Facile and straightforward method leading to substituted 4-amino-1-arylpyrazoles

Article abstract of DOI:10.1055/s-2008-1067042

A new method for the synthesis of substituted 4-amino-l-arylpyrazoles is described, starting from β-enaminones and variously substituted benzenediazonium tetrafluoroborates. The reaction proceeds under mild conditions, is very simple to perform, and is applicable to a relatively wide range of substituents, both at the β-enaminone and diazonium salt starting materials.

Full text of DOI:10.1055/s-2008-1067042

PAPER
1761
Facile and Straightforward Method Leading to Substituted
4-Amino-1-arylpyrazoles
Method Leadi
e
S
ubst
t
4
r
-Amino-1-aryl
Š
pyrazoles imůnek,*a Markéta Svobodová,a Valerio Bertolasi,b Vladimír Macháčeka
a
Department of Organic Chemistry, Faculty of Chemical Technology, University of Pardubice, Nám. Čs. Legií 565,
53210 Pardubice, Czech Republic
Fax +420(466)037068; E-mail: petr.simunek@upce.cz
Dipartimento di Chimica and Centro di Strutturistica Diffrattometrica, Università di Ferrara, Via L. Borsari 46, 44100 Ferrara, Italy
b
Received 14 February 2008; revised 21 February 2008
NR3R4
R2
Abstract: A new method for the synthesis of substituted 4-amino-
1-arylpyrazoles is described, starting from b-enaminones and vari-
ously substituted benzenediazonium tetrafluoroborates. The reac-
tion proceeds under mild conditions, is very simple to perform, and
is applicable to a relatively wide range of substituents, both at the b-
enaminone and diazonium salt starting materials.
X
N
N
N
R1
N
–
BF4
–
N2+ BF4
O
NR3R4
R2
Key words: diketones, enaminones, diazonium salts, pyrazoles,
heterocycles
X
3
+
R1
O
NR3R4
R2
X
1
2
R1
b-Enaminones are, thanks to their ability to react with
wide variety of both electrophilic and nucleophilic
agents,1 versatile intermediates in many synthetic trans-
formations, especially in heterocyclic syntheses.2–8 b-
Enaminones are also important precursors and building
blocks for syntheses of many biologically active com-
pounds, such as dopamine agonists,9 acetylcholinesterase
inhibitors,10 anticonvulsants,11 alkaloids,12 and anti-
inflammatory13 and antitumor14 drugs. Chiral enaminones
are useful ligands for diastereoselective syntheses.15
N
N
X
4
Scheme 1
The combination of b-enaminones with benzenediazoni-
um salts has shown to be a powerful tool for the synthesis
of some heterocyclic systems. We have previously de-
scribed the utilisation of b-enaminones in the syntheses of
pyridazinium salts,16,17 oxazaborines, and triazaborines.18
A small modification in the structure of the starting en-
aminone 1 (introduction of a methylene group next to the
enamino group) does not lead to the formation of 3-substi-
tuted pyridazinium salts 3, as expected in analogy with lit-
erature procedures16,17 (Scheme 1). On the basis of the
1
analysis of H and 13C NMR spectra, we concluded that
the reaction products are pyrazole derivatives
4
(Scheme 1). The pyrazole structure 4 was finally proved
also by 15N NMR spectra and by X-ray diffraction analy-
ses (Figure 1 and Figure 2).
The scope and limitation of the reaction was tested with
regard to the structure of the starting enaminone 1, the
type of amino group and the substitution on the diazonium
salt 2 (Scheme 1).
Figure 1 ORTEP19 view of compound 4b (thermal ellipsoids at
30% probability)
The starting b-diketones 5 were prepared by reaction of
(Scheme 2). We successfully used potassium tert-pentyl-
oxide (t-PentOK) as the base instead of sodium hydride or
amide (Scheme 2). The resulting b-diketones 5 were
(except for 5c) purified via the corresponding copper(II)
b-diketonates.
the corresponding methyl ketones with methyl esters
SYNTHESIS 2008, No. 11, pp 1761–1766
x
x.
x
x
.
2
0
0
8
Advanced online publication: 29.04.2008
DOI: 10.1055/s-2008-1067042; Art ID: Z04308SS
© Georg Thieme Verlag Stuttgart · New York

1762
P. Šimůnek et al.
PAPER
PhNH2, toluene, H+
or MeNH2, EtOH
or NH4OAc, EtOH
O
NR3R4
O
O
R2
R2
R1
R1
5a–c
1a–g
35–86%
O
Cl
morpholine, Et2O
(COCl)2
CH2Cl2
R2
R1
49%
R1 = Ph, R2 = Me
1a: R1 = Ph, R2 = Me, R3 = Ph, R4 = H
1b: R1 = Ph, R2 = Me, R3 = Me, R4 = H
1c: R1 = Ph, R2 = Me, R3 ,R4 = morpholin-4-yl
1d: R1 = c-Pr, R2 = Et, R3 = R4 = H
1e: R1 = Ph, R2 = Ph, R3 = Me, R4 = H
1f: R1 = Ph, R2 = Ph, R3 = Ph, R4 = H
1g: R1 = Et, R2 = Me, R3 = Me, R4 = H
Scheme 3
O
NR3R4
R2
–
N2+ BF4
O
NR3R4
R2
R1
Figure 2 ORTEP19 view of compound 4h (thermal ellipsoids at
30% probability)
AcONa
CH2Cl2
N
N
+
R1
40–80%
X
1a–g
2
O
O
O
X
4a–m
t-PentOK
4a: R1 = Ph, R2 = Me, R3 = Me, R4 = H, X = 4-Me
4b: R1 = Ph, R2 = Me, R3 = Me, R4 = H, X = 4-OMe
4c: R1 = Ph, R2 = Me, R3 = Ph, R4 = H, X = 4-Me
4d: R1 = Ph, R2 = Me, R3 = Ph, R4 = H, X = 3-Me
4e: R1 = Ph, R2 = Me, R3 = Ph, R4 = H, X = 4-Cl
4f: R1 = Ph, R2 = Me, R3 = Ph, R4 = H, X = 2-Me
R2
COOMe
R2
+
R1
Me
R1
THF–toluene
65–69%
5a: R1 = Ph, R2 = Me
5b: R1 = Ph, R2 = Ph
5c: R1 = c-Pr, R2 = Et
4g: R1 = Ph, R2 = Me, R3,R4 = morpholin-4-yl, X = 4-Me
4h: R1 = Ph, R2 = Ph, R3 = Me, R4 = H, X = 4-OMe
4i: R1 = Ph, R2 = Ph, R3 = Me, R4 = H, X = 4-Me
4j: R1 = Ph, R2 = Ph, R3 = Ph, R4 = H, X = 3-CF3
4k: R1 = Ph, R2 = Ph, R3 = Ph, R4 = H, X = 3-CO2Et
4l: R1 = c-Pr, R2 = Et, R3 = R4 = H, X = 4-Me
Scheme 2
b-Enaminones 1 with N-methyl and N-phenyl groups
were prepared by condensation of b-diketones 5 with
methylamine or aniline (Scheme 3). Preparation of 1c by
reaction of 5a with morpholine was not successful. In-
stead, product 1c was prepared by transformation of 5a
into 3-chloro-1-phenylpent-2-en-1-one by reaction with
oxalyl chloride. Subsequent reaction of 3-chloro-1-phe-
nylpent-2-en-1-one with morpholine led to nucleophilic
substitution of the chloro group to give 1c (Scheme 3).
