Synthesis of a focused chemical library based on derivatives of embelin, a natural product with proapoptotic and anticancer properties

Article abstract of DOI:10.1002/ejoc.201001627

The synthesis of new derivatives of embelin, a natural inhibitor of X-linked inhibitor of apoptosis protein (XIAP) is described. The design of these new molecules involved introduction of aromatic groups directly linked to the benzoquinone core. To allow a large flexibility in the nature and the length of the added chain, the strategy involves first aSuzuki-Miyaura reaction with functionalized aromatics, yielding a first generation of molecules. Then, by appropriate use of the functional groups, a second generation of representative embelin derivatives was prepared.

Full text of DOI:10.1002/ejoc.201001627

FULL PAPER
DOI: 10.1002/ejoc.201001627
Synthesis of a Focused Chemical Library Based on Derivatives of Embelin, a
Natural Product with Proapoptotic and Anticancer Properties
Guillaume Viault,[a] Danielle Grée,[a] Saibal Das,[b] Jhillu Singh Yadav,[b] and René Grée*[a]
Keywords: Embelin / Natural products / Chemical libraries / Suzuki–Miyaura coupling / Quinones
The synthesis of new derivatives of embelin, a natural inhibi-
tor of X-linked inhibitor of apoptosis protein (XIAP) is de-
scribed. The design of these new molecules involved intro-
duction of aromatic groups directly linked to the benzo-
quinone core. To allow a large flexibility in the nature and
the length of the added chain, the strategy involves first a
Suzuki–Miyaura reaction with functionalized aromatics,
yielding a first generation of molecules. Then, by appropriate
use of the functional groups, a second generation of repre-
sentative embelin derivatives was prepared.
Introduction
Embelin (1) is a natural product known for a very long
time in Indian and Chinese pharmacopoeias.[1] It has been
extracted from a plant (Embelia ribes) used in traditional
medicine to treat various diseases and employed as decoc-
tion, infusion of roots, aqueous extract, or even directly by
application of the seed or dried fruit. Embelin and its deriv-
atives possess analgesic, anti-inflammatory, antioxidant,
antitumor and antifertility properties.[2]
Scheme 1. Embelin and Wang’s derivatives.
It has been demonstrated recently that the inhibitor of
apoptosis proteins (IAPs) plays a key role in the regulation
of homeostasis in living cells.[3] Furthermore, it is frequently
overexpressed in cancer cells, contributing to the gravity of
the disease.[4] In this family, X-linked IAP is the most po-
tent inhibitor of apoptosis. Therefore, molecules that can
restore apoptosis in cancer cells by inhibition of XIAP
would be of much biological interest as well as of thera-
peutic value.
Through in silico screening of over 8000 molecules, S.
Wang et al. discovered embelin as a potential inhibitor of
XIAP protein.[5] They measured an IC50 of 4.7 μm for inhi-
bition of XIAP and demonstrated its strong proapoptotic
activity on cancer cells. More recently, they prepared a
series of new embelin derivatives with aromatic systems in-
corporated inside the hydrophobic chain. Some of these
molecules were even more potent inhibitors of XIAP (up to
1.0 μm) (Scheme 1).[6]
Several years ago, we started a program for the research
of new anticancer compounds through inhibition of anti-
apoptotic proteins. We first considered the Bcl-2 family,[7]
but more recently, we extended our program to new inhibi-
tors of XIAP, and embelin appeared very attractive as it
has a good activity, and, to the best of our knowledge, this
natural product is the only non-peptidic inhibitor of XIAP.
As a result, embelin was selected as the starting structure
for the development of new derivatives. Our design for new
molecules is indicated in Scheme 2. We chose to keep the
dihydroxybenzoquinone core and change the nature of the
hydrophobic chain by incorporation of aromatic groups in
the vicinal position to this core. It has been demonstrated
by S. Wang et al. that the length of the hydrophobic chain
[a] Université de Rennes 1, Laboratoire CPM CNRS UMR 6510
and Laboratoire SCR CNRS UMR 6226,
Avenue du général Leclerc, 35042 Rennes Cedex, France
Fax: +33-2-23236978
E-mail: rene.gree@univ-rennes1.fr
[b] Organic Chemistry Division I, Indian Institute of Chemical
Technology, CSIR,
Hyderabad 500607, AP, India
Scheme 2. General structures for our designed molecules.
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G. Viault, D. Grée, S. Das, J. S. Yadav, R. Grée
FULL PAPER
plays an important role in the interaction with XIAP.[6] other brominating agents (Br2 and HBr) did not improve
Therefore, our design involved the preparation of a first the selectivity and the yields.[11] Therefore, another syn-
generation benzoquinones with functional groups on the thetic route (Scheme 5) was studied to prepare monobromi-
new aromatic ring. Further use of these functions should nated compound 6. Bromination of hydroquinone in ether
give a good flexibility towards the preparation of a second afforded bromodiphenol 8 in 70% yield, as described in the
generation of molecules through variation of the nature and literature.[12] The oxidation of 8 with H2O2 gave brominated
length of the right part (R1 group).
Finally, our synthetic strategy allowed us to develop obtained by reaction of 9 with diazomethane (80% yield)
dihydroxybenzoquinone 9 in 62% yield. Bis(ether) 6 can be
[13]
automated procedures using a parallel synthesizer towards
easy and quick preparation of chemical libraries of de-
signed molecules.
or with trimethylsilyldiazomethane (71% yield).
Results and Discussion
Based on a previous design, our synthetic strategy in-
volves Suzuki–Miyaura coupling reactions,[8] as a key step,
in order to quickly and efficiently introduce all desired
functionalized aromatic substituents in position 3 to afford
the first generation analogues (Scheme 3). The first key in-
termediate is bromodimethoxybenzoquinone derivative 6,
which was envisaged to be obtained from hydroquinone.
Scheme 5. Second synthesis of monobrominated intermediates 6
and 9.
The next step involved Suzuki–Miyaura coupling reac-
tions to introduce the required functionalized aromatic
rings linked to the benzoquinone core. It is worth men-
tioning that we checked various conditions to perform such
couplings by starting directly from brominated dihydroxy-
benzoquinone 9 as such, but all of them failed. Therefore
bis(ether) 6 was used as key intermediate for this approach
(Scheme 6). Model studies were first performed to optimize
the reaction of 6 with phenylboronic acid. Compound 10
was obtained in 60% yield by reaction of 6 with phenyl-
boronic acid, sodium carbonate (2 equiv. each) and palla-
dium dichlorobis(triphenylphosphane) (10 mol-%) in a 4:1
dioxane/water mixture, at 80 °C for 1 h.[14] These conditions
were used for a series of representative boronic acids in an
automated parallel synthesizer (Chemspeed Accelerator®).
