New synthetic approaches to development of the chemistry of pentaerythritol bicyclophosphite

Article abstract of DOI:10.1134/S1070363212090058

Abstract-Syntheses of the original compact molecular systems were developed and the ways of their practical use were examined. A group of new substances was synthesized on the basis of available pentaerythritol bicyclophosphite and thionophosphate, includ

Full text of DOI:10.1134/S1070363212090058

ISSN 1070-3632, Russian Journal of General Chemistry, 2012, Vol. 82, No. 9, pp. 1485–1491. © Pleiades Publishing, Ltd., 2012.
Original Russian Text © D.A. Predvoditelev, M.A. Malenkovskaya, L.K. Vasyanina, E.E. Nifant’ev, 2012, published in Zhurnal Obshchei Khimii, 2012,
Vol. 82, No. 9, pp. 1427–1434.
New Synthetic Approaches to Development of the Chemistry
of Pentaerythritol Bicyclophosphite
D. A. Predvoditelev, M. A. Malenkovskaya, L. K. Vasyanina, and E. E. Nifant’ev
Moscow Pedagogical State University, Nesvizhskii per. 3, Moscow, 119021, Russia
e-mail: chemdept@mail.ru
Received July 7, 2011
Abstract—Syntheses of the original compact molecular systems were developed and the ways of their
practical use were examined. A group of new substances was synthesized on the basis of available penta-
erythritol bicyclophosphite and thionophosphate, including respective ammonium salts, phosphocholines, a
complex compound of molybdenum, and a hydrophosphoryl compound.
DOI: 10.1134/S1070363212090058
Extending our research in the chemistry of bicyclic
esters of phosphorus acids and oligools [1–5], we
studied the synthesis of new structures formed on the
basis of the transformation of the pentaerythritol
phosphobicycles. This work was developed along two
lines. The first one is devoted to the study of chemical
reactions of cyclic structure of pentaerythritol
bicyclophosphite I, the second is the study of chemical
reactions at the alcohol hydroxyl of the phospho-
framework compound and its derivatives. To this end
we have performed the sulfurization of the pentaery-
thritol bicyclophosphite I.
of compound I includes a singlet signal with δP
57.96 ppm, which is typical of this type of frame
1
systems [3, 9]. H NMR spectrum of the phos-
phocyclane II includes a pronounced singlet signal of
the methylene protons of CH OH group and a doublet
2
signal of methylene protons of CH O group in the
2
bicyclic fragment of the molecule with a spin-spin
3
coupling constants J 7.15 Hz. The assignment of the
HP
signals was performed with the use of a two-
dimensional heteronuclear correlation spectroscopy
1
13
( H– C HETCOR).
The resulting thionophosphonic derivative II was
hydrolyzed in the presence of an organic base,
triethylamine or cyclohexylamine (20-fold excess), at
O
O
O
O
[S]
НOCH C
P
НOCH C
2
2
P S
1
40°C over 10–20 h. After the reaction completion, the
O
O
products III and IV were obtained as ammonium salts,
their yield reached 75%.
I
II
The reaction was carried out at 120°C for 6 h with
8% yield. Thionophosphate II is a crystalline com-
pound stable at prolonged storage. Note that previously
6, 7] the oxidation with sulfur of such bicyclo-
phosphite on the basis of metriol was carried out for
min at 140°C with 89% yield. These data suggest
O O
H O
HOCH2
HOCH2
2
_
8
II
C
P
HR
NEt or H NC H
6 11
3
2
O S
III, IV
11 (IV).
[
+
+
R = NEt
3
(III), NH
2
C
6
H
5
that the frame system of I is rather conservative.
3
1
In the P NMR spectra of the salts III, IV instead
New phosphocyclic substance II was studied by
of the signal with δ 58 ppm of the original framework
compound II the signals were observed characteristic
of alkylenethionphosphates with δ 54 ppm. In the H
P
3
1
1
13
1
TLC and P, H, C NMR, the NMR spectra were
3
1
1
analyzed using the data of [8]. The P NMR spectrum
P
NMR spectra of compounds III, IV the main signals
of the protons of the skeleton remained and the signals
characteristic of the protons of the ammonium groups
1
The same methods were used to prove the homogeneity and the
structure of other substances obtained in this work.
1
485

1
486
PREDVODITELEV et al.
appeared. In the case of salt III it was a triplet (δ 1.14
ppm) and a quadruplet (δ 2.95 ppm) of the methyl and
methylene protons of triethylammonium groups, and in
the case of salt IV, the multiple signals (δ 0.99–2.03 ppm)
of axial and equatorial methylene protons and a
multiplet (δ 3.06 ppm) of the methine proton of the
cyclohexyl fragment of the molecule. The low-field
signals with δ 6.88–7.50 ppm in the spectra of
compounds III, IV belonged to the protons of hydroxy
groups. It should be noted that the chemical shift of the
methine proton in the cyclohexane fragment of
compound IV indicates that it occupies equatorial
position in accordance with published data [10]. We
also studied the acid hydrolysis of compound I.
protons of N-ethyl group appeared as a triplet and
quadruplet at δ 0.92 and 2.62 ppm, respectively. In
addition, the spectrum contains a doublet signal of the
2
PCH N group, J 10.65 Hz. The assignment of the
2
HP
signals is performed using two-dimensional heteronuc-
1
13
lear correlation spectroscopy ( H– C HETCOR).
We used an opportunity of obtaining a complex
compound of molybdenum on the basis of bicycle-
phosphite I. Such complexes have not been obtained
previously [9]. We found that compound I easily
enters into the ligand exchange reaction with, for
example, molybdenum hexacarbonyl, to form molyb-
denum compound VII.
