Gold(I)-catalyzed synthesis of highly substituted 2-cyclopentenones from 5-siloxypent-3-en-1-ynes

Article abstract of DOI:10.1002/chem.200901824

A highly efficient gold (I)-catalyzed approach towards densely functionalized cyclopentenones possessing a quaternary carbon center, was reported. Methylene chloride was added to a mixture of gold complex [Au{P(C₆F₅)₃}Cl]

Full text of DOI:10.1002/chem.200901824

COMMUNICATION
DOI: 10.1002/chem.200901824
Gold(I)-Catalyzed Synthesis of Highly Substituted 2-Cyclopentenones
from 5-Siloxypent-3-en-1-ynes
Sang Eun An, Jihee Jeong, Baburaj Baskar, Joopyung Lee, Junho Seo, and
Young Ho Rhee*[a]
Intramolecular addition of nucleophiles to the Lewis acid
activated alkynes represents one of the most powerful strat-
egies for the synthesis of cyclic compounds.[1] In this context,
recent advances in the catalytic reactions initiated by the in-
tramolecular addition of alkyl and aryl ethers to alkynes are
particularly noteworthy, because these groups are consid-
ered as relatively unreactive nucleophiles.[2,3] This type of re-
activity led mostly to the development of novel syntheses of
various cyclic ethers.[4]
In an effort to extend the scope of the reactions initiated
by this intriguing siloxycyclization, we considered a catalytic
reaction of 5-siloxypent-1-ynes 1 (Scheme 1). In this scenar-
Unlike the heterocycle formation, little is known about
the carbocycle synthesis through a tandem alkoxycycliza-
tion/skeletal-rearrangement pathway. Toste and co-workers
reported a gold(I)-catalyzed synthesis of indenyl ethers by
an intramolecular carboalkoxylation process.[5] More recent-
ly, we reported the transformation of various 3-siloxy-1,6-
enynes into 4-cycloheptenones through a tandem siloxycycli-
zation/sigmatropic rearrangement [Eq. (1)].[6,7] A remark-
able feature of this reaction is that even poorly reactive O-
silyl ethers can add efficiently to the alkynes in the presence
of cationic gold(I) complexes.[8]
Scheme 1. Proposed scheme for the gold(I)-catalyzed cyclopentanone for-
mation.
io, initial siloxycyclization of 1 followed by the ionization of
À
C O bond generates a carbocation intermediate B. Intramo-
lecular carbocyclization and the subsequent elimination of
cationic gold(I) via a cyclic intermediate C with the assis-
tance of iPrOH will produce highly substituted cyclopenta-
none 2.
Based on the proposed mechanism, we reasoned that the
cation-stabilizing groups might be needed at the C-5 posi-
tion.[9] This rationale was justified in preliminary studies
using triethylsiloxypentyne 3a [Eq. (2)]. The catalytic reac-
tion of this compound gave the cyclopentanone 4 in 20%
yield, when 6a (10 mol%) was used (entry 1, Table 1).[10]
Switching to a more electrophilic catalyst 6b based on our
previous experience in the related area significantly in-
creased the yield to 44% (entry 2).[6,11]
[a] S. E. An, J. Jeong, Dr. B. Baskar, J. Lee, J. Seo, Prof. Dr. Y. H. Rhee
Department of Chemistry
POSTECH (Pohang University of Science and Technology)
Hyoja-Dong san 31, Pohang, Kyungbook, 790-784 (South Korea)
Fax : (+82)54-279-3399
E-mail: yhrhee@postech.ac.kr
At this stage, we decided to establish the relative reactivi-
ty of the methoxypentyne 3b to siloxypentyne 3a. Initially,
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200901824.
Chem. Eur. J. 2009, 15, 11837 – 11841
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
11837

Table 1. Preliminary investigation of 3a and 3b.
Table 2. Optimization of the cyclization of substrate 8.
Entry
Substrate
Catalyst ([mol%])
Isolated yield [%]
Entry
Catalyst ([mol%])
T
t [h]
Yield [%][a]
1
2
3
3a
3a
3b
6a (10)/AgSbF6 (5)
6b (10)/AgSbF6 (5)
6b (10)/AgSbF6 (5)
20 [a,b]
44[a,b]
1
2
3
4
5
6
6a (10)/AgSbF6 (5)
6b (10)/AgSbF6 (5)
6b (5)/AgSbF6 (2.5)
6b (5)/AgSbF6 (2.5)
6a (10)/AgOTf (5)
AgSbF6 (5)
RT
RT
RT
1
0.16
0.16
0.16
1
94
96
93
trace[c]
À158C
97 (93[b]
53
)
[a] Only compound 4 was obtained.[12] [b] iPrOH (1 equiv) was added.
[c] Combined yield of compound 4 and 5b.
RT
RT
10
decomp
[a] NMR yield using 1,3,5-trimethoxybenzene as an internal standard.
[b] Isolated yield.
shortened the reaction time, and slightly increased the yield
of 9 (entry 2). Lowering the catalyst loading (5 mol% Au)
little affected the yield (entry 3). Notably, the reaction per-
formed at À158C was also successful with no negative effect
on the yield of 9 (entry 4). In this run, the desired ketone 9
was obtained in 93% isolated yield. On the other hand,
changing the counterion considerably decreased the yield of
9 (entry 5).[14,15] As illustrated in entry 6, using AgSbF6 alone
led to the decomposition of the starting material with no in-
dication of the product formation.
we surmised that 3b would show higher reactivity, because
the methoxy group is more nucleophilic than the triethylsi-
loxy group. Quite interestingly, methoxypentyne 3b proved
unreactive when catalyst 6b (10 mol% of Au) was used
(entry 3).
When 3a was tested, enone 7 (Scheme 2) was obtained in
40% yield. Formation of this compound can be reasonably
explained by the competing deprotonation from the carbo-
Using the optimized conditions in Table 2, an array of 5-
siloxy-pent-3-en-1-ynes were converted into the correspond-
ing cyclopentenones. As summarized in Table 3, the sub-
stituents on the phenyl ring significantly affected the yield
of the cyclopentenones (entries 1–3). Substrate 10, which
possesses a phenyl group, showed a comparable result to
compound 8 (entry 1), whereas, substrate 11, with a more
electron-donating p-methoxyphenyl group, significantly re-
duced the yield even though the starting material was com-
pletely consumed after 10 min (entry 2). On the other hand,
poorer conversion was seen for the substrate with a more
electron-withdrawing p-fluorophenyl group (12, entry 3). In
this case, the reaction was completed after 7 h, providing the
ketone 21 in 73% yield. As shown in entries 4 and 5, intro-
ducing longer alkyl group at the C-5 position little affected
the catalytic activity. The cyclic substrates 15 and 16 also
gave the bicyclic products in good yield (entries 6 and 7).
Remarkably, the scope of the reaction was not limited to
the substrates having aryl groups at the C-5 position. Thus,
the compounds possessing alkenyl groups (17 and 18) were
transformed smoothly into the cyclopentenones 26 and 27 in
good yield (entries 8 and 9). In these cases, the tandem si-
loxycyclization-sigmatropic rearrangement shown in Equa-
tion (1) can compete with the proposed catalytic cycle.
Scheme 2. Mechanism of the formation of compound 7.
cationic intermediate D and the subsequent alcoholysis of
the vinylgold species (Scheme 2). This analysis confirms the
involvement of the carbocationic intermediate in the pro-
posed catalytic cycle. Moreover, the competition study of 3a
and 3b strongly suggests that the efficiency of the proposed
catalytic cycle depends mainly upon the cyclization of inter-
mediate B rather than the initial formation of intermediate
A (Scheme 1).
