Simple approach to some N-(5-hydroxy-1-phenyl-1H-pyrazol-4-yl)benzamides#

Article abstract of DOI:10.3987/COM-07-S(U)32

Abstract - A series of substituted 5-hydroxy-lH-pyrazoles (5) was prepared by treatment of 4-hydroxymethylidene-2-phenyloxazol-5(4H)-one (1) with ethanol followed by reaction with phenylhydrazines and subsequent treatment with NaOH. Structures of the pyra

Full text of DOI:10.3987/COM-07-S(U)32

HETEROCYCLES, Vol. 73, 2007
555
HETEROCYCLES, Vol. 73, 2007, pp. 555 - 566. © The Japan Institute of Heterocyclic Chemistry
Received, 28th June, 2007, Accepted, 5th September, 2007, Published online, 7th September, 2007. COM-07-S(U)32
SIMPLE
APPROACH
TO
SOME
N-(5-HYDROXY-1-PHENYL-
1H-PYRAZOL-4-YL)BENZAMIDES#
Karmen Čuček, Amalija Golobič, and Bojan Verček*
Faculty of Chemistry and Chemical Technology, University of Ljubljana,
Aškerčeva 5, 1000 Ljubljana, Slovenia. E-mail: bojan.vercek@fkkt.uni-lj.si
Abstract – A series of substituted 5-hydroxy-1H-pyrazoles (5) was prepared by
treatment of 4-hydroxymethylidene-2-phenyloxazol-5(4H)-one (1) with ethanol
followed by reaction with phenylhydrazines and subsequent treatment with NaOH.
Structures of the pyrazoles (5p) and (5r) were confirmed by X-ray structure
analysis.
INTRODUCTION
Although the pyrazole system is a rare structural unit in naturally occurring compounds, numerous
synthetic pyrazoles have attracted a considerable interest in the last decades owing to their use as
pharmaceuticals, agrochemicals, dyes, plastics, and other materials.1 One of the most used methods for
the preparation of pyrazoles is treatment of 1,3-dicarbonyl or related difunctional compounds with
hydrazine derivatives. Starting 1,3-difunctional compounds are often easy available acyclic and cyclic
α,β-didehydroamino acid derivatives allowing synthesis of numerous highly substituted pyrazoles.2,3
These examples are mostly dealing with the synthesis of 3- or 5-hydroxypyrazoles,4 compounds which
are also well-known due to prototropic tautomerism studies.5
During the course of our investigations on novel approaches to various heterocyclic compounds based on
the functionalization of simple amino acid derivatives,6 the utility of 2-(benzoylamino)-3-chloropropenoic
acid and 4-hydroxymethylidene-2-phenyloxazol-5(4H)-one in the synthesis of α-heteroarylglycinates and
indoles has been studied.6a,c,g In principle, regarding their structures, these unsaturated amino acid
derivatives should be suitable starting compounds for the synthesis of 3- or/and 5-hydroxypyrazoles. It
turned out, that this is not the case with 2-benzoylamino-3-chloropropenoic acid. Reactions of this acid
with heteroarylhydrazines took place with decarboxylation resulting in the formation of N-(heteroaryl-
hydrazonoethyl)benzamides.6c On the other hand, treatment of 4-hydroxymethylidene-2-phenyl-
# Dedicated to the memory of Professor Ivar Ugi

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HETEROCYCLES, Vol. 73, 2007
oxazol-5(4H)-one (1) with heteroarylhydrazine in ethanol gave a mixture of the corresponding ethyl
2-benzoylamino-3-(heteroarylhydrazono)propanoate and 5-hydroxypyrazole derivative.6a Selective
transformation of 1 into hydrazones is possible through ethyl formylhippurate (2). 6a,g In this paper we
report on an unambiguous synthesis of a series of N-(5-hydroxy-1-phenyl-1H-pyrazol-4-yl)benzamides
(5) starting from 1 via the intermediate compounds (2) and (4) (Scheme 1).
Ar
1
1
3
O
N
iii
2
O
Ph
HO
ii
i
2
OHC
CO Et
2
CO Et
2
N
3
5
Ar NHN
N
4
NHCOPh
NHCOPh
PhCONH
OH
1
2
4
5
Ar:
phenyl (a)
3-chlorophenyl (g)
3-fluorophenyl (h)
3-methylphenyl (i)
4-fluorophenyl (m)
2-bromophenyl (b)
2-carboxyphenyl (c)
2-chlorophenyl (d)
2-fluorophenyl (e)
3-bromophenyl (f)
4-methylphenyl (n)
4-nitrophenyl (o)
3-(trifluoromethylphenyl (j)
4-bromophenyl (k)
4-(trifluoromethyl)phenyl (p)
2,5-difluorophenyl (q)
2,4,6-trichlorophenyl (r)
4-chlorophenyl (l)
Scheme 1. Reaction conditions: (i) EtOH, rt; (ii) ArNHNH2 (3a-r), rt; (iii) 1) 1M NaOH, rt.
RESULTS AND DISCUSSION
The first part of the preparation of hydrazones (4) is in situ generation of ethyl 2-formylhippurate (2),
achieved by simple stirring of 2-phenyl-4-hydroxymethylidene-5(4H)-oxazolone (1)7 in ethanol.
