The structure of 4-benzoyl-5-methyl-2-phenylpyrazol-3-one oxime and its methyl derivatives

Article abstract of DOI:10.1002/ejoc.200390175

¹H and ¹³C NMR spectroscopic investigations of 4-benzoyl-5-methyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one oxime (4) and different methylation products thereof (5-11) indicate that 4 exists predominantly as 4-enaminopyrazolone in [D₆]DMSO solution. Single-crystal X-ray analysis revealed that in the solid state the same tautomeric structure of 4 was present, and closely resembles that of the corresponding N-methylamino product (6). Both compounds are stabilised by an intramolecular hydrogen bond between the pyrazolone C=O group and the N-OH proton. A 1,2-dihydro-3H-pyrazol-3-one structure was found in a clathrate of O-methyloxime 5 and dichloromethane. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003.

Full text of DOI:10.1002/ejoc.200390175

FULL PAPER
The Structure of 4-Benzoyl-5-methyl-2-phenylpyrazol-3-one Oxime
and Its Methyl Derivatives
Wolfgang Holzer,*[a] Katharina Hahn,[a] Thomas Brehmer,[b] Rosa M. Claramunt,*[c] and
[c]
´
Marta Perez-Torralba
Keywords: Oximes / Tautomerism / X-ray diffraction / NMR spectroscopy / Density functional calculations
1H and 13C NMR spectroscopic investigations of 4-benzoyl-
5-methyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one oxime (4)
and different methylation products thereof (5−11) indicate
methylamino product (6). Both compounds are stabilised by
an intramolecular hydrogen bond between the pyrazolone
C=O group and the N-OH proton. A 1,2-dihydro-3H-pyrazol-
3-one structure was found in a clathrate of O-methyloxime 5
and dichloromethane.
that
4 exists predominantly as 4-enaminopyrazolone in
[D6]DMSO solution. Single-crystal X-ray analysis revealed
that in the solid state the same tautomeric structure of 4 was
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
present, and closely resembles that of the corresponding N- Germany, 2003)
Introduction
The tautomerism of 4-acylpyrazolones has been the sub-
ject of various studies.[1Ϫ5] In the solid state, some unam-
biguous results have been obtained by single-crystal X-ray
analyses,[3,5Ϫ8] which show the compounds to be present in
the chelated hydroxypyrazole form (AЈ), the NH form (B),
or as isomers with an exocyclic double bond being stabilised
by an intramolecular hydrogen bond (DЈ) (Figure 1). The
medium used for recrystallisation obviously plays a crucial
role in this context: the use of different solvents can lead
to the formation of different tautomeric forms of the same
compound.[7Ϫ9] The situation in solution is much more
complicated, as a fast (relative to the NMR timescale) in-
terconversion of OH and NH forms gives rise to averaged
sets of signals that call for a careful analysis. In the older
literature, contradictory Ϫ and also obviously incorrect Ϫ
proposals can be found.[9] More relevant investigations[4,5]
indicate such compounds to have a complex behaviour in
solution, with the chelated hydroxy form being predomin-
ant in CDCl3 or C6D6, and mixtures of OH and NH tauto-
mers seem to be present in the more-polar [D6]DMSO.
A related and even more sophisticated problem is the
structural assignment of oximes derived from 4-acylpyrazo-
lones. Here, as shown in Figure 2, in addition to tautomer-
Figure 1. Tautomeric forms of 4-acylpyrazolones
ism, also the E/Z diastereoisomerism at the CϭN double
bond must be considered (for isomers A, B, and C). More-
over, in a manner similar to 4-acylpyrazolones, forms sta-
bilised by intramolecular hydrogen bonds are also possible,
for instance DЈ and DЈЈ. Because a number of 4-acylpyrazo-
lone oximes recently synthesised in our group exhibited an
interesting reaction behaviour Ϫ namely, intramolecular
cyclisations to 6H-pyrazolo[4,3-d]isoxazoles F failed and,
instead, the formation of 7-methyl-1,5,6-triazaspiro-
[2.4]hepta-1,6-dien-4-ones of type G took place[10] (Fig-
ure 2) Ϫ we were interested in gaining a more detailed in-
sight into the structure and tautomerism of the title com-
pounds. Here we present NMR spectroscopic investi-
gations, as well as the results of single-crystal X-ray ana-
lyses, of 4-benzoyl-5-methyl-2-phenyl-3H-pyrazol-3-one
[a]
Institute of Pharmaceutical Chemistry, University of Vienna,
Pharmaziezentrum,
Althanstrasse 14, 1090 Vienna, Austria
[b]
Institute of Mineralogy and Crystallography, University of
Vienna,
Althanstrasse 14, 1090 Vienna, Austria
[c]
´
´
´
Departamento de Quımica Organica y Biologıa, Facultad de
Ciencias, UNED,
Senda del Rey 9, 28040 Madrid
1209
Eur. J. Org. Chem. 2003, 1209Ϫ1219  2003 WILEY-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim 1434Ϫ193X/03/0407Ϫ1209 $ 20.00ϩ.50/0

´
W. Holzer, K. Hahn, T. Brehmer, R. M. Claramunt, M. Perez-Torralba
FULL PAPER
Results and Discussion
oxime (4) and its methyl derivatives (5Ϫ11) (Scheme 1).
Most of the latter derivatives may be considered as ‘‘fixed’’
tautomeric forms that should deliver valuable data for the Chemistry
purpose of determining tautomeric composition of their
corresponding des-methyl congeners.
Compounds 2[11,12] and 3[12,13] are known, but a more
convenient synthesis of 2 was possible by reacting 1 with
methyl 4-toluenesulfonate (TosOMe). The synthesis of
oximes 4,[14Ϫ16] 8, 10, and 12 and those of oxime ethers 5,
9, and 11 was accomplished by treatment of the corres-
ponding ketones with hydroxylamine hydrochloride or O-
methylhydroxylamine hydrochloride, respectively, in eth-
anol/pyridine (Scheme 1). The N-hydroxy-N-methylenami-
none 6 resulted from reaction of 4 with one equivalent of
TosOMe, and methylation of 6 with a further equivalent of
TosOMe led to the formation of 7. All novel compounds
were fully characterised by spectroscopic methods (IR, MS,
1H NMR, 13C NMR) as well as by elemental analysis.
NMR Spectroscopic Investigations
The NMR spectroscopic data of compounds 4Ϫ12 are
given in Table 1Ϫ3. Complete and unambiguous assign-
ment of signals in the 1H and 13C NMR spectra was
achieved by a combination of different NMR techniques
such as fully 1H-coupled 13C NMR (gated decoupling),
APT,[17] NOE difference spectroscopy,[18] 1D TOCSY,[19]
13CϪ1H shift correlations via one bond couplings
(HMQC),[20] 1D HETCOR,[21] and long-range INEPT[22]
experiments with selective excitation.
Figure 2. Tautomeric forms of 4-acylpyrazolone oximes and their
reaction with trichloroacetyl isocyanate
1
Whereas the H and 13C NMR spectra of the title com-
[23]
pound 4 in CDCl3
exhibit sharp signals (except for the
resonance of the acidic protons), the corresponding spectra
in [D6]DMSO are characterised by marked line broadening,
indicating dynamic behaviour, especially for the signals of
the pyrazole C-4 (δ ϭ 96.0 ppm), pyrazole C-3(5) (δ ϭ
158.8 ppm), Ph-CϪN (δ ϭ 152.9 ppm), and C-phenyl C-1
(δ ϭ 132.1 ppm) units. A single broad signal (δ ϭ
12.90 ppm) is observed for the two acidic protons (Fig-
ure 3). The existence of a CH tautomer of 4 (form C in
Figure 2) can be ruled out because of the lack of signals
representing a C(sp3)ϪH fragment in the 1H and 13C NMR
spectra. Because NOE difference experiments revealed a
strong NOE, and thus spatial closeness, between the methyl
protons and 2,6-H of the C-phenyl unit (Figure 4), the (E)-
configured structure (E of Figure 2) can also be excluded.