They afforded the first generation of our chemical library
of embelin analogues in fair to good yields, except for entry
2 (Table 1).
Scheme 3. Retrosynthesis for the preparation of the first generation
of embelin derivatives.
The synthesis of bromo compound 6 is described in
Scheme 4. Commercial hydroquinone was oxidized with hy-
drogen peroxide in the presence of a concentrated NaOH
solution to give the desired dihydroxybenzoquinone 4 in
70% yield.[9]
Scheme 4. First synthesis of mono- and dibrominated intermedi-
ates 6 and 7.
Scheme 6. Synthesis of the first generation of embelin derivatives
through Suzuki–Miyaura coupling reactions using automated par-
allel synthesizer.
The two hydroxy groups were then protected by reaction
with methanol under acidic conditions to give bis(ether) 5
To study the structure–activity relationships of the new
in 73% yield.[10] Bromination of 5 with N-bromosuc- embelin analogues, it was important also to vary the nature
cinimide (NBS) afforded a mixture of monobrominated and and the length of the side chain. In order to do that, the
dibrominated intermediates 6 and 7, respectively, which functions present on the first generation of analogues were
were easily separated by silica gel column chromatography used in several ways (Scheme 7).
and isolated in 20% and 18% yields, respectively. Reactions
For instance, in the case of vinylic derivatives, cross-cou-
under different conditions (temperature, solvent) or with pling metathesis can be employed.[15] On reaction with ap-
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Synthesis of a Focused Chemical Library Based on Derivatives of Embelin
Table 1. Suzuki–Miyaura coupling reactions with 6.
Table 2. Cross-coupling metathesis reactions to prepare benzo-
quinones 18 to 21.
Scheme 7. Synthesis of second generation of embelin derivatives.
Scheme 9. Wittig reactions to prepare benzoquinones 22 to 24.
Table 3. Wittig reactions to prepare benzoquinones 22 to 24.
propriate alkenes and in the presence of a second genera-
tion Grubbs catalyst (10 mol-%), compounds 12 and 13
bearing vinyl functions on the aromatic rings afforded the
desired products 18 to 21 in 35% to 66% yields (Scheme 8
and Table 2). In all cases, the E isomers were obtained ex-
clusively.
[a] tBuOK, THF. [b] NaH, CH2Cl2.
Scheme 8. Cross-coupling metathesis reactions to prepare benzo-
quinones 18 to 21.
study the effect of the meta or para position on interaction
with the target protein.
A second alternative to access new analogues was the use
of Wittig reactions starting from aldehyde 14 in order to
introduce various chains (Scheme 9 and Table 3).
Another possibility was to introduce a chain with an es-
ter function in our molecule starting from phenol 15. Reac-
tion with benzoyl chloride and triethylamine in dichloro-
methane at 0 °C furnished analogue 25 in 71% yield
(Scheme 10).
On reaction with the appropriate phosphonium salt in
the presence of potassium tert-butoxide in THF, aldehyde
14 gave compound 22 in 45% yield. This Z alkene is the
isomer of product 21 obtained previously. These com-
pounds will allow us to study the effect of the stereochemis-
try of the double bond on interaction with XIAP protein.
In the same way, by reaction of 14 with the correspond-
ing phosphonium salts and sodium hydride in dichloro-
methane, the targeted analogues 23 and 24 were obtained
in 70% and 53% yields, respectively. Compounds 18 and 23
are regioisomers, and therefore they should allow us to Scheme 10. Esterification reaction to prepare benzoquinone 25.
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These flexible strategies open the route to various types Table 5. Model deprotection studies.
of embelin derivatives. However, in addition to previous
studies, it appeared of interest to prepare similar molecules
but with bromine in position 6 of the benzoquinone core.
Therefore, we also studied the possibility of mono- and di-
coupling through Suzuki–Miyaura reactions starting from
dibromo intermediate 7 (Scheme 11 and Table 4).
Scheme 11. Mono- and dicoupling by Suzuki–Miyaura reactions
on dibromo intermediate 7.
Table 4. Mono- or dicoupling on dibrominated compound 7.
[a] KOH, EtOH, 70 °C, 1 h. [b] BBr3, CH2Cl2, –78 °C to room
temp., 12 h.
products 29, 30, and 31 were obtained in 46%, 64%, and
28% yields, respectively. In the case of compound 11, de-
protection followed by intramolecular lactonization af-
forded 30 under basic conditions. In parallel, a second de-
protection method was used in the presence of a Lewis
acid.[17] Compounds 26 and 27 were treated with boron tri-
bromide in dichloromethane at –78 °C to afford depro-
tected products 32 and 33 in 81% and 72% yields, respec-
tively. Starting from bis(ether) 16, this method afforded di-
hydroxybenzoquinone derivative 31 in much higher yield
(71%) than that under basic conditions (28%).
[a] Boronic acid (1.5 equiv.), K2CO3 (2 equiv.). [b] Boronic acid
(4 equiv.), K2CO3 (5 equiv.).
Dibromo compound 7 was treated with phenylboronic
acid (1.5 or 4.0 equiv.), palladium dichlorobis(triphenyl-
phosphane) (10 mol-%), and potassium carbonate (2.0 or
5.0 equiv.) in dioxane at 110 °C for 24 h to give compound
26 and the natural product Betulinan A[16] (27) in 41% and
47% yields, respectively. Another molecule, 28, was synthe-
sized according to the first procedure (entry 3, Table 4) in
62% yield. In agreement with results obtained indepen-
dently by the group of Hu et al.,[17] it is possible to conduct
reactions of mono- or dicoupling by adjusting the number
of equivalents of base and boronic acids.
Conclusions
A flexible strategy has been developed in order to pre-
pare new benzoquinones derived from embelin, a natural
product with important proapoptotic and anticancer prop-
erties. Our methodology employs bromobenzoquinone 6 as
a key intermediate, which is first subjected to Suzuki–Mi-
yaura coupling reactions with various functionalized aro-
matic boronic acids. This sequence can be easily performed
with use of an automated parallel synthesizer (Chemspeed
Accelerator®). From the resulting first generation of com-
pounds, new analogues with extended lipophilic chains were
obtained by using various types of reaction, such as cross
metathesis, Wittig, or esterification reactions. This ap-
proach allowed access to a second generation of com-
pounds with a good molecular diversity around the benzo-
quinone core of embelin. Biological tests are ongoing on
these molecules and will be reported in due course.[19] The
Finally, in order to also obtain molecules closer to embe-
lin, it was necessary to check the possibility for methyl ether
deprotection. This was performed on a few selected exam-
ples (Scheme 12 and Table 5).
Scheme 12. Model deprotection studies.
