Synthesis and biological activity of dialkylamino-substituted phosphine oxides

Article abstract of DOI:10.1134/S1070363212100052

A series of dialkylamino-substituted phosphine oxides was synthesized and their physiological activity was studied. Pleiades Publishing, Ltd., 2012.

Full text of DOI:10.1134/S1070363212100052

ISSN 1070-3632, Russian Journal of General Chemistry, 2012, Vol. 82, No. 10, pp. 1659–1664. © Pleiades Publishing, Ltd., 2012.
Original Russian Text © A.N. Yarkevich, L.N. Petrova, S.O. Bachurin, 2012, published in Zhurnal Obshchei Khimii, 2012, Vol. 82, No. 10, pp. 1633–1638.
Synthesis and Biological Activity
of Dialkylamino-Substituted Phosphine Oxides
A. N. Yarkevich, L. N. Petrova, and S. O. Bachurin
Institute of Physiologically Active Compounds, Russian Academy of Sciences,
Severnyi proezd 1, Chernogolovka, 142432 Russia
e-mail: yarkevic@ipac.ac.ru
Received August 9, 2011
Abstract—A series of dialkylamino-substituted phosphine oxides was synthesized and their physiological
activity was studied.
DOI: 10.1134/S1070363212100052
The amino-containing phosphine oxides are of
interest as potential physiologically active substances,
since they contain two types of coordinating centers in
a single molecule with the properties largely dependent
on the nature of the substituents at the heteroatoms.
However, the methods of their synthesis are
insufficiently developed which hampers wide screen-
ing of these compounds. In this connection it is
interesting to synthesize the amino-containing phos-
phine oxides, differing primarily by the substituents at
the phosphorus atom and the length of the hydrocarbon
bridge between the coordinating sites, in order to study
the effect in vitro of these factors on the biological
activity of the compounds, their efficiency and
selectivity toward different receptors.
wide range of compounds I–IV distinguished by the
substituents at the phosphorus and nitrogen atoms, the
distance between the functional groups, and the number
of amino groups in the phosphine oxide molecule.
R1
R3
CH2NR22
Ia_Ii
(CH2)3NBu2
P
P
R1
R3
O
O
IIIa_IIId
Me
P
Ph
Ph
(CH2)nNBu2
CH2NBu2
P
Bu2NCH2
O
O
IIa, IIb
IV
I, R2 = Bu, R1 = Me (а), Ph (b), p-CH3C6H4 (c), p-
CH3OC6H4 (d), p-ClC6H4 (e), m-O2NC6H4 (f); R22 = (CH2)5,
R1 = Ph (g), p-CH3C6H4 (h); R2 = cyclo-C6H11, R1 = p-
CH3C6H4 (i); II, n = 2 (a), 5 (b); III, R3 = Ph (а), p-
CH3C6H4 (b), p-ClC6H4 (c), p-BrC6H4 (d).
In this work for the synthesis of dialkylamino-
substituted phosphine oxides containing P(O)(CH2)nN
fragment we used
a
reaction of nucleophilic
substitution of the halogen atom in the substituted
haloalkylphosphine oxides R2P(O)(CH2)nHlg by the
secondary amines. The choice of the synthesis condi-
tions was performed considering the data on the reac-
tivity of the synthesized and previously studied
halomethylphosphine oxides [1–3].
For the reactions with amines we used both the
most active chloro derivatives and the more reactive
diaryl(bromomethyl)phosphine oxides VIb–VId syn-
thesized specially from the corresponding diaryl(hyd-
roxymethyl)phosphine oxides Vb–Vd and PBr3.
The application of the most reactive haloalkyl
component allows performing the reaction in nonpolar
solvents (benzene, toluene). The transformation of the
resulting HBr (HCl) into an amine hydrohalide in-
soluble in these solvents at the use of the 2–3-fold
excess of a secondary amine also promotes this
reaction. This approach made it possible to obtain a
The diaryl(bromoalkyl) phosphine oxides VIIa–
VIId were prepared by the bromination of the
corresponding alcohols, obtained by the method [4]
starting from the secondary phosphine oxides and 3-
chloropropanol in a two-phase system (method a).
Compound IX was prepared in a one step similar to
1659

1660
YARKEVICH et al.
R1
R1
R1
R1
R1
PBr3
HNBu2
CH2OH
Vb_Vd
CH2Br
CH2NBu2
P
P
P
R1
O
O
O
VIb_VId
Ib_Id
the method [5] starting from the diphenylphosphine
oxide and 1,5-dibromopentane (method b). Com-
pounds VIIa–VIId and IX were transformed into the
corresponding amines IIIa–IIId and IIb.
a
R3
R3
R3
R3
R3
R3
R3
R3
PBr3
Cl(CH2)3OH
HNBu2
H
(CH2)3OH
(CH2)3Br
(CH2)3NBu2
P
P
P
P
O
O
O
O
VIIa_VIId
VIIIa_VIIId
IIIa_IIId
b
Ph
P
Ph
Ph
Ph
HNBu2
Br(CH2)5Br
H
(CH2)5Br
(CH2)5NBu2
P
P
Ph
Ph
O
O
O
IХ
IIb
For the initial evaluation of the biological activity
brian [6]. It is known that the glutamate receptors play
an important role in the central nervous system in the
development of the normal neurophysiologic processes
and in the pathogenesis of several neurodegenerative
diseases [7]. In this regard, the evaluation of the ability
of these compounds to influence the calcium flows
mediated by glutamate receptors allows the estimation
of their overall biological potential as a possible
neuroprotectors (for inhibition) or cognitive functions
stimulants (in the case of the activation).
of the synthesized compounds we investigated their
effect on the glutamate-induced uptake of calcium
ions into synaptosomes of the P2-fraction of the rat
Effect of the structure of phosphine oxides I–IV on a
glutamate-induced 45Са2+ uptake
Amount of 45Са2+
Comp. no.
IC50, μM
% relative to the control
81.7±2.0
18.5±5.4
4.6±4.6
–
53.8
14.5
57.5
8.3
–
Iа
The initial screening revealed some structure–
biological activity regularities for this set of com-
pounds. Almost all studied dialkylamino-sub-stituted
phosphine oxides inhibit 45Ca2+ uptake into the
synaptosomes, which makes it possible to consider this
class of compounds as a perspective object for the study
and creation on its basis of new neuroprotective drugs.
Ib
Ic
19.9±9.4
0.45±0.15
70.6±13.1
72.9±3.3
79.2±3.1
6±3.7
Id
Ie
If
–
Ig
–
Ih
The screening results are presented in the table.
Compounds that have a significant inhibitory effect on
45Ca2+ uptake into the cortical synaptosomes, were
examined in detail to determine their concentration
(IC50), at which inhibition of the a 50% 45Ca2+ ions
takes place.
19.1
–
Ii
71.3±6.5
55.6±1.5
76.2±3.5
63.4±1.6
40.4±13.5
32.8±3.7
0
IIа
IIb
IIIа
IIIb
IIIc
IIId
IV
–
–
–
In the (dibutylamino)methyl-substituted phosphine
oxides Ia–Ie series only two compounds with the least
(Ia) and the most (Ie) sterically hindered
conformations at the phosphorus atom exhibit a low
39.8
61.7
31.6
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SYNTHESIS AND BIOLOGICAL ACTIVITY
1661
activity. The other compounds of this group inhibit
significantly the 45Ca2+ uptake into the synaptosomes.
Depending on the substituents in the phenyl group, this
effect increases as follows: CH3O < H < CH3 < Cl. The
decrease in the size of the amino group in compounds
Ih and Ii owing to the conformationally rigid pipe-
ridine fragment prevents inhibition of 45Ca2+ uptake,
while the replacement of butyl substituents at the
amino group by the cyclohexyl moiety of the roughly
equal size has virtually no effect on the activity of
compounds Ib and Ig.
Before the biological screening, the substances
were additionally purified by the recrystallization or
chromatography on a silica gel column (L 100/160,
eluents chloroform, hexane–isopropanol, 10:1) and
dried in a vacuum.
General procedure for the synthesis of diaryl
(bromomethyl)phosphine oxides (VIb–VId). A mix-
ture of 0.015 mol of diaryl(hydroxymethyl)phosphine
oxide VIb–VId and 0.006 mol of PBr3 in 10 ml of
anhydrous benzene was refluxed for 1–3 h. Then the
reaction mixture was diluted with an equal volume of
chloroform. The organic solution was washed with
water, NaHCO3 saturated solution, water, and dried
over Na2SO4. The solvent was removed in a vacuum,
and the substances were crystallized on standing.
