Regioselective Synthesis, NMR, and Crystallographic Analysis of N1-Substituted Pyrazoles

Article abstract of DOI:10.1021/acs.joc.7b01006

A systematic study of the N-substitution reactions of 3-substituted pyrazoles under basic conditions has been undertaken. Regioselective N1-alkylation, -arylation, and -heteroarylation of 3-substituted pyrazoles have been achieved using K₂CO₃-DMSO. The regioselectivity is justified by the DFT calculations at the B3LYP/6-31G??(d) level. A consistent steric effect on chemical shift has been observed for N-alkyl pyrazole analogues. Twenty-five X-ray crystallographic structures have been obtained to confirm the regiochemistry of the major products.

Full text of DOI:10.1021/acs.joc.7b01006

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Article
Regioselective Synthesis, NMR, and Crystallographic
Analysis of N1-Substituted Pyrazoles
Adrian Huang, Kellie Wo, So Yeun Christine Lee, Nika Kneitschel, Jennifer Chang,
Kathleen Zhu, Tatsiana Mello, Laura Bancroft, Natalie Norman, and Shao-Liang Zheng
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01006 • Publication Date (Web): 18 Jul 2017
Downloaded from http://pubs.acs.org on July 18, 2017
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Regioselective Synthesis, NMR, and Crystallographic Analysis of N1-Substituted Pyrazoles
Adrian Huang,*,† Kellie Wo,† So Yeun Christine Lee,† Nika Kneitschel,† Jennifer Chang,† Kathleen Zhu,†
Tatsiana Mello,† Laura Bancroft,† Natalie Norman,† and ShaoꢀLiang Zheng‡
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†Department of Chemistry, Wellesley College, 106 Central Street, Wellesley, MA 02481; Email:
ahuang2@wellesley.edu
‡Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford St., Bauer B06
Cambridge, MA 02138
Abstract: A systematic study of the Nꢀsubstitution reactions of 3ꢀsubstituted pyrazoles under basic
conditions has been undertaken. Regioselective N1ꢀalkylation, ꢀarylation, and ꢀheteroarylation of 3ꢀ
substituted pyrazoles have been achieved using K2CO3ꢀDMSO. The regioselectivity is justified by the
DFT calculations at the B3LYP/6ꢀ31G**(d) level. A consistent steric effect on chemical shift has been
observed for Nꢀalkyl pyrazole analogs. 25 Xꢀray crystallographic structures have been obtained to
confirm the regiochemistry of the major products.
Introduction
Pyrazole derivatives have received increasing attention in chemical,1 agrochemical,2
pharmaceutical,3 and material science.4 NꢀSubstituted pyrazoles are of particular interest in medicinal
chemistry. For example, the nonꢀsteroidal antiꢀinflammatory drugs (NSAID) Celecoxib5 and Lonazolac6
as well as CRF1 receptor antagonist GW8760087 are Nꢀsubstituted pyrazoles (Figure 1). Recently, Nꢀ
substituted pyrazoles have been reported to possess inhibitory activities against various biological targets,
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such as PDE4,8 CCR2,9 cꢀMet protein kinase,10 and ALK5.11 Notably, the aminopyrazole derivative
AZD1152 has been clinically evaluated as an anticancer agent.12
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Figure 1. Representative Examples of Medicinally Important NꢀSubstituted Pyrazoles and Our Target
As part of a drug discovery project, we required N1ꢀsubstitutedꢀ3ꢀnitropyrazoles as key
intermediates to access 3ꢀaminopyrazoles and other synthetically challenging 3ꢀsubstituted pyrazoles
(Figure 1). Nꢀsubstituted pyrazoles are commonly prepared via condensation reactions of monosubstituted
hydrazines and 1, 3ꢀdielectrophiles (Scheme 1, Path A).13 However, this approach has major
shortcomings: (i) preparation of the intermediates for the condensation reactions can be lengthy and
challenging; (ii) requirement for early installation of the Nꢀsubstituents, which limits the diversity of the
Nꢀsubstitutions on the pyrazole ring; (iii) the pyrazoles obtained from these methods are often a mixture
of two regioisomers 1 and 2; and (iv) the distribution of these two regioisomers is generally
unpredictable.
Scheme 1. Methods to Prepare NꢀSubstituted Pyrazoles
As a result of these shortcomings and the difficulty to access 1, 3ꢀdielectrophiles containing a
nitro group, we believed the Nꢀsubstitution reaction of 1Hꢀpyrazoles (Scheme 1, Path B) would be a
better route to prepare our target than Path A. Path B has been occasionally investigated to prepare Nꢀ
substituted pyrazoles in the literature. In 2004, Buchwald and colleagues developed diamine ligands for
the Ullmannꢀtype reactions for Nꢀarylation of common nitrogen heterocycles with aryl halides.14 Three
unsymmetric 1Hꢀpyrazoles were reported, and “the less hindered nitrogen was selectively arylated” to
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give the corresponding N1 regioisomers. You and colleagues further modified the procedure by
developing ligandꢀfree procedures for several similar Ullmannꢀtype reactions.15 Only one unsymmetric
1Hꢀpyrazole, 3ꢀmethylpyrazole, was reported to react with iodobenzene. A mixture of the two
regioisomers was observed with the less hindered N1 isomer as the major product (3:1 ratio, 85% yield).
The authors agreed with Buchwald that steric hindrance was responsible for the regioselectivity observed.
Pyrazoles, as electronꢀrich heterocycles, readily participate in nucleophilic substitution reactions.
NꢀSubstitution of pyrazoles are usually carried out under basic conditions to prevent quaternization and
protonation of pyrazoles by alkyl halides (R4ꢀX) and XꢀH.16,17 However, when secondary halides are
employed as electrophiles, elimination and rearrangement of the halides predominate, which explains why
current methods are generally limited to primary halides and aromatic halides. Other conditions, such as
solventꢀfree,16 phase transfer,18 and microwave irradiation,19 have been explored to reduce side reactions.
However, these protocols require elevated temperatures and give low to moderate yields with low
regioselectivity.
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The current literature provides few examples on the Nꢀsubstitution reactions of pyrazoles,
including Nꢀalkylation20 and Nꢀarylation.21 Further, thorough regioselectivity studies are nonꢀexistent.
Therefore, studies of Nꢀsubstitution reactions of 1Hꢀpyrazoles represent a gap in synthetic organic
chemistry literature.
Given our need to prepare a series of pyrazole intermediates, we were motivated to develop a
simple and robust method for the synthesis of these derivatives in a regiocontrolled fashion. We reasoned
that, if the pyrazolate anion could be made nucleophilic enough, facile Nꢀsubstitution might proceed at
low temperature thereby providing both high regioselectivity and yield. To test our hypothesis, the wellꢀ
known “superbasic media”,22, 23 a mixture of an alkali metal base and DMSO, was employed. As an
excellent metalꢀcoordinating solvent, DMSO weakens the electrostatic interactions between metal cations
and the anions, thereby making not only alkali metal base more basic, but also the resulting pyrazolate
anion more nucleophilic. Our studies toward this end are described herein.
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Results and Discussion
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1. Synthesis. Commercially available 3ꢀnitropyrazole was selected as the first pyrazole to test our
hypothesis because the nitro moiety can be readily converted to amines and many other functional groups.