Enaminone 1d with a primary amino group was prepared
by heating 5c with ammonium acetate (Scheme 3).
4m: R1 = Et, R2 = Me, R3 = Me, R4 = H, X = 4-OMe
Scheme 4
Pyrazoles are potentially biologically active molecules.
Many of them have found use as agrochemicals.20 Some
pyrazole derivatives are used as ligands for homogeneous
catalysis – so-called scorpionates.21–23
Therefore, much attention has been given to the syntheses
of pyrazoles. Recently, a survey of the methods leading to
pyrazoles has been published.24 However, the large ma-
jority of the methods uses toxic and dangerous hydrazine
or phenylhydrazine derivatives. The method reported here
replaces the phenylhydrazine derivatives with consider-
ably safer benzenediazonium tetrafluoroborates. The re-
action proceeds under mild conditions, and the procedure
is very simple and applicable to a relatively wide range of
substituents both at the starting b-enaminone 1 and diazo-
nium salt 2. Further extension of the applicability of the
method is the subject of future research.
The scope of the described procedure for the synthesis of
pyrazoles 4 (Scheme 4) is significantly broader than that
described for pyridazinium salts 3.16,17 The method is ap-
plicable to b-enaminones 1 with aromatic, alicyclic, and
aliphatic scaffolds, with primary, N-methyl, N-phenyl,
and tertiary amino groups as well (Scheme 4). The re-
quirement for pyrazole formation is the presence of the
methylene group in the enamino group neighbourhood,
i.e., the arrangement =C(NR3R4)–CH2–R2 (R2 ≠ H). Re-
garding the substitution on the diazonium salt 2, pyrazoles
4 were formed from diazonium salts 2 with both electron-
donating
and
electron-withdrawing
substituents
THF was dried by refluxing over Na in the presence of benzophe-
none under an inert atmosphere until a blue-violet coloration ap-
peared; it was freshly distilled under an inert atmosphere before use.
Commercially available (Fluka) CH2Cl2 was dried over MS and
stored in a bottle with a Sure Seal cap. Diazonium tetrafluoroborates
(Scheme 4). A diazonium salt 2/enaminone 1 ratio of 2:1
appeared to be optimal in terms of yield. The presence of
sodium acetate is necessary to avoid the formation of
byproducts.
Synthesis 2008, No. 11, 1761–1766 © Thieme Stuttgart · New York

PAPER
Method Leading to Substituted 4-Amino-1-arylpyrazoles
1763
2 were prepared shortly before use by a previously described meth-
od,25 and dried in vacuo. Commercially available (Fluka) potassium
tert-pentoxide (t-PentOK) was used as ca. 1.7 M solns in toluene.
Commercially available (Aldrich) heptane-3,5-dione (5d) was used.
Commercially available anhyd NaOAc was used without further
purification. MeNH2 was used as a 33 wt% soln in EtOH (Aldrich).
NMR spectra of samples in CDCl3 were recorded on Bruker
AVANCE 500 (1H, 500 MHz; 13C, 125 MHz) and Bruker AMX 360
(1H, 360 MHz; 13C, 90 MHz) spectrometers. Hexamethyldisiloxane
was used as internal standard for 1H NMR spectroscopy (d = 0.05).
The 13C NMR spectra were standardised by means of the middle
signal of the solvent multiplet (d = 76.9). The 13C NMR spectra
were recorded by the standard method with broadband decoupling
of protons or by means of the APT pulse sequence.
Copper(II) b-Diketonates from Diketones 5: Preparation and
Decomposition
A soln of CuCl2·2 H2O (11.59 g, 0.068 mol) in EtOH (115 mL) was
added to a soln of crude b-diketone 5 (0.137 mol) in EtOH (55 mL).
Aq NaOH (0.137 mol in 30 mL) was added portionwise to the mix-
ture. At the end of the addition, the pH of the mixture was 6–7. The
mixture was left to cool and a dense precipitate was collected by
suction, washed with EtOH (50 mL) and Et2O (50 mL) and dried in
air; yield: almost quantitative. The dried complex was decomposed
by the addition of 10% aq H2SO4 (100 mL) under stirring and mild
heating (ca. 50 °C). After the whole complex had dissolved, the
mixture was cooled, and extracted with CH2Cl2 (3 × 50 mL). The
extract was dried (Na2SO4) and the solvent was evaporated in
vacuo. According to NMR analysis, the thus obtained b-diketone 5
was sufficiently pure for the next reaction step.
