Synthesis of Aminopyrazoles from Isoxazoles: Comparison of Preparative Methods by in situ NMR Analysis

Article abstract of DOI:10.1055/s-0035-1561861

A single-step method and a two-step method for the synthesis of aminopyrazoles from isoxazoles are presented and compared. Based on in situ NMR monitoring, both processes proceed through a ketonitrile. In the single-step process, hydrazine serves to both open the isoxazole to the unisolated ketonitrile intermediate and form the aminopyrazole. The two-step process involves ring opening of the isoxazole by deprotonation with hydroxide to generate the ketonitrile followed by the addition of acetic acid and hydrazine to form the aminopyrazole.

Full text of DOI:10.1055/s-0035-1561861

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–G
paper
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N. J. Kallman et al.
Paper
Synthesis
Synthesis of Aminopyrazoles from Isoxazoles: Comparison of Pre-
parative Methods by in situ NMR Analysis
Neil J. Kallman
Kevin P. Cole
Thomas M. Koenig
Jonas Y. Buser
Adam D. McFarland
LuAnne M. McNulty1
David Mitchell*
Lilly Research Laboratories, Eli Lilly and Company,
Indianapolis, IN 46285, USA
dmit@lilly.com
Received: 03.04.2016
Accepted: 20.04.2016
Published online: 24.05.2016
DOI: 10.1055/s-0035-1561861; Art ID: ss-2016-m0223-op
ones and isoxazoles. Limited methods exist in the literature
for the preparation of aminopyrazoles from both heterocy-
cles.
Substituted isoxazole to aminopyrazole reactions have
been described sparingly in the literature.7 The mechanism
of aminopyrazole formation from isoxazoles was proposed
as early as 1941;8 however, there has been little additional
mechanistic work on this reaction. Based on the methods in
the literature, the transformation can proceed by a two-
step process involving deprotonation to give a β-ketonitrile
intermediate that is then treated with a hydrazine deriva-
tive to provide the aminopyrazole product.7c There is also a
one-step procedure involving the addition of hydrazine
with added acid or base (one pot), or without any addi-
tives.7a In the latter procedure, which involves only the
isoxazole and the desired hydrazine source, the hydrazine
may function as an internal base.
In situ NMR spectroscopy is a powerful tool to analyze a
reaction for both kinetic and mechanistic data.9,10 The tech-
nique can be as simple as conducting a reaction on a small
scale in an NMR tube and collecting 1D and 2D NMR data
over the course of the reaction. A far more powerful ap-
proach involves continuously flowing a reaction mixture
through the NMR spectrometer in line with other instru-
mentation, for example an on-line HPLC system or IR spec-
trophotometer, which can often supplement the informa-
tion-rich NMR data.9b In this manner, large volumes of data
can be collected and analyzed concurrently to provide reac-
tion details such as rate, transient intermediates, tautomer-
ization equilibria, and side reactions. The wealth of infor-
mation afforded by the combination of small-scale and con-
tinuous-flow NMR experiments can provide strong support
for a proposed mechanism and, thereby, greatly facilitate
reaction optimization and scale-up.
Abstract A single-step method and a two-step method for the synthe-
sis of aminopyrazoles from isoxazoles are presented and compared.
Based on in situ NMR monitoring, both processes proceed through a ke-
tonitrile. In the single-step process, hydrazine serves to both open the
isoxazole to the unisolated ketonitrile intermediate and form the amino-
pyrazole. The two-step process involves ring opening of the isoxazole by
deprotonation with hydroxide to generate the ketonitrile followed by
the addition of acetic acid and hydrazine to form the aminopyrazole.
Key words aminopyrazoles, isoxazoles, in situ NMR analysis, ketoni-
triles, heterocycles, regioselectivity
Pyrazole molecular subunits are found in various active
pharmaceutical ingredients (API)2a–c and agrochemicals,2d
and are useful in materials science applications2e and also
as synthesis reagents.2f Aminopyrazoles can serve as build-
ing blocks for more complex heterocycles.3 Because of such
prevalence, methods for preparing substituted aminopyra-
zoles have been developed during the past years.4 More im-
portantly, there is a need to fully understand the requisite
methodologies that are being utilized for preparing these
important compounds. For example, understanding the
pyrazole ring formation provides control of product quality,
control of regioisomers, control of processing parameters,
and overall yield output of the targeted compound.5
Recently, our laboratory disclosed an aminopyrazole re-
gioselective methodology.6 Since the most common route
to 3-aminopyrazoles involves the addition of hydrazines to
β-ketonitriles or their synthetic equivalent, the reported
methodology provides an alternate means of transforming
heterocycles to aminopyrazoles. The heterocyclic synthetic
equivalents to ketonitriles include 2-aminochromen-4-
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N. J. Kallman et al.
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Synthesis
Despite some research on the isoxazole to aminopyra-
zole transformation, the reaction is underutilized and not
well understood. For example, we observed that the reac-
tion of 2-(isoxazol-5-yl)phenol with hydrazine to generate
an aminopyrazole did not proceed to completion even after
heating in ethanol for 15 hours.6 A similar reaction of 5-(4-
methylphenyl)isoxazole also did not go to completion. The
starting isoxazole remained unreacted in 10% to 15%. In or-
der to optimize the process, it was crucial to fully under-
stand the reaction, including the origin of the byproducts as
well as the kinetics of the reaction. This provided the op-
portunity to determine whether the two-step reaction was
equivalent or superior to the one-step reaction.
The goal of this work was to use experimental data in
conjunction with in situ NMR monitoring to determine the
optimal conditions for the preparation of aminopyrazoles
from isoxazoles and the reaction mechanism. Also, the util-
ity of in situ NMR analysis for obtaining reaction profiles
and for the determination of reactive intermediates will be
demonstrated.
