Silver nanoparticle-Catalyzed diels-alder cycloadditions of 2′-hydroxychalcones

Article abstract of DOI:10.1021/ja102482b

Metal nanoparticles are currently being employed as catalysts for a number of classical chemical transformations. In contrast, identification of novel reactions of nanoparticles, especially toward the synthesis of complex natural products and derivatives, is highly underdeveloped and represents a bourgeoning area in chemical synthesis. Herein, we report silica-supported silver nanoparticles as solid, recyclable catalysts for Diels-Alder cycloadditions of 2′-hydroxychalcones and dienes in high yield and turnover number. The use of silver nanoparticle catalysts is further demonstrated by the total synthesis of the cytotoxic natural product panduratin A employing a highly electron-rich dienophile and Lewis acid sensitive diene.

Full text of DOI:10.1021/ja102482b

Published on Web 05/05/2010
Silver Nanoparticle-Catalyzed Diels-Alder Cycloadditions of
2′-Hydroxychalcones
Huan Cong, Clinton F. Becker, Sean J. Elliott, Mark W. Grinstaff, and
John A. Porco, Jr.*
Department of Chemistry and Center for Chemical Methodology and Library DeVelopment
(CMLD-BU), Boston UniVersity, Boston, Massachusetts 02215
Received March 24, 2010; E-mail: porco@bu.edu
Abstract: Metal nanoparticles are currently being employed as catalysts for a number of classical chemical
transformations. In contrast, identification of novel reactions of nanoparticles, especially toward the synthesis
of complex natural products and derivatives, is highly underdeveloped and represents a bourgeoning area
in chemical synthesis. Herein, we report silica-supported silver nanoparticles as solid, recyclable catalysts
for Diels-Alder cycloadditions of 2′-hydroxychalcones and dienes in high yield and turnover number. The
use of silver nanoparticle catalysts is further demonstrated by the total synthesis of the cytotoxic natural
product panduratin A employing a highly electron-rich dienophile and Lewis acid sensitive diene.
Scheme 1. Retrosynthetic Analysis for Panduratin A and Synthetic
Challenges
Introduction
The 21st century is observing rapid progress in the nano-
sciences including preparation, characterization, and synthetic
applications of metal nanoparticles.1 Although nanoparticles are
promising heterogeneous catalysts due to their high surface area
and unique size-dependent properties,2 they have not found
substantial applications in complex natural product synthesis,
with most examples thus far being limited to previously known
transformations.3 This is in sharp contrast to homogeneous
catalysts which are widely established and extensively used for
a broad range of reaction types.4 Accordingly, the field of metal
nanoparticle catalysis should offer opportunities for mining new
chemical reactions,5 in particular, those which enable the
synthesis of biologically important and synthetically challenging
natural products and derivatives. Herein, we describe such an
application involving the total synthesis of the bioactive
cyclohexenyl chalcone natural product panduratin A which
features silver nanoparticle (AgNP)-catalyzed Diels-Alder
cycloadditions of 2′-hydroxychalcones and dienes.
derived from highly oxygenated 2′-hydroxychalcone dieno-
philes.8 Behind the seemingly simple structure and straightfor-
ward retrosynthetic design of 1 (Scheme 1) are a number of
synthetic challenges. The poorly reactive 2′-hydroxychalcone
dienophile (cf. 2) resists traditional Lewis acid promoted
conditions9 likely due to its electron-rich nature and the tendency
of undesired cyclizations to form flavanones such as 3. In
addition, the requisite diene trans-ꢀ-ocimene (4) has been found
to undergo olefin isomerization and polymerization under acidic
Since its isolation in 1984,6 panduratin A (1) has shown
promising anticancer, anti-HIV, and anti-inflammatory activi-
ties.7 This natural product belongs to the family of prenylfla-
vonoid and related Diels-Alder natural products which are
(1) Schmid, G. Nanoparticles: From Theory to Application; Wiley-VCH:
Weinheim, 2004.
