The reaction between hydrazines and β-dicarbonyl compounds: Proposal for a mechanism

Article abstract of DOI:10.1139/v00-104

The reaction between aryl or heteroarylhydrazines with fluorinated β-diketones (CF₃COCH₂COR) yields a variety of 3-, 5-, and 3,5-trifluoromethylpyrazoles and 5-trifluoromethyl-5-hydroxy-Δ²-pyrazolines. Twenty-one of such compounds have been isolated and identified by ¹³C and ¹⁹F NMR. Together with the results from the literature they provide a comprehensive overview of the reaction. Semi-empirical calculations at the PM3 level have been used to rationalize these results. The outcome that emerges seems to be that the dehydration of a pair of 3,5-dihydroxypyrazolidines kinetically controls the isomer formed.

Full text of DOI:10.1139/v00-104

1109
The reaction between hydrazines and β-dicarbonyl
compounds: proposal for a mechanism
Shiv P. Singh, Dalip Kumar, Hitesh Batra, Rajesh Naithani, Isabel Rozas, and
José Elguero
Abstract: The reaction between aryl or heteroarylhydrazines with fluorinated β-diketones (CF3COCH2COR) yields a
variety of 3-, 5-, and 3,5-trifluoromethylpyrazoles and 5-trifluoromethyl-5-hydroxy-∆2-pyrazolines. Twenty-one of such
compounds have been isolated and identified by 13C and 19F NMR. Together with the results from the literature they
provide a comprehensive overview of the reaction. Semi-empirical calculations at the PM3 level have been used to
rationalize these results. The outcome that emerges seems to be that the dehydration of a pair of 3,5-
dihydroxypyrazolidines kinetically controls the isomer formed.
Key words: hydrazines, 1,3-diketones, pyrazolines, pyrazoles, PM3 calculations.
Résumé : La réaction entre des aryl ou hétéroarylhydrazines et des β-dicétones fluorées (CF3COCH2COR) donne lieu a
une série des 3-, 5- et 3,5-trifluorométhylpyrazoles et 5-trifluorométhyl-5-hydroxy-∆2-pyrazolines. Vingt-et-un de ces
composés ont été isolés et caractérisés par RMN du 13C et 19F. Avec l’addition des résultats de la littérature, ils
donnent une image cohérente de la réaction. Des calculs semi-empiriques PM3 ont été utilisés pour expliquer ces
résultats. L’image qui apparaît est celle d’une réaction cinétiquement contrôlée qui correspond à la déshydratation
d’une paire de 3,5-dihydroxy-pyrazolidines en équilibre.
Mots clés : hydrazines, 1,3-dicétones, pyrazolines, pyrazoles, calculs PM3. Singh et al. 1120
Introduction
The reaction between a monosubstituted hydrazine (1) and a nonsymmetrical β-diketone (2) always leads to the formation
of a mixture of pyrazole isomers (3 and 4) even when one of them is present in a very small amount and the process can be
considered regioselective.
This apparently simple reaction, which constitutes the main synthetic approach to pyrazoles (1–5), conceals a complex
mechanistic problem. We have summarized in Scheme 1 the different routes that can lead to the two actually isolated com-
pounds making clear where the difficulty of the problem lies. Considering that hydrazine can react initially by the NH (D) or
the NH2 (E) and that a β-diketone has three tautomeric forms (A, B, and C) with two reactive centers, each isomer can be
formed by six different routes.
In some cases, it has been possible to isolate the 5-hydroxy-∆2-pyrazoline intermediates (7) (Scheme 2), but this does not
help to solve the mechanistic riddle: which are the route or routes operative in Scheme 1? From low-temperature NMR exper-
iments and from qualitative results, the mechanism represented in Scheme 2 is generally accepted for the synthesis of pyra-
zoles. The key intermediate is the 3,5-dihydroxypyrazolidine 5 and the formation of both N—C bonds (N2—C3 and N1—C5)
of the carbinolamine groups are considered reversible, i.e., when R2 and R3 are different, both dihydroxypyrazolidines 5′
and 5′′ should be in equilibrium.
Received May 23, 2000. Published on the NRC Research Press website on August 4, 2000.
S.P. Singh, D. Kumar, H. Batra, and R. Naithani. Department of Chemistry, Kurukshetra University, Kurukshetra-136 119, India.
I. Rozas and J. Elguero.1 Instituto de Química Médica, CSIC, Juan de la Cierva 3, E-28006 Madrid, Spain.
1Author to whom correspondence may be addressed. Fax: (34) 91 564 48 53. e-mail: iqmbe17@iqm.csic.es
Can. J. Chem. 78: 1109–1120 (2000)
© 2000 NRC Canada

