A simple synthesis of 4-(2-aminoethyl)-5-hydroxy-1H-pyrazoles

Article abstract of DOI:10.1016/j.tet.2007.07.052

A simple four-step synthesis of 4-(2-aminoethyl)-5-hydroxy-1H-pyrazoles 8 (or their 1H-pyrazol-3(2H)-one tautomers 8′) as the pyrazole analogues of histamine was developed. First, enamino lactam 3 was prepared as the key intermediate in two steps from 2-p

Full text of DOI:10.1016/j.tet.2007.07.052

Tetrahedron 63 (2007) 11213–11222
A simple synthesis of 4-(2-aminoethyl)-5-hydroxy-1H-pyrazoles
a
David Kralj, Uros Groselj, Anton Meden, Georg Dahmann,
a
a
b
ꢀ
ꢀ
Branko Stanovnika and Jurij Svetea,
*
aFaculty of Chemistry and Chemical Technology, University of Ljubljana, Asꢀkercꢀeva 5, PO Box 537, 1000 Ljubljana, Slovenia
bBoehringer Ingelheim Pharma GmbH & Co. KG, Department of Chemical Research, 88397 Biberach, Germany
Received 24 April 2007; revised 3 July 2007; accepted 19 July 2007
Available online 26 July 2007
Abstract—A simple four-step synthesis of 4-(2-aminoethyl)-5-hydroxy-1H-pyrazoles 8 (or their 1H-pyrazol-3(2H)-one tautomers 80) as the
pyrazole analogues of histamine was developed. First, enamino lactam 3 was prepared as the key intermediate in two steps from 2-pyrroli-
dinone (1). Next, acid-catalysed ‘ring switching’ transformations of 3 with monosubstituted hydrazines 4 gave N-[(1-substituted 5-hydroxy-
1H-pyrazol-4-yl)ethyl]benzamides 7a–k and N-[2-(2-heteroaryl-3-oxo-2,3-dihydro-1H-pyrazol-4-yl)ethyl]benzamides 70l–o. Benzamides
7a–k and 70l–o were finally hydrolysed by heating in 6 M hydrochloric acid to furnish 1-substituted 4-(2-aminoethyl)-5-hydroxy-1H-pyr-
azoles 8a–k and 4-(2-aminoethyl)-2-heteroaryl-1H-pyrazol-3(2H)-ones 80l–o in good overall yields.
Ó 2007 Published by Elsevier Ltd.
1. Introduction
enaminones were also employed in combinatorial synthesis
of dehydroalanines and their cyclic analogues23,24 and
(2S,4S)-4-aminopyroglutamic acid amides.25
Due to the crucial role of histamine, tyramine, dopamine,
tryptamine, serotonine and melatonin (Fig. 1) as chemical
messengers in biological processes, the preparation of their
novel synthetic analogues represents an important target in
medicinal and synthetic organic chemistry.1–3
A part of our research in the field of functionalised heterocy-
cles has been devoted to the synthesis of pyrazole derivatives
via cyclocondensations of enaminones with monosubsti-
tuted hydrazines.4–8,11,26–29 Within this context, we have
previously reported several regioselective syntheses of
various functionalised pyrazole derivatives containing
alanine,27,30 b-aminoalcohol,29,31 propane-1,2-diol,32 2-
phenylethylamine29 and terpene11 structural motifs. In con-
tinuation of our work in this field we now report a novel
application of the enaminone methodology in the synthesis
of 4-(2-aminoethyl)-5-hydroxy-1H-pyrazoles 8 (or their
1H-pyrazol-3(2H)-one tautomers 80) as the pyrazole ana-
logues of histamine.
2-Substituted alkyl 3-(dimethylamino)prop-2-enoates and re-
lated enaminones are a group of enamino masked alkyl a-for-
mylacetates, which are easily available and versatile reagents
in heterocyclic synthesis.4–6 In addition to their extensive use
in the synthesis of various heterocyclic systems, recent appli-
cations of enaminones are mostly orientated towards prepara-
tion of analogues of natural products,4–9 such as (+)-camphor
and related terpenes,10–17 tetramic acids,18 aplysinopsins,9,19
b-carbolines,19 meridianines20,21 and dipodazine.22 Recently,
HO
R
H
N
H
N
H
N
N
R
MeO
NH2
NH2
NHAc
NH2
tryptamine (R = H)
serotonine (R = OH)
melatonin
histamine
tyramine (R = H)
dopamine (R = OH)
Figure 1.
Keywords: Enaminones; Hydrazines; Cyclisation; Pyrazoles; Histamine analogues.
* Corresponding author. Tel.: +386 1 2419 100; fax: +386 1 2419 220; e-mail: jurij.svete@fkkt.uni-lj.si
0040–4020/$ - see front matter Ó 2007 Published by Elsevier Ltd.
doi:10.1016/j.tet.2007.07.052

11214
D. Kralj et al. / Tetrahedron 63 (2007) 11213–11222
COPh
COPh
N
NMe2
NMe2
H
N
1 N
t-BuO
2
toluene, reflux, 3 h
82%
O
O
O
5
PhCOCl, pyridine, r.t., 3 h
74%
3
4
3'
2
1
Me2N
3
COPh
N
COPh
N
COPh
N
HO
N
R
O
O
1-propanol, reflux, 4 h
H
R-NHNH2 HCl
N
R
N
H
H
N
4a-o
6
NMe2
H
H
5
3
R
N
R
1'
N1
2' N
2N
OH
1-propanol, reflux, 16 h
OH
5
5'
2 HCl
3
1
4
3'
4'
2'
2
1'
NHCOPh
NH2
8a-k
7a-k
R = heteroaryl
R = heteroaryl
R
R
N2
N 2'
H1N'
H1N
O
O
1-propanol, reflux, 16 h
3'
3
HCl
1
4
5
2'
5'
4'
1'
2
NH2
NHCOPh
7'l-o
8'l-o
4a, 7a, 8a:
R = H
4b-e, 7b-e, 8b-e:
4f-k, 7f-k, 8f-k:
4l-o, 7l-o, 8l-o:
R = alkyl
R = aryl
R = heteroaryl
Scheme 1.
2. Results and discussion
intermediate 6, which then tautomerises into 7 via opening of
the pyrrolidine ring.11,28,30–32,34 Finally, the N-benzoyl-2-
(pyrazolyl)ethylamines 7a–k and 70l–o were deprotected by
heating in 6 M hydrochloric acid for 16 h to furnish 1-
substituted 4-(2-aminoethyl)-5-hydroxy-1H-pyrazoles 8a–k
and 4-(2-aminoethyl)-2-heteroaryl-1H-pyrazol-3(2H)-ones
The key intermediate 3 was first prepared in two steps from 2-
pyrrolidinone (1). Treatment of a mixture of 1 and anhydrous
pyridine in a molar ratio of 1:1, respectively, with 1 equiv of
benzoyl chloride gave N-benzoylpyrrolidin-2-one (2) in
74% yield upon simple filtration workup. In comparison to
the literature procedure for benzoylation of 2-pyrrolidinone
(1),33 our simplified version is very convenient for a large-
scale preparation of 2, since it avoids extraction workup and
use of excess of noxious reagents. N-Benzoylpyrrolidin-2-
one (2) was then treated with bis(dimethylamino)-tert-but-
oxymethane (TBDMAM, Bredereck’s reagent) in refluxing
toluene to give (E)-1-benzoyl-3-[(dimethylamino)methylide-
ne]pyrrolidin-2-one (3) in 82% yield. Heating of the enamino
lactam 3 with hydrazine hydrochlorides 4a–o in n-propanol
under reflux for 4 h afforded N-[(1-substituted 5-hydroxy-
1H-pyrazol-4-yl)ethyl]benzamides7a–kandN-[2-(2-hetero-
aryl-3-oxo-2,3-dihydro-1H-pyrazol-4-yl)ethyl]benzamides
70l–o as products of the ‘ring switching’ transformations in
72–100% yields. The reaction mechanism can be explained
by initial 1,4-addition of hydrazine 4 to the vinylogous amide
3 followed by elimination of the dimethylamino group to give
the enehydrazine intermediate 5. Addition of the secondary
nitrogen atom to the lactone carbonylgroup givesthe bicyclic
Table 1. Experimental data for compounds 7a–k, 70l–o, 8a–k and 80l–o
Compound
R
Yield (%)
7
8
7a, 8a
7b, 8b
7c, 8c
7d, 8d
7e, 8e
7f, 8f
7g, 8g
7h, 8h
7i, 8i
H
Methyl
2,2,2-Trifluoroethyl
Benzyl
Cyclohexyl
81
100
100
92
62
100
50
87
83
78
86
91
65
34
51
86
94
72
96
82
92
97
91
87
79
84
72
81
Phenyl
4-Carboxyphenyl
3-Chlorophenyl
4-Chlorophenyl
3-Methoxyphenyl
4-Methoxyphenyl
Pyridin-2-yl
6-Chloropyridazin-2-yl
6-Phenylpyridazin-2-yl
Imidazo[1,2-b]pyridazin-6-yl
7j, 8j
7k, 8k
70l, 80l
70m, 80m
70n, 80n
70o, 80o
100
79

D. Kralj et al. / Tetrahedron 63 (2007) 11213–11222
11215
80l–o, respectively, in 34–100% yields. Compounds 8a–l
were isolated as dihydrochlorides, while 2-pyridazinyl
substituted 4-(2-aminoethyl)-1H-pyrazol-3(2H)-ones 8m–o
were obtained as monohydrochlorides (Scheme 1, Table 1).