Thus, 3ꢀnitropyrazole was treated with benzyl bromide at room temperature in order to examine a variety
of bases (Scheme 2 and Table S1). The use of Na2CO3, NaHCO3, NaOH, and Et3N gave 0ꢀ10%
conversions, and no reaction occurred in the absence of base. Among the bases screened, KOH, K2CO3,
and Cs2CO3 proved to be effective, affording high conversion (>95%) and good regioselectivity
(4:5=10:1). These results could be explained by the fact that DMSO solvates larger alkali metal cations
(e.g., K+ and Cs+) better than the smaller ones (e.g., Na+).24 The nature of the solvent was critical, and
DMSO afforded the best results as expected, whereas CH2Cl2 and THF were ineffective. For the reaction
carried out in K2CO3ꢀDMSO, the two regioisomeric products were separable via column
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chromatography.25 An Xꢀray crystallography of the major product unambiguously reveals it is the N1
pyrazole (See Supporting Information). Considering its high efficiency, good regioselectivity, low cost,
and nonꢀhygroscopic property, K2CO3 was chosen as the base for further experimentation.
Scheme 2. Optimization of Reaction Conditions for NꢀBenzylation of 3ꢀNitropyrazole (See Table S1)
Under the above optimized conditions shown in Scheme 2, the scope of the Nꢀsubstitution of 3ꢀ
nitropyrazole was evaluated. A series of alkyl electrophiles were first selected and the results are
summarized in Table 1. It appears that the more reactive (Entries 1 vs 2) and the less steric hindered
electrophiles (Entries 6 vs 7), the higher the yield and the regioselectivity. In addition, the secondary
halide substrates decreased the reaction rates, which suggests that the reactions exhibit SN2 character in
their mechanisms.
It is worth pointing out that bromocyclohexane and phenethyl halides, notorious for their low
yields due to elimination under literature reported conditions,17 afford the alkylated products in moderate
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Table 1. Substrate Scope of NꢀSubstitution Reactions of 3ꢀNitropyrazolea
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Entry
RꢀX
N1 Isomeric Product
Yieldb (%) (Ratio 6:7)c
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1
2
BnꢀBr
4
91 (10:1)
BzCH2ꢀBr
6a
92 (>20:1)
94 (>20:1)
3
pꢀCH3ꢀBzCH2ꢀBr
6b
4
5
6
pꢀCF3ꢀBzCH2ꢀBr
6c
6d
6e
91 (>20:1)
90 (8:1)
PhCH=CHCH2ꢀ
Br
PropylꢀI
84 (7:1)
7
iꢀPropylꢀI
6f
64 (5:1)
8
9
CyclohexylꢀCl
CyclohexylꢀBr
CyclohexylꢀI
<5d (n/ae)
67d (3:1)
28d (3:1)
6g
10
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13
PhCH2CH2ꢀBr
pꢀNO2ꢀPhꢀF
oꢀNO2ꢀPhꢀF
6h
8a
8b
87 (9:1)
93 (>99:1)
92d (>99:1)
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17
pꢀCNꢀPhꢀF
oꢀCNꢀPhꢀF
8c
8d
8e
8f
94 (>99:1)
92d (>99:1)
86 (>99:1)
95 (>99:1)
pꢀCO2EtꢀPhꢀF
pꢀSO2CH3ꢀPhꢀF
5ꢀNO2ꢀ2ꢀFꢀ
pyridine
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19
20
9a
9b
9c
96 (>99:1)
94 (>99:1)
93 (>99:1)
2ꢀNO2ꢀ3ꢀFꢀ
pyridine
5ꢀCNꢀ2ꢀFꢀ
pyridine
6ꢀCNꢀ3ꢀFꢀ
pyridine
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22
23
24
9d
9e
9f
91 (>99:1)
95 (>99:1)
90 (>99:1)
94 (>99:1)
5ꢀBrꢀ2ꢀFꢀ
pyridine
2ꢀFꢀ4ꢀIꢀpyridine
5ꢀBrꢀ2ꢀFꢀ
pyrimidine
9g
a Reaction conditions: 3ꢀNitropyrazole (1.83 mmol), K2CO3 (2.20 mmol), electrophile (1.98 mmol), and DMSO (5 mL).
b Total isolated yield of N1and N2 regioisomers.
c Based on GC/MS analysis of the reaction mixture.
d Reaction time was 2 days. Approximate 60% of iodocyclohexane underwent elimination based on NMR studies of the reaction
mixture.
e n/a = Not Applicable.
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yield and regioselectivity (Entries 9 and 11, respectively). The improved results are likely attributed to the
mild reaction conditions employed. The “superbasic media”, such as the K2CO3ꢀDMSO system in the
present study, facilitated the deprotonation of pyrazoles and increased the reactivity of the resulting
nucleophile, which allowed the alkylation to occur at room temperature and therefore reduced alkyl halide
elimination.
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Using the same conditions, aryl fluorides were also successfully employed as electrophiles.
Electronꢀwithdrawing groups in the ortho or para position activated the reactions via an assumed SNAr
mechanism (Entries 12 to 17), whereas substituents in the meta position failed to promote any reaction. 1ꢀ
Chloroꢀ4ꢀfluorobenzene was not reactive enough to yield any product. As for pyridines, the reactions took
place more readily although the reaction with 2ꢀfluoropyridine did not occur. Other πꢀdeficient aromatic
heterocyclics, such as 5ꢀbromoꢀ2ꢀfluoropyrimidine, underwent an SNAr reaction at the electron deficient
2ꢀposition (Entry 24).
The above N1ꢀsubstituted 3ꢀnitropyrazoles are valuable precursors to various 3ꢀsubstituted
pyrazoles through established reactions. For instance, hydrogenation of 8f went smoothly to provide 3ꢀ
aminopyrazole 8f-1 in 95% yield (Scheme 3). Of note, the analogs of 8f-1 have been prepared via either
Pdꢀcatalyzed aminations26 or an SNAr reaction21 of 3ꢀaminoꢀ1Hꢀpyrazoles, but the ratios of N1:N2
products range from 2:1 to 5:1. On the other hand, nitration of Nꢀsubstituted pyrazoles usually yielded 4ꢀ
nitropyrazoles.27,28 Thus, our method represents an efficient alternative route to 3ꢀaminopyrazoles.
Scheme 3. Reduction of Nitro 8f to Amine 8f-1
The regiochemistry of all the products listed in Table 1 was elucidated either by Xꢀray
crystallographic or NMRꢀnOe studies. Calculations were carried out to explain the regioselectivity. The
density functional theory (DFT) calculations at the B3LYP/6ꢀ31G**(d) level show that the N1 atom
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possesses a higher negative charge than the N2 in 10A and 10B (Table 2, entry 1). Therefore, N1 atom is
more nucleophilic than N2 and generally the N1 regioisomers are expected to be the major products.
When a primary alkyl halide is employed in the substitution step, the regioselectivity increases in order of
the bulkiness of the electrophile: αꢀbromoacetophenones (20:1) > benzyl bromide (10:1) > phenethyl
bromide (9:1) > allylic bromide (8:1) > iodopropane (7:1). This trend suggests that the substitution
reaction is the rateꢀdetermining step and exhibits SN2 character in the mechanism. For reactions with
secondary alkyl halides, the substitution reaction likely proceeds via both SN1 and SN2 mechanisms and
the products’ isomeric ratio N1:N2 decreased. As for Nꢀarylation, the bulky ArꢀF provides additional
preference of N1 over N2 and only the N1 regioisomers were observed.
