Phenyl and pyridyl Bis-Pyrazoles: Synthesis from the Bis(p-diketone) precursors and characterization by analytical and spectroscopic methods

Article abstract of DOI:10.2174/157017810790796273

The bis(β.-diketone) compounds, 3,3'-(pyridine-2,6-diyl)bis(1- phenylpropane-1,3-dione) monohydrated (1a-H₂O) and 3,3'-(pyridine-2,6-diyl)bis(1-(pyridin-2-yl)propane-1,3-dione) monohydrated (1b-H₂O) were prepared by Claisen condensation of the appropriate ketone and dimethyl pyridine-2,6-dicarboxylate ester. Compounds 2,6-bis(5- phenyl-17Y-pyrazol-3-yl)pyridine dihydrated (2a-2H₂O) and 2,6-bis(5-(pyridin-2-yl)-17Y-pyrazol-3-yl)pyridine monohydrated (2b-H ₂O) were synthesized by reaction of the appropriate bis(β.-diketone) compounds and hydrazine monohydrate.

Full text of DOI:10.2174/157017810790796273

1
78
Letters in Organic Chemistry, 2010, 7, 178-181
Phenyl and Pyridyl Bis-Pyrazoles: Synthesis from the Bis(ꢀ-diketone)
Precursors and Characterization by Analytical and Spectroscopic Methods
Josefina Pons*, Arafa Chadghan, Jordi García-Antón and Josep Ros
Departament de Química, Unitat de Química Inorgànica, Universitat Autònoma de Barcelona, Bellaterra, Barcelona,
Spain
Received August 06, 2009: Revised November 06, 2009: Accepted December 02, 2009
Abstract: The bis(ꢀ-diketone) compounds, 3,3'-(pyridine-2,6-diyl)bis(1-phenylpropane-1,3-dione) monohydrated
(
1a·H
Claisen condensation of the appropriate ketone and dimethyl pyridine-2,6-dicarboxylate ester. Compounds 2,6-bis(5-
phenyl-1H-pyrazol-3-yl)pyridine dihydrated (2a·2H O) and 2,6-bis(5-(pyridin-2-yl)-1H-pyrazol-3-yl)pyridine
O) were synthesized by reaction of the appropriate bis(ꢀ-diketone) compounds and hydrazine
2 2
O) and 3,3'-(pyridine-2,6-diyl)bis(1-(pyridin-2-yl)propane-1,3-dione) monohydrated (1b·H O) were prepared by
2
monohydrated (2b·H
2
monohydrate.
Keywords: Nitrogen heterocycles, bis-pyrazole, bis(ꢀ-diketone), NMR spectroscopy.
INTRODUCTION
the appropriate ketones and esters. In particular, 1a·H O was
2
prepared by reaction of methylphenylketone and dimethyl
pyridine-2,6-dicarboxylate in toluene at room temperature
during 12 h, and 1b·H O was prepared by reaction of
2
methyl-(2-pyridyl)ketone and dimethyl pyridine-2,6-
dicarboxylate in toluene at room temperature during 12 h.
Nucleophilic attack of two equivalents of hydrazine
monohydrate on the required bis(ꢀ-diketone) precursor
In recent years, considerable attention has been paid to
pyrazoles, pyrimidines and related N-containing heterocyclic
derivatives. The chemistry of the pyrazole and its derivatives
is well established [1]. A multitude of synthetic routes have
been worked out during the last few decades, as some
members of the pyrazole family play an economically
important role in pharmacy [2] and agrochemistry [3]. They
are also of particular interest to the chemical community
because they exhibit pesticide properties [4].
(
2 2
1a·H O and1b·H O) in toluene and under reflux for 18 h,
led to formation of the desired bis-pyrazoles. These products
are 2,6-bis(5-phenyl-1H-pyrazol-3-yl)pyridine dihydrated
Recently, our group has developed general synthesis and
characterisation of 3,5-substituted pyrazole [5], and 1,3,5-
substituted pyrazole derived ligands [6], which have in the 3
and 5 positions methyl, phenyl, pyridyl and trifluoromethyl
groups and in the N1 position ethyl, octyl and alkylamino
groups. These compounds are obtained by treatment of
hydrazine with 1,3-diketone compounds. The preparation of
pyrazole derivatives is well documented for simple ꢀ-
diketone precursors [7], but there are only limited reports of
bis(ꢀ-diketones) being employed as precursors for bis-
pyrazole derivatives [8].
(
2a·2H
yl)pyridine monohydrated (2b·H
4 %, respectively (Scheme 1).
2
O)
and
2,6-bis(5-(pyridin-2-yl)-1H-pyrazol-3-
2
O), with yields of 74 and
4
In DMSO-d solution, the bis-ꢀ(diketone) compounds
(1a·H O and 1b·H O) described here are in equilibrium with
the corresponding ketoenols [9]. These last species are the
dominant ones, in an approximate ratio of 60%
ketoenol:40% ꢀ-diketone. The ratio of the forms has been
6
2
2
1
calculated through H NMR experiments, especially from the
integration of the signals HOC=CH-C(O) and (O)C-CH2-
C(O).
In this paper, we research the synthesis and charac-
terization of two new bis(ꢀ-diketone) and, by reaction with
hydrazine, two new bis-pyrazole compounds (Scheme 1).
The reaction of 3,3'-(pyridine-2,6-diyl)bis(1-phenylpropane-
Both bis(ꢀ-diketone) (1a·H
pyrazole (2a·2H and 2b·H
characterized by melting point, elemental analyses, mass
2
O and 1b·H
2
O) and both bis-
2
O
2
O) compounds were
1
13
1
1
,3-dione) monohydrated (1a·H
diyl)bis(1-(pyridin-2-yl)propane-1,3-dione) monohydrated
1b·H O) with hydrazine hydrate are investigated.
2
O) or 3,3'-(pyridine-2,6-
spectrometry, IR, H, C{ H} and HSQC spectroscopies.
Elemental analyses confirm the proposed stoichiometry.
Molecular weight of 1a·H
(
2
2 2 2 2
O, 1b·H O, 2a·2H O, and 2b·H O
were confirmed by mass spectrometry studies. For 1a·H
2
O,
+
+
RESULTS AND DISCUSSION
the peaks at 371 and 105 correspond to [1a] and [phCO] ,
respectively, and for 1b·H O, the peaks at 374, 226, 148 and
2
2 2
The bis(ꢀ-diketone) compounds 1a·H O and 1b·H O
have been synthesized following a Claisen condensation of
+
+
7
CH
2
8 correspond to [1b+H] , [py-CO-CH
2
-CO-py] , [py-CO-
-CO] and [C N] , respectively. For the compounds
2
O and 2b·H O, peaks at 363 and 365 have been
+
+
2
5 4
H
a·2H
2
*
Address correspondence to this author at the Departament de Química,
+
+
observed, and they correspond to [2a] and [2b] ,
Universitat Autònoma de Barcelona, 08193-Bellaterra-Cerdanyola,
Barcelona, Spain; Tel: 34-935812895; Fax: 34-935813101;
E-mail: Josefina.Pons@uab.cat
respectively.
1
570-1786/10 $55.00+.00
© 2010 Bentham Science Publishers Ltd.

Synthesis of Dipyrazoles from Bis(ꢀ-diketones)
Letters in Organic Chemistry, 2010, Vol. 7, No. 2
179
2
HO
OH
R
N
R = CH, N
O
O
O
dry toluene
2 MeOH
H SO
4
2
CH CH ONa
2
3
2
2
CH Na
MeO
OMe
2
R
N
O
O
O
R = CH, N
dry toluene
R
N
R
O
O
O
O
R = CH (1a)
R = N (1b)
dry toluene
2
H NNH ·H O
2
2
2
R
N
R
R = CH (2a)
R = N (2b)
N
N
N
N
H
H
Scheme 1. Formation of bis(ꢂ-diketone) (1a, 1b) and bis-pyrazole (2a, 2b) compounds.
-
1
The IR spectra in the range 4000-400 cm , for 1a·H
and 1b·H O, show bands attributable to ꢀ(C=O), ꢀ(C=C),
and ꢁ(C-H)oop. Moreover, for 1b·H O we can observe the
band ꢀ(C=N). The IR spectra of 2a·2H O, and 2b·H O show
the bands ꢀ(C=C), ꢀ(C=N), and ꢁ(C-H)oop [10].
2
O
(1b·H
2
O), attributable to
Cph and
C
py
.