The first method involved basic conditions.[18] Com- structure–activity relationships obtained in these studies
pounds 10, 11, and 16 reacted with a 1 m potassium hydrox- should help to design more potent analogues of embelin,
ide solution in ethanol at 70 °C for 1 h, and deprotection which in turn should afford a better understanding of bio-
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Synthesis of a Focused Chemical Library Based on Derivatives of Embelin
BF3·OEt2 (12.5 mL). The mixture was stirred at 70 °C for 2 h, and
logical mechanisms regulating apoptosis and contribute to
the search for new anticancer therapies.
the solid was filtered and washed with cooled methanol to give 5
as a yellow solid (4.25 g, 71%). M.p. 240–242 °C. 1H NMR
(300 MHz, CDCl3): δ = 3.85 (s, 6 H, CH3), 5.87 (s, 2 H, CH) ppm.
13C NMR (75 MHz, CDCl3): δ = 56.6, 105.5, 159.5, 181.6 ppm.
Experimental Section
3-Bromo-2,5-dimethoxy-1,4-benzoquinone (6) and 2,5-Dibromo-3,6-
General: All reagents were obtained commercially and used without
further purification. All reactions were carried out under a nitrogen
atmosphere and dry conditions. The solvents used were freshly dis-
tilled under anhydrous conditions, unless otherwise specified. The
reaction mixtures were magnetically stirred with Teflon stirring
bars, and the temperatures were measured externally. Reactions
that require anhydrous conditions were carried out by using oven-
dried (120 °C, 24 h) glassware. Yields refer to chromatographically
and spectroscopically (1H NMR and 13C NMR) homogeneous ma-
terials, and the reactions were monitored by thin layer chromatog-
raphy (TLC), carried out on 0.25 mm Merck silica gel plates (60
F254). The eluents used were pentane (P) and ethyl acetate
(EtOAc), with detection by UV light, or a p-anisaldehyde staining
solution. Acros silica gel (60A, particle size 40–60 μm) was used for
column chromatography. NMR spectra were recorded with Bruker
dimethoxy-1,4-benzoquinone (7): To a solution of 5 (1.0 g,
5.95 mmol) in DMF (50 mL) was added a solution of NBS (1.8 g,
20.0 mmol, 1.7 equiv.) in DMF (10 mL). The reaction mixture was
stirred at room temperature for 2 h, quenched with water, and ex-
tracted with ethyl ether. The organic layers were collected and
washed with water then brine, dried with anhydrous MgSO4, and
concentrated under vacuum. After purification by flash column
chromatography on silica gel (pentane/ethyl acetate, 9:1), com-
pound 6 was obtained as an orange solid (310 mg, 20%) and com-
pound 7 was obtained as a red solid (300 mg, 18%). Compound 6:
1
M.p. 136–138 °C. H NMR (300 MHz, CDCl3): δ = 3.85 (s, 3 H,
CH3), 4.26 (s, 3 H, CH3), 5.80 (s, 1 H, CH) ppm. 13C NMR
(75 MHz, CDCl3): δ = 56.9, 62.1, 105.3, 114.7, 157.1, 158.6, 175.3,
180.9 ppm. HRMS: calcd. for C8H7O479BrNa [M + Na]+ 268.9425;
found 268.9429. Compound 7: M.p. 168–170 °C. 1H NMR
(300 MHz, CDCl3): δ = 4.24 (s, 6 H, OCH3) ppm. 13C NMR
(75 MHz, CDCl3): δ = 62.3, 114.9, 156.4, 174.7 ppm. HRMS:
calcd. for C9H10O579Br2Na [M + Na + CH3OH]+ 378.8792; found
378.8793.
1
Avance 500, 400, and 300 spectrometers. H NMR spectra: δ (H)
are given in ppm relative to tetramethylsilane (TMS), using [δ
(CHCl3) = 7.26 ppm] as internal reference. 13C NMR spectra: δ (C)
are given in ppm relative to TMS, using [δ (CDCl3) = 77.0 ppm]
as internal reference. Multiplicities were designated as singlet (s),
doublet (d), triplet (t), quadruplet (q), or multiplet (m).
2-Bromobenzene-1,4-diol (8): To a solution of hydroquinone (5.0 g,
45.4 mmol) in ethyl ether (30 mL) was added bromine (2.34 mL,
45.4 mmol) at 0 °C. The mixture was stirred at room temperature
for 2 h. The reaction mixture was then quenched by using 10%
aqueous sodium thiosulfate solution and extracted with ethyl ether.
The organic layers were collected and washed with water, then
brine, dried with anhydrous MgSO4, and concentrated under vac-
uum. Compound 8 was obtained as a white solid (5.9 g, 70%) after
purification by flash column chromatography on silica gel (pen-
tane/ethyl acetate, 9:1). Compound 8: M.p. 112 °C. 1H NMR
(300 MHz, CDCl3): δ = 6.40–6.50 (m, 1 H, ArH), 6.60–6.70 (m, 1
H, ArH), 6.75–6.80 (m, 1 H, ArH) ppm. 13C NMR (75 MHz,
CDCl3): δ = 109.1, 115.1, 116.3, 118.8, 146.2, 150.1 ppm.
Instrumentation: The Suzuki–Miyaura coupling reactions were per-
formed with a Chemspeed Accelerator SLT100 automated synthe-
sizer. The robot was equipped with a four-needle head and an array
of 16 parallel 13 mL glass reactors along with a solid dosing unit
(SDU) for solid additions. All reactors were connected to a Huber
Unistat (heating range: –70 to 300 °C) and were equipped with a
cold finger reflux condenser in which the temperature can be fixed
from –5 to 40 °C. The inert atmosphere in the glass reactors of
Accelerator SLT100 was obtained by flushing with nitrogen for at
least 30 min. Before the beginning of the coupling experiments, the
reaction vessels were heated to 80 °C, evacuated for 15 min, and
then filled with nitrogen. This procedure was repeated twice to per-
form the reactions under an inert atmosphere with a 1.5 bar flow
rate. Different amounts of substrates and reagents were adminis-
trated by using the SDU unit, and solvents were transferred from
the stock solutions with water and dioxane into the reaction vessels.
The reaction mixtures were heated at 80 °C and vortexed at
900 rpm. After 1 h, the reactors were diluted with dichloromethane
at 25 °C, and the liquid phase was then filtered through a pad of
Celite. After removal of solvents, the compounds were purified by
chromatography.
