Regioselective reaction of Ethyl 5-Acetyl-3,4-dihydropyridine-1(2 H)-carboxylate with hydrazines: A facile approach to new pyrazole derivatives

Article abstract of DOI:10.1055/s-0029-1219760

The reaction of ethyl 5-acetyl-3,4-dihydropyridine-1(2H)-carboxylate with diverse aliphatic as well as aromatic monosubstituted hydrazines resulted in the regioselective formation of N-substituted 3-methylpyrazoles. Georg Thieme Verlag Stuttgart - New Yor

Full text of DOI:10.1055/s-0029-1219760

PAPER
1781
Regioselective Reaction of Ethyl 5-Acetyl-3,4-dihydropyridine-1(2H)-carboxy-
late with Hydrazines: A Facile Approach to New Pyrazole Derivatives
A
Facile
A
pproach
a
to New Py
z
r
azole
D
eri
a
vative
s
r B. Maximov,a,b Pavel K. Mykhailiuk,*a,b Sergey M. Golovach,a Anton V. Tverdokhlebov,a,b
Zoya V. Voitenko,b Andrey A. Tolmacheva,b
a
Enamine Ltd., Alexandra Matrosova Street 23, Kiev 01103, Ukraine
Department of Chemistry, Kiev National Taras Shevchenko University, Volodymyrska Street 64, Kiev 01033, Ukraine
b
Fax +380(44)2351273; E-mail: Pashamk@gmx.de
Received 26 February 2010; revised 3 March 2010
isomer (Scheme 2). Moreover, the expected intermediate
Abstract: The reaction of ethyl 5-acetyl-3,4-dihydropyridine-
6 was also isolated when the reaction was performed at 78
1(2H)-carboxylate with diverse aliphatic as well as aromatic mono-
°C in ethanol. Hydrazone 6 was subsequently transformed
into pyrazole 5 by heating at 140 °C in aqueous ethylene
glycol (Scheme 2).
substituted hydrazines resulted in the regioselective formation of N-
substituted 3-methylpyrazoles.
Key words: pyrazole, hydrazine, tetrahydropyridine, regioselectiv-
ity
Ph
PhNHNH2
heat
N
O
N
+
N
Pyrazoles are an important class of organic compounds
used in the pharmaceutical industry. Compounds contain-
ing the pyrazole motif are being developed in a wide range
of therapeutic areas including CNS, metabolic diseases
and endocrine functions, and oncology.1 A number of
pyrazole-containing compounds have been successfully
commercialized, such as the blockbuster drugs Viagra,
Celebrex, and Acomplia. Substituted pyrazoles have also
been applied as ligands for transition-metal-catalyzed
cross-coupling reactions.2
N
Ph
NH2
N
H
NH2
1
2
3
Scheme 1 Synthesis of the mixture of pyrazoles 2/3 according to
ref. 3a
Ph
PhNHNH2
N
N
O
heat
(CH2OH)2
N
N
N
Ph
NH
NH
The chemistry of substituted pyrazoles has been exten-
sively studied, and many synthetic strategies for this het-
erocyclic system are known. One such method is based on
the reaction of hydrazines with b-enamino ketones to give
the corresponding pyrazoles.3,4 Herein we report a regio-
selective synthesis of new pyrazole derivatives from b-
enamino ketone 1 and diverse monosubstituted hydra-
zines.
CO2Et
CO2Et
CO2Et
4
5
not observed
PhNHNH2
heat
EtOH
heating
(CH2OH)2
N
HN
N
Ph
Despite the structural simplicity of 1-(1,4,5,6-tetrahydro-
pyridin-3-yl)ethanone (1) (readily available from 3-
acetylpyridine),3a there is, to the best of our knowledge,
only one report in the literature of the synthesis of pyra-
zoles from 1 (Scheme 1). In 1970, Quin and Pinion
showed, that 1 reacted with phenylhydrazine to form a
mixture of two isomeric pyrazoles 2/3 (Scheme 1).3a The
regioselective synthesis of the individual compounds 2
and 3, however, was not performed.
CO2Et
6
Scheme 2 Synthesis of pyrazole 5
NH2
HN
NH2
NH2
NH2
HN
HN
HN
F
NH
N
Cl
Cl
7
8
We suggested that changing the reactivity of the amino
group in 1 by using an N-protecting group might have an
influence on the regioselectivity of the reaction. In fact,
heating a mixture of N-ethoxycarbonyl-protected com-
pound 4 and phenylhydrazine in aqueous ethylene glycol
at 140 °C resulted in the formation of 5 as the sole regio-
9
10
NH2
NH2
NH2
HN
HN
HN
NH2
HN
Me
N
OH
13
11
12
14
SYNTHESIS 2010, No. 11, pp 1781–1786
Advanced online publication: 06.04.2010
x
x.
x
x
.