(7) For select references on biological activities of panduratin A, see: (a)
Kiat, T. S.; Pippen, R.; Yusof, R.; Ibrahim, H.; Khalid, N.; Rahman,
N. A. Bioorg. Med. Chem. Lett. 2006, 16, 3337–3340. (b) Yun, J. M.;
Kweon, M. H.; Kwon, H.; Hwang, J. K.; Mukhtar, H. Carcinogenesis
2006, 27, 1454–1464. (c) Cheenpracha, S.; Karalai, C.; Ponglimanont,
C.; Subhadhirasakul, S.; Tewtrakul, S. Bioorg. Med. Chem. 2006, 14,
1710–1714. (d) Kirana, C.; Jones, G. P.; Record, I. R.; McIntosh, G. H.
J. Nat. Med. 2007, 61, 131–137. (e) Shim, J. S.; Kwon, Y. Y.; Han,
Y. S.; Hwang, J. K. Planta Med. 2008, 74, 1446–1450. (f) Yoshikawa,
M.; Morikawa, T.; Funakoshi, K.; Ochi, M.; Pongpiriyadacha, Y.;
Matsuda, H. Heterocycles 2008, 75, 1639–1650. (g) Rukayadi, Y.;
Lee, K.; Han, S.; Yong, D.; Hwang, J. K. Antimicrob. Agents
Chemother. 2009, 53, 4529–4532.
(2) Henglein, A. Chem. ReV. 1989, 89, 1861–1873.
(3) Astruc, D. Nanoparticles and Catalysis; Wiley-VCH: Weinheim, 2007.
(4) Smith, M. B.; March, J. March’s AdVanced Organic Chemistry:
Reactions, Mechanisms, and Structure, 6th ed.; Wiley: Hoboken, NJ,
2007.
(5) For select references, see: (a) Mitsudome, T.; Arita, S.; Mori, H.;
Mizugaki, T.; Jitsukawa, K.; Kaneda, K. Angew. Chem., Int. Ed. 2008,
47, 7938–7940. (b) Shimizu, K.; Sato, R.; Satsuma, A. Angew. Chem.,
Int. Ed. 2009, 48, 3982–3986. (c) Murugadoss, A.; Goswami, P.; Paul,
A.; Chattopadhyay, A. J. Mol. Catal. A 2009, 304, 153–158. (d)
Witham, C. A.; Huang, W.; Tsung, C.; Kuhn, J. N.; Samorjai, G. A.;
Toste, F. D. Nature Chem. 2009, 2, 36–41.
(8) (a) Nomura, T. Pure Appl. Chem. 1999, 71, 1115–1118. (b) Nomura,
T. Yakugaku Zasshi 2001, 121, 535–556.
(6) Tuntiwachwuttikul, P.; Pancharoen, O.; Reutrakul, V.; Byrne, L. T.
Aust. J. Chem. 1984, 37, 449–453.
(9) Corbett, J. L.; Weavers, R. T. Synth. Commun. 2008, 38, 489–498.
9
7514 J. AM. CHEM. SOC. 2010, 132, 7514–7518
10.1021/ja102482b  2010 American Chemical Society

Ag Nanoparticle-Catalyzed Diels-Alder Cycloadditions
A R T I C L E S
Table 1. Discovery of AgNP-Catalyzed Diels-Alder
Cycloadditionsa
entry
AgX
conversion (%)
endo/exo
1
2
3
AgBF4
AgOTf
AgClO4
AgOAc
AgBF4
AgBF4
AgBF4
>99(98)
48
68
91
21
14
>99
76:24
71:29
60:40
53:47
67:33
-
4
5b
6c
7d
78:22
a Conversions and endo/exo ratios are based on 1H NMR integration.
Isolated yield is shown in parentheses. Single regioisomer was observed.
b 30 mol % AgBF4 only. c Black precipitate only. d Clear supernatant
only.
conditions10 which complicates chemical synthesis efforts. A
recent report11 outlined additional challenges in which thermal
Diels-Alder cycloaddition (150 °C) of 4 and a 2′-hydroxy-
chalcone dienophile afforded inseparable mixtures of 1 and its
regioisomer isopanduratin A.12
Results and Discussion
Development of AgNP-Catalyzed Cycloadditions. Attempts
to extend our reported methodology13 involving combined use
of a Lewis acid (ZnI2) and an electron donor (cobalt(I) complex
or Bu4NBH4) to synthesize panduratin A were unsuccessful,
underscoring the need for exploring alternative methodologies.
Building upon our previous studies, we initiated an extensive
screening of metal salts in combination with Bu4NBH4 for [4+2]
cycloadditions of 2′-hydroxychalcones and dienes. Our studies
revealed that using a mixture of 30 mol % AgBF4 and 10 mol
% Bu4NBH4, cycloaddition of 2′-hydroxychalcone 6 and
1-phenyl-3-methylbutadiene 7 afforded the desired cycloadduct
8 in 98% yield as a single regioisomer (Table 1, entry 1). A
significant counterion effect of the silver salts was observed
(entries 2-4), with AgPF6, AgSbF6, Ag2CO3, and Ag2O showing
poor reactivity. The success of the silver salt/borohydride
catalyzed conditions was surprising as Ag(I) is a mild oxidant
which is easily reduced to Ag(0) by borohydride.14 In contrast,
silver(I) salts alone (entry 5), Bu4NBH4,13 or commercially
available Ag powder15 displayed little or no reactivity in
cycloadditions. In our reactions, a black, metallic silver pre-
cipitate was observed immediately after mixing the silver(I) salt
and borohydride. Upon filtration, control experiments showed
that the black precipitate had little reactivity and that the clear
supernatant accounted for catalytic activity (Table 1, entries 6,
7). A strong Tyndall effect of the supernatant15 suggested the
Figure 1. TEM images with particle size distribution histograms. (a) AgNP
catalyst generated in situ from 3:1 AgBF4/Bu4NBH4 showing an average
particle size of 2.5 nm. Inset: high resolution TEM of a single particle with
lattice d-spacing of 2.30 Å and 2.03 Å, matching the (111) and (200) plane
of Ag with a face-centered cubic (fcc) structure, respectively. Inset scale
bar: 5 nm. (b) Silica-supported AgNP catalyst showing an average particle
size of 4.9 nm.
presence of AgNP’s16 which was further confirmed by transmis-
sion electron microscopy (TEM, Figure 1a), UV-vis spectros-
copy, and energy dispersive X-ray spectroscopy (EDS).15
Encouraged by these initial results, we next evaluated a
heterogeneous and reusable catalyst preparation by fixation of
the in situ generated, catalytically active AgNP’s onto silica
gel.17 In the optimized preparation, the AgNP-containing
supernatant prepared from 3:1 AgBF4/Bu4NBH4 in CH2Cl2 was
stirred with chromatography-grade silica gel for 3 h in the air
at 25 °C. Subsequent collection of the solid by filtration,
followed by calcination at 220 °C for 12 h, afforded silica-
supported AgNP’s as a light brown powder (Figure 1b)
containing 2.7 × 102 ppm of silver (approximately 70% Ag(0)
(10) Majetich, G.; Zhang, Y. J. Am. Chem. Soc. 1994, 116, 4979–4980.
(11) Chee, C. F.; Abdullah, I.; Buckle, M. J. C.; Rahman, N. A. Tetrahedron
Lett. 2010, 51, 495–498.
(12) For select references on isolation and biological activities of isopandu-
ratin A, see: (a) Pandji, C.; Grimm, C.; Wray, V.; Witte, L.; Proksch,
P. Phytochemistry 1993, 34, 415–419. (b) Hwang, J. K.; Chung, J. Y.;
Baek, N. I.; Park, J. H. Int. J. Antimicrob. Agents 2004, 23, 377–381.
(c) Win, N. N.; Awale, S.; Esumi, H.; Tezuka, Y.; Kadota, S. J. Nat.
Prod. 2007, 70, 1582–1587.
(16) The Tyndall effect refers to the capacity of disperse or colloidal systems
when illuminated unilaterally to scatter light in all directions; see: (a)
Kraemer, E. O.; Dexter, S. T. J. Phys. Chem. 1927, 31, 764–782. (b)
Roucoux, A.; Schulz, J.; Patin, H. Chem. ReV. 2002, 102, 3757–3778.
(17) Zheng, N.; Stucky, G. D. J. Am. Chem. Soc. 2006, 128, 14278–14280.
