Some new information on the formation of substituted 4-amino-1-substituted phenyl-1H-pyrazoles from β-enaminones and diazonium tetrafluoroborates

Article abstract of DOI:10.1002/jhet.579

Figure represented. Upon reaction of 2-methyl-, 3-ethoxycarbonyl, and 4-ethoxycarbonylbenzenediazonium tetrafluoroborate with 1-cyclopropyl-3- phenylaminohex-2-en-1-one 3-cyclopropylcarbonyl-1-(substituted phenyl)-5-ethyl-4-phenylamino-1H-pyrazoles are fo

Full text of DOI:10.1002/jhet.579

780
Some New Information on the Formation of Substituted
4-Amino-1-Substituted Phenyl-1H-Pyrazoles from b-Enaminones
and Diazonium Tetrafluoroborates
Vol 48
a
Petr Simunek, * Vladimır Machacek, Marketa Svobodova, and Ales Ruzicka
a
a
b
ˇ
˚
´
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˚ ˇ
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aUniversity of Pardubice, Faculty of Chemical Technology, Institute of Organic Chemistry and
´
Technology, Studentska 573, CZ 532 10 Pardubice, Czech Republic
bUniversity of Pardubice, Faculty of Chemical Technology, Department of General and Inorganic
´
Chemistry, Studentska 573, CZ 532 10 Pardubice, Czech Republic
*E-mail: petr.simunek@upce.cz
Received April 22, 2010
DOI 10.1002/jhet.579
Published online 1 April 2011 in Wiley Online Library (wileyonlinelibrary.com).
Upon reaction of 2-methyl-, 3-ethoxycarbonyl, and 4-ethoxycarbonylbenzenediazonium tetrafluoroborate
with 1-cyclopropyl-3-phenylaminohex-2-en-1-one 3-cyclopropylcarbonyl-1-(substituted phenyl)-5-ethyl-4-
phenylamino-1H-pyrazoles are formed. On the other hand, the reaction of 1-cyclopropyl-3-phenylaminohex-
2-en-1-one and 5-methylaminohept-4-en-3-one with sterically more demanding 2-ethoxycarbonylbenzenedia-
zonium tetrafluoroborate does not give the corresponding pyrazoles but the probable intermediates on the
route to the pyrazoles: 1-cyclopropyl-3-phenyliminohexane-1,2,4-trione 2,4-bis(2-ethoxycarbonylphenylhy-
drazone) and 3-methyliminoheptane-2,4,5-trione 2,4-bis(2-ethoxycarbonylphenylhydrazone), respectively.
All the compounds were identified on the basis of 1H- and 13C-NMR spectra. The structure of 1-cyclo-
propyl-3-phenyliminohexane-1,2,4-trione 2,4-bis(2-ethoxycarbonylphenylhydrazone) was confirmed by
means of 15N-NMR spectra and X-ray. The bis(2-ethoxycarbonylphenylhydrazones) were found to show
atropoisomerism due to a hindered rotation around the bond between the carbons of imino group and the
hydrazono group next to carbonyl. In the case of the crystalline cyclopropyl derivative, the unit cell was
found out to contain two molecules of opposite chirality.
J. Heterocyclic Chem., 48, 780 (2011).
INTRODUCTION
OABAN and NABAN arrangement [5] (Scheme 1).
The reaction procedures are simple, the reactions pro-
ceed under mild conditions and give products often not
easily available by other methods. Drawback of our
methods can be relatively low yields and a necessity of
chromatographic separation of the products. The hetero-
cyclic compounds obtained are, however, polysubsti-
tuted and then give a possibility of further synthetic
transformations.
