Chemoselective and Sequential Palladium-Catalyzed Couplings for the Generation of Stilbene Libraries via Immobilized Substrates

Article abstract of DOI:10.1021/acscombsci.6b00023

A versatile palladium-catalyzed tandem synthetic sequence to afford E-stilbenes libraries has been developed. Excellent regio- and stereocontrol have been achieved by means of the sequence of Hiyama and Heck cross-couplings. Undesirable homocoupling bypro

Full text of DOI:10.1021/acscombsci.6b00023

Letter
pubs.acs.org/acscombsci
Chemoselective and Sequential Palladium-Catalyzed Couplings for
the Generation of Stilbene Libraries via Immobilized Substrates
Carla I. Traficante,† Catherine Fagundez,‡ Gloria L. Serra,‡ Ernesto G. Mata,†
and Carina M. L. Delpiccolo*,†
†Instituto de Química Rosario (CONICETUNR), Facultad de Ciencias Bioquímicas y Farmaceu
́
ticas, Universidad Nacional de
Rosario, Suipacha 531, 2000 Rosario, Argentina
‡Laboratorio de Química Farmaceu
́
tica, (DQO), Facultad de Química, Universidad de la Republica, Gral. Flores 2124, Montevideo
́
11800, Uruguay
S
* Supporting Information
ABSTRACT: A versatile palladium-catalyzed tandem syn-
thetic sequence to afford E-stilbenes libraries has been
developed. Excellent regio- and stereocontrol have been
achieved by means of the sequence of Hiyama and Heck
cross-couplings. Undesirable homocoupling byproducts were
avoided employing immobilized substrates.
KEYWORDS: palladium cross-coupling reactions, solid-phase organic synthesis, Hiyama coupling, Heck coupling
tilbene compounds are widely distributed in nature and
have relevant applications in agriculture,1 drug discovery2
strategies, enabling fast and easy diversification by increasing
molecular complexity.8
S
and material science.3 Numerous stilbene-based derivatives,
such as resveratrol,4 piceatannol,5 and pterostilbene6 (Figure
1), have shown anti-inflammatory, antiproliferative, and
The development of new approaches for the generation of
single and double C−C bonds with regio- and stereoselectivity
control remains a challenge in organic synthesis. Methodologies
involving the use of inexpensive, easy to handle, low toxicity
reagents and catalysts are highly desirable since they enable
mild reaction conditions and good yields.9
Most reported strategies for the synthesis of symmetrical and
asymmetrical (E)-1,2-substituted diarylethenes10 involve reac-
tion conditions with limited diastereoselectivity and low
functional group tolerance. These include Wittig reactions,
cross metathesis of vinyl arenes and catalytic couplings, such as
Heck, Suzuki−Miyaura, Stille, and Hiyama reactions.10 The
presence of homocoupling products is one of the main
drawback for these catalytic techniques.11
An interesting high-yielding procedure for the synthesis of
diarylethenes with high regio- and stereoselectivity, using safe,
stable and low-toxicity reagents, is the Hiyama−Heck tandem
reaction.12 However, when this strategy was used in solution,
the formation of undesirable homocoupling products is difficult
to elude.11 This problem might be solved by applying a Hiyama
+ filtration + Heck tandem sequence on polymer-supported
substrates,13 as a practical way to decrease the formation of
byproducts. For solid-phase coupling reactions, spatial separa-
tion between the reactive sites in the immobilized substrate
made its homodimerization a less favorable process. Similarly,
the homodimer of the nonimmobilized substrate remains in the
Figure 1. Structures of biologically relevant stilbenes.
antioxidant properties among others. Schweinfurthins7 (Figure
2) are stilbene-related compounds which serve as potent and
selective inhibitors in different cancer cell lines. Scheweinfur-
thins act on an unexploited molecular target, becoming
promising drug candidates for untreated forms of this disease,
such as glioblastoma multiforme. In addition, stilbenes are
interesting substrates for diversity oriented synthesis (DOS)
Received: February 19, 2016
Revised: April 11, 2016
Figure 2. Some members of the schweinfurthin family.
© XXXX American Chemical Society
A
DOI: 10.1021/acscombsci.6b00023
ACS Comb. Sci. XXXX, XXX, XXX−XXX

ACS Combinatorial Science
Letter
solution phase and can be removed by a simple filtration.14
Besides, process simplicity would allow fast synthesis of
unexplored structures, resulting in a useful tool for DOS
development. In this work, we report the first solid-phase-based
tandem Hiyama−Heck cross-couplings and their application in
stilbene synthesis.
