A synthesis of 1-substituted 5-[2-(acylamino)ethyl]-1H-pyrazole-4-carboxamides

Article abstract of DOI:10.1016/j.tet.2009.06.021

A seven-step synthesis of 1-substituted 5-(2-acylaminoethyl)-1H-pyrazole-4-carboxamides 20 as the pyrazole analogues of histamine was developed. The synthesis starts with a three-step preparation of N(1)-substituted methyl 5-(2-tert-butoxycarbonylaminoethyl)-1H-pyrazole-4-carboxylates 7 from commercially available Boc-β-alanine (1). Subsequent four-step transformation of the key-intermediates 7 into the final products 20 was performed following two complementary reaction sequences comprising acidolytic removal of the Boc group, hydrolysis of the COOMe group, amidations of the COOH group, and acylations of the NH₂ group. The structures of pyrazole derivatives were determined by spectroscopic methods and by X-ray diffraction.

Full text of DOI:10.1016/j.tet.2009.06.021

Tetrahedron 65 (2009) 7151–7162
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A synthesis of 1-substituted 5-[2-(acylamino)ethyl]-1H-pyrazole-4-carboxamides
a
a
a
a
a
a
ˇ
ˇ
David Kralj , Miha Friedrich , Uros Groselj , Sonja Kiraly-Potpara , Anton Meden , Jernej Wagger ,
Georg Dahmann b, Branko Stanovnik a, Jurij Svete a
,
*
a
ˇ
ˇ
Faculty of Chemistry and Chemical Technology, University of Ljubljana, Askerceva 5, PO Box 537, 1000 Ljubljana, Slovenia
b Boehringer Ingelheim Pharma GmbH & Co. KG, Dept. Chemical Research, 88397 Biberach, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
A seven-step synthesis of 1-substituted 5-(2-acylaminoethyl)-1H-pyrazole-4-carboxamides 20 as the
pyrazole analogues of histamine was developed. The synthesis starts with a three-step preparation of
N(1)-substituted methyl 5-(2-tert-butoxycarbonylaminoethyl)-1H-pyrazole-4-carboxylates 7 from com-
Received 6 March 2009
Received in revised form 19 May 2009
Accepted 4 June 2009
mercially available Boc-b-alanine (1). Subsequent four-step transformation of the key-intermediates 7
Available online 10 June 2009
into the final products 20 was performed following two complementary reaction sequences comprising
acidolytic removal of the Boc group, hydrolysis of the COOMe group, amidations of the COOH group, and
acylations of the NH2 group. The structures of pyrazole derivatives were determined by spectroscopic
methods and by X-ray diffraction.
Keywords:
Enaminones
Hydrazines
Ó 2009 Published by Elsevier Ltd.
Pyrazoles
Carboxamides
Histamine analogues
1. Introduction
a C–N–N type 1,3-dipole (diazoalkane, nitrile imine, or azomethine
imine) to a C]C multiple bond.7
Functionalised heterocycles represent important scaffolds for
the preparation of compound libraries for medicinal and pharma-
ceutical applications, due to their ability to mimic structures of
peptides and reversibly bind proteins.1–4 Because of the crucial role
of histamine, tyramine, dopamine, tryptamine, serotonin, and
melatonin as chemical messengers in biological processes, the
preparation of their novel synthetic analogs based on the 2-(het-
eroaryl)ethylamine scaffold represents an important target in me-
dicinal and synthetic organic chemistry.5,6
Pyrazole and its derivatives certainly are important class of
heterocyclic compounds. Despite their rare occurrence in nature,
numerous pyrazole derivatives found use in various applications
and a general interest in the chemistry of pyrazoles is still con-
tinuing.7 Some examples of important pyrazole derivatives are
depicted in Figure 1.
Various b-(dimethylamino)enones are easily available and sta-
ble enamino analogues of 1,3-dicarbonyl compounds, which found
use as versatile reagents in heterocyclic synthesis.8–10 Some recent
applications also showed, that enaminones are suitable reagents
(or key-intermediates) for the combinatorial synthesis of hetero-
cyclic compounds as well.11
Recently, a substantial part of our research has been focused on
the synthesis of functionalised pyrazoles via (a) 1,3-dipolar cycload-
ditions of (4R
*
,5R )-4-benoylamino-5-phenyl-3-pyrazolidinone de-
*
rived azomethine imines to various dipolarophiles8c,9a,e,12 and (b)
cyclocondensations of functionalised enaminones with mono-
substituted hydrazines.8–10,11a,13–16 In this manner, various pyrazole
derivatives having amino acid,14 dipeptide,12 -aminoalcohol,15 1,2-
b
diol,16 2-phenylethylamine,15a and terpene13 structural motifs have
been synthesized. Within this context, we have recently reported
a simple enaminone-based synthesis of 4-(2-aminoethyl)-5-hy-
droxy-1H-pyrazoles10d and, soon after, a one-pot parallel solution
phase synthesis of these histamine analogues.11a In continuation, we
focused our attention on preparation of another type of histamine
analogues, 1-substituted 5-[2-(acylamino)ethyl]-1H-pyrazole-4-car-
boxamides. We found these compounds interesting, because the
substituents can easily be varied at three different nitrogen atoms: (a)
at the pyrazole ring nitrogen atom, (b) at the 4-carboxamido group,
and (c) at the 5-aminoethyl group. As a resultof our research efforts in
this field, we now report a new enaminone-based synthesis of a novel
type of histamine analogues.
Among numerous synthetic options for the construction of the
pyrazole ring, two classical approaches are most frequently
employed. The first one is based on a cyclocondensation reaction
between a 1,3-dicarbonyl compound (or its analogue) and a hydra-
zine derivative, whilst the second one is based on a cycloaddition of
* Corresponding author. Tel.: þ386 1 2419 100; fax: þ386 1 2419 220.
E-mail address: jurij.svete@uni-lj.si (J. Svete).
0040-4020/$ – see front matter Ó 2009 Published by Elsevier Ltd.
doi:10.1016/j.tet.2009.06.021

7152
D. Kralj et al. / Tetrahedron 65 (2009) 7151–7162
CONH2
HN
COOH
NH2
N
Ph
N
N
OH
HO
N
Me2N
Me
H
N
N
O
N
N
O
Ph
HO
OH
Ph
Difenamizole
Pyrazomycin
Withasomine
(S)-Pyrazolylalanine
(Citrulus vulgaris)
(Streptomyces candidus)
(Withania somnifera Dun)
O
Me
Me2N
N
MeO
MeO
Me
H
N
OEt
N
N
Ph
O
N
N
N
N
N
H
Pr
N
N
N
Phenidone
S O
O
N
HOOC
Me
Mepirizole
N
Me
Cl
Lonozolac
Sildenafil (Viagra®)
Figure 1.
2. Results and discussion
First, the -keto ester 3 was prepared from N-Boc-b-alanine (1)
and Meldrum’s acid following literature procedures for the prepa-
ration of closely related compounds.14a,17 Accordingly, the starting
compound 1 was treated with Meldrum’s acid and N,N-dicyclo-
hexylcarbodiimide (DCC) in the presence of 4-dimethylamino-
pyridine (DMAP) to give the cyclic intermediate 2. Heating of the
crude 2 in anhydrous methanol followed by chromatographic
(Scheme 2, Path B). First, synthetic Path A was explored. Base-cat-
alysed hydrolysis of methyl 5-[2-(tert-butoxycarbonylamino)ethyl]-
1H-pyrazole-4-carboxylates 7{1–5} in a mixture of methanol and
2 M aq sodium hydroxide at 50 ꢀC followed by careful acidification
b
afforded
5-[2-(tert-butoxycarbonylamino)ethyl]-1H-pyrazole-4-
carboxylic acids 14{1–5} in 37–94% yields. Further amidations of the
acids 14{1,2,4} with amines 11{1–5} were carried out with bis-
(pentafluorophenyl)carbonate (BPC) as coupling reagent and gave
the corresponding 5-[2-(tert-butoxycarbonylamino)ethyl]-1H-pyr-
azole-4-carboxamides 16{1,1}, 16{2; 2–4}, and 16{4; 5} in 40–80%
yields. Acidolytic removal of the Boc group from compounds 16{1,1},
16{2; 2–4}, and 16{4; 5} afforded the free 5-(2-aminoethyl)-1H-
pyrazole-4-carboxamides 18{1,1}, 18{2; 2–4}, and 18{4; 5}, re-
spectively, in 67–96% yields. Finally, acylation of the amine 18{1; 1}
with acetyl chloride 12{1} and acylations of amines 18{2; 2–4}, and
18{4; 5} with the in situ formed pentafluorophenyl carboxylates
130{2,3} furnished the final compounds 20{1; 1; 1}, 20{2; 2–4; 2},
and 20{4; 5; 3} in 52–89% yields (Scheme 2, Table 1).
workup gave the desired
(Scheme 1, Method A). Because the yield and the purity of the
keto ester 3 obtained by the Method A were only moderate and
sometimes non-reproducible as well, we prepared the -keto ester
3 from 1 by Masamune–Claisen type condensation following
b-keto ester 3 in 60% yield over two steps
b
-
b
slightly modified literature procedure.18 Activation of N-Boc-
b-al-
anine (1) with 1,10-carbonyldiimidazole (CDI) gave the imidazolide
4, which was subsequently reacted with potassium monomethyl
malonate in the presence of magnesium chloride to afford the
desired
b
-keto ester 3 in 90% upon simple extraction workup
Next, we envisaged the synthetic Path B. Treatment of the key-
intermediates 7{1–3} with 2 M HCl/EtOAc at 0–20 ꢀC resulted in
selective removal of the Boc group to give methyl 5-(2-aminoethyl)-
1H-pyrazole-4-carboxyaltes hydrochlorides 15{1–3} in 72–86%
(Scheme 1, Method B). In our hands, Method B was reproducible
and scalable and, hence, suitable for the preparation of 3 on
a 200 mmol scale. Further treatment of
b-keto ester 3 with
DMFDMA in dichloromethane at rt followed by evaporative workup
gave the crude oily enaminone 5, which was subsequently reacted
with hydrazine derivatives 6{1–13} to give the 1-substituted
methyl 5-[2-(tert-butoxycarbonylamino)ethyl]-1H-pyrazole-4-car-
boxylates 7{1–13} in 34–80% yields (Scheme 1, Table 1). It is note-
worthy, that the crude enaminone 5 had to be immediately
transformed further with hydrazine derivatives 6, because the
enamino ketone 5 slowly cyclised into methyl 4-oxo-1,4,5,6-tetra-
hydropyridine-3-carboxylate (10). For example, pyridone 10 was
isolated in 48% yield upon standing of the crude 5 at rt for 48 h.
Formation of 10 could be explained by intramolecular base-cata-
lysed cyclisation of 5 into the Boc-protected pyridone 8, followed by
addition of dimethylamine to the Boc group and elimination of tert-
butyl dimethylcarbamate (9) to afford 10 (Scheme 1).
Next, we studied a four-step transformation of the primary key-
intermediates 7 into the target compounds 20 by a series of
selective deprotection and N-acylation reactions. Two comple-
mentary synthetic pathways were employed: (a) transformation of
7 into 20 via the intermediates 14,16, and 18 (Scheme 2, Path A) and
(b) transformation of 7 into 20 via the intermediates 15, 17, and 19
yields(Scheme2, Table 1). N-Benzoylationof the d-aminoester 15{2}
with benzoyl chloride 12{2} then gave the N-benzoylated derivative
17, which was further hydrolysed in a mixture of 2 M aq sodium
hydroxide and methanol at 50 ꢀC to afford the
d-benzamido acid 19
in 71% yield over two steps. Activation of the carboxylic acid 19 with
BPC followed by treatment with amines 11{6–8} gave the final car-
boxamides 20{2; 6–8; 2} in very good yields (Scheme 2, Table 1).
3. Structure determination
The structures of novel compounds 5, 7, 10, and 14–20 were
determined by spectroscopic methods (IR, 1H and 13C NMR, NOESY
spectroscopy, and MS) and by elemental analyses for C, H, and N.
Compounds 5, 7{1,6,13}, 14{4}, 15{3}, 16{4; 5}, 17, 18{4; 5}, 19, 20{2;
6–8; 2}, and 20{4; 5; 3} 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
enaminone 5 was determined by HMBC spectroscopy on the basis
of long-range coupling constants (3JC–H) between the methylidene
proton (H–C(20)) and the carbonyl carbon atoms (O]C(1) and

