Highly regioselective synthesis of novel 4-O-phosphorylated paeonol analogs

Article abstract of DOI:10.1080/10426507.2011.627901

4-O-phosphorylated paeonol derivatives were conveniently prepared by a facile method. Resacetophenone was prepared by the Friedel-Crafts acylation reaction of acetic acid with resorcinol. It was then phosphorylated regioselectively at the 4-O position using the Atherton-Todd reaction. An efficient, highly regioselective method to synthesize 4-O-phosphorylated paeonol derivatives is provided, and the approach has the merits of mild reaction conditions. Supplemental materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file. Copyright Taylor and Francis Group, LLC 2012.

Full text of DOI:10.1080/10426507.2011.627901

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Highly Regioselective Synthesis of Novel
4-O-Phosphorylated Paeonol Analogs
Zhiyu Ju a , Gongchun Li a , Jie Wang b , Yong Ye b c , Fengling Yang a
b & Yufen Zhao b c
a College of Chemistry and Chemical Engineering , Xuchang
University , Xuchang , P.R. China
b Department of Chemistry, Key Laboratory of Chemical Biology
& Organic Chemistry of Henan Province , Zhengzhou University ,
Zhengzhou , P.R. China
c Department of Chemistry, The Key Laboratory of Bioorganic
Phosphorus Chemistry & Chemical Biology, Ministry of Education ,
Tsinghua University , Beijing , P.R. China
Published online: 30 May 2012.
To cite this article: Zhiyu Ju , Gongchun Li , Jie Wang , Yong Ye , Fengling Yang & Yufen Zhao (2012)
Highly Regioselective Synthesis of Novel 4-O-Phosphorylated Paeonol Analogs, Phosphorus, Sulfur, and
Silicon and the Related Elements, 187:7, 859-863, DOI: 10.1080/10426507.2011.627901
To link to this article: http://dx.doi.org/10.1080/10426507.2011.627901
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Phosphorus, Sulfur, and Silicon, 187:859–863, 2012
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2011.627901
HIGHLY REGIOSELECTIVE SYNTHESIS OF NOVEL
4-O-PHOSPHORYLATED PAEONOL ANALOGS
Zhiyu Ju,1 Gongchun Li,1 Jie Wang,2 Yong Ye,2,3
Fengling Yang,1,2 and Yufen Zhao2,3
1College of Chemistry and Chemical Engineering, Xuchang University,
Xuchang, P.R. China
2Department of Chemistry, Key Laboratory of Chemical Biology & Organic
Chemistry of Henan Province, Zhengzhou University, Zhengzhou, P.R. China
3Department of Chemistry, The Key Laboratory of Bioorganic Phosphorus
Chemistry & Chemical Biology, Ministry of Education, Tsinghua University,
Beijing, P.R. China
GRAPHICAL ABSTRACT
OH
OH
OH
O
O
O
b
a
HO
HO
RO
P
O
OR
2
1
3
Abstract 4-O-phosphorylated paeonol derivatives were conveniently prepared by a facile
method. Resacetophenone was prepared by the Friedel–Crafts acylation reaction of acetic
acid with resorcinol. It was then phosphorylated regioselectively at the 4-O position using
the Atherton–Todd reaction. An efficient, highly regioselective method to synthesize 4-O-
phosphorylated paeonol derivatives is provided, and the approach has the merits of mild
reaction conditions.
Supplemental materials are available for this article. Go to the publisher’s online edition of
Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file.
Keywords Resacetophenone; phosphorylation; paeonol; Atherton–Todd reaction
INTRODUCTION
Paeonol, a micromolecular phenolic compound (Scheme 1),1 is one of the main
components of a Chinese herbal medicine, which is prepared from the root bark of Paeo-
nia moutan and isolated from the herb Pycnostelma paniculatum K.S. and the root of
Received 16 August 2011; accepted 25 September 2011.
We are grateful to the National Natural Science Foundation of China (Nos. 20972143, 20732004, 20972130),
the Natural Science Foundation of Henan Province Educational Committee, China (No. 2010 A150021), and the
Foundation of Xuchang University (No. 2012064) for financial support.
Address correspondence to Zhiyu Ju, College of Chemistry and Chemical Engineering, Xuchang University,
Xuchang, P.R. China. E-mail: juz1696@yahoo.com.cn
859

860
ZHIYU JU ET AL.
OH
O
CH O
3
Scheme 1 Structure of paeonol (2-hydroxy-4-methoxyacetophenone).
the plant Paeonia suffruticosa Andrew. Paeonol exhibits different biological and phar-
macological activities, including analgesic, sedative, antioxidative, anti-inflammatory, and
antimicrobial properties,2 and has also been reported to have a beneficial effect in the
prevention and treatment of cardiovascular,3 immuno-regulation,4 antitumor,5 antiallergic,6
anti-atherosclerosis,7 and female genital diseases. Moreover, it is also a valuable artificial
spicery and is widely used in domestic chemistry.8 But the nature of its insolubility in water
and volatility makes difficult for paeonol to sufficiently exert its efficiency. Modification
to paeonol, such as packing with β-cyclodextrin and preparing derivatives,9–11 has been
an active research area for a long time because the modified paeonol can overcome the
above-mentioned disadvantages.
Phosphates are one of the most successful functional groups with increased aqueous
solubility developed over the past few decades.12 They also have an important physiological
function and their derivatives exhibit some biological importance.13,14
The Atherton–Todd reaction is an important organic reaction, with important ap-
plications in the design and synthesis of medicine.15 The Atherton–Todd reaction is an
important method for chemical modification that introduces a phosphoryl functional group
into a molecule. It develops a new field for the modification of natural products, and hence
has attracted an increasing number of researchers. To search for new compounds with higher
antitumor activities and lower toxicity, we report a convenient procedure that is introduced
to implement regioselective phosphorylation of resacetophenone via the Atherton–Todd
reaction and synthesize novel paeonol analogs (Scheme 2). The structures of these com-
pounds were confirmed by electrospray ionization–mass spectrometry (ESI–MS), nuclear
magnetic resonance (NMR), and infrared (IR) spectroscopies.
OH
OH
OH
O
O
O
a
b
HO
HO
RO
P
O
OR
1
2
3
Scheme 2 Synthesis of title paeonol analogs. Reagents and reaction conditions: (a) CH3COOH (4.5 equiv.),
ZnCl2 (1 equiv.), reflux 4 h; (b) Dialkyl phosphites (1.1 equiv.), Et3N (1.1 equiv.), CCl4 (2 equiv.), ice bath 0.5 h,
room temperature 10–12 h.
RESULTS AND DISCUSSION
In the present study, resacetophenone was successfully synthesized by the
Friedel–Crafts acylation of resorcinol (1) with acetic acid in the presence of anhydrous zinc
chloride as a catalyst. In order to gain 4-O-phosphorylated paeonol analogs, possible routes
for 4-O-phosphorylation of Resacetophenone are shown in Scheme 3. Resacetophenone

REGIOSELECTIVE PHOSPHORYLATION OF RESACETOPHENONE
861
(1) POCl3
OH
OH
O
O
O
(2) (RO)2P(O)Cl
(3) (RO)2P(O)H
HO
RO
P
O
OR
2
3
Scheme 3 Possible routes for 4-O-phosphorylation of Resacetophenone.
was phosphorylated with POCl3 or (RO)2P(O)Cl to gain title compounds with awfully
low yields in harsh experimental conditions. If it was reacted with (RO)2P(O)H by the
Atherton–Todd reaction, five 4-O-phosphorylated paeonol derivatives were synthesized
with high yields under mild reaction conditions. It is generally known that the reaction
pathway of the Atherton–Todd reaction depends on the nucleophilicity of substrate. The
Atherton–Todd reaction, under present experimental conditions, was found to proceed
regioselectively, favoring attack at 4-hydroxyl of resacetophenone (2). Therefore, 4-O is
supposed to be the main reaction site. This conclusion was also confirmed by 1H NMR of
compound 3a. For example, the proton spectrum of compound 3a showed that 2-OH at δ
12.46 ppm is in accord with the chemical shift of 2-hydroxyl shifted downfield owing to
the hydrogen bond between hydroxyl and ortho carbonyl. The resulting resacetophenone
(2) is then coupled with dialkyl phosphites to form a series of 4-O-phosphorylated paeonol
1
analogs (3) (Table 1). Samples of H NMR, 13C NMR, and 31P NMR spectra for 3a are
presented as Figures S1–S3 in the Supplemental Materials.
In conclusion, a convenient procedure for the preparation of novel 4-O-
phosphorylated paeonol analogs was reported using commercially available materials.
These compounds were synthesized in two steps: The Friedel–Crafts acylation and the
Atherton–Todd reaction. The Atherton–Todd reaction, under the present experimental con-
ditions, was found to proceed regioselectively, favoring attack at 4-O of resacetophenone.
The synthetic procedure of 4-O-phosphorylated paeonol analogs might be valuable for the
development of new paeonol pro-drugs. Investigations about the inhibition activities of the
modified 4-O-phosphoryl paeonol analogs are currently under way in our laboratory, and
the mechanism and structure–activity relationship remain to be further studied.
EXPERIMENTAL
All starting materials were obtained from commercial sources and used without
further purification. Melting points were recorded on a microscopical determinator XT4
(the thermometer was not calibrated). IR spectra were recorded on a Shimadazuir-408
Table 1 Series of 4-O-phosphorylated analogs (3)
Entry
R
Yield (%)
3a
3b
3c
3d
3e
CH3
CH2CH3
CH(CH3)2
CH2CH2CH2CH3
CH2CH(CH3)2
85
87
91
90
92

862
ZHIYU JU ET AL.
1
spectrophotomer. H NMR, 13C NMR, and 31P NMR spectra were obtained on a Bruker
Avance DPX-400 spectrophotomer; chemical shifts were expressed in parts per million
with positive values downfield from internal tetramethylsilane (TMS) and external 85%
H3PO4 (31P). Coupling constants were expressed in Hertz. ESI–MS was recorded on a
Bruker Esquire-3000 instrument.
Preparation of Intermediate (2)
Resacetophenone (2) was synthesized according to the previous literature.16 This
orange-red product, after drying, melted at 141–143 oC.
Preparation of Title Compounds (3)
A solution of dialkyl phosphonite (2.2 mmol) in CCl4 (0.6 mL) was added dropwise
to the solution of resacetophenone (2 mmol) in the mixture of Et3N (0.3 mL) and alcohol
(1 mL) at 0oC for 30 min. Then the reaction mixture was stirred at room temperature for
approximately 10 h. After the triethylamine hydrochloride was filtered, the solution was
evaporated in vacuum at setting temperature and the residue was purified on a column of
silica gel with ethyl acetate/petroleum ether (1:1) as eluent to yield compounds 3a–e.
Compound 3a. Yellow liquid. 1H NMR (CDCl3, 400 MHz) δ: 2.58 (s, 3H, COCH3),
3.86 (s, 6H, OCH3), 6.76 (s, 1H, Ar H ), 6.77 (d, 1H, Ar H), 7.71 (d, 1H, Ar H), 12.46
(s, 1H, OH). 13C NMR (CDCl3, 100 MHz) δ: 26.6 ( COCH3), 55.1 ( OCH3), 108.9
(2-C), 111.0 (6-C), 117.2 (4-C), 132.6 (5-C), 156.3 (3-C), 164.2 (1-C), 203.4 ( COCH3).
31P NMR (CDCl3, 162 MHz) δ: −7.4. IR (KBr): 3475.0 cm−1 ( OH), 1646.6 cm−1 (C O),
1285.6 cm−1 (P O), 3066.3 cm−1, 1591.3 cm−1, 1499.3 cm−1, 854.7 cm−1, 803.9 cm−1
(Ar H). ESI–MS, m/z: 261.0 [M + H]+.
Compound 3b. Yellow liquid. 1H NMR (CDCl3, 400 MHz) δ: 1.26 (m, 6H,
OCH2CH3), 4.13 (m, 4H, OCH2CH3), 2.51 (s, 3H, COCH3), 6.69(s, 1H, Ar H), 6.71
(d, 1H, Ar H), 7.65 (d, 1H, Ar H), 12.39 (s, 1H, OH). 13C NMR (CDCl3, 100 MHz)
δ: 15.9 ( OCH2CH3), 26.5 ( COCH3), 64.8 ( OCH2CH3), 108.8 (2-C), 111.0 (6-C),
116.9 (4-C), 132.5 (5-C), 156.5 (3-C), 164.1 (1-C), 203.4 ( COCH3). 31P NMR (CDCl3,
162 MHz) δ: −7.4. IR (KBr): 3492.0 cm−1 ( OH), 1643.0 cm−1 (C O), 1277.4 cm−1
(P O), 3074.6 cm−1, 1586.5 cm−1, 1500.4 cm−1, 888.6 cm−1, 808.1 cm−1 (Ar H).
ESI–MS, m/z: 289.0 [M + H]+.
1
Compound 3c. Yellow liquid. H NMR (CDCl3, 400 MHz) δ: 1.32 (m, 12H,
OCH(CH3)2), 4.73 (m, 2H, OCH(CH3)2), 2.56 (s, 3H, COCH3), 6.75(s, 1H, Ar H),
6.77(d, 1H, Ar H), 7.68 (d, 1H, Ar H), 12.44 (s, 1H, OH). 13C NMR (CDCl3, 100
MHz) δ: 23.5 ( OCH(CH3)2), 26.5 ( COCH3), 74.0 ( OCH(CH3)2), 108.9 (2-C), 111.1
(6-C), 116.8 (4-C), 132.3 (5-C), 156.8 (3-C), 164.1 (1-C), 203.3 ( COCH3). 31P NMR
(CDCl3, 162 MHz) δ: −9.2. IR (KBr): 3489.7 cm−1 ( OH), 1642.7 cm−1 (C O),
1276.3 cm−1 (P O), 3080.1 cm−1, 1586.5 cm−1, 1500.6 cm−1, 899.1 cm−1, 807.3 cm−1
(Ar H). ESI–MS, m/z: 317.1 [M + H]+.
Compound 3d. Yellow liquid. 1H NMR (CDCl3, 400 MHz) δ: 0.90 (m,
6H,
OCH2CH2CH2CH3), 1.38 (m, 4H,
OCH2CH2CH2CH3), 1.64 (m, 4H,
OCH2CH2CH2CH3), 4.13 (m, 4H, OCH2CH2CH2CH3), 2.57 (s, 3H, COCH3), 6.75
(s, 1H, Ar H ), 6.77 (d, 1H, Ar H), 7.70 (d, 1H, Ar H), 12.45 (s, 1H, OH). 13C NMR
(CDCl3, 100 MHz) δ: 13.4 ( OCH2CH2CH2CH3), 18.6 ( OCH2CH2CH2CH3), 26.5

REGIOSELECTIVE PHOSPHORYLATION OF RESACETOPHENONE
863
( COCH3), 32.2 ( OCH2CH2CH2CH3), 68.7 ( OCH2CH2CH2CH3), 108.9 (2-C), 111.1
(6-C), 117.0 (4-C), 132.5 (5-C), 156.5 (3-C), 164.9 (1-C), 203.3 ( COCH3). 31P NMR
(CDCl3, 162 MHz) δ: −7.2. IR (KBr): 3479.7 cm−1 ( OH), 1642.5 cm−1 (C O), 1279.8
cm−1 (P O), 3088.3 cm−1, 1587.0 cm−1, 1502.3 cm−1, 902.3 cm−1, 808.4 cm−1 (Ar H).
ESI–MS, m/z: 345.1 [M + H]+.
1
Compound 3e. Yellow liquid. H NMR (CDCl3, 400 MHz) δ: 0.92 (m, 12H,
OCH2CH(CH3)2), 1.96 (m, 2H, OCH2CH(CH3)2), 3.90 (m, 4H, OCH2CH(CH3)2),
2.56 (s, 3H, COCH3), 6.76 (s, 1H, Ar H), 6.78 (d, 1H, Ar H), 7.69 (d, 1H, Ar H),
12.44 (s, 1H, OH). 13C NMR (CDCl3, 100 MHz) δ: 18.4 ( OCH2CH(CH3)2), 29.0
( OCH2CH(CH3)2), 26.3 ( COCH3), 74.7 ( OCH2CH(CH3)2), 108.9 (2-C), 111.0 (6-
C), 117.0 (4-C), 132.5 (5-C), 156.5 (3-C), 164.8 (1-C), 203.3 ( COCH3). 31P NMR
(CDCl3, 162 MHz) δ: −7.3. IR (KBr): 3491.0 cm−1 ( OH), 1642.8 cm−1 (C O), 1285.4
cm−1 (P O), 3081.0 cm−1, 1587.9 cm−1, 1500.4 cm−1, 891.2 cm−1, 807.1 cm−1 (Ar H).
ESI–MS, m/z: 345.1 [M + H]+.
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