Parallel synthesis of 1-substituted 5-(5-oxopyrrolidin-3-yl)-1 H -pyrazole-4-carboxamides

Article abstract of DOI:10.1055/s-0030-1261034

A parallel solution-phase synthesis of 5-(5-oxo-1-phenylpyrrolidin-3-yl)- 1H-pyrazole-4-carboxamide derivatives as conformationally constrained pyrazole analogues of histamine starting from itaconic acid was developed. The synthetic method comprises a five-step preparation of 1-substituted 5-(5-oxo-1- phenylpyrrolidin-3-yl)-1H-pyrazole-4-carboxylic acids followed by parallel amidation with various primary and secondary amines to give a library of 24 histamine analogues in good overall yields and in very high purities. The method is general and substrate-independent. All the amidations proceed smoothly and no major difference in reactivity is observed with respect to the structures of the reactants. Georg Thieme Verlag Stuttgart, New York.

Full text of DOI:10.1055/s-0030-1261034

2822
PAPER
Parallel Synthesis of 1-Substituted 5-(5-Oxopyrrolidin-3-yl)-1H-pyrazole-4-
carboxamides
Synthesisof
5e
t
r
olidin-
e
3-yl)-1
H
-p
r
yrazole-4-carb
P
oxamides erdih,a Jernej Baškovč,a Georg Dahmann,b Uroš Grošelj,a Drago Kočar,a Ana Novak,a Branko Stanovnik,a
Jurij Svete*a
a
Faculty of Chemistry and Chemical Technology, University of Ljubljana, Aškerčeva 5, P.O. Box 537, 1000 Ljubljana, Slovenia
Fax +386(1)2419220; E-mail: Jurij.svete@fkkt.uni-lj.si
Boehringer Ingelheim Pharma GmbH & Co. KG, Medicinal Chemistry, 88397 Biberach, Germany
b
Received 5 May 2011; revised 20 June 2011
attention on another type of histamine analogue, 6, where
Abstract: A parallel solution-phase synthesis of 5-(5-oxo-1-phe-
the aminoethyl functionality is replaced by a 2-pyrrolidi-
nylpyrrolidin-3-yl)-1H-pyrazole-4-carboxamide derivatives as con-
none moiety. The structures of histamine (1) and its ana-
logues 2–6 are depicted in Figure 1.
formationally constrained pyrazole analogues of histamine starting
from itaconic acid was developed. The synthetic method comprises
a five-step preparation of 1-substituted 5-(5-oxo-1-phenylpyrroli-
din-3-yl)-1H-pyrazole-4-carboxylic acids followed by parallel ami-
dation with various primary and secondary amines to give a library
of 24 histamine analogues in good overall yields and in very high
purities. The method is general and substrate-independent. All the
amidations proceed smoothly and no major difference in reactivity
is observed with respect to the structures of the reactants.
R1
H
N
N
HO
N
N
H2N
H2N
histamine (1)
2
Key words: pyrrolidinone, pyrazole, cyclocondensations, amida-
refs. 9 and 10
tions, histamine analogues
R1
N
R1
N
N
N
H2N
Many heterocyclic compounds represent important scaf-
folds for the preparation of compound libraries for medic-
inal and pharmaceutical applications and for utilization in
materials science.1,2 Since 2-[(hetero)aryl]ethylamines,
such as dopamine, histamine, tryptamine, serotonin and
melatonin are representative chemical messengers that
play a crucial role in biological processes, the preparation
of their novel synthetic analogues represents an important
target in medicinal and synthetic organic chemistry. With-
in this context, the synthesis of libraries of novel 2-(het-
eroaryl)ethylamine derivatives and analogues is of
particular interest.1–3
N
O
R2
R2
O
N
R3
3
4
ref. 12
ref. 11
R1
N
R2
N
R1
N
N
N
O
NH2
O
5
R2
N
ref. 13
R3
A part of our research has focused on the synthesis of
functionalized heterocycles via 1,3-dipolar cycloadditions
6
Figure 1 Histamine (1) and its pyrazole analogues 2–6
of
(4R*,5R*)-4-benzoylamino-5-phenyl-3-pyrazolidi-
none derived azomethine imines to various dipolaro-
philes,4 and cyclocondensations of functionalized
enaminones with nucleophiles.5 Both approaches have
been applied in high-throughput6,7 and bioorganic synthe-
sis.8 We have reported a ‘ring-switching’ synthesis of 1-
substituted 4-(2-aminoethyl)-1H-pyrazol-5-ols 29 as pyra-
zole analogues of histamine (1), in addition to a one-pot,
parallel solution-phase synthesis of compounds 2.10 The
syntheses of 1-substituted 5-(2-aminoethyl)-1H-pyrazole-
4-carboxamides 3,11 their bicyclic analogues 4,12 and 5-(2-
aminophenyl)pyrazole derivatives 513 have also been de-
veloped. In continuation of this work, we concentrated our
As a result of our research efforts in this field, we now re-
port a simple enaminone-based parallel solution-phase
synthesis of 1-substituted 5-(5-oxo-1-phenylpyrrolidin-3-
yl)-1H-pyrazole-4-carboxamides 6 as novel types of con-
formationally constrained histamine analogues.
Initially, the starting compound 8 was prepared from com-
mercially available itaconic acid (7) and aniline following
the literature procedure.14 Masamune–Claisen condensa-
tion of 8 with potassium monomethyl malonate as a C2-
synthon was carried out using 1,1¢-carbonyldiimidazole
(CDI) as the activating agent in anhydrous acetonitrile at
room temperature to give the b-keto ester 9 in 83% yield.
Treatment of 9 with N,N-dimethylformamide–dimethyl
acetal (DMF–DMA) in toluene at reflux temperature gave
the enamino ketone intermediate 10, which was subse-
SYNTHESIS 2011, No. 17, pp 2822–2832
x
x.
x
x
.
2
0
1
1
Advanced online publication: 08.08.2011
DOI: 10.1055/s-0030-1261034; Art ID: T47211SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of 5-(5-Oxopyrrolidin-3-yl)-1H-pyrazole-4-carboxamides
2823
quently cyclized with methylhydrazine 11{1} or phenyl- lated by filtration. On the other hand, tertiary amides
hydrazine 11{2} to afford pyrazole-4-carboxylates 12{1} 6{1,2; 9} did not precipitate and the reaction mixtures
and 12{2} in 70% and 81% yields, respectively. Finally, were instead evaporated in vacuo to afford the crude prod-
hydrolysis of esters 12{1,2} with sodium hydroxide in ucts 6{1; 9} and 6{2; 9}. Crystallization of 6{1; 9} was
aqueous methanol at 50 °C furnished the corresponding induced by trituration with diethyl ether, whereas 6{2; 9}
carboxylic acids 13{1} and 13{2} in yields of 89% and precipitated upon similar treatment of the crude product
82% (Scheme 1).
with aqueous methanol. Once the reaction conditions and
workup had been established, a parallel synthesis of a li-
brary of 24 carboxamides 6{1,2; 1–12} was carried out.
Thus, the acids 13{1,2} were activated with triethylamine
and bis(pentafluorophenyl) carbonate in acetonitrile at
room temperature to give the intermediate pentafluo-
rophenyl esters, which were subsequently treated with
equimolar amounts of amines 14{1–12} and triethyl-
amine at room temperature for 12 hours to furnish carbox-
amides 6{1,2; 1–12}. A total of 24 products were isolated
by sequential filtration and evaporation in this way. Eight
compounds, 6{1; 3,7} and 6{2; 1–4,6,11}, precipitated
from the reaction mixtures and were isolated by filtration.
The remaining reaction mixtures were evaporated and the
residues triturated with diethyl ether. Four compounds,
6{1; 4–6,9}, which precipitated from these reaction mix-
tures, were collected by filtration. The remaining reaction
mixtures were again evaporated and the residues triturated
with aqueous methanol to afford 10 compounds, 6{1;
1,2,11,12} and 6{2; 5,7–10,12} as precipitates, which
were isolated by filtration. The last two compounds, 6{1;
8} and 6{1; 10}, were obtained by evaporation of the cor-
responding solutions. Finally, all the products were dried
thoroughly in vacuo at 80 °C. In this manner, the title
compounds 6{1,2; 1–12} were obtained in 29–100%
yields and in very high purities. Of the 24 library mem-
bers, 20 were ≥95% pure, one was 92% pure, and three
were 85–89% pure (Scheme 2, Table 1).
Ph
N
i
ii
O
COOH
HOOC
ref. 14
7
HOOC
8
Ph
Ph
iii
iv
N
O
N
O
O
O
NMe2
MeOOC
MeOOC
10
9
Ph
Ph
v
1' N
N
O
5'
O
2'
3'
5
R1
1 N
R1
N
4'
N
N
COOH
COOMe
4
2
3
12{1} (R1 = Me)
12{2} (R1 = Ph)
13{1} (R1 = Me)
13{2} (R1 = Ph)
hydrazines 11{1,2}:
MeNHNH2
11{1}
PhNHNH2
11{2}
Scheme 1 Reagents and conditions: (i) PhNH2, H2O, reflux (refe-
rence 14); (ii) CDI, MeCN, r.t., 1 h, then potassium monomethyl ma-
lonate, MgCl2, MeCN, r.t.; (iii) DMF–DMA, toluene, reflux; (iv)
R1NHNH2 11{1,2}, MeOH, r.t.→reflux; (v) NaOH, MeOH–H2O
(2:1), 50 °C.
The structures and purities of novel compounds 6{1,2; 1–
12}, 9, 12{1,2}, and 13{1,2} were determined by spectro-
scopic methods (IR, 1H NMR and 13C NMR, MS, HRMS),
by LC–MS, and by elemental analyses. Characterization
data for compounds 6{1,2; 1–12} are given in Tables 2
and 3.
Once the desired key intermediates 13{1,2} had been pre-
pared, the parallel solution-phase synthesis of 1-substitut-
Next, we tried to find suitable conditions for separation of
the enantiomers of racemic compounds 6 by HPLC using
an analytical chiral stationary phase column [Chiralcel®
OD-H (0.46 cm × 25 cm)] and n-hexane–isopropanol as
the mobile phase. To our surprise, 16 of the 24 racemic
compounds, 6{1; 1–5,9–12} and 6{2; 1–4,8,10,12}, were
resolved, while five racemic compounds, 6{1; 6,8} and
6{2; 5–7}, were partially resolved. We were unable to
find suitable conditions for the separation of only three ra-
cemic mixtures, 6{1; 7} and 6{2; 9,11}. Thus, the above
separation conditions were suitable for resolution of the
enantiomers of the majority of the racemic secondary and
tertiary carboxamides 6. We believe that the results ob-
tained using the analytical column should be applicable
for the (semi)preparative separation of enantiomers of
6{1; 1–6,8–12} and 6{2; 1–8,10,12}. Moreover, these
separation conditions could prove valuable for the resolu-
ed
5-(5-oxo-1-phenylpyrrolidin-3-yl)-1H-pyrazole-4-
carboxamides 6 was studied. First, suitable reaction con-
ditions and activating reagents for parallel amidation of
the acids 13 had to be found. Based on literature data,15
and on our previous experience with related amida-
tions,7i,11
2-ethoxy-1-ethoxycarbonyldihydroquinoline
(EEDQ), and bis(pentafluorophenyl) carbonate (BPC)
were our primary choices as activating reagents, as amida-
tions with these two substrates produce volatile by-prod-
ucts removable by evaporation. The acids 13{1} and
13{2} were subjected to amidation with benzylamine
14{3} and pyrrolidine 14{9} using the above activating
reagents. However, amidation of acids 13{1,2} did not
take place in the presence of 2-ethoxy-1-ethoxycarbon-
yldihydroquinoline, while bis(pentafluorophenyl) carbon-
ate mediated coupling proceeded smoothly with both
amines, 14{3} and 14{9}. N-Benzylcarboxamides 6{1,2;
3} precipitated from the reaction mixtures and were iso-
Synthesis 2011, No. 17, 2822–2832 © Thieme Stuttgart · New York

2824
P. Perdih et al.
PAPER
were obtained using a Perkin-Elmer CHN Analyzer 2400 II. LC–
MS/MS experiments were performed using a liquid chromatograph
Perkin Elmer Series 200 (Perkin Elmer, Shelton, CT, USA) with a
UV detector and a 3200 QTRAP LC/MS/MS System equipped with
ESI and APCI ion sources (Applied Biosystems/MDS Sciex, Foster
City, CA, USA). A Gemini HPLC column (150 mm × 4.6 mm, 3 mm
particles) supplied by Phenomenex (Torrance, CA, USA) was used.
The mobile phase consisted of a gradient of MeCN (A) and deion-
ized H2O (B): 0 min, 10% A; 25 min, 100% A; a 3 min equilibration
time with initial mobile phase (10% A) was allowed for column
equilibration. The mobile phase flow rate was 1 mL/min and the in-
jection volume was 20 mL. Signals were recorded using a UV detec-
tor at 254 nm, and mass spectra were obtained using positive (ESI+)
and negative (ESI–) ionization modes, simultaneously. The mass
range was from 70–500 amu. The electrospray ion source (ESI)
conditions were as follows: cone voltage 5500 V (ESI+) and –4500
V (ESI–), ion source temperature 4000 °C, curtain gas N2 pressure
was set to 10 psi, nebulizer gas N2 pressure was set to 20 psi and tur-
bo gas (air) pressure was set to 40 psi. A declustering potential of
30 V and an entrance potential of 10 V were employed. Resolution
of the enantiomers of 6{1,2; 1–12} was performed on a Agilent
Technologies 1260 Infinity HPLC apparatus equipped with a qua-
ternary pump and a UV detector. A Chiralcel® OD-H (0.46 cm × 25
cm, particle size 5 mm, Part No. 14325) HPLC column was used.
The mobile phase consisted of an isocratic mixture of n-hexane and
i-PrOH; the mobile phase flow rate was 1 mL/min and the injection
volume was 5 mL.
Ph
Ph
N
N
O
O
R1
N
R1
i, ii
N
O
N
N
COOH
N
R2
13{1,2}
R3
(R1 = Me, Ph)
6{1,2; 1–12}
amines 14{1–12}:
NH2
NH2
Ph
14{3}
NH2
14{1}
14{2}
NH2
HO
NH2
Ph
14{5}
14{4}
NH2
Me2N
NH2
N
14{6}
14{7}
H
N
N
H
NH
14{10}
14{8}
14{9}
MeN
14{12}
O
NH
NH
Itaconic acid (7), 1,1¢-carbonyldiimidazole, DMF–DMA, methyl-
hydrazine 11{1}, phenylhydrazine 11{2}, bis(pentafluorophenyl)
carbonate, and amines 14{1–12} were commercially available
(Sigma-Aldrich). 5-Oxo-1-phenylpyrrolidin-3-carboxylic acid (8)
was prepared according to the literature procedure.14 Parallel stir-
ring was carried out on a Büchi Syncore® Polyvap parallel reactor
(24 positions, vortex stirring, 400 rpm in all cases). Parallel filtra-
tions were carried out on a Mettler-Toledo Bohdan MiniBlock™
Compact Shaking and Washing Station and Vacuum Collection
Base (12 positions). Parallel evaporations and drying were carried
out on (a) a Büchi Syncore® Polyvap parallel evaporator (24 posi-
tions, vortex stirring, 400 rpm in all cases), and (b) a Hettlab IR-
Dancer Infra-Red Vortex-Evaporator (42 positions, vortex stirring,
400 rpm in all cases).
14{11}
Scheme 2 Reagents and conditions: (i) Et3N, bis(pentafluorophe-
nyl) carbonate, MeCN, r.t.; (ii) R2R3NH 14{1–12}, Et3N, MeCN, r.t.
tion of analogous racemic compounds (Table 4, and Sup-
porting Information).
In conclusion, 5-(5-oxo-1-phenylpyrrolidin-3-yl)-1H-
pyrazole-4-carboxamides 6, as novel conformationally-
constrained pyrazole analogues of histamine, are avail-
able in six steps from itaconic acid (7). The synthetic path-
way consists of a five-step preparation of pyrazole-4-
carboxylic acids 13{1,2} as the key intermediates fol-
lowed by parallel solution-phase, bis(pentafluorophenyl)
carbonate mediated amidation of 13{1,2} with primary
and secondary amines 14{1–12} to give the title com-
pounds 6{1,2; 1–12} in good overall yields and in very
high purities upon simple workup. The method is general
and substrate-independent. All 24 amidations proceeded
smoothly and no major difference in reactivity was ob-
served, neither with respect to the N(1) substituent on the
pyrazole-4-carboxylic acids 13, nor regarding the struc-
ture of the amine 14. These results also indicate that the
above synthetic method could also serve as a useful tool
for the preparation of novel compound libraries for phar-
maceutical and other practical applications.
Methyl 3-Oxo-3-(5-oxo-1-phenylpyrrolidin-3-yl)-propanoate
(9)
This compound was prepared from pyrrolidinone 8 following a
modified literature procedure.11 CDI (8.5 g, 52 mmol) was added to
a stirred suspension of 814 (10.2 g, 50 mmol) in anhyd MeCN (120
mL), and the mixture stirred at r.t. for 1.5 h. Next, a well homoge-
nized and powdered solid mixture of anhyd MgCl2 (4.1 g, 43 mmol)
and potassium monomethyl malonate (11.8 g, 75 mmol) was added
and the mixture stirred at r.t. for 16 h. Volatile components were
evaporated in vacuo, aq HCl (2 M, 150 mL) was added and the mix-
ture stirred at r.t. for 3 h. The resulting precipitate was collected by
filtration, washed with H2O (3 × 20 mL) and dried to give b-keto es-
ter 9.
Yield: 10.8 g (83%); white solid; mp 86–90 °C.
IR (KBr): 3358 (NH), 2959 (NH), 1748 (C=O), 1715 (C=O), 1682
(C=O), 1601, 1498, 1396, 1300, 1097, 1007, 757 cm–1.
Melting points were determined using a Stanford Research Systems
MPA100 OptiMelt automated melting point system. Compounds 6
and 13 were dried in a Büchi drying oven. IR spectra were obtained
using a Perkin-Elmer Spectrum BX FTIR spectrophotometer. The
NMR spectra were recorded on a Bruker Avance DPX 300 spec-
trometer at 300 MHz (1H) and 75.5 MHz (13C), using DMSO-d6 or
CDCl3 as solvent and TMS as the internal standard. Mass spectra
were recorded on a Q-Tof Premier spectrometer. Microanalyses
1H NMR (CDCl3): d = 2.75 (m, 2 H, CH2-4¢), 3.64 (m, 4 H, OMe,
H-3¢), 3.82 (s, 2 H, CH2-2), 4.00 (m, 2 H, CH2-2¢), 7.14 (tt, J = 1.2,
7.5 Hz, 1 H, ArH), 7.38 (tt, J = 2.1, 8.4 Hz, 2 H, ArH), 7.60–7.65
(m, 2 H, ArH).
13C NMR (DMSO-d6): d = 34.0, 42.1, 47.1, 48.5, 51.9, 119.5,
124.1, 128.7, 139.1, 167.6, 171.4, 202.6.
Synthesis 2011, No. 17, 2822–2832 © Thieme Stuttgart · New York

PAPER
Synthesis of 5-(5-Oxopyrrolidin-3-yl)-1H-pyrazole-4-carboxamides
2825
Table 1 Physical and Analytical Data on Histamine Analogues 6{1,2; 1–12}
Product
6{1; 1}
6{2; 1}
6{1; 2}
6{2; 2}
6{1; 3}
6{2; 3}
6{1; 4}
6{2; 4}
6{1; 5}
6{2; 5}
6{1; 6}
6{2; 6}
6{1; 7}
6{2; 7}
6{1; 8}
6{2; 8}
6{1; 9}
6{2; 9}
6{1; 10}
6{2; 10}
6{1; 11}
6{2; 11}
6{1; 12}
6{2; 12}
R1
R2R3NH 14
Workupa
Yield (%)
89
Purity (%)b
100c
100c
99c
Mp (°C)
Me
Ph
1-propylamine
1-propylamine
1-pentylamine
C
A
C
A
A
A
B
A
B
C
B
A
A
C
D
C
B
C
D
C
C
A
C
C
195–198
208–210
131–135
177–180
206–208
194–198
119–122
204–208
130–132
200–204
169–171
151–155
182–185
149–151
resin
29
Me
Ph
92
1-pentylamine
65
100c
100c
100c
100
Me
Ph
benzylamine
73
benzylamine
87
Me
Ph
2-phenylethylamine
2-phenylethylamine
3-amino-1-propanol
3-amino-1-propanol
3-dimethylamino-1-propylamine
3-dimethylamino-1-propylamine
2-picolylamine
2-picolylamine
diethylamine
82
66
100c
100c
100c
92c
Me
Ph
99
73
Me
Ph
56
42
100c
100c
100c
98c
Me
Ph
73
89
Me
Ph
100
67
diethylamine
89c
150–154
174–176
197–203
57–60
Me
Ph
pyrrolidine
92
100c
89c
pyrrolidine
90
Me
Ph
piperidine
100
80
97
piperidine
100c
100c
100c
97c
170–172
161–165
241–244
146–149
135–140
Me
Ph
morpholine
95
morpholine
93
Me
Ph
4-methylpiperazine
4-methylpiperazine
73
89
85c
a Workup A: filtration of the reaction mixture. Workup B: evaporation of the reaction mixture, trituration with Et2O, filtration. Workup C: evap-
oration of the reaction mixture, trituration with 50% aq MeOH, filtration. Workup D: evaporation of the reaction mixture.
b Determined by LC–MS and 1H NMR spectroscopy.
c Confirmed by elemental analysis. The found values for C, H, and N were within 0.4% with respect to the calculated values.
Table 2 Analytical Data for Compounds 6{1,2; 1–12}
Product Molecular Formula
Elem. Anal.
LC–MS Anal.a
Rt (min)
Area (%) m/zb
ESI-MS (m/z) ESI-HRMS (m/z)b
6{1; 1} C18H22N4O2 (326.39)
6{2; 1} C23H24N4O2 (388.46)
6{1; 2} C20H26N4O2 (354.45)
6{2; 2} C25H28N4O2 (416.52)
Calcd: C, 66.24; H, 6.79; N, 17.17. 11.69
Found: C, 66.38; H, 6.84; N, 17.45
100
100
99
327 327 [M + H]+ Calcd: 327.1821;
found: 327.1812
Calcd: C, 71.11; H, 6.23; N, 14.42. 15.49
Found: C, 71.03; H, 6.32; N, 14.34
389 389 [M + H]+ Calcd: 389.1978;
found: 389.1985
Calcd: C, 67.77; H, 7.39; N, 15.83. 14.63
Found: C, 67.58; H, 7.48; N, 15.83
355 355 [M + H]+ Calcd: 355.2134;
found: 355.2122
Calcd: C, 72.09; H, 6.78; N, 13.45. 18.43
Found: C, 72.26; H, 6.88; N, 13.46
100
417 417 [M + H]+ Calcd: 417.2291;
found: 417.2292
Synthesis 2011, No. 17, 2822–2832 © Thieme Stuttgart · New York

2826
P. Perdih et al.
PAPER
Table 2 Analytical Data for Compounds 6{1,2; 1–12} (continued)
Product Molecular Formula
Elem. Anal.
LC–MS Anal.a
Rt (min)
Area (%) m/zb
ESI-MS (m/z) ESI-HRMS (m/z)b
6{1; 3} C22H22N4O2 (374.44)
6{2; 3} C27H24N4O2 (436.51)
6{1; 4} C23H24N4O2·H2O (406.48)
6{2; 4} C28H26N4O2 (450.53)
6{1; 5} C18H22N4O3·1/8H2O (344.64)
Calcd: C, 70.57; H, 5.92; N, 14.96. 13.68
Found: C, 70.30; H, 5.99; N, 14.92
100
100
100
100
100
100
375 375 [M + H]+ Calcd: 375.1821;
found: 375.1823
Calcd: C, 74.29; H, 5.54; N, 12.84. 17.49
Found: C, 74.10; H, 5.66; N, 12.83
437 437 [M + H]+ Calcd: 437.1978;
found: 437.1976
Calcd: C, 67.96; H, 6.45; N, 13.78. 14.38
Found: C, 67.65; H, 6.48; N, 13.71
389 389 [M + H]+ Calcd: 389.1978;
found: 389.1969
Calcd: C, 74.65; H, 5.82; N, 12.44. 18.06
Found: C, 74.81; H, 5.88; N, 12.46
451 451 [M + H]+ Calcd: 451.2134;
found: 451.2138
Calcd: C, 62.73; H, 6.51; N, 16.26. 8.87
Found: C, 62.99; H, 6.55; N, 16.29
343 343 [M + H]+ Calcd: 343.1770;
found: 343.1768
6{2; 5} C23H23N4O3·H2O
Calcd: C, 67.55; H, 6.04; N, 13.70. 12.06
Found: C, 67.47; H, 5.97; N, 13.40.
405 403 [M – H]+ Calcd: 403.1770;
found: 403.1772.
(408.06)
6{1; 6} C20H27N5O2·C6F5OH (553.52) Calcd: C, 56.42; H, 5.10; N, 12.65. 1.54, 16.18c 92
370 370 [M + H]+ Calcd: 370.2243;
found: 370.2246
Found: C, 56.25; H, 5.01; N, 12.44
6{2; 6} C25H29N5O2·1/2C6F5OH·11/2H2OCalcd: C, 60.08; H, 5.95; N, 12.72. 1.99, 5.78c 100
432 432 [M + H]+ Calcd: 432.2400;
found: 432.2405
(550.58)
Found: C, 60.82; H, 5.72; N, 12.87
6{1; 7} C21H21N5O2·1/3H2O (381.43)
Calcd: C, 66.13; H, 5.73; N, 18.36. 10.31
Found: C, 66.14; H, 5.45; N, 18.36
100
100
98
376 376 [M + H]+ Calcd: 376.1774;
found: 376.1780
6{2; 7} C26H23N5O2·4/7C6F5OH
Calcd: C, 65.13; H, 4.38; N, 12.91. 13.40
Found: C, 65.21; H, 4.41; N, 12.94
438 438 [M + H]+ Calcd: 438.1930;
found: 438.1916
(542.67)
6{1; 8} C19H24N4O2·1/5C6F5OH
Calcd: C, 64.31; H, 6.47; N, 14.85. 11.31
Found: C, 64.18; H, 6.85; N, 15.19
341 341 [M + H]+ Calcd: 341.1972;
found: 341.1976
(377.23)
6{2; 8} C24H26N4O2·1/6C6F5OH
Calcd: C, 69.32; H, 6.09; N, 12.93. 14.93
Found: C, 69.44; H, 5.96; N, 12.82
89
403 403 [M + H]+ Calcd: 403.2134;
found: 403.2140
(433.17)
6{1; 9} C19H22N4O2 (338.40)
Calcd: C, 67.44; H, 6.55; N, 16.56. 10.53
Found: C, 67.50; H, 6.66; N, 16.93
100
89
339 339 [M + H]+ Calcd: 339.1821;
found: 339.1833
6{2; 9} C24H24N4O2·H2O
Calcd: C, 70.40; H, 6.15; N, 13.68. 13.93
Found: C, 70.65; H, 5.84; N, 13.36
401 401 [M + H]+ Calcd: 401.1978;
found: 401.1989
(409.48)
6{1; 10}C20H24N4O2·2/3C6F5OH
Calcd: C, 60.67; H, 5.23; N, 11.79. 11.67
Found: C, 60.82; H, 5.92; N, 11.94d
97
353 353 [M + H]+ Calcd: 353.1972;
found: 353.1977
(475.14)
6{2; 10}C25H26N4O2 (414.50)
Calcd: C, 72.44; H, 6.32; N, 13.52. 15.44
Found: C, 72.31; H, 6.41; N, 13.42
100
100
100
97
415 415 [M + H]+ Calcd: 415.2134;
found: 415.2119
6{1; 11}C19H22N4O3·1/5H2O (358.01)
6{2; 11}C24H24N4O3 (416.47)
Calcd: C, 63.74; H, 6.31; N, 15.63. 9.18
Found: C, 63.76; H, 6.30; N, 15.56
355 355 [M + H]+ Calcd: 355.1770;
found: 355.1772
Calcd: C, 69.21; H, 5.81; N, 13.45. 12.55
Found: C, 69.24; H, 6.02; N, 13.56
417 417 [M + H]+ Calcd: 417.1927;
found: 417.1926
6{1; 12}C20H25N5O2·1/3H2O (373.45)
Calcd: C, 64.32; H, 6.93; N, 18.75. 1.70
Found: C, 64.59; H, 6.76; N, 18.35
368 368 [M + H]+ Calcd: 368.2087;
found: 368.2078
6{2; 12}C25H27N5O2·C6F5OH (613.58) Calcd: C, 60.68; H, 4.60; N, 11.41. 1.99, 6.43c
5
430 430 [M + H]+ Calcd: 430.2243;
found: 430.2245
Found: C, 60.29; H, 4.76; N, 11.36
a Conditions: Gemini column, dimensions: 150 mm × 4.6 mm, 3 mm particles. Flow rate = 1 mL/min. Mobile phase = MeCN–H2O. Gradient
profile: MeCN–H2O = 10:90 (0→3 min), MeCN–H2O = 100:0 (3→25 min); a 3 min column equilibration time with the initial mobile phase
(MeCN–H2O = 10:90) was permitted.
b [M + H]+ values.
c The compound elutes in the protonated and non-protonated forms as two peaks of identical mass.
d The found value for %H was outside the 0.4% range with respect to the calculated value.
Synthesis 2011, No. 17, 2822–2832 © Thieme Stuttgart · New York

PAPER
Synthesis of 5-(5-Oxopyrrolidin-3-yl)-1H-pyrazole-4-carboxamides
2827
Table 3 Spectral Data for Compounds 6{1,2; 1–12}
Product IR (cm–1)
1H NMR (300 MHz) (d ppm)
6{1; 1} 3384, 2970, 2944, 1738,
1673, 1633, 1560, 1496,
1397, 1232, 983, 768,
694.
1H NMR (CDCl3): d = 0.96 (t, J = 7.2 Hz, 3 H, CH2CH2CH3), 1.60 (sext, J = 7.2 Hz, 2 H, CH2CH2CH3),
2.85 (dd, J = 9.6, 16.8 Hz, 1 H, H-4¢a), 3.30 (dd, J = 9.9, 16.8 Hz, 1 H, H-4¢b), 3.29–3.37 (m, 2 H,
CH2NH), 3.93 (s, 3 H, CH3-1), 4.02 and 4.39 [2 × t (1:1), J = 8.7 Hz, 2 H, CH2-2¢], 4.24 (quin, J = 9.0
Hz, 1 H, H-3¢), 5.84 (br s, 1 H, NHCO), 7.16 (tt, J = 1.2, 7.5 Hz, 1 H, ArH), 7.33–7.40 (m, 2 H, ArH),
7.62 (s, 1 H, H-3), 7.59–7.64 (m, 2 H, ArH).
13C NMR (CDCl3): d = 11.6, 23.2, 28.2, 37.6, 37.8, 41.4, 52.7, 115.8, 120.5, 125.0, 129.0, 137.4, 139.2,
143.9, 163.3, 172.6.
6{2; 1} 3303, 2954, 1739, 1685,
1642, 1561, 1498, 1398,
1282, 1237, 769, 754,
691.
1H NMR (CDCl3): d = 0.98 (t, J = 7.5 Hz, 3 H, CH2CH2CH3), 1.63 (sext, J = 7.2 Hz, 2 H, CH2CH2CH3),
2.63–2.74 (m, 1 H, H-4¢a), 3.33–3.48 (m, 3 H, H-4¢b, CH2NH), 3.81–3.93 (m, 2 H, H-2¢a, H-3¢), 4.51–
4.61 (m, 1 H, H-2¢b), 5.90 (br s, 1 H, NHCO), 7.12 (tt, J = 1.2, 7.5 Hz, 1 H, ArH), 7.30–7.39 (m, 4 H,
ArH), 7.50–7.60 (m, 5 H, ArH), 7.83 (s, 1 H, H-3).
13C NMR (CDCl3): d = 11.6, 23.2, 29.5, 38.3, 41.5, 53.1, 116.3, 120.5, 124.8, 126.4, 128.9, 129.76,
129.79, 138.8, 139.0, 139.3, 144.6, 163.1, 172.5.
6{1; 2} 3364, 2951, 1737, 1670,
1636, 1557, 1499, 1417,
1306, 1266, 854, 755,
688, 657.
1H NMR (CDCl3): d = 0.90 (t, J = 6.9 Hz, 3 H, CH3 of pentyl), 1.29–1.38 (m, 4 H, 2 × CH2 of pentyl),
1.57 (quin, J = 7.2 Hz, 2 H, CH2 of pentyl), 2.84 and 3.30 [2 × dd (1:1), J = 9.6, 16.8 Hz, 2 H, CH2-4¢],
3.35 (dd, J = 5.6, 7.0 Hz, 2 H, CH2NH), 3.92 (s, 3 H, CH3-1), 4.01 and 4.38 [2 × t (1:1), J = 8.7 Hz, 2 H,
CH2-2¢], 4.24 (quin, J = 9.0 Hz, 1 H, H-3¢), 5.88 (br t, J = 4.8 Hz, 1 H, NH), 7.15 (tt, J = 1.2, 7.5 Hz, 1
H, ArH), 7.33–7.40 (m, 2 H, ArH), 7.60–7.65 (m, 2 H, ArH), 7.62 (s, 1 H, H-3).
13C NMR (CDCl3): d = 14.1, 22.5, 28.2, 29.2, 29.6, 37.6, 37.8, 39.7, 52.7, 115.8, 120.5, 124.9, 128.9,
137.5, 139.1, 143.8, 163.2, 172.6.
6{2; 2} 3381, 2930, 1751, 1686,
1651, 1593, 1556, 1495,
1401, 1297, 959, 766,
755.
1H NMR (CDCl3): d = 0.92 (br t, J = 6.9 Hz, 3 H, CH3 of pentyl), 1.32–1.41 (m, 4 H, 2 × CH2 of pentyl),
1.60 (br quin, J = 7.0 Hz, 2 H, CH2 of pentyl), 2.64–2.74 (m, 1 H, H-4¢a), 3.36–3.49 (m, 3 H, H-4¢b,
CH2NH), 3.81–3.93 (m, 2 H, H-2¢a, H-3¢), 4.50–4.60 (m, 1 H, H-2¢b), 5.87 (br t, J = 5.4 Hz, 1 H, NHCO),
7.12 (tt, J = 1.2, 7.2 Hz, 1 H, ArH), 7.30–7.39 (m, 4 H, ArH), 7.50–7.60 (m, 5 H, ArH), 7.82 (s, 1 H, H-3).
13C NMR (CDCl3): d = 14.2, 22.5, 29.3, 29.5, 29.6, 38.3, 39.8, 53.1, 116.3, 120.5, 124.7, 126.4, 128.8,
129.7, 129.8, 138.8, 139.1, 139.2, 144.5, 163.0, 172.5.
6{1; 3} 3327, 3038, 2955, 1668,
1643, 1558, 1410, 1304,
1H NMR (CDCl3): d 2.86 and 3.31 [2 × dd (1:1), J = 9.6, 16.8 Hz, 2 H, CH2-4¢], 3.92 (s, 3 H, CH3-1),
4.03 and 4.38 [2 × t (1:1), J = 8.8 Hz, 2 H, CH2-2¢), 4.26 (quin, J = 8.7 Hz, 1 H, H-3¢), 4.55 (d, J = 6.0
Hz, 2 H, CH2NH), 6.11 (t, J = 5.1 Hz, 1 H, NH), 7.17 (tt, J = 1.2, 7.2 Hz, 1 H, ArH), 7.28–7.41 (m, 7 H,
ArH), 7.60–7.65 (m, 2 H, ArH), 7.62 (s, 1 H, H-3).
1288, 1269, 1241, 1226,
954, 855, 753, 685, 663.
13C NMR (CDCl3): d = 28.2, 37.7, 37.9, 43.7, 52.8, 115.5, 120.7, 125.1, 127.8, 128.1, 129.0, 129.1,
137.5, 138.4, 139.2, 144.3, 163.1, 172.5.
6{2; 3} 3318, 1738, 1647, 1561,
1498, 1284, 951, 765,
759, 692.
1H NMR (DMSO-d6): d = 2.74 and 3.20 [2 × dd (1:1), J = 9.9, 16.4 Hz, 2 H, CH2-4¢], 3.82 (quin, J = 9.3
Hz, 1 H, H-3¢), 4.02 and 4.23 [2 × t (1:1), J = 9.0 Hz, 2 H, CH2-2¢], 4.45 (d, J = 6.0 Hz, 2 H, CH2NH),
7.11 (tt, J = 1.0, 7.4 Hz, 1 H, ArH), 7.20–7.38 and 7.40–7.63 [2 × m (1:1), 14 H, ArH], 8.28 (s, 1 H, H-
3), 8.88 (t, J = 6.9 Hz, 1 H, NH).
13C NMR (CDCl3): d = 29.3, 38.3, 43.7, 53.2, 115.9, 120.6, 124.8, 126.4, 127.7, 128.0, 128.89, 128.91,
129.80, 129.81, 138.5, 138.7, 139.1, 139.2, 145.0, 163.0, 172.5.
6{1; 4} 3477, 3284, 2970, 1738,
1668, 1563, 1497, 1401,
1293, 1232, 742, 697,
683.
1H NMR (CDCl3): d = 2.84 and 3.27 [2 × dd (1:1), J = 9.9, 16.8 Hz, 2 H, CH2-4¢], 2.85 (t, J = 6.9 Hz, 2
H, CH2Ph), 3.63 (ddd, J = 1.0, 5.8, 6.9 Hz, 2 H, CH2NH), 3.91 (s, 3 H, CH3-1), 4.01 and 4.36 [2 × t (1:1),
J = 8.7 Hz, 2 H, CH2-2¢], 4.22 (quin, J = 9.0 Hz, 1 H, H-3¢), 5.81 (t, J = 5.3 Hz, 1 H, NH), 7.13–7.25 (m,
4 H, ArH), 7.28–7.42 (m, 4 H, ArH), 7.47 (s, 1 H, H-3), 7.59–7.65 (m, 2 H, ArH).
13C NMR (CDCl3): d = 27.9, 35.8, 37.5, 37.6, 40.6, 52.7, 115.5, 120.5, 124.9, 126.5, 128.6, 128.8, 128.9,
137.5, 139.00, 139.01, 143.8, 163.2, 172.6.
6{2; 4} 3334, 1666, 1641, 1561,
1500, 1432, 1288, 1135,
959, 767, 695.
1H NMR (CDCl3): d = 2.63–2.74 and 3.35–3.46 [2 × m (1:1), 2 H, CH2-4¢], 2.91 (t, J = 6.9 Hz, 2 H,
CH2Ph), 3.68 (dq, J = 1.8, 6.8 Hz, 2 H, CH2NH), 3.81–3.91 (m, 2 H, H-2¢a, H-3¢), 4.48–4.58 (m, 1 H, H-
2¢b), 5.87 (br t, J = 5.4 Hz, 1 H, NH), 7.13 (tt, J = 1.1, 7.4 Hz, 1 H, ArH), 7.21–7.29 (m, 3 H, ArH), 7.30–
7.38 (m, 6 H, ArH), 7.49–7.61 (m, 5 H, ArH), 7.68 (s, 1 H, H-3).
13C NMR (CDCl3): d = 29.4, 35.9, 38.2, 40.7, 53.1, 116.1, 120.6, 124.8, 126.3, 126.7, 128.8, 128.9,
129.0, 129.7, 129.8, 138.7, 139.0, 139.1, 139.2, 144.7, 163.0, 172.5.
6{1; 5} 3371, 3329, 2944, 1763,
1670, 1558, 1496, 1460,
1294, 1160, 985.
1H NMR (CDCl3): d = 1.76 (br tt, J = 5.5, 6.7 Hz, 2 H, CH2CH2CH2), 2.86 and 3.26 [2 × dd (1:1), J = 9.6,
16.8 Hz, 2 H, CH2-4¢], 3.54 (dq, J = 1.2, 6.3 Hz, 2 H, CH2NH), 3.71 (t, J = 5.4 Hz, 2 H, CH2OH), 3.93
(s, 3 H, CH3-1), 4.03 and 4.36 [2 × t (1:1), J = 8.7 Hz, 2 H, CH2-2¢], 4.24 (quin, J = 8.7 Hz, 1 H, H-3¢),
6.34 (t, J = 6.0 Hz, 1 H, NH), 7.17 (tt, J = 1.1, 7.4 Hz, 1 H, ArH), 7.34–7.41 (m, 2 H, ArH), 7.59–7.64
(m, 2 H, ArH), 7.63 (s, 1 H, H-3), OH not observed.
13C NMR (CDCl3): d = 28.0, 32.1, 36.8, 37.70, 37.73, 53.0, 59.9, 115.3, 120.9, 125.2, 129.0, 138.0,
139.0, 144.1, 164.1, 172.8.
Synthesis 2011, No. 17, 2822–2832 © Thieme Stuttgart · New York

2828
P. Perdih et al.
PAPER
Table 3 Spectral Data for Compounds 6{1,2; 1–12} (continued)
Product IR (cm–1)
1H NMR (300 MHz) (d ppm)
6{2; 5} 3442, 3343, 1737, 1646,
1497, 1297, 980, 971,
763, 696.
1H NMR (CDCl3): d = 1.77 (br quin, J = 5.7 Hz, 2 H, CH2CH2CH2), 2.67–2.77 and 3.33–3.45 [2 × m
(1:1), 2 H, CH2-4¢], 3.55 (q, J = 6.0 Hz, 2 H, CH2NH), 3.72 (t, J = 5.4 Hz, 2 H, CH2OH), 3.80–3.95 (m,
2 H, H-2¢a, H-3¢), 4.50–4.57 (m, 1 H, H-2¢b), 6.74 (t, J = 5.7 Hz, 1 H, NH), 7.13 (tt, J = 1.1, 7.4 Hz, 1 H,
ArH), 7.29–7.38 (m, 4 H, ArH), 7.50–7.56 (m, 5 H, ArH), 7.89 (s, 1 H, H-3), OH not observed.
13C NMR (CDCl3): d = 29.2, 32.1, 37.2, 38.3, 53.4, 60.3, 115.7, 121.0, 125.2, 126.4, 129.0, 129.88,
129.92, 138.6, 139.0, 139.3, 145.1, 164.0, 172.8.
6{1; 6} 3304, 2963, 2341, 1686,
1638, 1495, 1392, 1234,
1H NMR (CDCl3): d = 1.87–1.98 (m, 2 H, CH2CH2CH2), 2.55 (s, 6 H, NMe2), 2.79 (br dt, J = 2.6, 6.5
Hz, 2 H, CH2NMe2), 2.84 and 3.31 [2 × dd (1:1), J = 9.8, 16.8 Hz, 2 H, CH2-4¢], 3.38–3.58 (m, 2 H,
CH2NH), 3.92 (s, 3 H, CH3-1), 4.01 and 4.39 [2 × t (1:1), J = 8.9 Hz, 2 H, CH2-2¢], 4.21 (quin, J = 9.3
Hz, 1 H, H-3¢), 7.15 (tt, J = 1.2, 7.5 Hz, 1 H, ArH), 7.37 (tt, J = 1.9, 8.0 Hz, 2 H, ArH), 7.60–7.65 (m, 2
H, ArH), 7.78 (s, 1 H, H-3), 7.82 (br s, 1 H, NH), 8.10 (br s, 1 H, Me2NH+).
1161, 1009, 976, 760.
13C NMR (CDCl3): d = 25.2, 28.2, 37.3, 37.78, 37.79, 44.0, 52.9, 56.6, 115.5, 120.6, 125.0, 129.1, 138.2,
139.2, 144.1, 163.7, 172.8.
6{2; 6} 3277, 2970, 2466, 1737,
1691, 1637, 1494, 1387,
1H NMR (CDCl3): d = 1.84–1.97 (m, 2 H, CH2CH2CH2), 2.53 (s, 6 H, NMe2), 2.69 (dd, J = 9.2, 16.3 Hz,
1 H, H-4¢a), 2.73–2.84 (m, 2 H, CH2NMe2), 3.37–3.54 (m, 3 H, H-4¢b, CH2NH), 3.81–3.89 (m, 2 H, H-
2¢a, H-3¢), 4.50–4.57 (m, 1 H, H-2¢b), 7.12 (br t, J = 7.4 Hz, 1 H, ArH), 7.30–7.38 (m, 4 H, ArH), 7.48–
7.58 (m, 5 H, ArH), 8.01 (s, 1 H, H-3), 8.24 (br s, 1 H, NH), 11.45 (br s, 1 H, Me2NH+).
13C NMR (CDCl3): d = 25.1, 29.2, 37.7, 38.3, 44.0, 53.2, 56.8, 116.0, 120.5, 124.8, 126.4, 128.9, 129.7,
129.8, 138.8, 139.3, 139.7, 144.7, 163.4, 172.8.
1291, 1005, 981, 758.
6{1; 7} 3339, 3042, 3010, 1737,
1670, 1642, 1558, 1496,
1410, 1272, 959, 948,
744, 686.
1H NMR (DMSO-d6): d = 2.75 and 3.15 [2 × dd (1:1), J = 9.5, 16.5 Hz, 2 H, CH2-4¢], 3.90 (s, 3 H, CH3-
1), 4.00–4.23 (m, 3 H, CH2-2¢, H-3¢), 4.66 and 4.72 [2 × dd (1:1), J = 4.9, 17.1 Hz, 2 H, CH2NH], 7.12
(tt, J = 1.0, 7.5 Hz, 1 H, ArH), 7.24 (br dd, J = 4.8, 7.7 Hz, 1 H, H-5¢¢), 7.27 (br d, J = 7.7 Hz, 1 H, H-
3¢¢), 7.32–7.40 (m, 2 H, ArH), 7.60–7.66 (m, 2 H, ArH), 7.73 (dt, J = 1.8, 7.7 Hz, 1 H, H-4¢¢), 8.03 (s, 1
H, H-3), 8.48 (d, J = 4.8 Hz, 1 H, H-6¢¢), 8.76 (t, J = 6.0 Hz, 1 H, NH).
13C NMR (CDCl3): d = 28.2, 37.7, 37.8, 44.4, 52.8, 115.5, 120.6, 122.3, 122.6, 124.9, 129.0, 137.0,
137.9, 139.2, 144.1, 149.2, 156.3, 163.3, 172.6.
6{2; 7} 3469, 1755, 1687, 1615,
1499, 1460, 1398, 1308,
1288, 1132, 974, 760,
694.
1H NMR (CDCl3): d = 2.71 and 3.44 [2 × dd (1:1), J = 9.9, 16.4 Hz, 2 H, CH2-4¢], 3.81–3.95 (m, 2 H, H-
2¢a, H-3¢), 4.47–4.57 (m, 1 H, H-2¢b), 4.78 and 4.75 [2 × dd (1:1), J = 4.9, 15.9 Hz, 2 H, CH2NH], 7.13
(tt, J = 0.9, 7.2 Hz, 1 H, ArH), 7.24–7.40 (m, 7 H, ArH, H-5¢¢, H-3¢¢), 7.50–7.58 (m, 5 H, NH, ArH), 7.72
(td, J = 1.8, 7.8 Hz, 1 H, H-4¢¢), 8.00 (s, 1 H, H-3), (d, J = 5.1 Hz, 1 H, H-6¢¢).
13C NMR (CDCl3): d = 29.3, 38.3, 44.2, 53.3, 115.7, 120.7, 123.0, 123.1, 124.9, 126.4, 128.9, 129.84,
129.87, 137.8, 138.6, 139.1, 139.4, 145.0, 148.7, 156.4, 163.1, 172.8.
6{1; 8} 2972, 2941, 1698, 1614,
1554, 1500, 1394, 1282,
1269, 1222, 761.
1H NMR (DMSO-d6): d = 1.18 (t, J = 7.1 Hz, 6 H, 2 × CH2CH3), 2.90 (dd, J = 9.3, 16.7 Hz, 1 H, H-4¢a),
3.04 (dd, J = 9.8, 16.7 Hz, 1 H, H-4¢b), 3.44 (t, J = 6.8 Hz, 4 H, 2 × CH2CH3), 3.91 (s, 3 H, CH3-1), 3.97
(quin, J = 8.2 Hz, 1 H, H-3¢), 4.05 (t, J = 9.0 Hz, 1 H, H-2¢a), 4.32 (t, J = 8.8 Hz, 1 H, H-2¢b), 7.16 (t,
J = 7.4 Hz, 1 H, ArH), 7.37 (t, J = 8.0 Hz, 2 H, ArH), 7.46 (s, 1 H, H-3), 7.59 (d, J = 7.7 Hz, 2 H, ArH).
13C NMR (CDCl3): d = 12.8, 14.7, 28.9, 37.4, 37.7, 39.8, 43.6, 52.6, 115.8, 120.3, 125.0, 129.0, 136.6,
138.9, 141.4, 165.1, 172.0.
6{2; 8} 2963, 1753, 1686, 1619,
1498, 1395, 1305, 1277,
767, 755.
1H NMR (CDCl3): d = 1.23 (t, J = 7.2 Hz, 6 H, 2 × CH2CH3), 2.74 (dd, J = 9.1, 16.6 Hz, 1 H, H-4¢a),
3.06 (dd, J = 10.1, 16.6 Hz, 1 H, H-4¢b), 3.51 (q, J = 7.2 Hz, 4 H, 2 × CH2CH3), 3.80 (quin, J = 9.0 Hz,
1 H, H-3¢), 3.89 and 4.42 [2 × t (1:1), J = 8.7 Hz, 2 H, CH2-2¢], 7.31 (tt, J = 1.0, 7.5 Hz, 1 H, ArH), 7.30–
7.43 (m, 4 H, ArH), 7.48–7.61 (m, 5 H, ArH), 7.68 (s, 1 H, H-3).
13C NMR (CDCl3): d = 12.9, 14.9, 29.6, 38.5, 39.8, 43.6, 53.3, 116.4, 120.3, 124.9, 126.4, 128.9, 129.6,
129.8, 138.3, 138.93, 138.99, 142.4, 164.9, 171.8.
6{1; 9} 2981, 2871, 1737, 1681,
1594, 1432, 1385, 1352,
1226, 893, 760.
1H NMR (CDCl3): d = 1.94 (br quin, J = 3.4 Hz, 4 H, CH2-3¢¢, 4¢¢), 2.91 and 3.14 [2 × dd (1:1), J = 9.2,
16.8 Hz, 2 H, CH2-4¢], 3.46–3.63 (br m, 4 H, CH2-2¢¢, 5¢¢), 3.93 (s, 3 H, CH3-1), 4.08 (t, J = 8.7 Hz, 1 H,
H-2¢a), 4.18 (m, 1 H, H-3¢), 4.39 (dd, J = 7.5, 8.7 Hz, 1 H, H-2¢b), 7.18 (tt, J = 1.2, 7.5 Hz, 1 H, ArH),
7.39 (tt, J = 2.0, 8.0 Hz, 2 H, ArH), 7.61 (s, 1 H, H-3), 7.60–7.67 (m, 2 H, ArH).
13C NMR (CDCl3): d = 24.4, 26.5, 28.4, 37.6, 37.7, 46.3, 49.2, 52.6, 116.3, 120.2, 124.8, 128.9, 137.8,
139.0, 142.7, 163.5, 172.3.
6{2; 9} 2956, 2876, 1754, 1611,
1514, 1500, 1354, 1298,
993, 978, 766, 697.
1H NMR (CDCl3): d = 1.96 (br s, 4 H, CH2-3¢¢, 4¢¢), 2.73 (dd, J = 9.2, 16.5 Hz, 1 H, H-4¢a), 3.18 (dd,
J = 9.8, 16.5 Hz, 1 H, H-4¢b), 3.59 and 3.66 [2 × br s (1:1), 4 H, CH2-2¢¢, 5¢¢], 3.80–3.89 (m, 2 H, H-3¢,
H-2¢a), 4.46–4.68 (m, 1 H, H-2¢b), 7.12 (t, J = 7.5 Hz, 1 H, ArH), 7.29–7.43 (m, 4 H, ArH), 7.48–7.59
(m, 5 H, ArH), 7.82 (s, 1 H, H-3).
13C NMR (CDCl3): d = 24.4, 26.6, 29.5, 38.4, 46.4, 49.3, 53.2, 116.7, 120.3, 124.7, 126.4, 128.8, 129.6,
129.7, 138.9, 139.1, 139.4, 143.5, 163.4, 172.1.
Synthesis 2011, No. 17, 2822–2832 © Thieme Stuttgart · New York

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Synthesis of 5-(5-Oxopyrrolidin-3-yl)-1H-pyrazole-4-carboxamides
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Table 3 Spectral Data for Compounds 6{1,2; 1–12} (continued)
Product IR (cm–1)
1H NMR (300 MHz) (d ppm)
6{1; 10} 2942, 1699, 1617, 1515,
1500, 1444, 1397, 1282,
1254, 983, 761
1H NMR (DMSO-d6): d = 1.56 (br s, 4 H, CH2-3¢¢, 5¢¢), 1.67 (m, 2 H, CH2-4¢¢), 2.93 (dd, J = 9.3, 16.8 Hz,
1 H, H-4a), 3.02 (dd, J = 9.5, 16.9 Hz, 1 H, H-4b), 3.53 (br s, 4 H, CH2-2¢¢, 6¢¢), 3.91 (s, 3 H, CH3-1),
3.97 (quin, J = 9.1 Hz, 1 H, H-3¢), 4.07 (t, J = 9.0 Hz, 1 H, H-2¢a), 4.36 (dd, J = 8.1, 9.0 Hz, 1 H, H-2¢b),
7.17 (tt, J = 1.1, 7.4 Hz, 1 H, ArH), 7.38 (t, J = 8.0 Hz, 2 H, ArH), 7.43 (s, 1 H, H-3), 7.60 (dd, J = 0.9,
8.6 Hz, 2 H, ArH).
13C NMR (CDCl3): 24.2, 25.4, 26.5, 28.2, 36.8, 37.5, 42.8, 48.6, 52.4, 114.6, 119.9, 124.6, 128.5, 136.8,
138.6, 141.7, 164.0, 172.0.
6{2; 10} 2945, 1738, 1691, 1612,
1500, 1408, 1307, 1231,
756, 693.
1H NMR (CDCl3): d = 1.56–1.65 (m, 4 H, CH2-3¢¢, -5¢¢), 1.65–1.75 (m, 2 H, CH2-4¢¢), 2.76 (dd, J = 9.3,
16.7 Hz, 1 H, H-4¢a), 3.06 (dd, J = 9.9, 16.7 Hz, 1 H, H-4¢b), 3.61 (t, J = 4.5 Hz, 4 H, CH2-2¢¢, 5¢¢), 3.80
(quin, J = 9.0 Hz, 1 H, H-3¢), 3.91 and 4.45 [2 × t (1:1), J = 8.7 Hz, 2 H, CH2-2¢], 7.14 (tt, J = 1.2, 7.5
Hz, 1 H, ArH), 7.31–7.42 (m, 4 H, ArH), 7.49–7.57 (m, 5 H, ArH), 7.63 (s, 1 H, H-3).
13C NMR (CDCl3): d = 24.7, 25.9, 27.0, 29.6, 31.1, 38.7, 43.3, 48.9, 53.4, 115.9, 120.4, 124.9, 126.4,
129.0, 129.6, 129.8, 138.97, 139.02, 142.7, 164.0, 171.9.
6{1; 11} 2893, 1738, 1684, 1618,
1593, 1497, 1411, 1243,
1112, 987, 766, 695.
1H NMR (CDCl3): d = 2.95 and 3.04 [2 × dd (1:1), J = 9.2, 16.8 Hz, 2 H, CH2-4¢], 3.60–3.71 (m, 8 H, 4
× CH2 of morpholine), 3.94 (s, 3 H, CH3-1), 4.02 (br dd, J = 7.6, 8.7 Hz, 1 H, H-2¢a), 4.10 (quin, J = 8.9
Hz, 1 H, H-3¢), 4.37 (dd, J = 7.4, 9.1 Hz, 1 H, H-2¢b), 7.20 (tt, J = 1.2, 7.5 Hz, 1 H, ArH), 7.40 (tt, J = 2.0,
8.0 Hz, 2 H, ArH), 7.44 (s, 1 H, H-3), 7.61–7.66 (m, 2 H, ArH).
13C NMR (CDCl3): d = 28.6, 37.5, 37.9, 42.6, 48.1, 52.6, 66.9, 114.3, 120.2, 125.0, 129.0, 137.4, 138.9,
142.5, 164.3, 171.9.
6{2; 11} 2969, 1691, 1624, 1596,
1561, 1499, 1408, 1309,
1236, 1118, 974, 762,
756, 692.
1H NMR (CDCl3): d = 2.79 and 3.06 [2 × dd (1:1), J = 9.3, 16.8 Hz, 2 H, CH2-4¢], 3.64–3.76 (m, 8 H, 4
× CH2 of morpholine), 3.81 (quin, J = 8.7 Hz, 1 H, H-3¢), 3.93 (t, 1 H, J = 9.0 Hz, H-2¢a), 4.44 (dd,
J = 8.1, 8.7 Hz, 1 H, H-2¢b), 7.15 (tt, J = 0.9, 7.4 Hz, 1 H, ArH), 7.32–7.42 (m, 4 H, ArH), 7.50–7.59 (m,
5 H, ArH), 7.64 (s, 1 H, H-3).
13C NMR (CDCl3): d = 29.3, 38.7, 42.9, 48.1, 53.4, 67.1, 114.8, 120.3, 125.0, 126.3, 129.0, 129.7, 129.8,
138.7, 138.9, 139.0, 143.7, 164.1, 171.8.
6{1; 12} 2834, 1748, 1687, 1615,
1516, 1497, 1390, 1353,
1293, 1225, 1015, 982,
758, 692.
1H NMR (CDCl3): d = 2.36 (s, 3 H, CH3-4¢¢), 2.48 (br t, J = 4.5 Hz, 4 H, CH2-3¢¢, 5¢¢), 2.89–3.05 (m, 2
H, CH2-4¢), 3.61–3.81 (m, 4 H, CH2-2¢¢, 6¢¢), 3.92 (s, 3 H, CH3-1), 3.94–4.04 (m, 1 H, H-3¢), 4.08 (t,
J = 9.0 Hz, 1 H, H-2¢a), 4.36 (dd, J = 7.5, 9.3 Hz, 1 H, H-2¢b), 7.17 (tt, J = 1.2, 7.5 Hz, 1 H, ArH), 7.38
(tt, J = 2.0, 8.0 Hz, 2 H, ArH), 7.43 (s, 1 H, H-3), 7.59–7.65 (m, 2 H, ArH).
13C NMR (CDCl3): d = 28.5, 37.4, 37.9, 41.3, 45.4, 46.8, 52.7, 54.7, 114.3, 120.3, 125.1, 129.0, 137.5,
138.8, 142.7, 164.2, 172.0.
6{2; 12} 3466, 1755, 1687, 1615,
1501, 1410, 1309, 1288,
982, 761, 694.
1H NMR (CDCl3): d = 2.37 (s, 3 H, CH3-4¢¢), 2.51 (t, J = 4.8 Hz, 4 H, CH2-3¢¢, 5¢¢), 2.79 and 3.04 [2 × dd
(1:1), J = 9.3, 16.7 Hz, 2 H, CH2-4¢], 3.67–3.88 (m, 5 H, H-3¢, CH2-2¢¢, 6¢¢), 3.93 (t, J = 8.7 Hz, 1 H, H-
2¢a), 4.44 (dd, J = 0.6, 8.1 Hz, 1 H, H-2¢b), 7.14 (tt, J = 1.2, 7.5 Hz, 1 H, ArH), 7.31–7.41 (m, 4 H, ArH),
7.49–7.58 (m, 5 H, ArH), 7.65 (s, 1 H, H-3).
13C NMR (CDCl3): d = 29.3, 38.7, 41.6, 45.8, 47.2, 53.5, 55.0, 114.9, 120.4, 125.0, 126.4, 129.0, 129.78,
129.82, 138.7, 138.9, 139.1, 143.7, 164.1, 171.9.
Table 4 Separation of the Enantiomers of 6{1,2; 1–12} by HPLCa
Table 4 Separation of the Enantiomers of 6{1,2; 1–12} by HPLCa
(continued)
Product
n-hexane–i-PrOH Rt (min)
Enantiomer A Enantiomer B
Product
n-hexane–i-PrOH Rt (min)
Enantiomer A Enantiomer B
6{1; 1}
6{2; 1}
6{1; 2}
6{2; 2}
6{1; 3}
6{2; 3}
6{1; 4}
6{2; 4}
6{1; 5}
80:20
80:20
80:20
80:20
50:50
50:50
50:50
80:20
50:50
20.045
15.936
20.016
14.541
14.716
9.785
23.670
21.047
23.618
19.793
25.280
12.180
13.779
36.948
7.885
6{2; 5}
6{1; 6}
6{2; 6}
6{1; 7}
6{2; 7}
6{1; 8}
6{2; 8}
6{1; 9}
6{2; 9}
80:20
70:30
80:20
70:30
80:20
50:50
50:50
50:50
70:30
25.719
13.634
19.088
29.247b
39.932
9.452
27.962
16.526
24.227
29.247b
44.427
14.751
11.756
23.783
32.845b
10.715
31.121
6.484
8.059
13.939
32.845b
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P. Perdih et al.
PAPER
Table 4 Separation of the Enantiomers of 6{1,2; 1–12} by HPLCa
(continued)
Methyl 5-(5-Oxo-1-phenylpyrrolidin-3-yl)-1-phenyl-1H-pyra-
zole-4-carboxylate (12{2})
Prepared from 9 and phenylhydrazine 11{2} (4.33 g, 4.01 mL, 40
mmol).
Product
n-hexane–i-PrOH Rt (min)
Enantiomer A Enantiomer B
Yield: 11.73 g (81%); white solid; mp 151–154 °C.
IR (KBr): 2955 (NH), 1706 (C=O), 1682 (C=O), 1596, 1551, 1497,
1403, 1267, 1106, 973, 762, 693 cm–1.
6{1; 10}
6{2; 10}
6{1; 11}
6{2; 11}
6{1; 12}
6{2; 12}
50:50
50:50
50:50
50:50
50:50
80:20
9.630
10.370
17.374
36.187b
11.266
17.367
15.916
13.213
28.327
36.187b
17.321
28.620
1H NMR (CDCl3): d = 2.85 (dd, J = 10.5, 16.8 Hz, 1 H, H-4¢a), 3.00
(dd, J = 9.3, 17.1 Hz, 1 H, H-4¢b), 3.74 (s, 3 H, OMe), 3.92 (quin,
J = 9.3 Hz, 1 H, H-3¢), 4.12 (d, J = 9.0 Hz, 2 H, CH2-2¢), 7.14 (t,
J = 7.4 Hz, 1 H, ArH), 7.37 (t, J = 8.0 Hz, 2 H, ArH), 7.49–7.55 (m,
2 H, ArH), 7.55–7.61 (m, 3 H, ArH), 7.62–7.68 (m, 2 H, ArH), 8.14
(s, 1 H, H-3).
13C NMR (DMSO-d6): d = 27.0, 37.7, 51.5, 52.3, 111.3, 119.6,
124.1, 126.3, 128.7, 129.4, 129.6, 138.1, 139.2, 142.4, 147.5, 163.1,
171.9.
a Separation conditions: Chiralcel OD-H column, dimensions 0.46
cm × 25 cm, 5 mm particles. Flow rate = 1 mL/min. Mobile phase =
n-hexane–i-PrOH.
MS (ESI): m/z = 362 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C21H20N3O3: 362.1505; found:
b Enantiomers were not resolved.
362.1499.
Anal. Calcd for C21H19N3O3: C, 69.79; H, 5.30; N, 11.63. Found: C,
69.63; H, 5.35; N, 11.71.
LC–MS: Rt = 16.258 min, m/z = 362 [M + H]+, area = 100%.
MS (ESI): m/z = 262 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C14H16NO4: 262.1079; found:
262.1077.
Anal. Calcd for C14H15NO4: C, 64.36; H, 5.79; N, 5.36. Found: C,
64.30; H, 5.77; N, 5.35.
LC–MS: Rt = 11.317 min, m/z = 262 [M + H]+, area = 94%.
1-Substituted 5-(5-Oxo-1-phenylpyrrolidin-3-yl)-1H-pyrazole-
4-carboxylic Acids 13; General Procedure
Ester 12 (25 mmol) was dissolved in MeOH (100 mL), aq NaOH (2
M, 50 ml) was added and the mixture was stirred at 50 °C for 16 h.
The solvent was removed by evaporation in vacuo (40 °C/100
mbar) and the aq residue acidified with aq HCl (1 M) until pH ~1.
The resulting precipitate was collected by filtration and dried at 100
°C/2 mbar over P4O10–paraffin for 3 h to give carboxylic acid 13.
Methyl 5-(5-Oxo-1-phenylpyrrolidin-3-yl)-1H-pyrazole-4-car-
boxylates 12; General Procedure
A mixture of b-keto ester 9 (10.4 g, 40 mmol), anhyd toluene (40
mL), and DMF–DMA (6 mL, 40 mmol) was heated at reflux tem-
perature for 2 h. Volatile components were evaporated in vacuo to
give crude amine 10 as a yellow-brown oil. Crude 10 was dissolved
in MeOH (80 mL) and the appropriate hydrazine derivative 11 (40
mmol) added. The mixture was stirred at r.t. for 2 and then at reflux
temperature for another 2 h. The mixture was cooled to r.t. and the
resulting precipitate collected by filtration, and washed with MeOH
(2 × 20 mL) to give pyrazole-4-carboxylate 12.
1-Methyl-5-(5-oxo-1-phenylpyrrolidin-3-yl)-1H-pyrazole-4-
carboxylic Acid (13{1})
Prepared from ester 12{1} (7.71 g, 25 mmol).
Yield: 6.35 g (89%); white solid; mp 185–187 °C.
IR (KBr): 2942 (NH), 2521, 1693 (C=O), 1635 (C=O), 1497, 1481,
1417, 1303, 1207, 1143, 756, 738, 689 cm–1.
Methyl 1-Methyl-5-(5-oxo-1-phenylpyrrolidin-3-yl)-1H-pyra-
zole-4-carboxylate Hemihydrate (12{1})
Prepared from 9 and methylhydrazine 11{1} (1.84 g, 2.13 mL, 40
mmol).
1H NMR (DMSO-d6): d = 2.83 (dd, J = 9.9, 16.6 Hz, 1 H, H-4¢a),
3.03 (dd, J = 9.9, 16.6 Hz, 1 H, H-4¢b), 3.91 (s, 3 H, NMe), 4.05–
4.12 (m, 2 H, CH2-2¢), 4.20 (quin, J = 9.4 Hz, 1 H, H-3¢), 7.15 (t,
J = 7.4 Hz, 1 H, ArH), 7.38 (br t, J = 8.0 Hz, 2 H, ArH), 7.66 (br d,
J = 8.7 Hz, 2 H, ArH), 7.81 (s, 1 H, H-3), 12.43 (s, 1 H, COOH).
13C NMR (DMSO-d6): d = 26.7, 37.28, 37.31, 52.0, 111.5, 119.6,
124.1, 128.7, 139.3, 141.2, 146.2, 164.4, 172.3.
Yield: 8.38 g (70%); white solid; mp 199–204 °C.
IR (KBr): 3363 (NH), 2955 (NH), 1735 (C=O), 1697 (C=O), 1684
(C=O), 1599, 1550, 1498, 1468, 1391, 1248, 1144, 757 cm–1.
MS (ESI): m/z = 284 [M – H]+.
HRMS (ESI): m/z [M – H]+ calcd for C15H14N3O3: 284.1035; found:
1H NMR (CDCl3): d = 2.89 (dd, J = 9.6, 17.1 Hz, 1 H, H-4¢a), 3.20
(dd, J = 9.3, 17.1 Hz, 1 H, H-4¢b), 3.79 (s, 3 H, NMe), 3.94 (s, 3 H,
OMe), 4.04 (t, J = 8.1 Hz, 1 H, H-2¢a), 4.15 (quin, J = 8.1 Hz, 1 H,
H-3¢), 4.27 (t, J = 8.1 Hz, 1 H, H-2¢b), 7.18 (t, J = 7.4 Hz, 1 H, ArH),
7.39 (t, J = 8.0 Hz, 2 H, ArH), 7.62 (d, J = 7.7 Hz, 2 H, ArH), 7.91
(s, 1 H, 3-H).
13C NMR (DMSO-d6): d = 26.5, 37.2, 37.4, 51.2, 51.9, 110.3,
119.5, 124.1, 128.7, 139.2, 140.8, 146.6, 163.2, 172.2.
MS (ESI): m/z = 300 [M + H]+.
284.1041.
Anal. Calcd for C15H15N3O3: C, 63.15; H, 5.30; N, 14.73. Found: C,
63.01; H, 5.25; N, 14.71.
LC–MS: Rt = 13.642 min, m/z = 286 [M + H]+, area = 100%.
5-(5-Oxo-1-phenylpyrrolidin-3-yl)-1-phenyl-1H-pyrazole-4-
carboxylic Acid (13{2})
Prepared from ester 12{2} (9.03 g, 25 mmol).
HRMS (ESI): m/z [M + H]+ calcd for C16H18N3O3: 300.1348; found:
300.1352.
Yield: 7.12 g (82%); white solid; mp 237–239 °C.
Anal. Calcd for C16H17N3O3·H2O: C, 62.33; H, 5.88; N, 13.63.
Found: C, 62.30; H, 5.48; N, 13.70.
IR (KBr): 2954 (NH), 1693 (C=O), 1666 (C=O), 1549, 1499, 1401,
1283, 760, 691 cm–1.
LC–MS: Rt = 12.033 min, m/z = 300 [M + H]+, area = 100%.
1H NMR (DMSO-d6): d = 2.81 (dd, J = 10.2, 16.8 Hz, 1 H, H-4¢a),
3.07 (dd, J = 9.3, 16.8 Hz, 1 H, H-4¢b), 3.88 (quin, J = 9.3 Hz, 1 H,
Synthesis 2011, No. 17, 2822–2832 © Thieme Stuttgart · New York

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Synthesis of 5-(5-Oxopyrrolidin-3-yl)-1H-pyrazole-4-carboxamides
2831
H-3¢), 4.12 (dt, J = 9.3, 20.1 Hz, 2 H, CH2-2¢), 7.13 (tt, J = 1.0, 7.4
Hz, 1 H, ArH), 7.37 (tt, J = 1.9, 8.0 Hz, 2 H, ArH), 7.49–7.65 (m, 7
H, ArH), 8.08 (s, 1 H, H-3), 12.68 (br s, 1 H, COOH).
13C NMR (DMSO-d6): d = 27.3, 37.8, 52.5, 112.6, 119.7, 124.1,
126.3, 128.6, 129.2, 129.5, 138.3, 139.2, 142.8, 147.0, 164.3, 172.0.
MS (ESI): m/z = 348 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C20H18N3O3: 348.1348; found:
Catalysts, Materials, Vol. 2; Nicolaou, K. C.; Hanko, R.;
Hartwig, W., Eds.; Wiley-VCH: Weinheim, 2002, 725.
(2) (a) Dolle, R. E.; Le Bourdonnec, B.; Morales, G. A.;
Moriarty, K. J.; Salvino, J. M. J. Comb. Chem. 2008, 10,
753. (b) Dolle, R. E.; Le Bourdonnec, B.; Goodman, A. J.;
Morales, G. A.; Thomas, C. J.; Zhang, W. J. Comb. Chem.
2009, 11, 739. (c) Dolle, R. E.; Le Bourdonnec, B.; Worm,
K.; Morales, G. A.; Thomas, C. J.; Zhang, W. J. Comb.
Chem. 2010, 12, 765; and references cited therein.
(3) (a) Patrick, G. L. In An Introduction to Medicinal
Chemistry, 3rd ed.; Oxford University Press: Oxford, 2005.
(b) Kazuta, Y.; Hirano, K.; Natsume, K.; Yamada, S.;
Kimura, R.; Matsumoto, S.-i.; Furuichi, K.; Matsuda, A.;
Shuto, S. J. Med. Chem. 2003, 46, 1980. (c) Liebscher, J.;
Patzel, M. Synlett 1994, 471. (d) Elsner, J.; Boeckler, F.;
Davidson, K.; Sugden, D.; Gmeiner, P. Bioorg. Med. Chem.
2006, 14, 1949. (e) Nenajdenko, V. G.; Zakurdaev, E. P.;
Gololobov, A. M.; Balenkova, E. S. Russ. Chem. Bull. 2005,
54, 220. (f) Marshall, D. R.; Rodriguez, G.; Thomson, D. S.;
Nelson, R.; Capolina, A. Bioorg. Med. Chem. Lett. 2007, 17,
315.
348.1352.
Anal. Calcd for C20H17N3O3·1/5H2O: C, 68.44; H, 5.00; N, 11.97.
Found: C, 68.44; H, 4.76; N, 12.03.
LC–MS: Rt = 17.375 min, m/z = 348 [M + H]+, area = 100%.
Parallel Synthesis; General Procedure
A Syncore® Polyvap, equipped with 24 reaction tubes, was charged
with equimolar amounts of acids 13{1,2} and Et3N in anhyd MeCN
[0.125 M, 12 × 4 mL of acids 13{1,2} (24 × 0.5 mmol)]. A soln of
bis(pentafluorophenyl) carbonate in anhyd MeCN (0.504 M, 24 × 1
mL, 24 × 0.504 mmol) was added and the mixtures stirred at r.t. for
45 min. Next, amines 14{1–12} (24 × 0.5 mmol) and Et3N (24 × 70
mL, 24 × 0.5 mmol) were added, and stirring was continued at r.t.
for 16 h. Eight reactions gave precipitates which were collected by
filtration on a MiniBlock™ to give compounds, 6{1; 3,7} and 6{2;
1–4,6,11} (workup A).16 The remaining reaction mixtures were
evaporated in vacuo (40 °C/2 mbar→80 °C/2 mbar), then Et2O (16
× 5 mL) was added to the residues, and the mixtures stirred at r.t. for
3 h. Four precipitates formed which were collected by filtration to
give compounds 6{1; 4–6,9} (workup B). The remaining mixtures
were evaporated in vacuo (30 °C/2 mbar→80 °C/2 mbar), and 50%
aq MeOH (12 × 5 mL) was added to the residues, and the mixtures
stirred at r.t. for 12 h. The resulting precipitates were collected by
filtration to afford compounds 6{1; 1,2,11,12} and 6{2; 5,7–10,12}
(workup C). The final two reaction mixtures were evaporated in
vacuo (40 °C/2 mbar→80 °C/2 mbar) to give compounds, 6{1; 8}
and 6{1; 10} (workup D). All the products were dried at 80 °C/0.01
mbar over P4O10–paraffin for 3 h to give carboxylates 6. The exper-
imental, physical, analytical and spectral data, and details on the
resolution of the enantiomers of compounds 6{1,2; 1–12} are pro-
vided in Tables 1– 4.
(4) Svete, J. In (4R*,5R*)-4-Benzoylamino-5-phenyl-3-
pyrazolidinone – A Useful Building Block in the Synthesis of
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Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
Acknowledgment
Financial support from Boehringer-Ingelheim Pharma (Biberach,
Germany) and from the Slovenian Research Agency through grant
P1-0179 are gratefully acknowledged. We are grateful for financial
contributions from the pharmaceutical companies, Krka d.d. (Novo
mesto, Slovenia) and Lek d.d. [a new Sandoz Company (Ljubljana,
Slovenia)], which made the purchase of a Mettler-Toledo Bohdan
MiniBlock™ Compact Shaking and Washing Station and Vacuum
Collection Base possible. Resolution of enantiomers of 6 was sup-
ported through the infrastructure (Agilent Technologies 1260 Infinity
HPLC) of the EN-FIST Centre of Excellence, Ljubljana, Slovenia.
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