Mo(CO)6
O
O
I
C H O P Mo(CO)
5 10 4 5
+
HOCH2
HOCH2
H O (H )
2
I
C
P
VII
The process of decarboxylation was carried out at a
ligand–metal carbonyl molar ratio 1:1, in dioxane
under argon atmosphere at 120°C for 1h.
O
H
V
The reaction of bicycle I with acidified water (pH
The molybdenum complex VII was isolated from
the dioxane solution by precipitation into hexane, yield
83%. Complex VII is a white powder, stable at the
storage in an inert atmosphere for a long time. In the
5
) in dioxane proceeded over 20 h at 100–110°C. The
hydrolysis of phosphite I led to opening of the
framework fragment of the molecule and the formation
of dimethylol hydrophosphoryl compound V. The
desired product was isolated by precipitation from
dioxane solution into hexane. The yield of chromato-
graphically pure acid phosphite was 55%. P NMR
spectrum of the hydrophosphoryl compound contains a
signal at δ 3.81 ppm, J 676.32 Hz. In the H NMR
spectrum of the hydophosphoryl compound there are
characteristic signals of all proton groups. The proton
signals of the hydrophosphoryl fragments appear as a
doublet at δ 7.60 ppm split due to spin-spin coupling
with the phosphorus nucleus, JHP 631 Hz. The signals
of the protons of 1,3-dioxane functions are observed
3
1
P NMR spectrum of the pentaerythritol derivative
VII there is a signal with δ 140.73 ppm. Note that the
P
3
1
phosphorus chemical shifts of known molybdenum
complexes based on di- and tripentaerythritol bisbi-
1
1
cyclophosphites are similar: δ 138.96 [3] and 139.18 ppm
P
HP
P
1
[4], respectively. The H NMR spectrum of complex
VII contains all the signals characteristic of the ligand
I. Thus, at the complex formation the structure of
bicyclophosphite I was not destroyed. The composi-
tion and structure of molybdenum compound VII was
also confirmed by MALDI TOF spectrum.
1
for the equatorial and axial protons as a multiplets at δ
The next phase of the work consisted in the study
of reactions of the free hydroxy group of the frame-
work thionophosphate II. The work started with an
equimolar phosphorylation of compound II with
phosphoric hexaethyltriamide (VIII). In this way di-
amidophosphite IX was obtained.
4
.42 and 4.75 ppm respectively. In addition, in the
spectrum the signals are detected of methylene protons
of two methylol groups at δ 4.07 and 4.17 ppm.
The hydrophosphite V was used for obtaining the
aminomethylenephosphonate VI of a new type.
P(NEt2)3
O
O
O
O
HOCH2
Et NCH NEt
2
VIII
2
2
V
C
P
II
(Et
N)
POCH
C
P S
2
2
2
HOCH2
O
VI
2
CH NEt2
O
IX
3
1
In the P NMR spectrum of VI there is a singlet
The reaction with acyclic amidophosphite VIII was
performed in a solution of anhydrous dioxane at room
temperature within 10 h without removing the
1
signal δ 23.14 ppm.. In the H NMR spectrum of
compound VI the proton signals of the basic backbone
of the molecule remained and the signals of the
P
31
diethylamine liberated in the reaction. In the P NMR
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 82 No. 9 2012

NEW SYNTHETIC APPROACHES TO DEVELOPMENT
1487
spectrum of crude phosphite IX two singlet signals
were observed with a ratio of integral intensities 1:1, δP
using available phosphorylating means, namely, alkylene-
chlorophosphites XIII, XIV, at 0°C in a dioxane solution.
5
1
7.9 ppm, belonging to phosphobicycle, and δP
36.6 ppm, related to the phosphorus atom in the
O
O
O
ХIII, ХIV
II
R
POCH C
P
S
acyclic part of the amidophosphite molecule.
2
O
O
Phosphite IX was transformed without isolation
into the corresponding dithionphosphate X (60°C, 5 h).
ХV, ХVI
(ХIV, ХVI).
Formation of alkylenephosphites XV, XVI was
O
O
[
S]
(ХIII, ХV),
R =
IX
(Et N) POCH C
2
2
2
P S
S
O
31
X
monitored by P NMR spectroscopy: δ 58 and 138 ppm
P
3
1
In the P NMR spectrum of X two singlet signals
for compound XV, 58 and 123 ppm for compound
XVI, at a ratio of integral intensities 1:1. Then the
alkylenephosphites XV, XVI obtained were trans-
formed without isolation into the corresponding
thionophosphates XVII, XVIII. The sulfurization was
carried out for 3–5 h at 60–70°C in dioxane. Note that
the previously studied reactions [11] of pentaerythritol
phosphorylation with chloroalkylenophosphites did not
result in obtaining relevant pentaerythritol alkylene-
thionophosphates.
were observed, related to acyclic and cyclic phos-
phorus atoms, δ 57.43 and 81.27 ppm, respectively, at
a ratio of 1:1. In the H NMR spectrum, besides the
main signals of bicyclic fragment, the resonance of the
protons of N-ethyl groups as characteristic triplet and
multiplet in the δ areas of 1.11 and 3.05 ppm and a
P
1
doublet of methylene protons of POCH group with
2
3
JHP 6.9 Hz were detected.
The framework compound X with the hydroxyl
protected by amidothionophosphate function was sub-
jected to alkaline hydrolysis in the presence of a
nitrogen base, triethylamine or cyclohexylamine, under
the conditions of hydrolysis of compound II, as
described above.
O
O
[
S]
O
ХV, ХVI
R
POCH C
P
S
2
O
O
S
ХVII, ХVIII
Alkylenethionophosphates XVII, XVIII are
S
crystalline compounds, stable for a long time when
stored in an inert atmosphere. The P NMR spectra of
compounds XVII, XVIII contain singlets with δP
O O
H O
31
2
(Et N) POCH
2 2
2
Х
_
C
P
O S
HR
NEt or H NC H
3
2
6
11
HOCH2
5
8.28 and 63.00 ppm, 57.16 and 61.55 ppm. respec-
1
ХI, ХII
tively. In the H NMR spectra of alkylenethiono-
phosphates XVII, XVIII there are the signals of all
protons, thus they confirm the structure of the sub-
stances obtained. Besides the signals of methylene pro-
tons of bicyclic fragment, the resonance of the protons
+
+
R = NEt
3
(ХI), NH
C
2 6
H
11 (ХII).
