Synthesis of 4-substituted pyrazole-3,5-diamines: Via Suzuki-Miyaura coupling and iron-catalyzed reduction

Article abstract of DOI:10.1039/c7ob02373a

A general and efficient synthesis of 4-substituted-1H-pyrazole-3,5-diamines was developed to access derivatives with an aryl, heteroaryl, or styryl group, which are otherwise relatively difficult to prepare. The first step is based on the Suzuki-Miyaura cross-coupling reaction utilizing the XPhos Pd G2 precatalyst. The coupling reactions of 4-bromo-3,5-dinitro-1H-pyrazole with the electron-rich/deficient or sterically demanding boronic acids enabled the production of the corresponding dinitropyrazoles. The subsequent iron-catalyzed reduction of both nitro groups with hydrazine hydrate accomplished the synthesis. The additional demethylation of the 4-methoxystyryl derivative allowed the production of the carboanalog of CAN508 reported as a selective CDK9 inhibitor.

Full text of DOI:10.1039/c7ob02373a

View Article Online
View Journal
Organic &
Biomolecular
Chemistry
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: M. Tomanová, L.
Jedinak, J. Koša, L. Kvapil, P. Hradil and P. Canka, Org. Biomol. Chem., 2017, DOI: 10.1039/C7OB02373A.
This is an Accepted Manuscript, which has been through the
Volume 14 Number
1 7 January 2016 Pages 1–372
Royal Society of Chemistry peer review process and has been
accepted for publication.
Organic &
Biomolecular
Chemistry
www.rsc.org/obc
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
author guidelines.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the ethical guidelines, outlined
in our author and reviewer resource centre, still apply. In no
event shall the Royal Society of Chemistry be held responsible
for any errors or omissions in this Accepted Manuscript or any
consequences arising from the use of any information it contains.
ISSN 1477-0520
COMMUNICATION
Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
benzene
rsc.li/obc

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 1 of 13
View Article Online
DOI: 10.1039/C7OB02373A
Journal Name
ARTICLE
Synthesis of 4-Subsituted Pyrazole-3,5-diamines via Suzuki-
Miyaura Coupling and Iron-Catalyzed Reduction
Monika Tomanová,a Lukáš Jedinák,b Jan Košař,b Lubomír Kvapil,b Pavel Hradil,b and Petr Cankařb
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
The general and efficient synthesis of the 4-substituted-1H-pyrazole-3,5-diamines was develop to access the derivatives
with an aryl, heteroaryl, or styryl group, which are otherwise relatively difficult to prepare. The first step is based on the
Suzuki-Miyaura cross-coupling reaction utilizing the XPhos Pd G2 precatalyst. The coupling reactions of 4-bromo-3,5-
dinitro-1H-pyrazole with the electron-rich/deficient or sterically demanding boronic acids enabled to give the
corresponding dinitropyrazoles. Subsequent iron-catalyzed reduction of the both nitro groups with hydrazine hydrate
accomplished the synthesis. The additional demethylation of the 4-methoxystyryl derivative allowed to provide the
carboanalog of CAN508 reported as a selective CDK9 inhibitor.
www.rsc.org/
F
O
OH
Introduction
N
S
The compounds with a 1H-pyrazole-3,5-diamine moiety have
been often involved in the biological studies focused on the
antibacterial or antiviral activity.1, 2 This moiety has also been
used in the studies associated with the cell growth disorders to
find efficient inhibitors of Caspase-3,3 JAK2,4 and cyclin-
dependent kinase (CDK) proteins, which can be potentially
exploited as drugs for cancer therapy.5
HN
N
O
O
N
N
N
O
NH2
NH
H2N
NH2
NH2
N
N
N
NH
N
N
N
N
CAN508
CDK9 inhibitor
O
caspase-3 inhibitor
JAK2 inhibitor
Previously, we reported novel 4-arylazo-3,5-diamino-1H-pyrazoles
as potent and selective CDK inhibitors, where CAN508 was
identified as the first known selective CDK9 inhibitor (Figure 1).6, 7
The presence of the azo group in CAN508 can be potentially a
subject of metabolic reduction since there is a well-known example
described at the first sulfonamide drug, Prontosil.8
Cl
N
NH2
NH2
O
N
S
O
S
N
O
HN
HN
The metabolic lability of the azo group can be solved by its
O2N
substitution with a vinyl moiety resulting in carboanalog
1
O
N
O
(Scheme 1). A suitable precursor, styrylpyrazole was
4
,
N
H2N
reported by Shevelev using Knoevenagel condensation to form
the styryl moiety from an activated 4-methylpyrazole and p-
anisaldehyde. However, this method afforded unsatisfactory
yields and a limited reaction scope was demonstrated.9
Cl
antibacterial and antifungal activity anti-coxsackievirus B3 activity
Figure 1. Examples of biological active compounds with 1H-
pyrazole-3,5-diamine moiety.
An immediate precursor, pyrazole 5, and its derivatives have
not been described yet. Despite the cyclization of
mono(hetero)aryl malononitriles with hydrazine hydrate
seems at the first glance very simple to provide the 4-
substituted-1H-pyrazole-3,5-diamines, the yields can be
lowered by the competitive reactions revealed by Hartke10 and
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 2 of 13
View Article Online
DOI: 10.1039/C7OB02373A
ARTICLE
Journal Name
Sato.11 More complicated side reactions can occur with In the context of our research focused on the synthesis of CDK
styrylmalononitrile
8
or similar compounds.
inhibitors we have identified the 3,5-diamino-1H-pyrazole moiety as
an important pharmacophore binding to the CDK hinge region. A
cross-coupling reaction of styrylboronic acid directly with
bromopyrazole 9 can be potentially burden with side reactions
originating from a lower stability of styrylboronic acid,31 a significant
Another possible access to 1 can be utilization of the Suzuki-
Miyaura cross-coupling reaction (SMC) to join styryl 3 and pyrazole
2. Since the SMC reaction is compatible with many functional
groups and structural patterns, this strategy would offer to
synthesize not only pyrazole 1, but also a broad spectrum of
diversely 4-substituted-1H-pyrazole-3,5-diamines after reduction.
coordination activity of the both amino groups,
formation of pyrazole-bridged Pd complexes,17,
dehalogenation process.
a possible
32
and
a
OMe
OH
We hypothesized that introduction of the electron-withdrawing
nitro groups as a masked functionality for the both amino groups
resulting in pyrazole 2 should improve the reactivity, despite the
presence of the challenging factors representing the unprotected
pyrazole endocyclic NH group and two sterically demanding ortho-
positioned nitro groups. Good yields should be provided due to a
lower coordination activity of a substrate/product, a decreased
formation of the dimeric complexes, a significantly higher rate of
the oxidative addition step, and a diminished dehalogenation side
reaction, which we previously reported on the similar pyrazole
derivative independent on the Pd species.21, 29
OMe
N2H4
+
H2N
NH2
H2N
NH2
NC
CN
N
NH
N
NH
8
5
1
Br
Br
O2N
NO2
H2N
NH2
OMe
Herein, we report the development and the scope of a general and
efficient catalytic system for the SMC reaction of dinitropyrazole 2
with the aryl-, heteroaryl-, or styrylboronic acids to give
dinitropyrazoles 4 and their subsequent practical iron-catalyzed
reduction into the desired diaminopyrazoles 5.
N
NH
N NH
9
2
+
+
OMe
OMe
O2N
NO2
N
NH
Results and discussion
4
B(OH)2
Our study started with the synthesis of dinitropyrazole 2. 1H-
Pyrazole was firstly brominated with NBS according to the reported
procedure33 and then resulting 4-bromo-1H-pyrazole was nitrated
in a mixture of concentrated nitric and sulfuric acids. Subsequently,
dinitropyrazole 2 was treated under microwave irradiation at 100 °C
for 20 min with potassium phosphate, carbonate, and hydroxide to
evaluate a possible Pd-independent dehalogenation side reaction.
No dehalogenation occurred with phosphate, but dehalogenated
pyrazole 6 was detected as a trace (1%) with carbonate, and
hydroxide provided 14% of 6. A markedly lesser degree of
dehalogenation (hydroxide) or its complete suppression
(phosphate) in comparison with the previously studied
aminopyrazoles29 can be attributed to the electron-withdrawing
effect of the both nitro groups. We assume a formation of a more
stable pyrazole anion during annular tautomerism, which
diminishes a prototropic shift into a 4H-pyrazole tautomer and,
concurrently, a Pd-independent reductive dehalogenation.
B(OH)2
3
3
Scheme 1. Retrosynthetic analysis of carboanalog 1.
