On the tautomerism of pyrazolones: The geminal 2J[pyrazole C-4,H-3(5)] spin coupling constant as a diagnostic tool

Article abstract of DOI:10.1016/j.tet.2004.06.039

The tautomerism of pyrazolones unsubstituted at position 3(5) has been investigated by ¹³C- and ¹H NMR spectroscopic methods. Apart from chemical shift considerations and NOE effects the magnitude of the geminal ²J[pyrazole C-4,H3(5)] spin coupling constant permits the unambiguous differentiation between 1H-pyrazol-5-ol (OH) and 1,2-dihydro-3H-pyrazol-3-one (NH) forms. Whereas 1H-pyrazol-5-ols and 2,4-dihydro-3H-pyrazol-3-ones (CH-form) exhibit ²J values of approximately 9-11 Hz, in 1,2-dihydro-3H-pyrazol-3-ones this coupling constant is considerably reduced to 4-5 Hz. This can be mainly attributed to the removal of the lone-pair at pyrazole N-1 in the latter due to protonation or alkylation. According to the data obtained, 2-substituted 4-acyl-1,2-dihydro-3H-pyrazol-3- ones exist predominantly as pyrazol-5-ols in CDCl₃ or benzene-d ₆ solution, whereas in DMSO-d₆ also minor amounts of NH tautomer may contribute to the tautomeric composition. 2,4-Dihydro-2-phenyl-3H- pyrazol-3-one (1-phenyl-2-pyrazolin-5-one) exists in benzene-d₆ solely in the CH-form, in CDCl₃ as a mixture of CH and OH-form, whereas in DMSO-d₆ a fast equilibrium between OH and NH isomer (with the former far predominating) is probable. For 11 compounds, including neutral and protonated molecules, we have calculated at the B3LYP/6-311++G** level, the ²J(¹H,¹³C) coupling constants which are in good agreement with those measured experimentally.

Full text of DOI:10.1016/j.tet.2004.06.039

Tetrahedron 60 (2004) 6791–6805
On the tautomerism of pyrazolones: the geminal
2J[pyrazole C-4,H-3(5)] spin coupling constant as
a diagnostic toolq
a
a
b
Wolfgang Holzer,a Constanze Kautsch, Christian Laggner, Rosa M. Claramunt,
,
*
b
Marta Perez-Torralba, Ibon Alkorta and Jose Elguero
c
c
,
*
´
´
aDepartment of Pharmaceutical Chemistry, University of Vienna, Pharmaziezentrum, Althanstrasse 14, A-1090 Vienna, Austria
b
´
´
´
Departamento de Quımica Organica y Biologıa, Facultad de Ciencias, UNED, Senda del Rey, 9, E-28040 Madrid, Spain
´ ´ ´ ´
Instituto de Quımica Medica, Centro de Quımica Organica ‘Manuel Lora Tamayo’, C.S.I.C., Juan de la Cierva, 3, E-28006 Madrid, Spain
c
Received 5 April 2004; revised 28 May 2004; accepted 7 June 2004
Abstract—The tautomerism of pyrazolones unsubstituted at position 3(5) has been investigated by 13C- and 1H NMR spectroscopic
2
methods. Apart from chemical shift considerations and NOE effects the magnitude of the geminal J[pyrazole C-4,H3(5)] spin coupling
constant permits the unambiguous differentiation between 1H-pyrazol-5-ol (OH) and 1,2-dihydro-3H-pyrazol-3-one (NH) forms. Whereas
1H-pyrazol-5-ols and 2,4-dihydro-3H-pyrazol-3-ones (CH-form) exhibit 2J values of approximately 9–11 Hz, in 1,2-dihydro-3H-pyrazol-3-
ones this coupling constant is considerably reduced to 4–5 Hz. This can be mainly attributed to the removal of the lone-pair at pyrazole N21
in the latter due to protonation or alkylation. According to the data obtained, 2-substituted 4-acyl-1,2-dihydro-3H-pyrazol-3-ones exist
predominantly as pyrazol-5-ols in CDCl3 or benzene-d6 solution, whereas in DMSO-d6 also minor amounts of NH tautomer may contribute
to the tautomeric composition. 2,4-Dihydro-2-phenyl-3H-pyrazol-3-one (1-phenyl-2-pyrazolin-5-one) exists in benzene-d6 solely in the CH-
form, in CDCl3 as a mixture of CH and OH-form, whereas in DMSO-d6 a fast equilibrium between OH and NH isomer (with the former far
predominating) is probable. For 11 compounds, including neutral and protonated molecules, we have calculated at the B3LYP/6-311þþG**
level, the 2J(1H,13C) coupling constants which are in good agreement with those measured experimentally.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
(A0, D0, Fig. 1, lower line). Whereas in the solid state
unambiguous results were obtained on the basis of X-ray
crystallographic data,8–12 the situation in solution is much
more complicated and the determination of the tautomeric
composition can be difficult. The simultaneous presence of
several tautomeric forms can either result in distinct signal
sets in the NMR spectra due to the individual isomers (slow
interconversion rate on the NMR timescale) or in the
observation of one averaged signal set in case of rapid
chemical exchange. Fast exchange frequently occurs
between OH- and NH-tautomers, whereas those equilibria
which involve a proton moving from a carbon atom (CH-
tautomers) are normally slow.16
The tautomerism of pyrazolones is an old problem of
pyrazole chemistry and thus it has been the subject of a
considerable number of studies.2 –13 In principle, for
compounds unsubstituted at pyrazole C-4, OH- (A), CH-
(B) and NH-isomers (C) are possible (Fig. 1, upper line),
assigned as 1H-pyrazol-5-ols, 2,4-dihydro-3H-pyrazol-3-
ones and 1,2-dihydro-3H-pyrazol-3-ones according to
Chemical Abstracts nomenclature. In the case of 4-acyl
congeners, which are popular chelating and extracting
ligands for metal ions14 as well as starting materials for
biologically active compounds,15 additional species (D, E,
middle line) have to be considered since in this case the
4-substituent can participate in tautomerism and also
stabilization by intramolecular hydrogen bonds may occur
Nearly all investigations regarding pyrazolone tautomerism
were carried out with 3(5)-methyl substituted model
compounds (R3¼Me) due to the easy availability of the
latter upon reaction of alkyl acetoacetates with substituted
hydrazines. In a recent study, we concluded that 4-acyl-5-
methyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-ones (Fig. 1:
R1¼Ph, R3¼Me, R4¼Me, Ph, 2-thienyl, styryl) are present
in the chelated 5-hydroxypyrazole form (A0) in apolar
solvents such as CDCl3 or benzene-d6, whereas in
q See Ref. 1.
Keywords: Pyrazolones; Tautomerism; Methylation; Spin coupling
constants; NOE-difference spectroscopy; DFT-calculations.
*
Corresponding authors. Tel.: þ43-1-4277-55123; fax: þ43-1-4277-9551
(W.H.); tel.: þ34-91-562-29-00; fax: þ34-91-564-48-53 (I.A.);
e-mail addresses: holzer@merian.pch.univie.ac.at; ibon@iqm.csic.es
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.06.039