Moreover, only weak through-space interactions observed
between the acidic protons and 2,6-H of the N-phenyl
group make the dominance of an NH-tautomeric form B
less probable. Comparison of the NMR spectroscopic data
of 4 with those of methyl congeners 6, 8, and 10 provides
a strong hint for the existence of 4 predominantly in the
enaminopyrazolone form in [D6]DMSO solution. In par-
ticular, there is a close resemblance of the chemical shifts in
the 13C NMR spectra of 4 and 6, with no more than
1.4 ppm difference between the shifts of their corresponding
carbon atoms (Figure 3). On the other hand, there is mark-
edly more deviation in the comparison with the O-methyl
(8) or the N-methyl derivative (10), which are ‘‘normal’’ ox-
imes with a characteristic shift of the CϭNOH atom of ca.
Scheme 1. Synthesis of compounds 2Ϫ12
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Eur. J. Org. Chem. 2003, 1209Ϫ1219

4-Benzoyl-5-methyl-2-phenylpyrazol-3-one Oxime and Its Methyl Derivatives
FULL PAPER
1
Table 1. H NMR chemical shifts (δ/ppm) of 4Ϫ12
H of N-phenyl
H of C-phenyl
No.
Solvent
3(5)-Me
2,6-H
3,5-H
4-H
2,6-H
3,5-H
4-H
Other H
4
[D6]DMSO
CDCl3
[D6]DMSO
CDCl3
CDCl3
[D6]DMSO
CDCl3
[D6]DMSO
CDCl3
[D6]DMSO
CDCl3
[D6]DMSO
CDCl3
[D6]DMSO
CDCl3
[D6]DMSO
CDCl3
[D6]DMSO
[D6]DMSO
CDCl3
[D6]DMSO
CDCl3
1.61
1.61
1.91
1.69
1.60
1.22
1.35
1.27
1.41
1.89
2.06
1.85
2.02
1.91
2.06
2.13
2.00
2.25
2.11
2.11
2.33
2.36
7.89
7.92
7.74
7.82
7.85
7.91
7.94
8.01
8.03
7.67
7.72
7.65
7.72
7.62
7.67
7.36
7.42
7.31
7.35
7.42
7.61
7.66
7.44
7.43
7.45
7.45
7.47
7.43
7.41
7.35
7.37
7.47
7.43
7.47
7.43
7.47
7.42
7.50
7.21
7.24
7.24
7.30
7.27
7.20
7.20
7.06
7.10
7.30
7.28
7.32
7.28
7.33
7.28
7.32
7.57
7.53
7.56
7.54
7.37
7.58
7.39
7.55
7.53
7.60
7.67
7.60
7.68
7.49
7.60
7.59
7.61
7.36
7.59
7.65
7.52
7.53
7.39
7.44
7.45
7.57
7.53
7.55
7.48
7.40
7.40
7.43
7.40
7.42
7.40
7.35
7.53
7.62
7.39
7.43
7.45
7.62
7.54
7.62
7.57
7.40
7.40
7.43
7.39
7.43
7.42
7.38
12.90[a] (NH, OH)
4
12.17[a] (OH)
5
11.38[a] (NH, OH), 3.95 (OMe)
8.62[a] (NH, OH), 4.14 (OMe)
8.62[a] (NH, OH), 3.86 (OMe)
16.11 (OH), 3.44 (NMe)
16.03 (OH), 3.47 (NMe)
3.75 (NMe), 3.52 (OMe)
5a
5b
6
6
7
7
3.83 (NMe), 3.53 (OMe)
(Z)-8
(Z)-8
(Z)-9
(Z)-9
(E)-9
(E)-9
(Z)-10
(Z)-10
(E)-10
(Z)-11
(Z)-11
(E)-12
(E)-12
11.67 (ϭNOH), 3.71 (OMe)
8.78[a] (ϭNOH), 3.78 (OMe)
3.98 (ϭNOMe), 3.69 (5-OMe)
4.07 (ϭNOMe), 3.75 (5-OMe)
3.88 (ϭNOMe), 3.65 (5-OMe)
4.01 (ϭNOMe), 3.71 (5-OMe)
11.48 (ϭNOH), 3.19 (NMe)
9.54 (ϭNOH), 3.24 (NMe)
11.22 (ϭNOH), 3.15 (NMe)
3.93 (ϭNOMe), 3.21 (NMe)
4.02 (ϭNOMe), 3.18 (NMe)
10.99 (ϭNOH), 3.74 (5-OMe)
8.97 (ϭNOH), 3.76 (5-OMe)
7.49
7.35
7.35
7.35
[b]
[b]
[b]
[b]
7.50
7.42
7.48
7.44
7.34
7.28
7.33
7.30
7.38
7.33
7.39
7.33
2.11 (NϭC-Me)
2.27 (NϭC-Me)
[a]
[b]
Broad signal. Not unequivocally assigned because of overlap with signals of the predominant isomer (Z)-10.
Table 2. 13C NMR chemical shifts (δ/ppm) of 4Ϫ12
C of pyrazole system
C-Me C-4 C-O
C of N-phenyl
C-2,6 C-3,5 C-4 C-1
C of C-phenyl
C-2,6 C-3,5 C-4 Ph-CϭN Other C
No.