Despite the SMC reaction has been widely explored, there are still
encountered limits, predominantly, when the heterocyclic systems
are used as coupling partners.12-14 These synthetic limits have
obvious implications in drug development, since many biologically
active compounds are frequently comprised of the nitrogen-
containing heterocyclic moieties.15,
16
Generally, heterocyclic systems, especially N-azoles, are considered
as challenging substrates with regard to their increased
coordination susceptibility to a catalyst which usually leads to a
decreased rate or complete inhibition of
a cross-coupling
reaction.17-20 Further, the peripheral substitution of heterocyclic
moieties with the functional groups possessing a Lewis base
character can more complicate a cross-coupling reaction, especially
Reference
substitution in ortho position to a reaction center.21-Error!
source not found.24
The optimization process of a catalytic system for pyrazole 2 was
initiated at 100 °C with palladium acetate, potassium phosphate,
and dioxane (Table 1, entries 1-6). While pyrazole 4a was obtained
in a very good yield with the XPhos ligand (82%), the SPhos ligand
allowed only a fair yield (50%) as a consequence of a higher
homocoupling side reaction rate resulting in biphenyl 7 and a lower
conversion of bromopyrazole 2 (entries 3 and 4).
The APhos38 ligand (entry 5), which was previously also utilized for
the pyrazolyl bromides, afforded a good yield (76%). Comparable
results were observed with the BINAP39 ligand (entry 6). A classical
Coordination activity of reactants and/or products
can be overcome by utilization of protecting groups,25-27 higher
amount of
a catalyst, higher temperature, and/or prolonged
reaction time.17, Consequently, these factors have influence on
the stability of coupling partners and we can observe common side
reactions such as homocoupling, dehalogenation, and/or
protodeboronation.29, 30 To avoid these obstacles, the first choice is
usually optimization of a (pre)catalyst, use of boronic acid esters,
and/or higher amounts of reactants.
28
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 3 of 13
View Article Online
DOI: 10.1039/C7OB02373A
Journal Name
ARTICLE
ligand, triphenylphospine, also provided good yields and, moreover, dehalogenated pyrazole 6 was not detected (entries 7 and 8).
Table 1. Optimization of reaction conditions.
entry
1
[Pd]
ligand
PCy3
solvent
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
butanol
DMF
base
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K2CO3
KOAc
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
T (°C)
100°C
100°C
100°C
100°C
100°C
100°C
100°C
100°C
100°C
100°C
100°C
100°C
100°C
100°C
100°C
90°C
4ab
25
34
82
50
76
74
78
78
7
2b
39
27
3
6 b
4
7b
24
30
11
26
14
8
Pd(OAc)2
2
Pd(OAc)2
PAd2Bu
XPhos
SPhos
APhos
BINAP
Ph3P
5
3
Pd(OAc)2
2
4
Pd(OAc)2
17
4
7
5
Pd(OAc)2
4
6
Pd(OAc)2
6
2
7
PdCl2(Ph3P)2
Pd(Ph3P)4
2
0
16
10
22
9
8
Ph3P
4
0
9
PEPPSI
PEPPSI
XPhos
XPhos
XPhos
XPhos
XPhos
XPhos
XPhos
XPhos
XPhos
XPhos
XPhos
63
>1
0
1
10
11
12
13
14
15
16
17
18
19
20
XPhos Pd G2
XPhos Pd G2
XPhos Pd G2
XPhos Pd G2
XPhos Pd G2
XPhos Pd G2
XPhos Pd G2
XPhos Pd G2
XPhos Pd G2
XPhos Pd G3
XPhos Pd G4
90c
79
86
42
80
3
0
11
3
10
7
>1
27
2
toluene
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
2
24
13
2
>1
>1
1
40
1
88c
82
74
71
55
7
80°C
5
0
8
60°C
6
>1
0
10
16
22
100°C
100°C
11
14
0
aReaction condition: 2 (0.25 mmol), 3a (0.262 mmol), organic solvent (1.0 mL), H2O (0.25 mL), base (1.0 mmol), Pd-source (2.5 mol%),
b
ligand (5.0 mol%), 20 h. HPLC yield (%) determined from a crude reaction mixture with an inner standard (see Supporting Information for
more details). cReaction was carried out at a 1 mmol scale.
Carbene-based catalyst PEPPSI-IPr40 gave unsatisfactory yield (entry Subsequent experiments confirmed the best reaction conditions
9). After the XPhos ligand was proved the best (entry 3), the described at entry 10. Substitution of dioxane with DMF or butanol
evaluation of the isolation process at a 1 mmol scale pointed at provided a lower yield, which was further decreased when toluene
difficulties associated with separation of starting bromopyrazole 2 was used (entries 11-13). Utilization of potassium carbonate instead
from product 4a. It was necessary to provide a complete conversion of potassium phosphate did not improve the yield and potassium
of 2 into 4a. Gratifyingly, this issue was solved by the introduction acetate was almost ineffective (entries 14-15). Gradual lowering of
of the precatalyst XPhos Pd G2, which allowed to give 4a in the the reaction temperature led to decreased yields (entries 16-18).
excellent yield (90%) due to a nearly complete conversion and The third and fourth generation of the catalyst did not provide
eliminated dehalogenation side reaction (Table 1, entry 10).
better yields, since the reaction has to be performed at 100 °C
(entries 19-20).
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 4 of 13
View Article Online
DOI: 10.1039/C7OB02373A
ARTICLE
Journal Name
With optimized conditions in hands (Table 1, entry 10), the scope of aryl, styryl, and heteroaryl boronic acids or MIDA esters was
the SMC reaction of bis-ortho-substituted pyrazole 2 with various examined (Table 2).
Table 2. Scope of the Suzuki-Miyaura reaction using pyrazole 2.
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 5 of 13
View Article Online
DOI: 10.1039/C7OB02373A
Journal Name
ARTICLE
time
20 h
product
entry
time
20 h
product
entry
boronic acid
boronic acid
OMe
NO2
7
1
OMe
O2N
O2N
NO2
B(OH)2
B(OH)2
N
NH
N
NH
3g
3a
4a (64%)
4g (60%)
2
20 h
8
48 h
MeO
O2N
OMe
NO2
MeO
OMe
O2N
NO2
B(OH)2
B(OH)2
N
NH
N
NH
4b (64%)a
3h
3b
4h (84%)b
OMe
OMe
48 h
9
3
20 h
B(OH)2
O2N
NO2
N
NH
B(OH)2
O2N
NO2
3c
4c (72%)b
3i
N
NH
4i (65%)
NO2
NO2
10
48 h
4
48 h
O2N
NO2
B(OH)2
B(OH)2
O2N
NO2
N
NH
N
NH
3d
4d (no reaction)
3j
4j (75%)b
OMe
CF3
CF3
OMe
5
11
20 h
48 h
O2N
NO2
O2N
NO2
BY2
B(OH)2
N
NH
N
NH
3e
A: Y = OH
3k
4k A: (70%)b
B: (93%)b
4e (73%)
B: Y = pin
OH
OH
12
20 h
72 h
6
O2N
NO2
B(OH)2
O2N
NO2
NH
B(OH)2
N
NH
N
4f (16%)c
3f
3l
4l (62%)
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 6 of 13
View Article Online
DOI: 10.1039/C7OB02373A
ARTICLE
Journal Name
Table 2. Continued.
entry
boronic acid
product
OMe
entry
product
time
20 h
time
48 h
boronic acid
OMe
S
B(OH)2
18
13
S
NO2
O2N
O2N
NO2
NH
N
3r
B(OH)2
N
NH
4r (62%)b
3m
4m (66%)
OMe
F
F
MeO
19
14
48 h
B(OH)2
20 h
S
S
NO2
O2N
3s
O2N
NO2
B(OH)2
N
NH
N
NH
4s (70%)e
3n
4n (80%)
CF3
CF3
N
N
BY2
20
15
20 h
O2N
NO2
3t A: Y = OH
B: Y = MIDA
48h
48h
N
NH
O2N
NO2
B(OH)2
4t A: (trace)
B: (trace)
N
NH
3o
4o (45%)
N
S
S
21
BY2
16
20 h
O2N
NO2
NO2
O2N
N
BY2
N
NH
N
NH
3p
A: Y = OH
B: Y = pin
3u
4u A = (trace)
B = (trace)
A: Y = MIDA
72h
48h
4p A: (65%)
B: (65%)
B: Y = neopentylglycol
ester
S
S
48 h
17
BMIDA
NO2
O2N
N
NH
3q
4q (30%)d
aAfter 5 h addition of XPhos Pd G2 (2 mol%). bAfter 20 h addition of 3 (1.05 equiv.) and XPhos Pd (2 mol%). cHigher excess of 3f (1.5 equiv.)
was added, then after 20 h and 48 h additional amounts of 3f (1.5 equiv.) and XPhos Pd G2 (2 mol%) were added; NMR yield. dAfter 20 h
addition of 3q (1.5 equiv.) and XPhos Pd G2 (2 mol%). eHigher excess of 3s (1.5 equiv.) was added, then after 20 h additional amounts of 3s
(1.5 equiv.) and XPhos Pd G2 (2 mol%) were added.
