CuI/1,10-phen/PEG promoted decarboxylation of 2,3-diarylacrylic acids: Synthesis of stilbenes under neutral and microwave conditions with an in situ generated recyclable catalyst

Article abstract of DOI:10.1039/c3ob41588k

A series of trans- or cis-stilbenes have been synthesized in good to excellent yields via a functional group-dependent decarboxylation process from the corresponding 2,3-diaryl acrylic acids in a neutral CuI/1,10-phen/PEG-400 system under microwave conditions. The in situ generation of the recyclable catalytic complex, the use of environmentally benign solvent PEG-400, the operational simplicity, the short reaction times, as well as the functional group-dependent chemo- and stereo-selectivity have made the decarboxylation process a highly efficient and applicable protocol.

Full text of DOI:10.1039/c3ob41588k

Organic &
Biomolecular Chemistry
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CuI/1,10-phen/PEG promoted decarboxylation of 2,3-
diarylacrylic acids: synthesis of stilbenes under neutral
and microwave conditions with an in situ generated
recyclable catalyst†
Cite this: Org. Biomol. Chem., 2013, 11,
6967
Yong Zou,*a,d Qi Huang,a,b Tong-kun Huang,a Qing-chun Ni,c En-sheng Zhang,a,b
Tian-long Xu,a,b Mu Yuand and Jun Lie
A series of trans- or cis-stilbenes have been synthesized in good to excellent yields via a functional group-
dependent decarboxylation process from the corresponding 2,3-diaryl acrylic acids in a neutral CuI/1,10-
phen/PEG-400 system under microwave conditions. The in situ generation of the recyclable catalytic
complex, the use of environmentally benign solvent PEG-400, the operational simplicity, the short
reaction times, as well as the functional group-dependent chemo- and stereo-selectivity have made the
decarboxylation process a highly efficient and applicable protocol.
Received 3rd August 2013,
Accepted 16th August 2013
DOI: 10.1039/c3ob41588k
www.rsc.org/obc
anticancer and anti-ageing (SIRT1 activating) properties, and
have the potential to be used as chemopreventive, neuroprotec-
Introduction
In recent years, stilbenes, either in trans or cis forms, have tive or nutraceutical agents,2–5 whereas the cis-stilbenes such
aroused the attention of medicinal chemists owing to their as combretastatin A-4 (CA4), AVE-8063 (Fig. 1) are renowned
interesting biological activities.1 Studies have shown that for potent antitubulin and antivascular activities, and are
the trans-stilbenes, like resveratrol and pterostilbene regarded as the lead compounds of vascular disrupting agents
(Fig. 1), possess antioxidant, anti-infective, anti-inflammatory, (VDAs).6,7
Stilbenes can be obtained through decarboxylation of the
corresponding 2,3-diarylacrylic acids, which were readily
obtained via Perkin condensation between phenylacetic acids
and benzaldehydes.8 In fact, the decarboxylation process has
emerged as an intriguing strategy in organic synthesis owing
to the inducing and activating properties of the carboxylic
group which could then be cleaved or decarboxylatively
coupled thereafter.9 Typically, the decarboxylation protocol for
aromatic carboxylic acids had for a long time been represented
by the excessive use of Cu powder and quinoline as the cata-
lytic system at high temperatures since the initial work of
Shepard in 1930 and the later applications in various car-
Fig. 1 Chemical structures of resveratrol, pterostilbene, CA4 and AVE-8063.
boxylic substrates.10,11 Recently, this methodology has been
improved by Goossen,12 Larrosa,13 Lisitsyn,14 Kozlowski15 and
Sinha,16 with the development of catalytic systems using Cu2O/
aGuangzhou Institute of Chemistry, Chinese Academy of Sciences, Guangzhou
phenanthroline/NMP/quinoline, AgOAc/K2CO3/NMP, Ag2CO3/
510650, China. E-mail: zou_jinan@163.com; Fax: +86 20 85231119
AcOH/DMSO, Cun+/bipy/Ph2O, (CF3CO2)2Pd/CF3CO2H/DMSO/
bUniversity of Chinese Academy of Sciences, Beijing 100039, China
cGuangzhou General Pharmaceutical Research Institute, Guangzhou 510240, China
dGuangzhou Medical University, Guangzhou 510182, China
DMF and [Hmim]/PTSA respectively, to achieve decarboxyla-
tion for various aromatic carboxylic acids. Among them,
Sinha’s method performed in ionic liquid [Hmim]/PTSA under
microwave conditions is unique and impressive,16 for it rep-
resents a metal- and quinoline-free decarboxylative protocol
with a wide substrate scope. However, most of the reported
eSecond Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou
310009, China
†Electronic supplementary information (ESI) available. CCDC 919496. For
ESI and crystallographic data in CIF or other electronic format see DOI:
10.1039/c3ob41588k
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methods still suffer from disadvantages such as the use of
environmentally hazardous or nondegradable solvents, pro-
longed reaction times, difficulty in isolating the products.
Moreover, in most cases, the decarboxylative systems couldn’t
be recycled for the next runs. Thus, exploring for a milder,
more benign and recyclable catalytic system for decarboxyla-
tion would be highly desirable.