3-Bromo-2,5-dihydroxycyclohexa-2,5-diene-1,4-dione (9): To an
aqueous solution of NaOH (50%, 12 g) was added compound 8
(1.7 g, 8.9 mmol) dropwise at 50 °C. A solution of H2O2 (35%,
12 mL) was added slowly for 1.5 h, and the temperature was kept
between 45 and 55 °C. The mixture was then stirred at 45 °C for
2 h. After cooling to 0 °C, a solution of HCl (37%, 15 mL) and ice
(10 g) was added slowly. At the end of the addition, the solution
turned red, and the product was extracted with ethyl acetate. The
organic layers were collected and washed with brine, dried with
anhydrous MgSO4, and concentrated under vacuum to furnish
compound 9 as a red solid (1.2 g, 62%) Compound 9: M.p. 100 °C.
1H NMR (300 MHz, [D6]acetone): δ = 5.98 (s, 1 H), 10.20 (br. s, 2
H, OH) ppm. 13C NMR (75 MHz, [D6]acetone): δ = 103.2, 105.5,
161.0, 169.4 ppm.
2,5-Dihydroxy-1,4-benzoquinone (4): To an aqueous solution of
50% NaOH (100 g) was added hydroquinone (14 g, 0.13 mol) drop-
wise at 50 °C. A solution of H2O2 (35%, 70 mL) was added slowly
for 1.5 h, and the temperature was kept between 45 and 55 °C. The
mixture was stirred for 2 h at 45 °C. At 0 °C, a solution of 37%
HCl (115 mL) and ice (100 g) were added slowly. At the end of the
addition, the solution became yellow and compound 4 precipitated.
The solid was filtered and washed with dilute acid solution to give
the desired compound as a yellow solid (12 g, 70%). M.p. 210–
3-Bromo-2,5-dimethoxy-1,4-benzoquinone (6): To a solution of com-
pound 9 (50 mg, 0.23 mmol) in ethyl ether (5 mL) and methanol
(1 mL) was added slowly TMSCHN2 (2.0 m in Et2O, 0.75 mL,
1.5 mmol) at 0 °C. The mixture was stirred at 0 °C for 15 min and
concentrated under vacuum. Compound 6 was obtained (40 mg,
71%) after purification by flash column chromatography on silica
gel (pentane/ethyl acetate, 8:2).
1
212 °C. H NMR (500 MHz, CDCl3): δ = 6.11 (s, 2 H, CH), 7.74
(s, 2 H, OH) ppm. IR (neat): ν = 3297, 3093, 1604 cm–1. HRMS:
˜
calcd. for C6H3O4Na2 [M – H + 2Na]+ 184.9827; found 184.9825.
Procedure A. Suzuki Coupling: A mixture of compound 6 (1.0
equiv.), dichlorobis(triphenylphosphane)palladium(II) (0.1 equiv.),
sodium carbonate (2.0 equiv.), and boronic acid (2.0 equiv.) in 4:1
2,5-Dimethoxy-1,4-benzoquinone (5): To a solution of dihydroxy-
benzoquinone 4 (5.0 g, 36 mmol) in methanol (75 mL) was added
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G. Viault, D. Grée, S. Das, J. S. Yadav, R. Grée
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dioxane/water mixture was stirred at 80 °C for 1 h. After being
cooled down to room temperature, the solution was diluted with
CH2Cl2 and dried with anhydrous MgSO4. The reaction mixture
was filtered through a pad of Celite and concentrated under vac-
uum.
on silica gel (pentane/ethyl acetate, 8:2). M.p. 172–174 °C. 1H
NMR (300 MHz, CDCl3): δ = 3.76 (s, 3 H, CH3), 3.85 (s, 3 H,
CH3), 5.91 (s, 1 H), 6.05 (br. s, 1 H, OH), 6.74–6.88 (m, 3 H, ArH),
7.23–7.29 (m, 1 H, ArH) ppm. 13C NMR (75 MHz, CDCl3): δ =
56.6, 61.5, 105.4, 115.9, 117.6, 122.8, 125.4, 129.2, 131.3, 155.3,
155.5, 158.8, 181.8, 183.3 ppm. HRMS: calcd. for C14H12O5Na [M
+ Na]+ 283.0582; found 283.0582.
2,5-Dimethoxy-3-phenyl-1,4-benzoquinone (10): Compound 10 was
obtained as an orange solid (150 mg, 60%) by using Procedure A,
after purification by flash column chromatography on silica gel
(pentane/ethyl acetate, 9:1). M.p. 124–126 °C. 1H NMR (300 MHz,
CDCl3): δ = 3.80 (s, 3 H, CH3), 3.87 (s, 3 H, CH3), 5.91 (s, 1 H),
3-Biphenyl-4-yl-2,5-dimethoxy-1,4-benzoquinone (16): Compound
16 was obtained as an orange solid (80 mg, 62%) by using Pro-
cedure A, after purification by flash column chromatography on
7.20–7.40 (m, 5 H, ArH) ppm. 13C NMR (75 MHz, CDCl3): δ = silica gel (pentane/ethyl acetate, 8:2). M.p. 182–184 °C. 1H NMR
56.6, 61.6, 105.6, 126.2, 127.9, 128.6, 130.1, 130.6, 155.3, 158.8,
181.6, 183.4 ppm. HRMS: calcd. for C14H12O4Na [M + Na]+
267.0633; found 267.0634.
(300 MHz, CDCl3): δ = 3.87 (s, 3 H, CH3), 3.88 (s, 3 H, CH3), 5.92
(s, 1 H, CH), 7.36–7.39 (m, 3 H, ArH), 7.44–7.49 (m, 2 H, ArH),
7.63–7.67 (m, 4 H, ArH) ppm. 13C NMR (75 MHz, CDCl3): δ =
56.6, 61.7, 105.6, 126.1, 126.6, 127.1, 127.5, 128.8, 128.9, 131.0,
140.4, 141.3, 155.3, 158.7, 181.6, 183.3 ppm. HRMS: calcd. for
C20H16O4Na [M + Na]+ 343.0946; found 343.0947.
Ethyl 2-(2,5-Dimethoxy-3,6-dioxocyclohexa-1,4-dien-1-yl)benzoate
(11): Compound 11 was obtained as an orange oil (105 mg, 25%)
by using Procedure A, after purification by flash column
chromatography on silica gel (pentane/ethyl acetate, 9:1). 1H NMR
(300 MHz, CDCl3): δ = 1.26 (t, J = 7.0 Hz, 3 H), 3.67 (s, 3 H,
OCH3), 3.80 (s, 3 H, OCH3), 4.20 (q, J = 7.0 Hz, 2 H), 5.88 (s, 1
H), 7.15–7.25 (m, 1 H, ArH), 7.40–7.60 (m, 2 H, ArH). 8.00–8.10
N-[4-(2,5-Dimethoxy-3,6-dioxocyclohexa-1,4-dien-1-yl)phenyl]
Methanesulfonamide (17): Compound 17 was obtained as an
orange solid (300 mg, 55%) by using Procedure A, after purifica-
tion by flash column chromatography on silica gel (pentane/ethyl
(m, 1 H, ArH) ppm. 13C NMR (75 MHz, CDCl3): δ = 14.1, 56.5, acetate, 2:8). M.p. 204–206 °C. H NMR (300 MHz, CDCl3): δ =
1
61.0, 61.1, 105.7, 127.8, 128.8, 130.5, 130.6, 131.5, 131.9, 132.0,
153.6, 159.0, 166.3, 181.4, 183.3 ppm. HRMS: calcd. for
C17H16O6Na [M + Na]+ 339.0844; found 339.0844.