X-ray Crystallography of 4b and 4h
X-ray diffraction data for compounds 4b and 4h were collected at
r.t. (295 K) on a Nonius Kappa CCD diffractometer with graphite-
monochromated Mo Ka radiation (l = 0.7107 Å). The structures
were solved by direct methods (SIR97)26 and refined (SHELXL-
97)27 by full-matrix least squares with anisotropic non-hydrogen
atoms and isotropic hydrogens.
1-Phenylpentane-1,3-dione (5a)
Yield: 21.50 g (61%); bp 101–106 °C/1 kPa (Lit.28 151 °C/2.5 kPa).
1H NMR (500 MHz, CDCl3): d (enol form) = 1.20 (t, J = 7.6 Hz, 3
H, CH3), 2.46 (q, J = 7.6 Hz, 2 H, CH2), 6.16 (s, 1 H, =CH), 7.42–
7.47 (m, 2 H), 7.48–7.52 (m, 1 H), 7.86–7.87 (m, 2 H), 16.11 (br s,
1 H, OH); d (keto form) = 1.07 (t, 0.4 H, J = 7.2 Hz, CH3), 2.60 (t,
0.24 H, J = 7.2 Hz, CH2), 4.08 (s, 0.2 H, CH2), 7.57–7.59 (m, 0.18
H), 7.92–7.94 (m, 0.27 H) (the rest of the signals are overlapped by
the signals of the major form).
13C NMR (125 MHz, CDCl3): d (enol form) = 9.2, 31.9, 126.5,
128.1, 131.7, 134.4, 182.4, 197.7; d (keto form) = 7.1, 36.3, 52.8,
128.3, 133.2, 135.9, 193.7, 204.5.
Compound 4b
C24H21N3O2; triclinic, space group P1, a = 9.8447(3),
b = 9.8237(3), c = 11.9725(3) Å, a = 108.070(2), b = 99.118(2),
g = 105.685(1)°, V = 1021.96(5) Å3, Z = 2, Dc = 1.246 g cm–3. In-
tensity data collected with q £ 28°; 4880 independent reflections
measured; 3559 observed [I > 2s(I)]. Final R index = 0.0465 (ob-
served reflections), Rw = 0.1274 (all reflections), S = 1.020. CCDC
670161. The molecule (Figure 1) displays an intramolecular N3–
H···O1 hydrogen bond [N3···O1, 2.850(2) Å; H···O1, 2.16(2) Å;
N3–H···O3, 133(2)°] and forms dimers, in the crystal packing, by
means of intermolecular N3–H···O3(1 – x,–y,1 – z) hydrogen bonds
[N3···O1, 3.120(2) Å; H···O1, 2.35(2) Å; N3–H···O3, 144(2)°].
1,4-Diphenylbutane-1,3-dione (5b)
Yield: 32.88 g (69%); mp 44–48 °C (Lit.29 50–51 °C).
1H NMR (360 MHz, CDCl3): d = 3.71 (s, 2 H, CH2), 6.11 (s, 1
H, =CH), 7.24–7.50 (m, 8 H), 7.78–7.81 (m, 2 H), 16.03 (br s, 1 H,
OH).
13C NMR (90 MHz, CDCl3): d = 45.8, 96.0, 126.8, 126.9, 128.3,
Compound 4h
128.5, 129.2, 132.1, 134.4, 134.9, 183.1, 194.6.
C19H19N3O2; monoclinic, space group C2/c, a = 18.5976(3),
b = 8.2831(1), c = 21.6594(5) Å, b = 91.5999(8)°, V = 3335.2(1)
Å3, Z = 8, Dc = 1.280 g cm–3. Intensity data collected with q £ 28°;
3985 independent reflections measured; 2873 observed [I > 2s(I)].
Final R index = 0.0454 (observed reflections), Rw = 0.1316 (all re-
flections), S = 1.027. CCDC 670162. The molecule (Figure 2) ex-
1-Cyclopropylhexane-1,3-dione (5c)
Yield: 20.05 g (65%); bp 80–87 °C/0.7 kPa.
1H NMR (500 MHz, CDCl3): d (enol form) = 0.88–0.96 (m, 6 H),
1.07–1.11 (m, 2 H), 1.58–1.65 (m, 4 H), 2.21 (t, J = 7.5 Hz, 2 H),
5.59 (s, 1 H, =CH), 15.64 (br s, 1 H, OH); d (keto form) = 1.99–2.02
(m, 0.25 H), 2.49 (t, 0.45 H, J = 7.0 Hz), 3.66 (s, 0.55 H).
hibits
an
intramolecular
N3–H···O1
hydrogen
bond
[N3···O1, 2.808(2) Å; H···O1, 2.09(2) Å; N3–H···O3, 132(2)°].
13C NMR (125 MHz, CDCl3): d (enol form) = 10.1, 13.6, 18.5, 19.3,
38.6, 98.8, 187.6, 199.1; d (keto form) = 11.6, 13.4, 16.8, 21.2,
45.4, 57.9, 204.1, 204.2.
b-Diketones 5; General Procedure
The reaction was carried out under an inert atmosphere. A 500-mL
four-necked round-bottomed flask was charged with t-PentOK
(26.51 g, 0.21 mol) and freshly distilled THF (150 mL). The ketone
(0.2 mol) was added from a dropping funnel over 15 min to the
stirred and cooled reaction mixture. The temperature was main-
tained at <10 °C. After addition of the ketone, the mixture was
stirred for 5 min, and then the ester (0.2 mol) was added dropwise,
over 15 min, to the stirred and cooled reaction mixture. The cooling
bath was then removed and the mixture was allowed to warm to
25 °C and subsequently stirred overnight. Then 10% aq HCl (120
mL) was added, the organic layer was separated, and the aqueous
layer was extracted with EtOAc (2 × 50 mL). The combined organ-
ic layers were washed with sat. aq NaHCO3 (1 × 150 mL), H2O
(1 × 150 mL), and brine (1 × 150 mL). The organic phase was dried
(Na2SO4) and evaporated in vacuo. Except for 5c, the crude dike-
tones 5 were purified by their conversion into the corresponding
copper(II) b-diketonates (see below).
Anal. Calcd for C9H14O2: C, 70.10; H, 9.15. Found: C, 70.22; H,
8.96.
Enaminones 1a and 1f with Anilino Groups; General Procedure
Compounds 1a and 1f were prepared by heating of equimolar
amounts of the corresponding b-diketone 5 and PhNH2 in the pres-
ence of cat. PTSA. The H2O formed during the reaction was re-
moved by azeotropic distillation until only clear toluene distilled (7
h for 1a, 4.5 h for 1f). The toluene distilled off was continuously re-
placed by fresh toluene. After completion of the reaction, the sol-
vent was evaporated in vacuo and the residue was purified by
vacuum distillation or crystallisation.
3-Anilino-1-phenylpent-2-en-1-one (1a)
Yield: 59%; bp 197–200 °C/0.3 kPa; mp 43–47 °C (Lit.28 48–
49 °C).
1H NMR (500 MHz, CDCl3): d = 1.14 (t, J = 7.5 Hz, 3 H, CH3),
2.44 (q, J = 7.5 Hz, 2 H, CH2), 5.91 (s, 1 H, =CH), 7.17–7.18 (m, 2
Synthesis 2008, No. 11, 1761–1766 © Thieme Stuttgart · New York

1764
P. Šimůnek et al.
PAPER
H), 7.21–7.24 (m, 1 H), 7.34–7.37 (m, 2 H), 7.40–7.44 (m, 3 H),
7.90–7.92 (m, 2 H), 13.08 (br s, 1 H, NH).
(m, 1 H), 2.10 (t, J = 7.5 Hz, 2 H, CH2), 4.94 (br s, 1 H, NH), 5.18
(s, 1 H, =CH), 9.68 (br s, 1 H, NH).
13C NMR (125 MHz, CDCl3): d = 12.5, 25.5, 91.9, 125.2, 125.9,
126.9, 128.1, 129.1, 130.7, 138.3, 140.1, 167.9, 188.9.
13C NMR (125 MHz, CDCl3): d (major isomer) = 8.9, 13.8, 20.1,
21.1, 38.2, 94.6, 163.8, 198.6.
Anal. Calcd for C9H15NO: C, 70.55; H, 9.87; N, 9.14. Found: C,
70.28; H, 9.81; N, 9.11.
3-Anilino-1,4-diphenylbut-2-en-1-one (1f)
Yield: 75%; crystallisation (EtOH); mp 97–101.5 °C (Lit.30 100–
102 °C).
1H NMR (500 MHz, CDCl3): d = 3.74 (s, 2 H, CH2), 5.83 (s, 1
H, =CH), 7.08–7.10 (m, 4 H), 7.18–7.25 (m, 4 H), 7.27–7.30 (m, 2
H), 7.37–7.44 (m, 3 H), 7.83–7.84 (m, 2 H), 13.10 (br s, 1 H, NH).
13C NMR (125 MHz, CDCl3): d = 38.6, 94.6, 125.5, 126.1, 126.7,
127.0, 128.2, 128.5, 128.7, 129.0, 130.9, 136.6, 138.2, 139.9, 164.2,
188.9.
3-Morpholin-4-yl-1-phenylpent-2-en-1-one (1c)
3-Chloro-1-phenylpent-2-en-1-one: Oxalyl chloride (16.00 g,
0.126 mol) was added to a soln of 5a (8.81 g, 0.05 mol) in CHCl3
(40 mL). The mixture was stirred at 25 °C for 2 h, and then the vol-
atile components were distilled off in vacuo and the residue was
subjected to vacuum distillation. The product was immediately used
for the next reaction step.
Yield: 4.77 g (49%); bp 120–125 °C/0.9 kPa.
Enaminones 1b,e,g with Methylamino Groups; General Proce-
dure
A mixture of the appropriate b-diketone 5 (0.025 mol) and a soln of
MeNH2 (3.10 g, 0.1 mol) in EtOH (12.5 mL) was refluxed for 5 h
or stirred at 25 °C for 2 h (1g). The volatile components were evap-
orated in vacuo. Products 1b and 1e were sufficiently pure for fur-
ther use, and product 1g was purified by vacuum distillation.
3-Morpholin-4-yl-1-phenylpent-2-en-1-one (1c): A soln of mor-
pholine (4.36 g, 0.05 mol) in CH2Cl2 (10 mL) was slowly added
dropwise to a soln of 3-chloro-1-phenylpent-2-en-1-one (4.87 g,
0.025 mol) in CH2Cl2 (10 mL). The mixture was stirred at 25 °C for
14 h. The volatile components were evaporated in vacuo, the resi-
due was extracted with Et2O (30 mL) and dried (Na2SO4), and the
solvent was removed by distillation. The evaporation residue was
crystallised from n-hexane. The product exists in CDCl3 soln as a
mixture of E/Z isomers (ca. 10:1). The enaminones with tertiary
amino groups occur predominantly in the E-form.32
3-(Methylamino)-1-phenylpent-2-en-1-one (1b)
Yield: 2.94 g (62%); mp 62–64 °C (Lit.31 59–60 °C).
1H NMR (360 MHz, CDCl3): d = 1.22 (t, J = 7.5 Hz, 3 H, CH3),
2.33 (q, J = 7.5 Hz, 2 H, CH2), 3.01 (d, J = 5.3 Hz, 3 H, NCH3), 5.68
(br s, 1 H, =CH), 7.35–7.42 (m, 3 H), 7.83–7.85 (m, 2 H), 11.40 (br
s, 1 H, NH).
Yield: 2.15 g (35%); mp 70–74 °C.