As expected, the distance between the coordinating
sites is the determining factor for the manifestation of
the biological activity. Comparison of compounds Ib,
Ic, Ie and IIIa–IIIc, which differ only in the alkylene
bridge length, shows a marked decrease in the activity
of the compounds of III series. The general character
of the effect of substituents in the phenyl group in this
case is the same as for compounds containing one
methylene group. The effect of inhibiting 45Ca2+
uptake increases depending on the substituents in the
phenyl group as follows: H < CH3 < Cl < Br. The
halogen-substituted compounds IIIc and IIId are the
most active.
Bromomethyl(diphenyl)phosphine oxide (VIb).
Yield 80%, mp 169.5–170.5°С (methylethylketone).
1Н NMR spectrum (CDCl3), δ, ppm: 3.82 d (2Н,
2
СН2Р, JHP 6 Hz), 7.54 m (6Н, Ph), 7.81 m (4Н, Ph).
31Р NMR spectrum (CDCl3): δР 28.41 ppm.
Bromomethyl(di-p-tolyl)phosphine oxide (VIc).
1
Yield 83%, mp 61–63°С (CCl4). Н NMR spectrum
(CDCl3), δ, ppm: 3.79 d (2Н, СН2Р, 2JHP 6 Hz), 7.29 m
31
(4НAr), 7.64 m (4НAr). Р NMR spectrum (CDCl3): δР
28.00 ppm.
Attention is drawn to the fact that among the
amines Ia, IIa, IIIa, and IIb the activity of compounds
IIa and IIIa are first decreases while the substituent
includes 2 and 3 methylene units, and then increases
slightly (n = 5) for IIb as the distance between the
coordinating sites Ph2P(O) and NBu2 sequentially
increases. Bis(dialkylaminomethyl)-substituted phosphine
oxide IV is a more effective inhibitor of the 45Ca2+ ions
uptake.
Bromomethyl(di-p-anisyl)phosphine oxide (VId).
Yield 98%, mp 121–123°С (benzene–hexane). 1Н
NMR spectrum (CDCl3), δ, ppm: 3.75 d (2Н, СН2Р,
2JHP 6 Hz), 3.88 s (6Н, 2СН3О), 7.00 m (4НAr), 7.70 m
(4НAr). 31Р NMR spectrum (CDCl3): δР 27.73 ppm.
Bromomethyl(di-p-chlorophenyl)phosphine oxide
(VIe). Yield 91%, mp 138–140°С (benzene). 1Н NMR
spectrum (acetone-d6), δ, ppm: 4.32 d (2Н, СН2Р),
7.62 m (4НAr), 7.94 m (4НAr). 31Р NMR spectrum
(acetone-d6): δP 24.78 ppm.
Thus, the studied dialkylamino-substituted phos-
phine oxides are a convenient model for the iden-
tification of the main regularities of the influence of
the functional groups on the biological activity. The
new high-active inhibitors of a glutamate-induced
45Ca2+ ions uptake were found in a series of the
multifunctional amine-containing phosphine oxides. It
makes these compounds promising for further study as
alternative neuroprotectors.
3-[Bis(4-chlorophenyl)phosphinoyl]propanol (VIIc).
To a solution of 0.90 g (0.0033 mol) of p-(ClC6H4)2·
P(O)H and 0.31 g (0.0033 mol) of Cl(CH2)3OH in
10 ml of DMSO was added dropwise 50% aqueous
solution of 0.37 g (0.0065 mol) of KOH. The reaction
mixture was stirred for 2 h at 55–60°С. Then the
mixture was cooled, poured into 150 ml of water, and
extracted with chloroform (5×30 ml). The organic
extract was washed with water, dried with Na2SO4, and
concentrated. Yield 83% (0.90 g), mp 167–169°С
EXPERIMENTAL
1
The H and 31P NMR spectra were recorded on a
1
(benzene–acetone). Н NMR spectrum (CDCl3), δ,
Bruker CHR-200 spectrometer (Germany) relative to
internal Me4Si. The melting points were determined on
a Boetius PHMK instrument (Germany).
ppm: 1.84 m (2Н, СН2СР), 2.40 m (2Н, СН2Р), 3.70 m
(2Н, СН2OH), 7.46 m (4НAr), 7.66 m (4НAr). 31Р NMR
spectrum (CDCl3): δР 34.20 ppm.