3.10 (s, 3 H, CH3), 3.88 (s, 3 H, CH3), 3.90 (s, 3 H, CH3) 5.92 (s,
1 H), 6.80 (br. s, 1 H, NH), 7.25–7.35 (m, 4 H, ArH) ppm. 13C
NMR (75 MHz, CDCl3): δ = 39.8, 56.7, 61.7, 105.7, 119.2, 126.2,
126.7, 132.1, 137.0, 155.4, 158.7, 181.6, 183.2 ppm. HRMS: calcd.
for C15H15NO6SNa [M + Na]+ 360.0518; found 360.0518.
2,5-Dimethoxy-3-(4-vinylphenyl)-1,4-benzoquinone (12): Compound
12 was obtained as an orange solid (115 mg, 53%) by using Pro-
cedure A, after purification by flash column chromatography on
Procedure B. Cross Coupling Metathesis: A mixture of compound
silica gel (pentane/ethyl acetate, 8:2). M.p. 120–122 °C. 1H NMR 12 or 13 (1.0 equiv.), alkene (10.0 equiv.), and Grubbs II catalyst
(300 MHz, CDCl3): δ = 3.82 (s, 3 H, CH3), 3.86 (s, 3 H, CH3), 5.30
(dd, J = 0.7, J = 10.9 Hz, 1 H), 5.80 (dd, J = 0.7, J = 17.6 Hz, 1
H), 5.90 (s, 1 H), 6.74 (dd, J = 10.9, J = 17.6 Hz, 1 H), 7.25–7.27
(m, 2 H, ArH), 7.44–7.47 (m, 2 H, ArH) ppm. 13C NMR (75 MHz,
CDCl3): δ = 56.5, 61.6, 105.6, 114.7, 125.7, 126.0, 129.4, 130.8,
136.3, 137.8, 155.2, 158.7, 181.6, 183.3 ppm. HRMS: calcd. for
C16H14O4Na [M + Na]+ 293.0789; found 293.0787.
(0.1 equiv.) in CH2Cl2 was stirred for 18 h at reflux. The reaction
mixture was concentrated under vacuum.
(2E)-N-Butyl-3-[4-(2,5-dimethoxy-3,6-dioxocyclohexa-1,4-dien-1-
yl)phenyl]acrylamide (18): Compound 18 was obtained as a red so-
lid (20 mg, 35%) by using Procedure B, after purification by flash
column chromatography on silica gel (pentane/ethyl acetate, 7:3).
M.p. 188–190 °C. 1H NMR (300 MHz, CDCl3): δ = 0.95 (t, J =
7.2 Hz, 3 H, CH3), 1.38 (m, 2 H, CH2), 1.56 (m, 2 H, CH2), 3.39
(m, 2 H, CH2), 3.85 (s, 6 H, OCH3), 5.84 (br. s, 1 H, NH), 5.90 (s,
1 H), 6.43 (d, J = 15.6 Hz, 1 H, CH), 7.26–7.29 (m, 2 H, ArH),
2,5-Dimethoxy-3-(3-vinylphenyl)-1,4-benzoquinone (13): Compound
13 was obtained as an orange solid (230 mg, 53%) by using Pro-
cedure A, after purification by flash column chromatography on
silica gel (pentane/ethyl acetate, 8:2). M.p. 90–92 °C. 1H NMR 7.49–7.54 (m, 2 H, ArH), 7.63 (d, J = 15.6 Hz, 1 H, CH) ppm. 13
C
(300 MHz, CDCl3): δ = 3.81 (s, 3 H, CH3), 3.86 (s, 3 H, CH3), 5.28
(d, J = 10.9 Hz, 1 H), 5.76 (d, J = 17.6 Hz, 1 H), 5.91 (s, 1 H),
NMR (75 MHz, CDCl3): δ = 13.7, 20.1, 31.7, 39.5, 56.6, 61.7,
105.6, 121.6, 125.7, 126.0, 127.2, 131.0, 135.1, 140.0, 155.3, 158.7,
6.72 (dd, J = 10.9, J = 17.6 Hz, 1 H), 7.15–7.20 (m, 1 H, ArH), 165.6, 181.4, 183.1 ppm. HRMS: calcd. for C21H23NO5Na [M +
7.30–7.47 (m, 3 H, ArH) ppm. 13C NMR (75 MHz, CDCl3): δ = Na]+ 392.1473; found 392.1476.
56.6, 61.6, 105.5, 114.4, 126.0, 126.4, 128.1, 128.4, 129.9, 130.3,
3-{3-[(1E)-Hept-1-en-1-yl]phenyl}-2,5-dimethoxy-1,4-benzoquinone
136.4, 137.2, 155.3, 158.7, 181.6, 183.3. HRMS: calcd. for
(19): Compound 19 was obtained (50 mg, 66%) as an oil by using
C16H14O4Na [M + Na]+ 293.07898; found 293.0785.
Procedure B, after purification by flash column chromatography
3-(2,5-Dimethoxy-3,6-dioxocyclohexa-1,4-dien-1-yl)benzaldehyde
(14): Compound 14 was obtained as an orange solid (335 mg, 76%)
by using Procedure A, after purification by flash column
on silica gel (pentane/ethyl acetate, 7:3). 1H NMR (300 MHz,
CDCl3): δ = 0.90–0.95 (m, 3 H, CH3), 1.20–150 (m, 6 H, CH2),
2.18–2.22 (m, 2 H, CH2), 3.79 (s, 3 H, OCH3), 3.87 (s, 3 H, OCH3),
5.91 (s, 1 H), 6.23 (dt, J = 15.8, J = 6.7 Hz, 1 H, CH), 6.38 (d, J =
chromatography on silica gel (pentane/ethyl acetate, 8:2). M.p. 166–
1
168 °C. H NMR (300 MHz, CDCl3): δ = 3.88 (s, 3 H, CH3), 3.93 15.8, 1 H, CH), 7.05–7.35 (m, 4 H, ArH) ppm. 13C NMR (75 MHz,
(s, 3 H, CH3), 5.92 (s, 1 H), 7.53–7.62 (m, 2 H, ArH), 7.80–7.81
(m, 1 H, ArH), 7.89–7.82 (m, 1 H, ArH), 10.03 (s, 1 H, CHO) ppm.
