3): δ = 157.9, 152.0, 138.9, 136.6, 136.5, 130.4, 130.1, 130.0, 129.0,
128.8, 128.7, 127.9, 127.5, 126.8, 117.8, 113.8, 54.9, 21.4 ppm. HRMS: calcd. for
C20H18N3[M+H]+: 300.1497, found 300.1495.
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2-Benzyl-3-o-tolyl-2H-pyrazolo [3,4-b] pyridine 2d.
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Yield: (51 mg, 75%) yellow liquid. IR (neat): ν˜ = 3056, 1494, 1337, cm–1. H NMR (400
MHz, CDCl3): δ = 8.72 (dd, J = 4.1, 1.5 Hz, 1H), 7.71 (dd, J = 8.3, 1.5 Hz, 1H), 7.51 – 7.03
(m, 9H), 7.00 (dd, J = 8.3, 4.1 Hz, 1H), 5.45 (q, J = 14.4 Hz, 2H), 1.85 (s, 3H) ppm. 13C NMR
(101 MHz, CDCl3): δ = 157.7, 151.9, 138.6, 135.7, 135.5, 131.0, 130.7, 130.1, 129.8, 128.6,
128.3, 128.2, 128.1, 126.2, 117.7, 114.3, 55.2, 19.7 ppm. HRMS: calcd. for C20H18N3
[M+H]+: 300.1495, found 300.1497.
2-Benzyl-3-(3,5-dimethylphenyl)-2H-pyrazolo[3,4-b]pyridine 2e.
Yield: (60 mg, 84%) yellow solid, mp 111ꢀ112 °C. IR (neat): ν˜ = 3032, 2946, 1395, cm–1. 1H
NMR (400 MHz, CDCl3): δ = 8.74 (dd, J = 4.2, 1.3 Hz, 1H), 7.95 (dd, J = 8.3, 1.3 Hz, 1H),
7.28 (m, 5H), 7.15 (s, 1H), 7.04 (dd, J = 8.3, 4.2 Hz, 1H), 7.01 (s, 2H), 5.65 (s, 2H), 2.37 (s,
6H). 13C NMR (101 MHz, CDCl3): δ = 157.9, 151.9 138.8, 136.8, 136.7, 131.0, 130.1, 128.7,
128.6, 127.9, 127.6, 127.5, 117.7, 113.7, 54.9, 21.3 ppm. HRMS: calcd. for C21H20N3[M+H]+:
314.1652, found 314.1651.
2-Benzyl-3-(4-methoxyphenyl)-2H-pyrazolo[3,4-b] pyridine 2f.
Yield: (64 mg, 89%) White solid, mp 134ꢀ135 °C. IR (neat): ν˜ = 3007, 2961, 1606, 1250 cm–
1
1. H NMR (400 MHz, CDCl3): δ = 8.72 (dd, J = 4.2, 1.7 Hz, 1H), 7.91 (dd, J = 8.3, 1.7 Hz,
1H), 7.43 – 7.13 (m, 7H), 7.08 – 6.96 (m, 3H), 5.63 (s, 2H), 3.88 (s, 3H) ppm. 13C NMR (101
MHz, CDCl3): δ = 160.5, 158.0, 152.0, 136.6, 136.4, 131.1, 130.0, 128.7, 127.9, 127.4, 121.1,
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117.7, 114.7, 113.8, 55.5, 54.7 ppm. HRMS: calcd. for C20H18N3O[M+H]+: 316.1444, found
316.1446.