1110
Can. J. Chem. Vol. 78, 2000
Scheme 1.
Scheme 2.
© 2000 NRC Canada

Singh et al.
1111
Table 1. Summary of the most relevant results related to the mechanism of the reaction between hydrazines and β-dicarbonyl compounds.
Isolation of 5-hydroxy-
pyrazoline 7
Dehydration to pyrazole
3-CF3 4 and (or) 5-CF3 3
Ratio 4:3
or 4:7
R1
R2
R3
Ref.
a
Saccharina
C6H5
C6H5
p-Fluorophenyl
p-Chlorophenyl
p-Nitrophenyl
2-Benzothiazole
2-Quinolyl
Saccharina
CSNH2
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CCl3
CCl3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
Yes
Yes (3,5-diCH3)
Yes (5-CF3).
No (fails, SO4H2)
(5-CF3 + 3-CF3)
Yes (5-CF3)
(5-CF3) 3e
Yes (5-CF3)
Yes (5-CF3)
Yes (with loss of R1)
Yes (with loss of R1)
(3-CF3) 4j
(3-CF3) 4k
(3-CF3) 4l
Yes (5-CF3) 3m
Yes (5-CF3)
Not attempted
(3-CF3) 4p
(3-CF3) 4q
(3-CF3) 4r
—
5:1
—
4:1
4:1
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
(6)
(7)
(8)
This work
(7)
This work
(9)
(10)
This work
(11)
This work
This work
This work
This work
(10)
This work
This work
This work
This work
This work
This work
This work
This work
(12)
b
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
r
s
t
u
v
x
Yesb
Yes
No
Yesa
Yes 7e
Yes
Yes
Yes 7h
Yes
No
No
No
Yes 7m
Yes
Yes 7o
No
No
CH3
Cyclec
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
2-Thienyl
2-Thienyl
2-Thienyl
2-Thienyl
2-Thienyl
2-Pyridyl
2-Pyridyl
CH3
C6H5
p-Fluorophenyl
p-Nitrophenyl
2,4-Dinitrophenyl
2-Quinolyl
Saccharina
C6H5
p-Fluorophenyl
p-Nitrophenyl
2,4-Dinitrophenyl
Saccharine
p-Fluorophenyl
Saccharina
CONH2
CSNH2
C6F5
p-Fluorophenyl
p-Nitrophenyl
2,4-Dinitrophenyl
C6H5CO
No
Yes 7s
Yes 7t
No
Yes 7v
Yes
Yes
Yes
No
Yes
Yes
Yes
Yes
Yes 7ff
Yes (5-CF3) 3s
Yes (with loss of R1)
(3-CF3) 4u
Yes (with loss of R1)
y
z
CH3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
(12)
Yes
(13,14)
This work
(13,14)
(13)
(13)
(13)
aa
bb
cc
dd
ee
ff
(3,5-diCF3) 9aa
Yes (3,5-diCF3)
Yes
Not reported
Yes (3,5-diCF3)
Yes (with loss of R1)
2-Quinolyl
Saccharina
This work
aSaccharin stands for 1-(1′,2′-benzisothiazol-3′-yl)-1′,1′-dioxide substituent.
bFrom the pyrrolidino adduct on the COCF3.
cCycle stands for a medium size carbocycle (tri, tetra, and pentamethylene pyrazoles).
dinary ketones (R2 = CH3 or C6H5) have been widely
studied.
We will discuss, in the present paper, the effect of R1 on
the 3:4 ratio in the case of trifluoromethyl β-diketones and,
particularly, when R2 = CH3 and R3 = CF3. When R1 = H,
3 ϵ 4 due to the prototropic tautomerism of pyrazoles.
Results and discussion
We have gathered in Table 1 the most relevant experimen-
tal results for the present work, that is, the isolation of dif-
ferent 5-hydroxypyrazolines (7), the dehydration to the
corresponding pyrazoles (9) (3, R2 = CH3, Ar or Het, R3 =
CF3; 4, R2 = CF3, R3 = CH3, Ar or Het) and the orientation
of the reaction (3:4 ratio).
The dehydration steps (5 → 6 → 7 and 7 → 8 → 9 in
Scheme 2) are irreversible, therefore, the kinetic controlling
step is the first dehydration (5 → 7). All previous publica-
tions dealt with the influence of R2 and R3, i.e., the structure
of the β-dicarbonyl compound, on the relative ratio of the fi-
nal pyrazoles 3 and 4, for a given hydrazine. For instance,
the consequences over the 3:4 ratio of the fact that aldehydes
(R3 = H) are more reactive than ketones (R2 ≠ H), or that
trifluoromethylketones (R3 = CF3) are more reactive than or-
In the present work, we report complementary experi-
ments (marked “this work” in Table 1). This leads us to de-
scribe a series of new ∆2-pyrazolines and pyrazoles, which
1
have been fully characterized by H NMR and mass spec-
trometry (see experimental part). Particularly important for
this purpose have been 13C (Table 2) and 19F NMR (Table 3)
© 2000 NRC Canada

Table 2. 13C chemical shifts (ppm) and 13C – 19F coupling constants (Hz) of p-fluorophenylpyrazoles 3c, 4c, 9bb, 4l, 4r, 4v.
Comp
R3
R5
C3
C4
C5
C1′
C2′(6′)
C3′(5′)
C4′
R3
R5
C1 ′′
—
C2 ′′
—
C3 ′′
—
C4 ′′
—
C5 ′′
—
C6 ′′
—
3c
CH3
CF3
143.32
108.56
149.07
J = 38
140.80
134.93
127.23
J = 10
127.22
J = 9
116.30
J = 21
116.20
J = 22
116.41
J = 23
116.36
J = 24
116.23
J = 22
116.09
J = 23
163.83
J = 251
162.38
J = 250
163.35
J = 251
162.44
J = 250
162.73
J = 250
162.34
J = 250
13.19
121.05
J = 269
12.11
4c
CF3
CF3
CF3
CF3
CF3
CH3
142.75
J = 39
142.74
J = 43
143.55
J = 39
143.19
J = 39
143.96
J = 43
104.49
107.15
105.85
105.00
106.69
134.91
134.20
135.65
134.91
135.78
121.31
J = 268
119.60
J = 269
121.52
J = 270
121.59
J = 268
121.14
J = 270
—
—
—
—
—
—
9aa
4k
4q
4u
CF3
134.81
J = 42
145.08
127.89
J = 10
127.59
J = 9
118.71
J = 270
—
—
—
—
—
—
—
Phenyl
2-Thienyl
2-Pyridyl
129.21
129.43
129.36
148.05
129.06
127.64
123.60
129.06
128.17
136.70
129.06
127.57
122.93
129.43
—
138.92
150.00
128.27
J = 9
S
127.47
J = 9
N
150.00