6792
W. Holzer et al. / Tetrahedron 60 (2004) 6791–6805
Figure 1. Tautomeric forms of (4-acyl)pyrazolones.
DMSO-d6 solution additionally, some NH-tautomer (C)
seems to contribute to the tautomeric composition.12
Continuing with our previous studies12,15,17–23 on pyrazo-
lones (hydroxypyrazoles) we here present detailed NMR
spectroscopic investigations with representatives 2 unsub-
stituted at C-3(5), as well as with corresponding ‘fixed’
tautomers—such as O-methyl (3) and N-methyl derivatives
(4) (Fig. 2) or suitable condensed systems—in order to
obtain insight into the tautomeric behavior of the title
compounds 2. In compounds 2-4, the hydrogen atom at
pyrazole H-3(5) on one hand can act as an irradiation target
or as a probe in NOE experiments, on the other hand this
proton is involved in different 13C,1H spin couplings. The
value of the corresponding coupling constants and their
changes upon structural alterations may help to answer the
questions raised.
of xylene as solvent and performing the reaction without
addition of a base led to the corresponding N-methyl
derivative 4a. Products 3b-e and 4b-e were obtained by
methylation of compounds 2b-e: whereas heating of the
starting materials with dimethyl sulfate in alkaline medium
mainly afforded N-methyl derivatives 4, upon treatment
with trimethylsilyl-diazomethane/HBF4 in dichloromethane
isomeric mixtures were obtained, with the O-methyl
derivatives 3 far predominating.19 The 4-cinnamoyl-5-
methoxypyrazole 3e was synthesized from 2e via
Mitsunobu reaction (diethyl azodicarboxylate, triphenyl-
phosphine, methanol).20 All syntheses were devoted to
obtain material for the NMR-spectroscopic investigations,
thus no efforts were undertaken to optimize yields.
2.2. NMR spectroscopic investigations
The NMR data of the compounds investigated are presented
in Tables 1–7. It should be mentioned that for all proton
and carbon resonances complete and unambiguous assign-
ments were achieved by combined application of standard
NMR techniques (1H-coupled 13C NMR, APT,27 NOE-
difference,28 1D-TOCSY,29 1D-HETCOR,30 HMQC,31 and
long-range INEPT experiments with selective excitation in
a 1D32 and a 2D-version33) without relying on empirical
rules.
2. Results and discussion
2.1. Chemistry
Compound 1 was prepared in two steps from diethyl
ethoxymethylenemalonate and phenylhydrazine according
to literature,24,25 4-acylpyrazolones 2b-e were obtained
from 1 and the corresponding carboxylic acid chlorides via
the method described by Jensen (RCOCl, Ca(OH)2,
dioxane).26 Treatment of 1 with methyl 4-toluenesulfonate
in DMF in the presence of potassium carbonate afforded
5-methoxy-1-phenyl-1H-pyrazole (3a); in contrast, the use
2.2.1. Chemical shift considerations. The O-methyl (3)
and N-methylpyrazoles (4) can be seen as fixed OH or NH-
tautomers and thus can provide valuable data for the
Figure 2. Investigated pyrazolone (1;2a) and 4-acylpyrazol-5-ones (2b-e);(4-acyl)-5-hydroxypyrazoles and their fixed O-Me (3) and N-Me (4) derivatives.

W. Holzer et al. / Tetrahedron 60 (2004) 6791–6805
Table 1. H NMR chemical shifts (d, ppm) of compounds 1 and 2 (numbering of atoms for the hydroxypyrazole form)
6793
1
No.
Solvent
H-3
N-phenyl
OH
H of 4-substituent R
H-2,6
H-3,5
H-4
1a
CDCl3
CDCl3
C6D6
DMSO-d6
CDCl3
DMSO-d6
CDCl3
C6D6
DMSO-d6
CDCl3
C6D6
7.46
7.24
6.30
7.40
7.79
8.06
7.97
7.67
7.97
8.12
7.84
8.29
7.93
7.50
8.42
7.85
7.58
8.26
7.75
7.83
7.71
7.90
8.07
7.77
7.88
8.02
7.76
7.93
8.23
7.81
7.41
7.35
7.22
7.44
7.46
7.49
7.49
7.15
7.52
7.48
7.13
7.52
7.46
7.18
7.49
7.22
7.24
6.95
7.24
7.32
7.33
7.34
6.96
7.37
7.33
6.96
7.37
7.29
6.96
7.31
—
9.78
—
3.47 (d, 3J¼1.1 Hz, 2H, H-4)
1b
1a
5.38 (d, 3J¼2.2 Hz, 1H, H-4)
2.19 (d, 3J¼1.3 Hz, 2H, H-4)
5.54 (d, 3J¼1.9 Hz, 1H, H-4)
2.43 (Me)
1b
2b
2b
2c
2c
2c
2d
2d
2d
2e
2e
2e
11.57
10.18
10.32
11.80
10.68
9.12
11.10
11.68
10.63
12.05
10.75
11.79
2.38 (Me)
7.96 (Ph-2,6), 7.55 (Ph-3,5), 7.64 (Ph-4)
7.73 (Ph-2,6), 7.03 (Ph-3,5), 7.12 (Ph-4)
7.88 (Ph-2,6), 7.56 (Ph-3,5), 7.65 (Ph-4)
7.98 (Th-3), 7.23 (Th-4), 7.73 (Th-5)c
7.46 (Th-3), 6.54 (Th-4), 6.89 (Th-5)c
8.13 (Th-3), 7.29 (Th-4), 8.02 (Th-5)c
7.05 (COCH)d, 7.88 (CHPh)d, 7.64 (Ph-2,6), 7.44 (Ph-3,5), 7.44 (Ph-4)
6.57 (COCH)d, 7.81 (CHPh)d, 7.13 (Ph-2,6), 7.04 (Ph-3,5), 7.04 (Ph-4)
7.75 (COCH)d, 7.73 (CHPh)d, 7.82 (Ph-2,6), 7.46 (Ph-3,5), 7.46 (Ph-4)
DMSO-d6
CDCl3
C6D6
DMSO-d6
a
CH-isomer.
OH-isomer.
b
c
d
4
Thiophene ring: 3J(3,4)¼3.8 Hz, 3J(4,5)¼5.0 Hz, J(3,5)¼1.1 Hz.
3J¼15.9 Hz.
1
Table 2. H NMR chemical shifts (d, ppm) of 5-methoxy-1-phenyl-1H-pyrazoles 3
No.
Solvent
H-3
N-phenyl
OMe
H of 4-substituent R
H-2,6
H-3,5
H-4
3
3a
3a
3b
3c
3c
3d
3d
3d
3e
3e
CDCl3
7.50
7.50
7.92
7.78
7.85
8.00
7.91
8.17
8.08
8.52
7.72
7.66
7.63
7.70
7.68
7.69
7.71
7.67
7.70
7.66
7.42
7.46
7.46
7.48
7.55
7.48
7.10
7.55
7.48
7.55
7.27
7.29
7.35
7.37
7.43
7.37
6.97
7.44
7.37
7.45
3.93
3.92
4.05
4.10
4.01
4.10
3.68
4.02
4.11
4.11
5.66 (d, J¼2.0 Hz, H-4)
3
DMSO-d6
CDCl3
CDCl3
DMSO-d6
CDCl3
C6D6
DMSO-d6
CDCl3
DMSO-d6
5.87 (d, J¼2.0 Hz, H-4)
2.46 (Me)
7.89 (Ph-2,6), 7.50 (Ph-3,5), 7.59 (Ph-4)
7.84 (Ph-2,6), 7.56 (Ph-3,5), 7.65 (Ph-4)
7.81 (Th-3), 7.19 (Th-4), 7.69 (Th-5)a
7.48 (Th-3), 6.62 (Th-4), 6.96 (Th-5)a
7.93 (Th-3), 7.28 (Th-4), 8.05 (Th-5)a
7.34 (COCH)b, 7.80 (CHPh)b, 7.64 (Ph-2,6), 7.41 (Ph-3,5), 7.41 (Ph-4)
7.68 (COCH)b, 7.68 (CHPh)b, 7.85 (Ph-2,6), 7.45 (Ph-3,5), 7.45 (Ph-4)
a
4
Thiophene ring: 3J(3,4)¼3.8 Hz, 3J(4,5)¼5.0 Hz, J(3,5)¼1.1 Hz.
b
3J¼15.8 Hz.
1
Table 3. H NMR chemical shifts (d, ppm) of 1-methyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-ones 4
No.
Solvent
H-5
N-phenyl
NMe
H of 4-substituent R
H-2,6
H-3,5
H-4
4a
4a
4b
4c
4c
4d
4d
4e
4e
CDCl3
7.36
7.91
8.01
8.09
8.52
8.23
8.66
8.17
8.64
7.36
7.33
7.32
7.31
7.41
7.36
7.44
7.34
7.43
7.45
7.48
7.53
7.48
7.55
7.53
7.57
7.53
7.54
7.30
7.31
7.45
7.40
7.46
7.45
7.49
7.45
7.52
3.11
3.11
3.42
3.41
3.45
3.46
3.47
3.45
3.46
5.56 (d, 3J¼3.5 Hz, H-4)
5.42 (d, 3J¼3.5 Hz, H-4)
2.55 (Me)
DMSO-d6
CDCl3
CDCl3
DMSO-d6
CDCl3
DMSO-d6
CDCl3
DMSO-d6
7.98 (Ph-2,6), 7.40 (Ph-3,5), 7.49 (Ph-4)
7.83 (Ph-2,6), 7.46 (Ph-3,5), 7.56 (Ph-4)
8.95 (Th-3), 7.12 (Th-4), 7.60 (Th-5)a
8.69 (Th-3), 7.20 (Th-4), 7.91 (Th-5)a
8.21 (COCH)b, 7.79 (CHPh)b, 7.65 (Ph-2,6), 7.33 (Ph-3,4,5)
8.05 (COCH)c, 7.63 (CHPh)c, 7.64 (Ph-2,6), 7.41 (Ph-3,5), 7.40 (Ph-4)
a
4
Thiophene ring: 3J(3,4)¼3.8 Hz, 3J(4,5)¼5.0 Hz, J(3,5)¼1.1 Hz.
b
c
3J¼15.9 Hz.
3J¼16.0 Hz.
assignment of the tautomeric composition in the pyrazo-
lones 1 or 2. As a representative set of compounds, the
thenoyl substituted pyrazoles 2d, 3d, and 4d may serve for
the following discussion. A comparison of the 13C
chemicals shifts (in CDCl3) between these compounds
shows, that the data of the tautomeric pyrazolone 2d—in
comparable parts such as the 1-phenyl moiety—resemble
somewhat more those of the O-methyl 3d than those of the