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Yield: (54 mg, 75%) yellow liquid. IR (neat): ν˜ = 3058, 2960, 1615, 1495, cm–1. H NMR
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(400 MHz, CDCl3): δ= 8.70 (d, J = 8.3, 1H), 7.80 (dd, J = 8.3, 1.4 Hz, 1H), 7.49 (td, J = 8.3,
1.4 Hz, 1H), 7.22 – 7.04 (m, 8H), 7.92 (dd, J = 8.3, 1.4 Hz, 1H), 5.52 (s, 2H), 3.66 (s, 3H)
ppm. 13C NMR (101 MHz, CDCl3): δ = 158.0, 157.4, 151.7, 136.3, 133.1, 132.2, 131.4,
130.1, 128.4, 127.9, 127.7, 121.0, 117.8, 117.5, 114.6, 111.5, 55.5, 55.5 ppm. HRMS: calcd.
for C20H18N3O [M+H]+: 316.1444, found 316.1442.
2-Benzyl-3-(3-methoxyphenyl)-2H-pyrazolo[3,4-b] pyridine 2h.
Yield: (58 mg, 80%) White solid, mp 88ꢀ89 °C. IR (neat): ν˜ = 3059, 2938, 1604, 1283, cm–1.
1H NMR (400 MHz, CDCl3): δ= 8.74 (dd, J = 4.3, 1.7 Hz, 1H), 7.95 (dd, J = 8.3, 1.7 Hz, 1H),
7.48 – 7.34 (m, 1H), 7.34 – 7.15 (m, 5H), 7.09 – 6.95 (m, 3H), 6.88 (dd, J = 8.3, 4.3 Hz, 1H),
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5.67 (s, 2H), 3.73 (s, 3H) ppm. C NMR (101 MHz, CDCl3): δ = 160.0, 158.0, 152.1, 136.6,
136.3, 130.3, 130.1, 130.0, 128.8, 128.0, 127.4, 122.1, 118.0, 115.3, 115.0, 113.8, 55.4, 55.0
ppm. HRMS: calcd. for C20H18N3O[M+H]+: 316.1444, found 316.1444.
2-Benzyl-3-(4-chlorophenyl)-2H-pyrazolo[3,4-b]pyridine 2i.
Yield: (66 mg, 90%) yellow liquid. IR (neat): ν˜ = 3059, 1500, 706 cm–1. 1H NMR (400 MHz,
CDCl3): δ = 8.74 (dd, J = 4.3, 1.7 Hz, 1H), 7.89 (dd, J = 8.4, 1.7 Hz, 1H), 7.49 (d, J = 7.2 Hz,
2H), 7.37 – 7.23 (m, 5H), 7.16 (d, J = 7.2 Hz, 2H), 7.06 (dd, J = 8.4, 4.3 Hz, 1H), 5.64 (s, 2H)
ppm. 13C NMR (101 MHz, CDCl3): δ = 157.9, 152.2, 136.3, 135.8, 135.1, 131.0, 129.6,
129.6, 128.9, 128.2, 127.4, 127.3, 118.3, 114.0, 55.0 ppm. HRMS: calcd. for C19H15ClN3
[M+H]+: 320.0949, found 320.0948.
4-(2-Benzyl-2H-pyrazolo[3,4-b]pyridin-3-yl) benzamide 2j.
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Yield: (30 mg, 40%) Colorless liquid. IR (neat): ν˜ = 3351, 3200, 1611, cm–1. H NMR (400
MHz, CDCl3): δ= 8.76 (dd, J = 4.2, 1.7 Hz, 1H), 7.97 (d, J = 8.2 Hz, 2H), 7.92 (dd, J = 8.2,
1.7 Hz, 1H), 7.50 (d, J = 8.2 Hz, 2H), 7.36 – 7.13 (m, 7H), 7.09 (dd, J = 8.2, 4.2 Hz, 1H), 5.67
(s, 2H) ppm. 13C NMR (101 MHz, CDCl3): δ = 168.3, 157.9, 152.3, 136.2, 135.1, 134.1,
132.5, 130.0, 129.6, 128.9, 128.3, 128.2, 127.3, 118.6, 114.2, 55.2 ppm. HRMS: calcd. for
C20H17N4O[M+H]+: 329.1396, found 329.1397.
