Novel radical tandem 1,6-enynes thioacylation/cyclization: Au-Pd nanoparticles catalysis versus thermal activation as a function of the substrate specificity

Article abstract of DOI:10.1016/j.tet.2014.10.077

We studied the reactivity of 1,6-enynes with thioacetic acid (AcSH) under either thermal conditions or in the presence of catalytic amounts of supported Au or Au-Pd nanoparticles (NPs) under mild conditions. The 1,6-enynes undergo a tandem thioacylation/cyclization to original cyclic products featuring either a homoallylic thioester function or an enol thioester function depending on the substrate topology. Interestingly, the former process was found more efficient when performed in the presence of Au-Pd NPs while the latter process can be efficiently carried out under thermal conditions (100 °C). The reaction proceeds by a radical mechanism and the presence of precious metal NPs seems to stabilize the formation of free radical intermediates, as supported by experimental and theoretical results.

Full text of DOI:10.1016/j.tet.2014.10.077

Tetrahedron 70 (2014) 9635e9643
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Novel radical tandem 1,6-enynes thioacylation/cyclization: AuePd
nanoparticles catalysis versus thermal activation as a function
of the substrate specificity
Irene Notar Francesco a, Justine Giauffret a, Fabien Fontaine-Vive a, Jennifer K. Edwards b,
,
Christopher J. Kiely c, Graham J. Hutchings b, Sylvain Antoniotti a
*
a
ꢀ
Institut de Chimie de Nice, UMR 7272, Universite Nice Sophia Antipolis e CNRS, Parc Valrose, 06108 Nice Cedex 2, France
b Cardiff Catalysis Institute, School of Chemistry, Cardiff University, Park Place, Cardiff CF10 3AT, United Kingdom
c Department of Materials Science and Engineering, Lehigh University, 5 East Packer Avenue, Bethlehem, PA 18015, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 12 August 2014
Received in revised form 22 October 2014
Accepted 31 October 2014
Available online 6 November 2014
We studied the reactivity of 1,6-enynes with thioacetic acid (AcSH) under either thermal conditions or in
the presence of catalytic amounts of supported Au or AuePd nanoparticles (NPs) under mild conditions.
The 1,6-enynes undergo a tandem thioacylation/cyclization to original cyclic products featuring either
a homoallylic thioester function or an enol thioester function depending on the substrate topology.
Interestingly, the former process was found more efficient when performed in the presence of AuePd
NPs while the latter process can be efficiently carried out under thermal conditions (100 ꢀC). The reaction
proceeds by a radical mechanism and the presence of precious metal NPs seems to stabilize the for-
mation of free radical intermediates, as supported by experimental and theoretical results.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Cycloisomerisation
Nanocrystals
S-Nucleophile
Sustainable chemistry
Acetylthiyl radicals
1. Introduction
On the boundaries of these fields, nanostructured precious
metals, and notably gold nanoparticles, are expected to play a pre-
The need for sustainable chemical processes in the production of
fine chemicals has led to innovative concepts and paradigms such
as atom-, step-, and pot-economy, tandem reactions, and multi-
catalysis, among others.1 Ideally, these reactions are performed
with a limited energetic demand, typically at room temperature. To
achieve this goal, catalysis plays a prominent role by lowering the
activation energies. However, although highly efficient processes
have been described with homogenous catalysts, and in particular
transition metal-based catalysts, industrial applications are still in
demand of scale-up capabilities for these methodologies where the
economical and ecological costs cannot always be supported. On
the other side, heterogeneous catalysis provides efficient recycla-
bility of the catalysts, but has been mainly applied so far to the
production of commodity chemicals. It has become desirable to
design novel chemical processes taking into account the principles
of green and sustainable chemistry and offering the advantages of
both homogeneous and heterogeneous catalysis.2e5
mium role.6e8 However, while a fair amount of published research
involving metal nanoparticles is dedicated to oxidation/reduction
processes or coupling reactions, cycloisomerisation reactions and
in particular 1,n-enynes cycloisomerisation reactions catalyzed by
metal nanoparticles seem to have been neglected.9e11 In a 2012
report, the cycloisomerisation of 1,6-enynes catalyzed by gold
nanoparticles was described for the first time and intriguing dif-
ferences were observed compared to the homogeneous version of
the reaction.12
Cycloisomerisation of 1,n-enynes, combined with other re-
actions in tandem processes (e.g., addition of nucleophiles), pro-
vides both atom- and step economy with substantial waste
formation avoided. These methods have been successfully used in
the synthesis of complex scaffolds en route to valuable bio-active
molecules.13,14 Thus, tandem 1,6-enynes cycloisomerisation/nucle-
ophile addition reactions have been developed in homogeneous
catalysis with precious metal salts and complexes.15e17 Besides the
numerous examples existing with C- and O-nucleophiles involving
cationic intermediates and exhibiting Markovnikov regioselectiv-
ities, S-nucleophiles have been rarely studied in these reactions.
The combination of gold catalysis with the transformation of sulfur-
* Corresponding author. Fax: þ33 (0) 492076151; e-mail address: sylvain.anto-
niotti@unice.fr (S. Antoniotti).
http://dx.doi.org/10.1016/j.tet.2014.10.077
0040-4020/Ó 2014 Elsevier Ltd. All rights reserved.

9636
I. Notar Francesco et al. / Tetrahedron 70 (2014) 9635e9643
containing compounds in general have been moderately stud-
ied.18e21 As a result, reports on enynes tandem cycloisomerisation/
S-nucleophiles addition are limited to our best knowledge to the
use of thiophenol using gold catalysis22 or AIBN,23 and diphenyl
disulfide under single electron transfer (SET) conditions,24 leading
in both cases to enol phenyl thioethers with anti-Markovnikov
selectivities (Scheme 1). In contrast, the use of AcSH as nucleo-
phile in cyclopropene ring-opening reactions homogeneously cat-
alyzed by electrophilic Au(I) complexes proceeds with
Markovnikov selectivity following an ionic mechanism.25 Radical
reactions involving 1,6-enynes and triggered by AIBN have been
reported to allow for selective cyclization in spite of multiple pos-
sible directions for the radical attack by kinetic selection of the least
stable radical by 5-exo-trig ring closure.26,27
Fig. 1. Representative lower magnification (a) HAADF-STEM and (b) HR-TEM images
of the impregnated AuePd/TiO2 sample; (c) HRTEM image of an AuePd particle along
an <110> zone axis showing {111}, {200 and {220}-type surface faceting; (d) An
HAADF-STEM image of an individual AuePd exhibiting a coreeshell type morphology
in which the Au preferentially wets the TiO2; (e) Au-La and (f) Pd-La XEDS elemental
maps and (g)Ti (red)-Au (blue) -Pd (green) overlay map from one of the larger alloy
particles confirming a definite Au-rich core/Pd-rich shell morphology.
Scheme 1. Types of products and selectivities observed in tandem cyclization/nucle-
ophile addition of 1,6-enynes.
bright against the TiO2 particles by virtue of atomic number contrast.