2
0
1
0
Figure 1 Hydrazines 7–14
DOI: 10.1055/s-0029-1219760; Art ID: Z04810SS
© Georg Thieme Verlag Stuttgart · New York

1782
N. B. Maximov et al.
PAPER
Table 1 Reaction Conditions for the Synthesis of Pyrazoles 5, 15–22 from b-Enamino Ketone 4 and Hydrazines and Formation of Their Hy-
drochlorides
Hydrazine
Timea (h)
Product
Yield (%)
86
Hydrochlorideb Yield (%)
N
PhNHNH2
4
5
2
96
94
95
N
NH
CO2Et
N
F
7
8
4
4
15
16
80
85
23
24
N
NH
CO2Et
N
N
NH
Cl
CO2Et
N
9
4
17
18
N
85
73
25
26
94
95
NH
CO2Et
Cl
N
N
10
3.5
NH
NH
CO2Et
N
N
11
12
3
6
19
20
72
90
27
28
92
92
N
NH
Me
CO2Et
N
N
NH
CO2Et
N
13
14
4
4
21
22
82
83
29
30
97
95
N
NH
CO2Et
OH
N
N
NH
N
CO2Et
a Conditions: (CH2OH)2, 140 °C.
b For conditions see Scheme 3.
Synthesis 2010, No. 11, 1781–1786 © Thieme Stuttgart · New York

PAPER
A Facile Approach to New Pyrazole Derivatives
1783
Ethyl 5-Acetyl-3,4-dihydropyridine-1(2H)-carboxylate (4)
Thereafter, to show the applicability of the N-ethoxycar-
bonyl moiety in 4 as a ‘pucker’ for the regioselective syn-
thesis of various pyrazoles, a set of diverse hydrazines 7–
14 were tested (Figure 1).
Compound 4 was synthesized following the method of Wenkert and
Hudlicky;3e yield: 89%; mp 47–49 °C.
Ethyl 5-[(Z)-1-(Phenylhydrazono)ethyl]-3,4-dihydropyridine-
1(2H)-carboxylate (6)
Indeed, all the products were obtained as single regioiso-
mers 5, 15–22 in 72–90% yield (Table 1). Noteworthy,
the reaction was equally efficient with all types of hydra-
zine used: aromatic, e.g., PhNHH2 and 7–9, heteroaromat-
ic 10, and aliphatic 11–14.
A 50-mL reaction vessel equipped with a condenser was charged
with a soln of phenylhydrazine (10 mmol) and 4 (10 mmol) in EtOH
(30 mL); the soln was heated at reflux for 4 h. Thereafter, the soln
was evaporated under reduced pressure to give the corresponding
crude yellow hydrazone 6. The product was washed with H2O (30)
and hexane (25 mL) and dried in vacuo; yield: 97%; mp 126–127
°C.
The structures of the obtained pyrazoles were confirmed
by NOESY experiments (Figure 2).
1H NMR (500 MHz, DMSO-d6): d = 9.02 (s, 1 H, NH), 7.18 (m, 5
H, Ph), 6.71 (s, 1 H, CH), 4.19 (q, 3J = 6.5 Hz, 2 H, OCH2), 3.57 (t,
3J = 7 Hz, 2 H, NCH2), 2.48 (t, 3J = 7 Hz, 2 H, CH2C), 1.99 (s, 3 H,
NHCO2Et
NHCO2Et
3
3
CH3), 1.81 (m, J = 7 Hz, 2 H, CH2), 1.27 (t, J = 6.5 Hz, 3 H,
CH3CH2).
N
N
13C NMR (100 MHz, DMSO-d6): d = 153.22 (s, CO), 146.94 (s,
tert-C, CN), 142.04 (s, tert-C, Ph), 129.20 (s, 2 C, Ph), 123.84 (s,
CH), 119.72 (s, tert-C), 118.73 (s, Ph), 113.02 (s, 2 C, Ph), 62.20 (s,
OCH2), 42.54 (s, CH2N), 21.60 (s, CCH2), 21.31 (s, CH2), 14.91 (s,
CH3CH2), 11.58 (s, CH3).
OH
N
NOESY-correlation
N
H
H
H
H
Cl
H H
H
MS: m/z = 288.3 (M + 1)+.
16
21
Figure 2 The key NOESY correlations of the selected representa-
tives of pyrazoles with aromatic 16 and aliphatic 21 substituents
Pyrazoles 5, 15–22; General Procedure
A 25-mL reaction vessel equipped with a condenser was charged
with a soln of the corresponding monosubstituted hydrazine (10
mmol), 7 (10.5 mmol) and concd HCl (0.25 mL) in aq ethylene gly-
col (10–15 mL). The soln was stirred under an inert atmosphere at
140 °C for 3–6 h followed by concentration in vacuo. The gummy
residue was dissolved in CHCl3 (50 mL), washed with 5% aq HCl
(2 × 20 mL) and sat. aq NaHCO3 (2 × 30 mL), and dried (MgSO4).
The solvent was removed under reduced pressure to give the corre-
sponding pyrazoles 5, 15–22. Scale of the synthesis: 1–5 g of 7.
Finally, the protected pyrazoles 5, 15–22 were easily con-
verted into the corresponding amines 2, 23–30 by heating
at reflux in concentrated hydrochloric acid (Scheme 3,
Table 1).
N
N
HClaq
Ethyl 3-(3-Methyl-1-phenyl-1H-pyrazol-4-yl)propylcarbamate
(5)
Pale brown oil; yield: 86%.
N
N
reflux
92–96%
R
NH
R
NH2
CO2Et
⋅HCl
2, 23–30
1H NMR (500 MHz, CDCl3): d = 7.67 (s, 1 H, CH), 7.67 (d,
3J = 7.52 Hz, 2 H, Ph), 7.40 (t, 3J = 7.5 Hz, 2 H, Ph), 7.21 (t, 3J = 7.5
Hz, 1 H, Ph), 4.74 (br s, 1 H, NH), 4.12 (q, 3J = 6.5 Hz, 2 H, OCH2),
3.24 (m, 3J = 6 Hz, 2 H, CH2NH), 2.49 (t, 3J = 7.5 Hz, 2 H, CCH2),
2.28 (s, 3 H, CH3), 1.79 (m, 3J = 7 Hz, 2 H, CH2), 1.24 (t, 3J = 7 Hz,
3 H, CH3CH2).
13C NMR (100 MHz, CDCl3): d = 156.85 (s, CO), 149.06 (s, tert-C,
CCH3), 140.16 (s, tert-C, Ph), 129.32 (s, 2 C, Ph), 125.56 (s, CH),
125.32 (s, Ph), 120.73 (s, tert-C, CCH2), 118.37 (s, 2 C, Ph), 60.72
(s, OCH2), 40.47 (s, CH2NH), 30.44 (s, CH2), 20.97 (s, CCH2),
14.70 (s, CH3CH2), 11.95 (s, CH3).
5, 15–22
Scheme 3 Synthesis of amines 2, 23–30
In summary, we have shown, that the reaction of ethyl
5-acetyl-3,4-dihydropyridine-1(2H)-carboxylate (4) with
diverse aliphatic and aromatic hydrazines occurs in a re-
gioselective manner to provide N-substituted 3-methyl-
pyrazoles.
MS: m/z = 288.2 (M + 1)+.
Solvents were purified according to standard procedures. All other
materials were purchased from Aldrich and Enamine. Melting
points are uncorrected. Analytical TLC was performed using Poly-
chrom SI F254 plates. 1H and 13C NMR spectra were recorded either
on a Bruker Avance 500 spectrometer (at 499.9 MHz and 124.9
MHz) with TMS as internal standard. Mass spectra were recorded
on an Agilent 1100 LCMSD SL instrument by chemical ionization
(CI).
Ethyl 3-[1-(2-Fluorophenyl)-3-methyl-1H-pyrazol-4-yl]propyl-
carbamate (15)
Pale brown oil; yield: 80%.
1H NMR (500 MHz, CDCl3): d = 7.73 (s, 1 H, CH), 7.67 (t, 3JH–F = 8
Hz, 1 H, Ph), 7.20 (m, 3 H, Ph), 4.68 (br s, 1 H, NH), 4.12 (q,
3J = 6.5 Hz, 2 H, OCH2), 3.25 (m, 3J = 6 Hz, 2 H, CH2NH), 2.50 (t,
3J = 7.5 Hz, 2 H, CCH2), 2.29 (s, 3 H, CH3), 1.80 (m, 3J = 7 Hz, 2
H, CH2), 1.24 (t, 3J = 7 Hz, 3 H, CH3CH2).
1-(1,4,5,6-Tetrahydropyridin-3-yl)ethanone (1)
Compound 1 was prepared following the method of Quin and
Pinion.3a The product was purified by fractional distillation in vac-
uo; yield: 67%; bp 140–142 °C/1.33 mbar.
13C NMR (100 MHz, CDCl3): d = 156.78 (s, CO), 153.19 (d,
1JC,F = 198.1 Hz, CF) 148.90 (s, tert-C, CCH3), 129.33 (s, Ph),
126.73 (s, tert-C, Ph), 124.84 (s, CH), 125.32 (s, Ph), 123.74 (s, tert-
C, CCH2), 120.58 (s, Ph), 116.62 (s, Ph), 60.74 (s, OCH2), 40.56 (s,
Synthesis 2010, No. 11, 1781–1786 © Thieme Stuttgart · New York

1784
N. B. Maximov et al.
PAPER
CH2NH), 30.45 (s, CH2), 20.99 (s, CCH2), 14.66 (s, CH3CH2), 11.83
MS: m/z = 226.3 (M + 1)+.
(s, CH3).
Ethyl 3-(1-Isobutyl-3-methyl-1H-pyrazol-4-yl)propylcarba-
mate (20)
MS: m/z = 306.2 (M + 1)+.
Yellow oil; yield: 90%.
Ethyl 3-[1-(3-Chlorophenyl)-3-methyl-1H-pyrazol-4-yl]propyl-
carbamate (16)
Pale brown oil; yield: 85%.
1H NMR (500 MHz, CDCl3): d = 6.84 (s, 1 H, CH), 5.56 (br s, 1 H,
3
3
NH), 3.81 (q, J = 6 Hz, 2 H, OCH2), 3.48 (d, J = 6.5 Hz, 2 H,
NCH2CH), 2.91 (m, 2 H, CH2NH), 2.13 (t, 3J = 6.5 Hz, 2 H, CCH2),
1.88 (m, 4 H, CH3, CH), 1.56 (m, 3J = 6.5 Hz, 2 H, CH2), 1.06 (t,
3J = 6 Hz, 3 H, CH3CH2), 0.70 [d, 3J = 6.5 Hz, 6 H, CH(CH3)2].
1H NMR (500 MHz, CDCl3): d = 7.66 (s, 1 H, CH), 7.48 (s, 1 H,
Ph), 7.48 (d, 3J = 8 Hz, 1 H, Ph), 7.31 (t, 3J = 8 Hz, 1 H, Ph), 7.16
(d, 3J = 8 Hz, 1 H, Ph), 4.81 (br s, 1 H, NH), 4.12 (q, 3J = 6.5 Hz, 2
H, OCH2), 3.23 (m, 3J = 6 Hz, 2 H, CH2NH), 2.46 (t, 3J = 7.5 Hz, 2
H, CCH2), 2.27 (s, 3 H, CH3), 1.77 (m, 3J = 7 Hz, 2 H, CH2), 1.23
(t, 3J = 7 Hz, 3 H, CH3CH2).
13C NMR (100 MHz, CDCl3): d = 156.80 (s, CO), 149.61 (s, tert-C,
CCH3), 140.88 (s, tert-C, Ph), 135.18 (s, Ph) 130.47 (s, Ph), 130.36
(s, Ph), 125.59 (s, CH), 121.37 (s, tert-C, CCH2), 118.65 (s, Ph),
116.26 (s, Ph), 60.79 (s, OCH2), 40.45 (s, CH2NH), 30.37 (s, CH2),
20.90 (s, CCH2), 14.65 (s, CH3CH2), 11.82 (s, CH3).
13C NMR (100 MHz, CDCl3): d = 156.79 (s, CO), 145.82 (s, tert-C,
CCH3), 128.21 (s, CH), 117.40 (s, tert-C, CCH2), 60.14 (s,
NCH2CH), 58.99 (s, OCH2), 40.18 (s, CH2NH), 30.44 [s,
CH(CH3)2], 29.41 (s, CH2), 20.67 (s, CCH2), 19.68 [s, CH(CH3)2],
14.45 (s, CH3CH2), 11.40 (s, CH3).
MS: m/z = 268.4 (M + 1)+.
Ethyl 3-[1-(2-Hydroxyethyl)-3-methyl-1H-pyrazol-4-yl]propyl-
carbamate (21)
Yellow oil; yield: 82%.
MS: m/z = 322.7 (M + 1)+.
Ethyl 3-[1-(4-Chlorophenyl)-3-methyl-1H-pyrazol-4-yl]propyl-
carbamate (17)
Pale brown oil; yield: 85%.
1H NMR (500 MHz, CDCl3): d = 7.12 (s, 1 H, CH), 5.56 (br s, 1 H,
3
NH), 4.03 (t, J = 7.5 Hz, 2 H, NCH2CH2), 3.82 (m, 4 H, OCH2,
CH2OH), 2.75 (br s, 1 H, OH), 2.62 (t, 3J = 7.5 Hz, 2 H, CH2NH2),
3
2.33 (t, J = 7.5 Hz, 2 H, CCH2), 2.12 (s, 3 H, CH3), 1.58 (m,
1H NMR (500 MHz, CDCl3): d = 7.65 (s, 1 H, CH), 7.54 (d, 3J = 8
Hz, 2 H, Ph), 7.36 (d, 3J = 8 Hz, 1 H, Ph), 4.73 (br s, 1 H, NH), 4.11
(q, 3J = 6.5 Hz, 2 H, OCH2), 3.24 (m, 3J = 6 Hz, 2 H, CH2NH), 2.48
(t, 3J = 7 Hz, 2 H, CCH2), 2.27 (s, 3 H, CH3), 1.78 (m, 3J = 7 Hz, 2
H, CH2), 1.24 (t, 3J = 7 Hz, 3 H, CH3CH2).