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Table 2. DFT Calculations at B3LYP/6ꢀ31G**(d) Level of 3ꢀSubstituted 1HꢀPyrazolate Anions
Charge
Entry
1
R1
Anion
10A
Energya
N1
N2
N1ꢀN2
ꢀ430.1817
ꢀ430.1817
0
ꢀ0.27
ꢀ0.28
ꢀ0.16
ꢀ0.16
ꢀ0.11
ꢀ0.12
ꢀNO2
10B
10Bꢀ10A
10A
ꢀ492.8618
ꢀ492.8610
0.49
ꢀ0.26
ꢀ0.25
ꢀ0.23
ꢀ0.18
ꢀ0.03
ꢀ0.07
2
3
4
ꢀCO2Et
ꢀCF3
10B
10Bꢀ10A
10A
ꢀ562.7201
ꢀ562.7207
ꢀ0.34
ꢀ0.29
ꢀ0.36
ꢀ0.17
ꢀ0.10
ꢀ0.12
ꢀ0.26
10B
10Bꢀ10A
10A
ꢀ264.9559
ꢀ264.9554
0.26
ꢀ0.41
ꢀ0.37
ꢀ0.11
ꢀ0.15
ꢀ0.30
ꢀ0.22
ꢀCH3
10B
10Bꢀ10A
a Energies are given in Hartree, and relative energies are in kcal/mol.
Likewise, the calculation results can help to explain the regiochemistry of the Nꢀbenzylation of
other 3ꢀsubstituted pyrazoles. For instance, optimization for the 3ꢀCO2Et pyrazolate anions indicates the
N1 and N2 atoms have similar nucleophilicity and therefore the regioselectivity is expected to be low
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(Table 2, entry 2), which is consistent with the experimental observations (2:1, Table 3, entry 1). The
dramatic change in regioselectivity between the 3ꢀnitro and 3ꢀester pyrazoles suggests the electronic
effect of R1 plays the major role in regioselectivity when the R1 groups are similar in size (Aꢀvalues: ꢀNO2
= 1.1 vs ꢀCO2Et = 1.2 kcal/mol). Nonetheless, the steric effect of R1 does have a great influence on the
regioselectivity (Table 3, Entries 2 vs 3). It is noteworthy that the different effect of the methyl and
trifluoromethyl groups on the calculated properties of pyrazoles have been discussed in previous
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papers.29,30
Table 3. NꢀSubstitution Reaction of 3ꢀR1ꢀ1HꢀPyrazolea
Entry R1
R2ꢀX
N1 Isomeric Product
12a
Yieldb (%) (12:13)c
1
ꢀCO2Et
92(2:1)
2
3
4
ꢀCF3
ꢀCH3
ꢀNO2
12b
12c
4
92(10:1)
95(2:1)d
91(10:1)
5
ꢀCH3
12d
96(4:1)
6
7
8
ꢀCF3
ꢀCO2Et
ꢀBr
12e
12f
95(>99:1
92(>99:1
94(>99:1
)
)
)
(F-Ph-p-NO2)
12g
9
ꢀPh
12h
92(>99:1
)
a Reaction conditions: Pyrazole 11 (1.83 mmol), R2ꢀX (1.98 mmol), K2CO3 (2.20 mmol), and DMSO (5 mL).
b Total isolated yield of N1and N2 regioisomers.
c Based on GC/MS and NMR studies of the reaction mixture.
d Experimental results are consistent with those in ref 16.
2. NMR Studies. By correlating the regiochemistry resolved by Xꢀray crystallography/nOe with the 1H
NMR spectra, it was found that all of the N2ꢀCHn proton(s) are more deshielded than the corresponding
N1ꢀCHn. Moreover, it appears that the bulkier the R2 group or the R1, the greater the difference of the
chemical shift (δ2ꢀδ1, Table 4) of the NꢀCHn proton(s). This consistent difference could be attributed to a
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migration of the electron density from the sterically compressed proton(s) in N2ꢀCHn to its neighboring
atoms. Literature examples indicated that the same phenomena also exist for most of the Nꢀalkyl
pyrazoles 16,31,32,33 with few exceptions31,34 although all of these regioisomers were assigned tentatively
due to lack of the Xꢀray structures. Nonetheless, the data listed in Table 4 show the steric effect on
chemical shift and can serve as a supplementary reference for a quick regiochemical assignment of Nꢀ
alkyl pyrazole analogs.
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Table 4. 1H NMR Chemical Shift (δ) in CDCl3 of Representative N1ꢀ and N2ꢀAlkyl Pyrazoles
N1 Pyrazole
Compound
N2 Pyrazole
Compound
R1
R2
δ1
δ2
δ2ꢀδ1
iꢀPropyl
6f
4.58
4.19
7f
5.44
5.03
0.86
0.84
NO2
Cyclohexyl
Bn
6g
7g
4
5.37
5.39
5.35
5.24
5
5.79
5.78
5.43
5.29
0.42
0.39
0.08
0.05
CO2Et
CF3
12a
12b
12c16
13a
13b
13c16
Bn
CH3
3. X-Ray Crystallographic Analysis. To confirm the regiochemistry of the above N1ꢀsubstituted
pyrazoles, Xꢀray crystallographic structures of 25 products were obtained at 100 K. In Tables S2 and S3
are gathered the selected geometry data. For example purposes, a short version of Table S2 is included
here (Table 5), and the ORTEP plot of compound 8a is shown in Figure 2. Compound 8a crystallizes
into an orthorhombic crystal system.
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Table 5. Selected Bond Lengths (Å) and Angles (°) of 3ꢀNitropyrazoles
C4 C5
7
8
C3
N1
O2N
N2
C1'
C2'
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Compound
N1ꢀN2
N2ꢀC3
C3ꢀC4
C4ꢀC5
C5ꢀN1
N2ꢀN1ꢀC1'ꢀC2'
1.344 (5) 1.325 (5)
1.355 (2) 1.324 (3)
1.391 (7)
1.394 (3)
1.364 (6)
1.361 (3)
1.345 (4)
n/a
1H-Pyrazolea
8a
1.369 (3)
ꢀ0.9 (3)
8b
9a
9g
1.352 (2) 1.327 (2)
1.354 (4) 1.327 (5)
1.353 (2) 1.319 (2)
1.394 (3)
1.402 (5)
1.403 (3)
1.362 (3)
1.361 (5)
1.364 (3)
1.364 (2)
1.370 (4)
1.375 (2)
42.4 (2)
−1.4 (5)
16.4 (2)
a Data are taken from ref 35 and 36.
In light of the data in Tables S2 and S3, some key points are worth mentioning. For the N1ꢀaryl analogs,
moving the substituents from para/meta to ortho position leads to an increase of the dihedral angle (N2ꢀ
N1ꢀC1'ꢀC2') from 0.8ꢀ16.4° to ca. 40°, i.e., the pyrazole and the aryl rings are no longer coplanar (e.g.,
Figure 2, 8b vs 8a). In the N1ꢀpyridyl analogs, the nitrogen in the pyridyl ring is anti to the N2 atom in
the pyrazole ring presumably due to their electronic repulsion (e.g., 9a). The same repulsive effect could
be used to explain why the oꢀNO2 group is also preferred to be anti to the N2 atom in compound 8b. On
the contrary, the linear geometry of the oꢀCN group permits a possible attraction between the nitrile group
and the N2 atom in the pyrazole, resulting in a close contact between these two moieties (8d, a = 2.84 Å;
b = 3.30 Å).