6 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 7 of 13
View Article Online
DOI: 10.1039/C7OB02373A
Journal Name
ARTICLE
Pyrazoles 4a and 4b were isolated in fair yields (entries 1 and 2);
however, an additional amount of the catalyst was necessary for
4b. The reaction with o-tolylboronic acid afforded a slightly higher
yield, but with the extra support of the catalyst and boronic acid 3c
(entry 3).
unprotected pyrazole was used (entries 7 and 8). This very good
yield can be attributed to a lower steric hindrance of the methoxy
groups in comparison to the methyl groups when boronic acid 3d
was used.44 Further, the prolonged reaction time and an additional
amount of boronic acid 3h and XPhos Pd G2 was necessary to
improve the yield. The larger methoxynaphthalene moiety did not
affect negatively the yield of pyrazole 4i (entry 9).
The considerably more sterically demanding bis-ortho-substitution
led to the complete termination of the reaction (entry 4).
The electron-donating methoxy group at para position of boronic
acid 3e allowed the better yield in comparison to pyrazole 4a (entry
5). The similar reaction was also attempted with boronic acid 3f
bearing unprotected OH group, but the yield was significantly lower
(entry 6). A possible explanation of the unsatisfactory yield brought
the LCMS analysis of a crude product. Two compounds difficult to
separate with the identical molar mass were revealed. The NMR
spectrum of this mixture confirmed the presence of the two
compounds with the mono and para substituted benzene rings. It
The lower reactivity of benzeneboronic acids 3j and 3k with the
electron-withdrawing groups was overcome with an extra reaction
time and amount of the corresponding boronic acid together with
the catalyst to provide pyrazoles 4j and 4k in good to excellent
yields (entries 10 and 11). In contrast, the styryl boronic acids 3l-3o
were not added in the excess and the coupling was finished within
20 h to yield the pyrazoles in a range 45-80% (entries 12-15).
In the end, the study was focused on the several heteroaryl boronic
acids based on the thiophene and pyridine ring (entries 16-22).
Thienyl-3-ylboronic acid and the corresponding pinacol ester 3p
gave pyrazole 4p in a good yield, but isomer 3q afforded only 30%
of pyrazole 4q although the boronic acid was used as a MIDA ester
in the excess. Modification of thiophene with the ortho-fused
benzene ring brought a better reactivity of boronic acids 3r and 3s
giving bisheteroaryls 4r and 4s at the comparable yields with
pyrazole 4p. However, an extra addition of the corresponding
boronic acids and the catalyst was necessary. Unfortunately, all
attempts to react pyridineboronic acids or their MIDA or
neopentylglycol esters with pyrazole 2 failed (entries 20-22).
was hypothesized that boronic acid 3f underwent
a side
protodeboronation reaction resulting in phenol and the subsequent
Buchwald-Hartwig type coupling provided the isomeric phenoxy-
substituted pyrazole. Our hypothesis was supported by the stability
check of boronic acid 3f under the same reaction conditions
without the presence of the XPhos Pd G2 precatalyst and pyrazole
2, which confirmed the complete protodeboronation into phenol
within 2 hours. Further, the independent reaction of pyrazole 2 only
with phenol provided the identical compound observed in the
mixture of the two isomers after the coupling of pyrazole 2 with
boronic acid 3f (see Supporting Information).
Next, we sought for an efficient reduction method to convert the
both nitro groups into the amine functionality. For this purpose,
pyrazole 4a was chosen as a model compound. Initially, from a
broad spectrum of methods, we attempted to utilize the catalytic
hydrogenation on 10% Pd/C under various conditions. Desired
diaminopyrazole 5a was always detected as a major compound in a
reaction mixture, but also difficult to separate impurities were
formed.
Cheon proposed a protodeboronation mechanism based on a
formation of an ate complex, where the C-B bond was cleaved by
metathesis.41 Considering our previous mechanism proposal for the
Pd-independent dehalogenation reaction of the bromopyrazoles,
we can offer the annular tautomerism again as a key phenomenon
to explain the origin of the side protodeboronation reaction
(Scheme 2). The prototropic shift at the ipso-position is promoted
by the base. Subsequent irreversible reductive elimination of boric
acid is driven by rearomatization leading to the phenolate anion.
Cheon`s assumed formation of the ate complex can have the
synergy effect to form the phenol 4H-tautomer. In contrast, 4-
methoxyphenylboronic acid 3e was stable under the same
conditions, only a trace of anisole was detected after 2 hours.
However, the protodeboronation of 3e was significant after the
prolonged reaction time (24%, 20 h), which can be attributed to
other mechanisms.41
Consequently, we focused on the iron-catalyzed reduction with
hydrazine as a hydrogen source reported by Shelev.9 To reduce the
both nitro groups and to avoid a potentially problematic isolation
process after reduction, we modified the procedure and prepared
the catalyst by deposition of 5% Fe on activated charcoal. This
practical form of the catalyst allowed to give diaminopyrazoles 5a-
5s from the fair to excellent yields (Table 3). Only derivatives 5j, 5l,
5n, and 5o required additional chromatographic purification. No
trends between the structure and the yield were identified.
Since the hydroxyl group in CAN508 is essential for the CDK
inhibition,6 it was important to develop a demethylation method for
dinitropyrazole 3m or diaminopyrazole 6m to access desired
carboanalog 1. Preliminary demethylation attempts with the
methoxy-substituted pyrazoles 4e and 4i showed the problematic
use of boron tribromide and concentrated hydrobromic acid. The
LCMS analyses revealed the complicated reaction mixtures
containing brominated compounds. Demethylation occurred only
with pyrazole 4e if concentrated hydrobromic acid was used. The
attempts with diaminopyrazole 5i brought similar results together
with the expected worse conversion of the starting material.
Scheme 2. Proposed protodeboronation mechanism of boronic acid
3f.
Then, the attention was paid to the ortho-methoxy-substituted
boronic acids 3g and 3h. Pyrazole 4g was isolated in the good yield
and, surprisingly, the reaction conditions also allowed to give tetra-
ortho-substituted pyrazole 4h in the yield of 84%, even the
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 7
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 8 of 13
View Article Online
DOI: 10.1039/C7OB02373A
ARTICLE
Journal Name
Table 3. Iron-catalyzed reduction of nitropyrazoles 4 into aminopyrazoles 5.
rate of pyrazole 5m with sodium sulfide was fast. Nevertheless, it
was necessary to terminate the reaction already after 1 hour,
although the conversion of 5m was not completed. The reason was
a formation of a difficult to separate side product.
Afterwards, the demethylation tactic was focused on sulfur
reagents. The reactions with benzenethiol and 2-mercaptoethanol
gave the desired demethylated product of pyrazole 5i in the
unsatisfactory yields. The better result was observed with sodium
sulfide. However, the demethylation of 5i with sodium
ethanethiolate indicated more promising results. These conditions
were utilized to provide pyrazole 1 (Scheme 3). The demethylation
8 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 9 of 13
View Article Online
DOI: 10.1039/C7OB02373A
Journal Name
ARTICLE
at 100 °C for 20 h. If pyrazole 2 was still observed, an additional
amount of boronic acid and precatalyst XPhos Pd G2 was added
(see Table 2). After pyrazole 2 was consumed, vial was pulled out
from the oil bath and acidified by hydrochloric acid to reach pH 1.
Then the solvent was evaporated under reduced pressure to
dryness.
Isolation Method A: Water (40 mL) was added to the residue,
resulting precipitate was filtered-off, and thoroughly washed with
water. Wet precipitate of 4a, 4b, 4e, 4i, 4l and 4o was dissolved in
MeOH (5-10 mL) or EtOAc (4j, 4r, 4n, 4m and 4s), charcoal was
added, and the suspension was stirred for 15 minutes at room
temperature. Then, the suspension was filtered through Celite, the
filter cake was washed with MeOH (EtOAc), and the filtrate was
concentrated under reduced pressure. A crude product was applied
on a silica gel column and eluted with hexane:EtOAc:MeOH (70:30:0
to 70:30:10) to give the desired dinitropyrazole 4 as a solid or oil.
Isolation Method B: Water (30 mL) was added to the residue and a
resulting mixture was extracted with EtOAc (3 × 20 mL). Collected
organic layers were washed with water (20 mL) and dried over
MgSO4. After magnesium sulfate was filtered-off, charcoal was
added, and the suspension was stirred for 15 minutes. After that,
the suspension was filtered through Celite, the filter cake was
washed with EtOAc, and the filtrate was concentrated under
reduced pressure. A crude product was applied on a silica gel
column and eluted with hexane:EtOAc:MeOH (70:30:0 to 70:30:10)
to give the desired dinitropyrazole 4 as a solid or oil.