Target products XI, XII were isolated as
ammonium salts with a yield of 85%. The salts XI,
XII are oily substances stable at the storage. In their
NMR spectra, along with P signals in the region of δ
0 ppm belonging to the cyclic fragment, a singlet
of CH OR group as a doublet at δ 4.15–4.20 ppm with
2
31
characteristic coupling constants with phosphorus
atom were observed. In addition, in the spectrum of
trimethylenethionophosphate XVII the signals of axial
and equatorial protons of the phosphorylated ring were
observed as typical multiplets at δ 1.61, 2.03, and
P
8
signal was observed in 1:1 ratio, with δ 54 ppm,
P
1
characteristic of alkylenephosphates. In the H NMR
spectra of compounds XI, XII besides the signal of the
main frame of the molecules, the proton signals of
ammonium groups appeared, as in the case of salts III,
IV. In the case of salt XII the methine proton of
cyclohexyl fragment, as in the case of salt IV, occupies
equatorial position (δ 3.05 ppm).
4
.30 ppm. In the spectrum of dithionophosphate XVIII
the signals of axial and equatorial protons of the
phosphorylated ring have chemical shifts δ 3.92 and
4
.11 ppm, and there are two singlet signals at δ 0.66
and 1.05 ppm related to the protons of methyl groups.
In the final stage of this section we studied phos-
Propylenetionophosphate XVII was used for
phorylation of the free hydroxyl of phosphobicycle II
preparing from it original choline phosphoamphiphiles
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 82 No. 9 2012

1
488
PREDVODITELEV et al.
XIXa and XIXb, which contain in their structure,
along with phosphobicyclic fragment, the phos-
phocholine function.
For elemental analysis a Perkin-Elmer 2400 Analyzer
was used.
All syntheses involving compounds of trivalent
phosphrus were performed in a dry argon atmosphere.
Adsorption chromatography was performed on a
column of 10 mm diameter packed with L 100–250 μm
The synthesis of this phospholipid was carried out
by alkylation of trimethylamine with compound XV at
1
00–115°C for 5 h. The yield of target products XIXa
silica gel; R values were identified by TLC on Silufol
and XIXb was 65%.
f
UV-254 plates using systems of ethyl acetate–
acetonitrile, 2:1 (A), benzene–ethyl acetate–aceto-
nitrile, 3:1:1 (B), chloroform–methanol, 3:1 (C) me-
thanol–water, 3:1 (D), hexane–dioxane, 3:1 (E), ben-
zene–dioxane, 1:2 (F), benzene–dioxane, 3:1 (G).
O
O
_
S
N(CH3)3
+
XVII
S
P
CCH OPO(CH ) NH(CH )
2 2 3 3 3
O
O
XIXа
O
O _
Melting points were determined in sealed
capillaries, heating rate of 1 deg min .
O
+
–1
+
S
P
CCH
2
OPSH(CH
2
)
3
NH(CH )
3 3
O
Phosporic hexaethyltriamide (VIII) was prepared
by the method [14], 2-chloro-1,3,2-dioxaphos-phorinane
XIII) and 2-chloro-5,5-dimethyl-1,3,2-dioxaphospho-
rinane (XIV), according to techniques [15]. 1-Methyl-4-
phospha-3,5,8-trioxabicyclo[2,2,2]octane (I) was synthe-
sized by the method of [1] (mp 97–98°C). Constants of
these compounds were consistent with the published data.
O
XIXb
3
1
In the P NMR spectrum of the reaction mixture
besides the signal at δ 56.04 ppm belonging to the
thion form of the phosphobetain XIXa a signal was
observed in the region of δ 12.96 ppm, characteristic
(
P
P
of tiolophosphate XIXb (the integral intensities ratio
1
:1). The formation of tiolophosphate XIXb indicates
that in the reaction thion–thiol isomerization occurs
12, 13]. We failed to isolate individual thiono- (XIXa)
4
-Hydroxymethyl-2,6,7-trioxa-1-phosphabicyclo-
[
2,2,2]octane-1-thionooxide (II). A solution of 0.2 g
[
of bicyclophosphite (I) (δ 94.6 ppm) and 0.04 g of
P
and tiolophosphates (XIXb).
finely ground sulfur in 4 ml of anhydrous dioxane was
heated at 120°C for 6 h. Excess sulfur was filtered off,
dioxane was removed in a vacuum. To free the result-
ing reaction product II from traces of sulfur it was
dissolved in acetone (2×3 ml) followed by filtration
and distilling off the solvent. The residue was dried for
1
In the H NMR spectrum of a mixture of
compounds XIXa and XIXb the main signals of the
protons of the molecule backbone were retained, and
the signals of the methyl protons of ammonium groups
appeared (δ 3.25 ppm). An important characteristic of
the spectrum of the mixture of compounds is the
chemical shift of α-methylene protons of the
phosphothiol fragment (δ 2.82 ppm) of betaine XIXb.
3
(
(
h (40°C, 1 mm Hg). Yield of compound II 0.21 g
88.2%), mp 150–152°C, R 0.30 (A), 0.10 (B), 0.50
f
1
C). H NMR spectrum (C D N), δ, ppm: 3.51 (2H,
5
5
3
It is essential that the reaction of binuclear system
XV with a nucleophilic reagent proceeds selectively at
the mono-ring and does not affect the bulky fragment
of the system.