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YARKEVICH et al.
3-[Bis(4-bromophenyl)phosphinoyl]propanol (VIId)
in a vacuum. The residue was chromatographed on a
silica gel column. A dibromide excess was eluted with
hexane, then the target compound was eluted with a
hexane–isopropanol mixture (10:1). Yield 87% (3.11 g),
was obtained similarly. Yield 88%, mp 173–175°С
1
(ethyl acetate–hexane). Н NMR spectrum (CDCl3), δ,
ppm: 1.80 m (2Н, СН2СР), 2.40 m (2Н, СН2Р), 3.68 m
(2Н, СН2OH), 7.60 m (8НAr). 31Р NMR spectrum
(CDCl3): δР 34.48 ppm.
1
mp 72.5–73.5°С (diethyl ether). Н NMR spectrum
(CDCl3), δ, ppm: 1.60 m (4Н), 1.82 m (2Н), 2.30 m
(2Н, СН2СН2СН2СН2Р), 3.32 t (2Н, СН2Br), 7.46 m
(6Н, Ph), 7.76 m (4Н, Ph). 31Р NMR spectrum
(CDCl3): δР 32.97 ppm.
1-Bromo-3-(diphenylphosphinoyl)propane (VIIIa).
A solution of 2.44 g (0.009 mol, 0.85 ml) of PBr3 in
10 ml of anhydrous benzene was added dropwise with
stirring to a suspension of 6.30 g (0.024 mol) of VIIа
[4] in 20 ml of anhydrous benzene. The reaction
mixture was slightly refluxed for 1.5 h while stirring.
An equal volume of chloroform was added to the
reaction mixture. The organic solution was washed
with a NaHCO3 saturated solution and water, dried
with Na2SO4, and concentrated in a vacuum. The
substance crystallizes on standing. Yield 88% (6.82 g),
(Dimethylphosphinoylmethyl)dibutylamine (Iа).
A mixture of 2.52 g (0.02 mol) of Me2P(O)CH2Cl [9]
and 6.46 g (0.05 mol) of Bu2NH in 20 ml of anhydrous
benzene was slightly refluxed for 15 h. After cooling
the reaction mixture, Bu2NH·HCl was filtered off. The
solvent and an amine excess were removed in a
vacuum on a rotary evaporator. The residue was
distilled in a vacuum. Yield 84% (3.67 g), bp 140–
1
1
mp 94–96°С (benzene–hexane, 1:1). Н NMR spec-
142°С (1 mm Hg), hygroscopic. Н NMR spectrum
trum (CDCl3), δ, ppm: 2.20 m (2Н, СН2СР), 2.42 m
(2Н, СН2Р), 3.50 t (2Н, СН2Br), 7.56 m (6Н, Ph), 7.81
m (4Н, Ph). 31Р NMR spectrum (CDCl3): δР 32.97 ppm.
(CDCl3), δ, ppm: 0.90 t (6Н, 2CH3), 1.36 m (8H,
2
2CH2CH2), 1.51 d (6Н, CH3PCH3, JHP2 12 Hz), 2.54 t
(4H, CH2NCH2), 2.75 d (2H, CH2P, JHP 6 Hz). 31Р
NMR spectrum (CDCl3): δР 44.19 ppm.
1-Bromo-3-[bis(p-tolyl)phosphinoyl]propane (VIIIb)
was obtained similarly from alcohol VIIb [4]. Yield
(Diphenylphosphinoylmethyl)dibutylamine (Ib).
A solution of 0.89 g (0.003 mol) of bromide VIb and
1.52 g (0.009 mol) of Bu2NH in 10 ml of anhydrous
benzene was slightly refluxed for 25 h. After cooling
the reaction mixture, Bu2NH·HCl was filtered off. The
organic solution was washed with water and dried with
Na2SO4. The solvent was removed in a vacuum on a
rotary evaporator. Yield 89%, (0.92 г), mp 75–76°С
1
86%, mp 110–112°С (benzene–hexane, 1:3). Н NMR
spectrum (CDCl3), δ, ppm: 2.16 m (2Н, СН2СР), 2.38
m (2Н, СН2Р), 2.42 s (6Н, 2СН3), 3.48 t (2Н, СН2Br),
7.30 m (4НAr), 7.64 m (4НAr). 31Р NMR spectrum
(CDCl3): δР 32.40 ppm.