1H NMR (500 MHz, CDCl3): d (E) = 1.18 (t, J = 7.5 Hz, 3 H, CH3),
3.12 (q, J = 7.5 Hz, 2 H, CH2), 3.40–3.42 (m, 4 H, 2 × CH2–N),
3.75–3.77 (m, 4 H, 2 × CH2–O), 5.80 (s, 1 H, =CH), 7.36–7.43 (m,
3 H), 7.83–7.84 (m, 2 H); d (Z) = 2.45 (q, 0.2 H, J = 7.5 Hz, CH2),
2.88–2.90 (m, 0.4 H, 2 × CH2–N), 3.68–3.70 (m, 0.4 H, 2 × CH2–
N), 6.16 (s, 0.1 H, =CH), 7.85–7.87 (m, 0.2 H) (the other signals are
overlapped by the signals of the major form).
13C NMR (125 MHz, CDCl3): d (E) = 12.6, 21.7, 46.3, 66.3, 93.3,
127.2, 127.9, 130.5, 142.3, 168.1, 188.5; d (Z) = 45.9, 67.5, 95.3,
126.8, 128.4, 132.0 (owing to the low abundance of the minor form,
only some of the carbons were detected).
3-(Methylamino)-1,4-diphenylbut-2-en-1-one (1e)
Yield: 2.34 g (37%); mp 55–60 °C (Lit.18 51–55 °C).
1H NMR (500 MHz, CDCl3): d = 2.86 (d, J = 5.5 Hz, 3 H), 3.65 (s,
2 H, CH2), 5.69 (s, 1 H, =CH), 7.21–7.24 (m, 3 H), 7.28–7.31 (m, 2
H), 7.33–7.39 (m, 3 H), 7.81–7.82 (m, 2 H), 11.36 (br s, 1 H, NH).
13C NMR (125 MHz, CDCl3): d = 29.7, 38.7, 93.0, 126.8, 126.9,
128.1, 128.5, 128.8, 130.4, 135.6, 140.3, 166.7, 187.9.
Anal. Calcd for C15H19NO2: C, 73.44; H, 7.81; N, 5.71. Found:
C,73.23; H, 7.76; N, 5.89.
5-(Methylamino)hept-4-en-3-one (1g)
Yield: 3.05 g (86%); bp 85 °C/0.7 kPa.
1H NMR (500 MHz, CDCl3): d = 1.10 (t, J = 8.0 Hz, 3 H, CH3),
1.15 (t, J = 7.5 Hz, 3 H, CH3), 2.21–2.28 (m, 4 H, 2 × CH2), 2.94 (d,
J = 5.5 Hz, 3 H, NCH3), 4.99 (s, 1 H, =CH), 10.82 (br s, 1 H, NH).
13C NMR (125.77 MHz, CDCl3): d = 9.9, 11.4, 24.4, 28.6, 34.5,
91.6, 168.8, 198.5.
Pyrazoles 4a–m; General Procedure
The apparatus (Erlenmeyer flask and magnetic stirrer) used for the
procedure were dried in an oven before use. The appropriate b-
enaminone 1 (5 mmol) was dissolved in CH2Cl2 (30 mL). The soln
was treated with anhyd NaOAc (2.46 g, 30 mmol) followed by the
appropriate diazonium tetrafluoroborate 2 (10 mmol). The mixture
was stirred at r.t. for 24 h. The solid was removed by suction, the
filter cake was washed with a small amount of CH2Cl2, and the fil-
trate was evaporated in vacuo. The evaporation residue was subject-
ed to column chromatography (silica gel). (The yields given below
are for isolated compounds purified by chromatography.)
Anal. Calcd for C8H15NO: C, 68.04; H, 10.71; N, 9.92. Found: C,
68.17; H, 10.59; N 9.92.
3-Amino-1-cyclopropylhex-2-en-1-one (1d)
A mixture of b-diketone 5c (6.94 g, 45 mmol) and NH4OAc (13.80
g, 179 mmol) in EtOH (50 mL) was heated to ca. 50 °C for 24 h.
Concd aq NH3 (20 mL) and H2O (20 mL) were then added to the
cooled mixture. The mixture was extracted with CH2Cl2 (40 mL).
The organic layer was dried (Na2SO4) and the solvent was evaporat-
ed in vacuo. The residue was subjected to vacuum distillation. Al-
though according to the NMR spectrum the product contained about
10% of isomeric 1-amino-1-cyclopropylhex-1-en-3-one, it was
used for the pyrazole synthesis without further purification. The mi-
nor isomer is not able to form the pyrazole derivative, due to the ab-
sence of the methylene group next to the enamino group.
3-Benzoyl-5-methyl-4-(methylamino)-1-(4-tolyl)-1H-pyrazole
(4a)
Column chromatography (silica gel, CH2Cl2–EtOAc, 4:1); yield:
0.67 g (44%); crystallisation (EtOH); mp 114–117 °C.
1H NMR (500 MHz, CDCl3): d = 2.36 (s, 3 H, CH3), 2.39 (s, 3 H,
CH3), 2.94 (s, 3 H, NCH3), 5.06 (br s, 1 H, NH), 7.24–7.26 (m, 2 H),
7.32–7.34 (m, 2 H), 7.39–7.42 (m, 2 H), 7.46–7.49 (m, 1 H), 8.28–
8.30 (m, 2 H).
Yield: 1.83 g (48%); bp 105 °C/1 kPa.
1H NMR (500 MHz, CDCl3): d (major isomer) = 0.70–0.74 (m, 2
H), 0.93–0.97 (m, 5 H), 1.59 (sext, J = 7.4 Hz, 2 H, CH2), 1.65–1.70
13C NMR (125 MHz, CDCl3): d = 11.6, 21.0, 34.2, 124.9, 125.2,
127.8, 129.5, 130.3, 131.9, 137.0, 137.9, 137.9, 138.2, 138.5, 189.8.
Synthesis 2008, No. 11, 1761–1766 © Thieme Stuttgart · New York

PAPER
Method Leading to Substituted 4-Amino-1-arylpyrazoles
1765
Anal. Calcd for C19H19N3O: C, 74.73; H, 6.27; N, 13.76. Found: C,
74.87; H, 6.41; N, 13.96.