Table 4. 13C NMR chemical shifts (d, ppm) of compounds 1-3
No.
Solvent
Pyrazole–C
C-4
OMe
C of N-phenyl
CvO
C of 4-substituent R
C-3
C-5
C-1
C-2,6
C-3,5
C-4
1a
CDCl3
CDCl3
C6D6
DMSO-d6
CDCl3
DMSO-d6
CDCl3
C6D6
DMSO-d6
CDCl3
C6D6
147.0
138.6
146.3
139.6
138.7
140.4
139.6
139.4
141.0
138.4
138.4
140.0
137.9
40.9
90.3
40.1
87.9
105.0
106.1
103.2
103.6
104.0
102.3
102.6
103.3
105.2
170.0
156.8
169.4
153.1
158.2
155.7
160.8
161.7
156.9
160.2
161.0
156.7
162.3
—
—
—
—
—
—
—
—
—
—
—
—
—
137.8
137.2
139.2
138.9
137.3
137.4
137.3
138.2
137.3
137.3
138.2
137.2
137.6
118.9
122.3
118.4
121.0
120.9
121.6
120.9
120.8
121.8
121.0
120.9
121.8
120.2
128.8
128.8
129.1
128.8
129.1
129.0
129.1
129.2
129.1
129.1
129.2
129.1
129.0
125.4
126.6
125.0
125.5
127.0
126.6
127.0
126.7
127.0
127.0
126.8
127.0
126.4
—
—
—
—
195.1
191.1
189.4
188.7
187.7
180.5
180.5
179.0
180.4
—
—
—
—
1b
1a
1b
2b
2b
2c
2c
2c
2d
2d
2d
2e
25.8 (Me)
26.6 (Me)
136.7 (Ph-1), 128.5 (Ph-2,6), 128.9 (Ph-3,5), 133.0 (Ph-4)
136.9 (Ph-1), 128.77 (Ph-2,6), 128.8 (Ph-3,5), 132.7 (Ph-4)
137.8 (Ph-1), 128.4 (Ph-2,6), 128.6 (Ph-3,5), 132.3 (Ph-4)
141.2 (Th-2), 132.3 (Th-3), 128.4 (Th-4), 133.7 (Th-5)
141.6 (Th-2), 132.3 (Th-3), 128.2 (Th-4), 133.6 (Th-5)
143.2 (Th-2), 132.7 (Th-3), 128.8 (Th-4), 134.2 (Th-5)
119.6 (COCH), 144.0 (CHPh), 134.2 (Ph-1), 128.6 (Ph-2,6), 129.0 (Ph-3,5),
131.0 (Ph-4)
DMSO-d6
CDCl3
2e
2e
C6D6
137.9
140.1
105.7
106.1
163.5
159.4
—
—
138.7
137.5
120.1
120.6
129.2
128.9
126.3
126.2
179.7
178.9
119.9 (COCH), 143.6 (CHPh), 134.7 (Ph-1), 128.8 (Ph-2,6), 129.0 (Ph-3,5),
130.8 (Ph-4)
DMSO-d6
121.8 (COCH), 142.1 (CHPh), 134.5 (Ph-1), 128.7 (Ph-2,6), 129.0 (Ph-3,5),
130.6 (Ph-4)
3a
3a
3b
3c
3c
3d
3d
3d
3e
CDCl3
139.6
139.6
141.6
142.8
142.3
141.7
141.8
141.4
141.2
85.7
86.4
155.5
155.3
154.7
156.1
155.6
155.8
156.1
155.3
155.4
58.8
59.2
62.6
62.4
62.3
62.3
61.9
62.2
62.7
138.6
138.3
137.5
137.6
137.1
137.6
138.5
137.1
137.6
122.0
121.5
123.2
123.2
123.2
123.2
123.3
123.2
123.1
128.7
128.9
129.1
129.0
129.2
129.0
129.0
129.2
129.0
126.2
126.1
127.8
127.7
127.8
127.7
127.4
127.9
127.8
—
—
—
—
DMSO-d6
CDCl3
CDCl3
DMSO-d6
CDCl3
C6D6
109.7
107.4
107.1
107.1
107.6
106.6
110.0
191.1
188.4
187.4
179.5
179.0
178.6
182.9
28.4 (Me)
139.1 (Ph-1), 129.1 (Ph-2,6), 128.4 (Ph-3,5), 132.3 (Ph-4)
138.6 (Ph-1), 128.8 (Ph-2,6), 128.5 (Ph-3,5), 132.4 (Ph-4)
145.0 (Th-2), 132.7 (Th-3), 127.9 (Th-4), 133.3 (Th-5)
145.9 (Th-2), 132.5 (Th-3), 127.8 (Th-4), 132.9 (Th-5)
144.2 (Th-2), 133.4 (Th-3), 128.6 (Th-4), 134.5 (Th-5)
123.7 (COCH), 143.0 (CHPh), 134.8 (Ph-1), 128.3 (Ph-2,6), 128.9 (Ph-3,5),
130.3 (Ph-4)
DMSO-d6
CDCl3
3e
DMSO-d6
141.9
109.7
155.1
62.6
137.1
123.2
129.2
127.9
181.9
124.1 (COCH), 142.0 (CHPh), 134.6 (Ph-1), 128.6 (Ph-2,6), 128.8 (Ph-3,5),
130.3 (Ph-4)
a
CH-isomer.
OH-isomer.
b