(13) Cong, H.; Ledbetter, D.; Rowe, G. T.; Caradonna, J. P.; Porco, J. A.,
Jr. J. Am. Soc. Chem. 2008, 130, 9214–9215.
(14) Ganem, B.; Osby, J. O. Chem. ReV. 1986, 86, 763–780.
(15) See Supporting Information for complete experimental details.
9
J. AM. CHEM. SOC. VOL. 132, NO. 21, 2010 7515

A R T I C L E S
Cong et al.
Table 2. Silica-Supported AgNP-Catalyzed Diels-Alder
Cycloadditions
Scheme 2. Synthesis of (()-Panduratin Aa
a Reagents and conditions: (a) Silica-supported AgNP (0.5 mol % Ag
loading), CH2Cl2, 50 °C, 48 h, 85%. Major isomer shown; (b) aq. NaHCO3,
MeOH, 40 °C, 6 h, 87% (98% based on recovered starting material).
mild acidity of silica gel (cf. Scheme 1). We reasoned that a
less electron-rich chalcone containing fewer free hydroxyl
groups would be more optimal as a dienophile by minimizing
side reactions. To our delight, cycloaddition of acetylated
chalcone 1513 and the labile diene 4 catalyzed by silica-
supported AgNP’s (0.5 mol % Ag loading) predominantly
afforded the desired endo cycloadduct in excellent yield along
with a small amount (approximately 5%) of an exo stereoisomer
corresponding to the natural product nicolaioidesin A.15 Neither
isomerization nor polymerization of the labile diene was
observed. Final deacetylation provided panduratin A in 87%
yield (Scheme 2).
Mechanistic Studies. Given the observed high activity and
selectivity, we next conducted a series of experiments to probe
the mechanism for AgNP-catalyzed Diels-Alder cycloadditions.
First, by filtering off the silica-supported AgNP catalyst after
conducting the cycloaddition for 45 min, we observed no further
conversion during the next 5 h under the same conditions,15
indicating that the heterogeneous reaction involves minimal
catalyst leaching18 and mechanisms entailing chain reactions
are not likely operating. Second, kinetic data (Figure 2) of the
silica-supported AgNP-catalyzed cycloadditions were obtained
and are consistent with the Eley-Rideal kinetic model19 in
which the 2′-hydroxychalcone adsorbs to the AgNP followed
by reaction of the diene with the adsorbed substrate. Adsorption
of the 2′-hydroxychalcone substrate to the AgNP surface was
also evident by a significant red shift20 of the π-π* band
absorption of chalcone 6 from 318 to 370 nm in the absence
and presence of in situ generated AgNP’s, respectively.15 Third,
we conducted electron paramagnetic resonance (EPR) measure-
ments of a mixture of silica-supported AgNP catalyst, 2′-
hydroxychalcone 15, and CH2Cl2 in the presence of 5,5-
dimethyl-1-pyrroline N-oxide (DMPO) as a spin trap.21 We
found that DMPO, the AgNP catalyst, and 15 were all necessary
to observe EPR spectra (Scheme 3 and Figure 3) indicating the
formation of DMPO adducts22 derived from radical species
a Reactions conducted with 0.1 mmol 2′-hydroxychalcone substrate in
1 mL of CH2Cl2 in air using 100 mg of silica-supported AgNP catalyst
(contains 27 µg of Ag, 0.25 mol % Ag loading). b Isolated yields are
shown with endo/exo ratio in parentheses. Single regioisomers observed
for unsymmetrical dienes. c Using 4.5 mg of silica-supported AgNP
catalyst (contains 1.2 µg Ag, 0.01 mol % Ag loading).