13C NMR (100 MHz, CDCl3): d = 156.87 (s, CO), 149.43 (s, tert-C,
CCH3), 138.66 (s, tert-C, Ph), 130.76 (s, Ph), 129.32 (s, 2 C, Ph),
125.31 (s, CH), 121.17 (s, tert-C, CCH2), 119.41 (s, 2 C, Ph), 60.70
(s, OCH2), 40.38 (s, CH2NH), 30.33 (s, CH2), 20.87 (s, CCH2),
14.66 (s, CH3CH2), 11.86 (s, CH3).
3J = 7.5 Hz, 2 H, CH2), 1.06 (t, 3J = 6.5 Hz, 3 H, CH3CH2).
13C NMR (100 MHz, CDCl3): d = 156.66 (s, CO), 146.75 (s, tert-C,
CCH3), 128.94 (s, CH), 118.31 (s, tert-C, CCH2), 61.15 (s,
CH2OH), 59.37 (s, OCH2), 53.81 (s, NCH2), 41.53 (s, CH2NH2),
34.13 (s, CH2), 20.96 (s, CCH2), 14.50 (s, CH3CH2), 11.62 (s, CH3).
MS: m/z = 256.5 (M + 1)+.
Ethyl 3-[3-Methyl-1-(pyridin-2-ylmethyl)-1H-pyrazol-4-yl]pro-
pylcarbamate (22)
The product was obtained as a hydrochloride from the aqueous
phase as a yellow solid; yield: 83%; mp 169 °C (subl.).
MS: m/z = 322.9 (M + 1)+.
Ethyl 3-[1-(1H-Benzimidazol-2-yl)-3-methyl-1H-pyrazol-4-
yl]propylcarbamate (18)
Yellow solid; yield: 73%; mp 180 °C (subl.).
1H NMR (500 MHz, DMSO-d6): d = 8.81 (d, 3J = 5 Hz, 1 H, Py),
8.36 (t, 3J = 7 Hz, 1 H, Py), 7.83 (t, 3J = 6.5 Hz, 1 H, Py), 7.72 (s, 1
H, CH), 7.45 (d, 3J = 7.5 Hz, 1 H, Py), 7.11 (br s, 1 H, NH), 5.62 (s,
3
2 H, NCH2Py), 3.95 (q, J = 7 Hz, 2 H, OCH2), 2.97 (m, 2 H,
1H NMR (500 MHz, DMSO-d6): d = 8.68 (s, 1 H, CH), 7.60 (d,
3J = 6.5 Hz, 2 H, C7H6N2), 7.39 (t, 3J = 6.5 Hz, 2 H, C7H5N2), 7.17
(br s, 1 H, NH), 6.88 (br s, 1 H, NH), 3.94 (q, 3J = 6 Hz, 2 H, OCH2),
3.03 (m, 2 H, CH2NH), 2.43 (t, 3J = 6.5 Hz, 2 H, CCH2), 2.27 (s, 3
3
CH2NH), 2.32 (t, J = 7 Hz, 2 H, CCH2), 2.06 (s, 3 H, CH3), 1.59
(m, 3J = 7.5 Hz, 2 H, CH2), 1.12 (t, 3J = 7 Hz, 3 H, CH3CH2).
13C NMR (100 MHz, DMSO-d6): d = 156.79 (s, CO), 153.25 (s,
tert-C, Py), 147.41 (s, tert-C, CCH3), 144.97 (s, Py), 143.8 (s, Py),
130.88 (s, CH), 125.91 (s, Py), 125.45 (s, Py), 119.38 (s, tert-C,
CCH2), 59.91 (s, OCH2), 52.5 (s, NCH2Py), 31.18 (s, CH2NH),
30.47 (s, CH2), 20.76 (s, CCH2), 14.19 (s, CH3CH2), 11.78 (s, CH3).
3
H, CH3), 1.68 (m, 3J = 6.5 Hz, 2 H, CH2), 1.12 (t, J = 6 Hz, 3 H,
CH3CH2).
