Diarylphosphoryl-containing β-diketones: Methods of synthesis and transformation into pyrazoles

Full text of DOI:10.1134/S0012500813020018

ISSN 0012ꢀ5008, Doklady Chemistry, 2013, Vol. 448, Part 2, pp. 35–38. © Pleiades Publishing, Ltd., 2013.
Original Russian Text © A.A. Ambartsumyan, L.A. Sviridova, N.I. Vorozhtsov, E.I. Goryunov, G.V. Bodrin, I.B. Goryunova, A.B. Uryupin, T.T. Vasil’eva, O.V. Chakhovskaya,
K.A. Kochetkov, E.E. Nifant’ev, 2013, published in Doklady Akademii Nauk, 2013, Vol. 448, No. 4, pp. 413–416.
CHEMISTRY
DiarylphosphorylꢀContaining βꢀDiketones:
Methods of Synthesis and Transformation into Pyrazoles
A. A. Ambartsumyana, L. A. Sviridovab, N. I. Vorozhtsovb, E. I. Goryunova, G. V. Bodrina,
I. B. Goryunovaa, A. B. Uryupina, T. T. Vasil’evaa, O. V. Chakhovskayaa, K. A. Kochetkova,
and Corresponding Member of the RAS E. E. Nifant’eva
Received July 23, 2012
DOI: 10.1134/S0012500813020018
Functionalized phosphine oxides containing original potentially biologically active heterocyclic
systems containing diorganylphosphoryl substituents.
oxoalkyl substituents where phosphoryl and carbonyl
groups are separated by the ethylene fragment have
attracted much recent attention. For example, 4ꢀ
However, only one organophosphorus compound
of such a kind has been reported in the literature to
date, namely, 3ꢀ[αꢀ(diphenylphosphoryl)benzyl]penꢀ
taneꢀ2,4ꢀdione (II), which was isolated in minor yield
by the action of dry HCl on the adduct of 3ꢀbenꢀ
zylidenepentaneꢀ2,4ꢀdione (III) with MeOPPh2 [3].
(diorganylphosphoryl)ꢀ4ꢀmethylpentanꢀ2ꢀones
(I)
can be used as fire retardants for poly(vinyl chloride),
the best results having been obtained for diarylphosꢀ
phoryl compounds [1]. Later, phosphorylmonokeꢀ
tones of type I have been demonstrated to be efficient
extractants of lanthanides from acid solutions, better
In this work, by the example of compound II, we
suggest for the first time simple and efficient variants
than such a known bidentate organophosphorus
of preparation of diorganylphosphorylated
βꢀdikeꢀ
extractant as
N,Nꢀdibutylcarbamoylmethylphosphine
tones, using available chlorophosphines as initial
organophosphorus compounds.
oxide Ph2P(O)CH2C(O)N(Buꢀ
n)2 [2].
The introduction of an additional functional group
into the oxoalkyl group of ꢀoxoalkylphosphine oxide
molecule could be one of the most promising variants
to extend the area of practical application of the phosꢀ
phine oxides, in particular, to increase their extraction
capacity. In our opinion, diorganylphosphoryl derivaꢀ
It was found that the modified Conant reaction—
the reaction of chlorodiphenylphosphine (CDPP)
with α,βꢀenones in the presence of acetic acid in benꢀ
zene at ambient temperature—is suitable for the synꢀ
thesis of not only appropriate diphenylphosphorylated
monoketones [4, 5] but also diphenylphosphorylꢀconꢀ
taining diketones when alkylidenediones, for example
benzylidenedione III, are used as initial compounds
(Scheme 1).
γ
tives of
βꢀdiketones are the most interesting from this
point of view.
O
C
O
(C6H5)2PCl + PhCH=C[C(O)CH3]2
P C C
CDPP
III
C
O
O
O
C CH3
*
CH COOH
3
Moreover, bifunctionalized phosphine oxides of
such a kind can behave as intermediates for preparing
CH
(C6H5)2P CH
~20
°C, benzene
C CH3
O
Ph
II
Scheme 1.
a Nesmeyanov Institute of Organoelement Compounds,
Russian Academy of Sciences, ul. Vavilova 28, Moscow,
119991 Russia
b Moscow State University, Moscow, 119991 Russia
This reaction allows the preparation of target comꢀ
pound II in a rather high yield (85.1%); however, its
rate is relatively low. Therefore, we developed another
35

36
AMBARTSUMYAN et al.
twoꢀstep oneꢀpot method for preparing diketone III, starting from the same initial compounds, CDPP and benꢀ
zylidenedione II (Scheme 2).
H O
2
(C6H5)2PCl ~20
[(C6H5)2POH]
°C, THF
IV
O
O
C CH3
*
PhCH=C[C(O)CH ] (III), [TBD]
3 2
CH
(C6H5)2P CH
~20°C, THF
C CH3
O
Ph
II
Scheme 2.