8a
8b
9a
8d
Figure 2. Representative XꢀRay Structures of Pyrazoles: 8a, 8b, 9a, and 8d
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Conclusions
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In conclusion, a simple and regioselective reaction protocol has been established to functionalize
the pyrazole rings at the N1 position in good to excellent yields. The resulting functionalized pyrazoles
are useful in synthesis, e.g., N1ꢀsubstituted 3ꢀnitropyrazoles can be employed to prepare the analogs of
GW876008 (Figure 1). Our method also allows chemists to readily access other pyrazoles which are
difficult to prepare via traditional cycloaddition procedures (e.g., Nꢀcycloalkylpyrazole 6g). DFT
calculations at the B3LYP/6ꢀ31G**(d) level are helpful to explain the electronic effect of the C3
substituents plays an important role in the regiochemistry. Furthermore, a quick method for determining
product distribution by 1H NMR for 3ꢀsubstituted pyrazoles has been developed. Lastly, the obtained Xꢀ
ray crystal structures of the 25 new products will serve as a reliable source for theoretical studies of
pyrazole.
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The construction of functionalized heterocycles constitutes one of the most fundamental and
important endeavors in chemical synthesis. We believe this work will find reasonable application among
synthetic, medicinal, and physical organic chemists.
Experimental Section
General Methods. Reactions were run using commercially available starting materials and
anhydrous solvents without further purification unless otherwise stated. Melting points (°C) are
uncorrected. Highꢀresolution mass spectra (HRMS) were obtained by using electrospray ionization (ESI)
in the positive mode.
Theoretical Calculations. All the DFT calculations were carried out at the B3LYP/6ꢀ31G**(d)
level using Gaussian09.37 Charge is set to ꢀ1, and Spin to Singlet.
X-Ray Crystallography. A crystal mounted on a diffractometer was collected data at 100 K.
The intensities of the reflections were collected by means of a diffractometer (CuKα radiation, λ=1.54178
Å), and equipped with a nitrogen flow apparatus. The collection method involved 1.0° scans in
ω at 30°,
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55°, 80°, and 115° in 2
θ
. Data integration down to 0.84 Å resolution was carried out with reflection spot
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size optimization. Absorption corrections were made. The structure was solved by the direct methods
procedure and refined by leastꢀsquares methods again F2. Nonꢀhydrogen atoms were refined
anisotropically, and hydrogen atoms were allowed to ride on the respective atoms.
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General Procedure for the N-Substitution Reaction of 3-nitropyrazole with Alkyl, Aryl and
Heteroaryl Electrophiles. 3ꢀNitropyrazole (207 mg, 1.83 mmol, 1.0 equiv), potassium carbonate (303.6
mg, 2.20 mmol, 1.2 equiv), electrophile (1.98 mmol, 1.1 equiv), and a stirring bar were placed in a vial.
At 0 °C, 5 mL of DMSO was added. The resulting mixture was slowly warmed to room temperature and
stirred at this temperature for 24 h. The reaction was quenched with iced water (10 mL). The resulting
mixture was extracted with ethyl acetate (15 mL x 2). The combined organic layers were washed with
brine (20 mL), dried over MgSO4, and evaporated to give the crude product, which was purified via
column chromatography (silica gel, eluting with 0ꢀ100% of EtOAc in hexane) to provide the desired
product. All the compounds shown in Tables 1 and 3 were prepared according to this procedure.
1-Benzyl-3-nitro-1H-pyrazole (4). Obtained as a white solid (308 mg, 83%), which was
recrystallized from a mixture of EA and hexanes as fine colorless needles of m. p. 63ꢀ64 °C. The xꢀray
structure of this compound was obtained. 1H NMR (CDCl3, 300 MHz) δ 7.28ꢀ7.41 (m, 6H), 6.90 (d, J =
2.4 Hz, 1H), 5.37 (s, 2H); 13C NMR (CDCl3, 75.5 MHz) δ 155.7, 134.3, 132.3, 129.1, 128.8, 128.1, 103.4,
57.5; HRMS (ESI+) calcd for C10H9N3O2 ([M+H]+) 204.0773; found 204.0777.
2-Benzyl-3-nitro-1H-pyrazole (5). Obtained as a colorless oil (15 mg, 4%). 1H NMR (CDCl3,
500 MHz) δ 7.58 (d, J = 2.5 Hz, 1H), 7.26ꢀ7.33 (m, 6H), 7.08 (d, J = 2.5 Hz, 1H), 5.79 (s, 2H); 13C NMR
(CDCl3, 125.8 MHz) δ 145.5, 138.2, 135.2, 128.8, 128.4, 127.7, 107.2, 56.4; HRMS (ESI+) calcd for
C10H9N3O2 ([M+H]+) 204.0773; found 204.0771.
2-(3-Nitro-1H-pyrazol-1-yl)-1-phenylethan-1-one (6a). Obtained as a white solid (391 mg,
92%), which was recrystallized from a mixture of EA and hexanes as colorless needles of m. p. 118ꢀ120
°C. The xꢀray structure of this compound was obtained. 1H NMR (CDCl3, 300 MHz) δ 7.47 (d, J = 6.0
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Hz, 2H), 7.55ꢀ7.69 (m, 4H), 7.00 (d, J = 0.1 Hz, 1H), 5.72 (s, 2H); 13C NMR (CDCl3, 75.5 MHz) δ 190.6,
156.1, 134.7, 134.3, 133.7, 129.2, 128.0, 103.5, 58.9; HRMS (ESI+) calcd for C11H10N3O3 ([M+H]+)
232.0722; found 232.0725.
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2-(3-Nitro-1H-pyrazol-1-yl)-1-(p-tolyl)ethan-1-one (6b). Obtained as a light yellow solid (422
mg, 94%), which was recrystallized from a mixture of EA and hexanes as white needles of m. p. 165ꢀ166
°C. The xꢀray structure of this compound was obtained. 1H NMR (DMSOꢀd6, 300 MHz) δ 8.02 (d, J = 2.4
Hz, 1H), 7.95 (d, J = 8.4 Hz, 2H), 7.42 (d, J = 8.4 Hz, 2H), 7.14 (d, J = 2.4 Hz, 1H), 6.05 (s, 2H), 2.42 (s,
3H); 13C NMR (DMSOꢀd6, 75.5 MHz) δ 191.7, 155.2, 144.8, 135.8, 131.5, 129.4, 128.1, 102.9, 59.1,
21.2; HRMS (ESI+) calcd for C12H12N3O3 ([M+H]+) 246.0879; found 246.0878.
2-(3-Nitro-1H-pyrazol-1-yl)-1-(4-(trifluoromethyl)phenyl)ethan-1-one (6c). Obtained as a
light yellow solid (498 mg, 91%), which was recrystallized from a mixture of EA and hexanes as white
needles of m. p. 120ꢀ121 °C. The xꢀray structure of this compound was obtained. 1H NMR (CDCl3, 300
MHz) δ 8.08 (d, J = 7.5 Hz, 2H), 7.80 (d, J = 7.5 Hz, 2H), 7.61(d, J = 1.0 Hz, 1H), 7.00 (d, J = 1.0 Hz,
1H), 5.76 (s, 2H); 13C NMR (CDCl3, 75.5 MHz) δ 189.9, 156.3, 136.4, 135.7 (q, J = 33.1 Hz), 134.3,
128.5, 126.3 (q, J = 3.8 Hz), 123.3 (q, J = 272.6 Hz), 103.7, 59.0; 19F NMR (CDCl3, 470 MHz) δ ꢀ63.4
(s); HRMS (ESI+) calcd for C12H9F3N3O3 ([M+H]+) 300.0596; found 300.0594.