13C NMR (100 MHz, DMSO-d6): d = 156.86 (s, CO), 155.17 (s,
tert-C, C7H5N2), 131.34 (s, tert-C, C7H5N2), 129.08 (s, tert-C,
C7H5N2), 142.98 (s, tert-C, CCH3), 125.7 (s, CH), 125.26 (s, 2 C
C7H5N2), 120.88 (s, tert-C, CCH2), 113.98 (s, C7H5N2), 109.03 (s,
C7H5N2), 60.05 (s, OCH2), 39.04 (s, CH2NH), 29.56 (s, CH2), 20.73
(s, CCH2), 15.17 (s, CH3CH2), 12.19 (s, CH3).
MS: m/z = 303.3 (M + 1)+.
Aminopyrazoles 2, 23–30; General Procedure
A 1-necked 50-mL round-bottomed flask equipped with a reflux
condenser was charged with a soln of the corresponding ethyl car-
bamate 5, 15–22 (10 mmol) and concd HCl (25 mL). The soln was
heated at reflux for 16 h. Thereafter, the soln was evaporated under
reduced pressure to the corresponding crude aminopyrazole 2, 23–
30. The product was washed with CHCl3 (25 mL) and dried in
vacuo.
MS: m/z = 328.4 (M + 1)+.
Ethyl 3-(1,3-Dimethyl-1H-pyrazol-4-yl)propylcarbamate (19)
Yellow oil; yield: 72%.
1H NMR (500 MHz, CDCl3): d = 7.05 (s, 1 H, CH), 4.83 (br s, 1 H,
3
NH), 4.06 (q, J = 6.5 Hz, 2 H, OCH2), 3.73 (s, 3 H, NCH3), 3.15
Scale of the synthesis: 1–5 g of the corresponding pyrazole.
(m, 3J = 6 Hz, 2 H, CH2NH), 2.35 (t, 3J = 7 Hz, 2 H, CCH2), 2.13 (s,
3
3
3 H, CH3), 1.67 (m, J = 7 Hz, 2 H, CH2), 1.19 (t, J = 7 Hz, 3 H,
CH3CH2).
3-(3-Methyl-1-phenyl-1H-pyrazol-4-yl)propylamine Hydro-
chloride (2)
White solid; yield: 96%; mp >300 °C (dec.).
13C NMR (100 MHz, CDCl3): d = 156.77 (s, CO), 146.32 (s, tert-C,
CCH3), 129.10 (s, CH), 118.23 (s, tert-C, CCH2), 60.44 (s, OCH2),
40.48 (s, CH2NH), 38.53 (s, NCH3), 30.54 (s, CH2), 20.77 (s,
CCH2), 14.45 (s, CH3CH2), 11.50 (s, CH3).
1H NMR (500 MHz, DMSO-d6): d = 8.24 (s, 1 H, CH), 8.01 (br s, 3
+
H, NH3 ), 7.73 (d, 3J = 7.5 Hz, 2 H, Ph), 7.43 (t, 3J = 7.5 Hz, 2 H,
Synthesis 2010, No. 11, 1781–1786 © Thieme Stuttgart · New York

PAPER
A Facile Approach to New Pyrazole Derivatives
1785
Ph), 7.21 (t, 3J = 7.5 Hz, 1 H, Ph), 2.80 (m, 3J = 6 Hz, 2 H,
CH2NH2), 2.52 (t, 3J = 7.5 Hz, 2 H, CCH2), 2.19 (s, 3 H, CH3), 1.84
(m, 3J = 7.5 Hz, 2 H, CH2).
13C NMR (100 MHz, DMSO-d6): d = 149.06 (s, tert-C, CCH3),
137.70 (s, tert-C, Ph), 129.99 (s, 2 C, Ph), 129.79 (s, CH), 127.91
(s, Ph), 120.65 (s, tert-C, CCH2), 119.90 (s, 2 C, Ph), 39.06 (s,
CH2NH2), 27.16 (s, CH2), 19.81 (s, CCH2), 10.13 (s, CH3).
C, CCH2), 113.59 (s, C7H5N2), 109.11 (s, C7H5N2), 39.12 (s,
CH2NH2), 29.49 (s, CH2), 20.68 (s, CCH2), 12.21 (s, CH3).
MS: m/z = 256.4 (M + 1)+.
3-(1,3-Dimethyl-1H-pyrazol-4-yl)propylamine Hydrochloride
(27)
White solid; yield: 92%; mp 243 °C (subl.).
+
MS: m/z = 216.3 (M + 1)+.
1H NMR (500 MHz, DMSO-d6): d = 8.22 (br s, 3 H, NH3 ), 7.67 (s,
1 H, CH), 3.78 (s, 3 H, NCH3), 2.72 (m, 2 H, CH2NH2), 2.41 (t,
3J = 7 Hz, 2 H, CCH2), 2.14 (s, 3 H, CH3), 1.76 (m, 3J = 7 Hz, 2 H,
CH2).
