Study of the reactivity of α-acylenaminoketones. Synthesis of pyrazoles

Article abstract of DOI:10.1002/jhet.5570380116

The reactions of 4-(methylamino)-3-penten-2-one with diazoketones yielded the α-acylenaminoketones 1-3 in good yields. Preparation of the α-acylenaminoketone 4 was carried out by treatment of 4-(t-butylamino)-3-penten-2-one with benzoyl chloride being followed by reaction of transamination with methylamine. The reactions were carried out in five different solvents and were submitted to gas chromatography/mass spectrometry analysis, with the goal of obtaining substituted pyrazoles and determining which of the carbonyls would preferentially be attacked by the nucleophile. The reactions of compounds 1-4 with hydrazine reagents led to the formation of the pyrazoles 5-7a-q. Small amounts of 4-methylamino-2-pentenones 10a-q, amides 11a-q and pyrazoles 12a-q were also obtained in these reactions. The unexpected formation of pyrazoles 15d,h,q was detected when methanol and N,N-dimethylformamide were used as solvents in the reactions of α-acylenaminoketone 4 with hydrazine reagents.

Full text of DOI:10.1002/jhet.5570380116

Jan-Feb 2001
109
Study of the Reactivity of α-Acylenaminoketones.
Synthesis of Pyrazoles
Giuseppina Negri [a] and Concetta Kascheres* [b]
Universidade Estadual de Campinas, Chemical Institute, Caixa Postal 6154, 13083-970, Campinas, São Paulo, Brazil
Received March 6, 2000
The reactions of 4-(methylamino)-3-penten-2-one with diazoketones yielded the α-acylenaminoketones
1-3 in good yields. Preparation of the α-acylenaminoketone 4 was carried out by treatment of 4-(t-butyl-
amino)-3-penten-2-one with benzoyl chloride being followed by reaction of transamination with methyl-
amine. The reactions were carried out in five different solvents and were submitted to gas chromatogra-
phy/mass spectrometry analysis, with the goal of obtaining substituted pyrazoles and determining which of
the carbonyls would preferentially be attacked by the nucleophile. The reactions of compounds 1-4 with
hydrazine reagents led to the formation of the pyrazoles 5-7a-q. Small amounts of 4-methylamino-2-
pentenones 10a-q, amides 11a-q and pyrazoles 12a-q were also obtained in these reactions. The unexpected
formation of pyrazoles 15d,h,q was detected when methanol and N,N-dimethylformamide were used as
solvents in the reactions of α-acylenaminoketone 4 with hydrazine reagents.
J. Heterocyclic Chem., 38, 109 (2001).
Introduction.
in reactions with conjugated ketones, esters and nitriles
[26]. Reaction of hydrazines with acetoacetamides affords
pyrazoles retaining the amine moiety [27].
The ease of preparation of enaminones, whose regio-
and stereoselective syntheses and functionalization have
been subject of research for some time, makes them
attractive intermediates for organic synthesis [1,2].
Diazodiphenylethanone reacts with enaminones via its
copper(II)-stabilized carbene to form pyrroles [3] or via
diphenylketene under noncatalytic thermal conditions to
form nucleophilic addition products [4]. 3-Diazo-1,3-
dihydro-2H-indol-2-one derivatives react with enam-
inones to form triazoles [5]. The quinone diazides were
reacted with enaminones to produce the novel
azoenaminones. The potential usefulness [6] of the push-
pull azoenaminones in nonlinear optics, as second
harmonic generators, was proposed based on theoretical
finite-field static calculations. Enaminoketones and
enaminoesters [7-10] can be reduced to γ-aminoalcohols
or β-aminoacids, which are important classes of organic
compounds of proved biological and pharmacological
activity. β-Enaminoketones and esters have found
application as 1,3-bielectrophilic synthons in the
syntheses of heterocycles [11-20].
The most important derivatives of pyrazole are
pyrazolones, which have important pharmacological prop-
erties and of which a few naturally-occurring examples
exist. For this reason, there is increasing interest in the
development of a new procedure for the synthesis of
pyrazoles and their derivatives. The standard syntheses for
pyrazoles involve the reaction of β-dicarbonyl compounds
with hydrazine. N-Substituted pyrazoles are of interest as
chiral auxiliary for stereoselective synthesis and for the
resolution of certain racemic compounds. A great many
papers have been reported so far concerning the synthesis
or biological activity of pyrazole derivatives [21-24]. By
treatment with various nucleophiles, N-acylpyrazoles were
converted into the corresponding amides, esters, ketones
and β-keto esters [25]. Amongst pyrazole derivatives,
C-aminopyrazoles are the most used in heterocyclic
chemistry as starting materials because of their versatility
Solvent effects on organic reactivity [28-29] and on
absorption spectra have been studied for more than a
century. Organic chemists have usually attempted to
understand these solvent effects in terms of the polarity of
the solvent. Solvents whose molecules possess a
permanent dipole moment are designated dipolar as
opposed to apolar or nonpolar for those lacking a dipole
moment [30]. The dielectric constants play a particular
role in the characterization of solvents. Their importance
over other criteria is due to the simplicity of electrostatic
models of solvation and they have become a useful
measure of solvent polarity. The dielectric constant
represents the ability of a solvent to separate charge and to
orient its dipole [30].
Our continuing interest in the structure-reactivity
relationships of enaminones has led us to examine the
chemistry of 4-methylamino-3-penten-2-ones with acetyl
derivatives in the 3-position [4]. The study of the reactivity
of α-acylenaminoketones 1-4 and 18 aroused our interest
because of the different ways that the two ketonic
carbonyls could react; different kinds of heterocycles may
be formed depending on the reaction conditions employed.
Results and Discussions.
As part of this study, it has become necessary to
determine the structures of compounds 1-4 (Figure 1) in
greater detail than was obtained by spectroscopic data. The
presence of an intramolecular NH chelated proton in
1
compounds 1-4 and 18 is clearly observed in the H NMR
Figure 1. 1, R = CH(Ph) 2, R = CH(CH )Ph 3, R = CH(CH ) 4, R = Ph
2
3
3 2

110
Vol. 38
G. Negri and C. Kascheres
The AM1 molecular orbital calculations show that
compounds 1-4 have HOMOs with large coefficients on
both the α-carbon and nitrogen atoms. The absolute
magnitude of the two coefficients is somewhat greater at
the α-carbon atom. Compounds 1-3 have LUMOs with
large coefficients on both the β-carbon atom and carbonyl
carbon of the acetyl group. The absolute magnitude of the
two coefficients is somewhat greater at the β-carbon atom,
as shown in Table 2. The α-acylenaminoketone 4 has
LUMO with large coefficient on the benzoyl group. These
calculations do not take solvent effects into account. The
AM1 geometry optimization indicated a tendency for one
intramolecular hydrogen bond with the carbonyl carbon of
the acetyl group, favouring E configuration and
conjugation of the acetyl group with the double bond.
Crystallographic analysis of 1 was performed to identify
the key structural features of these molecules. X-ray
crystallographic data for 1 indicated good agreement
between X-ray and AM1 calculated geometries [33]. The
results obtained show that, whichever the configuration,
the diphenylacetyl group tends to be approximately
perpendicular to the plane of the enaminone, most likely
because of steric factors. The heat of formation for the Z
configuration is larger [compound 1 (-5.14 Kcal);
compound 2 (-40.16 Kcal) and compound 4 (-35.94 Kcal)]
than for the E configuration [compound 1 (-7.24 Kcal);
compound 2 (-43.65 Kcal); compound 3 (-79.97 Kcal) and
compound 4 (-37.42 Kcal)].
1
1
Figure 2. a)R = CH(Ph) , R = CH ; b) R = CH(CH )Ph, R = CH ;
2
3
3
3
1
1
1
c) R = CH(CH ) , R = CH ; d) R = Ph, R = CH ; e) R = CH(Ph) , R =
Ph; f) R = CH(CH )Ph, R = Ph; g) R = CH(CH ) , R = Ph; h) R = Ph,
R = Ph; i) R = CH(Ph) ,R = p-Ph-NO ; j) R = CH(CH )Ph, R = p-Ph-
NO ; l) R = CH(CH ) , R = p-Ph-NO ; m) R = Ph, R = p-Ph-NO ;
3 2
3
3
2
1
1
3
3 2
1
1
1
2
2
3
1
1
2
3 2
2
2
1
1
n) R = CH(Ph) , R = H(H O); o) R = CH(CH )Ph, R = H(H O);
2
2
3
2
1
1
p) R = CH(CH ) , R = H(H O); q) R = Ph, R = H(H O).
3 2
2
2
Considering that pyrazole formation involves reaction on
two of the electrophilic sites of compounds 1-4 (C and one
β
of the two carbonyl groups) and that their yields in
reactions with hydrazine reagents can be approximately
proportional to the LUMO energy of the α -acylen-
aminoketone reagent used, we felt that the reaction might
be frontier orbital controlled. When the HOMO/LUMO
interaction is the major factor governing differential
reactivity, the reaction is said to be frontier-orbital
controlled. Thus, a molecular orbital method that calculates
reliable energy levels of frontier orbitals as well as electron
density at each atom is needed in reactivity studies.
Reactions of 1-4 with hydrazines were carried out in
benzene, methylene chloride, tetrahydrofuran, methanol
and N,N-dimethylformamide with the aim of determining
the relative reactivity of the two carbonyls during a
nucleophilic attack in order to obtain information on the
solvent dependence of the regiochemistry of the pyrazole
formed. The reaction mixtures were submitted to gas
chromatography/mass spectrometry analyses, in an
attempt to identify all products (Figure 2) and any possible
intermediates formed during the reactions.
spectra at 12.40 ppm. Although the N-H chemical shift of
1-4 shows that it is intramolecularly hydrogen bonded, it is
not possible to determine which carbonyl is involved and
thus cis with respect to the nitrogen. Another aspect of the
structure that we consider important to its reactivity
involves the conformation of the second carbonyl with
respect to the conjugated enaminone system.
The AM1 package seems to be one of the most reliable
semiempirical methods known today [31] for calculation
of geometric structures, heats of formation, dipole
moments, and some other properties of molecules. Our
interest in understanding the reactivity of compounds 1-4
has led us to attempt to correlate experimental results
with theoretical studies in the case of the reactions of
these compounds with hydrazine reagents. Quantum
chemical calculations using the AM1 (Austin Model 1)
[32] semiempirical method were carried out for
compounds 1-4 using the AMPAC package which was
locally modified to handle a larger number of atoms.
Geometries were fully optimized without imposing any
symmetry constraints. Standard bond angles and bond
lengths were used as input and intramolecular hydrogen
bonding was assumed in both geometric forms. Frontier
orbital energies (eV) calculated by AM1 in the E config-
uration are given in Table 1.
The principal products obtained, the pyrazoles
5-7a-q, can be explained by a Michael-type reaction, in
which the amino group of the hydrazine reagents attacks
the β-carbon atom of compounds 1-4 to form adduct
8a-q, which reacts with elimination of methylamine to
form the β-hydrazino-unsaturated ketones 9a-q. The