and 30% Ag(I) as determined by X-ray photoelectron spectros-
copy).15 The silica-supported AgNP’s showed significantly
higher catalytic activity than the corresponding in situ prepared
AgNP’s especially for cases involving highly electron-rich
chalcones, likely due in part to removal of the capping ligands
on the surface of the AgNP during calcination.17
Cycloadditions catalyzed by the silica-supported AgNP
generally favored the endo Diels-Alder cycloadducts with a
single regioisomer observed for unsymmetrical dienes. Excellent
yields and high turnover numbers (TON > 340, based on Ag
loading) were obtained for cycloadditions between a number
of 2′-hydroxychalcones and dienes under mild conditions using
0.25 mol % Ag loading (Table 2). Use of the supported AgNP
catalyst at a loading as low as 0.01 mol % Ag afforded a nearly
quantitative yield of cycloadduct 8 at a slightly higher temper-
ature and prolonged reaction time (entry 2). Notably, reactions
catalyzed by the silica-supported AgNP’s were conducted in
air without exclusion of oxygen or water. Moreover, the silica-
supported AgNP catalyst could be stored on the benchtop for
months and recycled without significant loss of activity (entries
3-6).
(18) Pachon, A. D.; Rothenberg, G. Appl. Organomet. Chem. 2008, 22,
288–299.
(19) The Eley-Rideal mechanism refers to bimolecular, heterogeneous
reactions in which only one reactant adsorbs to the catalyst surface,
followed by a second reactant which reacts with the adsorbed reactant
directly; see: Masel, R. I. Principles of Adsorption and Reaction on
Solid Surfaces; Wiley: Hoboken, NJ, 1996.
(20) (a) Lim, I. S.; Goroleski, F.; Mott, D.; Kariuki, N.; Ip, W.; Luo, J.;
Zhong, C.-J. J. Phys. Chem. B 2006, 110, 6673–6682. (b) Nawrocka,
A.; Krawczyk, S. J. Phys. Chem. A 2008, 112, 10233–10241.
(21) For select examples outlining use of EPR spin trapping experiments
to probe mechanisms of nanoparticle-catalyzed reactions, see: (a)
Grirrane, A.; Corma, A.; Garc´ıa, H. Science 2008, 322, 1661–1664.
(b) Conte, M.; Miyamura, H.; Kobayashi, S.; Chechik, V. J. Am. Chem.
Soc. 2009, 131, 7189–7196.
The silica-supported AgNP catalyst was next investigated for
the synthesis of the cyclohexenyl chalcone natural product
panduratin A. Initial silica-supported AgNP-catalyzed cycload-
ditions employing the unprotected 2′,4′,6′-trisubstituted chalcone
213 as a dienophile were unsuccessful, with the undesired
flavanone 3 produced as a major byproduct likely due to the
(22) (a) Buettner, G. R. Free Radical Biol. Med. 1987, 3, 259–303. (b)
Cholvad, V.; Szaboova, K.; Stasko, A.; Nuyken, O.; Voit, B. Magn.
Reson. Chem. 1991, 29, 402–404. (c) Guo, Q.; Qian, S. Y.; Mason,
R. P. J. Am. Soc. Mass Spectrom. 2003, 14, 862–871. (d) Pinteala,
M.; Schlick, S. Polym. Degrad. Stab. 2009, 94, 1779–1787.
9
7516 J. AM. CHEM. SOC. VOL. 132, NO. 21, 2010

Ag Nanoparticle-Catalyzed Diels-Alder Cycloadditions
A R T I C L E S
Figure 3. EPR spectra and computer simulation of spin trapping. (a)
Experimental EPR spectrum obtained from a mixture of silica-supported
AgNP catalyst (150 mg), 2′-hydroxy-4′-methoxy-6′-acetoxychalcone 15
(11.2 mg, 0.05 mmol), and DMPO (20 µL, 0.18 mmol) in CH2Cl2 (0.5
mL) at 25 °C. (b) Overall composite simulation. (c) Simulated spectrum of
a DMPO/carbon-centered radical adduct. Composition: 71%. Line width:
0.85 G. Coupling constants: aN ) 15.3 G, aHꢀ ) 23.0 G. (d) Simulated
spectrum of a DMPO/carbon-centered radical adduct. Composition: 22%.