3-[1-(2-Fluorophenyl)-3-methyl-1H-pyrazol-4-yl]propylamine
Hydrochloride (23)
White solid; yield: 94%; mp 205–206 °C (subl.).
13C NMR (100 MHz, DMSO-d6): d = 146.39 (s, tert-C, CCH3),
129.32 (s, CH), 118.33 (s, tert-C, CCH2), 40.67 (s, CH2NH2), 39.66
(s, NCH3), 30.57 (s, CH2), 20.87 (s, CCH2), 11.73 (s, CH3).
1H NMR (500 MHz, DMSO-d6): d = 8.18 (br s, 3 H, NH3 ), 7.92 (t,
+
3JH–F = 8 Hz, 1 H, Ph), 7.73 (s, 1 H, CH), 7.37 (t, 1 H, Ph), 7.28 (m,
2 H, Ph), 3.41 (m, 3J = 7 Hz, 2 H, CH2NH2), 2.76 (t, 3J = 7.5 Hz, 2
H, CCH2), 2.18 (s, 3 H, CH3), 1.83 (m, 3J = 7 Hz, 2 H, CH2).
MS: m/z = 154.1 (M + 1)+.
13C NMR (100 MHz, DMSO-d6): d = 153.23 (d, 1JC,F = 198.10 Hz,
CF), 148.94 (s, tert-C, CCH3), 129.38 (s, Ph), 126.70 (s, tert-C, Ph),
126.31 (s, Ph), 125.01 (s, CH), 123.64 (s, tert-C, CCH2), 120.63 (s,
Ph), 116.66 (s, Ph), 40.39 (s, CH2NH2), 30.49 (s, CH2), 20.94 (s,
CCH2), 11.81 (s, CH3).
3-(1-Isobutyl-3-methyl-1H-pyrazol-4-yl)propylamine Hydro-
chloride (28)
White solid; yield: 92%; mp 164 °C.
+
1H NMR (500 MHz, DMSO-d6): d = 7.79 (br s, 3 H, NH3 ), 7.20 (s,
3
1 H, CH), 3.77 (d, J = 6.5 Hz, 2 H, NCH2CH), 2.73 (m, 2 H,
MS: m/z = 234.4 (M + 1)+.
CH2NH2), 2.52 [m, 1 H, CH(CH3)2], 2.38 (t, 3J = 7 Hz, 2 H, CCH2),
2.14 (s, 3 H, CH3), 1.72 (m, 3J = 7 Hz, 2 H, CH2), 0.81 [d, 3J = 6.5
Hz, 6 H, CH(CH3)2].
3-[1-(3-Chlorophenyl)-3-methyl-1H-pyrazol-4-yl]propylamine
Hydrochloride (24)
White solid; yield: 95%; mp 210–212 °C (subl.).
13C NMR (100 MHz, DMSO-d6): d = 146.82 (s, tert-C, CCH3),
127.21 (s, CH), 117.42 (s, tert-C, CCH2), 60.34 (s, NCH2CH), 40.48
(s, CH2NH2), 30.62 [s, CH(CH3)2], 30.10 (s, CH2), 20.63 (s, CCH2),
19.71 [s, CH(CH3)2], 11.40 (s, CH3).
1H NMR (500 MHz, DMSO-d6): d = 8.37 (s, 1 H, CH), 8.19 (br s, 3
+
H, NH3 ), 7.82 (s, 1 H, Ph), 7.72 (d, 3J = 7.5 Hz, 1 H, Ph), 7.44 (t,
3J = 7.5 Hz, 1 H, Ph), 7.24 (d, 3J = 7.5 Hz, 1 H, Ph), 2.79 (m, 2 H,
CH2NH2), 2.52 (t, 3J = 7.5 Hz, 2 H, CCH2), 2.18 (s, 3 H, CH3), 1.86
(m, 3J = 7.5 Hz, 2 H, CH2).
MS: m/z = 196.5 (M + 1)+.
2-[4-(3-Aminopropyl)-3-methyl-1H-pyrazol-1-yl]ethanol Hy-
drochloride (29)
White solid; yield: 97%; mp 74 °C.
13C NMR (100 MHz, DMSO-d6): d = 149.60 (s, tert-C, CCH3),
141.31 (s, tert-C, Ph), 134.41 (s, Ph), 131.63 (s, Ph), 126.89 (s, Ph),
125.32 (s, CH), 121.22 (s, tert-C, CCH2), 117.49 (s, Ph), 116.29 (s,
Ph), 38.71 (s, CH2NH), 27.49 (s, CH2), 20.65 (s, CCH2), 12.22 (s,
CH3).