Solvent
3(5)-Me C-1
4
[D6]DMSO 147.5 96.0[a] 158.8[b] 14.5
CDCl3 148.1 96.3 160.8 15.2
[D6]DMSO 147.3[a] 96.1[a] 152.5[b] 13.5
138.5 119.5 128.8 124.9 132.1[a] 128.8 128.6 130.7 152.9[b]
138.4 120.6 128.8 125.7 130.4 129.4 129.4 132.3 155.3
138.0[a] 120.4[a] 128.8 125.3 135.3 127.0 128.3 129.2 149.0
138.0 121.8 128.9 126.5 134.9 128.8 128.5 129.8 153.2
138.0 120.8 128.9 126.1 131.8 127.8 128.4 129.3 156.8
138.4 119.2 128.8 124.9 132.0 129.4 129.1 131.3 154.2
138.6 120.3 128.7 125.3 132.7 129.3 129.3 131.3 154.6
139.7 117.6 128.4 123.0 131.9 130.6 128.3 131.6 161.6
4
5
61.7 (ϭNOMe)
62.6 (ϭNOMe)
62.5 (ϭNOMe)
45.4 (NMe)
45.4 (NMe)
62.4 (OMe),
5a
5b
6
CDCl3
CDCl3
147.7 97.2 151.8 14.7
147.1 96.5 153.8 14.3
[D6]DMSO 147.7 97.4 160.2 14.4
CDCl3 148.4 98.1 160.4 14.7
[D6]DMSO 147.9 98.0 161.0 15.2
6
7
43.5 (NMe)
62.9 (OMe),
44.3 (NMe)
7
CDCl3
148.6 99.2 161.7 15.4
139.5 119.0 128.5 123.7 131.8 131.1 128.3 131.8 161.6
(Z)-8 [D6]DMSO 146.7 95.6 151.7 13.4
(Z)-8 CDCl3 148.0 94.8 152.5 13.7
(Z)-9 [D6]DMSO 146.5 95.6 151.8 13.3
138.1 121.7 128.9 126.2 136.4 126.4 128.6 129.0 148.5
138.3 122.5 128.7 126.5 135.9 127.1 128.8 129.7 151.4
137.9 121.8 128.9 126.4 135.3 126.7 128.7 129.6 149.1
59.0 (5-OMe)
59.4 (5-OMe)
61.9 (ϭNOMe),
59.4 (5-OMe)
62.3 (ϭNOMe),
59.4 (5-OMe)
61.8 (ϭNOMe),
61.4 (5-OMe)
62.3 (ϭNOMe),
61.3 (5-OMe)
35.4 (NMe)
35.2 (NMe)
35.2 (NMe)
61.8 (ϭNOMe),
35.2 (NMe)
62.2 (ϭNOMe),
35.5 (NMe)
(Z)-9 CDCl3
(E)-9 [D6]DMSO 147.5 102.1 152.4 13.8
(E)-9 CDCl3 148.7 102.4 152.8 14.0
147.8 95.8 152.3 13.7
138.4 122.4 128.8 126.3 136.0 127.1 128.6 129.5 149.8
137.8 122.0 129.0 126.6 133.0 129.0 128.0 129.1 149.4
138.3 122.5 128.9 126.6 133.3 129.5 128.0 129.3 149.9
(Z)-10 [D6]DMSO 155.7 100.9 162.6 12.6
(Z)-10 CDCl3 153.6 102.8 163.1 13.0
(E)-10 [D6]DMSO 155.1 105.6 163.5 11.5
(Z)-11 [D6]DMSO 155.2 100.3 162.1 12.4
135.1 123.9 129.0 126.3 135.8 126.4 128.2 128.6 148.0
135.7 125.2 129.4 127.6 134.2 127.6 128.4 129.3 151.4
[c]
[c]
[c]
[c]
[c]
[c]
124.0
133.4
148.1
135.0 124.2 129.0 126.5 134.8 126.7 128.3 129.2 148.8
135.0 124.2 129.0 126.6 135.1 127.1 128.3 129.2 148.8
(Z)-11 CDCl3
154.9 103.1 162.8 12.8
(E)-12 [D6]DMSO 146.5 104.1 151.8 14.7
137.9 122.0 129.2 126.7 13.8 (NϭC-Me)
138.1 122.5 129.0 126.8 14.1 (NϭC-Me)
147.7
150.7
62.1 (5-OMe)
62.0 (5-OMe)
(E)-12 CDCl3
147.5 103.8 152.5 14.7
[a]
[b]
[c]
Broad signal. Very broad signal. Not unequivocally assigned.
Eur. J. Org. Chem. 2003, 1209Ϫ1219
1211

´
W. Holzer, K. Hahn, T. Brehmer, R. M. Claramunt, M. Perez-Torralba
FULL PAPER
Table 3. Selected 13C,1H spin coupling constants (Hz) of 4Ϫ12
No.
Solvent
1J(3-Me)
1J(5-Me)
2J(C3,3-Me)
2J(C5,5-Me)
3J(C4,3-Me)
Other couplings
3J(C4,5-Me)
[a]
[a]
[a]
[a]
4
[D6]DMSO
[D6]DMSO
CDCl3
CDCl3
[D6]DMSO
CDCl3
[D6]DMSO
CDCl3
[D6]DMSO
CDCl3
[D6]DMSO
CDCl3
[D6]DMSO
CDCl3
128.0
128.2
128.4
128.4
128.2
128.4
127.9
128.3
127.5
128.1
127.6
127.9
127.8
128.1
129.7
130.0
129.7
129.8
129.8
127.7
7.0
[a]
3
5
1JOMe ϭ 143.5, J(CϭN,C-Ph H2,6) ϭ 3.9
5a
6.8
6.7
6.8
6.8
7.0
6.9
6.7
6.7
6.7
6.7
6.8
6.8
6.5
1JOMe ϭ 145.2
5b
1JOMe ϭ 143.9
6
2.4
2.5
2.3
2.3
3.2
3.4
3.1
3.2
1JNMe ϭ 143.2
6
1JNMe ϭ 142.5
1
7
1JNMe ϭ 142.9, JNOMe ϭ 146.3
1
7
1JNMe ϭ 142.6, JNOMe ϭ 146.2
3
(Z)-8
(Z)-8
(Z)-9
(Z)-9
(E)-9
(E)-9
(Z)-10
(Z)-10
(E)-10
(Z)-11
(Z)-11
(Z)-12
1JOMe ϭ 147.0, J(C5,OMe) ϭ 4.3
3
1JOMe ϭ 146.7, J(C5,OMe) ϭ 4.3
1J(5-OMe) ϭ 147.1, J(C5,OMe) ϭ 4.4, JNOMe ϭ 143.9
3
1
1J(5-OCH3) ϭ 146.6, J(C5,OMe) ϭ 4.3, JNOMe ϭ 143.7
3
1
3
1
2.8
1J(5-OMe) ϭ 147.1, J(C5,OMe) ϭ 4.2, JNOMe ϭ 143.5
[a]
3
1
1J(5-OMe) ϭ 146.7, J(C5,OMe) ϭ 4.0, JNOMe ϭ 143.5
3
[D6]DMSO
CDCl3
[D6]DMSO
[D6]DMSO
CDCl3
3.7
1JNMe ϭ 141.0, J(C5,NMe) ϭ 3.2
3
6.4
3.6
1JNMe ϭ 141.0, J(C5,NMe) ϭ 3.2
[b]
[b]
1JNMe ϭ 141.0
3
1
6.5
6.5
6.9
3.8
1JNMe ϭ 141.2, J(C5,NMe) ϭ 3.2, JNOMe ϭ 143.6
3
1
3.8
1JNMe ϭ 140.6, J(C5,NMe) ϭ 3.1, JNOMe ϭ 143.6
[a]
3
1
[D6]DMSO
1J(5-OMe) ϭ 147.1, J(C5,OMe) ϭ 4.0, J(NϭCMe) ϭ 128.9,
2J(NϭC,NϭCMe) ϭ 6.5, J(NϭC,OH) ϭ 8.2
3
3
1
(Z)-12
CDCl3
128.1
6.8
2.9
1J(5-OMe) ϭ 146.6, J(C5,OMe) ϭ 3.8, J(NϭCMe) ϭ 129.4,
2J(NϭC,NϭCMe) ϭ 6.5, J(C4,NϭCMe) ϭ 2.9
3
[a]
[b]
Not resolved. Not unequivocally determined (overlap with other signals).
1
Figure 3. 13C NMR chemical shifts and H NMR chemical shifts
Figure 4. Conformational and configurational analysis of 4Ϫ9, and
12 by characteristic NOEs (arrows) and 13C (1H) chemical shifts
(δ/ppm, in [D6]DMSO)
(in italics) of 4 and its methyl congeners 6, 8, and 10 in
[D6]DMSO solution
1212
Eur. J. Org. Chem. 2003, 1209Ϫ1219

4-Benzoyl-5-methyl-2-phenylpyrazol-3-one Oxime and Its Methyl Derivatives
FULL PAPER
δ ϭ 148 ppm (Figure 3). It should be noted that an enamino- pyrazole CϪO units (5a: δ ϭ 151.8 ppm, 5b: 153.8 ppm)
pyrazolone structure for 4 (form DЈ in Figure 2, stabilised better match a 5-hydroxypyrazole structure. Additionally,
by an intramolecular hydrogen bond between the NH and other diagnostic carbon resonances (pyrazole C-4, C-1 of
pyrazolone CϭO units) and related compounds was already C-phenyl) rule out that 5a and 5b are simple E/Z isomers
suggested in 1988 by Hennig and Mann, but no spectral about an oxime (ether) CϭN bond. In NOE difference ex-
support for these assumptions was provided.[14]
periments, saturation transfer between corresponding sig-
1
The H NMR spectra of 6 exhibit an extremely deshi- nals of 5a and 5b was observed (CMe, OMe), indicating an
elded OH proton (δ ϭ 16.11 ppm in [D6]DMSO, δ ϭ equilibrium process and, thus, the interconversion 5a ↔ 5b.
