Microwave-assisted direct amidation of ethyl 1-phenyl-5-hydroxy-1H-pyrazole-4-carboxylate

Article abstract of DOI:10.1002/jhet.2100

Microwave-assisted treatment of ethyl 5-hydroxy-1-phenyl-1H-pyrazole-4-carboxylate with excess primary aliphatic amines in 1-propanol at 140C and with excess pyrrolidine or piperidine in 2-methoxyethanol at 180C produced the corresponding carboxamides in

Full text of DOI:10.1002/jhet.2100

Month 2014
Microwave-Assisted Direct Amidation of Ethyl 1-Phenyl-5-hydroxy-1H-
pyrazole-4-carboxylate
Mladena Milošević,a Ines Šterbal,a Urban Feguš,a Jernej Baškovč,a Benjamin Prek,b Uroš Grošelj,a
Branko Stanovnik,a,b and Jurij Svetea,b
*
aFaculty of Chemistry and Chemical Technology, University of Ljubljana, Aškerčeva 5, 1000 Ljubljana, Slovenia
bCentre of Excellence EN-FIST, Dunajska 156, SI-1000 Ljubljana, Slovenia
*
E-mail: jurij.svete@fkkt.uni-lj.si
Received April 18, 2013
DOI 10.1002/jhet.2100
Published online 00 Month 2014 in Wiley Online Library (wileyonlinelibrary.com).
Microwave-assisted treatment of ethyl 5-hydroxy-1-phenyl-1H-pyrazole-4-carboxylate with excess primary
aliphatic amines in 1-propanol at 140°C and with excess pyrrolidine or piperidine in 2-methoxyethanol at
180°C produced the corresponding carboxamides in good yields.
J. Heterocyclic Chem., 00, 00 (2014).
INTRODUCTION
intermediate with amine [7]. Because carboxylic acids are
often available by hydrolysis of more readily available alkyl
esters, direct amidation of alkyl esters represents a valuable
shortcut to amides. However, this transformation is usually a
slow process requiring prolonged heating with excess amine
to achieve satisfactory conversion within a reasonable
time [7,8]. Nowadays, several methods for direct
amidation of esters are known, most of them utilizing acid
or base catalysis combined with microwave acceleration
of the process [9].
Pyrazoles [1] are important heterocyclic systems
because numerous pyrazole derivatives found widespread
applications in medicinal chemistry, catalysis, and material
science [2]. Among pyrazoles, hydroxypyrazoles or
pyrazolones and their saturated analogs are probably the
most important and useful group of pyrazole derivatives.
Typical examples of important pyrazolone derivatives
include antipyrine (A), phenidone (B), photographic
couples C, and azo dyes D (Fig. 1) [3].
Recently, a part of our research has been focused on
the synthesis of functionalized 3-pyrazolidinones [10]
and 3-pyrazolones [11]. Within the context of our work
on heterocyclic analogs of amino acids and peptides, we
also reported a three-step synthesis of 1-substituted
alkyl 5-hydroxy-1H-pyrazole-4-carboxylates from diethyl
malonate (1) [12]. In continuation, we were interested in
the preparation of the corresponding carboxamides,
because their calculated physicochemical properties showed
promising drug-likeness, meaning that they could be easily
available and interesting building blocks for pharmaceutical
applications. However, an attempted base-catalyzed
hydrolysis of ethyl 5-hydroxy-1H-pyrazole-4-carboxylate (3)
failed, and, consequently, we were prompted to find out
another way to access the desired carboxamides. As the
result of this study, we report the synthesis of 5-hydroxy-
1H-pyrazole-4-carboxamides 7a–q via a microwave-assisted
direct amidation of the corresponding ethyl 5-hydroxy-1H-
pyrazole-4-carboxylate (3).
Despite the fact that this chemistry started more than a
century ago, the interest in pyrazolones is still continuing.
Moreover, the number of publications on pyrazolone
increased again in the last decade, mostly because of the
preparation of novel biologically active derivatives [4]
and dyes [5] and also because of their recent applications
in asymmetric organocatalysis [6].
Because amide linkages are present in many biolo-
gically active molecules and natural products, formation
of amide bond belongs among the most frequently used
transformations in organic, bioorganic, and bioche-
mistry. There are numerous synthetic methods for the
preparation of amides, and most of them are based on
amidation of the most reactive carboxylic acid derivatives,
such as acid chlorides, anhydrides, active esters, and
imidazolides. In practice, amidation is usually carried out as
a two-step one-pot process starting with in situ activation of
carboxylic acid, followed by treatment of the reactive
© 2014 HeteroCorporation

M. Milošević, I. Šterbal, U. Feguš, J. Baškovč, B. Prek U. Grošelj, B. Stanovnik, and J. Svete
Vol 000
followed by conventional amidation of 4 using bis
(pentafluorophenyl) carbonate as the activating reagent
[11c,13]. Although hydrolysis of 3 into 4 by treatment with
sodium hydroxide in refluxing ethanol has already been
reported by Claisen and Haase more than a century ago
[14], this reaction did not work well in our hands. For
example, treatment of 3 with aqueous sodium hydroxide
in methanol at 50°C for 12 h, followed by cooling to room
temperature, and acidification of the reaction mixture
furnished mostly the unreacted starting material 3.
Although surprising at first glance, such resistance of the
ester 3 toward basic hydrolytic conditions is explainable
by deprotonation of the phenolic OH group leading to the
phenolate-type anion 5 with widely delocalized negative
charge as represented by the resonance structure 5′, where
electronic repulsion prevents the approach of the nucleo-
phile to the carbonyl group (Scheme 1).
Figure 1. Examples of important pyrazolones.
RESULTS AND DISCUSSION
The aforementioned experiment showed that the hydro-
lysis of the ester group was difficult and that trying
another amidation method would be more productive
thing to do in order to obtain the desired carboxamides.