Table 1 Screening of the reaction conditions for decarboxylation of 2,3-diaryl-
acrylic acid (1a)a
The use of PEG as an efficient, neutral and benign solvent
has grown rapidly in recent years.17 This is due to its green
properties such as ready availability, high stability, reduced
flammability, nontoxicity, odorlessness, easily degradability
and extensive miscibility. In 2007, Sinha and co-workers18
reported a microwave-assisted decarboxylation process by
using NaHCO3(aq)/PEG/MIm and piperidine/PEG/MIm as cata-
lysts to afford an interesting library of para-hydroxylated trans-
stilbenes. The above-mentioned drawbacks as well as the clues
for using PEG attracted our attention, and in continuation
of our work on green synthesis of natural stilbenes and
biomass-based conversion,8a,19 we herein report a facile,
efficient, environmentally benign and recyclable catalytic
system for decarboxylation of 2,3-diarylacrylic acids which
exhibit a broad substrate scope.
Entry Solvent
Cu source (mol%) Ligand (mol%) Yieldb (%)
1
Quinoline
NMP
Ionic liquid Cu (280)
Cu (280)
Cu (280)
L1 (10)
L1 (10)
L1 (10)
L1 (10)
L1 (10)
L1 (10)
L1 (10)
L1 (10)
L1 (10)
L1 (10)
L1 (10)
L1 (10)
L1 (10)
L1 (10)
L1 (10)
L1 (10)
L1 (15)
L1 (5)
73
2
Trace
Trace
71
72
76
75
37
41
80
81
84
84
83
53
ND
84
3c
4
5
6
7
8
9
Triglycol
PEG-200
PEG-400
PEG-600
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
Cu (280)
Cu (280)
Cu (280)
Cu (280)
CuSO4 (30)
Cu(OAc)2 (30)
Cu2O (30)
CuBr (30)
CuI (30)
CuI (20)
CuI (10)
CuI (5)
10
11
12
13
14
15
16
17
18
19
20
21
22
23d
24e
25f
26g
—
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
51
—
7
L2 (10)
L3 (10)
L4 (10)
L1 (10)
L1 (10)
L1 (10)
L1 (10)
61
48
Trace
79
81
36
79
Results and discussion
Initially, (E)-2-(3-amino-4-methoxyphenyl)-3-(3,4,5-trimethoxy
phenyl)acrylic acid (1a), which served as the key intermediate
for access to AVE-8063, was chosen as the model substrate to
screen the optimal conditions (Table 1). Although our pre-
viously established protocol which employed Cu/1,10-phen-
(1,10-phenanthroline hydrate) in quinoline under microwave
conditions could afford 2a in 73% isolated yield (Table 1,
entry 1), the excessive use of Cu powder, difficulty in isolating
the product from the quinoline mixture, as well as the environ-
mental and labour security concerns associated with quinoline
have made the process far from perfect and benign. Sub-
sequently, we investigated various high boiling point solvents
a Reaction conditions: 1a (5.0 mmol), Cu source, ligand (L1: 1,10-
phenanthroline hydrate, L2: bipyridine, L3: oxine, L4: PPh3), solvent
(20 ml), under N2 atmosphere, the mixture was stirred under
microwave irradiation (800 W, 180–190 °C) for 6 min (2 min irradiation
for each time with a 5 min interval between). ND: no desired product.
b Isolated yield. c Ionic liquid: [Bmim]Br (15 g). d Microwave irradiation
for 10 min. e Microwave irradiation for 8 min. f Microwave irradiation
for 4 min. g Under conventional heating (200 °C, 60 min).
with greener profiles, such as triglycol, PEG-200, PEG-400, obtained in only 6 min reaction under microwave irradiation.
PEG-600, NMP and [Bmim]Br in place of quinoline. To our Investigation on the different amounts of CuI revealed that
delight, experiments showed that a highly beneficial result was 10 mol% of CuI was the most optimal for this reaction, giving
obtained using PEG-400 as the solvent, giving 2a in 76% yield 2a in 83% yield (compare entries 12–15). However, no reaction
(entry 6). Other polymerized ethylene glycols like triglycol, occurred in the absence of CuI under otherwise identical con-
PEG-200 and PEG-600 gave slightly lower or almost the same ditions, indicating that CuI was essential for the decarboxyl-
yields (entries 4, 5, 7), whereas NMP and ionic liquid ation processes (entry 16). In addition, 10 mol% amount of
[Bmim]Br were not workable (entries 2, 3). Apart from the 1,10-phen proved to be the best choice for this reaction, as
solvent effect, the copper-containing catalyst is another crucial there was no significant improvement in yield when 15 mol%
factor which deserves further exploration. Although the influ- amounts of 1,10-phen were used (entry 17), whereas lower
ence of different Cu sources on decarboxylation reactions has yields were obtained with 5 mol% or without 1,10-phen
previously been investigated by Goossen et al. in their pioneer- (entries 14, 18, 19). Other commonly-used ligands such as
ing work,12a,b optimized catalytic system possessing green bipyridine, oxine and PPh3 were also tested, but were shown to
chemistry properties is still needed. Accordingly, we investi- be less effective or essentially unworkable (entries 20–22).