16.03 ppm in CDCl3; Figure 3) that can be explained by it A possible interpretation of these observations is that there
being involved in a strong intramolecular hydrogen bond to is a significant contribution made by the enamino form
the pyrazolone CϭO unit. This configurational fixation is (similar to form D in Figure 2) in CDCl3 solution, with spe-
also confirmed by a strong NOE on the C-Ph 2,6-H signal cies 5a and 5b resulting from restricted rotation around
upon irradiation of the N-methyl resonance (whereas such the ϭC-N bond (Figure 4), a phenomenon that already has
an interaction between the NMe group and the N-Ph 2,6- been observed with related enaminopyrazolones.[28Ϫ30] An
H protons was not detected) and an NOE between the OH unambiguous confirmation for this suspicion, however, can-
1
and N-Ph 2,6-H protons (Figure 4). From similar NOE dif- not be given since H NMR spectra recorded at elevated
ference experiments with 7, the O-methyl derivative of 6, a temperatures (up to 60 °C) did not exhibit any marked
conformation with the OMe group close to the C-phenyl changes.
ring emerged (Figure 4). Otherwise, the data of 7 closely
resemble those of 6 (Table 1Ϫ3).
Crystal Structures of Compounds 4, 5, and 6
The reaction of 2 with O-methylhydroxylamine hydro-
chloride afforded a pair of isomeric oxime ethers 9
(Scheme 1), which were discriminated and configurationally
assigned by considering γ-effects: carbon atoms in the γ-
position (α to CϭN) to a syn-located oxime (ether) oxygen
atom experience an upfield shift compared to the γ-atoms
in an anti position as a result of steric compression.[24]
Thus, the C-1 signal of the C-phenyl group in (E)-9 shows
a smaller 13C NMR chemical shift (δ ϭ 133.0 ppm in
[D6]DMSO) than that in the corresponding (Z)-9 (δ ϭ
135.3 ppm in [D6]DMSO), whereas a reverse trend is ob-
served for the pyrazole C-4 signal [(E)-9: δ ϭ 102.1 ppm,
(Z)-9: δ ϭ 95.6 ppm; Figure 4]. (E)-10 and (Z)-10 can be
distinguished in a similar way. In cases when only one iso-
meric form was present, comparison with the data of 9 and
10 and, particularly, NOE difference experiments allowed
an unambiguous determination of the stereochemistry at
the CϭN double bond.[25Ϫ27] Thus, for instance, a strong
NOE on the methyl signal upon irradiation of the OH pro-
ton unequivocally assigns a (Z) configuration to oxime 8
(Figure 4), whereas a clear through-space connection be-
tween OH and the protons of the ‘‘acetyl’’ methyl group
confirms an (E) configuration for oxime 12. The 13C NMR
chemical shifts for the pyrazole C-4 unit in 8 (δ ϭ
95.6 ppm) and 12 (δ ϭ 104.1 ppm) are in full agreement
with the assigned configurations (Figure 4).
Technical details on the crystal structure determinations
of 4-benzoyl-5-methyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-
one oxime (4), the O-methyloxime 5 and the N-methylam-
ino product 6 are described in the Exp. Sect., and views of
their molecular geometries encountered in the crystalline
state are shown in Figure 6Ϫ8, respectively. Selected bond
lengths of the three compounds are presented in Table 4.
[32]
˚
Figure 5. Comparison of selected bond lengths (A) in 4 and 13;
model compound 14 (form D according to Figure 2) was used in
the density functional calculations (Table 6).
An interesting phenomenon was observed with product
In all derivatives an extended planar structural motif is
5. In [D6]DMSO solution a single compound was detected formed by the pyrazolone ring (C3ϪC4ϪN5ϪN6ϪC7), the
and although marked line broadening for several signals methyl group C9, the oxygen atom O8 and the C2 atom.
1
was observed, the H NMR and especially the 13C NMR The oxime groups (N1ϪO22ϪH22) show a deviation from
chemical shift data hint to the presence of a partial struc- these structural units and they are situated above the ring
ture of an oxime ether (similar to form A in Figure 2, Ph- plane. The phenyl substituents are attached at different sites
CϭN: δ ϭ 149.0 ppm) in a (Z) configuration (pyrazole C- of the planar subunit and their planes form dihedral angles
4: δ ϭ 96.1 ppm, NOE between C-Me and OMe protons). of around 50°.
In CDCl3 solution, however, two sets of signals were found
In compounds 4 and 6, an intramolecular ring including
(5a/5b ഠ 1.4:1), with the corresponding Ph-CϪN signals at O22ϪH22···O8ϪC4ϪC3ϪC2ϪN1 (form DЈЈ in Figure 2) is
δ ϭ 153.2 (5a) and δ ϭ 156.8 ppm (5b) fitting an enaminop- closed by the hydrogen bond O22ϪH22···O8 (Table 5). The
yrazolone structure. On the other hand, the shifts of the NH-pyrazolone motif in compound 5 in the solid state
Eur. J. Org. Chem. 2003, 1209Ϫ1219
1213

´
W. Holzer, K. Hahn, T. Brehmer, R. M. Claramunt, M. Perez-Torralba
FULL PAPER
Figure 6. Molecular structure of 4 with atomic numbering
Figure 7. Molecular structure of 5 with atomic numbering
(form B1) is stabilised by co-crystallisation with dichlorome- ture (form B in Figure 2),[31] whereas 13,[32] the NЈ-
thane. In the oxime structure 4, there is an intermolecular benzoylhydrazone of 1, exhibited an enaminopyrazolone
˚
hydrogen bond (2.872 A) between the N1 (oxime) and the structure similar to that of 4 (Figure 5).
N6 (imino) atoms. In the crystalline structure of 6 two mo-
lecules, denoted A and B, were found in the asymmetric
DFT Calculations
unit.
To rationalise the experimental results on the tautomeric
Only a few X-ray crystal structures of related compounds forms of 4-acylpyrazolone oximes shown in Figure 2, we
are known. For instance, the thiosemicarbazone of 1, crys- performed density functional theory calculations at the
tallised from methanol, showed an NH-pyrazolone struc- B3LYP level using the Gaussian basis set 6Ϫ31G** on a
1214
Eur. J. Org. Chem. 2003, 1209Ϫ1219

4-Benzoyl-5-methyl-2-phenylpyrazol-3-one Oxime and Its Methyl Derivatives
FULL PAPER
Figure 8. Molecular structure of 6 with atomic numbering
Table 4. Comparison of selected bond lengths in the crystal struc-
tures 4, 5 and 6
simplified model 14 (Figure 5), in which the methyl and the
phenyl substituents (Figure 2) have been replaced by hydro-
gen atoms. Tautomers related to A, B, B1, C, DЈ, DЈЈ and E
have been fully optimised (no imaginary frequencies) and
their intrinsic properties are gathered in Table 6.
Bond lengths
4
5
6
mol A
mol B
C3ϪC2
C3ϪC4
C3ϪC7
C4ϪN5
N5ϪN6
N6ϪC7
C2ϪC10
C4ϪO8
C7ϪC9
N1ϪC2
N1ϪO22
N1ϪC23
1.421(2)
1.428(2)
1.428(2)
1.373(2)
1.398(2)
1.317(2)
1.476/2)
1.271(2)
1.496(2)
1.309(2)
1.373(2)
Ϫ
1.474(2)
1.420(2)
1.383(2)
1.393(2)
1.379(2)
1.332(2)
1.480(2)
1.260(2)
1.490(2)
1.290(2)
1.401(2)
Ϫ
1.424(2)
1.416(2)
1.439(2)
1.366(2)
1.396(2)
1.312(2)
1.487(2)
1.285(2)
1.491(2)
1.314(2)
1.374(2)
1.464(2)
1.425(2)
1.412(2)
1.438(2)
1.363(2)
1.398(2)
1.316(2)
1.482(2)
1.288(2)
1.488(2)
1.314(2)
1.373(2)
1.468(2)
As encountered for compounds 4 and 6 in the solid state,
the tautomeric form DЈЈ with an intramolecular O···HϪO
hydrogen bond in a seven membered ring is the most stable
one. The DЈ form with an intramolecular O···HϪN hydro-
gen bond in a six membered ring is higher in energy by
about 4 kcal·molϪ1. Calculations also predict form A to be
stable, but condensed phases (solution and solid state) fa-
vour tautomers with large values of dipole moment. The
existence of compound 5 in the solid state in the form B1 is
probably a consequence of packing forces.
Table 5. Donor (D) and acceptor (A) geometry of hydrogen bonds (N1-H1…N6 and O22-H22…O8) in the crystal structure of 4, 5 and 6
Compound
Type
DϪH…A
DϪH
H···A
D···A
DϪH···A
4
Inter
Intra
Inter
Inter
Inter
Inter
Intra
Intra
Intra
Intra
Intra
Intra
N(1)ϪH(1)···N(6)[a]
0.92(2)
1.075(9)
1.01(2)
0.99(2)
0.89(2)
0.98(2)
0.92(2)
0.97(3)
1.180(2)
1.204(3)
0.93(2)
0.94(2)
1.96(2)
1.39(2)
2.57(2)
2.54(2)
1.80(2)
2.44(2)
2.32(2)
2.48(2)
1.261(2)
1.227(2)
2.41(2)
2.39(2)
2.872(2)
2.455(2)
3.428(2)
3.486(2)
2.656(2)
3.315(2)
2.924(2)
3.033(2)
2.435(4)
2.423(5)
2.968(2)
2.964(2)
173.9(16)
168.8(15)
142.0(15)
160.3(18)
160.2(19)
148.3(15)
122.7(14)
115.5(19)
172.05(3)
170.44(3)
118.2(12)
119.1(12)
O(22)ϪH(22)···O(8)[b]
C(14)ϪH(14)···O(8)[c]
C(19)ϪH(19)···O(22)[d]
N(6)ϪH(1)···O(8)[e]
5
6
C(17)ϪH(17)···O(8)[e]
C(21)ϪH(21)···O(8)[b]
C(9)ϪH(9C)···O(22)[b]
O(22A)ϪH(22A)···O(8A)[b]
O(22B)ϪH(22B)···O(8B)[b]
C(21A)ϪH(21A)···O(8A)[b]
C(17B)ϪH(17B)···O(8B)[b]
A
B
A
B
[a]
[b]
[c]
[d]
Symmetry transformations used to generate equivalent atoms: Ϫ1/2 ϩ x, Ϫ1/2 Ϫ y, Ϫ1/2 ϩ 2. x, y, z. Ϫ1/2 ϩ x, Ϫ1/2 ϩ y, z.
[e]
1 ϩ x, 1 Ϫ y, 1/2 ϩ z. Ϫ1/2 ϩ x, y, 1/2 Ϫ z.
Eur. J. Org. Chem. 2003, 1209Ϫ1219
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W. Holzer, K. Hahn, T. Brehmer, R. M. Claramunt, M. Perez-Torralba
FULL PAPER
Table 6. Calculated (B3LYP/6-31G**) absolute energies (in hartrees) and relative stabilities (in kcal·molϪ1) of model compound 14
(Figure 5); dipole moments in D
Tautomer simlar to
Absolute value
Relative stability
Relative stability (with ZPE correction)
Dipole moment
A
470.065619
470.047702
470.055310
470.048571
470.059325
470.065769
470.048726
0.09
11.34
6.56
10.79
4.04
0
0
1.89
4.79
5.19
2.18
3.43
4.11
4.68
B
11.50
6.22
11.52
4.05
0.28
10.98
B1
C
DЈ
DЈЈ
E
10.70
bined etheral extracts were washed with water, dried (Na2SO4) and
the solvents evaporated in vacuo. The residue (2.572 g, containing
ca. 10% of N-methyl product 3 according to TLC) was recrys-
tallised from ethanol to afford yellowish crystals (1.903 g, 43%) of
Conclusions
On the basis of data obtained from detailed NMR spec-
troscopic investigations and X-ray crystal structural ana-
lysis, "oxime" 4 derived from 4-benzoyl-5-methyl-2-phenyl-
1,2-dihydro-3H-pyrazol-3-one (1) is present in an enamino-
pyrazolone form (isomer DЈЈ in Figure 2) in solution as well
as in the solid state. The latter is characterised by a high
degree of delocalisation and is stabilised by a strong intram-
olecular hydrogen bond. These findings are also supported
by ab initio calculations performed on a simplified model
compound. The structure of 4 also explains its particular
reaction behaviour when treated with trichloroacetyl isocy-
anate/potassium carbonate (Figure 2): the lack of the hy-
droxypyrazole form A prevents cyclisation to a 6H-pyra-
zolo[4,3-d]isoxazole (F). Instead, the isocyanate reagent
likely attacks the OH group of the hydroxyamino moiety of
the more stable form D. After proton abstraction, a Lossen-
type reaction occurs with formation of a nitrene that
cyclises to the spiro-aziridines G.[10]
1
m.p. 80Ϫ81 °C (ref.[12] m.p. 79Ϫ80 °C); H and 13C NMR spectra
identical with those of an authentic sample.[12]
General Procedure for the Preparation of Oximes 4, 8, 10, 12 and
Oxime Ethers 5, 9, 11: A mixture of 4-acylpyrazole (1, 2, or 3)
(10 mmol), H2NOR·HCl (R ϭ H, Me) (40 mmol), pyridine (3 mL),
and ethanol (20 mL) was heated under reflux for 4 h. After cooling,
the mixture was poured onto water (150 mL), resulting in the
formation of either a precipitate (a) or an emulsion (b). Workup
(a): After standing for 2 h in the refrigerator, the mixture was fil-
tered with suction, the residue was washed with water (several
times) and purified as described below, if necessary. Workup (b):
The mixture was exhaustively extracted with CH2Cl2, the combined
organic phases were washed with water (several times), dried
(Na2SO4), and the solvents evaporated in vacuo. The residue was
purified as described below, if necessary.
(Z)-2,4-Dihydro-4-[(hydroxyamino)(phenyl)methylene]-5-methyl-2-
phenyl-3H-pyrazol-3-one (4): Recrystallisation from ethanol (addi-
tion of charcoal) yielded cream-coloured crystals (2.229 g, 76%),
m.p. 162Ϫ170 °C (decomp) (ref.[14] m.p. 168Ϫ172 °C; ref.[15] m.p.
166 °C; ref.[16] m.p. 167Ϫ169 °C). IR (KBr): ν˜ ϭ 2722 (very broad,
OH), 1602 (CϭO) cmϪ1. MS: m/z (%) ϭ 293 (7) [Mϩ], 275 (15),
231 (28), 91 (56), 77 (100), 67 (22), 51 (59).
Experimental Section
General: Melting points were detected on a Kofler hot-stage micro-
scope and are uncorrected. Mass spectra were obtained on a Shim-
adzu QP 1000 spectrometer (EI, 70 eV). IR spectra were obtained
on a PerkinϪElmer FTIR 1605 spectrophotometer. All NMR spec-
(Z)-4-[(Methoxyamino)(phenyl)methylene]-5-methyl-2-phenyl-2,4-
dihydro-3H-pyrazol-3-one (5): Yield: 2.213 g (72%); colourless crys-
tals, pure according to TLC and NMR spectroscopy. For analytical
purposes a sample (100 mg) was recrystallised from ethanol to af-
ford 5 (76 mg), m.p. 168Ϫ170 °C (decomp). IR (KBr): ν˜ ϭ 1619
(CϭO) cmϪ1. MS: m/z (%) ϭ 307 (53) [Mϩ], 275 (61), 274 (37),
142 (28), 105 (23), 104 (26), 91 (100), 77 (81), 51 (28). C18H17N3O2
(307.35): calcd. C 70.34, H 5.58, N 13.67; found C 70.12, H 5.63,
N 13.54.
tra were recorded on
a Varian Unityplus 300 spectrometer
(299.95 MHz for 1H, 75.43 MHz for 13C) at 28 °C. The solvent
signals were used as internal standards which were related to TMS
with δ ϭ 7.26 ppm (1H, CDCl3), δ ϭ 2.49 ppm (1H, [D6]DMSO),
δ ϭ 77.0 ppm (13C, CDCl3), and δ ϭ 39.5 ppm (13C, [D6]DMSO).
The digital resolutions were 0.25 Hz/data point for the 1H NMR
spectra, 0.56 Hz/data point for the broad band decoupled 13C
NMR spectra and 0.33 Hz/data point for the gated decoupled 13C
NMR spectra. The elemental analyses were performed by the Mi-
kroanalytisches Laboratorium, Institute of Physical Chemistry,
University of Vienna. Light petroleum refers to the fraction of b.p.
50Ϫ70 °C. Pyrazolone 1 is commercially available, the N-methyl-
pyrazolone 3 was prepared according to the literature.[13]
(Z)-(5-Methoxy-3-methyl-1-phenyl-1H-pyrazol-4-yl)(phenyl)-
methanone Oxime (8): Yield: 2.643 g (86%); colourless crystals,
pure according to TLC and NMR spectroscopy. An analytical
sample recrystallised from ethanol had m.p. 198Ϫ202 °C. IR
(KBr): ν˜ ϭ 3143, 2844 (OH) cmϪ1. MS: m/z (%) ϭ 307 (30) [Mϩ],
275 (13), 248 (37), 188 (20), 105 (91), 91 (37), 77 (100), 51 (46).
C18H17N3O2 (307.35): calcd. C 70.34, H 5.58, N 13.67; found C
70.09, H 5.56, N 13.50.
(5-Methoxy-3-methyl-1-phenyl-1H-pyrazol-4-yl)(phenyl)methanone
(2): Methyl 4-toluenesulfonate (2.944 g, 15.8 mmol) was added to
a
mixture of 1 (4.190 g, 15.1 mmol) and K2CO3 (4.170 g, (Z)/(E)-(5-Methoxy-3-methyl-1-phenyl-1H-pyrazol-4-yl)(phenyl)-
30.2 mmol) in dry DMF (40 mL), and then the mixture was stirred
at 50 °C for 24 h. The reaction mixture was poured onto water
(400 mL) and extracted with diethyl ether (4 ϫ 100 mL). The com-
methanone O-Methyloxime [(Z)-9 and (E)-9]: The oily residue
(1.864 g, 58%; consisting of (Z)-9 and (E)-9 in a ratio of 3:4] was
subjected to medium-pressure liquid chromatography (silica gel;
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Eur. J. Org. Chem. 2003, 1209Ϫ1219

4-Benzoyl-5-methyl-2-phenylpyrazol-3-one Oxime and Its Methyl Derivatives
FULL PAPER
light petroleum/ethyl acetate, 95:5) to afford (Z)-9 (225 mg, 7%; (E)-1-(5-Methoxy-3-methyl-1-phenyl-1H-pyrazol-4-yl)ethanone Ox-
faster eluting component), a Z/E mixture (578 mg, 18%) and (E)-9 ime (12): Compound 12 was prepared from 1-(5-methoxy-3-methyl-
(418 mg, 13%), all as yellowish oils.
1-phenyl-1H-pyrazol-4-yl)ethanone[11,12] by treatment with hy-
droxylamine hydrochloride according to the general procedure
given above. Recrystallisation from diisopropyl ether afforded col-
ourless crystals (1.545 g, 63%), m.p. 142 °C. MS: m/z (%) ϭ 245
(39) [Mϩ], 228 (14), 118 (15), 105 (14), 91 (28), 77 (100), 69 (15),
67 (31), 51 (59), 43 (30). C13H15N3O2 (245.28): calcd. C 63.66, H
6.16, N 17.13; found C 63.48, H 6.27, N 17.00.
(Z)-9: MS: m/z (%) ϭ 321 (37) [Mϩ], 290 (78), 275 (33), 105 (62),
91 (37), 77 (100), 67 (23), 51 (37). C19H19N3O2 (321.38): calcd. C
71.01, H 5.96, N 13.07; found C 71.00, H 5.97, N 12.88.
(E)-9: MS: m/z (%) ϭ 321 (29) [Mϩ], 290 (62), 275 (31), 105 (56),
91 (36), 77 (100), 67 (27), 57 (23), 51 (34). C19H19N3O2 (321.38):
calcd. C 71.01, H 5.96, N 13.07; found C 71.20, H 5.87, N 12.82.
(Z)-2,4-Dihydro-4-[(N-hydroxy-N-methylamino)(phenyl)methylene]-
5-methyl-2-phenyl-3H-pyrazol-3-one (6): Methyl 4-toluenesulfonate
(2.00 g, 10.7 mmol) was added to a mixture of 4 (3.00 g, 10.2 mmol)
and K2CO3 (2.83 g, 20.5 mmol) in dry DMF (15 mL), and then the
mixture was stirred at room temperature for 2.5 h. Water (250 mL)
was added and then the mixture was continuously extracted with
diethyl ether (2 ϫ 350 mL). The combined ethereal extracts were
concentrated to a volume of 20 mL and then left in the refrigerator
for several hours. The precipitated crystals were filtered off and
washed with cold diethyl ether. Yield: 2.263 g (72%); yellow crys-
tals, m.p. 130 °C (recrystallisation from ethanol did not alter the
m.p.). MS: m/z (%) ϭ 307 (100) [Mϩ], 292 (25), 291 (65), 290 (74),
261 (40), 187 (22), 158 (68), 129 (18), 118 (41), 91 (83), 80 (22), 77
(94), 56 (33), 51 (43). C18H17N3O2 (307.35): calcd. C 70.34, H 5.58,
N 13.67; found C 70.64, H 5.47, N 13.70.
(Z)/(E)-1,2-Dihydro-4-[(hydroximino)(phenyl)methyl]-1,5-dimethyl-
2-phenyl-3H-pyrazol-3-one [(Z)-10 and (E)-10]: Yield: 2.490 g
(81%); colourless crystals, pure according to TLC and NMR (ratio
Z/E of 10:1). An analytical sample recrystallised from ethanol had
m.p. 184Ϫ187 °C. IR (KBr): ν˜ ϭ 3425, 3238 (OH), 1646 (CϭO)
cmϪ1. MS: m/z (%) ϭ 308 (17), 307 (100) [Mϩ], 306 (46), 290 (13),
288 (14), 105 (44), 77 (50), 56 (86), 51 (21). C18H17N3O2 (307.35):
calcd. C 70.34, H 5.58, N 13.67; found C 70.11, H 5.51, N 13.41.
(Z)-1,2-Dihydro-4-[(methoxyimino)(phenyl)methyl]-1,5-dimethyl-2-
phenyl-3H-pyrazol-3-one [(Z)-11]: Yield: 2.571 g (80%); colourless
crystals, pure according to TLC and NMR spectroscopy. An ana-
lytical sample recrystallised from ethanol had m.p. 150 °C. IR
(KBr): ν˜ ϭ 1663 (CϭO) cmϪ1. MS: m/z (%) ϭ 321 (7) [Mϩ], 291
(26), 290 (100), 105 (54), 77 (14), 56 (27). C19H19N3O2 (321.38): (Z)-2,4-Dihydro-4-[(N-methoxy-N-methylamino)phenylmethylene]-
calcd. C 71.01, H 5.96, N 13.07; found C 71.05, H 5.85, N 12.93. 5-methyl-2-phenyl-3H-pyrazol-3-one (7): Methyl 4-toluenesulfonate
Table 7. Crystal data and some selected experimental details from the crystal structures of compounds 4, 5 and 6
4
5
6
Crystallised from
Empirical formula
Molecular mass (g/mol)
Crystal system
toluene
C17H15N3O2
293.32
monoclinic
Cc
5.889(1)
17.718(4)
13.990(3)
90
96.66(3)
90
1452.6(5)
4
1.341
0.091
616
dichloromethane
C18H17N3O2·CH2Cl2
392.27
orthorhombic
Pbca
11.7581(3)
16.0078(4)
19.9912(5)
90
90
90
3762.7(2)
8
1.385
ethanol
C18H17N3O2
307.35
triclinic
¯
Space group
P1
˚
a (A)
9.123(2)
9.933(2)
17.845(4)
91.40(3)
102.79(3)
97.51(3)
1516.1(6)
4
˚
b (A)
˚
c (A)
α (°)
β (°)
γ (°)
3
˚
V (A )
Z
Dc (Mg·mϪ3
)
1.308
0.087
648
Absorb. µ (mmϪ1
F(000)
)
0.364
1632
Crystal size (mm)
Crystal habit
Crystal colour
Temperature (K)
Radiation used (λ, A)
Index ranges
0.31 ϫ 0.25 ϫ 0.20
cube
colourless
200(2)
Mo-Kα, 0.71073
h (Ϫ8.8)
k (Ϫ25.24)
l (Ϫ19.19)
4223
0.40 ϫ 0.35 ϫ 0.35
cube
transparent
200(2)
Mo-Kα, 0.71073
h (Ϫ13.13)
k (Ϫ18.18)
l (Ϫ23.23)
3311
0.25 ϫ 0.15 ϫ 0.15
cube
transparent yellow
200(2)
Mo-Kα, 0.71073
h (Ϫ10.10)
k (Ϫ11.11)
l (Ϫ21.21)
5481
˚
Unique reflections
Reflections [I Ͼ 2σ(I)]
Refinement method
Data/restraints/parameter
Goodness-of-fit on F2
R1 [I Ͼ 2σ(I)]
3563
2736
4305
Full-matrix/F2
4223/2/260
1.033
Full-matrix/F2
3311/0/311
1.036
Full-matrix/F2
5481/0/552
1.046
0.0405
0.0357
0.0399
R1 (all data)
wR2 (all data)
∆ρfin (max./min.) (e·A
0.0542
0.0839
0.19/Ϫ0.16
0.0459
0.0970
0.23/Ϫ0.38
0.0578
0.0975
0.16/Ϫ0.17
Ϫ3
˚
)
Eur. J. Org. Chem. 2003, 1209Ϫ1219
1217

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W. Holzer, K. Hahn, T. Brehmer, R. M. Claramunt, M. Perez-Torralba
FULL PAPER
[2] [2a]
J. Elguero, in Comprehensive Heterocyclic Chemistry: Pyr-
azoles and their Benzo Derivatives, vol. 5 (Eds.: A. R. Katritzky,
C. W. Rees), Pergamon Press, Oxford, 1984, pp. 167Ϫ303.
J. Elguero, in Comprehensive Heterocyclic Chemistry II: Pyra-
zoles, vol. 3 (Eds.: A. R. Katritzky, C. W. Rees, E. F. V. Scriven),
Pergamon Press, Oxford, 1996, pp. 1Ϫ75.
(132 mg, 0.71 mmol) was added to 6 (200 mg, 0.65 mmol) and
K2CO3 (187 mg, 1.35 mmol) in dry DMF (1 mL) and the resulting
mixture was stirred at room temperature for 2.5 h. The mixture was
poured onto water (15 mL) and extracted with CH2Cl2 (4 ϫ 6 mL).
The combined organic extracts were washed with water, dried
(Na2SO4) and then the solvents were evaporated in vacuo. The re-
maining orange oil (131 mg, 63%) slowly solidified on standing.
For analytical purposes, a sample was recrystallised from diisopro-
pyl ether to afford orange crystals of m.p. 147Ϫ149 °C. IR (KBr):
ν˜ ϭ 1642 (CϭO) cmϪ1. MS: m/z (%) ϭ 322 (13), 321 (52) [Mϩ],
291 (21), 290 (72), 278 (20), 261 (25), 187 (47), 118 (100), 105 (18),
91 (43), 77 (78), 51 (28). C19H19N3O2 (321.38): calcd. C 71.01, H
5.96, N 13.07; found C 71.09, H 5.82, N 12.95.
[2b]
[3]
M. J. O’Connell, C. G. Ramsay, P. J. Steel, Aust. J. Chem. 1985,
38, 401Ϫ409, and references cited therein.
[4]
L. N. Kurkovskaya, N. N. Shapet’ko, A. S. Vitvitskaya, I. Y.
Kvitko, J. Org. Chem. USSR (Engl. Transl.) 1977, 13,
1618Ϫ1625 (Original paper: Zh. Org. Khim. 1977, 13,
1750Ϫ1757).
[5]
W. Holzer, K. Mereiter, B. Plagens, Heterocycles 1999, 50,
799Ϫ818.
[6]
A. B. Uzoukwu, S. S. Al-Juaid, P. B. Hitchcock, J. D. Smith,
Polyhedron 1993, 12, 2719Ϫ2724.
Y. Akama, M. Shiro, T. Ueda, M. Kajitani, Acta Crystallogr.,
X-ray Structure Determination
[7]
Sect. C 1995, 51, 1310Ϫ1314, and references cited therein.
J. A. M. Guard, P. J. Steel, Aust. J. Chem. 1994, 47, 1453Ϫ1459.
Y. Akama, A. Tong, Microchem. J. 1996, 53, 34Ϫ41.
Presented at the 8th Blue Danube Symposium on Heterocyclic
Chemistry, Bled, September 2000, poster No. PO 30; W.