3. Structure determination
The structures of novel compounds 3, 7a–k, 70l–o, 8a–k and
80l–o were determined by spectroscopic methods (IR, 1H and
13C NMR, NOESY spectroscopy and MS) and by elemental
analyses for C, H and N. Compounds 70o, 8a,c,e,g and 80l–o
were not obtained in analytically pure form. Their identities
were confirmed by 13C NMR and/or EI-HRMS.
The (E)-configuration around the exocyclic C]C bond in
the enamino lactam 3 was determined by NOESY spectros-
copy. Absence of NOE between 30-H and the methylene
group at position 4 was in agreement with the (E)-configura-
tion. Unfortunately, measurement of NOE between the di-
methylamino group and the methylene group at position 4
was not possible due an overlap of these two signals. The
(E)-configuration of compound 3 is also in agreement with
typical configuration around the C]C double bond in
related enaminones (Fig. 2).4–6
Tautomeric forms of pyrazolone derivatives 7, 70, 8 and 80
were determined by IR, NMR and X-ray diffraction. First,
absence of C]O vibrations in the final products 8a–k and
the C]O absorption at w1640 cmꢀ1 in compounds 80l–o
indicated that pyrazoles 8a–k were obtained as the 5-
hydroxy-1H-pyrazole tautomers (OH tautomers), while 1-
heteroaryl substituted pyrazoles 8l–o were isolated as the
1H-pyrazol-3(2H)-one tautomers (NH tautomers). Such dis-
crimination was not possible in the case of the N-benzoyl-
ated compounds 7 and 70, due to the benzamide carbonyl
absorption at w1640 cmꢀ1. However, the tautomeric forms
of the N-benzoylated compounds 7 and 70 should most prob-
ably be the same as the tautomeric forms of the correspond-
ing final products 8 and 80. Higher stability of the NH
Figure 3. The asymmetric unit of compound 8f. Ellipsoids are plotted at
50% probability level. H atoms are drawn as circles of arbitrary radii.
tautomeric forms in the case of N-heteroaryl substituted pyr-
azoles 70l–o and 80l–o could be due to intramolecular N/H
bond between the H–N(1) and the azine ring nitrogen atom
(Fig. 2).27,35–41
1
Next, the H and 13C NMR spectra of compounds 7 and 8
usually exhibited broad signals for the heteroaromatic C
and H nuclei and for both CH2 groups. Broadening of these
signals can be explained by fast equilibration between the
5-hydroxy-1H-pyrazole form (OH tautomers 7 and 8) and
1H-pyrazol-3(2H)-one form (NH tautomers 70 and 80) in
DMSO-d6 solution (Fig. 2).35–41
COPh
Het
N
N
O
N
N
Finally, the structure of compound 8f was determined by X-
ray diffraction (Fig. 3). To our surprise, the bond lengths of
the pyrazole ring of 8f were between the typical values for
the OH tautomer and the NH tautomer.35–40 Furthermore,
the crystal cell consisted of 8f and HCl in a ratio of 2:3, re-
spectively, where two molecules of 8f were connected via
the O/H/O bridge with identical O/H distances and
identical C–O bond lengths (Fig. 4). Therefore, the structure
of 8f could be regarded as a hybrid between the OH tautomer
8f and the NH tautomer 80f as represented by the structural
formula 800f (Fig. 5).
H2C
Me2N
H
H
O
NHR'
Compounds 7'l-o ( R' = H)
Compounds 8'l-o (R' = COPh)
no n.O.e.
Compound 3
(E)-isomer
~1640 cm-1
R
R
N
DMSO-d6
R' = H, COPh
N
OH
O
N
HN
4. Conclusion
NHR'
NHR'
In summary, we developed a simple and efficient synthesis
of 1-substituted 2-(5-hydroxy-1H-pyrazol-4-yl)ethylamines
8 (or their 1H-pyrazol-3-(2H)-one tautomers 80) as
the pyrazole analogues of histamine. In this manner, 15
Compounds 7'l-o, 8'l-o
Compounds 7a-k, 8a-k
(NH-tautomers)
(OH-tautomers)
Figure 2. Structural determination by IR and NMR.

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D. Kralj et al. / Tetrahedron 63 (2007) 11213–11222
Figure 4. Packing of compound 8f in the crystal cell.
Cl
N
Cl
H3N
O
H3N
Cl
Cl
δ+
N
H
N
δ−
O
H
N
N
O H
O
H
N
δ−
N
H
N
δ+
H
NH3
NH3
Cl
Cl
8f
8'f
Compound 8''f
Figure 5.
2-(pyrazolyl)ethylamines 8a–o with various alkyl, aryl and
heteroaryl residues attached at position 1 in the pyrazole
ring were synthesised in four steps and in good overall yields
from pyrrolidin-2-one (1). The key step in this synthesis is
the acid-catalysed ‘ring switching’ transformation of the en-
amino lactam 3 with hydrazine derivatives 4. In addition to
the Young’s ‘ring switching’ synthesis of heteroarylala-
nines42–44 and our enaminone-based syntheses of heteroaryl
substituted alanines, b-amino alcohols, ethylamines and
terpenes,4–8,11,26–32 this work represents a novel synthetic
application of the enaminone method for the preparation
of histamine analogues.
DMSO-d6 and CDCl3 as solvents with TMS as the internal
standard. Mass spectra were recorded on an AutoSpecQ
spectrometer, IR spectra on a Perkin–Elmer Spectrum BX
FTIR spectrophotometer. Microanalyses were performed
on a Perkin–Elmer CHN Analyser 2400 II.
Pyrrolidin-2-one (1), bis(dimethylamino)-tert-butoxyme-
thane (Bredereck’s reagent), hydrazines 4a–i,k,l (Sigma–
Aldrich) and 3-methoxyphenylhydrazine hydrochloride
(4j) (Manchester Chemicals) are commercially available.
6-Chloro-3-hydrazinopyridazine (4m),45 3-hydrazino-6-
phenylpyridazine (4n)46 and 6-hydrazinoimidazo[1,2-b]pyr-
idazine (4o),47 were prepared according to the literature
procedures.
5. Experimental
5.1. General
5.2. 1-Benzoylpyrrolidin-2-one (2)
This compound was prepared according to the modified lit-
erature procedure.33 Benzoyl chloride (46 mL, 0.4 mol) was
added to a mixture of pyrrolidin-2-one (1) (32 mL, 0.42 mol)
and anhydrous pyridine (32.5 mL, 0.4 mol) and the mixture
Melting points were determined on a Kofler micro hot stage.