Line width: 0.70 G. Coupling constants: aN ) 14.8 G, aHꢀ ) 21.0 G. (e)
Simulated spectrum of a DMPO degradation radical. Composition: 7%. Line
width: 0.60 G. Coupling constants: aN ) 13.8 G, aHγ ) 1.0 G.
processes in metal nanoparticle-catalyzed reactions.3,21,25 We
also observed partial formation of p-benzoquinone when p-
hydroquinone was treated with the in situ generated AgNP
catalyst in the absence of an external oxidant,15 thus confirming
the oxidative properties of the AgNP’s.26 Finally, we conducted
cycloaddition of 2′-hydroxychalcone 6 and deuterium-labeled
diene D-727 using the silica-supported AgNP’s (Scheme 4). The
exclusive cis relationship of the deuterium and the phenyl group
derived from the diene in the cycloadducts supports a concerted
cycloaddition mechanism. In comparison, cycloaddition of 6
and D-7 using the ZnI2/Bu4NBH4 conditions13 afforded cy-
cloadducts with no preference for the position of deuterium,
indicating a stepwise cycloaddition mechanism.15
Although we cannot completely rule out Lewis acid catalysis
for [4 + 2] cycloadditions employing 2′-hydroxychalcones by
coordinatively unsaturated sites on the AgNP surface,28 based
on our experimental results we propose the working mechanism
(23) The experimental EPR spectrum was fitted by superposition of signals
from two DMPO adducts and a DMPO degradation radical. The
hyperfine coupling constants and the ratio of the 14N and Hꢀ splittings
of the simulated spectra are consistent with the DMPO adducts
originating from carbon-centered radicals. The observation of more
than one DMPO adduct could be attributed to multiple resonance
structures of the original radicals derived from 15.
(24) Branham, M. R.; Douglas, A. D.; Mills, A. J.; Tracy, J. B.; White,
P. S.; Murray, R. W. Langmuir 2006, 22, 11376–11383.
(25) For a recent example of an AgNP-catalyzed reaction involving electron
transfer, see: Sudrik, S. G.; Chaki, N. K.; Chavan, V. B.; Chavan,
S. P.; Chavan, S. P.; Sonawane, H. R.; Vijayamohanan, K.
Chem.sEur. J. 2006, 12, 859–864.
Figure 2. Kinetic plots of silica-supported AgNP-catalyzed Diels-Alder
cycloadditions. (a) Initial rate as a function of diene concentration, indicating
first-order kinetics in diene concentration. (b) Initial rate as a function of
chalcone concentration. (c) Lineweaver-Burk plot confirming saturation
kinetics in chalcone concentration.
Scheme 3. Chemical Transformations Leading to the Formation of
DMPO Spin Adducts and a DMPO Degradation Radical
(26) For select examples of AgNP-catalyzed oxidations, see: refs 5a-c
and (a) Xu, R.; Wang, D.; Zhang, J.; Li, Y. Chem. Asian J. 2006, 1,
888–893. (b) Debecker, D. P.; Faure, C.; Meyre, M.-E.; Derre, A.;
Gaigneaux, E. M. Small 2008, 4, 1806–1812. (c) Mitsudome, T.;
Mikami, Y.; Funai, H.; Mizugaki, T.; Jitsukawa, K.; Kaneda, K.
Angew. Chem., Int. Ed. 2008, 47, 138–141.
generated by the AgNP’s and 15.23 The existence of radical
species supports electron transfer processes between the AgNP
and chalcone substrate, consistent with the known size-depend-
ent redox potentials2 and multiple oxidation states of AgNP’s24
as well as literature reports documenting electron transfer
(27) Herndon, J. W.; Hill, D. K.; McMullen, L. Tetrahedron Lett. 1995,
36, 5687–5690.
(28) Shimizu, K.; Sugino, K.; Sawabe, K.; Satsuma, A. Chem.sEur. J.
2009, 15, 2341–2351.
9
J. AM. CHEM. SOC. VOL. 132, NO. 21, 2010 7517

A R T I C L E S
Cong et al.
Scheme 4. Use of a Deuterium-Labeled Dienea
between the activated dienophile 17a/b and diene provides 18
which generates 19 Via back electron transfer (BET) and
protonation. A final desorption step turns over the catalytic cycle
and releases cycloadduct 10 into solution. In the overall reaction,
the AgNP’s thus may serve as an “electron shuttle” catalyst25,33
leading to highly selective activation of 2′-hydroxychalcones
for cycloadditions. In addition, no cycloadducts were observed
when 2′-methoxychalcone was used as a dienophile employing
the silica-supported AgNP catalyst15 indicating the requirement
for the 2′-hydroxyl substituent of the chalcone substrate which
is also consistent with the proposed mechanism.
a Isolated cycloadducts contained a trace amount of 8 (less than 10%)
due to the presence of approximately 6% nondeuterium-labeled diene in
the starting material D-7.