Singh et al.
1113
Scheme 3.
Table 3. 19F chemical shifts (ppm) of some pyrazoles and
5-hydroxypyrazolines.
Yranzo (20) who first isolated a 3,5-dihydroxypyrazolidine
(5, R1 = H, R2 = R2 = CF3). Russian authors (21, 22) have
reported further studies and the reaction has been reviewed
(23–25). We have proposed that the dehydration 7 → 9 in-
volves the intermediate 8 to explain why when R1 is an elec-
tron-withdrawing group, the dehydration does not occur or
occurs with difficulty (3, 20). Besides, 4-hydroxy-∆2-
pyrazolines are much more stable than the 5-hydroxy ones
and more difficult to aromatize (26).
The results gathered in Table 1 are fully consistent with
the role of CF3 or, more generally, perfluoroalkyl substitu-
ents at position 5 and with electron-withdrawing substituents
at position 1 to stabilize the 5-hydroxypyrazolines 7. The
role of a 5-trifluoromethyl group is apparent in experiments
b, d, and z; that of R1 in experiment a (for brevity’s sake, we
will use saccharin instead of 1-(1′,2′-benzisothiazol-3′-yl)-
1′,1′-dioxide) and that of both in many cases (e–i, m–o, s, t,
v, bb–ff). Note that the CCl3 group behaves similarly to the
CF3 group (experiments x and y).
Comp
CF3 position
CF3
p-Fluorophenyl
3c
4c
4k
4l
4q
4u
7e
7h
7s
5
3
3
3
3
3
5
5
5
3
5
3
5
–58.2
–62.8
–62.8
–62.9
–62.8
–62.7
–71.2
–79.3
–72.1
–71.2
–78.2
–63.0
–58.7
–112.2
–112.6
–112.8
—
–111.4
–110.1
—
—
—
—
—
7ff
9aa
–110.0
—
data since they are characteristic of the different structures
(5, 7–10, 12–14).
The mechanism of the reaction of β-dicarbonyl com-
pounds and hydrazines has been studied in several occa-
sions, particularly by Selivanov and Ershov and co-workers
(15–19), who first used stop-flow NMR techniques to char-
The most difficult point is to rationalize the orientation or
4:3 ratio. To advance in this direction, we have carried out a
series of semi-empirical calculations, using the PM3
Hamiltonian. We have selected two cases (Scheme 3): the
reaction of 1,1,1-trifluoropentane-2,4-dione with phenylhy-
drazine and 2′,4′-dinitrophenylhydrazine (DNPh). The first
yields a mixture of 1-phenyl-3-trifluoro-methyl-5-methyl-
acterize the 3,5-dihydroxypyrazolidines
5 and the 5-
hydroxypyrazolines 7 as intermediates and by Elguero and
© 2000 NRC Canada

1114
Can. J. Chem. Vol. 78, 2000
Table 4. PM3 calculations of 1-phenyl-3,5-dihydroxypyrazolidines.
∆Hf
Dipole (µ)
q-N1
q-N2
q-O6
q-O8
5′ ddu
5′ uuu
5′ udu
5′ duu
5′ dud
5′ ddd
5′ udd
5′ uud
5′′ ddd
5′′ uuu
5′′ duu
5′′ ddu
5′′ udu
5′′ udd
5′′ uud
5′′ dud
–207.7
–207.4
–207.2
–206.2
–204.6
–204.6
–201.5
–201.4
–205.2
–204.6
–203.6
–199.6
–197.8
–204.9
–203.7
–204.0
4.25
3.93
3.31
3.44
3.43
3.76
5.21
4.09
1.45
3.17
4.50
1.88
1.11
2.10
2.47
2.31
–0.0702
–0.0629
–0.0726
–0.0632
–0.0325
–0.0477
0.0078
–0.0803
–0.0751
–0.0503
–0.0708
–0.0692
–0.0352
–0.0365
–0.0657
–0.0999
–0.0422
–0.0759
–0.0862
–0.0804
–0.0995
–0.0937
–0.0949
–0.2957
–0.2881
–0.2938
–0.2882
–0.2875
–0.3048
–0.3096
–0.2947
–0.3011
–0.3338
–0.3121
–0.3007
–0.3170
–0.3098
–0.3072
–0.2986
–0.3169
–0.3132
–0.3061
–0.3022
–0.3142
–0.3138
–0.2716
–0.2801
–0.2748
–0.2864
–0.2729
–0.2566
–0.2534
–0.2722
–0.2819
–0.2795
0.0005
–0.0324
–0.0399
–0.0461
0.0231
0.0129
–0.0399
–0.0483
–0.0539
Note: u = up, d = down.
pyrazole 10 and 1-phenyl-3-methyl-5-trifluoromethyl-5-
hydroxypyrazoline 11 in a ratio 5:1 (see Table 1, example b)
(7) (p-fluorophenylhydrazine, example c behaves similarly).
The pyrazoline can be dehydrated with HCl–CH2Cl2 into
pyrazole 12 (7) although other authors failed using H2SO4
(8). From DNPh only 1-(2′,4′-dinitrophenyl)-3-methyl-5-
trifluoro-methylpyrazole 14 should be formed considering
the 3m or 3s examples of Table 1.
The first hypothesis we tested was a thermodynamical
control related to the equilibrium 5′–5′′ between the 3,5-
dihydroxypyrazolidines (Scheme 3). The problem is rather
complicated because these compounds present three
stereogenic centers N1, C3, and C5 (the inversion at the ni-
trogen atoms has very low barriers and only that bearing the
phenyl ring was considered). The equilibrium between 5′
and 5′′ through the β-diketone implies the epimerization of
C3 and C5. In addition, in the case of the dinitrophenyl de-
rivatives, two conformations of this substituent, depending
on which side the o-nitro group lies, have to be considered.
Therefore, 16 and 32 conformations were calculated in the
cases of Ar = C6H5 and Ar = 2′,4′-(NO2)2-C6H4, respec-
tively. The results are given in Tables 4 and 5, which contain
heats of formation (in kcal mol–1), dipole moments µ (in D),
and charges (q) of N1, N2, O6, and O8 atoms.
The sixteen values of PM3 heats of formation can be ex-
pressed using an additive model with contributions of the
different structural features of the compounds. In the 5′ se-
ries, a phenyl down is 0 and up is 1 while in the 5 series
there is, respectively, 0 and –1. The OH substituents at the 5
position (that close to the phenyl group) is 0 when down and
1 or –1 when up for 5′ and 5′′. When the Ph and CF3 sub-
stituents are on the same side of the molecule, cis, or on op-
posite sides, trans, 1 or 0. The resulting eq. [1] for 16
compounds has an R2 = 0.935
[1]
∆Hf = –(205.2 ± 0.3) + (3.6 ± 0.3) Ph
– (1.6 ± 0.3) 5OH + (2.5 ± 0.4) CF3/Ph
That is, the intercept is close to the average heat of forma-
tion for the sixteen compounds. The N-phenyl substituent
prefers to be down in the 5′ series and up in the 5′′ ones,
otherwise it destabilizes the compound by 3.6 kcal mol–1.
The contrary happens with the 5-hydroxy substituent, but the
effect is lower. Finally, the presence of CF3 and Ph groups
on the same side, cis, destabilizes the molecule by an
amount of 2.5 kcal mol–1.
Since 5′udd is more stable that 5′′ddd, then, if the reac-
tion is thermodynamically controlled, the resulting N-
phenylpyrazole should have been 10, which is consistent
with the experiment.
In the case of the phenyl derivative, the most stable struc-
ture is 5′ (Ar close to the CH3) with the conformation repre-
sented in Fig. 1 (i.e., Ph up, 3-OH down and 5-OH down
(5′udd), –207.7 kcal mol–1). The most stable amongst 5′′
structures is 5 ddd, but it lies 2.5 kcal mol–1 higher.
A similar analysis of the thirty-two dinitrophenyl deriva-
tives (DNP), show that, here, the additive model is much less
satisfactory (eq. [2], n = 32, R2 = 0.56), but the effects are
© 2000 NRC Canada

