Palladium-Catalyzed Regioselective C?H Arylation of 4-Azaindazole at C3, C5 and C7 Positions

Article abstract of DOI:10.1002/adsc.202001421

Direct and site-selective C5 and C7 palladium-catalyzed C?H arylations of 4-azaindazole N-oxide have been achieved. A bidentate ligand and Pd(OAc)₂ catalyst in toluene promoted the activation of C5 position, while a phosphine ligand and PdCl₂ catalyst in DMA directed the arylation at C7 position. Using this new method, the synthesis of C5, C7-diarylated 4-azaindazole N-oxides as well as the C3, C5, C7-triarylated 4-azaindazoles was achieved towards future medicinal compounds development. (Figure presented.).

Full text of DOI:10.1002/adsc.202001421

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DOI: 10.1002/adsc.202001421
Very Important Publication
Palladium-Catalyzed Regioselective CÀ H Arylation of 4-
Azaindazole at C3, C5 and C7 Positions
Soukaina Faarasse,a, b Saïd El Kazzouli,b,* Otmane Bourzikat,a, b Stéphane Bourg,a
Samia Aci-Sèche,a Pascal Bonnet,a Franck Suzenet,a,* and Gérald Guillaumeta, b,*
a
Institute of Organic and Analytical Chemistry, University of Orleans, UMR CNRS 7311, BP 6759, 45067 Orleans Cedex 2,
France
E-mail: franck.suzenet@univ-orleans.fr; gerald.guillaumet@univ-orleans.fr
Euromed Research Centre, School of Engineering in Biomedical and Biotechnology, Euromed University of Fes (UEMF), Route
b
de Meknès, 30000 Fez, Morocco
E-mail: s.elkazzouli@ueuromed.org
Manuscript received: November 15, 2020; Revised manuscript received: March 8, 2021;
Version of record online: ■■■, ■■■■
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.202001421
C6 direct arylation of 7-azaindole N-oxide as well as
Abstract: Direct and site-selective C5 and C7
the C7 direct arylation of 6-azaindole N-oxide[26]
palladium-catalyzed CÀ H arylations of 4-azainda-
(Scheme 1). Remarkably, the direct arylation took
place only in the α-position of the N-oxide. So far,
only one example has been reported on direct site-
zole N-oxide have been achieved. A bidentate ligand
and Pd(OAc)2 catalyst in toluene promoted the
activation of C5 position, while a phosphine ligand
selective arylation of two different positions of the six
and PdCl2 catalyst in DMA directed the arylation at
membered ring of indole on 6,5 fused heterocyclic
C7 position. Using this new method, the synthesis
systems. In this case, a N-pivaloyl substituent at
of C5, C7-diarylated 4-azaindazole N-oxides as well
position C3 was used to direct the arylation at the C4
as the C3, C5, C7-triarylated 4-azaindazoles was
and C5 positions, depending on the catalyst system.[15]
achieved towards future medicinal compounds
Pyrazolo[4,3-b]pyridine (4-azaindazole) and pyrro-
development.
lo[2,3-b]pyridine (7-azaindole) belong to the family of
privileged scaffolds[27] and are widely studied in many
medicinal programs.[28] For a more efficient access to
Keywords: pyrazolo[4,3-b]pyridine N-oxide; 4-azin-
dazole; direct arylation; CÀ H activation; catalyst
various monosubstituted (on C3, C5 or C7 position) or
polysubstituted azaindazole (up to three different
substituents over four CÀ H activatable bonds), pyrazo-
lo[4,3-b]pyridine N-oxide (4-azaindazole N-oxide) ap-
Direct arylation of heterocycles is nowadays well- pears as an interesting starting substrate. In this paper,
established for selective arylation of one or two we report the direct arylation process leading to the
different positions on bicyclic heterocycles. Because of functionalization of two different positions of the 4-
the higher reactivity of the five membered ring azaindazole N-oxide. This regioselective CÀ H activa-
compared to the six membered ring in 6,5 fused tion, either on the C5 or C7 position of the azine ring,
heterocycles, its direct arylation is widely studied.[1–7] depends on the experimental conditions. This method-
In contrast, only few examples have been reported to ology was successfully applied to the direct arylation
date on direct arylation of the six membered ring[8–14] of three different CÀ H positions of 4-azaindazole
and a more rare and challenging issue is its selective (namely, C3, C5 and C7) a real breakthrough in the
arylation on two different positions. Indeed, the field of 5,6-fused heterocyclic chemistry (Scheme 1).