Anal. Calcd for C24H21N3O: C, 78.45; H, 5.76; N, 11.44. Found: C,
78.29; H, 5.95; N, 11.33.
3-Benzoyl-1-(4-methoxyphenyl)-5-methyl-4-(methylamino)-
1H-pyrazole (4b)
Column chromatography (silica gel, CH2Cl2–EtOAc, 4:1); yield:
3-Benzoyl-5-methyl-4-(morpholin-4-yl)-1-(4-tolyl)-1H-pyra-
zole (4g)
Column chromatography (silica gel, CHCl3); yield: 1.28 g (71%);
0.83 g (52%); mp 117–121 °C.
mp 127–130 °C.
1H NMR (500 MHz, CDCl3): d = 2.35 (s, 3 H, CH3), 2.95 (s, 3 H,
NCH3), 3.83 (s, 3 H, OCH3), 5.47 (br s, 1 H, NH), 6.95–6.98 (m, 2
H), 7.34–7.38 (m, 2 H), 7.40–7.43 (m, 2 H), 7.47–7.50 (m, 1 H),
8.27–8.29 (m, 2 H).
1H NMR (500.13 MHz, CDCl3): d = 2.31 (s, 3 H, CH3), 2.38 (s, 3
H, CH3), 3.09–3.10 (m, 4 H, 2 × CH2–N), 3.76–3.78 (m, 4 H,
2 × CH2–O), 7.24–7.26 (m, 2 H), 7.33–7.34 (m, 2 H), 7.41–7.44 (m,
2 H), 7.49–7.52 (m, 1 H), 8.12–8.14 (m, 2 H).
13C NMR (125 MHz, CDCl3): d = 11.5, 34.2, 55.4, 114.1, 125.4,
13C NMR (125.77 MHz, CDCl3): d = 10.4, 20.9, 51.5, 67.7, 124.5,
127.8, 129.5, 130.5, 132.3, 135.1, 135.6, 137.0, 137.9, 138.1, 145.1,
189.5.
126.5, 127.8, 130.3, 131.9, 132.5, 137.9, 138.0, 138.4, 159.4, 189.9.
Anal. Calcd for C19H19N3O2: C, 71.01; H, 5.96; N, 13.08. Found: C,
71.26; H, 5.97; N, 12.81.
Anal. Calcd for C22H23N3O2: C, 73.11; H, 6.41; N, 11.63. Found: C,
72.84; H, 6.33; N, 11.49.
4-Anilino-3-benzoyl-5-methyl-1-(4-tolyl)-1H-pyrazole (4c)
Column chromatography (silica gel, CH2Cl2); yield: 1.03 g (56%);
mp 132–134 °C.
3-Benzoyl-1-(4-methoxyphenyl)-4-(methylamino)-5-phenyl-
1H-pyrazole (4h)
Column chromatography (silica gel, CH2Cl2–EtOAc 4:1); yield:
1.42 g (74%); crystallisation (EtOH); mp 159–162.5 °C.
1H NMR (500 MHz, CDCl3): d = 3.74 (s, 3 H, OCH3), 6.00 (br s, 1
H, NH), 6.74–6.77 (m, 2 H), 7.12–7.15 (m, 2 H), 7.28–7.31 (m, 5
H), 7.44–7.47 (m, 2 H), 7.50–7.53 (m, 1 H), 8.33–8.34 (m, 2 H).
13C NMR (125 MHz, CDCl3): d = 33.4, 55.3, 113.7, 126.4, 127.4,
127.9, 128.0, 128.1, 130.3, 130.4, 131.0, 131.9, 133.0, 137.7, 138.1,
138.6, 158.8, 189.7.
1H NMR (500 MHz, CDCl3): d = 2.17 (s, 3 H, CH3), 2.42 (s, 3 H,
CH3), 6.81–6.84 (m, 3 H), 7.20–7.23 (m, 3 H), 7.29–7.31 (m, 2 H),
7.41–7.44 (m, 4 H), 7.50–7.53 (m, 1 H), 8.31–8.33 (m, 2 H).
13C NMR (125 MHz, CDCl3): d = 12.1, 21.0, 115.5, 119.5, 124.6,
128.0, 128.3, 129.0, 129.7, 130.6, 131.5, 132.5, 137.0, 137.1, 138.4,
141.8, 144.7, 189.4.
Anal. Calcd for C24H21N3O: C, 78.45; H, 5.76; N, 11.44. Found: C,
78.34; H, 5.86; N, 11.45.
Anal. Calcd for C24H21N3O2: C, 75.18; H, 5.52; N, 10.96. Found: C,
75.06; H, 5.60; N, 10.93.
4-Anilino-3-benzoyl-5-methyl-1-(3-tolyl)-1H-pyrazole (4d)
Column chromatography (silica gel, CH2Cl2); yield: 1.03 g (56%);
crystallisation (n-hexane); mp 90–93 °C.
1H NMR (500 MHz, CDCl3): d = 2.19 (s, 3 H, CH3), 2.45 (s, 3 H,
CH3), 6.82–6.85 (m, 3 H), 7.21–7.27 (m, 4 H), 7.34–7.42 (m, 3 H),
7.43–7.46 (m, 2 H), 7.52–7.55 (m, 1 H), 8.32–8.34 (m, 2 H).
13C NMR (125 MHz, CDCl3): d = 12.1, 21.3, 115.5, 119.5, 121.9,
125.5, 128.0, 128.3, 128.9, 129.0, 129.1, 130.6, 131.6, 132.5, 137.1,
139.3, 139.4, 141.9, 144.7, 189.4.
3-Benzoyl-4-(methylamino)-5-phenyl-1-(4-tolyl)-1H-pyrazole
(4i)
Column chromatography (silica gel, CH2Cl2); crystallisation
(EtOH); yield: 1.19 g (65%); mp 138–141 °C.