Scheme 3. Demethylation of 5m.
Conclusions
In summary, we developed the general and efficient synthetic
method, which enabled to provide the broad scope of 4-
substituted-1H-pyrazole-3,5-diamines. The first step is based on the
SMC reaction of pyrazole 2 with the boronic acids to provide aryl,
heteroaryl, or styryl dinitropyrazoles 4. The good results of the
coupling reaction were provided primarily by the two factors: (a)
The introduction of the electron-deficient nitro groups as a masked
amino functionality, which improved the rate of the oxidative
addition step and eliminated the Pd-independent side
dehalogenation reaction, and (b) The utilization of the XPhos Pd G2
precatalyst, which enabled the coupling with the electron-deficient,
-rich, or sterically demanding boronic acids. The subsequent general
and practical iron-catalyzed reduction of the nitro groups with
hydrazine hydrate accomplished the second step resulting in
diaminopyrazoles 5. Finally, desired carboanalog 1 was achieved by
the demethylation with sodium ethanethiolate.
3,5-Dinitro-4-(p-tolyl)-1H-pyrazole (4a). Isolation Method A.
yellow solid (158 mg, 64% yield); mp > 340 °C. 1H NMR (400 MHz,
DMSO-d6) : 7.35 (d, J=8.3 Hz, 2 H), 7.25 (d, J=8.3 Hz, 2 H), 2.37 (s, 3
H). 13C NMR (101 MHz, DMSO-d6)
A
δ
δ
: 148.2, 138.3, 129.8, 128.6,
124.0, 114.5, 21.0. HRMS (ESI-TOF): calcd for C10H7N4O4 [M - H]-
247.0467, found 247.0463.
Experimental
4-Bromo-3,5-dinitro-1H-pyrazole (2)
3,5-Dinitro-4-phenyl-1H-pyrazole (4b). Isolation Method A. A pale
1
Pyrazole (9.15 g, 0.134 mol) was dissolved in water (110 mL) and N-
bromosuccinimide (23.9 g, 0.134 mol) was slowly added under
continuous stirring and cooling to keep the temperature below 25
°C. The reaction mixture was then stirred for 30 min at room
temperature followed by stirring and cooling for 30 min. White
crystals were filtered-off and recrystallized from water.33
Subsequently, 4-bromo-1H-pyrazole (10 g, 0.07 mol) was dissolved
in 96% sulfuric acid (102 mL) and 98,5-99% fuming nitric acid (9 mL)
was added dropwise at 100°C and stirred for 5 h. Then, the reaction
mixture was poured into the ice, extracted with EtOAc, and
collected organic layers were dried with MgSO4. Ethyl acetate was
evaporated under reduced pressure to get a crude product, which
was recrystallized from water as a pale yellow solid (10.5 g, 65%);
yellow solid (153 mg, 65% yield); mp 170-176°C (DCM-hexanes). H
NMR (400 MHz, DMSO-d6)
δ: 7.40 - 7.31 (m, 3 H), 7.31 - 7.36 (m, 2
H). 13C NMR (101 MHz, DMSO-d6)
δ: 152.7, 130.7, 129.8, 127.7,
127.4, 113.9. HRMS (ESI-TOF): calcd for C9H5N4O4 [M - H]- 233.0311,
found 233.0305.
3,5-Dinitro-4-(o-tolyl)-1H-pyrazole (4c). Isolation Method B.
yellow solid (179 mg, 72% yield); mp 162-170 °C. 1H NMR (400 MHz,
DMSO-d6) : 7.26 - 7.19 (m, 2 H), 7.14 (td, J=7.3, 2.7 Hz, 1 H), 7.04
(d, J=7.3 Hz, 1 H), 1.97 (s, 3 H). 13C NMR (101 MHz, DMSO-d6)
A
δ
δ:
154.2, 136.3, 131.9, 129.3, 129.2, 127.2, 125.2, 113.1, 19.6. HRMS
(ESI-TOF): calcd for C10H7N4O4 [M - H]- 247.0467 found 247.0463.
4-(4-Methoxyphenyl)-3,5-dinitro-1H-pyrazole
Method A. A yellow solid (193 mg, 73% yield); mp 231-234 °C. 1H
NMR (400 MHz, DMSO-d6) : 7.28 (d, J=8.8 Hz, 2 H), 6.95 (d, J=8.3
Hz, 2 H), 3.80 (s, 3 H). 13C NMR (101 MHz, DMSO-d6)
: 158.9, 151.7,
(4e).
Isolation
mp 167-169°C. 1H NMR (400 MHz, DMSO-d6)
δ: 14.38 (br. s., 1H).
δ
13C NMR (101 MHz, DMSO-d6)
δ: 150.4, 88.0. HRMS (ESI-TOF): calcd
δ
for C3BrN4O4 [M-H]- 234.9103, found 234.9089.
131.3, 121.4, 113.9, 113.2, 55.1 HRMS (ESI-TOF): calcd for
C10H7N4O5 [M - H]- 263.0416 found 263.0415.
General procedure for dinitropyrazoles 4: See Table 2. A mixture of
pyrazole 2 (1.0 mmol), boronic acid 3 (1.05 mmol), and K3PO4 (848
mg, 4.0 mmol) was placed into a vial and suspended in dioxane (4
mL) and water (1 mL). The reaction mixture was degassed with
argon for 15 min. Then, precatalyst XPhos Pd G2 (16 mg, 0.02
mmol) was added and the vial was quickly closed and inserted into
an oil bath preheated to 100 °C. The mixture was vigorously stirred
4-(2-Methoxyphenyl)-3,5-dinitro-1H-pyrazole
Method B. A yellow solid (159 mg, 60% yield); mp 134-136 °C. 1H
NMR (400 MHz, DMSO-d6) : 7.35 (t, J=7.8 Hz, 1 H), 7.26 (d, J=7.3
(4g).
Isolation
δ
Hz, 1 H), 7.04 (d, J=8.3 Hz, 1 H), 6.97 (t, J=7.3 Hz, 1 H), 3.64 (s, 3 H).
13C NMR (101 MHz, DMSO-d6)
δ: 156.6, 152.0, 131.0, 129.5, 120.0,
118.6, 110.9, 110.0, 55.3.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 9
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 10 of 13
View Article Online
DOI: 10.1039/C7OB02373A
ARTICLE
Journal Name
4-(2,6-Dimethoxyphenyl)-3,5-dinitro-1H-pyrazole (4h). Isolation 3,5-Dinitro-4-(thiophen-3-yl)-1H-pyrazole (4p). Isolation Method B.
Method B. A yellow solid (242 mg, 84% yield); mp 178-84 °C. 1H A brown solid (155 mg, 65% yield – from boronic acid and pinacol
NMR (400 MHz, DMSO-d6)
Hz, 2 H), 3.64 (s, 6 H). 13C NMR (101 MHz, DMSO-d6)
130.3, 106.2, 106.1, 104.1, 55.7. HRMS (ESI-TOF): calcd for Hz, 1 H). 13C NMR (101 MHz, DMSO-d6)
C11H9N4O6 [M - H]- 293.0522, found 293.0521. 126.0, 124.6, 109.0. HRMS (ESI-TOF): calcd for C7H3N4O4S [M - H]-
δ
: 7.35 (t, J=8.6 Hz, 1 H), 6.72 (d, J=8.3 ester); mp 200-205 °C. 1H NMR (400 MHz, DMSO-d6)
δ
: 7.48 (dd,
: 157.4, 151.0, J=4.8, 3.0 Hz, 1 H), 7.44 (dd, J=2.7, 1.0 Hz, 1 H), 7.05 (dd, J=4.8, 1.1
: 151.7, 129.5, 128.1,
δ
δ
4-(6-Methoxynaphtalen-2-yl)-3,5-dinitro-1H-pyrazole (4i). Isolation 238.9875, found 238.9870.
Method A. A yellow solid (204 mg, 65% yield); mp 332-334 °C. 1H 3,5-Dinitro-4-(thiophen-2-yl)-1H-pyrazole (4q). Isolation Method B,
NMR (400 MHz, DMSO-d6)
Hz, 1 H), 7.72 (d, J=1.0 Hz, 1 H), 7.38 - 7.30 (m, 2 H), 7.16 (dd, J=8.7, yield); mp 123-124 °C. 1H NMR (400 MHz, DMSO-d6)
2.5 Hz, 1 H), 3.89 (s, 3 H). 13C NMR (101 MHz, DMSO-d6)
: 157.4, H), 7.77 (dd, J=5.0, 1.2 Hz, 1 H), 7.28 (dd, J=3.6, 1.2 Hz, 1 H), 7.16
154.1, 133.4, 129.4, 128.7, 128.2, 128.1, 126.8, 125.8, 118.5, 114.0, (dd, J=4.7, 3.6 Hz, 1 H). 13C NMR (101 MHz, DMSO-d6)
: 149.2,
105.8, 55.3. HRMS (ESI-TOF): calcd for C14H9N4O5 [M-H]- 313.0573, 130.8, 129.0, 127.0, 125.7, 107.4. HRMS (ESI-TOF): calcd for
found 313.0571.