Study of the Reactivity of α-Acylenaminoketones. Synthesis of Pyrazoles
111
Jan-Feb 2001
Table 1
Frontier Orbital Energies (eV) of 1-4 in E Configuration
Calculated by AM1.
HOMO
LUMO
1
2
3
4
-8.80
-8.79
-8.83
-8.82
0.118
0.115
0.131
-0.276
β-hydrazino-unsaturated ketones can exist in various
tautomeric and geometric forms. The carbonyl group of
the acetyl fragment in compounds 1-4 seems to be
sterically less hindered and therefore more active; so the
subsequent heterocyclization of (E)-isomers of
intermediates 9a-q yielded the pyrazoles 5a-q while the
pyrazoles 7a-q were obtained through the (Z)-isomers
of intermediates 9a-q (Figure 3). These intermediates
were not detected by GC/MS. This observed variation
can be attributed to a different isomeric form or the
possibility of an intermolecular hydrogen bond.
The formation of the deacetylated pyrazoles 6a-q can
be explained by the nucleophilic attack of the methyl-
amine eliminated in these reactions on the carbonyl
carbon of the acetyl group on compounds 1-3 leading to
the formation of two products: deacetylated enaminoke-
tones- 4-methylamino-2-pentenones (10a-q) and
N-methylacetamide. The subsequent nucleophilic attack
of hydrazine reagents on the β-carbon atom of deacetyl-
ated enaminoketones 10a-q with intramolecular hetero-
cyclisation followed by elimination of water, yield the
deacetylated pyrazoles 6a-q, as it is shown in Figure 4.
To test for the formation of 10f, compound 3 was reacted
with methylamine and produced deacetylated enaminone
10f in 66% yield.
Small amounts of amides 11a-q and pyrazole 12a-q
were also obtained in these reactions. The formation of
small amounts of pyrazoles 13-14a-q can be explained by
a Michael-type reaction in which the substituted nitrogen
of the hydrazine reagent attacks the β-carbon atom of
compounds 1-3.
Reactions of α-Acylenaminoketones 1-4 with Methyl-
hydrazine.
Reaction of compounds 1-4 with methylhydrazine
afforded mixtures of positional isomers 5a-d and 7a-d. The
pyrazoles 5b,c synthesized in high yield according to
Table 3 were favoured in benzene, methylene chloride and
methanol probably because in these solvents the (E)-isomers
of β-hydrazino-unsaturated ketones 9b,c were favoured.
This could be the result of more favorable intramolecular
interactions that occur during lattice packing. The stability
of the E configuration in intermediates 9b,c may be attrib-
uted to one intramolecular hydrogen bond between the
carbonyl carbon of the acetyl group and the hydrogen of the
amino group of the methylhydrazine at the β-position and
this configuration should also be preferred for its steric
effects. When tetrahydrofuran and N,N-dimethylformamide
were used as solvents, in these reactions, the (Z)-isomers of
9b,c were favoured leading to the formation of pyrazoles
7b,c. Only a very small amount of pyrazoles 6a,c and the
deacetylated enaminone 10c, formed by a deacetylation
process, was obtained.
Table 2
Site Selectivity - Largest Coefficients of Compounds 1-4.
Carbon*
HOMO/LUMO
1
1
1
1
2
2
2
2
3
3
3
3
4
4
4
4
C*=O(CH )
0.06/0.29
0.65/0.24
0.22/0.49
-0.05/0.10
0.07/0.36
0.68/0.29
0.23/0.60
-0.04/0.07
-0.06/0.39
-0.66/0.32
-0.23/0.62
-0.04/0.05
0.06/0.04
0.69/0.02
0.23/0.04
-0.02/0.37
3
C*α
C*β
C*=O(R)
C*=O(CH )
3
C*α
C*β
C*=O(R)
C*=O(CH )
3
C*α
C*β
C*=O(R)
Very interestingly, the pyrazole 5a was obtained as the
principal product in all solvents used. In compound 1, there
is one more acidic hydrogen, hence this compound has most
likely a keto-enolic equilibrium, rendering the nonconju-
gated carbonyl less reactive during a nucleophilic attack.
C*=O(CH )
3
C*α
C*β
C*=O(R)

112
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G. Negri and C. Kascheres
Table 3
Yields (in percentage) of Compounds 5-15 using Methylhydrazine
Entry
Substrate
Solvent
Main
5a (78) [a]
Products
7a (14) [a], 11a (5)
[a]Side
1
2
3
4
5
6
7
8
1
2
3
4
1
2
3
4
1
2
3
4
1
2
3
4
1
2
3
4
Benzene
Benzene
Benzene
Benzene
5b (60)
5c (37), 7c (37)
7d (54)
5a (70)
5b (58)
5c (58)
7d (53)
5a (73)
5b (43), 9b (43)
7c (49), 5c (39)
7d (68)
5a (42)
5b (52)
5c (35)
15d (34), 7d (30)
5a (62)
7b (55)
7c (73)
7b (7), 11b (25)
10c (3)
5d (30), 15d (5)
7a (8), 11a (11)
6b (16), 7b (17), 11b (4)
7c (25), 13c (2)
5d (28), 15d (3)
7a (14), 11a (4)
11b (7)
CH Cl
2
2
2
2
2
CH Cl
2
CH Cl
2
CH Cl
2
9
THF
THF
THF
THF
MeOH
MeOH
MeOH
MeOH
DMF
10
11
12
13
14
15
16
17
18
19
20
6c (1)
5d (23), 11d (8)
6a (9), 11a (9), 13a (4)
6b (23), 13b (7), 7b (5), 11b (7)
10c (20), 6c (7), 7c (9), 14c (2)
5d (24), 11d (12)
7a (19), 11a (8)
5b (32), 11b (6)
5c (24)
15d (36), 5d (13)
DMF
DMF
DMF
7d (51)
[a] The amounts of each pyrazole were determined by integration of the areas of the corresponding peaks, which was performed using HP-Chemstation
Software and comparison with the areas of isolated pyrazoles with known concentrations.
Only when methanol was used as solvent, was compound 5a
obtained in low yield. This may be attributed to a
combination of the effects of solvent polarity and the forma-
tion of the intermolecular hydrogen bonds between the
carbonyls of compound 1 and methanol. The keto/enol ratio
often depends on solvent polarity [30]. The enol is stabilized
in solvents that can act as hydrogen bond acceptors, while
the keto form is favored in protic solvents acting as
hydrogen bond donors, such as methanol [30].
5a-c and 7a-c, respectively, showing that they are isomers
resulting from the reaction of hydrazine reagents at different
electrophilic positions of the enaminone system. The struc-
tures of regioisomeric pyrazoles 6a-c and 13a-c, 7a-c and
14b,c were differentiated by their mass spectral fragmenta-
tion patterns obtained in GC/MS analyses.
The formation of small amounts of pyrazoles 13-14b,c
was observed, but in many cases only pyrazoles 6-7a-d
were obtained, corresponding to that formation derived
from the attack of the primary amino group on the β-carbon
atom of compounds 1-4. Therefore, the products formed
are consistent with a LUMO-controlled process in which
initial attack occurred at the β-carbon atom. The mass
spectra of compounds 14b,c show a fragment at m/z 137
(~90%) that corresponds to the loss of the R group.
Probably this loss is favoured when the R group is at the
3-position of the pyrazole moiety, or better, at β-position in
relation to substituted nitrogen of the pyrazole moiety. The
mass spectrum of compound 6a shows a fragment in
m/z 144 (~10%), which corresponds to the loss of methyl-
cyanide. The fragmentation of the pyrazolic rings involving
the loss of methylcyanide, are known [34].
Isomers 5a-c and 7a-c were distinguished based on the
α-cleavage fragments of these compounds observed in their
mass spectra. The presence of fragments ions corresponding
+
+
to (M -R) and (M -CH ) unambiguosly assigns isomers
3
The assignment of the structure of the positional isomers
was also carried out on the basis of detailed nmr investiga-
tions. The Nuclear Overhauser Enhancement (NOE)
difference spectroscopy utilizing a through-space
connection between the 5-position of the pyrazole moiety
and protons of the N-1 substituent is proposed as a simple
method for the assignment of pyrazole-H resonances and
for the differentiation between ''asymmetric'' isomers in

Study of the Reactivity of α-Acylenaminoketones. Synthesis of Pyrazoles
113
Jan-Feb 2001
Table 4
Yields (in percentage) of Compounds 5-15 using Phenylhydrazine
Entry
Substrate
Solvent
Main
Products
[a]Side
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
1
2
3
4
1
2
3
4
1
2
3
4
1
2
3
4
1
2
3
4
Benzene
Benzene
Benzene
Benzene
6e (39), 5e (21)
6f (51)
5g (30), 6g (24)
5h (43)
6e (39), 5e (20)
6f (61)
6g (38), 5g (33)
6h (70)
12e (10), 11e (11)
12f (8), 13f (2), 5f (1)
10g (2), 7g (4), 12g (4), 13g (4)
7h (24), 6h (6)
12e (18), 11e (14)
12f (19), 11f (6), 10f (4), 5f (8)
12g (5)
CH Cl
2
2
2
2
2
CH Cl
2
CH Cl
2
CH Cl
5h (7)
2
THF
THF
THF
THF
MeOH
MeOH
MeOH
MeOH
DMF
5e (56)
5f (57)
5g (54)
6e (9), 12e (14), 11e (7)
6f (25), 12f (14), 10f (4)
6g (15), 7g (8)
11h (17)
12e (9), 11e (8)
5h (48), 7h (32)
5e (27), 6e (26)
6f (39), 5f (21)
6g (44), 5g (30)
15h (28), 5h (26)
5e (61)
5f (28), 11f (21)
5g (38)
15h (44), 5h (42)
12f (13), 11f (10)
12g (14)
7h (19), 11h (13)
12e (13), 11e (8), 6e (6)
12f (14), 10f (6), 6f (4)
12g (10), 13g (5), 10g (6), 6g (6)
11h (2), 12h (8)
DMF
DMF
DMF
[a] The amounts of each pyrazole were determined by integration of the areas of the corresponding peaks, which was performed using HP-Chemstation
Software and comparison with the areas of isolated pyrazoles with known concentrations.
various pyrazole derivatives [35]. Irradiation of the N-
methyl resonance, in compound 7b in deuteriochloroform,
led to a significant enhancement of the signal attributable
to the benzylic proton resonance at δ 5.6 ppm, the methyl
group resonance at δ 1.6 ppm and of the phenyl group res-
onance at δ 7.2 ppm. All these protons are in the 1-phenyl-
ethyl group, whereas the high-field of two methyl signals
at δ 2.4 ppm remained unaffected. Thus, the resonance at δ
5.6, 1.6 and 7.2 ppm have to be attributed to the protons of
a 1-phenyl-ethyl group attached to the 5-position of the
pyrazole ring, due to the spatial closeness of these protons
and the methyl protons.
In the reactions of α-acylenaminoketone 4 with methyl-
hydrazine, when benzene, methylene chloride and tetrahy-
drofuran were used as solvents, the pyrazole 5d was
obtained in high yield (Table 3). Interestingly, the use of
N,N-dimethylformamide as solvent led to the formation of
pyrazole 5d, but a significant amount of an unexpected
pyrazole, the benzoyl pyrazole 15d was also formed. The
same reaction utilizing methanol as solvent gave a mixture
of four products, with predominance of pyrazole 15d. The
mass spectrum of pyrazole 15d showed a molecular ion at
m/z 276 (60%) which corresponds to the molecular ion of
pyrazole 5d plus 62 a.m.u, and fragments at m/z 275
(100%) and at m/z 199 (60%), which correspond to the
loss of 1 a.m.u and the loss of phenyl group, respectively.
N-Methylbenzamide 11d was also isolated as a product
in reactions of compound 4 with hydrazine reagents,
showing that the elimination of methylamine with
subsequent attack on the benzoyl carbonyl carbon of the
α-acylenaminoketone 4 occurred. Two reactions were tried
in order to find out how pyrazoles 15d,h,q were formed.
Initially we supposed that the 3-benzoyl-4-(methylamino)-
3-penten-2-one 4 would react with N-methylbenzamide
11d leading to the formation of 1-phenyl-2-benzoyl-3-
methylamino-2-butenone 16; the pyrazole 15d could then
be formed by simply treating 16 with methylhydrazine.
However, the reaction did not take place, only starting
material was isolated from the reaction, independent of the
conditions employed. Compound 16 could be also formed
through the reaction of 1-phenyl-3-methylamino-2-
butenone with N-methylbenzamide. The other attempt was
to react the pyrazole 5d with N-methylbenzamide 11d, but
the formation of pyrazole 15d was not observed and there-
fore there was a significant recovery of starting material.
All attempts to isolate the products, which might help
explain the formation of benzoyl pyrazoles 15, were
unsuccessful.
Reactions of α-Acylenaminoketones 1-4 with Phenyl-
hydrazine.
The use of phenylhydrazine as a nucleophile in the
reactions of α-acylenaminoketones 1-3, and the use of
benzene, methylene chloride and methanol as solvents
led to the formation of deacetylated pyrazoles 6e-g,
whereas with tetrahydrofuran and N,N-dimethyl-
formamide as solvents. The attack of the secondary
amino group of the hydrazine reagent on the carbonyl
carbon of acetyl group takes place, favouring the
formation of pyrazoles 5e-g. Only a very small amount

114
Vol. 38
G. Negri and C. Kascheres
of pyrazole 7g was obtained, while no pyrazoles 7e,f
were detected (Table 4). A more subtle effect of size
involves steric interaction between the nitrogen
substituent of hydrazine reagents and the carbonyl
bonded to R group, which can cause the substituted
nitrogen of hydrazine to bend toward the acetyl group.
Irradiation of the methyl-H resonance at δ 2.4 ppm in
compound 6e in deuteriochloroform solution led to a
significant enhancement of the signal attributable to
pyrazole-H resonance at δ 5.8 ppm, whereas the signal of
the protons of the N-phenyl group remained unaffected,
thus confirming that the methyl group is situated at the
3-position of the pyrazole moiety. The same perturbation
of pyrazole-H frequency in compound 6e led to smaller
negative NOE’s on the multiplet signals of the protons of
two phenyl groups at δ 7.1-7.4 ppm bonded to
1,1-diphenylmethyl group at the 5-position of the pyrazole
moiety. The smaller magnitude of the NOE is due to a
larger distance of the spins involved, but the observed
effect is strong enough to allow an unambiguous
assignment. The occurrence of negative NOEs is due to the
spatial closeness between this group and the proton that is
at 4-position of the pyrazole moiety, which is suffering the
effect of irradiation of the methyl group, whereas the
signal at δ 5.4 ppm (benzylic proton) remained unaffected.
Instead, a NOE is observed on the pyrazole H-4 signal,
which is consistent with one adjacent methyl group at the
3-position of the pyrazole moiety.
Irradiation of the methyl-H resonance in compound 6f in
deuteriochloroform solution led to a significant enhance-
ment of the signal attributable to pyrazole-H resonance at δ
6.2 ppm, whereas the low-field phenyl protons signal at δ
7.3 ppm remained unaffected. The resonance at δ 6.2 ppm
has to be attributed to pyrazole H-4 due to the spatial
closeness between H-4 and the methyl protons. In all cases
discussed above the perturbed resonances are singlets
being well separated from the pyrazole-H signals. In these
cases it turned out to be more advantageous to perturb the
pyrazole-H resonances and to observe NOE’s on the
protons of the benzene moiety. The assignment of the
structure of the other isomers can be made by analogy with
6e, 6f and 7b and were supported by NOE-experiments.
The principal isomers formed correspond to the initial
attack of primary amino group of hydrazine on the
β-carbon atom, and these data are in agreement with the
results of the theoretical data obtained by (AM1) semi-
empirical quantum chemical calculations.
was reacted with phenylhydrazine under the same
conditions, using methanol and N,N-dimethylformamide
as solvents the principal product was the pyrazole 15h.
This unexpected product was isolated and spectral data
and combustion analysis are in the experimental section.
These n-donor solvents are particularly important for the
solvation of cations and they are also known as
coordinating solvents [30]. Probably, the formation of
pyrazoles 15d,h,q involved a cation as a probable
intermediate, which was stabilized by solvation in these
solvents.
Reactions of α-Acylenaminoketones 1-4 with p-Nitro-
phenylhydrazine.
The reactions using p-nitrophenylhydrazine as
nucleophile were more sluggish and led to the formation of
deacetylated pyrazoles 6i-l, as can be seen in Table 5.
Small amounts of pyrazoles 5l and 7l were obtained when
we did the reaction of α-acylenaminoketone 3 with this
nucleophile using N,N-dimethylformamide as solvent.
The deacetylated pyrazole 6i was obtained as principal
product in the reactions of α-acylenaminoketone 1 with
p-nitrophenylhydrazine using methylene chloride and
methanol as solvents. Very interestingly, when these
reactions were carried out in benzene and tetrahydrofuran,
the formation of pyrazole 6i did not occur, only pyrazole
12i and N-methyl-1,1-diphenyl acetamide 11i were formed
as products. Under the same conditions, using
N,N-dimethylformamide as solvent, there was also
evidence for spurious side reactions of the solvent with the
methylamine eliminated in this reaction, as is shown in
Figure 5, and the yield of N,N-dimethyl-1,1-diphenyl-
ethanone 17 was 32%.
The reactions of α-acylenaminoketone 4 were not
successful with the less nucleophilic p-nitrophenyl-
hydrazine and the pyrazoles were isolated in low yield.
Using methylene chloride as solvent, the deacetylated
pyrazole 6m was obtained as major product and in
N,N-dimethylformamide the principal products formed
were the pyrazoles 5m and 7m. The use of N,N-dimethyl-
formamide as solvent favoured the reaction on the
nonconjugated carbonyl bonded to the phenyl group. In
the other solvents the reaction did not take place and
therefore there was a significant recovery of unreacted
starting material.
Reactions of α-Acylenaminoketones 1-4 with Hydrazine
Hydrate.
The pyrazole 5h was obtained as principal product in the
reaction of compound 4 with phenylhydrazine, utilizing
benzene and tetrahydrofuran as solvents. The same
reaction using methylene chloride as solvent led to forma-
tion of 3-methyl-1,5-diphenyl pyrazole (6h). The
3-methyl-1,5-diphenyl pyrazole and 5-methyl-1,3-
diphenyl pyrazole are already known. The isomer obtained
in this reaction was identified by comparison with reported
spectroscopic data [36a-d]. When α-acylenaminoketone 4
The reactions of α -acylenaminoketones 1-4 with
hydrazine hydrate, utilizing benzene, methylene
chloride, tetrahydrofuran and N,N-dimethylformamide
as solvents, gave a mixture of positional isomers, with
predominance of the pyrazoles 7n-q. The nucleophilic
attack on carbonyl bonded to the R group occurred pref-
erentially due to the high nucleophilic power of the two
nitrogens of the hydrazine hydrate. When methanol was

Study of the Reactivity of α-Acylenaminoketones. Synthesis of Pyrazoles
115
Jan-Feb 2001
Table 5
Yields (in percentage) of Compounds 5-15 using p-Nitrophenylhydrazine.
Entry
Substrate
Solvent
Main Products
Side Products
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
1
2
3
1
2
3
4
1
2
3
1
2
3
1
2
3
4
Benzene
Benzene
Benzene
11i (46)
6j (42)
6l (67)
7i (49)
6j (71)
12i (31)
12j (11), 11j (12)
13l (11), 12l (6)
12i (18), 11i (23)
12j (13), 11j (7)
13l (4), 12l (3)
-
12i (16)
12j (4), 11j (7)
13l (2)
CH Cl
2
2
2
2
2
CH Cl
2
CH Cl
6l (64)
2
CH Cl
6m (43)
11i (34)
6j (47)
6l (41)
7i (43)
6j (79)
6l (65)
11i (22), 12i (22)
6j (53)
5l (21), 6l (20), 7l (20)
7m (44)
2
THF
THF
THF
MeOH
MeOH
MeOH
DMF
DMF
DMF
DMF
12i (26), 11i (11)
12j (8)
12l (4)
-
12j (14), 11j (18)
12l (3)
5m (11), 6m (3)
used as solvent, the (E) isomers of intermediates 9n-q
were favoured leading to the formation of pyrazoles
5n-q. Protic solvents shift the alkene (E)/(Z) ratio in the
direction of the (E)-form [30]. Only when tetrahydro-
furan and N,N-dimethylformamide were used as
solvents, the formation of deacetylated products
occurred in small quantities, as can be seen in Table 6.
When methanol was used as solvent under the same
conditions, the reaction of α-acylenaminoketone 4 with
hydrazine hydrate led to the formation of pyrazole 15q.
This nucleophile favoured the reaction on the noncon-
jugated carbonyl group, bonded to the R group. The
tautomerism of 5(3)-methyl-3-(5)-phenylpyrazole was
studied by Parrilla [37] in the liquid state using multi-
nuclear nmr spectroscopy at low temperatures and in the
solid state by X-ray crystallography to determine the
tautomeric equilibrium constants.
Reactions of α-Acylenaminoketone 18 with Methyl-
hydrazine and Phenylhydrazine
The reactions of α-acylenaminoketone 18 with methyl-
hydrazine and phenylhydrazine were carried out utilizing
the same five solvents for a better understanding of the
deacetylation process and led to the formation of pyrazoles
19a,b, deacetylated pyrazoles 20a,b, N-t-butylacetamide
21 and 4-(t-butylamino)-3-penten-2-one 22 (Figure 6).
When methylhydrazine was used as nucleophile, the
principal product was the pyrazole 19a using benzene,
methylene chloride, tetrahydrofuran and N,N- dimethyl-
formamide as solvents. While, using methanol as solvent,
the deacetylated pyrazole 20a was preferentially formed. It
is interesting to observe that the utilization of methanol as
solvent favoured the nucleophilic attack of t-butylamine
formed in these reactions on the carbonyl carbon of the

116
Vol. 38
G. Negri and C. Kascheres
Table 6
Yields (in percentage) of Compounds 5-15 using Hydrazine Hydrate.
Entry
Substrate
Solvent
Main Products
Side Products
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
1
2
3
4
1
2
3
4
1
2
3
4
1
2
3
4
1
2
3
4
Benzene
Benzene
Benzene
Benzene
7n (35), 5n (25)
7o (46), 10o (27)
7p (38), 10p (30)
7q (48)
7n (45), 5n (21)
7o (33), 10o (27)
7p (64)
7q (53)
7n (73)
7o (59)
7p (67)
7q (60)
5n (68)
5o (49)
7p (36), 6p (34), 5p (30)
15q (45)
7n (50)
7o (75)
7p (81)
7q (43), 15q (31)
10n (11), 6n (8), 11n (13)
6o (10), 5o (8), 11o (4)
6p (24), 5p (7)
5q (18), 6q (7)
CH Cl
10n (9), 6n (13), 11n (8)
6o (3), 5o (3), 11o (13)
5p (13), 6p (13), 10p (5)
5q (22)
5n (14), 11n (7)
10o (13), 5o (8), 11o (14)
5p (16), 6p (17)
5q (18), 11q (22)
10n (6), 6n (10), 11n (8)
6o (37), 7o (8)
2
2
2
2
2
CH Cl
2
CH Cl
2
CH Cl
2
THF
THF
THF
THF
MeOH
MeOH
MeOH
MeOH
DMF
-
11q (39), 5q (13), 7q (3)
5n (33), 11n (17)
5o (16), 11o (9)
5q (19)
11q (15), 5q (10)
DMF
DMF
DMF
acetyl group, leading to the formation of 4-(t-butylamino)-
3-penten-2-one 22 by loss of the acetyl group and
consequent formation of N-t-butylacetamide 21, as can be
seen in Table 7.
the carbonyl carbon of the acetyl group. The products
19-20a,b were obtained in low yield, thus, the increase in
size of the nitrogen substituent of α-acylenaminoketone
may slow down reaction because of steric hindrance.
In summary, the deacetylation of the α-acylenamino-
ketones 1-3 and 18 was favoured by the decrease in the
nucleophilicity of secondary amino group of hydrazine,
favouring the formation of products obtained via a
deacetylation process. The N-methylamine eliminated in
these reactions was a nucleophile that competed with the
hydrazine reagents for the two carbonyls of α-acylen-
aminoketones susceptible to nucleophilic attack. The
carbonyl group of the acetyl fragment seems to be
sterically less hindered and therefore more active.
The reactions of compound 18 with phenylhydrazine in
all solvents used led to the formation of deacetylated
pyrazole 20b. In these reactions, the formation of 21 was
more favoured, principally when tetrahydrofuran was used
as solvent, showing that the reduction of nucleophilicity of
the substituted nitrogen of hydrazine increased the
nucleophilic attack of t-butylamine eliminated during the
reactions on the carbonyl carbon of the acetyl group. When
methylene chloride was used as solvent, the formation of
acetylphenylhydrazine was observed with 20% yield in the
chromatogram. Thus, the deacetylation of the α-acylen-
aminoketones can also occur through the nucleophilic
attack of the primary amino group of phenylhydrazine on
Tetrahydrofuran and N,N-dimethylformamide favoured
the (E)-isomers of possible intermediates 9a-q when
phenylhydrazine was used as nucleophile, showing that in
Table 7
Yields (in percentage) of Compounds 19-22 using Methylhydrazine and Phenylhydrazine as Nucleophiles.
Entry
Substrates
18 + CH -NH-NH
Solvent
Main Products
Side Products
78
79
80
81
82
83
84
85
86
87
Benzene
19a (42)
19a (33)
19a (94)
20a (25), 19a (23)
19a (39)
20b (63)
20b (53)
21 (47), 20b (42)
20b (39)
20b (25)
-
-
-
3
2
2
2
2
2
18 + CH -NH-NH
CH Cl
3
2
2
18 + CH -NH-NH
THF
MeOH
DMF
3
18 + CH -NH-NH
22 (10), 21 (3)
3
18 + CH -NH-NH
-
3
18 + Ph-NH-NH
18 + Ph-NH-NH
18 + Ph-NH-NH
18 + Ph-NH-NH
18 + Ph-NH-NH
Benzene
19b (12)
21 (9)
19b (6)
21 (11), 19b (4), 22 (6)
19b (12)
2
2
2
2
2
CH Cl
2
2
THF
MeOH
DMF

Study of the Reactivity of α-Acylenaminoketones. Synthesis of Pyrazoles
117
Jan-Feb 2001
phenylhydrazine the (E)-isomers were preferentially
adopted due to steric hindrance. The same solvents
favoured the (Z)-isomers of possible intermediates 9a-q
when methylhydrazine was used as nucleophile. In spite of
their simplicity, only some of the pyrazoles formed in this
study have been previously reported. Homonuclear NOE-
difference experiments have proven to be a versatile tool
for the unambiguous identification and thus for the
differentiation between regioisomers for a variety of
1-substituted pyrazoles.
3-Acetyl-1,1-diphenyl-4-(methylamino)-3-penten-2-one (1).
The product was eluted with hexane/CH Cl (40:60) and
2
2
recrystallized from methylene chloride/hexane to yield 0.9 g,
68% of 1; mp 122-124 °C; ir(potassium bromide): ν C=O 1653,
-1 1
1595 and (C=C) 1580 cm ; H nmr (deuteriochloroform): δ 1.85
[s, 3H, (C=C)CH ], 2.03 [s, 3H ,(C=O)CH ], 2.92 (d, 3H, J=4.0
3
3
Hz, N-CH ), 5.40 (s, 1H, CH), 7.23 (m, 10H, 2xPh), 12.40 (1H, l,
3
+
NH); ms m/z (relative intensity): 307(1) (M ), 167 (7)
+
+
+
[CH(Ph) ], 165 (7) (C H ), 140 (100) [M - CH(Ph) ], 98
2
+
13
9
2
(55) [M - CH(Ph) – CH CO].
2
2
3-Acetyl-1-phenyl-1-methyl-4-(methylamino)-3-penten-2-one (2).
EXPERIMENTAL
The product was eluted with hexane/methylene chloride
(50:50) and recrystallized from methylene chloride/hexane to
yield 0.81 g, 66% of 2; mp 70-4 °C; ir (potassium bromide): ν
Melting points, which are uncorrected, were obtained on a
Reichert apparatus. Infrared spectra, were recorded on Perkin-Elmer
model FTIR spectrometer and values are given in cm . The H nmr
-1
1
C=O 1649, 1581 and (C=C) 1568 cm ; H nmr (carbon
tetrachloride): δ 1.55 (d, 3H, J = 8.0 Hz, CH ), 1.70 [s, 3H,
-1
1
3
13
and C nmr spectra were recorded with Bruker model AW-80,
(C=C)CH ], 2.02 [s, 3H, (C=O)CH ], 2.91 (d, 3H, J = 4.0 Hz,
3
3
Bruker AC-300/P or Varian Gemini-300 spectrometer, chemical
shifts are given in ppm (d) with respect to tetramethylsilane and
coupling constants (J) are in Hertz. Ultraviolet spectra were obtained
for 1% solutions in ethanol using a Varian uv/vis spectrometer.
The analyses done using gas chromatography/mass spectro-
metry were recorded with Hewlett Packard model 5988A
coupled with a HP-5890 gas chromatography equipped with a HP
Ultra 1 fused silica column 25m x 0.3mm, temperature program
35-250 °C at 8 °C/min with a 10 minute hold at 250 °C, injector
temperature 250 °C, detector temperature 250 °C and the mass
spectrometer was set to scan 40-650 atomic mass units per
nominal second with an ionizing voltage of 70 eV. Combustion
analyses were obtained on Perkin-Elmer model 2400 equipment.
Mass spectra were recorded on a Varian MAT-311A with an
ionizing voltage of 70 eV. Chromatography was performed using
silica gel, Si 60 (70 - 230 mesh, E. Merck, Darmstadt, Germany).
The amount of each pyrazole was determined by integration of
the areas of the corresponding peaks, which was performed using
HP-Chemstation software and comparison with the areas
corresponding to known amounts of isolated pyrazoles 5-7a-q.
N-CH ), 4.12 (q, 1H, J = 8.0 Hz, CH), 7.32 (m, 5H, Ph), 12.20
3
+
(1H, l, NH); ms m/z (relative intensity): 245 (5) (M ), 230 (2)
+
+
(M - CH ), 140 (100) [M - CH(Ph)(CH )], 98 (50)
3
3
+
[M - CH(Ph)(CH ) – CH CO].
3
2
3-Acetyl-1,1-dimethyl-4-(methylamino)-3-penten-2-one (3).
The product was eluted with hexane/methylene chloride
(70:30) and recrystallized from methylene chloride/hexane to
yield 1.0 g, 61% of 3; mp 67-9 °C; ir (potassium bromide): ν
-1
1
C=O 1652, 1575 and (C=C) 1560 cm ; H rmn (carbon
tetrachloride): δ 1.03 (d, 6H, J = 7.7 Hz, 2xCH ), 1.90 [s, 3H,
3
(C=C)CH ], 2.13 [s, 3H, (C=O)CH ], 2.71 (m, 1H, J = 7.7 Hz,
3
3
CH), 3.00 (d, 3H, J = 4.0 Hz, N-CH ), 12-20 (1H, l, NH); ms m/z
3
+
+
(relative intensity): 183 (13) (M ), 140 (96) [M - CH(CH ) ], 98
3 2
+
(100) [M - CH(CH ) – CH CO].
3 2
2
Preparation of the α-Acylenaminoketones 4 and 18.
The α−acylenaminoketone 4 was prepared by reaction of
4-(t-butylamino)-3-penten-2-one (1.55g, 0.01 mol) with
benzoyl chloride (1.15 mL) using tetrahydrofuran (20 mL) as
solvent. In this reaction was added triethylamine (1.4 mL) and
pyridine (0.79 mL). The mixture was refluxed during two days
and 20 mL of distilled water were added. The organic layer
was washed with saturated solution of sodium bicarbonate,
dried over magnesium sulfate, filtered and the solvent was
evaporated in a rotary evaporator under vacuum. The product
was separated by column chromatography on neutral
aluminum oxide using mixtures of hexane, methylene chloride
and methanol as eluents. Solid product was recrystallized from
methylene chloride/hexane. Transamination reaction occurred
through the reaction of 3-benzoyl-4-(t-butylamino)-3-penten-
2-one (0.3 g, 1.15 mmol) initially obtained with an excess of
methylamine (3 mL) in methylene chloride (3 mL). The
mixture was agitated during two days and 10 mL of distilled
water were added. The organic layer was washed with water,
dried over magnesium sulfate, filtered and the solvent was
evaporated in a rotary evaporator under vacuum. The residual
semisolid was purified on neutral aluminum oxide column
(2.5 x 45 cm) using mixtures of hexane, methylene chloride
and methanol as eluents. Solid product was recrystallized from
methylene chloride/hexane.
General Procedure for Preparations of Enaminoketones 1-3.
Diazoketones reacted with acyclic enaminoketones to form
products of electrophilic attack of the ketocarbene on the α-carbon
of enaminoketone, confirming that the Wolff rearrangement
occurred. The 4-(methylamino)-3-penten-2-one was prepared by
reaction of acetylacetone with methylamine [4]. The 4-(methyl-
amino)-3-penten-2-one was reacted with 1,2-diphenyl-2-
diazoethanone to yield 1, with 2-diazo-1-phenylpropanone to yield
2 and with 3-diazo-2-butanone to yield 3. A solution of 5.0 mmol of
the corresponding diazoketone and 5.0 mmol of 4-(methylamino)-
3-penten-2-one in ethanol-free methylene chloride (25 mL) was left
at a temperature of 30 °C to yield 1 and at temperature 50 °C to
yield 2 and 3, in the absence of light for 7 days and stopped 2 days
after the disappearance of the characteristic absorption of the diazo
-1
bond at 2080 cm in the ir spectrum.
The absence of the Cα H vinylic proton signal in the H nmr
1
spectrum showed that the reaction occurred at the nucleophilic
Cα carbon position. After, evaporation of the solvent, the crude
material was submitted to column chromatography with neutral
aluminum oxide using mixtures of hexane, methylene chloride
and methanol as eluents. The α-acylenaminoketones were recrys-
tallized with methylene chloride/hexane.

118
Vol. 38
G. Negri and C. Kascheres
3-Benzoyl-4-(t-butylamino)-3-penten-2-one.
nucleophiles, ten days using p-nitrophenylhydrazine and one
day using hydrazine hydrate, after which 10 mL of distilled
water were added. The products were extracted with three
portions of 10 mL of methylene chloride and the organic layer
was washed with water, dried over magnesium sulfate, filtered
and the solvent was evaporated in a rotary evaporator under
vacuum. The crude material was submitted to column
chromatography on neutral aluminum oxide using mixtures of
hexane, methylene chloride and methanol as eluents. All the
isolated products were further purified by preparative thin-
layer chromatography (TLC). It was carried out on silica using
methanol/chloroform solution (1:100) as eluent.
The product was eluted with hexane/methylene chloride
(40:60) and recrystallized from methylene chloride/hexane to
yield 1.64 g, 63% of 3-benzoyl-4-(t-butylamino)-3-penten-2-one;
-1
ir (potassium bromide): ν C=O 1641, 1597 and (C=C) 1589 cm ;
1
H nmr (carbon tetrachloride): 1.42 (s, 9H, 3xCH ), 1.73 [s, 3H,
3
(C=C)CH ], 2.03 [s, 3H, (C=O)CH ], 7.32 - 7.95 (m, 5H, Ph),
3
3
+
12.50 (1H, l, NH); ms m/z (relative intensity): 259 (35) (M ), 202
+
+
(100)[M - C(CH ) ], 105 (65) (COPh ).
3 3
Anal. Calcd. for C
H O N: C, 74.23; N, 5.40; H, 8.10.
16 21 2
Found: C, 74.22; N, 5.42; H, 8.06.
3-Benzoyl-4-(methylamino)-3-penten-2-one (4).
4-(1,1-Diphenylacetyl)-1,3,5-trimethylpyrazole (5a).
The product was eluted with hexane/methylene chloride
(20:80) and recrystallized from methylene chloride/hexane to
yield 0.19 g, 79% of 4; mp 86-89 °C; ir (potassium bromide): ν
Utilizing tetrahydrofuran as solvent in the reaction of 1 with
methylhydrazine, the pyrazole 5a was preferentially obtained.
The product eluted with hexane/methylene chloride (40:60) and
was recrystallized from methylene chloride/hexane to give 68.32
mg (69%) of 5a; mp 139-41 °C; ir (potassium bromide): ν C=O
-1
1
C=O 1638, 1590 and (C=C) 1570 cm ; H nmr (carbon
tetrachloride): δ 1.83 [s, 3H, (C=C)CH ], 1.95 [s, 3H,
3
(C=O)CH ], 3.01 (d, 3H, J = 4.8 Hz, NCH ), 7.20 - 7.80 (m, 5H,
3
3
-1 1
1640 cm ; H nmr (carbon tetrachloride): δ 2.30 (s, 3H, CH ),
3
Ph), 12.40 (1H, l, NH); ms m/z (relative intensity): 217 (55)
2.45 (s, 3H, CH ), 3.61 (s, 3H, NCH ), 5.62 (s, 1H, CH), 7.25
3
3
+
+
+
(M ), 216 (50) (M - 1), 188 (50)(M - H - CO), 105 (100)
+
(s, 10H, 2xPh); ms m/z (relative intensity): 304 (1) (M ), 137
(100) [M - CH(Ph) ], 167(12) [ CH(Ph) ].
+
(PhCO ).
+
+
2
2
Anal. Calcd. for C
H O N: C, 71.88; N, 6.45; H, 6.91.
13 15 2
Anal. Calcd. for C
H N O: C, 78.94; N, 9.21; H, 6.57.
20 20 2
Found: C, 71.90; N, 6.41; H, 6.96.
Found: C, 78.90; N, 9.19; H, 6.56.
3-Acetyl-4-(t-butylamino)-3-penten-2-one (18).
4-(1-Phenyl-1-methyl-acetyl)-1,3,5-trimethylpyrazole (5b).
The α−acylenaminoketone 18 was prepared by reaction of
4-(t-butylamino)-3-penten-2-one (0.5 g, 3.22-mmol) with acetic
anhydride (3.59 g, 3.5-mmol) in methylene chloride (20 mL).
The mixture was refluxed during two days and saturated solution
of sodium bicarbonate was slowly added. The organic layer was
washed with water, dried over magnesium sulfate, filtered and
the solvent was evaporated in a rotary evaporator under vacuum.
The residual semisolid was purified on neutral aluminum oxide
column (2.5 x 45 cm) using mixtures of hexane, methylene
chloride and methanol as eluents. Solid product was recrystal-
lized from methylene chloride/hexane. The product was eluted
with hexane/methylene chloride (20:80) and recrystallized from
methylene chloride/hexane to yield 0.48 g, 63% of 18; m.p.
96-99 °C; ir (potassium bromide): ν C=O 1663, 1599 and (C=C)
Utilizing methylene chloride as solvent in the reaction of 2
with methylhydrazine, the pyrazole 5b was preferentially
obtained. The product eluted with hexane/methylene chloride
(30:70) and formed a colorless oil to give 54.32 mg (55%) of 5b;
-1 1
ir (neat): ν C=O 1654 cm ; H nmr (carbon tetrachloride): δ 1.45
(d, 3H, J = 8.0 Hz, CH ), 2.30 (s, 3H, CH ), 2.45 (s, 3H, CH ),
3
3
3
3.64 (s, 3H, NCH ), 4.21 (q, 1H, J = 8.0 Hz, CH), 7.20 (s, 5H,
3
+
Ph); ms m/z (relative intensity) 242 (1) (M ), 137 (100)
+
+
[M - CH(Ph)(CH )], 105 (2) [CH(Ph)(CH ) ].
3
3
Anal. Calcd. for C H N O: C, 74.38; H, 7.44; N, 11.57.
15 18
2
Found: C, 74.40; H, 7.48; N, 11.55.
4-Acetyl-5-(1-phenylethyl)-1,3-dimethylpyrazole (7b).
Utilizing N,N-dimethylformamide as solvent in the reaction of
2 with methylhydrazine, the pyrazole 7b was preferentially
obtained. The product eluted with hexane/methylene chloride
(50:50) and formed a colorless oil to give 49.38 mg (50%) of 7b;
-1
1
1581 cm ; H nmr (carbon tetrachloride): δ 1.41 [s, 9H,
C(CH ) ], 2.23 (s, 9H, 3xCH ), 12.60 (1H, l, NH); ms m/z
3 3
3
+
+
(relative intensity): 197 (15) (M ), 140 (25) [M - C(CH ) ], 126
3 3
+
(100) (C O H ).
-1 1
7
2
10
ir (neat): ν C=O 1655 cm ; H nmr (carbon tetrachloride): δ 1.63
Anal. Calcd. For C
H O N: C, 67.0; H, 9.64; N, 7.10.
11 19 2
(d, 3H, J = 8.0 Hz, CH ), 2.52 (s, 6H, 2xCH ), 3.30 (s, 3H,
3
3
Found: C, 66.98; H, 9.62; N, 7.10.
NCH ), 5.55 (q, 1H, J = 8.0 Hz, CH), 7.21-7.45 (m, 5H, Ph): ms
3
+
+
m/z (relative intensity): 242 (31) (M ), 227 (16) (M - CH ), 212
(45)(M - 2xCH ), 151 (100)(M - CH Ph); C nmr (carbon
3
General Procedure for Reactions of Compounds 1-4 with
Hydrazine Reagents using Five Different Solvents.
+
+
13
3
2
tetrachloride): δ 15.8 (CH ), 16.0 (CH ), 31.0 (C-H), 33.0
3
3
The reactions of α-acylenaminoketones 1-4 with methyl-
hydrazine, phenylhydrazine, p-nitrophenylhydrazine and
hydrazine hydrate needed a stoichiometric ratio of 1:4 between
α-acylenaminoketones and the hydrazine reagents.
The α-acylenaminoketones (100 mg) of 1 (0.32-mmol), 2
(0.4-mmol), 3 (0.54-mmol) and 4 (0.46-mmol) were dissolved
in 2 mL of the chosen solvent (benzene, methylene chloride,
tetrahydrofuran, metanol and N,N-dimethylformamide) and to
this solution was added 2.00 mmol of the hydrazine reagent.
The mixture was allowed to react at room temperature, for two
days using methylhydrazine and phenylhydrazine as
[(C=O)CH ], 37.89 (N-CH ), 119.0 (pyrazole C4), [126.0, 127.0,
128.0, 141.8] (benzenic ring), [147.0, 150.0] (pyrazolic ring),
192.8 (C=O).
3
3
Anal. Calcd. for C H N O: C, 74.38; N, 11.57; H, 7.44.
15 18
2
Found: C, 74.35; N, 11.58; H, 7.46.
4-(1,1-Dimethylacetyl)-1,3,5-trimethylpyrazole (5c).
Utilizing methylene chloride as solvent in the reaction of 3
with methylhydrazine, the pyrazole 5c was preferentially
obtained. The product eluted with hexane/methylene chloride
(40:60) and formed a colorless oil to give 52.13 mg (53%) of

Study of the Reactivity of α-Acylenaminoketones. Synthesis of Pyrazoles
119
Jan-Feb 2001
-1
1
5-(1,1-Diphenylmethyl)-3-methyl-1-phenylpyrazole (6e).
5c; ir ν (neat): C=O 1655 cm ; H nmr (carbon tetrachloride):
δ 1.12 (d, 6H, J = 8.0 Hz, 2xCH ), 2.33 (s, 3H, CH ), 2.48
3
3
Utilizing methylene chloride as solvent in the reaction of 1
with phenylhydrazine, the pyrazole 6e was preferentially
obtained. The product eluted with hexane/methylene chloride
(60:40) and was recrystallized from methylene chloride/hexane
(s, 3H, CH ), 3.01 (m, 1H, J = 8.0 Hz, CH), 3.63 (s, 3H,NCH );
ms m/z (relative intensity): 180 (5) (M ), 137 (100)
3
3
+
+
[M - CH(CH ) ].
3 2
Anal. Calcd. for C H N O: C, 66.66; H, 8.88; N, 15.55.
1
10 16
2
to give 38.08 mg (36%) of 6e; mp 130-32 °C; H nmr (carbon
Found: C, 66.64; H, 8.86; N, 15.52.
tetrachloride): δ 2.35 (s, 3H, CH ), 5.45 (s, 1H, CH), 5.80
3
(s, 1H, CH), 7.15 - 7.47 (m, 15H, 3xPh); ms m/z (relative
4-Acetyl-5-(1-methylethyl)-1,3-dimethylpyrazole (7c).
+
+
intensity): 324 (100) (M ), 323 (18) (M - H), 309 (9)
Utilizing N,N-dimethylformamide as solvent in the reaction of
3 with methylhydrazine, the pyrazole 7c was preferentially
obtained. The product eluted with hexane/methylene chloride
(60:40) and formed a colorless oil to give 68.85 mg (70%) of 7c;
+
(M+ - CH ), 165 (18) (C H ).
3
13 9
Anal. Calcd. for C H N : C, 85.18; N, 8.64; H, 6.17. Found:
23 20
2
C, 85.20; N, 8.65; H, 6.15.
-1
1
4-(1-Phenyl-1-methylacetyl)-3,5-dimethyl-1-phenylpyrazole (5f).
ir n(neat): C=O 1654 cm ; H nmr (carbon tetrachloride) δ 1.35
(d, 6H, J = 8.0 Hz, 2xCH ), 2.30 (s, 6H, CH ), 3.61 (m, 1H, J =
3
3
Utilizing tetrahydrofuran as solvent in the reaction of 2 with
phenylhydrazine, the pyrazole 5f was preferentially obtained.
The product eluted with hexane/methylene chloride (40:60) and
formed a colorless oil to give 65.76 mg (53%) of 5f; ir (neat): ν
8.0 Hz, CH), 3.75 (s, 3H, NCH ); ms m/z (relative intensity): 180
3
+
+
13
(27) (M ), 165 (100) (M - CH ); C nmr (deuteriochloroform):
3
δ 16.0 (CH ), 20.0 (2xCH ), 26.0 [(CO)CH ], 31.8 (CH), 38.0
3
3
3
(NCH ), 119.0 (pyrazole C4), 148.0 (pyrazole C5), 152.0
-1
1
3
C=O 1656 cm ; H nmr (carbon tetrachloride): δ 1.45 (d, 3H,
CH ), 2.40 (s, 3H, CH ), 2.45 (s, 3H, CH ), 4.34 (q, 1H, CH),
(pyrazole C3), 195.5 (C=O).
3
3
3
Anal. Calcd. for C H N O: C, 66.66; H, 8.88; N, 15.55.
10 16
2
7.20 (s, 5H, Ph), 7.42 (s, 5H,Ph); ms m/z (relative intensity): 304
Found: C, 66.64; H, 8.84; N, 15.52.
+
+
(1) (M ), 199 (100) [M - CH(Ph)(CH )]. uv - λmáx (ethanol)
3
nm 260, 254, 248 and 226.
4-Acetyl-5-phenyl-1,3-dimethylpyrazole (7d).
Anal. Calcd. for C
H N O: C, 78.94; N, 9.21; H, 6.58.
20 20 2
Utilizing tetrahydrofuran as solvent in the reaction of 4 with
methylhydrazine, the pyrazole 7d was preferentially obtained.
The product eluted with hexane/methylene chloride (20:80) and
formed a yellow oil to give 61.14 mg (62%) to 7d. ir (neat): ν
Found: C, 78.90; N, 9.20; H, 6.55.
5-(1-Phenylethyl)-3-methyl-1-phenylpyrazole (6f).
Utilizing methylene chloride as solvent in the reaction of 2
with phenylhydrazine, the pyrazole 6f was preferentially
obtained. The product eluted with hexane/methylene chloride
(60:40) and formed a colorless oil to give 64.14 mg (52%) of 6f;
-1
1
C=O 1638 cm ; H nmr (deuteriochloroform): δ 1.93 (s, 3H,
CH ), 2.55 [s, 3H, (C=O)CH ], 3.60 (s, 3H, NCH ), 7.31 - 7.62
3
3
3
+
(m, 5H, Ph); ms m/z (relative intensity): 214 (20) (M ), 199 (100)
+
(M - CH ).
1
3
H nmr (carbon tetrachloride): δ 1.57 (d, 3H, J = 8.0 Hz, CH ),
3
Anal. Calcd. for C H N O: C, 72.89; N, 13.08; H, 6.54.
2.33 (s, 3H, CH ), 4.12 (q, 1H, J = 8.0 Hz, CH), 6.28 (s, 1H, CH),
13 14
2
3
Found: C, 72.91; N, 13.08; H, 6.53.
7.05 - 7.55 (m, 10H, Ph); ms m/z (relative intensity): 262 (100)
+
+
+
(M ), 261 (34) (M - H), 247 (63) (M - CH ), 169 (42)
3
4-Benzoyl-1,3,5-trimethylpyrazole (5d).
+
(C N H ). uv λmáx. (ethanol) nm 244 and 209.
11
2 9
Utilizing tetrahydrofuran as solvent in the reaction of 4 with
methylhydrazine, the pyrazole 5d was isolated in 20% yield. The
product was eluted with methylene chloride and formed a yellow
Anal. Calcd. for C
Found: C, 82.42; N, 10.66; H, 6.82.
H N : C, 82.44; N, 10.68; H, 6.87.
18 18 2
4-(1,1-Dimethylacetyl)-3,5-dimethyl-1-phenylpyrazole (5g).
-1 1
oil to give 19.72 mg (20%) of 5d; ir (neat): ν C=O 1658 cm ; H
nmr (deuteriochloroform): δ 2.03 (s, 3H, CH ), 2.31
Utilizing tetrahydrofuran as solvent in the reaction of 3 with
phenylhydrazine, the pyrazole 5g was preferentially obtained.
The product eluted with hexane/methylene chloride (40:60) and
formed a colorless oil to give 66.12 mg (50%) of 5g; iv (neat): ν
3
(s, 3H, CH ), 3.82 (s, 3H, NCH ), 7.24 - 7.80 (m, 5H, Ph); ms
3
3
+
+
m/z (relative intensity): 214 (60) (M ), 213 (100) (M - H), 137
(85) (M - Ph).
+
-1 1
Anal. Calcd. for C H N O: C, 72.89; N, 13.08; H, 6.54.
C=O 1657 cm ; H mnr (carbon tetrachloride): δ 1.18 (d, 6H, J =
13 14
2
Found: C, 72.90; N, 13.1; H, 6.53.
8.0 Hz, 2xCH ), 2.51 (s, 6H, 2xCH ), 3.20 (m, 1H, J = 8.0
3 3
Hz, CH), 7.45 (s, 5H, Ph); ms m/z (relative intensity): 242 (5)
4-(1,1-Diphenyl-acetyl)-3,5-dimethyl-1-phenylpyrazole (5e).
+
+
(M ), 199 (100) [M - CH(CH ) ].
3 2
Anal. Calcd. for C H N O: C, 74.38; N, 11.57; H, 7.44.
Found: C, 74.35; N, 11.55; H, 7.48.
Utilizing N,N-dimethylformamide as solvent in the reaction of
1 with phenylhydrazine, the pyrazole 5e was preferentially
obtained. The product eluted with hexane/methylene chloride
(50:50) and was recrystallized from methylene chloride/hexane
to give 69.93 mg (57%) of 5e; mp 107-10 °C; ir (potassium
15 18
2
5-(1-Methylethyl)-3-methyl-1-phenylpyrazole (6g).
Utilizing methanol as solvent in the reaction of 3 with phenyl-
hydrazine, the pyrazole 6g was preferentially obtained. The
product eluted with hexane/methylene chloride (50:50) and
-1
1
bromide): ν C=O 1655 cm ; H nmr (carbon tetrachloride) δ
2.40 (s, 3H, CH ), 2.55 (s, 3H, CH ), 5.63 (s, 1H, CH), 7.25
3
3
1
(s, 10H, 2xPh), 7.40 (s, 5H, Ph); ms m/z (relative intensity): 366
formed a colorless oil to give 43.79 mg (40%) of 6g; H nmr
+
+
(1) (M ), 199 (100) [M - CH(Ph) ], 167 (19) [CH(Ph) ];
(carbon tetrachloride): δ 1.13 (d, 6H, J = 8.0 Hz, 2xCH ), 2.20
2
2
3
uv - λmáx.(ethanol) nm, 260, 254, 248 and 222.
(s, 3H, CH ), 3.03 (m, 1H, J = 8.0 Hz, CH), 5.95 (s, 1H, CH),
3
+
Anal. Calcd. for C
H N O: C, 81.96; N, 7.65; H, 6.01.
7.43 (s, 5H, Ph); ms m/z (relative intensity): 200 (63) (M ), 199
25 22 2
+
+
Found: C, 82.01; N, 7.68; H, 6.03.
(18) (M - H), 185 (100) (M - CH ).
3

120
Vol. 38
G. Negri and C. Kascheres
Anal. Calcd. for C
H
N : C, 78.00; H, 8.00; N, 14.00.
5-(1-Phenylethyl)-3-methyl-1-p-nitrophenylpyrazole (6j).
13 16
2
Found: C, 78.03; H, 7.98; N, 13.98.
Utilizing methanol as solvent in the reaction of 2 with p-nitro-
phenylhydrazine, the pyrazole 6j was preferentially obtained. The
product eluted with hexane/methylene chloride (30:70) and formed
4-Benzoyl-3,5-dimethyl-1-phenylpyrazole (5h).
Utilizing tetrahydrofuran as solvent in the reaction of 4 with
phenylhydrazine, the pyrazole 5h was preferentially obtained.
The product eluted with hexane/methylene chloride (50:50) and
formed a yellow oil to give 66.12 mg (50%) of 5h; ir (neat): ν
a yellow oil to give 92.88 mg (74%) of 6j; ir (neat): ν NO 1339
2
-1
1
cm ; H nmr (deuteriochloroform): δ 1.63 (d, 3H, J = 8.0
Hz, CH ), 2.33 (s, 3H, CH ), 4.21 (q, 1H, J = 8.0 Hz, CH), 6.24
3
3
(s, 1H, CH), 7.03 - 8.40 (m, 9H, 2xPh); ms m/z (relative intensity):
-1
1
C=O 1661 cm ; H nmr (carbon tetrachloride): δ 1.82 (s, 3H,
CH ), 2.53 (s, 3H, CH ), 7.01 - 7.94 (m, 10H, 2xPh); ms m/z
+
+
+
307 (100) (M ), 292 (68) (M - CH ), 246 (68) (M - CH –NO ).
3
3
2
3
3
Anal. Calcd. for C H N O : C, 70.35; N, 13.68; H, 5.53.
18 17
3 2
+
+
(relative intensity): 276 (70) (M ), 275 (100) (M - H), 199 (48)
Found: C, 70.32; N, 13.65; H, 5.51.
+
(M - Ph).
Anal. Calcd. for C H N O: C, 78.26; N, 10.14; H, 5.79.
3-Methyl-5-(1-methylethyl)-1-p-nitrophenylpyrazole (6l).
18 16
2
Found: C, 78.24; N, 10.12; H, 5.76.
Utilizing methylene chloride as solvent in the reaction of 3
with p-nitrophenylhydrazine, the pyrazole 6l was preferentially
obtained. The product eluted with hexane/methylene chloride
(30:70) and formed yellow crystals to give 80.90 mg (60%) of 6l;
4-Acetyl-3-methyl-1,5-diphenylpyrazole (7h).
Utilizing tetrahydrofuran as solvent in the reaction of 4 with
phenylhydrazine, the pyrazole 7h was isolated with 30%
yield. The product eluted with hexane/methylene chloride
(60:40) and formed a yellow oil to give 38.20 mg (30%) of 7h;
-1
1
mp 86-88 °C; ir (potassium bromide): ν NO 1343 cm ; H nmr
2
(carbon tetrachloride): δ 1.23 (d, 6H, J = 8.0 Hz, 2xCH ), 2.24
3
(s, 3H, CH ), 3.21 (m, 1H, J = 8.0 Hz, CH), 6.03 (s, 1H, CH),
-1
1
3
ir (neat): ν C=O 1640 cm ; H nmr (carbon tetrachloride): δ
2.23 (s, 3H, CH ), 2.40 (s, 3H, CH ), 7.04 - 7.95 (m, 10H,
7.40-8.45 (AA'BB',4H, J = 7.8 Hz, Ph); ms m/z (relative
3
3
+
+
intensity): 245 (100) (M ), 230 (36) (M - CH ), 184 (58)
+
3
2xPh); ms m/z (relative intensity): 276 (44) (M ), 261 (100)
+
(M - CH –NO ), 143 (32) (m/z 184 -CH CN); uv λmáx.
+
3
2
3
(M - CH ).
3
(ethanol) nm 310 and 237.
Anal. Calcd. for C H N O : C, 63.67; N, 17.14; H, 6.12.
Anal. Calcd. for C H N O: C, 78.26; N, 10.14; H, 5.79.
18 16
2
13 15
3 2
Found: C, 78.22; N, 10.12; H, 5.80.
Found: C, 63.64; N, 17.08; H, 6.11.
3-Methyl-1,5-diphenylpyrazole (6h).
4-(2,2-Dimethylacetyl)-3,5-dimethyl-1-p-nitrophenylpyrazole (5l).
Utilizing methylene chloride as solvent in the reaction of 4
with phenylhydrazine, the pyrazole 6h was preferentially
obtained. The product eluted with hexane/methylene chloride
Utilizing N,N-dimethylformamide as solvent in the reaction of
3 with p-nitrophenylhydrazine, the pyrazole 5l was isolated with
19% yield. The product eluted with hexane/methylene chloride
(20:80) and formed orange crystals to give 29.79 mg (19%) of 5l;
(50:50) and formed a yellow oil to give 73.35 mg (68%) of 6h;
1
H nmr (carbon tetrachloride): δ 2.45 (s, 3H, CH ), 6.20
3
mp 160-163 °C; ir (potassium bromide): ν C=O 1648, NO 1341
2
(s, 1H, CH), 7.23 (s, 10H, 2xPh); ms m/z (relative intensity): 234
-1
1
cm ; H nmr (deuteriochloroform): δ 1.21 (d, 6H, J = 8.0 Hz,
2xCH ), 2.50 (s, 3H, CH ), 2.65 (s, 3H, CH ), 3.22 (m, 1H, J =
+
+
(100) (M ), 233 (90) (M - H).
Anal. Calcd. for C N : C, 82.05; H, 5.98; N, 11.96.
H
3
3
3
16 14
2
8.0 Hz, CH), 7.60 - 8.40 (AA’BB’, 4H, J = 7.8 Hz, Ph); ms m/z
Found: C, 82.03; H, 5.97; N, 12.01.
+
+
(relative intensity): 287 (3) (M ), 244 (100) [M - CH(CH ) ],
3 2
4-Benzoyl-3-methyl-1,5-diphenylpyrazole (15h).
+
198 (39) [M - CH(CH ) – NO ].
3 2
2
Anal. Calcd. for C H N O : C, 62.71; N, 14.63; H, 5.92.
Found: C, 62.69; N, 14.60; H, 5.90.
15 17
3 3
Utilizing N,N-dimethylformamide as solvent in the reaction of
4 with phenylhydrazine, the pyrazole 15h was isolated with 39%
yield. The product eluted with hexane/methylene chloride
(40:60) and formed a yellow oil to give 60.79 mg (39%) of 15h;
4-Acetyl-5-(diphenylmethyl)-3-methylpyrazole (7n).
-1 1
Utilizing tetrahydrofuran as solvent in the reaction of 1 with
hydrazine hydrate, the pyrazole 7n was preferentially obtained.
The product eluted with methanol/methylene chloride (1:10) and
formed colorless crystals to give 64.81 mg (69%) of 7n; mp
ir (neat): ν C=O 1661 cm ; H nmr (carbon tetrachloride): δ 2.22
(s, 3H, CH ), 7.03 - 7.89 (m, 15H, 3xPh); ms m/z (relative
3
+
+
intensity): 338 (80) (M ), 337 (100) (M - H), 261 (40)
+
(M - Ph).
-1
240-5 °C; ir(potassium bromide): ν NH 3221, C=O 1655 cm ;
Anal. Calcd. for C
H N O: C, 81.65; H, 5.32; N, 4.14.
23 18 2
1
H nmr (deuteriochloroform): δ 2.34 (s, 3H, CH ), 2.50
Found: C, 81.62; H, 5.32; N, 4.12.
3
(s, 3H, CH ), 6.23 (s, 1H, CH), 7.03 - 7.45 (m, 10H, 2xPh); ms
3
5-Diphenylmethyl-3-methyl-1-p-nitrophenylpyrazole (6i).
+
+
m/z (relative intensity): 290 (68) (M ), 275 (45) (M - CH ), 199
3
+
+
(98) (M - CH Ph), 165 (100) (C H ).
Utilizing methylene chloride as solvent in the reaction of 1
with p-nitrophenylhydrazine, the pyrazole 6i was preferentially
obtained. The product eluted with hexane/methylene chloride
(10:90) and formed a orange oil to give 56.48 mg (47%) of 6i; ir
2
13 9
Anal. Calcd. for C
H N O: C, 78.62; N, 9.65; H, 6.20.
19 18 2
Found: C, 78.69; N, 9.67; H, 6.18.
3,5-Dimethyl-4-(2,2-diphenylacetyl)-pyrazole (5n).
-1
1
(neat): ν NO 1338 cm ; H nmr (deuteriochloroform): δ 2.31
2
Utilizing methanol as solvent in the reaction of 1 with
hydrazine hydrate, the pyrazole 5n was preferentially obtained.
The product eluted with methanol/methylene chloride (3:10) and
formed colorless crystals to give 58.56 mg (62%) of 5n; mp
164-166 °C: iv (potassium bromide): ν NH 3193, C=O 1654
(s, 3H, CH ), 5.43 (s, 1H, CH), 5.84 (s, 1H, CH), 7.03 - 8.41
3
+
(m, 14H, 3xPh); ms m/z (relative intensity): 369 (100) (M ), 292
+
+
(18) (M - Ph), 165 (25) (C H ).
13
9
Anal. Calcd. for C H N O : C, 74.79; H, 5.14; N, 11.38.
23 19
3 2
Found: C, 74.73; H, 5.12; N, 11.35.

Study of the Reactivity of α-Acylenaminoketones. Synthesis of Pyrazoles
121
Jan-Feb 2001
-1
1
formed a colorless oil to give 53.45 mg (58%) of 7q; ir (neat): ν
cm ; H nmr (deuteriochloroform): δ 2.41 (s, 6H, 2xCH ), 5.64
3
-1
1
NH 3167, C=O 1668 cm ; H nmr (deuteriochloroform): δ 2.03
(s, 3H, CH ), 2.25 (s, 3H, CH ), 7.44 (s, 5H, Ph); ms m/z (relative
(s, 1H, CH), 7.25 (s, 10H, 2xPh); ms m/z (relative intensity): 290
(1) (M ), 123 (100) [M - CH(Ph) ].
Anal. Calcd. for C
Found: C, 78.60; N, 9.67; H, 6.22.
+
+
3
3
2
+
+
intensity) 200 (35) (M ), 185 (100) (M - CH ).
H
N O: C, 78.62; N, 9.65; H, 6.20.
3
19 18
2
Anal. Calcd. for C H N O:C, 72.0; H, 6.0; N, 14.0. Found:
12 12 2
C, 72.08; H, 5.95; N, 13.92.
4-Acetyl-5-(1-phenylethyl)-3-methylpyrazole (7o).
4-Benzoyl-3,5-dimethylpyrazole (5q).
Utilizing N,N-dimethylformamide as solvent in the reaction of
2 with hydrazine hydrate, the pyrazole 7o was preferentially
obtained. The product eluted with methanol/methylene chloride
(1:10) and formed colorless crystals to give 60.9 mg (64%) of 7o;
mp 171-175 °C; ir (potassium bromide): ν NH 3170, C=O 1628
Utilizing tetrahydrofuran as solvent in the reaction of 4 with
hydrazine hydrate, the pyrazole 5q was isolated with 17% yield.
The product eluted with methanol/methylene chloride (2:100)
and formed a colorless oil to give 15.66 mg (17%) of 5q; ir
-1
1
-1
1
(neat): ν NH 3359, C=O 1637 cm
; H nmr (deuterio-
cm ; H nmr (deuteriochloroform): δ 1.64 (d, 3H, J = 8.0
chloroform): δ 2.25 (s, 6H, 2xCH ), 7.40 - 7.80 (m, 5H, Ph); ms
Hz, CH ), 2.35 (s, 3H, CH ), 2.55 (s, 3H, CH ), 4.81 (q, 1H, J =
3
3
3
3
+
+
m/z (relative intensity): 200 (60) (M ), 199 (100) (M - H), 123
8.0 Hz, CH), 7.23 (s, 5H, Ph). ms m/z (relative intensity): 228
+
+
+
+
(90) (M - Ph).
(64) (M ), 213 (82) (M - CH ), 169 (50) (C N H ), 137 (100)
3
11 2 9
Anal. Calcd. for C H N O: C, 72.0; H, 6.0; N, 14.0. Found:
+
12 12
2
(M - CH Ph); uv λmáx. (ethanol) nm 248 and 243.
Anal. Calcd. for C H N O: C, 73.68; N, 12.28; H, 7.01.
2
C, 71.98; H, 6.09; N, 13.99.
14 16
2
Found: C, 73.65; N, 12.31; H, 6.69.
N-Methyl-1,1-diphenylacetamide (11i).
3,5-Dimethyl-4-(2-phenyl-2-methylacetyl)-pyrazole (5o).
The compound was obtained in the reaction of 1 with p-nitro-
phenylhydrazine. The product eluted with hexane/methylene
chloride (20:80) and formed colorless crystals, mp 167-168 °C; ir
Utilizing methanol as solvent in the reaction of 2 with
hydrazine hydrate, the pyrazole 5o was preferentially obtained.
The product eluted with methanol/methylene chloride (3:10) and
formed colorless oil to give 42.80 mg (46%) of 5o; ir (neat): ν
-1
1
(potassium bromide): ν NH 3280, C=O 1640 cm ; H nmr
(deuteriochloroform): δ 2.75 (d, 3H, J = 4.0 Hz, NCH ), 4.90
3
-1
1
NH 3190, C=O 1654 cm ; H nmr (deuteriochloroform): δ 1.53
(s, 1H, CH), 6.10 (1H, l, NH), 7.30 (s, 10H, Ph); ms m/z (relative
+
+
(d, 3H, J = 8.0 Hz, CH ), 2.54 (s, 6H, 2xCH ), 4.31 (q, 1H, J =
intensity): 225 (5) (M ), 168 (100) (M - CONCH ).
3
3
3
8.0 Hz, CH), 7.20 - 7.45 (m, 5H, Ph); ms m/z (relative intensity):
N-Methyl-1-phenyl-1-methylacetamide (11b).
+
+
228 (3) (M ), 123 (100) [M - CH(CH )Ph].
3
Anal. Calcd. for C H N O: C, 73.68; N, 12.28; H, 7.01.
Found: C, 73.64; N, 12.26; H, 7.00.
14 16
2
The compound was obtained in the reaction of 2 with methyl-
hydrazine. The product eluted with hexane/methylene chloride
(60:40) and formed a yellow oil; ir (neat): ν NH 3369, C=O 1656
4-Acetyl-5-(1-methylethyl)-3-methylpyrazole (7p).
-1 1
cm ; H nmr (carbon tetrachloride): δ 1.56 (d, 3H, J = 8.0 Hz, CH );
3
Utilizing N,N-dimethylformamide as solvent in the reaction of 3
with hydrazine hydrate, the pyrazole 7p was preferentially obtained.
The product eluted with methanol/methylene chloride (1:10) and
formed a colorless crystals to give 70.72 mg (78%) of 7p; mp 63-65
2.81 (d, 3H, J = 4.8 Hz, NCH ); 3.62 (q, 1H, J = 8.0 Hz, CH);
3
+
7.23-7.60 (m, 5H, Ph); ms m/z (relative intensity): 163 (14) (M ),
106 (100) (M - CONCH ), 105 (77) [CH(CH )Ph ], 91 (90)
+
+
3
3
+
(CH Ph ).
-1
1
2
°C; ir (potassium bromide): ν NH 3187, C=O 1660 cm ; H nmr
(deuteriochloroform): δ 1.36 (d, 6H, J = 8.0 Hz, 2xCH ), 2.40 (s, 3H,
1,1-Dimethyl-4-(methylamino)-3-penten-2-one (10p).
3
CH ), 2.55 (s, 3H, CH ), 3.62 (m, 1H, J = 8.0 Hz, CH); ms m/z
3
3
The compound was obtained in the reaction of 3 with
+
+
(relative intensity): 166 (32) (M ), 151 (100) (M - CH ), 123 (36)
3
hydrazine hydrate. The product eluted with hexane/methylene
+
[M - CH(CH ) ]; uv λmáx. (ethanol) nm 248.
3 2
1
chloride (20:80) and formed a yellow oil; H nmr (carbon
Anal. Calcd. for C H N O: C, 65.06; N, 16.87; H, 8.43.
9
14 2
tetrachloride): δ 1.15 (d, 6H, J = 7.8 Hz, 2xCH ), 1.90
Found: C, 65.02; N, 16.84; H, 8.46.
3
(s, 3H, CH ), 2.95 (d, 3H, J = 4.0 Hz, NCH ); 3.60 (m, 1H, J =
3
3
3,5-Dimethyl-4-(2,2-dimethylacetyl)-pyrazole (5p).
7.8 Hz, CH); 6.05 (s,1H, CH); ms m/z (relative intensity): 141
+
+
(14) (M ), 98 (100) [M - CH(CH ) ].
Utilizing methanol as solvent in the reaction of 3 with
hydrazine hydrate, the pyrazole 5p was isolated with 27% yield.
The product eluted with methanol/methylene chloride (2:10) and
formed a colorless oil to give 24.47 mg (27%) of 5p; ir (neat): ν
3 2
Mass Spectral Data of Compound Obtained in Low Yield.
1-Methyl-1-phenyl-4-(methylamino)-3-penten-2-one(10o).
-1
1
NH 3200, C=O 1654 cm ; H nmr (deuteriochloroform): δ 1.23
(d, 6H, J = 8.0 Hz, 2xCH ), 2.55 (s, 6H, 2xCH ), 3.21 (m, 1H, J =
+
Ms m/z (relative intensity): 203 (7) (M ), 98 (100)
3
3
+
(M - COPh).
+
8.0 Hz, CH); ms m/z (relative intensity): 166 (1) (M ), 123 (100)
[M - CH(CH ) ]; uv λmáx (ethanol) nm 246.
+
3 2
N,N-Dimethyl-1,1-diphenylethanone (16).
Anal. Calcd. for C H N O: C, 65.06; N, 16.87; H, 8.43.
9
14 2
+
Ms m/z (relative intensity): 239 (32) (M ), 167 (72)
Found: C, 65.03; N, 16.86; H, 8.40.
+
+
[ CH(Ph) ], 165 (32), 72 (100) [(CH ) N-C=O ].
2
3 2
4-Acetyl-3-methyl-5-phenylpyrazole (7q).
5-(1,1-Diphenyl-methyl)-1,3-dimethylpyrazole (6a).
Utilizing tetrahydrofuran as solvent in the reaction of 4 with
hydrazine hydrate, the pyrazole 7q was preferentially obtained.
The product eluted with methanol/methylene chloride (1:100) and
+
Ms m/z (relative intensity): 262 (100) (M ), 247 (45)
+
+
+
(M - CH ), 185 (87)(M - Ph), 165 (32) (C H ).
3
13 9

122
Vol. 38
G. Negri and C. Kascheres
3-(1,1-Diphenyl-methyl)-1,5-dimethylpyrazole (13a).
5-(1-Methylethyl)-3-methylpyrazole (6p).
+
+
+
Ms m/z (relative intensity): 262 (73) (M ), 261 (100) (M - H),
Ms m/z (relative intensity): 124 (30) (M ), 109 (100)
+
+
+
247 (36) (M - CH ), 165 (73) (C H ).
(M - CH ).
3
13 9
3
4-Acetyl-5-(1,1-diphenyl-methyl)-1,3-dimethylpyrazole (7a).
4-Benzoyl-3,5-dimethyl-1-p-nitrophenylpyrazole (5m).
+
+
+
Ms m/z (relative intensity): 304 (50) (M ), 289 (18)
Ms m/z (relative intensity): 321 (60) (M ), 320 (100) (M - H).
+
+
+
(M - CH ), 213 (100) (M - CH Ph), 165 (27) (C H ).
3
2
13 9
3-Methyl-5-phenyl-1-p-nitrophenylpyrazole (6m).
5-(1-Phenyl-ethyl)-1,3-dimethylpyrazole (6b).
Ms m/z (relative intensity): 200 (36) (M ), 185 (100)
+
+
Ms m/z (relative intensity): 279 (100) (M ), 278 (50) (M - H),
+
+
232 (30) (M - H – NO ).
2
+
(M - CH ).
3
4-Acetyl-3-methyl-5-phenyl-1-p-nitro-phenylpyrazole (7m).
3-(1-Phenyl-ethyl)-1,5-dimethylpyrazole (13b).
+
+
Ms m/z (relative intensity): 321 (40) (M ), 320 (20) (M - H),
+
Ms m/z (relative intensity): 200 (64) (M ), 185 (100)
+
+
306 (100) (M - CH ), 260 (50) (M - CH – NO ).
3
3
2
+
+
(M - CH ), 144 (27) (m/z= 185 - CH CN), 77 (32) (Ph ).
3
3
4-Benzoyl-1,3-dimethyl-5-phenylpyrazole (15d).
4-Acetyl-3-(1-phenylethyl)-1,5-dimethylpyrazole (14b).
+
+
Ms m/z (relative intensity): 276 (60) (M ), 275 (100) (M - H),
+
Ms m/z (relative intensity): 242 (100) (M ), 227 (55)
+
+
199 (60) (M - Ph), 77 (20) (Ph ).
+
+
+
(M - CH ), 212 (45) (M - 2xCH ), 151 (64) (M - CH Ph), 137
3
3
2
+
(82) (M - COPh).
5-(1-Methyl-ethyl)-1,3-dimethylpyrazole (6c).
Ms m/z (relative intensity): 138 (32) (M ), 123 (100)
4-Benzoyl-3-methyl-5-phenylpyrazole (15q).
+
+
Ms m/z (relative intensity): 262 (64) (M ), 261 (100) (M - H),
+
+
+
185 (50) (M - Ph), 77 (30) (Ph ).
+
(M - CH ).
3
N-Methylbenzamide (11q).
4-Acetyl-3-(1-methylethyl)-1,5-dimethylpyrazole (14c).
The compound 11q was obtained in the reaction of 4 with
+
hydrazine and formed colorless crystals, mp 65-70 °C; ir
Ms m/z (relative intensity): 180 (49) (M ), 165 (100)
-1
1
+
+
(potassium bromide): ν NH 3324, C=O 1633 cm ; H nmr
(M - CH ), 137 (93) [M - CH(CH ) ].
3
3 2
(deuteriochloroform): δ 3.0 (d, 3H, J = 4.8 Hz, CH ), 6.5
3
3-(1-Phenyl-ethyl)-5-methyl-1-phenylpyrazole (13f).
(1H, l, NH), 7.2 -7.8 (m, 5H, Ph); MS m/z (relative intensity): 135
+
+
+
+
+
Ms m/z (relative intensity): 262 (100) (M ), 247 (98)
(27) (M ), 134 (41) (M - H), 105 (86) (COPh ), 77 (100) (Ph ).
+
+
+
(M - CH ), 232 (45) (M - 2xCH ), 118 (45) (CH CNPh ), 77
3
3
3
Reaction of α−Acylenaminoketone 18 with Methylhydrazine and
Phenylhydrazine.
+
(72) (Ph ).
3-(1-Methyl-ethyl)-5-methyl-1-phenylpyrazole (13g).
The reactions of α −acylenaminoketone 18 (25 mg,
0.12-mmol) with methylhydrazine and phenylhydrazine
(0.5 mmol) were carried out in the same five solvents and the
reaction mixtures were submitted to gas chromatography/mass
spectrometry analyses.
+
Ms m/z (relative intensity): 200 (41) (M ), 185 (100)
+
+
(M - CH ), 77 (32) (Ph ).
3
4-Acetyl-5-(1-methyl-ethyl)-3-methyl-1-phenylpyrazole (7g).
+
Ms m/z (relative intensity): 242 (36) (M ), 227 (100)
+
+
(M - CH ), 77 (27) (Ph ).
4-Acetyl-1,3,5-trimethylpyrazole (19a).
3
3-(1-Methylethyl)-5-methyl-1-p-nitrophenylpyrazole (13l).
This product was principally obtained using methylhydrazine
+
as nucleophile. Ms m/z (relative intensity): 152 (27) (M ), 137
Utilizing benzene as solvent in the reaction of 3 with p-nitro-
phenylhydrazine, the pyrazole 13l was formed with 11% of yield.
+
(100) (M - CH ).
3
+
+
Ms m/z (relative intensity): 245 (41) (M ), 230 (100) (M - CH ),
3
1,3,5-Trimethylpyrazole (20a).
+
184 (55) (M - CH - NO ).
3
2
This product was principally obtained using methylhydrazine
and methanol as solvent. Ms m/z (relative intensity): 110 (100)
4-Acetyl-5-(1-methylethyl)-3-methyl-1-p-nitrophenylpyrazole (7l).
+
+
+
(M ), 109 (98) (M - H), 95 (32) (M - CH ).
3
Utilizing N,N-dimethylformamide as solvent in the reaction
of 3 with p-nitrophenylhydrazine, the pyrazole 7l was formed
N-t-Butylacetamide (21).
+
with 20% of yield. Ms m/z (relative intensity): 287 (24) (M ),
+
+
+
286 (18) (M - H), 272 (100) (M - CH ), 226 (36)
MS m/z (relative intensity): 115 (15) (M ), 100 (15)
3
+
+
+
(M - CH - NO ).
(M - CH ), 58 (100) (NH COCH ).
3
2
3
2
2
5-(1,1-Diphenylmethyl)-3-methylpyrazole (6n).
4-(t-Butylamino)-3-penten-2-one (22).
Ms m/z (relative intensity): 155 (23) (M ), 140 (14)
+
+
+
Ms m/z (relative intensity): 248 (82) (M ), 247 (28) (M - H),
+
+
+
165 (100) (C H ).
(M - CH ), 84 (100) (C OH ).
13
9
3
5
8
5-(1-Phenyl-ethyl)-3-methylpyrazole (6o).
4-Acetyl-3,5-dimethyl-1-phenylpyrazole (19b).
+
+
Ms m/z (relative intensity): 186 (68) (M ), 171 (100)
Ms m/z (relative intensity): 214 (37) (M ), 199 (100)
+
+
+
(M - CH ), 77 (45) (Ph ).
(M - CH ).
3
3

Study of the Reactivity of α-Acylenaminoketones. Synthesis of Pyrazoles
123
Jan-Feb 2001
[14] T. T. Shawe, L. M. Landino, A. A. Ross, A. S. Prokopowicz,
P. M. Robinson and A. Cannon, Tetrahedron Letters, 37, 3823 (1996).
[15] R. Paul, W. A. Hallet, J. W. Hanifin, M. F. Reich, B. D.
Johnson, R. H. Lenhard, J. P. Dusza, S. S. Kerwar, Y. Lin, W. C. Pickett,
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[17] C. M. Moody and D. W. Young, J. Chem. Soc., Perkin Trans
1, 3519 (1997).
3,5-Dimethyl-1-phenylpyrazole (20b).
The compound 20b was principally obtained using phenyl-
hydrazine as nucleophile. Ms m/z (relative intensity): 172 (100)
+
+
(M ), 171 (73) (M - H).
Acetylphenylhydrazine.
The mass spectrum of acetylphenylhydrazine displayed
+
molecular ion at m/z=150 (32%) (C ON H ) and fragments
8
2 10
+
at m/z=108 (100%) [M - (CH =C=O)] and at m/z=77 (32%)
2
[18] R. Dalpozzo, A. Nino, E. Iantorno, G. Bartoli, M. Bosco and
L. Sambri, Tetrahedron, 53, 2585 (1997).
+
(Ph ).
[19] R. Dalpozzo, A. Nino, E. Iantorno, G. Bartoli, M. Bosco and
L. Sambri, J. Org. Chem., 63, 3745 (1998).
Acknowledgements.
The authors thanks CNPq (Conselho Nacional de
Desenvolvimento Científico e Tecnológico) and FAPESP
(Fundação de Amparo à Pesquisa do Estado de São Paulo) for
financial support.
[20] J-C. Zhuo, Magn. Reson. Chem., 34, 595 (1996).
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Chem., 35, 489 (1998).
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Tetrahedron, 53, 17735 (1997).
[23] K. Makino, H. S. Kin and Y. Kurasawa, J. Heterocyclic.
Chem. 36, 321 (1999)
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[a] Present address: Universidade Bandeirante de São Paulo. Rua
Maria Cândida, 1813, Vila Guilherme CEP - 02071-013. São Paulo - SP,
Brazil. E-mail: negrijun@zaz.com.br FAX: (011)-4533-4696
[b] Present address: Universidade Paulista UNIP. Avenida
Independência, 412. CEP –18087-050. Sorocaba, São Paulo, Brazil.
E-mail: conniek@iqm.unicamp.br
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