The AuePd particle size was found to vary widely between 2 and
200 nm with a mean size of 5e6 nm. The larger particles were always
found to have an Au-rich composition whereas the smaller ones
were invariably Pd-rich. Fig. 1b and c shows HR-TEM images of alloy
particles in which the structure from the AuePd can be determined
as FCC. The image (c) also illustrates the propensity of the particles to
form low energy {111}, {200} and {220} surface facets. The HAADF-
STEM image in Fig. 1d shows that the particles also have a ten-
dency to ‘wet’ the TiO2 forming a flat extended interface, which ul-
timately stabilizes the nanoparticles against excessive thermal
sintering. The AuePd particle in Fig.1d is also seen to adopt a definite
coreeshell morphology. Furthermore, the elemental maps acquired
from a large individual particle (30 nm) presented in Fig. 1e, (f) and
(g) confirm that such particles have a Pd-rich shell and Au-rich core.
Metal NPs were tested in various reaction conditions involving
substrate 1a as a model (not shown). The reactions yielded a 5-
membered ring carbocycle 1b, featuring a methylidene and a thio-
acetylmethyl group at the allylic position, or an exocyclic enol thio-
ester 1c (mostly the 5-membered ring isomer), in line with
previously reported reactions involving thiol functions. CH3CN was
identifiedasthemostadaptedsolventbasedonyieldsandselectivity.
We further screened a series of NPs as possible catalysts for the
reaction of 1a at 30 ꢀC (Fig. 2). The conversion of 1a, measured after
2 h reaction time was 0% with Au/TiO2, Au/CeO2, Au/Mg(OH)2, and
AuroliteÒ (a commercial form of Au NPs/TiO2). Gold nanoparticles
supported on graphite allowed the conversion to reach 78% but
a large amount of undesired 1b0 product was formed, resulting
from the addition of a second AcSH molecule to 1b. A conversion of
69% was obtained with AuePd alloy NPs at the remarkable 0.5 mol
% metal/substrate ratio with 80% selectivity in favor of 1b over 1c
without side product. Additional experiments at 60 ꢀC with Au NPs/
C and AuePd NPs/TiO2 allowed an improvement of the conversion
with the bimetallic catalyst. The stereochemistry of enol thioester
1c was predominantly Z (8:2).
In this context, we have been interested in studying the re-
activity of 1,6-enynes and thioacetic acid in tandem thio-
nucleophile addition/cyclization reactions. The effect of supported
noble metal NPs on the course of the reactions was studied under
mild heterogeneous conditions and compared with thermal con-
ditions (100 ꢀC). The particular choice of Au and AuePd NPs was
mainly guided by the known capacity of these metals to activate p-
bonds and the possible radical stabilization at the surface of Au
NPs.28,29 Even if the mechanisms involving metal nanoparticles are
not yet comprehensively known, it is admitted that at the nano-
metric scale, atoms located at edges or corners of nanocrystals
could behave as cations by electrons delocalization even at a zero
oxidation state.6,30 In regards of AcSH as sulfur transfer agent, we
privileged the ease of handling and the capacity of the thioester
products to be further transformed by hydrolysis or reduction, an
option not offered by the existing methods involving thiophenoxyl
radicals and leading to enol phenyl thioethers.
In this paper, we present our results showing that in the pres-
ence of AcSH and AuePd NPs, various 1,6-enynes bearing a meth-
allyl moiety (R1¼R2¼H, R3¼Me) undergo
a radical tandem
thioacylation/cyclization leading preferentially to cyclic products
featuring a homoallylic thioester function. With other type of 1,6-
enynes (R1, R2¼H, alkyl, aryl, R3¼H), rings with exocyclic enol
thioester functions are obtained efficiently under thermal condi-
tions following a more common route (Scheme 1).
2. Results and discussion
Precious metal NPs supported on TiO2 were prepared by im-
pregnation using an aqueous solution of tetrachloroauric acid, or
aqueous solutions of tetrachloroauric acid and palladium(II) chlo-
ride, added simultaneously to TiO2. The paste obtained was then
dried and further calcinated at 400 ꢀC.31,32
The structure and composition of AuePd/TiO2 catalyst were an-
alyzed by analytical electron microscopy. Fig. 1a shows a low mag-
nification HAADF-STEM image in which the metal particles appear
Control experiments were conducted with AuCl to compare
with a homogeneous system, without any metal nor support (ꢁ/ꢁ),
and with the support TiO2 without NPs (e/TiO2). With AuCl, or
without any added metal, no reaction took place. With TiO2 alone,

I. Notar Francesco et al. / Tetrahedron 70 (2014) 9635e9643
9637
could occur. With AuePd NPs, prolonged reaction times at 30 ꢀC did
not allow reaching a total conversion and resulted in the slow
degradation of product 1b to polyaddition products such as 1b0.
Improved conversions and yields were however obtained in similar
conditions with Au NPs/C and AuePd NPs/TiO2 at 60 ꢀC, which
seemed to be the best compromise for optimizing the yield of 1b.
The formation of 1b as the major product was rather unexpected
since thiols typically add to the alkyne terminus of enynes in the
presence of radical initiators such as AIBN.23 One might however
consider that mainly data on alkyl and aryl thiols are available in the
literature and that this shift of reactivity could be explained by the use
of AcSH instead of RSH, exhibiting an electron-withdrawing effect on
the sulfuratom.33 Another reactionwith 1a intheseconditionsat60ꢀC
was performed using PhSH instead of AcSH. Interestingly, only
a mixture of enol thioether products (E,Z)-1c were formed, along with
their 6-membered ring analogs and doubly thioacylated products
without selectivity, while 1b-analogwasnot formed. Thereplacement
of PhSH by AcSH therefore allowed a different and unprecedented
reactivity of 1,6-enynes, favored in the presence of AuePd NPs.
The formation of 1b selectively from the reaction of 1a with
AcSH in the presence of AuePd NPs/TiO2 was thus confirmed and
improved to 90% conversion upon heating at 60 ꢀC (Table 1, entry 1).
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
Conversion
1b
1c
1b'
l
*
2
iO
-
-/
2
2
2
2
2
iO
C
)
te
C
Au
i
l
/
C*
-
O
i
O
/
H
e
o
TiO
r
Au
O
/T
Au
/T
(
Au
-
/C
Au
/T
Pd
d/
g
Au
P
-
/M
Au
Au
Au
Metal source [M]
Table 1
Tandem reactions of 1ae7aa
Fig. 2. Metal source screening. Substrate 0.5 mmol, AcSH 1.5 mmol, anhydrous CH3CN,
30 ꢀC, 2 h, N2 atmosphere. Metal source 10 mg, titrating 5% w/w in metal excepted
Aurolite (1% w/w, 50 mg). Control experiment: -/TiO2 for the reaction with 10 mg TiO2,
e/e for the reaction without metal nor support. Reactions marked with (*) where
conducted at 60 ꢀC.
Entry
Substrate
[M]
Time Conv.
Products,
selectivityb
a conversion of 28% was observed but no product could be detected
in the reaction medium; degradation probably occurred.
1b, 82%
1c, 18%
1
AuePd/TiO2 28 h
90%
The possible leaching of cationic gold species from the NPs was
evaluated by ICP-MS analysis of residual Au in the reaction mixture
after 3 h with AuePd at 30 and 60 ꢀC. The gold concentrations in
solution were found to be 3, and 11 ppm, respectively (ꢂ2%). Such
very low concentrations represent 0.0024, and 0.0089 mol % metal/
substrate ratios, respectively, and could not account for the catal-
ysis. No conversion indeed was observed with 0.5 mol % homoge-
neous AuCl at 30 ꢀC and only 33% after 28 h at 60 ꢀC (not shown).