W. Holzer et al. / Tetrahedron 60 (2004) 6791–6805
6795
N-methyl derivative 4d (Fig. 3). This is also the case
considering the data in DMSO-d6 (Tables 4 and 5).
However, based on these data an unambiguous assignment
of 2d to one of the tautomeric forms seems questionable.
Moreover, occasional line broadening in the spectra of 2,
particularly in DMSO-d6 solution, points to a dynamic
behavior.
Also, the comparison of 1H NMR chemical shifts in 2d, 3d,
and 4d shows some remarkable features. Whereas the data
of 3d and 2d do not differ substantially, with 4d a drastic
downfield shift is observed for the signal due to thiophene
H-3 (Fig. 4). Thus, for instance, in benzene-d6 the difference
for thiophene H-3 proton shift between 2d and 4d is found to
be 2.3 ppm (Fig. 4). This can be explained by a substantial
contribution of conformational isomers having the pyrazo-
lone CvO group close to the thiophene H-3 proton (similar
to conformer Y), which would be markedly deshielded due
to the anisotropy of the bond magnetic susceptibility of the
CvO bond. The contribution of conformer X is less
probable due to the absence of an NOE between pyrazole
H-5 and thiophene H-3 in the NOE difference spectrum of
4d (Fig. 4). In contrast, such a through-space interaction can
be clearly observed in similar experiments with compounds
2d and 3d indicating also that those conformers displayed in
Figure 4 contribute to the overall situation.
Amongst the tautomeric pyrazolones investigated, com-
pound 1 occupies an exceptional position due to the lack of a
substituent at the 4-position of the heterocyclic ring.
Whereas in benzene-d6 solution the compound solely exists
as the CH-isomer [CH2-substructure with d(1H) 2.19 ppm
and d (13C) 40.1 ppm], in CDCl3 solution (c,0.2 mol/l) a
mixture of CH and—mainly—OH form (,1.7:1) was found
at 28 8C, confirming a sufficiently slow interconversion of
the CH-isomer compared to the NMR timescale. In contrast,
in polar aprotic DMSO-d6 only one signal set emerged,
which can be attributed to the OH form—possibly being in
fast exchange with the NH isomer. However, on the basis of
chemical shift considerations7 (d pyrazole C-5 153.1 ppm),
NOEs (only very weak NOE between acidic proton and Ph
H-2,6), and considering 1H,1H as well as 13C,1H spin
coupling constants (see below) dominance of the OH-form
can be concluded. These results are in accordance with those
reported for related 3-methyl-1-phenyl-2-pyrazolin-5-
one.34,35
2.2.2. NOE-difference experiments. NOE-difference
experiments show some differences between recordings in
apolar solvents such as CDCl3 or benzene-d6 compared to
those in polar ones such as DMSO-d6. In the latter solvent,
for 2d through-space connectivities can be observed
between the XH-proton and pyrazole H-3(5) as well as to
H-2/6 of N-phenyl (Fig. 5). A possible explanation of this
phenomenon is some contribution of the NH-isomer to the
tautomeric composition or the presence of intermolecular
effects. In contrast, in CDCl3 and benzene-d6 a spatial
closeness of XH and pyrazole H-3 is not detectable (Fig. 6)
indicating the absence of NH-tautomer. We believe
compounds 2 in these non-polar solvents to be present in
a chelated hydroxypyrazole form (isomer A0 in Fig. 1).
NOE-difference experiments with pyrazolone 1 in CDCl3
are characterized by strong saturation transfer effects (e.g.,
d

6796
W. Holzer et al. / Tetrahedron 60 (2004) 6791–6805
Table 6. 13C,1H spin coupling constants (Hz) of compounds 1-3
No.
Solvent
1J(C3,H3)
2J(C4,H3)
3J(C5,H3)
1J(OMe)
Other couplings
b
b
b
b
1a
CDCl3
CDCl3
C6D6
DMSO-d6
CDCl3
DMSO-d6
CDCl3
C6D6
DMSO-d6
CDCl3
196.2
185.4
195.5
184.1
188.6
189.3
190.7
190.4
190.1
189.6
11.1
8.1
11.1
d
—
—
—
—
—
—
—
—
—
—
1J(C4,H4)¼134.6 Hz; 2J(C3,H4)¼5.4 Hz
1J(C4,H4)¼180.2 Hz; 2J(C3,H4)¼6.0 Hz
1J(C4,H4)¼134.4 Hz; 2J(C3,H4)¼5.5 Hz
1J(C4,H4)¼177.2 Hz; 2J(C3,H4)¼4.9 Hz
1J(Me)¼127.9 Hz
1c
1a
1c
2b
2b
2c
2c
2c
2d
10.7
9.5
11.0
11.0
10.6
11.1
4.8
b
1J(Me)¼127.3 Hz; 3J(C4,Me)¼1.5 Hz
3J(CO,Ph-2,6)¼4.0 Hz
4.8
4.7
4.8
4.9
Th: 2J(C2,H3)¼6.5 Hz; 3J(C2,H4)¼9.2 Hz; 3J(C2,H5)¼5.8 Hz;
1J(C3,H3)¼168.6 Hz; 2J(C3,H4)¼5.7 Hz; J(C3,H5)¼9.2 Hz;
3
1J(C4,H4)¼170.5 Hz, 2J(C4,H3)¼3J(C4,H5)¼4.4 Hz;
1J(C5,H5)¼186.1 Hz; 2J(C5,H4)¼7.2 Hz; J(C5,H3)¼10.9 Hz
3
2d
2d
C6D6
189.4
190.0
11.2
10.6
4.9
5.0
—
—
Th: 2J(C2,H3)¼6.6 Hz; 3J(C2,H4)¼9.2 Hz; 3J(C2,H5)¼5.7 Hz;
1J(C3,H3)¼168.6 Hz; 2J(C3,H4)¼5.6 Hz; J(C3,H5)¼9.3 Hz;
3
1J(C4,H4)¼169.6 Hz, 2J(C4,H3)¼3J(C4,H5)¼4.5 Hz;
1J(C5,H5)¼185.5 Hz; 2J(C5,H4)¼7.6 Hz; J(C5,H3)¼10.8 Hz
3
DMSO-d6
Th: 2J(C2,H3)¼7.3 Hz; 3J(C2,H4)¼9.0 Hz; 3J(C2,H5)¼5.8 Hz;
1J(C3,H3)¼169.4 Hz; 2J(C3,H4)¼5.8 Hz; J(C3,H5)¼9.3 Hz;
3
1J(C4,H4)¼170.4 Hz, 2J(C4,H3)¼3J(C4,H5)¼4.4 Hz;
1J(C5,H5)¼188.0 Hz; 2J(C5,H4)¼7.3 Hz; J(C5,H3)¼10.6 Hz
3
1
2e
2e
2e
3a
3a
3b
CDCl3
C6D6
DMSO-d6
CDCl3
DMSO-d6
CDCl3
189.8
189.7
191.6
185.9
186.0
188.1
10.4
10.7
9.8
10.7
10.7
9.6
4.6
4.3
4.5
b
—
—
—
146.0
146.8
147.8
1J(COCH)¼157.9 Hz; 2J¼2.3 Hz; J(CHPh)¼156.5 Hz
1
1J(COCH)¼158.0 Hz; 2J¼2.4 Hz; J(CHPh)¼156.0 Hz
1
1J(COCH)¼161.9 Hz; 2J¼4.3 Hz; J(CHPh)¼157.6 Hz
1J(C4,H4)¼177.7 Hz; 2J(C3,H4)¼4.1 Hz
b
1J(C4,H4)¼179.2 Hz; 2J(C3,H4)¼4.2 Hz
2
4.4
1J(COMe)¼127.5 Hz; J(CO,COMe)¼5.9 Hz; 3J(C4,COMe) 1.3 Hz;
3J(C5,OMe)¼4.4 Hz
3c
3c
3d
CDCl3
DMSO-d6
CDCl3
189.8
190.5
190.0
9.8
9.9
9.9
4.9
4.4
5.1
147.9
148.2
147.9
3J(C5,OMe)¼4.4 Hz
3J(C5,OMe)¼4.4 Hz
Th: 2J(C2,H3)¼6.6 Hz; 3J(C2,H4)¼8.8 Hz; 3J(C2,H5)¼5.6 Hz;
1J(C3,H3)¼168.5 Hz; 2J(C3,H4)¼5.7 Hz; J(C3,H5)¼9.1 Hz;
3
1J(C4,H4)¼169.6 Hz, 2J(C4,H3)¼4.9 Hz; 3J(C4,H5)¼4.0 Hz;
1J(C5,H5)¼185.4 Hz; 2J(C5,H4)¼7.2 Hz; J(C5,H3)¼10.9 Hz;
3
3J(C5,OMe)¼4.2 Hz
3d
3d
C6D6
189.2
190.8
10.1
10.1
4.4
4.5
147.8
148.2
Th: 2J(C2,H3)¼6.8 Hz; 3J(C2,H4)¼8.8 Hz; 3J(C2,H5)¼5.5 Hz;
1J(C3,H3)¼168.2 Hz; 2J(C3,H4)¼5.6 Hz; J(C3,H5)¼9.2 Hz;
3
1J(C4,H4)¼169.2 Hz, 2J(C4,H3)¼4.6 Hz; 3J(C4,H5)¼4.6 Hz;
1J(C5,H5)¼184.8 Hz; 2J(C5,H4)¼7.5 Hz; J(C5,H3)¼11.0 Hz;
3
3J(C5,OMe)¼4.4 Hz
DMSO-d6
Th: 2J(C2,H3)¼7.0 Hz; 3J(C2,H4)¼8.7 Hz; 3J(C2,H5)¼5.6 Hz;
1J(C3,H3)¼169.6 Hz; 2J(C3,H4)¼5.7 Hz; J(C3,H5)¼9.2 Hz;
3
1J(C4,H4)¼170.7 Hz, 2J(C4,H3)¼4.5 Hz; 3J(C4,H5)¼4.5 Hz;
1J(C5,H5)¼188.0 Hz; 2J(C5,H4)¼7.3 Hz; J(C5,H3)¼10.6 Hz;
3
3J(C5,OMe)¼4.5 Hz
1
3e
3e
CDCl3
188.5
190.3
9.6
9.7
4.3
4.4
147.8
148.1
1J(COCH)¼155.9 Hz; 2J¼1.9 Hz; J(CHPh)¼154.9 Hz;
3J(C5,OMe)¼4.3 Hz
1
DMSO-d6
1J(COCH)¼160.1 Hz; 2J¼4.5 Hz; J(CHPh)¼156.9 Hz;
3J(C5,OMe)¼4.3 Hz
a
CH-isomer.
b
c
d
Not unequivocally determined.
OH-isomer.
Small couplings not resolved due to marked line broadening.
of pyrazole H-4 between forms A and B) confirming
interconversion between the tautomeric forms. In DMSO-
d6, where only one (averaged) signal set appeared, the
observed saturation transfer between pyrazole H-4 and the
acidic proton provides a possible hint for the involvement of
the CH-isomer into the proton transfer reactions. Due to an
NOE observed for the signal of NPh H-2,6 upon irradiation
of the transition of the acidic proton (11.57 ppm) also the
presence of a certain percentage of NH-tautomer cannot be
excluded.
noticeable that 2J[pyrazole C-4,H3(5)] suffers the most
remarkable change when switching from O-methyl com-
pounds 3 to the corresponding N-methyl derivatives 4.
Comparing compounds within the thenoyl series d reveals
the magnitude of this coupling to be reduced from ,10 Hz
in 3d to 4–5 Hz in 4d, very similar results were obtained for
4-acetyl (b), 4-benzoyl (c) and 4-cinnamoyl (e) congeners
(Tables 6 and 7). The tautomeric pyrazolones 2b-d showed
values in the range of 9.5 Hz (2b in DMSO-d6) to 11.2 Hz
(2d in benzene-d6), again giving a strong hint for the
preferential presence of compounds 2 in the hydroxy form.
2
2.2.3. The geminal J[pyrazole C4,H3(5)] spin coupling
constant as a structural probe. Comparing a variety of
13C,1H spin coupling constants of compounds 3 and 4 it is
A possible explanation for the remarkable changes in the
2
magnitude of J[C4,H3(5)] between structures 3 and 4 as

