Phosphorylation of 3′,4′,5,7-tetramethyldihydroquercetin

Article abstract of DOI:10.1023/B:RUGC.0000018642.90774.a1

3′,4′,5,7-Tetramethyldihydroquercetin was phosphorylated with phosphorous acid derivatives, and similar results were obtained with phosphorochloridites and phosphoramidites. The P^III derivatives obtained were subjected to oxidation. The structu

Full text of DOI:10.1023/B:RUGC.0000018642.90774.a1

Russian Journal of General Chemistry, Vol. 73, No. 11, 2003, pp. 1686 1690. Translated from Zhurnal Obshchei Khimii, Vol. 73, No. 11, 2003,
pp. 1782 1786.
Original Russian Text Copyright
2003 by Nifant’ev, Koroteev, Kaziev, Koroteev, Vasyanina, Zakharova.
Phosphorylation of 3 ,4 ,5,7-Tetramethyldihydroquercetin
E. E. Nifant’ev, M. P. Koroteev, G. Z. Kaziev,
A. M. Koroteev, L. K. Vasyanina, and I. S. Zakharova
Moscow Pedagogical State University, Moscow, Russia
Received November 19, 2001
Abstract 3 ,4 ,5,7-Tetramethyldihydroquercetin was phosphorylated with phosphorous acid derivatives,
and similar results were obtained with phosphorochloridites and phosphoramidites. The PIII derivatives ob-
tained were subjected to oxidation. The structures of the products were determined by NMR spectroscopy.
Dihydroquercetin is a widely occurring natural
flavanoid, which is of large importance for medicine
and food industry [1 5]. Molecules of this compound
contain reactive carbonyl and hydroxy groups. Ho-
wever, the reactivity of dihydroquercetin has been
studied inadequately. It was only shown that this
compound can be efficiently methylated with di-
methyl sulfate to form 3 ,4 ,5,7-tetramethyldihydro-
quercetin I [6]. Attempted complete methylation of
the pentaol resulted in breakdown of the flavanoid
system [7]. Recently, we initiated a study on phos-
phorylation of dihydroquercetin and obtained phos-
phites, which were formed by replacement of hydro-
gen atoms in the phenolic hydroxyls of the flavanoid
[8]. In this work we examined the possibility and
pathway of dihydroquercetin phosphorylation at the
alcoholic hydroxy groups. As the starting compound
we chose 3 ,4 ,5,7-tetramethyldihydroquercetin I.
The phosphorylation was performed using two
different procedure: halophosphite [with 5,5-dimethyl-
2-chloro-1,3,2-dioxaphosphorinane
(neopentylene
phosphorochloridite)] and amidophosphite (with a
phosphoramidite or -diamidite). In the first case, the
reaction was performed with continuous stirring at
20 C for 2 h in anhydrous benzene using triethyl-
amine as HCl acceptor.
In the amidophosphite procedure, 5,5-dimethyl-2-
dimethylamino-1,3,2-dioxaphosphorinane (neopenty-
lene dimethylphosphoramidite) was used as a phos-
phorylating agent. The reaction also occurred in an-
hydrous benzene, but required heating to 80 C for 6 h
in the presence of catalytic amounts of diethylamine
hydrochloride.
Me
O
O
P Cl
5
OMe
4
Me
OMe
6
1
8
1
3 OMe
MeO
O
O
2
MeO
9 O
OMe
13
CH3
14
CH3
7
6
2
3
O 11
Me
Me
O
O
12
C
4
P NMe2
OH
10
5
O P
MeO
MeO
O
O
11
I
II
After complete phosphorylation, the singlets in the
31P NMR spectrum with chemical shifts of 146 and
144 ppm, characteristic of the starting compound,
disappear, and a singlet at 120 ppm appears; its posi-
tion is typical of complete cyclic phosphites. The com-
pounds obtained by the above two procedures are iden-
tical. They are white crystalline substances with mp
142 144 C. Comparison of the two phosphorylation
procedures shows that the yields of the target com-
pounds are comparable. However, in the chlorophos-
phite method, the target compound contains a small
amount of triethylamine hydrochloride. The phos-
phorus derivatives isolated were characterized by 13C
NMR spectroscopy. The spectrum of neopentylene di-
hydroquercetin-3-yl phosphite (Table 1) contains
signals of all the carbon atoms of the dihydroquercetin
1070-3632/03/7311-1686$25.00 2003 MAIK Nauka/Interperiodica

PHOSPHORYLATION OF 3 ,4 ,5,7-TETRAMETHYLDIHYDROQUERCETIN
1687
13C NMR data [ C, ppm (2JCP, Hz)] for the compounds obtaineda
Comp.
no.
C2
C3
C4
C5
C6
C7
C8
C9
C10
C1
C2
I
II
IV
V
VI
VII
VIII
IX
X
83.6 72.5
189.7
163.7
163.7
163.8
163.9
164.3
164.5
163.8
163.8
163.8
93.8
94.4
94.1
94.2
93.9
93.7
94.2
94.6
94.6
165.7
166.7
166.6
166.7
166.2
166.2
166.6
166.5
166.6
93.1
93.2
93.3
93.3
93.4
93.5
93.3
93.1
93.3
161.7
162.7
162.8
162.9
162.7
162.7
162.8
162.9
162.8
103.7
104.2
104.1
104.2
105.0
105.1
104.1
104.4
104.4
129.9
128.3
127.9
128.5
128.4
128.4
128.2
128.3
128.5
112.5
112.4
112.1
112.2
112.1
112.1
112.3
112.4
112.6
82.3 77.6 (6.7) 189.3
81.7 77.3 (6.4) 189.1
82.8 77.05 (6.6) 189.2
82.8 77.9 (6.9) 185.1
82.7 78.7 (6.9) 185.0
82.1 77.8 (5.5) 189.3
82.1 77.8 (6.7) 189.4
82.2 77.7 (6.5) 188.9
Comp no.
C3
C4
C5
C6
OCH3
C11
C12
C13
C14
C15
I
II
IV
V
VI
VII
VIII
IX
X
148.9
149.3
149.2
149.3
149.9
150.1
149.4
149.5
149.5
149.5
150.1
150.3
150.3
150.7
150.7
150.3
150.3
150.2
112.3
111.8
111.8
111.8
111.7
111.4
111.9
111.9
111.9
120.6
121.5
121.2
121.3
121.7
121.7
121.3
121.6
121.6
55.9
56.5
56.3
56.3
55.5
55.6
56.3
56.7
56.6
73.5 (5.4) 31.9 (6.5)
73.6 (5.3) 31.8 (6.6)
73.5 (5.4) 32.1 (6.6)
22.4
24.3
21.4
13.9
13.9
22.2
22.1
22.2
21.1
20.0
20.4
40.3 (5.1)
40.2 (5.0)
13.8
13.9
63.4 (5.0) 15.8 (8.6)
63.3 (5.1) 15.6 (8.5)
73.4 (5.4) 31.7 (6.8)
73.3 (5.3) 31.7 (6.7)
73.2 (5.3) 32.1 (6.7)
21.2
21.4
21.3
a
Solvents: CDCl for I; C D for II, VI, VII, IX, and X; and [(CD ) N] PO for IV, V, and VIII.
3
6
6
3 2
3
tetramethyl ether and neopentylene moieties. The
signal of the C3 atom in dihydroquercetin tetramethyl
ether is a doublet with the coupling constant JCP
yield of the target compound can be estimated at 75
80% from the integral intensities of the 31P NMR
signals.
2
6.7 Hz.
Thus, we showed that trivalent phosphorus acid
chlorides and amides are convenient and promising
agents for preparing phosphorylated derivatives of
partially protected dihydroquercetin.
In the next step, we studied phosphorylation of di-
hydroquercetin tetramethyl ether with ethyl tetraethyl-
phosphorodiamidite.