Inspired by numerous examples of successful applications
of microwaves in condensation reactions [9,15], we
decided to try out a direct, microwave-assisted amidation
of the pyrazole ester 3. The first preliminary experiment
was performed by reacting 3 with 5 equiv of 1-butylamine
(6b) in 1-propanol at 150°C for 30 min under microwave
irradiation (P = 300 W). Under these reaction conditions,
a complete conversion of the starting material 3 into the
corresponding carboxamide 7b took place according to
TLC. In spite of this beginner’s luck, the screening for
optimal reaction conditions was performed by reacting 3
with 2–5 equiv of 1-butylamine (6b) in 1-propanol at
120–150°C for 10–30 min. First, it has been established
that microwave-assisted heating (P = 300 W) of 3 with
5 equiv of 1-butylamine (6b) in 1-propanol at 140°C for
20 min could be considered as safe to achieve a complete
conversion into the carboxamide 7b. Either shortening of
the reaction time to 10 min, or lowering excess amine 6 to
3 equiv, or lowering the temperature to 120°C resulted in
an incomplete conversion according to TLC. The same
was observed when the reaction of 3 with 1-butylamine
(6b) was performed by conventional heating. The use of
basic amidation promoters, such as K2CO3, Cs2CO3,
and DBU, did not improve the result. Amidation of 3 with
neat 1-butylamine (6b) at 140°C resulted in an uncon-
trolled explosive opening of the reaction vessel caused
by the exceeded pressure limit (20 bar). This accident
clearly indicated that this method is not suitable for neat
amidation with volatile aliphatic amines. To avoid such
accidents, final screening was performed in water, 1,4-
dioxane, and DMF (i.e., in solvents with bp ≥ 90°C).
Reaction of 3 with 1-butylamine (6b) in water showed
no conversion, whereas in 1,4-dioxane, the conversion
First, the central intermediate 3 was prepared in two
steps from diethyl malonate (1) utilizing a one-pot
simplified literature procedure for the preparation of
closely related compounds [12]. Treatment of 1 with N,
N-dimethylformamide dimethylacetal in refluxing toluene
for 1.5 h gave the intermediate enaminone 2, which was
directly reacted further with phenylhydrazine hydroc-
hloride in refluxing 1-propanol to afford 3 in 91% yield
(Scheme 1).
To obtain the desired carboxamides, we intended to
carry out a base-catalyzed hydrolysis of the ester 3 into
5-hydroxy-1-phenyl-1H-pyrazole-4-carboxylic acid (4),
Scheme 1. Reaction conditions: (i) DMFDMA, toluene, reflux; (ii)
PhNHNH2 · HCl, 1-propanol, reflux; (iii) 2M aq NaOH, MeOH, 50°C.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
Microwave-Assisted Direct Amidation of Ethyl 1-Phenyl-5-hydroxy-1H-pyrazole-4-
carboxylate
Scheme 2
was incomplete. When 3 was reacted with 1-butylamine
(6b) in DMF at 140°C, N-butylformamide was obtained
as the product, while the starting material did not react.
Thus, DMF acted also as a formylating reagent and not
only as a solvent. Finally, a series of amidations of the
ester 3 with aliphatic primary amines 6a–o under the op-
timized conditions (1-propanol, 5 equiv of 6, P = 300 W,
T = 140°C, t = 20 min) were performed. All these reactions
proceeded smoothly to give the corresponding
carboxamides 7a–o in 30–91% yields. On the other hand,
amidation of 3 with pyrrolidine (6p) as the representative
secondary amine was not successful under the aforemen-
tioned reaction conditions. This was not really surprising,
because acylations of the secondary amines are usually
substantially slower because of pronounced steric hin-
drance by the two alkyl groups. Nevertheless, the treat-
ment of 3 with 6p in 2-methoxyethanol at 180°C did
produce the corresponding amide 7p in 50% yield.
Similarly, the amidation of 3 with piperidine (6q) was
also successful under these conditions. Unfortunately,
attempts to carry out the amidation of 3 with some other
secondary amines, such as morpholine, diethylamine,
and dibenzylamine, failed (Scheme 2, Table 1).
The structures of all novel compounds 7a–q were
determined by spectroscopic methods (1H nmr, 13C nmr, ir,
ms, and hrms) and by elemental analyses for C, H, and N.
Spectral data for compounds 7a–q were in agreement with
the data for the related pyrazole derivatives [1,11,12].
CONCLUSION
In conclusion, a simple microwave-assisted direct
amidation of ethyl 1-phenyl-5-hydroxy-1H-pyrazole-4-
carboxylate (3) was developed. This is, to the best of
our knowledge, the shortest and the easiest way to pre-
pare 5-hydroxypyrazole-4-carboxamides 7, because the
ester 3 is somewhat reluctant to base-catalyzed hydrolysis
to the carboxylic acid 4. So far, the scope of this method is
limited to primary aliphatic amines and most reactive
cyclic secondary amines, such as pyrrolidine and piperidine,
and to the ester 3 as the model substrate. Most probably, this
method could also be applied for the preparation of related
(het)arenecarboxamides, especially when esters are more
easily available than the corresponding carboxylic acids.
EXPERIMENTAL
Table 1
General methods.
Kofler micro hot stage (Leica Microsystems GmbH, Wetzlar,
Melting points were determined on a
Experimental data on carboxamides 7a–q.
Germany). The nmr spectra were obtained on a Bruker Avance
III UltraShield 500 plus at 500 MHz for H and at 126 MHz for
Compound
R
Yield (%)
1
13C nuclei, using deuteriochloroform and DMSO-d6, with TMS
as the internal standard, as solvents (Bruker Corporation,
Billerica, MA). Mass spectra were recorded on an Agilent 6224
accurate mass TOF LC/MS (Agilent Technologies Inc., Santa
Clara, CA) and the ir spectra on a PerkinElmer Spectrum BX
FTIR spectrophotometer (Perkin-Elmer Inc., Waltham, MA).