CH OH), 4.71 q (8H, CH OP, J 7.15 Hz), 6.70 br.s
2 2 HP
1
3
(1H, OH). C NMR spectrum (C D N), δ , ppm: 38.99
d (>C<, J 3.47 Hz), 59.25 s (CH OH), 76.77 g
(CH OP, J 7.70 Hz). P NMR spectrum (pyridine),
5
5
C
3
CP
2
2
31
2
CP
δP, ppm: 57.96 s. Found, %: C 30.45, H 4.33, P 15.58.
C H O PS. Calculated, %: C 30.61, H 4.62, P 15.79. M
EXPERIMENTAL
31
5
9
4
1
13
H, C, and P NMR spectra were obtained on a
JEOL ECX-400 (400 MHz) instrument, chemical shifts
1
96.
2-Hydrotriethylammonium-5,5-dioxymethyl-2-
thio-1,3,2-dioxaphosphorinane (III). A solution of
.1 g of bicyclothionophosphate II, 0.18 g of water,
1
13
31
for H and C are relative to TMS, for P, to 85%
phosphoric acid. Assignment of proton signals was carried
out on the basis of double resonance and 2D hetero-
0
1
13
1.03 g of triethylamine (molar ratio 1:20:20) in 10 ml
of acetonitrile (pH > 10) was heated in a sealed tube at
140°C for 20 h. Acetonitrile, triethylamine, and water
were removed in a vacuum and the remaining oily
substance was dissolved in 2 ml of dioxane and
reprecipitated with hexane (2×3 ml). Salt III was kept
for 4 h at 80°C (1 mm Hg) Yield of compound III 0.1 g
nuclear correlation spectroscopy (HETCOR H – C).
Mass spectral studies were performed on a Bruker
Ultra Flex instrument with a time-of-flight detector
TOF) by the method of a matrix-assisted laser desorp-
tion and ionization (MALDI) (l 337 nm) using trihyd-
roxyanthracene as a template.
(
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 82 No. 9 2012

NEW SYNTHETIC APPROACHES TO DEVELOPMENT
1489
2
0
1
31
(
(
7
3
65.2%), nD 1.4930, R 0.45 (C). H NMR spectrum
631 Hz]. P NMR spectrum (dioxane), δ , ppm: 3.81
f
P
+
3
1
C D N), δ, ppm: 1.14 m {9H, [HN(CH CH ) ] , J
.5 Hz}, 2.95 q {6H,[HN(CH CH ) ] , J 11.95 Hz},
.95 s and 4.38 s (4H, CH OH), 4.55 m (2H ) and 5.15
m (2H ) (OCH CCH OR, J
s, J 676.32 Hz. Found, %: C 33.12, H 6.31, P 17.25.
C H O P. Calculated, %: C 32.97, H 06.09, P 17.01.
5
5
2
3 3
HH
PH
+
3
2
3 3
HP
5
11
5
2
e
M 182.
-Diethylaminomethyl-2-oxo-5,5-dioxymethyl-
,3,2-dioxaphosphorinane (VI). 0.1 g of hydrophos-
phite V and 0.93 g of tetraethylmethylenediamine in
0 ml of dioxane was heated in a flask with a reflux
condenser for 9 h at 110°C. Solvent and volatile
reaction products were removed in a vacuum, the
residual oil was washed with hexane (2×2 ml). The
target phosphоnate VI was kept for 3 h at 40°С (1 mm
2
3
10.6 Hz,, J 5.84
a
2
2
HaHe
HP
2
1
3
Hz,), 8.10 br.s (3H, NH, OH). C NMR spectrum
1
+
(
(
4
(
C D N), δ , ppm: 8.45 [HN(CH CH ) ] , 42.83 s
5 5 C 2 3 3
3
+
2
>C<, J 3.9 Hz), 45.71 d {[HN(CH CH ) ] , J
CP 2 3 3 CP
.95 Hz}, 60.79 and 61.99 (CH OH), 69.32 d
2
2
2
31
OCH CCH OR, J 3.08 Hz). P NMR spectrum
2 2 CP
(
pyridine), δ 53.89 ppm. Found, %: C 42.05, H 8.48,
P
P 10.03. C H NO PS. Calculated, %: C 41.89, H
1
1
26
5
8
.31, P 9.82. M 315.
-Hydrocyclohexylammonium-5,5-dioxymethyl-
-thio-1,3,2-dioxaphosphorinane (IV) was obtained
similar to salt III from 0.05 g of bicycle II, 0.09 g of
water, and 0.5 g of cyclohexylamine (molar ratio
:20:20) in 3 ml of acetonitrile (pH > 10) at 140°C for
0 h. Then, acetonitrile, cyclohexylamine, and water
were removed in a vacuum and the residue was
washed with hexane (2×2 ml). Salt IV was kept for 4 h
at 80°C (1 mm Hg). Yield 0.06 g (75%) n 1.5760, Rf
20
Hg). Yield of compound VI 0.1 g (68%), nD 25, Rf
1
0
.75 (C). H NMR spectrum (C D N), δ, ppm: 0.92 t
2
5
5
3
(
6H, NCH CH , J 7.2 Hz), 2.62 q (4H, NCH CH ,
2
2 3 HН 2 3
4
2
JHP 4.02 Hz), 2.92 br.d (2H, PCH N, J 10.65 Hz),
.04 s and 4.14 s (4Н, СН ОН), 4.76 br.m (2Н ) and
.80 br.m (2Н ) (CCH OР, J 6.23 Hz). C NMR
spectrum (C D N), δ , ppm: 13.57 (NCH CH ), 29.76
>C<), 46.77 d (NCH CH , J 15.3 Hz), 63.27 d
PCН NCH CH , J 11.58 Hz), 68.51 s and 69.51 s
CH OH), 76.92 d (CCH OР, J 10.5 Hz). P NMR
spectrum (dioxane), δ 23.14 ppm. Found, %: С 45.24;
2
HP
4
4
2 е
3
13
1
1
а
2
PH
5
5
C
2
3
3
(
(
(
2 3 CP
1
2
2
3
CP
2
31
2
D
0
2
2
CP
1
0
[
(
.33 (B). H NMR spectrum (C D N), δ, ppm: 0.99 m
1H , NCH(CH CH ) CH ], 1.11 m [2H , NCH
P
5
5
Н 8.57; Р 11.83. С Н NО Р. Calculated, %: С 44.94;
Н 8.30; Р 11.59. М 267.
