Utilization of the inherent nucleophile for regioselective O-acylation of polyphenols via an intermolecular cooperative transesterification

Article abstract of DOI:10.1016/j.tet.2016.05.048

A green and efficient method for regioselective O-acylation of polyphenols has been developed. The acylation can be carried out in potassium carbonate/dimethyl sulphoxide system by utilizing the ‘inherent nucleophile’ via an intermolecular cooperative transesterification under mild condition. This method shows particular advantage in regioselective acylation of polyphenols bearing 2′,4′-dihydroxyacetophenone moiety and can be extended to the synthesis of mono or multiple acetates of polyphenols without this moiety in good yields. Compared with other reported approaches, this method is endowed with atom economy and is more environment-friendly for avoiding the use of any metal-based catalysts.

Full text of DOI:10.1016/j.tet.2016.05.048

Accepted Manuscript
Utilization of the inherent nucleophile for regioselective O-acylation of polyphenols via
an intermolecular cooperative transesterification
Jingchao Liu, Junjie Fu, Wenlong Li, Yu Zou, Zhangjian Huang, Jinyi Xu, Sixun Peng,
Yihua Zhang
PII:
S0040-4020(16)30447-1
10.1016/j.tet.2016.05.048
TET 27775
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 18 April 2016
Revised Date: 16 May 2016
Accepted Date: 18 May 2016
Please cite this article as: Liu J, Fu J, Li W, Zou Y, Huang Z, Xu J, Peng S, Zhang Y, Utilization of the
inherent nucleophile for regioselective O-acylation of polyphenols via an intermolecular cooperative
transesterification, Tetrahedron (2016), doi: 10.1016/j.tet.2016.05.048.
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Utilization of the inherent nucleophile for
regioselective O-acylation of polyphenols via an
intermolecular cooperative transesterification
Jingchao Liu,‡a,b Junjie Fu,‡c Wenlong Li,a Yu Zou,a,b Zhangjian Huang,*a,b Jinyi Xu,*a Sixun Peng,a,b and Yihua
Zhang*a,b
aState Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, P. R. China. Email: jinyixu@china.com; Fax: (+86) 25-
83302827; Tel: (+86) 25-83271445
bJiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing 210009, P. R. China. Email:
zyhtgd@163.com; cpudahuang@163.com; Fax/Tel: (+86) 25-83271015
cDepartment of Medicinal Chemistry, School of Pharmacy, Nanjing Medical University, Nanjing 211166, P. R. China.

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Utilization of the inherent nucleophile for regioselective O-acylation of polyphenols
via an intermolecular cooperative transesterification
Jingchao Liu,‡a,b Junjie Fu,‡c Wenlong Li,a Yu Zou,a,b Zhangjian Huang,*a,b Jinyi Xu,*a Sixun Peng,a,b and
Yihua Zhang*a,b
aState Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, P. R. China. Email: jinyixu@china.com; Fax: (+86) 25-
83302827; Tel: (+86) 25-83271445
bJiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing 210009, P. R. China. Email: zyhtgd@163.com;
cpudahuang@163.com; Fax/Tel: (+86) 25-83271015
cDepartment of Medicinal Chemistry, School of Pharmacy, Nanjing Medical University, Nanjing 211166, P. R. China.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A green and efficient method for regioselective O-acylation of polyphenols has been developed.
The acylation can be carried out in potassium carbonate/dimethyl sulphoxide system by utilizing
the “inherent nucleophile” via an intermolecular cooperative transesterification under mild
condition. This method shows particular advantage in regioselective acylation of polyphenols
bearing 2′,4′-dihydroxyacetophenone moiety and can be extended to the synthesis of mono or
multiple acetates of polyphenols without this moiety in good yields. Compared with other
reported approaches, this method is endowed with atom economy and is more environment-
friendly for avoiding the use of any metal-based catalysts.
Available online
Keywords:
Regioselective
Acylation
2009 Elsevier Ltd. All rights reserved
.
Polyphenol
Green chemistry
Atom economy
Inherent nucleophile
1. Introduction
of natural products bearing 1 have been extensively studied such
as quercetin, galangin, hesperetin, isoliquiritigenin and
frangulaemodin. It is obvious that the 2′-hydroxyl in 1 cannot
primarily be acetylated due to the intramolecular hydrogen
bonding formed between 2′-phenolic proton and carbonyl
oxygen. As a result, the present synthetic route of 2′-acetoxy-4′-
Natural and synthetic polyphenols as well as related mono- or
multi-O-derivatives attract much attention from medicinal
chemists thanks to a large verity of pharmacological activities of
them such as cardioprotection, anti-inflammation, and anti-
oxidant.1-3 Acylation and deacylation are the common reactions
widely involved in the synthesis of mono- or multi-O-derivatives
of polyphenols. Usually, poor selectivity of the reactions
inevitably leads to redundant synthetic steps and low yields;
usage of some unfriendly reagents in the reaction often causes
pollution or toxicity to the environment. Accordingly, an
improved strategy is of great interest to assemble phenolic
derivatives with regioselectivity and environmental friendliness.
In addition, it is preferred that all molecules of starting materials
could be cooperatively converted into target compounds to
achieve atom economy.4
hydroxyacetophenone 1b requires diacetylation of
1 and
subsequent deacetylation of 4-O′-acetyl by candida cylindracea
lipase or porcine pancreatic lipase (Scheme 1a).5,6
Fig. 1. The structures of compounds 1 and 2.