The reaction of 5-(4-chlorophenyl)isoxazole (1a) and
hydrazine as a single-step process with DMSO as solvent
provided preliminary understanding of the direct transfor-
mation of isoxazole to aminopyrazole. The rate of the reac-
tion was independent of hydrazine concentration up to 2
equivalents of the hydrazine. In addition, regardless of tem-
perature, 100 °C or 120 °C, or source of hydrazine, the start-
ing isoxazole was not converted into 100% aminopyrazole
after 15 hours. The reaction also proceeded to form small
quantities of several undetermined byproducts.
The scope of the one-step transformation was probed.
Treatment of isoxazoles 1a–g with hydrazine resulted in
the formation of the desired aminopyrazoles 2a–g (Table 1).
In general, the yields of the single-step reaction ap-
peared to be unaffected by the electronics of the aryl sub-
stituent, except in the case of isoxazole 1b. A side reaction
of 1b was nucleophilic aromatic substitution of the fluoride
by hydrazine that resulted in lower isolated yield of 2b
when compared to the two-step method.
Hoping for increased yield and reaction performance
such as rate increase, the one-step reaction was directly
compared to a two-step process involving ring opening
with a base then addition of hydrazine to generate the ami-
nopyrazole. Therefore, isoxazoles 1a–g were treated with
KOH in aqueous ethanol to generate a β-ketonitrile species
at 50 °C (0.5 h). The β-ketonitrile was either isolated then
treated with hydrazine to provide the aminopyrazole or di-
rectly converted into the aminopyrazole by treatment with
hydrazine at 60 °C for 2.5 hours [Table 1, two-step yield (%)].
Three of the seven substrates (1b, 1f, 1g) for the two-step
process gave yield increases ranging from 7% to 13% with a
total reaction time of 3 hours and at a lower temperature
(60 °C) than the one-step transformation. We currently
have no explanation or experimental data for the lower
yields of the two-step process for product 2a (5% lower) and
2c (2% lower). Isoxazole 1e was converted into aminopyra-
zole 2e in 59% yield, which was significantly lower than the
single-step yield. The presence of the phenolic oxygen led
to the formation of a chromenone intermediate that with
only an equivalent of hydrazine was not converted further
into the desired product. Therefore, the lower yield is per-
haps due to the reaction proceeding through an alternative
mechanism which was observed during our previous inves-
tigations.6
The scope of the hydrazine source was also examined.
Because there were clearly some advantages of performing
the isoxazole to aminopyrazole reaction in a two-step fash-
ion rather than a single step, we extended our investigation
to include substituted hydrazines. In addition to yield or re-
action rate differences, the regioselectivities of these sub-
strates were also of interest.
Methylhydrazine, tert-butylhydrazine, and phenylhy-
drazine were selected for our substituted hydrazine study.
The reactions were conducted utilizing similar reaction pa-
rameters as were utilized previously for hydrazine. Also, a
similar comparison between the single-step and two-step
process was made.
Table 1 Synthesis of Aminopyrazoles 2 from Isoxazoles 1 and Hydra-
zinea
N
N
O
HN
H2NNH2
DMSO
R
NH2
R
1a–g
2a–g
Entry
1
R
2
Yield (%)
One-step
Two-step
1
2
3
4
5
6
7
a
b
c
4-Cl
a
b
c
84
82
74
92
87
77
82
79
92
72
89
59
90
93
4-F
4-Me
4-OMe
2-OH
3-NO2
3-CF3
d
e
f
d
e
f
Table 2 is a summary of the substituted hydrazine reac-
tion with isoxazole results. Good yields were obtained with
the single-step process, except for products 3a and 3e. The
lowest yields were both obtained in single-step reactions
utilizing 1f [5-(3-nitrophenyl)isoxazole]. This result seems
g
g
a Yields are the isolated yield from each reaction.
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N. J. Kallman et al.
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Synthesis
to indicate that the nitro group may have a negative impact
on the reaction yield. In comparing yields between the sin-
gle-step process and the two-step process, every reaction in
the two-step process, except for entry 3, provided a higher
yield ranging from 4% to 32% increase.
A mixture of regioisomers was formed in the case
where methylhydrazine was used as the hydrazine source
for both the single-step and two-step process (Table 2, en-
tries 1 and 2). The regioisomeric determination was made
based on 2D NMR characterization. Both procedures yield-
ed the 3-regioisomer 3 as the major substitution derivative.
With the bulkier tert-butylhydrazine, a single regioisomer
was isolated (Table 2, entries 3 and 4). In the case of phenyl-
hydrazine, only 37% of the product 3e was formed in the
one-step process based on HPLC analysis, thus the product
was not isolated.
The yields of the two-step process are, in general, com-
parable or higher than the single-step process. Materials
isolated are also lighter in color in comparison to those ob-
tained from the single-step process. The two-step process
also exhibits increased reaction rate (3 h compared to 15 h).
This rate increase is due to the formation of the β-ketoni-
trile prior to hydrazine addition, which is further described
in the in situ NMR mechanism study below. However, there
are substrate effects that influence choice of the one-step
process or the two-step process. For example, phenol 1e
produces an intermediate during the one-step reaction
which reduces the rate of reaction.
As indicated earlier, in situ NMR reaction characteriza-
tion and monitoring provides important information about
mechanistic pathways as well as rates of reaction. Based on
the analysis of the one-step reaction of several isoxazole
substrates by in situ NMR spectroscopy, a data-rich and
general mechanism for the conversion of isoxazole into 3-
aminopyrazoles may be proposed. A combination of tube
and continuous-flow NMR experiments was performed in
order to comprehensively characterize the isoxazole to pyr-
azole transformation.
Table 2 Synthesis of Aminopyrazoles 3 and 4 from Isoxazoles 1 and
Substituted Hydrazinesa
R'
N
N
NH2
R
The conversion of 5-(4-fluorophenyl)isoxazole (1b) into
3-(4-fluorophenyl)-1H-pyrazol-5-amine (2b) is selected for
discussion because the reaction can be easily monitored us-
ing the simplified fluorine NMR spectrum, while proton,
carbon, and nitrogen homonuclear, and/or heteronuclear
NMR spectra were used for structure elucidation of the var-
ious reaction species. The full proposed mechanism is
shown in Scheme 1. Included in the scheme are unique pro-
ton/carbon assignments that, along with the additional 1D
and 2D NMR data collected, support the molecular struc-
ture of the compounds observed throughout the course of
the reaction. Also included are intermediates that are not
explicitly observed under the reaction conditions, but are
likely based on current understanding in the field. As
shown in Scheme 1, the reaction proceeds through an eno-
late intermediate. The enolate must be neutralized to give
the ketonitrile, which reacts with hydrazine to form a
hemiaminal. Neither the ketonitrile nor the hemiaminal are
observed during the course of the reaction. This is likely an
effect of a fast rate of reaction of each intermediate. The de-
hydration of the hemiaminal leads to the formation of four
different intermediates that exist in a complex equilibrium:
two hydrazone nitriles and their tautomeric hydrazinylac-
rylonitriles. Three of the four intermediates are observed
under the reaction conditions, and are readily distinguished
by NMR data. Generation of the aminopyrazole product is
afforded through cyclization of the Z-hydrazinylacryloni-
trile or E-hydrazone nitrile.
N
a) NaOH
EtOH/H2O
O
3 (3-isomer)
R
+
b) R'HNNH2
R'
N
N
NH2
R
1
4 (5-isomer)
Entry
1
R′
3 and 4 One step
Two step
Yield (%)
3/4
Yield (%) 3/4
1
2
3
4
5
6
f
Me
a
b
c
d
e
f
58
70
86
95
37
80
5:1
75
87
84
99
69
99
15:1
g
f
Me
t-Bu
t-Bu
Ph
4:1
1:0
1:0
1:0
1:0
19:1
1:0
1:0
1:0
1:0
g
f
g
Ph
a Yields are isolated yields, except for entry 5, one step, which is based on the
HPLC area %.
The reaction of 5-(4-fluorophenyl)isoxazole (1b) with
base then hydrazine gave a 92% yield of aminopyrazole 2b
(Table 1, entry 2). The two-step process eliminated an un-
desired SNAr side reaction with the fluoride. A significant
yield improvement was also observed for 5-(3-nitrophe-
nyl)isoxazole (1f) in the two-step process (Table 1, entry 6;
Table 2, entries 1 and 5).
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N. J. Kallman et al.
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F
F
F
F
H2NNH2
O
O
C
O
C
O
C
N
1b
H
H
(4.32, 54.5)
N
N
(6.89, 101.9)
NH
ketonitrile
not observed
isoxazole
observed
ketenimine
not observed
enolate
observed
F
F
NH
H
N
OH
NHNH2
N
NH2
2b
NH2
N
H
H
(3.76, 25.9)
C
C
F
F
(5.83, 85.3)
aminopyrazole
observed
N
hemiaminal
not observed
(E)-hydrazone
NH
N
observed
NH
NH2
H
F
F
F
(5.73, 87.0)
NH2
H
H
N
hydrazinylpyrazole
observed
N
N
NH2
NH2
N
H
H
(minor product)
C
H
C
(4.09, 14.1)
C
N
N
(4.60, 57.9)
(Z)-hydrazone
observed
(E)-hydrazinylacrylonitrile
observed
(Z)-hydrazinylacrylonitrile
not observed
(1H, 13C)
(1H, 13C)
(1H, 13C) chemical shift assignments of positive correlation in HSQC (with multiplicity editing) CH or CH3
(1H, 13C) chemical shift assignments of negative correlation in HSQC (with multiplicity editing) CH2
Scheme 1 Proposed mechanism for the conversion of 5-(4-fluorophenyl)isoxazole (1b) into 3-(4-fluorophenyl)-1H-pyrazol-5-amine (2b)
The kinetics of the reaction were determined by in situ
NMR monitoring (Figure 1). It is evident from the kinetic
profile that the enolate is rapidly formed from the isoxazole
starting material. The E-hydrazone concentration then be-
gins to rise, continuing to increase until the concentrations
of enolate and isoxazole have decreased significantly. A
substantial buildup of E-hydrazone was observed in the re-
action; however, the concentrations of Z-hydrazone and E-
hydrazinylacrylonitrile remained low throughout the
course of the reaction. The prevalence of E-hydrazone sug-
gests that the rate-limiting step in this reaction is a combi-
nation of a relatively slow rate of cyclization to product and
isomerization to the other intermediates. Conversely, the Z-
hydrazinylacrylonitrile was not observed, likely due to the
rapid conversion of this species into the aminopyrazole
product. The isoxazole starting material was not fully con-
sumed after 19 hours although its concentration continued
to slowly decrease. Aminopyrazole formation slowed con-
siderably over the course of the reaction, which is attribut-
ed to the diminishing concentration of hydrazine and con-
current change in the system pH as the reaction progresses.
In summary, 1H and 19F NMR spectral data were used to
compile reaction profiles for all the species observed in
Scheme 1 (reaction temperature was 75 °C). These profiles
are useful for understanding the relative rates of starting
material consumption, the build-up of various intermedi-
ates, and subsequent reaction to form desired product and a
minor side product.
Figure 1 Reaction profile of 5-(4-fluorophenyl)isoxazole (1b) with hy-
drazine
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N. J. Kallman et al.
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1H NMR (400 MHz, CD3OD + 2 drops TFA): δ = 7.68 (d, J = 8.6 Hz, 2 H),
7.51 (d, J = 8.6 Hz, 2 H), 6.23 (s, 1 H).
13C NMR (100 MHz, CD3OD + 2 drops TFA): δ = 151.9, 148.6, 137.8,
130.7 (2 C), 129.1 (2 C), 127.3, 91.6 (t, JCD = 27.6 Hz, 1 C).
All commercial reagents were used as received without further purifi-
cation. Known compounds were prepared according to reported pro-
cedures or were purchased from commercial sources. Reactions were
monitored by HPLC utilizing the following method: Agilent 1100
HPLC instrument, XBridge C18 column: 4.6 × 75 mm, 2.5 μm particle
size; 1.0 mL/min flow, 40 °C column temperature, UV analysis: detec-
tion at 220 and 254 nm with slit = 1 nm, peakwidth >0.1 min,
bandwidth = 4 nm; solvent A = 1 mL/L formic acid in water, solvent
B = 1 mL/L formic acid in acetonitrile; gradient elution (min): T(0)
95% A to 95% B at T(11) to 95% A at T(13), 14 min runtime. Column
chromatography was performed by using 200–300 mesh silica gel;
UV detection at 254 nm and/or iodine staining. Melting points were
determined by DSC using a TA Instruments Discovery Series SA+ dif-
ferential scanning calorimeter, running the latest version of TRIOS
software. IR spectra were recorded with a Nicolet 6700 FT-IR spectro-
HRMS: m/z [M + H]+ calcd for C9H9N3Cl: 194.0480; found: 194.0476.
3-(4-Fluorophenyl)-1H-pyrazol-5-amine (2b)
Yield of one-step process: 0.72 g (82%); light-orange solid. Yield of
two-step process: 1.06 g (92%); tan solid.
Mp 117.3–119.5 °C (Lit.11b,12 130 °C).
IR (neat, ATR): 3143 (br), 1493 (vs), 1236 (s), 1116 (s), 1013 (s) cm–1
.
1H NMR (400 MHz, CD3OD + 2 drops TFA): δ = 7.77–7.72 (dd, J = 5.1,
3.9 Hz, 2 H), 7.28–7.22 (m, J = 8.8 Hz, 2 H), 6.18 (s, 1 H).
13C NMR (100 MHz, CD3OD + 2 drops TFA): δ = 165.6 (d, JCF = 125.1 Hz,
1 C), 152.4, 149.0, 129.9 (d, JCF = 8.8 Hz, 2 C), 125.0, 117.5 (d, JCF = 22.5
Hz, 2 C), 91.1 (t, JCD = 27.5 Hz, 1 C).
19F NMR (376 MHz, CD3OD): δ = –117.0.
HRMS: m/z [M + H]+ calcd for C9H9N3F: 178.0775; found: 178.0772.
photometer with a Smart OMNI-Sampler. 1H NMR (400 MHz) and 13
C
NMR (100 MHz) spectra were recorded in CD3OD, or as noted in each
analysis, on 400 MHz Bruker Ascend spectrometers. Flow NMR data
were collected with a 500 MHz Bruker Avance III spectrometer
equipped with a 5 mm BBO probe. HRMS analyses were performed
with a Thermo LTQ Orbitrap Discovery mass spectrometer, using the
electrospray ionization (ESI) technique, in the positive ion mode.
3-(p-Tolyl)-1H-pyrazol-5-amine (2c)
Yield of one-step process: 0.78 g (74%); tan solid. Yield of two-step
process: 0.72 g (72%); tan solid.
3-(4-Chlorophenyl)-1H-pyrazol-5-amine (2a)
Mp 151.3–152.8 °C.
Typical Procedure for the One-Step Reaction
Into a reaction vessel was added 5-(4-chlorophenyl)isoxazole (1a)
(997 mg, 5.55 mmol), DMSO (5 mL), and hydrazine (433 mg of 64
wt %, 8.65 mmol, 1.6 equiv). The vessel was sealed and heated at 90 °C
for 15 h, then cooled to 20 °C. H2O (15 g) was added, resulting in the
precipitation of product. The slurry was cooled in ice–H2O for 1.5 h
and filtered. The wet cake was washed with H2O (2 × 10 mL) and
dried, resulting in 3-(4-chlorophenyl)-1H-pyrazol-5-amine (2a) (925
mg of 93 wt %, 99.6 area %, 4.46 mmol, 80% yield). Another 4% yield
was contained in the mother liquor.
IR (neat, ATR): 3209 (br), 1626 (s), 1515 (vs), 999 (s) cm–1
.
1H NMR (400 MHz, CD3OD): δ = 7.47 (d, J = 8.2 Hz, 2 H), 7.17 (d, J = 8.0
Hz, 2 H), 5.85 (s, 1 H), 2.31 (s, 3 H).
13C NMR (100 MHz, CD3OD + 2 drops TFA): δ = 154.5, 148.3, 140.1,
130.5 (2 C), 128.2, 126.6 (2 C), 89.9 (t, JCD = 26.6 Hz, 1 C), 21.3.
HRMS: m/z [M + H]+ calcd for C10H12N3: 174.1026; found: 174.1020.
3-(4-Methoxyphenyl)-1H-pyrazol-5-amine (2d)
Yield of one-step process: 0.86 g (92%); tan solid. Yield of two-step
process: 0.93 g (89%); off-white solid.
Typical Procedure for the Two-Step Reaction
Into a reaction vessel was added KOH (391 mg of 85 wt %, 5.92 mmol,
1.04 equiv), EtOH (2.9 mL), and H2O (2.0 mL). The mixture was stirred
until a solution resulted. Next, 5-(4-chlorophenyl)isoxazole (1a)
(1026 mg, 5.71 mmol) was added, forming a slurry. The vessel was
sealed and heated at 50 °C for 0.5 h, consuming the starting material
and resulting in a solution. After cooling to 20 °C, THF (4.3 mL) and
HOAc (706 mg, 11.76 mmol, 2.1 equiv) were added, resulting in a slur-
ry. Finally, hydrazine (413 mg of 64 wt %, 8.25 mmol, 1.4 equiv) was
added, resulting in a solution. The mixture was heated at 60 °C for 2.5
h, then cooled to 20 °C. The reaction mixture was quenched with sat-
urated aq Na2CO3 (3.1 mL, 5.1 mmol, 0.9 equiv), resulting in pH 11.
The phases were separated. To the organic phase was added H2O (30
mL), resulting in the precipitation of product. The slurry was filtered.
The wet cake was washed with H2O (2 × 10 mL) and dried at 40 °C,
resulting in 3-(4-chlorophenyl)-1H-pyrazol-5-amine (2a) (910 mg of
87 wt %, 99.7 area %, 4.07 mmol, 71% yield). A second crop (140 mg of
64.9 wt %, 0.48 mmol, 8% yield) was recovered from the mother liquor
by extracting with MTBE (2 × 25 mL), drying over Na2SO4, and con-
centrating to dryness.
Mp 141.6–143.1 °C.
IR (neat, ATR): 3152 (br), 1617 (w), 1512 (vs), 1245 (vs), 1191 (s),
1030 (w) cm–1
.
1H NMR (400 MHz, CD3OD): δ = 7.52 (d, J = 8.6 Hz, 2 H), 6.91 (d, J = 8.8
Hz, 2 H), 5.81 (br s, 1 H), 3.78 (s, 3 H).
13C NMR (100 MHz, CD3OD + 2 drops TFA): δ = 162.0, 154.3, 148.6,
128.2 (2 C), 122.8, 115.3 (2 C), 89.6 (t, JCD = 26.6 Hz, 1 C), 55.7.
HRMS: m/z [M + H]+ calcd for C10H12ON3: 190.0975; found: 190.0968.
2-(5-Amino-1H-pyrazol-3-yl)phenol (2e)6
Yield of one-step process: 1.01 g (87%); brown solid. Yield of two-step
process: 0.78 g (59%); brown solid.
Mp 147.3–148.9 °C (Lit.6 148.7 °C).
IR (neat, ATR): 3432 (vs), 3148 (v br), 1618 (s), 1479 (s), 1259 (s), 1004
(s) cm–1
.
1H NMR (400 MHz, CD3OD + 2 drops TFA): δ = 7.61 (dd, J = 6.4, 1.5 Hz,
1 H), 7.31 (dt, J = 8.0, 1.8 Hz, 1 H), 7.01–6.92 (m, 2 H).
13C NMR (100 MHz, CD3OD + 2 drops TFA): δ = 156.9, 152.2, 147.4,
133.2, 129.7, 121.2, 117.6, 114.6, 90.7 (t, JCD = 27.3 Hz, 1 C).
Yield of one-step process: 0.92 g (84%); tan solid. Yield of two-step
process: 1.05 g (79%); off-white solid.
Mp 173.4–174.1 °C (Lit.11 173–174.5 °C).
HRMS: m/z [M + H]+ calcd for C9H10ON3: 176.0818; found: 176.0815.
IR (neat, ATR): 3210 (br), 1627 (s), 1501 (vs), 1108 (s) cm–1
.
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Paper
Synthesis
5-(3-Nitrophenyl)-1H-pyrazol-3-amine (2f)
1-Methyl-3-(3-(trifluoromethyl)phenyl)-1H-pyrazol-5-amine (3b)
Yield of one-step process: 0.75 g (77%); yellow solid. Yield of two-step
process: 1.80 g (90%); yellow solid.
Yield of one-step process: 0.37 g (70%); light-yellow solid. Yield of
two-step process: 1.84 g (87%); light-yellow solid.
Mp 142.5–144.0 °C; Rf (TLC) = 0.32 (EtOAc); tR (HPLC) = 4.46 min.
Mp 88.2–89.5 °C; Rf (TLC) = 0.28 (EtOAc–heptane, 7:3); tR (HPLC, see
general experimental conditions) = 6.54 min.
IR (neat, ATR): 3155 (br), 1598 (w), 1525 (vs), 1345 (vs) cm–1
.
IR (neat, ATR): 3414 (w), 3291 (w), 3170 (w), 2941 (w), 1616 (w),
1H NMR (400 MHz, CD3OD): δ = 8.50 (t, J = 2.0 Hz, 1 H), 8.13 (ddd,
J = 0.8, 2.4, 8.4 Hz, 1 H), 8.01 (d, J = 7.6 Hz, 1 H), 7.60 (t, J = 8.0 Hz, 1 H),
6.00 (s, 1 H).
1563 (vs), 1506 (w), 1322 (vs), 1161 (vs) cm–1
.
1H NMR (400 MHz, CD3OD): δ = 7.98 (s, 1 H), 7.90 (d, J = 6.8 Hz, 1 H),
7.56–7.50 (m, 2 H), 5.88 (s, 1 H), 3.67 (s, 3 H).
13C NMR (100 MHz, CD3OD + 2 drops TFA): δ = 151.8, 150.1, 147.2,
132.8, 132.7, 131.5, 124.6, 121.4, 91.5 (t, JCD = 27.0 Hz, 1 C).
HRMS: m/z [M + H]+ calcd for C9H9O2N4: 205.0720; found: 205.0714.
13C NMR (100 MHz, CD3OD): δ = 150.0, 149.8, 136.2, 132.0 (q,
JCF = 31.9 Hz, 1 C), 130.4, 129.9, 125.8 (q, JCF = 270.1 Hz, 1 C), 124.9 (q,
JCF = 3.8 Hz, 1 C), 122.8 (q, JCF = 3.8 Hz, 1 C), 88.2, 34.4.
19F NMR (376 MHz, CD3OD): δ = –64.2.
5-(3-(Trifluoromethyl)phenyl)-1H-pyrazol-3-amine (2g)
HRMS: m/z [M + H]+ calcd for C11H11N3F3: 242.0900; found: 242.0893.
Yield of one-step process: 0.84 g (82%); pale-orange solid. Yield of
two-step process: 1.86 g (93%); pale-orange solid.
1-Methyl-5-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine (4b)
Yield: isolated from 3b; brown oil.
Mp 127.3–128.3 °C; Rf (TLC) = 0.22 (EtOAc); tR (HPLC, see general ex-
perimental conditions) = 5.68 min.
IR (neat, ATR): 3422 (w), 3359 (w), 3136 (m, br), 2912 (w, br), 1504
Rf (TLC) = 0.16 (EtOAc–heptane, 7:3); tR (HPLC, see general experi-
mental conditions) = 6.13 min.
(m), 1332 (vs), 1323 (s), 1121 (vs) cm–1
.
1H NMR (400 MHz, CD3OD): δ = 7.96 (s, 1 H), 7.89 (d, J = 6.4 Hz, 1 H),
IR (neat, ATR): 3324 (br), 1556 (w), 1510 (w), 1326 (vs) cm–1
.
7.61–7.54 (m, 2 H), 5.99 (br s, 1 H).
1H NMR (400 MHz, CD3OD): δ = 7.73–7.65 (m, 4 H), 5.78 (s, 1 H), 3.65
13C NMR (100 MHz, CD3OD + 2 drops TFA): δ = 152.5, 147.3, 132.5 (q,
JCF = 32.3 Hz, 1 C), 132.0, 131.1, 130.5, 126.7 (q, JCF = 3.4 Hz, 1 C), 125.5
(q, JCF = 270.4 Hz, 1 C), 123.5 (q, JCF = 3.8 Hz, 1 C), 91.1 (t, JCD = 26.6 Hz,
1 C).
19F NMR (376 MHz, CD3OD): δ = –64.3.
HMRS: m/z [M + H]+ calcd for C10H9N3F3: 228.0734; found: 228.0736.
(s, 3 H).
13C NMR (100 MHz, CD3OD): δ = 155.9, 145.1, 133.4, 133.0, 132.2 (q,
JCF = 32.3 Hz, 1 C), 130.8, 126.3 (m, 2 C), 125.4 (q, JCF = 270.4 Hz, 1 C),
95.0, 36.8.
19F NMR (376 MHz, CD3OD): δ = –64.3.
HRMS: m/z [M + H]+ calcd for C11H11N3F3: 242.0900; found: 242.0893.
1-Methyl-3-(3-nitrophenyl)-1H-pyrazol-5-amine (3a)
1-tert-Butyl-3-(3-nitrophenyl)-1H-pyrazol-5-amine (3c)
Yield of one-step process: 0.58 g (58%); orange solid. Yield of two-step
process: 1.60 g (75%); orange solid.
Yield of one-step process: 1.02 g (86%); orange solid. Yield of two-step
process: 2.14 g (84%); orange solid.
Mp 170.3–171.2 °C; Rf (TLC) = 0.25 (EtOAc–heptane, 4:1); tR (HPLC,
see general experimental conditions) = 5.33 min.
Mp 74.2–75.5 °C; Rf (TLC) = 0.38 (EtOAc–heptane, 9:11).; tR (HPLC, see
general experimental conditions) = 8.23 min.
IR (neat, ATR): 3439 (m), 3387 (w), 3210 (w), 1650 (m), 1572 (m),
IR (neat, ATR): 3360 (w), 2973 (w), 1527 (s), 1505 (m), 1342 (vs) cm–1
1H NMR (400 MHz, CD3OD): δ = 8.51 (t, J = 2.0 Hz, 1 H), 8.08–8.03 (m,
2 H), 7.54 (t, J = 8.0 Hz, 1 H), 5.97 (s, 1 H), 1.67 (s, 9 H).
13C NMR (100 MHz, CD3OD): δ = 149.9, 149.4, 146.9, 137.8, 132.1,
130.6, 122.4, 120.5, 91.3, 60.1, 29.5 (3 C).
.
1531 (vs), 1349 (vs) cm–1
.
1H NMR (400 MHz, CD3OD): δ = 8.51 (t, J = 2.0 Hz, 1 H), 8.11 (ddd,
J = 0.8, 2.4, 8.0 Hz, 1 H), 8.03 (td, J = 1.2, 8.0 Hz, 1 H), 7.59 (t, J = 8.4 Hz,
1 H), 5.91 (s, 1 H), 3.68 (s, 3 H).
13C NMR (100 MHz, CD3OD): δ = 150.2, 150.1, 149.0, 137.1, 132.2,
130.8, 122.9, 120.7, 88.3, 34.5.
HRMS: m/z [M + H]+ calcd for C13H17O2N4: 261.1346; found: 261.1341.
HRMS: m/z [M + H]+ calcd for C10H11O2N4: 219.0877; found: 219.0871.
1-tert-Butyl-3-(3-(trifluoromethyl)phenyl)-1H-pyrazol-5-amine
(3d)
1-Methyl-5-(3-nitrophenyl)-1H-pyrazol-3-amine (4a)
Yield of one-step process: 1.18 g (95%); pale-yellow oil. Yield of two-
step process: 2.46 g (99%); pale-yellow oil.
Yield of one-step process: isolated from 3a; orange solid. Yield of
two-step process: isolated from 3a; orange solid.
Rf (TLC) = 0.29 (EtOAc–heptane, 3:7); tR (HPLC, see general experi-
mental conditions) = 9.30 min.
Mp 138.8–140.7 °C; Rf (TLC) = 0.11 (EtOAc–heptane, 4:1); tR (HPLC,
see general experimental conditions) = 4.69 min.
IR (neat, ATR): 3351 (w, br), 2983 (w), 1618 (w), 1555 (m), 1325 (vs)
IR (neat, ATR): 3444 (w), 3382 (w), 3316 (w), 3065 (w), 1525 (vs),
cm–1
.
1345 (vs) cm–1
.
1H NMR (400 MHz, CD3OD): δ = 8.00 (m, 1 H), 7.92 (m, 1 H), 7.52–7.47
(m, 2 H), 5.95 (s, 1 H), 1.67 (s, 9 H).
13C NMR (100 MHz, CD3OD): δ = 149.3, 147.8, 136.9, 131.7 (q,
JCF = 31.9 Hz, 1 C), 130.2, 129.8, 125.9 (q, JCF = 270.0 Hz, 1 C), 124.5 (q,
JCF = 3.8 Hz, 1 C), 122.7 (q, JCF = 3.8 Hz, 1 C), 91.2, 60.0, 29.5 (3 C).
1H NMR (400 MHz, CD3OD): δ = 8.29 (d, J = 1.6 Hz, 1 H), 8.28 (ddd,
J = 1.2, 2.4, 7.2 Hz, 1 H), 7.86 (td, J = 0.8, 8.0 Hz, 1 H), 7.28 (dt, J = 1.6,
7.6 Hz, 1 H), 5.83 (s, 1 H), 3.69 (s, 3 H).
13C NMR (100 MHz, CD3OD): δ = 155.9, 149.9, 144.3, 135.7, 133.6,
131.3, 124.3, 124.2, 95.2, 36.9.
19F NMR (376 MHz, CD3OD): δ = –64.1.
HRMS: m/z [M + H]+ calcd for C10H11O2N4: 219.0877; found: 219.0870.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

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N. J. Kallman et al.
Paper
Synthesis
HRMS: m/z [M + H]+ calcd for C14H17N3F3: 284.1369; found: 284.1364.
3-(3-Nitrophenyl)-1-phenyl-1H-pyrazol-5-amine (3e)
(2) (a) Dakshanamurthy, S.; Issa, N. T.; Assefnia, S.; Seshasayee, A.;
Peters, O. J.; Madhavan, S.; Uren, A.; Brown, M. L.; Byers, S. W. J.
Med. Chem. 2012, 55, 6832. (b) Estrada, A. A.; Chan, B. K.; Baker-
Glenn, C.; Beresford, A.; Burdick, D. J.; Chambers, M.; Chen, H.;
Dominguez, S. L.; Dotson, J.; Drummond, J.; Flagella, M.; Fuji, R.;
Gill, A.; Halladay, J.; Harris, S. F.; Heffron, T. P.; Kleinheinz, T.;
Lee, D. W.; Le Pichon, C. E.; Liu, X.; Lyssikatos, J. P.; Medhurst, A.
D.; Moffat, J. G.; Nash, K.; Scearce-Levie, K.; Sheng, Z.; Shore, D.
G.; Wong, S.; Zhang, S.; Zhang, X.; Zhu, H.; Sweeney, Z. K. J. Med.
Chem. 2014, 57, 921. (c) Farouz, F. S.; Holcomb, R. C.; Kasar, R.;
Myers, S. S. US Patent 20110144126 A, 2011. (d) Chen, H.; Li, Z.;
Han, Y. J. Agric. Food Chem. 2000, 48, 5312. (e) Aragay, G.; Pons,
J.; Ros, J.; Merkoçi, A. Langmuir 2010, 26, 10165. (f) Kotsuki, H.;
Wakao, M.; Hayakawa, H.; Shimanouchi, T.; Shiro, M. J. Org.
Chem. 1996, 61, 8915.
(3) Chan, B. K.; Estrada, A. A.; Chen, H.; Atherall, J.; Baker-Glenn, C.;
Beresford, A.; Burdick, D. J.; Chambers, M.; Dominguez, S. L.;
Drummond, J.; Gill, A.; Kleinheinz, T.; Le Pichon, C. E.;
Medhurst, A. D.; Liu, X.; Moffat, J. G.; Nash, K.; Scearce-Levie, K.;
Sheng, Z.; Shore, D. G.; Van de Poel, H.; Zhang, S.; Zhu, H.;
Sweeney, Z. K. ACS Med. Chem. Lett. 2013, 4, 85.
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759. (b) Shen, H.; Li, J.; Liu, Q.; Pan, J.; Huang, R.; Xiong, Y. J. Org.
Chem. 2015, 80, 7212. (c) Abdel-Latif, E.; Khalil, A. Res. Chem.
Intermed. 2015, 41, 4555.
Yield of one-step process: 37 HPLC area%; not isolated. Yield of two-
step process: 0.94 g (69%); yellow solid.
Mp 146.6–147.6 °C; Rf (TLC) = 0.24 (CH2Cl2); tR (HPLC, see general ex-
perimental conditions) = 7.89 min.
IR (neat, ATR): 3395 (m), 3317 (m), 3215 (w), 3079 (w), 1627 (m),
1599 (w), 1558 (m), 1529 (s), 1500 (s), 1348 (vs) cm–1
.
1H NMR (400 MHz, CD3OD): δ = 8.60 (t, J = 2.0 Hz, 1 H), 8.15 (ddt,
J = 1.2, 2.4, 8.4 Hz, 2 H), 7.65–7.61 (m, 3 H), 7.56 (t, J = 7.2 Hz, 2 H),
7.44 (tt, J = 1.2, 7.2 Hz, 1 H), 6.08 (s, 1 H).
13C NMR (100 MHz, CD3OD): δ = 150.9, 150.1 (2 C), 139.9, 136.8,
132.5, 130.9, 130.6 (2 C), 129.0, 125.7 (2 C), 123.3, 121.1, 88.6.
HRMS: m/z [M + H]+ calcd for C15H13O2N4: 281.1033; found: 281.1025.
1-Phenyl-3-(3-(trifluoromethyl)phenyl)-1H-pyrazol-5-amine (3f)
Yield of one-step process: 0.54 g (80%); off-white solid. Yield of two-
step process: 2.63 g (99%); off-white solid.
Mp 116.3–118.6 °C; Rf (TLC) = 0.32 (EtOAc–heptane, 2:3); tR (HPLC,
see general experimental conditions) = 8.95 min.
IR (neat, ATR): 3438 (w), 3323 (w), 3223 (w), 1627 (m), 1599 (w),
1562 (m), 1507 (m), 1482 (m), 1452 (m), 1326 (vs) cm–1
.
(5) Puello, J. Q.; Obando, B. I.; Foces-Foces, C.; Infantes, L.;
Claramunt, R. M.; Cabildo, P.; Jimenez, J. A.; Elguero, J. Tetrahe-
dron 1997, 53, 10783.
(6) Mitchell, D.; Yumei, L.; McNulty, L. M.; Buser, J. Y.; McFarland, A.
D. Synthesis 2015, 47, 235.
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B.; Damavarapub, R. Synthesis 2008, 699. (b) Sviridov, S. I.;
Vasil’ev, A. A.; Shorsnev, S. V. Tetrahedron 2007, 63, 12195.
(c) Alberola, A.; Antolin, L. F.; Gonzalez, A. M.; Laguna, M. A.;
Pulido, F. J. J. Heterocycl. Chem. 1986, 23, 1035.
1H NMR (400 MHz, DMSO-d6): δ = 8.08 (s, 1 H), 8.05 (m, 1 H), 7.70–
7.61 (m, 4 H), 7.53 (t, J = 7.6 Hz, 2 H), 7.37 (t, J = 7.6 Hz, 1 H), 6.06 (s, 1
H), 5.55 (br s, 2 H).
13C NMR (100 MHz, DMSO-d6): δ = 148.5, 148.5, 139.0, 134.6, 129.6,
129.3 (q, JCF = 31.6 Hz, 1 C), 129.1 (2 C), 128.9, 126.5, 124.2 (q,
JCF = 271.2 Hz, 1 C), 123.8 (q, JCF = 3.8 Hz, 1 C), 123.1 (2 C), 120.9 (q,
JCF = 3.8 Hz, 1 C), 87.2.
19F NMR (376 MHz, DMSO-d6): δ = –61.3.
HRMS: m/z [M + H]+ calcd for C16H13N3F3: 304.1056; found: 304.1049.
(8) (a) Bell, F. J. Chem. Soc. 1941, 285. (b) Donati, D.; Fusi, S.;
Ponticelli, F. J. Heterocycl. Chem. 1998, 35, 109.
(9) (a) Foley, D. A.; Doecke, C. W.; Buser, J. Y.; Merritt, J. M.;
Murphy, L.; Kissane, M.; Collins, S. G.; Maguire, A. R.; Kaerner, A.
J. Org. Chem. 2011, 76, 9630. (b) Magnus, N. A.; Astleford, B. A.;
Laird, D. L. T.; Maloney, T. D.; McFarland, A. D.; Rizzo, J. R.;
Ruble, J. C.; Stephenson, G. A.; Wepsiec, J. P. J. Org. Chem. 2013,
78, 5768. (c) Buser, J. Y.; McFarland, A. D. Chem. Commun. 2014,
50, 4234.
Acknowledgment
We thank Mr. James Aikins for valuable discussions during the re-
search effort. Support from the Small Molecule Design and Develop-
ment analytical group is acknowledged.
(10) Checchi, S.; Pecori Vettori, L.; Vincieri, F. Gazz. Chim. Ital. 1968,
98, 1488.
Supporting Information
(11) (a) Suryakiran, N.; Reddy, T. S.; Latha, K. A.; Prabhakar, P.;
Yadagiri, K.; Venkateswarlu, Y. J. Mol. Catal. A: Chem. 2006, 258,
371. (b) Moe, S. T.; Thompson, A. B.; Smith, G. M.; Fredenburg,
R. A.; Stein, R. L.; Jacobson, A. R. Bioorg. Med. Chem. 2009, 17,
3072.
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1561861.
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References
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(1) Current address: Butler University, Department of Chemistry,
4600 Sunset Avenue, Indianapolis, IN 46208, USA.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G