Singh et al.
1115
Table 5. PM3 calculations of 1-(2′,4′-dinitrophenyl)-3,5-dihydroxypyrazolidines.
∆Hf
Dipole µ
q-N1
q-N2
q-O6
q-O8
5′ddda
5′udda
5′ddua
5′udua
5′duda
5′uuda
5′duua
5′uuua
5′dddb
5′uddb
5′ddub
5′udub
5′dudb
5′uudb
5′duub
5′uuub
5′′ ddda
5′′ udda
5′′ ddua
5′′ udua
5′′ duda
5′′ uuda
5′′ duua
5′′ uuua
5′′ dddb
5′′ uddb
5′′ ddub
5′′ udub
5′′ dudb
5′′ uudb
5′′ duub
5′′ uuub
–211.4
–220.4
–211.6
–218.5
–208.1
–215.7
–204.1
–217.2
–216.0
–215.6
–213.8
–215.7
–214.5
–219.3
–213.8
–216.9
–215.1
–214.6
–212.3
–209.6
–215.1
–204.2
–212.5
–205.3
–213.7
–208.0
–212.4
–213.9
–217.5
–206.1
–212.7
–213.2
6.49
4.28
5.55
4.04
4.39
8.82
5.38
4.20
5.35
7.17
3.47
5.03
6.29
5.99
4.16
6.67
6.72
6.43
3.71
1.72
7.32
4.99
5.90
3.93
4.56
6.40
5.79
5.19
3.78
6.48
5.79
7.30
–0.0700
–0.1068
–0.0587
–0.1001
–0.0871
–0.0716
–0.0574
–0.1115
–0.0826
–0.0917
–0.0858
–0.0610
–0.0837
–0.1119
–0.0929
–0.0774
–0.0664
–0.0590
–0.0984
–0.1038
–0.0731
–0.0212
–0.0926
–0.0829
–0.0735
–0.0165
–0.0629
–0.0715
–0.0931
–0.0263
–0.0612
–0.0772
–0.0571
–0.0793
–0.0939
–0.0668
–0.0187
–0.0640
–0.0447
–0.0733
–0.0247
–0.0925
–0.0519
–0.0939
–0.0134
–0.0470
–0.0431
–0.0929
–0.1000
–0.0983
–0.0908
–0.0481
–0.0978
–0.0627
–0.0910
–0.0339
–0.0840
–0.0701
–0.1090
–0.0768
–0.1197
–0.0613
–0.0789
–0.0345
–0.2730
–0.2900
–0.2857
–0.2868
–0.3002
–0.2962
–0.2887
–0.2792
–0.3089
–0.2945
–0.2798
–0.2790
–0.3173
–0.2916
–0.2815
–0.2825
–0.2919
–0.2953
–0.2894
–0.3054
–0.3011
–0.3260
–0.3007
–0.2978
–0.3157
–0.2902
–0.2913
–0.3045
–0.3041
–0.3108
–0.3174
–0.3381
–0.3404
–0.3149
–0.3448
–0.2996
–0.2862
–0.2918
–0.2920
–0.3088
–0.3128
–0.3066
–0.3120
–0.2887
–0.2893
–0.3045
–0.2993
–0.2930
–0.2935
–0.3030
–0.2723
–0.2832
–0.2878
–0.2752
–0.2755
–0.2798
–0.3050
–0.2513
–0.2771
–0.2793
–0.2934
–0.2470
–0.2771
–0.2819
Note: u = up, d = down, a = NO2 towards N2.
the same including a term defining the position of the nitro
group (a towards N2, b towards the OH).
and 5 dudb (–217.5 kcal mol–1). Here again, the most stable
situation (2.9 kcal mol–1) corresponds to the 5′ series. Con-
sequently, isomer 13 should be formed which is contrary to
experiment (formation of 14, see Scheme 3).
Therefore, this first approach failed. Although the dipole
moments are different (Tables 4 and 5), they cannot be used
to explain why 14 is preferred over 12. Since it does not
seem to be a thermodynamical control we decided to explore
the hypothesis of a kinetic control: the orientation of the
pyrazole formation depends on the rate of dehydration of the
dihydroxypyrazolidines 5 and 5 . When Ar = Ph, dehydration
[2]
∆Hf = – (212.6 ± 0.8) + (4.3 ± 0.9) DNP
– (1.3 ± 0.9) 5OH + (1.7 ± 1.4) CF3/DNP
– (1.7±1.1) NO2
The effects are similar to those in eq. [1]: the structures are
more stable when the nitro group is b in dihydroxy-
pyrazolidines 5 and a in the other isomer 5 . The two most
stable compounds (see Fig. 1) are 5 udda (–220.4 kcal mol–1)
© 2000 NRC Canada

