Synthesis and characterization of some 3-acyl-4-amino-1-aryl-1H-pyrazoles

Article abstract of DOI:10.1002/jhet.127

(Chemical Equation Presented) A series of 3-acyl-4-amino-1-aryl-1H- pyrazoles has been prepared by reaction of β-enaminones with benzenediazonium tetrafluoroborates substituted especially by fluorine-containing groups (F, CF₃, and OCF₃

Full text of DOI:10.1002/jhet.127

650
Synthesis and Characterization of Some
3-Acyl-4-amino-1-aryl-1H-pyrazoles
Vol 46
ˇ
Petr Simunek,* Marketa Svobodova, and Vladimır Machacek
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Faculty of Chemical Technology, University of Pardubice, Institute of Organic Chemistry and
´
Technology, Studentska 573, CZ 532 10, Pardubice, Czech Republic
*E-mail: petr.simunek@upce.cz
Received January 23, 2009
DOI 10.1002/jhet.127
Published online 8 July 2009 in Wiley InterScience (www.interscience.wiley.com).
A series of 3-acyl-4-amino-1-aryl-1H-pyrazoles has been prepared by reaction of b-enaminones with
benzenediazonium tetrafluoroborates substituted especially by fluorine-containing groups (F, CF3, and
1
OCF3). The compounds prepared have been characterized by means of H and 13C NMR spectroscopy.
In the case of reaction of 5-phenylaminohept-4-en-3-one with 2,6-dichloro-4-trifluoromethylbenzenedia-
zonium tetrafluoroborate the product of azo coupling on phenylamino group of the corresponding pyraz-
ole has been isolated and identified. The intermediate (4-(4-methoxyphenyldiazenyl)-5-
methylaminohept-4-en-3-one) on the route from enaminone to pyrazole has been isolated.
J. Heterocyclic Chem., 46, 650 (2009).
INTRODUCTION
Great practical usability of pyrazole derivatives is
reflected in interest in their syntheses. Stanovnik and
Svete [8] published a review of the synthetic methods
leading to pyrazoles. Probably, the most used method
for synthesis of pyrazole skeleton is reaction of hydra-
zines with 1,3-difunctional compounds [8]. A drawback
of the methods is the possibility of formation of
regioisomers in the case of using of unsymmetrical 1,3-
difunctional compounds. Kumar et al. [9] published a
review dealing with a synthesis of trifluoromethylpyra-
zoles by reaction of corresponding trifluoromethyl-b-
diketones with hydrazines. Pyrazoles are also obtainable
from enaminones [10].
Fluorinated heterocycles represent an important class
of compounds. These compounds are widely used as
agrochemicals, pharmaceuticals, fluorinated polymers,
and catalysts [1]. It has been proved that the introduc-
tion of a CF3 group into heterocycle often leads to
enhancement of biological effect compared with a par-
ent compound, probably due to high lipophilicity of per-
fluoralkyl groups [2].
Compounds containing pyrazole moiety rank among
the compounds having broad spectrum of biological ac-
tivity [3]. A number of fluorine-containing pyrazoles
found application as insecticides [4] (e.g., fiproles), her-
bicides [4] (e.g., pyrasulfotole, fluazolate, azimsulfur-
one), and fungicides [4] (e.g., penthiopyrad). Pyrazole
ring is also an important pharmacophore. Celecoxib [5]
(Celebrex) is an example of fluorinated pyrazole used in
human medicine for treatment of osteoarthritis, rheuma-
toid arthritis, acute pain, painful menstruation and men-
strual symptoms, and to reduce numbers of colon and
rectum polyps in patients with familial adenomatous
polyposis. Pyrazole derivatives so-called scorpionates
work as metal ligands with promising perspective in ho-
mogeneous catalysis [6,7].
Combination of enaminones and diazonium salts is
useful for preparation of some heterocyclic systems: pyr-
idazinones [11], pyridazinium salts [12,13], and some
boron-containing heterocycles [14,15]. We also devel-
oped a method for synthesis of substituted 3-acyl-4-
amino-1-aryl-1H-pyrazoles using reaction of b-enami-
nones with substituted benzenediazonium tetrafluorobo-
rates [16]. Advantages of the method are mild reaction
conditions and easy performance. The method is applica-
ble for diazonium salts substituted by both electron-
donating and electron-withdrawing groups. The aim of
this study was to prepare and characterize some
C
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Synthesis and Characterization of Some 3-Acyl-4-amino-1-aryl-1H-pyrazoles
651
Scheme 1
potentially biologically active pyrazoles with one or
more fluorine atoms at various places of molecule and to
explore extension of its applicability for other substitu-
ents at the amino group of the starting b-enaminones.
none 2b, a product of azo coupling on benzene ring of
the group ¼¼CANHC6H5 of pyrazole 3 has been isolated
(Scheme 2). We have never observed formation of a
product of this type for any previously used diazonium
ions, including very reactive 4-nitrobenzenediazonium.
Indeed 2,6-Dichloro-4-trifluoromethylbenzenediazonium
is considerably more reactive than 4-nitrobenzenediazo-
nium. For 2,6-dichloro-4-trifluoromethylbenzenediazo-
nium was, from the kinetics of azo coupling with anion
of pentane-2,4-dione, found the value [17] Rr ¼ 1.73.
Difference in the values of rp constants [18] between
groups 4-NO2 and 4-CF3 is Dr ¼ 0.24, and the value of
the reaction constant of azo coupling at position 4- of
N,N-dimethylaniline is q ¼ 4.15 [19] and at position 4-
of N-methylaniline is q ¼ 3.98 [20]. It results that, for
azo coupling at position 4- of phenylamino group, 2,6-
dichloro-4-trifluoromethylbenzenediazonium is about 10
times more reactive than 4-nitrobenzenediazonium.