1-Cinnamyl-3-nitro-1H-pyrazole (6d). Obtained as a light yellow solid (337 mg, 80%), which
was recrystallized from a mixture of EA and hexanes as colorless needles of m. p. 71ꢀ72 °C. The xꢀray
structure of this compound was obtained. 1H NMR (CDCl3, 300 MHz) δ 7.54 (d, J = 0.1 Hz, 1H), 7.26ꢀ
7.37 (m, 5H), 6.91 (d, J = 0.1 Hz, 1H), 6.68 (d, J = 15.6 Hz, 1H), 6.30ꢀ6.39 (m, 1H), 4.96ꢀ4.50 (m, 1H),;
13C NMR (CDCl3, 75.5 MHz) δ 155.8, 136.0, 135.3, 131.6, 128.8, 128.7, 126.8, 121.3 103.3, 55.8; HRMS
(ESI+) calcd for C12H12N3O2 ([M+H]+) 230.0930; found 230.0931.
2-Cinnamyl-3-nitro-1H-pyrazole (7d). Obtained as a colorless oil (42 mg, 10%). 1H NMR
(CDCl3, 500 MHz) δ 7.56 (d, J = 2.0 Hz, 1H), 7.26ꢀ7.37 (m, 5H), 7.09 (d, J = 2.0 Hz, 1H), 6.63 (d, J =
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16.0 Hz, 1H), 6.35 (dd, J = 16.0, 6.5 Hz, 1H), 5.37 (d, J = 6.5 Hz, 2H); 13C NMR (CDCl3, 125.8 MHz) δ
145.6, 138.2, 135.8, 134.8, 128.6, 128.3, 126.7, 122.2, 106.9, 55.1; HRMS (ESI+) calcd for C12H12N3O2
([M+H]+) 230.0930; found 230.0934.
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3-Nitro-1-propyl-1H-pyrazole (6e). Obtained as a colorless oil (181 mg, 64%). 1H NMR
(CDCl3, 300 MHz) δ 7.47 (d, J = 1.8 Hz, 1H), 6.90 (d, J = 1.8 Hz, 1H), 4.18 (t, J = 6.9 Hz, 2H), 1.92ꢀ2.00
(m, 2H), 0.95 (t, J = 7.5 Hz, 3H); 13C NMR (CDCl3, 75.5 MHz) δ 155.7, 132.0, 102.8, 55.5, 23.5, 10.9;
HRMS (ESI+) calcd for C6H10N3O2 ([M+H]+) 156.0773; found 156.0771.
3-Nitro-1-propyl-1H-pyrazole (7e). A less polar mixture of 6e and 7e (6e:7e = 7:1) was obtained
as a colorless oil (56 mg, 20%). By comparing the spectra of the mixture with those of the pure 6e, the
peaks which belong to 7e can be identified. 1H NMR (CDCl3, 500 MHz) δ 7.50 (d, J = 2.0 Hz, 1H), 7.05
(d, J = 2.0 Hz, 1H), 4.56 (t, J = 7.5 Hz, 2H), 1.93ꢀ1.98 (m, 2H), 0.95 (t, J = 7.5 Hz, 3H); 13C NMR
(CDCl3, 125.8 MHz) δ 137.7, 131.6, 106.7, 54.7, 23.4, 10.9.
1-Isopropyl-3-nitro-1H-pyrazole (6f). Obtained as a white solid (144 mg, 51%), which was
recrystallized from a mixture of EA and hexanes as fine colorless needles of m. p. 63−64 °C. The xꢀray
structure of this compound was obtained. 1H NMR (CDCl3, 300 MHz) δ 7.56 (d, J = 2.1 Hz, 1H), 6.90 (d,
J = 2.1 Hz, 1H), 4.59ꢀ4.64 (m, 1H), 1.58 (d, J = 6.6 Hz, 6H); 13C NMR (CDCl3, 75.5 MHz) δ 155.4,
129.4, 102.7, 56.0, 22.6; HRMS (ESI+) calcd for C6H10N3O2 ([M+H]+) 156.0773; found 156.0777.
2-Isopropyl-3-nitro-1H-pyrazole (7f). A less polar mixture of 7f and 6f (7f:6f = 1:10) was
obtained as a colorless oil (37 mg, 11%). By comparing the spectra of the mixture with those of the pure
6f, the peaks which belong to 7f can be identified. 1H NMR (CDCl3, 500 MHz) δ 7.51 (d, J = 2.0 Hz,
1H), 7.02 (d, J = 2.0 Hz, 1H), 5.44 (Septet, J = 6.5 Hz, 1H), 1.53 (d, J = 6.5 Hz, 6H); 13C NMR
(CDCl3, 125.8 MHz) δ 145.4, 137.6, 106.7, 53.8, 22.3.
1-Cyclohexyl-3-nitro-1H-pyrazole (6g). Obtained as a colorless oil (171 mg, 48%). 1H NMR
(CDCl3, 500 MHz) δ 7.49 (d, J = 2.5 Hz, 1H), 6.88 (d, J = 2.5 Hz, 1H), 4.16ꢀ4.22 (tt, J = 12.0, 4.0 Hz,
1H), 2.18ꢀ2.21 (m, 2H), 1.91ꢀ1.95 (m, 2H), 1.72ꢀ1.79 (m, 2H), 1.39ꢀ1.48 (m, 2H), 1.24ꢀ1.32 (m, 2H); 13C
NMR (CDCl3, 75.5 MHz) δ 155.3, 129.4, 102.5, 63.1, 33.1, 25.1, 25.0; HRMS (ESI+) calcd for
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C9H14N3O2 ([M+H]+) 196.1086; found 196.1089.
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2-Cyclohexyl-3-nitro-1H-pyrazole (7g). Obtained as a colorless oil (68 mg, 19%). 1H NMR
(CDCl3, 500 MHz) δ 7.51 (d, J = 2.5 Hz, 1H), 7.03 (d, J = 2.5 Hz, 1H), 5.00ꢀ5.06 (m, 1H), 2.05ꢀ2.07 (m,
2H), 1.87ꢀ1.95 (m, 3H), 1.74ꢀ1.76 (m, 1H), 1.42ꢀ1.50 (m, 2H), 1.24ꢀ1.32 (m, 2H); 13C NMR (CDCl3,
125.8 MHz) δ 145.5, 137.5, 106.6, 61.0, 32.8, 25.5, 25.2; HRMS (ESI+) calcd for C9H14N3O2 ([M+H]+)
196.1086; found 196.1085.
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3-Nitro-1-phenethyl-1H-pyrazole (6h). Obtained as a white solid (312 mg, 78%), which was
recrystallized from a mixture of EA and hexanes as colorless rods of m. p. 100−101 °C. The xꢀray
structure of this compound was obtained. 1H NMR (CDCl3, 300 MHz) δ 7.18ꢀ7.31 (m, 4H), 7.09 (dd, J =
6.0, 1.5 Hz, 2H), 6.78 (d, J = 2.4 Hz, 1H), 4.43 (t, J = 7.8 Hz, 2H), 3.21 (t, J = 7.8 Hz, 2H); 13C NMR
(CDCl3, 75.5 MHz) δ 155.8, 136.8, 132.5, 128.8, 128.6, 127.1, 102.6, 55.3, 36.4; HRMS (ESI+) calcd for
C11H12N3O2 ([M+H]+) 218.0930; found 218.0928.
3-Nitro-2-phenethyl-1H-pyrazole (7h). Obtained as a colorless oil (35 mg, 9%). 1H NMR
(CDCl3, 500 MHz) δ 7.51 (d, J = 2.0 Hz, 1H), 7.24ꢀ7.31 (m, 3H), 7.16ꢀ7.18 (m, 2H), 7.02 (d, J = 2.0 Hz,
1H), 4.83 (t, J = 7.5 Hz, 2H), 3.16 (t, J = 7.5 Hz, 2H); 13C NMR (CDCl3, 125.8 MHz) δ 145.8, 138.0,
138.9, 128.8, 128.7, 127.0, 106.7, 54.2, 36.6; HRMS (ESI+) calcd for C11H12N3O2 ([M+H]+) 218.0930;
found 218.0934.
3-Nitro-1-(4-nitrophenyl)-1H-pyrazole (8a). Obtained as a white solid (400 mg, 93%), which
was recrystallized from a mixture of EA and hexanes as colorless crystals of m. p. 164−165 °C. The Xꢀ
ray crystallographic data for this compound are provided in the Supporting Information. 1H NMR
(DMSOꢀd6, 300 MHz) δ 8.99 (d, J = 2.7 Hz, 1H), 8.43 (d, J = 8.7 Hz, 2H), 8.22 (d, J = 8.7 Hz, 2H), 7.44
(d, J = 2.7 Hz, 1H); 13C NMR (DMSOꢀd6, 75.5 MHz) δ 157.6, 146.8, 143.0, 133.2, 125.8, 120.4, 105.8;
HRMS (ESI+) calcd for C9H7N4O4 ([M+H]+) 235.0467; found 235.0466.
3-Nitro-1-(2-nitrophenyl)-1H-pyrazole (8b). Obtained as a white solid (395 mg, 92%), which
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was recrystallized from a mixture of EA and hexanes as white crytals of m. p. 101−102 °C. The Xꢀray
crystallographic data for this compound are provided in the Supporting Information. 1H NMR (CDCl3,
300 MHz) δ 8.09 (dd, J = 7.8, 1.2 Hz, 1H), 7.66ꢀ7.84 (m, 4H), 7.11 (d, J = 2.4 Hz, 1H); 13C NMR (CDCl3,
75.5 MHz) δ 157.6, 144.6, 134.1, 133.8, 132.4, 131.0, 128.1, 125.8, 104.2; HRMS (ESI+) calcd for
C9H7N4O4 ([M+H]+) 235.0467; found 235.0468.
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4-(3-Nitro-1H-pyrazol-1-yl)benzonitrile (8c). Obtained as a white solid (370 mg, 94%), which
was recrystallized from a mixture of EA and hexanes as fine colorless grainꢀlike crystals of m. p.
203−204 °C. The xꢀray structure of this compound was obtained. 1H NMR (CDCl3, 300 MHz) δ 8.11 (d, J
= 2.4 Hz, 1H), 7.95 (d, J = 8.4 Hz, 2H), 7.85 (d, J = 8.4 Hz, 2H), 7.18 (d, J = 2.4 Hz, 1H); 13C NMR
(DMSOꢀd6, 75.5 MHz) δ 157.0, 141.3, 134.1, 132.5, 119.9, 118.0, 110.7, 105.2; HRMS (ESI+) calcd for
C10H7N4O2 ([M+H]+) 215.0569; found 215.0566.
2-(3-Nitro-1H-pyrazol-1-yl)benzonitrile (8d). Obtained as a white solid (370 mg, 92%), which
was recrystallized from a mixture of EA and hexanes as fine colorless grainꢀlike crystals of m. p.
133−134 °C. The Xꢀray crystallographic data for this compound are provided in the Supporting
Information. 1H NMR (DMSOꢀd6, 300 MHz) δ 8.70 (d, J = 2.7 Hz, 1H), 8.15 (d, J = 7.5 Hz, 1H), 7.93ꢀ
8.00 (m, 2H), 7.74ꢀ7.80 (m, 1H), 7.44 (d, J = 2.7 Hz, 1H); 13C NMR (DMSOꢀd6, 75.5 MHz) δ 157.0,
140.0, 135.2, 134.8, 134.7, 130.0, 125.7, 115.7, 106.8, 104.4; HRMS (ESI+) calcd for C10H7N4O2
([M+H]+) 215.0569; found 215.0567.
Ethyl 4-(3-nitro-1H-pyrazol-1-yl)benzoate (8e). Obtained as a light yellow solid (412 mg,
86%), which was recrystallized from a mixture of EA and hexanes as colorless short needles of m. p.
159−160 °C. The xꢀray structure of this compound was obtained. 1H NMR (CDCl3, 300 MHz) δ 8.20 (d, J
= 8.7 Hz, 2H), 8.09 (d, J = 2.7 Hz, 1H), 7.85 (d, J = 8.7 Hz, 2H), 7.14 (d, J = 2.7 Hz, 1H), 4.42 (q, J = 7.2
Hz, 2H), 1.43 (t, J = 7.2 Hz, 3H); 13C NMR (DMSOꢀd6, 75.5 MHz) δ 165.2, 157.3, 141.9, 132.7, 131.2,
129.6, 119.7, 105.4, 61.4, 14.5; HRMS (ESI+) calcd for C12H12N3O4 ([M+H]+) 262.0828; found
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1-[4-(Methylsulfonyl)phenyl]-3-nitro-1H-pyrazole (8f). Obtained as a light yellow solid (466
mg, 95%), which was recrystallized from a mixture of EA and hexanes as rectangular crystals of m. p.
192−193 °C. The xꢀray structure of this compound was obtained. 1H NMR (DMSOꢀd6, 300 MHz) δ 8.96
(d, J = 2.7 Hz, 1H), 8.23 (d, J = 8.7 Hz, 2H), 8.15 (d, J = 8.7 Hz, 2H), 7.44 (d, J = 2.7 Hz, 1H), 3.32 (s,
3H); 13C NMR (DMSOꢀd6, 75.5 MHz) δ 157.5, 144.4, 142.1, 133.0, 129.4, 120.3, 105.6, 43.8; HRMS
(ESI+) calcd for C10H10N3O4S([M+H]+) 268.0392; found 268.0391.
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5-Nitro-2-(3-nitro-1H-pyrazol-1-yl)pyridine (9a). Obtained as a light yellow solid (412 mg,
96%), which was recrystallized from a mixture of EA and hexanes as colorless needles of m. p. 173−174
°C. The Xꢀray crystallographic data for this compound are provided in the Supporting Information. 1H
NMR (CDCl3, 300 MHz) δ 9.34 (d, J = 2.4 Hz, 1H), 8.70ꢀ8.75 (m, 2H), 8.31 (d, J = 9.0 Hz, 1H), 7.16 (d,
J = 3.0 Hz, 1H); 13C NMR (DMSOꢀd6, 75.5 MHz) δ 157.8, 152.2, 144.8, 143.7, 135.9, 132.0, 113.3,
105.6; HRMS (ESI+) calcd for C8H6N5O4 ([M+H]+) 236.0420; found 236.0418.
2-Nitro-3-(3-nitro-1H-pyrazol-1-yl)pyridine (9b). Obtained as a white solid (404 mg, 94%),
which was recrystallized from a mixture of EA and hexanes as colorless crystals of m. p. 130−131 °C.
The xꢀray structure of this compound was obtained. 1H NMR (CDCl3, 300 MHz) δ 8.70 (d, J = 4.5 Hz,
1H), 8.22 (d, J = 7.8 Hz, 1H), 7.82ꢀ7.84 (m, 2H), 7.15ꢀ7.16 (m, 1H); 13C NMR (DMSOꢀd6, 75.5 MHz) δ
157.7, 151.4, 149.6, 137.9, 136.2, 130.1, 127.5, 105.2; HRMS (ESI+) calcd for C8H6N5O4 ([M+H]+)
236.0420; found 236.0418.
6-(3-Nitro-1H-pyrazol-1-yl)nicotinonitrile (9c). Obtained as a light yellow solid (368 mg,
93%), which was recrystallized from a mixture of EA and hexanes as fine colorless needles of m. p.