The plot of the conversion versus the course of time for AuePd
NPs/TiO2 and TiO2 alone at 30 ꢀC confirmed the catalytic effect of as
low as 0.5 mol % noble metal NPs on the reaction rate (Fig. 3). After
a period of induction of a few minutes, nearly 80% of 1a was con-
verted in 3 h to form predominantly product 1b. With TiO2 alone,
ca. 30% of 1a is consumed within 25 min without the formation of
detectable products, indicating that degradation or oligomerisation
1a
2a
2
AuePd/TiO2 24 h
29% Inseparable mixture
of 2aec, and polyaddition
products
3
AuePd/TiO2 24 h
30%
3c, 77%c
3a
1
0,9
0,8
0,7
0,6
0,5
0,4
0,3
0,2
0,1
0
8000
7000
6000
5000
4000
3000
2000
1000
0
4
5
Au/C
6 h
29%
4a
4a
4b, 100%
AuePd/TiO2 7.5 h
65%
4b, 100%
Au-Pd/TiO2
TiO2
Au-Pd/TiO2
-/TiO2
5b, 65% (67:33)
6
AuePd/TiO2 24 h
77%
0
20
40
60
80
100
120
140
160
180
200
Time (min)
5a
Fig. 3. Time course experiments for the reaction of 1a (0.5 mmol) with AcSH
(1.5 mmol) in CH3CN (0.5 M) in the presence 5% w/w AuePd NPs/TiO2 (10 mg,
equivalent to 0.5 mol %) (A) and TiO2 (10 mg) (-) expressed as the conversion
(primary axis). The cumulated formation of products 1b/1c is also given (AuePd
NPs/TiO2 (C) and TiO2 (:), absolute integration, secondary axis). Data obtained by
GC-TCD with external calibration for 1a.
5c, 21% (75:25)
5b’, 14%
(continued on next page)

9638
I. Notar Francesco et al. / Tetrahedron 70 (2014) 9635e9643
Table 1 (continued )
Table 2
Tandem reactions in CH3CNa
Products,
Entry
Substrate
[M]
Time Conv.
selectivityb
Entry
Substrate
Conv.b
17%
Products, selectivityb
7d
5a
AuePd/TiO2 24 h
AuePd/TiO2 5 h
100%
91%
5b, 45%
5c, 46%
5b0, 9%
1
8c, 100%c
8a
8
6b, 78%
2
3
24%
61%
(2 dias 1:1)
6c, 22%
9a
9c, 100%c
6a
7a
10c, 60%d, 1 dia
10a
9
AuePd/TiO2 9 h
40%
7b, 100%
a
Conditions: substrate (0.5 mmol, E¼COOMe), AcSH (1.5 mmol) in anhydrous
and degassed acetonitrile (1 mL), 60 ꢀC, N2. [M] 10 mg (0.5 mol % metal). Reactions
were quantitative.
4
47%
17%
b
Based on isolated yields.
11c, 100%e, 2 dias, 1:1
11a
c
Along with 23% of double addition product from 3a.
d
Reaction performed at 30 ꢀC.
5
The unusual reactivity observed leading to original structures
such as 1b prompted us to examine the behavior of other substrates
under these reaction conditions (Table 1). A first set of changes was
made on the double bond. With substrate 2a, the conversion
remained modest and a mixture of cyclized products was obtained,
including polyaddition products (entry 2). Substrate 3a delivered
selectively the cyclic product 3c, but the conversion remained
moderate (entry 3).
A second set of changes from 1a was made on the tether, either
by introducing a tosylamine moiety as in 4a or using a carvone-
derived substrate such as 5a. Substrate 4a with both methallyl
and propargyl substituents was cyclized in the presence of Au/C
and AuePd/TiO2 similarly to 1a leading selectively to product 4b,
with 29 and 65% conversion, respectively (entries 4, 5). Again, bi-
metallic AuePd NPs were superior to their monometallic counter-
part and we decided to focus on this catalyst.
Substrate 5a, derived from carvone, was converted into the
corresponding thioester 5b, obtained in the form of a mixture of
diastereomers (2 majs. 67:33), in 77% conversion and 65% selec-
tivity in the presence of AuePd/TiO2 (entry 6). As a side product, the
doubly thioacetylated product 5b0 was formed with 14% selectivity
by the formal addition of AcSH to 5b. With the same catalyst at
30 ꢀC, the conversion was improved up to 100% but the selectivity in
favor of 5b decreased (entry 7). It is worth mentioning that a side
reaction was observed consisting in the addition to AcSH to ace-
tonitrile, favored by the application of higher temperatures. This
reaction might be limited at 30 ꢀC, accounting for the higher con-
version due to a higher AcSH concentration in the reaction medium.
Finally, we modified the electron-withdrawing groups E on the
tether with substrates 6a and 7a, derived from ethyl acetoacetate
and pentane-2,4-dione, respectively. In the presence of AuePd NPs,
the cyclized products 6b and 7b were formed with good to excellent
selectivities and moderate to excellent conversions (entries 8, 9).
Returning to malonate derivatives related to 1a, we tested
substrates 8e12a, featuring variations on the alkenyl side chain
with di- and trisubstituted double bonds with NPs in acetonitrile
(Table 2). In general, with this type of substrates, we observed
a reactivity shift towards the formation of enol thioesters 8e12c
with good to excellent selectivities (60e100%) instead of homo-
allylic thioesters 8e12b, albeit with modest conversion (17e61%).
The stereochemistry of cyclic enol thioesters 8e12c was found
to be predominantly Z or predominantly E depending on the
12a
12c, 100%c
a
Conditions: substrate 0.5 mmol (E¼COOMe), AcSH (3 equiv), anhydrous and
degassed CH3CN, 60 ꢀC, 24 h, nitrogen atmosphere. AuePd/TiO2 (10 mg, 0.5 mol %
metal). Reactions were quantitative.
b
Based on isolated yields.
c Predominantly Z.
d
Predominantly E. Along with 17% of 10b (2 dias, 1:1) and 23% of doubly thio-
acylated product.
e
Predominantly E. Trace amount of doubly thioacylated product were formed.
substitution on the olefinic side chain. Substrates with small sub-
stituents such as H, or Me yielded mostly the Z isomer (cases of 2a,
8a, and 9a), while bulky substitution at this position yielded mostly
the E isomer (cases of 3a, 10a, 11a and 12a).
The position of the SAc group in the products attached in an
anti-Markovnikov fashion suggested that radical reactions could be
involved. This hypothesis was probed by running the reaction of
Fig. 2 at 60 ꢀC in the presence of TEMPO (0.2 equiv). Using either Au
NPs or AuePd NPs, no conversion of 1a was observed after 28 h in
the presence of the radical scavenger. Even if TEMPO is not sup-
posed to interact with thiyl radicals, it could react once a carbon-
centered radical is formed upon the attack of the thiyl radical and
therefore shut down the radical propagation. The reaction was
conducted in the absence of light, and no significant differences
were observed in terms of conversion and products selectivity. In
the presence of AIBN (20 mol %) instead of metal nanoparticles in
our conditions (Table 1), only 19% conversion was observed after 2 h
(to be compared to 90% with AuePd NPs) but the results in terms of
yield and selectivity towards 1b could be reproduced after 24 h. No
difference was observed when running the reaction in the presence
of both 20 mol % AIBN and 0.5 mol % AuePd NPs.
A radical-based mechanism has thus to be considered and
a couple of additional experiments were performed. It is known
that Au NPs have the ability to oxidize thiols to disulfides in the
presence of O2. In our cases, AcSH could be converted to AcSSAc,
further homolytically cleaved to generate AcSꢃ by heating or at the
precious metal surface. Dimeric AcSSAc could indeed be identified
in the reaction mixture by GC/MS but could not be isolated (see SI).