Because of no intermediate of the reaction has been
detected, the sequence of the reaction stages of forma-
tion of the compound 3k is unclear.
RESULTS AND DISCUSSION
The pyrazoles have been synthesized according to the
general Scheme 1. The starting components have been
selected so that a series of the pyrazoles containing fluo-
rine at various places of the molecule is prepared (fluo-
rinated diazonium salts, diketones, and amines). For
consideration of the applicability of the method some
new amines for preparation of the b-enaminones have
been used (aminoantipyrine, ethyl glycinate, 2-aminoe-
thanol) and polysubstituted diazonium salt (from 2,6-
dichloro-4-trifluoromethylaniline). For a review of the
prepared pyrazoles see Scheme 1. Pyrazoles 3b,c,h were
prepared in relative good yields 65–79%. In the most
cases, however, yields about 35% were obtained.
From the reaction mixture of enaminone 2g and 4-
methylbenzenediazonium tetrafluoroborate, only the
In the case of the reaction of 2,6-dichloro-4-trifluoro-
methylbenzenediazonium tetrafluoroborate with enami-
Scheme 2
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P. Simunek, M. Svobodova, and V. Machacek
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Vol 46
Scheme 3
starting enaminone has been isolated after 24 h and no
pyrazole was formed.
3i was 58%. Compound 4 was isolated in 18% yield.
Gas chromatography-mass spectrometry analysis of the
reaction mixture detected anisole. Extension of a reac-
The mechanisms of the pyrazole formation by reaction
of diazonium salts with b-enaminones is so far not clear.
A hypothesis assumes the primary attack of diazonium
ion at a-carbon of enaminone to form a product of azo
coupling undergoing subsequently oxidative cyclization
to pyrazole (Scheme 3). The hypothesis is supported by
the fact that by the reaction of 5-methylaminohept-4-en-
3-one (2j) with 4-methoxybenzenediazonium tetrafluoro-
borate at a molar ratio 1:1 of 4-methoxyphenyldiazenyl-
5-methylaminohept-4-en-3-one (4) (tautomeric form
assigned based on results of the structural study [21] per-
formed for similar compounds) was isolated as the main
product. Compound 4 exists in CDCl3 solution as Z iso-
mer (in analogy with similar compounds [21]) with traces
of E isomer. Corresponding pyrazole 3i was isolated as a
by-product. Oxidative cyclization of hydrazones to pyra-
zoles by number of oxidative agents (Pb(OAc)4, hyperva-
lent iodine compounds, MnO2. . .) is described in the liter-
ature [22–24]. An oxidative agent in the case of formation
of pyrazoles 3 is unclear; it could be the second molecule
of diazonium salt.
1
tion time to 2 h and subsequent H NMR analysis of the
reaction mixture proved pyrazole as practically a sole
product.
CONCLUSIONS
The method developed and described by us [16] has
been used for synthesis of pyrazole derivatives contain-
ing fluorine atoms. At the same time its usability in the
case of presence of new nitrogen substitutions of the
starting enaminone (2-hydroxyethyl, antipyrine-4-yl,
pyrrolidine-1-yl, and ethoxycarbonylmethyl) was tested.
While using 2,6-dichloro-4-trifluoromethylbenzenediazo-
nium tetrafluoroborate, the product of attack of N-phenyl
group of the starting enaminone has been isolated for
the first time.
Attack of diazonium ion at a-carbon of b-enaminone
has been proved to be the first step of our synthesis
of pyrazoles. An oxidation agent is probably the
second molecule of diazonium ion, being reduced to
substituted benzene (4-fluorobenzenediazonium to fluo-
robenzene, 4-methoxybenzenediazonium to anisole). The
mechanism of the pyrazole formation is currently under
examination.
To eliminate possibility of oxidation of primarily
formed azo compound (Scheme 3) by air oxygen, the
reaction of enaminone 2b with 4-fluorobenzenediazo-
nium tetrafluoroborate has been performed in an inert
atmosphere. After finishing the reaction, a test for diazo-
nium salt was negative and pyrazole was isolated in
69% yield (without inert atmosphere 42.5%). Presence
of fluorobenzene as a possible reduction product of dia-
zonium salt in the reaction mixture has been proved by
means of gas chromatography-mass spectrometry. Previ-
ously, anisol has been detected in the reaction of 4-
methoxybenzenediazonium tetrafluoroborate with 3-phe-
nylaminocyclopent-2-en-1-one [25].
EXPERIMENTAL
Tetrahydrofuran (THF) was dried by refluxing with sodium
benzophenone ketyl under inert atmosphere until blue–violet
coloration took place. THF was freshly distilled under inert
atmosphere before use. Dichloromethane was used commer-
cially (Fluka), dried over molecular sieves, and stored in the
bottle with Sure/Seal.
Diazonium tetrafluoroborates were freshly prepared before
using standard procedures (diazotization of corresponding ani-
line and subsequent treatment of diazonium chloride by so-
dium tetrafluoroborate) and dried in vacuo. Anhydrous sodium
acetate was purchased commercially and used without change.
NMR spectra were measured in CDCl3 using the Bruker
AVANCE 500 spectrometer operating at 500.13 MHz (1H),
125.77 MHz (13C).
The reaction of b-enaminones with benzenediazonium
salts in a molar ratio of 1:2 is accompanied by a color
change, i.e., after approximately 20–30 min the color of
the reaction mixture changes from dark red to orange.
