Gold-catalyzed reactivity of 3-silyloxy-1,5-enynes: a synthetic tool for the synthesis of complex structures and its limitations

Article abstract of DOI:10.1016/j.tet.2008.11.103

Gold-catalyzed reactions of 3-silyloxy-1,5-enynes in the presence of sterically demanding alcohols afford 4-acylcyclopentenes. The cascade process most likely proceeds through a 6-endo-dig carbocyclization and subsequent pinacol-type rearrangement. Studie

Full text of DOI:10.1016/j.tet.2008.11.103

Tetrahedron 65 (2009) 1880–1888
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Gold-catalyzed reactivity of 3-silyloxy-1,5-enynes: a synthetic tool for the
synthesis of complex structures and its limitations
Helge Menz, Jo¨rg T. Binder, Benedikt Crone, Alexander Duschek, Timm T. Haug,
*
´
´
Stefan F. Kirsch , Philipp Klahn, Clemence Liebert
¨
¨
Department Chemie, Technische Universitat Munchen, Lichtenbergstr. 4, D-85747 Garching, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Gold-catalyzed reactions of 3-silyloxy-1,5-enynes in the presence of sterically demanding alcohols afford
4-acylcyclopentenes. The cascade process most likely proceeds through a 6-endo-dig carbocyclization
and subsequent pinacol-type rearrangement. Studies that define scope and limitations of the cyclization–
migration strategy are also described. An alternative cascade yields highly substituted aryls through an
unprecedented cyclization–fragmentation pathway.
Received 8 September 2008
Received in revised form 26 November 2008
Accepted 26 November 2008
Available online 24 December 2008
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
a cyclization–pinacol cascade (Fig. 1). The initial coordination of
a soft gold complex to the alkynyl moiety would result in reactive
The use of noble metal catalysts1,2 to activate alkynes and to
induce a cascade reaction that evolves complex and structurally
diverse molecules is a steadily growing field of importance in
synthetic chemistry.3 Amongst other carbophilic Lewis acids,
gold(I) and gold(III) complexes are particularly attractive due to the
fact that they are typically employed under convenient and ex-
perimentally simple reaction conditions while showing out-
standing functional group tolerance. As part of our ongoing
research program that aims to construct heterocyclic2n,4 and carbo-
cyclic compounds with increased complexity and structural diversity
using noble metal-catalyzed cascade strategies, we developed
a powerful sequence for the construction of 3(2H)-furanones5–7
and 3-pyrrolones.8
intermediate C (or D) through 6-endo-dig carbocyclization. Due to
the silyloxy group at C3, the intermediate cation should then
trigger an irreversible 1,2-shift analogous to a pinacol rearrange-
ment and subsequent protonation of the carbon–transition-metal
bond should afford the 4-acylcyclopentene framework F and re-
generate the catalyst. The realization of this concept was recently
communicated in preliminary form.13 We herein disclose full de-
tails on the reactivity of 3-silyloxy-1,5-enynes in the presence of
gold catalysts. In particular with regard to the meanwhile reports
of closely related noble metal-catalyzed cascade reactions in-
volving carbocyclization and pinacol-type rearrangement,14 we
feel it might be beneficial to define the scope of the conversion
A/F more precisely. Therefore, the focus lies on pointing out
limitations and reaction pathways that are alternative to the one
depicted in Figure 1.
As shown for 2-hydroxy 2-alkynyl carbonyl compounds I, the
internal oxygen nucleophile facilitates an initial cyclization that
finally leads to the formation of spirocyclic 3-furanone II (Scheme
1). The putative oxonium ion is believed to undergo a 1,2-alkyl
Ph
migration analogous to a formal a-ketol rearrangement. Encour-
O
Ph
aged by these results and the works by Echavarren et al.9 and Toste
et al.,10 we envisaged an extension of the noble metal-catalyzed
cascade strategy by combining an initial carbocyclization with
a then pinacol-type rearrangement.11
OH
AuCl3 (5 mol %)
O
23 °C, CH2Cl2
(83%)
I
II
O
Ph
Based on the typical reactivity of 1,5-enynes,12 it was expected
that 3-silyloxy-1,5-enynes of type A are ideal substrates for
[M]
O
OH
* Corresponding author. Tel.: þ49 89 28913229; fax: þ49 89 28913315.
E-mail address: stefan.kirsch@ch.tum.de (S.F. Kirsch).
Scheme 1. Gold-catalyzed synthesis of 3(2H)-furanones.
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.11.103

H. Menz et al. / Tetrahedron 65 (2009) 1880–1888
1881
R1
O
3
OX
R2
XO
3
1
1
R4
R3
F
A
1i: R1 = Ph, R2 = H, R3 = R4 = -(CH2CH2CH2)-, X = Et3Si
1j: R1 = Ph, R2 = H, R3 = R4 = Me, X = t-BuMe2Si
1k: R1 = Ph, R2 = H, R3 = Me, R4 = H, X = t-BuMe2Si
1l: R1 = H, R2 = R3 = R4 = Me, X = Me3Si
XO
XO
H
[Au+]
+ H+ - Au+
O
[Au+]
[Au]
D
1m:R1 = Ph, R2 = R3 = R4 = Me, X = Et3Si
XO
[1,2]
- X+
1n: R1 = 2-thienyl, R2 = R3 = R4 = Me, X = Et3Si
OSiEt3
Ph
OSiMe3
E
[Au+]
B
[Au]
Ph
1p
1o
C
Scheme 3. 3-Siloxy-1,5-enynes 1i–1p used in this study.
Figure 1. Projected cyclization–pinacol pathway for the synthesis of 4-acyl
cyclopentenes.
regenerate the catalyst. Therefore, the yield of 39% might result
from the hygroscopicity of AgSbF6 under the open-flask conditions
employed for the transformations described in Table 1 (see Ex-
perimental). Our attempts to use the corresponding 3-hydroxy-1,5-
enyne with a free hydroxy group as internal proton source failed
due to competitive heterocyclizations.17 Gratifyingly, the use of
1.1 equiv of isopropanol as external proton source led to the desired
conversion into cis-fused carbocycle 4a (Table 1, entry 3). Moni-
toring revealed that the reaction was completed after 10 min at
room temperature in CH2Cl2. The reaction can be run at low catalyst
loadings (2 mol % [AuCl(PPh3)]/1 mol % AgSbF6) to afford 4a in 81%
yield, although a significantly increased period of time (150 min) is
required for the reaction to reach completion (Table 1, entry 4).
The use of proton sources other than isopropanol was also ex-
amined;18 however, utilizing water led to diminished yields that
lacked reproducibility. On the other hand, 1.1 equiv of tert-butyl
alcohol as another sterically demanding proton source gave the
desired product in good yields (Table 1, entry 8). The use of an
excess of t-BuOH did not influence the reaction outcome (result not
shown in Table 1). Unlike in the case of i-PrOH and t-BuOH, the
addition of methanol did not result in a clean and rapid reaction
providing instead a mixture of various unidentified compounds.
This might be attributed to the enhanced nucleophilicity of MeOH
leading to the trapping of intermediate C. However, compounds
originating from such a trapping were not identified during this
study.
Of primary importance for the optimization of reaction condi-
tions was the observation that even traces of AgSbF6 led to the rapid
and complete decomposition of both product and starting material.
Therefore, we switched to gold catalysts that were activated prior
to use by reaction with 0.5 equiv of AgSbF6 in CH2Cl2 at room
temperature followed by filtration of the resulting slurry over Celite
(Table 1, footnote c). The reaction conditions shown in Schemes 5–8
signify that [AuCl(PPh3)] was preactivated by the reaction with
0.5 equiv of AgSbF6. Catalysts generated in situ by dechlorination of
[AuCl(PPh3)] with AgSbF6 gave low yields. [AuCl(PPh3)] is not an
efficient catalyst for this conversion without counterion exchange
(Table 1, entry 10). To our surprise activation of the gold(I)-source
with AgBF4 instead of AgSbF6 under otherwise identical conditions
did not produce the desired product (Table 1, entry 12). The gold–
oxo complex, [{Au(PPh3)}3O]BF4, was not an alternative electro-
philic gold(I) species to catalyze the reaction (Table 1, entry 13).
Although not observed for the gold-catalyzed reactions at room
temperature, a competing aromatization was found at higher
temperatures leading to biaryl compound 5 (Scheme 4). Elimina-
tion in the proposed six-membered cationic intermediate C might
explain the product formation.19 However, gold complexes proved
to be the most reliable catalysts even at elevated temperatures
showing a much higher propensity for the 1,2-migration pathway
than copper- and platinum-catalysis.
2. Results and discussion
2.1. Synthesis of 3-silyloxy-1,5-enynes
In the present study, we have utilized a general synthesis route
to easily access a variety of 3-silyloxy-1,5-enynes 1 from enals and
enones. As exemplified for the preparation of 3-silyloxy-1,5-enyne
1a, 1,2-addition of the Grignard-reagent derived from propargyl
bromide15 in the presence of catalytic amounts of HgCl2 and iodine
gave secondary alcohol 3 in 93% yield. Protection of the free hy-
droxy group as triethylsilyl ether delivered the 3-silyloxy-1,5-enyne
skeleton required for the planned investigations. Subsequent
Sonogashira coupling16 with iodobenzene transformed terminal
alkyne 1b into internal alkyne 1a. Terminal alkyne 1b was reacted
to a series of 6-substituted 3-siloxy-1,5-enynes in large scale and
good overall yields as shown in Scheme 2. Accordingly, a variety of
acyclic 1,5-enynes 1i–1n depicted in Scheme 3 were obtained from
enals and enones other than cyclohex-1-enecarbaldehyde (2).
Enyne 1p was synthesized in enantiomerically pure form starting
from commercially available (S)-(þ)-carvone.
2.2. Optimization of reaction conditions
Our initial studies have been carried out on the transition metal-
catalyzed conversion of 3-triethylsilyloxy-1,5-enyne 1a into bicyclic
aldehyde 4a (Table 1). These results were promising, as product
formation was observed in the presence of cationic triphenyl-
phosphinegold(I) complex derived from activation of [AuCl(PPh3)]
with AgSbF6 (Table 1, entry 3). The low yield was attributed to the
fact that the mechanistic scheme discussed in Figure 1 requires an
external proton source for the proto-demetalation step to
Br
OH
O
Mg, HgCl2
Et3SiCl
I2 (1 mol %)
imidazole
-40 °C
r.t., Et2O
(93 %)
23 °C,DMF
(97%)
2
3
PhI
OSiEt3
OSiEt3
R1
PdCl2(PPh3)2 (4 mol%)
CuI (2 mol %)
60 °C, Et3N
1a: R1 = Ph (89%)
1b
1c: R1 = Me
1d: R1 = Bn
(54%)
(42%)
1e: R1 = TMS
(95%)
(75%)
(92%)
1f: R1 = 1-naphthyl
1g: R1 = 2-thienyl
1h: R1 = o-MeO(C6H4) (82%)
Scheme 2. Synthesis of 3-siloxy-1,5-enynes 1a–1h.

1882
H. Menz et al. / Tetrahedron 65 (2009) 1880–1888
Table 1
Optimization of conditions for the cyclization–pinacol reaction of 1a
Entry
Catalyst (mol %)
Conditions
Yielda [%] 1ab
Yielda [%] 4a
1
2
AuCl (5)
KAu(CN)2 (5)
Toluene, 80 ꢀC, 24 h
>95
>95
0
0
0
0
0
0
0
>95
0
>95
>95
0
0
Toluene, 80 ꢀC, 24 h
3c
4c
5c
6c
7c
8c
9c
10
11
12c
13
[AuCl(PPh3)] (10)/AgSbF6 (10)
[AuCl(PPh3)] (10)/AgSbF6 (5)
[AuCl(PPh3)] (2)/AgSbF6 (1)
[AuCl(PPh3)] (10)/AgSbF6 (5)
[AuCl(PPh3)] (10)/AgSbF6 (5)
[AuCl(PPh3)] (10)/AgSbF6 (5)
[AuCl(PMe3)] (10)/AgSbF6 (5)
[AuCl(PPh3)] (5)
CH2Cl2, 23 ꢀC, 30 min
39
93
81
39
12
86
50
0
i-PrOH (1.1 equiv), CH2Cl2, 23 8C, 10 min
i-PrOH (1.1 equiv), CH2Cl2, 23 ꢀC, 150 min
CH2Cl2/H2O (10:1), 23 ꢀC, 60 min
MeOH (1.1 equiv), CH2Cl2, 23 ꢀC, 30 min
t-BuOH (1.1 equiv), CH2Cl2, 23 ꢀC, 10 min
i-PrOH (1.1 equiv), CH2Cl2, 23 ꢀC, 10 min
i-PrOH (1.1 equiv), CH2Cl2, 23 ꢀC, 24 h
i-PrOH (1.1 equiv), CH2Cl2, 23 ꢀC, 60 min
i-PrOH (1.1 equiv), CH2Cl2, 23 ꢀC, 30 min
i-PrOH (1.1 equiv), CH2Cl2, 23 ꢀC, 24 h
AgSbF6 (5)
[AuCl(PPh3)] (10)/AgBF4 (5)
[{Au(PPh3)}3O]BF4 (5)
0
0
0
a
Yield of pure product after column chromatography.
Recovered starting material.
The precatalyst [AuCl(PPh3)] was preactivated by reaction with 0.5 equiv of AgSbF6 in CH2Cl2.
b
c
OSiEt3
Ph
i-PrOH (1.1 equiv)
CHO
H
react with equal facility, the latter producing ketones. As exem-
plified through the construction of complex spirocyclic (Table 2,
entry 14) or bicyclic compounds (Table 2, entry 15), a definite fea-
ture of this route to complex 4-acylcyclopentene of type F is that
all-carbon quaternary stereocenters are created through the 1,2-
shift. In all cases, the isolated cyclopentenes 4a–4p were efficiently
+
Ph
1a
4a
5
Ph
(Ph3P)AuSbF6 (5 mol %), 60 °C, CDCl3
PtCl2 (5 mol %), 100 °C, toluene
CuI (10 mol %), 80 °C, DMF
65%
37%
21%
6%
30%
15%
Plausible mechanism:
OX
OX
Table 2
[M+]
Gold-catalyzed cyclization–pinacol reactions
- [M+]
- HOX
1a
5
Producta
Yieldb [%]
[M]
Entry
Substrate
H
Ph
Ph
CHO
Scheme 4. Competing aromatization pathway at elevated temperatures.
1
1h
4h
83
H
R1
The influence of other trialkylsilyl ethers was also examined to
R1¼o-MeO(C6H4)
R1¼2-thienyl
R1¼1-naphthyl
R1¼TMS
define the scope of cyclization–pinacol cascades of this type
(Scheme 5). 3-Silyloxy-1,5-enynes with more robust silyl ethers
such as 6 (X¼t-BuMe2Si) and 7 (X¼i-Pr3Si) gave aldehyde 4a in
competitive yields. In the case of trimethylsilyl ether 8 (X¼Me3Si)
the partial loss of the SiMe3 group under the reaction conditions is
most likely responsible for the reduced yield.
2
1g
1f
1e
1b
1d
1c
4g
4f
4e
4b
4d
4c
81
71
d
3
4c
5
R1¼H
68
35
54
6
7
R1¼CH2Ph
R1¼Me
CHO
OX
Ph
(Ph3P)AuCl (10 mol %)
AgSbF6 (5 mol %)
8
9
1i
1j
4i
4j
73
72
i-PrOH ( 1.1 equiv)
H
Ph
4a
23 °C, CH2Cl2
O
R2
6: X = t-BuMe2Si
7: X = i-Pr3Si
8: X = Me3Si
95% (50 min)
86% (50 min)
35% (18 h)
R3
R4
R1
Scheme 5. Influence of the trialkylsilyl ether on the reaction outcome.
R1¼Ph, R2¼H, R3¼R4¼Me
R1¼Ph, R2¼H, R3¼Me, R4¼H
R1¼H, R2¼R3¼R4¼Me
10
11
12
13
1k
1l
1m
1n
4k
4l
4m
4n
28
50
55
58
R1¼Ph, R2¼R3¼R4¼Me
2.3. Reactivity of 3-silyoxy-1,5-enynes with different
substitution patterns
R1¼2-thienyl, R2¼R3¼R4¼Me
O
To probe the scope and limitations of the gold-catalyzed cycli-
zation–pinacol reactions, enynes 1b–1p were allowed to react. As
illustrated in Table 2, the cascade reaction is general for a range of
substrates bearing different aryl substituents (R1¼aryl) at the al-
kyne terminus (Table 2, entries 1–3). Unfortunately, substrates
containing alkyl substituents (R1¼Me or benzyl) reacted consider-
ably less clean than their aryl analogues. Treatment of TMS-
substituted enyne 1e did not afford the expected cyclopentene
(Table 2, entry 4). This novel cyclization–migration reaction is also
applicable to acyclic systems, although the yields were modest.
Substrates derived from both secondary and tertiary allylic alcohols
14
1o
1p
4o
65
Ph
O
Me
15
4p
67
H
Ph
a
The relative configuration was determined by 1H NMR NOE experiments.
Yield of pure product after column chromatography.
b
c
In this case, complete decomposition was observed.

H. Menz et al. / Tetrahedron 65 (2009) 1880–1888
1883
produced as a single diastereoisomer (d.r. >95:5). Diastereomeric
O
R3
H
R4
R1
XO
R2
XO
R2
H
products were not evident by 1H NMR analysis of crude reaction
mixtures. Notably, the carvone-derived substrate 1p was converted
into the enantiomerically pure bicycle 4p.
-X+
path A
R4
R1
R4
R1
R2
R3
C
R3
[Au+]
[Au]
[Au]
E
Noteworthy, 3-siloxy-1,5-enynes bearing a tetra-substituted
double-bond did not react in the gold-catalyzed cascade process.
Instead, starting material was completely recovered without loss
under the reaction conditions [5 mol % [AuCl(PPh3)]/10 mol %
AgSbF6; i-PrOH, CH2Cl2, 23 ꢀC].
B
path B
R2
R3
R1
-X+
OX
H2C
C
R4
[Au+]
Presumably due to the crucial stabilization of cationic in-
termediate C, the reaction proved strictly limited to 1,5-enynes
possessing a substituent at the C2-position. Product formation that
is consistent with an initial 6-endo-dig carbocyclization was not
obtained from 3-siloxy-1,5-enynes lacking an additional sub-
stituent at C2. Instead, in most cases, enynes of this type were inert
to the reaction conditions as illustrated for the failed conversion of
enyne 9 (Scheme 6). Interestingly, enyne 10 gave 2,4-dienone 11 as
an inseparable mixture of diastereoisomers in 78% yield under the
reaction conditions. The occurrence of 11 can be rationalized by
a sequence consisting of triple-bond hydration20 and subsequent
elimination. Alternatively, an initial elimination might be followed
by the hydration step. A similar reaction outcome was observed for
the conversion of enyne 12. In this case, the formation of the cor-
responding cyclization–pinacol product was not found despite the
C2-methyl group. This might be attributed to structural restraints
during the carbocyclization event resulting from the five-mem-
bered ring system.
G
Figure 2. Plausible pathways for the formation of vinylgold species E.
a rearrangement that is close to the classical semipinacol rear-
rangement. However, an alternative mechanism in which the six-
membered intermediate C collapses into the allenic compound G is
also plausible (path B). In this case, enyne A would undergo a formal
[3,3]-sigmatropic rearrangement based on a gold-catalyzed cycli-
zation-induced rearrangement (CIR)23 mechanism.4,18 An intra-
molecular 5-endo-trig cyclization then gives vinylgold intermediate
E.18
We have briefly examined the proposed proto-demetalation
step to set free the gold catalyst. When triethylsilyl ether 1a was
subjected to the standard gold-catalyzed conditions using an excess
of CD3OD as additive instead of i-PrOH, deuterium incorporation
into the cyclopentene core at C5 was observed (Scheme 7). This
result is consistent with the cyclization–migration mechanism as
proposed in Figures 1 and 2 in which the proto demetalation at C5
is believed to be the final step in the domino process. Nevertheless,
deuterium incorporation did not exceed 67%, a fact that we at-
tributed to both proton residues in CD3OD and experimental
problems to ensure water-free conditions when a mixture of
[AuCl(PPh3)] and AgSbF6 was used as catalytic system. We also
examined the use of other electrophiles.24 A useful iodine-in-
corporation results when N-iodosuccinimide (NIS) is added to the
reaction mixture instead of isopropyl alcohol as a proton source
(Scheme 7).25 Due to low yields and various by-products, a similar
reaction in the presence of N-bromosuccinimide or N-chloro-
succinimide that aimed to synthesize the corresponding alkenyl
bromides and chlorides was not of synthetic value.
t-BuMe2SiO
[AuCl(PPh3)] (10 mol %)
AgSbF6 (5 mol %)
Me
i-PrOH (1.1 equiv)
H
no reaction
23 °C, CH2Cl2
9
Ph
OSiMe3
[AuCl(PPh3)] (10 mol %)
AgSbF6 (5 mol %)
i-PrOH (1.1 equiv)
O
23 °C, CH2Cl2
(78%)
10
11
[AuCl(PPh3)] (10 mol %)
AgSbF6 (5 mol %)
i-PrOH (1.1 equiv)
OSiEt3
O
23 °C, CH2Cl2
(66%)
To further expand the scope of the gold-catalyzed process, we
investigated the possibility of chirality transfer from enantiomeri-
cally pure 3-silyloxy-1,5-enynes. To this end, the enantioenriched
3-siloxy-1,5-enynes (S)-1a (95% ee) and (R)-1a (99% ee) were
treated with isopropanol and catalytic amounts of silver-free
[(Ph3P)Au]SbF6 in CH2Cl2 at room temperature.26 Surprisingly, the
rearrangement products were obtained as racemic mixtures in both
cases (Scheme 8). This demonstrates that B most likely does not
possess a preferred conformation, as shown in Figure 2, in which
12
13
Scheme 6. Importance of the C2-substituent.
These results indicate that the behavior of the putative in-
termediate C/D can be better understood in terms of a cation C
rather than a gold–carbenoid of type D, although a strictly carbe-
noid description cannot be ruled out.21,22 However, considering the
latter, it would be hard to explain the massive difference in re-
activity between C2-substituted and C2-unsubstituted substrates.
More specifically, the 1,2-migration appears to be the result of
hyperconjugative interactions between
p
*
and the allylic sC–R
C]C
are maximized and interactions between the allylic
s
*
and the
C–O
alkene pC]C are minimized.27 The observed complete loss of
chirality limits future applications in total syntheses.28 Bicyclic
compound 4p was the only enantiomerically enriched cyclization–
pinacol product that was achieved during the course of this study.
In the case of its precursor 1p, the fact that the stereogenic center
OSiEt3 [Au(PPh3)]Cl (10 mol %)
CHO
AgSbF6 (5 mol %)
CD3OD (1.1 equiv)
D
23 °C, CH2Cl2
(10%)
(67% D)
Ph
H
14
1a
Ph
[AuCl(PPh3)] (10 mol %)
OSiEt3
[Au(PPh3)]Cl (10 mol %)
AgSbF6 (5 mol %)
NIS (1.1 equiv)
OSiEt3
Ph
CHO
H
CHO
AgSbF6 (5 mol %)
∗
i-PrOH (1.1 equiv)
I
23 °C, CH2Cl2
(48%)
23 °C, CH2Cl2
H
Ph
Ph
1a
15
Ph
1a, 95% ee
4a, 2% ee
Scheme 7. Electrophilic trapping.
Scheme 8. Attempted chirality transfer starting from 1a.

1884
H. Menz et al. / Tetrahedron 65 (2009) 1880–1888
within the 1,5-enyne system is part of a ring system leads to a clean
chirality transfer. To reveal additional 3-silyloxy-1,5-enynes bear-
ing a backbone that gives chirality transfer, further investigations
are ongoing and will be reported in due course.
As illustrated in Figure 3, this result may be rationalized through
an initial C–C-bond formation between C1 and C6. Instead of fa-
voring the pinacol-type 1,2-migration, intermediate H appears to
undergo a Grob-type fragmentation followed by elimination and
proto demetalation.30 The aromatic core created through this se-
quence features three substituents in a 1,2,3-assembly.
2.4. Alternative C–C-bond scission
While investigating 3-silyloxy-1,5-enynes with tetra-
substituted alkene moieties, we found that enyne 16 underwent an
unprecedented transformation into the aryl-containing aldehyde
18 in the presence of AuCl3 (Scheme 9; Table 3, entry 1). This re-
action took place in modest yield, whereas the cyclization–pinacol
product 17 was obtained in only 3% yield. As for all 3-silyloxy-1,5-
enynes with tetra-substituted alkenes, the formation of the cycli-
zation–pinacol product 17 was not observed employing the standard
catalyst system [5 mol % [AuCl(PPh3)]/10 mol % AgSbF6; i-PrOH,
CH2Cl2, 23 ꢀC]. Instead, aldehyde 18 was afforded in low yield (12%)
under these conditions (Table 3, entry 2). The best conditions we
found for this interesting aryl formation utilize PtCl2 as catalyst in
the presence of CO to give aldehyde 18 in 67% yield (Table 3, entry
6).29 It should be noted that internal alkynes (derived from 16
through Sonogashira cross-couplings) do not react under these
conditions.
3. Conclusions
In summary, as predicted by the mechanistic scheme originally
proposed for the gold-catalyzed reactivity of 3-silyloxy-1,5-enynes,
3-silyloxy-1,5-enynes are readily transformed into a variety of 4-
acylcyclopentenes possessing challenging elements of structure.
This reaction has been realized by using silver-free gold(I) com-
plexes (e.g., [(Ph3P)Au]SbF6) in the presence of sterically de-
manding proton sources such as isopropanol. The overall sequence
can be understood best as a cascade consisting of a 6-endo-dig
carbocyclization followed by a pinacol-type 1,2-shift within the
cationic intermediate. This mechanism is in agreement with the
observation that the reaction proved strictly limited to 1,5-enynes
possessing a substituent at the C2-position. A more severe limita-
tion comes from the fact that efficient chirality transfer depends on
the enyne structure. For example, 1p rearranged smoothly to give
the product in enantiomerically pure form, whereas the reaction of
(S)-1a resulted in a racemic mixture. Gold(I) also triggers a re-
markable rearrangement involving a Grob-type fragmentation that
finally leads to complex aryl systems such as 18. From a synthetic
point of view, the results described herein provide a convenient
access to structural units, which could find wide application in the
design of pharmaceutically active compounds.
Me
Me
CHO
Et3SiO
AuCl3 (10 mol %)
18 (51%)
i-PrOH (1.1 equiv)
+
4. Experimental
23 °C, CH2Cl2
Me(O)C
OSiMe2t-Bu
16
4.1. Synthesis of the 3-silyloxy1,5-enynes
OSiMe2t-Bu
17 (3%)
4.1.1. 1-Cyclohexenylbut-3-yn-1-ol (3)
In a flame dried flask magnesium (500 mg, 20 mmol, 2.0 equiv),
mercury dichloride (5 mg, 0.02 mmol, 0.5 mg/mmol aldehyde), and
iodine (10 mg) were dissolved in 10 mL diethyl ether. Some drops of
propargylbromide were added to start the reaction. The reaction
mixture was then cooled to ꢁ10 ꢀC and a solution of propargyl-
bromide (1190 mg, 10 mmol, 1.0 equiv) and cyclohex-1-encarbal-
dehyde (1100 mg, 10 mmol) in 10 mL diethyl ether was quickly
added via syringe. The reaction mixture was stirred at 0 ꢀC for
20 min and then at room temperature for additional 4 h. Saturated
aqueous NH4Cl solution (20 mL) and HCl (1 M, 20 mL) is carefully
added to quench the reaction and the resulting biphasic mixture
was stirred for 1 h. The mixture was extracted with diethyl ether
(3ꢂ15 mL) and the combined organic solution was washed with
saturated aqueous NaCl solution, dried over Na2SO4, and the sol-
vent was removed under reduced pressure. The residue was puri-
fied by flash chromatography on silica gel (pentanes/EtOAc¼9:1) to
afford 1-cyclohexenylbut-3-yn-1-ol (1400 mg, 93%) as a yellow oil.
Scheme 9. Alternative aromatization.
Table 3
Optimization of conditions for the formation of 18
Entry
Catalyst (mol %); conditionsa
Yieldb of 18 [%]
1c
2
AuCl3 (10); A
[AuCl(PPh3)] (10)/AgSbF6 (10); A
AuCl (10); A
KAuCl4 (10); A
CuI (10); B
PtCl2 (10); C
51
12
21
11
d
67
3
4d
5e
6
a
Conditions: A: i-PrOH (1.1 equiv), CH2Cl2, 23 ꢀC; B: i-PrOH (1.1 equiv), DMF,
80 ꢀC; C: CO (1 atm), i-PrOH (1.1 equiv), toluene, 80 ꢀC.
b
Yield of pure product after column chromatography.
Compound 17 was isolated in 3% yield.
Traces of 17 were detected.
Compound 16 was recovered in 98% yield.
c
d
e
1H NMR (250 MHz, CDCl3):
d
¼1.51–1.69 (m, 4H), 1.94–2.06 (m, 6H),
2.44–2.48 (m, 2H), 4.14 (m, 1H), 5.75 (m, 1H); 13C NMR (90.6 MHz,
16
18
H+, - [Au+]
CDCl3):
d
¼22.4, 22.5, 23.8, 24.9, 25.8, 70.5, 74.1, 81.1, 123.8, 138.0;
LRMS (EI): 150 (1%) (Mþ), 132 (20%), 111 (100%), 104 (34%), 91 (48%).
[Au+] 6-endo-dig
- HOX
4.1.2. (1-Cyclohexenylbut-3-ynyloxy)triethylsilane (1b)
XO
XO
[Au]
Imidazole (1120 mg, 16.4 mmol, 1.8 equiv) and triethylsilyl
chloride (2000 mg, 13.3 mmol, 1.5 equiv) were added to a solution
of 1-cyclohexenylbut-3-yn-1-ol (1370 mg, 9.1 mmol) in 10 mL DMF.
The solution was stirred for 30 min at room temperature. Then, the
reaction was quenched by addition of water (100 mL). The mixture
was extracted with diethyl ether (3ꢂ20 mL) and the combined
organic phases were washed with saturated aqueous NaCl solution,
Au
- X+
Me
CHO
OX
H
I
Figure 3. Plausible mechanism for the synthesis of 18.

H. Menz et al. / Tetrahedron 65 (2009) 1880–1888
1885
dried over Na2SO4, and the solvent was removed under reduced
pressure. The residue was purified by flash chromatography on
silica gel (pentanes/EtOAc¼98:2) to afford the title compound
NMR (500 MHz, CDCl3):
d
1.20–1.26 (m, 2H), 1.43–1.45 (m, 1H),
1.57–1.66 (m, 3H), 1.68–1.72 (m, 1H), 2.06–2.10 (m, 1H), 2.53 (d,
J¼16.7 Hz, 1H), 2.70 (dd, J¼16.7, 2.7 Hz, 1H), 3.16 (t, J¼5.8 Hz, 1H),
6.02 (s, 1H), 7.23 (t, J¼7.3 Hz, 1H), 7.32 (t, J¼7.4 Hz, 2H), 7.41 (d,
(2350 mg, 97%) as colorless oil. 1H NMR (250 MHz, CDCl3):
d¼0.59
(q, J¼5.5 Hz, 6H), 0.95 (t, J¼5.5 Hz, 9H), 1.49–1.71 (m, 4H), 1.85–2.12
(m, 4H), 1.94 (t, J¼1.8 Hz, 1H), 2.37–2.40 (m, 2H), 4.13 (t, J¼4.8 Hz,
J¼7.6 Hz, 2H), 9.52 (s, 1H); 13C NMR (90.6 MHz, CDCl3):
d 21.9, 22.9,
27.1, 28.5, 36.3, 44.1, 56.7, 123.5, 126.1, 127.4, 128.6, 135.4, 148.0,
205.6; LRMS (EI): 226 (58%) [Mþ], 197 (100%), 156 (52%); HRMS
226.1356 [226.1358 calcd for C16H18O (Mþ)].
1H), 5.64 (m, 1H); 13C NMR (90.6 MHz, CDCl3):
22.9, 25.1, 26.9, 69.5, 76.1, 82.2, 123.7, 139.0; LRMS (EI): 264 (1%)
(Mþ), 235 (17%), 225 (100%), 115 (19%), 103 (22%).
d
¼4.9, 7.0, 22.7, 22.8,
4.2.1.2. 3a,4,5,6,7,7a-Hexahydro-3H-indene-3a-carbaldehyde (4b).
Following the general procedure, 4b was obtained as a colorless
liquid (68%) after flash chromatography on silica (pentanes/
Et2O¼98:2). Rf¼0.44 (pentanes/EtOAc¼95:5); 1H NMR (250 MHz,
4.1.3. (1-Cyclohexenyl-4-phenylbut-3-ynyloxy)triethylsilane (1a)
Under argon atmosphere, iodobenzene (1000 mg, 4.9 mmol,
1.3 equiv), copper iodide (15 mg, 0.08 mmol, 2 mol %), and
PdCl2(PPh3)2 (112 mg, 0.16 mmol, 4 mol %) were mixed in triethyl-
amine (15 mL). The mixture was degassed with argon to remove
oxygen and heated to 60 ꢀC until the solids were dissolved. Com-
pound 1b (1000 mg, 3.79 mmol, 1.0 equiv) was added, and the
mixture was stirred at 60 ꢀC for 10 h. The resulting black reaction
mixture was cooled to room temperature and quenched with
30 mL saturated NHCl4 solution. The mixture was extracted three
times with 15 mL ethyl acetate, not dissolvable solids were re-
moved by filtration, and the combined organic phases were washed
with saturated aqueous NaCl solution, dried over Na2SO4, and the
solvent was removed under reduced pressure. The residue was
purified by flash chromatography on silica gel (pentanes/
EtOAc¼99:1) to afford the title compound 1a (1147 mg, 89%) as
CDCl3):
d
¼1.23–1.54 (m, 6H), 1.60–1.83 (m, 2H), 2.16 (d, J¼16.0 Hz,
1H), 2.57 (d, J¼16.0 Hz, 1H), 2.82–2.95 (m, 1H), 5.64–5.71 (m, 2H),
9.55 (s, 1H); 13C NMR (90.6 MHz, CDCl3):
d
¼22.0, 22.1, 27.4, 27.9,
39.1, 44.3, 56.6, 128.4, 135.8, 205.6; LRMS (EI): 150 (26%) [Mþ], 135
(19%), 121 (100%), 107 (38%); HRMS 150.1041 [150.1045 calcd for
C10H14O (Mþ)].
4.2.1.3. 1-Methyl-3a,4,5,6,7,7a-hexahydro-3H-indene-3a-carbalde-
hyde (4c). Following the general procedure, 4c was obtained as
a colorless liquid (54%) after flash chromatography on silica (pen-
tanes/Et2O¼98:2). Rf¼0.51 (pentanes/EtOAc¼95:5); 1H NMR
(360 MHz, CDCl3):
d
¼1.28–1.37 (m, 2H), 1.39–1.52 (m, 4H), 1.63–
1.80 (m, 5H), 2.09 (dq, J¼15.7, 2.0 Hz, 1H), 2.46 (dq, J¼15.7, 2.2 Hz,
yellowish oil. 1H NMR (360 MHz, CDCl3):
d¼0.57–0.64 (m, 6H), 0.95
1H), 2.62–2.71 (m, 1H), 5.27 (t, J¼1.6 Hz, 1H), 9.54 (s, 1H); 13C NMR
(t, J¼7.9 Hz, 9H), 1.49–1.71 (m, 4H), 1.89–2.17 (m, 4H), 2.56 (dd,
J¼6.3, 16.6 Hz, 1H), 2.62 (dd, J¼7.0, 16.6 Hz, 1H), 4.21 (t, J¼6.7 Hz,
1H), 5.66–5.69 (m, 1H), 7.25–7.28 (m, 3H), 7.34–7.37 (m, 2H); 13C
(90.6 MHz, CDCl3):
d
¼14.9, 22.3, 26.2, 27.8 (2ꢂC), 38.1, 46.6, 57.1,
121.8, 143.6, 205.6; LRMS (EI): 164 (6%) [Mþ], 149 (31%), 135 (100%),
121 (42%); HRMS 164.1203 [164.1201 calcd for C11H16O (Mþ)].
NMR (90.6 MHz, CDCl3):
d
¼5.0, 7.0, 22.8, 22.9, 23.1, 25.2, 28.0, 76.4,
81.9, 88.1, 123.6, 124.3, 127.6, 128.3, 131.6, 139.3; LRMS (EI): 311 (5%)
(MþꢁC2H5), 225 (100%), 208 (10%), 180 (12%), 165 (15%); HRMS
311.1826 [311.1831 calcd for C22H32OSi (MþꢁC2H5)].
4.2.1.4. 1-Benzyl-3a,4,5,6,7,7a-hexahydro-3H-indene-3a-carbalde-
hyde (4d). Following the general procedure, 4d was obtained as
a colorless liquid (35%) after flash chromatography on silica (pen-
tanes/Et2O¼98:2). Rf¼0.52 (pentanes/EtOAc¼95:5); 1H NMR
4.1.4. ((1R,5S)-2-Methyl-1-(3-phenylprop-2-ynyl)-5-(prop-1-en-2-
yl)cyclohex-2-enyloxy)-triethylsilane (1p)
Using the identical sequence that has been employed for the
preparation of compound 1a, the corresponding enyne 1p was
obtained from (S)-(þ)-carvone as a yellow oil (65% over three steps)
after flash chromatography on silica (pentanes/EtOAc¼95:5). 1H
(360 MHz, CDCl3):
d¼1.21–1.31 (m, 2H), 1.37–1.50 (m, 3H), 1.56–
1.64 (m, 1H), 1.65–1.78 (m, 2H), 2.15–2.21 (m, 1H), 2.49–2.55 (m,
1H), 2.67 (t, J¼5.84 Hz, 1H), 3.25–3.33 (m, 1H), 3.47 (d, J¼15.71 Hz,
1H), 5.26 (s, 1H), 7.16–7.24 (m, 3H), 7.28–7.32 (m, 2H), 9.48 (s, 1H);
13C NMR (90.6 MHz, CDCl3):
57.1, 123.5, 126.3, 128.5, 129.0, 139.3, 147.3, 205.7; HRMS 240.1520
[240.1514 calcd for C17H20O (Mþ)].
d
¼22.2, 22.5, 26.6, 27.7, 36.1, 37.4, 45.1,
NMR (500 MHz, CDCl3):
d
¼0.61–0.74 (m, 6H), 1.01 (t, J¼7.9 Hz, 9H),
1.70 (app t, J¼13.1 Hz, 1H), 1.79–1.80 (m, 6H), 1.94–2.00 (m, 1H),
2.12–2.16 (m, 1H), 2.48–2.53 (m, 2H), 2.71 (d, J¼16.9 Hz, 1H), 2.88
(d, J¼16.9 Hz,1H), 4.79 (s, 2H), 5.47–5.48 (m, 1H), 7.29–7.33 (m, 3H),
4.2.1.5. 1-(Naphthalen-1-yl)-3a,4,5,6,7,7a-hexahydro-3H-indene-3a-
carbaldehyde (4f). Following the general procedure, 4f was obtained
as a pale yellow liquid (71%) after flash chromatography on silica
(pentanes/Et2O¼80:20). Rf¼0.37 (pentanes/Et2O¼80:20); 1H NMR
7.41–7.43 (m, 2H); 13C NMR (62.9 MHz, CDCl3):
d
¼6.9, 7.3, 17.5, 21.0,
31.2, 32.4, 40.1, 41.7, 83.2, 87.7, 109.0, 123.2, 124.4, 127.6, 128.3, 131.6,
139.0, 149.2.
(500 MHz, CDCl3):
d
¼1.10–1.34 (m, 2H), 1.35–1.58 (m, 4H), 1.68–1.80
(m,1H),1.84–1.96 (m,1H), 2.47 (dt, J¼16.3 Hz, J¼1.9 Hz,1H), 2.82 (dt,
J¼16.3 Hz, J¼1.9 Hz, 1H), 3.42ꢁ3.54 (m, 1H), 5.76–5.85 (m, 1H), 7.31
(dd, J¼7.0 Hz, J¼1.2 Hz,1H), 7.40–7.58 (m, 3H), 7.78 (d, J¼8.2 Hz,1H),
7.81–7.92 (m, 1H), 8.03–8.13 (m, 1H), 9.78 (s, 1H); 13C NMR
4.2. Cyclization–pinacol reactions of 3-silyloxy1,5-enynes
4.2.1. General procedure for the gold(I)-catalyzed cyclization–
pinacol reaction
(90.6 MHz, CDCl3):
d
¼22.2, 22.4, 26.5, 28.1, 38.7, 47.5, 57.2, 125.3,
125.8,125.9,126.1,127.5,127.6,128.5,131.9,133.9,135.3,146.9, 205.4;
LRMS (EI): 276 (99%) [Mþ], 247 (100%), 165 (43%), 84 (43%); HRMS
276.1518 [276.1514 calcd for C20H20O (Mþ)].
4.2.1.1. 1-Phenyl-3a,4,5,6,7,7a-hexahydro-3H-indene-3a-carbalde-
hyde (4a). A solution of (Ph3P)AuCl (22.4 mg, 10 mol %) in CH2Cl2
(0.3 mL) was added to a solution of AgSbF6 (7.8 mg, 5 mol %) in
CH2Cl2 (0.3 mL), and the mixture was stirred at room temperature
for 10 min. The resulting suspension was filtered through Celite and
concentrated under reduced pressure. To this residue, a solution of
1a (156 mg, 0.45 mmol) and i-PrOH (0.04 mL, 0.50 mmol) in CH2Cl2
(4.5 mL) was added. The pale purple solution was stirred at room
temperature for 10 min. The mixture was concentrated under re-
duced pressure. Purification of the residue by flash chromatography
on silica gel (pentanes/EtOAc¼98:2) gave 4a as a colorless oil
(94.7 mg, 0.42 mmol, 93%). Rf¼0.42 (pentanes/EtOAc¼95:5); 1H
4.2.1.6. 1-(Thiophen-2-yl)-3a,4,5,6,7,7a-hexahydro-3H-indene-3a-
carbaldehyde (4g). Following the general procedure, 4g was
obtained as a yellow oil (81%) after flash chromatography on silica
(pentanes/EtOAc¼97:3). 1H NMR (250 MHz, CDCl3):
¼1.20–1.23
d
(m, 2H), 1.37–1.47 (m, 1H), 1.55–1.64 (m, 3H), 1.67–1.73 (m, 1H),
2.04–2.10 (m, 1H), 2.52 (d, J¼17.0 Hz, 1H), 2.67 (dd, J¼3.0, 17.0 Hz,
1H), 3.08 (dd, J¼6.2, 9.4 Hz,1H), 5.89 (t, J¼2.5 Hz,1H), 6.95–6.97 (m,
2H), 7.15 (dd, J¼2.0, 4.1 Hz, 1H), 9.47 (s, 1H); 13C NMR (62.9 MHz,
CDCl3):
d
¼21.9, 23.1, 26.8, 29.2, 35.8, 45.5, 56.8, 123.0, 124.0, 124.3,

1886
H. Menz et al. / Tetrahedron 65 (2009) 1880–1888
127.4, 139.7, 142.2, 205.4; HRMS (EI): 232 (100%) [Mþ], 203 (60%),
189 (51%), 161 (39%), 97 (31%); HRMS 232.0919 [232.0922 calcd for
C14H16OS (Mþ)].
(s, 3H), 2.34 (dt, J¼17.0, 2.1 Hz, 1H), 1.82 (dt, J¼17.0, 2.1 Hz, 1H), 3.50
(q, J¼7.1 Hz, 1H), 5.91 (s, 1H), 7.27 (dt, J¼31.2, 7.3 Hz, 3H), 7.38 (d,
J¼7.3 Hz, 2H); 13C NMR (90.6 MHz, CDCl3):
¼14.4, 19.5, 25.5, 42.1,
d
44.2, 58.1,123.6,126.4,127.3,128.5,136.2,147.5, 212.5; LRMS (EI) 214
(6%) [Mþ], 199 (12%), 185 (14%), 171 (100%), 143 (15%), 91 (15%), 43
(22%); HRMS 214.1357 [214.1358 calcd for C15H18O (Mþ)].
4.2.1.7. 1-(2-Methoxyphenyl)-3a,4,5,6,7,7a-hexahydro-3H-indene-
3a-carbaldehyde (4h). Following the general procedure, 4h was
obtained as a yellow oil (83%) after flash chromatography on
silica (pentanes/EtOAc¼95:5). 1H NMR (250 MHz, CDCl3):
4.2.1.13. 1-(1,2-Dimethyl-3-(thiophen-2-yl)cyclopent-3-enyl) (4n).
Following the general procedure, 4n was obtained as a pale yellow
oil (58%) after flash chromatography on silica (pentanes/
d
¼1.20–1.23 (m, 2H), 1.37–1.47 (m, 1H), 1.55–1.64 (m, 3H),
1.67–1.73 (m, 1H), 2.04–2.10 (m, 1H), 2.52 (d, J¼16.6 Hz, 1H),
2.67 (dd, J¼2.9, 16.6 Hz, 1H), 3.08 (dd, J¼6.8, 8.4 Hz, 1H), 3.80
(s, 3H), 5.88 (t, J¼2.4 Hz, 1H), 6.84–6.86 (m, 2H), 7.33–7.36 (m,
EtOAc¼97:3). 1H NMR (360 MHz, CDCl3):
¼1.15 (d, J¼7.0 Hz, 3H),
d
1.25 (s, 3H), 2.19 (s, 3H), 2.34 (td, J¼17.3, 2.1 Hz,1H), 2.95 (dd, J¼17.4,
3.1 Hz, 1H), 3.37 (q, J¼7.1 Hz, 1H), 5.86–5.85 (m, 1H), 6.98–6.96 (m,
2H), 9.50 (s, 1H); 13C NMR (62.9 MHz, CDCl3):
d
¼22.0, 23.0,
27.0, 28.7, 36.1, 44.2, 55.4, 56.6, 114.0, 121.3, 127.3, 128.2, 147.5,
159.1, 206.0; LRMS (EI): 256 (11%) [Mþ], 120 (48%), 105 (100%),
84 (44%), 43 (57%); HRMS 256.1461 [256.1463 calcd for
C17H20O2 (Mþ)].
2H), 7.15 (dd, J¼3.9, 2.3 Hz,1H); 13C NMR (90.6 MHz, CDCl3):
¼14.8,
d
19.3, 25.4, 41.6, 45.5, 58.4,123.5,123.7,124.1,127.4,140.1,141.6, 212.2.
4.2.1.14. 2-Phenyl-spiro[4.5]dec-2-en-6-one (4o). Following the
general procedure, 4o was obtained as a pale yellow liquid (65%)
after flash chromatography on silica (pentanes/Et2O¼80:20).
Rf¼0.37 (pentanes/Et2O¼80:20); 1H NMR (500 MHz, CDCl3):
4.2.1.8. 6-Phenyl-1,2,3,3a,4,6a-hexahydropentalene-3a-carbaldehyde
(4i). Following the general procedure, 4i was obtained as a color-
less liquid (73%) after flash chromatography on silica (pentanes/
EtOAc¼95:5). Rf¼0.33 (pentanes/EtOAc¼95:5); 1H NMR (360 MHz,
d
¼1.77–1.83 (m, 2H), 1.85–1.94 (m, 4H), 2.44 (d, J¼17.3 Hz, 1H), 2.49
(dt, J¼6.6, 1.7 Hz, 2H), 2.55 (d, J¼16.1 Hz, 1H), 3.03 (dd, J¼17.5,
2.2 Hz, 1H), 3.33 (dd, J¼15.9, 2.2 Hz, 1H), 5.98 (s, 1H), 7.20–7.25 (m,
1H), 7.31 (t, J¼7.4 Hz, 2H), 7.41 (d, J¼7.4 Hz, 2H); 13C NMR
CDCl3):
d
¼1.59–1.79 (m, 4H), 1.87–2.02 (m, 1H), 2.09–2.22 (m, 1H),
2.33 (dt, J¼18.2, 2.7 Hz, 1H), 3.18 (dd, J¼18.2, 1.8 Hz, 1H), 3.74 (d,
J¼8.9 Hz, 1H), 5.98–6.04 (m, 1H), 7.20–7.25 (m, 1H), 7.29–7.36 (m,
2H), 7.39–7.45 (m, 2H), 9.68 (s, 1H); 13C NMR (90.6 MHz, CDCl3):
(90.6 MHz, CDCl3):
d¼22.4, 27.5, 39.7, 40.5, 42.1, 42.3, 56.0, 122.7,
125.6, 127.3, 128.5, 136.3, 139.7, 213.0; LRMS (EI): 226 (100%) [Mþ],
211 (66%), 198 (37%), 169 (50%), 156 (80%), 142 (70%); HRMS
226.1358 [226.1358 calcd for C16H18O (Mþ)].
d
¼26.3, 32.5, 36.1, 40.4, 53.6, 64.2, 124.1, 126.4, 127.4, 128.6, 135.5,
143.7, 203.0; LRMS (EI): 212 (100%) [Mþ], 183 (42%), 155 (52%), 141
(26%); HRMS 212.1201 [212.1201 calcd for C15H16O (Mþ)].
4.2.1.15. (3aS,6S,7aR)-3a-Methyl-1-phenyl-6-(prop-1-en-2-yl)-3,3a,-
5,6,7,7a-hexahydroinden-4-one (4p). Following the general pro-
cedure, 4p was obtained as a pale yellow solid (67%) after flash
4.2.1.9. 1,2-Dimethyl-3-phenylcyclopent-3-enecarbaldehyde (4j).
Following the general procedure, 4j was obtained as a yellow oil
(72%) after flash chromatography on silica (pentanes/EtOAc¼99:1).
Rf¼0.4 (pentanes/EtOAc¼90:10); 1H NMR (250 MHz, CDCl3):
chromatography on silica (pure pentanes, then pentanes/
20
EtOAc¼95:5). [
a]
þ6.7 (c 0.51, CHCl3). 1H NMR (500 MHz, CDCl3):
D
d
¼1.07 (d, J¼7.0 Hz, 3H), 1.19 (s, 3H), 2.41 (dt, J¼17.3, 2.0 Hz, 1H),
d
¼1.31 (s, 3H),1.64 (s, 3H),1.84–1.94 (m, 2H), 2.28 (d, J¼17.0 Hz,1H),
2.81 (dd, J¼17.3, 3.2 Hz, 1H), 3.33 (q, J¼6.9 Hz, 1H), 5.97 (s, 1H),
2.40–2.46 (m, 2H), 2.61 (q, J¼10.1 Hz, 1H), 2.98 (d, J¼17.0 Hz, 1H),
7.20–7.26 (m,1H), 7.29–7.36 (m, 2H), 7.36–7.45 (m, 2H), 9.56 (s, 1H);
3.24 (br s, 1H), 4.63 (s, 1H), 4.76 (s, 1H), 6.04 (s, 1H), 7.26–7.29 (m,
13C NMR (90.6 MHz, CDCl3):
d
¼14.2, 16.1, 39.7, 42.7, 56.1, 123.2,
1H), 7.34–7.39 (m, 4H); 13C NMR (90.6 MHz, CDCl3):
d¼21.1, 24.1,
126.3, 127.5, 128.6, 135.5, 147.8, 205.1; LRMS (EI): 200 (23%) [Mþ],
185 (60%), 171 (100%), 157 (40%); HRMS 200.1202 [200.1201 calcd
for C14H16O (Mþ)].
30.7, 38.9, 43.5, 43.6, 52.2, 54.0, 110.2, 125.5, 126.4, 127.4, 128.6,
135.9, 145.5, 147.3, 215.8; LRMS (EI) 266 (100%) [Mþ], 223 (32%), 197
(36%), 185 (55%), 157 (88%), 155 (58%); HRMS 266.1671 [266.1671
calcd for C19H22O (Mþ)].
4.2.1.10. 1-Methyl-3-phenylcyclopent-3-enecarbaldehyde (4k).
Following the general procedure, 4k was obtained as a colorless
liquid (28%) after flash chromatography on silica (pentanes/
Et2O¼98:2). Rf¼0.64 (pentanes/EtOAc¼90:10); 1H NMR (250 MHz,
4.2.1.16. 1-(Cyclohex-2-enylidene)propan-2-one (11). Following the
general procedure, a 5:3 mixture of diastereoisomers 11 was
obtained as a pale yellow oil (78%) after flash chromatography on
CDCl3):
d
¼1.32 (s, 3H), 2.38 (dq, J¼17.5, 2.2 Hz,1H), 2.56 (dq, J¼16.2,
silica (pentanes/EtOAc¼95:5). 1H NMR (360 MHz, CDCl3):
¼(5:3
d
2.1 Hz, 1H), 2.97 (dq, J¼17.5, 2.3 Hz, 1H), 3.18 (dq, J¼16.0, 2.2 Hz,
mixture of diastereoisomers) 1.67 (qn, J¼6.3 Hz, 2H), 1.76 (qn,
J¼6.2 Hz, 1H), 2.14–2.20 (m, 8H), 2.32 (td, J¼6.4, 1.4 Hz, 1H), 2.88–
2.92 (m, 2H), 5.82 (br s, 0.5H), 5.92 (br s, 1H), 6.03 (dt, J¼9.8, 1.7 Hz,
1H), 6.20–6.29 (m, 1.5H), 7.42–7.45 (m, 0.5H); 13C NMR (90.6 MHz,
1H), 6.04–6.09 (m, 1H), 7.22–72.7 (m, 1H), 7.29–7.36 (m, 2H), 7.39–
7.44 (m, 2H), 9.64 (s, 1H); 13C NMR (90.6 MHz, CDCl3):
41.7. 52.9, 123.2, 125.7, 127.6, 128.5, 135.8, 140.5, 203.9; LRMS (EI):
186 (92%) [Mþ], 171 (100%), 157 (46%), 143 (94%); HRMS 186.1042
[186.1045 calcd for C13H14O (Mþ)].
d
¼21.9, 41.6,
CDCl3):
d
¼21.9, 22.9, 25.7, 26.4, 26.8, 31.9, 32.0, 32.6, 121.0, 122.7,
125.9, 130.6, 139.7, 139.8, 150.7, 152.4, 198.7, 199.1. The double-bond
configuration was not assigned.