gated a number of copper salts, including CuBr, CuI, Cu2O, Further inspection of the reaction time revealed that 6 min of
Cu(OAc)2 and CuSO4, for their catalytic behavior combined microwave irradiation was optimal for the reaction, while
with 1,10-phen in PEG-400 (entries 8–12). Results showed that longer or shorter reaction times were found to be unfavorable
when 30 mol% of CuI was utilized, about 84% of 2a was (entries 14, 23–25). In comparison to microwave irradiation,
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conventional heating was also studied under the same con-
ditions, which afforded lower yield in prolonged reaction time
(entry 26). The optimized reaction conditions were established
as: 2,3-diaryl acrylic acid (5 mmol), CuI (10 mol%), 1,10-phen
(10 mol%) in PEG-400 (20 ml) under microwave irradiation
(800 W, 180–190 °C) for 6 min.
Table 2 Decarboxylation of 2,3-diaryl acrylic acids (1a–1t) under optimized
conditionsa
Under the optimized conditions, the scope of the protocol
was explored using various 2,3-diaryl acrylic acids as sub-
strates. As shown in Table 2, almost all of the tested com-
pounds successfully produced the desired stilbenes with good
to excellent yields. The results showed that the functional
groups on the aryl rings exerted remarkable influences on the
decarboxylation processes. Electron-deficient substrates were
more favorable than electron-sufficient ones to provide the
corresponding products. For example, substrates with –Br,
–OH or –NH2 moieties which decrease in electron withdrawing
order provided product yields of 86%, 84% and 83% respect-
ively, under our standard conditions, whereas substrates with
the strong withdrawing –NO2 group 1d was efficiently decar-
boxylated to give an excellent yield of 94% under milder con-
ditions (Table 2, entries 1–4). It was also evident from Table 2
that the position of the carboxylic group on ethylene scaffold
had little influence on the yields (entries 2, 6–8, and 14–15).
Furthermore, it was notable that the substrates with para-
hydroxyl substitution at either aryl ring of (E)-2,3-diaryl acrylic
acids underwent an isomerization process during decarboxyla-
tion, which led to the formation of corresponding trans-stil-
benes in good to excellent yields (entries 9–11). The cis to trans
isomerization concerning the para-hydroxylated substrates
1i–k can be attributed to the formation of the para-quinone
intermediate.18,19a,b,20 However, when 2,3-diaryl acrylic acid
without a para-hydroxyl group on either aryl ring like (E)-2-
(4-methoxyphenyl)-3-(3,4,5-trimethoxyphenyl)acrylic acid (1l) was
decarboxylated, the reaction would retain the configuration
and give rise to the cis-stilbene as a sole product (entry 12).
Likewise, the reactions also performed well for (Z)-2,3-diaryl
acrylic acids, which gave trans-stilbenes as expected with satis-
factory yields (entries 13–17). It is worth mentioning that an
interesting and unambiguous ortho-effect leading to un-
expected products has been found in the synthesis of some
specific stilbenes and the precursors. For example, the ortho-
brominated substrate E-2-(2-bromo-3,5-dimethoxyphenyl)-3-
(4-hydroxyphenyl)acrylic acid (1s) underwent a tandem hydroxy-
lation/intramolecular addition/dehydrogenation process in the
presence of CuSO4/NaOH(aq) to give 2-(4-hydroxyphenyl)-5,7-
dimethoxybenzofuran-3-carboxylic acid (1r). Subsequent
decarboxylation of this compound under typical conditions
afforded livistone C (2r-1),21 a new 2-arylbenzofuran com-
pound recently isolated from the fruits of Livistona chinensis,
in moderate yield. In the meantime, trace amount of E-2,4′-
dihydroxyl-3,5-dimethoxylstilbene (2r-2) could also be detected
owing to the existence of 2-(2-hydroxy-3,5-dimethoxyphenyl)-
3-(4-hydroxyphenyl)acrylic acid in the crude product of 1r.
Moreover, compound 1s reacted under typical conditions and
unexpectedly gave a lactonated isoaurostatin derivative 2s,
which might be due to the copper-catalyzed C–Br cleavage
Entry
1
Substrate
Product
Yieldb (%)
83
2
84
3
86
94
4c
5
6
88
82
2b
7
8
84
85
2g
9
82
89
10
11
12
87
83
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It is worth mentioning that, during the decarboxylation
reactions, an appreciable amount of red crystalline powder
could readily be recovered from the mixture by filtration. The
low solubility in PEG-400, H2O and most organic solvents as
well as the high thermostability according to thermogravi-
metric analysis (ca. 2% weight loss at 294 °C, see ESI†)
suggested that it would be a CuI-related complex in situ gener-
ated during the reaction and therefore deserve further atten-
tion. Accordingly, analytical and spectroscopic studies have
been conducted for identification of this complex. The elemen-
tal analysis and FAB-MS spectra suggested it to be a 1,10-phen-
ligated CuI complex having the dimeric formula [CuI(1,10-
Table 2 (Contd.)
