Phosphorylation of 1,4-bis(hydroxymethyl)benzene with trivalent phosphorus derivatives

Article abstract of DOI:10.1134/S1070363207060126

Phosphorylation of 1,4-bis(hydroxymethyl)benzene with complete phosphorous acid amides and phenyl phosphorodichloridite is studied. Some phosphorus-containing linear systems, the phosphamacrocycle precursors, are synthesized. The possibility of synthesis

Full text of DOI:10.1134/S1070363207060126

ISSN 1070-3632, Russian Journal of General Chemistry, 2007, Vol. 77, No. 6, pp. 1028 1033.
Pleiades Publishing, Ltd., 2007.
Original Russian Text
No. 6, pp. 938 944.
P.V. Slitikov, V.A. Bogoyavlenskii, E.N. Rasadkina, E.E. Nifant’ev, 2007, published in Zhurnal Obshchei Khimii, 2007, Vol. 77,
Phosphorylation of 1,4-Bis(hydroxymethyl)benzene
with Trivalent Phosphorus Derivatives
P. V. Slitikov, V. A. Bogoyavlenskii, E. N. Rasadkina, and E. E. Nifant’ev
Moscow Pedagogical State University,
Nesvizhskii per. 3, Moscow, 119021 Russia
e-mail: chemdept@mtu-net.ru
Received February 13, 2007
Abstract Phosphorylation of 1,4-bis(hydroxymethyl)benzene with complete phosphorous acid amides and
phenyl phosphorodichloridite is studied. Some phosphorus-containing linear systems, the phosphamacrocycle
precursors, are synthesized. The possibility of synthesis of phosphamacrocyclic systems based on 1,4-bis(hy-
droxymethyl)benzene is considered; it was shown that this compound does not tend to form macrocycles.
DOI: 10.1134/S1070363207060126
Previously we prepared a series of phosphamacro-
cyclic compounds based on aromatic diols and phos-
phorous acid amides using methodologies of molec-
ular assembling, direct cyclophosphorylation, and
dismutation of aromatic diol tetraalkylphosphorodi-
amidites [1 6]. In this work we studied phosphoryla-
tion of alkylaromatic diols with both complete phos-
phorous acid amides and phosphorochloridites and
examined the possibility of using such systems for
constructing macrocycles. The first attempt of bring-
ing alkylaromatic diols into phosphorylation was
reported in [7]. As an object of our study we chose
the simplest aromatic glycol, 1,4-bis(hydroxymethyl)-
benzene I.
We started our work with carrying out phosphoryla-
tion of diol I with different phosphorylating reagents.
The reaction with complete phosphorous acid amides
IIa IIc at the reactant ratio of 1:2 was performed at
room temperature, unlike the phosphorylation of
benzyl alcohol with hexaethylphosphorous triamide
IIb on heating [8]. We used acetonitrile and 1,4-di-
oxane as solvents. With IIb, the reaction followed the
scheme:
Et2N
Et2N
NEt2
NEt2
P O CH2
HO CH2
CH2 O P
CH2 OH + 2P(NEt2)3
I
IIb
S
S
+S
CH2 O P NEt2
NEt2
Et2N P O CH2
NEt2
Vb
After two days, in the 31P NMR spectrum of the
reaction mixture in acetonitrile we found only one
The reaction of diol I with hexamethylphosphorous
triamide IIa or phosphorous tripiperidide IIc, both in
acetonitrile and in dioxane, yielded two products. For
example, the 31P NMR spectrum of the reaction mix-
signal, a singlet at
135.4 ppm, characteristic of
P
esters of phosphorous acid diamides with aliphatic
substituents. It should be noted that bisphosphorylated
product IIIb did not undergo dismutation in aceto-
nitrile solution even in the course of three weeks, in
contrast to the related diamido esters derived from
aromatic systems [5, 6].
ture from the synthesis of IIIa contained signals at
P
148.1 (amido diester), 137.5 (diamido ester), and
122.2 ppm (phosphorous acid triamide). The signal
with chemical shift
148.1 ppm is the strongest.
P
1028

PHOSPHORYLATION OF 1,4-BIS(HYDROXYMETHYL)BENZENE
1029
R2N
NR2
P O CH2
CH2 O P
3I + 6IIa, IIc
NR2
R2N
IIIa, IIIc
+
HO CH2
+
O P NR2 3IIa, IIc
CH2
2
IVa, IVc
S
S
CH2 O P NR2
NR2
+S
R2N P O CH2
NR2
Va, Vc
S
+
HO CH2
+
O P NR2 3S=P(NR2)3,
CH2
2
IVa, IVc
NR2 = NMe2 (a),
N
(c).