1-Bromo-3-[bis(4-chlorophenyl)phosphinoyl]-
propane (VIIIc) was obtained similarly from alcohol
VIIc. Yield 74%, mp 106–107.5°С (benzene–hexane).
1Н NMR spectrum (CDCl3), δ, ppm: 2.16 m (2Н,
СН2СР), 2.44 m (2Н, СН2Р), 3.50 t (2Н, СН2Br), 7.48
m (4НAr), 7.72 m (4НAr). Спектр ЯМР 31Р (CDCl3): δР
31.30 ppm.
1
(hexane). Н NMR spectrum (CDCl3), δ, ppm: 0.80 t
(6Н, 2CH3), 1.10 m (4H), 1.30 m (4H, CH2CH2·
CNCCH2CH2), 2.60 t (4H, CH2NCH2), 3.34 d (2H,
2
CH2P, JHP 6 Hz), 7.46 m (6H, Ph), 7.84 m (4H, Ph).
31Р NMR spectrum (CDCl3): δР 27.85 ppm.
[Bis(4-methylphenyl)phosphinoylmethyl]dibutyl-
amine (Ic) was obtained similarly from bromide VIc.
Yield 84%, mp 64–65°С (pentane). 1Н NMR spectrum
(CDCl3), δ, ppm: 0.80 t (6Н, 2CH3), 1.14 m (4H,
CH2ССNCСCH2), 1.34 m (4H, CH2СNCCH2), 2.36 s
(6Н, 2CH3), 2.58 t (4H, CH2NCH2), 3.36 d (2H, CH2P,
2JHP 6 Hz), 7.28 m (4H, Ph), 7.70 m (4H, Ph). 31Р
NMR spectrum (CDCl3): δР 28.40 ppm.
1-Bromo-3-[bis(4-bromophenyl)phosphinoyl]-
propane (VIIId) was obtained similarly from alcohol
VIId. Yield 83%, mp 141–143°С (benzene–hexane).
1Н NMR spectrum (CDCl3), δ, ppm: 2.16 m (2Н,
СН2СР), 2.42 m (2Н, СН2Р), 3.52 t (2Н, СН2Br), 7.62
m (8НAr). 31Р NMR spectrum (CDCl3): δР 31.35 ppm.
1-Bromo-5-(diphenylphosphinoyl)pentane (IX).
A solution of 2.02 g (0.01 mol) of Ph2P(O)H in 10 ml
of anhydrous THF was added dropwise to a mixture of
4.83 g (0.021 mol) of Br(CH2)5Br and 4.89 g
(0.015 mol) Cs2CO3 in 10 ml of anhydrous THF under
stirring, which was continued for another 20 h at 20°С.
The precipitate was filtered off, washed with THF on a
filter. The combined organic solution was concentrated
[Bis(4-methoxyphenyl)phosphinoylmethyl]dibutyl-
amine (Id) was obtained similarly from bromide VId.
Yield 68%, mp 53–55°С (cyclohexane). 1Н NMR
spectrum (CDCl3), δ, ppm: 0.82 t (6Н, СН3), 1.14 m
(4Н), 1.32 m (4Н, CH2CH2CNCCH2CH2), 2.56 m (4H,
2
CH2NCH2), 3.30 d (2H, CH2P, JHP 6 Hz), 3.82 s (6H,
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SYNTHESIS AND BIOLOGICAL ACTIVITY
1663
CH3О), 7.00 m (4H, Ph), 7.74 m (4H, Ph). 31Р NMR
spectrum (CDCl3): δР 28.72 ppm.
(CDCl3), δ, ppm: 1.36 m (2H, CH2CCN), 1.56 m (4H,
CH2CNCCH2), 2.40 s (6Н, 2СН3), 2.70 m (4H,
2
CH2NCH2), 3.32 d (2H, CH2P, JHP 6 Hz), 7.24 m
[Bis(4-chlorophenyl)phosphinoylmethyl]dibutyl-
(HAr), 7.74 m (4HAr). 31Р NMR spectrum (CDCl3): δР
27.40 ppm.
amine (Ie) was obtained similarly from bromide VIe.
1
Yield 90%, mp 54–55°С (hexane). Н NMR spectrum
[Bis(4-methylphenyl)phosphinoylmethyl]dicyclo-
hexylamine (Ii). A mixture of 0.80 g (0.0025 mol) of
bromide VIc and 0.1.36 g (0.0075 mol, 1.49 ml) of
cyclo-Hex2NH in 10 ml of anhydrous toluene was
refluxed for 45 h with stirring. After cooling the
reaction mixture, the precipitate of cyclo-Hex2NH·HBr
(0.57 г, 86%) was filtered off. The filtrate was washed
with water, dried with Na2SO4, and concentrated. The
oily residue was chromatographed on a column with
silica gel eluting with benzene. Yield 74% (0.78 g), mp
(CDCl3), δ, ppm: 0.84 t (6Н, 2CH3), 1.16 m (4H), 1.32
m (4H, CH2CH2CNCCH2CH2), 2.56 t (4H, CH2NCH2),
2
3.36 d (2H, CH2P, JHP 6 Hz), 7.48 m (4HAr), 7.78 m
(4HAr). 31Р NMR spectrum (CDCl3): δР 27.10 ppm.
[Bis(3-nitrophenyl)phosphinoylmethyl]dibutyl-
amine (If). A mixture of 0.42 g (0.0012 mol) of (m-
O2NC6H4)2P(O)CH2Cl [9] and 0.48 g (0.60 ml,
0.0036 mol) of Bu2NH in 10 ml of anhydrous toluene
was slightly refluxed for 8 h. After cooling the reaction
mixture, Bu2NH·HCl was filtered off. The organic
solution was washed with water and dried with
Na2SO4. The solvent was removed in a vacuum on a
rotary evaporator. The oily residue, which crystallizes
on standing, was chromatographed on a column with
silica gel eluting with a hexane–isopropanol mixture
(10:1). Compound If (0.33 g) crystallizes at the
1
93–95°С. Н NMR spectrum (CDCl3), δ, ppm: 1.04 m
(12Н, 6СН2), 1.60 m [8H, 2CH2(C–N)CH2], 2.40 s
(6H, 2CH3), 2.70 m (2Н, CH–N–CH), 3.46 d (2H,
2
CH2P, JHP 5 Hz), 7.24 m (4HAr), 7.68 m (4HAr). 31Р
NMR spectrum (CDCl3): δР 29.50 ppm.
[(2-Diphenylphosphinoyl)ethyl]dibutylamine (IIа).
A mixture of 1.00 g (0.0044 mol) of vinyl(diphenyl)
phosphine oxide, 0.65 g (0.005 mol, 0.84 ml) of
Bu2NH, 2.00 ml of water and 0.5 ml of DMSO was
stirred at 90°С for 4 h. After cooling, to the reaction
mixture was added 10 ml of chloroform and 5 ml of
water. The organic layer was separated, washed with
water (3×5 ml), and dried with Na2SO4. Then the
solvent was removed, and the residue crystallized.
Yield 94% (1.47 g). Then compound IIа was
recrystallized with charcoal from hexane. Yield 72%
(1.10 g), mp 62.5–63.5°С. 1Н NMR spectrum (CDCl3),
δ, ppm: 0.84 t (6Н, 2СН3), 1.28 m [8Н, (CCH2CH2C)2N],
2.36 t (4H, CH2NCH2), 2.46 m (2Н, NCH2CP), 2.84 m
(2Н, CH2P), 7.48 m (6H, Ph), 7.76 m (4H, Ph). 31Р
NMR spectrum (CDCl3): δР 32.04 ppm.
1
grinding with hexane. Yield 63%, mp 89–92°С. Н
NMR spectrum (CDCl3), δ, ppm: 0.81 t (6Н, 2CH3),
1.15 m (4H), 1.33 m (4H, CH2CH2CNCCH2CH2), 2.65
2
t (4H, CH2NCH2), 3.50 d (2H, CH2P, JHP 6 Hz), 7.75
m (2HAr), 8.20 m (2HAr), 8.42 m (2НAr), 8.70 m (2НAr).