We also studied oxidation of phosphite II and
amidophosphite III. The reactions of II with sulfur
and selenium were carried out in anhydrous benzene:
with sulfur, for 2 h at 50 C with a catalytic amount
of triethylamine, to obtain O-3 ,4 ,5,7-tetramethyldi-
hydroquercetin-3-yl O,O -neopentylene phosphoro-
thioate IV, and with selenium, for 8 h at the same
OMe
MeO
O
OMe
EtO P(NEt2)2
I
O P NEt2
OEt
MeO
O
III
OMe
The reaction occurs in refluxing absolute toluene
in 8 h in the presence of catalytic amounts of diethyl-
amine hydrochloride. The reaction completion was
judged from TLC and 31P NMR data. In the 31P spec-
trum, the singlet at 134.2 ppm characteristic of the
starting phosphorylating reagent is absent, and two
singlets of equal intensity, belonging to the diastereo-
mers of ethyl dihydroquercetin-3-yl diethylphosphor-
amidite III, appear at 151.02 and 151.90 ppm. The
MeO
O
OMe
O11CH2
O11CH2
X
13
II
CH3
C
14
O P
X
CH3
MeO
O
IV, V
X = S (IV), Se (V).
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 73 No. 11 2003

1688
NIFANT’EV et al.
temperature without catalyst, to obtain O-3 ,4 ,5,7-tetra-
methyldihydroquercetin-3-yl O,O -neopentylene phos-
phoroselenoate V. Compounds IV and V spontaneous-
ly precipitated from the reaction mixtures.
we obtained the cis complex with O-3 ,4 ,5,7-tetra-
methyldihydroquercetin-3-yl O,O -neopentylene phos-
phate (IX), which showed doublets at
66.13 and
P
64.66 ppm (JPPt 5940.95 and 5904.79 Hz) [9], and
with copper, an O-3 ,4 ,5,7-tetramethyldihydroquer-
cetin-3-yl O,O -neopentylene phosphate complex X
Compound III was brought into reactions with
sulfur and selenium without isolation because of its
high lability. The reaction was performed at 20 C
with continuous stirring. In the first case, O-3 ,4 ,5,7-
tetramethyldihydroquercetin-3-yl O-ethyl diethylphos-
phoramidothioate VI was formed in 8 h, and in the
second case O-3 ,4 ,5,7-tetramethyldihydroquercetin-
3-yl O-ethyl diethylphosphoramidoselenoate VII was
obtained after stirring for 10 h.
with a typical broad signal at
103.65 ppm.
P
O
Me
Me
R O P
O
Cl
Cl
C8H12PtCl2
Pt
O
O
Me
Me
R O P
OMe
II
IX
MeO
O
O
OMe
1C1 H2 CH3
X
12
O
III
CuBr
Me
Me
R O P
11
13
O P N
O
CH215CH3
MeO
X
O 14
BrCu
CH2 CH3
X
VI, VII
X = S (VI), Se (VII).
OMe
OMe
MeO
O
O
R =
.
Compounds VI and VII were isolated by column
chromatography on silica gel, but we failed to separate
the diastereomers.
MeO
The structure of all the synthesized compounds was
confirmed by 13C NMR spectroscopy and elemental
analysis. As a rule, in going from three- to four-
cordinate phosphorus derivatives, no significant
carbon shift was observed. The data obtained are
listed in the table.
We also prepared O-3 ,4 ,5,7-tetramethyldihydro-
quercetin-3-yl O,O -neopentylene phosphate VIII by
passing an oxygen flow through a solution of phos-
phite II in benzene at external UV irradiation. Due to
its low solubility in benzene, compound VIII also
spontaneously crystallizes and precipitates from the
reaction mixture.
Thus, we synthesized the first 3 ,4 ,5,7-tetramethyl-
dihydroquercetin derivatives by phosphorylation at the
alcoholic hydroxy groups. We found that the complete
phosphites and their derivatives are relatively stable
in storage.
The completion of all the above reactions was
judged from disappearance of the signals the starting
phosphites in the 31P NMR spectra. The reactions
occur with virtually quantitative yields.
OMe
EXPERIMENTAL
MeO
O
The 13C NMR spectra were recorded on a Bruker
AC-200 instrument at operating frequency of
OMe
[O]
II
O
O
Me
Me
O P
O
50.32 MHz, external reference TMS. The 31P NMR
spectra were obtained on a Bruker WP-80 instrument
at operating frequency of 32.4 MHz, external reference
85% phosphoric acid. Optical rotation angles were
measured in an EPO polarimeter. Thin-layer chro-
matography was performed on Silufol plates in 1:1
(A) and 3:1 (B) benzene dioxane systems; the plates
were developed with iodine vapor and by calcination.
Absorption column chromatography was performed
on silica gel L 100/160 m.
MeO
O
VIII
We studied the reaction of phosphite II with some
transition metal derivatives, with the aim to obtain
metal complexes promising as catalysts in enantio-
selective processes. Phosphite II was brought into
reactions with copper monobromide and (cyclooctadi-
ene)platinum dichloride. With the platinum derivative,
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 73 No. 11 2003

PHOSPHORYLATION OF 3 ,4 ,5,7-TETRAMETHYLDIHYDROQUERCETIN
1689
All syntheses were performed under argon, using
absolute solvents.
O-3 ,4 ,5,7-Tetramethyldihydroquercetin-3-yl
O,O -neopentylene phosphoroselenoate V. To a
solution of 0.3 g of II in 10 ml of benzene, 0.05 g of
selenium was added with vigorous stirring.The reac-
tion was performed at 50 C for 8 h. The phosphoro-
selenoate precipitated spontaneously. Compound V
was isolated similarly to IV. Yield 0.39 g (95%), mp
3 ,4 ,5,7-Tetramethyldihydroquercetin-3-yl
neopentylene phosphite II. a. To a solution of 1 g of
I in 20 ml of benzene, 0.47 g of neopentylene phos-
phorochloridite in 10 ml of benzene and 0.28 of
freshly distilled triethylamine in 10 ml of benzene
were added simultaneously with vigorous stirring, and
the mixture was stirred for 2 h at 20 C. The mixture
was filtered, and 150 ml of hexane was added to the
filtrate. In so doing, a colorless precipitate of II
formed, which was then filtered off, washed with
hexane (2 30 ml), and dried in a vacuum. Yield
0.96 g (70%), mp 142 144 C, Rf 0.82 (A), 0.6 (B),
206 207 C, Rf 0.81 (A), 0.58 (B), [ ]2D6 4 (c 0.16,
hexamethylphosphoramide). 31P NMR spectrum:
P
65.9 ppm (JPSe 992.01 Hz). Found, %: C 50.71; H
5.28; O 25.32; P 4.94; Se 13.75. C24H29O9PSe. Cal-
culated, %: C 50.44; H 5.08; O 25.22; P 5.43; Se
13.83.
O-3 ,4 ,5,7-Tetramethyldihydroquercetin-3-yl
O-ethyl diethylphosphoramidothioate VI. To a
solution of 0.87 g of III in 15 ml of toluene, 0.0544 g
of crystalline sulfur was added with vigorous stirring
over a period of 3 h at 20 C in the presence of a
catalytic amount of triethylamine. The solution was
filtered, the solvent was removed in a vacuum, and
the residue was chromatographed on a column packed
with silica gel (eluent B). The fraction with Rf 0.77
was collected, the solvent was removed, and the
product was dried in a vacuum. Yield 0.8 g (85%),
[ ]1D8 11.3 (c 0.01, benzene). 31P NMR spectrum:
120.10 ppm, s. Found, %: C 57.37; H 6.57; O 30.68P;
P 5.38. C24H9O9P. Calculated, %: C 58.54; H 5.89;
O 29.27; P 6.30.
b. To a solution of 1 g of I in 10 ml of benzene,
0.46 g of neopentylene dimethylphosphoramidite in
5 ml of benzene and a catalytic amount of diethyl-
amine hydrochloride were added with vigorous stir-
ring. The mixture was refluxed for 6 h. Compound II
was isolated as described above. Yield 1.1 g (80%),
mp 142 144 C. The other characteristics correspond
to those of the compound obtained by method a.
yellow sirupy substance, Rf 0.57 (A), 0.77 (B), [ ]D18
41 (c 0.01, benzene). 31P NMR spectrum:
75.58
and 76.9 ppm, d. Found, %: C 55.32; H 6.57; PN 2.78;
O 24.19; P 5.51; S 5.63. C25H34NO8PS. Calculated,
%: C 55.66; H 6.31; N 2.60; O 23.74; P 5.75; S 5.94.
3 ,4 ,5,7-Tetramethyldihydroquercetin-3-yl
ethyl diethylphosphoramidite III. To a solution of
0.5 g of I in 20 ml of toluene, 0.3 g of ethyl tetraethyl-
phosphorodiamidite in 10 ml of toluene was added
with vigorous stirring. The reaction mixture was
refluxed for 10 h. The reaction completion was judged
from the 31P NMR spectra of the reaction mixture.
Amidophosphite III was not isolated because of its
high lability. The integral intensities of the peaks in
the 31P NMR spectra showed that the target compound
was formed in 75 80% yield, Rf 0.45 (A), 0.65 (B).
O-3 ,4 ,5,7-Tetramethyldihydroquercetin-3-yl
O-ethyl diethylphosphoramidoselenoate VII. To a
solution of 0.3 g of III in 15 ml of toluene, 0.1343 g
of selenium was added over a period of 5 h with
vigorous stirring at 20 C. Phosphoroselenoate VII
was isolated similarly to VI. Yield 0.6 g (60%),
yellow sirupy substance, Rf 0.59 (A), 0.79 (B), [ ]D18
45 (c 0.01, benzene). 31P NMR spectrum:
78.86
31P NMR spectrum: P 151.02 and 151.90 ppm, d.
and 81.27 ppm, d (JPSe 995.71 Hz). Found,P %: C
51.39; H 5.61; N 2.59; O 22.02; P 5.15; Se 13.24.
C25H34NO8PSe. Calculated, %: C 55.66; H 6.31; N
2.60; O 23.74; P 5.75; Se 5.94.
O-3 ,4 ,5,7-Tetramethyldihydroquercetin-3-yl
O,O -neopentylene phosphorothioate IV. To a solu-
tion of 0.3 g of II in 10 ml of benzene, 0.02 g of
crystalline sulfur was added with vigorous stirring.
The reaction was carried out for 2 h at 50 C with
addition of a catalytic amount of triethylamine. The
phosphorothioate precipitated spontaneously. The
precipitate was filtered off, washed with benzene and
hexane (2 50 ml), and dried in a vacuum. Yield
0.31 g (96%), mp 200 201 C, Rf 0.83 (A), 0.58 (B),
3 ,4 ,5,7-Tetramethyldihydroquercetin-3-yl
neopentylene phosphate VIII. Through a solution
of 0.3 g of II in 10 ml of benzene in a fused quartz
tube, an oxygen flow was passed for 6 h at external
UV irradiation. The reaction product spontaneously
precipitated as a colorless substance. Compound VIII
was filtered off, washed with benzene and hexane
(2 50 ml), and dried in a vacuum. Yield 0.30 g
[ ]2D6
NMR spectrum:
7
(c 0.17, hexamethylphosphoramide). 31P
59.2 ppm. Found, %: C 55.29; H
(98%), mp 209 211 C, Rf 0.84 (A), 0.57 (B), [ ]D26
P
5.77; O 27.38; P 5.75; S 5.81. C24H29O9PS. Cal-
culated, %: C 54.96; H 5.53; O 27.48; P 5.92; S 6.11.
8
(c 0.17, hexamethylphosphoramide). 31P NMR
spectrum:
9.98 ppm, s. Found, %: C 56.20; H
P
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 73 No. 11 2003

1690
NIFANT’EV et al.
6.08; O 2.01; P 5.71. C24H29O10P. Calculated, %: C
56.69; H 5.71; O 31.50; P 6.10.
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103.6 ppm, br.m.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 73 No. 11 2003