Vinyltriethoxysilane has two reactive positions for under-
going cross-coupling in the presence of Pd catalyst (shown in
blue and green, Scheme 1). Each chemically differentiable
Scheme 1. Chemically Differentiable Carbon Atoms of 1
Figure 3. Structures and numbering of building blocks.
methylated. 1H NMR analysis of the crude showed the
presence of 8{1,1} as main product and absence of the methyl
esters derived from 4{1} and 5{1}. Compound 8{1,1} was
obtained in 51% yield after purification by column chromatog-
raphy. Increased reaction time (7 h) resulted in decreased
overall yields for the Hiyama reaction, probably due to
decomposition. A similar effect was observed for the Heck
cross-coupling performed without TEA, evidencing incomplete
transformation by the presence of the corresponding unreacted
styrene (acid derivative of 4{1}).
As discussed previously, changing the order of the reactions
sequence (Heck + filtration + Hiyama), should give the same
product. Then, resin 3{1} was treated with triethoxyvinylsilane
(1) under Heck conditions (Scheme 3). The presence of 5{1}
was confirmed by gel-phase 13C NMR spectrum that showed
signals at 58.9 and 18.3 ppm, corresponding to the carbons of
the ethoxy groups. The immobilized vinyl silane 5{1} was
finally transformed into the stilbene 7{1,1} by applying Hiyama
cross-coupling conditions. After cleavage, esterification and
further purification by column chromatography, 8{1,1} was
obtained in an overall yield of 30%.
reaction site can give a unique product with high regio- and
stereocontrol, by setting the conditions and additives. Under
Hiyama conditions, fluoride ions present in the reaction
mixture would react with the silicon atom generating a
pentacoordinated transition state, increasing the C−Si bond
polarity and therefore, facilitating the cross-coupling reaction.
Conversely, under Heck conditions, without fluorides influenc-
ing the olefin reactivity, carbon−carbon bond formation occurs
at the more electron-deficient and less hindered carbon.
For the development of the proposed synthetic strategy,
Hiyama cross-coupling conditions were applied on Wang resin-
supported aryl iodide 3{1} (Scheme 2 and Figure 3). 3{1} was
refluxed in THF in the presence of 5 equiv of triethox-
yvinylsilane (1), 10 mol % of tetrakis(triphenylphosphine)-
palladium(0) and 5 equiv of TBAF for 5 h.15 The exclusive
formation of 4{1} and absence of the product derived from
Heck coupling 5{1}, was verified by spectroscopic analysis of a
crude mixture after cleaving an aliquot from the resin. Then
Heck conditions were applied to the immobilized styrene
4{1}.16 This compound was treated with iodobenzene 6{1}, 10
mol % of Pd2(dba)3, P(o-tolyl)3 and 5 equiv of TEA in DMF as
solvent, heating at 110 °C during 24 h. To calculate purity and
reaction yield, 7{1,1} was cleaved from the resin and
Direct comparison of the two alternative synthetic routes to
8{1,1} indicates that the first strategy (Hiyama + filtration +
Heck) was more efficient. These results confirm that changes in
the reaction conditions over the triethoxyvinylsilane (1) are
enough to obtain selectively either Heck or Hiyama product.
Considering the Hiyama + filtration + Heck sequence the best
option (entry 1, Table 1), we decided to validate the Heck
Scheme 2. Solid-Phase Synthesis of 8{1,1} by Sequential Hiyama−Heck Cross-Couplings
B
DOI: 10.1021/acscombsci.6b00023
ACS Comb. Sci. XXXX, XXX, XXX−XXX

ACS Combinatorial Science
Letter
Scheme 3. Solid-Phase Synthesis of 8{1,1} by Sequential Heck−Hiyama Cross-Couplings
Table 1. Evaluation of Conditions of Hiyama−Heck Tandem Reactions Using the Immobilized Aryl Iodide 3{1}
a
b
entry
halide
X
R1
Heck conditions
product
yield (%)
1
2
3
4
5
6
6{1}
6{1′}
6{1′}
6{2}
6{3}
6{3}
I
H
H
H
A
A
8{1,1}
8{1,1}
8{1,1}
8{1,2}
8{1,3}
8{1,3}
73 (51)
57 (36)
Br
Br
I
c
d
A
51
d
4-COMe
4-Me
A
A
B
63
I
45 (10)
69 (40)
I
4-Me
a
Method A: 10 mol % Pd2(dba)3 and P(o-tolyl)3, 5 equiv TEA, DMF, 110 °C, 24 h. Method B: 50 mol % Pd(OAc)2, 10 equiv TEA, 0,5 equiv
b
Bu4NCl, DMF, 18 h. 110 °C. Yield of 8, calculated by weighing the crude mixture, prior to purification (based on initial loading level, five reaction
steps). Data in parentheses are isolated yields. 0.1 equiv of Bu4NCl was added. From H NMR spectrum of the crude mixture, which contains
starting material.
