Regioselective Synthesis of 4-Nitro- or 4-Chloro-Tetrasubstituted Pyrazoles from Hydrazones and β-Halo-β-nitrostyrenes

Article abstract of DOI:10.1002/ejoc.201301294

We report an acid-catalyzed cycloaddition reaction of hydrazones with β-bromo- or β-chloro-β-nitrostyrenes for the regioselective synthesis of 4-nitro- or 4-chloro-tetrasubstituted pyrazoles. Arising from a common 4-halo-4-nitropyrazolidine intermediate,

Full text of DOI:10.1002/ejoc.201301294

FULL PAPER
DOI: 10.1002/ejoc.201301294
Regioselective Synthesis of 4-Nitro- or 4-Chloro-Tetrasubstituted Pyrazoles
from Hydrazones and β-Halo-β-nitrostyrenes
Xiaohu Deng,*[a] Jimmy T. Liang,[a] and Neelakandha S. Mani[a]
Keywords: Nitrogen heterocycles / Hydrazones / Cyclization / Cycloaddition / Regioselectivity
We report an acid-catalyzed cycloaddition reaction of
hydrazones with β-bromo- or β-chloro-β-nitrostyrenes for the
regioselective synthesis of 4-nitro- or 4-chloro-tetrasubsti-
tuted pyrazoles. Arising from a common 4-halo-4-nitropyr-
azolidine intermediate, the identity of the pyrazole product
formed is dependent on the relative leaving group abilities
of the halo and nitro substituents.
proceeding via key 4-nitropyrazolidine intermediate I
(Scheme 1).[5] Slow oxidation of I by air followed by fast
Introduction
Substituted pyrazoles are an important class of com- elimination of HNO2 gives the desired pyrazole products.
pounds in the pharmaceutical industry, and they make up This versatile method gives easy and regioselective access
the core structures of drugs such as Celebrex®, Viagra®, to a wide range of substituted pyrazoles. However, only a
and Acomplia®, as well as numerous experimental drug few 4-substituted pyrazoles were prepared in those studies,
candidates.[1] The facile regioselective assembly of substi- primarily due to the limited availability of β-substituted β-
tuted pyrazoles from readily available building blocks is al- nitroalkenes. We envisioned that the introduction of an ad-
ways of great interest to medicinal chemists.[2] Synthetic ditional leaving group at the C-4 position in key intermedi-
methods that offer multiple points of variation, especially ate IV might potentially address this issue. In this paper,
at the late stage of a synthesis, are particularly appealing for we report that the reaction of hydrazones with β-halo-β-
the design of libraries and the rapid production of analogs. nitroalkenes, which are easily prepared from the corre-
Inspired by the pioneering work of Snider[3] and Gomez- sponding β-nitroalkenes[6] or by the condensation of alde-
Guillen,[4] we have recently demonstrated facile syntheses of hydes with bromonitromethane,[7] does indeed give either
substituted pyrazoles from hydrazones and β-nitroalkenes, the 4-nitro-tetrasubstituted pyrazole or the 4-chloro-tetra-
Scheme 1. Pyrazole synthesis from hydrazones and nitro olefins.
substituted pyrazole regioselectively. Which product is
[a] Janssen Research & Development LLC
formed appears to depend on the relative leaving-group
abilities of the substituents (BrϾ NO2 Ͼ Cl).
4-Nitro- and 4-halo-tetrasubstituted pyrazoles are inter-
esting synthetic targets, primarily because the reactive ni-
3210 Merryfield Row, San Diego, California 92121, USA
E-mail: xdeng@its.jnj.com
http://www.janssenrnd.com/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301294.
410
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Regioselective Synthesis of Tetrasubstituted Pyrazoles
tro[8] and halo[9,10] functional groups offer ample opportu- Table 1. Screening of conditions.
nities for further manipulations that would allow the prepa-
ration of numerous biologically interesting compounds.
Methods that are widely used for the synthesis of these
types of molecules often involve nitration and halogenation
of 4-unsubstituted-pyrazoles, whose preparation requires
multiple steps, most often achieved by the condensation re-
actions of hydrazines with 1,3-dicarbonyl compounds.[11]
Our operationally simple method provides an alternative ra-
pid synthesis of either 4-nitropyrazoles or 4-chloropyrazoles
from readily available starting materials. Therefore, we ex-
pect this method to become widely used by the synthetic
and medicinal chemistry communities.
Results and Discussion
Our initial experiments were conducted on in-situ-pre-
pared N-methylhydrazone 1 with either compound 2 or 3
(Table 1). Methanol, which was the optimal solvent for the
cycloaddition reaction of 1 with β-nitrostyrene,[5a] surpris-
ingly gave uncyclized product 5 exclusively with β-bromo-
β-nitrostyrene 2 (Table 1, Entry 1). Similarly, with β-chloro-
β-nitrostyrene 3, uncyclized product 6 was the major prod-
[a] Both starting materials were recovered.
uct (Table 1, Entry 2), along with 4-chloropyrazole 7, which
was formed in 35% yield. Other common solvents such as
THF, Et2O, DMF, iPrOH, EtOH, CH2Cl2, EtOAc, and
CH3CN also gave the uncyclized products as the major
Based on the above observations and on previous mech-
anistic studies,[5a,5b] plausible reaction pathways are pro-
posed (Scheme 2). Similar to the previously proposed reac-
tion mechanism, the proton-catalyzed stepwise cycload-
dition of the hydrazone and the β-halo-β-nitrostyrene gen-
erates 4-halo-4-nitropyrazolidine intermediate III. A com-
petitive Michael addition process produces 5 or 6 irrevers-
ibly. Intermediate III undergoes a slow oxidation by air to
give intermediate IV. Subsequent elimination of either HBr
or HNO2, depending on the relative leaving-group ability
of the halogen atoms and the nitro group, gives 4-nitropyr-
azole 4 or 4-chloropyrazole 7, respectively.
products. Our previous mechanistic studies showed that a
proton played a critical role in the cycloaddition process to
form the pyrazole products.[5a,5b] Indeed, when a more
acidic alcoholic solvent such as CF3CH2OH was used, the
formation of uncyclized products 5 or 6 was significantly
reduced, and the yields of cyclized pyrazole products 4 and
7 increased (Table 1, Entries 3 and 4). As expected, 4-nitro-
pyrazole 4 was preferably produced from β-bromo-β-nitro-
styrene 2 (Table 1, Entry 3), whereas 4-chloropyrazole 7 was
the major product with β-chloro-β-nitrostyrene 3 (Table 1,
Entry 4). Presumably, relative leaving-group abilities
(BrϾ NO2 Ͼ Cl) determined the product outcome. The ad-
dition of catalytic amounts of TFA (trifluoroacetic acid)
completely suppressed the formation of uncyclized products
5 or 6 (Table 1, Entries 5–8). With β-bromo-β-nitrostyrene
2 (Table 1, Entries 5 and 7), slightly better yields were ob-
tained with MeOH as the solvent. In contrast, with β-
chloro-β-nitrostyrene 3 (Table 1, Entries 6 and 8), better
yields and ratios of the desired product 7 were obtained
with CF3CH2OH as the solvent. A dependence of the reac-
tion profile on the combination of solvent and acid used
was also observed with other substrates. Therefore, individ-
ual reaction optimization could be necessary for new sub-
strates. Interestingly, when too much TFA (10 equiv.;
Table 1, Entries 9 and 10) was used, the cycloaddition reac-
tion was suppressed, and both starting materials were reco-
vered. It is worth noting that the isolated uncyclized prod-
Scheme 2. Plausible reaction pathways.
With a good understanding of the reaction mechanism,
ucts 5 or 6 would not cyclize to give the pyrazole products we then investigated the reaction scope in terms of other N-
under acidic conditions.
alkylhydrazones, which were mostly generated in situ.[12]
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X. Deng, J. T. Liang, N. S. Mani
FULL PAPER
Table 2. Reaction scope: N-alkylhydrazones.
[a] Isolated hydrazone was used. [b] The hydrazine HCl salt was used to form the hydrazone. Water (10 vol-%) was added as co-solvent.
The standard conditions were chosen to be TFA (20 mol- at the R1 and R2 positions. For example, when R2 was an
%) as the catalyst in either MeOH or CF3CH2OH, and the electron-donating group (Table 3, Entries 1–3), the cycload-
results are listed in Table 2. The general trend held that β- dition reaction was generally more favored, whereas elec-
bromo-β-nitrostyrene 2 gave mainly 4-nitropyrazole prod- tron-withdrawing groups (Table 3, Entries 4–6) required
ucts, whereas β-chloro-β-nitrostyrene 3 gave mainly 4-chloro- more forcing conditions. Similarly, when R1 was an elec-
pyrazole products. Variation of both the aldehyde (R2) and tron-donating group (Table 3, Entry 7), the reaction was fa-
hydrazine (R1) components was studied. The steric effects vored at room temperature, and with strongly electron-
on both the R1 and the R2 positions were obvious. For withdrawing R1 groups (Table 3, Entries 8 and 9), higher
example, benzyl (Table 2, Entries 1 and 6) and isopropyl reaction temperatures were required for the cycloaddition
(Table 2, Entries 2 and 7) groups were well tolerated on reaction to occur. With β-chloro-β-nitrostyrene 3, good
both positions. However, the presence of a bulky tert-butyl yields of the expected 4-chloropyrazole products were ob-
group (Table 2, Entries 3 and 8) at either position com- tained. However, in the case of β-bromo-β-nitrostyrene 2,
pletely shut down the cycloaddition reaction. Electronic ef- instead of the usual 4-nitropyrazole products, 4-bromopyr-
fects were also observed with the R2 substituent (Table 2, azole product 38 (Table 3, Entry 8) and 4-unsubstituted-pyr-
Entries 4 and 5). A higher reaction temperature was re- azole product 39 (Table 3, Entry 9) were the major products
quired in the presence of a strongly electron-withdrawing isolated. One possible explanation is that in the presence of
R2 group such as NO2 (Table 2, Entry 5). As previously ob- strongly electron-withdrawing R1 groups such as CN and
served, changes to the solvent/acid combination could re- NO2, under more forcing reaction conditions, the reaction
sult in altered reaction profiles (Table 2, Entry 4; X = Cl).
mechanism might be different. In these cases, elimination
Less reactive N-arylhydrazones were investigated next of HNO2 from 4-halo-4-nitropyrazolidine intermediate III
(Table 3). As a general rule, β-bromo-β-nitrostyrene 2 fa- might be favored (Scheme 3). Subsequent air oxidation gave
vored the formation of 4-nitropyrazole products, and β- 4-bromopyrazole 38. The formation of 4-unsubstituted pyr-
chloro-β-nitrostyrene 3 favored mainly 4-chloropyrazole azole derivative 40 most probably comes from a subsequent
products; however, a few exceptions were noted (Table 3, acid-mediated hydrodebromination process at elevated tem-
Entries 8 and 9). The electronic effects played out similarly perature.
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Regioselective Synthesis of Tetrasubstituted Pyrazoles
Table 3. Reaction scope: N-arylhydrazones.
[a] 10 equiv. of TFA were used.
Experimental Section
General: 1H and 13C NMR spectra were recorded with a 600 MHz
spectrometer. Flash column chromatography was performed using
Merck silica gel 60. HRMS (ESI) was performed with a microTOF
apparatus. All reagents and solvents were purchased from commer-
cial sources and were used without further purification.
Representative Procedure A: 4-Chlorobenzaldehyde (84 mg,
0.6 mmol, 1.2 equiv.) was dissolved in MeOH (2 mL), and then
methylhydrazine (28 mg, 0.6 mmol, 1.2 equiv.) was added. After the
mixture had been stirred at room temperature for 1 h, HPLC analy-
sis showed that the methylhydrazone had been formed. TFA (8 μL,
Scheme 3. Proposed mechanism for the formation of compounds
38 and 40.
0.1 mmol, 0.2 equiv.) and β-bromo-β-nitrostyrene
2 (114 mg,
0.5 mmol, 1.0 equiv.) were added sequentially, and the reaction
solution was stirred open to air at room temperature for 1 d. The
solvent was evaporated, and the residue was purified by flash col-
umn chromatography with EtOAc/hexanes as eluent to give com-
pound 4 (128 mg, 0.41 mmol, 82%).
Conclusions
Representative Procedure B: A mixture of β-bromo-β-nitrostyrene
2 (114 mg, 0.5 mmol, 1.0 equiv.) and N-(4-chlorobenzylidene)-NЈ-
phenylhydrazine (138 mg, 0.6 mmol, 1.2 equiv.) was dissolved in
CF3CH2OH (2 mL), and then TFA (8 μL, 0.1 mmol, 0.2 equiv.)
was added. The reaction mixture was stirred at room temperature
open to air for 1 d. The solvent was evaporated, and the residue
was purified by flash column chromatography with EtOAc/hexanes
as eluent to give compounds 20 (108 mg, 0.29 mmol, 58%) and 21
(30 mg, 0.075 mmol, 15%).
We have developed a facile, regioselective synthesis of 4-
nitro- or 4-chloro-tetrasubstituted pyrazoles from hydraz-
ones and β-halo-β-nitrostyrenes. This cycloaddition reac-
tion is believed to go via key 4-halo-4-nitropyrazolidine in-
termediate III. The regioselective formation of either a 4-
nitro- or a 4-chloro-tetrasubstituted pyrazole product is
mainly determined by the relative leaving group ability of
the halogen and nitro substituents.
Eur. J. Org. Chem. 2014, 410–417
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X. Deng, J. T. Liang, N. S. Mani
FULL PAPER
3-(4-Chlorophenyl)-1-methyl-4-nitro-5-phenyl-1H-pyrazole (4): The
NMR (600 MHz, CDCl3): δ = 7.51–7.47 (m, 2 H), 7.46–7.40 (m, 3
H), 3.81–3.73 (s, 3 H), 3.16–3.04 (dt, J = 14.0, 7.0 Hz, 1 H), 1.41–
title compound was isolated in 82% yield (128 mg; Table 1, en-
try 5). 1H NMR (600 MHz, CDCl3): δ = 7.66–7.62 (m, 2 H), 7.58– 1.30 (d, J = 7.0 Hz, 6 H) ppm. 13C NMR (151 MHz, CDCl3): δ =
7.54 (m, 3 H), 7.46–7.42 (m, 4 H), 3.80–3.65 (s, 3 H) ppm. 13C
NMR (151 MHz, CDCl3): δ = 146.2, 143.2, 135.3, 130.5, 130.4,
129.6, 129.0, 128.9, 128.5, 127.0, 38.0 (one overlapping carbon
peak) ppm. HRMS (ESI): calcd. for C16H13ClN3O2 [M + H]+
314.0691; found 314.0676.
153.5, 139.9, 129.6, 128.9, 128.6, 128.5, 106.3, 37.9, 26.4, 21.4 ppm.
HRMS (ESI): calcd. for C13H16ClN2 [M + H]+ 235.0997; found
235.0994.
3-(4-Methoxyphenyl)-1-methyl-4-nitro-5-phenyl-1H-pyrazole (12):
The title compound was isolated in 66% yield (102 mg; Table 2,
Entry 4). 1H NMR (600 MHz, CDCl3): δ = 7.67–7.63 (m, 2 H),
7.57–7.53 (ddd, J = 3.6, 2.4, 1.0 Hz, 3 H), 7.47–7.42 (m, 2 H), 7.01–
6.96 (m, 2 H), 3.88–3.85 (s, 3 H), 3.75–3.73 (s, 3 H) ppm. 13C NMR
(151 MHz, CDCl3): δ = 160.4, 147.1, 142.9, 130.5, 130.2, 129.6,
128.9, 127.3, 122.8, 113.7, 55.3, 37.8 ppm. HRMS (ESI): calcd. for
C17H16N3O3 [M + H]+ 310.1186; found 310.1175.
(E)-1-(2-Bromo-2-nitro-1-phenylethyl)-2-(4-chlorobenzylidene)-1-
methylhydrazine (5): The title compound was isolated in 90% yield
1
(178 mg; Table 1, Entry 1). H NMR (600 MHz, CDCl3) (two sets
of peaks): δ = 7.55–7.48 (m, 2 H), 7.38–7.28 (m, 7 H), 7.22–7.20
and 7.15–7.11 (s, 1 H), 6.91–6.86 and 6.85–6.80 (d, J = 10.0 Hz, 1
H), 4.95–4.90 and 4.79–4.74 (d, J = 10.0 Hz, 1 H), 2.88–2.85 and
2.77–2.73 (d, J = 0.9 Hz, 3 H) ppm. 13C NMR (151 MHz, CDCl3):
δ = 134.7, 134.6, 133.7, 133.6, 133.2, 133.1, 133.08, 133.05, 129.5,
129.2, 128.95, 128.89, 128.8, 128.7, 128.5, 128.1, 127.1, 127.0, 81.0,
78.9, 74.2, 73.5, 38.1, 37.5 ppm. HRMS (ESI): calcd. for
C16H16BrClN3O2 [M + H]+ 396.0109; found 396.0096.
4-Chloro-3-(4-methoxyphenyl)-1-methyl-5-phenyl-1H-pyrazole (13):
The title compound was isolated in 58% yield (86 mg; Table 2, En-
try 4). 1H NMR (600 MHz, CDCl3): δ = 7.90–7.85 (m, 2 H), 7.55–
7.50 (m, 2 H), 7.49–7.43 (m, 3 H), 7.01–6.95 (m, 2 H), 3.86–3.84
(s, 3 H), 3.84–3.82 (s, 3 H) ppm. 13C NMR (151 MHz, CDCl3): δ
= 159.5, 146.3, 141.0, 129.7, 129.2, 128.7, 128.6, 128.3, 124.5, 113.8,
106.1, 55.3, 38.1 ppm. HRMS (ESI): calcd. for C17H16ClN2O [M
+ H]+ 299.0946; found 299.0942.
(E)-1-(2-Chloro-2-nitro-1-phenylethyl)-2-(4-chlorobenzylidene)-1-
methylhydrazine (6): The title compound was isolated in 47% yield
1
(82 mg; Table 1, Entry 2). H NMR (600 MHz, CDCl3): δ = 7.53–
7.47 (m, 2 H), 7.38–7.29 (m, 7 H), 7.16–7.12 (s, 1 H), 6.82–6.77 (d,
J = 9.9 Hz, 1 H), 4.95–4.80 (d, J = 9.9 Hz, 1 H), 2.85–2.68 (d, J =
0.9 Hz, 3 H) ppm. 13C NMR (151 MHz, CDCl3): δ = 134.6, 133.7,
133.3, 133.0, 129.2, 128.84, 128.80, 128.6, 127.2, 90.1, 73.9,
37.4 ppm. HRMS (ESI): calcd. for C16H16Cl2N3O2 [M + H]+
352.0614; found 352.0601.
1-Methyl-4-nitro-3-(4-nitrophenyl)-5-phenyl-1H-pyrazole (14): The
title compound was isolated in 54% yield (87 mg; Table 2, Entry 5).
1H NMR (600 MHz, CDCl3): δ = 8.35–8.28 (m, 2 H), 7.92–7.84
(m, 2 H), 7.63–7.53 (m, 3 H), 7.50–7.40 (m, 2 H), 3.83–3.74 (s, 3
H) ppm. 13C NMR (151 MHz, CDCl3): δ = 148.1, 145.0, 143.6,
137.0, 130.6, 130.2, 129.6, 129.0, 126.6, 123.4, 38.2 (one overlap-
ping carbon peak) ppm. HRMS (ESI): calcd. for C16H13N4O4 [M
+ H]+ 325.0931; found 325.0931.
4-Chloro-3-(4-chlorophenyl)-1-methyl-5-phenyl-1H-pyrazole (7): The
title compound was isolated in 35% yield (53 mg; Table 1, Entry 2).
1H NMR (600 MHz, CDCl3): δ = 7.92–7.88 (m, 2 H), 7.55–7.43
(m, 5 H), 7.42–7.38 (m, 2 H), 3.83 (s, 3 H) ppm. 13C NMR
(151 MHz, CDCl3): δ = 145.3, 141.4, 133.9, 130.5, 129.7, 129.3,
128.8, 128.6, 128.5, 128.0, 106.5, 38.2 ppm. HRMS (ESI): calcd.
for C16H13Cl2N2 [M + H]+ 303.0450; found 303.0453.
4-Chloro-1-methyl-3-(4-nitrophenyl)-5-phenyl-1H-pyrazole (15): The
title compound was isolated in 70% yield (109 mg; Table 2, En-
try 5). 1H NMR (600 MHz, CDCl3): δ = 8.31–8.27 (m, 2 H), 8.20–
8.15 (m, 2 H), 7.58–7.49 (m, 3 H), 7.49–7.44 (m, 2 H), 3.99–3.81
(s, 3 H) ppm. 13C NMR (151 MHz, CDCl3): δ = 147.1, 143.9,
141.9, 138.4, 129.7, 129.6, 128.9, 127.6, 127.5, 123.7, 107.4,
38.5 ppm. HRMS (ESI): calcd. for C16H13ClN3O2 [M + H]+
314.0691; found 314.0684.
3-Benzyl-1-methyl-4-nitro-5-phenyl-1H-pyrazole (8): The title com-
pound was isolated in 41% yield (60 mg; Table 2, Entry 1). 1H
NMR (600 MHz, CDCl3): δ = 7.54–7.48 (m, 3 H), 7.42–7.37 (m, 2
H), 7.37–7.33 (m, 2 H), 7.33–7.28 (m, 2 H), 7.25–7.21 (m, 1 H),
4.37–4.33 (s, 2 H), 3.69–3.65 (s, 3 H) ppm. 13C NMR (151 MHz,
CDCl3): δ = 148.2, 142.8, 137.8, 130.2, 129.5, 129.1, 128.8, 128.4,
127.4, 126.6, 37.7, 33.5 (one overlapping carbon peak) ppm.
HRMS (ESI): calcd. for C17H16N3O2 [M + H]+ 294.1237; found
294.1234.
1-Benzyl-3-(4-chlorophenyl)-4-nitro-5-phenyl-1H-pyrazole (16): The
title compound was isolated in 55% yield (107 mg; Table 2, En-
try 6). 1H NMR (600 MHz, CDCl3): δ = 7.69–7.65 (m, 2 H), 7.56–
7.51 (m, 1 H), 7.51–7.46 (m, 2 H), 7.44–7.41 (m, 2 H), 7.33–7.26
(m, 5 H), 5.21–5.13 (s, 2 H) ppm. 13C NMR (151 MHz, CDCl3): δ
= 146.3, 143.3, 135.4, 135.1, 130.6, 130.4, 129.7, 129.0, 128.8, 128.8,
128.5, 128.3, 127.5, 127.5, 126.9, 54.3 ppm. HRMS (ESI): calcd.
for C22H17ClN3O2 [M + H]+ 390.1004; found 390.0993.
3-Benzyl-4-chloro-1-methyl-5-phenyl-1H-pyrazole (9): The title
1
compound was isolated in 19% yield (26 mg; Table 2, Entry 1). H
NMR (600 MHz, CDCl3): δ = 7.51–7.46 (m, 2 H), 7.46–7.42 (m, 1
H), 7.42–7.38 (m, 2 H), 7.38–7.34 (m, 2 H), 7.32–7.28 (m, 2 H),
1-Benzyl-4-chloro-3-(4-chlorophenyl)-5-phenyl-1H-pyrazole
(17):
7.23–7.18 (m, 1 H), 4.11–3.96 (s, 2 H), 3.83–3.67 (s, 3 H) ppm. 13
C
The title compound was isolated in 63% yield (119 mg; Table 2,
Entry 6). 1H NMR (600 MHz, CDCl3): δ = 7.97–7.91 (m, 2 H),
7.48–7.39 (m, 5 H), 7.35–7.30 (m, 2 H), 7.29–7.22 (m, 3 H), 7.09–
7.03 (dd, J = 7.8, 1.6 Hz, 2 H), 5.34–5.19 (s, 2 H) ppm. 13C NMR
(151 MHz, CDCl3): δ = 145.7, 141.7, 136.7, 134.0, 130.4, 129.9,
129.5, 128.8, 128.7, 128.6, 128.6, 128.0, 127.8, 127.0, 107.1,
54.3 ppm. HRMS (ESI): calcd. for C22H17Cl2N2 [M + H]+
379.0763; found 379.0759.
NMR (151 MHz, CDCl3): δ = 147.5, 140.0, 138.9, 129.6, 129.0,
128.8, 128.7, 128.4, 128.3, 126.2, 107.6, 38.0, 32.4 ppm. HRMS
(ESI): calcd. for C17H16ClN2 [M + H]+ 283.0997; found 283.0998.
3-Isopropyl-1-methyl-4-nitro-5-phenyl-1H-pyrazole (10): The title
1
compound was isolated in 57% yield (70 mg; Table 2, Entry 2). H
NMR (600 MHz, CDCl3): δ = 7.55–7.49 (m, 3 H), 7.39–7.34 (m, 2
H), 3.65 (s, 3 H), 3.70–3.62 (dt, J = 14.0, 7.0 Hz, 1 H), 1.39–1.33
(d, J = 6.9 Hz, 6 H) ppm. 13C NMR (151 MHz, CDCl3): δ = 154.6,
142.7, 130.0, 129.5, 128.7, 127.7, 37.6, 27.0, 21.3 (one overlapping
carbon peak) ppm. HRMS (ESI): calcd. for C13H16N3O2 [M +
H]+ 246.1237; found 246.1225.
3-(4-Chlorophenyl)-1-isopropyl-4-nitro-5-phenyl-1H-pyrazole (18):
The title compound was isolated in 34% yield (58 mg; Table 2, En-
try 7). 1H NMR (600 MHz, CDCl3): δ = 7.69–7.65 (m, 2 H), 7.59–
7.53 (m, 3 H), 7.45–7.39 (m, 4 H), 4.38–4.25 (sept, J = 6.6 Hz, 1
H), 1.52–1.45 (d, J = 6.6 Hz, 6 H) ppm. 13C NMR (151 MHz,
CDCl3): δ = 146.0, 142.1, 135.2, 130.9, 130.6, 130.2, 129.5, 129.1,
4-Chloro-3-isopropyl-1-methyl-5-phenyl-1H-pyrazole (11): The title
1
compound was isolated in 38% yield (44 mg; Table 2, Entry 2). H
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Regioselective Synthesis of Tetrasubstituted Pyrazoles
128.9, 128.4, 127.3, 51.6, 22.4 ppm. HRMS (ESI): calcd. for
C18H17ClN3O2 [M + H]+ 342.1004; found 342.1006.
3-(4-Bromo-1,5-diphenyl-1H-pyrazol-3-yl)phenol (26): The title
compound was isolated in 25% yield (49 mg; Table 3, Entry 3). H
1
NMR (600 MHz, CDCl3): δ = 7.62–7.57 (dt, J = 7.7, 1.2 Hz, 1 H),
7.50–7.46 (dd, J = 2.6, 1.5 Hz, 1 H), 7.40–7.36 (m, 3 H), 7.35–7.30
(m, 3 H), 7.30–7.24 (m, 5 H), 6.90–6.82 (ddd, J = 8.2, 2.7, 1.0 Hz,
1 H), 5.44–5.30 (s, 1 H) ppm. 13C NMR (151 MHz, CDCl3): δ =
155.6, 149.3, 142.2, 139.7, 133.3, 130.2, 129.6, 129.0, 128.9, 128.8,
128.5, 127.7, 124.8, 120.5, 115.6, 114.9, 94.9 ppm. HRMS (ESI):
calcd. for C21H16BrN2O [M + H]+ 391.0441; found 391.0426.
4-Chloro-3-(4-chlorophenyl)-1-isopropyl-5-phenyl-1H-pyrazole (19):
The title compound was isolated in 41% yield (67 mg; Table 2, En-
try 7). 1H NMR (600 MHz, CDCl3): δ = 7.96–7.90 (m, 2 H), 7.57–
7.46 (m, 3 H), 7.45–7.38 (m, 4 H), 4.52–4.36 (sept, J = 6.6 Hz, 1
H), 1.56–1.54 (s, 2 H), 1.51–1.45 (d, J = 6.6 Hz, 6 H) ppm. 13C
NMR (151 MHz, CDCl3): δ = 145.0, 140.4, 133.7, 130.9, 129.9,
129.2, 128.8, 128.6, 128.5, 128.4, 106.1 ppm. HRMS (ESI): calcd.
for C18H17Cl2N2 [M + H]+ 331.0763; found 331.0765.
3-(4-Chloro-1,5-diphenyl-1H-pyrazol-3-yl)phenol (27): The title
compound was isolated in 62% yield (107 mg; Table 3, Entry 3).
1H NMR (600 MHz, CDCl3): δ = 7.61–7.56 (dt, J = 7.7, 1.3 Hz, 1
H), 7.51–7.48 (d, J = 2.2 Hz, 1 H), 7.40–7.34 (m, 3 H), 7.33–7.30
(m, 2 H), 7.30–7.24 (m, 6 H), 6.85–6.80 (ddd, J = 8.2, 2.6, 0.9 Hz,
1 H), 5.89–4.46 (br. s, 1 H) ppm. 13C NMR (151 MHz, CDCl3): δ
= 155.8, 147.9, 140.5, 139.6, 132.7, 130.0, 129.7, 129.0, 128.9, 128.5,
128.2, 127.7, 124.9, 120.1, 115.7, 114.6, 109.0 ppm. HRMS (ESI):
calcd. for C21H16ClN2O [M + H]+ 347.0946; found 347.0943.
3-(4-Chlorophenyl)-4-nitro-1,5-diphenyl-1H-pyrazole (20): The title
compound was isolated in 58% yield (108 mg; Table 3, Entry 1).
1H NMR (600 MHz, CDCl3): δ = 7.74–7.69 (m, 2 H), 7.49–7.42
(m, 3 H), 7.42–7.37 (m, 2 H), 7.37–7.29 (m, 5 H), 7.28–7.21 (m, 2
H) ppm. 13C NMR (151 MHz, CDCl3): δ = 146.9, 142.4, 138.3,
135.5, 131.7, 130.5, 130.2, 130.2, 129.1, 128.8, 128.7, 128.6, 128.6,
126.8, 125.3 ppm. HRMS (ESI): calcd. for C21H15ClN3O2 [M +
H]+ 376.0847; found 376.0834.
Methyl 4-(4-Nitro-1,5-diphenyl-1H-pyrazol-3-yl)benzoate (28): The
title compound was isolated in 30% yield (60 mg; Table 3, Entry 4).
1H NMR (600 MHz, CDCl3): δ = 8.17–8.13 (m, 2 H), 7.87–7.82
(m, 2 H), 7.49–7.43 (m, 1 H), 7.43–7.38 (ddd, J = 8.3, 7.1, 0.9 Hz,
2 H), 7.38–7.30 (m, 5 H), 7.29–7.24 (m, 2 H), 4.01–3.83 (s, 3 H)
ppm. 13C NMR (151 MHz, CDCl3): δ = 166.7, 147.0, 142.4, 138.3,
134.7, 131.9, 130.8, 130.3, 130.2, 129.6, 129.1, 129.1, 128.9, 128.6,
126.7, 125.3, 52.3 ppm. HRMS (ESI): calcd. for C23H18N3O4 [M +
H]+ 400.1292; found 400.1287.
4-Bromo-3-(4-chlorophenyl)-1,5-diphenyl-1H-pyrazole (21): The title
compound was isolated in 15% yield (30 mg; Table 3, Entry 1). H
1
NMR (600 MHz, CDCl3): δ = 8.01–7.95 (m, 2 H), 7.46–7.41 (m, 2
H), 7.40–7.35 (m, 3 H), 7.35–7.25 (m, 7 H) ppm. 13C NMR
(151 MHz, CDCl3): δ = 148.6, 142.3, 139.7, 134.4, 130.5, 130.2,
129.3, 129.1, 128.9, 128.8, 128.6, 128.5, 127.7, 124.8, 94.8 ppm.
HRMS (ESI): calcd. for C21H15BrClN2 [M + H]+ 409.0102; found
409.0082.
4-Chloro-3-(4-chlorophenyl)-1,5-diphenyl-1H-pyrazole (22): The title
compound was isolated in 74% yield (135 mg; Table 3, Entry 1).
1H NMR (600 MHz, CDCl3): δ = 8.02–7.97 (m, 2 H), 7.46–7.42
(m, 2 H), 7.39–7.36 (m, 3 H), 7.34–7.27 (m, 7 H) ppm. 13C NMR
(151 MHz, CDCl3): δ = 146.9, 140.5, 139.6, 134.3, 130.1, 129.9,
129.0, 128.9, 128.8, 128.6, 128.5, 128.1, 127.7, 124.8, 108.8 ppm.
HRMS (ESI): calcd. for C21H15Cl2N2 [M + H]+ 365.0607; found
365.0593.
Methyl 4-(4-Chloro-1,5-diphenyl-1H-pyrazol-3-yl)benzoate (29):
The title compound was isolated in 67% yield (130 mg; Table 3,
Entry 4). 1H NMR (600 MHz, CDCl3): δ = 8.18–8.11 (m, 4 H),
7.43–7.36 (m, 3 H), 7.35–7.27 (m, 7 H), 3.95–3.92 (s, 3 H) ppm.
13C NMR (151 MHz, CDCl3): δ = 166.9, 146.9, 140.7, 139.6, 136.0,
129.9, 129.7, 129.7, 129.1, 129.0, 128.6, 128.0, 127.8, 127.3, 124.8,
109.2, 52.1 ppm. HRMS (ESI): calcd. for C23H18ClN2O2 [M +
H]+ 389.1051; found 389.1043.
4-Nitro-3-(4-nitrophenyl)-1,5-diphenyl-1H-pyrazole (30): The title
compound was isolated in 16% yield (31 mg; Table 3, Entry 5). H
3-(4-Methoxyphenyl)-4-nitro-1,5-diphenyl-1H-pyrazole (23): The
title compound was isolated in 32% yield (59 mg; Table 3, Entry 2).
1H NMR (600 MHz, CDCl3): δ = 7.74–7.69 (m, 2 H), 7.46–7.41
(m, 1 H), 7.41–7.37 (m, 2 H), 7.36–7.33 (m, 2 H), 7.33–7.28 (m, 3
H), 7.28–7.23 (m, 2 H), 7.02–6.97 (m, 2 H), 3.96–3.73 (s, 3 H) ppm.
13C NMR (151 MHz, CDCl3): δ = 160.5, 147.7, 142.1, 138.5, 132.0,
131.7, 130.4, 130.2, 130.0, 129.0, 128.6, 128.6, 127.1, 125.3, 122.5,
113.8, 55.3 ppm. HRMS (ESI): calcd. for C22H18N3O3 [M + H]+
372.1343; found 372.1325.
1
NMR (600 MHz, CDCl3): δ = 8.37–8.31 (m, 2 H), 7.99–7.94 (m, 2
H), 7.49–7.44 (m, 1 H), 7.44–7.38 (m, 2 H), 7.38–7.31 (m, 5 H),
7.29–7.25 (m, 2 H) ppm. 13C NMR (151 MHz, CDCl3): δ = 148.3,
145.8, 142.8, 138.2, 136.7, 130.4, 130.3, 130.2, 129.2, 129.1, 128.7,
126.5, 125.3, 123.5 (one overlapping carbon peak) ppm. HRMS
(ESI): calcd. for C21H15N4O4 [M + H]+ 387.1088; found 387.1084.
4-Bromo-3-(4-nitrophenyl)-1,5-diphenyl-1H-pyrazole (31): The title
1
compound was isolated in 25% yield (52 mg; Table 3, Entry 5). H
4-Chloro-3-(4-methoxyphenyl)-1,5-diphenyl-1H-pyrazole (24): The
title compound was isolated in 68% yield (122 mg; Table 3, En-
try 2). 1H NMR (600 MHz, CDCl3): δ = 8.01–7.95 (m, 2 H), 7.40–
7.35 (m, 3 H), 7.35–7.31 (m, 2 H), 7.30–7.25 (m, 4 H), 7.03–6.97
(m, 2 H), 3.97–3.73 (s, 3 H) ppm. 13C NMR (151 MHz, CDCl3): δ
= 159.8, 147.9, 140.2, 139.9, 130.0, 129.0, 128.9, 128.8, 128.5, 128.5,
127.4, 124.8, 124.2, 113.9, 108.6, 55.3 ppm. HRMS (ESI): calcd.
for C22H18ClN2O [M + H]+ 361.1102; found 361.1097.
NMR (600 MHz, CDCl3): δ = 8.35–8.30 (m, 2 H), 8.29–8.24 (m, 2
H), 7.43–7.38 (m, 3 H), 7.36–7.31 (m, 5 H), 7.30–7.27 (m, 2 H)
ppm. 13C NMR (151 MHz, CDCl3): δ = 147.5, 147.2, 142.9, 139.5,
138.4, 130.2, 129.3, 129.0, 128.6, 128.5, 128.4, 128.1, 124.8, 123.6,
95.2 ppm. HRMS (ESI): calcd. for C21H15BrN3O2 [M + H]+
420.0342; found 420.0326.
4-Chloro-3-(4-nitrophenyl)-1,5-diphenyl-1H-pyrazole (32): The title
compound was isolated in 59% yield (110 mg; Table 3, Entry 5).
1H NMR (600 MHz, CDCl3): δ = 8.35–8.30 (m, 2 H), 8.30–8.25
(m, 2 H), 7.43–7.37 (m, 3 H), 7.36–7.26 (m, 7 H) ppm. 13C NMR
(151 MHz, CDCl3): δ = 147.5, 145.6, 141.1, 139.5, 138.0, 129.9,
129.3, 129.0, 128.7, 128.1, 128.0, 127.8, 124.8, 123.7, 109.5 ppm.
HRMS (ESI): calcd. for C21H15ClN3O2 [M + H]+ 376.0847; found
376.0840.
3-(4-Nitro-1,5-diphenyl-1H-pyrazol-3-yl)phenol (25): The title com-
pound was isolated in 58% yield (103 mg; Table 3, Entry 3). 1H
NMR (600 MHz, CDCl3): δ = 7.45–7.40 (m, 1 H), 7.40–7.35 (m, 2
H), 7.35–7.32 (m, 2 H), 7.32–7.27 (m, 5 H), 7.27–7.23 (m, 2 H),
7.22–7.19 (dd, J = 3.0, 1.4 Hz, 1 H), 6.91–6.86 (dt, J = 6.5, 2.7 Hz,
1 H) ppm. 13C NMR (151 MHz, CDCl3): δ = 155.7, 147.6, 142.2,
138.3, 131.9, 131.3, 130.2, 130.1, 129.6, 129.1, 128.7, 128.6, 126.8,
125.4, 121.3, 116.7, 116.0 ppm. HRMS (ESI): calcd. for
C21H16N3O3 [M + H]+ 358.1186; found 358.1190.
3-(4-Nitro-1,5-diphenyl-1H-pyrazol-3-yl)benzonitrile (33): The title
1
compound was isolated in 23% yield (42 mg; Table 3, Entry 6). H
Eur. J. Org. Chem. 2014, 410–417
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
415

X. Deng, J. T. Liang, N. S. Mani
FULL PAPER
NMR (600 MHz, CDCl3): δ = 8.12–8.09 (t, J = 1.7 Hz, 1 H), 8.03–
7.99 (dt, J = 7.9, 1.5 Hz, 1 H), 7.78–7.73 (dt, J = 7.8, 1.4 Hz, 1 H),
7.61–7.57 (t, J = 7.8 Hz, 1 H), 7.49–7.43 (m, 1 H), 7.44–7.39 (m, 2
H), 7.38–7.30 (m, 5 H), 7.29–7.22 (m, 2 H) ppm. 13C NMR
1
try 9). H NMR (600 MHz, CDCl3): δ = 8.33–8.29 (t, J = 2.2 Hz,
1 H), 8.16–8.11 (ddd, J = 8.2, 2.2, 1.0 Hz, 1 H), 7.88–7.82 (m, 2
H), 7.63–7.59 (ddd, J = 8.0, 2.1, 1.0 Hz, 1 H), 7.50–7.44 (m, 1 H),
7.44–7.35 (m, 5 H), 7.31–7.27 (m, 2 H), 6.83–6.81 (s, 1 H) ppm.
(151 MHz, CDCl3): δ = 145.9, 142.7, 138.2, 133.6, 132.8, 132.7, 13C NMR (151 MHz, CDCl3): δ = 151.8, 148.5, 145.0, 140.9, 134.3,
131.8, 131.6, 130.3, 130.2, 129.2, 129.1, 129.0, 128.7, 126.5, 125.3,
131.0, 130.1, 129.8, 129.6, 129.1, 128.95, 128.94, 128.8, 127.1,
118.3, 112.7 ppm. HRMS (ESI): calcd. for C22H15N4O2 [M + H]+ 121.7, 119.7, 106.3 ppm. HRMS (ESI): calcd. for C21H15ClN3O2
367.1190; found 367.1177.
[M + H]+ 376.0847; found 376.0829.
3-(4-Bromo-1,5-diphenyl-1H-pyrazol-3-yl)benzonitrile (34): The title
compound was isolated in 14% yield (28 mg; Table 3, Entry 6). H
4-Chloro-3-(4-chlorophenyl)-1-(3-nitrophenyl)-5-phenyl-1H-pyrazole
(41): The title compound was isolated in 85% yield (173 mg;
Table 3, Entry 9). 1H NMR (600 MHz, CDCl3): δ = 8.27–8.23 (t,
J = 2.2 Hz, 1 H), 8.16–8.10 (ddd, J = 8.2, 2.2, 1.1 Hz, 1 H), 8.04–
7.98 (m, 2 H), 7.59–7.54 (ddd, J = 8.1, 2.2, 1.0 Hz, 1 H), 7.50–7.42
(m, 6 H), 7.37–7.31 (m, 2 H) ppm. 13C NMR (151 MHz, CDCl3):
δ = 148.5, 148.0, 140.9, 140.5, 134.9, 129.9, 129.8, 129.7, 129.6,
129.5, 129.1, 128.9, 128.8, 127.5, 122.0, 119.3, 110.2 ppm. HRMS
(ESI): calcd. for C21H14Cl2N3O2 [M + H]+ 410.0458; found
410.0449.
1
NMR (600 MHz, CDCl3): δ = 8.38–8.34 (td, J = 1.7, 0.6 Hz, 1 H),
8.33–8.27 (ddd, J = 7.9, 1.8, 1.2 Hz, 1 H), 7.71–7.66 (dt, J = 7.7,
1.4 Hz, 1 H), 7.60–7.55 (td, J = 7.8, 0.6 Hz, 1 H), 7.43–7.38 (m, 3
H), 7.35–7.26 (m, 7 H) ppm. 13C NMR (151 MHz, CDCl3): δ =
147.4, 142.6, 139.5, 133.4, 132.0, 131.7, 131.4, 130.1, 129.3, 129.2,
129.0, 128.6, 128.5, 127.9, 124.8, 118.7, 112.7, 94.7 ppm. HRMS
(ESI): calcd. for C22H15BrN3 [M + H]+ 400.0444; found 400.0444.
3-(4-Chloro-1,5-diphenyl-1H-pyrazol-3-yl)benzonitrile (35): The title
1
compound was isolated in 31% yield (55 mg; Table 3, Entry 6). H
Supporting Information (see footnote on the first page of this arti-
1
cle): H and 13C NMR spectra of compounds 4–41.
NMR (600 MHz, CDCl3): δ = 8.40–8.36 (t, J = 1.7 Hz, 1 H), 8.33–
8.29 (dt, J = 7.9, 1.5 Hz, 1 H), 7.71–7.64 (dt, J = 7.5, 1.4 Hz, 1 H),
7.61–7.53 (t, J = 7.8 Hz, 1 H), 7.43–7.36 (m, 3 H), 7.36–7.27 (m, 7
H) ppm. 13C NMR (151 MHz, CDCl3): δ = 145.8, 140.9, 139.5,
133.0, 131.6, 131.6, 131.0, 129.9, 129.3, 129.2, 129.0, 128.6, 128.0,
127.9, 124.8, 118.7, 112.8, 108.9 ppm. HRMS (ESI): calcd. for
C22H15ClN3 [M + H]+ 356.0949; found 356.0947.
Acknowledgments
We wish to thank Dr. Daniel J. Pippel for proof reading this manu-
script, and Ms. Heather McAllister for analytical support.
3-(4-Chlorophenyl)-1-(4-methoxyphenyl)-4-nitro-5-phenyl-1H-pyr-
azole (36): The title compound was isolated in 63% yield (127 mg;
Table 3, Entry 7). H NMR (600 MHz, CDCl3): δ = 7.72–7.67 (m,
2 H), 7.48–7.36 (m, 5 H), 7.36–7.31 (m, 2 H), 7.18–7.12 (m, 2 H),
6.83–6.78 (m, 2 H), 3.84–3.66 (s, 3 H) ppm. 13C NMR (151 MHz,
CDCl3): δ = 159.6, 146.6, 142.3, 135.4, 131.4, 131.3, 130.5, 130.2,
130.0, 128.8, 128.6, 128.5, 126.9, 126.7, 114.2, 55.5 ppm. HRMS
(ESI): calcd. for C22H17ClN3O3 [M + H]+ 406.0953; found
406.0966.
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1
4-Chloro-3-(4-chlorophenyl)-1-(4-methoxyphenyl)-5-phenyl-1H-pyr-
azole (37): The title compound was isolated in 72% yield (141 mg;
1
Table 3, Entry 7). H NMR (600 MHz, CDCl3): δ = 8.01–7.96 (m,
2 H), 7.45–7.40 (m, 2 H), 7.40–7.35 (m, 3 H), 7.34–7.29 (m, 2 H),
7.22–7.17 (m, 2 H), 6.85–6.80 (m, 2 H), 3.80–3.77 (s, 3 H) ppm.
13C NMR (151 MHz, CDCl3): δ = 159.0, 146.6, 140.5, 134.2, 132.9,
130.2, 129.9, 128.9, 128.8, 128.6, 128.5, 128.2, 126.3, 114.1, 108.3,
55.5 ppm. HRMS (ESI): calcd. for C22H17Cl2N2O [M + H]+
395.0712; found 395.0702.
4-[4-Bromo-3-(4-chlorophenyl)-5-phenyl-1H-pyrazol-1-yl]benzo-
nitrile (38): The title compound was isolated in 45% yield (97 mg;
[6] a) M. Ganesh, I. N. N. Namboothiri, Tetrahedron 2007, 63,
11973; b) L. V. Romashov, Y. A. Khomutova, V. M. Danilenko,
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1
Table 3, Entry 8). H NMR (600 MHz, CDCl3): δ = 8.01–7.93 (m,
2 H), 7.62–7.56 (m, 2 H), 7.51–7.43 (m, 5 H), 7.43–7.38 (m, 2 H),
7.35–7.30 (m, 2 H) ppm. 13C NMR (151 MHz, CDCl3): δ = 149.7,
142.8, 142.5, 134.9, 132.9, 130.0, 129.8, 129.8, 129.2, 129.0, 128.7,
128.4, 124.4, 118.0, 110.9, 96.6 ppm. HRMS (ESI): calcd. for
C22H14BrClN3 [M + H]+ 434.0054; found 434.0046.
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46, 1144; e) E. J. Hanan, B. K. Chan, A. A. Estrada, D. G.
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g) Y. Takahashi, S. Hibi, Y. Hoshino, K. Kikuchi, K. Shin, K.
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Med. Chem. 2012, 55, 5255; h) D. J. Rawson, S. Ballard, C.
4-[4-Chloro-3-(4-chlorophenyl)-5-phenyl-1H-pyrazol-1-yl]benzo-
nitrile (39): The title compound was isolated in 45% yield (87 mg;
1
Table 3, Entry 8). H NMR (600 MHz, CDCl3): δ = 8.01–7.96 (m,
2 H), 7.62–7.58 (m, 2 H), 7.50–7.44 (m, 5 H), 7.43–7.39 (m, 2 H),
7.35–7.30 (dd, J = 7.7, 1.8 Hz, 2 H) ppm. 13C NMR (151 MHz,
CDCl3): δ = 148.2, 142.8, 140.8, 134.9, 132.9, 129.8, 129.8, 129.5,
129.1, 128.9, 128.8, 127.6, 124.4, 118.1, 110.9, 110.5 ppm. HRMS
(ESI): calcd. for C22H14Cl2N3 [M + H]+ 390.0559; found 390.0551.
3-(4-Chlorophenyl)-1-(3-nitrophenyl)-5-phenyl-1H-pyrazole (40):
The title compound was isolated in 41% yield (76 mg; Table 3, En-
416
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Eur. J. Org. Chem. 2014, 410–417

Regioselective Synthesis of Tetrasubstituted Pyrazoles
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[12] No difference was observed in the behavior of the reactions
with in situ prepared or isolated hydrazone. The choice of one
or the other was made primarily on the basis of operational
convenience.
Received: August 27, 2013
Published Online: October 29, 2013
Eur. J. Org. Chem. 2014, 410–417
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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