10 22
5
e
2
2 2
2
e
CH CH ) CH ], 1.15 m [2H , NCH(CH CH ) CH ], 1.34
2 2 2 2 e 2 2 2 2
2
m [1H , NCH(CH CH ) CH , J
2H , NCH(CH CH ) CH , J 10.73 Hz], 2.03 m
2H , NCH(CH CH ) CH , J 11.3 Hz], 3.06 m
HaHe
1H, H N CH), 3.95 br.s (4H, CH OH), 4.57 m (2H )
and 4.72 m (2H ) (OCH CCH OR, J
Hz, J 6.40 Hz), 6.88–7.50 br.s (5H, OH, H N ). C
NMR spectrum (C D N), δ , ppm: 23.09 [NCH
9.73 Hz], 1.46 m
a
2
2 2
2
HaHe
1-Methyl-4-phospha-3,5,8-trioxabicyclo[2,2,2]-
octane molibdenum complex (VII). An ampule with
a solution of 0.09 g of bicyclophosphite I and 0.14 g of
molibdenum hexacarbonyl (reagent ratio 1: 1) in 5 ml
of dioxane was heated for 1 h at 120°С. The formed
complex VII was precipitated from the reaction
mixture with hexane. The solvents were decanted and
the precipitate was washed with hexane (2×5 ml) and
dried for 1 h at 50°C (1 mm Hg). Yield of the complex
2
[
[
(
a
2
2 2
2
HaHe
2
a
2
2 2
2
+
3
2
e
2
11.5
a
2
2
HaHe
3
+
13
HP
3
5
5
C
(
[
(
(
(
CH CH ) CH ], 25.70 [NCH(CH CH ) CH ], 33.26
2 2 2 2 2 2 2 2
NCH (CH2 CH ) CH ], 42.69 (1C, >C<), 48.39
CH OH) 50.36 [NCH(CH CH ) CH ], 69.24
2 2
2
d
2
2
2 2
31
2
VII 0.18 g (83%), mp 243°C (decomp.), R 0.45 (C).
H NMR spectrum (C D N), δ, ppm: 3.35 br.s (2Н,
f
2
1
OCH CCH OP, J 10.54 Hz). P NMR spectrum
2
2
CP
5
5
3
pyridine), δ 54.80 ppm. Found, %: C 42.61, H 13.88,
P
СН ОН), 4.43 br.d (6Н, СН ОР, J 1.83 Hz), 6.75
2 2 НР
1
3
P 10.16. C H NO PS. Calculated, %: C 42.43, H
1
1
24
5
br.s (1Н, СН ОН). C NMR spectrum (C D N), δ ,
2 5 5 C
ppm: 37.76 (>C<), 60.79 (CH OH), 72.71 d (CCH OР,
JCP 7.24 Hz), 207.30 d.d and 211.84 d.d (5СО, J
3.37 and 17.25 Hz). Р NMR spectrum (pyridine), δ
40.73 ppm. Found, %: С 30.25; Н 2.84; Р 7.98.
С Н О Р·Мо(СО) . Calculated, %: С 29.95; Н 2.51; Р
.72. М 401. Mass spectrum, m/е (I, %), found 316.811
100) [М – 3СО], calculated 316.965 [М – 3СО].
1
3.55, P 9.95. M 311.
2
2
2
1
CP
2
-Hydro-2-oxo-5,5-dioxymethyl-1,3,2-dioxaphos-
phorinane (V). A suspension of 0.2 g of bisbi-
cyclophosphite I (δ 94.61 ppm) and 0.06 g of water
pH 5) (molar ratio 1:3) in 5 ml of anhydrous dioxane
was heated in a sealed ampule for 20 h at 100–110°C.
The solution was decanted and acidic phosphite V was
precipitated by hexane and washed with the same
solvent (2×2 ml). The desired product was kept for 3 h
at 50°C (1 mm Hg). Yield 0.12 g (55%) 1.5039, R
.85 (D). H NMR spectrum (C D N), δ, ppm: 4.07 s
3
1
1
1
Р
P
5
10
4
5
(
7
(
4-Diethylamidothionophosphatoxymethyl-2,6,7-
trioxa-1-phosphabicyclo[2,2,2]octane-1-thionooxide
(Х). 0.15 g of bicyclic compound II and 0.19 g of
phosphorous hexaethyltriamide VIII in 5 ml of
anhydrous dioxane was stirred for 10 h at 25°C. The
formation of diamidophosphite IХ was monitored by
f
1
0
5
5
and 4.17 s (4H, CH OH), 4.42 m (2H ) and 4.51 m,
.75 m (2H ) (CH OP), 7.60 d [1H, P(O)H, JPH
2
e
1
4
a 2
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 82 No. 9 2012

1
490
PREDVODITELEV et al.
3
1
the method of Р NMR spectroscopy (dioxane), δР,
ppm: 57.86 s and 136.69 s (integral intensity ratio 1:1).
Then to the reaction mixtre was added 0.03 g of finely
ground sulfur, and the mixture was kept at 60°С for
1,3,2-dioxaphosphorinane (ХII) was synthesized
analogous to salt IV from 0.13 g of diamide Х, 0.12 g
of water, and 1.1 g of cyclohexylamine (mole ratio
1:20:20) in 8 ml of acetonitrile (рН > 10) at 140°С
over 8 h. Then acetonitrile, cyclohexylamine, and
water were removed in a vacuum, and the residue was
washed with hexane (2×3 ml). Salt ХII was kept for
5
h. The sulfur excess was filtered off, and dioxane
was removed in a vacuum. The diamidodithionophosphate
Х was purified by chromatography on a column
packed with silica gel (5 g), filled with benzene.
Compound Х was eluted with 20 ml of a benzene–
dioxane 1:2 mixture. The solvents were removed in a
2
0
3 h at 80°c (1 mm Hg). Yield 0.14 g (85%), nD
1
1.5870, R 0.35 (C). H NMR spectrum (СDCl ), δ,
f
3
3
ppm: 1.05 t (12H, NCH CH , J 7.1 Hz), 1.08 m
2
3
HН
vacuum, the residue was kept for 3 h at 40°C (1 mm Hg).
[1Н , NСН(CH CH ) CH ], 1.19 m [2Н , NСН·
е 2 2 2 2 е
о
Yield of compound Х 0.22 g (70 %), mp 83–84 С, R
(CH CH ) CH ], 1.28 m [1Н , NСН(CH CH ) CH ],
2 2 2 2 е 2 2 2 2
f
1
2
0
1
.35 (E), 0.55 (F). H NMR spectrum (СDCl ), δ, ppm:
1.55 m [1Н , NСН(CH CH ) CH , J(Н Н )11.63 Hz],
3
а 2 2 2 2 а е
3
2
.11 t (12Н, NСН СН , J 6.9 Hz), 3.05 m (8Н,
1.69 m [2Н , NСН(CH CH ) CH , J(Н Н ) 12.32 Hz],
а 2 2 2 2 а е
2
3
НН
3
3
2
NСН СН , J 12.4 Hz), 3.72 d (2Н, СН ОР, J
1.98 m [2Н , NСН(CH CH ) CH , J(Н Н )11.03 Hz],
2
3
НР
2
НР
а 2 2 2 2 а е
3
13
+
3
6
.9 Hz), 4.53 d (6Н, CCH OР, J 6.8 Hz). C NMR
3.05 m (1H, H N CH), 3.06 (8Н, NCH CH , J
3 2 3 HP
2
PH
spectrum (СDCl ), δ , ppm: 14.19 (NСН СН ), 40.24
12.53 Hz), 3.37 br.s (2H, CH OH), 3.91 m (2Н ) and
3
С
2
3
2 е
2
’
2
3
d (NСН СН , JСР 5.8 Hz ), 61.38 (>C<), 67.18
4.27 m (2Н ) [OCH CCH OР, J(Н Н )11.56 Hz, J
а 2 2 а е HР
2
3
2
31
3
(
РОСН ), 75.63 d (РОСН С, J 7.7 Hz). Р NMR
4.86 Hz], 4.13 d (2Н, СН ОРN, J 8.89 Hz), 5.98
2
2
СР
2 HР
+
13
spectrum (chloroform), δ , ppm: 57.43 s and 81.27 s
br.s (4Н, OH, H N ). C NMR spectrum (С D N), δ ,
3 5 5 C
Р
(
integral intensity ratio 1:1). Found, %: С 39.01; Н
ppm: 14.49 (NCH CH ), 24.94 [NCH(CH CH ) CH ],
2 3 2 2 2 2
7
3
.28; Р 15.51. С Н N О Р S . Calculated, %: С
8.80; Н 7.01; Р 15.39. М 402.
25.07 [NCH(CH CH ) CH ], 32.34 [NCH(CH CH ) CH ],
13
28
2
4
2
2
2
2 2
2
2
2 2
2
2
40.19 d (NCH
CH , JСP 3.87 Hz), 40.39 (>C<), 50.69
2
3
[
NCH(CH CH ) CH ], 60.05 (СН ОН), 60.08 br.d
2 2 2 2 2
5
-Diethylamidothionophosphatoxymethyl-5-oxy-
2
2
(РОСН С, J 4.00 Hz), 68.80 d (OCH CCH OР, J
2 СP 2 2 CP
methyl-2-hydrotriethylammonium-2-thio-1,3,2-dioxy-
phosphorinane (ХI) was synthesized similar to salt
III from 0.1 g of diamide Х, 0.09 g of water, and 0.50
g of triethylamine (mole ratio 1:20:20) in 5 ml of
acetonitrile (рН > 10) at 130–140°C for 15 h. Then
acetonitrile, triethylamine, and water were removed in
a vacuum, the residue was washed with hexane (2×
3
1
5
5
%
.66 Hz). P NMR spectrum (chloroform), δ , ppm:
P
4.32 and 80.57 (integral intensity ratio 1:1). Found,
: С 44.13; Н 8.61; Р 12.21. С Н N О Р S .
19 43 3 5 2 2
Calculated, %: С 43.91; Н 8.34; Р 11.92. М 520.
1,3-Propylenethionophosphate-4-oxymethyl-2,6,7-
trioxa-1-phosphabicyclo[2,2,2]octane-1-thionooxide
(ХVII). To a solution of 0.14 g of 2-chloro-1,3,2-
dioxaphosphorinane ХIII in 5 ml of the water-free
dioxane at stirring and cooling to 0°C was added
dropwise a mixture of 0.2 g of bicyclophosphite II and
0.1 g of triethylamine in 5 ml of the same solvent. The
reaction mixture was kept at this temperature for 0.5 h,
аnd then the temperature was raised in 0.5 h to the
room temperature. The formation of propylenephos-
3
ml). Salt ХI was kept for 3 h at 80°C (1 mm Hg).
