Optimized synthesis of 7-azaindazole by a diels-alder cascade and associated process safety

Article abstract of DOI:10.1021/acs.oprd.0c00184

Although pyrimidines are not among the most reactive partners in intramolecular inverse-electron-demand [4π_s + 2π_s] reactions with alkynes, they can be activated under mild and practical conditions, leading to fused nitrogen-containing heterocycles. We report an optimized synthesis of a 5-iodo-7-azaindazole by a one-pot Diels-Alder cascade that starts from a pyrimidine substituted at the 2-position by an (alkynyl)hydrazone. The safety of the process and the environmental impact were thoroughly evaluated. Eventually, a selection of cross-coupling reactions of 17 were studied and found to allow the introduction of carbon- and nitrogen-based nucleophiles at the 5-position in good to excellent yields.

Full text of DOI:10.1021/acs.oprd.0c00184

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Full Paper
Optimized synthesis of 7-aza-indazole by Diels–
Alder cascade and associated process safety
Nicolas Brach, Vincent Le Fouler, Vincent Bizet, Marian Lanz, Fabrice Gallou,
Corinne BAILLY, Pascale Hoehn, Michael Parmentier, and Nicolas Blanchard
Org. Process Res. Dev., Just Accepted Manuscript • Publication Date (Web): 29 Apr 2020
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Optimized synthesis of 7-aza-indazole by Diels–Alder cascade and
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⫦
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⫩
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⫨
Nicolas Brach, Vincent Le Fouler, Vincent Bizet, Marian Lanz, Fabrice Gallou, Corinne Bailly,
⫩
⫩
⫦
Pascale Hoehn, Michael Parmentier, * Nicolas Blanchard *
⫦
⫩
⫨
Université de Haute-Alsace, Université de Strasbourg, CNRS, LIMA, UMR 7042, 68000 Mulhouse, France
Chemical and Analytical Development, Novartis Pharma AG, CH-4056 Basel, Switzerland
Service de Radiocristallographie, Fédération de Chimie Le Bel - FR2010, Université de Strasbourg, 1 rue Blaise Pascal,
6
7008 Strasbourg, France
Supporting Information Placeholder
ABSTRACT: Although pyrimidines are not among the
most reactive partners in intramolecular inverse-electron
demand [4 +2 ] reactions with alkynes, they could be
trifluoroacetic acid was rapid at 60 °C in THF, leading to
hydrazone 4a.
s
s
Upon N-trifluoroacetylation of hydrazone 4a, 4b is
obtained which possesses a distorted conformation,
perfectly organized for a [4 +2 ] cycloaddition leading
to the primary cycloadduct 5. The latter could not be
detected and spontaneously undergoes a retro-[4 +2 ]
delivering the N-trifluoroacetylated cycloadduct 6 and
activated under mild and practical conditions, leading to
fused nitrogen-containing heterocycles. We report an
optimized synthesis of a 5-iodo-7-aza-indazole by a one-
pot Diels–Alder cascade that starts from a pyrimidine
substituted in the 2-position by an (alkynyl)hydrazone.
The safety of the process and the environmental impact
were thoroughly evaluated. Eventually, a selection of
cross-coupling reactions of 17 was studied and allowed
the introduction of carbon- and nitrogen-based
nucleophiles at the C5-position in good to excellent
yields.
s
s
s
s
21
hydrogen cyanide. Extensive studies by Martin at
Hoffmann-La Roche demonstrated that 3-pentanone was
the most efficient trapping agent for HCN in such inverse
electron demand Diels-Alder, likely via the formation of
cyanohydrin 7 (although we were not able to detect 7 by
H NMR studies nor hydrogen cyanide by specific
detector). Upon aqueous work-up, 7-aza-indazole 8 is
obtained as a single product of this Diels–Alder cascade.
The reaction is general, and a wide functional group
tolerance was observed.
1
20
Keywords: cycloaddition, pyrimidine, aza-indazole,
cascade, safety process, process mass intensity
20
Having demonstrated the concept of pyrimidines
activations towards [4 +2 ] cycloadditions under mild
Introduction
s
s
conditions, we focused on the optimization of the one-pot
Diels–Alder sequence on a preparative scale (in terms of
yields, ease of implementation and purification), on the
safety of all the reactions at play, and also on cross-
coupling reactions of a representative 5-iodo-7-aza-
indazole for the synthesis of C–C and C–N bonds
(Scheme 1, B). The results of these investigations are
reported herein.
Diels–Alder cycloadditions between alkynes and
pyrimidines are classified as inverse electron demand
[4 +2 ] cycloadditions that lead to pyridines upon
s
s
spontaneous retro-Diels-Alder reaction of the primary
1
-5
cycloadduct.
Limitations of this conceptually
interesting synthesis of pyridines are the high temperature
6
(up to 280 °C under classical conditions ) and very long
7
-9
reaction times that are required
to overcome the
1
0-19
intrinsic lack of reactivity of these aza-dienes.
On the
other hand, we recently reported that pyrimidines
substituted in the 2-position by an (alkynyl)hydrazone
could be exceptionally activated towards intramolecular
[4 +2 ] cycloadditions by a simple activation (Scheme
s
s
2
0
1, A). In a practical one-pot procedure starting from 2-
hydrazinopyrimidine 2, it was shown that condensation
with ynone 3 in the presence of catalytic amount of
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Purity of ynone 15 was
2
3-25
Scheme 1. Diels-Alder cycloadditions of pyrimidines
under mild conditions.
detrimental in the next steps.
found to be 93% by H NMR.
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26,27
Synthesis of 2-hydrazinopyrimidine 10. We next
focused on the synthesis of 2-hydrazinopyrimidine 10 by
aromatic nucleophilic substitution of 2-chloro-5-
iodopyrimidine 9. This reaction occurred smoothly in
ethanol (0.75 M) at 60 °C for 2 h. Upon cooling of the
reaction mixture, 10 precipitated as grey powder that
could be easily filtered. The reaction can be run on a
preparative scale, and more than 9 g could be produced in
a single run.
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Optimization of the Diels–Alder/retro-Diels–Alder.
Careful optimization of the Diels–Alder cascade
demonstrated that condensation reaction between 2-
hydrazino-5-iodo-pyrimidine 10 and ynone 15 (1.3
equivalent) was best conducted in the presence of
2
8
trifluoroacetic acid (15 mol%) and 3Å molecular sieves
in THF (0.25 M) at 60 °C for 10 min. Upon addition of
trifluoroacetic anhydride (3 equivalents) and 3-pentanone
(3 equivalents), heating of the solution at 60 °C was
continued for 2 h.
Scheme 2. Optimization of the Diels–Alder cascade on
gram-scale.