c
d
1
Table 2. Substrate Scope for the Sequential Hiyama−Heck Cross-Couplings Using Immobilized Aryl Iodides
a
b
entry
X
Z
R2
R1
Heck conditions
product
yield (%)
1
I
CH
CH
CH
CH
CH
CH
CH
CH
CH
N
H (6{1})
H (4{1})
H (4{1})
NO2 (4{2})
H(4{1})
A
A
B
B
B
A
A
B
B
A
A
B
B
A
B
A
B
B
B
8{1,1}
8{1,1}
8{2,1}
8{1,4}
8{2,4}
8{1,5}
8{1,6}
8{1,2}
8{2,2}
8{1,7}
8{1,3}
8{1,3}
8{2,3}
8{1,8}
8{1,8}
8{1,9}
8{1,9}
8{1,10}
8{1,11}
51
36
36
65
30
38
44
47
79
24
10
40
21
8
2
Br
I
H (6{1′})
H (6{1})
3
4
Br
Br
Br
Br
I
4-NO2 (6{4′})
4-NO2 (6{4′})
4-CHO (6{5′})
4-Cl (6{6′})
4-COMe (6{2})
4-COMe (6{2})
H (6{7})
5
NO2 (4{2})
H (4{1})
H (4{1})
H (4{1})
NO2 (4{2})
H (4{1})
H (4{1})
H (4{1})
NO2 (4{2})
H (4{1})
H (4{1})
H (4{1})
H (4{1})
H (4{1})
H (4{1})
6
7
8
9
I
10
11
12
13
14
15
16
17
18
19
I
I
CH
CH
CH
CH
CH
CH
CH
CH
CH
4-Me (6{3})
4-Me (6{3})
4-Me (6{3})
4-CO2Me (6{8})
4-CO2Me (6{8})
4-OH (6{9})
4-OH (6{9})
4-NEt2 (6{10})
3-OMe (6{11′})
I
I
I
I
46
21
15
19
10
I
I
I
Br
a
Method A: 10 mol % Pd2(dba)3 and P(o-tolyl)3, 5 equiv TEA, DMF, 110 °C, 24 h. Method B: 50 mol % Pd(OAc)2, 10 equiv TEA, 0,5 equiv
b
Bu4NCl, DMF, 18 h. 110 °C. Overall isolated yield of 8 after column chromatography (based on initial loading level, five reaction steps).
reaction using bromo derivatives. In this case, using
bromobenzene as substrate (6{1′}), compound 8{1,1} was
obtained in 36% yield after purification (entry 2). Addition of
catalytic amounts of tetrabutylammonium chloride is described
in literature as a valid tool to produce higher yields.16a,b
However, when this salt was added to the Heck reaction under
conditions described in entry 2, lower yields were obtained
(entry 3). Although reaction performance for the bromide
C
DOI: 10.1021/acscombsci.6b00023
ACS Comb. Sci. XXXX, XXX, XXX−XXX

ACS Combinatorial Science
Letter
substrates (6{1′}, entry 2) was lower than in the case of iodides
(6{1}, entry 1), yields were still acceptable. Therefore, we can
conclude that both halides could be potentially employed as
starting materials for this reaction improving substrate
availability for the generation of prospective libraries. Testing
this methodology for aryl iodides 6{2} (R1 = 4-COMe) and
6{3} (R1 = 4-Me) resulted in lower yields (entries 4 and 5,
Table 1). As a consequence, additional Heck reaction
conditions were evaluated. Substantial improvement was
found for the iodide 6{3} using 50 mol % of Pd(OAc)2, 10
equiv of triethylamine, 0.5 equiv of tetrabutylammonium
chloride in DMF during 18 h at 110 °C (entry 6).