Entry
13
Substrate
Product
Yieldb (%)
84
14
15
87
86
22
phen)]2 (Anal. calcd for C24H16N4Cu2I2: C, 38.88; H, 2.18;
N, 7.56; found: C, 39.00; H, 2.13; N, 7.51; FAB-MS: m/z 741.17
1
[M + 1]+). In the H NMR spectrum of the complex, note the
2n
appearance of four broad singlets in the region of aromatic
protons at 9.17, 8.79, 8.23, and 8.06 ppm, corresponding to the
eight symmetrical protons of 2-H, 9-H; 4-H, 7-H; 5-H, 6-H; 3-H,
8-H for 1,10-phen, respectively. The formation of singlets can
be attributed to the high chemical exchange rate between a
bound and unbound 1,10-phen, thus resulting in each proton
16
17
2j
92
89
1
signal being averaged to be a single broad band. The H NMR
2k
spectrum also showed that all of the protons in the conjugated
1,10-phen underwent
a remarkable downfield shift with
respect to the free ligand due to the coordination between
N–Cu–N. The IR spectra of the complex clearly showed the
existence of the 1,10-phen framework, strong absorptions at
1498, 1415 cm−1 were assigned to the νas (CvN) stretching
vibration which showed a red shift compared to the free ligand
(1504, 1421 cm−1, respectively). Scanning electron microscopy
(SEM) image revealed that this copper complex had a regular
parallelepiped microcrystal morphology with an average crystal
size of 5 × 20 × 50 μm (Fig. 2).
18
69
Trace
19d
63
With the in situ generated [CuI(1,10-phen)]2 complex in
hand, we were eager to find out its catalytic activity for decar-
boxylation by using (E)-2-(3,5-dimethoxyphenyl)-3-(3-hydroxy-
4-methoxy-phenyl)acrylic acid (1g) as a model substrate. Much
to our delight, this complex revealed a high efficiency in decar-
boxylation reactions and gave the desired (Z)-3′-hydroxyl-3,4′,5-
trimethoxystilbene (2g) which had been reported to be a
potent vascular disrupting agent,23 in comparable yields over
five consecutive runs (Table S1†). The structure of 2g was con-
firmed by single crystal X-ray diffraction (Fig. 3). The results
demonstrated that the catalytic CuI-related complex still
retained its physicochemical and morphological properties
during repeated reactions, and could be readily recycled and
reused without significant loss of activity. To the best of our
20e
ND
a Reaction conditions: 2,3-diarylacrylic acid (5.0 mmol), CuI (10 mol%),
1,10-phen (10 mol%), PEG-400 (20 ml), under N2 atmosphere, the
mixture was stirred under microwave irradiation (800 W, 180–190 °C)
for 6 min (2 min irradiation each time with a 5 min interval between).
The configuration of cis and trans-stilbenes is confirmed by coupling
constant of alkene protons ( J(CHvCH) = 12.4 Hz for cis-stilbenes, and
J(CHvCH) = 16.4 Hz for trans-stilbenes). ND: no desired product.
b Isolated yields. c Reaction was performed at 150 °C under microwave
irradiation (720 W). d Microwave irradiation (800 W, 180–190 °C) for
8 min. e Microwave irradiation (800 W, 180–190 °C) for 12 min.
followed by a sterically favorable lactone formation process.
However, 3-arylcoumarin was found to be inactive for
decarboxylation even in prolonged irradiation time (Table 2,
entry 20).16
Fig. 2 SEM of [CuI(1,10-phen)]2.
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Fig. 3 X-ray crystal structure of 2g.25
knowledge, although the combinative use of CuI/1,10-phen
has been widely employed as a hallmark in catalytic processes
in recent years,24 the in situ generation of a stable complex
under reaction conditions as well as the excellent recyclability
and reusability have not yet been reported.
A plausible mechanism for this decarboxylative process
including the pathway for cis-to-trans isomerization is outlined
in Scheme 1. The combination of CuI and 1,10-phen in
PEG-400 under reaction conditions generates a monomer CuI-
(1,10-phen), which would serve as an active state of the more
stable dimeric complex [CuI(1,10-phen)]2. An initial reaction of
A and CuI(1,10-phen) affords the copper carboxylate B with the
loss of a hydriodic acid, followed by decarboxylation to give
the organocopper intermediate C, which is subsequently
protonated by hydriodic acid to yield stilbene D and regenerate
the CuI(1,10-phen) catalyst. Finally, the reactive CuI(1,10-phen)
species may be converted into [CuI(1,10-phen)]2 as the solvent
cools down (Scheme 1a). On the other hand, when a substrate
bearing an para-hydroxyl group in either of the phenyl rings
like 1k is subjected to the reaction conditions, a para-quinone
intermediate would be generated, thus leading to the cis to
trans isomerization via rotation around the single bond and
resulting in the formation of a more stable trans-stilbene, like
2k (Scheme 1b). It is noteworthy that control experiments for
decarboxylation reactions catalyzed by CuI and 1,10-phen in
the presence of quinoline have failed to regenerate the corres-
ponding [CuI(1,10-phen)]2 complex, indicating the importance
and effectiveness for using PEG-400 as the solvent in
decarboxylation.
Scheme 1 A plausible mechanism for the CuI(1,10-phen)-catalyzed decarboxy-
lation of 2,3-diarylacrylic acids. (a) Mechanism for substrate without a para- and
ortho-hydroxyl group in either of the phenyl rings, which provided a configur-
ation-retained product. (b) Representative mechanism for substrates bearing an
para-hydroxyl group in either of the phenyl rings, which lead to the cis to trans
isomerization (taking 1k–2k as an example).
Experimental section
General information
Conclusions
In summary, we have developed a green and efficient method 2,3-Diaryl acrylic acids were directly obtained through Perkin
for decarboxylation of 2,3-diaryl acrylic acids in the CuI/1,10- reaction except 1a and 1r. Other reagents and chromatography
phen/PEG-400 system under microwave conditions. The results grade solvents were obtained from commercial sources and
demonstrated that the in situ generated [CuI(1,10-phen)]2 used without further purification unless otherwise stated.
complex, which could be readily recovered from the reaction Petroleum ether (PE) used refers to the boiling fraction of
mixture, revealed excellent catalytic activity, stability, and reu- 60–90 °C. All microwave assisted reactions were carried out
sability. In addition, the use of environmentally benign solvent with a Microwave Synthesizer (WBFY-205, Gongyi City Yu Hua
(PEG-400), the operational simplicity, short reaction times, as Instrument Co. Ltd, China), and the reaction temperature was
well as the functional group-dependent chemo- and stereo- detected using an infrared thermometer. The melting points
selectivity have all made the decarboxylation process a highly are uncorrected. 1H NMR and 13C NMR spectra were measured
efficient and applicable protocol.
using a 400 MHz spectrometer (1H 400 MHz, 13C 100 MHz)
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using CDCl3 or DMSO-d6 as the solvent at room temperature. crude product, which was further recrystallized from EtOAc–PE
Chemical shifts are reported in parts per million (ppm) and are to give the desired product 2.
calibrated using residual undeuterated solvent as an internal
Recyclability of [CuI(1,10-phen)]2
reference. HRMS spectra were recorded using a LC-Q-TOF (ESI)
apparatus. The single X-ray diffraction measurement was per- Run 1: 1g (0.05 mol, 16.5 g), the recovered [CuI(1,10-phen)]2
formed using a X-ray diffractometer. The morphology was (5 mol%, 1.85 g) from the initial reaction and PEG-400
characterized using scanning electron microscopy (SEM, 15 kV). (100 ml) were added into a 250 ml round bottom flask. The
Thermogravimetric analysis (TGA) was carried out at a heating flask was then placed in the microwave synthesizer, charged
rate of 3° min−1 under a flowing argon atmosphere.
with N2, and irradiated (800 W, 180–190 °C) with stirring for
6 min (2 min irradiation for three times with a 5 min interval
between). After completion of the reaction, the mixture was
cooled to r.t., water (50 ml) and ethyl acetate (50 ml) were
Procedure for preparing (E)-2-(3-amino-4-methoxyphenyl)-
3-(3,4,5-trimethoxyphenyl)acrylic acid (1a)
A tube equipped with a magnetic stir bar was charged with 1c added, the resulting red crystalline powder [CuI(1,10-phen)]2
(10 mmol, 4.23 g), CuI (20 mol%, 0.38 g), ammonia water (wt = was filtered off, washed with water and ethyl acetate, dried and
28%, 15 ml) and PEG-400 (15 ml). The tube was sealed and stored for next runs. The filtrate was extracted with ethyl
the mixture was stirred at 80 °C for 48 h. The reaction mixture acetate (2 × 50 ml). The combined organic phases were washed
was cooled to room temperature, adjusted with 10% HCl solu- with water, dried over anhydrous MgSO4 and then concen-
tion to pH 7, the insoluble CuI was filtered off, and the result- trated to afford the crude product, which was further recrystal-
ing filtrate was further acidified to pH 5 with 10% HCl lized from EtOAc–PE to give the pure product 2g in 84%
solution to give a yellow solid, which was collected by filtration isolated yield. Reaction conditions of Runs 2–5 were the same
1
to afford 1a (3.27 g, 91.1% yield). H NMR (400 MHz, DMSO- as those of Run 1 with 83%, 82%, 82%, 82% yield, respectively
d6): δ = 12.21 (s, 1H, COOH), 7.57 (s, 1H), 6.83 (d, J = 8.4 Hz, (Table S1†).
1H), 6.49 (s, 2H), 6.46 (d, J = 1.6 Hz, 1H), 6.34 (dd, J = 8.4 Hz,
(Z)-3′-Amino-3,4,4′,5-tetramethoxystilbene (2a)7b
J = 1.6 Hz, 1H), 4.43 (s, 2H, NH2), 3.75 (s, 3H), 3.60 (s, 3H),
1
3.48 (s, 6H); MS (m/z): 359 (M+), 344, 329, 299, 284, 269, 255, Yellow oil (yield: 1.31 g, 83%). H NMR (400 MHz, DMSO-d6):
241, 183, 156, 148, 134.
δ = 6.72 (d, J = 8 Hz, 1H), 6.66 (d, J = 1.6 Hz, 1H), 6.60 (s, 2H),
6.47 (dd, J = 1.6 Hz, J = 8 Hz, 1H), 6.41 (d, J = 12.4 Hz, 1H),
6.31 (d, J = 12.4 Hz, 1H), 4.71 (s, 2H), 3.72 (s, 3H), 3.62 (s, 3H),
3.58 (s, 6H); 13C NMR (100 MHz, CDCl3): 152.7, 146.5, 135.6,
Procedure for preparing 2-(4-hydroxyphenyl)-5,7-
dimethoxybenzofuran-3-carboxylic acid (1r)
A tube equipped with a magnetic stir bar was charged with 1s 132.9, 129.9, 128.3, 128.2, 126.2, 119.5, 115.2, 109.9, 105.9,
(10 mmol, 3.79 g), CuSO4 (30 mmol, 4.8 g), NaOH (100 mmol, 60.8, 56.0, 55.8; HRMS (ESI): m/z calcd for C18H22NO4
4.0 g) and H2O (36 ml). The mixture was stirred at 120 °C for [M + H]+: 316.1543; found: 316.1555.
72 h. The reaction mixture was cooled to room temperature
(Z)-3′-Hydroxyl-3,4,4′,5-tetramethoxystilbene (2b)19a
filtrate was acidified to pH 4–5 using 10% HCl solution and a White solid (yield: 1.33 g, 84%). m.p. 116–117 °C; 1H NMR
white solid 1r (1.48 g, 46.8% yield) was separated by filtration. (400 MHz, CDCl3): δ = 6.91 (d, J = 2.0 Hz, 1H), 6.79 (dd, J =
and the insoluble substance was filtered off. The resulting
1
HRMS (ESI): m.p. 212–214 °C; H NMR (400 MHz, DMSO-d6): 8.0 Hz, J = 2.0 Hz, 1H), 6.71 (d, J = 8.0 Hz, 1H), 6.51 (s, 2H),
δ = 12.4 (s, COOH), 12.4 (s, OH), 7.82 (d, J = 8.0 Hz, 2H), 7.01 6.45 (d, J = 12.4 Hz, 1H), 6.42 (d, J = 12.4 Hz, 1H), 5.49 (s, 1 H),
(d, J = 4.0 Hz, 1H), 6.87 (d, J = 8.0 Hz, 2H), 6.58 (d, J = 4.0 Hz, 3.89 (s, 3H), 3.84 (s, 3H), 3.68 (s, 6H); 13C NMR (100 MHz,
1H), 3.93 (s, 3H), 3.79 (s, 3H); HRMS (ESI): m/z calcd for CDCl3): δ = 152.6, 145.7, 145.1, 136.9, 132.5, 130.3, 129.3,
C17H14NaO6 [M + Na]+: 337.0683; found: 337.0677.
128.8, 120.9, 114.9, 110.2, 105.9, 60.7, 55.7; HRMS (ESI): m/z
calcd for C18H21O5 [M + H]+: 317.1384; found: 317.1399.
General procedures for decarboxylation
(Z)-3′-Bromo-3,4,4′,5-tetramethoxystilbene (2c)
2,3-Diaryl acrylic acid 1 (5 mmol), CuI (0.5 mmol), 1,10-phe-
nanthroline monohydrate (0.5 mmol) and PEG-400 (20 ml) Yellow solid (yield: 1.63 g, 86%). m.p. 76–77 °C. 1H NMR
were added into a 50 ml round bottom flask. The flask was (400 MHz, DMSO-d6): δ = 7.55 (d, J = 2.0 Hz, 1H), 7.19 (dd, J =
then placed in the microwave synthesizer, charged with N2, 8.4 Hz, J = 2.0 Hz, 1H), 6.77 (d, J = 8.4 Hz, 1H), 6.50 (s, 2H),
and irradiated (800 W, 180–190 °C) with stirring for 4–12 min 6.45 (d, J = 12 Hz, 1H), 6.42 (d, J = 12 Hz, 1H), 3.87 (s, 3H), 3.84
(2 min irradiation each time with a 5 min interval between). (s, 3H), 3.70 (s, 6H); 13C NMR (100 MHz, CDCl3): δ = 154.7,
After completion of the reaction, the mixture was cooled to r.t., 152.8, 133.5, 132.1, 130.7, 129.7, 129.1, 127.7, 111.2, 110.9,
water (20 ml) and ethyl acetate (20 ml) were added, the result- 105.8, 103.2, 60.8, 56.0, 55.9; HRMS (ESI): m/z calcd for
ing red crystalline powder [CuI(1,10-phen)]2 was filtered off, C18H20BrO4 [M + H]+: 379.0539; found: 379.0546.
washed with water and ethyl acetate, dried and stored for next
(Z)-3′-Nitro-3,4,4′,5-tetramethoxystilbene (2d)7b
The combined organic phases were washed with water, dried Yellow solid (yield: 1.62 g, 94%). m.p. 118–120 °C, 1H NMR
over anhydrous MgSO4 and then concentrated to afford the (400 MHz, CD3COCD3): δ = 7.74 (d, J = 2.0 Hz, 1H), 7.53–7.57
runs. The filtrate was extracted with ethyl acetate (2 × 20 ml).
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(dd, J = 8.8, 2.0 Hz, 1H), 7.26 (d, J = 8.8 Hz, 1H), 6.62 (d, J = (Z)-3,4,4′,5-Tetramethoxystilbene (2l)19a
12.4 Hz, 1H), 6.58 (s, 2H), 6.54 (d, J = 12.4 Hz, 1H), 3.71 (s,
3H), 3.95 (s, 3H), 3.67 (s, 6H); 13C NMR (100 MHz, CDCl3): δ =
153.2, 151.7, 139.4, 137.6, 134.6, 131.8, 129.7, 126.8, 125.9,
113.0, 105.8, 60.9, 56.5, 56.0; HRMS (ESI): m/z calcd for
C18H19NnaO6 [M + Na]+: 368.1105; found: 368.1105.
1
Yellow oil (yield: 1.25 g, 83%). H NMR (400 MHz, DMSO-d6):
δ = 7.21 (d, J = 8.4 Hz, 2H), 6.77 (d, J = 8.4 Hz, 2H), 6.49 (s, 2H),
6.48 (d, J = 12.4 Hz, 1H), 6.40 (d, J = 12.4 Hz, 1H), 3.84 (s, 3H),
3.82 (s, 3H), 3.67 (s, 6H); 13C NMR (100 MHz, CDCl3): δ =
158.5, 152.7, 136.8, 132.7, 130.1, 129.4, 129.3, 128.5, 113.4,
105.7, 60.7, 55.7, 55.0; HRMS (ESI): m/z calcd for C18H21O4
[M + H]+: 301.1434; found: 301.1431.
(Z)-3′-Bromo-3,4′,5-trimethoxystilbene (2e)
1
Yellow oil (yield: 1.54 g, 88%). H NMR (400 MHz, DMSO-d6):
(E)-3′-Amino-3,4,4′,5-tetramethoxystilbene (2m)
δ = 7.46 (d, J = 2.4 Hz, 1H), 7.22 (dd, J = 8.8 Hz, J = 2.0, 1H),
7.01 (d, J = 8.8 Hz, 1H), 6.50 (t, J = 12.8 Hz, 2H), 6.37–6.39 (m,
3H), 3.81 (s, 3H), 3.63 (s, 6H); 13C NMR (100 MHz, CDCl3): δ =
160.6, 154.8, 138.7, 133.7, 130.9, 129.8, 128.5, 111.3, 111.0,
106.5, 99.9, 56.1, 55.2; HRMS (ESI): m/z calcd for
C17H17NaBrO3 [M + Na]+: 371.0253; found: 371.0250.
White solid (yield: 1.32 g, 84%). m.p. 110–112 °C. 1H NMR
(400 MHz, DMSO-d6): δ = 7.03 (d, J = 16.4 Hz, 1H), 6.88 (d, J =
1.6 Hz, 1H), 6.85 (d, J = 16.4 Hz, 1H), 6.84 (s, 2H), 6.78 (d, J =
8.4 Hz, 1H), 6.74 (dd, J = 1.6 Hz, J = 8.4 Hz, 1H), 4.74 (s, 2H),
3.81 (s, 6H), 3.76 (s, 3H), 3.65 (s, 3H); 13C NMR (100 MHz,
CDCl3): δ = 153.3, 147.4, 138.4, 136.0, 133.5, 130.3, 128.2,
126.3, 117.8, 112.2, 110.3, 103.2, 60.9, 56.0, 55.5; HRMS (ESI):
m/z calcd for C18H22NO4 [M + H]+: 316.1543; found: 316.1547.
(Z)-3′-Hydroxyl-3,4′,5-trimethoxystilbene (2g)19a
White solid (yield: 1.20 g, 84%). m.p. 93–95 °C. 1H NMR
(400 MHz, CDCl3): δ = 6.87 (d, J = 2.0 Hz, 1H), 6.77 (dd, J = 8.4
Hz, J = 2.0 Hz, 1H), 6.69 (d, J = 8.4 Hz, 1H), 6.47 (d, J = 12.4 Hz,
1H), 6.43 (d, J = 2.0 Hz, 2H), 6.42 (d, J = 12.4 Hz, 1H), 6.30 (t,
J = 2.0 Hz, 1H), 5.42 (s, 1H), 3.84 (s, 3H), 3.66 (s, 6H); 13C NMR
(100 MHz, CDCl3): δ = 160.4, 145.8, 145.0, 139.2, 130.3, 130.1,
128.9, 121.1, 115.0, 110.2, 106.6, 99.6, 55.7, 55.1; HRMS (ESI):
(E)-3′-Hydroxyl-3,4,4′,5-tetramethoxystilbene (2n)27
White solid (yield: 1.37 g, 87%). m.p. 102–104 °C. 1H NMR
(400 MHz, DMSO-d6): δ = 9.01 (s, 1H), 7.08–7.04 (d, J = 16.4 Hz,
1H), 7.01 (s, 1H), 6.97–6.89 (m, 3H), 6.86 (s, 2H), 3.81 (s, 6H),
3.77 (s, 3H), 3.65 (s, 3H); 13C NMR (100 MHz, CDCl3): δ =
153.3, 146.3, 145.7, 137.5, 133.2, 130.9, 127.7, 126.9, 119.1,
111.6, 110.6, 103.2, 60.9, 56.0, 55.9; HRMS (ESI): m/z calcd for
C18H20NaO5 [M + Na]+: 339.1203; found: 339.1208.
m/z calcd for C17H18NaO4 [M
+
Na]+: 309.1097; found:
309.1097.
(E)-3,4′,5-Trihydroxystilbene (2i)19a
5,7-Dimethoxy-2-(4′-hydroxyphenyl)benzofuran (2r-1)21
White solid (yield: 0.93 g, 82%). m.p. 263–264 °C. 1H NMR
(400 MHz, CD3COCD3): δ = 8.43 (s, 1H, OH), 8.23 (s, 2H,
2 × OH), 7.43 (d, J = 8.8 Hz, 2H), 7.01 (d, J = 16.4 Hz, 1H), 6.89
(d, J = 16.4 Hz, 1H), 6.84 (d, J = 8.8 Hz, 2H), 6.55 (d, J = 2.0 Hz,
2H), 6.28 (t, J = 2.0 Hz, 1H); 13C NMR (100 MHz, DMSO-d6): δ =
158.6, 157.3, 139.3, 128.1, 127.9, 125.7, 115.6, 104.4, 101.8;
HRMS (ESI): m/z calcd for C14H13O3 [M + H]+: 229.0859; found:
229.0859.
White solid (yield: 0.93 g, 69%). m.p. 122–124 °C. 1H NMR
(400 MHz, DMSO-d6): δ = 9.83 (s, 1H), 7.68 (d, J = 8.8 Hz, 2H),
7.05 (s, 1H), 6.76 (d, J = 8.8 Hz, 2H), 6.65 (d, J = 2.4 Hz, 1H),
6.47 (d, J = 2.4 Hz, 1H), 3.89 (s, 3H), 3.76 (s, 3H); 13C NMR
(100 MHz, DMSO-d6): δ = 158.2, 156.6, 156.3, 144.9, 130.5,
127.9, 126.2, 121.0, 115.8, 100.0, 96.6, 94.5, 55.8, 55.5; HRMS
(ESI): m/z calcd for C16H15O4 [M + H]+: 271.0965; found:
271.0962.
(E)-4′-Hydroxyl-4-methoxystilbene (2j)26
3-(4-Hydroxybenzylidene)-5,7-dimethoxybenzofuran-2(3H)-one
(2s) (Z/E = 1 : 1)
Gray solid (yield: 1.01 g, 89%). m.p. 182–184 °C. 1H NMR
(400 MHz, CDCl3): δ = 7.48 (d, J = 8.8 Hz, 2H), 7.40 (d, J =
8.8 Hz, 2H), 7.10 (d, J = 16.4 Hz, 1H), 6.96 (d, J = 16.4 Hz, 1H),
6.92 (d, J = 8.8 Hz, 2H), 6.83 (d, J = 8.8 Hz, 2H), 3.80 (s, 3H);
13C NMR (100 MHz, DMSO-d6): δ = 158.5, 157.0, 130.2, 128.4,
127.5, 127.3, 126.2, 124.8, 115.5, 114.1, 55.1; MS (EI): m/z (%)
226 (100%), 221 (60), 165 (30), 113 (27).
Yellow solid (yield: 0.94 g, 63%). 1H NMR (400 MHz, DMSO-
d6): δ = 10.47 (s, 1H), 10.36 (s, 1H), 8.25 (d, J = 8.4 Hz, 2H),
7.95 (s, 1H), 7.75 (s, 1H), 7.70 (d, J = 8.4 Hz, 2H), 7.01 (d, J =
2.0 Hz, 1H), 6.95 (d, J = 8.8 Hz, 2H), 6.91 (d, J = 2.0 Hz, 1H),
6.88 (d, J = 8.8 Hz, 2H), 6.71 (d, J = 2.0 Hz, 1H), 6.58 (d, J =
2.0 Hz, 1H), 3.88 (s, 3H), 3.85 (s, 3H), 3.82 (s, 3H), 3.80 (s, 3H);
HRMS (ESI): m/z calcd for C17H14NaO5 [M + Na]+: 321.0733;
found: 321.0734.
(E)-4′-Hydroxyl-3,5-dimethoxystilbene (2k)9a
White solid (yield: 1.11 g, 87%). m.p. 85–86 °C. 1H NMR
(400 MHz, DMSO-d6): δ = 9.58 (s, 1H), 7.40 (d, J = 8.4 Hz, 2H),
7.15 (d, J = 16.4 Hz, 1H), 6.93 (d, J = 16.4 Hz, 1H), 6.76 (d, J =
8.8 Hz, 2H), 6.74 (d, J = 2.4 Hz, 2H), 6.36 (t, J = 2.4 Hz, 1H),
Acknowledgements
3.75 (s, 6H); 13C NMR (100 MHz, CDCl3): δ = 160.9, 155.3, We are grateful for financial support from the National Science
139.6, 130.1, 128.7, 128.0, 126.6, 115.6, 104.4, 99.6, 55.4; Foundation of P. R. China (no. 21272280, 81201716), Science &
HRMS (ESI): m/z calcd for C16H17O3 [M + H]+: 257.1172; found: Technology Program of Guangdong Province and Guangzhou
257.1167.
City (no. 2009B091300125, 2011A081401002, 2012J4300097),
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National Significant New Drugs Development (no. 12 (a) L. J. Goossen, F. Manjolinho, B. A. Khan and
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