Results and discussion
Synthesis of ynone 15. A first task was dedicated to the
synthesis of a representative ynone, such as 1-cyclohexyl-
3
-phenylprop-2-yn-1-one 15 (Scheme 2). As reported by
2
2
Cox,
the Sonogashira cross-coupling between
phenylacetylene 13 and cyclohexanecarbonyl chloride 14
in the presence of catalytic amounts of palladium(II) and
copper(I) delivers 15 in excellent yields in 1 h at room
temperature on more than 5 g in a single run. A simple
filtration on a small pad of silica gel was found to be
important to remove metallic traces that could be
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1
2
Aqueous work-up delivered aza-indazole 16 in 89±3%
yield (92% on 3.5 mmol and 86% on 10.8 mmol) as a
white solid, only slightly soluble in organic solvents. A
simple filtration allows the recovery of the cycloadduct.
While this procedure is simple and reliable on multigram
scale, it should be kept in mind that the retro-Diels-Alder
step is generating one equivalent of hydrogen cyanide
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(
see also Scheme 1). Further optimizations are required
on larger scales either to find more efficient trapping
agents or finely tuned Diels-Alder precursors. As an
example, a 4,6-dimethyl substituted pyrimidine core
would lead to the elimination of acetonitrile in the retro-
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[
4 +2 ] cycloaddition, instead of hydrogen cyanide.
s
s
Cycloadduct 16 is next engaged in a benzylation
reaction using benzyl bromide and cesium carbonate in
2
9 1
DMF (0.2 M). H NMR of the crude reaction mixture
showed that benzylation of N2 of 7-aza-indazole 16
occurs at 5% only (N1-Bn/N2-Bn = 95:5) and both
compounds could be easily separated by chromatography
on silica gel. Cycloadduct 17 was obtained in 85% yield
as a white solid soluble in common organic solvents
(toluene, tetrahydrofuran, dichloromethane, ethyl
acetate…).
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Figure 1. DSC analysis of compound 10
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Figure 2. DSC analysis of phenylacetylene 13
Figure 3. DSC analysis of 15
Single X-ray diffraction of 7-aza-indazole 17
synthesis of a complex 5-iodo-7-aza-indazole from a
simple and inexpensive pyrimidine building block.
(CCDC1989511,
see
Supporting
Information)
unambiguously proved the structure of this pericyclic
cascade product. Overall, two precipitations and a single
chromatography are required in this straightforward
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thermal stability of all the starting materials neither the
Process safety investigations.
1
2
3
product used during this synthetic step. Nevertheless,
drying should be carefully controlled as it might be
quality relevant (e.g. time and temperature) looking at the
isothermal test combined with the determination of the
residual heat release.
The process safety studies for the sequential steps were
carried out with the major goal to design a safe process to
support potential use on preparative scale. As our first
step to explore the feasibility of applying this reaction on
a pilot scale, we evaluated the thermal stability of all of
the reagents and intermediates that are in sufficient
concentrations under the reaction conditions using
differential scanning calorimetry (DSC).
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Scheme 3. Synthesis of 18
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We first observed that the 2-chloro-5-iodopyrimidine 9
shows the onset of a very strong exothermal reaction
starting above ca. 275 °C of at least -630 kJ/kg (see
Supporting
Information
for
DSC
diagrams).
Nevertheless, considering the reaction conditions used to
produce 10 and the likelihood to reach such a high
temperature, no specific measures needs to be
implemented concerning its thermal stability. The use of
hydrazine as reagent from an industrial manufacturing
point of view is always safety relevant as hydrazine
hydrate is a highly toxic, potentially carcinogenic, and
corrosive liquid with a relatively low boiling point (120
30
°
C). In particular, the accumulation of this volatile
reaction component in the headspace of a batch reactor
can result in violent explosions. In accordance with
literature data, the dilution of the system has a non-
negligible impact on the flash point of hydrazine,
compressibility and its potential deflagration. The current
process is using hydrazine hydrate which is further
diluted at 2 wt% with EtOH prior to be heated to 60 °C.
This high dilution in addition to the moderate temperature
ensure a process that can be safely operated.
The Sonogashira cross-coupling step to form 15 uses
phenylacetylene as starting material. This commonly
used starting material appears to be much less stable than
expected; DSC analysis revealed its strong
decomposition reaction starting at 115 °C: This highly
exothermic event is characteristic of
a
violent
decomposition (ΔH = -1921 kJ/Kg) (Figure 2). The DSC
measurement was conducted in a standard gold crucible
and one could imagine that specific interaction between
the compound and the crucible material can be
responsible for this behavior. However, running the same
experiment in a specific glass setup shows the same
decomposition pattern.
The resulting product 10 has been submitted to DSC
analysis and reveals an extremely strong exothermal
reaction starting above ca. 155 °C (approx. -1111 kJ/kg)
potentially leading to an adiabatic temperature increase of
3
1
about 741 °C (Figure 1). The very high decomposition
energy in compound 10, lead us to further investigate its
decomposition behavior. An isoDSC at 110 °C (reaction
temp + 50 °C) over 12 h followed by a cooling step and a
subsequent dynamic DSC run has been performed. It
provided knowledge on potential decomposition behavior
under the reaction temperature with sufficient safety
margin. After ca. 460 min at 110 °C a very weak heat
release is detected indicating a potential autocatalytic
decomposition. In the determination test of the residual
energy (after the isothermal measurement), the
decomposition reaction is still registered. However, the
overall energy is slightly lower than in the dynamic DSC
test run on the fresh sample and the peak shape is
In light of these results, we were then concerned about
the potential impact of the palladium and copper catalyst
used in the Sonogashira reaction (13+1415, Schemes 2
and 3) and their potential influence on the onset of the
decomposition. The dynamic SEDEX thermostability test
of phenylacetylene 13, in presence of the palladium and
copper catalyst, shows no significant heat release up to
1
65 °C. The test was run on the reaction mixture (13+14
with catalyst) and it shows a first moderate exothermal
reaction starting above ca. 0 °C (approximatively -60
kJ/kg, Tadiab = 40 °C) most likely due to the reaction
itself and a second one starting above ca. 115 °C
(approximatively -37 kJ/kg) that may corresponds to the
beginning of the decomposition of the reaction product
15. The isolated product 15 has a very high
decomposition energy of -720 kJ/kg starting above 170
°C, making the process safely scalable considering the
reaction conditions (reaction temperature = 25 °C).
substantially
decomposition is shifted towards lower temperature (110
C vs 155 °C). In light of these data, we concluded that
different.
Moreover,
the
onset
°
the process to synthesize the compound 10 can be safely
operated at the proposed temperature and that no specific
measures needs to be implemented in regard to the
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Figure 4. DSC and isoDSC analysis of 18
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The condensation of 10 and 15 followed by the Diels-
Alder reaction leading to 16 is performed at 60 °C for a
very short period. In order to study carefully the safety of
the reaction, the stable hydrazone intermediate 18 has
been prepared (Scheme 3) and submitted to DSC (Figure
Table 1. Calculated PMI for each step
Reaction Reagents and substrates Solvents
Water
PMI
1
3 → 15
→ 10
10 → 16
6 → 17
2
1
5
2
24
8
55
2
82
12
68
57
4
). As it can be envisioned considering its structure
9
closely related to the hydrazine 10, a substantial amount
of energy can be released upon degradation (approx. -815
kJ/kg), starting at 175 °C after the melting of the
compound. Nevertheless, no significant heat release
could be observed when isoDSC was run at 110 °C
14
39
49
16
1
(reaction temp + 50 °C). By increasing the temperature of
the isoDSC measurement just below the endothermic
point (160 °C), the onset of the decomposition could be
observed but with a loss of energy of about 40%. Partial
decomposition of the compound 18 can potentially
explain this observation.
Figure 5. Calculated PMI by step and cumulative
The final cycloadduct 16 resulting from the Diels-Alder
cascade of the hydrazone intermediate 18 shows the onset
of a moderate exothermal reaction starting above ca. 320
°
C (approx. -153 kJ/kg) which is not of a concern
regarding the very mild reaction conditions applied.
In conclusion, the thorough study of the sequential
transformation of the pyrimidine 9 to the bicyclic
cycloadduct 16 involving two highly energetic compound
(namely phenylacetylene and hydrazine hydrate) can be
safely operated using the described mild process. All the
exotherms observed are well above the reaction
temperature used during the process. Moreover, no
significant onset shifts were observed due to the presence
of catalysts.
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Figure 6. Estimated cumulative PMI
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The cumulative PMI of 344 is not representative of the
potential of such a streamlined and efficient synthetic
sequence. While scaling up each step, one can see
opportunities for optimizing the solvent and/or water
consumption. For the sake of comparison and to have a
better idea on how far the process can be optimized in
term of waste generation, we used the recently developed
PMI prediction tool by Borovika et al. accessible online
Environmental Impact Evaluation
While keeping in mind that the process to make the
protected compound 17 is still at its research stage, we
were interested to evaluate its environmental impact.
Using a publicly available tool developed by the ACS
Green Chemistry Institute Pharmaceutical Roundtable,
we were able to calculate the overall waste generation
to produce one mass unit of the final material 17 including
organic solvent and aqueous waste (see Table 1, Figure 5
and detailed calculations in the Supporting Information).
The Sonogashira cross-coupling step from 13 to 15 (see
3
2-
36-38
(
Figures 6 and 7).
The estimated cPMI range has a
3
4
mean of 128 (see Supporting Information for details) with
a 95% confidence interval. This is obviously below the
value of 344 calculated with real data from the process.
This theoretical cPMI value should be taken as a basis for
future development opportunity as it represents an
estimation of the waste generation of a given process for
similar transformations, based on existing data from
2
2
Scheme 2 for details) is based on a described process
and was not fully optimized. Looking at generation of
wastes, it can easily be seen that optimization of the
aqueous workup will greatly improve the overall
efficiency as two-third of the total mass accounts for
water. This step represents by itself 45% of the total water
consumption of the overall process and will be a topic to
address over the future development. The aromatic
nucleophilic substitution of 9 using hydrazine has a low
PMI as the product 10 precipitated from the reaction
mixture and requires only minimum washings to reach the
targeted quality. The sequential Diels-Alder retro-Diels-
Alder sequence (10+1516, see Scheme 2 for details)
has a good overall PMI of 68 as it combines two steps.
The minimum amount of operations and washings make
this step particularly efficient from a process point of
39
several pharmaceutical companies (at >1 kg scale).
Figure 7. Cumulative PMI for synthesis sequence up
to compound 17 – predicted and actual values
a
analyzed by the PMI Predictor tool.
35
view. Finally, the benzylation step (1617) was
processed using standard literature protocol and suffers
the most from the use of DMF as organic solvent resulting
by an increasing number of extractions during the
downstream operations.
29
a
Blue circles denote the actual cumulative PMI for each
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Page 8 of 15
intermediate in the synthetic route. Orange bars represent the
predicted cPMI.
DMF, 100 °C, 12 h). 5-Trifluoromethyl-7-aza-indazole
21 was obtained in quantitative yield (Scheme 4, B).
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3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
For example, optimization of the Sonogashira cross-
coupling reaction can potentially lead to a significant gain
of a minimum of 35% when reaching the high end of the
typical range (1315, Figure 7), while the N-benzylation
can be reduced by 38% minimum (1617, Figure 7).
Future work upon scaling up will therefore focus on
reducing the PMI of relevant steps.
Scheme 5. Palladium-catalyzed and copper-mediated
amination and amidation of 7-aza-indazole 17.
A: Palladium-catalyzed amination reaction
Aniline (22)
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Pd2(dba)3 (10 mol%)
xantphos (10 mol%)
Cs2CO3
H
I
N
N
N
Scheme
4.
Arylation,
vinylation
and
N
N
1,4-dioxane
90 °C
N
N
Bn
Bn
trifluoromethylation reactions of 7-aza-indazole 17.
12 h
23, 65%
17
A: Palladium-catalyzed arylation and vinylation reactions
R
B(OH)2
B: Copper-catalyzed amidation reactions
R1
N
Pd(PPh3)4 (5 mol%)
Na2CO3
R
I
R2
24a,b
N
H
N
DME/H2O
N
N
O
N
N
100 °C
Bn
CuI (5 mol%)
Bn
4 h
17
19a-c
(±)-trans-1,2-diaminocyclo-
hexane (10 mol%)
K3PO4
R1
R2
I
N
N
N
O
N
N
N
1,4-dioxane
110 °C
N
Bn
Bn
17
24-72 h
25a,b
S
N
N
N
N
N
N
N
N
N
N
Bn
Bn
Bn
H
N
Ph
N
19a, 71%
19b, 99%
19c, 93%
N
O
N
O
N
N
N
N
B: Copper-mediated trifluoromethylation reaction
Bn
Bn
25a, 72%
25b, 95%
F
F
F
S
O
CO2Me
20
CuI
O
I
CF3
Cross-coupling reactions of cycloadduct 17 for the
creation of C–N bonds. The formation of C–N bonds
from 17 was also explored (Scheme 5). Aniline 22 could
be efficiently cross-coupled to 17 using Pd (dba) (10
N
N
N
N
DMF
100 °C
N
N
Bn
Bn
12 h
17
21, 99%
2
3
mol%), xantphos (10 mol%), cesium carbonate in 1,4-
4
4
Cross-coupling reactions of cycloadduct 17 for the
creation of C–C bonds. Having at hand a scalable
synthesis of 5-iodo-7-aza-indazole 17, it was of interest
to evaluate the late-stage diversification of this scaffold
for the creation of C–C and C–N bonds on a limited
dioxane at 90 °C for 12 h (Scheme 5, A). Compound 23
was isolated in 65%. Introduction of amides and lactams
was also evaluated under copper(I)-catalyzed cross-
coupling
conditions,
with
(±)-trans-1,2-
diaminocyclohexane (10 mol%) as a ligand and
potassium phosphate as a base in 1,4-dioxane at 110 °C
4
0
number of examples. Arylation and vinylation reactions
4
5
of 17 were first investigated (Scheme 4, A), using three
(Scheme 5, B). Benzamide 24a and azetidinone 24b
were competent partners in these conditions and lead to
25a (72%) and 25b (95%) as the sole products.
representative aryl- or vinylboronic acid, Pd(PPh ) (5
3
4
mol%) and sodium carbonate in a DME/H O (2:1)
2
mixture at 100 °C for 4 h. 7-Aza-indazoles having a 5-
(pyridin-3-yl),
a
5-(thiophen-3-yl)
or
a
5-
(cyclopropylvinyl) motif were obtained in good to
Conclusions
excellent yields (19a, 71%; 19b, 99%; 19c, 93%
respectively). Trifluoromethylation of 17 was also
straightforward under Chen’s copper(I)-mediated
Pyrimidines are simple building blocks that can be
activated
towards
intramolecular
[4 +2 ]
s
s
cycloadditions with alkynes under mild conditions. We
have optimized the reaction conditions of a one-pot
4
1-43
conditions
(methyl fluorosulfonyldifluoroacetate 20,
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1
Organic Process Research & Development
methoxybenzaldehyde) as visualizing agents. All
s
condensation/[4 +2 ]/retro-[4 +2 ] sequence that
s
s
s
delivers 5-iodo-7-aza-indazole 16 in a straightforward
manner, on a multigram scale. Extensive investigations of
the safety of the process were conducted and the
environmental impact was evaluated. Eventually,
diversification of 5-iodo-7-aza-indazole 17 was studied
in a variety of transition-metal catalyzed cross-coupling
reactions allowing the introduction of heteroaryl, vinyl,
trifluoromethyl, aniline, amide and lactam in the C5-
position with good to excellent yields. Synthetic
strategies aiming at efficient disconnections in
heterocyclic chemistry are a focus of many research
groups. In this regard, pyrimidines are relevant
separations were performed by column chromatography
on Merck silica gel 60 (40-63 μm). DSC thermograms
were recorded on Mettler Toledo DSC1, in high-pressure
gold-plated DSC crucible closed under argon atmosphere.
SEDEX thermograms were recorded on SYSTAG
TSC511 SEDEX in autoclave under stirring.
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2
2
-Hydrazinyl-5-iodo-pyrimidine (10). To a solution of
-chloro-5-iodo-pyrimidine 9 (10 g, 41.6 mmol) in
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
ethanol (55 mL, 0.75 M) was added hydrazine hydrate (4
mL, 83.2 mmol, 2 equiv.) at room temperature. The
reaction mixture was heated at 60 °C for 2 h then cooled
down to room temperature. The precipitate was filtered
on a Büchner, rinsed with water (20 mL), ethanol (20 mL)
and diethyl ether (20 mL) and dried under high vacuum
until constant weight. 2-Hydrazinyl-5-iodo-pyrimidine
(fused)pyridines precursors in terms of operational
simplicity, process safety and diversification potential of
the cycloadducts.
1
0 was obtained as a grey powder (9.38 g, 96 %).
Spectroscopic data for 2-hydrazinyl-5-iodo-pyrimidine
EXPERIMENTAL SECTION
4
6 1
1
0 are in agreement with reported data.
H NMR
General information. NMR spectra were recorded on
(DMSO 400 MHz, ppm) : 8.44 (s, 2H), 8.41 (s, 1H),
,
1
3
Brucker AV 400 or AV 500 spectrometer at 400 MHz or
4.18 (s, 2H). C NMR (DMSO 100 MHz, ppm) : 162.5,
,
1
13
-
1
500 MHz for H NMR, at 100 MHz or 125 MHz for C
1
1
62.3, 76.0. IR (cm )  1580, 1553, 1506, 1426, 1364,
max
1
9
NMR and at 471 MHz for F. The spectra were calibrated
using NMR solvent residual peaks as internal reference
267, 1201, 1184, 1156, 1111, 988, 935, 852, 788, 643.
Mp: 179 °C (lit. 196-197 °C after recrystallization from
1
13
4
6
for H NMR and C NMR. Coupling constants (J) were
reported in Hertz. Multiplicities are designed as singlet
(s), doublet (d), triplet (t), quartet (q), quintuplet (quint),
multiplet (m), broad (br) and possible combinations
between them. Melting points were measured on a
Heizank, system Kofler Type WME (Wagne and Munz).
High resolution mass spectra (HRMS) in positive modes
were recorded using a 6520 series quadrupole time-of-
flight (Q-TOF) mass spectrometer (Agilent) fitted with a
multimode ion source (in mixed mode that enables both
electrospray ionization, ESI, and atmospheric pressure
chemical ionization, APCI). All sensitive reactions were
carried out in oven-dried glassware under a nitrogen
atmosphere using dry solvents, unless otherwise noted.
Infrared spectra were recorded using a Spectrum Two FT-
IR Spectrometer (PerkinElmer). THF was distilled under
nitrogen from sodium-benzophenone; dichloromethane
and 1,4-dioxane were distilled from calcium hydride. All
other anhydrous solvents were purchased from Sigma-
Aldrich. Molecular sieves were heated (either using a
heat-gun or by flame-drying) under high vacuum just
before use. Reagents were purchased from Merck, TCI,
Fluorochem or Strem and used without further
purification, unless otherwise noted. Concentration under
reduced pressure was performed by rotary evaporation at
appropriate temperature and pressure. Yields refer to
toluene).
-Cyclohexyl-3-phenylprop-2-yn-1-one (15).22 To a
1
solution of cyclohexanecarbonyl chloride (5 mL, 37.17
mmol) in THF (50 mL) under nitrogen were added
successively phenylacetylene (2.72 mL, 24.78 mmol),
Pd(PPh ) Cl (73 mg, 0.22 mmol, 0.9 mol%) and CuI
3
2
2
(
3
0.14 g, 0.74 mmol, 3 mol%). After 1 min, Et N (4.3 mL,
3
0.98 mmol) was added to the suspension and stirring was
continued for 1 h at room temperature. The reaction
mixture was diluted with diethyl ether (20 mL) and
washed with water (50 mL). The combined organic
phases were washed with a saturated aqueous solution of
Na CO (3x 75 mL), dried over MgSO , filtered and
2
3
4
concentrated under vacuum. The residue was diluted in
ethyl acetate (50 mL) and filtered through a pad of silica
gel (approximately 3 cm height, 7 cm in diameter),
eluting with ethyl acetate. The filtrate was concentrated
under vacuum, offering 1-cyclohexyl-3-phenylprop-2-
yn-1-one 15 as a dark red oil (5.44 g, >100 %, 93% pure
1
by H NMR) which was used without further purification.
Spectroscopic data for 1-cyclohexyl-3-phenylprop-2-yn-
22 1
1
(
=
2
1
-one 15 are in agreement with reported data. H NMR
CDCl 400 MHz, ppm) : 7.59-7.57 (m, 2H), 7.44 (tt, J
3
,
7.6, 1.5 Hz, 1H), 7.38 (2H, m, ArH), 2.55-2.47 (m, 1H),
.08-2.03 (m, 2H), 1.81 (dt, J = 13.2, 3.9 Hz 2H), 1.71-
1
3
.66 (m, 1H), 1.57-1.45 (m, 2H), 1.39-1.10 (m, 3H). C
1
13
chromatographically and spectroscopically ( H, C and
NMR (CDCl 100 MHz, ppm) : 191.4, 133.0 (2C),
1
9
3,
F NMR) homogenous materials, unless otherwise
1
2
30.6, 128.6 (2C), 120.2, 91.3, 87.2, 52.3, 28.5 (2C),
5.8, 25.4 (2C).
noted. Reactions were monitored by thin-layer
chromatography (TLC) carried out on Merck TLC silica
gel 60 F254 glass-coated plates, using UV light,
potassium permanganate or vanillin (2-hydroxy-3-
3-Cyclohexyl-5-iodo-4-phenyl-1H-pyrazolo[3,4-
b]pyridine (16). From 18: To a solution of (Z)-2-(2-(1-
ACS Paragon Plus Environment

Organic Process Research & Development
Page 10 of 15
cyclohexyl-3-phenylprop-2-yn-1-ylidene)hydrazinyl)-5-
iodopyrimidine 18 (924 mg, 2.15 mmol) in THF (2.1 mL,
M) under nitrogen were added dropwise 3-pentanone
0.34 mL, 3.22 mmol, 1.5 equiv.) and trifluoroacetic
gel (PE/AcOEt = 90:10 to 55:45). 1-Benzyl-3-
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
cyclohexyl-5-iodo-4-phenyl-1H-pyrazolo[3,4-b]pyridine
17 was obtained as a white solid (1.03 g, 84 %). Upon
scaling-up of this reaction on 3.77 g of 16, 1-benzyl-3-
cyclohexyl-5-iodo-4-phenyl-1H-pyrazolo[3,4-b]pyridine
1
(
anhydride (0.3 mL, 2.15 mmol, 1 equiv.). The reaction
mixture was heated at 60 °C for 2 h, cooled down to room
temperature, diluted with ethyl acetate (3 mL) and
washed with a saturated aqueous solution of Na CO (3x
1
17 was obtained in 85% yield (3.9 g). H NMR (CDCl
3
,
400 MHz, ppm) : 8.80 (s, 1H), 7.51 (m, 3H), 7.32-7.24
2
3
(m, 7H), 5.66 (s, 2H), 2.01-1.94 (m, 1H), 1.61-1.37 (m,
13
1
5 mL). The precipitate was filtered on a Büchner and
7H), 1.14-1.07 (m, 1H), 0.83-0.73 (m, 2H). C NMR
washed with the minimum amount of ethyl acetate. 3-
Cyclohexyl-5-iodo-4-phenyl-1H-pyrazolo[3,4-
(
1
1
CDCl 100 MHz, ppm) : 155.0, 150.1, 149.7, 149.0,
3
,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
40.3, 137.2, 128.8, 128.5, (2C), 128.4, (2C), 128.3, (2C),
b]pyridine 16 was obtained as a white thin powder (822
mg, 94 %), sparingly soluble in DMSO. One-pot
synthesis from 10: To a round bottom flask containing
dry 3Å molecular sieves (1 g) were successively added 2-
hydrazinyl-5-iodo-pyrimidine 10 (0.86 g, 3.62 mmol),
THF (14.5 mL, 0.25 M), 1-cyclohexyl-3-phenylprop-2-
yn-1-one 15 (1 g, 4.71 mmol, 1.3 equiv.) and
trifluoroacetic acid (0.04 mL, 0.54 mmol, 15 mol%)
under nitrogen. The reaction mixture was heated at 60 °C
for 10 min, then 3-pentanone (1.15 mL, 10.87 mmol, 3
equiv.) and trifluoroacetic anhydride (1.51 mL, 10.87
mmol, 3 equiv.) were added dropwise. The reaction
mixture was heated at 60 °C for 2 h, cooled down to room
temperature, concentrated under vacuum to half its
volume, and diluted with ethyl acetate (5 mL). The
resulting solution was washed with a saturated aqueous
solution of Na CO (3x 20 mL). The precipitate was
27.8 (2C), 127.5, 114.8, 89.5, 50.7, 36.9, 32.8 (2C), 26.5
-1
(2C), 25.9. IR (cm ) max: 3034, 2929, 2851, 1551, 1483,
1
1
442, 1347, 1271, 1189, 1175, 767, 707, 693, 543. Mp:
59 °C.
(Z)-2-(2-(1-Cyclohexyl-3-phenylprop-2-yn-1-
ylidene)hydrazinyl)-5-iodopyrimidine (18). To
a
Schlenk tube containing dry 3Å molecular sieves (100
mg) were successively added 2-hydrazinyl-5-iodo-
pyrimidine 10 (112.5 mg, 0.48 mmol), THF (2.4 mL, 0.2
M), 1-cyclohexyl-3-phenylprop-2-yn-1-one 15 (131.55
mg, 0.62 mmol) and trifluoroacetic acid (5 μL, 0.067
mmol, 15 mol%) under nitrogen. The reaction mixture
was heated at 60 °C for 10 min, cooled down to room
temperature and evaporated under vacuum. The residue
was dissolved in dichloromethane (5 mL) and the solid
was filtered on a Büchner. The solution was evaporated
under vacuum, the resulting solid was triturated in
acetone (10 mL) and filtered on a Büchner. (Z)-2-(2-(1-
Cyclohexyl-3-phenylprop-2-yn-1-ylidene)hydrazinyl)-5-
iodopyrimidine 18 was obtained as a white powder (142
2
3
filtered on a Büchner and washed with the minimum
amount of ethyl acetate. 3-Cyclohexyl-5-iodo-4-phenyl-
1
H-pyrazolo[3,4-b]pyridine 16 was obtained as a white
solid (1.34 g, 92 %). Starting from 2.57 g (10.87 mmol)
1
mg, 70 %). H NMR (CDCl 400 MHz, ppm) : 9.12 (s,
3
,
of 10, a slightly diminished yield was obtained (86%, 3.77
1H), 8.60 (s, 2H), 7.60-7.57 (m, 2H), 7.44-7.38 (m, 3H),
2.70 (tt, J = 12.0, 3.6 Hz, 1H), 1.93-1.90 (m, 2H), 1.83-
1.80 (m, 2H), 1.73-1.70 (m, 1H), 1.55 (qd, J = 12.4, 3.1
1
g of cycloadduct 16). H NMR (DMSO 400 MHz, ppm)
,

2
2
1
1
: 13.51 (s, 1H), 8.80 (s, 1H), 7.56 (m, 3H), 7.31-7.33 (m,
H), 1.94-1.90 (m, 1H), 1.57-1.47 (m, 5H), 1.34-1.27 (m,
1
3
Hz, 2H), 1.40-1.20 (m, 3H). C NMR (CDCl 100 MHz,
3
,
1
3
H), 1.05 (m, 1H), 0.74-0.66 (m, 2H). C NMR (DMSO
,
ppm) : 163.5 (2C), 157.8, 140.4, 132.1 (2C), 129.9,
00 MHz, ppm) : 155.0, 152.0, 149.7, 148.8, 140.4,
128.6, (2C), 120.9, 104.1, 79.7, 78.5, 44.7, 30.9 (2C),
29.1, 128.8 (2C), 128.7 (2C), 113.8, 90.1, 36.9, 32.8
-1
2
1
9
5.8 (2C), 25.7. IR (cm ) max: 3319, 2922, 2850, 1559,
502, 1406, 1363, 1311, 1257, 1195, 1146, 1123, 1103,
92, 915, 782, 755, 742, 687, 639. Mp: 184 °C.
-1
(2C), 26.6 (2C), 25.9. IR (cm ) max: 3180, 3127, 3010,
2
6
926, 2847, 1585, 1446, 1282, 1196, 1172, 846, 756, 698,
555. Mp: > 265 °C.
1-Benzyl-3-cyclohexyl-5-iodo-4-phenyl-1H-
1
-Benzyl-3-cyclohexyl-4-phenyl-5-(pyridin-3-yl)-
pyrazolo[3,4-b]pyridine (17). To a solution of 3-
cyclohexyl-5-iodo-4-phenyl-1H-pyrazolo[3,4-b]pyridine
16 (1 g, 2.48 mmol) in DMF (12.4 mL, 0.2 M) under
nitrogen were added Cs CO (888.8 mg, 2.73 mmol) and
1
H-pyrazolo[3,4-b]pyridine (19a). To a solution of 1-
benzyl-3-cyclohexyl-5-iodo-4-phenyl-1H-pyrazolo[3,4-
b]pyridine 17 (50 mg, 0.1 mmol) in DME/H O (1:0.5 mL,
2
2
3
0
.07 M) under nitrogen were added 3-pyridylboronic acid
benzyl bromide (0.33 mL, 2.73 mmol) at 0 °C. The
reaction mixture was allowed to warm to room
temperature and was stirred for 3 h, quenched with water
(16 mL) then extracted with ethyl acetate (3x 15 mL). The
(
14.9 mg, 0.12 mmol, 1.2 equiv.), Na CO (12.9 mg, 0.12
2
3
mmol, 1.2 equiv.) and Pd(PPh ) (5.8 mg, 5 mol%). The
3
4
reaction mixture was heated at 100 °C for 4 h, cooled
down to room temperature and quenched with an aqueous
combined organic phases were dried over MgSO , filtered
4
1
solution of NaHCO (10% in water, 3 mL). It was diluted
3
then concentrated under vacuum. H NMR (CDCl , 400
3
in ethyl acetate (5mL) and filtered through a pad of silica
gel. The pad was washed with EtOAc, and the filtrate
washed with brine (5% in water). The organic phase was
MHz) of the crude reaction mixture shows that 2
regioisomers were obtained in a N1/N2 ratio of 95:5,
separable by flash chromatography on silica gel. The
residue was purified by flash chromatography on silica
separated, dried over MgSO , filtered and evaporated
4
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Organic Process Research & Development
under vacuum. The residue was purified by flash
an aqueous solution of NaHCO (10% in water, 3 mL). It
was diluted in EtOAc (5 mL) and filtered through a pad
of silica gel. The pad was washed with EtOAc, and the
filtrate washed with brine (5% in water). The organic
3
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
chromatography on silica gel (PE/AcOEt = 90:10). 1-
Benzyl-3-cyclohexyl-4-phenyl-5-(pyridin-3-yl)-1H-
pyrazolo[3,4-b]pyridine 19a was obtained as a white
1
solid (32 mg, 71 %). H NMR (CDCl 400 MHz, ppm) :
phase was separated, dried over MgSO , filtered and
4
3
,
8
3
7
1
0
1
1
1
.50 (s, 1H), 8.42 (dd, J = 4.7, 1.6 Hz, 2H), 7.40-7.37 (m,
H), 7.34-7.30 (m, 5H), 7.27-7.26 (m, 1H), 7.20 (m, 2H),
.13-7.11 (m, 1H), 5.74 (s, 2H), 2.23-2.19 (m, 1H), 1.62-
.58 (m, 4H), 1.51-1.42 (m, 3H), 1.15-1.11 (m, 1H), 0.88-
evaporated under vacuum. The residue was purified by
flash chromatography on silica gel (PE/AcOEt = 90:10).
(E)-1-Benzyl-3-cyclohexyl-5-(2-cyclopropylvinyl)-4-
phenyl-1H-pyrazolo[3,4-b]pyridine 19c was obtained as
1
1
3
a grey solid (41 mg, 93 %). H NMR (CDCl 400 MHz,
.77 (m, 2H). C NMR (CDCl 100 MHz, ppm) : 150.8,
3,
3
,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
50.6, 150.5, 149.5, 147.8, 143.8, 137.5 (2C), 137.4,
35.9, 134.0, 129.5 (2C), 128.5 (2C), 128.2, 128.0 (2C),
27.8 (2C) 127.5, 125.9, 122.7, 112.7, 50.6, 37.1, 32.8
ppm) : 8.66 (s, 1H), 7.50-7.47 (m, 3H), 7.33-7.20 (m,
7H), 6.23 (d, J = 16.0 Hz, 1H), 5.67 (s, 2H), 5.58 (dd, J =
16.0, 9.0 Hz, 1H), 2.08-2.02 (m, 1H), 1.61-1.58 (m, 4H),
-1
1
0
.52-1.46 (m, 1H), 1.44-1.36 (m, 3H), 1.13-1.10 (m, 1H),
.87-0.7 (m, 4H), 0.43-0.40 (m, 2H). C NMR (CDCl3,
(2C), 26.6 (2C), 25.9. IR (cm ) max: 3054, 3030, 2926,
1
3
2
6
851, 1859, 1742, 1551, 1493, 1258, 1170, 1022, 712,
98, 647. Mp: 151 °C.
100 MHz, ppm) : 150.3, 150.0, 146.9, 141.3, 137.7,
36.6, 135.3, 129.1 (2C), 128.4 (2C), 128.1 (3C) 127.7
2C), 127.3, 124.7, 122.8, 112.6, 50.4, 36.9, 32.8 (2C),
1
1
-Benzyl-3-cyclohexyl-4-phenyl-5-(thiophen-3-yl)-
(
1
H-pyrazolo[3,4-b]pyridine (19b). To a solution of 1-
-1
2
2
6
6.6 (2C), 25.9, 14.9, 7.30 (2C). IR (cm ) max: 3003,
928, 2846, 1645, 1573, 1493, 1257, 1045, 958, 706, 698,
48, 556. Mp: 144 °C.
benzyl-3-cyclohexyl-5-iodo-4-phenyl-1H-pyrazolo[3,4-
b]pyridine 17 (50 mg, 0.1 mmol) in DME/H O (1:0.5 mL,
2
0
.07 M) under nitrogen were added 3-thiopheneboronic
acid (15.5 mg, 0.12 mmol, 1.2 equiv.), Na CO (12.9 mg,
1-Benzyl-3-cyclohexyl-4-phenyl-5-
2
3
0
.12 mmol, 1.2 equiv.) and Pd(PPh ) (5.8 mg, 5 mol%).
(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridine (21). To
a solution of 1-benzyl-3-cyclohexyl-5-iodo-4-phenyl-1H-
pyrazolo[3,4-b]pyridine 17 (100 mg, 0.2 mmol) in DMF
(0.9 mL, 0.23 M) under nitrogen were added CuI (57.9
mg, 0.3 mmol, 1.5 equiv.) and MFSDA (51 µL, 0.4 mmol,
2 equiv.). The flask was equipped with a bubbler and the
reaction mixture was heated at 100 °C overnight. The
solvent was removed under vacuum and the residue was
purified by flash chromatography on silica gel
(PE/AcOEt = 90:10). 1-Benzyl-3-cyclohexyl-4-phenyl-5-
(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridine 21 was
3 4
The reaction mixture was heated at 100 °C for 4 h, cooled
down to room temperature and quenched with an aqueous
solution of NaHCO (10% in water, 3 mL). It was diluted
3
in EtOAc (5 mL) and filtered through a pad of silica gel.
The pad was washed with EtOAc, and the filtrate washed
with brine (5% in water). The organic phase was
separated, dried over MgSO , filtered and evaporated
4
under vacuum. The residue was purified by flash
chromatography on silica gel (PE/AcOEt = 90:10). 1-
Benzyl-3-cyclohexyl-4-phenyl-5-(thiophen-3-yl)-1H-
pyrazolo[3,4-b]pyridine 19b was obtained as a yellow
1
obtained as a white solid (87 mg, 99 %). H NMR (CDCl
3
,
1
solid (45 mg, 99 %). H NMR (CDCl 400 MHz, ppm) :
400 MHz, ppm) : 8.81 (s, 1H), 7.54-7.45 (m, 3H), 7.38-
3
,
8.62 (s, 1H), 7.39-7.35 (m, 5H), 7.32-7.29 (m, 2H), 7.26-
7.23 (m, 3H), 7.13 (dd, J = 5.0, 3.0 Hz, 1H), 6.94 (dd, J =
3.0, 1.3 Hz, 1H), 6.75 (dd, J = 5.0, 1.3 Hz, 1H), 5.72 (s,
2H), 2.20-2.14 (m, 1H), 1.63-1.58 (m, 4H), 1.53-1.41 (m,
7.28 (m, 7H), 5.70 (s, 2H), 1.87-1.80 (m, 1H), 1.62-1.38
1
3
(m, 7H), 1.15-1.07 (m, 1H), 0.81-0.71 (m, 2H). C NMR
(CDCl 100 MHz, ppm) : 151.7, 151.3, 145.9 (q, J = 5.6
3
,
Hz), 145.6, 137.0, 134.3, 128.8, 128.5 (2C), 128.4 (2C),
127.9 (2C), 127.7 (3C), 124.5 (q, J = 273.8 Hz), 117.6 (q,
J = 28.9 Hz), 113.3, 50.7, 36.8, 32.8 (2C), 26.5 (2C), 25.8.
1
3
3H), 1.17-1.09 (m, 1H), 0.88-0.77 (m, 2H). C NMR
(CDCl 100 MHz, ppm) : 150.4, 150.3, 149.8, 142.8,
3
,
19
-1
1
38.3, 137.6, 136.9, 129.2 (2C), 129.1 (2C), 128.5 (2C),
F NMR (CDCl 471 MHz, ppm) : - 54.5. IR (cm )
3
,
128.1, 128.0 (2C), 127.7 (2C), 127.4, 124.7, 124.3, 123.5,
max: 3034, 2932, 2850, 1887, 1577, 1563, 1323, 1279,
204, 1120. Mp: 158 °C.
-Benzyl-3-cyclohexyl-N,4-diphenyl-1H-
-1
112.8, 50.5, 37.05, 32.8 (2C), 26.6 (2C), 25.9. IR (cm )
1
max: 3096, 3026, 2923, 2850, 1744, 1558, 1489, 1258,
1
1
169, 784, 698, 666. Mp: 142 °C.
pyrazolo[3,4-b]pyridin-5-amine (23). To a solution of
1-benzyl-3-cyclohexyl-5-iodo-4-phenyl-1H-
(
E)-1-benzyl-3-cyclohexyl-5-(2-cyclopropylvinyl)-4-
phenyl-1H-pyrazolo[3,4-b]pyridine (19c). To a solution
of 1-benzyl-3-cyclohexyl-5-iodo-4-phenyl-1H-
pyrazolo[3,4-b]pyridine 17 (50 mg, 0.1 mmol) in 1,4-
dioxane (0.5 mL, 0.2 M) under nitrogen were added
aniline (14 µL, 0.15 mmol, 1.5 equiv.), Cs CO (66 mg,
pyrazolo[3,4-b]pyridine 17 (50 mg, 0.1 mmol) in
2
3
DME/H O (1:0.5 mL, 0.07 M) under nitrogen were added
0.2 mmol, 2 equiv.), Pd (dba) (9.2 mg, 10 mol%) and
2
2 3
2
-[(E)-2-cyclopropylethenyl]-4,4,5,5-tetramethyl-1,3,2-
xantphos (5.9 mg, 10 mol%). The reaction mixture was
heated at 90 °C for 12 h. The mixture was diluted with
EtOAc (5 mL), washed 3 times with water (10 mL), the
dioxaborolane (23.6 mg, 0.12 mmol, 1.2 equiv.), Na CO3
2
(
12.9 mg, 0.12 mmol, 1.2 equiv.) and Pd(PPh ) (5.8 mg,
3 4
5
4
mol%). The reaction mixture was heated at 100 °C for
h, cooled down to room temperature and quenched with
organic phase was dried over MgSO , filtered and the
4
solvent removed under vacuum. The residue was purified
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Organic Process Research & Development
Page 12 of 15
1
by flash chromatography on silica gel (PE/AcOEt = 99:1).
-Benzyl-3-cyclohexyl-N,4-diphenyl-1H-pyrazolo[3,4-
b]pyridin-5-amine 23 was obtained as a dark oil (30 mg,
25b was obtained as a white solid (42 mg, 95 %). H
NMR (CDCl 400 MHz, ppm) : 8.90 (s, 1H), 7.52-7.47
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
3
,
(m, 3H), 7.40-7.37 (m, 2H), 7.34-7.27 (m, 4H), 7.25-7.22
(m, 1H), 5.68 (s, 2H), 2.93-2.87 (m, 4H), 2.12-2.06 (m,
1H), 1.61-1.38 (m, 7H), 1.18-1.06 (m, 1H), 0.84-0.77 (m,
2H). C NMR (CDCl 100 MHz, ppm) : 166.6, 150.2,
148.8, 145.6, 137.4, 137.2, 134.3, 129.0 (2C), 128.9,
128.4 (2C), 128.3 (2C), 127.8 (2C), 127.5, 126.1, 112.5,
1
6
7
7
8
1
0
1
1
1
3
2
5 %). H NMR (CDCl 400 MHz, ppm) : 8.60 (s, 1H),
3
,
.48-7.46 (m, 3H), 7.40-7.35 (m, 6H), 7.27-7.25 (m, 1H),
.19-7.15 (m, 2H), 6.83 (t, J = 7.3 Hz, 1H), 6.78 (d, J =
.1 Hz, 2H), 5.70 (s, 2H), 5.13 (s, 1H), 2.21-2.14 (m, 1H),
.63-1.61 (m, 4H), 1.54-1.41 (m, 3H), 1.17-1.09 (m, 1H),
1
3
3
,
1
3
-
.87-0.77 (m, 2H). C NMR (CDCl 100 MHz, ppm) :
50.6, 42.5, 37.2, 37.0, 32.7 (2C), 26.5 (2C), 25.9. IR (cm
) max: 2922, 2846, 1742, 1570, 1511, 1490, 1371, 1271,
3
,
1
49.4, 148.2, 146.2, 146.1, 137.7, 136.5, 134.3, 129.8,
29.4 (2C), 129.0 (2C), 128.7, 128.6 (2C), 128.5 (2C),
27.8 (2C), 127.4, 120.0, 115.5 (2C), 113.0, 50.5, 37.0,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1146, 1048, 758, 699, 535. Mp: 95 °C.
-1
2.8 (2C), 26.6 (2C), 25.9. IR (cm ) max: 3400, 3030,
927, 2851, 2245, 1731, 1600, 1495, 1270, 906, 727, 692.
N-(1-Benzyl-3-cyclohexyl-4-phenyl-1H-
pyrazolo[3,4-b]pyridin-5-yl)benzamide (25a). To a
solution of 1-benzyl-3-cyclohexyl-5-iodo-4-phenyl-1H-
pyrazolo[3,4-b]pyridine 17 (50 mg, 0.1 mmol) in 1,4-
dioxane (1 mL, 0.1 M) under nitrogen were added
ASSOCIATED CONTENT
Supporting Information. The Supporting Information is
available free of charge on the ACS Publications website at
DOI: 10.1021/....
DSC and SEDEX studies, PMI calculations, parameters for
cPMI simulation, step yield vs step PMI estimation, X-ray
crystallography data, copies of NMR spectra and references.
Crystallographic data for the structure reported in this
Article has been deposited at the Cambridge
Crystallographic Data Centre under deposition number
CCDC 1989511 (17, CIF).
benzamide (14.73 mg, 0.12 mmol, 1.2 equiv.), K PO (43
3
4
mg, 0.2 mmol, 2 equiv.), CuI (1 mg, 5 mol%) and 1,2-
cyclohexanediamine (1.2 µL, 10 mol%). The reaction
mixture was heated at 110 °C for 72 h. The mixture was
diluted with EtOAc (5 mL), filtered through a pad of
silica gel, the pad was then washed with EtOAc and the
solvent was removed under vacuum. The residue was
purified by flash chromatography on silica gel
(
PE/AcOEt
=
65:35). N-(1-Benzyl-3-cyclohexyl-4-
phenyl-1H-pyrazolo[3,4-b]pyridin-5-yl)benzamide 25a
was obtained as a white solid (35 mg, 72 %). H NMR
AUTHOR INFORMATION
1
Corresponding Authors
M. Parmentier: michael.parmentier@novartis.com
N. Blanchard: n.blanchard@unistra.fr
(CDCl 400 MHz, ppm) : 9.30 (s, 1H), 7.58-7.54 (m,
3
,
5H), 7.49-7.45 (m, 2H), 7.46-7.41 (m, 2H), 7.39-7.35 (m,
4H), 7.32-7.28 (m, 2H), 7.26-7.22 (m, 1H), 5.72 (s, 2H),
2.19-2.12 (m, 1H), 1.63-1.41 (m, 7H), 1.16-1.08 (m, 1H),
ORCID
1
3
0.86-0.76 (m, 2H). C NMR (CDCl 100 MHz, ppm) :
3
,
Nicolas Brach: 0000-0002-4416-6550
Vincent Bizet: 0000-0002-0870-1747
Fabrice Gallou: 0000-0001-8996-6079
Michael Parmentier: 0000-0002-1732-9641
Nicolas Blanchard: 0000-0002-3097-0548
165.9, 149.8, 148.7, 145.4, 137.5, 136.2, 134.2, 133.6,
131.9, 129.3, 129.0 (2C), 128.8 (2C), 128.7 (2C), 128.5
(2C), 127.7 (2C), 127.4, 126.9 (2C), 125.2, 112.2, 50.6,
-1
3
3
7
7.0, 32.7 (2C), 26.5 (2C), 25.9. IR (cm ) max: 3281,
059, 2936, 2852, 1650, 1574, 1494, 1483, 1274, 863,
58, 704. Mp: 91 °C.
Author Contributions
NBr and VLF optimized the synthetic chemistry part and
analyzed data. PH, ML, FG and MP conducted the safety
studies and analyzed data. CB solved the crystal structure.
VB and NB designed and supervised the study. The
manuscript was written through contributions of all authors.
All authors have given approval to the final version of the
manuscript.
1
-(1-Benzyl-3-cyclohexyl-4-phenyl-1H-
pyrazolo[3,4-b]pyridin-5-yl)azetidin-2-one (25b). To a
solution of 1-benzyl-3-cyclohexyl-5-iodo-4-phenyl-1H-
pyrazolo[3,4-b]pyridine 17 (50 mg, 0.1 mmol) in 1,4-
dioxane (1 mL, 0.1 M) under nitrogen were added
azetidin-2-one (8.6 mg, 0.12 mmol, 1.2 equiv.), K PO
43 mg, 0.2 mmol, 2 equiv.), CuI (1 mg, 5 mol%) and 1,2-
cyclohexanediamine (1.2 µL, 10 mol%). The reaction
mixture was heated at 110 °C for 24 h. The mixture was
diluted with EtOAc (5 mL), filtered through a pad of
silica gel, the pad was then washed with EtOAc and the
solvent was removed under vacuum. The residue was
purified by flash chromatography on silica gel
3
4
(
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The authors acknowledge funding from the Université de
Haute-Alsace, the Université de Strasbourg and the CNRS
(
PE/AcOEt
=
65:35). 1-(1-Benzyl-3-cyclohexyl-4-
(NBR, VLF, VB, NBL).
phenyl-1H-pyrazolo[3,4-b]pyridin-5-yl)azetidin-2-one
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Page 13 of 15
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Organic Process Research & Development
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-1
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