Hence a reaction with 3a was carried out with PhCOSH and at the
end of the reaction, the thiobenzoylated analog of 3c was formed,
and (PhCOS)2 was isolated by column chromatography. The dimer

I. Notar Francesco et al. / Tetrahedron 70 (2014) 9635e9643
Table 3 (continued )
9639
was further engaged in a reaction with both fresh substrate and NPs
but no conversion was observed, ruling out the hypothesis of
BzSSBz as an active species in our conditions. With AcSK or with
AcSH in the presence of Et3N at 60 ꢀC, no conversion was observed
after 18 and 22 h of heating, respectively. Having demonstrated that
neither AcSSAc or AcSꢁ were active in these reactions, we had to
consider unmodified AcSH as the active species. Molecule-assisted
homolysis (MAH)34 could also be of concern here, allowing the
initial radical addition of AcSH to a multiple bond, which could be
followed by a radical chain transfer involving AcSꢃ. It is worth
noting that in our case, the radical reaction could be conducted
without using AIBN or irradiation, as it is typically the case in re-
actions involving thiyl radicals,35 and only 0.5 mol % of AuePd NPs
at 30 ꢀC were enough to trigger the reaction (Figs. 1 and 2). At el-
evated temperatures, the SeH bond of AcSH (dissociation energy:
88 kcal/mol) is likely to be homolytically cleaved.36 This hypothesis
was probed when substrate 1a, 13a, and 14a were treated by AcSH
in toluene at 100 ꢀC in the absence of catalyst. In these conditions,
the anti-Markovnikov products 13d and (E/Z)-14d were obtained
quantitatively in 3 h. These experiments showed that upon heating,
both the double and the triple bonds could be attacked by AcSH.
This attack led selectively and quantitatively to the corresponding
addition products, thereby suggesting that one or the other moiety
within substrate 1a could react. These thermal conditions however
failed to lead selectively to 1b, suggesting a role of NPs in the cy-
clization process (Scheme 2).
Entry
Substrate
Conversion
100%
Products, yields
5
10a
10c, 73%, 1 dia
6
100%
11c, 55%c, 2 dias, 1:1
11a
a
Conditions: substrate 0.5 mmol (E¼COOMe), AcSH (3 equiv), anhydrous and
degassed toluene, 100 ꢀC, nitrogen atmosphere, 1e4 h reaction time.
b
Product 2a0 is formed upon the double addition of AcSH to 2a.
c Together with small amounts of non cyclized thioacylated product.
This change was rewarded by the formation of enol thioester
products c in short reaction times and high conversions. Only in the
case of 2a, product 2c was formed in 40% yield, along with poly-
addition products (entry 1). However, with substrates 3a and 8a,
enol thioester products 3c and 8c were formed in 73e79% yields
with good to excellent conversions (entries 2, 3). Substrate 9a yiel-
ded 9c in a modest 48% (entry 4). Cyclohexenyl substituted substrate
10a delivered diastereoselectively cis-fused cyclized product 10c in
73% yield (entry 5). Geranyl substituted substrate 11a was converted
to 11c in 55% as an equal mixture of diastereomers (entry 6).
Although the reactivity of methallyl-bearing substrates towards
the formation of type b products required the presence of AuePd
NPs at lower temperatures, an alternative procedure for the for-
mation of type c products by thermal activation could thus be
proposed.
A working mechanism was envisaged to explain the formation
of products of type b and c (Scheme 3).
Scheme 2. Addition of AcSH to CeC multiple bonds without initiators or additives.
If the procedure involving AuePd NPs in acetonitrile allowed the
best results with terminal disubstituted double bonds (Table 1), the
modest conversion rates observed with other substrates, leading to
type c products (Table 2), prompted us to use toluene as the solvent
under thermal conditions by heating the reaction at 100 ꢀC (Table 3).
Table 3
Tandem reactions under thermal conditions in toluenea
Entry
1
Substrate
Conversion
Products, yields
2b, 21%
2c, 40%
2a0, 20%b
100%
2a
Scheme 3. Hypothetical mechanism accounting for the product selectivity during the
propagation of the radical reaction. E¼COOMe.
2
100%
3a
3c, 73%
8c, 79%
NPs could be involved in generation of AcSꢃ at low temperature
(e.g., 30 ꢀC), in radicals stabilization during the course of the re-
action, and in radical transfer termination. Radical stabilization at
the surface of Au NPs has been indeed recently invoked in the
cyclotrimerisation of electron-deficient alkynes in the presence of
molecular oxygen28 and with AuePd NPs in the oxidation of tolu-
ene by TBHP.29
3
4
85%
8a
9a
100%
9c, 48%c
For R¼Me such as with substrate 1a, the anti-Markovnikov
(continued)
attack of AcSH following the ‘ene’ path, favored with RsH, leads

9640
I. Notar Francesco et al. / Tetrahedron 70 (2014) 9635e9643
to intermediate A, featuring a stabilized tertiary radical, and further
undergoing 5-exo-dig cyclization to intermediate B further leading
to product 1b after Hꢃ abstraction from AcSH, liberating AcSꢃ. At this
point, we could not discard that B undergoes a 1,4-shift of the
thioacetyl group to intermediate D, the Z stereochemistry being
favored also in that case. While the slightly electrophilic alkyl thiyl
radicals generally react preferentially with the triple bond of enyne
substrates,33 it is plausible that the action of AcSꢃ, of higher elec-
trophilicity, is oriented towards the attack of the double bond of 1a,
both electronically enriched and sterically accessible by the sub-
Interestingly, while intermediate A featuring a sp3-carbon
centered radical is attached through to the surface both by the
sulfur atom and the radical, intermediate B is only attached by the
sp2-carbon centered radical, which suggests a stronger interaction
with the surface accounting for the selectivity. With respect to the
ꢁ
ꢁ
bond lengths, AueS is of 2.63 A in A and 3.18 A in B and AueCꢃ is
ꢁ
ꢁ
2.24 A in A and 2.08 A in B. Binding energies between both A and B
on the gold surface were calculated to be ꢁ119.6 and ꢁ165.6 kJ/mol,
respectively. If substrate 1a reacts through the triple bond first,
leading eventually to 1c, an energy barrier of 148.1 kJ/mol is nec-
essary for the cyclization to proceed on the surface, leading to
a cyclic product at ꢁ69.1 kJ/mol. The same reaction in the gas phase
requires only 12.2 kJ/mol and leads to the cyclic product at ꢁ96.9 kJ/
mol.
stitution with donating groups at the b-position.
With R¼H as in substrate 2a, the attack of AcSH occurs pre-
dominantly on the triple bond yielding C, and the 5-exo-trig cy-
clization gives rise to intermediate (Z)-D further reduced to product
(Z)-2c after Hꢃ abstraction from AcSH, liberating AcSꢃ. The stereo-
chemistry is probably defined by the relative stability of C and C0
and the energy of cyclization C/D; with substrates featuring a low
substitution degree of the double bond like 2a, the selection of the
more stable isomer C, exhibiting minimized steric hindrance leads
to (Z)-D. With substrates bearing bulky substituents on the olefinic
side chain, the less stable isomer C0 is most likely involved to
minimize the repulsion during the ring closure and yields products
with an E stereochemistry (see Tables 2 and 3). The activity of noble
metal NPs, and particularly AuePd alloy NPs, seems to increase the
initial conversion rate of the starting 1,6-enynes and to control the
addition of AcSH, limiting the formation of products of type a0 or b0.