1H NMR (500 MHz, CDCl3): d = 2.30 (s, 3 H, CH3), 2.51 (s, 3 H,
CH3), 6.00 (br s, 1 H, NH), 7.04–7.05 (m, 2 H), 7.09–7.10 (m, 2 H),
7.29–7.32 (m, 5 H), 7.44–7.47 (m, 2 H), 7.51–7.54 (m, 1 H), 8.33–
8.35 (m, 2 H).
13C NMR (125 MHz, CDCl3): d = 20.9, 33.4, 124.9, 127.3, 127.9,
127.9, 128.1, 129.1, 130.3, 130.5, 131.0, 131.9, 137.4, 137.5, 137.9,
138.1, 138.7, 189.8.
Anal. Calcd for C24H21N3O: C, 78.45; H, 5.76; N, 11.44. Found: C,
78.29; H, 5.94; N, 11.40.
4-Anilino-3-benzoyl-1-(4-chlorophenyl)-5-methyl-1H-pyrazole
(4e)
Column chromatography (silica gel, CH2Cl2); yield: 1.44 g (74%);
mp 51–53 °C; crystallisation (aq EtOH).
Anal. Calcd for C24H21N3O: C, 78.45; H, 5.76; N, 11.44. Found: C,
78.24; H, 5.92; N, 11.42.
4-Anilino-3-benzoyl-5-phenyl-1-[3-(trifluoromethyl)phenyl]-
1H-pyrazole (4j)
Column chromatography (silica gel, CH2Cl2); crystallisation
1H NMR (500 MHz, CDCl3): d = 2.19 (s, 3 H, CH3), 6.80–6.86 (m,
3 H), 7.21–7.24 (m, 2 H), 7.42–7.46 (m, 2 H), 7.47–7.54 (m, 5 H),
8.29–8.31 (m, 2 H) (signal of NH proton is missing).
13C NMR (125 MHz, CDCl3): d = 12.2, 115.6, 119.7, 125.8, 128.0,
128.7, 129.0, 129.4, 130.5, 131.4, 132.7, 134.1, 137.0, 137.9, 142.2,
144.4, 189.3.
(EtOH); yield: 1.93 g (80%); mp 145–147 °C.
1H NMR (500 MHz, CDCl3): d = 6.60–6.62 (m, 2 H), 6.63–6.66 (m,
1 H), 6.90–6.93 (m, 2 H), 7.12–7.14 (m, 2 H), 7.15–7.20 (m, 3 H),
7.42–7.52 (m, 5 H), 7.57–7.60 (m, 2 H), 7.63 (br s, 1 H), 8.34–8.36
(m, 2 H).
13C NMR (125 MHz, CDCl3): d = 116.6, 119.9, 122.3 (q, JC,F = 3.9
Hz), 123.2 (q, JC,F = 272.5 Hz), 124.6 (q, JC,F = 3.8 Hz), 128.2,
128.3, 128.5, 128.5, 128.7, 129.1, 129.3, 129.4, 130.4, 131.4 (q,
JC,F = 33.1 Hz), 132.8, 133.1, 137.0, 140.2, 142.5, 142.8, 189.3.
Anal. Calcd for C23H18ClN3O: C, 71.22; H, 4.68; N, 10.83. Found:
C, 71.29; H, 4.87; N, 10.84.
4-Anilino-3-benzoyl-5-methyl-1-(2-tolyl)-1H-pyrazole (4f)
Column chromatography (silica gel, CH2Cl2); yield: 1.07 g (58%);
crystallisation (n-hexane); mp 127–128 °C.
Anal. Calcd for C29H20F3N3O: C, 72.04; H, 4.17; N, 8.69. Found: C,
72.04; H, 4.35; N, 8.83.
1H NMR (500 MHz, CDCl3): d = 1.96 (s, 3 H), 2.16 (s, 3 H), 6.78–
6.83 (m, 3 H), 7.19–7.23 (m, 3 H), 7.32–7.33 (m, 2 H), 7.35–7.42
(m, 4 H), 7.48–7.51 (m, 1 H), 8.26–8.28 (m, 2 H).
13C NMR (125 MHz, CDCl3): d = 11.0, 17.3, 115.5, 119.5, 126.6,
127.2, 127.4, 128.0, 129.0, 129.6, 130.4, 131.1, 132.5, 132.6, 135.7,
137.1, 138.1, 141.8, 144.7, 189.5.
4-Anilino-3-benzoyl-1-[3-(ethoxycarbonyl)phenyl]-5-phenyl-
1H-pyrazole (4k)
Column chromatography (silica gel, CH2Cl2); crystallisation (aq
EtOH); yield: 0.98 g (40%); mp 129–132 °C.
Synthesis 2008, No. 11, 1761–1766 © Thieme Stuttgart · New York

1766
P. Šimůnek et al.
PAPER
1H NMR (500 MHz, CDCl3): d = 1.34 (t, J = 7.0 Hz, 3 H, CH3),
4.33 (q, J = 7.0 Hz, 2 H, CH2), 6.60–6.66 (m, 3 H), 6.90–6.93 (m, 2
H), 7.15–7.17 (m, 5 H), 7.36–7.40 (m, 1 H), 7.43–7.44 (m, 1 H),
7.48–7.51 (m, 3 H), 7.56–7.59 (m, 1 H), 7.99–8.01 (m, 1 H), 8.08
(br s, 1 H), 8.35–8.37 (m, 2 H).
13C NMR (125 MHz, CDCl3): d = 14.1, 61.2, 116.5, 119.8, 126.5,
128.1, 128.2, 128.3, 128.4, 128.8, 128.9, 129.0, 129.1, 129.5, 130.5,
131.5, 132.7, 133.2, 137.1, 140.0, 142.3, 143.0, 165.3, 189.4.
(6) Greenhill, J. V.; Chaaban, I. J. Heterocycl. Chem. 1992, 29,
1375.
(7) Al-Shiekh, M. A. Org. Prep. Proced. Int. 2005, 37, 223.
(8) Svete, J. Monatsh. Chem. 2004, 135, 629.
(9) Caprathe, B. W.; Jaen, J. C.; Wise, L. D.; Heffner, T. G.;
Pudsley, T. A.; Melther, L. T.; Parvez, M. J. Med. Chem.