185−186 °C. The xꢀray structure of this compound was obtained.1H NMR (CDCl3, 300 MHz) δ 8.78 (d, J
= 2.1 Hz, 1H), 8.71 (d, J = 2.7 Hz, 1H), 8.77 (d, J = 8.7 Hz, 1H), 8.20 (dd, J = 8.7, 2.1 Hz, 1H), 7.14 (d, J
= 2.7 Hz, 1H); 13C NMR (DMSOꢀd6, 75.5 MHz) δ 158.0, 152.9, 151.6, 144.4, 132.2, 116.7, 113.4, 109.0,
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105.8; HRMS (ESI+) calcd for C9H6N5O2 ([M+H]+) 216.0521; found 216.0520.
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5-(3-Nitro-1H-pyrazol-1-yl)picolinonitrile (9d). Obtained as a white solid (358 mg, 91%),
which was recrystallized from a mixture of EA and hexanes as colorless crystals of m. p. 147−148 °C.
The xꢀray structure of this compound was obtained. 1H NMR (CDCl3, 300 MHz) δ 9.16 (s, 1H), 8.35 (dd,
J = 9.3, 3.0 Hz, 1H), 8.15 (d, J = 2.4 Hz, 1H), 7.91 (d, J = 9.3 Hz, 1H), 7.23 (d, J = 2.4 Hz, 1H); 13C NMR
(DMSOꢀd6, 75.5 MHz) δ 157.8, 142.4, 137.3, 133.5, 131.6, 130.2, 128.2, 117.2, 105.7; HRMS (ESI+)
calcd for C9H6N5O2 ([M+H]+) 216.0521; found 216.0523.
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5-Bromo-2-(3-nitro-1H-pyrazol-1-yl)pyridine (9e). Obtained as a light yellow solid (466 mg,
95%), which was recrystallized from a mixture of EA and hexanes as white needles of m. p. 210−211 °C.
The xꢀray structure of this compound was obtained. 1H NMR (CDCl3, 300 MHz) δ 8.62 (d, J = 1.5 Hz,
1H), 8.53 (s, 1H), 8.03 (d, J = 0.9 Hz, 2H), 7.10 (d, J = 1.5 Hz, 1H); 13C NMR (DMSOꢀd6, 75.5 MHz) δ
156.9, 149.2, 148.3, 142.6, 130.9, 119.3, 114.6, 104.9; HRMS (ESI+) calcd for C8H6BrN4O2 ([M+H]+)
268.9674; found 268.9673.
4-Iodo-2-(3-nitro-1H-pyrazol-1-yl)pyridine (9f). Obtained as a light yellow solid (522 mg,
90%), which was recrystallized from a mixture of EA and hexanes as colorless rodꢀlike crystals of m. p.
238−239 °C. The xꢀray structure of this compound was obtained. 1H NMR (CDCl3, 300 MHz) δ 8.63 (s,
1H), 8.52 (d, J = 0.9 Hz, 1H), 8.12 (d, J = 6.3 Hz, 1H), 7.72 (d, J = 6.3 Hz, 1H), 7.09 (d, J = 0.9 Hz, 1H);
13C NMR (DMSOꢀd6, 75.5 MHz) δ 157.0, 149.0, 132.7, 131.1, 126.3, 121.3, 109.5, 104.8; HRMS (ESI+)
calcd for C8H6IN4O2 ([M+H]+) 316.9535; found 316.9534.
5-Bromo-2-(3-nitro-1H-pyrazol-1-yl)pyrimidine (9g). Obtained as a light yellow solid (464
mg, 94%), which was recrystallized from a mixture of EA and hexanes as colorless crystals of m. p.
224−225 °C. The xꢀray structure of this compound was obtained. 1H NMR (CDCl3, 300 MHz) δ 8.88 (s,
2H), 8.65 (d, J = 2.7 Hz, 1H), 7.12 (d, J = 2.7 Hz, 1H); 13C NMR (DMSOꢀd6, 75.5 MHz) δ 160.5, 158.1,
153.3, 133.6, 119.2, 105.4; HRMS (ESI+) calcd for C7H5BrN5O2 ([M+H]+) 269.9627; found 269.9624.
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1-(4-(Methylsulfonyl)phenyl)-1H-pyrazol-3-amine (8f-1). A mixture of 8f (20 mg, 0.075
mmol), Pd/C (10 wt%, 2 mg), and 5 mL ethanol was stirred under hydrogen balloon at 25 °C for 20 h.
The resulting mixture was filtrated through celite. The filtrate was concentrated to give a light yellow
solid, which was purified via column chromatography (silica gel, eluting with 0ꢀ100% of EtOAc in
hexane) to provide 8f-1 (17 mg, 95%) as a white solid. m. p. 185ꢀ186 °C. 1H NMR (CDCl3, 500 MHz) δ
7.96 (d, J = 9.0 Hz, 1H), 7.78 (d, J = 2.5 Hz, 1H), 7.74 (d, J = 9.0 Hz, 1H), 7.78 (d, J = 2.5 Hz, 1H), 5.94
(d, J = 2.5 Hz, 1H), 3.93 (bs, 2H), 3.07 (s, 3H); 13C NMR (CDCl3, 125.8 MHz) δ 156.8, 143.8, 135.8,
129.1, 128.0, 117.2, 98.4, 44.7; HRMS (ESI+) calcd for C10H12N3O2S([M+H]+) 238.0650; found
238.0651.
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Ethyl 1-benzyl-1H-pyrazole-3-carboxylate (12a). Obtained as a white solid (257 mg, 61%),
which was recrystallized from a mixture of EA and hexanes as colorless crystals of m. p. 44.5ꢀ45.5 °C.
1H NMR (CDCl3, 500 MHz) δ 7.22ꢀ7.36 (m, 6H), 6.82 (d, J = 2.5 Hz, 1H), 5.39 (s, 2H), 4.40 (q, J = 7.0
Hz, 2H), 1.39 (t, J = 7.0 Hz, 3H); 13C NMR (CDCl3, 125.8 MHz) δ 162.4, 143.6, 135.5, 130.5, 128.9,
128.4, 127.9, 109.5, 60.9, 56.8, 14.4; HRMS (ESI+) calcd for C13H15N2O2 ([M+H]+) 231.1134; found
231.1136.
Ethyl 1-benzyl-1H-pyrazole-5-carboxylate (13a). Obtained as a colorless oil (76 mg, 18%). 1H
NMR (CDCl3, 500 MHz) δ 7.54 (d, J = 2.0 Hz, 1H), 7.22ꢀ7.31 (m, 5H), 6.87 (d, J = 2.0 Hz, 1H), 5.78 (s,
2H), 4.30 (q, J = 7.0 Hz, 2H), 1.32 (t, J = 7.0 Hz, 3H); 13C NMR (CDCl3, 125.8 MHz) δ 159.7, 138.4,
137.2, 132.2, 128.2, 127.6, 127.5, 111.7, 61.0, 54.9, 14.2; HRMS (ESI+) calcd for C13H15N2O2 ([M+H]+)
231.1134; found 231.1137.
1-Benzyl-3-(trifluoromethyl)-1H-pyrazole (12b). Obtained as a colorless oil (294 mg, 71%). 1H
NMR (CDCl3, 500 MHz) δ 7.31ꢀ7.37 (m, 4H), 7.21ꢀ7.24 (m, 2H), 6.52 (d, J = 2.5 Hz, 1H), 5.33 (s, 2H);
13C NMR (CDCl3, 125.8 MHz) δ 142.4 (q, J = 38.1 Hz), 135.5, 130.6, 129.0, 128.6, 128.0, 121.4 (q, J =
268.3 Hz), 104.9, 56.6; 19F NMR (CDCl3, 470 MHz) δ ꢀ61.8 (s); HRMS (ESI+) calcd for C11H10F3N2
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([M+H]+) 227.0796; found 227.0794.