Based upon the mechanistic analysis of the preliminary
studies, we envisioned that cis-5-trialkylsiloxypent-3-ene-1-
ynes such as 8 would be more efficient than 5-trialkylsiloxy-
pent-1-ynes, because the key cyclization should be faster for
the former compounds.[13] Indeed, using substrate 8 provided
the cyclopentenone 9 in 94% yield in the presence of cata-
lyst 6a [Eq. (3), Table 2, entry 1]. Using 6b significantly
11838
www.chemeurj.org
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 11837 – 11841

Homogeneous Catalysis
COMMUNICATION
Table 3. Examples of cyclopentenone formation.[a,b]
tant building blocks in organic
synthesis.[16,17] For example, the
structural motif in compound 9
can be found in a number of
bioactive cyclopentane sesqui-
terpene natural products pos-
sessing aryl groups[18] and in
more structurally complex alka-
loids such as meloscine and
scandine.[19] Moreover, the car-
bocyclic structures of com-
pounds 26 and 27 could be
easily expanded to the synthesis
of linear- and angular triqui-
nane natural products.[20] In
order to illustrate the synthetic
potential of the proposed reac-
tion, racemic synthesis of the
key intermediate to cuparenone
(31a) was pursued.[21] As shown
in Scheme 3, this compound
was obtained in moderate 50%
yield from substrate 30a under
the optimized conditions A
(Table 3). On the other hand,
substrate 30b possessing trime-
thylsilyl group at the C-2 posi-
tion afforded the corresponding
ketone 31b in significantly in-
creased 90% yield. Desilylation
with TBAF using a modified lit-
erature procedure[22] smoothly
proceeded to provide the target
enone 31a in 92% yield.
Entry
Substrate
Method
t [h]
Product
Yield [%][c]
1
2
3
10 (X=H)
11 (X=OMe)
12 (X=F)
B
A
B
0.16
0.16
7
19 (X=H)
20 (X=OMe)
21 (X=F)
97
44
73
4
5
13 (R1 =Et, R2 =H)
A
A
0.16
0.16
22 (R1 =Et, R2 =H)
91
87
14 (R1 =nC8H17, R2 =CH3)
23 (R1 =nC8H17, R2 =CH3)
6
7
15 (n=1)
16 (n=2)
A
A
0.16
6
24 (n=1)
25 (n=2)
73
62
8
9
17 (R=H)
18 (R=CH3)
B
B
12
10
26 (R=H)
27 (R=CH3)
60
62
[a] Method A: catalyst 6b (10 mol%)/AgSbF6 (5 mol%) was used; Method B: catalyst 6b (5 mol%)/AgSbF6
(2.5 mol%) was used. [b] All reactions were performed at RT. [c] Isolated yield.
Quite interestingly, no seven-membered carbocyclic prod-
ucts generated from this competing process were detected.
As illustrated by the examples in Table 3, cation-stabiliz-
ing groups such as phenyl and alkenyl should be installed at
the C-5 position for the efficient transformation. In fact, the
substrate possessing two aliphatic alkyl groups at the C-5
position (such as compound 28), and the substrate derived
from secondary alcohol (such as compound 29) gave the cor-
responding cyclopentenones only in trace yield.
Scheme 3. A formal synthesis of racemic cuparenone.
In summary, we have developed a highly efficient gold(I)-
catalyzed approach towards densely functionalized cyclo-
pentenones possessing a quaternary carbon center. It is
worth noting that the activating power of the cationic
gold(I) species allows the addition of relatively unreactive
O-silyl ether nucleophiles, and also the efficiency of 5-siloxy-
pent-3-en-1-ynes in the formation of 2-cyclopentenones.
Also, the results described here provide a new insight into
From a synthetic viewpoint, the catalytic reaction present-
ed herein provides a highly efficient approach to 2-cyclopen-
tenones with a quaternary carbon center; these are impor-
Chem. Eur. J. 2009, 15, 11837 – 11841
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
11839

Y. H. Rhee et al.
[5] P. Dubꢂ, F. D. Toste, J. Am. Chem. Soc. 2006, 128, 12062–12063.
[6] B. Baskar, H. J. Bae, S. E. An, J. Y. Cheong, Y. H. Rhee, A. Du-
schek, S. F. Kirsch, Org. Lett. 2008, 10, 2605–2607.
[7] For the gold(I)-catalyzed thiosilylation, see: I. Nakamura, T. Sato,
M. Terada, Y. Yamamoto, Org. Lett. 2007, 9, 4081–4083.
the role of O-silyl ethers in organic synthesis. The scope of
this reaction as well as further application to the synthesis
of bioactive natural products with structural complexity is
under investigation and will be reported in due course.
[8] For catalytic reactions of other 3-siloxy-1,n-enynes, see: a) H. Menz,
J. T. Binder, B. Crone, Tetrahedron 2009, 65, 1880–1888; b) T. T.
Haug, T. Harschnek, A. Duschek, C. U. Lee, J. T. Binder, H. Menz,
S. F. Kirsch, J. Organomet. Chem. 2009, 694, 510–514; c) S. F.
Kirsch, J. T. Binder, B. Crone, A. Duschek, T. T. Haug, C. Liꢂbert,
H. Menz, Angew. Chem. 2007, 119, 2360–2363; Angew. Chem. Int.
Ed. 2007, 46, 2310–2313.
[9] For the related studies of benzylic alcohol substrates, see: a) K. Mer-
tins, I. Lovel, J. Kischel, A. Zapf, M. Beller, Adv. Synth. Catal. 2006,
348, 691–695; b) A. S. K. Hashmi, L. Schwarz, P. Rubenbauer, M. C.
Blanco, Adv. Synth. Catal. 2006, 348, 705–708; c) V. Nair, N. Vidya,
K. G. Abhilash, Tetrahedron Lett. 2006, 47, 2871–2873; d) V. Nair,
K. G. Abhilash, N. Vidya, Org. Lett. 2005, 7, 5857–5859.
Experimental Section
Preparation of compound 9: Methylene chloride (3 mL) was added to a
mixture of gold complex [Au{PACHTUNRGTNE(UNG C6F5)3}Cl] (11.1 mg, 0.0145 mmol) and
AgSbF6 (2.5 mg, 0.0073 mmol); the resulting solution was stirred for
10 min. The reaction mixture was filtered through a pad of Celite and
concentrated. The residue was dried over high vacuum for 2 h, and then
cooled to À158C. A solution of 8 (121 mg, 0.29 mmol) and isopropyl al-
cohol (24.5 mL, 0.32 mmol) in CH2Cl2 (5.8 mL, 0.05m, pre-cooled to
À158C) was added to this residue. After stirring at room temperature for
10 min, the yellow mixture was passed through a pad of Celite and con-
centrated. The residual oil was purified by flash chromatography on silica
gel (hexane/ethyl acetate 95:5) to give the compound 9 as a yellow oil
(82 mg, 0.27 mmol, 93% yield). Rf =0.42 (hexane/ethyl acetate=95:5);
1H NMR (300 MHz, CDCl3): d=0.89 (t, J=6.7 Hz, 3H), 1.21–1.31 (m,
10H), 1.48–1.56 (m, 2H), 1.58 (s, 3H), 2.20–2.25 (m, 2H), 2.33 (s, 3H),
2.57 (d, J=19 Hz, 1H), 2.68 (d, J=19 Hz, 1H), 7.11–7.18 (m, 4H),
7.25 ppm (s, 1H); 13C NMR (75 MHz, CDCl3): d=14.3, 21.1, 22.9, 24.7,
27.8, 27.9, 29.4, 29.5, 29.6, 32.0, 45.4, 52.7, 125.8, 129.5, 136.3, 143.4, 144.0,
[10] a) Using 1:1 complex of the Au catalyst and AgSbF6 significantly
lower the yield of the reaction. At this stage, it is unclear why the
2:1 complex gave higher yields of the product. It has been noted
that that the chloro-bridged dinuclear gold complex is formed under
´
this condition; A. S. K. Hashmi, M. C. Blanco, E. Kurpejovic, W.
Frey, J. W. Bats, Adv. Synth. Catal. 2006, 348, 709–713.
[11] H. J. Bae, B. Baskar, S. E. An, J. Y. Cheong, D. T. Thangadurai, I.-C.
Hwang, Y. H. Rhee, Angew. Chem. 2008, 120, 2295–2298; Angew.
Chem. Int. Ed. 2008, 47, 2263–2266.
[12] As observed in the previous study for the siloxycyclization-[3,3]-sig-
matropic pathway of 3-siloxy-1,6-enynes, the reaction gave no silyl
ether 5a, even in the absence of any alcohol additives.
164.8, 209.8 ppm; IR: n˜ =2957, 2925, 2855, 1709, 1514, 1456, 816 cmÀ1
HRMS calcd for C21H30O: 298.2297; found: 298. 2298.
;
[13] a) For the detailed procedure for the synthesis of the substrates, see
the Supporting Information; b) we also tried to investigate the reac-
tivity of 5-methoxypent-3-en-yne derivative of 8. However, all our
efforts to prepare the 5-methoxy-3-en-1-ynes from the correspond-
ing alcohols proved troublesome, because of the poor stability of the
corresponding alcohols under the reaction condition. The reaction
conditions investigated include; i) NaH/MeI in THF or DMF;
ii) Ag2O/MeI in various solvents; iii) CH3OC=NHCCl3 with various
Lewis acids.
Acknowledgements
This work was supported by KOSEF through EPB center (2009-
0063313). The authors thank the Korean Ministry of Education for the
BK21 project for our graduate program.
[14] a) Using other solvents (CH3CN, THF, EtOAc) significantly de-
creased the yield of the reaction; b) we also examined various trial-
kylsilyl ethers: trimethylsilyl ethers provided the target in somewhat
smaller yield, while triisopropylsilyl ethers significantly dropped the
yield.
Keywords: carboalkoxylation
homogeneous catalysis · quaternary carbon
· cyclopentenone · gold ·
[15] a) The reaction performed in the presence of HF (up to 1 equiv)
gave led to the complete decomposition of the starting material with
no indication of the product formation; b) the catalytic reaction
under aerobic conditions (open flask condition) gave comparable re-
sults to the reactions under N2 atmosphere; c) the reaction of the
corresponding alcohol led to decomposition of the staring material
with no indication of the product formation; also, we found out that
the TES silyl ethers of tertiary alcohols are stable in general under
the reaction condition—based on these experiments, alternative ex-
planation on the cyclopentenone formation promoted by the initial
desilylation and the subsequent cyclization can be reasonably ex-
cluded; d) it should be noted that the scope of the reaction was
strictly limited to the terminal alkynes; reaction of internal alkynes
led to the decomposition of the staring material with no indication
of formation of the cyclopentenones.
[16] For selected examples on the 2-cyclopentenone formation: a) T. Shi-
bata, K. Takagi, J. Am. Chem. Soc. 2000, 122, 9852–9853; b) G.
Liang, D. Trauner, J. Am. Chem. Soc. 2004, 126, 9544–9545; c) K.
Tanaka, G. C. Fu, J. Am. Chem. Soc. 2002, 124, 10296–10297;
d) C. P. Davie, R. L. Danheiser, Angew. Chem. 2005, 117, 6017–
6020; Angew. Chem. Int. Ed. 2005, 44, 5867–5870; e) N. Jeong, B. K.
Sung, Y. K. Choi, J. Am. Chem. Soc. 2000, 122, 6771–6772.
[17] For gold(I)-catalyzed approaches towards cyclopentenone synthesis,
see: a) X. Shi, D. J. Gorin, F. D. Toste, J. Am. Chem. Soc. 2005, 127,
5802–5803; b) L. Zhang, S. Wang, J. Am. Chem. Soc. 2006, 128,
[1] For reviews, see: a) T. Hosokawa, S.-I. Murahashi in Handbook of
Organopalladium Chemistry for Organic Synthesis, Vol. 3.2.1 (Ed.:
E. Negishi), Wiley-VCH, Weinheim, 2000, pp. 2169–2190; b) C.
Aubert, O. Buisine, M. Malacria, Chem. Rev. 2002, 102, 813–834;
c) G. Zeni, R. C. Larock, Chem. Rev. 2004, 104, 2285–2310.
[2] For a review on the metal-catalyzed carboalkoxylation process: Y.
Yamamoto, J. Org. Chem. 2007, 72, 7817–7831.
[3] For selected examples on the metal-catalyzed carboalkoxylation
process, see: a) I. Nakamura, C. S. Chan, T. Araki, M. Terada, Y. Ya-
mamoto, Org. Lett. 2008, 10, 309–312; b) A. Fꢁrstner, P. W. Davies,
J. Am. Chem. Soc. 2005, 127, 15024–15025; c) A. Fꢁrstner, H. Szil-
lat, F. Stelzer, J. Am. Chem. Soc. 2000, 122, 6785–6786; d) A. Fꢁrst-
ner, F. Stelzer, H. Szillat, J. Am. Chem. Soc. 2001, 123, 11863–
11869; e) I. Nakamura, T. Sato, Y. Yamamoto, Angew. Chem. 2006,
118, 4585–4587; Angew. Chem. Int. Ed. 2006, 45, 4473–4475; f) M,
Uemura, I. D. G. Watson, M. Katuskawa, F. D. Toste, J. Am. Chem.
Soc. 2009, 131, 3464–3465.
[4] For reviews on the gold(I)-catalyzed reactions, see: a) D. J. Gorin,
B. D. Sherry, F. D. Toste, Chem. Rev. 2008, 108, 3351–3378; b) Z. Li,
C. Brouwer, C. He, Chem. Rev. 2008, 108, 3239–3265; c) A. Arcadi,
Chem. Rev. 2008, 108, 3266–3325; d) E. Jimenez-Nunez, A. M.
Echavarren, Chem. Rev. 2008, 108, 3326–3350; e) D. J. Gorin, F. D.
Toste, Nature 2007, 446, 395–403; f) A. S. K. Hashmi, G. J. Hutch-
ings, Angew. Chem. 2006, 118, 8064–8105; Angew. Chem. Int. Ed.
2006, 45, 7896–7936.
11840
www.chemeurj.org
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 11837 – 11841

Homogeneous Catalysis
COMMUNICATION
1442–1443; c) T. Jin, Y. Yamamoto, Org. Lett. 2008, 10, 3137–3139;
d) C. H. Oh, S. Karmakar, J. Org. Chem. 2009, 74, 370–374.
[18] J. Sun, D. Shi, M. Ma, S. Li, S. Wang, L. Han, Y. Yang, X. Fan, J.
Shi, L. He, J. Nat. Prod. 2005, 68, 915–919.
[21] For examples of the synthesis of cuparenones, see: A. Natarajan, D.
Ng, Z. Yang, M. A. Garcia-Garibay, Angew. Chem. 2007, 119, 6605–
6607; Angew. Chem. Int. Ed. 2007, 46, 6485–6487, and references
therein.
[19] a) Meloscine: P. Selig, T. Bach, Angew. Chem. 2008, 120, 5160–
5162; Angew. Chem. Int. Ed. 2008, 47, 5082–5084; b) Scandine: S. E.
Denmark, J. J. Cottell, Adv. Synth. Catal. 2006, 348, 2397–2402.
[20] For reviews on triquinane sesquiterpene natural products, see: a) T.
Hudlicky, J. D. Price, Chem. Rev. 1989, 89, 1467–1486; b) G. Mehta,
A. Srikrishna, Chem. Rev. 1997, 97, 671–719.
[22] J. Barluenga, P. Barrio, L. Riesgo, L. A. Lopez, M. Tomas, J. Am.
Chem. Soc. 2007, 129, 14422–14426.
Received: July 2, 2009
Published online: October 5, 2009
Chem. Eur. J. 2009, 15, 11837 – 11841
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
11841