Accordingly, using Hiyama and the two Heck methodologies
previously described, a library of stilbene derivatives was
synthesized, using substrates with different structural and
electronic features (Table 2). Compounds 8{1−2,1−11}
could be obtained in acceptable to high isolated yields (five
reaction steps). Crude mixtures showed very high purity, and
excellent trans-selectivity (the Z isomers could not be detected
at all).17 Best efficiencies for the Heck reaction were obtained
when aryl halides bearing electron-withdrawing groups served
as substrates (entries 3−9, 14, and 15).18 Withdrawing
substituents led to an increase in the C−X bond polarization,
facilitating oxidative addition in the palladium catalytic cycle,
which may be responsible for the better efficiency. This effect is
quite evident when comparing entries 9 and 13. Using the same
immobilized vinyl substrate 4{2} and aryl halides with different
electronic characteristics in the Heck reaction, we noticed a
decrease in yields from 79 to 21% when replacing an electron-
withdrawing substituent (p-COMe) by a donating one (p-Me).
In conclusion, we have developed an efficient solid-phase
strategy based on a palladium cross-coupling tandem reaction
for the fast generation of stilbenes. A library of multifunctional
olefins with structural diversity was prepared from substrates
with different steric and electronic properties, using both aryl
iodides and bromides for the Heck cross-coupling. Products
were obtained with excellent E stereoselectivity. This strategy
could be potentially applied for the synthesis of compounds
with higher structural complexity and prospective biological
activity. Biological activity against several tumor cell lines for
the hereby-synthesized compounds is currently under evalua-
tion.
THF). The flask was fitted with a condenser and the reaction
mixture was stirred 5 h at 80 °C. Subsequently, the resin was
filtered and washed successively with CH2Cl2 (×3), THF (×3),
DMF (×3), and MeOH (×3), and finally, with CH2Cl2 thus
obtaining the support-bound vinyl arene 4{1}. Then, the resin
was dried under high vacuum and used for the Heck cross-
coupling reaction.
Representative Procedure for the Solid-Phase Heck
Cross-Coupling Reaction: Method A. Support-bound vinyl
arene 4{1} (0.96 mmol/g, 0.19 mmol) was suspended in
anhydrous DMF (5 mL), and were added in sequential order
under a nitrogen atmosphere, Pd2(dba)3 (0.018 g, 10 mol %),
P(o-tolyl) (0.005 g,10 mol %), aryl halide 6{1} (0.064 mL, 0.57
mmol), and TEA (133 mL, 0.95 mmol). The flask was fitted
with a condenser and the reaction mixture was stirred 24 h at
110 °C. Subsequently, the resin was filtered and washed
successively with CH2Cl2 (×3), THF (×3), DMF (×3), MeOH
(×3), and finally, with CH2Cl2. After drying under high
vacuum, the compound was cleaved from the support with 5
mL of a 10% TFA in CH2Cl2 for 50 min at room temperature.
Then the mixture was filtered and washed with CH2Cl2 (×2),
and the filtrate was evaporated under reduced pressure.
Esterification with diazomethane afforded the crude product
1
that was analyzed by H NMR and GC/MS and then purified
by column chromatography (hexane-EtOAc), yielding 20 mg of
pure (E)-Methyl 4-styrylbenzoate (8{1,1}) (51%).
Method B. Support-bound vinyl arene 4{1} (0.96 mmol/g,
0.19 mmol) was suspended in anhydrous DMF (5 mL), and
Pd(OAc)2 (0.021 g, 50 mol %), Bu4NCl (0.026 g, 0.095 mmol),
aryl halide 6{3} (0.207 g, 0.95 mmol), and TEA (0.267 mL, 1.9
mmol) were added in sequential order under a nitrogen
atmosphere. The flask was fitted with a condenser, and the
reaction mixture was stirred 18 h at 110 °C. Subsequently, the
resin was filtered and washed successively with CH2Cl2 (×3),
THF (×3), DMF (×3), MeOH (×3), and finally with CH2Cl2.
After drying under high vacuum, the compound was cleaved
from the support with 5 mL of a 10% TFA in CH2Cl2 for 50
min at room temperature. Then the mixture was filtered,
washed with CH2Cl2 (×2) and the filtrate was evaporated
under reduced pressure. Esterification with diazomethane
1
afforded the crude product that was analyzed by H NMR
and GC/MS and then purified by column chromatography
(hexane-EtOAc) yielding 17 mg of pure (E)-methyl 4-(4-
methylstyryl)benzoate (8{1,3}) (40%).