2
0
1
Yield 0.1 g (80%), nD 1.5440, R 0.49 (C). H NMR
f
spectrum (CDCl ), δ, ppm: 1.03 t (12H, NCH CH ,
3
2
3
3
+ 3
JHН 6.9 Hz), 1.29 t {9H, [HN(CH CH ) ] , J 7.20
2
3 3
HH
+
3
Hz}, 3.04 q {6H, [HN(CH CH ) ] , J 13.8 Hz}, 3.08
q (8H, NCH CH , J 12.2 Hz), 3.35 br.s (2H,
CH OH), 3.95
2
3 3
HР
3
2
3
HP
m
а
(2Не) and 4.30
m
(2На)
2
2
3
[OCH CCH O, J(Н Н )11.31 Hz, J 4.7 Hz], 4.17 d
2
2
е
HР
3
+
(
2H, РOСН , J 9.87 Hz), 5.74 br.s (1Н, HN ), 6.34
2
HР
31
1
3
phite ХV was monitored by Р NMR spectroscopy
br.s (1Н, OH). C NMR spectrum (СDCl ), δ , ppm:
3
С
+
3
(dioxane), δ , ppm: 57.64 s and 138.48 s (integral
Р
8
3
5
6
.72 [HN(CH CH ) ] ,14.49 d (NCH CH , J 3.75 Hz),
2 3 3 2 3 СР
+
2
intensity ratio 1:1). Pyridine hydrochloride was filtered
off, and to the filtrate was added 0.04 g of finely
ground sulfur, then temperature was raised to 60°С,
and the reaction mixture was kept at this temperature
for 3 h. The sulfur excess was filtered off, dioxane was
removed in a vacuum. To remove the sulfur traces
reaction product ХVII obtained was dissolved in
acetone (2×3 ml) followed by filtrartion and distilling
the solvent off. The propylenedithionophosphate ХVII
was purified additionally by chromatography on a
9.62 [HN(CH CH ) ] , 45.82 d (NCH CH , JСP
2
3 3
2
3
2
.82 Hz), 60.81 (>C<), 62.05 d (РОСН , J 4.01 Hz),
2
СP
2
31
8.84 d (РOCH С, J 5.86 Hz). P NMR spectrum
2
СР
(
chloroform), δ , ppm: 54.16 s and 79.93 s (integral
P
intensity ratio 1:1). Found, %: С 43.91; Н 8.93; Р
1
8
2.01. С Н N О Р S . Calculated, %: С 43.74; Н
19 45 3 5 2 3
.69; Р 11.88. М 522.
-Diethylamidothionophosphatoxymethyl-5-hyd-
5
roxymethyl-2-hydrocyclohexylammonium-2-thio-
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 82 No. 9 2012

NEW SYNTHETIC APPROACHES TO DEVELOPMENT
1491
column with silica gel (5 g) filled with benzene.
Compound ХVII was eluted with 10 ml of a benzene–
dioxane 2:1 mixture. The solvents were removed in a
vacuum, the residue was kept for 2 h at 40°C (1 mm
0.09 g of trimethylamine in 20 ml of anhydrous aceto-
nitrile was kept for 5 h at 100–115°C. The solvents were
removed in a vacuum, the oily residue was washed
consecutively with benzene (2×5 ml) and hexane (2×5 ml),
and dried for 2 h at 40°C (1 mm Hg). The mixture of
homocholines ХIХa and ХIХb, yield 0.1 g ( 65%), mp
Hg). Yield of compound ХVII 0.25 g (75%), mp. 203–
1
2
05°С, R 0.49 (G), 0.00 (E). H NMR spectrum
f
(
(
C D N), δ, ppm: 1.61 m (1Н ) and 2.03 m (1Н )
238–241°C (wetting at 135°C ), R 0.00 (G), 0.52 (D).
5
5
е
а
f
3
1
ОСН СН СН О), 4.15 d (2Н, ССН ОР, J 11.99
H NMR spectrum (СDСl – CD OD, 99:1), δ, ppm:
2
2
2
2
РН
3
3
+
Hz), 4.30 br.m (4Н, ОСН СН СН О), 4.79 d (6Н,
РОСН С, J 6.9 Hz). C NMR spectrum (C D N),
δ , ppm: 26.14 d (ОСН СН СН О, J 7.6 Hz), 37.62
d.d (>С<, JРС 3.8 Hz), 64.26 d (ССН ОР, JРС
1.15 br.m (2Н, РОСН · СН СН N ), 2.82 br.m (2Н,
2
2
2
2 2 2
2
13
+
3
+
РSСН СН СН N , J 5.48 Hz), 3.25 br.s [9Н, N
2 2 2 РН
2
РН
5
5
2
+
(CH ) ], 3.55 br.m (2Н, СН N ), 3.65 br.m (2Н,
С
2
2
2
РС
3 3 2
3
2
+
3
РОСН СН СН N ), 3.95 d (2Н, СН ОР, J 13.81 Hz),
2 2 2 2 РН
4.55 d (6Н, ОСН О, J 6.69 Hz). Р NMR spectrum
2
2
3
31
6
.95 Hz), 69.10 d (ОСН СН СН О, J 7.7 Hz), 75.69
2
2
2
РС
2 РН
2
31
d (РОСН , J 7.6 Hz). Р NMR spectrum (pyridine),
(chloroform–methanol, 99:1), δ , ppm: 12.96 br.s
2
РС
Р
δР, ppm: 58.28 s and 63.00 s (integral intensity ratio
:1). Found, %: С 29.23; Н 4.56; Р 18.93. С Н О ·
ХIХb and 56.04 br.s ХIХа, integral intensity ratio 1:1.
Found, %: С 35.38; Н 6.31; Р 16.72. С Н NО · Р S .
1
8
14
6
11 23
5
2 2
Р S . Calculated, %: С 28.92; Н 4.25; Р 18.64. М 332.
Calculated, %: С 35.19; Н 6.18; Р 16.50. М 375.