1116
Can. J. Chem. Vol. 78, 2000
Fig. 1. Optimized PM3 structures of the isomers of minimum energy of derivatives 5′ and 5′′ (5′udd, 5′′ ddd, 5′udda, and 5′′ dudb).
is faster in 5′ than in 5′′; the contrary should happen when
Ar = DNP.
In the second case, the dehydration should involve the N2
lone pair and the OH group at position 3. Although less sta-
ble, 5′′dudb has more negative charge on N2 (+0.0404) and
on O6 (+0.0141) than 5′udda (Table 6). Consequently either
neutral or assisted by protonation on O6, the easier loss of
water should be that from 5′′dudb, the less stable
dihydroxypyrazolidine, yielding 14 in agreement with exper-
imental results (see Scheme 3).
For Ar = Ph, the results are the same, i.e., the less stable
dihydroxypyrazolidine 5′′ddd, would yield 11, which is the
minor isomer, instead of 10. Note, however, that the differ-
ences of q-N2 and q-O6 although positive are smaller
© 2000 NRC Canada

Singh et al.
1117
Table 6. PM3 calculations of 3,5-dihydroxypyrazolidines.
Experimental
result
∆Hf
Comp
q-N1
q-N2
q-O6
q-O8
5′udd
5′′ ddd
Difference
5′udda
5′′ dudb
Difference
–207.7
–205.2
–2.5
–220.4
–217.5
–2.9
–0.0702
–0.0324
–0.0378
–0.1068
–0.0931
–0.0137
–0.0803
–0.0999
+0.0196
–0.0793
–0.1197
+0.0404
–0.2957
–0.3011
+0.0054
–0.2900
–0.3041
+0.0141
–0.3169
–0.2748
–0.0421
–0.3149
–0.2934
–0.0215
10
11
ratio 10:11 = 5:1
13
14
ratio 13:14 = 0
Fig. 2. Optimized PM3 structures corresponding to the protonation on O6 of 5′udd and 5′′ ddd to yield 6′udd·H2O and 6′′ ddd·H2O.
(+0.0196 and +0.0054) than in the preceding case, pointing
out that the preference of 11 over 10 should be smaller than
Conclusions
that of 13 over 14, which is what is found experimentally. It
is possible that in this case, the experimental rate of forma-
tion of 10 and 11 would include the equilibrium constants
between 5′udd and 5′′ddd.
We tried to calculate the energies of the four dihydroxy-
pyrazolidines protonated on O6 but the resulting cations are
not stable and during the process of optimization, they
isomerize to cations 6 (see Scheme 2) solvated by a water
molecule, something like 5H+ → 6·H2O. We have repre-
sented two of such complexes, those formed from 5′udd and
5 ddd in Fig. 2.
Literature results plus those reported in this work prove
that the orientation in the reaction of hydrazines with
β-diketones depends on the substituent in the hydrazine. Al-
though the differences in orientation between alkyl and
arylhydrazines have been assigned to differences in reactiv-
ity of both nitrogen atoms (R1NH, D, in alkyl- and NH2, E,
in aryl-hydrazines, see Scheme 1), this is certainly not the
case of the reactions reported in Table 1, because all of them
should start reacting by the NH2. We propose that the orien-
tation is the result of the difference in the rates of dehydra-
tion of the two 3,5-dihydroxy-pyrazolidines in equilibrium.
© 2000 NRC Canada