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Ethyl 4-(2-benzyl-2H-pyrazolo[3,4-b]pyridin-3-yl)benzoate 2k.
Yield: (65 mg, 80%) yellow solid, mp 112ꢀ113 °C. IR (neat): ν˜ = 2977, 1712, 1606, 1162,
cm–1. 1H NMR (400 MHz, CDCl3): δ= 8.75 (dd, J = 4.2, 1.4 Hz, 1H), 8.18 (d, J = 8.2 Hz, 2H),
7.93 (dd, J = 8.2, 1.4 Hz, 1H), 7.50 (d, J = 8.2 Hz, 2H), 7.30 – 7.13 (m, 5H), 7.08 (dd, J = 8,2,
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4.2 Hz, 1H), 5.68 (s, 2H), 4.44 (q, J = 7.1 Hz, 2H), 1.43 (t, J = 7.1 Hz, 3H) ppm. C NMR
(101 MHz, CDCl3): δ = 165.9, 157.9, 152.2, 136.1, 135.2, 133.2, 131.2, 130.3, 129.6, 129.6,
128.8, 128.1, 127.3, 118.5, 114.0, 61.5, 55.2, 14.4 ppm. HRMS: calcd. for
C22H20N3O2[M+H]+: 358.1550, found 358.1550.
2-Benzyl-3-(4-nitrophenyl)-2H-pyrazolo[3,4-b] pyridine 2l.
Yield: (68 mg, 90%) yellow solid, mp 150ꢀ151 °C. IR (neat): ν˜ = 3059, 1576, 1541, 1328,
cm–1. 1H NMR (400 MHz, CDCl3): δ= 8.78 (dd, J = 4.2, 1.7 Hz, 1H), 8.36 (d, J = 8.4 Hz, 2H),
7.93 (dd, J = 8.4, 1.7 Hz, 1H), 7.60 (d, J = 8.4 Hz, 2H), 7.32 – 7.24 (m, 3H), 7.18 – 7.10 (m,
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3H), 5.70 (s, 2H) ppm. C NMR (101 MHz, CDCl3): δ = 157.8, 152.4, 148.1, 135.8, 135.3,
133.7, 130.5, 129.1, 129.0, 128.4, 127.2, 124.4, 119.1, 114.2, 55.5 ppm. HRMS: calcd. for
C19H15N4O2[M+H]+: 331.1189, found 331.1190.
4-(2-Benzyl-2H-pyrazolo[3,4-b]pyridin-3-yl) benzonitrile 2m.
Yield: (60 mg, 85%) Colorless liquid. IR (neat): ν˜ = 3350, 3187, 2221, 1608, cm1. H NMR
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(400 MHz, CDCl3): δ= 8.76 (dd, J = 4.2, 1.3 Hz, 1H), 7.96 (d, J = 8.3 Hz, 2H), 7.92 (dd, J =
8.3, 1.3 Hz, 1H), 7.50 (d, J = 8.3 Hz, 2H), 7.36 – 7.22 (m, 3H), 7.20 – 7.14 (m, 2H), 7.09 (dd,
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J = 8.3, 4.2 Hz, 1H), 5.67 (s, 2H) ppm. 13C NMR (101 MHz, CDCl3): δ = 168.6, 158.2, 157.1,
152.6, 136.5, 134.4, 132.9, 130.3, 129.9, 129.2, 128.6, 128.5, 127.6, 118.9, 114.4, 55.5 ppm.
HRMS: calcd. for C20H15N4[M+H]+: 311.1396, found 311.1397.
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3-(Benzo[d][1,3]dioxol-5-yl)-2-benzyl-2H pyrazolo[3,4-b]pyridine 2n.
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Yield: (30 mg, 40%) yellow solid, mp 151ꢀ152 °C. IR (neat): ν˜ = 3057, 2916, 1602,
1035,cm–1. 1H NMR (400 MHz, CDCl3): δ= 8.72 (dd, J = 4.3, 1.7 Hz, 1H), 7.91 (dd, J = 8.4,
1.7 Hz, 1H), 7.33 – 7.11 (m, 5H), 7.03 (dd, J = 8.4, 4.3 Hz, 1H), 6.96 – 6.80 (m, 2H), 6.06 (s,
2H), 5.64 (s, 2H)). 13C NMR (101 MHz, CDCl3): δ= 157.9, 152.0, 148.7, 148.3, 136.4, 136.1,
129.9, 129.1, 128.8, 128.3, 128.0, 127.4, 117.9, 113.8, 109.9, 109.0, 101.7, 54.8 ppm. HRMS:
calcd. for C20H16N3O2[M+H]+: 330.1237, found 330.1237.
2-Benzyl-3-(pyridin-4-yl)-2H-pyrazolo[3,4-b] pyridine 2o.
Yield: (40 mg, 60%) yellow solid, mp 138ꢀ139 °C. IR (neat): ν˜ = 3369, 2849, 1398, 1275
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cm–1. H NMR (400 MHz, CDCl3): δ= 8.83 – 8.73 (m, 3H), 7.97 (dd, J = 8.4, 1.7 Hz, 1H),
7.37 – 7.27 (m, 5H), 7.17 – 7.10 (m, 2H), 7.13 (dd, J = 8.4, 4.3 Hz, 1H), 5.71 (s, 2H) ppm. 13C
NMR (101 MHz, CDCl3): δ = 158.0, 152.4, 150.8, 136.8, 135.9, 133.3, 129.2, 129.0, 128.3,
127.2, 123.8, 119.0, 114.0, 55.3 ppm. HRMS: calcd. for C18H15N4 [M+H]+: 287.1291, found
287.1290.
2-Benzyl-3-(pyrazin-2-yl)-2H-pyrazolo[3,4-b]pyridine 2p.
Yield: (51 mg, 77%) White solid, mp 148ꢀ149 °C. IR (neat): ν˜ = 3057, 2919, 1603, 1395,
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1187 cm–1. H NMR (400 MHz, CDCl3): δ= 8.94 (d, J = 1.7 Hz, 1H), 8.84 – 8.68 (m, 2H),
8.59 (dd, J = 2.5, 0.3 Hz, 1H), 8.20 (dd, J = 8.4, 1.7 Hz, 1H), 7.32 – 7.07 (m, 6H), 6.15 (s,
2H). 13C NMR (101 MHz, CDCl3): δ= 157.4, 151.7, 144.5, 144.1, 144.1, 143.3, 135.8, 129.8,
128.9, 128.3, 127.7, 127.5, 119.2, 113.7, 55.9 ppm. HRMS: calcd. for C17H14N5[M+H]+:
288.1243, found 288.1243.
2-(4-Methoxybenzyl)-3-phenyl-2H-pyrazolo[3,4-b]pyridine 2q.
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Yield: (60 mg, 95%) Colorless liquid. IR (neat): ν˜ = 3410, 2928, 1173 cm–1. H NMR (400
MHz, CDCl3): δ= 8.73 (d, J= 8.3 Hz, 1H), 7.92 (d, J = 8.3 Hz, 1H), 7.52 (d, J = 5.2 Hz, 3H),
7.45 – 7.37 (m, 2H), 7.14 (d, J = 8.3 Hz, 2H), 7.04 (dd, J = 8.3, 3.7 Hz, 1H), 6.79 (d, J = 8.3
Hz, 2H), 5.59 (s, 2H), 3.76 (s, 3H) ppm. 13C NMR (101 MHz, CDCl3): δ = 159.1, 157.7,
151.7, 136.1, 129.8, 129.7, 129.3, 129.1, 129.0, 128.9, 128.5, 128.4, 117.8, 114.0, 55.2, 54.3
ppm. HRMS: calcd. for C20H18N3O [M+H]+: 316.1443, found 316.1444.
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2-(4-Methoxybenzyl)-3-(3,5-dimethylphenyl)-2H-pyrazolo[3,4-b]pyridine 2r.
Yield: (62 mg, 91%) Colorless liquid. IR (neat): ν˜ = 3201, 3088, 2818 , 1290 cm–1. 1H NMR
(400 MHz, CDCl3): δ= 8.70 (dd, J = 5.2, 1.4 Hz, 1H), 7.91 (dd, J = 8.4, 1.4 Hz, 1H), 7.21 –
7.12 (m, 3H), 7.01 (d, J = 5.2 Hz, 3H), 6.80 (d, J = 8.4 Hz, 2H), 5.56 (s, 2H), 3.76 (s, 3H),
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2.37 (s, 6H) ppm. C NMR (101 MHz, CDCl3): δ= 159.7, 158.2, 152.1, 139.1, 136.9, 131.3,
130.4, 129.5, 129.2, 129.0, 127.9, 118.0, 114.3, 114.1, 55.6, 54.7, 21.7 ppm. HRMS: calcd.
for C22H22N3O [M+H]+: 344.1756, found 344.1757.
3-Phenyl-2-((2-(trimethylsilyl) ethoxy) methyl)-2H-pyrazolo[3,4-b]pyridine 2s.
Yield: (52 mg, 80%) White solid, mp 79ꢀ81 °C. IR (neat): ν˜ = 3105, 2953, 2927, 1600 cm–1.
1H NMR (250 MHz, CDCl3) δ 8.75 (dd, J = 4.1, 1.6 Hz, 1H), 8.05 (dd, J = 8.4, 1.6 Hz, 1H),
7.74 (d, J = 7.1 Hz, 2H), 7.60 – 7.44 (m, 3H), 7.07 (dd, J = 8.4, 4.1 Hz, 1H), 5.74 (s, 2H), 3.93
(t, J = 8.0 Hz, 2H), 0.98 (t, J = 8.0 Hz, 2H), ꢀ0.01 (s, 9H) ppm. 13C NMR (101 MHz, CDCl3)
δ 157.7, 152.7, 137.1, 130.5, 129.8, 129.3, 129.2, 128.9, 118.3, 113.6, 79.6, 68.2, 18.2, ꢀ1.2
ppm. HRMS: calcd. for C18H24N3OSi[M+H]+: 326.1680, found 326.1683.
3-(3,5-Dimethylphenyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-pyrazolo[3,4-b]pyridine
2t.
1
Yield: (58 mg, 83%) Colorless liquid IR (neat): ν˜ = 3137, 2913, 1604 cm–1. H NMR (250
MHz, CDCl3) δ 8.75 (dd, J = 4.1, 1.8 Hz, 1H), 8.04 (dd, J = 8.4, 1.8 Hz, 1H), 7.33 (s, 2H),
7.15 (s, 1H), 7.05 (dd, J = 8.4, 4.1 Hz, 1H), 5.73 (s, 2H), 3.9 (t, J = 8.0 Hz, 2H), 2.42 (s, 6H),
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0.87 (t, J = 8.0 Hz, 2H), ꢀ0.01 (s, 9H) ppm. 13C NMR (101 MHz, CDCl3) δ 157.7, 152.6,
138.9, 137.5, 131.1, 130.7, 128.7, 127.5, 118.1, 113.5, 79.6, 68.1, 21.5, 18.1, ꢀ1.1 ppm.
HRMS: calcd. for C20H28N3OSi[M+H]+: 354.1993, found 354.1996.