C7H3N4O4S [M - H]- 254.9824, found 238.9871.
δ: 7.79 (d, J=8.7 Hz, 1 H), 7.78 (d, J=8.7 then crystallization from water. A brown-green solid (36 mg, 30%
δ: 9.27 (br. s., 1
δ
δ
3,5-Dinitro-4-(4-nitropenyl)-1H-pyrazole (4j). Isolation Method A. 4-(Benzo[b]thiophen-2-yl)-3,5-dinitro-1H-pyrazole (4r). Isolation
A yellow solid (209 mg, 75% yield); mp 150-152 °C. 1H NMR (400 Method B. A brown solid (179 mg, 62% yield); mp 310-314 °C. 1H
MHz, DMSO-d6)
NMR (101 MHz, DMSO-d6)
111.8. HRMS (ESI-TOF): calcd for C9H4N5O6 [M - H]- 278.0162 found 140.1, 139.3, 131.1, 125.2, 124.4, 124.3, 123.7, 122.2, 105.8. HRMS
278.0159.
(ESI-TOF): calcd for C11H5N4O4S [M - H]- 289.0032, found 289.0030.
δ
: 8.22 (d, J=8.7 Hz, 2 H), 7.61 (d, J=8.7 Hz, 1 H). 13
C
NMR (400 MHz, DMSO-d6) δ: 8.00 - 7.93 (m, 1 H), 7.88 - 7.80 (m, 1
δ
: 153.2, 146.6, 139.0, 131.3, 122.8, H), 7.43 - 7.32 (m, 3 H). 13C NMR (101 MHz, DMSO-d6)
δ: 153.3,
3,5-Dinitro-4-(4-trifluoromethyl)phenyl)-1H-pyrazole (4k). Isolation 4-(5-Methoxybenzo[b]thiophen-2-yl)-3,5-dinitro-1H-pyrazole (4s).
1
Method A. A pale yellow solid (211 mg, 70% yield; 93% yield – from Isolation Method A. A dark brown oil (112 mg, 70% yield). H NMR
1
pinacol ester); mp 188-89 °C. H NMR (400 MHz, DMSO-d6)
δ
: 7.74 (400 MHz, DMSO-d6) δ: 7.80 (d, J=8.8 Hz, 1 H), 7.37 (d, J=2.6 Hz, 1
(d, J=8.2 Hz, 2 H), 7.57 (d, J=8.2 Hz, 2 H). 13C NMR (101 MHz, DMSO- H), 7.25 (s, 1 H), 6.99 (dd, J=8.8, 2.6 Hz, 1 H), 3.82 (s, 3 H). 13C NMR
d6) : 152.5, 135.4, 130.7, 127.9 (q, J=32.6 Hz), 124.5 (q, J=3.8 Hz), (101 MHz, DMSO-d6) : 157.0, 154.5, 140.6, 133.5, 132.3, 124.5,
124.4 (q, J=272.2 Hz), 112.5. HRMS (ESI-TOF): calcd for C10H4F3N4O4 122.8, 114.3, 105.8, 105.4, 55.3. HRMS (ESI-TOF): calcd for
[M - H]- 301.0185 found 301.0181. 12H7N4O5S [M - H]- 319.0137, found 319.0134.
δ
δ
C
(E)-3,5-Dinitro-4-styryl-1H-pyrazole (4l). Isolation Method B. An General procedure for diaminopyrazoles 5: Pyrazole 4 (1 equiv.)
orange solid (162 mg, 62% yield); mp 336-338 °C. 1H NMR (400 MHz, was dissolved in ethanol, methanol, or dioxane (see Table 3). A
DMSO-d6)
7.28 (m, 2 H). 13C NMR (101 MHz, DMSO-d6)
128.9, 128.5, 126.6, 114.9, 111.5. HRMS (ESI-TOF): calcd for suspension was heated to 55°C in on oil bath. The reduction was
δ: 7.56 (d, J=7.3 Hz, 2 H), 7.41 (t, J=7.3 Hz, 2 H), 7.38 - catalyst (5% Fe on activated charcoal, see the following procedure)
δ: 151.2, 136.6, 136.4, and hydrazine hydrate (12 equiv.) was added and the resulting
C11H7N4O4 [M - H]- 259.0467, found 259.0465.
monitored by TLC (CHCl3:MeOH 10:1). After dinitropyrazole 4 was
(E)-4-(4-Methoxystyryl)-3,5-dinitro-1H-pyrazole (4m).9 Isolation completely reduced, the catalyst was filtered-off through Celite,
Method A. A red solid (191 mg, 66% yield); mp 318-322 °C. 1H NMR resulting filtrate was filtered through a microfilter, and solvent was
(400 MHz, DMSO-d6)
H), 7.24 (d, J=16.6 Hz, 1 H), 6.97 (d, J=8.8 Hz, 2 H), 3.78 (s, 3 H). 13
NMR (101 MHz, DMSO-d6) : 159.5, 152.4, 135.2, 129.6, 128.0, (CHCl3:MeOH from 30:1 to 5:1).
δ: 7.49 (d, J=8.8 Hz, 2 H), 7.32 (d, J=16.6 Hz, 1 evaporated under reduced pressure to give a crude product. If
C
necessary, pyrazoles were purified by flash chromatography
δ
114.3, 113.4, 111.7, 55.2. HRMS (ESI-TOF): calcd for C12H9N4O5 Preparation of the catalyst (5% Fe on activated charcoal)
[M - H]- 289.0573, found 289.0572.
Iron(II) sulfate heptahydrate (1.24 g, 4.4 mmol) was dissolved in
(E)-4-(4-Flourostyryl)-3,5-dinitro-1H-pyrazole
(4n).
Isolation water (20 mL). The solution was acidified with one drop of conc.
Method A. A brown solid (228 mg, 82% yield); mp 332-334 °C. 1H sulfuric acid, diluted with another two portions of water (2 × 20
NMR (400 MHz, DMSO-d6)
J=16.6 Hz, 1 H), 7.28 (d, J=16.6 Hz, 1 H), 7.23 (t, J=8.8 Hz, 2 H). (0.5 mL, 10.3 mmol) was added to the suspension, which was
13C NMR (101 MHz, DMSO-d6)
: 162.1 (d, J=246.3 Hz), 151.7, 134.6, continuously stirred at room temperature for 1 minute. Then, the
δ: 7.61 (dd, J=8.8, 5.7 Hz, 2 H), 7.35 (d, mL), and activated charcoal (4.75 g) was added. Hydrazine hydrate
δ
133.4 (d, J=2.9 Hz), 128.6 (d, J=8.6 Hz), 115.8 (d, J=21.1 Hz), 115.8, temperature was increased to 100 °C and the suspension was
111.2. HRMS (ESI-TOF): calcd for C11H6FN4O4 [M - H]- 277.0373, boiled for 5 minute. After that, the suspension was allowed to cool
found 277.0371.
to room temperature. The catalyst was filtered-off, washed with
(E)-3,5-Dinitro-4-(4-(trifluoromethyl)styryl)-1H-pyrazole
(4o). water, and dried on air.
Isolation Method A. A yellow solid (148 mg, 45% yield); mp 318-322 4-(p-Tolyl)-1H-pyrazole-3,5-diamine (5a).43 Title product 5a was
1
°C. H NMR (400 MHz, DMSO-d6)
δ
: 7.75 (d, J=8.8 Hz, 2 H), 7.73 (d, prepared under General procedure, pyrazole 4a (112 mg, 0.45
J=8.8 Hz, 2 H), 7.57 (d, J=16.6 Hz, 1 H), 7.31 (d, J=16.6 Hz, 1 H). 13C mmol), EtOH (4.5 mL), catalyst 5% Fe on activated charcoal (503
.
NMR (101 MHz, DMSO-d6)
δ: 153.5, 141.3, 132.7, 127.8 (q, J=31.6 mg, 0.45 mmol), N2H4 H2O (264 µl, 5.4 mmol), 2 h. Beige solid
1
Hz), 127.0, 125.71 (q, J=3.8 Hz), 124.3 (q, J=272.2 Hz), 119.6, 110.1. (67 mg, 79% yield); mp 182-188°C. H NMR (400 MHz, DMSO-d6)
HRMS (ESI-TOF): calcd for C12H6F3N4O4 [M - H]- 327.0341, found 10.22 (br. s., 1H), 7.25 (d, J = 7.8 Hz, 2H), 7.13 (d, J = 7.8 Hz, 2H),
δ:
327.0339.
4.48 (br. s, 4H), 2.28 (s, 3H). 13C NMR (101 MHz, DMSO-d6)
δ: 148.3,
10 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 11 of 13
View Article Online
DOI: 10.1039/C7OB02373A
Journal Name
ARTICLE
132.7, 131.5, 129.1, 126.7, 90.1, 20.7. HRMS (ESI-TOF): calcd for 1 H), 7.58 (dd, J=8.6, 1.3 Hz, 1 H), 7.25 (d, J=2.1 Hz, 1 H), 7.11 (dd,
C10H13N4 [M + H]+ 189.1140, found 189.1135. J=8.8, 2.6 Hz, 1 H), 4.84 (br. s, 2 H), 4.32 (br. s, 2 H), 3.86 (s, 3 H). 13C
4-Phenyl-1H-pyrazole-3,5-diamine (5b).43 Title product 5b was NMR (101 MHz, DMSO-d6)
: 156.4, 152.1, 131.5, 129.8, 129.1,
δ
prepared under General procedure, pyrazole 4b (70 mg, 0.32 128.9, 126.7, 126.6, 124.0, 118.2, 105.7, 90.4, 55.1. HRMS (ESI-
mmol), EtOH (3.0 mL), catalyst 5% Fe on activated charcoal (335 TOF): calcd for C14H15N4O [M + H]+ 255.1246, found 255.1241.
.
mg, 0.32 mmol), N2H4 H2O (174 µl, 3.6 mmol), 1 h. White solid 4-(4-Aminophenyl)-1H-pyrazole-3,5-diamine (5j). Title product 5j
(43 mg, 83% yield); mp 206-210°C. 1H NMR (400 MHz, DMSO-d6) was prepared under General procedure, pyrazole 4j (178 mg, 0.64
δ
: 10.32 (br. s., 1 H), 7.37 (d, J=7.8 Hz, 1 H), 7.32 (t, J=7.3 Hz, 2 H), mmol), EtOH (7.0 mL), catalyst 5% Fe on activated charcoal (715
.
7.08 (t, J=7.3 Hz, 1 H), 4.50 (br. s., 4 H). 13C NMR (101 MHz, DMSO- mg, 0.64 mmol), N2H4 H2O (560 µl, 11.52 mmol), 5 h. The products
d6) : 148.3, 134.6, 128.5, 126.6, 123.7, 90.4. HRMS (ESI-TOF): calcd 5j was purified via a column chromatography to yield title product
for C9H11N4 [M + H]+ 175.0984, found 175.0979.
δ
1
as a bright brown solid (62 mg, 51% yield); mp 186-188°C. H NMR
4-(o-(Tolyl)-1H-pyrazole-3,5-diamine (5c).43 Title product 5c was (400 MHz, DMSO-d6) δ: 10.22 (br. s., 1 H), 7.00 (d, J=8.3 Hz, 2 H),
prepared under General procedure, pyrazole 4c (82 mg, 0.33 6.57 (d, J=8.3 Hz, 2 H), 4.85 (s, 2 H), 4.26 (br. s., 4 H). 13C NMR (101
mmol), MeOH (2.5 mL), catalyst 5% Fe on activated charcoal (367 MHz, DMSO-d6) δ: 146.0, 145.4, 127.9, 121.7, 114.4, 90.8. HRMS
.
mg, 0.33 mmol), N2H4 H2O (195 µl, 3.98 mmol), 1 h. The product 5c (ESI-TOF): calcd for C9H12N5 [M + H]+ 190.1093, found 190.1088.
was purified via a column chromatography to yield title product as 4-(4-(Trifluoromethyl)phenyl)-1H-pyrazole-3,5-diamine (5k). Title
pale yellow oil (39 mg, 62% yield). 1H NMR (400 MHz, DMSO-d6) product 5k was prepared under General procedure, pyrazole 4k (66
δ: 9.89 (br. s, 1 H), 7.20 - 7.26 (m, 1 H), 7.09 - 7.18 (m, 3 H), 4.18 mg, 0.21 mmol), MeOH (3.0 mL), catalyst 5% Fe on activated
.
(br. s, 4 H), 2.20 (s, 3 H). 13C NMR (101 MHz, DMSO-d6)
δ
: 148.4, charcoal (242 mg, 0.21 mmol), N2H4 H2O (125 µl, 2.52 mmol), 2 h.
137.3, 132.6, 131.0, 130.1, 126.0, 125.5, 90.1, 19.8. HRMS (ESI- Pale yellow solid (50 mg, 97% yield); mp 160-162°C. 1H NMR (400
TOF): calcd for C10H13N4 [M + H]+ 189.1140, found 189.1135.
MHz, DMSO-d6)
δ
: 10.61 (br. s, 1 H), 7.62 (d, J=9.3 Hz, 2 H), 7.59 (d,
4-(4-Methoxyphenyl)-1H-pyrazole-3,5-diamine (5e).43 Title product J=9.3 Hz, 2 H), 4.74 (br. s., 4 H). 13C NMR (101 MHz, DMSO-d6)
5e was prepared under General procedure, pyrazole 4e (92 mg, δ: 149.1, 139.3, 126.4, 125.1 (q, J=3.8 Hz), 123.4 (q, J=32.6 Hz),
0.35 mmol), EtOH (3.0 mL), catalyst 5% Fe on activated charcoal 124.8 (q, J=270.3 Hz), 89.5. HRMS (ESI-TOF): calcd for C10H10F3N4 [M
.
(389 mg, 0.35 mmol), N2H4 H2O (202 µl, 4.2 mmol), 1 h. Beige solid + H]+ 243.0858, found 243.0852.
1
(59 mg, 85% yield); mp 220-222°C. H NMR (400 MHz, DMSO-d6) δ: (E)-4-Styryl-1H-pyrazole-3,5-diamine (5l). Title product 5l was
10.05 (br. s, 1 H), 7.27 (d, J=8.8 Hz, 2 H), 6.91 (d, J=8.8 Hz, 2 H), 4.42 prepared under General procedure, pyrazole 4l (114 mg, 0.44
(br. s., 4 H), 3.74 (s, 3 H). 13C NMR (101 MHz, DMSO-d6) δ: 156.2, mmol), MeOH (7.0 mL), catalyst 5% Fe on activated charcoal (488
.
148.6, 128.1, 126.8, 114.1, 90.1, 55.0. HRMS (ESI-TOF): calcd for mg, 0.44 mmol), N2H4 H2O (255 µl, 5.2 mmol), 1 h. The products 5l
C
10H13N4O [M + H]+ 205.1089, found 205.1085.
was purified via a column chromatography to yield title product as a
4-(2-Methoxyphenyl)-1H-pyrazole-3,5-diamine (5g).43 Title product white solid (53 mg, 61 % yield) ; mp 212-214°C. H NMR (400 MHz,
5g was prepared under General procedure, pyrazole 4g (102 mg, DMSO-d6) : 10.16 (br. s., 1 H), 7.42 (d, J=7.3 Hz, 2 H), 7.26 (t, J=7.3
0.39 mmol), MeOH (5.0 mL), catalyst 5% Fe on activated charcoal Hz, 1 H), 7.06 (t, J=7.3 Hz, 1 H), 7.03 (d, J=16.6 Hz, 1 H), 6.45 (d,
1
δ
(431 mg, 0.39 mmol), N2H4 H2O (135 µl, 4.63 mmol), 1 h. The J=16.6 Hz, 1 H), 4.92 (br. s., 1 H). 13C NMR (101 MHz, DMSO-d6)
δ:
.
products 5g was purified via a column chromatography to yield title 149.7, 139.9, 128.3, 124.9, 124.7, 120.6, 117.9, 88.9. HRMS (ESI-
1
product as a pale yellow oil (56 mg, 82% yield). H NMR (400 MHz, TOF): calcd for C11H13N4 [M + H]+ 201.1140, found 201.1135.
DMSO-d6)
δ: 10.26 (br. s, 1 H), 7.24 (dd, J=7.3, 1.6 Hz, 1 H), 7.17 (td, (E)-4-(4-Methoxystyryl)-1H-pyrazole-3,5-diamine (5m).
Title
J=7.3, 2.1 Hz, 1 H), 7.01 (dd, J=8.3, 1.0 Hz, 1 H), 6.94 (td, J=7.3, 1.0 product 5m was prepared under General procedure, pyrazole 4m
Hz, 1 H), 4.24 (br. s, 4 H), 3.78 (s, 3 H). 13C NMR (101 MHz, DMSO- (235 mg, 0.81 mmol), dioxane (16.0 mL), catalyst 5% Fe on activated
.
d6)
δ
: 155.6, 148.7, 129.8, 126.3, 122.6, 120.6, 111.4, 87.7, 55.3. charcoal (905 mg, 0.415 mmol), N2H4 H2O (475 µl, 9.7 mmol), 3 h.