2
2
REFERENCES
1
,3-(5,5-Dimethyl)propylenethionophosphate-4-
oxymethyl-2,6,7-trioxa-1-phosphabicyclo[2,2,2]-
octane-1-thionoxide (ХVIII) was synthesized by
analogy with compound ХVII from 0.21 g of 2-chloro-
1. Nifant’ev, E.E. and Petrova, I.M, Zh. Obshch. Khim.,
1970, vol. 40, no. 10, p. 2196.
2. Nifant’ev, E.E, Predvoditelev, D.A., Strebkova, E.V.,
and Malenkovskaya, M.A, Dokl. Akad. Nauk, 2007,
vol. 416, no. 2, p. 203.
5
,5-dimethyl-1,3,2-dioxaphosphorinane ХIV, 0.25 g of
II, 0.13 g of triethylamine, and 0.05 g of sulfur in 8 ml
of anhydrous dioxane (5 h, 80°C ). Phosphite ХVI
3
. Predvoditelev, D.A., Malenkovskaya, M.A, Strebko-
va, E.V., Lysenko, K.A., and Nifant’ev, E.E., Zh.
Obshch. Khim., 2009, vol. 79, no. 1, p. 51.
31
formation was monitored by Р.NMR spectroscopy
dioxane), δ , ppm: 57.27 s and 122.95 s (integral
(
Р
4
. Malenkovskaya, M.A., V’yunskovskaya, O.V., Vasya-
nina, L.K., Predvoditelev, D.A., and Nifant’ev, E.E., Zh.
Obshch. Khim., 2009, vol.79, no. 12, p. 1980.
intensity ratio 1:1). Dithionophosphate ХVIII was
purified by chromatography on a column with silica
gel (10 g) filled with benzene, eluent 25 ml of a benzene–
dioxane 3:1 mixture. The solvents were re-moved in a
vacuum, and the precipitate was kept for 2 h at 40°C
5. Malenkovskaya, M.A., V’yunskovskaya, O.V., Vasya-
nina, L.K., Predvoditelev, D.A., and Nifant’ev, E.E., Zh.
Obshch. Khim., Zh. Obshch. Khim., 2011, vol. 81, no. 7,
p. 1104.
6. Verkade, J.G. and Reynolds, L.T., J. Org. Chem., 1960,
vol. 25, p. 663.
(
0
0
1 mm Hg). Yield 0.37 g (80%), mp 230–232°C, R
.50 (G), 0.1 (E). H NMR spectrum (C D N), δ, ppm:
5 5
f
1
.66 br.s and 1.05 br.s [6Н, ОСН С·(СН ) СН О], 3.92
2
3 2
2
2
7. Wadsworth, W.S. and Emmons, W.D., J. Amer. Chem.
Soc., 1962, vol. 84, p. 610.
m (2Н ) and 4.11 m (2Н ) [ОСН С· (СН ) СН О, J
е
а
2
3 2
2
3
(
Н Н ) 11.09 Hz, J 3.64 Hz], 4.20 br.d (2Н, СН ОР,
а е HР 2
8
. Boros, E.J., Coskran, K.J., King, R.W., and Ver-
3
3
JРН 7.09 Hz), 4.79 br.d (6Н, ССН ОР,
JРН
2
kade, J.G., J. Am. Chem. Soc., 1966, vol. 84, p. 610.
9. Verkade, J.G., Coord. Chem. Rev., 1972, vol. 9, no. 1,
p. 1.
10. Pretsch, E., Bullman, P., and Affolter, C., Structure
Determination of Organic Compounds: Tables of
Spectral Data, Moscow: Mir; 2009, p. 438.
1
3
6
.75 Hz). C NMR spectrum (C D N), δ , ppm: 14.21
5
5
С
(
>C<), 20.12 [ОСН С(СН )СН О], 37.62 d.d (>C<,
2 3 2
3
2
J 4.02 Hz), 64.66 d (ССН ОР, J 3.46 Hz), 75.68
d (РОСН , J 7.6 Hz), 77.80 d [2С, ОСН С(СН )·
СН О, J 7.6 Hz]. Р NMR spectrum (pyridine), δ ,
РС
2
РС
2
2
РС
2
3
2
31
2
РС
Р
1
1. Mukmenev, E.T. and Kamai, G., Dokl. Akad. Nauk
SSSR, 1963, vol. 153, no. 3, p. 605.
ppm: 57.16 s and 61.55 s (integral intensity ratio 1:1).
Found, %: С 33.61; Н 5.24; Р 17.36. С Н О Р S .
1
0
18
6 2 2
1
2. Nifantyev, E.E., Predvoditelev, D.A., Rasadkina, E.N.,
and Bekker, A.R., Phosphorus and Sulfur, 1987,
vol. 34, p. 109.
Calculated, %: С 33.33; Н 5.03; Р 17.19. М 360.
О,О'-Thionophosphоhomocholine-4-oxymethyl-
1
3. Nifant’ev, E.E., Predvoditelev, D.A., Malenkov-
skaya, M.A., and V’yunskovskaya, O.V., Zh. Obshch.
Khim., 2011, vol. 81, no. 8, p. 1246.
2,6,7-trioxa-1-phosphabicyclo[2,2,2]octane-1-thiono-
oxide (ХIХa) and О,S-thiolophosphоhomocholine-
-oxymethyl-2,6,7-trioxa-1-phosphabicyclo[2,2,2]-
4
1
1
4. Zwierzak,, A., Canad. J. Chem., 1967, vol. 21, p. 2501.
5. Lucas, H.J., Mitchel, F.N., and Scally, C.N., J. Am.
Chem. Soc., 1950, vol. 72, p. 5491.
octane-1-thionooxide (ХIХb). A sealed ampule with a
solution of 0.15 g of dithionophosphate ХVII and
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 82 No. 9 2012