Synthesis of functionalized carbo- and heterocycles via gold-catalyzed cycloisomerization reactions of enynes

Article abstract of DOI:10.1016/j.tet.2008.11.105

The PPh₃AuCl/AgSbF₆ catalytic system promotes a tandem Friedel-Crafts' type addition of electron-rich aromatic and heteroaromatic derivatives to unactivated alkene followed by a C-C bond cyclization reaction. The efficiency of this s

Full text of DOI:10.1016/j.tet.2008.11.105

Tetrahedron 65 (2009) 1911–1918
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of functionalized carbo- and heterocycles via gold-catalyzed
cycloisomerization reactions of enynes
Lucie Leseurre, Chung-Meng Chao, Tomohiro Seki, Emilie Genin, Patrick Y. Toullec,
*
ˆ
´
Jean-Pierre Genet, Veronique Michelet
`
´
Laboratoire de Synthese Selective Organique et Produits Naturels, ENSCP, UMR 7573, 11 rue P. et M. Curie, F-75231 Paris Cedex 05, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 20 October 2008
Received in revised form 23 November 2008
Accepted 24 November 2008
Available online 24 December 2008
The PPh3AuCl/AgSbF6 catalytic system promotes a tandem Friedel–Crafts’ type addition of electron-rich
aromatic and heteroaromatic derivatives to unactivated alkene followed by a C–C bond cyclization re-
action. The efficiency of this system allowed room temperature reactions in a very short time. The scope
and limitations of this reaction were investigated. The reaction conditions were compatible with various
functional groups on the nucleophiles. Severe limitations were observed when the allylic position of the
enyne is substituted by electron-withdrawing groups. The mechanism of the reaction was investigated
via the synthesis of a deuterated aromatic ring: we showed that the source of proton involved in the
protodemetallation step originates from the acidic activated C–H bond of the nucleophile.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
development of catalytic cycloisomerization reactions,10,11 we have
been interested in the use of gold for hydroarylation reactions. In
Over the past 10 years, significant efforts have been made to
develop catalytic C–H bond activation reactions.1 It indeed repre-
sent an ideal environmentally friendly and atom-economical con-
cept as no by-products are produced during the whole process.
Several metals have been recognized as excellent candidates for
aromatic or heteroaromatic C–H bond activation.2 In 1931, Kharash
and Isbell were the first to show that Au(III) could activate aromatic
compounds at room temperature.3 In 1973, Braunstein described
and characterized trihalogenoarylgold(III) complexes.4 Since their
seminal discovery, homogeneous gold catalysis was forsaken and
it’s only recently that gold was recognized as a fascinating metal,
enable to promote a myriad of transformations and to surprise the
organic chemist.5 The use of gold for C–H activation followed by C–
C bond formations was explored by Hashmi’s group in 2000:6 the
addition of 2-methylfuran to methyl vinyl ketones was proven to be
highly efficient. These findings opened the way to further studies:
several groups then reported the addition of electron-rich arenes to
various electrophiles such as alkynes, activated alkenes or allenes.7
The groups of Nolan, Echavarren and Wang reported the hydro-
arylation of propargylic acetates, sulfides and dithiacetals leading
to functionalized indenes or acyclic enol esters in good to excellent
yields.8 The addition of arenes to carbonyl derivatives (C]O and
C]N), epoxides and N-protected aziridines has also been recently
described.9 As part of our ongoing program towards the
our preliminary communication, we have presented an efficient
and atom-economical method for the synthesis of original and
functionalized carbo- and heterocycles via a tandem Friedel–Crafts’
type addition/cyclization process.12,13 Here we report a detailed
study based on our preliminary research with the emphasis on
showing the scope and limitations of the above method.
2. Results and discussion
In order to test the feasibility of the reaction, enyne 1 as the
substrate and 1,3-dimethoxybenzene as the nucleophile were
reacted in the presence of different metal catalysts and solvents
(Table 1). Disappointing results were obtained using AuCl3/AgSbF6
and PtCl2/AgSbF6 systems (Table 1, entries 1 and 2). No conversion
was observed with AgSbF6, Cu(OTf)2, In(OTf)3 or Sc(OTf)3 (Table 1,
entries 3–6). A moderate activity was found when AuCl was asso-
ciated with silver salts (Table 1, entry 7). These results prompted us
to further investigate a catalytic system based on gold. The use of
cationic Au(III) and Au(I) in the presence of triphenylphosphane as
an external ligand or in the gold precursor led to a total conversion
(Table 1, entries 8 and 9). The best reproducible system was found
to be 3 mol % of the commercially available PPh3AuCl and 3 mol % of
AgSbF6, the functionalized alkene 2 being isolated in 73% yield
(Table 1, entry 9). The desired cyclic derivative 2 was detected as
a unique diastereoisomer, fully characterized by NMR spectroscopy
and the stereochemistry of the reaction was unambiguously
established by X-ray analysis of a related derivative.12 A screening
* Corresponding author. Tel.: þ33 1 44276742; fax: þ33 1 44071062.
E-mail address: veronique-michelet@enscp.fr (V. Michelet).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.11.105

1912
L. Leseurre et al. / Tetrahedron 65 (2009) 1911–1918
Table 1
the system PPh3AuCl/AgSbF6 with various enyne substrates and its
efficiency in the presence of other nucleophiles was then examined
(Tables 2 and 3, Schemes 1 and 2).
Optimization of the catalytic system for the Friedel–Crafts’ type addition/cyclization
OMe
The addition of 1,3-dimethoxybenzene and 1,3,5-trimethoxy-
benzene to substrates containing carbon and heteroatom tethers,
where Z¼C(CO2R)2, C(SO2Ph)2, O or NTs, afforded the desired al-
kenes 8–19 in good to excellent isolated yields (Scheme 1 and Table
2, entries 1–8). The carbon tether could either be methyl, isopropyl
or benzyl malonates (Table 2, entries 1–3), even though more
hindered ester groups slowed down the reaction.
Catalyst
OMe
3 mol%
H
MeO2C
MeO2C
AgSbF6 (x mol%)
Ph
MeO2C
Ph
1,3-(MeO)2-C6H4
(x eq.)
MeO2C
1a
2
RT, 30 min - 3 h
A prochiral enyne 1d was prepared and reacted smoothly under
theoptimized conditions(Table 2, entry4). Thereaction led this time
to a mixture of two diastereoisomers 15a,b in 68% isolated yield.12
The generality of the addition/cyclization of carbon, oxygen and
nitrogen tethered 1,6-enynes in the presence of electron-rich 1,3,5-
trimethoxybenzene was fully demonstrated (Table 2, entries 5–8).
Interestingly the addition of this latter was possible directly on
a trisubstituted alkene 5b, leading to disulfone 16 in 72% yield
(Table 2, entry 5). The presence of halides may also be desirable for
further organometallic couplings. We therefore examined the
Entry Catalyst
AgSbF6 (mol %) Solvent
NuH (equiv) Conv (yield) [%]
1
2
AuCl3
PtCl2
9
Ether
3
3
3
3
3
3
3
3
3
3
3
3
3
1.2
5
d
6
Ether
d
3
AgSbF6
d
d
d
d
3
Ether
Ether
Ether
Ether
d
4
5
Cu(OTf)2
In(OTf)3
d
d
6
Sc(OTf)3
AuCl
d
7
Ether
17
8a
9
AuCl3/PPh3
PPh3AuCl
PPh3AuCl
PPh3AuCl
PPh3AuCl
PPh3AuCl
PPh3AuCl
PPh3AuCl
9
Ether
100
100 (73)
<10
100b
100c
100b
100d
100e
3
Ether
10
11
12
13
14
15
3
3
3
3
3
3
CH3CN
CH2Cl2
Acetone
Toluene
Toluene
Toluene
addition of 1-bromo-2,4-dimethoxybenzene as
a nucleophile
(Scheme 2). The reaction of both 1,6-enynes 5a and 6b proceeded
smoothly and led to the corresponding brominated alkenes in 67%
and 63% yield (Scheme 2, Eqs. 1 and 2).