As far as 7-O-derivatives of quercetin 2 (Fig. 1) to be
concerned, 3,3′,4′,5-tetra-O-acetylquercetin 2b (Table 1) is firstly
synthesized by 7-deacetylation of penta-O-acetyl-quercetin 2c
(Fig. 2) using thiophenol (PhSH)/N-methylpyrrolidinone (NMP)7
2′,4′-Dihydroxyacetophenone 1 (Fig. 1) is a well-known
structural moiety embedded in the molecules of flavones,
flavanones, flavonols, chalcones and anthraquinones. A myriad
———
* Corresponding authors. E-mail addresses: zyhtgd@163.com (Y. Zhang), jinyixu@china.com (J. Xu), cpudahuang@163.com (Z. Huang).

2
Tetrahedron
ACCEPTED MANUSCRIPT
8
or imidazole/dichloromethane (Scheme 1). Compound 2b is then
subjected to 7-O-alkylation or other chemical modifications to
produce 7-O-derivatives of 2. This method was widely used in
the synthesis of various pharmacologically important 7-O-
derivatives of flavones such as galangin,9,10 naringenin,
hesperetin,11 and kaempferol.12 However, PhSH is highly irritant
and toxic.13 Long term exposure to PhSH may cause muscle
weakness, headache, respiratory depression and coma, and high
concentrations of PhSH induce pulmonary edema and even
death.14,15 Besides, both methods require low temperature (0 °C7
or -15 °C8), and neither NMP nor dichloromethane is a green
solvent. All of these disadvantages call for the necessity to
improve the synthetic routes of 2b.
Compound 1a, which represents the backbone of 2c for PhSH-
mediated transesterification, was selected to test our hypothesis.
For transacetylation, DMSO was selected as the solvent in view
of its good capability to competitively form intermolecular H-
bond with 2′-OH.20-22 DMSO is acceptable to use for green
chemistry according to the Pfizer solvent selection guide,23 and it
is used for the green synthesis of important synthetic building
blocks such as vinyl ethers of alcohols.24 Besides, K2CO3 was
employed to abstract a proton from 2′-OH. We anticipated that
the joint driving forces from DMSO and K2CO3 could facilitate
the formation of 2′-O-, onto which 4′-O-acetyl could be
transferred (Scheme 2). Fortunately, when 1a was treated with
one equivalent K2CO3 in DMSO at 25 °C for 4 h, 1b was
obtained as expected (Conv. 90.1%). Detailed optimization of
reaction conditions is summarized in Tables S1 and S2.
Scheme 2. The synthesis of 2′-acetoxyl-4′-hydroxyacetophenone 1b from 4′-
acetoxyl-2′-hydroxyacetophenone 1a via transacetylation.
Scheme 1. a) Previously reported deacetylation methods. b) Present
intermolecular transesterification method via an environment-friendly
K2CO3/DMSO system.
Next, we further hypothesized that the similar transacetylation
could take place to convert 3,3′,4′,7-tetra-O-acetylquercetin 2a
into 3,3′,4′,5-tetra-O-acetylquercetin 2b under the above
conditions. To verify the hypothesis, 2a was treated with one
equivalent K2CO3 in DMSO at 25 °C and the reaction was
monitored by HPLC. One hour later, the peak of 2a almost
disappeared and a new peak emerged. Mass spectrum indicated
that it had the same molecular weight as 2a, and 1H-NMR
spectrum showed its five aromatic (6.66–7.84 ppm) and twelve
acetyl (2.31–2.34 ppm) proton signals characteristic of quercetin.
However, the proton signal of hydroxyl in 2a (12.09 ppm) was
shifted to 11.3 ppm, which might be assigned to 7-hydroxyl. This
was confirmed by a long range coupling of the proton with C-6
and C-8 in HMBC spectrum (Fig. S1).
The derivatives of mono-O-substituted-(p-, m-, or o-
)dihydroxybenzene are widely used in chemical industry, and lots
of their mono-O-derivatives such as acetate, propionylate and
methylether are important intermediates for the synthesis of
pharmaceutical and chemical products. Usually, the preparation
of these compounds is conducted by strict controlling ratio of
starting materials to minimize the yield of di-O-derivatives. For
example, p-dihydroxybenzene mono-acetate 3b is usually
synthesized by the reaction of excessive p-dihydroxybenzene 3
with one equivalent acetic acid16 or acetic anhydride in pyridine17
at high temperatures. Despite this effort, it is still hard to prevent
the formation of the diacetate 3a. Additionally, the case could
become more complicated when aromatic mono-substituted
dihydroxybenzenes are subjected to the same reaction conditions.
Subsequently, we tried to optimize the reaction conditions
using various solvents and bases. As shown in Table 1, 2b was
obtained in medium to high yields (52.6–78.2%) after the
reaction of 2a with one equivalent K2CO3 at 25 °C for 1 h in
DMF, dimethylacetamide (DMAC), NMP and DMSO,
respectively (entries 1–4). In contrast, 2b could not be obtained
even prolonging the reaction time from 1 h to 2 h when 2a was
treated with K2CO3 in MeCN, Me2CO, THF or heptane (entries
5–8). The best solvent was DMSO, which gave the highest yield.
Next, the effects of different bases in DMSO at 25 °C on the
yields were examined. Results indicated that K2CO3 gave the best
yield (1 h, 78.2%) (entry 2) compared with other bases (Na2CO3,
NaHCO3, Et3N, DIPEA, imidazole) (entries 9–13). Based on
these results, K2CO3/DMSO was selected as the reaction system
for further investigations.
In view of the above-mentioned problems occurred in the
synthesis of mono- or multi-O-derivatives of polyphenols, we
have developed a novel strategy for phenolic acylation with atom
economy, regioselectivity and environmental friendliness.
2. Results and Discussion
2.1. Regioselective 2′-O-acetylation in the molecules bearing
2′,4′-dihydroxyacetophenone moiety
The aforementioned selective deacetylation of 7-O-acetyl in
2c7,8 is substantially
a
transesterification reaction. The
mechanism underlying the deacylation is based on the fact that
the 7-OH is at para position of the electron-withdrawing pyrone
carbonyl and possesses the highest acidity among all the
hydroxyl groups in the molecule,7,18 and that the corresponding 7-
phenolate (7-O-) is the most stable owing to the existence of
cross-conjugated system.19 These features enable the selective
attack of 7-O-acetyl by the nucleophilic reagent PhSH to
generate PhSAc. Accordingly, we hypothesized that an inherent
oxygen anion (O-) within partially O-acetylated quercetin could
be employed to nucleophilically attack 7-O-acetyl group under
certain conditions via an intermolecular cooperative
transacetylation to form 2b. The question so raised is under what
conditions the transacetylation does take place.
Next, the effects of temperature, concentrations of 2a and
K2CO3, as well as the reaction time on the transacetylation were
further explored. The results are summarized in Table 2.
Evidently, a lower temperature (15 °C, entry 1) led to decreased
conversion rate of 2a and lower yield of 2b compared with the
same reaction conducted at 25 °C (entry 2). Reactions at high
temperatures (50 and 100 °C) (entries 3 and 4) failed to yield 2b
due to the hydrolysis of acetyls. In terms of the concentrations,
reaction of 2a at 25 mM with equivalent K2CO3 for 1 h resulted
in high yield of 2b (84.6%, entry 2). Less than one equivalent
K2CO3 (cat. amount or 0.5 e.q.) (entry 5 or 6) or reduced

3
ACCEPTED MANUSCRIPT
concentrations of 2a (5 mM) with equivalent K2CO3 (entry 9) led
to a drop in yields (7.4–25.6%). Using larger equivalents of
K2CO3 (2 and 5 e.q.) (entries 7 and 8) or increased concentrations
of 2a (50 and 100 mM) with equivalent K2CO3, respectively,
(entries 10 and 11) didn’t benefit the yield of 2b (79.7% and
81.0%, respectively). Finally, the highest conversion rate of 2a
(97.4%) and best yield of 2b (92.9%) could be achieved when 25
mM of 2a was treated with equivalent K2CO3 at 25 °C for 4 h
(entry 13).
acetylquercetin 2d (Rt = 7.5 min), and 2c (Rt = 9.5 min),
respectively, by comparison of their retention times (Rt) with
corresponding standard compounds. It was observed that along
with the shrinkage of peak 2a, peak 2b grew gradually (60 min,
78.2%; 120 min, 91.3%), whereas the peaks of intermediates 2d
and 2c initially increased and then diminished.
Table 1
Solvents and bases tested for conversion of 3,3′,4′,7-tetra-O-acetylquercetin
2aa to 3,3′,4′,5-tetra-O-acetyl- quercetin 2b
Entry
1
Base (1 eq.)
K2CO3
Solvent
DMF
Time (h)
Yield of 2b (%)b
1
1
1
1
2
2
2
2
1
1
1
1
1
49.9
78.2
70.5
52.6
0c
0c
0c
Fig. 2. The conversion of 2a to 2b in the presence of K2CO3 in DMSO at
2
K2CO3
K2CO3
DMSO
NMP
indicated time point.
3
The occurrence of intermediates 2c and 2d during the above
reactions led us to assume that the reactions proceed not
intramolecularly but intermolecularly as we previously expected.
Therefore, preliminary kinetic study was performed using
different concentrations of 2a in K2CO3/DMSO system. It was
observed that an increased concentration of 2a resulted in an
accelerated reaction rate to form 2b (Fig. 3), which is consistent
with the feature of an intermolecular reaction.
4
K2CO3
DMAC
MeCN
Me2CO
THF
5
K2CO3
6
K2CO3
7
K2CO3
8
K2CO3
heptane
DMSO
DMSO
DMSO
DMSO
DMSO
0
9
Na2CO3
NaHCO3
Et3N
23.5
20.3
13.4
11.5
29.9
10
11
12
13
DIPEA
imidazole
aThe initial concentration of 2a was 25 mM. All reactions were conducted at
25 °C with one equivalent base.
bCalculated from HPLC at indicated time points.
cOnly the peaks of compounds 2c and 2d were detected.
Table 2
Optimization for the formation of 2b from 2a in K2CO3/DMSO system
2a
(mM)
25
K2CO3
Time
(h)
1
T
(oC)
15
25
50
100
25
25
25
25
25
25
25
25
25
25
Conv.a
Yielda
Entry
(e.q.)
(%)
(%)
Fig. 3. Effect of the initial concentration of 2a on the reaction rate to form 2b.
Compound 2a was dissolved in DMSO at three concentrations (5, 25 and 50
mM), and its decomposition behavior within 30 min upon the addition of
K2CO3 (1 e.q.) was monitored by HPLC. The percentage of 2a in the reaction
mixture at indicated time point was shown as mean ± SD from three separate
experiments.
1
2
1
1
77.9
85.0
100
45.6
84.6.2
0b
25
1
3
25
1
1
4
25
1
1
100
0b
5
25
cat.
0.5
2
1
48.2
53.9
73.6
71.8
77.2
84.9
84.9
91.6
97.4
98.9
7.4
6
25
1
11.7
63.7
70.9
25.6
79.7
81.0
91.3
92.9
65.1
7
25
1
8
25
5
1
9
5
1
1
10
11
12
13
14
50
1
1
100
25
1
1
1
2
25
1
4
25
1
7
aCalculated from HPLC.
bCompound 2a was dehydrolyzed.
In order to investigate the reaction mechanism, HPLC was
utilized to monitor the transacetylation from 2a to 2b. As shown
in Fig. 2, very soon (5 min) after the addition of K2CO3 into the
reaction system, three new peaks appeared. These new
components were identified as 2b (Rt = 5.5 min), 3,3′,4′-tri-O-
Scheme 3. Proposed mechanism of an intermolecular transacetylation for
formation of 2b from 2a.
Based on the above results, we exemplify the reaction of 2a to
propose the intermolecular transacetylation mechanism (Scheme

4
Tetrahedron
ACCEPTED MANUSCRIPT
3). In K2CO3/DMSO system, 5-hydroxyl of 2a is firstly
deprotonated to generate phenolic oxygen anion 2e, which is the
key step. Different base/solvent systems contribute variously to
the formation of 2e. The sulfinyl of DMSO is a strong H-bond
acceptor, and has large dielectric constant (47.2 at 20 °C),25
which stabilizes the negative charge of 5-O-. On the other hand,
K2CO3 has the best solubility in DMSO relative to other
solvents,26 which also benefits the deprotonation of 5-hydroxyl.
Upon formation of phenolic oxygen anion, the 5-O- in one
molecule of 2e functions as the “inherent nucleophile” to
predominantly attack the 7-O-acetyl in another molecule of 2e.
As a result, intermediates 2f and 2c are produced and interacted
with each other to produce two molecules of 2g, and finally
generating 2b via protonation (Route A, Scheme 3).
Alternatively, 2e may interact respectively with 2f (Route B,
Scheme 3) and 2c (Route C, Scheme 3) to form 2g as well as 2f
and 2c, which undergo the same reactions as those in Route A to
produce 2b. In order to verify the mechanism, 2d (protonated 2f)
was reacted with equivalent 2c in K2CO3/DMSO at 25 °C for 1 h,
and 2b was expectedly obtained in 87% yield (Scheme S1).
Table 3
Major and minor mono-O-acetylated products of aromatic mono-substituted dihydroxybenzenes via the intermolecular transacetylationa
Entry
Compounds
6
R1
R2
R3
Major product A
Minor product B
Conversion (%)b
Ratio A:B
1
OH
Me
OH
86.1
83:17c
2
3
4
5
7
8
OH
OH
OH
OH
OMe
tert-Butyl
OH
OH
OH
76.2
70.0
100
87:13d
60:40d
90:10c
86:14c
9
CHO
10
Cl
OH
80.1
aAll reactions with equivalent reactants were conducted at 25 °C for 1 h. The initial concentrations of 6–10 and 6a–10a were 100 mM, respectively.
bDetermined by HPLC.
cCalculated from1H-NMR.
dIsolated yields.
Encouraged by this result, we further assumed that it might be
possible to apply this method to build other mono-O-acetyl-
polyphenols without the 2′,4′-dihydroxy- acetophenone moiety.
The scope of this transacetylation was extended to aromatic
mono-substituted dihydroxybenzenes 6–10 (Table 3) with
hydroxyls in different chemical enironments. Their
corresponding diacetates 6a–10a were reacted with equivalent 6–
10 in K2CO3/DMSO at 25 °C for 1 h, respectively. The results
are summarized in Table 3. In most cases (entries 1−3, 5), two
types of products A and B with opposite acetylation positions
were simultaneously obtained. Interestingly, the direct
acetylation of 6, 8 and 10 using the reported procedures mainly
gave product B32 while our transacetylation conditions produced
A as the major products, which were inaccessible through known
chemical approaches. The ratios of A to B were 83:17 and 87:13
when R2 represented electron-donating methyl and methoxyl
(entries 1 and 2), respectively. When R2 was tert-butyl, its steric
hindrance significantly impeded acetylation of ortho-phenol
when using the known chemical approaches. However, 8b was
still obtained as major product by the transacetylation (entry 3),
which could only be reportedly prepared via the lipase assisted
hydrolysis of 8a.33 In the case of 9a, R3 was electron-
withdrawing formyl and the acetyl was preferentially transferred
to the meta-phenol in 9 (entry 4). Compared with the documented
preparative methods for 9b,34,35 our method has no need to
employ flammable NaH or toxic PhSH. When R2 was chlorine,
its electron withdrawing effect dominated the selectivity of
transacetylation process giving 10b as the major product (entry
5). Apparently, acetyl was preferably transferred to the phenolate
with higher electron density to achieve good atom economy
(Scheme 5).
2.2. Regioselective mono-O-acetylation of dihydroxybenzene
(p-, m- and o-) Dihydroxybenzenes 3–5 were selected as
substrates due to their straightforward structures. The reported
direct acetylation of 3–5 to give mono-O-acetates 3b–5b
proceeds at high temperature and/or high pressure, using metal
catalyst(s), pyridine or strong acid(s).17,27-31 Despite this, the
selectivity and yields are not always satisfactory.16,17 Using the
similar method for the generation of 2b from 2c and 2d in
K2CO3/DMSO, monoacetates 3b–5b were readily obtained in
high yields (90–99%) after 1,4-diacetoxybenzenes 3a–5a were
reacted with equivalent dihydroxybenzenes 3–5 respectively
under the optimal transacetylation conditions (Scheme 4).
Scheme 4. Mono-acetylation of dihydroxybenzenes via an intermolecular
transacetylation.

5
ACCEPTED MANUSCRIPT
In addition to acetyl, the intermolecular transesterification can
be successfully applied to other acyls such as propionyl, benzoyl
and pivaloyl (Scheme 8). This is exemplified by the synthesis of
13a and 14a in 71–80% yields, as well as preparation of 4-
pivaloyloxy-4′-hydroxybenzophenone 15b in 83% yield.
Compound 15b is the crucial intermediate to assemble 4-
hydroxytamoxifen (Afimoxifene), a selective estrogen receptor
modulator for the treatment of cyclical mastalgia in a phase II
clinical trial.41 In contrast to our approach, the documented
synthetic method using NaH/THF at low temperature gave 15b in
less than 40% yield.42-44
.
Scheme 5. Cooperative intermolecular transacetylation between aromatic
mono-substituted dihydroxybenzenes and their corresponding diacetates. Due
to the different electronic effects of R group, oxygen atom in red shows
stronger nucleophilic ability, and acetyl group in blue exhibits larger
electrophilic ability.
2.3. Applications
of
intermolecular
cooperative
transesterification to the synthesis of mono- or multi-O-
derivatives of polyphenols
Interestingly, our methodology could be applied to simplify
synthetic routes of many chemical and pharmaceutical products.
For example, 7-O-alkyl derivatives of quercetin 11a–11c could
be readily produced by the reaction of 2a with halides in
K2CO3/DMSO system via a one-pot procedure without using
toxic PhSH (Scheme 6).9-12
Scheme 8. The extended application of transesterification from acetyl to
propionyl, benzoyl and pivaloyl.
3. Conclusions
In summary, we have developed a novel and green strategy for
phenolic acylation with atom economy, regioselectivity and less
environmental toxicity by using “inherent nucleophile” in
K2CO3/DMSO system. It is noteworthy that this methodology
provides useful tools to synthesize mono- or multi-O-acetyl
derivatives of various polyphenols such as dihydroxybenzene,
Scheme 6. One-pot synthesis of 7-O-alkylated quercetin derivatives from 2a
stilbenes
and
molecules embedded
with
a
2′,4′-
and alkyl bromides in K2CO3/DMSO system.
dihydroxyacetophenone moiety. Additionally, the acetyl could be
extended to other acyls to achieve transpropionylation,
transbenzoylation and transpivaloylation. The high efficiency of
this strategy suggests its extensive use in fields of medicinal
chemistry, agrochemistry and material sciences.
Our aforementioned results indicated that the cooperative
transacetylation could be successfully applicable to molecules
without the 2′,4′-dihydroxyacetophenone moiety. “Is it possible
to extend this methodology to other pharmacologically important
polyphenols with different structural motif?” was our next
concern.
4. Experimental Section
4.1. General
Resveratrol 12 is a strong antioxidant with good protective
effects on cardiovascular system.36,37 However, the present
preparative procedures38-40 of its mono- or di-acetates were
cumbersome, which limit the further pharmacological
development of its derivatives. Importantly, both 3,5-di-O-acetyl-
resveratrol 12b and 3-O-acetylresveratrol 12c could be
simultaneously synthesized when two equivalents of 12a were
reacted with one equivalent of 12 in K2CO3/DMSO at 25 °C for 2
h (Scheme 7). Compared with the reported chemical approaches
to 12b and 12c, our strategy is green, facile and catalyst-free in
good yield. Moreover, this methodology might be feasible to
other polyphenolic stilbenes.
Melting points were determined on a Mel-TEMP II melting
1
point apparatus and were uncorrected. H NMR and 13C NMR
spectra were recorded with a Bruker Avance 300 MHz
spectrometer at 300 K, using TMS as an internal standard. MS
spectra were recorded on a Mariner Mass Spectrum (ESI)
instrument. High resolution mass spectrometry was recorded on
Agilent Technologies LC/MSD TOF instrument. Analytical and
preparative TLC was performed on silica gel (200–300 mesh)
GF/UV 254 plates, and the chromatograms were visualized under
UV light at 254 and 365 nm. All solvents and chemicals
purchased were reagent grade and, when necessary, some
solvents were purified and dried by standard methods. HPLC
analysis was operated on the LC-10A HPLC system consisting of
LC-10ATvp pumps and an SPD-10Avp UV detector.
4.2. General procedure for the synthesis of 1b and 2b
To the DMSO solution of 1a (1 mmol) or 2a (1 mmol) was
added K2CO3 (1 mmol) and the reaction mixture was stirred at
25 °C. After the reaction was complete, the reaction mixture was
extracted with ethyl acetate (20 mL), and washed successively by
Scheme 7. Mono- and di-acetylated products of resveratrol obtained by an
intermolecular transacetylation.

6
Tetrahedron
ACCEPTED MANUSCRIPT
water and brine, and then dried by anhydrous Na2SO4, filtered,
and evaporated to give the crude product which was purified by
column chromatography to yield the pure target compound.
This compound was obtained as an inseparable mixture with
4-hydroxy-3-methylphenyl acetate (83:17). Major product: H
1
NMR (DMSO-d6, 300 MHz, δ ppm) 9.29 (s, 1H, OH), 6.81 (d,
1H, J = 8.4 Hz, ArH), 6.64 (s, 1H, ArH), 6.56 (t, 1H, J = 2.1 Hz,
8.4 Hz, ArH), 2.24 (s, 3H, CH3CO), 2.01 (s, 3H, CH3); ESI-MS
165.0 [M -H]-.
2′-Acetoxy-4′-hydroxyacetophenone (1b)
The pure target compound was obtained in 71% yield as a
1
white solid, m.p. 119–120 °C; H NMR (DMSO-d6, 300 MHz, δ
4-Acetoxy-2-methoxyphenol (7b)
ppm) 10.67 (s, 1H, OH), 7.77 (dd, 1H, J = 1.9Hz, 8.6 Hz, ArH),
6.75 (dd, 1H, J = 2.0, 8.6 Hz, ArH), 6.53 (dd, 1H, J = 2.0 Hz,
ArH), 2.51 (s, 3H, CH3CO), 2.26 (s, 3H, CH3CO); 13C NMR
(CDCl3, 75 MHz, δ ppm) 199.92, 170.44, 161.57, 151.32,
133.01, 122.15, 113.36, 111.11, 28.78, 21.18; HRMS calculated
for C10H10NaO4 [M + Na]+ 217.0477, found 217.0483.
This compound was obtained in 56% yield as a white solid:
m.p. 122–124 °C; 1H NMR (DMSO-d6, 300 MHz, δ ppm) 9.49 (s,
1H,OH), 6.83 (d, 1H, J = 8.5 Hz, ArH), 6.48 (d, 1H, J = 2.4 Hz,
ArH), 6.30 (dd, 1H, J = 2.4 Hz, 8.5 Hz, ArH), 3.70 (s, 3H, CH3O),
2.20 (s, 3H, CH3CO); 13C NMR (DMSO-d6, 75 MHz, δ ppm)
168.91, 156.07, 151.30, 131.55, 122.80, 106.10, 100.28, 55.40,
20.33; HRMS calculated for C9H9O4 [M - H]- 181.0501, found
181.0504.
3,3′,4′,5-Tetra-O-acetylquercetin (2b)
The pure product was obtained in 85% yield as an off-white
1
solid, m.p. 188−190 °C; H NMR (DMSO-d6, 300 MHz, δ ppm)
4-Acetoxy-2-tert-butyphenol (8b)
11.32 (s, 1H, OH), 7.81−7.84 (m, 2H, ArH), 7.51 (d, J = 8.9 Hz,
1H, ArH), 6.94 (s, 1H, ArH), 6.65 (s, 1H, ArH), 2.33 (s, 6H, 2 ×
CH3), 2.31 (s, 6H, 2 × CH3); 13C NMR (DMSO-d6, 75 MHz, δ
ppm) 169.44, 169.20, 168.64, 168.47, 168.35, 163.28, 158.04,
152.86, 150.69, 144.66, 142.61, 133.27, 127.91, 126.92, 124.87,
123.99, 109.78, 109.55, 101.46, 21.30, 20.85, 20.78, 20.66;
HRMS calculated for C23H18O11 [M - H]- 469.0776, found
469.0771.
This compound was obtained in 37% yield as a white solid:
m.p. 128–130 °C; 1H NMR (DMSO-d6, 300 MHz, δ ppm) 9.55 (s,
1H, ArH), 6.99 (s, 2H, ArH), 6.85 (s, 1H, ArH), 2.51 (s, 3H,
CH3CO), 2.33 (s, 3H, CH3CO), 1.49 (s, 9H, CH3); 13C NMR
(DMSO-d6, 75 MHz, δ ppm): 169.60, 154.49, 141.37, 140.99,
124.88, 113.30, 112.86, 33.90, 29.80, 21.27; HRMS calculated
for C12H15O3 [M - H]- 207.1021, found 207.1025.
4.3. General procedure for the synthesis of 3b–10b
5-Formyl-2-hydroxyphenyl acetate (9b)
This compound was obtained as an inseparable mixture with
4-formyl-2-hydroxyphenyl acetate (90:10). Major product: H
NMR (DMSO-d6, 300 MHz, δ ppm) 10.91 (s, 1H, OH), 7.68 (d,
1H, J = 2.5Hz, 8.3Hz, ArH), 7.57 (d, 1H, J = 2.5 Hz, ArH), 7.09
(d, 1H, J = 8.3Hz, ArH), 2.28 (s, 3H, CH3CO); ESI-MS 137.0 [M
- CH3CO]-.
Diacetylated compound 3a–10a (1 mmol) and its
corresponding dihydroxyl compound 3–10 (1 mmol) were
dissolved in DMSO, respectively, and then K2CO3 (1 mmol) was
added. The reaction mixture was stirred at 25 °C. After the
reaction was complete, the mixture was poured into water and
extracted by ethyl acetate (3 × 25 mL). The organic phase was
washed successively by water (3 × 25 mL) and brine (2 × 25 mL),
and then dried over anhydrous Na2SO4, filtered. The filtrate was
evaporated in vacuum and the residue was purified by column
chromatography to give pure target compounds.
1
4-Acetoxy-2-chlorophenol (10b)
This compound was obtained as an inseparable mixture with
4-acetoxy-3-chlorophenol (86:14). Major product: 1H NMR
(DMSO-d6, 300 MHz, δ ppm) 10.20 (s, 1H, OH), 7.18 (d, 1H, J =
2.5 Hz, ArH), 6.97 (d, 1H, J = 8.6 Hz, ArH), 6.91 (dd, 1H, J =
2.5 Hz, 8.6 Hz, ArH), 2.22 (s, 3H, CH3); ESI-MS 185.0 [M - H]-.
4-Acetoxyphenol (3b)
This compound was obtained in 99% yield as a white solid:
1
m.p. 79–81 °C; H NMR (DMSO-d6, 300 MHz, δ ppm) 9.42 (s,
4.4. General procedure for the one-pot synthesis of 11a–c
1H, OH), 6.91 (d, 2H, J = 8.9 Hz, ArH), 6.76 (d, 2H, J = 8.9 Hz,
ArH), 2.20 (s, 3H, CH3); 13C NMR (DMSO-d6, 75 MHz, δ ppm)
174.27, 159.65, 147.34, 127.15, 120.22, 25.48; HRMS calculated
for C8H7O3 [M - H]- 151.0395, found 151.0400.
Compound 2b (1 mmol) was dissolved in DMSO (10 mL)
followed by the addition of K2CO3 (1 mmol) and alkyl bromide
(1 mmol). The solution was stirred at 25 °C and monitored by
TLC. Upon completion of the reaction, the mixture was poured
into water and extracted by ethyl acetate (3 × 50 mL). The
combined organic phase was washed successively by water (3 ×
50 mL) and brine (2 × 50 mL), and then dried over anhydrous
Na2SO4, filtered, and evaporated in vacuo to give the crude
product which was further purified by column chromatography to
yield the pure target compound.
3-Acetoxyphenol (4b)
This compound was obtained in 93% yield as colorless oil: 1H
NMR (DMSO-d6, 300 MHz, δ ppm) 9.72 (s, 1H, OH), 7.15 (t, 1H,
J = 8.2Hz, 8.7Hz, ArH), 6.64 (t, 1H, J = 2.0Hz, 8.7 Hz, ArH),
6.51 (s, 1H, ArH), 6.49 (s, 1H, ArH), 2.21 (s, 3H, CH3CO); 13C
NMR (DMSO-d6, 75 MHz, δ ppm) 169.05, 158.20, 151.35,
129.77, 112.12, 108.95, 20.82; HRMS calculated for C8H7O3 [M
- H]- 151.0395, found 151.0399.
7-(2-Chloroethoxy)-2-(3,4-diacetoxyphenyl)-4-oxo-4H-
chromene-3,5-diyl diacetate (11a)
2-Acetoxyphenol (5b)
This compound was obtained in 67% yield as a white solid:
m.p. 160–162 °C; 1H NMR (CDCl3, 300 MHz, δ ppm) 7.71–7.72
(m, 2H, ArH), 7.34 (d, 1H, J = 8.2 Hz, ArH), 6.84 (d, 1H, J = 1.9
Hz, ArH), 6.66 (d, 1H, J = 2.0 Hz, ArH), 4.11 (t, 2H, J = 2.0 Hz,
CH2), 3.83 (t, 2H, J = 2.0 Hz, CH2), 2.42 (s, 9H, CH3CO), 2.34 (s,
3H, 3 ×CH3CO); 13C NMR (CDCl3, 75 MHz, δ ppm) 169.93,
169.40, 167.95, 167.77, 167.70, 162.29, 157.97, 153.24, 150.90,
144.23, 142.20, 133.91, 127.11, 126.37, 123.89, 123.70, 113.56,
108.93, 99.58, 68.64, 41.10, 21.10, 21.03, 20.60, 20.48; HRMS
This compound was obtained in 90% yield as a yellow solid:
m.p. 65–67°C; 1H NMR (DMSO-d6, 300 MHz, δ ppm) 9.57 (s,
1H, OH), 7.04 (t, 1H, J = 7.3Hz, 7.7Hz, ArH), 6.96 (d, 1H, J =
7.7 Hz, ArH), 6.89 (1H, d, J = 7.7 Hz, ArH), 6.77 (t, 1H, J =
7.3Hz, 7.7 Hz, ArH), 2.22 (s, 3H, CH3CO); 13C NMR (DMSO-d6,
75 MHz, δ ppm) 168.70, 148.92, 138.29, 126.56, 123.04, 119.01,
116.77, 20.58; ESI-MS 109.0 [M - CH3CO]-.
4-Acetoxy-2-methylphenol (6b)

7
calculated for C25H21ClNaO11 [M + Na]+ 555.0670, found
555.0682.
To a DMSO solution of 13 (1 mmol) or 14 (1 mmol) was
added K2CO3 (1 mmol) and the reaction mixture was stirred at
25 °C. After the reaction was complete, the mixture was poured
into water and extracted by ethyl acetate (3 × 50 mL). The
combined organic phase was washed successively by water (3 ×
50 mL) and brine (2 × 50 mL), and then dried over anhydrous
Na2SO4, filtered, and evaporated in vacuo to give the crude
product which was further purified by column chromatography to
give the pure compound.
ACCEPTED MANUSCRIPT
4-(3,5-Diacetoxy-4-oxo-7-(prop-2-yn-1-yloxy)-4H-chromen-2-
yl)-1,2-phenylene diacetate (11b)
This compound was obtained in 63% yield as a white solid:
m.p. 168–170 °C; 1H NMR (CDCl3, 300 MHz, δ ppm) 7.68–7.73
(m, 2H, ArH), 7.34 (d, 1H, J = 8.5 Hz, ArH), 6.95 (d, 1H, J = 2.0
Hz, ArH), 6.71 (d, 1H, J = 2.0 Hz, ArH), 4.76−4.80 (m, 2H, CH2),
2.70 (s, 1H, CH≡C), 2.24 (s, 9H, 3 × CH3), 2.22 (s, 3H, CH3); 13
C
2′-Propionyl-4′-hydroxyacetophenone (13a)
NMR (CDCl3, 75 MHz, δ ppm) 169.89, 169.32, 167.89, 167.74,
167.65, 161.53, 157.80, 153.21, 150.70, 144.19, 142.14, 133.85,
127.92, 126.30, 123.79, 123.65, 111.56, 109.23, 99.98, 76.86,
76.73, 56.40, 20.97, 20.52, 20.46, 20.40; HRMS calculated for
C26H20NaO11 [M + Na]+ 531.0903, found 531.0915.
The pure product was obtained in 80% yield as a white solid;
m.p. 79−80 °C; 1H NMR (DMSO-d6, 300 MHz, δ ppm) 10.61 (s,
1H, OH), 7.82 (d, 1H, J = 8.6 Hz, ArH), 6.75 (d, 1H, J = 8.6 Hz,
ArH), 6.52 (s, 1H, ArH), 2.59 (q, 2H, J = 7.4 Hz, CH2), 2.42 (s,
3H, CH3CO), 1.14 (t, 3H, J = 7.4 Hz, CH3); 13C NMR (DMSO-d6,
75 MHz, δ ppm): 195.05, 172.12, 162.30, 151.14, 132.86, 121.33,
112.82, 110.48, 28.88, 26.98, 8.56; HRMS calculated for
C11H12NaO4 [M + Na]+ 231.0633, found 231.0638.
4-(3,5-Diacetoxy-7-(2-ethoxy-2-oxoethoxy)-4-oxo-4H-
chromen-2-yl)-1,2-phenylene diacetate (11c)
This compound was obtained in 71% yield as a white solid:
m.p. 176–178 °C; 1H NMR (CDCl3, 300 MHz, δ ppm) 7.67−7.72
(m, 2H, ArH), 7.35 (d, 1H, J = 8.5 Hz, ArH), 6.80 (s, 1H, ArH),
6.69 (s, 1H, ArH), 4.72 (2H, s, OCH2), 4.31 (q, 2H, J = 7.1 Hz,
CH2), 2.44 (s, 3H, CH3), 2.34 (s, 9H, 3 × CH3), 1.31 (t, 3H, J =
7.1 Hz, CH3); 13C NMR (CDCl3, 75 MHz, δ ppm) 167.90, 167.76,
167.69, 167.41,167.29, 161.89, 157.87, 153.30, 150.94, 144.24,
142.19, 133.92, 127.95, 126.33, 123.83, 123.71, 111.82, 109.00,
99.78, 21.01, 20.59, 20.45, 14.08; HRMS calculated for
C27H24NaO13 [M + Na]+ 579.1115, found 579.1128.
2′-Benzoyl-4′-hydroxyacetophenone (14a)
The pure product was obtained in 71% yield as a white solid:
m.p. 137–139 °C; 1H NMR (DMSO-d6, 300MHz, δ ppm) 8.11 (d,
2H, J = 7.7 Hz, ArH), 7.89 (d, 1H, J = 8.4 Hz, ArH), 7.71–7.76
(m, 1H, ArH), 7.57–7.62 (m, 2H, ArH), 6.83 (d, 1H, J = 8.6 Hz,
ArH), 6.68 (s, 1H, ArH), 2.41 (s, 3H, CH3CO); 13C NMR
(DMSO-d6, 75 MHz, δ ppm) 194.94, 164.39, 162.35, 151.11,
133.78, 132.94, 129.83, 129.19, 128.80, 121.50, 113.12, 110.69,
28.90; HRMS calculated for C15H12NaO4 [M + Na]+ 279.0633,
found 279.0628.
4.5. General procedure for the synthesis of 12b and 12c
3,5,4′-Tri-O-acetylresveratrol (2 mmol) and resveratrol (1
mmol) were dissolved in DMSO, and K2CO3 (2 mmol) was
added. The reaction mixture was stirred at 25 °C. After the
reaction was complete, the mixture was poured into water and
extracted by ethyl acetate (3 × 50 mL). The combined organic
phase was washed successively by water (3 × 50 mL) and brine
(2 × 50 mL), and then dried over anhydrous Na2SO4, filtered,
followed by evaporation in vacuo to give the crude product,
which was further purified by column chromatography to yield
12b and 12c, successively.
4-Pivaloyloxy-4′-hydroxybenzophenone (15b)
This compound was prepared using the general synthetic
procedure for 3b–10b as described above, and the pure product
was obtained in 83% yield as a white solid: m.p. 171–173 °C; 1H
NMR (CDCl3, 400 MHz, δ ppm) 7.80 (d, 2H, J = 8.0 Hz, ArH),
7.76 (d, 2H, J = 8.0 Hz, ArH), 7.17 (d, 2H, J = 8.0 Hz, ArH),
6.90 (d, 2H, J = 8.0 Hz, ArH), 1.38 (s, 9H, CH3); 13C NMR
(DMSO-d6, 100 MHz, δ ppm) 194.73, 176.92, 159.91, 154.03,
135.43, 132.83, 131.34, 130.04, 121.41, 115.19, 39.23, 27.08;
ESI-MS 297.2 [M - H]-.
3,5-Di-O-acetylresveratrol (12b)
5. Acknowledgements
The pure target compound was obtained in 76% yield as a
white solid: m.p. 153–155 °C; H NMR (DMSO-d6, 300 MHz, δ
1
We are grateful to professors Tao Lu and Yadong Chen as
well as Dr. Haoliang Yuan for their kind help on the presentation
of reaction mechanisms.
ppm) 9.55 (s, 1H, OH), 7.63 (d, 2H, J = 8.4 Hz, ArH), 7.14 (m,
4H, ArH), 6.83 (d, 2H, J = 9.7 Hz, CH=), 6.45 (s, 1H, ArH), 2.27
(s, 3H, CH3CO), 2.26 (s, 3H, CH3CO); 13C NMR (DMSO-d6, 75
MHz, δ ppm) 169.11, 169.01, 158.31, 151.64, 149.98, 139.00,
134.43, 128.22, 127.87, 127.52, 122.05, 111.09, 110.14, 108.39,
20.83; HRMS calculated for C18H16NaO5 [M + Na]+ 335.0895,
found 335.0901.
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