D. Kralj et al. / Tetrahedron 65 (2009) 7151–7162
7153
O
iv
iii
BocHN
N
N
Method B
4
O
O
HO
O
O
i
ii
v
BocHN
COOH
COOMe
BocHN
Method A
O
3
1
BocHN
2
R1
N1
Me2N
2'
1'
5
vi
R4NHNH2 6{1-13}
N 2
2'
3
5
BocHN
BocHN
4
2
COOMe
4
1
3
O
MeOOC
5
7{1-13}
6
Hydrazines {1-13}
N
F3C
Me NHNH2 Ph NHNH2
NHNH2
6{3}
Cl
NHNH2
NHNH2
MeO
NHNH2
NHNH2
6{5}
NHNH2
6{6}
6{1}
6{2}
6{7}
6{4}
N
N
N
N N
N N
N N
N N
N
NHNH2
O2N
NHNH2
Cl
F
NHNH2
Ph
NHNH2
NHNH2
6{9}
6{13}
6{8}
6{11}
6{10}
6{12}
Boc
H
Me2NH
O
O
N
O
H
O
N
NMe2
COOMe
vii
N
O
and
O
NMe2
COOMe
COOMe
9
O
5
10
8
Scheme 1. Reaction conditions: (i) Meldrum’s acid, DCC, DMAP, CH2Cl2, 0 ꢀC; (ii) MeOH, reflux; (iii) CDI, THF, rt; (iv) potassium monomethyl malonate, MgCl2, THF, rt; (v) DMFDMA,
CH2Cl2, rt; (vi) R1NHNH2 6{1–13}, MeOH or n-PrOH, rt or reflux; (vii) standing rt for 48 h.
O]C(3)), measured from the antiphase splitting of cross peaks in
methyl 5-[(2-acylamino)ethyl]-1H-pyrazole-4-carboxamides 20
were then prepared in good yields over four steps from the key-
intermediates 7, following two complementary deprotection/acyl-
ation reaction sequences (synthetic Paths A and B, cf. Scheme 2). In
conclusion, this work represents a useful synthetic application of
enaminones as versatile reagents in the diversity-oriented synthesis
of functionalised heterocycles.
the HMBC spectrum. Generally, the magnitude of coupling con-
3
stant, JC–H, for nuclei with cis-configuration around the C]C
double bond are smaller (2–6 Hz) than that for trans-oriented nu-
clei (8–12 Hz).8–14,19 In compound 5, the magnitudes of coupling
constants, 3JC(1)–H(2 )¼7 Hz (trans) and 3JC(3)–H(2 )¼5 Hz (cis) showed
the (E)-configuration around the exocyclic C]C double bond
(Fig. 2).
0
0
The structure of compound 7{10} was determined by X-ray
diffraction (Fig. 3).
5. Experimental
5.1. General
4. Conclusion
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 DMSO-d6 and
CDCl3 with TMS as the internal standard, as solvents. Mass spectra
were recorded on an AutoSpecQ spectrometer, IR spectra on a Per-
kin–Elmer Spectrum BX FTIR spectrophotometer. Microanalyses
were performed on a Perkin–Elmer CHN Analyser 2400 II.
In summary, a seven-step synthesis of 1-substituted 5-(2-acyl-
aminoethyl)-1H-pyrazole-4-carboxamides 20 was developed. The
synthesis starts with a three-step one-pot transformation of com-
mercially available Boc-
[(2-tert-butoxycarbonylamino)ethyl]-1H-pyrazole-4-carboxylates
7 comprising (a) Masamune–Claisen transformation of N-Boc-
alanine (1) into the
-keto ester 3,18 (b) condensation of 3 with
b-alanine (1) into 1-substituted methyl 5-
b
-
b
Boc-b-alanine (1), 2,2-dimethyl-1,3-dioxane-4,6-dione (Meldrum’s
DMFDMA to give the enaminone 5, and cyclisation of 5 with mono-
substituted hydrazines 6. Compounds 7 are useful intermediates for
further derivatisations, since they can be selectively deprotected,
either at the amino, or at the carboxy group. Several 1-substituted
acid), N,N0-dicyclohexylcarbodiimide (DCC), 4-dimethylminopyridine
(DMAP), di(1H-imidazol-1-yl)methanone (1,10-carbonyldiimidazole),
N,N-dimethylformamide dimethylacetal (DMFDMA), hydrazines
6{1–9}, bis(pentafluorophenyl) carbonate (BPC), amines 11{1–9},

7154
D. Kralj et al. / Tetrahedron 65 (2009) 7151–7162
Table 1
Experimental data for compounds 7 and 14–20
Synthesis of the key-intermediates 7, 14, and 15
Compound
R1
Yield (%)
7
14
15
7{1}, 14{1}, 15{1}
7{2}, 14{2}, 15{2}
7{3}, 14{3}, 15{3}
7{4}, 14{4}
7{5}, 14{5}
7{6}
7{7}
7{8}
7{9}
7{10}
Methyl
Phenyl
Pyridin-2-yl
4-Methoxyphenyl
tert-Butyl
2,2,2-Trifluoroethyl
4-Chlorophenyl
4-Fluorophenyl
72
65
65
77
69
58
34
39
55
47
80
62
68
59
64
88
94
52
d
d
d
d
d
d
d
d
82
72
86
d
d
d
d
d
d
d
d
d
d
4-Nitrophenyl
6-Chloropyridazin-2-yl
6-Phenylpyridazin-2-yl
Imidazo[1,2-b]pyridazin-6-yl
Tetrazolo[1,5-b]pyridazin-6-yl
7{11}
7{12}
7{13}
Synthesis of compounds 20 by Path A (14/16/18/20)
Compound
R1
–NR2R3
R4
Yield (%)
16
18
20
16{1; 1}, 18{1; 1}, 20{1; 1; 1}
16{2; 2}, 18{2; 2}, 20{2; 2; 2}
16{2; 3}, 18{2; 3}, 20{2; 3; 2}
16{2; 4}, 18{2; 4}, 20{2; 4; 2}
16{4; 5}, 18{4; 5}, 20{4; 5; 3}
Me
Ph
Ph
Ph
–NHMe
–NHCH2Ph
Piperidin-1-yl
–NH(CH2)3NMe2
–NH(CH2)2COOEt
Me
Ph
83
80
93
40
52
67
96
91
85
85
65
78
89
52
71
Ph
Ph
4-MeO–C6H4
Z-GlyGlyb
Synthesis of compounds 20 by Path B (15/17/19/20)
Compound
R1
–NR2R3
R4
Yield (%)
17
19
88
20
17, 19, 20{2; 6; 2}
20{2; 7; 2}
20{2; 8; 2}
Ph
Ph
Ph
–NHCH2Pya
3-(2-Oxopyrrolidin-1-yl)propylamino
3-(Diethylcarbamoyl)piperidin-1-yl
Ph
Ph
Ph
81
91
90
97
a
Py¼pyridin-2-yl.
b
Z-GlyGly¼N-[N-(benzyloxycarbonyl)aminoacetyl]aminoacetyl.
acidchlorides 12{1,2}, andcarboxylicacids 13{1–3} are commercially
available (Sigma–Aldrich). 6-Chloro-3-hydrazinopyridazine 6{10},20
3-hydrazino-6-phenylpyridazine 6{11},21 6-hydrazinoimidazo[1,2–
b]pyridazine 6{12},22 and 6-hydrazinotetrazolo[1,5–b]pyridazine
6{13},23 were prepared according to the literature procedures.
Method B
Compound 3 was prepared according to a slightly modified lit-
erature procedure.18c Under argon, 1,10-carbonyldiimidazole (38.8 g
244 mmol) was added portion wise (w3–5 min.) to a solution of
Boc-b-alanine (1) (37.8 g, 200 mmol) in anhydrous THF (700 mL)
and the mixture was stirred at rt for 1 h. Then, a well homogenised
and powdered solid mixture of MgCl2 (18.4 g, 193 mmol) and po-
tassium hydrogen methyl malonate (47.0 g, 300 mmol) was added
and the reaction mixture was stirred at rt for 14 h. Volatile com-
ponents were evaporated in vacuo, ethyl acetate (600 mL) was
added, and the so formed suspension was washed subsequently
with 1 M aq NaHSO4 (3ꢁ200 mL) and brine (200 mL). The organic
phase was dried over anhydrous Na2SO4, filtered, and the filtrate
was evaporated in vacuo to give the title compound 3. Yield: 44.2 g
(90%) of colourless oil. Spectral data of compound 3 were in
agreement with the literature data.18b,c Compound 3 was used in
the next step without any further purification.
5.2. Synthesis of methyl 5-(tert-butoxycarbonylamino)-
3-oxopentanoate (3)
Method A
Compound 3 was prepared according to a slightly modified lit-
erature procedure for the preparation of a closely related com-
pound.14a A solution of DCC (5.674 g, 27.5 mmol) in anhydrous
dichloromethane (25 mL) was added slowly to a stirred solution of
Meldrum’s acid (3.603 g, 25 mmol), Boc-b-alanine (1) (4.730 g,
25 mmol), and DMAP (3.360 g, 27.5 mmol) in anhydrous dichloro-
methane (55 mL) at 0 ꢀC (ice-bath). The reaction mixture was
stirred at 0 ꢀC for 16 h and the precipitated N,N0-dicyclohexylurea
(DCU) was removed by filtration and washed with anhydrous
dichloromethane (25 mL). The filtrate was washed subsequently
with 1 M aq NaHSO4 (2ꢁ170 mL) and brine (2ꢁ170 mL), dried with
anhydrous Na2SO4, filtered, and the filtrate was evaporated in
vacuo. The residue (crude compound 8) was dissolved in anhydrous
methanol (150 mL) and the solution was refluxed under argon for
5 h. Volatile components were evaporated in vacuo and the residue
was purified by column chromatography (silica gel, EtOAc). Frac-
tions containing the product were combined and evaporated in
vacuo to give the title compound 3. Yield: 3.65 g (60%) of yellow oil.
Spectral data of compound 3 were in agreement with the literature
data.18b,c The crude compound 3 was used in the next step without
any further purification.
5.3. Synthesis of methyl (E)-5-(tert-butoxycarbonylamino)-
2-[(dimethylamino)methylidene]-3-oxopentanoate (5)
The crude
b-keto ester 3 from the previous step (24.5 g,
100 mmol) was dissolved in anhydrous dichloromethane (100 mL),
N,N0-dimethylformamide dimethylacetal (DMFDMA) (18 mL,
130 mmol) was added, the so formed solution was left at rt for 12 h,
and volatile components were evaporated in vacuo to give the title
compound 3, which was used for further transformations without
purification. Yield: 30 g (99%) of yellow oil; Rf (EtOAc) 0.26; nmax
(liquid film) 3362, 2977, 2930, 1707, 1642, 1578, 1502, 1426, 1366,
1172, 1113, 1046, 965, 863 cmꢂ1
s, t-Bu), 2.59 (2H, t, J¼7.2 Hz, 4-CH2), 2.86 (6H, br s, NMe2), 3.04 (2H,
; dH (300 MHz, DMSO-d6) 1.28 (9H,

D. Kralj et al. / Tetrahedron 65 (2009) 7151–7162
7155
R1
N
R1
N
R1
N
2HCl
H2N
iii (amidation)
ii (acidolysis)
N
N
N
BocHN
BocHN
11
{1-5}
O
O
HOOC
R2
R2
N
N
R3
R3
14{1-5}
16{1,2,4; 1-5}
18{1,2,4; 1-5}
12
{1},
Path A
(acylation) iv
13'
{2,3}
R1
N
R1
N
7,14,15{R1}
16,18{R1; R2R3N}
H
N
N
BocHN
N
R4
O
MeOOC
O
1
2
3
4
R2
N
20
{R ; R R N; R }
R3
7{1-5}
20{1,2,4; 1-8; 1-3}
Path B
ii (acidolysis)
R1
11
{6-8}
(amidation) iii
Ph
Ph
N
2HCl
H2N
N
N
H
H
N
iv (acylation)
i (hydrolysis)
N
N
N
N
Ph
Ph
13'
{2}
O
O
MeOOC
HOOC
MeOOC
15{1-3}
19
17
11
Amines {1-8}
Et2NOC
N
NH2
N
Me2N
NH
11{3}
NH2
NH2
NH2
Me NH2
NH
EtOOC
NH2
O
11
{1}
11
{2}
11
{5}
11
{6}
11{4}
11{7}
11
{8}
Acid chloride 12{1} and pentafluorophenyl esters 13{1-3}
O
O
O
BPC
13/13'{2}: R = Ph
13/13'{3}: R = CH2NHCOCH2NHCOOBn
R
Me
R
OC6F5
Cl
OH
in situ
12
{1}
13
{2,3}
13'{1-3}
Scheme 2. Reaction conditions: (i) 2 M aq NaOH, MeOH, 50 ꢀC; (ii) 2 M HCl–EtOAc, 0–20 ꢀC; (iii) BPC, Et3N, MeCN, rt, then R2R3NH 11{1–8}, Et3N, MeCN, rt; (iv) MeCOCl 12{1}, Et3N,
EtOH, 0–20 ꢀC or R4COOC6F5 130 (obtained R4COOH 13, BPC, and Et3N), MeCN, Et3N, rt.
1221, 1184, 1074, 1032, 784 cmꢂ1
; dH (300 MHz, DMSO-d6) 2.29
2'
2
H
NMe2
H
NMe2
(2H, t, J¼7.8 Hz, 5-CH2), 3.51 (2H, J¼7.8 Hz, 6-CH2), 3.55 (3H, s,
OMe), 8.17 (1H, s, 2-H), 8.89 (1H, br s, NH); dC (75.5 MHz, DMSO-d6)
36.6, 41.1, 50.9, 99.5, 158.7, 165.8, 187.2; m/z 156 (100, MHþ), 124
(81%); HRMS (ESI): MHþ, found 156.0662, C7H10NO3 requires
156.0661.
4
3
C
5
1
BocHN
OMe
BocHN
OMe
C
O
O
3
O
O
Compound
3
Compound
3
3
J
C-H = 4.8 Hz (cis)
J
C-H = 7.0 Hz (trans)
5.4. Reactions of the enaminone 5 with hydrazine derivatives
6{1–13}. General procedures for the preparation of 1-substi-
tuted methyl 5-[2-(tert-butoxycarbonylamino)ethyl]-1H-
pyrazole-4-carboxylates 7{1–13}
Figure 2.
m, 5-CH2), 3.55 (3H, s, OMe), 6.47 (1H, t, NH), 7.56 (1H, 20-H); dC
(75.5 MHz, DMSO-d6) 28.2, 32.0, 36.6, 41.1, 50.7, 77.4, 101.4, 155.5,
156.1, 167.9, 194.1; m/z 301 (77, MHþ), 245 (97), 201 (85), 184 (70),
169 (100), 156 (66), 130 (39%); HRMS (ESI): MHþ, found 301.1749,
C14H25N2O5 requires 301.1763.
General procedure A
Hydrazine derivative 6 (10 mmol) was added to a stirred solu-
tion of the enaminone 5 (3.0 g, 10 mmol) in methanol (20 mL) and
the mixture was stirred at rt for 3 h. The precipitate was collected
by filtration to give the title compound 7. Compounds 7{3,7,8,12}
were prepared in this manner.
5.3.1. Intramolecular cyclisation of (E)-methyl 5-(tert-butoxy-
carbonylamino)-2-[(dimethylamino)methyidene]-3-
oxopentanoate (5) into methyl 4-oxo-1,4,5,6-
tetrahydropyridine-3-carboxylate (10)
General procedure B
The crude oily enaminone 5 (15 g, 50 mmol) was left to stand at
rt for two days. The solid residue was triturated with ethyl acetate
(50 mL) and the precipitate was collected by filtration to give the
title compound 10. Yield: 3.76 g (48%) of a white solid, mp 230–
235 ꢀC; [Found: C, 54.40; H, 5.95; N; 9.04. C7H9NO3 requires: C,
54.19; H, 5.85; N, 9.03%]; Rf (17% EtOH/EtOAc) 0.15; nmax (KBr)
3165, 2982, 2944, 1705, 1687, 1591, 1502, 1440, 1388, 1329, 1289,
Hydrazine derivative 6 (10 mmol) was added to a stirred solu-
tion of the enaminone 5 (3.0 g, 10 mmol) in methanol (20 mL) or 1-
propanol (20 mL) and the mixture was stirred at rt or under reflux
for 3 h. Volatile components were evaporated in vacuo and the
residue was triturated with water or ethanol/water. The precipitate
was collected by filtration to give the title compound 7. Compounds
7{1,2,5,6,9,13} were prepared in this manner.