The signals
2
corresponding to HOC=CH-C(O) and (O)C-CH
observed, in each case, at 93.4 and 48.5 ppm (1a·H
94.4 and 48.3 ppm (1b·H O),
2
-C(O) are
2
2
O) and
2
2
2
1
2
2
For compounds 2a·2H O and 2b·H O, H NMR spectra
1
13
1
The H, C{ H} and HMQC spectra for 1a·H
b·H O, 2a·2H O, and 2b·H O were recorded in DMSO-d
10]. HSQC spectra were used to assign signals of most of
2
O,
6
display one broad band at 11.0 and 11.7 ppm, respectively,
attributable to Npz-H. The signals corresponding to Hph and
1
[
2
2
2
H
py are observed, in each case, at 8.10-7.70 ppm (2a·2H
and 8.64-7.55 ppm (2b·H O). Finally, at 7.18 ppm (2a·2H
and 7.36 ppm (2b·H
2
O)
O)
the hydrogen and carbon atoms.
2
2
1
2
O) appears a singlet attributable to
CHpz. The C{ H} NMR spectra display signals between
66.0-118.0 ppm (2a·2H O) and 149.5-123.3 ppm (2b·H O),
attributable to Cph and Cpy. At 101.2 ppm (2a·2H O) and
02.6 ppm (2b·H O), the signal corresponding to CHpz is
For 1a·H
2
O and 1b·H
2
O, H NMR spectra display signals
13
1
between 8.36-7.40 ppm (1a·H
1b·H O), attributable to
corresponding to HOC=CH-C(O) and (O)C-CH
observed in each case at 7.22 and 5.01 ppm (1a·H
.45 and 4.92 ppm (1b·H O). The proportion of the keto/enol
tautomers is 45/55 and 35/65, for 1a·H O and 1b·H O,
respectively. These values have been calculated from the H
2
O) and 9.00-7.80 ppm
py. The signals
-C(O) are
O) and
1
2
2
(
2
H
ph and
H
2
2
1
2
2
observed.
7
2
2
2
1
CONCLUSION
1
3
1
NMR spectra. The C{ H} NMR spectra display signals
between 190.0-120.0 ppm (1a·H O) and 185.0-121.0 ppm
In summary, we have presented the synthesis and
characterization of two new bis(ꢂ-diketones) (1a and 1b),
2

1
80 Letters in Organic Chemistry, 2010, Vol. 7, No. 2
Pons et al.
and the corresponding bis-pyrazoles (2a and 2b). The bis-
pyrazoles have been obtained, in good yields, by reaction of
the bis(ꢀ-diketone) precursors and hydrazine hydrate.
under vacuum. Dry toluene (25-30 ml), dimethyl pyridine-
2,6-dicarboxylate (20.8 mmol, 4.05 g) and methyl-(2-
pyridyl)ketone (81.8 mmol, 9.90 g) were added, in this order,
always slowly, to the white residuum of sodium ethanolate.
The mixture was stirred until a yellowish precipitate
separated (2h), and then it was gently warmed until the
sodium salt of bis(ꢀ-diketone) was formed (12 h). The salt
was filtered off and dried under vacuum. The resulting solid
was slowly added to a vigorously stirred solution of ethanoic
acid (30 ml), water (30 ml) and ice (100 g), yielding a white
solid, which was filtered and dried under vacuum.
EXPERIMENTAL
General
All reagents were commercial grade materials and were
used without further purification. All solvents (ethanol and
toluene) were previously deoxygenated in a vacuum line and
all reactions were routinely carried out under nitrogen
atmosphere.
-
1
Yield: 58% (4.70 g), mp 155-157º. IR (KBr, cm ) 3056
ꢂ(C-H)ar, 1615 ꢂ(C=O)as, 1566 (ꢂ(C=C), ꢂ(C=N))ar, 1437
The elemental analyses (C, H, N) were carried out by the
staff of the Chemical Analyses Service of the Universitat
Autònoma de Barcelona on a Carlo Erba CHNS EA-1108
instrument. Infrared spectra were run on a Perkin-Elmer FT
(
ꢁ
7
ꢁ(C=C), ꢁ(C=N))ar, 1290 ꢂ(C=O)
s
, 1075 ꢁ(C-H)ip, 971, 746
solution, 250 MHz) ꢁ: 9.00-
Hph), 7.45 (HOC=CH-C(O)), 4.92 ((O)C-
1
(C-H)oop. H NMR (DMSO-d
6
.80 (11H, m, Hpy,
-C(O)) ppm. C{ H} NMR (DMSO-d solution, 63
2 6
13
1
CH
MHz) ꢁ: 185.0-121.0 (Cpy, Cph), 94.4 (HOC=CH-C(O)), 48.3
(O)C-CH -C(O)) ppm. Found: C, 64.20; H, 4.12; N, 10.53;
Calc. for C21 ·H O: C, 64.45; H, 4.38; N, 10.74%.
MS(EI): m/z (%) 374 [(1b+H) , < 1], 226 [py- CO-CH
-
1
spectrophotometer series 2000 cm as KBr pellets in the
-
1
1
range 4000-400 cm under a nitrogen atmosphere. The H,
(
2
1
3
1
C{ H} NMR and HSQC spectra were run on a NMR-FT
Bruker 250 MHz spectrometer in DMSO-d solutions and
H
15
N
3
O
4
2
+
6
2
-CO-
1
13
1
room temperature. H and C{ H} NMR chemical shifts (ꢁ)
were determined relative to internal TMS and are given in
ppm. Electronic impact mass spectra were measured on a
Hewlett-Packard HP-5989A apparatus (GC/MS).
+
+
+
py , 9], 148 [py-CO-CH
,6-Bis(5-phenyl-1H-pyrazol-3-yl)pyridine dihydrated
2a·2H O)
A 100 ml Schlenk flask connected to a Dean-Stark
2 5 4
-CO , 61], 78 [C H N , 100].
2
(
2
3
,3'-(Pyridine-2,6-diyl)bis(1-phenylpropane-1,3-dione)
apparatus was charged with 3,3'-(pyridine-2,6-diyl)bis(1-
phenylpropane-1,3-dione) monohydrated (2.57 mmol, 1.00
g) and hydrazine monohydrated (4.00 mmol, 0.20 g).
Toluene (30-40 ml) was added, and the mixture was then
refluxed for 18 h. After this time, the solution was allowed to
cool to room temperature and then filtered, obtaining the
desired product as a white solid.
monohydrated (1a·H O)
2
Under a nitrogen atmosphere, a 250 ml Schlenk flask was
charged with sodium (60.9 mmol, 1.40 g). Deoxygenated
ethanol (40 ml) was added and the mixture was stirred until
all the sodium was consumed. The ethanol was eliminated
under vacuum. Dry toluene (25-30 ml), dimethyl pyridine-
2
,6-dicarboxylate
(20.8
mmol,
4.05
g)
and
-
1
Yield: 74% (0.59 g), mp 155-157º. IR (KBr, cm ) 3256
ꢂ(N-H), 3064 ꢂ(C-H)ar, 1599, 1563 (ꢂ(C=C), ꢂ(C=N))ar
470, 1453 (ꢁ(C=C), ꢁ(C=N))ar, 1074 ꢁ(C-H)ip, 764, 695
methylphenylketone (80.5 mmol, 9.66 g) were added, in this
order, always slowly, to the white residuum of sodium
ethanolate. The mixture was stirred until a yellowish
precipitate was formed (2h), and then it was gently warmed
until the sodium salt of bis(ꢀ-diketone) was formed (12 h).
The salt was filtered off and dried under vacuum. The
resulting solid was slowly added to a vigorously stirred
solution of ethanoic acid (30 ml), water (30 ml) and ice (100
g), yielding a white solid, which was filtered and dried under
vacuum.
,
1
1
ꢁ(C-H)oop. H NMR (DMSO-d
6
solution, 250 MHz) ꢁ: 11.0
ph), 7.18 (2H, s, CHpz
solution, 63 MHz) ꢁ: 166.0-
18.0 (Cpy, Cph), 101.2 (CHpz) ppm. Found: C, 69.20; H,
.28; N, 17.60; Calc. for C23 ·2H O: C, 69.16; H, 5.30;
(
br, N1pzH), 8.10-7.70 (13H, m, Hpy,
H
)
3
1
ppm. C{ H} NMR (DMSO-d
6
1
5
H
17
N
5
2
+
N, 17.53%. MS(EI): m/z (%) 363 [(2a) , 100].
,6-Bis(5-(pyridin-2-yl)-1H-pyrazol-3-yl)pyridine monohy-
drated (2b·H O)
2
-
1
Yield: 76% (6.16 g), mp 150-152º. IR (KBr, cm ) 3063
2
ꢂ(C-H)ar, 1629 ꢂ(C=O)as, 1566 (ꢂ(C=C), ꢂ(C=N))ar, 1490
A 100 ml Schlenk flask connected to a Dean-Stark
apparatus was charged with 3,3'-(pyridine-2,6-diyl)bis(1-
(
ꢁ
7
ꢁ(C=C), ꢁ(C=N))ar, 1300 ꢂ(C=O)
s
, 1072 ꢁ(C-H)ip, 774, 685
solution, 250 MHz) ꢁ: 8.36-
Hph), 7.22 (HOC=CH-C(O)), 5.01 ((O)C-
3
1
(C-H)oop. H NMR (DMSO-d
6
(
1
pyridin-2-yl)propane-1,3-dione) monohydrated (2.56 mmol,
.00 g) and hydrazine monohydrated (4.00 mmol, 0.20 g).
.40 (13H, m, Hpy,
-C(O)) ppm. C{ H} NMR (DMSO-d solution, 63
2 6
1
1
CH
MHz) ꢁ: 190.0-120.0 (Cpy, Cph), 93.4 (HOC=CH-C(O)), 48.5
(O)C-CH -C(O)) ppm. Found: C, 71.16; H, 4.75; N, 3.82;
Calc. for C23 ·H O: C, 70.94; H, 4.92; N, 3.60%.
MS(EI): m/z (%) 371 [(1a) , 27], 105 [phCO , 100].
Toluene (30-40 ml) was added, and the mixture was then
refluxed for 18 h. After this time, the solution was allowed to
cool to room temperature and then filtered, obtaining the
desired product as a white solid.
(
2
H
17NO
4
2
+
+
-
1
Yield: 44% (0.34 g), mp 156-158º. IR (KBr, cm ) 3191
ꢂ(N-H), 3060 ꢂ(C-H)ar, 1598, 1567 (ꢂ(C=C), ꢂ(C=N))ar
456, 1378 (ꢁ(C=C), ꢁ(C=N))ar, 1091 ꢁ(C-H)ip, 780, 745
3
,3'-(Pyridine-2,6-diyl)bis(1-(pyridin-2-yl)propane-1,3-di-
,
one) monohydrated (1b·H O)
2
1
1
ꢁ(C-H)oop. H NMR (DMSO-d
6
solution, 250 MHz) ꢁ: 11.7
Under a nitrogen atmosphere, a 250 ml Schlenk flask was
charged with sodium (60.9 mmol, 1.40 g). Deoxygenated
ethanol (40 ml) was added and the mixture was stirred until
all the sodium was consumed. The ethanol was eliminated
(
br, NpzH), 8.64 (2H, d, o-Hpy), 8.50-7.55 (11H, m, Hpy,
Hph),
1
3
1
7
6
.36 (2H, s, CHpz) ppm. C{ H} NMR (DMSO-d
3 MHz) ꢁ: 149.5-123.3 (Cpy, Cph), 102.6 (CHpz) ppm.
·H O:
6
solution,
Found: C, 65.67; H, 4.43; N, 25.42; Calc. for C21
H
15
N
7
2

Synthesis of Dipyrazoles from Bis(ꢀ-diketones)
Letters in Organic Chemistry, 2010, Vol. 7, No. 2
181
+
Polyhedron, 2001, 20, 2531-2536; (c) Chadghan, A.; Pons, J.;
Caubet, A.; Casabó, J.; Ros, J.; Alvarez-Larena, A.; Piniella, J. F.
Cobalt(II) complexes with pyrazole-derived ligands: crystal
structure of {bis[3-phenyl-5-(2-pyridyl)pyrazole]aquachlorocobalt
C, 65.79; H, 4.47; N, 25.57%. MS(EI): m/z (%) 365 [(2b) ,
+
+
5
5 4
1], 222 [py-pz-py , 100], 78 [C H N , 29].
(
II)} chloride monohydrate. Polyhedron, 2000, 19, 855-862; (d)
ACKNOWLEDGEMENT
Pons, J.; López, X.; Benet, E.; Casabó, J.; Teixidor, F.; Sánchez, F.
J. Dinuclear μ-pyrazole nickel(II), cobalt(II), cadmium(II) and
zinc(II) complexes with dinucleating pyrazole-derived ligands.
Polyhedron, 1990, 9, 2839-2845.
(a) Aragay, G.; Pons, J.; García-Antón, J.; Solans, X.; Font-Bardía,
M.; Ros, J. Synthesis, characterization and X-ray crystal structure
This work was supported by the Spanish Ministerio de
Educación y Cultura (CTQ2007-63913 BQU).
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2
-
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Chem., 2008, 693, 3396-3404; (b) Montoya, V.; Pons, J.; García-
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