EXPERIMENTAL PROCEDURES
■
Procedure for Immobilization of Aryl Iodide 3{1}.
Wang resin (0.2 g, 1.1 mmol/g, 0.22 mmol) was swelled by
gentle stirring in anhydrous DMF (5 mL). Then, 4-iodobenzoic
acid 2{1} (0.098 g, 0.66 mmol), DCC (N,N′-diisopropylcarbo-
diimide) (0.102 mL, 0.66 mmol), and DMAP (catalytic
amount) were added. The mixture was stirred overnight at
room temperature. After filtration, the resin was sequentially
washed with CH2Cl2 (×3), DMF (×3), EtOAc (×3), MeOH
(×3), and CH2Cl2 and, finally, dried under high vacuum thus
obtaining the immobilized aryl iodide 3{1}. Mass recovery was
used to determine resin loading after cleavage of an aliquot with
10% TFA/CH2Cl2. In general, coupling was achieved with
greater than 95% efficiency.
Representative Procedure for the Solid-Phase Hiyama
Cross−Coupling Reaction. Support-bound aryl halide 3{1}
(0.88 mmol/g, 0.18 mmol) was suspended in anhydrous THF
(5 mL), and were added in sequential order under a nitrogen
atmosphere Pd(PPh3)4 (0.020 g, 10 mol %), vinyltriethox-
ysilane 1 (0.189 mL, 0.9 mmol) and TBAF (0.9 mL, 1 M in
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acscombs-
ci.6b00023.
1
Experimental details and spectroscopic data: H NMR
and 13C NMR spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: delpiccolo@iquir-conicet.gov.ar. Fax: +54 341
4370477.
Notes
The authors declare no competing financial interest.
D
DOI: 10.1021/acscombsci.6b00023
ACS Comb. Sci. XXXX, XXX, XXX−XXX

ACS Combinatorial Science
Letter
Carbon Coupling Reactions Catalyzed by Heterogeneous Palladium
Catalysts. Chem. Rev. 2007, 107, 133−173.
́
(10) (a) Ferre-Filmon, K.; Delaude, L.; Demonceau, A.; Noels, A. F.
ACKNOWLEDGMENTS
■
Support from CONICET, ANPCyT, Fundacion
and Universidad Nacional de Rosario is gratefully acknowl-
edged. C.I.T. thanks CONICET for fellowship. Special thanks
́
Prats, AUGM,
Catalytic methods for the synthesis of stilbenes with an emphasis on
their phytoalexins. Coord. Chem. Rev. 2004, 248, 2323−2336.
(b) Joucla, L.; Cusati, G.; Pinel, C.; Djakovitch, L. One-Pot Suzuki/
Heck Sequence for the Synthesis of (E)-Stilbenes Featuring a
Recyclable Silica-Supported Palladium Catalyst via a Multi-Compo-
nent Reaction in 1,3-Propanediol. Adv. Synth. Catal. 2010, 352, 1993−
2001. (c) Kormos, C. M.; Leadbeater, N. E. Preparation of
Nonsymmetrically Substituted Stilbenes in a One-Pot Two-Step
Heck Strategy Using Ethene As a Reagent. J. Org. Chem. 2008, 73,
3854−3858.
́
to Dr. Hernan D. Biava for careful proofreading the manuscript.
REFERENCES
■
(1) He, D.; Jian, W.; Liu, X.; Shen, H.; Song, S. Synthesis, Biological
Evaluation, and Structure−Activity Relationship Study of Novel
Stilbene Derivatives as Potential Fungicidal Agents. J. Agric. Food
Chem. 2015, 63, 1370−1377.
(11) (a) Denmark, S. E.; Butler, C. R. Vinylation of Aryl Bromides
Using an Inexpensive Vinylpolysiloxane. Org. Lett. 2006, 8, 63−66.
(b) Mowery, M. E.; DeShong, P. Cross-Coupling Reactions of
Hypervalent Siloxane Derivatives: An Alternative to Stille and Suzuki
Couplings. J. Org. Chem. 1999, 64, 1684−1688.