The possible role of NPs through a template effect for the re-
action was investigated by molecular modeling comparing reaction
pathways A/B (with E¼H) and energies in the gas phase and on
a model gold surface (DFT studies). As anticipated, the presence of
a surface resulted in a stabilization of ca. 50.2 kJ/mol for the cyclized
radical B, while the energy barrier to reach TSAB was calculated to be
37.9 kJ/mol in the gas phase and 34.1 kJ/mol on the surface (Fig. 4).
These theoretical results support the hypothesis that a radical
stabilization on the precious metal surface of the nanoparticle en-
ables an equilibrium shift in favor of the formation of the cyclized
product 1b with respect to 1c. This stabilization phenomenon, and
the possible role of NPs in the homolytic cleavage of the sulfhydryl
bond of AcSH, could account for the overall improved yields ob-
served in the presence of Au and AuePd NPs with enyne substrates
bearing a terminal disubstituted double bond.
3. Conclusions
In summary, we described the reactivity of 1,6-enynes in the
presence of AcSH and small amounts of supported Au or AuePd NPs
under mild conditions. 1,6-Enynes featuring a methallyl side chain
underwent an anti-Markovnikov tandem thioacylation/cyclization
to original cyclic products bearing a homoallylic thioester function.
The heterogeneously catalyzed reaction proceeded at atmospheric
pressure and at temperature as low as 30 ꢀC and did not require the
use of additives, radical initiators or ligands. A radical mechanism
has been proposed that is supported by preliminary theoretical
studies. This involves the unusual electrophilic AcSꢃ radical, with
the role of NPs to stabilize the radical ground state in favor of the
formation of cyclized products. An alternative thermal procedure
was proposed for substrates leading to enol thioester products.
+37.9
4. Experimental section
1H NMR and 13C NMR spectra were recorded on BRUCKER AC
200 (200 MHz) and BRUCKER AVANCE 500 (500 MHz). 1H NMR
0
spectra are reported as follows: chemical shift in ppm (d) relative to
the chemical shift of CDCl3 at 7.26 ppm, integration, multiplicities
(s¼singlet, d¼doublet, t¼triplet, q¼quartet, m¼multiplet and
br¼broadened), and coupling constants (Hz). 13C NMR spectra re-
-32.6
+34.1
ported in ppm (d) relative to CDCl3 at 77.16 ppm. The stereo-
chemistry of the enol thioester double bonds was determined by
comparison of the 13C chemical shifts at the allylic positions.
Column chromatography was carried out employing silica gel
(spherical, neutral, 63e200 um, Geduran Si 60, Merck KGaA).
Samples of AuePd/TiO2 catalysts were prepared for TEM/STEM
analysis by dry dispersing the catalyst powder onto a holey carbon
TEM grid. High resolution transmission electron microscopy (HR-
TEM) and high-angle annular dark field (HAADF) imaging experi-
ments were carried out using a 200 kV JEOL 2200FS (scanning)
transmission electron microscope equipped with a CEOS aberration
corrector. XEDS spectrum images were acquired on a 300 kV VG HB
603 STEM equipped with a Nion Inc. aberration corrector. Multi-
variate statistical analysis (MSA) of the XEDS data cubes was car-
ried out utilizing the MSA plug-in for Digital Micrograph.
0
-82.3
GC-TCD analysis were carried out using a Shimadzu 2010 plus
gas chromatograph, under the following operation conditions:
vector gas, He; injector temperature, 250 ꢀC; detector temperature,
210 ꢀC at 60 mA; split ratio, 1/20; total flow, 22,5 mL/min;
Fig. 4. Optimized geometries and energies (kJ/mol) of the reaction A/B (E¼H) in the
gas phase (top) and on a gold surface (bottom). See Supplementary data for calculation
details.

I. Notar Francesco et al. / Tetrahedron 70 (2014) 9635e9643
9641
Phenomenex Zebron ZB5MS column, polydimethylsiloxane (10 m,
HRMS calculated for C13H19O5S (MHþ) 287.0953; found 287.0945.
inside diameter 0.10 mm, film thickness 0.10
m
m); temperature
D
¼2.8 ppm.
program, 80e200 ꢀC at 10 ꢀC/min and 200 ꢀC for 8 min.
(E)-Dimethyl
3-((acetylthio)methylene)-4-benzylcyclo-pen-
GCeMS analysis were performed by using a Shimadzu QP2010
gas chromatograph (conditions: carrier gas, He; injector and de-
tane-1,1-dicarboxylate (E)-3c. 1H NMR (CDCl3, 200 MHz):
d
7.39e7.22 (5H, m); 6.46 (1H, ddd, 4J¼4.8 Hz, 4J¼2.4 Hz, 4Jw0 Hz);
tector temperatures, 250 ꢀC; injected volume, 0.5
mL; split ratio, 1/
3.74 (3H, s); 3.23e3.00 (4H, m); 2.61e2.40 (1H, m); 3.77(3H, s);
2.59 (1H, dd, 2J¼13.2 Hz, 3J¼8.4 Hz); 2.43 (3H, s); 1.94 (1H, dd,
100; (pressure, 180 kPa); SLB-5ms capillary column (thickness:
0.25 mm, length: 30 m, inside diameter: 0.25 mm); temperature
program, 60e250 ꢀC at 2 ꢀC/min, and 250 ꢀC for 10 min, coupled to
a mass selective detector. Mass spectra were obtained by electron
ionization at 70 eV, m/z 35e400, source temperature 250 ꢀC; only
the most abundant ions are given.
High resolution mass spectrometry (HRMS) was performed at
ERINI platform (Grasse, FRANCE) using a Waters APGC coupled
with a Waters Xevo G2 QTOF spectrometer.
Inductively-coupled plasma mass spectrometry (ICP-MS) was
performed using a PerkineElmer Elan DRCII spectrometer.
Starting 1,6-enynes were prepared by conventional procedures
of alkylation of dialkyl malonate or N-tosylamine in the presence of
K2CO3/DMF or NaH/THF.37 Substrate 5a derived from (R)-carvone
was prepared in the presence of LDA/THF following a procedure
adapted from the literature.38 Precious metal NPs preparation and
characterization have been previously reported.31,32
2J¼13 Hz, 3J¼10.4 Hz). 13C NMR (50 MHz, CDCl3)
d 191.90; 171.76;
146.20; 139.62; 128.93; 128.53; 126.32; 108.92; 58.32; 52.97;
52.9þ4,; 45.14; 39.99; 39.87; 39.78; 30.60. MS (EI, 70 eV) 286(19)
[M]ꢃ 271(4), 228(3), 226(31), 211(10), 197(9), 169(43), 137(31),
109(9), 91(80), 65(16), 59(15), 43(100). HRMS calculated for
C
19H23O5S (MHþ) 363.1275; found 363.1266.
D¼2.5 ppm.
S-(3-Methyl-4-methylene-1-tosylpyrrolidin-3-yl)methyl etha-
nethioate 4b. 1H NMR (CDCl3; 200 MHz):
d
7.69 (2H; d; J¼8 Hz);
7.33 (2H; d; J¼8 Hz); 4.92 (1H; bt; 4J¼2 Hz); 4.90 (1H; bt; 4J¼2 Hz);
4.00e3.75 (2H; m); 3.17 (1H; d; 2J¼10 Hz); 3.05 (1H; d; 2J¼13 Hz);
2.95 (1H; d; 2J¼10 Hz); 2.89 (1H; d; 2J¼13 Hz); 2.43 (3H; s); 2.30
(3H; s); 1.08 (3H; s). 13C NMR (CDCl3; 50 MHz):
d 194.91; 176.62;
150.34; 143.85; 132.64; 129.80; 127.91; 107.28; 58.55; 52.22; 45.90;
37.10; 30.62; 23.17; 21.64. MS (EI; 70 eV) 339(0) [Mþꢃ], 296(4),
264(1), 250(56), 184(45), 155(28), 142(29), 108(31), 94(43), 91(100),
67(14), 65(26), 53(8), 43(56).
General procedure for the tandem cyclization/thioacylation of
1,6-enynes. In a Schlenk tube, the substrate (0.5 mmol), supported
1,5-Dimethyl-2-methylene-4-oxo-2,3,3a,4,7,7a-hexahydro-1H-
inden-1-yl)methyl) ethanethioate 5b (diastereomeric mixture,
NPs (2.5
degassed solvent (1 mL) are introduced under a nitrogen atmo-
sphere. AcSH (1.5 mmol, 108 L) is then added, the tube close
m
mol of metal, 10 mg of material) and anhydrous and
major). 1H NMR (CDCl3, 200 MHz):
d 6.58e6.76 (1H, m); 5.03e4.93
(1H, m); 4.78e4.85 (1H, m); 3.25 (1H, d, 2J¼13.8 Hz); 2.95 (1H, d,
m
2J¼13.8 Hz); 2.34 (3H, s); 2.75e1.18 (6H, m); 1.75 (3H, s); 1.05 (3H,
with a septum and mounted with a N2 balloon. The mixture is
stirred at the desired temperature. After completion of the re-
action, monitored by TLC or GC-TCD analysis of samples with-
drawn from the reaction medium, the mixture is filtered through
a pad of silica gel (fluent: diethyl ether). After concentration and
purification by flash chromatography over silica gel (petroleum
ether/Et2O 95/5 to 80/20) the cyclized products are obtained,
typically in the form of colorless or pale yellow oils, except 12c
obtained as a solid.
s). 13C NMR (50 MHz, CDCl3) mixture with 5c
d 201.68; 201.42;
195.60; 195.37; 144.19; 143.92; 143.68; 135.87; 135.81; 53.98;
51.38; 51.13; 50.88; 49.59; 49.02; 46.50; 45.27; 45.18; 45.12; 37.01;
36.23; 31.69; 30.86; 30.79; 30.74; 30.50; 30.34; 30.22; 28.90; 27.97;
22.97; 15.95; 15.77; 15.39. MS (EI, 70 eV) major diastereomer
264(1) [Mþꢃ]; 221(17), 204 (5), 188 (14), 175(52), 159(16), 147(21),
121(18), 105(21), 91(37), 77(27), 65(14), 53(20), 43(100).
1,1,5-Trimethyl-4-oxo-3a,4,7,7a-tetrahydro-1H-inden-2(3H)-
yli-dene)methyl) ethanethioate 5c (major isomer, ratio E/Z not
Spectral data of the main products are given below. Detailed
data and spectra for the compounds presented in this paper and
calculation details are provided in Supplementary data.
determined). 1H NMR (CDCl3, 200 MHz):
d 6.58e6.76 (1H, m);
6.30e6.37 (1H, m); 2.75e1.18 (6H, m); 2.38 (3H, s); 1.75 (3H, s); 1.17
(3H, s); 0.96 (3H, s). 13C NMR (50 MHz, CDCl3) mixture with 5b
Dimethyl
3-(acetylthiomethyl)-3-methyl-4-methylenecyclo-
4.97
d 201.68; 201.42; 195.60; 195.37; 144.19; 143.92; 143.68; 135.87;
pen-tane-1,1-dicarboxylate 1b. 1H NMR (CDCl3, 200 MHz):
d
135.81; 53.98; 51.38; 51.13; 50.88; 49.59; 49.02; 46.50; 45.27;
45.18; 45.12; 37.01; 36.23; 31.69; 30.86; 30.79; 30.74; 30.50; 30.34;
30.22; 28.90; 27.97; 22.97; 15.95; 15.77; 15.39. MS (EI, 70 eV) major
isomer 264(7) [Mþꢃ]; 222(6), 189 (61), 173(31), 161(4), 145(15),
133(9), 121(17), 113(9), 105(13), 99(20), 91(22), 77(16), 43(100).
HRMS calculated for C15H20O2S (Mþ) 264.1184; found 264.1171.
(1H, t, J¼2 Hz); 4.85 (1H, t, J¼2 Hz); 3.72e3.73 (6H, m); 3.07 (2H, m);
3.07 (1H, d, J¼14 Hz); 2.91 (1H, d, J¼14 Hz); 2.39 (1H, d, J¼14 Hz);
2.33 (3H, s); 2.27 (1H, d, J¼14 Hz); 1.10 (3H, s). 13C NMR (CDCl3,
50 MHz):
d 195.49; 172.38; 154.91; 107.32; 57.61; 53.00; 45.50;
41.38; 40.07; 30.76; 26.64. MS (EI, 70 eV) 300(0.2) [Mþꢃ],
257(3), 227(14), 224(20), 211(26), 197(8), 179(49), 164(22), 151(85),
137(10), 123(27), 105(25), 91(58), 77(22), 59(34), 43(100). HRMS
D¼4.9 ppm.
1,2-Bis(acetylthiomethyl)-1,5-dimethyl-3,3a,7,7a-tetrahydro-
calculated for
¼0.7 ppm.
(Z)-Dimethyl 4-(acetylthiomethylene)-3,3-dimethylcyclo-pen-
tane-1,1-dicarboxylate (Z)-1c. 1H NMR (CDCl3, 200 MHz):
6.29
(1H, t, J¼3 Hz); 3.73 (6H, s); 3.04 (2H, d, J¼3 Hz); 2.30e2.40 (5H, m);
1.12 (6H, s). 13C NMR (CDCl3, 50 MHz):
192.11; 172.40; 172.40;
C
14H21O5S (MHþ) 301.1110; found 301.1112.
1H-inden-4(2H)-one 5b0 (diastereomeric mixture, 2 majs): 1H NMR
D
(CDCl3, 200 MHz):
(11H, m); 1.76 (3H, s); 1.01 (3H, s). 13C NMR (50 MHz, CDCl3)
201.68; 201.42; 195.82; 195.60; 195.42; 195.38; 144.20; 143.69;
d 6.53e6.77 (1H, m); 2.31 (6H, s); 3.27e1.53
d
d
135.91; 135.86; 51.43; 51.18; 50.93; 49.63; 49.07; 46.54; 45.31;
45.17; 37.05; 36.27; 31.73; 30.89; 30.83; 30.78; 30.54; 30.26; 28.94;
28.01; 27.12; 23.01; 15.98; 15.80; 15.42. MS (EI, 70 eV) 340(0.74)
[Mþꢃ]; 298(3), 265 (6), 255(9); 222 (4), 207(3), 189 (16),175(13),
147(9), 121(46), 105(8), 91(13), 77(19), 55(6), 43(100). HRMS cal-
d
152.11; 107.49; 58.07; 53.12; 53.12; 48.43; 43.78; 39.40; 30.70;
29.30; 29.30. MS (EI, 70 eV) 300(2) [Mþꢃ]; 269(1), 258(7), 240(5),
225(1),198(42),183(5),165(7),151(7),139(9),121(6),105(15), 93(8),
91(12), 79(10), 77(10), 59(22), 43(100). HRMS calculated for
culated for C17H25O3S2 (MHþ) 341.1245; found 341.1241.
D
¼1.2 ppm.
C
14H21O5S (MHþ) 301.1110; found 301.1114.
(Z)-Dimethyl
D
¼1.3 ppm.
Ethyl 1-acetyl-3-((acetylthio)methyl)-3-methyl-4-methylene-
3-((acetylthio)methylene)-4-methylcyclo-pen-
cyclopentanecarboxylate 6b (2 diastereomers, 1:1). 1H NMR (CDCl3,
tane-1,1-dicarboxylate (Z)-2c. 1H NMR (CDCl3, 200 MHz):
d
6.27
200 MHz): d 4.98e4.87 (2H, bm); 4.87e4.73 (2H, bm); 4.18 (2H, t,
(1H, ddd, 4J¼4.8 Hz, 4J¼2.4 Hz, 4Jw0 Hz); 3.72 (6H, s); 2.36 (3H, s)
3J¼7.2 Hz); 4.17 (2H, t, 3J¼7.2 Hz); 3.12e2.93 (6H, m); 2.88 (1H, d,
2J¼13.6 Hz); 2.86 (1H, d, 2J¼13.4 Hz); 2.42e2.08 (4H, m); 2.314 (3H,
s); 2.31 (3H, s); 2.13 (6H, s); 1.24 (3H, t, 3J¼7 Hz); 1.23 (3H, t,
3J¼7.2 Hz); 1.10 (3H, s); 1.06 (3H, s). 13C NMR (50 MHz, CDCl3)
2.25e3.11 (4H, m); 1.66e1.84 (1H, m); 1.17 (3H, d, J¼6 Hz). 13C NMR
(50 MHz, CDCl3)
d 192.16; 172.04; 171.91; 148.12; 107.87; 58.46;
53.05; 52.99; 42.44; 39.46; 38.78; 30.67; 17.69. MS (EI, 70 eV).

9642
I. Notar Francesco et al. / Tetrahedron 70 (2014) 9635e9643
d
203.09; 195.48; 195.40; 172.62; 172.55; 154.92; 154.79; 107.17;
142.07; 138.67; 132.48; 129.88; 128.89; 128.75; 127.91; 126.74;
109.80; 52.85; 51.29; 45.68; 38.91; 30.68; 21.65. MS (EI, 70 eV)
107.10; 64.34; 64.01; 61.95; 61.87; 45.58; 45.50; 44.00; 43.94;
39.94; 39.76; 39.50; 30.69; 26.63; 26.33; 26.22; 26.05; 14.08. MS
(EI; 70 eV) diastereomer 1 298(0) [Mþꢃ], 256(6), 237(1), 210(12),
191(3), 179(2), 167(14), 163(3), 149(5), 135(23), 121(8), 107(5),
93(14), 77(6), 65(3), 43(100). Diastereomer 2 298(0) [Mþꢃ], 256(5),
238(1), 210(13), 191(3), 179(2), 167(14), 163(3), 149(5), 135(18),
121(10), 107(6), 105(4), 93(14), 91(10), 79(4), 77(6), 65(3), 43(100).
S-((4,4-diacetyl-1-methyl-2-methylenecyclopentyl)methyl)-
ꢃ
401(0.22) [Mþ ]; 358(2), 326(18), 310(6), 268(2), 234(26), 204(3),
170(9), 155(19), 143(7), 112(15), 91(100), 80(13), 65(15), 43(45).
HRMS calculated for C21H24NO3S2 (MHþ) 402.1198; found 402.1189.
D
¼2.2 ppm.
Diethyl 2-(3-(acetylthio)-2-methylpropyl)malonate 13d. 1H
NMR (CDCl3, 200 MHz):
d
4.19 (4H, q, J¼7 Hz); 3.45 (1H, dd, J¼8 Hz,
J¼6 Hz); 2.86 (2H, m); 2.32 (3H, s); 2.02 (1H, m); 1.76 (2H, m); 1.26
ethanethioate 7b. 1H NMR (CDCl3, 200 MHz):
d
4.94 (1H, t, 4J¼2 Hz);
(6H, t, J¼7 Hz); 0.96 (3H, d, J¼6 Hz). 13C NMR (50 MHz, CDCl3)
4.79 (1H, t, 4J¼2.2 Hz); 3.13e2.87 (2H, m); 2.99 (1H, d, 2J¼13.4 Hz);
2.81 (1H, d, 2J¼13.4 Hz); 2.38e2.012 (2H, m); 2.31 (3H, s); 2.08 (6H,
d 195.56; 169.54; 169.35; 61.56; 61.52; 49.98; 35.49; 34.63; 31.52;
30.72; 18.92; 14.15(2). MS (EI, 70 eV) 290(0) [Mþꢃ]; 247(30), 229(2),
203(25), 173(69), 155(14), 145(11), 127(29), 101(19), 99(20), 87(9),
73(9), 67(7), 55(25), 43(100).
s); 1.04 (3H, s). 13C NMR (50 MHz, CDCl3)
d 204.94; 195.42; 154.45;
107.31; 72.42; 45.59; 42.63; 39.59; 38.00; 30.69; 26.53; 26.41;
26.23. MS (EI, 70 eV) 268(0) [Mþꢃ]; 225(2), 208(1), 179(2), 149(21),
137(17), 121(2), 107(5), 95(9), 91(5), 77(4), 65(2), 43(100).
(Z)-dimethyl 3-((acetylthio)methylene)-4-isopropylcyclo-pen-
(E/Z)-Dimethyl 2-(3-(acetylthio)allyl)malonate 14d. 1H NMR
(CDCl3, 200 MHz):
d
6.66 (1H, d, 3JZ¼10 Hz); 6.57 (1H, d,
3JE¼16 Hz); 5.90e5.60 (2H, m); 3.74 (12H, s); 3.47 (2H, t, J¼7 Hz);
tane-1,1-dicarboxylate (Z)-8c. 1H NMR (CDCl3, 200 MHz):
d 6.26
2.80e2.55 (4H, m); 2.39 (3H, s); 2.33 (3H, s). 13C NMR (50 MHz,
(1H, ddd, 4J¼4.8 Hz, 4J¼2.4 Hz, 4Jw0 Hz); 3.70 (3H, s); 3.72 (3H, s);
2.99 (1H, br d, 2J¼18 Hz); 2.35 (3H, s); 2.31e2.77 (3H, m); 1.86e2.16
(2H, m); 0.95 (3H, d, J¼6.8 Hz); 0.81 (3H, d, J¼6.8 Hz). 13C NMR
CDCl3) d 193.04 (2),191.59 (2),169.02,168.99,129.80,127.42,120.39,
120.24, 52.78 (2), 51.28, 50.72, 32.38, 30.96 (2), 30.46 (2), 29.76. MS
(EI, 70 eV) 246(1) [Mþꢃ]; 204(5), 173(7), 171(14), 145(5), 113(15),
111(20), 100(2), 85(100), 72(4), 59(9), 65(11), 43(100).
(50 MHz, CDCl3)
d 192.21; 171.91; 171.87; 145.99; 108.74; 58.53;
53.01; 52.96; 49.61; 40.35; 34.70; 30.61; 29.66; 21.29; 16.90. MS (EI,
70 eV). HRMS calculated for C19H23O5S (MHþ) 315.1259; found
Acknowledgements
315.1266.