When the reaction of 4-methoxybenzenediazonium tetra-
fluoroborate with 5-methylaminohept-4-en-3-one (2j)
was stopped after the color change, the yield of pyrazole
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Synthesis and Characterization of Some 3-Acyl-4-amino-1-aryl-1H-pyrazoles
653
Hexamethyldisiloxane was used as internal standard for 1H
(d ¼ 0.05). The 13C NMR spectra were standardized by means
of the middle signal of the solvent multiplet (d ¼ 76.9). The
carbon spectra were measured by standard way with the broad-
band decoupling of protons or by means of the APT pulse
sequence.
Diketones 1a,b,d and enaminones 2a,h,j were prepared
according to the procedure described in the literature [10].
Diketone 1c was purchased commercially (Aldrich).
CHAr), 134.7, 150.9, 161.9, 168.0, 200.2 (5 ꢀ Cq). Anal. Calcd
for C18H23N3O2: C, 68.98; H, 7.40; N, 13.41. Found: C,
69.23; H, 7.32; N, 13.48.
3-(3,4-Difluorophenylamino)-1-phenylpent-2-en-1-one
(2d). A mixture of diketone 1a (1.39 g, 7.9 mmol), 3,4-difluor-
oaniline (1.02 g, 7.9 mmol), and catalytic amount of TsOH in
toluene (15 mL) has been boiled and water formed was
removed azeotropically. After 3 h, solvent was distilled off
and the rest was suspended in n-hexane. Solid product was iso-
lated by suction and recrystallized from n-hexane. Yield: 1.12
1,1,1-Trifluoro-6-methylheptane-2,4-dione (1e). The reac-
tion has been performed in an inert atmosphere. Sodium
hydride (9.6 g, 0.4 mol) and THF (240 mL) were added to a
500-mL four-necked flask equipped with reflux condenser,
thermometer, magnetic stirrer, and dropping funnel. Methyl tri-
fluoroacetate (25.61 g, 0.2 mol) was added dropwise for
30 min. Then, 4-methylpentane-2-one (20.03 g, 0.2 mol) was
added under cooling for 30 min. The mixture was stirred under
inert atmosphere at laboratory temperature overnight. Reaction
was quenched by ethanol (10 mL) and the mixture was poured
into a flask containing 10% HCl (120 mL). Aqueous layer was
extracted by ethyl acetate (2 ꢀ 50 mL). Combined organic
layers were washed by saturated aqueous sodium bicarbonate
(1 ꢀ 150 mL), water (1 ꢀ 150 mL), and brine (1 ꢀ 150 mL),
dried with sodium sulfate, and evaporated. Diketone has been
purified through copper diketonate [16]. After complex decom-
position by dilute sulfuric acid, the product was distilled, bp
153–154ꢁC ([26] 136ꢁC). Yield: 7.66 g (19.5%). 1H NMR: d
0.94 (d, 6H, J ¼ 7.0 Hz, 2 ꢀ CH3), 2.09 (sp, 1H, J ¼ 6.5 Hz,
CH), 2.26 (d, 2H, J ¼ 7.5 Hz, CH2), 5.87 (s, 1H, ¼¼CAH),
14.28 (brs, 1H, NH). 13C NMR: d 22.1 (CH3), 26.3 (CH), 47.0
(CH2), 96.0 (q, J ¼ 1.8 Hz, ¼¼CH), 116.9 (q, J ¼ 283.3, CF3),
176.3 (q, J ¼ 36.2 Hz, ¼¼CAOH), 196.3 (C¼¼O).