W. Holzer et al. / Tetrahedron 60 (2004) 6791–6805
Table 7. 13C,1H spin coupling constants (Hz) of compounds 4
6797
No.
Solvent
1J(C5,H5)
2J(C4,H5)
3J(C3,H5)
1J(NMe)
Other couplings
4a
4a
CDCl3
186.3
189.0
6.3
6.7
8.6
8.6
140.6
140.8
1J(C4,H4)¼182.4 Hz; 2J(C3,H4)¼5.3 Hz; 2J(C5,H4)¼7.1 Hz;
3J(C5,NMe)¼3.5 Hz; 3J(NMe,H5)¼1.6 Hz
DMSO-d6
1J(C4,H4)¼181.3 Hz; 2J(C3,H4)¼5.8 Hz; 2J(C5,H4)¼7.0 Hz;
3J(C5,NMe)¼3.5 Hz; 3J(NMe,H5)¼1.6 Hz
4b
4c
4c
4d
CDCl3
CDCl3
DMSO-d6
CDCl3
190.1
190.7
192.9
191.3
4.2
4.6
5.3
4.0
7.0
6.8
6.9
6.6
142.4
142.6
143.0
142.5
1J(Me)¼128.0 Hz; 3J(C5,NMe)¼3.3 Hz; 3J(NMe,H5)¼2.0 Hz
3J(C5,NMe)¼3.3 Hz; 3J(NMe,H5)¼2.0 Hz
3J(C5,NMe)¼3.3 Hz; 3J(NMe,H5)¼2.0 Hz
Th: 2J(C2,H3)¼6.3 Hz; 3J(C2,H4)¼8.9 Hz; 3J(C2,H5)¼6.3 Hz;
1J(C3,H3)¼172.0 Hz; 2J(C3,H4)¼5.8 Hz; 3J(C3,H5)¼8.8 Hz;
1J(C4,H4)¼169.2 Hz, 2J(C4,H3)¼5.0 Hz; 3J(C4,H5)¼4.0 Hz;
1J(C5,H5)¼183.8 Hz; 2J(C5,H4)¼7.1 Hz; 3J(C5,H3)¼11.1 Hz;
3J(C5,NMe)¼3.3 Hz; 3J(NMe,H5)¼2.0 Hz
4d
DMSO-d6
193.7
5.0
6.7
143.3
Th: 2J(C2,H3)¼6.5 Hz; 3J(C2,H4)¼8.8 Hz; 3J(C2,H5)¼5.8 Hz;
1J(C3,H3)¼171.1 Hz; 2J(C3,H4)¼6.0 Hz; 3J(C3,H5)¼9.0 Hz;
1J(C4,H4)¼169.6 Hz, 2J(C4,H3)¼5.2 Hz; 3J(C4,H5)¼4.3 Hz;
1J(C5,H5)¼186.8 Hz; 2J(C5,H4)¼7.3 Hz; 3J(C5,H3)¼10.8 Hz;
3J(C5,NMe)¼3.3 Hz; 3J(NMe,H5)¼2.0 Hz
4e
4e
CDCl3
190.6
193.2
4.4
5.1
6.9
6.9
142.3
143.2
1J(COCH)¼159.9 Hz; 2J(COCHvCH)¼2.1 Hz; 1J(CHPh)¼154.4 Hz;
3J(vCHPh,Ph-2,6)¼4.7 Hz; 3J(C5,NMe)¼3.3 Hz; 3J(NMe,H-5)¼2.0 Hz
1J(COCH)¼158.3 Hz; 2J(COCHvCH)¼2.0 Hz; 1J(CHPh)¼154.4 Hz;
3J(vCHPh,Ph-2,6)¼4.6 Hz; 3J(C5,NMe)¼3.4 Hz; 3J(NMe,H-5)¼2.0 Hz
DMSO-d6
Figure 3. 13C NMR chemical shifts of 2d, 3d, and 4d (CDCl3).
Figure 4. 1H NMR chemical shifts (d, ppm) for pyrazole H-3(5) and thiophene H-3 (framed) and observed NOEs (arrows) with compounds 2d, 3d, and 4d.
well as between OH (CH) isomers (A, B in Fig. 1) on the one
hand, and NH-forms (C in Fig. 1) on the other hand can be
given on the basis of lone-pair effect considerations. It is
well known from the literature that lone-pair effects can
drastically influence a large variety of different spin
pair in a-position at pyrazole N2(1), what according to
theory should lead to a positive effect and, inversely, to a
decrease in magnitude upon removal of such a lone-pair by
alkylation, protonation, oxidation or complexation.36
A
2
related, well known example is the reduction of J(C3,H2)
in pyridine (þ8.5 Hz) to 5.1 Hz on protonation and to
4.2 Hz on N-oxide formation (Fig. 7, upper trace).37,38 The
2
coupling constants.36 In the case of pyrazole J[C4,H3(5)]
the H-C–C axis is coplanar with the sp2-hybridized lone-

6798
W. Holzer et al. / Tetrahedron 60 (2004) 6791–6805
Figure 5. NOE-difference spectrum of 2d obtained upon irradiation of the XH-resonance (7.0–11.5 ppm, in DMSO-d6).
Figure 6. NOE-difference spectrum of 2d obtained upon irradiation of the XH-resonance (6.0–12.5 ppm, in benzene-d6).
value of this coupling indicates that 2-aminopyridines are
present in the NH2-form (2J¼7 Hz), but 2-hydroxypyridines
exist as pyridones (2J¼3 Hz), whereas in the fixed
2-methoxypyridine the ‘intact’ coplanar lone-pair increases
2J(C5,H6) again to 8 Hz (Fig. 7, middle trace).39 Similarly,
all pyrazole derivatives investigated in the present study
characterized by an intact lone-pair at pyrazole N–2(1) (a
‘pyridine’-type nitrogen atom) exhibit a large value for
2J[(C4,H3(5)], whereas N-methyl compounds of type 4
show markedly lower ones (Fig. 7, lower trace). Similar sp2-
hybridized nitrogen atoms are not only present in 5-alkoxy
or 5-hydroxypyrazoles, but also in 2,4-dihydro-3H-pyrazol-
3-ones (e.g., the CH-isomer of 1), the latter exhibiting even
slightly larger values. Thus, in 1B—the CH-isomer of 1—
this 2J coupling constant was found to be 11.1 Hz in CDCl3
or benzene-d6 solution (Fig. 7, lower trace).
It should be noted that the magnitude of the considered
geminal 13C,1H spin coupling constant is also dependent
from additional factors such as bond lengths, bond angles
and substituents.37 However, within the different types of
pyrazoles investigated the changes within these parameters
are not anticipated to lead to such drastic changes. Thus, we
believe the described lone-pair effects to play the dominant
role here.
In Figure 8, the pyrazole 2J[C4,H3(5)] spin coupling
constants for a variety of pyrazole derivatives are dis-
played.40 – 49 In the two lowest rows, the effects of
protonation, alkylation, N-oxidation and complexation are
presented for pyrazole (16), 1-methyl (18), and 1-phenyl-
pyrazole (22), respectively. Thus, pyrazole (16) in CDCl3 or
2
acetone-d6 exhibits J(C4,H3)¼9.9 Hz,40,41 being identical

W. Holzer et al. / Tetrahedron 60 (2004) 6791–6805
6799
Figure 7. Geminal spin coupling constants in pyridine and pyrazole derivatives (in Hz).
2
with J(C4,H5) due to fast prototropic exchange at room
constants we decided to complete them with some literature
data and carry out DFT calculations to determine the
generality of our assumptions. In Table 8 are collected the
experimental values and their origin.
temperature. According to this situation, the observed 9.9 Hz
represent a mean value between the larger 2J(C4,H3) coupling
and the smaller 2J(C4,H5) one. In fixed 1-methylpyrazole (18)
the different magnitudes of these geminal couplings clearly
emerge [2J(C4,H3)¼10.5 Hz; 2J(C4,H5)¼8.7 Hz].42 How-
ever, switching from pyrazole (16) to its cation 17 (in H2SO4)
reduces 2J(C4,H3) [and also 2J(C4,H5)] from 9.9 to 6.7 Hz.43
The same or a similar value of 2J was found in N-
methylpyrazolium salt 19 (6.7 Hz in H2SO4,44 7.2 Hz in
CF3CO2H45) and in 1,2-dimethyl-pyrazolium cation 20
(7.1 Hz in DMSO-d6, 6.8 Hz in TFA).45 The effect caused
by involvement of the lone-pair in the complexation is
obviously somewhat smaller than that of protonation, as
2J(C4,H3) in the ruthenium complexes 21 was found to be 7.6
For all these situations we carried out DFT calculations of
the four terms (see Table 9) that are involved in coupling
constants: diamagnetic spin orbit (DSO), Fermi contact
(FC), paramagnetic spin orbit (PSO) and spin dipole (SD)
terms. As it is well known for atoms of the first rows
excluding 19F, the FC largely dominates.52
We should note that according to the calculations,
2J(13C,1H) is always positive and that the calculated sign
is in general correct52 (this is known experimentally for
benzene).37
and 9.1 Hz, respectively.46 Comparison of J(C4,H3) in 1-
2
phenylpyrazole (22) (10.5 Hz),45 and in the corresponding
cations 23 (6.7 Hz in conc. H2SO4),43 and 24 (7.0 Hz in
CF3CO2D) support the above considerations, as well as the
value found for N-oxide 25.47
The line corresponds to Experimental J¼(0.90^0.03),
Calculated J, n¼11, r 2¼0.988. The effect of the lone pair
on the adjacent 13C,1H coupling constant is clearly observed
in the upper corner of Figure 10.
3
2.2.4. The vicinal J[pyrazole H3(5),H4] spin coupling
constant in compounds 1, 3a and 4a. The 4-unsubstituted
compounds 1, 3a and 4a exhibit interesting differences
regarding the magnitude of the vicinal pyrazole H3(5),H4
coupling constant.6 Whereas this coupling constant in
N-methyl derivative 4a was found to be 3.5 Hz (in CDCl3 as
well as in DMSO-d6), for the corresponding O-methyl isomer
3a a considerably reduced value of 2.0 Hz was determined
(Fig. 9). Thus, the observed values for pyrazolone 1 (2.2 Hz in
CDCl3, 1.9 Hz in DMSO-d6) suggest the predominance of the
OH-form 1A, what is in full accordance with the findings
basedonothercriteria. IntheCH-isomer1Bthe corresponding
coupling is further reduced to 1.1 Hz (CDCl3) and 1.3 Hz
(benzene-d6), respectively (Fig. 9).
3. Conclusion
Considering the—easily obtainable—magnitude of the
geminal pyrazole C-4,H-3(5) spin coupling constant, the
observed NOEs as well as the chemical shifts it can be
concluded that N-phenyl-4-acylpyrazolones 2 are present as
5-hydroxypyrazoles in CDCl3 or benzene-d6 solution. In
polar DMSO-d6, a minor contribution of the NH-forms
seems to be probable. In contrast, the NMR recordings
unambiguously assign compound 1 to be present solely as
the CH-isomer in benzene-d6 solution. In CDCl3 solution, a
mixture of CH-isomer and—probably—OH-form
[2J(C4,H3)¼8.1 Hz] was found, whereas 1 occurs mainly
as hydroxypyrazole in DMSO-d6. Theoretical calculations
2.3. DFT-calculations
2
of the J(C4,H3) coupling constants for a wide variety of
compounds assess that they always have a positive sign and
Having thus collected a large number of 13C,1H coupling

6800
W. Holzer et al. / Tetrahedron 60 (2004) 6791–6805
Figure 8. Pyrazole 2J[C4,H3(5)] spin coupling constants (Hz) in different pyrazole derivatives.

W. Holzer et al. / Tetrahedron 60 (2004) 6791–6805
6801
3
Figure 9. The vicinal J[pyrazole H3(5),H4] spin coupling constant in compounds 1, 3a and 4a.
recorded on an ATI Mattson Genesis Series FTIRe
spectrophotometer. Mass spectra were obtained on a
Shimadzu DI-QP1000 instrument (EI, 70 eV). The NMR
spectra were recorded on a Varian Unity Plus 300
Table 8. Experimental values
2J(13C,1H)
Source
Ref. 50
Ref. 51
Ref. 51
Ref. 51
Ref. 51
This work
Ref. 42
Refs. 42,44
This work
This work
This work
1
spectrometer (299.95 MHz for H, 75.43 MHz for 13C) at
Molecule
Point
28 8C. The center of the solvent signal was used as an
internal standard which was related to TMS with d 7.26 ppm
(1H, CDCl3), d 2.49 ppm (1H, DMSO-d6), d 7.16 ppm (1H,
benzene-d6), d 77.0 ppm (13C, CDCl3), d 39.5 ppm (13C,
DMSO-d6), d 128.0 ppm (13C, benzene-d6). The digital
resolutions in the gated-decoupled 13C NMR spectra were
0.33 Hz/data point. Preparative layer chromatography was
performed on Merck 60F254 20£20 cm glass plates (2 mm
thickness). Column chromatographic separations were
performed on Merck Kieselgel 60 (70–230 mesh). As not
otherwise indicated all reagents are commercially available,
C6H6
1
2
3
4
5
6
7
8
1.15
8.47
3.12
4.09
4.62
4.2
10.5
6.7
10
10
Pyridine (C3–H2)
Pyridine (C2–H3)
Pyridiniumþþ (C3–H2)
Pyridinium (C2–H3)
Pyridinium N–O
Pyrazole
Pyrazolium (Hþ)
5-OH Pyrazole
4H-D2-Pyrazolinone
2H-D3-Pyrazolinone
9
10
11
4.5
Table 9. Calculations of the four terms that contribute to the total 2J(13C,1H)
Molecule (Point)
DSO
FC
PSO
SD
C6H6 (1)
20.35
20.34
20.31
20.41
20.32
20.38
20.44
20.50
20.39
20.35
20.49
3.12
10.13
5.04
5.08
6.91
5.87
12.21
7.58
12.20
11.62
6.24
20.90
20.75
20.97
20.74
20.95
20.68
20.42
20.43
20.41
0.11
0.00
0.03
20.02
20.02
20.05
0.00
Pyridine (C3–H2) (2)
Pyridine (C2–H3) (3)
Pyridiniumþþ (C3–H2) (4)
Pyridinium (C2–H3) (5)
Pyridinium N-oxide (6)
Pyrazole (7)
0.03
Pyrazolium (Hþ) (8)
5-OH Pyrazole (9)
20.02
0.02
0.06
4H-D2-Pyrazolinone (10)
2H-D3-Pyrazolinone (11)
20.62
20.03
Total J
1.87
9.07
3.74
3.91
5.59
4.81
11.38
6.63
Experimental J (Table 1)
Fitted
1.69
8.18
3.37
3.52
4.34
5.04
10.26
5.98
10.29
10.31
4.61
C6H6 (1)
1.15
8.47
3.12
4.09
4.62
4.2
10.5
6.7
10
10
Pyridine (C3–H2) (2)
Pyridine (C2–H3) (3)
Pyridiniumþþ (C3–H2) (4)
Pyridinium (C2–H3) (5)
Pyridinium N–O (6)
Pyrazole (7)
Pyrazolium (Hþ) (8)
5-OH Pyrazole (9)
11.42
11.44
5.10
4H-D2-Pyrazolinone (10)
2H-D3-Pyrazolinone (11)
4.5
that the adjacent lone pair makes an important contribution
to their value.
the yields given below are not optimized and refer to
analytically pure compounds.
4.2. 4-Acylpyrazolones 2; general procedure
4. Experimental
4.1. General
To a mixture of pyrazolone 1 (3.204 g, 20 mmol) and
Ca(OH)2 (2.932 g, 40 mmol) in dioxane (35 mL, stored over
˚
4 A molsieve) was added the appropriate carboxylic acid
chloride (20 mmol) in dioxane (10 mL) within 5 min. The
resulting mixture was heated to reflux for 2 h and then
Melting points were determined on a Reichert-Kofler hot-
stage microscope and are uncorrected. The IR spectra were

6802
W. Holzer et al. / Tetrahedron 60 (2004) 6791–6805
Figure 10. Plot of experimental versus calculated 2J(13C,1H) coupling constants (Hz).
allowed to cool to room temperature. After addition of 2 N
HCl (50 mL) the mixture was stirred for 1 h, then poured
onto H2O (150 mL). The precipitated product was filtered
off, washed several times with H2O and recrystallized from
the solvent given below.
1.563 mmol). After stirring for 15 h at room temperature
the mixture was poured onto 2 N HCl (20 mL) and washed
with light petroleum (3 times). The aqueous phase was made
alkaline with solid Na2CO3 and extracted with Et2O (3
times). The combined etheral phases were washed with H2O
and brine, dried (Na2SO4) and evaporated under reduced
pressure to afford a nearly colorless oil. Yield: 152 mg
(56%).
4.2.1. 1-(5-Hydroxy-1-phenyl-1H-pyrazol-4-yl)ethan-1-
one (2b).53 Yield 2.18 g (54%) of colorless crystals, mp
124 8C (EtOH). IR: 1664 cm21 (CvO). MS (Th, %): 203
(Mþþ1, 17), 202 (Mþ, 100), 187 (77), 77 (40), 51 (34), 43
(48). Anal. calcd for C11H10N2O2: C, 65.34; H, 4.98; N,
13.85. Found: C, 65.37; H, 5.26; N, 13.95.
4.3.2. (5-Methoxy-1-phenyl-1H-pyrazol-4-yl)ethan-1-
one (3b) and 4-acetyl-1,2-dihydro-1-methyl-2-phenyl-
3H-pyrazol-3-one (4b). Under vigorous stirring, to a
solution of 2b (1.011 g, 5 mmol) in CH2Cl2 (20 mL)
was added a 40% aqueous solution of HBF4 (1.100 g,
5 mmol) at 0 8C. Then a 2 M solution of trimethyl-
silyldiazomethane in n-hexane (2.5 mL, 5 mmol) was
added dropwise and the mixture was stirred at 0 8C for
1 h. After a second portion of reagent (2.5 mL, 5 mmol)
had been added and stirring was continued for another
1 h, the mixture was poured onto H2O (45 mL). After
extraction with CH2Cl2 (3£50 mL) the combined organic
phases were washed with 2 N NaOH (2£75 mL) and H2O
(2£75 mL), dried (Na2SO4) and evaporated. The residual
tan oil (531 mg), which crystallized on standing, was
subjected to preparative layer chromatography (silica gel,
CH2Cl2/EtOAc 7:3) giving 3b as the less retarded and 4b
as the more polar fraction. The compounds were removed
from the stationary phase by repeated extraction with
warm EtOAc.
4.2.2. 1-(5-Hydroxy-1-phenyl-1H-pyrazol-4-yl)(phenyl)-
methanone (2c). Yield 4.02 g (76%) of yellowish leaflets,
mp 159–161 8C (EtOH) (lit.54 mp 160–161 8C). MS (Th,
%): 265 (Mþþ1, 13), 264 (Mþ, 68), 186 (39), 105 (100), 91
(89), 77 (98), 69 (32), 55 (25), 53 (68), 51 (62), 43 (27).
Anal. calcd for C16H12N2O2: C, 72.72; H, 4.58; N, 10.60.
Found: C, 72.42; H, 4.65; N, 10.50.
4.2.3. (5-Hydroxy-1-phenyl-1H-pyrazol-4-yl)(2-thienyl)-
methanone (2d). Yield 3.53 g (65%) of yellowish crystals,
mp 161 8C (EtOH). MS (Th, %): 270 (Mþ, 48), 186 (100),
118 (35), 111 (86), 91 (38), 81 (24), 77 (34), 69 (51), 57
(20), 55 (27), 53 (92), 51 (39), 43 (24), 41 (39). Anal. calcd
for C14H10N2O2S: C, 62.21; H, 3.37; N, 10.36. Found: C,
62.07; H, 3.95; N, 10.40.
4.2.4. (E)-1-(5-Hydroxy-1-phenyl-1H-pyrazol-4-yl)-3-
phenylprop-2-en-1-one (2e).23 Yield 3.52 g (61%) of
orange needles, mp 182–183 8C (EtOH).23
Compound 3b. Yield: 299 mg (28%) of tan crystals, mp
63 8C. IR: 1656 cm21 (CvO). MS (Th, %): 216 (Mþ, 7),
201 (20), 91 (22), 77 (33), 51 (26), 43 (100), 41 (20). Anal.
calcd for C12H12N2O2: C, 66.65; H, 5.59; N, 12.95. Found:
C, 66.94; H, 5.55; N, 12.77.
4.3. Preparation of O-methyl (3) and N-methyl
derivatives (4)
4.3.1. 5-Methoxy-1-phenyl-1H-pyrazole (3a).55 To a
stirred mixture of pyrazolone 1 (250 mg, 1.561 mmol),
K2CO3 (432 mg, 3.126 mmol) and dry DMF (3 mL) was
added dropwise methyl 4-toluenesulfonate (291 mg,
Compound 4b. Yield: 50 mg (5%) of colorless crystals after
recrystallization from diisopropyl ether, mp 220–222 8C
(lit.56 mp 216–217 8C). HRMS: Th (Mþ); calcd for
C12H12N2O2: 216.0900. Found: 216.0903^0.0011.

W. Holzer et al. / Tetrahedron 60 (2004) 6791–6805
6803
4.3.3. (5-Methoxy-1-phenyl-1H-pyrazol-4-yl)(phenyl)-
methanone (3c). Compound 3c was obtained from 2c
(1.321 g, 5 mmol) and Me3SiCHN2/HBF4 similarly as
described for the synthesis of 3b from 2b. Preparative
layer chromatography (CH2Cl2/EtOAc 7:3) afforded 3c as
the less retarded component accompanied by small amounts
(5%) of isomer 4c.
1.135 mmol) and dimethyl sulfate (430 mg, 3.41 mmol)
was heated to reflux on an oil bath (T¼190–200 8C) for
15 min. Then, the mixture was poured onto hot H2O (5 mL),
stirred for 20 min, made alkaline with solid Na2CO3 and 2 N
NaOH and extracted exhaustively with CH2Cl2. The
combined organic phases were washed twice with H2O
and then brine, dried (Na2SO4) and evaporated. The residue
was recrystallized from toluene (ca. 30 mL) to afford a
colorless solid; yield: 148 mg (47%); mp 157–159 8C. MS
(Th, %): 279 (Mþþ1, 10), 278 (Mþ, 52), 201 (15), 158 (47),
121 (74), 105 (100), 91 (12), 77 (85), 51 (23). HRMS: Th
(Mþ); calcd for C17H14N2O2: 278.1055. Found:
278.1049^0.0014. Anal. calcd for C17H14N2O2: C, 73.37;
H, 5.07; N, 10.07. Found: C, 73.11; H, 5.33; N, 10.02.
Compound 3c. Yield: 473 mg (34%) of a reddish oil. IR:
1656 cm21 (CvO). MS (Th, %): 278 (Mþ, 5), 105 (41), 91
(36), 77 (100), 51 (29). Anal. calcd for C17H14N2O2: C,
73.37; H, 5.07; N, 10.07. Found: C, 73.02; H, 5.00; N, 9.82.
4.3.4. (5-Methoxy-1-phenyl-1H-pyrazol-4-yl)(2-thienyl)-
methanone (3d). Compound 3d was obtained from 2d
(1.352 g, 5 mmol) and Me3SiCHN2/HBF4 similarly as
described for the synthesis of 3b from 2b. Preparative
layer chromatography (CH2Cl2/EtOAc 3:2) afforded 3d as
the less retarded component accompanied by traces of
isomer 4d. The product was crystallized from diisopropyl
ether with addition of charcoal. Yield: 341 mg (24%) of
yellowish crystals, mp 105 8C. IR: 1622 cm21 (CvO). MS
(Th, %): 285 (Mþþ1, 11), 284 (Mþ, 55), 144 (23), 111
(100), 91 (53), 77 (74), 53 (34), 51 (64). Anal. calcd for
C15H12N2O2S: C, 63.36; H, 4.25; N, 9.85. Found: C, 63.06;
H, 4.33; N, 9.82.
4.3.8. 1,2-Dihydro-1-methyl-2-phenyl-4-(2-thienylcar-
bonyl)-3H-pyrazol-3-one (4d). A mixture of 2d (811 mg,
3 mmol), 1 N aq. NaOH (9 mL), H2O (6 mL), and dimethyl
sulfate (756 mg, 6 mmol) was heated to reflux for 4 h before
it was stirred at rt for additional 16 h. The combined organic
phases obtained after extraction with CH2Cl2 (3£10 mL)
were washed with H2O, dried (Na2SO4) and evaporated.
The residue (610 mg) was subjected to preparative layer
chromatography (CH2Cl2/EtOAc 1:9). From the central area
the product was desorbed by repeated extraction with
EtOAc. Yield: 40 mg (5%) of colorless crystals; mp 209 8C.
MS (Th, %): 285 (Mþþ1, 10), 284 (Mþ, 51), 111 (100),
97 (29), 77 (33), 53 (14). Anal. calcd for C15H12N2O2-
S·0.5H2O: C, 61.42; H, 4.47; N, 9.55. Found: C, 61.31; H,
4.32; N, 9.36.
4.3.5. (E)-1-(5-Methoxy-1-phenyl-1H-pyrazol-4-yl)-3-
phenyl-2-propen-1-one (3e). To a mixture of 2e (871 mg,
3 mmol), PPh3 (1.179 g, 4.5 mmol) and MeOH (120 mg,
3.75 mmol) in CH2Cl2 (60 mL) was added dropwise diethyl
azodicarboxylate (783 mg, 4.5 mmol). After stirring for
20 h at room temperature, MeOH (3 mL) was added and the
mixture was poured onto H2O (60 mL). After exhaustive
extraction with CH2Cl2, the combined organic phases were
washed several times with 2 N NaOH and then with
H2O. After drying (Na2SO4), the solvent was evaporated
and the residue was subjected to preparative layer
chromatography (CH2Cl2/EtOAc 3:2). The less retarded
zone was removed and extracted several times with warm
EtOAc. The residue obtained after filtration and evaporation
of the solvent was recrystallized from diisopropyl ether.
Yield: 307 mg (34%) of colorless crystals, mp 165 8C. IR:
1654 cm21 (CvO). MS (Th, %): 304 (Mþ, 24), 213 (19),
187 (28), 186 (21), 131 (16), 103 (32), 91 (33), 77 (100), 51
(42). Anal. calcd for C19H16N2O2: C, 74.98; H, 5.30; N,
9.20. Found: C, 74.80; H, 5.33; N, 9.12.
4.3.9. (E)-1,2-Dihydro-1-methyl-2-phenyl-4-(3-phenyl-
A mixture of 2e
acryloyl)-3H-pyrazol-3-one (4e).
(450 mg, 1.55 mmol) and dimethyl sulfate (1.95 g,
15.45 mmol) was heated to 100 8C for 24 h with stirring.
Then the excess reagent was removed by bulb-to-bulb
distillation (75 8C). The residue was stirred with sat.
aqueous Na2CO3 (2 mL) and extracted with CH2Cl2
(3£10 mL). The combined CH2Cl2-phases were dried
(Na2SO4) and evaporated to dryness. The oily residue
crystallized upon treatment with water, and was washed
with cold ethanol and then recrystallization from EtOH.
Yield: 179 mg (38%) of nearly colorless crystals; mp 201 8C
[lit.58 mp 234 8C, Beilstein (Reg. Nr. 30915) mp 198–
199 8C, lit.59 mp 190–192 8C]. MS (Th, %): 305 (Mþþ1,
21), 304 (Mþ, 100), 303 (30), 275 (31), 193 (19), 184 (63),
174 (22), 131 (32), 121 (65), 103 (45), 77 (38). HRMS: Th
(Mþ); calcd for C19H16N2O2: 304.1212. Found:
304.1208^0.0015.
4.3.6. 1,2-Dihydro-1-methyl-2-phenyl-3H-pyrazol-3-one
(4a). A mixture of pyrazolone 1 (250 mg, 1.561 mmol),
methyl 4-toluenesulfonate (291 mg, 1.561 mmol) and dry
xylene (5 mL) was heated to reflux for 24 h under anhydrous
conditions. After cooling, to the mixture was added light
petroleum (3 mL), the organic phase was cautiously
removed, the remaining oil was taken up in 2 N NaOH
(3 mL) and exhaustively extracted with CHCl3 (6 times).
The combined CHCl3 phases were dried (Na2SO4) and
evaporated under reduced pressure. The residue was
recrystallized from EtOAc to afford cream crystals. Yield:
183 mg (67%); mp 115–117 8C (lit.57 mp 117–118 8C).
Computational part. The optimization was carried out at
the B3LYP/6-311þþG** level60,61 and the calculation of
the four components of the coupling constant at the same
level using the facilities provided by the Gaussian 03
package.62,63
Acknowledgements
We thank Dr. L. Jirovetz for recording the mass spectra.
Financial support was provided by the Spanish DGI/MCYT
(Projects no. BQU2003-00976 and BQU2003-01251).
4.3.7. 4-Benzoyl-1,2-dihydro-1-methyl-2-phenyl-3H-
pyrazol-3-one (4c).
A
mixture of 2c (300 mg,

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W. Holzer et al. / Tetrahedron 60 (2004) 6791–6805
23. Holzer, W.; Krca, I. Heterocycles 2003, 60, 2323–2342.
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