a
Surprisingly, the addition of 1,2-benzodioxolane was un-
successful as no conversion was observed in the case of standard
enyne 1a (Scheme 3, Eq. 3). The presence of a formyl group on the
aromatic also inhibited the reaction. Other nucleophiles such as
thiophene and ferrocene did not give better results. We also ob-
served that the substitution of the alkenyl side chain turned to be
a key parameter for the outcome of the reaction (Scheme 3, Eqs. 4
and 5). Indeed, the substitution by a methyl group at the internal or
the external position of the alkenyl chain was detrimental to the
tandem process, which was unexpected for us as the latter reacted
particularlywell inthe presence ofoxygennucleophilesuchas water
or methanol (Scheme 3, Eq. 4).10c In the same manner, no reaction
was observed in the case of a 1,6-enyne bearing a geranyl side chain
or a 1,7-enyne.10c,14 We anticipated and verified that the substitution
of the enyne by an electron-withdrawing group such as an ester
group (R1¼CO2Me for the carbon-tethered enyne and propargylic
ester as a substrate) completely inhibited any rearrangement
(Scheme 3, Eqs. 4 and 5). Substituted alkynes (carbon or oxygen
tethered) did not react under the standard conditions (Scheme 3, Eq.
5). More surprisingly nitrogen tethered enyne bearing a 3-methyl-
but-2-enyl side chain did not react at room temperature or at 40 ꢀC
(Scheme 3, Eq. 5). Theonly moderateactivity was observed forenyne
1e, which participated in the tandem reaction, leading to the
substituted alkene 22 in 31% isolated yield (Scheme 3, Eq. 6).
Considering the occurrence of indolic skeleton in several phar-
maceuticals, we also studied the introduction of electron-rich
heteroaromatic derivatives (Table 3). Indoles have also been
PPh3 (3 mol %).
b
c
Compound 4: 10%.
Compound 3: 40%.
Compound 4: 30%.
Compound 4: 23%.
d
e
OMe
OMe
Ph
OH
H
MeO2C
MeO2C
MeO2C
MeO2C
Ph
3
4
of different solvents such as CH3CN, CH2Cl2, acetone and toluene
was then performed leading generally to a total conversion of the
enyne except in the case of acetonitrile (Table 1, entries 10–13).
Using acetone as the solvent, a mixture of alkene 2 and alcohol
3, resulting from the competitive addition of water instead of the
aromatic ring, was obtained in a 6/4 ratio. When the reaction was
conducted in CH2Cl2 or toluene, the formation of side-product 4,
resulting from the internal isomerization of the alkene, was ob-
served. In the case of toluene, the influence of the substrate to
nucleophile ratio on the course of the reaction was investigated
(Table 1, entries 14 and 15), the best result being observed in the
presence of 3 equiv of 1,3-dimethoxybenzene. The compatibility of
2,4-(MeO)2C6H3
H
PPh3AuCl (3 mol%)
OMe
MeO
+
R1
AgSbF6 (3 mol%)
ether, RT, t
R1
Z
Z
8-11
5a Z = C(SO2Ph)2, R1 = Ph; 6a Z = O, R1 = Ph; 6b Z = O, R1 = 3,4-(OCH2O)C6H3; 7 Z = NTs, R1 = Ph
2,4-(MeO)2C6H3
2,4-(MeO)2C6H3
O
2,4-(MeO)2C6H3
Ph
2,4-(MeO)2C6H3
H
H
H
H
PhO2S
PhO2S
Ph
O
Ph
O
TsN
O
8
9
10
11
2 h, 99%
2.5 h, 50%
0.5 h, 91%
2.5 h, 60%
Scheme 1. Friedel–Crafts’ type addition/cyclization in the presence of 1,3-dimethoxybenzene.

L. Leseurre et al. / Tetrahedron 65 (2009) 1911–1918
1913
Table 2
Table 3
Friedel–Crafts’ type addition/cyclization in the presence of 1,3,5-trimethoxybenzene
Gold-catalyzed diastereoselective tandem addition/carbocyclization of hetero-
aromatic derivativesa
R2
2,4,6-(MeO)3C6H2
R2
R1
H
Entry
1
t [h]
Product
Yieldb [%]
PPh3AuCl (3 mol%)
AgSbF6 (3 mol%)
MeO
OMe
R1
+
Z
Z
ether, RT, t
NR
12-19
R¼Me, 81,
R¼Ac, 36,
R¼Bn, 78
OMe
1a Z = C(CO2Me)2, R1 = Ph, R2 = H; 1b Z = C(CO2i-Pr)2, R1 = Ph, R2 = H;
1c Z = C(CO2Bn)2, R1 = Ph, R2= H; 1d Z = C(CO2Et)(COPh), R1 = Ph, R2 = H;
5b Z = C(SO2Ph)2, R1 = Me, R2 = Me; 6b Z = O, R1 = 3,4-(OCH2O)C6H3,
R2 = H; 6c Z = O, R1 = 3,4,5-(MeO)3C6H2, R2 = H; 7 Z = NTs, R1 = Ph, R2 = H
1a
0.5
23a, 23b, 23c
H
MeO2C
Ph
MeO2C
NMe
Ph
Entry
1
t [h]
Product
Yielda [%]
68
2
3
4
5
5a
5b
7
3.5
24
25
26
27
99
82
47c
77
H
2,4,6-(MeO)3C6H2
H
PhO2S
PhO2S
MeO2C
MeO2C
1a
1b
1c
1d
5b
1
12
Ph
NMe
2,4,6-(MeO)3C6H2
H
i-PrO2C
i-PrO2C
2b
3b
4c
5
16
16
55
1
13
76
45
68
72
2
Ph
PhO2S
PhO2S
2,4,6-(MeO)3C6H2
H
BnO2C
BnO2C
NMe
14
Ph
6
H
Ph
2,4,6-(MeO)3C6H2
H
TsN
H
EtO2C
PhOC
15a,b
16
Ph
*
NMe
2,4,6-(MeO)3C6H2
6b
0.75
PhO2S
PhO2S
O
O
O
2,4,6-(MeO)3C6H2
Ph
NMe
Ph
H
6
7
7
20
3
17
18
44
60
6d
1b
17
28
72
TsN
O
H
i-PrO2C
i-PrO2C
2,4,6-(MeO)3C6H2
O
H
H
6b
O
NH
MeO
7
8
6b
1a
2.5
29
30
43
68
H
2,4,6-(MeO)3C6H2
OMe
O
O
O
8b
6c
16
19
67
O
OMe
OMe
NH
Ph
a
Isolated yield.
2
H
b
c
AgOTf instead of AgSbF6.
Mixture (1/1) of 2 diastereomers.
MeO2C
MeO2C
described as excellent nucleophilic partners in gold-catalyzed car-
bon–carbon bond forming reactions.15 Methyl-, acetyl and benzyl
substituted indoles were suitable nucleophiles for the Friedel–
Crafts’ type addition and carbocyclization tandem reaction of enyne
1a (Table 3, entry 1). As the N-Me-indole derivative 23a was iso-
lated in a higher yield, we screened the reactivity of other enynes
(Table 3, entries 2–5). The corresponding N-Me-indole heterocycles
24–27 were obtained in 47–99% isolated yields. Both hindered and
free indoles were also introduced in moderate to excellent yields
(Table 3, entries 6–9). Varying the enyne/nucleophilic indole
combination, a total regioselectivity in C-3 position was observed,
with only one exception. The addition of 4-methoxy-2-methyl-
indole did not occur regioselectively in the case of enyne 5b
(Scheme 4) as two isomers 32 and 33 were isolated, respectively, in
NH
9
6b
2.5
31
99
H
O
O
O
a
General conditions: PPh3AuCl (3 mol %), AgSbF6 (3 mol %), ether, rt.