1
g (49.3%), mp 54–57ꢁC. H NMR: d 1.14 (t, 3H, J ¼ 7.5 Hz,
CH3), 2.40 (q, 2H, J ¼ 7.5 Hz, CH2), 5.94 (s, 1H, ¼¼CAH),
6.89–6.92 (m, 1H, NPh), 7.02 (ddd, 1H, J ¼ 10.9, 7.0, 2.7 Hz,
NPh), 7.13 (dt, 1H, J ¼ 8.8, 9.5 Hz, NPh), 7.40–7.47 (m, 3H,
Ph), 7.89–7.91 (m, 2H, Ph), 12.98 (brs, 1H, NH). 13C NMR: d
12.4 (CH3), 25.4 (CH2), 92.5 (¼¼CH), 114.7 (d, J ¼ 18.5 Hz,
NPh), 117.5 (d, J ¼ 18.1 Hz, NPh), 121.5 (dd, J ¼ 6.0, 3.4
Hz, NPh), 127.0, 128.2, 131.0 (3 ꢀ CH, Ph), 134.9 (dd, J ¼
7.7, 3.5 Hz, NPh), 139.7 (Ph), 148.3 (dd, J ¼ 198.7, 13.5 Hz,
NPh), 150.3 (dd, J ¼ 200.7, 13.5 Hz, NPh), 167.2 (Cq), 189.42
(C¼¼O). Anal. Calcd for C17H15F2NO: C, 71.07; H, 5.26; N,
4.88. Found: C, 71.27; H, 5.01; N, 5.10.
3-(Ethoxycarbonylmethylamino)-1-phenylpent-2-en-1-one
(2e). A mixture of ethyl glycinate hydrochloride (2.38 g, 17
mmol), 1a (3 g, 17 mmol) and NaHCO3 (1.43 g, 17 mmol) in
ethanol (30 mL) has been refluxed for 5.5 h. The mixture was
then cooled, filtered, and the solvent was distilled off. The res-
idue was extracted with dichloromethane (20 mL), filtered, and
the filtrate was evaporated. The residue was recrystallized
from hexane–cyclohexane mixture. Yield: 3.90 g (87%), mp
1
69–71.5ꢁC. H NMR: d 1.18 (t, 3H, J ¼ 7.5 Hz, CH3), 1.26 (t,
3H, J ¼ 7.0 Hz, CH3), 2.28 (q, 2H, J ¼ 7.5 Hz, CH2), 4.06 (d,
2H, J ¼ 6.0 Hz, NACH2), 4.21 (q, 2H, J ¼ 7.0 Hz, OACH2),
5.75 (s, 1H, ¼¼CAH), 7.34–7.40 (m, 3H, Ph), 7.83–7.85 (m,
2H, Ph), 11.55 (brs, 1H, NH). 13C NMR d: 11.9, 14.0 (2 ꢀ
CH3), 25.2, 44.3, 61.6 (3 ꢀ CH2), 91.0 (¼¼CH), 126.9, 128.0,
130.5 (3 ꢀ CHAr), 140.2, 168.6, 168.9 (3 ꢀ Cq), 188.8
(C¼¼O). Anal. Calcd for C15H19NO3: C, 68.94; H, 7.33; N,
5.36. Found: C, 69.12; H, 7.28; N, 5.26.
5-Phenylaminohept-4-en-3-one (2b). A mixture of 1c (6.61
g, 0.05 mol), aniline (4.65 g, 0.05 mol), and catalytic amount
of TsOH in toluene (30 mL) has been boiled on an oil bath for
2.5 h. Reaction water was removed azeotropically. After com-
pletion of the reaction, volatile components were distilled off
in vacuo and the rest was subjected to a vacuum distillation.
1
Yield: 7.54 g (74%), bp 142–144ꢁC/0.5 kPa. H NMR: d 1.04
1-Phenyl-3-(pyrrolidine-1-yl)pent-2-en-1-one
(2f). The
(t, 3H, J ¼ 7.5 Hz, CH3), 1.13 (t, 3H, J ¼ 7.5 Hz, CH3), 2.31
(q, 2H, J ¼ 7.5 Hz, CH2), 2.36 (q, 2H, J ¼ 7.5 Hz, CH2), 5.20
(s, 1H, ¼¼CAH), 7.09–7.10 (m, 2H, Ph), 7.16–7.19 (m, 1H,
Ph), 7.30–7.33 (m, 2H, Ph), 12.48 (brs, 1H, NH). 13C NMR: d
9.7 (CH3), 12.3 (CH3), 25.0 (CH2), 35.1 (CH2), 94.2 (¼¼CH),
125.0, 125.5, 128.9 (3 ꢀ CHAr), 138.5, 165.8, 200.0 (3 ꢀ Cq).
Anal. Calcd for C13H17NO: C, 76.81; H, 8.43; N, 6.89. Found:
C, 76.65; H, 8.49; N, 6.96.
5-(1,5-Dimethyl-3-oxo-2-phenyl-1,2-dihydropyrazol-4-yl)-
aminohept-4-en-3-one (2c). A mixture of 1c (3.84 g, 0.03
mol) and 4-aminoantipyrine (4.06 g, 0.02 mol) has been stirred
at laboratory temperature overnight. The mixture was then
diluted by petroleum ether (70 mL). Separated oil solidified on
standing. The solidified product was thoroughly washed with
petroleum ether. Yield: 5.72 g (91.3%), mp 94–96.5ꢁC. 1H
NMR: d 1.04 (t, 3H, J ¼ 7.5 Hz, CH3), 1.10 (t, 3H, J ¼ 7.5
Hz, CH3), 2.21 (s, 3H, ¼¼CACH3), 2.30 (q, 2H, J ¼ 7.5 Hz,
CH2), 2.34 (q, 2H, J ¼ 7.5 Hz, CH2), 3.05 (s, 3H, NACH3),
5.21 (s, 1H, ¼¼CAH), 7.25–7.29 (m, 1H, Ph), 7.36–7.38 (m,
2H, Ph), 7.42–7.45 (m, 2H, Ph), 11.54 (brs, 1H, NH). 13C
NMR: d 9.6, 10.4, 11.5 (3 ꢀ CH3), 25.0, 35.1 (2 ꢀ CH2), 36.0
(CH3), 94.0 (¼¼CAH), 110.4 (Cq), 123.8, 126.6, 129.0 (3 ꢀ
procedure from Ref. [27] has been adopted. A mixture of dike-
tone 1a (2.05 g, 11.6 mmol), pyrrolidine (1.03 g, 14.4 mmol),
and CoCl2ꢂ6H2O (0.14 g, 0.58 mmol) has been stirred at labo-
ratory temperature for 72 h, then mixed with CH2Cl2 and fil-
tered. Filtrate was evaporated and the residue was recrystal-
lized from cyclohexane. Yield: 1.50 g (56.4%) mp 105–108ꢁC.
1H NMR: d 1.24 (t, 3H, J ¼ 7.5 Hz, CH3), 1.96 (brs, 4H, 2 ꢀ
CH2), 3.12 (q, 2H, J ¼ 7.5 Hz, CH2), 3.33 (brs, 2H, CH2),
3.56 (brs, 2H, CH2), 5.55 (s, 1H, ¼¼CAH), 7.34–7.38 (m, 3H,
Ph), 7.85–7.86 (m, 2H, Ph). 13C NMR: d 12.2 (CH3), 24.4,
24.8, 25.4, 47.3, 48.7 (5 ꢀ CH2), 91.5 (¼¼CH), 127.2, 128.0,
130.1 (3 ꢀ CHAr), 143.1, 167.0 (2 ꢀ Cq), 187.0 (C¼¼O). Anal.
Calcd for C15H19NO: C, 78.56; H, 8.35; N, 6.11. Found: C,
78.60; H, 8.29; N, 6.14.