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General protocol for arylation/deprotection sequence
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A sealed tube was charged with 2ꢀRꢀ2Hꢀpyrazolo[3,4ꢀb]pyridine 1b or 1c (1equiv), benzene
iodide (2 equiv), Pd(PPh3)2Cl2 ( 5 mol%), Ag2CO3 (1 equiv) and PPh3 (10 mol%). A magnetic
stirrer bar was added and the mixture of solids was gently shaken for a few seconds to ensure
all solids were well mixed. Distilled water (3 mL) was added and the tube was covered with a
cap. The tube and its contents were then heated and stirred in a preheated oil bath at 70 °C for
24 h. After this time the reaction mixture was cooled down to room temperature. CH2Cl2 (5
mL) was added and the contents of the tube were filtered through a short pad of celite. The
tube was rinsed once with an additional 2 mL of CH2Cl2. The organic layer was separated,
and the aqueous phase extracted once with CH2Cl2. The organic layers were combined and
concentrated in vacuo. For the gross of 2ꢀPMBꢀ3ꢀphenylꢀ2Hꢀpyrazolo [3,4ꢀb] pyridine 2q, 3
mL of anisole was added with 10 equiv of aluminum chloride. The mixture was then stirred at
0°C for 1 hour then poured into ice. The precipitate was filtered off, washed with water, to
afford compound 3a in 90% yield. For the gross of 2ꢀSEMꢀ3ꢀphenylꢀ2Hꢀpyrazolo [3,4ꢀb]
pyridine 2s, tetrabutylammonium fluoride (1M in THF, 3 equiv) and ethylenediamine (6
equiv) were added in N,Nꢀdimethylformamide (2 mL). The mixture was then stirred at 50°C
for 2h. After cooling, the volatiles were removed by evaporation in vacuo and coꢀevaporation
with toluene. The residue was purified by column chromatography on silica to afford
compound 3a in 88% yield.
3-Phenyl-1H-pyrazolo[3,4-b]pyridine 3a
Yield: (34 mg, 88%) green solid, mp 164ꢀ165 °C. IR (neat): ν˜ = 3209, 3146, 3055, 1600,
1292 cm–1. 1H NMR (400 MHz, CDCl3): δ= 12.83 (s, 1H), 8.69 (d, J = 4.5 Hz, 1H), 8.43 (d, J
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= 8.1 Hz, 1H), 8.01 (d, J = 8.1 Hz, 2H), 7.54 (t, J = 7.6 Hz, 2H), 7.46 (t, J = 7.6 Hz, 1H), 7.26
4
5
6
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(dd, J = 8.1, 4.5 Hz, 1H) ppm. C NMR (101 MHz, CDCl3): δ= 153.0, 148.7, 144.7, 133.1,
130.9, 129.0, 128.5, 127.2, 117.2, 113.4 ppm. HRMS: calcd. for C12H10N3 [M+H]+: 196.0871,
found 196.0869.
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3-(3,5-Dimethylphenyl)-1H-pyrazolo[3,4-b]pyridine 3b:
Yield: (23 mg, 72%) White solid, mp 172ꢀ173 °C. IR (neat): ν˜ = 3206, 3090, 1604,
1
1289 cm–1. H NMR (400 MHz, CDCl3): δ= 13.42 (s, 1H), 8.69 (dd, J = 4.7, 1.5 Hz,
1H), 8.42 (dd, J = 8.0, 1.5 Hz, 1H), 7.62 (s, 2H), 7.23 (dd, J = 8.0, 4.7 Hz, 1H), 7.08 (s,
13
1H), 2.43 (s, 6H) ppm. C NMR (101 MHz, CDCl3): δ= 153.0, 148.5, 144.8, 138.5,
133.0, 131.1, 130.2, 125.0, 117.0, 113.5, 21.4 ppm. HRMS: calcd. for C14H14N3
[M+H]+: 224.1184, found 224.1182.pectra of
Associated Content
Figures giving proton and carbon NMR spectra of the reported compounds, NOESY
NMR of 1b and 1c compounds. This material is available free of charge via the
internet at http://pubs.acs.org.
Acknowledgements
This work was partially supported by the Labex SynOrg (ANRꢀ11ꢀLABXꢀ0029),
University of Orleans, Euromed University of Fes and the region CentreꢀVal de Loire.
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