1118
Can. J. Chem. Vol. 78, 2000
1-p-Fluorophenyl-3-trifluoromethyl-5-(2′-pyridyl) pyrazole
(4u)
Experimental
Mp 72–74°C, yield 73%. 1H NMR (CDCl3) δ: 7.01 (s, 1H,
C4-H), 7.08 (m, 2H, C3′- and C5′-H, J = 8.1 and 8.8 Hz),
7.22–7.35 (m, 4H, C3′′ -, C5′′ -, C2′- and C6′-H), 7.64 (unre-
solved dd, 1H, C4 ′′ -H, J = 1.8 and 7.8 Hz), 8.58 (dd, 1H,
C6′′ -H, J = 3.9 and 7.8 Hz). Anal. calcd. for C15H9F4N3: C
58.64, H 2.95, N 13.68; found C 58.39, H 3.00, N 13.54.
Melting points were determined in open capillaries and
1
are uncorrected. The H NMR spectra were obtained at 270,
300, and 400 MHz, 13C NMR spectra at 67.5 and 100 MHz,
and 19F NMR spectra at 75 and 376 MHz using Jeol-GX270,
Jeol-EX400, Bruker-300, and Bruker-400 instruments. The
internal standard for H and 13C was TMS and for 19F NMR
1
it was CFCl3 (δ = 0.00). The coupling constants reported for
the 13C NMR data correspond to couplings with 19F. Mass
spectra were recorded on a Kratos-MS-50 instrument and
microanalyses were performed on a Perkin–Elmer 2400 in-
strument.
Synthesis of 1-phenyl-3-trifluoromethylpyrazoles
1,5-Diphenyl-3-trifluoromethylpyrazole (4j)
An ethanolic solution (30 mL) of phenylhydrazine
(0.64 g, 6 mmol) and sodium acetate (0.5 g, 6 mmol) was
refluxed for 15 min. An equimolar amount of benzoyltri-
fluoroacetone (0.9 g, 6 mmol) was subsequently added and
the solution was refluxed for 3 h. On cooling, a solid ap-
peared which was recrystallized from ethanol, mp 80°C (lit.
Synthesis of 1-( p-fluorophenyl)-3(5)-trifluoromethylpyrazoles
1-p-Fluorophenyl-3-methyl-5-trifluoromethylpyrazole (3c)
and 1-p-fluorophenyl-3-trifluoro-methyl-5-methylpyrazole (4c)
An ethanolic solution (30 mL) of p-fluorophenylhydrazine
(1 g, 6 mmol) and sodium acetate (0.5 g, 6 mmol) was
refluxed for 15 min. 1,1,1-Trifluoropentane-2,4-dione (0.9 g,
6 mmol) was subsequently added and the solution was
refluxed for 2 h. The solvent was evaporated and the residue
obtained was extracted with chloroform. The organic phase
was dried over anhydrous sodium sulfate and the chloroform
was distilled off. The TLC and 1H NMR of the gummy mass
showed formation of both isomers in a 4:1 (4c:3c) ratio.
Column chromatographic separation using silica gel (60–120
mesh) and light petroleum (60–80°) as eluent afforded 4c.
1
(27) mp 95°C), yield 50%. H NMR (CDCl3) δ: 6.80 (s, 1H,
C4-H), 6.85 (d, 2H, C3′′ - and C5′′ -H), 6.36 (dd, 1H, C4′′ -H),
7.31 (dd, 2H, C2′′ - and C6′′ -H), 7.42–7.47 (m, 5H, Ar-H).
M+ 288. Anal. calcd. for C16H11F3N2: C 66.66, H 3.85, N
9.72; found C 66.47, H 3.81; N 9.70.
1-Phenyl-3-trifluoromethyl-5-thienylpyrazole (4p)
This compound was prepared similarly from thienoyl-
1
trifluoroacetone, mp 92°C, yield 51%. H NMR (CDCl3) δ:
6.75 (s, 1H, C4-H), 7.20–7.37 (m, 8H, Ar-H). M+ 294. Anal.
calcd. for C14H9F3N2S: C 57.14, H 3.08, N 9.52; found C
57.33, H 3.17, N 9.36.
1
4c: Oil, yield 0.8 g (53%). H NMR (CDCl3) δ: 2.32 (s,
3H, C5-CH3), 6.45 (s, 1H, C4-H), 7.17 (unresolved dd, 2H,
C3′- and C5′-H, J = 8.1 and 8.8 Hz), 7.42 (m, 2H, C2′- and
C6′-H). Anal. calcd. for C11H8F4N2: C 54.11, H 3.30, N
11.47; found C 53.92, H 3.28, N 11.21.
Further elution of the column with light petroleum af-
forded the other isomer 3c.
Synthesis of 1-p-nitrophenyl-3-trifluoromethylpyrazoles
1-p-Nitrophenyl-3-trifluoromethyl-5-phenylpyrazole (4l)
An ethanolic solution (30 mL) of p-nitrophenylhydrazine
(0.95 g, 6 mmol) and sodium acetate (0.5 g, 6 mmol) was
refluxed for 15 min. An equimolar amount of
benzoyltrifluoroacetone was subsequently added and the so-
lution was refluxed for 4 h. After solvent evaporation, the
residue obtained was crystallized from ethanol, mp 91°C,
1
3c: Oil, yield 0.2 g (13%). H NMR (CDCl3) δ: 2.35 (s, 3H,
C3-CH3), 6.59 (s, 1H, C4-H), 7.25 (unresolved dd, 2H, C3′-
and C5′-H, J = 8.2 and 8.7 Hz), 7.42 (m, 2H, C2′- and C6′-H).
Anal. calcd. for C11H8F4N2: C 54.11, H 3.30, N 11.47; found
C 54.05, H 3.13, N 11.34.
Three other pyrazoles 4k, 4q, 4u were prepared and puri-
fied similarly.
1
yield 62%. H NMR (CDCl3) δ: 6.79 (s, 1H, C4-H), 7.23–
7.52 (m, 5H, Ar-H), 7.50 (d, 2H, C2′- and C6′-H), 8.22 (d,
2H, C3′- and C5′-H). M+ 333. Anal. calcd. for C16H10F3N3O2:
C 57.66, H 3.02, N 12.61; found C 57.81, H 2.88; N 12.71.
1-p-Nitrophenyl-3-trifluoromethyl-5-(2-thienyl)pyrazole (4r)
1-p-Fluorophenyl-3-trifluoromethyl-5-phenylpyrazole (4k)
Mp 102–103°C, yield 72%. H NMR (CDCl3) δ: 6.74 (s,
This compound was prepared similarly from thienoyl-
1
1
trifluoroacetone, mp 97°C, yield 60%. H NMR (CDCl3) δ:
1H, C4-H), 7.18–7.22 (m, 2H, C2 ′′ - and C6 ′′ -H), 7.30 (m,
5H, Ar-H, C3 ′′ - C4 ′′ - C5 ′′ -, C2 ′-, and C6′-H), 7.03 (unre-
solved dd, 2H, C3 ′- and C5′-H, J = 8.1 and 8.8 Hz). Anal.
calcd. for C16H10F4N2: C 62.75, H 3.27, N 9.15; found C
62.67, H 3.41, N 8.84.
6.84 (s, 1H, C4-H), 6.93 (dd, 1H, C3′′ -H), 7.04 (dd, 1H, C4′′ -H),
7.44 (dd, 1H, C5′′ -H), 7.69 (dd, 1H, C2′- and C6′-H), 8.28
(dd, 1H, C3′- and C5′-H). M+ 339. Anal. calcd. for C14H8F3N3O2S:
C 49.56, H 2.38, N 12.38; found C 49.51, H 2.18, N 12.67.
1-p-Nitrophenyl-3-methyl-5-trifluoromethyl-5-
1-p-Fluorophenyl-3-trifluoromethyl-5-(2′-thienyl)pyrazole (4q)
Mp 81–82°C, yield 74%. H NMR (CDCl3) δ: 6.70 (s,
hydroxypyrazoline (7e)
1
An ethanolic solution (30 mL) of p-nitrophenylhydrazine
(0.95 g, 6 mmol) and sodium acetate (0.5 g, 6 mmol) was
refluxed for 15 min. An equimolar amount of 1,1,1-
trifluoropentane-2,4-dione (0.9 g, 6 mmol) was subsequently
added and the solution was refluxed for 2 h. After solvent
evaporation, the residue obtained was crystallized from etha-
nol, mp 102°C, yield 54%. 1H NMR (CDCl3) δ : 2.09 (s, 3H,
1H, C4-H), 6.78 (dd, 1H, C3 ′′ -H, J = 1.0 and 3.7 Hz), 6.88
(dd, 1H, C4 ′′ -H, J = 3.7 and 5.0 Hz), 7.03 (unresolved dd,
2H, C3′- and C5′-H, J = 8.1 and 8.8 Hz), 7.23 (dd, 1H, C5′′ -H,
J = 1.0 and 5.0 Hz), 7.28 (m, 2H, C2′- and C6′-H). Anal.
calcd. for C14H8F4N2S: C 53.85, H 2.58, N 8.97; found C
54.02, H 2.46, N 8.63.
© 2000 NRC Canada