Presumably, products IV are formed concurrently
with bisphosphorylated derivatives III.
The time of complete phosphorylation and the 31P
chemical shifts of the compounds prepared are listed
in the table.
phorylated with IIa with cooling to 5 C, the reaction
was initially slower than at room temperature and
yielded only one product, phosphorous acid diamido
ester IIIa. However, with the reaction progress, ac-
cumulation of IVa was observed, and the further re-
action course was similar to that at room temperature.
That is, on the whole, the reaction is slower, but the
general trend remains the same. Thus, the activity of
complete phosphorous acid amides IIa and IIb in the
reactions with diol I depends on the reaction tempera-
ture.
Such a difference in the phosphorylation pathways
with compounds IIa, IIc, and IIb may be due to the
difference in the activity of the leaving groups. To
confirm this assumption, we changed the phosphoryla-
tion temperature. The reaction of I with IIb was
carried out at 70 C. We found that, under these condi-
tions, compound IIb behaved in the same manner as
did IIa at room temperature.
To confirm our assumptions about the structure of
the products, we performed sulfurization of the reac-
tion mixtures. The 31P NMR spectrum of the reaction
Both in dioxane and in acetonitrile, two products
were formed, namely, phosphorous acid diamido ester
mixture after sulfurization contained two signals at
P
76 79 ppm, characteristic of the phosphorothioic acid
mono- and diamides. The products Va Vc, VIa, and
VIc were isolated by column chromatography.
IIIb and amido diester with chemical shifts
135.1
and 147.9 ppm, respectively. When diol I waPs phos-
Time of complete phosphorylation of 1,4-bis(hydroxymethyl)benzene I and the 31P NMR data for compounds IIIa IIIc,
IVa, and IVc
31P NMR spectrum, P, ppm
(ratio of integral intensities of signals)
Comp. no.
R
1,4-Dioxane (days)
Acetonitrile (days)
IIIa, IVa
IIIb
IIIc, IVc
NMe2
NEt2
2
4
5
2
2
2
148.1, 137.5 (8:5)
135.4
145.6, 130.6 (1:2)
N
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1030
SLITIKOV et al.
Compounds Va Vc are low-melting solids. All the
Va Vc. We failed to isolate compound VIc pure be-
cause of similar chromatographic mobilities of the
products formed.
compounds were characterized by physicochemical
1
methods such as TLC and H and 31P NMR spec-
troscopy, and compound Vb was additionally ex-
amined by single crystal X-ray diffraction [7].
In the phosphorylation of diol I with phenyl phos-
phorodichloridite VII in the presence of triethylamine,
we observed the same pattern as in the case of amides
IIa and IIc.
Compound VIa was isolated by column chromatog-
raphy as oily substance in a considerably lower yield
than the corresponding phosphorodiamidothioates
Cl
P
Cl
O
Cl
Cl
NEt3
3I + 6
P O CH2
CH2 O P
OPh
PhO
VII
VIII
+
HO CH2
+
O P OPh2 3VIIc.
CH2
2
IX
The 31P NMR spectrum of the reaction mixture,
recorded 30 min after the start of the reaction, con-
After sulfurization of the reaction mixture, we
isolated by column chromatography product X as
individual compound in 5% yield; in the 31P NMR
spectrum, it gave a signal with the chemical shift
tained signals at
178.5, 157.1, and 135.4 ppm,
P
corresponding to the starting dichloride VII, chloride
VIII, and phosphorous acid triester IX, respectively.
63.8 ppm.
P
S
HO CH2
CH2 OH
CH2 O P O CH2
OPh
X
The structure and purity of X were confirmed by
From diol I, we prepared oligomeric systems con-
taining fragments of resorcinol XI and 2,7-dihydroxy-
naphthalene XII. These syntheses were carried out by
the schemes suggested earlier for the similar structures
derived from aromatic diols [1, 2, 9].
1
physicochemical methods (TLC; H and 31P NMR
spectroscopy) and elemental analysis.
With the aim to prepare compounds VI and X, we
performed their synthesis at a 2:1 ratio of the starting
diol and phosphorylating reagent in acetonitrile
in the case of IIb and in dioxane in the presence of
triethylamine in the case of VII.