Condensation of this key compound (2) with phenylhydrazines (3a-r) gave the corresponding ethyl
2-benzoylamino-3-phenylhydrazonopropanoates (4) in 56-90% yield. In order to achieve easy
precipitation of sufficiently pure hydrazones (4) from reaction mixtures and high yields of products, we
carried out reactions with various hydrazine derivatives under slightly different reaction conditions. The
best yields with the hydrazine derivatives used as hydrochlorides were obtained when an equivalent
amount of NaHCO3 in a mixture of water and ethanol was added to the corresponding hydrazine
hydrochloride and the resulting mixture was then poured into a solution of 2 (formation of 4b-g, 4i, 4k, 4l,
and 4n). Exceptions are reactions with the hydrochlorides of 3h and 3m which gave good yields of
relatively pure hydrazones (4h) and (4m) in the absence of NaHCO3. Hydrazine derivatives available as
free bases were added without a solvent (formation of 4a, 4o, 4p, and 4r) or with a small amount of water
(formation of 4j and 4q). Treatment of hydrazones (4) with 1M NaOH resulted in the formation of
5-hydroxypyrazoles (4) in 56-99% yield. All reactions were performed at room temperature (Table 1).

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557
Table 1. Reaction conditions for the preparation of hydrazones (4) and hydroxypyrazoles (5).
Synthesis of 4
Continuation of reaction after addition of 3
Synthesis of 2a
Synthesis of 5
Yieldc 4/EtOH/1M NaOH Time
1
EtOH
3
H2O/EtOH
(mL)/(mL)
-/-
NaHCO3
Time
(h)
24
3
Yieldc
(%)
95d
77d
56d
88e
94f
Ar-
(mmol)
(mL)
5
(mmol)
(mmol)
(%)
77
56
89
89
71
61
90
85
76
86
85
86
66
76
78
85
73
75
(mmol/mL/mL)
1/2/2
(h)
0.5
2
a
b
c
d
e
f
2
1
1
1
10
1
1
1
1
3
1
1
1
1
1
5
1
1
2
1b
-
1
1/2
1
1
1
10
1
1
-
0.5/2/1
0.5/2/1
0.5/2/1
0.5/2/1
0.5/2/1
0.5/2/1
0.5/2/1
0.5/2/1
0.5/2/1
0.5/2/1
0.5/2/1
0.5/2/1
0.5/2/1
1/5/2
1
1 b
1 b
10 b
1b
1 b
1 b
1 b
3
1 b
1 b
1 b
1 b
1
1.5/2.5
1/2
3
5
1
3
2
7
5/5
12
3
2
1
1/1
2
99f
g
h
i
1
1.5/1.5
1/-
3
2
99g
95d
89d
96d
85g
99e
84d
99g
88d
92d
74h
67i
2
2
2
2
1.5/2.5
0.5/-
2/2
1
-
5
1.5
2
j
6
2
k
l
1
1
1
-
1
1.5
1
1
2/2
1
m
n
o
p
q
r
2
1.5/-
2/2
3.5
1
2
1
1
-
1.5
1
6
-/-
10
4
12
2
5
-/-
-
0.5/2/1
0.5/3/1
0.5/2/1
1
1
0.5/-
-/-
-
24
2
2
1.5
1
-
1.5
a Reaction time: 1h; b Corresponding arylhydrazine hydrochloride was used; c Yield of crude product; d Filtration at pH = 3;
e Filtration at pH = 7; f Filtration at pH = 2; g Filtration at pH = 6; h Filtration after acidification to pH = 3, evaporation of
solvent, and addition of 2 mL of H2O; i Isolation after acidification to pH = 7 by extraction with CHCl3.
Both types of products, hydrazones (4) and pyrazoles (5) can exist in several tautomeric forms. The
structures of 4 and 5 were established on the basis of NMR spectra, MS, and elemental analyses.
1H NMR spectra of 4 in DMSO-d6 show doublet of doublet for H-2 in the range of 5.0−5.2 ppm, doublet
for H-3 in the range of 7.2−7.8 ppm, and doublet for NHCO around 9.2 ppm indicating
−NHN=CHCHNHCO− sequence.
In the cases of 1H NMR spectra of pyrazoles (5) in DMSO-d6 solution a broad singlet around 12 ppm can
13
be most likely ascribed to OH proton. In addition, C NMR spectra of 5d and 5l in DMSO-d6 show a
signal around 145 ppm which can be ascribed to C-5.
The hydroxypyrazole structure of 5 was also confirmed by X-ray structure analysis of 5p and 5r (Figure 1
and 2).

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HETEROCYCLES, Vol. 73, 2007
Figure 1. ORTEP view of the asymmetric unit of 5p with labeling of nonhydrogen atoms.
(Ellipsoids are drawn at 50% probability level.)
Figure 2. ORTEP view of the asymmetric unit of 5r with labelling of nonhydrogen atoms.
(Ellipsoids are drawn at 50% probability level.)
EXPERIMENTAL
Melting points were determined on a Kofler micro hot stage. NMR spectra were recorded on a Bruker
AVANCE DPX-300 spectrometer (300 MHz for 1H and 75.5 MHz for 13C) in DMSO-d6 with TMS as an
internal standard. Coupling constants (J) are given in Hz. MS spectra were obtained on a VG-Analytical
AutoSpec Q instrument. Elemental analyses were recorded on Perkin-Elmer CHN Analyzer 2400.
2-Phenyl-4-hydroxymethylidene-5(4H)-oxazolone (1) was prepared as described in the literature.7
General procedure for the synthesis of ethyl 2-benzoylamino-3-(phenylhydrazono)propanoates
(4a-r). A mixture of the oxazolone (1) and ethanol was stirred for 1 h at rt. A solution of an equivalent
amount of arylhydrazine derivative (3) in water (or in a mixture of ethanol and water) or hydrazine
derivative alone was then added. When arylhydrazine hydrochloride was used, it was in most cases first
neutralized by an equivalent amount of NaHCO3 in water/ethanol mixture and this mixture was added to a

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559
solution of 2. The reaction mixture was then stirred for 1-24 h at rt, cooled, and the precipitated crude
product (4) was filtered off (Table 1).
1
Ethyl 2-benzoylamino-3-(phenylhydrazono)propanoate (4a). mp 132-134 °C (EtOH). H-NMR δ:
1.22 (t, 3H, J = 7.0 Hz, CH2CH3), 4.20 (q, 2H, J = 7.0 Hz, CH2CH3), 5.15 (dd, 1H, J = 6.0, 7.0 Hz, 2-H),
6.58−7.68 (m, 9H, 3-H, 3H of Ph, 5H of Ar), 7.84−8.10 (m, 2H, Ph), 9.22 (d, 1H, J = 7.0 Hz, NHCOPh),
10.22 (s, 1H, NNH). MS (EI, m/z, %): 325 (M+, 15). Anal. Calcd for C18H19N3O3: C, 66.45; H, 5.89; N,
12.91. Found: C, 66.46; H, 5.85; N, 13.27.
Ethyl 2-benzoylamino-3-[(2-bromophenyl)hydrazono]propanoate (4b). mp 119-121 °C (EtOH).
1H-NMR δ: 1.23 (t, 3H, J = 7.2 Hz, CH2CH3), 4.19 (q, 2H, J = 7.2 Hz, CH2CH3), 5.16 (dd, 1H, J = 5.6,
7.2 Hz, 2-H), 6.72 (ddd, 1H, J = 1.6, 7.0, 7.9 Hz, Ar), 7.24 (ddd, 1H, J = 1.4, 7.0, 8.3 Hz, Ar), 7.33 (dd,
1H, J = 1.6, 8.3 Hz, Ar), 7.44−7.60 (m, 4H, 3H of Ph, 1H of Ar), 7.78 (d, 1H, J = 5.6 Hz, 3-H), 7.90−7.95
(m, 2H, Ph), 9.21 (d, 1H, J = 7.2 Hz, NHCOPh), 9.66 (s, 1H, NNH). MS (EI, m/z, %): 403 (M+, 8). Anal.
Calcd for C18H18BrN3O3: C, 53.48; H, 4.49; N, 10.39. Found: C, 53.51; H, 4.52; N, 10.37.
Ethyl 2-benzoylamino-3-[(2-carboxyphenyl)hydrazono]propanoate (4c). mp 192-195 °C (EtOH).
1H-NMR δ: 1.23 (t, 3H, J = 7.1 Hz, CH2CH3), 4.20 (q, 2H, J = 7.1 Hz, CH2CH3), 5.20 (dd, 1H, J = 5.3,
7.1 Hz, 2-H), 6.80 (ddd, 1H, J = 1.9, 6.3, 8.0 Hz, Ar), 7.42−7.61 (m, 6H, 3H of Ph, 2H of Ar, 3-H), 7.83
(ddd, 1H, J = 0.7, 1.3, 8.0 Hz, Ar), 7.89−7.96 (m, 2H, Ph), 9.19 (d, 1H, J = 7.1 Hz, NHCOPh), 11.13 (s,
1H, NNH), 13.05 (br s, 1H, COOH). MS (EI, m/z, %): 369 (M+, 7). Anal. Calcd for C19H19N3O5: C,
61.78; H, 5.18; N, 11.38. Found: C, 62.02; H, 4.99; N, 11.47.
Ethyl 2-benzoylamino-3-[(2-chlorophenyl)hydrazono]propanoate (4d). mp 127-129 °C (EtOH/H2O).
1H-NMR δ: 1.23 (t, 3H, J = 7.1 Hz, CH2CH3), 4.19 (q, 2H, J = 7.1 Hz, CH2CH3), 5.16 (dd, 1H, J = 5.5,
7.2 Hz, 2-H), 6.77 (ddd, 1H, J = 1.6, 7.3, 8.0 Hz, Ar), 7.16−7.24 (m, 1H, Ar), 7.30 (dd, 1H, J = 1.4, 8.0
Hz, Ar), 7.35 (dd, 1H, J = 1.4, 8.0 Hz, Ar), 7.46−7.60 (m, 3H, Ph), 7.75 (d, 1H, J = 5.5 Hz, 3-H),
7.89−7.96 (m, 2H, Ph), 9.22 (d, 1H, J = 7.2 Hz, NHCOPh), 9.87 (s, 1H, NNH). MS (EI, m/z, %): 359 (M+,
10). Anal. Calcd for C18H18ClN3O3: C, 60.09; H, 5.04; N, 11.68. Found: C, 60.18; H, 5.10; N, 11.66.
Ethyl 2-benzoylamino-3-[(2-fluorophenyl)hydrazono]propanoate (4e). mp 110-112 °C (EtOH).
1H-NMR δ: 1.22 (t, 3H, J = 7.1 Hz, CH2CH3), 4.19 (q, 2H, J = 7.1 Hz, CH2CH3), 5.17 (dd, 1H, J = 5.7,
7.2 Hz, 2-H), 6.70−6.78 (m, 1H, Ar), 7.02−7.16 (m, 2H, Ar), 7.28−7.36 (m, 1H, Ar), 7.46−7.63 (m, 4H,
3H of Ph, 3-H), 7.89−7.96 (m, 2H, Ph), 9.22 (d, 1H, J = 7.2 Hz, NHCOPh), 10.17 (s, 1H, NNH).
13C-NMR δ: 14.09, 55.36, 60.92, 113.70, 115.04, 118.71, 124.81, 127.46, 128.34, 131.63, 133.25, 133.38,
1
136.10, 148.89, 166.22, 169.39. F-NMR δ: -134.08. MS (EI, m/z, %): 343 (M+, 24). Anal. Calcd for
C18H18FN3O3: C, 62.97; H, 5.28; N, 12.24. Found: C, 62.73; H, 5.46; N, 12.02.

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Ethyl 2-benzoylamino-3-[(3-bromophenyl)hydrazono]propanoate (4f). mp 148-150 °C (EtOH/H2O).
1H-NMR δ: 1.23 (t, 3H, J = 7.1 Hz, CH2CH3), 4.14−4.23 (m, 2H, CH2CH3), 5.14 (dd, 1H, J = 5.5, 7.2 Hz,
2-H), 6.83−6.90 (m, 2H, Ar), 7.09−7.16 (m, 2H, Ar), 7.35 (d, 1H, J = 5.5 Hz, 3-H), 7.46−7.60 (m, 3H,
Ph), 7.88−7.94 (m, 2H, Ph), 9.21 (d, 1H, J = 7.2 Hz, NHCOPh), 10.40 (s, 1H, NNH). MS (EI, m/z, %):
403 (M+, 8). Anal. Calcd for C18H18BrN3O3: C, 53.48; H, 4.49; N, 10.39. Found: C, 53.47; H, 4.53; N,
10.67.
Ethyl 2-benzoylamino-3-[(3-chlorophenyl)hydrazono]propanoate (4g). mp 145-147 °C (EtOH).
1H-NMR δ: 1.22 (t, 3H, J = 7.1 Hz, CH2CH3), 4.14−4.23 (m, 2H, CH2CH3), 5.15 (dd, 1H, J = 5.6, 7.2 Hz,
2-H), 6.74 (ddd, 1H, J = 0.8, 2.1, 8.0 Hz, Ar), 6.82 (ddd, 1H, J = 0.9, 2.1, 8.0 Hz, Ar), 6.97 (dd, 1H, J =
2.1, 2.1 Hz, Ar), 7.19 (dd, 1H, J = 8.0, 8.0 Hz, Ar), 7.36 (d, 1H, J = 5.6 Hz, 3-H), 7.46−7.61 (m, 3H, Ph),
7.89−7.94 (m, 2H, Ph), 9.21 (d, 1H, J = 7.1 Hz, NHCOPh), 10.42 (s, 1H, NNH). MS (EI, m/z, %): 359
(M+, 16). Anal. Calcd for C18H18ClN3O3: C, 60.09; H, 5.04; N, 11.68. Found: C, 59.90; H, 4.98; N, 11.58.
Ethyl 2-benzoylamino-3-[(3-fluorophenyl)hydrazono]propanoate (4h). mp 125-127 °C (EtOH/H2O).
1H-NMR δ: 1.22 (t, 3H, J = 7.1 Hz, CH2CH3), 4.19 (q, 2H, J = 7.1 Hz, CH2CH3), 5.14 (dd, 1H, J = 5.3,
7.2 Hz, 2-H), 6.46−6.54 (m, 1H, Ar), 6.67−6.73 (m, 1H, Ar), 7.15−7.23 (m, 1H, Ar), 7.35 (d, 1H, J = 5.3
Hz, 3-H), 7.46−7.60 (m, 3H, Ph), 7.89−7.94 (m, 2H, Ph), 9.21 (d, 1H, J = 7.2 Hz, NHCOPh), 10.43 (s,
1H, NNH). 1F-NMR δ: -113.03. MS (EI, m/z, %): 343 (M+, 24). Anal. Calcd for C18H18FN3O3: C, 62.97;
H, 5.28; N, 12.24. Found: C, 62.60; H, 5.30; N, 12.40.
Ethyl 2-benzoylamino-3-[(3-methylphenyl)hydrazono]propanoate (4i). mp 126-128 °C (EtOH).
1H-NMR δ: 1.22 (t, 3H, J = 7.1 Hz, CH2CH3), 2.22 (s 3H, CH3), 4.14−4.22 (m, 2H, CH2CH3), 5.11 (dd,
1H, J = 5.6, 7.2 Hz, 2-H), 6.52−6.56 (m, 1H, Ar), 6.68−6.72 (m, 1H, Ar), 6.76−6.78 (m, 1H, Ar), 7.05 (dd,
1H, J = 7.7, 7.7 Hz, Ar), 7.30 (d, 1H, J = 5.6 Hz, 3-H), 7.46−7.60 (m, 3H, Ph), 7.88−7.94 (m, 2H, Ph),
9.19 (d, 1H, J = 7.2 Hz, NHCOPh), 10.13 (s, 1H, NNH). MS (EI, m/z, %): 339 (M+, 30). Anal. Calcd for
C19H21N3O3: C, 67.24; H, 6.24; N, 12.38. Found: C, 66.89; H, 6.53; N, 12.18.
Ethyl 2-benzoylamino-3-{[(3-trifluoromethyl)phenyl]hydrazono}propanoate (4j). mp 149-151 °C
(EtOH/H2O). 1H-NMR δ: 1.22 (t, 3H, J = 7.1 Hz, CH2CH3), 4.14−4.25 (m, 2H, CH2CH3), 5.17 (dd, 1H, J
= 5.4, 7.3 Hz, 2-H), 7.01−7.06 (m, 1H, Ar), 7.10−7.15 (m, 1H, Ar), 7.22−7.25 (m, 1H, Ar), 7.37−7.43 (m,
2H, 1H of Ar, 3-H), 7.46−7.60 (m, 3H, Ph), 7.89−7.94 (m, 2H, Ph), 9.23 (d, 1H, J = 7.3 Hz, NHCOPh),
10.57 (s, 1H, NNH). 1F-NMR δ: -61.96. MS (EI, m/z, %): 393 (M+, 19). Anal. Calcd for C19H18F3N3O3: C,
58.01; H, 4.61; N, 10.68. Found: C, 57.75; H, 4.48; N, 10.57.
Ethyl 2-benzoylamino-3-[(4-bromophenyl)hydrazono]propanoate (4k). mp 144-146 °C (EtOH).
1H-NMR δ: 1.21 (t, 3H, J = 7.1 Hz, CH2CH3), 4.18 (q, 2H, J = 7.1 Hz, CH2CH3), 5.12 (dd, 1H, J = 5.7,
7.2 Hz, 2-H), 6.85−6.90 (m, 2H, Ar), 7.30−7.36 (m, 3H, 2H of Ar, 3-H), 7.46−7.60 (m, 3H, Ph),

HETEROCYCLES, Vol. 73, 2007
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7.88−7.93 (m, 2H, Ph), 9.20 (d, 1H, J = 7.2 Hz, NHCOPh), 10.35 (s, 1H, NNH). MS (EI, m/z, %): 403
(M+, 8). Anal. Calcd for C18H18BrN3O3: C, 53.48; H, 4.49; N, 10.39. Found: C, 53.37; H, 4.38; N, 10.35.
Ethyl 2-benzoylamino-3-[(4-chlorophenyl)hydrazono]propanoate (4l). mp 137-139 °C (EtOH/H2O).
1H-NMR δ: 1.22 (t, 3H, J = 7.1 Hz, CH2CH3), 4.19 (q, 2H, J = 7.1 Hz, CH2CH3), 5.14 (dd, 1H, J = 5.7,
7.2 Hz, 2-H), 6.91−6.97 (m, 2H, Ar), 7.19−7.24 (m, 2H, Ar), 7.36 (d, 1H, J = 5.7 Hz, 3-H), 7.46−7.60 (m,
13
3H, Ph), 7.90−7.95 (m, 2H, Ph), 9.22 (d, 1H, J = 7.2 Hz, NHCOPh), 10.40 (s, 1H, NNH). C-NMR δ:
14.09, 55.27, 60.92, 113.16, 121.98, 127.45, 128.34, 128.84, 131.62, 133.37, 134.14, 144.12, 166.21,
169.42. MS (EI, m/z, %): 359 (M+, 10). Anal. Calcd for C18H18ClN3O3: C, 60.09; H, 5.04; N, 11.68.
Found: C, 59.91; H, 4.98; N, 11.73.
Ethyl 2-benzoylamino-3-[(4-fluorophenyl)hydrazono]propanoate (4m). mp 110-112 °C (EtOH/H2O).
1H-NMR δ: 1.21 (t, 3H, J = 7.1 Hz, CH2CH3), 4.18 (q, 2H, J = 7.1 Hz, CH2CH3), 5.11 (dd, 1H, J = 5.7,
7.1 Hz, 2-H), 6.88−6.94 (m, 2H, Ar), 6.99−7.06 (m, 2H, Ar), 7.30 (d, 1H, J = 5.7 Hz, 3-H), 7.45−7.60 (m,
1
3H, Ph), 7.88−7.95 (m, 2H, Ph), 9.18 (d, 1H, J = 7.1 Hz, NHCOPh), 10.18 (s, 1H, NNH). F-NMR δ:
-126.56. MS (EI, m/z, %): 343 (M+, 8). Anal. Calcd for C18H18FN3O3: C, 62.97; H, 5.28; N, 12.24. Found:
C, 62.76; H, 5.27; N, 12.20.
Ethyl 2-benzoylamino-3-[(4-methylphenyl)hydrazono]propanoate (4n). mp 130-132 °C (EtOH).
1H-NMR δ: 1.21 (t, 3H, J = 7.1 Hz, CH2CH3), 2.18 (s 3H, CH3), 4.17 (q, 2H, J = 7.1 Hz, CH2CH3), 5.10
(dd, 1H, J = 5.7, 7.1 Hz, 2-H), 6.83 (d, 2H, J = 8.3 Hz, Ar), 6.99 (d, 2H, J = 8.3 Hz, Ar), 7.27 (d, 1H, J =
5.7 Hz, 3-H), 7.45−7.60 (m, 3H, Ph), 7.88−7.95 (m, 2H, Ph), 9.17 (d, 1H, J = 7.1 Hz, NHCOPh), 10.07 (s,
1H, NNH). MS (EI, m/z, %): 339 (M+, 20). Anal. Calcd for C19H21N3O3: C, 67.24; H, 6.24; N, 12.38.
Found: C, 66.86; H, 6.45; N, 12.48.
Ethyl 2-benzoylamino-3-[(4-nitrophenyl)hydrazono]propanoate (4o). mp 174-176 °C (EtOH).
1H-NMR δ: 1.22 (t, 3H, J = 7.0 Hz, CH2CH3), 4.20 (q, 2H, J = 7.0 Hz, CH2CH3), 5.17 (dd, 1H, J = 5.5,
7.0 Hz, 2-H), 7.01 (d, 2H, J = 9.5 Hz, Ar), 7.33−7.63 (m, 4H, J = 5.7 Hz, 3-H, 3H of Ph), 7.76−8.01 (m,
2H, Ph), 8.10 (d, 2H, J = 9.5 Hz, Ar), 9.27 (d, 1H, J = 7.0 Hz, NHCOPh), 11.18 (s, 1H, NNH). MS (EI,
m/z, %): 370 (M+, 29). Anal. Calcd for C18H18N4O5: C, 58.37; H, 4.90; N, 15.13. Found: C, 58.48; H,
5.15; N, 15.25.
Ethyl 2-benzoylamino-3-{[(4-trifluoromethyl)phenyl]hydrazono}propanoate (4p). mp 175-178 °C
(EtOH). 1H-NMR δ: 1.22 (t, 3H, J = 7.1 Hz, CH2CH3), 4.19 (q, 2H, J = 7.1 Hz, CH2CH3), 5.15 (dd, 1H, J
= 5.7, 7.2 Hz, 2-H), 7.05 (d, 2H, J = 8.4 Hz, Ar), 7.43 (d, 1H, J = 5.7 Hz, 3-H), 7.46−7.60 (m, 5H, 3H of
Ph, 2H of Ar), 7.89−7.93 (m, 2H, Ph), 9.24 (d, 1H, J = 7.2 Hz, NHCOPh), 10.68 (s, 1H, NNH). 1F-NMR
δ: -59.84. MS (EI, m/z, %): 393 (M+, 24). Anal. Calcd for C19H18F3N3O3: C, 58.01; H, 4.61; N, 10.68.
Found: C, 58.10; H, 4.43; N, 10.70.

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Ethyl 2-benzoylamino-3-[(2,5-difluorophenyl)hydrazono]propanoate (4q). mp 122-125 °C
(EtOH/H2O). 1H-NMR δ: 1.22 (t, 3H, J = 7.1 Hz, CH2CH3), 4.15−4.23 (m, 2H, CH2CH3), 5.18 (dd, 1H, J
= 5.4, 7.3 Hz, 2-H), 6.48−6.56 (m, 1H, Ar), 6.97−7.05 (m, 1H, Ar), 7.10−7.20 (m, 1H, Ar), 7.45−7.61 (m,
3H, Ph), 7.64 (d, 1H, J = 5.4 Hz, 3-H), 7.89−7.95 (m, 2H, Ph), 9.23 (d, 1H, J = 7.3 Hz, NHCOPh), 10.41
1
(s, 1H, NNH). F-NMR δ: -117.82, -139.24. MS (EI, m/z, %): 361 (M+, 27). Anal. Calcd for
C18H17F2N3O3: C, 59.83; H, 4.74; N, 11.63. Found: C, 59.77; H, 4.99; N, 11.48.
Ethyl 2-benzoylamino-3-[(2,4,6-trichlorophenyl)hydrazono]propanoate (4r). mp 112-114 °C (EtOH).
1H-NMR δ: 1.19 (t, 3H, J = 7.1 Hz, CH2CH3), 4.14 (q, 2H, J = 7.1 Hz, CH2CH3), 5.07 (dd, 1H, J = 5.5,
7.2 Hz, 2-H), 7.43−7.66 (m, 6H, 3H of Ph, 2H of Ar, 3-H), 7.86−7.92 (m, 2H, Ph), 9.10 (d, 1H, J = 7.2
Hz, NHCOPh), 9.49 (s, 1H, NNH). MS (EI, m/z, %): 427 (M+, 4). Anal. Calcd for C18H16Cl3N3O3: C,
50.43; H, 3.76; N, 9.80. Found: C, 50.09; H, 3.53; N, 9.59.
General procedure for the synthesis of N-(1-phenyl-5-hydroxy-1H-pyrazol-4-yl)benzamides (5a-r).
To a mixture of 4 and ethanol, 1M NaOH was slowly added. The reaction mixture was then stirred for
0.5−5 h at rt and neutralized or acidified with 7% HCl. After cooling, the precipitate was usually filtered
off and washed with water to give crude 5 (Table 1).
N-(5-Hydroxy-1-phenyl-1H-pyrazol-4-yl)benzamide (5a). mp 199-202 °C (EtOH)(lit,7 204-205 °C).
1H-NMR δ: 7.27−7.33 (m, 1H, Ar), 7.45−7.69 (m, 6H, 3-H, 3H of Ph, 2H of Ar), 7.74−7.79 (m, 2H, Ar),
7.97−8.02 (m, 2H, Ph), 10.13 (br s, 1H, NHCOPh), 11.86 (br s, 1H, OH).
N-[1-(2-Bromophenyl)-5-hydroxy-1H-pyrazol-4-yl]benzamide (5b). mp 183-185 °C (CH2Cl2).
1H-NMR δ: 7.41−7.64 (m, 7H, 3-H, 3H of Ph, 3H of Ar), 7.81 (ddd, 1H, J = 0.5, 1.5, 7.9 Hz, Ar),
7.95−8.00 (m, 2H, Ph), 10.14 (br s, 1H, NHCOPh), 11.51 (br s, 1H, OH). MS (EI, m/z, %): 357 (M+, 22).
Anal. Calcd for C16H12BrN3O2: C, 53.65; H, 3.38; N, 11.73. Found: C, 53.68; H, 3.32; N, 11.48.
N-[1-(2-Carboxyphenyl)-5-hydroxy-1H-pyrazol-4-yl]benzamide (5c). mp 235-240 °C (EtOH).
1H-NMR δ: 7.47−7.70 (m, 7H, 3-H, 3H of Ph, 3H of Ar), 7.80 (dd, 1H, J = 1.5, 7.9 Hz, Ar), 7.95−8.00 (m,
2H, Ph), 10.19 (br s, 1H, NHCOPh), 11.74 (br s, 1H, OH), 12.72 (br s, 1H, COOH). MS (FAB, m/z, %):
324 (MH+, 54). Anal. Calcd for C17H13N3O4: C, 63.16; H, 4.05; N, 13.00. Found: C, 63.29; H, 4.08; N,
12.99.
N-[1-(2-Chlorophenyl)-5-hydroxy-1H-pyrazol-4-yl]benzamide (5d). mp 177-180 °C (EtOH/H2O).
1H-NMR δ: 7.48−7.68 (m, 8H, 3-H, 3H of Ph, 4H of Ar), 7.96−8.01 (m, 2H, Ph), 10.14 (br s, 1H,
13
NHCOPh), 11.52 (br s, 1H, OH). C-NMR δ: 102.17, 127.58, 127.87, 128.38, 129.90, 130.00, 130.45,
131.12, 131.65, 133.40, 134.79, 135.64, 144.75, 164.99. MS (EI, m/z, %): 313 (M+, 39). Anal. Calcd for
C16H12ClN3O2: C, 61.25; H, 3.86; N, 13.39. Found: C, 61.16; H, 3.88; N, 13.34.

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N-[1-(2-Fluorophenyl)-5-hydroxy-1H-pyrazol-4-yl]benzamide (5e). mp 135-137 °C (EtOH/H2O).
1H-NMR δ: 7.32−7.63 (m, 7H, 3H of Ph, 4H of Ar), 7.72 (s, 1H, 3-H), 7.98−8.02 (m, 2H, Ph), 10.11 (s,
.
1H, NHCOPh). MS (EI, m/z, %): 297 (M+, 56). Anal. Calcd for C16H12FN3O2 0.25 H2O: C, 63.68; H,
4.14; N, 13.93. Found: C, 63.56; H, 3.81; N, 14.02.
N-[1-(3-Bromophenyl)-5-hydroxy-1H-pyrazol-4-yl]benzamide (5f). mp 154-157 °C (CH2Cl2).
1H-NMR δ: 7.42−7.64 (m, 5H, 3H of Ph, 2H of Ar), 7.71 (br s, 1H, 3-H), 7.83 (ddd, 1H, J = 1.9, 1.9, 7.4
Hz, Ar), 7.95−8.01 (m, 3H, 2H of Ph, 1H of Ar), 10.08 (br s, 1H, NHCOPh), 12.05 (br s, 1H, OH). MS
(EI, m/z, %): 357 (M+, 19). Anal. Calcd for C16H12BrN3O2: C, 53.65; H, 3.38; N, 11.73. Found: C, 53.49;
H, 3.31; N, 11.42.
N-[1-(3-Chlorophenyl)-5-hydroxy-1H-pyrazol-4-yl]benzamide (5g). mp 102-104 °C (EtOH/H2O).
1H-NMR δ: 7.35 (ddd, 1H, J = 1.0, 2.0, 8.1 Hz, Ar), 7.48−7.63 (m, 4H, 3H of Ph, 1H of Ar), 7.72 (br s,
1H, 3-H), 7.79 (ddd, 1H, J = 1.0, 2.0, 8.1 Hz, Ar), 7.85 (dd, 1H, J = 2.0, 2.0 Hz, Ar), 7.96−8.00 (m, 2H,
Ph), 10.09 (s, 1H, NHCOPh), 12.05 (br s, 1H, OH). MS (EI, m/z, %): 313 (M+, 46). Anal. Calcd for
.
C16H12ClN3O2 0.5 H2O: C, 59.54; H, 4.03; N, 13.02. Found: C, 59.45; H, 4.10; N, 13.05.
N-[1-(3-Fluorophenyl)-5-hydroxy-1H-pyrazol-4-yl]benzamide (5h). mp 173-175 °C (CHCl3).
1H-NMR δ: 7.13 (dddd, 1H, J = 0.9, 2.6, 8.4, 8.5 Hz, Ar), 7.49−7.77 (m, 7H, 3-H, 3H of Ph, 3H of Ar),
7.96−8.01 (m, 2H, Ph), 10.09 (br s, 1H, NHCOPh), 12.05 (br s, 1H, OH). MS (EI, m/z, %): 297 (M+, 35).
Anal. Calcd for C16H12FN3O2: C, 64.64; H, 4.07; N, 14.13. Found: C, 64.79; H, 4.10; N, 14.31.
N-[5-Hydroxy-1-(3-methylphenyl)-1H-pyrazol-4-yl]benzamide (5i). mp 93-95 °C (EtOAc/hexane).
1H-NMR δ: 2.37 (s, 3H, CH3), 7.12 (br d, 1H, J = 7.9 Hz, Ar), 7.36 (dd, 1H, J = 7.9, 7.9 Hz, Ar),
7.50−7.71 (m, 6H, 3-H, 3H of Ph, 2H of Ar), 7.96−8.01 (m, 2H, Ph), 10.12 (br s, 1H, NHCOPh), 11.79
.
(br s, 1H, OH). MS (EI, m/z, %): 293 (M+, 47). Anal. Calcd for C17H15N3O2 0.5 H2O: C, 67.55; H, 5.30;
N, 13.91. Found: C, 67.43; H, 5.67; N, 13.99.
N-{5-Hydroxy-1-[3-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}benzamide (5j). mp 166-169 °C
(CH2Cl2/EtOAc). 1H-NMR δ: 7.51−7.68 (m, 4H, 3H of Ph, 1H of Ar), 7.71−7.78 (m, 2H, 3-H, 1H of Ar),
7.96−8.01 (m, 2H, Ph), 8.11−8.16 (m, 2H, Ar), 10.10 (s, 1H, NHCOPh), 12.25 (br s, 1H, OH). MS (EI,
m/z, %): 347 (M+, 40). Anal. Calcd for C17H12F3N3O2 : C, 58.79; H, 3.48; N, 12.10. Found: C, 58.75; H,
3.42; N, 12.25.
N-[1-(4-Bromophenyl)-5-hydroxy-1H-pyrazol-4-yl]benzamide (5k). mp 199-202 °C (CHCl3).
1H-NMR δ: 7.50−7.71 (m, 6H, 3-H, 3H of Ph, 2H of Ar), 7.76 (ddd, 1H, J = 2.4, 2.4, 9.3 Hz, Ar),
7.96−8.01 (m, 2H, Ph), 10.10 (br s, 1H, NHCOPh), 12.02 (br s, 1H, OH). MS (EI, m/z, %): 357 (M+, 18).
Anal. Calcd for C16H12BrN3O2: C, 53.65; H, 3.38; N, 11.73. Found: C, 53.56; H, 3.46; N, 11.59.
N-[1-(4-Chlorophenyl)-5-hydroxy-1H-pyrazol-4-yl]benzamide (5l).6g

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N-[1-(4-Fluorophenyl)-5-hydroxy-1H-pyrazol-4-yl]benzamide (5m). mp 203-205 °C (CHCl3).
1H-NMR δ: 7.28−7.37 (m, 2H, Ar), 7.50−7.68 (m, 4H, 3-H, 3H of Ph), 7.74−7.81 (m, 2H, Ar), 7.95−8.01
(m, 2H, Ph), 10.10 (s, 1H, NHCOPh), 11.88 (br s, 1H, OH). MS (EI, m/z, %): 297 (M+, 33). Anal. Calcd
for C16H12FN3O2: C, 64.64; H, 4.07; N, 14.13. Found: C, 64.73; H, 4.13; N, 14.29.
N-[5-Hydroxy-1-(4-methylphenyl)-1H-pyrazol-4-yl]benzamide (5n). mp 200-203 °C (CHCl3).
1H-NMR δ: 2.34 (s, 3H, CH3), 7.28 (d, 2H, J = 7.9 Hz, Ar), 7.50−7.66 (m, 6H, 3-H, 2H of Ar, 3H of Ph),
7.96−8.01 (m, 2H, Ph), 10.12 (br s, 1H, NHCOPh), 11.80 (br s, 1H, OH). MS (EI, m/z, %): 293 (M+, 49).
Anal. Calcd for C17H15N3O2: C, 69.61; H, 5.15; N, 14.33. Found: C, 69.32; H, 5.18; N, 14.34.
N-[5-Hydroxy-1-(4-nitrophenyl)-1H-pyrazol-4-yl]benzamide (5o). mp 223-226 °C (DMF/EtOH).
1H-NMR δ: 7.51−7.64 (m, 3H, Ph), 7.84 (br s, 1H, 3-H), 7.97−8.02 (m, 2H, Ph), 8.10−8.16 (m, 2H, Ar),
8.34−8.40 (m, 2H, Ar), 10.08 (s, 1H, NHCOPh), 12.35 (br s, 1H, OH). MS (EI, m/z, %): 324 (M+, 49).
Anal. Calcd for C16H12N4O4: C, 59.26; H, 3.73; N, 17.28. Found: C, 58.99; H, 3.61; N, 17.09.
N-{5-Hydroxy-1-[4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}benzamide (5p). mp 203-204 °C
(CHCl3). 1H-NMR δ: 7.50−7.64 (m, 3H of Ph), 7.77 (br s, 1H, 3-H), 7.83-7.89 (m, 2H, Ar), 7.96−8.01 (m,
2H, Ph), 8.03−8.08 (m, 2H, Ar), 10.08 (s, 1H, NHCOPh), 12.20 (br s, 1H, OH). MS (EI, m/z, %): 347
(M+, 51). Anal. Calcd for C17H12F3N3O2 : C, 58.79; H, 3.48; N, 12.10. Found: C, 59.00; H, 3.33; N, 12.14.
N-[1-(2,5-Difluorophenyl)-5-hydroxy-1H-pyrazol-4-yl]benzamide (5q). mp 106-108 °C (EtOH/H2O).
1H-NMR δ: 7.34−7.63 (m, 6H, 3H of Ar, 3H of Ph), 7.73 (s, 1H, 3-H), 7.96−8.01 (m, 2H, Ph), 10.05 (s,
.
1H, NHCOPh), 11.83 (br s, 1H, OH). MS (EI, m/z, %): 315 (M+, 39). Anal. Calcd for C16H11F2N3O2 0.5
H2O : C, 59.26; H, 3.70; N, 12.96. Found: C, 59.01; H, 3.73; N, 12.97.
N-[5-Hydroxy-1-(2,4,6-trichlorophenyl)-1H-pyrazol-4-yl]benzamide
(5r).
mp
211-213
°C
(EtOAc/hexane). 1H-NMR δ: 7.49−7.63 (m, 3H, Ph), 7.69 (br s, 1H, 3-H), 7.93 (s, 2H, Ar), 7.95−8.01 (m,
2H, Ph), 10.10 (br s, 1H, NHCOPh), 11.69 (br s, 1H, OH). MS (EI, m/z, %): 381 (M+, 11). Anal. Calcd
for C16H10Cl3N3O2: C, 50.22; H, 2.63; N, 10.98. Found: C, 50.07; H, 2.64; N, 10.78.
X-Ray structure analysis of 5p and 5r
Structures were solved by direct methods using SIR92.8 The XTAL3.49 system of crystallographic
programs was used for the correlation and reduction of data, structure refinement and interpretation. The
crystallographic plots were made with ORTEPII.10 The crystallographic data for both compounds have
been deposited with the Cambridge Crystallographic Data Center as supplementary material with the
deposition numbers CCDC 658310 (5r) and CCDC 658311 (5p). These data can be obtained free of charge
via http://www.ccdc.cam.ac.uk/conts/retrieving.html (or from the Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: (+44) 1223-336-033; or e-mail:
deposit@ccdc.cam.ac.uk).

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ACKNOWLEDGEMENTS
We thank the Slovenian Research Agency and the Ministry of Higher Education, Science and Technology
of Slovenia for financial support (P1-0230-0103).
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