1,1,1-Trifluoro-5-methyl-4-(3,4-difluorophenylamino)hept-
3-en-2-one (2g). A mixture of 1e (2.94 g, 15 mmol), 3,4-
difluoroaniline (1.94 g, 15 mmol), and catalytic amount of
TsOH in toluene (10 mL) has been heated to 110ꢁC for 3 h.
The mixture solidified on cooling. The solidified mixture was
subjected to column chromatography (silicagel/CHCl3-EtOAc
6:1). Yield: 2.66 g (57.7%). Recrystallization from aqueous
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ethanol, mp 50–56ꢁC. 1H NMR: d 0.86 (d, 6H, J ¼ 6.6 Hz,
2 ꢀ CH3), 1.80 (sp, 1H, J ¼ 6.8 Hz, CH), 2.24 (d, 2H, J ¼
7.4 Hz, CH2), 5.56 (s, 1H, ¼¼CAH), 6.90–6.94 (m, 1H, NPh),
7.02 (ddd, 1H, J ¼ 2.6, 6.9, 10.0 Hz, NPh), 7.22 (dt, 1H, J ¼
8.7, 9.8 Hz, NPh), 12.54 (brs, 1H, NH). 13C NMR: d 22.1
(CH3), 27.8 (CH), 40.8 (CH2), 90.5 (¼¼CH), 115.6 (d, J ¼ 18.8
Hz, NPh), 117.2 (q, J ¼ 288.3 Hz, CF3), 117.9 (d, J ¼ 18.4
Hz, NPh), 122.4 (dd, J ¼ 6.3, 3.6 Hz, NPh), 133.2 (dd, J ¼
7.5, 3.6 Hz, NPh), 149.5 (dd, J ¼ 250.6, 12.4 Hz, CAF),
150.1 (dd, J ¼ 251.9, 13.6 Hz, CAF), 171.4, 177.1 (q, J ¼
33.3, C¼¼O). Anal. Calcd for C14H14F5NO: C, 54.73; H, 4.59;
N, 4.56. Found: C, 55.11; H, 4.41; N, 4.77.
3-Benzoyl-1-(4-fluorophenyl)-5-phenyl-4-phenylamino-1H-
pyrazole (3c). This is prepared from enaminone 2a and 4-fluo-
robenzenediazonium tetrafluoroborate. Chromatography silica-
gel/CH2Cl2, yield 79%, recrystallization from ethanol, mp
1
148–150ꢁC. H NMR: d 6.56–6.61 (m, 3H, Ph), 6.86–6.89 (m,
2H, Ph), 6.97–7.00 (m, 2H, Ph), 7.10–7.13 (m, 5H), 7.26–7.28
(m, 2H, Ph), 7.42–7.46 (m, 2H), 7.50–7.53 (m, 2H), 8.31–8.33
(m, 2H). 13C NMR: d 115.8 (d, JCF ¼ 23.0 Hz, CH), 116.4,
119.7 (2 ꢀ CH), 127.3 (d, JCF ¼ 8.7 Hz, CH), 128.1, 128.2,
128.3 (3 ꢀ CH), 128.9, 128.9 (2 ꢀ Cq), 129.0, 130.4, 132.6
(3 ꢀ CH), 133.0 (Cq), 135.9 (d, JCF ¼ 3.2 Hz, Cq), 137.1,
141.9, 142.9 (3 ꢀCq), 161.8 (d, JCF ¼ 248.9 Hz, CAF), 189.3
(C¼¼O). Anal. Calcd for C28H20FN3O: C, 77.58; H, 4.65; N,
9.69. Found: C, 77.55; H, 4.90; N, 9.71.
1-Cyclopropyl-3-(2-hydroxyethyl)hex-2-en-1-one (2i). A
mixture of diketone 1d (3.08 g, 0.02 mol) and ethanolamine
(1.22 g, 0.02 mol) in toluene (10 mL) has been refluxed in the
presence of catalytic amount of TsOH for 5.5 h. The mixture
was then cooled and washed by water (10 mL). Organic phase
was separated, dried by sodium sulfate, and solvent was
evaporated. The residue was recrystallized from n-hexane.
1-(4-Fluorophenyl)-5-methyl-4-(1,5-dimethyl-2-phenyl-1,2-
dihydropyrazol-3-one-4-ylamino)-3-propanoyl-1H-pyrazole
(3d). This compound is prepared from enaminone 2c and 4-
fluorobenzenediazonium tetrafluoroborate. Chromatography sil-
icagel/CHCl3-EtOAc 3:2, yield 37.2%, recrystallization from
ethanol, mp 184–189.5ꢁC. 1H NMR: d 1.08 (t, 3H, J ¼ 7.0
Hz, CH3), 1.91 (s, 3H, CH3), 2.13 (s, 3H, CH3), 2.89–2.95 (m,
5H, CH2 þ CH3), 6.99–7.03 (m, 2H, Ph), 7.13–7.16 (m, 1H,
Ph), 7.26–7.32 (m, 6H, Ph). 13C NMR: d 7.7, 9.9, 10.0 (3 ꢀ
1
Yield: 2.5 g (63.4%), mp 68–71ꢁC. H NMR: d 0.67–0.71 (m,
2H, cPr CH2), 0.88–0.91 (m, 2H, cPr CH2), 0.98 (t, 3H, J ¼
7.0 Hz, CH3), 1.54–1.64 (m, 3H, cPr CH þ CH2), 2.17–2.20
(m, 2H, CH2), 3.37 (q, 2H, J ¼ 5.7 Hz, CH2N), 3.71 (brt, 2H,
J ¼ 5.6 Hz, CH2O), 3.85 (brs, 1H, OH), 5.13 (s, 1H, ¼¼CAH),
10.81 (brs, 1H, NH). 13C NMR: d 8.5 (CH2), 13.8 (CH3), 19.7
(CH), 21.1, 33.9, 44.7, 61.2 (4 ꢀ CH2), 94.0 (¼¼CH), 166.3
(¼¼CAN), 196.6 (C¼¼O). Anal. Calcd for C11H19NO2: C,
66.97; H, 9.71; N, 7.10. Found: C, 67.31; H, 9.39; N, 7.23.
Pyrazoles synthesis. The following pyrazoles have been
prepared according to the published procedure [16].
CH3), 31.2 (CH2), 35.7 (NCH3), 112.9 (Cq), 115.5 (d, JCF
¼
23.0 Hz, CH), 123.5 (CH), 124.5 (Cq), 126.3 (CH), 126.7 (d,
JCF ¼ 8.7 Hz, CH), 128.7, 131.2, 134.4 (2 ꢀ Cq), 135.0 (d,
JCF ¼ 2.9 Hz, Cq), 138.0, 150.9 (2 ꢀ Cq), 161.6 (d, JCF
¼
248.5 Hz, CAF), 163.2 (Cq), 199.2 (C¼¼O). Anal. Calcd for
C24H24FN5O2: C, 66.50; H, 5.58; N, 16.16. Found: C, 66.67;
H, 5.32; N, 15.92.
1-(4-Fluorophenyl)-5-methyl-4-phenylamino-3-propanoyl-
1H-pyrazole (3a). This is prepared from enaminone 2b and 4-
fluorobenzenediazonium tetrafluoroborate. Chromatography sil-
icagel/CH2Cl2, yield 42.5%, recrystallization from ethanol, mp
100–102ꢁC. 1H NMR: d 1.16 (t, 3H, J ¼ 7.5 Hz, CH3), 2.10
(s, 3H, CH3), 3.04 (q, 2H, J ¼ 7.5 Hz, CH2), 6.76–6.78 (m,
2H, Ph), 6.81–6.84 (m, 1H, Ph), 6.91 (brs, 1H, NH), 7.17–7.23
(m, 4H, Ph), 7.48–7.51 (m, 2H, Ph). 13C NMR: d 7.7, 12.0
(2 ꢀ CH3), 32.0 (CH2), 115.6 (CHAr), 116.2 (d, JCF ¼ 23.0
Hz, CHAr), 119.7 (CHAr), 126.6 (d, JCF ¼ 8.7 Hz, CHAr),
126.6 (Cq), 129.0 (CHAr), 131.6, 135.4 (d, JCF ¼ 2.9 Hz, Cq),
141.6, 144.5, 162.1 (d, JCF ¼ 249.0 Hz, CAF), 199.3 (C¼¼O).
Anal. Calcd for C19H18FN3O: C, 70.57; H, 5.61; N, 12.99.
Found: C, 70.77; H, 5.37; N, 12.99.
3-Benzoyl-1-(2-fluorophenyl)-4-methylamino-5-phenyl-1H-
pyrazole (3e). This is prepared from enaminone 2h and 2-fluo-
robenzenediazonium tetrafluoroborate. Chromatography silica-
gel/CH2Cl2, yield 39.5%, recrystallization from ethanol, mp
140–145ꢁC. 1H NMR: d 2.54 (s, 3H, CH3), 5.94 (brs, 1H.
NH), 7.00–7.04 (m, 1H, Ph), 7.07–7.10 (m, 1H, Ph), 7.24–7.31
(m, 7H), 7.42–7.45 (m, 2H), 7.49–7.53 (m, 1H), 8.29–8.31 (m,
2H). 13C NMR: d 33.3 (CH3), 116.4 (d, JCF ¼ 19.7 Hz, CH),
124.1 (d, JCF ¼ 3.9 Hz, CH), 127.7, 127.9, 128.2, 129.2 (3 ꢀ
CH), 129.7 (Cq), 130.3 (CH), 130.4 (d, JCF ¼ 7.7 Hz, CH),
130.5, 132.1 (2 ꢀ CH), 137.9 (d, JCF ¼ 9.9 Hz, Cq), 138.7
(Cq), 157.0 (d, JCF ¼ 253.4 Hz, CAF), 190.0 (C¼¼O). Anal.
Calcd for C23H18FN3O: C, 74.38; H, 4.88; N, 11.31. Found: C,
74.16; H, 5.17; N, 11.06.
3-Benzoyl-1-(4-fluorophenyl)-4-(3,4-difluorophenylamino)-
5-methyl-1H-pyrazole (3b). This compound is prepared from
enaminone 2d and 4-fluorobenzenediazonium tetrafluoroborate.
Chromatography silicagel/CH2Cl2, yield 70%, recrystallization
3-Benzoyl-4-ethoxycarbonylmethylamino-1-(4-fluorophenyl)-
5-methyl-1H-pyrazole (3f). The compound 3f is prepared from
enaminone 2e and 4-fluorobenzenediazonium tetrafluoroborate.
Chromatography silicagel/CHCl3-EtOAc 6:1, yield 56%, oil.
1H NMR: d 1.21 (t, 3H, J ¼ 7.0 Hz, CH3), 2.31 (s, 3H, CH3),
3.96 (s, 2H, CH2), 4.17 (q, 2H, J ¼ 7.0 Hz, CH2), 6.02 (brs,
1H, NH), 7.15–7.18 (m, 2H), 7.41–7.44 (m, 4H), 7.50–7.53
(m, 1H), 8.28–8.29 (m, 2H). It was not possible to purify the
compound sufficiently for elemental analysis.
1
from ethanol, mp 190–193ꢁC. H NMR: d 2.14 (s, 3H, CH3),
6.50–6.51 (m, 1H, Ph), 6.56 (ddd, 1H, J ¼ 12.3, 6.7, 2.7 Hz,
Ph), 6.99 (dt, 1H, J ¼ 8.9, 9.9 Hz, Ph), 7.09 (brs, 1H, NH),
7.18–7.22 (m, 2H, Ph), 7.42–7.45 (m, 2H, Ph), 7.50–7.55 (m,
3H, Ph), 8.30–8.31 (m, 2H, Ph). 13C NMR: d 11.8 (CH3),
104.2 (d, JCF ¼ 20.8 Hz), 111.1 (dd, JCF ¼ 5.4, 2.9 Hz), 116.2
3-Benzoyl-1-(3-trifluoromethylphenyl)-5-methyl-4-(pyrroli-
dine-1-yl)-1H-pyrazole (3g). This is prepared from enaminone
2f and 3-trifluoromethylbenzenediazonium tetrafluoroborate.
(d, JCF ¼ 23.0 Hz), 117.3 (d, JCF ¼ 17.9 Hz), 126.6 (d, JCF
¼
8.7 Hz), 128.0, 128.1, 130.5, 131.9, 132.8, 135.3 (d, JCF ¼ 3.1
Hz), 136.8, 141.6 (dd, JCF ¼ 8.2, 2.0 Hz), 142.0, 144.3 (dd,
JCF ¼ 239.1, 12.8 Hz), 150.6 (dd, JCF ¼ 246.2, 13.8 Hz),
162.2 (d, JCF ¼ 249.2 Hz), 189.2 (C¼¼O). Anal. Calcd for
C23H16F3N3O: C, 67.81; H, 3.96; N, 10.31. Found: C, 67.94;
H, 4.04; N, 10.32.
1
Chromatography silicagel/CH2Cl2, yield 38.3%, oil. H NMR:
d 1.94–1.97 (m, 4H, CH2 pyrr.), 2.37 (s, 3H, CH3), 3.18–3.20
(m, 4H, CH2, pyrr.), 7.44–7.47 (m, 2H), 7.53–7.56 (m, 1H),
7.60–7.62 (m, 1H), 7.64–7.66 (m, 1H), 7.69–7.71 (m, 1H),
7.77 (brs, 1H), 8.11–8.13 (m, 2H). 13C NMR: d 11.0 (CH3),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2009
Synthesis and Characterization of Some 3-Acyl-4-amino-1-aryl-1H-pyrazoles
655
25.9, 52.4 (2 ꢀ CH2), 121.5 (q, JCF ¼ 3.9 Hz, CH), 123.3 (q,
JCF ¼ 273.0 Hz, CF3), 124.5 (q, JCF ¼ 3.7 Hz, CH), 127.8,
128.0, 129.7, 130.5 (4 ꢀ CH), 131.6 (q, JCF ¼ 33.2 Hz, Cq),
132.6 (CH), 134.5, 134.6, 137.9, 140.1, 145.1 (5 ꢀ Cq), 189.8
(C¼¼O). Anal. Calcd for C22H20F3N3O: C, 66.16; H, 5.05; N,
10.52. Found: C, 66.08; H, 5.34; N, 10.34.
3-Cyclopropylcarbonyl-5-ethyl-4-(2-hydroxyethylamino)-1-
(4-methylphenyl)-1H-pyrazole (3h). This is prepared from
enaminone 2i and 4-methylbenzenediazonium tetrafluoroborate.
Chromatography silicagel/CH2Cl2-EtOAc 4:1, yield 65.7%,
recrystallization from n-hexane, mp 112–114ꢁC. 1H NMR: d
0.90–0.94 (m, 2H, cPr CH2), 0.98 (t, 3H, J ¼ 7.5 Hz, CH3),
1.13–1.16 (m, 2H), 2.38 (s, 3H, CH3Ph), 2.63 (q, 2H, J ¼ 7.5
Hz, CH2), 3.02 (tt, 1H, J ¼ 4.6, 8.0 Hz, cPr CH), 3.16–3.18 (m,
2H, NCH2), 3.60–3.62 (m, 2H, CH2O), 4.63 (brs, 1H, OH),
7.24–7.29 (m, 4H, Ph). 13C NMR: d 11.4 (cPr CH2), 12.9, 17.0
(2 ꢀ CH3), 17.7 (CH2), 21.0 (cPr CH), 50.4, 61.0 (2 ꢀ CH2),
125.4, 129.6 (2 ꢀ CHAr), 131.8, 134.5, 137.0, 138.8, 140.9 (5 ꢀ
Cq), 199.2 (C¼O). Anal. Calcd for C18H23N3O2: C, 68.98; H,
7.40; N, 13.41. Found: C, 69.27; H, 7.45; N, 13.58.
200.4. Anal. Calcd for C15H21N3O2: C, 65.43; H, 7.69; N,
15.26. Found: C, 65.28; H, 7.40; N, 15.46.
Acknowledgments. The authors are indebted to the Ministry of
Education, Youth and Sports of the Czech Republic (Project No.
MSM 002 162 7501) and Czech Science Foundation (Project No.
203/07/0469) for financial support. The authors also thank Mr.
´
Radim Horak for his help with some experiments and Ms. Gabri-
ela Adamova for preliminary results in this field.
´
REFERENCES AND NOTES
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1-(4-Methoxyphenyl)-4-methylamino-5-methyl-3-propanoyl-
1H-pyrazole (3i). This is prepared from enaminone 2j and 4-
methoxybenzenediazonium tetrafluoroborate. Chromatography
silicagel/CH2Cl2-EtOAc 4:1. Yield 62.9% mp 79–82ꢁC ([16]
79–82ꢁC).
[6] Trofimenko, S. Scorpionates. The Coordination Chemistry of
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Imperial College Press: London, 2008.
1-(2-Trifluoromethoxyphenyl)-5-methyl-4-phenylamino-3-
propanoyl-1H-pyrazole (3j). Prepared from enaminone 2b and
2-trifluoromethoxybenzendiazonium tetrafluoroborate. Chroma-
tography silicagel/CH2Cl2, yield 23% (in an inert atmosphere
[8] Stanovnik, B.; Svete, J. In Science of Synthesis; Neier R.
Ed.; Thieme: Stuttgart, 2002; Vol. 12, pp 15–226.
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1
34%). H NMR: d 1.16 (t, 3H, J ¼ 7.4 Hz CH3), 1.98 (s, 3H,
CH3), 3.04 (q, 2H, J ¼ 7.4 Hz CH2), 6.76–6.77 (m, 2H), 6.83–
6.86 (m, 1H), 6.87 (brs, 1H, NH), 7.20–7.23 (m, 2H), 7.45–
7.50 (m, 2H), 7.54–7.59 (m, 2H).
[10] Stanovnik, B.; Svete, J. Chem Rev 2004, 104, 2433.
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[11] Pahovnik, D.; Ursic, U.; Groselj, U.; Meden, A.; Svete, J.;
1-(2,6-Dichloro-4-trifluoromethyl)-4-[4-(2,6-dichloro-4-tri-
fluoromethylphenyldiazenyl)phenylamino]-5-methyl-3-propa-
noyl-1H-pyrazole (3k). Prepared from enaminone 2b and 2,6-
dichloro-4-trifluoromethylbenzenediazonium tetrafluoroborate.
Chromatography silicagel/CH2Cl2, yield 27.3%, recrystalliza-
tion from ethanol, mp 192–194ꢁC. 1H NMR: d 1.18 (t, 3H,
J ¼ 7.3 Hz, CH3), 2.02 (s, 3H, CH3), 3.05 (q, 2H, J ¼ 7.3 Hz,
CH2), 6.81–6.83 (AA0, 2H), 7.03 (s, 1H, NH), 7.64 (s, 2H,
CHAr), 7.81 (s, 2H, CHAr), 7.90–7.92 (XX0, 2H). 13C NMR: d
Stanovnik, B. Z Naturforsch 2008, 63b, 407.
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[12] Simunek, P.; Peskova, M.; Bertolasi, V.; Lycka, A.; Macha-
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cek, V. Eur J Org Chem 2004, 5055.
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[13] Simunek, P.; Peskova, M.; Bertolasi, V.; Machacek, V.;
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´
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Lycka, A. Tetrahedron 2005, 61, 8130.
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[14] Peskova, M.; Simunek, P.; Bertolasi, V.; Machacek, V.;
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Lycka, A. Organometallics 2006, 25, 2025.
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[15] Svobodova, M.; Barta, J.; Simunek, P.; Bertolasi, V.;
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Machacek, V. J Organomet Chem 2009, 694, 63.
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[16] Simunek, P.; Svobodova, M.; Bertolasi, V.; Machacek, V.
7.6, 10.3 (2 ꢀ CH3), 32.4 (CH2), 114.5 (Cq), 121.9 (q, JCF
¼
˚
´
´ˇ
Synthesis 2008, 1761.
ˇ
[17] Machacek, V.; Panchartek, J.; Sterba, V.; Vecera, M. Col-
273.5 Hz, CF3), 122.5 (q, JCF ¼ 273.1 Hz, CF3), 123.3 (Cq),
125.7 (CH), 125.9 (q, JCF ¼ 3.7 Hz, CH), 126.0 (q, JCF ¼ 3.5
Hz, CH), 127.6 (CH), 134.0 (q, JCF ¼ 34.6 Hz, 2 ꢀ Cq), 135.2
(Cq), 136.0 (Cq), 137.5 (Cq), 144.0 (Cq), 145.8 (Cq), 149.3
(Cq), 151.4 (Cq), 198.8 (C¼¼O). Anal. Calcd for
C27H17Cl4F6N5O: C, 47.46; H, 2.51; N, 10.25. Found: C,
47.71; H, 2.21; N, 10.29.
´ˇ
ˇ
ˇ ˇ
lect Czech Chem Commun 1969, 34, 844.
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[21] Simunek, P.; Svobodova, M.; Bertolasi, V.; Pretto, L.;
4-Methoxyphenyldiazenyl-5-methylaminohept-4-en-3-one
(4). The compound has been prepared by the same procedure
as pyrazoles 3a–j but the molar ratio of diazo:enaminone was
1:1. The reaction was performed for 24 h under inert atmos-
phere. Chromatography silicagel/CH2Cl2-EtOAc 4:1. Yield
˚
´
ˇ
´ˇ
Lycka, A.; Machacek, V. New J Chem 2007, 31, 429.
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1
45.2%, oil. H NMR (major isomer only) d: 1.14 (t, 3H, J ¼
[24] Kotali, A. Curr Org Chem 2002, 6, 965.
ˇ
7.5 Hz, CH3), 1.25 (t, 3H, J ¼ 7.5 Hz, CH3), 2.99–3.03 (m,
4H, 2 ꢀ CH2), 3.13 (s, 3H, NACH3), 3.83 (s, 3H, OCH3),
6.92–6.94 (m, 2H, AA0), 7.53–7.55 (brm, 2H, XX0), 14.53
(brs, 1H, NH). 13C NMR: (major isomer only) d 9.4, 11.5,
21.8, 28.8, 32.7, 55.3, 114.1, 121.1, 127.0, 145.8, 158.6, 165.1,
˚
´ ´
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Lycka, A.; Machacek, V. Magn Reson Chem 2007, 45, 330.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet