“On Water” Palladium Catalyzed Direct Arylation of 1H‐Indazole and 1H‐7‐Azaindazole

Article abstract of DOI:10.3390/molecules25122820

The C3 direct arylation of 1H-indazole and 1H-7-azaindazole has been a significant challenge due to the lack of the reactivity at this position. In this paper, we describe a mild and an efficient synthesis of new series of C3-aryled 1H-indazoles and C3-aryled 1H-7-azaindazoles via a C3 direct arylation using water as solvent. On water, PPh3 was effective as a ligand along with a lower charge of the catalyst Pd(OAc)2 (5 mol%) at 100 oC, leading to C3-aryled 1H-indazoles or C3-aryled 1H-7-azaindazoles in moderate to good yields.

Full text of DOI:10.3390/molecules25122820

Article
“On Water” Palladium Catalyzed Direct Arylation of
1H‐Indazole and 1H‐7‐Azaindazole
1,2,3,†
2,3,†
2,3
2
Khadija Gambouz
, Abdelmoula El Abbouchi , Sarah Nassiri , Franck Suzenet ,
3
1
2,3,
3,
Mostapha Bousmina , Mohamed Akssira , Gérald Guillaumet * and Saïd El Kazzouli *
1
Faculty of Sciences and Technologies Mohammedia, University Hassan 2, URAC 22 FSTM University
Hassan II – Casablanca, BP 146, Mohammedia 28800, Morocco; gambouzkhadija@gmail.com (K.G.);
akssira.m@gmail.com (M.A.)
Institut de Chimie Organique et Analytique, University of Orléans, UMR CNRS 7311, BP 6759,
2
Cedex 2, 54067 Orléans, France; a.elabbouchi@ueuromed.org (A.E.A.);
sarah.nassiri@femg.ueuromed.org (S.N.); franck.suzenet@univ‐orleans.fr (F.S.)
Euromed Research Center, Euromed Institute of Technology, Euromed University of Fes (UEMF),
3
Route de Meknès, Rond‐point de Bensouda, Fes 30000, Morocco; m.bousmina@ueuromed.org
* Correspondence: gerald.guillaumet@univ‐orleans.fr. (G.G.); s.elkazzouli@ueuromed.org (S.E); Tel.: +212‐
6612‐99‐565 (MO)
† Both authors contributed equally to this manuscript
Received: 1 June 2020; Accepted: 16 June 2020; Published: 18 June 2020
Abstract: The C3 direct arylation of 1H‐indazole and 1H‐7‐azaindazole has been a significant
challenge due to the lack of the reactivity at this position. In this paper, we describe a mild and an
efficient synthesis of new series of C3‐aryled 1H‐indazoles and C3‐aryled 1H‐7‐azaindazoles via a
C3 direct arylation using water as solvent. On water, PPh
3
was effective as a ligand along with a
lower charge of the catalyst Pd(OAc) (5 mol%) at 100 °C, leading to C3‐aryled 1H‐indazoles or C3‐
2
aryled 1H‐7‐azaindazoles in moderate to good yields.
Keywords: indazole; azaindazole; arylation; green chemistry; C–H functionalization; water.
1. Introduction
In recent years, the C−H activation has risen as an increasingly powerful tool for molecular
sciences with notable applications in organic synthesis [1–5]. This method has gained considerable
recent momentum as a significantly environmentally and economically attractive alternative to
classical cross‐coupling such as Suzuki–Miyaura, Negishi, and Stille reactions [6–10]. With fewer
steps and accessible reagents, complex organic molecules are nowadays easily accessible with C–H
activation [11–20]. Nevertheless, this reaction usually requires high temperatures and organic
2
2
solvents to achieve new C(sp )–C(sp ) bonds [21]. For economic and environmental concerns, we are
aiming at developing a new C–H direct arylation of 1H‐indazole and 1H‐7‐azaindazole by using
water as a green solvent. Water is nature’s primordial solvent to carry out synthesis [22]. It is known
that water can increase the rate and affect the selectivity of a wide variety of organic reactions [23–
26]. It was also found that on watery conditions, the heterogeneous mixture of substrates and catalyst
can be very effective for direct arylation under mild conditions [27].
1H‐indazoles and 2H‐indazoles have widespread utility as highly bioactive molecules [28]. For
such reasons, various researchers were inspired to develop and optimize new methods for their
synthesis and functionalization [29–32]. Recently, different research groups have investigated the C3
direct arylation of indazole, including our own. In 2012, our group [33] in parallel with the Itami
group [34] developed, for the first time, conditions to realize the direct arylation of 1H‐indazole series.
The key of this success was the use of bidentate ligand (1,10‐phenanthroline) with a high catalyst
loading (10 to 20 mol%). Later, the reaction conditions have been optimized by the Yu group by
Molecules 2020, 25, 2820; doi:10.3390/molecules25122820
www.mdpi.com/journal/molecules

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reducing catalyst and ligand loading [35]. In this report, only one example of C3 arylation of 1H-7‐
azaindazole was reported using Pd(OAc)2 as a catalyst, and Phen as a ligand in toluene at 160 °C
(Scheme 1). Very recently, our group [36,37] and later Popowycz’s [38] group reported independently
that the C3 direct arylation of azaindazoles was feasible but using again 1,10‐phenanthroline (Phen)
as a crucial ligand in the case of 1H series for both 4‐azaindazoles and 7‐azaindazoles. In 2017, Doucet
and his group reported a phosphine free C3 arylation of 2H‐indazoles in dimethylacetamide DMA
using 5 mol% of Pd(OAc)2 as catalyst at 150 °C [39]. We noticed in their report that the C3 direct
arylation of 1H‐indazole was feasible for the first time without the use of bidentate ligands by
employing PdCl(C3H5)(dppb) as catalyst and KOAc as base in DMA at 150 °C. Nevertheless, the
expected products were obtained in moderate to low yields, and the reaction was achieved in organic
solvent. It is noteworthy that all the reported methods on C3 arylation of 1H‐indazole discussed
above were carried out in organic solvents and at high temperatures. In 2010, Greaney et al. [32]
reported that 2‐phenyl‐2H‐indazole could be directly arylated at the C3 position in high yields using
aryl bromides as coupling partners on water in the presence of Pd(dppf)Cl2 (5 mol%) and Ph3P (10
mol%) as catalyst and ligand, respectively. Unfortunately, under these reaction conditions, the
authors failed to achieve direct arylation on 1‐phenyl‐1H‐indazole, yet they concluded that, in this
case, the C3 position is non‐reactive toward substitution.
Herein, we reported a new path for the direct and selective C3 arylation of 1H‐indazoles on
water. We showed, for the first time, that a phosphine ligand (PPh3), contrary to the bidentate (Phen)
ligand used in the case of organic solvent, is crucial to achieve the arylation reaction (Scheme 1). We
are striving also to report the first examples of “on water” C3 arylation of 1H-7‐azaindazoles. We
showed as well that a low charge of the catalyst (5 mol%) and ligand (10 mol%) leads to desired
products in acceptable to good yields.
It is noticed that Knochel et al. used 3‐zincated indazoles which undergo palladium‐catalyzed
Negishi cross‐couplings to give the C3 substituted indazole derivatives [40], while, Burton et al.
described a regioselective iridium‐catalyzed C3 borylation of 1H‐indazoles, followed by subsequent
Suzuki–Miyaura coupling with aryl chlorides [41]. Compared to the methodology described in our
manuscript, the two methodologies cited above are more difficult to implement and also less
economical.
Scheme 1. Reported methods on C3 arylation of 1H‐indazoles and 1H‐azaindazoles versus our new
procedure.

Molecules 2020, 25, 2820
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2. Results
Firstly, we tested Greaney’s reaction conditions [Ag2CO3 (1 equivalent), PPh3 (10 mol%),
Pd(dppf)Cl2∙DCM (5 mol%), 4‐iodotoluene (1.1 equivalent), water at 50 °C for 16 h] [32] on 1‐methyl‐
1H‐indazole 1. The arylation reaction did not occur, and only starting material 1 was recovered (Table
1, entry 1).
Then, in the presence of palladium(II)acetate and 1,10‐phenanthroline as a bidentate ligand,
again no reaction was observed, and only starting material 1 was recovered (Table 1, entry 2).
Changing the type of the ligand to triphenylphosphine, a monodentate ligand, which may form a
stronger coordination with Pd(II) centers, led to the desired arylated product 1a in 40% yield (Table
1, entry 3). Encouraged by this result, we decided to improve the reaction’s conversion by screening
different conditions. At first, we tried to increase the temperature and to change the heating system
with our efforts leading to no avail (Table 1, entries 4–6). Water/ethanol solution was also used to
increase the solubility, but only a decrease of the reaction yield (17%) was observed (Table 1, entry
7). Using (2 equiv.) of iodotoluene slightly improved the reaction yield (entry 8). Luckily, increasing
the amount of iodotoluene to (3 equiv.) furnished 1a to 86% isolated yield and with a total conversion
(Table 1, entry 9). Furthermore, we succeeded in reducing the loading of both palladium and PPh3
ligand to 5 and 10% respectively (Table 1, entry 11). When the reaction was run for 24 h instead of 48
h, the yield dramatically decreased (Table 1, entry 12). Notably, the reaction temperature can be
reduced to 100 °C without affecting the reaction yield (Table 1, entry 13). Using Phen instead of Ph3P
as a ligand, under the optimized reaction conditions, led to a total loss of the reactivity (Table 1, entry
14). The reaction under reflux of water in an open flask was not total and 10% of starting material 1
was recovered (Table 1, entry 15). In addition, when 4‐iodotoluene was replaced by 4‐bromotoluene,
the arylation did not occur, and only starting material 1 was recovered (Table 1, entry 16).
Table 1. Optimization of the ‘’on water’’ direct arylation of 1‐methyl‐7‐nitro‐1H‐indazole.
X
X
(equiv)
1.1
Cat
(equiv)
5%
Ligand
(equiv)
10% PPh3
T °C
Time
(h)
16
Solvent
Yield
(%)
0[a](85) [b]
Entry
1
I
50
Water
Pd(dppf)Cl2∙DCM
20% Pd(OAc)2
20% Pd(OAc)2
20% Pd(OAc)2
20% Pd(OAc)2
2
3
4
5
I
I
I
I
1.1
1.1
1.1
1.1
40% Phen
40% PPh3
40% PPh3
40% PPh3
70
70
Reflux
Sealed
tube 140
°C
48
48
48
48
Water
Water
Water
Water
0(80)
40[c] (32)
37 (29)
45 (28)
6
7
I
I
I
I
I
I
1.1
1.1
2
20% Pd(OAc)2
20% Pd(OAc)2
20% Pd(OAc)2
20% Pd(OAc)2
10% Pd(OAc)2
5% Pd(OAc)2
40% PPh3
40% PPh3
40% PPh3
40% PPh3
10% PPh3
10% PPh3
Sealed
tube 140
°C
Sealed
tube 140
°C
Sealed
tube 140
°C
Sealed
tube 140
°C
Sealed
tube 140
°C
Sealed
tube 140
°C
48
48
48
48
48
48
Water
47[d](26)
17(25)
50 (21)
86 (0)
Water/EtOH
1:1
8
Water
Water
Water
Water
9
3
10
11
3
84 (0)
3
81
(traces)

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37 (58)
12
13
14
I
I
I
3
3
3
5% Pd(OAc)2
5% Pd(OAc)2
5% Pd(OAc)2
10% PPh3
10% PPh3
10% Phen
Sealed
tube 140
°C
Sealed
tube 100
°C
Sealed
tube 100
°C
24
48
48
Water
Water
Water
80
(traces)
Traces
(83)
15
16
I
Br
3
3
5% Pd(OAc)2
5% Pd(OAc)2
10% PPh3
10% PPh3
Reflux
Sealed
tube 100
°C
48
48
Water
Water
76 (10)
0 (98)
[a] Greaney’s conditions, [b] Percent of recovered starting material, [c] Yield of isolated product 2a,
[d] 10% Pd(OAc)2 and 20% PPh3 were used and after 24 h the same quantity of Pd(OAc)2 and PPh3
were added.
The scope and limitation of the C3 arylation reaction of various substituted indazoles 1 and 2
were examined (their preparation is described in the Supporting Information). We used various
iodoaryl derivatives carrying electron‐donating or electron‐withdrawing groups (such as methoxy,
chlorine, ester, nitro, trifluoromethyl, or methyl groups) under the most optimal reaction conditions
[5 mol% Pd(OAc)2 as the catalyst, 10% PPh3 as the ligand, and Ag2CO3 as the base in water at 100 °C
(Scheme 2)]. The results showed that the expected C3‐arylated products 1a–g were regioselectivity
obtained. First, using indazole 1 with 4‐iodotoluene gave 1a in 80% yield (Scheme 2). Afterwards, the
coupling of 1 with various aryl iodides was studied. Thus, the reactions with iodobenzene, 4‐
iodoanisole, 4‐iodobenzotrifluoride, 1‐chloro‐4‐iodobenzene, ethyl 4‐iodobenzoate, and 1‐iodo‐4‐
nitrobenzene afforded 1b–g in 54–87% yields (Scheme 2). A moderate yield was observed when 3‐
iodoanisole was used. In this case, the desired product 1h was isolated in 45% yield. No reaction was
observed when indazole 1 was treated by 2‐iodoanisole presumably as a result of its steric hindrance
(methoxy group at the 2‐position of the aromatic ring) and 4‐iodopyridine (Scheme 2). It is noticeable
that iodoaryl, containing electron‐donating groups, was crucial for the achievement of C3 arylation
reactions in good reaction yields (63–87%). In our second attempt, we used indazole 2 in order to see
if the nitro group on position C7 affects the arylation regioselectivity. The treatment of indazole 2
with various substituted aryl iodides as coupling partners showed that the nature of the substituents
(electron‐donating or electron‐withdrawing groups) did not affect the reaction yields or
regioselectivity (compounds 2a–f). Thus, the desired products 2a–f were obtained in yields ranging
between 41 and 68%. As described in the previous results, we also observed no arylation when
indazole 2 was treated by 2‐iodoanisole and hetero‐aryl iodide as coupling partners (compounds 2g–
h) (Scheme 2).

Molecules 2020, 25, 2820
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Scheme 2. Scope and limitation of the ‘’on water’’ direct arylation of 1‐methyl‐7‐nitro‐1H‐indazole
and 1‐methyl‐1H‐indazole. a Percent of recovered starting material, b 72 h.
Finally, we decided to run the reaction under our reaction conditions using the starting material
3 previously used without success by Greaney and his group [32]. As expected, we succeeded in
achieving the desired arylated products 3a and 3b in 58 and 51% yield, respectively (Scheme 3).
Scheme 3. Direct arylation of 1‐phenyl 1H‐indazole 3.
After succeeding in developing a “greener” pathway to synthesize C3‐arylated 1H‐indazole, we
extended the methodology to prepare C3‐arylated pyrazolo[3,4‐b]pyridine, also known as
azaindazole, which is an 1H‐indazole isostere and is often used as a key pharmacophore in drug
design [42–57]. Despite the enormous biological interest of C3‐arylated pyrazolo [3,4‐b]pyridines,
only one work has been reported by Lavard and Popowycz [38], addressing the functionalization of
this motif via direct arylation. Although this reported method is efficient, it is relatively energy‐
wasting, using heating at 160 °C for a long period of 3 days and organic solvent. For this reason, we
decided to test our conditions developed to prepare C3‐arylated pyrazolo[3,4‐b]pyridine using the
starting material 4 containing a benzyl group (the preparation of starting material 4 is described in
the Supporting Information) with various aryl iodides as arylating partners. As expected, this
procedure also showed a very high tolerance to various substituents on the aryl rings and the arylated
products 4b–d were isolated with yields ranging between 56 and 67% (Scheme 4).

Molecules 2020, 25, 2820
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Scheme 4. Direct arylation ʺon waterʺ of pyrazolo [3,4‐b] pyridine.
3. Materials and Methods
3.1. Instrumenttion
The reactions were monitored by thin‐layer chromatography (TLC) analysis using silica gel (60
F254) plates. Compounds were visualized by UV irradiation. Flash column chromatography was
performed on silica gel 60 (230–400.13 mesh, 0.040, 0.063 mm). Melting points (mp [°C]) were taken
on samples in open capillary tubes and are uncorrected. The infrared spectra of compounds were
1
13
recorded at room temperature on a Thermo Scientific Nicolet IS50 FT‐IR. H and C NMR spectra
13
were recorded on a Bruker Avance II 400 MHz ( C, 100 MHz) or on a Bruker Avance DPX 250 MHz
13
( C, 62.9 MHz). Chemical shifts are given in parts per million from tetramethylsilane (TMS) as
internal standard. The multiplicities of the spectra are reported as follows: singlet (s), doublet (d),
triplet (t), quartet (q), and multiplet (m). Coupling constants (J) are reported in hertz (Hz). High‐
resolution mass spectra (HRMS) were performed on a Maxis Bruker 4G.
3.2. Preparation of Starting Compounds 1–4
N‐Methylation of indazole [33]: the indazole (1 g, 1 equivalent) was dissolved in acetone (10 mL)
at 0 °C in a 50 mL flask. KOH (3 equivalent) was added, and then CH3I (1.5 equivalent) was added
dropwise. The reaction mixture was filtered and separated by flash chromatography on silica gel
(75% yield).
N‐Arylation of indazole [42]: iodobenzene (204 mg, 1 mmol) and dimethyl sulfoxide 1 mL was
added to the mixture of 1H-indazole (141.7 mg, 1.2 mmol), KOH (67.3 mg, 1.2 mmol), and copper
iodide (I) (19.1 mg, 0.1 mmol), and the reaction was for 12 h at 120 °C. After the completion of the
reaction, cooled to room temperature, 2 mL of water and ethyl acetate 2 mL was added, and liquid
separation was done. 1‐phenyl indazole was obtained as a main component of the organic layer (80%
yield).
N‐Benzylation of 1H‐pyrazolo[3,4‐b]pyridine [33]: 1H‐pyrazolo[3,4‐b]pyridine (1 g, 8.39 mmol,
1.00 equivalent) was dissolved in acetone (10 mL) at 0 °C in a 50 mL flask, along with KOH (1.41 g,
25.19 mmol, 3.00 equivalent). After few minutes of stirring, benzyl chloride (1.59 g, 12.59 mmol, 1.50
equivalent) was added dropwise. The reaction mixture was filtered, and the two isomers N1 and N2
were separated by flash chromatography on silica gel (N1: 50%/N2: 45%).
3.3. General Experimental Procedure for the Synthesis of Products 1a–h, 2a–f, 3a–b and 4a–d
A 5 mL sealed tube was charged with 1‐methyl‐7‐nitro‐1H‐indazole 1, 1‐methyl‐1H‐indazole 2,
1‐phenyl‐1H‐indazole 3, or 1‐benzyl‐1H‐pyrazolo[3,4‐b]pyridine 4 (1.0 equivalent), iodoaryl (3.0
equivalent), Pd(OAc)2 (0.05 equivalent), PPh3 (0.1 equivalent) and Ag2CO3 (1.5 equivalent). The
mixture of solids was stirred for a few seconds to ensure all solids were well mixed. Then, 3 mL of
distilled water was added, the mixture was degassed for few minutes, and the vial was covered with
a serum cap. Then, the vial and its contents were heated and stirred at 100 °C for 24 h. After it was
cooled to room temperature, the mixture was filtered through celite, and the organic phase was

Molecules 2020, 25, 2820
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extracted three times with ethyl acetate, dried over magnesium sulfate, and then concentrated under
reduced pressure. The residue was purified by flash chromatography to provide the desired
products.
1
1‐Methyl‐7‐nitro‐3‐(p‐tolyl)‐1H‐indazole 1a: Yield: 80%; yellow solid; mp = 154–156 °C; H NMR
(400 MHz, CDCl3) δ 8.15 (dd, J = 8.1, 1.0 Hz, 1H), 8.06 (dd, J= 8.1, 1.0 Hz, 1H), 7.66 (d, J = 7.6 Hz, 2H),
13
7.23 (d, J = 7.6 Hz, 2H), 7.20–7.12 (m, 1H), 4.18 (s, 3H), 2.35 (s, 3H); C NMR (101 MHz, CDCl3) δ 145.5,
138.9, 135.3, 132.6, 129.8 (2 × C–H), 129.1, 128.3, 127.9 (2 × C–H), 126.9, 124.7, 119.9, 40.9, 21.5; HRMS
+
(m/z) [M + H] calculated mass for C15H14N3O2, 268.1081, mass found 268.1079; IR (neat) ῠ = 1303, 1325,
−1
1471, 1509, 2918, 3099 cm .
1‐Methyl‐7‐nitro‐3‐phenyl‐1H‐indazole 1b: Data for compound 1b were previously reported [11]
1
3‐(4‐Methoxyphenyl)‐1‐methyl‐7‐nitro‐1H‐indazole 1c: Yield: 63%; yellow solid; mp = 182–184 °C; H
NMR (400 MHz, CDCl3) δ 8.27 (dd, J= 8.1, 1.0 Hz, 1H), 8.17 (dd, J = 8.1, 1.0 Hz, 1H), 7.84 (d, J = 8.7 Hz,
13
2H), 7.31 (t, J = 7.9 Hz, 1H), 7.11 (d, J = 8.7 Hz, 2H), 4.31 (s, 3H), 3.93 (s, 3H); C NMR (101 MHz,
CDCl3) δ 160.3, 145.3, 139.2, 132.7, 129.3 (2 × C–H), 128.3, 126.9, 124.7, 124.5, 119.9, 114.6 (2 × C–H),
+
55.5, 29.8; HRMS (m/z) [M + H] calculated mass for C15H14N3O3, 284.1030, mass found 284.1030; IR
−1
(neat) ῠ = 1321, 1361, 1514, 1530, 1612, 2849, 2919 cm .
1‐Methyl‐7‐nitro‐3‐(4‐(trifluoromethyl)phenyl)‐1H‐indazole 1d: Yield: 55%; yellow solid; mp = 201–
1
203 °C; H NMR (400 MHz, CDCl3) δ 8.25 (dd, J = 8.1, 1.0 Hz, 1H), 8.15 (dd, J =8.1, 1.0 Hz, 1H), 8.07–
13
7.95 (m, 2H), 7.85–7.73 (m, 2H), 7.32 (t, J = 7.9 Hz, 1H), 4.30 (s, 3H); C NMR (101 MHz, CDCl3) δ
3
143.8, 139.4, 135.6, 132.5, 131.0 (q, JCq‐F= 32.3 Hz, Cq‐F), 128.1 (2 × C–H), 127.6, 126.5, 126.1 (q, JCHAr‐F=
1
+
3.8 Hz, 2C, CHAr), 125.0 (q, JC‐F= 272.1 Hz, CF3), 124.8, 120.1, 29.8;HRMS (m/z) [M + H] calculated
mass for C15H11F3N3O2, 322.0798 mass found 322.0796; IR (neat) ῠ = 1275, 1329, 1346, 1498, 1540, 3020
cm .
−1
1
3‐(4‐Chlorophenyl)‐1‐methyl‐7‐nitro‐1H‐indazole 1e: Yield: 87%; yellow solid; mp = 172–173 °C; H
NMR (400 MHz, CDCl3) δ 8.22 (dd, J = 8.1, 1.0 Hz, 1H), 8.15 (dd, J= 8.1, 1.0 Hz, 1H), 7.82 (d, J = 8.5 Hz,
13
2H), 7.51 (d, J = 8.5 Hz, 2H), 7.34–7.23 (m, 1H).4.29 (s, 3H); C NMR (101 MHz, CDCl3) δ 144.2, 135.5,
134.9, 132.7, 130.5, 129.4 (2 × C–H), 129.2 (2 × C–H), 127.8, 126.6, 124.8, 120.4, 29.8; HRMS (m/z) [M +
+
H] calculated mass for C14H11ClN3O2, 288.0534, mass found 288.0534; IR (neat) ῠ =763, 1336, 1358,
−1
1488, 1510, 3018 cm .
1
Ethyl 4‐(1‐methyl‐7‐nitro‐1H‐indazol‐3‐yl)benzoate 1f: Yield: 54%; yellow solid; mp = 206–208 °C; H
NMR (400 MHz, CDCl3) δ 8.27 (dd, J = 8.1, 1.0 Hz, 1H), 8.20 (m, 2H), 8.17 (d, J = 8.1 Hz, 1H), 7.98 (m,
13
2H), 7.32 (t, J = 7.9 Hz, 1H), 4.43 (q, J = 7.1 Hz, 2H), 4.31 (s, 3H), 1.44 (t, J = 7.1 Hz, 3H); C NMR (101
MHz, CDCl3) δ 166.3, 144.2, 136.3, 135.6, 132.7, 130.6, 130.3 (2 × C–H), 127.9, 127.7 (2 × C–H), 126.7,
+
124.8, 120.6, 61.3, 41.2, 14.5 ; HRMS (m/z) [M + H] calculated mass for C17H16N3O4, 326.1135, mass
−1
found 326.1135; IR (neat) ῠ = 1100, 1259, 1320, 1365, 1514, 1708, 2850, 2919, 2986, 3104 cm .
1
1‐Methyl‐7‐nitro‐3‐(4‐nitrophenyl)‐1H‐indazole 1g: Yield: 56%; yellow solid; mp = 242–244 °C; H
NMR (400 MHz, CDCl3) δ 8.40 (d, J = 8.9 Hz, 2H), 8.28 (dd, J = 8.1, 1.0 Hz, 1H), 8.18 (dd, J = 8.1, 1.0 Hz,
13
1H), 8.10 (d, J = 8.9 Hz, 2H), 7.37 (t, J = 7.9 Hz, 1H), 4.32 (s, 3H); C NMR (101 MHz, CDCl3) δ 148.5,
142.8, 138.5 (2 × C–H), 132.8, 132.2, 128.4 (2 × C–H), 127.4, 124.9, 124.4 (2 × C–H), 121.2, 29.8; HRMS
+
(m/z) [M + H] calculated mass for C14H11N4O4, 299.0775 mass found 299.0774; IR (neat) ῠ =1325, 1345,
−1
1455, 1518, 3076, 1601 cm .
1
3‐(3‐Methoxyphenyl)‐1‐methyl‐7‐nitro‐1H‐indazole 1h: Yield: 45%; yellow solid; mp = 164–166°C; H
NMR (400 MHz, CDCl3) δ 8.27 (dd, J = 8.1, 1.0 Hz, 1H), 8.14 (dd, J= 8.1, 1.0 Hz, 1H), 7.51–7.37 (m, 3H),
13
7.28 (d, J = 7.9 Hz, 1H), 7.00 (m, 1H), 4.29 (s, 3H), 3.91 (s, 3H); C NMR (101 MHz, CDCl3) δ 160.2,
145.3, 133.3, 132.7, 130.2, 128.7,128.2, 126.8, 124.7, 120.5, 120.1, 114.7, 113.4, 55.5, 41.0; HRMS (m/z) [M
+
+ H] calculated mass for C15H14N3O3, 284.1030, mass found 284.1029; IR (neat) ῠ = 1250, 1319, 1472,
−1
1514, 1596, 2850, 2920 cm .

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1‐Methyl‐3‐(p‐tolyl)‐1H‐indazole 2a: Data for compound 2a were previously reported [35]
1‐Methyl‐3‐phenyl‐1H‐indazole 2b: Data for compound 2b were previously reported [35]
3‐(4‐Methoxyphenyl)‐1‐methyl‐1H‐indazole 2c: Data for compound 2c were previously reported
[35]
1‐Methyl‐3‐(4‐(trifluoromethyl)phenyl)‐1H‐indazole 2d: Data for compound 2d were previously
reported [35]
1
1‐Methyl‐3‐(4‐nitrophenyl)‐1H‐indazole 2e: Yield: 68%; white solid; mp = 209–211°C; H NMR (400
MHz, CDCl3) δ 8.37 (d, J = 8.8 Hz, 2H), 8.18 (d, J = 8.8 Hz, 2H), 8.03 (dd, J = 8.1, 1.1 Hz, 1H), 7.48 (d, J
13
= 3.4 Hz, 2H), 7.30 (dt, J = 8.1, 3.4 Hz, 1H), 4.17 (s, 3H); C NMR (101 MHz, CDCl3) δ 147.1, 141.7,
141.2, 140.4, 127.5 (2 × C–H), 126.8, 124.3 (2 × C–H), 122.1, 121.7, 120.9, 109.8, 29.8; HRMS (m/z) [M +
+
H] calculated mass forC14H12N3O2, 254.0924, mass found 254.0922; IR (neat) ῠ =2931, 1543, 1486, 1352,
−1
1347, 1260, 780 cm .
1
3‐(3‐Methoxyphenyl)‐1‐methyl‐1H‐indazole 2f: Yield: 41%; white solid; mp = 112–113 °C; H NMR
(400 MHz, CDCl3) δ 8.04 (d, J = 8.1 Hz, 1H), 7.57 (dd, J = 7.4, 1.4 Hz, 1H), 7.54 (d, J = 1.4 Hz, 1H), 7.49–
13
7.37 (m, 3H), 7.22 (ddd, J = 8.1, 5.1, 2.7 Hz, 1H), 6.96 (d, J = 5.8 Hz, 1H), 4.13 (s, 3H), 3.91 (s, 3H);
C
NMR (101 MHz, CDCl3) δ 160.1, 143.6, 141.5, 135.1, 129.9, 126.3, 121.7, 121.4, 121.0, 120.0, 113.9, 112.6,
+
109.3, 55.4, 29.8; HRMS (m/z) [M + H] calculated mass for C15H15N2O, 239.1179 mass found 239.1176;
−1
IR (neat) ῠ =2931, 1486, 1347, 1289, 1260, 780 cm .
1,3‐Diphenyl‐1H‐indazole 3a: Data for compound 3a were previously reported [34]
1‐Phenyl‐3‐(p‐tolyl)‐1H‐indazole 3b: Data for compound 3b were previously reported [34]
1
1‐Benzyl‐3‐phenyl‐1H‐pyrazolo[3,4‐b]pyridine 4a: Yield: 63%; white solid; mp = 133–135 °C; H NMR
(400 MHz, CDCl3) δ 8.60 (dd, J = 4.5, 1.5 Hz, 1H), 8.35 (dd, J = 8.1, 1.5 Hz, 1H), 8.04–7.95 (m, 2H), 7.52
(dd, J = 8.3, 6.8 Hz, 2H), 7.46–7.40 (m, 3H), 7.35–7.25 (m, 3H), 7.18 (dd, J = 8.1, 4.5 Hz, 1H), 5.82 (s, 2H);
13
C NMR (101 MHz, CDCl3) δ 151.45, 148.90, 143.11, 137.24, 133.33, 130.50, 128.99 (2 × C–H), 128.65 (2
× C–H), 128.38, 127.98 (2 × C–H), 127.72 (2 × C–H), 127.22, 117.20, 113.77, 50.87, 14.25; HRMS (m/z) [M
+
+ H] calculated mass for C19H17N3, 286.1339, mass found 286.1338; IR (neat) ῠ = 3050, 3031, 1610, 1330
−1
cm .
1
1‐Benzyl‐3‐(p‐tolyl)‐1H‐pyrazolo[3,4‐b]pyridine 4b: Yield: 67%; Yellow solid; mp = 85–90 °C; H
NMR (400 MHz, CDCl3) δ 8.59 (dd, J = 4.5, 1.5 Hz, 1H), 8.34 (dd, J = 8.1, 1.5 Hz, 1H), 7.98–7.79 (m, 2H),
13
7.45–7.38 (m, 2H), 7.35–7.24 (m, 5H), 7.18 (dd, J = 8.1, 4.5 Hz, 1H), 5.80 (s, 2H), 2.44 (s, 3H); C NMR
(101 MHz, CDCl3) δ 151.49, 148.87, 143.25, 138.32, 137.34, 130.59, 130.54, 129.72 (2 × C–H), 128.66 (2 ×
+
C–H), 127.98 (2 × C–H), 127.70, 127.14 (2 × C–H), 117.09, 113.81, 50.84, 21.48; HRMS (m/z) [M + H]
calculated mass for C20H18N3, 300.1495, mass found 300.1499; IR (neat) ῠ = 2922, 2852, 1735, 1465, 772,
−1
511 cm .
1‐Benzyl‐3‐(4‐nitrophenyl)‐1H‐pyrazolo[3,4‐b]pyridine 4c: Yield: 59%; Yellow solid; mp = 157–162
1
°C; H NMR (400 MHz, CDCl3) δ 8.66 (dd, J = 4.5, 1.5 Hz, 1H), 8.42–8.32 (m, 3H), 8.17 (d, J = 8.8 Hz,
13
2H), 7.45 (dd, J = 6.7, 1.7 Hz, 2H), 7.36–7.27 (m, 4H), 5.83 (s, 2H); C NMR (101 MHz, CDCl3) δ 151.50,
149.39, 147.38, 140.52, 139.71, 136.70, 130.04, 128.79 (2 × C–H), 128.17 (2 × C–H), 128.03, 127.39 (2 × C–
+
H), 124.35 (2 × C–H), 118.14, 113.76, 51.23; HRMS (m/z) [M + H] calculated mass for C19H15N4O2,
−1
331.1190, mass found 331.1191; IR (neat) ῠ = 2923, 2852, 1516, 1342, 771 cm .
1
1‐Benzyl‐3‐(3‐methoxyphenyl)‐1H‐pyrazolo[3,4‐b]pyridine 4d: Yield: 56%; Yellow oil; H NMR (400
MHz, CDCl3) δ 8.58 (dd, J = 4.5, 1.5 Hz, 1H), 8.35 (dd, J = 8.1, 1.5 Hz, 1H), 7.58–7.48 (m, 2H), 7.46–7.36
(m, 3H), 7.30 (t, J = 7.2 Hz, 2H), 7.19 (dd, J = 8.1, 4.5 Hz, 1H), 6.96 (ddd, J = 8.2, 2.6, 1.0 Hz, 1H), 5.79 (s,
13
2H), 3.90 (s, 3H); C NMR (101 MHz, CDCl3) δ 160.19, 151.51, 148.99, 143.02, 137.26, 134.68, 130.58,
130.06, 128.70 (2 × C–H), 128.01 (2 × C–H), 127.76, 119.78, 117.30, 114.24, 113.87, 112.63, 55.55, 50.92;
+
HRMS (m/z) [M + H] calculated mass for C20H18N3O, 316.1444, mass found 316.1443; IR (neat) ῠ =
−1
2936, 2805, 1601, 1280 cm .

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4. Conclusions
In summary, we have developed a new palladium catalyzed direct C3 arylation of 1H‐indazole
using a low charge of 5 mol% of Pd(OAc)2 along with 10 mol % of PPh3 on water as solvent at 100 °C.
This new procedure afforded a board of arylated indazoles differently substituted at the C3 position
in moderate to good yields. The application of this protocol on 1H 7‐azaindazole was fruitful, and
four examples of C3‐arylated pyrazolo[3,4‐b]pyridine were successfully reported.
Supplementary Materials: The following are available online, Spectral Data of All the Synthesized Products,
NMR Spectra of All the Products.
Author Contributions: Conceptualization, S.E.; G.G.; M.A.; and F.S.; methodology, S.E., G.G, M.A. and F.S.;
validation, S.E.; G.G.; M.A.; M.B.; and F.S.; formal analysis, S.E.; G.G.; M.A.; M.B.; and F.S.; investigation, S.E.;
G.G.; M.A.; M.B.; and F.S.; resources, K.G.; A.E.; S.N.; data curation, K.G.; A.E.; S.N.; writing—original draft
preparation, K.G.; A.E.; S.N.; S.E., G.G.; writing—review and editing, K.G.; A.E.; S.N.; S.E., G.G.; visualization,
K.G.; A.E.; S.N.; S.E., G.G.; supervision, S.E., G.G, M.A.; and F.S. project administration, S.E., G.G ; funding
acquisition, S.E., G.G, M.A. M.B. and F.S.
Funding: This research was funded by Euromed University of Fes, CNRST of Morocco and University of
Orleans.
Acknowledgments: This work was supported by CNRST of Morocco, University of Orleans, University Hassan
II of Casablanca, and the Euromed University of Fes.
Conflicts of Interest: The authors declare no conflict of interest.
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Sample Availability: Not available.
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