Isolated yield.
b
c
Catalyst (10 mol %), 40 ꢀC.
PPh3AuNTf2 (3 mol %).16
d
33% and 25% yield. Formation of alkene 33 could be explained via
a Friedel–Crafts’ type addition of the phenyl ring of the indole
followed by the cyclization. The regioselectivity of the addition was

1914
L. Leseurre et al. / Tetrahedron 65 (2009) 1911–1918
OMe
Br
NH
NH
MeO
OMe
H
PPh3AuCl (3 mol%)
AgSbF6 (3 mol%)
CH2Cl2, RT
MeO
E
PPh3AuCl (3 mol%)
AgOTf (3mol%)
PhO2S
PhO2S
H
H
PhO2S
PhO2S
E
E
Ph
Ph
E
E
Ph
(1)
(2)
Ph
+
Ph
(7)
1-Br-3,5-(MeO)2C6H3
(3 eq.)
E
NH
5a
20
ether, RT
16 h, 67%
E = SO2Ph, 5b
32, 33%
33, 25%
MeO
OMe
Br
Scheme 4. Friedel–Crafts’ type addition/cyclization in the presence of 4-methoxy-2-
methylindole.
OMe
PPh3AuCl (3 mol%)
AgSbF6 (3 mol%)
1-Br-3,5-(MeO)2C6H3
H
O
O
O
O
be highly dependent on the conformation of the enyne.17 Indeed we
observed a good reactivity of enyne 1f, bearing two hindered tert-
butylic esters, the functionalized alkene 38 was obtained in 80%
yield. A contrario, the presence of a cyclic rigid diester completely
inhibited the reaction (Scheme 6).
In the same manner as previously observed with 1,3-dimeth-
oxybenzene and 1,3,5-trimethoxybenzene as the nucleophiles
(Scheme 3), a strong influence of the electronic effects for
substituted enynes has been observed. All the enynes bearing elec-
tron-withdrawing groups at the allylic position were unreactive. A
peculiar example is described in Scheme 7. Propargylic ester 6d did
not react according the Friedel–Crafts’ type addition/cyclization
process, but a total conversion of the starting material was observed
(Scheme 7, Eq. 12).
O
O
(3 eq.)
ether, RT
2.5 h, 63%
6b
21
Scheme 2. Friedel–Crafts’ type addition/cyclization in the presence of 1-bromo-2,4-
dimethoxybenzene.
not total in the case of pyrrole for enynes 1a and 5b (Scheme 5, Eq.
8). As expected, the 2- and 3-substituted isomers 34a,b and 35a,b
were obtained, the overall yield being, respectively, 58% and 90%.
The addition of a furanyl moiety was also investigated. As
a mixture of unseparable isomers was obtained in the case of fu-
rane, we used 2,5-dimethylfurane as nucleophile (Scheme 5, Eq. 9).
The tandem reaction proceeded smoothly with enynes 1a and 5b
and afforded the corresponding heterocycles 36 and 37 in 39% and
67% yield.
The formation of the isolated products 39 and 40 could be
explained via a gold-catalyzed Michael-type 1,4-addition of the
nucleophile to the activated alkyne (for 39) and a second addition
The addition of N-Me-indole was evaluated varying the carbon
tether on the enyne. We anticipated that the tandem process would
to the resulting a,b-unsaturated ester (for 40). This reactivity was
similar to the previously published work by several groups.18,5 We
also showed that another nucleophile such as 1,3,5-trimethoxy-
benzene reacted in the same manner, the mono- and di-hydro-
arylated products 41 and 42 being isolated in 15% and 22% yield,
respectively (Scheme 7, Eq. 13).
PPh3AuCl (3 mol%)
MeO2C
AgSbF6 (3 mol%)
Ph
(3)
Nu-H
+
no reaction
ether, RT
MeO2C
Nu-H =
In consideration of the tandem Friedel–Crafts’ addition/cycli-
zation reaction mechanism, we and others had previously pro-
posed the formation of a cationic gold catalyst in the presence of
silver salts followed by the complexation of the Lewis acid cationic
gold catalyst to the alkyne function leading to intermediate A
(Scheme 8). The cyclization step may then occur directly via
a concerted diastereoselective Friedel–Crafts’ type addition/carbo-
cyclization sequence leading to vinylaurate intermediate B or may
proceed transiently by stereoselective attack of the nucleophile on
CHO
1a
R
OMe
O
O
Fe
S
OMe
R = MeO, H
R3
PPh3AuCl (3 mol%)
AgSbF6 (3 mol%)
R1
MeO OMe
MeO2C
MeO2C
R2
(4)
(5)
no reaction
+
ether, RT
R1 = Me, R2 = H, R3 = H
a
carbenic species, as advocated in several metal-catalyzed
R
1 = H, R2 = Me, R3 = H
R1 = CO2Me, R2 = R3 = H
R2
PPh AuCl (3 mol%)
MeO
OMe
3
HN
AgSbF6 (3 mol%)
ether, RT to 40°C
R1
n
no reaction
+
HN
H
Z
PPh3AuCl (3 mol%)
R3
H
E
E
AgSbF6 (3 mol%)
OMe
O
E
E
Ph
E
E
Ph
+
Ph
(8)
R2
ether, RT
N
R1
R3
MeO2C
Ph
Ph
n
TsN
O
O
H
E = CO2Me, 34a, 47%
E = SO2Ph, 35a, 80%
34b, 11%
35b, 10%
E = CO2Me 1a
E = SO2Ph 5b
MeO2C
n = 1, R1 = CH2CH=CMe2, R2 = H, R3 = H
O
n = 2, R1 = R2 = Me, R3 = H
OMe
n = 1, R1 = Ph, R2 = H, R3 = SiMe3
n = 1, R1 = Ph, R2 = H, R3 = Ph
PPh3AuCl (5 mol%)
AgSbF6 (5 mol%)
H
E
Ph
E
E
(9)
MeO
OMe
Ph
Et
Ph
PPh3AuCl (3 mol%)
AgSbF6 (3 mol%)
H
MeO2C
MeO2C
Ph
Et
E
MeO2C
MeO2C
(6)
CH2Cl2, RT
O
1,3,5-(MeO)3C6H3
(3 eq.)
E = CO2Me 1a
E = SO2Ph 5b
E = CO2Me, 36, 39%
E = SO2Ph, 37, 67%
ether, RT, 2h, 31%
1e
22
Scheme 3. Limitations in terms of nucleophiles and enynes for the Friedel–Crafts’ type
Scheme 5. Friedel–Crafts’ type addition/cyclization in the presence of pyrrole or 1,4-
addition/cyclization.
dimethylfurane as nucleophiles.

L. Leseurre et al. / Tetrahedron 65 (2009) 1911–1918
1915
OMe
D
MeN
H
OMe
D
D
conditions
(16)
PPh3AuCl (3 mol%)
AgOTf (3 mol%)
t-BuO2C
t-BuO2C
MeO
OMe
MeO
OMe
Ph
(10)
(11)
RO2C
R'O2C
43
Ph
7 h, 80%, 38
1,4-dioxane/D2O = 1/3
95 °C, sealed, 2 weeks
25% yield
97% yield
N
O
Me
O
O
KAuCl4 5 mol%
Ph
1,4-dioxane/D2O = 1/1
100 ºC, sealed, 20 h
OMe
ether, RT
R = R' = t-Bu, 1f
R,R' = CMe2, 1g
D
D
O
SM after 5 days reaction
MeO
OMe
Ph
H
PPh3AuCl (3 mol%)
Scheme 6. Friedel–Crafts’ type addition/cyclization of enynes 1f and 1g.
MeO2C
MeO2C
MeO2C
MeO2C
AgSbF6 (3 mol%)
Ph
(17)
ether, RT, 5 h, 78%
OMe
D
1a
D
D
12-d1
Ph
6%, 39
O
PPh3AuCl (3 mol%)
AgSbF6 (3 mol%)
ether, RT, 2h
NH
NH
MeO
OMe
Ph
D
O
(12)
O
+
Scheme 9. Deuteration experiments.
O
Ph
O
29%, 40
6d
N
H
O
For further mechanistic study, we envisaged to demonstrate
that the protodemetallation step occurred selectively in the pres-
ence of a deuterated nucleophile. We decided to prepare the deu-
terated compound 43 (Scheme 9, Eq. 16).
HN
We used a published procedure based on an hydrogen/deute-
rium exchange in the absence of any acidic catalyst, however, most
of the starting material left without reacting even though the re-
action mixture was heated in a dioxane/D2O (1/3) mixture over 2
weeks.19 We decided to take advantage of the ability of Au(III)
catalyst to activate an aromatic C–H bond and thus we accom-
plished the desired reaction in the presence of a catalytic amount of
KAuCl4 to obtain 97% deuterium exchanged product. The cyclo-
isomerization reaction accomplished using this perdeuterio nu-
cleophile furnished product 12-d1 in 78% yield (Scheme 9, Eq. 17);
thus proving that the source of proton involved in the proto-
demetallation step originates from the acidic activated C–H bond of
the nucleophile.
Ph
15%, 41
O
PPh3AuCl (3 mol%)
AgSbF6 (3 mol%)
2,4,6-(MeO)3C6H
2 (13)
Ph
O
O
+
ether, RT, 2h
MeO
OMe
Ph
O
22%, 42
O
6d
2,4,6-(MeO)3C6H2
2,4,6-(MeO)3C6H2
O
OMe
Scheme 7. Michael-type addition/cyclization of enynes 6d.
PPh3AuCl
AgSbF6
Ar
Ar
H
H
enyne
3. Conclusion
AgCl
H+
R
R
Ar-H
R
[Au]+
Z
Z
Z
We have therefore showed that the gold-catalyzed cyclo-
isomerization of 1,6-enynes in the presence of an external nucle-
ophile such as an electron-rich aromatic ring lead to carbo- and
heterocycles in good to excellent yields. A simple catalytic system
based on the association of Au(I) and silver salts was found to be
highly efficient. The scope and limitations have been studied and
we observed that carbon, oxygen and nitrogen tethered 1,6-enynes
reacted smoothly with methoxysubstituted benzene, indoles, pyr-
roles and furane nucleophilic partners. The reaction conditions
were compatible with the presence of bromide on the aromatic
nucleophile, allowing further potential functionalization. Never-
theless, some severe limitations come from the fact that several
enynes are not reactive under the reaction conditions tested. For
example, we proved that electron-withdrawing groups on 1,6-
enynes or 1,7-enynes are not tolerated. The substitution of the al-
kene is also crucial, as a crotyl side chain does not react at all
compared to a cinnamyl side chain. From a mechanistic point of
view, we demonstrated that the tandem process implies a stereo-
selective protodemetallation, the transferred proton coming from
the nucleophile. Further studies will be dedicated to the con-
struction of elaborated structural units, whose skeleton could be
integrated in pharmaceutically active compounds.
[Au]
A
B
[Au]+
2,4,6-(MeO)3C6H2
H
PPh3AuCl (3 mol%)
AgSbF6 (3 mol%)
O
(15)
Ar
D
O
O
1,3,5-(MeO)3C6H3
(3 eq.)
D
O
ether, RT, 2h, 54%
6b-d1
18-d1
Scheme 8. Mechanistic rationale.
cycloisomerization reactions.5,11 The last step is the proto-
demetallation of the aurate intermediate. We previously showed
that the process is completely stereoselective, since the deuterated
enyne 6b-d1 (>95% D) underwent a clean tandem reaction in the
presence of 3 mol % PPh3AuCl/AgSbF6 and 3 equiv of 1,3,5-trime-
thoxybenzene leading to the unique deuterated alkene 18-d1. The
alkene (>95% D, 1H NMR of crude product) was isolated in 54% yield
(Scheme 8, Eq. 15).

1916
L. Leseurre et al. / Tetrahedron 65 (2009) 1911–1918
4. Experimental
4.4.2. Diisopropyl 3-methylene-4-(phenyl(2,4,6-
trimethoxyphenyl)methyl)cyclopentane-1,1-dicarboxylate (13)
1HNMR (CDCl3, 300 MHz;
ppm): 1.15–1.23 (m,12H),1.58 (s,1H),
4.1. General
d
1.69 (dd, J¼12.9, 2.1 Hz, 1H), 2.27 (dd, J¼12.9, 5.1 Hz, 1H), 2.91–3.04
(m, 2H), 3.76 (d, J¼7.2 Hz, 9H), 3.89–3.99 (m, 1H), 4.24 (d, J¼1.5 Hz,
1H), 4.50 (d, J¼10.8 Hz, 1H), 4.71 (d, J¼1.5 Hz, 1H), 4.97 (quint,
J¼6.3 Hz, 1H), 5.06 (quint, J¼6.3 Hz, 1H), 6.07 (s, 2H), 7.04–7.09 (m,
1H), 7.15–7.20 (m, 2H), 7.43 (d, J¼7.2 Hz, 1H). 13C NMR (CDCl3,
PPh3AuCl was purchased from Cortecnet. AgSbF6 and AgOTf
were purchased from Acros. All manipulations were carried out
under argon. 1H NMR and 13C NMR were recorded on a Bruker AV
300 instrument. All signals for 1H and 13C NMR were expressed as
parts per million downfield from Me4Si used as an internal stan-
75 MHz; d ppm): 21.5, 39.6, 41.6, 42.7, 44.1, 55.2, 55.6, 57.7, 68.4, 68.6,
dard (
d
). Coupling constants (J) are reported in hertz and refer to
91.0, 107.8, 113.8, 125.3, 127.5, 128.7, 144.7, 151.8, 158.7, 159.4, 171.6.
DCI/NH3-MS: m/z 533.5 [MþNa]þ, 528.6 [MþNH4]þ, 511.5 [MþH]þ.
DCI/CH4-HRMS calculated for C30H39O7: 511.2696; found: 511.2682.
apparent peak multiplicities. Mass spectrometry analyses (direct
introduction by chemical ionization with ammoniac or electro-
´
spray) were performed at the Ecole Nationale Superieure de Chimie
de Paris. High resolution mass spectra were performed on a Varian
MAT311 instrument at the Ecole Normale Superieure (Paris).
4.4.3. (1R
*
,4R
*
,10R
*
) and (1R
*
,4S
*
,10S
) Ethyl-1-benzoyl-3-
*
methylene-4-[phenyl-(20,40,60-trimethoxyphenyl)phenylmethyl]-
´
Enynes 1a–c, 5a,b, 6a–d and 7 were prepared according to the
published procedures.10,20 Enynes 1d and 1e were prepared in
analogy with a published procedure.10 1H, 13C NMR and mass
spectroscopy data for compounds 2, 3, 8–12, 14–16, 21, 24–26, 29–
31, 34, 35, 37 and 38 were described elsewhere.10k,12
cyclopentanecarboxylates (15a,b)
1H NMR (CDCl3, 300 MHz;
d
ppm): 0.98 (t, J¼5.3 Hz, 3H), 1.99
(dd, J¼9.9, 8.1 Hz, 1H), 2.30 (dd, J¼9.9, 5.6 Hz, 1H), 3.11 (d,
J¼12.3 Hz, 1H), 3.19 (d, J¼12.2 Hz, 1H), 3.74–3.79 (m, 9H), 4.06 (q,
J¼5.3 Hz, 2H), 4.11 (m, 1H), 4.34 (s, 1H), 4.53 (d, J¼8.3 Hz, 1H), 4.72
(s, 1H), 6.04 (s, 2H), 7.05–7.81 (m, 10H). 13C NMR (CDCl3, 75 MHz;
d
ppm): 13.8, 39.8, 42.0, 42.8, 43.6, 55.3 (2C), 55.7, 56.3, 61.4, 91.1,
4.2. Analytical and spectroscopic data of enynes
92.0, 107.8, 113.8, 125.4, 127.7 (2C), 128.5 (2C), 128.7 (2C), 128.8 (2C),
132.8, 135.7, 144.7, 151.7, 159.5 (2C),160.0, 174.3,195.8. DCI/NH3-MS:
532 (MþNH4)þ, 515 (MþH)þ. DCI/CH4-HRMS calculated for
C32H35O6: 515.2434; observed: 515.2438.
4.2.1. (E) Ethyl 2-benzoyl-5-phenyl-2-(prop-2-ynyl)pent-4-
enoate 1d
1H NMR (CDCl3, 300 MHz;
d
ppm): 1.04 (t, J¼6.9 Hz, 3H), 1.99 (t,
1H NMR (CDCl3, 300 MHz;
d
ppm): 0.93 (t, J¼7.1 Hz, 3H), 1.78
J¼3.0 Hz, 1H), 2.91 (d, J¼3.0 Hz, 2H), 2.99–3.15 (m, 2H), 4.10 (q,
J¼9 Hz, 2H), 5.82 (dt, J¼15.6, 7.5 Hz, 1H), 6.35 (d, J¼15.6 Hz, 1H),
7.09–7.20 (m, 5H), 7.33–7.38 (m, 2H), 7.44–7.50 (m, 1H), 7.77–7.81
(dd, J¼12.7, 11.2 Hz,1H), 2.48 (m,1H), 3.23 (m, 2H), 3.75 (s, 9H), 3.94
(m, 1H), 3.98 (q, J¼7.1 Hz, 2H), 4.29 (s, 1H), 4.56 (d, J¼10.9 Hz, 1H),
4.71 (s, 1H), 6.05 (s, 2H), 7.06–7.86 (m, 10H). 13C (CDCl3, 75 MHz;
(m, 2H). 13C NMR (CDCl3, 75 MHz;
d ppm): 13.9, 23.7, 36.4, 60.5,
d
ppm): 13.8, 39.8, 42.0, 42.8, 43.6, 55.3 (2C), 55.7, 56.3, 61.4, 91.1,
61.9, 72.2, 78.9, 122.8, 126.3 (2C), 127.5, 128.5 (4C), 128.7 (2C), 133.0,
134.8, 135.6, 136.9, 171.6, 195.0. ES-MS: 369.4 [MþNa]þ.
92.0, 107.8, 113.8, 125.4, 127.7 (2C), 128.5 (2C), 128.7 (2C), 128.8 (2C),
132.8, 135.7, 144.7, 151.7, 159.5 (2C),160.0, 174.3,195.8. DCI/NH3-MS:
532 (MþNH4)þ, 515 (MþH)þ. DCI/CH4-HRMS calculated for
C32H35O6: 515.2434; observed: 515.2438.
4.2.2. Dimethyl 2-[3-(E)-cinnamyl]-2-pent-2-ynyl malonate 1e
1H NMR (CDCl3, 300 MHz;
d
ppm): 1.02 (t, J¼7.2 Hz, 3H), 2.07
(m, 2H), 2.71 (dd, J¼4.5, 2.4 Hz, 2H), 2.85 (dd, J¼7.5, 0.9 Hz, 2H),
4.4.4. 3-[1-(20,40,60-Trimethoxyphenyl)phenylmethyl]-4-methylene-
N-tosyl-pyrrolidine (17)
3.64 (s, 6H), 5.94 (dt, J¼15.6, 7.8 Hz, 1H), 6.40 (d, dt, J¼15.9 Hz, 1H),
7.11–7.24 (m, 5H). 13C NMR (CDCl3, 75 MHz;
d ppm): 12.4, 14.2, 23.3,
1H NMR (CDCl3, 300 MHz;
d
ppm): 2.43 (s, 3H), 2.77 (dd, J¼9.6,
36.0, 52.6 (2C), 57.7, 73.7, 85.2, 123.6, 126.3 (2C), 127.4, 128.5 (2C),
134.3, 137.1, 170.5 (2C). EIMS: 315 (MþH)þ.
8.1 Hz,1H), 3.31 (dd, J¼9.6, 7.5 Hz,1H), 3.69 (s, 3H), 3.78 (s, 6H), 3.80
(d, J¼10.2 Hz,1H), 3.95 (d, J¼13.8 Hz,1H), 3.92–4.03 (m,1H), 4.36 (br
s, 1H), 4.47 (d, J¼11.4 Hz, 1H), 4.70 (br s, 1H), 6.06 (s, 2H), 7.06–7.33
(m, 7H), 7.65 (d, J¼8.4 Hz, 2H). 13C NMR (CDCl3, 75 MHz;
d ppm):
4.3. General procedure for the Friedel–Crafts’ type addition/
cyclization
21.5, 41.9, 43.4, 53.0, 53.2, 55.2 (2C), 55.6, 91.1 (2C), 108.5, 112.4,
125.6,127.7 (2C),127.8 (2C),128.5 (2C),129.5 (2C),133.4,143.3,143.4,
147.4, 158.6, 159.9 (2C). DCI/NH3-MS: 494 (MþH)þ. DCI/CH4-HRMS
calculated for C28H31NO5SNaþ: 516.1815; observed: 516.1804.
A mixture of PPh3AuCl (3 mol %) and AgSbF6 (3 mol %) in dis-
tilled ether (2.5 M) was stirred under argon atmosphere at room
temperature for 3 min. The aromatic nucleophile (3 equiv) was
then added and the mixture was stirred for 3 min. The enyne
(1 equiv) was finally added and the mixture was stirred for 0.5–
3.5 h (Tables 2 and 3, Schemes 1–8). After completion of the
reaction, the mixture was filtered through a short pad of silica
(cyclohexane/EtOAc, 50/50) and the solvents were evaporated un-
der reduced pressure. The crude product was purified by silica gel
flash chromatography if necessary.
4.4.5. 3-[1-(3,4-Methylenedioxy)-(20,40,60-trimethoxyphenyl)-
phenylmethyl]-4-methylene-tetrahydrofuran (18)
1H NMR (CDCl3, 300 MHz;
d
ppm): 3.38 (dd, J¼8.5, 7.1 Hz, 1H),
3.77 (s, 3H), 3.80 (s, 6H), 3.82 (dd, J¼8.4, 7.2 Hz, 1H), 3.95–4.10 (m,
1H), 4.38–4.48 (m, 4H), 4.76 (br s, 1H), 5.88 (s, 2H), 6.08 (s, 2H), 6.67
(d, J¼8.0 Hz, 1H), 6.93 (dd, J¼8.2, 1.7 Hz, 1H), 7.05 (s, 1H). 13C NMR
(CDCl3, 75 MHz; d ppm): 30.9, 42.2, 44.8, 55.2 (2C), 55.6, 72.3, 73.8,
90.9, 100.5, 105.2, 107.5, 109.2, 112.8, 121.8, 138.1, 145.3, 147.0, 151.4,
158.6, 159.6 (2C). DCI/NH3-MS: 402 (MþNH4)þ, 385 (MþH)þ. DCI/
CH4-HRMS calculated for C21H25O6: 385.1651; observed: 385.1646.