D
¼2.2 ppm.
(Z)-Dimethyl 3-((acetylthio)methylene)-4-ethylcyclopentane-
This work was supported by the University Nice Sophia Antip-
olis, the CNRS, and the ANR program CD2I (Nanocausys project,
grant number 12-CDII-0010-02). We are grateful to Dr. A. Barats for
ICP-MS analysis, Dr. L. Feray for fruitful discussion on radical
mechanisms, and Ms C. Diefoldo for her technical assistance.
1,1-dicarboxylate (Z)-9c. 1H NMR (CDCl3, 200 MHz):
d 6.29 (1H, ddd,
4J¼4.6 Hz, 4J¼2.2 Hz, 4Jw0 Hz); 3.72 (6H, s); 2.77e3.04 (2H, m);
2.49e2.67 (2H, m); 2.36 (3H, s); 1.69e1.94 (2H, m); 1.24e1.42 (1H,
m); 0.93 (3H, t, J¼7.2 Hz). 13C NMR (50 MHz, CDCl3)
d 192.11; 171.94;
171.92; 146.87; 108.15; 77.80; 77.16; 76.52; 58.49; 53.01; 52.95;
45.23; 39.70; 39.61; 30.61; 26.35; 11.69. MS (EI, 70 eV) 300(1)
[Mþꢃ], 269(2), 225(15), 198(29), 165(51), 139(25), 105(27), 77(13),
59(32), 43(100). HRMS calculated for C14H21O5S (MHþ) 301.1110;
Supplementary data
Experimental details, characterization data, and 1H, 13C NMR
and MS spectra of the cyclized products, computational details.
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2014.10.077.
found 301.1117.
D
¼2.3 ppm.
(E)-Dimethyl 3-((acetylthio)methylene)octahydro-1H-indene-
1;1-dicarboxylate (E)-10c (1 dia: cis fusion). 1H NMR (CDCl3,
200 MHz):
d
6.22 (1H, ddd, 4J¼5.4 Hz, 4J¼2.6 Hz, 4Jw0 Hz); 3.96 (3H,
s); 3.96 (3H, s); 3.24 (1H, ddd, 2J¼19 Hz, 4J¼2.6 Hz, 4J¼2.6 Hz);
3.00e2.85 (1H, m); 2.64e2.79 (1H, m); 2.74 (1H, br d, J¼18 Hz); 2.36
(3H, s); 2.02 (1H, br d, J¼14.2 Hz); 1.54e1.82 (3H, m); 1.04e1.33(3H,
References and notes
1. Anastas, P.; Warner, J. Green Chemistry: Theory and Practice; Oxford University:
Oxford, UK, 1998.
m); 0.69e0.89 (1H, m). 13C NMR (50 MHz, CDCl3)
d 192.24; 171.94;
169.98; 144.38; 107.50; 62.19; 52.92; 52.68; 45.13; 43.98; 37.00;
30.62; 24.94; 24.47; 24.27; 20.39. MS (EI; 70 eV) 328(0) [Mþꢃ];
295(1); 250(19); 218(13); 191(36); 190(49); 165(12); 131(42);
115(5); 105(13); 91(25); 77(10); 59(24); 41(100). HRMS calculated
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6. Nanoparticles and Catalysis; Astruc, D., Ed.; Wiley-VCH GmbH & KGaA, Wein-
heim: 2008.
for C16H23O5S (MHþ) 326.1266; found 327.1272.
D¼1.8 ppm.
(E)-dimethyl 3-((acetylthio)methylene)-4-(6-methylhept-5-en-
2-yl)cyclopentane-1,1-dicarboxylate (E)-11c (2 diastereomers 1:1).
1H NMR (CDCl3, 200 MHz):
d
6.22e6.28 (2H, m); 4.97e5.17 (2H, m);
7. Stratakis, M.; Garcia, H. Chem. Rev. 2012, 112, 4469e4506.
8. Pagliaro, M.; Pandarus, V.; Ciriminna, R.; Beland, F.; Demma Cara, P. Chem-
ꢀ
ꢂ
3.72 (6H,s); 3.71 (6H, s); 3.00 (2H, br d, 2J¼17.6 Hz); 2.72 (2H, br d,
2J¼17.8 Hz); 2.35 (6H, s); 1.67 (6H, s); 1.58 (6H, s); 1.20e2.95 (16H,
m); 0.95 (3H, d, J¼6.8 Hz); 0.79 (3H, d, J¼6.6 Hz). 13C NMR (50 MHz,
CatChem 2012, 4, 432e445.
9. Ranu, B. C.; Dey, R.; Chatterjee, T.; Ahammed, S. ChemSusChem 2012, 5, 22e44.
10. Heshmatpour, F.; Abazari, R.; Balalaie, S. Tetrahedron 2012, 68, 3001e3011.
11. Heugebaert, T. S. A.; De Corte, S.; Sabbe, T.; Hennebel, T.; Verstraete, W.; Boon,
N.; Stevens, C. V. Tetrahedron Lett. 2012, 53, 1410e1412.
CDCl3)
d 192.22; 191.98; 171.86; 146.13; 145.54; 131.80; 131.71;
124.53; 124.38; 108.74; 108.26; 58.53; 52.99; 52.94; 49.53; 47.72;
40.54; 40.50; 35.81; 35.40; 34.22; 34.06; 33.75; 31.78; 30.60; 26.22;
26.02; 25.81; 25.76; 18.08; 17.74; 13.96. MS (EI, 70 eV) 382(1)
12. Gryparis, C.; Efe, C.; Raptis, C.; Lykakis, I. N.; Stratakis, M. Org. Lett. 2012, 14,
2956e2959.
^
13. Michelet, V.; Toullec, P. Y.; Genet, J.-P. Angew. Chem., Int. Ed. 2008, 47,
4268e4315.
ꢃ
[Mþ ]; 339(6), 306(3), 247(7), 203(5), 187(7), 169(12), 137(19),
€
14. Furstner, A.; Davies, P. W. Angew. Chem., Int. Ed. 2007, 46, 3410e3449.
109(17), 82(43), 69(67), 43(100), 41(79). HRMS calculated for
15. Buzas, A. K.; Istrate, F. M.; Gagosz, F. Angew. Chem., Int. Ed. 2007, 46, 1141e1144.
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C
19H23O5S (MHþ) 382.1814; found 382.1804. ¼2.6 ppm.
D
(Z)-S-((4-benzyl-1-tosylpyrrolidin-3-ylidene)methyl) ethane-
^
17. Toullec, P. Y.; Genin, E.; Leseurre, L.; Genet, J.-P.; Michelet, V. Angew. Chem., Int.
thioate (Z)-12c. White solid, mp¼108.1 ꢀC. 1H NMR (CDCl3,
Ed. 2006, 45, 7427e7430.
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200 MHz):
d
2.37 (3H, s); 2.44 (3H, s); 2.56 (2H, dd, 2J¼14 Hz,
J¼8 Hz); 2.85e3.10 (3H, m); 3.12e3.29 (1H, m); 3.64e3.87 (2H, br
m); 6.27e6.38 (1H, br m); 7.11 (2H, d, J¼6.4 Hz), 7.20e7.48 (5H, m);
7.67 (2H, d,¼8.2 Hz). 13C NMR (50 MHz, CDCl3)
d 191.08; 144.00;

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