Synthesis of Novel Phosphoric Esters of Flavone and Isoflavone by Atherton-Todd Reaction

Article abstract of DOI:10.1081/SCC-120027289

7-hydroxyflavone, chrysin, 4′-chloro-7-hydroxyisoflavone and 4′-fluo-7-hydroxy-isoflavone were phosphoylated by the Atheron-Todd reaction. The expected phosphates are obtained in good yields.

Full text of DOI:10.1081/SCC-120027289

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Synthesis of Novel Phosphoric Esters of Flavone and
Isoflavone by Atherton–Todd Reaction
a
a
a
a
a b
Xiaolan Chen , Youzhu Yu , Lingbo Qu , Xincheng Liao & Yufen Zhao
a
Department of Chemistry , Zhengzhou University , 75 Daxue Road, Henan Province,
Zhengzhou, 450052, P.R. China
b
The Key Laboratory for Bioorganic Phosphorus Chemistry, Department of Chemistry
School of Life Sciences and Engineering , Tsinghua University , Beijing, P.R. China
Published online: 16 Aug 2006.
To cite this article: Xiaolan Chen , Youzhu Yu , Lingbo Qu , Xincheng Liao & Yufen Zhao (2004) Synthesis of Novel
Phosphoric Esters of Flavone and Isoflavone by Atherton–Todd Reaction, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 34:3, 493-499, DOI: 10.1081/SCC-120027289
To link to this article: http://dx.doi.org/10.1081/SCC-120027289
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w
SYNTHETIC COMMUNICATIONS
Vol. 34, No. 3, pp. 493–499, 2004
Synthesis of Novel Phosphoric Esters
of Flavone and Isoflavone by
Atherton–Todd Reaction
1
Xiaolan Chen, Youzhu Yu, Lingbo Qu, Xincheng Liao,
1
1,*
1
1
,2,
*
and Yufen Zhao
1
Department of Chemistry, Zhengzhou University, Zhengzhou,
P.R. China
2
The Key Laboratory for Bioorganic Phosphorus Chemistry, Department
of Chemistry School of Life Sciences and Engineering, Tsinghua
University, Beijing, P.R. China
ABSTRACT
0 0
-hydroxyflavone, chrysin, 4 -chloro-7-hydroxyisoflavone and 4 -fluo-7-
7
hydroxy-isoflavone were phosphoylated by the Atheron–Todd reaction.
The expected phosphates are obtained in good yields.
Key Words: Phosphoric esters; Flavone; Isoflavone; Atherton–Todd
reaction.
*
Correspondence: Lingbo Qu and Yufen Zhao, Department of Chemistry, Zhengzhou
University, 75 Daxue Road, Henan Province, Zhengzhou 450052, P.R. China; E-mail:
qulingbo@zzu.edu.cn.
4
93
DOI: 10.1081/SCC-120027289
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

ORDER
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4
94
Chen et al.
Phosphates and phosphoroamidates have wide bio-activities. Ester and
amides of phosphoric acid play a vital role in many biological process and they
appear to be synthesized and to undergo interconversion in living organisms
[
1]
with great ease. With respect to introducing these functionalities into
biomolecules, Atherton–Todd reaction is a useful synthetic approach. It
involves the oxidation of diakyl phosphates with chlorocarbons into dialkyl or
trialkyl phosphates. The versatility of the reaction results from the fact that the
initial products in the reaction are the highly reactive dialkyl chlorophos-
phates, which in the presence of amines or alcohols are converted in situ into
the corresponding dialkyl phosphoramides or trialkyl phosphates, respect-
[
2]
ively. Among several methods, which have been used to prepare DIPP
protected amino acids, Zhao’s modification of the classical Atherton–Todd
procedure, by mixing amino acid with diisopropylphosphite(DIPPH) in the
presence of water, ethanol, carbon tetrachloride and triethyl amine, is very
[3]
successfully one with good yields of objective products.
In recent years, flavones and isoflavones have attracted increasing
[4–6]
interests due to their various beneficial pharmacological effects.
We have
been able to enlarge the scope of the Atherton–Todd reaction to flavone
phosphorlation (Scheme 1). Our procedures are practical. The target products
were obtained with good yields. All the structures of target products were
determined by ESI-MS/MS, NMR and IR for the first time. The structure of
phosphated chrysin was further confirmed by x-ray diffraction.
EXPERIMENTAL
1
31
IR spectra were recorded on a Shimadazuir-408. H and P NMR spectra
were on a Bruker-DTX-400. Chemical shifts are expressed in parts per million
1
positive values downfield from internal TMS ( H) and external 85% H PO
3
4
3
1
(
P). Coupling constants are expressed in Hertz.TLC was performed on silica
gel plates and preparative chromatograph on columns of silica gel (200–300
mesh). MS were recorded on Bruke Esquire-3000.
Compound a. C H O P. 0.5253 g 7-hydroxyflavone was added to a
1
9
19
6
solution of 40 mL ethanol and 10 mL triethylamine. The mixture was stirred
until 7-hydroxyflavone was dissolved and then a solution of diethylphosphite
(
DEPH) and CCl (0.3042 g DEPH þ 10 mLCCl ) was added dropwise with
4
4
vigorous stirring in ice-water bath. The reaction proceeded for 24 hours at
room temperature. The resulting salt of triethyl amine was precipitated. Then
the organic phase was dried over MgSO and evaporated in vacuo below 508C.
4
Then 10 mL water was added. The solution was extracted by ethyl acetate. The
product was further purified by column chromatography (CHCl : CH CH
2-
3
3
OH ¼ 100 : 1). 0.7594 g white plate compound a was obtained. m.p 60–618C.

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Atherton–Todd Reaction
495
Scheme 1.
yield: 92%. Anal (Calcd)% for C H O P (compound a): C 60.92 (60.96),
1
9 19 6
1
H 5.05 (5.08), P 8.26 (8.29); H NMR (400 MHz, CD Cl) d: 8.23 (d, 1H,
3
0
0
0
J ¼ 8.4,), 7.92 (m, 2H, 2 -H), 7.54 (m, 4H, 3 -H, 4 -H, 8-H), 7.27 (d, 1H,
3
1
J ¼ 8.3, 6-H), 6.82 (s, 1H,3-H), 4.29(m, 4H, CH2), 1.41 (m, 6H, CH );
P
3
þ
NMR (400 MHz, D O), d: 26.77; ESI-MS/MS, m/z 375 [M þ H] , 374, 347
2
þ
þ
[
M-C H þ H ], 319 [M-2C H þ H ]. IR 1265 (PO).
21 23 6
2
4
2 4
Compound b. C H O P. 0.2310 g 7-hydroxyflavone was added to a
solution of 20 mL ethanol and 10 mL triethylamine. The mixture was stirred
until 7-hydroxyflavone was dissolved and then a solution of diisopropylpho-
phite (DIPPH) and CCl (0.166 g DIPPH þ 10 mLCCl ) was added dropwise
4
4
with vigorous stirring in ice-water bath. The reaction proceeded for 24 hours at
room temperature. The resulting salt of triethyl amine was precipitated. Then
the organic phase was dried over MgSO and evaporated in vacuo below 508C.
4
Then 10 mL water was added. The solution was extracted by ethyl acetate. The
product was further purified by column chromatography (CHCl : CH CH
2-
3
3
OH ¼ 80 : 1). 0.3705 g white plate compound b was obtained. m.p. 58–598C.
yield: 95%. Anal (Calcd)% for C H O P (compound b): C 62.64 (62.68),
1
9 19 6
1
H 5.73 (5.76), P 7.68 (7.70); H NMR (400 MHz, CD Cl) d: 8.22 (d, 1H,
3
0
0
0
J ¼ 8.8), 7.92 (m, 2H, 2 -H), 7.55 (m, 4H, 3 -H, 4 -H, 8-H), 7.27 (d, 1H,
J ¼ 8.3, 6-H), 6.81 (s, 1H,3-H), 4.81(m, 2H, CH), 1.35 (m, 12H, CH );
3
3
1
þ
P NMR (400 MHz, D O), d: 29.32; ESI-MS/MS, m/z 403 [M þ H] , 361
2
þ
þ
[
M-C H þ H ], 319 [M-2C H þ H ]. IR 1265 (PO).
3
6
3 6

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4
96
Chen et al.
Scheme 2. Positive ion ESI mass spectral fragmentation pathway of protonated
compound c.
Compound c. C H O P . 0.5631 g chrysin was added to a solution of
28 10 2
2
3
40 mL dioxane 10 mL triethylamine. The mixture was stirred until chrysin was
dissolved and a solution of DEPH and CCl (0.6120 g DEPH þ 10 mLCCl )
4
4
was then added dropwise vigorous stirring in ice-water bath. The reaction
proceeded for 24 hours at room temperature. The resultiong salt of triethyl
amine was precipitated. The filtrate was evaporated in vacuo below 508C.
Then 10 mL water was added. The solution was extracted by ethylacetate. The
organic phase was dried over MgSO . The needle crystalline residue 1.026 g
4
were separated out. m.p. 62–648C. yield: 88%. Anal (Calcd)% for
1
C H O P : C 52.44 (52.47) H 5.27 (5.31), P 11.74 (11.76); H NMR
2
3 28 10 2
0
0
0
(
400 MHz, CD Cl) d: 7.88 (d, 2H 2 -H J ¼ 7.6 Hz), 7.54 (m, 3H, 3 -H, 4 -H),
3
7
1
.41(s, 1H, 6-H), 7.26 (s, 1H,8-H), 6.69 (s,1H,3-H), 4.33 (m, 8H, 2CH2),
3
.41(m, 12H 2CH3); P NMR (400 MHz, D2O), d: P-1: 27.078,
1
þ
þ
P-2 : 27.1548; ESI-MS/MS, m/z 527 [M þ H] , 499 [M-C H þ H ],
2
4
þ
þ
4
71 [M-C H þ H ], 453 [M-C H -H O þ H ], 419 [M-(O) POCH CH þ
þ þ
2 2 3 2 4 2 2 3
2
4
2
4
2
2
2
3
H ], 391 [M-(O) POCH CH -C H þ H ], 363 [M-(O) POCH CH -
þ
þ
2
C H þ H ], 335 [M-(O) POCH CH -3C H þ H ]. IR 1264 (PO).
2
4
2
2
3
2 4
Structure of compound c was also confirmed by X-ray diffraction (Fig. 1).
Compound d. C H O P. 0.5063 g chrysin was added to a solution of
2
1
23
7
30 mL dioxane and 20 mL triethylamine. The mixture was stirred until

ORDER
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Atherton–Todd Reaction
497
Figure 1. Crystal structure of compound c.
chrysin was dissolved and then a solution of DIPPH and CCl (0.7747 g
4
DIPPH þ 10 mLCCl ) was added dropwise with vigorous stirring in ice-water
4
bath. The reaction proceeded for 24 hours at room temperature. The resulting
salt of triethyl amine was precipitated. Then the organic phase was drived over
MgSO . The filtrate was evaporated in vacuo below 508C. Then 10 mL water
4
was added. The solution was extracted by ethyl acetate. The product was
further purified by column chromatography (CHCl : CH CH OH ¼ 25 : 1).
3
3
2
0.708 g white yellow compound d was obtained. m.p. 95–968C. Yield: 85%.
Anal (Calcd)% for C H O P (compound d): C 60.25 (60.29), H 5.51 (5.54),
2
1 23 7
1
O 26.75 (26.77), P 7.38 (7.40). H NMR (400 MHz, CD Cl) d: 12.7 (s, 1H,
3
0
0
0
OH), 7.89 (d, J ¼ 8.16, 2H, 2 -H), 7.55 (m, 3H, 3 -H, 4 -H), 7.01 (s, 1H, 6-H),
3
.72 (s, 1H, 3-H), 6.66 (s, 1H, 8-H), .81(m, 2H), 1.38 (m,12H). P NMR
1
6
þ
(
400 MHz, D O), d: P: 29.118. ESI-MS/MS: m/z: 419 [M þ H] , 376
2
þ
þ
[
M-C H þ H ], 334 [M-2C H þ H ]. IR 1263 (PO).
3
6
3 6
0
Compound e. C H ClO P. 0.0955 g 4 -chloro-7-hydroxy-isoflavone
1
9
18
6
was added to a solution of 10 mL ethanol and 2 mL triethylamine. The mixture
0
was stirred until 4 -chloro-7-hydroxy-isoflavone was dissolved and then a sol-
ution of DEPH and CCl (0.048 g DEPH þ 5 mLCCl ) were added dropwise
4
4
with vigorous stirring in ice-water bath. The reaction proceeded for 24 hours at
room temperature. The resulting salt of triethyl amine was precipitated. The
organic phase was dried over MgSO . The filtrate was evaporated in vacuo
4
below 508C. Then 10 mL water was added. The solution was extracted by
ethyl acetate. The product was further purified by column chromatography
(
CHCl : CH CH OH ¼ 100 : 1). 0.117 g white power compound e was
3
3
2
obtained. m.p. 126–1278C yield: 81.7%. Anal (Calcd)% for C H ClO P
19 18 6

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4
98
Chen et al.
(
compound e): C 55.80 (55.83), H 4.42 (4.44), Cl 8.63 (8.67), O 23.45 (23.48),
1
P 7.55 (7.58). H NMR (400 MHz, CD Cl) d: 8.285 (d, J ¼ 8.8, 1H, 5-H), 8.0
3
0
0
(
s, 1H, 2-H), 7.50 (d, 2H, J ¼ 8.4,2 -H), 7.43 (s, 1H), 7.42 (d, 2H, J ¼ 6.0, 3 -
H), 7.28 (d, 1H, J ¼ 8.8, 6-H), 4.27 (m, J ¼ 5.2, 4H), 1.39 (m, J ¼ 6.8,6H).
3
1
þ
P NMR (400 MHz, D O), d: P: 27.061. ESI-MS/MS, m/z: 431 [M þ Na ],
2
þ
þ
4
03 [M-C H þ Na ], 475 [M-2C H þ Na ]. IR 1267 (PO).
0
19 18 6
2
4
2 4
Compound f. C H FlO P. 0.120 g 4 -fluo-7-hydroxy-isoflavone was
added to a solution of 10 mL ethanol and 2 mL triethlyamine. The mixture was
0
stirred until 4 -fluo-7-hydroxy-isoflavone was dissolved and then a solution of
DEPH and CCl (0.064 g DEPH þ 3 mLCCl ) were added dropwise with
4
4
vigorous stirring in ice-water bath. The reaction proceeded for 24 hours at
room temperature. The resulting salt of triethyl amine was precipitated. The
filtrate was evaporated in vacuo below 508C. Then 10 mL water was added.
The solution was extracted by ethyl acetate. Then the organic phase was
drived over MgSO . The filtrate was evaporated to give 0.1591 g white power
4
compound f. m.p. 146–1478C. Yield: 86.6%. Anal (Calcd)% for C H FO P
1
9
18
6
(
compound f): C 58.15 (58.17), H 4.60 (4.62), F 4.84 (4.84), O 24.45 (24.47),
1
P 7.88 (7.90). H NMR (400 MHz, CD Cl) d: 8.30 (d, 1H, J ¼ 8.8,5-H), 7.98
3
0
(
s, 1H, 2-H), 7.54 (m, 2H, 2 -H), 7.42 (s, 1H, 8-H), 7.284 (d, 1H, J ¼ 8.84,
0
31
6
-H) 7.137 (m, 2H, 3 -H,), 4.27 (m, J ¼ 5.2, 4H), 1.39 (m, J ¼ 6.8, 6H).
P
NMR (400 MHz, D O), (d ¼ 0), d: P: 27.055. ESI-MS/MS, m/z: 393
2
þ
þ
þ
[
M þ H ], 365 [M-C H þ H ], 337 [M-2C H þ H ]. IR 1266 (PO)
2
4
2 4
ACKNOWLEDGMENTS
The author would like to thank the Chinese National Science Foundation
No. 20175026) and Henan Academic Foundation of Science and Technology
for their financial support.
(
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Received in Japan June 2, 2003

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