A number of possibilities of synthetic utility of the
reaction between b-enaminones and substituted diazo-
nium salts is published [1]. Considering that the hydro-
lysis of the enamino group into corresponding carbonyl
compounds during the azo coupling reaction is relatively
easy, we have started to deal with the reaction of ben-
zenediazonium salts with b-enaminones in nonaqueous
media, where the enamino group remains intact during
the course of the reaction. During the last several years,
we have described a number of products of the reactions
from the structural aspects (tautomerism, E/Z isomerism,
dynamic behavior, hydrogen bonding . . .) both in a solu-
tion and in a crystalline state [2]. Besides, we have also
established methods for synthesis of several types of
heterocyclic systems such as pyridazinium salts [3], pyr-
azoles [4], and boron-containing heterocycles with
The mechanism of the pyrazole formation (reaction a
in Scheme 1) is so far not quite clear. In the previous
work [4(b)], the hypothesis was pronounced that the pri-
marily formed product of the attack of diazonium salt at
a-carbon of the enaminone undergoes an oxidative cy-
clization to form the corresponding pyrazole. The inter-
mediate primary product Int was, in the case shown in
Scheme 2, isolated and characterized [4(b)]. After the
C
V
2011 HeteroCorporation

July 2011
Some New Information on the Formation of Substituted 4-Amino-1-Substituted
Phenyl-1H-Pyrazoles from b-Enaminones and Diazonium Tetrafluoroborates
781
Scheme 1
reaction was over, anisole was detected in the reaction
mixture. This indicates the possibility that the second
molecule of the diazonium salt could act as the oxida-
tion agent. An excess of the diazonium salt is important
for achieving the maximal yield of the pyrazole. Upon
using the equimolar ratio of the reactants, the yield of
the pyrazole was lower (63 vs. 26% for molar ratios 2:1
resp. 1:1 in the case of the reaction from Scheme 2) and
unreacted starting enaminone was also isolated from the
reaction mixture.
RESULTS AND DISCUSSION
To obtain additional information about the mechanism
of the pyrazole formation, we have explored a steric
effect of the substituents at diazonium salt on the reac-
tion path.
Upon reaction of the enaminone 1a with 2-ethoxycar-
bonylbenzenediazonium tetrafluoroborate at molar ratio
1:2 under the same conditions as described for the pyraz-
ole formation [4] the compound 2a, identified on the basis
of H- and 13C-NMR spectra, was formed (Scheme 3).
1
A clarification of the way how the pyrazoles are
formed by the above-mentioned reaction can extend the
use of the synthetic method, which is significant, owing
to the importance of the pyrazoles. The work brings
some new facts on this reaction.
From the shape of the multiplets, belong to the meth-
ylene groups, the compound 2a is obvious not to have a
plane of symmetry (diastereotopic methylene groups).
On account of the absence of any stereogenic centre in
Scheme 2
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Scheme 3
the molecule of 2a the chirality must be the expression
of steric factors (probably atropoisomerism) [6(a)]. Due
to an oily consistence of the compound 2a, it was not
possible to confirm the structure by means of X-ray.
An analogous reaction of the enaminone 1b with 2-
ethoxycarbonylbenzenediazonium tetrafluoroborate gave
nificant shortening of CAN separation, when compared
with standard double bond data (CAN 1.32 A) found in
the literature [7]. The supramolecular structure of 2b is
layered with p-p systems of phenyl rings connectivity (the
distance of the planes of two coplanar benzene rings
˚
˚
C10AC15 is 3.473 A, their centroids have distance 3.983
1
the compound 2b. H- and 13C-NMR data were consist-
A) the neighboring entities are interconnected by a non-
˚
ent with the structure depicted in Scheme 4, which is
similar to the compound 2a. Chirality of the compound
2b, as well as in the case of 2a, was manifested by the
presence of diastereotopic methylene groups. 15N-NMR
parameters (Scheme 4) confirmed the tautomeric form
bis(hydrazono)imino [6(b)].
classical hydrogen bonding (CAHꢀꢀꢀO).
A series of proton NMR spectra of the compound 2b
in toluene-d8 at various temperatures was measured
(Fig. 3). The barrier to rotation is relatively high, even
at 100ꢁC the coalescence point was not achieved. That
means that the energy barrier for mutual interconversion
of the atropoisomers is higher than 150 kJ/mol [8].
The products 2a and 2b can be prepared also when
using an equimolar ratios of the reactants but in this
case the reaction mixture is contaminated with unreacted
starting enaminone.
The structure of the compound 2b was confirmed by
means of X-ray diffraction (Fig. 1). In accordance with
1
the character of H-NMR spectrum, witnessing to an axial
chirality of the compound 2b and with the fact that the
compound crystallizes in centric space group P-1 the com-
pound 2b forms racemic crystals having two molecules of
opposite chirality in an unit cell (Fig. 2). The chirality is
apparently caused by a hindered rotation along C7AC8
single bond (atropoisomerism), similarly as in the cases of
binaphthyls. In every molecule, two intramolecular hydro-
gen bonds NAHꢀꢀꢀO having distances O4ꢀꢀꢀH 1.964 a
When 3- or 4-ethoxycarbonyl derivative was used
instead of 2-ethoxycarbonyl derivative, the result of the
reaction was different. Upon reaction of the enaminone
1b with 3- or 4-ethoxycarbonylbenzenediazonium tetra-
fluoroborate, the corresponding 1-aryl-4-phenylamino-
1H-pyrazoles 3a or 3b were isolated as the reaction
products with yields around 60% (Scheme 5).
˚
O1ꢀꢀꢀH 2.023 A, (see Fig. 1) are present. The molecule
consists of two fragments connected with C7AC8 single
bond, each of these fragments can be described by a plane
defined by the part C¼¼NAN (C7N3N1/C9N4N2) where
the interplanar angle is 71.6(2)ꢁ. The double bond charac-
ter was found for N3AC7 1.285(3), O1AC16 1.210(3),
C8AN5 1.276(3), O3AC19 1.221(3), O4AC31 1.217(4),
From this dependence of the structure of the product on
the position of ethoxycarbonyl group, one can assume on
the steric effect on the reaction course. For proving the
hypothesis, a reaction of the enaminone 1b with sterically
less demanding 2-methylbenzenediazonium tetrafluorobo-
rate was performed. This reaction gave the pyrazole 3c
with yield 54% (Scheme 6).
˚
and N4AC9 1.288(3) A connections where there is a sig-
Scheme 4
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Some New Information on the Formation of Substituted 4-Amino-1-Substituted
Phenyl-1H-Pyrazoles from b-Enaminones and Diazonium Tetrafluoroborates
783
Figure 1. ORTEP view of the compound 2b. Thermal ellipsoids are
drawn at 50% probability level.
CONCLUSIONS
Additional information about the scope and limita-
tions of the formation of pyrazoles by reaction of diazo-
nium salts with enaminones has been obtained. From
the observed dependence of the structure of the reaction
products on the position of the substituent at the diazo-
nium salt (group COOEt in the positions ortho, meta, or
para) and volume of the group at ortho position (COOEt
vs. CH3), it can be stated that the steric effect of the
substituent at the diazonium salt plays a certain role in
the formation of pyrazole by reaction of diazonium tet-
rafluoroborate with b-enaminone. Upon increasing the
steric demands of the ortho substituent, the products of
double azo coupling 2a,b were isolated and the pyraz-
ole, in contrast to the reaction of sterically less demand-
ing isomeric diazonium tetrafluoroborates, was not
formed [9]. The mechanism of the formation of pyra-
Figure 3. Temperature-dependent 1H-NMR spectra of the diastereo-
topic CH3ACHaHb arrangement in the compound 2b in toluene-d8.
zoles by means of the above-discussed reaction is still
under examination.
EXPERIMENTAL
General procedures. The melting points were measured on
a hot-stage microscope and were not corrected. The elemental
analyses were carried out on an automatic analyzer FISONS
EA 1108.
NMR measurements. NMR spectra were measured in
CDCl3 using the Bruker AVANCE 500 spectrometer operating
at 500.13 MHz (1H), 125.77 MHz (13C) and 50.69 (15N) and
Bruker AVANCE III 400 operating at 400.13 MHz (1H) and
100.62 MHz (13C). TMS was used as an internal standard for
1H (d ¼ 0.00). The 13C-NMR spectra were measured in a
standard way and by means of the APT pulse sequence. The
direction of the individual signals as well as those of the sol-
vent is depicted by arrows ; or :. The 13C-NMR spectra were
calibrated on the middle signal of the solvent multiplet (d ¼
77.0). The 15N-NMR spectra were calibrated on an external
neat nitromethane placed in a coaxial capillary (d 0.0).
The proton signals were assigned with the help of H,H
COSY pulse sequence.
The assignment of the individual carbon signals was carried
out by means of 2D pulse sequences gs 1HA13C HMQC and
Figure 2. Packing diagram of the compound 2b as viewed down the
crystallographic c axis.
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Scheme 5
multiplicity-edited 1HA13C HSQC allowing to distinguish
between CH2 and CH/CH3 carbons (experiments performed
Material. Dichloromethane was used commercial (Fluka)
stored over molecular sieves in the bottle equipped with Sure/
Seal. Diazonium tetrafluoroborates were prepared by the litera-
ture method [2(c)] and dried in vacuo. Anhydrous sodium ace-
tate was purchased commercially and was used without change.
1-Cyclopropylhexane-1,3-dione and enaminone 1a were pre-
pared according to the described procedures [4(a)].
1-Cyclopropyl-3-phenylaminohex-2-en-1-one (1b). A mix-
ture of 1-cyclopropylhexane-1,3-dione (3.08 g, 0.02 mol), ani-
line (1.86 g, 0.02 mol), and catalytic amount of p-toluenesul-
fonic acid in 20 mL of toluene was refluxed for 4.5 h. The
reaction water was removed azeotropically and the toluene dis-
tilled off was periodically replaced with the fresh one. After
the reaction was over, the solvent was distilled off in vacuo,
and the rest was subjected to a column chromatography (silica
gel/CH2Cl2). Yield 3.43 g (75%). Boiling point 145–150ꢁC/6
kPa, melting point 46–50ꢁC.
1H-NMR (500 MHz, CDCl3) d: 0.82–0.86 (m, 2H, cycloPr),
0.93 (t, 3H, J ¼ 7.4, CH3), 1.05–1.08 (m, 2H, cycloPr), 1.52–
1.59 (m, 2H, CH2), 1.77–1.82 (m, 1H, cycloPr), 2.33–2.36 (m,
2H, CH2), 5.42 (s, 1H, ¼¼CH), 7.14–7.16 (m, 2H, CHortho),
7.22–7.25 (m, 1H, CHpara), 7.36–7.39 (m, 2H, CHmeta), 12.50
(brs, 1H, NH). 13C-NMR (125 MHz, CDCl3) d: 9.2, 13.8,
20.3, 21.4, 33.8, 96.1, 125.0, 125.5, 129.0, 138.7, 163.5, 198.0.
1
with the CH coupling 145 Hz) and gs HA13C HMBC (experi-
ment performed with the long-range CH coupling 10 Hz).
The 15N chemical shifts were measured by indirect detection
using 2D gs 1HA15N HMBC. The gradient ratios were
70:30:50.1. Experiments were performed with the NH one-
bond coupling 90 Hz, and NH long-range coupling 5 Hz. All
the pulse sequences were taken from Bruker software library.
Temperature-dependent NMR spectra of the compound 2b
were measured in toluene-d8.
The concentration was 20 mg 2b/0.6 mL of the solvent. The
field homogeneity was maintained by checking the shimming
quality after every temperature change.
X-ray crystallography. The X-ray data were collected on a
Nonius Kappa CCD diffractometer fitted with MoKa radiation (k
˚
¼ 0.71073 A) at 150(1) K. The absorption correction was per-
formed using a Gaussian procedure [10], the structure was solved
by direct methods (SIR92) [11] and full-matrix least-squares
refinements on F2 were carried out using the program SHELXL97
[12]. (For crystallographic data, see Table 1).
The compound has been assigned the CCDC reference num-
ber 705671. See http://www.rsc.org.suppdata/*** for crystallo-
graphic data in cif or another electronic format.
Scheme 6
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Some New Information on the Formation of Substituted 4-Amino-1-Substituted
Phenyl-1H-Pyrazoles from b-Enaminones and Diazonium Tetrafluoroborates
785
Table 1
Ar1), 120.4 (CH Ar2), 130.7, 131.0 (2 ꢂ CH Ar1 þ Ar2),
134.3, 134.4 (2 ꢂ CH Ar1 þ Ar2), 142.3 (C¼¼NANH), 144.3
(C¼¼NANH), 145.6 (CANHAN¼¼), 146.7 (CANHAN¼¼), 163.2
(C¼¼NACH3), 167.6 (COOEt), 168.3 (COOEt), 198.5 (C¼¼O).
Due to the oily consistency of the compound and to its
lability, it was not possible to prepare the sample in purity suf-
ficient to elemental analysis.
1-Cyclopropyl-3-phenyliminohexane-1,2,4-trione 2,4-bis(2-
ethoxycarbonylphenylhydrazone) 2b. Anhydrous sodium ace-
tate (1.81 g, 22.05 mmol) was added to a solution of the
enaminone 1b (0.84 g, 3.67 mmol) in CH2Cl2 (20 mL) under
stirring followed by 2-ethoxycarbonylbenzenediazonium tetra-
fluoroborate (1.94 g, 7.35 mmol). The mixture was stirred at
laboratory temperature 24 h, then filtered by suction, the filter
cake was washed with dichloromethane, and the filtrate was
evaporated in vacuo. The residue was subjected to a column
chromatography (silica gel/CH2Cl2 changed to EtOAc during
the separation).
Crystal data of the compound 2b.
Formula
Formula weight
C33H35N5O5
581.66
Triclinic
Crystal system
Space group
P-1 (No. 2)
9.2420(6)
10.8120(5)
16.5300(9)
99.128(5)
95.157(6)
106.520(5)
1547.53(16)
2
˚
a (A)
˚
b (A)
˚
c (A)
a (ꢁ)
b (ꢁ)
c (ꢁ)
3
˚
U (A )
Z
Dc (gꢀcmꢃ3
)
1.248
150
Temperature (K)
l(MoKa) (mmꢃ1
F(000)
)
0.086
616
Crystal size (mm)
˚
0.08 ꢂ 0.16 ꢂ 0.35
MoKa 0.71073
1.3, 27.5
ꢃ12:11; ꢃ13:14; ꢃ21:21
23,733
A yellow crystalline compound was obtained. Yield (1.29 g)
60%. Recrystallization from ethanol, mp 158–161ꢁC.
Radiation (A)
min, Hmax (ꢁ)
H
Dataset
1H-NMR (400 MHz, CDCl3) d: 0.87–0.92 (m, 1H, cycloPr),
0.97–1.06 (m, 2H, cycloPr), 1.12–1.17 (m, 1H, cycloPr), 1.35–
1.41 (m, 9H, 3 ꢂ CH3), 2.88 (dq, J ¼ 15.0, 7.5, 1H,
Tot.
Uniq. data
6964
0.094
R(int)
Observed data [I > 2.0 r(I)]
CHaHbACH3), 3.05–3.14 (m, 2H, CHaHbACH3
þ
CH
4258
6964
cycloPr), 4.31–4.39 (m, 4H, 2 ꢂ OCH2), 6.80 (t, J ¼ 7.5, 1H,
Ar1), 6.89 (t, J ¼ 7.6, 1H, Ar2), 6.91–6.93 (m, 2H, NPh,
ortho), 6.99–7.02 (m, 1H, NPh, para), 7.15–7.18 (m, 2H, NPh,
meta), 7.33 (t, J ¼ 7.8, 1H, Ar1), 7.43 (t, J ¼ 7.8, 1H, Ar2),
7.52 (d, J ¼ 8.3, 1H, Ar1), 7.72 (d, J ¼ 8.4, 1H, Ar2), 7.90–
7.92 (m, 2H, Ar1 þ Ar2), 11.52 (br s, 2H, NH). 13C-NMR
(APT, 125 MHz, CDCl3 ;) d: 9.1: (CH3CH2), 10.7;, 10.8; (2
ꢂ CH2, cyclopropyl), 14.20:, 14.23: (2 ꢂ CH3CH2O), 15.3:
(CH, cyclopropyl), 17.4; (CH3CH2), 60.9;, 61.1; (2 ꢂ
CH3CH2O), 111.1;, 112.3; (2 ꢂ CACOOEt), 114.1: (CH,
Ar1), 114.3: (CH, Ar2),119.0: (CH, ortho), 119.04: (CH,
Ar1), 120.1: (CH, Ar2), 124.6: (CH, para), 128.3: (CH,
meta), 130.65:, 130.72: (2 ꢂ CH, Ar1 þ Ar2), 134.2: (CH
Ar2), 134.3: (CH, Ar1), 143.8; (C¼¼NANH), 145.6;, 146.5;
(2 ꢂ CANHAN¼¼), 148.6; (C¼¼NANH), 150.0; (CqAN¼¼),
161.1; (C¼¼NAPh), 167.5;, 168.3; (2 ꢂ COOEt), 197.8;
(C¼¼O).
Nref
Npar
R
388
0.0757
0.1710
1.19
wR2
S
3
˚
Dqmin, Dqmax (e/A )
ꢃ0.33, 0.27
Anal. Calcd. for C15H19NO: C 78.56, H 8.35, N 6.11.
Found: C 78.75, H 8.23, N 6.26.
3-Methyliminoheptane-2,4,5-trione, 2,4-bis(2-ethoxycar-
bonylphenylhydrazone) 2a. Anhydrous sodium acetate (1.85
g, 22.5 mmol) was added to a solution of the enaminone 1a
(0.53 g, 3.75 mmol) in CH2Cl2 (75 mL) under stirring fol-
lowed by 2-ethoxycarbonylbenzenediazonium tetrafluoroborate
(1.98 g, 7.5 mmol). The mixture was stirred under inert at lab-
oratory temperature for 140 min (negative test for the presence
of the diazonium salt by means of 4,5-dihydroxynaphthalene-
2,7-disulfonic acid). The mixture was then filtered by suction,
the filter cake was washed with dichloromethane and the
filtrate was evaporated in vacuo. The residue was subjected to
Anal. Calcd. for C33H35N5O5: C 68.14, H 6.06, N 12.04.
Found: C 68.29, H 6.31, N 12.00.
3-Cyclopropylcarbonyl-1-(3-ethoxycarbonylphenyl)-5-ethyl-
4-phenylamino-1H-pyrazole (3a). The compound was prepared
from 3-ethoxycarbonylbenzenediazonium tetrafluoroborate and
enaminone 1b adopting the same procedure as in the case of
2b. Reaction time 22 h. Chromatography silica gel/n-hexane-
EtOAc 3:1 (v/v) Yield 68%, oil.
1H-NMR (400 MHz, CDCl3) d: 0.87 (t, 3H, J ¼ 7.0, CH3),
0.97–1.00 (m, 2H, cycloPr), 1.17–1.20 (m, 2H, cycloPr), 1.42
(t, 3H, J ¼ 7.0, CH3), 2.65 (q, 2H, J ¼ 7.5, CH2), 3.03–3.08
(m, 1H, cycloPr), 4.43 (q, 2H, J ¼ 7.5, CH2O), 6.82–6.86 (m,
3H), 6.88 (brs, 1H), 7.21–7.24 (m, 2H), 7.62 (t, 1H, J ¼ 8.0),
7.76 (ddd, 1H, J ¼ 1.2, 2.5, 8.0), 8.16 (dt, 1H, J ¼ 1.2, 8.0),
8.26 (t, 1H, J ¼ 1.7). 13C-NMR (APT, 125 MHz, CDCl3 ;) d:
11.6 ;, 11.7 :, 14.3 :, 17.3 :, 18.9 ;, 61.5 ;, 115.7 :, 119.9 :,
125.7 ;, 126.3 :, 129.1 :, 129.5 :, 129.6 :, 131.9 ;, 137.5 ;,
140.0 ;, 143.0 ;, 144.8 ;, 165.4 ;, 198.1 ;.
a
column chromatography (silica gel/CH2Cl2 changed to
CH2Cl2-EtOAc 4:1 v/v during the separation). Obtained 0.97 g
(52%) of a red oil.
1H-NMR (400 MHz, CDCl3) d: 1.24 (t, 3H, J ¼ 7.4,
CH2CH3), 1.30 (t, 3H, J ¼ 7.1, OCH2CH3), 1.36 (t, 3H, J ¼
7.1, OCH2CH3), 2.31 (s, 3H, CH3), 3.10 (dq, 2H, J ¼ 12.5,
7.4, CH2CH3), 3.28 (s, 3H, NCH3), 4.27 (dq, 2H, J ¼ 7.1, 1.4,
OCH2CH3), 4.32 (dq, 2H, J ¼ 7.1, 1.0, OCH2CH3), 6.75
(ddd, 1H, J ¼ 8.2, 7.0, 1.4 Ar1), 6.92 (ddd, 1H, J ¼ 8.2, 7.3,
1.1 Ar2), 7.28–7.33 (m, 1H, Ar1), 7.35–7.37 (m, 1H, Ar1),
7.49–7.53 (m, 1H, Ar2), 7.85–7.88 (m, 2H, Ar1þAr2), 7.91
(dd, 1H, J ¼ 8.0, 1.4, Ar2), 11.14 (s, 1H, NH), 11.26 (s, 1H,
NH). 13C-NMR (100 MHz, CDCl3) d: 8.7 (CH3CH2), 10.0
(CH3),14.15, 14.25 (2 ꢂ CH3CH2O), 30.2 (CH3CH2), 41.4
(NCH3), 60.9, 61.1 (2 ꢂ CH2CH3), 110.8 (CACOOEt), 112.5
(CACOOEt), 113.6 (CH Ar2), 114.1 (CH Ar1), 118.7 (CH
Anal. Calcd. for C24H25N3O3: C 71.44, H 6.25, N 10.41.
Found: C 71.61, H 6.30, N 10.32.
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[2] (a) Machacek, V.; Lycka, A.; Simunek, P.; Weidlich, T.
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3-Cyclopropylcarbonyl-1-(4-ethoxycarbonylphenyl)-5-ethyl-
ˇ
Magn Reson Chem 2000, 39, 293. (b) Lokaj, J.; Kettmann, V.; Simu-
˚
4-phenylamino-1H-pyrazole (3b). The compound was prepared
from 4-ethoxycarbonylbenzenediazonium tetrafluoroborate and
enaminone 1b adopting the same procedure as in the case of
2b. Reaction time 22 h. Chromatography silica gel/n-hexane-
EtOAc 3:1 (v/v) Yield 60%, oil.
1H-NMR (400 MHz, CDCl3) d: 0.88 (t, 3H, J ¼ 7.5, CH3),
0.98–1.03 (m, 2H, cycloPr), 1.17–1.22 (m, 2H, cycloPr), 1.44
(t, 3H, J ¼ 7.0, CH3), 2.68 (q, 2H, J ¼ 7.5, CH2), 3.03–3.10
(m, 1H, cycloPr), 4.43 (q, 2H, J ¼ 7.5, OCH2), 6.80–6.88 (m,
4H), 7.21–7.25 (m, 2H), 7.64–7.66 (m, 2H), 8.20–8.22 (m,
2H). 13C-NMR (APT, 125 MHz, CDCl3 ;) d: 11.6 ;, 11.7:,
14.3 :, 17.3 :, 19.1 ;, 61.4 ;, 115.7 :, 120.0 :, 124.7 :, 126.1
;, 129.1 :, 130.3 ;, 130.7 :, 137.3 ;, 143.1 ;, 143.3 ;, 144.7
;, 165.6 ;, 198.1 ;.
ˇ
nek, P.; Machacek, V. Acta Crystallogr C 2001, 57, 737. (c) Simunek,
´ˇ
˚
ˇ
P.; Lycka, A.; Machacek, V. Eur J Org Chem 2002, 2764. (d) Simu-
ˇ
´ˇ
˚
´ˇ
nek, P.; Bertolasi, V.; Machacek, V. J Mol Struct 2002, 642, 41. (e)
ˇ
Simunek, P.; Bertolasi, V.; Machacek, V.; Lycka, A. Org Biomol
˚
´ˇ
ˇ
ˇ
Chem 2003, 3250. (f) Simunek, P.; Bertolasi, V.; Peskova, M.; Macha-
˚
ˇ
´
´
ˇ
cek, V.; Lycka, A. Org Biomol Chem 2005, 3, 1217. (g) Simunek, P.;
ˇ
ˇ
˚
´ ˇ ´ˇ
Svobodova, M.; Bertolasi, V.; Pretto, L.; Lycka, A.; Machacek, V.
ˇ
New J Chem 2007, 31, 429. (h) Simunek, P.; Luskova, L.; Svobodova,
˚
´
´
ˇ ´ˇ
M.; Bertolasi, V.; Lycka, A.; Machacek, V. Magn Reson Chem 2007,
ˇ
45, 330. (i) Simunek, P.; Machacek, V. Dyes Pigm 2010, 86, 197.
˚
´ˇ
ˇ
[3] (a) Simunek, P.; Peskova, M.; Bertolasi, V.; Lycka, A.;
˚
ˇ
´
ˇ
ˇ
Machacek, V. Eur J Org Chem 2004, 5055. (b) Simunek, P.; Peskova,
´ˇ
˚
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´
´ˇ ˇ
M.; Bertolasi, V.; Machacek, V.; Lycka, A. Tetrahedron 2005, 61,
8130.
[4] (a) Simunek, P.; Svobodova, M.; Bertolasi, V.; Machacek,
ˇ
V. Synthesis 2008, 11, 1761. (b) Simunek, P.; Svobodova, M.; Macha-
Anal. Calcd. for C24H25N3O3: C 71.44, H 6.25, N 10.41.
Found: C 71.61, H 6.54, N 10.33.
˚
´
´ˇ
ˇ
˚
´
´
3-Cyclopropylcarbonyl-5-ethyl-1-(2-methylphenyl)-4-phe-
nylamino-1H-pyrazole (3c). The compound was prepared
from 2-methylbenzenediazonium tetrafluoroborate and enami-
none 1b adopting the same procedure as in the case of 2b.
Reaction time 135 min. Chromatography silica gel/n-hexane-
EtOAc 3:1 (v/v) Yield 54%, oil.
1H-NMR (400 MHz, CDCl3) d: 0.81 (t, 3H, J ¼ 7.5, CH3),
0.94–0.98 (m, 2H, cycloPr), 1.16–1.19 (m, 2H, cycloPr), 2.16
(s, 3H, CH3), 2.41 (q 2H, J ¼ 7.5, CH2), 2.98–3.04 (m, 1H,
cycloPr), 6.78–6.86 (m, 4H, Ar þ NH), 7.19–7.23 (m, 2H,
Ar), 7.34–7.43 (m, 4H, Ar). 13C-NMR (APT, 100 MHz,
CDCl3) d: 11.5 ;, 11.6 :, 17.27 :, 17.29 :, 18.6 ;, 115.7 :,
119.8 :, 124.7 ;, 126.8 :, 127.6 :, 129.0 :, 129.7 :, 131.2 :,
135.9 ;, 138.3 ;, 138.5 ;, 142.7 ;, 145.1 ;, 198.2 ;.
Anal. Calcd. for C22H23N3O: C 76.49, H 6.71, N 12.16.
Found: C 76.32, H 6.97, N 11.92.
ˇ
cek, V. J Heterocycl Chem 2009, 46, 650.
ˇ
[5] (a) Peskova, M.; Simunek, P.; Bertolasi, V.; Machacek, V.;
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´
˚
´ˇ
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Lycka, A. Organometallics 2006, 25, 2025. (b) Svobodova, M.; Barta,
ˇ
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J.; Simunek, P.; Bertolasi, V.; Machacek, V. J Organomet Chem 2009,
694, 63.
[6] (a) Eliel, E. L.; Wilen, S. H. In Stereochemistry of Organic
Compounds; Wiley: New York, 1994; p 1142. (b) Witanowski, M.;
Stefaniak, L.; Webb, G. A. In Annual Reports on NMR Spectroscopy,
Vol. 25; Webb, G. A., Ed.; Academic Press: London, 1993, p 336.
[7] (a) Allen, F. H.; Kennard, O.; Watson, D. G.; Brammer, L.;
Orpen, A. G.; Taylor, R. J Chem Soc Perkin Trans 2 1987, (12), S1.
(b) Orpen, A. G.; Brammer, L.; Allen, F. H.; Kennard, O.; Watson, D.
G.; Taylor, R. J Chem Soc Dalton Trans 1989, (12), S1.
¨
[8] Sandstrom, J. Dynamic NMR Spectroscopy; Academic
Press: London, 1982; Chapter 7, p 93.
[9] (a) Referee suggests that the incapability of the 2-ethoxycar-
bonylbenzenediazonium to oxidize the primarily formed 1-cyclopropyl-
3-phenyliminohexane-1,2-dione 2-(2-ethoxycarbonyl)phenylhydrazone
to 3-cyclopropylcarbonyl-1-(2-ethoxycarbonylphenyl)-5-ethyl-4-phenyl-
aminopyrazole could be, beside the steric effect, caused also by reac-
tion between the diazonium group and 2-ethoxycarbonyl group in the
starting diazonium salt. (b) Friedman, L.; Logullo, F. M. J Am Chem
Soc 1963, 85, 1549. (c) Nishikubo, T.; Takaoka, T. Nippon Kagaku
Kaishi 1975, 2, 327.
Acknowledgments. Authors thank Prof. Valerio Bertolasi (Uni-
`
versita di Ferrara) for his very useful help with some crystallo-
graphic problems. The work was financially supported by
Ministry of Education, Youth, and Sports of the Czech Republic
(project MSM 002 162 7501).
[10] (a) Blessing, R. H. J Appl Crystallogr 1997, 30, 421. (b) Cop-
pens, P. Crystallographic Computing; Munksgaard: Copenhagen, 1970.
[11] Altomare, A.; Cascarone, G.; Giacovazzo, C.; Guagliardi,
A.; Burla, M. C.; Polidori, G.; Camalli, M. J Appl Crystallogr 1994,
27, 435.
REFERENCES AND NOTES
[1] (a) Elassar, A.-Z. A.; Dib, H. H.; Al-Awadi, N. A.; Elnagdi,
M. H. ARKIVOC 2007, ii, 272. (b) Al-Shiekh, M. A.; Medrassi, H.
Y.; Elnagdi, M. H.; Hafez, E. A. J Chem Res 2007, 7, 432.
[12] Sheldrick, G. M. SHELXL-97,
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Structure Refinement, University of Gottingen, 1997.
A
Program for Crystal
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet