Cyclization of 1,6-enynes catalyzed by gold nanoparticles supported on TiO2: Significant changes in selectivity and mechanism, as compared to homogeneous Au-catalysis

Article abstract of DOI:10.1021/ol301212j

Gold nanoparticles supported on TiO₂ (1.2 mol %) catalyze, for the first time under heterogeneous conditions, the cycloisomerization of a series of 1,6-enynes in high yields. In several cases, the product selectivity differs significantly as compared to homogeneous Au(I)-catalysis. Based on product analysis and stereoisotopic studies it is proposed that the major or exclusive pathway involves a 5-exo cyclization mode to form stereoselectively gold cyclopropyl carbenes that undergo a single cleavage pathway, in contrast to homogeneous Au-catalysis where the double cleavage pathway operates substantially.

Full text of DOI:10.1021/ol301212j

ORGANIC
LETTERS
2012
Vol. 14, No. 12
2956–2959
Cyclization of 1,6-Enynes Catalyzed by
Gold Nanoparticles Supported on TiO2:
Significant Changes in Selectivity and
Mechanism, as Compared to
Homogeneous Au-Catalysis
Charis Gryparis, Christina Efe, Christos Raptis, Ioannis N. Lykakis,† and
Manolis Stratakis*
Department of Chemistry, University of Crete, Voutes 71003 Iraklion, Greece
stratakis@chemistry.uoc.gr
Received April 5, 2012
ABSTRACT
Gold nanoparticles supported on TiO2 (1.2 mol %) catalyze, for the first time under heterogeneous conditions, the cycloisomerization of a series of
1,6-enynes in high yields. In several cases, the product selectivity differs significantly as compared to homogeneous Au(I)-catalysis. Based on
product analysis and stereoisotopic studies it is proposed that the major or exclusive pathway involves a 5-exo cyclization mode to form
stereoselectively gold cyclopropyl carbenes that undergo a single cleavage pathway, in contrast to homogeneous Au-catalysis where the double
cleavage pathway operates substantially.
The homogeneous Au(I)-catalyzed cyclization of 1,6-
enynes has been extensively studied during the past decade,
revealing a variety of unprecedented modes of skeletal
rearrangements.1 The puzzling mechanistic peculiarity of
cycloisomerizations and the discussions over the nature of
the intermediates (carbenes or carbocations) continue to
fascinate.2 Under heterogenized conditions the reaction
has been marginally studied. A specific example was
recently presented using a gold(I) complex covalently
bound on a polystyrene resin that provides the typical
product selectivity of homogeneous Au(I) catalysts.3 The
identification of stabilizedionic gold speciesonmetal oxide
supported gold nanoparticles (Au NPs),4 and the fact that
epoxides5 and silanes6 are readily activated by Au NPs
on titania (Au/TiO2),7 let us recently examine its catalytic
† Current address: Department of Chemistry, Aristotle University of
Thessaloniki, 54124 Thessaloniki, Greece.
(1) Recent review articles: (a) Zhang, L.; Sun, J.; Kozmin, S. A. Adv.
Synth. Catal. 2006, 348, 2271. (b) Jimenez-Nunez, E.; Echavarren, A. M.
Chem. Commun. 2007, 333. (c) Furstner, A.; Davies, P. W. Angew.
Chem., Int. Ed. 2007, 46, 3410. (d) Gorin, D. J.; Toste, F. D. Nature 2007,
446, 395. (e) Michelet, V.; Toullec, P. Y.; Genet, J.-P. Angew. Chem., Int.
Ed. 2008, 47, 4268. (f) Echavarren, A. M.; Jimenez-Nunez, E. Chem. Rev.
2008, 108, 3326. (g) Soriano, E.; Marco-Contelles, J. Acc. Chem. Res.
2009, 42, 1026. (h) Belmont, P.; Parker, E. Eur. J. Org. Chem. 2009, 6075.
(i) Shapiro, N. D.; Toste, F. D. Synlett 2010, 675. (j) Echavarren, A. M.;
Jimenez-Nunez, E. Top. Catal. 2010, 53, 924.
(2) (a) Nieto-Oberhuber, C.; Lopez, S.; Jimenez-Nunez, E.;
Echavarren, A. M. Chem.;Eur. J. 2006, 12, 5916. (b) Cabello, N.;
Jimenez-Nunez, E.; Bunuel, E.; Cardenas, D. J.; Echavarren, A. M. Eur.
J. Org. Chem. 2007, 4217. (c) Furstner, A.; Morency, L. Angew. Chem.,
Int. Ed. 2008, 47, 5030. (d) Hashmi, A. S. K. Angew. Chem., Int. Ed. 2008,
47, 6754. (e) Seidel, G.; Mynott, R.; Furstner, A. Angew. Chem., Int. Ed.
2009, 48, 2510. (f) Perez-Galan, P.; Herrero-Gomez, E.; Hog, D. T.;
Martin, N. J. A.; Maseras, F.; Echavarren, A. M. Chem. Sci. 2011, 2,
141. (g) Perez-Galan, P.; Martin, N. J. A.; Campana, A. G.; Cardenas,
D. J.; Echavarren, A. M. Chem.;Asian J. 2011, 6, 482.
(3) Cao, W.; Yu, B. Adv. Synth. Catal. 2011, 353, 1903.
(4) (a) Carrettin, S.; Blanco, M. C.; Corma, A.; Hashmi, A. S. K. Adv.
Synth. Catal. 2006, 348, 1283. (b) Fierro-Gonzaleza, J. C.; Gates, B. C.
Chem. Soc. Rev. 2008, 37, 2127. (c) Boronat, M.; Concepcion, P.;
Corma, A. J. Phys. Chem. C 2009, 113, 16772. (d) Naya, K.; Ishikawa,
R.; Fukui, K.-I. J. Phys. Chem. C 2009, 113, 10726. (e) Brown, M. A.;
Fujimori, Y.; Ringleb, F.; Shao, X.; Stavale, F.; Nilius, N.; Sterrer, M.;
Freund, H.-J. J. Am. Chem. Soc. 2011, 133, 10668.
(5) Raptis, C.; Garcia, H.; Stratakis, M. Angew. Chem., Int. Ed. 2009,
48, 3133.
(6) Lykakis, I. N.; Psyllaki, A.; Stratakis, M. J. Am. Chem. Soc. 2011,
133, 10426.
(7) Au/TiO2 (∼1 wt % in Au) is commercially available.
r
10.1021/ol301212j
Published on Web 06/05/2012
2012 American Chemical Society

efficiency in heterogeneous alkyne activation. Thus, we
found that Au/TiO2 catalyzes the cycloisomerization of
aryl propargyl ethers into (2H)-chromenes.8 Byproducts
from oxidative dimerization promoted by molecular oxy-
gen were also formed. It was postulated that formation
of (2H)-chromenes is catalyzed by positively charged Au
species, whereas dimeric 2H,20H-3,30-bichromenes derive
via a redox AuIIIꢀAuI catalytic cycle. Although Au/CeO2
have reported to be inactive against 1,6-enyne cyclization,9
we were prompted to test Au/TiO2 as a catalyst for
such a purpose and develop the first heterogeneous gold-
catalyzed approach in this well-studied under homoge-
neous conditions reaction.
revealed by GC-MS analysis. Diene 5a is produced in the
PtCl2-catalyzed cyclization of 5.15 Under homogeneous
Au(I)-conditions 5a was seen only if the reaction solvent is
polar DMSO,11 while in DCM 5b (a minor product under
our reaction conditions) is exclusively formed.
Scheme 1. Cyclization of Enynes 1ꢀ5a Catalyzed by Au/TiO2
b,c
To our delight, gold nanoparticles (1.2% mol in overall
Au content) catalyze in high yields the cyclization of a
series of 1,6-enynes in refluxing DCE, which provides once
more proof for the existence of ionic gold species on
Au/TiO2 as the potent catalytic sites. However, on many
occasions the observed product selectivity differs signifi-
cantly from that under homogeneous Au(I) conditions.
The initial examples using 1,6-enynes bearing a simple
propargylmoietyarepresentedinScheme1.Parentenyne1
provides exclusively the five-membered ring carbocycle 1a
in 94% isolated yield. This selectivity resembles its Pd(II)-,
Pt(II)-, Ir(I)-, In(III)-, or Ru(II)-catalyzed cyclization10
in contradiction to homogeneous Au(I)-catalysis,11 which
provides primarily a six-membered ring cyclization prod-
uct, with 1a being a minor one. For the case of 2, diene 2a
is formed as occurs under homogeneous conditions,12
accompanied by ∼5% of 2b. Crotyl-substituted 3 (E/Z =
3/1) not only led primarily to product 3a11 (E/Z ≈ 3/1)
but also formed a minor amount (12%) of the six-
membered 3b (Z/E ≈ 3/1). Product 3b had been reported
as a minor one in the In-catalyzed cyclization of 310d and
as major in the Ru-catalyzed13 cyclization. Cinnamyl-
substituted 4 decomposes under the reaction conditions
suffering oxidative cleavage of the double bond. Enyne 5
mainly affords the nonconjugated diene 5a (65% relative
yield), conjugated diene 5b (5%), a minor fraction of
two six-membered ring isomers 5c and 5d (total 23%),
oxidative dimerization product 5e14 (5%) as an equimolar
mixture of diastereomers (meso and dl), and a small
fraction (∼2%) of two other dimers (isomeric to 5e) as
a Z = C(COOMe)2. b1.2 mol % of catalyst. cDCE, 70 °C.
For further exploration we examined the cyclization of
internal enynes 6ꢀ11 (Scheme 2). Generally, their reaction
rates are lower; however with one exception high yields
were obtained. The cyclization of 6 provides a striking
difference among homogeneous and heterogeneous gold
catalysis. In the presence of Au/TiO2, diene 6a (single
cleavage product) is exclusively formed, in contrast to
homogeneous Au(I)-conditions, where the isomeric (E)-
3a is formed via a double cleavage rearrangement
mechanism.16 An identical cyclization mode was found
in the case of 7 which selectively provides the acid-sensitive
carbocycle 7a in 75% yield. Enyne 8 affords primarily a
mixture of five-membered ring allene 8a (major), the six-
membered nonconjugated diene 8b (minor), and a mixture
of three dimeric products (GC-MS) in an approximately
6% relative ratio, which could not be separated and
characterized properly. The formation of allenes in the
gold-catalyzed cyclization of some benzyl-substituted
(8) Efe, C.; Lykakis, I. N.; Stratakis, M. Chem. Commun. 2011, 47,
803.
(9) Garcia-Mota, M.; Cabello, N.; Maseras, F.; Echavarren, A. M.;
Perez-Ramirez, J.; Lopez, N. ChemPhysChem. 2008, 9, 1624.
(10) (a) Trost, B. M.; Tanoury, G. J. J. Am. Chem. Soc. 1988, 110,
1636. (b) Chatani, N.; Furukawa, N.; Sakurai, H.; Murai, S. Organo-
metallics 1996, 15, 901. (c) Chatani, N.; Inoue, H.; Morimoto, T.; Muto,
T.; Murai, S. J. Org. Chem. 2001, 66, 4433. (d) Miyanohana, Y.; Chatani,
N. Org. Lett. 2006, 8, 2155. (e) Chatani, N.; Morimoto, T.; Muto, T.;
Murai, S. J. Am. Chem. Soc. 1994, 116, 6049.
(11) Nieto-Oberhuber, C.; Paz Munoz, M.; Lopez, S.; Jimenez-
Nunez, E.; Nevado, C.; Herrero-Gomez, E.; Raducan, M.; Echavarren,
A. M. Chem.;Eur. J. 2006, 12, 1677.
(12) Nieto-Oberhuber, C.; Paz Munoz, M.; Bunuel, E.; Nevado, C.;
Cardenas, D. J.; Echavarren, A. M. Angew. Chem., Int. Ed. 2004, 43,
2402.
(15) Mendez, M.; Paz Munoz, M.; Nevado, C.; Cardenas, D. J.;
Echavarren, A. M. J. Am. Chem. Soc. 2001, 123, 10511.
(16) Nieto-Oberhuber, C.; Lopez, S.; Paz Munoz, M.; Cardenas,
D. J.; Bunuel, E.; Nevado, C.; Echavarren, A. M. Angew. Chem., Int. Ed.
2005, 44, 6146.
(13) Faller, J. W.; Fontaine, P. P. J. Organomet. Chem. 2006, 691,
1912.
(14) Porcel, S.; Echavarren, A. M. Angew. Chem., Int. Ed. 2007, 46,
2672.
Org. Lett., Vol. 14, No. 12, 2012
2957

Scheme 2. Cyclization of Enynes 6ꢀ11a Catalyzed by Au/TiO2
Scheme 3. Cyclization of Some Deuterium Labelled 1,6-Enynes
b,c
Partial deuterium exchange in terminal alkynes is also
known under homogeneous Au(I)-conditions20 and most
likely involves the reversible formation of Au-acetylides.21
Despite the partial deuterium depletion22 on the starting
materials for the case of enynes 2-d and 5-d, tentative
conclusions regarding the disposition of the D-atom
were acquired. Thus, in product 2a-d, deuterium resides
on the exocyclic secondary sp2-carbon of the pentacycle. In
the cyclization of 5-d, deuterium is stereoselectively at-
tached on the exocyclic double bond of the major product
5a-d (tentative assignment due to the 70% isotopic deple-
tion in cyclization product; see Supporting Information).
An identical stereochemical conclusion has been reported
in the cyclization of 5-d catalyzed by a homogeneous Au(I)
complex in DMSO.11 This stereoselective deuterium dis-
position excluded the participation of an Alder ene- type
process. Additionally, the stereoselective introduction of D
in the side allyl chain of enynes 1 and 6, either by LiAlD4
addition to propargyl alcohol23 (synthesis of 1-d) or by
LiAlH4 addition to propargyl alcohol followed by quench-
ing with D2O (synthesis of 10-d and 6-d), was achieved.24
Regarding the cyclization of 1-d, the D-atom appeared
exclusively on the endocyclic secondary sp2-carbon,
whereas, for 10-d and 6-d, stereospecific disposition of the
stereochemical integrity of the terminal olefinic carbon
atom was found in cyclized products 10a-d and 6a-d,
respectively.
a Z = C(COOMe)2. b1.2% mol of catalyst. cDCE, 70 °C. dA mixture
of three products from an oxidative dimerization pathway was also
formed in ∼6% relative yield (GC-MS analysis).
internal enynes has been recently demonstrated.17 Con-
cerning phenyl substituted internal enynes, 9 lead to the
five-membered ring carbocycle 9a in 81% isolated yield,
in contrast to homogeneous Au(I)-catalysis where a fused
bicyclic cyclobutene derivative18 is primarily formed. It is
also known that 9 mainly cyclizes into 9a yet under Rh(II)
catalysis conditions.19 Substrate 10 was unreactive even
under prolonged refluxing conditions, while 11 afforded
the fused tricycle 11a in 83% yield, in accordance to the
homogeneous gold catalysis conditions.2f,18
Useful mechanistic information was acquired upon
studying the Au/TiO2-catalyzed cycloisomerization of
some deuterium labeled 1,6-enynes, presented in Scheme 3.
Generally, sp-C deuterium labeled terminal alkynes
suffer gradual isotopic depletion under our reaction con-
ditions; thus for substrates requiring a prolonged time
to cyclize, mechanistic conclusions could not be drawn.
(17) Harrak, Y.; Simonneau, A.; Malacria, M.; Gandon, V.;
Fensterbank, L. Chem. Commun. 2010, 46, 865.
(18) Nieto-Oberhuber, C.; Perez-Galan, P.; Herrero-Gomez, E.;
Lauterbach, T.; Rodriguez, C.; Lopez, S.; Bour, C.; Rosellon, A.;
Cardenas, D. J.; Echavarren, A. M. J. Am. Chem. Soc. 2008, 130, 269.
(19) Ota, K.; Chatani, N. Chem. Commun. 2008, 2906.
(22) sp-Deuterium labeled enyne 1 undergoes complete isotopic
depletion under the prolonged reaction time of cyclization, not allowing
thus any mechanistic conclusions. For labeled 2-d and 5-d, approxi-
mately 60% and 90% depletion of D respectively was seen on unreacted
starting materials at ∼90% consumption. After reaction completion,
44% isotope depletion was seen in 2a-d and 70% in 5a-d.
(23) Minsek, D. W.; Chen, P. J. Phys. Chem. 1993, 97, 13375.
(24) The deuterium-content in 10-d and 5-d was 60%, while, in 1-d, it
was 95%.
(20) Odabachian, Y.; Le Goff, X. F.; Gagosz, F. Chem.;Eur. J.
2009, 15, 8966.
(21) (a) Simonneau, A.; Jaroschik, F.; Lesage, D.; Karanik, M.;
Guillot, R.; Malacria, M.; Tabet, J.-C.; Goddard, J.-P.; Fensterbank,
L.; Gandon, V.; Gimbert, Y. Chem. Sci. 2011, 2, 2417. (b) Grirrane, A.;
Garcia, H.; Corma, A.; Alvarez, E. ACS Catal. 2011, 1, 1647.
(c) Hashmi, A. S. K.; Braun, I.; Rudolph, M.; Rominger, F. Organo-
metallics 2012, 31, 644.
2958
Org. Lett., Vol. 14, No. 12, 2012

shift17 to form allene 8a. A single cleavage pathway
(especially in the cyclization of 1 and 6) forming an
exocyclic carbocation, as suggested2a,b under homoge-
neous Au(I)-catalysis conditions, is less likely to partici-
pate under our heterogeneous conditions due to the
requirement for the formation of a pseudoprimary carbo-
cation (see Supporting Information, p S38). Analogously,
the most likely fate of the minor 6-endo cyclization mode is
to form stereoselectively cyclopropyl carbene IV, which
depending on the substituents may lead either to fused
bicyclic carbocation V or to monocyclic VI. The minor
products of oxidative dimerization (cyclization of enynes 5
and 8) more likely arise via a redox AuIIIꢀAuI catalytic
cycle primarily from deprotonated intermediate III, as
postulated earlier in the case of aryl propargyl ethers.8
Therefore, Au/TiO2 catalyzes the cyclization of non-
prenyl-substituted 1,6-enynes exclusively via a single
skeletal rearrangement of gold cyclopropyl carbenes into
cyclobutyl carbocations, in contrast to homogeneous cat-
alysis by Au(I) and Au(III) complexes or salts that proceed
via mixed single and double cleavage pathways.27 It is
possible that the polar support plays a crucial role in our
case, through stabilizing the transformation of cyclopropyl
carbenes into rearranged cyclobutyl carbocations or, alter-
natively, their opening into carbocation III for the case of
prenyl-substituted enynes.
Scheme 4. A General Mechanistic Scenario for the Cyclization
of 1,6-Enynes Catalyzed by Au/TiO2
In conclusion, we have presented for the first time a
heterogeneous gold-based catalytic approach regarding
the cyclization of 1,6-enynes. Product analysis and stereo-
isotopic studies reveal that the main pathway involves an
initial 5-exo cyclization by Au(I) species to form stereo-
selectively gold cyclopropyl carbenes. Isomerization of
carbenes into bicyclic cyclobutyl carbocations via a single
cleavage pathway, followed by conrotatory ring opening,
results in the stereoselective disposition of the terminal
olefinic bond of reacting enynes. Depending on the sub-
stituents, ring opening of cyclopropyl carbenes into open
carbocations may also take place. By contrast, based on
the literature data, in the homogeneous Au-catalyzed
cyclization of 1,6-enynes, the double cleavage pathway
operates substantially. The current work exemplifies the
unique nature of Au nanoparticles in catalysis.28
Prior to the mechanistic discussion, we propose that the
stereoselective disposition of H and D in product 5a-d
indicates catalysis by monodentate to the enynes, gold(I)
bearing, oxidized nanoclusters.25 Based on the product
analysis of Schemes 1ꢀ2, and the stereoisotopic results in
Scheme 3, we present in Scheme 4 a general mechanistic
scenario for the Au/TiO2-catalyzed cycloisomerization of
1,6-enynes, considering catalysis by Au(I) species. It is
clear that in all cases the major pathway is a 5-exo cycliza-
tion to form stereoselectively cyclopropyl carbene I, as
proposed earlier.1f Depending on the substituents, I may
undergo ring expansion to cyclobutyl tertiary carbocation
II or isomerize to monocyclic III (typical example, the
cyclization of 5). Carbocation II in turn eliminates Auþ in
a conrotatory fashion26 (typical examples, the cyclization
of 10-d and 6-d). If R1 = H and R2, R3, and R4 = Me,
carbocation III undergoes an intramolecular hydride
Acknowledgment. This work was supported by the
project “IRAKLEITOS II - University of Crete” of the
Operational Programme for Education and Lifelong
Learning 2007-2013 (E.P.E.D.V.M.) of the NSRF (2007-
2013), which is cofunded by the European Union
(European Social Fund) and National Resources.
Supporting Information Available. Copies of H, 13C
NMR of all products and key compounds. This material
is available free of charge via the Internet at http://pubs.
acs.org.
1
(25) PtCl2 which is bidentate to alkyne and alkene provides opposite
stereochemical H/D disposition during the cyclization of enyne 5-d. See
refs 1g and 15.
(26) (a) Tobisu, M.; Chatani, N. Chem. Soc. Rev. 2008, 37, 300.
(b) Lee, S. I.; Chatani, N. Chem. Commun. 2009, 371.
(27) Nakai, H.; Chatani, N. Chem. Lett. 2007, 36, 1494.
(28) Zhang, Y.; Cui, X.; Shi, F.; Deng, Y. Chem. Rev. 2012, 112, 2467.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 12, 2012
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