4.4. Analytical and spectroscopic data of products
4.4.1. Dimethyl-3-[1-(2,4-dimethoxyphenyl)phenylmethyl]-4-
methyl-cyclopent-3-ene-1,1-dicarboxylate (4)
4.4.6. 3-Methylene-4-((2,4,6-trimethoxyphenyl)(3,4,5-
trimethoxyphenyl)methyl)tetrahydrofuran (19)
1H NMR (300 MHz, CDCl3;
d
ppm): 1.60 (s, 3H), 2.74 (q, J¼9.0 Hz,
2H), 2.94 (q, J¼6.0 Hz, 2H), 3.67 (s, 3H), 3.71 (s, 6H), 3.79 (s, 3H), 5.38
1H NMR (CDCl3, 300 MHz;
d
ppm):3.37 (dd, J¼8.7,1.5 Hz,1H), 3.76
(s,1H), 6.32–6.38 (m, 2H), 6.82 (d, J¼8.4 Hz,1H), 7.06–7.26 (m, 5H).13C
(s, 3H), 3.78 (s, 3H), 3.81 (s,12H), 3.83 (s,1H), 3.99–4.09 (m,1H), 4.37
NMR (75.5 MHz, CDCl3;
d
ppm): 13.6, 41.8, 42.9, 45.9, 52.7, 55.3, 55.5,
(s, 2H), 4.43 (s, 2H), 4.75 (d, J¼2.1 Hz,1H), 6.09 (s, 2H), 6.77 (s, 2H).13C
57.3, 98.5, 103.9, 123.8, 125.7, 128.0, 128.4, 130.1, 131.3, 133.0, 143.2,
NMR (CDCl3, 75 MHz; d ppm): 42.8, 44.6, 55.2, 55.6, 55.9, 60.8, 72.4,
158.2, 159.3, 172.8, 172.9. MS-CI (NH3): m/z 425 (MHþ), 442 (MNH4þ).
73.8, 91.1,105.2,106.0,112.7,136.1,139.8,151.4,152.4,158.6,159.7. DCI/

L. Leseurre et al. / Tetrahedron 65 (2009) 1911–1918
1917
NH3-MS: m/z 453.2 [MþNa]þ, 448.4 [MþNH4]þ, 431.2 [MþH]þ. ESI-
3.60 (s, 3H), 3.86–3.93 (m, 1H), 4.09 (d, J¼11.1 Hz, 1H), 4.27 (d,
J¼1.2 Hz, 1H), 4.81 (d, J¼1.5 Hz, 1H), 4.94 (quint, J¼6.3 Hz, 1H), 5.04
(quint, J¼6.3 Hz, 1H), 7.02–7.23 (m, 6H), 7.41 (d, J¼7.2 Hz, 2H), 7.76
HRMS calculated for C24H31O7: 431.2070; found: 431.2056.
4.4.7. 1-Bromo-2,4-dimethoxy-5-(2-methylene-4,4-
bis(phenylsulfonyl)cyclopentyl)(phenyl)methyl)benzene (20)
(d, J¼7.5 Hz, 1H). 13C NMR (CDCl3, 75 MHz; DEPT;
d ppm): 10.8, 21.4,
21.5, 29.5, 30.3, 39.6, 41.6, 45.1, 48.0, 58.0, 68.7, 68.8, 108.6, 109.0,
113.8, 119.0, 119.4, 120.2, 125.5, 125.7, 126.7, 128.1, 133.1, 135.8, 136.8,
145.0, 150.6, 171.4, 171.5. DCI/NH3-MS: 510.4 [MþNa]þ, 505.4
[MþNH4]þ, 488.4 [MþH]þ. DCI/CH4-HRMS calculated for
C31H38NO4: 488.2801; found: 488.2784.
1H NMR (CDCl3, 300 MHz;
d
ppm): 2.44 (d, J¼9.6 Hz, 2H), 3.26–
3.48 (m, 2H), 3.92 (s, 6H), 4.24 (d, J¼2.1 Hz, 1H), 4.33 (d, J¼11.4 Hz,
1H), 4.70 (d, J¼1.8 Hz, 1H), 6.47 (s, 1H), 7.18–7.31 (m, 4H), 7.57–7.81
(m, 8H), 8.02–8.09 (m, 5H). 13C (CDCl3, 75 MHz;
d ppm): 36.7, 39.3,
45.2, 46.3, 55.9, 56.3, 90.2, 97.0, 102.2, 110.1, 126.0, 126.3, 127.9,
128.3, 128.6, 128.9, 131.2, 132.1, 134.5, 134.7, 136.0, 136.7, 142.8,
4.4.13. 1,1-Bis(phenylsulfonyl)-3-[1-(2-methyl-5-methoxy-indol-3-
146.8, 155.1, 156.7. DCI/NH3-MS: m/z 684.1 [MþNH4]þ, 667.1
yl)-phenylmethyl]-4-methylenecyclopentane (32)
79
[MþH]þ. ESI-HRMS calculated for C33
H
BrO6S2: 667.0824; found:
1H NMR (CDCl3, 300 MHz;
d ppm): 1.67 (s, 1H), 2.36 (s, 3H), 2.39
32
667.0813.
(m, 2H), 3.35 (m, 2H), 3.85 (s, 3H), 4.09 (m, 2H), 4.45 (s, 1H), 4.77
(s, 1H), 6.79 (dd, J¼11.1, 2.4 Hz, 1H), 7.11 (m, 3H), 7.23 (m, 1H), 7.36–
7.50 (m, 6H), 7.61 (m, 3H), 7.84 (d, J¼8.6 Hz, 2H), 7.90 (d, J¼8.2 Hz,
4.4.8. Dimethyl-3-[1-(20,40,60-trimethoxyphenyl)phenylmethyl]-4-
propylidene-cyclopentane-1,1-dicarboxylate (22)
2H). 13C NMR (CDCl3, 75 MHz;
d ppm): 12.4, 36.7, 39.0, 44.9,
1H NMR (CDCl3, 300 MHz;
d
ppm): 0.44 (t, J¼7.5 Hz, 3H), 1.85
46.1, 55.9, 90.4, 101.8, 109.9, 110.3, 111.1, 113.9, 127.9 (2C), 128.2 (2C),
128.6 (4C), 130.5, 131.2 (2C), 131.3 (2C), 132.2, 134.5 (2C),
135.7, 136.4, 143.4, 148.0, 153.9. DCI/NH3-MS: 634.4 (MþNa)þ. DCI/
CH4-HRMS calculated for C35H33NO5S2Naþ: 634.1692; observed:
634.1682.
(dd, J¼14.1, 3.3 Hz, 1H), 2.61 (m, 2H), 3.32 (d, J¼15.9 Hz, 1H), 3.60 (s,
3H), 3.64 (s, 3H), 3.72 (s, 3H), 3.77 (s, 6H), 3.73–3.94 (m, 3H), 4.16 (d,
J¼11.7 Hz, 1H), 5.03 (m, 1H), 6.13 (s, 2H), 7.05–7.15 (m, 3H), 7.28–
7.36 (m, 2H). 13C NMR (CDCl3, 75 MHz;
d ppm): 13.8, 21.4, 27.0, 38.6,
41.2, 43.0, 46.4, 52.4, 52.6, 55.2, 55.4, 58.1, 91.1 (2C), 112.4, 125.6,
126.2, 127.6 (2C), 129.3 (2C), 139.2, 145.0, 159.4 (2C), 159.5, 172.6,
172.8. DCI/NH3-MS: 483 (MþH)þ, 500 (MþNH4)þ. DCI/CH4-HRMS
calculated for C28H34O7Naþ: 505.2197; observed: 505.2187.