4.2.1.11. 1-(1,2-Dimethylcyclopent-3-enyl)ethanone (4l). Following
the general procedure, 4l was obtained as a colorless oil (50%) after
flash chromatography on silica (pentanes/EtOAc¼80:20). 1H NMR
4.2.1.17. (1Z)-1-(2-Methylcyclopent-2-enylidene)propan-2-one (13).
Following the general procedure, 13 was obtained as a pale yellow
oil (66%) after flash chromatography on silica (pentanes/
(500 MHz, CDCl3):
d
¼0.99 (d, J¼7.3 Hz, 3H), 1.11 (s, 3H), 2.14 (s, 3H),
2.82 (dq, J¼16.6, 2.1 Hz, 1H), 3.01–3.06 (m, 1H), 5.47–5.48 (m, 1H),
EtOAc¼95:5). 1H NMR (360 MHz, CDCl3):
¼1.81–1.82 (m, 3H), 2.23
d
5.56–5.58 (m, 1H); 13C NMR (90.6 MHz, CDCl3):
43.9, 44.6, 57.4, 127.0, 135.4, 212.6.
d¼14.9, 19.3, 25.8,
(s, 3H), 2.47–2.51 (m, 2H), 3.06 (td, J¼4.3, 2.3 Hz, 2H), 6.06 (s, 1H),
6.44 (s, 1H); 13C NMR (90.6 MHz, CDCl3):
114.4, 141.2, 146.3, 167.6, 198.5. The double-bond configuration was
assigned according to NOE experiments.
d
¼12.7, 31.5, 31.8, 32.0,
4.2.1.12. 1-(1,2-Dimethyl-3-phenylcyclopent-3-enyl)ethanone (4m).
Following the general procedure, 4m was obtained as a colorless oil
(55%) after flash chromatographyon silica (pentanes/EtOAc¼80:20).
4.2.1.18. 2-Iodo-1-phenyl-3a,4,5,6,7,7a-hexahydro-3H-indene-3a-
carbaldehyde (15). Following the general procedure, 15 was
1H NMR (360 MHz, CDCl3):
d
¼1.06 (d, J¼7.0 Hz, 3H),1.26 (s, 3H), 2.21

H. Menz et al. / Tetrahedron 65 (2009) 1880–1888
1887
obtained as a yellow oil (48%) after flash chromatography on silica
216 (2) [Mþ], 198 (1) [MþꢁH2O], 175 (1), 172 (5), 120 (11), 119 (100),
(pentanes/EtOAc¼97:3). 1H NMR (360 MHz, CDCl3):
d
¼1.27–1.30
97 (11), 43 (12).
(m, 2H), 1.45–1.50 (m, 3H), 1.62–1.70 (m, 2H), 1.79–1.86 (m, 1H),
2.71 (dd, J¼1.6, 16.1 Hz, 1H), 3.02 (dd, J¼1.8, 16.1 Hz, 1H), 3.25 (t,
J¼6.4 Hz, 1H), 7.29–7.40 (m, 5H), 9.63 (s, 1H); 13C NMR (90.6 MHz,
4.3.3. 1-((3aS,4S,6S,7aR)-3a,4,5,6,7,7a-Hexahydro-4-(tert-
butyl)dimethylsilyloxy-3a-methyl-6-(prop-1-en-2-yl)-1H-inden-
7a-yl)ethanone (17)
Obtained in 3% yield in the AuCl3-catalyzed reaction of 16. The
relative configuration was assigned according to NOE experiments.
CDCl3):
d
¼21.8, 21.9, 26.6, 27.8, 47.3, 50.3, 57.2, 89.2, 128.0, 128.2,
128.4, 136.7, 151.4, 203.6; LRMS (EI): 352 (20%) [Mþ], 225 (35%), 197
(100%), 115 (25%), 91 (31%); HRMS 352.0320 [352.0324 calcd for
C16H17IO (Mþ)].
1H NMR (500 MHz, CDCl3):
d
¼5.91 (dd, J¼5.8, 2.2 Hz,1H), 5.56–5.55
(m, 1H), 4.66 (S, 1H), 4.63 (s, 1H), 4.00 (dd, J¼11.5, 4.6 Hz, 1H), 2.91
(app dt, J¼15.3, 1.8 Hz, 1H), 2.19 (dd, J¼15.5, 2.8 Hz, 1H), 2.16 (s, 3H),
2.11–2.05 (m, 1H), 1.73–1.70 (m, 1H), 1.65 (s, 3H), 1.53–1.49 (m, 2H),
1.27–1.23 (m, 1H), 0.93 (s, 3H), 0.89 (s, 9H), 0.06 (s, 6H); 13C NMR
4.3. Aromatization reactions of 3-silyloxy1,5-enynes
4.3.1. (1S,5S)-3-(2-Triethylsilyloxypent-4-yn-2-yl)-2-methyl-5-
(prop-1-en-2-yl)cyclohex-2-enyloxy(tert-butyl)dimethylsilane (16)
To a solution of the alcohol precursor (1.00 g, 2.87 mmol) in
DMF (5.7 mL) were added imidazole (449.0 mg, 6.60 mmol) and
triethylsilyl chloride (0.97 mL, 5.74 mmol) in two portions. The
reaction mixture was stirred at room temperature for 3 h and then
quenched with water. The aqueous layer was extracted with Et2O
and the combined organic layer dried over Na2SO4 and concen-
trated under reduced pressure. The residue was purified on a silica
gel column (from 1% Et2O/pentanes) to provide compound 16
(922.0 mg, 1.99 mmol, 69% mixture of diastereoisomers, ratio 1:1)
as a light yellow oil. Diastereoisomer 1: 1H NMR (250 MHz, CDCl3):
(90.6 MHz, CDCl3):
d
¼211.6, 149.2, 137.9, 125.5, 109.1, 74.8, 62.3,
54.3, 42.3, 38.2, 38.0, 37.9, 28.8, 26.0, 20.9, 20.5, 18.2, ꢁ3.8, ꢁ4.6. MS
(EI, 70 eV), m/z (%): 348 (19) [Mþ], 291 (100) [Mþꢁt-Bu], 249 (14),
211 (15), 199 (23), 157 (40), 119 (50), 75 (100), 43 (51); HRMS
348.2482 [348.2485 calcd for C21H36O2Si (Mþ)].
Acknowledgements
This project was supported by the Fonds der Chemischen
Industrie (FCI) and the Deutsche Forschungsgemeinschaft (DFG).
We thank Prof. Dr. Th. Bach and his group for helpful discussions
and generous support.
d
¼4.73 (br s, 2H), 4.17 (dd, J¼9.7, 6.1 Hz, 1H), 2.56 (t, J¼2.8 Hz, 2H),
2.36–2.29 (m, 1H), 2.14–2.04 (m, 1H), 1.99–1.92 (m, 2H), 1.93 (t,
J¼2.6 Hz, 1H), 1.86 (br s, 3H), 1.74 (s, 3H), 1.53 (s, 3H), 1.42 (app
td, J¼12.4, 10.3 Hz, 1H), 0.95 (t, J¼7.8 Hz, 9H), 0.91 (s, 9H), 0.62 (q,
J¼8.0 Hz, 6H), 0.10 (s, 3H), 0.09 (s, 3H); 13C NMR (62.9 MHz, CDCl3):
References and notes
d
¼149.2, 137.0, 133.1, 109.1, 82.2, 77.1, 74.6, 69.8, 40.5, 38.1, 34.3,
1. For leading reviews, see: (a) Fu¨rstner, A.; Davies, P. W. Angew. Chem., Int. Ed.
2007, 46, 3410; (b) Hashmi, A. S. K. Chem. Rev. 2007, 107, 3180; (c) Jime´nez-
33.7, 28.3, 26.1, 20.5, 18.3, 17.5, 7.3, 6.8, ꢁ3.7, ꢁ4.6. Diastereoisomer
2: 1H NMR (250 MHz, CDCl3):
d¼4.73–4.72 (m, 2H), 4.21–4.17 (m,
´ ˜
Nunez, E.; Echavarren, A. M. Chem. Commun. 2007, 333; (d) Hashmi, A. S. K.;
Hutchings, G. J. Angew. Chem., Int. Ed. 2006, 45, 7896; (e) Arcadi, A.; Di Guiseppe,
S. Curr. Org. Chem. 2004, 8, 795; (f) Hashmi, A. S. K. Angew. Chem., Int. Ed. 2005,
44, 6990; (g) Hashmi, A. S. K. Catal. Today 2007, 122, 211; (h) Gorin, D. J.; Toste,
F. D. Nature 2007, 446, 395; (i) Muzart, J. Tetrahedron 2008, 64, 5815; (j) Shen,
H. C. Tetrahedron 2008, 64, 3885; (k) Li, Z.; Brouwer, C.; He, C. Chem. Rev. 2008,
108, 3239; (l) Gorin, D. J.; Sherry, B. D.; Toste, F. D. Chem. Rev. 2008, 108, 3351;
(m) Arcadi, A. Chem. Rev. 2008, 108, 3266.