(2) (a) Pettit, G. R.; Rhodes, M. R.; Herald, D. L.; Hamel, E.;
Schmidt, J. M.; Pettit, R. K. Antineoplastic Agents. 445. Synthesis and
Evaluation of Structural Modifications of (Z)- and (E)-Combretastatin
A-4. J. Med. Chem. 2005, 48, 4087−4099. (b) Acerson, M. J.; Fabick,
K. M.; Wong, Y.; Blake, C.; Lephart, E. D.; Andrus, M. B. A new
synthesis of 40-resveratrol esters and evaluation of the potential for
anti-depressant activity. Bioorg. Med. Chem. Lett. 2013, 23, 2941−2944.
(c) Nicolaou, K. C.; Roecker, A. J.; Barluenga, S.; Pfefferkorn, J. A.;
Cao, G.-Q. Discovery of Novel Antibacterial Agents Active Against
Methicillin-Resistant Staphylococcus aureus from Combinatorial
Benzopyran Libraries. ChemBioChem 2001, 6, 460−465. (d) Mao,
F.; Yan, J.; Li, J.; Jia, X.; Miao, H.; Sun, Y.; Huang, L.; Li, X. New
multi-target-directed small molecules against Alzheimer’s disease: a
combination of resveratrol and clioquinol. Org. Biomol. Chem. 2014,
12, 5936−5944.
(12) For related solution-phase procedure, see: (a) Itami, K.;
Nokami, T.; Ishimura, Y.; Mitsudo, K.; Kamei, T.; Yoshida, J.
Diversity-Oriented Synthesis of Multisubstituted Olefins through the
Sequential Integration of Palladium-Catalyzed Cross-Coupling Re-
actions. 2-Pyridyldimethyl(vinyl)silane as a Versatile Platform for
Olefin Synthesis. J. Am. Chem. Soc. 2001, 123, 11577−11585.
́
́
(b) Gordillo, A.; de Jesus, E.; Lopez-Mardomingo, C. Consecutive
palladium-catalyzed Hiyama−Heck reactions in aqueous media under
ligand-free conditions. Chem. Commun. 2007, 4056−4058.
(13) For selected examples on solid-phase stilbene synthesis, see:
(a) Kang, S. S.; Cuendet, M.; Endringer, D. C.; Croy, V. L.; Pezzuto, J.
M.; Lipton, M. A. Synthesis and biological evaluation of a library of
resveratrol analogues as inhibitors of COX-1, COX-2 and NF-kB.
Bioorg. Med. Chem. 2009, 17, 1044−1054. (b) Kim, C. B.; Cho, C. H.;
Jo, M. J.; Park, K. Solid-Phase Synthesis of Unfunctionalized Arenes
Via the Traceless Cleavage of Sulfonate Linkers. Bull. Korean Chem.
(3) (a) Hrobar
́
ik, P.; Hrobar
́
ikova,
́
V.; Semak, V.; Kasak
́
, P.;
Rakovsky, E.; Polyzos, J.; Fakis, M.; Persephonis, P. Quadrupolar
́
Benzobisthiazole-Cored Arylamines as Highly Efficient Two-Photon
Absorbing Fluorophores. Org. Lett. 2014, 16, 6358−6361. (b) Kraft,
A.; Grimsdale, A. C.; Holmes, A. B. Electroluminescent Conjugated
Polymers-Seeing Polymers in a New Light. Angew. Chem., Int. Ed.
1998, 37, 402−428.
́
Soc. 2011, 32, 3655−3659. (c) Boggian, D. B.; Mata, E. G. Efficient
alkene Synthesis on solid support using the Julia-Kocienski coupling.
Mol. Diversity 2010, 14, 847−853.
(4) Carrizzo, A.; Forte, M.; Damato, A.; Trimarco, V.; Salzano, F.;
Bartolo, M.; Maciag, A.; Puca, A. A.; Vecchione, C. Antioxidant effects
of resveratrol in cardiovascular, cerebral and metabolic diseases. Food
Chem. Toxicol. 2013, 61, 215−226.
(5) Piotrowska, H.; Kucinska, M.; Murias, M. Biological activity of
piceatannol: Leaving the shadow of resveratrol. Mutat. Res., Rev. Mutat.
Res. 2012, 750, 60−82.
(6) Gastaminza, P.; Whitten-Bauer, C.; Chisari, F. V. Unbiased
probing of the entire hepatitis C virus life cycle identifies clinical
compounds that target multiple aspects of the infection. Proc. Natl.
Acad. Sci. U. S. A. 2010, 107, 291−296.