regioselective arylation is more easily achieved by
In the optimization of the reaction conditions, ratios
functionalization of a first position on the five of all isomers were determined by LC/MS, (see
membered ring and then a second position on the six supporting information). This investigation began with
membered ring.[9,10,12,15–18] A major breakthrough by iodobenzene as substrate, Pd(OAc)2 as catalyst, 1,10-
°
Fagnou and collaborators, was the development of phenanthroline (phen) as ligand in toluene at 130 C
direct arylation of azine N-oxides,[19–25] allowing the and two different bases (entries 1–2).[29,30] The most
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and only traces of compounds 2a and 4a were
observed (entry 11). We noticed that, the use of toluene
°
instead of DMA at 140 C led to a total loss of
reactivity since 76% of the starting material 1 was
observed by LC/MS (entry 12). We observed that the
use of either bromobenzene or chlorobenzene instead
of iodobenzene under the optimized reaction condi-
tions, led to low yields in the case of bromobenzene
and no product was detected in the case of chloroben-
zene for which only starting material was recovered.
We noticed also that either Fagnou reaction
conditions[26] or Hartwig reaction conditions[32] were
also tested on starting material 1 but no reaction was
observed and only starting material 1 was recovered.
Thanks to the optimized reaction conditions for
regioselective arylation at either C5 or C7 position, we
explored the scope and limitations of this method. We
first prepared a series of C5-arylated-4-azaindazole N-
oxides using various aryl iodides as coupling partners
under the following reaction conditions [Pd(OAc)2
(5 mol%), phen (10 mol%), K2CO3 (1.5 equiv.),
Scheme 1. Direct arylation of azaindole N-oxides and of
azaindazole N-oxides.
°
toluene, 140 C, 24 h] (Table 2).
In general, all the reactions proceeded smoothly to
reaction was not complete (20% of the starting material give the expected C5 arylated products 2a–m in
interesting result was obtained with K2CO3 despite the
is recovered, entry 3). The regiochemistry for C5 moderate to good yields (40 to 75%). Both electron
1
arylation was assumed by comparison of H NMR with drawing groups and electron donating groups on
chemical shifts of the protons at C5, C6 and C7 the aryl iodide moiety afforded good substrates. The
positions. In addition, NOESY experiments carried out reaction was compatible with various valuable func-
on compounds 1 and 2a showed the correlation tional groups such as Cl, CF3, ethyl ester, CN, meth-
between the proton at C7 and the protons of the methyl oxy, and NO2 (Table 2). It is noticed that the use of 2-
group at N1 (see supporting information). The replace- iodotoluene as arylating agent led to desired product
ment of phen by PPh3 as ligand led to a total loss of but the reaction mixture was very difficult to purify
the reactivity and the starting material was only and the corresponding C5-arylated product was no
observed (entry 4). When the reaction mixture was isolated as pure product. Unfortunately, heteroaryl
°
heated at 140 C (entry 5) the reaction was complete iodides such as 4-iodopyridine and 2-iodopyrazine
and the desired product 2a was obtained in 70% were not effective to achieve their corresponding C5-
isolated yield. In this case, compound 3a was also arylated products (Table 2).
isolated in 12% yield (entry 5). Finally, when
The scope and limitations of C7 direct arylation of
1.5 equiv. of K2CO3 was used instead of 2 equiv., the 4-azaindazole N-oxide was then explored under the
isomer 2a was isolated with an improved yield (75%) optimized reaction conditions [PdCl2 (5 mol%), PPh3
°
and only traces of 3a were observed (entry 6). The (10 mol%), K2CO3 (2 equiv.), DMA, 165 C, 24 h]
efforts to reduce ligand loading failed (entry 7). Very (Table 3).
interestingly, when DMA at higher temperature
Again, various aryl iodides were used as coupling
°
(165 C), was used instead of toluene, the reaction was partners which led to desired C7-arylated 4-azainda-
complete and more selective towards the C7-arylated zole N-oxides 3a–l in isolated yields ranging between
product 3a, (30% conversion), however 68% of C5, 40 and 68%. Good compatibility with various valuable
C7-diarylated product 4a was also identified (entry 8). functional groups was also observed. In addition, no
The replacement of phen by PPh3 under the same real effect of the electronic nature of the substituents
reaction conditions discussed above led almost to the on the aryl iodides (coupling partners) was observed.
same result (entry 9). While, the use of PdCl2 instead Unfortunately, when using ethyl 2-iodobenzoate or
of Pd(OAc)2 led to C7 arylated product in 70% ethyl 3-iodobenzoate as arylating agents, only traces of
conversion while, diarylated product 4a and C5- the desired C7-arylated products were observed.
arylated product 2a were obtained in 11 and 19%
Again, when using 4-iodopyridine and 2-iodopyr-
conversion, respectively (entry 10). Finally, the best azine as arylating agents, the reaction did not give their
result was obtained when phen was replaced by Ph3P corresponding C7-arylated products (Table 3).
under the same reaction conditions. In this case, the
In order to understand the observed regioselectivity,
desired product 3a was obtained in 65% isolated yield we looked at pKa values on 4-azaindazole and 4-
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Table 1. Optimisation of C5 and C7 direct arylations on 4-
Table 2. Summarized results of C5-arylated 4-azaindazole N-
azaindazole.
oxides.
[b]
entry conditions[a]
T C 1:2a:3a:4a
yield[c]
2a:3a
°
1
2
3
4
5
Pd(OAc)2, phen, Cs2CO3, 130 6:18:50:26
toluene
Pd(OAc)2, phen, Ag2CO3, 130 88:7:5:0
toluene
Pd(OAc)2, phen, K2CO3, 130 20:70:10:0
toluene
Pd(OAc)2, PPh3, K2CO3, 130 100: 0: 0:0
toluene
–
–
–
–
Pd(OAc)2, phen, K2CO3, 140 0:74:26:0
toluene
70:12
6 [d] Pd(OAc)2, phen, K2CO3, 140 0:98:2:0
75:0
toluene
7 [e] Pd(OAc)2, phen, K2CO3, 140 15:85:0:0
toluene
–
8
Pd(OAc)2, phen, K2CO3, 165 0:2:30:68
–
DMA
9
Pd(OAc)2, PPh3, K2CO3, 165 0:8:30:62
DMA
–
10
11
12
PdCl2, phen, K2CO3,
DMA
PdCl2, PPh3, K2CO3,
DMA
PdCl2, PPh3,K2CO3,
toluene
165 0:19:70:11
165 0:7:88:5
140 76:2:5:17
–
0:65
–
Reaction conditions: [a] 1 equiv. of 1, 2 equiv. of aryl iodide, Pd
(5 mol%), ligand (10 mol%), base (2 equiv.), solvent, 24 h.
[b] Conversions calculated by LC/MS.
[c] isolated yields.
[d] 1.5 equiv. of base was used.
Reaction conditions. 1 equiv. of 1, 2 equiv. of aryl iodide, Pd
(OAc)2 (5 mol%), phen (10 mol%), K2CO3 (1.5 equiv.), toluene,
°
140 C, 24 h.
[e] 1.5 equiv. of base and 5 mol% of ligand were used.
For the two compounds, we observe significant
azaindazole-N-oxide which were predicted by Jaguar electron density of the HOMO at positions 5 and 7
pKa software.[32] Regarding the 4-azaindazole, the while the position 6 appears unfavorable for substitu-
lowest pKa values correspond to C3 and C7 positions, tion. For the 4-azaindazole compound, the highest
in contrast to the 4-azaindazole N-oxide 1 where the electron density is observed at position 3 whereas the
lowest pKa values correspond to C5 and C7 positions electron density is lower at position 3 for the 4-
(Figure 1).
azaindazole N-oxide. This observation could explain
the lack of arylation at position 3.
For the 4-azaindazole compound, we observe
similar values of electrophile activity (Ea) at positions
5 and 6. Ea is a theoretical parameter recently proposed
to characterize reactivity and positional selectivity in
CÀ H functionalisation16. For more information, see
Koleva et al.[33] and Galabov et al..[34] The lowest value
of Ea is obtained at position 7 (144.9 kcal/mol), the
highest at position 3 (161.3 kcal/mol). For the 4-
azaindazole N-oxide compound, we observe similar
Figure 1. pKa values calculated for 4-azaindazole and 4-
azaindazole N-oxide 1.
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Table 3. Summarized results of C7-arylated 4-azaindazole N-
oxides.
Figure 2. Ea and HOMO calculations for 4-azaindazole (A) and
compound 1 (B).
pathway for formation of PdIIArAr’ is steel unclear.
The combination of palladium acetate with phen was
critical.[36,37] In our case, for the arylation at C5
position, the calculations are more suggestive of an
electrophilic aromatic substitution rather than a con-
certed CÀ H activation. However, the majority of recent
experimental and computational studies indicate that
SEAr mechanism is less likely to occur as part of this
type of transformation and rather supports CÀ H bond
cleavage by CMD mechanisms.[38]
The acidic nature of H5 (vide supra) and the use of
carbonate which is known for its crucial role in CMD
process during direct arylation of the CÀ H bond, imply
that this reaction is likely to occur through CMD
process, as proposed by many literature reports.[39]
However, for the CMD process to be operational, an
open coordination site is needed which can be
approached by the CÀ H bond of the arene with the
carbonate coordinated to the Pd center to direct the
CÀ H cleavage. In our case, this coordination is not
favored due to the presence of a relatively strong
coordinating L-type ligand such as phen. Because of
phen‘s lack of flexibility to rotate, it would rigidly
bind to Pd as a bidentate ligand[40] (Figure 3).
Reaction conditions. 1 equiv. of 1, 2 equiv. of aryl iodide, PdCl2
Alternatively, in recent years, another mechanistic
pathway consisting of a cooperative bimetallic mecha-
nism involving parallel CÀ H activation at two separate
PdII centers followed by transmetalation between the
two PdIIÀ aryl species, was proposed by Hartwig for the
°
(5 mol%), PPh3 (10 mol%), K2CO3 (2 equiv.), DMA, 165 C,
24 h.
values of Ea at positions 5 and 7 and the lowest value
of Ea (154.8 kcal/mol) at position 3. The Ea and
HOMO calculations clearly validate the absence of
reactivity at C3 position (through a SEAr type
mechanism) for the 4-azaindazole N-oxide compound
and are in agreement with the experimental results
(Figure 2).
Whereas the mechanism of arene CÀ H activation
by PdII has been the subject of much research,[35] the
Figure 3. Coordination of phen and carbonate to Pd center.
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CÀ H arylation of pyridine N-oxide and was supported group of the second Pd species H’ binds to the open
by the studies of the direct arylation of simple site of the transition state G’, and sequentially, the
arenes.[27]
anion IÀ induces the transfer of the aryl group,
Thus, for a plausible mechanism of C5 arylation of completing the transmetalation step to give the
4-azaindazole N-oxide, first catalytic cycle begins with ArÀ PdÀ Ar’ intermediate E’. Then a reductive elimi-
the oxidative addition of aryl iodide to Pd(0). The nation furnished the desired C7 arylated compound 3a
generated B complex undergoes transmetallation in the and generated complex A’. The complete loss of the
presence of the 2nd cyclometallated complex C to give reactivity with the use of toluene instead of DMA
the ArÀ PdÀ Ar’ intermediate E. The latter undergoes a (Table 1, entry 12) demonstrates a significant influence
reductive elimination to led to 2a and to Pd complex of the solvent on the outcome of the reaction. This
(0). In the other catalytic cycle, the monomeric cyclo- result could be attributed to the involvement of an
metallic complex D is involved in the CÀ H activation ionic intermediate transition state, stabilized by the
step at position 5 of the 4-azaindazole N-oxide polar solvent (DMA)[42] (Scheme 3).
(Scheme 2).
In order to demonstrate the valuable access to the
The selectivity for the C5 position with the azaindazole privileged scaffold in drug design with the
combination of Pd(OAC)2 and phen is reversed for the present methodology, we decided to generate the
C7 position with the use of PdCl2 and PPh3. This time, deoxygenated 5-arylated-4-azaindazoles 5a–c and 7-
following a similar approach, we conjectured a aryled-4-azaindazoles 6a–c from their corresponding
functioning biometallic cooperative pathway[32,41] to N-oxide precursors. In the case of C5 arylated 4-
explain the functionalization at the C7 position.
azaindazole N-oxides 2a, 2b, 2f, their treatment with
The complex B’ undergoes dissociation, generating zinc dust and NH4Cl in THF for 5 h led to desired
a complex G’ with a vacant coordination site. The aryl products 5a–c in very good yields ranging between 80
and 85%. When 3a, 3b and 3f were treated under the
same reaction conditions, acceptable isolated yields
ranging between 68 and 75% were obtained for desired
C7 arylated analogues 6a–c (Scheme 4).
At this stage, we decided to validate another
strength of this methodology by preparing C5, C7-
unsymetrical diaryled 4-azaindazole N-oxides. The
treatment of the monoarylated azaindazole 2a with
3 equivalents of either 4-iodoluene or 4-iodotrifluoro-
benzene in the presence of PdCl2 as catalyst, PPh3 as
°
ligand, and K2CO3 in DMA for 24 h at 165 C led to
C5-, C7-diarylated compounds 7a and 7b in 60 and
63% yield, respectively (Scheme 5). It is noticed that
Scheme 2. Tentative mechanism for C5 direct arylation.
the arylation was also investigated starting from the C7
arylated product 3b which was with the C5 arylation
conditions using iodobenzene, Pd(OAc)2, phen,
°
K2CO3, in toluene at 140 C for 24 h. In this case, the
C5 arylation reaction was not total and the C5, C7-
diarylated product 7a was isolated in low yield of 30%
while 40% the starting material was recovered
(Scheme 5).
More interestingly, this method in combination with
others from the literature[29,30] could enable the syn-
thesis of C3, C5, C7 triarylated azaindazoles by
Scheme 4. Deoxygenation of C5 and C7 arylated 4-azaindazole
Scheme 3. Tentative mechanism for C7 direct arylation.
N-oxides.
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report[26] (see supporting information) and treated by 4-
iodotoluene in the presence of Pd(OAc)2, phen, K2CO3,
°
in toluene at 140 C for 24 h which led to the desired
product 11 in 57% yield. When using 4-bromotoluene,
the arylated compound was isolated in low yield
(20%). In both cases, the starting material 10 was
recovered. We noticed that the treatment of 10 with 4-
bromotoluene under the reaction conditions developed
for C7 arylation (see vide supra) did not lead to the
desired product and only starting material was recov-
ered (Scheme 7).
In summary, we have developed reaction conditions
for regioselective C5 and C7 direct arylations of 4-
azaindazole N-oxides. We have achieved an original
access to C5, C7 diarylated 4-azaindazole N-oxides.
Importantly, for the first time the CÀ H activation of
three of the four CÀ H bonds available on the 4-
azaindazole scaffold can be now controlled and offer
unsymmetrical C3, C5, C7 triarylated 4-azaindazoles.
Scheme 5. Synthesis of C5, C7 diarylatedazaindazole-N-oxides.
successive regioselective CÀ H activation. In prelimi- This result in the area of direct arylation of 5,6-fused
nary screens, the C3 arylation was investigated from heterocyclic systems, encouraged us to continue the
the C5, C7-disubstituted azaindazole N-oxide 7a with development of site-selective CÀ H arylation of hetero-
1-iodo-4-methoxybenzene using selective reported ex- arenes.
perimental conditions [Pd(PPh3)4, phen, Ag2CO3, H2O,
[29,30]
°
24 h, 100 C].
As obtained by the theoretical
Experimental Section
calculations (vide supra), the deactivation at C3
position by the N-oxide inhibits the reaction and only General Procedure for the Synthesis of 1H-pyrazolo
the starting material 7a was recovered. This behavior [4,3-b]pyridine
was also observed by Fagnou et al. for the direct
Hydrazine hydrate (10 mL) was added to a mixture of 3- fluoro-
2-formylpyridine (3.00 g, 24 mmol) and p-TsOH (2.06 g,
arylation of the azole ring of azaindole N-oxide.[26]
Consequently, we decided to first deoxygenate com-
°
12 mmol). The reaction mixture was stirred for 3 h at 130 C.
pounds 7a and 7b with zinc dust and NH4Cl in THF
for 3 h. The C5, C7-diarylated 4-azaindazoles 8a and
8b were isolated in 80% yields. Then, the C3 arylation
Upon cooling with cold water, the mixture was extracted three
times with ethyl acetate. The combined organic extracts were
dried over anhydrous MgSO4. After filtration, the solvent was
of either 8a or 8b under the reaction conditions removed in vacuum. The residue was purified by flash
previously mentioned [Ar2À I, Pd(PPh3)4, phen,
chromatography to give 1H-pyrazolo[4,3-b]pyridine (2 g) in
70% yield as a white solid.
[29,30]
°
Ag2CO3, H2O, 24 h, 100 C]
successfully led to
C3, C5, C7 triarylated 4-azaindazoles 9a and 9b in 75
and 85% yield, respectively (Scheme 6).
Finally, we decided to extend the scope of the
reaction conditions developed for either C5 or C7
arylation to the arylation of 7-azaindole N-oxide. Thus,
starting martial 10 was prepared following Fagnou’s
General Procedure for N-Methylation of 1H-pyra-
zolo[4,3-b]pyridine
Potassium hydroxide (3 eq) was added to a solution of 1H-
pyrazolo[4,3-b]pyridine (1 g, 8.40 mmol) in acetone (30 mL),
°
and the mixture was maintained for 60 min at 0 C. Then,
iodomethane (1.5 eq) was added. The reaction mixture was
warmed to room temperature and maintained for 2 h. The
Scheme 6. Synthesis of C3, C5, C7 triarylatedazaindazoles.
Scheme 7. C6 direct arylation of 7-azaindole N-oxide.
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reaction mixture was quenched with water and extracted with
ethyl acetate. 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/ethyl acetate, 9/1) which led
to the regioisomeric N1 and N2 methylated products with 60
and 30%yield, respectively.
24 hours. After returning to ambient temperature, the contents
of the tube were filtered through a short pad of celite. The
organic layer is then separated and the aqueous layer is
extracted with CH2Cl2. The organics are combined, dried with
MgSO4, filtered and concentrated under reduced pressure then
the crude residue is purified by chromatography on a column of
silica gel (toluene/acetone, 5/5).
General Procedures for N-oxidation
General Procedure for the Preparation of Com-
pounds 7a–b
To a solution of 1-methyl-1H-pyrazolo[4,3-b]pyridine (2 g,
°
15 mmol) in DCM (100 mL) at 0 C was added mCPBA
In a dried sealed tube placed under an argon atmosphere, 1-
methyl-1H-pyrazolo[4,3-b]pyridine-4-oxide (solubilized in 2 ml
of toluene), K2CO3 (1.5 eq), 1,10-phenanthroline (10 mol%) and
iodobenzene (2 eq) were added. The mixture was then degassed
with argan for 10 min and Pd(OAc)2 (5 mol%) is introduced.
(1,1 eq). After 1 h, the ice-bath was removed and the reaction
mixture was stirred overnight at rt. The reaction mixture was
diluted with DCM, washed with NaHCO3 (sat), and dried.
Concentration followed by purification with flash chromatog-
raphy afforded 1-methyl-1H-pyrazolo[4,3-b]pyridine-4-oxide in
90% yield as a yellow solid.
°
The reaction mixture was allowed to stir at 140 C for 24 hours.
After returning to ambient temperature, the reaction is filtered
on celite (washing with CH2Cl2), the filtrate is concentrated and
the residue was purified via silica gel column chromatography
using (toluene/acetone, 6/4) to give 1-methyl-5-phenyl-1H-
pyrazolo[4,3-b]pyridine-4-oxide. This compound (0.26 mmol)
is then solubilized in 2 ml of DMA in a dry sealed tube placed
under an argon atmosphere. After the introduction of K2CO3
(2 eq), PPh3 (10 mol%) and Ar2À I (3 eq), the reaction mixture is
degassed with argan for 10 min and PdCl2 (5 mol%) is
General Procedure for the Preparation of Com-
pounds 5a–c and 6a–c
The 5-arylated-4-azaindazole N-oxide (0.2 mmol) is dissolved
in THF (3 mL). To this mixture is then added saturated NH4Cl
solution (3 mL) and zinc dust (4,5 eq) and mixture is stirred for
3–5 hours. The deposit is then collected by filtration on celite
and washed with CH2Cl2. The organic layer is then separated
and the aqueous layer is extracted with CH2Cl2. The organics
are combined, dried with MgSO4, filtered and concentrated
under reduced pressure. The products are then purified via silica
gel column chromatography (petroleum ether/ethyl acetate, 4/1)
to give the corresponding deoxygenated products.
°
introduced. The reaction mixture was allowed to stir at 165 C
for 24 hours. After returning to ambient temperature, the
reaction is filtered on celite (washing with CH2Cl2), the filtrate
is concentrated and the residue was purified via silica gel
column chromatography using (petroleum ether/ethyl acetate,
4/6) to give 1-methyl-5-phenyl-7-Ar2-1H-pyrazolo[4,3-b]
pyridine-4-oxide.
General Procedure for the Preparation of Com-
pounds 2a–m, and 11
General Procedure for the Preparation of Com-
pounds 9a–b
In a dry sealed tube placed under an argon atmosphere, 100 mg
de 1-methyl-1H-pyrazolo[4,3-b]pyridine-4-oxide is solubilized
in 2 ml of toluene. After the introduction of K2CO3 (1,5 eq),
1,10-phenanthroline (10 mol%) and aryl iodide (3 eq), the tube
and its contents were then purged under argan for 10 minutes
and, Pd(OAc)2 (5 mol%) is introduced. The reaction mixture
The 1-methyl-5-phenyl-7-Ar2-1H-pyrazolo[4,3-b]pyridine, syn-
thesized by general procedure of double direct arylation is
dissolved in THF (2 mL). To this mixture is then added
saturated NH4Cl solution (2 mL) and zinc dust (4,5 eq). This
mixture is then stirred for 2 hours and the deposit is then
collected by filtration on celite and washed with CH2Cl2. The
organic layer is then separated and the aqueous layer is
extracted with CH2Cl2. The organics are combined, dried with
MgSO4, filtered and concentrated under reduced pressure. The
products are then purified via silica gel column chromatography
(petroleum ether/ethyl acetate, 4/1) to give the corresponding
deoxygenated products. These compounds are placed in sealed
tubes and Ar3À I (2 eq), Pd(PPh3)4 (5 mol%), Ag2CO3 (2 eq) and
phenanthroline (10 mol%) were added. Magnetic stirrer bars
were added and the mixtures of solids were gently shaken for a
few seconds to ensure all solids were well mixed. Distilled
water (3 ml) was added and the tubes were covered with a cap.
The tubes and their contents were then heated and stirred at
°
was then heated at 140 C for 24 hours. After returning to
ambient temperature, the contents of the tube were filtered
through a short pad of celite. The organic layer is then separated
and the aqueous layer is extracted with CH2Cl2. The organics
are combined, dried with MgSO4, filtered and concentrated
under reduced pressure then the crude residue is purified by
chromatography on a column of silica gel (toluene/acetone,
6/4).
General Procedure for the Preparation of Com-
pounds 3a–l
In a dry sealed tube placed under an argon atmosphere, 100 mg
de 1-methyl-1H-pyrazolo[4,3-b]pyridine-4-oxide is solubilized
in 2 ml of DMA. After the introduction of K2CO3 (2 eq), PPh3
(10 mol%) and aryl iodide (3 eq), the tube and its contents were
then purged under argan for 10 minutes and, PdCl2 (5 mol%) is
°
100 C for 24 h. After this time the reaction mixtures were
cooled down to rt. CH2Cl2 (5 ml) was added and the contents of
the tubes were filtered through a short pad of celite. The filtrates
were extracted with CH2Cl2 and the organic phase is concen-
trated under vacuum. The crudes were purified by silica gel
°
introduced. The reaction mixture was then heated at 165 C for
Adv. Synth. Catal. 2021, 363, 1–10
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column chromatography (petroleum ether/ethyl acetate, 9/1) to
give
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1-methyl-3-Ar3-5-phenyl-7-Ar2-1H-pyrazolo[4.3-b]
pyridine tri-aryleted products at C5, C7 and C3.
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Pyrrolo[2,3-b]pyridine-7-oxide and 10
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Acknowledgements
This work was supported by the Euromed University of Fes
(Morocco), LabexSynOrg (ANR-11-LABX-0029), Labex IRON
(ANR-11-LABX-0018-01), the University of Orléans and the
Centre Val de Loire Région.
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Palladium-Catalyzed Regioselective CÀ H Arylation of 4-
Azaindazole at C3, C5 and C7 Positions
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S. Faarasse, S. El Kazzouli*, O. Bourzikat, S. Bourg, S. Aci-
Sèche, P. Bonnet, F. Suzenet*, G. Guillaumet*