The first procedure involved the addition of diol I
to bisphosphorylated resorcinol XIII or 2,7-dihy-
droxynaphthalene XIV.
Compounds VIa and X were isolated by column
chromatography. The purposeful synthesis gave the
target compounds in four times higher yields.
The synthesis was performed in acetonitrile, be-
cause the rate of the phosphorylation of compounds
XI and XII in this solvent is much higher than that in
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PHOSPHORYLATION OF 1,4-BIS(HYDROXYMETHYL)BENZENE
S
1031
(1) RPX2
P
CH2 OH
2I
HO CH2
CH2
O
O CH2
(2) +S
OPh
VIa, X
RPX2 = IIa, VII; R = NMe (VIa), OPh (X).
1
other polar solvents [9, 10]. To the synthesized di-
amido esters XIII and XIV, we added two molar
equivalents of diol I. Five days after adding 1,4-bis-
(hydroxymethyl)benzene I to the reaction mixture
containing XIV, an oily substance readily soluble in
methylene chloride and dioxane separated out. Its 31P
lated by column chromatography. The H NMR spec-
tra showed that, in the case of the resorcinol deriva-
tive, the product with
72.5 ppm was linear phos-
P
phoramidothioate XIX, and that with
66 ppm was
P
cyclic bis(phosphoramidothioate) XXI described
previously [1, 2]. The yield of XIX was as low as 8%.
We failed to isolate pure the acyclic derivative of 2,7-
dihydroxynaphthalene XX.
NMR spectrum contained a signal at
140.7 ppm,
P
characteristic of phosphorous acid amido diester with
aromatic substituents. The solution over the oil
showed a signal at
145.5 ppm in the 31P NMR
The low yield of the desired oligomers XIX and
XX is probably due to the competing dismutation of
bis(phosphorodiamidites) XIII and XIV [5, 6]. In our
case, dismutation is more favorable than phosphoryla-
tion of diol I with diamido esters XIII and XIV,
especially in the case of bisphosphorylated derivative
of 2,7-dihydroxynaphthalene XIV. The second as-
sumed pathway of the reaction involves phosphoryla-
tion of 2,7-dihydroxynaphthalene XII with bis(phos-
phorodiamidite) IIIb. Here dismutation as a compet-
P
spectrum. In the experiment with XI, no precipitate
formed, and the 31P NMR spectrum of the reaction
mixture contained the signals at
141.4 ppm in 1:3 ratio.
145.5 and
P
After sulfurization of the reaction mixtures in me-
thylene chloride, the 31P NMR spectra of the reaction
solutions contained the signals at
72.5 ppm and
P
66 67 ppm in both cases. The compounds were iso-
NEt2
Et2N
1:2
P O Ar O P
HO Ar OH + IIb
Et2N
NEt2
XI, XII
XIII, XIV
+I, 1:2
CH2 OH
HO CH2
O Ar O O CH2
CH2
O
P
P
NEt2
XV, XVI
NEt2
O Ar O
O Ar O
P NEt2
+
Et2N P
XVII, XVIII
S
Et2N
O Ar O
O Ar O
S
S
+S
P
+
P
CH2 OH
HO CH2
O Ar O
O CH2
CH2
O
NEt2
P
S
P
XXI, XXII
NEt2
NEt2
XIX, XX
(XI, XIII, XV, XVII, XIX, XXI);
(XII, XIV, XVI, XVIII, XX, XXII).
Ar =
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 77 No. 6 2007

1032
SLITIKOV et al.
1:2
IIIb + XIV
P
P
OH
CH2
O
O
O CH2
O
HO
NEt2
NEt2
XXIII
ing process will be absent, because compound IIIb is
spectra were measured on a Bruker AC-200 spectrom-
eter operating at 250 MHz (internal reference TMS);
the 31P NMR spectra were recorded on a Bruker WP-
80SY apparatus operating at 32.4 MHz (external
reference 85% H3PO4).
resistant to dismutation.
After the bisphosphorylation of diol I in dioxane, a
solution of 2,7-dihydroxynaphthalene in dioxane was
added to the reaction mixture in a stoichiometric
amount. A day later, a glassy precipitate insoluble in
organic solvents formed. According to the TLC data,
the solution over the precipitate contained naphthale-
nic diol XII only. The same pattern was observed
when a mixture of bisphosphite IIIb and naphthalenic
diol XII in 1:2.5 or 1:3 ratio was used. Thus,
changing the synthesis scheme did not lead to the
desired increase in the yield of linear oligomers de-
rived from diol I.