4.4.14. 1,1-Bis(phenylsulfonyl)-3-[1-(2-methyl-5-methoxy-indol-6-
yl)-phenylmethyl]-4-methylenecyclopentane (33)
1H NMR (CDCl3, 300 MHz;
d ppm): 1.61 (s, 1H), 2.38 (s, 3H), 2.47
(m, 2H), 3.18 (d, J¼17.7 Hz, 1H), 3.38 (d, J¼17.6 Hz, 1H), 3.71 (m, 1H),
3.88 (s, 3H), 4.22 (s, 1H), 4.45 (d, J¼11.1 Hz, 1H), 4.63 (s, 1H), 6.09 (s,
1H), 6.93 (s, 1H), 7.04 (s, 1H), 7.09 (m, 1H), 7.19 (t, J¼7.2 Hz, 2H), 7.28
(m, 1H), 7.48 (m, 4H), 7.65 (m, 3H), 7.90 (d, J¼7.3 Hz, 2H), 8.01 (d,
4.4.9. Dimethyl-3-[1-(1-acetyl-1H-indol-3-yl)phenylmethyl]-4-
methylenecyclopentane-1,1-dicarboxylate (23b)
1H NMR (300 MHz, CDCl3;
d
ppm): 2.05 (dd, J¼13.2, 5.1 Hz, 1H),
2.59 (s, 3H), 2.69 (ddd, J¼13.8, 7.8, 1.5 Hz, 1H), 2.84 (d, J¼15.9 Hz,
1H), 3.05 (d, J¼15.9 Hz, 1H), 3.42 (q, J¼9.9 Hz, 1H), 3.58 (s, 3H), 3.65
(s, 3H), 4.01–4.05 (m, 2H), 4.73 (s, 1H), 7.08–7.38 (m, 14H), 8.27 (d,
J¼7.3 Hz, 2H). 13C NMR (CDCl3, 75 MHz;
d ppm): 13.7, 37.0, 39.3,
46.2, 47.5, 56.1, 90.5, 100.0, 101.1, 109.8, 110.1, 125.9, 126.9, 127.8,
128.0 (2C), 128.3 (2C), 128.5 (2C), 128.6 (2C), 131.2 (2C), 131.3 (2C),
134.4,134.5,135.6,136.2,136.6,144.1,147.3 (2C),151.5. DCI/NH3-MS:
634.4 (MþNa)þ. DCI/CH4-HRMS: Calculated for C35H33NO5S2Naþ:
634.1692; observed: 634.1682.
J¼8.1 Hz, 1H). 13C NMR (75.5 MHz, CDCl3;
d ppm): 24.2, 39.6, 41.6,
46.4, 47.6, 52.8, 58.4, 110.4, 116.5, 119.5, 122.0, 123.5, 124.6, 125.3,
126.7, 128.3, 128.5, 130.3, 135.9, 142.4, 148.3, 168.4, 172.0, 172.1. ESI-
HRMS calculated for C27H27O5NNa: 468.1781; observed: 468.1774.
4.4.15. Dimethyl-3-[1-(2,5-dimethylfuran-3-yl)-phenylmethyl]-4-
4.4.10. Dimethyl-3-[1-(1-acetyl-1H-indol-3-yl)phenylmethyl]-4-
methylenecyclopentane-1,1-dicarboxylate (23c)
methylenecyclopentane-1,1-dicarboxylate (36)
1H NMR (CDCl3, 300 MHz;
d
ppm): 2.18 (s, 6H), 2.88 (d, J¼15 Hz,
1H NMR (300 MHz, CDCl3;
d
ppm): 2.05 (dd, J¼13.5, 8.1 Hz, 1H),
1H), 3.08 (d, J¼15 Hz, 1H), 3.28 (m, 1H), 3.58 (d, J¼10.7 Hz, 1H), 3.69
(d, J¼7.6 Hz,1H), 3.71 (s, 3H), 3.73 (s, 3H), 3.75 (d, J¼7.6 Hz,1H), 4.12
(s, 1H), 4.75 (s, 1H), 5.95 (1H), 7.05–7.30 (m, 5H). 13C NMR (CDCl3,
2.81 (dd, J¼13.5, 7.8 Hz, 1H), 2.93 (d, J¼15.9 Hz, 1H), 3.15 (d,
J¼16.2 Hz, 1H), 3.56 (q, J¼9.3 Hz, 1H), 3.68 (s, 3H), 3.75 (s, 3H), 4.18
(s, 1H), 4.84 (s, 1H), 5.34 (s, 2H), 7.06–7.39 (m, 14H), 7.60 (d,
75 MHz;
d ppm): 11.6, 13.6, 39.6, 41.8, 46.2, 47.0, 52.8, 58.1, 60.6,
J¼8.1 Hz, 1H). 13C NMR (75.5 MHz, CDCl3;
d
ppm): 39.8, 41.8, 46.9,
105.7, 109.6, 121.8, 127.9 (2C), 128.1, 128.3 (2C), 144.2, 145.3, 149.1,
149.6, 172.2, 172.5. ESMS: 384 (MþH)þ. DCI/CH4-HRMS calculated
for C23H26O5Naþ: 405.1672; observed: 405.1671.
48.0, 50.0, 52.7, 52.8, 58.5, 109.7, 110.0, 117.8, 119.2, 119.6, 121.8,
125.7,126.1,126.6,127.5,128.0,128.1,128.5,128.8,136.6,137.7,144.4,
148.9, 172.1, 172.3. ESI-HRMS calculated for C32H31O4NNa:
516.2145; observed: 516.2136.
4.4.16. (E,E)-3-Phenyl-allyl 3-(1H-indol-3-yl)acrylate (39)
1H NMR (CDCl3, 300 MHz;
d
ppm): 4.89 (d, J¼6.2 Hz, 2H), 6.41
4.4.11. 3-[1-(1-Methyl-1H-indol-3-yl)-(3,4-methylenedioxy)-
(dt, J¼16.0, 6.2 Hz, 1H), 6.51 (d, J¼16.0 Hz, 1H), 6.73 (d, J¼16.1 Hz,
phenylmethyl]-4-methylenetetrahydrofuran (27)
1H), 7.17–7.50 (m, 10H), 7.97 (d, J¼15.9 Hz, 1H), 8.49 (s, 1H). 13C
1H NMR (CDCl3, 300 MHz;
d
ppm): 3.43–3.47 (m, 1H), 3.77 (s,
(CDCl3, 75 MHz; d ppm): 64.8, 111.1, 118.6, 119.3, 119.5, 121.7, 122.0,
3H), 3.85 (dd, J¼8.9, 4.5 Hz, 1H), 3.99 (dd, J¼8.9, 6.4 Hz, 1H), 4.18 (d,
J¼10.9 Hz, 1H), 4.38 (d, J¼23.2 Hz, 1H), 4.43 (s, J¼21.6 Hz, 1H), 4.84
(app s, 1H), 5.88 (d, J¼8.4 Hz, 2H), 6.69–7.57 (m, 8H). 13C NMR
123.3, 126.6 (2C), 126.7, 127.9, 128.5 (2C), 129.2, 129.3, 132.0, 133.6,
136.6, 172.3. DCI/NH3-MS (m/z): 304 (MþH)þ. DCI/CH4-HRMS cal-
culated for C20H17NO2Naþ: 326.1151; observed: 326.1149.
(CDCl3, 75 MHz,
d ppm): 43.5, 45.5, 48.8, 71.8, 73.6, 100.8, 106.9,
107.8, 108.9, 109.2, 117.5, 119, 119.5, 121.7, 121.8, 125.6, 127.6, 137,
138.1, 145.7, 147.4, 149. DCI/NH3-MS: 365 (MþNH4)þ, 348 (MþH)þ.
DCI/CH4-HRMS calculated for C22H22O3N: 348.1600; observed:
348.1603.
4.4.17. (E)-3-Phenyl-allyl 3,3-bis-(1H-indol-3-yl)propanoate (40)
F¼128 ꢀC. 1H NMR (CDCl3, 300 MHz;
d
ppm): 3.26 (d, J¼7.7 Hz,
2H), 4.65 (d, J¼5.8 Hz, 2H), 5.17 (t, J¼7.5 Hz, 1H), 6.00–6.09 (m, 1H),
6.44 (d, J¼15.7 Hz, 1H), 6.94 (s, 2H), 7.04–7.63 (m, 13H), 7.99 (s, 2H).
13C NMR (CDCl3, 75 MHz;
d ppm): 31.0, 41.2, 64.8, 111.2 (2C), 118.5
4.4.12. Diisopropyl 3-((1,2-dimethyl-1H-indol-3-yl)-
(2C), 119.3 (2C), 119.5 (2C), 121.8, 121.9 (2C), 123.3 (2C), 126.6, 127.9,
128.5 (2C), 133.6, 136.3 (2C), 136.6 (4C), 172.4. DCI/NH3-MS (m/z):
438 (MþNH4)þ. DCI/CH4-HRMS calculated for C28H24N2O2Naþ:
443.1730; observed: 443.1723.
(phenyl)methyl)-4-methylenecyclopentane-1,1-dicarboxylate (28)
1H NMR (CDCl3, 300 MHz;
1.20 (m, 9H), 1.83 (dd, J¼13.5, 3.9 Hz, 2H), 2.43 (s, 3H), 3.02 (s, 2H),
d
ppm): 1.10 (d, J¼6.3 Hz, 3H), 1.15–

1918
L. Leseurre et al. / Tetrahedron 65 (2009) 1911–1918
Shibata, T.; Fujiwara, R.; Takano, D. Synlett 2005, 2062; (j) Hashmi, A. S. K.;
Blanco, M. C. Eur. J. Org. Chem. 2006, 4340; (k) Alfonsi, M.; Arcadi, A.; Bianchi, G.;
Marinelli, F.; Nardini, A. Eur. J. Org. Chem. 2006, 2393; (l) Nguyen, R. V.; Yao,
X.-Q.; Li, C.-J. Org. Lett. 2006, 8, 2397; (m) Reich, N. W.; Yang, C.-G.; Shi, Z.; He, C.
Synlett 2006, 1278; (n) Ferrer, C.; Echavarren, A. M. Angew. Chem., Int. Ed. 2006,
45, 1105; (o) Zhang, Z.; Liu, C.; Kinder, R. E.; Han, X.; Qian, H.; Widenhoefer, R. A.
J. Am. Chem. Soc. 2006, 128, 9066; (p) Hashmi, A. S. K.; Blanco, M. C.; Kurpejovic,
E.; Frey, W.; Bats, J. W. Adv. Synth. Catal. 2006, 348, 705; (q) Arcadi, A.; Alfonsi,
M.; Bianchi, G.; D’Anniballe, G.; Marinelli, F. Adv. Synth. Catal. 2006, 348, 709; (r)
Mertins, K.; Iovel, I.; Kischel, J.; Zapf, A.; Beller, M. Adv. Synth. Catal. 2006, 348,
691; (s) Lemie`re, G.; Gandon, V.; Agenet, N.; Goddard, J.-P.; de Kozak, A.; Aubert,
C.; Fensterbank, L.; Malacria, M. Angew. Chem., Int. Ed. 2006, 45, 7596; (t)
Hashmi, A. S. K.; Salathe, R.; Frey, W. Eur. J. Org. Chem. 2007, 1648; (u) Arcadi, A.;
Cacchi, S.; Fabrizi, G.; Marinelli, F. Synlett 2007,1775; (v) Rozenman, M. M.; Kanan,
M. W.; Liu, D. R. J. Am. Chem. Soc. 2007, 129, 14933; (w) Ferrer, C.; Amijs, C. H. M.;
Echavarren, A. M. Chem.dEur. J. 2007, 13, 1358; (x) Luo, T.; Schreiber, S. L. Angew.
Chem., Int. Ed. 2007, 46, 8250; (y) Liu, C.; Widenhoefer, R. A. Org. Lett. 2007, 9,1935;
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4.4.18. (E,E)-3-Phenyl-allyl 3-(2,4,6-trimethoxyphenyl)acrylate (41)
F¼128 ꢀC. 1H NMR (CDCl3, 300 MHz;
d ppm): 3.84 (s, 3H), 3.87
(s, 6H), 4.85 (d, J¼6.3 Hz, 2H), 6.11 (s, 2H), 6.39 (dt, J¼22.2, 6.3 Hz,
1H), 6.70 (d, J¼16.0 Hz, 1H), 6.80 (d, J¼16.2 Hz, 1H), 7.24–7.42 (m,
5H), 8.14 (d, J¼16.2 Hz, 1H). 13C NMR (CDCl3, 75 MHz;
d ppm): 55.3,
55.7 (2C), 64.6, 90.4 (2C), 105.9, 117.1, 124.1, 126.6 (2C), 127.8, 128.5
(2C), 133.6, 135.9, 136.6, 161.3 (2C), 162.8, 168.7. DCI/NH3-MS: 355
(MþH)þ. DCI/CH4-HRMS calculated for C21H22O5Naþ: 377.1359;
observed: 377.1357.
4.4.19. (E)-3-Phenyl-allyl 3,3-bis-(2,4,6-trimethoxy-
phenyl)propanoate (42)
F¼92 ꢀC. 1H NMR (CDCl3, 300 MHz;
d
ppm): 3.13 (d, J¼8.6 Hz,
2H), 3.66 (s, 12H), 3.74 (s, 6H), 4.68 (d, J¼6.2 Hz, 2H), 5.23 (t,
J¼8.8 Hz,1H), 6.05 (s, 4H), 6.16–6.21 (m, 1H), 6.51 (d, J¼15.9 Hz,1H),
`
´
8. (a) Marion, N.; Diez-Gonzalez, S.; de Fremont, P.; Noble, A. R.; Nolan, S. P. An-
gew. Chem., Int. Ed. 2006, 45, 3647; (b) Peng, L.; Zhang, X.; Zhang, S.; Wang, J.
7.23–7.33 (m, 5H). 13C (CDCl3, 75 MHz;
d ppm): 29.0, 37.9, 55.1 (2C),
´
J. Org. Chem. 2007, 72, 1192; (c) Amijs, C. H. M.; Lopez-Carillo, V.; Echavarren, A.
M. Org. Lett. 2007, 9, 4021.
55.7 (4C), 64.0, 91.1 (4C), 113.8 (2C), 124.2, 126.5 (2C), 127.8, 128.5
(2C), 133.0, 136.6, 158.8 (2C), 159.3 (4C), 173.3. DCI/NH3-MS: 540
(MþNH4)þ, 523 (MþH)þ. DCI/CH4-HRMS calculated for
C30H34O8Naþ: 545.2146; observed: 545.2136.
9. (a) Luo, Y.; Li, C.-J. Chem. Commun. 2004, 1930; (b) Shi, Z.; He, C. J. Am. Chem. Soc.
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10. (a) Nevado, C.; Charruault, L.; Michelet, V.; Nieto-Oberhuber, C.; Mun˜oz, M. P.;
Me´ndez, M.; Rager, M.-N.; Geneˆt, J.-P.; Echavarren, A. M. Eur. J. Org. Chem. 2003,
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Acknowledgements
ˆ
chelet, V. Synlett 2007, 1780; (d) Leseurre, L.; Toullec, P. Y.; Genet, J.-P.; Michelet,
This project was supported by the Centre National de Recherche
V. Org. Lett. 2007, 9, 4049; (e) Genin, E.; Toullec, P. Y.; Antoniotti, S.; Brancour,
`
Scientifique (CNRS) and the Ministere de l’Education et de la
ˆ
C.; Genet, J.-P.; Michelet, V. J. Am. Chem. Soc. 2006, 128, 3112; (f) Genin, E.;
Antoniotti, S.; Michelet, V.; Geneˆt, J.-P. Angew. Chem., Int. Ed. 2005, 44, 4949; (g)
Antoniotti, S.; Genin, E.; Michelet, V.; Geneˆt, J.-P. J. Am. Chem. Soc. 2005, 127,
9976; (h) Genin, E.; Toullec, P. Y.; Marie, P.; Antoniotti, S.; Brancour, C.; Genet,
`
Recherche. C.-M.C. and E.G. thank the Ministere de l’Education et de
la Recherche for grants. T.S. thanks the Fondation Renault for
a fellowship.
ˆ
J.-P.; Michelet, V. Arkivoc 2007, v, 67; (i) Neatu, F.; Li, Z.; Richards, R.; Toullec,
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P. Y.; Genet, J.-P.; Dumbuya, K.; Gottfried, J. M.; Steinruck, H.-P.; Parvulescu, V. I.;
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