(7) Topczewski, J. J.; Kodet, J. G.; Wiemer, D. F. Exploration of
Cascade Cyclizations Terminated by Tandem Aromatic Substitution:
Total Synthesis of (+)-Schweinfurthin A. J. Org. Chem. 2011, 76, 909−
919.
(14) (a) Young, D. D.; Deiters, A. A general approach to chemo- and
regioselective cyclotrimerization reactions. Angew. Chem., Int. Ed. 2007,
46, 5187−5190. (b) Poeylaut-Palena, A. A.; Mata, E. G. Unravelling
the olefin cross metathesis on solid support. Factors affecting the
reaction outcome. Org. Biomol. Chem. 2010, 8, 3947−3956. (c) La-
Venia, A.; Testero, S. A.; Mischne, M.; Mata, E. G. Gold catalysis on
immobilized substrates: a heteroannulation approach to the solid-
supported synthesis of indoles. Org. Biomol. Chem. 2012, 10, 2514−
2517.
(15) Traficante, C. I.; Delpiccolo, C. M. L.; Mata, E. G. Palladium-
Catalyzed Cross-Coupling Reactions of Arylsiloxanes with Aryl
Halides: Application to Solid-Supported Organic Synthesis. ACS
Comb. Sci. 2014, 16, 211−214.
(16) (a) Yu, K.-L.; Deshpande, M. S.; Vyas, D. M. Heck Reactions in
Solid Phase Synthesis. Tetrahedron Lett. 1994, 35, 8919−8922.
(b) Brase, S.; Kirchhoff, J. H.; Kobberling, J. Palladium-catalysed
reactions in solid phase organic synthesis. Tetrahedron 2003, 59, 885−
939. (c) Hanessian, S.; Xie, F. Exploring Functional and Molecular
Diversity with Polymer, Bound p-Alkoxybenzyl Ethers - Scope and
Applications of Preparatively Useful Organic Reactions. Tetrahedron
Lett. 1998, 39, 737−740.
(8) (a) Sore, H. F.; Blackwell, D. T.; MacDonald, S. J. F.; Spring, D.
R. Diversity-Oriented Synthesis of Disubstituted Alkenes Using
Masked Silanols. Org. Lett. 2010, 12, 2806−2809. (b) Husemoen,
V.; Olsson, R.; Andersson, C. M.; Harvey, S. C.; Hansen, H. C.
Solution-Phase Parallel Wittig Olefination: Synthesis of Substituted
1,2-Diarylethanes. J. Comb. Chem. 2003, 5, 606−609. (c) Zhang, W.;
́
Ning, F.; Varadi, L.; Hibbs, D. E.; Platts, J. A.; Nyerges, M.; Anderson,
J. R.; Groundwater, P. W. An investigation of the scope of the 1,7-
electrocyclization of α,β:γ,δ-conjugated azomethine ylides. Tetrahedron
2014, 70, 3621−3629. (d) Fatima, S.; Sharma, A.; Saxena, R.; Tripathi,
R.; Shukla, S. K.; Pandey, S. K.; Tripathi, R.; Tripathi, R. P. One pot
efficient diversity oriented synthesis of polyfunctional styryl
thiazolopyrimidines and their bio-evaluation as antimalarial and anti-
HIV agents. Eur. J. Med. Chem. 2012, 55, 195−204.
(17) Synthesis of 8{2,3} was performed in homogeneous phase
under similar conditions to those of the solid-phase strategy obtaining
a complex crude mixture difficult to purify.
(18) Nobre, S. M.; Muniz, M. N.; Seferin, M.; da Silva, W. M.;
Monteiro, A. L. The synthesis of non-symmetrical stilbene analogs of
trans-resveratrol using the same Pd catalyst in a sequential double-
Heck arylation of ethylene. Appl. Organomet. Chem. 2011, 25, 289−
293.
(9) For recent reviews on C−C bond forming reactions, see: (a) de
Meijere, A.; Brase, S.; Oestreich, M. Metal-Catalyzed Cross-Coupling
̈
Reactions and More; Wiley-VCH: Weinheim, Germany, 2014.
(b) Miyaura, N. Cross-Coupling Reactions. A Practical Guide. Top.
Curr. Chem. 2002, 219, 11−59. (c) Yin, L. X.; Liebscher, J. Carbon−
E
DOI: 10.1021/acscombsci.6b00023
ACS Comb. Sci. XXXX, XXX, XXX−XXX