7156
D. Kralj et al. / Tetrahedron 65 (2009) 7151–7162
Figure 3. The asymmetric unit of compound 7{10}. Ellipsoids are plotted at 50% probability level. H atoms are drawn as circles of arbitrary radii.
General procedure C
C18H23N3O4 requires C, 62.59; H, 6.71; N, 12.17%]; Rf (33% EtOAc/
hexanes) 0.33; nmax (KBr) 3345, 2972, 1720, 1701, 1554, 1510, 1361,
Hydrazine derivative hydrochloride 6 (10 mmol) was added to
a stirred solution of the enaminone 5 (3.0 g, 10 mmol) in methanol
(20 mL) or 1-propanol (20 mL) and the mixture was stirred under
refluxed for 3 h. Volatile components were evaporated in vacuo and
the residue was purified by flash chromatography (FC) over silica
gel. Fractions containing the product were combined and evapo-
rated in vacuo to give the title compound 7. Compounds 7{4,10,11}
were prepared in this manner.
1281, 1255, 1243, 1195, 1009, 759 cmꢂ1
; dH (300 MHz, DMSO-d6)
1.36 (9H, s, t-Bu), 3.12 (2H, t, J¼6.6 Hz, 10-CH2), 3.36 (2H, m, 20-CH2),
3.87 (3H, s, OMe), 4.86 (1H, br s, NH), 7.36–7.59 (5H, m, Ph), 8.02 (1H,
s, 3-H); dC (75.5 MHz, DMSO-d6) 25.7, 28.1, 39.5, 51.0, 77.5, 112.2,
126.1, 128.9, 129.3, 138.5, 141.2, 145.1, 155.3, 163.1.
5.4.3. Methyl 5-[2-(tert-butoxycarbonylamino)ethyl]-1-(pyridin-2-
yl)-1H-pyrazole-4-carboxylate 7{3}. Prepared from 5 and 2-hydra-
zinopyridine 6{3} (1.090 g, 10 mmol) in methanol at rt; General
Procedure A. Yield: 2.263 g (65%) of a yellowish solid; mp 117–
121 ꢀC; [Found: C, 58.93; H, 6.49; N; 16.02. C17H22N4O4 requires C,
58.95; H, 6.40; N, 16.17%]; Rf (EtOAc) 0.60; nmax (KBr) 3393, 2978,
The following compounds were prepared in this manner:
5.4.1. Methyl 5-[2-(tert-butoxycarbonylamino)ethyl]-1-methyl-1H-
pyrazole-4-carboxylate 7{1}. Prepared from
5 and methyl-
hydrazine 6{1} (0.46 g, 0.53 mL, 10 mmol) in methanol at rt;
General Procedure B; trituration with water. Yield: 2.036 g (72%)
of a yellowish solid; mp 80–82 ꢀC; Rf (33% EtOAc/hexanes) 0.28;
nmax (KBr) 3370, 2983, 1703, 1684, 1556, 1535, 1498, 1444, 1373,
1711, 1699, 1561, 1507, 1436, 1290, 1164, 1099, 787 cmꢂ1
; dH
(300 MHz, CDCl3) 1.36 (9H, s, t-Bu), 3.54–3.65 (4H, m, CH2CH2), 3.87
(3H, s, OMe), 5.68 (1H, br s, NH), 7.28–7.35 (1H, m, 500-H), 7.84–7.92
(2H, m, 400-H, 600-H), 8.03 (1H, s, 3-H), 8.50 (1H, dt, J¼1.2, 4.8 Hz, 300-
H); dC (75.5 MHz, DMSO-d6) 25.9, 28.1, 39.5, 51.1, 77.3, 113.7, 118.0,
123.2, 139.4, 141.8, 146.0, 147.9, 152.1, 155.2, 163.0.
1281, 1238, 1162, 1086, 1026, 990, 784 cmꢂ1
; dH (300 MHz, DMSO-
d6) 1.36 (9H, s, t-Bu), 3.02–3.10 (2H, m, 10-CH2), 3.11–3.22 (2H, m,
20-CH2), 3.74 (3H, s, NMe), 3.80 (3H, s, OMe), 6.94 (1H, t, J¼5.7 Hz,
NH), 7.75 (1H, s, 3-H); dC (75.5 MHz, DMSO-d6) 24.9, 28.1, 36.2,
40.7, 50.7, 77.6, 110.8, 139.7, 144.5, 155.5, 163.2; m/z 284 (35, MHþ),
228 (39), 214 (18), 184 (100%); HRMS (ESI): MHþ, found 284.1621,
C13H22N3O4 requires 284.1610.
5.4.4. Methyl 5-[2-(tert-butoxycarbonylamino)ethyl]-1-(4-methoxy-
phenyl)-1H-pyrazole-4-carboxylate 7{4}. Prepared from 5 and 4-
methoxyphenylhydrazine hydrochloride 6{4} (1.74 g, 10 mmol) in
methanol under reflux; General Procedure C; FC: EtOAc/hexanes,
1:1. Yield: 2.893 g (77%) of an orange solid; mp 108–110 ꢀC; [Found:
C, 60.49; H, 6.81; N; 11.14. C19H25N3O5 requires C, 60.79; H, 6.71; N,
11.19%]; Rf (33% EtOAc/hexanes) 0.28; nmax (KBr) 3289, 2977, 1714,
5.4.2. Methyl 5-[2-(tert-butoxycarbonylamino)ethyl]-1-phenyl-1H-
pyrazole-4-carboxylate 7{2}. Prepared from 5 and phenylhydrazine
6{2} (1.08 g, 10 mmol) in methanol at rt; General Procedure B;
trituration with ethanol/water (1:2). Yield: 2.238 g (65%) of a yel-
lowish solid; mp 102–105 ꢀC; [Found: C, 62.41; H, 6.91; N; 12.12.
1561, 1519, 1288, 1253, 1173, 1094, 990, 848 cmꢂ1
; dH (300 MHz,
CDCl3) 1.36 (9H, s, t-Bu), 3.08 (2H, t, J¼6.6 Hz, 10-CH2), 3.30–3.42 (2H,

D. Kralj et al. / Tetrahedron 65 (2009) 7151–7162
7157
m, 20-CH2), 3.88 and 3.89 (6H, 2s, 1:1, 2ꢁOMe), 4.84 (1H, br s, NH),
6.99–7.06 and 7.34–7.41 (4H, 2m, 1:1, C6H4), 8.01 (1H, s, 3-H); dC
(75.5 MHz, CDCl3) 26.1, 28.7, 40.0, 51.7, 55.9, 79.5, 112.9, 114.9, 128.1,
132.0, 142.0, 145.7, 156.2, 160.4, 164.8; m/z 375 (58, Mþ), 319 (31), 302
(51), 258 (34), 246 (100%); HRMS (EI): Mþ, found 375.180320,
C19H25N3O5 requires 375.179421.
C, 55.38; H, 5.68; N; 14.35%]; Rf (EtOAc) 0.72; nmax (KBr) 3383, 3124,
1713, 1702, 1596, 1567, 1523, 1394, 1344, 1266, 1252, 1201, 1162, 967,
953, 937, 854 cmꢂ1
; dH (300 MHz, DMSO-d6) 1.36 (9H, s, t-Bu), 3.21
(2H, t, J¼6.7 Hz, 10-CH2), 3.42 (2H, q, J¼6.7 Hz, 20-CH2), 3.89 (3H, s,
OMe), 4.82 (1H, br s, NH), 7.79 and 8.39 (4H, 2d, 1:1, J¼8.7 Hz, C6H4),
8.07 (1H, s, 3-H); dC (75.5 MHz, CDCl3) 26.3, 28.5, 39.7, 51.7, 79.7,
114.2, 125.0, 126.7, 143.0, 143.9, 145.6, 147.6, 156.1, 164.0.
5.4.5. Methyl 5-[2-(tert-butoxycarbonylamino)ethyl]-1-(tert-butyl)-
1H-pyrazole-4-carboxylate 7{5}. Prepared from 5 and tert-butylhy-
drazine hydrochloride 6{5} (1.246 g, 10 mmol) in 1-propanol under
reflux; General Procedure B; trituration with water. Yield: 2.245 g
(69%) of a yellowish solid; mp 89–92 ꢀC; [Found: C, 59.19; H, 8.54; N;
12.95. C16H27N3O4 requires C, 59.06; H, 8.36; N, 12.91%]; Rf (33%
EtOAc/hexanes) 0.29; nmax (KBr) 3343, 2978, 1721, 1706, 1550, 1525,
5.4.10. Methyl 5-[2-(tert-butoxycarbonylamino)ethyl]-1-(6-chloro-
pyridazin-3-yl)-1H-pyrazole-4-carboxylate 7{10}. Prepared from 5
and 6-chloro-3-hydrazinopyridazine 6{10} (1.446 g, 10 mmol) in
methanol under reflux; General Procedure C; FC: EtOAc/hexanes,
1:2. Yield: 1.783 g (47%) of a brownish solid; mp 146–148 ꢀC;
[Found: C, 50.46; H, 5.47; N; 17.99. C16H20ClN5O4 requires C, 50.33;
H, 5.28; N, 18.34%]; Rf (33% EtOAc/hexanes) 0.49; nmax (KBr) 3365,
3062, 2979, 1718, 1702, 1570, 1540, 1484, 1428, 1371, 1284, 1242,
1471, 1394, 1365, 1279, 1241, 1241, 1172, 1006, 940, 780 cmꢂ1
; dH
(300 MHz, DMSO-d6) 1.38 (9H, s, t-Bu), 1.63 (9H, s, t-Bu), 3.11–3.29
(4H, m, CH2CH2), 3.74 (3H, s, OMe), 7.08 (1H, t, NH), 7.74 (1H, s, 3-H);
dC (75.5 MHz, CDCl3) 26.7, 28.2, 30.1, 38.7, 50.8, 61.2, 77.6, 112.5,
138.4, 143.9, 155.5, 163.2.
1161, 1095, 1013, 941, 868, 781 cmꢂ1
; dH (300 MHz, CDCl3) 1.32 (9H,
s, t-Bu), 3.55 (2H, q, J¼6.3 Hz, 20-CH2), 3.79 (2H, t, J¼6.3 Hz, 10-CH2),
3.90 (3H, s, OMe), 5.00 (1H, br s, NH), 7.68 (1H, d, J¼7.2 Hz, 400-H),
8.08 (1H, s, 3-H), 8.17 (1H, d, J¼7.2 Hz, 500-H); dC (75.5 MHz, DMSO-
d6) 25.8, 28.1, 39.5, 51.3, 77.4, 114.7, 126.0, 131.7, 143.1, 147.1, 155.2,
155.3, 155.7, 162.7.
5.4.6. Methyl 5-[2-(tert-butoxycarbonylamino)ethyl]-1-(2,2,2-tri-
fluoroethyl)-1H-pyrazole-4-carboxylate 7{6}. Prepared from 5 and
2,2,2-trifluoroethylhydrazine 6{6} (70% in water, 1.26 mL, 10 mmol)
in methanol at rt; General Procedure B; trituration with water.
Yield: 2.045 g (58%) of a white solid; mp 127–129 ꢀC; Rf (33% EtOAc/
hexanes) 0.66; nmax (KBr) 3406, 2981, 1716, 1687, 1566, 1523, 1268,
5.4.11. Methyl 5-[2-(tert-butoxycarbonylamino)ethyl]-1-(6-phenyl-
pyridazin-3-yl)-1H-pyrazole-4-carboxylate 7{11}. Prepared from 5
and 3-hydrazino-6-phenylpyridazine 6{11} (1.862 g, 10 mmol) in
methanol under reflux; General Procedure C; FC: EtOAc–hexanes,
1:2. Yield: 3.404 g (80%) of a white solid; mp 123–125 ꢀC; [Found: C,
62.11; H, 6.01; N; 16.54. C22H25N5O4 requires C, 62.40; H, 5.95; N,
16.54%]; Rf (33% EtOAc/hexanes) 0.32; nmax (KBr) 3410, 3315, 2977,
1721, 1710, 1569, 1545, 1453, 1404, 1278, 1260, 1170, 1091, 980,
1242, 1165,1092,1066, 930, 783 cmꢂ1
; dH (300 MHz, DMSO-d6) 1.42
(9H, s, t-Bu), 3.25 (2H, t, J¼6.6 Hz, 10-CH2), 3.40 (2H, m, 20-CH2), 3.86
(3H, s, OMe), 4.83 (3H, q, J¼8.1 Hz, CH2CF3 and NH), 7.95 (1H, s, 3-
H); dC (75.5 MHz, DMSO-d6) 24.5, 28.0, 38.8, 49.2, 51.1, 77.8, 111.9,
125.2, 140.6, 141.5, 155.6, 162.8. m/z 352 (50, MHþ), 296 (58), 252
(100), 225 (33%); HRMS (ESI): MHþ, found 352.1487, C14H21F3N3O4
requires 352.1484.
780 cmꢂ1
; dH (300 MHz, CDCl3) 1.33 (9H, s, t-Bu), 3.61 (2H, q,
J¼6.3 Hz, 20-CH2), 3.87 (2H, t, J¼6.3 Hz, 10-CH2), 3.91 (3H, s, OMe),
5.19 (1H, br s, NH), 7.50–7.61 (3H, m, 3H of Ph), 8.05 (1H, d, J¼9.3 Hz,
400-H), 8.07–8.11 (3H, m, 2H of Ph, 3-H), 8.22 (1H, d, J¼9.3 Hz, 500-H);
dC (75.5 MHz, DMSO-d6) 25.8, 28.1, 39.5, 51.3, 77.3, 114.4, 123.4,
127.0, 127.2, 129.1, 130.4, 135.0, 142.9, 146.8, 155.2, 155.3, 158.1,
162.9.
5.4.7. Methyl 5-[2-(tert-butoxycarbonylamino)ethyl]-1-(4-chloro-
phenyl)-1H-pyrazole-4-carboxylate 7{7}. Prepared from 5 and 4-
chlorophenylhydrazine hydrochloride 6{7} (1.79 g, 10 mmol) in
methanol under reflux; General Procedure A. Yield: 1.291 g (34%) of
a brownish solid; mp 136–137 ꢀC; [Found: C, 56.74; H, 5.90; N;
11.00. C18H22ClN3O4 requires: C, 56.92; H, 5.84; N, 11.06%]; Rf
(EtOAc) 0.72; nmax (KBr) 3412, 3115, 2987, 1722, 1697, 1555, 1504,
5.4.12. Methyl 5-[2-(tert-butoxycarbonylamino)ethyl]-1-(imidazo-
[1,2-b]pyridazin-3-yl)-1H-pyrazole-4-carboxylate 7{12}. Prepared
from 5 and 6-hydrazinoimidazo[1,2-b]pyridazine 6{12} (1.492 g,
10 mmol) in methanol at rt; General Procedure A. Yield: 2.380 g
(62%) of a white solid; mp 178–180 ꢀC; [Found: C, 56.02; H, 5.82; N;
22.0. C18H22N6O4 requires C, 55.95; H, 5.74; N, 21.75%]; Rf (33%
EtOAc/hexanes) 0.30; nmax (KBr) 3238, 3140, 2981, 1720, 1706, 1424,
1434, 1361, 1280, 1261, 1193, 1094, 996, 837, 782 cmꢂ1
; dH
(300 MHz, DMSO-d6) 1.30 (9H, s, t-Bu), 2.97–3.14 (4H, m, CH2CH2),
3.79 (3H, s, OMe), 6.77 (1H, br t, NH), 7.48–7.58 and 7.59–7.66 (4H,
2m, 1:1, C6H4), 8.02 (1H, s, 3-H); dC (75.5 MHz, DMSO-d6) 25.6, 28.1,
39.5, 51.1, 77.5, 112.3, 127.9, 129.3, 133.5, 137.4, 141.4, 145.4, 155.3,
163.0.
1272, 1170, 1130, 979, 815, 781 cmꢂ1
; dH (300 MHz, CDCl3) 1.38 (9H,
s, t-Bu), 3.57–3.69 (4H, m, CH2CH2), 3.90 (3H, s, OMe), 5.07 (1H, br s,
NH), 7.74 (1H, d, J¼9.7 Hz, 700-H), 7.85 (1H, d, J¼0.9 Hz, 200-H), 8.08
(1H, s, 3-H), 8.10 (1H, d, J¼9.5 Hz, 800-H), 8.16 (1H, br s, 300-H); dC
(75.5 MHz, DMSO-d6) 27.1, 29.0, 40.4, 52.2, 78.3, 115.0, 115.2, 118.8,
128.6, 135.6, 143.5, 147.5, 148.8, 156.2, 163.6.
5.4.8. Methyl 5-[2-(tert-butoxycarbonylamino)ethyl]-1-(4-fluoro-
phenyl)-1H-pyrazole-4-carboxylate 7{8}. Prepared from 5 and 4-
fluorophenylhydrazine hydrochloride 6{8} (1.625 g, 10 mmol) in
methanol under reflux; General Procedure A. Yield: 1.409 g (39%) of
a brownish solid; mp 134–136 ꢀC; [Found: C, 59.48; H, 6.29; N;
11.39. C18H22FN3O4 requires C, 59.49; H, 6.10; N, 11.56%]; Rf (EtOAc)
0.71; nmax (KBr) 3373, 3114, 2985, 1723, 1698, 1557, 1518, 1476, 1437,
5.4.13. Methyl 5-[2-(tert-butoxycarbonylamino)ethyl]-1-(tetrazolo-
[1,5-b]pyridazin-3-yl)-1H-pyrazole-4-carboxylate 7{13}. Prepared
from 5 and 6-hydrazinotetrazolo[1,2-b]pyridazine 6{13} (1.511 g,
10 mmol) in methanol at rt; General Procedure B; trituration with
methanol/water. Yield: 3.633 g (68%) of a brownish solid; mp
130–134 ꢀC; [Found: C, 49.36; H, 5.29; N; 28.34. C16H20N8O4 re-
quires C, 49.48; H, 5.19; N, 28.85%]; Rf (33% EtOAc/hexanes) 0.20;
nmax (KBr) 3391, 3084, 1734, 1624, 1574, 1547, 1417, 1379, 1267, 1245,
1363,1281, 1220, 1098, 998, 841, 782 cmꢂ1
; dH (300 MHz, DMSO-d6)
1.30 (9H, s, t-Bu), 2.95–3.13 (4H, m, CH2CH2), 3.79 (3H, s, OMe), 6.77
(1H, br s, NH), 7.34–7.44 and 7.48–7.61 (4H, 2m, 1:1, C6H4), 8.00 (1H,
s, 3-H); dC (75.5 MHz, CDCl3) 25.9, 28.4, 39.7, 51.5, 79.4, 113.0, 116.5,
128.5, 134.9, 142.0, 145.5, 156.0, 161.2, 164.4.
5.4.9. Methyl5-[2-(tert-butoxycarbonylamino)ethyl]-1-(4-nitrophenyl)-
1H-pyrazole-4-carboxylate 7{9}. Prepared from 5 and 4-nitro-
phenylhydrazine 6{9} (1.531 g, 10 mmol); General Procedure B;
trituration with water. Yield: 2.119 g (55%) of a brownish solid; mp
119–123 ꢀC; [Found: C, 55.37; H, 5.76; N, 14.37. C18H22N4O6 requires
1175, 1163, 986, 828 cmꢂ1
; dH (300 MHz, CDCl3) 1.27 (9H, s, t-Bu),
3.64 (2H, q, J¼6.3 Hz, 20-CH2), 3.87 (2H, t, J¼6.3 Hz, 10-CH2), 3.92 (3H,
s, OMe), 4.87 (1H, br t, NH), 8.12 (1H, s, 3-H), 8.44 (1H, d, J¼9.9 Hz,
700-H), 8.50 (1H, d, J¼9.9 Hz, 800-H), dC (75.5 MHz, DMSO-d6) 25.6,
28.0, 38.8, 51.5, 77.4, 115.4, 123.1, 127.5, 142.5, 143.8, 147.8, 150.9,

7158
D. Kralj et al. / Tetrahedron 65 (2009) 7151–7162
155.2, 162.5; m/z 389 (41, MHþ), 374 (21), 333 (45), 289 (78), 252
(32), 272 (20), 225 (61), 214 (59), 164 (76), 159 (100%); HRMS
(ESI): MHþ, found 389.1688, C16H21N8O4 requires 389.1686.
161.9, 164.4; m/z 362 (84, MHþ), 306 (37), 262 (43), 244 (100), 225
(18%); HRMS (ESI): MHþ, found 362.1718, C18H24N3O5 requires
362.1716.
5.5. Base-catalysed hydrolysis of the methyl esters 7. General
procedure for the preparation of 1-substituted 5-[2-(acylamino)-
ethyl]-1H-pyrazole-4-carboxylic acids 14{1–5}
5.5.5. 5-[2-(tert-Butoxycarbonylamino)ethyl]-1-tert-butyl-1H-
pyrazole-4-carboxylic acid 14{5}
Prepared from 7{5} (3.254 g, 10 mmol). Yield: 1.628 g (52%) of
a white solid; mp 187–190 ꢀC; [Found: C, 57.46; H, 8.30; N; 13.36.
C15H25N3O4 requires C, 57.86; H, 8.09; N, 13.49%]; Rf (EtOAc) 0.43;
nmax (KBr) 3451, 3317, 3258, 3103, 2981, 2940, 1690, 1545, 1475,
A mixture of 7 (10 mmol), methanol (30 mL), and 2 M aq NaOH
(15 mL, 30 mmol) was stirred at 50 ꢀC for 12 h. Methanol was re-
moved by careful evaporation in vacuo (100 mbar, 40 ꢀC) and the
residual aqueous solution was cooled to 0 ꢀC (ice-bath) and acidi-
fied, first with 6 M hydrochloric acid (4.5 mL, 27 mmol) and then
with 1 M aq NaHSO4 (5 mL, 5 mmol). The precipitate was collected
by filtration, and washed with cold water (0 ꢀC, 5 mL) to give the
title compound 14.
1462, 1410, 1368, 1292, 1247, 1139, 984, 748 cmꢂ1
; dH (300 MHz,
DMSO-d6) 1.36 (9H, s, t-Bu), 1.60 (9H, s, t-Bu), 3.11–3.35 (4H, m,
CH2CH2), 7.04 (1H, br s, NH), 7.67 (1H, s, 3-H),12.13 (1H, br s, COOH);
dC (75.5 MHz, DMSO-d6) 26.4, 28.2, 30.2, 41.3, 61.0, 77.6,113.4,138.8,
143.8, 155.6, 164.4.
The following compounds were prepared in this manner:
5.6. Acidolytic removal of the Boc group from tert-butyl
carbamates 7. General procedure for the preparation of
1-substituted methyl 5-(2-aminoethyl)-1H-pyrazole-
4-carboxylates 15
5.5.1. 5-[2-(tert-Butoxycarbonylamino)ethyl]-1-methyl-1H-
pyrazole-4-carboxylic acid 14{1}
Prepared from 7{1} (2.833 g, 10 mmol). Yield: 1.574 g (59%) of
a white solid; mp 162–165 ꢀC; [Found: C, 53.38; H, 7.31; N; 15.34.
C12H19N3O4 requires C, 53.52; H, 7.11; N, 15.60%]; Rf (EtOAc) 0.53;
nmax (KBr) 3373, 2980, 1682, 1536, 1499, 1446, 1280, 1250, 1163,
HCl/EtOAc (2 M, 30 mL, 60 mmol) was added to a stirred mix-
ture of 7 (10 mmol), anhydrous EtOH (5 mL), and EtOAc (10 mL) at
0 ꢀC and the mixture was stirred at 0 ꢀC for 30 min and then at rt for
2 h. The precipitate was collected by filtration, washed with EtOAc
(2ꢁ20 mL), and dried in vacuo at rt over NaOH pellets for 12 h to
give the title compound 15.
780 cmꢂ1
; dH (300 MHz, DMSO-d6) 1.35 (9H, s, t-Bu), 3.00–3.20 (4H,
m, CH2CH2), 3.78 (3H, s, OMe), 6.94 (1H, br t, J¼5.4 Hz, NH), 7.70
(1H, s, 3-H), 12.17 (1H, br s, COOH); dC (75.5 MHz, DMSO-d6) 24.8,
28.2, 36.2, 39.5, 77.7, 111.8, 140.1, 144.3, 155.6, 164.4.
The following compounds were prepared in this manner:
5.5.2. 5-[2-(tert-Butoxycarbonylamino)ethyl]-1-phenyl-1H-
pyrazole-4-carboxylic acid 14{2}
5.6.1. Methyl 5-(2-aminoethyl)-1-methyl-1H-pyrazole-4-
carboxylate hydrochloride 15{1}
Prepared from 7{2} (3.454 g, 10 mmol). Yield: 1.920 g (64%) of
a white solid; mp 157–160 ꢀC; [Found: C, 61.38; H, 6.58; N; 12.70.
C17H21N3O4 requires C, 61.62; H, 6.39; N, 12.68%]; Rf (EtOAc) 0.41;
nmax (KBr) 3315, 3264, 3102, 2980, 1685, 1656, 1552, 1503, 1405,
Prepared from 7{1} (2.833 g, 10 mmol). Yield: 1.663 g (82%) of
a white solid; mp 228–231 ꢀC; [Found: C, 43.64; H, 6.64; N; 18.95.
C8H14ClN3O2 requires C, 43.74; H, 6.42; N, 19.13%]; Rf (EtOAc) 0.0;
nmax (KBr) 3392, 3007, 1703, 1567, 1494, 1469, 1437, 1374, 1287, 1237,
1368, 1292, 1271, 1165, 1144, 948, 762 cmꢂ1
;
dH (300 MHz, DMSO-
1112, 1040, 937, 779 cmꢂ1
; dH (300 MHz, DMSO-d6) 2.91–3.05 (2H,
d6) 1.30 (9H, s, t-Bu), 3.01 (2H, t, J¼6.5 Hz, 10-CH2), 3.11 (2H, q,
J¼6.5 Hz, 20-CH2), 6.79 (1H, br t, J¼5.0 Hz, NH), 7.46–7.58 (5H, m,
Ph), 7.95 (1H, s, 3-H), 12.42 (1H, br s, COOH); dC (75.5 MHz, DMSO-
d6) 25.5, 28.1, 39.5, 77.5, 113.1, 126.1, 128.8, 129.2, 138.7, 141.6, 144.9,
155.3, 164.3.
m, 20-CH2), 3.24–3.34 (2H, m, 10-CH2), 3.76 (3H, s, NMe), 3.87 (3H, s,
OMe), 7.80 (1H, s, 3-H), 8.29 (3H, br s, NHþ3 ); dC (75.5 MHz, DMSO-
d6) 22.5, 36.8, 37.2, 51.1, 111.3, 139.9, 142.3, 163.1.
5.6.2. Methyl 5-(2-aminoethyl)-1-phenyl-1H-pyrazole-
4-carboxylate hydrochloride 15{2}
5.5.3. 5-[2-(tert-Butoxycarbonylamino)ethyl]-1-(pyridin-2-yl)-
1H-pyrazole-4-carboxylic acid 14{3}
Prepared from 7{2} (3.454 g, 10 mmol). Yield: 2.04 g (72%) of
a white solid; mp 220–225 ꢀC; [Found: C, 55.43; H, 5.93; N; 14.75.
C13H16ClN3O2 requires C, 55.42; H, 5.72; N, 14.91%]; Rf (EtOAc)
0.0; nmax (KBr) 3416, 2949, 1719, 1612, 1556, 1495, 1271, 1232,
Prepared from 7{3} (3.464 g, 10 mmol). Yield: 2.923 g (88%) of
a white solid; mp 147–150 ꢀC; [Found: C, 57.69; H, 6.20; N; 16.69.
C16H20N4O4 requires: C, 57.82; H, 6.07; N, 16.86%]; Rf (EtOAc) 0.11;
nmax (KBr) 3330, 2980, 1721, 1697, 1558, 1477, 1436, 1402, 1294, 1190,
1100, 941, 767 cmꢂ1
; dH (300 MHz, DMSO-d6) 2.91–3.01 (2H, m,
20-CH2), 3.17–3.26 (2H, m, 10-CH2), 3.83 (3H, s, OMe), 7.51–7.63
(5H, m, Ph), 8.08 (1H, s, 3-H), 8.22 (3H, br s, NHþ3 ); dC (75.5 MHz,
DMSO-d6) 23.3, 37.0, 51.4, 112.5, 126.0, 129.2, 129.6, 138.1, 141.4,
142.8, 163.0.
1170, 963, 779, 753 cmꢂ1
; dH (300 MHz, DMSO-d6) 1.28 (9H, s, t-Bu),
3.22 (2H, q, J¼6.1 Hz, 20-CH2), 3.51 (2H, t, J¼6.6 Hz,10-CH2), 6.74 (1H,
t, J¼5.0 Hz, NH), 7.49 (1H, ddd, J¼0.9, 4.9, 7.5 Hz, 500-H), 7.78 (1H, dt,
J¼0.9, 8.2 Hz, 300-H), 8.01 (1H, s, 3-H), 8.06 (1H, ddd, J¼1.9, 7.5,
8.2 Hz, 400-H), 8.54 (1H, ddd, J¼0.9,1.9, 4.9 Hz, 600-H), OH exchanged;
dC (75.5 MHz, DMSO-d6) 25.6, 28.1, 40.3, 77.3, 114.6, 118.0, 123.1,
139.4, 142.2, 145.8, 147.9, 152.2, 155.2, 164.2
5.6.3. Methyl 5-(2-aminoethyl)-1-(pyridin-2-yl)-1H-pyrazole-
4-carboxylate hydrochloride 15{3}
Prepared from 7{3} (3.464 g, 10 mmol). Yield: 2.42 g (86%) of
a white solid; mp 205–210 ꢀC; Rf (EtOAc) 0.0; nmax (KBr) 3416,
2976, 1718, 1591, 1557, 1473, 1435, 1297, 1266, 1233, 1192, 1145,
5.5.4. 5-[2-(tert-Butoxycarbonylamino)ethyl]-1-(4-methoxy-
phenyl)-1H-pyrazole-4-carboxylic acid 14{4}
1102, 994, 932, 785, 715 cmꢂ1
; dH (300 MHz, DMSO-d6) 3.14–
Prepared from 7{4} (3.754 g, 10 mmol). Yield: 3.420 g (94%) of
a white solid; mp 190–194 ꢀC; Rf (EtOAc) 0.48; nmax (KBr) 3305,
2984, 2937, 1708, 1678, 1552, 1518, 1279, 1255, 1166, 986,
3.24 (2H, m, 20-CH2), 3.63 (2H, t, J¼7.5 Hz, 10-CH2), 3.84 (3H, s,
OMe), 7.53 (1H, ddd, J¼1.1, 4.9, 7.5 Hz, 500-H), 7.86 (1H, ddd,
J¼0.9, 1.1, 8.2 Hz, 300-H), 8.09 (1H, ddd, J¼1.9, 7.5, 8.2 Hz, 400-H),
8.13 (1H, s, 3-H), 8.27 (3H, br s, NHþ3 ), 8.62 (1H, ddd, J¼0.8, 1.9,
4.9 Hz, 600-H); dC (75.5 MHz, DMSO-d6) 24.7, 39.1, 52.8, 115.3,
118.7, 124.8, 141.0, 143.2, 144.3, 149.1, 151.9, 164.5; m/z 247 (100,
MHþ), 230 (96%); HRMS (ESI): MHþ, found 247.1204, C12H15N4O2
requires 247.1195.
843 cmꢂ1
; dH (300 MHz, DMSO-d6) 1.38 (9H, s, t-Bu), 3.11 (2H, t,
J¼6.6 Hz, 10-CH2), 3.30–3.41 (2H, m, 20-CH2), 3.86 (3H, s, OMe),
4.81 (1H, br s, NH), 6.98–7.03 and 7.32–7.42 (4H, 2m, 1:1, C6H4),
8.06 (1H, s, 3-H), OH exchanged; dC (75.5 MHz, DMSO-d6) 25.5,
28.2, 55.4, 77.5, 112.8, 114.3, 127.6, 131.7, 141.3, 145.1, 155.3, 159.3,

D. Kralj et al. / Tetrahedron 65 (2009) 7151–7162
7159
5.7. BPC-mediated amidation of carboxylic acids 14. General
procedure for the preparation of 1-substituted 5-[2-(acyla-
mino)ethyl]-1H-pyrazole-4-carboxamides 16
7.89; N; 16.66. C22H33N5O3 requires C, 63.59; H, 8.00; N, 16.85%]; Rf
(17% MeOH/CHCl3) 0.10; nmax (KBr) 3328, 2980, 1689, 1654, 1560,
1523, 1499, 1404, 1367, 1281, 1251, 1165, 1016, 976, 945, 764,
695 cmꢂ1
; dH (300 MHz, DMSO-d6) 1.30 (9H, s, t-Bu), 1.75 (2H, p,
Under argon, BPC (197 mg, 0.5 mmol) was added to a stirred
mixture of 14 (0.5 mmol), anhydrous acetonitrile (3 mL), and tri-
J¼7.2 Hz, CH2CH2CH2NMe2), 2.43 (6H, s, NMe2), 2.64 (2H, t,
J¼7.2 Hz, CH2CH2CH2NMe2), 2.98–3.15 (4H, m, CH2CH2), 3.27 (2H, q,
J¼6.9 Hz, CH2CH2CH2NMe2), 6.81 (1H, br s, NHBoc), 7.43–7.58 (5H,
m, Ph), 8.09 (1H, s, 3-H), 8.23 (1H, t, J¼5.7 Hz, NH); dC (75.5 MHz,
DMSO-d6) 26.1, 27.3, 29.0, 37.5, 40.1, 45.1, 57.1, 78.3, 116.6, 126.9,
129.5, 130.1, 132.4, 139.7, 144.0, 156.3, 163.6; m/z 415 (54, Mþ), 342
(32), 244 (28), 214 (51), 185 (36), 101 (25), 84 (23), 72 (25), 58
(100%); HRMS (EI): Mþ, found 415.2595, C22H33N5O3 requires
415.2583.
ethylamine (70
mL, 0.5 mmol) and the mixture was stirred at rt for
1 h. Then, the amine 11 (0.5 mmol) and triethylamine (70
mL,
0.5 mmol) were added,y and the mixture was at rt for 5 h. The
volatile components were evaporated in vacuo and the residue was
purified by FC (silica gel, EtOAc/hexanes). Fractions containing the
product were combined and evaporated in vacuo to give the title
compound 16.
The following compounds were prepared in this manner:
5.7.5. 5-[2-(tert-Butoxycarbonylamino)ethyl]-1-(4-methoxy-
phenyl)-1H-pyrazol-4-{N-[2-(ethoxycarbonyl)ethyl]
carboxamide} 16{4; 5}
5.7.1. 5-[2-(tert-Butoxycarbonylamino)ethyl]-1-methyl-1H-
pyrazole-4-(N-methylcarboxamide) 16{1; 1}
Prepared from 14{1} (135 mg, 0.5 mmol) and methylamine hy-
drochloride 11{1} (34 mg, 0.5 mmol); FC: EtOAc. Yield: 117 mg
(83%) of a white solid; mp 175–178 ꢀC; [Found: C, 55.38; H, 8.02; N,
19.91. C13H22N4O3 requires C, 55.30; H, 7.85; N; 19.84%]; Rf (EtOAc)
0.16; nmax (KBr) 3369, 3289, 2986,1684,1631,1575,1537,1444,1299,
Prepared from 14{4} (361 mg, 1 mmol) and ethyl b-alaninate
hydrochloride 11{5} (77 mg, 0.5 mmol); FC: EtOAc–hexanes, 1:1.
Yield: 120 mg (52%) of a yellow oil; Rf (50% EtOAc/hexanes) 0.19;
nmax (liquid film) 3335, 2978, 2937, 1730, 1712, 1639, 1611, 1565,
1515, 1464, 1391, 1366, 1293, 1250, 1171, 1026, 969, 837, 779 cmꢂ1
;
1278, 1169, 1111, 996, 877, 677 cmꢂ1
;
dH (300 MHz, DMSO-d6) 1.35
dH (300 MHz, DMSO-d6) 1.27 (3H, t, J¼6.3 Hz, CH3CH2), 1.37 (9H, s,
t-Bu), 2.64 (2H, t, J¼6.2 Hz, CH2COOEt), 3.08 (2H, t, J¼6.5 Hz,
CH2CH2NHBoc), 3.29 (2H, q, J¼6.2 Hz, CH2NHBoc), 3.66 (2H, q,
J¼6.2 Hz, CH2CH2COOEt), 3.85 (3H, s, OMe), 4.17 (2H, q, J¼7.2 Hz,
CH3CH2), 5.73 (1H, br t, NH), 6.98 and 7.33 (4H, 2d, 1:1, J¼8.8 Hz,
C6H4), 7.00 (1H, br s, NH), 7.83 (1H, s, 3-H); dC NMR (75.5 MHz,
CDCl3) 14.2, 25.0, 28.4, 34.2, 35.0, 40.2, 55.6, 60.8, 78.9, 114.5, 115.7,
127.8, 131.6, 138.2, 143.8, 156.2, 160.0, 164.0, 172.7; m/z 461 (61,
MHþ), 405 (24), 361 (100), 323 (25), 244 (18), 210 (67%); HRMS
(ESI): MHþ, 461.2404, C23H33N4O6 requires 461.2400.
(9H, s, t-Bu), 2.70 (3H, d, J¼4.6 Hz, MeNH), 2.99–3.17 (4H, m,
CH2CH2), 3.75 (3H, s, NMe), 6.96 (1H, br s, NHCH2), 7.80 (1H, s, 3-H),
7.92 (1H, q, J¼4.4 Hz, NHMe); dC (75.5 MHz, DMSO-d6) 25.2, 26.2,
29.1, 36.8, 40.1, 78.5, 115.4, 137.9, 143.3, 156.5, 164.2.
5.7.2. 5-[2-(tert-Butoxycarbonylamino)ethyl]-1-phenyl-1H-
pyrazole-4-(N-benzylcarboxamide) 16{2; 2}
Prepared from 14{2} (166 mg, 0.5 mmol) and benzylamine 11{2}
(54 mg, 0.5 mmol); FC: EtOAc–hexanes, 1:1. Yield: 175 mg (80%) of
a white solid; mp 105–107 ꢀC; [Found: C, 68.80; H, 6.99; N; 13.23.
C24H28N4O3 requires C, 68.55; H, 6.71; N, 13.32%]; Rf (50% EtOAc/
hexanes) 0.24; nmax (KBr) 3375, 3280, 1686, 1659, 1562, 1525, 1501,
5.8. Methyl 5-(2-benzamidoethyl)-1-phenyl-1H-pyrazole-
4-carboxylate (17)
1401,1288,1171, 764, 695 cmꢂ1
; dH (300 MHz, DMSO-d6) 1.37 (9H, s,
t-Bu), 3.16 (2H, t, J¼6.3 Hz, 10-CH2), 3.33 (2H, q, J¼6.3 Hz, 20-CH2),
4.62 (2H, d, J¼5.8 Hz, CH2Ph), 5.65 (1H, br s, NHBoc), 7.05 (1H, br s,
NHBn), 7.25–7.54 (10H, m, 2ꢁPh), 7.93 (1H, s, 3-H); dC (75.5 MHz,
DMSO-d6) 25.3, 28.1, 39.2, 41.9, 77.4, 115.5, 126.1, 126.6, 127.1, 128.2,
128.6, 129.2, 138.8, 138.9, 139.9, 143.4, 155.4, 162.6.
Benzoyl chloride (0.64 mL, 5.5 mmol) was added to a stirred
cold (0 ꢀC) solution of the amine hydrochloride 15{2} (1.13 g,
4 mmol) in a mixture of ethanol (20 mL) and Et3N (1.68 mL,
12 mmol) and the mixture was stirred at 0 ꢀC for 30 min and then at
rt for 2 h. Volatile components were evaporated in vacuo and the
residue was purified by FC on silica gel (EtOAc). Fractions con-
taining the product were combined and evaporated in vacuo to give
the title compound 17. Yield: 1.14 g (81%) of a white solid; mp 120–
123 ꢀC; Rf (EtOAc) 0.30; nmax (KBr) 3328, 2950, 1708, 1656, 1599,
1580, 1534, 1499, 1469, 1432,1388, 1295, 1243,1200,1107, 1091, 973,
5.7.3. 5-[2-(tert-Butoxycarbonylamino)ethyl]-1-phenyl-
4-[(piperidin-1-yl)carbonyl]-1H-pyrazole 16{2; 3}
Prepared from 14{2} (166 mg, 0.5 mmol) and piperidine 11{3}
(42 mg, 0.5 mmol); FC: EtOAc–hexanes, 1:1. Yield: 185 mg (93%) of
a white solid; mp 119–122 ꢀC; [Found: C, 66.36; H, 7.78; N; 14.02.
C22H30N4O3 requires C, 66.31; H, 7.59; N, 14.06%]; Rf (50% EtOAc/
hexanes) 0.15; nmax (KBr) 3293, 2980, 2932, 1694, 1608, 1524, 1450,
805, 779 cmꢂ1
;
dH (300 MHz, DMSO-d6) 3.18 (2H, t, J¼6.6 Hz, 10-
CH2), 3.43 (2H, q, J¼6.6 Hz, 20-CH2), 3.75 (3H, s, OMe), 7.38–7.54 and
7.67–7.73 (10H, 2m, 8:2, 2ꢁPh), 8.02 (1H, s, 3-H), 8.48 (1H, t,
J¼5.7 Hz, NH); dC (75.5 MHz, CDCl3) 26.0, 39.0, 51.9, 113.1, 127.0,
128.0, 128.9,129.8,130.1,131.9,135.1,139.4,142.2,146.1,164.1,166.9;
m/z 350 (100, MHþ), 318 (73%); HRMS (ESI): MHþ, found 350.1512,
C20H20N3O3 requires 350.1505.
1282, 1177, 1052, 977, 772, 700 cmꢂ1
; dH (300 MHz, DMSO-d6) 1.31
(9H, s, t-Bu), 1.49–1.69 (6H, m, 3ꢁCH2 of piperidine), 2.84–3.03 (4H,
m, 2ꢁCH2), 3.50–3.59 (4H, m, 2ꢁCH2), 6.86 (1H, br s, NHBoc), 7.46–
7.59 (5H, m, Ph), 7.70 (1H, s, 3-H); dC (75.5 MHz, DMSO-d6) 24.1,
25.1, 25.6, 25.7, 28.1, 39.5, 77.5, 116.2, 125.7, 128.5, 129.2, 138.2,
138.9, 141.3, 155.3, 163.3.
5.9. Acidic removal of the Boc group from tert-butyl carba-
mates 16. General procedure for the preparation
of 1-substituted 5-(2-aminoethyl)-1H-pyrazole-
4-carboxamides 18
5.7.4. 5-[2-(tert-Butoxycarbonylamino)ethyl]-1-phenyl-1H-pyra-
zole-4-[N-(3-dimethylamino-1-prop-1-yl)carboxamide] 16{2; 4}
Prepared from 14{2} (166 mg, 0.5 mmol) and 3-dimethylamino-
1-pyropylamine 11{4} (51 mg, 0.5 mmol); FC: CHCl3–MeOH, 5:1,
followed by filtration through CeliteÒ, and evaporation. Yield:
82 mg (40%) of a white solid; mp 116–119 ꢀC; [Found: 63.37; H,
HCl–EtOAc (2 M, 3 mL, 6 mmol) was added to a stirred mixture
of 16 (1 mmol) and EtOAc (3 mL) at 0 ꢀC and the mixture was stirred
at 0 ꢀC for 30 min and then at rt for 2 h. The precipitate was col-
lected by filtration, washed with EtOAc (2ꢁ5 mL), and dried in
vacuo at rt over NaOH pellets for 12 h to give the title compound 18.
The following compounds were prepared in this manner:
y
2 Equiv of Et3N (140 mL, 1 mmol) were added, if amine hydrochloride 11 was
used.

7160
D. Kralj et al. / Tetrahedron 65 (2009) 7151–7162
5.9.1. 5-(2-Aminoethyl)-1-methyl-1H-pyrazole-4-(N-methylcarbo-
xamide) hydrochloride 18{1; 1}
q, J¼7.1 Hz, CH2CH3), 7.05–7.15 and 7.36–7.46 (4H, 2m, 1:1, C6H4),
8.07 (3H, s, NHþ3 ), 8.14 (1H, s, 3-H), 8.49 (1H, t, J¼5.5 Hz, NH); dC
Prepared from 16{1; 1} (282 mg,1 mmol). Yield: 147 mg (67%) of
a white solid; mp 155–161 ꢀC; [Found: C, 39.72; H, 6.77; N; 22.65.
C8H14N4O$1.7HCl requires C, 39.35; H, 6.48; N, 22.94%]; Rf (EtOAc)
0.0; nmax (KBr) 3362, 3291, 3220, 1649, 1575, 1475, 1449, 1415, 1350,
(75.5 MHz, DMSO-d6): d 14.2, 23.5, 34.0, 35.0, 37.4, 55.6, 60.0, 114.6,
115.6, 127.7, 131.3, 138.8, 141.3, 159.5, 162.9, 171.4. m/z 361 (100,
MHþ), 244 (96%); HRMS (ESI): MHþ, found 361.1873, C18H25N4O4
requires 361.1876.
1292, 1195, 1103, 888, 818, 537 cmꢂ1
; dH (300 MHz, DMSO-d6) 2.72
(3H, br s, NHMe), 2.96–3.07 (2H, m, 20-CH2), 3.25 (2H, t, J¼7.5 Hz, 10-
CH2), 3.82 (3H, s, NMe), 7.88 (1H, s, 3-H), 8.18 (3H, br s, NHþ3 ), NH
exchanged; dC (75.5 MHz, DMSO-d6) 22.5, 25.5, 36.4, 37.6, 115.2,
137.4, 140.4, 163.4, m/z 183 (56, MHþ), 166 (20), 158 (62), 152 (100),
141 (49%); HRMS (ESI): MHþ, found 183.1249, C8H15N4O requires
183.1246.
5.10. 5-[2-(Benzoylamino)ethyl]-1-phenyl-1H-pyrazole-4-
carboxylic acid (19)
A mixture of 17 (1.05 g, 3 mmol), methanol (10 mL), and 2 M aq
NaOH (5 mL, 10 mmol) was stirred at 50 ꢀC for 12 h. Methanol was
removed by careful evaporation in vacuo (100 mbar, 40 ꢀC). The
residual aqueous solution was cooled to 0 ꢀC (ice-bath) and acidi-
fied, first with 6 M hydrochloric acid (0.45 mL, 2.7 mmol) and then
with 1 M aq NaHSO4 (1 mL, 1 mmol). The precipitate was collected
by filtration, and washed with cold water (0 ꢀC, 5 mL) to give the
title compound 19. Yield: 0.888 g (88%) of a white solid; mp 180–
185 ꢀC; Rf (EtOAc) 0.28; nmax (KBr) 3334, 3054, 2934, 1672, 1659,
5.9.2. 5-(2-Aminoethyl)-1-phenyl-1H-pyrazole-4-(N-benzyl-
carboxamide) hydrochloride 18{2; 2}
Prepared from 16{2; 2} (420 mg, 1 mmol). Yield: 343 mg (96%)
of a white solid; mp 143–147 ꢀC; [Found: C, 59.17; H, 5.87; N; 14.44.
C19H20N4O$1.8HCl requires C, 59.12; H, 5.69; N, 14.50%]; Rf (EtOAc)
0.0; nmax (KBr) 3269, 3030, 1630, 1569, 1498, 1294, 770, 697 cmꢂ1
;
1546, 1473, 1434, 1291, 1253, 1105, 969, 776, 696 cmꢂ1
; dH
dH (300 MHz, DMSO-d6) 2.93–3.06 (2H, m, 20-CH2), 3.14–3.22 (2H,
m, 10-CH2), 4.48 (2H, d, J¼6.0 Hz, CH2Ph), 7.21–7.38 (5H, m, Ph),
7.47–7.63 (5H, m, Ph), 8.08 (3H, br s, NHþ3 ), 8.28 (1H, s, 3-H), 8.99
(1H, t, J¼6.0 Hz, NH); dC (75.5 MHz, DMSO-d6) 24.2, 38.3, 42.9,116.8,
127.0,127.6, 128.1,129.1,129.8, 130.4, 139.2, 140.1, 140.6, 142.1, 163.5;
m/z 321 (100, MHþ), 214 (45%); HRMS (ESI): MHþ, found 321.1718,
C19H21N4O requires 321.1715.
(300 MHz, DMSO-d6) 3.19 (2H, t, J¼6.6 Hz, 10-CH2), 3.45 (2H, q,
J¼6.6 Hz, 20-CH2), 7.38–7.53 and 7.68–7.74 (10H, 2m, 8:2, 2ꢁPh),
7.97 (1H, s, 3-H), 8.49 (1H, t, J¼5.6 Hz, NH), 12.47 (1H, br s, COOH);
dC (75.5 MHz, DMSO-d6) 25.0, 38.4, 113.2, 126.2, 127.2, 128.1, 128.8,
129.2, 131.0, 134.3, 138.7, 141.7, 145.1, 164.5, 166.1; m/z 336 (68,
MHþ), 318 (100%); HRMS (ESI): MHþ, found 336.1339, C19H18N3O3
requires 336.1348.
5.9.3. 5-(2-Aminoethyl)-1-phenyl-4-[(piperidin-1-yl)carbonyl]-
1H-pyrazole hydrochloride 18{2; 3}
5.11. General procedures for the preparation of 1-substituted
5-[2-(acylamino)ethyl]-1H-pyrazole-4-carboxamides 20
Prepared from 16{2; 3} (398 mg,1 mmol). Yield: 303 mg (91%) of
a white solid; mp 127–132 ꢀC; [Found: C, 59.39; H, 7.42; N; 15.67.
C17H22N4O$HCl requires: C, 60.98; H, 6.92; N, 16.73%]; Rf (EtOAc)
0.0; nmax (KBr) 3256, 3029, 1630, 1569, 1498, 1454, 1412, 1294, 770,
Procedure A. Acylation of amine 18{1; 1} with acetyl chloride 12{1}
Acetyl chloride 12{1} (50
cold (0 ꢀC) solution of the amine 18{1; 1} (110 mg, 0.5 mmol) in
a mixture of ethanol (4 mL) and Et3N (210 L, 1.5 mmol) and the
mL, 0.7 mmol) was added to a stirred
697 cmꢂ1
;
dH (300 MHz, DMSO-d6) 1.49–1.70 (6H, m, 3ꢁCH2 of
m
piperidine), 2.80–2.92 (2H, m, 20-CH2), 3.02–3.11 (2H, m, 10-CH2),
3.53–3.63 (4H, m, 3ꢁCH2 of piperidine), 7.50–7.62 (5H, m, Ph), 7.79
(1H, s, 3-H), 8.14 (3H, br s, NHþ3 ); dC (75.5 MHz, DMSO-d6) 23.9, 24.9,
26.5, 26.7, 37.9, 117.2, 126.7, 129.7, 130.4, 139.3, 139.4, 140.4, 164.0;
m/z 299 (50, MHþ), 269 (86), 185 (100%); HRMS (ESI): MHþ, found
299.1872, C17H23N4O requires 299.1872.
mixture was stirred at 0 ꢀC for 30 min and then at rt for 2 h. The
volatile components were evaporated in vacuo and the residue was
purified by FC on silica gel (EtOAc–EtOH, 20:1). Fractions containing
the product were combined and evaporated in vacuo to give the title
compound 20. Compound 20{1; 1; 1} was prepared in this manner.
Procedure B. BPC-mediated acylations of amines 18 with carboxylic
acids 13{2,3}
Under argon, BPC (131.4 mg, 0.33 mmol) was added to a solution
of carboxylic acid 13 (0.33 mmol) in a mixture of DMF (2 mL) and
5.9.4. 5-(2-Aminoethyl)-1-phenyl-1H-pyrazole-4-{N-[3-(dimethyl-
amino)prop-1-yl]carboxamide} dihydrochloride 18{2; 4}
Prepared from 16{2; 4} (415 mg,1 mmol). Yield: 300 mg (85%) of
a white solid; mp 156–159 ꢀC; [Found: C, 52.26; H, 6.96; N; 17.69.
C17H25N5O$2HCl requires C, 52.58; H, 7.01; N, 18.03%]; Rf (EtOAc)
0.0; nmax (KBr) 2965, 1630, 1570, 1500, 1411, 1296, 1159,
Et3N (47
mL, 0.33 mmol) and the mixture was stirred at rt for 1 h.
Then, amine hydrochloride 18 (0.33 mmol) and Et3N (94
m
L,
0.66 mmol) were added and stirring at rt was continued for 18 h.
The volatile components were evaporated in vacuo and the residue
was purified by FC on silica gel (EtOAc–hexanes). Fractions con-
taining the product were combined and evaporated in vacuo to give
the title compound 20. Compounds 20{2; 2; 2}, 20{2; 3; 2}, 20{2; 4;
2}, and 20{4; 5; 3}, were prepared in this manner.
772, 698 cmꢂ1
; dH (300 MHz, DMSO-d6) 1.87–2.00 (2H, m,
CH2CH2CH2NMe2), 2.73 and 2.75 (6H, 2s, 1:1, NMe2), 2.95–3.22 (6H,
m, 3ꢁCH2), 3.33 (2H, q, J¼6.2 Hz, CH2CH2NHþ3 ), 7.46–7.64 (5H, m,
Ph), 8.15 (3H, br s, NHþ3 ), 8.27 (1H, s, 3-H), 8.64 (1H, t, J¼5.6 Hz, NH),
Me2NHþ exchanged; dC (75.5 MHz, DMSO-d6) 23.3, 24.3, 35.8, 37.4,
41.9, 56.0, 116.0, 126.1, 129.0, 129.5, 138.3, 139.4, 141.0, 162.8; m/z
315 (15, Mþ), 286 (62), 244 (87), 214 (55), 185 (50), 77 (40), 72 (59),
58 (100%); HRMS (EI): Mþ, found 315.2061, C17H25N5O requires
315.2059.
Procedure C. BPC-mediated amidations of carboxylic acid 19
Under argon, BPC (197 mg, 0.5 mmol) was added to a stirred
mixture of 19 (168 mg, 0.5 mmol), anhydrous acetonitrile (3 mL),
and Et3N (70 mL, 0.5 mmol) and the mixture was stirred at rt for
5.9.5. 5-(2-Aminoethyl)-1-(4-methoxyphenyl)-1H-pyrazole-4-{N-
[2-(ethoxycarbonyl)ethyl]carboxamide} hydrochloride 18{4; 5}
Prepared from 16{4; 5} (460 mg,1 mmol). Yield: 338 mg (85%) of
a white solid; mp 135–145 ꢀC; Rf (EtOAc) 0.0; nmax (KBr) 3221, 3049,
1 h. Then, the amine 11 (0.5 mmol) and Et3N (70 mL, 0.5 mmol)
were added,z and the mixture was at rt for 5 h. The volatile
components were evaporated in vacuo and the residue was pu-
rified by FC (silica gel, EtOAc–hexanes). Fractions containing the
2986, 1734, 1610, 1574, 1515, 1268, 1188, 1023, 841 cmꢂ1
; dH
(300 MHz, DMSO-d6) 1.19 (3H, t, J¼7.1 Hz, CH2CH3), 2.58 (2H, t,
J¼7.0 Hz, CH2COOEt), 2.89–3.03 (2H, m, 20-CH2), 3.05–3.16 (2H, m,
10-CH2), 3.48 (2H, q, J¼6.8 Hz, CH2NH), 3.83 (3H, s, OMe), 4.08 (2H,
z
2 Equiv of Et3N (140 mL, 1 mmol) were added, if amine hydrochloride 11 was
used.

D. Kralj et al. / Tetrahedron 65 (2009) 7151–7162
7161
product were combined and evaporated in vacuo to give the title
compound 20. Compounds 20{2; 6–8; 2} were prepared in this
manner.
5.11.5. 5-(3,6,9-Trioxo-1-phenyl-2-oxa-4,7,10-triazadodecan-12-yl)-1-
(4-methoxyphenyl)-1H-pyrazole-4-{N-[2-(ethoxycarbonyl)ethyl]carb-
oxamide} 20{4; 5; 3}. Prepared from 18{4; 5} (132 mg, 0.33 mmol)
and Z-glycylglycine (89 mg, 0.33 mmol); Procedure B; FC: EtOAc–
EtOH, first 20:1, then 5:1. Yield: 129 mg (71%) of a white solid; mp
70–75 ꢀC; Rf (5% EtOH/EtOAc) 0.09; nmax (KBr) 3312, 3068, 2938,
1726, 1654, 1550, 1516, 1455, 1409, 1373, 1252, 1183, 1045, 1025, 965,
The following compounds were prepared in this manner:
5.11.1. 5-(2-Acetamidoethyl)-1-phenyl-1H-pyrazole-4-(N-methylcarb-
oxamide) 20{1; 1; 1}. Prepared from 18{1; 1} (110 mg, 0.5 mmol)
and acetyl chloride 12{1} (0.7 mmol); Procedure A. Yield: 73 mg
(65%) of a white solid; mp 153–156 ꢀC; [Found: C, 53.30; H, 7.35;
N; 24.87. C10H16N4O2 requires C, 53.56; H, 7.19; N, 24.98%]; Rf (5%
EtOH/EtOAc) 0.18; nmax (KBr) 3274, 3101, 2994, 2951, 1663, 1644,
1569, 1528, 1492, 1455, 1408, 1359, 1299, 1264, 1245, 1100, 986,
838, 698 cmꢂ1
;
dH (300 MHz, DMSO-d6) 1.18 (3H, t, J¼7.1 Hz,
CH2CH3), 2.56 and 2.99 (4H, 2 t, 1:1, J¼7.0, 7.0 Hz, 2ꢁCH2), 3.21 (2H,
q, J¼6.7 Hz, CH2NH), 3.40–3.50 (2H, m, CH2), 3.58 (2H, d, J¼5.7 Hz,
CH2 of GlyGly), 3.65 (2H, d, J¼6.0 Hz, CH2 of GlyGly), 3.82 (3H, s,
OMe), 4.07 (2H, q, J¼7.1 Hz, CH2CH3), 5.03 (2H, s, CH2Ph), 7.02–7.09
(2H, m, 2H of C6H4), 7.26–7.40 (7H, m, 2H of C6H4, 3H of Ph, 2ꢁNH),
7.45 (1H, br t, J¼5.9 Hz, NH), 7.92–8.02 (2H, m, 2H of Ph), 8.04 (1H, s,
3-H), 8.23 (1H, t, J¼5.5 Hz, NH); dH (300 MHz, CDCl3) 1.23 (3H, t,
J¼7.1 Hz, CH3CH2), 2.57 (2H, t, J¼6.0 Hz, CH2), 3.02 (2H, t, J¼6.2 Hz,
CH2), 3.30 (2H, q, J¼5.1 Hz, CH2NH), 3.60 (2H, q, J¼6.2 Hz, CH2NH),
3.80 (3H, s, OMe), 3.81 (2H, br s, CH2 of GlyGly), 3.89 (2H, d,
J¼5.2 Hz, CH2 of GlyGly), 4.12 (2H, q, J¼7.1 Hz, CH2CH3), 5.07 (2H, s,
CH2Ph), 6.26 (1H, t, J¼5.6 Hz, NH), 6.94 (2H, d, J¼8.9 Hz, 2H of C6H4),
7.20–7.36 (9H, m, Ph, 2H of C6H4, 2ꢁNH), 7.81 (1H, s, 3-H), 8.17 (1H,
br s, NH); dC (75.5 MHz, CDCl3) 14.5, 24.2, 29.3, 32.2, 34.4, 35.6, 39.9,
42.9, 44.6, 55.9, 67.4, 114.9, 116.4, 128.1, 128.4, 128.5, 128.8, 131.6,
136.6, 138.6, 143.7, 157.2, 160.5, 164.8, 169.6, 172.9; m/z¼609 (100%,
MHþ); HRMS (ESI): MHþ, found 609.2670, C30H37N6O8 requires
609.2673.
957, 885, 814, 777, 605 cmꢂ1
; dH (300 MHz, DMSO-d6) 1.77 (3H, s,
MeCO), 2.71 (3H, d, J¼4.4 Hz, MeNH), 3.06 (2H, t, J¼6.6 Hz, 10-CH2),
3.21 (2H, q, J¼6.6 Hz, 20-CH2), 3.75 (3H, s, NMe), 7.80 (1H, s, 3-H),
7.94 (1H, q, J¼4.4 Hz, NHMe), 8.10 (1H, t, J¼5.2 Hz, NHCH2); dC
(75.5 MHz, DMSO-d6) 23.4, 25.0, 26.3, 36.8, 38.9, 115.5, 138.0,
143.2, 164.3, 170.2.
5.11.2. 5-(2-Benzamidoethyl)-1-phenyl-1H-pyrazole-4-(N-benzylcar-
boxamide) 20{2; 2; 2}. Prepared from 18{2; 2} (119 mg, 0.33 mmol)
and benzoic acid 13{2} (40 mg, 0.33 mmol); Procedure B; FC:
EtOAc–hexanes, 1:1. Yield: 110 mg (78%) of a white solid; mp 107–
109 ꢀC; [Found: C, 73.28; H, 5.75; N; 13.23. C26H24N4O2 requires C,
73.56; H, 5.70; N, 13.20%]; Rf (50% EtOAc/hexanes) 0.21; nmax (KBr)
3303, 3062, 2930, 1667, 1636, 1565, 1452, 1410, 1293, 1096, 952, 768,
696 cmꢂ1
;
dH (300 MHz, DMSO-d6) 3.22 (2H, t, J¼6.8 Hz, 10-CH2),
3.44 (2H, q, J¼6.8 Hz, 20-CH2), 4.48 (2H, d, J¼6.0 Hz, CH2Ph), 7.21–
7.30 (1H, m,1H of Ph), 7.32–7.38 (4H, m, 4H of Ph), 7.38–7.43 (2H, m,
2H of Ph), 7.43–7.52 (6H, m, 6H of Ph), 7.70–7.75 (2H, m, 2H of Ph),
8.19 (1H, s, 3-H), 8.65 (1H, t, J¼5.1 Hz, NH), 8.78 (1H, t, J¼6.0 Hz,
NH); dC (75.5 MHz, DMSO-d6) 24.5, 42.0, 54.9, 115.6, 126.1, 126.7,
127.1, 127.2, 128.1, 128.3, 128.7, 129.2, 131.0, 134.2, 138.7, 139.0, 139.8,
143.6, 162.9, 166.0.
5.11.6. 5-(2-Benzamidoethyl)-1-phenyl-1H-pyrazole-4-{N-(pyridin-2-
yl)methyl]carboxamide} 20{2; 6; 2}. Prepared from 19 (168 mg,
0.5 mmol) and 2-picolylamine 11{6} (54 mg, 0.5 mmol); Procedure
C; FC: EtOAc. Yield: 195 mg (91%) of a white solid; mp 114–118 ꢀC; Rf
(EtOAc) 0.14; nmax (KBr) 3321, 3296, 3056, 2951, 1648, 1633, 1590,
1566, 1527, 1472, 1361, 1295, 1206, 1155, 1105, 1077, 990, 965, 774,
755, 646 cmꢂ1
;
dH (300 MHz, DMSO-d6) 3.21 (2H, t, J¼6.7 Hz, 10-
CH2), 3.43 (2H, q, J¼6.7 Hz, 20-CH2), 4.56 (2H, d, J¼6.0 Hz, NHCH2Py),
7.27 (1H, ddd, J¼1.0, 4.8, 7.5 Hz, 500-H), 7.32–7.41 (3H, m, 300-H, 2H of
Ph), 7.45–7.51 (6H, m, 6H of Ph), 7.69–7.79 (3H, m, 400-H and 2H of
Ph), 8.22 (1H, s, 3-H), 8.52 (1H, ddd, J¼1.0,1.9, 4.8 Hz, 600-H), 8.62 (1H,
t, J¼5.1 Hz, NH), 8.87 (1H, t, J¼6.0 Hz, NH); dC (75.5 MHz, CDCl3) 23.3,
40.4, 44.2, 115.8, 121.5, 122.1, 126.1, 127.0, 127.9, 129.1, 129.2, 130.8,
133.8, 136.7, 138.2, 138.3, 143.7, 148.7, 156.6, 164.3, 167.5; m/z¼426
(100%, MHþ); HRMS (ESI): MHþ, found 426.1950, C25H24N5O2 re-
quires 426.1930.
5.11.3. 5-(2-Benzamidoethyl)-1-phenyl-4-[N-(piperidin-1-yl)carbonyl]-
1H-pyrazole 20{2; 3; 2}. Prepared from 18{2; 3} (119 mg,
0.33 mmol) and benzoic acid 13{2} (40 mg, 0.33 mmol); Pro-
cedure B; FC: EtOAc–hexanes, 1:1. Yield: 120 mg (89%) of a white
solid; mp 165–167 ꢀC; [Found: C, 71.68; H, 6.83; N; 13.97.
C24H26N4O2 requires C, C, 71.62; H, 6.51; N, 13.92%]; Rf (50%
EtOAc/hexanes) 0.20; nmax (KBr) 3228, 3056, 2934, 2850, 1654,
1588, 1545, 1440, 1406, 1359, 1340, 130, 1270, 976, 956, 761, 696,
660 cmꢂ1
;
dH (300 MHz, DMSO-d6) 1.44–1.64 (6H, m, 3ꢁCH2 of
piperidine), 3.06 (2H, t, J¼6.9 Hz, 10-CH2), 3.27–3.35 (2H, m, 20-
CH2), 3.45–3.54 (4H, m, 2ꢁCH2 of piperidine), 7.38–7.57 (8H, m,
8H of Ph), 7.72 (1H, s, 3-H), 7.73–7.80 (2H, m, 2H of Ph), 8.64 (1H,
t, J¼5.2 Hz, NH); dC (75.5 MHz, DMSO-d6) 24.1, 24.4, 25.7, 25.8,
38.4, 116.3, 125.8, 127.1, 128.1, 128.5, 129.2, 131.0, 134.1, 138.2,
138.9, 141.6, 163.3, 165.9.
5.11.7. 5-(2-Benzamidoethyl)-1-phenyl-1H-pyrazole-4-{N-[3-(2-oxo-
pyrrolidin-1-yl)prop-1-yl]carboxamide} 20{2; 7; 2}. Prepared from
19 (168 mg, 0.5 mmol) and 1-(3-aminoprop-1-yl)pyrrolidin-2-one
11{7} (71 mg, 0.5 mmol); Procedure C; FC: EtOAc–EtOH, 20:1. Yield:
206 mg (90%) of a yellow oil; Rf (5% EtOH/EtOAc) 0.16; nmax (liquid
film) 3305, 2936, 1650, 1567, 1536, 1515, 1501, 1465, 1434, 1293,
1014, 995, 981, 754 cmꢂ1
. dH (300 MHz, DMSO-d6) 1.68 (2H, p,
5.11.4. 5-(2-Benzamidoethyl)-1-phenyl-1H-pyrazole-4-{N-[3-(dimethyl-
amino)prop-1-yl]carboxamide} 20{2; 4; 2}. Prepared from 18{2; 4}
(119 mg, 0.33 mmol) and benzoic acid 13{2} (40 mg, 0.33 mmol);
Procedure B; FC: CHCl3–MeOH, 5:1, followed by filtration through
CeliteÒ. Yield: 66 mg (52%) of a yellowish oil; Rf (17% MeOH/
CHCl3) 0.14; nmax (liquid film) 3284, 2946, 1638, 1599, 1567, 1539,
J¼7.1 Hz, CH2CH2CH2), 1.85–1.96 (2H, m, 400-CH2), 2.21 (2H, t,
J¼8.1 Hz, 300-CH2), 3.15–3.45 (10H, m, 500-CH2, CH2CH2CH2, and
CH2CH2), 7.36–7.51 (8H, m, 8H of Ph), 7.70–7.75 (2H, m, 2H of
Ph),8.08 (1H, s, 3-H), 8.18 (1H, t, J¼5.8 Hz, NH), 8.63 (1H, t, J¼5.2 Hz,
NH); dC (75.5 MHz, CDCl3) 17.7, 23.2, 26.2, 26.3, 30.7, 35.3, 39.5, 40.6,
47.3, 126.3, 127.1, 127.9, 129.1, 129.2, 130.9, 134.0, 138.4, 138.5, 143.4,
164.2, 167.6, 176.1; m/z¼460 (100%, MHþ); HRMS (ESI): MHþ, found
460.2368, C26H30N5O3 requires 460.2349.
1499, 1408, 1296, 1158, 1005, 981, 768, 695 cmꢂ1
; dH (300 MHz,
DMSO-d6) 1.63–1.74 (2H, m, CH2CH2CH2), 2.25 (6H, s, NMe2), 2.40
(2H, t, J¼7.1 Hz, CH2), 3.16–3.32 (4H, m, 2ꢁCH2), 3.38–3.47 (2H,
m, CH2), 7.37–7.54 (8H, m, 8H of Ph), 7.70–7.78 (2H, m, 2H of Ph),
8.10 (1H, s, 3-H), 8.28 (1H, t, J¼5.1 Hz, NH), 8.67 (1H, br t, NH); dC
(75.5 MHz, DMSO-d6) 24.3, 24.5, 35.7, 28.9, 54.4, 59.7, 115.6, 126.1,
127.1, 128.1, 128.6, 129.2, 131.0, 134.2, 138.7, 139.2, 143.3, 163.1,
166.0; m/z¼420 (100, MHþ), 375 (20%); HRMS (ESI): MHþ, found
420.2417, C24H30N5O2 requires 420.2400.
5.11.8. 5-(2-Benzamidoethyl)-4-{N-3-[(N,N-diethylcarboxamido)-
piperidin-1-yl]carbonyl}-1-phenyl-1H-pyrazole 20{2; 8; 2}. Prepared
from 19 (168 mg, 0.5 mmol) and N,N-diethylnipecotamide 11{8}
(92 mg, 0.5 mmol); Procedure C; FC: EtOAc. Yield: 245 mg (97%) of
a yellow oil; Rf (EtOAc) 0.21; nmax (liquid film) 3448, 2936, 1618,1551,
1501, 1438, 1402, 1307, 1264, 1085, 982, 766, 697 cmꢂ1
; dH (300 MHz,

7162
D. Kralj et al. / Tetrahedron 65 (2009) 7151–7162
DMSO-d6) 1.04 (6H, t, J¼7.0 Hz, 2ꢁCH3CH2),1.42–1.86 (4H, m, 400-CH2
and 500-CH2), 2.65–2.77 (1H, m, 300-H), 3.04 (2H, t, J¼7.0 Hz, 10-CH2),
3.24–3.37 (4H, m, 20-CH2, 600-CH2), 3.43 (4H, q, J¼7.0 Hz, 2ꢁCH2CH3),
4.18–4.53 (2H, m, 200-CH2), 7.36–7.55 (8H, m, 8H of Ph), 7.70–7.78 (2H,
m, 2H of Ph), 7.74 (1H, s, 3-H), 8.62 (1H, t, J¼5.2 Hz, NH); dC
(75.5 MHz, CDCl3) 12.8, 14.7, 18.1, 23.3, 39.3, 40.1, 41.7, 57.7, 57.8,
126.0, 127.1, 127.9, 129.1, 129.3, 130.9, 133.8, 138.0, 138.1, 138.4, 143.1,
164.6, 167.5, 171.9. m/z¼502 (100%, MHþ); HRMS (ESI): MHþ, found
502.2822, C29H36N5O3 requires 502.2818.
Kimura, R.; Matsumoto, S.-i.; Furuichi, K.; Matsuda, A.; Shuto, S. J. Med. Chem.
2003, 46, 1980–1989; (c) Liebscher, J.; Patzel, M. Synlett 1994, 471–478.
6. (a) Paillet-Loilier, M.; Fabis, F.; Lepailleur, A.; Bureau, R.; Butt-Gueulle, S.;
Dauphin, F.; Lesnard, A.; Delarue, C.; Vaudryb, H.; Rault, S. Bioorg. Med. Chem.
Lett. 2007, 17, 3018–3022; (b) Pullagurla, M.; Dukat, M.; Roth, B. L.; Setola, V.;
Glennon, R. A. Med. Chem. Res. 2005, 14, 1–18.
7. For a review see: (a) Elguero, J. In Pyrazoles; Katritzky, A. R., Rees, C. W., Scriven,
E. F. V., Eds.; Comprehensive Heterocyclic Chemistry II; Elsevier Science: Ox-
ford, 1996; Vol. 3, pp 1–75 and references cited therein; (b) Stanovnik, B.; Svete,
J. In Pyrazoles; Neier, R., Ed.; Science of Synthesis, Houben-Weyl Methods of
Organic Transformations; Georg Thieme: Stuttgart, 2002; Vol. 12, pp 15–225
and references cited therein.
8. For a review see: (a) Stanovnik, B.; Svete, J. Chem. Rev. 2004, 104, 2433–2480;
(b) Stanovnik, B.; Svete, J. Synlett 2000, 1077–1091; (c) Stanovnik, B.; Svete, J.
Targets in Heterocyclic Systems; 2000; Vol. 4, 105–137.
5.12. X-ray structure analysis for compound 7{10}
9. For a review see: (a) Svete, J. ARKIVOC 2006, vii, 35–46; (b) Stanovnik, B.; Svete,
ˇ
ˇ
J. Mini-Rev. Org. Chem. 2005, 2, 211–224; (c) Pirc, S.; Bevk, D.; Jakse, R.; Recnik,
Single crystal X-ray diffraction data of compound 7{10} were
collected at rt on a Nonius Kappa CCD diffractometer using the
Nonius Collect Software.24 DENZO and SCALEPACK25 were used for
indexing and scaling of the data and the structure was solved by
means of SIR97.26 Refinement and plotting were done using
Xtal3.427 program package. Crystal structure was refined on F
values using the full-matrix least-squares procedure. The non-hy-
drogen atoms were refined anisotropically in all cases, while the
positions of hydrogen atoms were geometrically calculated and
their positional and isotropic atomic displacement parameters
were not refined. Absorption correction was not necessary.
Regina28 weighting scheme was used in all cases.
ˇ
ˇ
S.; Golic, L.; Golobic, A.; Meden, A.; Stanovnik, B.; Svete, J. Synthesis 2005, 2969–
2988; (d) Svete, J. Monatsh. Chem. 2004, 135, 629–641; (e) Svete, J. J. Heterocycl.
Chem. 2002, 39, 437–454.
ˇ
10. Some recent publications: (a) Groselj, U.; Meden, A.; Stanovnik, B.; Svete, J.
ˇ
Tetrahedron: Asymmetry 2008, 19, 330–342; (b) Wagger, J.; Groselj, U.; Meden,
A.; Svete, J.; Stanovnik, B. Tetrahedron 2008, 64, 2801–2815; (c) Recnik, S.;
Meden, A.; Stanovnik, B.; Svete, J. Aust. J. Chem. 2008, 61, 107–114; (d) Kralj, D.;
Groselj, U.; Meden, A.; Dahmann, G.; Stanovnik, B.; Svete, J. Tetrahedron 2007,
63, 11213–11222; (e) Groselj, U.; Meden, A.; Stanovnik, B.; Svete, J. Tetrahedron:
Asymmetry 2007, 18, 2746–2757; (f) Groselj, U.; Meden, A.; Stanovnik, B.; Svete, J.
Tetrahedron: Asymmetry 2007, 18, 2365–2376; (g) Wagger, J.; Golic Grdadolnik, S.;
Groselj, U.; Meden, A.; Stanovnik, B.; Svete, J. Tetrahedron: Asymmetry 2007, 18,
ˇ
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ˇ
ˇ
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464–475.
ˇ
11. (a) Kralj, D.; Novak, A.; Dahmann, G.; Groselj, U.; Meden, A.; Svete, J. J. Comb.
ꢀ
ꢀ
ˇ ˇ
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Chem. 2008, 10, 664–670; (b) Malavasic, C.; Brulc, B.; Cebasek, P.; Dahmann, G.;
ˇ
Heine, N.; Bevk, D.; Groselj, U.; Meden, A.; Stanovnik, B.; Svete, J. J. Comb. Chem.
Crystallographic data (excluding structure factors) for com-
pound 7{10} have been deposited with the Cambridge Crystallo-
graphic Data Centre as supplementary publication number CCDC
716590. Copy of the data can be obtained, free of charge, on ap-
plication to CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK [fax:
þ44(0) 1223 336033 or e-mail: deposit@ccdc.cam.ac.uk.
ꢀ
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2007, 9, 219–229; (c) Cebasek, P.; Bevk, D.; Pirc, S.; Stanovnik, B.; Svete, J.
J. Comb. Chem. 2006, 8, 95–102; (d) Cebasek, P.; Wagger, J.; Bevk, D.; Jakse, R.;
Svete, J.; Stanovnik, B. J. Comb. Chem. 2004, 6, 356–362; (e) Pirc, S.; Bevk, D.;
Golic Grdadolnik, S.; Svete, J. ARKIVOC 2003, xiv, 37–48; (f) Westman, J.; Lundin,
R. Synthesis 2003, 1025–1030.
ꢀ
ˇ
ˇ
ˇ
ˇ
12. (a) Pezdirc, L.; Jovanovski, V.; Bevk, D.; Jakse, R.; Pirc, S.; Meden, A.; Stanovnik,
B.; Svete, J. Tetrahedron 2005, 61, 3977–3990; (b) Pezdirc, L.; Cerkovnik, J.; Pirc,
S.; Stanovnik, B.; Svete, J. Tetrahedron 2007, 63, 991–999; (c) Pezdirc, L.; Groselj,
ˇ
U.; Meden, A.; Stanovnik, B.; Svete, J. Tetrahedron Lett. 2007, 48, 5205–5208; (d)
Acknowledgements
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Pezdirc, L.; Groselj, U.; Meden, A.; Stanovnik, B.; Svete, J. J. Comb. Chem. 2007, 9,
ˇ
717–723; (e) Pezdirc, L.; Groselj, U.; Meden, A.; Stanovnik, B.; Svete, J. J. Het-
erocycl. Chem. 2008, 45, 181–188.
We acknowledge with thanks the financial support from
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13. (a) Groselj, U.; Bevk, D.; Jakse, R.; Recnik, S.; Meden, A.; Stanovnik, B.; Svete, J.
Boehringer-Ingelheim Pharma GmbH
Germany).
& Co. KG (Biberach,
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Tetrahedron 2005, 61, 3991–3998; (b) Groselj, U.; Recnik, S.; Meden, A.; Sta-
novnik, B.; Svete, J. Acta Chim. Slov. 2006, 53, 245–256.
ˇ ˇ
14. (a) Ursic, U.; Bevk, D.; Pirc, S.; Pezdirc, L.; Stanovnik, B.; Svete, J. Synthesis 2006,
The financial support from the Slovenian Research Agency
through grants P1-0179, and J1-6689-0103-04 is gratefully
acknowledged.
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2376–2384; (b) Skof, M.; Svete, J.; Stanovnik, B. Heterocycles 2000, 53, 339–346.
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15. (a) Pirc, S.; Bevk, D.; Golobic, A.; Stanovnik, B.; Svete, J. Helv. Chim. Acta 2006,
ˇ
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89, 30–44; (b) Skof, M.; Svete, J.; Stanovnik, B.; Golic Grdadolnik, S. Helv. Chim.
Acta 2000, 83, 760–766.
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16. Mihelic, D.; Jakse, R.; Svete, J.; Stanovnik, B.; Golic Grdadolnik, S. J. Heterocycl.
Chem. 2001, 38, 1307–1312.
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