2. For a review on the reactivity of propargylic esters, see: (a) Marion, N.; Nolan,
S. P. Angew. Chem., Int. Ed. 2007, 46, 2750; (b) Marco-Contelles, J.; Soriano, E.
Chem.dEur. J. 2007, 13, 1350; For a review on the cycloisomerization of
enynes, see: (c) Zhang, L.; Sun, J.; Kozmin, S. A. Adv. Synth. Catal. 2006, 348,
2271; (d) Nieto-Oberhuber, C.; Lo´ pez, S.; Jime´nez-Nu´ n˜ez, E.; Echavarren, A.
M. Chem.dEur. J. 2006, 12, 5916; (e) Ma, S.; Yu, S.; Gu, Z. Angew. Chem., Int. Ed.
2006, 45, 200; (f) Aubert, C.; Buisine, O.; Malacria, M. Chem. Rev. 2002, 102,
1H), 2.65 (dd, J¼16.4, 2.6 Hz, 1H), 2.49 (dd, J¼16.4, 2.7 Hz, 1H), 2.17–
2.07 (m, 1H), 2.02–1.95 (m, 2H), 1.92 (t, J¼2.4 Hz, 1H), 1.89 (br s, 3H),
1.73 (s, 3H), 1.50 (s, 3H), 1.45–1.32 (m, 1H), 0.95 (t, J¼7.8 Hz, 9H),
0.89 (s, 9H), 0.65–0.56 (m, 6H), 0.09 (s, 3H), 0.07 (s, 3H); 13C NMR
(62.9 MHz, CDCl3):
d
¼149.6,136.7, 134.1,109.0, 82.0, 74.4, 70.0, 40.0,
38.2, 35.5, 33.4, 27.0, 25.9, 20.7, 18.2, 17.8, 7.3, 6.7, ꢁ3.7, ꢁ4.8. MS (EI,
70 eV), m/z (%): 462 (1) [Mþ], 423 (49) [MþꢁC3H3], 291 (100), 265
(21), 197 (13), 159 (20), 115 (30), 87 (41), 73 (39), 59 (15); HRMS
423.3112 [423.3115 calcd for C24H47O2Si2 (MþꢁC3H3)].
4.3.2. (S)-3-(2,6-Dimethylbenzyl)-4-methylpent-4-enal (18)
Method C using PtCl2: to a solution of enyne 16 (80.0 mg,
0.17 mmol) in dry toluene (8.5 mL) was added platinum(II) chloride
(12.6 mg, 0.04 mmol). The suspension was then purged under CO
atmosphere and isopropanol (0.08 mL, 1.04 mmol) was added. The
resulting mixture was stirred at 80 ꢀC for 1 h. Then the reaction
mixture was quenched with water, extracted with Et2O, dried over
Na2SO4, and concentrated under reduced pressure.
Method A using AuCl3: to a solution of enyne 16 (50.0 mg,
0.11 mmol) in dry toluene (5.4 mL) was added a solution of pre-
diluted gold(III) chloride (3.3 mg, 0.01 mmol) in MeCN (0.05 mL).
Then, isopropanol (0.05 mL, 0.65 mmol) was added and the
resulting mixture stirred at room temperature for 1 h. The reaction
mixture was quenched with water, extracted with Et2O, dried over
Na2SO4, and concentrated under reduced pressure.
ˆ
813; (g) Michelet, V.; Toullec, P. Y.; Genet, J.-P. Angew. Chem., Int. Ed. 2008, 47,
4268; (h) Jime´nez-Nu´ n˜ez, E.; Echavarren, A. M. Chem. Rev. 2008, 108, 3326;
For a review on the hydroamination of alkynes, see: (i) Widenhoefer, R. A.;
Han, X. Eur. J. Org. Chem. 2006, 4555; For a review on the reactions of oxo-
alkynes, see: (j) Patil, N. P.; Yamamoto, Y. ARKIVOC 2007, 5, 6; For a review on
stereoselective catalysis, see: (k) Bongers, N.; Krause, N. Angew. Chem., Int. Ed.
2008, 47, 2178; For a review on C,H activation, see: (l) Skouta, R.; Li, C.-J.
Tetrahedron 2008, 64, 4917; For a review on heterocycle synthesis, see: (m)
Patil, N. T.; Yamamoto, Y. Chem. Rev. 2008, 108, 3395; (n) Kirsch, S. F. Synthesis
2008, 3183; For a review on 1,2-alkyl migrations, see: (o) Crone, B.; Kirsch, S.
F. Chem.dEur. J. 2008, 14, 3514.
3. For recent reviews on cascade reaction, see: (a) Tietze, L. F. Chem. Rev. 1996, 96,
115; (b) Tietze, L. F.; Modi, A. Med. Res. Rev. 2000, 20, 304; (c) Tietze, L. F.;
Brasche, G.; Gericke, G. Domino Reactions in Organic Synthesis; Wiley-VCH:
Weinheim, 2006; (d) Nicolaou, K. C.; Edmonds, D. J.; Bulger, P. G. Angew. Chem.,
Int. Ed. 2006, 45, 7134; (e) Pellisier, H. Tetrahedron 2006, 62, 2143.
4. (a) Suhre, M. H.; Reif, M.; Kirsch, S. F. Org. Lett. 2005, 7, 3925; (b) Binder, J. T.;
Kirsch, S. F. Org. Lett. 2006, 8, 2151; (c) Menz, H.; Kirsch, S. F. Org. Lett. 2006, 8,
4795.
´
5. (a) Kirsch, S. F.; Binder, J. T.; Liebert, C.; Menz, H. Angew. Chem., Int. Ed. 2006, 45,
The residue was purified on a silica gel column (from 2% to 5%
Et2O/pentanes) to provide compound 18 (12.1 mg, 0.056 mmol,
5878; (b) Crone, B.; Kirsch, S. F. J. Org. Chem. 2007, 72, 5435.
6. For related studies, see: (a) Bunnelle, E. M.; Smith, C. R.; Lee, S. K.; Singaram, W.
S.; Rhodes, A. J.; Sarpong, R. Tetrahedron 2008, 64, 7008; (b) Smith, C. R.;
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V.; Gevorgyan, V. J. Am. Chem. Soc. 2006, 128, 12050.
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Chem. Soc. 2004, 126, 11164; (b) Yao, T.; Zhang, X.; Larock, R. C. J. Org. Chem.
2005, 70, 7679; (c) Zhang, J.; Schmalz, H.-G. Angew. Chem., Int. Ed. 2006, 45,
6704.
51%) as a pale yellow oil. [
a
]
þ0.89 (c 0.63, CH2Cl2). 1H NMR
20
D
(500 MHz, CDCl3):
d
¼1.79 (s, 3H), 2.33 (ddd, J¼15.8, 5.0, 1.5 Hz, 1H),
2.34 (br s, 6H), 2.54 (ddd, J¼16.0, 10.1, 3.3 Hz, 1H), 2.73 (dd, J¼13.9,
9.8 Hz,1H), 2.83 (dd, J¼13.9, 5.4 Hz,1H), 2.95 (tt, J¼10.0, 5.0 Hz,1H),
4.80 (s, 1H), 4.83–4.84 (m, 1H), 7.00–7.05 (m, 3H), 9.46 (dd, J¼3.1,
1.5 Hz, 1H); 13C NMR (90.6 MHz, CDCl3):
d¼20.6, 20.2, 20.6, 32.3,
´
8. Binder, J. T.; Crone, B.; Kirsch, S. F.; Liebert, C.; Menz, H. Eur. J. Org. Chem. 2007,
41.8, 46.0, 112.0, 126.4, 128.7, 136.7, 136.9, 147.0, 202.3; LRMS (EI):
1636.

1888
H. Menz et al. / Tetrahedron 65 (2009) 1880–1888
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Tang, J.-M.; Bhunia, S.; Sohel, S.; Md, A.; Lin, M.-Y.; Liao, H.-Y.; Datta, S.; Das, A.;
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23. Overman, L. E. Angew. Chem., Int. Ed. Engl. 1984, 23, 579.
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(d) Yu, M.; Zhang, G.; Zhang, L. Org. Lett. 2007, 9, 2147.
25. For more details regarding this iodine-incorporation, see Ref. 13.
26. [(Ph3P)Au]SbF6 is not a well-characterized complex and most likely exists as
[(Ph3P)Au(H2O)]SbF6 under these conditions.
27. (a) Houk, K. N.; Paddon-Row, M. N.; Rondan, N. G.; Wu, Y. D.; Brown, F. K.;
Spellmeyer, D. C.; Metz, J. T.; Li, Y.; Loncharich, R. J. Science 1986, 231, 1108; (b)
Graham, T. C.; Overman, L. E. Tetrahedron 2002, 58, 6473.
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ˆ
Genet, J.-P. J. Am. Chem. Soc. 2005,127, 9976; (b) Li, Y.; Zhou, F.; Forsyth, C. J. Angew.
Chem., Int. Ed. 2007, 46, 279; (c) Liu, B.; De Brabander, J. K. Org. Lett. 2006, 8, 4907;
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F. D. Angew. Chem., Int. Ed. 2006, 45, 5991.
28. For chirality transfer in related reactions, see Refs. 14a,b.
29. For the use of CO in reactions catalyzed by PtCl2, see inter alia: (a) Cho, E. J.;
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19. For a related aromatization, see: Huang, X.; Zhang, L. Org. Lett. 2007, 9, 4627.