Adsorption chromatography was performed on a
column packed with silica gel L 100/250; TLC was
performed on Silufol plates with the followings elut-
ing systems: hexane dioxane, 5:1 (A); hexane di-
oxane, 3:1 (B); benzene dioxane, 5:1 (C); chloro-
form (D); and ethyl acetate (E). The substance spots
were developed by iodine vapor and by calcination.
Hexaalkylphosphorous triamides IIa and IIb [10],
phosphorous acid tripiperidide IIc [11], and phenyl
phosphorodichloridite VII [12] were prepared by
published procedures.
The second part of our study concerned finding the
conditions for preparing macrocyclic systems from
phosphorus-containing
zene derivatives VIIa, X, and XIX.
1,4-bis(hydroxymethyl)ben-
1,4-Bis(diaminothiophosphoryloxy)xylenes
(Va Vc). To 1 mol of IIa IIc, a solution of 0.5 mol
of 1,4-bis(hydroxymethyl)benzene I in 100 ml of di-
oxane was added at room temperature with stirring.
After 48 h, 1 mol of sulfur was added to the reaction
mixture, and the mixture was allowed to stand for an
additional 3 days. Then the solution was filtered, the
solvent was removed in a vacuum, and the residue
was purified by column chromatography. The prod-
ucts were eluted by the followings systems: hexane
dioxane, 7:1 (IVa, IVc); hexane dioxane, 10:1
(IVb). The compounds prepared were dried in a
vacuum for 2 h (1 mm Hg, 70 C).
We expected that the use of 1,4-bis(hydroxyme-
thyl)benzene I as a building block in the synthesis of
a macrocyclic system would lead to the formation of
bulkier configurations than with rigid aromatic diols.
Recently we showed that direct cyclophosphoryla-
tion of diol I with IIb yielded oligomeric structures
with the number of units from 3 to 6 [7]. The same
results were obtained with 1,4-bis(hydroxymethyl)-
benzene I itself and with other diols taken for molec-
ular assembling. As diol I cannot be directly used
for cyclophosphorylation, we used its phosphorus-
containing analogs VIa, X, and XIX. However,
regardless of the nature of the phosphorylating agent
(complete phosphorous acid amides and dichlorides)
and the synthesis conditions (lowering temperature,
decreasing concentrations, varying a solvent), a
viscous gelatinous substance insoluble in dioxane,
acetonitrile, and acetone but swelling in DMF sep-
arated out.
1,4-Bis(tetramethyldiaminothiophosphoryloxy)-
xylene (Va), yield 20%, mp 140 142 C, Rf 0.49 (A).
1H NMR spectrum, , ppm, (CDCl3): 2.58 d (24H,
3
3
CH3, JPH 12.1 Hz), 5.00 d (4H, CH2, JPH 8.3 Hz),
7.36 s (4H, Ar). 31P NMR spectrum, P, ppm (1,4-
dioxane): 81.7. Found, %: C 43.55; H 7.40; N 12.59;
P 14.28. C16H32N4O2P2S2. Calculated, %: C 43.82;
H 7.36; N, 12.78; P 14.13.
Thus, our results show that 1,4-bis(hydroxymethyl)-
benzene I is readily phosphorylated with trivalent
phosphorus reagents, forming linear structures; no
tendency to the formation of cyclic structures was
observed.
1,4-Bis(tetraethyldiaminothiophosphoryloxy)-
xylene (Vb), yield 73%, mp 132 133 C, Rf 0.65 (A),
1
0.68 (D). H NMR spectrum, , ppm (CDCl3): 1.07 t
3
3
(24H, CH3, JHH 7.6 Hz), 3.11 m (16H, CH2N, JPH
4.7 Hz), 4.96 d (4H, CH2O, 3JPH 8.2 Hz), 7.34 s (4H,
Ar). 31P NMR spectrum, P, ppm (1,4-dioxane): 79.4.
EXPERIMENTAL
All the syntheses were carried out in anhydrous
solvents in a dry nitrogen atmosphere. The H NMR
1,4-Bis(dipiperidylthiophosphoryloxy)xylene
1
1
(Vc), yield 32%, oily substance, Rf 0.60 (B). H NMR
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PHOSPHORYLATION OF 1,4-BIS(HYDROXYMETHYL)BENZENE
1033
3
spectrum, , ppm (CDCl3): 1.55 t (24H, CH2, JHH
in 10 ml of acetonitrile was added. The reaction mix-
ture was allowed to stand for 5 days at room tempera-
ture, after which 0.064 g of sulfur was added. Two
days later, the solvent was removed in a vacuum, and
the residue was purified by column chromatography,
eluent benzene dioxane, 7:1. The product was dried
in a vacuum for 2 h (1 mm Hg, 70 C). Yield 0.052 g
3
6.1 Hz), 3.07 m (16H, CH2N, JPH 4.7 Hz), 4.98 d
(4H, CH2O, JPH 9.2 Hz), 7.37 s (4H, Ar). 31P NMR
3
spectrum, P, ppm (1,4-dioxane): 76.8.
O,O -Bis[(4-(hydroxymethyl)benzyl] dimethyl-
phosphoramidothioate (IVa). To a solution of
0.247 g of IIa in 5 ml of dry benzene, a solution of
0.345 g of diol I in 10 ml of anhydrous acetonitrile
was added at room temperature with stirring. Then,
2 days later, 0.032 g of sulfur was added to the solu-
tion, and the mixture was allowed to stand for an
additional 2 days. The solvent was removed in a
vacuum, and the residue was purified on a chromato-
graphic column; the product was eluted with ethyl
acetate. The resulting substance was dried in a
vacuum for 2 h (1 mm Hg, 70 C) to yield 0.072 g
(20%) of IVa as oily substance, Rf 0.38 (C), 0.75 (E).
1
(8%); oil, Rf 0.67 (C), 0.89 (E). H NMR spectrum, ,
3
ppm [(CD3)2CO]: 1.10 t (12H, CH3, JHH 6.9 Hz),
3.35 m (8H, CH2, 3JPH 14.3 Hz), 4.19 br.s (2H, OH),
3
4.63 s (4H, CH2OH), 5.07 d.d (4H, CH2O, JPH 8.8,
3
8.4 Hz), 7.06 d (2H, CH, JHH 8.4 Hz), 7.32 s (1H,
3
CH), 7.37 t (1H, CH, JPH 8.4 Hz), 7.39 s (8H,
CHBzl). 31P NMR spectrum, P, ppm (CH3CN): 72.5.
ACKNOWLEDGMENTS
This study was financially supported by Program
of the President of the Russian Federation for support-
ing leading scientific schools (no. NSh-5515.2006.3).
1H NMR spectrum, , ppm [(CD3)2CO]: 2.69 d (6H,
3
CH3, JPH 11.9 Hz), 3.34 br.s (2H, OH), 4.63 s (4H,
CH2OH), 4.98 d (4H, CH2O, 3JPH 9.2 Hz), 7.37 s (8H,
Ar). 31P NMR spectrum, P, ppm (1,4-dioxane): 77.4.
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phosphorothioate (X). To a solution of 0.276 g of
diol I in 15 ml of dry dioxane, a mixture of 0.195 g
of phenyl phosphorodichloridite and 0.253 g of tri-
ethylamine in 10 ml of dioxane was slowly added at
5 7 C with stirring. After addition of the whole
amount of the dichloride, cooling of the reaction
mixture was stopped, and the reaction mixture was
allowed to stand for 3 h at room temperature. Then
triethylammonium chloride was filtered off, the sol-
vent was removed in a vacuum, and the residue was
dissolved in a minimal amount of methylene chloride;
the solution was filtered, diluted with methylene
chloride, and 0.032 g of sulfur was added. The reac-
tion mixture was allowed to stand for 3 days at room
temperature. Then the solvent was evaporated, and the
residue was purified by column chromatography,
eluent benzene dioxane, 10:1. The product was dried
in a vacuum for 2 h (1 mm Hg, 70 C); yield 0.086 g
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(20%), mp 121 123 C, Rf 0.95 (C). H NMR spec-
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1,3-Bis[(4-hydroxymethylbenzyl)(diethylamino)-
thiophosphoryloxy]benzene (XIX). To a solution of
0.494 g of IIb in 10 ml of acetonitrile, a solution of
0.11 g of resorcinol XI in 6 ml of acetonitrile was
added at room temperature, and the reaction mixture
was vigorously stirred for 1 h. Then 0.345 g of diol I
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 77 No. 6 2007