Singh et al.
1119
CH3), 3.21 and 3.46 (AB system, 2H, CH2, J = 18 Hz), 7.42
(d, 2H, C2 ′- and C6 ′-H), 8.04 (d, 2H, C3 ′- and C5 ′-H). M+
289. Anal. calcd. for C11H10F3N3O3: C 45.68, H 3.48, N
14.53; found C 45.81, H 3.60, N 14.68.
7.26–7.42 (m, 5H, Ar-H), 7.75–7.82 (m, 3H, C5′-, C6′-, and
C7′-H), 8.53 (s, 1H, C4′-H). M+ 395. Anal. calcd. for
C17H12F3N3O3S: C 51.65, H 3.06, N 10.63; found C 51.42,
H 321, N 10.65.
1-p-Nitrophenyl-3-methyl-5-trifluoromethylpyrazole (3e)
An ethanolic solution of (7e) and 2 mL of conc. HCl was
refluxed for 10 h. The solvent was evaporated and the resi-
1-(2′,4′-Dinitrophenyl)-3-(2-thienyl)-5-trifluoromethyl-5-
hydroxypyrazoline (7s)
This compound was prepared using the procedure de-
1
due crystallized from ethanol, mp 80–81°C, yield 56%. H
1
scribed for 7m, mp 152°C, yield 58%. H NMR (CDCl3) δ:
NMR (CDCl3) δ: 2.36 (CH3), 6.54 (s, 1H, C4-H), 7.72 (d,
2H, C2 ′- and C6 ′-H), 8.33 (d, 2H, C3 ′- and C5 ′-H). M+ 271.
Anal. calcd. for C11H8F3N3O2: C 48.72, H 2.97, N 15.49;
found C 49.01, H 3.11, N 15.39.
4.42 (m, 2H, CH2), 7.28 (m, 1H, C3′′ -H), 7.92 (d, 1H, C4′′ -H),
8.02 (d, 1H, C5′′ -H), 8.04 (d, 1H, C6′-H), 8.44 (dd, 1H, C5′-H),
9.07 (d, 1H, C3′-H). Anal. calcd. for C14H9F3N4O5S: C
41.80, H 2.25, N 13.93; found C 42.03, H 2.41, N 13.71.
1-(1′,2′-Benzisothiazol-3′-yl)-3-methyl-5-trifluoromethyl-5-
hydroxypyrazoline 1′,1′-dioxide (7h)
1-(2′,4′-Dinitrophenyl)-3-(2-thienyl)-5-trifluoromethylpyra-
zole (3s)
An ethanolic solution (50 mL) of 3-hydrazino-2-
benzisothiazole-1′,1′-dioxide (1.2 g, 6 mmol) and sodium ac-
etate (0.5 g, 6 mmol) was refluxed for 15 min. An equimolar
amount of 1,1,1-trifluoropentane-2,4-dione (0.9 g, 6 mmol)
was subsequently added and the solution was refluxed for
2 h. The solvent was evaporated and the residue extracted
with chloroform. The organic phase was dried over anhyd
sodium sulfate and the chloroform distilled off, mp 180°C
Following the same procedure as described for 3m, com-
pound 3s was prepared, mp 61°C, yield 53%. 1H NMR
(CDCl3) δ: 6.88 (s, 1H, C4-H), 6.92–7.80 (m, 5H, ArH), 7.90
(d, 1H, C6′-H), 8.66 (m, 1H, C5′-H), 8.88 (d, 1H, C3′-H).
M+ 384. Anal. calcd. for C14H7F3N4O4S: C 43.76, H 1.84, N
14.58; found 43.71, H 1.56, N 14.61.
1
(ethanol), yield 54%. H NMR (CDCl3 + DMSO-d6) δ: 2.14
1-(1′,2′-Benzisothiazol-3′-yl) 3-(2-thienyl)-5-
trifluoromethyl-5-hydroxypyrazoline-1′,1′-dioxide (7t)
(CH3), 3.38 (m, 2H, CH2), 7.72–7.83 (m, 3H, C5 ′-, C6 ′-, and
C7 ′-H), 8.67 (m, 1H, C4 ′-H). M+ 333. Anal. calcd. for
C12H10F3N3O3S: C 43.25, H 3.02, N 12.61; found C 43.38,
H 2.87, N 12.45.
With the same method used in the case of 7h, compound
1
7t was obtained, mp 190°C, yield 56%. H NMR (CDCl3 +
DMSO-d6) δ: 3.75 (m, 2H, CH2), 7.5–7.7 (m, 3H, thienyl),
8.0–8.3 (m, 3H, C5′-, C6′-, and C7′-H), 8.71 (m, 1H, C4′-H).
M+ 401. Anal. calcd. for C15H10F3N3O3S2: C 44.89, H 2.51,
N 10.47; found C 45.00, H 2.69, N 10.30.
1-(2′,4′-Dinitrophenyl)-3-phenyl-5-trifluoromethyl-5-
hydroxypyrazoline (7m)
An ethanolic solution (50 mL) of 2,4-dinitrophenyl-
hydrazine (0.95 g, 6 mmol) and sodium acetate (0.5 g,
6 mmol) was refluxed for 15 min. An equimolar amount of
benzoyltrifluoroacetone (0.9 g, 6 mmol) was subsequently
added and the solution was refluxed for 4 h. The solvent was
evaporated and the residue crystallized from ethanol, mp
1-(1′,2′-Benzisothiazol-3′-yl)-3-(2-pyridyl)-5-trifluoromethyl-
5-hydroxypyrazoline 1′,1′-dioxide (7v)
With the same method used in the case of 7h, compound
1
7v was obtained, mp 224°C, yield 67%. H NMR (CDCl3 +
1
142°C, yield 54%. H NMR (CDCl3) δ: 4.51 (m, 2H, CH2),
DMSO-d6) δ: 3.70 (AB system, 2H, CH2, J = 19 Hz), 7.70–
7.90 (m, 3H, C5′-, C6′-, and C7′-H), 8.70–8.80 (m, 5H,
pyridine and C4-H of the benzisothiazolyl). M+ 396. Anal.
calcd. for C16H11F3N4O3S: C 48.49, H 2.80, N 14.14; found
C 48.36, H 2.71, N 13.85.
7.38–7.99 (m, 5H, ArH), 8.06 (d, 1H, C6 ′-H), 8.45 (dd, 1H,
C5 ′-H), 9.05 (d, 1H, C3 ′-H). M+ 396. Anal. calcd. for
C16H11F3N4O5: C 48.49, H 2.80. N 14.14; found C 48.22, H
2.66, N 13.81.
1-(2′,4′-Dinitrophenyl)-3-phenyl-5-trifluoromethylpyrazole
(3m)
1-(1′,2′-Benzisothiazol-3′-yl)-3,5-bis-trifluoromethyl-5-
hydroxypyrazoline 1′,1′-dioxide (7ff)
To a solution of 7m (0.2 g, 0.5 mmol) in acetic acid was
added 2 mL of pure sulfuric acid. The mixture was refluxed
for 24 h. The solvent was evaporated and the residue was ex-
tracted with chloroform. The organic phase was dried over
anhyd sodium sulfate and the chloroform distilled off, mp
Using the same method as in the case of 7h, compound
1
7ff was obtained, mp 208°C (ethanol), yield 54%. H NMR
(CDCl3 + DMSO-d6) δ: 3.27 (m, 2H, CH2), 7.8–7.9 (m, 3H,
C5′-, C6′-, and C7′-H), 8.46 (m, 1H, C4′-H). M+ 387. Anal.
calcd. for C12H7F6N3O3S: C 37.22, H 1.82, N 10.85; found
C 36.98, H 2.07, N 10.70.
1
56°C (ethanol), yield 53%. H NMR (CDCl3) δ: 6.84 (s, 1H,
C4-H), 7.30 (m, 1H, C6 ′-H), 7.92 (d, 1H, C5 ′-H), 8.06–9.05
(m, 6 H, Ar-H). M+ 378. Anal. calcd. for C16H9F3N4O4: C
50.80, H 2.40, N 15.07; found C 50.66, H 2.37, N 14.86.
1-(p-Fluorophenyl)-3,5-bis-trifluoromethylpyrazole (9aa)
This compound was prepared like 3c and 4c but using
1-(1′,2′-Benzisothiazole-1′,1′-dioxide)-3-phenyl-5-
trifluoromethyl-5-hydroxypyrazoline (7o)
1,1,1,5,5,5-hexafluoropentane-2,4-dione. Mp 54°C (ethanol),
1
yield 65%. H NMR (CDCl3) δ: 6.97 (s, 1H, C4-H), 7.12
With the same method used in the case of 7i, compound
7o was obtained, mp 160°C (ethanol), yield 48%. H NMR
(CDCl3) δ: 3.35 and 3.69 (AB system, 2H, CH2, J = 18 Hz),
(unresolved dd, 2H, C3′- and C5′-H, J = 8.0 and 8.9 Hz),
7.38 (m, 2H, C2′- and C6′-H). Anal. calcd. for C11H5F7N2: C
44.31, H 1.69, N 9.40; found C 44.28, H 1.41, N 9.12.
1
© 2000 NRC Canada

1120
Can. J. Chem. Vol. 78, 2000
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Computational details
All the possible isomers considered for compounds 5′ and
5′′ (for both R = C6H5 (Ph) and R = 2′,4′-(NO2)2-C6H4
(DNP)), see Fig. 1 for four representative examples, have
been studied at semi-empirical level, optimizing all the geo-
metrical parameters. The different configuration of the C3
and C5 atoms of the pyrazolidine ring was considered (rela-
tive orientation of both OH groups, and of the CH3 and CF3
groups). Besides, considering the rotation between the rings,
two different orientations for the NO2 group in ortho in the
dinitrophenyl derivatives were taken into account. The
protonated species of the most stable of each one of the
compounds (5′ and 5′′, R = Ph and DNP) were also com-
puted. At semi-empirical level, the PM3 Hamiltonian (28),
as implemented in the MOPAC 6.0 package (29), was used
increasing the precision in a factor of 100 and optimizing
until a gradient of 0.01 was reached. This Hamiltonian was
chosen since good results had been previously obtained pre-
dicting the “stereoselectivity” of certain Michael type reac-
tions (for example ref. (30)). In all the cases, the
corresponding heats of formation, dipole moments, and
charges of the atoms involved in the possible dehydration
(N1, N2, O6, and O8) were calculated and gathered in Ta-
bles 4 and 5.
17. S.I. Selivanov, K.G. Goldova, Ya.A. Abbasov, and B.A.
Ershov. Zh. Org. Khim. 20, 1494 (1984).
18. S.I. Selivanov, K.G. Golodova, and B.A. Ershov. Zh. Org.
Khim. 22, 2073 (1986).
Acknowledgements
We are grateful to Ranbaxy Research Laboratories, Coun-
cil of Scientific and Industrial Research, and to the Univer-
sity Grants Commission, New Delhi for financial assistance.
Thanks are due to RSIC, Chandigarh, for NMR spectra and
elemental analysis. We are also thankful to Mass Spectrome-
try Facility, California University, San Francisco, U.S.A., for
mass spectra. Two of us (IR and JE) thank the Spanish
DGICYT (Project no. SAF 97-0044-C02).
19. N.S. Zefirov, S.I. Kozhushkov, T.S. Kuznetsova, B.A. Ershov,
and S.I. Selivanov. Tetrahedron, 42, 709 (1986).
20. J. Elguero and G.I. Yranzo. J. Chem. Res. Synop. 120 (1990).
21. P.P. Kondrat’ev, Z.E. Scryabina, V.I. Soloutin, and L.M.
Khalilov. Zh. Org. Khim. 28, 1380 (1992).
22. K.N. Zelenin, V.V. Alekseyev, and A.R. Tygysheva. Tetrahe-
dron, 51, 11251 (1995).
23. A.R. Katritzky, D.L. Ostercamp, and T.I. Yousaf. Tetrahedron,
43, 5171 (1987).
24. K.N. Zelenin. Org. Prep. Proced. Int. 27, 519 (1995).
25. K.N. Zelenin and S.I. Yakimovitch. Targets Heterocycl. Syst.
2, 207 (1998).
26. C. Dittli, J. Elguero, and R. Jacquier. Bull. Soc. Chim. Fr.
1038 (1971).
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