At the first stage of this process, CDPP was treated
with a twofold excess of water in an appropriate
organic solvent, for example THF, to give dipheꢀ
O
O
C CH3
*
+ RNH–NH2
V–VII
CH
(C6H5)2P CH
1
C CH3
O
nylphosphinous acid (IV), which was reacted without
Ph
additional purification with benzylidenedione III in
the presence of 10 mol % of 1,5,7ꢀtriazabicyꢀ
clo[4.4.0]decꢀ5ꢀene (TBD) as a catalyst. According to
31Р{1H} NMR spectra, acid IV under these conditions
II
CH3
R
O
N
N
*
EtOH
(C6H5)2P CH
Ph
2
undergoes regiospecific addition to the C=C bond of
benzylidenedione III to give phosphorylꢀcontaining
diketone II in 86.9% yield. Both stages of the process
are carried out at ambient temperature, and the total
reaction time does not exceed 24 h.
CH3
VIII–X
R = H (
V
), (VIII); isoꢀPr (VI), (IX); Ph (VII), (X)
The suggested alternative methods for the synthesis
Scheme 3.
of diphenylphosphorylated pentanꢀ2,4ꢀdione II
,
Diketone II and unsubstituted hydrazine
react even at ambient temperature. The reactions of
ꢀisopropylhydrazine VI and especially ꢀphenylhyꢀ
drazine VII proceed less vigorously than with unsubꢀ
stituted hydrazine and require refluxing for several
hours to complete.
V readily
especially the oneꢀpot process based on acid IV, are
simple, industrially feasible and, if necessary, can be
readily used for the preparation of other diarylphosꢀ
N
N
phorylꢀcontaining
βꢀdiketones.
βꢀDiketones and some of their derivatives are
The structure of the synthesized diphenylphosphoꢀ
known to react readily with hydrazine and substituted
hydrazines to form pyrazoles [7]. The reaction of
diphenylphosphorylated diketone II with hydrazine
rylated pyrazoles VIII
1H NMR spectra and, in the case of 1ꢀphenyl derivaꢀ
tive
, also by 31P{1H} NMR and mass spectra.
–X was confirmed by the data of
X
hydrate (
VII) in ethanol is also regioselective and yields phosꢀ
phorylꢀcontaining 3,5ꢀdimethylpyrazoles (VIII
respectively) (Scheme 3). This is the first example of
V) and monosubstituted hydrazines (VI and
In the 1H NMR spectrum of Nꢀunsubstituted pyraꢀ
zole derivative VIII, the chemical shifts of methyl
groups at the 3ꢀ and 5ꢀpositions of the pyrazole ring
–X,
the preparation of substituted pyrazoles containing coincide, which results from the prototropic tautomꢀ
erism of 1,2ꢀpyrazoles [8]. Thus, the effect of the
chiral benzyl carbon atom does not appear in the H
diorganylphosphoryl group in the side chain of the
heterocycle.
1
NMR spectrum of this compound as distinct from the
spectrum of initial diketone II, whose methyl groups
are diastereotopic and show different chemical shifts
in H NMR spectra [3]. On the contrary, in the H
NMR spectra of 1ꢀsubstituted pyrazole derivatives IX
1
Acid IV was isolated in almost quantitative yield, its purity
31
1
according to P{ H} NMR spectra was ~97%, which is identiꢀ
cal to that of the commercially available but very expensive
product offered by Aldrich and Acros.
1
1
2
According to the literature data, the addition of diorganylphosꢀ
phosphinic acids, including acid IV, to αꢀbenzylideneketones at
ambient temperature in the absence of catalysts occurs, on the
contrary, at the C=O group of benzylideneketone molecule [6].
and
X, the methyl groups at the 3ꢀ and 5ꢀpositions of
the pyrazole ring have different chemical shifts, the
DOKLADY CHEMISTRY Vol. 448
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2013

DIARYLPHOSPHORYLꢀCONTAINING
β
ꢀDIKETONES
37
largest Δδ is observed for 1ꢀphenylꢀsubstituted comꢀ
pound
Synthesis of 3ꢀ[
α
ꢀ(diphenylphosphoryl)benzyl]penꢀ
X
. The presence of asymmetric center in the taneꢀ2,4ꢀdione (II). (a) Benzylidenedione III (2.16 g,
molecule of pyrazole IX causes the diastereotopy of 11.15 mmol) was added dropwise to a solution of
the methyl groups of the 1ꢀisopropyl moiety, which 2.46 g (11.14 mmol) of CDPP in 10 mL of anhydrous
appear in the 1H NMR spectrum as two doublets. It is
noteworthy that changes in structure on passing from
benzene. Then, a solution of 0.73 g (12.16 mmol) of
glacial acetic acid in 10 mL of anhydrous benzene was
added with magnetic stirring, the reaction mixture was
kept in the dark at ambient temperature for 48 h, and
the resultant precipitate was separated, recrystallized
from ethyl acetate, and dried in a vacuum (~10 mmHg)
diketone II (
δ
= 31.0 ppm [3]) to 1ꢀphenylpyrazole
X (δ = 32.0 ppm) have only slight effect
31P
31P
derivative
on the chemical shift of 31P nuclei in these comꢀ
pounds. The results of mass spectral analysis of comꢀ
for 2 h at 120
phoryl)benzyl]pentaneꢀ2,4ꢀdione (II). Yield 85.1%,
mp 189–190 . Lit.: mp 182–184 [3].
°С to give 3.7 g of 3ꢀ[αꢀ(diphenylphosꢀ
pound
X correspond to those expected for pyrazole
°
С
°С
derivatives.
For C24H23O3P anal. calcd. (%): C, 73.83; H, 5.94;
P, 7 . 9 3 .
According to the data of preliminary testing in the
Frumkin Institute of Physical Chemistry and Electroꢀ
chemistry, Russian Academy of Sciences, dipheꢀ
nylphosphorylated diketone II prepared in this work,
in contrast to corresponding monoketones, can
extract platinum group metals from acid solutions,
and this fact confirms the promise of further synthetic
studies in this direction.
Found (%): C, 73.88; H, 5.69; P, 7.95.
(b) Chlorodiphenylphosphine (1.098 g, 0.00498 mol)
was added dropwise to a solution of 0.2 g (0.0111 mol)
of distilled water in 7 mL of THF, and the mixture was
magnetically stirred for 15 min. The solvent, excess
water, and resultant HCl were removed by keeping the
reaction mixture first in a vacuum of a waterꢀjet pump
As for phosphorylꢀcontaining pyrazoles VIII–X,
the presence of potentially pharmacophoric groups in
these molecules make these original heterocyclic
compounds interesting in the context of their possible
application in medicine.
(~15 mmHg) at 30–35
uum of a rotary vane pump (~1 mmHg) at 50–55
°С for 0.5 h and then in a vacꢀ
°С
for 1 h. The residue was dissolved in 12 mL of THF, a
solution of 0.937 g (0.00498 mol) of benzylidenediꢀ
one III and 68 mg (0.498 mmol) of TBD in 10 mL of
THF were added dropwise to that solution, and the
mixture was magnetically stirred for 2 h at ambient
temperature and allowed to stand overnight. The solꢀ
vent was removed in a vacuum, the residue was disꢀ
solved in 10 mL of chloroform, the resultant solution
was filtered through 3 g of basic Al2O3, the solvent was
removed from the filtrate in a vacuum, the residue was
triturated with hexane, and the resultant crystalline prodꢀ
EXPERIMENTAL
1
The H and 31P{1H} NMR spectra of the comꢀ
pounds were recorded on a Bruker AVꢀ400 spectromꢀ
eter operating at 400.13 MHz for 1H and 161.98 MHz
for 31P{1H}. The solvent was (CD3)2SO or CDCl3
.
Residual proton signals of the deuterated solvent were
used as the internal reference for 1H NMR, and 85%
H3PO4 was used as the external reference for 31Р{1H}
NMR spectra.
uct was washed with distilled water (
dried in air to give 1.69 g of 3ꢀ[ ꢀ(diphenylphosphoꢀ
ryl)benzyl]pentaneꢀ2,4ꢀdione (II). Yield 86.9%, mp
190.5–191.5 (hexane–chloroform).
2 × 10 mL) and
α
Initial benzylidenedione III (Aldrich) was used
without additional purification. Chlorodiphenylphosꢀ
phine (Acros) was purified by vacuum distillation prior
to use.
°С
For C24H23O3P anal. calcd. (%): C, 73.83; H, 5.94;
P, 7 . 9 3 .
Found (%): C, 73.94; H, 5.77; P, 7.91.
Synthesis of 4ꢀ[ ꢀ(diphenylphosphoryl)benzyl]ꢀ
3,5ꢀdimethylpyrazole (VIII). A mixture of 0.1 g
(0.26 mmol) of diketone II, 0.015 mL (0.26 mmol) of
Benzene was dried by distillation over P2O5 prior to
use. Other organic solvents used in the work were puriꢀ
fied by common procedures [9].
α
All manipulations with CDPP were carried out in
an argon atmosphere.
hydrazine hydrate V and 5 mL of ethanol was magnetꢀ
ically stirred for 8 h at ambient temperature. The
resultant precipitate was separated by filtration,
washed with ethanol, and twice with ethyl acetate, and
Mass spectra were obtained on a Finnigan SSQ
7000 mass spectrometer.
Elemental analysis was performed in the Laboraꢀ dried in a vacuum over calcined calcium chloride to
tory of Microanalysis, Nesmeyanov Institute of Orgaꢀ give 0.05 g of 4ꢀ[ ꢀ(diphenylphosphoryl)benzyl]ꢀ3,5ꢀ
noelement Compounds, Russian Academy of Sciꢀ dimethylpyrazole (VIII). Yield 50.5%, mp > 240
ences.
(dec.).
α
°С
DOKLADY CHEMISTRY Vol. 448
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38
AMBARTSUMYAN et al.
31P{1H} NMR ((CD3)2SO
, δ, ppm): 32.0 s.
For C24H23N2OP anal. calcd. (%): C, 74.60; H,
6.00; N, 7.25; P, 8.01.
MS
118, 91, 77.
(
m
/
z
): 462.261 [M]+(100%), 220, 201, 144,
Found (%): C, 74.03; H, 5.84; N, 6.86; P, 8.35.
1H NMR ((CD3)2SO
, δ, ppm, J, Hz): 2.08 (s, 6Н,
3ꢀ + 5ꢀСН3), 3.51 (br s, 1H, NH), 4.70 (d, 1H, CHP,
2JН–Р = 10.7), 7.16–7.80 (m, 15H, С6Н5).
ACKNOWLEDGMENTS
This work was supported by the Russian Academy
of Sciences (basic research programs of the Presidium
of the RAS Pꢀ5 “Fundamental Sciences for Mediꢀ
cine” and Pꢀ8 “Development of Methods for the Synꢀ
thesis of Chemical Compounds and Design of Novel
Materials” and basic research program of the Division
of Chemistry and Materials Science OKhꢀ09 “Biomoꢀ
lecular and Medicinal Chemistry”).
Synthesis of 4ꢀ[αꢀ(diphenylphosphoryl)benzyl]ꢀ1ꢀ
isopropylꢀ3,5ꢀdimethylpyrazole (IX). A mixture of
0.1 g (0.26 mmol) of diketone II, 0.025 mL (0.27 mmol)
of isopropylhydrazine VI and 5 mL of ethanol was
magnetically stirred for 3 h at ambient temperature
and then heated at reflux for 3 h. The solvent was
removed, and the resultant precipitate was recrystalꢀ
lized from benzene to give 0.06 g of 4ꢀ[
nylphosphoryl)benzyl]ꢀ1ꢀisopropylꢀ3,5ꢀdimethylpyraꢀ
zole (IX). Yield 54.5%, mp 186
αꢀ(dipheꢀ
°С.
REFERENCES
For C27H29N2OP anal. calcd. (%): C, 75.68; H,
6.82; N, 6.54; P, 7.23.
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,
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, Hz): 1.32 (d, 3H,
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3
СН(СН3)2, JH–H = 6.4), 1.34 (d, 3H, СН(СН3)2,
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5ꢀ or 3ꢀСН3), 4.18–4.27 (m, 1H, СН(СН3)2), 4.65 (d,
1H, CHP, 2JН–Р = 10.8), 7.08–7.82 (m, 15H, С6Н5).
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3,5ꢀdimethylꢀ1ꢀphenylpyrazole (X). A mixture of 0.1 g
(0.26 mmol) of diketone II, 0.035 g (0.32 mmol) of
phenylhydrazine VII and 5 mL of ethanol was heated
at reflux for 6 h. The solvent was removed, and the resꢀ
idue was recrystallized from benzene to give 0.06 g of
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4ꢀ[
α
ꢀ(diphenylphosphoryl)benzyl]ꢀ3,5ꢀdimethylꢀ1ꢀ
). Yield 50.1%, mp > 240 (dec.).
phenylpyrazole (
X
°С
8. Joule, J.A. and Mills, K., Heterocyclic Chemistry
,
For C30H27N2OP anal. calcd. (%): C, 77.90; H,
5.88; N, 6.06; P, 6.70.
Blackwell, 2000. Translated under the title Khimiya
geterotsiklicheskikh soedinenii, Moscow: Mir, 2004.
Found (%): C, 77.54; H, 5.71; N, 5.68; P, 6.93.
1H NMR ((CD3)2SO
, δ, ppm, J, Hz): 1.61 (s, 3H,
3ꢀ or 5ꢀСН3), 1.97 (s, 3H, 5ꢀ or 3ꢀСН3), 4.76 (d, 1H,
CHP, 2JН–Р = 10.7), 7.06–7.96 (m, 20H, С6Н5).
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Methods of Application, New York: Interscience, 1955.
Translated under the title Organicheskie rastvoriteli,
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DOKLADY CHEMISTRY Vol. 448
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