HRMS (ESI-TOF): calcd for C10H13N4O [M + H]+ 205.1089, found Yellow solid (157 mg, 84 % yield); mp 190-194°C. 1H NMR (400 MHz,
205.1085. DMSO-d6) : 7.35 (d, J = 8.8 Hz, 2H), 6.85 (d, J = 8.8 Hz, 2H), 6.85 (d,
4-(2,6-Dimethoxyphenyl))-1H-pyrazole-3,5-diamine (5h). Title J = 16.6 Hz, 1H), 6.40 (d, J = 16.6 Hz, 1H), 4.44 - 5.26 (m, 4H), 3.73 (s,
product 5h was prepared under General procedure, pyrazole 4h 3H). 13C NMR (101 MHz, DMSO-d6)
: 157.1, 149.5, 132.6, 125.8,
δ
δ
(181 mg, 0.61 mmol), EtOH (5.0 mL), catalyst 5% Fe on activated 118.5, 118.0, 113.9, 88.8, 55.0 HRMS (ESI-TOF): calcd for C12H15N4O
charcoal (686 mg, 0.61 mmol), N2H4 H2O (360 µl, 7.4 mmol), 1 h. [M + H]+ 231.1246, found 231.1241.
.
Yellow solid (139 mg, 97 % yield); mp 83-86°C. 1H NMR (400 MHz,
(E)-4-(4-Fluorostyryl)-1H-pyrazole-3,5-diamine (5n). Title product
DMSO-d6) δ: 7.19 (t, J = 8.3 Hz, 1H), 6.67 (d, J = 8.3 Hz, 2H), 4.02 (br. 5n was prepared under General procedure, pyrazole 4n (162 mg,
s), 3.74 (s, 6H). 13C NMR (101 MHz, DMSO-d6) δ: 157.1, 149.4, 0.584 mmol), MeOH (6.0 mL), catalyst 5% Fe on activated charcoal
.
127.2, 110.3, 104.2, 84.0, 55.5. HRMS (ESI-TOF): calcd for (652 mg, 0.584 mmol), N2H4 H2O (340 µl, 7.0 mmol), 1 h. The
C11H15N4O2 [M + H]+ 235.1195, found 235.1190.
products 5n was purified via a column chromatography to yield title
4-(6-Methoxynaphtalen-2-yl)-1H-pyrazole-3,5-diamine (5i). Title product as a white solid (64 mg, 51 % yield); mp 192-198°C. 1H NMR
product 5i was prepared under General procedure, pyrazole 4i (100 (400 MHz, DMSO-d6) : 10.23 (br. s, 1 H), 7.44 (dd, J=8.8, 5.7 Hz, 2
mg, 0.32 mmol), MeOH (10.0 mL), catalyst 5% Fe on activated H), 7.09 (t, J=8.8 Hz, 2 H), 6.97 (d, J=16.6 Hz, 1 H), 6.44 (d, J=16.6 Hz,
δ
.
charcoal (357 mg, 0.32 mmol), N2H4 H2O (185 µl, 3.8 mmol), 1 h. 1 H), 4.89 (br. s., 4 H). 13C NMR (101 MHz, DMSO-d6)
Pale yellow solid (70 mg, 86% yield); mp 220-226°C. 1H NMR (400 J=240.6 Hz, 1 C), 149.69, 136.49 (d, J=2.9 Hz, 4 C), 126.11 (d, J=7.7
MHz, DMSO-d6) : 10.40 (br. s., 1 H), 7.75 (t, J=8.3 Hz, 1 H), 7.73 (s,
δ: 160.14 (d,
δ
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 11
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 12 of 13
View Article Online
DOI: 10.1039/C7OB02373A
ARTICLE
Journal Name
Hz, 5 C), 120.53, 116.75, 115.09 (d, J=21.1 Hz, 6 C), 88.74. HRMS
Conflicts of interest
(ESI-TOF): calcd for C11H12FN4 [M + H]+ 219.1046, found 219.1041.
There are no conflicts to declare.
(E)-4-(4-(Trifluoromethyl)styryl)-1H-pyrazole-3,5-diamine
(5o).
Title product 5o was prepared under General procedure, pyrazole
4o (95 mg, 0.289 mmol), MeOH (3.0 mL), catalyst 5% Fe on
Acknowledgements
.
activated charcoal (323 mg, 0.289 mmol), N2H4 H2O (170 µl, 3.5
This work was supported by the Czech National Program for
Sustainability (project LO1304), the Operational Programme
Enterprise and Innovations for Competitiveness (project
CZ.01.1.02/0.0/0.0/15_019/0004431), and the internal Palacky
University IGA projects (IGA_PrF_2017_009 and IGA_LF_2017_028).
mmol), 2 h. The products 6o was purified via
chromatography to yield title product as a pale yellow solid (39 mg,
50 % yield); mp 190-196°C. 1H NMR (400 MHz, DMSO-d6)
: 10.34
a column
δ
(br. s, 1H), 7.60 (d, J = 8.8 Hz, 2H), 7.58 - 7.65 (m, 2H), 7.58 (d, J =
8.8 Hz, 2H), 7.25 (d, J = 16.6 Hz, 1H), 6.51 (d, J = 16.6 Hz, 7H), 5.05
(br. s., 4H). 13C NMR (101 MHz, DMSO-d6)
δ: 150.2, 144.3, 125.2 (q,
J=3.8 Hz), 124.7, 124.5 (q, J=31.6 Hz), 123.7, 124.7 (q, J=270.3 Hz),
115.72, 89.0. HRMS (ESI-TOF): calcd for C12H12F3N4 [M + H]+
269.1014, found 269.1010.
Notes and references
1. A. Padmaja, T. Payani, G. D. Reddy, and V. Padmavathi, Eur. J.
Med. Chem., 2009, 44, 4557.
4-(Thiophen-3-yl)-1H-pyrazole-3,5-diamine (5p). Title product 5p
was prepared under General procedure, pyrazole 4p (60 mg,
0.25 mmol), MeOH (2.0 mL), catalyst 5% Fe on activated charcoal
2. V. A. Makarov, O. B. Riabova, V. G. Granik, H.-M. Dahse, A.
Stelzner, P. Wutzlerc and M. Schmidtkec, Bioorg. Med. Chem.,
2005, 15, 37.
.
(280 mg, 0.25 mmol), N2H4 H2O (147 µl, 3.0 mmol), 2 h. Yellow solid
(36 mg, 80 % yield); mp 192-196°C. 1H NMR (400 MHz, DMSO-d6) δ:
7.51 (dd, J=5.0, 2.7 Hz, 1 H), 7.33 (dd, J=5.0, 1.4 Hz, 1 H), 7.23 (dd,
J=2.7, 1.4 Hz, 1 H), 4.62 (br. s., 4 H). 13C NMR (101 MHz, DMSO-d6)
3. D. V. Kravchenko, V. M. Kysil, S. E. Tkachenko, S. Maliarchouk, I.
M. Okun and A. V. Ivachtchenko, Eur. J. Med. Chem., 2005, 40,
1377.
δ
: 148.3, 134.3, 126.7, 125.0, 116.0, 87.3 HRMS (ESI-TOF): calcd for
4. M. W. Ledeboer, A. C. Pierce, J. P. Duffy, H. Gao, D.
Messersmith, F. G. Salituro, S. Nanthakumar, J. Come, H. J.
Zuccola, L. Swenson, D. Shlyakter, S. Mahajan, T. Hoock, B. Fajn,
W.-J. Tsai, E. Kolaczkowski, S. Carrier, J. K. Hogan, R. Zessis, S.
Pazhanisamy and Y. L. Bennani, Bioorg. Med. Chem. Lett., 2009,
19, 6529.
C7H9N4S [M + H]+ 181.0548, found 181.0543.
4-(Benzo[b]thiophen-2-yl)-1H-pyrazole-3,5-diamine (5r).
Title
product 5r was prepared under General procedure, pyrazole 4r (87
mg, 0.3 mmol), MeOH (6.0 mL), catalyst 5% Fe on activated charcoal
.
(334 mg, 0.3 mmol), N2H4 H2O (175 µl, 3.6 mmol), 1.5 h. Yellow
solid (43 mg, 62 % yield); mp 224-226°C. 1H NMR (400 MHz, DMSO-
5. G. I. Shapiro, J. Clin. Oncol., 2006, 24, 1770.
6. V. Kryštof, P. Cankař, I. Fryšová, J. Slouka, G. Kontopidis, P.
Džubák, M. Hajdúch, J. Srovnal, W. F. de Azevedo Jr., M. Orság,
M. Paprskářová, J. Rolčík, A. Látr, P. M. Fischer and M. Strnad, J.
Med. Chem., 2006, 49, 6500.
d6)
H), 7.30 (t, J=7.3 Hz, 1 H), 7.23 (s, 1 H), 7.20 (t, J=7.3 Hz, 1 H), 4.82
(br. s., 4 H). 13C NMR (101 MHz, DMSO-d6)
: 149.5, 140.6, 137.1,
136.8, 124.2, 122.5, 121.9, 121.7, 115.7, 86.1. HRMS (ESI-TOF):
calcd for C11H11N4S [M + H]+ 231.0704, found 231.0700.