The NMR spectra were obtained on a Bruker Avance DPX
300 at 300 MHz for 1H and 75.5 MHz for 13C nucleus, using

D. Kralj et al. / Tetrahedron 63 (2007) 11213–11222
11217
was stirred at rt for 3 h. To the so formed solid cake water
(200 mL) was added, the mixture was heated on water
bath until the solid cake melted completely. Then vigorous
stirring was started and the so formed emulsion was allowed
to cool to rt. The precipitate was collected by filtration and
washed with water (3ꢁ50 mL). The crude 2 was re-sus-
pended in water (200 mL), heated on water bath until the
solid melted completely. The vigorously stirred mixture
was then allowed to cool to rt, the precipitate was collected
by filtration, washed with water (3ꢁ100 mL) and crystal-
lised from acetone–water (2:1,w200 mL) to give the purified
title compound 2 (140 g, 74%) as a slightly yellowish solid.
Mp and spectral data for compound 2 were in agreement
with the literature data.33
(2H, m, 2H of Ph). dC NMR (75.5 MHz, DMSO-d6) 22.5,
40.1, 100.9, 127.2, 128.3, 128.4, 131.1, 134.7, 159.6,
166.4. [Found: C, 62.34; H, 5.81; N, 18.31. C12H13N3O2 re-
quires: C, 62.33; H, 5.67; N, 18.17.] nmax (KBr) 3422, 3007,
2837, 1686, 1454, 1425, 1327, 1293, 935, 708 cmꢀ1
.
5.4.2. N-[2-(5-Hydroxy-1-methyl-1H-pyrazol-4-yl)ethyl]-
benzamide (7b). Prepared from 3, methylhydrazine (4b)
(920 mg, 20 mmol) and 37% hydrochloric acid; trituration
with water. Yield: 4.22 g (86%) of a white solid; mp 192–
195 ꢂC. dH (300 MHz, DMSO-d6) 2.51 (2H, t, J¼7.3 Hz,
2-CH2), 3.37 (2H, br td, J¼7.3, 5.7 Hz, 1-CH2), 3.45 (3H,
br s, Me), 7.26 (1H, br s, 30-H), 7.42–7.54 (3H, m, 3H of
Ph), 7.80–7.87 (2H, m, 2H of Ph), 8.54 (1H, br s, NH),
10.02 (1H, br s, OH). dH (300 MHz, CD3OD) 2.62 (2H, t,
J¼7.2 Hz, 2-CH2), 3.48 (3H, s, Me), 3.51 (2H, t,
J¼7.2 Hz, 1-CH2), 7.38 (1H, br s, 30-H), 7.42–7.54 (3H,
m, 3H of Ph), 7.80–7.84 (2H, m, 2H of Ph). dC NMR
(75.5 MHz, DMSO-d6) 22.6, 32.4, 40.2, 99.9, 127.0,
128.1, 130.9, 134.6, 136.1, 152.8, 166.0. [Found: C, 63.39;
H, 6.07; N, 16.92. C13H15N3O2 requires: C, 63.66; H,
6.16; N, 17.13.] nmax (KBr) 3430, 3269, 1638, 1545, 1382,
5.3. (3E)-1-Benzoyl-3-(dimethylamino)methylidenepyr-
rolidin-2-one (3)
A mixture of N-acylpyrrolidin-2-one (2) (18.9 g, 0.1 mol),
anhydrous toluene (100 mL) and Bredereck’s reagent
(22 mL, 0.11 mol) was heated under reflux for 3 h. The vol-
atile components were evaporated in vacuo and the residue
was crystallised from EtOAc to give the title compound 3
(20.1 g, 82%) as yellowish crystals; mp 126–128 ꢂC (from
EtOAc). dH (300 MHz, DMSO-d6) 2.98 (2H, t, J¼7.7 Hz,
4-CH2), 3.04 (6H, s, NMe2), 3.72 (2H, t, J¼7.7 Hz, 5-
CH2), 6.99 (1H, s, 30-H), 7.32–7.38 (5H, m, Ph). dC NMR
(75.5 MHz, DMSO-d6) 21.9, 42.5, 43.9, 93.6, 128.1,
129.2, 131.3, 137.0, 147.3, 170.1, 170.7. [Found: C, 68.60;
H, 6.55; N, 11.82. C14H16N2O2 requires: C, 68.83; H,
6.60; N, 11.47.] nmax (KBr) 3438, 1695, 1644, 1607, 1337,
1312, 1155, 952, 705 cmꢀ1
.
5.4.3. N-{2-[5-Hydroxy-1-(2,2,2-trifluoroethyl)-1H-pyr-
azol-4-yl]ethyl}benzamide (7c). Prepared from 3, 2,2,2-tri-
fluoroethylhydrazine (4c) (70% in water, 3.26 g, 20 mmol)
and 37% hydrochloric acid; trituration with water. Yield:
5.89 g (94%) of a white solid; mp 183–186 ꢂC. dH
(300 MHz, DMSO-d6) 2.53 (2H, t, J¼7.3 Hz, 2-CH2), 3.36
(2H, br td, J¼7.3, 5.7 Hz, 1-CH2), 4.67 (2H, q, J¼8.8 Hz,
CH2CF3), 7.24 (1H, br s, 30-H), 7.40–7.54 (3H, m, 3H of
Ph), 7.79–7.84 (2H, m, 2H of Ph), 8.50 (1H, br s, NH),
10.68 (1H, br s, OH). dC NMR (75.5 MHz, DMSO-d6)
22.3, 39.8, 46.3, 118.1, 121.8, 125.5, 127.0, 128.1, 130.9,
134.6, 139.3, 166.1. [Found: C, 53.78; H, 4.72; N, 13.37.
C14H14F3N3O2 requires: C, 53.67; H, 4.50; N, 13.41.] nmax
(KBr) 3309, 3068, 2932, 1650, 1615, 1575, 1557, 1252,
1304, 1269, 1236, 1202, 985, 885 cmꢀ1
.
5.4. ‘Ring switching’ reactions of enamino lactam 3 with
hydrazine derivatives 4. General procedure for the
preparation of N-[2-(1-substituted 5-hydroxy-1H-
pyrazol-4-yl)ethyl]benzamides 7a–k and N-
[2-(2-heteroaryl-3-oxo-2,3-dihydro-1H-
pyrazol-4-yl)ethyl]benzamides 70l–o
1160, 693 cmꢀ1
.
Enaminone 3 (4.80 mg, 20 mmol) was added to a stirred mix-
ture of hydrazine derivative 4$hydrochloride (20 mmol) and
1-propanol (80 mL) or to a stirred mixture of hydrazine
derivative 4 (20 mmol), 37% hydrochloric acid (1.8 mL,
20 mmol) and 1-propanol (80 mL). The mixturewas refluxed
for 4 h, cooled and volatile components were evaporated in
vacuo. The residue was triturated with water (80 mL) or
ethanol–water (80 mL) and the precipitate was collected by
filtration to give 7.
5.4.4. N-[2-(1-Benzyl-5-hydroxy-1H-pyrazol-4-yl)ethyl]-
benzamide (7d). Prepared from 3 and benzylhydrazine di-
hydrochloride (4d) (3.90 g, 20 mmol); trituration with
ethanol–water (1:1). Yield: 4.63 g (72%) of a greyish solid;
mp 144–149 ꢂC. EIMS: m/z¼321 (M+). dH (300 MHz,
DMSO-d6) 2.58 (2H, t, J¼7.2 Hz, 2-CH2), 3.40 (2H, td,
J¼7.2, 5.7 Hz, 1-CH2), 5.09 (2H, s, CH2Ph), 7.14–7.17
(2H, m, 2H of Ph), 7.23–7.34 (3H, m, 3H of Ph), 7.39 (1H,
s, 30-H), 7.42–7.54 (3H, m, 3H of Ph), 7.82–7.87 (2H, m,
2H of Ph), 8.58 (1H, br t, J¼5.7 Hz, NH), 10.25 (1H, br s,
OH). dC NMR (75.5 MHz, DMSO-d6) 22.6, 40.1, 48.6,
127.0, 127.0, 128.1, 128.2, 130.9, 134.6, 136.8, 137.7,
166.0. [Found: C, 70.84; H, 5.98; N, 13.32. C19H19N3O2
requires: C, 71.01; H, 5.96; N, 13.08.] nmax (KBr) 3366,
The following compounds were prepared in this manner.
5.4.1. N-[2-(5-Hydroxy-1H-pyrazol-4-yl)ethyl]benz-
amide (7a). Prepared from 3 and hydrazine hydrochloride
(4a) (1.370 g, 20 mmol), trituration with ethanol–water
(1:2). Yield: 3.74 g (81%) of a white solid; mp 182–
184 ꢂC. dH (300 MHz, DMSO-d6) 2.51 (2H, br s, 2-CH2),
3.38 (2H, br dt, J¼5.5, 7.9 Hz, 1-CH2), 7.26 (1H, s, 30-H),
7.42–7.55 (3H, m, 3H of Ph), 7.80–7.88 (2H, m, 2H of
Ph), 8.47 (1H, t, J¼5.5 Hz, NHCH2), 9.59 (1H, br s, 10-H),
1630, 1574, 1542, 1492, 1411, 1312, 1268, 699 cmꢀ1
.
EI-HRMS: m/z¼321.146800 (M+); C19H19N3O2 requires:
m/z¼321.147727 (M+).
5.4.5. N-[2-(1-Cyclohexyl-5-hydroxy-1H-pyrazol-4-yl)-
ethyl]benzamide (7e). Prepared from 3 and cyclohexylhy-
drazine hydrochloride (4e) (3.01 g, 20 mmol); trituration
with water. Yield: 6.01 g (96%) of a white solid; mp 208–
210 ꢂC. dH (300 MHz, DMSO-d6) 1.06–1.23 (1H, m, 1H
1
11.24 (1H, br s, OH). H NMR (CD3OD): d 2.62 (2H, t,
J¼7.0 Hz, 2-CH2), 3.51 (2H, t, J¼7.0 Hz, 1-CH2), 7.38
(1H, br s, 30-H), 7.41–7.55 (3H, m, 3H of Ph), 7.80–7.85

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D. Kralj et al. / Tetrahedron 63 (2007) 11213–11222
of C6H11), 1.28–1.45 (2H, m, 2H of C6H11), 1.57–1.84 (7H,
m, 7H of C6H11), 2.52 (2H, br s, 2-CH2), 3.36 (2H, br dt,
J¼5.9, 7.0 Hz, 1-CH2), 4.03 (1H, br m, 1H of C6H11),
7.42–7.55 (4H, m, 3H of Ph, 30-H), 7.81–7.88 (2H, m, 2H
of Ph), 8.48 (1H, br s, NH), 9.88 (1H, br s, OH). dH
(300 MHz, CD3OD) 1.25 (1H, qt, J¼3.3, 12.8 Hz, 1H of
C6H11), 1.46 (2H, br qt, J¼3.2, 12.8 Hz, 2H of C6H11),
1.61–1.79 (3H, m, 3H of C6H11), 1.83–1.95 (4H, m, 4H of
C6H11), 2.64 (2H, t, J¼7.0 Hz, 2-CH2), 3.53 (2H, t,
J¼7.0 Hz, 1-CH2), 4.26 (1H, tt, J¼3.6, 12.0 Hz, 1H of
C6H11), 7.42 (1H, s, 30-H), 7.43–7.57 (3H, m, 3H of Ph),
7.81–7.87 (2H, m, 2H of Ph). dC NMR (75.5 MHz,
DMSO-d6) 22.6, 24.9, 25.1, 31.6, 40.2, 53.7, 98.5, 127.0,
128.1, 130.9, 134.6, 136.0, 148.4, 166.0. [Found: C, 68.79;
H, 7.60; N, 13.48. C18H23N3O2 requires: C, 68.98; H,
7.40; N, 13.41.] nmax (KBr) 3348, 2936, 2853, 1631, 1547,
120.4, 125.7, 128.0, 129.1, 131.5, 131.9, 134.1, 135.5,
140.9, 167.1. [Found: C, 63.15; H, 4.99; N, 12.15.
C18H16ClN3O2 requires: C, 63.25; H, 4.72; N, 12.29.] nmax
(KBr) 3385, 3295, 3072, 1629, 1589, 1559, 1323, 700 cmꢀ1
.
5.4.9. N-{2-[1-(4-Chlorophenyl)-5-hydroxy-1H-pyrazol-
4-yl]ethyl}benzamide (7i). Prepared from 3 and 4-chloro-
phenylhydrazine hydrochloride (4i) (3.58 g, 20 mmol);
trituration with ethanol–water (1:2). Yield: 6.22 g (91%) of
a white solid; mp 190–193 ꢂC. EIMS: m/z¼341 (M+). dH
(300 MHz, DMSO-d6) 2.61 (2H, br t, J¼7.0 Hz, 2-CH2),
3.44 (2H, br td, J¼7.0, 5.6 Hz, 1-CH2), 7.42–7.55 (6H, m,
5H of Ar, 30-H), 7.78 (2H, d, J¼8.9 Hz, 2H of Ar), 7.83–
7.88 (2H, m, 2H of Ar), 8.59 (1H, br t, J¼5.6 Hz, NH),
10.23 (1H, br s, OH). dC NMR (75.5 MHz, DMSO-d6)
22.4, 39.6, 102.3, 121.7, 127.1, 128.2, 128.8, 129.2, 131.0,
134.6, 137.3, 139.6, 166.2. [Found: C, 63.23; H, 4.72; N,
12.26. C18H16ClN3O2 requires: C, 63.25; H, 4.72; N,
12.29.] nmax (KBr) 3311, 1633, 1575, 1490, 1330, 893,
696 cmꢀ1. EI-HRMS:m/z¼341.093680(M+);C18H16ClN3O2
requires: m/z¼341.093105 (M+).
1296, 804 cmꢀ1
.
5.4.6. N-[2-(5-Hydroxy-1-phenyl-1H-pyrazol-4-yl)ethyl]-
benzamide (7f). Prepared from 3 and phenylhydrazine
hydrochloride (4f) (2.89 g, 20 mmol); trituration with
ethanol–water (1:1). Yield: 5.04 g (82%) of a white solid;
mp 164–167 ꢂC. dH (300 MHz, DMSO-d6) 2.60 (2H, br s,
2-CH2), 3.44 (2H, br dt, J¼5.7, 7.2 Hz, 1-CH2), 7.23 (1H,
t, J¼7.5 Hz, 1H of Ph), 7.42–7.55 (6H, m, 5H of Ph, 30-
H), 7.72 (2H, d, J¼7.5 Hz, 2H of Ph), 7.83–7.87 (2H, m,
2H of Ph), 8.58 (1H, br s, NH), 10.75 (1H, br s, OH). dC
NMR (75.5 MHz, DMSO-d6) 22.5, 120.7, 125.2, 127.0,
128.2, 128.8, 130.9, 134.6, 138.9, 166.2. [Found: C, 70.38;
H, 5.69; N, 13.73. C18H17N3O2 requires: C, 70.34; H,
5.58; N, 13.67.] nmax (KBr) 3429, 3304, 1633, 1539, 1500,
5.4.10. N-{2-[5-Hydroxy-1-(3-methoxyphenyl)-1H-pyra-
zol-4-yl]ethyl}benzamide (7j). Prepared from 3 and
3-methoxyphenylhydrazine hydrochloride (4j) (3.49 g,
20 mmol); trituration with ethanol–water (1:2). Yield:
5.85 g (87%) of a beige solid; mp 69–72 ꢂC. dH (300 MHz,
DMSO-d6) 2.60 (2H, br s, 2-CH2), 3.44 (2H, br dt, J¼5.7,
7.1 Hz, 1-CH2), 3.79 (3H, s, OMe), 6.79–6.86 (1H, m, 1H
of Ar), 7.34 (1H, br s, 30-H), 7.32–7.36 (2H, m, 2H of Ar),
7.43–7.55 (4H, m, 3H of Ph, 1H of Ar), 7.78–7.88 (2H, m,
2H of Ph), 8.58 (1H, br s, NH), 10.81 (1H, br s, OH). dC
NMR (75.5 MHz, DMSO-d6) 23.4, 56.1, 107.1, 111.7,
113.3, 128.0, 129.1, 130.6, 131.9, 135.6, 140.0, 140.5,
160.4, 167.1. [Found: C, 67.47; H, 5.82; N, 12.41.
C19H19N3O3 requires: C, 67.64; H, 5.68; N, 12.46.] nmax
(KBr) 3333, 1634, 1600, 1541, 1495, 1467, 1403, 1290,
1416, 1317, 1097, 754, 692 cmꢀ1
.
5.4.7. 4-[4-(2-Benzamidoethyl)-5-hydroxy-1H-pyrazol-1-
yl]benzoic acid (7g). Prepared from 3, 4-hydrazinobenzoic
acid (4g) (3.04 g, 20 mmol) and 37% hydrochloric acid; trit-
uration with ethanol–water (1:1). Yield: 6.46 g (92%) of
a greyish solid; mp 260–264 ꢂC. EIMS: m/z¼351 (M+). dH
(300 MHz, DMSO-d6) 2.60 (2H, br t, J¼7.2 Hz, 2-CH2),
3.44 (2H, br td, J¼7.2, 5.5 Hz, 1-CH2), 7.43–7.54 (4H, m,
3H of Ph and 30-H), 7.83–7.86 (2H, m, 2H of Ph), 7.90–
7.93 (2H, m, 2H of Ph), 8.00–8.03 (2H, m, 2H of Ph), 8.56
(1H, br t, J¼5.5 Hz, NH), 11.08 (1H, br s, OH), 12.87
(1H, br s, COOH). dC NMR (75.5 MHz, DMSO-d6) 22.5,
39.6, 103.6, 119.2, 127.0, 127.2, 128.3, 130.4, 131.1,
134.7, 140.3, 141.9, 155.3, 166.4, 166.9. [Found: C, 63.66;
H, 5.17; N, 11.75. C19H17N3O4$½H2O requires: C, 63.33;
H, 5.03; N, 11.66.] nmax (KBr) 3289, 3060, 1682, 1627,
1585, 1517, 1489, 1431, 1306, 769 cmꢀ1. EI-HRMS:
m/z¼351.122500 (M+); C19H17N3O4 requires: m/z¼
351.121906 (M+).
1237, 1100, 994, 865 cmꢀ1
.
5.4.11. N-{2-[5-Hydroxy-1-(4-methoxyphenyl)-1H-pyr-
azol-4-yl]ethyl}benzamide (7k). Prepared from 3 and
4-methoxyphenylhydrazine hydrochloride (4k) (3.49 g,
20 mmol); trituration with ethanol–water (1:2). Yield:
5.33 g (79%) of a grey solid; mp 170–174 ꢂC. dH
(300 MHz, DMSO-d6) 2.59 (2H, br t, J¼7.1 Hz, 2-CH2),
3.43 (2H, br dt, J¼7.1, 5.7 Hz, 1-CH2), 3.78 (3H, s, OMe),
7.01 (2H, d, J¼9.0 Hz, 2H of Ar), 7.40 (1H, br s, 30-H),
7.42–7.55 (3H, m, 3H of Ph), 7.59 (2H, d, J¼9.0 Hz, 2H
of Ar), 7.83–7.88 (2H, m, 2H of Ph), 8.60 (1H, br s, NH),
10.66 (1H, br s, OH). dC NMR (75.5 MHz, DMSO-d6)
22.5, 39.8, 55.2, 113.9, 122.6, 127.1, 128.2, 130.9, 131.9,
134.6, 138.5, 157.0, 166.2. [Found: C, 67.89; H, 5.76; N,
12.48. C19H19N3O3 requires: C, 67.64; H, 5.68; N, 12.46.]
nmax (KBr) 3301, 3067, 1632, 1539, 1512, 1426, 1248,
5.4.8. N-{2-[1-(3-Chlorophenyl)-5-hydroxy-1H-pyrazol-
4-yl]ethyl}benzamide (7h). Prepared from 3 and 3-chloro-
phenylhydrazine hydrochloride (4h) (3.58 g, 20 mmol);
trituration with ethanol–water (1:1). Yield: 6.63 g (97%) of
a white solid; mp 168–171 ꢂC. dH (300 MHz, DMSO-d6)
2.60 (2H, br t, J¼7.1 Hz, 2-CH2), 3.44 (2H, br td, J¼7.1,
5.5 Hz, 1-CH2), 7.29 (1H, ddd, J¼0.7, 1.9, 8.0 Hz, 1H of
Ar), 7.43–7.55 (4H, m, 4H of Ar), 7.48 (1H, s, 30-H), 7.75
(1H, ddd, J¼0.9, 2.0, 8.3 Hz, 1H of Ar), 7.83–7.88 (3H,
m, 3H of Ar), 8.57 (1H, br t, J¼5.5 Hz, NH), 11.07 (1H,
br s, OH). dC NMR (75.5 MHz, DMSO-d6) 23.4, 119.4,
835 cmꢀ1
.
5.4.12. N-{2-[3-Oxo-2-(pyridin-2-yl)-2,3-dihydro-1
H-pyrazol-4-yl]ethyl}benzamide (70l). Prepared from 3,
2-hydrazinopyridine (4l) (2.18 g, 20 mmol) and 37% hydro-
chloric acid; trituration with ethanol–water (1:2). Yield:
5.17 g (84%) of a white solid; mp 153–154 ꢂC. dH
(300 MHz, DMSO-d6) 2.50 (2H, br s, 2-CH2), 3.46 (2H,
br td, J¼7.2, 5.3 Hz, 1-CH2), 7.28 (1H, br t, J¼6.8 Hz,

D. Kralj et al. / Tetrahedron 63 (2007) 11213–11222
11219
500-H), 7.42–7.54 (3H, m, 3H of Ph), 7.61 (1H, br s, 50-H),
7.83–7.86 (2H, m, 2H of Ph), 7.98 (1H, br t, J¼6.8 Hz, 400-
H), 8.23 (1H, broad signal, 300-H), 8.43 (1H, dd, J¼1.1,
4.9 Hz, 600-H), 8.60 (1H, br t, J¼5.3 Hz, NH), 12.02 (1H, br
s, 10-H). dC NMR (75.5 MHz, DMSO-d6) 22.4, 39.3, 111.5,
120.4, 127.1, 128.2,130.9, 134.6, 139.5, 146.9,166.2.[Found:
C, 66.36; H, 5.30; N, 18.18. C17H16N4O2 requires: C, 66.22;
H, 5.23; N, 18.17.] nmax (KBr) 3310, 3198, 2940, 1650,
3155, 1634, 1605, 1542, 1487, 1400, 1306, 1216, 1150, 966,
698 cmꢀ1. EI-HRMS: m/z¼348.134050 (M+); C18H16N6O2
requires: m/z¼348.133474 (M+).
5.5. Hydrolytic removal of the benzoyl N-protecting
group. General procedure for the preparation of
1-substituted 4-(2-aminoethyl)-5-hydroxy-1H-pyrazoles
8a–k and 4-(2-aminoethyl)-2-heteroaryl-1H-pyrazol-
3(2H)-ones 80l–o
1631, 1572, 1472, 1434, 1364, 1323, 1295, 774, 704 cmꢀ1
.
5.4.13. N-{2-[2-(6-Chloropyridazin-3-yl)-3-oxo-2,3-dihy-
dro-1H-pyrazol-4-yl]ethyl}benzamide (70m). Prepared
from 3, 6-chloro-3-hydrazinopyridazine (4m) (2.89 g,
20 mmol) and 37% hydrochloric acid; trituration with etha-
nol–water (1:2). Yield: 4.95 g (72%) of a yellowish solid; mp
222–225 ꢂC. dH (300 MHz, DMSO-d6) 2.50 (2H, br s, 2-
CH2), 3.48 (2H, br td, J¼7.2, 5.5 Hz, 1-CH2), 7.43–7.55
(3H, m, 3H of Ph), 7.84–7.87 (3H, m, 2H of Ph and 50-H),
8.03 (1H, d, J¼9.0 Hz, 400-H), 8.57 (1H, br t, J¼5.5 Hz,
NH), 8.77 (1H, br s, 500-H), 12.30 (1H, br s, 10-H). dC
NMR (75.5 MHz, DMSO-d6) 22.5, 34.0, 103.8, 119.6,
127.1, 128.1, 130.8, 130.9, 134.5, 139.4, 151.3, 152.2,
163.5, 166.1. [Found: C, 55.67; H, 4.20; N, 20.35.
C16H14ClN5O2 requires: C, 55.90; H, 4.10; N, 20.37.] nmax
(KBr) 3314, 3075, 1638, 1578, 1542, 1460, 1424, 1225,
A mixture of 7 (10 mmol) and 6 M hydrochloric acid (50 mL)
was heated to reflux for 16 h. Volatile components were evap-
orated in vacuo, anhydrous ethanol (20 mL) was added to the
residue and the mixture was evaporated in vacuo again. The
semi-solid residue was triturated with anhydrous ethanol
(20 mL) until a crystalline precipitatewas formed. Then, ethyl
acetate(20 mL)wasadded,theprecipitatewascollectedbyfil-
tration and washed with ethanol–ethyl acetate (1:1, 10 mL),
ethyl acetate (20 mL) and diethyl ether (20 mL) to give 8.
The following compounds were prepared in this manner.
5.5.1. 4-(2-Aminoethyl)-5-hydroxy-1H-pyrazole dihydro-
chloride (8a). Prepared from 7a (2.31 g, 10 mmol). Yield:
2.00 g (100%) of a white solid; mp 161–166 ꢂC. EIMS:
m/z¼127 (M+). dH (300 MHz, DMSO-d6) 2.73 (2H, br t,
J¼7.1 Hz, 10-CH2), 2.97 (2H, br sextet, J¼7.1 Hz, 20-
CH2), 7.87 (1H, s, 3-H), 8.19 (3H, br s, NH+3), OH ex-
changed. dC NMR (75.5 MHz, DMSO-d6) 19.9, 38.3,
100.3, 133.7, 155.1. [Found: 30.79; H, 5.71; N, 20.94.
C5H9N3O$1.93HCl requires: C, 30.39; H, 5.58; N, 21.26.]
nmax (KBr) 3392, 3042, 2971, 1612, 1578, 1484, 1385,
1150, 1067, 878, 703 cmꢀ1. EI-HRMS: m/z¼127.074950
(M+); C5H9N3O requires: m/z¼127.074562 (M+).
1196, 1142, 854, 693 cmꢀ1
.
5.4.14. N-{2-[3-Oxo-2-(6-phenylpyridazin-3-yl)-2,3-dihy-
dro-1H-pyrazol-4-yl]ethyl}benzamide (70n). Prepared
from 3, 3-hydrazino-6-phenylpyridazine (4n) (3.72 g,
20 mmol) and 37% hydrochloric acid; trituration with etha-
nol–water (1:2). Yield: 6.24 g (81%) of a pale yellowish
solid; mp 234–238 ꢂC. EIMS: m/z¼385 (M+). dH
(300 MHz, DMSO-d6) 2.50 (2H, br s, 2-CH2), 3.48 (2H, br
td, J¼7.2, 5.5 Hz, 1-CH2), 7.43–7.61 (6H, m, 6H of Ph),
7.84–7.87 (3H, m, 2H of Ph and 50-H), 8.13–8.17 (2H, m,
1H of Ph and 400-H), 8.37–8.44 (1H, m, 1H of Ph), 8.61
(1H, br t, J¼5.5 Hz, NH), 8.76 (1H, br s, 500-H), 12.39
(1H, br s, 10-H). dC NMR (75.5 MHz, DMSO-d6) 22.5,
39.0, 103.6, 117.0, 126.4, 126.6, 127.0, 128.1, 128.9, 129.8,
130.9, 131.9, 134.6, 135.4, 138.7, 150.5, 156.0, 166.1.
[Found: C, 66.96; H, 4.88; N, 17.73. C22H19N5O2$½H2O
requires: C, 66.99; H, 5.11; N, 17.76.] nmax (KBr) 3431,
3333, 1635, 1549, 1455, 1427, 1370, 1313, 1203, 1084,
689 cmꢀ1. EI-HRMS: m/z¼385.154500 (M+), C22H19N5O2
requires: m/z¼385.153875 (M+).
5.5.2. 4-(2-Aminoethyl)-5-hydroxy-1-methyl-1H-pyr-
azole dihydrochloride (8b). Prepared from 7b (2.45 g,
10 mmol). Yield: 2.14 g (100%) of a white solid; mp 169–
174 ꢂC. EIMS: m/z¼141 (M+). dH (300 MHz, DMSO-d6)
2.70 (2H, br t, J¼7.2 Hz, 10-CH2), 2.94 (2H, br sextet,
J¼7.2 Hz, 20-CH2), 3.61 (3H, s, Me), 7.74 (1H, s, 3-H), 8.13
(3H, br s, NH+3), OH exchanged. [Found: C, 33.22; H, 6.40;
N, 19.09. C6H13Cl2N3O$1⁄4H2O requires: C, 32.97; H, 6.22;
N, 19.22.] nmax (KBr) 3593, 3493, 2925, 1610, 1566, 1529,
1438, 1261, 836, 693 cmꢀ1. EI-HRMS: m/z¼141.090650
(M+); C6H11N3O requires: m/z¼141.090212 (M+).
5.4.15. N-{2-[2-(Imidazo[1,2-b]pyridazin-6-yl)-3-oxo-2,3-
dihydro-1H-pyrazol-4-yl]ethyl}benzamide (70o). Pre-
pared from 3, 6-hydrazinoimidazo[1,2-b]pyridazine (4o)
(2.98 g, 20 mmol) and 37% hydrochloric acid; trituration
with ethanol–water (1:2). Yield: 6.95 g (100%) of a pale
brownish solid; mp 119–122 ꢂC. EIMS: m/z¼348 (M+). dH
(300 MHz, DMSO-d6) 2.55 (2H, br s, 2-CH2), 3.46 (2H, br
td, J¼7.2, 5.3 Hz, 1-CH2), 7.43–7.54 (3H, m, 3H of Ph),
7.78 (1H, br s, 50-H), 7.79 (1H, d, J¼1.1 Hz, 300-H), 7.83–
7.86 (2H, m, 2H of Ph), 8.20 (1H, br s, 200-H), 8.24 (1H, d,
J¼9.4 Hz, 700-H), 8.41 (1H, broad signal, 800-H), 8.58 (1H,
br t, J¼5.3 Hz, NH), 11.61 (1H, br s, 10-H). dC NMR
(75.5 MHz, DMSO-d6) 22.6, 39.0, 103.8, 110.7, 117.1,
127.1, 128.2, 131.0, 133.6, 134.6, 137.1, 139.8, 146.0, 166.2.
[Found: C, 60.53; H, 5.05; N, 23.62. C18H16N6O2$½H2O
requires: C, 60.50; H, 4.79; N, 23.72.] nmax (KBr) 3400,
5.5.3. 4-(2-Aminoethyl)-5-hydroxy-1-(2,2,2-trifluoro-
ethyl)-1H-pyrazole dihydrochloride (8c). Prepared from
7c (3.13 g, 10 mmol). Yield: 2.60 g (92%) of a white solid;
mp 166–168 ꢂC. EIMS: m/z¼209 (M+). dH (300 MHz,
DMSO-d6) 2.62 (2H, t, J¼7.4 Hz, 10-CH2), 2.92 (2H, br sex-
tet, J¼7.4 Hz, 20-CH2), 4.72(2H, q, J¼9.2 Hz, CH2CF3), 7.35
(1H, br s, 3-H), 8.07 (3H, br s, NH+3), OH exchanged. dC NMR
(75.5 MHz, DMSO-d6) 20.7, 46.5, 97.4, 121.7, 125.4, 139.0,
153.0. [Found: C, 30.96; H, 4.59; N, 15.32. C7H10F3N3O$
13⁄4HCl requires: C, 30.80; H, 4.34; N, 15.39.] nmax (KBr)
3422, 2967, 1594, 1571, 1389, 1297, 1263, 1179, 1159, 836,
699 cmꢀ1. EI-HRMS: m/z¼209.077700 (M+); C7H10F3N3O
requires: m/z¼209.077597 (M+).
5.5.4. 4-(2-Aminoethyl)-1-benzyl-5-hydroxy-1H-pyr-
azole dihydrochloride (8d). Prepared from 7d (3.21 g,

11220
D. Kralj et al. / Tetrahedron 63 (2007) 11213–11222
10 mmol). Yield: 1.80 g (62%) of a greyish solid; mp 144–
149 ꢂC. dH (300 MHz, DMSO-d6) 2.70 (2H, br t,
J¼7.2 Hz, 10-CH2), 2.95 (2H, br sextet, J¼7.2 Hz, 20-
CH2), 5.20 (2H, s, CH2Ph), 7.22–7.38 (5H, m, Ph), 7.70
(1H, s, 3-H), 8.18 (3H, br s, NH+3), OH exchanged. dC
NMR (75.5 MHz, DMSO-d6) 20.4, 38.4, 48.7, 100.1,
127.7, 128.0, 128.6, 134.7, 135.1, 153.5. [Found: C, 49.43;
H, 6.06; N, 14.41. C12H17Cl2N3O requires: C, 49.67; H,
5.90; N, 14.48.] nmax (KBr) 3428, 3102, 2954, 2861, 1606,
br sextet, J¼7.3 Hz, 20-CH2), 7.31 (1H, ddd, J¼0.9, 2.1,
8.1 Hz, 1H of Ar), 7.49 (1H, t, J¼8.1 Hz, 1H of Ar), 7.60
(1H, s, 3-H), 7.75 (1H, ddd, J¼0.9, 2.1, 8.1 Hz, 1H of Ar),
7.86 (1H, t, J¼2.1 Hz, 1H of Ar), 8.01 (3H, br s, NH+3),
OH exchanged. [Found: C, 42.56; H, 4.66; N, 13.48.
C11H14Cl3N3O requires: C, 42.54; H, 4.54; N, 13.53.] nmax
(KBr) 3057, 2878, 2754, 2632, 1589, 1560, 1477, 1444,
1258, 781, 677 cmꢀ1. EI-HRMS: m/z 237.067000 (M+);
C11H12ClN3O requires: m/z¼237.066890 (M+).
1573, 1434, 1237, 729, 693 cmꢀ1
.
5.5.9. 4-(2-Aminoethyl)-1-(4-chlorophenyl)-5-hydroxy-
1H-pyrazole dihydrochloride (8i). Prepared from 7i
(3.42 g, 10 mmol). Yield: 2.42 g (78%) of a greyish solid;
mp 206–210 ꢂC. EIMS: m/z¼237 (M+). dH (300 MHz,
DMSO-d6) 2.69 (2H, br t, J¼7.3 Hz, 10-CH2), 2.96 (2H, br
sextet, J¼7.3 Hz, 20-CH2), 7.50 (2H, dt, J¼2.6, 9.0 Hz, 2H
of Ar), 7.55 (1H, s, 3-H), 7.76 (2H, dt, J¼2.6, 9.0 Hz, 2H
of Ar), 8.09 (3H, br s, NH+3), OH exchanged. dC NMR
(75.5 MHz, DMSO-d6) 20.1, 38.8, 100.3, 122.8, 129.0,
130.3, 136.2, 139.0, 153.9. [Found: C, 42.80; H, 4.61; N,
13.33. C11H14Cl3N3O requires: C, 42.54; H, 4.54; N,
13.53.] nmax (KBr) 3434, 3078, 2871, 2361, 1594, 1560,
1483, 1425, 1251, 1226, 1090, 669 cmꢀ1. EI-HRMS:
m/z¼236.058500 (M+ꢀ1); C11H11ClN3O requires:
m/z¼236.059065 (M+ꢀ1).
5.5.5. 4-(2-Aminoethyl)-1-cyclohexyl-5-hydroxy-1H-pyr-
azole dihydrochloride (8e). Prepared from 7e (3.13 g,
10 mmol). Yield: 2.82 g (100%) of a white solid; mp 133–
138 ꢂC. EIMS: m/z¼209 (M+). dH (300 MHz, DMSO-d6)
1.12–1.23 (1H, m, 1H of C6H11), 1.28–1.46 (2H, m, 2H of
C6H11), 1.64 (1H, br d, J¼12.3 Hz, 1H of C6H11), 1.75–
1.95 (6H, m, 6H of C6H11), 2.72 (2H, br t, J¼7.2 Hz, 10-
CH2), 2.98 (2H, br sextet, J¼7.2 Hz, 20-CH2), 4.22–4.35
(1H, m, 1H of C6H11), 7.78 (1H, s, 3-H), 8.16 (3H, br s,
NH+3), OH exchanged. dC NMR (75.5 MHz, DMSO-d6)
21.2, 25.3, 25.8, 31.6, 39.2, 56.5, 101.1, 135.0, 153.4.
[Found: C, 46.02; H, 8.19; N, 14.69. C11H21Cl2N3O$
1⁄3H2O requires: C, 45.84; H, 7.58; N, 14.58.] nmax (KBr)
3331, 2949, 1589, 1566, 1498, 1431, 1320, 1109,
896 cmꢀ1. EI-HRMS: m/z¼209.153450 (M+); C11H19N3O
requires: m/z¼209.152812 (M+).
5.5.10. 4-(2-Aminoethyl)-5-hydroxy-1-(3-methoxy-
phenyl)-1H-pyrazole dihydrochloride (8j). Prepared
from 7j (3.37 g, 10 mmol). Yield: 2.62 g (86%) of a greyish
solid; mp 150–154 ꢂC. EIMS: m/z¼233 (M+). dH (300 MHz,
DMSO-d6) 2.68 (2H, br t, J¼7.3 Hz, 10-CH2), 2.99 (2H, br
sextet, J¼6.8 Hz, 20-CH2), 3.79 (3H, s, OMe), 6.85 (1H,
dt, J¼2.6, 6.5 Hz, 1H of Ar), 7.32–7.40 (3H, m, 3H of Ar),
7.58 (1H, br s, 3-H), 8.12 (3H, br s, NH+3), OH exchanged.
dC NMR (75.5 MHz, DMSO-d6) 20.8, 38.7, 55.3, 100.5,
107.1, 111.9, 113.4, 129.8, 138.1, 138.2, 154.2, 159.5.
[Found: C, 47.64; H, 5.69; N, 13.79. C12H15N3O2$1.9HCl
requires: C, 47.64; H, 5.63; N, 13.89.] nmax (KBr) 3428,
5.5.6. 4-(2-Aminoethyl)-5-hydroxy-1-phenyl-1H-pyr-
azole dihydrochloride (8f). Prepared from 7f (3.07 g,
10 mmol). Yield: 1.38 g (50%) of a white solid; mp 210–
212 ꢂC. EIMS: m/z¼203 (M+). dH (300 MHz, DMSO-d6)
2.68 (2H, br t, J¼7.2 Hz, 10-CH2), 2.97 (2H, br sextet,
J¼7.2 Hz, 20-CH2), 7.26 (1H, tt, J¼1.1, 7.4 Hz, 1H of Ph),
7.40–7.48 (2H, m, 2H of Ph), 7.57 (1H, s, 3-H), 7.68–7.73
(2H, m, 2H of Ph), 8.12 (3H, br s, NH+3), OH exchanged.
[Found: C, 47.85; H, 5.63; N, 15.19. C11H15Cl2N3O
requires: C, 47.84; H, 5.47; N, 15.22.] nmax (KBr)
3362, 3001, 1597, 1569, 1503, 1421, 1081, 693 cmꢀ1
.
2887, 1607, 1564, 1469, 1266, 1237, 1039, 684 cmꢀ1
.
EI-HRMS: m/z¼203.106000 (M+); C11H13N3O requires:
EI-HRMS: m/z¼233.117500 (M+); C12H15N3O2 requires:
m/z¼203.105862 (M+).
m/z¼233.116427 (M+).
5.5.7. 4-(4-(2-Aminoethyl)-5-hydroxy-1H-pyrazol-1-yl)-
benzoic acid dihydrochloride (8g). Prepared from 7g
(3.51 g, 10 mmol). Yield: 2.79 g (87%) of a white solid;
mp 265–272 ꢂC. EIMS: m/z¼247 (M+). dH (300 MHz,
DMSO-d6) 2.68 (2H, br t, J¼7.3 Hz, 10-CH2), 3.00 (2H, br
sextet, J¼7.3 Hz, 20-CH2), 7.63 (1H, s, 3-H), 7.92 (2H, dt,
J¼1.9, 8.9 Hz, 2H of Ar), 8.02 (2H, dt, J¼1.9, 8.9 Hz, 2H
of Ar), 8.06 (3H, br s, NH+3), OH and COOH exchanged.
dC NMR (75.5 MHz, DMSO-d6) 20.7, 38.3, 100.4, 112.2,
121.0, 138.7, 140.0, 146.9, 149.2, 158.4. [Found: C, 46.72;
H, 5.05; N, 13.52. C12H13N3O3$12⁄3HCl requires: C, 46.79;
H, 4.80; N, 13.64.] nmax (KBr) 3422, 3022, 2912, 1716,
1683, 1588, 1419, 1313, 1227, 1117, 767 cmꢀ1. EI-
HRMS: m/z 247.096000 (M+); C12H13N3O3 requires: m/z¼
247.095691 (M+).
5.5.11. 4-(2-Aminoethyl)-5-hydroxy-1-(4-methoxy-
phenyl)-1H-pyrazole dihydrochloride (8k). Prepared
from 7k (3.37 g, 10 mmol). Yield: 2.77 g (91%) of a greyish
solid; mp 211–214 ꢂC. dH (300 MHz, DMSO-d6) 2.71 (2H,
br t, J¼7.3 Hz, 10-CH2), 2.99 (2H, br sextet, J¼6.6 Hz, 20-
CH2), 3.79 (3H, s, OMe), 7.03 (2H, d, J¼9.0 Hz, 2H of
Ar), 7.58 (1H, br s, 3-H), 7.59 (2H, d, J¼9.0 Hz, 2H of
Ar), 8.14 (3H, br s, NH+3), OH exchanged. [Found: C,
47.27; H, 5.83; N, 13.43. C12H17Cl2N3O2 requires: C,
47.07; H, 5.60; N, 13.72.] nmax (KBr) 3434, 2894, 1558,
1522, 1437, 1273, 1024, 834 cmꢀ1
.
5.5.12. 4-(2-Aminoethyl)-1-(pyridin-2-yl)-1H-pyrazol-
3(2H)-one dihydrochloride (80l). Prepared from 7l
(3.08 g, 10 mmol). Yield: 1.79 g (65%) of a white solid;
mp 137–142 ꢂC. EIMS: m/z¼204 (M+). dH (300 MHz,
DMSO-d6) 2.61 (2H, br t, J¼7.1 Hz, 10-CH2), 2.98 (2H, br
q, J¼7.1 Hz, 20-CH2), 7.30 (1H, br dt, J¼5.4, 6.8 Hz, 500-
H), 7.72 (1H, s, 5-H), 7.99 (1H, br dt, J¼1.8, 6.8 Hz, 400-
H), 8.19 (3H, br s, NH3+), 8.24 (1H, br d, J¼6.8 Hz, 300-H),
8.45 (1H, br d, J¼5.4 Hz, 600-H), 1-H exchanged. dC NMR
5.5.8. 4-(2-Aminoethyl)-1-(3-chlorophenyl)-5-hydroxy-
1H-pyrazole dihydrochloride (8h). Prepared from 7h
(3.42 g, 10 mmol). Yield: 2.58 g (83%) of a greyish solid;
mp 206–207 ꢂC. EIMS: m/z¼237 (M+). dH (300 MHz,
DMSO-d6) 2.68 (2H, br t, J¼7.3 Hz, 10-CH2), 2.99 (2H,

D. Kralj et al. / Tetrahedron 63 (2007) 11213–11222
11221
(75.5 MHz, DMSO-d6) 20.7, 38.3, 100.4, 112.2, 121.0,
138.7, 140.0, 146.9, 149.2, 158.4. [Found: C, 40.76; H,
5.51; N, 18.81. C10H14Cl2N4O$H2O requires: C, 40.69; H,
5.46; N, 18.98.] nmax (KBr) 4363, 3037, 3011, 1645, 1629,
parameters were not refined. Absorption correction was
not necessary. Regina52 weighting scheme was used in all
cases.
1612, 1548, 1479, 1212, 768 cmꢀ1
.
Crystallographic data (excluding structure factors) for com-
pound 8f have been deposited at the Cambridge Crystallo-
graphic Data Centre as supplementary publication number
CCDC 643600. Copy of the data can be obtained, free of
charge, on application to CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK [fax: +44(0) 1223 336033 or e-mail: deposit@
ccdc.cam.ac.uk.
5.5.13. 4-(2-Aminoethyl)-1-(6-chloropyridazin-3-yl)-1H-
pyrazol-3(2H)-one hydrochloride (80m). Prepared from
7m (3.44 g, 10 mmol). Yield: 1.06 g (34%) of a yellowish
solid; mp 258 ꢂC (decomp.). EIMS: m/z¼239 (M+). dH
(300 MHz, DMSO-d6) 2.58 (2H, br t, J¼7.2 Hz, 10-CH2),
2.99 (2H, br sextet, J¼7.2 Hz, 20-CH2), 7.93 (1H, br s, 5-
H), 7.99 (3H, br s, NH3+), 8.05 (1H, d, J¼9.4 Hz, 500-H),
8.75 (1H, d, J¼9.4 Hz, 400-H), 12.63 (1H, br s, 1-H). dC
NMR (75.5 MHz, DMSO-d6) 20.7, 37.9, 101.3, 119.6,
130.8, 137.4, 139.6, 151.1, 152.3. [Found: C, 39.88; H,
4.28; N, 24.07. C9H11Cl2N5O requires: C, 39.15; H, 4.02;
N, 25.36.] nmax (KBr) 3428, 3077, 1638, 1561, 1476, 1423,
Acknowledgements
The financial support from the Slovenian Research Agency
through grants P1-0179, and J1-6689-0103-04 is gratefully
acknowledged. We acknowledge with thanks the financial
support from Boehringer-Ingelheim Pharma GmbH & Co.
KG (Biberach, Germany).
1138, 702 cmꢀ1
.
EI-HRMS: m/z¼239.058200 (M+);
C9H10ClN5O requires: m/z¼239.057388 (M+).
5.5.14. 4-(2-Aminoethyl)-1-(6-phenylpyridazin-3-yl)-1H-
pyrazol-3(2H)-one hydrochloride (80n). Prepared from
7n (3.85 g, 10 mmol). Yield: 1.81 g (51%) of a greyish solid;
mp 252–255 ꢂC. EIMS: m/z¼281 (M+). dH (300 MHz,
DMSO-d6) 2.60 (2H, br t, J¼7.1 Hz, 10-CH2), 2.99 (2H, br
sextet, J¼7.1 Hz, 20-CH2), 7.48–7.60 (3H, m, 3H of Ph),
7.90 (1H, br s, 5-H), 8.05–8.16 (5H, m, 2H of Ph and
NH+3), 8.40 (1H, d, J¼9.4 Hz, 500-H), 8.71 (1H, br s, 400-H),
12.70 (1H, br s, 1-H). dC NMR (75.5 MHz, DMSO-d6)
21.7, 39.0, 102.1, 117.8, 127.4, 127.7, 129.4, 129.9, 130.8,
132.9, 135.5, 136.3, 157.1. [Found: C, 55.13; H, 4.96; N,
21.59. C15H15N5O$11⁄4HCl requires: C, 55.11; H, 5.01; N,
21.42.] nmax (KBr) 3392, 3063, 1634, 1591, 1549, 1452,
References and notes
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