Conclusion
We have developed a novel method for Diels-Alder cy-
cloadditions of 2′-hydroxychalcones employing a silica-sup-
ported silver nanoparticle (AgNP) catalyst. The methodology
has enabled highly efficient syntheses of cyclohexenyl chalcones
which are found in a number of biologically active “Diels-Alder”
natural products8 and the total synthesis of the natural product
panduratin A using nanoparticle catalysis. To the best of our
knowledge, this transformation represents the first example of
a metal nanoparticle-catalyzed Diels-Alder cycloaddition. Initial
mechanistic studies including EPR spin trapping experiments
suggest that the cycloaddition involves a concerted process
mediated by the AgNP’s likely serving as an electron shuttle/
redox catalyst. As communicated here, metal nanoparticles
including AgNP’s should find increasing applications for new
chemical transformations, including those which enable the
synthesis of complex natural products and derivatives. Further
studies along these lines are currently in progress and will be
reported in due course.
Scheme 5. Generalized Mechanism for AgNP-Catalyzed
Cycloadditions
shown in Scheme 5. Proton removal and single electron transfer
(SET)29 from the adsorbed chalcone 6 to the AgNP21a,25 may
generate the AgNP-stabilized phenoxyl radical30 intermediate
17a which is in resonance with carbon-centered radical 17b, a
reactivity consistent with the antioxidant properties of natural
2′-hydroxychalcones.31 Concerted [4 + 2] cycloaddition32
Acknowledgment. Financial support from the NIH (GM-
073855 to J.A.P., Jr. and GM-072663 to S.J.E.), Merck, Wyeth,
and AstraZeneca (graduate fellowship to H.C.) is gratefully
acknowledged. This work made use of the MRSEC Shared
Experimental Facilities at MIT, supported by the NSF (DMR-08-
19762). We thank Professors J. Caradonna, L. Doerrer, B. Reinhard,
S. Schaus (Boston University), and K. Moeller (Washington
University, St. Louis) for helpful discussions. We also thank Drs.
L. Yang, B. Liang, Y. Xiao, C. Prata, K. Milidakis, A. Griset, P.
Tarves, B. Yan, S. Cantalupo (Boston University), L. Hu
(Washington University, St. Louis), E. Shaw, and Dr. Y. Zhang
(MIT) for instrumental assistance.
(29) For select reviews on SET-initiated reactions, see: (a) Floreancig, P. E.
Synlett 2007, 191–203. (b) Moeller, K. D. Synlett 2009, 1208–1218.
(c) Li, C.-J. Acc. Chem. Res. 2009, 42, 335–344.
(30) Zhang, Z.; Berg, A.; Levanon, H.; Fessenden, R. W.; Meisel, D. J. Am.
Chem. Soc. 2003, 125, 7959–7963.
(31) Kozlowski, D.; Trouillas, P.; Calliste, C.; Marsal, P.; Lazzaroni, R.;
Duroux, J.-L. J. Phys. Chem. A 2007, 111, 1138–1145.
(32) For pioneering studies on electron transfer-initiated, radical cation-
mediated Diels-Alder cycloadditions, see: Bauld, N. L. Tetrahedron
1989, 45, 5307–5363. Attempts to apply Bauld’s aminium ion catalyst
[tris(4-bromophenyl)ammoniumyl hexachloroantimonate] to Diels-
Alder cycloadditions of 2′-hydroxychalcones and dienes were unsuc-
cessful thus illustrating the unique catalytic properties of AgNP’s.
(33) Mallick, K.; Witcomb, M.; Scurrell, M. Mater. Chem. Phys. 2006,
97, 283–287.
Supporting Information Available: Experimental procedures
and characterization data for AgNP catalyst and all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
JA102482B
9
7518 J. AM. CHEM. SOC. VOL. 132, NO. 21, 2010