δ: 10.59 (br. s, 1 H), 7.83 (d, J=8.3 Hz, 1 H), 7.67 (d, J=7.8 Hz, 1
δ
7. R. Jorda, J. Navrátilová, Jana; Zlata Husková, E. Schüetznerová,
P. Cankař, M. Strnad and V. Kryštof, Chem. Biol. Drug Des.,
2014, 84, 402.
4-(5-Methoxybenzo[b]thiophene-2-yl)-1H-pyrazole-3,5-diamine
(5s). Title product 5s was prepared under General procedure,
pyrazole 4s (77 mg, 0.24 mmol), MeOH (4.0 mL), catalyst 5% Fe on
8. T. Owa and T. Nagasu, Expert. Opin. Ther. Pat., 2000, 10, 1725.
9. A. A. Zaitsev, I. A. Vatsadze, I. L. Dalinger, V. V. Kachala, Yu. V.
Nelyubina and S. A. Shevelev, Russ. Chem. Bull., 2009, 58, 2109.
10. E. C. Taylor and K. H. Hartke, J. Am. Chem. Soc., 1959, 81, 2452.
11. T. Sato, J. Org. Chem., 1959, 24, 936.
.
activated charcoal (268 mg, 0.24 mmol), N2H4 H2O (140 µl, 2.9
mmol), 1 h. Beige solid (40 mg, 64 % yield); mp 210°C. 1H NMR
(400 MHz, DMSO-d6)
7.20 (d, J=2.1 Hz, 1 H), 7.16 (s, 1 H), 6.81 - 6.86 (m, 1 H), 4.88 (br. s,
4 H), 3.79 (s, 4 H). 13C NMR (101 MHz, DMSO-d6)
: 157.1, 148.6,
δ: 10.65 (br. s, 1 H), 7.69 (d, J=8.3 Hz, 1 H),
δ
12. E. Bratt, O. Verho, M. J. Johansson and J.-E. Bäckvall, J. Org.
Chem., 2014, 79, 3946.
141.8, 138.2, 128.9, 122.4, 115.7, 112.0, 104.7, 86.2, 55.2. HRMS
(ESI-TOF): calcd for C12H13N4OS [M + H]+ 261.0810, found 261.0806.
4-(2-(3,5-Diamino-1H-pyrazol-4-yl)vinyl)phenol (1). Pyrazole 5m
(210 mg, 0.87 mmol) was dissolved in 12 mL DMSO, EtSNa (1.5 g,
17.5 mmol) was added, the vial inserted into an oil bath preheated
to 140°C and the mixture was vigorously stirred for 1 h. Then the
mixture was added into water (3 mL), neutralized by NH4Cl and the
product was then purified by column chromatography (CHCl3:MeOH
40-5:1) immediately. Beige solid (42 mg, 22 % yield); m.p. 182-
13. K. Billingsley and S. L. Buchwald, J. Am. Chem. Soc., 2007, 129,
3358.
14. G. Manolikakes, C. M. Hernandez, M. A. Schade, A. Metzger and
P. Knochel, J. Org. Chem., 2008, 73, 8422.
15. M. L. Crawley, B. M. Trost, Applications of Transition Metal
Catalysis in Drug Discovery and Development, Wiley: New York.
2012.
16. T. Eicher, S. Hauptmann, A. Speicher, The Chemistry of
Heterocycles: Structure, Reactions, Syntheses, and Applications,
Weinheim: Wiley-VCH. 2003.
188°C. 1H NMR (400 MHz, DMSO-d6)
δ: 9.22 (br. s., 1 H), 7.23 (d,
J=8.2 Hz, 2 H), 6.77 (d, J=16.6 Hz, 1 H), 6.68 (d, J=8.7 Hz, 2 H), 6.36
(d, J=16.6 Hz, 1 H), 4.90 (br. s, 1H). 13C NMR (101 MHz, DMSO-
17. M. A. Düfert, K. L. Billingsley and S. L. Buchwald, J. Am. Chem.
Soc. 2013, 135, 12877.
d6) δ: 155.3, 149.5, 130.9, 125.9, 118.8, 117.4, 115.2, 88.8. HRMS
(ESI-TOF): calcd for C11H13N4O [M + H]+ 216.1089, found 217.1085.
18. S. Vichier-Guerre, L. Dugué and S. Pochet, Tetrahedron Lett.,
2014, 55, 6347.
12 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 13 of 13
View Article Online
DOI: 10.1039/C7OB02373A
Journal Name
ARTICLE
19. L. J. Kershaw Cook, R. Kearsey, J. V. Lamb, E. J. Pace and J. A.
Gould, Tetrahedron Lett., 2016, 57, 895.
20. M. S. Ermolenko, S. Guillou and Y. L. Janin, Tetrahedron, 2013,
69, 257.
21. L. Jedinák and P. Cankař, Eur. J. Org. Chem., 2016, 2013.
22. T. Itoh and T. Mase, Tetrahedron Lett., 2005, 46, 3573.
23. K. Wang, Q. Fu, R. Zhou, X. Zheng, H. Fu, H. Chen and R. Li, Appl.
Organometal. Chem., 2013, 27, 232.
24. A. E. Thompson, G. Hughes, A. S. Batsanov, M. R. Bryce, P. R.
Parry and B. Tarbit, J. Org. Chem., 2005, 70, 388.
25. E. Schütznerová, I. Popa, V. Kryštof, H. Koshino, Z. Trávníček, P.
Hradil and P. Cankař, Tetrahedron, 2012, 68, 3996.
26. N. Kudo, M. Perseghini and G. Fu, Angew. Chem. Int. Ed., 2006,
45, 1282.
27. M. Prieto, E. Zurita, E. Rosa, L. Muñoz, P. Lloyd-Williams, E.
Giralt, J . Org. Chem., 2004, 69, 6812.
28. K. L. Billingsley, K. W. Anderson and S. L. Buchwald, Angew.
Chem. Int. Ed., 2006, 45, 3484.
29. L. Jedinák, R. Zátopková, H. Zemánková, Alena Šustková and
Petr Cankař, J. Org. Chem., 2017, 82, 157.
30. E. Tyrrell, and P. Brookes, Synthesis, 2004, 469.
31. P. Schäfer, T. Palacin, M. Sidera and S. P. Fletcher, Nat.
Commun., 2017, 8, 15762.
32. P. Agarwal, N. Thirupathi and M. Nethaji, Organometallics,
2016, 35, 3112.
33. Z.-G. Zhao and Z.-X. Wang, Synth. Commun., 2007, 37, 137.
34. J. Tan, Y. Chen, H. Li and N. Yasuda, J. Org. Chem., 2014, 79,
8871.
35. G. C. FU, Acc. Chem. Res., 2008, 41, 1555.
36. T. E. Barder, S. D. Walker, J. R. Martinelli and S. L. Buchwald, J.
Am. Chem. Soc., 2005, 127, 4685.
37. S. D. Walker, T. E. Barder, J. R. Martinelli and S. L. Buchwald,
Angew. Chem. Int. Ed., 2004, 43, 1871.
38. A. S. Guram, A. O. King, J. G. Allen, X. Wang, L. B. Schenkel, J.
Chan, E. E. Bunel, M. M. Faul, R. D. Larsen, M. J. Martinelli and
P. J. Reide, Org. Lett., 2006, 8, 1787.
39. K. Mikami, T. Miyamoto and M. Hatano, Chem. Commun., 2004,
2082.
40. E. A. B. Kantchev, C. J. O'Brien and M. G. Organ, Angew. Chem.
Int. Ed., 2007, 46, 2768.
41. C.-Y. Lee, S.-J. Ahn and C.-H. Cheon, J. Org. Chem., 2013, 78,
12154.
42. P. A. Cox, A. G. Leach, A. D. Campbell and G. C. Lloyd-Jones, J.
Am. Chem. Soc., 2016, 138, 9145.
43. N. S. Wilson, A. T. Osuma, J. A. Van Camp and X. Xu,
Tetrahedron Lett., 2012, 53, 4498.
44. L. Lunazzi, M. Mancinelli, A. Mazzanti, S. Lepri, R. Ruzziconi and
M. Schlosser, Org. Biomol. Chem., 2012, 10, 1847-1855.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 13
Please do not adjust margins