1H NMR (500 MHz, CDCl3): d = 7.12 (s, 1 H, CH), 4.03 (t, 3J = 7.5
Hz, 2 H, NCH2CH2), 3.83 (d, 3J = 7.5 Hz, 2 H, CH2OH), 2.75 (br s,
+
3 H, OH, NH3 ), 2.61 (t, 3J = 7.5 Hz, 2 H, CH2NH2), 2.33 (t, 3J = 7.5
MS: m/z = 250.6 (M + 1)+.
Hz, 2 H, CCH2), 2.12 (s, 3 H, CH3), 1.58 (m, 3J = 7.5 Hz, 2 H, CH2).
13C NMR (100 MHz, CDCl3): d = 146.72 (s, tert-C, CCH3), 128.90
(s, CH), 118.29 (s, tert-C, CCH2), 61.16 (s, CH2OH), 53.84 (s,
NCH2), 41.51 (s, CH2NH2), 34.03 (s, CH2), 20.97 (s, CCH2), 11.62
(s, CH3).
3-[1-(4-Chlorophenyl)-3-methyl-1H-pyrazol-4-yl]propylamine
Hydrochloride (25)
White solid; yield: 94%; mp 211 °C (subl.).
1H NMR (500 MHz, DMSO-d6): d = 8.28 (s, 1 H, CH), 8.16 (br s, 3
MS: m/z = 184.2 (M + 1)+.
+
H, NH3 ), 7.75 (d, 3J = 8 Hz, 2 H, Ph), 7.45 (d, 3J = 8 Hz, 2 H, Ph),
2.78 (m, 3J = 6 Hz, 2 H, CH2NH2), 2.46 (t, 3J = 7.5 Hz, 2 H, CCH2),
3-[3-Methyl-1-(pyridin-2-ylmethyl)-1H-pyrazol-4-yl]propyl-
amine Hydrochloride (30)
White solid; yield: 95%; mp >300 °C (dec.).
2.17 (s, 3 H, CH3), 1.85 (m, 3J = 7.5 Hz, 2 H, CH2).
13C NMR (100 MHz, DMSO-d6): d = 149.32 (s, tert-C, CCH3),
138.96 (s, tert-C, Ph), 131.62 (s, Ph), 129.77 (m, 2 C, Ph), 126.7 (s,
CH), 122.02 (s, tert-C, CCH2), 119.48 (s, 2 C, Ph), 38.74 (s,
CH2NH2), 27.53 (s, CH2), 20.63 (s, CCH2), 12.17 (s, CH3).
1H NMR (500 MHz, DMSO-d6): d = 8.75 (d, 3J = 5 Hz, 1 H, Py),
+
8.25 (t, 3J = 7 Hz, 1 H, Py), 8.14 (br s, 3 H, NH3 ), 7.72 (m, 2 H, Py,
CH), 7.38 (d, 3J = 6.5 Hz, 1 H, Py), 5.55 (s, 2 H, NCH2Py), 2.75 (m,
2 H, CH2NH2), 2.41 (t, 3J = 7 Hz, 2 H, CCH2), 2.07 (s, 3 H, CH3),
1.77 (m, 3J = 7 Hz, 2 H, CH2).
MS: m/z = 250.7 (M + 1)+.
3-[1-(1H-Benzimidazol-2-yl)-3-methyl-1H-pyrazol-4-yl]propyl-
amine Hydrochloride (26)
White solid; yield: 95%; mp >300 °C (dec.).
13C NMR (100 MHz, DMSO-d6): d = 154.25 (s, tert-C, Py), 147.56
(s, tert-C, CCH3), 145.65 (s, Py), 142.91 (s, Py), 129.34 (s, CH),
125.37 (s, Py), 124.85 (s, Py), 119.44 (s, tert-C, CCH2), 52.52 (s,
NCH2Py), 39.44 (s, CH2NH2), 30.89 (s, CH2), 20.76 (s, CCH2),
11.78 (s, CH3).
1H NMR (500 MHz, DMSO-d6): d = 8.58 (s, 1 H, CH), 8.19 (br s, 4
H, NH, NH3 ), 7.53 (d, 3J = 6.5 Hz, 2 H, H-C7H6N2), 7.28 (t,
+
3J = 6.5 Hz, 2 H, H-C7H5N2), 3.17 (m, 2 H, CH2NH2), 2.81 (t,
3J = 6.5 Hz, 2 H, CCH2), 2.28 (s, 3 H, CH3), 1.87 (m, 3J = 6.5 Hz, 2
H, CH2).
MS: m/z = 231.2 (M + 1)+.
13C NMR (100 MHz, DMSO-d6): d = 156.77 (s, tert-C, C7H5N2),
141.32 (s, tert-C, CCH3), 130.38 (s, tert-C, C7H5N2), 129.45 (s, tert-
C, C7H5N2), 125.74 (s, CH), 125.36 (s, 2 C, C7H5N2), 120.78 (s, tert-
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