CDCl3): δ = 14.1, 22.5, 30.0, 31.4, 33.0, 56.6, 61.6, 105.5, 126.1,
126.2, 128.0, 128.1, 128.9, 129.2, 130.2, 132.0, 137.7, 155.3, 158.8,
13C NMR (75 MHz, CDCl3): δ = 56.6, 61.8, 105.7, 125.1, 128.6, 181.7, 183.3 ppm. HRMS: calcd. for C21H24O4Na [M + Na]+
129.4, 131.1, 132.1, 136.0, 136.5, 155.5, 158.6, 181.1, 183.0, 363.1566; found 363.1567.
191.9 ppm. HRMS: calcd. for C15H12O5Na [M + Na]+ 295.0582;
3-{3-[(1E)-Oct-1-en-1-yl]phenyl}-2,5-dimethoxy-1,4-benzoquinone
found 295.0581.
(20): Compound 20 was obtained as an oil (120 mg, 53%) by using
3-(3-Hydroxyphenyl)-2,5-dimethoxy-1,4-benzoquinone (15): Com-
pound 15 was obtained as an orange solid (130 mg, 69%) by using
Procedure A, after purification by flash column chromatography
Procedure B, after purification by flash column chromatography
on silica gel (pentane/ethyl acetate, 8:2). 1H NMR (300 MHz,
CDCl3): δ = 0.80–0.85 (m, 3 H, CH3), 1.20–1.30 (m, 6 H, CH2),
1238
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 1233–1241

Synthesis of a Focused Chemical Library Based on Derivatives of Embelin
1.35–1.45 (m, 2 H, CH2), 2.11–2.15 (m, 2 H, CH2), 3.71 (s, 3 H,
OCH3), 3.78 (s, 3 H, OCH3), 5.82 (s, 1 H), 6.17 (dt, J = 6.8, J =
15.8 Hz, 1 H, CH), 6.30 (d, J = 15.8, 1 H, CH), 7.01–7.03 (m, 1
H, ArH), 7.16–7.20 (m, 1 H, ArH), 7.25–7.30 (m, 2 H, ArH) ppm.
13C NMR (75 MHz, CDCl3): δ = 14.1, 22.6, 28.9, 29.3, 31.8, 33.1,
56.6, 61.6, 105.6, 126.2, 126.3, 128.1, 128.1, 128.9, 129.3, 130.3,
132.0, 137.7, 155.3, 158.8, 181.7, 183.3 ppm. HRMS: calcd. for
C22H26O4Na [M + Na]+ 377.1723; found 377.1726.
(2E)-3-[3-(2,5-Dimethoxy-3,6-dioxocyclohexa-1,4-dien-1-yl)phen-
yl]-N-phenylacrylamide (24): Compound 24 was obtained as a red
solid (120 mg, 53%) by using Procedure C, after purification by
flash column chromatography on silica gel (pentane/ethyl acetate,
5:5). M.p. 138–140 °C. 1H NMR (300 MHz, CDCl3): δ = 3.85 (s, 3
H, OCH3), 3.87 (s, 3 H, OCH3), 5.92 (s, 1 H), 6.56 (d, J = 15.5 Hz,
1 H, CH), 7.10–7.62 (m, 9 H, ArH), 7.74 (d, J = 15.5 Hz, 1 H,
CH) ppm. 13C NMR (75 MHz, CDCl3): δ = 56.6, 56.7, 61.7, 61.8,
105.6, 105.7, 119.8, 121.5, 124.4, 125.5, 128.1, 128.5, 129.0, 130.0,
130.7, 132.0, 134.4, 138.0, 141.6, 141.7, 155.4, 158.7, 163.8, 181.5,
183.2 ppm. HRMS: calcd. for C23H19NO5Na [M + Na]+ 412.1161;
found 412.1160.
2,5-Dimethoxy-3-{3-[(E)-2-phenylvinyl]phenyl}-1,4-benzoquinone
(21): Compound 21 was obtained as an orange solid (120 mg, 60%)
by using Procedure B, after purification by flash column
chromatography on silica gel (pentane/ethyl acetate, 8:2). M.p. 164–
3-(2,5-Dimethoxy-3,6-dioxocyclohexa-1,4-dien-1-yl)phenyl Benzoate
(25): To a solution of phenol 15 (130 mg, 0.5 mmol, 1.0 equiv.) in
CH2Cl2 (10 mL) were added slowly triethylamine (0.35 mL,
2.5 mmol, 5.0 equiv.) and benzoyl chloride (0.29 mL, 2.5 mmol,
5.0 equiv.) at 0 °C. The mixture was stirred at 0 °C for 30 min. It
was quenched with a saturated aqueous NH4Cl solution and ex-
tracted with CH2Cl2. The collected organic layers were washed with
water, then brine, dried with anhydrous MgSO4, and concentrated
under vacuum. Compound 25 was obtained as a red solid (120 mg,
71%) after purification by flash column chromatography on silica
gel (pentane/ethyl acetate, 8:2). M.p. 156–158 °C. 1H NMR
(300 MHz, CDCl3): δ = 3.86 (s, 3 H, CH3), 3.88 (s, 3 H, CH3), 5.91
(s, 1 H), 7.10–7.30 (m, 3 H, ArH), 7.40–7.55 (m, 3 H, ArH), 7.60–
7.70 (m, 1 H, ArH), 8.15–8.25 (m, 2 H, ArH) ppm. 13C NMR
(75 MHz, CDCl3): δ = 56.6, 61.8, 105.6, 121.9, 124.1, 124.8, 128.2,
128.6, 128.9, 129.4, 130.1, 131.5, 133.6, 150.4, 155.4, 158.7, 165.0,
181.3, 183.1 ppm. C21H16O6 (364.35): calcd. C 69.23, H 4.43; found
C 69.05, H 4.51.
1
166 °C. H NMR (300 MHz, CDCl3): δ = 3.84 (s, 3 H, CH3), 3.88
(s, 3 H, CH3), 5.93 (s, 1 H), 7.12 (s, 2 H), 7.15–7.60 (m, 9 H, ArH)
ppm. 13C NMR (75 MHz, CDCl3): δ = 56.6, 61.7, 105.6, 125.9,
126.6, 126.7, 127.7, 128.1, 128.3, 128.7, 128.7, 129.2, 129.7, 130.5,
137.0, 137.1, 155.3, 158.8, 181.6, 183.3 ppm. C22H18O4 (346.38):
calcd. C 76.29, H 5.24; found C 75.97, H 5.27.
2,5-Dimethoxy-3-{3-[(Z)-2-phenylvinyl]phenyl}-1,4-benzoquinone
(22): To a solution of benzyltriphenylphosphonium iodide (560 mg,
1.17 mmol, 2.7 equiv.) in anhydrous THF (6 mL) was added slowly
at 0 °C potassium tert-butoxide (132 mg, 1.17 mmol, 2.7 equiv.).
The mixture was stirred at 0 °C for 30 min. Then, a solution of
aldehyde 14 (115 mg, 0.42 mmol, 1.0 equiv.) in THF (3 mL) was
added at –78 °C. The reaction mixture was stirred for 1 h until
room temperature was attained and then quenched with saturated
aqueous NH4Cl solution and extracted with CH2Cl2. The collected
organic layers were washed with water, then brine, dried with anhy-
drous MgSO4, and concentrated under vacuum. Compound 22 was
obtained as a red solid (90 mg, 45%) after purification by flash
column chromatography on silica gel (pentane/ethyl acetate, 7:3).
2-Bromo-3,6-dimethoxy-5-phenyl-1,4-benzoquinone (26): A mixture
of compound 7 (326 mg, 1.0 mmol, 1.0 equiv.), dichlorobis(triphen-
ylphosphane)palladium(II) (70 mg, 0.1 mmol, 0.1 equiv.), potas-
sium carbonate (276 mg, 2.0 mmol, 2.0 equiv.), and phenylboronic
acid (200 mg, 1.5 mmol, 1.5 equiv.) in dioxane (10 mL) was stirred
at 110 °C for 24 h. The dark solution obtained was diluted with
CH2Cl2 and dried with anhydrous MgSO4. The mixture was filtered
through a pad of Celite and concentrated under vacuum. Com-
pound 26 was obtained as an orange solid (132 mg, 41%) after
purification by flash column chromatography on silica gel (pent-
1
M.p. 132–134 °C. H NMR (300 MHz, CDCl3): δ = 3.72 (s, 3 H,
CH3), 3.85 (s, 3 H, CH3), 5.88 (s, 1 H, CH), 6.62 (s, 2 H), 7.15–
7.30 (m, 9 H, ArH) ppm. 13C NMR (75 MHz, CDCl3): δ = 56.5,
61.6, 105.5, 125.9, 127.2, 127.9, 128.2, 128.9, 129.0, 129.2, 129.7,
130.2, 130.7, 130.9, 136.9, 137.1, 155.2, 158.7, 181.7, 183.3 ppm.
HRMS: calcd. for C22H18O4Na [M + Na]+ 369.1103; found
369.1099.
Procedure C. Wittig Reaction: To a suspension of sodium hydride
(7.0 equiv.) in anhydrous CH2Cl2 was added slowly a solution of
phosphonium salt (3.0 equiv.) in anhydrous CH2Cl2 at 0 °C. The
reaction mixture was stirred at 0 °C for 30 min. Then, a solution
of compound 14 (1.0 equiv.) in anhydrous CH2Cl2 was added at
–78 °C. The reaction mixture was stirred 1 h to reach room tem-
perature and then quenched with saturated aqueous NH4Cl solu-
tion and extracted with CH2Cl2. The combined organic layers were
washed with water, then brine, dried with anhydrous MgSO4, and
concentrated under vacuum.
1
ane/dichloromethane, 4:6). M.p. 210–212 °C. H NMR (300 MHz,
CDCl3): δ = 3.84 (s, 3 H, CH3), 4.24 (s, 3 H, CH3), 7.25–7.45 (m,
5 H, ArH) ppm. 13C NMR (75 MHz, CDCl3): δ = 61.8, 62.0, 114.9,
126.3, 128.0, 128.8, 129.6, 130.4, 154.7, 156.6, 177.0, 181.2 ppm.
C14H11BrO4 (323.14): calcd. C 52.04, H 3.43; found C 51.78, H
3.39.
2,5-Dimethoxy-3,6-diphenyl-1,4-benzoquinone (27): A mixture of
compound 7 (326 mg, 1.0 mmol, 1.0 equiv.), dichlorobis(triphenyl-
phosphane)palladium(II) (70 mg, 0.1 mmol, 0.1 equiv.), potassium
carbonate (690 mg, 5.0 mmol, 5.0 equiv.), and phenylboronic acid
(533 mg, 4.0 mmol, 4.0 equiv.) in dioxane (10 mL) was stirred at
110 °C for 24 h. The resulting dark solution was diluted with
CH2Cl2 and dried with anhydrous MgSO4. The mixture was filtered
through a pad of Celite and concentrated under vacuum. Com-
pound 27 was obtained as an orange solid (150 mg, 47%) after
purification by flash column chromatography on silica gel (pent-
(2E)-N-Butyl-3-[3-(2,5-dimethoxy-3,6-dioxocyclohexa-1,4-dien-1-
yl)phenyl]acrylamide (23): Compound 23 was obtained as a red so-
lid (150 mg, 70%) by using Procedure C, after purification by flash
column chromatography on silica gel (pentane/ethyl acetate, 5:5).
M.p. 150–152 °C. 1H NMR (300 MHz, CDCl3): δ = 0.95 (t, J =
7.2 Hz, 3 H, CH3), 1.30–1.40 (m, 2 H, CH2), 1.50–1.60 (m, 2 H,
CH2), 3.35–3.45 (m, 2 H, CH2), 3.85 (s, 3 H, OCH3), 3.87 (s, 3 H,
OCH3), 5.71 (br. s, 1 H, NH), 5.91 (s, 1 H), 6.38 (d, J = 15.5 Hz,
1 H, CH), 7.20–7.52 (m, 4 H, ArH), 7.63 (d, J = 15.5 Hz, 1 H,
CH) ppm. 13C NMR (75 MHz, CDCl3): δ = 13.7, 20.1, 31.7, 39.5,
56.6, 61.7, 105.6, 121.4, 125.7, 127.9, 128.4, 129.8, 130.1, 131.6,
134.7, 140.3, 155.4, 158.7, 165.6, 181.4, 183.2 ppm. HRMS: calcd.
for C21H23NO5Na [M + Na]+ 392.1474; found 392.1475.
1
ane/dichloromethane, 4:6). M.p. 148–150 °C. H NMR (300 MHz,
CDCl3): δ = 3.84 (s, 6 H, CH3), 7.30–7.50 (m, 10 H, ArH) ppm.
13C NMR (75 MHz, CDCl3): δ = 61.5, 126.6, 127.9, 128.6, 130.1,
130.5, 154.6, 183.4 ppm. HRMS: calcd. for C20H16O4Na [M +
Na]+ 343.0943; found 343.0944.
2-Biphenyl-4-yl-5-bromo-3,6-dimethoxy-1,4-benzoquinone (28):
A
mixture of compound 7 (260 mg, 0.8 mmol, 1.0 equiv.), dichloro-
Eur. J. Org. Chem. 2011, 1233–1241
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1239

G. Viault, D. Grée, S. Das, J. S. Yadav, R. Grée
FULL PAPER
bis(triphenylphosphane)palladium(II) (60 mg, 0.08 mmol, 0.1
equiv.), potassium carbonate (220 mg, 1.6 mmol, 2.0 equiv.), and
4–diphenylboronic acid (240 mg, 1.2 mmol, 1.5 equiv.) in dioxane
(10 mL) was stirred at 110 °C for 24 h. The resulting dark solution
was diluted with CH2Cl2 and dried with anhydrous MgSO4. The
mixture was filtered through a pad of Celite and concentrated un-
der vacuum. Compound 28 was obtained as an orange solid
(200 mg, 62%) after purification by flash column chromatography
on silica gel (pentane/ethyl acetate, 9:1). M.p. 170–172 °C. 1H
NMR (300 MHz, CDCl3): δ = 3.80 (s, 3 H, CH3), 3.87 (s, 3 H,
CH3), 5.91 (s, 1 H), 7.20–7.40 (m, 5 H, ArH) ppm. 13C NMR
(75 MHz, CDCl3): δ = 56.6, 61.6, 105.6, 126.2, 127.9, 128.6, 130.1,
130.6, 155.3, 158.8, 181.6, 183.4 ppm. HRMS: calcd. for
C20H15O479BrNa [M + Na]+ 421.0051; found 421.0052.
from dioxane. M.p. 258–260 °C. 1H NMR (300 MHz, [D6]acetone):
δ = 7.30–7.60 (m, 10 H, ArH), 10.30 (br. s, 2 H, OH) ppm. 13C
NMR (75 MHz, [D6]acetone): δ = 127.6, 127.8, 130.5, 130.8,
132.5 ppm. HRMS: calcd. for C18H11O4Na2 [M – H + 2Na]+
337.0453; found 337.0451.
Acknowledgments
This research has been performed as part of the Indo-French “Joint
Laboratory for Sustainable Chemistry at Interfaces”. We thank
Centre National de la Recherche Scientifique (CNRS), Council for
Scientific and Industrial Research (CSIR), Indo French Centre for
the Promotion of Advanced Research (IFCPAR), and “Ligue con-
tre le Cancer” for support of this research. We thank “Ligue contre
le Cancer (35)” and Région Bretagne for a fellowship to G. V. We
thank Drs P. Juin and S. Barillé-Nion for fruitful discussions. We
thank Centre Régional de Mesures Physiques de l’Ouest (CRMPO,
Rennes) for the mass spectral studies and microanalyses.
Procedure D. KOH Deprotection: To a solution of bis(ether)
(0.53 mmol) in ethanol (10 mL) was added a KOH solution (1 m,
5 mL) at room temperature. The resulting dark red mixture was
then heated whilst stirring at 70 °C for 1 h. The reaction mixture
was quenched with HCl solution (1 m) and extracted with ethyl
acetate. The combined organic layers were washed with water,
brine, dried with anhydrous MgSO4, and concentrated under vac-
uum.
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after purification by recrystallization in ethyl acetate. M.p. 218–
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1
220 °C. H NMR (300 MHz, CDCl3): δ = 6.17 (s, 1 H), 7.40–7.50
(m, 5 H, ArH), 7.95 (br. s, 2 H, OH) ppm. 13C NMR (75 MHz,
CDCl3): δ = 102.6, 128.2, 128.6, 128.7, 130.1 ppm. HRMS: calcd.
for C12H8O4Na [M + Na]+ 239.0320; found 239.0324.
2-Hydroxy-1H-benzo[c]chromene-1,4,6-trione (30): Compound 30
was obtained as a dark red solid (53 mg, 64%) by using Procedure
D, after purification by recrystallization in ethyl acetate. M.p.180–
1
182 °C. H NMR (300 MHz, [D6]acetone): δ = 6.03 (s, 1 H), 7.40–
7.55 (m, 3 H, ArH), 8.00–8.20 (m, 1 H, ArH) ppm. 13C NMR
(75 MHz, [D6]acetone): δ = 103.4, 118.9, 129.1, 131.2, 131.8, 132.7,
132.8, 132.9, 167.8 ppm. HRMS: calcd. for C13H6O5Na [M +
Na]+ 265.0113; found 265.0116.
3-Biphenyl-4-yl-2,5-dihydroxy-1,4-benzoquinone (31): To a solution
of compound 16 (45 mg, 0.12 mmol) in anhydrous CH2Cl2
(4.0 mL) was added slowly a solution of BBr3 in CH2Cl2 (1.0 m,
0.50 mL) at –78 °C. The reaction mixture was stirred under argon
for 12 h until room temperature was attained. The reaction was
quenched with methanol, and the resulting solution was concen-
trated under vacuum. Compound 31 was obtained as a black solid
(29 mg, 71% yield) after recrystallization from dioxane. M.p. 248–
1
250 °C. H NMR (300 MHz, CDCl3): δ = 6.20 (s, 1 H), 7.38–7.67
(m, 9 H, ArH), 8.00 (br. s, 2 H, OH) ppm. 13C NMR (100 MHz,
[D6]DMSO):
δ = 104.0, 125.7, 126.6, 127.4, 128.9, 131.0,
139.9 ppm. HRMS: calcd. for C18H11O4Na2 [M – H + 2Na]+
337.0453; found 337.0454.
Compounds 32 and 33 were synthesized by following the same pro-
[7] a) F. Manero, F. Gautier, T. Gallenne, N. Cauquil, D. Grée, P.-
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cedure.
2-Bromo-3,6-dihydroxy-5-phenyl-1,4-benzoquinone (32): Compound
32 was obtained as a black solid (43 mg, 81%) after recrystalli-
zation from dioxane. M.p. 152–154 °C. 1H NMR (300 MHz,
CDCl3): δ = 7.40–7.50 (m, 5 H, ArH), 8.13 (br. s, 2 H, OH) ppm.
13C NMR (75 MHz, CDCl3): δ = 128.2, 129.0, 130.1 ppm. HRMS:
calcd. for C12H6O479BrNa2 [M – H + 2Na]+ 338.9245; found
338.9247.
2,5-Dihydroxy-3,6-diphenyl-1,4-benzoquinone (33): Compound 33
was obtained as a black solid (53 mg, 72%) after recrystallization
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Eur. J. Org. Chem. 2011, 1233–1241

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significant proapoptotic affect against Cal51 cell lines and also
a strong synergistic proapoptotic effect in combination with
other reagents such as TRAIL or ABT 737.
Received: December 3, 2010
Published Online: January 26, 2011
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Eur. J. Org. Chem. 2011, 1233–1241
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