31Р NMR spectrum (CDCl3): δР 25.20 ppm.
1-Diphenylphosphinoylmethylpiperidine (Ig). A mix-
ture of 1.48 g (0.005 mol) of bromide VIb and 1.88 g
(0.022 mol) of piperidine in 15 ml of anhydrous
benzene was slightly refluxed for 4 h. The reaction
mixture was cooled, and piperidine hydrobromide was
filtered off. The organic layer was washed with water
and dried with Na2SO4. The solvent and piperidine
excess were removed on a rotary evaporator. The
residue was recrystallized from hexane. Yield 82%
(1.23 g), mp 120.0–121.5°С. 1Н NMR spectrum
(CDCl3), δ, ppm: 1.36 m (2H, CH2CCN), 1.52 m (4H,
CH2CNCCH2), 2.54 m (4H, CH2NCH2), 3.23 d (2H,
[(5-Diphenylphosphinoyl)pentyl)]dibutylamine
(IIb). A mixture of 0.50 g (0.0014 mol) of Ph2P(O)·
(CH2)5Br (IX) and 0.78 g (0.0059 mol) of Bu2NH in
5 ml of anhydrous toluene was slightly refluxed for
4 h. Then the reaction mixture was cooled, and the
precipitated Bu2NH·HBr, was filtered off. The organic
solution was washed with water, dried with Na2SO4,
and concentrated. The dark-yellow oily residue was
chromatographed on a column with silica gel eluting
2
CH2P, JHP 6 Hz), 7.44 m (6H, Ph), 7.83 m (4H, Ph).
31Р NMR spectrum (CDCl3): δР 27.10 ppm.
1-[Bis(4-methylphenyl)phosphinoylmethyl]pipe-
ridine (Ih). A mixture of 0.65 g (0.002 mol) of
bromide VIc and 0.34 g (0.004 mol) of piperidine in
5 ml of anhydrous benzene was slightly refluxed for
1 h. The reaction mixture was cooled, and piperidine
hydrobromide was filtered off. The solvent was
removed on a rotary evaporator. Yield 85% (0.55 g),
1
with chloroform. Yield 71% (0.40 g). Н NMR spec-
trum (CDCl3), δ, ppm: 0.92 t (6Н, 2CH3), 1.36 m
(12H, 3CH2CH2CN), 1.67 m (2H, CH2CP), 2.40 m
[8H, (CH2)3N + CH2P], 7.45 m (6H, Ph), 7.76 m (4H,
Ph). 31Р NMR spectrum (CDCl3): δР 32.82 ppm.
1
mp 137–139°С (benzene–pentane). Н NMR spectrum
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 82 No. 10 2012

1664
YARKEVICH et al.
[(3-Diphenylphosphinoyl)propyl)]dibutylamine
organic solution was washed with water, dried with
Na2SO4, and concentrated in a vacuum. The oily
residue (3.97 g, 72%) crystallized on standing. The
product was distilled in a vacuum. Yield 57% (3.15 g),
(IIIа). A mixture of 3.88 g (0.012 mol) of Ph2P(O)·
(CH2)3Br (VIIIа) and 4.65 g (6.06 ml, 0.036 mol) of
Bu2NH in 20 ml of anhydrous benzene was slightly
refluxed for 5 h. After cooling, the precipitated
Bu2NH·HBr was filtered off. The organic solution was
washed with water, dried with Na2SO4, and concen-
trated in a vacuum. The residue crystallizes. Yield 96%
1
bp 174–178°С (0.5 mm Hg), hygroscopic. Н NMR
spectrum (CDCl3), δ, ppm: 0.93 t (12Н, 4СН3), 1.36 m
(16Н, 2СCH2CH2CNCCH2CH2С), 1.48 d (3H, CH3P,
2JНР 14 Hz), 2.55 m (8H, 2CH2NCH2), 2.79 m (4H,
CH2PCH2). 31Р NMR spectrum (CDCl3): δР 48.10 ppm.
1
(4.30 g), mp 37–39°С (hexane). Н NMR spectrum
(CDCl3), δ, ppm: 0.88 t (6Н, СН3), 1.28 m [8Н,
(CCH2CH2С)2N], 1.76 t (2Н, CH2СР), 2.16–2.40 m
(6H, 3CH2N), 2.50 t (2Н, CH2P), 7.46 m (6H, Ph),
7.76 m (4H, Ph). 31Р NMR spectrum (CDCl3): δР 33.37
ppm.
ACKNOWLEDGMENTS
The authors are grateful to Z.V. Safronova for the
synthesis of some compounds, V.O. Zavel’skii and
V.I. Shestov for the NMR spectra registration, and
A.V. Gabrel’yan for the assistance in analyzing the
results of biological tests.
[3-Bis(4-methylphenyl)phosphinoylpropyl]dibutyl-
amine (IIIb) was obtained similarly from bromide
1
VIIIb. Yield 86%, mp 73–74.5°С (hexane). Н NMR
REFERENCES
spectrum (CDCl3), δ, ppm: 0.86 t (6Н, CH3), 1.30 m
[8H, (CCH2CH2С)2N], 1.72 m (2H, CH2СP), 2.17–
2.48 and 2.62 two m (8H, 3CH2N+CH2P), 2.36 s (6Н,
2CH3), 7.24 m (4HAr), 7.60 m (4HAr). 31Р NMR
spectrum (CDCl3): δР 33.73 ppm.
1. Patsanovskii, I.I., Ishmaeva, E.A., Sundukova, E.N.,
Yarkevich, A.N., and Tsvetkov, E.N., Zh. Obshch.
Khim., 1986, vol. 56, no. 3, p. 567.
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[3-Bis(4-chlorophenyl)phosphinoylpropyl]dibutyl-
amine (IIIc) was obtained similarly from bromide
1
VIIIc. Yield 67%, mp 86–87.5°С (hexane). Н NMR
spectrum (CDCl3), δ, ppm: 0.90 t (6Н, 2CH3), 1.30 m
[8H, (CCH2CH2С)2N], 1.70 m (2H, CH2СP), 2.22–
2.40 m (6Н, 3CH2N), 2.50 t (2Н, CH2P), 7.42 m
31
(4HAr), 7.66 m (4HAr). Р NMR spectrum (CDCl3): δР
27.10 ppm.
5. Bondarenko, N.A., Yarkevich, A.N., Bovin, A.N., and
Tsvetkov, E.N., Izv. Akad. Nauk, Ser. Khim., 1991,
no. 8, p. 1933.
[3-Bis(4-bromophenyl)phosphinoylpropyl]dibutyl-
amine (IIId) was obtained similarly from bromide
1
VIIId. Yield 69%, mp 93–94.5°С (hexane). Н NMR
6. Petrova, L.N. and Bachurin, S.O., Bull. Eksp. Biol. i
spectrum (CDCl3), δ, ppm: 0.92 t (6Н, 2CH3), 1.34 m
[8H, (CCH2CH2С)2N], 1.78 m (2Н, CH2СP), 2.26–
2.46 m (6Н, 3CH2N), 2.52 t (2Н, CH2P), 7.64 m
(8HAr). 31Р NMR spectrum (CDCl3): δР 32.70 ppm.
Med., 2006, vol. 142, no. 7, p. 51.
7. Kew, J.N. and Kemp, J.A., Psychopharmacology, 2005,
vol. 179, no. 1, p. 4.
8. Tsvetkov, E.N., Kron, Т.Е., and Kabachnik, M.I., Izv.
Methyl[bis(N,N-dibutylaminomethyl)]phosphine
oxide (IV). A mixture of 2.61 g (0.016 mol) of
MeP(O)(CH2Cl)2 [10] and 8.27 g (0.064 mol, 10.78 ml)
of Bu2NH in 10 ml of anhydrous toluene was slightly
refluxed for 3 h. After cooling, the precipitated
Bu2NH·HCl (4.87 g, 91%) was filtered off. The
Akad. Nauk SSSR, Ser. Khim., 1980, no. 3, p. 669.
9. Tsvetkov, E.N., Malevannaya, R.A., and Kabachnik, M.I.,
Zh. Obshch. Khim., 1969, vol. 39, no. 7, p. 1520.
10. Tsvetkov, E.N., Borisov, G., Sivriev, Kh., Male-
vannaya, R.A., and Kabachnik, M.I., Zh. Obshch.
Khim., 1970, vol. 40, no. 2, p. 285.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 82 No. 10 2012