1991, 34, 3726.
(10) Gatta, F.; Del Giudice, M. R.; Pomponi, M.; Marta, M.
Heterocycles 1992, 34, 991.
(11) Scott, K. R.; Edafiogho, I. O.; Richardson, E. C.; Farrar, V.
A.; Moore, J. A.; Tietz, E. I.; Hinko, C. N.; Chang, H.; El-
Assadi, A.; Nicholson, J. M. J. Med. Chem. 1993, 36, 1947.
(12) Michael, J. P.; de Koning, C. B.; Gravestock, D.; Hosken, G.
D.; Howard, A. S.; Jungmann, C. M.; Krause, R. W. M.;
Parsons, A. S.; Pelly, S. C.; Stanbury, T. V. Pure Appl.
Chem. 1999, 71, 979.
Anal. Calcd for C31H25N3O3: C, 76.37; H, 5.17; N, 8.62. Found: C,
76.22; H, 5.39; N, 8.74.
4-Amino-3-(cyclopropylcarbonyl)-5-ethyl-1-(4-tolyl)-1H-pyra-
zole (4l)
Column chromatography (silica gel, CH2Cl2–EtOAc, 4:1); yield:
0.70 g (52%); mp 108–111 °C.
1H NMR (360 MHz, CDCl3): d = 0.92–0.97 (m, 2 H), 1.06 (t,
J = 7.6 Hz, 3 H, CH3), 1.16–1.20 (m, 2 H), 2.40 (s, 3 H, CH3), 2.59
(q, J = 7.6 Hz, 2 H, CH2), 3.00–3.05 (m, 1 H), 3.99 (br s, 2 H, NH2),
7.25–7.28 (m, 2 H), 7.30–7.32 (m, 2 H).
13C NMR (90 MHz, CDCl3): d = 10.9, 12.4, 16.7, 17.0, 21.0, 125.1,
129.7, 130.1, 130.4, 137.2, 138.5, 139.0, 198.2.
(13) Dannhardt, G.; Bauer, A.; Nowe, U. J. Prakt. Chem. 1998,
340, 256.
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Kitos, P. A.; Suntornwat, O. J. Am. Chem. Soc. 1989, 111,
6461.
(15) Popov, S. A.; Gatilov, Y. V.; Rybalova, T. V.; Tkachev, A.
V. Tetrahedron: Asymmetry 2003, 14, 233.
Anal. Calcd for C16H19N3O: C, 71.35; H, 7.11; N, 15.60. Found: C,
71.24; H, 7.04; N, 15.88.
(16) Šimůnek, P.; Pešková, M.; Bertolasi, V.; Lyčka, A.;
Macháček, V. Eur. J. Org. Chem. 2004, 5055.
(17) Šimůnek, P.; Pešková, M.; Bertolasi, V.; Macháček, V.;
Lyčka, A. Tetrahedron 2005, 61, 8130.
1-[(4-Methoxy)phenyl]-5-methyl-4-(methylamino)-3-pro-
panoyl-1H-pyrazole (4m)
(18) Pešková, M.; Šimůnek, P.; Bertolasi, V.; Macháček, V.;
Column chromatography (silica gel, CH2Cl2–EtOAc, 4:1); crystal-
lisation (n-hexane); yield: 1.02 g (75%); mp 79–82 °C.
1H NMR (500.13 MHz, CDCl3): d = 1.16 (t, J = 7.5 Hz, 3 H, CH3),
2.28 (s, 3 H, CH3), 2.89 (s, 3 H, NCH3), 3.00 (q, J = 7.5 Hz, 2 H,
CH2), 3.84 (s, 3 H, OCH3), 4.95 (br s, 1 H, NH), 6.97–6.98 (m, 2 H),
7.31–7.33 (m, 2 H).
Lyčka, A. Organometallics 2006, 25, 2025.
(19) Burnett, M. N.; Johnson, C. K. ORTEP-III, Report ORNL-
6895; Oak Ridge National Laboratory: Oak Ridge TN, 1996.
(20) Lamberth, C. Heterocycles 2007, 71, 1467.
(21) Trofimenko, S. J. Am. Chem. Soc. 1970, 92, 5118.
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(23) Trofimenko, S. In Scorpionates: The Coordination
Chemistry of Polypyrazolylborate Ligands; Imperial
College Press: London, 1999.
13C NMR (125.77 MHz, CDCl3): d = 8.0, 11.4, 31.5, 34.0, 55.4,
114.1, 125.6, 126.5, 132.4, 135.6, 138.3, 159.3, 199.7.
(24) Stanovnik, B.; Svete, J. In Science of Synthesis, Vol. 12;
Neier, R., Ed.; Thieme: Stuttgart, 2002, 15.
(25) Šimůnek, P.; Lyčka, A.; Macháček, V. Eur. J. Org. Chem.
Anal. Calcd for C15H19N3O2: C, 65.91; H, 7.01; N, 15.37. Found: C,
65.75; H, 7.06; N, 15.27.
2002, 2764.
Acknowledgment
(26) Altomare, A.; Burla, M. C.; Camalli, M.; Cascarano, G.;
Giacovazzo, C.; Guagliardi, A.; Moliterni, A. G.; Polidori,
G.; Spagna, R. J. Appl. Crystallogr. 1999, 32, 115.
(27) Sheldrick, G. M. SHELXL-97, Program for Refinement of
Crystal Structures; University of Göttingen: Göttingen
Germany, 1997.
The authors (P.Š., M.S. and V.M.) are indebted to the Ministry of
Education, Youth and Sports of the Czech Republic (Project No.
MSM 002 162 7501) for financial support.
(28) Lovett, A. B. E.; Roberts, E. J. Chem. Soc. 1928, 1975.
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1999, 11, 666.
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Alekseeva, N. V.; Vereshchagin, L. I. Zh. Org. Khim. 1972,
8, 1879.
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Synthesis 2008, No. 11, 1761–1766 © Thieme Stuttgart · New York