Holzer, T. Brehmer, D. Guggi, M. Perez-Torralba, R. M. Clara-
Preparation of Crystallography Sample: Crystals suitable for X-ray
investigation were prepared by slow evaporation of solutions of the
respective compounds. Crystals were grown from toluene in the
case of 4, and from ethanol in the case of 6. Crystallisation of 5
from dichloromethane gave the clathrate [5·CH2Cl2 (1:1)].
[8]
[9]
[10]
munt, manuscript in preparation.
A. S. Sarenko, I. Y. Kvitko, L. S. Efros, Chem. Heterocyclic
Comp. (Engl. Transl.) 1972, 722Ϫ727 (Original paper: Khim.
Geterotsikl. Soedin. 1972, 799Ϫ804).
Data Collection, Structural Analysis and Refinement: Crystallo-
graphic data of the oxime structures 4, 5 and 6 are summarised in
Table 7. Intensity data for all structures where obtained on a Non-
ius Kappa instrument with CCD detector at 200 K with a crystal-
to-detector distance of 35 mm. All three structures were solved by
direct methods, using the program SIR92[34] and refined with
SHELXL-97.[35] The geometrical analyses were calculated with
programs implemented in PLATON,[36] structure drawings were
prepared using Diamond 2.1a.[37] WINGX v.1.63.01[38] was used
for the coordination of the programs.
[11]
´
[12]
[13]
W. Holzer, B. Plagens, Sci. Pharm. 1996, 64, 455Ϫ462.
A. Michaelis, F. Engelhardt, Ber. Dtsch. Chem. Ges. 1908, 41,
2668Ϫ2676.
L. Hennig, G. Mann, Z. Chem. 1988, 28, 364Ϫ365.
A. K. Rana, J. R. Shah, Indian J. Chem. 1981, 20A, 142Ϫ144.
L. Avar, K. Hofer (Sandoz), Ger. Offen. DE 2529052, 1976,
Chem. Abstr. 1976, 85, 6648.
S. L. Patt, J. N. Shoolery, J. Magn. Reson. 1982, 46, 535Ϫ539.
D. Neuhaus, M. P. Williamson, The Nuclear Overhauser Effect
in Structural and Conformational Analysis, VCH Publishers,
New York, 1989.
D. G. Davis, A. Bax, J. Am. Chem. Soc. 1985, 107, 7197Ϫ7198.
A. Bax, S. Subramanian, J. Magn. Reson. 1986, 67, 565Ϫ569.
S. K. Sarkar, A. Bax, J. Magn. Reson. 1985, 62, 109Ϫ112.
A. Bax, J. Magn. Reson. 1984, 57, 314Ϫ318.
Owing to the low solubility of 4 in CDCl3 the recording of a
1H-coupled 13C NMR spectrum was not possible, but a satis-
factory broad-band decoupled spectrum emerged after per-
forming 16000 scans.
[14]
[15]
[16]
[17]
[18]
In structure 4 the residual peaks of electron density are situated
meanly around the ring atoms. The systematic absences permit the
space group to be either Cc or C2/c; Cc was chosen and confirmed
by analysis (MISSYM-algorithm, Le Page, implemented in PLA-
TON[36]). In addition, the structure could not be solved in space
group C2/c.
[19]
[20]
[21]
[22]
[23]
To avoid decomposition of the clathrate [5·CH2Cl2 (1:1)], a single
crystal of reasonable quality and appropriate size was cooled down,
and the orthorhombic space group was uniquely determined by the
systematic absences.
[24]
[25]
G. E. Hawkes, K. Herwig, J. D. Roberts, J. Org. Chem. 1974,
39, 1017Ϫ1028.
CCDC-186899 (4), 186900 (5) and CCDC-186901 (6) contain the
supplementary crystallographic data for this paper. These data
can be obtained free of charge at www.ccdc.cam.ac.uk/conts/
retrieving.html [or from the Cambridge Crystallographic Data
Centre, 12, Union Road, Cambridge CB2 1EZ, UK; Fax: (in-
ternat.) ϩ44-1223/336-033; E-mail: deposit@ccdc.cam.ac.uk].
G. Heinisch, W. Holzer, Tetrahedron Lett. 1990, 31,
3109Ϫ3112.
G. Heinisch, W. Holzer, Monatsh. Chem. 1990, 121, 837Ϫ846.
G. Heinisch, W. Holzer, Collect. Czech. Chem. Communn. 1991,
56, 2251Ϫ2257.
W. Freyer, J. Prakt. Chem. 1977, 319, 911Ϫ918.
H.-H. Otto, H. Schmelz, Monatsh. Chem. 1980, 111, 53Ϫ61.
U. Kölle, B. Kolb, A. Mannschreck, Chem. Ber. 1980, 113,
2545Ϫ2565.
X.-C. Tang, D.-Z. Jia, K. Liang, X.-G. Zhang, X. Xia, Z.-Y.
Zhou, J. Phtochem. Photobiol. A 2000, 134, 23Ϫ29.
H. Kraudelt, U. Schilde, H. Hefele, E. Ludwig, E. Uhlemann,
Z. Naturforsch., Teil B 1996, 51b, 1240Ϫ1244.
TITAN v1.0.5, Wavefunction Inc., Irvine, CA 92612, USA,
1999.
SIR92 Ϫ A program for crystal structure solution: A. Altom-
are, G. Cascarano, C. Giacovazzo, A. Guagliardi, J. Appl. Crys-
tallogr. 1993, 26, 343Ϫ350.
SHELX97 Ϫ Programs for Crystal Structure Analysis (Release
97Ϫ2), G. M. Sheldrick, Institut für Anorganische Chemie der
Universität Göttingen, Tammanstrasse 4, 3400 Göttingen,
Germany, 1998.
[26]
[27]
[28]
[29]
[30]
Acknowledgments
[31]
[32]
[33]
[34]
Marta Perez Torralba thanks the Ministry of Science and Techno-
logy of Spain for a grant (BQU2000Ϫ0252). Moreover, we are
grateful to Dr. L. Jirovetz for recording the mass spectra and to
Dr. Palwinder Singh for the synthesis of compound 12.
[1]
[35]
J. Elguero, C. Marzin, A. R. Katritzky, P. Linda, in Advances
in Heterocyclic Chemistry: The Tautomerism of Heterocycles,
Suppl. 1, Academic Press, New York, 1976, pp. 313Ϫ336, and
references cited therein.
1218
Eur. J. Org. Chem. 2003, 1209Ϫ1219

4-Benzoyl-5-methyl-2-phenylpyrazol-3-one Oxime and Its Methyl Derivatives
FULL PAPER
[36] [36a]
[36b]
A. L. Spek, Acta Crystallogr., Sect. A 1990, 46, C34.
Solution, Refinement and Analysis of Single Crystal X-ray Dif-
fraction Data: L. J. Farrugia, J. Appl. Crystallogr. 1999, 32,
837Ϫ838.
A. L. Spek, PLATON Ϫ A Multipurpose Crystallographic
Tool, Utrecht University, Utrecht, The Netherlands, 1998.
DIAMOND 2.1a Ϫ Visual crystal structure information sys-
tems, K. Brandenburg, 1999.
[37]
[38]
Received October 12, 2002
[O02564]
WINGX v1.63. 01 Ϫ System of Windows Programs for the
Eur. J. Org. Chem. 2003, 1209Ϫ1219
1219