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1-Benzyl-5-(trifluoromethyl)-1H-pyrazole (13b). A more polar mixture of 12b and 13b
(12b:13b = 1.8:1) was obtained as a colorless oil (87 mg, 21%). By comparing the spectra of the mixture
with those of the pure 12b, the peaks which belong to 13b can be identified. 1H NMR (CDCl3, 500 MHz)
δ 7.56 (d, J = 1.5 Hz, 1H), 7.23ꢀ7.37 (m, 3H), 7.20ꢀ7.21 (m, 2H), 6.65 (d, J = 1.5 Hz, 1H), 5.43 (s, 2H);
13C NMR (CDCl3, 125.8 MHz) δ 138.9, 135.7, 132.0 (q, J = 39.1 Hz), 128.7, 128.1, 127.4, 120.2 (q, J =
268.3 Hz), 107.8, 54.7; 19F NMR (CDCl3, 470 MHz) δ ꢀ59.0 (s); HRMS (ESI+) calcd for C11H10F3N2
([M+H]+) 227.0796; found 227.0798.
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3-Methyl-1-(4-nitrophenyl)-1H-pyrazole (12d). Obtained as a white solid (237 mg, 64%),
which was recrystallized from a mixture of EA and hexanes as colorless crystals of m. p. 161−162 °C.
The xꢀray structure of this compound was obtained. 1H NMR (CDCl3, 500 MHz) δ 8.31 (d, J = 9.5 Hz,
2H), 7.92 (d, J = 2.5 Hz, 1H), 7.82 (d, J = 9.5 Hz, 2H), 6.34 (d, J = 2.5 Hz, 1H), 2.39 (s, 3H); 13C NMR
(CDCl3, 125.8 MHz) δ 152.6, 144.9, 144.4, 127.6, 125.4, 118.0, 109.6, 13.8; HRMS (ESI+) calcd for
C10H10N3O2 ([M+H]+) 204.0776; found 204.0773.
5-Methyl-1-(4-nitrophenyl)-1H-pyrazole (13d). A more polar mixture of 12d and 13d (12d:13d
= 1:1.5) was obtained as a white solid (120 mg, 32%). By comparing the spectra of the mixture with those
of the pure 12d, the peaks which belong to 13d can be identified. 1H NMR (CDCl3, 500 MHz) δ 8.36 (d, J
= 7.0 Hz, 2H), 7.71 (d, J = 7.0 Hz, 2H), 7.64 (d, J = 1.5 Hz, 1H), 6.28 (d, J = 1.5 Hz, 1H), 2.48 (s, 3H);
13C NMR (CDCl3, 125.8 MHz) δ 146.1, 145.0, 141.4, 139.1, 124.7, 124.1, 109.0, 13.1; HRMS (ESI+)
calcd for C10H10N3O2 ([M+H]+) 204.0776; found 204.0778.
1-(4-Nitrophenyl)-3-(trifluoromethyl)-1H-pyrazole (12e). Obtained as a white solid (447 mg,
95%), which was recrystallized from a mixture of EA and hexanes as colorless crystals of m. p. 111−112
°C. The xꢀray structure of this compound was obtained. 1H NMR (CDCl3, 300 MHz) δ 8.34 (d, J = 10.2
Hz, 2H), 8.11 (d, J = 2.4 Hz, 1H), 7.91 (d, J = 10.2 Hz, 2H), 6.82 (d, J = 2.4 Hz, 1H); 13C NMR (CDCl3,
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75.5 MHz) δ 146.5, 145.6 (q, J = 39.2 Hz), 143.5, 128.7, 125.5, 120.8 (q, J = 268.8 Hz), 119.6, 107.4; 19F
NMR (CDCl3, 470 MHz) δ ꢀ62.6 (s); HRMS (ESI+) calcd for C10H7F3N3O2 ([M+H]+) 258.0490; found
258.0494.
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Ethyl 1-(4-nitrophenyl)-1H-pyrazole-3-carboxylate (12f). Obtained as a white solid (439 mg,
92%), which was recrystallized from a mixture of EA and hexanes as colorless crystals of m. p. 158ꢀ160
°C. The xꢀray structure of this compound was obtained. 1H NMR (CDCl3, 500 MHz) δ 8.37 (d, J = 9.0
Hz, 2H), 8.06 (d, J = 2.7 Hz, 1H), 7.98 (d, J = 9.0 Hz, 2H), 7.07 (d, J = 2.7 Hz, 1H), 4.47 (q, J = 7.2 Hz,
2H), 1.44 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3, 125.5 MHz) δ 161.7, 146.8, 146.4, 143.8, 128.6, 125.4,
119.8, 111.5, 61.5, 14.3; HRMS (ESI+) calcd for C12H12N3O4 ([M+H]+) 262.0828; found 262.0825.
3-Bromo-1-(4-nitrophenyl)-1H-pyrazole (12g). Obtained as a white solid (459 mg, 94%), which
was recrystallized from a mixture of EA and hexanes as colorless crystals of m. p. 145ꢀ146 °C. The xꢀray
structure of this compound was obtained. 1H NMR (CDCl3, 300 MHz) δ 8.33 (d, J = 8.7 Hz, 2H), 7.93 (d,
J = 2.1 Hz, 1H), 7.85 (d, J = 8.7 Hz, 2H), 6.58 (d, J = 2.1 Hz, 1H); 13C NMR (DMSOꢀd6, 75.5 MHz) δ
145.8, 143.5, 130.5, 128.8, 125.4, 118.4, 112.3; HRMS (ESI+) calcd for C9H7BrN3O2 ([M+H]+) 267.9722;
found 267.9720.
1-(4-Nitrophenyl)-3-phenyl-1H-pyrazole (12h). Obtained as a white solid (446 mg, 92%),
which was recrystallized from a mixture of EA and hexanes as colorless crystals of m. p. 168ꢀ169 °C. The
xꢀray structure of this compound was obtained. 1H NMR (CDCl3, 300 MHz) δ 8.35 (d, J = 9.0 Hz, 2H),
8.06 (d, J = 2.4 Hz, 1H), 7.91ꢀ7.97 (m, 3H), 7.26ꢀ7.48 (m, 2H), 6.87 (d, J = 2.4 Hz, 1H); 13C NMR
(DMSOꢀd6, 75.5 MHz) δ 153.5, 144.6, 143.9, 131.9, 130.5, 128.8, 128.6, 125.7, 125.4, 118.2, 107.0;
HRMS (ESI+) calcd for C15H12N3O2 ([M+H]+) 266.0930; found 266.0927.
Acknowledgments. We thank Drs. Paul Fleming, Ted Johnson, and Ying Zhang, as well as
anonymous reviewers for discussions and comments. Financial support for this research from the Faculty
Award and the Brachman Hoffman Grant at Wellesley College is gratefully acknowledged.
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Supporting Information Available: Tables S1ꢀS3, the DFT optimized geometries and energies
for anions 10A and 10B, copies of 1H NMR, 13C NMR, and 19F NMR spectra for all new compounds,
crystallographic data for 8a, 8b, 9a, and 8d, and the CIF files of the 25 compounds can be found in the
supporting information. This material is available free of charge via the Internet at http://pubs.acs.org.
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