Directional phosphorylation of dihydroquercetin with phosphorous acids amides

Article abstract of DOI:10.1134/S1070363208080069

The monophosphorylated products were obtained by phosphorylation of 2,3-dihydroquercetin with phosphorous acid amides. Sulfur addition to these compounds was studied.

Full text of DOI:10.1134/S1070363208080069

ISSN 1070-3632, Russian Journal of General Chemistry, 2008, Vol. 78, No. 8, pp. 1497–1499. © Pleiades Publishing, Ltd., 2008.
Original Russian Text © E.E. Nifant’ev, Yu.A. Knyaz’kova, T.S. Kukhareva, L.K. Vasyanina, M.P. Koroteev, G.Z. Kaziev, 2008, published in Zhurnal
Obshchei Khimii, 2008, Vol. 78, No. 8, pp. 1262–1264.
Directional Phosphorylation of Dihydroquercetin
with Phosphorous Acids Amides
E. E. Nifant’ev, Yu. A. Knyaz’kova, T. S. Kukhareva,
L. K. Vasyanina, M. P. Koroteev, and G. Z. Kaziev
Moscow Pedagogical State University
Nesvizhskii per. 3, Moscow,119021 Russia
e-mail: chemdept@mtu-net.ru
Received March 3, 2008
Abstract—The monophosphorylated products were obtained by phosphorylation of 2,3-dihydroquercetin with
phosphorous acid amides. Sulfur addition to these compounds was studied.
DOI: 10.1134/S1070363208080069
An available product of wood chemistry, 2,3-
dihydroquercetin flavonoid [1], is an effective
antioxidant. Therefore it is presently used as a food
additive. Yet the structure of this compound is not
congeneric to the human biological tissue that hampers
its application as bioregulator in medical practice.
its structure of biogenic phosphorous groups [2]. In
this communication we report on the design of singular
dihydroquercetin phosphates and amidophosphates.
All these compounds were obtained by phosphoryla-
tion of the flavonoid with available and convenient in
handling phosphorous acid amides [3].
In terms of the aforesaid we began an investigation
of dihydroquercetin modification by incorporation into
We established that the dihydroquercetin pentaol
was selectively phosphorylated at the hydroxy group in
5'
OH
OH
4'
6'
1
O
8
3'
X2P
O
O
R2NPX2
HO
9
2
7
1'
OH
OH
2'
3
6
10
OH
OH
5
4
OH
O
OH
O
I
II
O
H
R2N
R2N
[S]
P
OH
OH
OH
OH
S
O
P
X2P
O
O
H
O
O
O
R2N
OH
OH
OH
O
OH
IV
III
O
O
N
(b),
(c).
X = NEt2 (a),
1497

1498
NIFANT’EV et al.
position 7 in the reaction with phosphamide reagents
under the conditions we developed. We believe it to
result from the passivation of the four remaining
hydroxy groups owing to formation of hydrogen bonds
with the adjacent functional groups.
2,3-dihydroquercetin in 3 ml of dioxane was slowly
added dropwise at 0–5°С a solution of 1 mmol of
phosphorous acid hexaethyltriamide in 5 ml of di-
oxane. Then the reaction mixture was stirred for 15 min
at room temperature. In the 31Р NMR spectrum a signal
at 131.2 ppm was observed. To the reaction mixture
was added 1 mmol of the powdered elemental sulfur
and the stirring was continued for 2 h. Then the solvent
was evaporated under a vacuum and the dry residue
was dissolved in benzene. This solution was filtered
and product was precipitated with hexane from the
benzene solution. The product isolated was washed
with hexane and dried for 3 h (1 mm Hg, 40°С). Yield
0.215 g (42.1%), yellow powder, decomposition point
The structure of the phosphorylating agent affects
strongly the reaction course and yield of the desired
product. The phosphorous acid triamides with the
sterically hindered phosphorus atom, for example,
tripiperidide, favor a more selective process and
provide a better yield of the final compounds,
thionophosphates III. The use of cyclic monoamido-
phosphite considerably hinders the reaction course
(reaction proceeds at 70°С) and decreases the product
yield. In this work we pioneered an application of
hydrophosphoryl compound, phosphorous acid tetra-
ethyldiamide, as the phosphorylating agent. Reaction
proceeds at 40ºC for 4 h. The product yield is not high.
1
80–85°C, Rf 0.54 (A), 0.82 (B). Н NMR spectrum, δ,
ppm: 1.08 t (12H, CH3CH2N, 3JHH 6.9 Hz), 3.1 m (8H,
3
3
CH3CH2N, JHH 6.9 Hz, JHP 13.5 Hz), 4.64 d (1H, H3,
3JHH 11.3 Hz), 5.09 d (1H, H2, JHH 11.3 Hz), 5.7 br.s
3
(1Н, C3OH), 6.20 s (1H, H8), 6.25 s (1H, H6), 6.75 s
(2H, H5' and H6'), 6.9 s (1H, H2'), 9.1 (2H, C4'OH and
C3'OH), 11.7 (1H, С5ОН). 31P NMR spectrum, δ, ppm:
75.8. Found, %: С 54.15; Н 6.07; N 5.44; Р 6.05; S
6.05. Calculated, % : С 54.12; Н 6.08; N 5.49; Р 6.07;
S 6.07.
Compounds II were involved into reaction with
sulfur without isolation from the reaction mixture
followed by isolation of pure thionophosphates III.
All new compounds obtained were isolated in pure
state and characterized with physicochemical methods.
1
In the H NMR spectra of all compounds obtained the
2,3-Dihydroquercetin 7-dipiperidylthionophos-
phate (IIIb) was prepared similarly from 0.304 g of
2,3-dihydroquercetin and 0.283 g of tripiperidylphos-
phite. Yield 0.313 g (58.7%), yellow powder, mp 83–
signal of hydroxy groups protons in 7 position is
absent, but signals of all others hydroxy group protons
are observed.
1
85°C, Rf 0.34(A), 0.85 (B), 0.72 (C). Н NMR spec-
EXPERIMENTAL
trum, δ, ppm: 1.56 m (12H, CH2mCH2p3CH2m piperidine
,
3JHH 6.5 Hz), 3.09 m (8H, CH2NCH2 JHP 12.4 Hz,
The 1Н NMR spectra were taken on a Bruker WM-
250 spectrometer (250 МHz), internal reference TMS.
Assignment of proton signals was made on the basis of
double resonance data. 31Р–{1H} NMR spectra were re-
gistered on a Bruker WР-80 SY spectrometer (32.4 МHz)
relative to external 85% phosphoric acid.
3
3JHH 6.5 Hz), 4.43 d (1H, H3, JHH 10.7 Hz), 4.96 d
3
(1H, H2, JHH 10.7 Hz), 5.3 br.s. (1Н, C3OH), 5.80 s
4
4
(1H, H8, JHH 2.1 Hz), 5.85 s (1H, H6, JHH 2.1 Hz),
6,74 s (2H, H5' and H6'), 6.87 s (1H, H2'), 9.18 (2H,
C4'OH and C3'OH), 11.5 (1H, С5ОН). 31P NMR
spectrum, δ, ppm: 74.6. Found, %: С 56.22; Н 5.82; N
5.27; Р 5.83. Calculated, %: С 56.21; Н 5.85; N 5.23;
Р 5.84.
All the syntheses with the trivalent phosphorus
compounds were carried out under the dry nitrogen
atmosphere in anhydrous solvents dried by standard
procedures.
2,3-Dihidroquercetin 7-neopentylenethionophos-
phate (IIIc). To a stirred solution of 1 mmol of
dihydroquercetin in 3 ml of dioxane was added
dropwise at 10°С 1 mmol of neopentylenamidophos-
phite in 2 ml of dioxane. The reaction mixture was
stirred for 5 h at 70°С. In the 31Р NMR spectrum a
signal was observed in the range 115.1 ppm. Then to
the reaction mixture was added 1 mmol of the
powdered elemental sulfur, and it was stirred for 1.5 h.
The solvent was evaporated under a vacuum and the
dry residue was dissolved in benzene. This solution
Analysis by thin-layer chromatography was accom-
plished on Silufol UV-254 plates using the systems
benzene-dioxane 3:1 (А), hexane-dioxane 1:1 (B) and
benzene-dioxane 1:1 (C). Development was performed
with iodine vapor and by calcination.
The starting materials were synthesized by the
known procedures.
2,3-Dihydroquercetin 7-tetraethyldiamidothiono-
phosphate (IIIa). To a stirred solution of 1 mmol of
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 78 No. 8 2008

DIRECTIONAL PHOSPHORYLATION OF DIHYDROQUERCETIN
1499
was filtered and the product was isolated by
precipitation with hexane from benzene. The isolated
product was washed with hexane and dried for 3 h (1
mm Hg, 40°С). Yield 0.170 g (35.6%), light yellow
powder, mp 90–92°C, Rf 0.29 (A), 0.62 (B), 0.77 (C).
1Н NMR spectrum, δ, ppm: 0.88 s (3H, CH3e), 1.13 s
ppm: 1.03 t (3H, CH3CH2N, 3JHH 6.9 Hz), 2.95 m (2H,
CH3CH2NP, JHH 6.9 Hz, JPH 12.1 Hz), 4.16 d (1H,
3
3
3
3
H3, JHH 10.6 Hz), 4.96 d (1H, H2, JHH 10.6 Hz), 5.64
br.s (1H, C3OH), 5.83 s (1H, H8, JHH1 1.8 Hz), 5.88 s
4
(1H, H6, JHH 1.8 Hz), 6.6 (1H, HP, JPH 566.86 Hz),
4
6.74 s (2H, H5' and H6'), 6.81 s (1H, H2'), 8.9 br.s (2H,
C3'OH and C4'OH), 11.9 br.s (1H, C5OH). 31P NMR
spectrum, δ, ppm: 20.2 s (1JPH 582 Hz). Found, %: С
53.89; Н 5.22; N 3.30; Р 7.35. Calculated, %: С 53.90;
Н 5.20; N 3.31; Р 7.33.
3
(3H, CH3a), 3.50 s (2H, CH2e, JHP 10.6 Hz), 4.03 s
(2H, CH2a, 4JHaHe 5.9 Hz), 4.78 d (1H, H3, 3JHH 10.4 Hz),
3
4.99 d (1H, H2, JHH 10.4 Hz), 5.6 br.s (1Н, C3OH),
4
4
5.89 s (1H, H8, JHH 2.1 Hz), 5.93 s (1H, H6, JHH
2.1 Hz), 6,77 s (2H, H5' and H6'), 6.9 s (1H, H2'), 8.9
(2H, C4'OH and C3'OH), 11,8 (1H, С5ОН). 31P NMR
spectrum, δ, ppm: 65.1. Found, %: С 51.31; Н 4.55; Р
6.63. Calculated, %: С 51.30; Н 4.57; Р 6.64.
REFERENCES
1. Nifant’ev, E.E., Kukhareva, T.S., Dzgoeva, Z.M.,
Vasyanina, L.K., Koroteev, M.P., and Kaziev, G.Z.,
Heteroatom Chem., 2003, vol. 14, no. 5, p. 399.
2. Nifant’ev, E.E., Kukhareva, T.S., Koroteev, M.P.,
Dzgoeva, Z.M., Kaziev, G.Z., and Vasyanina, L.K.,
Bioorg. Khim., 2001, vol. 27, no. 4, p. 314.
3. Nifant’ev, E.E., Koroteev, M.P., Kukhareva, T.S., Ka-
ziev, G.Z., and Nifant’ev, N.E., Abstracts of Papers,
The 4-th All-Russian Conference “Chemistry and Tech-
nology of Plant Chemistry,” Syktyvkar, 2006, p. 286.
2,3-Dihidroquercetin 7-diethylaminophosphite
(V). To a stirred solution of 1 mmol of dihyd-
roquercetin in 15 ml of dioxane was added at room
temperature 1.3 mmol of tetraethyldiamidophosphite.
Then the reaction mixture was stirred for 4 h at 40ºC.
The precipitate was washed with benzene and dried in
a vacuum. Yield 0.143 g (32.7%), colorless powder,
1
mp 118–120°C, Rf 0.61 (C). Н NMR spectrum, δ,
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 78 No. 8 2008