Microanalyses were performed on a PerkinElmer CHN Analyzer
2400 II (Perkin-Elmer Inc., Waltham, MA). Microwave irradiations
were performed on a CEM Discover laboratory microwave oven
(CEM Corporation, Matthews, NC). Flash column
chromatography was performed on a silica gel (Fluka, silica gel
60, particle size 0.035–0.070 mm) (Fluka, Buchs, Switzerland).
6a, 7a
6b, 7b
6c, 7c
6d, 7d
6e, 7e
6f, 7f
6g, 7g
6h, 7h
6i, 7i
6j, 7j
6k, 7k
6l, 7l
6m, 7m
6n, 7n
6o, 7o
6p, 7p
6q, 7q
1-Propyl
1-Butyl
1-Pentyl
1-Hexyl
Benzyl
4-Methoxybenzyl
2-Phenylethyl
3-Phenylprop-1-yl
Cyclopropyl
87
85
86
52
70
91
63
64
30
72
69
75
77
61
58
50
46
Cyclobutyl
Cyclopentyl
Cyclohexyl
2-Methoxyethyl
2-Hydroxyethyl
3-Hydroxypropyl
À(CH2)4À
Amines 6a–q are commercially available (Sigma-Aldrich)
(Sigma-Aldrich, St. Louis, MO). Ethyl 5-hydroxy-1-phenyl-1H-
pyrazole-4-carboxylate (3) was prepared following the literature
procedure [5].
À(CH2)5À
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

M. Milošević, I. Šterbal, U. Feguš, J. Baškovč, B. Prek U. Grošelj, B. Stanovnik, and J. Svete
Vol 000
General procedure for the microwave-assisted amidation
ethyl 5-hydroxy-1-phenyl-1H-pyrazole-4-carboxylate
A mixture of ester 3 (0.232 g, 1 mmol), 1-propanol
(2 mL), and amine 6 (5 mmol) was stirred in a sealed vessel
under microwave irradiation (P = 300W) at 140°C (P~ 10bar) for
20min. The reaction mixture was cooled to room temperature,
diluted with ethyl acetate (50mL), and washed with 1M aqueous
sodium hydrogen sulfate (2× 20mL). The combined organic
phase was dried over anhydrous sodium sulfate and filtered, and
the filtrate was evaporated in vacuo to give 7.
and 1-hexylamine (6d) (0.505 g, 5 mmol). Yield: 0.150 g
(52%) of a light brown solid; mp 93–95°C; ir (KBr): 3402,
2580, 1633, 1556, 1538, 1503, 1352, 1240, 1124 cmÀ1
of
(3).
.
1H nmr (DMSO-d6): 0.87 (3H, t, J = 6.8 Hz, CH3(CH2)5),
1.24–1.34 (6H, m, 3 × CH2), 1.49 (2H, quintet, J = 6.8 Hz,
CH3CH2), 3.26 (2H, t, J = 7.0 Hz, CH2NH), 7.32 (1H, t,
J = 7.4 Hz, p-Ph), 7.50 (2H, t, J = 8.0 Hz, m-Ph), 7.74 (2H, d,
J = 7.7 Hz, o-Ph), 8.12 (1H, s, 3-H), 8.41 (1H, br s, NH), 10.90
(1H, br s, OH). 13C nmr (DMSO-d6): 13.9, 22.1, 26.1, 29.3, 31.0,
38.1, 97.9, 120.7, 126.3, 129.1, 137.0, 137.5, 157.9, 163.6. ms:
m/z 288 (MH+); hrms Calcd for C16H22N3O2: m/z 288.1707
(MH+); found: m/z 288.1708 (MH+). Anal. Calcd for
C16H21N3O2 · 4/10H2O (294.56): C, 65.32; H, 7.46; N, 14.29.
Found: C, 65.38; H, 7.43; N, 14.01.
The following compounds were prepared in this manner.
5-Hydroxy-1-phenyl-N-propyl-1H-pyrazole-4-carboxamide
(7a). This compound was prepared from 3 (0.232 g, 1 mmol)
and 1-propylamine (6a) (0.296 g, 5 mmol). Yield: 0.213 g
(87%) of a white solid; mp 125–130°C; ir (potassium
bromide): 3272, 1693, 1636, 1595, 1576, 1533, 1499, 1459,
N-Benzyl-5-hydroxy-1-phenyl-1H-pyrazole-4-carboxamide
(7e). This compound was prepared from 3 (0.232 g, 1 mmol)
and benzylamine (6e) (0.536 g, 5 mmol). Yield: 0.205 g (70%)
of a white solid; mp 122–128°C; ir (potassium bromide):
3275, 1644, 1558, 1532, 1499, 1455, 1351, 1241, 1185,
1425, 1323, 1281, 1197, 1084, 962 cmÀ1 1H nmr (DMSO-
.
d6): 0.99 (3H, t, J = 7.1 Hz, CH2CH3), 1.64 (2H, br sextet,
J = 7.1 Hz, CH2CH3), 3.23 (2H, br t, J = 7.1 Hz, CH2NH),
7.33 (1H, br t, J = 7.4 Hz, p-Ph), 7.51 (2H, br t, J = 7.6 Hz,
m-Ph), 7.82 (2H, br d, J = 7.8 Hz, o-Ph), 8.13 (1H, s, 3-H),
8.43 (1H, br s, NH), 10.94 (1H, br s, OH). 13C nmr (DMSO-
d6): 11.4, 22.6, 39.6, 104.5, 126.4, 129.2, 129.5, 129.5,
137.5, 160.3, 161.9. ms: m/z 246 (MH+); hrms Calcd for
C13H16N3O2: m/z 246.1243 (MH+); found: m/z 246.1250
(MH+). Anal. Calcd for C13H15N3O2 (245.28): C, 63.66; H,
6.16; N, 17.13. Found: C, 63.57; H, 6.36; N, 17.01.
901 cmÀ1 1H nmr (deuteriochloroform): 4.41 (2H, br d,
.
J = 4.5 Hz, CH2Ph), 7.16–7.38 (8H, m, 8H of Ph), 7.50–7.60
(2H, m, 2H of Ph), 7.68 (1H, s, 3-H), 8.19 (1H, br s, NH),
10.30 (1H, br s, OH). 13C nmr (deuteriochloroform): 42.8,
99.2, 121.1, 127.2, 127.7, 127.7, 128.7, 129.2, 135.8, 136.1,
137.9, 159.1, 164.4. ms: m/z 294 (MH+); hrms Calcd for
C17H16N3O2: m/z 294.1243 (MH+); found: m/z 294.1248
(MH+). Anal. Calcd for C17H15N3O2 (293.32): C, 69.61; H,
5.15; N, 14.33. Found: C, 69.38; H, 5.20; N, 14.17.
N-Butyl-5-hydroxy-1-phenyl-1H-pyrazole-4-carboxamide
(7b). This compound was prepared from 3 (0.232 g, 1 mmol)
and 1-butylamine (6b) (0.366 g, 5 mmol). Yield: 0.221 g (85%)
of a white solid; mp 100–104°C; ir (potassium bromide): 3301,
1688, 1635, 1595, 1577, 1497, 1458, 1425, 1313, 1292, 1199,
5-Hydroxy-N-(4-methoxybenzyl)-1-phenyl-1H-pyrazole-4-
carboxamide (7f).
This compound was prepared from 3
(0.232 g, 1 mmol) and 4-methoxybenzylamine (6f) (0.686 g,
5 mmol). Yield: 0.294g (91%) of a white solid; mp 147–156°C;
ir (potassium bromide): 3266, 1651, 1351, 1242, 1032, 756 cmÀ1
.
1085, 1060, 964 cmÀ1 1H nmr (deuteriochloroform): 0.93
.
1H nmr (DMSO-d6): 3.73 (3H, s, OMe), 4.41 (2H, d, CH2Ph),
6.90 (2H, br d, J = 8.6 Hz, 2H of C6H4), 7.25 (2H, br d,
J = 8.6 Hz, 2H of C6H4), 7.32 (1H, br t, J = 7.5 Hz, p-Ph), 7.50
(2H, br t, J = 7.6 Hz, m-Ph), 7.72 (2H, br t, J = 7.7 Hz, o-Ph),
8.16 (1H, br s, 3-H), 8.78 (1H, br s, NH), 10.93 (1H, br s,
OH). 13C nmr (deuteriochloroform): 41.2, 55.1, 104.4, 113.8,
117.8, 117.9, 120.8, 126.5, 128.7, 129.2, 129.5, 137.6, 158.3,
163.4. ms: m/z 324 (MH+); hrms Calcd for C18H18N3O3: m/z
324.1248 (MH+); found: m/z 324.1330 (MH+). Anal. Calcd
for C18H17N3O3 (323.35): C, 66.86; H, 5.30; N, 13.00.
Found: C, 66.64; H, 5.32; N, 12.95.
(3H, t, J = 7.1 Hz, CH2CH2CH3), 1.39 (2H, br sextet,
J = 7.1 Hz, CH2CH2CH3), 1.55 (2H, br sextet, J = 7.1 Hz,
CH2CH2CH3), 3.38 (2H, br q, J = 7.1 Hz, CH2NH), 6.27
(1H, br s, NH), 7.25–7.51 (3H, m, 3H of Ph), 7.63 (1H, s,
3-H), 7.70–7.80 (2H, m, 2H of Ph), 8.92 (1H, br s, OH).
13C nmr (deuteriochloroform): 13.8, 20.2, 31.8, 39.0, 104.7, 119.0,
121.1, 127.0, 129.3, 129.6, 129.7, 135.7, 161.0, 163.6. ms: m/z 260
(MH+); hrms Calcd for C14H18N3O2: m/z = 260.1399 (MH+);
found: m/z 260.1402 (MH+). Anal. Calcd for C14H17N3O2 (259.30):
C, 64.85; H, 6.61; N, 16.20. Found: C, 64.62; H, 6.75; N, 15.84.
5-Hydroxy-N-pentyl-1-phenyl-1H-pyrazole-4-carboxamide
(7c). This compound was prepared from 3 (0.232 g, 1 mmol)
and 1-pentylamine (6c) (0.436 g, 5 mmol). Yield: 0.235 g
(86%) of a white solid; mp 108–113°C; ir (potassium
bromide): 3128, 1700, 1636, 1594, 1576, 1498, 1458, 1425,
5-Hydroxy-1-phenyl-N-(2-phenylethyl)-1H-pyrazole-4-
carboxamide (7g).
This compound was prepared from 3
(0.232 g, 1 mmol) and 2-phenylethylamine (6g) (0.606g, 5 mmol).
Yield: 0.193 g (63%) of a white solid; mp 127–132°C; ir
(potassium bromide): 3319, 1638, 1595, 1579, 1528, 1495, 1359,
1295, 1201, 1084, 955 cmÀ1 1H nmr (deuteriochloroform):
.
.
1313, 1197, 957 cmÀ1 1H nmr (deuteriochloroform): 2.80
0.83 (3H, t, J = 7.1 Hz, CH2CH2CH3), 1.23–1.30 (4H, m,
CH2CH2CH3), 1.47–1.55 (2H, m, CH2CH2NH), 3.27–3.34
(2H, m, CH2NH), 6.18 (1H, br s, NH), 7.33 (1H, m, p-Ph),
7.43 (2H, m, m-Ph), 7.64 (1H, s, 3-H), 7.68–7.74 (2H, m,
o-Ph), 8.65 (1H, br s, OH). 13C nmr (deuteriochloroform):
14.1, 22.5, 29.2, 29.5, 39.3, 119.1, 121.1, 127.0, 129.3,
135.6, 138.6, 156.8, 162.9. ms: m/z = 274 (MH+); hrms Calcd
for C15H20N3O2: m/z 274.1556 (MH+); found: m/z 274.1564
(MH+). Anal. Calcd for C15H19N3O2 (273.33): C, 65.91; H,
7.01; N, 15.37. Found: C, 65.62; H, 7.06; N, 14.97.
(2H, t, J = 7.1 Hz, CH2Ph), 3.52 (2H, br q, J = 7.1Hz, CH2NH),
7.11–7.34 (9H, m, Ph and 4H of Ph), 7.55–7.63 (2H, m, 1H of
Ph, NH), 7.69 (1H, s, 3-H), 10.42 (1H, br s, OH). 13C nmr
(deuteriochloroform): 35.8, 40.4, 99.1, 118.9, 121.4, 126.6, 127.2,
128.6, 128.7, 129.2, 135.9, 138.6, 158.9, 164.7. ms: m/z 308
(MH+); hrms Calcd for C18H18N3O2: m/z 308.1394 (MH+); found:
m/z 308.1391 (MH+). Anal. Calcd for C18H17N3O2 (307.35): C,
65.91; H, 7.01; N, 15.37. Found: C, 70.11; H, 5.58; N, 13.63.
5-Hydroxy-1-phenyl-N-(3-phenylprop-1-yl)-1H-pyrazole-4-
carboxamide (7h).
This compound was prepared from 3
N-Hexyl-5-hydroxy-1-phenyl-1H-pyrazole-4-carboxamide
(7d). This compound was prepared from 3 (0.232 g, 1 mmol)
(0.232 g, 1 mmol) and 3-phenylpropylamine (6h) (0.675g,
5 mmol). Yield: 0.207 g (64%) of a light brown solid; mp 77–
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
Microwave-Assisted Direct Amidation of Ethyl 1-Phenyl-5-hydroxy-1H-pyrazole-4-
carboxylate
82°C; ir (potassium bromide): 3440, 2923, 1634, 1610, 1526, 1498,
1458, 1320, 1294, 1180, 1080, 1062, 958cmÀ1 1H nmr
N-Cyclohexyl-5-hydroxy-1-phenyl-1H-pyrazole-4-carboxamide
(7l). This compound was prepared from 3 (0.232g, 1 mmol) and
cyclohexylamine (6l) (0.496 g, 5 mmol). Yield: 0.214g (75%) of a
white solid; mp 160–168°C; ir (potassium bromide): 3286, 3117,
1700, 1630, 1596, 1575, 1527, 1498, 1458, 1427, 1321, 1290,
1058, 961cmÀ1. 1H nmr (deuteriochloroform): 1.14–1.29 (3H, m,
3H of C6H11), 1.32–1.44 (2H, m, 2H of C6H11), 1.61–1.68
(1H, m, 1H of C6H11), 1.72–1.88 (2H, m, 2H of C6H11),
1.93–2.02 (2H, m, 2H of C6H11), 3.86–3.95 (1H, m, CH of
C6H11), 5.82 (1H, br s, NH), 7.30 (1H, br t, J =7.3 Hz, p-Ph),
7.45 (2H, br t, J = 7.8 Hz, m-Ph), 7.68 (1H, br s, 3-H), 7.79
(2H, br d, J = 7.2Hz, o-Ph), 8.18 (1H, br s, OH). 13C nmr
(deuteriochloroform): 25.0, 25.6, 33.3, 48.3, 121.1, 127.0, 129.3,
129.6, 135.4, 137.6, 158.0, 164.5. ms: m/z 286 (MH+); hrms
Calcd for C16H20N3O2: m/z 286.1556 (MH+); found:
m/z 286.1565 (MH+). Anal. Calcd for C16H19N3O2 (285.34): C,
67.35; H, 6.71; N, 14.73. Found: C, 67.11; H, 6.78; N, 14.61.
5-Hydroxy-N-(2-methoxyethyl)-1-phenyl-1H-pyrazole-4-
.
(DMSO-d6): 1.81 (2H, quintet, J = 7.4Hz, CH2CH2CH2), 2.63
(2H, t, J = 7.7 Hz, CH2Ph), 3.27 (2H, t, J = 7.1 Hz, CH2NH), 7.17
(1H, t, J = 7.2 Hz, p-Ph), 7.74 (2H, d, J = 6.4Hz, o-Ph), 7.28
(2H, t, J =7.5 Hz, m-Ph), 7.32 (1H, t, J = 7.2 Hz, p-Ph), 7.50
(2H, t, J = 7.9 Hz, m-Ph), 7.74 (2H, d, J = 7.8 Hz, o-Ph), 8.12
(1H, s, 3-H), 8.46 (1H, br s, NH), 10.91 (1H, br s, OH). 13C nmr
(DMSO-d6): 31.0, 32.5, 37.7, 97.9, 120.6, 125.7, 126.3, 128.3,
128.3, 129.1, 137.0, 137.5, 141.5, 157.8, 163.6. ms: m/z = 320
([M À H]À); hrms: m/z = 320.1408 ([M À H]À); C19H18N3O2
requires: m/z = 320.1405 ([MÀ H]À). Anal. Calcd for
C19H19N3O2 · ⅔H2O (333.38): C, 68.45; H, 6.13; N, 12.60.
Found: C, 68.48; H, 6.23; N, 12.28.
N-Cyclopropyl-5-hydroxy-1-phenyl-1H-pyrazole-4-carboxamide
(7i). This compound was prepared from 3 (0.232g, 1 mmol) and
cyclopropylamine (6i) (0.285g, 5 mmol). The product was purified
by flash column chromatography (ethyl acetate). Fractions
containing the product were combined and evaporated in vacuo to
give 6i. Yield: 0.070 g (30%) of a light brown solid; mp 184–186°C;
ir (KBr): 3417, 2964, 1621, 1558, 1504, 1455, 1362, 1085,
carboxamide (7m).
This compound was prepared from 3
(0.232 g, 1 mmol) and 2-methoxyethylamine (6m) (0.376g,
5 mmol). Yield: 0.201g (77%) of a white solid; mp 110–116°C;
ir (potassium bromide): 3301, 3134, 1709, 1616, 1583, 1507,
1
936 cmÀ1. H nmr (DMSO-d6): 0.53 (2H, br s, CH2), 0.71 (2H,
br d, J =5.7Hz, CH2), 2.81 (1H, br s, CHNH), 7.29 (1H, t,
J =7.4Hz, p-Ph), 7.47 (2H, t, J= 8.0Hz, m-Ph), 7.71 (2H, d,
J =7.8Hz, o-Ph), 8.09 (1H, s, 3-H), 8.46 (1H, br s, NH), 10.82
(1H, br s, OH). 13C nmr (DMSO-d6): 6.1, 21.4, 118.0, 122.3,
126.9, 129.1, 137.9, 140.3, 155.1, 163.0. ms: m/z 244 (MH+);
hrms Calcd for C13H14N3O2: m/z 244.1081 (MH+): m/z 244.1081
(MH+). Anal. Calcd for C13H13N3O2 · 1/5H2O (246.86): C, 57.55;
H, 5.98; N, 15.48. Found: C, 57.66; H, 5.31; N, 14.87.
1461, 1429, 1315, 1264, 1194, 1114, 963 cmÀ1 1H nmr
.
(deuteriochloroform): 3.41 (3H, s, OMe), 3.54 (2H, br t,
J = 4.8 Hz, CH2NH), 3.61 (2H, br q, J = 4.8 Hz, CH2OMe), 6.42
(1H, br s, NH), 7.29 (1H, br t, J = 7.3 Hz, p-Ph), 7.43 (2H, br t,
J = 7.4 Hz, m-Ph), 7.69 (1H, br s, 3-H), 7.75–7.81 (2H, m, o-Ph),
9.17 (1H, br s, OH). 13C nmr (deuteriochloroform): 38.9, 59.0,
71.1, 119.0, 121.1, 127.0, 129.2, 129.7, 135.7, 157.6, 165.8. ms:
m/z 262 (MH+); hrms Calcd for C13H16N3O3: m/z 262.1192
(MH+); found: m/z 262.1165 (MH+). Anal. Calcd for C13H15N3O3
(261.28): C, 59.76; H, 5.79; N, 16.08. Found: C, 59.44; H, 5.82;
N, 16.00.
N-Cyclobutyl-5-hydroxy-1-phenyl-1H-pyrazole-4-carboxamide
(7j). This compound was prepared from 3 (0.232g, 1 mmol) and
cyclobutylamine (6j) (0.355g, 5mmol). Yield: 0.190g (72%) of a
white solid; mp 165–169°C; ir (KBr): 2964, 1634, 1595, 1575,
1533, 1498, 1459, 1425, 1312, 1293, 1212, 1128, 1094, 1060,
5-Hydroxy-N-(2-hydroxyethyl)-1-phenyl-1H-pyrazole-4-
carboxamide (7n).
This compound was prepared from 3
1
1028, 964 cmÀ1. H nmr (DMSO-d6): 1.63–1.72 (2H, m, CH2),
(0.232 g, 1 mmol) and 2-aminoethanol (6n) (0.305 g, 5 mmol).
Yield: 0.150 g (61%) of a white solid; mp 135–138°C; ir (KBr):
3449, 3248, 2941, 2876, 1653, 1581, 1520, 1497, 1460, 1440,
1406, 1354, 1290, 1249, 1228, 1185, 1089, 1060, 1047,
1.99 (2H, doublet of quintet, J = 2.8, 9.3 Hz, CH2), 2.20–2.27
(2H, m, CH2), 4.39 (1H, quintet, J = 7.3Hz, CHNH), 7.33
(1H, t, J =7.5 Hz, p-Ph), 7.50 (2H, t, J = 7.9Hz, m-Ph), 7.74
(2H, d, J = 7.8Hz, o-Ph), 8.11 (1H, s, 3-H), 8.58 (1H, br s, NH),
10.91 (1H, br s, OH). 13C nmr (DMSO-d6): 17.8, 30.5, 43.5,
59.4, 117.9, 120.7, 126.5, 129.2, 137.1, 137.5, 157.7, 162.8. ms:
m/z 256 ([M À H]À); hrms Calcd for C14H16N3O2: m/z 258.1237
(MH+); found: m/z 258.1236 (MH+). Anal. Calcd for
C14H15N3O2 · 1/7H2O (259.86): C, 64.71; H, 5.93; N, 16.17.
Found: C, 64.82; H, 5.82; N, 15.52.
1
933 cmÀ1. H nmr (DMSO-d6): 3.33 (2H, t, J = 5.9Hz, CH2NH),
3.51 (2H, t, J = 5.9 Hz, CH2OH), 4.68 (1H, br s, CH2OH), 7.32
(1H, t, J = 7.4Hz, p-Ph), 7.50 (2H, t, J = 8.0Hz, m-Ph), 7.73
(2H, d, J = 7.7Hz, o-Ph), 8.17 (1H, s, 3-CH), 8.46 (1H, br s, NH),
10.93 (1H, br s, OH). 13C nmr (DMSO-d6): 41.0, 59.9, 117.9,
120.7, 126.4, 129.2, 136.9, 137.7, 158.1, 163.6. ms: m/z 248
(MH+); hrms Calcd for C12H14N3O3: m/z 246.0884 ([MÀ H]À);
found: m/z 246.0884 ([MÀ H]À). Anal. Calcd for C12H13N3O3
(247.25): C, 58.29; H, 5.30; N, 16.99. Found: C, 58.19; H, 5.07;
N, 16.82.
N-Cyclopentyl-5-hydroxy-1-phenyl-1H-pyrazole-4-carboxamide
(7k). This compound was prepared from 3 (0.232g, 1 mmol) and
cyclopentylamine (6k) (0.425g, 5 mmol). Yield: 0.190g (69%) of
a light brown solid; mp 180–183°C; ir (KBr): 3446, 2957, 2868,
1688, 1633, 1595, 1574, 1498, 1459, 1427, 1320, 1293, 1204,
5-Hydroxy-N-(3-hydroxypropyl)-1-phenyl-1H-pyrazole-4-
carboxamide (7o).
This compound was prepared from 3
1135, 1088, 1059, 1028, 958 cmÀ1
.
1H nmr (DMSO-d6): 1.49
(0.232 g, 1 mmol) and 3-amino-1-propanol (6o) (0.376g, 5 mmol).
Yield: 0.150 g (58%) of a white solid; mp 160–163°C; ir
(potassium bromide): 3450, 1637, 1570, 1458, 1352, 1295, 1209,
(2H, sextet, J = 6.5Hz, CH2), 1.52–1.60 (2H, m, CH2), 1.64–1.72
(2H, m, CH2), 1.49 (2H, sextet, J = 6.3Hz, CH2), 4.20
(1H, quintet, J = 6.8 Hz, CHNH), 7.32 (1H, t, J = 7.4 Hz, p-Ph),
7.50 (2H, t, J = 7.9Hz, m-Ph), 7.73 (2H, d, J = 8.1 Hz, o-Ph), 8.14
(1H, s, 3-H), 8.34 (1H, br s, NH), 10.93 (1H, br s, OH). 13C nmr
(DMSO-d6): 23.5, 32.5, 50.0, 98.0, 120.6, 126.4, 129.2, 136.9,
137.5, 158.0, 163.3. ms: m/z 272 (MH+); hrms Calcd for
C15H18N3O2: m/z 272.1394 (MH+); found: m/z 272.1367 (MH+).
Anal. Calcd for C15H17N3O2 · 1/5H2O (274.92): C, 65.51; H, 6.38;
N, 15.29. Found: C, 65.57; H, 6.40; N, 15.02.
1080, 1063, 944 cmÀ1 1H nmr (DMSO-d6): 1.66 (2H, quintet,
.
J = 6.6 Hz, CH2CH2CH2), 3.32 (2H, t, J = 7.0Hz, CH2NH), 3.47
(2H, t, J = 6.3 Hz, CH2OH), 4.53 (1H, br s, CH2OH), 7.33 (1H, t,
J = 7.4 Hz, p-Ph), 7.50 (2H, t, J = 8.0 Hz, m-Ph), 7.74 (2H, d,
J = 7.7 Hz, o-Ph), 8.31 (1H, s, 3-H), 8.42 (1H, br s, NH), 10.95
(1H, br s, OH). 13C nmr (DMSO-d6): 32.5, 35.5, 58.5, 118.0,
120.7, 126.5, 129.2, 137.5, 139.1, 160.4, 162.0. ms: m/z 262
(MH+); hrms Calcd for C13H16N3O3: m/z 262.1186 (MH+); found:
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

M. Milošević, I. Šterbal, U. Feguš, J. Baškovč, B. Prek U. Grošelj, B. Stanovnik, and J. Svete
Vol 000
m/z 262.1185 (MH+). Anal. Calcd for C13H15N3O3 (261.28): C,
59.76; H, 5.79; N, 16.08. Found: C, 59.90; H, 5.75; N, 15.85.
(5-Hydroxy-1-phenyl-1H-pyrazol-4-yl)(pyrrolidin-1-yl)methanone
(7p). This compound was prepared from 3 (0.232g, 1 mmol) and
pyrrolidine (6p) (0.355 g, 5 mmol). Yield: 0.130 g (50%) of a light
reddish solid; mp 142–144°C; ir (potassium bromide): 3417,
[3] (a) Hamama, W. S.; El-Gohary, H. G.; Kuhnert, N.; Zoorob,
H. H. Curr Org Chem 2012, 16, 373; (b) Mariappan, G.; Sana, B. P.;
Sutharson, L.; Ankit, G. S.; Pandey, L.; Kumar, D. J Pharm Res 2010,
3, 2856; (c) Varvounis, G. Adv Heterocycl Chem 2009, 98, 143.
[4] (a) Dohutia, C.; Kaishap, P. P.; Chetia, D. Int J Pharm Sci
2013, 5, 86; (b) Nathani, V.; Arora, K. Asian J Chem 2012, 24, 5803;
(c) Gadhave, A.; Kuchekar, S.; Karale, B. J Chem 2013, 741953, 9.; (d)
Trippier, P. C.; Benmohammed, R.; Kirsch, D. R.; Silverman, R. B.
Bioorg Med Chem Lett 2012, 22, 6647; (e) Huang, Z.; Aimone, L. D.;
Cheng, M.; Dorsey, B. D. Bioorg Med Chem Lett 2011, 21, 7261.
[5] (a) Bagdatli, E.; Ocal, N. J Heterocycl Chem 2012, 49,
1179; (b) Singh, A.; Choi, R.; Choi, B.; Koh, J. Dyes Pigments
2012, 95, 580.
[6] (a) Liang, J.; Chen, Q.; Liu, L.; Jiang, X.; Wang, R. Org
Biomol Chem 2013, 11, 1441; (b) Chen, Q.; Liang, J.; Wang, S.; Wang,
D.; Wang, R. Chem Commun 2013, 49, 1657; (c) Šimek, M.; Remeš,
M.; Veselý, J.; Rios, R. Asian J Org Chem 2013, 2, 64; (d) Liu, L.; Zhong,
Y.; Zhang, P.; Jiang, X.; Wang, R. J Org Chem 2012, 77, 10228.
[7] For a review, see Montalbetti, C. A. G. N.; Falque, V.
Tetrahedron 2005, 61, 10827.
2958, 1636, 1615, 1506, 1616, 1356,1054, 973cmÀ1 1H nmr
.
(DMSO-d6): 1.82–2.03 (4H, m, CH2CH2), 3.47–3.76 (4H, m,
2 × CH2N), 7.32 (1H, t, J = 7.4Hz, p-Ph), 7.51 (2H, t, J = 8.0Hz,
m-Ph), 7.84 (2H, d, J = 7.5 Hz, o-Ph), 7.96 (1H, s, 3-H), 10.23
(1H, br s, OH). 13C nmr (DMSO-d6): 23.6, 25.4, 46.5, 47.2, 118.1,
120.0, 126.3, 129.2, 137.7, 138.1, 160.1, 164.1. ms: m/z = 258
(MH+); hrms Calcd for C14H16N3O2: m/z = 258.1237 (MH+);
found: m/z 258.1237 (MH+). Anal. Calcd for C14H15N3O2 (259.29):
C, 65.35; H, 5.88; N, 16.33. Found: C, 65.30; H, 5.97; N, 16.07.
(5-Hydroxy-1-phenyl-1H-pyrazol-4-yl)(piperidin-1-yl)methanone
(7q). This compound was prepared from 3 (0.232g, 1 mmol) and
piperidine (6q) (0.425 g, 5 mmol). Yield: 0.130g (46%) of a light
brownish solid; mp 97–100°C; ir (KBr): 4338 (NH), 2934, 1637
[8] McFarland, C.; Vicic, D. A.; Debnath, A. K. Synthesis 2006,
807.
(C═O), 1601, 1560, 1298, 1205, 1116, 1058, 1008, 963cmÀ1
.
[9] For an illustration, see (a) Chakrabarti, J. K.; Hotten, T. M.;
Pullar, I. A.; Tye, N. C. J Med Chem 1989, 32, 2573; (b) Ohshima, T.;
Hayashi, Y.; Agura, K.; Fujii, Y.; Yoshiyama, A.; Mashima, K. Chem
Commun 2012, 48, 5434; (c) Varma, R. S.; Naicker, K. P. Tetrahedron
Lett 1999, 40, 6177; (d) Bundesmann, M. W.; Coffey, S. B.; Wright,
S. W. Tetrahedron Lett 2010, 51, 3879; (e) Glynn, D.; Bernier, D.;
Woodward, S. Tetrahedron Lett 2008, 49, 5687.
[10] (a) Svete J. In (4R*,5R*)-4-Benzoylamino-5-phenyl-3-
pyrazolidinone—A Useful Building Block in the Synthesis of Functional-
ized Pyrazoles; Horvat, M. A.; Golob, J. H., Eds.; Nova Science
Publishers, Inc.: New York, 2008; pp. 129–181; and references cited
there in; (b) Novak, A.; Bezenšek, J.; Pezdirc, L.; Grošelj, U.; Kasunič,
M.; Podlipnik, Č.; Stanovnik, B.; Šimůnek, P., Svete, J. Tetrahedron
2011, 67, 9729, and references cited therein.
1H nmr (DMSO-d6): 1.48–1.59 (6H, m, CH2CH2CH2), 3.36–3.67
(4H, m, 2 × CH2N), 7.23 (1H, t, J = 6.8Hz, p-Ph), 7.43 (2H, t,
J = 7.8Hz, m-Ph), 7.72 (2H, d, J = 7.2Hz, o-Ph), 7.93 (1H, s,
3-H), 10.60 (1H, br s, OH). 13C nmr (DMSO-d6): 24.0, 25.6,
44.9, 116.8, 120.7, 126.4, 128.8, 138.6, 139.6, 160.3, 171.2. ms:
m/z = 270 ([MÀ H]À); hrms Calcd for C15H18N3O2: m/z
272.1394 (MH+); found: 272.1395 (MH+). Anal. Calcd for
C15H17N3O2 · ⅛H2O (273.57): C, 65.86; H, 6.36; N, 15.36.
Found: C, 65.98; H, 6.25; N, 15.20.
[11] (a) Grošelj, U.; Kralj, D.; Wagger, J.; Dahmann, G.;
Stanovnik, B.; Svete, J. ARKIVOC 2012, Part iii, 49; (b) Kralj, D.;
Novak, A.; Dahmann, G.; Grošelj, U.; Meden, A.; Svete, J. J Comb Chem
2008, 10, 664; (c) Kralj, D.; Grošelj, U.; Meden, A.; Dahmann, G.;
Stanovnik, B.; Svete, J. Tetrahedron 2007, 63, 11213.
Acknowledgment. The financial support from the Slovenian
Research Agency through grant P1-0179 is gratefully
acknowledged.
[12] Kralj, D.; Mecinović, J.; Bevk, D.; Grošelj, U.; Stanovnik, B.;
Svete, J. Heterocycles 2006, 68, 897.
REFERENCES AND NOTES
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D.; Stanovnik, B.; Svete, J. ACS Comb Sci 2012, 14, 513; (b) Črček, B.;
Baškovč, J.; Grošelj, U.; Kočar, D.; Dahmann, G.; Stanovnik, B.; Svete, J.
Molecules 2012, 17, 5363; (c) Perdih, P.; Baškovč, J.; Dahmann, G.;
Grošelj, U.; Kočar, D.; Stanovnik, B.; Svete, J. Synthesis 2011, 2822;
(d) Grošelj, U.; Bezenšek, J.; Meden, A.; Svete, J.; Stanovnik, B.; Oblak,
M.; Štefanič Anderluh, P.; Urleb, U. Heterocycles 2008, 75, 1355.
[14] Claisen, L.; Haase, E. Chem Ber 1895, 28, 35.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet