Phosphates, phosphinate, and hydrophosphoryl compound derived from flavonoid dihydroquercetin

Full text of DOI:10.1134/S0012500811110085

ISSN 0012ꢀ5008, Doklady Chemistry, 2011, Vol. 441, Part 1, pp. 330–333. © Pleiades Publishing, Ltd., 2011.
Original Russian Text © E.E. Nifant’ev, M.S. Krymchak, T.S. Kukhareva, L.K. Vasyanina, 2011, published in Doklady Akademii Nauk, 2011, Vol. 441, No. 2, pp. 201–204.
CHEMISTRY
Phosphates, Phosphinate, and Hydrophosphoryl Compound Derived
from Flavonoid Dihydroquercetin
Corresponding Member of the RAS E. E. Nifant’ev, M. S. Krymchak,
T. S. Kukhareva, and L. K. Vasyanina
Received April 20, 2011
DOI: 10.1134/S0012500811110085
In recent years, there has been growing interest of alkyl thiophosphoric and selenophosphoric acids [3].
organic chemists in plantꢀderived products. Thus,
studies were carried out to convert flavonoid dihydroꢀ
quercetin into a series of efficient pharmaceuticals
[1, 2]. In this context, our aim was to develop the synꢀ
thesis of organophosphorus compounds based on the
above flavonoid using trivalent phosphorus derivatives.
Thus, we obtained interesting results on the synthesis
It is significant that these compounds show high cytoꢀ
toxic activity [4]. Nonetheless, this method of syntheꢀ
sis has certain limitations. For example, we failed to
obtain dihydroquercetin phosphates and phosphinates
in good yield. Therefore we studied the phosphorylaꢀ
tion of dihydroquercetin (
I) with dialkyl phosphoroꢀ
of modified dihydroquercetins containing residues of chloridates and diphenylphosphinic chloride.
5'
OH
4'
6'
O
P
OH
OH
RO
RO
1
O
8
O
Py
HO
2
3
+
O
O
O
(RO)2P
1'
3'
–Py · HCl
OH
7
6
9
Cl
2'
10
4
OH
OH
5
II–IV
I
OH
O
OH
O
II: R = Me;
III: R = Et;
Py
–Py · HCl
Ph2P
Cl
O
OH
OH
IV: R =
Ph
Ph
P
O
O
OH
V
OH
O
Scheme 1.
The reactions were carried out in an anhydrous quercetin at the hydroxy groups at the 7ꢀ, 3'ꢀ, and
dioxane medium in a nitrogen atmosphere in the presꢀ
ence of anhydrous pyridine as a hydrogen chloride
scavenger and a catalyst at an equimolar ratio of the
reagents.
4'ꢀpositions of the flavonoid core [5], the phosphorylꢀ
ation with pentavalent phosphorus reagents proceeds
only at the most reactive hydroxy group at the 7ꢀposiꢀ
tion.
It should be noted that, in contrast to tris(diethylꢀ
amino)phosphine that readily reacted with dihydroꢀ
Phosphorylation with phosphorochloridates proꢀ
ceeded with low rates. However, the use of microwave
radiation allows a considerable increase in reaction
rate. At the same time, the phosphorylation with phosꢀ
phinic acid chloride required a much shorter time.
Moscow State Pedagogical University,
ul. Malaya Pirogovskaya 1, Moscow, 119899 Russia
330

PHOSPHATES, PHOSPHINATE, AND HYDROPHOSPHORYL COMPOUND
331
The phosphorylation course and reaction mixture and alkyl and aryl substituents with corresponding
3
spin–spin coupling constants JPH.
13C NMR spectra
composition were monitored by thin layer chromatogꢀ
raphy (TLC) and 31P NMR spectroscopy. 31P NMR
spectra showed singlet signals with chemical shifts –
9.4 ppm (II), –12.6 ppm (III), –20.0 ppm (IV), and
fully confirm the structure of the above compounds
(see Experimental).
One of important aims of our study was to obtain
hydrophosphoryl compounds based on dihydroquerꢀ
cetin. Common hydrogen phosphites do not react
with dihydroquercetin, therefore we used the hydrolyꢀ
sis of phosphoramidite VI prepared from dihydroquerꢀ
25.9 ppm (V). Compounds II–V were isolated by colꢀ
umn chromatography. Their structure was confirmed
by 1H and 13C NMR spectroscopy. The 1H NMR specꢀ
tra of these compounds show the lack of proton signal
of the hydroxy group at the 7 position in the region of
10.8 ppm and show signals typical for flavonoid core cetin (I):
O
C2H5O
P
OH
OH
(C2H5)2N
O
O
O
C2H5O
I +
P N(C2H5)2
(C2H5)2N
OH
VI
OH
O
P
OH
OH
VII
H
C2H5O
O
O
H2O, T, °C
OH
OH
O
Scheme 2.
Phosphoramidite VI without isolation from reacꢀ
tion mixture was hydrolyzed using an equimolar
amount of water. Reaction course was monitored by
EXPERIMENTAL
NMR spectra were recorded on a JNMꢀECX 400
spectrometer (operating at 161.83 MHz for 31P,
TLC and 31P NMR spectroscopy. When reaction mixꢀ 100.5 MHz for 13C, and 400 MHz for 1H) using TMS
1
as an internal reference for H and 13C NMR spectra
and 85% H3PO4 as an external reference for 31P{1H}
NMR spectra. Elemental analyzes were made with a
PerkinElmer 2400 analyzer. Certain syntheses were
carried out using CEM Discover microwave reactor.
All syntheses were performed in a dry nitrogen atmoꢀ
sphere in solvents dried using standard procedures.
ture was kept at 40–50°
C for 14 h, 31P NMR spectrum
showed the disappearance of the signal of compound
VI at 145.1 ppm and appearance of a singlet at 2.9 ppm
with 1JPH = 647 Hz corresponding to compound VII
.
Increase in temperature above this range favored
destructive processes and reduced the yield of comꢀ
pound VII
.
TLC analysis was conducted with Silica gel 60 F254
plates using benzene–dioxane (3 : 1, A), benzene–
dioxane (1 : 1, B), and hexane–dioxane (1 : 3, C) sysꢀ
tems. Compounds were visualized with iodine vapor or
by calcination.
The noted ethyl phosphite VII was isolated in pure
state and characterized by 1H and 13C NMR spectrosꢀ
copy. The 1H NMR spectrum shows the lack of signal
corresponding to hydroxy group at the 7' position and
shows the proton signals of flavonoid core and phosꢀ
Melting points were determined in sealed capillary
tubes at heating rate of 1 K/min. The phosphorylating
phorusꢀcontaining substituent. 13C NMR spectrum reagents were obtained by standard procedures, and
their constants coincided with literature data.
2,3ꢀDihydroquercetin 7ꢀ ꢀ(dimethyl phosphate) (II).
Dimethyl phosphorochloridate (0.143 g) was added
to a mixture of 0.304 g of dihydroquercetin ( ) and
0.08 mL of pyridine dissolved in 50 mL of dioxane at
ambient temperature under continuous stirring.
fully confirms the structure of compound VII
.
O
Thus, we synthesized for the first time in satisfacꢀ
tory yield novel phosphorusꢀcontaining dihydroquerꢀ
cetins that are of interest as potential biologically
active compounds.
I
DOKLADY CHEMISTRY Vol. 441
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2011

332
NIFANT’EV et al.
(
C6'), 116.93 (C5'), 121.29 (C2'), 127.15 (C1'), 146.24
(1) The reaction mixture was kept for 48 h at ambiꢀ
ent temperature.
(C4'), 146.92 (C3'), 162.91 (C9), 164.62 (C5), 167.49
(C7), 197.74 (C4).
(2) The reaction mixture was kept for 3 h at 25
the CEM Discover microwave reactor.
°C in
For C19H21O10P anal. calcd. (%): C, 51.82; H, 4.81;
P, 7.03.
In the case of compounds II–IV, the reaction mixꢀ
ture was filtered. The solvent was removed in a vacꢀ
uum. The solid residue was dissolved in dioxane and
purified by column chromatography using system B as
an eluent. All prepared compounds are yellow powꢀ
ders.
Found (%): C, 51.78; H, 4.99; P, 7.30.
2,3ꢀDihydroquercetin 7ꢀOꢀ(neopentylene phosꢀ
phate) (IV). Neopentylene phosphorochloridate
(0.185 g) was added to a mixture of 0.304 g of dihydroꢀ
quercetin (I) and 0.08 mL of pyridine dissolved in
50 mL of dioxane at ambient temperature and continꢀ
uous stirring.
Compound II: yield 0.103 g (25%), mp. 66–68
°C,
f 0.38 (B), 0.69 (C).
R
31P NMR (acetoneꢀd6
1H NMR (acetoneꢀd6
CH3О)2Р
,
δ
, ppm): –9.4 s.
(1) The reaction mixture was kept for 96 h at ambiꢀ
ent temperature.
,
δ, ppm, , Hz): 3.6 (d, 6H,
J
3
(
,
3JРН 11.04), 4.6 (d, 1H, C3H, JHH 11.9),
(2) The reaction mixture was kept for 5 h at 30
the CEM Discover microwave reactor.
°
C in
4.97 (d, 1H, C2H, 3JHH 11.9), 5.91 (d, 1H, C8H, 4JHH
4
2.4), 5.96 (d, 1H, C6H, JHH 2.4), 6.83 (s, 2H, C5'H
Compound IV: yield 0.11 g (24%), mp. 78–80
f 0.35 (B), 0.58 (C).
°
C,
and C6'H), 7.07 (s, 1H, C2'H), 8.69 (br s, 2H, С3'OH
R
and С4'OH), 11.5 (s, 1H, C5OH).
31P NMR (acetoneꢀd6
1H NMR (acetoneꢀd6
1.25 (both s, 6H, CН3), 4.02 (m, 2H,
,
δ
, ppm): –20.0 s.
13C NMR (acetoneꢀd6
,
δ, ppm,
J
, Hz): 54.19 (d,
,
δ
, ppm, , Hz): 0.85 and
J
СН3, JCP 5.82), 72.35 (С3), 83.64 (С2), 95.38 (С8),
96.41 (C6), 100.63 (C10), 115.7 (C6'), 115.23 (C5'),
120.07 (C2'), 128.85 (C1'), 145.84 (C4'), 146.12 (C3'),
e 3
2
,
11.3,
CH2
J
PHэ
2JHH 7.1), 4.48 (m, 2H, CНa
,
2JHH 7.1), 4.58 (d, 1H,
H2
3
3
C3H, JHH 11.0), 4.99 (d, 1H, C2H, JHH 11.0), 5.90
163.25 (C9), 164.07 (C5), 167.3 (C7), 197.27 (C4)
For C17H17O10P anal. calcd. (%): C, 49.52; H, 4.16;
P, 7 . 5 1 .
Found (%): C, 49.34; H, 4.32; P, 7.82.
2,3ꢀDihydroquercetin 7ꢀ ꢀ(diethyl phosphate)
(III). Diethyl phosphorochloridate (0.173 g) was
added to a mixture of 0.304 g of dihydroquercetin (
.
4
4
(d, 1H, C8H, JHH 2.3), 5.97 (d, 1H, C6H, JHH 2.3),
3
3
6.8 (d, 1H, C5'H, JHH 8.1), 6.87 (d, 1H, C6'H, JHH
8.1), 7.04 (s, 1H, C2'H), 8.1 (br s, 2H, C3'OH and
C4'OH), 11.6 (s, 1H, C5OH).
O
13C NMR (acetoneꢀd6
, δ, ppm, J, Hz): 18.7 and
20.76 (CH3), 31.88(С), 72.28 (С3), 79.34 с, 83.66 (С2),
95.25 (С8), 96.18 (C6), 100.65 (C10), 115.05 (C5'),
115.14 (C2'), 120.00 (C6'), 128.94 (C1'), 141.47 (C4'),
144.88 (C3'), 163.32 (C9), 164.94 (C7), 163.89 (C5),
I)
and 0.08 mL of pyridine dissolved in 50 mL of dioxane
at ambient temperature and continuous stirring.
(1) The reaction mixture was kept for 72 h at ambiꢀ
ent temperature.
197.32 (C4)
For C21H24O10P anal. calcd. (%): C, 53.97; H, 5.18;
P, 6.63.
Found (%): C, 53.69; H, 5.92; P, 6.38.
2,3ꢀDihydroquercetin 7ꢀ ꢀdiphenylphosphinate (V).
Diphenylchlorophosphinate (0.19 mL) was added to a
mixture of 0.304 g of dihydroquercetin ( ) and
.
(2) The reaction mixture was kept for 3 h at 25°C in
the CEM Discover microwave reactor.
Compound III: yield 0.1 g (22%), mp. 73–75°C,
f 0.43 (B), 0.65 (C).
R
O
31P NMR (acetoneꢀd6
,
δ, ppm): –12.6 s.
1H NMR (acetoneꢀd6
,
δ
, ppm, , Hz): 1.21 (t, 6H,
J
I
0.08 mL of pyridine dissolved in 50 mL of dioxane at
ambient temperature and continuous stirring. The
reaction mixture was kept for 10 h at ambient temperꢀ
ature and filtered. The solvent was removed in a vacꢀ
uum. The solid residue was dissolved in benzene and
purified by column chromatography using system B as
an eluent.
3
3
CH3
,
3JHH 7.4), 3.99 (m, 4H, СН2, JРH 8.69, JHH
3
7.4), 4.60 (d, 1H, C3H, JHH 11.4), 5.0 (d, 1H, C2H,
3JHH 11.4), 5.96 (d, 1H, C8H, JHH 1.8), 5.99 (d, 1H,
4
C6H, 4JHH 1.8), 6.8 (s, 2H, C5'H and C6'H), 7.1 (s, 1H,
C2'H), 7.9 (br s, 2H, С3'OH and С4'OH), 11.8 (s, 1H,
С5OH).
13C NMR (acetoneꢀd6
,
δ, ppm, J, Hz): 15.36
Compound
V: yield 0.09 g (18%), mp. 75–77°C,
f 0.42 (B), 0.64 (C).
31P NMR (acetoneꢀd6
, δ, ppm): 25.9 s.
R
2
(CH3), 58.59 (d, СН2, JCP 6.13), 71.73 (C3), 84.43
(C2), 94.27 (C8), 95.16 (C6), 101.87 (C10), 116.41
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PHOSPHATES, PHOSPHINATE, AND HYDROPHOSPHORYL COMPOUND
333
1
1H NMR (DMSOꢀd6
,
δ
, ppm,
J
, Hz): 4.56 (d, 1H,
31P NMR (acetoneꢀd6
647 Hz).
1H NMR (acetoneꢀd6
, δ, ppm): 2.89 (d, JРН
C3H, JHH 11.4), 4.98 (d, 1H, C2H, JHH 11.4), 5.94
3
3
4
4
(d, 1H, C8H, JHH 1.8), 5.97 (d, 1H, C6H, JHH 1.8),
,
δ
, ppm,
CH3, JHH 7.2), 3.68 (m, 2H, СН2
3JHH 7.2), 4.44 (d, 1H, C3H, 3JHH 11.74), 4.94 (d, 1H,
J
, Hz): 1.14 (t, 3H,
6.82 (d, 2H, C5'H and C6'H, JHH 12.4), 7.04 (s, 1H,
3
3
,
3JРН 8.68,
C2'H), 7.32–7.77 (m, 10H, Ph), 12.3 (s, 1H, C5'OH).
C2H, JHH 11.74), 5.83 (d, 1H, C8H, JHH 2.8), 6.02
(d, 1H, C6H, 4JHH 2.8), 6.55 (d, 1H, 2JРH 580), 6.74 (d,
1H, C5'H, 3JHH 5.3), 6.78 (d, 1H, C6'H, 3JHH 5.3), 6.84
(s, 1H, C2'H), 9.2 (br s, 2H, C3'OH, C4'OH), 11.79 (s,
1H, C5'OH).
3
4
13C NMR (acetoneꢀd6 , ppm): 71.95 (C3), 84.14
, δ
(C2), 94.68 (C8), 95.11 (C6), 102.81 (C10), 114.7 (C6'),
117.53 (C5'), 121.27 (C2'), 128.93–131.6 (Ph), 132.65
(C1'), 146.34 (C4'), 147.52 (C3'), 156.7 (C9), 159.25
(C5), 163.06 (C7), 196.98 (C4).
13C NMR (acetoneꢀd6
, δ, ppm): 17.17 (s, CH3),
For C27H21O8P anal. calcd. (%): C, 64.29; H, 4.20;
P, 6 . 1 4 .
58.69 (d, CН2, 2JCP 8.9), 72.05 (С3), 83.56 (С2), 95.57
(С8), 96.56 (C6), 100.83 (C10), 115.66 (C5'), 115.91
(C2'), 119.8 (C6'), 128.86 (C1'), 145.52 (C3'), 146.34
Found (%): C, 64.67; H, 4.76; P, 6.25.
2,3ꢀDihydroquercetin 7ꢀ
phoramidite) (VI). ',
diamidite (0.22 mL) was added to a mixture of 0.304 g
of dihydroquercetin ( ) and 0.08 mL of pyridine disꢀ
Oꢀ(O,N,Nꢀtriethylphosꢀ
2
(C4'), 163.04 (C9), 163.83 (C5), 167.82 (C7, JCP
O,N,N,N N'ꢀPentaethylphosphorꢀ
0.97 Hz), 198.23 (C4)
.
For C17H17O9P anal. calcd. (%): C, 51.52; H, 4.32;
P, 7.82.
I
solved in 50 mL of dioxane at ambient temperature
and continuous stirring. The reaction mixture was
kept for 2 h at ambient temperature. The product was
not isolated from the reaction mixture.
Found (%): C, 51.58; H, 4.51; P, 7.81.
REFERENCES
Compound VI
31P NMR (dioxane,
2,3ꢀDihydroquercetin 7ꢀ
:
R
f 0.55 (A), 0.75 (B).
, ppm): 145.1 s.
ꢀ(ethyl hydrogen phosꢀ
1. Kolkhir, V.K., Tyukavkina, N.A., Bykov, V.A., et al.,
Khim.ꢀFarm. Zh., 1995, no. 9, pp. 61–64.
δ
2. Habtermarian, S., J. Nat. Prod., 1997, vol. 60, no. 8,
O
pp. 775–778.
phite) (VII). Water (0.018 mL) was added to a solution
of 0.451 g of compound VI in 50 mL of dioxane and
stirred at 40°C for 14 h. The reaction mixture was filꢀ
3. Nifant’ev, E.E., Kukhareva, T.S., Koroteev, M.P., et al.,
Russ. J. Bioorg. Chem., 2001, vol. 27, no. 4, pp. 278–
279.
tered. The solvent was removed in a vacuum. The solid
residue was dissolved in dioxane. The reaction product
4. Rogovskii, V.S., Matyushin, A.I., Shimanovskii, N.L.,
et al., Eksp. Klin. Farmokol., 2010, vol. 73, no. 9,
pp. 39–42.
5. Nifant’ev, E.E., Krymchak, M.S., Kukhareva, T.S.,
et al., Russ. J. Gen. Chem., 2010, vol. 80, no. 3, pp. 423–
427.
(
VII) was precipitated from dioxane with hexane.
Compound VII: yield 0.1 g (26%), mp. 62–64
f 0.64 (B), 0.72 (C).
°
C,
R
DOKLADY CHEMISTRY Vol. 441
Part 1
2011